Process for preparing HIV capsid inhibitors

Abstract

This disclosure relates to a process for preparing compounds useful for the prevention or treatment of retroviral virus infections, including infections caused by human immunodeficiency virus (HIV). Compound 1 is a prodrug renacapavir (compound of formula III, N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide, an HIV capsid inhibitor under development as a long-acting treatment for HIV. TIFF2026519000000418.tif59128

Description

[Technical Field] 【0001】 (Cross-reference of related applications) This application claims the benefits of U.S. Provisional Application No. 63 / 505,320, filed on 31 May 2023, the entire contents of which are incorporated herein by reference. 【0002】 This disclosure relates to a process for preparing compounds useful for the prevention or treatment of retroviral virus infections, including infections caused by human immunodeficiency virus (HIV). [Background technology] 【0003】 Positive-sense single-stranded RNA viruses, including the retroviridae family, encompass the subfamily orthoretroviruses and the genera alpha-retroviruses, beta-retroviruses, gamma-retroviruses, delta-retroviruses, epsilon-retroviruses, lentiviruses, and supmaviruses, which cause many diseases in humans and animals. Human infection with HIV-1, a lentivirus, leads to T helper cell depletion and immunodeficiency, resulting in immunodeficiency and increased susceptibility to opportunistic infections. Treatment of HIV-1 infections with highly active antiretroviral therapies (HAART) has been shown to be effective in reducing the viral load and significantly slowing 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, the discovery of new antiretroviral agents that are active against drug-resistant HIV variants is urgently needed. In the field of HIV therapy and treatment, an interesting aspect is providing patients with regimens that have improved pharmacokinetic properties, including, for example, enhanced potency, long-acting pharmacokinetics, low solubility, low clearance, and / or other characteristics. While current regimens for treating HIV have advanced so much that patients no longer need to take tablets multiple times a day, today's patients still need to take tablets daily for the duration of their predictable lifespan. Therefore, it would be beneficial to have HIV therapies that require patients to take medication less than once a day (e.g., every other day, once a week, once every two weeks, once a month, etc.), or to take smaller effective doses of medication on a daily, weekly, monthly, or longer-term basis. [Prior art documents] [Non-patent literature] 【0004】 [Non-Patent Document 1] Hammer,SM,et al.;JAMA 2008,300:555-570 [Non-Patent Document 2] Taiwo, B., International Journal of Infectious Diseases 2009,13:552-559 [Non-Patent Document 3] Smith,RJ,et al.,Science 2010,327:697-701 [Overview of the Initiative] [Means for solving the problem] 【0005】 This disclosure, in particular, includes formula XIII: [ka] A process for preparing a compound or salt thereof of formula XIV: [ka] The compound or a salt thereof is reacted with an activator in the presence of zinc and optionally an alkali metal halide to form a first mixture. The first mixture and formula XI-a: [ka] The present invention provides a process comprising mixing a compound or a salt thereof with a coupling catalyst, wherein the components are as defined herein. 【0006】 This disclosure, in particular, includes formula XIII: [ka] A process for preparing a compound or salt thereof of formula XIV: [ka] The first mixture is formed by reacting the compound or salt thereof with an activator in the presence of zinc and an alkali metal halide. The first mixture and formula XI-a: [ka] The present invention provides a process comprising mixing a compound or a salt thereof with a coupling catalyst, wherein the components are as defined herein. 【0007】 This disclosure is based on formula VI: [ka] A process for preparing a compound or salt thereof of formula VII: [ka] The compound or salt thereof and di(C 1~6 The present invention further provides a process comprising reacting an alkyl phosphite with an oxidizing agent and a base, wherein the components are as defined herein. 【0008】 The present disclosure relates to a process for preparing a compound of formula VI: [Chemical formula] which comprises reacting a compound of formula VII: [Chemical formula] or a salt thereof with tetra(C 6~10 aryl-C 1~6 alkyl-)pyrophosphate in the presence of a base, and further provides a process wherein the components are as defined herein. 【0009】 The present disclosure relates to a process for preparing a compound of formula VI: [Chemical formula] which comprises reacting a compound of formula VII: [Chemical formula] or a salt thereof with di(C 1~6 alkyl),N,N-di(C 1~6 alkyl)phosphoramidate in the presence of a base and an acid to form a first mixture, and mixing the first mixture with an oxidizing agent, and further provides a process wherein the components are as defined herein. 【0010】 The present disclosure relates to a process for preparing a compound of formula I: [Chemical formula] which comprises reacting 3-bromo-5-methylphenol with methyl 3,3-dimethylacrylate in the presence of sulfuric acid to form a compound of formula XI-a: [Chemical formula] or a salt thereof, and a compound of formula XIV-a: [ka] The first mixture is formed by reacting the compound or a salt thereof with trimethylsilyl chloride in the presence of zinc, The first mixture and the compound of formula XI-a or a salt thereof are mixed in the presence of bis(dibenzylideneacetone)palladium(0) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl to obtain formula XIII-a: [ka] To form a compound or salt thereof, The compound of formula XIII-a or a salt thereof is reacted with di-tert-butyl phosphite, bromoform, and sodium trimethylsilanolate to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of propanephosphonic anhydride and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention further provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0011】 This disclosure is based on formula I: [ka] A process for preparing a compound or salt thereof, Formula XIV-a: [ka] Reacting a compound of or a salt thereof with diisobutylaluminum hydride in the presence of zinc and lithium chloride to form a first mixture, Mixing the first mixture with a compound of formula XI-a: 【Chem.】 in the presence of palladium(II) acetate and 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl to form a compound of formula XIII-a: 【Chem.】 or a salt thereof, Reacting the compound of formula XIII-a or a salt thereof with di-tert-butyl phosphite, bromoform, and trimethylsilanolate to form a compound of formula IV-a: 【Chem.】 or a salt thereof, Linking the compound of formula IV-a or a salt thereof with a compound of formula III: 【Chem.】 in the presence of N,N,N’,N’-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form a compound of formula II-a: 【Chem.】 or a salt thereof, Deprotecting the compound of formula II-a or a salt thereof with phosphoric acid to form the compound of formula I or a salt thereof, and further providing a process comprising. 【0012】 The present disclosure relates to a process for preparing a compound of formula I: 【Chem.】 or a salt thereof, comprising Formula VII-a: [ka] The compound or a salt thereof is reacted with di-tert-butyl phosphite in the presence of bromoform and cesium carbonate to produce formula VI-a: [ka] To form a compound or salt thereof, Deprotecting the compound of formula VI-a or a salt thereof in the presence of tetrabutylammonium fluoride yields formula Va: [ka] To form a compound or salt thereof, A compound of formula Va or a salt thereof is oxidized in the presence of (diacetoxyiodo)benzene, dibasic sodium phosphate, and 2,2,6,6-tetramethylpiperidine 1-oxyl to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention further provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0013】 This disclosure is based on formula I: [ka] A process for preparing a compound or salt thereof, Formula VII-a: [ka] The compound or a salt thereof is reacted with tetrabenzyl pyrophosphate in the presence of sodium hydride to produce formula VI-b: [ka] To form a compound or salt thereof, Deprotecting a compound of formula VI-b or a salt thereof in the presence of tetrabutylammonium fluoride yields formula Vb: [ka] To form a compound or salt thereof, The compound of formula Vb or a salt thereof is oxidized in the presence of (diacetoxyiodo)benzene, dibasic sodium phosphate, and 2,2,6,6-tetramethylpiperidine 1-oxyl to obtain formula IV-b: [ka] To form a compound or salt thereof, Compound of formula IV-b or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form formula II-b: [ka] To form a compound or salt thereof, The present invention further provides a process comprising deprotecting a compound of formula II-b or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0014】 This disclosure is based on formula I: [ka] A process for preparing a compound or salt thereof, Formula VII-a: [ka] The first mixture is formed by reacting the compound or a salt thereof with di-tert-butyl N,N-diisopropyl phosphoramidate in the presence of 1-methylimidazole and trifluoroacetic acid. Mix the first mixture with hydrogen peroxide to obtain formula VI-a: [ka] To form a compound or salt thereof, Deprotecting the compound of formula VI-a or a salt thereof in the presence of tetrabutylammonium fluoride yields formula Va: [ka] To form a compound or salt thereof, A compound of formula Va or a salt thereof is oxidized in the presence of (diacetoxyiodo)benzene, dibasic sodium phosphate, and 2,2,6,6-tetramethylpiperidine 1-oxyl to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention further provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0015】 This disclosure is based on formula XIII: [ka] A process for preparing a compound or salt thereof of formula XI-b: [ka] Compounds of or salts thereof and formula XIV: [ka] The present invention further provides a process comprising reacting a compound or salt thereof with Suzuki coupling conditions, wherein the components are as defined herein. 【0016】 This disclosure is based on formula I: [ka] A process for preparing a compound or salt thereof, 3-bromo-5-methylphenol and methyl 3,3-dimethyl acrylate are reacted in the presence of sulfuric acid to form formula XI-a: [ka] To form a compound or salt thereof, The compound of formula XI-a or a salt thereof is reacted with bis(pinacolate)diborone in the presence of bis(dibenzylideneacetone)palladium(O), triphenylphosphine, and potassium propionate to obtain formula XI-b: [ka] To form a compound or salt thereof, Compound of formula XI-b or its salt and formula XIV-a: [ka] The compound or a salt thereof was reacted in the presence of bis(dibenzylideneacetone)palladium(O), tribasic sodium phosphate, and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane to obtain formula XIII-a: [ka] To form a compound or salt thereof, The compound of formula XIII-a or a salt thereof is reacted with di-tert-butyl phosphite, bromoform, and sodium trimethylsilanolate to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of propanephosphonic anhydride and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention further provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0017】 This disclosure is based on formula VI-a: [ka] A process for preparing a compound or salt thereof, wherein formula VII-a: [ka] The present invention further provides a process comprising reacting a compound or a salt thereof with di-tert-butyl N,N-diisopropyl phosphoramidate in the presence of 1-methylimidazole and trifluoroacetic acid to form a first mixture, and mixing the first mixture with hydrogen peroxide to form a compound of formula VI-a or a salt thereof. [Modes for carrying out the invention] 【0018】 This disclosure relates to 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2- The present invention relates to a process for preparing trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetamide (i.e., Compound 1 shown below, see, for example, U.S. Patent Application No. 18 / 061,375, granted on October 17, 2023, as U.S. Patent No. 11,787,825, the disclosure of which is incorporated herein by reference in its entirety). [ka] 【0019】 Compound 1 is as follows: 19 It has two restricted rotation axes, resulting in four atropisomers detectable by 1F-NMR. In deuterated DMSO at 25°C, the half-life for the conversion from the major atropisomer to the minor atropisomer for biaryl rotation is approximately 71.6 hours at an equilibrium ratio of approximately 3:1, and the half-life for interconversion on the second rotation axis is approximately 7 minutes at an equilibrium ratio of approximately 4:3. [ka] 【0020】 Compound 1 is the prodrug renacapavir (compound of formula III, N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide, an HIV capsid inhibitor under development as a long-acting treatment for HIV. [ka] 【0021】 The synthesis and characterization of lenacapavir and its salts are described, for example, in U.S. Patent Publication Nos. 20180051005 and 20190300505, the contents of which are incorporated herein by reference in their entirety. Various forms and / or uses of lenacapavir compounds are disclosed, for example, in U.S. Patent Publication Nos. 20190083478, 20190084963, 20200038389(A1), and 20210188815, the contents of which are incorporated herein by reference in their entirety. 【0022】 Currently, there is a need for synthetic methods and intermediates that can be used to prepare compounds of formula I and their cocrystals, solvates, or salts. 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, or salts. Improved methods and intermediates could reduce the costs, time, and / or waste associated with existing methods for preparing compounds of formula I and their cocrystals, solvates, salts, and combinations. 【0023】 The following description is made with the understanding that this disclosure should be considered as an illustration of the subject matter claimed, and that the appended claims are not intended to limit the scope of the specific embodiments illustrated. The headings used throughout this disclosure are for convenience only and should not be construed as limiting the scope of the claims. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. 【0024】 Where trade names are used in this specification, they are intended to refer separately to the trade name product and the active pharmaceutical ingredient of the trade name product. 【0025】 As used herein and in the appended claims, the singular forms "a," "an," and "the" include multiple references unless otherwise explicitly indicated in the context. Thus, for example, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes one or more assays, and so on. 【0026】 "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers. 【0027】 "Stereoisomers" are isomers that differ only in the arrangement of atoms in space. 【0028】 An "enantiomer" is a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "scaremic" mixture. 【0029】 A "diastereoisomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other. 【0030】 Absolute stereochemistry is specified according to the Kahn-Ingold-Prelogue RS system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by either R or S. Split compounds whose absolute configuration is unknown may be designated (+) or (-) depending on the direction of rotation of plane polarization at the wavelength of the sodium D line (dextrorotatory or levorotatory). Certain compounds described herein may contain one or more chiral centers and / or constraining rotations around a bonding axis, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry. This disclosure is intended to include all such possible isomers, including racemic mixtures, scaremic mixtures, diastereomixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or they may be split using conventional techniques. 【0031】 Unless expressly defined otherwise, this disclosure includes all tautomers of the compounds detailed herein, even if only one tautomer is expressly represented (for example, if a pair of two tautomers may exist, both tautomer forms are intended and described by the presentation of one tautomer form). For example, when referring to a compound containing an amide (e.g., by its structural or chemical name), it is understood that the corresponding imido acid tautomer is included in this disclosure and described in the same way as if the amide were expressly represented alone or together with the imido acid. If more than two tautomers may exist, this disclosure includes all such tautomers, even if only a single tautomer form is indicated by its chemical name and / or structure. 【0032】 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 isomers, enantiomers, diastereoisomers, and geometric isomers are included. Where a compound is represented in its chiral form, the embodiments are understood to include, but are not limited to, specific diastereomeric or enantiomerically enriched forms. Where chirality is not specified but present, the embodiments are understood to cover either a specific diastereomeric or enantiomerically enriched form, or a racemic or scaremic mixture of such a compound. As used herein, “scaremic mixture” is a mixture of stereoisomers in a ratio other than 1:1. 【0033】 This specification also provides pharmaceutically acceptable hydrates, solvates, cocrystals, tautomers, polymorphs, and prodrugs of the compounds described herein. 【0034】 The term "hydrate" refers to a complex formed by combining a compound of formula I or any of the formulas disclosed herein with water. 【0035】 The term "solvate" refers to a complex formed by combining a compound of formula I or any other formula disclosed herein with a solvent or crystalline solid containing an amount of the solvent incorporated into its crystalline structure. As used herein, the term "solvate" includes hydrates. 【0036】 The term "cocrystal" refers to a crystalline material formed by combining a compound of Formula I or any of the formulas disclosed herein with one or more cocrystal formers (i.e., molecules, ions, or atoms). In some cases, the cocrystal may have improved properties compared to the parent form (i.e., free molecule, zwitterion, etc.) or a salt of the parent compound. Improved properties can include increased solubility, increased decomposition, increased bioavailability, increased dose response, decreased hygroscopicity, a crystalline form of a compound that is normally amorphous, a crystalline form of a compound that is difficult or impossible to form a salt, decreased conformational diversity, a more desirable form, and the like. Methods for making and characterizing cocrystals are known to those of skill in the art. 【0037】 Any formula or structure given herein that includes Formula I or any of the formulas disclosed herein is also intended to represent both unlabeled and isotopically labeled forms of the compound. An isotopically labeled compound has a structure shown by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 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, but are not limited thereto. Various isotopically labeled compounds of the present disclosure are, for example, 3 H, 13 C and 14These compounds incorporate radioactive isotopes such as 13C. Such isotope-labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiotherapy for patients. 【0038】 This disclosure also includes compounds of formula I or any of the formulas disclosed herein, in which 1 to "n" hydrogen atoms bonded to a carbon atom are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful in extending the half-life of any compound of formula I 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 means well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium. 【0039】 The deuterium-labeled or deuterium-substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may result in certain therapeutic benefits due to greater metabolic stability, e.g., increased half-life in vivo, reduced dosage, and / or improved therapeutic index. 18F-labeled compounds may be useful in PET or SPECT studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by substituting readily available isotope-labeling reagents for non-isotope-labeling reagents, by performing the procedures disclosed in the scheme or the examples and preparations described below. Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), may result in certain therapeutic benefits due to greater metabolic stability, e.g., extended half-life in vivo, reduced dosage, or improved therapeutic index. In this context, deuterium is understood to be a substituent in a compound of formula I or any of the formulas disclosed herein. 【0040】 The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in the isotopic composition of the natural abundance of hydrogen. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium. 【0041】 The modifier "approximately," when used in relation to quantity, includes the stated value and has a meaning determined by the context (for example, including the degree of error related to the measurement of a particular quantity). 【0042】 The term "chiral" refers to molecules that possess the property of non-superimposability of their mirror image partners, while the term "achiral" refers to molecules that can be superimposed on their mirror image partners. 【0043】 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 8 carbon atoms (i.e., (C1-C8) alkyl), 1 to 6 carbon atoms (i.e., (C1-C6) alkyl), or 1 to 4 carbon atoms (i.e., (C1-C4) alkyl). Suitable examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), and 2-butyl (s-Bu, s-butyl, -CH(CH 3)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(-CH2CH 2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH(CH3)CH2CH3), 4 Examples include, but are not limited to, 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). 【0044】 The terms "halo" or "halogen" as used herein refer to fluoro, chloro, bromo, or iodine. 【0045】 As used herein, the term “aryl” refers to an all-carbon aromatic monocyclic or all-carbon ring-fused polycyclic system in which at least one of the rings is aromatic. For example, in certain embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Examples of aryls include phenyl radicals. Aryls also include fused polycyclic systems (e.g., ring systems with 2, 3, or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and the other rings may or may not be aromatic (i.e., carbon rings). Such multiple fused ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups for any carbon ring portion of the multiple fused ring system. The rings of the multiple fused ring system may be linked to one another by condensation bonds, spiro bonds, and bridging bonds, where permitted by the valence requirements. It should be understood that the bond points of the multiple fused ring systems defined above can be at any position in the ring system, including the aromatic or carbon ring portions of the rings. When referring to aryl groups with a specific range of member numbers (e.g., 6- to 12-membered aryls), it should be understood that the atomic range refers to the entire ring of aryl atoms. For example, phenyl is a 6-membered aryl, and naphthyl and 1,2,3,4-tetrahydronaphthyl are 10-membered aryls. Non-exclusive examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracenyl. 【0046】 When used herein, "C n-mThe term "alkoxy" refers to a group of the formula -O-alkyl, where the alkyl group has n to m carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and butoxy (e.g., n-butoxy and tert-butoxy). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. 【0047】 When used herein, "C o-p Aryl-C n-m "Alkyl-" refers to the group of the formula aryl-alkylene-, where the aryl group has 0 to p carbon atoms and the alkylene linking group has n to m carbon atoms. In some embodiments, C o~p Aryl-C n~m Ariel- is C- 6~10 Aryl-C 1~6 It is alkyl. In some embodiments, C o~p Aryl-C n~m Alkyl- or C 6~10 Aryl-C 1~6 The alkyl group is benzyl. 【0048】 As used herein, “alkylene linking group” refers to a divalent linear or branched alkyl linking group. For example, “C o-p Aryl-C n-m The prefix "alkyl-" includes an alkylene linking group. Examples of "alkylene linking groups" include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, and propane-1,1-diyl. 【0049】 As used herein, the phrase "optionally substituted" means either unsubstituted or substituted. Substituents are independently selected, and substitutions may occur at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It should be understood that substitutions at a given atom are limited by their valence. 【0050】 The term "n-membered," where n is an integer, typically refers to the number of ring-forming atoms in a part of the ring where the number of ring-forming atoms is n. For example, pyridyl is an example of a six-membered heteroaryl ring. 【0051】 As used herein, the term “independently selected from” means that each occurrence of a variable or substituent is independently selected in each occurrence from the applicable list. 【0052】 Unless otherwise noted, the methods and techniques described herein are generally carried out in accordance with the prior art well known in the art and as described in the various general and more specific references cited and discussed herein. For example, Loudon, Organic Chemistry, 5 th edition, New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th See edition, Wiley-Interscience, 2013. 【0053】 In some cases, the processes disclosed herein involve the step of forming a salt of the compound of this disclosure. 【0054】 The compounds described herein can be purified by any method known in the art, including chromatographic techniques such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography, supercritical fluid chromatography (SFC), and ion exchange chromatography. Any suitable stationary phase, such as normal-phase, reverse-phase, and ionic resins, can be used. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd ed., ed. LRSnyder and JJ Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969. 【0055】 During any step in the process of preparing the target compound, it may be necessary and / or desirable to protect the sensitive or reactive groups in any of the molecules involved. This is described in TWGreene and PGMWuts, Protective Groups in Organic Synthesis, 4. th This can be achieved by conventional protecting groups, as described in standard studies such as Wiley, New York 2006. The protecting groups can be removed in a convenient subsequent step using methods known from the art. 【0056】 Here, exemplary chemicals useful in the methods of the embodiments are described by reference to the exemplary synthesis schemes for their general preparations herein and the following specific examples. Those skilled in the art will understand that the transformations shown in the following schemes can be carried out in any order that suits the functionality of a particular pendant group. In some embodiments, each of the reactions shown in the general scheme is carried out at a temperature of about -80°C to reflux temperature of the organic solvent used. 【0057】 The compounds disclosed herein may exhibit atropisomerism arising from steric hindrance affecting the axial rotation rate around single bonds. The resulting conformational isomers can be observed as distinct entities by characterization techniques such as NMR and HPLC. The compounds disclosed herein may exist as mixtures of atropisomers. However, the detection of atropisomers depends on factors such as temperature, solvent, purification conditions, and the time scale of the spectroscopic technique. Interconversion rates at room temperature have half-lives ranging from minutes to hours, hours to days, or days to years. The ratio of atropisomers at equilibrium may not be 1. The characterization data presented herein may not represent equilibrium, depending on the isolation and characterization conditions (including, but not limited to, handling, solvents used, and temperature). 【0058】 In some embodiments, this disclosure provides processes and intermediates for preparing compounds of formula I, as well as their cocrystals, solvates, salts, and combinations. In other embodiments, this disclosure provides processes for preparing intermediates that can be used to prepare compounds of formula I, as well as their cocrystals, solvates, salts, and combinations. 【0059】 Therefore, this disclosure relates to formula XIII: [ka] A process for preparing a compound of formula XIV or its cocrystal, solvate, or salt, wherein formula XIV: [ka] The first mixture is formed by reacting the compound or its cocrystal, solvate, or salt with an activator in the presence of zinc and optionally an alkali metal halide. The first mixture and formula XI: [ka] The process involves mixing a compound or its cocrystal, solvate, or salt in the presence of a coupling catalyst, wherein the formula includes, X 1 But it's a halo, X 2 However, selected from the group consisting of halo, (4-methylbenzenesulfonyl)oxyl, (methylsulfonyl)oxyl, (trifluoromethylsulfonyl)oxyl, dihydroxyboranyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, 5,5-dimethyl-1,3,2-dioxabolinan-2-yl, and benzo[d][1,3,2]dioxabolinol-2-yl, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 The process is provided by substitution with alkoxy. 【0060】 In some embodiments, this disclosure relates to formula XIII: [ka] A process for preparing a compound of formula XIV or its cocrystal, solvate, or salt, wherein formula XIV: [ka] The first mixture is formed by reacting the compound or its cocrystal, solvate, or salt with an activator in the presence of zinc and optionally an alkali metal halide. The first mixture and formula XI: [ka] The process involves mixing a compound or its cocrystal, solvate, or salt in the presence of a coupling catalyst, wherein the formula includes, X 1 But it's a halo, X 2 However, selected from the group consisting of halo, (4-methylbenzenesulfonyl)oxyl, (methylsulfonyl)oxyl, and (trifluoromethylsulfonyl)oxyl, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 The process is provided by substitution with alkoxy. 【0061】 In some embodiments, X 2 It is a halo. 【0062】 In some embodiments, X 2 These are bromo, chloro, or iodine. 【0063】 In some embodiments, X 2 It is Bromo. 【0064】 In some embodiments, X 2The compound is selected from the group consisting of halo, dihydroxyboranyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, 5,5-dimethyl-1,3,2-dioxabolinan-2-yl, and benzo[d][1,3,2]dioxabolinol-2-yl. 【0065】 In some embodiments, X 2 The is selected from the group consisting of dihydroxyboranyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, 5,5-dimethyl-1,3,2-dioxabolinan-2-yl, and benzo[d][1,3,2]dioxabolinol-2-yl. 【0066】 In some embodiments, X 2 This is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl. 【0067】 In some embodiments, this disclosure relates to formula XIII: [ka] A process for preparing a compound of formula XIV or its cocrystal, solvate, or salt, wherein formula XIV: [ka] The first mixture is formed by reacting the compound or its cocrystal, solvate, or salt with an activator in the presence of zinc and optionally an alkali metal halide. The first mixture and formula XI-a: [ka] The process involves mixing a compound, or a cocrystal, solvate, or salt thereof, in the presence of a coupling catalyst, wherein the formula includes, X 1 But it's a halo, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 The process is provided by substitution with alkoxy. 【0068】 In some embodiments, this disclosure relates to formula XIII: [ka] A process for preparing a compound of formula XI-b, or a cocrystal, solvate, or salt thereof, wherein formula XI-b: [ka] A compound of, or its cocrystal, solvate, or salt, and formula XIV: [ka] The process involves reacting a compound, or its cocrystal, solvate, or salt, under Suzuki coupling conditions, wherein, X 1 But it's a halo, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 The process is provided by substitution with alkoxy. 【0069】 In some embodiments, this disclosure relates to formula XIII: [ka] A process for preparing a compound of formula XI-b or a salt thereof, comprising reacting a compound of formula XI-b: [Chemical formula] or a salt thereof with a compound of formula XIV: [Chemical formula] or a salt thereof under Suzuki coupling conditions, wherein X 1 is halo, R 1 is selected from the group consisting of C 1~6 alkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and C 6~10 aryl-C 1~6 alkyl-, wherein C 6~10 aryl, 5- to 10-membered heteroaryl, and C 6~10 aryl-C 1~6 alkyl- are each optionally substituted with C 1~6 alkoxy, provides a process. 【0070】 In some embodiments, R 1 is selected from the group consisting of C 1~6 alkyl, phenyl, pyridyl, and benzyl, wherein phenyl, pyridyl, and benzyl are each optionally substituted with methoxy. 【0071】 In some embodiments, R 1 is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0072】 In some embodiments, a process for preparing a compound of formula XIII: [Chemical formula] or a salt thereof is a compound of formula XIV: [ka] The first mixture is formed by reacting the compound or salt thereof with an activator in the presence of zinc and an alkali metal halide. The first mixture and formula XI-a: [ka] The process involves mixing a compound or a salt thereof in the presence of a coupling catalyst, wherein the formula includes, X 1 But it's a halo, R 1 However, C 1~6 It is alkyl. 【0073】 In some embodiments, R 1 C 1~6 It is alkyl. In some embodiments, R 1 R is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 1 It is tert-butyl. 【0074】 In some embodiments, X 1 It is Bromo. 【0075】 In some embodiments, the activator is selected from the group consisting of trialkylsilyl halides (e.g., trimethylsilyl chloride, triethylsilyl chloride, trimethylsilyl iodide), dihaloethanes (e.g., dibromoethane, dichloroethane), alkylaluminum hydrides (e.g., diisobutylaluminum hydride), and iodine. 【0076】 In some embodiments, the activator is selected from the group consisting of diisobutylaluminum hydride, trimethylsilyl chloride, triethylsilyl chloride, trimethylsilyl iodide, dibromoethane, dichloroethane, and iodine. In some embodiments, the activator is diisobutylaluminum hydride. In some embodiments, the activator is trimethylsilyl chloride. 【0077】 In some embodiments, the alkali metal halide is lithium halide. In some embodiments, the alkali metal halide is lithium chloride. In some embodiments, the alkali metal halide is absent. 【0078】 In some embodiments, the coupling catalyst includes a palladium catalyst. 【0079】 In some embodiments, the palladium catalyst is a palladium salt (II) (e.g., palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate, palladium complex (O) (e.g., bis(dibenzylideneacetone)palladium(O), tris(dibenzylideneacetone)dipalladium(O), tetrakis(triphenylphosphine)palladium(O)), G3-Pd complex (e.g., methanesulfonic acid (2-dicyclohexylphosphin-2',4',6') Selected from the group consisting of (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium(XPhos-Pd-G4)). 【0080】 In some embodiments, the palladium catalyst is a palladium salt (II) (e.g., palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate), a palladium complex (0) (e.g., tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0)), a G3-Pd complex (e.g., methanesulfonic acid (2-dicyclohexylphosphin-2',4',6'-triisopropyl-1, Selected from the group consisting of 1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)(XPhos-Pd-G3)) and G4-Pd complexes (e.g., (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium(XPhos-Pd-G4)). 【0081】 In some embodiments, the palladium catalyst is selected from the group consisting of palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate, bis(dibenzylideneacetone)palladium(O), tris(dibenzylideneacetone)dipalladium(O), tetrakis(triphenylphosphine)palladium(O), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. 【0082】 In some embodiments, the palladium catalyst is selected from the group consisting of palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate, tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. 【0083】 In some embodiments, the palladium catalyst is selected from the group consisting of palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate, bis(dibenzylideneacetone)palladium(0), tetrakis(triphenylphosphine)palladium(0), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. 【0084】 In some embodiments, the coupling catalyst comprises a palladium catalyst and optionally a phosphine ligand. In some embodiments, the phosphine ligand is absent. In some embodiments, the phosphine ligand is selected from the group consisting of trialkylphosphines (e.g., tricyclohexylphosphine, tri-tert-butylphosphine), triarylphosphines (e.g., triphenylphosphine), dialkylarylphosphines (e.g., 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), and alkyldiarylphosphines (e.g., ethylenebis(diphenylphosphine) (DPPE)). 【0085】 In some embodiments, the phosphine ligand is selected from the group consisting of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tricyclohexylphosphine, tri-tert-butylphosphine, triphenylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and ethylenebis(diphenylphosphine). In some embodiments, the phosphine ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. 【0086】 In some embodiments, the coupling catalyst comprises a palladium catalyst and a phosphine ligand. In some embodiments, the coupling catalyst comprises palladium(II) acetate and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. In some embodiments, the coupling catalyst comprises bis(dibenzylideneacetone)palladium(O) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. 【0087】 In some embodiments, the mixing of the first mixture with the compound of formula XI is carried out at a temperature of about 0°C to about 100°C. In some embodiments, the mixing of the first mixture with the compound of formula XI is carried out at a temperature of about 0°C to about 35°C. 【0088】 In some embodiments, the mixing of the first mixture and the compound of formula XI is carried out in a solvent selected from the group consisting of ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide), or any combination thereof. In some embodiments, the mixing of the first mixture and the compound of formula XI is carried out in a solvent containing tetrahydrofuran and 2-methyltetrahydrofuran. 【0089】 In some embodiments, formula XIII: [ka] The process for preparing the compound, or its cocrystal, solvate, or salt, is given by formula XI-b: [ka] A compound of, or its cocrystal, solvate, or salt, and formula XIV: [ka] The process involves reacting a compound, or its cocrystal, solvate, or salt, under Suzuki coupling conditions, wherein, X 1 But it's a halo, R 1 However, C 1~6 It is alkyl. 【0090】 In some embodiments, formula XIII: [ka] The process for preparing the compound or salt thereof is given by formula XI-b: [ka] Compounds of or salts thereof and formula XIV: [ka] The process involves reacting a compound or salt thereof with Suzuki coupling conditions, in which, X 1 But it's a halo, R 1 However, C 1~6 It is alkyl. 【0091】 In some embodiments, the Suzuki coupling conditions include reacting a compound of formula XI-b or a salt thereof with a compound of formula XIV or a salt thereof in the presence of a palladium catalyst, a base, and optionally a ligand. 【0092】 In some embodiments, the Suzuki coupling conditions involve reacting a compound of formula XI-b or a salt thereof with a compound of formula XIV or a salt thereof in the presence of a palladium catalyst and a base. 【0093】 In some embodiments, the palladium catalyst (i.e., Suzuki coupling palladium catalyst) is a palladium salt (II) (e.g., palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate), palladium complex (O) (e.g., bis(dibenzylideneacetone)palladium(O), tetrakis(triphenylphosphine)palladium(O)), G3-Pd complex (e.g., methanesulfonic acid (2-dicyclohexylphosphine-2',4', Selected from 6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)(XPhos-Pd-G3)) and G4-Pd complexes (e.g., (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium(XPhos-Pd-G4)). 【0094】 In some embodiments, the palladium catalyst (i.e., Suzuki coupling palladium catalyst) is selected from palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate, bis(dibenzylideneacetone)palladium(O), tetrakis(triphenylphosphine)palladium(O), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. In some embodiments, the palladium catalyst (i.e., Suzuki coupling palladium catalyst) is bis(dibenzylideneacetone)palladium(0). 【0095】 In some embodiments, the base (i.e., Suzuki coupling base) is selected from inorganic bases (e.g., sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, potassium propionate) and tertiary amine bases (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine). 【0096】 In some embodiments, the base (i.e., Suzuki coupling base) is selected from sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, potassium propionate, triethylamine, N-methylmorpholine, tripropylamine, and N,N-diisopropylethylamine. In some embodiments, the base (i.e., Suzuki coupling base) is tribasic potassium phosphate. 【0097】 In some embodiments, the Suzuki coupling of the compound of formula XI-b or a salt thereof with the compound of formula XIV is carried out in the presence of a ligand. 【0098】 In some embodiments, the ligand (i.e., Suzuki coupling ligand) is selected from trialkylphosphines (e.g., tricyclohexylphosphine, tri-tert-butylphosphine), triarylphosphines (e.g., triphenylphosphine), dialkylarylphosphines (e.g., 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (SPhos)), alkyldiarylphosphines (e.g., ethylenebis(diphenylphosphine) (DPPE)), and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane. 【0099】 In some embodiments, the ligand (i.e., Suzuki coupling ligand) is selected from tricyclohexylphosphine, tri-tert-butylphosphine, triphenylphosphine, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, ethylenebis(diphenylphosphine), and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane. In some embodiments, the ligand (i.e., Suzuki coupling ligand) is 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane. 【0100】 In some embodiments, the reaction of the compound of formula XI-b or a salt thereof with the compound of formula XIV or a salt thereof is carried out at a temperature of about -20°C to about 150°C. In some embodiments, the reaction of the compound of formula XI-b or a salt thereof with the compound of formula XIV or a salt thereof is carried out at a temperature of about 0°C to about 90°C. In some embodiments, the reaction of the compound of formula XI-b or a salt thereof with the compound of formula XIV or a salt thereof is carried out at a temperature of about 70°C to about 90°C. In some embodiments, the reaction of the compound of formula XI-b or a salt thereof with the compound of formula XIV or a salt thereof is carried out at a temperature of about 75°C to about 85°C. 【0101】 In some embodiments, the reaction of the compound of formula XI-b or a salt thereof and the compound of formula XIV or a salt thereof is carried out in a solvent selected from esters (e.g., ethyl acetate, n-butyl acetate), ethers (e.g., 2-methyltetrahydrofuran, tert-butyl methyl ether), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide), and protic solvents (e.g., methanol, ethanol), or any combination thereof. 【0102】 In some embodiments, the reaction of the compound of formula XI-b or a salt thereof with the compound of formula XIV or a salt thereof is carried out in a solvent selected from ethyl acetate, n-butyl acetate, 2-methyltetrahydrofuran, tert-butyl methyl ether, toluene, xylene, trifluorotoluene, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, propylnitrile, butylnitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, methanol, and ethanol, or any combination thereof. In some embodiments, the reaction of the compound of formula XI-b or a salt thereof with the compound of formula XIV or a salt thereof is carried out in a solvent containing isopropyl acetate. In some embodiments, the reaction of the compound of formula XI-b or a salt thereof with the compound of formula XIV or a salt thereof is carried out in a solvent containing isopropyl acetate and water. 【0103】 In some embodiments, formula XI: [ka] The compound, or its cocrystal, solvate, or salt, is of formula XI-a: [ka] The compound, or its cocrystal, solvate, or salt, is prepared by borylation with a diboron reagent in the presence of a palladium catalyst, a base, and optionally a ligand, wherein, X 2 The selected substance is from the group consisting of dihydroxyboranyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, 5,5-dimethyl-1,3,2-dioxabolinan-2-yl, and benzo[d][1,3,2]dioxabolinol-2-yl. 【0104】 In some embodiments, formula XI: [ka] The compound or salt thereof is of formula XI-a: [ka] The compound or a salt thereof is prepared by borylation with a diboron reagent in the presence of a palladium catalyst, a base, and optionally a ligand, in the formula, X 2 The selected substance is from the group consisting of dihydroxyboranyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, 5,5-dimethyl-1,3,2-dioxabolinan-2-yl, and benzo[d][1,3,2]dioxabolinol-2-yl. 【0105】 In some embodiments, the diborone reagent is selected from bis(pinacolate)diborone, bis(neopentyl glycolate)diborone, tetrahydroxydiborone, 2,2'-bibenzo[d][1,3,2]dioxabolol, and 4,4,4',4',6,6,6',6'-octamethyl-2,2'-bi(1,3,2-dioxaborinane). In some embodiments, the diborone reagent is bis(pinacolate)diborone. 【0106】 In some embodiments, the compound of formula XI is formula XI-b: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0107】 In some embodiments, the compound of formula XI is formula XI-b: [ka] It is a compound or salt thereof. 【0108】 In some embodiments, the compound of formula XI is formula XI-b: [ka] It is a compound of [the compound]. 【0109】 In some embodiments, the compound of formula XI-b or a salt thereof is of formula XI-a: [ka] The compound, or its cocrystal, solvate, or salt, is prepared by borylation with a diboron reagent in the presence of a palladium catalyst, a base, and optionally a ligand. 【0110】 In some embodiments, the compound of formula XI-b or a salt thereof is of formula XI-a: [ka] The compound or a salt thereof is prepared by borylation with a diboron reagent in the presence of a palladium catalyst, a base, and optionally a ligand. 【0111】 In some embodiments, the diborone reagent is bis(pinacolate)diborone. 【0112】 In some embodiments, the palladium catalyst (i.e., palladium boronate catalyst) is a palladium salt (II) (e.g., palladium chloride (II), palladium bromide (II), palladium acetate (II), palladium trifluoroacetate (II)), a palladium complex (O) (e.g., bis(dibenzylideneacetone)palladium (O), tetrakis(triphenylphosphine)palladium (O)), a G3-Pd complex (e.g., methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-tri) Selected from the group consisting of sopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)(XPhos-Pd-G3)) and G4-Pd complexes (e.g., (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium(XPhos-Pd-G4)). 【0113】 In some embodiments, the palladium catalyst (i.e., boronated palladium catalyst) is selected from palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate, tetrakis(triphenylphosphine)palladium(0), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. In some embodiments, the palladium catalyst (i.e., palladium borydate catalyst) is bis(dibenzylideneacetone)palladium(0). 【0114】 In some embodiments, the boration of the compound of formula XI-a or a salt thereof is carried out in the presence of a ligand. 【0115】 In some embodiments, the ligand (i.e., borated ligand) is selected from trialkylphosphines (e.g., tricyclohexylphosphine, tri-tert-butylphosphine), triarylphosphines (e.g., triphenylphosphine, tri(o-tolyl)phosphine), dialkylarylphosphines (e.g., 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (SPhos)), and alkyldiarylphosphines (e.g., ethylenebis(diphenylphosphine) (DPPE)). 【0116】 In some embodiments, the ligand (i.e., the boronated ligand) is selected from tricyclohexylphosphine, tri-tert-butylphosphine, triphenylphosphine, tri(o-tolyl)phosphine, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, and ethylenebis(diphenylphosphine). In some embodiments, the ligand (i.e., the boronated ligand) is triphenylphosphine. 【0117】 In some embodiments, the base (i.e., borated base) is selected from sodium acetate, inorganic bases (e.g., sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, potassium propionate), and tertiary amine bases (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine). 【0118】 In some embodiments, the base (i.e., the borated base) is selected from sodium acetate, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, potassium propionate, triethylamine, N-methylmorpholine, tripropylamine, and N,N-diisopropylethylamine. In some embodiments, the base (i.e., the borated base) is potassium propionate. 【0119】 In some embodiments, the boration of the compound of formula XI-a or its salt is carried out at a temperature of about 0°C to about 150°C. In some embodiments, the boration of the compound of formula XI-a or its salt is carried out at a temperature of about 50°C to about 95°C. In some embodiments, the boration of the compound of formula XI-a or its salt is carried out at a temperature of about 70°C to about 90°C. In some embodiments, the boration of the compound of formula XI-a or its salt is carried out at a temperature of about 80°C to about 90°C. 【0120】 In some embodiments, the boration of the compound of formula XI-a or a salt thereof is carried out in a solvent selected from the group consisting of esters (e.g., ethyl acetate, n-butyl acetate), ethers (e.g., 2-methyltetrahydrofuran, tert-butyl methyl ether), hydrocarbons (e.g., toluene, xylene), halogenating solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, trifluorotoluene), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide), and protic solvents (e.g., methanol, ethanol). 【0121】 In some embodiments, the boration of the compound of formula XI-a or a salt thereof is carried out in a solvent selected from the group consisting of ethyl acetate, isopropyl acetate, n-butyl acetate, 2-methyltetrahydrofuran, tert-butyl methyl ether, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, trifluorotoluene, acetonitrile, propylnitrile, butylnitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, methanol, and ethanol, or any combination thereof. In some embodiments, the boration of the compound of formula XI-a or a salt thereof is carried out in a solvent containing isopropyl acetate. 【0122】 In some embodiments, the compound of formula XIV is formula XIV-a: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. In some embodiments, the compound of formula XIV is formula XIV-a: [ka] It is a compound or salt thereof. 【0123】 In some embodiments, the compound of formula XIV is formula XIV-a: [ka] It is a compound of [the compound]. 【0124】 In some embodiments, the compound of formula XIII is formula XIII-a: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0125】 In some embodiments, the compound of formula XIII is formula XIII-a: [ka] It is a compound or salt thereof. 【0126】 In some embodiments, the compound of formula XIII is formula XIII-a: [ka] It is a compound of [the compound]. 【0127】 In some embodiments, the process for preparing the compound of formula XIII, or its cocrystal, solvate, or salt, involves phosphorylating the compound of formula XIII, or its cocrystal, solvate, or salt, to produce formula IV: [ka] The further comprising forming a compound or a cocrystal, solvate, or salt thereof, wherein, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group is C, chosen at will. 1~6 Substituted with alkoxy, R 2 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 It is substituted with an alkoxy. 【0128】 In some embodiments, R 1 C 1~6 A molecule is selected from the group consisting of alkyl, phenyl, pyridyl, and benzyl, and each of the phenyl, pyridyl, and benzyl molecules is optionally substituted with methoxy. 【0129】 In some embodiments, R 1 The compound is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0130】 In some embodiments, R 2 Independently, C 1~6A molecule is selected from the group consisting of alkyl, phenyl, pyridyl, and benzyl, and each of the phenyl, pyridyl, and benzyl molecules is optionally substituted with methoxy. 【0131】 Several embodiments, each R 2 The compounds are independently selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0132】 In some embodiments, the process for preparing the compound of formula XIII or a salt thereof involves phosphorylating the compound of formula XIII or a salt thereof to produce formula IV: [ka] The further comprising forming a compound or salt thereof, in which, R 1 However, C 1~6 It is alkyl, Each R 2 However, independently, C 1~6 Selected from the group consisting of alkyl groups. 【0133】 In some embodiments, R 1 R is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 1 It is tert-butyl. 【0134】 Several embodiments, each R 2 R is independently selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 2 is tert-butyl. In some embodiments, each R 1 and each R 2 It is tert-butyl. 【0135】 In some embodiments, phosphorylation involves reacting a compound of formula XIII, or its cocrystal, solvate, or salt, with a phosphorylating agent in the presence of an optionally selected oxidizing agent and a base. 【0136】 In some embodiments, phosphorylation involves reacting a compound of formula XIII or a salt thereof with a phosphorylating agent in the presence of an optionally selected oxidizing agent and a base. 【0137】 In some embodiments, phosphorylation involves reacting a compound of formula XIII or a salt thereof with a phosphorylating agent. 【0138】 In some embodiments, phosphorylation involves reacting a compound of formula XIII or a salt thereof with a phosphorylating agent in the presence of an oxidizing agent and a base. 【0139】 In some embodiments, the phosphorylating agent is selected from the group consisting of di-tert-butyl phosphite, dialkyl phosphoryl halide (e.g., di-t-butyl phosphoryl chloride, di-t-butyl phosphoryl bromide, di-ethyl phosphoryl chloride, di-propyl phosphoryl chloride), dibenzyl phosphorochloride, and dibenzyl phosphorobromide. 【0140】 In some embodiments, the phosphorylating agent is selected from the group consisting of di-tert-butyl phosphite, di-tert-butyl phosphoryl chloride, di-tert-butyl phosphoryl bromide, di-ethyl phosphoryl chloride, di-isopropyl phosphoryl chloride, dibenzyl phosphorochloride, and dibenzyl phosphorobromide. In some embodiments, the phosphorylating agent is di-tert-butyl phosphite. 【0141】 In some embodiments, no oxidizing agent is present. In some embodiments, the oxidizing agent is selected from the group consisting of alkyl halides (e.g., carbon tetrabromide, carbon tetrachloride, bromoform, dibromomethane, dibromoethane, bromotrichloromethane, N-halosuccinimide (e.g., N-chlorosuccinimide, N-bromosuccinimide), N-halosulfonamides (e.g., sodium N-chlorotosylamide, bromine (Br2), chlorine (Cl2), iodine (I2), and hypochlorites (e.g., sodium hypochlorite)). 【0142】 In some embodiments, the oxidizing agent is selected from the group consisting of bromoform, carbon tetrabromide, carbon tetrachloride, dibromomethane, dibromoethane, bromotrichloromethane, N-chlorosuccinimide, N-bromosuccinimide, sodium N-chlorotosylamide, bromine, chlorine, iodine, and sodium hypochlorite. In some embodiments, the oxidizing agent is bromoform. 【0143】 In some embodiments, the base is selected from the group consisting of hydroxide bases (e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide), siloxide bases (e.g., sodium trimethylsilanolate), alkoxide bases (e.g., sodium tert-butoxide), hydride bases (e.g., sodium hydride), and carbonate bases (e.g., cesium carbonate). 【0144】 In some embodiments, the base is selected from the group consisting of sodium trimethylsilanolate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium trimethylsilanolate, sodium tert-butoxide, sodium hydride, and cesium carbonate. In some embodiments, the base is sodium trimethylsilanolate. In some embodiments, the base is cesium carbonate. 【0145】 In some embodiments, phosphorylation is carried out at a temperature of approximately 0°C to approximately 40°C. In some embodiments, phosphorylation is carried out at a temperature of approximately 0°C to approximately 35°C. In some embodiments, phosphorylation is carried out at approximately room temperature. 【0146】 In some embodiments, phosphorylation is carried out in a solvent selected from the group consisting of ethers (e.g., 2-methyltetrahydrofuran), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide), or any combination thereof, optionally in combination with water. In some embodiments, phosphorylation is carried out in a solvent containing 2-methyltetrahydrofuran and water. 【0147】 In some embodiments, the compound of formula IV is: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0148】 In some embodiments, the compound of formula IV is: [ka] It is a compound or salt thereof. 【0149】 In some embodiments, the compound of formula IV is: [ka] It is a compound of [the compound]. 【0150】 In some embodiments, this disclosure relates to formula VI: [ka] A process for preparing a compound of formula VII or its cocrystal, solvate, or salt, wherein formula VII: [ka] The compound or its cocrystal, solvate, or salt and di(C 1~6 The method further comprises reacting an alkyl with an oxidizing agent and a base, in which, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl groups, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, R 2 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl groups, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 3 However, independently, C 1~6 Alkyl and C 6~10 Further processes are provided, selected from a group consisting of aryl groups. 【0151】 In some embodiments, R 1 C 1~6 A molecule is selected from the group consisting of alkyl, phenyl, pyridyl, and benzyl, and each of the phenyl, pyridyl, and benzyl molecules is optionally substituted with methoxy. 【0152】 In some embodiments, R 1 The compound is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0153】 In some embodiments, R 2 Independently, C 1~6 A molecule is selected from the group consisting of alkyl, phenyl, pyridyl, and benzyl, and each of the phenyl, pyridyl, and benzyl molecules is optionally substituted with methoxy. 【0154】 Several embodiments, each R 2 The compounds are independently selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0155】 Several embodiments, each R 3 The following are independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl, and phenyl. 【0156】 In some embodiments, this disclosure relates to formula VI: [ka] A process for preparing a compound or salt thereof of formula VII: [ka] The compound or salt thereof and di(C 1~6 This involves reacting an alkyl phosphite with an oxidizing agent and a base, R 1 However, C 1~6 It is alkyl, Each R 2 However, independently, C 1~6 Selected from the group consisting of alkyl groups, Each R 3 However, independently, C 1~6 Further processes selected from the group consisting of alkyl groups are provided. 【0157】 In some embodiments, R 1 R is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 1 It is tert-butyl. 【0158】 Several embodiments, each R 2 R is independently selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 2 is tert-butyl. In some embodiments, each R 1 and each R 2 It is tert-butyl. 【0159】 Several embodiments, each R 3 This is independently selected from methyl and tert-butyl. In some embodiments, di(C) 1~6 Alkyl phosphite is di-tert-butyl phosphite. 【0160】 In some embodiments, the oxidizing agent is selected from the group consisting of alkyl halides (e.g., carbon tetrabromide, carbon tetrachloride, bromoform, dibromomethane, dibromoethane, bromotrichloromethane), N-halosuccinimides (e.g., N-chlorosuccinimide, N-bromosuccinimide), N-halosulfonamides (e.g., sodium N-chlorotosylamide, bromine (Br2), chlorine (Cl2), iodine (I2), and hypochlorites (e.g., sodium hypochlorite). 【0161】 In some embodiments, the oxidizing agent is selected from the group consisting of bromoform, carbon tetrabromide, carbon tetrachloride, dibromomethane, dibromoethane, bromotrichloromethane, N-chlorosuccinimide, N-bromosuccinimide, sodium N-chlorotosylamide, bromine, chlorine, iodine, and sodium hypochlorite. In some embodiments, the oxidizing agent is bromoform. 【0162】 In some embodiments, the base is selected from the group consisting of inorganic bases (e.g., sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate), tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO)), aromatic amines (e.g., pyridine, 2,6-lutidine, colidine, 1-methylimidazole), and hydride bases (e.g., sodium hydride). 【0163】 In some embodiments, the base is selected from the group consisting of cesium carbonate, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, 1-methylimidazole, and sodium hydride. In some embodiments, the base is cesium carbonate. 【0164】 In some embodiments, the reaction is carried out at a temperature of approximately -20°C to 100°C. In some embodiments, the reaction is carried out at a temperature of approximately 0°C to approximately 40°C. In some embodiments, the reaction is carried out at a temperature of approximately 15°C to approximately 25°C. 【0165】 In some embodiments, the reaction is carried out in a solvent selected from the group consisting of ethers (e.g., 2-methyltetrahydrofuran, tert-butylmethyl ether), ketones (e.g., acetone, 2-butanone), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), or any combination thereof. In some embodiments, the reaction is carried out in a solvent containing tetrahydrofuran. 【0166】 In some embodiments, the compound of formula VI is formula VI-a: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0167】 In some embodiments, the compound of formula VI is formula VI-a: [ka] It is a compound or salt thereof. 【0168】 In some embodiments, the compound of formula VI is formula VI-a: [ka] It is a compound of [the compound]. 【0169】 In some embodiments, this disclosure relates to formula VI: [ka] A process for preparing a compound of formula VII, or its cocrystal, solvate, or salt, wherein formula VII: [ka] A phosphorylating agent selected from the compound, or its cocrystal, solvate, or salt, and tetra(C) 6~10 Aryl-C 1~6 ) Pyrophosphate, tetra(C 1~6 Alkyl) pyrophosphate, di(C 1~6 Alkyl phosphorohalides, di(C) 1~6 Alkyl)phosphorosulfonates, and (R 4 O)2P(=O)-LG 2 This involves reacting the two in the presence of a base, in the formula, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group is C, chosen at will. 1~6 Substituted with alkoxy, Each R 2 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 3 However, independently, C 1~6 Alkyl and C 6~10 Selected from the group consisting of aryls, Each R 4 However, independently, C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, and LG 2However, the present invention further provides a process selected from the group consisting of halo and 4-methylbenzylsulfonyloxy. 【0170】 In some embodiments, this disclosure relates to formula VI: [ka] A process for preparing a compound of formula VII, or its cocrystal, solvate, or salt, wherein formula VII: [ka] Compounds of or their cocrystals, solvates, or salts with tetra(C) 6~10 Aryl-C 1~6 Alkyl-)pyrophosphate or R 4 O2P(=O)-LG 2 This involves reacting the two in the presence of a base, in the formula, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~ Each of the 6 alkyl groups can be optionally selected as C. 1~6 Substituted with alkoxy, Each R 2 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 3 However, independently, C 1~6 Alkyl and C 6~10 Selected from the group consisting of aryls, Each R 4 However, independently, C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, and LG 2 However, the present invention further provides a process selected from the group consisting of halo and 4-methylbenzylsulfonyloxy. 【0171】 In some embodiments, this disclosure relates to formula VI: [ka] A process for preparing a compound of formula VII, or its cocrystal, solvate, or salt, wherein formula VII: [ka] Compounds of the same, or its cocrystals, dissolved products, or salts with tetra(C) 6~10 Aryl-C 1~6 Alkyl-)pyrophosphate or (R 4 O)2P(=O)-LG 2 This involves reacting the two in the presence of a base, in the formula, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~ Each of the 6 alkyl groups can be optionally selected as C. 1~6 Substituted with alkoxy, Each R 2 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C1~6 Substituted with alkoxy, Each R 3 However, independently, C 1~6 Alkyl and C 6~10 Selected from the group consisting of aryls, Each R 4 However, independently, C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, and LG 2 However, the present invention further provides a process selected from the group consisting of halo and 4-methylbenzylsulfonyloxy. 【0172】 In some embodiments, this disclosure relates to formula VI: [ka] A process for preparing a compound or salt thereof of formula VII: [ka] A compound or salt thereof, and tetra(C 6~10 Aryl-C 1~6 ) Pyrophosphate, tetra(C 1~6 Alkyl) pyrophosphate, di(C 1~6 Alkyl phosphorohalides, di(C) 1~6 Alkyl)phosphorosulfonates, and (R 4 O)2P(=O)-LG 2 The process involves reacting a phosphorylating agent selected from the following in the presence of a base, in the formula, R 1 However, C 1~6 It is alkyl, Each R 2 However, independently, C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, Each R 3 However, independently, C 1~6 Selected from the group consisting of alkyl groups, Each R 4 However, independently, C 6~10 Aryl-C 1~6Selected from the group consisting of alkyl-, and LG 2 However, the present invention further provides a process selected from the group consisting of halo and 4-methylbenzylsulfonyloxy. 【0173】 In some embodiments, the phosphorylating agent is tetra(C) 6~10 Aryl-C 1~6 Selected from alkyl-)pyrophosphate, tetramethylpyrophosphate, tetraethylpyrophosphate, dimethylphosphochloride, diethylphosphochloride, and dimethylphosphomethanesulfonic acid. 【0174】 In some embodiments, this disclosure relates to formula VI: [ka] A process for preparing a compound or salt thereof of formula VII: [ka] A compound or salt thereof, and tetra(C 6~10 Aryl-C 1~6 Alkyl-)pyrophosphate or (R 4 O)2P(=O)-LG 2 This includes reacting the two in the presence of a base, R 1 However, C 1~6 It is alkyl, Each R 2 However, independently, C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, Each R 3 However, independently, C 1~6 Selected from the group consisting of alkyl groups, Each R 4 However, independently, C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, and LG 2 However, the present invention further provides a process selected from the group consisting of halo and 4-methylbenzylsulfonyloxy. 【0175】 In some embodiments, R 1 R is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 1 It is tert-butyl. 【0176】 Several embodiments, each R 2 It is independently phenyl-C 1~6 Selected from the group consisting of alkyl groups. In some embodiments, each R 2 It is benzyl. 【0177】 In some embodiments, R 1 It is tert-butyl, and each R 2 It is benzyl. 【0178】 Several embodiments, each R 3 The phosphorylation agent is independently selected from methyl and tert-butyl. In some embodiments, the phosphorylation agent is tetra(C) 6~10 Aryl-C 1~6 It is an alkyl-)pyrophosphate. In some embodiments, tetra(C 6~10 Aryl-C 1~6 Alkyl-)pyrophosphate is tetrabenzylpyrophosphate. 【0179】 In some embodiments, the phosphorylating agent is (R 4 O)2P(=O)-LG 2 And in the formula Each R 4 However, independently, C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, and LG 2 However, it is selected from the group consisting of halo and 4-methylbenzylsulfonyloxy. 【0180】 In some embodiments, the phosphorylating agent is (R 4 O)2P(=O)-LG 2 And in the formula Each R 4 However, it is benzyl, LG 2 However, it is selected from the group consisting of chloro, bromo, iodine, and 4-methylbenzylsulfonyloxy. 【0181】 In some embodiments, the base is selected from the group consisting of inorganic bases (e.g., sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate), tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO)), and aromatic amines (e.g., pyridine, 2,6-lutidine, colidine, 1-methylimidazole). 【0182】 In some embodiments, the base is selected from the group consisting of sodium hydride, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, and 1-methylimidazole. In some embodiments, the base is sodium hydride. 【0183】 In some embodiments, the reaction is carried out at a temperature of approximately -40°C to approximately 100°C. In some embodiments, the reaction is carried out at a temperature of approximately -20°C to 40°C. In some embodiments, the reaction is carried out at a temperature of approximately -10°C to approximately 10°C. 【0184】 In some embodiments, the reaction is carried out in a solvent selected from the group consisting of ethers (e.g., 2-methyltetrahydrofuran, tert-butylmethyl ether), ketones (e.g., acetone, 2-butanone), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), or any combination thereof. In some embodiments, the reaction is carried out in a solvent containing tetrahydrofuran. 【0185】 In some embodiments, the compound of formula VI is formula VI-b: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0186】 In some embodiments, the compound of formula VI is formula VI-b: [ka] It is a compound or salt thereof. 【0187】 In some embodiments, the compound of formula VI is formula VI-b: [ka] It is a compound of [the compound]. 【0188】 In some embodiments, this disclosure relates to formula VI: [ka] A process for preparing a compound of formula VII, or its cocrystal, solvate, or salt, wherein formula VII: [ka] Compounds of the same, or cocrystals, solubles, or salts of the same (C 1~6 Alkyl)N,N-di(C 1~6 The alkyl phosphoramide is reacted with a base and an acid to form a first mixture. The process includes mixing a first mixture with an oxidizing agent, in which, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~ Each of the 6 alkyl groups can be optionally selected as C. 1~6 Substituted with alkoxy, Each R 2 However, C 1~6 Alkyl, C 6~1 0-membered aryls, 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 3 However, C 1~6 Alkyl and C 6~10 Aryl-C 1~6 Independently selected from the group consisting of alkyl-, C 6~10 Aryl-C 1~6 Alkyl- is C 1~6 Further processes are provided that can be optionally replaced by alkoxys. 【0189】 In some embodiments, R 1 C 1~6A molecule is selected from the group consisting of alkyl, phenyl, pyridyl, and benzyl, and each of the phenyl, pyridyl, and benzyl molecules is optionally substituted with methoxy. 【0190】 In some embodiments, R 1 The compound is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0191】 In some embodiments, R 2 Independently, C 1~6 A molecule is selected from the group consisting of alkyl, phenyl, pyridyl, and benzyl, and each of the phenyl, pyridyl, and benzyl molecules is optionally substituted with methoxy. 【0192】 Several embodiments, each R 2 The compounds are independently selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0193】 Several embodiments, each R 3 The following are independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0194】 In some embodiments, this disclosure relates to formula VI: [ka] A process for preparing a compound or salt thereof of formula VII: [ka] The compound or salt thereof and di(C 1~6 Alkyl)N,N-di(C 1~6The alkyl phosphoramide is reacted with a base and an acid to form a first mixture. The process includes mixing a first mixture with an oxidizing agent, in which, R 1 However, C 1~6 It is alkyl, Each R 2 However, independently, C 1~6 Selected from the group consisting of alkyl groups, Each R 3 However, independently, C 1~6 Further processes selected from the group consisting of alkyl groups are provided. 【0195】 In some embodiments, R 1 R is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 1 It is tert-butyl. 【0196】 Several embodiments, each R 2 R is independently selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 2 is tert-butyl. In some embodiments, each R 1 and each R 2 It is tert-butyl. 【0197】 Several embodiments, each R 3 This is independently selected from methyl and tert-butyl. In some embodiments, di(C) 1~6 Alkyl), N,N-di(C 1~6 Alkyl phosphoramidate is di-tert-butyl N,N-diisopropyl phosphoramidate. 【0198】 In some embodiments, the base is selected from the group consisting of tertiary amines (e.g., N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO)) and aromatic amines (e.g., pyridine, 2,6-lutidine, colidine, and 1-methylimidazole). 【0199】 In some embodiments, the base is selected from the group consisting of 1-methylimidazole, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, and colidine. In some embodiments, the base is 1-methylimidazole. 【0200】 In some embodiments, the acid is selected from the group consisting of carboxylic acids (e.g., trichloroacetic acid, formic acid), inorganic acids (e.g., hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid), organic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid), tetrazoles (e.g., 1H-tetrazole, 5-phenyltetrazole), arylsulfonyltetrazoles (e.g., benzylthiotetrazole or ethylthiotetrazole), phenols (e.g., 2,4-dinitrophenol, 4-cyanophenol), imidazoles (e.g., 2-bromo-4,5-dicyanoimidazole, 4,5-dicyanoimidazole), and saccharin. 【0201】 In some embodiments, the acid is selected from the group consisting of trifluoroacetic acid, trichloroacetic acid, formic acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, 1H-tetrazole, 5-phenyltetrazole, benzylthiotetrazole, ethylthiotetrazole, 2,4-dinitrophenol, 4-cyanophenol, 2-bromo-4,5-dicyanoimidazole, 4,5-dicyanoimidazole, and saccharin. In some embodiments, the acid is trifluoroacetic acid. 【0202】 In some embodiments, the oxidizing agent is selected from the group consisting of N-halosuccinimide (e.g., N-chlorosuccinimide salt, N-bromosuccinimide), N-halosulfonamide (e.g., N-chlorotosylamide sodium salt), bromine (Br2), chlorine (Cl2), iodine (I2), hypochlorite (e.g., sodium hypochlorite), peroxide (e.g., sodium peroxide, t-butyl hydrogen peroxide, sodium perborate), and potassium peroxymonosulfate (Oxon). 【0203】 In some embodiments, the oxidizing agent is selected from the group consisting of hydrogen peroxide, N-chlorosuccinimide, N-bromosuccinimide, N-chlorotosylamide sodium salt, bromine, chlorine, iodine, sodium hypochlorite, sodium peroxide, tert-butyl hydrogen peroxide, sodium perborate, and potassium peroxymonosulfate. In some embodiments, the oxidizing agent is hydrogen peroxide. 【0204】 In some embodiments, the reaction is carried out at a temperature of approximately -20°C to 100°C. In some embodiments, the reaction is carried out at a temperature of approximately 0°C to approximately 40°C. In some embodiments, the reaction is carried out at a temperature of approximately 10°C to approximately 30°C. 【0205】 In some embodiments, the reaction is carried out in a solvent selected from the group consisting of ethers (e.g., 2-methyltetrahydrofuran, tert-butylmethyl ether), ketones (e.g., acetone, 2-butanone), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), or any combination thereof. In some embodiments, the reaction is carried out in a solvent containing tetrahydrofuran and water. 【0206】 In some embodiments, the compound of formula VI is formula VI-a: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0207】 In some embodiments, the compound of formula VI is formula VI-a: [ka] It is a compound or salt thereof. 【0208】 In some embodiments, the compound of formula VI is formula VI-a: [ka] It is a compound of [the compound]. 【0209】 In some embodiments, the compound of formula VII is formula VII-a: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0210】 In some embodiments, the compound of formula VII is formula VII-a: [ka] It is a compound or salt thereof. 【0211】 In some embodiments, the compound of formula VII is formula VII-a: [ka] It is a compound of [the compound]. 【0212】 In some embodiments, the process provided herein involves deprotecting a compound of formula VI or a salt thereof, and formula V: [ka] The further comprises forming a compound of the same, or a cocrystal, solvate, or salt thereof. 【0213】 In some embodiments, the process provided herein involves deprotecting a compound of formula VI or a salt thereof, and formula V: [ka] The further comprising forming a compound or salt thereof, in which, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 2 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 It is substituted with an alkoxy. 【0214】 In some embodiments, R 1 C 1~6 A molecule is selected from the group consisting of alkyl, phenyl, pyridyl, and benzyl, and each of the phenyl, pyridyl, and benzyl molecules is optionally substituted with methoxy. 【0215】 In some embodiments, R 1 The compound is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0216】 In some embodiments, R 2 C 1~6 A molecule is selected from the group consisting of alkyl, phenyl, pyridyl, and benzyl, and each of the phenyl, pyridyl, and benzyl molecules is optionally substituted with methoxy. 【0217】 In some embodiments, R 2 The compound is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0218】 In some embodiments, the process provided herein involves deprotecting a compound of formula VI or a salt thereof, and formula V: [ka] The further comprising forming a compound or salt thereof, in which, R 1 However, C 1~6 It is alkyl, Each R 2 However, independently, C 1~6 It is alkyl. 【0219】 In some embodiments, the process provided herein involves deprotecting a compound of formula VI or a salt thereof, and formula V: [ka] The further comprising forming a compound or salt thereof, in which, R 1 However, C 1~6 It is alkyl, Each R 2 However, independently, C 1~6 It is alkyl. 【0220】 In some embodiments, R 1 R is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 1 It is tert-butyl. 【0221】 Several embodiments, each R 2 R is independently selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 2 is tert-butyl. In some embodiments, each R 1 and each R 2 It is tert-butyl. 【0222】 In some embodiments, deprotection involves reacting a compound of formula VI, or its cocrystal, solvate, or salt, with a deprotecting agent selected from the group consisting of tetrabutylammonium fluoride, potassium hydrogen fluoride, potassium fluoride, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, 1-methylimidazole, hydrofluoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, N-chlorosuccinimide, potassium peroxymonosulfate, and iodine. 【0223】 In some embodiments, deprotection involves reacting a compound of formula VI or a salt thereof with a deprotective agent that is a silyl cleavage agent. In some embodiments, the silyl cleavage agent is selected from fluorides (e.g., potassium hydrogen fluoride, potassium fluoride, tetrabutylammonium fluoride), inorganic bases (e.g., sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate), tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO)), aromatic amines (e.g., pyridine, 2,6-lutidine, colidine, 1-methylimidazole), acids (e.g., hydrofluoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid), and oxidizing agents (e.g., N-chlorosuccinimide, potassium peroxymonosulfate (Oxon), iodine). 【0224】 In some embodiments, deprotection involves reacting a compound of formula VI or a salt thereof with a deprotecting agent (e.g., a silyl cleaving agent) selected from the group consisting of tetrabutylammonium fluoride, potassium hydrogen fluoride, potassium fluoride, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, 1-methylimidazole, hydrofluoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, N-chlorosuccinimide, potassium peroxymonosulfate, and iodine. In some embodiments, deprotection involves reacting a compound of formula VI, or a cocrystal, solvate, or salt thereof, with tetrabutylammonium fluoride. In some embodiments, deprotection involves reacting a compound of formula VI or a salt thereof with tetrabutylammonium fluoride. 【0225】 In some embodiments, deprotection is carried out at temperatures of approximately -20°C to 100°C. In some embodiments, deprotection is carried out at temperatures of approximately 0°C to approximately 60°C. In some embodiments, deprotection is carried out at temperatures of approximately 10°C to approximately 30°C. 【0226】 In some embodiments, deprotection is carried out in a solvent selected from the group consisting of ethers (e.g., 2-methyltetrahydrofuran tert-butyl methyl ether), ketones (e.g., acetone, 2-butanone), hydrocarbons (e.g., halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), polar aprotic solvents (e.g., NN-dimethylformamide, NN-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), and protic solvents (e.g., methanol, ethanol, propanol t-butanol), or any combination thereof, optionally in combination with water. In some embodiments, deprotection is carried out in a solvent containing tetrahydrofuran. 【0227】 In some embodiments, the process provided herein involves oxidizing a compound of formula V, or its cocrystal, solvate, or salt, to a compound of formula IV: [ka] The further comprising forming a compound of, or a cocrystal, solvate, or salt thereof, in the formula, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 2 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 It is substituted with an alkoxy. 【0228】 In some embodiments, the process provided herein involves oxidizing a compound of formula V or a salt thereof to form formula IV: [ka] The further comprising forming a compound or salt thereof, in which, R 1 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 2 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group is C, chosen at will. 1~6 It is substituted with an alkoxy. 【0229】 In some embodiments, R 1 C 1~6 A molecule is selected from the group consisting of alkyl, phenyl, pyridyl, and benzyl, and each of the phenyl, pyridyl, and benzyl molecules is optionally substituted with methoxy. 【0230】 In some embodiments, R 1The compound is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0231】 In some embodiments, R 2 C 1~6 A molecule is selected from the group consisting of alkyl, phenyl, pyridyl, and benzyl, and each of the phenyl, pyridyl, and benzyl molecules is optionally substituted with methoxy. 【0232】 In some embodiments, R 2 The compound is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0233】 In some embodiments, the process provided herein involves oxidizing a compound of formula V or a salt thereof to form formula IV: [ka] The further comprising forming a compound or salt thereof, in which, R 1 However, C 1~6 It is alkyl, Each R 2 However, independently, C 1~6 It is alkyl. 【0234】 In some embodiments, R 1 R is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 1 It is tert-butyl. 【0235】 Several embodiments, each R 2 R is independently selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 2is tert-butyl. In some embodiments, each R 1 and each R 2 It is tert-butyl. 【0236】 In some embodiments, oxidation involves reacting a compound of formula V, or its cocrystal, solvate, or salt, with an oxidizing agent in the presence of a base and an oxidation catalyst. 【0237】 In some embodiments, oxidation involves reacting a compound of formula V or a salt thereof with an oxidizing agent in the presence of a base and an oxidation catalyst. 【0238】 In some embodiments, the oxidizing agent is selected from the group consisting of hypervalent iodine reagents (e.g., (bis(trifluoroacetoxy)iodo)benzene, 2-iodoxybenzoic acid (IBX)), N-halosuccinimide (e.g., N-chlorosuccinimide, N-bromosuccinimide), N-halosulfonamides (e.g., sodium N-chlorotosylamide, bromine (Br2), chlorine (Cl2), iodine (I2), hypochlorite (e.g., sodium hypochlorite), chlorite (e.g., sodium chlorite), peroxides (e.g., hydrogen peroxide, sodium peroxide, t-butyl hydrogen peroxide, sodium perborate), potassium peroxymonosulfate (Oxon), and periodates (e.g., sodium periodate), or any combination thereof. 【0239】 In some embodiments, the oxidizing agent is selected from the group consisting of (diacetoxyiodo)benzene, (bis(trifluoroacetoxy)iodo)benzene, 2-iodoxybenzoic acid, N-chlorosuccinimide, N-bromosuccinimide, N-chlorotosylamide sodium salt, bromine, chlorine, iodine, sodium hypochlorite, sodium chlorite, hydrogen peroxide, sodium peroxide, t-butyl hydrogen peroxide, sodium perborate, potassium peroxymonosulfate, and sodium periodate, or any combination thereof. In some embodiments, the oxidizing agent is (diacetoxyiodo)benzene. 【0240】 In some embodiments, the base is selected from the group consisting of inorganic salts (e.g., sodium hydroxide, potassium hydroxide, monobasic potassium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate), tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO)), aromatic amines (e.g., pyridine, 2,6-lutidine, colidine, 1-methylimidazole), and tetraalkylammonium salts (e.g., tetrabutylammonium bisulfate, tetrabutylammonium chloride). 【0241】 In some embodiments, the base is selected from the group consisting of dibasic sodium phosphate, sodium hydroxide, potassium hydroxide, monobasic potassium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, 1-methylimidazole, tetrabutylammonium bisulfate, and tetrabutylammonium chloride. In some embodiments, the base is dibasic sodium phosphate. 【0242】 In some embodiments, the oxidation catalyst is selected from the group consisting of radicals (e.g., 2-adamantane N-oxyl, 2,2,6,6-tetramethylpiperidine 1-oxyl) and metal salts (e.g., ruthenium trichloride, ruthenium tetroxide, osmium tetroxide). 【0243】 In some embodiments, the oxidation catalyst is selected from the group consisting of 2,2,6,6-tetramethylpiperidine 1-oxyl, 2-azaadamantane N-oxyl, ruthenium trichloride, ruthenium tetroxide, and osmium tetroxide. In some embodiments, the oxidation catalyst is 2,2,6,6-tetramethylpiperidine 1-oxyl. 【0244】 In some embodiments, oxidation is carried out at a temperature of approximately -20°C to 100°C. In some embodiments, oxidation is carried out at a temperature of approximately 0°C to approximately 40°C. In some embodiments, oxidation is carried out at a temperature of approximately 10°C to approximately 30°C. 【0245】 In some embodiments, oxidation is carried out in a solvent selected from the group consisting of ethers (e.g., 2-methyltetrahydrofuran, tert-butyl methyl ether), ketones (e.g., acetone, 2-butanone), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), or any combination thereof, optionally in combination with water. In some embodiments, oxidation is carried out in a solvent comprising methyl tert-butyl ether, acetonitrile, and water. 【0246】 In some embodiments, the process provided herein involves using a compound of formula VII, or its cocrystal, solvate, or salt, as shown in formula VIII: [ka] The preparation further comprises deprotecting a compound, or a cocrystal, solvate, or salt thereof, wherein, R 1 However, C 1~6 Alkyl, C 6~10 Aryls, and 5-10 membered heteroaryls, and C6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryls, and 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 3 However, independently, C 1~6 Alkyl and C 6~10 Selected from a group consisting of aryl groups. 【0247】 In some embodiments, the process provided herein involves using a compound of formula VII or a salt thereof, with respect to formula VIII: [ka] The preparation further comprises deprotecting a compound or salt thereof, wherein, R 1 However, C 1~6 Alkyl, C 6~10 Aryls, and 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryls, and 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 3 However, independently, C 1~6 Alkyl and C 6~10 Selected from a group consisting of aryl groups. 【0248】 In some embodiments, R 1 The compound is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0249】 In some embodiments, the process provided herein involves using a compound of formula VII or a salt thereof, with respect to formula VIII: [ka] The preparation further comprises deprotecting a compound or salt thereof, wherein, R 1 However, C 1~6 It is alkyl, Each R 3 However, independently, C 1~6 It is alkyl. 【0250】 In some embodiments, R 1 R is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 1 It is tert-butyl. 【0251】 Several embodiments, each R 3 These are independently selected from methyl and tert-butyl. 【0252】 In some embodiments, deprotection involves reacting a compound of formula VII with a deprotecting agent that is a silyl cleaving agent. In some embodiments, the silyl cleaving agent is a fluoride (e.g., potassium hydrogen fluoride, tetrabutylammonium fluoride, potassium fluoride), an inorganic base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate), a tertiary amine (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4]) The process is carried out optionally in combination with water in a solvent selected from the group consisting of [0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO)), aromatic amines (e.g., pyridine, 2,6-lutidine, colidine, 1-methylimidazole), acids (e.g., hydrofluoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid), and oxidizing agents (e.g., N-chlorosuccinimide, potassium peroxymonosulfate (Oxon), iodine), or any combination thereof. 【0253】 In some embodiments, deprotection involves reacting a compound of formula VII with a deprotecting agent (e.g., a silyl cleaving agent) selected from the group consisting of lithium hydroxide, potassium hydrogen fluoride, tetrabutylammonium fluoride, potassium fluoride, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, 1-methylimidazole, hydrofluoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, N-chlorosuccinimide, potassium peroxymonosulfate, and iodine, or any combination thereof, in the presence of water. In some embodiments, the deprotecting agent is lithium hydroxide. 【0254】 In some embodiments, deprotection is carried out at a temperature of about 0°C to about 100°C. In some embodiments, deprotection is carried out at a temperature of about 20°C to about 60°C. In some embodiments, deprotection is carried out at a temperature of about 30°C to about 50°C. 【0255】 In some embodiments, deprotection is carried out in a solvent selected from the group consisting of ethers (e.g., 2-methyltetrahydrofuran tert-butyl methyl ether), ketones (e.g., acetone, 2-butanone), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), polar aprotic solvents (e.g., NN-dimethylformamide, NN-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), and protic solvents (e.g., methanol, ethanol, propanol t-butanol), or any combination thereof, optionally in combination with water. In some embodiments, deprotection is carried out in a solvent containing tetrahydrofuran and water. 【0256】 In some embodiments, the compound of formula VIII is formula VIII-a: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0257】 In some embodiments, the compound of formula VIII is formula VIII-a: [ka] It is a compound or salt thereof. 【0258】 In some embodiments, the compound of formula VIII is formula VIII-a: [ka] It is a compound of [the compound]. 【0259】 In some embodiments, the process provided herein involves using a compound of formula VIII, or its cocrystal, solvate, or salt, of formula XIV: [ka] The first mixture is formed by reacting the compound, or its cocrystal, solvate, or salt thereof, with an activator in the presence of zinc. The first mixture and formula IX: [ka] The preparation further comprises mixing a compound of, or a cocrystal, solvate, or salt thereof, in the presence of a coupling catalyst, and a process comprising, X 1 However, Halo and C 1~6 Selected from the group consisting of alkyl sulfonates, R 1 However, C 1~6 Alkyl, C 6~10 Aryls, and 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryls, and 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 3 However, independently, C 1~6 Alkyl and C 6~10 Selected from a group consisting of aryl groups. 【0260】 In some embodiments, the process provided herein involves using a compound of formula VIII or a salt thereof, with formula XIV: [ka] The first mixture is formed by reacting the compound or a salt thereof with an activator in the presence of zinc, The first mixture and formula IX: [ka] The preparation further comprises mixing a compound or a salt thereof in the presence of a coupling catalyst, wherein the formula is: X 1 However, Halo and C 1~6 Selected from the group consisting of alkyl sulfonates, R 1 However, C 1~6 Alkyl, C 6~10 Aryls, and 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryls, and 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Each alkyl group is C, chosen at will. 1~6 Substituted with alkoxy, Each R 3 However, independently, C 1~6 Alkyl and C 6~10 Selected from a group consisting of aryl groups. 【0261】 In some embodiments, X 1 The compound is selected from bromo, chloro, iodine, and trifluoromethylsulfonate. 【0262】 In some embodiments, R 1 The compound is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0263】 In some embodiments, the process provided herein involves using a compound of formula VIII or a salt thereof, with formula XIV: [ka] The first mixture is formed by reacting the compound or a salt thereof with an activator in the presence of zinc, The first mixture and formula IX: [ka] The preparation further comprises mixing a compound or a salt thereof in the presence of a coupling catalyst, wherein the compound is prepared by a process comprising, X 1 But it's a halo, R 1 However, C 1~6 It is alkyl, Each R 3 However, independently, C 1~6 It is alkyl. 【0264】 In some embodiments, X 1 It is Bromo. 【0265】 In some embodiments, R 1 R is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 1 It is tert-butyl. 【0266】 Several embodiments, each R 3 The activator is independently selected from methyl and tert-butyl. In some embodiments, the activator is selected from the group consisting of trialkylsilyl halides (e.g., trimethylsilyl chloride, triethylsilyl chloride, trimethylsilyl iodide), dihaloethanes (e.g., dibromoethane, dichloroethane), alkylaluminum hydrides (e.g., diisobutylaluminum hydride), and iodine. 【0267】 In some embodiments, the activator is selected from the group consisting of trimethylsilyl chloride, triethylsilyl chloride, trimethylsilyl iodide, dibromoethane, dichloroethane, diisobutylaluminum hydride, and iodine. In some embodiments, the activator is trimethylsilyl chloride. 【0268】 In some embodiments, the coupling catalyst includes a palladium catalyst. 【0269】 In some embodiments, the palladium catalyst is tris(dibenzylideneacetone)dipalladium(0), palladium salt(II) (e.g., palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate), palladium complex(0) (e.g., tetrakis(triphenylphosphine)palladium(0)), G3-Pd complex (e.g., methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1, Selected from the group consisting of 1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)(XPhos-Pd-G3)) and G4-Pd complexes (e.g., (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium(XPhos-Pd-G4)). 【0270】 In some embodiments, the palladium catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium(0), palladium chloride(II), palladium bromide(II), palladium acetate(II), palladium trifluoroacetate(II), tetrakis(triphenylphosphine)palladium(0), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. In some embodiments, the palladium catalyst is tris(dibenzylideneacetone)dipalladium(0). 【0271】 In some embodiments, the coupling catalyst comprises a palladium catalyst and optionally a phosphine ligand. 【0272】 In some embodiments, the phosphine ligand is absent. In some embodiments, the phosphine ligand is selected from the group consisting of trialkylphosphines (e.g., tricyclohexylphosphine, tri-tert-butylphosphine), triarylphosphines (e.g., triphenylphosphine), dialkylarylphosphines (e.g., 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos)), and alkyldiarylphosphines (e.g., ethylenebis(diphenylphosphine) (DPPE)). 【0273】 In some embodiments, the phosphine ligand is selected from the group consisting of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tricyclohexylphosphine, tri-tert-butylphosphine, triphenylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and ethylenebis(diphenylphosphine). In some embodiments, the coupling catalyst comprises tris(dibenzylideneacetone)dipalladium and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. 【0274】 In some embodiments, the mixing of the first mixture with the compound of formula IX is carried out at a temperature of about 0°C to about 100°C. In some embodiments, the mixing of the first mixture with the compound of formula IX is carried out at a temperature of about 30°C to about 80°C. In some embodiments, the mixing of the first mixture with the compound of formula IX is carried out at a temperature of about 45°C to about 65°C. 【0275】 In some embodiments, the mixing of the first mixture with the compound of formula IX is carried out in a solvent selected from the group consisting of ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide), or any combination thereof. In some embodiments, the mixing of the first mixture with the compound of formula IX is carried out in a solvent containing tetrahydrofuran. 【0276】 In some embodiments, the process provided herein involves using a compound of formula IX, or its cocrystal, solvate, or salt, as described by formula X: [ka] The preparation further includes silylation of the compound or its cocrystal, solvate, or salt. 【0277】 In some embodiments, the process provided herein is based on formula X: [ka] The method further includes preparing a compound of formula IX or a salt thereof by silylation of the compound or a salt thereof. 【0278】 In some embodiments, silylation is performed with a compound of formula IX, or its cocrystal, solvate, or salt, and formula: Si(R 3 )3-LG The process involves reacting a silylating agent with a base and a silylating catalyst in the presence of the formula, Each R 3 However, independently, C 1~6 Alkyl and C 6~10 Selected from the group consisting of aryls, LG is the leaving group. 【0279】 In some embodiments, silylation is performed with a compound of formula IX or a salt thereof and formula: Si(R 3 )3-LG The process involves reacting a silylating agent with a base and a silylating catalyst in the presence of the formula, Each R 3 However, independently, C 1~6 It is alkyl, LG is the leaving group. 【0280】 Several embodiments, each R 3 This is independently selected from the group consisting of methyl and tert-butyl. 【0281】 In some embodiments, LG is selected from the group consisting of chlorides, bromides, iodides, methanesulfonates, trifluoromethanesulfonates, and p-toluenesulfonates. In some embodiments, LG is a chloride. 【0282】 In some embodiments, the silylating agent is tert-butyl(chloro)dimethylsilane. 【0283】 In some embodiments, the base is selected from the group consisting of tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO)), aromatic amines (e.g., pyridine, 2,6-lutidine, colidine, 1-methylimidazole), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (e.g., monobasic, dibasic, or tribasic), sodium phosphate (e.g., monobasic, dibasic, or tribasic)). 【0284】 In some embodiments, the base is selected from the group consisting of imidazole, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, 1-methylimidazole, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, monobasic potassium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, monobasic sodium phosphate, dibasic sodium phosphate, and tribasic sodium phosphate. In some embodiments, the base is imidazole. 【0285】 In some embodiments, the silylation catalyst is selected from the group consisting of N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), and tetraalkylammonium halides (e.g., tetrabutylammonium bromide, tetrabutylammonium iodide). 【0286】 In some embodiments, the silylation catalyst is selected from the group consisting of 4-dimethylaminopyridine, N-methylimidazole, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, tetrabutylammonium bromide, and tetrabutylammonium iodide. In some embodiments, the silylation catalyst is 4-dimethylaminopyridine. 【0287】 In some embodiments, silylation is carried out at a temperature of about 0°C to about 100°C. In some embodiments, silylation is carried out at a temperature of about 45°C to about 85°C. In some embodiments, silylation is carried out at a temperature of about 55°C to about 75°C. 【0288】 In some embodiments, silylation is carried out in a solvent selected from the group consisting of ethers (e.g., 2-methyltetrahydrofuran, tert-butylmethyl ether), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone), and nitriles (e.g., acetonitrile, propylnitrile, butylnitrile), or any combination thereof. In some embodiments, silylation is carried out in a solvent containing N,N-dimethylformamide. 【0289】 In some embodiments, the process provided herein involves using a compound of formula X, or a cocrystal, solvate, or salt thereof, of formula XI: [ka] The further method involves preparing a compound, or a cocrystal, solvate, or salt thereof, by reduction, wherein the formula X 2 However, it is selected from the group consisting of halo, (4-methylbenzenesulfonyl)oxyl, (methylsulfonyl)oxyl, and (trifluoromethylsulfonyl)oxyl. 【0290】 In some embodiments, the process provided herein involves using a compound of formula X, or a cocrystal, solvate, or salt thereof, of formula XI-a: [ka] The preparation further includes reducing the compound or its cocrystal, solvate, or salt. 【0291】 In some embodiments, the process provided herein involves using a compound of formula X or a salt thereof, with formula XI: [ka] The further method involves preparing the compound or its cocrystal, solvate, or salt by reduction, wherein the formula X 2 The selected compound is from the group consisting of halo, (4-methylbenzenesulfonyl)oxyl, (methylsulfonyl)oxyl, (trifluoromethylsulfonyl)oxyl, dihydroxyboranyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, 5,5-dimethyl-1,3,2-dioxabolinan-2-yl, and benzo[d][1,3,2]dioxabolinol-2-yl. 【0292】 In some embodiments, the process provided herein involves using a compound of formula X or a salt thereof, with formula XI: [ka] The further comprising preparing by reducing a compound or salt thereof, in the formula, X 2 The selected compound is from the group consisting of halo, (4-methylbenzenesulfonyl)oxyl, (methylsulfonyl)oxyl, (trifluoromethylsulfonyl)oxyl, dihydroxyboranyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, 5,5-dimethyl-1,3,2-dioxabolinan-2-yl, and benzo[d][1,3,2]dioxabolinol-2-yl. 【0293】 In some embodiments, the process provided herein involves using a compound of formula X or a salt thereof, with formula XI: [ka] The further comprising preparing by reducing a compound or salt thereof, in the formula, X 2 However, it is selected from the group consisting of halo, (4-methylbenzenesulfonyl)oxyl, (methylsulfonyl)oxyl, and (trifluoromethylsulfonyl)oxyl. 【0294】 In some embodiments, X 2 The compound is selected from the group consisting of halo, dihydroxyboranyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, 5,5-dimethyl-1,3,2-dioxabolinan-2-yl, and benzo[d][1,3,2]dioxabolinol-2-yl. 【0295】 In some embodiments, X 2 The is selected from the group consisting of dihydroxyboranyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, 5,5-dimethyl-1,3,2-dioxabolinan-2-yl, and benzo[d][1,3,2]dioxabolinol-2-yl. 【0296】 In some embodiments, X 2 This is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl. 【0297】 In some embodiments, X 2 It is a halo. 【0298】 In some embodiments, reduction involves reacting a compound of formula X or a salt thereof in the presence of a reducing agent and optionally a catalyst. 【0299】 In some embodiments, the catalyst is selected from Lewis acid catalysts. In some embodiments, the Lewis acid catalyst is selected from the group consisting of boron trifluoride, boron trichloride, boron tribromide, and aluminum trichloride. In some embodiments, there is no catalyst. 【0300】 In some embodiments, reduction involves reacting a compound of formula X or a salt thereof in the presence of a reducing agent (for example, in the absence of a catalyst). In some embodiments, the reducing agent is selected from the group consisting of diisobutylaluminum hydride, aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, boranetetrahydrofuran complex, diborane, I2 / NaBH4, and borane dimethyl sulfide complex. 【0301】 In some embodiments, the reducing agent is selected from the group consisting of lithium aluminum hydride, diisobutylaluminum hydride, aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, boranetetrahydrofuran complex, diborane, I2 / NaBH4, and borane dimethyl sulfide complex. In some embodiments, the reducing agent is lithium aluminum hydride. 【0302】 In some embodiments, the reduction is carried out at a temperature of approximately -20°C to approximately 100°C. In some embodiments, the reduction is carried out at a temperature of approximately 0°C to approximately 60°C. In some embodiments, the reduction is carried out at a temperature of approximately 20°C to approximately 40°C. 【0303】 In some embodiments, the reduction is carried out in a solvent selected from the group consisting of ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone), or any combination thereof, optionally in combination with water. In some embodiments, the reduction is carried out in a solvent containing tetrahydrofuran. 【0304】 In some embodiments, the processes provided herein further include preparing a compound of formula XI, or a cocrystal, solvate, or salt thereof, by reacting 3-bromo-5-methylphenol with methyl 3,3-dimethyl acrylate in the presence of an acid. 【0305】 In some embodiments, the processes provided herein further include preparing a compound of formula XI or a salt thereof by reacting 3-bromo-5-methylphenol with methyl 3,3-dimethyl acrylate in the presence of an acid. 【0306】 In some embodiments, the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, carboxylic acids (e.g., acetic acid, pivalic acid), phosphoric acid, sulfonic acid (e.g., p-toluenesulfonic acid), metal halides (e.g., boron trichloride, lithium bromide, magnesium chloride, aluminum chloride), and metal triflates (e.g., lithium triflate, magnesium triflate, aluminum triflate). In some embodiments, the acid is selected from the group consisting of methanesulfonic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, pivalic acid, phosphoric acid, p-toluenesulfonic acid, boron trichloride, lithium bromide, magnesium chloride, aluminum chloride, lithium triflate, magnesium triflate, and aluminum triflate. In some embodiments, the acid is methanesulfonic acid. In some embodiments, the acid is sulfuric acid. 【0307】 In some embodiments, the reaction is carried out at a temperature of approximately 0°C to approximately 200°C. In some embodiments, the reaction is carried out at a temperature of approximately 80°C to approximately 160°C. In some embodiments, the reaction is carried out at a temperature of approximately 110°C to approximately 130°C. 【0308】 In some embodiments, the reaction is carried out in a solvent selected from the group consisting of hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone), or any combination thereof, optionally in combination with water. In some embodiments, the reaction is carried out in the absence of a solvent. 【0309】 In some embodiments, the compound of formula XI, or its cocrystal, solvate, or salt, is of formula XI-a: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0310】 In some embodiments, the compound of formula XI or a salt thereof is of formula XI-a: [ka] It is a compound or salt thereof. 【0311】 In some embodiments, the compound of formula XI is formula XI-a: [ka] It is a compound of [the compound]. 【0312】 In some embodiments, this disclosure relates to formula XV: [ka] A process for preparing a compound of formula XVI or its cocrystal, solvate, or salt, wherein formula XVI: [ka] The method involves reacting a compound, or a cocrystal, solvate, or salt thereof, with 1-(2,6-dihydroxy-4-methylphenyl)ethane-1-one in the presence of a base, wherein the formula is: Each R 5 However, independently, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Alkyl is negative, and each can be optionally selected as C. 1~6 The process is provided by substitution with alkoxy. 【0313】 In some embodiments, this disclosure relates to formula XV: [ka] A process for preparing a compound or salt thereof of formula XVI: [ka] This involves reacting a compound or salt thereof with 1-(2,6-dihydroxy-4-methylphenyl)ethane-1-one in the presence of a base. Each R 5 However, independently, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 The process is provided by substitution with alkoxy. 【0314】 Several embodiments, each R 5 The compounds are independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0315】 Several embodiments, each R 5 Independently, C 1~6 Selected from the group consisting of alkyl groups. 【0316】 Several embodiments, each R 5 It is ethyl. 【0317】 In some embodiments, the base is selected from the group consisting of inorganic bases (e.g., sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxide, tribasic potassium phosphate, cesium carbonate, tertiary amine bases (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]unde-7-ene (DBU)), and aromatic amine bases (e.g., pyridine, 2,6-lutidine, colidine, 1-methylimidazole). 【0318】 In some embodiments, the base is selected from the group consisting of sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxide, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), pyridine, 2,6-lutidine, colidine, and 1-methylimidazole. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undeca-7-ene. 【0319】 In some embodiments, the reaction of the compound of formula XVI or a salt thereof with 1-(2,6-dihydroxy-4-methylphenyl)ethane-1-one is carried out at a temperature of about 0°C to about 200°C. In some embodiments, the reaction of the compound of formula XVI or a salt thereof with 1-(2,6-dihydroxy-4-methylphenyl)ethane-1-one is carried out at a temperature of about 60°C to about 140°C. In some embodiments, the reaction of the compound of formula XVI or a salt thereof with 1-(2,6-dihydroxy-4-methylphenyl)ethane-1-one is carried out at a temperature of about 90°C to about 110°C. In some embodiments, the reaction of the compound of formula XVI or a salt thereof with 1-(2,6-dihydroxy-4-methylphenyl)ethane-1-one is carried out at a temperature of about 95°C to about 105°C. 【0320】 In some embodiments, the reaction of a compound of formula XVI or a salt thereof with 1-(2,6-dihydroxy-4-methylphenyl)ethane-1-one is carried out in the presence of a solvent selected from the group consisting of ethers (e.g., 2-methyltetrahydrofuran, tert-butylmethyl ether), hydrocarbons (e.g., toluene, xylene, trifluorotoluene, chlorobenzene), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, sulfolane). 【0321】 In some embodiments, the reaction of a compound of formula XVI or a salt thereof with 1-(2,6-dihydroxy-4-methylphenyl)ethane-1-one is carried out in the absence of a solvent. 【0322】 In some embodiments, the compound of formula XVI is formula XVI-a: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0323】 In some embodiments, the compound of formula XVI is formula XVI-a: [ka] It is a compound or salt thereof. 【0324】 In some embodiments, the compound of formula XVI is formula XVI-a: [ka] It is a compound of [the compound]. 【0325】 In some embodiments, the compound of formula XV is formula XV-a: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0326】 In some embodiments, the compound of formula XV is formula XV-a: [ka] It is a compound or salt thereof. 【0327】 In some embodiments, the compound of formula XV is formula XV-a: [ka] It is a compound of [the compound]. 【0328】 In some embodiments, this disclosure relates to formula XVII: [ka] A process for preparing a compound of formula XV, or its cocrystal, solvate, or salt, wherein formula XV: [ka] The method involves contacting the compound, or its cocrystal, solvate, or salt thereof, with a methyl metallized reagent in the presence of a copper reagent and optionally an additive. R 5 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 The process is provided by substitution with alkoxy. 【0329】 In some embodiments, this disclosure relates to formula XVII: [ka] A process for preparing a compound or salt thereof of formula XV: [ka] This involves contacting the compound or a salt thereof with a methyl metallized reagent in the presence of a copper reagent and optionally in the presence of an additive. R 5 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 The process is provided by substitution with alkoxy. 【0330】 In some embodiments, R 5R is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). In some embodiments, R 5 C 1~6 Selected from the group consisting of alkyl groups. In some embodiments, R 5 It is ethyl. 【0331】 In some embodiments, the metallized methyl reagent is selected from the group consisting of methylmagnesium bromide, methylmagnesium chloride, methyllithium, methylzinc chloride, and methylzinc bromide. In some embodiments, the metallized methyl reagent is methylmagnesium bromide. 【0332】 In some embodiments, the copper reagent is selected from the group consisting of copper(I) iodide, copper(I) chloride, copper(I) bromide, and copper(I) cyanide. In some embodiments, the copper reagent is copper(I) iodide. 【0333】 In some embodiments, the reaction of a compound of formula XVII or a salt thereof with a methyl metallized reagent is carried out in the presence of an additive. 【0334】 In some embodiments, the additive is selected from the group consisting of lithium chloride, lithium bromide, and hexamethylphosphoramide. In some embodiments, the additive is lithium chloride. 【0335】 In some embodiments, the reaction of the compound of formula XVII or its salt with the methyl metallized reagent is carried out at a temperature of about -78°C to about 50°C. In some embodiments, the reaction of the compound of formula XVII or its salt with the methyl metallized reagent is carried out at a temperature of about -60°C to about 0°C. In some embodiments, the reaction of the compound of formula XVII or its salt with the methyl metallized reagent is carried out at a temperature of about -50°C to about -30°C. In some embodiments, the reaction of the compound of formula XVII or its salt with the methyl metallized reagent is carried out at a temperature of about -45°C to about -35°C. 【0336】 In some embodiments, the reaction of a compound of formula XVII or a salt thereof with a methyl metallized reagent is carried out in the presence of a solvent selected from the group consisting of ethers (e.g., tert-butyl methyl ether), hydrocarbons (e.g., toluene, trifluorotoluene), and polar aprotic solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and sulfolane), or any combination thereof. In some embodiments, the reaction of a compound of formula XVII or a salt thereof with a methyl metallized reagent is carried out in the presence of a solvent containing tetrahydrofuran. In some embodiments, the reaction of a compound of formula XVII or a salt thereof with a methyl metallized reagent is carried out in the presence of a solvent containing 2-methyltetrahydrofuran. In some embodiments, the reaction of a compound of formula XVII or a salt thereof with a methyl metallized reagent is carried out in the presence of a solvent containing tetrahydrofuran and 2-methyltetrahydrofuran. 【0337】 In some embodiments, the compound of formula XVII is formula XVII-a [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0338】 In some embodiments, the compound of formula XVII is formula XVII-a [ka] It is a compound or salt thereof. 【0339】 In some embodiments, the compound of formula XVII is formula XVII-a [ka] It is a compound of [the compound]. 【0340】 In some embodiments, this disclosure relates to formula XVIII: [ka] A process for preparing a compound of formula XVII, or its cocrystal, solvate, or salt, wherein formula XVII: [ka] The process involves decarboxylating a compound, or its cocrystal, solvate, or salt thereof, in which, R 5 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 The process is provided by substitution with alkoxy. 【0341】 In some embodiments, this disclosure relates to formula XVIII: [ka] A process for preparing a compound or salt thereof of formula XVII: [ka] This involves decarboxylating a compound or salt thereof, in which, R 5 However, C 1~6 Alkyl, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryl, 5-10 member heteroaryl, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6The process is provided by substitution with alkoxy. 【0342】 In some embodiments, R 5 R is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). In some embodiments, R 5 C 1~6 Selected from the group consisting of alkyl groups. In some embodiments, R 5 It is ethyl. 【0343】 In some embodiments, the decarboxylation reaction involves reacting a compound of formula XVII or a salt thereof with a decarboxylation reagent selected from the group consisting of concentrated hydrochloric acid, lithium chloride, lithium bromide, and lithium cyanide, or hydrolyzing a compound of formula XVII or a salt thereof with a base selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide, and then acidifying the reaction mixture in the presence of a solvent using an acid selected from the group consisting of hydrochloric acid, sulfuric acid, and trifluoroacetic acid. 【0344】 In some embodiments, the decarboxylation reaction involves reacting a compound of formula XVII or a salt thereof with a decarboxylase reagent selected from the group consisting of concentrated hydrochloric acid, lithium chloride, lithium bromide, and lithium cyanide. In some embodiments, the decarboxylation reaction involves reacting a compound of formula XVII or a salt thereof with concentrated hydrochloric acid. 【0345】 In some embodiments, the decarboxylation reaction is carried out at a temperature of approximately 20°C to 130°C. In some embodiments, the decarboxylation reaction is carried out at a temperature of approximately 20°C to 80°C. In some embodiments, the decarboxylation reaction is carried out at a temperature of approximately 50°C to 60°C. 【0346】 In some embodiments, the decarboxylation reaction is carried out in a solvent selected from the group consisting of protic solvents (e.g., water, methanol, ethanol, isopropanol, propanol), ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran), hydrocarbons (e.g., toluene, trifluorotoluene), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), and polar aprotic solvents (e.g., acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and sulfolane, or any combination thereof). In some embodiments, the decarboxylation reaction is carried out in a solvent containing acetone. 【0347】 In some embodiments, the compound of formula XVIII is: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0348】 In some embodiments, the compound of formula XVIII is: [ka] It is a compound or salt thereof. 【0349】 In some embodiments, the compound of formula XVIII is: [ka] It is a compound of [the compound]. 【0350】 In some embodiments, this disclosure relates to formula XIX: [ka] A process for preparing a compound of formula XVIII, or its cocrystal, solvate, or salt, wherein formula XVIII: [ka] The present invention provides a process comprising triflating a compound, or a cocrystal, solvate, or salt thereof, in the presence of a base. 【0351】 In some embodiments, this disclosure relates to formula XIX: [ka] A process for preparing a compound or salt thereof of formula XVIII: [ka] The present invention provides a process comprising triflate a compound or salt thereof in the presence of a base. 【0352】 In some embodiments, the triflate reaction involves reacting a compound of formula XVIII or a salt thereof with a triflate reagent selected from the group consisting of trifluoromethanesulfonic anhydride, bis(trifluoromethanesulfonyl)aniline, and N-(5-chloro-2-pyridyl)trifluimide in the presence of a base. 【0353】 In some embodiments, the triflate reaction involves reacting a compound of formula XVIII or a salt thereof with trifluoromethanesulfonic anhydride in the presence of a base. 【0354】 In some embodiments, the base is selected from the group consisting of amine bases (e.g., diisopropylethylamine, 4-methylmorpholine, triethylamine, N,N-diisopropylethylamine), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, 4-dimethylaminopyridine), carbonate bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate), bicarbonate bases (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate), and phosphate bases (e.g., sodium phosphate, potassium phosphate). In some embodiments, the base is pyridine. 【0355】 In some embodiments, the triflate reaction is carried out at a temperature of approximately -78°C to 80°C. In some embodiments, the triflate reaction is carried out at a temperature of approximately -20°C to 40°C. In some embodiments, the triflate reaction is carried out at a temperature of approximately -10°C to 10°C. 【0356】 In some embodiments, the triflate reaction is carried out in a solvent selected from the group consisting of ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran), hydrocarbons (e.g., toluene, trifluorotoluene), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), halogenated solvents (e.g., dichloromethane), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and sulfolane), or any combination thereof. In some embodiments, the triflate reaction is carried out in a solvent containing dichloromethane. 【0357】 In some embodiments, the compound of formula XIX is: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0358】 In some embodiments, the compound of formula XIX is: [ka] It is a compound or salt thereof. 【0359】 In some embodiments, the compound of formula XIX is: [ka] It is a compound of [the compound]. 【0360】 In some embodiments, this disclosure relates to formula XIII: [ka] A process for preparing a compound of formula XIV, or a cocrystal, solvate, or salt thereof, wherein formula XIV: [ka] The first mixture is formed by reacting the compound or its cocrystal, solvate, or salt with an activator in the presence of zinc and optionally an alkali metal halide. The first mixture and formula XIX: [ka] The process involves mixing a compound, or a cocrystal, solvate, or salt thereof, in the presence of a coupling catalyst, wherein the formula includes, X 1 But it's a halo, R 1 However, C 1~6 It provides an alkyl process. 【0361】 In some embodiments, this disclosure relates to formula XIII: [ka] A process for preparing a compound or salt thereof of formula XIV: [ka] The first mixture is formed by reacting the compound or salt thereof with an activator in the presence of zinc and an alkali metal halide. The first mixture and formula XIX: [ka] This includes mixing a compound or a salt thereof in the presence of a coupling catalyst, X 1 But it's a halo, R 1 However, C 1~6 It provides an alkyl process. 【0362】 In some embodiments, R 1 C 1~6 A molecule is selected from the group consisting of alkyl, phenyl, pyridyl, and benzyl, and each of the phenyl, pyridyl, and benzyl molecules is optionally substituted with methoxy. 【0363】 In some embodiments, R 1 The compound is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl, phenyl, pyridyl (e.g., 2-pyridyl or 4-pyridyl), benzyl, and methoxybenzyl (e.g., 4-methoxybenzyl). 【0364】 In some embodiments, R 1 C 1~6 It is alkyl. In some embodiments, R 1 R is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 1 It is tert-butyl. 【0365】 In some embodiments, X 1 It is Bromo. 【0366】 In some embodiments, the activator is selected from the group consisting of trialkylsilyl halides (e.g., trimethylsilyl chloride, triethylsilyl chloride, trimethylsilyl iodide), dihaloethanes (e.g., dibromoethane, dichloroethane), alkylaluminum hydrides (e.g., diisobutylaluminum hydride), and iodine. 【0367】 In some embodiments, the activator is selected from the group consisting of diisobutylaluminum hydride, trimethylsilyl chloride, triethylsilyl chloride, trimethylsilyl iodide, dibromoethane, dichloroethane, and iodine. In some embodiments, the activator is diisobutylaluminum hydride. 【0368】 In some embodiments, the alkali metal halide is lithium halide. In some embodiments, the alkali metal halide is lithium chloride. 【0369】 In some embodiments, the coupling catalyst includes a palladium catalyst. 【0370】 In some embodiments, the palladium catalyst is a palladium salt (II) (e.g., palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate), a palladium complex (0) (e.g., tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0)), a G3-Pd complex (e.g., methanesulfonic acid (2-dicyclohexylphosphin-2',4',6'-triisopropyl-1, Selected from the group consisting of 1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)(XPhos-Pd-G3)) and G4-Pd complexes (e.g., (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium(XPhos-Pd-G4)). 【0371】 In some embodiments, the palladium catalyst is selected from the group consisting of palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate, tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. 【0372】 In some embodiments, the coupling catalyst comprises a palladium catalyst and optionally a phosphine ligand. In some embodiments, the phosphine ligand is absent. In some embodiments, the phosphine ligand is selected from the group consisting of trialkylphosphines (e.g., tricyclohexylphosphine, tri-tert-butylphosphine), triarylphosphines (e.g., triphenylphosphine), dialkylarylphosphines (e.g., 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), and alkyldiarylphosphines (e.g., ethylenebis(diphenylphosphine) (DPPE)). 【0373】 In some embodiments, the phosphine ligand is selected from the group consisting of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tricyclohexylphosphine, tri-tert-butylphosphine, triphenylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and ethylenebis(diphenylphosphine). In some embodiments, the phosphine ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. 【0374】 In some embodiments, the coupling catalyst comprises a palladium catalyst and a phosphine ligand. In some embodiments, the coupling catalyst comprises palladium(II) acetate and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. 【0375】 In some embodiments, the mixing of the first mixture with the compound of formula XIX is carried out at a temperature of about 0°C to about 100°C. In some embodiments, the mixing of the first mixture with the compound of formula XIX is carried out at a temperature of about 0°C to about 70°C. In some embodiments, the mixing of the first mixture with the compound of formula XIX is carried out at a temperature of about 45°C to about 65°C. 【0376】 In some embodiments, the mixing of the first mixture and the compound of formula XIX is carried out in a solvent selected from the group consisting of ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide), or any combination thereof. In some embodiments, the mixing of the first mixture and the compound of formula XIX is carried out in a solvent containing tetrahydrofuran and 2-methyltetrahydrofuran. 【0377】 In some embodiments, the process provided herein involves a compound of formula IV, or a cocrystal, solvate, or salt thereof, and formula III: [ka] By linking the compound, or its cocrystal, solvate, or salt, formula II: [ka] The further comprising forming a compound of, or a cocrystal, solvate, or salt thereof, in the formula, R 1 However, C 1~6 Alkyl, C 6~10 Aryls, and 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryls, and 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 3 However, independently, C 1~6 Alkyl and C6~10 Selected from a group consisting of aryl groups. 【0378】 In some embodiments, the process provided herein involves a compound of formula IV or a salt thereof and formula III: [ka] By linking the compound or salt thereof, Formula II: [ka] The further comprising forming a compound or salt thereof, in which, R 1 However, C 1~6 Alkyl, C 6~10 Aryls, and 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl-, in the formula, C 6~10 Aryls, and 5-10 membered heteroaryls, and C 6~10 Aryl-C 1~6 Each alkyl group can be arbitrarily selected as C 1~6 Substituted with alkoxy, Each R 3 However, independently, C 1~6 Alkyl and C 6~10 Selected from a group consisting of aryl groups. 【0379】 In some embodiments, the process provided herein involves a compound of formula IV or a salt thereof and formula III: [ka] By linking the compound or salt thereof, Formula II: [ka] The further comprising forming a compound or salt thereof, in which, R 1 However, C 1~6 It is alkyl, Each R 3 However, independently, C 1~6Selected from alkyl groups. 【0380】 In some embodiments, R 1 R is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 1 It is tert-butyl. 【0381】 Several embodiments, each R 3 These are independently selected from methyl and tert-butyl. 【0382】 In some embodiments, coupling involves reacting a compound of formula IV or a salt thereof with a compound of formula III or a salt thereof in the presence of a coupling agent, a base, and optionally a catalyst. 【0383】 In some embodiments, the catalyst is selected from the group consisting of dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole (HOBt), and 1-hydroxy-7-azabenzotriazole (HOAt). In some embodiments, there is no catalyst. 【0384】 In some embodiments, coupling involves reacting a compound of formula IV or a salt thereof with a compound of formula III or a salt thereof in the presence of a coupling agent and a base (for example, in the absence of a catalyst). 【0385】 In some embodiments, the coupling agent is selected from the group consisting of 1,1'-carbonyldiimidazole, thionyl chloride, phosgene, triphosgene, alkyl chloroformate (e.g., ethyl chloroformate, isobutyl chloroformate), carbodiimide (e.g., dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), propanephosphonic anhydride (T3P), and peptide coupling reagents (e.g., HATU, HBTU, TATU, TBTU, HCTU, BOP, PyBOP, COMU). 【0386】 In some embodiments, the coupling agent is selected from the group consisting of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate, 1,1'-carbonyldiimidazole, thionyl chloride, phosgene, triphosgene, ethyl chloroformate, isobutyl chloroformate, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, propanephosphonic anhydride, HATU, HBTU, TATU, TBTU, HCTU, BOP, PyBOP, and COMU. In some embodiments, the coupling agent is N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate. In some embodiments, the coupling agent is propanephosphonic anhydride. 【0387】 In some embodiments, the base is selected from the group consisting of amines (e.g., diisopropylethylamine, 4-methylmorpholine), basic aromatic compounds (e.g., pyridine, 2,6-lutidine, imidazole), carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate), and phosphates (e.g., sodium phosphate, potassium phosphate). 【0388】 In some embodiments, the base is selected from the group consisting of 1-methylimidazole, diisopropylethylamine, 4-methylmorpholine, pyridine, 2,6-lutidine, imidazole, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, and potassium phosphate. In some embodiments, the base is 1-methylimidazole. 【0389】 In some embodiments, the coupling is performed at temperatures ranging from approximately -30°C to approximately 60°C. In some embodiments, the coupling is performed at temperatures ranging from approximately 0°C to approximately 30°C. In some embodiments, the coupling is performed at temperatures ranging from approximately 0°C to approximately 20°C. 【0390】 In some embodiments, the coupling is carried out in a solvent selected from the group consisting of esters (e.g., ethyl acetate, isopropyl acetate), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene), hydrocarbons (e.g., toluene, n-heptane), nitriles (e.g., propylnitrile, butyronitrile), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone), or any combination thereof, optionally in combination with water. In some embodiments, the coupling is carried out in a solvent containing acetonitrile. 【0391】 In some embodiments, the compound of formula II is formula II-a: [ka] It is a compound of the same, or its cocrystal, solvate, or salt. 【0392】 In some embodiments, the compound of formula II is formula II-a: [ka] It is a compound or salt thereof. 【0393】 In some embodiments, the compound of formula II is formula II-a: [ka] It is a compound of [the compound]. 【0394】 In some embodiments, the process provided herein involves deprotecting a compound of formula II, or its cocrystal, solvate, or salt, to form formula I: [ka] The further comprises forming a compound of the same, or a cocrystal, solvate, or salt thereof. 【0395】 In some embodiments, the process provided herein involves deprotecting a compound of formula II or a salt thereof, thereby eliminating the need for formula I: [ka] The further comprises forming a compound or salt thereof. 【0396】 In some embodiments, deprotection involves reacting a compound of formula II, or its cocrystal, solvate, or salt, in the presence of an acid. 【0397】 In some embodiments, the acid is selected from the group consisting of carboxylic acids (e.g., trifluoroacetic acid, trichloroacetic acid, formic acid), inorganic acids (e.g., hydrofluoric acid, hydrochloric acid, sulfuric acid), and organic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid). 【0398】 In some embodiments, the acid is selected from the group consisting of phosphoric acid, trifluoroacetic acid, trichloroacetic acid, formic acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid. In some embodiments, the acid is phosphoric acid. 【0399】 In some embodiments, deprotection involves reacting a compound of formula II, or its cocrystal, solvate, or salt, in the presence of an oxidizing agent. 【0400】 In some embodiments, the oxidizing agent is selected from the group consisting of N-halosuccinimide (e.g., N-chlorosuccinimide, N-bromosuccinimide), N-halosulfonamide (e.g., sodium N-chlorotosylamide), bromine (Br2), chlorine (Cl2), iodine (I2), hypochlorite (e.g., sodium hypochlorite), peroxide (e.g., sodium peroxide t-butyl hydrogen peroxide, sodium perborate), and potassium peroxymonosulfate (Oxon). In some embodiments, deprotection is carried out at a temperature of about -20°C to about 100°C. In some embodiments, deprotection is carried out at a temperature of about 0°C to about 40°C. In some embodiments, deprotection is carried out at a temperature of about 10°C to about 30°C. 【0401】 In some embodiments, the coupling is carried out in a solvent selected from the group consisting of ethers (e.g., 2-methyltetrahydrofuran, tert-butylmethyl ether), ketones (e.g., acetone, 2-butanone), hydrocarbons (e.g., toluene, xylene, trifluorotoluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride), nitriles (e.g., acetonitrile, propylnitrile, butyronitrile), protic solvents (e.g., methanol, ethanol, propanol, t-butanol), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), or any combination thereof, in optional combinations thereof. In some embodiments, the coupling is carried out in a solvent containing acetonitrile and water. 【0402】 In some embodiments, this disclosure relates to formula I: [ka] A process for preparing a compound, or a cocrystal, solvate, or salt thereof, Formula XIV-a: [ka] The first mixture is formed by reacting the compound, or its cocrystal, solvate, or salt thereof, with trimethylsilyl chloride in the presence of zinc. The first mixture and formula XI-a: [ka] A compound, or its cocrystal, solvate, or salt thereof, is mixed in the presence of bis(dibenzylideneacetone)palladium(O) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl to obtain formula XIII-a: [ka] To form a compound, or a cocrystal, solvate, or salt thereof, A compound of formula XIII-a, or its cocrystal, solvate, or salt, is reacted with di-tert-butyl phosphite, bromoform, and sodium trimethylsilanolate to obtain formula IV-a: [ka] To form a compound or salt thereof, A compound of formula IV-a, or its cocrystal, solvate, or salt, and formula III: [ka] The compound, or its cocrystal, solvate, or salt, is linked in the presence of propanephosphonic anhydride and 1-methylimidazole to form formula II-a: [ka] To form a compound, or a cocrystal, solvate, or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a, or its cocrystal, solvate, or salt, with phosphoric acid to form a compound of formula I, or its cocrystal, solvate, or salt. 【0403】 In some embodiments, this disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, 3-bromo-5-methylphenol and methyl 3,3-dimethyl acrylate are reacted in the presence of sulfuric acid to form formula XI-a: [ka] To form a compound or salt thereof, Formula XIV-a: [ka] The first mixture is formed by reacting the compound or a salt thereof with trimethylsilyl chloride in the presence of zinc, The first mixture and the compound of formula XI-a or a salt thereof are mixed in the presence of bis(dibenzylideneacetone)palladium(0) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl to obtain formula XIII-a: [ka] To form a compound or salt thereof, The compound of formula XIII-a or a salt thereof is reacted with di-tert-butyl phosphite, bromoform, and sodium trimethylsilanolate to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of propanephosphonic anhydride and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0404】 In some embodiments, this disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, Formula XIV-a: [ka] The first mixture is formed by reacting the compound or a salt thereof with trimethylsilyl chloride in the presence of zinc, The first mixture and formula XI-a: [ka] A compound or a salt thereof is mixed in the presence of bis(dibenzylideneacetone)palladium(0) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl to obtain formula XIII-a: [ka] To form a compound or salt thereof, The compound of formula XIII-a or a salt thereof is reacted with di-tert-butyl phosphite, bromoform, and sodium trimethylsilanolate to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of propanephosphonic anhydride and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0405】 In some embodiments, this disclosure relates to formula I: [ka] A process for preparing a compound, or a cocrystal, solvate, or salt thereof, 3-bromo-5-methylphenol and methyl 3,3-dimethyl acrylate are reacted in the presence of sulfuric acid to form formula XI-a: [ka] To form a compound or salt thereof, The compound of formula XI-a, or its cocrystal, solvate, or salt, is reacted with bis(pinacolate)diborone in the presence of bis(dibenzylideneacetone)palladium(O), triphenylphosphine, and potassium propionate to obtain formula XI-b: [ka] To form a compound, or a cocrystal, solvate, or salt thereof, A compound of formula XI-b, or its cocrystal, solvate, or salt, and formula XIV-a: [ka] The compound, or its cocrystal, solvate, or salt, is reacted in the presence of bis(dibenzylideneacetone)palladium(O), tribasic potassium phosphate, and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane to obtain formula XIII-a: [ka] To form a compound, or a cocrystal, solvate, or salt thereof, A compound of formula XIII-a, or its cocrystal, solvate, or salt, is reacted with di-tert-butyl phosphite, bromoform, and sodium trimethylsilanolate to obtain formula IV-a: [ka] To form a compound, or a cocrystal, solvate, or salt thereof, A compound of formula IV-a, or its cocrystal, solvate, or salt, and formula III: [ka] The compound, or its cocrystal, solvate, or salt, is linked in the presence of propanephosphonic anhydride and 1-methylimidazole to form formula II-a: [ka] To form a compound, or a cocrystal, solvate, or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a, or its cocrystal, solvate, or salt, with phosphoric acid to form a compound of formula I, or its cocrystal, solvate, or salt. 【0406】 In some embodiments, this disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, 3-bromo-5-methylphenol and methyl 3,3-dimethyl acrylate are reacted in the presence of sulfuric acid to form formula XI-a: [ka] To form a compound or salt thereof, The compound of formula XI-a or a salt thereof is reacted with bis(pinacolate)diborone in the presence of bis(dibenzylideneacetone)palladium(O), triphenylphosphine, and potassium propionate to obtain formula XI-b: [ka] To form a compound or salt thereof, Compound of formula XI-b or its salt and formula XIV-a: [ka] The compound or a salt thereof was reacted in the presence of bis(dibenzylideneacetone)palladium(O), tribasic potassium phosphate, and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane to obtain formula XIII-a: [ka] To form a compound or salt thereof, The compound of formula XIII-a or a salt thereof is reacted with di-tert-butyl phosphite, bromoform, and sodium trimethylsilanolate to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of propanephosphonic anhydride and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0407】 In some embodiments, this disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, Formula XI-a: [ka] The compound or a salt thereof is reacted with bis(pinacolate)diborone in the presence of bis(dibenzylideneacetone)palladium(O), triphenylphosphine, and potassium propionate to obtain formula XI-b: [ka] To form a compound or salt thereof, Compound of formula XI-b or its salt and formula XIV-a: [ka] The compound or a salt thereof was reacted in the presence of bis(dibenzylideneacetone)palladium(O), tribasic potassium phosphate, and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane to obtain formula XIII-a: [ka] To form a compound or salt thereof, The compound of formula XIII-a or a salt thereof is reacted with di-tert-butyl phosphite, bromoform, and sodium trimethylsilanolate to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of propanephosphonic anhydride and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0408】 In some embodiments, this disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, Formula XIV-a: [ka] The first mixture is formed by reacting the compound or salt thereof with diisobutylaluminum hydride in the presence of zinc and lithium chloride. The first mixture and formula XI-a: [ka] A compound or a salt thereof is mixed in the presence of palladium(II) acetate and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl to obtain formula XIII-a: [ka] To form a compound or salt thereof, A compound of formula XIII-a or a salt thereof is reacted with di-tert-butyl phosphite, bromoform, and trimethylsilanolate to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0409】 In some embodiments, this disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, Formula VII-a: [ka] The compound or a salt thereof is reacted with di-tert-butyl phosphite in the presence of bromoform and cesium carbonate to produce formula VI-a: [ka] To form a compound or salt thereof, Deprotecting the compound of formula VI-a or a salt thereof in the presence of tetrabutylammonium fluoride yields formula Va: [ka] To form a compound or salt thereof, A compound of formula Va or a salt thereof is oxidized in the presence of (diacetoxyiodo)benzene, dibasic sodium phosphate, and 2,2,6,6-tetramethylpiperidine 1-oxyl to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0410】 In some embodiments, this disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, Formula VII-a: [ka] The compound or a salt thereof is reacted with tetrabenzyl pyrophosphate in the presence of sodium hydride to produce formula VI-b: [ka] To form a compound or salt thereof, Deprotecting a compound of formula VI-b or a salt thereof in the presence of tetrabutylammonium fluoride yields formula Vb: [ka] To form a compound or salt thereof, The compound of formula Vb or a salt thereof is oxidized in the presence of (diacetoxyiodo)benzene, dibasic sodium phosphate, and 2,2,6,6-tetramethylpiperidine 1-oxyl to obtain formula IV-b: [ka] To form a compound or salt thereof, Compound of formula IV-b or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form formula II-b: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-b or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0411】 In some embodiments, this disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, Formula VII-a: [ka] The first mixture is formed by reacting the compound or a salt thereof with di-tert-butyl N,N-diisopropyl phosphoramidate in the presence of 1-methylimidazole and trifluoroacetic acid. Mix the first mixture with hydrogen peroxide to obtain formula VI-a: [ka] To form a compound or salt thereof, Deprotecting the compound of formula VI-a or a salt thereof in the presence of tetrabutylammonium fluoride yields formula Va: [ka] To form a compound or salt thereof, A compound of formula Va or a salt thereof is oxidized in the presence of (diacetoxyiodo)benzene, dibasic sodium phosphate, and 2,2,6,6-tetramethylpiperidine 1-oxyl to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0412】 In some embodiments, the compound of formula III, or its cocrystal, solvate, or salt, is the sodium salt of the compound of formula III. 【0413】 In some embodiments, the compound of formula III, or a salt thereof, is the sodium salt of the compound of formula III. 【0414】 In some embodiments, this disclosure relates to formula VI-a: [ka] A process for preparing a compound of formula VII-a, or its cocrystal, solvate, or salt, wherein formula VII-a: [ka] The present invention provides a process comprising reacting a compound, or a cocrystal, solvate, or salt thereof, with di-tert-butyl N,N-diisopropyl phosphoramidate in the presence of 1-methylimidazole and toluenesulfonic acid to form a first mixture, and mixing the first mixture with hydrogen peroxide. 【0415】 In some embodiments, this disclosure relates to formula VI-a: [ka] A process for preparing a compound or salt thereof, wherein formula VII-a: [ka] The present invention provides a process comprising: reacting a compound or a salt thereof with di-tert-butyl N,N-diisopropyl phosphoramidate in the presence of 1-methylimidazole and toluenesulfonic acid to form a first mixture; and mixing the first mixture with hydrogen peroxide to form a compound of formula VI-a or a salt thereof. 【0416】 In some embodiments, the disclosure provides intermediate compounds (for example, intermediate compounds prepared according to the processes provided herein). 【0417】 In some embodiments, this disclosure relates to formula XIII-a: [ka] The disclosure provides compounds of formula XIII-a, or cocrystals, solvates, or salts thereof. In some embodiments, the disclosure provides compounds of formula XIII-a, or salts thereof. In some embodiments, the disclosure provides compounds of formula XIII-a. 【0418】 This disclosure is based on formula VI-b: [ka] Further disclosures provide compounds of formula VI-b or their cocrystals, solvates, or salts. In some embodiments, the disclosure provides compounds of formula VI-b or their salts. In some embodiments, the disclosure provides compounds of formula VI-b. [Examples] 【0419】 Typical synthesis of the compounds of this disclosure is described in the following scheme and subsequent specific examples. These examples are provided for illustrative purposes only and are not intended to limit the disclosure. It should be understood that the individual steps described herein can be combined. It should also be understood that separate batches of compounds can be combined and carried over to subsequent synthesis steps. Example 1. Synthesis of 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid [ka] Step 1. Synthesis of 5-bromo-4,4,7-trimethylchroman-2-one [ka] 【0420】 3-Bromo-5-methylphenol (1.00 equivalent, scaling factor) and methanesulfonic acid (MSA, 2.00 equivalent) were packed into the reactor. The mixture was heated to approximately 110°C and methyl 3,3-dimethyl acrylate (2.00 equivalent) was added in small increments. The mixture was stirred at approximately 110°C until the reaction was considered complete. The mixture was cooled to approximately 20°C and then packed into another reactor containing water (2.7 vol). The mixture was extracted twice with ethyl acetate (4.1 vol), and the combined organic layer was successively washed with saturated sodium bicarbonate solution (4.3 vol) and 10% brine solution (2.3 vol). The organic layer was dried over sodium sulfate and concentrated to the minimum volume. The crude product was pulverized with a mixture of n-heptane (2.0 vol) and ethyl acetate (0.2 vol) at approximately 0°C for approximately 1 hour. The slurry was filtered, the filtrate was concentrated to the minimum volume, and then purified by column chromatography on silica to obtain 5-bromo-4,4,7-trimethylchroman-2-one. 1 H NMR (400MHz, CDCl3): δ 7.14 (s, 1H), 6.75 (s, 1H), 2.56 (s, 2H), 2.21 (s, 3H), 1.48 (s 6H) ppm. Step 2. Synthesis of 3-bromo-2-(4-hydroxy-2-methylbutan-2-yl)-5-methylphenol [ka] 【0421】 5-Bromo-4,4,7-trimethylchroman-2-one (1.00 equivalent, scaling factor) and tetrahydrofuran (3.0 volume) were packed into reactor A. Lithium aluminum hydride solution (2.5 M, 2.00 equivalent in tetrahydrofuran) was packed into reactor B. The contents of reactor A and reactor B were simultaneously pumped through a flow reactor (preheated to approximately 35°C) at approximately 82 mL / min and 115 mL / min, respectively. The reaction mixture exiting the flow reactor contained hydrochloric acid (1.0 M, 35.0 volume) that had been pre-cooled to approximately 0°C. The reaction mixture was quenched in reactor C. The reaction mixture was extracted with ethyl acetate (10.0 vol.), and the organic layer was successively washed with saturated sodium bicarbonate solution (11.6 vol.) and 10% brine solution (5.8 vol.). The organic layer was dried over sodium sulfate and concentrated to the minimum volume. The crude product was pulverized with a mixture of n-heptane (1.8 vol.) and methyl t-butyl ether (0.2 vol.) at approximately 0°C for approximately 5 hours. The slurry was filtered and then dried to obtain 3-bromo-2-(4-hydroxy-2-methylbutan-2-yl)-5-methylphenol. 1 H NMR (400MHz, CDCl3): δ 7.05(s,1H),6.48(s,1H),3.65(t,J=6.8Hz,2H),2.29(t,J=6.8Hz,2H),2.19(s,3H),1.68(s,6H)ppm. Step 3. Synthesis of (3-bromo-2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-5-methylphenoxy)(tert-butyl)dimethylsilane [ka] 【0422】 3-Bromo-2-(4-hydroxy-2-methylbutan-2-yl)-5-methylphenol (1.00 equivalent, scaling factor) and N,N-dimethylformamide (4.0 volume) were packed into the reactor, followed by 4-dimethylaminopyridine (DMAP, 0.10 equivalent), imidazole (5.00 equivalent), and t-butyldimethylsilyl chloride (5.20 equivalent). The mixture was stirred at approximately 60°C until the reaction was considered complete. The mixture was quenched with water (7.0 volume) and then extracted with n-heptane (6.0 volume). The organic layer was washed with 10% brine solution (3 volume), dried over sodium sulfate, and then concentrated to obtain (3-bromo-2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-5-methylphenoxy)(tert-butyl)dimethylsilane. 1 H NMR(400MHz,CDCl3):δ 7.06(s,1H),6.55(s,1H),3.50(t,J=7.8Hz,2H),2.27(t,J=7.8Hz,2H),2.19( s,3H),1.62(s,6H),1.02(s,9H),0.86(s,9H),0.31(s,6H),-0.01(s,6H)ppm. Step 4. Synthesis of tert-butyl 2-(3-((tert-butyldimethylsilyl)oxy)-2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-5-methylphenyl) acetate [ka] 【0423】 Preparation of the Reformatoski reagent: Zinc (15.0 equivalents), tetrahydrofuran (14.0 volume), and chlorotrimethylsilane (0.25 equivalents) were packed into the reactor. 1,2-dibromoethane (0.25 equivalents) was added, and the resulting suspension was heated to approximately 50°C for approximately 2 hours. The reaction mixture was cooled to approximately 40°C, and t-butyl bromoacetate (5.00 equivalents) was gradually added. The reaction mixture was stirred at approximately 50°C for approximately 0.5 hours, and then allowed to stand at approximately 20°C for approximately 3 hours. The supernatant was transferred to another reactor and diluted with lithium chloride solution in tetrahydrofuran (0.5 M, 12.0 volume). 【0424】 Negishi coupling: A reactor containing the Reformatoski reagent was packed with a solution of (3-bromo-2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-5-methylphenoxy)(tert-butyl)dimethylsilane (1.00 equivalent, scaling factor) in tetrahydrofuran (7.0 volume), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 0.05 equivalent), and tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 0.02 equivalent). The reaction mixture was stirred at approximately 50°C for approximately 3 hours. The reaction mixture was quenched in 0.5 M aqueous citric acid solution (20.0 volume) and extracted with n-heptane (8.0 volume). The organic layer was successively washed with 10% brine solution (3.0 vol), saturated sodium bicarbonate solution (5.0 vol), and 10% brine solution (3.0 vol). The organic layer was concentrated to the minimum volume and then purified by column chromatography on silica to obtain tert-butyl 2-(3-((tert-butyldimethylsilyl)oxy)-2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-5-methylphenyl) acetate. 1H NMR(400MHz,CDCl3):δ 6.55(s,1H),6.49(s,1H),3.77(s,2H),3.46(t,J=7.2Hz,2H),2.21(s,3H),2.17(t,J=7.2H z,2H),1.49(s,6H),1.47(s,9H),1.03(s,9H),0.84(s,9H),0.30(s,6H),-0.03(s,6H)ppm. Step 5. Synthesis of tert-butyl 2-(2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3-hydroxy-5-methylphenyl) acetate [ka] 【0425】 1.00 equivalent, scaling factor, tert-butyl 2-(3-((tert-butyldimethylsilyl)oxy)-2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-5-methylphenyl) acetate (1.00 equivalent) and tetrahydrofuran (6.0 volume) were packed into the reactor, followed by lithium hydroxide monohydrate (5.00 equivalent) and water (6.0 volume). The mixture was stirred at approximately 40°C until the reaction was considered complete. The reaction mixture was diluted with 0.5 M aqueous citric acid (4.8 volume) and extracted with methyl t-butyl ether (4.1 volume). The organic layer was successively washed with saturated sodium bicarbonate solution (5.0 volume) and 10% brine solution (3.0 volume), and then dried over sodium sulfate. The organic layer was concentrated to the minimum volume and then pulverized with n-heptane. The slurry was filtered, and the filtered cake was dried under vacuum to obtain tert-butyl 2-(2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3-hydroxy-5-methylphenyl) acetate. 1H NMR(400MHz,CDCl3):δ 6.48(s,1H),5.85(s,1H),3.75(s,2H),3.58(t,J=7.2Hz,2H),2.20(s,3H),2 .14(t,J=7.2Hz,2H),1.52(s,6H),1.46(s,9H),0.88(s,9H),0.03(s,6H)ppm. Step 6. Synthesis of tert-butyl 2-(2-(4-(tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl) acetate [ka] 【0426】 Di-t-butyl phosphite (1.20 equivalents) and tetrahydrofuran (2.0 volume) were packed into the reactor, followed by bromoform (1.22 equivalents) at approximately 15°C. The mixture was stirred at approximately 15°C for approximately 1 hour, and then another reactor containing tert-butyl 2-(2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3-hydroxy-5-methylphenyl) acetate (1.00 equivalent, scaling factor), cesium carbonate (1.70 equivalents), and tetrahydrofuran (4.0 volume) was packed at approximately 15°C. The mixture was stirred at approximately 25°C until the reaction was considered complete. The reaction mixture was diluted with 5% aqueous potassium phosphate (5.0 volume) and methyl t-butyl ether (5.0 volume). The two-phase mixture was stirred at approximately 25°C for approximately 16 hours. The organic layer was separated, washed with a 10% brine solution (3.0 volume), and then concentrated to the minimum volume to obtain tert-butyl 2-(2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl)acetate. 1H NMR(400MHz,CDCl3):δ 7.33(s,1H),6.69(s,1H),3.80(s,2H),3.50(t,J=7.2Hz,2H),2.24(s,3H),2.09(t,J =7.2Hz,2H),1.53(s,24H),1.49(s,18H),1.45(s,9H),0.84(s,9H),-0.03(s,6H)ppm. Step 7. Synthesis of tert-butyl 2-(3-((di-tert-butoxyphosphoryl)oxy)-2-(4-hydroxy-2-methylbutan-2-yl)-5-methylphenyl) acetate [ka] 【0427】 1.00 equivalents of tert-butyl 2-(2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl) acetate (scaling factor) and tetrahydrofuran (6.0 volume) were packed into the reactor, followed by packing the tetrahydrofuran with 1 M tetrabutylammonium fluoride solution (2.00 volume). The mixture was stirred at approximately 25°C until the reaction was considered complete. The reaction mixture was quenched with water (4.0 volume) and extracted with methyl t-butyl ether (6.0 volume). The organic layer was separated and successively washed with 5% dibasic potassium phosphate solution (6.0 volume), 10% sodium bicarbonate solution (4.0 volume), and 10% brine solution (4.0 volume). The organic layer was concentrated to the minimum volume to obtain tert-butyl 2-(3-((di-tert-butoxyphosphoryl)oxy)-2-(4-hydroxy-2-methylbutan-2-yl)-5-methylphenyl) acetate. 1 H NMR(400MHz,CDCl3):δ 7.33(s,1H),6.70(s,1H),3.83(s,2H),3.52(t,J=6.8Hz 2H),2.24(s,3H),2.17(t,J=6.8Hz,2H),1.51(s,24H),1.46(s,9H)ppm. Step 8. Synthesis of 3-(2-(2-(tert-butoxy)-2-oxoethyl)-6-((di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid [ka] 【0428】 The reactor was filled with tert-butyl 2-(3-((di-tert-butoxyphosphoryl)oxy)-2-(4-hydroxy-2-methylbutan-2-yl)-5-methylphenyl) acetate (1.00 equivalent, scaling factor), acetonitrile (2.7 volume), and methyl t-butyl ether (5.4 volume), followed by filling with 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO, 0.50 equivalent), water (8.0 volume), dibasic sodium phosphate (6.00 equivalent), and (diacetoxyiodo)benzene (DAIB, 2.80 equivalent). The mixture was stirred at approximately 25°C until the reaction was considered complete. The reaction mixture was diluted with methyl t-butyl ether (6.5 volume), and the organic layer was separated. The organic layer was successively washed with 10% sodium thiosulfate solution (8.6 volume) and 10% brine solution (5.4 volume). The organic layer was concentrated to the minimum volume and then crystallized twice in a mixture of dichloromethane (1.1 vol) and n-heptane (16.2 vol). The slurry was filtered, the filter cake was washed with n-heptane (0.6 vol), and then dried to obtain 3-(2-(2-tert-butoxy)-2-oxoethyl)-6-((di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid. 1 H NMR(400MHz,d6-DMSO):δ 11.69(s,1H),7.19(s,1H),6.70(s,1H),3.82(s,2H),2.83(s,2H),2.18(s,3H),1.47(s,6H),1.42(s,18H),1.40(s,9H)ppm. Step 9. Synthesis of tert-butyl 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl)acetate [ka] 【0429】 3-(2-(2-tert-butoxy)-2-oxoethyl)-6-((di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid (1.15 equivalents), acetonitrile (2.7 volume), and 1-methylimidazole (9.00 equivalents) were packed into the reactor, and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH, 1.40 equivalents) was added at approximately 10°C. The mixture was stirred at approximately 10°C for approximately 2 hours, and then GS-6207-02 (1.00 equivalent, scaling factor) was added. The mixture was stirred at approximately 10°C until the reaction was considered complete. The reaction mixture was diluted with methyl t-butyl ether (12.8 volume) and then quenched with an aqueous solution (10 volume) containing 2% dibasic potassium phosphate and 5% potassium chloride. The two-phase mixture was diluted with cyclohexane (2.6 vol.), and the organic layer was separated. The organic layer was washed with an aqueous solution containing 2% dibasic potassium phosphate and 5% potassium chloride (10 vol.), and then washed twice with a 5% potassium chloride solution (10 vol.). The organic layer was diluted with methyl t-butyl ether (4.0 vol.), and then evaporated to about 2.0 vol. The residue was evaporated twice with methyl t-butyl ether (12.0 vol.) to about 2.0 vol. The residue was diluted with methyl t-butyl ether (3.0 vol.), and then loaded into n-heptane (14.6 vol.). The mixture was stirred at about 25°C for about 4 hours, and then filtered. The filtration cake is washed twice with n-heptane (7.3 volume), then dried, and tert-butyl 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-( 3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl)acetate was obtained.1 ¹H NMR (400MHz, d6-DMSO, all atropisomers): δ 9.25-8.84 (m,1H), 8.02-6.41 (m,9H), 5.04-4.50 (m,4H), 4.25-2.82 (m,13H), 2.61-2.42 (m,2H), 2.18 (s,3H), 1.75 (s,6H), 1.53-0.92 (m,35H) ppm. 19 1F NMR (377MHz, d6-DMSO, all atropisomers): δ -60.28--60.43 (m,3F), -68.84--69.17 (m,3F), -79.25--80.41 (m,1F), -101.96--103.31 (m,1F), -110.05--110.43 (m,2F) ppm. 31 3P NMR (162MHz, d6-DMSO, all atrop isomers): -16.88, -17.07, -17.18, -17.56 ppm. Step 10. Synthesis of 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid [ka] 【0430】 tert-butyl2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta- 1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl)acetate (1.00 equivalent, scaling factor) and acetonitrile (1.4 volume) were packed into the reactor and adjusted to approximately 22°C. Phosphoric acid (85% by weight, 37 equivalents) was packed in while maintaining the mixture below 27°C, followed by the packing of acetonitrile (0.45 volume). The mixture was stirred at approximately 22°C until the reaction was considered complete. Acetonitrile (5.3 volume) was added, and then the mixture was washed twice with 14% aqueous NaCl solution (5 volume). Acetonitrile (5.3 volume) was added, and then the mixture was washed twice with 8% aqueous NaCl solution (5 volume). Acetonitrile (2.6 vol) was added, and the mixture was then washed with an 8% NaCl aqueous solution and a 4% NaHSO4 aqueous solution (5 vol). The mixture was concentrated under reduced pressure to approximately 3.0 vol. The residue was co-evaporated with acetonitrile (8.7 vol) to approximately 3.0 vol, and this was repeated twice. Acetonitrile (6.9 vol) was added, and the mixture was polish-filtered into another reactor. The mixture was concentrated under reduced pressure to approximately 3.0 vol. Trifluoroacetic acid (0.26 equivalents), acetonitrile (1.0 vol), and a seed of the compound of formula I (0.0017 equivalents) were added, and the mixture was stirred for approximately 16 hours. Di-n-butyl ether (8.0 vol) was added over approximately 4 hours at approximately 22°C, and the resulting slurry was stirred for approximately 24 hours.The slurry was filtered, the filter cake was rinsed with acetonitrile (3.3 vol) solution in 23% diisopropyl ether, and then dried to obtain 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid. 11H NMR (400 MHz, d6-DMSO, major atropisomer): δ 9.18 (d, 1H, J = 8.2 Hz), 9.16 (m, 1H), 7.87 (d, 1H, J = 8.0 Hz), 7.83 (d, 1H, J = 8.1 Hz), 7.77 (d, 1H, J = 8.3 Hz), 7.75 (m, 1H), 7.44 (d, 1H, J = 7.7 Hz), 7.36 (d, 1H, J = 7.7 Hz), 7.15 (s, 1H), 7.02 (m, 1H), 7.01 (m, 1H), 6.66 (s, 1H), 6.63 (s, 1H), 6.61 (m, 1H), 6.48 (m, 2H), 4.93 (d, 1H, J = 16.4 Hz), 4.85 (d, 1H, J = 16.5 Hz), 4.77 (m, 1H), 4.76 (d, 1H, J = 16.7 Hz), 4.71 (m, 1H), 4.68 (m, 1H), 4.66 (d, 1H, J = 16.4 Hz), 4.63 (m, 1H), 4.24 (dq, 1H, J = 16.3, 8.2 Hz), 4.01 (dq, 1H, J = 16.4, 8.1 Hz), 3.87 (d, 1H, J = 17.7 Hz), 3.86 (d, 1H, J = 17.5 Hz), 3.72 (d, 1H, J = 17.8 Hz), 3.59 (d, 1H, J = 17.7 Hz), 3.48 (s, 3H), 3.46 (s, 3H), 3.44 (br m, 1H), 3.27 (s, 3H), 3.27 (s, 3H), 3.22 (br m, 1H), 3.06 (dd, 1H, J = 13.5, 7.2 Hz), 2.99 (m, 1H), 2.57 (m, 1H), 2.53 (m, 1H), 2.53 (m, 1H), 2.18 (s, 3H), 1.75 (s, 3H), 1.75 (s, 3H), 1.75 (s, 3H), 1.75 (s, 3H), 1.45 (s, 3H), 1.38 (m, 1H), 1.34 (s, 3H), 1.30 (s, 3H), 1.18 (s, 3H), 1.02 (m, 1H), 0.97 (m, 1H). 13 Note: There seems to be a repeated "1.75 (s, 3H)" in the original text which is underlined in the translation for clarity. If this is a mistake in the original, it should be corrected before translation for a more accurate result.C NMR (101MHz, d6-DMSO, main non-isotropic form): δ 173.7,173.6,171.8,171.6,164.6,164.4,162.1,158.8,158.5,150.7,142.8 ,142.7,142.4,142.1,141.9,141.7,140.0,139.6,139.3,137.6,134.9,134.6 ,134.5,134.5,134.0,133.7,132.5,132.2,132.2,132.0,131.8,131.3,130.5,130.3,129.9,129.8,126.9,126.7,125.6,125.5,123.1,122.8,122.8,120. 7,120.7,120.0,119.9,119.7,119.6,119.4,119.2,118.8,118.7,112.1,102.2,88.5,88.3,84.5,57.3,57.3,53.2,53.0,53.0,52.7,52.7,52.1,50.8,50. 8,50.4,50.4,47.3,42.2,42.2,42.0,42.0,41.6,41.5,39.7,39.2,35.1,35.1,30.6,30.3,30.3,30.2,27.6,23.2,22.4,22.4,22.3,22.3,20.0,11.7,11.6. 19 F NMR (376MHz, d6-DMSO, main atropion anisotropy): δ -60.32(s, 3F), -60.38(s, 3F), -68.98(t, 3F, J=8.2Hz), -69.22(t, 3F, J=8.3Hz), -79.59(dd, 1F, J=253.6, 12.7Hz), -80.00(m, 1F), -101.82(m, 1F), -103.03(dd, 1F, J=253.6, 9.6Hz), -109.96(m, 2F), -110.06(m, 2F). 31 P NMR (162MHz, d6-DMSO, main atropion variant): δ -7.10(s, 1P), -7.14(s, 1P). IR (ATR): 2931, 1735, 1624-1477, 1448, 1381-1315, 1259-1107, 1057-1032 cm⁻¹ -1 HRMS(ESI)[M+Na] + C 53 H 49 ClF10 N7NaO 12 PS2 + Calculated value: 1318.20393, measured value: 1318.20239. Example 2. Synthesis of tert-butyl 2-(3-((bis(benzyloxy)phosphoryl)oxy)-2-(4-(tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-5-methylphenyl) acetate [ka] 【0431】 tert-butyl 2-(2-(4-(tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3-hydroxy-5-methylphenyl) acetate (1.00 equivalent, scaling factor) was dissolved in tetrahydrofuran (10 vol). Sodium hydride (3.40 equivalent) and tetrabenzyl pyrophosphate (1.52 equivalent) were added at approximately 0°C. The mixture was stirred at approximately 25°C until the reaction was considered complete. The reaction mixture was diluted with water and methyl t-butyl ether (17 vol). The two-phase mixture was stirred at approximately 25°C until the residual tetrabenzyl pyrophosphate was completely consumed. The organic layer was separated, washed twice with water (17 vol), and then concentrated to the minimum volume to obtain the desired phosphate product. MS(ESI):C after TBS removal 32 H 42 O7P + [M+H] + Calculated value: 569.27, Measured value: 569.11. Example 3. Alternative synthesis of tert-butyl 2-(2-(4-(tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl) acetate. [ka] 【0432】 The reactor was filled with tert-butyl 2-(2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3-hydroxy-5-methylphenyl) acetate (1.00 equivalent, scaling factor) and tetrahydrofuran (23.0 volume), followed by 1-methylimidazole (3.50 equivalents), trifluoroacetic acid (2.00 equivalents), and di-t-butyl N,N-diisopropyl phosphoramidate (2.00 equivalents). The mixture was stirred until the reaction was considered complete. The reaction mixture was cooled to approximately 0°C and filled with 35% aqueous hydrogen peroxide (2.80 equivalents). The reaction mixture was stirred for approximately 3 hours and then quenched with sodium sulfite (2.00 equivalents). The reaction mixture was filtered, and the filter cake was rinsed with tetrahydrofuran (11.0 volume). The combined filtrate and washing solution were diluted with n-heptane (44.0 vol.) and passed through a silica gel pad. The filtrate was then evaporated to the minimum volume to obtain tert-butyl 2-(2-(4-(tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl)acetate. 1 H NMR(400MHz,CDCl3):δ 7.33(s,1H),6.69(s,1H),3.80(s,2H),3.50(t,J=7.2Hz,2H),2.24(s,3H),2.09(t,J =7.2Hz,2H),1.53(s,24H),1.49(s,18H),1.45(s,9H),0.84(s,9H),-0.03(s,6H)ppm. Example 4.3 Alternative synthesis of 3-(2-(2-(tert-butoxy)-2-oxoethyl)-6-((di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid [ka] Step 1. Synthesis of tert-butyl 2-(4,4,7-trimethyl-2-oxochroman-5-yl)acetate [ka] 【0433】 Formation of the Reformatski reagent: Zinc (3 equivalents) and lithium chloride in tetrahydrofuran solution (0.5 M, 5 volumes) were packed into the reactor and heated to approximately 35°C. Tert-butyl bromoacetate (0.09 equivalents) and diisobutylaluminum hydride (0.07 equivalents) were then packed into the reactor. The reactor was then heated to approximately 40°C, tert-butyl bromoacetate (2 equivalents) was gradually added, and the mixture was stirred for approximately 1.5 hours. After that, it was cooled to approximately 22°C and used for the Negishi coupling. 【0434】 Negishi coupling: In a separate reactor, palladium(II) acetate (0.015 equivalents), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 0.015 equivalents), GS-1178687 (1.00 equivalent, scaling factor), 2-methyltetrahydrofuran (10 volumes), and Reformatoski reagent solution (1.3 equivalents) were added. The reaction mixture was stirred at approximately 55°C for approximately 1 hour, then cooled to approximately 22°C and quenched with acetic acid (1.1 equivalents). The organic layer was successively washed with 10% NAC solution (10 volumes), 20% ammonium chloride solution (10 volumes), and 10% brine solution (10 volumes). The organic layer was then concentrated to approximately 3 volumes and then packed with 2-propanol (10 volumes). The obtained solution was filtered and concentrated to approximately 3 volumes, then 2-propanol (3 volumes) was added, followed by water (3 volumes). The resulting slurry was cooled to approximately 0°C and then filtered. The filtered cake was washed with a solution of 2-propanol (1.6 volumes) and water (3 volumes), and then dried to obtain tert-butyl 2-(4,4,7-trimethyl-2-oxochroman-5-yl)acetate. 1 H NMR (400MHz, CDCl3): δ 6.81(s,1H), δ 6.79(s,1H), δ 3.70(s,2H), δ 2.57(s,2H), δ 2.29(s,3H), δ 1.47(s,9H), δ 1.41(s,6H). Step 2.3 Synthesis of 3-(2-(2-(tert-butoxy)-2-oxoethyl)-6-((di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid [ka] 【0435】 1.00 equivalent of tert-butyl 2-(4,4,7-trimethyl-2-oxochroman-5-yl) acetate (scaling factor), 4 equivalents of sodium trimethylsilanolate, 20 volumes of 2-methyltetrahydrofuran, and 0.08 volumes of water were packed into the reactor, followed by 2 equivalents of bromoform and 2 equivalents of di-tert-butyl phosphite. The mixture was stirred at approximately 22°C until the reaction was considered complete. The reaction mixture was washed with 10% potassium dihydrogen phosphate (10 volumes) and 10% brine solution (10 volumes). The organic layer was concentrated under vacuum to approximately 5 volumes and then packed with n-heptane (10 volumes). The resulting slurry was cooled to approximately 0°C and then filtered. The filtered cake was washed with a solution of n-heptane (1.5 vol) and 2-methyltetrahydrofuran (1.5 vol), and then dried to obtain 3-(2-(2-tert-butoxy)-2-oxoethyl)-6-(di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid. 1 H NMR(400MHz,d6-DMSO):δ 11.74(s,1H),7.23(s,1H),6.74(s,1H),3.86(s,2H),2.87(s,2H),2.22(s,3H),1.51(s,6H),1.46(s,18H),1.44(s,9H)ppm. Example 5. Alternative composition of 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid [ka] Step 1. Synthesis of 5-bromo-4,4,7-trimethylchroman-2-one [ka] 【0436】 3-Bromo-5-methylphenol (1.00 equivalent, scaling factor) and 3,3-dimethyl acrylate (1.70 equivalents) were packed into the reactor. The mixture was stirred and adjusted to approximately 10°C. Sulfuric acid (2.00 volume) was added while maintaining the mixture temperature below approximately 35°C. The reaction mixture was heated to approximately 90°C and stirred until the reaction was complete. The mixture was cooled to 0-10°C, dichloromethane (2 volume) was added, and the mixture was stirred for approximately 10 minutes to homogenize it. Water (3 volume) was added to a separate reactor, stirred, and cooled to approximately 10°C. The solution was transferred to pre-cooled water and rinsed with additional dichloromethane (2 volume). The mixture was adjusted to approximately 22°C for at least 30 minutes, and the layers were separated after sedimentation. The organic layer was washed with an aqueous solution of 1.9 wt% sodium hydroxide and 5 wt% sodium chloride (5.4 volume) and 10% brine (5.0 volume). If necessary, the mixture was treated with charcoal by mixing it with charcoal powder (0.03 parts) at 20-30°C for about 45 minutes to remove the dark color, and then filtered through a Celite pad to remove the charcoal. The organic solution was concentrated to about 2 volumes under vacuum using a reactor jacket at a temperature of 50°C or lower. 2-propanol (8 volumes) was added, and the mixture was adjusted to about 65°C and stirred for more than 1 hour. The resulting slurry was cooled to 0-5°C over more than 5 hours. The slurry was filtered, and the wet cake was rinsed twice with n-heptane (3 volumes each rinse). The filtrate was concentrated to about 3 volumes under vacuum at a jacket temperature of 50°C or lower. Water (1 volume) was added, and the mixture was adjusted to about 22°C and stirred for more than 1 hour. Water (2 volumes) was added over more than 1 hour. The slurry was cooled to about 0°C over about 4 hours and stirred for about 5 hours. The slurry was filtered, the wet cake was rinsed with a mixture of water (1 volume) and 2-propanol (2 volumes), and the wet cake was dried to obtain 5-bromo-4,4,7-trimethylchroman-2-one. 1 H NMR (400MHz, CDCl3): δ 7.14 (s, 1H), 6.75 (s, 1H), 2.56 (s, 2H), 2.21 (s, 3H), 1.48 (s 6H) ppm. Step 2: Synthesis of tert-butyl 2-(4,4,7-trimethyl-2-oxochroman-5-yl)acetate [ka] 【0437】 Tetrahydrofuran (15 vol) and zinc granules (20-30 mesh) (4.50 equivalents) were packed into the reactor under nitrogen. The reactor was degassed for 3 cycles by placing it under vacuum and refilling it with nitrogen after each cycle. The mixture was stirred and adjusted to 35-45°C. TMSCl (0.20 equivalents) was packed in, followed by the addition of tert-butyl bromoacetate (1.5 equivalents) while maintaining the reactor at a constant temperature below 50°C. The mixture was adjusted to approximately 40°C and stirred until the reaction was complete. The mixture was adjusted to approximately 22°C. 5-bromo-4,4,7-trimethylchroman-2-one (1.0 equivalent, scaling factor), Pd(dba)2 (0.02 equivalents), and Xphos (0.02 equivalents) were packed in, and the reaction mixture was degassed for 3 cycles by placing the reactor under vacuum and refilling it with nitrogen after each cycle. The mixture was adjusted to approximately 40°C and stirred. After the reaction was complete, the mixture was adjusted to approximately 22°C, transferred to another reactor via a filter, and rinsed with 2-MeTHF (6 volumes). Acetic acid (1.10 equivalents) was added, followed by a 10 wt% aqueous solution of N-acetyl-L-cysteine ​​(10 volumes). The mixture was heated to approximately 50°C for approximately 14 hours, stirred for approximately 14 hours, and then cooled to approximately 22°C. Stirring was stopped, and the aqueous layer was removed after phase separation. The organic layer was sequentially washed with a 33.3 wt% aqueous solution of NH4Cl (6 volumes) and a 10% brine (10 volumes). The organic layer was concentrated to approximately 3 volumes under vacuum at a jacket temperature of 50°C or less. 2-propanol (2 volumes) was added, and the mixture was concentrated again to approximately 3 volumes. The mixture was adjusted to approximately 22°C and diluted with 2.5 volumes of 2-propanol. Water (2.5 vol.) was added over a period of approximately 1.5 hours or more, the mixture was cooled to approximately 0°C over approximately 1 hour, and stirred for approximately 2 hours. The slurry was filtered, and the wet cake was rinsed with a mixture of water (3.0 vol.) and 2-propanol (1.6 vol.). The wet cake was dried under vacuum at 50°C to obtain tert-butyl 2-(4,4,7-trimethyl-2-oxochroman-5-yl)acetate. 1H NMR (400MHz, CDCl3): δ 6.81(s,1H), δ 6.79(s,1H), δ 3.70(s,2H), δ 2.57(s,2H), δ 2.29(s,3H), δ 1.47(s,9H), δ 1.41(s,6H). Step 3. Synthesis of 3-(2-(2-(tert-butoxy)-2-oxoethyl)-6-((di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid [ka] 【0438】 1.00 equivalent of tert-butyl 2-(4,4,7-trimethyl-2-oxochroman-5-yl) acetate (scaling factor), 4 equivalents of sodium trimethylsilanolate, 20 volumes of 2-methyltetrahydrofuran, and 0.08 volumes of water were packed into the reactor, followed by 2 equivalents of bromoform and 2 equivalents of di-tert-butyl phosphite. The mixture was stirred at approximately 22°C until the reaction was considered complete. The reaction mixture was washed with 10% potassium dihydrogen phosphate (10 volumes) and 10% brine solution (10 volumes). The organic layer was concentrated under vacuum to approximately 5 volumes and then packed with n-heptane (10 volumes). The resulting slurry was cooled to approximately 0°C and then filtered. The filtered cake was washed with a solution of n-heptane (1.5 vol) and 2-methyltetrahydrofuran (1.5 vol), and then dried to obtain 3-(2-(2-tert-butoxy)-2-oxoethyl)-6-(di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid. 1 H NMR(400MHz,d6-DMSO):δ 11.74(s,1H),7.23(s,1H),6.74(s,1H),3.86(s,2H),2.87(s,2H),2.22(s,3H),1.51(s,6H),1.46(s,18H),1.44(s,9H)ppm. Step 4: Synthesis of tert-butyl 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-3-((diisopropoxyphosphoryl)oxy)-5-methylphenyl)acetate [ka] 【0439】 3-(2-(2-tert-butoxy)-2-oxoethyl)-6-((di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid (1.10 equivalents), acetonitrile (5.3 equivalents), 1-methylimidazole (7.00 equivalents), and 50 wt% propanephosphonic anhydride (T3P) (T3P, 2.00 equivalents) in acetonitrile were packed into a reactor at 10°C, followed by packing with GS-6207-02 (i.e., 1.00 equivalent, lenacapavir sodium, scaling factor). The mixture was stirred at approximately 10°C until the reaction was considered complete. The reaction mixture was diluted with methyl t-butyl ether (12.8 vol.) and then quenched with 5% aqueous potassium chloride (10 vol.). The two-phase mixture was diluted with cyclohexane (2.6 vol.) and then the organic layer was separated. The organic layer was washed three more times (10.0 vol. each time) with a 5% potassium chloride aqueous solution. The organic layer was evaporated under vacuum to approximately 2.5 vol. The residue was evaporated twice in methyl t-butyl ether (12.2 vol.) to approximately 3.0 vol. The residue was diluted with methyl t-butyl ether (4.1 vol.) and then packed into n-heptane (14.6 vol.). The slurry was stirred at approximately 22°C for approximately 4 hours and then filtered. The filtered cake was washed with n-heptane (7.3 vol.) and then dried to obtain tert-butyl 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3 ,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl)acetate was obtained. 1¹H NMR (400MHz, d6-DMSO, all atropisomers): δ 9.25-8.84 (m,1H), 8.02-6.41 (m,9H), 5.04-4.50 (m,4H), 4.25-2.82 (m,13H), 2.61-2.42 (m,2H), 2.18 (s,3H), 1.75 (s,6H), 1.53-0.92 (m,35H) ppm. 19 1F NMR (377MHz, d6-DMSO, all atropisomers): δ -60.28--60.43 (m,3F), -68.84--69.17 (m,3F), -79.25--80.41 (m,1F), -101.96--103.31 (m,1F), -110.05--110.43 (m,2F) ppm. 31 3P NMR (162MHz, d6-DMSO, all atrop isomers): -16.88, -17.07, -17.18, -17.56 ppm. Step 5. Synthesis of 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid [ka] 【0440】 tert-butyl2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta- 1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl)acetate (1.00 equivalent, scaling factor) and acetonitrile (1.4 volume) were packed into the reactor and adjusted to approximately 10°C. Phosphoric acid (85% by weight, 37 equivalents) was added while maintaining the mixture for approximately 30 minutes, followed by the addition of acetonitrile (0.45 volume). The mixture was stirred at approximately 22°C until the reaction was considered complete. 2-methyltetrahydrofuran (9.4 volume) and cyclohexane (1.9 volume) were added, and the mixture was then washed twice with 3% aqueous NaCl solution (6 volume each time) and once with 4% aqueous NaHSO4 solution (8 volume). The mixture was concentrated under reduced pressure to approximately 3.0 volumes. The residue was co-evaporated with acetonitrile (10.2 volumes) to approximately 3.0 volumes. Acetonitrile (7.9 volumes) was added, the mixture was polish-filtered into another reactor, and then rinsed with acetonitrile (1.8 volumes). The mixture was concentrated under reduced pressure to approximately 3.0 volumes.Trifluoroacetic acid (1.09 equivalents), acetonitrile (1.0 equivalent), and 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrrole-1-yl)acetamide)-2-(3,5-difluoro Phenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid (0.0014 equivalents) was added, and the mixture was stirred for about 18 hours. Di-n-butyl ether (8.1 volume) was added over about 2 hours at about 22°C, and the resulting slurry was stirred for about 24 hours. The slurry is filtered, the filter cake is rinsed with a mixture of acetonitrile (1.0 vol) and di-n-butyl ether (2.3 vol), and then dried to obtain 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyra (Zol-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid was obtained. 11H NMR (400 MHz, d6-DMSO, major atropisomer): δ 9.18 (d, 1H, J = 8.2 Hz), 9.16 (m, 1H), 7.87 (d, 1H, J = 8.0 Hz), 7.83 (d, 1H, J = 8.1 Hz), 7.77 (d, 1H, J = 8.3 Hz), 7.75 (m, 1H), 7.44 (d, 1H, J = 7.7 Hz), 7.36 (d, 1H, J = 7.7 Hz), 7.15 (s, 1H), 7.02 (m, 1H), 7.01 (m, 1H), 6.66 (s, 1H), 6.63 (s, 1H), 6.61 (m, 1H), 6.48 (m, 2H), 4.93 (d, 1H, J = 16.4 Hz), 4.85 (d, 1H, J = 16.5 Hz), 4.77 (m, 1H), 4.76 (d, 1H, J = 16.7 Hz), 4.71 (m, 1H), 4.68 (m, 1H), 4.66 (d, 1H, J = 16.4 Hz), 4.63 (m, 1H), 4.24 (dq, 1H, J = 16.3, 8.2 Hz), 4.01 (dq, 1H, J = 16.4, 8.1 Hz), 3.87 (d, 1H, J = 17.7 Hz), 3.86 (d, 1H, J = 17.5 Hz), 3.72 (d, 1H, J = 17.8 Hz), 3.59 (d, 1H, J = 17.7 Hz), 3.48 (s, 3H), 3.46 (s, 3H), 3.44 (br m, 1H), 3.27 (s, 3H), 3.27 (s, 3H), 3.22 (br m, 1H), 3.06 (dd, 1H, J = 13.5, 7.2 Hz), 2.99 (m, 1H), 2.57 (m, 1H), 2.53 (m, 1H), 2.53 (m, 1H), 2.18 (s, 3H), 1.75 (s, 3H), 1.75 (s, 3H), 1.75 (s, 3H), 1.75 (s, 3H), 1.45 (s, 3H), 1.38 (m, 1H), 1.34 (s, 3H), 1.30 (s, 3H), 1.18 (s, 3H), 1.02 (m, 1H), 0.97 (m, 1H). 13C NMR (101MHz, d6-DMSO, main non-isotropic form): δ 173.7,173.6,171.8,171.6,164.6,164.4,162.1,158.8,158.5,150.7,142.8 ,142.7,142.4,142.1,141.9,141.7,140.0,139.6,139.3,137.6,134.9,134.6 ,134.5,134.5,134.0,133.7,132.5,132.2,132.2,132.0,131.8,131.3,130.5,130.3,129.9,129.8,126.9,126.7,125.6,125.5,123.1,122.8,122.8,120. 7,120.7,120.0,119.9,119.7,119.6,119.4,119.2,118.8,118.7,112.1,102.2,88.5,88.3,84.5,57.3,57.3,53.2,53.0,53.0,52.7,52.7,52.1,50.8,50. 8,50.4,50.4,47.3,42.2,42.2,42.0,42.0,41.6,41.5,39.7,39.2,35.1,35.1,30.6,30.3,30.3,30.2,27.6,23.2,22.4,22.4,22.3,22.3,20.0,11.7,11.6. 19 F NMR (376MHz, d6-DMSO, main atropion anisotropy): δ -60.32(s, 3F), -60.38(s, 3F), -68.98(t, 3F, J=8.2Hz), -69.22(t, 3F, J=8.3Hz), -79.59(dd, 1F, J=253.6, 12.7Hz), -80.00(m, 1F), -101.82(m, 1F), -103.03(dd, 1F, J=253.6, 9.6Hz), -109.96(m, 2F), -110.06(m, 2F). 31 P NMR (162MHz, d6-DMSO, main atropion variant): δ -7.10(s, 1P), -7.14(s, 1P). IR (ATR): 2931, 1735, 1624-1477, 1448, 1381-1315, 1259-1107, 1057-1032 cm⁻¹ -1 HRMS(ESI)[M+Na] + C 53 H 49 ClF10 N7NaO 12 PS2 + Calculated value: 1318.20393, measured value: 1318.20239. Example 6. Alternative composition of 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid [ka] Step 1. Synthesis of 5-bromo-4,4,7-trimethylchroman-2-one [ka] 【0441】 3-Bromo-5-methylphenol (1.00 equivalent, scaling factor) and 3,3-dimethyl acrylate (1.70 equivalents) were packed into the reactor. The mixture was stirred and adjusted to approximately 10°C. Sulfuric acid (2.00 volume) was added while maintaining the mixture temperature below approximately 35°C. The reaction mixture was heated to approximately 90°C and stirred until the reaction was complete. The mixture was cooled to 0 to -10°C, dichloromethane (2 volume) was added, and the mixture was stirred for approximately 10 minutes to homogenize it. Water (3 volume) was added to a separate reactor, stirred, and cooled to approximately 10°C. The solution was transferred to pre-cooled water and rinsed with additional dichloromethane (2 volume). The mixture was adjusted to approximately 22°C for at least 30 minutes, and the layers were separated after sedimentation. The organic layer was washed with an aqueous solution of 1.9 wt% sodium hydroxide and 5 wt% sodium chloride (5.4 volume) and 10% brine (5.0 volume). If necessary, the mixture was treated with charcoal by mixing it with charcoal powder (0.03 parts) at 20-30°C for about 45 minutes to remove the dark color, and then filtered through a Celite pad to remove the charcoal. The organic solution was concentrated to about 2 volumes under vacuum using a reactor jacket at a temperature of 50°C or lower. 2-propanol (8 volumes) was added, and the mixture was adjusted to about 65°C and stirred for more than 1 hour. The resulting slurry was cooled to 0-5°C over more than 5 hours. The slurry was filtered, and the wet cake was rinsed twice with n-heptane (3 volumes each rinse). The filtrate was concentrated to about 3 volumes under vacuum at a jacket temperature of 50°C or lower. Water (1 volume) was added, and the mixture was adjusted to about 22°C and stirred for more than 1 hour. Water (2 volumes) was added over more than 1 hour. The slurry was cooled to about 0°C over about 4 hours and stirred for about 5 hours. The slurry was filtered, the wet cake was rinsed with a mixture of water (1 volume) and 2-propanol (2 volumes), and the wet cake was dried to obtain 5-bromo-4,4,7-trimethylchroman-2-one. 1 H NMR (400MHz, CDCl3): δ 7.14 (s, 1H), 6.75 (s, 1H), 2.56 (s, 2H), 2.21 (s, 3H), 1.48 (s 6H) ppm. Step 2. Synthesis of 4,4,7-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-2-one [ka] 【0442】 The reactor was packed with 5-bromo-4,4,7-trimethylchroman-2-one (1.00 equivalent, scaling factor), bis(pinacolate)diborone (1.3 equivalents), potassium propanoate (2.9 equivalents), and isopropyl acetate (12 volumes). The mixture was distilled under vacuum at a jacket temperature of 45°C to 3 volumes. Then, isopropyl acetate (9 volumes) was added, and the distillation was repeated under vacuum to a concentration of 3 volumes. Next, isopropyl acetate (9 volumes) was added, followed by bis(dibenzylideneacetone)dipalladium (0) (0.015 equivalents) and triphenylphosphine (0.015 equivalents). The mixture was degassed three times, with the reactor placed under vacuum for approximately 30 seconds each time, and then filled with nitrogen to atmospheric pressure. The reaction mixture was then stirred at approximately 85°C for approximately 21 hours. After the reaction was complete, the mixture was cooled to approximately 60°C and a solution of N-acetylcysteine ​​(0.1 part) in water (9 vols) was added. The mixture was adjusted to approximately 60°C and stirred for approximately 12 hours. The mixture was then cooled to approximately 22°C, followed by stopping the stirring, allowing it to settle and separate into layers. The organic layer was washed with a solution of sodium chloride (1 part) in water (9 vols). The organic layer was filtered, concentrated to approximately 3 vols, and diluted with ethanol (10 vols). The mixture was concentrated to 3 vols under vacuum and diluted with ethanol (1 vols). Water (1.5 vols) was added, the resulting slurry was cooled to approximately 0°C, and then filtered. The filtered cake was washed with a mixture of ethanol (2 vols) and water (1 vols), and then with n-heptane (2 vols). The wet case was dried to obtain 4,4,7-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-2-one. 1 H NMR (400MHz, d6-DMSO): δ 7.12(s,1H), δ 6.89(s,1H), δ 2.55(s,2H), δ 2.31(s,3H), δ 1.45(s,6H), δ 1.38(s,12H). Step 3. Synthesis of tert-butyl 2-(4,4,7-trimethyl-2-oxochroman-5-yl)acetate [ka] 【0443】 The reactor was packed with 4,4,7-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-2-one (1.00 equivalent, scaling factor), tribasic potassium phosphate (4 equivalents), bis(dibenzylideneacetone)palladium (0) (0.033 equivalents), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (Ph-PA, 0.06 equivalents), isopropyl acetate (11.4 vol.), tert-butyl bromoacetate (2.5 vol.), and water (2 vol.). The reaction mixture was stirred at approximately 81°C for approximately 2 hours, and then cooled to approximately 22°C. The organic layer was successively washed with 10% N-acetyl-L-cysteine ​​(NAC) solution (10 vols), 20% ammonium chloride solution (10 vols), and 10% brine solution (10 vols). The organic layer was then concentrated to approximately 3 vols and then packed with 2-propanol (10 vols). The resulting solution was filtered and concentrated to approximately 3 vols, then 2-propanol (3 vols) followed by water (2.5 vols). The resulting slurry was cooled to approximately 0°C and then filtered. The filtered cake was washed with a solution of 2-propanol (2.5 vols) and water (4 vols) and then dried to obtain tert-butyl 2-(4,4,7-trimethyl-2-oxochroman-5-yl) acetate. 1 H NMR (400MHz, CDCl3): δ 6.81(s,1H), δ 6.79(s,1H), δ 3.70(s,2H), δ 2.57(s,2H), δ 2.29(s,3H), δ 1.47(s,9H), δ 1.41(s,6H). Step 4. Synthesis of 3-(2-(2-(tert-butoxy)-2-oxoethyl)-6-((di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid [ka] 【0444】 1.00 equivalent of tert-butyl 2-(4,4,7-trimethyl-2-oxochroman-5-yl) acetate (scaling factor), 4 equivalents of sodium trimethylsilanolate, 20 volumes of 2-methyltetrahydrofuran, and 0.08 volumes of water were packed into the reactor, followed by 2 equivalents of bromoform and 2 equivalents of di-tert-butyl phosphite. The mixture was stirred at approximately 22°C until the reaction was considered complete. The reaction mixture was washed with 10% potassium dihydrogen phosphate (10 volumes) and 10% brine solution (10 volumes). The organic layer was concentrated under vacuum to approximately 5 volumes and then packed with n-heptane (10 volumes). The resulting slurry was cooled to approximately 0°C and then filtered. The filtered cake was washed with a solution of n-heptane (1.5 vol) and 2-methyltetrahydrofuran (1.5 vol), and then dried to obtain 3-(2-(2-tert-butoxy)-2-oxoethyl)-6-(di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid. 1 H NMR(400MHz,d6-DMSO):δ 11.74(s,1H),7.23(s,1H),6.74(s,1H),3.86(s,2H),2.87(s,2H),2.22(s,3H),1.51(s,6H),1.46(s,18H),1.44(s,9H)ppm. Step 5: Synthesis of tert-butyl 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl)acetate [ka] 【0445】 3-(2-(2-tert-butoxy)-2-oxoethyl)-6-(di-tert-butoxyphosphoryl)oxy)-4-methylphenyl)-3-methylbutanoic acid (1.10 equivalents), acetonitrile (5.3 equivalents), 1-methylimidazole (7.00 equivalents), and 50 wt% propanephosphonic anhydride (T3P) in acetonitrile (T3P, 2.00 equivalents) were packed into a reactor at 10°C, followed by packing with GS-6207-02 (i.e., 1.00 equivalent of lenacapavir sodium, scaling factor). The mixture was stirred at approximately 10°C until the reaction was considered complete. The reaction mixture was diluted with methyl t-butyl ether (12.8 vol.) and then quenched with 5% aqueous potassium chloride (10 vol.). The two-phase mixture was diluted with cyclohexane (2.6 vol.) and then the organic layer was separated. The organic layer was washed three more times (10.0 vol. each time) with a 5% potassium chloride aqueous solution. The organic layer was evaporated under vacuum to approximately 2.5 vol. The residue was evaporated twice in methyl t-butyl ether (12.2 vol.) to approximately 3.0 vol. The residue was diluted with methyl t-butyl ether (4.1 vol.) and then packed into n-heptane (14.6 vol.). The slurry was stirred at approximately 22°C for approximately 4 hours and then filtered. The filtered cake was washed with n-heptane (7.3 vol.) and then dried to obtain tert-butyl 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3 ,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl)acetate was obtained. 1¹H NMR (400MHz, d6-DMSO, all atropisomers): δ 9.25-8.84 (m,1H), 8.02-6.41 (m,9H), 5.04-4.50 (m,4H), 4.25-2.82 (m,13H), 2.61-2.42 (m,2H), 2.18 (s,3H), 1.75 (s,6H), 1.53-0.92 (m,35H) ppm. 19 1F NMR (377MHz, d6-DMSO, all atropisomers): δ -60.28--60.43 (m,3F), -68.84--69.17 (m,3F), -79.25--80.41 (m,1F), -101.96--103.31 (m,1F), -110.05--110.43 (m,2F) ppm. 31 3P NMR (162MHz, d6-DMSO, all atrop isomers): -16.88, -17.07, -17.18, -17.56 ppm. Step 6. Synthesis of 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid [ka] 【0446】 tert-butyl2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta- 1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-3-((di-tert-butoxyphosphoryl)oxy)-5-methylphenyl)acetate (1.00 equivalent, scaling factor) and acetonitrile (1.4 volume) were packed into the reactor and adjusted to approximately 10°C. Phosphoric acid (85% by weight, 37 equivalents) was added while maintaining the mixture for approximately 30 minutes, followed by the addition of acetonitrile (0.45 volume). The mixture was stirred at approximately 22°C until the reaction was considered complete. 2-methyltetrahydrofuran (9.4 volume) and cyclohexane (1.9 volume) were added, and the mixture was then washed twice with 3% aqueous NaCl solution (6 volume each time) and once with 4% aqueous NaHSO4 solution (8 volume). The mixture was concentrated under reduced pressure to approximately 3.0 volumes. The residue was co-evaporated with acetonitrile (10.2 volumes) to approximately 3.0 volumes. Acetonitrile (7.9 volumes) was added, the mixture was polish-filtered into another reactor, and then rinsed with acetonitrile (1.8 volumes). The mixture was concentrated under reduced pressure to approximately 3.0 volumes.Trifluoroacetic acid (1.09 equivalents), acetonitrile (1.0 equivalent), and 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrrole-1-yl)acetamide)-2-(3,5-difluoro Phenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid (0.0014 equivalents) was added, and the mixture was stirred for about 18 hours. Di-n-butyl ether (8.1 volume) was added over about 2 hours at about 22°C, and the resulting slurry was stirred for about 24 hours. The slurry is filtered, the filter cake is rinsed with a mixture of acetonitrile (1.0 vol) and di-n-butyl ether (2.3 vol), and then dried to obtain 2-(2-(4-(N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyra (Zol-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)methylsulfonamide)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid was obtained. 11H NMR (400 MHz, d6-DMSO, major atropisomer): δ 9.18 (d, 1H, J = 8.2 Hz), 9.16 (m, 1H), 7.87 (d, 1H, J = 8.0 Hz), 7.83 (d, 1H, J = 8.1 Hz), 7.77 (d, 1H, J = 8.3 Hz), 7.75 (m, 1H), 7.44 (d, 1H, J = 7.7 Hz), 7.36 (d, 1H, J = 7.7 Hz), 7.15 (s, 1H), 7.02 (m, 1H), 7.01 (m, 1H), 6.66 (s, 1H), 6.63 (s, 1H), 6.61 (m, 1H), 6.48 (m, 2H), 4.93 (d, 1H, J = 16.4 Hz), 4.85 (d, 1H, J = 16.5 Hz), 4.77 (m, 1H), 4.76 (d, 1H, J = 16.7 Hz), 4.71 (m, 1H), 4.68 (m, 1H), 4.66 (d, 1H, J = 16.4 Hz), 4.63 (m, 1H), 4.24 (dq, 1H, J = 16.3, 8.2 Hz), 4.01 (dq, 1H, J = 16.4, 8.1 Hz), 3.87 (d, 1H, J = 17.7 Hz), 3.86 (d, 1H, J = 17.5 Hz), 3.72 (d, 1H, J = 17.8 Hz), 3.59 (d, 1H, J = 17.7 Hz), 3.48 (s, 3H), 3.46 (s, 3H), 3.44 (br m, 1H), 3.27 (s, 3H), 3.27 (s, 3H), 3.22 (br m, 1H), 3.06 (dd, 1H, J = 13.5, 7.2 Hz), 2.99 (m, 1H), 2.57 (m, 1H), 2.53 (m, 1H), 2.53 (m, 1H), 2.18 (s, 3H), 1.75 (s, 3H), 1.75 (s, 3H), 1.75 (s, 3H), 1.75 (s, 3H), 1.45 (s, 3H), 1.38 (m, 1H), 1.34 (s, 3H), 1.30 (s, 3H), 1.18 (s, 3H), 1.02 (m, 1H), 0.97 (m, 1H). 13C NMR (101MHz, d6-DMSO, main non-isotropic form): δ 173.7,173.6,171.8,171.6,164.6,164.4,162.1,158.8,158.5,150.7,142.8 ,142.7,142.4,142.1,141.9,141.7,140.0,139.6,139.3,137.6,134.9,134.6 ,134.5,134.5,134.0,133.7,132.5,132.2,132.2,132.0,131.8,131.3,130.5,130.3,129.9,129.8,126.9,126.7,125.6,125.5,123.1,122.8,122.8,120. 7,120.7,120.0,119.9,119.7,119.6,119.4,119.2,118.8,118.7,112.1,102.2,88.5,88.3,84.5,57.3,57.3,53.2,53.0,53.0,52.7,52.7,52.1,50.8,50. 8,50.4,50.4,47.3,42.2,42.2,42.0,42.0,41.6,41.5,39.7,39.2,35.1,35.1,30.6,30.3,30.3,30.2,27.6,23.2,22.4,22.4,22.3,22.3,20.0,11.7,11.6. 19 F NMR (376MHz, d6-DMSO, main atropion anisotropy): δ -60.32(s, 3F), -60.38(s, 3F), -68.98(t, 3F, J=8.2Hz), -69.22(t, 3F, J=8.3Hz), -79.59(dd, 1F, J=253.6, 12.7Hz), -80.00(m, 1F), -101.82(m, 1F), -103.03(dd, 1F, J=253.6, 9.6Hz), -109.96(m, 2F), -110.06(m, 2F). 31 P NMR (162MHz, d6-DMSO, main atropion variant): δ -7.10(s, 1P), -7.14(s, 1P). IR (ATR): 2931, 1735, 1624-1477, 1448, 1381-1315, 1259-1107, 1057-1032 cm⁻¹ -1 HRMS(ESI)[M+Na] + C 53 H 49 ClF10 N7NaO 12 PS2 + Calculated value: 1318.20393, measured value: 1318.20239. Example 7. Synthesis of ethyl 5-hydroxy-4,7-dimethyl-2-oxo-2H-chromene-3-carboxylate [ka] 【0447】 1-(2,6-dihydroxy-4-methylphenyl)ethane-1-one (1.00 equivalent, scaling factor) and DBU (3.8 volume) were packed into the reactor. Diethyl malonate (1.40 equivalent) was added dropwise. The reaction mixture was stirred at approximately 100°C for approximately 14 hours. An additional 0.60 equivalent of diethyl malonate was added, and the reaction mixture was stirred at approximately 100°C for approximately 2 hours. The reaction mixture was acidified by adding a 1 M aqueous solution. It was washed with HCl (25 volume) and then diluted with water (50 volume). The resulting slurry was filtered, and the residue was dried overnight in a vacuum oven at approximately 45°C to obtain a crude solid. The crude solid was purified by column chromatography on silica gel to obtain ethyl 5-hydroxy-4,7-dimethyl-2-oxo-2H-chromene-3-carboxylate. 1 H NMR(300MHz,DMSO-d6):δ 10.85(s,1H),6.71-6.66(m,1H),6.65-6.60(m,1H),4.30(q,J=7.2Hz,2H),2.53(s,3H),2.30(s,3H),1.28(t,J=7.1Hz,3H). Example 8. Synthesis of ethyl 5-hydroxy-4,4,7-trimethyl-2-oxochroman-3-carboxylate [ka] 【0448】 LiCl (8.50 equivalents) was placed in the reactor. The LiCl was dried under vacuum while being heated for about 3 minutes. CuI (6.00 equivalents) and dry THF (38.2 vols) were added under N2. The slurry was stirred at room temperature for about 10 minutes until the solid dissolved. The flask was cooled to about -40°C. A solution of 3.4 M MeMgBr in 2-MeTHF (8.2 equivalents) was added dropwise via syringe and stirred for about 10 minutes. 5-hydroxy-4,7-dimethyl-2-oxo-2H-chromene-3-carboxylate ethyl (1.00 equivalent, scaling factor) was dissolved in dry THF (38.1 vols), and the solution was added dropwise via an addition funnel over about 1 hour. The reaction mixture was stirred at about -40°C for about 5 minutes and then allowed to warm naturally by removing the dry ice. The reaction was quenched by adding saturated NH4Cl aqueous solution (11.5 vol), acetone (7.6 vol), toluene (19 vol), and water (7.6 vol). The resulting mixture was stirred for approximately 1 hour. The deep blue aqueous layer was extracted with toluene. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel column chromatography to provide ethyl 5-hydroxy-4,4,7-trimethyl-2-oxochroman-3-carboxylate. 1 H NMR(300MHz,DMSO-d6)δ 9.70(s,1H),6.48-6.41(m,1H),6.39-6.33(m,1H),4.11(qd,J=7.1,0.7Hz,2H ),3.79(s,1H),2.17(s,3H),1.45(s,3H),1.39(s,3H),1.14(t,J=7.1Hz,3H). Example 9. Synthesis of 5-hydroxy-4,4,7-trimethylchroman-2-one [ka] 【0449】 The reactor was packed with ethyl 5-hydroxy-4,4,7-trimethyl-2-oxochroman-3-carboxylate (1.00 equivalent, scaling factor) and acetone (6.2 volume). 16.9 volume of 37% aqueous solution HCl was added, and the reaction mixture was refluxed for approximately 7 hours, followed by stirring overnight at room temperature. The mixture was extracted three times with ethyl HCl. The combined organic layers were washed with saturated aqueous solution NaHCO3, dried over Na2SO4, and evaporated to dryness to obtain 5-hydroxy-4,4,7-trimethylchroman-2-one. 1 H NMR (300MHz, DMSO-d6) δ 9.63 (s, 1H), 6.46-6.39 (m, 1H), 6.35-6.28 (m, 1H), 2.62 (s, 2H), 2.16 (s, 3H), 1.34 (s, 6H). Example 10. Synthesis of 4,4,7-trimethyl-2-oxochroman-5-yltrifluoromethanesulfonate [ka] 【0450】 The reactor was packed with 5-hydroxy-4,4,7-trimethylchroman-2-one (1.00 equivalent, scaling factor) and dry DCM (22.7 vol). Pyridine (2.00 equivalent) was added at approximately 0°C, followed by dropwise addition of Tf2O (1.50 equivalent). The reaction mixture was stirred at approximately 22°C for approximately 1.5 hours. The mixture was washed with 1 M aqueous HCl, aqueous saturated NaHCO3, and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel to provide 4,4,7-trimethyl-2-oxochroman-5-yltrifluoromethanesulfonate. 1 ¹H NMR (300 MHz, chloroform-d) δ 6.96-6.88 (m, 2H), 2.62 (s, 2H), 2.37 (s, 3H), 1.49 (s, 6H). 19 F NMR (282 MHz, chloroform-d) δ-73.74. Example 11. Alternative synthesis of tert-butyl 2-(4,4,7-trimethyl-2-oxochroman-5-yl)acetate [ka] 【0451】 Formation of zinc enolate: A reactor equipped with a magnetic stirring rod, N2 inlet and outlet, and a condenser was filled with Zn powder (1.70 equivalents). The flask was flushed with N2 for about 15 minutes. Dry THF (100 volts) was added and the slurry was heated to about 35°C. Tert-butyl-2-bromoacetic acid (0.050 equivalents) was added all at once, followed by the dropwise addition of a 25% DIBAL-H solution in toluene (0.040 equivalents). The reaction mixture was stirred at about 35°C for 15 minutes. The reaction mixture was then heated to about 40°C. While maintaining the temperature of the contents below 50°C, tert-butyl-2-bromoacetic acid (1.00 equivalent, scaling factor) was added dropwise. After the addition was complete, the reaction mixture was stirred overnight at about 40°C. Stirring was stopped and the mixture was cooled to about 22°C. The excess Zn powder settled at the bottom, and aliquots of the clear solution at the top were titrated with I2-LiCl / THF solution. 【0452】 Negishi Coupling: The reactor was packed with 4,4,7-trimethyl-2-oxochroman-5-yltrifluoromethanesulfonate (1.00 equivalent, scaling factor), Pd(OAc)2 (0.050 equivalent), XPhos (0.050 equivalent), and dry THF (11.8 vol). The mixture was degassed under vacuum and repacked three times with N2. Zinc enolate solution (2.50 equivalent) was added dropwise at approximately 22°C. The reaction mixture was stirred at approximately 55°C for approximately 2 hours. After the reaction was complete, the mixture was quenched with water, 1 M aqueous HCl solution, ethyl acetate, and brine. The mixture was filtered. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by column chromatography on silica gel to obtain tert-butyl 2-(4,4,7-trimethyl-2-oxochroman-5-yl)acetate. 1¹H NMR (300 MHz, chloroform-d) δ: 6.83-6.80 (m, 1H), 6.80-6.77 (m, 1H), 3.70 (s, 2H), 2.58 (s, 2H), 2.30 (t, J=0.7Hz, 3H), 1.47 (s, 9H), 1.42 (s, 6H). 13 ¹³C NMR (75MHz, chloroform-d) δ 170.97, 168.19, 151.59, 137.79, 132.35, 130.51, 127.18, 117.47, 81.23, 45.70, 41.58, 34.74, 27.99, 27.76, 20.57. Other Embodiments 1. In some embodiments, this disclosure relates to formula XIII: [ka] A process for preparing a compound or salt thereof of formula XIV: [ka] The first mixture is formed by reacting the compound or salt thereof with an activator in the presence of zinc and an alkali metal halide. The first mixture and formula XI-a: [ka] The process involves mixing a compound or a salt thereof in the presence of a coupling catalyst, wherein the formula includes, X 1 But it's a halo, R 1 However, C 1~6 It provides an alkyl process. 2. The process according to Embodiment 1, wherein the activator is selected from the group consisting of diisobutylaluminum hydride, trimethylsilyl chloride, triethylsilyl chloride, trimethylsilyl iodide, dibromoethane, dichloroethane, and iodine. 3. The process according to Embodiment 1, wherein the activator is diisobutylaluminum hydride. 4. The process according to any one of Embodiments 1 to 3, wherein the alkali metal halide is lithium chloride. 5. The process according to any one of Embodiments 1 to 4, wherein the coupling catalyst comprises a palladium catalyst. 6. The process according to any one of Embodiments 1 to 5, wherein the coupling catalyst comprises a palladium catalyst and a phosphine ligand. 7. The process according to Embodiment 5 or 6, wherein the palladium catalyst is selected from the group consisting of palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate, tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. 8. The process according to Embodiment 6 or 7, wherein the phosphine ligand is selected from the group consisting of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tricyclohexylphosphine, tri-tert-butylphosphine, triphenylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and ethylenebis(diphenylphosphine). 9. The process according to any one of Embodiments 1 to 6, wherein the coupling catalyst comprises palladium(II) acetate and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. 10. The process according to any one of Embodiments 1 to 9, wherein the mixing of the first mixture and the compound of formula XI-a is carried out at a temperature of about 0°C to about 100°C. 11. The process according to any one of Embodiments 1 to 10, wherein the mixing of the first mixture and the compound of formula XI-a is carried out in a solvent containing tetrahydrofuran and 2-methyltetrahydrofuran. 12. The compound of formula XIV is, formula XIV-a: [ka] The process according to any one of Embodiments 1 to 11, wherein the compound is or a salt thereof. 13. The compound of formula XIII is, formula XIII-a: [ka] The process according to any one of Embodiments 1 to 12, wherein the compound is or a salt thereof. 14. Phosphorylate the compound of formula XIII or its salt to obtain formula IV: [ka] The further comprising forming a compound or salt thereof, wherein each R 2 However, independently, C 1~6 A process according to any one of embodiments 1 to 13, selected from the group consisting of alkyl groups. 15. The process according to Embodiment 14, wherein phosphorylation comprises reacting a compound of formula XIII or a salt thereof with a phosphorylating agent in the presence of an optionally selected oxidizing agent and a base. 16. The process according to Embodiment 15, wherein the phosphorylating agent is selected from the group consisting of di-tert-butyl phosphite, di-tert-butyl phosphoryl chloride, di-tert-butyl phosphoryl bromide, di-ethyl phosphoryl chloride, di-isopropyl phosphoryl chloride, dibenzyl phosphorochloride, and dibenzyl phosphorobromide. 17. The process according to Embodiment 15, wherein the phosphorylating agent is di-tert-butyl phosphite. 18. The process according to any one of Embodiments 15 to 17, wherein the oxidizing agent is selected from the group consisting of bromoform, carbon tetrabromide, carbon tetrachloride, dibromomethane, dibromoethane, bromotrichloromethane, N-chlorosuccinimide, N-bromosuccinimide, sodium N-chlorotosylamide, bromine, chlorine, iodine, and sodium hypochlorite. 19. The process according to any one of embodiments 15 to 17, wherein the oxidizing agent is bromoform. 20. The process according to any one of Embodiments 15 to 19, wherein the base is selected from the group consisting of sodium trimethylsilanolate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium tert-butoxide, sodium hydride, and cesium carbonate. 21. The process according to any one of Embodiments 15 to 19, wherein the base is sodium trimethylsilanolate. 22. The process according to any one of embodiments 14 to 21, wherein the phosphorylation is carried out at a temperature of approximately 0°C to approximately 40°C. 23. The process according to any one of Embodiments 14 to 22, wherein the phosphorylation is carried out in a solvent containing 2-methyltetrahydrofuran and water. 24. Each R 2 The process according to any one of embodiments 14 to 23, wherein the tert-butyl is used. 25. The compound of formula IV, formula IV-a: [ka] The process according to any one of Embodiments 14 to 24, wherein the compound is or a salt thereof. 26. In some embodiments, the present disclosure is based on formula VI: [ka] A process for preparing a compound or salt thereof of formula VII: [ka] The compound or salt thereof and di(C1~6 The process involves reacting an alkyl phosphite with an oxidizing agent and a base, in which, R 1 However, C 1~6 It is alkyl, Each R 2 However, independently, C 1~6 Selected from the group consisting of alkyl groups, Each R 3 However, independently, C 1~6 The process is provided, selected from the group consisting of alkyl groups. 27. Ji (C 1~6 The process according to Embodiment 26, wherein the alkyl) phosphite is di-tert-butyl phosphite. 28. The process according to Embodiment 26 or 27, wherein the oxidizing agent is selected from the group consisting of bromoform, carbon tetrabromide, carbon tetrachloride, dibromomethane, dibromoethane, bromotrichloromethane, N-chlorosuccinimide, N-bromosuccinimide, sodium N-chlorotosylamide, bromine, chlorine, iodine, and sodium hypochlorite. 29. The process according to embodiment 26 or 27, wherein the oxidizing agent is bromoform. 30. The process according to any one of Embodiments 26 to 29, wherein the base is selected from the group consisting of cesium carbonate, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, 1-methylimidazole, and sodium hydride. 31. The process according to any one of embodiments 26 to 29, wherein the base is cesium carbonate. 32. The process according to any one of embodiments 26 to 31, wherein the reaction is carried out at a temperature of approximately -20°C to approximately 100°C. 33. The process according to any one of embodiments 26 to 32, wherein the reaction is carried out in a solvent containing tetrahydrofuran. 34. The compound of formula VI is, formula VI-a: [ka] The process according to any one of embodiments 26 to 33, wherein the compound is or a salt thereof. 35. In some embodiments, the present disclosure is based on formula VI: [ka] A process for preparing a compound or salt thereof of formula VII: [ka] A compound or salt thereof, and tetra(C 6~10 Aryl-C 1~6 Alkyl-)pyrophosphate or (R 4 O)2P(=O)-LG 2 This involves reacting the two in the presence of a base, in the formula, R 1 However, C 1~6 It is alkyl, Each R 2 However, independently, C 6~10 Aryl-C 1~6 Selected from the group consisting of alkyl groups, Each R 3 However, independently, C 1~6 Selected from the group consisting of alkyl groups, Each R 4 However, independently, C 6~10 Aryl-C 1~6 Independently selected from the group consisting of alkyls, LG 2 The present invention provides a process selected from the group consisting of halo and 4-methylbenzylsulfonyloxy. 36. Tetra (C 6~10 Aryl-C 1~6 The process according to Embodiment 35, wherein the alkyl-)pyrophosphate is tetrabenzylpyrophosphate. 37. The process according to Embodiment 35, wherein each R4 is benzyl. 38. The process of Embodiment 35, wherein LG is selected from the group consisting of chloro, bromo, iodine, and 4-methylbenzylsulfonyloxy. 39. The process according to any one of embodiments 35 to 38, wherein the base is selected from the group consisting of sodium hydride, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, and 1-methylimidazole. 40. The process according to any one of embodiments 35 to 38, wherein the base is sodium hydride. 41. The process according to any one of embodiments 35 to 40, wherein the reaction is carried out at a temperature of approximately -40°C to approximately 100°C. 42. The process according to any one of embodiments 35 to 41, wherein the reaction is carried out in a solvent containing tetrahydrofuran. 43. The compound of formula VI is, formula VI-b: [ka] The process according to any one of embodiments 35 to 42, wherein the compound is or a salt thereof. 44. In some embodiments, the present disclosure is based on formula VI: [ka] A process for preparing a compound or salt thereof of formula VII: [ka] The compound or salt thereof and di(C 1~6 Alkyl)N,N-di(C 1~6The alkyl phosphoramide is reacted with a base and an acid to form a first mixture. The process includes mixing a first mixture with an oxidizing agent, in which, R 1 However, C 1~6 It is alkyl, Each R 2 However, independently, C 1~6 Selected from the group consisting of alkyl groups, Each R 3 However, independently, C 1~6 The process is provided, selected from the group consisting of alkyl groups. 45. Ji (C 1~6 Alkyl)N,N-di(C 1~6 The process according to Embodiment 44, wherein the alkyl)phosphoramide is di-tert-butyl N,N-diisopropylphosphoramide. 46. ​​The process according to Embodiment 44 or 45, wherein the base is selected from the group consisting of 1-methylimidazole, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, and colidine. 47. The process according to Embodiment 44 or 45, wherein the base is 1-methylimidazole. 48. The process according to any one of Embodiments 44 to 47, wherein the acid is selected from the group consisting of trifluoroacetic acid, trichloroacetic acid, formic acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, 1H-tetrazole, 5-phenyltetrazole, benzylthiotetrazole, ethylthiotetrazole, 2,4-dinitrophenol, 4-cyanophenol, 2-bromo-4,5-dicyanoimidazole, 4,5-dicyanoimidazole, and saccharin. 49. The process according to any one of embodiments 44 to 47, wherein the base is trifluoroacetic acid. 50. The process according to any one of Embodiments 44 to 49, wherein the oxidizing agent is selected from the group consisting of hydrogen peroxide, N-chlorosuccinimide, N-bromosuccinimide, N-chlorotosylamide sodium salt, bromine, chlorine, iodine, sodium hypochlorite), sodium peroxide, tert-butyl hydrogen peroxide, sodium perborate, and potassium peroxymonosulfate. 51. The process according to any one of embodiments 44 to 49, wherein the oxidizing agent is hydrogen peroxide. 52. The process according to any one of embodiments 44 to 51, wherein the reaction is carried out at a temperature of approximately -20°C to approximately 100°C. 53. The process according to any one of Embodiments 44 to 52, wherein the reaction is carried out in a solvent containing tetrahydrofuran and water. 54. The compound of formula VI is, formula VI-a: [ka] The process according to any one of embodiments 44 to 53, wherein the compound is or a salt thereof. 55. The compound of formula VII is, formula VII-a: [ka] The process according to any one of embodiments 26 to 54, wherein the compound is or a salt thereof. 56. Deprotect the compound of formula VI or its salt to obtain formula V: [ka] The process according to any one of embodiments 26 to 55, further comprising forming a compound or a salt thereof. 57. The process according to Embodiment 56, wherein deprotection comprises reacting a compound of formula VI or a salt thereof with a deprotecting agent selected from the group consisting of tetrabutylammonium fluoride, potassium hydrogen fluoride, potassium fluoride, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, 1-methylimidazole, hydrofluoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, N-chlorosuccinimide, potassium peroxymonosulfate, and iodine. 58. The process according to Embodiment 56, wherein deprotection comprises reacting a compound of formula VI or a salt thereof with tetrabutylammonium fluoride. 59. The process according to any one of embodiments 56 to 58, wherein the deprotection is carried out at a temperature of about -20°C to about 100°C. 60. The process according to any one of embodiments 56 to 59, wherein deprotection is carried out in a solvent containing tetrahydrofuran. 61. Oxidize a compound of formula V or a salt thereof to obtain formula IV: [ka] The process according to any one of embodiments 56 to 60, further comprising forming a compound or a salt thereof. 62. The process according to Embodiment 61, wherein oxidation comprises reacting a compound of formula V or a salt thereof with an oxidizing agent in the presence of a base and an oxidation catalyst. 63. The process according to Embodiment 62, wherein the oxidizing agent is selected from the group consisting of (diacetoxyiodo)benzene, (bis(trifluoroacetoxy)iodo)benzene, 2-iodoxybenzoic acid, N-chlorosuccinimide, N-bromosuccinimide, N-chlorotosylamide sodium salt, bromine, chlorine, iodine, sodium hypochlorite, sodium chlorite, hydrogen peroxide, sodium peroxide, t-butyl hydrogen peroxide, sodium perborate, potassium peroxymonosulfate, and sodium periodate, or any combination thereof. 64. The process according to Embodiment 62, wherein the oxidizing agent is (diacetoxyiodo)benzene. 65. The process according to any one of Embodiments 61 to 64, wherein the base is selected from the group consisting of dibasic sodium phosphate, sodium hydroxide, potassium hydroxide, monobasic potassium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, 1-methylimidazole, tetrabutylammonium bisulfate, and tetrabutylammonium chloride. 66. The process according to any one of embodiments 61 to 64, wherein the base is dibasic sodium phosphate. 67. The process according to any one of embodiments 61 to 66, wherein the oxidation catalyst is selected from the group consisting of 2,2,6,6-tetramethylpiperidine 1-oxyl, 2-azaadamantane N-oxyl, ruthenium trichloride, ruthenium tetroxide, and osmium tetroxide. 68. The process according to any one of embodiments 61 to 66, wherein the oxidation catalyst is 2,2,6,6-tetramethylpiperidine 1-oxyl. 69. The process according to any one of embodiments 61 to 68, wherein the oxidation is carried out at a temperature of about -20°C to about 100°C. 70. The process according to any one of embodiments 61 to 69, wherein the oxidation is carried out in a solvent comprising methyl tert-butyl ether, acetonitrile, and water. 71. A compound of formula VII or a salt thereof, of formula VIII: [ka] Prepared by deprotecting the compound or salt thereof, each R 3 However, independently, C 1~6 The process according to any one of embodiments 26 to 70, wherein the alkyl group is involved. 72. The process according to Embodiment 71, wherein deprotection comprises reacting a compound of formula VII with a deprotecting agent selected from the group consisting of lithium hydroxide, potassium hydrogen fluoride, tetrabutylammonium fluoride, potassium fluoride, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, 1-methylimidazole, hydrofluoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, N-chlorosuccinimide, potassium peroxymonosulfate, and iodine, or any combination thereof, in the presence of water. 73. The process according to Embodiment 72, wherein the deprotecting agent is lithium hydroxide. 74. The process according to any one of embodiments 71 to 73, wherein the deprotection is carried out at a temperature of about 0°C to about 100°C. 75. The process according to any one of embodiments 71 to 74, wherein deprotection is carried out in a solvent containing tetrahydrofuran and water. 76. Each R 3 However, the process according to any one of embodiments 71 to 75, independently selected from the group consisting of methyl and tert-butyl. 77. The compound of formula VIII is, formula VIII-a: [ka] The process according to any one of embodiments 71 to 76, wherein the compound is or a salt thereof. 78. A compound of formula VIII or a salt thereof, of formula XIV: [ka] The first mixture is formed by reacting the compound or a salt thereof with an activator in the presence of zinc, The first mixture and formula IX: [ka] Prepared by a process comprising mixing a compound or salt thereof with a coupling catalyst, wherein X 1 However, the process described in any one of embodiments 71 to 77 is a halo. 79. The process according to Embodiment 78, wherein the activator is selected from the group consisting of trimethylsilyl chloride, triethylsilyl chloride, trimethylsilyl iodide, dibromoethane, dichloroethane, diisobutylaluminum hydride, and iodine. 80. The process according to Embodiment 78, wherein the activator is trimethylsilyl chloride. 81. The process according to any one of embodiments 78 to 80, wherein the coupling catalyst comprises a palladium catalyst. 82. The process according to any one of embodiments 78 to 81, wherein the coupling catalyst comprises a palladium catalyst and a phosphine ligand. 83. The process according to Embodiment 81 or 82, wherein the palladium catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium(0), palladium chloride(II), palladium bromide(II), palladium acetate(II), palladium trifluoroacetate(II), tetrakis(triphenylphosphine)palladium(0), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. 84. The process according to Embodiment 82, wherein the phosphine ligand is selected from the group consisting of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tricyclohexylphosphine, tri-tert-butylphosphine, triphenylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and ethylenebis(diphenylphosphine). 85. The process according to any one of Embodiments 78 to 80, wherein the coupling catalyst comprises tris(dibenzylideneacetone)dipalladium and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. 86. The process according to any one of embodiments 78 to 85, wherein the mixing of the first mixture and the compound of formula IX is carried out at a temperature of about 0°C to about 100°C. 87. The process according to any one of embodiments 78 to 86, wherein the mixing of the first mixture and the compound of formula IX is carried out in a solvent containing tetrahydrofuran. 88. A compound of formula IX or a salt thereof, formula X: [ka] The process according to any one of embodiments 78 to 87, which is prepared by silylation of the compound or a salt thereof. 89. Silylation is performed with a compound of formula IX or a salt thereof, and formula: Si(R 3 )3-LG The process involves reacting a silylating agent with a base and a silylating catalyst in the presence of the formula, Each R 3 However, independently, C 1~6 It is alkyl, The process according to Embodiment 88, wherein LG is a leaving group. 90. Each R 3 The process according to Embodiment 89, wherein the substance is independently selected from the group consisting of methyl and tert-butyl. 91. The process according to Embodiment 89 or 90, wherein LG is selected from the group consisting of chloride, bromide, iodide, methanesulfonate, trifluoromethanesulfonate, and p-toluenesulfonate. 92. The process according to Embodiment 89, wherein the silylating agent is tert-butyl(chloro)dimethylsilane. 93. The process according to any one of Embodiments 89 to 92, wherein the base is selected from the group consisting of imidazole, triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, colidine, 1-methylimidazole, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, monobasic potassium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, monobasic sodium phosphate, dibasic sodium phosphate, and tribasic sodium phosphate. 94. The process according to any one of embodiments 89 to 92, wherein the base is an imidazole. 95. The process according to any one of Embodiments 89 to 94, wherein the silylation catalyst is selected from the group consisting of 4-dimethylaminopyridine, N-methylimidazole, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, tetrabutylammonium bromide, and tetrabutylammonium iodide. 96. The process according to any one of embodiments 89 to 94, wherein the silylation catalyst is 4-dimethylaminopyridine. 97. The process according to any one of embodiments 88 to 96, wherein the phosphorylation is carried out at a temperature of about 0°C to about 100°C. 98. The process according to any one of embodiments 88 to 97, wherein the silylation is carried out in a solvent containing N,N-dimethylformamide. 99. A compound of formula X or a salt thereof, of formula XI-a: [ka] The process according to any one of embodiments 88 to 98, which is prepared by reducing a compound or a salt thereof. 100. The process according to Embodiment 99, wherein the reduction involves reacting a compound of formula X or a salt thereof in the presence of a reducing agent selected from the group consisting of lithium aluminum hydride, diisobutylaluminum hydride, aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, boranetetrahydrofuran complex, diborane, I2 / NaBH4, and borane dimethyl sulfide complex. 101. The process according to Embodiment 100, wherein the reducing agent is lithium aluminum hydride. 102. The process according to any one of embodiments 99 to 101, wherein the reduction is carried out at a temperature of approximately -20°C to approximately 100°C. 103. The process according to any one of embodiments 99 to 102, wherein the reduction is carried out in a solvent containing tetrahydrofuran. 104. The process according to any one of Embodiments 1 to 103, wherein the compound of formula XI-a or a salt thereof is prepared by reacting 3-bromo-5-methylphenol with methyl 3,3-dimethyl acrylate in the presence of an acid. 105. The process according to Embodiment 104, wherein the acid is selected from the group consisting of methanesulfonic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, pivalic acid, phosphoric acid, p-toluenesulfonic acid, boron trichloride, lithium bromide, magnesium chloride, aluminum chloride, lithium triflate, magnesium triflate, and aluminum triflate. 106. The process according to Embodiment 104, wherein the acid is methanesulfonic acid. 107. The process according to any one of embodiments 104 to 106, wherein the reaction is carried out at a temperature of approximately 0°C to approximately 200°C. 108. The process according to any one of embodiments 104 to 107, wherein the reaction is carried out in the absence of a solvent. 109. Compounds of formula IV or their salts and formula III: [ka] By linking the compound or salt thereof, Formula II: [ka] The process according to any one of embodiments 14-25 and 61-108, further comprising forming a compound or a salt thereof. 110. The process according to Embodiment 109, wherein coupling comprises reacting a compound of formula IV or a salt thereof with a compound of formula III or a salt thereof in the presence of a coupling agent and a base. 111. The process according to Embodiment 110, wherein the coupling agent is selected from the group consisting of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate, 1,1'-carbonyldiimidazole, thionyl chloride, phosgene, triphosgene, ethyl chloroformate, isobutyl chloroformate, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), propanephosphonic anhydride, HATU, HBTU, TATU, TBTU, HCTU, BOP, PyBOP, and COMU. 112. The process according to Embodiment 110, wherein the coupling agent is N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate or propanephosphonic anhydride. 113. The process according to any one of Embodiments 110 to 112, wherein the base is selected from the group consisting of 1-methylimidazole, diisopropylethylamine, 4-methylmorpholine, pyridine, 2,6-lutidine, imidazole, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, and potassium phosphate. 114. The process according to any one of embodiments 110 to 112, wherein the base is 1-methylimidazole. 115. The process according to any one of embodiments 109 to 114, wherein the coupling is carried out at a temperature of approximately -30°C to approximately 60°C. 116. The process according to any one of embodiments 109 to 115, wherein the coupling is carried out in a solvent containing acetonitrile. 117. The compound of formula II is, formula II-a: [ka] The process according to any one of embodiments 109 to 116, wherein the compound is or a salt thereof. 118. Deprotect a compound of formula II or its salt to obtain formula I: [ka] The process according to any one of embodiments 109 to 117, further comprising forming a compound or a salt thereof. 119. The process according to Embodiment 118, wherein deprotection comprises reacting a compound of formula II or a salt thereof in the presence of an acid. 120. The process according to Embodiment 119, wherein the acid is selected from the group consisting of phosphoric acid, trifluoroacetic acid, trichloroacetic acid, formic acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid. 121. The process of Embodiment 119, wherein the acid is phosphoric acid. 122. The process according to any one of embodiments 118 to 121, wherein the deprotection is carried out at a temperature of about -20°C to about 100°C. 123. The process according to any one of embodiments 118 to 122, wherein the coupling is carried out in a solvent containing acetonitrile and water. 124. In some embodiments, the present disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, Formula XIV-a: [ka] The first mixture is formed by reacting the compound or salt thereof with diisobutylaluminum hydride in the presence of zinc and lithium chloride. The first mixture and formula XI-a: [ka] A compound or a salt thereof is mixed in the presence of palladium(II) acetate and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl to obtain formula XIII-a: [ka] To form a compound or salt thereof, A compound of formula XIII-a or a salt thereof is reacted with di-tert-butyl phosphite, bromoform, and trimethylsilanolate to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 125. In some embodiments, the present disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, Formula VII-a: [ka] The compound or a salt thereof is reacted with di-tert-butyl phosphite in the presence of bromoform and cesium carbonate to produce formula VI-a: [ka] To form a compound or salt thereof, Deprotecting the compound of formula VI-a or a salt thereof in the presence of tetrabutylammonium fluoride yields formula Va: [ka] To form a compound or salt thereof, A compound of formula Va or a salt thereof is oxidized in the presence of (diacetoxyiodo)benzene, dibasic sodium phosphate, and 2,2,6,6-tetramethylpiperidine 1-oxyl to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 126. In some embodiments, the present disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, Formula VII-a: [ka] The compound or a salt thereof is reacted with tetrabenzyl pyrophosphate in the presence of sodium hydride to produce formula VI-b: [ka] To form a compound or salt thereof, Deprotecting a compound of formula VI-b or a salt thereof in the presence of tetrabutylammonium fluoride yields formula Vb: [ka] To form a compound or salt thereof, The compound of formula Vb or a salt thereof is oxidized in the presence of (diacetoxyiodo)benzene, dibasic sodium phosphate, and 2,2,6,6-tetramethylpiperidine 1-oxyl to obtain formula IV-b: [ka] To form a compound or salt thereof, Compound of formula IV-b or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form formula II-b: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-b or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 127. In some embodiments, the present disclosure relates to formula I: [ka] A process for preparing a compound or salt thereof, Formula VII-a: [ka] The first mixture is formed by reacting the compound or a salt thereof with di-tert-butyl N,N-diisopropyl phosphoramidate in the presence of 1-methylimidazole and trifluoroacetic acid. Mix the first mixture with hydrogen peroxide to obtain formula VI-a: [ka] To form a compound or salt thereof, Deprotecting the compound of formula VI-a or a salt thereof in the presence of tetrabutylammonium fluoride yields formula Va: [ka] To form a compound or salt thereof, A compound of formula Va or a salt thereof is oxidized in the presence of (diacetoxyiodo)benzene, dibasic sodium phosphate, and 2,2,6,6-tetramethylpiperidine 1-oxyl to obtain formula IV-a: [ka] To form a compound or salt thereof, Compound of formula IV-a or its salt and formula III: [ka] The compound or a salt thereof is linked in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methylimidazole to form formula II-a: [ka] To form a compound or salt thereof, The present invention provides a process comprising deprotecting a compound of formula II-a or a salt thereof with phosphoric acid to form a compound of formula I or a salt thereof. 【0453】 All references, including publications, patents, and patent documents, are incorporated herein by reference as if they were individually incorporated by reference. This disclosure provides references to various embodiments and techniques. However, it should be understood that many variations and modifications are possible, while remaining within the spirit and scope of this disclosure. The descriptions should be considered illustrative of the claimed subject matter and are not intended to limit the appended claims to any particular embodiment illustrated.

Claims

[Claim 1] Equation XIII: 【Chem.385】 A process for preparing a compound or salt thereof of formula XIV: [[ID = 0]]【Chemical 386】[[ID = 1]] The compound or a salt thereof is reacted with an activator in the presence of zinc and optionally an alkali metal halide to form a first mixture. The first mixture and formula XI-a: 【Chemistry 387】 The process involves mixing a compound or a salt thereof in the presence of a coupling catalyst, wherein the formula includes, X １ But it's a halo, R １ However, C １～６ Alkyl process. [Claim 2] The process according to claim 1, wherein the activator is selected from the group consisting of diisobutylaluminum hydride, trimethylsilyl chloride, triethylsilyl chloride, trimethylsilyl iodide, dibromoethane, dichloroethane, and iodine. [Claim 3] The process according to claim 1, wherein the activator is trimethylsilyl chloride. [Claim 4] The process according to any one of claims 1 to 3, wherein the optionally selected alkali metal halide is lithium chloride. [Claim 5] The process according to any one of claims 1 to 4, wherein the coupling catalyst includes a palladium catalyst. [Claim 6] The process according to any one of claims 1 to 5, wherein the coupling catalyst comprises a palladium catalyst and a phosphine ligand. [Claim 7] The process according to claim 5 or 6, wherein the palladium catalyst is selected from the group consisting of palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate, bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. [Claim 8] The process according to claim 6 or 7, wherein the phosphine ligand is selected from the group consisting of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tricyclohexylphosphine, tri-tert-butylphosphine, triphenylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and ethylenebis(diphenylphosphine). [Claim 9] The process according to any one of claims 1 to 6, wherein the coupling catalyst comprises bis(dibenzylideneacetone)palladium(O) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. [Claim 10] The process according to any one of claims 1 to 9, wherein the mixing of the first mixture and the compound of formula XI-a is carried out at a temperature of about 0°C to about 100°C. [Claim 11] The process according to any one of claims 1 to 10, wherein the mixing of the first mixture and the compound of formula XI-a is carried out in a solvent containing tetrahydrofuran and 2-methyltetrahydrofuran. [Claim 12] Equation XIII: 【Chemical 388】 A process for preparing a compound or salt thereof, wherein formula XI-b: 【Chem.389】 Compounds or salts thereof and formula XIV: 【Chemical 390】 The process involves reacting a compound or salt thereof with Suzuki coupling conditions, in which, X １ But it's a halo, R １ However, C １～６ Alkyl process. [Claim 13] The process according to claim 12, wherein the Suzuki coupling conditions include reacting the compound of formula XI-b or a salt thereof with the compound of formula XIV or a salt thereof in the presence of a palladium catalyst, a base, and optionally a ligand. [Claim 14] The process according to claim 13, wherein the palladium catalyst is selected from palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate, bis(dibenzylideneacetone)palladium(0), tetrakis(triphenylphosphine)palladium(0), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. [Claim 15] The process according to claim 13, wherein the palladium catalyst is bis(dibenzylideneacetone)palladium(0). [Claim 16] The process according to any one of claims 13 to 15, wherein the base is selected from sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, potassium propionate, triethylamine, N-methylmorpholine, tripropylamine, and N,N-diisopropylethylamine. [Claim 17] The process according to any one of claims 13 to 15, wherein the base is tribasic potassium phosphate. [Claim 18] The process according to any one of claims 13 to 17, wherein the reaction is carried out in the presence of a ligand. [Claim 19] The process according to any one of claims 13 to 17, wherein the ligand is selected from tricyclohexylphosphine, tri-tert-butylphosphine, triphenylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, ethylenebis(diphenylphosphine), and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane. [Claim 20] The process according to any one of claims 13 to 17, wherein the ligand is 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphanadamantane. [Claim 21] The process according to any one of claims 12 to 20, wherein the reaction is carried out at a temperature of about 0°C to about 90°C. [Claim 22] The process according to any one of claims 12 to 21, wherein the reaction is carried out at a temperature of about 70°C to about 90°C. [Claim 23] The process according to any one of claims 12 to 22, wherein the reaction is carried out in a solvent containing isopropyl acetate and water. [Claim 24] The compound of formula XI-b or a salt thereof is of formula XI-a: 【Chemistry 391】 The process according to any one of claims 12 to 23, wherein a compound or salt thereof is prepared by borylation with a diboron reagent in the presence of a palladium catalyst, a base, and optionally a ligand. [Claim 25] The process according to claim 24, wherein the diborone reagent is bis(pinacolate)diborone. [Claim 26] The process according to claim 24 or 25, wherein the palladium catalyst is selected from palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) trifluoroacetate, bis(dibenzylideneacetone)palladium(0), tetrakis(triphenylphosphine)palladium(0), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. [Claim 27] The process according to claim 24 or 25, wherein the palladium catalyst is bis(dibenzylideneacetone)palladium(0). [Claim 28] The process according to any one of claims 24 to 27, wherein the boration is carried out in the presence of a ligand. [Claim 29] The process according to any one of claims 24 to 28, wherein the ligand is selected from tricyclohexylphosphine, tri-tert-butylphosphine, triphenylphosphine, tri(o-tolyl)phosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and ethylenebis(diphenylphosphine). [Claim 30] The process according to any one of claims 24 to 28, wherein the ligand is triphenylphosphine. [Claim 31] The process according to any one of claims 24 to 30, wherein the base is selected from sodium acetate, sodium hydroxide, potassium hydroxide, dibasic potassium phosphate, tribasic potassium phosphate, cesium carbonate, potassium propionate, triethylamine, N-methylmorpholine, tripropylamine, and N,N-diisopropylethylamine. [Claim 32] The process according to any one of claims 24 to 30, wherein the base is potassium propionate. [Claim 33] The process according to any one of claims 24 to 32, wherein the boration is carried out at a temperature of about 50°C to about 95°C. [Claim 34] The process according to any one of claims 24 to 33, wherein the boronation is carried out in a solvent containing isopropyl acetate. [Claim 35] The compound of formula XIV is formula XIV-a: 【Chemistry 392】 The process according to any one of claims 1 to 34, wherein the compound is or a salt thereof. [Claim 36] The compound of formula XIII is formula XIII-a: 【Chemistry 393】 The process according to any one of claims 1 to 35, wherein the compound is or a salt thereof. [Claim 37] The compound of formula XIII or a salt thereof is phosphorylated to obtain formula IV: 【Chem. 394】 The further comprising forming a compound or salt thereof, wherein each R ２ However, independently, C １～６ The process according to any one of claims 1 to 36, selected from the group consisting of alkyl groups. [Claim 38] The process according to claim 37, wherein the phosphorylation includes reacting the compound of formula XIII or a salt thereof with a phosphorylating agent in the presence of an oxidizing agent and a base, optionally. [Claim 39] The process according to claim 38, wherein the phosphorylating agent is selected from the group consisting of di-tert-butyl phosphite, di-tert-butyl phosphoryl chloride, di-tert-butyl phosphoryl bromide, di-ethyl phosphoryl chloride, di-isopropyl phosphoryl chloride, dibenzyl phosphorochloride, and dibenzyl phosphorobromide. [Claim 40] The process according to claim 38, wherein the phosphorylating agent is di-tert-butyl phosphite. [Claim 41] The process according to any one of claims 38 to 40, wherein the oxidizing agent is selected from the group consisting of bromoform, carbon tetrabromide, carbon tetrachloride, dibromomethane, dibromoethane, bromotrichloromethane, N-chlorosuccinimide, N-bromosuccinimide, N-chlorotosylamide sodium salt, bromine, chlorine, iodine, and sodium hypochlorite. [Claim 42] The process according to any one of claims 38 to 40, wherein the oxidizing agent is bromoform. [Claim 43] The process according to any one of claims 38 to 42, wherein the base is selected from the group consisting of sodium trimethylsilanolate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium tert-butoxide, sodium hydride, and cesium carbonate. [Claim 44] The process according to any one of claims 38 to 42, wherein the base is sodium trimethylsilanolate. [Claim 45] The process according to any one of claims 37 to 44, wherein the phosphorylation is carried out at a temperature of about 0°C to about 40°C. [Claim 46] The process according to any one of claims 37 to 45, wherein the phosphorylation is carried out in a solvent containing 2-methyltetrahydrofuran and water. [Claim 47] Each R ２ The process according to any one of claims 37 to 46, wherein R is tert-butyl. [Claim 48] The compound of formula IV is formula IV-a: 【Chemical 395】 The process according to any one of claims 37 to 47, wherein the compound is or a salt thereof. [Claim 49] The process according to any one of claims 1 to 11 and 24 to 48, wherein the compound of formula XI-a or a salt thereof is prepared by reacting 3-bromo-5-methylphenol with methyl 3,3-dimethyl acrylate in the presence of an acid. [Claim 50] The process according to claim 49, wherein the acid is selected from the group consisting of methanesulfonic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, pivalic acid, phosphoric acid, p-toluenesulfonic acid, boron trichloride, lithium bromide, magnesium chloride, aluminum chloride, lithium triflate, magnesium triflate, and aluminum triflate. [Claim 51] The process according to claim 49, wherein the acid is sulfuric acid. [Claim 52] The process according to any one of claims 49 to 51, wherein the reaction is carried out at a temperature of about 0°C to about 200°C. [Claim 53] The process according to any one of claims 49 to 52, wherein the reaction is carried out in the absence of a solvent. [Claim 54] The compound of formula IV or a salt thereof and formula III: 【Chemistry 396】 By linking the compound or salt thereof, formula II: 【Chemistry 397】 The process according to any one of claims 37 to 53, further comprising forming a compound or a salt thereof. [Claim 55] The process according to claim 54, wherein the coupling includes reacting the compound of formula IV or a salt thereof with the compound of formula III or a salt thereof in the presence of a coupling agent and a base. [Claim 56] The process according to claim 55, wherein the coupling agent is selected from the group consisting of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate, 1,1'-carbonyldiimidazole, thionyl chloride, phosgene, triphosgene, ethyl chloroformate, isobutyl chloroformate, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), propanephosphonic anhydride, HATU, HBTU, TATU, TBTU, HCTU, BOP, PyBOP, and COMU. [Claim 57] The process according to claim 55, wherein the coupling agent is N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate or propanephosphonic anhydride. [Claim 58] The process according to any one of claims 55 to 57, wherein the base is selected from the group consisting of 1-methylimidazole, diisopropylethylamine, 4-methylmorpholine, pyridine, 2,6-lutidine, imidazole, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, and potassium phosphate. [Claim 59] The process according to any one of claims 55 to 57, wherein the base is 1-methylimidazole. [Claim 60] The process according to any one of claims 54 to 59, wherein the coupling is carried out at a temperature of about -30°C to about 60°C. [Claim 61] The process according to any one of claims 54 to 60, wherein the coupling is carried out in a solvent containing acetonitrile. [Claim 62] The compound of formula II is formula II-a: 【Chem.398】 The process according to any one of claims 54 to 61, wherein the compound is or a salt thereof. [Claim 63] Deprotecting the compound of formula II or its salt yields formula I: 【Chem.399】 The process according to any one of claims 55 to 63, further comprising forming a compound or a salt thereof. [Claim 64] The process according to claim 63, wherein the deprotection includes reacting the compound of formula II or a salt thereof in the presence of an acid. [Claim 65] The process according to claim 64, wherein the acid is selected from the group consisting of phosphoric acid, trifluoroacetic acid, trichloroacetic acid, formic acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid. [Claim 66] The process according to claim 64, wherein the acid is phosphoric acid. [Claim 67] The process according to any one of claims 63 to 66, wherein the deprotection is carried out at a temperature of about -20°C to about 100°C. [Claim 68] The process according to any one of claims 63 to 67, wherein the coupling is carried out in a solvent comprising acetonitrile and water. [Claim 69] Formula I: 【Chemical 400】 A process for preparing a compound or salt thereof, 3-bromo-5-methylphenol and methyl 3,3-dimethyl acrylate are reacted in the presence of sulfuric acid to obtain formula XI-a: 【Chemical 401】 To form a compound or salt thereof, Formula XIV-a: 【Chemical 402】 The first mixture is formed by reacting the compound or a salt thereof with trimethylsilyl chloride in the presence of zinc, The first mixture and the compound of formula XI-a or a salt thereof are mixed in the presence of bis(dibenzylideneacetone)palladium(0) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl to obtain formula XIII-a: 【Chemical 403】 To form a compound or salt thereof, The compound of formula XIII-a or a salt thereof is reacted with di-tert-butyl phosphite, bromoform, and sodium trimethylsilanolate to obtain formula IV-a: 【Chemical 404】 To form a compound or salt thereof, The compound of formula IV-a or a salt thereof and formula III: 【Chemical 405】 The compound or a salt thereof is linked in the presence of propanephosphonic anhydride and 1-methylimidazole to form formula II-a: 【Chemical 406】 To form a compound or salt thereof, A process comprising deprotecting the compound of formula II-a or a salt thereof with phosphoric acid to form the compound of formula I or a salt thereof. [Claim 70] Formula I: 【Chemical 407】 A process for preparing a compound or salt thereof, 3-bromo-5-methylphenol and methyl 3,3-dimethyl acrylate are reacted in the presence of sulfuric acid to obtain formula XI-a: 【Chemical 408】 To form a compound or salt thereof, The compound of formula XI-a or a salt thereof is reacted with bis(pinacolate)diborone in the presence of bis(dibenzylideneacetone)palladium(0), triphenylphosphine, and potassium propionate to obtain formula XI-b: 【Chemical 409】 To form a compound or salt thereof, The compound of formula XI-b or a salt thereof and formula XIV-a: 【Chemical 410】 The compound or a salt thereof is reacted in the presence of bis(dibenzylideneacetone)palladium(O), tribasic potassium phosphate, and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane to obtain formula XIII-a: 【Chemical 411】 To form a compound or salt thereof, The compound of formula XIII-a or a salt thereof is reacted with di-tert-butyl phosphite, bromoform, and sodium trimethylsilanolate to obtain formula IV-a: 【Chemical 412】 To form a compound or salt thereof, The compound of formula IV-a or a salt thereof and formula III: 【Chemical 413】 The compound or a salt thereof is linked in the presence of propanephosphonic anhydride and 1-methylimidazole to form formula II-a: 【Chemical 414】 To form a compound or salt thereof, A process comprising deprotecting the compound of formula II-a or a salt thereof with phosphoric acid to form the compound of formula I or a salt thereof. [Claim 71] The process according to claim 69 or 70, wherein the compound of formula III or a salt thereof is a sodium salt of the compound of formula III. [Claim 72] Formula VI-a: 【Chemical 415】 A process for preparing a compound or salt thereof, wherein formula VII-a: 【Chemical 416】 A process comprising: reacting a compound or salt thereof with di-tert-butyl N,N-diisopropyl phosphoramidate in the presence of 1-methylimidazole and trifluoroacetic acid to form a first mixture; and mixing the first mixture with hydrogen peroxide to form a compound of formula VI-a or a salt thereof.

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