Methods and intermediates for preparing therapeutic compounds useful for treating retroviridae viral infection

Abstract

To provide organic synthetic methods for preparation of antiviral compounds, and their synthetic intermediates.SOLUTION: The present disclosure relates to methods and intermediates useful for preparing a compound of formula I in the figure or a co-crystal, solvate, salt or combination thereof. The present disclosure relates to methods and intermediates for synthesis of novel compounds for use in treatment of a Retroviridae viral infection, including an infection caused by the HIV virus. The present disclosure relates generally to the field of organic synthetic methods for preparation of antiviral compounds and their synthetic intermediates.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Citation of Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 710,575, filed February 16, 2018, the entire contents of which are incorporated herein by reference. Field The present disclosure relates to methods and intermediates for the synthesis of novel compounds for use in the treatment of Retroviridae viral infections, including infections caused by the HIV virus. [Background technology]

[0002] background The present disclosure relates generally to the field of organic synthesis methods for the preparation of antiviral compounds and their synthetic intermediates.

[0003] Positive-sense single-stranded RNA viruses, including those in the Retroviridae family, include the Orthoretrovirinae subfamily, the genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus, which cause numerous diseases in humans and animals. Among the Lentiviruses, HIV-1 infection leads to a loss of helper T cells and immune dysfunction in humans, resulting in immunodeficiency and vulnerability to opportunistic infections. Treating HIV-1 infection with highly active antiretroviral therapy (HAART) has proven effective in reducing viral load and significantly delaying disease progression (Hammer, SM, et al.; JAMA 2008, 300:555-570). However, these treatments have sometimes led to the emergence of HIV strains that are resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559; Smith, RJ, et al., Science 2010, 327:697-701). Thus, there is an urgent need to discover and synthesize new antiretroviral agents that are active against emerging drug-resistant HIV mutants.

[0004] U.S. Patent Application No. 15 / 680,041 discloses novel compounds useful for treating Retroviridae viral infections, including infections caused by the HIV virus. One specific compound identified therein has the formula I: [ka] is a compound of There is currently a need for improved synthetic methods and intermediates that can be used to prepare the compound of Formula I and its co-crystals, solvates, salts, and combinations. There is also a need for improved methods for preparing intermediate compounds that can be used to prepare the compound of Formula I and its co-crystals, solvates, salts, and combinations thereof. The improved methods and intermediates may reduce the cost, time, and / or amount of waste associated with existing methods for preparing the compound of Formula I and its co-crystals, solvates, salts, and combinations. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent Application Serial No. 15 / 680,041 [Non-patent literature]

[0006] [Non-Patent Document 1] Hammer,SM,et al.;JAMA 2008,300:555-570 [Non-patent document 2] Taiwo, B., International Journal of Infectious Diseases 2009,13:552-559 [Non-patent document 3] Smith,RJ,et al.,Science 2010,327:697-701 Summary of the Invention [Means for solving the problem]

[0007] Abstract In some embodiments, the present disclosure provides a compound of formula I: [ka] or a co-crystal, solvate, salt, or combination thereof. The compound of Formula I may also be named or identified as N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

[0008] In some embodiments, compounds of formula I are described herein: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises: (a) Formula VIII: [ka] or a co-crystal, solvate, salt, or combination thereof, of formula IX: [ka] or a co-crystal, solvate, or combination thereof, under alkynylation conditions to form a compound of formula VI: [ka] or a co-crystal, solvate, salt, or combination thereof; (b) reacting a compound of formula VI, or a co-crystal, solvate, salt, or combination thereof, with a compound of formula VII: [ka] or a co-crystal, solvate, salt, or combination thereof under amide coupling conditions to form a compound of formula IV: [ka] or a co-crystal, solvate, salt, or combination thereof; (c) reacting a compound of formula IV, or a co-crystal, solvate, salt, or combination thereof, with a compound of formula V: [ka] or a co-crystal, solvate, salt, or combination thereof (wherein R 1 is combined with B(OH), B(OCH(Me)CHC(Me)O), B((1,2-di-O)CH), B(OCHC(Me)CHO), BFK, B(OCCHN(Me)CHCO), or B(OC(Me)C(Me)O) under palladium catalyzed cross-coupling conditions to give formula III: [ka] or a co-crystal, solvate, salt, or combination thereof; and (d) a compound of formula III or a co-crystal, solvate, salt, or combination thereof, with a silylating reagent under mesylation conditions to provide a compound of formula I or a co-crystal, solvate, salt, or combination thereof. Includes.

[0009] In some embodiments, provided herein are novel intermediates for the formation of compounds of Formula I or co-crystals, solvates, salts, or combinations thereof (e.g., the intermediates of Formulas II, III, IV, VI, and VIII identified above).

[0010] Thus, in one embodiment, a compound of formula II: [ka] or a co-crystal, solvate, salt, or combination thereof.

[0011] In another embodiment, a compound of formula III: [ka] or a co-crystal, solvate, salt, or combination thereof.

[0012] In another embodiment, a compound of formula IV: [ka] or a co-crystal, solvate, salt, or combination thereof.

[0013] In another embodiment, a compound of formula VI: [ka] or a co-crystal, solvate, salt, or combination thereof.

[0014] In another embodiment, a compound of formula VIII: [ka] or a co-crystal, solvate, salt, or combination thereof.

[0015] The synthetic routes and intermediates disclosed herein reduce the cost, time, and amount of waste associated with preparing the compound of Formula I and its co-crystals, solvates, and salts, and combinations thereof. Thus, the synthetic methods disclosed herein provide the compound of Formula I in fewer steps than previous synthetic methods (e.g., carbamate protection and amino group deprotection are avoided), and atropisomers are introduced later in the sequence than previous synthetic methods.

[0016] Further embodiments of the present disclosure are provided herein, including additional novel synthetic intermediates and methods for preparing such intermediates. DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description The following description is made with the understanding that the present disclosure should be considered an exemplification of the claimed subject matter, and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience and should not be construed in any way as limiting the scope of the claims. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0018] When a trade name is used herein, it is intended to independently include the trade name product and the active pharmaceutical ingredient(s) of that trade name product.

[0019] As used herein and in the appended claims, the singular forms "a" and "a" are used interchangeably. "An," as well as "the," include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays, etc.

[0020] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0021] "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.

[0022] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "scalemic" mixture.

[0023] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0024] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and / or hindered rotation about a bond axis and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-. The present disclosure is intended to encompass all such possible isomers, including racemic mixtures, scalemic mixtures, diastereomeric mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0025] Unless expressly specified otherwise, the present disclosure encompasses all tautomers of the compounds detailed herein, even when only one tautomer is explicitly presented (e.g., when two tautomeric pairs may exist, both tautomeric forms are intended and described by providing one tautomeric form). For example, when a compound containing an amine is referenced (e.g., by structure or chemical name), it should be understood that the corresponding imidic acid tautomer is encompassed in the present disclosure and is described to the same extent as if the amide, either alone or together with the imidic acid, were explicitly described. When more than two tautomers are possible, the present disclosure encompasses all such tautomers as if a single tautomeric form were depicted by chemical name and / or structure.

[0026] The compounds described herein may have chiral and / or geometric isomeric centers (E- and Z-isomers), and it is to be understood that all such optical, enantiomeric, diastereomeric, and geometric isomers are encompassed. Where compounds are represented in their chiral form, it is understood that the embodiment includes, but is not limited to, the specific diastereomeric or enantiomerically enriched form. Where chirality is not specified, it is understood that the embodiment relates to either the specific diastereomeric or enantiomerically enriched form, or a racemic or scalemic mixture of such compound(s). As used herein, a "scalemic mixture" refers to a 1:1 ratio of stereoisomers. It is a mixture of ratios other than

[0027] The terms "amine transaminase" and "ATA," as used herein, refer to a polypeptide having the enzymatic ability to exchange the amino group of a donor amine with the carbonyl group of an acceptor molecule. This transamination reaction is carried out in the presence of pyridoxal phosphate (PLP), which serves as a cofactor. In a transamination reaction using a transaminase enzyme, the amine group of the amino donor is transferred to the cofactor to generate a ketone as a by-product, while pyridoxal-5'-phosphate is converted to pyridoxamine phosphate. Transfer of the amine group from pyridoxamine phosphate to the ketone substrate generates a chiral amine and regenerates the coenzyme. S-selective transaminases include, but are not limited to, ATA-1, ATA-2, ATA-007, ATA-013, ATA-025, ATA-113, ATA-117, ATA-200, ATA-217, ATA-234, ATA-237, ATA-238, ATA-251, ATA-254, ATA-256, ATA-260, ATA-301, ATA-303, ATA-412, ATA-415, ATA-P1-B04, ATA-P1-F03, ATA-P1-G05, ATA-P2-A01, ATA-P2-A07, ATA-P2-B01, and mixtures thereof.

[0028] The term "asymmetric catalyst," as used herein, refers to a catalyst that promotes the enantioselective and / or diastereoselective conversion of an achiral center or molecule to a chiral center or molecule, respectively. For example, an asymmetric catalyst can produce an enantiomeric excess of a product. Exemplary asymmetric catalysts include transition metals and chiral ligands. Non-limiting examples of chiral ligands include BINAP / SEGPHOS®, salens, bisoxazolines, tartaric acid ligands, cinchona alkaloids, DuPhos phosphoranes, BPE phosphoranes, DSM phosphoramidites, Solvias® Josiphos family, phosphine-oxazolines, Reetz and Trost ligands, and ChiralQuest phosphines.

[0029] Pharmaceutically acceptable hydrates, solvates, co-crystals, tautomeric forms, polymers, and prodrugs of the compounds described herein are also provided.

[0030] The term "hydrate" refers to the complex formed by combining a compound of Formula I, or any formula disclosed herein, with water.

[0031] The term "solvate" refers to a complex formed by combining a compound of Formula I, or any other formula disclosed herein, with a solvent, or a crystalline solid that contains an amount of solvent incorporated within the crystalline structure. As used herein, the term "solvate" includes hydrates.

[0032] The term "cocrystal" refers to a crystalline material formed by combining a compound of Formula I or any formula disclosed herein with one or more cocrystal formers (i.e., molecules, ions, or atoms). In certain instances, a cocrystal may have improved properties compared to the parent form (i.e., the free molecule, zwitterion, etc.) or a salt of the parent compound. The improved properties can be increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity, crystalline forms of compounds that are normally amorphous, crystalline forms of compounds that are difficult or unstable to salt, reduced form diversity, more desirable forms, etc. Methods for making and characterizing cocrystals are known to those of skill in the art.

[0033] Any formula or structure set forth herein, including Formula I or any formula disclosed herein, also represents unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas set forth herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include: 2 H (deuterium, D), 3 H (tritium),11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 1. Isotopically labeled compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, I. Various isotopically labeled compounds of the present disclosure can be used in 3 H, 13 C and 14 and those into which a radioactive isotope such as C is incorporated. Such isotopically labeled compounds may be useful in metabolism studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiation treatment of patients.

[0034] The present disclosure also includes compounds of Formula I or any formula disclosed herein in which one to "n" hydrogens bonded to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound of Formula I when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0035] Deuterium-labeled or substituted therapeutic compounds of the present disclosure can improve DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, can result in certain therapeutic advantages due to improved metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. 18F-labeled compounds can be useful for PET or SPECT studies. Isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the following schemes or examples and preparations by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), can result in certain therapeutic advantages due to improved metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, or improved therapeutic index. It is understood that deuterium in this context is considered a substituent in compounds of Formula I or any formula disclosed herein.

[0036] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0037] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity).

[0038] The term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image counterpart, while the term "achiral" refers to a molecule that is superimposable on its mirror image counterpart. Refers to...

[0039] An "alkyl" is a straight-chain or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 8 carbon atoms (i.e., (C1-C8) alkyl), or 1 to 6 carbon atoms (i.e., (C1-C6 alkyl), or 1 to 4 carbon atoms (i.e., (C1-C4) alkyl). Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-B u, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2 CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH2CH3), 3-methyl-2-pentyl butyl (-CH(CH)CH(CH)CH), 4-methyl-2-pentyl (-CH(CH)CHCH(CH)), 3-methyl-3-pentyl (-C(CH)(CHCH)), 2-methyl-3-pentyl (-CH(CHCH)CH(CH)), 2,3-dimethyl-2-butyl (-C(CH)CH(CH)), 3,3-dimethyl-2-butyl (-CH(CH)C(CH)), and octyl (-(CH)CH).

[0040] "Alkenyl" means at least one carbon-carbon sp2 It is a straight-chain or branched-chain hydrocarbon containing a double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C2-C8 alkenyl) or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0041] An "alkynyl" is a straight or branched chain hydrocarbon containing at least one carbon-carbon triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., a C2-C8 alkyne) or 2 to 6 carbon atoms (i.e., a C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0042] The term "halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo.

[0043] The term "haloalkyl," as used herein, refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are each independently replaced by a halo substituent. For example, a (C-C)haloalkyl is a (C-C)alkyl in which one or more of the hydrogen atoms of the (C-C)alkyl are replaced by a halo substituent. Examples of haloalkyl include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1, trifluoroethyl, and pentafluoroethyl.

[0044] The term "aryl," as used herein, refers to a single all-carbon aromatic ring or a system of fused all-carbon rings, in which at least one of the rings is aromatic. For example, in certain embodiments, aryl groups have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl encompasses the phenyl radical. Aryl also encompasses fused ring systems (e.g., ring systems containing two, three, or four rings) having about 9 to 20 carbon atoms, in which at least one ring is aromatic and the other rings may or may not be aromatic (i.e., carbocyclic). Such fused ring systems are optionally substituted with one or more (e.g., one, two, or three) oxo groups on any carbocyclic portion of the fused ring system. The rings of this fused multi-ring system may be connected to each other via fused, spiro, or bridging bonds, if permitted by valency requirements. It should be understood that the point of attachment of a fused multi-ring system, as defined above, may be at any position on the ring system, including the aromatic or carbocyclic portions of the ring. When a specific atom range of aryls (e.g., 6- to 12-membered aryls) is referenced, it should also be understood that this atom range refers to all ring atoms of that aryl. For example, a 6-membered aryl includes phenyl, and a 10-membered aryl includes naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0045] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one non-carbon atom selected from the group consisting of oxygen, nitrogen, and sulfur in the ring; "heteroaryl" also includes fused ring systems having at least one such aromatic ring, which fused ring systems are further described below. Thus, "heteroaryl" includes a single aromatic ring having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may be present in oxidized form, provided the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also includes fused ring systems (e.g., ring systems containing two, three, or four rings), where a heteroaryl group as defined above is fused with one or more rings selected from heteroaryl (e.g., to form 1,8-naphthyridinyl), heterocycle (e.g., to form 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., to form 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., to form indazolyl) to form a fused ring system. Thus, a heteroaryl (single aromatic ring or fused ring system) has about 1 to 20 carbon atoms and about 1 to 6 heteroatoms in the heteroaryl ring. Such fused ring systems may be optionally substituted with one or more (e.g., one, two, three, or four) oxo groups on the carbocyclic or heterocyclic portion of the fused ring. The rings of a fused ring system can be connected to each other via fused, spiro, and bridged bonds, where permitted by valency requirements. It should be understood that the individual rings of a fused ring system can be connected to each other in any order. It should also be understood that the point of attachment of a fused ring system (as defined above for heteroaryl) can be at any position of the fused ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portion of the fused ring system.It should also be understood that the point of attachment of a heteroaryl or heteroaryl-fused ring system can be any suitable atom of the heteroaryl or heteroaryl-fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). When a heteroaryl with a particular atom range of member numbers (e.g., a 5- to 14-membered heteroaryl) is referred to, it should also be understood that the atom range is a range of all ring atoms of the heteroaryl, including carbon atoms and heteroatoms. For example, a 5-membered heteroaryl is thia. 10-membered heteroaryl includes quinolinyl, and 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

[0046] As used herein, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic ring having at least one non-carbon atom selected from the group consisting of oxygen, nitrogen, and sulfur in the ring; this term also includes fused ring systems having at least one such saturated or partially unsaturated ring, which are further described below. Thus, this term includes saturated or partially unsaturated monocyclic rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having about 1 to 6 carbon atoms in the ring and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. The term "heterocycle" also includes fused ring systems (e.g., ring systems containing two, three, or four rings), where a single heterocycle (as defined above) may be fused with one or more groups selected from heterocycle (e.g., to form 1,8-decahydronapthyridinyl), carbocycle (e.g., to form decahydroquinolyl), and aryl to form a fused ring system. Thus, a heterocycle (saturated or partially unsaturated, monocyclic, or fused ring system) has about 2 to 20 carbon atoms and 1 to 6 heteroatoms within the heterocyclic ring. Such fused ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocycle or heterocycle portion of the multiple fused ring system. The rings of a fused ring system can be connected to each other via fused, spiro, and bridged bonds, where permitted by valency requirements. It should be understood that the individual rings of a fused ring system can be connected to each other in any order. It should also be understood that the point of attachment of a fused ring system (as defined above for heterocycles) can be at any position of the fused ring system, including the heterocyclic, aryl, and carbocyclic portions of the ring.It should also be understood that the point of attachment of a heterocyclic ring or heterocyclic-fused ring system can be any suitable atom of the heterocyclic ring or heterocyclic-fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). When a heterocyclic ring having a specific atom range of member numbers (e.g., a 3- to 14-membered heterocyclic ring) is mentioned, it should also be understood that the atom range is a range of all ring atoms of the heterocyclic ring, including carbon atoms and heteroatoms. For example, a 3-membered heterocyclic ring includes aziridinyl, and a 10-membered heterocyclic ring includes 1,2,3,4-tetrahydroquinolyl. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one, and pyrrolidin-2-one.

[0047] The term "cycloalkyl" refers to cyclic alkyl and alkenyl groups. Cycloalkyl groups can have one or more cyclic rings and include fully saturated or partially unsaturated fused and bridging groups. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, methylcycloproyl (cyclopropylmethyl), cyclohexenyl, and the like.

[0048] The term "fused" refers to rings that are joined to adjacent rings.

[0049] "Bridged" refers to a ring fusion in which non-adjacent atoms on the ring are linked by a divalent substituent (e.g., an alkylenyl or heteroalkylenyl group) or a heteroatom. Quinuclidinyl and adamantanyl are examples of bridged ring systems.

[0050] "Spiro" refers to a ring substituent that is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are each spiro substituents.

[0051] The term "azide" refers to the group [ka] This refers to...

[0052] The term "keto" or "oxo" refers to the group =O.

[0053] The term "carboxyl" refers to the group --C(O)--OH.

[0054] The term "hydroxy" or "hydroxyl" refers to the group --OH.

[0055] The term "amine protecting group" is well understood by those skilled in the art of synthetic organic chemistry as a moiety that can be selectively introduced and removed from an appropriate amine functional group and that masks or alters the properties of that amine functional group. The field of protecting group methodology is advanced, and many amine protecting groups and methods for using them are described in the authoritative treatise on the subject, P.G.M. Butts and T.W. Greene, "Greene's Protective Groups in Organic Synthesis," 4 th These methods are well known in the art, such as those described in the "Synthetic Methods for the Treatment of Acute Myocardial Infarction" in The Journal of Clinical Chemistry, Vol.

[0056] The term "borylating agent" is also well understood in the field of organic synthesis as a reagent useful for introducing any one of a wide variety of boronate moieties into a suitable substrate to provide an organoboron reagent, as described in T. Ishiyama et al., J. Org. Chem. 1995, 60, 7508-7510 and N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457-2483.

[0057] As used herein, the term "alkynylation conditions" refers to a condition in which a terminal alkyne is coupled with another compound (e.g., a suitable aryl or heteroaryl halide substrate) in the presence of a catalyst, a solvent, and optionally a base to form an alkyne (e.g., an internal alkyne). "Alkynylation conditions" refer to reaction conditions that form an alkylene. Non-limiting examples of catalysts for "alkynylation conditions" include palladium catalysts such as [(π-allyl)PdCl], Pd(acac), (SIPr)PdCl, PdCl(PPh), PdCl, Pd(OAc), PdCl(CHCN), Pd(dba), and the like, in combination with tertiary phosphines such as triphenylphosphine, tri-cyclohexylphosphine, tri-tert-butylphosphine, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphino)propane, and 1,1'-bis(diphenylphosphino)ferrocene (e.g., dichlorobis(triphenylphosphine)palladium(II)); copper catalysts such as copper(I) iodide, copper(I) bromide, and copper(I) chloride; and combinations thereof. In some embodiments, the catalyst is PdCl2(PPh3)2.

[0058] As used herein, "alkynylation conditions" typically include a base. Non-limiting examples of the base include amines (e.g., triethylamine, diisopropylamine, ethyldiisopropylamine, pyrrolidine, 1,4-diazabicyclo[2.2.2]-octane (1,4-diazabicyclo[2.2.2]-octane), 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo-4.3.0]non-5-ene, pyridine, piperidine, etc.), carbonates (e.g., cesium carbonate, potassium carbonate, etc.), phosphates (e.g., potassium phosphate, etc.), and tetraalkylammonium salts (e.g., tetrabutylammonium fluoride). In some embodiments, the base is triethylamine.

[0059] These alkynylation conditions further include a solvent. Non-limiting examples of the solvent include ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), aromatic solvents (e.g., benzene, xylene, etc.), polar protic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, etc.), water, and combinations thereof. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0060] In some embodiments, the alkynylation conditions comprise a temperature range of about 120° C. or less. In some embodiments, the alkynylation conditions comprise a temperature range of about 0° C. to about 120° C. In certain embodiments, the alkynylation conditions comprise a temperature range of about 50° C. to about 80° C.

[0061] The term "amide coupling conditions" refers to reaction conditions in which an amine and a carboxylic acid are coupled to form an amide in the presence of a base using a coupling reagent and, optionally, a coupling additive. Non-limiting examples of coupling reagents include n-propylphosphoric anhydride, oxalyl chloride, thionyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), carbonyldiimidazole, isobutyl chloroformate, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium-hexafluorophosphate, O-(7- Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate phosphate, and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate. In some embodiments, the coupling reagent is n-propylphosphoric acid anhydride. Non-limiting examples of coupling additives include 4-(dimethylamino)pyridine, 1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole.

[0062] Non-limiting examples of bases used for the "amide coupling conditions" include aliphatic amines (e.g., triethylamine, tributylamine, ethyldiisopropylamine, N-methylmorpholine, etc.) and aromatic amines (e.g., pyridine, 2,6-lutidine, N-methylimidazole, etc.). In some embodiments, the base is triethylamine.

[0063] The amide coupling conditions further include a solvent. Non-limiting examples of the solvent include nitriles (e.g., propionitrile, butyronitrile, acetonitrile, etc.), esters (e.g., ethyl acetate, butyl acetate, isobutyl acetate, etc.), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, etc.), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform, etc.), and combinations thereof. In some embodiments, the solvent is acetonitrile.

[0064] In some embodiments, the amide coupling conditions include a temperature range of about 120° C. or less. In some embodiments, the amide coupling conditions include a temperature range of about −20° C. to about 120° C. In certain embodiments, the amide coupling conditions include a temperature range of about 0° C. to about 40° C.

[0065] As used herein, the term "palladium-catalyzed cross-coupling conditions" refers to reaction conditions in which an aryl halide or aryl sulfonate (e.g., triflate, mesylate, tosylate) is coupled with an organoboron reagent in the presence of a palladium catalyst and a base to form a compound, such as a biaryl compound. In some embodiments, the organoboron reagent is aryl-R' (where R' is B(OH)2), B(OR)2 (where R is unsubstituted or substituted alkyl), BF4K, and the like. Non-limiting examples of organoboron reagents include arylboronic acids (aryl-B(OH)), arylboronic esters (e.g., aryl-B(OR) (e.g., aryl-B(OC(Me)C(Me)O), aryl-B(OCH(Me)CHC(Me)O), aryl-B((1,2-di-O)CH), and aryl-B(OCHC(Me)CHO))), and aryltrifluoroborates (e.g., aryl-BFK). In some embodiments, the organoboron reagent is aryl-B(OC(Me)C(Me)O).

[0066] In some embodiments, non-limiting examples of palladium catalysts for "palladium-catalyzed cross-coupling conditions" include dichlorobis(tricyclohexylphosphine)palladium(II), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, dichlorobis(triphenylphosphine)palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II), Examples of suitable catalysts include tetrakis(triphenylphosphine)palladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II), palladium(II) catalysts (palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate), or palladium(0) catalysts (tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0) in combination with a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine). In some embodiments, the palladium catalyst is dichlorobis(tricyclohexylphosphine)palladium(II).

[0067] In some embodiments, non-limiting examples of bases for the "palladium-catalyzed cross-coupling conditions" include carbonates (e.g., potassium bicarbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), inorganic bases (e.g., potassium fluoride, dipotassium phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, etc.), and aliphatic amines (e.g., dicyclohexylamine, N-methylmorpholine, triethylamine, etc.). In some embodiments, the base is potassium bicarbonate.

[0068] In some embodiments, the "palladium-catalyzed cross-coupling conditions" further comprise a solvent. In some embodiments, non-limiting examples of the solvent include ethers (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, etc.), aromatic hydrocarbon solvents (e.g., toluene, xylene, etc.), esters (ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, etc.), alcohols (ethanol, isopropanol, etc.), polar aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine, etc.), water, and combinations thereof. In some embodiments, the solvent is a mixture of n-butyl acetate and water.

[0069] In some embodiments, the palladium-catalyzed cross-coupling conditions comprise a temperature range of 120° C. or less. In some embodiments, the palladium-catalyzed cross-coupling conditions comprise a temperature range of from about 20° C. to about 120° C. In some embodiments, the palladium-catalyzed cross-coupling conditions comprise a temperature range of from about 75° C. to about 95° C.

[0070] As used herein, the term "mesylating reagent" refers to a reagent used to introduce a mesyl, i.e., methanesulfonyl (i.e., CHSO-) group onto a suitable hydroxy or amino group. In some embodiments, non-limiting examples of mesylation reagents include methanesulfonyl chloride, methanesulfonic anhydride, and methanesulfonic acid in combination with an activating agent (e.g., oxalyl chloride, thionyl chloride, or cyanuric chloride). In some embodiments, the mesylation reagent is methanesulfonic anhydride. In some embodiments, the mesylation reagent is methanesulfonyl chloride.

[0071] As used herein, the term "mesylation conditions" refers to reaction conditions under which a mesyl, i.e., methanesulfonyl (i.e., CHSO-) group is introduced into a suitable hydroxy group or a suitable amino group. When introducing a methanesulfonyl group into a suitable hydroxy group, the mesylation conditions disclosed herein typically include a base, a catalyst, and a solvent.

[0072] In some embodiments, when a methanesulfonyl group is introduced into a suitable hydroxy group, non-limiting examples of bases for mesylation conditions include aliphatic amines (e.g., triethylamines, In some embodiments, the base is triethylamine.

[0073] In some embodiments, when a methanesulfonyl group is introduced onto a suitable hydroxy group, non-limiting examples of suitable catalysts for "mesylation conditions" include 4-dimethylaminopyridine (DMAP), and the like.

[0074] In some embodiments, when a methanesulfonyl group is introduced into a suitable hydroxy group, non-limiting examples of solvents for mesylation conditions include ethers (e.g., diethyl ether, 1,4-dioxane, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, etc.), aromatic hydrocarbon solvents (e.g., toluene, xylene, etc.), esters (e.g., ethyl acetate, isopropyl acetate, isobutyl acetate, etc.), chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane, etc.), nitriles (e.g., acetonitrile, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidinone, etc.), and combinations thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is tetrahydrofuran and the catalyst is DMAP.

[0075] In some embodiments, when introducing a methanesulfonyl group onto a suitable hydroxy group, the mesylation conditions include a temperature range of about 60° C. or less. In some embodiments, the mesylation conditions include a temperature range of about −80° C. to about 60° C. In some embodiments, the mesylation conditions include a temperature range of about 0° C. to about 40° C.

[0076] When introducing a methanesulfonyl group into a suitable amino group, the mesylation conditions disclosed herein typically include a solvent and, optionally, a base.

[0077] In some embodiments, when a methanesulfonyl group is introduced into a suitable amino group, non-limiting examples of bases for the mesylation conditions include alkylamines (e.g., triethylamine, N-methylmorpholine, tri-n-propylamine, ethyldiisopropylamine, tri-n-butylamine, etc.), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, etc.), carbonates (e.g., sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate), inorganic bases (e.g., monosodium phosphate, disodium phosphate, monopotassium phosphate, dipotassium phosphate, etc.), and alkoxide bases (e.g., sodium tert-amylate, sodium tert-butoxide, etc.). In some embodiments, the base is triethylamine.

[0078] In some embodiments, when a methanesulfonyl group is introduced into a suitable amino group, non-limiting examples of solvents for the mesylation conditions include ethers (e.g., diethyl ether, 1,4-dioxane, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, etc.), aromatic hydrocarbon solvents (e.g., toluene, xylene, etc.), esters (e.g., ethyl acetate, isopropyl acetate, isobutyl acetate, etc.), chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane, etc.), nitriles (e.g., acetonitrile, etc.), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, etc.), and combinations thereof. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is cyclohexane. It is cyclopentyl methyl ether.

[0079] In some embodiments, when introducing a methanesulfonyl group into a suitable amino group, the mesylation conditions include a temperature range of about 100°C or less. In some embodiments, the mesylation conditions include a temperature range of about -20°C to about 100°C. In some embodiments, the mesylation conditions include a temperature range of about -10°C to about 20°C. In some embodiments, the mesylation conditions include a temperature range of about 20°C to about 120°C. In some embodiments, the mesylation conditions include a temperature range of about 70°C to about 90°C.

[0080] The term "borylation conditions" refers to reaction conditions under which a compound such as an aryl halide is converted to an organoboron reagent (e.g., an arylboron derivative, such as a compound of Formula V). The borylation conditions disclosed herein typically include a borylation agent and either an organometallic reagent or a catalyst. When the borylation conditions include a borylation agent and an organometallic reagent, non-limiting examples of the borylation agent include trimethyl borate, triethyl borate, pinacolborane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaboralane, B-catecholborane, 2-bromo-1,3,2-benzodioxaborole, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the borylation agent is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or isopropylboronic acid pinacol ester. Non-limiting examples of organometallic reagents include metallic lithium, metallic magnesium, n-butyllithium, s-butylmagnesium chloride-lithium chloride complex, tert-butylmagnesium chloride, isopropylmagnesium chloride-lithium chloride complex, and isopropylmagnesium chloride. In some embodiments, the organometallic reagent is isopropylmagnesium chloride. In some embodiments, the organometallic reagent is isopropylmagnesium chloride. In some embodiments, the organometallic reagent is isopropylmagnesium chloride-lithium chloride complex.

[0081] In some embodiments, the borylation conditions further include a solvent. Non-limiting examples of solvents include ethers (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, etc.), hydrocarbons (e.g., n-hexane, n-heptane, etc.), aromatic hydrocarbons (e.g., toluene, xylene, etc.), and combinations thereof. In some embodiments, the solvent is tetrahydrofuran.

[0082] In some embodiments, the borylation conditions comprise a temperature range of about 40° C. or less. In some embodiments, the borylation conditions comprise a temperature range of about −80° C. to about 40° C. In some embodiments, the borylation conditions comprise a temperature range of about −40° C. to about 20° C. In some embodiments, the borylation conditions comprise a temperature range of about −20° C. to about 20° C.

[0083] In some embodiments, when the borylation conditions include a borylation agent and a catalyst, non-limiting examples of the borylation agent include bis(neopentylglycolato)diboron, tetrahydroxydiboron, bis(hexyleneglycolato)diboron, and bis(pinacolato)diboron. In some embodiments, the borylation reagent is bis(pinacolato)diboron. Non-limiting examples of the catalyst include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, dichlorobis(triphenylphosphine)palladium(II), and [1,1'- In one embodiment, the catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0084] In some embodiments, non-limiting examples of solvents for the borylation conditions include ethers (e.g., diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidinone, etc.), aromatic hydrocarbon solvents (e.g., benzene, toluene, xylene, etc.), chlorinated solvents (e.g., dichloromethane, etc.), alcohols (e.g., methanol, ethanol, isopropanol, etc.), esters (e.g., ethyl acetate, isopropyl acetate, etc.), and combinations thereof. In some embodiments, the solvent is a mixture of dioxane and N,N-dimethylformamide.

[0085] In some embodiments, the borylation conditions comprise a temperature range of about 130° C. or less. In some embodiments, the borylation conditions comprise a temperature range of about 10° C. to about 130° C. In some embodiments, the alkynylation conditions comprise a temperature range of about 80° C. to about 110° C.

[0086] Additionally, the abbreviations used herein have the following respective meanings: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0087] Except where otherwise noted, the methods and techniques of the present disclosure are generally carried out according to conventional methods well known to those of skill in the art and as described in various general and more specific references cited and discussed throughout the specification. See, for example, Loudon, Organic Chemistry, 5 th edition, New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th See the full text of the paper, Wiley-Interscience, 2013.

[0088] In certain instances, the processes disclosed herein include forming a salt of a compound of the present disclosure.

[0089] The compounds described herein can be purified by any of the means known in the art, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, supercritical fluid chromatography (SFC), and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase, and ionic resins. Most typically, the compounds of the present disclosure are purified by silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2000. nd ed., ed. L.R.Snyder and J.J.Kirkland, John Wiley and Sons, 1979; and Th See in Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0090] During any of the processes for preparation of the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is discussed in detail in T.W. Greene and P.G.M. Buts, Protective Groups Groups in Organic Synthesis, 4 th This can be achieved by conventional protecting groups, as described in standard works such as "Protective Groups for the Synthesis of Novel Compounds," ed., Wiley, New York 2006. The protecting groups can be removed at a later convenient stage using methods known in the art.

[0091] Exemplary chemical entities useful in the methods of these embodiments are now described by way of exemplary synthetic schemes for their general preparation, followed by specific examples herein. One skilled in the art will recognize that the transformations shown in the schemes below can be carried out in any order that is compatible with the functionality of the particular pendant groups. In some embodiments, each of the reactions depicted in the general schemes is carried out at a temperature from about -80°C to the reflux temperature of the organic solvent used.

[0092] The compounds disclosed herein may exhibit atropisomerism, resulting from steric hindrance affecting the rate of axial rotation around a single bond. Each resulting conformer may be observed as a distinct entity by characterization techniques such as NMR or HPLC. The compounds disclosed herein may exist as a mixture of atropisomers. However, detection of atropisomers depends on factors such as temperature, solvent, purification conditions, and the timescale of the spectroscopic technique. Interconversion rates at room temperature have half-lives ranging from minutes to hours, hours to days, or days to years. The ratio of atropisomers at equilibrium may not be uniform. The characterization data provided herein may not represent equilibrium, depending on isolation and characterization conditions, which may include, but are not limited to, handling, solvents used, and temperature.

[0093] In some embodiments, the present disclosure provides processes and intermediates for preparing compounds of Formula I and their co-crystals, solvates, salts, and combinations. In other embodiments, the present disclosure provides processes for preparing intermediates that can be used to prepare compounds of Formula I and their co-crystals, solvates, salts, and combinations.

[0094] In some embodiments, the compound of formula VI: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula VIII: [ka] or a co-crystal, solvate, salt, or combination thereof, Formula IX: [ka] or a co-crystal, solvate, or combination thereof, base, a solvent, and catalyst in combination to provide a compound of formula VI, or a co-crystal, solvate, salt, or combination thereof.

[0095] In certain embodiments, the compound of formula VIII has formula VIII-02: [ka] or a co-crystal, solvate, or combination thereof, wherein HX is a chiral or achiral acid.

[0096] In certain embodiments, HX is selected from the group consisting of L-lactic acid, L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(-)-malic acid, D-glucuronic acid, (1R,3S)-(+)-camphoric acid, (1S)-(+)-camphor-10-sulfonic acid, (R)-(+)-N-(1-phenylethyl)succinamic acid, carbobenzyloxy-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methyladipic acid, (+)-menthyloxyacetic acid, (R)-(+)-methyl-L-propanol ... (R)-(-)-citramalic acid, (-)-camphanic acid, and (R)-mandelic acid.

[0097] In certain embodiments, HX is a chiral acid. In certain embodiments, HX is L-lactic acid, L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(-) -Malic acid, D-glucuronic acid, (1R,3S)-(+)-camphoric acid, (1S)-(+)-camphor-10-sulfonic acid, (R)-(+)-N-(1-phenylethyl)succinamic acid, carbobenzyloxy-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methyladipic acid, (+)-menthyloxyacetic acid, (-)-pyroglutamic acid, (-)-N-adipic acid In some embodiments, HX is selected from the group consisting of cetyl-L-leucine, N-Boc-D-leucine, N-(+)-BOC-phenylalanine, (-)-quinic acid, (+)-n-acetyl-L-phenylalanine, (+)-N-BOC-isoleucine, L-(-)-acetylglutamic acid, (-)-acetylmandelic acid, (R)-(-)-citramalic acid, (-)-camphanic acid, and (R)-mandelic acid. In some embodiments, HX is (R)-mandelic acid. In some embodiments, HX is N-Boc-D-leucine.

[0098] In some embodiments, HX is (-)-N-acetyl-D-leucine.

[0099] In certain embodiments, HX is an achiral acid. In certain embodiments, HX is selected from the group consisting of hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and phosphoric acid. In some embodiments, HX is methanesulfonic acid.

[0100] In certain embodiments, the catalyst comprises a palladium catalyst and a copper catalyst. In certain embodiments, the palladium catalyst is selected from the group consisting of [(π-allyl)PdCl], Pd(acac), (SIPr)PdCl, PdCl(PPh), PdCl, Pd(OAc), PdCl(CHCN), and Pd(dba), optionally in combination with a tertiary phosphine. In some embodiments, the tertiary phosphine is selected from the group consisting of triphenylphosphine, tri-cyclohexylphosphine, tri-tert-butylphosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, and 1,1'-bis(diphenylphosphino)ferrocene. In certain embodiments, the copper catalyst is selected from the group consisting of copper(I) iodide, copper(I) bromide, copper(I) chloride, and combinations thereof. In certain embodiments, the catalyst comprises PdCl2(PPh3)2 and copper(I) iodide.

[0101] In certain embodiments, the catalyst is a palladium catalyst. In certain embodiments, the palladium catalyst is selected from the group consisting of [(π-allyl)PdCl], Pd(acac), (SIPr)PdCl, PdCl(PPh), PdCl, Pd(OAc), PdCl(CHCN), and Pd(dba), optionally in combination with a tertiary phosphine. In some embodiments, the tertiary phosphine is selected from the group consisting of triphenylphosphine, tri-cyclohexylphosphine, tri-tert-butylphosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, and 1,1'-bis(diphenylphosphino)ferrocene. In some embodiments, the palladium catalyst is PdCl(PPh).

[0102] In certain embodiments, the copper catalyst is selected from the group consisting of copper(I) iodide, copper(I) bromide, copper(I) chloride, and combinations thereof.

[0103] In certain embodiments, the catalyst is a copper catalyst, hi certain embodiments, the copper catalyst is selected from the group consisting of copper(I) iodide, copper(I) bromide, and copper(I) chloride.

[0104] In certain embodiments, the base is triethylamine, diisopropylamine, ethoxylated methylamine, ethyl amine, methyl amine, ethyl ... In certain embodiments, the base is selected from the group consisting of ethyldiisopropylamine, pyrrolidine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, cesium carbonate, potassium carbonate, sodium carbonate, piperidine, potassium phosphate, and tetrabutylammonium fluoride. In certain embodiments, the base is triethylamine.

[0105] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., benzene, toluene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), water, acetonitrile, and combinations thereof.

[0106] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., benzene, toluene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), water, and combinations thereof. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0107] In some embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about 0° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of about 50° C. to about 80° C.

[0108] In some embodiments, Formula IV: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula VI: [ka] or a co-crystal, solvate, salt, or combination thereof, of formula VII: [ka] or a co-crystal, solvate, salt, or combination thereof, base, solvent, a coupling agent, if desired, and Activator if necessary The method includes combining the

[0109] In some embodiments, Formula IV: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula VI: [ka] or a co-crystal, solvate, salt, or combination thereof, of formula VII: [ka] or a co-crystal, solvate, salt, or combination thereof, Coupling or activating agents, bases, and solvent to provide a compound of formula IV, or a co-crystal, solvate, salt, or combination thereof.

[0110] In certain embodiments, the coupling reagent is an arylboronic acid. Non-limiting examples of arylboronic acids include phenylboronic acid, 3,5-bis(trifluoromethyl)phenylboronic acid, 3-nitrophenylboronic acid, and 2-iodophenylboronic acid.

[0111] In certain embodiments, the coupling reagent is n-propylphosphonic acid cyclic anhydride, n-propylphosphonic acid anhydride, 2-chloro-4,6-dimethoxy-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 2-chloro-1-methylpyridinium iodide, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole, chloroform ... Isobutyl benzoate, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium-hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-( 6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate, 4-(4,6-dimethoxybenzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, N,N,N',N'-tetramethylformamidinium hexafluorophosphate, triisopropyl borate, phenylboronic acid, 3,5-bis(trifluoromethyl)phenylboronic acid, 3-nitrophenylboronic acid, and 2-iodophenylboronic acid.

[0112] In certain embodiments, the coupling reagent is n-propylphosphonic anhydride, 2-chloro-4,6-dimethoxy-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 2-chloro-1-methylpyridinium iodide, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole, isobutyl chloroformate, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N, N',N'-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate. In certain embodiments, the coupling reagent is n-propylphosphonic acid anhydride. In certain embodiments, the coupling reagent is n-propylphosphonic acid cyclic anhydride.

[0113] In certain embodiments, the activating agent is selected from the group consisting of oxalyl chloride, thionyl chloride, diphenylphosphinic chloride, pivaloyl chloride, cyanuric chloride, and methanesulfonyl chloride, in which case the activating agent is of Formula VII-B: [ka] or a co-crystal, solvate, salt, or combination thereof is produced from a compound of formula VII or a co-crystal, solvate, salt, or combination thereof.

[0114] In certain embodiments, the activating agent is selected from the group consisting of oxalyl chloride, thionyl chloride, and diphenylphosphinic chloride, in which case the activating agent is of Formula VII-B: [ka] or a co-crystal, solvate, salt, or combination thereof is produced from a compound of formula VII or a co-crystal, solvate, salt, or combination thereof.

[0115] In certain embodiments, the base is selected from the group consisting of triethylamine, tributylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine, 2,6-lutidine, and N-methylimidazole. In certain embodiments, the base is triethylamine.

[0116] In certain embodiments, the solvent is selected from the group consisting of esters (e.g., ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform), nitriles (e.g., propionitrile, butyronitrile, acetonitrile), and combinations thereof. In certain embodiments, the solvent is acetonitrile.

[0117] In some embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of about 0° C. to about 40° C.

[0118] In some embodiments, the process further comprises a coupling additive. In certain embodiments, the coupling additive is selected from the group consisting of 4-(dimethylamino)pyridine, N-hydroxysuccinimide, ethyl cyanohydroxyiminoacetate, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, and N-methylimidazole. In certain embodiments, the coupling additive is selected from the group consisting of 4-(dimethylamino)pyridine, N-hydroxysuccinimide, ethyl cyanohydroxyiminoacetate, 1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole.

[0119] In some embodiments, the compound of formula III: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula IV: [ka] or a co-crystal, solvate, salt, or combination thereof, Formula V: [ka] or a co-crystal, solvate, salt, or combination thereof (wherein R 1is B(OH), B(OCH(Me)CHC(Me)O), B((1,2-di-O)CH), B(OCHC(Me)CHO), BFK, B(OCCHN(Me)CHCO), or B(OC(Me)C(Me)O)); Palladium catalyst, bases, and solvent to provide a compound of formula III, or a co-crystal, solvate, salt, or combination thereof.

[0120] In some embodiments, the compound of formula III: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula IV: [ka] or a co-crystal, solvate, salt, or combination thereof, Formula V: [ka] or a co-crystal, solvate, salt, or combination thereof (wherein R 1 is B(OH), B(OCH(Me)CHC(Me)O), B((1,2-di-O)CH), B(OCHC(Me)CHO), BFK, B(OCCHN(Me)CHCO), or B(OC(Me)C(Me)O) palladium catalyst, bases, and solvent to provide a compound of formula III, or a co-crystal, solvate, salt, or combination thereof.

[0121] In certain embodiments, R 1 is B(OC(Me)C(Me)O).

[0122] In certain embodiments, the palladium catalyst is selected from the group consisting of dichlorobis(tricyclohexylphosphine)palladium(II), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, dichlorobis(triphenylphosphine)palladium(II), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II), chloro[(tricyclohexylphosphine)-2-(2′-aminobiphenyl)]palladium(II), [(tricyclohexylphosphine)-2-(2′-aminobiphenyl)]palladium(II) methanesulfonate, PCyPd G4, palladium chloride, palladium acetate, and palladium trifluoroacetate. In certain embodiments, the palladium catalyst further comprises a phosphine ligand, wherein the palladium catalyst is selected from the group consisting of palladium chloride, palladium acetate, palladium trifluoroacetate, dichloro(1,5-cyclooctadiene)palladium(II), allylpalladium(II) chloride dimer, palladium(II) acetylacetonate, (tetrakis(triphenylphosphine)palladium(0), and bis(dibenzylideneacetone)palladium(0).In certain embodiments, the phosphine ligand is di-tert-butyl(4-dimethylaminophenyl)phosphine, dicyclohexyl(4-dimethylaminophenyl)phosphine, 1,2-bis(diphenylphosphino)ethane, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, 1,3-bis(diphenylphosphino)propane, ethylenebis(diphenylphosphine), 1,3-bis(diphenylphosphino)propane, ethylenebis(diphenylphosphine), 1,3-bis(diphenylphosphine), 1,3-bis(diphenylphosphino)propane, ethylenebis(diphenylphosphine), 1,3-bis(diphenylphosphine), 1,3-bis(diphenylphosphino)propane, 1,3-bis(diphenylphosphine), ... ,1'-ferrocenediyl-bis(diphenylphosphine), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine, tri-tert-butylphosphine, cyclohexyldi-tert-butylphosphine, and dicyclohexyl-tert-butylphosphine. In some embodiments, the palladium catalyst is dichlorobis(tricyclohexylphosphine)palladium(II).

[0123] In certain embodiments, the base is selected from the group consisting of potassium bicarbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, dipotassium phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, and triethylamine. In certain embodiments, the base is potassium bicarbonate.

[0124] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, n-butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate), alcohols (e.g., ethanol, isopropanol), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), water, and combinations thereof. In certain embodiments, the solvent is a mixture of n-butyl acetate and water.

[0125] In some embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about 20° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of from about 75°C to about 95°C.

[0126] In some embodiments, the compound of formula III: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) combining a compound of formula III, or a co-crystal, solvate, salt, or combination thereof, with a second solvent and an acid to form a compound of formula III-02: [ka] or a co-crystal, solvate, or combination thereof, wherein in formula III-02, HY is selected from the group consisting of acetic acid, oxalic acid, sulfuric acid, hydrochloric acid, phosphoric acid, chloroacetic acid, citric acid, nitric acid, formic acid, lactic acid, ascorbic acid, benzoic acid, propionic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; and (b) freebasing the compound of formula III-02, or a co-crystal, solvate, or combination thereof, by combining it with a second base and a third solvent to provide a compound of formula III, or a co-crystal, solvate, salt, or combination thereof. It further includes:

[0127] In certain embodiments, HY is methanesulfonic acid.

[0128] In certain embodiments, the second solvent is selected from the group consisting of alcohols (e.g., methanol, ethanol, 1-propanol, isopropanol, tert-amyl alcohol), nitriles (e.g., acetonitrile), ketones (e.g., methyl isobutyl ketone), chlorinated solvents (e.g., dichloromethane), esters (e.g., ethyl acetate, isopropyl acetate), aromatic hydrocarbon solvents (e.g., toluene), ethers (e.g., methyl tert-butyl ether, cyclopentyl methyl ether, 2-methyltetrahydrofuran), and combinations thereof.

[0129] In certain embodiments, the compound of formula III-02 is produced as the bis-methanesulfonic acid.

[0130] In certain embodiments, the compound of Formula III-02 is produced as a solvate. In certain embodiments, the compound of Formula III-02 is produced as a solvate of 1-propanol, isopropanol, ethanol, methanol, tert-amyl alcohol, acetonitrile, methyl isobutyl ketone, dichloromethane, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, toluene, or cyclopentyl methyl ether. In some embodiments, the compound of Formula III-02 is produced as an ethanol solvate. In other embodiments, the compound of Formula III-02 is produced as a 1-propanol solvate. In other embodiments, the compound of Formula III-02 is produced as an isopropanol solvate. In other embodiments, the compound of Formula III-02 is produced as a methanol solvate. In other embodiments, the compound of Formula III-02 is produced as a tert-amyl alcohol solvate. In other embodiments, the compound of Formula III-02 is produced as an acetonitrile solvate. In other embodiments, the compound of Formula III-02 is produced as a methyl isobutyl ketone solvate. In another embodiment, the compound of formula III-02 is produced as a dichloromethane solvate. In another embodiment, the compound of formula III-02 is produced as a 2-methyltetrahydrofuran solvate. In another embodiment, the compound of formula III-02 is produced as an ethyl acetate solvate. In another embodiment, the compound of formula III-02 is produced as an isopropyl acetate solvate. In another embodiment, the compound of formula III-02 is produced as a methyl tert-butyl ether solvate. In another embodiment, the compound of formula III-02 is produced as a toluene solvate. In another embodiment, the compound of formula III-02 is produced as a cyclopentyl methyl ether solvate.

[0131] In some embodiments, the compound of formula III-02 is produced at a temperature range of about 20° C. or less. In certain embodiments, the compound of formula III-02 is produced at a temperature range of about −20° C. to about 20° C.

[0132] In certain embodiments, the second base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, benzyltrimethylammonium hydroxide, choline hydroxide, sodium or potassium methoxide, sodium or potassium ethoxide, triethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, ammonium hydroxide, and diethylamine. In certain embodiments, the second base is sodium hydroxide.

[0133] In certain embodiments, the third solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, isopropyl acetate), water, and combinations thereof. In certain embodiments, the third solvent is a mixture of 2-methyltetrahydrofuran and water.

[0134] In some embodiments, the freebasing step is carried out at a temperature range of about 80° C. or less. In certain embodiments, the freebasing step is carried out at a temperature range of about −20° C. to about 80° C. In certain embodiments, the freebasing step is carried out at a temperature range of about 0° C. to about 50° C.

[0135] In some embodiments, the compound of formula III: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) combining a compound of formula III, or a co-crystal, solvate, salt, or combination thereof, with a second solvent and an acid to form a compound of formula III-02: [ka] or a co-crystal, solvate, or combination thereof, wherein in formula III-02, HY is selected from the group consisting of acetic acid, oxalic acid, sulfuric acid, hydrochloric acid, phosphoric acid, chloroacetic acid, citric acid, nitric acid, formic acid, lactic acid, ascorbic acid, benzoic acid, propionic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; and (b) freebasing the compound of formula III-02, or a co-crystal, solvate, or combination thereof, by combining it with a second base and a third solvent to provide a compound of formula III, or a co-crystal, solvate, salt, or combination thereof. It further includes:

[0136] In certain embodiments, HY is methanesulfonic acid.

[0137] In certain embodiments, the second solvent is selected from the group consisting of alcohols (e.g., methanol, ethanol, 1-propanol, isopropanol, tert-amyl alcohol), nitriles (e.g., acetonitrile), ketones (e.g., methyl isobutyl ketone), chlorinated solvents (e.g., dichloromethane), esters (e.g., ethyl acetate, isopropyl acetate), aromatic hydrocarbon solvents (e.g., toluene), ethers (e.g., methyl tert-butyl ether, cyclopentyl methyl ether, 2-methyltetrahydrofuran), and combinations thereof.

[0138] In certain embodiments, the compound of formula III-02 is produced as a solvate. In certain embodiments, the compound of formula III-02 is produced as a solvate in 1-propanol, isopropanol, ethanol, methanol, tert-amyl alcohol, acetonitrile, methyl isobutyl ketone, dichloromethane, 2-methyltetrahydrofuran, ethyl acetate, isoacetate, methyl methyl ketone, dichloromethane, methyl methyl tetrahydrofuran, ethyl acetate, isopropanol, methyl methyl ketone, dichloromethane, 2-methyl ... In some embodiments, the compound of Formula III-02 is produced as a solvate with propyl, methyl tert-butyl ether, toluene, or cyclopentyl methyl ether. In some embodiments, the compound of Formula III-02 is produced as an ethanol solvate. In other embodiments, the compound of Formula III-02 is produced as a 1-propanol solvate. In other embodiments, the compound of Formula III-02 is produced as an isopropanol solvate. In other embodiments, the compound of Formula III-02 is produced as a methanol solvate. In other embodiments, the compound of Formula III-02 is produced as a tert-amyl alcohol solvate. In other embodiments, the compound of Formula III-02 is produced as an acetonitrile solvate. In other embodiments, the compound of Formula III-02 is produced as a methyl isobutyl ketone solvate. In other embodiments, the compound of Formula III-02 is produced as a dichloromethane solvate. In other embodiments, the compound of Formula III-02 is produced as a 2-methyltetrahydrofuran solvate. In other embodiments, the compound of Formula III-02 is produced as an ethyl acetate solvate. In other embodiments, the compound of Formula III-02 is produced as an isopropyl acetate solvate. In another embodiment, the compound of formula III-02 is prepared as a methyl tert-butyl ether solvate. In another embodiment, the compound of formula III-02 is prepared as a toluene solvate. In another embodiment, the compound of formula III-02 is prepared as a cyclopentyl methyl ether solvate.

[0139] In some embodiments, the compound of formula III-02 is produced at a temperature range of about 20° C. or less. In certain embodiments, the compound of formula III-02 is produced at a temperature range of about −20° C. to about 20° C.

[0140] In certain embodiments, the second base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, benzyltrimethylammonium hydroxide, choline hydroxide, sodium or potassium methoxide, sodium or potassium ethoxide, triethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, ammonium hydroxide, and diethylamine. In certain embodiments, the second base is sodium hydroxide.

[0141] In certain embodiments, the third solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, isopropyl acetate), water, and combinations thereof. In certain embodiments, the third solvent is a mixture of 2-methyltetrahydrofuran and water.

[0142] In some embodiments, the freebasing step is carried out at a temperature range of about 80° C. or less. In certain embodiments, the freebasing step is carried out at a temperature range of about −20° C. to about 80° C. In certain embodiments, the freebasing step is carried out at a temperature range of about 0° C. to about 50° C.

[0143] In some embodiments, Formula I: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula III: [ka] or a co-crystal, solvate, salt, or combination thereof, a mesylating reagent, and solvent to provide a compound of formula I, or a co-crystal, solvate, salt, or combination thereof.

[0144] In certain embodiments, the mesylation reagent is selected from the group consisting of methanesulfonyl chloride and methanesulfonic anhydride. In certain embodiments, the mesylation reagent is methanesulfonic anhydride.

[0145] In certain embodiments, the solvent is selected from the group consisting of esters (e.g., ethyl acetate, isopropyl acetate), ethers (e.g., cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), nitriles (e.g., acetonitrile), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic hydrocarbon solvents (e.g., toluene, xylene), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform), and combinations thereof. In certain embodiments, the solvent for the mesylation step is cyclopentyl methyl ether.

[0146] In some embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about 20° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of about 70° C. to about 90° C.

[0147] In some embodiments, Formula I: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) Formula III: [ka] or a co-crystal, solvate, salt, or combination thereof, in combination with a mesylating reagent, a base, and a solvent to form a compound of formula II: [ka] or a co-crystal, solvate, salt, or combination thereof; and (b) hydrolyzing the compound of formula II, or a co-crystal, solvate, salt, or combination thereof, with a nucleophile and, optionally, a phase transfer catalyst in a solvent to provide a compound of formula I, or a co-crystal, solvate, salt, or combination thereof. Includes.

[0148] In certain embodiments, the mesylating reagent is selected from the group consisting of methanesulfonyl chloride and methanesulfonic anhydride, hi certain embodiments, the mesylating reagent is methanesulfonyl chloride.

[0149] In certain embodiments, a phase transfer catalyst is used in step (b). In some embodiments, the phase transfer catalyst used in step (b) is an ammonium salt or a phosphonium salt. In certain embodiments, the phase transfer catalyst is selected from the group consisting of tetra-n-butylammonium chloride, benzyltri-n-butylammonium bromide, 1-methylimidazolium hydrogen sulfate, tetra-n-butylammonium hydrogen sulfate, and tetra-n-butylphosphonium chloride. In certain embodiments, the phase transfer catalyst is tetra-n-butylammonium hydrogen sulfate.

[0150] In certain embodiments, the base is selected from the group consisting of N-methylmorpholine, tri-n-propylamine, ethyldiisopropylamine, tri-n-butylamine, triethylamine, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, monosodium phosphate, disodium phosphate, potassium bicarbonate, potassium carbonate, monopotassium phosphate, dipotassium phosphate, sodium tert-amylate, and sodium tert-butoxide. In certain embodiments, the base is triethylamine.

[0151] In certain embodiments, the solvent for the mesylation step is selected from the group consisting of ethers (e.g., diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., isobutyl acetate, isopropyl acetate), chlorinated solvents (e.g., dichloromethane), nitriles (e.g., acetonitrile), and combinations thereof. In certain embodiments, the solvent for the mesylation step is 2-methyltetrahydrofuran.

[0152] In certain embodiments, the mesylation step is carried out at a temperature range of about 100° C. or less. In certain embodiments, the mesylation step is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, the mesylation step is carried out at a temperature range of about −10° C. to about 20° C.

[0153] In certain embodiments, the nucleophilic reagent for the hydrolysis step is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiolate, N-acetylcysteine, sodium thiophenolate, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium t-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine. In certain embodiments, the nucleophilic reagent for the hydrolysis step is sodium hydroxide.

[0154] In certain embodiments, the solvent for the hydrolysis step is selected from the group consisting of alcohols (e.g., methanol, ethanol, 1-propanol, isopropanol, n-butanol, sec-butanol), ethers (e.g., diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., isobutyl acetate, isopropyl acetate), chlorinated solvents (e.g., dichloromethane), nitriles (e.g., acetonitrile), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), water, and combinations thereof. In certain embodiments, the solvent for the hydrolysis step is water and 2-methyltetrahydrofuran.

[0155] In some embodiments, the hydrolyzing step is carried out at a temperature range of about 100° C. or less. In certain embodiments, the hydrolyzing step is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, the hydrolyzing step is carried out at a temperature range of about 10° C. to about 60° C.

[0156] In some embodiments, Formula I: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) Formula VIII: [ka] or a co-crystal, solvate, salt, or combination thereof, of formula IX: [ka] or a co-crystal, solvate, or combination thereof, under alkynylation conditions to form a compound of formula VI: [ka] or a co-crystal, solvate, salt, or combination thereof; (b) reacting a compound of formula VI, or a co-crystal, solvate, salt, or combination thereof, with a compound of formula VII: [ka] or a co-crystal, solvate, salt, or combination thereof under amide coupling conditions to form a compound of formula IV: [ka] or a co-crystal, solvate, salt, or combination thereof; (c) reacting a compound of formula IV, or a co-crystal, solvate, salt, or combination thereof, with a compound of formula V: [ka] or a co-crystal, solvate, salt, or combination thereof (wherein R 1 is combined with B(OH), B(OCH(Me)CHC(Me)O), B((1,2-di-O)CH), B(OCHC(Me)CHO), BFK, B(OCCHN(Me)CHCO), or B(OC(Me)C(Me)O) under palladium catalyzed cross-coupling conditions to give formula III: [ka] or a co-crystal, solvate, salt, or combination thereof; and (d) a compound of formula III or a co-crystal, solvate, salt, or combination thereof, with a silylating reagent under mesylation conditions to provide a compound of formula I or a co-crystal, solvate, salt, or combination thereof. Includes.

[0157] In some embodiments, Formula I: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) Formula VIII: [ka] or a co-crystal, solvate, salt, or combination thereof, of formula IX: [ka] or a co-crystal, solvate, or combination thereof, under alkynylation conditions to form a compound of formula VI: [ka] or a co-crystal, solvate, salt, or combination thereof; (b) reacting a compound of formula VI, or a co-crystal, solvate, salt, or combination thereof, with a compound of formula VII: [ka] or a co-crystal, solvate, salt, or combination thereof under amide coupling conditions to form a compound of formula IV: [ka] or a co-crystal, solvate, salt, or combination thereof; (c) reacting a compound of formula IV, or a co-crystal, solvate, salt, or combination thereof, with a compound of formula V: [ka] or a co-crystal, solvate, salt, or combination thereof, wherein in formula V, R 1 is combined with a compound, or a co-crystal, solvate, salt, or combination thereof, which is B(OH), B(OCH(Me)CHC(Me)O), B((1,2-di-O)CH), B(OCHC(Me)CHO), BFK, B(OCCHN(Me)CHCO), or B(OC(Me)C(Me)O), under palladium catalyzed cross-coupling conditions to form a compound of formula III: [ka] or a co-crystal, solvate, salt, or combination thereof; and (d) combining the compound of formula III, or a co-crystal, solvate, salt, or combination thereof, with a mesylation reagent under mesylation conditions to provide a compound of formula I, or a co-crystal, solvate, salt, or combination thereof. Includes.

[0158] In some embodiments, Formula I: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) forming the sodium salt of the compound of Formula I by combining the compound of Formula I with a sodium source and a solvent to form a compound of Formula I-02: [ka] providing a compound of formula (I); and (b) neutralizing the compound of formula I-02 with an acid in a solvent to provide a compound of formula I It further includes:

[0159] In some embodiments, Formula I: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) forming the sodium salt of the compound of Formula I by combining the compound of Formula I with a sodium source and a solvent to form a compound of Formula I-02: [ka] providing a compound of formula (I); (b) neutralizing the compound of formula I-02 with an acid to provide a compound of formula I It further includes:

[0160] In certain embodiments, the sodium source for step (a) of forming the sodium salt is selected from the group consisting of sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium phosphate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium t-butoxide, sodium hexamethyldisilazide, and sodium metal and an alcohol, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, n-butanol, and sec-butanol. In certain embodiments, the sodium source is sodium ethoxide. In certain embodiments, the sodium source is sodium hydroxide.

[0161] In certain embodiments, the solvent for step (a) of forming the sodium salt is selected from the group consisting of ethers (e.g., diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), hydrocarbon solvents (e.g., n-heptane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, isobutyl acetate, isopropyl acetate), chlorinated solvents (e.g., dichloromethane), nitriles (e.g., acetonitrile), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), alcohols (e.g., methanol, ethanol, 1-propanol, isopropanol, n-butanol, sec-butanol), and combinations thereof. In certain embodiments, the solvent for the step of forming the sodium salt is ethanol and n-heptane.

[0162] In certain embodiments, step (a) of forming the sodium salt is carried out at a temperature range of about 100° C. or less. In certain embodiments, the sodium salt forming step is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, the sodium salt forming step is carried out at a temperature range of about 0° C. to about 50° C.

[0163] In certain embodiments, the acid for the neutralizing step (b) is selected from the group consisting of acetic acid, oxalic acid, sulfuric acid, hydrochloric acid, phosphoric acid, chloroacetic acid, citric acid, nitric acid, formic acid, lactic acid, ascorbic acid, benzoic acid, and propionic acid. In certain embodiments, the acid for the neutralizing step is acetic acid.

[0164] In certain embodiments, the solvent for the neutralizing step (b) is water, an ether (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether), a hydrocarbon solvent (e.g., n-hexane, n The solvent for neutralizing step (b) is selected from the group consisting of hexane, toluene, xylene), esters (e.g., ethyl acetate, isopropyl acetate, isobutyl acetate), dichloromethane, acetonitrile, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), alcohols (e.g., methanol, ethanol, isopropyl alcohol, tert-butyl alcohol), and combinations thereof. In certain embodiments, the solvent for neutralizing step (b) is water and alcohol (e.g., methanol, ethanol, isopropyl alcohol, tert-butyl alcohol). In certain embodiments, the solvent for neutralizing step (b) is water and ethanol. In certain embodiments, the solvent for neutralizing step (b) is water. In certain embodiments, the ratio of acid to water is from 2:5 to 2:30. In certain embodiments, the ratio of acetic acid to water is from 2:5 to 2:30.

[0165] In certain embodiments, the neutralizing step (b) is carried out at a temperature range of about 100° C. or less. In certain embodiments, the neutralizing step is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, the neutralizing step is carried out at a temperature range of about 0° C. to about 50° C.

[0166] In some embodiments, Formula I: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) Formula IV: [ka] or a co-crystal, solvate, salt, or combination thereof, base, solvent, catalysts, and Formula V-04-A: [ka] or a co-crystal, solvate, salt, or combination thereof, In Formula V-04-A, R is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(OCCH2N(Me)CH2CO2), or B(OC(Me)2C(Me)2O), or a co-crystal, solvate, salt, or combination thereof. Combined with II: [ka] or a co-crystal, solvate, salt, or combination thereof; and (b) hydrolyzing the compound of formula II or a co-crystal, solvate, salt, or combination thereof using a base, a solvent, and, optionally, a phase transfer catalyst to provide a compound of formula I or a co-crystal, solvate, salt, or combination thereof. Includes.

[0167] In certain embodiments, R is B(OC(Me)C(Me)O).

[0168] In certain embodiments, the catalyst used in step (a) is selected from the group consisting of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, dichlorobis(triphenylphosphine)palladium(II), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II), and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II). In certain embodiments, the catalyst used in step (a) is a palladium(II) catalyst (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or a palladium(0) catalyst (e.g., tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0)), and the catalyst used in step (a) further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine). In certain embodiments, the catalyst used in step (a) is palladium(II) chloride (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or a palladium(0) catalyst (e.g., tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0)). In some embodiments, the palladium catalyst used in step (a) is selected from the group consisting of palladium(II) chloride and cyclohexyldiphenylphosphine.

[0169] In certain embodiments, the base used in step (a) is selected from the group consisting of sodium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, dipotassium phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine. In certain embodiments, the base used in step (a) is potassium bicarbonate.

[0170] In certain embodiments, the solvent used in step (a) is selected from the group consisting of water, ethers (e.g., 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate), alcohols (e.g., ethanol, isopropanol), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine), and combinations thereof. In certain embodiments, the solvent used in step (a) is selected from the group consisting of water, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine, and combinations thereof. In certain embodiments, the solvent used in step (a) is 2-methyltetrahydrofuran and water.

[0171] In some embodiments, step (a) is carried out at a temperature range of about 120° C. or less. In certain embodiments, step (a) is carried out at a temperature range of about 20° C. to about 120° C. In certain embodiments, step (a) is carried out at a temperature range of about 65° C. to about 75° C.

[0172] In some embodiments, the base used in step (b) is selected from the group consisting of hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide), carbonate bases (sodium carbonate, potassium carbonate), bicarbonate bases (e.g., sodium bicarbonate, potassium bicarbonate), tetraalkylammonium hydroxides (e.g., benzyltrimethylammonium hydroxide, choline hydroxide), alkoxide bases (e.g., sodium or potassium methoxide, sodium or potassium ethoxide), and amine bases (e.g., triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diethylamine). In some embodiments, the base used in step (b) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, bicarbonate base, sodium bicarbonate, potassium bicarbonate, benzyltrimethylammonium hydroxide, choline hydroxide, sodium or potassium methoxide, sodium or potassium ethoxide, triethylamine, DABCO, DBU, and diethylamine. In certain embodiments, the base used in step (b) is sodium hydroxide.

[0173] In some embodiments, the solvent used in step (b) is selected from the group consisting of ethers (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., isopropyl acetate, isobutyl acetate), dichloromethane, acetonitrile, polar aprotic solvents (e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide), and combinations thereof. In some embodiments, the solvent used in step (b) is selected from the group consisting of diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and combinations thereof. In certain embodiments, the solvent used in step (b) is 2-methyltetrahydrofuran.

[0174] In some embodiments, a phase transfer catalyst is used in step (b). In some embodiments, the phase transfer catalyst used in step (b) is selected from the group consisting of ammonium salts (e.g., tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium hydrogen sulfate) and phosphonium salts (e.g., tetrabutylphosphonium chloride). In certain embodiments, the phase transfer catalyst used in step (b) is selected from the group consisting of tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium hydrogen sulfate, and tetrabutylphosphonium chloride.

[0175] In some embodiments, step (b) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (b) is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, step (b) is carried out at a temperature range of about 10° C. to about 60° C.

[0176] In some embodiments, Formula I: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula IV: [ka] or a co-crystal, solvate, salt, or combination thereof, base, solvent, catalysts, and Formula V-03-A: [ka] or a co-crystal, solvate, salt, or combination thereof, In Formula V-03-A, R is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(OCCH2N(Me)CH2CO2), or B(OC(Me)2C(Me)2O), together with a co-crystal, solvate, salt, or combination thereof; providing a compound of Formula I or a co-crystal, solvate, salt, or combination thereof.

[0177] In certain embodiments, R is B(OC(Me)C(Me)O).

[0178] In certain embodiments, the catalyst is selected from the group consisting of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, dichlorobis(triphenylphosphine)palladium(II), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II), and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II). In certain embodiments, the catalyst is a palladium(II) catalyst (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or a palladium(0) catalyst (e.g., tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0)), and the catalyst further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine). In some embodiments, the catalyst is palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetrakis(triphenylphosphine), bis(dibenzylideneacetone)palladium(0). In some embodiments, the palladium catalyst is selected from the group consisting of palladium(II) chloride and cyclohexyldiphenylphosphine.

[0179] In certain embodiments, the base is selected from the group consisting of potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, dipotassium phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine. In certain embodiments, the base is potassium bicarbonate.

[0180] In certain embodiments, the solvent is selected from the group consisting of water, ethers (e.g., 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate), alcohols (e.g., ethanol, isopropanol), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine), and combinations thereof. In certain embodiments, the solvent is selected from the group consisting of water, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine, and combinations thereof. In certain embodiments, the solvent is 2-methyltetrahydrofuran and water.

[0181] In some embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about 20° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of about 65° C. to about 75° C.

[0182] In some embodiments, the compound of formula V-03-A: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) Formula V: [ka] or a co-crystal, solvate, salt, or combination thereof (wherein R is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CHO), BF3K, B(OCCH2N(Me)CH2CO2), or B(OC(Me)2C(Me)2O)), in combination with a mesylating reagent, a base, and a solvent to produce V-04-A: [ka] or a co-crystal, solvate, salt, or combination thereof; and (b) hydrolyzing the compound of formula V-04-A or a co-crystal, solvate, salt, or combination thereof using a nucleophile, a solvent, and, optionally, a phase transfer catalyst to provide a compound of formula V-03-A or a co-crystal, solvate, salt, or combination thereof.

[0183] In certain embodiments, R is B(OC(Me)C(Me)O).

[0184] In certain embodiments, the mesylation reagent used in step (a) is methanesulfonic anhydride. In some embodiments, the mesylation reagent used in step (a) is methanesulfonyl chloride.

[0185] In certain embodiments, the base used in step (a) is selected from the group consisting of tertiary amines (e.g., triethylamine, N-methylmorpholine, tri-n-propylamine, ethyldiisopropylamine, tri-n-butylamine), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine), inorganic bases (e.g., sodium bicarbonate, sodium carbonate, monosodium phosphate, disodium phosphate, potassium bicarbonate, potassium carbonate, monopotassium phosphate, dipotassium phosphate), and alkoxide bases (e.g., sodium tert-amylate, sodium tert-butoxide). In certain embodiments, the base used in step (a) is selected from the group consisting of triethylamine, N-methylmorpholine, tri-n-propylamine, ethyldiisopropylamine, tri-n-butylamine, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, monosodium phosphate, disodium phosphate, potassium bicarbonate, potassium carbonate, monopotassium phosphate, dipotassium phosphate, sodium tert-amylate, and sodium tert-butoxide. In certain embodiments, the base used in step (a) is triethylamine.

[0186] In certain embodiments, the solvent used in step (a) is selected from the group consisting of ethers (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., isopropyl acetate, isobutyl acetate), dichloromethane, acetonitrile, and combinations thereof. In certain embodiments, the solvent used in step (a) is selected from the group consisting of diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof. In certain embodiments, the solvent used in step (a) is 2-methyltetrahydrofuran.

[0187] In certain embodiments, step (a) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (a) is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, step (a) is carried out at a temperature range of about −10° C. to about 20° C.

[0188] In certain embodiments, the nucleophile used in step (b) is selected from the group consisting of hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide), sulfur nucleophiles (e.g., sodium ethanethiolate, N-acetylcysteine, sodium thiophenolate), choline, alkoxide bases (e.g., sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium i-propoxide, sodium t-butoxide), and amines (e.g., methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, hydroxylamine). In certain embodiments, the nucleophilic reagent used in step (b) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiolate, N-acetylcysteine, sodium thiophenolate, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium i-propoxide, sodium t-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine. In certain embodiments, the base used in step (b) is sodium hydroxide.

[0189] In certain embodiments, the solvent used in step (b) is selected from the group consisting of ethers (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., isopropyl acetate, isobutyl acetate), dichloromethane, acetonitrile, polar aprotic solvents (e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide), and combinations thereof. In certain embodiments, the solvent used in step (b) is selected from the group consisting of diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and combinations thereof. In certain embodiments, the solvent used in step (b) is 2-methyltetrahydrofuran and water.

[0190] In certain embodiments, a phase transfer catalyst is used in step (b). In certain embodiments, the phase transfer catalyst used in step (b) is an ammonium salt (e.g., tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium hydrogen sulfate), and phosphatidylcholine. In certain embodiments, the phase transfer catalyst used in step (b) is selected from the group consisting of tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium hydrogen sulfate, and tetrabutylphosphonium chloride. In certain embodiments, the phase transfer catalyst used in step (b) is tetrabutylammonium hydrogen sulfate.

[0191] In certain embodiments, step (b) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (b) is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, step (b) is carried out at a temperature range of about 10° C. to about 60° C.

[0192] In some embodiments, Formula V-5: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises: (a) Formula VA: [ka] or a co-crystal, solvate, salt, or combination thereof, together with a mesylating reagent, a base, and a solvent to form V-6: [ka] or a co-crystal, solvate, salt, or combination thereof; and (b) hydrolyzing the compound of formula V-6, or a co-crystal, solvate, salt, or combination thereof, with a nucleophile, a solvent, and, optionally, a phase transfer catalyst to provide a compound of formula V-5, or a co-crystal, solvate, salt, or combination thereof. do.

[0193] In certain embodiments, the mesylation reagent used in step (a) is methanesulfonic anhydride or methanesulfonyl chloride. In certain embodiments, the mesylation reagent used in step (a) is methanesulfonic anhydride. In certain embodiments, the mesylation reagent used in step (a) is methanesulfonyl chloride.

[0194] In certain embodiments, the base used in step (a) is selected from the group consisting of tertiary amines (such as triethylamine, N-methylmorpholine, tri-n-propylamine, ethyldiisopropylamine, tri-n-butylamine, etc.), aromatic amines (such as pyridine, 2,6-lutidine, collidine, etc.), inorganic bases (such as sodium bicarbonate, sodium carbonate, monosodium phosphate, disodium phosphate, potassium bicarbonate, potassium carbonate, monopotassium phosphate, dipotassium phosphate, etc.), and alkoxide bases (such as sodium tert-amylate, sodium tert-butoxide, etc.). In certain embodiments, the base used in step (a) is selected from the group consisting of triethylamine, N-methylmorpholine, tri-n-propylamine, ethyldiisopropylamine, tri-n-butylamine, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, monosodium phosphate, disodium phosphate, potassium bicarbonate, potassium carbonate, monopotassium phosphate, dipotassium phosphate, sodium tert-amylate, and sodium tert-butoxide. In certain embodiments, the base used in step (a) is triethylamine.

[0195] In certain embodiments, the solvent used in step (a) is selected from the group consisting of ethers (diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, etc.), hydrocarbon solvents (toluene, xylene, etc.), esters (isopropyl acetate, isobutyl acetate, etc.), dichloromethane, acetonitrile, and combinations thereof. In certain embodiments, the solvent used in step (a) is selected from the group consisting of diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof. In certain embodiments, the solvent used in step (a) is 2-methyltetrahydrofuran.

[0196] In certain embodiments, step (a) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (a) is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, step (a) is carried out at a temperature range of about −10° C. to about 20° C.

[0197] In certain embodiments, the nucleophilic reagent used in step (b) is selected from the group consisting of hydroxide bases (such as sodium hydroxide, lithium hydroxide, and potassium hydroxide), sulfur nucleophiles (such as sodium ethanethiolate, N-acetylcysteine, and sodium thiophenolate), choline, alkoxide bases (such as sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium i-propoxide, and sodium t-butoxide), and amines (such as methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine). In certain embodiments, the base used in step (b) is sodium hydroxide.

[0198] In certain embodiments, the solvent used in step (b) is an ether (diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, etc.), a hydrocarbon solvent (toluene, xylene, etc.), an ester (isopropyl acetate, isopropyl alcohol, butyl, dichloromethane, acetonitrile, polar aprotic solvents (N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, etc.), and combinations thereof. In certain embodiments, the solvent used in step (b) is 2-methyltetrahydrofuran and water.

[0199] In certain embodiments, the phase transfer catalyst used in step (b) is selected from the group consisting of ammonium salts (such as tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium hydrogen sulfate, etc.) and phosphonium salts (such as tetrabutylphosphonium chloride). In certain embodiments, the phase transfer catalyst used in step (b) is tetrabutylammonium hydrogen sulfate.

[0200] In certain embodiments, step (b) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (b) is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, step (b) is carried out at a temperature range of about 10° C. to about 60° C.

[0201] In some embodiments, the compound of formula V-04-A: [ka] or a co-crystal, solvate, salt, or combination thereof, wherein in formula V-04-A, R is B(OH), B(OCH(Me)CHC(Me)O), B((1,2-di-O)CH), B(OCHC(Me)CHO), BFK, B(OCCHN(Me)CHCO), or B(OC(Me)C(Me)O), and the process comprises preparing a compound of formula V-6: [ka] or a co-crystal, solvate, salt, or combination thereof with a boron coupling agent, a base and a solvent, and a catalyst to provide a compound of formula V-04-A, or a co-crystal, solvate, salt, or combination thereof.

[0202] In certain embodiments, R is B(OC(Me)C(Me)O).

[0203] In certain embodiments, the boron coupling agent is selected from the group consisting of bis(pinacolato)diboron, bis(neopentylglycolato)diboron, bisboronic acid, and bis(ethyleneglycolatodiboron). The pulling agent is bis(pinacolato)diboron.

[0204] In certain embodiments, the base is selected from the group consisting of cesium acetate, potassium propionate, sodium propionate, potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, dipotassium phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine. In certain embodiments, the base is potassium acetate.

[0205] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate), alcohols (e.g., ethanol, isopropanol), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine), and combinations thereof. In certain embodiments, the solvent is selected from the group consisting of 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine, and combinations thereof. In certain embodiments, the solvent is toluene and N,N-dimethylformamide.

[0206] In certain embodiments, the catalyst is selected from the group consisting of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, bis(triphenylphosphine)palladium(II) dichloride, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II). In certain embodiments, the palladium catalyst is a palladium(II) catalyst (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or a palladium(0) catalyst (e.g., tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0)), and optionally further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine). In certain embodiments, the catalyst is palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetrakis(triphenylphosphine)palladium(0), or bis(dibenzylideneacetone)palladium(0), and optionally further comprises a phosphine ligand selected from the group consisting of tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, and dicyclohexylphenylphosphine. In certain embodiments, the palladium catalyst is bis(triphenylphosphine)palladium(II) dichloride.

[0207] In certain embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about 20° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of about 95° C. to about 105° C.

[0208] In some embodiments, Formula V-5: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula V-6: [ka] or a co-crystal, solvate, salt, or combination thereof using a base, a solvent, and optionally a phase transfer catalyst to provide a compound of formula V5 or a co-crystal, solvate, salt, or combination thereof.

[0209] In certain embodiments, the base is selected from the group consisting of hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide), sulfur nucleophiles (e.g., sodium ethanethiolate, N-acetylcysteine, sodium thiophenolate), choline, alkoxide bases (e.g., sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium i-propoxide, sodium t-butoxide), and amines (e.g., methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, hydroxylamine). In certain embodiments, the base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiolate, N-acetylcysteine, sodium thiophenolate, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium i-propoxide, sodium t-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine. In certain embodiments, the base is sodium hydroxide.

[0210] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., isopropyl acetate, isobutyl acetate), dichloromethane, acetonitrile, polar aprotic solvents (e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide), water, and combinations thereof. In certain embodiments, the solvent is selected from the group consisting of diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, water, and combinations thereof. In certain embodiments, the solvent is 2-methyltetrahydrofuran and water.

[0211] In some embodiments, the process includes a phase transfer catalyst. In some embodiments, the phase transfer catalyst is selected from the group consisting of ammonium salts (e.g., tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium hydrogen sulfate) and phosphonium salts (e.g., tetrabutylphosphonium chloride). In some embodiments, the phase transfer catalyst is selected from the group consisting of tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium hydrogen sulfate, phosphonium salts, and tetrabutylphosphonium chloride. In certain embodiments, the phase transfer catalyst is tetrabutylammonium hydrogen sulfate.

[0212] In some embodiments, the process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, the process is carried out at a temperature range of about 10° C. to about 60° C.

[0213] In some embodiments, the compound of formula V-03-A: [ka] or a co-crystal, solvate, salt, or combination thereof, wherein in formula V-03-A, R is B(OH), B(OCH(Me)CHC(Me)O), B((1,2-di-O)CH), B(OCHC(Me)CHO), BFK, B(OCCHN(Me)CHCO), or B(OC(Me)C(Me)O), the process comprising preparing a compound of formula V-5: [ka] or a co-crystal, solvate, salt, or combination thereof with a boron coupling agent, a base, a solvent, and a catalyst to provide a compound of formula V-03-A, or a co-crystal, solvate, salt, or combination thereof.

[0214] In certain embodiments, R is B(OC(Me)C(Me)O).

[0215] In certain embodiments, the boron coupling agent is selected from the group consisting of bis(pinacolato)diboron, bis(neopentylglycolato)diboron, bisboronic acid, and bis(ethyleneglycolatodiboron). In certain embodiments, the boron coupling agent is bis(pinacolato)diboron.

[0216] In certain embodiments, the base is selected from the group consisting of cesium acetate, potassium propionate, sodium propionate, potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, dipotassium phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine. In certain embodiments, the base is potassium acetate.

[0217] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate), alcohols (e.g., ethanol, isopropanol), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine, etc.), and combinations thereof. In certain embodiments, the solvent is selected from the group consisting of 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine, and combinations thereof. In certain embodiments, the solvent is toluene and N,N-dimethylformamide.

[0218] In certain embodiments, the catalyst is selected from the group consisting of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, bis(triphenylphosphine)palladium(II) dichloride, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II), and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II). In certain embodiments, the catalyst is a palladium(II) catalyst (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or a palladium(0) catalyst (e.g., tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0)) and further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine). In certain embodiments, the catalyst comprises palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetrakis(triphenylphosphine)palladium(0), or bis(dibenzylideneacetone)palladium(0), and the catalyst optionally further comprises a phosphine ligand selected from the group consisting of tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, and dicyclohexylphenylphosphine. In certain embodiments, the palladium catalyst is bis(triphenylphosphine)palladium(II) dichloride.

[0219] In certain embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about 20° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of about 95° C. to about 105° C.

[0220] In some embodiments, the compound of formula VIII: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula X: [ka] or a co-crystal, solvate, salt, or combination thereof with a chiral acid in a solvent and optionally in the presence of an aldehyde catalyst and / or optionally a metal catalyst to provide a compound of formula VIII or a co-crystal, solvate, salt, or combination thereof.

[0221] In some embodiments, the compound of formula VIII: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula X: [ka] or a co-crystal, solvate, salt, or combination thereof with a chiral acid in a solvent to provide a compound of formula VIII or a co-crystal, solvate, salt, or combination thereof.

[0222] In some embodiments, the compound of formula VIII has formula VIII-02: [ka] or a co-crystal, solvate, or combination thereof, wherein in Formula VIII-02, HX is selected from the group consisting of lactic acid, L-lactic acid, L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(-)-malic acid, D-glucuronic acid, (1R,3S)-(+)-camphoric acid, (1S)-(+)-camphor-10-sulfonic acid, (R)-(+)-N-(1-phenylethyl)succinamic acid, carbobenzyloxy-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methyladipic acid, (+ (R)-menthyloxyacetic acid, (-)-pyroglutamic acid, (-)-N-acetyl-L-leucine, (-)-N-acetyl-D-leucine, N-Boc-D-leucine, N-(+)-BOC-phenylalanine, (-)-quinic acid, (+)-n-acetyl-L-phenylalanine, (+)-N-BOC-isoleucine, L-(-)-acetylglutamic acid, (-)-acetylmandelic acid, (R)-(-)-citramalic acid, (-)-camphanic acid, and (R)-mandelic acid.

[0223] In some embodiments, the compound of formula VIII has formula VIII-02: [ka]

[0224] or a co-crystal, solvate, or combination thereof, wherein in formula VIII-02, HX is selected from the group consisting of lactic acid, L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(-)-malic acid, D-glucuronic acid, (1R,3S)-(+)-camphoric acid, (1S)-(+)-camphor-10-sulfonic acid, (R)-(+)-N-(1-phenylethyl)succinamic acid, carbobenzyloxy-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methyl-L-propanol, The chiral acid is selected from the group consisting of dipic acid, (+)-menthyloxyacetic acid, (-)-pyroglutamic acid, (-)-N-acetyl-L-leucine, N-Boc-D-leucine, N-(+)-BOC-phenylalanine, (-)-quinic acid, (+)-n-acetyl-L-phenylalanine, (+)-N-BOC-isoleucine, L-(-)-acetylglutamic acid, (-)-acetylmandelic acid, (R)-(-)-citramalic acid, (-)-camphanic acid, and (R)-mandelic acid. In some embodiments, HX is N-Boc-D-leucine or (-)-N-acetyl-D-leucine. In some embodiments, HX is (R)-mandelic acid. In some embodiments, HX is N-Boc-D-leucine.

[0225] In some embodiments, HX is (-)-N-acetyl-D-leucine.

[0226] In certain embodiments, the solvent is selected from the group consisting of hydrocarbon solvents (e.g., n-heptane), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane), alcohols (e.g., methanol, ethanol, 1-propanol, isopropanol), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), water, esters (e.g., ethyl acetate, butyl acetate, isobutyl acetate), dichloroethane, chloroform, polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), and combinations thereof.

[0227] In certain embodiments, the solvent is selected from the group consisting of hydrocarbon solvents (e.g., n-heptane), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane), alcohols (e.g., methanol, ethanol, 1-propanol, isopropanol), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), water, and combinations thereof. In certain embodiments, the solvent is methyl tert-butyl ether and toluene.

[0228] In certain embodiments, the solvent is toluene.

[0229] In certain embodiments, the process is carried out in the presence of an aldehyde catalyst and / or a metal catalyst. In certain embodiments, the aldehyde catalyst is an aromatic aldehyde (e.g., benzaldehyde, 2,4-dichlorobenzaldehyde, 2-methoxybenzaldehyde, 4-(dimethylamino)benzaldehyde, 2-(dimethylamino)benzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, 2-hydroxy-5-nitrobenzaldehyde, 5-chloro-2-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 2-hydroxybenzaldehyde, 3,5-dichlorobenzaldehyde, 4-(dimethylamino) ... The aldehyde is selected from the group consisting of 2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, 2-hydroxy-3-nitrobenzaldehyde), heteroaromatic aldehydes (e.g., 2-formylpyridine, 3-(trifluoromethyl)picolinaldehyde, 4-chloropicolinaldehyde, nicotinaldehyde, quinolone-4-carbaldehyde, quinolone-2-carbaldehyde, etc.), and aliphatic aldehydes (e.g., formaldehyde, ethyl glyoxylate, glyoxylic acid). In certain embodiments, the metal catalyst is selected from the group consisting of zinc salts (e.g., zinc(II) oxide, zinc(II) acetate, zinc(II) trifluoromethanesulfonate, zinc(II) trifluoroacetate, zinc(II) chloride, zinc(II) stearate, zinc(II) neodecanoate, zinc(II) tetrafluoroborate); nickel salts (e.g., nickel(II) acetate, nickel(II) chloride, nickel(II) triflate); indium salts (e.g., indium(III) acetate); copper salts (e.g., copper(II) acetate); cobalt (e.g., cobalt(II) acetate); and manganese salts (e.g., manganese(II) acetate). In certain embodiments, the process is carried out in the presence of an aldehyde catalyst and / or a metal catalyst. In certain embodiments, the process is carried out in the presence of an aldehyde catalyst and a metal catalyst. In certain embodiments, the aldehyde catalyst is 2-formylpyridine and the metal catalyst is zinc(II) oxide.

[0230] In some embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about -20°C to about 120°C. In certain embodiments, the process is carried out at a temperature range of about -20°C to about 50°C. In some embodiments, the process is carried out at a temperature of about 35°C.

[0231] In some embodiments, the process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 20° C. In certain embodiments, the process is carried out at a temperature of about 35° C.

[0232] In certain embodiments, the compound of formula X may be treated with a base in a first solvent prior to resolution. In certain embodiments, the base is selected from the group consisting of potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, ammonium hydroxide, dipotassium phosphate, tripotassium phosphate, disodium phosphate, and trisodium phosphate. In certain embodiments, the base is sodium hydroxide. In certain embodiments, the first solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., benzene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In certain embodiments, the first solvent is selected from the group consisting of diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, aromatic solvents, dichloromethane, and combinations thereof. In certain embodiments, the solvent is 2-methyltetrahydrofuran. In certain embodiments, the compound of formula X is treated with a base in a first solvent at a temperature range from about 0° C. to about 100° C. In certain embodiments, the compound of formula X is treated with a base in a first solvent at a temperature range from about 10° C. to about 50° C.

[0233] In some embodiments, Formula 1a: [ka] or a co-crystal, solvate, salt, or combination thereof, the process comprising: [ka] with an electrophile, a base, and a solvent to provide a compound of Formula 1a, or a co-crystal, solvate, salt, or combination thereof.

[0234] In some embodiments, the electrophile is a formylated amine (e.g., N,N-diethylformamide, 1-formylpyrrolidine, 4-formylmorpholine, N-methylformanilide); a formate ester (e.g., cyanomethyl formate, phenyl formate, ethyl formate, trifluoroethyl formate); an orthoester (e.g., trimethyl orthoformate, diethylphenyl orthoformate); a formamide acetal (e.g., N,N-dimethylformamide dipropyl acetal, N,N-dimethylformamide dimethyl acetal); and (chloromethylene)dimethyliminium chloride. In certain embodiments, the electrophile is N,N-dimethylformamide.

[0235] In some embodiments, the base is selected from the group consisting of 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex, n-butyllithium, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride lithium chloride complex, phenyllithium, phenylmagnesium chloride, n-butyllithium lithium N,N-dimethylaminoethanol complex, mesityllithium, lithium di-isopropylamide, phenyllithium, lithium 2,2,6,6-tetramethylpiperidide, lithium dichloro(2,2,6,6-tetramethylpiperidinato)zincate, and lithium di-tert-butyl-(2,2,6,6-tetramethylpiperidino)zincate. In certain embodiments, the base is 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex.

[0236] In some embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), aromatic solvents (e.g., benzene, toluene, xylene), amines (e.g., triethylamine, ethyldiisopropylamine), cyclic amides (e.g., N-ethyl-2-pyrrolidone, N-methyl-2-pyrrolidone, N-butyl-2-pyrrolidone), urea derivatives (e.g., N,N-dimethylpropylene urea), and combinations thereof. In certain embodiments, the solvent is tetrahydrofuran. In some embodiments, the process is carried out at a temperature range of about 50° C. or less. In certain embodiments, the process is carried out at a temperature range of about −80° C. to about 50° C. In certain embodiments, the process is carried out at a temperature range of about −40° C. to about 0° C.

[0237] In some embodiments, the compound of formula X: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) Formula 1a: [ka] or a co-crystal, solvate, salt, or combination thereof with a suitable amine (e.g., aminodiphenylmethane) in a solvent and, optionally, in the presence of an additive, to produce a compound of formula 1b: [ka] or a co-crystal, solvate, salt, or combination thereof, wherein in formula 1b, R 4 and R 5are each independently hydrogen, methyl, phenyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzylamine, or 4-methoxybenzyl; (b) reacting a compound of Formula 1b, or a co-crystal, solvate, salt, or combination thereof, with a compound of Formula 1c: [ka] wherein Y is Br, Cl, I, OMs, OTs, or OSO2CF3, by alkylation in a solvent in the presence of a base and, optionally, a phase transfer catalyst to give a compound of formula 1d: [ka] or a co-crystal, solvate, salt, or combination thereof; and (c) deprotecting the compound of formula 1d with an acid in a solvent to give the compound of formula X: [ka] or a co-crystal, solvate, salt, or combination thereof. Includes.

[0238] In some embodiments, the compound of formula X: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) Formula 1a: [ka] or a co-crystal, solvate, salt, or combination thereof with an appropriate amine (e.g., aminodiphenylmethane) in a solvent to give a compound of formula 1b: [ka] or a co-crystal, solvate, salt, or combination thereof, wherein in formula 1b, R 4 and R 5 are each independently hydrogen, methyl, phenyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzylamine, or 4-methoxybenzyl; (b) reacting a compound of Formula 1b, or a co-crystal, solvate, salt, or combination thereof, with a compound of Formula 1c: [ka] wherein Y is Br, Cl, I, OMs, OTs, or OSO2CF3, by alkylation in a solvent in the presence of a base and, optionally, a phase transfer catalyst to give a compound of formula 1d: [ka] or a co-crystal, solvate, salt, or combination thereof; and (c) deprotecting the compound of formula 1d with an acid in a solvent to give the compound of formula X: [ka] or a co-crystal, solvate, salt, or combination thereof. Includes.

[0239] In some embodiments, a suitable amine for forming the compound of Formula 1b, or a co-crystal, solvate, salt, or combination thereof, is aminodiphenylamine, benzylamine, 4-nitrobenzylamine, 4-chlorobenzylamine, 4-bromobenzylamine, 4-methoxybenzylamine, or α-methylbenzylamine. In some embodiments, a suitable amine for forming the compound of Formula 1b, or a co-crystal, solvate, salt, or combination thereof, is aminodiphenylamine.

[0240] In some embodiments, the compound of Formula 1b, or a co-crystal, solvate, salt, or combination thereof, has the formula 1b-02: [ka] or a co-crystal, solvate, salt, or combination thereof.

[0241] In some embodiments, the compound of Formula 1d, or a co-crystal, solvate, salt, or combination thereof, has the formula 1d-02: [ka] or a co-crystal, solvate, salt, or combination thereof.

[0242] In certain embodiments, the solvent for the condensing step (a) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), esters (e.g., ethyl acetate, isopropyl acetate), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), nitriles (e.g., acetonitrile), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In certain embodiments, the solvent for the condensing step (a) is toluene.

[0243] In some embodiments, the condensing step (a) is carried out in the presence of an additive. In certain embodiments, the additive used in the condensing step (a) is a dehydrating reagent (e.g., magnesium sulfate).

[0244] In certain embodiments, the condensing step (a) is carried out at a temperature range of about 120° C. or less. In certain embodiments, the condensing step (a) is carried out at a temperature range of about −20° C. to about 120° C. In certain embodiments, the condensing step (a) is carried out at a temperature range of about 20° C. to about 90° C. In certain embodiments, the condensing step (a) is carried out at a temperature range of about 20° C. to about 80° C.

[0245] In certain embodiments, Y is Br, Cl, or I. In certain embodiments, Y is Br.

[0246] In certain embodiments, the base for the alkylating step (b) is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium ethoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, lithium chloride complex, n-butyllithium, lithium N,N-dimethylaminoethanol complex, mesityllithium, lithium di-isopropylamide, and phenyllithium. In certain embodiments, the base for the alkylating step (b) is potassium hydroxide.

[0247] In certain embodiments, a phase transfer catalyst is used in the alkylating step (b).

[0248] In certain embodiments, the phase transfer catalyst for the alkylating step (b) is tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetramethylammonium hydrogen sulfate, tetraethylammonium chloride, tetraethylammonium bromide, tetra-n-butyl-ammonium bromide, In certain embodiments, the phase transfer catalyst for alkylating step (b) is selected from the group consisting of tetraethylammonium iodide, tetraethylammonium hydrogen sulfate, and benzyltrimethylammonium.

[0249] In certain embodiments, the solvent for the alkylating step (b) is selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, benzene, xylene, toluene, dichloromethane, water, and combinations thereof. In certain embodiments, the solvent for the alkylating step (b) is a mixture of toluene and water.

[0250] In certain embodiments, the compound of formula 1c is selected from the group consisting of 3,5-difluorobenzyl bromide, 3,5-difluorobenzyl chloride, 3,5-difluorobenzyl mesylate, 3,5-difluorobenzyl iodide, 3,5-difluorobenzyl triflate, and 3,5-difluorobenzyl tosylate. In certain embodiments, the compound of formula 1c is 3,5-difluorobenzyl bromide.

[0251] In certain embodiments, the alkylating step (b) is carried out at a temperature range of about 120° C. or less. In certain embodiments, the alkylating step (b) is carried out at a temperature range of about −20° C. to about 120° C. In certain embodiments, the alkylating step (b) is carried out at a temperature range of about 10° C. to about 80° C.

[0252] In certain embodiments, the acid for deprotecting step (c) is selected from the group consisting of hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, formic acid, and oxalic acid. In certain embodiments, the acid for deprotecting step (c) is methanesulfonic acid.

[0253] In certain embodiments, the acid equivalents are 1 to 10. In certain embodiments, the acid equivalents are 1 to 3.

[0254] In certain embodiments, the solvent for the deprotecting step (c) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In certain embodiments, the solvent for the deprotecting step (c) is 2-methyltetrahydrofuran.

[0255] In certain embodiments, the deprotecting step (c) is carried out at a temperature range of about 120° C. or less. In certain embodiments, the deprotecting step (c) is carried out at a temperature range of about −40° C. to about 120° C. In certain embodiments, the deprotecting step (c) is carried out at a temperature range of about 10° C. to about 40° C.

[0256] In some embodiments, the compound of formula X: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises: (a) Formula XIII: [ka] or a co-crystal, solvate, salt, or combination thereof, together with a mesylation reagent, a base, a solvent, and optionally an additive to form a compound of formula XIII-A: [ka] or a co-crystal, solvate, salt, or combination thereof; and (b) combining a compound of formula XIII-A, or a co-crystal, solvate, salt, or combination thereof, with an aminating reagent and optionally a solvent to obtain a compound of formula X: [ka] or a co-crystal, solvate, salt, or combination thereof. Includes.

[0257] In certain embodiments, the mesylating reagent for mesylation step (a) is selected from the group consisting of methanesulfonyl chloride and methanesulfonic anhydride, hi certain embodiments, the mesylating reagent is methanesulfonyl chloride.

[0258] In certain embodiments, the base for the mesylation step (a) is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 2,3,5-collidine, 2,4,6-collidine, N,N-dicyclohexylmethylamine, and N-methylimidazole. In certain embodiments, the base for the mesylation step is triethylamine.

[0259] In certain embodiments, the mesylation step (a) uses an additive. In certain embodiments, the additive for step (a) is selected from the group consisting of 4-(dimethylamino)pyridine (DMAP), N-methylimidazole, pyridine N-oxide, diphenylcyclopropane, and antimony pentachloride. In some embodiments, the additive for step (a) is 4-(dimethylamino)pyridine (DMAP).

[0260] In certain embodiments, the solvent for the mesylation step (a) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In certain embodiments, the solvent for the mesylation step (a) is tetrahydrofuran.

[0261] In certain embodiments, the mesylation step (a) is carried out at a temperature range of about 60° C. or less. In certain embodiments, the mesylation step (a) is carried out at a temperature range of about −80° C. to about 60° C. In certain embodiments, the mesylation step (a) is carried out at a temperature range of about 0° C. to about 40° C.

[0262] In certain embodiments, the aminating reagent for the aminating step (b) is ammonia.

[0263] In certain embodiments, the aminating step (b) comprises a solvent.

[0264] In certain embodiments, the solvent for the aminating step (b) is selected from the group consisting of alcohols (e.g., methanol, ethanol, 1-propanol, isopropanol), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), water, and combinations thereof. In certain embodiments, the solvent for the aminating step (b) is methanol and water.

[0265] In certain embodiments, the aminating step (b) is carried out at a temperature range of about 100° C. or less. In certain embodiments, the aminating step (b) is carried out at a temperature range of about 0° C. to about 100° C. In certain embodiments, the aminating step (b) is carried out at a temperature range of about 40° C. to about 80° C.

[0266] In an alternative embodiment, the compound of formula XIII-A: [ka] or a co-crystal, solvate, salt, or combination thereof is combined with an amine equivalent (e.g., di-tert-butyl-iminodicarboxylate, phthalimide, benzylamine, dibenzylamine, hexamethyldisilazane) and then deprotected (e.g., using hydrochloric acid, hydrazine, hydrogen, Pd / C) to give a compound of formula X: [ka] or a co-crystal, solvate, salt, or combination thereof.

[0267] In some embodiments, the compound of formula VIII: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) Formula XI: [ka] or a co-crystal, solvate, salt, or combination thereof, in the presence of an asymmetric catalyst and a solvent to obtain a compound of formula XII: [ka] or a co-crystal, solvate, salt, or combination thereof; (b) using an azidation reagent in the presence of a base and a solvent to form an azide of a compound of formula XII or a co-crystal, solvate, salt, or combination thereof to obtain a compound of formula XVI: [ka] or a co-crystal, solvate, salt, or combination thereof; and (c) reducing the compound of formula XVI using a reducing agent to provide a compound of formula VIII or a co-crystal, solvate, salt, or combination thereof. Includes.

[0268] In certain embodiments, the asymmetric catalyst for hydrolyzing step (a) is selected from the group consisting of [Rh(cod)((S)-segphos]BF, ​​IrCl(cod)((S)-segphos), [RuCl(p-cymene)(segphos)]Cl, Ru(OAc)(segphos), (MeNH)[RuCl((S)-segphos)](μ-Cl), and (R)-RuCY-XylBINAP. In certain embodiments, the asymmetric catalyst is (R)-RuCY-XylBINAP.

[0269] In certain embodiments, the solvent for the hydrolyzing step (a) is selected from the group consisting of esters (e.g., isopropyl acetate, n-propyl acetate), alcohols (e.g., ethanol, 1-propanol, isopropanol), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform), and combinations thereof. In certain embodiments, the solvent for the hydrogenating step is ethanol and isopropanol.

[0270] In certain embodiments, the hydrolyzing step (a) is carried out at a temperature range of about 150° C. or less. In certain embodiments, the hydrolyzing step (a) is carried out at a temperature range of about −20° C. to about 150° C. In certain embodiments, the hydrolyzing step (a) is carried out at a temperature range of about −20° C. to about 150° C. a) is carried out in a temperature range of about 0°C to about 60°C.

[0271] In certain embodiments, step (b) is methanesulfonyl chloride and sodium azide or diphenylphosphoryl azide. In certain embodiments, the azidation reagent is diphenylphosphoryl azide.

[0272] In certain embodiments, the base for step (b) is selected from the group consisting of triethylamine, diisopropylethylamine, N,N-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene. In certain embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0273] In certain embodiments, the solvent for steps (b) and (c) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In certain embodiments, the solvent for steps (b) and (c) is tetrahydrofuran.

[0274] In certain embodiments, steps (b) and (c) are carried out at a temperature range of about 60° C. or less. In certain embodiments, steps (b) and (c) are carried out at a temperature range of about −10° C. to about 60° C. In certain embodiments, steps (b) and (c) are carried out at a temperature range of about 0° C. to about 40° C. In certain embodiments, the reducing agent for reducing step (c) is selected from the group consisting of trimethylphosphine, triethylphosphine, trimethylphosphite, triethylphosphine, tributylphosphine, trifurylphosphine, tris(hydroxymethyl)phosphine, and triphenylphosphine. In certain embodiments, the reducing agent is triphenylphosphine.

[0275] In certain embodiments, the reducing step (c) is carried out at a temperature range of about 60° C. or less. In certain embodiments, the reducing step (c) is carried out at a temperature range of about −10° C. to about 60° C. In certain embodiments, the reducing step (c) is carried out at a temperature range of about 0° C. to about 40° C.

[0276] In some embodiments, the compound of formula VIII: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) Formula XI: [ka] or a co-crystal, solvate, salt, or combination thereof, in combination with a hydroxylamine source, a base, and a solvent to form a compound of formula 1e: [ka] or a co-crystal, solvate, salt, or combination thereof; (b) combining the compound of formula 1e with a reducing agent, an acylating agent, and a solvent to form a compound of formula 1f-1: [ka] or a co-crystal, solvate, salt, or combination thereof, wherein in formula 1f-1, R 6 is selected from the group consisting of acetyl, benzyl, trichloroacetyl, trifluoroacetyl, and propionyl; and (c) hydrogenating the compound of formula 1f-1 using a catalyst and a solvent to obtain a compound of formula 1g-1: [ka] or a co-crystal, solvate, salt, or combination thereof; and to (d) deprotecting the compound of 1g-1 using an acid and a solvent to provide a compound of formula VIII or a co-crystal, solvate, salt, or combination thereof. Includes.

[0277] In certain embodiments, R 6 is selected from the group consisting of acetyl, benzyl, trichloroacetyl, trifluoroacetyl, and propionyl. 6 is acetyl.

[0278] In certain embodiments, the hydroxylamine source for step (a) is selected from hydroxylamine hydroxide.

[0279] In certain embodiments, the solvent for step (a) is selected from the group consisting of esters (e.g., n-propyl acetate, isopropyl acetate), alcohols (e.g., methanol, 1-propanol or 2-propanol, ethanol), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane, chloroform, 1,2-dichloroethane), and combinations thereof. In certain embodiments, the solvent for step (a) is selected from the group consisting of n-propyl acetate, isopropyl acetate, methanol, 1-propanol or 2-propanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, and combinations thereof. In certain embodiments, the solvent for step (a) is ethanol.

[0280] In certain embodiments, the base for step (a) is selected from the group consisting of tertiary amines (e.g., pyridine, triethylamine, tri-n-propylamine, tri-n-butylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), carboxylate bases (e.g., sodium acetate, lithium pivalate), alkoxide bases (e.g., sodium ethoxide, potassium ethoxide, sodium tert-butoxide), sodium hydride, and disilazide bases (e.g., lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide). In certain embodiments, the base for step (a) is selected from the group consisting of pyridine, triethylamine, tri-n-propylamine, tri-n-butylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, lithium pivalate, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide. In certain embodiments, the base for step (a) is pyridine.

[0281] In certain embodiments, step (a) is carried out at a temperature range of about 150° C. or less. In certain embodiments, step (a) is carried out at a temperature range of about 0° C. to about 150° C. In certain embodiments, step (a) is carried out at a temperature range of about 10° C. to about 60° C. In certain embodiments, step (a) is carried out at a temperature range of about 20° C.

[0282] In certain embodiments, the reducing agent for step (b) is a hydrogenating agent (e.g., palladium on carbon, hydrogen), iron(II) acetate, samarium diiodide, titanium(IV) tetrachloride / salt. In certain embodiments, the reducing agent for step (b) is selected from the group consisting of palladium on carbon, hydrogen, iron(II) acetate, samarium diiodide, titanium(IV) tetrachloride / tin(II) chloride, and zinc metal. In certain embodiments, the reducing agent is iron(II) acetate. In some embodiments, the reducing agent is iron(II) acetate prepared in situ.

[0283] In certain embodiments, the acylating agent for step (b) is selected from the group consisting of acid chlorides (e.g., acetyl chloride, trichloroacetyl chloride), acid anhydrides (e.g., acetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride), and alkyl halides (e.g., benzyl chloride, benzyl bromide). In certain embodiments, the acylating agent for step (b) is selected from the group consisting of acetyl chloride, trichloroacetyl chloride, acetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, benzyl chloride, and benzyl bromide. In certain embodiments, the acylating agent is acetic anhydride.

[0284] In certain embodiments, the solvent for step (b) is selected from the group consisting of acetic acid, esters (e.g., n-propyl acetate, isopropyl acetate, acetate), alcohols (e.g., methanol, 1-propanol, 2-propanol), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane, chloroform, 1,2-dichloroethane), and combinations thereof. In certain embodiments, the solvent for step (b) is selected from the group consisting of acetic acid, n-propyl acetate, isopropyl acetate, acetate, methanol, 1-propanol or 2-propanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, and combinations thereof. In certain embodiments, the solvent for step (b) is isopropyl acetate and acetic acid.

[0285] In certain embodiments, step (b) is carried out at a temperature range of about 150° C. or less. In certain embodiments, step (b) is carried out at a temperature range of about 0° C. to about 150° C. In certain embodiments, step (b) is carried out at a temperature range of about 30° C. to about 70° C. In certain embodiments, step (b) is carried out at a temperature range of about 50° C.

[0286] In certain embodiments, the catalyst for step (c) is selected from the group consisting of IrCl(cod)((S)-segphos), Rh(cod)((S)-segphos]BF, ​​and (MeNH)[RuCl((S)-segphos)](μ-Cl). In certain embodiments, the catalyst is (IrCl(cod)((S)-segphos).

[0287] In certain embodiments, the solvent for steps (c) and (d) is selected from the group consisting of esters (e.g., ethyl acetate, n-propyl acetate, isopropyl acetate), alcohols (e.g., ethanol, 1-propanol, 2-propanol), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane, chloroform, 1,2-dichloroethane), and combinations thereof. In certain embodiments, the solvent for steps (c) and (d) is selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, ethanol, 1-propanol or 2-propanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, In certain embodiments, the solvent for steps (c) and (d) is selected from the group consisting of hexane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, and combinations thereof. In certain embodiments, the solvent for steps (c) and (d) is ethyl acetate.

[0288] In certain embodiments, step (c) is carried out at a temperature range of about 150° C. or less. In certain embodiments, step (c) is carried out at a temperature range of about 0° C. to about 150° C. In certain embodiments, step (c) is carried out at a temperature range of about 80° C. to about 150° C.

[0289] In certain embodiments, the acid for step (d) is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, methanesulfonic acid, and p-toluenesulfonic acid. In certain embodiments, the acid for step (d) is hydrochloric acid.

[0290] In certain embodiments, step (d) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (d) is carried out at a temperature range of about 20° C. to about 100° C. In certain embodiments, step (d) is carried out at a temperature range of about 20° C. to about 80° C.

[0291] In some embodiments, the compound of formula VIII: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula XI: [ka] or a co-crystal, solvate, salt, or combination thereof, a hydrogen source, catalyst, amine, acid, and solvent to provide a compound of formula VIII or a co-crystal, solvate, salt, or combination thereof.

[0292] In certain embodiments, the hydrogen source is selected from the group consisting of hydrogen gas, ammonium formate, and formate triethylamine complex. In certain embodiments, the hydrogen source is hydrogen gas.

[0293] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic hydrocarbon solvents (e.g., benzene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide), alcohols (e.g., methanol, isopropanol, tert-amyl alcohol), water, and combinations thereof. In certain embodiments, the solvent is methanol.

[0294] In certain embodiments, the water has a pH of 6-10.

[0295] In certain embodiments, the catalyst is an asymmetric catalyst or an enzymatic catalyst.

[0296] In certain embodiments, the catalyst is an asymmetric catalyst. In some embodiments, the asymmetric catalyst is a ruthenium or iridium catalyst with a chiral ligand (e.g., SegPhos, DM-SegPhos, tert-butyl-Josiphos, DuPhos, MonoPhos, or BINAP). In certain embodiments, the catalyst is a ruthenium or iridium catalyst selected from the group consisting of RuCl, ruthenium(III) acetylacetonate, chlorocyclopentadienylbis(triphenylphosphine)ruthenium(II), chlorohydridotris(triphenylphosphine)ruthenium(II) toluene adduct, chlorotris(triphenylphosphine)ruthenium(II) acetate, [Ru(Cl)H(CO)(PPh)], [Ir(COD)Cl], (acetylacetonato)(1,5-cyclooctadiene)iridium(I), and (acetylacetonato)dicarbonyliridium(I). In some embodiments, the catalyst is Ru(OAc)((R)-SegPhos).

[0297] In certain embodiments, the catalyst is an enzyme catalyst. In some embodiments, the enzyme catalyst is an amine transaminase and a cofactor in a buffer. In certain embodiments, the amine transaminase is an ω-transaminase selected from the group consisting of ATA-1, ATA-2, ATA-007, ATA-013, ATA-025, ATA-113, ATA-117, ATA-200, ATA-217, ATA-234, ATA-237, ATA-238, ATA-251, ATA-254, ATA-256, ATA-260, ATA-301, ATA-303, ATA-412, ATA-415, ATA-P1-B04, ATA-P1-F03, ATA-P1-G05, ATA-P2-A01, ATA-P2-A07, and ATA-P2-B01.

[0298] In certain embodiments, the buffer is selected from the group consisting of triethanolamine, Tris, Tricine, BES, MOPS, HEPES, sodium phosphate, and potassium phosphate.

[0299] In certain embodiments, the cofactor is pyridoxal phosphate.

[0300] In certain embodiments, the amine is selected from the group consisting of ammonia, ammonium acetate, ammonium salicylate, ammonium formate, α-methylbenzylamine, isopropylamine, benzhydrylamine, DL-alanine, and aspartame. In certain embodiments, the amine is ammonia.

[0301] In certain embodiments, the acid is selected from the group consisting of p-toluenesulfonic acid, hydrochloric acid, and phosphoric acid. In certain embodiments, the acid is p-toluenesulfonic acid.

[0302] In certain embodiments, the catalyst is an asymmetric catalyst and the process is carried out at a pressure of from about 100 to about 1000 psi. In certain embodiments, the catalyst is an asymmetric catalyst and the process is carried out at a pressure of from about 200 to about 600 psi.

[0303] In some embodiments, the catalyst is an asymmetric catalyst and the process is carried out at a temperature range of 120° C. or less. In certain embodiments, the catalyst is an asymmetric catalyst and the process is carried out at a temperature range of from about 0° C. to about 120° C. In certain embodiments, the catalyst is an asymmetric catalyst and the process is carried out at a temperature range of from about 55° C. to about 65° C.

[0304] In certain embodiments, the catalyst is an enzyme catalyst and the process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the catalyst is an enzyme catalyst and the process is carried out at a temperature range of about 5° C. to about 100° C.

[0305] In some embodiments, compounds of formula V are described herein: [ka] or a co-crystal, solvate, salt, or combination thereof, wherein in formula V, R 1 is B(OH), B(OCH(Me)CHC(Me)O), B((1,2-di-O)CH), B(OCHC(Me)CHO), BFK, B(OCCHN(Me)CHCO), or B(OC(Me)C(Me)O), and this process is (a) Formula VA: [ka] or a co-crystal, solvate, salt, or combination thereof, silylating agents, bases, and Together with the solvent, the compound of formula 7a: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: In formula 7a, each R 2 independently, C 1~6 alkyl or C6 aryl, 1~6 Alkyl and C6 aryl are independently unsubstituted or have 1 to 5 C 1~6 substituted with an alkyl group; and (b) reacting a compound of formula 7a with organometallic reagents, and borylation reagents to provide a compound of formula V or a co-crystal, solvate, salt, or combination thereof. Includes.

[0306] In some embodiments, compounds of formula V are described herein: [ka] or a co-crystal, solvate, salt, or combination thereof, wherein in formula V, R 1 is B(OH), B(OCH(Me)CHC(Me)O), B((1,2-di-O)CH), B(OCHC(Me)CHO), BFK, B(OCCHN(Me)CHCO), or B(OC(Me)C(Me)O), and this process is (a) Formula VA: [ka] or a co-crystal, solvate, salt, or combination thereof, silylating agents, bases, and Together with the solvent, the compound of formula 7a: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: In formula 7a, each R 2 are independently unsubstituted or 1 to 5 C 1~6 Alkyl-substituted C 1~6 is alkyl; and (b) reacting a compound of formula 7a with organometallic reagents, and borylation reagents to provide a compound of formula V or a co-crystal, solvate, salt, or combination thereof. Includes.

[0307] In certain embodiments, the base for step (a) is selected from the group consisting of sodium hydride, potassium hydride, methyl magnesium bromide, phenyl magnesium bromide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and lithium hexamethyldisilazide. In certain embodiments, the base for step (a) is lithium hexamethyldisilazide.

[0308] In certain embodiments, the silylating agent for step (a) is selected from the group consisting of trimethylsilyl bromide, N,O-bis(trimethylsilyl)acetamide, trimethylsilyl chloride, chloro(dimethyl)phenylsilane, chloro(methyl)diphenylsilane, and 1,2-bis(chlorodimethylsilyl)ethane.

[0309] In certain embodiments, the silylating agent for step (a) is selected from the group consisting of trimethylsilyl bromide, N,O-bis(trimethylsilyl)acetamide, and trimethylsilyl chloride. In certain embodiments, the silylating agent for step (a) is trimethylsilyl chloride.

[0310] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), hydrocarbon solvents (e.g., n-hexane), aromatic hydrocarbon solvents (e.g., toluene, xylene), and combinations thereof. In certain embodiments, the solvent is tetrahydrofuran.

[0311] In certain embodiments, the organometallic reagent for step (b) is selected from the group consisting of n-butyllithium, s-butylmagnesium chloride-lithium chloride complex, tert-butylmagnesium chloride, isopropylmagnesium chloride, and isopropylmagnesium chloride-lithium chloride complex.

[0312] In certain embodiments, the organometallic reagent for step (b) is selected from the group consisting of n-butyllithium, sec-butylmagnesium chloride-lithium chloride complex, tert-butylmagnesium chloride, and isopropylmagnesium chloride-lithium chloride complex. In certain embodiments, the organometallic reagent is isopropylmagnesium chloride-lithium chloride complex.

[0313] In certain embodiments, the borylation reagent for step (b) is selected from the group consisting of trimethyl borate, triethyl borate, pinacolborane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, B-catecholborane, and 2-bromo-1,3,2-benzodioxaborole. In certain embodiments, the borylation reagent is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0314] In certain embodiments, the process for preparing the compound of Formula V, or a co-crystal, solvate, salt, or combination thereof, is carried out at a temperature range of about 40° C. or less. In certain embodiments, the process is carried out at a temperature range of about −80° C. to about 40° C. In certain embodiments, the process is carried out at a temperature range of about −40° C. to about 20° C.

[0315] In certain embodiments, R 1 is B(OC(Me)C(Me)O).

[0316] In some embodiments, a compound of Formula VII: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula VII-A: [ka] or a co-crystal, solvate, salt, or combination thereof in the presence of a base and a solvent to provide a compound of formula VII.

[0317] In certain embodiments, the base is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, and potassium trimethylsilanoate. In certain embodiments, the base is potassium hydroxide.

[0318] In certain embodiments, the solvent is selected from the group consisting of chlorinated solvents (e.g., dichloromethane), alcohols (e.g., ethanol, methanol, 1-propanol, 2-propanol), ethers (e.g., diethyl ether, methyl tertbutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic hydrocarbon solvents (e.g., benzene, toluene, xylene), water, and combinations thereof.

[0319] In certain embodiments, the solvent is a chlorinated solvent (e.g., dichloromethane), alkane, or the like. The solvent is selected from the group consisting of coal (e.g., ethanol), ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran), aromatic hydrocarbon solvents (e.g., toluene), water, and combinations thereof. In certain embodiments, the solvent is a mixture of dichloromethane and ethanol.

[0320] In certain embodiments, the solvent is a mixture of dichloromethane, water, and ethanol. In certain embodiments, the solvent is a mixture of water and ethanol.

[0321] In certain embodiments, the process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the process is carried out at a temperature range of about 10° C. to about 100° C. In certain embodiments, the process is carried out at a temperature range of about 10° C. to about 60° C.

[0322] In some embodiments, the compound of formula VII-A: [ka] or a co-crystal, solvate, salt, or combination thereof, the process comprising preparing a compound of formula 5h-1: [ka] or a co-crystal, solvate, salt, or combination thereof with a fluorinating reagent in a solvent in the presence of an activator to provide a compound of Formula VII-A or a co-crystal, solvate, salt, or combination thereof.

[0323] In certain embodiments, n is 1. In certain embodiments, n is 2.

[0324] In certain embodiments, the fluorination reagent is selected from the group consisting of hydrogen fluoride pyridine, calcium fluoride, potassium hydrogen fluoride, triethylamine trihydrofluoride, elemental fluorine, bromine trifluoride, iodine pentafluoride, tetra-N-butylammonium dihydrogen trifluoride, 4-iodotoluene difluoride, and hydrogen fluoride melamine. In certain embodiments, the fluorination reagent is hydrogen fluoride pyridine.

[0325] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In certain embodiments, the solvent is selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, polar aprotic solvents (e.g., acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. The solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, benzene, toluene, xylene, dichloromethane, and combinations thereof. In certain embodiments, the solvent is dichloromethane.

[0326] In certain embodiments, the activator is selected from the group consisting of 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide, N-iodosuccinimide, nitrosonium tetrafluoroborate, sulfuryl fluoride chloride, triflic acid, and mercuric fluoride. In certain embodiments, the activator is 1,3-dibromo-5,5-dimethylhydantoin.

[0327] In certain embodiments, the process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the process is carried out at a temperature range of about −70° C. to about 100° C. In certain embodiments, the process is carried out at a temperature range of about −30° C. to about 20° C.

[0328] In some embodiments, n is 1 or 2, and formula 5h-1: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula XIV: [ka] or a co-crystal, solvate, salt, or combination thereof with a dithiol reagent and a promoter in a solvent to provide a compound of Formula 5h-1, or a co-crystal, solvate, salt, or combination thereof.

[0329] In certain embodiments, n is 1. In certain embodiments, n is 2.

[0330] In certain embodiments, the dithiol reagent is 1,2-ethanedithiol or 1,2-propanedithiol. In certain embodiments, the reagent is 1,2-ethanedithiol.

[0331] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. The solvent is selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxaneacetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, benzene, toluene, xylene, dichloromethane, and combinations thereof. In certain embodiments, the solvent is dichloromethane.

[0332] In certain embodiments, the promoter is selected from the group consisting of boron trifluoride acetate complex, p-toluenesulfonic acid, iodine, 1,3-dibromo-5,5-dimethylhydantoin, copper(II) dodecyl sulfate, ytterbium(III) triflate, yttrium(III) triflate, bismuth(III) triflate, bismuth(III) chloride, tungstophosphoric acid, perchloric acid, praseodymium triflate, hafnium(IV) triflate, iron(III) chloride, hydrogen chloride, p-dodecylbenzenesulfonic acid, BF3·OEt2, BF3·OMe2, BF3·THF, BF3·OBu2, BF3·MeOH, BF3·Me2S, and BF3·PhOHBF3·2H2O. In certain embodiments, the promoter is boron trifluoride acetate complex.

[0333] In certain embodiments, the process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, the process is carried out at a temperature range of about 0° C. to about 40° C.

[0334] In some embodiments, a compound of formula XIV: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula XIV-A: [ka] or a co-crystal, solvate, salt, or combination thereof with an alkylating agent in the presence of a base, a solvent, and optionally a phase transfer catalyst to provide a compound of formula XIV, or a co-crystal, solvate, salt, or combination thereof.

[0335] In certain embodiments, the alkylating agent is selected from the group consisting of ethyl chloroacetate, ethyl iodoacetate, ethyl (methanesulfonyloxy)acetate, ethyl (p-tosyloxy)acetate, ethyl (((trifluoromethyl)sulfonyl)oxy)acetate, and ethyl bromoacetate. In certain embodiments, the alkylating agent is ethyl bromoacetate.

[0336] In certain embodiments, the base is ethyldiisopropylamine, triethylamine In certain embodiments, the base is selected from the group consisting of ethyldiisopropylamine, tri-n-propylamine, tri-n-butylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, sodium hydride, lithium hexamethyldisilazide, sodium hexamethylsilazide, and potassium hexamethyldisilazide.

[0337] In certain embodiments, the process includes a phase transfer catalyst.

[0338] In certain embodiments, the phase transfer catalyst is selected from the group consisting of tetra-N-butylammonium hydrogen sulfate and tetra-N-butylammonium iodide.

[0339] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane), esters (e.g., ethyl acetate, n-butyl acetate, isopropyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), nitriles (e.g., acetonitrile), water, and combinations thereof. In certain embodiments, the solvent is acetonitrile.

[0340] In certain embodiments, the process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 30° C.

[0341] In some embodiments, the compound of formula XIV-A: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula 3c: [ka] or a co-crystal, solvate, salt, or combination thereof, using an oxidizing agent, a promoter, a solvent, and a catalyst to provide a compound of formula XIV-A or a co-crystal, solvate, salt, or combination thereof.

[0342] In certain embodiments, the oxidizing agent is tert-butyl hydroperoxide, peracetic acid, hydrogen peroxide, molecular oxygen, air, sodium hypochlorite, sodium chlorite, periodate, or the like. The oxidizing agent is selected from the group consisting of sodium urate, potassium peroxymonosulfate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,4-benzoquinone, periodic acid, potassium bromate, meta-chloroperoxybenzoic acid (mCPBA or m-CPBA), and magnesium monoperoxypthalate. In certain embodiments, the oxidizing agent is tert-butyl hydroperoxide.

[0343] In certain embodiments, the promoter is selected from the group consisting of pyridine, bipyridine, neocuproine, 1,10-phenanthroline, 2,6-lutidine, 4-picoline, 2-picoline, 3-methylpyridine, isonicotinamide, nicotinamide, picolinic acid, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, and dodecyldimethylammonium bromide. In certain embodiments, the promoter is pyridine.

[0344] In certain embodiments, the solvent is selected from the group consisting of acetic acid, acetonitrile, n-butyl acetate, isopropyl acetate, ethyl acetate, acetone, dichloromethane, diethyl carbonate, tetrahydrofuran, methanol, tert-butanol, dichloromethane, sulfolane, water, and combinations thereof. In certain embodiments, the solvent is water.

[0345] In certain embodiments, the catalyst is selected from the group consisting of manganese(II) triflate, copper(II) chloride, (2S,2'S-(-)-[N,N'-bis(2-pyridylmethyl)]-2,2'-bipyrrolidinebis(acetonitrile)iron(II) hexafluoroantimonate, bismuth, cobalt(II) acetate, manganese(III) acetate, ruthenium(III) chloride, N-hydroxyphthalimide, bis(cyclopentadienyl)vanadium(IV) dichloride, and manganese dioxide. In certain embodiments, the catalyst is copper(II) chloride.

[0346] In certain embodiments, the process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the process is carried out at a temperature range of about −40° C. to about 100° C. In certain embodiments, the process is carried out at a temperature range of about 10° C. to about 50° C.

[0347] In some embodiments, compounds of formula 3c are described herein: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises: (a) Formula 3a: [ka] or a co-crystal, solvate, or combination thereof, is cyclized in a solvent with a hydrazine derivative and a promoter to give a compound of formula 3b: [ka] or a co-crystal, solvate, salt, or combination thereof; and (b) isolating the compound of formula 3b, or a co-crystal, solvate, salt, or combination thereof, to provide a compound of formula 3c, or a co-crystal, solvate, salt, or combination thereof.

[0348] In certain embodiments, the hydrazine derivative in step (a) is selected from the group consisting of anhydrous hydrazine, hydrazine monohydrate, aqueous hydrazine, hydrazine acetate, hydrazine dihydrochloride, hydrazine monohydrochloride, hydrazine sulfate, hydrazine hemisulfate, and hydrazine monohydrobromide. In certain embodiments, the hydrazine derivative in step (a) is hydrazine hydrate.

[0349] In certain embodiments, the solvent in step (a) is selected from the group consisting of water, alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanol, etc.), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), carboxylic acids (e.g., acetic acid, formic acid, propionic acid, butanoic acid), and combinations thereof. In certain embodiments, the solvent in step (a) is selected from the group consisting of water, methanol, ethanol, 1-propanol or 2-propanol diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, benzene, toluene, xylene, a carboxylic acid, acetic acid, formic acid, propionic acid, butanoic acid, and combinations thereof. In certain embodiments, the solvent used in step (a) is acetic acid.

[0350] In certain embodiments, the promoter in step (a) is selected from the group consisting of Bronsted acids (e.g., hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, toluenesulfonic acid) and Lewis acids (e.g., zinc chloride, magnesium chloride, titanium tetrachloride). In certain embodiments, the promoter in step (a) is selected from the group consisting of hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, zinc chloride, magnesium chloride, and titanium tetrachloride.

[0351] In some embodiments, step (a) is carried out at a temperature range of about 120° C. or less. In certain embodiments, step (a) is carried out at a temperature range of from about -40 to about 120°C. In certain embodiments, step (a) is carried out at a temperature range of from about 30 to about 70°C.

[0352] In some embodiments, compounds of formula 3c are described herein: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises: (b) Formula 3a: [ka] or a co-crystal, solvate, or combination thereof, is cyclized in a solvent with a hydrazine derivative and a promoter to give a compound of formula 3b: [ka] or a co-crystal, solvate, salt, or combination thereof; and (b) chromatographically separating the compound of formula 3b, or a co-crystal, solvate, salt, or combination thereof, using a chiral stationary phase and a solvent to provide a compound of formula 3c, or a co-crystal, solvate, salt, or combination thereof. Includes.

[0353] In certain embodiments, the hydrazine derivative in step (a) is selected from the group consisting of anhydrous hydrazine, hydrazine monohydrate, hydrous hydrazine, hydrazine acetate, hydrazine dihydrochloride, hydrazine monohydrochloride, hydrazine sulfate, hydrazine hemisulfate, and hydrazine monohydrobromide. In certain embodiments, the hydrazine derivative in step (a) is hydrazine hydrate.

[0354] In certain embodiments, the solvent in step (a) is selected from the group consisting of water, alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanol, etc.), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), carboxylic acids (e.g., acetic acid, formic acid, propionic acid, butanoic acid), and combinations thereof. In certain embodiments, the solvent in step (a) is selected from the group consisting of water, methanol, ethanol, 1-propanol or 2-propanol diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, benzene, toluene, xylene, a carboxylic acid, acetic acid, formic acid, propionic acid, butanoic acid, and combinations thereof. In certain embodiments, the solvent used in step (a) is acetic acid.

[0355] In certain embodiments, the promoter in step (a) is selected from the group consisting of Bronsted acids (e.g., hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, toluenesulfonic acid) and Lewis acids (e.g., zinc chloride, magnesium chloride, titanium tetrachloride). In certain embodiments, the promoter in step (a) is selected from the group consisting of hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, zinc chloride, magnesium chloride, and titanium tetrachloride.

[0356] In some embodiments, step (a) is carried out at a temperature range of about 120° C. or less. In certain embodiments, step (a) is carried out at a temperature range of about −40 to about 120° C. In certain embodiments, step (a) is carried out at a temperature range of about 30 to about 70° C.

[0357] In certain embodiments, the chiral stationary phase used in step (b) is Chiralpak AD, AS, AY, AZ, T101, OD, IA, IB, IC, ID, IE, IF, IG (Chiral Technologies); Lux Cellulose 2, 3, 4 (Phenomenex); and (R,R)Whelk-O, (R,R)ULMO, (S,S)Dach DNB (Regis Technologies). In certain embodiments, the chiral stationary phase used in step (b) is selected from the group consisting of Chiralpak AD, AS, AY, AZ, T101, OD, IA, IB, IC, ID, IE, IF, IG; Lux Cellulose 2, 3, 4; and (R,R)Whelk-O, (R,R)ULMO, and (S,S)Dach DNB. In certain embodiments, the chiral stationary phase is Chiralpak IG.

[0358] In certain embodiments, the solvent used in step (b) is selected from the group consisting of hydrocarbons (e.g., hexane, heptane, octane), esters (e.g., ethyl acetate, n-propyl acetate, isopropyl acetate), alcohols (e.g., methanol, ethanol, 1-propanol or 2-propanol), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane, chloroform, 1,2-dichloroethane), acetonitrile, and combinations thereof. In certain embodiments, the solvent used in step (b) is selected from the group consisting of hexane, heptane, octane, ester, ethyl acetate, n-propyl acetate, isopropyl acetate, methanol, ethanol, 1-propanol or 2-propanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, and combinations thereof. In certain embodiments, the solvent is acetonitrile.

[0359] In certain embodiments, step (b) is carried out at a temperature range of about 50° C. or less. In certain embodiments, step (b) is carried out at a temperature range of about 10 to about 50° C. can be.

[0360] In some embodiments, a compound of formula XIV: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula XVII: [ka] or a co-crystal, solvate, or combination thereof, catalyst, a reducing agent, and solvent to provide a compound of formula XIV, or a co-crystal, solvate, salt, or combination thereof.

[0361] In certain embodiments, the catalyst for resolving the compound of formula XVII or a co-crystal, solvate, or combination thereof is (R)-(+)-o-tolyl-CBS-oxazaborolidine, (R)-(+)-2-butyl-CBS-oxazaborolidine, (R)-(-)-2-methyl-CBS-oxazaborolidine The catalyst is selected from the group consisting of trans-RuCl2[(R)-xylbinap]-[(R)-diapen], RuBr2[(R)-BINAP], [RuCl(PhH)(R)-BINAP)]Cl, RuCl(p-cymene)[(S,S)-Ts-DPEN], RuCl(mesitylene)[(S,S)-Ts-DPEN], RuBF4(p-cymene)[(S,S)-Ts-DPEN], RuCl(p-cymene)[(S,S)-Fs-DPEN], RuCl(p-cymene)[(R,R)-Teth-Ts-DPEN], and baker's yeast. In certain embodiments, the catalyst is (R)-(-)-2-methyl-CBS-oxazoborolidine.

[0362] In certain embodiments, the reducing agent is selected from the group consisting of borane dimethyl sulfide complex, borane tetrahydrofuran complex, borane trimethylamine complex, borane triethylamine complex, borane N,N-diethylaniline complex, catecholborane, hydrogen gas, formic acid / triethylamine, and 2-propanol. In certain embodiments, the reducing agent is borane dimethyl sulfide complex.

[0363] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), hydrocarbon solvents (e.g., n-hexane, n-heptane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, isobutyl acetate, isopropyl acetate), chlorinated solvents (e.g., dichloromethane), nitriles (e.g., acetonitrile), and combinations thereof. In certain embodiments, the solvent is tetrahydrofuran.

[0364] In certain embodiments, the process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, the process is carried out at a temperature range of about 0° C. to about 10° C.

[0365] In some embodiments, compounds of formula XIV are described herein: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises: (c) Formula XVII: [ka] or a co-crystal, solvate, or combination thereof, catalyst, a reducing agent, and solvent to kinetically resolve a compound of formula XIV or a co-crystal, solvate, or combination thereof with a compound of formula XVIII: [ka] or a co-crystal, solvate, salt, or combination thereof; (b) combining the first mixture with an alcohol derivatizing agent (e.g., succinic anhydride), a catalyst (e.g., DMAP), and a solvent to provide a second mixture; and (c) extracting the second mixture with a base and a solvent to provide a compound of formula XIV or a co-crystal, solvate, salt, or combination thereof. Includes.

[0366] In some embodiments, step (c) provides a compound of Formula XIV or a co-crystal, solvate, salt, or combination thereof that is substantially free of a compound of Formula XVIII or a co-crystal, solvate, salt, or combination thereof. In some embodiments, step (c) provides a compound of Formula XIV or a co-crystal, solvate, salt, or combination thereof that is 99-95% free of a compound of Formula XVIII or a co-crystal, solvate, salt, or combination thereof. In some embodiments, step (c) removes between 95 and 85% of the compound of Formula XVIII or a co-crystal, solvate, salt, or combination thereof. In some embodiments, step (c) removes between 85 and 75% of the compound of Formula XVIII or a co-crystal, solvate, salt, or combination thereof.

[0367] In certain embodiments, the solvent used in step (a), the resolving step, is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), hydrocarbon solvents (e.g., n-hexane, n-heptane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, isobutyl acetate, isopropyl acetate), chlorinated solvents (e.g., dichloromethane), nitriles (e.g., acetonitrile), ketones (e.g., acetone), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), and combinations thereof. In certain embodiments, the solvent is tetrahydrofuran.

[0368] In certain embodiments, the catalyst for resolving step (a) is (R)-(+)-o-tolyl-CBS-oxazaborolidine, (R)-(+)-2-butyl-CBS-oxazaborolidine, (R)-(-)-2-methyl-CBS-oxazaborolidine The catalyst is selected from the group consisting of trans-RuCl2[(R)-xylbinap]-[(R)-diapen], RuBr2[(R)-BINAP], [RuCl(PhH)(R)-BINAP)]Cl, RuCl(p-cymene)[(S,S)-Ts-DPEN], RuCl(mesitylene)[(S,S)-Ts-DPEN], RuBF4(p-cymene)[(S,S)-Ts-DPEN], RuCl(p-cymene)[(S,S)-Fs-DPEN], RuCl(p-cymene)[(R,R)-Teth-Ts-DPEN], and baker's yeast. In certain embodiments, the catalyst is (R)-(-)-2-methyl-CBS-oxazoborolidine.

[0369] In certain embodiments, the reducing agent for the resolving step (a) is selected from the group consisting of borane dimethyl sulfide complex, borane tetrahydrofuran complex, borane trimethylamine complex, borane triethylamine complex, borane N,N-diethylaniline complex, catecholborane, hydrogen gas, formic acid / triethylamine, and 2-propanol. In certain embodiments, the reducing agent is borane dimethyl sulfide complex.

[0370] In some embodiments, the dividing step (a) process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the step (a) process is carried out at a temperature range of about −40° C. to about 100° C. In certain embodiments, the step (a) process is carried out at a temperature range of about 10° C. to about 60° C.

[0371] In certain embodiments, the process of step (a) is carried out at a temperature range of from about −20° C. to about 100° C. In certain embodiments, the process of step (a) is carried out at a temperature range of from about 0° C. to about 10° C.

[0372] In certain embodiments, the alcohol derivatizing agent used in step (b) is selected from the group consisting of succinic anhydride, maleic anhydride, phthalic anhydride, glutaric anhydride, and diglycolic anhydride. In certain embodiments, the alcohol derivatizing agent is succinic anhydride.

[0373] In certain embodiments, the catalyst used in step (b) is 4-(dimethylamino)pyridine, diethylaniline, scandium triflate, silica sulfate In certain embodiments, the catalyst is selected from the group consisting of 4-(dimethylamino)pyridine (DMAP).

[0374] In certain embodiments, the extraction base used in step (c) is selected from the group consisting of potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, and ammonium hydroxide. In certain embodiments, the extraction base is potassium carbonate.

[0375] In certain embodiments, the extraction solvent in step (c) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), hydrocarbon solvents (e.g., n-hexane, n-heptane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, isobutyl acetate, isopropyl acetate), chlorinated solvents (e.g., dichloromethane), water, and combinations thereof. In certain embodiments, the extraction solvent is tetrahydrofuran, methyl tert-butyl ether, and water.

[0376] In certain embodiments, steps (b) and (c) are carried out at a temperature range of about 100° C. or less. In certain embodiments, steps (b) and (c) are carried out at a temperature range of about −40° C. to about 100° C. In certain embodiments, steps (b) and (c) are carried out at a temperature range of about −10° C. to about 60° C.

[0377] In some embodiments, a compound of formula XIV: [ka] or a co-crystal, solvate, or combination thereof, comprising: (a) Formula 5a: [ka] or a co-crystal, solvate, or combination thereof, with an oxidizing agent, a base, and a solvent to obtain a compound of formula 5b: [ka] or a co-crystal, solvate, or combination thereof, wherein in formula 5b, each R 3 are independently unsubstituted or 1 to 5 C 1~6 Alkyl C substituted with a group 1~6 is alkyl; (b) further oxidizing the compound of formula 5b, or a co-crystal, solvate, or combination thereof, with an oxidizing agent, a base, and a solvent to obtain a compound of formula 5c: [ka] or a co-crystal, solvate, or combination thereof; (c) combining a compound of Formula 5c, or a co-crystal, solvate, or combination thereof, with a trifluoroacetylating agent and a lithium base in a solvent to form a compound of Formula 3d: [ka] or a co-crystal, solvate, or combination thereof; and (d) combining the compound of formula 3d, or a co-crystal, solvate, or combination thereof, with ethyl hydrazinoacetate hydrochloride, an acid, and optionally an additive to provide a compound of formula XIV, or a co-crystal, solvate, salt, or combination thereof. Includes.

[0378] In certain embodiments, the oxidizing agent used in step (a) is selected from the group consisting of iodine, thianthrenium tetrafluoroborate, diacetoxyiodobenzene, and potassium iodide / platinum electrode. In certain embodiments, the oxidizing agent used in step (a) is diacetoxyiodobenzene.

[0379] In certain embodiments, the base used in step (a) is selected from the group consisting of sodium hydroxide, lithium hydroxide, and potassium hydroxide. In certain embodiments, the base used in step (a) is potassium hydroxide.

[0380] In certain embodiments, the solvent used in step (a) is an alcohol (e.g., methanol, ethanol, 1-propanol, ethylene glycol). In certain embodiments, the solvent used in step (a) is methanol.

[0381] In certain embodiments, step (a) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (a) is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, step (a) is carried out at a temperature range of about −15° C. to about 30° C.

[0382] In certain embodiments, the oxidizing agent used in step (b) is dimethyl sulfoxide and cyanuric chloride, oxalyl chloride, dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N-chlorosuccinimide, benzoic anhydride, methanesulfonic anhydride, tosylic anhydride, triflic anhydride, methyl chloroglyoxylate, thionyl chloride, diphosgene, triphosgene, methanesulfonyl chloride, tosyl chloride, benzenesulfonyl chloride, trichloroacetonitrile, 2-chloro-1,2-dimethylimidazolinium chloride, polyphosphoric acid, PCl3, triphenylphosphine dichloride, chlorine, triphenylphosphine dibromide, POCl3, phosphorus pentoxide, acetyl chloride, benzoyl chloride, acetyl bromide, phenyl dichlorophosphate, diphenyl chlorophosphate, diethyl chlorophosphate, and ethoxyacetylene, TEMPO and an activator selected from the group consisting of bleach, chromium trioxide, Dess-Martin periodinane, 2-iodoxybenzoic acid, and sulfur trioxide pyridine complex. In certain embodiments, the oxidizing agent used in step (b) is dimethyl sulfoxide and oxalyl chloride.

[0383] In certain embodiments, the base used in step (b) is selected from the group consisting of diisopropylethylamine, tri-n-propylamine, triethylamine, pyridine, and 2,6-lutidine. In certain embodiments, the base used in step (b) is triethylamine.

[0384] In certain embodiments, the solvent used in step (b) is selected from the group consisting of chlorinated solvents (e.g., dichloromethane, 1,2-dichloroethane), aromatic hydrocarbon solvents (e.g., toluene), and combinations thereof. In certain embodiments, the solvent used in step (b) is dichloromethane.

[0385] In certain embodiments, step (b) is carried out at a temperature range of about 50° C. or less. In certain embodiments, step (b) is carried out at a temperature range of about −80° C. to about 50° C. In certain embodiments, step (b) is carried out at a temperature range of about −60° C. to about −10° C.

[0386] In certain embodiments, R 3 is methyl, ethyl, or propyl. In some embodiments, R 3 is methyl.

[0387] In certain embodiments, the trifluoroacetylating agent used in step (c) is selected from the group consisting of trifluoroacetic anhydride, phenyl trifluoroacetate, methyl trifluoroacetate, ethyl trifluoroacetate, and trifluoroethyl trifluoroacetate. In certain embodiments, the trifluoroacetylating agent is ethyl trifluoroacetate.

[0388] In certain embodiments, the lithium base used in step (c) is selected from the group consisting of lithium hexamethyldisilazide, lithium diisopropylamine, lithium tetramethylpiperidide, lithium methoxide, lithium ethoxide, and lithium tert-butoxide. In certain embodiments, the lithium base is lithium hexamethyldisilazide.

[0389] In certain embodiments, the solvent used in step (c) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), hydrocarbon solvents (e.g., n-hexane, n-heptane), aromatic hydrocarbon solvents (e.g., toluene, xylene), chlorinated solvents (e.g., dichloromethane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), nitriles (e.g., acetonitrile), and combinations thereof. In certain embodiments, the solvent used in step (c) is tetrahydrofuran.

[0390] In certain embodiments, step (c) is carried out at a temperature range of about 30° C. or less. In certain embodiments, step (c) is carried out at a temperature range of about −30° C. to about 30° C. In certain embodiments, step (c) is carried out at a temperature range of about -80°C to about 60°C. In certain embodiments, step (c) is carried out at a temperature range of about -80°C to about 30°C.

[0391] In certain embodiments, step (c) is carried out at a temperature range of about 60° C. or less. In certain embodiments, step (c) is carried out at a temperature range of about −80° C. to about 60° C. In certain embodiments, step (c) is carried out at a temperature range of about −30° C. to about 30° C.

[0392] In certain embodiments, the acid used in step (d) is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, hydrogen bromide, methanesulfonic acid, p-toluenesulfonic acid, magnesium chloride, zinc chloride, scandium triflate, and bismuth chloride. In certain embodiments, the acid is sulfuric acid.

[0393] In certain embodiments, step (d) includes an additive.

[0394] In certain embodiments, the additive used in step (d) is selected from the group consisting of ethyl orthoacetate, ethyl orthoformate, molecular sieves, and Dean-Stark distillate. In certain embodiments, the additive is ethyl orthoformate.

[0395] In certain embodiments, the solvent used in step (d) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), ketones (e.g., acetone), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), esters (e.g., ethyl acetate, isopropyl acetate), alcohols (e.g., methanol, ethanol, isopropanol, ethylene glycol, propylene glycol), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In certain embodiments, the solvent used in step (d) is ethanol.

[0396] In certain embodiments, step (d) is performed at a temperature range of about 60° C. or less. In certain embodiments, step (d) is performed at a temperature range of about −20° C. to about 60° C. In certain embodiments, step (d) is performed at a temperature range of about −20° C. to about 20° C.

[0397] In some embodiments, the compound of formula XV: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula 3d-02: [ka] or a co-crystal, solvate, or combination thereof, with a hydrazine source and a solvent to provide a compound of formula XV or a co-crystal, solvate, salt, or combination thereof.

[0398] In certain embodiments, the hydrazine source is selected from the group consisting of hydrazine sulfate, hydrazine hemisulfate, hydrazine hydrochloride, hydrazine dihydrochloride, hydrazine acetate, hydrazine hydrobromide, hydrazine hydrate, and anhydrous hydrazine, hi certain embodiments, the hydrazine source is hydrazine sulfate.

[0399] In certain embodiments, the solvent is selected from the group consisting of alcohols (e.g., methanol, ethanol, ethylene glycol), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In certain embodiments, the solvent is ethylene glycol.

[0400] In certain embodiments, the process is carried out at a temperature range of about 80° C. or less. In certain embodiments, the process is carried out at a temperature range of about 0° C. to about 80° C. In certain embodiments, the process is carried out at a temperature range of about 20° C. to about 60° C. In certain embodiments, the process is carried out at a temperature of about 40° C.

[0401] In some embodiments, the compound of formula XV: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula 3k: [ka] or a co-crystal, solvate, salt, or combination thereof with a reagent to provide a compound of formula XV or a co-crystal, solvate, salt, or combination thereof.

[0402] In certain embodiments, the reagent is selected from the group consisting of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), diammonium cerium(IV) nitrate, hydrogen chloride, hydrogen bromide, methanesulfonic acid (MsOH), triflic acid (TfOH), trifluoroacetic acid (TFA), Pd / C (with H, NHHCO, or EtSiH), BCl, BBr, and lithium naphthalenide. In certain embodiments, the reagent is trifluoroacetic acid.

[0403] In certain embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about 0° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of about 40° C. to about 80° C.

[0404] In some embodiments, a compound of formula 3k: [ka]

[0405] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula 3j: [ka] or a co-crystal, solvate, salt, or combination thereof, with a base and a solvent to provide a compound of Formula 3k or a co-crystal, solvate, salt, or combination thereof.

[0406] In certain embodiments, the base is lithium diisopropylamide, 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex, n-butyllithium , phenyllithium, phenylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride lithium chloride complex, n-butyllithium, lithium N,N-dimethylaminoethanol complex, and mesityllithium disilazide bases (e.g., lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide). In certain embodiments, the base is lithium diisopropylamide.

[0407] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., benzene, toluene, xylene), and combinations thereof. In certain embodiments, the solvent is tetrahydrofuran.

[0408] In certain embodiments, the process is carried out at a temperature range of about 50° C. or less. In certain embodiments, the process is carried out at a temperature range of about −80° C. to about 50° C. In certain embodiments, the process is carried out at a temperature range of about −80° C. to about −20° C.

[0409] In some embodiments, the compound of formula 3j: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula 3f: [ka] or a co-crystal, solvate, salt, or combination thereof, of formula 3i: [ka] or a co-crystal, solvate, salt, or combination thereof, together with a base, a solvent, and a catalyst to provide a compound of Formula 3j or a co-crystal, solvate, salt, or combination thereof.

[0410] In certain embodiments, the base is selected from the group consisting of cesium fluoride, sodium bicarbonate, dipotassium phosphate, sodium carbonate, potassium carbonate, tripotassium phosphate, sodium hydroxide, and and potassium hydroxide. In certain embodiments, the base is cesium fluoride.

[0411] In certain embodiments, the solvent is selected from the group consisting of water and ethers (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), hydrocarbon solvents (e.g., toluene, xylene), dimethylformamide, esters (e.g., isopropyl acetate, isobutyl acetate), and combinations thereof. In certain embodiments, the solvent is dimethylformamide.

[0412] In certain embodiments, the catalyst is selected from the group consisting of palladium catalysts (e.g., palladium(II) acetate / triphenylphosphine, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, dichlorobis(triphenylphosphine)palladium(II), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)). In certain embodiments, the catalyst is palladium(II) acetate / triphenylphosphine.

[0413] In certain embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about 20° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of about 40° C. to about 100° C.

[0414] In some embodiments, the compound of formula 3i-1: [ka] or a co-crystal, solvate, salt, or combination thereof, the process comprising the step of preparing a compound of formula 3h: [ka] or a co-crystal, solvate, salt, or combination thereof, with a borylation reagent, a solvent, and a catalyst to provide a compound of formula 3i-1, or a co-crystal, solvate, salt, or combination thereof; In formula 3i-1, each R 7 are independently H, alkyl, or aryl, or both R 7 and the atom to which they are attached form a 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heterocyclyl is a 5- to 5-C 1~3 Optionally substituted with alkyl.

[0415] In certain embodiments, both R 7 The atoms to which they are bonded are 1 to 5 C 1~3 In certain embodiments, both R 7 The atoms to which they are bonded are 1 to 4 C 1~3 In certain embodiments, both R 7 and the atom to which they are attached form a 5-membered heterocyclyl substituted with four methyl groups. 7and the atom to which they are attached form pinacolboranyl.

[0416] In certain embodiments, the compound of formula 3i-1 has formula 3i: [ka] is a compound of

[0417] In certain embodiments, the borylation reagent is selected from the group consisting of bis(pinacolato)diboron, bis(neopentylglycolato)diboron, tetrahydroxydiboron, bis(hexyleneglycolato)diboron, and bis(catecholato)diboron. In certain embodiments, the borylation reagent is bis(pinacolato)diboron.

[0418] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), alcohols (e.g., methanol, ethanol, isopropanol), esters (e.g., ethyl acetate, isopropyl acetate), and combinations thereof. In certain embodiments, the solvent is dioxane and N,N-dimethylformamide.

[0419] In certain embodiments, the catalyst is selected from the group consisting of palladium catalysts (e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, dichlorobis(triphenylphosphine)palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)). In certain embodiments, the catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0420] In certain embodiments, the process is carried out at a temperature range of about 130° C. or less. In certain embodiments, the process is carried out at a temperature range of about 10° C. to about 130° C. In certain embodiments, the process is carried out at a temperature range of about 80° C. to about 110° C.

[0421] In some embodiments, the compound of formula 3i-1: [ka] or a co-crystal, solvate, salt, or combination thereof, the process comprising the step of preparing a compound of formula 3h: [ka] or a co-crystal, solvate, salt, or combination thereof, with a borylation reagent, an organometallic reagent, and a solvent to provide a compound of Formula 3i-1, or a co-crystal, solvate, salt, or combination thereof; In formula 3i-1, each R 7 are independently H, alkyl, or aryl, or both R 7 and the atom to which they are attached form a 5- to 6-membered heterocyclyl, wherein the 5- to 6-membered heterocyclyl is a 5- to 5-C 1~3Optionally substituted with alkyl.

[0422] In certain embodiments, both R 7 The atoms to which they are bonded are 1 to 5 C 1~3 In certain embodiments, both R 7 The atoms to which they are bonded are 1 to 4 C 1~3 In certain embodiments, both R 7 and the atom to which they are attached form a 5-membered heterocyclyl substituted with four methyl groups. 7 and the atom to which they are attached form pinacolboranyl.

[0423] In certain embodiments, the compound of formula 3i-1 has formula 3i: [ka] is a compound of

[0424] In certain embodiments, the borylation reagent is selected from the group consisting of trialkylborate (e.g., trimethyl borate, triethyl borate), pinacolborane, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, B-catecholborane, and 2-bromo-1,3,2-benzodioxaborole. In the above, the borylation reagent is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0425] In certain embodiments, the organometallic reagent is selected from the group consisting of metallic lithium, metallic magnesium, isopropylmagnesium chloride, n-butyllithium, sec-butylmagnesium chloride-lithium chloride complex, tert-butylmagnesium chloride, and isopropylmagnesium chloride-lithium chloride complex. In certain embodiments, the organometallic reagent is isopropylmagnesium chloride.

[0426] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane), hydrocarbon solvents (e.g., n-hexane, n-heptane, toluene, xylene), and combinations thereof. In certain embodiments, the solvent is tetrahydrofuran.

[0427] In certain embodiments, the process is carried out at a temperature range of about 40° C. or less. In certain embodiments, the process is carried out at a temperature range of about −80° C. to about 40° C. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 20° C.

[0428] In some embodiments, a compound of formula 3h: [ka] or a co-crystal, solvate, salt, or combination thereof, the process comprising the step of preparing a compound of formula 3h: [ka] or a co-crystal, solvate, salt, or combination thereof, with an alkylating agent, a base, and a solvent to provide a compound of Formula 3h, or a co-crystal, solvate, salt, or combination thereof.

[0429] In certain embodiments, the alkylating agent is selected from the group consisting of 4-methoxybenzyl chloride, 4-methoxybenzyl bromide, 4-methoxybenzyl-2,2,2-trichloroacetimidate, and (4-methoxybenzyloxy)-4-methylquinoline. In certain embodiments, the alkylating agent is 4-methoxybenzyl chloride.

[0430] In certain embodiments, the base is a tertiary amine (e.g., triethylamine, tri-n-propylamine, tri-n-butylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine), a carbonate base (e.g., sodium carbonate, The base is selected from the group consisting of sodium hydride, alkoxide bases (e.g., sodium ethoxide, potassium ethoxide, sodium tert-butoxide), sodium hydride, and disilazide bases (e.g., lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide). In certain embodiments, the base is sodium hydride.

[0431] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In certain embodiments, the solvent is dimethylformamide.

[0432] In certain embodiments, the process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, the process is carried out at a temperature range of about 0° C. to about 40° C.

[0433] In some embodiments, the compound of formula 3f: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula 3e: [ka] or a co-crystal, solvate, salt, or combination thereof, with a coupling agent and a solvent to provide a compound of Formula 3f, or a co-crystal, solvate, salt, or combination thereof.

[0434] In certain embodiments, the coupling agent is selected from the group consisting of carbonyldiimidazole, oxalyl chloride, thionyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, isobutyl chloroformate, hexafluorophosphate azabenzotriazole tetramethyluronium (HATU), hexafluorophosphate benzotriazole tetramethyluronium (HBTU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), tri-n-propylphosphonic anhydride, and 2-chloro-4,6-dimethoxy-1,3,5-triazine. It is carbonyldiimidazole.

[0435] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., benzene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), dichloromethane, and combinations thereof. In certain embodiments, the solvent is tetrahydrofuran.

[0436] In certain embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of about 0° C. to about 40° C.

[0437] In some embodiments, the compound of formula 3n-1: [ka] A process for preparing a compound of formula (I) is provided, the process comprising: (a) Formula 3a: [ka] or a co-crystal, solvate, or combination thereof, in combination with an acid to form a compound of formula 3l [ka] or a co-crystal, solvate, or combination thereof; and (b) combining a compound of formula 3l, or a co-crystal, solvate, or combination thereof, with a chiral amine and a solvent to provide a compound of formula 3n-1.

[0438] In certain embodiments, the acid used in step (a) is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, and trifluoroacetic acid. In certain embodiments, the acid used in step (a) is hydrochloric acid or sulfuric acid. In certain embodiments, the acid used in step (a) is hydrochloric acid. In certain embodiments, the acid used in step (a) is sulfuric acid.

[0439] In certain embodiments, the chiral amine used in step (b) is quinine, (S)-(-)-α-methylbenzylamine, (R)-(+)-α-methylbenzylamine, (S)-(+)-2-phenylglycinol, (R)-(-)-2-phenylglycinol, (S)-valinol, (R)-valinol, quinidine, quinine, brucine, cinchonine, cinchonidine, (+)-dehydroabietylamine, (1R,2S)-(-)-ephedrine, (1S,2R)-(+)-ephedrine hemihydrate, (1S,2R)-(-)-cis-1-amino-2-indanol ((1S,2R) In certain embodiments, the chiral amine is selected from the group consisting of (1R,2S)-(-)-cis-1-amino-2-indanol, (S)-(+)-1-cyclohexylethylamine, (R)-(-)-1-cyclohexylethylamine, (S)-(-)-1-(1-naphthyl)ethylamine, (R)-(+)-1-(1-napthyl)ethylamine, (S)-(+)-2-amino-1-butanol, (R)-(-)-2-amino-1-butanol, (S)-2-aminohexane, (R)-2-aminohexane, (R)-phenylglycine, and (R)-(1-naphthyl)ethylamine.

[0440] In certain embodiments, the solvent used in step (b) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), alcohols (e.g., methanol, ethanol, isopropanol), esters (e.g., ethyl acetate, isopropyl acetate), and combinations thereof. In certain embodiments, for example, the solvent used in step (b) is acetone.

[0441] In certain embodiments, the process is carried out at a temperature range of about 80° C. or less. In certain embodiments, the process is carried out at a temperature range of about −30° C. to about 80° C. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 60° C.

[0442] In some embodiments, a compound of formula 5h: [ka] or a co-crystal, solvate, or combination thereof, comprising: (a) Formula 5b-02: [ka] or a co-crystal, solvate, or combination thereof, in combination with 1,2-ethanedithiol, a solvent, and a promoter to form a compound of formula 5d-01: [ka] or a co-crystal, solvate, or combination thereof; (b) oxidizing a compound of formula 5d-01, or a co-crystal, solvate, or combination thereof, with an oxidizing agent, a base, and a solvent to obtain a compound of formula 5e: [ka] or a co-crystal, solvate, or combination thereof; (c) combining a compound of formula 5e, or a co-crystal, solvate, or combination thereof, with a trifluoroacetylating agent, a base, and a solvent to form a compound of formula 5f-1: [ka] or a co-crystal, solvate, or combination thereof, wherein in formula 5f-1, M is selected from the group consisting of alkali metals (e.g., Li, Na, K, Mg, Ca), transition metals (e.g., Zn, Sr), aliphatic ammonium (e.g., diisopropylammonium, dicyclohexylammonium, diethylammonium, triethylammonium), and aromatic ammonium (e.g., pyridinium); and (d) combining a compound of formula 5f-1, or a co-crystal, solvate, or combination thereof, with ethyl hydrazinoacetate hydrochloride and an acid to provide a compound of formula 5h, or a co-crystal, solvate, salt, or combination thereof. Includes.

[0443] In certain embodiments, the promoter used in step (a) is p-toluenesulfonyl ether. In certain embodiments, the promoter used in step (a) is selected from the group consisting of benzenesulfonic acid, copper(II) dodecyl sulfate, ytterbium(III) triflate, yttrium(III) triflate, bismuth(III) triflate, bismuth(III) chloride, tungstophosphoric acid, perchloric acid, praseodymium triflate, hafnium(IV) triflate, iron(III) chloride, hydrogen chloride, p-dodecylbenzenesulfonic acid, BiCl, BF·HOAc, BF·OEt, BF·OMe, BF·THF, BF·OBu, BF·MeOH, BF·MeS, BF·PhOH, and BF·2H0. In certain embodiments, the promoter used in step (a) is BiCl.

[0444] In certain embodiments, the solvent used in step (a) is an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), a polar aprotic solvent (e.g., acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), an aromatic solvent (e.g., benzene, toluene, xylene), a chlorinated solvent (e.g., dichloromethane), an ester (e.g., ethyl acetate, isopropyl acetate), a nitrile (e.g., acetonitrile), or a combination thereof. In certain embodiments, the solvent used in step (a) is acetonitrile.

[0445] In certain embodiments, step (a) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (a) is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, step (a) is carried out at a temperature range of about 0° C. to about 80° C.

[0446] In certain embodiments, the oxidizing agent used in step (b) is dimethyl sulfoxide (DMSO) and an activating agent (e.g., SO.pyridine complex, oxalyl chloride, cyanuric chloride, dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), N-chlorosuccinimide (NCS), benzoic anhydride, methanesulfonic anhydride, tosylic anhydride, triflic anhydride, methyl chloroglyoxylate, thionyl chloride, diphosgene, triphosgene, methanesulfonyl chloride, tosyl chloride, benzenesulfonyl chloride, trichloroacetonitrile, 2-chloropropanediol ... The oxidizing agent used in step (b) is selected from the group consisting of methyl para-1,2-dimethylimidazolinium chloride, polyphosphoric acid (PPA), PCl, PO, triphenylphosphine dichloride (TPP·Cl), triphenylphosphine dibromide (TPP·Br), POCl, acetyl chloride, benzoyl chloride, acetyl bromide, phenyl dichlorophosphate, diphenyl chlorophosphate, diethyl chlorophosphate, and ethoxyacetylene, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl / bleach (TEMPO / bleach), chromium trioxide, Dess-Martin periodinane, and 2-iodoxybenzoic acid. In certain embodiments, the oxidizing agent used in step (b) is DMSO and SO.pyridine complex.

[0447] In certain embodiments, the base used in step (b) is selected from the group consisting of aliphatic amines (e.g., triethylamine, diisopropylethylamine, tri-n-propylamine) and aromatic amines (e.g., pyridine, 2,6-lutidine). In certain embodiments, the base used in step (b) is triethylamine.

[0448] In certain embodiments, the solvent used in step (b) is dichloromethane, dichloroethane, toluene, DMSO, ethyl acetate, and combinations thereof. In certain embodiments, the solvent used in step (b) is dichloromethane.

[0449] In certain embodiments, step (b) is carried out at a temperature range of about 80° C. or less. In certain embodiments, step (b) is carried out at a temperature range of about -80°C to about 80°C. In certain embodiments, step (a) is carried out at a temperature range of about -60°C to about 60°C.

[0450] In certain embodiments, M is selected from the group consisting of alkali metals (e.g., Li, Na, K, Mg, Ca), transition metals (e.g., Zn), aliphatic ammonium (e.g., diisopropylammonium, dicyclohexylammonium, diethylammonium, triethylammonium), and aromatic ammonium (e.g., pyridinium). In certain embodiments, M is aliphatic ammonium. In certain embodiments, M is diisopropylammonium.

[0451] In certain embodiments, the trifluoroacetylating agent used in step (c) is selected from the group consisting of ethyl trifluoroacetate, trifluoroacetic anhydride, phenyl trifluoroacetate, trifluoroacetic acid alkyl esters, and 1-(trifluoroacetyl)imidazole. In certain embodiments, the trifluoroacetylating agent is ethyl trifluoroacetate.

[0452] In certain embodiments, the base used in step (c) is selected from the group consisting of lithium hexamethyldisilazide, lithium diisopropylamine, lithium tetramethylpiperidide, lithium methoxide, lithium ethoxide, lithium tert-butoxide, alkali metal alkoxides, and alkali metal amides. In certain embodiments, the lithium base is lithium hexamethyldisilazide.

[0453] In certain embodiments, the salt used in step (c) is selected from the group consisting of alkali metals (e.g., Na, K, Mg, Ca), transition metals (e.g., Zn), aliphatic ammonium (e.g., diisopropylammonium, dicyclohexylammonium, diethylammonium, triethylammonium), and aromatic ammonium (e.g., pyridinium). In certain embodiments, the salt is diisopropylammonium.

[0454] In certain embodiments, the solvent used in step (c) is selected from the group consisting of ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether), hydrocarbon solvents (e.g., n-hexane, n-heptane, toluene, xylene), dichloromethane, acetonitrile, and combinations thereof. In certain embodiments, the solvent used in step (c) is tetrahydrofuran.

[0455] In certain embodiments, the acid used in step (d) is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, hydrogen bromide, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, and BF3·2HOAc. In certain embodiments, the acid is sulfuric acid. In certain embodiments, the acid is hydrochloric acid.

[0456] In certain embodiments, the solvent used in step (d) is selected from the group consisting of ethanol, esters (e.g., ethyl acetate, isopropyl acetate), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aprotic solvents (e.g., acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In certain embodiments, the solvent used in step (d) is ethanol.

[0457] In certain embodiments, step (d) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (d) is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, step (d) is carried out at a temperature range of about 0° C. to about 40° C.

[0458] In some embodiments, a compound of formula 5h: [ka] or a co-crystal, solvate, or combination thereof, comprising: (a) Formula 5f-1a: [ka] or a co-crystal, solvate, or combination thereof (in formula 5f-1a, M 1 is condensed with an ammonium compound of formula 5g, selected from the group consisting of an alkali metal (e.g., Li, Na, K, Mg, Ca), a transition metal (e.g., Zn, Sr), an aliphatic ammonium (e.g., diisopropylammonium, dicyclohexylammonium, diethylammonium, triethylammonium), an aromatic ammonium (e.g., pyridinium) using a hydrazine derivative, a solvent, and a promoter to give a compound of formula 5g: [ka] or a co-crystal, solvate, or combination thereof; (b) alkylating the compound of formula 5g, or a co-crystal, solvate, or combination thereof, with an alkylating agent, a base, a solvent, and optionally a phase transfer catalyst to provide a compound of formula 5h, or a co-crystal, solvate, salt, or combination thereof. Includes.

[0459] In certain embodiments, M 1are alkali metals (e.g., Li, Na, K, Mg, Ca), transition metals (e.g., Zn, Sr), aliphatic amines (e.g., diisopropyl ammonium In certain embodiments, M is selected from the group consisting of ammonium, dicyclohexylamine, diethylamine, triethylamine, and aromatic ammonium (e.g., pyridinium). 1 is an alkali metal. In certain embodiments, M 1 is lithium.

[0460] In certain embodiments, the hydrazine derivative used in step (a) is selected from the group consisting of anhydrous hydrazine, hydrazine monohydrate, hydrazine acetate, hydrazine dihydrochloride, hydrazine hydrate (e.g., hydrazine monohydrochloride), hydrazine sulfate, hydrazine hemisulfate, and hydrazine monohydrobromide. In certain embodiments, the hydrazine derivative used in step (a) is hydrazine hydrate.

[0461] In certain embodiments, the promoter used in step (a) is selected from the group consisting of carboxylic acids (e.g., formic acid, propionic acid, butanoic acid, acetic acid), Bronsted acids (e.g., hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, toluenesulfonic acid), and Lewis acids (e.g., zinc chloride, magnesium chloride, titanium tetrachloride). In certain embodiments, the promoter used in step (a) is a carboxylic acid. In certain embodiments, the promoter used in step (a) is acetic acid.

[0462] In certain embodiments, the solvent used in step (a) is selected from the group consisting of water, alcohols (e.g., methanol, ethanol, 1-propanol, or 2-propanol), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), alkylcarboxylic acids (e.g., formic acid, acetic acid, propanoic acid, butanoic acid), and combinations thereof. In certain embodiments, the solvent used in step (a) is water.

[0463] In certain embodiments, step (a) is carried out at a temperature range of about 120° C. or less. In certain embodiments, step (a) is carried out at a temperature range of about 0° C. to about 120° C. In certain embodiments, step (a) is carried out at a temperature range of about 20° C. to about 100° C.

[0464] In certain embodiments, the alkylating agent used in step (b) is selected from the group consisting of ethyl bromoacetate, ethyl chloroacetate, ethyl iodoacetate, ethyl (methanesulfonyloxy)acetate, ethyl (p-tosyloxy)acetate, and ethyl (((trifluoromethyl)sulfonyl)oxy)acetate. In certain embodiments, the alkylating agent used in step (b) is ethyl bromoacetate.

[0465] In certain embodiments, the base used in step (b) is selected from the group consisting of tertiary amines (e.g., triethylamine, tri-n-propylamine, tri-n-butylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), alkoxide bases (e.g., sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide), sodium hydride, disilazide bases (e.g., sodium hexamethyldisilazide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide), and combinations thereof. In certain embodiments, the base used in step (b) is sodium hexamethyldisilazide.

[0466] In certain embodiments, the solvent used in step (b) is an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyl The solvent used in step (b) is selected from the group consisting of tetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, acetonitrile), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), esters (e.g., ethyl acetate, isopropyl acetate, n-butyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), alcohols (e.g., methanol, ethanol), water, and combinations thereof. In certain embodiments, the solvent used in step (b) is tetrahydrofuran.

[0467] In certain embodiments, step (b) includes a phase transfer catalyst. In certain embodiments, the phase transfer catalyst used in step (b) is selected from the group consisting of tetra-alkylammonium salts. In certain embodiments, the tetra-alkylammonium salt is tetra-N-butylammonium hydrogen sulfate and / or tetra-N-butylammonium iodide.

[0468] In certain embodiments, step (b) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (b) is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, step (b) is carried out at a temperature range of about −20° C. to about 50° C.

[0469] In some embodiments, the compound of formula 5e: [ka] or a co-crystal, solvate, or combination thereof, comprising: (a) Formula 5a: [ka] or a co-crystal, solvate, or combination thereof, with an oxidizing agent, a base, and a solvent to obtain a compound of formula 4a [ka] or a co-crystal, solvate, or combination thereof; (b) a compound of Formula 4a, or a co-crystal, solvate, or combination thereof, with a 1,2- Together with ethanedithiol, a solvent, and a catalyst, a compound of formula 5i: [ka] or a co-crystal, solvate, or combination thereof; and (c) hydrolyzing the compound of formula 5i, or a co-crystal, solvate, or combination thereof, using an acid, a solvent, and a promoter to provide a compound of formula 5e, or a co-crystal, solvate, salt, or combination thereof. Includes.

[0470] In certain embodiments, the oxidizing agent used in step (a) is selected from the group consisting of alkyl nitrite esters (e.g., isopentyl nitrite, n-butyl nitrite, tert-butyl nitrite, ethyl nitrite), nitrite salts (e.g., sodium nitrite, potassium nitrite), nitrosyl chloride, nitrosyl sulfate, and nitrosonium salts (e.g., tetrafluoroborate, hydrogen sulfate). In certain embodiments, the oxidizing agent used in step (a) is selected from the group consisting of isopentyl nitrite, n-butyl nitrite, tert-butyl nitrite, ethyl nitrite, sodium nitrite, potassium nitrite, nitrosyl chloride, nitrosyl sulfate, tetrafluoroborate, and hydrogen sulfate. In certain embodiments, the oxidizing agent used in step (a) is tert-butyl nitrite.

[0471] In certain embodiments, the base used in step (a) is selected from the group consisting of alkali metal alkoxides (e.g., potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium isopropoxide, sodium ethoxide, sodium methoxide), alkali metal halides (e.g., sodium hydride), amide bases (e.g., lithium tetramethylpiperidide, lithium hexamethyldisilazide), and phosphazenes. In certain embodiments, the base used in step (a) is selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium isopropoxide, sodium ethoxide, sodium methoxide, sodium hydride, lithium tetramethylpiperidide, lithium hexamethyldisilazide, and phosphazenes. In certain embodiments, the base used in step (a) is potassium tert-butoxide.

[0472] In certain embodiments, the solvent used in step (a) is selected from the group consisting of tetrahydrofuran, ethers (e.g., diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methyltetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), halogenated solvents (e.g., dichloromethane), alcohols (methanol, ethanol, isopropanol), sulfolane, and combinations thereof. In certain embodiments, the solvent used in step (a) is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dichloromethane, methanol, ethanol, isopropanol, sulfolane, and combinations thereof. In certain embodiments, the solvent used in step (a) is tetrahydrofuran.

[0473] In certain embodiments, step (a) is carried out at a temperature range of about 70° C. or less. In certain embodiments, step (a) is carried out at a temperature range of about −78° C. to about 70° C. In certain embodiments, step (a) is carried out at a temperature range of about −10° C. to about 10° C.

[0474] In certain embodiments, the catalyst used in step (b) is a mineral acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid), a sulfonic acid (e.g., para-toluenesulfonic acid monohydrate, methanesulfonic acid, benzenesulfonic acid), trifluoroacetic acid, phosphoric acid, iodine, 1,3-dibromo-5,5-dimethylhydantoin, copper(II) dodecyl sulfate, ytterbium(III) triflate, yttrium(III) triflate. , bismuth(III) triflate, bismuth(III) chloride, tungstophosphoric acid, perchloric acid, praseodymium triflate, hafnium(IV) triflate, iron(III) chloride, hydrogen chloride, p-dodecylbenzenesulfonic acid, BF3·OEt2, BF3·OMe2, BF3·THF, BF3·OBu2, BF3·MeOH, BF3·Me2S, BF3·PhOH, and BF3·2H2O. In certain embodiments, the catalyst used in step (b) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, para-toluenesulfonic acid monohydrate, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, iodine, 1,3-dibromo-5,5-dimethylhydantoin, copper(II) dodecyl sulfate, ytterbium(III) triflate, yttrium(III) triflate, bismuth(III) triflate, bismuth(III) chloride, tungstophosphoric acid, perchloric acid, praseodymium triflate, hafnium(IV) triflate, iron(III) chloride, hydrogen chloride, p-dodecylbenzenesulfonic acid, BF3·OEt2, BF3·OMe2, BF3·THF, BF3·OBu2, BF3·MeOH, BF3·Me2S, BF3·PhOH, and BF3·2H2O. In certain embodiments, the catalyst used in step (b) is para-toluenesulfonic acid monohydrate.

[0475] In certain embodiments, the solvent used in step (b) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., benzene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), acetonitrile, halogenated solvents (e.g., dichloromethane, dichloroethane), carboxylic acids (e.g., acetic acid, propionic acid), sulfolane, and combinations thereof. In certain embodiments, the solvent used in step (b) is a carboxylic acid. In certain embodiments, the solvent used in step (b) is selected from the group consisting of diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, acetonitrile, dichloromethane, dichloroethane, acetic acid, propionic acid, sulfolane, and combinations thereof. In certain embodiments, the solvent used in step (b) is acetic acid.

[0476] In certain embodiments, step (b) is carried out at a temperature range of about 80° C. or less. In certain embodiments, step (b) is carried out at a temperature range of about 0° C. to about 80° C.

[0477] In certain embodiments, the acid used in step (c) is a mineral acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid), a sulfonic acid (e.g., methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid monohydrate), trifluoroacetic acid, phosphoric acid, levulinic acid, glyoxalic acid, or the like. The acid used in step (c) is selected from the group consisting of silicic acid, alkali metal bisulfites (e.g., sodium bisulfite, sodium metabisulfite, potassium bisulfite), and sodium dithionite. In certain embodiments, the acid used in step (c) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid monohydrate, trifluoroacetic acid, phosphoric acid, levulinic acid, glyoxylic acid, sodium bisulfite, sodium metabisulfite, potassium bisulfite, and sodium dithionite. In certain embodiments, the acid used in step (c) is a sulfonic acid. In certain embodiments, the acid used in step (c) is para-toluenesulfonic acid monohydrate.

[0478] In certain embodiments, the solvent used in step (c) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., benzene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), acetonitrile, halogenated solvents (e.g., dichloromethane, dichloroethane), ketones (e.g., methyl ethyl ketone, acetone, methyl isobutyl ketone), aldehydes (e.g., formaldehyde / formalin, acetaldehyde, isobutyraldehyde), water, and combinations thereof. In certain embodiments, the solvent used in step (c) is selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, acetonitrile, dichloromethane, dichloroethane, methyl ethyl ketone, acetone, methyl isobutyl ketone, formaldehyde / formalin, acetaldehyde, isobutyraldehyde, water, and combinations thereof. In certain embodiments, the solvent used in step (c) is methyl ethyl ketone and water.

[0479] In certain embodiments, step (c) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (c) is carried out at a temperature range of about 20° C. to about 100° C.

[0480] In some embodiments, the compound of formula 5a: [ka] or a co-crystal, solvate, or combination thereof, which process comprises preparing a compound of formula 4e: [ka] or a co-crystal, solvate, salt, or combination thereof, together with a catalyst, an acid, a base, a solvent, and optionally an additive to provide a compound of formula 5a or a co-crystal, solvate, or combination thereof; In Equation 5a, X 1 is selected from the group consisting of tosyloxy, chloro, bromo, iodo, mesyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2,4,6-triisopropylbenzenesulfonyloxy, acetoxy, trichloroacetoxy, and trifluoroacetoxy.

[0481] In certain embodiments, X 1 is tosyloxy.

[0482] In certain embodiments, the catalyst is selected from the group consisting of (8α,9S)-6'-methoxycinchonan-9-amine trihydrochloride, cinchona alkaloid derivatives, amino acids (e.g., D- or L-phenylglycine, D- or L-cyclopentylglycine, D- or L-proline), primary amines (e.g., 1-phenylethylamine), secondary amines (e.g., 2-methylpyrrolidine, 2,5-dimethylpyrrolidine), and aldolases. In certain embodiments, the catalyst is selected from the group consisting of (8α,9S)-6'-methoxycinchonan-9-amine trihydrochloride, cinchona alkaloid derivatives, D- or L-phenylglycine, D- or L-cyclopentylglycine, D- or L-proline, 1-phenylethylamine, 2-methylpyrrolidine, 2,5-dimethylpyrrolidine, and aldolases. In certain embodiments, the catalyst is (8α,9S)-6'-methoxycinchonan-9-amine trihydrochloride.

[0483] In certain embodiments, the acid is selected from the group consisting of carboxylic acids (e.g., acetic acid, trifluoroacetic acid, trichloroacetic acid, tartaric acid), sulfonic acids (e.g., camphorsulfonic acid), sulfuric acid, phosphonic acid, phosphoric acid, and triflic acid. In certain embodiments, the acid is selected from the group consisting of acetic acid, trifluoroacetic acid, trichloroacetic acid, tartaric acid, camphorsulfonic acid, sulfuric acid, phosphonic acid, phosphoric acid, and triflic acid. In certain embodiments, the acid is trifluoroacetic acid.

[0484] In certain embodiments, the base is selected from the group consisting of carboxylates (e.g., lithium acetate, sodium acetate, potassium acetate, lithium benzoate, sodium benzoate), carbonates (e.g., lithium bicarbonate, lithium carbonate, sodium bicarbonate, sodium carbonate), sulfates (e.g., lithium sulfate, sodium sulfate), phosphates (e.g., sodium phosphate, potassium phosphate), and organic amines (e.g., imidazole, triethylamine, DABCO). In certain embodiments, the base is selected from the group consisting of lithium acetate, sodium acetate, potassium acetate, lithium benzoate, sodium benzoate, lithium bicarbonate, lithium carbonate, sodium bicarbonate, sodium carbonate, lithium sulfate, sodium sulfate, sodium phosphate, potassium phosphate, imidazole, triethylamine, and DABCO. In certain embodiments, the base is lithium acetate.

[0485] In certain embodiments, the solvent is selected from the group consisting of alcohols (e.g., methanol, ethanol, 2-propanol), esters (e.g., ethyl acetate, butyl acetate, isobutyl acetate), ethers (e.g., diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., toluene, benzene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), water, and combinations thereof. In certain embodiments, the solvent is methanol, ethanol, 2-propanol, ethyl acetate, butyl acetate, isobutyl acetate, diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl In certain embodiments, the solvent is selected from the group consisting of methyl sulfoxide, dichloromethane, dichloroethane, chloroform, acetonitrile, propionitrile, butyronitrile, water, and combinations thereof. In certain embodiments, the solvent is 2-methyltetrahydrofuran and water. In certain embodiments, the solvent is 2-methyltetrahydrofuran.

[0486] In certain embodiments, the process includes an additive. In certain embodiments, the additive is an alcohol. In certain embodiments, the additive is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, and water. In certain embodiments, the additive is water.

[0487] In certain embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about −40° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of about 0° C. to about 40° C. In certain embodiments, the process is carried out at about 20° C.

[0488] In some embodiments, the compound of formula V-02: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) Equation 6d: [ka] or a co-crystal, solvate, salt, or combination thereof, in combination with a formyl source, a base, and a solvent to form a compound of formula 6a: [ka] or a co-crystal, solvate, salt, or combination thereof; (b) combining a compound of Formula 6a, or a co-crystal, solvate, salt, or combination thereof, with a reagent, a dehydrating reagent, and a solvent to obtain a compound of Formula 6b: [ka] or a co-crystal, solvate, salt, or combination thereof; (c) combining a compound of Formula 6b, or a co-crystal, solvate, salt, or combination thereof, with a hydrazine source and a solvent to form a compound of Formula 6c: [ka] or a co-crystal, solvate, salt, or combination thereof; (d) combining a compound of formula 6c, or a co-crystal, solvate, salt, or combination thereof, with an alkylating reagent, a base, a solvent, and optionally an alkylating additive to obtain a compound of formula VA: [ka] or a co-crystal, solvate, salt, or combination thereof; and (e) combining the compound of formula VA or a co-crystal, solvate, salt, or combination thereof with a boron coupling agent, a base, a palladium catalyst, and a solvent to provide a compound of formula V-02 or a co-crystal, solvate, salt, or combination thereof. Includes.

[0489] In certain embodiments, the formyl source used in step (a) is selected from the group consisting of carbon monoxide and hydrogen chloride; hydrogen cyanide and hydrogen chloride; metal cyanide and hydrogen chloride; phosphorus oxychloride; N,N-dimethylformamide; hexamine acetic acid; dichloromethyl methyl ether; and formamide. In certain embodiments, the formyl source used in step (a) is N,N-dimethylformamide.

[0490] In certain embodiments, the base used in step (a) is selected from the group consisting of sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide, sodium diisopropylamide or potassium diisopropylamide, lithium tetramethylpiperidide, and lithium amide or sodium amide. In certain embodiments, the base used in step (a) is lithium diisopropylamide. In certain embodiments, the base used in step (a) is lithium diisopropylamide, which is prepared in situ from diisopropylamine and n-butyllithium.

[0491] In certain embodiments, the solvent used in step (a) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform), non-polar solvents (e.g., hexane, heptane, cyclohexane), and combinations thereof. In certain embodiments, the solvent used in step (a) is tetrahydrofuran.

[0492] In certain embodiments, step (a) is carried out at a temperature range of about 60° C. or less. In certain embodiments, step (a) is carried out at a temperature range of about −80° C. to about 60° C. In certain embodiments, step (a) is carried out at a temperature range of about −30° C. to about 40° C.

[0493] In certain embodiments, the reagent used in step (b) is selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine-O-sulfonic acid, sodium azide, trifluoromethanesulfonic acid, and propylphosphonic anhydride. In certain embodiments, the reagent used in step (b) is hydroxylamine hydrochloride.

[0494] In certain embodiments, the dehydrating reagent used in step (b) is selected from the group consisting of acetic anhydride, an acid (e.g., formic acid, hydrochloric acid, sulfuric acid, citric acid, phosphoric acid), copper(II) acetate, and cyanuric chloride / dimethylformamide. In certain embodiments, the base used in step (b) is acetic anhydride.

[0495] In certain embodiments, the solvent used in step (b) is selected from the group consisting of acids (e.g., acetic acid, formic acid), polar solvents (e.g., dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, water, tert-butyl alcohol), non-polar solvents (e.g., toluene), and combinations thereof. In certain embodiments, the solvent used in step (b) is acetic acid.

[0496] In certain embodiments, step (b) is carried out at a temperature range of about 95° C. or less. In certain embodiments, step (b) is carried out at a temperature range of about 20° C. to about 95° C. In certain embodiments, step (b) is carried out at a temperature range of about 40° C. to about 70° C.

[0497] In certain embodiments, the hydrazine source used in step (c) is selected from the group consisting of hydrazine, hydrazine hydrochloride, hydrazine hydrobromide, hydrazine sulfate, and hydrazine acetate. In certain embodiments, the hydrazine source used in step (c) is hydrazine hydrate.

[0498] In certain embodiments, the solvent used in step (c) is selected from the group consisting of alcohols (e.g., ethanol, methanol, isopropanol), water, and combinations thereof. In certain embodiments, the solvent used in step (c) is water and isopropanol.

[0499] In certain embodiments, step (c) is carried out at a temperature range of about 85° C. or less. In certain embodiments, step (c) is carried out at a temperature range of about 75° C. to about 85° C.

[0500] In certain embodiments, the alkylating reagent used in step (d) is triflate The reagent used in step (d) is selected from the group consisting of 2,2,2-trifluoroethyl trifluoromethanesulfonate, 2,2,2-trifluoroethyl trichloromethanesulfonate, 1,1,1-trifluoro-2-iodoethane, 2-bromo-1,1,1-trifluoroethane, 1,1,1-trifluoro-2-chloroethane, 2,2,2-trifluoroethyl methanesulfonate, and 2,2,2-trifluoroethyl p-toluenesulfonate. In a specific embodiment, the reagent used in step (d) is 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0501] In certain embodiments, step (d) comprises an alkylation additive. In certain embodiments, the alkylation additive used in step (d) is selected from the group consisting of symmetrical quaternary ammonium salts (e.g., tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium hydrogen sulfate), asymmetrical quaternary ammonium salts (e.g., benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, benzyltributylammonium chloride, benzyltributylammonium bromide, benzyltributylammonium iodide, phenyltrimethylammonium chloride, phenyltrimethylammonium bromide, phenyltrimethylammonium iodide, decyltrimethylammonium bromide), lithium chloride, and phosphonium salts (e.g., methyltriphenoxyphosphonium iodide, tetrabutylphosphonium bromide).

[0502] In certain embodiments, the base used in step (d) is cesium carbonate, a lithium base (e.g., lithium hydroxide, lithium phosphate, lithium carbonate, lithium ethoxide, lithium methoxide, lithium trifluoromethanesulfonate), a sodium base (e.g., sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium pivalate, sodium propionate, sodium hydride), a potassium base (e.g., potassium phosphate, potassium hydroxide, potassium carbonate, potassium bicarbonate, potassium tert-butoxide, dipotassium phosphate, monopotassium phosphate, The base used in step (d) is selected from the group consisting of potassium acetate, potassium pivalate), calcium bases (e.g., calcium hydroxide, calcium carbonate), amine bases (e.g., triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, pyridine, 1-methylimidazole, imidazole, 2,6-lutidine, 4-methylmorpholine, 2,6-ditertbutylpyridine), and barium bases (e.g., barium hydroxide, barium carbonate). In certain embodiments, the base used in step (d) is a potassium base. In certain embodiments, the base used in step (d) is potassium phosphate.

[0503] In certain embodiments, the solvent used in step (d) is a polar aprotic solvent (e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, pyridine, dimethyl sulfoxide, sulfolane), a ketone solvent (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), a hydrocarbon solvent (e.g., toluene, heptane, hexane), an alcohol solvent (e.g., methanol, ethanol, isopropyl alcohol, tert-amyl alcohol, tert-butyl alcohol, 1-butanol, n-butanol), an ether solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether), an acetate solvent (e.g., ethyl acetate, isopropyl acetate), acetonitrile, dichloromethane, and the like. In certain embodiments, the solvent used in step (d) is a polar aprotic solvent. In certain embodiments, the solvent used in step (d) is N,N-dimethylformamide.

[0504] In certain embodiments, step (d) is performed at a temperature range of about 60° C. or less. In certain embodiments, step (d) is performed at a temperature range of about −20° C. to about 60° C. In certain embodiments, step (d) is performed at a temperature range of about 0° C. to about 40° C. In certain embodiments, step (d) is performed at about 20° C.

[0505] In certain embodiments, the boron coupling agent used in step (e) is selected from the group consisting of bis(pinacolato)diboron, bis(neopentylglycolato)diboron, bisboronic acid, and bis(ethyleneglycolatodiboron). In certain embodiments, the boron coupling agent used in step (e) is bis(pinacolato)diboron.

[0506] In certain embodiments, the base used in step (e) is selected from the group consisting of cesium acetate, potassium propionate, sodium propionate, potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, dipotassium phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine. In certain embodiments, the base used in step (e) is potassium acetate.

[0507] In certain embodiments, the palladium catalyst used in step (e) is selected from the group consisting of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, dichlorobis(triphenylphosphine)palladium(II), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II), and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II). In certain embodiments, the palladium catalyst used in step (e) is a palladium(II) catalyst (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or a palladium(0) catalyst (e.g., tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0)), and further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine). In certain embodiments, the palladium catalyst used in step (e) is bis(triphenylphosphine)palladium(II) dichloride.

[0508] In certain embodiments, the solvent used in step (e) is selected from the group consisting of ethers (e.g., 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylene), esters (e.g., ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate), alcohols (e.g., ethanol, isopropanol), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine), and combinations thereof. In certain embodiments, the solvent used in step (e) is toluene and N,N-dimethylformamide.

[0509] In certain embodiments, step (e) is carried out at a temperature range of about 120° C. or less. In certain embodiments, step (e) is carried out at a temperature range of about 20° C. to about 120° C. In certain embodiments, step (e) is carried out at a temperature range of about 95° C. to about 105° C.

[0510] In some embodiments, the compound of Formula 1b-02: [ka] or a co-crystal, solvate, salt, or combination thereof, comprising: (a) Equation 1j: [ka] or a co-crystal, solvate, salt, or combination thereof, together with an oxidizing agent, a base, a solvent, and optionally a catalyst, or optionally an additive, to form a compound of formula 1h: [ka] or a co-crystal, solvate, salt, or combination thereof; (b) hydrolyzing the compound of formula 1h, or a co-crystal, solvate, salt, or combination thereof, with a reagent and solvent to obtain a compound of formula 1a: [ka] or a co-crystal, solvate, salt, or combination thereof; (c) combining the compound of Formula 1a, or a co-crystal, solvate, salt, or combination thereof, with a bisulfite source and a solvent to form a compound of Formula 1i: [ka] or a co-crystal, solvate, salt, or combination thereof, wherein in formula 1i, M 2 is K + or Na + and (d) combining the compound of formula 1i, or a co-crystal, solvate, salt, or combination thereof, with benzhyhydrylamine, a base, and a solvent to provide a compound of formula 1b-02, or a co-crystal, solvate, salt, or combination thereof. Includes.

[0511] In certain embodiments, the oxidizing agent used in step (a) is selected from the group consisting of alkyl nitrite esters (e.g., iso-amyl nitrite, n-butyl nitrite, n-propyl nitrite, tert-butyl nitrite). In certain embodiments, the oxidizing agent used in step (a) is tert-butyl nitrite.

[0512] In certain embodiments, the base used in step (a) is selected from the group consisting of metal alkoxides (e.g., sodium tert-butoxide, sodium methoxide, sodium iso-propoxide, potassium tert-butoxide, potassium iso-propoxide, sodium ethoxide) and metal amides (e.g., potassium amide, sodium amide, LDA). In certain embodiments, the base used in step (a) is potassium tert-butoxide.

[0513] In certain embodiments, the solvent used in step (a) is selected from the group consisting of tetrahydrofuran, ethers (e.g., MTBE, diethyl ether, CPME), nitriles (e.g., acetonitrile), DMSO, and combinations thereof. In certain embodiments, the solvent used in step (a) is tetrahydrofuran.

[0514] In certain embodiments, step (a) includes a catalyst or additive. In certain embodiments, the catalyst or additive used in step (a) is selected from the group consisting of benzoic acid and a copper salt (e.g., copper diacetate).

[0515] In certain embodiments, step (a) does not include a catalyst or an additive.

[0516] In certain embodiments, step (a) is carried out at a temperature range of about 40° C. or less. In certain embodiments, step (a) is carried out at a temperature range of about −20° C. to about 40° C. In certain embodiments, step (a) is carried out at a temperature range of about 0° C. to about 10° C.

[0517] In certain embodiments, the reagent used in step (b) is selected from the group consisting of glyoxylic acid, pyruvic acid, sodium dithionite, sodium bisulfite, potassium metabisulfite, 3-methoxypropionic acid, sodium nitrite, nitrosyl chloride, tert-butyl nitrite, and potassium persulfate. In certain embodiments, the reagent used in step (b) is glyoxylic acid.

[0518] In certain embodiments, the solvent used in step (b) is selected from the group consisting of ketones (e.g., acetone, methyl ethyl ketone (MEK)), alcohols (e.g., methanol, ethanol), THF, water, and combinations thereof. In certain embodiments, the solvent used in step (b) is water.

[0519] In certain embodiments, step (b) is carried out at a temperature range of about 100° C. or less. In certain embodiments, step (b) is carried out at a temperature range of about 0° C. to about 100° C. In certain embodiments, step (b) is carried out at a temperature range of about 50° C. to about 90° C.

[0520] In certain embodiments, the bisulfite source used in step (c) is selected from the group consisting of potassium metabisulfite and sodium bisulfite, hi certain embodiments, the bisulfite source used in step (c) is potassium metabisulfite.

[0521] In certain embodiments, the solvent used in step (c) is selected from the group consisting of alcohols (e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, t-butanol), ethers (e.g., MTBE, THF, 2-methyltetrahydrofuran, CPME, diethyl ether, diisopropyl ether), water, and combinations thereof. In certain embodiments, the solvent used in step (c) is water and isopropanol.

[0522] In certain embodiments, step (c) is carried out at a temperature range of about 60° C. or less. In certain embodiments, step (c) is carried out at a temperature range of about 0° C. to about 60° C. In certain embodiments, step (c) is carried out at a temperature range of about 20° C. to about 30° C.

[0523] In certain embodiments, the base used in step (d) is selected from the group consisting of hydroxides (e.g., potassium hydroxide, sodium hydroxide), bicarbonates (e.g., potassium or sodium bicarbonate), carbonates (e.g., potassium or sodium carbonate), and phosphates (e.g., potassium or sodium phosphate, monobasic, dibasic, or tribasic). In certain embodiments, the base used in step (d) is potassium hydroxide.

[0524] In certain embodiments, the solvent used in step (d) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, xylene), chlorinated solvents (e.g., dichloromethane), water, and combinations thereof. In certain embodiments, the solvent used in step (d) is water and 2-methyltetrahydrofuran.

[0525] In certain embodiments, step (d) is carried out at a temperature range of about 120° C. or less. In certain embodiments, step (d) is carried out at a temperature range of about −20° C. to about 120° C. In certain embodiments, step (d) is carried out at a temperature range of about 20° C. to about 80° C.

[0526] In some embodiments, the compound of formula IX: [ka] or a co-crystal, solvate, salt, or combination thereof, the process comprising the step of: 3-chloro-3-methylbut-1-yne (3-CMB): [ka] with a reagent, a ligand, a solvent, an acid, and a catalyst to provide a compound of formula IX or a co-crystal, solvate, salt, or combination thereof.

[0527] In certain embodiments, the reagent is selected from the group consisting of sodium methanesulfinate, lithium methanesulfinate, and potassium methanesulfinate. In certain embodiments, the reagent is sodium methanesulfinate.

[0528] In certain embodiments, the reagent is selected from the group consisting of N,N,N',N'-tetramethylethylenediamine (TMEDA), L-proline, DMAP, 2,2'-bipyridine, TEA, DIPEA, pyridine, ethylenediamine, 1,2-diaminocyclohexane, and N,N'-dimethylcyclohexane-1,2-diamine. In certain embodiments, the ligand is N,N,N',N'-tetramethylethylenediamine.

[0529] In certain embodiments, the catalyst is selected from the group consisting of CuCl, CuCl2, CuBr, CuI, CuSO4, CuO, Cu2O, Cu(OAc), Cu(OAc)2, FeCl2, FeBr3, CuBr2, Cu(NO3)2, FeCl3, and Fe(NO3)3·9H2O. In certain embodiments, the catalyst is copper(II) acetate.

[0530] In certain embodiments, the solvent is selected from the group consisting of esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., toluene, benzene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide), polar protic solvents (e.g., methanol, ethanol, 2-propanol, t-butyl alcohol, sec-butyl alcohol, t-amyl alcohol), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform), nitriles (e.g., propionitrile, butyronitrile), ketones (e.g., acetone, 2-butanone, methyl isobutyl ketone), and combinations thereof. In certain embodiments, the solvent is isopropyl acetate.

[0531] In certain embodiments, the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, ammonium chloride, ammonium hydroxide, phosphoric acid, acetic acid, and citric acid. In certain embodiments, the acid is an aqueous acid. In certain embodiments, the acid is selected from the group consisting of 5% aqueous sulfuric acid, 5% aqueous hydrochloric acid, 10% aqueous ammonium chloride, 10% aqueous ammonium hydroxide, 5% aqueous phosphoric acid, 5% aqueous acetic acid, and 5% aqueous citric acid. In certain embodiments, the acid is 5% aqueous sulfuric acid.

[0532] In certain embodiments, the process is carried out at a temperature range of about 120° C. or less. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 120° C. In certain embodiments, the process is carried out at a temperature range of about 20° C. to about 60° C. In certain embodiments, the process is carried out at about 40° C.

[0533] In some embodiments, the compound of formula X: [ka] or a co-crystal, solvate, salt, or combination thereof, which process comprises preparing a compound of formula VIII: [ka] or an enantiomer of a compound of formula VIII, or a mixture of a compound of formula VIII and an enantiomer of a compound of formula VIII, or a co-crystal, solvate, salt, or a combination of any of the foregoing, with an aldehyde, a solvent, and one reagent selected from the group consisting of a metal catalyst and a base to provide a compound of formula X or a co-crystal, solvate, salt, or combination thereof.

[0534] In certain embodiments, the process involves contacting a compound of Formula VIII, an enantiomer of a compound of Formula VIII, or a mixture of a compound of Formula VIII and an enantiomer of a compound of Formula VIII, or a co-crystal, solvate, salt, or any combination of the foregoing, with an aldehyde, a solvent, and a metal catalyst to provide a compound of Formula X. In certain embodiments, the process involves contacting a compound of Formula VIII, an enantiomer of a compound of Formula VIII, or a mixture of a compound of Formula VIII and an enantiomer of a compound of Formula VIII. contacting the mixture with the omer, or the co-crystal, solvate, salt, or any combination of the above, with an aldehyde, a solvent, and a base to provide a compound of formula X.

[0535] In certain embodiments, the aldehyde is an aromatic aldehyde (e.g., benzaldehyde, 2,4-dichlorobenzaldehyde, 2-methoxybenzaldehyde, 4-(dimethylamino)benzaldehyde, 2-(dimethylamino)benzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, 2-hydroxy-5-nitrobenzaldehyde, 5-chloro-2-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 2-hydroxybenzaldehyde, 3,5-dichlorobenzaldehyde, 4-(dimethylamino) ... The aldehyde is selected from the group consisting of 2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, 2-hydroxy-3-nitrobenzaldehyde; heteroaromatic aldehydes (e.g., 2-formylpyridine, 3-(trifluoromethyl)picolinaldehyde, 4-chloropicolinaldehyde, nicotinaldehyde, quinolone-4-carbaldehyde, quinolone-2-carbaldehyde); and aliphatic aldehydes (e.g., formaldehyde, ethyl glyoxylate, glyoxylic acid). In certain embodiments, the aldehyde is 2-formylpyridine.

[0536] In certain embodiments, the metal catalyst is selected from the group consisting of zinc salts (e.g., zinc(II) oxide, zinc(II) acetate, zinc(II) trifluoromethanesulfonate, zinc(II) trifluoroacetate, zinc(II) chloride, zinc(II) stearate, zinc(II) neodecanoate, zinc(II) tetrafluoroborate); nickel salts (e.g., nickel(II) acetate, nickel(II) chloride, nickel(II) triflate); indium salts (e.g., indium(III) acetate); copper salts (e.g., copper(II) acetate); cobalt (e.g., cobalt(II) acetate); and manganese salts (e.g., manganese(II) acetate). In certain embodiments, the metal catalyst is zinc(II) acetate.

[0537] In certain embodiments, the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, DBU, DBN, DABCO, tetramethylguanidine, BEMP, and 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)-phosphoranylideneamino]-2λ 5 ,4λ 5 -catena di(phosphazene) (t-Bu-P4).

[0538] In certain embodiments, the solvent is selected from the group consisting of esters (e.g., ethyl acetate, isopropyl acetate), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aprotic solvents (e.g., acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), alcohols (e.g., methanol, ethanol, isopropanol), and combinations thereof. In certain embodiments, the solvent is toluene.

[0539] In certain embodiments, the process is carried out at a temperature range of about 100° C. or less. In certain embodiments, the process is carried out at a temperature range of about −20° C. to about 100° C. In certain embodiments, the process is carried out at a temperature range of about 20° C. to about 80° C. In certain embodiments, the process is carried out at about 60° C.

[0540] Alternative reagents and reaction conditions to those disclosed above can also be used, for example, other ethers (e.g., diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, benzene Alternative solvents may be used, such as toluene, hexane, xylene, nitriles (e.g., propionitrile, butyronitrile, acetonitrile), esters (e.g., ethyl acetate, n-butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide), alcohols (e.g., methanol, ethanol, 1-propanol, isopropanol, tert-amyl alcohol, n-butanol, sec-butanol), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform), hydrocarbon solvents (e.g., n-hexane, cyclohexane, n-heptane), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), and water. These reactions may also be carried out in combination with or without the above solvents. Additionally, temperatures ranging from about -80°C to about 130°C may be used.

[0541] In some embodiments, the compound of formula VI: [ka] or a co-crystal, solvate, or combination thereof.

[0542] In some embodiments, the compound of formula VIII: [ka] or a co-crystal, solvate, salt or combination thereof.

[0543] In certain embodiments, the compound of formula VIII has formula VIII-02: [ka] or a co-crystal, solvate, or combination thereof, wherein HX is a chiral or achiral acid.

[0544] In certain embodiments, HX is a chiral acid, such as L-lactic acid, L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(-)-malic acid, D-glucuronic acid, (1R,3S)-(+)-camphoric acid, (1S)-(+)-camphor-10-sulfonic acid, (R)-(+)-N-(1-phenylethyl)succinamic acid, carbobenzyloxy-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methyladipic acid, (+)-menthyl hydroxybenzoate, (R)-(+)-3-methyladipic acid, (R)-( ...3-methyladipic acid, (R)-(+)-3-methyladipic acid, (R)-(+)-3-methyladipic acid, (R)-(+)-3-methyladipic acid, (R In some embodiments, HX is selected from the group consisting of (R)-acetylacetic acid, (-)-pyroglutamic acid, (-)-n-acetyl-L-leucine, N-Boc-D-leucine, N-(+)-BOC-phenylalanine, (-)-quinic acid, (+)-n-acetyl-L-phenylalanine, (+)-N-BOC-isoleucine, L-(-)-acetylglutamic acid, (-)-acetylmandelic acid, (R)-(-)-citramalic acid, (-)-camphanic acid, and (R)-mandelic acid. In some embodiments, HX is (R)-mandelic acid. In some embodiments, HX is N-Boc-D-leucine.

[0545] In certain embodiments, HX is an achiral acid (i.e., a compound of formula VIII-04). In certain embodiments, HX is selected from the group consisting of sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and phosphoric acid. In some embodiments, HX is methanesulfonic acid.

[0546] In some embodiments, Formula IV: [ka] or a co-crystal, solvate, salt, or combination thereof.

[0547] In certain embodiments, the compound of formula III: [ka] or a co-crystal, solvate, salt, or combination thereof.

[0548] In certain embodiments, the compound of formula III is: [ka] or a co-crystal or solvate thereof, or a combination thereof.

[0549] In certain embodiments, the compound of formula III is: [ka] or a cocrystal thereof.

[0550] In certain embodiments, the compound of formula III is: [ka] or a cocrystal thereof.

[0551] In certain embodiments, Formula II: [ka] or a co-crystal, solvate, salt, or combination thereof. [Example]

[0552] Representative syntheses of compounds of the present disclosure are described in the following schemes and subsequent specific examples. The following examples are merely illustrative and are not intended to limit the present disclosure in any way. It is understood that the inventive steps described herein can be combined. It should also be understood that separate batches of compounds can be combined and carried over to the next synthetic step. I. Synthesis of Starting Materials and Intermediates Example 1a: Preparation of (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (VIII-02), or a co-crystal, solvate, salt, or combination thereof, and starting materials and / or intermediates therein [ka] where R 4 and R 5 are each independently hydrogen, methyl, phenyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzylamine, or 4-methoxybenzyl. Synthesis of 3,6-dibromopicolinaldehyde (1a) [ka]

[0553] A dry reaction flask equipped with a magnetic stir bar was charged with 2,5-dibromopyridine (1.0 g). The flask was made inert under nitrogen, THF (4.2 mL) was added, and the thin slurry was stirred. Separately, a dry glass reactor was charged with 2,2,6,6-tetramethylpiperidinyl magnesium chloride, lithium chloride complex (TMPMgCl·LiCl) (5.8 mL, 6.3 mmol). The TMPMgCl·LiCl solution was stirred and cooled to approximately −20 °C. The 2,5-dibromopyridine solution was added to the TMPMgCl·LiCl solution over approximately 30 minutes, maintaining the temperature below approximately −18 °C. After the addition was complete, the flask was rinsed with three additional portions of THF (1 mL × 2) and the reactor was aged at approximately −20 °C for approximately 1 hour. A solution of N,N-dimethylformamide (1.6 mL, 20 mmol) in THF (1.6 mL) was added to the reactor over approximately 15 minutes. The reaction mixture was aged for an additional 15 minutes, and then The reaction mixture was quenched by adding a solution of acetic acid (1.9 mL, 34 mmol) in water (10 mL) over approximately 20 minutes, maintaining the temperature below approximately 0°C. Isopropyl acetate (10 mL) was added to the reactor, and the reaction mixture was allowed to warm to approximately 20°C. After aging for 30 minutes, the mixture was filtered through diatomaceous earth, and the reactor was rinsed with a mixture of isopropyl acetate (10 mL), saturated aqueous ammonium chloride (10 mL), and 0.2 M aqueous hydrochloric acid (10 mL). The reactor rinse was filtered, and the pH of the combined reaction mixture was adjusted to approximately 8-9 by the addition of 10% aqueous sodium hydroxide solution (approximately 6 mL). The mixture was filtered a second time to remove magnesium salts and transferred to a separatory funnel. The phases were separated, and the aqueous phase was extracted with isopropyl acetate (3 × 10 mL). The combined organic extracts were washed with 50% saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, and filtered. The solution was concentrated to dryness by rotary evaporation and purified by chromatography (eluting with 0-100% ethyl acetate in heptane) to give 3,6-dibromopicolinaldehyde (1a) as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (q, J = 0.6 Hz, 1H), 8.19 (dq, J = 8.4, 0.6 Hz, 1H), 7.82 (dt, J = 8.4, 0.7 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 189.33, 148.59, 145.66, 140.17, 133.19, 120.27. Synthesis of 3,6-dibromopicolinaldehyde (1a) [ka]

[0554] A solution of 2,5-dibromo-6-methylpyridine (8.03 g) in THF (81 mL) was cooled to approximately 0° C. To this solution was charged tert-butyl nitrite (4.33 g), followed by dropwise addition of potassium tert-butoxide (28 mL, 1.5 equivalents, 20 wt % solution in THF). The reaction mixture was stirred at approximately 0° C. until the reaction was complete. The reaction mixture was diluted with THF (24 mL) and quenched with ammonium chloride (6.38 g, 119 mmol) in water (43 mL). The reaction mixture was vacuum distilled to approximately 55 mL to give a slurry, which was filtered and washed twice with water (2×24 mL) to give 1h. 1 H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H).

[0555] A solution of glyoxylic acid (407 L, 50 wt % in water) was heated to about 80° C., and 1h (40.69 kg, 145.4 mol) was added portionwise. The reaction mixture was held at this temperature until the reaction was complete. The reaction mixture was cooled to about 20° C., filtered, and the filter cake was washed with water until the filtrate had a pH of ≥ 5 to give 1a. 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 1H). Synthesis of (E)-N-benzhydryl-1-(3,6-dibromopyridin-2-yl)methanimine (1b-02) [ka]

[0556] Compound 1a (5.0 g, 18.0 mmol) in toluene (20 mL) was heated to approximately 50° C., and benzhydrylamine (3.47 g, 18.9 mmol) was added in one portion and stirred at this temperature until the reaction was deemed complete. Methanol (61 mL) was charged, and the reaction mixture was distilled to a volume of approximately 25 mL. Methanol (40 mL) was charged, and the reaction mixture was distilled to a volume of approximately 30 mL. The resulting slurry was filtered and rinsed with two portions of methanol (15 mL each), and dried under reduced pressure to provide 1b-02.

[0557] Alternatively, compound 1a (10.0 g, 37.8 mmol) in 2-methyltetrahydrofuran (50 mL) was heated to approximately 50° C., and benzhydrylamine (7.28 g, 39.7 mmol) was added dropwise. The reaction was stirred at this temperature until deemed complete. The reaction mixture was distilled to a volume of approximately 30 mL. To the reaction mixture was added heptane (100 mL) and seeds of 1b-02 (59.3 mg, 0.138 mmol). The resulting slurry was filtered, rinsed with two portions of heptane (2×20 mL), and dried under reduced pressure to provide 1b-02. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.44 - 7.40 (m, 4H), 7.38 - 7.32 (m, 4H), 7.28 - 7.22 (m, 2H), 5.88 (s, 1H). Synthesis of (E)-N-benzhydryl-1-(3,6-dibromopyridin-2-yl)methanimine (1b-02) [ka]

[0558] 1a (2.00 g) was combined with isopropanol (7.6 mL) and stirred at ambient temperature. To this mixture was added potassium metabisulfite (0.96 g) in water (3.8 mL) dropwise. The mixture was stirred for at least 90 minutes, and the resulting slurry was filtered. The filter cake was rinsed twice with isopropanol (6 mL, then 12 mL) to give 1i-1. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 5.48 - 5.38 (m, 2H).

[0559] 1i-1 (1.00 g) was combined with 2-methyltetrahydrofuran (3.5 mL) and stirred at ambient temperature. To this slurry was added potassium hydroxide (443.8 mg, 7.91 mmol) in water (4 mL), and the biphasic mixture was stirred for 2 h. The layers were separated, and the aqueous layer was extracted with additional 2-methyltetrahydrofuran (3.5 mL). To the combined organics was added benzhydrylamine (0.47 mL, 2.7 mmol). The mixture was concentrated in vacuo (ca. 300 mbar, bath at 45° C.) to a volume of approximately 3 mL. Heptane (7 mL) was added and the mixture was stirred. The resulting slurry was filtered to give 1b-02. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.44 - 7.40 (m, 4H), 7.38 - 7.32 (m, 4H), 7.28 - 7.22 (m, 2H), 5.88 (s, 1H) . Synthesis of (E)-N-benzhydryl-1-(3,6-dibromopyridin-2-yl)methanimine (1b-02) [ka]

[0560] Compound 1a (1.0 g) was added to a reactor, and toluene (6.0 mL) was added to the reactor. The mixture was stirred. Aminodiphenylmethane (0.73 g, 1.05 equivalents) was added to the reaction mixture. The jacket was heated to about 60° C., and the mixture was aged for about 1 hour. After about 1 hour, the mixture was carried on to the next step. 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 4H), 7.40 - 7.34 (m, 7H), 7.29 (td, J = 6.9, 6.5, 1.7 Hz, 5H), 7.22 - 7.16 (m, 3H), 5.81 (s, 1H). Synthesis of N-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-1,1-diphenylmethanimine (1d-02) [ka]

[0561] A solution of 1b-02 in toluene (1.0 g in 3.8 mL) was stirred in a reactor at approximately 60 °C. Tetrabutylammonium bromide (0.08 g, 0.10 equiv.) was added, 3,5-difluorobenzyl bromide (0.60 g, 1.20 equiv.) was added, and potassium hydroxide (50% in water, 1.3 g, 5 equiv.) was added. The mixture was aged for approximately 4 hours and sampled for conversion. When the reaction was complete, the aqueous phase was removed, and water (3.1 mL) was added to the reactor. The contents were stirred, and the phases were allowed to settle. The aqueous phase was removed, and the toluene solution of 1d-02 was carried over to the next step. 1 H NMR (400 MHz, chloroform-d) δ 7.78 (dd, J = 8.6, 1.0 Hz, 1H), 7.64 - 7.60 (m, 2H), 7.59 - 7.53 (m, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.47 (s, 0H), 7.45 (s, 0H), 7.43 (d, J = 0.7 Hz, 0H), 7.41 - 7.34 (m, 3H), 7.33 (t, J = 1.4 Hz, 1H), 7.28 (t, J = 7.3 Hz, 2H), 7.22 (s, 0H), 7.18 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 7.7, 1.7 Hz, 2H), 6.55 (dt, J = 9.0, 2.3 Hz, 1H), 6.50 (dd, J = 7.0, 4.9 Hz, 3H), 5.26 (s, 0H), 5.16 (t, J = 6.9 Hz, 1H), 3.32 (dd, J = 13.2, 6.6 Hz, 1H), 3.16 (dd, J = 13.1, 7.2 Hz, 1H). N-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)- Synthesis of 1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (X) from (3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (1d-02) [ka]

[0562] A solution of 1d-02 in toluene (1.0 g in 3.0 mL) was stirred in a reactor at approximately 60° C. Sulfuric acid (0.93 g, 5 equivalents) was diluted with water (3.5 mL) and added to the reactor. The mixture was aged for approximately 4 hours. When the reaction was complete, the aqueous phase was removed. The aqueous phase was recharged to the reactor, and heptane (2.5 mL) was added. The mixture was stirred, and stirring was stopped and the layers were allowed to settle. The aqueous phase was removed, and the heptane was discarded to drain. Toluene (5.0 mL) and potassium hydroxide (50% in water, 2.1 g, 10 equivalents) were added to the reactor. The acidic aqueous solution was added to the reactor. The mixture was stirred for approximately 10 minutes, and stirring was stopped and the layers were allowed to settle. The aqueous phase was discarded to drain. Water (2.5 mL) was added to the reactor and the mixture was stirred for about 5 minutes, then the stirring was stopped and the phases were allowed to settle. The aqueous phase was discarded to drain. The toluene solution of 1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (X) was carried on to the next step. 1 H NMR (400 MHz, Roform-d) δ 7.60 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.74 - 6.67 (m, 2H), 6.66 - 6.58 (m, 1H), 4.57 - 4.45 (m, 1H), 3.02 (dd, J = 13.5, 5.2 Hz, 1H), 2.72 (dd, J = 13.5, 8.6 Hz, 1H), 1.77 (s, 3H). Synthesis of (R)-2-hydroxy-2-phenylacetic acid (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (VIII-03) [ka]

[0563] A solution of X in toluene (1.0 g in 7.1 mL) was stirred in a reactor at approximately 60° C. The mixture was distilled to a minimum volume (2.9 mL) and methyl tert-butyl ether was added (7.1 mL). (R)-(−)-Mandelic acid (0.41 g, 1 equiv.) was added and the mixture was cooled to approximately 0° C. The newly formed slurry was filtered to give (R)-2-hydroxy-2-phenylacetic acid (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (VIII-03). 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 7.3 Hz, 2H), 7.28 - 7.14 (m, 4H), 7.01 (tt, J = 9.4, 2.3 Hz, 1H), 6.79 (d, J = 7.4 Hz, 3H), 4.77 (s, 1H), 4.55 (d, J = 6.6 Hz, 1H), 3.02 (s, 1H), 2.92 (d, J = 6.7 Hz, 2H), 1.05 (s, 2H). Synthesis of (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine N-acetyl-D-leucine (VIII-04) [ka]

[0564] A reactor was charged with X (15.0 g), N-acetyl-D-leucine (8.28 g), and zinc oxide (0.311 g). Toluene (375 mL) was charged to the reactor, followed by 2-pyridinecarboxaldehyde (183 μL). The mixture was aged at about 55° C. for about 6 hours and then held at about 35° C. for about 4 days. The mixture was cooled to about 0° C. and then held for about 17 hours. The product was isolated by filtration, and the filter cake was washed with cold toluene (2×75 mL). The filter cake was recharged to the reactor. Ethanol (150 mL) was added, and the mixture was distilled to remove residual toluene. Once the toluene was removed, the reactor volume was adjusted to about 90 mL with ethanol, and the mixture was cooled to about 25° C. Water (210 mL) was added over approximately 10 minutes, and the mixture was aged for approximately 12 hours. The slurry was filtered and the solid was dried to give VIII-04. 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.03 (tt, J = 9.5, 2.4 Hz, 1H), 6.87 (dtd, J = 8.4, 6.2, 2.2 Hz, 2H), 5.49 (s, 3H), 4.42 (dd, J = 7.9, 5.9 Hz, 1H), 4.18 (q, J = 7.8 Hz, 1H), 2.93 (dd, J = 13.3, 5.9 Hz, 1H), 2.85 (dd, J = 13.2, 8.0 Hz, 1H), 1.83 (s, 3H), 1.71 - 1.54 (m, 1H), 1.47 (dd, J = 8.4, 6.2 Hz, 2H), 0.88 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 174.72, 169.03, 162.07 (dd, J = 245.5, 13.3 Hz), 161.79, 143.51, 142.82 (t, J = 9.4 Hz), 139.72, 128.39, 119.30, 113.36 - 111.39 (m), 101.73 (t, J = 25.7 Hz), 55.19, 50.69, 41.74 (d, J = 2.3 Hz), 40.51, 24.36, 22.91, 22.44, 21.46. Example 1b: Preparation of alternative starting materials and intermediates for use in the formation of (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (VIII), or a co-crystal, solvate, salt, or combination thereof Synthesis of (R)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-ol (XII) [ka]

[0565] Compound XI (1.00 g) and (R)-RuCY-XylBINAP (16 mg, 0.05 equiv.) were placed in a stainless steel autoclave equipped with a glass inner tube. EtOH (1.0 mL) and IPA (1.0 mL) were added to the autoclave, followed by tert-BuOK (1.0 M solution in THF, 0.51 mL, 0.2 equiv.). After purging with H2, the autoclave was charged with 3 MPa (≈435 psi) of H2. The mixture was stirred at about 20 °C for about 10 hours. Concentrated aqueous HCl was added to the mixture, and the pH was adjusted to 2. 1 H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.80 -6.72 (m, 2H), 6.68 (tt, J = 9.2, 2.4 Hz, 1H), 5.16 (dd, J = 8.2, 3.4 Hz, 1H), 3.60 (br, 1H), 3.12 (dd, J = 13.8, 3.4 Hz, 1H), 2.81 (dd, J = 13.8, 8.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 162.8 (dd, J = 246.4, 12.9 Hz), 160.1, 143.0, 141.3 (t, J = 9.1 Hz), 139.8, 128.7 (t, J = 35.7 Hz), 117.9, 112.3 (m), 102.1 (t, J = 25.0 Hz), 72.0, 43.0. 19F NMR (376 MHz...

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[Claim 1] There is an urgent need for new antiretroviral agents.

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