Methods and intermediates for making therapeutic compounds useful in the treatment of retroviridae virus infections

Abstract

The present disclosure relates to processes and intermediates useful for preparing a compound of Formula (I), or a co-crystal, solvate, salt, or combination thereof:

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980026177.X, filed on February 15, 2019, entitled "Method and intermediate for preparing therapeutic compounds that can be used to treat retroviral virus infections".

[0002] Cross-references to related applications

[0003] This application claims the benefit of U.S. Provisional Application 62 / 710,575, filed February 16, 2018, the entire contents of which are incorporated herein by reference. Technical Field

[0004] This disclosure relates to methods and intermediates for synthesizing novel compounds for treating retroviral infections, including those caused by HIV. Background Technology

[0005] This disclosure generally relates to the field of organic synthetic methodologies for the preparation of antiviral compounds and their synthetic intermediates.

[0006] The family Retroviridae comprises positive single-stranded RNA viruses, including those from the subfamily Orthoretrovirinae, and those from the genera α-retroviruses, β-retroviruses, γ-retroviruses, δ-retroviruses, ε-retroviruses, lentiviruses, and foamy retroviruses that cause disease in many people and animals. Among lentiviruses, HIV-1 infection in humans leads to the depletion of helper T cells and immune dysfunction, resulting in immunodeficiency and vulnerability to opportunistic infections. Treatment of HIV-1 infection with highly active antiretroviral therapy (HAART) has been shown to effectively reduce viral load and significantly delay disease progression (Hammer, SM et al.; JAMA 2008, 300:555-570). However, these treatments may lead to the emergence of HIV strains resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559; Smith, RJ, et al., Science 2010, 327:697-701). Therefore, there is an urgent need to discover and synthesize new antiretroviral agents with activity against emerging drug-resistant HIV variants.

[0007] U.S. Patent Application No. 15 / 680,041 discloses novel compounds that can be used to treat retroviral infections, including those caused by HIV. One specific compound identified therein is a compound of Formula I:

[0008]

[0009] There is a need for improved synthetic methods and intermediates for the preparation of compounds of formula I and their cocrystals, solvates, salts, and combinations thereof. There is also a need for improved methods for preparing intermediate compounds that can be used to prepare compounds of formula I and their cocrystals, solvates, salts, and combinations thereof. These improved methods and intermediates can reduce the costs, time, and / or waste associated with existing methods for the preparation of compounds of formula I and their cocrystals, solvates, salts, and combinations thereof. Summary of the Invention

[0010] In some embodiments, this disclosure provides methods for preparing compounds of formula I or their eutectics, solvates, salts, or combinations thereof:

[0011]

[0012] Compound of Formula I can also be named or identified as: N-((S)-1-(3-(4-chloro-3-(methanesulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indol-7-yl)-6-(3-methyl-3-(methanesulfonyl)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-cyclopropenzo[3,4]cyclopentadienozo[1,2-c]pyrazol-1-yl)acetamide.

[0013] In some embodiments, methods for preparing compounds of formula I or their eutectics, solvates, salts, or combinations thereof are disclosed herein:

[0014]

[0015] The method includes:

[0016] (a) Compound VIII under alkynylation conditions:

[0017]

[0018] Or its eutectic, solvate, salt or combination thereof, with compounds of formula IX:

[0019]

[0020] Or its eutectic, solvate, or combination thereof, to provide a compound of formula VI:

[0021]

[0022] Or its eutectic, solvate, salt or combination thereof;

[0023] (b) Under amide coupling conditions, react the compound of formula VI or its eutectic, solvate, salt or combination thereof with the compound of formula VII:

[0024]

[0025] Or its eutectic, solvate, salt, or combination thereof, to provide a compound of formula IV:

[0026]

[0027] Or its eutectic, solvate, salt or combination thereof;

[0028] (c) Under palladium-catalyzed cross-coupling conditions, the compound of formula IV or its eutectic, solvate, salt, or combination thereof is reacted with a compound of formula V:

[0029]

[0030] Or its eutectic, solvate, salt or combination thereof, wherein R 1 B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF4K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O) are used to provide compounds of formula III:

[0031]

[0032] or its eutectic, solvate, salt or combination thereof; and

[0033] (d) Under methanesulfonation conditions, the compound of formula III or its eutectic, solvate, salt or combination thereof is combined with a methanesulfonating agent to provide the compound of formula I or its eutectic, solvate, salt or combination thereof.

[0034] In some embodiments, this document provides novel intermediates for forming compounds of formula I or their eutectics, solvates, salts or combinations thereof (e.g., intermediates of formulas II, III, IV, VI and VIII below).

[0035] Therefore, in one embodiment, a compound of formula II is provided:

[0036]

[0037] Or its eutectic, solvate, salt or combination thereof.

[0038] In another embodiment, a compound of formula III is provided:

[0039]

[0040] Or its eutectic, solvate, salt or combination thereof.

[0041] In another embodiment, a compound of formula IV is provided:

[0042]

[0043] Or its eutectic, solvate, salt or combination thereof.

[0044] In another embodiment, a compound of formula VI is provided:

[0045]

[0046] Or its eutectic, solvate, salt or combination thereof.

[0047] In another embodiment, a compound of formula VIII is provided:

[0048]

[0049] Or its eutectic, solvate, salt or combination thereof.

[0050] The synthetic routes and intermediates disclosed herein reduce the cost, time, and waste associated with the preparation of Formula I compounds and their cocrystals, solvates, salts, and combinations thereof. Furthermore, the synthetic methods disclosed herein provide the Formula I compounds with fewer steps compared to previous synthetic methods (e.g., avoiding urethane protection and amino deprotection), and introduce the transisomer in a sequence later than previous synthetic methods.

[0051] This document provides further embodiments of the present disclosure, including additional novel synthetic intermediates and methods for preparing such intermediates.

[0052] This article also covers the following items.

[0053] 1. A method for preparing a compound of formula VI or its eutectic, solvate, salt, or combination thereof:

[0054]

[0055] The method includes using a compound of formula VIII:

[0056]

[0057] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[0058] Compound of formula IX:

[0059]

[0060] Or its eutectic, solvate or combination thereof,

[0061] Alkali,

[0062] Solvent, and

[0063] catalyst,

[0064] To provide a compound of formula VI or a eutectic, solvate, salt or combination thereof.

[0065] 2. The method described in Project 1, wherein the compound of formula VIII is a compound of formula VIII-02:

[0066]

[0067] Or its eutectic, solvate or combination thereof, wherein HX is a chiral or achiral acid.

[0068] 3. The method described in Project 2, wherein HX is a chiral acid.

[0069] 4. The method described in Project 2 or 3, wherein HX is selected from 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)succinic acid, benzyloxycarbonyl-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methylhexanoic acid, (+)- Menthoxyacetic 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, (–)-acetylmynic acid, (R)-(–)-citric acid, (–)-camphoric acid, and (R)-mandelic acid.

[0070] 5. The method described in Project 2 or 3, wherein HX is (R)-mandelic acid.

[0071] 6. The method described in item 2 or 3, wherein HX is N-Boc-D-leucine or (–)-N-acetyl-D-leucine.

[0072] 7. The method described in Project 2, wherein HX is a non-chiral acid.

[0073] 8. The method described in item 2 or 7, wherein HX is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and phosphoric acid.

[0074] 9. The method of any one of items 1-8, wherein the catalyst is a palladium catalyst.

[0075] 10. The method of any one of items 1-8, wherein the catalyst is a copper catalyst.

[0076] 11. The method described in Project 9, wherein the palladium catalyst is selected from [(π-allyl)PdCl]2, Pd(acac)2, (SIPr)PdCl2, PdCl2(PPh3)2, PdCl2, Pd(OAc)2, PdCl2(CH3CN)2 and Pd2(dba)3, optionally combined with a tertiary phosphine selected from triphenylphosphine, tricyclohexylphosphine, tritertiary-tert-butylphosphine, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane and 1,1'-bis(diphenylphosphine)ferrocene.

[0077] 12. The method described in Item 11, wherein the palladium catalyst is PdCl2(PPh3)2.

[0078] 13. The method of Item 10, wherein the copper catalyst is selected from copper iodide (I), copper bromide (I), and copper chloride (I).

[0079] 14. The method described in any one of items 1-13, wherein the base is selected from triethylamine, diisopropylamine, ethyl diisopropylamine, 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.

[0080] 15. The method of any one of items 1-13, wherein the base is triethylamine.

[0081] 16. The method of any one of items 1-15, wherein the solvent is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, water, and combinations thereof.

[0082] 17. The method of any one of items 1-15, wherein the solvent is 2-methyltetrahydrofuran.

[0083] 18. The method of any one of items 1-17, wherein the method is performed in a temperature range of about 0°C to about 120°C.

[0084] 19. The method of any one of items 1-17, wherein the method is performed in a temperature range of about 50°C to about 80°C.

[0085] 20. A method for preparing a compound of formula IV or a eutectic, solvate, salt, or combination thereof:

[0086]

[0087] The method includes using a compound of formula VI:

[0088]

[0089] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[0090] Compound of Formula VII:

[0091]

[0092] Or its eutectic, solvate, salt or combination thereof,

[0093] Alkali,

[0094] Solvent,

[0095] Optional, coupling agent

[0096] And optionally, activator,

[0097] To provide a compound of formula IV or a eutectic, solvate, salt or combination thereof.

[0098] 21. The method described in Project 20, wherein the coupling agent is selected from 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, boric acid, tetramethyl orthosilicate, trimethoxysilane, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyl diimidazole, isobutyl chloroformate, diphenylphosphine chloride, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate, O-benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate, O-(7- (Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate, O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinium phosphonium hexafluorophosphate, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, and (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholinium-carbomonium hexafluorophosphate.

[0099] 22. The method of item 20, wherein the coupling agent is n-propylphosphonic anhydride.

[0100] 23. The method of Item 20, wherein the activator is selected from oxalyl chloride, thionyl chloride, neopentyl chloride, cyanuryl chloride, methanesulfonyl chloride and diphenylphosphine chloride.

[0101] 24. The method of any one of items 20-23, wherein the base is selected from triethylamine, tributylamine, ethyl diisopropylamine, N-methylmorpholine, pyridine, 2,6-dimethylpyridine and N-methylimidazole.

[0102] 25. The method of any one of items 20-23, wherein the base is triethylamine.

[0103] 26. The method of any one of items 20-25, wherein the solvent is selected from acetonitrile, ethyl acetate, n-butyl acetate, isopropyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, dichloroethane, chloroform, propionitrile, butyronitrile, and combinations thereof.

[0104] 27. The method of any one of items 20-25, wherein the solvent is acetonitrile.

[0105] 28. The method of any one of items 20-27, wherein the method is performed in a temperature range of about -20°C to about 120°C.

[0106] 29. The method of any one of items 20-27, wherein the method is performed in a temperature range of about 0°C to about 40°C.

[0107] 30. The method of any one of items 20-29, further comprising coupling additives.

[0108] 31. The method of Item 30, wherein the coupling additive is selected from 4-(dimethylamino)pyridine, N-hydroxysuccinimide, ethyl cyanohydroxyimino, 1-hydroxybenzotriazole, N-methylimidazole and 1-hydroxy-7-azabenzotriazole.

[0109] 32. A method for preparing a compound of formula III or its eutectic, solvate, salt, or combination thereof:

[0110]

[0111] The method includes using a compound of formula IV:

[0112]

[0113] Or its eutectic, solvate, salt or combination thereof, in combination with the following:

[0114] Compound of formula V:

[0115]

[0116] Or its eutectic, solvate, salt or combination thereof, wherein R 1 It is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O).

[0117] Palladium catalyst,

[0118] alkali, and

[0119] Solvent,

[0120] To provide the compound of formula III or its eutectic, solvate, salt or combination thereof.

[0121] 33. The method described in Project 32, wherein R 1It is B(OC(Me)2C(Me)2O).

[0122] 34. The method described in item 32 or 33, wherein the palladium catalyst is selected from dichlorobis(tricyclohexylphosphine)palladium(II), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II)dichloride, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II)dichlorobis(triphenylphosphine)palladium(II), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II)dichloride, [1,2-bis(diphenylphosphine)ethane]palladium(II)dichloride, dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium(II), chloro[(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II), [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II)methanesulfonate, PCy3PdG4, palladium chloride, palladium acetate, and palladium trifluoroacetate.

[0123] 35. The method of Item 28, further comprising a phosphine ligand, wherein the palladium catalyst is selected from palladium chloride, palladium acetate, palladium trifluoroacetate, dichloro(1,5-cyclooctadiene)palladium(II), allyl palladium(II) chloride dimer, palladium(II) acetylacetone, (tetra(triphenylphosphine)palladium(O) and bis(dibenzylacetone)palladium(O).

[0124] 36. The method of Item 35, wherein the phosphine ligand is selected from di-tert-butyl(4-dimethylaminophenyl)phosphine, dicyclohexyl(4-dimethylaminophenyl)phosphine, 1,2-bis(diphenylphosphine)ethane, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1,3-bis(diphenylphosphine)propane, ethylene bis(diphenylphosphine), 1,1'-ferrocene di-bis(diphenylphosphine), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene, tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine, tri-tert-butylphosphine, cyclohexyldi-tert-butylphosphine, and dicyclohexyltert-butylphosphine.

[0125] 37. The method described in item 32 or 33, wherein the palladium catalyst is dichlorobis(tricyclohexylphosphine)palladium(II).

[0126] 38. The method of any one of items 32-37, wherein the base is selected from potassium bicarbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, dipotassium hydrogen phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, and triethylamine.

[0127] 39. The method of any one of items 32-37, wherein the base is potassium bicarbonate.

[0128] 40. The method of any one of items 32-39, wherein the solvent is selected from n-butyl acetate, water, di-n-butyl ether, 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.

[0129] 41. The method of any one of items 32-39, wherein the solvent is a mixture of n-butyl acetate and water.

[0130] 42. The method of any one of items 32-41, wherein the method is performed in a temperature range of about 20°C to about 120°C.

[0131] 43. The method of any one of items 32-41, wherein the method is performed in a temperature range of about 75°C to about 95°C.

[0132] 44. The method of any one of items 32-43, further comprising:

[0133] (a) Combining the compound of formula III or its eutectic, solvate, salt or combination thereof with a second solvent and an acid to provide the compound of formula III-02 or its eutectic, solvate or combination thereof:

[0134]

[0135] HY is selected from 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

[0136] (b) The compound of formula III-02 or its eutectic, solvate or combination thereof is alkalized by combining the compound of formula III-02 or its eutectic, solvate or combination thereof with a second base and a third solvent to provide the compound of formula III or its eutectic, solvate or combination thereof to be free alkalized.

[0137] 45. The method described in Item 44, wherein HY is methanesulfonic acid.

[0138] 46. ​​The method of item 44 or 45, wherein the second solvent is selected from 1-propanol, isopropanol, ethanol, methanol, tert-amyl alcohol, acetonitrile, methyl isobutyl ketone, dichloromethane, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, toluene, and cyclopentylmethyl ether.

[0139] 47. The method of any one of items 44-46, wherein the compound of formula III-02 is produced as a solvate.

[0140] 48. The method of any one of items 44-46, wherein the compound of formula III-02 is produced as an ethanol solvate.

[0141] 49. The method of any one of items 44-46, wherein the compound of formula III-02 is produced as a 1-propanol solvate.

[0142] 50. The method of any one of items 44-49, wherein the compound of formula III-02 is produced in a temperature range of about -20°C to about 20°C.

[0143] 51. The method of any one of items 44-50, wherein the second base is selected from 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.

[0144] 52. The method of any one of items 44-50, wherein the second base is sodium hydroxide.

[0145] 53. The method of any one of items 44-52, wherein the third solvent is selected from water, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, toluene, xylene, ethyl acetate, isopropyl acetate, and combinations thereof.

[0146] 54. The method of any one of items 44-52, wherein the third solvent is 2-methyltetrahydrofuran and water.

[0147] 55. The method of any one of items 44-54, wherein the free alkalization step is carried out in a temperature range of about -20°C to about 80°C.

[0148] 56. The method of any one of items 44-54, wherein the free alkalization step is carried out in a temperature range of about 0°C to about 50°C.

[0149] 57. A method for preparing a compound of formula I or a eutectic, solvate, salt, or combination thereof:

[0150]

[0151]

[0152] The method includes using a compound of formula III:

[0153]

[0154] Or its eutectic, solvate, salt or combination thereof, in combination with the following:

[0155] Methanesulfonating reagent, and

[0156] Solvent,

[0157] To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

[0158] 58. The method of item 57, wherein the methanesulfonating agent is selected from methanesulfonyl chloride and methanesulfonic anhydride.

[0159] 59. The method described in item 57, wherein the methanesulfonating agent is methanesulfonic anhydride.

[0160] 60. The method of any one of items 57-59, wherein the solvent used in the methanesulfonation step is selected from ethyl acetate, isopropyl acetate, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, chloroform, dichloroethane, and combinations thereof.

[0161] 61. The method of any one of items 57-59, wherein the solvent used in the methanesulfonation step is cyclopentylmethyl ether.

[0162] 62. The method of any one of items 57-61, wherein the method is performed in a temperature range of about 20°C to about 120°C.

[0163] 63. The method of any one of items 57-61, wherein the method is performed in a temperature range of about 70°C to about 90°C.

[0164] 64. A method for preparing a compound of formula I or a eutectic, solvate, salt, or combination thereof:

[0165]

[0166] The method includes:

[0167] (a) To make compound III:

[0168]

[0169] Or its eutectic, solvate, salt, or combination thereof, combined with a methanesulfonating agent, a base, and a solvent, to provide a compound of formula II:

[0170]

[0171] or its eutectic, solvate, salt or combination thereof; and

[0172] (b) Hydrolyzing the compound of formula II or its eutectic, solvate, salt or combination thereof in a solvent with a nucleophile and optionally a phase-transfer catalyst to provide the compound of formula I or its eutectic, solvate, salt or combination thereof.

[0173] 65. The method of item 64, wherein the methanesulfonating agent is selected from methanesulfonyl chloride and methanesulfonic anhydride.

[0174] 66. The method of item 64, wherein the methanesulfonating agent is methanesulfonyl chloride.

[0175] 67. The method of any one of items 64-66, wherein the phase transfer catalyst is selected from tetra-n-butylammonium chloride, benzyltri-n-butylammonium bromide, 1-methylimidazolium hydrogen sulfate, tetra-n-butylammonium hydrogen sulfate and tetra-n-butylphosphonium chloride.

[0176] 68. The method of any one of items 64-66, wherein the phase transfer catalyst is tetra-n-butylammonium bisulfate.

[0177] 69. The method of any one of items 64-68, wherein the base is selected from N-methylmorpholine, tri-n-propylamine, ethyl diisopropylamine, tri-n-butylamine, triethylamine, pyridine, 2,6-dimethylpyridine, chloridine, sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium tert-amyl alcohol, and sodium tert-butoxide.

[0178] 70. The method of any one of items 64-68, wherein the base is triethylamine.

[0179] 71. The method of any one of items 64-70, wherein the solvent used in the methanesulfonation step is selected from diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof.

[0180] 72. The method of any one of items 64-70, wherein the solvent used in the methanesulfonation step is 2-methyltetrahydrofuran.

[0181] 73. The method of any one of items 64-72, wherein the methanesulfonation step is carried out in a temperature range of about -20°C to about 100°C.

[0182] 74. The method of any one of items 64-72, wherein the methanesulfonation step is carried out in a temperature range of about -10°C to about 20°C.

[0183] 75. The method of any one of items 64-74, wherein the nucleophile is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiol, N-acetylcysteine, sodium thiophene, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium tert-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine.

[0184] 76. The method of any one of items 64-74, wherein the nucleophile is sodium hydroxide.

[0185] 77. The method of any one of items 64-76, wherein the solvent used in the hydrolysis step is selected from water, methanol, ethanol, isopropanol, 1-propanol, n-butanol, sec-butanol, 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.

[0186] 78. The method of any one of items 64-76, wherein the solvent used for the hydrolysis step is water and 2-methyltetrahydrofuran.

[0187] 79. The method of any one of items 64-78, wherein the hydrolysis step is carried out in a temperature range of about -20°C to about 100°C.

[0188] 80. The method of any one of items 64-78, wherein the hydrolysis step is carried out in a temperature range of about 10°C to about 60°C.

[0189] 81. A method for preparing a compound of formula I or a eutectic, solvate, salt, or combination thereof:

[0190]

[0191] The method includes:

[0192] (a) Compound VIII under alkynylation conditions:

[0193]

[0194] Or its eutectic, solvate, salt, or combination with compounds of formula IX:

[0195]

[0196] Or its eutectic, solvate, or combination thereof, to provide a compound of formula VI:

[0197]

[0198] Or its eutectic, solvate, salt or combination thereof;

[0199] (b) Under amide coupling conditions, react the compound of formula VI or its eutectic, solvate, salt or combination thereof with the compound of formula VII:

[0200]

[0201] Or its eutectic, solvate, salt, or combination thereof, to provide a compound of formula IV:

[0202]

[0203] Or its eutectic, solvate, salt or combination thereof;

[0204] (c) Combining the compound of formula IV or its eutectic, solvate, salt or combination thereof with the compound of formula V or its eutectic, solvate, salt or combination thereof under palladium-catalyzed cross-coupling conditions:

[0205]

[0206] Where R 1 B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O) are used to provide compounds of formula III:

[0207]

[0208] or its eutectic, solvate, salt or combination thereof; and

[0209] (d) Under methanesulfonation conditions, the compound of formula III or its eutectic, solvate, salt or combination thereof is combined with a methanesulfonating agent to provide the compound of formula I or its eutectic, solvate, salt or combination thereof.

[0210] 82. The method described in item 81, further comprising:

[0211] (a) By combining the compound of formula I with a sodium source and a solvent, a sodium salt of the compound of formula I is formed to provide the compound of formula I-02:

[0212]

[0213] (b) Neutralize the compound of formula I-02 with an acid and a solvent to provide the compound of formula I.

[0214] 83. The method of Item 82, wherein the sodium source is selected from sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium phosphate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium tert-butoxide, sodium hexamethyldisilazane, and metallic sodium and alcohols selected from methanol, ethanol, isopropanol, 1-propanol, n-butanol and sec-butanol.

[0215] 84. The method described in item 82, wherein the sodium source is sodium hydroxide.

[0216] 85. The method of any one of items 82-84, wherein the solvent used in the salt formation step is selected from diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, n-heptane, toluene, xylene, ethyl acetate, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropanol, 1-propanol, n-butanol, sec-butanol, and combinations thereof.

[0217] 86. The method of any one of items 82-84, wherein the solvent used in the salt formation step is ethanol and n-heptane.

[0218] 87. The method of any one of items 82-86, wherein the salt formation step is carried out in a temperature range of about -20°C to about 100°C.

[0219] 88. The method of any one of items 82-86, wherein the salt formation step is carried out in a temperature range of about 0°C to about 50°C.

[0220] 89. The method of any one of items 82-88, wherein the acid used in the neutralization step is selected from 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.

[0221] 90. The method of any one of items 82-88, wherein the acid used in the neutralization step is acetic acid.

[0222] 91. The method of any one of items 82-90, wherein the neutralization step is carried out in a temperature range of about -20°C to about 100°C.

[0223] 92. The method of any one of items 82-90, wherein the neutralization step is carried out in a temperature range of about 0°C to about 50°C.

[0224] 93. The method of any one of items 82-92, wherein the solvent in step (b) is water and ethanol.

[0225] 94. A method for preparing a compound of formula I or a eutectic, solvate, salt, or combination thereof:

[0226]

[0227] The method includes:

[0228] (a) To combine the following:

[0229] Compounds of formula IV:

[0230]

[0231] Or its eutectic, solvate, salt or combination thereof, with compounds of formula V-04-A:

[0232]

[0233] Or its eutectic, 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)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O),

[0234] Alkali,

[0235] Solvent, and

[0236] catalyst,

[0237] To provide compounds of formula II:

[0238]

[0239] or its eutectic, solvate, salt or combination thereof; and

[0240] (b) Hydrolyzing the compound of formula II or its eutectic, solvate, salt or combination thereof with a base, solvent and optionally a phase transfer catalyst to provide the compound of formula I or its eutectic, solvate, salt or combination thereof.

[0241] 95. The method described in Project 94, wherein R is B(OC(Me)2C(Me)2O).

[0242] 96. The method described in item 94 or 95, wherein the catalyst used in step (a) is selected from bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, [1,2-bis(diphenylphosphino)ethane]palladium(II) dichloride, and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)oxanthracene]palladium(II).

[0243] 97. The method of any one of items 94-96, wherein the catalyst used in step (a) is selected from palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetra(triphenylphosphine) palladium(O) and bis(dibenzylideneacetone) palladium(O).

[0244] 98. The method of any one of items 94-97, wherein the catalyst further comprises a phosphine ligand selected from tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine and dicyclohexylphenylphosphine.

[0245] 99. The method of any one of items 94-98, wherein the palladium catalyst used in step (a) is palladium(II) chloride and cyclohexyldiphenylphosphine.

[0246] 100. The method of any one of items 94-99, wherein the base used in step (a) is selected from 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 hydrogen phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine and diisopropylethylamine.

[0247] 101. The method of any one of items 94-100, wherein the base used in step (a) is sodium hydroxide or potassium bicarbonate.

[0248] 102. The method of any one of items 94-101, wherein the solvent used in step (a) is selected from 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.

[0249] 103. The method of any one of items 94-102, wherein the solvent used in step (a) is 2-methyltetrahydrofuran and water.

[0250] 104. The method of any one of items 94-103, wherein step (a) is carried out in a temperature range of about 20°C to about 120°C.

[0251] 105. The method of any one of items 94-104, wherein the base used in step (b) is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, bicarbonate, sodium bicarbonate, potassium bicarbonate, benzyltrimethylammonium hydroxide, choline hydroxide, sodium or potassium methoxide, sodium or potassium ethoxide, triethylamine, DABCO, DBU and diethylamine.

[0252] 106. The method of any one of items 94-105, wherein the base used in step (b) is sodium hydroxide.

[0253] 107. The method of any one of items 94-106, wherein the solvent used in step (b) is selected from 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.

[0254] 108. The method of any one of items 94-107, wherein the solvent used in step (b) is 2-methyltetrahydrofuran.

[0255] 109. The method of any one of items 94-108, wherein the phase transfer catalyst used in step (b) is selected from tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium hydrogen sulfate and tetrabutylphosphonium chloride.

[0256] 110. The method of any one of items 94-109, wherein step (b) is carried out in a temperature range of about 10°C to about 60°C.

[0257] 111. A method for preparing a compound of formula I or a eutectic, solvate, salt, or combination thereof:

[0258]

[0259] The method combines the following:

[0260] Compounds of formula IV or their eutectics, solvates, salts, or combinations thereof:

[0261]

[0262] With compounds of formula V-03-A or their eutectic, solvate, salt or combination thereof:

[0263]

[0264] Where R is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O).

[0265] Alkali,

[0266] Solvent, and

[0267] catalyst,

[0268] To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

[0269] 112. The method described in Project 111, wherein R is B(OC(Me)2C(Me)2O).

[0270] 113. The method of any one of items 111-112, wherein the catalyst is selected from bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, [1,2-bis(diphenylphosphine)ethane]palladium(II) dichloride, and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)oxanthracene]palladium(II); or

[0271] The catalyst is selected from palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetra(triphenylphosphine)palladium(O) and bis(dibenzylideneacetone)palladium(O) and the catalyst further comprises a phosphine ligand selected from tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine and dicyclohexylphenylphosphine.

[0272] 114. The method of any one of items 111-113, wherein the catalyst is palladium(II) chloride and cyclohexyldiphenylphosphine.

[0273] 115. The method of any one of items 111-114, wherein the base is selected from 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 hydrogen phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine.

[0274] 116. The method of any one of items 111-115, wherein the base is potassium bicarbonate.

[0275] 117. The method of any one of items 111-116, wherein the solvent is selected from 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.

[0276] 118. The method of any one of items 111-117, wherein the solvent is 2-methyltetrahydrofuran and water.

[0277] 119. The method of any one of items 111-118, wherein the method is performed in a temperature range of about 20°C to about 120°C.

[0278] 120. A method for preparing a compound of the formula V-03-A or its eutectic, solvate, salt, or combination thereof:

[0279]

[0280] The method includes:

[0281] (a) Make compound V:

[0282]

[0283] Or its eutectic, 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)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O), combined with a methanesulfonating agent, a base, and a solvent to provide compound V-04-A:

[0284]

[0285] or its eutectic, solvate, salt or combination thereof; and

[0286] (b) Hydrolyzing the compound of formula V-04-A or its eutectic, solvate, salt or combination thereof with a nucleophile, solvent and optionally a phase-transfer catalyst to provide the compound of formula V-03-A or its eutectic, solvate, salt or combination thereof.

[0287] 121. The method described in Project 120, wherein R is B(OC(Me)2C(Me)2O).

[0288] 122. The method of item 120 or 121, wherein the methanesulfonating agent used in step (a) is methanesulfonic anhydride or methanesulfonyl chloride.

[0289] 123. The method of any one of items 120-122, wherein the base used in step (a) is selected from triethylamine, N-methylmorpholine, tri-n-propylamine, ethyl diisopropylamine, tri-n-butylamine, pyridine, 2,6-dimethylpyridine, chloridine, sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium tert-amyl alcohol, and sodium tert-butoxide.

[0290] 124. The method of any one of items 120-123, wherein the base used in step (a) is triethylamine.

[0291] 125. The method of any one of items 120-124, wherein the solvent used in step (a) is selected from diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof.

[0292] 126. The method of any one of items 120-125, wherein the solvent used in step (a) is 2-methyltetrahydrofuran.

[0293] 127. The method of any one of items 120-126, wherein step (a) is carried out in a temperature range of about -20°C to about 100°C.

[0294] 128. The method of any one of items 120-127, wherein the nucleophile used in step (b) is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiol, N-acetylcysteine, sodium thiophene, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium tert-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine.

[0295] 129. The method of any one of items 120-128, wherein the nucleophile used in step (b) is sodium hydroxide.

[0296] 130. The method of any one of items 120-129, wherein the solvent used in step (b) is selected from 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.

[0297] 131. The method of any one of items 120-130, wherein the solvent used in step (b) is 2-methyltetrahydrofuran and water.

[0298] 132. The method of any one of items 120-131, wherein the phase transfer catalyst used in step (b) is selected from tetrabutylammonium bisulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium bisulfate and tetrabutylphosphonium chloride.

[0299] 133. The method of any one of items 120-132, wherein the phase transfer catalyst used in step (b) is tetrabutylammonium bisulfate.

[0300] 134. The method of any one of items 120-133, wherein step (b) is carried out in a temperature range of about -20°C to about 100°C.

[0301] 135. A method for preparing a compound of formula V-5 or its eutectic, solvate, salt, or combination thereof:

[0302]

[0303] The method includes:

[0304] (a) To make a compound of formula VA or its eutectic, solvate, salt or combination thereof:

[0305]

[0306] Combined with methanesulfonating agents, bases, and solvents to provide V-6 compounds:

[0307]

[0308] or its eutectic, solvate, salt or combination thereof; and

[0309] (b) Hydrolyzing the compound of formula V-6 or its eutectic, solvate, salt or combination thereof with a nucleophile, solvent and optionally a phase-transfer catalyst to provide the compound of formula V-5 or its eutectic, solvate, salt or combination thereof.

[0310] 136. The method of item 135, wherein the methanesulfonating agent used in step (a) is methanesulfonic anhydride or methanesulfonyl chloride.

[0311] 137. The method of any one of items 135-136, wherein the base used in step (a) is selected from triethylamine, N-methylmorpholine, tri-n-propylamine, ethyl diisopropylamine, tri-n-butylamine, pyridine, 2,6-dimethylpyridine, chloridine, sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium tert-amyl alcohol, and sodium tert-butoxide.

[0312] 138. The method of any one of items 135-137, wherein the base used in step (a) is triethylamine.

[0313] 139. The method of any one of items 135-138, wherein the solvent used in step (a) is selected from diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof.

[0314] 140. The method of any one of items 135-139, wherein the solvent used in step (a) is 2-methyltetrahydrofuran.

[0315] 141. The method of any one of items 135-140, wherein step (a) is carried out in a temperature range of about -20°C to about 100°C.

[0316] 142. A method for preparing a compound of the formula V-04-A or its eutectic, solvate, salt, or combination thereof:

[0317]

[0318] Where R is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O).

[0319] The method includes making a compound of formula V-6 or its eutectic, solvate, salt, or combination thereof:

[0320]

[0321] Combined with boron coupling agents, bases, solvents, and catalysts to provide the V-04-A compound or its eutectic, solvate, salt, or combination thereof.

[0322] 143. The method described in Project 142, wherein R is B(OC(Me)2C(Me)2O).

[0323] 144. The method of any one of items 142-143, wherein the boron coupling agent is selected from bis(pinacol)diboron, bis(neopentylethylene glycol)diboron, bisboronic acid, and bis(vinyl glycolate diboron).

[0324] 145. The method of any one of items 142-144, wherein the base is selected from 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 hydrogen phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine.

[0325] 146. The method of any one of items 142-145, wherein the base is potassium acetate.

[0326] 147. The method of any one of items 142-146, wherein the solvent is selected from 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.

[0327] 148. The method of any one of items 142-147, wherein the solvent is toluene and N,N-dimethylformamide.

[0328] 149. The method of any one of items 142-148, wherein the catalyst is selected from bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) dichloride, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, [1,2-bis(diphenylphosphino)ethane]palladium(II) dichloride, and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)oxanthracene]palladium(II).

[0329] 150. The method of any one of items 142-149, wherein the catalyst is palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetra(triphenylphosphine)palladium(O) or bis(dibenzylacetone)palladium(O); and the catalyst optionally further comprises a phosphine ligand selected from tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine and dicyclohexylphenylphosphine.

[0330] 151. The method of any one of items 142-150, wherein the catalyst is bis(triphenylphosphine)palladium(II) dichloride.

[0331] 152. The method of any one of items 142-151, wherein the method is performed in a temperature range of about 20°C to about 120°C.

[0332] 153. A method for preparing a compound of formula V-5 or its eutectic, solvate, salt, or combination thereof:

[0333]

[0334] The method includes hydrolyzing a V-6 compound or its eutectic, solvate, salt, or combination thereof using a base, solvent, and optionally a phase-transfer catalyst.

[0335]

[0336] To provide the compound of formula V5 or its eutectic, solvate, salt or combination thereof.

[0337] 154. The method described in Item 153, wherein the base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiol, N-acetylcysteine, sodium thiophene, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium tert-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine.

[0338] 155. The method of any one of items 153-154, wherein the base is sodium hydroxide.

[0339] 156. The method of any one of items 153-155, wherein the solvent is selected from 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.

[0340] 157. The method of any one of items 153-156, wherein the solvent is 2-methyltetrahydrofuran and water.

[0341] 158. The method of any one of items 153-157, wherein the phase transfer catalyst is selected from tetrabutylammonium bisulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium bisulfate, phosphonium salt and tetrabutylphosphonium chloride.

[0342] 159. The method of any one of items 153-158, wherein the phase transfer catalyst is tetrabutylammonium bisulfate.

[0343] 160. The method of any one of items 153-159, wherein the method is performed in a temperature range of about 10°C to about 60°C.

[0344] 161. A method for preparing a compound of the formula V-03-A or its eutectic, solvate, salt, or combination thereof:

[0345]

[0346] Where R is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O).

[0347] The method includes making a compound of formula V-5 or its eutectic, solvate, salt, or combination thereof:

[0348]

[0349] Combined with boron coupling agents, bases, solvents, and catalysts to provide the V-03-A compound or its eutectic, solvate, salt, or combination thereof.

[0350] 162. The method described in Project 161, wherein R is B(OC(Me)2C(Me)2O).

[0351] 163. The method of any one of items 161-162, wherein the boron coupling agent is selected from bis(pinacol)diboron, bis(neopentylethylene glycol)diboron, bisboronic acid, and bis(vinyl glycolate diboron).

[0352] 164. The method of any one of items 161-163, wherein the boron coupling agent is bis(pinacol)diboron.

[0353] 165. The method of any one of items 161-164, wherein the base is selected from 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 hydrogen phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine.

[0354] 166. The method of any one of items 161-165, wherein the base is potassium acetate.

[0355] 167. The method of any one of items 161-166, wherein the solvent is selected from 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.

[0356] 168. The method of any one of items 161-167, wherein the solvent is toluene and N,N-dimethylformamide.

[0357] 169. The method of any one of items 161-168, wherein the catalyst is selected from bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, [1,2-bis(diphenylphosphine)ethane]palladium(II) dichloride, dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium(II), or wherein the catalyst comprises palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetra(triphenylphosphine)palladium(O) or bis(dibenzylideneacetone)palladium(O), and the catalyst optionally further comprises a phosphine ligand selected from tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine and dicyclohexylphenylphosphine.

[0358] 170. The method of any one of items 161-169, wherein the palladium catalyst is bis(triphenylphosphine)palladium(II) dichloride.

[0359] 171. The method of any one of items 161-170, wherein the method is performed in a temperature range of about 20°C to about 120°C.

[0360] 172. A method for preparing a compound of formula VIII or its eutectic, solvate, salt, or combination thereof:

[0361]

[0362]

[0363] The method includes resolving compound X in a solvent with a chiral or achiral acid, optionally in the presence of an aldehyde catalyst and / or optionally a metal catalyst.

[0364]

[0365] Or its eutectic, solvate, salt or combination thereof, to provide a compound of formula VIII or its eutectic, solvate or salt or combination thereof.

[0366] 173. The method described in item 172, wherein the compound of formula VIII is a compound of formula VIII-02:

[0367]

[0368] Or its eutectic, solvate or combination thereof, wherein HX is a chiral acid.

[0369] 174. The method described in item 172 or 173, wherein HX is selected from 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)succinic acid, benzyloxycarbonyl-L-proline, dibenzoyl-L-tartaric acid, and (R)-(+)-3-methylhexanoic acid. (+)-Menthoxyacetic 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, (–)-acetylmynic acid, (R)-(–)-citric acid, (–)-camphoric acid and (R)-mandelic acid.

[0370] 175. The method of any one of items 172-174, wherein HX is N-Boc-D-leucine or (–)-N-acetyl-D-leucine.

[0371] 176. The method of any one of items 172-175, wherein HX is (R)-mandelic acid.

[0372] 177. The method of any one of items 172-176, wherein the solvent is selected from n-heptane, ethyl acetate, butyl acetate, isobutyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, xylene, toluene, dichloromethane, dichloroethane, chloroform, methanol, ethanol, 2-propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile, water, and combinations thereof.

[0373] 178. The method of any one of items 172-177, wherein the solvent is methyl tert-butyl ether and toluene, or toluene.

[0374] 179. The method of any one of items 172-178, wherein the method is performed in a temperature range of about -20°C to about 120°C.

[0375] 180. The method of any one of items 172-179, wherein the method is performed in a temperature range of about -20°C to about 50°C.

[0376] 181. The method of any one of items 172-180, wherein the compound of formula X is treated with a base in a first solvent prior to resolution.

[0377] 182. The method described in Item 181, wherein the base is selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, ammonium hydroxide, dipotassium hydrogen phosphate, tripotassium phosphate, disodium hydrogen phosphate, and trisodium phosphate.

[0378] 183. The method described in item 181 or 182, wherein the base is sodium hydroxide.

[0379] 184. The method of any one of items 181-183, wherein the first solvent is selected from diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, aromatic solvents, dichloromethane, and combinations thereof.

[0380] 185. The method of any one of items 181-184, wherein the first solvent is 2-methyltetrahydrofuran.

[0381] 186. The method of any one of items 181-185, wherein the compound of formula X is treated with a base in a first solvent in a temperature range of about 0°C to about 100°C.

[0382] 187. The method of any one of items 172-180, further comprising:

[0383] (a) Condensation of compound of form 1a or its eutectic, solvate, salt or combination thereof in a solvent with aminodiphenylmethane:

[0384]

[0385] Optionally, in the presence of an additive, to provide a compound of formula 1b-02:

[0386]

[0387] Or its eutectic, solvate, salt or combination thereof;

[0388] (b) Alkylating the compound of formula 1b-02 or its eutectic, solvate, salt or combination thereof with a compound of formula 1c in a solvent in the presence of a base and optionally a phase-transfer catalyst:

[0389]

[0390] Where Y is Br, Cl, I, OMs, OTs, or OSO2CF3 to provide compounds of formula 1d-02:

[0391]

[0392] or its eutectic, solvate, salt or combination thereof; and

[0393] (c) Deprotecting the compound of formula 1d-02 in a solvent with an acid to provide compound of formula X:

[0394]

[0395] Or its eutectic, solvate, salt or combination thereof.

[0396] 188. The method of item 187, wherein the solvent used in the condensation step is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, xylene, toluene, and dichloromethane.

[0397] 189. The method of item 187 or 188, wherein the solvent used in the condensation step is toluene.

[0398] 190. The method of any one of items 187-189, wherein the additive used in the condensation step is a dehydrating agent.

[0399] 191. The method of any one of items 187-189, wherein the additive used in the condensation step is magnesium sulfate.

[0400] 192. The method of any one of items 187-191, wherein the condensation step is performed in a temperature range of about -20°C to about 120°C.

[0401] 193. The method of any one of items 187-192, wherein the condensation step is performed in a temperature range of about 20°C to about 90°C.

[0402] 194. The method of any one of items 187-193, wherein Y is Br, Cl or I.

[0403] 195. The method of any one of items 187-194, wherein Y is Br.

[0404] 196. The method of any one of items 187-195, wherein the base used in the alkylation step is selected from 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]octane, isopropyl magnesium chloride lithium chloride complex, sec-butyl magnesium chloride lithium chloride complex, n-butyllithium, N,N-dimethylaminoethanol lithium complex, isopropylidene acetone lithium, diisopropylaminolithium and phenyllithium.

[0405] 197. The method of any one of items 187-196, wherein the base used in the alkylation step is potassium hydroxide.

[0406] 198. The method of any one of items 187-197, wherein the phase transfer catalyst used in the alkylation step is selected from tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetramethylammonium bisulfate, tetraethylammonium chloride, tetraethylammonium bromide, tetra-n-butylammonium bromide, tetraethylammonium iodide, tetraethylammonium bisulfate and benzyltrimethylammonium.

[0407] 199. The method of any one of items 187-198, wherein the phase transfer catalyst used for the alkylation step is tetrabutylammonium bromide.

[0408] 200. The method of any one of items 187-199, wherein the solvent used in the alkylation step is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, benzene, xylene, toluene, dichloromethane, water, and combinations thereof.

[0409] 201. The method of any one of items 187-200, wherein the solvent used for the alkylation step is toluene and water.

[0410] 202. The method of any one of items 187-201, wherein the compound of formula 1c is selected from 3,5-difluorobenzyl bromide, 3,5-difluorobenzyl chloride, 3,5-difluorobenzyl methanesulfonate, 3,5-difluorobenzyl iodide, 3,5-difluorobenzyl trifluoromethanesulfonate and 3,5-difluorobenzyl toluenesulfonate.

[0411] 203. The method of any one of items 187-202, wherein the compound of formula 1c is 3,5-difluorobenzyl bromide.

[0412] 204. The method of any one of items 187-203, wherein the alkylation step is carried out in a temperature range of about -20°C to about 120°C.

[0413] 205. The method of any one of items 187-204, wherein the alkylation step is carried out in a temperature range of about 10°C to about 80°C.

[0414] 206. The method of any one of items 187-205, wherein the acid used in the deprotection step is selected from hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, formic acid and oxalic acid.

[0415] 207. The method of any one of items 187-206, wherein the acid used in the deprotection step is methanesulfonic acid.

[0416] 208. The method of any one of items 187-207, wherein the solvent used in the deprotection step is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, xylene, toluene, dichloromethane, and combinations thereof.

[0417] 209. The method of any one of items 187-208, wherein the solvent used in the deprotection step is 2-methyltetrahydrofuran.

[0418] 210. The method of any one of items 187-209, wherein the deprotection step is performed in a temperature range of about -40°C to about 120°C.

[0419] 211. The method of any one of items 187-210, wherein the deprotection step is performed in a temperature range of about 10°C to about 40°C.

[0420] 212. The method of any one of items 187-211, wherein the acid is selected from hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, formic acid and oxalic acid.

[0421] 213. The method of any one of items 187-212, wherein the acid is methanesulfonic acid.

[0422] 214. The method of any one of items 172-180, further comprising:

[0423] (a) To make a compound of formula XIII or its eutectic, solvate, salt or combination thereof:

[0424]

[0425] Combined with a methanesulfonating agent, a base, a solvent, and optionally an additive, to provide a compound of formula XIII-A:

[0426]

[0427] or its eutectic, solvate, salt or combination thereof; and

[0428] (b) Combining the compound of formula XIII-A or its eutectic, solvate, salt or combination thereof with an amination agent and optionally a solvent to provide compound X:

[0429]

[0430]

[0431] Or its eutectic, solvate, salt or combination thereof.

[0432] 215. The method of item 214, wherein the methanesulfonating agent is selected from methanesulfonyl chloride and methanesulfonic anhydride.

[0433] 216. The method of item 214 or 215, wherein the methanesulfonating agent is methanesulfonyl chloride.

[0434] 217. The method of any one of items 214-216, wherein the base used in the methanesulfonation step is selected from triethylamine, diisopropylethylamine, pyridine, 2,3,5-coridine, 2,4,6-coridine, N,N-dicyclohexylmethylamine and N-methylimidazole.

[0435] 218. The method of any one of items 214-217, wherein the base used in the methanesulfonation step is triethylamine.

[0436] 219. The method of any one of items 214-218, wherein the additive used in the methanesulfonation step is 4-(dimethylamino)pyridine.

[0437] 220. The method of any one of items 214-219, wherein the solvent used in the methanesulfonation step is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, and combinations thereof.

[0438] 221. The method of any one of items 214-220, wherein the solvent used in the methanesulfonation step is tetrahydrofuran.

[0439] 222. The method of any one of items 214-221, wherein the methanesulfonation step is carried out in a temperature range of about -80°C to about 60°C.

[0440] 223. The method of any one of items 214-222, wherein the methanesulfonation step is carried out in a temperature range of about 0°C to about 40°C.

[0441] 224. The method of any one of items 214-223, wherein the amination agent is ammonia.

[0442] 225. The method of any one of items 214-224, wherein the solvent used in the amination step is selected from ethanol, 1-propanol, 2-propanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, water, and combinations thereof.

[0443] 226. The method of any one of items 214-225, wherein the solvent used for the amination step is methanol and water.

[0444] 227. The method of any one of items 214-226, wherein step (b) is carried out in a temperature range of about 0°C to about 100°C.

[0445] 228. The method of any one of items 214-227, wherein step (b) is carried out in a temperature range of about 40°C to about 80°C.

[0446] 229. A method for preparing a compound of formula V or its eutectic, solvate, salt, or combination thereof:

[0447]

[0448] Where R 1It is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O,

[0449] The method includes:

[0450] (a) Compounds of formula VA:

[0451]

[0452] Or its eutectic, solvate, salt or combination thereof, with

[0453] Silylating agent,

[0454] alkali, and

[0455] Solvent binding to provide compound of formula 7a:

[0456]

[0457] Or its eutectic, solvate, salt or combination thereof,

[0458] Each R 2 Independently for unsubstituted or by one to five C 1-6 Alkyl-substituted C 1-6 Alkyl; and

[0459] (b) Mix the compound of formula 7a with...

[0460] Organometallic reagents, and

[0461] Boronizing reagent combination,

[0462] To provide the compound of formula V or its eutectic, solvate, salt or combination thereof.

[0463] 230. The method of item 229, wherein the base used in step (a) is selected from sodium hydride, potassium hydride, methyl magnesium bromide, phenyl magnesium bromide, sodium hexamethyldisilazane, potassium hexamethyldisilazane, and lithium hexamethyldisilazane.

[0464] 231. The method of item 229 or 230, wherein the base used in step (a) is lithium hexamethyldisilazane.

[0465] 232. The method of any one of items 229-231, wherein the silylating agent used in step (a) is selected from trimethylsilane bromide, N,O-bis(trimethylsilyl)acetamide and trimethylsilane chloride.

[0466] 233. The method of any one of items 229-232, wherein the silylating agent used in step (a) is trimethylsilane chloride.

[0467] 234. The method of any one of items 229-233, wherein the solvent is selected from diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, dimethoxyethane, n-hexane, toluene, xylene, and combinations thereof.

[0468] 235. The method of any one of items 229-234, wherein the solvent is tetrahydrofuran.

[0469] 236. The method of any one of items 229-235, wherein the organometallic reagent used in step (b) is selected from n-butyllithium, sec-butylmagnesium chloride-lithium chloride complex, tert-butylmagnesium chloride and isopropylmagnesium chloride-lithium chloride complex.

[0470] 237. The method of any one of items 229-236, wherein the organometallic reagent used in step (b) is an isopropyl magnesium chloride-lithium chloride complex.

[0471] 238. The method of any one of items 229-237, wherein the boronizing agent used in step (b) is selected from trimethyl borate, triethyl borate, pinacolborane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane, β-catecholborane, and 2-bromo-1,3,2-benzodioxacyclopentene.

[0472] 239. The method of any one of items 229-238, wherein the boronizing agent used in step (b) is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxane.

[0473] 240. The method of any one of items 229-239, wherein the method is performed in a temperature range of about -80°C to about 40°C.

[0474] 241. The method of any one of items 229-240, wherein the method is performed in a temperature range of about -40°C to about 20°C.

[0475] 242. The method of any one of items 229-241, wherein R 1 It is B(OC(Me)2C(Me)2O).

[0476] 243. A method for preparing a compound of formula VIII or a eutectic, solvate, salt, or combination thereof:

[0477]

[0478] The method includes

[0479] (a) Hydrogenation of compound XI in the presence of an asymmetric catalyst and solvent:

[0480]

[0481] Or its eutectic, solvate, salt or combination thereof, to provide a compound of formula XII:

[0482]

[0483] Or its eutectic, solvate, salt or combination thereof;

[0484] (b) In the presence of a base and a solvent, an azide reagent is used to form the compound of formula XII or its eutectic, solvate, salt, or combination thereof as an azide to produce the compound of formula XVI:

[0485]

[0486] or its eutectic, solvate, salt or combination thereof; and

[0487] (c) Reducing the compound of formula XVI using a reducing agent to provide a compound of formula VIII or a eutectic, solvate, salt or combination thereof.

[0488] 244. The method described in Item 243, wherein the asymmetric catalyst is selected from [Rh(cod)((S)-segphos]BF4, IrCl(cod)((S)-segphos), [RuCl(p-isopropyltoluene)(segphos)]Cl, Ru(OAc)2(segphos), (Me2NH2)[RuCl((S)-segphos)]2(μ-Cl)3 and (R)-RuCY-XylBINAP.

[0489] 245. The method described in item 243 or 244, wherein the asymmetric catalyst is (R)-RuCY-XylBINAP.

[0490] 246. The method of any one of items 243-245, wherein the solvent used in the hydrogenation step is selected from n-propyl acetate, isopropyl acetate, ethanol, 1-propanol, 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.

[0491] 247. The method of any one of items 243-246, wherein the solvent used in the hydrogenation step is ethanol and 2-propanol.

[0492] 248. The method of any one of items 243-247, wherein the hydrogenation step is carried out in a temperature range of about -20°C to about 150°C.

[0493] 249. The method of any one of items 243-248, wherein the hydrogenation step is carried out in a temperature range of about 0°C to about 60°C.

[0494] 250. The method of any one of items 243-249, wherein the azide reagent is methanesulfonyl chloride and sodium azide or diphenylphosphohydride.

[0495] 251. The method of any one of items 243-250, wherein the azide reagent is a diphenylphosphohydride.

[0496] 252. The method of any one of items 243-251, wherein the base is selected from triethylamine, diisopropylethylamine, N,N-dimethylaminopyridine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0497] 253. The method of any one of items 243-252, wherein the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0498] 254. The method of any one of items 243-253, wherein the solvent used in steps (b) and (c) is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, and combinations thereof.

[0499] 255. The method of any one of items 243-254, wherein the solvent used in steps (b) and (c) is tetrahydrofuran.

[0500] 256. The method of any one of items 243-255, wherein steps (b) and (c) are carried out in a temperature range of about -10°C to about 60°C.

[0501] 257. The method of any one of items 243-256, wherein steps (b) and (c) are carried out in a temperature range of about 0°C to about 40°C.

[0502] 258. The method of any one of items 243-257, wherein the reducing agent is selected from trimethylphosphine, triethylphosphine, trimethyl phosphite, triethyl phosphite, tributylphosphine, trifuranylphosphine, tri(hydroxymethyl)phosphine and triphenylphosphine.

[0503] 259. The method of any one of items 243-258, wherein the reducing agent is triphenylphosphine.

[0504] 260. The method of any one of items 243-259, wherein the reduction step is carried out in a temperature range of about -10°C to about 60°C.

[0505] 261. The method of any one of items 243-260, wherein the reduction step is carried out in a temperature range of about 0°C to about 40°C.

[0506] 262. A method for preparing a compound of formula VIII or its eutectic, solvate, salt, or combination thereof:

[0507]

[0508] The method includes:

[0509] (a) To make a compound of formula XI or its eutectic, solvate, salt or combination thereof:

[0510]

[0511] Combined with a hydroxylamine source, a base, and a solvent to provide a compound of formula 1e:

[0512]

[0513] Or its eutectic, solvate, salt or combination thereof;

[0514] (b) Combining the compound of formula 1e with a reducing agent, an acylation agent, and a solvent to provide the compound of formula 1f-1:

[0515]

[0516] Or its eutectic, solvate, salt or combination thereof, wherein R 6 Selected from acetyl, benzyl, trichloroacetyl, trifluoroacetyl, and propionyl; and

[0517] (c) Hydrogenation of the compound of formula 1f-1 in a solvent using an asymmetric catalyst to provide

[0518] Compound of formula 1 g-1:

[0519]

[0520] or its eutectic, solvate, salt or combination thereof; and

[0521] (d) Deprotect the 1 g-1 compound with an acid and a solvent to provide a compound of formula VIII or a eutectic, solvate, salt or combination thereof.

[0522] 263. The method described in Project 262, wherein R 6 It is an acetyl group.

[0523] 264. The method of item 262 or 263, wherein the hydroxylamine source used in step (a) is hydroxylamine hydroxide.

[0524] 265. The method of any one of items 262-264, wherein the solvent used in step (a) is selected from n-propyl acetate, isopropyl acetate, methanol, 1- 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.

[0525] 266. The method of any one of items 262-265, wherein the solvent used in step (a) is ethanol.

[0526] 267. The method of any one of items 262-266, wherein the base used in step (a) is selected from pyridine, triethylamine, tri-n-propylamine, tri-n-butylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, lithium neopentanoate, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, sodium hydride, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and potassium hexamethyldisilazane.

[0527] 268. The method of any one of items 262-267, wherein the base used in step (a) is pyridine.

[0528] 269. The method of any one of items 262-268, wherein step (a) is carried out in a temperature range of about 10°C to about 60°C.

[0529] 270. The method of any one of items 262-269, wherein the reducing agent used in step (b) is selected from palladium on carbon, hydrogen, ferric acetate (II), samarium diiodide, titanium tetrachloride (IV) / tin chloride (II), and zinc.

[0530] 271. The method of any one of items 262-270, wherein the reducing agent used in step (b) is ferric acetate (II).

[0531] 272. The method of any one of items 262-271, wherein the acylation agent used in step (b) is selected from acetyl chloride, trichloroacetyl chloride, acetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, benzyl chloride and benzyl bromide.

[0532] 273. The method of any one of items 262-272, wherein the acylation agent used in step (b) is acetic anhydride.

[0533] 274. The method of any one of items 262-273, wherein the solvent used in step (b) is selected from acetic acid, n-propyl acetate, isopropyl acetate, acetate, methanol, 1- 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.

[0534] 275. The method of any one of items 262-274, wherein the solvent used in step (b) is isopropyl acetate and acetic acid.

[0535] 276. The method of any one of items 262-275, wherein step (b) is carried out in a temperature range of about 30°C to about 70°C.

[0536] 277. The method of any one of items 262-276, wherein the asymmetric catalyst used in step (c) is selected from IrCl(cod)((S)-segphos), Rh(cod)((S)-segphos)BF4 and (Me2NH2)[RuCl((S)-segphos)]2(μ-Cl)3.

[0537] 278. The method of any one of items 262-277, wherein the asymmetric catalyst used in step (c) is (IrCl(cod)((S)-segphos).

[0538] 279. The method of any one of items 262-278, wherein the solvent used in steps (c) and (d) is selected from ethyl acetate, n-propyl acetate, isopropyl acetate, ethanol, 1- 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.

[0539] 280. The method of any one of items 262-279, wherein the solvent used in steps (c) and (d) is ethyl acetate.

[0540] 281. The method of any one of items 262-280, wherein step (c) is carried out in a temperature range of about 80°C to about 150°C.

[0541] 282. The method of any one of items 262-281, wherein the acid used in step (d) is selected from hydrochloric acid, hydrobromic acid, nitric acid, methanesulfonic acid and p-toluenesulfonic acid.

[0542] 283. The method of any one of items 262-282, wherein the acid used in step (d) is hydrochloric acid.

[0543] 284. The method of any one of items 262-283, wherein step (d) is carried out in a temperature range of about 20°C to about 80°C.

[0544] 285. A method for preparing a compound of formula VIII or its eutectic, solvate, salt, or combination thereof:

[0545]

[0546] The method includes using:

[0547] Hydrogen source,

[0548] catalyst,

[0549] amine,

[0550] acid, and

[0551] Solvent-reduced amination of XI compounds:

[0552]

[0553] Or its eutectic, solvate, salt or combination thereof,

[0554] To provide a compound of formula VIII or a eutectic, solvate, salt or combination thereof.

[0555] 286. The method described in Item 285, wherein the hydrogen source is selected from hydrogen, ammonium formate, and triethylamine formate complex.

[0556] 287. The method described in item 285 or 286, wherein the hydrogen source is hydrogen gas.

[0557] 288. The method of any one of items 285-287, wherein the solvent is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methanol, isopropanol, tert-amyl alcohol, water, dimethyl sulfoxide, and combinations thereof.

[0558] 289. The method of any one of items 285-288, wherein the solvent is methanol.

[0559] 290. The method of any one of items 285-289, wherein the catalyst is an asymmetric catalyst or an enzyme catalyst.

[0560] 291. The method of any one of items 285-290, wherein the asymmetric catalyst is a ruthenium or iridium catalyst having a chiral ligand selected from SegPhos, DM-SegPhos, tert-butyl-Josiphos, DuPhos, MonoPhos and BINAP.

[0561] 292. The method of any one of items 285-290, wherein the catalyst is a ruthenium or iridium catalyst selected from RuCl3, ruthenium acetylacetonate (III), cyclopentadienyl bis(triphenylphosphine)ruthenium (II), ruthenium (II) chlorohydrotri(triphenylphosphine)acetate (II), ruthenium (II) chlorotri(triphenylphosphine)acetate, [Ru(Cl)H(CO)(PPH3)3], [Ir(COD)Cl]2, (acetylacetonyl)(1,5-cyclooctadiene)iridium (I) and (acetylacetonyl)dicarbonyliridium (I).

[0562] 293. The method of any one of items 285-290, wherein the catalyst is Ru(OAc)2((R)-SegPhos).

[0563] 294. The method of any one of items 285-290, wherein the enzyme catalyst is an aminotransferase and a cofactor in a buffer.

[0564] 295. The method described in Item 294, wherein the aminotransferase is an ω-transferase selected from 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.

[0565] 296. The method of item 294 or 295, wherein the buffer is selected from triethanolamine, Tris, Tricine, BES, MOPS, HEPES, sodium phosphate, and potassium phosphate.

[0566] 297. The method of any one of items 294-296, wherein the cofactor is pyridoxal phosphate.

[0567] 298. The method of any one of items 285-297, wherein the amine is selected from ammonia, ammonium acetate, ammonium salicylate, ammonium formate, α-methylbenzylamine, isopropylamine, diphenylmethylamine, DL-alanine, and aspartame.

[0568] 299. The method of any one of items 285-298, wherein the amine is ammonia.

[0569] 300. The method of any one of items 285-299, wherein the acid is selected from p-toluenesulfonic acid, hydrochloric acid and phosphoric acid.

[0570] 301. The method of any one of items 285-300, wherein the acid is p-toluenesulfonic acid.

[0571] 302. The method of any one of items 285-290 and 298-301, wherein the catalyst is an asymmetric catalyst, and the method is carried out at a pressure of about 100 to about 1000 psi.

[0572] 303. The method of any one of items 285-290 and 298-302, wherein the catalyst is an asymmetric catalyst, and the method is carried out at a pressure of about 200 to about 600 psi.

[0573] 304. The method of any one of items 285-290 and 298-303, wherein the catalyst is an asymmetric catalyst, and the method is carried out in a temperature range of about 0°C to about 120°C.

[0574] 305. The method of any one of items 285-290 and 298-304, wherein the catalyst is an asymmetric catalyst, and the method is carried out in a temperature range of about 55°C to about 65°C.

[0575] 306. The method of any one of items 285-290 and 298-301, wherein the catalyst is an enzyme catalyst, and the method is carried out in a temperature range of about 5°C to about 100°C.

[0576] 307. A method for preparing compounds of formula VII or their eutectics, solvates, salts, or combinations thereof:

[0577]

[0578] The method involves hydrolyzing compound VII-A in the presence of a base and a solvent:

[0579]

[0580] Or its eutectic, solvate, salt or combination thereof, to provide a compound of formula VII.

[0581] 308. The method described in Item 307, wherein the base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide and potassium trimethylsilanolate.

[0582] 309. The method described in item 307 or 308, wherein the base is potassium hydroxide.

[0583] 310. The method of any one of items 307-309, wherein the solvent is selected from dichloromethane, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, water, and combinations thereof.

[0584] 311. The method of any one of items 307-310, wherein the solvent is dichloromethane and ethanol.

[0585] 312. The method of any one of items 307-311, wherein the method is performed in a temperature range of about 10°C to about 100°C.

[0586] 313. The method of any one of items 307-312, wherein the method is performed in a temperature range of about 10°C to about 60°C.

[0587] 314. A method for preparing compounds of formula VII-A or their eutectic, solvate, salt, or combination thereof:

[0588]

[0589] The method comprises fluorinating a compound of formula 5h⁻¹ in a solvent with a fluorinating agent and in the presence of an activator:

[0590]

[0591] Or a eutectic, solvate, salt or combination thereof, wherein n is 1 or 2, to provide a compound of formula VII-A or a eutectic, solvate, salt or combination thereof.

[0592] 315. The method described in Project 314, where n is 1.

[0593] 316. The method described in Item 314 or 315, wherein the fluorinating agent is selected from pyridine hydrogen fluoride, calcium fluoride, potassium hydrogen fluoride, triethylamine trifluoride, elemental fluorine, bromine trifluoride, iodine pentafluoride, tetra-n-butyldihydrotrifluoride, 4-iodotoluene difluoride, and melamine hydrofluoride.

[0594] 317. The method of any one of items 314-316, wherein the fluorinating agent is pyridine hydrogen fluoride.

[0595] 318. The method of any one of items 314-317, wherein the solvent is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, xylene, dichloromethane, and combinations thereof.

[0596] 319. The method of any one of items 314-318, wherein the solvent is dichloromethane.

[0597] 320. The method of any one of items 314-319, wherein the activator is selected from 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide, N-iodosuccinimide, nitrosium tetrafluoroborate, thioyl chloride fluoride, trifluoromethanesulfonic acid and mercuric fluoride.

[0598] 321. The method of any one of items 314-320, wherein the activator is 1,3-dibromo-5,5-dimethylhydantoin.

[0599] 322. The method of any one of items 314-321, wherein the method is performed in a temperature range of about -30°C to about 20°C.

[0600] 323. A method for preparing a compound of the formula 5h⁻¹ or its eutectic, solvate, salt, or combination thereof:

[0601]

[0602] Where n is 1 or 2

[0603] The method includes reacting a compound of formula XIV or its eutectic, solvate, salt, or combination thereof in a solvent:

[0604]

[0605] Combined with dithiol reagents and accelerators to provide the compound of formula 5h-1 or its eutectic, solvate, salt or combination thereof.

[0606] 324. The method described in item 323, wherein the dithiol reagent is 1,2-ethanedithiol or 1,2-propanedithiol.

[0607] 325. The method described in item 323 or 324, wherein the solvent is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, xylene, dichloromethane, and combinations thereof.

[0608] 326. The method of any one of items 323-325, wherein the accelerator is selected from boron trifluoride acetic acid complex, p-toluenesulfonic acid, iodine, 1,3-dibromo-5,5-dimethylhydantoin, copper dodecyl sulfate (II), ytterbium trifluoromethanesulfonate (III), yttrium trifluoromethanesulfonate (III), bismuth trifluoromethanesulfonate (III), bismuth chloride (III), tungstic phosphate, perchloric acid, praseodymium trifluoromethanesulfonate, hafnium trifluoromethanesulfonate (IV), ferric chloride (III), hydrogen chloride, p-dodecylbenzenesulfonic acid, BF3·OEt2, BF3·OMe2, BF3·THF, BF3·OBu2, BF3·MeOH, BF3·Me2S and BF3·PhOHBF3·2H2O.

[0609] 327. The method of any one of items 323-326, wherein the accelerator is a boron trifluoride acetic acid complex.

[0610] 328. The method of any one of items 323-327, wherein the method is performed in a temperature range of about -20°C to about 100°C.

[0611] 329. A method for preparing a compound of formula XIV or a eutectic, solvate, salt, or combination thereof:

[0612]

[0613] The method comprises alkylating compound XIV-A with an alkylating agent in the presence of a base, a solvent, and optionally a phase-transfer catalyst:

[0614]

[0615] Or its eutectic, solvate, salt or combination thereof, to provide the compound of formula XIV or its eutectic, solvate, salt or combination thereof.

[0616] 330. The method of Item 329, wherein the alkylating agent is selected from ethyl chloroacetate, ethyl iodoacetate, ethyl (methanesulfonyloxy)acetate, ethyl (p-toluenesulfonyloxy)acetate, ethyl (((trifluoromethyl)sulfonyl)oxy)acetate, and ethyl bromoacetate.

[0617] 331. The method of item 329 or 330, wherein the alkylating agent is ethyl bromoacetate.

[0618] 332. The method of any one of items 329-331, wherein the base is selected from ethyl diisopropylamine, triethylamine, 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 hexamethyldisilazane, sodium hexamethyldisilazane, and potassium hexamethyldisilazane.

[0619] 333. The method of any one of items 329-332, wherein the base is ethyl diisopropylamine.

[0620] 334. The method of any one of items 329-333, wherein the phase transfer catalyst is selected from tetra-n-butylammonium bisulfate and tetra-n-butylammonium iodide.

[0621] 335. The method of any one of items 329-334, wherein the solvent is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, xylene, dichloromethane, ethyl acetate, isopropyl acetate, n-butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, water, and combinations thereof.

[0622] 336. The method of any one of items 329-335, wherein the solvent is acetonitrile.

[0623] 337. The method of any one of items 329-336, wherein the method is performed in a temperature range of about -20°C to about 100°C.

[0624] 338. The method of any one of items 329-337, wherein the method is performed in a temperature range of about -20°C to about 30°C.

[0625] 339. A method for preparing a compound of formula XIV-A or its eutectic, solvate, salt, or combination thereof:

[0626]

[0627] The method includes oxidizing compound C3 with an oxidant, a promoter, a solvent, and a catalyst.

[0628]

[0629] Or its eutectic, solvate, salt or combination thereof, to provide a compound of formula XIV-A or its eutectic, solvate or salt or combination thereof.

[0630] 340. The method of Item 339, wherein the oxidant is selected from tert-butyl hydroperoxide, peracetic acid, hydrogen peroxide, molecular oxygen, air, sodium hypochlorite, sodium chlorite, sodium periodate, potassium peroxymonosulfate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,4-benzoquinone, periodic acid, potassium bromate, m-CPBA, and magnesium monoperoxyphthalate.

[0631] 341. The method of item 339 or 340, wherein the oxidant is tert-butyl hydroperoxide.

[0632] 342. The method of any one of items 339-341, wherein the accelerator is selected from pyridine, bipyridine, neocopper reagent, 1,10-phenanthroline, 2,6-dimethylpyridine, 4-methylpyridine, 2-methylpyridine, 3-methylpyridine, isonicotinamide, nicotinamide, pyridinecarboxylic acid, (2,2,6,6-tetramethylpiperidin-1-yl)oxide and bis(dodecyl)dimethylammonium bromide.

[0633] 343. The method of any one of items 339-342, wherein the accelerator is pyridine.

[0634] 344. The method of any one of items 339-343, wherein the solvent is selected from acetic acid, acetonitrile, n-butyl acetate, isopropyl acetate, ethyl acetate, acetone, dichloromethane, dimethyl carbonate, tetrahydrofuran, methanol, tert-butanol, dichloromethane, sulfolane, water, and combinations thereof.

[0635] 345. The method of any one of items 339-344, wherein the solvent is water.

[0636] 346. The method of any one of items 339-345, wherein the catalyst is selected from manganese trifluoromethanesulfonate (II), copper chloride (II), (2S,2'S-(–)[N,N'-bis(2-pyridylmethyl)]-2,2'-dipyrrolidinebis(acetonitrile)iron(II)hexafluoroantimonate, bismuth, cobalt acetate (II), manganese acetate (III), ruthenium chloride (III), N-hydroxyphthalimide, bis(cyclopentadienyl)vanadium dichloride (IV), and manganese dioxide.

[0637] 347. The method of any one of items 339-346, wherein the catalyst is copper(II) chloride.

[0638] 348. The method of any one of items 339-347, wherein the method is performed in a temperature range of about 10°C to about 50°C.

[0639] 349. A method for preparing a compound of formula 3c or its eutectic, solvate, salt or combination thereof:

[0640]

[0641]

[0642] The method includes:

[0643] a) Cycling of compound 3a in a solvent using a hydrazine derivative and an accelerator:

[0644]

[0645] Or its eutectic, solvate, or combination thereof, to provide a compound of formula 3b:

[0646]

[0647] or its eutectic, solvate, salt or combination thereof; and

[0648] (b) Separating the compound of formula 3b or its eutectic, solvate, salt or combination thereof by chiral stationary phase and solvent chromatography to provide the compound of formula 3c or its eutectic, solvate or salt or combination thereof.

[0649] 350. The method of item 349, wherein the hydrazine derivative in step (a) is selected from anhydrous hydrazine, hydrazine monohydrate, aqueous hydrazine, hydrazine acetate, hydrazine dihydrochloride, hydrazine monohydrochloride, hydrazine sulfate, hydrazine hemisulfate, and hydrazine monohydrobromide.

[0650] 351. The method described in item 349 or 350, wherein the hydrazine derivative in step (a) is hydrated hydrazine.

[0651] 352. The method of any one of items 349-351, wherein the solvent in step (a) is selected from water, methanol, ethanol, 1- or 2-propanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, xylene, carboxylic acids, acetic acid, formic acid, propionic acid, butyric acid, and combinations thereof.

[0652] 353. The method of any one of items 349-352, wherein the solvent in step (a) is acetic acid.

[0653] 354. The method of any one of items 349-353, wherein the accelerator in step (a) is selected from hydrogen chloride, hydrobromic acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, zinc chloride, magnesium chloride and titanium tetrachloride.

[0654] 355. The method of any one of items 349-354, wherein step (a) is carried out in a temperature range of about -40 to about 120°C.

[0655] 356. The method of any one of items 349-355, wherein the chiral stationary phase used in step (b) is selected from 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.

[0656] 357. The method of any one of items 349-356, wherein the chiral stationary phase used in step (b) is Chiralpak IG.

[0657] 358. The method of any one of items 349-357, wherein the solvent used in step (b) is selected from hexaane, heptane, octane, ester, ethyl acetate, n-propyl acetate, isopropyl acetate, methanol, ethanol, 1- 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.

[0658] 359. The method of any one of items 349-358, wherein the solvent used in step (b) is acetonitrile.

[0659] 360. The method of any one of items 349-359, wherein step (b) is carried out in a temperature range of about 10°C to about 50°C.

[0660] 361. A method for preparing a compound of formula XIV or a eutectic, solvate, salt, or combination thereof:

[0661]

[0662] The method includes employing:

[0663] catalyst,

[0664] Reducing agent, and

[0665] Solvent-based kinetic resolution of compound XVII:

[0666]

[0667] Or its eutectic, solvate or combination thereof,

[0668] To provide a compound of formula XIV or a eutectic, solvate, salt or combination thereof.

[0669] 362. The method of Item 361, wherein the catalyst is selected from (R)-(+)-o-tolyl-CBS-oxazolborane, (R)-(+)-2-butyl-CBS-oxazolborane, (R)-(–)-2-methyl-CBS-oxazolborane, trans-RuCl2[(R)-XylBINAP]-[(R)-DPEN], RuBr2[(R)-BINAP], [RuCl(PhH)(R)-BI NAP)]Cl, RuCl(p-isopropyltoluene)[(S,S)-Ts-DPEN], RuCl(trimethylbenzene)[(S,S)-Ts-DPEN], RuBF4(p-isopropyltoluene)[(S,S)-Ts-DPEN], RuCl(p-isopropyltoluene)[(S,S)-Fs-DPEN], RuCl(p-isopropyltoluene)[(R,R)-Teth-Ts-DPEN] and Baker's yeast.

[0670] 363. The method of item 361 or 362, wherein the catalyst is (R)-(–)-2-methyl-CBS-oxazolborane.

[0671] 364. The method of any one of items 361-363, wherein the reducing agent is selected from boron dimethyl sulfide complex, boron tetrahydrofuran complex, boron trimethylamine complex, boron triethylamine complex, boron N,N-diethylaniline complex, catechol borane, hydrogen, formic acid / triethylamine and 2-propanol.

[0672] 365. The method of any one of items 361-364, wherein the reducing agent is a boron dimethyl sulfide complex.

[0673] 366. The method of any one of items 361-365, wherein the solvent is selected from diethyl ether, methyl tert-butyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, dimethoxyethane, n-hexane, heptane, toluene, xylene, ethyl acetate, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof.

[0674] 367. The method of any one of items 361-366, wherein the solvent is tetrahydrofuran.

[0675] 368. The method of any one of items 361-367, wherein the method is performed in a temperature range of about -20°C to about 100°C.

[0676] 369. The method of any one of items 361-368, wherein the method is performed in a temperature range of about 0°C to about 10°C.

[0677] 370. A method for preparing a compound of formula XIV or a eutectic, solvate, or combination thereof:

[0678]

[0679] The method includes:

[0680] (a) Oxidation of compound 5a with an oxidizing agent, a base, and a solvent:

[0681]

[0682] Or its eutectic, solvate, or combination thereof, to provide a compound of formula 5b:

[0683]

[0684] Or its eutectic, solvate or combination thereof, wherein each R 3 Independently for unsubstituted or by one to five C 1-6 Alkyl-substituted C 1-6 alkyl;

[0685] (b) Further oxidation of the compound of formula 5b or its eutectic, solvate or combination thereof with an oxidizing agent, a base and a solvent to provide the compound of formula 5c:

[0686]

[0687] Or its eutectic, solvate, or combination thereof;

[0688] (c) Combining the compound of formula 5c or its eutectic, solvate or combination thereof with a trifluoroacetylating agent and a lithium base in a solvent to provide a compound of formula 5d:

[0689]

[0690] or its eutectic, solvate, or combination thereof; and

[0691] (d) Combining the compound of formula 5d or its eutectic, solvate or combination thereof with hydrazine ethyl acetate hydrochloride, an acid and optionally an additive to provide the compound of formula XIV or its eutectic, solvate, salt or combination thereof.

[0692] 371. The method of Item 370, wherein the oxidant used in step (a) is selected from iodine, thiaanthraium tetrafluoroborate, diacetoxyiodobenzene and potassium iodide / platinum electrode.

[0693] 372. The method of item 370 or 371, wherein the oxidant used in step (a) is diacetoxyiodobenzene.

[0694] 373. The method of any one of items 370-372, wherein the base used in step (a) is selected from sodium hydroxide, lithium hydroxide and potassium hydroxide.

[0695] 374. The method of any one of items 370-373, wherein the base used in step (a) is potassium hydroxide.

[0696] 375. The method of any one of items 370-374, wherein the solvent used in step (a) is selected from methanol, ethanol, 1-propanol and ethylene glycol.

[0697] 376. The method of any one of items 370-375, wherein the solvent used in step (a) is methanol.

[0698] 377. The method of any one of items 370-376, wherein step (a) is carried out in a temperature range of about -20°C to about 100°C.

[0699] 378. The method of any one of items 370-377, wherein step (a) is carried out in a temperature range of about -15°C to about 30°C.

[0700] 379. The method of any one of items 370-378, wherein the oxidant used in step (b) is selected from dimethyl sulfoxide and an activator selected from cyanuric chloride, oxalyl chloride, dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N-chlorosuccinimide, benzoic anhydride, methanesulfonic anhydride, p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, methyl oxalyl chloride, thionyl chloride, diphosgene, triphosgene, methanesulfonyl chloride, toluenesulfonyl chloride, benzenesulfonyl chloride. Trichloroacetonitrile, 2-chloro-1,2-dimethylimidazolium chloride, polyphosphoric acid, PCl3, triphenylphosphine dichloride, triphenylphosphine dibromide, POCl3, phosphorus pentoxide, acetyl chloride, benzoyl chloride, acetyl bromide, phenyl dichlorophosphate, diphenyl chlorophosphate, diethyl chlorophosphate and ethoxyacetylene, TEMPO and bleaching agents, chromium trioxide, Dess-Martin periodoyl alkyl, 2-iodobenzoic acid and sulfur trioxide pyridine complex.

[0701] 380. The method of any one of items 370-379, wherein the oxidant used in step (b) is dimethyl sulfoxide and oxalyl chloride.

[0702] 381. The method of any one of items 370-380, wherein the base used in step (b) is selected from diisopropylethylamine, tri-n-propylamine, triethylamine, pyridine and 2,6-dimethylpyridine.

[0703] 382. The method of any one of items 370-381, wherein the base used in step (b) is triethylamine.

[0704] 383. The method of any one of items 370-382, wherein the solvent used in step (b) is selected from dichloroethane, dichloromethane, toluene, and combinations thereof.

[0705] 384. The method of any one of items 370-383, wherein the solvent used in step (b) is dichloromethane.

[0706] 385. The method of any one of items 370-384, wherein step (b) is carried out in a temperature range of about -80°C to about 50°C.

[0707] 386. The method of any one of items 370-385, wherein step (b) is carried out in a temperature range of about -60°C to about -10°C.

[0708] 387. The method of any one of items 370-386, wherein R 3 It is a methyl group.

[0709] 388. The method of any one of items 370-387, wherein the trifluoroacetylation agent is selected from trifluoroacetic anhydride, phenyl trifluoroacetate, methyl trifluoroacetate, ethyl trifluoroacetate and trifluoroethyl trifluoroacetate.

[0710] 389. The method of any one of items 370-388, wherein the trifluoroacetylation agent is ethyl trifluoroacetate.

[0711] 390. The method of any one of items 370-389, wherein the lithium base is selected from lithium hexamethyldisilazane, lithium diisopropylamine, lithium tetramethylpiperidine, lithium methoxide, lithium ethoxide and lithium tert-butoxide.

[0712] 391. The method of any one of items 370-390, wherein the lithium base is lithium hexamethyldisilazane.

[0713] 392. The method of any one of items 370-391, wherein the solvent used in step (c) is selected from diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, n-hexane, n-heptane, toluene, xylene, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and acetonitrile.

[0714] 393. The method of any one of items 370-392, wherein the solvent used in step (c) is tetrahydrofuran.

[0715] 394. The method of any one of items 370-393, wherein step (c) is carried out in a temperature range of about -30°C to about 30°C.

[0716] 395. The method of any one of items 370-394, wherein step (c) is carried out in a temperature range of about -80°C to about 60°C.

[0717] 396. The method of any one of items 370-395, wherein the acid is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, magnesium chloride, zinc chloride, scandium trifluoromethanesulfonate, and bismuth chloride.

[0718] 397. The method of any one of items 370-396, wherein the acid is sulfuric acid.

[0719] 398. The method of any one of items 370-397, wherein the additive is selected from ethyl orthoethyl, ethyl orthoformate, molecular sieves and Dean-Stark distillation.

[0720] 399. The method of any one of items 370-398, wherein the additive is ethyl orthoformate.

[0721] 400. The method of any one of items 370-399, wherein the solvent used in step (d) is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, xylene, ethyl acetate, isopropyl acetate, ethylene glycol, propylene glycol, methanol, ethanol, isopropanol, dichloromethane, and combinations thereof.

[0722] 401. The method of any one of items 370-400, wherein the solvent used in step (d) is ethanol.

[0723] 402. The method of any one of items 370-401, wherein step (d) is carried out in a temperature range of about -20°C to about 60°C.

[0724] 403. The method of any one of items 370-402, wherein step (d) is carried out in a temperature range of about -20°C to about 20°C.

[0725] 404. A compound of formula VI:

[0726]

[0727] Or its eutectic, solvate, or combination thereof.

[0728] 405. A compound of formula VIII:

[0729]

[0730] Or its eutectic, solvate, salt or combination thereof.

[0731] 406. The compound described in item 405, wherein the compound of formula VIII is:

[0732]

[0733] Or its eutectic, solvate, or combination thereof, wherein HX is selected from hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic 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)succinic acid, benzyloxycarbonyl-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methyl Adipic acid, (+)-mentholoxyacetic 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, (–)-acetylmynic acid, (R)-(–)-citric acid, (–)-camphoric acid, and (R)-mandelic acid.

[0734] 407. The compound described in item 406, wherein HX is N-Boc-D-leucine or (–)-N-acetyl-D-leucine.

[0735] 408. The compound described in item 406, wherein HX is (R)-mandelic acid.

[0736] 409. A compound of formula IV:

[0737]

[0738] Or its eutectic, solvate, salt or combination thereof.

[0739] 410. A compound of formula III:

[0740]

[0741] Or its eutectic, solvate, salt or combination thereof.

[0742] 411. Compounds of Item 410, wherein the compound of Formula III is:

[0743]

[0744] Or its eutectic or solvate or combination thereof.

[0745] 412. The compound described in item 410, wherein the compound of formula III is:

[0746]

[0747] Or a eutectic or a combination thereof.

[0748] 413. The compound described in item 410, wherein the compound of formula III is:

[0749]

[0750] Or a eutectic or a combination thereof.

[0751] 414. A compound of formula II:

[0752]

[0753] Or its eutectic, solvate, salt or combination thereof.

[0754] 415. A method for preparing a compound of formula 5e or a eutectic, solvate, or combination thereof:

[0755]

[0756] The method includes:

[0757]

[0758] (a) Oxidation of compound 5a with an oxidizing agent, a base, and a solvent:

[0759]

[0760] Or its eutectic, solvate, or combination thereof, to provide a compound of formula 4a

[0761]

[0762] Or its eutectic, solvate, or combination thereof;

[0763] (b) Combining the compound of formula 4a or its eutectic, solvate or combination thereof with 1,2-ethylenedithiol, a solvent and a catalyst to provide the compound of formula 5i:

[0764]

[0765] or its eutectic, solvate, or combination thereof; and

[0766] (c) Hydrolyzing the compound of formula 5i or its eutectic, solvate or combination thereof with an acid, solvent and accelerator to provide the compound of formula 5e or its eutectic, solvate, salt or combination thereof.

[0767] 416. The method of item 415, wherein the oxidant used in step (a) is selected from isoamyl nitrite, n-butyl nitrite, tert-butyl nitrite, ethyl nitrite, sodium nitrite, potassium nitrite, nitrosyl chloride, nitrosyl sulfate, tetrafluoroborate and hydrogen sulfate.

[0768] 417. The method described in item 415 or 416, wherein the oxidant used in step (a) is tert-butyl nitrite.

[0769] 418. The method of any one of items 415-417, wherein the base used in step (a) is selected from potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium isopropoxide, sodium ethoxide, sodium methoxide, sodium hydride, lithium tetramethylpiperidine, lithium hexamethyldisilazane, and phosphazene.

[0770] 419. The method of any one of items 415-418, wherein the base used in step (a) is potassium tert-butoxide.

[0771] 420. The method of any one of items 415-419, wherein the solvent used in step (a) is selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, cyclopentylmethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, methanol, ethanol, isopropanol, sulfolane, and combinations thereof.

[0772] 421. The method of any one of items 415-420, wherein the solvent used in step (a) is tetrahydrofuran.

[0773] 422. The method of any one of items 415-421, wherein step (a) is carried out in a temperature range of about -78°C to about 70°C.

[0774] 423. The method of any one of items 415-422, wherein step (a) is carried out in a temperature range of about -10°C to about 10°C.

[0775] 424. The method of any one of items 415-423, wherein the catalyst used in step (b) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid monohydrate, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, iodine, 1,3-dibromo-5,5-dimethylhydantoin, copper dodecyl sulfate (II), ytterbium trifluoromethanesulfonate (III), yttrium trifluoromethanesulfonate (III), bismuth trifluoromethanesulfonate (III), bismuth chloride (III), tungsten phosphoric acid, perchloric acid, praseodymium trifluoromethanesulfonate, hafnium trifluoromethanesulfonate (IV), ferric chloride (III), hydrogen chloride, p-dodecylbenzenesulfonic acid, BF3·OEt2, BF3·OMe2, BF3·THF, BF3·OBu2, BF3·MeOH, BF3·Me2S, BF3·PhOH, and BF3·2H2O.

[0776] 425. The method of any one of items 415-424, wherein the catalyst used in step (b) is p-toluenesulfonic acid monohydrate.

[0777] 426. The method of any one of items 415-425, wherein the solvent used in step (b) is selected from diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, dichloromethane, dichloroethane, acetic acid, propionic acid, sulfolane, and combinations thereof.

[0778] 427. The method of any one of items 415-426, wherein the solvent used in step (b) is acetic acid.

[0779] 428. The method of any one of items 415-427, wherein step (b) is performed in a temperature range of about 80°C or lower.

[0780] 429. The method of any one of items 415-428, wherein step (b) is carried out in a temperature range of about 0°C to about 80°C.

[0781] 430. The method of any one of items 415-429, wherein the acid used in step (c) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid monohydrate, trifluoroacetic acid, phosphoric acid, levulinic acid, glyoxylic acid, sodium bisulfite, sodium metabisulfite, potassium bisulfite, and sodium dithionite.

[0782] 431. The method of any one of items 415-430, wherein the acid used in step (c) is p-toluenesulfonic acid monohydrate.

[0783] 432. The method of any one of items 415-431, wherein the solvent used in step (c) is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, dichloromethane, dichloroethane, methyl ethyl ketone, acetone, methyl isobutyl ketone, formaldehyde / formalin, acetaldehyde, isobutyraldehyde, water, and combinations thereof.

[0784] 433. The method of any one of items 415-432, wherein the solvent used in step (c) is methyl ethyl ketone and water.

[0785] 434. The method of any one of items 415-433, wherein step (c) is performed at a temperature of about 100°C or lower.

[0786] 435. The method of any one of items 415-434, wherein step (c) is carried out in a temperature range of about 20°C to about 100°C.

[0787] 436. A method for preparing a compound of formula 5a or its eutectic, solvate, or combination thereof:

[0788]

[0789] The method includes using a compound of formula 4e:

[0790]

[0791] Or its eutectic, solvate, salt, or combination thereof, combined with a catalyst, acid, base, solvent, and optionally additives, to provide the compound of formula 5a or its eutectic, solvate, or combination thereof.

[0792] Where X 1 It is selected from toluenesulfonyloxy, chlorine, bromine, iodine, methanesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2,4,6-triisopropylbenzenesulfonyloxy, acetoxy, trichloroacetoxy, and trifluoroacetoxy.

[0793] 437. The method described in project 436, wherein X 1 It is toluenesulfonyloxy.

[0794] 438. The method described in item 436 or 437, wherein the catalyst is selected from (8α,9S)-6′-methoxycinnamine-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 aldolase.

[0795] 439. The method of any one of items 436-438, wherein the catalyst is (8α,9S)-6′-methoxycincanine-9-amine trihydrochloride.

[0796] 440. The method of any one of items 436-439, wherein the acid is selected from acetic acid, trifluoroacetic acid, trichloroacetic acid, tartaric acid, camphor sulfonic acid, sulfuric acid, phosphonic acid, phosphoric acid and trifluoromethanesulfonic acid.

[0797] 441. The method of any one of items 436-440, wherein the acid is trifluoroacetic acid.

[0798] 442. The method of any one of items 436-441, wherein the base is selected from 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.

[0799] 443. The method of any one of items 436-442, wherein the base is lithium acetate.

[0800] 444. The method of any one of items 436-443, wherein the solvent is selected from 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-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, dichloroethane, chloroform, acetonitrile, propionitrile, butyronitrile, water, and combinations thereof.

[0801] 445. The method of any one of items 436-444, wherein the solvent is 2-methyltetrahydrofuran and water.

[0802] 446. The method of any one of items 436-445, wherein the method is performed in a temperature range of about 120°C or lower.

[0803] 447. The method of any one of items 436-446, wherein the method is performed at about 20°C. Detailed Implementation

[0804] The following description was made with the understanding that this disclosure should be considered as an example of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments shown. Headings used throughout this disclosure are provided for convenience and should not be construed as limiting the claims in any way. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

[0805] When a trade name is used in this document, it is intended to refer independently to the product under that trade name and the active pharmaceutical ingredient of that product.

[0806] As used herein and in the appended claims, the singular forms “a / an” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, reference to “compound” includes multiple such compounds, reference to “test” includes reference to one or more tests, and so on.

[0807] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0808] "Stereoisomers" are isomers that are distinguished only by the way their atoms are arranged in space.

[0809] An enantiomer is a pair of stereoisomers that are non-overlapping 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.

[0810] A "diastere" is a stereoisomer with at least two asymmetric atoms that are not mirror images of each other.

[0811] Absolute stereochemistry is defined according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be defined by R or S. Resolved compounds whose absolute configuration is unknown can be defined as (+) or (–) according to the direction (right-handed or left-handed) of the plane-polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers and / or hindered rotation around the bond axis, thus producing enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- in terms of absolute stereochemistry. This disclosure is intended to include all such possible isomers, including racemic mixtures, proportional mixtures, diastereomer mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0812] Unless otherwise expressly defined, this disclosure includes all tautomers of the compounds detailed herein, even if only one tautomer is explicitly indicated (e.g., both tautomer forms are indicated and described by the presentation of one tautomer form, in which case a pair of two tautomers may exist). For example, if a compound containing an amide is referred to (e.g., by its structure or chemical name), it should be understood that the corresponding imidic acid tautomer is included in this disclosure and described as if the amide alone or together with the imidic acid were explicitly stated. Where more than two tautomers may exist, this disclosure includes all such tautomers, even if only a single tautomer form is described by its chemical name and / or structure.

[0813] The compounds described herein may have chiral centers and / or geometric isomer centers (E- and Z-isomers), and it should be understood that all such optical, enantiomers, diastereomers, and geometric isomers are included. When a compound is represented in its chiral form, it should be understood that the embodiment includes, but is not limited to, a specific diastereomer or enantiomer-enriched form. When chirality is not specified but present, it should be understood that the embodiment is for a specific diastereomer or enantiomer-enriched form; or a racemic or proportional mixture of such compounds. As used herein, a “proportional mixture” is a mixture of stereoisomers in a ratio other than 1:1.

[0814] As used herein, the terms "amine transaminase" and "ATA" refer to polypeptides with the enzymatic ability to exchange the amino group of a donor amine with the carbonyl group of an acceptor molecule. The transamination reaction occurs in the presence of pyridoxal phosphate (PLP), which acts as a cofactor. In transamination reactions using transaminases, the amino group of the amino donor is transferred to coenzyme A to produce a ketone as a byproduct, while 5'-pyridoxal phosphate is converted to pyridoxamine phosphate. The amino group is then transferred from pyridoxamine phosphate to the ketone substrate to produce a chiral amine and regenerate 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.

[0815] As used herein, the term "asymmetric catalyst" 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 product. Exemplary asymmetric catalysts comprise a transition metal and a chiral ligand. Non-limiting examples of chiral ligands include BINAP / Salen, bisoxazoline, tartrate ligands, cinchona alkaloids, DuPhos phosphaceane, BPE phosphaceane, DSM phosphorusamide Josiphos family, phospho-oxazoline, Reetz and Trost ligands, and ChiralQuest phosphine.

[0816] Also provided are pharmaceutically acceptable hydrates, solvates, cocrystals, tautomers, polymorphs, and prodrugs of the compounds described herein.

[0817] The term "hydrate" refers to a complex formed by the combination of a compound of formula I or any of the formulas disclosed herein with water.

[0818] The term "solvent" refers to a complex formed by reacting a compound of formula I or any other formula disclosed herein with a solvent, or a crystalline solid containing an amount of solvent incorporated in a crystal structure. As used herein, the term "solvent" includes hydrates.

[0819] The term "eutectic" refers to a crystalline material formed by combining a compound of Formula I or any of the formulas disclosed herein with one or more eutectic forming agents (i.e., molecules, ions, or atoms). In some cases, eutectics can have improved properties compared to the parent form (i.e., free molecules, zwitterions, etc.) or a salt of the parent compound. Improved properties may include increased solubility, increased dissolution rate, increased bioavailability, increased dose response, reduced hygroscopicity, a crystalline form that is typically amorphous, a crystalline form of a compound that is difficult or non-salt-forming, reduced form diversity, a more desirable morphology, and so on. Methods for preparing and characterizing eutectics are known to those skilled in the art.

[0820] Any formula or structure given herein, including Formula I or any other formula disclosed herein, is intended to represent both the unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structures depicted by the formulas given herein, differing in that one or more atoms are substituted with atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, but not limited to, those of other elements. 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 I. Various isotope-labeled compounds disclosed herein, for example, those doped with radioactive isotopes such as 3 H, 13 C and 14 Those containing C. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or matrix tissue distribution determination or in patients undergoing radiotherapy.

[0821] This disclosure also includes compounds of Formula I or any of the formulas disclosed herein, wherein one to "n" hydrogen atoms bonded to a carbon atom are replaced with deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased antimetabolite activity and can therefore be used to increase the half-life of any Formula I compound when administered to mammals. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0822] The deuterium-labeled or substituted therapeutic compounds of this disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties, which involve distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope, such as deuterium, can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirement. 18F-labeled compounds can be used in PET or SPECT studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents, by performing the procedures in the schemes or examples below and in the preparations described below. Furthermore, substitution with a heavier isotope, especially deuterium (i.e., 2H or D), can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirement or improved therapeutic index. It should be understood that deuterium in this context is considered a substituent in compounds of Formula I or any of the formulas disclosed herein.

[0823] The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, that position should be understood to have hydrogen in its native isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0824] The modifier “about” used with a quantity includes the value and has a contextual indication meaning (e.g., including the degree of error associated with the measurement of a particular quantity).

[0825] The term "chirality" refers to a molecule that has a non-overlapping mirror pair, while the term "chirality" refers to a molecule that can overlap its mirror pair.

[0826] "Alkyl" is a straight-chain or branched saturated hydrocarbon. For example, an alkyl group may have 1 to 8 carbon atoms (i.e., (C1-C8)alkyl), 1 to 6 carbon atoms (i.e., C1-C6alkyl), or 1 to 4 carbon atoms (i.e., (C1-C4)alkyl). Examples of suitable alkyl groups include, but are not limited to: 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 -Bu, 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)2CH2CH3), 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 (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH)CH2CH2CH2CH3) 3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3).

[0827] "Alkenyl" is a group having at least one carbon-carbon sp. 2 A straight-chain or branched hydrocarbon with a double bond. For example, the alkenyl group may 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, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0828] "Alynyl" is a straight-chain or branched hydrocarbon having at least one carbon-carbon sp triple bond. For example, an alkynyl can have 2 to 8 carbon atoms (i.e., C2-C8 alkynyl) or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Suitable examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), etc.

[0829] As used in this article, the terms "halogenated" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0830] As used herein, the term "haloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are each independently substituted with a halogen substituent. For example, a (C1-C6)haloalkyl is a (C1-C6)alkyl group in which one or more hydrogen atoms of the (C1-C6)alkyl group have been substituted with a halogen substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0831] As used herein, the term "aryl" refers to a single all-carbon aromatic ring or a polycondensed all-carbon ring system in which at least one ring is aromatic. For example, in some embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl groups include phenyl groups. Aryl groups also include polycondensed ring systems having about 9 to 20 carbon atoms (e.g., ring systems comprising 2, 3, or 4 rings), in which at least one ring is aromatic, while the other rings may be aromatic or non-aromatic (i.e., carbocyclic). Such polycondensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxygens at any carbocyclic portion of the polycondensed ring system. When valence requirements permit, the rings of a polycondensed ring system can be interconnected by fusion, spirolysis, and bridging. It should be understood that, as defined above, the connection points of a polycondensed ring system can be at any location within the ring system, including the aromatic or carbocyclic portions of the ring. It should also be understood that when referring to an aryl group within a certain atomic range (e.g., 6-12-membered aryl groups), the atomic range refers to the total number of ring atoms in the aryl group. For example, a 6-membered aryl group would include a phenyl group, and a 10-membered aryl group would include a naphthyl group and a 1,2,3,4-tetrahydronaphthyl group. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracene, etc.

[0832] As used herein, the term "heteroaryl" refers to a monoaromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from oxygen, nitrogen, and sulfur; "heteroaryl" also includes polycondensed ring systems having at least one such aromatic ring, which will be further described below. Thus, "heteroaryl" comprises a monoaromatic ring with about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be present in oxidized forms, provided the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes polycondensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a heteroaryl group (as defined above) condenses with one or more rings selected from the following to form a polycondensed ring system: heteroaryl (to form, for example, 1,8-naphthidyl), heterocyclic (to form, for example, 1,2,3,4-tetrahydro-1,8-naphthidyl), carbocyclic (to form, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (to form, for example, indazole). Thus, a heteroaryl (monoaromatic ring or polycondensed ring system) has about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such a polycondensed ring system may optionally have one or more (e.g., 1, 2, 3, or 4) oxosubstituted on the carbocyclic or heterocyclic portion of the condensed ring. Where valence bonds permit, the rings of a polycondensed ring system can be interconnected by fusion, spirolysis, and bridging. It should be understood that the rings of a polycondensed ring system can be connected in any order relative to each other. It should also be understood that the connection points of a polycondensed ring system (as defined above for heteroaryl groups) can be anywhere within the polycondensed ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portions of the polycondensed ring system. It should also be understood that the connection points of a heteroaryl group or a heteroaryl polycondensed ring system can be on any suitable atom of the heteroaryl group or a heteroaryl polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when referring to an atomic range of heteroaryl groups (e.g., 5-14 membered heteroaryl groups), the atomic range is the total number of ring atoms in the heteroaryl group, including carbon atoms and heteroatoms. For example, a 5-membered heteroaryl group would contain a thiazolyl group, and a 10-membered heteroaryl group would contain a quinolinyl group. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, inzolyl, quinoxolinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, thionyl, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and 3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadienozo[1,2-c]pyrazole.

[0833] As used herein, the term "heterocyclic group" or "heterocycle" refers to a single saturated or partially unsaturated ring having at least one atom other than carbon, wherein the atom is selected from oxygen, nitrogen, and sulfur; the term also includes polycondensed ring systems having at least one such saturated or partially unsaturated ring, which are further described below. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3, 4, 5, 6, or 7-membered ring) having about 1-6 carbon atoms and about 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxygen atoms, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, nitrogen-containing heterocyclic butyl, tetrahydrofuranyl, and piperidinyl. The term "heterocycle" also includes polycondensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a single ring (as defined above) can condense with one or more groups selected from the following to form a polycondensed ring system: heterocycle (to form, for example, 1,8-decahydronaphthidyl), carbocycle (to form, for example, decahydroquinoline), and aryl. Thus, a heterocycle (a single saturated or single partially unsaturated ring or a polycondensed ring system) has about 2-20 carbon atoms and 1-6 heteroatoms within the heterocyclic ring. Such polycondensed ring systems may optionally have one or more (e.g., 1, 2, 3, or 4) oxo groups substituted on the carbocycle or heterocyclic portion of the polycondensed ring system. When valence bonds permit, the rings of a polycondensed ring system can be interconnected by fusion, spirolysis, and bridging. It should be understood that the individual rings of a polycondensed ring system can be connected relative to each other in any order. It should also be understood that the junction point of a polycondensed ring system (as defined above) can be anywhere in the polycondensed ring system, including the heterocyclic, aryl, and carbocyclic portions of the ring. It should also be understood that the junction point of a heterocycle or a heterocyclic polycondensed ring system can be on any suitable atom of the heterocycle or the heterocyclic polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when referring to a range of atomically isolated heterocycles (e.g., 3-14 membered heterocycles), the atomic range refers to the total number of ring atoms in the heterocycle, including both carbon atoms and heteroatoms. For example, a 3-membered heterocycle would include acridineyl, and a 10-membered heterocycle would include 1,2,3,4-tetrahydroquinolinyl. Exemplary heterocycles include, but are not limited to, acridinel, azacyclic butyl, pyrrolyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazine, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiaranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazine, dihydrooxazolyl, benzodihydropyranyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxacyclopentenyl, 1,4-benzodioxylyl, spirocyclic...

[0834]

[0835] [Propane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptyl, imidazolidin-2-one and pyrrolidine-2-one.

[0836] The term "cycloalkyl" refers to cyclic alkyl and alkenyl groups. A cycloalkyl group may have one or more rings and includes fully saturated or partially unsaturated fused and bridging groups. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, methylcyclopropyl (cyclopropylmethyl), ethylcyclopropyl, cyclohexenyl, etc.

[0837] The term "convergence" refers to a ring that is connected to an adjacent ring.

[0838] "Bridged" refers to the following ring fusion, in which non-adjacent atoms on the ring are connected by divalent substituents, such as alkylene or heteroalkylene or a single heteroatom. Quinine cycloyl and adamantyl are examples of bridged ring systems.

[0839] "Spiro" refers to a cyclic substituent linked by two bonds on the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents, respectively.

[0840] The term "azido group" refers to a group

[0841] The term "ketone" or "oxo" refers to the =O group.

[0842] The term "carboxyl group" refers to the -C(O)-OH group.

[0843] The term "hydroxyl" or "hydroxyl group" refers to the –OH group.

[0844] The term "amine protecting group" is well understood by those skilled in the art of synthetic organic chemistry to refer to a portion that can be selectively attached to or removed from a suitable amine functional group, thereby masking or altering its properties. The field of protecting group methodology is advanced, and many amine protecting groups and their methods of use are well-known in the art, for example, those described in authoritative treatises on the subject, such as those in PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis, 4th edition (Wiley, 2006).

[0845] The term "borylating agent" in organic synthesis is also fully understood to refer to any of a wide range of borate moieties that can be mounted onto a suitable substrate to provide an organoboron reagent. Non-limiting examples of borylation agents and related synthetic methods can be found in T. Ishiyama et al., J. Org. Chem. 1995, 60, 7508-7510 and N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457-2483.

[0846] As used herein, the term "alkynylation conditions" refers to reaction conditions under which a terminal alkyne is coupled with another compound (e.g., a suitable aryl or heteroaryl halide substrate) to form an alkyne (e.g., an internal alkyne) in the presence of a catalyst, solvent, and optionally a base. Non-limiting examples of catalysts used for "alkynylation conditions" include combinations of palladium catalysts with tertiary phosphines, such as [(π-allyl)PdCl]2, Pd(acac)2, (SIPr)PdCl2, PdCl2(PPh3)2, PdCl2, Pd(OAc)2, PdCl2(CH3CN)2, Pd2(dba)3, etc.; tertiary phosphines such as triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, and 1,1'-bis(diphenylphosphine)ferrocene, such as dichlorobis(diphenylphosphine)palladium(II); copper catalysts such as copper iodide(I), copper bromide(I), copper chloride(I), etc.; and combinations thereof. In some embodiments, the catalyst is PdCl2(PPH3)2.

[0847] The "alkynylation conditions" disclosed herein 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, 1,8-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), etc. In some embodiments, the base is triethylamine.

[0848] The 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-methylpyrrolidone, etc., water, and combinations thereof). In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0849] In some embodiments, the alkynylation conditions include a temperature range of about 120°C or lower. In some embodiments, the alkynylation conditions include a temperature range of about 0°C to about 120°C. In some embodiments, the alkynylation conditions include a temperature range of about 50°C to about 80°C.

[0850] The term "amide coupling conditions" refers to the reaction conditions under which an amine and a carboxylic acid are coupled to form an amide in the presence of a base, using a coupling agent and optionally a coupling additive. Non-limiting examples of coupling agents include n-propylphosphonic anhydride, oxalyl chloride, thionyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), carbonyl diimidazole, isobutyl chloroformate, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate, O-benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate, and O-(7-aza-benzotriazol-1-yl)-N,N,N' Examples of coupling agents include N'-tetramethylurea tetrafluoroborate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate, O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate, and (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholine-carbomony hexafluorophosphate. In some embodiments, the coupling agent is n-propionic acid anhydride. Non-limiting examples of coupling additives include 4-(dimethylamino)pyridine, 1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole.

[0851] Non-limiting examples of bases used for "amide coupling conditions" include aliphatic amines (e.g., triethylamine, tributylamine, ethyl diisopropylamine, N-methylmorpholine, etc.), aromatic amines (e.g., pyridine, 2,6-dimethylpyridine, N-methylimidazole, etc.), and so on. In some embodiments, the base is triethylamine.

[0852] 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-methylpyrrolidone, dimethyl sulfoxide, etc.), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform, etc.), and combinations thereof. In some embodiments, the solvent is acetonitrile.

[0853] In some embodiments, the amide coupling conditions include a temperature range of about 120°C or lower. In some embodiments, the amide coupling conditions include a temperature range of about -20°C to about 120°C. In some embodiments, the amide coupling conditions include a temperature range of about 0°C to about 40°C.

[0854] As used herein, the term "palladium-catalyzed cross-coupling conditions" refers to reaction conditions under which an aryl halide or aryl sulfonate (e.g., trifluoromethanesulfonate, methanesulfonate, toluenesulfonate) is coupled with an organoboron reagent to form a compound (e.g., a biaryl compound) in the presence of a palladium catalyst and a base. In some embodiments, the organoboron reagent is aryl-R', where R' is B(OH)2, B(OR)2, where R is an unsubstituted or substituted alkyl group, BF4K, etc. Non-limiting examples of organoboron reagents include arylboronic acids (aryl-B(OH)2), arylboronic esters (e.g., aryl-B(OR)2, such as aryl-B(OC(Me)2C(Me)2O), aryl-B(OCH(Me)CH2C(Me)2O), aryl-B((1,2-di-O)C6H4) and aryl-B(OCH2C(Me)2CH2O)), and aryl trifluoroborates (e.g., aryl-BF3K). In some embodiments, the organoboron reagent is aryl-B(OC(Me)2C(Me)2O).

[0855] 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)palladium(II) dichloride, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, dichlorobis(triphenylphosphine)palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and [1,2-bis(diphenylphosphino)ethane]palladium(II) dichloride. The palladium (II) catalyst is composed of dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium(II), a palladium (II) precatalyst (palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate), or a palladium (O) precatalyst (tetra(triphenylphosphine)palladium(O), bis(dibenzylacetone)palladium(O), combined with a phosphine ligand, such as tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine, etc. In some embodiments, the palladium catalyst is dichlorobis(tricyclohexylphosphine)palladium(II).

[0856] In some embodiments, non-limiting examples of bases used for "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 hydrogen phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, etc.), aliphatic amines (e.g., dicyclohexylamine, N-methylmorpholine, triethylamine, etc.), and so on. In some embodiments, the base is potassium bicarbonate.

[0857] In some embodiments, the "palladium-catalyzed cross-coupling conditions" further include 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.

[0858] In some embodiments, the palladium-catalyzed cross-coupling conditions include a temperature range of 120°C or lower. In some embodiments, the palladium-catalyzed cross-coupling conditions include a temperature range of about 20°C to about 120°C. In some embodiments, the palladium-catalyzed cross-coupling conditions include a temperature range of about 75°C to about 95°C.

[0859] As used herein, the term "methanesulfonating agent" refers to an agent used to attach a methanesulfonyl or methanesulfonyl (i.e., CH3SO2-) group to a suitable hydroxyl or suitable amino group. In some embodiments, non-limiting examples of methanesulfonating agents include combinations of methanesulfonyl chloride, methanesulfonic anhydride, and methanesulfonic acid with activators such as oxalyl chloride, thionyl chloride, or cyanuryl chloride. In some embodiments, the methanesulfonating agent is methanesulfonic anhydride. In some embodiments, the methanesulfonating agent is methanesulfonyl chloride.

[0860] As used herein, the term "methanesulfonation conditions" refers to reaction conditions under which a methanesulfonyl or methanesulfonyl (i.e., CH3SO2-) group is attached to a suitable hydroxyl or suitable amino group. When attaching a methanesulfonyl group to a suitable hydroxyl group, the methanesulfonation conditions disclosed herein typically include a base, a catalyst, and a solvent.

[0861] In some embodiments, non-limiting examples of bases used for methanesulfonation conditions when the methanesulfonyl group is attached to a suitable hydroxyl group include aliphatic amines (e.g., triethylamine, diisopropylethylamine, N,N-dicyclohexylmethylamine, etc.) and aromatic amines (e.g., pyridine, 2,3,5-coridine, 2,4,6-coridine, N-methylimidazole, etc.). In some embodiments, the base is triethylamine.

[0862] In some embodiments, non-limiting examples of suitable catalysts for “methanesulfonation conditions” when the methanesulfonyl group is attached to a suitable hydroxyl group include 4-dimethylaminopyridine (DMAP), etc.

[0863] In some embodiments, non-limiting examples of solvents used for methanesulfonylation conditions when the methanesulfonyl group is attached to a suitable hydroxyl group include ethers (e.g., diethyl ether, 1,4-dioxane, cyclopentylmethyl 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-methylpyrrolidone, etc.), and combinations thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is tetrahydrofuran, and the catalyst is DMAP.

[0864] In some embodiments, when the methanesulfonyl group is attached to a suitable hydroxyl group, the methanesulfonation conditions include a temperature range of about 60°C or lower. In some embodiments, the methanesulfonation conditions include a temperature range of about -80°C to about 60°C. In some embodiments, the methanesulfonation conditions include a temperature range of about 0°C to about 40°C.

[0865] When a methanesulfonyl group is attached to a suitable amino group, the methanesulfonylation conditions disclosed herein typically include a solvent and optionally a base.

[0866] In some embodiments, non-limiting examples of bases used for methanesulfonylation conditions when the methanesulfonyl group is attached to a suitable amino group include alkylamines (e.g., triethylamine, N-methylmorpholine, tri-n-propylamine, ethyldiisopropylamine, tri-n-butylamine, etc.), aromatic amines (e.g., pyridine, 2,6-dimethylpyridine, methylpyridine, etc.), carbonates (e.g., sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, inorganic bases (e.g., sodium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, etc.), and alkoxide bases (e.g., sodium tert-amyl alcohol, sodium tert-butoxide, etc.). In some embodiments, the base is triethylamine.

[0867] In some embodiments, non-limiting examples of solvents used for methanesulfonylation conditions when the methanesulfonyl group is attached to a suitable amino group include ethers (e.g., diethyl ether, 1,4-dioxane, cyclopentylmethyl 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-methylpyrrolidone, etc.), and combinations thereof. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is cyclopentylmethyl ether.

[0868] In some embodiments, when the methanesulfonyl group is attached to a suitable amino group, the methanesulfonation conditions include a temperature range of about 100°C or lower. In some embodiments, the methanesulfonation conditions include a temperature range of about -20°C to about 100°C. In some embodiments, the methanesulfonation conditions include a temperature range of about -10°C to about 20°C. In some embodiments, the methanesulfonation conditions include a temperature range of about 20°C to about 120°C. In some embodiments, the methanesulfonation conditions include a temperature range of about 70°C to about 90°C.

[0869] The term "borylation conditions" refers to the reaction conditions under which a compound (e.g., an aryl halide) is converted into an organoboron reagent (e.g., an arylboron derivative, such as compound V). Borylation conditions disclosed herein generally include a boronizing agent and an organometallic reagent or catalyst. Non-limiting examples of boronizing agents when boronation conditions include both a boronizing agent and an organometallic reagent include trimethyl borate, triethyl borate, pinacolborane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane, β-catecholborane, 2-bromo-1,3,2-benzodioxacyclopentaborene, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. In some embodiments, the boronizing agent is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane or pinacolborane isopropoxyborate. Non-limiting examples of organometallic reagents include lithium metal, magnesium metal, n-butyllithium, sec-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-lithium chloride complex.

[0870] In some embodiments, the boronization 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.

[0871] In some embodiments, the borylation conditions include a temperature range of about 40°C or lower. In some embodiments, the borylation conditions include a temperature range of about -80°C to about 40°C. In some embodiments, the borylation conditions include a temperature range of about -40°C to about 20°C. In some embodiments, the borylation conditions include a temperature range of about -20°C to about 20°C.

[0872] In some embodiments, when the boronizing conditions include a boronizing agent and a catalyst, non-limiting examples of the boronizing agent include bis(neopentylethylene glycol)diboron, tetrahydroxydiboron, bis(hexenyl glycol)diboron, and bis(pinacolyl)diboron. In some embodiments, the boronizing agent is bis(pinacolyl)diboron. Non-limiting examples of the catalyst include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II) dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. In one embodiment, the catalyst is [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

[0873] In some embodiments, non-limiting examples of solvents used for the boronization conditions include ethers (e.g., diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, etc.), aromatic hydrocarbon solvents (e.g., benzene, toluene, xylene, etc.), chlorinated solvents (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.

[0874] In some embodiments, the borylation conditions include a temperature range of about 130°C or lower. In some embodiments, the borylation conditions include a temperature range of about 10°C to about 130°C. In some embodiments, the alkynylation conditions include a temperature range of about 80°C to about 110°C.

[0875] In addition, the abbreviations used in this article have the following meanings:

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882] Unless otherwise stated, the methods and techniques disclosed herein are generally performed in accordance with conventional methods well known in the art and as described in the various general and more specific references cited and discussed throughout this specification. See, for example, Loudon, Organic Chemistry, 5th ed., New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th ed., Wiley-Interscience, 2013.

[0883] In some cases, the methods disclosed herein include the step of forming a salt of the compounds disclosed herein.

[0884] The compounds described herein can be purified by any method known in the art, including chromatographic methods such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, rapid column chromatography, supercritical fluid chromatography (SFC), and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases, as well as ion exchange resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2 nd ed., ed. LRSnyder and JJ Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0885] In any process of preparing the compounds of this invention, it may be necessary and / or desirable to protect any sensitive or reactive groups on the relevant molecules. This can be achieved by conventional protecting groups as described in standard work, for example, TWGreene and PGMUTS, Protective Groups in Organic Synthesis, 4 th ed., Wiley, New York 2006. The protecting base can be removed at a convenient subsequent stage using methods known in the art.

[0886] Exemplary chemical entities that can be used in the methods of implementation will now be described with reference to illustrative synthetic schemes used herein for their general preparation and subsequent specific examples. Those skilled in the art will recognize that the conversions shown in the following schemes can be carried out in any order compatible with the functionality of the particular side-chain groups. In some embodiments, each reaction described in the general scheme is operated at a temperature from about -80°C to the reflux temperature of the organic solvent used.

[0887] The compounds disclosed herein exhibit atropisomerism caused by steric hindrance affecting the axial rotation rate around single bonds. Characterization techniques such as NMR and HPLC reveal that the resulting conformational isomers are distinct entities. The compounds disclosed herein can exist as mixtures of atropisomers. However, the 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 proportions of atropisomers in equilibrium can be inconsistent. Depending on the separation and characterization conditions (which may include, but are not limited to, treatment, solvents used, and temperature), the characterization data provided herein may not represent equilibrium states.

[0888] This disclosure provides, in some embodiments, methods and intermediates for preparing compounds of formula I and their eutectics, solvates, salts, and combinations thereof. In other embodiments, this disclosure provides methods for preparing intermediates that can be used to prepare compounds of formula I and their eutectics, solvates, salts, and combinations thereof.

[0889] In some embodiments, a method is provided for preparing a VI compound or its eutectic, solvate, salt, or combination thereof:

[0890]

[0891] The method includes using a compound of formula VIII:

[0892]

[0893] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[0894] Compound of formula IX:

[0895]

[0896] Or its eutectic, solvate or combination thereof,

[0897] Alkali,

[0898] Solvent, and

[0899] catalyst,

[0900] To provide a compound of formula VI or a eutectic, solvate, salt or combination thereof.

[0901] In some embodiments, the compound of formula VIII is a compound of formula VIII-02:

[0902]

[0903] Or its eutectic, solvate or combination thereof, wherein HX is a chiral or achiral acid.

[0904] In a specific embodiment, HX is selected from 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)succinic acid, benzyloxycarbonyl-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methylhexanoic acid, (+)-mentholoxy Glycoacetic 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, (–)-acetylmynic acid, (R)-(–)-citric acid, (–)-camphoric acid and (R)-mandelic acid.

[0905] In some embodiments, HX is a chiral acid. In specific embodiments, HX is selected from 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)succinic acid, benzyloxycarbonyl-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methylhexanoic acid, (+)-mentholoxy The compounds include glycolic 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, (–)-acetylmethylenediamine, (R)-(–)-citric acid, (–)-camphoric acid, and (R)-mandelic acid. In some embodiments, HX is (R)-mandelic acid. In some embodiments, HX is N-Boc-D-leucine.

[0906] In some implementations, HX is (–)-N-acetyl-D-leucine.

[0907] In some embodiments, HX is a non-chiral acid. In certain embodiments, HX is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and phosphoric acid. In some embodiments, HX is methanesulfonic acid.

[0908] In some embodiments, the catalyst comprises a palladium catalyst and a copper catalyst. In a particular embodiment, the palladium catalyst is selected from [(π-allyl)PdCl]2, Pd(acac)2, (SIPr)PdCl2, PdCl2(PPh3)2, PdCl2, Pd(OAc)2, PdCl2(CH3CN)2, and Pd2(dba)3, optionally in combination with a tertiary phosphine. In some embodiments, the tertiary phosphine is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, and 1,1'-bis(diphenylphosphine)ferrocene. In a particular embodiment, the copper catalyst is selected from copper iodide (I), copper bromide (I), copper chloride (I), and combinations thereof. In a particular embodiment, the catalyst comprises PdCl2(PPh3)2 and copper iodide (I).

[0909] In some embodiments, the catalyst is a palladium catalyst. In specific embodiments, the palladium catalyst is selected from [(π-allyl)PdCl]2, Pd(acac)2, (SIPr)PdCl2, PdCl2(PPh3)2, PdCl2, Pd(OAc)2, PdCl2(CH3CN)2, and Pd2(dba)3, optionally in combination with a tertiary phosphine. In some embodiments, the tertiary phosphine is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, and 1,1'-bis(diphenylphosphine)ferrocene. In some embodiments, the palladium catalyst is PdCl2(PPh3)2.

[0910] In a particular embodiment, the copper catalyst is selected from copper iodide (I), copper bromide (I), copper chloride (I), and combinations thereof.

[0911] In some embodiments, the catalyst is a copper catalyst. In specific embodiments, the copper catalyst is selected from copper iodide (I), copper bromide (I), and copper chloride (I).

[0912] In some embodiments, the base is selected from triethylamine, diisopropylamine, 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 some embodiments, the base is triethylamine.

[0913] In some embodiments, the solvent is selected from 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-methylpyrrolidone), water, acetonitrile, and combinations thereof.

[0914] In some embodiments, the solvent is selected from 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-methylpyrrolidone), water, and combinations thereof. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0915] In some embodiments, the method is performed in a temperature range of about 120°C or lower. In some embodiments, the method is performed in a temperature range of about 0°C to about 120°C. In a particular embodiment, the method is performed in a temperature range of about 50°C to about 80°C.

[0916] In some embodiments, a method is provided for preparing a compound of formula IV or a eutectic, solvate, salt, or combination thereof:

[0917]

[0918] The method includes using a compound of formula VI:

[0919]

[0920] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[0921] Compound of Formula VII:

[0922]

[0923] Or its eutectic, solvate, salt or combination thereof,

[0924] Alkali,

[0925] Solvent,

[0926] Optional, coupling agent

[0927] And optionally, an activator.

[0928] In some embodiments, a method is provided for preparing a compound of formula IV or a eutectic, solvate, salt, or combination thereof:

[0929]

[0930] The method includes using a compound of formula VI:

[0931]

[0932] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[0933] Compound of Formula VII:

[0934]

[0935] Or its eutectic, solvate, salt or combination thereof,

[0936] Coupling agent or activator,

[0937] alkali, and

[0938] Solvent,

[0939] To provide a compound of formula IV or a eutectic, solvate, salt or combination thereof.

[0940] In some embodiments, the coupling agent 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.

[0941] In some embodiments, the coupling agent is selected from n-propylphosphonic anhydride, 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, and 1-ethyl-3-(3-dimethylamino) Propyl) carbodiimide, carbonyl diimidazole, isobutyl chloroformate, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate, O-benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate, O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate, O-(benzotriazol-1-yl)-N, N,N',N'-Tetramethylurea tetrafluoroborate, O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate, (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholinocarbium Hexafluorophosphate, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, boric acid, tetramethyl orthosilicate, trimethoxysilane, diphenylphosphine chloride, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, triisopropyl borate, phenylboronic acid, 3,5-bis(trifluoromethyl)phenylboronic acid, 3-nitrophenylboronic acid, and 2-iodophenylboronic acid.

[0942] In some embodiments, the coupling agent is selected from 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, carbonyl diimidazole, isobutyl chloroformate, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate, O-benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate, etc. The formulations include methylurea hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate, O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate, and (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholine-carbomony hexafluorophosphate. In a specific embodiment, the coupling agent is n-propylphosphonic anhydride. In a specific embodiment, the coupling agent is n-propylphosphonic cyclic anhydride.

[0943] In some embodiments, the activator is selected from oxalyl chloride, thionyl chloride, diphenylphosphine chloride, neopentyl chloride, cyanuryl chloride, and methanesulfonyl chloride, wherein compounds of formula VII-B are:

[0944]

[0945] Its eutectic, solvate, salt or combination is produced from the compound of formula VII or its eutectic, solvate, salt or combination.

[0946] In some embodiments, the activator is selected from oxalyl chloride, thionyl chloride, and diphenylphosphine chloride, wherein the compound of formula VII-B is:

[0947]

[0948] It or its eutectic, solvate, salt or combination thereof is prepared from a compound of formula VII or its eutectic, solvate or salt or combination thereof.

[0949] In some embodiments, the base is selected from triethylamine, tributylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine, 2,6-dimethylpyridine, and N-methylimidazole. In a particular embodiment, the base is triethylamine.

[0950] In some embodiments, the solvent is selected from 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-methylpyrrolidone, dimethyl sulfoxide), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform), nitriles (propionitrile, butyronitrile, acetonitrile), and combinations thereof. In a particular embodiment, the solvent is acetonitrile.

[0951] In some embodiments, the method is performed in a temperature range of about 120°C or lower. In some embodiments, the method is performed in a temperature range of about -20°C to about 120°C. In a particular embodiment, the method is performed in a temperature range of about 0°C to about 40°C.

[0952] In some embodiments, the method further comprises a coupling additive. In some embodiments, the coupling additive is selected from 4-(dimethylamino)pyridine, N-hydroxysuccinimide, ethyl cyanohydroxyimino, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, and N-methylimidazole.

[0953] In some embodiments, a method is provided for preparing a compound of formula III or a eutectic, solvate, salt, or combination thereof:

[0954]

[0955] The method includes using a compound of formula IV:

[0956]

[0957] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[0958] Compound of formula V:

[0959]

[0960] Or its eutectic, solvate, salt or combination thereof, wherein R 1 It is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O).

[0961] Palladium catalyst,

[0962] alkali, and

[0963] Solvent,

[0964] To provide a compound of formula III or a eutectic, solvate, salt or combination thereof.

[0965] In some embodiments, methods are provided for preparing compounds of formula III or their eutectics, solvates, salts, or combinations thereof:

[0966]

[0967] The inclusion includes compounds of formula IV:

[0968]

[0969] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[0970] Compound of formula V:

[0971]

[0972] Or its eutectic, solvate, salt or combination thereof, wherein R 1 It is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF4K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O).

[0973] Palladium catalyst,

[0974] alkali, and

[0975] Solvent,

[0976] To provide a compound of formula III or a eutectic, solvate, salt or combination thereof.

[0977] In some implementations, R 1 It is B(OC(Me)2C(Me)2O).

[0978] In some embodiments, the palladium catalyst is selected from dichlorobis(tricyclohexylphosphine)palladium(II), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II)dichloride, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II), dichlorobis(triphenylphosphine)palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II), [1,2-bis(diphenylphosphine)ethane]palladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)oxanthracene]palladium(II), chloro[(tricyclohexylphosphine)-2-(2′-aminodiphenyl)]palladium(II), [(tricyclohexylphosphine)-2-(2′-aminodiphenyl)]methanesulfonate palladium(II), PCy3PdG4, palladium chloride, palladium acetate, and palladium trifluoroacetate. In some embodiments, the palladium catalyst further comprises a phosphine ligand, wherein the palladium catalyst is selected from palladium chloride, palladium acetate, palladium trifluoroacetate, dichloro(1,5-cyclooctadiene)palladium(II), allyl palladium(II) chloride dimer, palladium(II) acetylacetone, tetra(triphenylphosphine)palladium(O), and bis(dibenzylacetone)palladium(O). In a particular embodiment, the phosphine ligand is selected from di-tert-butyl(4-dimethylaminophenyl)phosphine, dicyclohexyl(4-dimethylaminophenyl)phosphine, 1,2-bis(diphenylphosphine)ethane, 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl Diphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxydiphenyl, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1,3-bis(diphenylphosphino)propane, ethylene bis(diphenylphosphine), 1,1′-ferrocene di-bis(diphenylphosphine), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene, tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine, tri-tert-butylphosphine, cyclohexyldi-tert-butylphosphine, and dicyclohexyltert-butylphosphine. In some embodiments, the palladium catalyst is dichlorobis(tricyclohexylphosphine)palladium(II).

[0979] In some embodiments, the base is selected from potassium bicarbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, dipotassium hydrogen phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, and triethylamine. In a particular embodiment, the base is potassium bicarbonate.

[0980] In some embodiments, the solvent is selected from 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-methylpyrrolidone), water, and combinations thereof. In a particular embodiment, the solvent is a mixture of n-butyl acetate and water.

[0981] In some embodiments, the method is performed in a temperature range of about 120°C or lower. In some embodiments, the method is performed in a temperature range of about 20°C to about 120°C. In a particular embodiment, the method is performed in a temperature range of about 75°C to about 95°C.

[0982] In some embodiments, the method for preparing the compound of formula III or its eutectic, solvate, salt, or combination thereof:

[0983]

[0984] Further includes:

[0985] (a) Combining a compound of formula III or its eutectic, solvate, salt or combination thereof with a second solvent and an acid to provide a compound of formula III-02:

[0986]

[0987] Or its eutectic, solvate, or combination thereof, wherein HY is selected from 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

[0988] (b) Free-basing the compound of formula III-02 or its eutectic, solvate or combination thereof by combining the compound of formula III-02 or its eutectic, solvate or combination thereof with a second base and a third solvent to provide the compound of formula III or its eutectic, solvate or combination thereof.

[0989] In some implementations, HY is methanesulfonic acid.

[0990] In some embodiments, the second solvent is selected from 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.

[0991] In some embodiments, the compound of formula III-02 is produced as dimethylsulfonic acid.

[0992] In some embodiments, the compound of formula III-02 is produced as a solvate. In specific 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 cyclopentylmethyl 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 other embodiments, the compound of formula III-02 is produced as a methyl tert-butyl ether solvate. In other embodiments, the compound of formula III-02 is produced as a toluene solvate. In other embodiments, the compound of formula III-02 is produced as a cyclopentylmethyl ether solvate.

[0993] In some embodiments, the compound of formula III-02 is produced in a temperature range of about 20°C or lower. In some embodiments, the compound of formula III-02 is produced in a temperature range of about -20°C to about 20°C.

[0994] In some embodiments, the second base is selected from 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 a particular embodiment, the second base is sodium hydroxide.

[0995] In some embodiments, the third solvent is selected from 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 a particular embodiment, the third solvent is a mixture of 2-methyltetrahydrofuran and water.

[0996] In some embodiments, the free alkalization step is performed in a temperature range of about 80°C or lower. In some embodiments, the free alkalization step is performed in a temperature range of about -20°C to about 80°C. In a particular embodiment, the free alkalization step is performed in a temperature range of about 0°C to about 50°C.

[0997] In some embodiments, the method for preparing the compound of formula III or its eutectic, solvate, salt, or combination thereof:

[0998]

[0999] Further includes:

[1000] (a) Combining a compound of formula III or its eutectic, solvate, salt or combination thereof with a second solvent and an acid to provide a compound of formula III-02:

[1001]

[1002] Or its eutectic, solvate, or combination thereof, wherein HY is selected from 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

[1003] (b) The compound of formula III-02 or its eutectic, solvate or combination thereof is alkalized by combining the compound of formula III-02 or its eutectic, solvate or combination thereof with a second base and a third solvent to provide the compound of formula III or its eutectic, solvate or combination thereof.

[1004] In some implementations, HY is methanesulfonic acid.

[1005] In some embodiments, the second solvent is selected from 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.

[1006] In some embodiments, the compound of formula III-02 is produced as a solvate. In specific 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 cyclopentylmethyl 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 other embodiments, the compound of formula III-02 is produced as a methyl tert-butyl ether solvate. In other embodiments, the compound of formula III-02 is produced as a toluene solvate. In other embodiments, the compound of formula III-02 is produced as a cyclopentylmethyl ether solvate.

[1007] In some embodiments, the compound of formula III-02 is produced in a temperature range of about 20°C or lower. In some embodiments, the compound of formula III-02 is produced in a temperature range of about -20°C to about 20°C.

[1008] In some embodiments, the second base is selected from 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 a particular embodiment, the second base is sodium hydroxide.

[1009] In some embodiments, the third solvent is selected from 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 a particular embodiment, the third solvent is a mixture of 2-methyltetrahydrofuran and water.

[1010] In some embodiments, the free alkalization step is performed in a temperature range of about 80°C or lower. In some embodiments, the free alkalization step is performed in a temperature range of about -20°C to about 80°C. In a particular embodiment, the free alkalization step is performed in a temperature range of about 0°C to about 50°C.

[1011] In some embodiments, methods are provided for preparing compounds of formula I or their eutectics, solvates, salts, or combinations thereof:

[1012]

[1013] The method includes using a compound of formula III:

[1014]

[1015] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[1016] Methanesulfonating reagent, and

[1017] Solvent,

[1018] To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

[1019] In some embodiments, the methanesulfonating agent is selected from methanesulfonyl chloride and methanesulfonic anhydride. In a particular embodiment, the methanesulfonating agent is methanesulfonic anhydride.

[1020] In some embodiments, the solvent is selected from esters (e.g., ethyl acetate, isopropyl acetate), ethers (e.g., cyclopentylmethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), nitriles (e.g., acetonitrile), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), aromatic hydrocarbon solvents (e.g., toluene, xylene), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform), and combinations thereof. In a particular embodiment, the solvent used in the methanesulfonation step is cyclopentylmethyl ether.

[1021] In some embodiments, the method is performed in a temperature range of about 120°C or lower. In some embodiments, the method is performed in a temperature range of about 20°C to about 120°C. In a particular embodiment, the method is performed in a temperature range of about 70°C to about 90°C.

[1022] In some embodiments, methods are provided for preparing compounds of formula I or their eutectics, solvates, salts, or combinations thereof:

[1023]

[1024] The method includes:

[1025] (a) To make compound III:

[1026]

[1027] Or its eutectic, solvate, salt, or combination thereof, combined with a methanesulfonating agent, a base, and a solvent, to provide a compound of formula II:

[1028]

[1029] or its eutectic, solvate, salt or combination thereof; and

[1030] (b) Hydrolyzing the compound of formula II or its eutectic, solvate, salt or combination thereof in a solvent with a nucleophile and optionally a phase-transfer catalyst to provide the compound of formula I or its eutectic, solvate, salt or combination thereof.

[1031] In some embodiments, the methanesulfonating agent is selected from methanesulfonyl chloride and methanesulfonic anhydride. In a particular embodiment, the methanesulfonating agent is methanesulfonyl chloride.

[1032] In some 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 some embodiments, the phase transfer catalyst is selected from tetra-n-butylammonium chloride, benzyltri-n-butylammonium bromide, 1-methylimidazolium hydrogen sulfate, tetra-n-butylammonium hydrogen sulfate, and tetra-n-butylphosphonium chloride. In a particular embodiment, the phase transfer catalyst is tetra-n-butylammonium hydrogen sulfate.

[1033] In some embodiments, the base is selected from N-methylmorpholine, tri-n-propylamine, ethyl diisopropylamine, tri-n-butylamine, triethylamine, pyridine, 2,6-dimethylpyridine, cefadiol, sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium tert-amyl alcohol, and sodium tert-butoxide. In a particular embodiment, the base is triethylamine.

[1034] In some embodiments, the solvent used in the methanesulfonation step is selected from 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), chlorinating solvents (e.g., dichloromethane), nitriles (e.g., acetonitrile), and combinations thereof. In a particular embodiment, the solvent used in the methanesulfonation step is 2-methyltetrahydrofuran.

[1035] In some embodiments, the methanesulfonation step is performed in a temperature range of about 100°C or lower. In some embodiments, the methanesulfonation step is performed in a temperature range of about -20°C to about 100°C. In a particular embodiment, the methanesulfonation step is performed in a temperature range of about -10°C to about 20°C.

[1036] In some embodiments, the nucleophile used in the hydrolysis step is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiol, N-acetylcysteine, sodium thiophene, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium tert-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine. In a particular embodiment, the nucleophile used in the hydrolysis step is sodium hydroxide.

[1037] In some embodiments, the solvent used for the hydrolysis step is selected from 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-methylpyrrolidone), water, and combinations thereof. In a particular embodiment, the solvent used for the hydrolysis step is water and 2-methyltetrahydrofuran.

[1038] In some embodiments, the hydrolysis step is carried out in a temperature range of about 100°C or lower. In some embodiments, the hydrolysis step is carried out in a temperature range of about -20°C to about 100°C. In a particular embodiment, the hydrolysis step is carried out in a temperature range of about 10°C to about 60°C.

[1039] In some embodiments, methods are provided for preparing compounds of formula I or their eutectics, solvates, salts, or combinations thereof:

[1040]

[1041] The method includes:

[1042] (a) Compound VIII under alkynylation conditions:

[1043]

[1044] Or its eutectic, solvate, salt, or combination with compounds of formula IX:

[1045]

[1046] Or its eutectic, solvate, or combination thereof to provide a compound of formula VI:

[1047]

[1048] Or its eutectic, solvate, salt or combination thereof;

[1049] (b) Under amide coupling conditions, reacting a compound of formula VI or its eutectic, solvate, salt, or combination with a compound of formula VII:

[1050]

[1051] Or its eutectic, solvate, salt or combination thereof to provide a compound of formula IV:

[1052]

[1053] Or its eutectic, solvate, salt or combination thereof;

[1054] (c) Under palladium-catalyzed cross-coupling conditions, reacting a compound of formula IV or its eutectic, solvate, salt, or combination with a compound of formula V:

[1055]

[1056] Or its eutectic, solvate, salt or combination thereof, wherein R 1 B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O) are used to provide compounds of formula III:

[1057]

[1058] or its eutectic, solvate, salt or combination thereof; and

[1059] (d) Under methanesulfonation conditions, a compound of formula III or its eutectic, solvate, salt or combination thereof is combined with a methanesulfonating agent to provide a compound of formula I or its eutectic, solvate, salt or combination thereof.

[1060] In some embodiments, methods are provided for preparing compounds of formula I or their eutectics, solvates, salts, or combinations thereof:

[1061]

[1062] The method includes:

[1063] (a) Compound VIII under alkynylation conditions:

[1064]

[1065] Or its eutectic, solvate, salt, or combination with compounds of formula IX:

[1066]

[1067] Or its eutectic, solvate, or combination thereof to provide a compound of formula VI:

[1068]

[1069] Or its eutectic, solvate, salt or combination thereof;

[1070] (b) Under amide coupling conditions, reacting a compound of formula VI or its eutectic, solvate, salt, or combination with a compound of formula VII:

[1071]

[1072] Or its eutectic, solvate, salt or combination thereof to provide a compound of formula IV:

[1073]

[1074] Or its eutectic, solvate, salt or combination thereof;

[1075] (c) Under palladium-catalyzed cross-coupling conditions, reacting a compound of formula IV or its eutectic, solvate, salt, or combination with a compound of formula V:

[1076]

[1077]

[1078] Or its eutectic, solvate, salt or combination thereof, wherein R 1 B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF4K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O) are used to provide compounds of formula III:

[1079]

[1080] or its eutectic, solvate, salt or combination thereof; and

[1081] (d) Under methanesulfonation conditions, a compound of formula III or its eutectic, solvate, salt or combination thereof is combined with a methanesulfonating agent to provide a compound of formula I or its eutectic, solvate, salt or combination thereof.

[1082] In some embodiments, the method for preparing the compound of formula I or its eutectic, solvate, salt, or combination thereof:

[1083]

[1084] Further includes:

[1085] (a) To provide compound I-02 by combining the compound of formula I with a sodium source and a solvent to form a sodium salt of the compound of formula I:

[1086]

[1087] and

[1088] (b) Neutralize compound I-02 in a solvent with acid to provide compound I.

[1089] In some embodiments, the method for preparing the compound of formula I or its eutectic, solvate, salt, or combination thereof:

[1090]

[1091] Further includes:

[1092] (a) To provide compound I-02 by combining the compound of formula I with a sodium source and a solvent to form a sodium salt of the compound of formula I:

[1093]

[1094] and

[1095] (b) Neutralize compound I-02 with acid to provide compound I.

[1096] In some embodiments, the sodium source used in step (a) of sodium salt formation is selected from sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium phosphate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium tert-butoxide, sodium hexamethyldisilazane, and metallic sodium, and alcohols selected from methanol, ethanol, isopropanol, 1-propanol, n-butanol, and sec-butanol. In a particular embodiment, the sodium source is sodium ethoxide. In a particular embodiment, the sodium source is sodium hydroxide.

[1097] In some embodiments, the solvent used in the sodium salt formation step (a) is selected from 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 a particular embodiment, the solvent for the sodium salt formation step is ethanol and n-heptane.

[1098] In some embodiments, the sodium salt formation step (a) is performed at a temperature range of about 100°C or lower. In some embodiments, the sodium salt formation step is performed at a temperature range of about -20°C to about 100°C. In a particular embodiment, the sodium salt formation step is performed at a temperature range of about 0°C to about 50°C.

[1099] In some embodiments, the acid used in neutralization step (b) is selected from 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 a particular embodiment, the acid used in the neutralization step is acetic acid.

[1100] In some embodiments, the solvent used in neutralization step (b) is selected from water, ethers (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether), hydrocarbon solvents (e.g., n-hexane, n-heptane, 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, isopropanol, tert-butanol), and combinations thereof. In a particular embodiment, the solvent used in neutralization step (b) is water and an alcohol (e.g., methanol, ethanol, isopropanol, tert-butanol). In a particular embodiment, the solvent used in neutralization step (b) is water and ethanol. In a particular embodiment, the solvent used in neutralization step (b) is water. In a particular embodiment, the ratio of acid to water is 2:5 to 2:30. In a particular embodiment, the ratio of acetic acid to water is 2:5 to 2:30.

[1101] In some embodiments, the neutralization step (b) is performed at a temperature range of about 100°C or lower. In some embodiments, the neutralization step is performed at a temperature range of about -20°C to about 100°C. In a particular embodiment, the neutralization step is performed at a temperature range of about 0°C to about 50°C.

[1102] In some embodiments, methods are provided for preparing compounds of formula I or their eutectics, solvates, salts, or combinations thereof:

[1103]

[1104] The method includes:

[1105] (a) To make compound IV:

[1106]

[1107] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[1108] Alkali,

[1109] Solvent,

[1110] Catalyst, and

[1111] Compound of formula V-04-A:

[1112]

[1113] Or its eutectic, solvate, salt or combination thereof,

[1114] Where R is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O).

[1115] To provide compound II:

[1116]

[1117] or its eutectic, solvate, salt or combination thereof; and

[1118] (b) Hydrolyzing a compound of formula II or its eutectic, solvate, salt or combination thereof with a base, solvent and optionally a phase transfer catalyst to provide a compound of formula I or its eutectic, solvate, salt or combination thereof.

[1119] In some implementations, R is B(OC(Me)2C(Me)2O).

[1120] In some embodiments, the catalyst used in step (a) is selected from bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium dichloride (II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium dichloride (II), dichlorobis(triphenylphosphine)palladium (II), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II), [1,2-bis(diphenylphosphino)ethane]palladium dichloride (II), and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)oxanthracene]palladium (II). In some embodiments, the catalyst used in step (a) is a palladium (II) precatalyst (e.g., palladium (II) chloride, palladium (II) acetate, palladium (II) trifluoroacetate or palladium (O) precatalyst (e.g., tetrakis(triphenylphosphine)palladium (O), bis(dibenzylacetone)palladium (O)) and the catalyst used in step (a) further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine). In some embodiments, the catalyst used in step (a) is selected from palladium (II) chloride, palladium (II) acetate, palladium (II) trifluoroacetate, tetrakis(triphenylphosphine)palladium (O) and bis(dibenzylacetone)palladium (O). In some embodiments, the palladium catalyst used in step (a) is palladium (II) chloride and cyclohexyldiphenylphosphine.

[1121] In some embodiments, the base used in step (a) is selected from 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, dipotassium hydrogen phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine. In a particular embodiment, the base used in step (a) is potassium bicarbonate.

[1122] In some embodiments, the solvent used in step (a) is selected from 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 some embodiments, the solvent used in step (a) is selected from 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 a particular embodiment, the solvent used in step (a) is 2-methyltetrahydrofuran and water.

[1123] In some embodiments, step (a) is performed at a temperature range of about 120°C or lower. In some embodiments, step (a) is performed at a temperature range of about 20°C to about 120°C. In a particular embodiment, step (a) is performed at a temperature range of about 65°C to about 75°C.

[1124] In some embodiments, the base used in step (b) is selected from 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]octane (DABCO)). In some embodiments, the base used in step (b) is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, bicarbonate bases, sodium bicarbonate, potassium bicarbonate, benzyltrimethylammonium hydroxide, choline hydroxide, sodium or potassium methoxide, sodium or potassium ethoxide, triethylamine, DABCO, DBU, and diethylamine. In a particular embodiment, the base used in step (b) is sodium hydroxide.

[1125] In some embodiments, the solvent used in step (b) is selected from 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 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 a particular embodiment, the solvent used in step (b) is 2-methyltetrahydrofuran.

[1126] 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 ammonium salts (e.g., tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium hydrogen sulfate) and phosphonium salts (e.g., tetrabutylphosphonium chloride). In a particular embodiment, the phase transfer catalyst used in step (b) is selected from tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium hydrogen sulfate, and tetrabutylphosphonium chloride.

[1127] In some embodiments, step (b) is performed in a temperature range of about 100°C or lower. In some embodiments, step (b) is performed in a temperature range of about -20°C to about 100°C. In a particular embodiment, step (b) is performed in a temperature range of about 10°C to about 60°C.

[1128] In some embodiments, methods are provided for preparing compounds of formula I or their eutectics, solvates, salts, or combinations thereof:

[1129]

[1130] The method includes using a compound of formula IV:

[1131]

[1132] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[1133] Alkali,

[1134] Solvent,

[1135] Catalyst, and

[1136] Compound of formula V-03-A:

[1137]

[1138] Or its eutectic, solvate, salt or combination thereof,

[1139] Where R is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O).

[1140] To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

[1141] In some implementations, R is B(OC(Me)2C(Me)2O).

[1142] In some embodiments, the catalyst is selected from bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, [1,2-bis(diphenylphosphine)ethane]palladium(II) dichloride, and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium(II). In some embodiments, the catalyst is a palladium(II) precatalyst (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or a palladium(O) precatalyst (e.g., tetra(triphenylphosphine)palladium(O), bis(dibenzylideneacetone)palladium(O)) and the catalyst further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine). In some embodiments, the catalyst is selected from palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetra(triphenylphosphine)palladium(O), and bis(dibenzylacetone)palladium(O), and the catalyst further comprises a phosphine ligand selected from tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, and dicyclohexylphenylphosphine. In some embodiments, the palladium catalyst is palladium(II) chloride and cyclohexyldiphenylphosphine.

[1143] In some embodiments, the base is selected from 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 hydrogen phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine. In a particular embodiment, the base is potassium bicarbonate.

[1144] In some embodiments, the solvent is selected from 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 some embodiments, the solvent is selected from 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 a particular embodiment, the solvent is 2-methyltetrahydrofuran and water.

[1145] In some embodiments, the method is performed in a temperature range of about 120°C or lower. In some embodiments, the method is performed in a temperature range of about 20°C to about 120°C. In a particular embodiment, the method is performed in a temperature range of about 65°C to about 75°C.

[1146] In some embodiments, a method for preparing a compound of formula V-03-A is provided:

[1147]

[1148] The method includes:

[1149] (a) Make compound v:

[1150]

[1151] Or its eutectic, 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)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O), combined with a methanesulfonating agent, a base and a solvent to provide compound V-04-A:

[1152]

[1153] or its eutectic, solvate, salt or combination thereof; and

[1154] (b) Hydrolyzing a compound of formula V-04-A or its eutectic, solvate, salt or combination thereof using a nucleophile, solvent and optionally a phase-transfer catalyst to provide a compound of formula V-03-A or its eutectic, solvate, salt or combination thereof.

[1155] In some implementations, R is B(OC(Me)2C(Me)2O).

[1156] In some embodiments, the methanesulfonating agent used in step (a) is methanesulfonic anhydride. In some embodiments, the methanesulfonating agent used in step (a) is methanesulfonyl chloride.

[1157] In some embodiments, the base used in step (a) is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, tri-n-propylamine, ethyldiisopropylamine, tri-n-butylamine), aromatic amines (e.g., pyridine, 2,6-dimethylpyridine, pyridine), inorganic bases (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, potassium monohydrogen phosphate), and alkoxide bases (e.g., sodium tert-amyloxide, sodium tert-butoxide). In some embodiments, the base used in step (a) is selected from triethylamine, N-methylmorpholine, tri-n-propylamine, ethyldiisopropylamine, tri-n-butylamine, pyridine, 2,6-dimethylpyridine, chloridine, sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium tert-amyloxide, and sodium tert-butoxide. In a particular embodiment, the base used in step (a) is triethylamine.

[1158] In some embodiments, the solvent used in step (a) is selected from 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 some embodiments, the solvent used in step (a) is selected from diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof. In a particular embodiment, the solvent used in step (a) is 2-methyltetrahydrofuran.

[1159] In some embodiments, step (a) is performed in a temperature range of about 100°C or lower. In some embodiments, step (a) is performed in a temperature range of about -20°C to about 100°C. In a particular embodiment, step (a) is performed in a temperature range of about -10°C to about 20°C.

[1160] In some embodiments, the nucleophile used in step (b) is selected from hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide), thiophiles (e.g., sodium ethanethiol, N-acetylcysteine, sodium thiophene), choline, alkoxide bases (e.g., sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium tert-butoxide), and amines (e.g., methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, hydroxylamine). In some embodiments, the nucleophile used in step (b) is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiol, N-acetylcysteine, sodium thiophene, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium tert-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine. In a particular embodiment, the base used in step (b) is sodium hydroxide.

[1161] In some embodiments, the solvent used in step (b) is selected from 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 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 a particular embodiment, the solvent used in step (b) is 2-methyltetrahydrofuran and water.

[1162] 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 ammonium salts (e.g., tetrabutylammonium bisulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium bisulfate) and phosphonium salts (e.g., tetrabutylphosphonium chloride). In some embodiments, the phase transfer catalyst used in step (b) is selected from tetrabutylammonium bisulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium bisulfate, and tetrabutylphosphonium chloride. In a particular embodiment, the phase transfer catalyst used in step (b) is tetrabutylammonium bisulfate.

[1163] In some embodiments, step (b) is performed in a temperature range of about 100°C or lower. In some embodiments, step (b) is performed in a temperature range of about -20°C to about 100°C. In a particular embodiment, step (b) is performed in a temperature range of about 10°C to about 60°C.

[1164] In some embodiments, methods are provided for preparing compounds of formula V-5 or their eutectics, solvates, salts, or combinations thereof:

[1165]

[1166] The method includes:

[1167] (a) Compounds of formula VA:

[1168]

[1169]

[1170] Or its eutectic, solvate, salt, or combination thereof, combined with a methanesulfonating agent, a base, and a solvent to provide a V-6 compound:

[1171]

[1172] or its eutectic, solvate, salt or combination thereof; and

[1173] (b) Hydrolyzing a V-6 compound or its eutectic, solvate, salt or combination thereof using a nucleophile, solvent and optionally a phase-transfer catalyst to provide a V-5 compound or its eutectic, solvate, salt or combination thereof.

[1174] In some embodiments, the methanesulfonating agent used in step (a) is methanesulfonic anhydride or methanesulfonyl chloride. In some embodiments, the methanesulfonating agent used in step (a) is methanesulfonic anhydride. In some embodiments, the methanesulfonating agent used in step (a) is methanesulfonyl chloride.

[1175] In some embodiments, the base used in step (a) is selected from tertiary amines (triethylamine, N-methylmorpholine, tri-n-propylamine, ethyldiisopropylamine, tri-n-butylamine, etc.), aromatic amines (pyridine, 2,6-dimethylpyridine, methylpyridine, etc.), inorganic bases (sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, etc.), and alkoxy bases (sodium tert-amyl alcohol, sodium tert-butoxide, etc.). In some embodiments, the base used in step (a) is selected from triethylamine, N-methylmorpholine, tri-n-propylamine, ethyldiisopropylamine, tri-n-butylamine, pyridine, 2,6-dimethylpyridine, chloridine, sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium tert-amyl alcohol, and sodium tert-butoxide. In a particular embodiment, the base used in step (a) is triethylamine.

[1176] In some embodiments, the solvent used in step (a) is selected from 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 some embodiments, the solvent used in step (a) is selected from diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof. In a particular embodiment, the solvent used in step (a) is 2-methyltetrahydrofuran.

[1177] In some embodiments, step (a) is performed in a temperature range of about 100°C or lower. In some embodiments, step (a) is performed in a temperature range of about -20°C to about 100°C. In a particular embodiment, step (a) is performed in a temperature range of about -10°C to about 20°C.

[1178] In some embodiments, the nucleophile used in step (b) is selected from hydroxide bases (sodium hydroxide, lithium hydroxide, potassium hydroxide, etc.), sulfur nucleophiles (sodium ethanethiol, N-acetylcysteine, sodium thiophene, etc.), choline, alkoxide bases (sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium propoxy, sodium tert-butoxide, etc.), and amines (methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, hydroxylamine, etc.). In a particular embodiment, the base used in step (b) is sodium hydroxide.

[1179] In some embodiments, the solvent used in step (b) is selected from ethers (diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, etc.), hydrocarbon solvents (toluene, xylene, etc.), esters (isopropyl acetate, isobutyl acetate, etc.), dichloromethane, acetonitrile, polar aprotic solvents (N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, etc.), and combinations thereof. In a particular embodiment, the solvent used in step (b) is 2-methyltetrahydrofuran and water.

[1180] In some embodiments, the phase transfer catalyst used in step (b) is selected from ammonium salts (tetrabutylammonium bisulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium bisulfate, etc.) and phosphonium salts (tetrabutylphosphonium chloride, etc.). In a particular embodiment, the phase transfer catalyst used in step (b) is tetrabutylammonium bisulfate.

[1181] In some embodiments, step (b) is performed in a temperature range of about 100°C or lower. In some embodiments, step (b) is performed in a temperature range of about -20°C to about 100°C. In a particular embodiment, step (b) is performed in a temperature range of about 10°C to about 60°C.

[1182] In some embodiments, methods are provided for preparing compounds of the formula V-04-A or their eutectic, solvate, salt, or combination thereof:

[1183]

[1184] Wherein R is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2), or B(OC(Me)2C(Me)2O), and the method includes making a compound of formula V-6:

[1185]

[1186] Or its eutectic, solvate, salt or combination thereof, combined with a boron coupling agent, base and solvent and catalyst to provide V-04-A compound or its eutectic, solvate or salt or combination thereof.

[1187] In some implementations, R is B(OC(Me)2C(Me)2O).

[1188] In some embodiments, the boron coupling agent is selected from bis(pinacol)diboron, bis(neopentylethylene glycol)diboron, bisboronic acid, and bis(vinyl glycolate diboron). In a particular embodiment, the boron coupling agent is bis(pinacol)diboron.

[1189] In some embodiments, the base is selected from 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 hydrogen phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine. In a particular embodiment, the base is potassium acetate.

[1190] In some embodiments, the solvent is selected from 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 some embodiments, the solvent is selected from 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, ethyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine, and combinations thereof. In a particular embodiment, the solvent is toluene and N,N-dimethylformamide.

[1191] In some embodiments, the catalyst is selected from bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) dichloride, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, [1,2-bis(diphenylphosphino)ethane]palladium(II) dichloride, and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)oxanthracene]palladium(II). In some embodiments, the palladium catalyst is a palladium(II) precatalyst (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or a palladium(O) precatalyst (e.g., tetra(triphenylphosphine)palladium(O), bis(dibenzylideneacetone)palladium(O)), and optionally 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, tetra(triphenylphosphine)palladium(O), or bis(dibenzylacetone)palladium(O); and the catalyst optionally further comprises a phosphine ligand selected from tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, and dicyclohexylphenylphosphine. In a particular embodiment, the palladium catalyst is bis(triphenylphosphine)palladium(II) chloride.

[1192] In some embodiments, the method is performed in a temperature range of about 120°C or lower. In some embodiments, the method is performed in a temperature range of about 20°C to about 120°C. In a particular embodiment, the method is performed in a temperature range of about 95°C to about 105°C.

[1193] In some embodiments, methods are provided for preparing compounds of formula V-5 or their eutectics, solvates, salts, or combinations thereof:

[1194]

[1195] The method includes hydrolyzing V-6 compounds using a base, a solvent, and optionally a phase-transfer catalyst:

[1196]

[1197] Or its eutectic, solvate, salt or combination thereof to provide a compound of formula V5 or its eutectic, solvate or salt or combination thereof.

[1198] In some embodiments, the base is selected from hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide), thiophiles (e.g., sodium ethanethiol, N-acetylcysteine, sodium thiophene), choline, alkoxide bases (e.g., sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium tert-butoxide), and amines (e.g., methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, hydroxylamine). In some embodiments, the base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiol, N-acetylcysteine, sodium thiophene, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium tert-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine. In a particular embodiment, the base is sodium hydroxide.

[1199] In some embodiments, the solvent is selected from 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 some embodiments, the solvent is selected from 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 a particular embodiment, the solvent is 2-methyltetrahydrofuran and water.

[1200] In some embodiments, the method includes a phase transfer catalyst. In some embodiments, the phase transfer catalyst is selected from ammonium salts (e.g., tetrabutylammonium bisulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium bisulfate) and phosphonium salts (e.g., tetrabutylphosphonium chloride). In some embodiments, the phase transfer catalyst is selected from tetrabutylammonium bisulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1-methylimidazolium bisulfate, phosphonium salts, and tetrabutylphosphonium chloride. In a particular embodiment, the phase transfer catalyst is tetrabutylammonium bisulfate.

[1201] In some embodiments, the method is performed in a temperature range of about 100°C or lower. In some embodiments, the method is performed in a temperature range of about -20°C to about 100°C. In a particular embodiment, the method is performed in a temperature range of about 10°C to about 60°C.

[1202] In some embodiments, methods are provided for preparing compounds of the formula V-03-A or their eutectic, solvate, salt, or combination thereof:

[1203]

[1204] Wherein R is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O), and the method includes making a compound of formula V-5:

[1205]

[1206] Or its eutectic, solvate, salt or combination thereof, combined with a boron coupling agent, base, solvent and catalyst to provide V-03-A compound or its eutectic, solvate or salt or combination thereof.

[1207] In some implementations, R is B(OC(Me)2C(Me)2O).

[1208] In some embodiments, the boron coupling agent is selected from bis(pinacol)diboron, bis(neopentylethylene glycol)diboron, bisboronic acid, and bis(vinyl glycolate diboron). In a particular embodiment, the boron coupling agent is bis(pinacol)diboron.

[1209] In some embodiments, the base is selected from 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 hydrogen phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, triethylamine, and diisopropylethylamine. In a particular embodiment, the base is potassium acetate.

[1210] In some embodiments, the solvent is selected from 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 some embodiments, the solvent is selected from 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 a particular embodiment, the solvent is toluene and N,N-dimethylformamide.

[1211] In some embodiments, the catalyst is selected from bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) dichloride, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(biphenylphosphino)ferrocene]palladium(II) dichloride, [1,2-bis(biphenylphosphine)ethane]palladium(II) dichloride, and dichloro[9,9-dimethyl-4,5-bis(biphenylphosphine)oxanthracene]palladium(II). In some embodiments, the catalyst is a palladium(II) precatalyst (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or a palladium(O) precatalyst (e.g., tetra(triphenylphosphine)palladium(O), bis(dibenzylideneacetone)palladium(O)) and further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine). In some embodiments, the catalyst comprises palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetra(triphenylphosphine)palladium(O), or bis(dibenzylacetone)palladium(O), and the catalyst optionally further comprises a phosphine ligand selected from tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, and dicyclohexylphenylphosphine. In a particular embodiment, the palladium catalyst is bis(triphenylphosphine)palladium(II) chloride.

[1212] In some embodiments, the method is performed in a temperature range of about 120°C or lower. In some embodiments, the method is performed in a temperature range of about 20°C to about 120°C. In a particular embodiment, the method is performed in a temperature range of about 95°C to about 105°C.

[1213] In some embodiments, methods are provided for preparing compounds of formula VIII or their eutectics, solvates, salts, or combinations thereof:

[1214]

[1215] The method includes resolving compound X in a solvent with a chiral acid, optionally in the presence of an aldehyde catalyst and / or optionally a metal catalyst.

[1216]

[1217] Or its eutectic, solvate, salt or combination thereof, with a chiral acid, to provide a compound of formula VIII or its eutectic, solvate or salt or combination thereof.

[1218] In some embodiments, methods are provided for preparing compounds of formula VIII or their eutectics, solvates, salts, or combinations thereof:

[1219]

[1220] The method involves resolving compound X in a solvent using a chiral acid:

[1221]

[1222] Or its eutectic, solvate, salt or combination thereof to provide a compound of formula VIII or its eutectic, solvate or salt or combination thereof.

[1223] In some embodiments, the compound of formula VIII is the compound of formula VIII-02:

[1224]

[1225] Or its eutectic, solvate, or combination thereof, wherein HX is a chiral acid selected from the following: 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)succinic acid, benzyloxycarbonyl-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methylhexanediol Acids, (+)-mentholoxyacetic 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, (–)-acetylmynic acid, (R)-(–)-citric acid, (–)-camphoric acid and (R)-mandelic acid.

[1226] In some embodiments, the compound of formula VIII is the compound of formula VIII-02:

[1227]

[1228] Or its eutectic, solvate, or combination thereof, wherein HX is a chiral acid selected from the following: 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)succinic acid, benzyloxycarbonyl-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3 -Methyl adipic acid, (+)-mentholoxyacetic 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, (–)-acetylmethylenediamine, (R)-(–)-citric acid, (–)-camphoric 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.

[1229] In some implementations, HX is (–)-N-acetyl-D-leucine.

[1230] In some embodiments, the solvent is selected from 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-methylpyrrolidone, dimethyl sulfoxide), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), and combinations thereof.

[1231] In some embodiments, the solvent is selected from 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 a particular embodiment, the solvent is methyl tert-butyl ether and toluene.

[1232] In a particular embodiment, the solvent is toluene.

[1233] In some embodiments, the method is carried out in the presence of an aldehyde catalyst and / or a metal catalyst. In some embodiments, the aldehyde catalyst is selected from aromatic aldehydes (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-dichloro-2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, 2-hydroxy-3-nitrobenzaldehyde), heteroaromatic aldehydes (e.g., 2-pyridinecarboxaldehyde, 3-(trifluoromethyl)pyridinecarboxaldehyde, 4-chloropyridinecarboxaldehyde, trifluoromethylnicotinaldehyde, quinolone-4-carboxaldehyde, quinolone-2-carboxaldehyde, etc.), and aliphatic aldehydes (e.g., formaldehyde, ethylglyoxylate, glyoxylic acid). In some embodiments, the metal catalyst is selected from 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) trifluoromethanesulfonate); indium salts (e.g., indium(III) acetate); copper salts (e.g., copper(II) acetate); cobalt salts (e.g., cobalt(II) acetate); and manganese salts (e.g., manganese(II) acetate). In some embodiments, the method is carried out in the presence of an aldehyde catalyst and / or a metal catalyst. In a particular embodiment, the method is carried out in the presence of an aldehyde catalyst and a metal catalyst. In a particular embodiment, the aldehyde catalyst is 2-pyridinecarboxaldehyde, and the metal catalyst is zinc(II) oxide.

[1234] In some embodiments, the method is performed in a temperature range of about 120°C or lower. In some embodiments, the method is performed in a temperature range of about -20°C to about 120°C. In a particular embodiment, the method is performed in a temperature range of about -20°C to about 50°C. In some embodiments, the method is performed at a temperature of about 35°C.

[1235] In some embodiments, the method is performed in a temperature range of about 100°C or lower. In some embodiments, the method is performed in a temperature range of about -20°C to about 100°C. In a particular embodiment, the method is performed in a temperature range of about -20°C to about 20°C. In a particular embodiment, the method is performed at a temperature of about 35°C.

[1236] In some embodiments, prior to resolution, the compound of formula X may be treated with a base in a first solvent. In some embodiments, the base is selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, ammonium hydroxide, dipotassium hydrogen phosphate, tripotassium phosphate, disodium hydrogen phosphate, and trisodium phosphate. In a particular embodiment, the base is sodium hydroxide. In some embodiments, the first solvent is selected from 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 some embodiments, the first solvent is selected from diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, aromatic solvents, dichloromethane, and combinations thereof. In a particular embodiment, the solvent is 2-methyltetrahydrofuran. In some embodiments, the compound of formula X is treated with a base in the first solvent at a temperature ranging from about 0°C to about 100°C. In some embodiments, the compound of formula X is treated with an alkali in a first solvent at a temperature ranging from about 10°C to about 50°C.

[1237] In some embodiments, methods for preparing compounds of formula 1a or their eutectics, solvates, salts, or combinations thereof are provided:

[1238]

[1239] The method includes using 2,5-dibromopyridine:

[1240]

[1241] Combined with electrophilic agents, bases and solvents to provide a compound of formula 1a or a eutectic, solvate, salt or combination thereof.

[1242] In some embodiments, the electrophilic agent is selected from formylated amines (e.g., N,N-diethylformamide, 1-formylpyrrolidine, 4-formylmorpholine, N-methylformaniline); formate esters (e.g., methyl cyanobenamate, phenyl formate, ethyl formate, ethyl trifluoroformate); orthoformate esters (e.g., triethyl orthoformate, diethyl orthoformate phenyl ester); formamide acetals (e.g., N,N-dimethylformamide dipropyl acetal, N,N-dimethylformamide diethyl acetal); and (chloromethylene)dimethylimine onium chloride. In a particular embodiment, the electrophilic agent is N,N-dimethylformamide.

[1243] In some embodiments, the base is selected from 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex, n-butyllithium, isopropyl magnesium chloride lithium chloride complex, sec-butyl magnesium chloride lithium chloride complex, phenyllithium, phenyl magnesium chloride, n-butyllithium, N,N-dimethylaminoethanol complex, mestrimethyllithium, diisopropylamide lithium, phenyllithium, 2,2,6,6-tetramethylpiperidinyllithium, dichloro(2,2,6,6-tetramethylpiperidinyl)zinc oxide, and di-tert-butyl-(2,2,6,6-tetramethylpiperidinyl)zinc oxide. In a particular embodiment, the base is 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex.

[1244] In some embodiments, the solvent is selected from 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 a particular embodiment, the solvent is tetrahydrofuran.

[1245] In some embodiments, the method is performed in a temperature range of about 50°C or lower. In some embodiments, the method is performed in a temperature range of about -80°C to about 50°C. In a particular embodiment, the method is performed in a temperature range of about -40°C to about 0°C.

[1246] In some embodiments, methods are provided for preparing compound X or its eutectic, solvate, salt, or combination thereof:

[1247]

[1248] The method includes:

[1249] (a) Optionally, in the presence of an additive, the compound of formula 1a is condensed in a solvent with a suitable amine (e.g., aminodiphenylmethane):

[1250]

[1251] Or its eutectic, solvate, salt or combination thereof, to provide a compound of formula 1b:

[1252]

[1253] Where R 4 and R 5 Each can be independently hydrogen, methyl, phenyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzylamine, or 4-methoxybenzyl;

[1254] (b) Alkylation of compound 1b or its eutectic, solvate, salt or combination thereof with compound 1c in a solvent in the presence of a base and optionally a phase-transfer catalyst:

[1255]

[1256] Where Y is Br, Cl, I, OMs, OTs, or OSO2CF3 to provide compounds of formula 1d:

[1257]

[1258] or its eutectic, solvate, salt or combination thereof; and

[1259] (c) Deprotecting the compound of formula 1d in a solvent with an acid to provide the compound of formula X:

[1260]

[1261] Or its eutectic, solvate, salt or combination thereof.

[1262] In some embodiments, methods are provided for preparing compound X or its eutectic, solvate, salt, or combination thereof:

[1263]

[1264] The method includes:

[1265] (a) Condensation of compound 1a in a solvent with a suitable amine (e.g., aminodiphenylmethane):

[1266]

[1267] Or its eutectic, solvate, salt or combination thereof to provide a compound of formula 1b:

[1268]

[1269] Where R 4 and R 5 Each can be independently hydrogen, methyl, phenyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzylamine, or 4-methoxybenzyl;

[1270] (b) Alkylation of compound 1b or its eutectic, solvate, salt or combination thereof with compound 1c in a solvent in the presence of a base and optionally a phase-transfer catalyst:

[1271]

[1272] Where Y is Br, Cl, I, OMs, OTs, or OSO2CF3 to provide compounds of formula 1d:

[1273]

[1274] or its eutectic, solvate, salt or combination thereof; and

[1275] (c) Deprotecting the compound of formula 1d in a solvent with an acid to provide the compound of formula X:

[1276]

[1277] Or its eutectic, solvate, salt or combination thereof.

[1278] In some embodiments, a suitable amine for forming the compound of formula 1b or its eutectic, 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 its eutectic, solvate, salt, or combination thereof is aminodiphenylamine.

[1279] In some embodiments, the compound of formula 1b or its eutectic, solvate, salt or combination is a compound of formula 1b-02:

[1280]

[1281] Or its eutectic, solvate, salt or combination thereof.

[1282] In some embodiments, the compound of formula 1d or its eutectic, solvate, salt or combination thereof is a compound of formula 1d-02:

[1283]

[1284] Or its eutectic, solvate, salt or combination thereof.

[1285] In some embodiments, the solvent used in the condensation step (a) is selected from 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-methylpyrrolidone), nitriles (e.g., acetonitrile), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In a particular embodiment, the solvent used in the condensation step (a) is toluene.

[1286] In some embodiments, the condensation step (a) is carried out in the presence of an additive. In some embodiments, the additive used in the condensation step (a) is a dehydrating agent (e.g., magnesium sulfate).

[1287] In some embodiments, the condensation step (a) is performed in a temperature range of about 120°C or lower. In some embodiments, the condensation step (a) is performed in a temperature range of about -20°C to about 120°C. In a particular embodiment, the condensation step (a) is performed in a temperature range of about 20°C to about 90°C. In a particular embodiment, the condensation step (a) is performed in a temperature range of about 20°C to about 80°C.

[1288] In some implementations, Y is Br, Cl, or I. In a particular implementation, Y is Br.

[1289] In some embodiments, the base used in the alkylation step (b) is selected from 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, isopropyl magnesium chloride-lithium chloride complex, sec-butyl magnesium chloride, lithium chloride complex, n-butyllithium, N,N-dimethylaminoethanol-lithium complex, isopropylidene acetone-lithium, diisopropylaminolithium, and phenyllithium. In a particular embodiment, the base in the alkylation step (b) is potassium hydroxide.

[1290] In some embodiments, a phase transfer catalyst is used in the alkylation step (b).

[1291] In some embodiments, the phase transfer catalyst used in the alkylation step (b) is selected from tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetramethylammonium sulfate, tetraethylammonium chloride, tetra-n-butylammonium bromide, tetraethylammonium iodide, tetraethylammonium sulfate, and benzyltrimethylammonium. In a particular embodiment, the phase transfer catalyst used in the alkylation step (b) is tetra-n-butylammonium bromide.

[1292] In some embodiments, the solvent used in the alkylation step (b) is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, benzene, xylene, toluene, dichloromethane, water, and combinations thereof. In a particular embodiment, the solvent for the alkylation step (b) is a mixture of toluene and water.

[1293] In some embodiments, the compound of formula 1c is selected from 3,5-difluorobenzyl bromide, 3,5-difluorobenzyl chloride, 3,5-difluorobenzyl methanesulfonate, 3,5-difluorobenzyl iodide, 3,5-difluorobenzyl trifluoromethanesulfonate, and 3,5-difluorobenzyl toluenesulfonate. In a particular embodiment, the compound of formula 1c is 3,5-difluorobenzyl bromide.

[1294] In some embodiments, the alkylation step (b) is performed at a temperature range of about 120°C or lower. In some embodiments, the alkylation step (b) is performed at a temperature range of about -20°C to about 120°C. In a particular embodiment, the alkylation step (b) is performed at a temperature range of about 10°C to about 80°C.

[1295] In some embodiments, the acid used in deprotection step (c) is selected from hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, formic acid, and oxalic acid. In a particular embodiment, the acid used in deprotection step (c) is methanesulfonic acid.

[1296] In a particular embodiment, the acid equivalent is 1 to 10. In a particular embodiment, the acid equivalent is 1 to 3.

[1297] In some embodiments, the solvent for the deprotection step (c) is selected from 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 a particular embodiment, the solvent for the deprotection step (c) is 2-methyltetrahydrofuran.

[1298] In some embodiments, the deprotection step (c) is performed in a temperature range of about 120°C or lower. In some embodiments, the deprotection step (c) is performed in a temperature range of about -40°C to about 120°C. In a particular embodiment, the deprotection step (c) is performed in a temperature range of about 10°C to about 40°C.

[1299] In some embodiments, methods are provided for forming a compound of formula X or a eutectic, solvate, salt, or combination thereof:

[1300]

[1301] The method includes:

[1302] (a) To make compound XIII:

[1303]

[1304] Or its eutectic, solvate, salt or combination thereof, combined with a methanesulfonating agent, a base, a solvent and optionally an additive to provide a compound of formula XIII-A:

[1305]

[1306] or its eutectic, solvate, salt or combination thereof; and

[1307] (b) Combining a compound of formula XIII-A or its eutectic, solvate, salt or combination thereof with an amination agent and optionally a solvent to provide a compound of formula X:

[1308]

[1309] Or its eutectic, solvate, salt or combination thereof.

[1310] In some embodiments, the methanesulfonating agent used in the methanesulfonation step (a) is selected from methanesulfonyl chloride and methanesulfonic anhydride. In a particular embodiment, the methanesulfonating agent is methanesulfonyl chloride.

[1311] In some embodiments, the base used in the methanesulfonation step (a) is selected from triethylamine, diisopropylethylamine, pyridine, 2,3,5-corridin, 2,4,6-corridin, N,N-dicyclohexylmethylamine, and N-methylimidazole. In a particular embodiment, the base used in the methanesulfonation step is triethylamine.

[1312] In some embodiments, the methanesulfonation step (a) uses an additive. In a particular embodiment, the additive used in step (a) is selected from 4-(dimethylamino)pyridine (DMAP), N-methylimidazolium, N-pyridine oxide, diphenylcyclopropenone, and antimony pentachloride. In some embodiments, the additive used in step (a) is 4-(dimethylamino)pyridine (DMAP).

[1313] In some embodiments, the solvent used in the methanesulfonation step (a) is selected from 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-methylpyrrolidone), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In a particular embodiment, the solvent used in the methanesulfonation step (a) is tetrahydrofuran.

[1314] In some embodiments, the methanesulfonation step (a) is performed at a temperature range of about 60°C or lower. In some embodiments, the methanesulfonation step (a) is performed at a temperature range of about -80°C to about 60°C. In a particular embodiment, the methanesulfonation step (a) is performed at a temperature range of about 0°C to about 40°C.

[1315] In some embodiments, the amination reagent used in amination step (b) is ammonia.

[1316] In some embodiments, the amination step (b) includes a solvent.

[1317] In some embodiments, the solvent used for the amination step (b) is selected from 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 a particular embodiment, the solvent for the amination step (b) is methanol and water.

[1318] In some embodiments, the amination step (b) is performed at a temperature range of about 100°C or lower. In some embodiments, the amination step (b) is performed at a temperature range of about 0°C to about 100°C. In some embodiments, the amination step (b) is performed at a temperature range of about 40°C to about 80°C.

[1319] In an alternative embodiment, compound XIII-A:

[1320]

[1321] Alternatively, a eutectic, solvate, salt, or combination thereof may be conjugated with an amine equivalent (e.g., di-tert-butyliminodicarboxylate, phthalimide, benzylamine, dibenzylamine, hexamethyldisilazane) and then deprotected (e.g., using hydrochloric acid, hydrazine, hydrogen, Pd / C) to provide a compound of formula X:

[1322]

[1323] Or its eutectic, solvate, salt or combination thereof.

[1324] In some embodiments, methods are provided for preparing compounds of formula VIII or their eutectics, solvates, salts, or combinations thereof:

[1325]

[1326] The method includes:

[1327] (a) Hydrogenation of compound XI in the presence of an asymmetric catalyst and solvent:

[1328]

[1329] Or its eutectic, solvate, salt or combination thereof to provide a compound of formula XII:

[1330]

[1331] Or its eutectic, solvate, salt or combination thereof;

[1332] (b) In the presence of a base and a solvent, using an azide reagent to form a compound of formula XII or its eutectic, solvate, salt, or combination of azides to produce a compound of formula XVI:

[1333]

[1334] or its eutectic, solvate, salt or combination thereof; and

[1335] (c) Using a reducing agent to reduce a compound of formula XVI to provide a compound of formula VIII or a eutectic, solvate, salt or combination thereof.

[1336] In some embodiments, the asymmetric catalyst used for hydrogenation step (a) is selected from [Rh(cod)((S)-segphos]BF4, IrCl(cod)((S)-segphos), [RuCl(p-isopropyltoluene)(segphos)]Cl, Ru(OAc)2(segphos), (Me2NH2)[RuCl((S)-segphos)]2(μ-Cl)3, and (R)-RuCY-XylBINAP. In a particular embodiment, the asymmetric catalyst is (R)-RuCY-XylBINAP.

[1337] In some embodiments, the solvent used in the hydrogenation step (a) is selected from 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 a particular embodiment, the solvent for the hydrogenation step is ethanol and isopropanol.

[1338] In some embodiments, the hydrogenation step (a) is performed at a temperature range of about 150°C or lower. In some embodiments, the hydrogenation step (a) is performed at a temperature range of about -20°C to about 150°C. In a particular embodiment, the hydrogenation step (a) is performed at a temperature range of about 0°C to about 60°C.

[1339] In some embodiments, the azide agent used in step (b) is methanesulfonyl chloride and sodium azide or diphenylphosphine azide. In a particular embodiment, the azide agent is diphenylphosphine azide.

[1340] In some embodiments, the base used in step (b) is selected from triethylamine, diisopropylethylamine, N,N-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene. In a particular embodiment, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[1341] In some embodiments, the solvents used in steps (b) and (c) are selected from 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-methylpyrrolidone), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In a particular embodiment, the solvent used in steps (b) and (c) is tetrahydrofuran.

[1342] In some embodiments, steps (b) and (c) are performed in a temperature range of about 60°C or lower. In some embodiments, steps (b) and (c) are performed in a temperature range of about -10°C to about 60°C. In a particular embodiment, steps (b) and (c) are performed in a temperature range of about 0°C to about 40°C. In some embodiments, the reducing agent used in reducing step (c) is selected from trimethylphosphine, triethylphosphine, trimethyl phosphite, triethyl phosphite, tributylphosphine, trifuranylphosphine, tris(hydroxymethyl)phosphine, and triphenylphosphine. In a particular embodiment, the reducing agent is triphenylphosphine.

[1343] In some embodiments, the reduction step (c) is performed in a temperature range of about 60°C or lower. In some embodiments, the reduction step (c) is performed in a temperature range of about -10°C to about 60°C. In a particular embodiment, the reduction step (c) is performed in a temperature range of about 0°C to about 40°C.

[1344] In some embodiments, methods are provided for preparing compounds of formula VIII or their eutectics, solvates, salts, or combinations thereof:

[1345]

[1346] The method includes:

[1347] (a) Make compounds of formula XI:

[1348]

[1349] Or its eutectic, solvate, salt, or combination thereof, combined with a hydroxylamine source, a base, and a solvent, to provide a compound of formula 1e:

[1350]

[1351] Or its eutectic, solvate, salt or combination thereof;

[1352] (b) Combining the compound of formula 1e with a reducing agent, an acylation agent, and a solvent to provide the compound of formula 1f-1:

[1353]

[1354] Where R 6 Selected from acetyl, benzyl, trichloroacetyl, trifluoroacetyl, and propionyl; and

[1355] (c) Hydrogenation of compound 1f-1 with a catalyst and solvent to provide compound 1g-1:

[1356]

[1357] or its eutectic, solvate, salt or combination thereof; and

[1358] (d) Deprotecting 1 g⁻¹ of a compound with an acid and a solvent to provide a compound of formula VIII or a eutectic, solvate, salt or combination thereof.

[1359] In some implementations, R 6 Selected from acetyl, benzyl, trichloroacetyl, trifluoroacetyl, and propionyl. In a particular embodiment, R 6 It is an acetyl group.

[1360] In some embodiments, the hydroxylamine source used in step (a) is selected from hydroxylamine hydroxide.

[1361] In some embodiments, the solvent used in step (a) is selected from esters (e.g., n-propyl acetate, isopropyl acetate), alcohols (e.g., methanol, 1- 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 some embodiments, the solvent used in step (a) is selected from n-propyl acetate, isopropyl acetate, methanol, 1- 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 a particular embodiment, the solvent used in step (a) is ethanol.

[1362] In some embodiments, the base used in step (a) is selected from 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 trimethylacetate), alkoxide bases (e.g., sodium ethoxide, potassium ethoxide, sodium tert-butoxide), sodium hydride, and disilazane bases (e.g., lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane). In some embodiments, the base used in step (a) is selected from pyridine, triethylamine, tri-n-propylamine, tri-n-butylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, lithium trimethylacetate, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, sodium hydride, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and potassium hexamethyldisilazane. In a particular embodiment, the base used in step (a) is pyridine.

[1363] In some embodiments, step (a) is performed in a temperature range of about 150°C or lower. In some embodiments, step (a) is performed in a temperature range of about 0°C to about 150°C. In a particular embodiment, step (a) is performed in a temperature range of about 10°C to about 60°C. In a particular embodiment, step (a) is performed in a temperature range of about 20°C.

[1364] In some embodiments, the reducing agent used in step (b) is selected from hydrogenating agents (e.g., palladium on carbon, hydrogen), ferric acetate (II), samarium diiodide, titanium tetrachloride (IV) / tin chloride (II), and zinc. In certain embodiments, the reducing agent is ferric acetate (II). In some embodiments, the reducing agent is in-situ prepared ferric acetate (II).

[1365] In some embodiments, the acylation agent used in step (b) is selected from 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 some embodiments, the acylation agent used in step (b) is selected from acetyl chloride, trichloroacetyl chloride, acetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, benzyl chloride, and benzyl bromide. In a particular embodiment, the acylation agent is acetic anhydride.

[1366] In some embodiments, the solvent used in step (b) is selected from acetic acid, esters (e.g., n-propyl acetate, isopropyl acetate, acetate esters), 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 some embodiments, the solvent used in step (b) is selected from acetic acid, n-propyl acetate, isopropyl acetate, acetate esters, methanol, 1- 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 a particular embodiment, the solvent used in step (b) is isopropyl acetate and acetic acid.

[1367] In some embodiments, step (b) is performed in a temperature range of about 150°C or lower. In some embodiments, step (b) is performed in a temperature range of about 0°C to about 150°C. In a particular embodiment, step (b) is performed in a temperature range of about 30°C to about 70°C. In a particular embodiment, step (b) is performed in a temperature range of about 50°C.

[1368] In some embodiments, the catalyst used in step (c) is selected from IrCl(cod)((S)-segphos), Rh(cod)((S)-segphos)BF4, and (Me2NH2)[RuCl((S)-segphos)]2(μ-Cl)3. In a particular embodiment, the catalyst is (IrCl(cod)((S)-segphos).

[1369] In some embodiments, the solvents for steps (c) and (d) are selected from 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 some embodiments, the solvents for steps (c) and (d) are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, ethanol, 1- 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 a particular embodiment, the solvent for steps (c) and (d) is ethyl acetate.

[1370] In some embodiments, step (c) is performed at a temperature range of about 150°C or lower. In some embodiments, step (c) is performed at a temperature range of about 0°C to about 150°C. In a particular embodiment, step (c) is performed at a temperature range of about 80°C to about 150°C.

[1371] In some embodiments, the acid used in step (d) is selected from hydrochloric acid, hydrobromic acid, nitric acid, methanesulfonic acid, and p-toluenesulfonic acid. In a particular embodiment, the acid used in step (d) is hydrochloric acid.

[1372] In some embodiments, step (d) is performed at a temperature range of about 100°C or lower. In some embodiments, step (d) is performed at a temperature range of about 20°C to about 100°C. In a particular embodiment, step (d) is performed at a temperature range of about 20°C to about 80°C.

[1373] In some embodiments, methods are provided for preparing compounds of formula VIII or their eutectics, solvates, salts, or combinations thereof:

[1374]

[1375] The method includes using:

[1376] Hydrogen source,

[1377] catalyst,

[1378] amine,

[1379] acid, and

[1380] Solvent-reduced amination of XI compounds:

[1381]

[1382] To provide a compound of formula VIII or its eutectic, solvate, salt or combination thereof.

[1383] In some embodiments, the hydrogen source is selected from hydrogen gas, ammonium formate, and triethylamine formate complex. In a particular embodiment, the hydrogen source is hydrogen gas.

[1384] In some embodiments, the solvent is selected from 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-methylpyrrolidone, dimethyl sulfoxide), alcohols (e.g., methanol, isopropanol, tert-amyl alcohol), water, and combinations thereof. In a particular embodiment, the solvent is methanol.

[1385] In some implementations, the pH of the water is 6-10.

[1386] In some embodiments, the catalyst is an asymmetric catalyst or an enzyme catalyst.

[1387] In some embodiments, the catalyst is an asymmetric catalyst. In some embodiments, the asymmetric catalyst is a ruthenium or iridium catalyst having a chiral ligand (e.g., SegPhos, DM-SegPhos, tert-butyl-Josiphos, DuPhos, MonoPhos, or BINAP). In specific embodiments, the catalyst is a ruthenium or iridium catalyst selected from RuCl3, ruthenium(III) acetylacetonate, ruthenium(II) chlorocyclopentadienylbis(triphenylphosphine) ruthenium(II) chlorohydrogenated (triphenylphosphine) ruthenium(II) toluene adduct, ruthenium(II) chlorotri(triphenylphosphine)acetate, [Ru(Cl)H(CO)(PPH3)3], [Ir(COD)Cl]2, (acetylacetonyl)(1,5-cyclooctadiene)iridium(I), and (acetylacetonyl)dicarbonyliridium(I). In some embodiments, the catalyst is Ru(OAc)2((R)-SegPhos).

[1388] In some embodiments, the catalyst is an enzyme catalyst. In some embodiments, the enzyme catalyst is an aminotransferase and a cofactor in a buffer. In a specific embodiment, the aminotransferase is an ω-transferase selected from 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-BO4, ATA-P1-F03, ATA-P1-G05, ATA-P2-A01, ATA-P2-A07, and ATA-P2-BO1.

[1389] In some embodiments, the buffer is selected from triethanolamine, Tris, Tricine, BES, MOPS, HEPES, sodium phosphate, and potassium phosphate.

[1390] In some implementations, the cofactor is pyridoxal phosphate.

[1391] In some embodiments, the amine is selected from ammonia, ammonium acetate, ammonium salicylate, ammonium formate, α-methylbenzylamine, isopropylamine, diphenylmethylamine, DL-alanine, and aspartame. In a particular embodiment, the amine is ammonia.

[1392] In some embodiments, the acid is selected from p-toluenesulfonic acid, hydrochloric acid, and phosphoric acid. In a particular embodiment, the acid is p-toluenesulfonic acid.

[1393] In some embodiments, the catalyst is an asymmetric catalyst, and the method is carried out at a pressure of about 100 to about 1000 psi. In some embodiments, the catalyst is an asymmetric catalyst, and the method is carried out at a pressure of about 200 to about 600 psi.

[1394] In some embodiments, the catalyst is an asymmetric catalyst, and the method is carried out in a temperature range of 120°C or lower. In some embodiments, the catalyst is an asymmetric catalyst, and the method is carried out in a temperature range of about 0°C to about 120°C. In some embodiments, the catalyst is an asymmetric catalyst, and the method is carried out in a temperature range of about 55°C to about 65°C.

[1395] In some embodiments, the catalyst is an enzyme catalyst, and the method is carried out in a temperature range of about 100°C or lower. In some embodiments, the catalyst is an enzyme catalyst, and the method is carried out in a temperature range of about 5°C to about 100°C.

[1396] In some embodiments, methods for preparing compounds of formula V or their eutectics, solvates, salts, or combinations thereof are disclosed herein:

[1397]

[1398] Where R 1 The method comprises B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O), wherein the method includes:

[1399] (a) Compounds of formula VA:

[1400]

[1401] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[1402] Silylating agent,

[1403] alkali, and

[1404] Solvent, to provide compound of formula 7a:

[1405]

[1406] Or its eutectic, solvate, salt or combination thereof,

[1407] Each R 2 Independently for C 1-6alkyl or C6 aryl, wherein C 1-6 Alkyl and C6 aryl groups are independently unsubstituted or occupied by one to five C groups. 1-6 Alkyl substitution; and

[1408] (b) To combine the compound of formula 7a with the following

[1409] Organometallic reagents, and

[1410] Borylating reagent,

[1411] To provide a compound of formula V or its eutectic, solvate, salt or combination thereof.

[1412] In some embodiments, methods for preparing compounds of formula V or their eutectics, solvates, salts, or combinations thereof are disclosed herein:

[1413]

[1414] Where R 1 The method comprises B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2) or B(OC(Me)2C(Me)2O), wherein the method includes:

[1415] (a) Compounds of formula VA:

[1416]

[1417] Or its eutectic, solvate, salt or combination thereof, in combination with the following

[1418] Silylating agent,

[1419] alkali, and

[1420] Solvent, to provide compound of formula 7a:

[1421]

[1422] Or its eutectic, solvate, salt or combination thereof,

[1423] Each R 2 Independently for unsubstituted or by one to five C 1-6 Alkyl-substituted C 1-6 Alkyl; and

[1424] (b) To combine the compound of formula 7a with the following

[1425] Organometallic reagents, and

[1426] Borylating reagent,

[1427] To provide a compound of formula V or its eutectic, solvate, salt or combination thereof.

[1428] In some embodiments, the base used in step (a) is selected from sodium hydride, potassium hydride, methyl magnesium bromide, phenyl magnesium bromide, sodium hexamethyldisilazane, potassium hexamethyldisilazane, and lithium hexamethyldisilazane. In a particular embodiment, the base used in step (a) is lithium hexamethyldisilazane.

[1429] In some embodiments, the silylating agent used in step (a) is selected from trimethylsilane bromide, N,O-bis(trimethylsilyl)acetamide, trimethylsilane chloride, chloro(dimethyl)phenylsilane, chloro(methyl)diphenylsilane and 1,2-bis(chlorodimethylsilyl)ethane.

[1430] In some embodiments, the silylating agent used in step (a) is selected from trimethylsilane bromide, N,O-bis(trimethylsilyl)acetamide, and trimethylsilane chloride. In a particular embodiment, the silylating agent used in step (a) is trimethylsilane chloride.

[1431] In some embodiments, the solvent is selected from 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 a particular embodiment, the solvent is tetrahydrofuran.

[1432] In some embodiments, the organometallic reagent used in step (b) is selected from n-butyllithium, sec-butylmagnesium chloride-lithium chloride complex, tert-butylmagnesium chloride, isopropylmagnesium chloride, and isopropylmagnesium chloride-lithium chloride complex.

[1433] In some embodiments, the organometallic reagent used in step (b) is selected from n-butyllithium, sec-butylmagnesium chloride-lithium chloride complex, tert-butylmagnesium chloride, and isopropylmagnesium chloride-lithium chloride complex. In a particular embodiment, the organometallic reagent is isopropylmagnesium chloride-lithium chloride complex.

[1434] In some embodiments, the boronizing agent used in step (b) is selected from trimethyl borate, triethyl borate, pinacolborane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxolaneborane, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxolaneborane, β-catecholborane, and 2-bromo-1,3,2-benzodioxolanecyclopentene. In a particular embodiment, the boronizing agent is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxolaneborane.

[1435] In some embodiments, the method for preparing compound V or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about 40°C or lower. In some embodiments, the method is carried out in a temperature range of about -80°C to about 40°C. In a particular embodiment, the method is carried out in a temperature range of about -40°C to about 20°C.

[1436] In some implementations, R 1 It is B(OC(Me)2C(Me)2O).

[1437] In some embodiments, methods are provided for preparing compounds of formula VII or their eutectics, solvates, salts, or combinations thereof:

[1438]

[1439] The method involves hydrolyzing compound VII-A in the presence of a base and a solvent:

[1440]

[1441] Or its eutectic, solvate, salt or combination thereof to provide a compound of formula VII.

[1442] In some embodiments, the base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, and potassium trimethylsilanolate. In a particular embodiment, the base is potassium hydroxide.

[1443] In some embodiments, the solvent is selected from chlorinated solvents (e.g., dichloromethane), alcohols (e.g., ethanol, methanol, 1-propanol, 2-propanol), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane), aromatic hydrocarbon solvents (e.g., benzene, toluene, xylene), water, and combinations thereof.

[1444] In some embodiments, the solvent is selected from chlorinated solvents (e.g., dichloromethane), alcohols (e.g., ethanol), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran), aromatic hydrocarbon solvents (e.g., toluene), water, and combinations thereof. In a particular embodiment, the solvent is a mixture of dichloromethane and ethanol.

[1445] In a particular embodiment, the solvent is a mixture of dichloromethane, water, and ethanol. In another particular embodiment, the solvent is a mixture of water and ethanol.

[1446] In some embodiments, the method is performed in a temperature range of about 100°C or lower. In some embodiments, the method is performed in a temperature range of about 10°C to about 100°C. In a particular embodiment, the method is performed in a temperature range of about 10°C to about 60°C.

[1447] In some embodiments, methods are provided for preparing compounds of formula VII-A or their eutectics, solvates, salts, or combinations thereof:

[1448]

[1449] The method comprises fluorinating the compound of formula 5h⁻¹ in a solvent and in the presence of an activator with a fluorinating agent:

[1450]

[1451] Or a eutectic, solvate, salt or combination thereof, wherein n is 1 or 2, to provide a compound of formula VII-A or a eutectic, solvate or salt or combination thereof.

[1452] In some implementations, n is 1. In some implementations, n is 2.

[1453] In some embodiments, the fluorinating agent is selected from pyridine hydrogen fluoride, calcium fluoride, potassium hydrogen fluoride, triethylamine trihydrofluoride, elemental fluorine, bromine trifluoride, iodine pentafluoride, tetra-n-butyldihydrotrifluoride, 4-iodotoluene difluoride, and melamine hydrofluoride. In a particular embodiment, the fluorinating agent is pyridine hydrogen fluoride.

[1454] In some embodiments, the solvent is selected from 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-methylpyrrolidone), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In some embodiments, the solvent is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, xylene, dichloromethane, and combinations thereof. In a particular embodiment, the solvent is dichloromethane.

[1455] In some embodiments, the activator is selected from 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide, N-iodosuccinimide, nitrosium tetrafluoroborate, thioyl chloride fluoride, trifluoromethanesulfonic acid, and mercuric fluoride. In a particular embodiment, the activator is 1,3-dibromo-5,5-dimethylhydantoin.

[1456] In some embodiments, the method is performed in a temperature range of about 100°C or lower. In some embodiments, the method is performed in a temperature range of about -70°C to about 100°C. In a particular embodiment, the method is performed in a temperature range of about -30°C to about 20°C.

[1457] In some embodiments, methods are provided for preparing compounds of formula 5h-1 or their eutectic, solvate, salt, or combinations thereof:

[1458]

[1459] Where n is 1 or 2, the method includes reacting the compound of formula XIV in a solvent:

[1460]

[1461] Or its eutectic, solvate, salt or combination thereof, combined with a dithiol reagent and a promoter to provide a compound of formula 5h-1 or its eutectic, solvate or salt or combination thereof.

[1462] In some implementations, n is 1. In some implementations, n is 2.

[1463] In some embodiments, the dithiol reagent is 1,2-ethanedithiol or 1,2-propanedithiol. In a particular embodiment, the reagent is 1,2-ethanedithiol.

[1464] In some embodiments, the solvent is selected from 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-methylpyrrolidone), aromatic solvents (e.g., benzene, toluene, xylene), chlorinated solvents (e.g., dichloromethane), and combinations thereof. In some embodiments, the solvent is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane-acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, xylene, dichloromethane, and combinations thereof. In a particular embodiment, the solvent is dichloromethane.

[1465] In some embodiments, the accelerator is selected from boron trifluoride acetic acid complex, p-toluenesulfonic acid, iodine, 1,3-dibromo-5,5-dimethylhydantoin, copper dodecyl sulfate (II), ytterbium trifluoromethanesulfonate (III), yttrium trifluoromethanesulfonate (III), bismuth trifluoromethanesulfonate (III), bismuth chloride (III), tungstic acid, perchloric acid, praseodymium trifluoromethanesulfonate, hafnium trifluoromethanesulfonate (IV), ferric chloride (III), hydrochloric acid, p-dodecylbenzenesulfonic acid, BF3·OEt2, BF3·OMe2, BF3·THF, BF3·OBu2, BF3·MeOH, BF3·Me2S, and BF3·PhOHBF3·2H2O. In a particular embodiment, the accelerator is boron trifluoride acetic acid complex.

[1466] In some embodiments, the method is performed in a temperature range of about 100°C or lower. In some embodiments, the method is performed in a temperature range of about -20°C to about 100°C. In a particular embodiment, the method is performed in a temperature range of about 0°C to about 40°C.

[1467] In some embodiments, methods are provided for preparing compounds of formula XIV or their eutectics, solvates, salts, or combinations thereof:

[1468]

[1469] The method comprises alkylating a compound of formula XIV-A with an alkylating agent in the presence of a base, a solvent, and optionally a phase-transfer catalyst:

[1470]

[1471] Or its eutectic, solvate, salt or combination thereof, to provide a compound of formula XIV or its eutectic, solvate, salt or combination thereof.

[1472] In some embodiments, the alkylating agent is selected from ethyl chloroacetate, ethyl iodoacetate, ethyl (methanesulfonyloxy)acetate, ethyl (p-toluenesulfonyloxy)acetate, ethyl (((trifluoromethyl)sulfonyl)oxy)acetate, and ethyl bromoacetate. In a particular embodiment, the alkylating agent is ethyl bromoacetate.

[1473] In some embodiments, the base is selected from ethyldiisopropylamine, triethylamine, 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 hexamethyldisilazane, sodium hexamethyldisilazane, and potassium hexamethyldisilazane. In a particular embodiment, the base is ethyldiisopropylamine.

[1474] In some embodiments, the method includes a phase transfer catalyst.

[1475] In some embodiments, the phase transfer catalyst is selected from tetra-n-butylammonium bisulfate and tetra-n-butylammonium iodide.

[1476] In some embodiments, the solvent is selected from 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-methylpyrrolidone), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), chlorinated solvents (e.g., dichloromethane), esters (e.g., ethyl acetate, n-butyl acetate, isopropyl acetate), and ketones (e.g., in certain embodiments, the solvent is acetonitrile).

[1477] In some embodiments, the method is performed in a temperature range of about 100°C or lower. In some embodiments, the method is performed in a temperature range of about -20°C to about 100°C. In a particular embodiment, the method is performed in a temperature range of about -20°C to about 30°C.

[1478] In some embodiments, methods are provided for preparing compounds of formula XIV-A or their eutectics, solvates, salts, or combinations thereof:

[1479]

[1480] The method includes oxidizing compound C3 with an oxidant, a promoter, a solvent, and a catalyst.

[1481]

[1482] Or its eutectic, solvate, salt or combination thereof, to provide a compound of formula XIV-A or its eutectic, solvate or salt or combination thereof.

[1483] In some embodiments, the oxidant is selected from tert-butyl hydroperoxide, peracetic acid, hydrogen peroxide, molecular oxygen, air, sodium hypochlorite, sodium chlorite, sodium periodate, potassium peroxymonosulfate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,4-benzoquinone, periodic acid, potassium bromate, m-chloroperoxybenzoic acid (mCPB or m-CPBA), and magnesium monoperoxyphthalate. In a particular embodiment, the oxidant is tert-butyl hydroperoxide.

[1484] In some embodiments, the accelerator is selected from pyridine, bipyridine, neocopper hydroxide, 1,10-phenanthroline, 2,6-dimethylpyridine, 4-methylpyridine, 2-methylpyridine, 3-methylpyridine, isonicotinamide, nicotinamide, pyridinecarboxylic acid, (2,2,6,6-tetramethylpiperidin-1-yl)oxide, and didodecyldimethylammonium bromide. In a particular embodiment, the accelerator is pyridine.

[1485] In some embodiments, the solvent is selected from acetic acid, acetonitrile, n-butyl acetate, isopropyl acetate, ethyl acetate, acetone, dichloromethane, dimethyl carbonate, tetrahydrofuran, methanol, tert-butanol, dichloromethane, sulfolane, water, and combinations thereof. In a particular embodiment, the solvent is water.

[1486] In some embodiments, the catalyst is selected from manganese trifluoromethanesulfonate (II), copper chloride (II), manganese chloride (2S,2'S-(-)[N,N'-bis(2-pyridylmethyl)]2,2'-dipyrrolidinebis(acetonitrile)ferric(II)hexafluoroantimonate, bismuth, cobalt acetate (II), manganese acetate (III), ruthenium chloride (III), N-hydroxyphthalimide, bis(cyclopentadienyl)vanadium dichloride (IV), and manganese dioxide. In a particular embodiment, the catalyst is copper chloride (II).

[1487] In some embodiments, the method is performed in a temperature range of about 100°C or lower. In some embodiments, the method is performed in a temperature range of about -40°C to about 100°C. In a particular embodiment, the method is performed in a temperature range of about 10°C to about 50°C.

[1488]

[1489] conduct.

[1490] In some embodiments, methods for preparing compounds of formula 3c or their eutectics, solvates, salts, or combinations thereof are disclosed herein:

[1491]

[1492] Or its eutectic, solvate, salt or combination thereof, the method comprising:

[1493] Cycloning compound 3a in a solvent using a hydrazine derivative and a promoter:

[1494]

[1495] Or its eutectic, solvate, or combination thereof to provide a compound of formula 3b:

[1496]

[1497] or its eutectic, solvate, salt or combination thereof; and

[1498] (b) A 3b compound or its eutectic, solvate, salt or combination thereof to provide a 3c compound or its eutectic, solvate or salt or combination thereof.

[1499] In some embodiments, the hydrazine derivative in step (a) is selected from anhydrous hydrazine, hydrazine monohydrate, aqueous hydrazine, hydrazine acetate, hydrazine dihydrochloride, hydrazine monohydrochloride, hydrazine sulfate, hydrazine hemisulfate, and hydrazine monohydrobromide. In a particular embodiment, the hydrazine derivative in step (a) is hydrazine hydrate.

[1500] In some embodiments, the solvent in step (a) is selected from 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-methylpyrrolidone), aromatic solvents (e.g., benzene, toluene, xylene), carboxylic acids (e.g., acetic acid, formic acid, propionic acid, butyric acid), and combinations thereof. In some embodiments, the solvent in step (a) is selected from water, methanol, ethanol, 1- or 2-propanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, xylene, carboxylic acids, acetic acid, formic acid, propionic acid, butyric acid, and combinations thereof. In a particular embodiment, the solvent used in step (a) is acetic acid.

[1501] In some embodiments, the accelerator in step (a) is selected from Brønsted acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid) and Lewis acids (e.g., zinc chloride, magnesium chloride, titanium tetrachloride). In some embodiments, the accelerator in step (a) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, zinc chloride, magnesium chloride, and titanium tetrachloride.

[1502] In some embodiments, step (a) is performed in a temperature range of about 120°C or lower. In some embodiments, step (a) is performed in a temperature range of about -40°C to about 120°C. In a particular embodiment, step (a) is performed in a temperature range of about 30°C to about 70°C.

[1503] In some embodiments, methods for preparing compounds of formula 3c or their eutectics, solvates, salts, or combinations thereof are disclosed herein:

[1504]

[1505] The method includes:

[1506] Cycloning compound 3a in a solvent using a hydrazine derivative and a promoter:

[1507]

[1508] Or its eutectic, solvate, or combination thereof to provide a compound of formula 3b:

[1509]

[1510]

[1511] or its eutectic, solvate, salt or combination thereof; and

[1512] (b) Separate a compound of formula 3b or its eutectic, solvate, salt or combination thereof by chiral stationary phase and solvent chromatography to provide a compound of formula 3c or its eutectic, solvate or salt thereof.

[1513] In some embodiments, the hydrazine derivative in step (a) is selected from anhydrous hydrazine, hydrazine monohydrate, aqueous hydrazine, hydrazine acetate, hydrazine dihydrochloride, hydrazine monohydrochloride, hydrazine sulfate, hydrazine hemisulfate, and hydrazine monohydrobromide. In a particular embodiment, the hydrazine derivative in step (a) is hydrazine hydrate.

[1514] In some embodiments, the solvent in step (a) is selected from 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-methylpyrrolidone), aromatic solvents (e.g., benzene, toluene, xylene), carboxylic acids (e.g., acetic acid, formic acid, propionic acid, butyric acid), and combinations thereof. In some embodiments, the solvent in step (a) is selected from water, methanol, ethanol, 1- or 2-propanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, benzene, toluene, xylene, carboxylic acids, acetic acid, formic acid, propionic acid, butyric acid, and combinations thereof. In a particular embodiment, the solvent used in step (a) is acetic acid.

[1515] In some embodiments, the accelerator in step (a) is selected from Brønsted acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid) and Lewis acids (e.g., zinc chloride, magnesium chloride, titanium tetrachloride). In some embodiments, the accelerator in step (a) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, zinc chloride, magnesium chloride, and titanium tetrachloride.

[1516] In some embodiments, step (a) is performed in a temperature range of about 120°C or lower. In some embodiments, step (a) is performed in a temperature range of about -40°C to about 120°C. In a particular embodiment, step (a) is performed in a temperature range of about 30°C to about 70°C.

[1517] In some embodiments, the chiral stationary phase used in step (b) is selected from Chiralpak AD, AS, AY, AZ, T101, OD, IA, IB, IC, ID, IE, IF, IG (Chiral Technologies); Lu×Cellulose 2, 3, 4 (Phenomenex); and (R,R)Whelk-O, (R,R)ULMO, and (S,S)DachDNB (Regis Technologies). In some embodiments, the chiral stationary phase used in step (b) is selected from Chiralpak AD, AS, AY, AZ, T101, OD, IA, IB, IC, ID, IE, IF, IG; Lu×Cellulose 2, 3, 4; and (R,R)Whelk-O, (R,R)ULMO, and (S,S)DachDNB. In a particular embodiment, the chiral stationary phase is Chiralpak IG.

[1518] In some embodiments, the solvent used in step (b) is selected from hydrocarbons (e.g., hexane, heptane, octane), esters (e.g., ethyl acetate, n-propyl acetate, isopropyl acetate), alcohols (e.g., methanol, ethanol, 1- 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 some embodiments, the solvent used in step (b) is selected from hexane, heptane, octane, esters, ethyl acetate, n-propyl acetate, isopropyl acetate, methanol, ethanol, 1- 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 a particular embodiment, the solvent is acetonitrile. [151...

Claims

1. A method for preparing a compound of formula I or a salt thereof: I The method includes: (a) To make compound III: III Or a salt thereof, combined with a methanesulfonating agent selected from methanesulfonyl chloride and methanesulfonic anhydride; a base selected from N-methylmorpholine, tri-n-propylamine, ethyl diisopropylamine, tri-n-butylamine, triethylamine, pyridine, 2,6-dimethylpyridine, cefadiol, sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium tert-amyl alcohol, and sodium tert-butoxide; and a solvent selected from diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylene, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof, to provide a compound of formula II: II or its salt; and (b) The compound of formula II or a salt thereof is hydrolyzed in a solvent selected from water, methanol, ethanol, isopropanol, 1-propanol, n-butanol, sec-butanol, 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, with a nucleophile selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiol, N-acetylcysteine, sodium thiophene, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium tert-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine and hydroxylamine to provide the compound of formula I or a salt thereof.

2. The method of claim 1, wherein the methanesulfonating agent is methanesulfonyl chloride.

3. The method of claim 1, wherein the base is triethylamine.

4. The method of claim 1, wherein the solvent used in the methanesulfonation step is 2-methyltetrahydrofuran.

5. The method of claim 1, wherein the methanesulfonation step is performed in a temperature range of -10°C to 20°C.

6. The method of claim 1, wherein the nucleophile is sodium hydroxide.

7. The method of claim 1, wherein the solvent used in the hydrolysis step is water and 2-methyltetrahydrofuran.

8. The method of claim 1, wherein the hydrolysis step is carried out in a temperature range of 10°C to 60°C.

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