Improved chemical methods for manufacturing a phosphoramidite used in RNA synthesis

Abstract

Provided herein are methods of preparing a compound of Formula (I) or (I'), or a salt or tautomer thereof, comprising coupling a compound of Formula (Il-a) or (II'-a), or a salt or tautomer thereof, with a compound of Formula (Il-b), or a salt thereof, to obtain the compound of Formula (I) or (I'), or salt or tautomer thereof, wherein the compound of Formula (Il-a) or (II'-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (III) or (III'), or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (Il-a) or (II'-a), or salt or tautomer thereof.

Description

IMPROVED CHEMICAL METHODS FOR MANUFACTURING A PHOSPHORAMIDITE USED IN RNA SYNTHESISCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority under 35 U.S.C. § 119(e) to U.S.Provisional Application Number 63 / 696,033, filed September 18, 2024, the contents of which are herein incorporated by reference in their entirety.BACKGROUND OF THE INVENTION

[0002] Therapeutic nucleic acids such as messenger RNAs, small interfering RNAs, antisense oligonucleotides, and gene-editing tools like CRISPR, offer targeted treatments for genetic disorders and other diseases and conditions. The efficient, large-scale preparation of such complex molecules requires solutions to problems of chemical synthesis related to stereo- and chemo-selectivity (including, e.g., functional group compatibility and protecting group orthogonality) toxicity and safety at scale, and ease of handling at scale.

[0003] Small molecule phosphoramidites are used in the synthesis of such therapeutic nucleic acids, and methods for their efficient, large-scale preparation are needed.SUMMARY OF THE INVENTION

[0004] In one aspect, provided herein is a method of preparing a compound of Formula (I):or a salt or tautomer thereof, comprising coupling a compound of Formula (II-a):or a salt or tautomer thereof, with a compound of Formula (Il-b):E0585.70022WO00 1 / 117#14402392vlor a salt thereof, to obtain the compound of Formula (I), or salt or tautomer thereof, wherein the compound of Formula (II-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (III):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II- a), or salt or tautomer thereof.

[0005] In another aspect, provided herein is a method of preparing a compound of Formula (I'):or a salt or tautomer thereof, comprising coupling a compound of Formula (Il'-a):or a salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain the compound of Formula (I'), or salt or tautomer thereof, wherein the compound of Formula (Il'-a), or salt or tautomer thereof, is prepared by reacting a compound ofE0585.70022WO00 2 / 117#14402392vlFormula (III'):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'- a), or salt or tautomer thereof.

[0006] In another aspect, provided herein is a method of preparing a compound of Formula (I):or a salt or tautomer thereof, comprising coupling a compound of Formula (II-a):or a salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain the compound of Formula (I), or salt or tautomer thereof, wherein: the compound of Formula (II-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (III):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II- a), or salt or tautomer thereof;E0585.70022WO00 3 / 117#14402392vlthe compound of Formula (III), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IV-a):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III), or salt or tautomer thereof; the compound of Formula (IV-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (V):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV- a), or salt or tautomer thereof; the compound of Formula (V), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof; the compound of Formula (VI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof; the compound of Formula (VII), or salt or tautomer thereof, is prepared by reacting aE0585.70022WO00 4 / 117#14402392vlcompound of Formula (VIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof; the compound of Formula (VIII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IX):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof; the compound of Formula (IX), or salt or tautomer thereof, is prepared by reacting a compound of Formula (X):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof; the compound of Formula (X), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof; the compound of Formula (XI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI),E0585.70022WO00 5 / 117#14402392vlor salt or tautomer thereof; and the compound of Formula (XII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof.

[0007] In another aspect, provided herein is a method of preparing a compound of Formula (I'):or a salt or tautomer thereof, comprising coupling a compound of Formula (Il'-a):or a salt or tautomer thereof, with a compound of Formula (Il-b):or a salt thereof, to obtain the compound of Formula (I'), or salt or tautomer thereof, wherein: the compound of Formula (Il'-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (III'):E0585.70022WO00 6 / 117#14402392vlor a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'- a), or salt or tautomer thereof; the compound of Formula (III'), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IV-a):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III'), or salt or tautomer thereof; the compound of Formula (IV-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (V):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV- a), or salt or tautomer thereof; the compound of Formula (V), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof; the compound of Formula (VI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof;E0585.70022WO00 7 / 117#14402392vlthe compound of Formula (VII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof; the compound of Formula (VIII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IX):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof; the compound of Formula (IX), or salt or tautomer thereof, is prepared by reacting a compound of Formula (X):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof; the compound of Formula (X), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof; the compound of Formula (XI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XII):E0585.70022WO00 8 / 117#14402392vlor a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof; and the compound of Formula (XII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof.

[0008] In another aspect, provided herein is a method of synthesis comprising one or more of the following steps:(a) reacting a compound of Formula (XIII):or a salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (XII):or a salt or tautomer thereof;(b) reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (XI):or a salt or tautomer thereof;(c) reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (X):or a salt or tautomer thereof;(d) reacting the compound of Formula (X), or salt or tautomer thereof, under suitableE0585.70022WO00 9 / 117#14402392vlconditions to obtain a compound of Formula (IX):or a salt or tautomer thereof;(e) reacting the compound of Formula (IX), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (VIII):or a salt or tautomer thereof;(f) reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (VII):or a salt or tautomer thereof;(g) reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (VI):or a salt or tautomer thereof;(h) reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (V):or a salt or tautomer thereof;(i) reacting the compound of Formula (V), or salt or tautomer thereof, under suitableE0585.70022WO00 10 / 117#14402392vlconditions to obtain a compound of Formula (IV-a):or a salt or tautomer thereof;(j) reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (III):or a salt or tautomer thereof;(k) reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (II-a):or a salt or tautomer thereof;(1) coupling the compound of Formula (II-a), or salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain a compound of Formula (I):or a salt or tautomer thereof;E0585.70022WO00 11 / 117#14402392vl(m) reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (III'):or a salt or tautomer thereof;(n) reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (Il'-a):or a salt or tautomer thereof; and(o) coupling the compound of Formula (Il'-a), or salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain a compound of Formula (I'):or a salt or tautomer thereof.

[0009] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosureE0585.70022WO00 12 / 117#14402392vlwill become apparent from the following detailed description of various non-limiting embodiments.DEFINITIONS

[0010] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March ’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0011] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, in some embodiments, the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen el al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0012] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.E0585.70022WO00 13 / 117#14402392vl

[0013] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided.

[0014] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0015] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), / -butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), / -butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3 -bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxy cyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl 5,5-dioxide, l-[(2-chloro-4- methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl,1 -methyl- l-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl)ethyl, / -butyl, allyl, / 2-chlorophenyl, -methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), -methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, -nitrobenzyl, p- halobenzyl, 2,6-dichlorobenzyl, / 2-cyanobenzyl, / 2-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl A-oxido, diphenylmethyl, p,p ’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4'-dimethoxytrityl (4,4'-dimethoxytriphenylmethyl or DMT), a-naphthyldiphenylmethyl, - methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri( / - methoxyphenyl)methyl, 4-(4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4, 4', 4"- tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl (IDTr), 4,4’- Dimethoxy-3 " ‘ -[N-(imidazolylethyl)carbamoyl]trityl (lETr), 1 , 1 -bis(4-methoxyphenyl)- 1 pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3- benzodithiolan-2-yl, benzisothiazolyl 5,5-dioxido, trimethyl silyl (TMS), triethyl silyl (TES), triisopropylsilyl (TIPS), dimethylisopropyl silyl (IPDMS), diethylisopropylsilyl (DEIPS),E0585.70022WO00 14 / 117#14402392vldimethylthexylsilyl, Z-butyldimethylsilyl (TBDMS), Z-butyldiphenyl silyl (TBDPS), tribenzylsilyl, tri- / ?-xylylsilyl, triphenylsilyl, diphenylmethyl silyl (DPMS), Z- butylmethoxyphenyl silyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, di chloroacetate, tri chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, -chlorophenoxy acetate, 3 -phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenyl sulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, Z-butyl carbonate (BOC or Boc), / 2-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p- nitrobenzyl carbonate, 5-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarb onate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6- dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(l,l,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(l,l-dimethylpropyl)phenoxy acetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (£)-2-methyl-2-butenoate, o-(methoxyacyl )benzoate, a-naphthoate, nitrate, alkyl N,N,N ’,7V’- tetramethylphosphorodiamidate, alkyl 7V-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0016] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0017] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present disclosure is not limited in any manner by the above exemplary listing of substituents.

[0018] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid,E0585.70022WO00 15 / 117#14402392vlphosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, di gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, -toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(CI-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0019] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,E0585.70022WO00 16 / 117#14402392vlpropionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0020] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (z.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to- imine, and enamine-to-(a different enamine) tautomerizations.

[0021] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0022] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (z.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0023] The term “about X,” where X is a number or percentage, refers to a number or percentage that is between 99.5% and 100.5%, between 99% and 101%, between 98% and 102%, between 97% and 103%, between 96% and 104%, between 95% and 105%, between 92% and 108%, or between 90% and 110%, inclusive, of X.

[0024] The term “substantially Y,” where Y is a characteristic (e.g., anhydrous), refers to a characteristic that is at least 99.5%, at least 99%, at least 98%, at least 97%, at least 96%, at least 95%, at least 92%, or at least 90% the same as Y, unless expressly provided otherwise.E0585.70022WO00 17 / 117#14402392vlDETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0025] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.Methods of Preparation and Synthesis

[0026] In one aspect, provided herein is a method of preparing a compound of Formula (I):or a salt or tautomer thereof, comprising coupling a compound of Formula (II-a):or a salt or tautomer thereof, with a compound of Formula (Il-b):or a salt thereof, to obtain the compound of Formula (I), or salt or tautomer thereof, wherein the compound of Formula (II-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (III):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II- a), or salt or tautomer thereof.E0585.70022WO00 18 / 117#14402392vl

[0027] In another aspect, provided herein is a method of preparing a compound of Formula (I'):or a salt or tautomer thereof, comprising coupling a compound of Formula (Il'-a):or a salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain the compound of Formula (I'), or salt or tautomer thereof, wherein the compound of Formula (Il'-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (III'):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'- a), or salt or tautomer thereof.E0585.70022WO00 19 / 117#14402392vl

[0028] In another aspect, provided herein is a method of preparing a compound of Formula (I):or a salt or tautomer thereof, comprising coupling a compound of Formula (II-a):or a salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain the compound of Formula (I), or salt or tautomer thereof, wherein: the compound of Formula (II-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (III):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II- a), or salt or tautomer thereof; the compound of Formula (III), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IV-a):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III), or salt or tautomer thereof;E0585.70022WO00 20 / 117#14402392vlthe compound of Formula (IV-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (V):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV- a), or salt or tautomer thereof; the compound of Formula (V), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof; the compound of Formula (VI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof; the compound of Formula (VII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof; the compound of Formula (VIII), or salt or tautomer thereof, is prepared by reacting aE0585.70022WO00 21 / 117#14402392vlcompound of Formula (IX):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula(VIII), or salt or tautomer thereof; the compound of Formula (IX), or salt or tautomer thereof, is prepared by reacting a compound of Formula (X):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof; the compound of Formula (X), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof; the compound of Formula (XI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof; and the compound of Formula (XII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII),E0585.70022WO00 22 / 117#14402392vlor salt or tautomer thereof.

[0029] In another aspect, provided herein is a method of preparing a compound of Formula (I'):or a salt or tautomer thereof, comprising coupling a compound of Formula (Il'-a):or a salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain the compound of Formula (I'), or salt or tautomer thereof, wherein: the compound of Formula (Il'-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (III'):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'- a), or salt or tautomer thereof; the compound of Formula (III'), or salt or tautomer thereof, is prepared by reacting aE0585.70022WO00 23 / 117#14402392vlcompound of Formula (IV-a):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III'), or salt or tautomer thereof; the compound of Formula (IV-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (V):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV- a), or salt or tautomer thereof; the compound of Formula (V), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof; the compound of Formula (VI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof; the compound of Formula (VII), or salt or tautomer thereof, is prepared by reacting aE0585.70022WO00 24 / 117#14402392vlcompound of Formula (VIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof; the compound of Formula (VIII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IX):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof; the compound of Formula (IX), or salt or tautomer thereof, is prepared by reacting a compound of Formula (X):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof; the compound of Formula (X), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof; the compound of Formula (XI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XII):E0585.70022WO00 25 / 117#14402392vlor a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof; and the compound of Formula (XII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof.

[0030] In another aspect, provided herein is a method of synthesis comprising one or more of the following steps:(a) reacting a compound of Formula (XIII):or a salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (XII):or a salt or tautomer thereof;(b) reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (XI):or a salt or tautomer thereof;(c) reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (X):or a salt or tautomer thereof;(d) reacting the compound of Formula (X), or salt or tautomer thereof, under suitableE0585.70022WO00 26 / 117#14402392vlconditions to obtain a compound of Formula (IX):or a salt or tautomer thereof;(e) reacting the compound of Formula (IX), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (VIII):or a salt or tautomer thereof;(f) reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (VII):or a salt or tautomer thereof;(g) reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (VI):or a salt or tautomer thereof;(h) reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (V):or a salt or tautomer thereof;(i) reacting the compound of Formula (V), or salt or tautomer thereof, under suitableE0585.70022WO00 27 / 117#14402392vlconditions to obtain a compound of Formula (IV-a):or a salt or tautomer thereof;(j) reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (III):or a salt or tautomer thereof;(k) reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (II-a):or a salt or tautomer thereof;(1) coupling the compound of Formula (II-a), or salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain a compound of Formula (I):or a salt or tautomer thereof;E0585.70022WO00 28 / 117#14402392vl(m) reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (III'):or a salt or tautomer thereof;(n) reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (Il'-a):or a salt or tautomer thereof; and(o) coupling the compound of Formula (Il'-a), or salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain a compound of Formula (I'):or a salt or tautomer thereof.E0585.70022WO00 29 / 117#14402392vlFormula (I) and (I')

[0031] As generally described herein, the compound of Formula (I):or a salt or tautomer thereof, is prepared by coupling a compound of Formula (II-a):or a salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain the compound of Formula (I), or salt or tautomer thereof.

[0032] As generally described herein, the compound of Formula (I'):or a salt or tautomer thereof, is prepared by coupling a compound of Formula (Il'-a):E0585.70022WO00 30 / 117#14402392vlor a salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain the compound of Formula (I'), or salt or tautomer thereof.

[0033] In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to a coupling activator selected from the group consisting of l-methyl-lH-benzimidazol-3-ium trifluoromethanesulfonate (N-MeBIT), l-phenyl-lH-imidazol-3-ium trifluoromethanesulfonate (N-PhIMT), lH-benzimidazol-3-ium trifluoromethanesulfonate (BIT), lH-imidazol-3-ium trifluoromethanesulfonate (IMT), 5-nitro-lH-benzimidazol-3-ium trifluoromethanesulfonate (NBT), 5-(ethylthio)-lH-tetrazole (ETT), 5-(benzylthio)-lH-tetrazole (BTT), 4,5- dicyanoimidazole (DCI), 2-bromo-4,5-dicyanoimidazole (Br-DCI), pyridinium chloride (PyHCl), pyridinium trifluoroacetate (PyTFA), and l-(cyanomethyl)piperidinium tetrafluorob orate, and salts thereof. In some embodiments, the coupling activator is 4,5- dicyanoimidazole (DCI), or a salt thereof. In some embodiments, the coupling activator is 4,5- dicyanoimidazole (DCI).

[0034] In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to a coupling activator, wherein the coupling activator is 4,5-dicyanoimidazole (DCI), or a salt thereof. In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to a coupling activator, wherein the coupling activator is 4,5-dicyanoimidazole (DCI).

[0035] In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to a halogenated solvent selected from dichloromethane, chloroform, and 1,2-di chloroethane, optionally wherein the halogenated solvent is dichloromethane. In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to a halogenated solvent selected from di chloromethane, chloroform, and 1,2-di chloroethane. In some embodiments, the halogenated solvent is dichloromethane. In some embodiments, the halogenated solvent is chloroform. In some embodiments, the halogenated solvent is 1,2-di chloroethane.E0585.70022WO00 31 / 117#14402392vl

[0036] In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to a halogenated solvent, wherein the halogenated solvent is dichloromethane.

[0037] In some embodiments, a molar ratio of the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, to the compound of Formula (II-b), or salt thereof, is between about 1 : 1 and about 1:1.5, about 1:1 and about 1:1.4, about 1:1 and about 1:1.3, about 1:1.1 and about 1:1.5, about 1:1.1 and about 1:1.4, about 1:1.1 and about 1:1.3, about 1:1.2 and about 1:1.5, about 1:1.2 and about 1:1.4, about 1:1.2 and about 1:1.3, or about 1 : 1.25 and 1 : 1.35. In some embodiments, the molar ratio of the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, to the compound of Formula (II-b), or salt thereof, is between about 1:1.2 and about 1 : 1.4 or about 1 : 1.25 and 1:1.35. In some embodiments, the molar ratio of the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, to the compound of Formula (II-b), or salt thereof, is about 1:1.2, 1:1.25, 1:1.26, 1:1.27, 1:1.28, 1:1.29, 1:1.30, 1:1.31, 1:1.32, 1:1.33, 1 : 1.34, 1:1.35, or 1:1.4. In some embodiments, the molar ratio of the compound of Formula (II- a) or (Il'-a), or salt or tautomer thereof, to the compound of Formula (II-b), or salt thereof, is about 1:1.30.

[0038] In some embodiments, a molar ratio of the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, to the coupling activator is between about 1 : 1 and about 1:1.2, about 1 : 1 and about 1:1.15, about 1 : 1 and about 1 : 1.1 , or about 1 : 1 and about 1 : 1.05. In some embodiments, a molar ratio of the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, to the coupling activator is about 1:1, about 1:1.01, about 1 : 1.02, about 1 : 1.03, 1 : 1.04, 1 : 1.05, 1 : 1.06, 1:1.07, 1 : 1.08, 1 : 1.09, or 1 : 1.1. In some embodiments, a molar ratio of the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, to the coupling activator is about 1:1.05.

[0039] In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises a reaction temperature of between about -20 °C and about 25 °C, about -20 °C and about 20 °C, about -20 °C and about 15 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -15 °C and about 25 °C, about -15 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about -5 °C and about 5 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, about 0 °C and about 5 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, about 5 °C and about 15 °C,E0585.70022WO00 32 / 117#14402392vlor about 5 °C and about 10 °C. In some embodiments, the reaction temperature is between about -20 °C and about 15 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about 0 °C and about 15 °C, or about 0 °C and about 10 °C. In some embodiments, the reaction temperature is between about -5 °C and about 15 °C. In some embodiments, the reaction temperature is between about 0 °C and about 10 °C.

[0040] In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises a reaction temperature of between about 0 °C and about 10 °C. In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises a reaction temperature of about 0 °C, about 1 °C, about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, or about 10 °C.

[0041] In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, produces a reaction mixture that is maintained at the reaction temperature.

[0042] In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to: a coupling activator selected from the group consisting of l-methyl-lH-benzimidazol-3-ium trifluoromethanesulfonate (N-MeBIT), l-phenyl-lH-imidazol-3-ium trifluoromethanesulfonate (N-PhIMT), lH-benzimidazol-3-ium trifluoromethanesulfonate (BIT), lH-imidazol-3-ium trifluoromethanesulfonate (IMT), 5-nitro-lH-benzimidazol-3-ium trifluoromethanesulfonate (NBT), 5-(ethylthio)-lH-tetrazole (ETT), 5-(benzylthio)-lH-tetrazole (BTT), 4,5- dicyanoimidazole (DCI), 2-bromo-4,5-dicyanoimidazole (Br-DCI), pyridinium chloride (PyHCl), pyridinium trifluoroacetate (PyTFA), and l-(cyanomethyl)piperidinium tetrafluorob orate, and salts thereof; and a halogenated solvent selected from dichloromethane, chloroform, and 1,2-di chloroethane; and comprises a reaction temperature of between about -20 °C and about 25 °C, about -20 °C and about 20 °C, about -20 °C and about 15 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -15 °C and about 25 °C, about -15 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about -5 °C and about 5 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °CE0585.70022WO00 33 / 117#14402392vland about 15 °C, about 0 °C and about 10 °C, about 0 °C and about 5 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, about 5 °C and about 15 °C, or about 5 °C and about 10 °C.

[0043] In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to: a coupling activator, wherein the coupling activator is 4,5-dicyanoimidazole (DCI), or a salt thereof; and a halogenated solvent selected from di chloromethane, chloroform, and 1,2- di chloroethane; and comprises a reaction temperature of between about -20 °C and about 25 °C, about -20 °C and about 20 °C, about -20 °C and about 15 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -15 °C and about 25 °C, about -15 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about -5 °C and about 5 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, about 0 °C and about 5 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, about 5 °C and about 15 °C, or about 5 °C and about 10 °C.

[0044] In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to: a coupling activator, wherein the coupling activator is 4,5-dicyanoimidazole (DCI), or a salt thereof; and a halogenated solvent, wherein the halogenated solvent is dichloromethane; and comprises a reaction temperature of between about -20 °C and about 25 °C, about -20 °C and about 20 °C, about -20 °C and about 15 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -15 °C and about 25 °C, about -15 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about -5 °C and about 5 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, about 0 °C and about 5 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, about 5 °C and about 15 °C, or about 5 °C and about 10 °C.

[0045] In some embodiments, coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to: a coupling activator, wherein the coupling activator is 4,5-dicyanoimidazole (DCI), or a salt thereof; and a halogenated solvent, wherein the halogenated solvent is dichloromethane; and comprises a reaction temperature of between about 0 °C and about 10 °C.E0585.70022WO00 34 / 117#14402392vlFormula (Il-a) and (Il'-a)

[0046] As generally described herein, the compound of Formula (II-a):or salt or tautomer thereof, is prepared by reacting a compound of Formula (III):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II- a), or salt or tautomer thereof.

[0047] As generally described herein, the compound of Formula (Il'-a):or salt or tautomer thereof, is prepared by reacting a compound of Formula (III'):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'- a), or salt or tautomer thereof.

[0048] In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (Il'-a), or salt or tautomer thereof, comprises exposure to a fluoride source selected from tetrabutylammonium fluoride (TBAF), hydrogen fluoride pyridine (HF-pyridine), triethylamine trihydrofluoride (Et3N»3HF), hydrofluoric acid,E0585.70022WO00 35 / 117#14402392vltris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), and ammonium fluoride, and salts thereof. In some embodiments, the fluoride source is tetrabutylammonium fluoride (TBAF), or a salt thereof. In some embodiments, the fluoride source is hydrogen fluoride pyridine (HF-pyridine), or a salt thereof. In some embodiments, the fluoride source is triethylamine trihydrofluoride (Et3N»3HF), or a salt thereof. In some embodiments, the fluoride source is triethylamine trihydrofluoride (Et3N»3HF). In some embodiments, the fluoride source is hydrofluoric acid, or a salt thereof. In some embodiments, the fluoride source is tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), or a salt thereof. In some embodiments, the fluoride source is ammonium fluoride, or a salt thereof.

[0049] In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises exposure to a fluoride source, wherein the fluoride source is triethylamine trihydrofluoride (Et3N»3HF), or a salt thereof. In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises exposure to a fluoride source, wherein the fluoride source is triethylamine trihydrofluoride (Et3N»3HF).

[0050] In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises exposure to an alcohol solvent selected from methanol, ethanol, and isopropanol, optionally wherein the alcohol solvent is methanol. In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises exposure to an alcohol solvent selected from methanol, ethanol, and isopropanol. In some embodiments, the alcohol solvent is methanol. In some embodiments, the alcohol solvent is ethanol. In some embodiments, the alcohol solvent is isopropanol.

[0051] In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitableE0585.70022WO00 36 / 117#14402392vlconditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises exposure to an alcohol solvent, wherein the alcohol solvent is methanol.

[0052] In some embodiments, a molar ratio of the compound of Formula (III) or (III'), or salt or tautomer thereof, to the fluoride source is between about 1 : 1 and about 1 : 10, about 1 : 1 and about 1 :9, about 1 : 1 and about 1 :8, about 1 :1 and about 1 :7, about 1 : 1 and about 1 :6, about 1 : 1 and about 1 :5, about 1 :5 and about 1 : 10, about 1 :5 and about 1 :9, about 1 :5 and about 1 :8, about 1 :6 and about 1 : 10, about 1 :6 and about 1 :9, about 1 :6 and about 1 :8, about 1 :7 and about 1 : 10, about 1 :7 and about 1 :9, about 1 :7 and about 1 :8, or about 1 :7 and about 1 :7.5. In some embodiments, the molar ratio of the compound of Formula (III) or (III'), or salt or tautomer thereof, to the fluoride source is between about 1 :6 and about 1 :8, about 1 :7 and about 1 :8, or about 1 :7 and about 1 :7.5. In some embodiments, the molar ratio of the compound of Formula (HI) or (in ), or salt or tautomer thereof, to the fluoride source is about 1 :6, about 1 :6.5, about 1 :7, about 1 :7.1, about 1 :7.2, about 1 :7.3, about 1 :7.4, about 1 :7.5, about 1 :7.6, about 1 :7.7, about 1 :7.8, about 1 :7.9, or about 1 :8. In some embodiments, the molar ratio of the compound of Formula (III) or (III'), or salt or tautomer thereof, to the fluoride source is about 1 :7.3.

[0053] In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises a reaction temperature of between about 25 °C and about 95 °C, about 30 °C and about 90 °C, about 35 °C and about 85 °C, about 40 °C and about 80 °C, about 45 °C and about 75 °C, about 50 °C and about 70 °C, about 55 °C and about 65 °C, about 40 °C and about 75 °C, about 40 °C and about 70 °C, about 40 °C and about 65 °C, about 40 °C and about 60 °C, about 45 °C and about 70 °C, about 45 °C and about 65 °C, about 45 °C and about 60 °C, about 50 °C and about 75 °C, about 50 °C and about 65 °C, about 50 °C and about 60 °C, about 55 °C and about 75 °C, about 55 °C and about 70 °C, about 55 °C and about 60 °C, about 55 °C and about 85 °C, about 60 °C and about 80 °C, about 65 °C and about 80 °C, about 70 °C and about 80 °C, or about 75 °C and about 80 °C. In some embodiments, the reaction temperature is between about 45 °C and about 75 °C, about 50 °C and about 70 °C, about 55 °C and about 65 °C, about 45 °C and about 70 °C, about 45 °C and about 65 °C, about 50 °C and about 75 °C, about 50 °C and about 65 °C, about 55 °C and about 70 °C. In some embodiments, the reaction temperature is between about 50 °C and about 70 °C. In some embodiments, the reaction temperature is between about 55 °C and about 65 °C.

[0054] In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomerE0585.70022WO00 37 / 117#14402392vlthereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises a reaction temperature of between about 55 °C and about 65 °C. In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (nr), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises a reaction temperature of about 55 °C, about 56 °C, about 57 °C, about 58 °C, about 59 °C, about 60 °C, about 61 °C, about 62 °C, about 63 °C, about 64 °C, or about 65 °C.

[0055] In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, produces a reaction mixture that is maintained at the reaction temperature.

[0056] In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises exposure to: a fluoride source selected from tetrabutylammonium fluoride (TBAF), hydrogen fluoride pyridine (HF-pyridine), triethylamine trihydrofluoride (Et3N»3HF), hydrofluoric acid, tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), and ammonium fluoride, and salts thereof; and an alcohol solvent selected from methanol, ethanol, and isopropanol; and comprises a reaction temperature of between about 25 °C and about 95 °C, about 30 °C and about 90 °C, about 35 °C and about 85 °C, about 40 °C and about 80 °C, about 45 °C and about 75 °C, about 50 °C and about 70 °C, about 55 °C and about 65 °C, about 40 °C and about 75 °C, about 40 °C and about 70 °C, about 40 °C and about 65 °C, about 40 °C and about 60 °C, about 45 °C and about 70 °C, about 45 °C and about 65 °C, about 45 °C and about 60 °C, about 50 °C and about 75 °C, about 50 °C and about 65 °C, about 50 °C and about 60 °C, about 55 °C and about 75 °C, about 55 °C and about 70 °C, about 55 °C and about 60 °C, about 55 °C and about 85 °C, about 60 °C and about 80 °C, about 65 °C and about 80 °C, about 70 °C and about 80 °C, or about 75 °C and about 80 °C.

[0057] In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprisesE0585.70022WO00 38 / 117#14402392vlexposure to: a fluoride source, wherein the fluoride source is triethylamine trihydrofluoride (Et3N»3HF), or a salt thereof; and an alcohol solvent selected from methanol, ethanol, and isopropanol; and comprises a reaction temperature of between about 25 °C and about 95 °C, about 30 °C and about 90 °C, about 35 °C and about 85 °C, about 40 °C and about 80 °C, about 45 °C and about 75 °C, about 50 °C and about 70 °C, about 55 °C and about 65 °C, about 40 °C and about 75 °C, about 40 °C and about 70 °C, about 40 °C and about 65 °C, about 40 °C and about 60 °C, about 45 °C and about 70 °C, about 45 °C and about 65 °C, about 45 °C and about 60 °C, about 50 °C and about 75 °C, about 50 °C and about 65 °C, about 50 °C and about 60 °C, about 55 °C and about 75 °C, about 55 °C and about 70 °C, about 55 °C and about 60 °C, about 55 °C and about 85 °C, about 60 °C and about 80 °C, about 65 °C and about 80 °C, about 70 °C and about 80 °C, or about 75 °C and about 80 °C.

[0058] In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises exposure to: a fluoride source, wherein the fluoride source is triethylamine trihydrofluoride (Et3N»3HF), or a salt thereof; and an alcohol solvent, wherein the alcohol solvent is methanol; and comprises a reaction temperature of between about 50 °C and about 70 °C, about 55 °C and about 65 °C, about 40 °C and about 70 °C, about 40 °C and about 65 °C, about 40 °C and about 60 °C, about 45 °C and about 70 °C, about 45 °C and about 65 °C, about 45 °C and about 60 °C, about 50 °C and about 65 °C, about 50 °C and about 60 °C, about 55 °C and about 70 °C, or about 55 °C and about 60 °C. In some embodiments, reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises exposure to: a fluoride source, wherein the fluoride source is triethylamine trihydrofluoride (Et3N»3HF), or a salt thereof; and an alcohol solvent, wherein the alcohol solvent is methanol; and comprises a reaction temperature of between about 55 °C and about 65Formula (III) and (III)

[0059] As generally described herein, the compound of Formula (III), or salt or tautomerE0585.70022WO00 39 / 117#14402392vlthereof, is prepared by reacting a compound of Formula (IV-a):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III), or salt or tautomer thereof.

[0060] In some embodiments, reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III), or salt or tautomer thereof, comprises exposure of a compound of Formula (IV-b):or salt thereof, to a base and a first solvent, to produce a first solution.

[0061] As generally described herein, the compound of Formula (III'), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IV-a):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III'), or salt or tautomer thereof.

[0062] In some embodiments, reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III'), or salt or tautomer thereof, comprises exposure of a compound of Formula (IV'-b):or salt thereof, to a base and a first solvent, to produce a first solution.

[0063] In some embodiments, the base is potassium ZerZ-butoxide (Z-BuOK), sodium tert- butoxide (Z-BuONa), or lithium Zc / V-butoxide (Z-BuOLi). In some embodiments, the base is potassium ZerZ-butoxide (Z-BuOK). In some embodiments, the base is sodium ZerZ-butoxide (Z- BuONa). In some embodiments, the base is lithium ZerZ-butoxide (Z-BuOLi).E0585.70022WO00 40 / 117#14402392vl

[0064] In some embodiments, the first solvent comprises acetonitrile, tetrahydrofuran, or a combination thereof. In some embodiments, the first solvent comprises acetonitrile. In some embodiments, the first solvent comprises tetrahydrofuran. In some embodiments, the first solvent comprises acetonitrile and tetrahydrofuran. In some embodiments, the first solvent is acetonitrile, tetrahydrofuran, or a combination thereof. In some embodiments, the first solvent is acetonitrile. In some embodiments, the first solvent is tetrahydrofuran. In some embodiments, the first solvent is acetonitrile and tetrahydrofuran.

[0065] In some embodiments, a molar ratio of the compound of Formula (IV-b) or (IV'-b), or salt thereof, to the base is between about 1 : 1 and about 1 :0.8, about 1 : 1 and about 1 :0.85, about 1:1 and about 1:0.9, about 1:0.95 and about 1:0.8, about 1:0.95 and about 1:0.85, or about 1:0.95 and about 1:0.9. In some embodiments, the molar ratio of the compound of Formula (IV-b) or (IV'-b), or salt thereof, to the base is between about 1 : 1 and about 1 :0.9 or about 1 :0.95 and about 1:0.9. In some embodiments, the molar ratio of the compound of Formula (IV-b) or (IV'- b), or salt thereof, to the base is about 1 :0.9, about 1 :0.91, about 1 :0.92, about 1 :0.93, about 1:0.94, about 1:0.95, about 1:0.96, about 1:0.97, about 1:0.98, about 1:0.99, or about 1:1. In some embodiments, the molar ratio of the compound of Formula (IV-b) or (IV'-b), or salt thereof, to the base is about 1 :0.94.

[0066] In some embodiments, a molar ratio of the compound of Formula (IV-a), or salt thereof, to the compound of Formula (IV-b) or (IV'-b), or salt or tautomer thereof, is between about 1 : 1 and about 1:3, about 1:1 and about 1:2.5, about 1:1 and about 1:2, about 1:1 and about 1:1.75, about 1:1.5 and about 1:3, about 1:1.5 and about 1:2.5, about 1:1.5 and about 1:2, about 1:1.5 and about 1 : 1.75, about 1:1.6 and about 1 : 1.9, or about 1:1.7 and about 1 : 1.8. In some embodiments, a molar ratio of the compound of Formula (IV-a), or salt thereof, to the compound of Formula (IV-b) or (IV'-b), or salt or tautomer thereof, is between about 1 : 1 and about 1:2.5, about 1:1.5 and about 1:2, about 1:1.6 and about 1:1.9, or about 1:1.7 and about 1:1.8. In some embodiments, a molar ratio of the compound of Formula (IV-a), or salt thereof, to the compound of Formula (IV-b) or (IV'-b), or salt or tautomer thereof, is about 1:1.5, about 1:1.55, about 1:1.6, about 1:1.65, about 1:1.7, about 1:1.75, about 1:1.8, about 1:1.85, about 1:1.9, about 1 : 1.95, or about 1 :2. In some embodiments, a molar ratio of the compound of Formula (IV-a), or salt thereof, to the compound of Formula (IV-b) or (IV'-b), or salt or tautomer thereof, is about 1 : 1.75.

[0067] In some embodiments, exposure of the compound of Formula (IV-b) or (IV'-b), or salt thereof, to the base comprises a first reaction temperature of between about -20 °C and about 25 °C, about -20 °C and about 20 °C, about -20 °C and about 15 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -15 °C and about 25 °C, about -15 °C and about 20 °C,E0585.70022WO00 41 / 117#14402392vlabout -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about -5 °C and about 5 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, about 0 °C and about 5 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, about 5 °C and about 15 °C, or about 5 °C and about 10 °C. In some embodiments, the first reaction temperature is between about -20 °C and about 15 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about 0 °C and about 15 °C, or about 0 °C and about 10 °C. In some embodiments, the first reaction temperature is between about -5 °C and about 15 °C. In some embodiments, the first reaction temperature is between about 0 °C and about 10 °C.

[0068] In some embodiments, exposure of the compound of Formula (IV-b) or (IV'-b), or salt thereof, to the base comprises a first reaction temperature of between about 0 °C and about 10 °C. In some embodiments, exposure of the compound of Formula (IV-b) or (IV'-b), or salt thereof, to the base comprises a first reaction temperature of about 0 °C, about 1 °C, about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, or about 10 °C.

[0069] In some embodiments, the first solution is maintained at the first reaction temperature.

[0070] In some embodiments, the base is potassium ZerZ-butoxide (Z-BuOK), sodium tert- butoxide (Z-BuONa), or lithium Zc / V-butoxide (Z-BuOLi); the first solvent comprises acetonitrile, tetrahydrofuran, or a combination thereof; and the first reaction temperature is between about - 20 °C and about 25 °C, about -20 °C and about 20 °C, about -20 °C and about 15 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -15 °C and about 25 °C, about -15 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about -5 °C and about 5 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, about 0 °C and about 5 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, about 5 °C and about 15 °C, or about 5 °C and about 10 °C.

[0071] In some embodiments, the base is potassium ZerZ-butoxide (Z-BuOK); the first solvent comprises acetonitrile, tetrahydrofuran, or a combination thereof; and the first reaction temperature is between about -20 °C and about 15 °C, about -15 °C and about 15 °C, about -15E0585.70022WO00 42 / 117#14402392vl°C and about 10 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about 0 °C and about 15 °C, or about 0 °C and about 10 °C. In some embodiments, the base is potassium tert-butoxide (7-BuOK); the first solvent comprises acetonitrile, tetrahydrofuran, or a combination thereof; and the first reaction temperature is between about -5 °C and about 15 °C. In some embodiments, the base is potassium tert-butoxide (7-BuOK); the first solvent is acetonitrile and tetrahydrofuran; and the first reaction temperature is between about -5 °C and about 15 °C.

[0072] In some embodiments, reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III) or (nr), or salt or tautomer thereof, comprises adding a second solution to the first solution, wherein the second solution comprises the compound of Formula (IV-a), or salt or tautomer thereof, and a second solvent.

[0073] In some embodiments, the second solvent comprises acetonitrile, tetrahydrofuran, or a combination thereof. In some embodiments, the second solvent comprises acetonitrile. In some embodiments, the second solvent comprises tetrahydrofuran. In some embodiments, the second solvent comprises acetonitrile and tetrahydrofuran. In some embodiments, the second solvent is acetonitrile, tetrahydrofuran, or a combination thereof. In some embodiments, the second solvent is acetonitrile. In some embodiments, the second solvent is tetrahydrofuran. In some embodiments, the second solvent is acetonitrile and tetrahydrofuran.

[0074] In some embodiments, adding the second solution to the first solution comprises a second reaction temperature of between about -40 °C and about -0 °C, about -35 °C and about - 0 °C, about -30 °C and about -0 °C, about -25 °C and about -0 °C, about -20 °C and about -0 °C, about -15 °C and about -0 °C, about -40 °C and about -5 °C, about -35 °C and about -5 °C, about -30 °C and about -5 °C, about -25 °C and about -5 °C, about -20 °C and about -5 °C, about -15 °C and about -5 °C, about -40 °C and about -10 °C, about -35 °C and about -10 °C, about -30 °C and about -10 °C, about -25 °C and about -10 °C, about -20 °C and about -10 °C, about -15 °C and about -10 °C, about -40 °C and about -15 °C, about -35 °C and about -15 °C, about -30 °C and about -15 °C, about -25 °C and about -15 °C, or about -20 °C and about -15 °C. In some embodiments, the second reaction temperature is between about -30 °C and about - 0 °C, about -25 °C and about -0 °C, about -20 °C and about -0 °C, about -25 °C and about -5 °C, about -20 °C and about -5 °C, about -25 °C and about -10 °C, or about -20 °C and about - 10 °C. In some embodiments, the second reaction temperature is between about -30 °C and about -0 °C. In some embodiments, the second reaction temperature is between about -20 °C and about -10 °C.E0585.70022WO00 43 / 117#14402392vl

[0075] In some embodiments, adding the second solution to the first solution comprises a second reaction temperature of between about -20 °C and about -10 °C. In some embodiments, adding the second solution to the first solution comprises a second reaction temperature of about -20 °C, about -19 °C, about -18 °C, about -17 °C, about -16 °C, about -15 °C, about -14 °C, about -13 °C, about -12 °C, about -11 °C, or about -10 °C.

[0076] In some embodiments, the second solution is maintained at the second reaction temperature.

[0077] In some embodiments, the second solvent comprises acetonitrile, tetrahydrofuran, or a combination thereof; and adding the second solution to the first solution comprises a second reaction temperature of between about -40 °C and about -0 °C, about -35 °C and about -0 °C, about -30 °C and about -0 °C, about -25 °C and about -0 °C, about -20 °C and about -0 °C, about -15 °C and about -0 °C, about -40 °C and about -5 °C, about -35 °C and about -5 °C, about -30 °C and about -5 °C, about -25 °C and about -5 °C, about -20 °C and about -5 °C, about -15 °C and about -5 °C, about -40 °C and about -10 °C, about -35 °C and about -10 °C, about -30 °C and about -10 °C, about -25 °C and about -10 °C, about -20 °C and about -10 °C, about -15 °C and about -10 °C, about -40 °C and about -15 °C, about -35 °C and about -15 °C, about -30 °C and about -15 °C, about -25 °C and about -15 °C, or about -20 °C and about -15 °C.

[0078] In some embodiments, the second solvent is acetonitrile; and adding the second solution to the first solution comprises a second reaction temperature of between about -30 °C and about -0 °C, about -25 °C and about -0 °C, about -20 °C and about -0 °C, about -25 °C and about -5 °C, about -20 °C and about -5 °C, about -25 °C and about -10 °C, or about -20 °C and about - 10 °C. In some embodiments, the second solvent is acetonitrile; and adding the second solution to the first solution comprises a second reaction temperature of between about -20 °C and about -10 °C.

[0079] In some embodiments, the compound of Formula (III) or (nr), or salt or tautomer thereof, is obtained in a diastereomeric ratio of greater than about 50:50, about 55:45, about 60:40, about 65:35, about 70:30, about 75:25, about 80:20, about 85: 15, about 90: 10, about 91 :9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, about 99: 1, or about 99.9:0.1. In some embodiments, the diastereomeric ratio is greater than about 50:50, about 55:45, about 60:40, about 65:35, about 70:30, about 75:25, about 80:20, about 85: 15, about 90:10, about 91 :9, about 92:8, about 93:7, about 94:6, or about 95:5. In some embodiments, the diastereomeric ratio is greater than about 95:5.

[0080] In some embodiments, reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III), or salt or tautomerE0585.70022WO00 44 / 117#14402392vlthereof, does not comprise epimerization of the compound of Formula (IV-a), or salt or tautomer thereof, to produce a compound of Formula (IV-a-epi):or a salt or tautomer thereof, or epimerization of the compound of Formula (III), or salt or tautomer thereof, to produce a compound of Formula (III-epi):or a salt or tautomer thereof.

[0081] In some embodiments, reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III'), or salt or tautomer thereof, does not comprise epimerization of the compound of Formula (IV-a), or salt or tautomer thereof, to produce a compound of Formula (IV-a-epi):or a salt or tautomer thereof, or epimerization of the compound of Formula (III'), or salt or tautomer thereof, to produce a compound of Formula (Ill'-epi):or a salt or tautomer thereof.

[0082] In some embodiments, reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III) or (IH ), or salt or tautomer thereof, does not comprise epimerization of the compound of Formula (IV-a), or salt or tautomer thereof, to produce the compound of Formula (IV-a-epi), or salt or tautomer thereof. In some embodiments, reacting the compound of Formula (IV-a), or salt or tautomer thereof,E0585.70022WO00 45 / 117#14402392vlunder suitable conditions to obtain the compound of Formula (III), or salt or tautomer thereof, does not comprise epimerization of the compound of Formula (III), or salt or tautomer thereof, to produce the compound of Formula (III-epi), or salt or tautomer thereof. In some embodiments, reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III'), or salt or tautomer thereof, does not comprise epimerization of the compound of Formula (III'), or salt or tautomer thereof, to produce the compound of Formula (Ill'-epi), or salt or tautomer thereof.Formula (IV-a)

[0083] As generally described herein, the compound of Formula (IV-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (V):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV- a), or salt or tautomer thereof.

[0084] In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to a base. In some embodiments, the base is an organic base. In some embodiments, the base is an amine base. In some embodiments, the base is selected from imidazole, triethylamine, diisopropylethylamine, 7V-methylpyrrolidine, 7V-methylpiperidine, N- methylmorpholine, pyridine, and 2,6-lutidine. In some embodiments, the base is N- methylmorpholine.

[0085] In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to a base, wherein the base is V-methylmorpholine.

[0086] In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to an oxidant. In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to an oxidant, wherein the oxidant is Dess-Martin periodinane (DMP). In some embodiments, the oxidant is not 2- iodoxybenzoic acid (IBX).E0585.70022WO00 46 / 117#14402392vl

[0087] In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent comprises acetonitrile, dichloromethane, or a combination thereof. In some embodiments, the solvent comprises acetonitrile. In some embodiments, the solvent comprises dichloromethane. In some embodiments, the solvent comprises acetonitrile and dichloromethane. In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is acetonitrile, dichloromethane, or a combination thereof. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is acetonitrile and dichloromethane.

[0088] In some embodiments, a molar ratio of the compound of Formula (V), or salt or tautomer thereof, to the base is between about 1 :0.4 and about 1:1, about 1 :0.45 and about 1:1, about 1 :0.5 and about 1:1, about 1:0.55 and about 1:1, about 1:0.4 and about 1:0.8, about 1:0.45 and about 1:0.8, about 1:0.5 and about 1:0.8, about 1:0.55 and about 1:0.8, about 1:0.4 and about 1:0.6, about 1:0.45 and about 1:0.6, about 1:0.5 and about 1:0.6, or about 1:0.55 and about 1:0.6. In some embodiments, the molar ratio of the compound of Formula (V), or salt or tautomer thereof, to the base is between about 1:0.45 and about 1:0.6, about 1:0.5 and about 1:0.6, or about 1:0.55 and about 1:0.6. In some embodiments, the molar ratio of the compound of Formula (V), or salt or tautomer thereof, to the base is about 1:0.45, about 1:0.5, about 1:0.51, about 1:0.52, about 1:0.53, about 1:0.54, about 1:0.55, about 1:0.56, about 1:0.57, about 1:0.58, about 1:0.59, about 1:0.6, or about 1:0.65. In some embodiments, the molar ratio of the compound of Formula (V), or salt or tautomer thereof, to the base is about 1 :0.56 or about 1 :0.57.

[0089] In some embodiments, a molar ratio of the compound of Formula (V), or salt or tautomer thereof, to the oxidant is between about 1 : 1 and about 1 :2, about 1:1.1 and about 1:1.5, about 1:1.2 and about 1:1.5, about 1:1.3 and about 1:1.5, about 1:1.3 and about 1:1.4, about 1 : 1.25 and about 1 : 1.45, about 1:1.3 and about 1 : 1.45, or about 1:1.3 and about 1 : 1.35. In some embodiments, the molar ratio of the compound of Formula (V), or salt or tautomer thereof, to the oxidant is about 1:1.2, about 1:1.25, about 1:1.3, about 1:1.31, about 1:1.32, about 1:1.33, about 1:1.34, about 1:1.35, about 1:1.36, about 1:1.37, about 1:1.38, about 1:1.39, about 1:1.4, about 1:1.45, or about 1:1.5. In some embodiments, the molar ratio of the compound of Formula (V), or salt or tautomer thereof, to the oxidant is about 1:1.35.

[0090] In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises a reaction temperature of between about 0 °C and about 60 °C, about 5 °CE0585.70022WO00 47 / 117#14402392vland about 60 °C, about 10 °C and about 60 °C, about 15 °C and about 60 °C, about 20 °C and about 60 °C, about 25 °C and about 60 °C, about 0 °C and about 55 °C, about 5 °C and about 55 °C, about 10 °C and about 55 °C, about 15 °C and about 55 °C, about 20 °C and about 55 °C, about 25 °C and about 55 °C, about 0 °C and about 50 °C, about 5 °C and about 50 °C, about 10 °C and about 50 °C, about 15 °C and about 50 °C, about 20 °C and about 50 °C, about 25 °C and about 50 °C, about 0 °C and about 45 °C, about 5 °C and about 45 °C, about 10 °C and about 45 °C, about 15 °C and about 45 °C, about 20 °C and about 45 °C, about 25 °C and about 45 °C, about 0 °C and about 40 °C, about 5 °C and about 40 °C, about 10 °C and about 40 °C, about 15 °C and about 40 °C, about 20 °C and about 40 °C, about 25 °C and about 40 °C, about 0 °C and about 35 °C, about 5 °C and about 35 °C, about 10 °C and about 35 °C, about 15 °C and about 35 °C, about 20 °C and about 35 °C, or about 25 °C and about 35 °C. In some embodiments, the reaction temperature is between about 10 °C and about 50 °C, about 15 °C and about 50 °C, about 20 °C and about 50 °C, about 10 °C and about 45 °C, about 15 °C and about 45 °C, about 20 °C and about 45 °C, about 25 °C and about 45 °C, about 15 °C and about 40 °C, about 20 °C and about 40 °C, about 25 °C and about 40 °C, about 15 °C and about 35 °C, about 20 °C and about 35 °C, or about 25 °C and about 35 °C. In some embodiments, the reaction temperature is between about 20 °C and about 40 °C. In some embodiments, the reaction temperature is between about 25 °C and about 35 °C.

[0091] In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises a reaction temperature of between about 25 °C and about 35 °C. In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises a reaction temperature of about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, about 30 °C, about 31 °C, about 32 °C, about 33 °C, about 34 °C, or about 35 C.

[0092] In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, produces a reaction mixture that is maintained at the reaction temperature.

[0093] In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to a base, wherein the base is selected from imidazole, triethylamine, diisopropylethylamine, A-methylpyrrolidine, A-methylpiperidine, N- methylmorpholine, pyridine, and 2,6-lutidine; an oxidant, wherein the oxidant is Dess-Martin periodinane (DMP); and a solvent, wherein the solvent comprises acetonitrile, dichloromethane, or a combination thereof; and comprises a reaction temperature of between about 0 °C and aboutE0585.70022WO00 48 / 117#14402392vl60 °C, about 5 °C and about 60 °C, about 10 °C and about 60 °C, about 15 °C and about 60 °C, about 20 °C and about 60 °C, about 25 °C and about 60 °C, about 0 °C and about 55 °C, about 5 °C and about 55 °C, about 10 °C and about 55 °C, about 15 °C and about 55 °C, about 20 °C and about 55 °C, about 25 °C and about 55 °C, about 0 °C and about 50 °C, about 5 °C and about 50 °C, about 10 °C and about 50 °C, about 15 °C and about 50 °C, about 20 °C and about 50 °C, about 25 °C and about 50 °C, about 0 °C and about 45 °C, about 5 °C and about 45 °C, about 10 °C and about 45 °C, about 15 °C and about 45 °C, about 20 °C and about 45 °C, about 25 °C and about 45 °C, about 0 °C and about 40 °C, about 5 °C and about 40 °C, about 10 °C and about 40 °C, about 15 °C and about 40 °C, about 20 °C and about 40 °C, about 25 °C and about 40 °C, about 0 °C and about 35 °C, about 5 °C and about 35 °C, about 10 °C and about 35 °C, about 15 °C and about 35 °C, about 20 °C and about 35 °C, or about 25 °C and about 35 °C.

[0094] In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to a base, wherein the base is 7V-methylmorpholine; an oxidant, wherein the oxidant is Dess-Martin periodinane (DMP); and a solvent, wherein the solvent comprises acetonitrile, dichloromethane, or a combination thereof; and comprises a reaction temperature of between about 10 °C and about 50 °C, about 15 °C and about 50 °C, about 20 °C and about 50 °C, about 10 °C and about 45 °C, about 15 °C and about 45 °C, about 20 °C and about 45 °C, about 25 °C and about 45 °C, about 15 °C and about 40 °C, about 20 °C and about 40 °C, about 25 °C and about 40 °C, about 15 °C and about 35 °C, about 20 °C and about 35 °C, or about 25 °C and about 35 °C. In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to a base, wherein the base is N- methylmorpholine; an oxidant, wherein the oxidant is Dess-Martin periodinane (DMP); and a solvent, wherein the solvent comprises acetonitrile, dichloromethane, or a combination thereof; and comprises a reaction temperature of between about 25 °C and about 35 °C. In some embodiments, reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to a base, wherein the base is 7V-methylmorpholine; an oxidant, wherein the oxidant is Dess-Martin periodinane (DMP); and a solvent, wherein the solvent is acetonitrile and di chloromethane; and comprises a reaction temperature of between about 25 °C and about 35 °C.Formula (V)

[0095] As generally described herein, the compound of Formula (V), or salt or tautomer thereof,E0585.70022WO00 49 / 117#14402392vlis prepared by reacting a compound of Formula (VI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof.

[0096] In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to an acid. In some embodiments, the acid is selected from acetic acid, chloroacetic acid, di chloroacetic acid (DCA), trichloroacetic acid, and trifluoroacetic acid. In some embodiments, the acid is di chloroacetic acid (DCA).

[0097] In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to an acid, wherein the acid is di chloroacetic acid (DCA).

[0098] In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to a thiol. In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to a thiol, wherein the thiol is dodecane- 1- thiol.

[0099] In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to a solvent. In some embodiments, the solvent is selected from A / A-dimethylforrn amide (DMF), A, Ar-di methyl acetamide (DMA), A-methyl-2-pyrrolidone (NMP), A-butyl-2-pyrrolidone (NBP), acetone, acetonitrile, ethyl acetate, and dimethyl sulfoxide (DMSO). In some embodiments, the solvent is acetonitrile.

[0100] In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is acetonitrile.

[0101] In some embodiments, a molar ratio of the compound of Formula (VI), or salt or tautomer thereof, to the acid is between about 1 :0.4 and about 1 : 1, about 1 :0.45 and about 1 : 1, about 1 :0.5 and about 1 : 1, about 1 :0.55 and about 1 : 1, about 1 :0.4 and about 1 :0.8, about 1 :0.45 and about 1 :0.8, about 1 :0.5 and about 1 :0.8, about 1 :0.55 and about 1 :0.8, about 1 :0.4 and about 1 :0.6, about 1 :0.45 and about 1 :0.6, about 1 :0.5 and about 1 :0.6, or about 1 :0.5 and about 1 :0.55.E0585.70022WO00 50 / 117#14402392vlIn some embodiments, a molar ratio of the compound of Formula (VI), or salt or tautomer thereof, to the acid is between about 1:0.45 and about 1:0.6, about 1:0.5 and about 1:0.6, or about 1:0.5 and about 1:0.55. In some embodiments, the molar ratio of the compound of Formula (V), or salt or tautomer thereof, to the base is about 1 :0.45, about 1 :0.5, about 1:0.51, about 1:0.52, about 1:0.53, about 1:0.54, about 1:0.55, about 1:0.56, about 1:0.57, about 1:0.58, about 1:0.59, about 1:0.6, or about 1:0.65. In some embodiments, the molar ratio of the compound of Formula (V), or salt or tautomer thereof, to the base is about 1 :0.53.

[0102] In some embodiments, a molar ratio of the compound of Formula (VI), or salt or tautomer thereof, to the thiol is between about 1 : 1 and about 1:3, about 1 : 1 and about 1 :2.5, about 1:1 and about 1:2, about 1:1 and about 1:1.75, about 1:1.5 and about 1:3, about 1:1.5 and about 1 :2.5, about 1:1.5 and about 1 :2, about 1:1.5 and about 1 : 1.75, or about 1:1.5 and about 1:1.6. In some embodiments, a molar ratio of the compound of Formula (VI), or salt or tautomer thereof, to the thiol is between about 1 : 1 and about 1 :2, about 1 : 1 and about 1 : 1.75, about 1:1.5 and about 1:2, about 1:1.5 and about 1:1.75, or about 1:1.5 and about 1:1.6. In some embodiments, a molar ratio of the compound of Formula (VI), or salt or tautomer thereof, to the thiol is about 1:1.4, about 1:1.45, about 1:1.5, about 1:1.51, about 1:1.52, about 1:1.53, about 1:1.54, about 1:1.55, about 1:1.56, about 1:1.57, about 1:1.58, about 1:1.59, about 1:1.6, about 1:1.65, or about 1:1.7. In some embodiments, a molar ratio of the compound of Formula (VI), or salt or tautomer thereof, to the thiol is about 1:1.56.

[0103] In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises a reaction temperature of between about 20 °C and about 70 °C, about 25 °C and about 70 °C, about 30 °C and about 70 °C, about 35 °C and about 70 °C, about 40 °C and about 70 °C, about 45 °C and about 70 °C, about 20 °C and about 65 °C, about 25 °C and about 65 °C, about 30 °C and about 65 °C, about 35 °C and about 65 °C, about 40 °C and about 65 °C, about 45 °C and about 65 °C, about 20 °C and about 60 °C, about 25 °C and about 60 °C, about 30 °C and about 60 °C, about 35 °C and about 60 °C, about 40 °C and about 60 °C, about 45 °C and about 60 °C, about 20 °C and about 55 °C, about 25 °C and about 55 °C, about 30 °C and about 55 °C, about 35 °C and about 55 °C, about 40 °C and about 55 °C, about 45 °C and about 55 °C, about 20 °C and about 50 °C, about 25 °C and about 50 °C, about 30 °C and about 50 °C, about 35 °C and about 50 °C, about 40 °C and about 50 °C, or about 45 °C and about 50 °C. In some embodiments, the reaction temperature is between about 20 °C and about 70 °C, about 25 °C and about 65 °C, about 30 °C and about 60 °C, about 35 °C and about 60 °C, about 40 °C and about 60 °C, about 35 °C and about 55 °C, about 40 °C and about 55 °C, about 30 °C and about 50 °C, about 35 °C and about 50 °C, or about 40 °C and about 50 °C. In some embodiments, theE0585.70022WO00 51 / 117#14402392vlreaction temperature is between about 30 °C and about 60 °C. In some embodiments, the reaction temperature is between about 40 °C and about 50 °C.

[0104] In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises a reaction temperature of between about 40 °C and about 50 °C. In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises a reaction temperature of about 40 °C, about 41 °C, about 42 °C, about 43 °C, about 44 °C, about 45 °C, about 46 °C, about 47 °C, about 48 °C, about 49 °C, or about 50 °C.

[0105] In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, produces a reaction mixture that is maintained at the reaction temperature.

[0106] In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to: an acid selected from acetic acid, chloroacetic acid, di chloroacetic acid (DCA), trichloroacetic acid, and trifluoroacetic acid; a thiol; and a solvent selected from-di methyl form am ide (DMF), 7V,7V-di methyl acetamide (DMA), A-methyl-2- pyrrolidone (NMP), A-butyl-2-pyrrolidone (NBP), acetone, acetonitrile, ethyl acetate, and dimethylsulfoxide (DMSO); and comprises a reaction temperature of between about 20 °C and about 70 °C, about 25 °C and about 70 °C, about 30 °C and about 70 °C, about 35 °C and about 70 °C, about 40 °C and about 70 °C, about 45 °C and about 70 °C, about 20 °C and about 65 °C, about 25 °C and about 65 °C, about 30 °C and about 65 °C, about 35 °C and about 65 °C, about 40 °C and about 65 °C, about 45 °C and about 65 °C, about 20 °C and about 60 °C, about 25 °C and about 60 °C, about 30 °C and about 60 °C, about 35 °C and about 60 °C, about 40 °C and about 60 °C, about 45 °C and about 60 °C, about 20 °C and about 55 °C, about 25 °C and about 55 °C, about 30 °C and about 55 °C, about 35 °C and about 55 °C, about 40 °C and about 55 °C, about 45 °C and about 55 °C, about 20 °C and about 50 °C, about 25 °C and about 50 °C, about 30 °C and about 50 °C, about 35 °C and about 50 °C, about 40 °C and about 50 °C, or about 45 °C and about 50 °C.

[0107] In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to: an acid, wherein the acid is di chloroacetic acid (DCA); a thiol, wherein the thiol is dodecane- 1 -thiol; and a solvent, wherein the solvent is acetonitrile; and comprises a reaction temperature of between about 20 °C and about 70 °C, about 25 °C and about 65 °C, about 30 °C and about 60 °C, about 35 °C and about 60 °C, about 40 °C and aboutE0585.70022WO00 52 / 117#14402392vl60 °C, about 35 °C and about 55 °C, about 40 °C and about 55 °C, about 30 °C and about 50 °C, about 35 °C and about 50 °C, or about 40 °C and about 50 °C. In some embodiments, reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to: an acid, wherein the acid is di chloroacetic acid (DCA); a thiol, wherein the thiol is dodecane- 1 -thiol; and a solvent, wherein the solvent is acetonitrile; and comprises a reaction temperature of between about 40 °C and about 50 °C.Formula (VI)

[0108] As generally described herein, the compound of Formula (VI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof.

[0109] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to a base. In some embodiments, the base is selected from sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, potassium Zc / V-butoxide, sodium / c77-butoxide, and lithium tert-butoxide. In some embodiments, the base is sodium hydride.

[0110] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to a base, wherein the base is sodium hydride.[OHl] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to l-bromo-2-methoxy ethane, or a salt thereof. In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to l-bromo-2-m ethoxy ethane.

[0112] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to a solvent. In some embodiments, the solvent is selected from AA-dimethylform amide (DMF), -di methyl acetamide (DMA), A-methyl-2-pyrrolidoneE0585.70022WO00 53 / 117#14402392vl(NMP), and 7V-butyl-2-pyrrolidone (NBP). In some embodiments, the solvent is 7V-Methyl-2- pyrrolidone (NMP).

[0113] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is V-Methyl-2-pyrrolidone (NMP).

[0114] In some embodiments, the base is sodium hydride, and the solvent is 7V-Methyl-2- pyrrolidone (NMP). In some embodiments, the base is sodium hydride, and the solvent is not 7V,7V-dimethylformamide (DMF).

[0115] In some embodiments, a molar ratio of the compound of Formula (VII), or salt or tautomer thereof, to the base is between about 1 : 1 and about 1:5, about 1 : 1 and about 1 :4.5, about 1:1 and about 1:4, about 1:1 and about 1:3.5, about 1:2 and about 1:5, about 1:2 and about 1:4.5, about 1:2 and about 1:4, about 1:2 and about 1:3.5, about 1:3 and about 1:5, about 1:3 and about 1:4.5, about 1:3 and about 1:4, about 1:3.5 and about 1:5, about 1:3.5 and about 1:4.5, about 1:3.5 and about 1:4, or about 1:3.5 and about 1:3.6. In some embodiments, a molar ratio of the compound of Formula (VII), or salt or tautomer thereof, to the base is about 1 :3, about 1:3.25, about 1:3.3, about 1:3.35, about 1:3.4, about 1:3.45, about 1:3.5, about 1:3.55, about 1:3.6, about 1:3.65, about 1:3.7, or about 1:3.75. In some embodiments, a molar ratio of the compound of Formula (VII), or salt or tautomer thereof, to the base is about 1 :3.55.

[0116] In some embodiments, a molar ratio of the compound of Formula (VII), or salt or tautomer thereof, to l-bromo-2-methoxy ethane is between about 1:1 and about 1:5, about 1:1 and about 1:4.5, about 1:1 and about 1:4, about 1:1 and about 1:3.5, about 1:2 and about 1:5, about 1:2 and about 1:4.5, about 1:2 and about 1:4, about 1:2 and about 1:3.5, about 1:3 and about 1:5, about 1:3 and about 1:4.5, about 1:3 and about 1:4, about 1:3.2 and about 1:3.5, or about 1:3.3 and about 1:3.4. In some embodiments, a molar ratio of the compound of Formula (VII), or salt or tautomer thereof, to l-bromo-2-methoxy ethane is about 1:3, about 1:3.05, about 1:3.1, about 1:3.15, about 1:3.2, about 1:3.25, about 1:3.3, about 1:3.35, about 1:3.4, or about 1:3.45. In some embodiments, a molar ratio of the compound of Formula (VII), or salt or tautomer thereof, to l-bromo-2-methoxy ethane is about 1:3.35.

[0117] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises a first reaction temperature of between about -20 °C and about 20 °C, about - 20 °C and about 15 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -20 °C and about 0 °C, about -15 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -15 °C and about 0 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C andE0585.70022WO00 54 / 117#14402392vlabout 5 °C, about -10 °C and about 0 °C, about -5 °C and about 20 °C, about -5 °C and about 15°C, about -5 °C and about 10 °C, about -5 °C and about 5 °C, or about -5 °C and about 0 °C. In some embodiments, the first reaction temperature is between about -20 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, or about -5 °C and about 5 °C. In some embodiments, the first reaction temperature is between about -10 °C and about 10 °C. In some embodiments, the first reaction temperature is between about -5 °C and about 5 °C.

[0118] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises a first reaction temperature of between about -5 °C and about 5 °C. In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises a first reaction temperature of about -5 °C, about -4 °C, about -3 °C, about -2 °C, about -1 °C, about 0 °C, about 1 °C, about 2 °C, about 3 °C, about 4 °C, or about 5 °C.

[0119] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises a second reaction temperature of between about -10 °C and about 30 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -5 °C and about 30 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about 0 °C and about 30 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, about 5 °C and about 30 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, about 5 °C and about 15 °C, or about 5 °C and about 10 °C. In some embodiments, the second reaction temperature is between about -10 °C and about 30 °C, about - 5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, or about 5 °C and about 15 °C. In some embodiments, the second reaction temperature is between about 0 °C and about 20 °C. In some embodiments, the second reaction temperature is between about 5 °C and about 15 °C.

[0120] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises a second reaction temperature of between about 5 °C and about 15 °C. In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof,E0585.70022WO00 55 / 117#14402392vlcomprises a second reaction temperature of about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, about 10 °C, about 11 °C, about 12 °C, about 13 °C, about 14 °C, or about 15 °C.

[0121] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises the first reaction temperature followed by the second reaction temperature. In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, produces a reaction mixture that is maintained at the first reaction temperature and subsequently maintained at the second reaction temperature.

[0122] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises a first reaction temperature of between about -20 °C and about 20 °C, about - 20 °C and about 15 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -20 °C and about 0 °C, about -15 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -15 °C and about 0 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -10 °C and about 0 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about -5 °C and about 5 °C, or about -5 °C and about 0 °C; and a second reaction temperature of between about -10 °C and about 30 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -5 °C and about 30 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about 0 °C and about 30 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, about 5 °C and about 30 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, about 5 °C and about 15 °C, or about 5 °C and about 10 °C.

[0123] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises a first reaction temperature of between about -20 °C and about 20 °C, about - 15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, or about -5 °C and about 5 °C; and a second reaction temperature of between about -10 °C and about 30 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, or about 5 °C and about 15 °C.E0585.70022WO00 56 / 117#14402392vl

[0124] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises a first reaction temperature of between about -5 °C and about 5 °C and a second reaction temperature of between about 5 °C and about 15 °C. In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises a first reaction temperature of about -5 °C, about -4 °C, about -3 °C, about -2 °C, about -1 °C, about 0 °C, about 1 °C, about 2 °C, about 3 °C, about 4 °C, or about 5 °C; and a second reaction temperature of about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, about 10 °C, about 11 °C, about 12 °C, about 13 °C, about 14 °C, or about 15 °C.

[0125] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to: a base, wherein the base is selected from sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, potassium te / 7-butoxide, sodium Zc / V-butoxide, and lithium Zc / V-butoxide; l-bromo-2-methoxy ethane; and a solvent selected from-di methyl form am ide (DMF), A / V-di methyl acetamide (DMA), V-methyl-2-pyrrolidone (NMP), and A-butyl-2-pyrrolidone (NBP); and comprises a first reaction temperature of between about -20 °C and about 20 °C, about -20 °C and about 15 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -20 °C and about 0 °C, about -15 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -15 °C and about 0 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -10 °C and about 0 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about -5 °C and about 5 °C, or about -5 °C and about 0 °C; and a second reaction temperature of between about -10 °C and about 30 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -5 °C and about 30 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about 0 °C and about 30 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, about 5 °C and about 30 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, about 5 °C and about 15 °C, or about 5 °C and about 10 °C.

[0126] In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to: a base, wherein the base is sodium hydride; l-bromo-2- methoxyethane; and a solvent, wherein the solvent is V-Methyl-2-pyrrolidone (NMP); and comprises a first reaction temperature of between about -20 °C and about 20 °C, about -15 °CE0585.70022WO00 57 / 117#14402392vland about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, or about -5 °C and about 5 °C; and a second reaction temperature of between about -10 °C and about 30 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, or about 5 °C and about 15 °C. In some embodiments, reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to: a base, wherein the base is sodium hydride; l-bromo-2-methoxy ethane; and a solvent, wherein the solvent is A-Methyl-2-pyrrolidone (NMP); and comprises a first reaction temperature of between about -5 °C and about 5 °C; and a second reaction temperature of between about 5 °C and about 15 °C.Formula (VII)

[0127] As generally described herein, the compound of Formula (VII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof.

[0128] In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises exposure to a hydroxide salt. In some embodiments, the hydroxide salt is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. In some embodiments, the hydroxide salt is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide. In some embodiments, the hydroxide salt is sodium hydroxide.

[0129] In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises exposure to a hydroxide salt, wherein the hydroxide salt is sodium hydroxide.

[0130] In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises exposure to a solvent. In some embodiments, the solvent comprises 2- methyltetrahydrofuran, ethanol, water, or a combination thereof. In some embodiments, theE0585.70022WO00 58 / 117#14402392vlsolvent comprises 2-methyltetrahydrofuran. In some embodiments, the solvent comprises ethanol. In some embodiments, the solvent comprises water. In some embodiments, the solvent comprises 2-methyltetrahydrofuran and ethanol. In some embodiments, the solvent comprises 2- methyltetrahydrofuran and water. In some embodiments, the solvent comprises ethanol and water. In some embodiments, the solvent comprises 2-methyltetrahydrofuran, ethanol, and water.

[0131] In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent comprises 2- methyltetrahydrofuran, ethanol, water, or a combination thereof.

[0132] In some embodiments, a molar ratio of the compound of Formula (VIII), or salt or tautomer thereof, to the hydroxide salt is between about 1 : 1 and about 1 :3, about 1 : 1 and about 1 :2.5, about 1 : 1 and about 1 :2, about 1 : 1.5 and about 1 :3, about 1 : 1.5 and about 1 :2.5, about 1 : 1.5 and about 1 :2, or about 1 : 1.75 and about 1 :2.25. In some embodiments, a molar ratio of the compound of Formula (VIII), or salt or tautomer thereof, to the hydroxide salt is about 1 : 1.5, about 1 : 1.75, about 1 : 1.8, about 1 : 1.85, about 1 : 1.9, about 1 : 1.95, about 1 :2, about 1 :2.05, about 1 :2.1, about 1 :2.15, about 1 :2.2, about 1 :2.25, or about 1 :2.5. In some embodiments, a molar ratio of the compound of Formula (VIII), or salt or tautomer thereof, to the hydroxide salt is about 1 :2.

[0133] In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises a reaction temperature of between about -10 °C and about 30 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -5 °C and about 30 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about 0 °C and about 30 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, about 5 °C and about 30 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, about 5 °C and about 15 °C, or about 5 °C and about 10 °C. In some embodiments, the reaction temperature is between about -10 °C and about 30 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, or about 5 °C and about 15 °C. In some embodiments, the reaction temperature is between about 0 °C and about 20 °C. In some embodiments, the reaction temperature is between about 5 °C and about 15 °C.

[0134] In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomerE0585.70022WO00 59 / 117#14402392vlthereof, comprises a reaction temperature of between about 5 °C and about 15 °C. In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises a reaction temperature of about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, about 10 °C, about 11 °C, about 12 °C, about 13 °C, about 14 °C, or about 15 °C.

[0135] In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, produces a reaction mixture that is maintained at the reaction temperature.

[0136] In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises exposure to: a hydroxide salt, wherein the hydroxide salt is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide; and a solvent, wherein the solvent comprises 2-methyltetrahydrofuran, ethanol, water, or a combination thereof; and comprises a reaction temperature of between about -10 °C and about 30 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -5 °C and about 30 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about 0 °C and about 30 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, about 5 °C and about 30 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, about 5 °C and about 15 °C, or about 5 °C and about 10 °C.

[0137] In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises exposure to: a hydroxide salt, wherein the hydroxide salt is sodium hydroxide; and a solvent, wherein the solvent comprises 2-methyltetrahydrofuran, ethanol, water, or a combination thereof; and comprises a reaction temperature of between about -10 °C and about 30 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 5 °C and about 25 °C, about 5 °C and about 20 °C, or about 5 °C and about 15 °C. In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises exposure to: a hydroxide salt, wherein the hydroxide salt is sodium hydroxide; and a solvent, wherein the solvent comprises 2-methyltetrahydrofuran, ethanol, water, or a combination thereof; and comprises a reaction temperature of between about 5 °C and about 15 °C. In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises exposure to: a hydroxideE0585.70022WO00 60 / 117#14402392vlsalt, wherein the hydroxide salt is sodium hydroxide; and a solvent, wherein the solvent comprises 2-methyltetrahydrofuran, ethanol, and water; and comprises a reaction temperature of between about 5 °C and about 15 °C.

[0138] In some embodiments, reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, produces a reaction mixture that is substantially free of a compound of Formula (X):or a salt or tautomer thereof. In some embodiments, the reaction mixture comprises an amount of the compound of Formula (X), or salt or tautomer thereof, that is less than 5 mol % of the total amount of the compound of Formula (VIII), or salt or tautomer thereof, and the compound of Formula (VII), or salt or tautomer thereof, present in the reaction mixture. In some embodiments, the reaction mixture comprises an amount of the compound of Formula (X), or salt or tautomer thereof, that is less than 1 mol % of the total amount of the compound of Formula (VIII), or salt or tautomer thereof, and the compound of Formula (VII), or salt or tautomer thereof, present in the reaction mixture.Formula (VIII)

[0139] As generally described herein, the compound of Formula (VIII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IX):or a salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof.

[0140] In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to a base. In some embodiments, the base is an organic base. In some embodiments, the base is an amine base. In some embodiments, the base is selected from imidazole, triethylamine, diisopropylethylamine, A-methylpyrrolidine, A-m ethyl pi peri dine, A-methylmorpholine, pyridine, and 2,6-lutidine. In some embodiments, the base is imidazole.E0585.70022WO00 61 / 117#14402392vl

[0141] In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to a base, wherein the base is imidazole.

[0142] In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to a catalyst. In some embodiments, the catalyst is 4-dimethylaminopyridine.

[0143] In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to a catalyst, wherein the catalyst is 4-dimethylaminopyridine.

[0144] In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to a solvent. In some embodiments, the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane, methyl tert-butyl ether (MTBE), and cyclopentyl methyl ether (CPME). In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0145] In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is 2-methyltetrahydrofuran.

[0146] In some embodiments, a molar ratio of the compound of Formula (IX), or salt or tautomer thereof, to the triisopropyl silyl chloride is between about 1 : 1 and about 1 :5, about 1 : 1 and about 1 :4, about 1 : 1 and about 1 :3, about 1 : 1 and about 1 :2.5, about 1 :2 and about 1 :5, about 1 :2 and about 1 :4, about 1 :2 and about 1 :3, about 1 :2 and about 1 :2.5, about 1 :2.25 and about 1 :2.75, about 1 :2.4 and about 1 :2.6, and about 1 :2.45 and about 1 :2.55. In some embodiments, a molar ratio of the compound of Formula (IX), or salt or tautomer thereof, to the triisopropyl silyl chloride is about 1 :2, about 1 :2.25, about 1 :2.4, about 1 :2.45, about 1 :2.5, about 1 :2.55, about 1 :2.6, about 1 :2.75, or about 1 :3. In some embodiments, a molar ratio of the compound of Formula (IX), or salt or tautomer thereof, to the triisopropyl silyl chloride is about 1 :2.5.

[0147] In some embodiments, a molar ratio of the compound of Formula (IX), or salt or tautomer thereof, to the base is between about 1 : 1 and about 1 :5, about 1 : 1 and about 1 :4.5, about 1 : 1 and about 1 :4, about 1 : 1 and about 1 :3.5, about 1 :2 and about 1 :5, about 1 :2 and about 1 :4.5, about 1 :2 and about 1 :4, about 1 :2 and about 1 :3.5, about 1 :3 and about 1 :5, about 1 :3 andE0585.70022WO00 62 / 117#14402392vlabout 1 :4.5, or about 1 :3 and about 1 :4. In some embodiments, a molar ratio of the compound of Formula (IX), or salt or tautomer thereof, to the base is about 1 :2.5, about 1 :2.75, about 1 :2.8, about 1 :2.9, about 1 :2.95, about 1 :3, about 1 :3.05, about 1 :3.1, about 1 :3.15, about 1 :3.2, about 1 :3.25, or about 1 :3.5. In some embodiments, a molar ratio of the compound of Formula (IX), or salt or tautomer thereof, to the base is about 1 :3.

[0148] In some embodiments, a molar ratio of the compound of Formula (IX), or salt or tautomer thereof, to the catalyst is about 1 :0.01, about 1 :0.02, about 1 :0.03, about 1 :0.04, about 1 :0.05, about 1 :0.06, about 1 :0.07, about 1 :0.08, about 1 :0.09, or about 1 :0.1. In some embodiments, a molar ratio of the compound of Formula (IX), or salt or tautomer thereof, to the catalyst is about 1 :0.05.

[0149] In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises a reaction temperature of between about 30 °C and about 80 °C, about 35 °C and about 80 °C, about 40 °C and about 80 °C, about 45 °C and about 80 °C, about 50 °C and about 80 °C, about 55 °C and about 80 °C, about 30 °C and about 75 °C, about 35 °C and about 75 °C, about 40 °C and about 75 °C, about 45 °C and about 75 °C, about 50 °C and about 75 °C, about 55 °C and about 75 °C, about 30 °C and about 70 °C, about 35 °C and about 70 °C, about 40 °C and about 70 °C, about 45 °C and about 70 °C, about 50 °C and about 70 °C, about 55 °C and about 70 °C, about 30 °C and about 65 °C, about 35 °C and about 65 °C, about 40 °C and about 65 °C, about 45 °C and about 65 °C, about 50 °C and about 65 °C, about 55 °C and about 65 °C, about 30 °C and about 60 °C, about 35 °C and about 60 °C, about 40 °C and about 60 °C, about 45 °C and about 60 °C, about 50 °C and about 60 °C, about 55 °C and about 60 °C, about 30 °C and about 55 °C, about 35 °C and about 55 °C, about 40 °C and about 55 °C, about 45 °C and about 55 °C, or about 50 °C and about 55 °C. In some embodiments, the reaction temperature is between about 30 °C and about 80 °C, about 35 °C and about 75 °C, about 40 °C and about 70 °C, about 45 °C and about 70 °C, about 50 °C and about 70 °C, about 45 °C and about 65 °C, about 50 °C and about 65 °C, about 40 °C and about 60 °C, about 45 °C and about 60 °C, or about 50 °C and about 60 °C. In some embodiments, the reaction temperature is between about 40 °C and about 70 °C. In some embodiments, the reaction temperature is between about 50 °C and about 60 °C.

[0150] In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises a reaction temperature of between about 50 °C and about 60 °C. In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain theE0585.70022WO00 63 / 117#14402392vlcompound of Formula (VIII), or salt or tautomer thereof, comprises a reaction temperature of about 50 °C, about 51 °C, about 52 °C, about 53 °C, about 54 °C, about 55 °C, about 56 °C, about 57 °C, about 58 °C, about 59 °C, or about 60 °C.

[0151] In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, produces a reaction mixture that is maintained at the reaction temperature.

[0152] In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to: a base, wherein the base is selected from imidazole, triethylamine, diisopropylethylamine, 7V-methylpyrrolidine, N- methylpiperidine, 7V-methylmorpholine, pyridine, and 2,6-lutidine; a catalyst; and a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether (MTBE), and cyclopentyl methyl ether (CPME); and comprises a reaction temperature of between about 30 °C and about 80 °C, about 35 °C and about 80 °C, about 40 °C and about 80 °C, about 45 °C and about 80 °C, about 50 °C and about 80 °C, about 55 °C and about 80 °C, about 30 °C and about 75 °C, about 35 °C and about 75 °C, about 40 °C and about 75 °C, about 45 °C and about 75 °C, about 50 °C and about 75 °C, about 55 °C and about 75 °C, about 30 °C and about 70 °C, about 35 °C and about 70 °C, about 40 °C and about 70 °C, about 45 °C and about 70 °C, about 50 °C and about 70 °C, about 55 °C and about 70 °C, about 30 °C and about 65 °C, about 35 °C and about 65 °C, about 40 °C and about 65 °C, about 45 °C and about 65 °C, about 50 °C and about 65 °C, about 55 °C and about 65 °C, about 30 °C and about 60 °C, about 35 °C and about 60 °C, about 40 °C and about 60 °C, about 45 °C and about 60 °C, about 50 °C and about 60 °C, about 55 °C and about 60 °C, about 30 °C and about 55 °C, about 35 °C and about 55 °C, about 40 °C and about 55 °C, about 45 °C and about 55 °C, or about 50 °C and about 55 °C.

[0153] In some embodiments, reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to: a base, wherein the base is imidazole; a catalyst, wherein the catalyst is 4-dimethylaminopyridine; and a solvent, wherein the solvent is 2-methyltetrahydrofuran; and comprises a reaction temperature of between about 30 °C and about 80 °C, about 35 °C and about 75 °C, about 40 °C and about 70 °C, about 45 °C and about 70 °C, about 50 °C and about 70 °C, about 45 °C and about 65 °C, about 50 °C and about 65 °C, about 40 °C and about 60 °C, about 45 °C and about 60 °C, or about 50 °C and about 60 °C. In some embodiments, reacting the compound of Formula (IX), or salt or tautomerE0585.70022WO00 64 / 117#14402392vlthereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to: a base, wherein the base is imidazole; a catalyst, wherein the catalyst is 4-dimethylaminopyridine; and a solvent, wherein the solvent is 2-methyltetrahydrofuran; and comprises a reaction temperature of between about 50 °C and about 60 °C.Formula (IX)

[0154] As generally described herein, the compound of Formula (IX), or salt or tautomer thereof, is prepared by reacting a compound of Formula (X):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof.

[0155] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to a lipase. In some embodiments, the lipase is a 1,3 specific lipase. In some embodiments, the lipase originates from Thermomyces lanuginosus. In some embodiments, the lipase is immobilized on a carrier. In some embodiments, the lipase is immobilized on a non-compressible silica gel carrier. In some embodiments, the lipase is a 1,3 specific lipase originating from Thermomyces lanuginosus. In some embodiments, the lipase is a 1,3 specific lipase, wherein the lipase is immobilized on a non-compressible silica gel carrier. In some embodiments, the lipase is a 1,3 specific lipase originating from Thermomyces lanuginosus, wherein the lipase is immobilized on a non-compressible silica gel carrier. In some embodiments, the lipase is Lipozyme® TL IM (Novozymes).

[0156] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to a lipase, wherein the lipase is a 1,3 specific lipase originating from Thermomyces lanuginosus, and wherein the lipase is immobilized on a non-compressible silica gel carrier.

[0157] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to an acylating agent. In some embodiments, the acylating agent is selected from benzoic anhydride, benzoyl chloride, benzoic acid, and methyl benzoate. In some embodiments, the acylating agent is benzoic anhydride.E0585.70022WO00 65 / 117#14402392vl

[0158] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to an acylating agent, wherein the acylating agent is benzoic anhydride.

[0159] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to a solvent. In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent does not comprise toluene. In some embodiments, the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether (MTBE), and cyclopentyl methyl ether (CPME). In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent does not comprise toluene. In some embodiments, the solvent is not toluene.

[0160] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is 2-methyltetrahydrofuran.

[0161] In some embodiments, a molar ratio of the compound of Formula (X), or salt or tautomer thereof, to the acylating agent is between about 1 : 1 and about 1 :2, about 1 : 1 and about 1 : 1.75, about 1:1 and about 1:1.5, about 1:1 and about 1:1.4, about 1:1 and about 1:1.35, about 1:1 and about 1:1.3, about 1:1.2 and about 1:1.5, about 1: 1.2 and about 1:1.4, about 1: 1.2 and about 1:1.35, or about 1: 1.2 and about 1:1.3. In some embodiments, a molar ratio of the compound of Formula (X), or salt or tautomer thereof, to the acylating agent is about 1:1, about 1:1.1, about 1:1.15, about 1:1.2, about 1:1.25, about 1:1.26, about 1:1.27, about 1:1.28, about 1:1.29, about 1:1.30, about 1:1.31, about 1:1.32, about 1:1.33, about 1:1.34, about 1:1.35, about 1:1.4, or about 1:1.5. In some embodiments, a molar ratio of the compound of Formula (X), or salt or tautomer thereof, to the acylating agent is about 1:1.30.

[0162] In some embodiments, a mass ratio of the compound of Formula (X), or salt or tautomer thereof, to the lipase is about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.4, or about 1:0.5. In some embodiments, a mass ratio of the compound of Formula (X), or salt or tautomer thereof, to the lipase is about 1:0.2.

[0163] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises a reaction temperature of between about 10 °C and about 70 °C, about 10 °C and about 65 °C, about 10 °C and about 60 °C, about 10 °C and about 55 °C, about 10 °C andE0585.70022WO00 66 / 117#14402392vlabout 50 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 15 °C and about 70 °C, about 15 °C and about 65 °C, about 15 °C and about 60 °C, about 15 °C and about 55 °C, about 15 °C and about 50 °C, about 15 °C and about 45 °C, about 15 °C and about 40 °C, about 20 °C and about 70 °C, about 20 °C and about 65 °C, about 20 °C and about 60 °C, about 20 °C and about 55 °C, about 20 °C and about 50 °C, about 20 °C and about 45 °C, about 20 °C and about 40 °C, about 25 °C and about 70 °C, about 25 °C and about 65 °C, about 25 °C and about 60 °C, about 25 °C and about 55 °C, about 25 °C and about 50 °C, about 25 °C and about 45 °C, about 25 °C and about 40 °C, about 30 °C and about 70 °C, about 30 °C and about 65 °C, about 30 °C and about 60 °C, about 30 °C and about 55 °C, about 30 °C and about 50 °C, about 30 °C and about 45 °C, about 30 °C and about 40 °C, about 35 °C and about 70 °C, about 35 °C and about 65 °C, about 35 °C and about 60 °C, about 35 °C and about 55 °C, about 35 °C and about 50 °C, about 35 °C and about 45 °C, or about 35 °C and about 40 °C. In some embodiments, the reaction temperature is between about 10 °C and about 70 °C, about 15 °C and about 65 °C, about 20 °C and about 60 °C, about 25 °C and about 55 °C, about 25 °C and about 50 °C, about 25 °C and about 45 °C, about 30 °C and about 55 °C, about 30 °C and about 50 °C, about 30 °C and about 45 °C, about 35 °C and about 55 °C, about 35 °C and about 50 °C, or about 35 °C and about 45 °C. In some embodiments, the reaction temperature is between about 30 °C and about 40 °C. In some embodiments, the reaction temperature is between about 35 °C and about 45 °C.

[0164] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises a reaction temperature of between about 35 °C and about 45 °C. In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises a reaction temperature of about 35 °C, about 36 °C, about 37 °C, about 38 °C, about 39 °C, about 40 °C, about 41 °C, about 42 °C, about 43 °C, about 44 °C, or about 45 °C.

[0165] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, produces a reaction mixture that is maintained at the reaction temperature.

[0166] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to: a lipase; an acylating agent selected from benzoic anhydride, benzoyl chloride, benzoic acid, and methyl benzoate; and a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether (MTBE), and cyclopentyl methyl ether (CPME); and comprises a reaction temperature of between about 10 °C and about 70 °C, about 10 °C and about 65 °C, about 10 °C and about 60 °C, about 10 °C andE0585.70022WO00 67 / 117#14402392vlabout 55 °C, about 10 °C and about 50 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 15 °C and about 70 °C, about 15 °C and about 65 °C, about 15 °C and about 60 °C, about 15 °C and about 55 °C, about 15 °C and about 50 °C, about 15 °C and about 45 °C, about 15 °C and about 40 °C, about 20 °C and about 70 °C, about 20 °C and about 65 °C, about 20 °C and about 60 °C, about 20 °C and about 55 °C, about 20 °C and about 50 °C, about 20 °C and about 45 °C, about 20 °C and about 40 °C, about 25 °C and about 70 °C, about 25 °C and about 65 °C, about 25 °C and about 60 °C, about 25 °C and about 55 °C, about 25 °C and about 50 °C, about 25 °C and about 45 °C, about 25 °C and about 40 °C, about 30 °C and about 70 °C, about 30 °C and about 65 °C, about 30 °C and about 60 °C, about 30 °C and about 55 °C, about 30 °C and about 50 °C, about 30 °C and about 45 °C, about 30 °C and about 40 °C, about 35 °C and about 70 °C, about 35 °C and about 65 °C, about 35 °C and about 60 °C, about 35 °C and about 55 °C, about 35 °C and about 50 °C, about 35 °C and about 45 °C, or about 35 °C and about 40 °C.

[0167] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to: a lipase; an acylating agent, wherein the acylating agent is benzoic anhydride; and a solvent, wherein the solvent is 2-methyltetrahydrofuran; and comprises a reaction temperature of between about 10 °C and about 70 °C, about 15 °C and about 65 °C, about 20 °C and about 60 °C, about 25 °C and about 55 °C, about 25 °C and about 50 °C, about 25 °C and about 45 °C, about 30 °C and about 55 °C, about 30 °C and about 50 °C, about 30 °C and about 45 °C, about 35 °C and about 55 °C, about 35 °C and about 50 °C, or about 35 °C and about 45 °C. In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to: a lipase, wherein the lipase is a 1,3 specific lipase originating from Thermomyces laniiginosus. and wherein the lipase is immobilized on a non-compressible silica gel carrier; an acylating agent, wherein the acylating agent is benzoic anhydride; and a solvent, wherein the solvent is 2-methyltetrahydrofuran; and comprises a reaction temperature of between about 10 °C and about 70 °C, about 15 °C and about 65 °C, about 20 °C and about 60 °C, about 25 °C and about 55 °C, about 25 °C and about 50 °C, about 25 °C and about 45 °C, about 30 °C and about 55 °C, about 30 °C and about 50 °C, about 30 °C and about 45 °C, about 35 °C and about 55 °C, about 35 °C and about 50 °C, or about 35 °C and about 45 °C.

[0168] In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to: a lipase; an acylating agent, wherein the acylating agent is benzoic anhydride; and a solvent, wherein the solvent is 2-methyltetrahydrofuran; and comprisesE0585.70022WO00 68 / 117#14402392vla reaction temperature of between about 35 °C and about 45 °C. In some embodiments, reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to: a lipase, wherein the lipase is a 1,3 specific lipase originating from Thermomyces lanuginosus, and wherein the lipase is immobilized on a non-compressible silica gel carrier; an acylating agent, wherein the acylating agent is benzoic anhydride; and a solvent, wherein the solvent is 2- methyltetrahydrofuran; and comprises a reaction temperature of between about 35 °C and about 45 °C.Formula (X)

[0169] As generally described herein, the compound of Formula (X), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof.

[0170] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises exposure to a reducing agent. In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises exposure to a reducing agent, wherein the reducing agent is a borohydride. In some embodiments, the borohydride is sodium borohydride, potassium borohydride, calcium borohydride, magnesium borohydride, tetramethylammonium borohydride, tetraethylammonium borohydride, tetrabutylammonium borohydride, methyltrioctylammonium borohydride, cetyltrimethylammonium borohydride, bis(triphenylphosphine)copper(I) borohydride, potassium tri(l-pyrazolyl)borohydride, potassium tri(3,5-dimethyl-l-pyrazolyl)borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride , or polymer-supported borohydride. In some embodiments, the borohydride is sodium borohydride. In some embodiments, the reducing agent is sodium borohydride.

[0171] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises exposure to a reducing agent, wherein the reducing agent is sodium borohydride.E0585.70022WO00 69 / 117#14402392vl

[0172] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises exposure to a solvent. In some embodiments, the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether (MTBE), and cyclopentyl methyl ether (CPME). In some embodiments, the solvent is 2- methyltetrahydrofuran.

[0173] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is 2-methyltetrahydrofuran.

[0174] In some embodiments, a molar ratio of the compound of Formula (XI), or salt or tautomer thereof, to the reducing agent is between about 1 : 1 and about 1 : 1.5, about 1 : 1 and about 1 : 1.25, about 1 : 1 and about 1 : 1.2, about 1 : 1 and about 1 : 1.1, or about 1 : 1 and about 1 : 1.05. In some embodiments, a molar ratio of the compound of Formula (XI), or salt or tautomer thereof, to the reducing agent is about 1: 1, about 1 : 1.01, about 1 : 1.02, about 1 : 1.03, about 1 :1.04, or about 1 : 1.05. In some embodiments, a molar ratio of the compound of Formula (XI), or salt or tautomer thereof, to the reducing agent is about 1 : 1.01.

[0175] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises a first reaction temperature of between about -15 °C and about 25 °C, about - 15 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about -5 °C and about 5 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, or about 0 °C and about 5 °C. In some embodiments, the first reaction temperature is between about -15 °C and about 25 °C, about -15 °C and about 20 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, or about 0 °C and about 10 °C. In some embodiments, the first reaction temperature is between about -5 °C and about 15 °C. In some embodiments, the first reaction temperature is between about 0 °C and about 10 °C.

[0176] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises a first reaction temperature of between about 0 °C and about 10 °C. In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, underE0585.70022WO00 70 / 117#14402392vlsuitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises a first reaction temperature of about 0 °C, about 1 °C, about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, or about 10 °C.

[0177] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises a second reaction temperature of between about 0 °C and about 50 °C, about 0 °C and about 45 °C, about 0 °C and about 40 °C, about 0 °C and about 35 °C, about 0 °C and about 30 °C, about 0 °C and about 25 °C, about 5 °C and about 50 °C, about 5 °C and about 45 °C, about 5 °C and about 40 °C, about 5 °C and about 35 °C, about 5 °C and about 30 °C, about 5 °C and about 25 °C, about 10 °C and about 50 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 10 °C and about 35 °C, about 10 °C and about 30 °C, about 10 °C and about 25 °C, about 15 °C and about 50 °C, about 15 °C and about 45 °C, about 15 °C and about 40 °C, about 15 °C and about 35 °C, about 15 °C and about 30 °C, about 15 °C and about 25 °C, about 20 °C and about 50 °C, about 20 °C and about 45 °C, about 20 °C and about 40 °C, about 20 °C and about 35 °C, about 20 °C and about 30 °C, or about 20 °C and about 25 °C. In some embodiments, the second reaction temperature is between about 0 °C and about 50 °C, about 5 °C and about 45 °C, about 5 °C and about 40 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 15 °C and about 35 °C, about 15 °C and about 30 °C, about 20 °C and about 40 °C, about 20 °C and about 35 °C, or about 20 °C and about 30 °C. In some embodiments, the second reaction temperature is between about 10 °C and about 40 °C. In some embodiments, the second reaction temperature is between about 20 °C and about 30 °C.

[0178] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises a second reaction temperature of between about 20 °C and about 30 °C. In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises a second reaction temperature of about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, or about 30 °C.

[0179] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises the first reaction temperature followed by the second reaction temperature. In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, produces a reaction mixture that is maintained at the first reaction temperature and subsequently maintained at the second reaction temperature.E0585.70022WO00 71 / 117#14402392vl

[0180] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises a first reaction temperature of between about -15 °C and about 25 °C, about - 15 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about -5 °C and about 5 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, or about 0 °C and about 5 °C; and a second reaction temperature of between about 0 °C and about 50 °C, about 0 °C and about 45 °C, about 0 °C and about 40 °C, about 0 °C and about 35 °C, about 0 °C and about 30 °C, about 0 °C and about 25 °C, about 5 °C and about 50 °C, about 5 °C and about 45 °C, about 5 °C and about 40 °C, about 5 °C and about 35 °C, about 5 °C and about 30 °C, about 5 °C and about 25 °C, about 10 °C and about 50 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 10 °C and about 35 °C, about 10 °C and about 30 °C, about 10 °C and about 25 °C, about 15 °C and about 50 °C, about 15 °C and about 45 °C, about 15 °C and about 40 °C, about 15 °C and about 35 °C, about 15 °C and about 30 °C, about 15 °C and about 25 °C, about 20 °C and about 50 °C, about 20 °C and about 45 °C, about 20 °C and about 40 °C, about 20 °C and about 35 °C, about 20 °C and about 30 °C, or about 20 °C and about 25 °C.

[0181] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises a first reaction temperature of between about -15 °C and about 25 °C, about - 15 °C and about 20 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, or about 0 °C and about 10 °C; and a second reaction temperature of between about 0 °C and about 50 °C, about 5 °C and about 45 °C, about 5 °C and about 40 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 15 °C and about 35 °C, about 15 °C and about 30 °C, about 20 °C and about 40 °C, about 20 °C and about 35 °C, or about 20 °C and about 30 °C.

[0182] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises a first reaction temperature of between about 0 °C and about 10 °C and a second reaction temperature of between about 20 °C and about 30 °C. In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises a first reactionE0585.70022WO00 72 / 117#14402392vltemperature of about 0 °C, about 1 °C, about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, or about 10 °C; and a second reaction temperature of about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, or about 30 °C.

[0183] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises exposure to: a reducing agent; and a solvent selected from tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether (MTBE), and cyclopentyl methyl ether (CPME); and comprises a first reaction temperature of between about -15 °C and about 25 °C, about -15 °C and about 20 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -10 °C and about 25 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -5 °C and about 25 °C, about -5 °C and about 20 °C, about -5 °C and about 15 °C, about - 5 °C and about 10 °C, about -5 °C and about 5 °C, about 0 °C and about 25 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, about 0 °C and about 10 °C, or about 0 °C and about 5 °C; and a second reaction temperature of between about 0 °C and about 50 °C, about 0 °C and about 45 °C, about 0 °C and about 40 °C, about 0 °C and about 35 °C, about 0 °C and about 30 °C, about 0 °C and about 25 °C, about 5 °C and about 50 °C, about 5 °C and about 45 °C, about 5 °C and about 40 °C, about 5 °C and about 35 °C, about 5 °C and about 30 °C, about 5 °C and about 25 °C, about 10 °C and about 50 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 10 °C and about 35 °C, about 10 °C and about 30 °C, about 10 °C and about 25 °C, about 15 °C and about 50 °C, about 15 °C and about 45 °C, about 15 °C and about 40 °C, about 15 °C and about 35 °C, about 15 °C and about 30 °C, about 15 °C and about 25 °C, about 20 °C and about 50 °C, about 20 °C and about 45 °C, about 20 °C and about 40 °C, about 20 °C and about 35 °C, about 20 °C and about 30 °C, or about 20 °C and about 25 °C.

[0184] In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises exposure to: a reducing agent, wherein the reducing agent is sodium borohydride; and a solvent, wherein the solvent is 2-methyltetrahydrofuran; and comprises a first reaction temperature of between about -15 °C and about 25 °C, about -15 °C and about 20 °C, about -10 °C and about 20 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -5 °C and about 15 °C, about -5 °C and about 10 °C, about 0 °C and about 20 °C, about 0 °C and about 15 °C, or about 0 °C and about 10 °C; and a second reaction temperature of between about 0 °C and about 50 °C, about 5 °C and about 45 °C, about 5 °C and about 40 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 15 °C and about 35 °C, aboutE0585.70022WO00 73 / 117#14402392vl15 °C and about 30 °C, about 20 °C and about 40 °C, about 20 °C and about 35 °C, or about 20 °C and about 30 °C. In some embodiments, reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises exposure to: a reducing agent, wherein the reducing agent is sodium borohydride; and a solvent, wherein the solvent is 2-methyltetrahydrofuran; and comprises a first reaction temperature of between about 0 °C and about 10 °C; and a second reaction temperature of between about 20 °C and about 30 °C.Formula (XI)

[0185] As generally described herein, the compound of Formula (XI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof.

[0186] In some embodiments, reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises exposure to a periodate salt. In some embodiments, the periodate salt is selected from sodium periodate and potassium periodate. In some embodiments, the periodate salt is sodium periodate.

[0187] In some embodiments, reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises exposure to a periodate salt, wherein the periodate salt is sodium periodate.

[0188] In some embodiments, reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises exposure to a solvent. In some embodiments, the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether (MTBE), and cyclopentyl methyl ether (CPME). In some embodiments, the solvent is 2- methyltetrahydrofuran.

[0189] In some embodiments, reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is 2-methyltetrahydrofuran.

[0190] In some embodiments, a molar ratio of the compound of Formula (XII), or salt or tautomer thereof, to the periodate salt is between about 1 : 1 and about 1 : 1.5, about 1 : 1 and aboutE0585.70022WO00 74 / 117#14402392vl1 : 1.25, about 1 : 1 and about 1 : 1.2, about 1 : 1 and about 1 : 1.1, or about 1 : 1.05 and about 1 : 1.15. In some embodiments, a molar ratio of the compound of Formula (XI), or salt or tautomer thereof, to the periodate salt is about 1 : 1, about 1 : 1.05, about 1 : 1.1, about 1 : 1.15, or about 1 : 1.2. In some embodiments, a molar ratio of the compound of Formula (XI), or salt or tautomer thereof, to the periodate salt is about 1 : 1.1.

[0191] In some embodiments, reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises a reaction temperature of between about 0 °C and about 50 °C, about 0 °C and about 45 °C, about 0 °C and about 40 °C, about 0 °C and about 35 °C, about 0 °C and about 30 °C, about 0 °C and about 25 °C, about 5 °C and about 50 °C, about 5 °C and about 45 °C, about 5 °C and about 40 °C, about 5 °C and about 35 °C, about 5 °C and about 30 °C, about 5 °C and about 25 °C, about 10 °C and about 50 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 10 °C and about 35 °C, about 10 °C and about 30 °C, about 10 °C and about 25 °C, about 15 °C and about 50 °C, about 15 °C and about 45 °C, about 15 °C and about 40 °C, about 15 °C and about 35 °C, about 15 °C and about 30 °C, about 15 °C and about 25 °C, about 20 °C and about 50 °C, about 20 °C and about 45 °C, about 20 °C and about 40 °C, about 20 °C and about 35 °C, about 20 °C and about 30 °C, or about 20 °C and about 25 °C. In some embodiments, the reaction temperature is between about 0 °C and about 50 °C, about 5 °C and about 45 °C, about 5 °C and about 40 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 15 °C and about 35 °C, about 15 °C and about 30 °C, about 20 °C and about 40 °C, about 20 °C and about 35 °C, or about 20 °C and about 30 °C. In some embodiments, the reaction temperature is between about 10 °C and about 40 °C. In some embodiments, the reaction temperature is between about 20 °C and about 30 °C.

[0192] In some embodiments, reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises a reaction temperature of between about 20 °C and about 30 °C. In some embodiments, reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises a reaction temperature of about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, or about 30 °C.

[0193] In some embodiments, reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, produces a reaction mixture that is maintained at the reaction temperature.

[0194] In some embodiments, reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomerE0585.70022WO00 75 / 117#14402392vlthereof, comprises exposure to: a periodate salt selected from sodium periodate and potassium periodate; and a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether (MTBE), and cyclopentyl methyl ether (CPME); and comprises a reaction temperature of between about 0 °C and about 50 °C, about 0 °C and about 45 °C, about 0 °C and about 40 °C, about 0 °C and about 35 °C, about 0 °C and about 30 °C, about 0 °C and about 25 °C, about 5 °C and about 50 °C, about 5 °C and about 45 °C, about 5 °C and about 40 °C, about 5 °C and about 35 °C, about 5 °C and about 30 °C, about 5 °C and about 25 °C, about 10 °C and about 50 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 10 °C and about 35 °C, about 10 °C and about 30 °C, about 10 °C and about 25 °C, about 15 °C and about 50 °C, about 15 °C and about 45 °C, about 15 °C and about 40 °C, about 15 °C and about 35 °C, about 15 °C and about 30 °C, about 15 °C and about 25 °C, about 20 °C and about 50 °C, about 20 °C and about 45 °C, about 20 °C and about 40 °C, about 20 °C and about 35 °C, about 20 °C and about 30 °C, or about 20 °C and about 25 °C.

[0195] In some embodiments, reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises exposure to: a periodate salt, wherein the periodate salt is sodium periodate; and a solvent, wherein the solvent is 2-methyltetrahydrofuran; and comprises a reaction temperature of between about 0 °C and about 50 °C, about 5 °C and about 45 °C, about 5 °C and about 40 °C, about 10 °C and about 45 °C, about 10 °C and about 40 °C, about 15 °C and about 35 °C, about 15 °C and about 30 °C, about 20 °C and about 40 °C, about 20 °C and about 35 °C, or about 20 °C and about 30 °C. In some embodiments, reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises exposure to: a periodate salt, wherein the periodate salt is sodium periodate; and a solvent, wherein the solvent is 2-methyltetrahydrofuran; and comprises a reaction temperature of between about 20 °C and about 30 °C.Formula (XII)

[0196] As generally described herein, the compound of Formula (XII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof.E0585.70022WO00 76 / 117#14402392vl

[0197] In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to 4,4'-dimethoxytrityl chloride. In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to a 4,4'- dimethoxytriphenylmethylcarbonium ion.

[0198] In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to a base. In some embodiments, the base is an organic base. In some embodiments, the base is an amine base. In some embodiments, the base is selected from triethylamine, diisopropylethylamine, A-methylpyrrolidine, A-methylpiperidine, N- methylmorpholine, pyridine, and 2,6-lutidine. In some embodiments, the base is N- methylmorpholine.

[0199] In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to a base, wherein the base is A-methylmorpholine.

[0200] In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to a solvent. In some embodiments, the solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), A / A-dimethylformamide (DMF), 7V,7V-dimethylacetamide (DMA), A-methyl-2-pyrrolidone (NMP), -butyl -2-pyrroli done (NBP), acetone, acetonitrile, ethyl acetate, or dimethylsulfoxide (DMSO), or a combination thereof. In some embodiments, the solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether (MTBE), or cyclopentyl methyl ether (CPME), or a combination thereof. In some embodiments, the solvent comprises 2-methyltetrahydrofuran. In some embodiments, the solvent comprises A',A'-di methyl form am ide (DMF), A / A'-di methyl acetamide (DMA), A'-m ethyl - 2-pyrrolidone (NMP), A-butyl-2-pyrrolidone (NBP), acetone, acetonitrile, ethyl acetate, or dimethylsulfoxide (DMSO), or a combination thereof. In some embodiments, the solvent comprises A',A -di methyl form am ide (DMF). In some embodiments, the solvent comprises 2- methyltetrahydrofuran, A / A-dimethylformamide (DMF), or a combination thereof. In some embodiments, the solvent comprises 2-methyltetrahydrofuran and A / A-dimethylformamide (DMF).

[0201] In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomerE0585.70022WO00 77 / 117#14402392vlthereof, comprises exposure to a solvent, wherein the solvent comprises 2- methyltetrahydrofuran, 7V,7V-dimethylformamide (DMF), or a combination thereof.

[0202] In some embodiments, a molar ratio of the compound of Formula (XIII), or salt or tautomer thereof, to the 4,4'-dimethoxytrityl chloride is between about 1 : 1 and about 1 : 1.5, about 1 : 1 and about 1 : 1.25, about 1 : 1 and about 1 : 1.2, about 1 : 1 and about 1 : 1.1 , or about 1 : 1 and about 1 : 1.05. In some embodiments, a molar ratio of the compound of Formula (XIII), or salt or tautomer thereof, to the 4,4'-dimethoxytrityl chloride is about 1 : 1, about 1 : 1.01, about 1 : 1.02, about 1 : 1.03, about 1 : 1.04, or about 1 : 1.05. In some embodiments, a molar ratio of the compound of Formula (XIII), or salt or tautomer thereof, to the 4,4'-dimethoxytrityl chloride is about 1 :1.01.

[0203] In some embodiments, a molar ratio of the compound of Formula (XIII), or salt or tautomer thereof, to the base is between about 1 : 1 and about 1 :1.5, about 1 : 1 and about 1 : 1.35, about 1 : 1 and about 1 : 1.3, about 1 : 1 and about 1 : 1.2, about 1 : 1.1 and about 1 : 1.3, or about 1 : 1.15 and about 1 : 1.25. In some embodiments, a molar ratio of the compound of Formula (XIII), or salt or tautomer thereof, to the base is about 1 :1.1, about 1 : 1.15, about 1 : 1.2, about 1 : 1.25, or about 1 : 1... In some embodiments, a molar ratio of the compound of Formula (XIII), or salt or tautomer thereof, to the base is about 1 : 1.2.

[0204] In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises a reaction temperature of between about -25 °C and about 15 °C, about -25 °C and about 10 °C, about -25 °C and about 5 °C, about -25 °C and about 0 °C, about -25 °C and about -5 °C, about -20 °C and about 15 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -20 °C and about 0 °C, about -20 °C and about -5 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -15 °C and about 0 °C, about -15 °C and about -5 °C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -10 °C and about 0 °C, or about -10 °C and about -5 °C. In some embodiments, the reaction temperature is between about -25 °C and about 15 °C, about - 25 °C and about 10 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -15 °C and about 5 °C, about -15 °C and about 0 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, or about -10 °C and about 0 °C. In some embodiments, the reaction temperature is between about -15 °C and about 5 °C. In some embodiments, the reaction temperature is between about -10 °C and about 0 °C.

[0205] In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises a reaction temperature of between about -10 °C and about 0 °C. In someE0585.70022WO00 78 / 117#14402392vlembodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises a reaction temperature of about -10 °C, about -9 °C, about -8 °C, about -7 °C, about -6 °C, about -5 °C, about -4 °C, about -3 °C, about -2 °C, about -1 °C, or about 0 °C.

[0206] In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, produces a reaction mixture that is maintained at the reaction temperature.

[0207] In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to: 4,4'-dimethoxytrityl chloride; a base selected from triethylamine, diisopropylethylamine, A-methylpyrrolidine, A-methylpiperidine, N- methylmorpholine, pyridine, and 2,6-lutidine; and a solvent, wherein the solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), A / A-dimethylformamide (DMF), 7V,7V-dimethylacetamide (DMA), A-methyl-2-pyrrolidone (NMP), -butyl -2-pyrroli done (NBP), acetone, acetonitrile, ethyl acetate, or dimethylsulfoxide (DMSO), or a combination thereof; and comprises a reaction temperature of between about -25 °C and about 15 °C, about -25 °C and about 10 °C, about -25 °C and about 5 °C, about -25 °C and about 0 °C, about -25 °C and about -5°C, about -20 °C and about 15 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -20 °C and about 0 °C, about -20 °C and about -5 °C, about -15 °C and about 15 °C, about -15 °C and about 10 °C, about -15 °C and about 5 °C, about -15 °C and about 0 °C, about -15 °C and about -5°C, about -10 °C and about 15 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, about -10 °C and about 0 °C, or about -10 °C and about -5 °C.

[0208] In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to: 4,4'-dimethoxytrityl chloride; a base, wherein the base is N- methylmorpholine; and a solvent, wherein the solvent comprises 2-methyltetrahydrofuran, N,N- dimethylformamide (DMF), or a combination thereof; and comprises a reaction temperature of between about -25 °C and about 15 °C, about -25 °C and about 10 °C, about -20 °C and about 10 °C, about -20 °C and about 5 °C, about -15 °C and about 5 °C, about -15 °C and about 0 °C, about -10 °C and about 10 °C, about -10 °C and about 5 °C, or about -10 °C and about 0 °C. In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to: 4,4'-dimethoxytrityl chloride; a base, wherein the base is N- methylmorpholine; and a solvent, wherein the solvent comprises 2-methyltetrahydrofuran, N,N-E0585.70022WO00 79 / 117#14402392vldimethylformamide (DMF), or a combination thereof; and comprises a reaction temperature of between about -10 °C and about 0 °C. In some embodiments, reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to: 4,4'-dimethoxytrityl chloride; a base, wherein the base is 7V-methylmorpholine; and a solvent, wherein the solvent comprises 2- methyltetrahydrofuran and 7V,7V-dimethylformamide (DMF); and comprises a reaction temperature of between about -10 °C and about 0 °C.Compounds

[0209] In another aspect, provided herein is a compound of Formula (XIV):or a salt or tautomer thereof, wherein:R1is selected from triphenylmethyl, 4,4'-dimethoxytrityl (4,4'-dimethoxytriphenylmethyl or DMT), 4,4’-dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl (IDTr), and 4,4’-dimethoxy-3"‘-[N- (imidazolylethyl)carbamoyl]trityl (lETr); andR2is selected from benzoate (Bz), / ?-methoxybenzoate, -phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), 4-bromobenzoate, 2,5-difluorobenzoate, pentafluorobenzoate, p- nitrobenzoate, 2-iodobenzoate, o-(dibromomethyl)benzoate, 2- (methylthiomethoxymethyl)benzoate, o-(methoxyacyl )benzoate, formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, -chlorophenoxy acetate, 3 -phenylpropionate, 4- oxopentanoate (levulinate), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, 4- azidobutyrate, 4-nitro-4-methylpentanoate, 4-(methylthiomethoxy)butyrate, 2,6-dichloro-4- methylphenoxy acetate, 2, 6-dichloro-4-( 1,1, 3 ,3 -tetramethylbutyl)phenoxy acetate, 2,4-bi s( 1 , 1 - dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2- methyl-2-butenoate, a-naphthoate, methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2- (phenyl sulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, / -butyl carbonate (BOC or Boc), / ?- nitrophenyl carbonate, benzyl carbonate, p-m ethoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, -nitrobenzyl carbonate, 4-ethoxy-l-napththyl carbonate, 2- (methylthiomethoxy)ethyl carbonate (MTMEC-OR), methanesulfonate (mesylate), benzylsulfonate, 2-formylbenzenesulfonate, and tosylate (Ts).E0585.70022WO00 80 / 117#14402392vl

[0210] In some embodiments, R1is triphenylmethyl. In some embodiments, R1is 4,4'- dimethoxytrityl (4,4'-dimethoxytriphenylmethyl or DMT). In some embodiments, R1is 4,4’- dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl (IDTr). In some embodiments, R1is 4,4’- dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl (lETr).

[0211] In some embodiments, R2is selected from benzoate (Bz), / ?-methoxybenzoate, p- phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), 4-bromobenzoate, 2,5-difluorobenzoate, pentafluorobenzoate, -nitrobenzoate, 2-iodobenzoate, o-(dibromomethyl)benzoate, 2- (methylthiomethoxymethyl)benzoate, and o-fmethoxyacyl (benzoate. In some embodiments, R2is benzoate (Bz). In some embodiments, R2is / 2-methoxybenzoate. In some embodiments, R2is / 2-phenylbenzoate. In some embodiments, R2is 2,4,6-trimethylbenzoate (mesitoate). In some embodiments, R2is 4-bromobenzoate. In some embodiments, R2is 2,5-difluorobenzoate. In some embodiments, R2is pentafluorobenzoate. In some embodiments, R2is -nitrobenzoate. In some embodiments, R2is 2-iodobenzoate. In some embodiments, R2is o- (dibromomethyl)benzoate. In some embodiments, R2is 2-(methylthiomethoxymethyl)benzoate. In some embodiments, R2is o-(methoxyacyl)benzoate.

[0212] In some embodiments, the compound of Formula (XIV) is of Formula (XlV-a):or a salt or tautomer thereof.

[0213] In some embodiments, the compound of Formula (XIV) is of Formula (XlV-b):or a salt or tautomer thereof.

[0214] In some embodiments, the compound of Formula (XIV) is of Formula (VIII):or a salt or tautomer thereof.EXAMPLES

[0215] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application areE0585.70022WO00 81 / 117#14402392vloffered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope.

[0216] List of abbreviations:Example 1: Synthesis of 2-cyanoethyl ((R,E)-4-(dimethoxyphosphoryl)-2-((R)-l-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-(2-methoxyethoxy)ethoxy)but-3-en-l-yl) diisopropylphosphoramiditeSTEP-1~ 78%XIII XII

[0217] Step 1: l-((2R,3R,4S,5R)-5-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (Compound XII). To the mixture of l-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine- 2,4(lH,3H)-dione (Compound XIII) (84.6 kg, 346.4 mol) in DMF (338 L) was added NMM (42.6 kg, 421.1 mol). To the above mixture was added the mixed solution of DMTrCI (118 kg, 348.3 mol) in DMF (85 L) and 2-MeTHF (423 L) while maintaining the temperature at -10-0°C. Stirred at -10-0°C for 4 h until Compound XIII is less than 13% as measured by HPLC. The mixture was diluted by 2-MeTHF (1533 L) and quenched by water (426 kg). The organic phase was separated and washed by aq. solution of 8% Na2SO4 (2 x 423 kg) to afford the 2-MeTHF solution containing 147.7 kg of Compound XII with above 90% purity: yield 78%.E0585.70022WO00 82 / 117#14402392vl

[0218] Step 2: (R)-3-(Bis(4-methoxyphenyl)(phenyl)methoxy)-2-((R)-l-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-oxoethoxy)propanal (Compound XI). To the solution of Compound XII (80.0 kg, 146.4 mol) in 2-MeTHF (800 L) was added the aq. solution of NalCh (34.4 kg, 160.8 mol) in water (400 kg) while maintaining the temperature at 20-30°C. Stirred for 2 h until no Compound XII is observed as measured by TLC. The mixture was quenched by aq. solution of 8% Na2SO4 (802 kg). The organic phase was separated and washed by aq. solution of 8% Na2SO4 (780 kg). The organic solution was diluted with 2-MeTHF (699 kg).

[0219] Step 3: l-((R)-l-(((S)-l-(Bis(4-methoxyphenyl)(phenyl)methoxy)-3-hydroxypropan- 2-yl)oxy)-2-hydroxyethyl)pyrimidine-2,4(lH,3H)-dione (Compound X). To the above solution of Compound XI (Step 2) was added NaBH4 (5.6 kg, 148.0 mol) in portions while maintaining the temperature at 0-10°C. Warmed to 20-30°C and stirred for 0.5 h until no Compound XI is observed as measured by TLC. The mixture was quenched by Acetone (64 kg) and added aq. solution of 20% acetic acid (22.6 kg) for adjusting pH to around 7. The mixture was washed successively by aq. solution of 8% Na2SO4 (800 kg), aq. solution of 5% Na2COs (402 kg) and aq. solution of 8% Na2SO4 (2 x 800 kg). The organic phase was concentrated to around 5 V, switched to around 8 V with 2-MeTHF (2 x 690 kg) to afford the 2-MeTHF solution containing 71.0 kg of Compound X with above 85% purity: yield 88%.

[0220] Characterization data for Compound X: 'H NMR (DMSO-d6) 5 = 2.96-3.02 (m, 2H), 3.32-3.41 (m, 5H), 3.59 (m, 1H), 3.73 (s, 6H), 4.74 (t, J = 5.2 Hz, 1H), 5.13 (t, J = 8.0 Hz, 1H), 5.52 (d, J = 8.0 Hz, 1H), 5.83 (t, J = 6.4 Hz, 1H), 6.86 (d, J = 12.0 Hz, 4H), 7.15-7.19 (m, 5H), 7.27-7.29 (m, 4H), 7.63 (d, J = 8.0 Hz, 1H); ESLLCMS: 549.2 [M+H]+.E0585.70022WQ00 83 / 117#14402392vl

[0221] Step 4: (R)-2-(((S)-l-(Bis(4-methoxyphenyl)(phenyl)methoxy)-3-hydroxypropan-2- yl)oxy)-2-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)ethyl benzoate (Compound IX). To the solution of Compound X (142.4 kg, 259.6 mol) in 2-MeTHF (2130 L) were added Lipozyme TL IM (55.4 kg) and BZ2O (75.8 kg, 335.0 mol). Warmed to 35-45°C and stirred for 1.5 h until the Compound X is less than 2% as measured by HPLC. Filtered the mixture to give a filtrate. To the aq. solution of Na2COs (143 kg) and glycine (53.4 kg) in water (1430 L) was added the above filtrate dropwise while maintaining the temperature at 20-30°C. The organic phase was separated and washed successively by 5% NaHCCh (720 kg) and water (716 kg). The organic solution was concentrated to around 5 V, switched to around 5 V with 2-MeTHF (2860 kg). To n-heptane (2685 L) was added the residual solution and beaten to slurry in mixed solvents. Filtration and drying afford 144.0 kg of Compound IX with above 80% purity as a solid: yield 85%.

[0222] Characterization data for Compound IX: 'H NMR (DMSO-d6) 5 = 3.72 (m, 2H), 3.72 (s, 6H), 4.06 (m, 1H), 4.40 - 4.51 (m, 4H), 5.58 (d, J = 8.0 Hz, 1H), 6.28 (t, J = 4 Hz, 1H), 6.84 (d, J = 8 Hz, 4H), 7.20 (dd, J = 4, 8 Hz, 5H), 7.28-7.33 (m, 4H), 7.45-7.49 (m, 4H), 7.63 (m, 2H), 7.78 (d, J = 8 Hz, 1H), 7.83 (t, J = 8 Hz, 4H), 11.47 (s, 1H); ESI-LCMS: 651.4 [M-H]'.STEP-5a

[0223] Step 5: l-((R)-l-(((R)-l-(Bis(4-methoxyphenyl)(phenyl)methoxy)-3-((triisopropylsilyl)oxy)propan-2-yl)oxy)-2-hydroxyethyl)pyrimidine-2,4(lH,3H)-dione(Compound VII). To the mixture of Compound IX (70.2 kg, 107.6 mol) in 2-MeTHF (353 L)E0585.70022WQ00 84 / 117#14402392vlwere added Imidazole (21.7 kg, 318.7 mol), DMAP (0.65 kg, 5.3 mol), and TIPSC1 (51.6 g, 267.6 mol), successively. Warmed to 50-60°C and stirred for 20 h until the Compound IX is less than 1% as measured by HPLC. The resulting mixture containing (R)-2-(((R)-l-(bis(4- methoxyphenyl)(phenyl)methoxy)-3-((triisopropylsilyl)oxy)propan-2-yl)oxy)-2-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)ethyl benzoate (Compound VIII) was diluted by 2-MeTHF (352 L) and quenched by water (350 kg). The organic phase was separated and added EtOH (114 kg). To the organic solution was added the aq. solution of NaOH (8.54 kg, 213.7 mol) in water (69 kg) dropwise while maintaining the temperature at 5-15°C. Stirred for 2 h until the Compound VIII is less than 1% as measured by HPLC. The mixture was diluted by 2-MeTHF (301 kg) and aq. solution of 8% Na2SO4 (352 kg). Quenched by acetic acid (12.0 kg) and the organic phase was separated. The organic solution was washed by aq. solution of 8% Na2SO4 (348 kg) and added n-heptane (702 L). The upper layer was separated and the above upper solution was subjected into the pad (SiCh, 2-MeTHF / n-heptane / NMM = 1 / 1.5 / 0.1%). Collected needed fractions and concentrated to afford the solution containing 60.6 kg of Compound VII with above 80% purity: yield 80%.

[0224] Characterization data for Compound VII: ESLLCMS: 705.4 [M+H]+.

[0225] Step 6: l-((7R,9R)-9-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-12,12- diisopropyl-13-methyl-2,5,8,ll-tetraoxa-12-silatetradecan-7-yl)pyrimidine-2,4(lH,3H)- dione (Compound VI). To the solution of Compound VII (62.6 kg, 88.8 mol) in NMP (788 kg) was added 60% NaH (21.0 kg, 315.0 mol) in portions while maintaining the temperature at -5- 5°C. To the above mixture was added MOEBr (41.4 kg, 297.9 mol) dropwise while maintaining the temperature at -5-5°C. Warmed to 5-15°C and stirred for 7 h until the Compound VII is less than 3% as measured by HPLC. The mixture was quenched by aq. solution of 10% NH4CI (713 kg) and the mixture was extracted by MTBE (393 L). The organic phase was separated and washed by water (372 kg) and aq. solution of 8% Na2SO4 (376 kg) and concentrated to around 250 L. The residual solution was added n-heptane (363 L), TEA (0.6 kg) and the above solution was subjected into column (SiCh, EtOAc / n-heptane / TEA = 1 / 5 / 0.1% to 1 / 0 / 0.1%). Collected needed fractions and concentrated to afford the solution containing 49.0 kg of Compound VI with above 78% purity: yield 72%.E0585.70022WO00 85 / 117#14402392vl

[0226] Characterization data for Compound VI: ESI-LCMS: 763.4 [M+H]+.STEP-7

[0227] Step 7: l-((7R,9R)-9-(Hydroxymethyl)-12,12-diisopropyl-13-methyl-2,5,8,ll- tetraoxa-12-silatetradecan-7-yl)pyrimidine-2,4(lH,3H)-dione (Compound V). The solution of Compound VI (49.0 kg, 64.3 mol) was switched to around 300 L with Acetonitrile (2 x 490 L). To the residual solution were added DCA (4.4 kg, 34.1 mol) and dodecane- 1 -thiol (20.4 kg, 100.5 mol). Warmed to 40-50°C and stirred for 8 h until the Compound VI is less than 1% as measured by HPLC. Cooled to 20-30°C and the mixture was washed by n-heptane (3 x 166 kg) to afford the ACN solution containing 25.9 kg of Compound V with above 80% purity: yield 88%.

[0228] Characterization data for Compound V: ESI-LCMS: 459.3 [M-H]'.

[0229] Step 8: (S)-2-((R)-l-(2,4-Dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-(2- methoxyethoxy)ethoxy)-3-((triisopropylsilyl)oxy)propanal (Compound IV-a). The solution of Compound V (25.7 kg, 55.8 mol) in Acetonitrile was concentrated to around 90 L. Diluted the mixture by DCM (517 L) and to the solution was added NMM (3.2 kg, 31.6 mol). To the above mixture was added DMP (32.0 kg, 75.4 mol) in portions while maintaining the temperature at 25-35°C. Stirred for 3.5 h until the Compound V is less than 5% as measured by HPLC. Cooled to 0-10°C and added aq. solution of 15% KHCO3 (193 kg). The mixture was quenched by aq. solution of 15% Na2S2O3 (176 kg). Filtered the mixture through the pad of diatomite to give a filtrate. The organic phase was separated and concentrated to around 90 L. The residual solution was switched to 90 L with MTBE (257 L). To the residual solution was added MTBE (497 L) and washed successively by aq. solution of 50% DMF (207 kg + 155 kg),E0585.70022WO00 86 / 117#14402392vlaq. solution of 10% Na2SO4 (52 kg) and water (260 kg). The organic phase was concentrated to around 130 L, switched to 90 L with Acetonitrile (3 x 205 kg) to the ACN solution containing 25.5 kg of Compound IV-a with above 60% purity: yield 100%.

[0230] Step 9: Dimethyl ((R,E)-3-((R)-l-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-(2- methoxyethoxy)ethoxy)-4-((triisopropylsilyl)oxy)but-l-en-l-yl)phosphonate (Compound III). To the mixed solution of tetramethyl methylenebis(phosphonate) (Compound IV-b) (2275 g, 9.80 mol) in ACN (20.5 L) and THF (10.3 L) was added t-BuOK (1037 g, 9.24 mol) in portions while maintaining the temperature at 0-10°C. Cooled to -20 ~ -10°C and to the above mixture was added the solution of Compound IV-a (2.57 kg) in ACN (~ 5 L) dropwise while maintaining the temperature at -20 ~ -10°C. Stirred for 0.5 h until the Compound IV-a is less than 2% as measured by HPLC. The mixture was quenched by aq. solution of 10% NH4CI (12.9 L). The organic phase was separated and concentrated to around 13 L. The residual solution was diluted by MTBE (26 L) and washed successively with water (13 L) and aq. solution of 10% NaCl (13 L). Concentrated the solution to afford the solution containing 1.63 kg of Compound III with above 60% purity: yield 51%.

[0231] Characterization data for Compound III: ESI-LCMS: 565.6 [M+H]+.

[0232] Compound II may be prepared according to a similar procedure, using Compound IV'-b in place of Compound IV-b.

[0233] Step 10: Dimethyl ((R,E)-3-((R)-l-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-(2- methoxyethoxy)ethoxy)-4-hydroxybut-l-en-l-yl)phosphonate (Compound Il-a). To the solution of crude Compound III (1.31 kg, 2.32 mol) in MeOH (9.6 L) was added TEA3HF (2.72E0585.70022WO00 87 / 117#14402392vlkg, 16.87 mol). Warmed to 55-65°C and stirred for 2 h until the Compound III is less than 1% as measured by HPLC. Concentrated the mixture to give a residue. The above residue was purified by column chromatography (SiCh, EtOAc / Acetone = 1 / 0 to 0 / 1) to give crude Compound Il-a with around 60% purity as an oil. The above residue was purified by Prep. HPLC (YMC Triart Prep C18-S, Phase A: Purified water, Phase B: Acetonitrile; gradient 2-85% over 32 min) to afford 536 g of Compound ILa with above 99.0% purity as an oil: yield 57%.

[0234] Compound II'-a may be prepared according to a similar procedure, using Compound II in place of Compound III.

[0235] Step 11: 2-Cyanoethyl ((R,E)-4-(dimethoxyphosphoryl)-2-((R)-l-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-(2-methoxyethoxy)ethoxy)but-3-en-l-yl) diisopropylphosphoramidite (Compound I). To the mixture of DCI (123.5 g, 1.10 mol) and Compound Il-b (409.8 g, 1.36 mol) in DCM (2135 mL) was added the solution of Compound II- a (427.1 g, 1.05 mol) in DCM (2135 mL) by dropwise while maintaining the temperature at 0- 10°C. Stirred for 2 h until the Compound ILa is less than 1% as measured by HPLC. The mixture was diluted by n-heptane (1280 mL) and quenched by aq. solution of 7% NaHCCh (8.6 L) below 10°C. The organic phase was separated, washed successively by aq. solution of 7% NaHCCh (4.3 L), aq. solution of 10% Na2SO4 (4.3 L) and dried over anhydrous Na2SO4. The above solution of crude Compound I was subjected into column chromatography (SiCh, EtOAc / n-heptane / TEA = 1 / 5 / 0.3% to 1 / 0 / 0.3%), collected qualified fractions and concentrated to afford 356.3 g of Compound I with above 98.0% purity and above 97.0%31PNMR purity as a pale-yellow liquid: yield 56%.

[0236] Characterization data for Compound I:31PNMR (CD3CN) 5 = 149.3, 148.9, 19.35, 19.31; ESLLCMS: 609.5 [M+H]+.

[0237] Compound I' may be prepared according to a similar procedure, using Compound II'-a in place of Compound ILa.E0585.70022WO00 88 / 117#14402392vlINCORPORATION BY REFERENCE

[0238] The present application refers to various issued patent, published patent applications, scientific journal articles, and other publications, all of which are incorporated herein by reference. The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Figures, the Examples, and the Claims.EQUIVALENTS AND SCOPE

[0239] In the articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Embodiments or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0240] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claims that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.E0585.70022WO00 89 / 117#14402392vl

[0241] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the embodiments. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any embodiment, for any reason, whether or not related to the existence of prior art.

[0242] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended embodiments. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.E0585.70022WO00 90 / 117#14402392vl

Claims

CLAIMSWhat is claimed is:

1. A method of preparing a compound of Formula (I):or a salt or tautomer thereof, comprising coupling a compound of Formula (II-a):or a salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain the compound of Formula (I), or salt or tautomer thereof, wherein the compound of Formula (II-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (III):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof.E0585.70022WO00 91 / 117#14402392vl2. A method of preparing a compound of Formula (I'):or a salt or tautomer thereof, comprising coupling a compound of Formula (II'-a):or a salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain the compound of Formula (I'), or salt or tautomer thereof, wherein the compound of Formula (II'-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (III'):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II '-a), or salt or tautomer thereof.

3. The method of claim 1 or 2, wherein coupling the compound of Formula (Il-a) or (II'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to a coupling activator selected from the group consisting of 1 -methyl-E0585.70022WO00 92 / 117#14402392vllH-benzimidazol-3-ium trifluoromethanesulfonate (N-MeBIT), l-phenyl-lH-imidazol-3-ium trifluoromethanesulfonate (N-PhIMT), lH-benzimidazol-3-ium trifluoromethanesulfonate (BIT), lH-imidazol-3-ium trifluoromethanesulfonate (IMT), 5-nitro-lH-benzimidazol-3-ium trifluoromethanesulfonate (NBT), 5-(ethylthio)-lH-tetrazole (ETT), 5-(benzylthio)-lH- tetrazole (BTT), 4,5-dicyanoimidazole (DCI), 2-bromo-4,5-dicyanoimidazole (Br-DCI), pyridinium chloride (PyHCl), pyridinium trifluoroacetate (PyTFA), and 1- (cyanomethyl)piperidinium tetrafluoroborate, and salts thereof.

4. The method of claim 3, wherein the coupling activator is 4,5-dicyanoimidazole (DCI), or a salt thereof.

5. The method of any one of claims 1-4, wherein coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises exposure to a halogenated solvent selected from di chloromethane, chloroform, and 1,2-di chloroethane, optionally wherein the halogenated solvent is di chi oromethane .

6. The method of any one of claims 1-5, wherein coupling the compound of Formula (Il-a) or (Il'-a), or salt or tautomer thereof, with the compound of Formula (II-b), or salt thereof, comprises a reaction temperature of between about 0 °C and about 10 °C.

7. The method of any one of claims 1-6, wherein reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (Il-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (Il'-a), or salt or tautomer thereof, comprises exposure to a fluoride source selected from tetrabutylammonium fluoride (TBAF), hydrogen fluoride pyridine (HF-pyridine), triethylamine trihydrofluoride (Et3N»3HF), hydrofluoric acid, tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), and ammonium fluoride, and salts thereof.

8. The method of claim 7, wherein the fluoride source is triethylamine trihydrofluoride (Et3N»3HF), or a salt thereof.E0585.70022WO00 93 / 117#14402392vl9. The method of any one of claims 1-8, wherein reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises exposure to an alcohol solvent selected from methanol, ethanol, and isopropanol, optionally wherein the alcohol solvent is methanol.

10. The method of any one of claims 1-9, wherein reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof, or reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II'-a), or salt or tautomer thereof, comprises a reaction temperature of between about 55 °C and about 65 °C.

11. The method of any one of claims 1-10, wherein the compound of Formula (III) or (IH ), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IV-a):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (HI) or (in ), or salt or tautomer thereof.

12. The method of claim 11, wherein: reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III), or salt or tautomer thereof, comprises exposure of a compound of Formula (IV-b):or salt thereof, to a base and a first solvent, to produce a first solution; or reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III'), or salt or tautomer thereof, comprisesE0585.70022WO00 94 / 117#14402392vlexposure of a compound of Formula (IV'-b):or salt thereof, to the base and the first solvent, to produce the first solution.

13. The method of claim 12, wherein the base is potassium / c77-butoxide (t-BuOK), sodium / c77-butoxide (t-BuONa), or lithium tert-butoxide (7-BuOLi).

14. The method of claim 12 or claim 13, wherein a molar ratio of the compound of Formula (IV-b) or (IV'-b), or salt thereof, to the base is between about 1 : 1 and about 1 :0.9.

15. The method of any one of claims 12-14, wherein the first solvent comprises acetonitrile, tetrahydrofuran, or a combination thereof.

16. The method of any one of claims 12-15, wherein the first solvent comprises acetonitrile and tetrahydrofuran.

17. The method of any one of claims 12-16, wherein exposure of the compound of Formula (IV-b) or (IV'-b), or salt thereof, to the base comprises a first reaction temperature of between about 0 °C and about 10 °C.

18. The method of any one of claims 12-17, wherein reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III) or (III'), or salt or tautomer thereof, comprises adding a second solution to the first solution, wherein the second solution comprises the compound of Formula (IV-a), or salt or tautomer thereof, and a second solvent.

19. The method of claim 18, wherein the second solvent comprises acetonitrile.

20. The method of claim 18 or claim 19, wherein adding the second solution to the first solution comprises a second reaction temperature of between about -20 °C and about -10 °C.E0585.70022WO00 95 / 117#14402392vl21. The method of any one of claims 1-20, wherein the compound of Formula (III) or (nr), or salt or tautomer thereof, is obtained in a diastereomeric ratio of greater than about 95:5.

22. The method of any one of claims 11-21, wherein reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (III) or (III'), or salt or tautomer thereof, does not comprise epimerization of the compound of Formula (IV-a), or salt or tautomer thereof, to produce a compound of Formula(IV-a-epi):or a salt or tautomer thereof, epimerization of the compound of Formula (III), or salt or tautomer thereof, to produce a compound of Formula (III-epi):or a salt or tautomer thereof, or epimerization of the compound of Formula (III'), or salt or tautomer thereof, to produce a compound of Formula (Ill'-epi):epi), or a salt or tautomer thereof.

23. The method of any one of claims 11-22, wherein the compound of Formula (IV-a), orE0585.70022WO00 96 / 117#14402392vlsalt or tautomer thereof, is prepared by reacting a compound of Formula (V):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof.

24. The method of claim 23, wherein reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to a base, wherein the base is 7V-methylmorpholine.

25. The method of claim 24, wherein reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises exposure to an oxidant, wherein the oxidant is Dess-Martin periodinane (DMP).

26. The method of claim 24 or claim 25, wherein reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV- a), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is acetonitrile, dichloromethane, or a combination thereof.

27. The method of any one of claims 23-26, wherein reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof, comprises a reaction temperature of between about 25 °C and about 35 °C.

28. The method of any one of claims 23-27, wherein the compound of Formula (V), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VI):E0585.70022WO00 97 / 117#14402392vlor a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof.

29. The method of claim 28, wherein reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to an acid, wherein the acid is dichloroacetic acid (DCA).

30. The method of claim 28 or claim 29, wherein reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to a thiol, wherein the thiol is dodecane- 1- thiol.

31. The method of any one of claims 28-30, wherein reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is acetonitrile.

32. The method of any one of claims 28-31, wherein reacting the compound of Formula (VI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof, comprises a reaction temperature of between about 40 °C and about 50 °C.

33. The method of any one of claims 28-32, wherein the compound of Formula (VI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof.E0585.70022WO00 98 / 117#14402392vl34. The method of claim 33, wherein reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to a base, wherein the base is sodium hydride.

35. The method of claim 33 or claim 34, wherein reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to l-bromo-2-m ethoxy ethane, or a salt thereof.

36. The method of any one of claims 33-35, wherein reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is V-Methyl-2-pyrrolidone.

37. The method of any one of claims 33-36, wherein reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof, comprises a first reaction temperature of between about -5 °C and about 5 °C and a second reaction temperature of between about 5 °C and about 15 °C.

38. The method of any one of claims 33-37, wherein the compound of Formula (VII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof.

39. The method of claim 38, wherein reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises exposure to a hydroxide salt.E0585.70022WO00 99 / 117#14402392vl40. The method of claim 38 or claim 39, wherein reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent comprises 2-methyltetrahydrofuran, ethanol, water, or a combination thereof.

41. The method of any one of claims 38-40, wherein reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof, comprises a reaction temperature of between about 5 °C and about 15 °C.

42. The method of any one of claims 38-41, wherein the method produces a reaction mixture that is substantially free of a compound of Formula (X):or a salt or tautomer thereof.

43. The method of any one of claims 38-42, wherein the compound of Formula (VIII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IX):or a salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof.

44. The method of claim 43, wherein reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to a base, wherein the base is imidazole.

45. The method of claim 43 or claim 44, wherein reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropyl silyl chloride under suitable conditions to obtainE0585.70022WO00 100 / 117#14402392vlthe compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to a catalyst, wherein the catalyst is 4-dimethylaminopyridine.

46. The method of any one of claims 43-45, wherein reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropylsilyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is 2-methyltetrahydrofuran.

47. The method of any one of claims 43-46, wherein reacting the compound of Formula (IX), or salt or tautomer thereof, with triisopropylsilyl chloride under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof, comprises a reaction temperature of between about 50 °C and about 60 °C.

48. The method of any one of claims 43-47, wherein the compound of Formula (IX), or salt or tautomer thereof, is prepared by reacting a compound of Formula (X):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula(IX), or salt or tautomer thereof.

49. The method of claim 48, wherein reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to a lipase, wherein the lipase is a 1,3 specific lipase originating from Thermomyces lanuginosus, and wherein the lipase is immobilized on a non- compressible silica gel carrier.

50. The method of claim 48 or claim 49, wherein reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises exposure to an acylating agent, wherein the acylating agent is benzoic anhydride.E0585.70022WO00 101 / 117#14402392vl51. The method of any one of claims 48-50, wherein reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula(IX), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is 2- methyltetrahydrofuran.

52. The method of any one of claims 48-51, wherein reacting the compound of Formula(X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula(IX), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent does not comprise toluene.

53. The method of any one of claims 48-52, wherein reacting the compound of Formula(X), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof, comprises a reaction temperature of between about 35 °C and about 45 °C.

54. The method of any one of claims 48-53, wherein the compound of Formula (X), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof.

55. The method of claim 54, wherein reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises exposure to a reducing agent, wherein the reducing agent is sodium borohydride.

56. The method of claim 54 or claim 55, wherein reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is 2- methyltetrahydrofuran.E0585.70022WO00 102 / 117#14402392vl57. The method of any one of claims 54-56, wherein reacting the compound of Formula (XI), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (X), or salt or tautomer thereof, comprises a first reaction temperature of between about 0 °C and about 10 °C and a second reaction temperature of between about 20 °C and about 30 °C.

58. The method of any one of claims 54-57, wherein the compound of Formula (XI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula(XI), or salt or tautomer thereof.

59. The method of claim 58, wherein reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises exposure to a periodate salt.

60. The method of claim 58 or claim 59, wherein reacting the compound of Formula(XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent is 2-methyltetrahydrofuran.

61. The method of any one of claims 58-60, wherein reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XI), or salt or tautomer thereof, comprises a reaction temperature of between about 20 °C and about 30 °C.

62. The method of any one of claims 58-61, wherein the compound of Formula (XII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XIII):E0585.70022WO00 103 / 117#14402392vlor a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof.

63. The method of claim 62, wherein reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to 4,4'-dimethoxytrityl chloride.

64. The method of claim 62 or claim 63, wherein reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to a base, wherein the base is 7V-methylmorpholine.

65. The method of any one of claims 62-64, wherein reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises exposure to a solvent, wherein the solvent comprises 2-methyltetrahydrofuran, 7V,7V-dimethylformamide (DMF), or a combination thereof.

66. The method of any one of claims 62-65, wherein reacting the compound of Formula (XIII), or salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof, comprises a reaction temperature of between about -10 °C and about 0 °C.

67. A method of preparing a compound of Formula (I):E0585.70022WO00 104 / 117#14402392vlor a salt or tautomer thereof, comprising coupling a compound of Formula (II-a):or a salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain the compound of Formula (I), or salt or tautomer thereof, wherein: the compound of Formula (II-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (III):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (II-a), or salt or tautomer thereof; the compound of Formula (III), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IV-a):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (HI), or salt or tautomer thereof; the compound of Formula (IV-a), or salt or tautomer thereof, is prepared by reacting aE0585.70022WO00 105 / 117#14402392vlcompound of Formula (V):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof; the compound of Formula (V), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof; the compound of Formula (VI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof; the compound of Formula (VII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof; the compound of Formula (VIII), or salt or tautomer thereof, is prepared by reacting aE0585.70022WO00 106 / 117#14402392vlcompound of Formula (IX):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula(VIII), or salt or tautomer thereof; the compound of Formula (IX), or salt or tautomer thereof, is prepared by reacting a compound of Formula (X):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IX), or salt or tautomer thereof; the compound of Formula (X), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula(X), or salt or tautomer thereof; the compound of Formula (XI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula(XI), or salt or tautomer thereof; and the compound of Formula (XII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XIII):E0585.70022WO00 107 / 117#14402392vlor a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof.

68. A method of preparing a compound of Formula (I'):or a salt or tautomer thereof, comprising coupling a compound of Formula (Il'-a):or a salt or tautomer thereof, with a compound of Formula (II-b):or a salt thereof, to obtain the compound of Formula (I'), or salt or tautomer thereof, wherein: the compound of Formula (Il'-a), or salt or tautomer thereof, is prepared by reacting a compound of Formulaor a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (Il'-a), or salt or tautomer thereof; the compound of Formula (III'), or salt or tautomer thereof, is prepared by reacting aE0585.70022WO00 108 / 117#14402392vlcompound of Formula (IV-a):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (nr), or salt or tautomer thereof; the compound of Formula (IV-a), or salt or tautomer thereof, is prepared by reacting a compound of Formula (V):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (IV-a), or salt or tautomer thereof; the compound of Formula (V), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (V), or salt or tautomer thereof; the compound of Formula (VI), or salt or tautomer thereof, is prepared by reacting a compound of Formula (VII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VI), or salt or tautomer thereof; the compound of Formula (VII), or salt or tautomer thereof, is prepared by reacting aE0585.70022WO00 109 / 117#14402392vlcompound of Formula (VIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VII), or salt or tautomer thereof; the compound of Formula (VIII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (IX):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (VIII), or salt or tautomer thereof; the compound of Formula (IX), or salt or tautomer thereof, is prepared by reacting a compound of Formula (X):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula(IX), or salt or tautomer thereof; the compound of Formula (X), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XI):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula(X), or salt or tautomer thereof; the compound of Formula (XI), or salt or tautomer thereof, is prepared by reacting aE0585.70022WO00 110 / 117#14402392vlcompound of Formula (XII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula(XI), or salt or tautomer thereof; and the compound of Formula (XII), or salt or tautomer thereof, is prepared by reacting a compound of Formula (XIII):or a salt or tautomer thereof, under suitable conditions to obtain the compound of Formula (XII), or salt or tautomer thereof.

69. A method of synthesis comprising one or more of the following steps:(a) reacting a compound of Formula (XIII):or a salt or tautomer thereof, under suitable conditions to obtain a compound of Formula(XII)or a salt or tautomer thereof;(b) reacting the compound of Formula (XII), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (XI):or a salt or tautomer thereof;(c) reacting the compound of Formula (XI), or salt or tautomer thereof, under suitableE0585.70022WO00 111 / 117#14402392vlconditions to obtain a compound of Formula (X):or a salt or tautomer thereof;(d) reacting the compound of Formula (X), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (IX):or a salt or tautomer thereof;(e) reacting the compound of Formula (IX), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (VIII):or a salt or tautomer thereof;(f) reacting the compound of Formula (VIII), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (VII):or a salt or tautomer thereof;(g) reacting the compound of Formula (VII), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (VI):or a salt or tautomer thereof;(h) reacting the compound of Formula (VI), or salt or tautomer thereof, under suitableE0585.70022WO00 112 / 117#14402392vlconditions to obtain a compound of Formula (V):or a salt or tautomer thereof;(i) reacting the compound of Formula (V), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (IV-a):or a salt or tautomer thereof;(j) reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (III):or a salt or tautomer thereof;(k) reacting the compound of Formula (III), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (II-a):or a salt or tautomer thereof;(1) coupling the compound of Formula (II-a), or salt or tautomer thereof, with aE0585.70022WO00 113 / 117#14402392vlcompound of Formula (II-b):or a salt thereof, to obtain a compound of Formula (I):or a salt or tautomer thereof;(m) reacting the compound of Formula (IV-a), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (III'):or a salt or tautomer thereof;(n) reacting the compound of Formula (III'), or salt or tautomer thereof, under suitable conditions to obtain a compound of Formula (Il'-a):or a salt or tautomer thereof; and(o) coupling the compound of Formula (Il'-a), or salt or tautomer thereof, with aE0585.70022WO00 114 / 117#14402392vlcompound of Formula (II-b):or a salt or tautomer thereof.

70. A compound of Formula (XIV):or a salt or tautomer thereof, wherein:R1is selected from triphenylmethyl, 4,4'-dimethoxytrityl (4,4'- dimethoxytriphenylmethyl or DMT), 4,4’-dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl (IDTr), and 4,4’-dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl (lETr); andR2is selected from benzoate (Bz), / ?-methoxybenzoate, -phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), 4-bromobenzoate, 2,5-difluorobenzoate, pentafluorobenzoate, / 2-nitrobenzoate, 2-iodobenzoate, o-(dibromomethyl)benzoate, 2- (methylthiomethoxymethyl)benzoate, o-(methoxyacyl )benzoate, formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, -chlorophenoxy acetate, 3 -phenylpropionate, 4- oxopentanoate (levulinate), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, 4- azidobutyrate, 4-nitro-4-methylpentanoate, 4-(methylthiomethoxy)butyrate, 2,6-dichloro-4- methylphenoxy acetate, 2, 6-dichloro-4-( 1,1, 3 ,3 -tetramethylbutyl)phenoxy acetate, 2,4-bi s( 1 , 1 - dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-E0585.70022WO00 115 / 117#14402392vlmethyl-2-butenoate, a-naphthoate, methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, / -butyl carbonate (BOC or Boc), -nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4- dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, -nitrobenzyl carbonate, 4-ethoxy-l- napththyl carbonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), methanesulfonate (mesylate), benzylsulfonate, 2-formylbenzenesulfonate, and tosylate (Ts).

71. The compound of claim 70, wherein R2is selected from benzoate (Bz), / >- methoxybenzoate, -phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), 4-bromobenzoate, 2,5-difluorobenzoate, pentafluorobenzoate, -nitrobenzoate, 2-iodobenzoate, o- (dibromomethyl)benzoate, 2-(methylthiomethoxymethyl)benzoate, and o- (methoxyacyl)benzoate.

72. The compound of claim 70 or claim 71, wherein the compound is of Formula (XlV-a) or (XlV-b):or a salt or tautomer thereof.

73. The compound of any one of claims 70-72, wherein the compound is of Formula(VIII)or a salt or tautomer thereof.E0585.70022WO00 116 / 117#14402392vl

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