Methods and intermediates for preparing therapeutic compounds

Abstract

The present disclosure relates to methods and intermediates useful for preparing a compound of Formula I: or a salt thereof.

Description

METHODS AND INTERMEDIATES FOR PREPARING THERAPEUTIC COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 560,122, filed March 1, 2024. The entire contents of this application are hereby incorporated by reference in their entirety. FIELD

[0002] The present disclosure relates to methods and intermediates for the synthesis of substituted pyridotriazine compounds for use in the treatment of human immunodeficiency virus (HIV) infection. BACKGROUND

[0003] The present disclosure relates generally to the field of organic synthetic methodology for the preparation of antiviral compounds and their synthetic intermediates.

[0004] Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains may limit their usefulness (Palella, et al. N. Engl. J Med. (1998) 338:853–860; Richman, D. D. Nature (2001) 410:995–1001). Accordingly, there is a need for new agents that inhibit the replication of HIV.

[0005] U.S. Patent No. 11,613,546 discloses novel compounds useful for treating an infection caused by the HIV virus. One specific compound identified therein is a compound of Formula I-A:

[0006] There is currently a need for synthetic methods and intermediates that can be used to prepare the compound of Formula I-A and salts thereof. SUMMARY

[0007] The present disclosure is directed to a novel synthetic process for preparing a compound of Formula I: or a salt thereof, whereinprotecting group.

[0008] In some embodiments, the present disclosure provides a process for preparing a compound of Formula I-A:or a salt thereof. The compound of Formula I-A may also be named or identified as (1S,2R,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9- tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.

[0009] The present disclosure is also directed to particular individual steps of this process and intermediates used in this process.

[0010] In some embodiments, disclosed herein is a process for preparing a compound of Formula I or a salt thereof, wherein R1is selected from hydrogen and a hydroxyl protecting group; comprising reacting a compound of Formula II: or a salt thereof, with aof Formula I or a salt thereof.

[0011] In some embodiments, disclosed herein is a process for preparing a compound of Formula I-A:or a salt thereof, comprising deprotecting a compound of Formula I or a salt thereof, wherein R1is a hydroxyl protecting group, to provide the compound of Formula I-A or a salt thereof.

[0012] In some embodiments, disclosed herein is a process for preparing a compound of Formula I or a salt thereof, wherein R1is selected from hydrogen and a hydroxyl protecting group; comprising: reacting a compound of Formula R-1:or a salt thereof, with: a methylene reagent, and an eighth acid or a fourteenth base, to provide the compound of Formula I or a salt thereof.

[0013] Additional embodiments of the disclosure, including additional synthetic intermediates and methods for preparing such intermediates, are provided herein. DETAILED DESCRIPTION

[0014] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0015] When trade names are used herein, it is intended to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product. Definitions

[0016] The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as alimitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0017] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0018] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-8 alkyl” indicates that the alkyl group has from 1 to 8 carbon atoms.

[0019] “Isomers” are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers and diastereomers.

[0020] “A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.

[0021] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers at a ratio other than 1:1 is a “scalemic” mixture.

[0022] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0023] The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (─) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and / or hindered rotation about a bond axis and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present disclosure is meant to include all such possible isomers, including racemic mixtures, scalemic mixtures, diastereomericmixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0024] Except as expressly defined otherwise, the present disclosure includes all tautomers of compounds detailed herein, even if only one tautomer is expressly represented (e.g., both tautomeric forms are intended and described by the presentation of one tautomeric form where a pair of two tautomers may exist). For example, if reference is made to a compound containing an amide (e.g., by structure or chemical name), it is understood that the corresponding imidic acid tautomer is included by this disclosure and described the same as if the amide were expressly recited either alone or together with the imidic acid. Where more than two tautomers may exist, the present disclosure includes all such tautomers even if only a single tautomeric form is depicted by chemical name and / or structure.

[0025] Compounds described herein may have chiral centers and / or geometric isomeric centers (E- and Z- isomers), and it is to be understood that all such optical, enantiomeric, diastereoisomeric and geometric isomers are encompassed. Where compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s).

[0026] Compounds described herein may be in any morphological form such as, for example, crystalline or amorphous, as well as disordered crystals, liquid crystals, plastic crystals, mesophases, and the like, or any combination thereof.

[0027] Also provided are pharmaceutically acceptable hydrates, solvates, co-crystals, tautomeric forms, polymorphs, and prodrugs of the compounds described herein.

[0028] Any formula or structure given herein, including Formula I, or any Formula disclosed herein, is also intended to represent unlabeled forms as well as isotopicallylabeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to2H (deuterium, D),3H (tritium),11C,13C,14C,15N,18F,31P,32P,35S,36Cl and125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H,13C, and14C are incorporated, may be useful to help determine or measure the effectiveness of the compounds by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0029] The disclosure also includes compounds of Formula I, or any Formula disclosed herein, in which from 1 to “n” hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0030] Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. An18F labeled compound may be useful for PET or SPECT studies. Isotopically labeledcompounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. Further, substitution with heavier isotopes, particularly deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent in the compound of the Formula I, or any Formula disclosed herein.

[0031] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0032] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity).

[0033] The term “coupling agent” as used herein refers to a reagent used to couple an amine and a carboxylic acid to form an amide. Non-limiting examples of coupling agents include n-propyl phosphonic anhydride, oxalyl chloride, thionyl chloride, phosgene, triphosgene, propanephosphonic acid anhydride, acetic anhydride, pivalic anhydride, benzoic anhydride, 2,4,6-trichlorobenzoyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1,1’- carbonyldiimidazole, ethyl chloroformate, isobutyl chloroformate, 2-(7-aza-1H- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O- benzotriazole-N,N,N’,N’-tetramethyluronium-hexafluoro-phosphate (HBTU), O-(7- azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), O-(6- chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (1- cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), a peptide coupling agent, and the like.

[0034] A “peptide coupling agent” includes, but is not limited to, 2-(7-aza-1H- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O- benzotriazole-N,N,N’,N’-tetramethyluronium-hexafluoro-phosphate (HBTU), O-(7- azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O- (benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), O-(6- chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (1- cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), and the like.

[0035] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12alkyl), 1 to 8 carbon atoms (i.e., C1-8alkyl), 1 to 6 carbon atoms (i.e., C1-6alkyl), 1 to 4 carbon atoms (i.e., C1-4alkyl), 1 to 3 carbon atoms (i.e., C1-3alkyl), or 1 to 2 carbon atoms (i.e., C1-2 alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. -(CH2)3CH3), sec-butyl (i.e. -CH(CH3)CH2CH3), isobutyl (i.e. -CH2CH(CH3)2) and tert-butyl (i.e. -C(CH3)3); and “propyl” includes n-propyl (i.e. -(CH2)2CH3) and isopropyl (i.e. -CH(CH3)2).

[0036] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

[0037] The term “halo” or “halogen” includes fluoro, chloro, bromo and iodo.

[0038] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0039] “Hydroxyl” and “hydroxy” are used interchangeably and refer to –OH. “Oxo” refers to the group (=O) or (O). Where tautomeric forms of the compound exist, hydroxyl and oxo groups are interchangeable.

[0040] The term “protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. The term “deprotecting” refers to removing the protecting group. The term “deprotecting agent” refers to a reagent useful for removing a protecting group from a compound.

[0041] The term “hydroxyl protecting group” refers to a moiety that masks or alters the properties of a hydroxyl group. Exemplary hydroxyl protecting groups include, but are not limited to, methyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4- dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyl-diphenylsilyl (TBDPS), triphenylsilyl, benzoylformate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivaloate, benzoate, p-phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate, and tosylate.

[0042] The term “amine protecting group” refers to a moiety that masks or alters the properties of an amine group. Exemplary amine protecting groups include, but are not limited to, phthalimide, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (Fmoc), toluenesulfonyl (Ts), saccharin, methoxyphenyl, para-methoxyphenyl, ortho-methoxy phenyl, acetate, 2,5-dimethylpyrrole, 4- methoxybenzyl, 2,4-dimethoxybenzyl, 2,2-diphenyl, allyl, and triphenylmethyl. Abbreviations

[0043] Abbreviations as used herein have respective meanings as follows: aq. aqueous Bn benzyl br broad d doublet DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane dd doublet of doublets ddd doublet of doublet of doublets DMSO dimethylsulfoxide dt doublet of triplets Et ethyl EtOH ethanol h hour(s)HATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate Hz hertz J coupling constant m multiplet M Molar MTBE methyl tert-butyl ether Me methyl MeOH methanol MeTHF 2-methyltetrahydrofuran MHz megahertz min. minute(s) MS mass spectroscopy MTBE methyl-tert-butyl ether m / z Mass to charge N normal NMR nuclear magnetic resonance q quartet s singlet t triplet tol toluene TsOH or p-TsOH p-toluenesulfonic acid wt% weight percent Methods and Intermediates

[0044] Except as otherwise noted, the methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, 5thedition, New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7thedition, Wiley-Interscience, 2013.

[0045] In certain instances, the processes disclosed herein involve a step of forming a salt of a compound of the present disclosure.

[0046] Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, supercritical fluid chromatography (SFC), and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and / or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nded., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0047] Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. One of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. In some embodiments, each of the reactions depicted in the general schemes is run at a temperature from about –80 °C to the reflux temperature of the organic solvent used.

[0048] The compounds disclosed herein may display atropisomerism resulting from steric hindrance affecting the axial rotation rate around a single bond. The resultant conformational isomers may each be observed as distinct entities by characterization techniques such as NMR and HPLC. The compounds disclosed herein may exist as a mixture of atropisomers. However, the detection of atropisomers is dependent on factors such as temperature, solvent, conditions of purification, and timescale of spectroscopic technique. The interconversion rate at room temperature has a half-life of minutes to hours, hours to days, or days to years. The ratio of atropisomers at equilibrium may notbe unity. Characterization data presented herein may not represent the equilibrium state depending on the conditions of isolation and characterization which may include but not limited to handling, solvents used, and temperature.

[0049] In some embodiments, the present disclosure provides processes and intermediates for preparing the compound of Formula I and salts thereof. In other embodiments, the disclosure provides processes for preparing intermediates that can be used to prepare the compound of Formula I and salts thereof.

[0050] Provided herein is a method of preparing a compound of Formula I: or a salt thereof, whereinprotecting group; comprising reacting a compound of Formula II: or a salt thereof,with a first catalyst to provide the compound of Formula I or a salt thereof.

[0051] In some embodiments, R1is selected from hydrogen, C1-4alkyl, and benzyl. In some embodiments, R1is hydrogen. In some embodiments, R1is C1-4alkyl. In some embodiments, R1is selected from hydrogen, methyl, ethyl, and benzyl. In some embodiments, R1is selected from methyl, ethyl, and benzyl. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is benzyl.

[0052] In some embodiments, the compound of Formula I or a salt thereof is a compound of Formula I-A:or a salt thereof.

[0053] In some embodim , p I or a salt thereof is a compound of Formula I-B:or a salt thereof.

[0054] In some embodiments, the compound of Formula II or a salt thereof is a compound of Formula II-A:or a salt thereof.

[0055] In some embodiments, the first catalyst is a metathesis catalyst. In some embodiments, the first catalyst is selected from a ruthenium-based catalyst, a molybdenum-based catalyst, and a tungsten-based catalyst. In some embodiments, the first catalyst is a ruthenium-based catalyst. In some embodiments, the first catalyst is selected from Hoveyda-Grubbs second generation catalyst, Hoveyda-Grubbs first generation catalyst, Zhan 1B, nitro Grela, M721, M203, and M730. In some embodiments, the first catalyst is Hoveyda-Grubbs second generation catalyst.

[0056] In some embodiments, a molar ratio of the compound of Formula II or a salt thereof to the first catalyst is from about 1:0.001 to about 1:0.05. In some embodiments, a molar ratio of the compound of Formula II or a salt thereof to the first catalyst is from about 1:0.01 to about 1:0.03. In some embodiments, a molar ratio of the compound of Formula II or a salt thereof to the first catalyst is from about 1:0.01 to about 1:0.02. In some embodiments, a molar ratio of the compound of Formula II or a salt thereof to the first catalyst is about 1:0.015.

[0057] In some embodiments, the reacting of the compound of Formula II or a salt thereof is performed in the presence of a first additive. In some embodiments, the first additive can minimize the amount of impurity (i.e., reaction by-product) formed in the reaction. In some embodiments, the first additive comprises dimethyl maleate, 1,4- benzoquinone, 6-dichloro-1,4-benzoquinone, 2-chloro-1,4-benzoquinone, tetrafluoro-1,4- benzoquinone, 2-methylbenzoquinone, dimethyl fumarate, maleic acid, fumaric acid, maleic anhydride, trans-methyl cinnamate, acetic acid, trifluoroacetic acid, or a combination thereof. In some embodiments, the first additive comprises dimethyl maleate.

[0058] In some embodiments, the reacting of the compound of Formula II or a salt thereof is performed in a first solvent. In some embodiments, the first solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3- dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), or a combination thereof. In some embodiments, the first solvent comprises an ester. In some embodiments, the first solvent comprises ethyl acetate,methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate, or a combination thereof. In some embodiments, the reacting of the compound of Formula II or a salt thereof is performed in a first solvent comprising ethyl acetate.

[0059] In some embodiments, the reacting of the compound of Formula II or a salt thereof is carried out in a temperature range of from about 20 °C to about 120 °C. In some embodiments, the reacting of the compound of Formula II is carried out in a temperature range of from about 50 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula II is carried out in a temperature range of from about 70 °C to about 90 °C. In some embodiments, the reacting of the compound of Formula II is carried out at a temperature of about 80 °C.

[0060] In some embodiments, R1is a hydroxyl protecting group; and the process further comprises deprotecting the compound of Formula I, or a salt thereof; to provide a compound of Formula I-A:or a salt thereof.

[0061] In some embodiments, deprotecting the compound of Formula I or a salt thereof comprises treating the compound of Formula I or a salt thereof with a first deprotecting agent. Any suitable deprotecting agent can be used for the deprotection of the compound of Formula I. In some embodiments, suitable deprotecting agents include metal halide salts (e.g., magnesium bromide, lithium chloride, potassium iodide, sodium iodide, calcium chloride, copper (I) chloride, copper (II) chloride, zinc chloride), hydrogen halides (e.g., hydrogen chloride, hydrogen bromide, hydrogen iodide), boron reagents (e.g., boron trichloride, boron tribromide), aluminum reagents (e.g., aluminum trichloride, aluminum tribromide), titanium reagents (e.g., titanium tetrachloride, titaniumtribromide, titanium tetrabromide), pyridinium halide salts (e.g., pyridinium chloride, pyridinium perbromide, pyridinium iodide), ammonium halides (e.g., ammonium chloride, tetrabutylammonium chloride, tetrabutylammonium iodide), and silyl halides (e.g., trimethylsilyl chloride, trimethylsilyl iodide).

[0062] In some embodiments, the first deprotecting agent is selected from a metal halide, a hydrogen halide, a boron reagent, an aluminum reagent, a titanium reagent, a pyridinium halide salt, an ammonium halide, and a silyl halide. In some embodiments, the first deprotecting agent is a metal halide. In some embodiments, the first deprotecting agent comprises magnesium bromide, lithium chloride, potassium iodide, sodium iodide, calcium chloride, copper (I) chloride, copper (II) chloride, zinc chloride, or a combination thereof. In some embodiments, the first deprotecting agent is lithium chloride.

[0063] In some embodiments, the deprotecting the compound of Formula I or a salt thereof is performed in a second solvent. In some embodiments, the second solvent comprises water, an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the second solvent comprises a polar aprotic solvent. In some embodiments, the second solvent comprises N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2- pyrrolidone, N-butyl pyrrolidone (NBP), or a combination thereof. In some embodiments, the deprotecting the compound of Formula I or a salt thereof is performed in a second solvent comprising N-methyl-2-pyrrolidone.

[0064] In some embodiments, the deprotecting the compound of Formula I or a salt thereof is carried out in a temperature range of from about 0 °C to about 130 °C. In some embodiments, the deprotecting the compound of Formula I or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C. In some embodiments, the deprotecting the compound of Formula I or a salt thereof is carried out in a temperature range of from about 70 °C to about 90 °C. In some embodiments, the deprotecting the compound of Formula I or a salt thereof is carried out in a temperature of about 80 °C.

[0065] In some embodiments, the process further comprising preparing the compound of Formula II or a salt thereof by a process comprising: reacting a compound of Formula III: or a salt thereof, witha methylene reagent, and a first acid or a first base, to provide the compound of Formula II or a salt thereof.

[0066] In some embodiments, the compound of Formula III is a compound of Formula III-A:or a salt thereof.

[0067] In some embodiments, the methylene reagent is a formaldehyde reagent or a dihalomethane. In some embodiments, suitable formaldehyde reagents include formaldehyde acetals (e.g., dimethoxymethane, diethoxymethane), formaldehyde solution, paraformaldehyde, and 1,3,5-trioxane. In some embodiments, suitable methylene reagents include dihalomethanes (e.g., dibromomethane, diiodomethane).

[0068] In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, a formaldehyde acetal, formaldehyde, paraformaldehyde, or a dihalomethane. In some embodiments, the methylene reagent is a formaldehyde reagent. In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, a formaldehyde acetal, formaldehyde, and paraformaldehyde. In some embodiments, the methylene reagent is 1,3,5-trioxane.

[0069] In some embodiments, the compound of Formula III or a salt thereof is reacted with the first acid. In some embodiments, suitable first acids include carboxylic acids (e.g., oxalic acid, trichloroacetic acid, trifluoroacetic acid), sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, camphorsulfonic acid), Lewis acids (e.g., boron trifluoride methyl etherate, boron trifluoride dibutyl etherate, boron trichloride, boron tribromide, aluminum chloride, aluminum bromide), inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid), or a combination thereof.

[0070] In some embodiments, the first acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof. In some embodiments, the first acid comprises a carboxylic acid. In some embodiments, the first acid is selected from oxalic acid, trichloroacetic acid, trifluoroacetic acid, or a combination thereof. In some embodiments, the first acid is trifluoroacetic acid.

[0071] In some embodiments, the compound of Formula III or a salt thereof is reacted with the first base. In some embodiments, suitable first bases include amines (e.g., n- propylamine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine), amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidines (e.g., triazabicyclodecene (TBD),1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert- butoxide, etc.), amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole), or a combination thereof.

[0072] In some embodiments, the first base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound, or a combination thereof.

[0073] In some embodiments, the reacting of the compound of Formula III or a salt thereof is performed in a third solvent. In some embodiments, the third solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3- dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), or a combination thereof. In some embodiments, the third solvent comprises a hydrocarbon. In some embodiments, the third solvent comprises toluene, methylcyclohexane, n-heptane, hexanes, limonene, or a combination thereof. In some embodiments, the reacting of the compound of Formula III or a salt thereof is performed in a third solvent comprising toluene.

[0074] In some embodiments, the reacting of the compound of Formula III or a salt thereof is carried out in a temperature range of from about 60 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula III or a salt thereof is carried out in a temperature range of from about 75 °C to about 85 °C. In some embodiments, the reacting of the compound of Formula III or a salt thereof is carried out at a temperature of about 80 °C.

[0075] In some embodiments, the process further comprises preparing the compound of Formula III or a salt thereof by a process comprising: deprotecting a compound of Formula IV: or a salt thereof,to provide the compound of Formula III or a salt thereof.

[0076] In some embodiments, R2is tert-butyloxycarbonyl (Boc). In some embodiments, R1is selected from hydrogen, methyl, ethyl and benzyl and R2is tert- butyloxycarbonyl. In some embodiments, R1is C1-4alkyl and R2is tert-butyloxycarbonyl. In some embodiments, R1is selected from methyl and ethyl and R2is tert- butyloxycarbonyl.

[0077] In some embodiments, the compound of Formula IV is a compound of Formula IV-A:IV-A or a salt thereof.

[0078] In some embodiments, deprotecting the compound of Formula IV or a salt thereof comprises treating the compound of Formula IV or a salt thereof with a second acid. Any suitable acid can be used for the deprotection of the compound of Formula IV or a salt thereof. In some embodiments, suitable second acids include sulfonic acids (e.g., p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid), inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric, phosphoric acid), organic acids (e.g., trifluoroacetic acid, formic acid, acetic acid, oxalic acid, citric acid), acid chlorides (e.g., acetyl chloride), Lewis acids (e.g., aluminum chloride, boron tribromide, lanthanum triflate)

[0079] In some embodiments, the second acid comprises a sulfonic acid, an inorganic acid, an organic acid, an acid chloride, a Lewis acid, or a combination thereof. In some embodiments, the second acid comprises a sulfonic acid. In some embodiments, the second acid is selected from p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, or a combination thereof. In some embodiments, the second acid comprises methanesulfonic acid.

[0080] In some embodiments, deprotecting the compound of Formula IV or a salt thereof is performed without an acid.

[0081] In some embodiments, deprotecting the compound of Formula IV or a salt thereof is performed in a fourth solvent. In some embodiments, the fourth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), an alcohol (e.g.,methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), water, or a combination thereof. In some embodiments, the fourth solvent comprises an ether. In some embodiments, the fourth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments, deprotecting the compound of Formula IV or a salt thereof is performed in a fourth solvent comprising cyclopentyl methyl ether.

[0082] In some embodiments, deprotecting the compound of Formula IV or a salt thereof is carried out in a temperature range of from about 0 °C to about 120 °C. In some embodiments, deprotecting the compound of Formula IV or a salt thereof is carried out in a temperature range of from about 10 °C to about 60 °C. In some embodiments, deprotecting the compound of Formula IV or a salt thereof is carried out in a temperature range of from about 30 °C to about 40 °C. In some embodiments, deprotecting the compound of Formula IV or a salt thereof is carried out at a temperature range of about 35 °C.

[0083] In some embodiments, the process further comprises preparing the compound of Formula IV or a salt thereof by a process comprising: reacting a compound of Formula V:or a salt thereof, with: a compound of Formula VI:VI wherein Y is an anion or a salt,a coupling agent, and a second base, to provide the compound of Formula V or a salt thereof.

[0084] In some embodiments, the compound of Formula V is a compound of Formula V-A: or a salt thereof.

[0085] In some embodiments, Y is selected from tosylate, mesylate, and HCl salt. In some embodiments, Y is tosylate. In some embodiments, Y is mesylate. In some embodiments, Y is an HCl salt.

[0086] In some embodiments, the compound of Formula VI or a salt thereof is a compound of Formula VI-A: .

[0087] In some embodiments, include an acid chloride (e.g., thionyl chloride, oxalyl chloride, phosphorus(V) oxychloride), a mixed anhydride (e.g., with reagents such as acetic anhydride, pivaloyl chloride, diphenylphosphinic anhydride, propanephosphinic anhydride, boric acid, isobutyl chloroformate, methanesulfonyl chloride, p-toluenesulfonyl chloride), a carbonyl diimidazole, an activated ester, 4-(4,6- dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 2-chloro-4,6,-dimethoxy-1,3,5-triazine, cyanuric chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5‑b]pyridinium 3-oxide hexafluorophosphate, and other reagents known to promote the coupling of amines with carboxylic acids.

[0088] In some embodiments, the coupling agent comprises 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), an acid chloride, an acid anhydride, a carbonyl diimidazole, an activated ester, or a combination thereof. In some embodiments, the coupling agent comprises thionyl chloride, oxalyl chloride, phosphorus(V) oxychloride, acetic anhydride, pivaloyl chloride, diphenylphosphinic anhydride, propanephosphinic anhydride, boric acid, isobutyl chloroformate, methanesulfonyl chloride, p- toluenesulfonyl chloride, a carbonyl diimidazole, an activated ester, 4-(4,6-dimethoxy- 1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 2-chloro-4,6,-dimethoxy-1,3,5- triazine, cyanuric chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, HATU, or a combination thereof. In some embodiments, the coupling reagent is a peptide coupling reagent. In some embodiments, the coupling agent is HATU.

[0089] In some embodiments, suitable second bases include amines (e.g., N-methyl morpholine, triethylamine, diisopropylethylamine), amidines (e.g., 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate, etc.), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide,sodium ethoxide, potassium tert-butoxide), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole, etc.), or a combination thereof.

[0090] In some embodiments, the second base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a hydroxide, an alkoxide, a basic aromatic compound, or a combination thereof. In some embodiments, the second base comprises an amine. In some embodiments, the second base comprises N-methyl morpholine, triethylamine, diisopropylethylamine, or a combination thereof. In some embodiments, the second base is N-methyl morpholine.

[0091] In some embodiments, reacting of the compound of Formula V or a salt thereof is performed in a fifth solvent. In some embodiments, the fifth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), water, or a combination thereof. In some embodiments, the fifth solvent comprises an ether. In some embodiments, the fifth solvent comprises tetrahydrofuran, 2- methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments, the reacting of the compound of Formula V or a salt thereof is performed in a fifth solvent comprising N,N- dimethylacetamide and cyclopentyl methyl ether.

[0092] In some embodiments, the reacting of the compound of Formula V or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C. In some embodiments, the reacting of the compound of Formula V or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, thereacting of the compound of Formula V or a salt thereof is carried out in at a temperature of about 20 °C.

[0093] In some embodiments, the process further comprises preparing the compound of Formula V or a salt thereof by a process comprising: reacting a compound of Formula VII:or a salt thereof, wherein R3is a hydroxyl protecting group; with a first reagent to provide the compound of Formula V or a salt thereof.

[0094] In some embodiments, R3is selected from C1-4alkyl and benzyl. In some embodiments, R3is selected from methyl, ethyl, and benzyl. In some embodiments, R3is C1-4alkyl. In some embodiments, R3is selected from methyl and ethyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is benzyl.

[0095] In some embodiments, R1is selected from hydrogen, methyl, ethyl, and benzyl and R3is selected from methyl, ethyl, and benzyl. In some embodiments, R1and R3are each independently C1-4alkyl. In some embodiments, R1and R3are each independently selected from methyl and ethyl. In some embodiments, R1and R3are each methyl.

[0096] In some embodiments, R2is tert-butyloxycarbonyl and R3is selected from methyl, ethyl, and benzyl. In some embodiments, R2is tert-butyloxycarbonyl and R3is C1-4alkyl. In some embodiments, R2is tert-butyloxycarbonyl and R3selected from methyl and ethyl. In some embodiments, R2is tert-butyloxycarbonyl and R3selected from methyl.

[0097] In some embodiments, R2is tert-butyloxycarbonyl and R1and R3are each independently selected from methyl, ethyl, and benzyl. In some embodiments, R2is tert- butyloxycarbonyl and R1and R3are each independently C1-4alkyl. In some embodiments, R2is tert-butyloxycarbonyl and R1and R3are each independently selected from methyl and ethyl.

[0098] In some embodiments, the compound of Formula VII is a compound of Formula VII-B:

[0099] In some embodiments, the first reagent is selected from a third base and a hydrolase enzyme.

[0100] In some embodiments, the first reagent is the third base. In some embodiments, suitable third bases include amines (e.g., n-propylamine, triethylamine, N,N- diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine), amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), phosphates (e.g., M(n)H(3-n)PO4such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, lithium hydroxide potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert- butoxide), amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide), or a combination thereof.

[0101] In some embodiments, the third base comprises an amine, an amidine, a guanidine, a carbonate, a phosphate, a hydroxide, an alkoxide, an amide, or acombination thereof. In some embodiments, the third base comprises a hydroxide. In some embodiments, the third base comprises an alkali metal hydroxide. In some embodiments, the third base is selected from sodium hydroxide, lithium hydroxide potassium hydroxide, cesium hydroxide, or a combination thereof. In some embodiments, the third base is lithium hydroxide.

[0102] In some embodiments, the reacting of the compound of Formula VII or a salt thereof is performed in a sixth solvent. In some embodiments, the sixth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), water, or a combination thereof. In some embodiments, the sixth solvent comprises an ether. In some embodiments, the sixth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments, the sixth solvent comprises cyclopentyl methyl ether. In some embodiments, the sixth solvent comprises an alcohol. In some embodiments, the sixth solvent comprises methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol, or a combination thereof. In some embodiments, the sixth solvent comprises methanol. In some embodiments, the sixth solvent comprises water. In some embodiments, the sixth solvent comprises an ether, an alcohol, and water.

[0103] In some embodiments, the reacting of the compound of Formula VII or a salt thereof is performed in a sixth solvent comprising cyclopentyl methyl ether, methanol, and water. In some embodiments, the reacting of the compound of FormulaVII or a salt thereof is performed in a sixth solvent comprising cyclopentyl methyl ether, methanol, and water, wherein a volume ratio of the cyclopentyl methyl ether : methanol : water is about 1-3 : 3-5 : 1. In some embodiments, the reacting of the compound of Formula VII or a salt thereof is performed in a sixth solvent comprising cyclopentyl methyl ether, methanol, and water, wherein a volume ratio of the cyclopentyl methyl ether : methanol : water is about 2 : 4 : 1.

[0104] In some embodiments, the reacting of the compound of Formula VII or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C. In some embodiments, the reacting of the compound of Formula VII or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula VII or a salt thereof is carried out at a temperature of about 30 °C.

[0105] In some embodiments, the process further comprises preparing the compound of Formula VII or a salt thereof by a process comprising: reacting a compound of Formula VIII:or a salt thereof, with: a compound of Formula IX:or a salt thereof, a phosphorus-based reagent, andan azodicarboxylate, to provide the compound of Formula VII or a salt thereof.

[0106] In some embodiments, the compound of Formula VIII is a compound of Formula VIII-B:or a salt thereof.

[0107] In some embodiments, suitable phosphorus-based reagents include tri-aryl phosphines (e.g., triphenyl phosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine, tris-(dimethylaminophenyl) phosphine, triphenylphosphoranylidene acetonitrile), tri-alkyl phosphines (e.g., tricyclohexyl phosphine, tributyl phosphine) and phosphoranes (e.g., (cyanomethylene) tributylphosphorane).

[0108] In some embodiments, the phosphorus-based reagent is selected from a tri- aryl phosphine, a tri-alkyl phosphine, and a phosphorane. In some embodiments, the phosphorus-based reagent is a phosphine. In some embodiments, the phosphorus-based reagent is a tri-aryl phosphine. In some embodiments, the phosphorus-based reagent is selected from triphenyl phosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine, tris-(dimethylaminophenyl) phosphine, and triphenylphosphoranylidene acetonitrile. In some embodiments, the phosphorus-based reagent is triphenylphosphine.

[0109] In some embodiments, the azodicarboxylate is selected from diisopropyl azodicarboxylate, di-tertbutyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate. In some embodiments, the azodicarboxylate is diisopropyl azodicarboxylate.

[0110] In some embodiments, the reacting of the compound of Formula VIII or a salt thereof is performed in a seventh solvent. In some embodiments, the seventh solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), or a combination thereof. In some embodiments, the seventh solvent comprises an ether. In some embodiments, the seventh solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments, the reacting of the compound of Formula VIII or a salt thereof is performed in a seventh solvent comprising 2-methyltetrahydrofuran.

[0111] In some embodiments, the reacting of the compound of Formula VIII or a salt thereof is carried out in a temperature range of from about 0 °C to about 50 °C. In some embodiments, the reacting of the compound of Formula VIII or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula VIII or a salt thereof is carried out in a temperature range of about 20 °C. Alternative process for preparing the compound of Formula VII

[0112] In some embodiments, the process comprises preparing the compound of Formula VII or a salt thereof by a process comprising: reacting a compound of Formula VIII:or a salt thereof, with: a second reagent comprising a crotyl group or an allyl group, a second catalyst, and a sixth base to provide the compound of Formula VII or a salt thereof. In some embodiments, the compound of Formula VII is a compound of Formula VII-B.

[0113] In some embodiments, the second reagent comprises a crotyl group (i.e., but-2-en-1-yl). In some embodiments, the second reagent comprises an allyl group (i.e., but-3-en-2-yl).

[0114] In some embodiments, suitable second reagents include crotyl carbonates (e.g., crotyl methyl carbonate, crotyl ethyl carbonate), crotyl esters (e.g., crotyl acetate, crotyl trifluoromethylacetate), crotyl halides (e.g., crotyl chloride, crotyl bromide), crotyl alcohol, 1-methylallyl esters (e.g., 1-methylallyl acetate, 1-methylallyl trifluoroacetate), 1-methylallyl carbonates (e.g., 1-methylallyl methyl carbonate, 1-methylallyl ethyl carbonate), 1-methylallyl halides (e.g., 3-chloro-1-butene, 3-bromo-1-butene), 3-buten-2- ol, or a combination thereof.

[0115] In some embodiments, the second reagent is selected from a crotyl carbonate, a crotyl ester, a crotyl halide, crotyl alcohol, a 1-methylallyl ester, a 1-methyl allyl carbonate, a 1-methylallylhalide, and 3-buten-2-ol. In some embodiments, the second reagent is selected from crotyl methyl carbonate, crotyl ethyl carbonate, or a combination thereof. In some embodiments, the second reagent is a crotyl carbonate. In some embodiments, the second reagent is crotyl methyl carbonate.

[0116] In some embodiments, the second catalyst is a transition metal catalyst. In some embodiments, the transition metal catalyst is selected from an iridium compound, a palladium compound, a cobalt compound, and a rhodium compound. In some embodiments, the transition metal catalyst is an iridium compound.

[0117] In some embodiments, the second catalyst is formed in situ from a precatalyst and a ligand. In some embodiments, suitable precatalysts include iridium compounds (e.g., bis(1,5-cyclooctadiene)diiridium(I) dichloride, (1,5- cyclooctadiene)(methoxy)iridium(I) dimer), palladium compounds (e.g., tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3], palladium(II) acetate, allylpalladium(II) chloride dimer), cobalt compounds (e.g., cobalt(II) tetrafluoroborate, cobalt(II) bromide), and rhodium compounds (e.g., chloro(1,5-cyclooctadiene)rhodium(I) dimer, hydroxy(cyclooctadiene)rhodium(I) dimer).

[0118] In some embodiments, the precatalyst is selected from an iridium compound, a palladium compound, a cobalt compound, and a rhodium compound. In some embodiments, the precatalyst is an iridium compound. In some embodiments, the precatalyst is bis(1,5-cyclooctadiene)diiridium(I) dichloride or (1,5- cyclooctadiene)(methoxy)iridium(I) dimer. In some embodiments, the precatalyst is bis(1,5-cyclooctadiene)diiridium(I) dichloride.

[0119] In some embodiments, a molar ratio of the compound of Formula VIII or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.10. In some embodiments, a molar ratio of the compound of Formula VIII or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.07. In some embodiments, a molar ratio of the compound of Formula VIII or a salt thereof to the precatalyst is about 1:0.04.

[0120] In some embodiments, suitable ligands include phosphoramidites (e.g., (S,S,S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a’]dinaphthalene-4-yl)bis(1- phenylethyl)amine, (S)-(+)-N-(3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4- a′]dinaphthalen-4-yl)-dibenzo[b,f]azepine, (S)-(+)-(3,5-Dioxa-4-phosphacyclohepta[2,1- a;3,4- a′]dinaphthalen-4-yl)dimethylamine), and Trost ligands (e.g., (1S,2S)-(^)-1,2- diaminocyclohexane-N,N’-bis(2-diphenylphosphinobenzoyl) [(S,S)-DACH-phenyl Trostligand], (1S,2S)-(^)-1,2-diaminocyclohexane-N,N’-bis(2-diphenylphosphino-1- naphthoyl) [(S,S)-DACH-naphthyl Trost ligand). In some embodiments, the ligand is selected from a phosphoramidite and a Trost ligand. In some embodiments, the ligand is a phosphoramidite. In some embodiments, the ligand is selected from (S,S,S)-(+)-(3,5- dioxa-4-phosphacyclohepta[2,1-a:3,4-a’]dinaphthalene-4-yl)bis(1-phenylethyl)amine, (S)-(+)-N-(3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)- dibenzo[b,f]azepine, and (S)-(+)-(3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4- a′]dinaphthalen-4-yl)dimethylamine. In some embodiments, the ligand is (S,S,S)-(+)-(3,5- dioxa-4-phosphacyclohepta[2,1-a:3,4-a’]dinaphthalene-4-yl)bis(1-phenylethyl)amine.

[0121] In some embodiments, suitable sixth bases include amines (e.g., n- propylamine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine), amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert- butoxide), amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide), and basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole). In some embodiments, the sixth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound. In some embodiments, the sixth base is an amine. In some embodiments, the sixth base comprises n- propylamine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, or a combination thereof. In some embodiments, the sixth base is n-propylamine.

[0122] In some embodiments, the reacting of the compound of Formula VIII or a salt thereof is performed in a twelfth solvent. In some embodiments, the twelfth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), or a combination thereof. In some embodiments, the twelfth solvent comprises a polar aprotic solvent. In some embodiments, the twelfth solvent comprises N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), or a combination thereof. In some embodiments, the reacting of the compound of Formula VIII or a salt thereof is performed in a twelfth solvent comprising N,N-dimethylacetamide.

[0123] In some embodiments, the reacting of the compound of Formula VIII or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C. In some embodiments, the reacting of the compound of Formula VIII or a salt thereof is carried out in a temperature range of from about 20 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula VIII or a salt thereof is carried out at a temperature of about 25 °C. Process for preparing the compound of Formula VIII

[0124] In some embodiments, the process comprises preparing the compound of Formula VIII or a salt thereof by a process comprising: reacting a compound of Formula X:or a salt thereof, with a com r a salt thereof, to provide the compound of Formula VIII or a salt thereof.

[0125] In some embodiments, the compound of Formula X is a compound of Formula X-B:or a salt thereof.

[0126] In some embodiments, the compound of Formula NH2NHR2 or a salt thereof is NH2NHBoc.

[0127] In some embodiments, the reacting of the compound of Formula X or a salt thereof is carried out in the presence of a fourth base. In some embodiments, suitable fourth bases include amines (e.g., triethylamine, N,N-diisopropylethylamine, 1,4- diazabicyclo[2.2.2]octane (DABCO), quinuclidine), amidines (e.g., 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2- n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide,potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, etc.), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole).

[0128] In some embodiments, the fourth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound, or a combination thereof. In some embodiments, the fourth base is a carbonate. In some embodiments, the fourth base is an alkali metal carbonate. In some embodiments, the fourth base comprises sodium carbonate, potassium bicarbonate, cesium carbonate, or a combination thereof. In some embodiments, the fourth base is sodium bicarbonate.

[0129] In some embodiments, the reacting of the compound of Formula X is performed in the absence of a base.

[0130] In some embodiments, the reacting of the compound of Formula X or a salt thereof is performed in an eighth solvent. In some embodiments, the eighth solvent comprises an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or a combination thereof. In some embodiments, the eight solvent comprises an alcohol. In some embodiments, the eighth solvent comprises methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol, or a combination thereof. In some embodiments, the eighth solvent comprises methanol. In some embodiments, the eighth solvent comprises water.

[0131] In some embodiments, the reacting of the compound of Formula X or a salt thereof is performed in an eighth solvent comprising methanol and water. In some embodiments, the reacting of the compound of Formula X or a salt thereof is performedin an eighth solvent comprising methanol and water, wherein a volume ratio of the methanol to the water is about 1-10 : 0.1-1.0. In some embodiments, the reacting of the compound of Formula X or a salt thereof is performed in an eighth solvent comprising methanol and water, wherein a volume ratio of the methanol to the water is about 6 : 0.4.

[0132] In some embodiments, the reacting of the compound of Formula X or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C. In some embodiments, the reacting of the compound of Formula X or a salt thereof is carried out in a temperature range of from about 35 °C to about 55 °C. In some embodiments, the reacting of the compound of Formula X or a salt thereof is carried out at a temperature of about 45 °C.

[0133] In some embodiments, the process further comprises preparing the compound of Formula X or a salt thereof by a process comprising: reacting a compound of Formula XII:or a salt thereof, with: a promoter, a dialkyl oxalate, and a fifth base, to provide the compound of Formula X or a salt thereof.

[0134] In some embodiments, the compound of Formula XII is a compound of Formula XII-A:

[0135] In some embodiments, suitable promoters include carboxylic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid), sulfonic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid), halogenated alcohols (e.g., 2,2,2- trichloroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol), Lewis acids (e.g., boron trifluoride methyl etherate, boron trifluoride dibutyl etherate, boron trichloride, boron tribromide, aluminum chloride, aluminum bromide), and inorganic acids (e.g., hydrochloric acid, sulfuric acid).

[0136] In some embodiments, the promoter comprises a carboxylic acid, a sulfonic acid, a halogenated alcohol, a Lewis acid, an inorganic acid, or a combination thereof. In some embodiments, the promoter comprises a halogenated alcohol. In some embodiments, the promoter comprises 2,2,2-trichloroethanol, 1,1,1,3,3,3-hexafluoro-2- propanol, or a combination thereof. In some embodiments, the promoter is 2,2,2- trifluoroethanol.

[0137] In some embodiments, the reacting of the compound of Formula XII or a salt thereof is carried out in the presence of a third acid. In some embodiments, the third acid is an inorganic acid. In some embodiments, the third acid is hydrochloric acid.

[0138] In some embodiments, the dialkyl oxalate is a di-C1-4alkyl oxalate. In some embodiments, the dialkyl oxalate is selected from dimethyl oxalate and diethyl oxalate. In some embodiments, the dialkyl oxalate is dimethyl oxalate.

[0139] In some embodiments, suitable fifth bases include amines (e.g., ethylamine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine), amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD),1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert- butoxide), alkyl and aryl lithium reagents (e.g., n-butyllithium, phenyllithium), amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide), and basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole).

[0140] In some embodiments, the fifth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an alkyl lithium reagent, an aryl lithium reagent, an amide, a basic aromatic compound, or a combination thereof. In some embodiments, the fifth base comprises a metal alkoxide. In some embodiments, the fifth base comprises sodium methoxide, sodium ethoxide, potassium tert-butoxide, or a combination thereof. In some embodiments, the fifth base is sodium alkoxide.

[0141] In some embodiments, the reacting of the compound of Formula XII or a salt thereof is performed in a tenth solvent. In some embodiments, the tenth solvent comprises an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or a combination thereof. In some embodiments, the tenth solvent comprises a polar aprotic solvent. In some embodiments, the tenth solvent comprises N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), or a combination thereof. In some embodiments, the reacting of the compound of Formula XII or a salt thereof is performed in a tenth solvent comprising N,N-dimethylacetamide.

[0142] In some embodiments, the reacting of the compound of Formula XII or a salt thereof is carried out in a temperature range of from about -10 °C to about 50 °C. In some embodiments, the reacting of the compound of Formula XII or a salt thereof is carried out in a temperature range of from about 0 °C to about 20 °C. In some embodiments, the reacting of the compound of Formula XII or a salt thereof is carried out at a temperature of about 10 °C.

[0143] In some embodiments, the process comprises preparing the compound of Formula X or a salt thereof by a process comprising: reacting a compound of Formula XI:or a salt thereof, with a promoter to provide the compound of Formula X or a salt thereof.

[0144] In some embodiments, the promoter comprises a carboxylic acid, a sulfonic acid, a halogenated alcohol, a Lewis acid, an inorganic acid, or a combination thereof. In some embodiments, the promoter comprises a halogenated alcohol. In some embodiments, the promoter is 2,2,2-trifluoroethanol.

[0145] In some embodiments, the reacting of the compound of Formula XI or a salt thereof is carried out in the presence of a third acid. In some embodiments, the third acid is an inorganic acid. In some embodiments, the third acid is hydrochloric acid.

[0146] In some embodiments, the reacting of the compound of Formula XI or a salt thereof is performed in a ninth solvent comprising dichloromethane.

[0147] In some embodiments, the reacting of the compound of Formula XI or a salt thereof is carried out in a temperature range of from about -10 °C to about 50 °C.

[0148] In some embodiments, the compound of Formula XI is a compound of Formula XI-A:or a salt thereof.

[0149] In some embodiments, the reacting of the compound of Formula XI or a salt thereof is carried out in the presence of a third acid. In some embodiments, the third acid is an inorganic acid. In some embodiments, the third acid is hydrochloric acid. In some embodiments, a weight ratio of the compound of Formula XI to the third acid is about 1:0.01-0.25. In some embodiments, a weight ratio of the compound of Formula XI to the third acid is about 1:0.1.

[0150] In some embodiments, the reacting of the compound of Formula XI or a salt thereof is performed in a ninth solvent comprising dichloromethane.

[0151] In some embodiments, the reacting of the compound of Formula XI or a salt thereof is carried out in a temperature range of from about -10 °C to about 50 °C.

[0152] In some embodiments, the process further comprises preparing the compound of Formula XI or a salt thereof by a process comprising: reacting a compound of Formula XII:XII or a salt thereof, with: a dialkyl oxalate, and a fifth base, to provide the compound of Formula XI or a salt thereof.

[0153] In some embodiments, the dialkyl oxalate is selected from dimethyl oxalate and diethyl oxalate. In some embodiments, the dialkyl oxalate is dimethyl oxalate. In some embodiments, the dialkyl oxalate is diethyl oxalate.

[0154] In some embodiments, the fifth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an alkyl lithium reagent, an aryl lithium reagent, an amide, a basic aromatic compound, or a combination thereof. In some embodiments, the fifth base comprises a metal alkoxide. In some embodiments, the fifth base is sodium alkoxide.

[0155] In some embodiments, the reacting of the compound of Formula XII or a salt thereof is performed in a tenth solvent comprising N,N-dimethylacetamide.

[0156] In some embodiments, the reacting of the compound of Formula XII or a salt thereof is carried out in a temperature range of from about -10 °C to about 50 °C.

[0157] In some embodiments, the process further comprises preparing the compound of Formula XII or a salt thereof by a process comprising: reacting a compound of Formula XIII:or a salt thereof, with N,N-dimethylformamide dimethyl acetal,to provide the compound of Formula XII or a salt thereof. Methods of preparing the compound of Formula XII or a salt thereof are described in WO 2015195656, which is incorporated by reference herein.

[0158] In some embodiments, provided herein is a process for preparing a compound of Formula I: or a salt thereof, whereinhydroxyl protecting group, comprising: (a) reacting a compound of Formula VII:or a salt thereof, wherein R2is an amine protecting group and R3is a hydroxyl protecting group, with a first reagent to provide a compound of Formula V:or a salt thereof; (b) reacting the compound of Formula V or a salt thereof, with: a compound of Formula VI:wherein Y is an anion or salt, a coupling agent, and a second base, to provide a compound of Formula IV: or a salt thereof;(c) deprotecting the compound of Formula IV or a salt thereof to provide a compound of Formula III:or a salt thereof; (d) reacting the compound of Formula III or a salt thereof, with:a methylene reagent, and a first acid or a first base, to provide a compound of Formula II: or a salt thereof; and(e) reacting the compound of Formula II or a salt thereof with a first catalyst to provide the compound of Formula I or a salt thereof.

[0159] In some embodiments, provided herein is a process for preparing a compound of Formula I-A: or a salt thereof,(a) reacting a compound of Formula VII:or a salt thereof, wherein R1and R3are each independently hydroxyl protecting groups, and R2is an amine protecting group, with a first reagent to provide a compound of Formula V: or a salt thereof;(b) reacting the compound of Formula V or a salt thereof, with: a compound of Formula VI:wherein Y is an anion or salt, a coupling agent, and a second base, to provide a compound of Formula IV:or a salt thereof;(c) deprotecting the compound of Formula IV or a salt thereof to provide a compound of Formula III: or a salt thereof;(d) reacting the compound of Formula III or a salt thereof, with a methylene reagent, and a first acid or a first base, to provide a compound of Formula II: or a salt thereof;(e) reacting the compound of Formula II or a salt thereof with a first catalyst to provide a compound of Formula I:or a salt thereof; and(f) deprotecting the compound of Formula I, or a salt thereof; to provide the compound of Formula I-A or a salt thereof.

[0160] In some embodiments, provided herein is a process for preparing a compound of Formula II: or a salt thereof,(a) reacting a compound of Formula VII:or a salt thereof, wherein R1and R3are each independently hydroxyl protecting groups, and R2is an amine protecting group, with a first reagent to provide a compound of Formula V:or a salt thereof; (b) reacting the compound of Formula V or a salt thereof, with:a compound of Formula VI:wherein Y is an anion or salt, a coupling agent, and a second base, to provide a compound of Formula IV: or a salt thereof;(c) deprotecting the compound of Formula IV or a salt thereof to provide a compound of Formula III:or a salt thereof; (d) reacting the compound of Formula III or a salt thereof, with a methylene reagent, and a first acid or a first base,to provide the compound of Formula II or a salt thereof.

[0161] In some embodiments, provided herein is a process for preparing a compound of Formula III:or a salt thereof, comprising: (a) reacting a compound of Formula VII:or a salt thereof, wherein R1and R3are each independently hydroxyl protecting groups, and R2is an amine protecting group, with a first reagent to provide a compound of Formula V:or a salt thereof; (b) reacting the compound of Formula V or a salt thereof, with: a compound of Formula VI:wherein Y is an anion or salt, a coupling agent, and a second base, to provide a compound of Formula IV: or a salt thereof;(c) deprotecting the compound of Formula IV or a salt thereof to provide the compound of Formula III or a salt thereof.

[0162] In some embodiments, provided herein is a process for preparing a compound of Formula IV:or a salt thereof, (a) reacting a compound of Formula VII:or a salt thereof, wherein R1and R3are each independently hydroxyl protecting groups, and R2is an amine protecting group, with a first reagent to provide a compound of Formula V: or a salt thereof;(b) reacting the compound of Formula V or a salt thereof, with: a compound of Formula VI:wherein Y is an anion or salt, a coupling agent, and a second base, to provide the compound of Formula IV or a salt thereof.

[0163] In some embodiments, provided herein is a process for preparing a compound of Formula V:or a salt thereof, comprising: reacting a compound of Formula VII:or a salt thereof, wherein R1and R3are each independently hydroxyl protecting groups, and R2is an amine protecting group, with a first reagent to provide the compound of Formula V or a salt thereof.

[0164] In some embodiments of the processes disclosed herein, the compound of Formula VII or a salt thereof is prepared by a process comprising: (a) reacting a compound of Formula XIII:or a salt thereof, wherein R1is a hydroxyl protecting group, with N,N-dimethylformamide dimethyl acetal, to provide a compound of Formula XII:or a salt thereof; (b) reacting the compound of Formula XII or a salt thereof, with: a promoter, a dialkyl oxalate, and a fifth base, to provide a compound of Formula X: or a salt thereof;(c) reacting the compound of Formula X or a salt thereof, with a compound of Formula NH2NHR2 or a salt thereof, to provide the compound of Formula VIII:or a salt thereof; and(d) reacting the compound of Formula VIII or a salt thereof, with: a compound of Formula IX:or a salt thereof, a phosphorus-based reagent, and an azodicarboxylate, to provide the compound of Formula VII or a salt thereof.

[0165] In some embodiments of the processes disclosed herein, the compound of Formula VII or a salt thereof is prepared by a process comprising: (a) reacting a compound of Formula XIII:or a salt thereof, wherein R1is a hydroxyl protecting group, with N,N-dimethylformamide dimethyl acetal, to provide a compound of Formula XII:or a salt thereof;(b) reacting the compound of Formula XII or a salt thereof, with: a promoter, a dialkyl oxalate, and a fifth base, to provide a compound of Formula X: or a salt thereof;(c) reacting the compound of Formula X or a salt thereof, with a compound of Formula NH2NHR2or a salt thereof, to provide the compound of Formula VIII:or a salt thereof; and (e) reacting the compound of Formula VIII or a salt thereof, with: a second reagent comprising a crotyl group or an allyl group, a second catalyst, and a sixth base to provide the compound of Formula VII or a salt thereof.Alternative process for preparing the compound of Formula III

[0166] In some embodiments, the process comprises preparing the compound of Formula III or a salt thereof by a process comprising: reacting a compound of Formula VII-A:or a salt thereof, with a first reagent to hydrolyze the compound of Formula VII-A; and reacting the hydrolyzed compound of Formula VII-A with: a compound of Formula VI:wherein Y is an anion or salt, a coupling agent, and a second base, to provide the compound of Formula III or a salt thereof.

[0167] In some embodiments, the first reagent is selected from a third base and a hydrolase enzyme.

[0168] In some embodiments, the first reagent is the third base. In some embodiments, the third base comprises an amine, an amidine, a guanidine, a carbonate, a phosphate, a hydroxide, an alkoxide, an amide, or a combination thereof. In some embodiments, the third base is lithium hydroxide.

[0169] In some embodiments, Y is selected from tosylate, mesylate, and HCl salt. In some embodiments, Y is tosylate.

[0170] In some embodiments, the coupling agent comprises 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), an acid chloride, an acid anhydride, a carbonyl diimidazole, an activated ester, or a combination thereof. In some embodiments, the coupling agent is HATU.

[0171] In some embodiments, the second base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a hydroxide, an alkoxide, a basic aromatic compound, or a combination thereof. In some embodiments, the second base comprises an amine. In some embodiments, the second base is N-methyl morpholine.

[0172] In some embodiments, the process further comprises preparing the compound of Formula VII-A or a salt thereof by a process comprising: reacting a compound of Formula VIII-A:or a salt thereof, with: a second reagent comprising a crotyl group or an allyl group, a second catalyst, and a sixth base, to provide the compound of Formula VII-A or a salt thereof.

[0173] In some embodiments, the second reagent comprises a crotyl group (i.e., but-2-en-1-yl). In some embodiments, the second reagent comprises an allyl group (i.e., but-3-en-2-yl).

[0174] In some embodiments, suitable second reagents include crotyl carbonates (e.g., crotyl methyl carbonate, crotyl ethyl carbonate), crotyl esters (e.g., crotyl acetate, crotyl trifluoromethylacetate), crotyl halides (e.g., crotyl chloride, crotyl bromide), crotyl alcohol, 1-methylallyl esters (e.g., 1-methylallyl acetate, 1-methylallyl trifluoroacetate), 1-methylallyl carbonates (e.g., 1-methylallyl methyl carbonate, 1-methylallyl ethyl carbonate), 1-methylallyl halides (e.g., 3-chloro-1-butene, 3-bromo-1-butene), 3-buten-2- ol, or a combination thereof.

[0175] In some embodiments, the second reagent is selected from a crotyl carbonate, a crotyl ester, a crotyl halide, crotyl alcohol, a 1-methylallyl ester, a 1-methyl allyl carbonate, a 1-methylallylhalide, and 3-buten-2-ol. In some embodiments, the second reagent is selected from crotyl methyl carbonate, crotyl ethyl carbonate, or a combination thereof. In some embodiments, the second reagent is a crotyl carbonate. In some embodiments, the second reagent is crotyl methyl carbonate. In some embodiments, the second reagent is crotyl methyl carbonate, wherein the crotyl methyl carbonate is a mixture of cis and trans.

[0176] In some embodiments, the second catalyst is a transition metal catalyst. In some embodiments, the transition metal catalyst is selected from an iridium compound, a palladium compound, a cobalt compound, and a rhodium compound. In some embodiments, the transition metal catalyst is an iridium compound.

[0177] In some embodiments, the second catalyst is formed in situ from a precatalyst and a ligand. In some embodiments, suitable precatalysts include iridium compounds (e.g., bis(1,5-cyclooctadiene)diiridium(I) dichloride, (1,5- cyclooctadiene)(methoxy)iridium(I) dimer), palladium compounds (e.g., tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3], palladium(II) acetate, allylpalladium(II) chloride dimer), cobalt compounds (e.g., cobalt(II) tetrafluoroborate, cobalt(II) bromide), and rhodium compounds (e.g., chloro(1,5-cyclooctadiene)rhodium(I) dimer, hydroxy(cyclooctadiene)rhodium(I) dimer).

[0178] In some embodiments, the precatalyst is selected from an iridium compound, a palladium compound, a cobalt compound, and a rhodium compound. Insome embodiments, the precatalyst is an iridium compound. In some embodiments, the precatalyst is bis(1,5-cyclooctadiene)diiridium(I) dichloride or (1,5- cyclooctadiene)(methoxy)iridium(I) dimer. In some embodiments, the precatalyst is bis(1,5-cyclooctadiene)diiridium(I) dichloride.

[0179] In some embodiments, a molar ratio of the compound of Formula VIII-A or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.10. In some embodiments, a molar ratio of the compound of Formula VIII-A or a salt thereof to the precatalyst is from about 1:0.005 to about 1:0.05. In some embodiments, a molar ratio of the compound of Formula VIII-A or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.03. In some embodiments, a molar ratio of the compound of Formula VIII-A or a salt thereof to the precatalyst is about 1:0.02.

[0180] In some embodiments, suitable ligands include phosphoramidites (e.g., (S,S,S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a’]dinaphthalene-4-yl)bis(1- phenylethyl)amine, (S)-(+)-N-(3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4- a′]dinaphthalen-4-yl)-dibenzo[b,f]azepine, (S)-(+)-(3,5-Dioxa-4-phosphacyclohepta[2,1- a;3,4- a′]dinaphthalen-4-yl)dimethylamine), and Trost ligands (e.g., (1S,2S)-(^)-1,2- diaminocyclohexane-N,N’-bis(2-diphenylphosphinobenzoyl) [(S,S)-DACH-phenyl Trost ligand], (1S,2S)-(^)-1,2-diaminocyclohexane-N,N’-bis(2-diphenylphosphino-1- naphthoyl) [(S,S)-DACH-naphthyl Trost ligand). In some embodiments, the ligand is selected from a phosphoramidite and a Trost ligand. In some embodiments, the ligand is a phosphoramidite. In some embodiments, the ligand is selected from (S,S,S)-(+)-(3,5- dioxa-4-phosphacyclohepta[2,1-a:3,4-a’]dinaphthalene-4-yl)bis(1-phenylethyl)amine, (S)-(+)-N-(3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)- dibenzo[b,f]azepine, and (S)-(+)-(3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4- a′]dinaphthalen-4-yl)dimethylamine. In some embodiments, the ligand is (S,S,S)-(+)-(3,5- dioxa-4-phosphacyclohepta[2,1-a:3,4-a’]dinaphthalene-4-yl)bis(1-phenylethyl)amine.

[0181] In some embodiments, suitable sixth bases include amines (e.g., n- propylamine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine), amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert- butoxide), amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide), and basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole). In some embodiments, the sixth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound. In some embodiments, the sixth base is an amine. In some embodiments, the sixth base comprises n- propylamine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, or a combination thereof. In some embodiments, the sixth base is 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0182] In some embodiments, the reacting of the compound of Formula VIII-A or a salt thereof is performed in a twelfth solvent. In some embodiments, the twelfth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the twelfth solvent comprises a polar aprotic solvent. In some embodiments, the twelfth solvent comprises N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), or a combination thereof. In some embodiments, the reacting of the compound of Formula VIII-A or a salt thereof is performed in a twelfth solvent comprising N,N-dimethylacetamide.

[0183] In some embodiments, the reacting of the compound of Formula VIII-A or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C. In some embodiments, the reacting of the compound of Formula VIII-A or a salt thereof is carried out in a temperature range of from about 45 °C to about 55 °C. In some embodiments, the reacting of the compound of Formula VIII-A or a salt thereof is carried out at a temperature of about 50 °C. Alternative process for preparing the compound of Formula I-A

[0184] In some embodiments, provided herein is a process for preparing a compound of Formula I-A:or a salt thereof, comprising deprotecting a compound of Formula I:or a salt thereof, wherein to provide the compound of Formula I-A or a salt thereof.

[0185] In some embodiments, R1is selected from C1-4alkyl, benzyl, and -COOR4; wherein R4is selected from C1-4alkyl and phenyl. In some embodiments, R1is selectedfrom methyl, ethyl, benzyl, acetate, propionate, and benzoate. In some embodiments, R1is selected from C1-4alkyl and benzyl. In some embodiments, R1is C1-4 alkyl. In some embodiments, R1is selected from methyl, ethyl, and benzyl. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is benzyl. In some embodiments, R1is -COOR4. In some embodiments, R4is C1-4alkyl. In some embodiments, R4is methyl or ethyl. In some embodiments, R4is phenyl.

[0186] In some embodiments, the compound of Formula I is a compound of Formula I-B.

[0187] In some embodiments, deprotecting the compound of Formula I or a salt thereof comprises treating the compound of Formula I or a salt thereof with a first deprotecting agent. In some embodiments, suitable first deprotecting agents include metal halide salts (e.g., magnesium bromide, magnesium chloride, lithium chloride, potassium iodide, sodium iodide, calcium chloride, calcium bromide, calcium iodide, copper (I) chloride, copper (II) chloride, zinc chloride), hydrogen halides (e.g., hydrogen chloride, hydrogen bromide, hydrogen iodide), boron reagents (e.g., boron trichloride, boron tribromide), aluminum reagents (e.g., aluminum trichloride, aluminum tribromide), titanium reagents (e.g., titanium tetrachloride, titanium tribromide, titanium tetrabromide), pyridinium halide salts (e.g., pyridinium chloride, pyridinium perbromide, pyridinium iodide), ammonium halides (e.g., ammonium chloride, tetrabutylammonium chloride, tetrabutylammonium iodide), silyl halides (e.g., trimethylsilyl chloride, trimethylsilyl iodide).

[0188] In some embodiments, suitable first deprotecting agents include metal halide salts (e.g., magnesium bromide, lithium chloride, potassium iodide, sodium iodide, calcium chloride, copper (I) chloride, copper (II) chloride, zinc chloride), hydrogen halides (e.g., hydrogen chloride, hydrogen bromide, hydrogen iodide), boron reagents (e.g., boron trichloride, boron tribromide), aluminum reagents (e.g., aluminum trichloride, aluminum tribromide), titanium reagents (e.g., titanium tetrachloride, titanium tribromide, titanium tetrabromide), pyridinium halide salts (e.g., pyridinium chloride, pyridinium perbromide, pyridinium iodide), ammonium halides (e.g., ammoniumchloride, tetrabutylammonium chloride, tetrabutylammonium iodide), silyl halides (e.g., trimethylsilyl chloride, trimethylsilyl iodide).

[0189] In some embodiments, the first deprotecting agent is selected from a metal halide, a hydrogen halide, a boron reagent, an aluminum reagent, a titanium reagent, a pyridinium halide salt, an ammonium halide, and a silyl halide. In some embodiments, the first deprotecting agent is a metal halide. In some embodiments, the first deprotecting agent comprises magnesium bromide, magnesium chloride, lithium chloride, potassium iodide, sodium iodide, calcium chloride, copper (I) chloride, copper (II) chloride, zinc chloride, calcium bromide, calcium iodide, or a combination thereof. In some embodiments, the first deprotecting agent comprises magnesium bromide, lithium chloride, potassium iodide, sodium iodide, calcium chloride, copper (I) chloride, copper (II) chloride, zinc chloride, or a combination thereof. In some embodiments, the first deprotecting agent is lithium chloride. In some embodiments, the first deprotecting agent is calcium bromide. In some embodiments, the first deprotecting agent is magnesium chloride.

[0190] In some embodiments, the deprotecting the compound of Formula I or a salt thereof is performed in a second solvent. In some embodiments, the second solvent comprises water, an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the second solvent comprises a polar aprotic solvent. In some embodiments, the second solvent comprises N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), or a combination thereof. In some embodiments, the deprotecting the compound of Formula I or a salt thereof is performed in a second solvent comprising N-methyl-2-pyrrolidone.

[0191] In some embodiments, the second solvent comprises an alcohol. In some embodiments, the second solvent comprises methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol, or a combination thereof. In some embodiments, the deprotecting the compound of Formula I or a salt thereof is performed in a second solvent comprising 2-propanol.

[0192] In some embodiments, the deprotecting the compound of Formula I or a salt thereof is carried out in a temperature range of from about 0 °C to about 130 °C. In some embodiments, the deprotecting the compound of Formula I or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C. In some embodiments, the deprotecting the compound of Formula I or a salt thereof is carried out in a temperature range of from about 70 °C to about 90 °C. In some embodiments, the deprotecting the compound of Formula I or a salt thereof is carried out in a temperature of about 80 °C.

[0193] In some embodiments, the process further comprises preparing the compound of Formula I or a salt thereof by a process comprising: reacting a compound of Formula A:or a salt thereof, a methylene reagent, and a first acid or a first base,to provide the compound of Formula I or a salt thereof.

[0194] In some embodiments, R3Ais selected from C1-4alkyl, C1-4haloalkyl, and benzyl. In some embodiments, R3Ais selected from methyl, ethyl, isopropyl, trifluoroethyl, and benzyl. In some embodiments, R3Ais C1-4alkyl. In some embodiments, R3Ais selected from methyl, ethyl, and isopropyl. In some embodiments, R3Ais methyl. In some embodiments, R3Ais C1-4haloalkyl. In some embodiments, R3Ais trifluoroethyl. In some embodiments, R3Ais benzyl.

[0195] In some embodiments, R1is C1-4alkyl and R3Ais selected from C1-4alkyl, C1-4haloalkyl, and benzyl. In some embodiments, R1and R3Aare each independently C1-4alkyl. In some embodiments, R1and R3Aare each independently selected from methyl, ethyl, and isopropyl.

[0196] In some embodiments, the compound of Formula A is a compound of Formula A-1: or a salt thereof.

[0197] In some embodiments, the methylene reagent is a formaldehyde reagent or a dihalomethane. In some embodiments, suitable formaldehyde reagents include formaldehyde acetals (e.g., dimethoxymethane, diethoxymethane), formaldehyde solution, paraformaldehyde, and 1,3,5-trioxane. In some embodiments, suitable methylene reagents include dihalomethanes (e.g., dibromomethane, diiodomethane).

[0198] In some embodiments, the methylene reagent is selected from 1,3,5- trioxane, a formaldehyde acetal, formaldehyde, paraformaldehyde, or a dihalomethane. In some embodiments, the methylene reagent is a formaldehyde reagent. In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, a formaldehydeacetal, formaldehyde, and paraformaldehyde. In some embodiments, the methylene reagent is 1,3,5-trioxane.

[0199] In some embodiments, the compound of Formula A or a salt thereof is reacted with the first acid. In some embodiments, suitable first acids include carboxylic acids (e.g., oxalic acid, trichloroacetic acid, trifluoroacetic acid), sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, camphorsulfonic acid), Lewis acids (e.g., boron trifluoride methyl etherate, boron trifluoride dibutyl etherate, boron trichloride, boron tribromide, aluminum chloride, aluminum bromide), inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid), or a combination thereof.

[0200] In some embodiments, the first acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof. In some embodiments, the first acid comprises a carboxylic acid. In some embodiments, the first acid is selected from oxalic acid, trichloroacetic acid, trifluoroacetic acid, or a combination thereof. In some embodiments, the first acid is trifluoroacetic acid.

[0201] In some embodiments, the compound of Formula A or a salt thereof is reacted with the first base. In some embodiments, suitable first bases include amines (e.g., n-propylamine, triethylamine, N,N-diisopropylethylamine, 1,4- diazabicyclo[2.2.2]octane (DABCO), quinuclidine), amidines (e.g., 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2- n)CO3such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amides (e.g., lithium bis(trimethylsilyl)amide,potassium bis(trimethylsilyl)amide, lithium diisopropylamide), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole), or a combination thereof.

[0202] In some embodiments, the first base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound, or a combination thereof.

[0203] In some embodiments, the reacting of the compound of Formula A or a salt thereof is performed in a third solvent. In some embodiments, the third solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), or a combination thereof. In some embodiments, the third solvent comprises a hydrocarbon. In some embodiments, the third solvent comprises toluene, methylcyclohexane, n-heptane, hexanes, limonene, or a combination thereof. In some embodiments, the reacting of the compound of Formula A or a salt thereof is performed in a third solvent comprising toluene.

[0204] In some embodiments, the reacting of the compound of Formula A or a salt thereof is carried out in a temperature range of from about 20 °C to about 140 °C. In some embodiments, the reacting of the compound of Formula A or a salt thereof is carried out in a temperature range of from about 90 °C to about 110 °C. In some embodiments, the reacting of the compound of Formula III or a salt thereof is carried out at a temperature of about 100 °C. Alternative process for preparing the compound of Formula I

[0205] In some embodiments of the process disclosed herein, the process comprises preparing the compound of Formula I or a salt thereof, by a process comprising: reacting a compound of Formula R-1: or a salt thereof with:a methylene reagent, and an eighth acid or a fourteenth base, to provide the compound of Formula I or a salt thereof, wherein R1is a hydroxyl protecting group. In some embodiments, R1is selected from C1-4alkyl, benzyl, and - COOR4; wherein R4is selected from C1-4alkyl and phenyl, as described herein. In some embodiments, the compound of Formula I is a compound of Formula I-B.

[0206] In some embodiments, the compound of Formula R-1 or a salt thereof is a compound of Formula R-1-A:or a salt thereof.

[0207] In some embodiments, the methylene reagent is a formaldehyde reagent or a dihalomethane. In some embodiments, suitable formaldehyde reagents include formaldehyde acetals (e.g., dimethoxymethane, diethoxymethane), formaldehydesolution, paraformaldehyde, and 1,3,5-trioxane. In some embodiments, suitable methylene reagents include dihalomethanes (e.g., dibromomethane, diiodomethane).

[0208] In some embodiments, the methylene reagent is selected from 1,3,5- trioxane, a formaldehyde acetal, formaldehyde, paraformaldehyde, or a dihalomethane. In some embodiments, the methylene reagent is a formaldehyde reagent. In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, a formaldehyde acetal, formaldehyde, and paraformaldehyde. In some embodiments, the methylene reagent is formaldehyde (i.e., formalin). In some embodiments, the methylene reagent is 1,3,5-trioxane.

[0209] In some embodiments, the compound of Formula R-1 or a salt thereof is reacted with the eighth acid. In some embodiments, suitable eighth acids include carboxylic acids (e.g., oxalic acid, trichloroacetic acid, trifluoroacetic acid), sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, camphorsulfonic acid), Lewis acids (e.g., boron trifluoride methyl etherate, boron trifluoride dibutyl etherate, boron trichloride, boron tribromide, aluminum chloride, aluminum bromide), inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid), or a combination thereof.

[0210] In some embodiments, the eighth acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof. In some embodiments, the eighth acid is a sulfonic acid. In some embodiments, the eight acid comprises methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, camphorsulfonic acid, or a combination thereof. In some embodiments, the eighth acid is methanesulfonic acid.

[0211] In some embodiments, the eighth acid is an inorganic acid. In some embodiments, the eighth acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, or a combination thereof. In some embodiments, the eighth acid is phosphoric acid.

[0212] In some embodiments, the compound of Formula R-1 or a salt thereof is reacted with the fourteenth base. In some embodiments, suitable fourteenth bases include amines (e.g., n-propylamine, triethylamine, N,N-diisopropylethylamine, 1,4- diazabicyclo[2.2.2]octane (DABCO), quinuclidine), amidines (e.g., 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2- n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole), or a combination thereof.

[0213] In some embodiments, the fourteenth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound, or a combination thereof.

[0214] In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is performed in an eleventh solvent. In some embodiments, the eleventh solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane,chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the eleventh solvent comprises an ether. In some embodiments, the eleventh solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3- dioxolane, cyclopentyl methyl ether, 1,4-dioxane or a combination thereof. In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is performed in an eleventh solvent comprising tetrahydrofuran.

[0215] In some embodiments, the eleventh solvent comprises a hydrocarbon. In some embodiments, the eleventh solvent comprises toluene, methylcyclohexane, n- heptane, hexanes, limonene, or a combination thereof. In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is performed in an eleventh solvent comprising toluene.

[0216] In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is carried out in a temperature range of from about 50 °C to about 90 °C. In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is carried out in a temperature range of from about 50 °C to about 70 °C. In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is carried out at a temperature of about 65 °C. In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is carried out at a temperature of about 80 °C.

[0217] In some embodiments, the process further comprises preparing the compound of Formula R-1 or a salt thereof by a process comprising: reacting a compound of Formula R-2:or a salt thereof, with: a coupling agent, and a fifteenth base, to provide the compound of Formula R-1 or a salt thereof.

[0218] In some embodiments, the compound of Formula R-2 or a salt thereof is a compound of Formula R-2-A: or a salt thereof

[0219] In some embodiments, suitable coupling agents include an acid chloride (e.g., thionyl chloride, oxalyl chloride, phosphorus(V) oxychloride), a mixed anhydride (e.g., with reagents such as acetic anhydride, pivaloyl chloride, diphenylphosphinic anhydride, propanephosphinic anhydride, boric acid, isobutyl chloroformate, methanesulfonyl chloride, p-toluenesulfonyl chloride), a carbonyl diimidazole, an activated ester, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 2- chloro-4,6,-dimethoxy-1,3,5-triazine, cyanuric chloride, 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5‑b]pyridinium 3-oxide hexafluorophosphate, and other reagents known to promote the coupling of amines with carboxylic acids.

[0220] In some embodiments, suitable coupling agents include an acid chloride (e.g., thionyl chloride, oxalyl chloride, phosphorus(V) oxychloride), a mixed anhydride (e.g., with reagents such as acetic anhydride, pivaloyl chloride, diphenylphosphinic anhydride, propanephosphinic anhydride, boric acid, isobutyl chloroformate, methanesulfonyl chloride, p-toluenesulfonyl chloride), organophosphorus compounds(e.g., diphenylphosphinic chloride, diphenyl phosphoryl chloride, bis(2-oxo-3- oxazolidinyl)phosphinic chloride) a carbonyl diimidazole, an activated ester, 4-(4,6- dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 2-chloro-4,6,-dimethoxy- 1,3,5-triazine, cyanuric chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5‑b]pyridinium 3-oxide hexafluorophosphate, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate), and other reagents known to promote the coupling of amines with carboxylic acids.

[0221] In some embodiments, the coupling agent comprises 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), an acid chloride, an acid anhydride, a carbonyl diimidazole, an activated ester, or a combination thereof. In some embodiments, the coupling agent comprises 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU), an acid chloride, an acid anhydride, a carbonyl diimidazole, an activated ester, or a combination thereof. In some embodiments, the coupling agent comprises thionyl chloride, oxalyl chloride, phosphorus(V) oxychloride, acetic anhydride, pivaloyl chloride, diphenylphosphinic anhydride, propanephosphinic anhydride, boric acid, isobutyl chloroformate, methanesulfonyl chloride, p-toluenesulfonyl chloride, a carbonyl diimidazole, an activated ester, 4-(4,6- dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 2-chloro-4,6,-dimethoxy- 1,3,5-triazine, cyanuric chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, HATU, or a combination thereof. In some embodiments, the coupling reagent is a peptide coupling reagent. In some embodiments, the coupling agent is HATU.

[0222] In some embodiments, the coupling agent comprises an organophosphorus compound. In some embodiments, the coupling agent comprises diphenylphosphinic chloride, diphenyl phosphoryl chloride, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, or a combination thereof. In some embodiments, the coupling agent comprises diphenyl phosphoryl chloride.

[0223] In some embodiments, suitable fifteenth bases include amines (e.g., N- methyl morpholine, triethylamine, N,N-diisopropylethylamine), amidines (e.g., 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate, etc.), carbonates (e.g., M(n)H(2-n)CO3such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole, etc.), or a combination thereof.

[0224] In some embodiments, the fifteenth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a hydroxide, an alkoxide, a basic aromatic compound, or a combination thereof. In some embodiments, the fifteenth base comprises an amine. In some embodiments, the fifteenth base comprises N-methyl morpholine, triethylamine, N,N-diisopropylethylamine, or a combination thereof. In some embodiments, the fifteenth base is N,N-diisopropylethylamine.

[0225] In some embodiments, the reacting of the compound of Formula R-2 or a salt thereof is performed in a twenty-eighth solvent. In some embodiments, the twenty- eighth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane,chlorobenzene, α,α,α-trifluorotoluene), water, or a combination thereof. In some embodiments, the twenty-eighth solvent comprises a polar aprotic solvent. In some embodiments, the twenty-eighth solvent comprises N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), or a combination thereof. In some embodiments, the reacting of the compound of Formula R- 2 or a salt thereof is performed in a twenty-eighth solvent comprising N,N- dimethylacetamide.

[0226] In some embodiments, the reacting of the compound of Formula R-2 or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C. In some embodiments, the reacting of the compound of Formula R-2 or a salt thereof is carried out in a temperature range of from about 20 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula R-2 or a salt thereof is carried out in at a temperature of about 20 °C.

[0227] In some embodiments, the process further comprises preparing the compound of Formula R-2 or a salt thereof by a process comprising: reacting a compound of Formula A:or a salt thereof, wherein R3Ais hydrogen or a hydroxyl protecting group, with: a reagent selected from a metal hydroxide, a metal halide, and a trialkylsilyl halide; to provide the compound of Formula R-2 or a salt thereof.

[0228] In some embodiments, R3Ais selected from hydrogen, C1-4alkyl, and benzyl. In some embodiments, R3Ais selected from hydrogen, methyl, ethyl, isopropyl,and benzyl. In some embodiments, R3Ais methyl. In some embodiments, the compound of Formula A or a salt thereof is the compound of Formula A-1 or a salt thereof.

[0229] In some embodiments, the compound of Formula A is reacted with a metal hydroxide. In some embodiments, the metal hydroxide is an alkali metal hydroxide. In some embodiments, the metal hydroxide comprises sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, or a combination thereof. In some embodiments, the metal hydroxide is sodium hydroxide.

[0230] In some embodiments, the compound of Formula A is reacted with a metal halide. In some embodiments, the metal halide comprises lithium chloride, magnesium bromide, zinc chloride, sodium iodide, or a combination thereof.

[0231] In some embodiments, the compound of Formula A is reacted with a trialkylsilyl halide. In some embodiments, the trialkylsilyl halide comprises trimethylsilyl chloride, trimethylsilyl iodide or a combination thereof.

[0232] In some embodiments, the reacting of the compound of Formula A or a salt thereof is performed in a twenty-ninth solvent. In some embodiments, the twenty- ninth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol), water, or a combination thereof. In some embodiments, the twenty-ninth solvent comprises an alcohol. In some embodiments, the twenty-ninth solvent comprises methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, or a combination thereof. In some embodiments, the reacting of the compound of Formula A or a salt thereof is performed in a twenty-ninth solvent comprising methanol.

[0233] In some embodiments, the reacting of the compound of Formula A or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula A or a salt thereof iscarried out in a temperature range of from about 20 °C to about 70 °C. In some embodiments, the reacting of the compound of Formula A or a salt thereof is carried out in at a temperature of about 65 °C. Alternative process for preparing the compound of Formula R-1

[0234] In some embodiments of the process disclosed herein, the process comprises preparing the compound of Formula R-1 or a salt thereof by a process comprising: reacting a compound of Formula A:or a salt thereof, wherein R3Ais a hydroxyl protecting group, with: a sixteenth base; to provide the compound of Formula R-1 or a salt thereof.

[0235] In some embodiments, R3Ais selected from C1-4alkyl, C1-4haloalkyl, and benzyl. In some embodiments, R3Ais selected from methyl, ethyl, isopropyl, trifluoroethyl, and benzyl. In some embodiments, R3Ais methyl. In some embodiments, the compound of Formula A or a salt thereof is the compound of Formula A-1 or a salt thereof.

[0236] In some embodiments, suitable sixteenth bases include amines (e.g., N- methyl morpholine, triethylamine, N,N-diisopropylethylamine), amidines (e.g., 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate, etc.), carbonates (e.g., M(n)H(2-n)CO3such as sodium carbonate, potassium bicarbonate, cesium carbonate),metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole, etc.), or a combination thereof.

[0237] In some embodiments, the sixteenth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a hydroxide, an alkoxide, a basic aromatic compound, or a combination thereof. In some embodiments, the sixteenth base is a guanidine. In some embodiments, the sixteenth base comprises 1,5,7- triazabicyclodec-5-ene, 1,1,3,3-tetramethylguanidine, or a combination thereof. In some embodiments, the sixteenth base is 1,5,7-triazabicyclodec-5-ene.

[0238] In some embodiments, the reacting of the compound of Formula A or a salt thereof is performed in a thirtieth solvent. In some embodiments, the thirtieth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), water, or a combination thereof. In some embodiments, the thirtieth solvent comprises an ether. In some embodiments, the thirtieth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments, reacting of the compound of Formula A or a salt thereof is performed in a thirtieth solvent comprising 2-methyltetrahydrofuran.

[0239] In some embodiments, the reacting of the compound of Formula A or a salt thereof is carried out in a temperature range of from about 20 °C to about 110 °C. In some embodiments, the reacting of the compound of Formula A or a salt thereof is carried out in a temperature range of from about 50 °C to about 70 °C. In some embodiments, the reacting of the compound of Formula A or a salt thereof is carried out in at a temperature of about 60 °C. Process for preparing the compound of Formula A

[0240] In some embodiments of the processes disclosed herein, the process comprises preparing the compound of Formula A or a salt thereof by a process comprising: reacting a compound of Formula X-A:or a salt thereof, with: a compound of Formula C:or a salt thereof, and a seventh base, to provide the compound of Formula A or a salt thereof.

[0241] In some embodiments, the compound of Formula X-A or a salt thereof is the compound of Formula X-B or a salt thereof.

[0242] In some embodiments, the process comprises reacting the compound of Formula X-A with a salt of the compound of Formula C. In some embodiments, the salt of the compound of Formula C is a sulfonic acid salt. In some embodiments, the salt ofthe compound of Formula C is a methanesulfonic acid salt. In some embodiments, the salt of the compound of Formula C is a toluenesulfonic acid salt.

[0243] In some embodiments, suitable seventh bases include tertiary amines (e.g., N-methyl morpholine, N-methyl piperidine, 1,4-dimethylpiperazine, triethylamine, N,N- diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine), secondary amines (e.g., morpholine, piperidine, pyrrolidine, N,N-diisopropylamine), bis(triethylsilyl)amine (HMDS), anilines (e.g., N,N-dimethylaniline, 1,8- bis(dimethylamino)naphthalene (proton sponge)), pyridines (e.g., pyridine, 2,4,6- collidine, 2,6-lutidine), imidazole, amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium carbonate, cesium carbonate), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), and alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide).

[0244] In some embodiments, the seventh base is selected from a tertiary amine, a secondary amine, an aniline, a pyridine, an imidazole, an amidine, a guanidine, a carbonate, a phosphate, a hydroxide, an alkoxide, or a combination thereof. In some embodiments, the seventh base is an amine. In some embodiments, the seventh base is a tertiary amine. In some embodiments, the seventh base comprises N-methyl morpholine, N-methyl piperidine, 1,4-dimethylpiperazine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, or a combination thereof. In some embodiments, the seventh base is N-methyl morpholine.

[0245] In some embodiments, the reacting of the compound of Formula X-A or a salt thereof is performed in a fourteenth solvent. In some embodiments, the fourteenth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene,methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the fourteenth solvent comprises an alcohol. In some embodiments, the fourteenth solvent comprises methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, or a combination thereof. In some embodiments, the reacting of the compound of Formula X-A or a salt thereof is performed in a fourteenth solvent comprising methanol.

[0246] In some embodiments, the reacting of the compound of Formula X-A or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula X-A or a salt thereof is carried out in a temperature range of from about 40 °C to about 60 °C. In some embodiments, the reacting of the compound of Formula X-A or a salt thereof is carried out in at a temperature of about 50 °C.

[0247] In some embodiments, the process further comprises reacting the compound of Formula A with a fourth acid to provide a salt of the compound of Formula A.

[0248] In some embodiments, suitable fourth acids include trifluoroacetic acid, hydrochloric acid, hydrobromic acid, acetic acid, oxalic acid, orotic acid, succinic acid, malonic acid, adipic acid, fumaric acid, benzenesulfonic acid, benzoic acid, citric acid, 1,8-naphthalenedisulfonic acid, tartaric acid (L / D and common esters thereof, including dibenzoyl), p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid (S / R), maleic acid, xinafoic acid, and L-pyroglutamic acid.

[0249] In some embodiments, the fourth acid is selected from trifluoroacetic acid, hydrochloric acid, hydrobromic acid, acetic acid, oxalic acid, orotic acid, succinic acid, malonic acid, adipic acid, fumaric acid, benzenesulfonic acid, benzoic acid, citric acid,1,8-naphthalenedisulfonic acid, tartaric acid or an ester thereof (L / D and esters thereof such as dibenzoyl), p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid (S / R), maleic acid, xinafoic acid, and L-pyroglutamic acid.

[0250] In some embodiments, the fourth acid is oxalic acid. In some embodiments, the reaction provides an oxalate salt of the compound of Formula A.

[0251] In some embodiments, the process further comprises preparing the compound of Formula C or a salt thereof by a process comprising: deprotecting a compound of Formula D: or a salt thereof,R5is selected from hydrogen and R9, wherein R9is an amine protecting group; and R7and R8are each independently an amine protecting group; to provide the compound of Formula C or a salt thereof.

[0252] In some embodiments, R5is hydrogen. In some embodiments, R5is R9. In some embodiments, R5is an amine protecting group. In some embodiments, R5is tert- butyloxycarbonyl.

[0253] In some embodiments, R7is tert-butyloxycarbonyl. In some embodiments, R8is tert-butyloxycarbonyl. In some embodiments, R7and R8are tert-butyloxycarbonyl.

[0254] In some embodiments, the compound of Formula D or a salt thereof is a compound of Formula D-2:D-2 or a salt thereof.

[0255] In some embodiments, deprotecting the compound of Formula D or a salt thereof comprises treating the compound of Formula D or a salt thereof with a fifth acid. In some embodiments, suitable fifth acids include sulfonic acids (e.g., p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid), sulfuric acid, sulfurous acid, carboxylic acids (e.g., trifluoroacetic acid, trichloroacetic acid, oxalic acid), hydrogen halides (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid), in situ generated hydrogen halides (e.g., by combination of acetyl chloride and methanol, trimethylsilyl chloride and methanol, thionyl chloride and methanol), phosphoric acid, and phosphorous acid.

[0256] In some embodiments, the fifth acid is selected from a sulfonic acid, sulfuric acid, sulfurous acid, a carboxylic acid, a hydrogen halide, phosphoric acid, phosphorous acid, or a combination thereof. In some embodiments, the fifth acid is a sulfonic acid. In some embodiments, the fifth acid is selected from p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, or a combination thereof. In some embodiments, the fifth acid comprises methanesulfonic acid. In some embodiments, the fifth acid comprises p-toluenesulfonic acid.

[0257] In some embodiments, deprotecting the compound of Formula D or a salt thereof is performed in a fifteenth solvent. In some embodiments, the fifteenth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or a combination thereof. In some embodiments, the fifteenth solvent comprises an alcohol. In some embodiments, the fifteenth solvent comprises methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol, or a combination thereof. In some embodiments, deprotecting the compound of Formula D or a salt thereof is performed in a fifteenth solvent comprising methanol. In some embodiments, deprotecting the compound of Formula D or a salt thereof is performed in a fifteenth solvent comprising ethanol.

[0258] In some embodiments, deprotecting the compound of Formula D or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C. In some embodiments, deprotecting the compound of Formula D or a salt thereof is carried out in a temperature range of from about 40 °C to about 60 °C. In some embodiments, deprotecting the compound of Formula D or a salt thereof is carried out in a temperature range of from about 45 °C to about 55 °C. In some embodiments, deprotecting the compound of Formula D or a salt thereof is carried out at a temperature of about 50 °C.

[0259] In some embodiments, the process further comprises preparing the compound of Formula D or a salt thereof, wherein the compound of Formula D is a compound of Formula D-1:or a salt thereof, by a process comprising: deprotecting a compound of Formula E:or a salt thereof, wherein:R9is an amine protecting group and R10is hydrogen; or optionally: R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group; to provide the compound of Formula D or a salt thereof.

[0260] In some embodiments, R7and R8are tert-butyloxycarbonyl.

[0261] In some embodiments, R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group.

[0262] In some embodiments, R9and R10together with the nitrogen atom to which they are attached form phthalimide. In some embodiments, R7and R8are tert- butyloxycarbonyl and R9and R10together with the nitrogen atom to which they are attached form phthalimide

[0263] In some embodiments, R9is tert-butyloxycarbonyl.

[0264] In some embodiments, deprotecting the compound of Formula E or a salt thereof comprises treating the compound of Formula E or a salt thereof with a second deprotecting agent. In some embodiments, suitable second deprotecting agents include hydrazines (e.g., hydrazine, methylhydrazine, phenylhydrazine), amines (e.g., ethanolamine, 1,3-diaminopropane, methylamine, ethylamine, propylamine, hydroxylamine), alkoxides (e.g., potassium methoxide, lithium isopropoxide), thiols (e.g., decanethiol, sodium sulfide), and hydrolase enzymes (e.g., phthalyl amidase, dihydropyrimidinase, hydantoinase, imidase, lipase).

[0265] In some embodiments, deprotecting the compound of Formula E or a salt thereof comprises treating the compound of Formula E or a salt thereof with a second deprotecting agent. In some embodiments, suitable second deprotecting agents include hydrazines (e.g., hydrazine, methylhydrazine, phenylhydrazine), amines (e.g., ethanolamine, 1,3-diaminopropane, methylamine, ethylamine, propylamine, hydroxylamine), alkoxides (e.g., potassium methoxide, lithium isopropoxide), thiols (e.g., decanethiol, sodium sulfide), hydrolase enzymes (e.g., phthalyl amidase, dihydropyrimidinase, hydantoinase, imidase, lipase), and hydrides (e.g., sodiumborohydride, sodium acetoxyborohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride).

[0266] In some embodiments, the second deprotecting agent is selected from a hydrazine, an amine, an alkoxide, a thiol, a hydrolase enzyme, a hydride, or a combination thereof. In some embodiments, the second deprotecting agent is selected from a hydrazine, an amine, an alkoxide, a thiol, a hydrolase enzyme, or a combination thereof. In some embodiments, the second deprotecting agent is an amine. In some embodiments, the second deprotecting agent comprises ethanolamine, 1,3- diaminopropane, methylamine, ethylamine, propylamine, hydroxylamine, or a combination thereof. In some embodiments, the second deprotecting agent is ethylenediamine. In some embodiments, the second deprotecting agent is a hydride. In some embodiments, the second deprotecting agent comprises sodium borohydride, sodium acetoxyborohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, or a combination thereof. In some embodiments, the second deprotecting agent is sodium borohydride.

[0267] In some embodiments, the deprotecting the compound of Formula E or a salt thereof is performed further in the presence of a ninth acid. In some embodiments, suitable ninth acids include carboxylic acids (e.g., acetic acid, pivalic acid, formic acid) and strong acids (e.g., methanesulfonic acid, para-toluenesulfonic acid, hydrochloric acid). In some embodiments, the ninth acid comprises a carboxylic acid, a strong acid, or a combination thereof. In some embodiments, the deprotecting the compound of Formula E or a salt thereof is performed in absence of an acid.

[0268] In some embodiments, the deprotecting the compound of Formula E or a salt thereof is performed in a sixteenth solvent. In some embodiments, the second solvent comprises water, an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate,dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the sixteenth solvent comprises an alcohol. In some embodiments, the sixteenth solvent comprises methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol, or a combination thereof. In some embodiments, the deprotecting the compound of Formula E or a salt thereof is performed in a sixteenth solvent comprising methanol.

[0269] In some embodiments, the deprotecting the compound of Formula E or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C. In some embodiments, the deprotecting the compound of Formula E or a salt thereof is carried out in a temperature range of from about 40 °C to about 60 °C. In some embodiments, the deprotecting the compound of Formula E or a salt thereof is carried out in a temperature of about 50 °C. Alternative process for preparing the compound of Formula A

[0270] In some embodiments of the processes disclosed herein, the process comprises preparing the compound of Formula A or a salt thereof by a process comprising: reacting a compound of Formula Q-1: or a salt thereof,with a reagent selected from a hydrazine, an amine, an alkoxide, and a hydrolase enzyme; to provide the compound of Formula A or a salt thereof.

[0271] In some embodiments, the compound of Formula Q-1 or a salt thereof is a compound of Formula Q-1-A: or a salt thereof.

[0272] In some embodiments, the process comprises reacting the compound of Formula Q-1 with a hydrazine. In some embodiments, the hydrazine is selected from hydrazine, methylhydrazine, phenylhydrazine, or a combination thereof. In some embodiments, the process comprises reacting the compound of Formula Q-1 with hydrazine. In some embodiments, the process comprises reacting the compound of Formula Q-1 with hydrazine hydrate.

[0273] In some embodiments, the process comprises reacting the compound of Formula Q-1 with an amine. In some embodiments, the amine is selected from ethanolamine, 1,3-diaminopropane, methylamine, ethylamine, propylamine, hydroxylamine, or a combination thereof.

[0274] In some embodiments, the process comprises reacting the compound of Formula Q-1 with an alkoxide. In some embodiments, the alkoxide is selected from potassium methoxide, lithium isopropoxide, or a combination thereof.

[0275] In some embodiments, the process comprises reacting the compound of Formula Q-1 with a hydrolase enzyme. In some embodiments, the hydrolase enzyme is selected from phthalyl amidase, dihydropyrimidinase, hydantoinase, imidase, lipase, or a combination thereof.

[0276] In some embodiments, the reacting of the compound of Formula Q-1 or a salt thereof is performed in a thirty-first solvent. In some embodiments, the thirty-firstsolvent comprises water, an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the thirty-first solvent comprises a hydrocarbon. In some embodiments, the thirty-first solvent comprises toluene, methylcyclohexane, n-heptane, hexanes, limonene, or a combination thereof. In some embodiments, the reacting of the compound of Formula Q- 1 or a salt thereof is performed in a thirty-first solvent comprising toluene.

[0277] In some embodiments, the reacting of the compound of Formula Q-1 or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula Q-1 or a salt thereof is carried out in a temperature range of from about 75 °C to about 95 °C. In some embodiments, the reacting of the compound of Formula Q-1 or a salt thereof is carried out in a temperature of about 100 °C.

[0278] In some embodiments, the process further comprises preparing the compound of Formula Q-1 or a salt thereof by a process comprising: reacting a compound of Formula Q-2:or a salt thereof, with:a compound of Formula X-A:or a salt thereof, and a thirteenth base; to provide the compound of Formula Q-1 or a salt thereof. In some embodiments, the compound of Formula X-A or a salt thereof is a compound of Formula X-B or a salt thereof.

[0279] In some embodiments, suitable thirteenth bases include tertiary amines (e.g., N-methyl morpholine, N-methyl piperidine, 1,4-dimethylpiperazine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine), secondary amines (e.g., morpholine, piperidine, pyrrolidine, N,N-diisopropylamine), bis(triethylsilyl)amine (HMDS)), anilines (e.g., N,N-dimethylaniline, 1,8- bis(dimethylamino)naphthalene (proton sponge)), pyridines (e.g., pyridine, 2,4,6- collidine, 2,6-lutidine), imidazole, amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonates (e.g., M(n)H(2-n)CO3such as sodium carbonate, potassium carbonate, cesium carbonate), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), and alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide).

[0280] In some embodiments, the thirteenth base is selected from a tertiary amine, a secondary amine, an aniline, a pyridine, an imidazole, an amidine, a guanidine, a carbonate, a phosphate, a hydroxide, an alkoxide, or a combination thereof. In someembodiments, the seventh base is an amine. In some embodiments, the seventh base is a tertiary amine. In some embodiments, the thirteenth base comprises N-methyl morpholine, N-methyl piperidine, 1,4-dimethylpiperazine, triethylamine, N,N- diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, or a combination thereof. In some embodiments, the thirteenth base is N-methyl morpholine.

[0281] In some embodiments, the reacting of the compound of Formula Q-2 or a salt thereof is performed in a thirty-second solvent. In some embodiments, the thirty- second solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the thirty-second comprises an alcohol. In some embodiments, the thirty-second solvent comprises methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, or a combination thereof. In some embodiments, the reacting of the compound of Formula Q-2 or a salt thereof is performed in a thirty-second solvent comprising methanol.

[0282] In some embodiments, the reacting of the compound of Formula Q-2 or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula Q-2 or a salt thereof is carried out in a temperature range of from about 40 °C to about 60 °C. In some embodiments, the reacting of the compound of Formula Q-2 or a salt thereof is carried out in at a temperature of about 50 °C.Process for preparing the compound of Formula E

[0283] In some embodiments of the processes disclosed herein, the process comprises preparing the compound of Formula E or a salt thereof by a process comprising: reacting a compound of Formula F:or a salt thereof, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula E or a salt thereof.

[0284] In some embodiments of the compound of Formula F, R9and R10together with the nitrogen atom to which they are attached form phthalimide.

[0285] In some embodiments, the compound of Formula R7-NH-NH-R8is .some embodiments, suitable phosphine reagents include triaryl phosphines (e.g., triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine), trialkyl phosphines (e.g., tricyclohexyl phosphine, tributyl phosphine, trimethyl phosphine), tris-(dimethylaminophenyl) phosphine, (triphenylphosphoranylidene) acetonitrile, and phosphoranes (e.g., (cyanomethylene) tributylphosphorane).

[0287] In some embodiments, the phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane. In some embodiments, the phosphine reagent is a triarylphosphine. In some embodiments, the phosphine reagent comprises triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine, or a combination thereof. In some embodiments, the phosphine reagent is triphenylphosphine.

[0288] In some embodiments, the azodicarboxylate is selected from di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate. In some embodiments, the azodicarboxylate is di-tert-butyl azodicarboxylate.

[0289] In some embodiments, the reacting of the compound of Formula F or a salt thereof is performed in a seventeenth solvent. In some embodiments, the seventeenth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the seventeenth solvent comprises an ether. In some embodiments, the seventeenth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3- dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments the reacting of the compound of Formula F or a salt thereof is performed in a seventeenth solvent comprising 2-methyltetrahydrofuran. In some embodiments, the seventeenth solvent comprises an ester. In some embodiments, the seventeenth solvent comprises isopropyl acetate.

[0290] In some embodiments, the reacting of the compound of Formula F or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C. In some embodiments, the reacting of the compound of Formula F or a salt thereof is carried out in a temperature range of from about 0 °C to about 22 °C.

[0291] In some embodiments, the process further comprises preparing the compound of Formula F or a salt thereof by a process comprising: reacting a compound of Formula G:or a salt thereof, with: a third catalyst, and a hydrogen source; to provide the compound of Formula F or a salt thereof.

[0292] In some embodiments, the process comprises preparing the compound of Formula F or a salt thereof by a process comprising reacting a compound of Formula G or a salt thereof, with a third catalyst, and hydrogen; to provide the compound of Formula F or a salt thereof.

[0293] In some embodiments of the compound of Formula G, R9and R10together with the nitrogen atom to which they are attached form phthalimide.

[0294] In some embodiments, suitable third catalysts include palladium catalysts (e.g., palladium, 5 wt% on carbon, palladium, 10 wt% on carbon, palladium, 1 wt% on carbon, palladium, 5 wt% on calcium carbonate, palladium, 5 wt% on aluminum oxide, palladium hydroxide, palladium acetate, palladium acetate / manganese, palladium chloride, palladium trifluoroacetate, palladium propionate, palladium pivalate, tris(dibenzylideneacetone) dipalladium, palladium bromide, palladium (II)bis(acetylacetonate), bis(benzonitrile)palladium dichloride, 20 wt% on carbon, lead poisoned palladium, with, e.g., barium sulfate or calcium carbonate), bimetallic catalysts (e.g., palladium,4 wt% and platinum, 1 wt% on carbon, palladium, 9 wt% and copper, 1 wt% on carbon, palladium, 4 wt% and copper, 1 wt% on carbon), and platinum catalysts (e.g., platinum on carbon, platinum oxide).

[0295] In some embodiments, suitable third catalysts include palladium catalysts (e.g., palladium, 5 wt% on carbon, palladium, 10 wt% on carbon, palladium, 1 wt% on carbon, palladium, 5 wt% on calcium carbonate, palladium, 5 wt% on aluminum oxide, palladium hydroxide, 20 wt% on carbon, lead poisoned palladium), bimetallic catalysts (e.g., palladium,4 wt% and platinum, 1 wt% on carbon, palladium, 9 wt% and copper, 1 wt% on carbon, palladium, 4 wt% and copper, 1 wt% on carbon), and platinum catalysts (e.g., platinum on carbon, platinum oxide).

[0296] In some embodiments, the third catalyst is selected from a palladium catalyst, a platinum catalyst, and a bimetallic catalyst, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

[0297] In some embodiments, the third catalyst is a palladium catalyst. In some embodiments, the third catalyst comprises palladium on carbon, palladium on calcium carbonate, or palladium on aluminum oxide. In some embodiments, the third catalyst is selected from 5 wt% palladium on carbon, 10 wt% palladium on carbon, 1 wt% palladium on carbon, 5 wt% palladium on calcium carbonate, 5 wt% palladium on aluminum oxide, 20 wt% palladium on carbon, and lead poisoned palladium.

[0298] In some embodiments, the third catalyst is a Lindlar catalyst. In some embodiments, the third catalyst comprises 5 wt.% palladium on lead-poisoned calcium carbonate.

[0299] In some embodiments, a molar ratio of the compound of Formula G or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.05. In some embodiments, a molar ratio of the compound of Formula G or a salt thereof to the thirdcatalyst is from about 1:0.001 to about 1:0.005. In some embodiments, a molar ratio of the compound of Formula G or a salt thereof to the third catalyst is about 1:0.002.

[0300] In some embodiments, the hydrogen source comprises hydrogen, formic acid, water, or a combination thereof. In some embodiments, the hydrogen source comprises hydrogen, a mixture of formic acid and potassium carbonate, water, or a combination thereof. In some embodiments, the hydrogen source is hydrogen.

[0301] In some embodiments, the reacting of the compound of Formula G or a salt thereof is carried out in the presence of a second additive. In some embodiments, suitable second additives include quinoline, pyridine, triethylamine, carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), phosphates (e.g., trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), 1,8- diazabicyclo[5.4.0] undec-7-ene, formates (e.g., potassium formate, sodium formate, ammonium formate), acetates (e.g., potassium acetate, sodium acetate, cesium acetate), alkoxides (e.g., potassium tert-butoxide, sodium tert-butoxide), halides (e.g., potassium iodide, lithium chloride, sodium chloride, calcium chloride), and hydroxides (e.g., potassium hydroxide). In some embodiments, the second additive comprises quinoline, pyridine, triethylamine, a carbonate, a bicarbonate, a phosphate, 1,8-diazabicyclo[5.4.0] undec-7-ene, potassium carbonate, potassium formate, sodium formate, ammonium formate, potassium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium iodide, lithium chloride, sodium chloride, calcium chloride, or a combination thereof.

[0302] In some embodiments, the reacting of the compound of Formula G or a salt thereof is carried out at a pressure of about 1 psi to about 100 psi. In some embodiments, the reacting of the compound of Formula G or a salt thereof is carried out at a pressure of about 25 psi to about 75 psi. In some embodiments, the reacting of the compound of Formula G or a salt thereof is carried out at a pressure of about 50 psi.

[0303] In some embodiments, the reacting of the compound of Formula G or a salt thereof is performed in an eighteenth solvent. In some embodiments, the eighteenth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, tert-amyl alcohol), a glycol (e.g., polyethylene glycol 400), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), or a combination thereof. In some embodiments, the eighteenth solvent comprises a polar aprotic solvent. In some embodiments, the eighteenth solvent comprises N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N- butyl pyrrolidone (NBP), or a combination thereof. In some embodiments, the reacting of the reacting of the compound of Formula G or a salt thereof is performed in an eighteenth solvent comprising N,N-dimethylformamide.

[0304] In some embodiments, the reacting of the compound of Formula G or a salt thereof is performed in an eighteenth solvent. In some embodiments, the eighteenth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene, anisole), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, tert-amyl alcohol, 1-butanol), a glycol (e.g., polyethylene glycol 400), ahalogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), or a combination thereof.

[0305] In some embodiments, the reacting of the compound of Formula G or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula G or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula G or a salt thereof is carried out at a temperature of about 20 °C.

[0306] In some embodiments, the process further comprises preparing the compound of Formula G or a salt thereof by a process comprising: reacting a compound of Formula H:or a salt thereof, wherein R11is selected from C1-20alkyl, phenyl, and -CH2NH2; with a sixth acid or an eighth base, to provide the compound of Formula G or a salt thereof.

[0307] In some embodiments, R11is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl, and -CH2NH2. In some embodiments, R11is C1- 20alkyl. In some embodiments, R11is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, and pentadecyl. In some embodiments, R11is methyl. In some embodiments, R11is phenyl. In some embodiments, R11is -CH2NH2.

[0308] In some embodiments, the compound of Formula H or a salt thereof is a compound of Formula H-2:or a salt thereof.

[0309] In some embodiments, the compound of Formula H or a salt thereof is reacted with the sixth acid. In some embodiments, suitable sixth acids include mineral acids (e.g., concentrated hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid), trifluoroacetic acid, and sulfonic acids (e.g., methanesulfonic acid, p- toluenesulfonic acid, benzene sulfonic acid, camphor sulfonic acid).

[0310] In some embodiments, the sixth acid is selected from a mineral acid, trifluoroacetic acid, a sulfonic acid, or a combination thereof. In some embodiments, the sixth acid is a sulfonic acid. In some embodiments, the sixth acid comprises methanesulfonic acid, p-toluenesulfonic acid, benzene sulfonic acid, camphor sulfonic acid, or a combination thereof. In some embodiments, the sixth acid is p-toluenesulfonic acid.

[0311] In some embodiments, the compound of Formula H or a salt thereof is reacted with the eighth base. In some embodiments, suitable eighth bases include carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide), and amines (e.g., methylamine, diethylamine, isopropylamine, diisopropylethylamine, triethylamine, diisopropylethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2] octane, Bis(trimethylsilyl)amine.

[0312] In some embodiments, the compound of Formula H or a salt thereof is reacted with the eighth base. In some embodiments, suitable eighth bases include carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide), and amines (e.g., methylamine, diethylamine, isopropylamine, diisopropylethylamine, triethylamine, diisopropylethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2] octane, Bis(trimethylsilyl)amine, 1,1,3,3,-tetramethylguanidine, triazabicyclodecene (TBD)).

[0313] In some embodiments, the eighth base is selected from a guanidine, a carbonate, a bicarbonate, a metal alkoxide, an amine, or a combination thereof.

[0314] In some embodiments, the reacting of the compound of Formula H or a salt thereof is performed in a thirty-fourth solvent. In some embodiments, the thirty- fourth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the thirty-fourth solvent comprises an alcohol. In some embodiments, the thirty-fourth solvent comprises methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, or a combination thereof. In some embodiments, the reacting of the compound of Formula H or a salt thereof is performed in a thirty-fourth solvent comprising methanol.

[0315] In some embodiments, the reacting of the compound of Formula H or a salt thereof is carried out in a temperature range of from about 0 °C to about 70 °C. Insome embodiments, the reacting of the compound of Formula H or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula H or a salt thereof is carried out in at a temperature of about 20 °C. Alternative process for preparing the compound of Formula F

[0316] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula F or a salt thereof by a process comprising: reacting a compound of Formula W:or a salt thereof, with: a sixth catalyst, and a reducing agent; to provide the compound of Formula F or a salt thereof.

[0317] In some embodiments of the compound of Formula W or a salt thereof, R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group.

[0318] In some embodiments, the compound of Formula W or a salt thereof is a compound of Formula W-1:or a salt thereof.

[0319] In some embodiments of the compound of Formula F or a salt thereof, R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group.

[0320] In some embodiments, the compound of Formula F or a salt thereof is a compound of Formula F-2:or a salt thereof.

[0321] In some embodiments, suitable sixth catalysts include a Corey-Bakshi-Shibata (CBS) catalyst and a transition metal catalyst (e.g., a ruthenium catalyst). In some embodiments, the sixth catalyst is selected from (R)-1-Methyl-3,3- diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole), (R)-(+)-2-methyl-CBS- oxazaborolidine (R)-nBu-CBS,any other derivative of CBS, and RuCl [(R,R)- TSDPEN](mesitylene). In some embodiments, the sixth catalyst is selected from (R)-(+)- 2-methyl-CBS-oxazaborolidine and RuCl [(R,R)-TSDPEN](mesitylene). In some embodiments, the sixth catalyst is a CBS catalyst. In some embodiments, the sixth catalyst is selected from (R)-(+)-2-methyl-CBS-oxazaborolidine, (R)-nBu-CBS, and any other derivative of CBS. In some embodiments, the sixth catalyst is (R)-(+)-2-methyl- CBS-oxazaborolidine. In some embodiments, the sixth catalyst is (R)-1-Methyl-3,3- diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole.

[0322] In some embodiments, suitable reducing agents include formic acid / triethylamine, NaBH4, LiBH4, CeCl3∙7H2O with NaBH4, LiAlH4, MgBu2 with HBpin, Red-Al, LiAlH(OtBu)3, BH3∙SMe2, catecholborane, or combinations thereof. In some embodiments, the reducing agent comprises formic acid and triethylamine, NaBH4, LiBH4, CeCl3∙7H2O with NaBH4, LiAlH4, MgBu2with HBpin, Red-Al, LiAlH(OtBu)3,BH3∙SMe2, catecholborane, or a combination thereof. In some embodiments, the reducing agent comprises catecholborane.

[0323] In some embodiments, the reacting of the compound of Formula W or a salt thereof is performed in a forty-third solvent. In some embodiments, the forty-third solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a chlorinated solvent (e.g., dichloromethane, CHCl3, CCl4, chlorobenzene), or a combination thereof. In some embodiments, the forty-third solvent comprises a chlorinated solvent. In some embodiments, the forty-third solvent comprises dichloromethane, CHCl3, CCl4, chlorobenzene, or a combination thereof. In some embodiments, the reacting of the compound of Formula W or a salt thereof is performed in a forty-third solvent comprising dichloromethane.

[0324] In some embodiments, the reacting of the compound of Formula W or a salt thereof is carried out in a temperature range of from about -78 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula W or a salt thereof is carried out in a temperature range of from about -30 °C to about 10 °C. In some embodiments, the reacting of the compound of Formula W or a salt thereof is carried out at a temperature of about -10 °C.

[0325] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula W or a salt thereof by a process comprising: reacting a compound of Formula S:or a salt thereof, with:a compound of Formula T: or a salt thereof,wherein R15is selected from phenyl and C1-4haloalkyl, wherein the phenyl is optionally substituted with 1-4 substituents selected from C1-4alkyl, halo, C1-4haloalkyl, and cyano; a seventeenth base, and a fourth additive; to provide the compound of Formula W or a salt thereof.

[0326] In some embodiments of the compound of Formula W or a salt thereof, R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group. In some embodiments, the compound of Formula W or a salt thereof is a compound of Formula W-1 or a salt thereof.

[0327] In some embodiments of the compound of Formula S or a salt thereof, R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group.

[0328] In some embodiments, the compound of Formula S or a salt thereof is a compound of Formula S-1:or a salt thereof.

[0329] In some embodiments, R15is selected from trifluoroethyl, hexafluoroisopropyl, trichloroethyl, phenyl, chlorophenyl (e.g., 4-chlorophenyl), fluorophenyl (e.g., 2-fluorophenyl), trifluoromethylphenyl (e.g., 2- trifluoromethylphenyl), cyanophenyl (e.g., 3-cyanophenyl), and methylphenyl (e.g., 2- methylphenyl). In some embodiments, R15is selected from phenyl and C1-4haloalkyl, wherein the phenyl is optionally substituted with halo. In some embodiments, R15is selected from trifluoroethyl, trichloroethyl, phenyl, and chlorophenyl (e.g., 4- chlorophenyl). In some embodiments, R15is phenyl.

[0330] In some embodiments, suitable seventeenth bases include amides (e.g., lithium, sodium, or potassium hexamethyl disilazide), amine bases (e.g., N-methyl morpholine, triethylamine, diisopropylethylamine), amidines (e.g., 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (.e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., trisodium phosphate, tripotassium phosphate), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole), or combinations thereof.

[0331] In some embodiments, the seventeenth base is selected from an amide, an amine base, an amidine, a guanidine, a carbonate, a metal hydride, phosphate, an alkoxide, a basic aromatic compound, and combinations thereof. In some embodiments, the seventeenth base is an amide. In some embodiments, the seventeenth base is potassium hexamethyl disilazide.

[0332] In some embodiments, suitable fourth additives include ethers (e.g., 18- crown-6, bis(2-methoxyethyl) ether), metal salts (e.g., lithium chloride, magnesium chloride, zinc bromide), or combinations thereof. In some embodiments, the fourth additive is selected from an ether, a metal salt, or a combination thereof. In some embodiments, the fourth additive is selected from an ether, a metal halide, or acombination thereof. In some embodiments, the fourth additive is an ether. In some embodiments, the fourth additive is 18-crown-6.

[0333] In some embodiments, the reacting of the compound of Formula S or a salt thereof is performed in a forty-fourth solvent. In some embodiments, the forty-fourth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α trifluorotoluene), water, or a combination thereof. In some embodiments, the forty-fourth solvent comprises an ether. In some embodiments, the forty-fourth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments, the reacting of the compound of Formula S or a salt thereof is performed in a forty-fourth solvent comprising tetrahydrofuran.

[0334] In some embodiments, the reacting of the compound of Formula S or a salt thereof is carried out in a temperature range of from about -100 °C to about 25 °C. In some embodiments, the reacting of the compound of Formula S or a salt thereof is carried out in a temperature range of from about -80 °C to about -50 °C. In some embodiments, the reacting of the compound of Formula S or a salt thereof is carried out at a temperature of about -60 °C. Second Alternative process for preparing the compound of Formula F

[0335] In some embodiments of the processes disclosed herein, the process comprises preparing the compound of Formula F or a salt thereof by a process comprising: reacting a compound of Formula W:or a salt thereof, with: a second enzyme in the presence of a second buffer; to provide the compound of Formula F or a salt thereof.

[0336] In some embodiments of the compound of Formula F or a salt thereof, R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group. In some embodiments, the compound of Formula F or a salt thereof is a compound of Formula F-2 or a salt thereof.

[0337] In some embodiments of the compound of Formula W or a salt thereof, R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group. In some embodiments, the compound of Formula W or a salt thereof is a compound of Formula W-1 or a salt thereof.

[0338] In some embodiments, suitable second enzymes include ketoreductases, alcohol oxidase, and P450. In some embodiments, the second enzyme is selected from a ketoreductase, alcohol oxidase, or P450. In some embodiments, the second enzyme is a ketoreductase. In some embodiments, the second enzyme is KRED NADH 101 (Codexis®).

[0339] In some embodiments, suitable second buffers include citrate buffers, phosphate buffers, tris(hydroxymethyl)aminomethane (Tris), and (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid) (HEPES). In some embodiments, the second buffer is selected from a citrate buffer, a phosphate buffer, tris(hydroxymethyl)aminomethane, and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES). In some embodiments, the second buffer is a phosphate buffer. In some embodiments, the second buffer is a sodium phosphate buffer.

[0340] In some embodiments, the reacting of the compound of Formula W or a salt thereof is performed in a cosolvent. In some embodiments, the cosolvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3- dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), dimethyl sulfoxide), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2- methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2- pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the cosolvent comprises a polar protic solvent. In some embodiments, the cosolvent comprises N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N- butyl pyrrolidone (NBP), dimethyl sulfoxide, or a combination thereof. In some embodiments, the reacting of the compound of Formula W or a salt thereof is performed in a cosolvent comprising dimethylsulfoxide.

[0341] In some embodiments, the reacting of the compound of Formula W or a salt thereof is carried out in a temperature range of from about 5 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula W or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula W or a salt thereof is carried out at a temperature of about 20 °C.

[0342] In some embodiments, the process further comprises preparing the compound of Formula W or a salt thereof according to a process described herein. Third alternative process for preparing the compound of Formula F

[0343] In some embodiments of the processes disclosed herein, the compound of Formula F or a salt thereof is prepared by a process comprising:reacting a compound of Formula G:or a salt thereof, with: a third reducing agent, and an activator; to provide the compound of Formula F or a salt thereof.

[0344] In some embodiments, the compound of Formula F or a salt thereof is a compound of Formula F-1:or a salt thereof. In some embodiments of the compound of Formula F-1, R9is tert- butyloxycarbonyl.

[0345] In some embodiments, the compound of Formula G or a salt thereof is a compound of Formula G-1:or a salt thereof. In some embodiments of the compound of Formula G-1, R9is tert- butyloxycarbonyl.

[0346] In some embodiments of the compound of Formula F or a salt thereof, R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group. In some embodiments of the compound of Formula F or a salt thereof, R9and R10together with the nitrogen atom to which they are attached form phthalimide or saccharin. In some embodiments, the compound of Formula F or a salt thereof is a compound of Formula F-2 or a salt thereof.

[0347] In some embodiments of the compound of Formula G or a salt thereof, R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group. In some embodiments of the compound of Formula G or a salt thereof, R9and R10together with the nitrogen atom to which they are attached form phthalimide or saccharin.

[0348] In some embodiments, suitable third reducing agents include zinc (e.g., zinc dust, zinc on graphite, Rieke zinc), metals (e.g., iron, manganese), diimide (e.g., o- nitrobenzenesulfonylhydrazide), copper / bis(pinacolato)diboron, imidazolinium salts (e.g., 1,3-Bis-(2,6-diisopropylphenyl)imidazolinium chloride, 1,3-Bis(2,4,6- trimethylphenyl)imidazoliniumchloride,1,3-Bis(2,6-diisopropylphenyl)imidazolium chloride, 1,3-Bis(2,4,6-trimethylphenyl)imidazolium chloride), or combinations thereof.

[0349] In some embodiments, the third reducing agent comprises zinc, a metal, a diimide, copper and bis(pinacolato)diboron, an imidazolinium salt, or a combination thereof. In some embodiments, the third reducing agent comprises zinc. In some embodiments, the third reducing agent comprises zinc dust, zinc on graphite, or Rieke zinc. In some embodiments, the third reducing agent comprises zinc dust.

[0350] Any suitable activator (e.g., entrainment agent) can be used to activate the third reducing agent. In some embodiments, the activator activates the third reducing agent, wherein the third reducing agent comprises zinc (e.g., by removing zinc oxide on the surface of the zinc). In some embodiments, suitable activators include an organosilicon compound, an organobromine compound, a strong acid, a hydride, or a combination thereof. In some embodiments, the activator is selected fromchlorotrimethylsilane, dibromoethane, hydrochloric acid, and diisobutylaluminum hydride. In some embodiments, the activator is chlorotrimethylsilane.

[0351] In some embodiments, the reacting of the compound of Formula G or a salt thereof is performed in a forty-fifth solvent. In some embodiments, the forty-fifth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, tert-amyl alcohol), a glycol (e.g., polyethylene glycol 400), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), or a combination thereof. In some embodiments, the forty-fifth solvent comprises an alcohol. In some embodiments, the forty-fifth solvent comprises methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, tert-amyl alcohol, or a combination thereof. In some embodiments, the reacting of the compound of Formula G or a salt thereof is performed in a forty-fifth solvent comprising ethanol.

[0352] In some embodiments, the reacting of the compound of Formula G or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula G or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula G or a salt thereof is carried out at a temperature of about 20 °C. Process for preparing the compound of Formula D

[0353] In some embodiments of the processes disclosed herein, the process comprises preparing the compound of Formula D or a salt thereof, wherein R5is R9, by a process comprising: reacting a compound of Formula F-1:or a salt thereof, wherein R9is an amine protecting group, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula D or a salt thereof.

[0354] In some embodiments of the compound of Formula F-1 or a salt thereof, wherein R9is tert-butyloxycarbonyl.

[0355] In some embodiments, the compound of Formula R7-NH-NH-R8is .some embodiments, suitable phosphine reagents include triaryl phosphines (e.g., triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine), trialkyl phosphines (e.g., tricyclohexyl phosphine, tributyl phosphine, trimethyl phosphine), tris-(dimethylaminophenyl) phosphine, (triphenylphosphoranylidene) acetonitrile, and phosphoranes (e.g., (cyanomethylene) tributylphosphorane).

[0357] In some embodiments, the phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane. In some embodiments, the phosphine reagent is a triarylphosphine. In someembodiments, the phosphine reagent comprises triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine, or a combination thereof. In some embodiments, the phosphine reagent is triphenylphosphine.

[0358] In some embodiments, the azodicarboxylate is selected from di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate. In some embodiments, the azodicarboxylate is di-tert-butyl azodicarboxylate.

[0359] In some embodiments, the reacting of the compound of Formula F-1 or a salt thereof is performed in a thirty-fifth solvent. In some embodiments, the thirty-fifth comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a hydrocarbon (e.g., toluene, n-heptane) a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the thirty-fifth comprises an ether. In some embodiments, the thirty-fifth solvent comprises tetrahydrofuran, 2- methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments the reacting of the compound of Formula F-1 or a salt thereof is performed in a thirty-fifth solvent comprising 2-methyltetrahydrofuran.

[0360] In some embodiments, the reacting of the compound of Formula F-1 or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C. In some embodiments, the reacting of the compound of Formula F-1 or a salt thereof is carried out in a temperature range of from about 15 °C to about 30 °C. In someembodiments, the reacting of the compound of Formula F-1 or a salt thereof is carried out at a temperature range of about 22 °C.

[0361] In some embodiments, the process further comprises preparing the compound of Formula F-1 or a salt thereof by a process comprising: reacting a compound of Formula G-1:or a salt thereof, with: a third catalyst, an aromatic amine or a sulfur-containing reagent; and hydrogen; to provide the compound of Formula F-1 or a salt thereof.

[0362] In some embodiments of the compound of Formula G-1, R9is tert- butyloxycarbonyl.

[0363] In some embodiments, suitable third catalysts include palladium catalysts (e.g., palladium, 5 wt% on carbon, palladium, 10 wt% on carbon, palladium, 1 wt% on carbon, palladium, 5 wt% on calcium carbonate, palladium, 5 wt% on aluminum oxide, palladium hydroxide, 20 wt% on carbon, lead poisoned palladium), bimetallic catalysts (e.g., palladium,4 wt% and platinum, 1 wt% on carbon, palladium, 9 wt% and copper, 1 wt% on carbon, palladium, 4 wt% and copper, 1 wt% on carbon), and platinum catalysts (e.g., platinum on carbon, platinum oxide).

[0364] In some embodiments, the third catalyst is selected from a palladium catalyst, a platinum catalyst, and a bimetallic catalyst, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

[0365] In some embodiments, the third catalyst is a palladium catalyst. In some embodiments, the third catalyst comprises palladium on carbon, palladium on calcium carbonate, or palladium on aluminum oxide. In some embodiments, the third catalyst is selected from 5 wt% palladium on carbon, 10 wt% palladium on carbon, 1 wt% palladium on carbon, 5 wt% palladium on calcium carbonate, 5 wt% palladium on aluminum oxide, 20 wt% palladium on carbon, and lead poisoned palladium.

[0366] In some embodiments, the third catalyst is a Lindlar catalyst. In some embodiments, the third catalyst comprises 5 wt.% palladium on lead-poisoned calcium carbonate.

[0367] In some embodiments, a molar ratio of the compound of Formula G-1 or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.05. In some embodiments, a molar ratio of the compound of Formula G-1 or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.005. In some embodiments, a molar ratio of the compound of Formula G-1 or a salt thereof to the third catalyst is about 1:0.002.

[0368] In some embodiments, the reacting of the compound of Formula G-1 or a salt thereof is carried out at a pressure of about 1 psi to about 100 psi. In some embodiments, the reacting of the compound of Formula G-1 or a salt thereof is carried out at a pressure of about 1 psi to about 40 psi. In some embodiments, the reacting of the compound of Formula G-1 or a salt thereof is carried out at a pressure of about 22 psi.

[0369] In some embodiments, the compound of Formula G-1 or a salt thereof is reacted with an aromatic amine. In some embodiments, the compound of Formula G-1 or a salt thereof is reacted with an aromatic amine selected from quinoline and pyridine. In some embodiments, the aromatic amine is quinoline.

[0370] In some embodiments, the compound of Formula G-1 or a salt thereof is reacted with a sulfur-containing compound. In some embodiments, the compound of Formula G-1 or a salt thereof is reacted with a sulfur-containing compound selected from a thiol and a sulfide.

[0371] In some embodiments, the reacting of the compound of Formula G-1 or a salt thereof is performed in a thirty-sixth solvent. In some embodiments, the thirty-sixth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, tert-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2- dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the thirty-sixth solvent comprises a polar aprotic solvent. In some embodiments, the thirty-sixth solvent comprises N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), or a combination thereof. In some embodiments, the reacting of the compound of Formula G- 1 or a salt thereof is performed in a thirty-sixth solvent comprising N,N- dimethylformamide.

[0372] In some embodiments, the reacting of the compound of Formula G-1 or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula G-1 or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula G-1 or a salt thereof is carried out at a temperature of about 22 °C.

[0373] In some embodiments, the process further comprises preparing the compound of Formula G-1 or a salt thereof by a process comprising: reacting a compound of Formula H having Formula H-1:or a salt thereof, wherein R11is selected from C1-20alkyl, phenyl, and -CH2NH2; with a twelfth base, to provide the compound of Formula G-1 or a salt thereof.

[0374] In some embodiments, R11is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl, and -CH2NH2. In some embodiments, R11is C1-20alkyl. In some embodiments, R11is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, and pentadecyl. In some embodiments, R11is methyl. In some embodiments, R11is phenyl. In some embodiments, R11is -CH2NH2.

[0375] In some embodiments, the compound of Formula H-1 or a salt thereof is a compound of Formula H-1-A:or a salt thereof.

[0376] In some embodiments, the compound of Formula H-1 or a salt thereof is reacted with a twelfth base. In some embodiments, suitable twelfth bases include guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert- butoxide), and amines (e.g., methylamine, diethylamine, isopropylamine,diisopropylethylamine, triethylamine, diisopropylethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2] octane, Bis(trimethylsilyl)amine).

[0377] In some embodiments, the twelfth base is selected from a guanidine, a carbonate, a bicarbonate, a metal alkoxide, an amine, or a combination thereof. In some embodiments, the twelfth base comprises triazabicyclodecene, tetra-methyl guanidine, or a combination thereof. In some embodiments, the twelfth base is tetra-methyl guanidine.

[0378] In some embodiments, the reacting of the compound of Formula H-1 or a salt thereof is performed in a thirty-seventh solvent. In some embodiments, the thirty- seventh solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the thirty-seventh solvent comprises an alcohol. In some embodiments, the thirty-seventh solvent comprises methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, or a combination thereof. In some embodiments, the reacting of the compound of Formula H- 1 or a salt thereof is performed in a thirty-seventh solvent comprising methanol.

[0379] In some embodiments, the reacting of the compound of Formula H-1 or a salt thereof is carried out in a temperature range of from about 0 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula H-1 or a salt thereof is carried out in a temperature range of from about 10 °C to about 20 °C. In some embodiments, the reacting of the compound of Formula H-1 or a salt thereof is carried out in at a temperature of about 20 °C. Alternative process for preparing the compound of Formula G-1

[0380] In some embodiments of the processes disclosed herein, the compound of Formula G-1 or a salt thereof is prepared by a process comprising: reacting a compound of Formula U-1: U-1 or a salt thereof, with a second amine protecting group reagent to provide the compound of Formula G-1 or a salt thereof.

[0381] In some embodiments of the compound of Formula G-1 or a salt thereof, R9is tert-butyloxycarbonyl.

[0382] In some embodiments, the second amine protecting group reagent is di- tert-butyl dicarbonate.

[0383] In some embodiments, the reacting of the compound of Formula U-1 or a salt thereof is performed in a forty-sixth solvent. In some embodiments, the forty-sixth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, tert-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2- dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the forty-sixth solvent comprises an ether. In some embodiments, the forty-sixth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. Insome embodiments, the reacting of the compound of Formula U-1 or a salt thereof is performed in a forty-sixth solvent comprising 2-methytetrahydrofuran.

[0384] In some embodiments, the reacting of the compound of Formula U-1 or a salt thereof is carried out in a temperature range of from about 5 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula U-1 or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula U-1 or a salt thereof is carried out at a temperature of about 20 °C.

[0385] In some embodiments, the process further comprising preparing the compound of Formula U-1 or a salt thereof is prepared by a process comprising: reacting a compound of Formula U-2:or a salt thereof, with: a third enzyme in the presence of a third buffer; to provide the compound of Formula U-1 or a salt thereof.

[0386] In some embodiments, suitable third enzymes include transaminase (e.g., ATA-238 from Codexis®), amine hydrogenase, and imine reductase. In some embodiments, the third enzyme is selected from a transaminase, an amine hydrogenase, an imine reductase, and a combination thereof. In some embodiments, the third enzyme is a transaminase. In some embodiments, the third enzyme is ATA-238, ATA-P1-G05, or ATA-P1-B02.

[0387] In some embodiments, suitable third buffers include citrate buffers, phosphate buffers, tris(hydroxymethyl)aminomethane (Tris), and (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid) (HEPES). In some embodiments, the third buffer is selected from a citrate buffer, a phosphate buffer, a tris(hydroxymethyl)aminomethane(Tris) buffer, and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES). In some embodiments, the third buffer is a Tris buffer.

[0388] In some embodiments, the reacting of the compound of Formula U-2 or a salt thereof is performed further in the presence of a coenzyme. In some embodiments, the coenzyme is pyridoxal phosphate. In some embodiments, the third enzyme is a transaminase and the coenzyme is pyridoxal phosphate.

[0389] In some embodiments, the reacting of the compound of Formula U-2 or a salt thereof is performed in a second cosolvent. In some embodiments, the second cosolvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, tert-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2- dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the second cosolvent comprises a polar aprotic solvent. In some embodiments, the second cosolvent comprises DMSO, N,N-dimethylacetamide, N- methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), Limonene, or a combination thereof. In some embodiments, the reacting of the compound of Formula U-2 or a salt thereof is performed in a second cosolvent comprising dimethylsulfoxide.

[0390] In some embodiments, the reacting of the compound of Formula U-2 or a salt thereof is carried out in a temperature range of from about 5 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula U-2 or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula U-2 or a salt thereof is carried out at a temperature of about 20 °C.

[0391] In some embodiments, the process further comprising preparing the compound of Formula U-2 or a salt thereof is prepared by a process comprising: reacting a compound of Formula L:or a salt thereof, with: a fourth enzyme in the presence of a fourth buffer; to provide the compound of Formula U-2 or a salt thereof.

[0392] In some embodiments, suitable fourth enzymes include ketoreductase (e.g., KRED-476 from Codexis®), alcohol oxidase, and P450. In some embodiments, the fourth enzyme is selected from a ketoreductase, an alcohol oxidase, P450, and a combination thereof. In some embodiments, the fourth enzyme is a ketoreductase. In some embodiments, the fourth enzyme is KRED-476.

[0393] In some embodiments, suitable fourth buffers include citrate buffers, phosphate buffers, tris(hydroxymethyl)aminomethane (Tris), and (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid) (HEPES). In some embodiments, the fourth buffer is selected from a citrate buffer, a phosphate buffer, tris(hydroxymethyl)aminomethane, and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES). In some embodiments, the fourth buffer is a Tris buffer.

[0394] In some embodiments, the reacting of the compound of Formula L or a salt thereof comprises reacting the compound of Formula L with a second reducing agent. In some embodiments, the reducing agent is beta-nicotinamide adenine dinucleotide sodium salt.

[0395] In some embodiments, the reacting of the compound of Formula L or a salt thereof is performed in a third cosolvent. In some embodiments, the third cosolvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methylether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, tert-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), or a combination thereof. In some embodiments, the third cosolvent comprises a polar aprotic solvent. In some embodiments, the second cosolvent comprises DMSO, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), Limonene, or a combination thereof. In some embodiments, the reacting of the compound of Formula L or a salt thereof is performed in a third cosolvent comprising dimethylsulfoxide.

[0396] In some embodiments, the reacting of the compound of Formula L or a salt thereof is carried out in a temperature range of from about 5 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula L or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula L or a salt thereof is carried out at a temperature of about 20 °C. Process for preparing the compound of Formula H

[0397] In some embodiments of the processes disclosed herein, the process comprises preparing the compound of Formula H or a salt thereof by a process comprising: reacting a compound of Formula J:J or a salt thereof, with: a second phosphine reagent, a second azodicarboxylate, and an amine protecting group reagent; to provide the compound of Formula H or a salt thereof.

[0398] In some embodiments of the compound of Formula J, R11is methyl.

[0399] In some embodiments, suitable second phosphine reagents include triaryl phosphines (e.g., triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine), trialkyl phosphines (e.g., tricyclohexyl phosphine, tributyl phosphine, trimethyl phosphine), tris-(dimethylaminophenyl) phosphine, (triphenylphosphoranylidene) acetonitrile, and phosphoranes (e.g., (cyanomethylene) tributylphosphorane).

[0400] In some embodiments, the second phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane. In some embodiments, the second phosphine reagent is a triarylphosphine. In some embodiments, the second phosphine reagent comprises triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine, or a combination thereof. In some embodiments, the second phosphine reagent is triphenylphosphine.

[0401] In some embodiments, the second azodicarboxylate is selected from di- tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate. In some embodiments, the second azodicarboxylate is diisopropyl azodicarboxylate.

[0402] In some embodiments, the amine protecting group reagent is an imide. In some embodiments, the amine protecting group reagent is an imide selected fromphthalimide, tert-butyl methyl iminodicarbonate, and di-tert-butyliminodicarboxylate. In some embodiments, the amine protecting group reagent is phthalimide.

[0403] In some embodiments, the reacting of the compound of Formula J or a salt thereof is performed in a thirty-eighth solvent. In some embodiments, the thirty-eighth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), dimethyl sulfoxide), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the thirty-eighth solvent comprises an ether. In some embodiments, the thirty-eighth solvent comprises tetrahydrofuran, 2- methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments the reacting of the compound of Formula J or a salt thereof is performed in a thirty-eighth solvent comprising 2-methyltetrahydrofuran.

[0404] In some embodiments, the reacting of the compound of Formula J or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C. In some embodiments, the reacting of the compound of Formula J or a salt thereof is carried out in a temperature range of from about -5 °C to about 15 °C. In some embodiments, the reacting of the compound of Formula J or a salt thereof is carried out at a temperature range of about 5 °C. Alternative process for preparing the compound of Formula H

[0405] In some embodiments of the processes disclosed herein, the process comprises preparing the compound of Formula H or a salt thereof by a process comprising: reacting a compound of Formula N:or a salt thereof, wherein: R12is -S(O)3R13or -OC(=N)R14; R13is selected from C1-4alkyl, C1-4haloalkyl, and phenyl optionally substituted with C1-4alkyl; and R14is C1-4haloalkyl; with an amine protecting group reagent, to provide the compound of Formula H or a salt thereof.

[0406] In some embodiments, R12is -S(O)3R13. In some embodiments, R13is selected from tolyl, methyl, and trifluoromethyl. In some embodiments, R13is C1-4alkyl. In some embodiments, R13is methyl. In some embodiments, R13is tolyl.

[0407] In some embodiments, R12is -OC(=N)R14. In some embodiments, R14is selected from trichloromethyl and tribromomethyl.

[0408] In some embodiments, the amine protecting group reagent is selected from phthalimide, para-methoxyaniline, ortho, para-dimethoxyaniline, acetamide, 2,5- dimethylpyrrole, 4-methoxybenzylamine, 2,4-dimethoxybenzylamine, 2,2- diphenylamine, allylamine, triphenylmethylamine, di-tert-butyl iminodicarbonate, tert- butyl carbamate, or a salt thereof. In some embodiments, the amine protecting group reagent is selected from phthalimide, para-methoxyaniline, ortho, para-dimethoxyaniline,acetamide, 2,5-dimethylpyrrole, 4-methoxybenzylamine, 2,4-dimethoxybenzylamine, 2,2-diphenylamine, allylamine, triphenylmethylamine, or a salt thereof. In some embodiments, the amine protecting group reagent is phthalimide or a salt thereof. In some embodiments, the amine protecting group reagent is a salt of phthalimide. In some embodiments, the amine protecting group reagent is potassium phthalimide.

[0409] In some embodiments, the reacting of the compound of Formula N or a salt thereof is carried out further in the presence of a third additive. In some embodiments, suitable third additives include 18-crown-6, tetrabutylammonium salts (e.g., chloride, bromide, sulfate, iodide), hexamethylphosphoramide, and water. In some embodiments, the third additive comprises 18-crown-6, a tetrabutylammonium salt, hexamethylphosphoramide, water, or a combination thereof. In some embodiments, the third additive comprises 18-crown-6. In some embodiments, the reacting of the compound of Formula N is carried out in the absence of a third additive.

[0410] In some embodiments, the reacting of the compound of Formula N or a salt thereof is carried out in the presence of a tenth base. In some embodiments, suitable tenth bases include amines (e.g., n-propylamine, triethylamine, N,N- diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine), amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole), or a combination thereof. In some embodiments, the tenth base is selected from an amine, an amidine, a guanidine, a carboxylate, acarbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, and a basic aromatic compound.

[0411] In some embodiments, the reacting of the compound of Formula N or a salt thereof is performed in a twentieth solvent. In some embodiments, the twentieth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or a combination thereof. In some embodiments, the twentieth solvent comprises a polar aprotic solvent. In some embodiments, the twentieth solvent N,N-dimethylformamide, N,N-dimethylacetamide, N- methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), or a combination thereof. In some embodiments, the reacting of the compound of Formula N or a salt thereof is performed in a twentieth solvent comprising N,N-dimethylacetamide.

[0412] In some embodiments, the reacting of the compound of Formula N or a salt thereof is performed in a twentieth solvent. In some embodiments, the twentieth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), dimethyl sulfoxide), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or a combination thereof. In some embodiments, the twentieth solvent comprises a polar aprotic solvent. In some embodiments, the twentieth solvent N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), limonene, dimethyl sulfoxide, or a combination thereof.

[0413] In some embodiments, the reacting of the compound of Formula N or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula N or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C.

[0414] In some embodiments, the process further comprises preparing the compound of Formula N or a salt thereof by a process comprising: reacting a compound of Formula J: J or a salt thereof, with: an eleventh base, and a third reagent selected from a sulfonyl chloride, a sulfonyl anhydride, a halonitrile, an imidoyl chloride, or an acid halide; to provide the compound of Formula N or a salt thereof.

[0415] In some embodiments, the process further comprises preparing the compound of Formula N or a salt thereof by a process comprising: reacting a compound of Formula J or a salt thereof, with an eleventh base, and a third reagent selected from a sulfonyl chloride, a sulfonyl anhydride, a halonitrile, or an imidoyl chloride; to provide the compound of Formula N or a salt thereof.

[0416] In some embodiments, the third reagent is a sulfonyl chloride. In some embodiments, the third reagent is selected from methane sulfonyl chloride and 4-toluene sulfonyl chloride. In some embodiments, the third reagent is methane sulfonyl chloride. In some embodiments, the third reagent is benzene sulfonyl chloride, toluene sulfonyl chloride, 4-nitrobenzene sulfonyl chloride, 2-nitrobezene sulfonyl chloride, 4- bromobenzene sulfonyl chloride, triisopropylbenzene sulfonyl chloride, trimethylbenzene sulfonyl chloride, naphthalene sulfonyl chloride, 2-chlorobenzene sulfonyl chloride, 2,4- dichlorobenzene sulfonyl chloride, or methane sulfonyl chloride.

[0417] In some embodiments, the third reagent is a sulfonyl anhydride. In some embodiments, the sulfonyl anhydride is selected from methane sulfonyl anhydride and trifluoromethanesulfonic anhydride. In some embodiments, the third reagent is a sulfonyl anhydride (e.g., hexanoic anhydride, isobutyric anhydride, benzoic anhydride, propionic anhydride, octanoic anhydride, decanoic anhydride).

[0418] In some embodiments, the third reagent is a halonitrile. In some embodiments, the halonitrile is selected from trichloroacetonitrile and trifluoroacetonitrile.

[0419] In some embodiments, the third reagent is an imidoyl chloride. In some embodiments, the imidoyl chloride is (N-phenyl)trifluoroacetimidoyl chloride.

[0420] In some embodiments, the third reagent is an acid halide. In some embodiments, the acid halide is selected from acetyl chloride, acetyl bromide, and benzoyl chloride.

[0421] In some embodiments, suitable eleventh bases include amines (e.g., triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,1,3,3-tetramethylguanidine, 2,2,6,6- tetramethylpiperidine, pyridine, 2,6-lutidine, N,N-diisopropylethylamine, quinuclidine, diisopropylamine, N,N-diisopropylethylamine, tributylamine), carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate),and metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide).

[0422] In some embodiments, the eleventh base is an amine. In some embodiments, the eleventh base comprises triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5- diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,1,3,3- tetramethylguanidine, 2,2,6,6-tetramethylpiperidine, pyridine, 2,6-lutidine, N,N- diisopropylethylamine, quinuclidine, diisopropylamine, N,N-diisopropylethylamine, tributylamine, or a combination thereof. In some embodiments, the eleventh base is triethylamine.

[0423] In some embodiments, the reacting of the compound of Formula J or a salt thereof is performed in a twenty-first solvent. In some embodiments, the twenty-first solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the twenty-first solvent comprises a polar aprotic solvent. In some embodiments, the twenty-first solvent comprises N,N-dimethylformamide, N,N-dimethylacetamide, N- methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), or a combination thereof. In some embodiments, the reacting of the compound of Formula J or a salt thereof is performed in a twenty-first solvent comprising N,N-dimethylacetamide.

[0424] In some embodiments, the reacting of the compound of Formula J or a salt thereof is carried out in a temperature range of from about -15 °C to about 60 °C. In some embodiments, the reacting of the compound of Formula J or a salt thereof is carried out in a temperature range of from about -10 °C to about 10 °C. In some embodiments, thereacting of the compound of Formula J or a salt thereof is carried out at a temperature of about 0 °C. Alternative process for preparing the compound of Formula H-1

[0425] In some embodiments of the processes disclosed herein, the process comprises preparing the compound of Formula H-1 or a salt thereof by a process comprising: reacting a compound of Formula P-1:or a salt thereof, with an amine protecting group reagent to provide the compound of Formula H-1 or a salt thereof. In some embodiments of the compound of Formula P-1 or a salt thereof, R11is methyl.

[0426] In some embodiments, the amine protecting group reagent is di-tert-butyl dicarbonate.

[0427] In some embodiments, the process further comprises preparing the compound of Formula P-1 or a salt thereof by a process comprising: reacting a compound of Formula N:or a salt thereof, wherein: R12is -S(O)3R13; andR13is selected from C1-4alkyl and phenyl optionally substituted with C1-4alkyl; with: an azide, and a third phosphine reagent; to provide the compound of Formula P-1 or a salt thereof.

[0428] In some embodiments, the azide is selected from sodium azide, diphenylphosphoryl azide, and trimethylsilyl azide. In some embodiments, the azide is sodium azide.

[0429] In some embodiments, suitable third phosphine reagents include triaryl phosphines (e.g., triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine), trialkyl phosphines (e.g., tricyclohexyl phosphine, tributyl phosphine, trimethyl phosphine), tris-(dimethylaminophenyl) phosphine, (triphenylphosphoranylidene) acetonitrile, and phosphoranes (e.g., (cyanomethylene) tributylphosphorane).

[0430] In some embodiments, the third phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane. In some embodiments, the third phosphine reagent is a triarylphosphine. In some embodiments, the third phosphine reagent comprises triphenylphosphine, tris (2- pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine, or a combination thereof. In some embodiments, the third phosphine reagent is triphenylphosphine.

[0431] In some embodiments, the reacting of the compound of Formula N or a salt thereof is performed in a twenty-seventh solvent. In some embodiments, the twenty- seventh solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate,dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the twenty-seventh solvent comprises a polar aprotic solvent. In some embodiments, the twenty-seventh solvent comprises N,N-dimethylformamide, N,N-dimethylacetamide, N- methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), or a combination thereof. In some embodiments the reacting of the compound of Formula N or a salt thereof is performed in a twenty-seventh solvent comprising N,N-dimethylformamide.

[0432] In some embodiments, the reacting of the compound of Formula N or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C. In some embodiments, the reacting of the compound of Formula N or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. Alternative process for preparing the compound of Formula H-1

[0433] In some embodiments of the processes disclosed herein, the process comprises preparing the compound of Formula H-1 or a salt thereof by a process comprising: reacting a compound of Formula P-2:or a salt thereof, with: a fourth phosphine reagent; and an amine protecting group reagent; to provide the compound of Formula H-1 or a salt thereof. In some embodiments of the compound of Formula P-2 or a salt thereof, R11is methyl.

[0434] In some embodiments, suitable fourth phosphine reagents include triaryl phosphines (e.g., triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine), trialkyl phosphines (e.g., tricyclohexyl phosphine, tributyl phosphine, trimethyl phosphine), tris-(dimethylaminophenyl) phosphine, (triphenylphosphoranylidene) acetonitrile, and phosphoranes (e.g., (cyanomethylene) tributylphosphorane).

[0435] In some embodiments, the fourth phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane. In some embodiments, the fourth phosphine reagent is a triarylphosphine. In some embodiments, the fourth phosphine reagent comprises triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine, or a combination thereof. In some embodiments, the fourth phosphine reagent is triphenylphosphine.

[0436] In some embodiments, the amine protecting group reagent is di-tert-butyl dicarbonate.

[0437] In some embodiments, the process further comprises preparing the compound of Formula P-2 or a salt thereof by a process comprising: reacting a compound of reacting a compound of Formula J: or a salt thereof, with:an azide, a third phosphine reagent, and a third azodicarboxylate; to provide the compound of Formula P-2 or a salt thereof.

[0438] In some embodiments, the azide is selected from sodium azide, diphenylphosphoryl azide, and trimethylsilyl azide. In some embodiments, the azide is sodium azide.

[0439] In some embodiments, suitable third phosphine reagents include triaryl phosphines (e.g., triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine), trialkyl phosphines (e.g., tricyclohexyl phosphine, tributyl phosphine, trimethyl phosphine), tris-(dimethylaminophenyl) phosphine, (triphenylphosphoranylidene) acetonitrile, and phosphoranes (e.g., (cyanomethylene) tributylphosphorane).

[0440] In some embodiments, the third phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane. In some embodiments, the third phosphine reagent is a triarylphosphine. In some embodiments, the third phosphine reagent comprises triphenylphosphine, tris (2- pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine, or a combination thereof. In some embodiments, the third phosphine reagent is triphenylphosphine.

[0441] In some embodiments, the third azodicarboxylate is selected from di-tert- butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate. In some embodiments, the third azodicarboxylate is diisopropyl azodicarboxylate.

[0442] In some embodiments, the reacting of the compound of Formula J or a salt thereof is performed in a thirty-ninth solvent. In some embodiments, the thirty-ninth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), dimethyl sulfoxide), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g.,acetone, 2-butanone, 4-methyl-2-pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the thirty-eighth solvent comprises an ether. In some embodiments, the thirty-ninth solvent comprises tetrahydrofuran, 2- methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments the reacting of the compound of Formula J or a salt thereof is performed in a thirty-ninth solvent comprising tetrahydrofuran.

[0443] In some embodiments, the reacting of the compound of Formula J or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C. In some embodiments, the reacting of the compound of Formula J or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. Process for preparing the compound of Formula J

[0444] In some embodiments of the processes disclosed herein, the process comprises preparing the compound of Formula J or a salt thereof by a process comprising: reacting a compound of Formula K:or a salt thereof, with: an enzyme, and a buffer; to provide the compound of Formula J or a salt thereof.

[0445] In some embodiments of the compound of Formula K or a salt thereof, R11is selected from C1-20 alkyl and phenyl. In some embodiments of the compound of FormulaK or a salt thereof, R11is selected from methyl, hexyl, isopropyl, and benzyl. In some embodiments of the compound of Formula K or a salt thereof, R11is methyl.

[0446] In some embodiments, suitable enzymes include hydrolases (such as Candida antarctica lipase A and B, lipase AK, lipase PS, candida rugosa lipase, L-092, etc.) Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26, and Novozyme 435.

[0447] In some embodiments, the enzyme is selected from a hydrolase enzyme, Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26, and Novozyme 435. In some embodiments, the enzyme is a hydrolase enzyme. In some embodiments, the enzyme is selected from L-092, Candida antarctica lipase A and B, lipase AK, lipase PS, candida rugosa lipase. In some embodiments, the enzyme is L-092 hydrolase enzyme.

[0448] In some embodiments, a molar ratio of the enzyme to the compound of Formula K or a salt thereof is about 0.00001:1 to about 2:1. In some embodiments, a molar ratio of the enzyme to the compound of Formula K or a salt thereof is about 0.00001:1 to about 0.01:1. In some embodiments, a molar ratio of the enzyme to the compound of Formula K or a salt thereof is about 0.001:1 to about 0.01:1. In some embodiments, a molar ratio of the enzyme to the compound of Formula K or a salt thereof is about 0.001:1 to about 0.005:1.

[0449] In some embodiments, suitable buffers include citrate buffers, phosphate buffers (e.g., potassium phosphate, citrate phosphate), tris(hydroxymethyl)aminomethane (Tris), and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES). In some embodiments, suitable buffers include phosphate buffers (e.g., potassium phosphate, citrate phosphate), tris(hydroxymethyl)aminomethane (Tris), and (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid) (HEPES). In some embodiments, the buffer is selected from a citrate buffer, a phosphate buffer, tris(hydroxymethyl)aminomethane, and (4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES). In some embodiments, the buffer is selected from a phosphate buffer, tris(hydroxymethyl)aminomethane, and (4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES). In some embodiments, the buffer is a phosphate buffer. In some embodiments, the buffer is a potassium phosphatebuffer. In some embodiments, the buffer has a concentration of about 0.1M to about 1.5 M.

[0450] In some embodiments, the process comprises adjusting a pH of the reaction mixture comprising the compound of Formula K or a salt thereof to a range of about pH 8 to pH 12. In some embodiments, the process comprises adjusting a pH of the reaction mixture comprising the compound of Formula K or a salt thereof to about pH 10.

[0451] In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out at a pH of about 5 to about 10. In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out at a pH of about 7 to about 10. In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out at a pH of about 6 to about 8. In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out at a pH of about 7. In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out at a pH of about 10.

[0452] In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out in the presence of a metal ion. In some embodiments, the metal ion is an ion of zinc, nickel, calcium, iron, magnesium, or manganese. In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out in the presence of a metal halide. In some embodiments, the metal ion or metal halide comprises zinc, nickel, calcium, iron, magnesium, or manganese. In some embodiments, the metal halide is a metal chloride. In some embodiments, the metal halide comprises zinc chloride, nickel (II) chloride, calcium chloride, iron (II) chloride, iron (III) chloride, magnesium chloride, manganese(II) chloride, or a combination thereof.

[0453] In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out in the presence of a surfactant. In some embodiments, the surfactant is selected from sodium dodecyl sulfate, polypropylene glycol, and a polyoxyethylene fatty ether. In some embodiments, the surfactant is selected from sodium dodecyl sulfate, polypropylene glycol 2000, and Brij surfactants (e.g., L23, 58, S20, O20, L4, O10, S10, C10).

[0454] In some embodiments, the reacting of the compound of Formula K or a salt thereof is performed in a fortieth solvent. In some embodiments, the fortieth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), dimethyl sulfoxide), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2- methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2- pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the fortieth solvent comprises dimethylsulfoxide, tert-butyl methyl ether, heptane, cyclopentyl methyl ether, tolune, 2-methylhydrofuran, or a combination thereof.

[0455] In some embodiments, the fortieth solvent comprises an ether. In some embodiments, the fortieth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments the reacting of the compound of Formula K or a salt thereof is performed in a fortieth solvent comprising tert-butyl methyl ether.

[0456] In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out in a temperature range of from about 0 °C to about 70 °C. In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out in a temperature range of from about 30 °C to about 50 °C. In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out in a temperature range of from about 20 °C to about 40 °C. In some embodiments, the reacting of the compound of Formula K or a salt thereof is carried out at a temperature of about 30 °C.

[0457] In some embodiments, provided herein is a process for preparing a compound of Formula J or a salt thereof by a process comprising: reacting a compound of Formula K or a salt thereof, with an enzyme, and a buffer;to provide the compound of Formula J or a salt thereof.

[0458] In some embodiments, provided herein is a process for preparing a compound of Formula I or a salt thereof by a process comprising: preparing a compound of Formula J or a salt thereof by a process comprising: reacting a compound of Formula K or a salt thereof, with an enzyme, and a buffer; to provide the compound of Formula J or a salt thereof.

[0459] In some embodiments, the process further comprises preparing the compound of Formula K or a salt thereof by a process comprising: reacting a compound of Formula L:or a salt thereof; with: a ninth base, a fourth catalyst; and a compound of Formula M-1 or Formula M-2:;wherein X is a halide; to provide the compound of Formula K or a salt thereof.

[0460] In some embodiments, the compound of Formula L or a salt thereof is reacted with the compound of Formula M-1. In some embodiments, the compound of Formula M-1 is selected from acetic anhydride, hexanoic anhydride, isobutyric anhydride, benzoic anhydride, propionic anhydride, octanoic anhydride, and decanoic anhydride. In some embodiments, the compound of Formula M-1 is acetic anhydride (i.e., R11is methyl).

[0461] In some embodiments, the compound of Formula L or a salt thereof is reacted with the compound of Formula M-2. In some embodiments, the halide is chloride or bromide. In some embodiments, the compound of Formula M-2 is selected from acetyl chloride, acetyl bromide, and benzoyl chloride.

[0462] In some embodiments, suitable ninth bases include carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate), metal alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide), amines (e.g., diethylamine, triethylamine, isopropylamine, diisopropylethylamine, N-methyl morpholine, 1,4-diazabicyclo[2.2.2] octane, Diazabicycloundecene, Bis(trimethylsilyl)amine), metal hydroxides (e.g., sodium hydroxide).

[0463] In some embodiments, the ninth base is selected from a carbonate, a metal alkoxide, an amine, a metal hydroxide, or a combination thereof. In some embodiments, the ninth base is an amine. In some embodiments, the ninth base comprises diethylamine, triethylamine, isopropylamine, diisopropylethylamine, N-methyl morpholine, 1,4- diazabicyclo[2.2.2] octane, diazabicycloundecene, bis(trimethylsilyl)amine, or a combination thereof. In some embodiments, the ninth base is triethylamine.

[0464] In some embodiments, the fourth catalyst is an aromatic amine. In some embodiments, the fourth catalyst is selected from 4-dimethylaminopyridine, N-methyl imidazole, and pyridine. In some embodiments, the fourth catalyst is 4- dimethylaminopyridine.

[0465] In some embodiments, the reacting of the compound of Formula L or a salt thereof is performed in a forty-first solvent. In some embodiments, the forty-firstsolvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), dimethyl sulfoxide), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the forty-first solvent comprises an ether. In some embodiments, the forty-first solvent comprises tetrahydrofuran, 2- methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments, the reacting of the compound of Formula L or a salt thereof is performed in a forty-first solvent comprising tert-butyl methyl ether.

[0466] In some embodiments, the reacting of the compound of Formula L or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula L or a salt thereof is carried out in a temperature range of from about 15 °C to about 25 °C. In some embodiments, the reacting of the compound of Formula L or a salt thereof is carried out at a temperature of about 20 °C. Alternative Process for preparing the compound of Formula E

[0467] In some embodiments of the processes disclosed herein, the process comprises preparing the compound of Formula E or a salt thereof by a process comprising: reacting a compound of Formula O-1: NHR8O-1 or a salt thereof, with: an amine protecting group reagent, a phosphine reagent, and an azodicarboxylate, to provide the compound of Formula E or a salt thereof.

[0468] In some embodiments of the compound of Formula O-1, R7and R8are tert-butyloxycarbonyl.

[0469] In some embodiments, the amine protecting group reagent is selected from phthalimide, di-tert-butyl-iminodicarboxylate , ethyl 2-((tert-butoxycarbonyl)amino)-2- oxoacetate, methyl 2-((tert-butoxycarbonyl)amino)-2-oxoacetate, tert-butyl methyl iminodicarbonate, and dimethyl iminodicarbonate. In some embodiments, the amine protecting group reagent is phthalimide.

[0470] In some embodiments, suitable phosphine reagents include triaryl phosphines (e.g., triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine), trialkyl phosphines (e.g., tricyclohexyl phosphine, tributyl phosphine, trimethyl phosphine), tris-(dimethylaminophenyl) phosphine, (triphenylphosphoranylidene) acetonitrile, and phosphoranes (e.g., (cyanomethylene) tributylphosphorane).

[0471] In some embodiments, the phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane. In some embodiments, the phosphine reagent is a triarylphosphine. In some embodiments, the phosphine reagent comprises triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine, or a combination thereof. In some embodiments, the phosphine reagent is triphenylphosphine.

[0472] In some embodiments, the azodicarboxylate is selected from di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxyethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate. In some embodiments, the azodicarboxylate is di-tert-butyl azodicarboxylate.

[0473] In some embodiments, the reacting of the compound of Formula O-1 or a salt thereof is performed in a twenty-second solvent. In some embodiments, the twenty- second solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the twenty-second solvent comprises an ether. In some embodiments, the twenty-second solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3- dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments the reacting of the compound of Formula O-1 or a salt thereof is performed in a twenty-second solvent comprising 2-methyltetrahydrofuran.

[0474] In some embodiments, the reacting of the compound of Formula O-1 or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C. In some embodiments, the reacting of the compound of Formula O-1 or a salt thereof is carried out in a temperature range of from about 0 °C to about 22 °C.

[0475] In some embodiments, the process further comprises preparing the compound of Formula O-1 or a salt thereof by a process comprising: reacting a compound of Formula O-2:or a salt thereof, with: a fifth catalyst, and hydrogen; to provide the compound of Formula O-1 or a salt thereof.

[0476] In some embodiments, suitable fifth catalysts include palladium catalysts (e.g., palladium, 5 wt% on carbon, palladium, 10 wt% on carbon, palladium, 1 wt% on carbon, palladium, 5 wt% on calcium carbonate, palladium, 5 wt% on aluminum oxide, palladium hydroxide, 20 wt% on carbon, lead poisoned palladium), bimetallic catalysts (e.g., palladium,4 wt% and platinum, 1 wt% on carbon, palladium, 9 wt% and copper, 1 wt% on carbon, palladium, 4 wt% and copper, 1 wt% on carbon), and platinum catalysts (e.g., platinum on carbon, platinum oxide).

[0477] In some embodiments, suitable fifth catalysts include palladium catalysts (e.g., palladium, 5 wt% on carbon, palladium, 10 wt% on carbon, palladium, 1 wt% on carbon, palladium, 5 wt% on calcium carbonate, palladium, 5 wt% on aluminum oxide, palladium hydroxide, palladium acetate, palladium acetate / manganese, palladium chloride, palladium trifluoroacetate, palladium propionate, palladium pivalate, tris(dibenzylideneacetone) dipalladium, palladium bromide, palladium (II) bis(acetylacetonate), bis(benzonitrile)palladium dichloride, 20 wt% on carbon, lead poisoned palladium with, barium sulfate or calcium carbonate), bimetallic catalysts (e.g., palladium,4 wt% and platinum, 1 wt% on carbon, palladium, 9 wt% and copper, 1 wt% on carbon, palladium, 4 wt% and copper, 1 wt% on carbon), and platinum catalysts (e.g., platinum on carbon, platinum oxide).

[0478] In some embodiments, the fifth catalyst is selected from a palladium catalyst, a platinum catalyst, and a bimetallic catalyst, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

[0479] In some embodiments, the fifth catalyst is a palladium catalyst. In some embodiments, the fifth catalyst comprises palladium on carbon, palladium on calcium carbonate, or palladium on aluminum oxide. In some embodiments, the fifth catalyst is selected from 5 wt% palladium on carbon, 10 wt% palladium on carbon, 1 wt% palladium on carbon, 5 wt% palladium on calcium carbonate, 5 wt% palladium on aluminum oxide, 20 wt% palladium on carbon, and lead poisoned palladium.

[0480] In some embodiments, the fifth catalyst is a Lindlar catalyst. In some embodiments, the fifth catalyst comprises 5 wt.% palladium on lead-poisoned calcium carbonate.

[0481] In some embodiments, the hydrogen is from a hydrogen source. In some embodiments, the hydrogen source is the hydrogen gas or a combination of formic acid, potassium carbonate, and water. In some embodiments, the hydrogen source is the hydrogen gas. In some embodiments, the hydrogen source is a combination of formic acid, potassium carbonate, and water.

[0482] In some embodiments, the preparation of the compound of Formula O-1 by a process comprising reacting a compound of Formula O-2 or a salt thereof, with the fifth catalyst and hydrogen is done further in presence of an additive. In some embodiments, the additive is selected from the group consisting of quinoline, pyridine, triethylamine, carbonates (such as lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (such as lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), phosphates M(n)H(3-n)PO4 (such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, etc.), 1,8-diazabicyclo[5.4.0] undec-7-ene, potassium carbonate, potassium formate, sodium formate, ammonium formate, potassium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium tert-butoxide,sodium tert-butoxide, potassium iodide, lithium chloride, sodium chloride, calcium chloride, triethylamine, and potassium hydroxide.

[0483] In some embodiments, a molar ratio of the compound of Formula O-2 or a salt thereof to the fifth catalyst is from about 1:0.001 to about 1:0.05. In some embodiments, a molar ratio of the compound of Formula O-2 or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.005. In some embodiments, a molar ratio of the compound of Formula O-2 or a salt thereof to the third catalyst is about 1:0.003.

[0484] In some embodiments, the reacting of the compound of Formula O-2 or a salt thereof is carried out at a pressure of about 1 psi to about 100 psi. In some embodiments, the reacting of the compound of Formula O-2 or a salt thereof is carried out at a pressure of about 25 psi to about 75 psi. In some embodiments, the reacting of the compound of Formula O-2 or a salt thereof is carried out at a pressure of about 50 psi.

[0485] In some embodiments, the reacting of the compound of Formula O-2 or a salt thereof is performed in a twenty-third solvent. In some embodiments, the twenty- third solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, iso-amyl alcohol, tert-amyl alcohol), a glycol (e.g., polyethylene glycol 400), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α- trifluorotoluene), or a combination thereof. In some embodiments, the twenty-third solvent comprises a polar aprotic solvent. In some embodiments, the twenty-third solvent comprises N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N- butyl pyrrolidone (NBP), or a combination thereof. In some embodiments, the reacting ofthe compound of Formula O-2 or a salt thereof is performed in a twenty-third solvent comprising N,N-dimethylformamide.

[0486] In some embodiments, the twenty-third solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene, anisole), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol (e.g. 1-butanol), iso-amyl alcohol, tert-amyl alcohol), a glycol (e.g., polyethylene glycol 400), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof.

[0487] In some embodiments, the reacting of the compound of Formula O-2 or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula O-2 or a salt thereof is carried out in a temperature range of from about 15 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula O-2 or a salt thereof is carried out at a temperature of about 22 °C.

[0488] In some embodiments, the process further comprises preparing the compound of Formula O-2 or a salt thereof by a process comprising: reacting a compound of Formula O-3:or a salt thereof, wherein R11is selected from C1-20alkyl, phenyl, and -CH2NH2; with:a twelfth base; to provide the compound of Formula O-2 or a salt thereof.

[0489] In some embodiments of the compound of Formula O-3 or a salt thereof, R11is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl, and -CH2NH2. In some embodiments of the compound of Formula O-3 or a salt thereof, R11is methyl.

[0490] In some embodiments, suitable twelfth bases include guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide), amines (e.g., methylamine, diethylamine, isopropylamine, diisopropylethylamine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2] octane, Bis(trimethylsilyl)amine), metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide).

[0491] In some embodiments, the twelfth base is a guanidine. In some embodiments, the twelfth base is selected from triazabicyclodecene and tetra-methyl guanidine. In some embodiments, the twelfth base is tetra-methyl guanidine.

[0492] In some embodiments, the reacting of the compound of Formula O-3 or a salt thereof is performed in a twenty-fourth solvent. In some embodiments, the twenty- fourth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol,iso-amyl alcohol, tert-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2- dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the twenty-fourth solvent comprises an alcohol. In some embodiments, the twenty-fourth solvent comprises methanol, ethanol, 2-propanol, butanol, glycerol, iso- amyl alcohol, tert-amyl alcohol, or a combination thereof. In some embodiments, the reacting of the compound of Formula O-3 or a salt thereof is performed in a twenty- fourth solvent comprising methanol.

[0493] In some embodiments, the reacting of the compound of Formula O-3 or a salt thereof is carried out in a temperature range of from about -10 °C to about 80 °C. In some embodiments, the reacting of the compound of Formula O-3 or a salt thereof is carried out in a temperature range of from about 10 °C to about 30 °C. In some embodiments, the reacting of the compound of Formula O-3 or a salt thereof is carried out at a temperature of about 20 °C.

[0494] In some embodiments, the process further comprises preparing the compound of Formula O-3 or a salt thereof by a process comprising: reacting a compound of Formula O-4:or a salt thereof, with: a second phosphine reagent, a second azodicarboxylate, and a compound of Formula R7-NH-NH-R8or methyl (1,3-dioxoisoindolin-2-yl) carbamate; to provide the compound of Formula O-3 or a salt thereof.

[0495] In some embodiments, suitable second phosphine reagents include triaryl phosphines (e.g., triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine), trialkyl phosphines (e.g., tricyclohexyl phosphine, tributyl phosphine, trimethyl phosphine), tris-(dimethylaminophenyl) phosphine, (triphenylphosphoranylidene) acetonitrile, and phosphoranes (e.g., (cyanomethylene) tributylphosphorane).

[0496] In some embodiments, the second phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane. In some embodiments, the second phosphine reagent is a triarylphosphine. In some embodiments, the second phosphine reagent comprises triphenylphosphine, tris (2-pyridyl) phosphine, tris-(4-methoxyphenyl) phosphine, or a combination thereof. In some embodiments, the second phosphine reagent is triphenylphosphine.

[0497] In some embodiments, the second azodicarboxylate is selected from di- tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate. In some embodiments, the second azodicarboxylate is di-tert-butylazodicarboxylate.

[0498] In some embodiments, the compound of Formula R7-NH-NH-R8is .some embodiments, the reacting of the compound of Formula O-4 or a salt thereof is performed in a twenty-fifth solvent. In some embodiments, the twenty-fifth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP), dimethyl sulfoxide), an ester (e.g., ethyl acetate, methyl acetate,isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the twenty-fifth solvent comprises an ether. In some embodiments, the twenty-fifth solvent comprises tetrahydrofuran, 2- methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments the reacting of the compound of Formula O-4 or a salt thereof is performed in a twenty-fifth solvent comprising 2-methyltetrahydrofuran.

[0500] In some embodiments, the reacting of the compound of Formula O-4 or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C. In some embodiments, the reacting of the compound of Formula O-4 or a salt thereof is carried out in a temperature range of from about 0 °C to about 22 °C.

[0501] In some embodiments, the process further comprises preparing the compound of Formula O-4 or a salt thereof by a process comprising: reacting a compound of Formula L:or a salt thereof, with: an alkyl ester, an alkenyl ester or an oxime ester; and an enzyme, to provide the compound of Formula O-4 or a salt thereof.

[0502] In some embodiments, the compound of Formula L or a salt thereof is reacted with an alkenyl ester. In some embodiments, the compound of Formula L or a salt thereof is reacted with an alkenyl ester is selected from vinyl acetate, isopropenylacetate, and vinyl butyrate. In some embodiments, the alkenyl ester is isopropenyl acetate.

[0503] In some embodiments, the compound of Formula L or a salt thereof is reacted with an alkyl ester. In some embodiments, the compound of Formula L or a salt thereof is reacted with an alkyl ester selected from ethyl acetate, methyl acetate, isopropyl acetate, and methyl butyrate.

[0504] In some embodiments, the compound of Formula L or a salt thereof is reacted with an oxime ester. In some embodiments, the compound of Formula L or a salt thereof is reacted with an oxime ester is selected from propan-2-one O-acetyl oxime and propan-2-one O-butyryl oxime.

[0505] In some embodiments, suitable enzymes include hydrolases (e.g., Candida antarctica lipase A and B, lipase AK, lipase PS, candida rugosa lipase), Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26, and Novozyme 435. In some embodiments, the enzyme is selected from a hydrolase enzyme, Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26, and Novozyme 435. In some embodiments, the enzyme is a hydrolase enzyme. In some embodiments, the enzyme is Lipase AK.

[0506] In some embodiments, the reacting of the compound of Formula L or a salt thereof is performed in a twenty-sixth solvent. In some embodiments, the twenty- sixth solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a hydrocarbon (e.g., toluene, n-heptane) an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol, tert-amyl alcohol), or a combination thereof. In some embodiments, the twenty-sixth solvent comprises an ether. In some embodiments, the twenty-sixth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof. In some embodiments, the reacting of the compound of Formula L or a salt thereof is performed in a twenty-sixth solvent comprising tert-butyl methyl ether.

[0507] In some embodiments, the reacting of the compound of Formula L or a salt thereof is carried out in a temperature range of from about 10 °C to about 70 °C. In some embodiments, the reacting of the compound of Formula L or a salt thereof is carried out in a temperature range of from about 30 °C to about 60 °C. In some embodiments, the reacting of the compound of Formula L or a salt thereof is carried out at a temperature of about 50 °C.

[0508] In some embodiments, provided herein is a process for preparing a compound of Formula I-A:or a salt thereof, comprising: (a) reacting a compound of Formula A:or a salt thereof, group, with: a methylene reagent, and a first acid or a first base, to provide a compound of Formula I:or a salt thereof, w group; and (b) deprotecting the compound of Formula I or a salt thereof, to provide the compound of Formula I-A or a salt thereof.

[0509] In some embodiments, provided herein is a process for preparing a compound of Formula I-A: or a salt thereof,(a) reacting a compound of Formula R-1:or a salt thereof, a methylene reagent, and an eighth acid or a fourteenth base, to provide a compound of Formula I:or a salt thereof, w group; and (b) deprotecting the compound of Formula I or a salt thereof, to provide the compound of Formula I-A or a salt thereof.

[0510] In some embodiments of the processes disclosed herein, the compound of Formula R-1 or a salt thereof by a process comprising: (c) reacting a compound of Formula A: or a salt thereof,protecting group, with: a reagent selected from a metal hydroxide, a metal halide, and a trialkylsilyl halide; to provide a compound of Formula R-2:or a salt thereof; and(d) reacting the compound of Formula R-2 or a salt thereof, with: a coupling agent, and a fifteenth base, to provide the compound of Formula R-1 or a salt thereof

[0511] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula R-1 or a salt thereof by a process comprising: reacting a compound of Formula A: or a salt thereof,a sixteenth base; to provide the compound of Formula R-1 or a salt thereof.

[0512] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula A or a salt thereof by a process comprising: (e) deprotecting a compound of Formula D:or a salt thereof, wherein or wherein R9is an amine protecting group, and R7and R8are each independently an amine protecting group;to provide a compound of Formula C: or a salt thereof; and(f) reacting a compound of Formula X-A: or a salt thereof,the compound of Formula C or a salt thereof, and a seventh base; to provide the compound of Formula A or a salt thereof.

[0513] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula D or a salt thereof by a process comprising: (g) deprotecting a compound of Formula E:or a salt thereof, R7and R8are each independently an amine protecting group; and R9is an amine protecting group and R10is hydrogen; or optionally:R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group; to provide the compound of Formula D or a salt thereof having Formula D-1:or a salt thereof.

[0514] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula A by a process comprising: (e) reacting a compound of Formula E: or a salt thereof,the nitrogen atom to which they are attached form phthalimide; with a seventh acid to provide a compound of Formula Q-2: or a salt thereof;(f) reacting the compound of Formula Q-2 or a salt thereof, with: a compound of Formula X-A:or a salt thereof, and a thirteenth base; to provide a compound of Formula Q-1: or a salt(g) reacting the compound of Formula Q-1 or a salt thereof, with a reagent selected from a hydrazine, an alkoxide, and a hydrolase enzyme; to provide the compound of Formula A or a salt thereof.

[0515] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula E by a process comprising: (h) reacting a compound of Formula H:or a salt thereof, wherein R11is selected from C1-20alkyl, phenyl, and -CH2NH2; with a sixth acid or an eighth base,to provide a compound of Formula G:or a salt thereof; (i) reacting the compound of Formula G or a salt thereof, with: a third catalyst, and hydrogen; to provide a compound of Formula F:or a salt thereof; and (j) reacting the compound of Formula F or a salt thereof, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula E or a salt thereof.

[0516] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula E by a process comprising: (h) reacting a compound of Formula F:or a salt thereof, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula E or a salt thereof.

[0517] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula F by a process comprising: (i) reacting a compound of Formula S:or a salt thereof, with: a compound of Formula T: T or a salt thereof, wherein R15is selected from phenyl and C1-4haloalkyl, wherein the phenyl is optionally substituted with 1-4 substituents selected from C1-4alkyl, halo, C1-4 haloalkyl, and cyano; a seventeenth base, and a fourth additive;to provide a compound of Formula W:or a salt thereof; and (j) reacting the compound of Formula W or a salt thereof, with: a sixth catalyst, and a reducing agent; to provide the compound of Formula F or a salt thereof.

[0518] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula F by a process comprising: (i) reacting a compound of Formula W:or a salt thereof, with: a second enzyme in the presence of a second buffer; to provide the compound of Formula F or a salt thereof.

[0519] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula F by a process comprising: (i) reacting a compound of Formula S:or a salt thereof, with: a compound of Formula T: or a salt thereof,wherein R15is selected from phenyl and C1-4haloalkyl, wherein the phenyl is optionally substituted with 1-4 substituents selected from C1-4alkyl, halo, C1-4haloalkyl, and cyano; a seventeenth base, and a fourth additive; to provide a compound of Formula W: or a salt thereof; and(j) reacting the compound of Formula W or a salt thereof, with: a sixth catalyst, and a reducing agent; to provide the compound of Formula F or a salt thereof.

[0520] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula F by a process comprising: (i) reacting a compound of Formula G:G or a salt thereof, with: a third reducing agent, and an activator; to provide the compound of Formula F or a salt thereof.

[0521] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula D or a salt thereof by a process comprising: (g) reacting a compound of Formula H having Formula H-1:or a salt thereof, wherein: R9is an amine protecting group; and R11is selected from C1-20alkyl, phenyl, and -CH2NH2; with a twelfth base, to provide a compound of Formula G-1:or a salt thereof; (h) reacting the compound of Formula G-1 or a salt thereof, with: a third catalyst,an aromatic amine or a sulfur-containing reagent; and hydrogen; to provide the compound of Formula F-1:or a salt thereof; and (i) reacting the compound of Formula F-1 or a salt thereof, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula D or a salt thereof.

[0522] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula D or a salt thereof by a process comprising: (g) reacting a compound of Formula G-1:or a salt thereof, with: a third catalyst, an aromatic amine or a sulfur-containing reagent; and hydrogen; to provide a compound of Formula F-1:or a salt thereof; and (h) reacting the compound of Formula F-1 or a salt thereof, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula D or a salt thereof.

[0523] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula G or a salt thereof, wherein the compound of Formula G or a salt thereof is a compound of Formula G-1 or a salt thereof, by a process comprising: (j) reacting a compound of Formula L:or a salt thereof, with: a fourth enzyme in the presence of a fourth buffer; to provide a compound of Formula U-2:or a salt thereof; (k) reacting the compound of Formula U-2 or a salt thereof, with: a third enzyme in the presence of a third buffer; to provide a compound of Formula U-1:U-1 or a salt thereof; and (l) reacting the compound of Formula U-1 or a salt thereof, with: a second amine protecting group reagent to provide the compound of Formula G-1 or a salt thereof.

[0524] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula H or a salt thereof by a process comprising: (k) reacting a compound of Formula J:or a salt thereof, with: a second phosphine reagent, a second azodicarboxylate, and an amine protecting group reagent; to provide the compound of Formula H or a salt thereof.

[0525] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula H or a salt thereof by a process comprising: (k) reacting a compound of Formula J:J or a salt thereof, wherein:R12is -S(O)3R13or -OC(=N)R14; R13is selected from C1-4alkyl, C1-4haloalkyl, and phenyl optionally substituted with C1-4alkyl; and R14is C1-4haloalkyl; with: an eleventh base, and a third reagent selected from methane sulfonyl chloride, an anhydride, or an acid halide; to provide a compound of Formula N: or a salt thereof; and(l) reacting the compound of Formula N or a salt thereof with an amine protecting group reagent, to provide the compound of Formula H or a salt thereof.

[0526] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula H-1 or a salt thereof by a process comprising: (k) reacting a compound of Formula N:or a salt thereof, wherein: R12is -S(O)3R13or -OC(=N)R14; and R13is selected from C1-4alkyl, C1-4haloalkyl, and phenyl optionally substituted with C1-4alkyl; with: an azide, and a third phosphine reagent; to provide a compound of Formula P-1:or a salt thereof; and (l) reacting the compound of Formula P-1 or a salt thereof with an amine protecting group reagent to provide the compound of Formula H-1 or a salt thereof.

[0527] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula H-1 or a salt thereof by a process comprising: (k) reacting a compound of reacting a compound of Formula J:or a salt thereof, with: an azide, a third phosphine reagent, and a third azodicarboxylate; to provide a compound of Formula P-2:or a salt thereof; and (l) reacting the compound of Formula P-2 or a salt thereof, with: a fourth phosphine reagent; and an amine protecting group reagent; to provide the compound of Formula H-1 or a salt thereof.

[0528] In some embodiments of the processes disclosed herein, the process further comprises preparing the compound of Formula J or a salt thereof by a process comprising: (m) reacting a compound of Formula L:or a salt thereof; with: a ninth base, a fourth catalyst; and a compound of Formula M-1 or Formula M-2: M-1 ; M-2 wherein X is a halide; to provide a compound of Formula K: K or a salt thereof; and (n) reacting the compound of Formula K or a salt thereof, with: an enzyme, and a buffer; to provide the compound of Formula J or a salt thereof.

[0529] In some embodiments of the processes disclosed herein, the process further comprises comprising preparing the compound of Formula E by a process comprising: (h) reacting a compound of Formula L:or a salt thereof, with: an alkyl ester, an alkenyl ester or an oxime ester; and an enzyme, to provide a compound of Formula O-4:or a salt thereof; (i) reacting the compound of Formula O-4 or a salt thereof, with: a second phosphine reagent, a second azodicarboxylate, and a compound of Formula R7-NH-NH-R8or methyl (1,3-dioxoisoindolin-2- yl) carbamate; to provide a compound of Formula O-3:or a salt thereof; (j) reacting the compound of Formula O-3 or a salt thereof, wherein R11is selected from C1- 20alkyl, phenyl, and -CH2NH2; with: a twelfth base;to provide a compound of Formula O-2:or a salt thereof; (k) reacting the compound of Formula O-2 or a salt thereof, with: a fifth catalyst, and hydrogen; to provide the compound of Formula O-1: NHR8or a salt thereof; and (l) reacting the compound of Formula O-1 or a salt thereof, with: an amine protecting group reagent, a phosphine reagent, and an azodicarboxylate, to provide the compound of Formula E or a salt thereof. Alternative process for preparing the compound of Formula I

[0530] In some embodiments, provided herein is a process comprising preparing a compound of Formula I:or a salt thereof, wherein a hydroxyl protecting group; comprising: reacting a compound of Formula R-1: or a salt thereof,a methylene reagent, and an eighth acid or a fourteenth base, to provide the compound of Formula I or a salt thereof.

[0531] In some embodiments, the methylene reagent is a formaldehyde reagent or a dihalomethane. In some embodiments, suitable formaldehyde reagents include formaldehyde acetals (e.g., dimethoxymethane, diethoxymethane), formaldehyde solution, paraformaldehyde, and 1,3,5-trioxane. In some embodiments, suitable methylene reagents include dihalomethanes (e.g., dibromomethane, diiodomethane).

[0532] In some embodiments, the methylene reagent is selected from 1,3,5- trioxane, a formaldehyde acetal, formaldehyde, paraformaldehyde, or a dihalomethane. In some embodiments, the methylene reagent is a formaldehyde reagent. In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, a formaldehyde acetal, formaldehyde, and paraformaldehyde. In some embodiments, the methylene reagent is formaldehyde.

[0533] In some embodiments, the compound of Formula R-1 or a salt thereof is reacted with the eighth acid. In some embodiments, suitable eighth acids include carboxylic acids (e.g., oxalic acid, trichloroacetic acid, trifluoroacetic acid), sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, camphorsulfonic acid), Lewis acids (e.g., boron trifluoride methyl etherate, boron trifluoride dibutyl etherate, boron trichloride, boron tribromide, aluminum chloride, aluminum bromide), inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid), or a combination thereof.

[0534] In some embodiments, the eighth acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof. In some embodiments, the eighth acid comprises a sulfonic acid. In some embodiments, the eight acid comprises methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, camphorsulfonic acid, or a combination thereof. In some embodiments, the eighth acid is methanesulfonic acid.

[0535] In some embodiments, the compound of Formula R-1 or a salt thereof is reacted with the fourteenth base. In some embodiments, suitable fourteenth bases include amines (e.g., n-propylamine, triethylamine, N,N-diisopropylethylamine, 1,4- diazabicyclo[2.2.2]octane (DABCO), quinuclidine), amidines (e.g., 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2- n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amides (e.g., lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole), or a combination thereof.

[0536] In some embodiments, the fourteenth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound, or a combination thereof.

[0537] In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is performed in a forty-second solvent. In some embodiments, the forty- second solvent comprises an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert- butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), a nitrile (e.g., acetonitrile, propionitrile, butyronitrile), a hydrocarbon (e.g., toluene, methylcyclohexane, n-heptane, hexanes, limonene), a polar aprotic solvent (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-butyl pyrrolidone (NBP)), an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methyl glutarate, propylene carbonate), a ketone (e.g., acetone, 2-butanone, 4- methyl-2-pentanone), an alcohol (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, iso-amyl alcohol), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or a combination thereof. In some embodiments, the forty-second solvent comprises an ether. In some embodiments, the forty-second solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3- dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or a combination thereof.

[0538] In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C. In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is carried out in a temperature range of from about 50 °C to about 70 °C. In some embodiments, the reacting of the compound of Formula R-1 or a salt thereof is carried out at a temperature of about 65 °C.

[0539] In some embodiments, the process further comprises preparing the compound of Formula R-1 or a salt thereof by a process comprising reacting a compound of Formula R-2 or a salt thereof with a coupling agent and a fifteenth base to provide the compound of Formula R-1 or a salt thereof, as described herein.

[0540] In some embodiments, the process further comprises preparing the compound of Formula R-2 or a salt thereof by a process comprising reacting a compound of Formula A or a salt thereof with a reagent selected from a metal hydroxide, a metal halide, and a trialkylsilyl halide; to provide the compound of Formula R-2 or a salt thereof, as described herein.

[0541] In some embodiments, provided herein is a process for preparing a compound of Formula I: or a salt thereof, whereinhydroxyl protecting group; comprising: (a) reacting a compound of Formula A: or a salt thereof,protecting group, with: a reagent selected from a metal hydroxide, a metal halide, and a trialkylsilyl halide; to provide a compound of Formula R-2:R-2 or a salt thereof;(b) reacting the compound of Formula R-2 or a salt thereof, with: a coupling agent, and a fifteenth base, to provide a compound of Formula R-1with: a methylene reagent, and an eighth acid or a fourteenth base, to provide the compound of Formula I or a salt thereof. Intermediates

[0542] In some embodiments, provided herein are intermediates for the formation of a compound of Formula I (e.g., a compound of Formula I-A) or salts thereof.

[0543] Accordingly, in some embodiments, a compound of Formula I:I or a salt thereof, wherein R1is a hydroxylgroup, is provided.

[0544] In some embodiments, the compound of Formula I or a salt thereof is a compound of formula I-B:or a salt thereof.

[0545] In some embodiments, a compound of Formula II: or a salt thereof, wherein

[0546] In some embodiments, the compound of Formula II or a salt thereof is a compound of formula II-A: or a salt thereof.

[0547] In some embodiments, a compound of Formula III:or a salt thereof, wherein s provided.

[0548] In some embodiments, the compound of Formula III or a salt thereof is a compound of Formula III-A:or a salt thereof.

[0549] In some embodiments, a compound of Formula IV: or a salt thereof, wherein R2is an amine protectinggroup, is provided.

[0550] In some embodiments, the compound of Formula IV or a salt thereof is a compound of Formula IV-A:IV-A or a salt thereof.

[0551] In some embodiments, a compound of Formula V: or a salt thereof, wherein R1R2is an amine protecting group, is provided.

[0552] In some embodiments, the compound of Formula V or a salt thereof is a compound of Formula V-A: or a salt thereof.

[0553] In some embodiments, a compound of Formula VII: or a salt thereof, wherein R1protecting groups and R2is hydrogen or an amine protecting group, is provided.

[0554] In some embodiments, the compound of Formula VII or a salt thereof is a compound of Formula VII-A:or a salt thereof.

[0555] In some embodiments, the compound of Formula VII or a salt thereof is a compound of Formula VII-B:or a salt thereof.

[0556] In some embodiments, a compound of Formula VIII: or a salt thereof, wherein R1protecting groupsand R2is hydrogen or an amine protecting group, is provided.

[0557] In some embodiments, the compound of Formula VIII or a salt thereof is a compound of Formula VIII-A:or a salt thereof.

[0558] In some embodiments, the compound of Formula VIII or a salt thereof is a compound of Formula VIII-B:or a salt thereof.

[0559] In some embodiments, a compound of Formula X: or a salt thereof, whereinhydroxyl protecting groups and R2is hydrogen or an amine protecting group, is provided.

[0560] In some embodiments, the compound of Formula X or a salt thereof is a compound of Formula X-A:or a salt thereof.

[0561] In some embodiments, the compound of Formula X or a salt thereof is a compound of Formula X-B:or a salt thereof.

[0562] In some embodiments, a compound of Formula XI: or a salt thereof, whereinhydroxyl protecting groups, is provided.

[0563] In some embodiments, the compound of Formula XI or a salt thereof is a compound of Formula XI-A:or a salt thereof.

[0564] In some embodiments, a compound of Formula XII:XII or a salt thereof, wherein R1is a hydroxyl protecting group, is provided.

[0565] In some embodiments, the compound of Formula XII or a salt thereof is a compound of Formula XII-A:or a salt thereof.

[0566] In some embodiments, a compound of Formula A: or a salt thereof,from hydrogen and a hydroxyl protecting group, is provided.

[0567] In some embodiments, the compound of Formula A or a salt thereof is a compound of Formula A-1:or a salt thereof.

[0568] In some embodiments, a compound of Formula R-1:or a salt thereof, wherein R1hydroxyl protecting group, is provided.

[0569] In some embodiments, the compound of Formula R-1 or a salt thereof is a compound of Formula R-1-A: or a salt thereof.

[0570] In some embodiments, provided herien is a compound of Formula R-2: or a salt thereof, wherein protecting group,is provided.

[0571] In some embodiments, the compound of Formula R-2 or a salt thereof is a compound of Formula R-2-A:R-2-A or a salt thereof.

[0572] In some embodiments, a compound of Formula Q-1: or a salt thereof, wherein groups, is provided.

[0573] In some embodiments, the compound of Formula Q-1 or a salt thereof is a compound of Formula Q-1-A: or a salt thereof.

[0574] In some embodiments, a compound of Formula Q-2: or a salt thereof, is provided.

[0575] In some embodiments, a compound of Formula C:or a salt therof, is provided.

[0576] In some embodiments, a compound of Formula D:or a salt therof, wherein: R5is selected from hydrogen and R9, wherein R9is an amine protecting group; and R7and R8are each independently an amine protecting group; is provided.

[0577] In some embodiments, the compound of Formula D or a salt thereof is a compound of Formula D-1:or a salt thereof.

[0578] In some embodiments, the compound of Formula D or a salt thereof is a compound of Formula D-2:or a salt thereof.

[0579] In some embodiments, a compound of Formula E:or a salt therof, wherein: R9is an amine protecting group and R10is hydrogen; or optionally: R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group; is provided.

[0580] In some embodiments, a compound of Formula F: or a salt therof, wherein:R9is an amine protecting group and R10is hydrogen; or optionally: R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group; is provided.

[0581] In some embodiments, the compound of Formula F or a salt thereof is a compound of Formula F-1:or a salt thereof.

[0582] In some embodiments, the compound of Formula F is a compound of Formula F-2:or a salt thereof.

[0583] In some embodiments, a compound of Formula G:or a salt therof, wherein: R9is an amine protecting group and R10is hydrogen; or optionally: R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group; is provided.

[0584] In some embodiments, the compound of Formula G or a salt thereof is a compound of Formula G-1:or a salt thereof.

[0585] In some embodiments, a compound of Formula H:or a salt therof, wherein: R9is an amine protecting group and R10is hydrogen; or optionally: R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group; and R11is selected from C1-20alkyl, phenyl, and -CH2NH2; is provided.

[0586] In some embodiments, the compound of Formula H or a salt thereof is a compound of Formula H-1: or a salt thereof.

[0587] In some embodiments, the compound of Formula H-1 or a salt thereof is a compound of Formula H-1-A:or a salt thereof.

[0588] In some embodiments, the compound of Formula H or a salt thereof is a compound of Formula H-2:or a salt thereof.

[0589] In some embodiments, a compound of Formula J: J or a salt therof, wherein R11is selected from C1-20alkyl, phenyl, and -CH2NH2; is provided.

[0590] In some embodiments, a compound of Formula N:or a salt therof, wherein: R11is selected from C1-20alkyl, phenyl, and -CH2NH2; R12is -S(O)3R13or -OC(=N)R14; R13is selected from C1-4alkyl, C1-4haloalkyl, and phenyl optionally substituted with C1-4alkyl; and R14is C1-4haloalkyl; is provided.

[0591] In some embodiments, a compound of Formula P-1:or a salt therof, wherein: R11is selected from C1-20alkyl, phenyl, and -CH2NH2; is provided.

[0592] In some embodiments, a compound of Formula P-2:or a salt therof, wherein: R11is selected from C1-20alkyl, phenyl, and -CH2NH2; is provided.

[0593] In some embodiments, a compound of Formula K:or a salt therof, is provided.

[0594] In some embodiments, a compound of Formula O-1: NHR8O-1 or a salt therof, wherein R7and R8are each independently an amine protecting group, is provided.

[0595] In some embodiments, a compound of Formula O-2:or a salt therof, wherein R7and R8are each independently an amine protecting group, is provided.

[0596] In some embodiments, a compound of Formula O-3:or a salt therof, wherein: R7and R8are each independently an amine protecting group; and R11is selected from C1-20alkyl, phenyl, and -CH2NH2; is provided.

[0597] In some embodiments, a compound of Formula O-4:or a salt therof, wherein R11is selected from C1-20alkyl, phenyl, and -CH2NH2; is provided.

[0598] In some embodiments, a compound of Formula W:or a salt therof, wherein: R9is an amine protecting group and R10is hydrogen; or optionally: R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group; is provided.

[0599] In some embodiments, the compound of Formula W or a salt thereof is a compound of Formula W-1:or a salt therof.

[0600] In some embodiments of the processes and compounds disclosed herein, R1is selected from C1-4alkyl, benzyl, and -COOR4; wherein R4is selected from C1-4alkyl and phenyl. In some embodiments, R1is selected from methyl, ethyl, benzyl, acetate, propionate, and benzoate. In some embodiments, R1is selected from C1-4alkyl and benzyl. In some embodiments, R1is C1-4alkyl. In some embodiments, R1is selected from methyl, ethyl, and benzyl. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is benzyl. In some embodiments, R1is -COOR4. In some embodiments, R4is C1-4alkyl. In some embodiments, R4is methyl or ethyl. In some embodiments, R4is phenyl.

[0601] In some embodiments of the processes and compounds disclosed herein, R1is selected from hydrogen, C1-4alkyl, and benzyl. In some embodiments, R1is hydrogen. In some embodiments, R1is C1-4alkyl. In some embodiments, R1is selected from hydrogen, methyl, ethyl, and benzyl.

[0602] In some embodiments of the processes and compounds disclosed herein, R2is tert-butyloxycarbonyl.

[0603] In some embodiments of the compounds disclosed herein, R3is selected from C1-4alkyl and benzyl. In some embodiments, R3is selected from methyl, ethyl, and benzyl. In some embodiments, R3is C1-4alkyl. In some embodiments, R3is selected from methyl and ethyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is benzyl.

[0604] In some embodiments of the processes and compounds disclosed herein, R3Ais selected from C1-4alkyl, C1-4haloalkyl, and benzyl. In some embodiments, R3Ais selected from methyl, ethyl, isopropyl, trifluoroethyl, and benzyl. In some embodiments, R3Ais C1-4alkyl. In some embodiments, R3Ais selected from methyl, ethyl, and isopropyl. In some embodiments, R3Ais methyl. In some embodiments, R3Ais C1-4haloalkyl. In some embodiments, R3Ais trifluoroethyl. In some embodiments, R3Ais benzyl.

[0605] In some embodiments of the processes and compounds disclosed herein, R3Ais selected from hydrogen, C1-4alkyl, and benzyl. In some embodiments, R3Ais selected from hydrogen, methyl, ethyl, isopropyl, and benzyl.

[0606] In some embodiments of the processes and compounds disclosed herein, R5is hydrogen. In some embodiments, R5is R9. In some embodiments, R5is an amine protecting group. In some embodiments, R5is tert-butyloxycarbonyl.

[0607] In some embodiments of the processes and compounds disclosed herein, R7is tert-butyloxycarbonyl. In some embodiments, R8is tert-butyloxycarbonyl. In some embodiments, R7and R8are tert-butyloxycarbonyl.

[0608] In some embodiments of the processes and compounds disclosed herein, R9is tert-butyloxycarbonyl.

[0609] In some embodiments of the processes and compounds disclosed herein, R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group. In some embodiments of the processes and compounds disclosed herein, R9and R10together with the nitrogen atom to which they are attached form phthalimide.

[0610] In some embodiments of the processes and compounds disclosed herein, R11is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl, and - CH2NH2. In some embodiments, R11is C1-20alkyl. In some embodiments, R11is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, and pentadecyl. In some embodiments, R11is methyl. In some embodiments, R11is phenyl. In some embodiments, R11is -CH2NH2.

[0611] In some embodiments of the processes and compounds disclosed herein, R12is -S(O)3R13. In some embodiments, R13is selected from tolyl, methyl, and trifluoromethyl. In some embodiments, R13is C1-4alkyl. In some embodiments, R13is methyl.

[0612] In some embodiments of the processes and compounds disclosed herein, R12is -OC(=N)R14. In some embodiments, R14is selected from trichloromethyl and tribromomethyl. EXAMPLES

[0613] Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow. The following examples are merely illustrative, and not intended to limit this disclosure in any way. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and carried forth in the next synthetic step.Example 1: Preparation of methyl 3-methoxy-4-oxo-5-((2,4,6- trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (X-B)

[0614] Dimethyl oxalate (5 equiv.) was charged to reactor A followed by N,N- dimethylacetamide (12 V). The mixture was agitated at about 22 °C for about 30 mins. 25% sodium methoxide in methanol (1.5 equiv.) was charged to the reaction mixture followed by a rinse forward with N,N-dimethylacetamide (0.1 V). The reaction mixture was cooled to about 10 °C. (E)-2-((dimethylamino)methylene)-4-methoxy-3-oxo-N- (2,4,6-trifluorobenzyl)butanamide (XII-A, 1.00 equiv. scaling factor) was charged to reactor A followed by N,N-dimethylacetamide (0.5 V). The contents were agitated for about 2 hrs at about 10 °C. 2,2,2-trifluoroethanol (1.2 V) was added to the reactor A followed by N,N-dimethylacetamide (0.1 V). The contents agitated for about 16 h at about 10 °C. 10 wt.% Hydrochloric acid (5 V) was charged to reactor B followed by dichloromethane (15 V) and the contents were adjusted to about 20 °C. The contents in reactor A were slowly charged to reactor B maintaining pot temperature about 30 °C. The contents of reactor B were agitated for about 30 mins and then allowed to settle for about 30 mins. The bottom organic layer was transferred to reactor A and washed with water 2 x (5 V). The organic layer was distilled to about 8 V then solvent swapped to 2-propanol (12 V). The reactor contents were held to about 45 °C for about 1 hr then cooled to about 0 °C over about 3 hrs. The reactor contents were filtered and dried at about 50 °C to afford compound X-B.1H NMR (400 MHz, DMSO-d6) δ 9.38 (t, J = 5.8 Hz, 1H), 8.91 (s, 1H), 7.21 (m, 2H), 4.55 (d, J = 5.8 Hz, 2H), 3.89 (s, 3H), 3.86 (s, 3H).Example 2: Preparation of methyl 1-((tert-butoxycarbonyl)amino)-3-methoxy-4-oxo-5- ((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (VIII-B), and sodium bicarbonate (2 equiv) were charged to reactor A followed by methanol (6 V) and water (0.4 V). The mixture was agitated at about 45 °C for about 3 hours. The contents of the reactor were distilled to 6 V and the temperature was adjusted to about 35 °C. Water (6 V) was charged over about 1 hour and the temperature was adjusted to about 22 °C over about 1 hour and stirred for about 1 hour. The reactor contents were filtered, washed with water (3 V),...

Claims

What is claimed is:

1. A process for preparing a compound of Formula I: or a salt thereof, wherein hydroxyl protecting group;comprising reacting a compound of Formula II: or a salt thereof,with a first catalyst to provide the compound of Formula I or a salt thereof.

2. The process of claim 1, wherein R1is selected from hydrogen, C1-4alkyl, and benzyl.

3. The process of claim 1 or 2, wherein R1is selected from hydrogen, methyl, ethyl, and benzyl.

4. The process of any one of claims 1-3, wherein R1is methyl.

5. The process of any one of claims 1-4, wherein the first catalyst is a metathesis catalyst.

6. The process of any one of claims 1-5, wherein the first catalyst is selected from a ruthenium-based catalyst, a molybdenum-based catalyst, and a tungsten-based catalyst.

7. The process of any one of claims 1-6, wherein the first catalyst is a ruthenium- based catalyst.

8. The process of any one of claims 1-7, wherein the first catalyst is selected from Hoveyda-Grubbs second generation catalyst, Hoveyda-Grubbs first generation catalyst, Zhan 1B, nitro Grela, M721, M203, and M730.

9. The process of any one of claims 1-8, wherein the first catalyst is Hoveyda- Grubbs second generation catalyst.

10. The process of any one of claims 1-9, wherein a molar ratio of the compound of Formula II or a salt thereof to the first catalyst is from about 1:0.001 to about 1:0.

05.

11. The process of any one of claims 1-10, wherein the reacting is performed in the presence of a first additive.

12. The process of any one of claims 1-11, wherein the first additive comprises dimethyl maleate, 1,4-benzoquinone, 6-dichloro-1,4-benzoquinone, 2-chloro-1,4- benzoquinone, tetrafluoro-1,4-benzoquinone, 2-methylbenzoquinone, dimethyl fumarate, maleic acid, fumaric acid, maleic anhydride, trans-methyl cinnamate, acetic acid, trifluoroacetic acid, or a combination thereof.

13. The process of any one of claims 1-12, wherein the first additive comprises dimethyl maleate.

14. The process of any one of claims 1-13, wherein the reacting is performed in a first solvent comprising ethyl acetate.

15. The process of any one of claims 1-14, wherein the reacting is carried out in a temperature range of from about 20 °C to about 120 °C.

16. The process of any one of claims 1-15, wherein R1is a hydroxyl protecting group; and wherein the process further comprises deprotecting the compound of Formula I, or a salt thereof; to provide a compound of Formula I-A:or a salt thereof.

17. The process of claim 16, wherein deprotecting the compound of Formula I or a salt thereof comprises treating the compound of Formula I or a salt thereof with a first deprotecting agent.

18. The process of claim 17, wherein the first deprotecting agent is selected from a metal halide, a hydrogen halide, a boron reagent, an aluminum reagent, a titanium reagent, a pyridinium halide salt, an ammonium halide, and a silyl halide.

19. The process of claim 17 or 18, wherein the first deprotecting agent is a metal halide.

20. The process of any one of claims 17-19, wherein the first deprotecting agent is lithium chloride.

21. The process of any one of claims 17-20, wherein the deprotecting the compound of Formula I or a salt thereof is performed in a second solvent comprising N-methyl-2- pyrrolidone.

22. The process of any one of claims 17-21, wherein the deprotecting the compound of Formula I or a salt thereof is carried out in a temperature range of from about 0 °C to about 130 °C.

23. The process of any one of claims 1-22, further comprising preparing the compound of Formula II or a salt thereof by a process comprising: reacting a compound of Formula III: or a salt thereof, witha methylene reagent, and a first acid or a first base, to provide the compound of Formula II or a salt thereof.

24. The process of claim 23, wherein the methylene reagent is a formaldehyde reagent or a dihalomethane.

25. The process of claim 23 or 24, wherein the methylene reagent is selected from 1,3,5-trioxane, a formaldehyde acetal, formaldehyde, paraformaldehyde, or a dihalomethane.

26. The process of any one of claims 23-25, wherein the methylene reagent is 1,3,5- trioxane.

27. The process of any one of claims 23-26, wherein the compound of Formula III or a salt thereof is reacted with the first acid.

28. The process of any one of claims 23-27, wherein the first acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof.

29. The process of any one of claims 23-28, wherein the first acid is trifluoroacetic acid.

30. The process of any one of claims 23-26, wherein the compound of Formula III or a salt thereof is reacted with the first base.

31. The process of any one of claims 23-26 and 30, wherein the first base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound, or a combination thereof.

32. The process of any one of claims 23-31, wherein the reacting of the compound of Formula III or a salt thereof is performed in a third solvent comprising toluene.

33. The process of any one of claims 23-32, wherein the reacting of the compound of Formula III or a salt thereof is carried out in a temperature range of from about 60 °C to about 100 °C.

34. The process of any one of claims 23-33, further comprising preparing the compound of Formula III or a salt thereof by a process comprising: deprotecting a compound of Formula IV:or a salt thereof, wherein to provide the compound of Formula III or a salt thereof.

35. The process of claim 34, wherein R2is tert-butyloxycarbonyl.

36. The process of claim 34 or 35, wherein deprotecting the compound of Formula IV or a salt thereof comprises treating the compound of Formula IV or a salt thereof with a second acid.

37. The process of claim 36, wherein the second acid comprises a sulfonic acid, an inorganic acid, an organic acid, an acid chloride, a Lewis acid, or a combination thereof.

38. The process of claim 36 or 37, wherein the second acid comprises methanesulfonic acid.

39. The process of any one of claims 34-38, wherein deprotecting the compound of Formula IV or a salt thereof is performed in a fourth solvent comprising cyclopentyl methyl ether.

40. The process of any one of claims 34-39, wherein deprotecting the compound of Formula IV or a salt thereof is carried out in a temperature range of from about 0 °C to about 120 °C.

41. The process of any one of claims 34-40, further comprising preparing the compound of Formula IV or a salt thereof by a process comprising:reacting a compound of Formula V:or a salt thereof, with: a compound of Formula VI:wherein Y is an anion or a salt, a coupling agent, and a second base, to provide the compound of Formula V or a salt thereof.

42. The process of claim 41, wherein Y is selected from tosylate, mesylate, and HCl salt.

43. The process of claim 41 or 42, wherein Y is tosylate.

44. The process of any one of claims 41-43, wherein the coupling agent comprises 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), an acid chloride, an acid anhydride, a carbonyl diimidazole, an activated ester, or a combination thereof.

45. The process of any one of claims 41-44, wherein the coupling agent is HATU.

46. The process of any one of claims 41-45, wherein the second base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a hydroxide, an alkoxide, a basic aromatic compound, or a combination thereof.

47. The process of any one of claims 41-46, wherein the second base comprises an amine.

48. The process of any one of claims 41-47, wherein the second base is N-methyl morpholine.

49. The process of any one of claims 41-48, wherein the reacting of the compound of Formula V or a salt thereof is performed in a fifth solvent comprising N,N- dimethylacetamide and cyclopentyl methyl ether.

50. The process of any one of claims 41-49, wherein the reacting of the compound of Formula V or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C.

51. The process of any one of claims 41-50, further comprising preparing the compound of Formula V or a salt thereof by a process comprising: reacting a compound of Formula VII:or a salt thereof, wherein R3is a hydroxyl protecting group; with a first reagent to provide the compound of Formula V or a salt thereof.

52. The process of claim 51, wherein R3is selected from C1-4alkyl and benzyl.

53. The process of claim 51 or 52, wherein R3is selected from methyl, ethyl, and benzyl.

54. The process of any one of claims 51-53, wherein R3is methyl.

55. The process of any one of claims 51-54, wherein the first reagent is selected from a third base and a hydrolase enzyme.

56. The process of any one of claims 51-55, wherein the first reagent is the third base.

57. The process of any one of claims 51-56, wherein the third base comprises an amine, an amidine, a guanidine, a carbonate, a phosphate, a hydroxide, an alkoxide, an amide, or a combination thereof.

58. The process of any one of claims 51-57, wherein the third base is lithium hydroxide.

59. The process of any one of claims 51-58, wherein the reacting of the compound of Formula VII or a salt thereof is performed in a sixth solvent comprising cyclopentyl methyl ether, methanol, and water.

60. The process of any one of claims 51-59, wherein the reacting of the compound of Formula VII or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C.

61. The process of any one of claims 51-60, further comprising preparing the compound of Formula VII or a salt thereof by a process comprising: reacting a compound of Formula VIII:or a salt thereof, with: a compound of Formula IX:or a salt thereof, a phosphorus-based reagent, and an azodicarboxylate, to provide the compound of Formula VII or a salt thereof.

62. The process of claim 61, wherein the phosphorus-based reagent is selected from a tri-aryl phosphine, a tri-alkyl phosphine, and a phosphorane.

63. The process of claim 61 or 62, wherein the phosphorus-based reagent is triphenylphosphine.

64. The process of any one of claims 61-63, wherein the azodicarboxylate is selected from diisopropyl azodicarboxylate, di-tertbutyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1- azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate.

65. The process of any one of claims 61-64, wherein the azodicarboxylate is diisopropyl azodicarboxylate.

66. The process of any one of claims 61-65, wherein the reacting of the compound of Formula VIII or a salt thereof is performed in a seventh solvent comprising 2- methyltetrahydrofuran.

67. The process of any one of claims 61-66, wherein the reacting of the compound of Formula VIII or a salt thereof is carried out in a temperature range of from about 0 °C to about 50 °C.

68. The process of any one of claims 51-60, further comprising preparing the compound of Formula VII or a salt thereof by a process comprising: reacting a compound of Formula VIII:or a salt thereof, with: a second reagent comprising a crotyl group or an allyl group, a second catalyst, and a sixth base to provide the compound of Formula VII or a salt thereof.

69. The process of claim 68, wherein the second reagent is selected from a crotyl carbonate, a crotyl ester, a crotyl halide, crotyl alcohol, a 1-methylallyl ester, a 1-methyl allyl carbonate, a 1-methylallylhalide, and 3-buten-2-ol.

70. The process of claim 68 or 69, wherein the second reagent is a crotyl carbonate.

71. The process of any one of claims 68-70, wherein the second reagent is crotyl methyl carbonate.

72. The process of any one of claims 68-71, wherein the second catalyst is a transition metal catalyst.

73. The process of any one of claims 68-72, wherein the second catalyst is formed in situ from a precatalyst and a ligand.

74. The process of claim 73, wherein the precatalyst is selected from an iridium compound, a palladium compound, a cobalt compound, and a rhodium compound.

75. The process of claim 73 or 74, wherein the precatalyst is bis(1,5- cyclooctadiene)diiridium(I) dichloride.

76. The process of any one of claims 73-75, wherein a molar ratio of the compound of Formula VIII or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.

10.

77. The process of any one of claims 73-76, wherein the ligand is selected from a phosphoramidite and a Trost ligand.

78. The process of any one of claims 73-77, wherein the ligand is (S,S,S)-(+)-(3,5- dioxa-4-phosphacyclohepta[2,1-a:3,4-a’]dinaphthalene-4-yl)bis(1-phenylethyl)amine.

79. The process of any one of claims 68-78, wherein the sixth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound.

80. The process of any one of claims 68-79, wherein the sixth base is an amine.

81. The process of any one of claims 68-80, wherein the sixth base is n-propylamine.

82. The process of any one of claims 68-81, wherein the reacting of the compound of Formula VIII or a salt thereof is performed in a twelfth solvent comprising N,N- dimethylacetamide.

83. The process of any one of claims 68-82, wherein the reacting of the compound of Formula VIII or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C.

84. The process of any one of claims 61-83, further comprising preparing the compound of Formula VIII or a salt thereof by a process comprising: reacting a compound of Formula X:or a salt thereof, with a compound of Formula NH2NHR2or a salt thereof, to provide the compound of Formula VIII or a salt thereof.

85. The process of claim 84, wherein the reacting of the compound of Formula X or a salt thereof is carried out in the presence of a fourth base.

86. The process of claim 84 or 85, wherein the fourth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound, or a combination thereof.

87. The process of any one of claims 84-86, wherein the fourth base is sodium bicarbonate.

88. The process of any one of claims 84-87, wherein the reacting of the compound of Formula X or a salt thereof is performed in an eighth solvent comprising methanol and water.

89. The process of any one of claims 84-88, wherein the reacting of the compound of Formula X or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C.

90. The process of any one of claims 84-89, further comprising preparing the compound of Formula X or a salt thereof by a process comprising: reacting a compound of Formula XII:or a salt thereof, with: a promoter, a dialkyl oxalate, and a fifth base, to provide the compound of Formula X or a salt thereof.

91. The process of claim 90, wherein the promoter comprises a carboxylic acid, a sulfonic acid, a halogenated alcohol, a Lewis acid, an inorganic acid, or a combination thereof.

92. The process of claim 90 or 91, wherein the promoter comprises a halogenated alcohol.

93. The process of any one of claims 90-92, wherein the promoter is 2,2,2- trifluoroethanol.

94. The process of any one of claims 90-93, wherein the reacting of the compound of Formula XII or a salt thereof is carried out in the presence of a third acid.

95. The process of claim 94, wherein the third acid is an inorganic acid.

96. The process of claim 94 or 95, wherein the third acid is hydrochloric acid.

97. The process of any one of claims 90-96, wherein the dialkyl oxalate is selected from dimethyl oxalate and diethyl oxalate.

98. The process of any one of claims 90-97, wherein the dialkyl oxalate is dimethyl oxalate.

99. The process of any one of claims 90-98, wherein the fifth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an alkyl lithium reagent, an aryl lithium reagent, an amide, a basic aromatic compound, or a combination thereof.

100. The process of any one of claims 90-99, wherein the fifth base comprises a metal alkoxide.

101. The process of any one of claims 90-100, wherein the fifth base is sodium alkoxide.

102. The process of any one of claims 90-101, wherein the reacting of the compound of Formula XII or a salt thereof is performed in a tenth solvent comprising N,N- dimethylacetamide.

103. The process of any one of claims 90-102, wherein the reacting of the compound of Formula XII or a salt thereof is carried out in a temperature range of from about -10 °C to about 50 °C.

104. The process of any one of claims 90-103, further comprising preparing the compound of Formula XII or a salt thereof by a process comprising: reacting a compound of Formula XIII:or a salt thereof, with N,N-dimethylformamide dimethyl acetal, to provide the compound of Formula XII or a salt thereof.

105. A process for preparing a compound of Formula I: or a salt thereof, whereinhydroxyl protecting group, comprising: (a) reacting a compound of Formula VII:VII or a salt thereof, wherein R2is an amine protecting group and R3is a hydroxyl protecting group, with a first reagent to provide a compound of Formula V: or a salt thereof;(b) reacting the compound of Formula V or a salt thereof, with: a compound of Formula VI: wherein Y is an aniona coupling agent, and a second base, to provide a compound of Formula IV: or a salt thereof;(c) deprotecting the compound of Formula IV or a salt thereof to provide a compound of Formula III:III or a salt thereof;(d) reacting the compound of or a salt thereof, with a methylene reagent, and a first acid or a first base, to provide a compound of Formula II: or a salt thereof;(e) reacting the compound of Formula II or a salt thereof; with a first catalyst to provide the compound of Formula I or a salt thereof.

106. A process for preparing a compound of Formula I-A:or a salt thereof, comprising: (a) reacting a compound of Formula VII:or a salt thereof, wherein R1and R3are each independently hydroxyl protecting groups, and R2is an amine protecting group, with a first reagent to provide a compound of Formula V:or a salt thereof; (b) reacting the compound of Formula V or a salt thereof, with: a compound of Formula VI: wherein Y is ana coupling agent, and a second base, to provide a compound of Formula IV: or a salt thereof;(c) deprotecting the compound of Formula IV or a salt thereof to provide a compound of Formula III:or a salt thereof; (d) reacting the compound of Formula III or a salt thereof, witha methylene reagent, and a first acid or a first base, to provide a compound of Formula II: or a salt thereof;(e) reacting the compound of Formula II or a salt thereof; with a first catalyst to provide a compound of Formula I: or a salt thereof;(f) deprotecting the compound of Formula I, or a salt thereof; to provide the compound of Formula I-A or a salt thereof.

107. A process for preparing a compound of Formula II: or a salt thereof,(a) reacting a compound of Formula VII:or a salt thereof, wherein R1and R3are each independently hydroxyl protecting groups, and R2is an amine protecting group, with a first reagent to provide a compound of Formula V: or a salt thereof;(b) reacting the compound of Formula V or a salt thereof, with: a compound of Formula VI:wherein Y is an anion or salt, a coupling agent, and a second base, to provide a compound of Formula IV:or a salt thereof;(c) deprotecting the compound of Formula IV or a salt thereof to provide a compound of Formula III: or a salt thereof; and(d) reacting the compound of Formula III or a salt thereof, with a methylene reagent, and a first acid or a first base, to provide the compound of Formula II or a salt thereof.

108. A process for preparing a compound of Formula III:or a salt thereof, comprising: (a) reacting a compound of Formula VII:or a salt thereof, wherein R1and R3are each independently hydroxyl protecting groups, and R2is an amine protecting group, with a first reagent to provide a compound of Formula V:or a salt thereof; (b) reacting the compound of Formula V or a salt thereof, with: a compound of Formula VI: wherein Y is ana coupling agent, and a second base, to provide a compound of Formula IV: or a salt thereof;(c) deprotecting the compound of Formula IV or a salt thereof to provide the compound of Formula III or a salt thereof.

109. A process for preparing a compound of Formula IV:or a salt thereof, comprising: (a) reacting a compound of Formula VII: or a salt thereof, wherein hydroxyl protecting groups,and R2is an amine protecting group, with a first reagent to provide a compound of Formula V: or a salt thereof; and(b) reacting the compound of Formula V or a salt thereof, with: a compound of Formula VI:wherein Y is an anion or salt, a coupling agent, and a second base, to provide the compound of Formula IV or a salt thereof.

110. A process for preparing a compound of Formula V:or a salt thereof, comprising: reacting a compound of Formula VII:or a salt thereof, wherein R1and R3are each independently hydroxyl protecting groups, and R2is an amine protecting group, with a first reagent to provide the compound of Formula V or a salt thereof.

111. The process of any one of claims 106-110, wherein the compound of Formula VII or a salt thereof is prepared by a process comprising: (a) reacting a compound of Formula XIII:or a salt thereof, wherein R1is a hydroxyl protecting group, with N,N-dimethylformamide dimethyl acetal, to provide a compound of Formula XII:or a salt thereof; (b) reacting the compound of Formula XII or a salt thereof, with: a promoter, a dialkyl oxalate, and a fifth base, to provide a compound of Formula X: or a salt thereof;(c) reacting the compound of Formula X or a salt thereof, with a compound of Formula NH2NHR2 or a salt thereof, to provide the compound of Formula VIII:or a salt thereof; (d) reacting the compound of Formula VIII or a salt thereof, with: a compound of Formula IX:or a salt thereof, a phosphorus-based reagent, and an azodicarboxylate, to provide the compound of Formula VII or a salt thereof.

112. The process of any one of claims 106-110, wherein the compound of Formula VII or a salt thereof is prepared by a process comprising: (a) reacting a compound of Formula XIII:or a salt thereof, wherein R1is a hydroxyl protecting group, with N,N-dimethylformamide dimethyl acetal, to provide a compound of Formula XII:or a salt thereof; (b) reacting the compound of Formula XII or a salt thereof, with: a promoter, a dialkyl oxalate, and a fifth base, to provide a compound of Formula X:or a salt thereof; (c) reacting the compound of Formula X or a salt thereof, with a compound of Formula NH2NHR2 or a salt thereof, to provide the compound of Formula VIII:or a salt thereof; and (d) reacting the compound of Formula VIII or a salt thereof, with: a second reagent comprising a crotyl group or an allyl group, a second catalyst, and a sixth base to provide the compound of Formula VII or a salt thereof.

113. A compound of Formula I: or a salt thereof, wherein114. A compound of Formula II:or a salt thereof, wherein R1is a hydroxyl protecting group.

115. A compound of Formula III:or a salt thereof, wherein R1is a hydroxyl protecting group.

116. A compound of Formula IV: or a salt thereof,R2is an amine protecting group.

117. A compound of Formula V:or a salt thereof, wherein R1is a hydroxyl protecting group and R2is an amine protecting group.

118. A compound of Formula VII:or a salt thereof, wherein R1and R3are each independently hydroxyl protecting groups and R2is hydrogen or an amine protecting group.

119. A compound of Formula VIII:or a salt thereof, wherein R1and R3are each independently hydroxyl protecting groups and R2is hydrogen or an amine protecting group.

120. The compound of any one of claims 113-119, wherein R1is selected from C1-4alkyl and benzyl.

121. The compound of any one of claims 113-120, wherein R1is methyl.

122. The compound of any one of claims 116-119, wherein R2is tert-butoxycarbonyl.

123. The compound of claim 118 or 119, wherein R3is selected from C1-4alkyl and benzyl.

124. The compound of any one of claims 118, 119, and 123, wherein R3is methyl.

125. The process of any one of claims 23-33, further comprising preparing the compound of Formula III or a salt thereof by a process comprising: reacting a compound of Formula VII-A:or a salt thereof, with a first reagent to hydrolyze the compound of Formula VII-A; and reacting the hydrolyzed compound of Formula VII-A with: a compound of Formula VI: wherein Y is an aniona coupling agent, and a second base, to provide the compound of Formula III or a salt thereof.

126. The process of claim 125, wherein the first reagent is selected from a third base and a hydrolase enzyme.

127. The process of claim 126, wherein the first reagent is the third base.

128. The process of claim 126 or 127, wherein the third base comprises an amine, an amidine, a guanidine, a carbonate, a phosphate, a hydroxide, an alkoxide, an amide, or a combination thereof.

129. The process of any one of claims 126-128, wherein the third base is lithium hydroxide.

130. The process of any one of claims 125-129, wherein Y is selected from tosylate, mesylate, and HCl salt.

131. The process of any one of claims 125-130, wherein Y is tosylate.

132. The process of any one of claims 125-131, wherein the coupling agent comprises 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), an acid chloride, an acid anhydride, a carbonyl diimidazole, an activated ester, or a combination thereof.

133. The process of any one of claims 125-132, wherein the coupling agent is HATU.

134. The process of any one of claims 125-133, wherein the second base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a hydroxide, an alkoxide, a basic aromatic compound, or a combination thereof.

135. The process of any one of claims 125-134, wherein the second base comprises an amine.

136. The process of any one of claims 125-135, wherein the second base is N-methyl morpholine.

137. The process of any one of claims 125-136, further comprising preparing the compound of Formula VII-A or a salt thereof by a process comprising: reacting a compound of Formula VIII-A:or a salt thereof, with: a second reagent comprising a crotyl group or an allyl group, a second catalyst, and a sixth base, to provide the compound of Formula VII-A or a salt thereof.

138. The process of claim 137, wherein the second reagent is selected from a crotyl carbonate, a crotyl ester, a crotyl halide, crotyl alcohol, a 1-methylallyl ester, a 1-methyl allyl carbonate, a 1-methylallylhalide, and 3-buten-2-ol.

139. The process of claim 137 or 138, wherein the second reagent is a crotyl carbonate.

140. The process of any one of claims 137-139, wherein the second reagent is crotyl methyl carbonate.

141. The process of any one of claims 137-140, wherein the second catalyst is a transition metal catalyst.

142. The process of any one of claims 137-141, wherein the second catalyst is formed in situ from a precatalyst and a ligand.

143. The process of claim 142, wherein the precatalyst is selected from an iridium compound, a palladium compound, a cobalt compound, and a rhodium compound.

144. The process of claim 142 or 143, wherein the precatalyst is bis(1,5- cyclooctadiene)diiridium(I) dichloride.

145. The process of any one of claims 142-144, wherein a molar ratio of the compound of Formula VIII-A or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.10.

146. The process of any one of claims 142-145, wherein the ligand is selected from a phosphoramidite and a Trost ligand.

147. The process of any one of claims 142-146, wherein the ligand is (S,S,S)-(+)-(3,5- dioxa-4-phosphacyclohepta[2,1-a:3,4-a’]dinaphthalene-4-yl)bis(1-phenylethyl)amine.

148. The process of any one of claims 137-147, wherein the sixth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound.

149. The process of any one of claims 137-148, wherein the sixth base is an amine.

150. The process of any one of claims 137-149, wherein the sixth base is 1,4- diazabicyclo[2.2.2]octane (DABCO).

151. The process of any one of claims 137-150, wherein the reacting of the compound of Formula VIII-A or a salt thereof is performed in a twelfth solvent comprising N,N- dimethylacetamide.

152. The process of any one of claims 137-151, wherein the reacting of the compound of Formula VIII-A or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C.

153. A process for preparing a compound of Formula I-A:or a salt thereof, comprising deprotecting a compound of Formula I: or a salt thereof, wherein to provide the compound ofFormula I-A or a salt thereof.

154. The process of claim 153, wherein R1is selected from C1-4alkyl, benzyl, and - COOR4; wherein R4is selected from C1-4alkyl and phenyl.

155. The process of claims 153 or 154, wherein R1is selected from methyl, ethyl, benzyl, acetate, propionate, and benzoate.

156. The process of any one of claims 153-155, wherein R1is selected from C1-4alkyl and benzyl.

157. The process of any one of claims 153-156, wherein R1is selected from methyl, ethyl, and benzyl.

158. The process of any one of claims 153-157, wherein R1is methyl.

159. The process of any one of claims 153-158, wherein deprotecting the compound of Formula I or a salt thereof comprises treating the compound of Formula I or a salt thereof with a first deprotecting agent.

160. The process of claim 159, wherein the first deprotecting agent is selected from a metal halide, a hydrogen halide, a boron reagent, an aluminum reagent, a titanium reagent, a pyridinium halide salt, an ammonium halide, and a silyl halide.

161. The process of claim 159 or 160, wherein the first deprotecting agent is a metal halide.

162. The process of any one of claims 159-161, wherein the first deprotecting agent is lithium chloride.

163. The process of any one of claims 159-161, wherein the first deprotecting agent is calcium bromide.

164. The process of any one of claims 153-163, wherein the deprotecting the compound of Formula I or a salt thereof is performed in a second solvent comprising N- methyl-2-pyrrolidone.

165. The process of any one of claims 153-164, wherein the deprotecting the compound of Formula I or a salt thereof is carried out in a temperature range of from about 0 °C to about 130 °C.

166. The process of any one of claims 153-165, further comprising preparing the compound of Formula I or a salt thereof by a process comprising: reacting a compound of Formula A: or a salt thereof,a methylene reagent, and a first acid or a first base, to provide the compound of Formula I or a salt thereof.

167. The process of claim 166, wherein R3Ais selected from C1-4alkyl, C1-4haloalkyl, and benzyl.

168. The process of claim 166 or 167, wherein R3Ais selected from methyl, ethyl, isopropyl, trifluoroethyl, and benzyl.

169. The process of any one of claims 166-168, wherein R3Ais methyl.

170. The process of any one of claims 166-169, wherein the methylene reagent is a formaldehyde reagent or a dihalomethane.

171. The process of any one of claims 166-170, wherein the methylene reagent is selected from 1,3,5-trioxane, a formaldehyde acetal, formaldehyde, paraformaldehyde, or a dihalomethane.

172. The process of any one of claims 166-171, wherein the methylene reagent is 1,3,5-trioxane.

173. The process of any one of claims 166-172, wherein the compound of Formula A or a salt thereof is reacted with the first acid.

174. The process of any one of claims 166-173, wherein the first acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof.

175. The process of any one of claims 166-174, wherein the first acid is a carboxylic acid.

176. The process of any one of claims 166-175, wherein the first acid is trifluoroacetic acid.

177. The process of any one of claims 166-173, wherein the compound of Formula A or a salt thereof is reacted with the first base.

178. The process of any one of claims 166-173 and 177, wherein the first base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound, or a combination thereof.

179. The process of any one of claims 166-178, wherein the reacting of the compound of Formula A or a salt thereof is performed in a thirteenth solvent comprising toluene.

180. The process of any one of claims 166-179, wherein the reacting of the compound of Formula A or a salt thereof is carried out in a temperature range of from about 20 °C to about 140 °C.

181. The process of any one of claims 153-165, further comprising preparing the compound of Formula I or a salt thereof by a process comprising: reacting a compound of Formula R-1:or a salt thereof, with:a methylene reagent, and an eighth acid or a fourteenth base, to provide the compound of Formula I or a salt thereof.

182. The process of claim 181, wherein the methylene reagent is a formaldehyde reagent or a dihalomethane.

183. The process of claim 181 or 182, wherein the methylene reagent is selected from 1,3,5-trioxane, a formaldehyde acetal, formaldehyde, paraformaldehyde, or a dihalomethane.

184. The process of any one of claims 181-183, wherein the methylene reagent is formaldehyde.

185. The process of any one of claims 181-183, wherein the methylene reagent is 1,3,5-trioxane.

186. The process of any one of claims 181-185, wherein the compound of Formula R-1 or a salt thereof is reacted with the eighth acid.

187. The process of any one of claims 181-186, wherein the eighth acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof.

188. The process of any one of claims 181-187, wherein the eighth acid is a sulfonic acid.

189. The process of any one of claims 181-188, wherein the eighth acid is methanesulfonic acid.

190. The process of any one of claims 181-187, wherein the eighth acid is an inorganic acid.

191. The process of any one of claims 181-187 and 190, wherein the eighth acid is phosphoric acid.

192. The process of any one of claims 181-185, wherein the compound of Formula R-1 or a salt thereof is reacted with the fourteenth base.

193. The process of any one of claims 181-185 and 192, wherein the fourteenth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound, or a combination thereof.

194. The process of any one of claims 181-193, wherein the reacting of the compound of Formula R-1 or a salt thereof is performed in an eleventh solvent comprising tetrahydrofuran.

195. The process of any one of claims 181-194, wherein the reacting of the compound of Formula R-1 or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C.

196. The process of any one of claims 181-195, further comprising preparing the compound of Formula R-1 or a salt thereof by a process comprising: reacting a compound of Formula R-2:or a salt thereof, with: a coupling agent, and a fifteenth base, to provide the compound of Formula R-1 or a salt thereof.

197. The process of claim 196, wherein the coupling agent comprises comprises 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), an acid chloride, an acid anhydride, a carbonyl diimidazole, an activated ester, an organophosphorus compound, or a combination thereof.

198. The process of claim 197, wherein the coupling agent comprises 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), an acid chloride, an acid anhydride, a carbonyl diimidazole, an activated ester, or a combination thereof.

199. The process of any one of claims 197 or 198, wherein the coupling agent is HATU.

200. The process of any one of claims 197-199, wherein the coupling agent is diphenyl phosphoryl chloride.

201. The process of any one of claims 197-200, wherein the fifteenth base is selected from an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, a basic aromatic compound, or a combination thereof.

202. The process of any one of claims 197-201, wherein the fifteenth base is an amine.

203. The process of any one of claims 197-202, wherein the fifteenth base is N,N- diisopropylethylamine.

204. The process of any one of claims 197-203, wherein the reacting of the compound of Formula R-2 or a salt thereof is performed in a twenty-eighth solvent comprising N,N- dimethylacetamide.

205. The process of any one of claims 197-204, wherein the reacting of the compound of Formula R-2 or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C.

206. The process of any one of claims 197-205, further comprising preparing the compound of Formula R-2 or a salt thereof by a process comprising: reacting a compound of Formula A:or a salt thereof, wherein R3Ais hydrogen or a hydroxyl protecting group, with: a reagent selected from a metal hydroxide, a metal halide, and a trialkylsilyl halide; to provide the compound of Formula R-2 or a salt thereof.

207. The process of claim 206, wherein R3Ais selected from hydrogen, C1-4alkyl, and benzyl.

208. The process of claim 206 or 207, wherein R3Ais selected from hydrogen, methyl, ethyl, isopropyl, and benzyl.

209. The process of any one of claims 206-208, wherein R3Ais methyl.

210. The process of any one of claims 206-209, wherein the compound of Formula A is reacted with a metal hydroxide.

211. The process of any one of claims 206-210, wherein the metal hydroxide is sodium hydroxide.

212. The process of any one of claims 206-211, wherein the reacting of the compound of Formula A or a salt thereof is performed in a twenty-ninth solvent comprising methanol.

213. The process of any one of claims 206-212, wherein the reacting of the compound of Formula A or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C.

214. The process of any one of claims 181-195, further comprising preparing the compound of Formula R-1 or a salt thereof by a process comprising: reacting a compound of Formula A: or a salt thereof,a sixteenth base; to provide the compound of Formula R-1 or a salt thereof.

215. The process of claim 214, wherein R3Ais selected from C1-4alkyl, C1-4haloalkyl, and benzyl.

216. The process of claim 214 or 215, wherein R3Ais selected from methyl, ethyl, isopropyl, trifluoroethyl, and benzyl.

217. The process of any one of claims 214-216, wherein R3Ais methyl.

218. The process of any one of claims 214-217, wherein the sixteenth base is selected from an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an amide, a basic aromatic compound, or a combination thereof.

219. The process of any one of claims 214-218, wherein the sixteenth base is a guanidine.

220. The process of any one of claims 214-219, wherein the sixteenth base is 1,5,7- triazabicyclodec-5-ene.

221. The process of any one of claims 214-220, wherein the reacting of the compound of Formula A or a salt thereof is performed in a thirtieth solvent comprising 2- methyltetrahydrofuran.

222. The process of any one of claims 214-221, wherein the reacting of the compound of Formula A or a salt thereof is carried out in a temperature range of from about 20 °C to about 110 °C.

223. The process of any one of claims 166-180 and 206-222, further comprising preparing the compound of Formula A or a salt thereof by a process comprising: reacting a compound of Formula X-A:a seventh base, to provide the compound of Formula A or a salt thereof.

224. The process of claim 223, comprising reacting the compound of Formula X-A with a salt of the compound of Formula C.

225. The process of claim 223 or 224, wherein the salt of the compound of Formula C is a methanesulfonic acid salt.

226. The process of claim 223 or 224, wherein the salt of the compound of Formula C is a toluenesulfonic acid salt.

227. The process of any one of claims 223-226, wherein the seventh base is selected from a tertiary amine, a secondary amine, an aniline, a pyridine, an imidazole, an amidine, a guanidine, a carbonate, a phosphate, a hydroxide, an alkoxide, or a combination thereof.

228. The process of any one of claims 223-227, wherein the seventh base is N-methyl morpholine.

229. The process of any one of claims 223-228, wherein the reacting of the compound of Formula X-A or a salt thereof is performed in a fourteenth solvent comprising methanol.

230. The process of any one of claims 223-229, wherein the reacting of the compound of Formula X-A or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C.

231. The process of any one of claims 223-230, further comprising reacting the compound of Formula A with a fourth acid to provide a salt of the compound of Formula A.

232. The process of claim 231, wherein the fourth acid is selected from trifluoroacetic acid, hydrochloric acid, hydrobromic acid, acetic acid, oxalic acid, orotic acid, succinic acid, malonic acid, adipic acid, fumaric acid, benzenesulfonic acid, benzoic acid, citric acid, 1,8-naphthalenedisulfonic acid, tartaric acid or an ester thereof, p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, maleic acid, xinafoic acid, and L- pyroglutamic acid.

233. The process of claim 231 or 232, wherein the fourth acid is oxalic acid.

234. The process of any one of claims 223-233, further comprising preparing the compound of Formula C or a salt thereof by a process comprising: deprotecting a compound of Formula D:or a salt thereof, wherein:R5is selected from hydrogen and R9, wherein R9is an amine protecting group; and R7and R8are each independently an amine protecting group; to provide the compound of Formula C or a salt thereof.

235. The process of claim 234, wherein R5is hydrogen.

236. The process of claim 234, wherein R5is R9, and R9is an amine protecting group.

237. The process of claim 234 or 236, wherein R5is tert-butyloxycarbonyl.

238. The process of any one of claims 234-237, wherein R7and R8are tert- butyloxycarbonyl.

239. The process of any one of claims 234-238, wherein deprotecting the compound of Formula D or a salt thereof comprises treating the compound of Formula D or a salt thereof with a fifth acid.

240. The process of claim 239, wherein the fifth acid is selected from a sulfonic acid, sulfuric acid, sulfurous acid, a carboxylic acid, a hydrogen halide, phosphoric acid, phosphorous acid, or a combination thereof.

241. The process of claim 239 or 240, wherein the fifth acid is a sulfonic acid.

242. The process of any one of claims 239-241, wherein the fifth acid is methanesulfonic acid.

243. The process of any one of claims 239-241, wherein the fifth acid is p- toluenesulfonic acid.

244. The process of any one of claims 234-243, wherein the deprotecting the compound of Formula D or a salt thereof is performed in a fifteenth solvent comprising methanol.

245. The process of any one of claims 234-244, wherein the deprotecting the compound of Formula D or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C.

246. The process of any one of claims 234-245, further comprising preparing the compound of Formula D or a salt thereof, wherein the compound of Formula D is a compound of Formula D-1:or a salt thereof, by a process comprising: deprotecting a compound of Formula E:or a salt thereof, wherein: R9is an amine protecting group and R10is hydrogen; or optionally: R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group; to provide the compound of Formula D or a salt thereof.

247. The process of claim 246, wherein R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group.

248. The process of claim 246 or 247, wherein R9and R10together with the nitrogen atom to which they are attached form phthalimide.

249. The process of claim 246, wherein R9is tert-butyloxycarbonyl.

250. The process of any one of claims 246-249, wherein deprotecting the compound of Formula E or a salt thereof comprises treating the compound of Formula E or a salt thereof with a second deprotecting agent.

251. The process of claim 250, wherein the second deprotecting agent is selected from a hydrazine, an amine, an alkoxide, a thiol, a hydrolase enzyme, a hydride, or a combination thereof.

252. The process of claim 250 or 251, wherein the second deprotecting agent is selected from a hydrazine, an amine, an alkoxide, a thiol, a hydrolase enzyme, or a combination thereof.

253. The process of any one of claims 250-252, wherein the second deprotecting agent is an amine.

254. The process of any one of claims 250-253, wherein the second deprotecting agent is ethylenediamine.

255. The process of claim 250 or 251, wherein the second deprotecting agent is a hydride.

256. The process of any one of claims 250, 251, and 255, wherein the second deprotecting agent is sodium borohydride.

257. The process of any one of claims 250-256, wherein the deprotecting the compound of Formula E or a salt thereof is performed in the presence of a ninth acid.

258. The process of claim 257, wherein the ninth acid comprises a carboxylic acid, a strong acid, or a combination thereof.

259. The process of any one of claims 246-258, wherein the deprotecting the compound of Formula E or a salt thereof is performed in a sixteenth solvent comprising methanol.

260. The process of any one of claims 246-259, wherein the deprotecting the compound of Formula E or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C.

261. The process of any one of claims 166-180 and 206-222, further comprising preparing the compound of Formula A or a salt thereof by a process comprising: reacting a compound of Formula Q-1:or a salt thereof, with a reagent selected from a hydrazine, an amine, an alkoxide, and a hydrolase enzyme; to provide the compound of Formula A or a salt thereof.

262. The process of claim 261, comprising reacting the compound of Formula Q-1 with a hydrazine.

263. The process of claim 261 or 262, comprising reacting the compound of Formula Q-1 with hydrazine hydrate.

264. The process of any one of claims 261-263, wherein the reacting of the compound of Formula Q-1 or a salt thereof is performed in a thirty-first solvent comprising toluene.

265. The process of any one of claims 261-264, wherein the reacting of the compound of Formula Q-1 or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C.

266. The process of any one of claims 261-265, further comprising preparing the compound of Formula Q-1 or a salt thereof by a process comprising: reacting a compound of Formula Q-2:or a salt thereof, with: a compound of Formula X-A:or a salt thereof, and a thirteenth base; to provide the compound of Formula Q-1 or a salt thereof.

267. The process of claim 266, wherein the thirteenth base is selected from a tertiary amine, a secondary amine, an aniline, a pyridine, an imidazole, an amidine, a guanidine, a carbonate, a phosphate, a hydroxide, an alkoxide, or a combination thereof.

268. The process of claim 266 or 267, wherein the thirteenth base is a tertiary amine.

269. The process of any one of claims 266-268, wherein the thirteenth base is N- methyl morpholine.

270. The process of any one of claims 266-269, wherein the reacting of the compound of Formula Q-2 or a salt thereof is performed in a thirty-second solvent comprising methanol.

271. The process of any one of claims 266-270, wherein the reacting of the compound of Formula Q-2 or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C.

272. The process of any one of claims 266-271, further comprising preparing the compound of Formula Q-2 or a salt thereof by a process comprising: reacting a compound of Formula E: or a salt thereof, wherein R9nitrogen atom to which they are attached form phthalimide; with a seventh acid to provide the compound of Formula Q-2 or a salt thereof.

273. The process of claim 272, wherein the seventh acid is selected from a sulfonic acid, sulfuric acid, sulfurous acid, a carboxylic acid, a hydrogen halide, an in situ generated hydrogen halide, phosphoric acid, phosphorous acid, or a combination thereof.

274. The process of claim 272 or 273, wherein the seventh acid is a sulfonic acid.

275. The process of any one of claims 272-274, wherein the seventh acid is para- toluene sulfonic acid.

276. The process of any one of claims 272-275, wherein the reacting of the compound of Formula E or a salt thereof is performed in a thirty-third solvent comprising methanol.

277. The process of any one of claims 272-276, wherein the reacting of the compound of Formula E or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C.

278. The process of any one of claims 246-260 and 272-277, further comprising preparing the compound of Formula E or a salt thereof by a process comprising: reacting a compound of Formula F:or a salt thereof, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula E or a salt thereof.

279. The process of claim 278, wherein the phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane.

280. The process of claim 278 or 279, wherein the phosphine reagent is a triarylphosphine.

281. The process of any one of claims 278-280, wherein the phosphine reagent is triphenylphosphine.

282. The process of any one of claims 278-281, wherein the azodicarboxylate is selected from di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1- azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate.

283. The process of any one of claims 278-282, wherein the azodicarboxylate is di- tert-butyl azodicarboxylate.

284. The process of any one of claims 278-283, wherein the compound of Formula R7- .

285. The process of any one of claims 278-284, wherein the reacting of the compound of Formula F or a salt thereof is performed in a seventeenth solvent comprising 2- methyltetrahydrofuran.

286. The process of any one of claims 278-285, wherein the reacting of the compound of Formula F or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C.

287. The process of any one of claims 278-286, further comprising preparing the compound of Formula F or a salt thereof by a process comprising: reacting a compound of Formula G:or a salt thereof, with: a third catalyst, and a hydrogen source; to provide the compound of Formula F or a salt thereof.

288. The process of claim 287, wherein the third catalyst is selected from a palladium catalyst, a platinum catalyst, and a bimetallic catalyst, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

289. The process of claim 287 or 288, wherein the third catalyst is a palladium catalyst.

290. The process of any one of claims 287-289, wherein the third catalyst is a Lindlar catalyst.

291. The process of any one of claims 287-290, wherein the third catalyst comprises 5 wt.% palladium on lead-poisoned calcium carbonate.

292. The process of any one of claims 287-291, wherein a molar ratio of the compound of Formula G or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.

05.

293. The process of any one of claims 287-292, wherein the hydrogen source comprises hydrogen, formic acid, water, or a combination thereof.

294. The process of any one of claims 287-293, wherein the hydrogen source is hydrogen.

295. The process of any one of claims 287-294, wherein the reacting of the compound of Formula G or a salt thereof is carried out in the presence of a second additive.

296. The process of claim 295, wherein the second additive comprises quinoline, pyridine, triethylamine, a carbonate, a bicarbonate, a phosphate, 1,8-diazabicyclo[5.4.0] undec-7-ene, potassium carbonate, potassium formate, sodium formate, ammonium formate, potassium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium iodide, lithium chloride, sodium chloride, calcium chloride, or a combination thereof.

297. The process of any one of claims 287-296, wherein the reacting of the compound of Formula G or a salt thereof is carried out at a pressure of about 1 psi to about 100 psi.

298. The process of any one of claims 287-297, wherein the reacting of the compound of Formula G or a salt thereof is carried out at a pressure of about 50 psi.

299. The process of any one of claims 287-298, wherein the reacting of the compound of Formula G or a salt thereof is performed in an eighteenth solvent comprising N,N- dimethylformamide.

300. The process of any one of claims 287-299, wherein the reacting of the compound of Formula G or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C.

301. The process of any one of claims 287-300, further comprising preparing the compound of Formula G or a salt thereof by a process comprising: reacting a compound of Formula H:H or a salt thereof, wherein R11is selected from C1-20alkyl, phenyl, and -CH2NH2; with a sixth acid or an eighth base, to provide the compound of Formula G or a salt thereof.

302. The process of claim 301, wherein R11is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl, and -CH2NH2.

303. The process of claim 301 or 302, wherein R11is methyl.

304. The process of any one of claims 301-303, wherein the compound of Formula H or a salt thereof is reacted with the sixth acid.

305. The process of any one of claims 301-304, wherein the sixth acid is selected from a mineral acid, trifluoroacetic acid, a sulfonic acid, or a combination thereof.

306. The process of any one of claims 301-305, wherein the sixth acid is a sulfonic acid.

307. The process of any one of claims 301-306, wherein the sixth acid is p- toluenesulfonic acid.

308. The process of any one of claims 301-303, wherein the compound of Formula H or a salt thereof is reacted with the eighth base.

309. The process of any one of claims 301-303 and 308, wherein the eighth base is selected from a guanidine, a carbonate, a bicarbonate, a metal alkoxide, an amine, or a combination thereof.

310. The process of any one of claims 301-309, wherein the reacting of the compound of Formula H or a salt thereof is performed in a thirty-fourth solvent comprising methanol.

311. The process of any one of claims 301-310, wherein the reacting of the compound of Formula H or a salt thereof is carried out in a temperature range of from about 0 °C to about 70 °C.

312. The process of any one of claims 278-286, further comprising preparing the compound of Formula F or a salt thereof by a process comprising: reacting a compound of Formula W: or a salt thereof, with:a sixth catalyst, and a reducing agent; to provide the compound of Formula F or a salt thereof.

313. The process of claim 312, wherein R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group.

314. The process of claim 312 or 313, wherein the compound of Formula W or a salt thereof is a compound of Formula W-1:or a salt thereof.

315. The process of any one of claims 312-314, wherein the compound of Formula F or a salt thereof is a compound of Formula F-2:or a salt thereof.

316. The process of any one of claims 312-315, wherein the sixth catalyst is a CBS catalyst or a ruthenium catalyst.

317. The process of any one of claims 312-316, wherein the sixth catalyst is a CBS catalyst.

318. The process of any one of claims 312-317, wherein the sixth catalyst is (R)-(+)-2- methyl-CBS-oxazaborolidine.

319. The process of any one of claims 312-318, wherein the reducing agent comprises formic acid and triethylamine, NaBH4, LiBH4, CeCl3∙7H2O with NaBH4, LiAlH4, MgBu2with HBpin, Red-Al, LiAlH(OtBu)3, BH3∙SMe2, catecholborane, or a combination thereof.

320. The process of any one of claims 312-319, wherein the reducing agent comprises catecholborane.

321. The process of any one of claims 312-320, wherein the reacting of the compound of Formula W or a salt thereof is performed in a forty-third solvent comprising dichloromethane.

322. The process of any one of claims 312-321, wherein the reacting of the compound of Formula W or a salt thereof is carried out in a temperature range of from about -78 °C to about 30 °C.

323. The process of any one of claims 312-322, further comprising preparing the compound of Formula W or a salt thereof by a process comprising: reacting a compound of Formula S:or a salt thereof, with: a compound of Formula T: or a salt thereof,wherein R15is selected from phenyl and C1-4haloalkyl, wherein the phenyl is optionally substituted with 1-4 substituents selected from C1-4alkyl, halo, C1-4 haloalkyl, and cyano; a seventeenth base, and a fourth additive; to provide the compound of Formula W or a salt thereof.

324. The process of claim 323, wherein the compound of Formula S or a salt thereof is a compound of Formula S-1:or a salt thereof.

325. The process of claim 323 or 324, wherein R15is selected from phenyl, trifluoroethyl, trichloroethyl, phenyl, and chlorophenyl.

326. The process of any one of claims 323-325, wherein R15is phenyl.

327. The process of any one of claims 323-326, wherein the seventeenth base is selected from an amide, an amine base, an amidine, a guanidine, a carbonate, a metal hydride, phosphate, an alkoxide, a basic aromatic compound, and combinations thereof.

328. The process of any one of claims 323-327, wherein the seventeenth base is an amide.

329. The process of any one of claims 323-328, wherein the seventeenth base is potassium hexamethyl disilazide.

330. The process of any one of claims 323-329, wherein the fourth additive is selected from an ether, a metal salt, or a combination thereof.

331. The process of any one of claims 323-330, wherein the fourth additive is an ether.

332. The process of any one of claims 323-331, wherein the fourth additive is 18- crown-6.

333. The process of any one of claims 323-332, wherein the reacting of the compound of Formula S or a salt thereof is performed in a forty-fourth solvent comprising tetrahydrofuran.

334. The process of any one of claims 323-333, wherein the reacting of the compound of Formula S or a salt thereof is carried out in a temperature range of from about -100 °C to about 25 °C.

335. The process of any one of claims 278-286, further comprising preparing the compound of Formula F or a salt thereof by a process comprising: reacting a compound of Formula W: or a salt thereof, with:a second enzyme in the presence of a second buffer; to provide the compound of Formula F or a salt thereof.

336. The process of claim 335, wherein R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group.

337. The process of claim 335 or 336, wherein the compound of Formula W or a salt thereof is a compound of Formula W-1:or a salt thereof.

338. The process of any one of claims 335-337, wherein the compound of Formula F or a salt thereof is a compound of Formula F-2:or a salt thereof.

339. The process of any one of claims 335-338, wherein the second enzyme is selected from a ketoreductase, alcohol oxidase, or P450.

340. The process of any one of claims 335-339, wherein the second enzyme is a ketoreductase.

341. The process of any one of claims 335-340, wherein the second buffer is selected from a citrate buffer, a phosphate buffer, tris(hydroxymethyl)aminomethane, and (4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES).

342. The process of any one of claims 335-341, wherein the second buffer is a phosphate buffer.

343. The process of any one of claims 335-342, wherein the reacting of the compound of Formula W or a salt thereof is performed in a cosolvent comprising dimethylsulfoxide.

344. The process of any one of claims 335-343, wherein the reacting of the compound of Formula W or a salt thereof is carried out in a temperature range of from about 5 °C to about 100 °C.

345. The process of any one of claims 278-286, further comprising preparing the compound of Formula F or a salt thereof by a process comprising: reacting a compound of Formula G: or a salt thereof, with:a third reducing agent, and an activator; to provide the compound of Formula F or a salt thereof.

346. The process of claim 345, wherein the compound of Formula F or a salt thereof is a compound of Formula F-1:or a salt thereof.

347. The process of claim 345 or 346, wherein R9is tert-butyloxycarbonyl.

348. The process of any one of claims 345-347, wherein the compound of Formula G or a salt thereof is a compound of Formula G-1:or a salt thereof.

349. The process of claim 345, wherein R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group.

350. The process of claims 345 or 349, wherein R9and R10together with the nitrogen atom to which they are attached form phthalimide or saccharin.

351. The process of any one of claims 345-350, wherein the third reducing agent comprises zinc, a metal, a diimide, copper and bis(pinacolato)diboron, an imidazolinium salt, or a combination thereof.

352. The process of any one of claims 345-351, wherein the third reducing agent comprises zinc.

353. The process of any one of claims 345-352, wherein the activator is selected from chlorotrimethylsilane, dibromoethane, hydrochloric acid, and diisobutylaluminum hydride.

354. The process of any one of claims 345-353, wherein the activator is chlorotrimethylsilane.

355. The process of any one of claims 345-354, wherein the reacting of the compound of Formula G or a salt thereof is performed in a forty-fifth solvent comprising ethanol.

356. The process of any one of claims 345-355, wherein the reacting of the compound of Formula G or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C.

357. The process of any one of claims 234-245, further comprising preparing the compound of Formula D or a salt thereof, wherein R5is R9, by a process comprising: reacting a compound of Formula F-1:or a salt thereof, wherein R9is an amine protecting group, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula D or a salt thereof.

358. The process of claim 357, wherein R9is tert-butyloxycarbonyl.

359. The process of claim 357 or 358, wherein the phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane.

360. The process of any one of claims 357-359, wherein the phosphine reagent is a triarylphosphine.

361. The process of any one of claims 357-360, wherein the phosphine reagent is triphenylphosphine.

362. The process of any one of claims 357-361, wherein the azodicarboxylate is selected from di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1- azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate.

363. The process of any one of claims 357-362, wherein the azodicarboxylate is di- tert-butyl azodicarboxylate.

364. The process of any one of claims 357-363, wherein the compound of Formula R7- .

365. The process of any one of claims 357-364, wherein the reacting of the compound of Formula F-1 or a salt thereof is performed in a thirty-fifth solvent comprising 2- methyltetrahydrofuran.

366. The process of any one of claims 357-365, wherein the reacting of the compound of Formula F-1 or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C.

367. The process of any one of claims 357-366, further comprising preparing the compound of Formula F-1 or a salt thereof by a process comprising: reacting a compound of Formula G-1:or a salt thereof, with: a third catalyst, an aromatic amine or a sulfur-containing reagent; and hydrogen; to provide the compound of Formula F-1 or a salt thereof.

368. The process of claim 367, wherein the third catalyst is selected from a palladium catalyst, a platinum catalyst, and a bimetallic catalyst, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

369. The process of claim 367 or 368, wherein the third catalyst is a palladium catalyst.

370. The process of any one of claims 367-369, wherein the third catalyst is a Lindlar catalyst.

371. The process of any one of claims 367-370, wherein the third catalyst comprises 5 wt.% palladium on lead-poisoned calcium carbonate.

372. The process of any one of claims 367-371, wherein a molar ratio of the compound of Formula G-1 or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.

05.

373. The process of any one of claims 367-372, wherein the compound of Formula G- 1 is reacted with an aromatic amine selected from quinoline and pyridine.

374. The process of any one of claims 367-373, wherein the aromatic amine is quinoline.

375. The process of any one of claims 367-374, wherein the compound of Formula G- 1 is reacted with a sulfur-containing compound selected from a thiol and a sulfide.

376. The process of any one of claims 367-375, wherein the reacting of the compound of Formula G-1 or a salt thereof is carried out at a pressure of about 1 psi to about 100 psi.

377. The process of any one of claims 367-376, wherein the reacting of the compound of Formula G-1 or a salt thereof is carried out at a pressure of about 20 psi.

378. The process of any one of claims 367-377, wherein the reacting of the compound of Formula G-1 or a salt thereof is performed in a thirty-sixth solvent comprising N,N- dimethylformamide.

379. The process of any one of claims 367-378, wherein the reacting of the compound of Formula G-1 or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C.

380. The process of any one of claims 367-379, further comprising preparing the compound of Formula G-1 or a salt thereof by a process comprising: reacting a compound of Formula H having Formula H-1:or a salt thereof, wherein R11is selected from C1-20alkyl, phenyl, and -CH2NH2; with a twelfth base, to provide the compound of Formula G-1 or a salt thereof.

381. The process of claim 380, wherein R11is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl, and -CH2NH2.

382. The process of claim 380 or 381, wherein R11is methyl.

383. The process of any one of claims 380-382, wherein the twelfth base is selected from a guanidine, a carbonate, a bicarbonate, a metal alkoxide, an amine, or a combination thereof.

384. The process of any one of claims 380-383, wherein the twelfth base is a guanidine.

385. The process of any one of claims 380-384, wherein the twelfth base is tetra- methyl guanidine.

386. The process of any one of claims 380-385, wherein the reacting of the compound of Formula H-1 or a salt thereof is performed in a thirty-seventh solvent comprising methanol.

387. The process of any one of claims 380-386, wherein the reacting of the compound of Formula H-1 or a salt thereof is carried out in a temperature range of from about 0 °C to about 30 °C.

388. The process of any one of claims 380-387, further comprising preparing the compound of Formula G-1 or a salt thereof by a process comprising: reacting a compound of Formula U-1: U-1 or a salt thereof, with a second amine protecting group reagent to provide the compound of Formula G-1 or a salt thereof.

389. The process of claim 388, wherein R9of the compound of Formula G-1 or a salt thereof is tert-butyloxycarbonyl.

390. The process of claim 388 or 389, wherein the second amine protecting group is di-tert-butyl dicarbonate.

391. The process of any one of claims 388-390, wherein the reacting of the compound of Formula U-1 or a salt thereof is performed in a forty-sixth solvent comprising 2- methytetrahydrofuran.

392. The process of any one of claims 388-391, wherein , the reacting of the compound of Formula U-1 or a salt thereof is carried out in a temperature range of from about 5 °C to about 100 °C.

393. The process of any one of claims 388-392, further comprising preparing the compound of Formula U-1 or a salt thereof by a process comprising: reacting a compound of Formula U-2:or a salt thereof, with: a third enzyme in the presence of a third buffer; to provide the compound of Formula U-1 or a salt thereof.

394. The process of claim 393, wherein the third enzyme is selected from a transaminase, an amine hydrogenase, an imine reductase, and a combination thereof.

395. The process of claim 393 or 394, wherein the third enzyme is a transaminase.

396. The process of any one of claims 393-395, wherein the third buffer is selected from a citrate buffer, a phosphate buffer, a tris(hydroxymethyl)aminomethane (Tris) buffer, and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES).

397. The process of any one of claims 393-396, wherein the third buffer is a Tris buffer.

398. The process of any one of claims 393-397, wherein the reacting of the compound of Formula U-2 or a salt thereof is performed in a second cosolvent comprising dimethylsulfoxide.

399. The process of any one of claims 393-398, wherein the reacting of the compound of Formula U-2 or a salt thereof is carried out in a temperature range of from about 5 °C to about 100 °C.

400. The process of any one of claims 393-399, further comprising preparing the compound of Formula U-2 or a salt thereof by a process comprising: reacting a compound of Formula L:or a salt thereof, with: a fourth enzyme in the presence of a fourth buffer; to provide the compound of Formula U-2 or a salt thereof.

401. The process of claim 400, wherein the fourth enzyme is selected from a ketoreductase, an alcohol oxidase, P450, and a combination thereof.

402. The process of claim 400 or 401, wherein the fourth enzyme is a ketoreductase.

403. The process of any one of claims 400-402, wherein the fourth buffer is selected from a citrate buffer, a phosphate buffer, a tris(hydroxymethyl)aminomethane (Tris) buffer, and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES).

404. The process of any one of claims 400-403, wherein the fourth buffer is a Tris buffer.

405. The process of any one of claims 400-404, wherein the reacting of the compound of Formula L or a salt thereof is performed in a third cosolvent comprising dimethylsulfoxide.

406. The process of any one of claims 400-405, wherein the reacting of the compound of Formula L or a salt thereof is carried out in a temperature range of from about 5 °C to about 100 °C.

407. The process of any one of claims 301-311 and 380-387, further comprising preparing the compound of Formula H or a salt thereof by a process comprising: reacting a compound of Formula J:or a salt thereof, with: a second phosphine reagent, a second azodicarboxylate, and an amine protecting group reagent; to provide the compound of Formula H or a salt thereof.

408. The process of claim 407, wherein the second phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane.

409. The process of claim 407 or 408, wherein the second phosphine reagent is a triarylphosphine.

410. The process of any one of claims 407-409, wherein the second phosphine reagent is triphenylphosphine.

411. The process of any one of claims 407-410, wherein the second azodicarboxylate is selected from di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1- azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate.

412. The process of any one of claims 407-411, wherein the second azodicarboxylate is diisopropyl azodicarboxylate.

413. The process of any one of claims 407-412, wherein the amine protecting group reagent is an imide.

414. The process of any one of claims 407-413, wherein the amine protecting group reagent is an imide selected from phthalimide, tert-butyl methyl iminodicarbonate, and di-tert-butyliminodicarboxylate.

415. The process of any one of claims 407-414, wherein the amine protecting group reagent is phthalimide.

416. The process of any one of claims 407-415, wherein the reacting of the compound of Formula J or a salt thereof is performed in a thirty-eighth solvent comprising 2- methyltetrahydrofuran.

417. The process of any one of claims 407-416, wherein the reacting of the compound of Formula J or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C.

418. The process of any one of claims 301-311 and 380-387, further comprising preparing the compound of Formula H or a salt thereof by a process comprising: reacting a compound of Formula N:or a salt thereof, wherein: R12is -S(O)3R13or -OC(=N)R14; R13is selected from C1-4alkyl, C1-4haloalkyl, and phenyl optionally substituted with C1-4alkyl; and R14is C1-4haloalkyl; with an amine protecting group reagent, to provide the compound of Formula H or a salt thereof.

419. The process of claim 418, wherein R12is -S(O)3R13.

420. The process of claim 418 or 419, wherein R13is selected from tolyl, methyl, and trifluoromethyl.

421. The process of any one of claims 418-420, wherein R13is methyl.

422. The process of any one of claims 418-420, wherein R13is tolyl.

423. The process of claim 418, wherein R12is -OC(=N)R14.

424. The process of any one of claims 418 and 423, wherein R14is selected from trichloromethyl and tribromomethyl.

425. The process of any one of claims 418-424, wherein the amine protecting group reagent is selected from phthalimide, para-methoxyaniline, ortho, para-dimethoxyaniline, acetamide, 2,5-dimethylpyrrole, 4-methoxybenzylamine, 2,4-dimethoxybenzylamine,2,2-diphenylamine, allylamine, triphenylmethylamine, di-tert-butyl iminodicarbonate, tert-butyl carbamate, or a salt thereof.

426. The process of any one of claims 418-425, wherein the amine protecting group reagent is a salt of phthalimide.

427. The process of any one of claims 418-426, wherein the amine protecting group reagent is potassium phthalimide.

428. The process of any one of claims 418-427, wherein the reacting of the compound of Formula N or a salt thereof is carried out in the presence of a third additive.

429. The process of claim 428, wherein the third additive comprises 18-crown-6, a tetrabutylammonium salt, hexamethylphosphoramide, water, or a combination thereof.

430. The process of claim 428 or 429, wherein the third additive comprises 18-crown- 6.

431. The process of any one of claims 418-430, wherein the reacting of the compound of Formula N or a salt thereof is carried out in the presence of a tenth base.

432. The process of claim 431, wherein the tenth base is selected from an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, and a basic aromatic compound.

433. The process of any one of claims 418-432, wherein the reacting of the compound of Formula N or a salt thereof is performed in a twentieth solvent comprising N,N- dimethylacetamide.

434. The process of any one of claims 418-433, wherein the reacting of the compound of Formula N or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C.

435. The process of any one of claims 418-434, further comprising preparing the compound of Formula N or a salt thereof by a process comprising: reacting a compound of Formula J: J or a salt thereof, with: an eleventh base, and a third reagent selected from a sulfonyl chloride, a sulfonyl anhydride, a halonitrile, an imidoyl chloride, or an acid halide; to provide the compound of Formula N or a salt thereof.

436. The process of claim 435, wherein the third reagent is selected from a sulfonyl chloride, a sulfonyl anhydride, a halonitrile, or an imidoyl chloride.

437. The process of claim 435 or 436, wherein the third reagent is a sulfonyl chloride.

438. The process of claim 437, wherein the sulfonyl chloride is selected from methane sulfonyl chloride and 4-toluene sulfonyl chloride.

439. The process of any one of claims 435-438, wherein the third reagent is methane sulfonyl chloride.

440. The process of claim 435 or 436, wherein the third reagent is a sulfonyl anhydride.

441. The process of any one of claims 435, 436, and 440, wherein the sulfonyl anhydride is selected from methane sulfonyl anhydride and trifluoromethanesulfonic anhydride.

442. The process of claim 435 or 436, wherein the third reagent is a halonitrile.

443. The process of any one of claims 435, 436, and 442, wherein the halonitrile is selected from trochloroacetonitrile and trifluoroacetonitrile.

444. The process of claim 435 or 436, wherein the third reagent is an imidoyl chloride.

445. The process of any one of claims 435, 446, and 444, wherein the imidoyl chloride is (N-phenyl)trifluoroacetimidoyl chloride.

446. The process of claim 435, wherein the third reagent is an acid halide.

447. The process of claim 435 or 446, wherein the acid halide is selected from acetyl chloride, acetyl bromide, and benzoyl chloride.

448. The process of any one of claims 435-447, wherein the eleventh base is selected from an amine, a carbonate, a bicarbonate, a metal alkoxide, or a combination thereof.

449. The process of any one of claims 435-448, wherein the eleventh base is an amine.

450. The process of any one of claims 435-449, wherein the eleventh base is triethylamine.

451. The process of any one of claims 435-450, wherein the reacting of the compound of Formula J or a salt thereof is performed in a twenty-first solvent comprising N,N- dimethylacetamide.

452. The process of any one of claims 435-451, wherein the reacting of the compound of Formula J or a salt thereof is carried out in a temperature range of from about -15 °C to about 60 °C.

453. The process of any one of claims 380-387, further comprising preparing the compound of Formula H-1 or a salt thereof by a process comprising: reacting a compound of Formula P-1:or a salt thereof, with an amine protecting group reagent to provide the compound of Formula H-1 or a salt thereof.

454. The process of claim 453, wherein the amine protecting group reagent is di-tert- butyl dicarbonate.

455. The process of claim 453 or 454, further comprising preparing the compound of Formula P-1 or a salt thereof by a process comprising: reacting a compound of Formula N:or a salt thereof, wherein: R12is -S(O)3R13; andR13is selected from C1-4alkyl and phenyl optionally substituted with C1-4alkyl; with: an azide, and a third phosphine reagent; to provide the compound of Formula P-1 or a salt thereof.

456. The process of claim 455, wherein the azide is selected from sodium azide, diphenylphosphoryl azide, and trimethylsilyl azide.

457. The process of claim 455 or 456, wherein the azide is sodium azide.

458. The process of any one of claims 455-457, wherein the third phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane.

459. The process of any one of claims 455-458, wherein the third phosphine reagent is a triarylphosphine.

460. The process of any one of claims 455-459, wherein the third phosphine reagent is triphenylphosphine.

461. The process of any one of claims 455-460, wherein the reacting of the compound of Formula N or a salt thereof is performed in a twenty-seventh solvent comprising N,N- dimethylformamide.

462. The process of any one of claims 455-461, wherein the reacting of the compound of Formula N or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C.

463. The process of any one of claims 380-387, further comprising preparing the compound of Formula H-1 or a salt thereof by a process comprising: reacting a compound of Formula P-2:or a salt thereof, with: a fourth phosphine reagent; and an amine protecting group reagent; to provide the compound of Formula H-1 or a salt thereof.

464. The process of claim 463, wherein the fourth phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane.

465. The process of claim 463 or 464, wherein the fourth phosphine reagent is a triarylphosphine.

466. The process of any one of claims 463-465, wherein the fourth phosphine reagent is triphenylphosphine.

467. The process of any one of claims 463-466, wherein the amine protecting group reagent is di-tert-butyl dicarbonate.

468. The process of any one of claims 463-467, further comprising preparing the compound of Formula P-2 or a salt thereof by a process comprising: reacting a compound of reacting a compound of Formula J:or a salt thereof, with: an azide, a third phosphine reagent, and a third azodicarboxylate; to provide the compound of Formula P-2 or a salt thereof.

469. The process of claim 468, wherein the azide is selected from sodium azide, diphenylphosphoryl azide, and trimethylsilyl azide.

470. The process of claim 468 or 469, wherein the azide is sodium azide.

471. The process of any one of claims 468-470, wherein the third phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane.

472. The process of any one of claims 468-471, wherein the third phosphine reagent is a triarylphosphine.

473. The process of any one of claims 468-472, wherein the third phosphine reagent is triphenylphosphine.

474. The process of any one of claims 468-473, wherein the third azodicarboxylate is selected from di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1- azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate.

475. The process of any one of claims 468-474, wherein the third azodicarboxylate is diisopropyl diazodicarboxylate.

476. The process of any one of claims 468-475, wherein the reacting of the compound of Formula J or a salt thereof is performed in a thirty-ninth solvent comprising tetrahydrofuran.

477. The process of any one of claims 468-476, wherein the reacting of the compound of Formula J or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C.

478. The process of any one of claims 407-417, 345-355, and 468-477, further comprising preparing the compound of Formula J or a salt thereof by a process comprising: reacting a compound of Formula K:or a salt thereof, with: an enzyme, and a buffer; to provide the compound of Formula J or a salt thereof.

479. The process of claim 478, wherein the enzyme is selected from a hydrolase enzyme, Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26, and Novozyme 435.

480. The process of claim 478 or 479, wherein the enzyme is a hydrolase enzyme.

481. The process of any one of claims 478-480, wherein the enzyme is L-092 hydrolase enzyme.

482. The process of any one of claims 478-481, wherein a molar ratio of the enzyme to the compound of Formula K or a salt thereof is about 0.00001:1 to about 0.01:

1.

483. The process of any one of claims 478-482, wherein the buffer is selected from a citrate buffer, a phosphate buffer, tris(hydroxymethyl)aminomethane, and (4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES).

484. The process of any one of claims 478-483, wherein the buffer is a potassium phosphate buffer.

485. The process of any one of claims 478-484, wherein the reacting of the compound of Formula K or a salt thereof is carried out in the presence of a metal halide.

486. The process of claim 485, wherein the metal halide comprises zinc, nickel, calcium, iron, magnesium, or manganese.

487. The process of any one of claims 478-486, wherein the reacting of the compound of Formula K or a salt thereof is carried out in the presence of a surfactant.

488. The process of claim 487, wherein the surfactant is selected from sodium dodecyl sulfate, polypropylene glycol, and a polyoxyethylene fatty ether.

489. The process of any one of claims 478-488, wherein the reacting of the compound of Formula K or a salt thereof is performed in a fortieth solvent comprising tert-butyl methyl ether.

490. The process of any one of claims 478-489, wherein the reacting of the compound of Formula K or a salt thereof is carried out in a temperature range of from about 0 °C to about 70 °C.

491. The process of any one of claims 478-490, further comprising preparing the compound of Formula K or a salt thereof by a process comprising: reacting a compound of Formula L:or a salt thereof; with: a ninth base, a fourth catalyst; and a compound of Formula M-1 or Formula M-2:wherein X is a halide; to provide the compound of Formula K or a salt thereof.

492. The process of claim 491, wherein the ninth base is selected from a carbonate, a metal alkoxide, an amine, a metal hydroxide, or a combination thereof.

493. The process of claim 491 or 492, wherein the ninth base is an amine.

494. The process of any one of claims 491-493, wherein the ninth base is triethylamine.

495. The process of any one of claims 491-494, wherein the fourth catalyst is an aromatic amine.

496. The process of any one of claims 491-495, wherein the fourth catalyst is selected from 4-dimethylaminopyridine, N-methyl imidazole, and pyridine.

497. The process of any one of claims 491-496, wherein the reacting of the compound of Formula L or a salt thereof is performed in a forty-first solvent comprising tert-butyl methyl ether.

498. The process of any one of claims 491-497, wherein the reacting of the compound of Formula L or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C.

499. The process of any one of claims 246-260 and 272-277, further comprising preparing the compound of Formula E or a salt thereof by a process comprising: reacting a compound of Formula O-1: O-1 or a salt thereof, with: an amine protecting group reagent, a phosphine reagent, and an azodicarboxylate, to provide the compound of Formula E or a salt thereof.

500. The process of claim 499, wherein the amine protecting group reagent is selected from phthalimide, di-tert-butyl-iminodicarboxylate , ethyl 2-((tert-butoxycarbonyl)amino)-2-oxoacetate, methyl 2-((tert-butoxycarbonyl)amino)-2- oxoacetate, tert-butyl methyl iminodicarbonate, and dimethyl iminodicarbonate.

501. The process of claim 499 or 500, wherein the amine protecting group reagent is phthalimide.

502. The process of any one of claims 499-501, wherein the phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane.

503. The process of any one of claims 499-502, wherein the phosphine reagent is a triarylphosphine.

504. The process of any one of claims 499-503, wherein the phosphine reagent is triphenylphosphine.

505. The process of any one of claims 499-504, wherein the azodicarboxylate is selected from di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1- azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate.

506. The process of any one of claims 499-505, wherein the azodicarboxylate is diisopropyl azodicarboxylate.

507. The process of any one of claims 499-506, wherein the reacting of the compound of Formula O-1 or a salt thereof is performed in a twenty-second solvent comprising 2- methyltetrahydrofuran.

508. The process of any one of claims 499-507, wherein the reacting of the compound of Formula O-1 or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C.

509. The process of any one of claims 499-508, further comprising preparing the compound of Formula O-1 or a salt thereof by a process comprising: reacting a compound of Formula O-2:or a salt thereof, with: a fifth catalyst, and hydrogen; to provide the compound of Formula O-1 or a salt thereof.

510. The process of claim 509, wherein the fifth catalyst is selected from a palladium catalyst, a platinum catalyst, and a bimetallic catalyst, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

511. The process of claim 509 or 510, wherein the fifth catalyst is a palladium catalyst.

512. The process of any one of claims 509-511, wherein the fifth catalyst is a Lindlar catalyst.

513. The process of any one of claims 509-512, wherein the fifth catalyst comprises 5 wt.% palladium on lead-poisoned calcium carbonate.

514. The process of any one of claims 509-513, wherein a molar ratio of the compound of Formula O-2 or a salt thereof to the fifth catalyst is from about 1:0.001 to about 1:0.05.

515. The process of any one of claims 509-514, wherein the reacting of the compound of Formula O-2 or a salt thereof is carried out at a pressure of about 1 psi to about 100 psi.

516. The process of any one of claims 509-515, wherein the reacting of the compound of Formula O-2 or a salt thereof is carried out at a pressure of about 50 psi.

517. The process of any one of claims 509-516, wherein the reacting of the compound of Formula O-2 or a salt thereof is performed in a twenty-third solvent comprising N,N- dimethylformamide.

518. The process of any one of claims 509-517, wherein the reacting of the compound of Formula O-2 or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C.

519. The process of any one of claims 509-518, further comprising preparing the compound of Formula O-2 or a salt thereof by a process comprising: reacting a compound of Formula O-3:or a salt thereof, wherein R11is selected from C1-20alkyl, phenyl, and -CH2NH2; with: a twelfth base; to provide the compound of Formula O-2 or a salt thereof.

520. The process of claim 519, wherein R11is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl, and -CH2NH2.

521. The process of claim 519 or 520, wherein R11is methyl.

522. The process of any one of claims 519-521, wherein the twelfth base is selected from a guanidine, a carbonate, a bicarbonate, a metal alkoxide, an amine, a hydroxide, or a combination thereof.

523. The process of any one of claims 519-522, wherein the twelfth base is a guanidine.

524. The process of any one of claims 519-523, wherein the twelfth base is tetra- methyl guanidine.

525. The process of any one of claims 519-524, wherein the reacting of the compound of Formula O-3 or a salt thereof is performed in a twenty-fourth solvent comprising methanol.

526. The process of any one of claims 519-525, wherein the reacting of the compound of Formula O-3 or a salt thereof is carried out in a temperature range of from about -10 °C to about 80 °C.

527. The process of any one of claims 519-526, further comprising preparing the compound of Formula O-3 or a salt thereof by a process comprising: reacting a compound of Formula O-4:or a salt thereof, with: a second phosphine reagent, a second azodicarboxylate, anda compound of Formula R7-NH-NH-R8or methyl (1,3-dioxoisoindolin-2-yl) carbamate; to provide the compound of Formula O-3 or a salt thereof.

528. The process of claim 527, wherein the second phosphine reagent is selected from a trialkyl phosphine, a triaryl phosphine, (triphenylphosphoranylidene) acetonitrile, and a phosphorane.

529. The process of claim 527 or 528, wherein the second phosphine reagent is a triarylphosphine.

530. The process of any one of claims 527-529, wherein the second phosphine reagent is triphenylphosphine.

531. The process of any one of claims 527-530, wherein the second azodicarboxylate is selected from di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethylazodicarboxylate, azodicarboxylic dimorpholide, 1,1- azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarboxylate.

532. The process of any one of claims 527-531, wherein the second azodicarboxylate is di-tert-butylazodicarboxylate.

533. The process of any one of claims 527-532, wherein the compound of Formula R7- .

534. The process of any one of claims 527-533, wherein the reacting of the compound of Formula O-4 or a salt thereof is performed in a twenty-fifth solvent comprising 2- methyltetrahydrofuran.

535. The process of any one of claims 527-534, wherein the reacting of the compound of Formula O-4 or a salt thereof is carried out in a temperature range of from about -20 °C to about 50 °C.

536. The process of any one of claims 527-535, further comprising preparing the compound of Formula O-4 or a salt thereof by a process comprising: reacting a compound of Formula L:or a salt thereof, with: an alkyl ester, an alkenyl ester or an oxime ester; and an enzyme, to provide the compound of Formula O-4 or a salt thereof.

537. The process of claim 536, wherein the compound of Formula L or a salt thereof is reacted with an alkenyl ester is selected from vinyl acetate, isopropenyl acetate, and vinyl butyrate.

538. The process of claim 536 or 537, wherein the alkenyl ester is isopropenyl acetate.

539. The process of any one of claims 536-538, wherein the compound of Formula L or a salt thereof is reacted with an alkyl ester selected from ethyl acetate, methyl acetate, isopropyl acetate, and methyl butyrate.

540. The process of any one of claims 536-539, wherein the compound of Formula L or a salt thereof is reacted with an oxime ester is selected from propan-2-one O-acetyl oxime and propan-2-one O-butyryl oxime.

541. The process of any one of claims 536-540, wherein the enzyme is selected from a hydrolase enzyme, Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26, and Novozyme 435.

542. The process of any one of claims 536-541, wherein the enzyme is a hydrolase enzyme.

543. The process of any one of claims 536-542, wherein the enzyme is Lipase AK.

544. The process of any one of claims 536-543, wherein the reacting of the compound of Formula L or a salt thereof is performed in a twenty-sixth solvent comprising tert- butyl methyl ether.

545. The process of any one of claims 536-544, wherein the reacting of the compound of Formula L or a salt thereof is carried out in a temperature range of from about 10 °C to about 70 °C.

546. A process for preparing a compound of Formula I-A: or a salt thereof,(a) reacting a compound of Formula A:or a salt thereof, wherein R3Ais a hydroxyl protecting group, with: a methylene reagent, and a first acid or a first base, to provide a compound of Formula I: or a salt thereof, wherein and(b) deprotecting the compound of Formula I or a salt thereof, to provide the compound of Formula I-A or a salt thereof.

547. A process for preparing a compound of Formula I-A: or a salt thereof,(a) reacting a compound of Formula R-1: or a salt thereof, with:a methylene reagent, and an eighth acid or a fourteenth base, to provide a compound of Formula I:or a salt thereof, wherein and (b) deprotecting the compound of Formula I or a salt thereof, to provide the compound of Formula I-A or a salt thereof.

548. The process of claim 547, further comprising preparing the compound of Formula R-1 or a salt thereof by a process comprising: (c) reacting a compound of Formula A: or a salt thereof,group, with: a reagent selected from a metal hydroxide, a metal halide, and a trialkylsilyl halide; to provide a compound of Formula R-2:or a salt thereof; and (d) reacting the compound of Formula R-2 or a salt thereof, with: a coupling agent, and a fifteenth base,to provide the compound of Formula R-1 or a salt thereof 549. The process of claim 547, further comprising preparing the compound of Formula R-1 or a salt thereof by a process comprising: (c) reacting a compound of Formula A: or a salt thereof,a sixteenth base; to provide the compound of Formula R-1 or a salt thereof 550. The process of any one of claims 546-549, further comprising preparing the compound of Formula A or a salt thereof by a process comprising: (e) deprotecting a compound of Formula D:or a salt thereof, wherein R5is hydrogen or R9, wherein R9is an amine protecting group, and R7and R8are each independently an amine protecting group; to provide a compound of Formula C:or a salt thereof; and (f) reacting a compound of Formula X-A:or a salt thereof, with: the compound of Formula C or a salt thereof, and a seventh base; to provide the compound of Formula A or a salt thereof.

551. The process of claim 550, further comprising preparing the compound of Formula D or a salt thereof by a process comprising: (g) deprotecting a compound of Formula E:or a salt thereof, wherein: R7and R8are each independently an amine protecting group; and R9is an amine protecting group and R10is hydrogen; or optionally: R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring protecting group; to provide the compound of Formula D or a salt thereof having Formula D-1:or a salt thereof.

552. The process of any one of claims 546 and 548-551, further comprising preparing the compound of Formula A by a process comprising: (e) reacting a compound of Formula E:or a salt thereof, wherein R9and together with the nitrogen atom to which they are attached form phthalimide; with a seventh acid to provide a compound of Formula Q-2: or a salt thereof;(f) reacting the compound of Formula Q-2 or a salt thereof, with: a compound of Formula X-A:or a salt thereof, and a thirteenth base; to provide a compound of Formula Q-1:or a salt thereof; and (g) reacting the compound of Formula Q-1 or a salt thereof, with a reagent selected from a hydrazine, an alkoxide, and a hydrolase enzyme; to provide the compound of Formula A or a salt thereof.

553. The process of claim 551 or 552, further comprising preparing the compound of Formula E by a process comprising: (h) reacting a compound of Formula H:or a salt thereof, wherein R11is selected from C1-20alkyl, phenyl, and -CH2NH2; with a sixth acid or an eighth base, to provide a compound of Formula G:or a salt thereof; (i) reacting the compound of Formula G or a salt thereof, with: a third catalyst, and hydrogen; to provide a compound of Formula F:or a salt thereof; and(j) reacting the compound of Formula F or a salt thereof, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula E or a salt thereof.

554. The process of claim 551 or 552, further comprising preparing the compound of Formula E by a process comprising: (h) reacting a compound of Formula F:or a salt thereof, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula E or a salt thereof.

555. The process of claim 554, further comprising preparing the compound of Formula F by a process comprising: (i) reacting a compound of Formula S: or a salt thereof, with:a compound of Formula T:or a salt thereof, wherein R15is selected from phenyl and C1-4haloalkyl, wherein the phenyl is optionally substituted with 1-4 substituents selected from C1-4alkyl, halo, , C1-4 haloalkyl, and cyano; a seventeenth base, and a fourth additive; to provide a compound of Formula W:or a salt thereof; and (j) reacting the compound of Formula W or a salt thereof, with: a sixth catalyst, and a reducing agent; to provide the compound of Formula F or a salt thereof.

556. The process of claim 554, further comprising preparing the compound of Formula F by a process comprising: (i) reacting a compound of Formula W:or a salt thereof, with: a second enzyme in the presence of a second buffer; to provide the compound of Formula F or a salt thereof.

557. The process of claim 554, further comprising preparing the compound of Formula F by a process comprising: (i) reacting a compound of Formula G:or a salt thereof, with: a third reducing agent, and an activator; to provide the compound of Formula F or a salt thereof.

558. The process of claim 550 or 551, further comprising preparing the compound of Formula D or a salt thereof by a process comprising: (g) reacting a compound of Formula H having Formula H-1:or a salt thereof, wherein: R9is an amine protecting group; and R11is selected from C1-20alkyl, phenyl, and -CH2NH2; with a twelfth base, to provide a compound of Formula G-1:or a salt thereof; (h) reacting the compound of Formula G-1 or a salt thereof, with: a third catalyst, an aromatic amine or a sulfur-containing reagent; and hydrogen; to provide the compound of Formula F-1: or a salt thereof; and(i) reacting the compound of Formula F-1 or a salt thereof, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula D or a salt thereof.

559. The process of claim 550 or 551, further comprising preparing the compound of Formula D or a salt thereof by a process comprising: (g) reacting a compound of Formula G-1:or a salt thereof, with: a third catalyst,an aromatic amine or a sulfur-containing reagent; and hydrogen; to provide a compound of Formula F-1:or a salt thereof; and (h) reacting the compound of Formula F-1 or a salt thereof, with: a phosphine reagent, an azodicarboxylate, and a compound of formula R7-NH-NH-R8; to provide the compound of Formula D or a salt thereof.

560. The process of claim 557 or 559, further comprising preparing the compound of Formula G or a salt thereof, wherein the compound of Formula G or a salt thereof is a compound of Formula G-1 or a salt thereof, by a process comprising: (j) reacting a compound of Formula L:or a salt thereof, with: a fourth enzyme in the presence of a fourth buffer; to provide a compound of Formula U-2:or a salt thereof; (k) reacting the compound of Formula U-2 or a salt thereof, with: a third enzyme in the presence of a third buffer;to provide a compound of Formula U-1:or a salt thereof; and (l) reacting the compound of Formula U-1 or a salt thereof, with: a second amine protecting group reagent to provide the compound of Formula G-1 or a salt thereof.

561. The process of claim 553 or 558, further comprising preparing the compound of Formula H or a salt thereof by a process comprising: (k) reacting a compound of Formula J:or a salt thereof, with: a second phosphine reagent, a second azodicarboxylate, and an amine protecting group reagent; to provide the compound of Formula H or a salt thereof.

562. The process of claim 553 or 558, further comprising preparing the compound of Formula H or a salt thereof by a process comprising: (k) reacting a compound of Formula J:or a salt thereof, wherein:R12is -S(O)3R13or -OC(=N)R14; R13is selected from C1-4alkyl, C1-4haloalkyl, and phenyl optionally substituted with C1-4alkyl; and R14is C1-4haloalkyl; with: an eleventh base, and a third reagent selected from methane sulfonyl chloride, an anhydride, or an acid halide; to provide a compound of Formula N:or a salt thereof; and (l) reacting the compound of Formula N or a salt thereof with an amine protecting group reagent, to provide the compound of Formula H or a salt thereof.

563. The process of claim 558, further comprising preparing the compound of Formula H-1 or a salt thereof by a process comprising: (k) reacting a compound of Formula N:or a salt thereof, wherein: R12is -S(O)3R13or -OC(=N)R14; and R13is selected from C1-4alkyl, C1-4haloalkyl, and phenyl optionally substituted with C1-4alkyl; with:an azide, and a third phosphine reagent; to provide a compound of Formula P-1:or a salt thereof; and (l) reacting the compound of Formula P-1 or a salt thereof with an amine protecting group reagent to provide the compound of Formula H-1 or a salt thereof.

564. The process of claim 558, further comprising preparing the compound of Formula H-1 or a salt thereof by a process comprising: (k) reacting a compound of reacting a compound of Formula J: J or a salt thereof, with: an azide, a third phosphine reagent, and a third azodicarboxylate; to provide a compound of Formula P-2:or a salt thereof; and (l) reacting the compound of Formula P-2 or a salt thereof, with: a fourth phosphine reagent; andan amine protecting group reagent; to provide the compound of Formula H-1 or a salt thereof.

565. The process of any one of claims 561, 562, and 564, further comprising preparing the compound of Formula J or a salt thereof by a process comprising: (m) reacting a compound of Formula L:or a salt thereof; with: a ninth base, a fourth catalyst; and a compound of Formula M-1 or Formula M-2: M-1 ; M-2 wherein X is a halide; to provide a compound of Formula K: K or a salt thereof; and (n) reacting the compound of Formula K or a salt thereof, with: an enzyme, and a buffer; to provide the compound of Formula J or a salt thereof.

566. The process of claim 551 or 552, further comprising preparing the compound of Formula E by a process comprising: (h) reacting a compound of Formula L:or a salt thereof, with: an alkyl ester, an alkenyl ester or an oxime ester; and an enzyme, to provide a compound of Formula O-4:or a salt thereof; (i) reacting the compound of Formula O-4 or a salt thereof, with: a second phosphine reagent, a second azodicarboxylate, and a compound of Formula R7-NH-NH-R8or methyl (1,3-dioxoisoindolin-2-yl) carbamate; to provide a compound of Formula O-3:or a salt thereof; (j) reacting the compound of Formula O-3 or a salt thereof, wherein R11is selected from C1-20alkyl, phenyl, and -CH2NH2; with:a twelfth base; to provide a compound of Formula O-2:or a salt thereof; (k) reacting the compound of Formula O-2 or a salt thereof, with: a fifth catalyst, and hydrogen; to provide the compound of Formula O-1:or a salt thereof; and (l) reacting the compound of Formula O-1 or a salt thereof, with: an amine protecting group reagent, a phosphine reagent, and an azodicarboxylate, to provide the compound of Formula E or a salt thereof.

567. A process for preparing a compound of Formula I: or a salt thereof, whereinhydroxyl protecting group; comprising:reacting a compound of Formula R-1: or a salt thereof, with:a methylene reagent, and an eighth acid or a fourteenth base, to provide the compound of Formula I or a salt thereof.

568. The process of claim 567, wherein the methylene reagent is a formaldehyde reagent or a dihalomethane.

569. The process of claim 567 or 568, wherein the methylene reagent is selected from 1,3,5-trioxane, a formaldehyde acetal, formaldehyde, paraformaldehyde, or a dihalomethane.

570. The process of any one of claims 567-569, wherein the methylene reagent is formaldehyde.

571. The process of any one of claims 567-570, wherein the compound of Formula R-1 or a salt thereof is reacted with the eighth acid.

572. The process of any one of claims 567-571, wherein the eighth acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof.

573. The process of any one of claims 567-572, wherein the eighth acid is a sulfonic acid.

574. The process of any one of claims 567-573, wherein the eighth acid is methanesulfonic acid.

575. The process of claims 567-570, wherein the compound of Formula R-1 or a salt thereof is reacted with the fourteenth base.

576. The process of any one of claims 567-570 and 575, wherein the fourteenth base comprises an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, an amide, a basic aromatic compound, or a combination thereof.

577. The process of any one of claims 567-576, wherein the reacting of the compound of Formula R-1 or a salt thereof is performed in a forty-second solvent comprising tetrahydrofuran.

578. The process of any one of claims 567-577, wherein the reacting of the compound of Formula R-1 or a salt thereof is carried out in a temperature range of from about 20 °C to about 100 °C.

579. The process of any one of claims 567-578, further comprising preparing the compound of Formula R-1 or a salt thereof by a process comprising: reacting a compound of Formula R-2:or a salt thereof, with: a coupling agent, anda fifteenth base, to provide the compound of Formula R-1 or a salt thereof.

580. The process of claim 579, wherein the coupling agent comprises 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), an acid chloride, an acid anhydride, a carbonyl diimidazole, an activated ester, or a combination thereof.

581. The process of claim 579 or 580, wherein the coupling agent is HATU.

582. The process of any one of claims 579-581, wherein the fifteenth base is selected from an amine, an amidine, a guanidine, a carboxylate, a carbonate, a metal hydride, a phosphate, a hydroxide, an alkoxide, a basic aromatic compound, or a combination thereof.

583. The process of any one of claims 579-582, wherein the fifteenth base is an amine.

584. The process of any one of claims 579-583, wherein the fifteenth base is N,N- diisopropylethylamine.

585. The process of any one of claims 579-584, wherein the reacting of the compound of Formula R-2 or a salt thereof is performed in a twenty-eighth solvent comprising N,N- dimethylacetamide.

586. The process of any one of claims 579-585, wherein the reacting of the compound of Formula R-2 or a salt thereof is carried out in a temperature range of from about 0 °C to about 80 °C.

587. The process of any one of claims 579-586, further comprising preparing the compound of Formula R-2 or a salt thereof by a process comprising:reacting a compound of Formula A:or a salt thereof, wherein is hydrogen or a hydroxyl protecting group, with: a reagent selected from a metal hydroxide, a metal halide, and a trialkylsilyl halide; to provide the compound of Formula R-2 or a salt thereof.

588. The process of claim 587, wherein R3Ais selected from hydrogen, C1-4alkyl, and benzyl.

589. The process of claim 587 or 588, wherein R3Ais selected from hydrogen, methyl, ethyl, isopropyl, and benzyl.

590. The process of any one of claims 587-589, wherein R3Ais methyl.

591. The process of any one of claims 587-590, wherein the compound of Formula A is reacted with a metal hydroxide.

592. The process of any one of claims 587-591, wherein the metal hydroxide is sodium hydroxide.

593. The process of any one of claims 587-592, wherein the reacting of the compound of Formula A or a salt thereof is performed in a forty-forth solvent comprising methanol.

594. The process of any one of claims 587-593, wherein the reacting of the compound of Formula A or a salt thereof is carried out in a temperature range of from about 0 °C to about 100 °C.

595. A process for preparing a compound of Formula I: or a salt thereof, whereinhydroxyl protecting group; comprising: (a) reacting a compound of Formula A: or a salt thereof,protecting group, with: a reagent selected from a metal hydroxide, a metal halide, and a trialkylsilyl halide; to provide a compound of Formula R-2:or a salt thereof; (b) reacting the compound of Formula R-2 or a salt thereof, with: a coupling agent, anda fifteenth base, to provide a compound of Formula R-1 or a salt thereof; and(c) reacting the compound of Formula R-1 or a salt thereof, with: a methylene reagent, and an eighth acid or a fourteenth base, to provide the compound of Formula I or a salt thereof.

596. A compound of Formula A: or a salt thereof,from hydrogen and a hydroxyl protecting group.

597. A compound of Formula R-1: or a salt thereof, whereinhydroxyl protecting group.

598. A compound of Formula R-2:or a salt thereof, wherein is selected from hydrogen and a hydroxyl protecting group.

599. A compound of Formula Q-1:or a salt thereof, wherein R1and R3Aare each hydroxyl protecting groups.

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