Synthesis of oxepanoprolines

Abstract

Provided herein are methods for preparing oxepanoprolines and associated synthetic intermediates. These routes allow access to oxepanoprolinamide antibiotics, which are lincosamide analogues useful for the treatment and prevention of infectious diseases. The methods are scalable and provide access to multigram quantities of the oxepanoproline (southern) fragments of the oxepanoprolinamide antibiotics.

Description

SYNTHESIS OF OXEPANOPROLINES RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N.63 / 685,245, filed August 20, 2024, which is incorporated herein by reference. GOVERNMENT SUPPORT

[0002] This invention was made with government support under AI168228 awarded by National Institutes of Health (NIH). The government has certain rights in this invention. BACKGROUND OF THE INVENTION

[0003] The lincosamide class of antibiotics inhibits the bacterial 50S ribosomal subunit by binding to the peptidyl transferase center (PTC) and inhibiting protein translation. The early members of the class, lincomycin and clindamycin, received FDA approval for human use in 1964 and 1970, respectively. Since then, no new lincosamide antibiotics have been approved, and antimicrobial resistance toward both lincomycin and clindamycin has become widespread in the clinic. Recently, Applicant has reported the discovery of three potent antibiotics within this class—iboxamycin (IBX), cresomycin (CRM), and BT-33 — all of which share a common oxepanoproline scaffold as their southern fragments. See International Application No. PCT / US2018 / 046167, filed August 10, 2018 (published as International Publication No. WO 2019 / 032936, published February 14, 2019); International Application No. PCT / US2023 / 019059, filed April 19, 2023 (published as International Publication No. WO 2023 / 205206, published October 26, 2023); both of which are incorporated herein by reference in their entireties.

[0004] The fused bicyclic oxepanoproline scaffold rigidly presents an isobutyl sidechain toward a hydrophobic A-site cleft near the PTC and is believed to be important for the improved antibacterial efficacy of these antibiotics. In view of their promising antibacterial activity and pharmacokinetic profiles, all three candidates are advancing toward pre-clinical, investigational new drug (IND)– enabling studies, but these experiments require multi-gram quantities of the southern oxepanoproline fragment 1.H0824.70449WO00 1 / 250 #14309532v1

[0005] Accordingly, the development of new scalable routes for the synthesis of oxepanoprolines represents a currently unmet need. SUMMARY OF THE INVENTION

[0006] The present disclosure stems from the recognition that macrobicyclic thiolincosamides, such as IBX, BT-33, and CRM, are potent, broad-spectrum antibiotics, but current synthetic routes may not allow for facile access to the multi-gram quantities needed for pre-clinical, investigational new drug (IND)–enabling studies or for later clinical studies.

[0007] Thus, disclosed are novel synthetic routes to access multigram amounts of oxepanoprolines, such as 1 (FIG.2). These processes include novel one-pot procedures for the aldol addition of a titanium enolate, generated upon conjugate addition of an allylsilane to a chiral acryloyl oxazolidinone, to set all the stereocenters within 1 in a single step.

[0008] In one aspect, the present disclosure provides methods of preparing compounds of Formula (I):, and salts thereof, comprising oxidizing a compound of Formula (II):, or a salt thereof, under suitable conditions to provide the compound of Formula (I), or salt thereof, wherein X, Y, R8, R9, n, and p are as defined herein.

[0009] In another aspect, the present disclosure provides methods of preparing compounds of Formula (XIII):,H0824.70449WO00 2 / 250 #14309532v1and pharmaceutically acceptable salts thereof, comprising: oxidizing a compound of Formula (II):, or a salt thereof, under suitable conditions to provide a compound of Formula (I):, or a salt thereof; and coupling the compound of Formula (I), or salt thereof, with a compound of Formula (XIV):or a salt thereof, to provide the compound of Formula (XIII), or pharmaceutically acceptable salt thereof, wherein X, Y, R7, R8, R9, R′, A1, A2, Ring A, n, and p are as defined herein.

[0010] In another aspect, the present disclosure provides methods of preparing compounds of Formula (II):, or a salt thereof, comprising cyclizing a compound of Formula (III):or a salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, wherein X, Y, R8, R9, R11, n, p, and RA1are as defined herein.H0824.70449WO00 3 / 250 #14309532v1

[0011] In another aspect, the present disclosure provides methods of preparing compounds of Formula (III):and salts thereof, comprising deprotecting a compound of Formula (IV):, or a salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, wherein X, Y, R8, R9. R11, n, p, R′′, and RA1are as defined herein.

[0012] In another aspect, the present disclosure provides methods of preparing compounds of Formula (IV):, and salts thereof, comprising hydrofunctionalization of a compound of Formula (V):or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, wherein X, Y, R8, R9, R11, n, p, R′′, and RA1are as defined herein.

[0013] In another aspect, the present disclosure provides methods of preparing compounds of Formula (V):and salts thereof, comprising protecting a compound of Formula (VI):H0824.70449WO00 4 / 250 #14309532v1or a salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, wherein X, Y, R8, R9, n, p, R′′, and RA1are as defined herein.

[0014] In another aspect, the present disclosure provides methods of preparing compounds of Formula (VI):and salts thereof, comprising reducing a compound of Formula (VII):, or a salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, wherein X, Y, R8, R9, n, p, R′′, and RA1are as defined herein.

[0015] In another aspect, the present disclosure provides methods of preparing compounds of Formula (VII):and salts thereof, comprising protecting a compound of Formula (VIII):, or a salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, wherein X, Y, R8, R9, n, p, R′′, and RA1are as defined herein.H0824.70449WO00 5 / 250 #14309532v1

[0016] In another aspect, the present disclosure provides methods of preparing compounds of Formula (VIII):and salts thereof, comprising cyclizing a compound of Formula (IX):or a salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, wherein X, Y, R8, R9, R13, n, p, RO, and RNare as defined herein.

[0017] In another aspect, the present disclosure provides methods of preparing compounds of Formula (IX):and salts thereof, comprising combining a compound of Formula (X):or a salt thereof, with a compound of Formula (XI):, or a salt thereof, and a compound of Formula (XII):, or a salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, wherein X, Y, X′, Y′, R9, R13, R14, n, p, RO, and RNare as defined herein

[0018] In another aspect, the present disclosure provides compounds of Formula (II):H0824.70449WO00 6 / 250 #14309532v1and salts thereof, wherein X, Y, R8, R9, n, and p are as defined herein.

[0019] In another aspect, the present disclosure provides compounds of Formula (III):, and salts thereof, wherein X, Y, R8, R9, R11, n, and p are as defined herein.

[0020] In another aspect, the present disclosure provides compounds of Formula (IV):and salts thereof, wherein X, Y, R8, R9, R11, n, p, R′′, and RA1are as defined herein.

[0021] In another aspect, the present disclosure provides compounds of Formula (V):and salts thereof, wherein X, Y, R8, R9, n, p, R′′, and RA1are as defined herein.

[0022] In another aspect, the present disclosure provides compounds of Formula (VI):and salts thereof, wherein X, Y, R9, n, p, R′′, and RA1are as defined herein.

[0023] In another aspect, the present disclosure provides compounds of Formula (VII):H0824.70449WO00 7 / 250 #14309532v1and salts thereof, wherein X, Y, R8, R9, n, p, R′′, and RA1are as defined herein.

[0024] In another aspect, the present disclosure provides compounds of Formula (VIII):and salts thereof, wherein X, Y, R8, R9, n, and p are as defined herein.

[0025] In another aspect, the present disclosure provides compounds of Formula (IX):and salts thereof, wherein X, Y, R9, R13, n, p, RO, and RNare as defined herein.

[0026] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG.1 shows thermal ellipsoids from single-crystal X-ray diffraction for compound 1.

[0028] FIG.2 shows the overall synthetic scheme. DEFINITIONS

[0029] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0030] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer orH0824.70449WO00 8 / 250 #14309532v1geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0031] In a formula, is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified (e.g., cis or trans alkene), is absent or a single bond, and or is a single or double bond.

[0032] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0033] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0034] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0035] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1- 8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In certain embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n- hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstitutedH0824.70449WO00 9 / 250 #14309532v1alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10alkyl (such as unsubstituted C1-6alkyl, e.g., −CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i- Bu)). In certain embodiments, the alkyl group is a substituted C1-10alkyl (such as substituted C1-6alkyl, e.g., −CF3, Bn).

[0036] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In certain embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). Examples of haloalkyl groups include −CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0037] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-7 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-5alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1-4alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstitutedH0824.70449WO00 10 / 250 #14309532v1heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10alkyl.

[0038] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3 or) may be an (E)- or (Z)-double bond.

[0039] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2- 10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkenyl”). In certain embodiments, aH0824.70449WO00 11 / 250 #14309532v1heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1or 2 heteroatoms within the parent chain (“heteroC2-4alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10 alkenyl.

[0040] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.

[0041] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parentH0824.70449WO00 12 / 250 #14309532v1chain (“heteroC2-7alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC2-4alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl.

[0042] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the numberH0824.70449WO00 13 / 250 #14309532v1of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0043] In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.

[0044] “Carbocyclylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a carbocyclyl group, wherein the point of attachment is on the alkyl moiety.

[0045] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstitutedH0824.70449WO00 14 / 250 #14309532v1heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0046] In certain embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In certain embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0047] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl- 2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H- furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-H0824.70449WO00 15 / 250 #14309532v1dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo- [2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0048] “Heterocyclylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an heterocyclyl group, wherein the point of attachment is on the alkyl moiety.

[0049] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In certain embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In certain embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.

[0050] “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0051] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can beH0824.70449WO00 16 / 250 #14309532v1on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0052] In certain embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In certain embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0053] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.H0824.70449WO00 17 / 250 #14309532v1

[0054] “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0055] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0056] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.

[0057] Exemplary carbon atom substituents include, but are not limited to, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−,−N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa,H0824.70449WO00 18 / 250 #14309532v1−OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3−C(=S)N(Rbb)2, −C(=O)SRaa, −C(=S)SRaa,−B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)2Raa, −P(=O)(Raa)2, −P(=O)2N(Rcc)2, −P(=O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1- 10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−,−N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree,H0824.70449WO00 19 / 250 #14309532v1−SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)2Ree, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; each instance of Reeis, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3- 10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1-6 alkyl, −ON(C1-6 alkyl)2, −N(C1-6 alkyl)2, −N(C1-6 alkyl)3+X−,−NH(C1-6 alkyl)2+X−,−NH2(C1-6 alkyl)+X−,−NH3+X−,−N(OC1-6 alkyl)(C1-6 alkyl), −N(OH)(C1-6 alkyl), −NH(OH), −SH, −SC1-6 alkyl, −SS(C1-6 alkyl), −C(=O)(C1-6 alkyl), −CO2H, −CO2(C1-6 alkyl), −OC(=O)(C1-6 alkyl), −OCO2(C1-6 alkyl), −C(=O)NH2, −C(=O)N(C1-6 alkyl)2, −OC(=O)NH(C1-6 alkyl), −NHC(=O)( C1-6 alkyl), −N(C1-6 alkyl)C(=O)( C1-6 alkyl), −NHCO2(C1-6 alkyl), −NHC(=O)N(C1-6 alkyl)2, −NHC(=O)NH(C1-6 alkyl), −NHC(=O)NH2, −C(=NH)O(C1-6 alkyl), −OC(=NH)(C1-6 alkyl), −OC(=NH)OC1-6 alkyl, −C(=NH)N(C1-6 alkyl)2, −C(=NH)NH(C1-6 alkyl), −C(=NH)NH2, −OC(=NH)N(C1-6 alkyl)2, −OC(NH)NH(C1-6 alkyl), −OC(NH)NH2, −NHC(NH)N(C1-6 alkyl)2, −NHC(=NH)NH2, −NHSO2(C1-6 alkyl), −SO2N(C1-6alkyl)2, −SO2NH(C1-6alkyl), −SO2NH2, −SO2C1-6alkyl, −SO2OC1-6alkyl, −OSO2C1-6alkyl, −SOC1-6alkyl, −Si(C1-6alkyl)3, −OSi(C1-6alkyl)3−C(=S)N(C1-6alkyl)2, C(=S)NH(C1-6alkyl), C(=S)NH2, −C(=O)S(C1-6alkyl), −C(=S)SC1-6alkyl, −SC(=S)SC1-6alkyl, −P(=O)2(C1-6alkyl), −P(=O)(C1-6alkyl)2, −OP(=O)(C1-6alkyl)2, −OP(=O)(OC1-6alkyl)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X−is a counterion.

[0058] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).H0824.70449WO00 20 / 250 #14309532v1

[0059] The term “hydroxyl” or “hydroxy” refers to the group −OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from −O −OC(=NRbb)Raa,, −OP(Rcc)2, −OP(Rcc)3, −OP(=O)2Raa, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, −OP(=O)2N(Rbb)2, and −OP(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein.

[0060] The term “amino” refers to the group −NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0061] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from −NH(Rbb), −NHC(=O)Raa, −NHCO2Raa, −NHC(=O)N(Rbb)2, −NHC(=NRbb)N(Rbb)2, −NHSO2Raa, −NHP(=O)(ORcc)2, and −NHP(=O)(NRbb)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group −NH(Rbb) is not hydrogen.

[0062] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from −N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, and −NRbbP(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0063] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from −N(Rbb)3 and −N(Rbb)3+X−,wherein Rbband X−are as defined herein.

[0064] The term “sulfonyl” refers to a group selected from −SO2N(Rbb)2, −SO2Raa, and −SO2ORaa, wherein Raaand Rbbare as defined herein.

[0065] The term “sulfinyl” refers to the group −S(=O)Raa, wherein Raais as defined herein.

[0066] The term “acyl” refers to a group having the general formula −C(=O)RX1, −C(=O)ORX1,RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstitutedH0824.70449WO00 21 / 250 #14309532v1heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0067] The term “silyl” refers to the group −Si(Raa)3, wherein Raais as defined herein.

[0068] The term “oxo” refers to the group =O, and the term “thiooxo” refers to the group =S.

[0069] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRbb)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)2Raa, −P(=O)(Raa)2, −P(=O)2N(Rcc)2, −P(=O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10alkyl, heteroC2- 10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0070] In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1-10alkyl (e.g., aralkyl, heteroaralkyl), C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described inH0824.70449WO00 22 / 250 #14309532v1detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0071] For example, nitrogen protecting groups such as amide groups (e.g., −C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.

[0072] Nitrogen protecting groups such as carbamate groups (e.g., −C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1- dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m- nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6- nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-H0824.70449WO00 23 / 250 #14309532v1dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1- (3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1- phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0073] Nitrogen protecting groups such as sulfonamide groups (e.g., −S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4’,8’-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0074] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N’-p-toluenesulfonylaminoacyl derivative, N’-phenylaminothioacyl derivative, N- benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N- phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5- triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5- dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N- triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9- phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N- (N’,N’-dimethylaminomethylene)amine, N,N’-isopropylidenediamine, N-p-nitrobenzylideneamine, N- salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1- cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenylH0824.70449WO00 24 / 250 #14309532v1phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0075] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3, −P(=O)2Raa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)2N(Rbb)2, and −P(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0076] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4- methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2- chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1- ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1- methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’- dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4- (4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1- yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9- phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,H0824.70449WO00 25 / 250 #14309532v1phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t- butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S- benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4- azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2- methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0077] In certain embodiments, the substituent present on an sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3, −P(=O)2Raa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)2N(Rbb)2, and −P(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0078] As used herein, a “leaving group” (LG) is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo), −ORaa(when the O atom is attached to a carbonyl group, wherein Raais as defined herein), −O(C=O)RLG, or −O(SO)2RLG(e.g., tosyl, mesyl, besyl), wherein RLGis optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, the leaving group is a halogen. In certain embodiments, the leaving group is Cl.

[0079] As used herein, use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.H0824.70449WO00 26 / 250 #14309532v1

[0080] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0081] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

[0082] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0083] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)4−salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0084] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0085] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When aH0824.70449WO00 27 / 250 #14309532v1compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0086] The methods disclosed herein provide synthetic routes to macrobicyclic thiolincosamines and associated synthetic intermediates. These routes allow access to lincosamide analogues including those disclosed in International Application No. PCT / US2023 / 019059, filed April 19, 2023 (published as International Publication No. WO 2023 / 205206, published October 26, 2023), which is incorporated herein by reference.

[0087] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting. In certain embodiments, two are more sequential steps may be combined into one embodiment and / or claim.

[0088] In one aspect, the present disclosure provides methods of preparing compounds of Formula (I):and salts thereof, comprising oxidizing a compound of Formula (II):or a salt thereof, under suitable conditions to provide the compound of Formula (I), or salt thereof, wherein: X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=;H0824.70449WO00 28 / 250 #14309532v1R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and represents a single or double bond.

[0089] In another aspect, the present disclosure provides methods of preparing compounds of Formula (II):or a salt thereof, comprising cyclizing a compound of Formula (III):,H0824.70449WO00 29 / 250 #14309532v1or a salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, wherein: X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.H0824.70449WO00 30 / 250 #14309532v1

[0090] In another aspect, the present disclosure provides methods of preparing compounds of Formula (III):, and salts thereof, comprising deprotecting a compound of Formula (IV):, or a salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstitutedH0824.70449WO00 31 / 250 #14309532v1aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0091] In another aspect, the present disclosure provides methods of preparing compounds of Formula (IV):and salts thereof, comprising hydrofunctionalization of a compound of Formula (V):, or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,H0824.70449WO00 32 / 250 #14309532v1substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0092] In another aspect, the present disclosure provides methods of preparing compounds of Formula (V):, and salts thereof, comprising protecting a compound of Formula (VI):H0824.70449WO00 33 / 250 #14309532v1or a salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring;H0824.70449WO00 34 / 250 #14309532v1RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0093] In another aspect, the present disclosure provides methods of preparing compounds of Formula (VI):and salts thereof, comprising reducing a compound of Formula (VII):, or a salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1;H0824.70449WO00 35 / 250 #14309532v1p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0094] In another aspect, the present disclosure provides methods of preparing compounds of Formula (VII):and salts thereof, comprising protecting a compound of Formula (VIII):or a salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=;H0824.70449WO00 36 / 250 #14309532v1R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.H0824.70449WO00 37 / 250 #14309532v1

[0095] In another aspect, the present disclosure provides methods of preparing compounds of Formula (VIII):and salts thereof, comprising cyclizing a compound of Formula (IX):, or a salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; n is 0 or 1;H0824.70449WO00 38 / 250 #14309532v1p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; each instance of ROis independently hydrogen or an oxygen protecting group; and each instance of RNis independently hydrogen or a nitrogen protecting group; or an ROgroup and an RNgroup are joined to form a substituted or unsubstituted heterocyclyl ring; and represents a single or double bond.

[0096] In another aspect, the present disclosure provides methods of preparing compounds of Formula (IX):and salts thereof, comprising combining a compound of Formula (X):or a salt thereof, with a compound of Formula (XI):or a salt thereof, and a compound of Formula (XII):or a salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; X′ is =O, =S, or =NR9;H0824.70449WO00 39 / 250 #14309532v1Y′ is =C(R9)2, =CHR9, or =CH2; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; each instance of R14is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;H0824.70449WO00 40 / 250 #14309532v1each instance of ROis independently hydrogen or an oxygen protecting group; and each instance of RNis independently hydrogen or a nitrogen protecting group; or an ROgroup and an RNgroup are joined to form a substituted or unsubstituted heterocyclyl ring; and represents a single or double bond.

[0097] In another aspect, the present disclosure provides methods of preparing compounds of Formula (XIII):, and pharmaceutically acceptable salts thereof, comprising: oxidizing a compound of Formula (II):, or a salt thereof, under suitable conditions to provide a compound of Formula (I):, or a salt thereof; and coupling the compound of Formula (I), or salt thereof, with a compound of Formula (XIV):,H0824.70449WO00 41 / 250 #14309532v1or a salt thereof, to provide the compound of Formula (XIII), or pharmaceutically acceptable salt thereof, wherein: A1is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, or –SRA; A2is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or A1and A2are optionally joined to form Ring A, which is represented by “- - -” and is a substituted or unsubstituted heterocyclic ring; or A2and R7are joined to form a substituted or unsubstituted heterocyclic ring; X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; each instance of R′ is independently hydrogen or an oxygen protecting group; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted orH0824.70449WO00 42 / 250 #14309532v1unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and represents a single or double bond.

[0098] In certain embodiments, the method of preparing the compound of Formula (I), or salt thereof, further comprises cyclizing a compound of Formula (III):, or a salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, wherein: R11is a leaving group; and RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group.

[0099] In certain embodiments, the method of preparing the compound of Formula (I) or (II), or salt thereof, further comprises deprotecting a compound of Formula (IV):, or a salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, wherein: X is –O–, –S–, or –NR9–; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; and RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstitutedH0824.70449WO00 43 / 250 #14309532v1heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group.

[0100] In certain embodiments, the method of preparing the compound of Formula (I), (II), or (III), or salt thereof, further comprises hydrofunctionalization of a compound of Formula (V):or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof.

[0101] In certain embodiments, the method of preparing the compound of Formula (I), (II), (III), or (IV), or salt thereof, further comprises protecting a compound of Formula (VI):or a salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof.

[0102] In certain embodiments, the method of preparing the compound of Formula (I), (II), (III), (IV), or (V), or salt thereof, further comprises reducing a compound of Formula (VII):or a salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof.

[0103] In certain embodiments, the method of preparing the compound of Formula (I), (II), (III), (IV), (V), or (VI), or salt thereof, further comprises protecting a compound of Formula (VIII):or a salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof.H0824.70449WO00 44 / 250 #14309532v1

[0104] In certain embodiments, the method of preparing the compound of Formula (I), (II), (III), (IV), (V), (VI), or (VII), or salt thereof, further comprises cyclizing a compound of Formula (IX):or a salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, wherein: each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and each instance of ROis independently hydrogen or an oxygen protecting group; and each instance of RNis independently hydrogen or a nitrogen protecting group; or an ROgroup and an RNgroup are joined to form a substituted or unsubstituted heterocyclyl ring.

[0105] In certain embodiments, the method of preparing the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or salt thereof, further comprises combining a compound of Formula (X):or a salt thereof, with a compound of Formula (XI):or a salt thereof, and a compound of Formula (XII):or a salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, wherein: X′ is =O, =S, or =NR9; Y′ is =C(R9)2, =CHR9, or =CH2;H0824.70449WO00 45 / 250 #14309532v1each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and each instance of R14is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl.

[0106] In another aspect, the present disclosure provides compounds of Formula (II):, and salts thereof, wherein: X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,H0824.70449WO00 46 / 250 #14309532v1substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and represents a single or double bond.

[0107] In another aspect, the present disclosure provides compounds of Formula (III):, and salts thereof, wherein: X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted orH0824.70449WO00 47 / 250 #14309532v1unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0108] In another aspect, the present disclosure provides compounds of Formula (IV):, and salts thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group;H0824.70449WO00 48 / 250 #14309532v1n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0109] In another aspect, the present disclosure provides compounds of Formula (V):, and salts thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitutedH0824.70449WO00 49 / 250 #14309532v1aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0110] In another aspect, the present disclosure provides compounds of Formula (VI):, and salts thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=;H0824.70449WO00 50 / 250 #14309532v1each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0111] In another aspect, the present disclosure provides compounds of Formula (VII):, and salts thereof, wherein:H0824.70449WO00 51 / 250 #14309532v1X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0112] In another aspect, the present disclosure provides compounds of Formula (VIII):H0824.70449WO00 52 / 250 #14309532v1and salts thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and represents a single or double bond.

[0113] In another aspect, the present disclosure provides compounds of Formula (IX):H0824.70449WO00 53 / 250 #14309532v1, and salts thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to aH0824.70449WO00 54 / 250 #14309532v1sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; each instance of ROis independently hydrogen or an oxygen protecting group; and each instance of RNis independently hydrogen or a nitrogen protecting group; or an ROgroup and an RNgroup are joined to form a substituted or unsubstituted heterocyclyl ring; and represents a single or double bond. Embodiments of Formula (I) and Preparation Thereof

[0114] As generally described herein, a compound of Formula (I):, or a salt thereof, is prepared by oxidizing a compound of Formula (II):, or a salt thereof, under suitable conditions to provide the compound of Formula (I), or a salt thereof, wherein: X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring;H0824.70449WO00 55 / 250 #14309532v1n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and represents a single or double bond.

[0115] In certain embodiments, the compound of Formula (I) is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), or (I-g):, or a salt thereof.

[0116] In certain embodiments, the compound of Formula (I) is of Formula (I-a), or a salt thereof. In certain embodiments, the compound of Formula (I) is of Formula (I-b), or a salt thereof. In certain embodiments, the compound of Formula (I) is of Formula (I-c), or a salt thereof. In certain embodiments, the compound of Formula (I) is of Formula (I-d), or a salt thereof. In certain embodiments, the compound of Formula (I) is of Formula (I-e), or a salt thereof. In certain embodiments, the compound of Formula (I) is of Formula (I-f), or a salt thereof. In certain embodiments, the compound of Formula (I) is of Formula (I-g), or a salt thereof.

[0117] In certain embodiments, the compound of Formula (I-a) is of Formula (I-a-1):H0824.70449WO00 56 / 250 #14309532v1or a salt thereof.

[0118] In certain embodiments, the compound of Formula (I-b) is of Formula (I-b-1):, or a salt thereof.

[0119] In certain embodiments, the compound of Formula (I-c) is of Formula (I-c-1):, or a salt thereof.

[0120] In certain embodiments, the compound of Formula (I-d) is of Formula (I-d-1):or a salt thereof.

[0121] In certain embodiments, the compound of Formula (I-e) is of Formula (I-e-1) or (I-e-2):or a salt thereof.

[0122] In certain embodiments, the compound of Formula (I-e) is of Formula (I-e-1), or a salt thereof. In certain embodiments, the compound of Formula (I-e) is of Formula (I-e-2), or a salt thereof.

[0123] In certain embodiments, the compound of Formula (I-f) is of Formula (I-f-1) or (I-f-2):,H0824.70449WO00 57 / 250 #14309532v1or a salt thereof.

[0124] In certain embodiments, the compound of Formula (I-f) is of Formula (I-f-1), or a salt thereof. In certain embodiments, the compound of Formula (I-f) is of Formula (I-f-2), or a salt thereof.

[0125] In certain embodiments, the compound of Formula (I-g) is of Formula (I-g-1):or a salt thereof.

[0126] In certain embodiments, the compound of Formula (I) is of formula:, or a salt thereof.

[0127] In certain embodiments, the compound of Formula (I) is of formula:, or a salt thereof.

[0128] In certain embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposing the compound of Formula (II), or salt thereof, to a nitroxyl radical, a chlorite salt, and / or a hypochlorite salt. In certain embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposing the compound of Formula (II), or salt thereof, to a nitroxyl radical. In certain embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposing the compound of Formula (II), or salt thereof, to a chlorite salt. In certain embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposing the compound of Formula (II), or salt thereof, to a hypochlorite salt. In certainH0824.70449WO00 58 / 250 #14309532v1embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposing the compound of Formula (II), or salt thereof, to a nitroxyl radical, a chlorite salt, and a hypochlorite salt.

[0129] In certain embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposing the compound of Formula (II), or salt thereof, to a hypervalent iodine reagent or Swern oxidation conditions, followed by Pinnick oxidation conditions. In certain embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposing the compound of Formula (II), or salt thereof, to Collins reagent (pyridine - trioxochromium (2:1)).

[0130] In certain embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposing the compound of Formula (II), or salt thereof, to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 molar equivalents of the nitroxyl radical relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 molar equivalents of the nitroxyl radical relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 0.7 molar equivalents of the nitroxyl radical relative to the compound of Formula (II), or salt thereof.

[0131] In certain embodiments, the nitroxyl radical is 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 1-methyl-2-azaadamantane-N-oxyl (1-Me-AZADO), 2-azaadamantane-N-oxyl (AZADO), 9-azanoradamantane N-oxyl (Nor-AZADO), or 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO). In certain embodiments, the nitroxyl radical is 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO).

[0132] In certain embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposing the compound of Formula (II), or salt thereof, to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the chlorite salt relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 molar equivalents of the chlorite salt relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 2.0 molar equivalents of the chlorite salt relative to the compound of Formula (II), or salt thereof.

[0133] In certain embodiments, the chlorite salt is sodium chlorite or potassium chlorite. In certain embodiments, the chlorite salt is sodium chlorite.

[0134] In certain embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposing the compound of Formula (II), or salt thereof, to 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.15, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35,H0824.70449WO00 59 / 250 #14309532v10.36, 0.37, 0.38, 0.39, 0.40, 0.45, or 0.50 molar equivalents of the hypochlorite salt relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.10 molar equivalents of the hypochlorite salt relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 0.02 molar equivalents of the hypochlorite salt relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, or 0.35 molar equivalents of the hypochlorite salt relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 0.30 molar equivalents of the hypochlorite salt relative to the compound of Formula (II), or salt thereof.

[0135] In certain embodiments, the hypochlorite salt is sodium hypochlorite or potassium hypochlorite. In certain embodiments, the hypochlorite salt is sodium hypochlorite.

[0136] In certain embodiments, the nitroxyl radical is 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 1-methyl-2-azaadamantane-N-oxyl (1-Me-AZADO), 2-azaadamantane-N-oxyl (AZADO), 9-azanoradamantane N-oxyl (Nor-AZADO), or 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO); the chlorite salt is sodium chlorite or potassium chlorite; and the hypochlorite salt is sodium hypochlorite or potassium hypochlorite. In certain embodiments, the nitroxyl radical is 2,2,6,6- tetramethylpiperidine 1-oxyl (TEMPO); the chlorite salt is sodium chlorite; and the hypochlorite salt is sodium hypochlorite.

[0137] In certain embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises a reaction temperature of greater than ambient temperature, about 25 ℃ to about 60 ℃, or about 35 ℃. In certain embodiments, the reaction temperature is about 25 ℃ to about 60 ℃. In certain embodiments, the reaction temperature is about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, about 50 ℃, about 55 ℃, or about 60. In certain embodiments, the reaction temperature is about 35 ℃.

[0138] In certain embodiments, oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises acetonitrile and / or water. In certain embodiments, the solvent is or comprises acetonitrile. In certain embodiments, the solvent is or comprises water. In certain embodiments, the solvent is or comprises acetonitrile and water. In certain embodiments, water is or comprises an aqueous buffer. In certain embodiments, the solvent is or comprises ethyl acetate and / or water. In certain embodiments, the solvent is or comprises ethyl acetate. In certain embodiments, the solvent is or comprises ethyl acetate and water. In certain embodiments, the water is or comprises a phosphate buffer at pH 7.

[0139] In certain embodiments, the methods further comprise purifying the compound of Formula (I), or salt thereof. In certain embodiments, purifying the compound of Formula (I), or salt thereof, comprises recrystallization. In certain embodiments, purifying the compound of Formula (I), or saltH0824.70449WO00 60 / 250 #14309532v1thereof, comprises recrystallization from ethanol. In certain embodiments, purifying the compound of Formula (I), or salt thereof, comprises flash column chromatography. Embodiments of Formula (II) and Preparation Thereof

[0140] As generally described herein, a compound of Formula (II):, or a salt thereof, is prepared by cyclizing a compound of Formula (III):, or a salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, wherein: X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4;H0824.70449WO00 61 / 250 #14309532v1each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0141] In certain embodiments, the compound of Formula (II) is of Formula (II-a), (II-b), (II-c), (II- d), (II-e), (II-f) or (II-g):or a salt thereof.

[0142] In certain embodiments, the compound of Formula (II) is of Formula (II-a), or a salt thereof. In certain embodiments, the compound of Formula (II) is of Formula (II-b), or a salt thereof. In certain embodiments, the compound of Formula (II) is of Formula (II-c), or a salt thereof. In certain embodiments, the compound of Formula (II) is of Formula (II-d), or a salt thereof. In certain embodiments, the compound of Formula (II) is of Formula (II-e), or a salt thereof. In certain embodiments, the compound of Formula (II) is of Formula (II-f), or a salt thereof. In certain embodiments, the compound of Formula (II) is of Formula (II-g), or a salt thereof.H0824.70449WO00 62 / 250 #14309532v1

[0143] In certain embodiments, the compound of Formula (II-a) is of Formula (II-a-1):or a salt thereof.

[0144] In certain embodiments, the compound of Formula (II-b) is of Formula (II-b-1):, or a salt thereof.

[0145] In certain embodiments, the compound of Formula (II-c) is of Formula (II-c-1):or a salt thereof.

[0146] In certain embodiments, the compound of Formula (II-d) is of Formula (II-d-1):or a salt thereof.

[0147] In certain embodiments, the compound of Formula (II-e) is of Formula (II-e-1) or (II-e-2):, or a salt thereof.

[0148] In certain embodiments, the compound of Formula (II-e) is of Formula (II-e-1), or a salt thereof. In certain embodiments, the compound of Formula (II-e) is of Formula (II-e-2), or a salt thereof.H0824.70449WO00 63 / 250 #14309532v1

[0149] In certain embodiments, the compound of Formula (II-f) is of Formula (II-f-1) or (II-f-2):, or a salt thereof.

[0150] In certain embodiments, the compound of Formula (II-f) is of Formula (II-f-1), or a salt thereof. In certain embodiments, the compound of Formula (II-f) is of Formula (II-f-2), or a salt thereof.

[0151] In certain embodiments, the compound of Formula (II-g) is of Formula (II-g-1):or a salt thereof.

[0152] In certain embodiments, the compound of Formula (II) is of formula:, or a salt thereof.

[0153] In certain embodiments, the compound of Formula (II) is of formula:, or a salt thereof.

[0154] In certain embodiments, the method comprises cyclizing the compound of Formula (III), or salt thereof, under suitable conditions to provide the compound of Formula (II), or the salt thereof, comprises exposing the compound of Formula (III), or salt thereof, to a base.H0824.70449WO00 64 / 250 #14309532v1

[0155] In certain embodiments, cyclizing the compound of Formula (III), or salt thereof, under suitable conditions to provide the compound of Formula (II), or the salt thereof, comprises exposing the compound of Formula (III), or salt thereof, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 molar equivalents of the base relative to the compound of Formula (III), or salt thereof. In certain embodiments, the method comprises exposure to 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 molar equivalents of the base relative to the compound of Formula (III), or salt thereof. In certain embodiments, the method comprises exposure to 25 molar equivalents of the base relative to the compound of Formula (III), or salt thereof.

[0156] In certain embodiments, the base is an inorganic base. In certain embodiments, the base is a hydroxide salt. In certain embodiments, the base is lithium hydroxide, sodium hydroxide, or potassium hydroxide. In certain embodiments, the base is lithium hydroxide. In certain embodiments, the base is sodium hydroxide. In certain embodiments, the base is potassium hydroxide. In certain embodiments, the base is a carbonate salt. In certain embodiments, the base is sodium carbonate or potassium carbonate. In certain embodiments, the base is sodium carbonate. In certain embodiments, the base is potassium carbonate.

[0157] In certain embodiments, cyclizing the compound of Formula (III), or salt thereof, under suitable conditions to provide the compound of Formula (II), or the salt thereof, comprises exposing the compound of Formula (III), or salt thereof, to a phase transfer catalyst.

[0158] In certain embodiments, cyclizing the compound of Formula (III), or salt thereof, under suitable conditions to provide the compound of Formula (II), or the salt thereof, comprises exposing the compound of Formula (III), or salt thereof, to 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, or 2.00 molar equivalents of the phase transfer catalyst relative to the compound of Formula (III), or salt thereof. In certain embodiments, the method comprises exposure to 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, or 1.25 molar equivalents of the phase transfer catalyst relative to the compound of Formula (III), or salt thereof. In certain embodiments, the method comprises exposure to 1.05 molar equivalents of the phase transfer catalyst relative to the compound of Formula (III), or salt thereof.

[0159] In certain embodiments, the phase transfer catalyst is an ammonium salt. In certain embodiments, the phase transfer catalyst is tetrabutylammonium hydrogen sulfate, benzyltriethylammonium chloride, or methyltributylammonium chloride. In certain embodiments, the phase transfer catalyst is tetrabutylammonium hydrogen sulfate. In certain embodiments, the phase transfer catalyst is benzyltriethylammonium chloride. In certain embodiments, the phase transfer catalyst is methyltributylammonium chloride. In certain embodiments, the phase transfer catalyst is a crown ether. In certain embodiments, the phase transfer catalyst is 12-crown-4, 15-crown-5, 18- crown-6, dibenzo-18-crown-6, or an aza-crown ether. In certain embodiments, the phase transfer catalyst is 12-crown-4. In certain embodiments, the phase transfer catalyst is 15-crown-5. In certainH0824.70449WO00 65 / 250 #14309532v1embodiments, the phase transfer catalyst is 18-crown-6. In certain embodiments, the phase transfer catalyst is dibenzo-18-crown-6. In certain embodiments, the phase transfer catalyst is an aza-crown ether.

[0160] In certain embodiments, cyclizing the compound of Formula (III), or salt thereof, under suitable conditions to provide the compound of Formula (II), or the salt thereof, comprises a reaction temperature of about 0 ℃ to about 40 ℃, or about 25 ℃. In certain embodiments, the reaction temperature is about 0 ℃ to about 40 ℃. In certain embodiments, the reaction temperature is about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 26 ℃, about 27 ℃, about 28 ℃, about 29 ℃, about 30 ℃, about 35 ℃, or about 40 ℃. In certain embodiments, the reaction temperature is about 20 ℃. In certain embodiments, the reaction temperature is about 21 ℃. In certain embodiments, the reaction temperature is about 22 ℃. In certain embodiments, the reaction temperature is about 23 ℃. In certain embodiments, the reaction temperature is about 24 ℃. In certain embodiments, the reaction temperature is about 25 ℃.

[0161] In certain embodiments, cyclizing the compound of Formula (III), or salt thereof, under suitable conditions to provide the compound of Formula (II), or the salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises toluene and / or water. In certain embodiments, the solvent is or comprises toluene. In certain embodiments, the solvent is or comprises water. In certain embodiments, the solvent is or comprises toluene and water. In certain embodiments, the solvent is or comprises toluene, dichloromethane, chloroform, 1,2-dichloroethane, or diethyl ether, and water. In certain embodiments, the solvent is or comprises chloroform and / or water. In certain embodiments, the solvent is or comprises chloroform. In certain embodiments, the solvent is or comprises chloroform and water. In certain embodiments, the solvent is or comprises dichloromethane. In certain embodiments, the solvent is or comprises 1,2-dichloroethane. In certain embodiments, the solvent is or comprises diethyl ether.

[0162] In certain embodiments, the methods further comprise purifying the compound of Formula (II), or salt thereof. In certain embodiments, purifying the compound of Formula (II), or salt thereof, comprises recrystallization. In certain embodiments, purifying the compound of Formula (II), or salt thereof, comprises flash column chromatography. Embodiments of Formula (III) and Preparation Thereof

[0163] As generally described herein, a compound of Formula (III):, or a salt thereof, is prepared by deprotecting a compound of Formula (IV):H0824.70449WO00 66 / 250 #14309532v1, or a salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;H0824.70449WO00 67 / 250 #14309532v1R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0164] In certain embodiments, the compound of Formula (III) is of Formula (III-a), (III-b), (III-c), (III-d), or (III-e):or a salt thereof.

[0165] In certain embodiments, the compound of Formula (III) is of Formula (III-a), or a salt thereof. In certain embodiments, the compound of Formula (III) is of Formula (III-b), or a salt thereof. In certain embodiments, the compound of Formula (III) is of Formula (III-c), or a salt thereof. In certain embodiments, the compound of Formula (III) is of Formula (III-d), or a salt thereof.

[0166] In certain embodiments, the compound of Formula (III-a) is of Formula (III-a-1):or a salt thereof.H0824.70449WO00 68 / 250 #14309532v1

[0167] In certain embodiments, the compound of Formula (III-b) is of Formula (III-b-1):or a salt thereof.

[0168] In certain embodiments, the compound of Formula (III-c) is of Formula (III-c-1) or (III-c-2):or a salt thereof.

[0169] In certain embodiments, the compound of Formula (III-c) is of Formula (III-c-1), or a salt thereof. In certain embodiments, the compound of Formula (III-c) is of Formula (III-c-2), or a salt thereof.

[0170] In certain embodiments, the compound of Formula (III-d) is of Formula (III-d-1) or (III-d- 2):or a salt thereof.

[0171] In certain embodiments, the compound of Formula (III-d) is of Formula (III-d-1), or a salt thereof. In certain embodiments, the compound of Formula (III-d) is of Formula (III-d-2), or a salt thereof.

[0172] In certain embodiments, the compound of Formula (III-e) is of Formula (III-e-1) or (III-e-2):, or a salt thereof.H0824.70449WO00 69 / 250 #14309532v1

[0173] In certain embodiments, the compound of Formula (III-e) is of Formula (III-e-1), or a salt thereof. In certain embodiments, the compound of Formula (III-e) is of Formula (III-e-2), or a salt thereof.

[0174] In certain embodiments, the compound of Formula (III) is of formula:, or a salt thereof.

[0175] In certain embodiments, the compound of Formula (III) is of formula:, or a salt thereof.

[0176] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, comprises exposing the compound of Formula (IV), or salt thereof, to an acid.

[0177] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, comprises exposing the compound of Formula (IV), or salt thereof, to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the acid relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 molar equivalents of the acid relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 2.0 molar equivalents of the acid relative to the compound of Formula (IV), or salt thereof.

[0178] In certain embodiments, the acid is a sulfonic acid. In certain embodiments, the acid is (±)- camphor-10-sulfonic acid. In certain embodiments, the acid is p-toluenesulfonic acid. In certain embodiments, the acid is pyridinium p-toluenesulfonate.

[0179] In certain embodiments, the acid is an aqueous acid. In certain embodiments, the acid is aqueous hydrochloric acid.

[0180] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, comprises a reaction temperature of about 0 ℃ to about 40 ℃, or about 25 ℃. In certain embodiments, the reactionH0824.70449WO00 70 / 250 #14309532v1temperature is about 0 ℃ to about 40 ℃. In certain embodiments, the reaction temperature is about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 26 ℃, about 27 ℃, about 28 ℃, about 29 ℃, about 30 ℃, about 35 ℃, or about 40 ℃. In certain embodiments, the reaction temperature is about 20 ℃. In certain embodiments, the reaction temperature is about 21 ℃. In certain embodiments, the reaction temperature is about 22 ℃. In certain embodiments, the reaction temperature is about 23 ℃. In certain embodiments, the reaction temperature is about 24 ℃. In certain embodiments, the reaction temperature is about 25 ℃.

[0181] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises methanol. In certain embodiments, the solvent is or comprises ethanol. In certain embodiments, the solvent is or comprises ethylene glycol. In certain embodiments, the solvent is or comprises water and diethyl ether. In certain embodiments, the solvent is or comprises water and tetrahydrofuran. In certain embodiments, the solvent is or comprises water and dichloromethane.

[0182] In certain embodiments, the methods further comprise purifying the compound of Formula (III), or salt thereof. In certain embodiments, purifying the compound of Formula (III), or salt thereof, comprises recrystallization. In certain embodiments, purifying the compound of Formula (III), or salt thereof, comprises flash column chromatography. Embodiments of Formula (IV) and Preparation Thereof

[0183] As generally described herein, a compound of Formula (IV):or a salt thereof, is prepared by hydrofunctionalization of a compound of Formula (V):, or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted orH0824.70449WO00 71 / 250 #14309532v1unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.H0824.70449WO00 72 / 250 #14309532v1

[0184] In certain embodiments, the compound of Formula (IV) is of Formula (IV-a), (IV-b), or (IV- c):, or a salt thereof, wherein each instance of R12is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaliphatic.

[0185] In certain embodiments, the compound of Formula (IV) is of Formula (IV-a), or a salt thereof. In certain embodiments, the compound of Formula (IV) is of Formula (IV-b), or a salt thereof. In certain embodiments, the compound of Formula (IV) is of Formula (IV-c), or a salt thereof.

[0186] In certain embodiments, the compound of Formula (IV-a) is of Formula (IV-a-1):or a salt thereof.

[0187] In certain embodiments, the compound of Formula (IV-b) is of Formula (IV-b-1) or (IV-b- 2):, or a salt thereof.

[0188] In certain embodiments, the compound of Formula (IV-b) is of Formula (IV-b-1), or a salt thereof. In certain embodiments, the compound of Formula (IV-b) is of Formula (IV-b-2), or a salt thereof.H0824.70449WO00 73 / 250 #14309532v1

[0189] In certain embodiments, the compound of Formula (IV-c) is of Formula (IV-c-1) or (IV-c-2):, or a salt thereof.

[0190] In certain embodiments, the compound of Formula (IV-c) is of Formula (IV-c-1), or a salt thereof. In certain embodiments, the compound of Formula (IV-c) is of Formula (IV-c-2), or a salt thereof.

[0191] In certain embodiments, the compound of Formula (IV) is of formula:, or a salt thereof.

[0192] In certain embodiments, the compound of Formula (IV) is of formula:, or a salt thereof.

[0193] In certain embodiments, hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises hydroboration of the compound of Formula (V) by exposing the compound of Formula (V), or salt thereof, to a borane.

[0194] In certain embodiments, hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises exposing the compound of Formula (V), or salt thereof, to 1, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the borane relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 molar equivalents of theH0824.70449WO00 74 / 250 #14309532v1borane relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 2.5 molar equivalents of the borane relative to the compound of Formula (V), or salt thereof.

[0195] In certain embodiments, the borane is dicyclohexylborane, borane-dimethyl sulfide, disiamylborane, or 9-borabicyclo(3.3.1)nonane (9-BBN). In certain embodiments, the borane is dicyclohexylborane. In certain embodiments, the borane is borane-dimethyl sulfide. In certain embodiments, the borane is disiamylborane. In certain embodiments, the borane is 9-BBN.

[0196] In certain embodiments, the hydrofunctionalization strategy comprises hydroboration- oxidation by borane-dimethyl sulfide followed by NaOH / H2O2, then Appel iodination with I2 and PPh3.

[0197] In certain embodiments, hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises hydrozirconation of the compound of Formula (V) by exposing the compound of Formula (V), or salt thereof, to an organozirconium compound.

[0198] In certain embodiments, hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises exposing the compound of Formula (V), or salt thereof, to 1, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the organozirconium compound relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 molar equivalents of the organozirconium compound relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 2.5 molar equivalents of the organozirconium compound relative to the compound of Formula (V), or salt thereof.

[0199] In certain embodiments, the organozirconium compound is Schwartz's reagent (Cp2ZrHCl).

[0200] In certain embodiments, hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises a first reaction temperature of about -20 ℃ to about 30 ℃, or about 0 ℃. In certain embodiments, the first reaction temperature is about -20 ℃ to about 30 ℃. In certain embodiments, the first reaction temperature is about -20 ℃, about -15 ℃, about -10 ℃, about -5 ℃, about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, or about 30 ℃. In certain embodiments, the first reaction temperature is about 0 ℃.

[0201] In certain embodiments, hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, further comprises addition of an oxidant. In certain embodiments, the oxidant comprises iodine. In certain embodiments, the oxidant comprises an acetate salt and iodine. In certain embodiments, the acetate salt is sodium acetate or potassium acetate. In certain embodiments, the acetate salt is sodium acetate. In certain embodiments, the oxidant comprises sodium acetate and iodine.H0824.70449WO00 75 / 250 #14309532v1

[0202] In certain embodiments, hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises addition of 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, or 15.0 molar equivalents of the acetate salt relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, or 12.5 molar equivalents of the acetate salt relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 10.0 molar equivalents of the acetate salt relative to the compound of Formula (V), or salt thereof.

[0203] In certain embodiments, hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises addition of 5.0, 5.5, 6.0, 6.5, 7.0, 7.25, 7.5, 7.75, 8.0, 8.25, 8.5, 8.75, 9.0, 9.25, 9.5, 9.75, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, or 15.0 molar equivalents of iodine relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 7.0, 7.25, 7.5, 7.75, 8.0, 8.25, 8.5, 8.75, 9.0, 9.25, 9.5, 9.75, or 10.0 molar equivalents of iodine relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 8.75 molar equivalents of iodine relative to the compound of Formula (V), or salt thereof.

[0204] In certain embodiments, hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises a second reaction temperature of about -20 ℃ to about 50 ℃, about 0 ℃, or about 25 ℃. In certain embodiments, the second reaction temperature is about -20 ℃ to about 50 ℃. In certain embodiments, the second reaction temperature is about -20 ℃, about -15 ℃, about -10 ℃, about -5 ℃, about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, or about 50 ℃. In certain embodiments, the second reaction temperature is about 0 ℃. In certain embodiments, the second reaction temperature is about 20 ℃. In certain embodiments, the second reaction temperature is about 21 ℃. In certain embodiments, the second reaction temperature is about 22 ℃. In certain embodiments, the second reaction temperature is about 23 ℃. In certain embodiments, the second reaction temperature is about 24 ℃. In certain embodiments, the second reaction temperature is about 25 ℃.

[0205] In certain embodiments, hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises tetrahydrofuran and / or methanol. In certain embodiments, the solvent is or comprises tetrahydrofuran. In certain embodiments, the solvent is or comprises methanol, ethanol, or isopropanol. In certain embodiments, the solvent is or comprises methanol. In certain embodiments, the solvent is or comprises ethanol. In certain embodiments, the solvent is or comprises isopropanol. In certain embodiments, the solvent isH0824.70449WO00 76 / 250 #14309532v1or comprises tetrahydrofuran and methanol. In certain embodiments, the solvent is or comprises tetrahydrofuran, 2-methyltetrahydrofuran, or diethyl ether. In certain embodiments, the solvent is or comprises 2-methyltetrahydrofuran. In certain embodiments, the solvent is or comprises diethyl ether. In certain embodiments, the solvent is or comprises methanol, ethanol, or isopropanol, and is or comprises tetrahydrofuran, 2-methyltetrahydrofuran, or diethyl ether.

[0206] In certain embodiments, the methods further comprise purifying the compound of Formula (IV), or salt thereof. In certain embodiments, purifying the compound of Formula (IV), or salt thereof, comprises recrystallization. In certain embodiments, purifying the compound of Formula (IV), or salt thereof, comprises flash column chromatography. Embodiments of Formula (V) and Preparation Thereof

[0207] As generally described herein, a compound of Formula (V):or a salt thereof, is prepared by protecting a compound of Formula (VI):or a salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,H0824.70449WO00 77 / 250 #14309532v1–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0208] In certain embodiments, the compound of Formula (V) is of Formula (V-a), (V-b), or (V-c):, or a salt thereof, wherein each instance of R12is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaliphatic.

[0209] In certain embodiments, the compound of Formula (V) is of Formula (V-a), or a salt thereof. In certain embodiments, the compound of Formula (V) is of Formula (V-b), or a salt thereof. In certain embodiments, the compound of Formula (V) is of Formula (V-c), or a salt thereof.H0824.70449WO00 78 / 250 #14309532v1

[0210] In certain embodiments, the compound of Formula (V-a) is of Formula (V-a-1):, or a salt thereof.

[0211] In certain embodiments, the compound of Formula (V-b) is of Formula (V-b-1) or (V-b-2):, or a salt thereof.

[0212] In certain embodiments, the compound of Formula (V-b) is of Formula (V-b-1), or a salt thereof. In certain embodiments, the compound of Formula (V-b) is of Formula (V-b-2), or a salt thereof.

[0213] In certain embodiments, the compound of Formula (V-c) is of Formula (V-c-1) or (V-c-2):, or a salt thereof.

[0214] In certain embodiments, the compound of Formula (V-c) is of Formula (V-c-1), or a salt thereof. In certain embodiments, the compound of Formula (V-c) is of Formula (V-c-2), or a salt thereof.

[0215] In certain embodiments, the compound of Formula (V) is of formula:, or a salt thereof.H0824.70449WO00 79 / 250 #14309532v1

[0216] In certain embodiments, the compound of Formula (V) is of formula:, or a salt thereof.

[0217] In certain embodiments, protecting the compound of Formula (VI), or salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, comprises exposing the compound of Formula (VI), or salt thereof, to a base, catalyst, and protecting group reagent.

[0218] In certain embodiments, protecting the compound of Formula (VI), or salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, comprises exposing the compound of Formula (VI), or salt thereof, to 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, or 1.00 molar equivalents of the base relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 molar equivalents of the base relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 0.30 molar equivalents of the base relative to the compound of Formula (VI), or salt thereof.

[0219] In certain embodiments, the base is an inorganic base. In certain embodiments, the base is a hydroxide salt. In certain embodiments, the base is lithium hydroxide, sodium hydroxide, or potassium hydroxide. In certain embodiments, the base is lithium hydroxide. In certain embodiments, the base is sodium hydroxide. In certain embodiments, the base is potassium hydroxide. In certain embodiments, the base is a carbonate salt. In certain embodiments, the base is sodium carbonate or potassium carbonate. In certain embodiments, the base is sodium carbonate. In certain embodiments, the base is potassium carbonate.

[0220] In certain embodiments, protecting the compound of Formula (VI), or salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, comprises exposing the compound of Formula (VI), or salt thereof, to 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 016, 0.17, 0.18, 0.19, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, or 1.00 molar equivalents of the catalyst relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, or 0.15 molar equivalents of the catalyst relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 0.10 molar equivalents of the catalyst relative to the compound of Formula (VI), or salt thereof.

[0221] In certain embodiments, the catalyst is 4-(dimethylamino)pyridine.H0824.70449WO00 80 / 250 #14309532v1

[0222] In certain embodiments, protecting the compound of Formula (VI), or salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, comprises exposing the compound of Formula (VI), or salt thereof, to 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, or 2.00 molar equivalents of the protecting group reagent relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, or 1.50 molar equivalents of the protecting group reagent relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 1.20 molar equivalents of the protecting group reagent relative to the compound of Formula (VI), or salt thereof.

[0223] In certain embodiments, the protecting group reagent is Boc2O, FmocCl, CbzCl, TrocCl, Teoc-Osu, or an allylating reagent. In certain embodiments, the protecting group installed with the protecting group reagent is Boc, Fmoc, Cbz, Troc, Teoc, Alloc, Adoc, or Pnz. In certain embodiments, the protecting group reagent is Boc2O.

[0224] In certain embodiments, protecting the compound of Formula (VI), or salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, comprises a reaction temperature of about 0 ℃ to about 50 ℃, or about 25 ℃. In certain embodiments, the reaction temperature is about 0 ℃ to about 50 ℃. In certain embodiments, the reaction temperature is about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, or about 50 ℃. In certain embodiments, the reaction temperature is about 20 ℃. In certain embodiments, the reaction temperature is about 21 ℃. In certain embodiments, the reaction temperature is about 22 ℃. In certain embodiments, the reaction temperature is about 23 ℃. In certain embodiments, the reaction temperature is about 24 ℃. In certain embodiments, the reaction temperature is about 25 ℃.

[0225] In certain embodiments, protecting the compound of Formula (VI), or salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises tetrahydrofuran, diethyl ether, 2- methyltetrahydrofuran, water, dichloromethane, toluene, and / or chloroform. In certain embodiments, the solvent is or comprises tetrahydrofuran, water, and / or dichloromethane. In certain embodiments, the solvent is or comprises tetrahydrofuran. In certain embodiments, the solvent is or comprises diethyl ether. In certain embodiments, the solvent is or comprises 2-methyltetrahydrofuran. In certain embodiments, the solvent is or comprises water. In certain embodiments, the solvent is or comprises dichloromethane. In certain embodiments, the solvent is or comprises toluene. In certain embodiments, the solvent is or comprises chloroform. In certain embodiments, the solvent is or comprises tetrahydrofuran and water. In certain embodiments, the solvent is or comprises tetrahydrofuran, water, and dichloromethane.H0824.70449WO00 81 / 250 #14309532v1

[0226] In certain embodiments, the methods further comprise purifying the compound of Formula (V), or salt thereof. In certain embodiments, purifying the compound of Formula (V), or salt thereof, comprises recrystallization. In certain embodiments, purifying the compound of Formula (V), or salt thereof, comprises flash column chromatography. Embodiments of Formula (VI) and Preparation Thereof

[0227] As generally described herein, a compound of Formula (VI):or a salt thereof, is prepared by reducing a compound of Formula (VII):, or a salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4;H0824.70449WO00 82 / 250 #14309532v1each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0228] In certain embodiments, the compound of Formula (VI) is of Formula (VI-a), (VI-b), or (VI- c):, or a salt thereof, wherein each instance of R12is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaliphatic.

[0229] In certain embodiments, the compound of Formula (VI) is of Formula (VI-a), or a salt thereof. In certain embodiments, the compound of Formula (VI) is of Formula (VI-b), or a salt thereof. In certain embodiments, the compound of Formula (VI) is of Formula (VI-c), or a salt thereof.H0824.70449WO00 83 / 250 #14309532v1

[0230] In certain embodiments, the compound of Formula (VI-a) is of Formula (VI-a-1):or a salt thereof

[0231] In certain embodiments, the compound of Formula (VI-b) is of Formula (VI-b-1) or (VI-b- 2):, or a salt thereof.

[0232] In certain embodiments, the compound of Formula (VI-b) is of Formula (VI-b-1), or a salt thereof. In certain embodiments, the compound of Formula (VI-b) is of Formula (VI-b-2), or a salt thereof.

[0233] In certain embodiments, the compound of Formula (VI-c) is of Formula (VI-c-1) or (VI-c-2):or a salt thereof.

[0234] In certain embodiments, the compound of Formula (VI-c) is of Formula (VI-c-1), or a salt thereof. In certain embodiments, the compound of Formula (VI-c) is of Formula (VI-c-2), or a salt thereof.

[0235] In certain embodiments, the compound of Formula (VI) is of formula:, or a salt thereof.H0824.70449WO00 84 / 250 #14309532v1

[0236] In certain embodiments, the compound of Formula (VI) is of formula:, or a salt thereof.

[0237] In certain embodiments, reducing the compound of Formula (VII), or salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, comprises exposing the compound of Formula (VII), or salt thereof, to a metal hydride.

[0238] In certain embodiments, reducing the compound of Formula (VII), or salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, comprises exposing the compound of Formula (VII), or salt thereof, to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the metal hydride relative to the compound of Formula (VII), or salt thereof. In certain embodiments, the method comprises exposure to 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 molar equivalents of the metal hydride relative to the compound of Formula (VII), or salt thereof. In certain embodiments, the method comprises exposure to 2.0 molar equivalents of the metal hydride relative to the compound of Formula (VII), or salt thereof.

[0239] In certain embodiments, the metal hydride is lithium aluminum hydride.

[0240] In certain embodiments, reducing the compound of Formula (VII), or salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, comprises exposing the compound of Formula (VII), or salt thereof, to a silane, borane, or organoboronate.

[0241] In certain embodiments, reducing the compound of Formula (VII), or salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, comprises a first reaction temperature of about -20 ℃ to about 25 ℃, or about 0 ℃. In certain embodiments, the first reaction temperature is about -20 ℃ to about 25 ℃. In certain embodiments, the first reaction temperature is about -20 ℃, about -15 ℃, about -10 ℃, about -5 ℃, about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, or about 25 ℃. In certain embodiments, the first reaction temperature is about 0 ℃.

[0242] In certain embodiments, reducing the compound of Formula (VII), or salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, comprises a second reaction temperature of greater than ambient temperature, about 25 ℃ to about 100 ℃, or about 70 ℃. In certain embodiments, the second reaction temperature is greater than ambient temperature. In certain embodiments, the second reaction temperature is about 25 ℃ to about 100 ℃. In certain embodiments, the second reaction temperature is about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃,H0824.70449WO00 85 / 250 #14309532v1about 45 ℃, about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, about 80 ℃, about 85 ℃, about 90 ℃, about 95 ℃, or about 100 ℃. In certain embodiments, the second reaction temperature is about 70 ℃.

[0243] In certain embodiments, reducing the compound of Formula (VII), or salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises tetrahydrofuran. In certain embodiments, the solvent is or comprises diethyl ether. In certain embodiments, the solvent is or comprises 2- methyltetrahydrofuran.

[0244] In certain embodiments, the methods further comprise purifying the compound of Formula (VI), or salt thereof. In certain embodiments, purifying the compound of Formula (VI), or salt thereof, comprises recrystallization. In certain embodiments, purifying the compound of Formula (VI), or salt thereof, comprises flash column chromatography. Embodiments of Formula (VII) and Preparation Thereof

[0245] As generally described herein, a compound of Formula (VII):or a salt thereof, is prepared by protecting a compound of Formula (VIII):or a salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substitutedH0824.70449WO00 86 / 250 #14309532v1or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

[0246] In some embodiments the compound of Formula (VII) is of Formula (VII-a), (VII-b), (VII- c), or (VII-d):H0824.70449WO00 87 / 250 #14309532v1or a salt thereof, wherein each instance of R12is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaliphatic.

[0247] In some embodiments the compound of Formula (VII) is of Formula (VII-a), or a salt thereof. In some embodiments the compound of Formula (VII) is of Formula (VII-b), or a salt thereof. In some embodiments the compound of Formula (VII) is of Formula (VII-c), or a salt thereof. In some embodiments the compound of Formula (VII) is of Formula (VII-d), or a salt thereof.

[0248] In some embodiments the compound of Formula (VII-a) is of Formula (VII-a-1):or a salt thereof.

[0249] In some embodiments the compound of Formula (VII-b) is of Formula (VII-b-1):or a salt thereof.

[0250] In certain embodiments, the compound of Formula (VII-c) is of Formula (VII-c-1) or (VII-c- 2):, or a salt thereof.H0824.70449WO00 88 / 250 #14309532v1

[0251] In certain embodiments, the compound of Formula (VII-c) is of Formula (VII-c-1), or a salt thereof. In certain embodiments, the compound of Formula (VII-c) is of Formula (VII-c-2), or a salt thereof.

[0252] In certain embodiments, the compound of Formula (VII-d) is of Formula (VII-d-1) or (VII- d-2):, or a salt thereof.

[0253] In certain embodiments, the compound of Formula (VII-d) is of Formula (VII-d-1), or a salt thereof. In certain embodiments, the compound of Formula (VII-d) is of Formula (VII-d-2), or a salt thereof.

[0254] In certain embodiments, the compound of Formula (VII) is of formula:, or a salt thereof.

[0255] In certain embodiments, the compound of Formula (VII) is of formula:, or a salt thereof.

[0256] In certain embodiments, protecting the compound of Formula (VIII), or salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to 2,2-dimethoxypropane and / or acetone. In certain embodiments, protecting the compound of Formula (VIII), or salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to 2,2-dimethoxypropane. In certain embodiments, protecting theH0824.70449WO00 89 / 250 #14309532v1compound of Formula (VIII), or salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to acetone. In certain embodiments, protecting the compound of Formula (VIII), or salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to 2,2-dimethoxypropane and acetone.

[0257] In certain embodiments, protecting the compound of Formula (VIII), or salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, comprises a ratio of 2,2-dimethoxypropane to acetone of 1.0:1.0, 1.1:1.0, 1.2:1.0, 1.3:1.0, 1.4:1.0, 1.5:1.0, 1.6:1.0, 1.7:1.0, 1.8:1.0, 1.9:1.0, 2.0:1.0, 2.1:1.0, 2.2:1.0, 2.3:1.0, 2.4:1.0, 2.5:1.0, 2.6:1.0, 2.7:1.0, 2.8:1.0, 2.9:1.0, 3.0:1.0, 3.5:1.0, 4.0:1.0, 4.5:1.0, or 5.0:1.0 (v:v). In certain embodiments, the ratio of 2,2- dimethoxypropane to acetone is 1.5:1.0, 1.6:1.0, 1.7:1.0, 1.8:1.0, 1.9:1.0, 2.0:1.0, 2.1:1.0, 2.2:1.0, 2.3:1.0, 2.4:1.0, or 2.5:1.0 (v:v). In certain embodiments, the ratio of 2,2-dimethoxypropane to acetone is 2.0:1.0 (v:v).

[0258] In certain embodiments, protecting the compound of Formula (VIII), or salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to an acid.

[0259] In certain embodiments, protecting the compound of Formula (VIII), or salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 molar equivalents of the acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 2.0 molar equivalents of the acid relative to the compound of Formula (VIII), or salt thereof.

[0260] In certain embodiments, the acid is a sulfonic acid. In certain embodiments, the acid is (±)- camphor-10-sulfonic acid. In certain embodiments, the acid is p-toluenesulfonic acid. In certain embodiments, the acid is pyridinium p-toluenesulfonate. In certain embodiments, the acid is H2SO4.

[0261] In certain embodiments, protecting the compound of Formula (VIII), or salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, comprises a reaction temperature of about 0 ℃ to about 40 ℃, or about 25 ℃. In certain embodiments, the reaction temperature is about 0 ℃ to about 40 ℃. In certain embodiments, the reaction temperature is about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, or about 40 ℃. In certain embodiments, the reaction temperature is about 20 ℃. In certain embodiments, the reaction temperature is about 21 ℃. In certain embodiments, the reaction temperature is about 22 ℃. In certain embodiments, the reaction temperature is about 23 ℃. In certain embodiments, the reaction temperature is about 24 ℃. In certain embodiments, the reaction temperature is about 25 ℃.H0824.70449WO00 90 / 250 #14309532v1

[0262] In certain embodiments, the methods further comprise purifying the compound of Formula (VII), or salt thereof. In certain embodiments, purifying the compound of Formula (VII), or salt thereof, comprises recrystallization. In certain embodiments, purifying the compound of Formula (VII), or salt thereof, comprises flash column chromatography. Embodiments of Formula (VIII) and Preparation Thereof

[0263] As generally described herein, a compound of Formula (VIII):, or a salt thereof, is prepared by cyclizing a compound of Formula (IX):, or a salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted orH0824.70449WO00 91 / 250 #14309532v1unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; each instance of ROis independently hydrogen or an oxygen protecting group; and each instance of RNis independently hydrogen or a nitrogen protecting group; or an ROgroup and an RNgroup are joined to form a substituted or unsubstituted heterocyclyl ring; and represents a single or double bond.

[0264] In certain embodiments, the compound of Formula (VIII) is of Formula (VIII-a) or (VIII-b):, or a salt thereof.

[0265] In certain embodiments, the compound of Formula (VIII) is of Formula (VIII-a), or a salt thereof. In certain embodiments, the compound of Formula (VIII) is of Formula (VIII-b), or a salt thereof.

[0266] In certain embodiments, the compound of Formula (VIII-a) is of Formula (VIII-a-1):or a salt thereof.H0824.70449WO00 92 / 250 #14309532v1

[0267] In certain embodiments, the compound of Formula (VIII-b) is of Formula (VIII-b-1) or (VIII-b-2):or a salt thereof.

[0268] In certain embodiments, the compound of Formula (VIII-b) is of Formula (VIII-b-1), or a salt thereof. In certain embodiments, the compound of Formula (VIII-b) is of Formula (VIII-b-2), or a salt thereof.

[0269] In certain embodiments, the compound of Formula (VIII) is of formula:, or a salt thereof.

[0270] In certain embodiments, the compound of Formula (VIII) is of formula:, or a salt thereof.

[0271] In certain embodiments, cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises exposing the compound of Formula (IX), or salt thereof, to an acid, thereby forming a reaction mixture.

[0272] In certain embodiments, cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises exposing the compound of Formula (IX), or salt thereof, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 molar equivalents of the acid relative to the compound of Formula (IX), or salt thereof. In certain embodiments, the method comprises exposure to 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 molar equivalents of the acid relative to the compound of Formula (IX), or salt thereof. In certain embodiments, the method comprises exposure to 10 molar equivalents of the acid relative to the compound of Formula (IX), or salt thereof.H0824.70449WO00 93 / 250 #14309532v1

[0273] In certain embodiments, the acid is an aqueous acid. In certain embodiments, the acid is HCl. In certain embodiments, the acid is an aqueous solution of HCl. In certain embodiments, the acid is HCl in methanol. In certain embodiments, the HCl in methanol is prepared by reacting trimethylsilyl chloride (TMSCl) and methanol. In certain embodiments, the HCl in methanol is prepared by reacting acetyl chloride and methanol. In certain embodiments, the acid is trifluoroacetic acid. In certain embodiments, the acid is p-toluenesulfonic acid. In certain embodiments, the acid is H2SO4. In certain embodiments, the acid is H3PO4.

[0274] In certain embodiments, cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises a first reaction temperature of about 0 ℃ to about 40 ℃, or about 25 ℃. In certain embodiments, the first reaction temperature is about 0 ℃ to about 40 ℃. In certain embodiments, the first reaction temperature is about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, or about 40 ℃. In certain embodiments, the first reaction temperature is about 20 ℃. In certain embodiments, the first reaction temperature is about 21 ℃. In certain embodiments, the first reaction temperature is about 22 ℃. In certain embodiments, the first reaction temperature is about 23 ℃. In certain embodiments, the first reaction temperature is about 24 ℃. In certain embodiments, the first reaction temperature is about 25 ℃.

[0275] In certain embodiments, cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, further comprises addition of a base to the reaction mixture.

[0276] In certain embodiments, cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises exposing the compound of Formula (IX), or salt thereof, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 molar equivalents of the base relative to the compound of Formula (IX), or salt thereof. In certain embodiments, the method comprises exposure to 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 molar equivalents of the base relative to the compound of Formula (IX), or salt thereof. In certain embodiments, the method comprises exposure to 15 molar equivalents of the base relative to the compound of Formula (IX), or salt thereof.

[0277] In certain embodiments, the base is ammonia. In certain embodiments, the base is triethylamine. In certain embodiments, the base is DBU. In certain embodiments, the base is diisopropylethylamine.

[0278] In certain embodiments, cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises a second reaction temperature of about 0 ℃ to about 40 ℃, or about 25 ℃. In certain embodiments, the second reaction temperature is about 0 ℃ to about 40 ℃. In certain embodiments, the second reaction temperature is about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 21 ℃, aboutH0824.70449WO00 94 / 250 #14309532v122 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, or about 40 ℃. In certain embodiments, the second reaction temperature is about 20 ℃. In certain embodiments, the second reaction temperature is about 21 ℃. In certain embodiments, the second reaction temperature is about 22 ℃. In certain embodiments, the second reaction temperature is about 23 ℃. In certain embodiments, the second reaction temperature is about 24 ℃. In certain embodiments, the second reaction temperature is about 25 ℃.

[0279] In certain embodiments, cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises methanol. In certain embodiments, the solvent is or comprises ethanol. In certain embodiments, the solvent is or comprises isopropanol.

[0280] In certain embodiments, the methods further comprise purifying the compound of Formula (VIII), or salt thereof. In certain embodiments, purifying the compound of Formula (VIII), or salt thereof, comprises recrystallization. In certain embodiments, purifying the compound of Formula (VIII), or salt thereof, comprises flash column chromatography. Embodiments of Formula (IX) and Preparation Thereof

[0281] As generally described herein, a compound of Formula (IX):, or a salt thereof, is prepared by combining a compound of Formula (X):or a salt thereof, with a compound of Formula (XI):, or a salt thereof, and a compound of Formula (XII):or a salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=;H0824.70449WO00 95 / 250 #14309532v1X′ is =O, =S, or =NR9; Y′ is =C(R9)2, =CHR9, or =CH2; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; each instance of R14is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;H0824.70449WO00 96 / 250 #14309532v1each instance of ROis independently hydrogen or an oxygen protecting group; and each instance of RNis independently hydrogen or a nitrogen protecting group; or an ROgroup and an RNgroup are joined to form a substituted or unsubstituted heterocyclyl ring; and represents a single or double bond.

[0282] In certain embodiments, the compound of Formula (IX) is of Formula (IX-a), (IX-b), or (IX- c):or a salt thereof.

[0283] In certain embodiments, the compound of Formula (IX) is of Formula (IX-a), or a salt thereof. In certain embodiments, the compound of Formula (IX) is of Formula (IX-b), or a salt thereof. In certain embodiments, the compound of Formula (IX) is of Formula (IX-c), or a salt thereof.

[0284] In certain embodiments, the compound of Formula (IX-a) is of Formula (IX-a-1):, or a salt thereof.

[0285] In certain embodiments, the compound of Formula (IX-b) is of Formula (IX-b-1) or (IX-b- 2):or a salt thereof.H0824.70449WO00 97 / 250 #14309532v1

[0286] In certain embodiments, the compound of Formula (IX-b) is of Formula (IX-b-1), or a salt thereof. In certain embodiments, the compound of Formula (IX-b) is of Formula (IX-b-2), or a salt thereof.

[0287] In certain embodiments, the compound of Formula (IX-c) is of Formula (IX-c-1) or (IX-c-2):or a salt thereof.

[0288] In certain embodiments, the compound of Formula (IX-c) is of Formula (IX-c-1), or a salt thereof. In certain embodiments, the compound of Formula (IX-c) is of Formula (IX-c-2), or a salt thereof.

[0289] In certain embodiments, the compound of Formula (IX) is of formula:, or a salt thereof.

[0290] In certain embodiments, the compound of Formula (IX) is of formula:, or a salt thereof.

[0291] In certain embodiments, cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprisesH0824.70449WO00 98 / 250 #14309532v1deprotecting the compound of Formula (IX), or salt thereof, under suitable conditions to provide a compound of Formula (IX′):or a salt thereof, wherein X, Y, R9, R13, n, and p are as defined for Formula (IX).

[0292] In certain embodiments, the compound of Formula (IX′) is of Formula (IX′-a) or (IX′-b):or a salt thereof.

[0293] In certain embodiments, the compound of Formula (IX′) is of Formula (IX′-a), or a salt thereof. In certain embodiments, the compound of Formula (IX′) is of Formula (IX′-b), or a salt thereof.

[0294] In certain embodiments, the compound of Formula (IX′-a) is of Formula (IX′-a-1) or (IX′-a- 2):, or a salt thereof.

[0295] In certain embodiments, the compound of Formula (IX′-a) is of Formula (IX′-a-1), or a salt thereof. In certain embodiments, the compound of Formula (IX′-a) is of Formula (IX′-a-2), or a salt thereof.

[0296] In certain embodiments, the compound of Formula (IX′-b) is of Formula (IX′-b-1), (IX′-b-2), (IX′-b-3), or (IX′-b-4):H0824.70449WO00 99 / 250 #14309532v1or a salt thereof.

[0297] In certain embodiments, the compound of Formula (IX′-b) is of Formula (IX′-b-1), or a salt thereof. In certain embodiments, the compound of Formula (IX′-b) is of Formula (IX′-b-2), or a salt thereof. In certain embodiments, the compound of Formula (IX′-b) is of Formula (IX′-b-3), or a salt thereof. In certain embodiments, the compound of Formula (IX′-b) is of Formula (IX′-b-4), or a salt thereof.

[0298] In certain embodiments, the compound of Formula (IX′) is of formula:, or a salt thereof.

[0299] In certain embodiments, the compound of Formula (IX′) is of formula:, or a salt thereof.

[0300] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to a Lewis acid, thereby forming a reaction mixture.

[0301] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to 1.00, 1.10, 1.20, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36,H0824.70449WO00 100 / 250 #14309532v11.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.60, 1.70, 1.80, 1.90, 2.00, 2.10, 2.20, 2.30, 2.40, 2.50, 2.60, 2.70, 2.80, 2.90, 3.00, 3.50, 4.00, 4.50, or 5.00 molar equivalents of the Lewis acid relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, or 1.50 molar equivalents of the Lewis acid relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 1.40 molar equivalents of the Lewis acid relative to the compound of Formula (XI), or salt thereof.

[0302] In certain embodiments, the Lewis acid is a titanium (IV) compound. In certain embodiments, the Lewis acid is TiCl4. In certain embodiments, the Lewis acid is an organoboron Lewis acid. In certain embodiments, the Lewis acid is dibutylboron trifluoromethanesulfonate. In certain embodiments, the Lewis acid is TiCl4 or dibutylboron trifluoromethanesulfonate. In certain embodiments, the Lewis acid is anhydrous FeCl3.

[0303] In some embodiments, a reaction temperature associated with the exposure of the compound of Formula (XI), or salt thereof, to the Lewis acid is referred to as a “first reaction temperature.”

[0304] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises a first reaction temperature of about -78 ℃ to about 0 ℃, or about -78 ℃. In certain embodiments, the first reaction temperature is about -78 ℃, about -75 ℃, about -70 ℃, about -65 ℃, about -60 ℃, about - 55 ℃, about -50 ℃, about -45 ℃, about -40 ℃, about -35 ℃, about -30 ℃, about -25 ℃, about - 20 ℃, about -15 ℃, about -10 ℃, about -5 ℃, or about 0 ℃. In certain embodiments, the first reaction temperature is about -78 ℃.

[0305] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises addition of the compound of Formula (X), or salt thereof, to the reaction mixture.

[0306] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.30, 1.40, 1.50, 1.60, 1.70, 1.80, 1.90, 2.00, 2.10, 2.20, 2.30, 2.40, 2.50, 2.60, 2.70, 2.80, 2.90, 3.00, 3.50, 4.00, 4.50, or 5.00 molar equivalents of the compound of Formula (X), or salt thereof, relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, or 1.20 molar equivalents of the compound of Formula (X), or salt thereof, relative to the compound ofH0824.70449WO00 101 / 250 #14309532v1Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 1.10 molar equivalents of the compound of Formula (X), or salt thereof, relative to the compound of Formula (XI), or salt thereof.

[0307] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises addition of an amine base to the reaction mixture.

[0308] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the amine base relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 molar equivalents of the amine base relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 2.5 molar equivalents of the amine base relative to the compound of Formula (XI), or salt thereof.

[0309] In certain embodiments, the amine base is tetramethylethylenediamine (TMEDA).

[0310] In some embodiments, a reaction temperature associated with the addition of the compound of Formula (X), or salt thereof, and / or the amine base to the reaction mixture is referred to as a “second reaction temperature.” In some embodiments, a reaction temperature associated with the addition of the compound of Formula (X), or salt thereof, and the amine base to the reaction mixture is referred to as a “second reaction temperature.”

[0311] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises a second reaction temperature of about -78 ℃ to about 0 ℃, or about 0 ℃. In certain embodiments, the second reaction temperature is about -78 ℃, about -75 ℃, about -70 ℃, about -65 ℃, about -60 ℃, about - 55 ℃, about -50 ℃, about -45 ℃, about -40 ℃, about -35 ℃, about -30 ℃, about -25 ℃, about - 20 ℃, about -15 ℃, about -10 ℃, about -5 ℃, or about 0 ℃. In certain embodiments, the second reaction temperature is about 0 ℃.

[0312] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises addition of the compound of Formula (XII), or salt thereof, to the reaction mixture.

[0313] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, underH0824.70449WO00 102 / 250 #14309532v1suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to 1.00, 1.10, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.50, 1.60, 1.70, 1.80, 1.90, 2.00, 2.10, 2.20, 2.30, 2.40, 2.50, 2.60, 2.70, 2.80, 2.90, 3.00, 3.50, 4.00, 4.50, or 5.00 molar equivalents of the compound of Formula (XII), or salt thereof, relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, or 1.40 molar equivalents of the compound of Formula (XII), or salt thereof, relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 1.30 molar equivalents of the compound of Formula (XII), or salt thereof, relative to the compound of Formula (XI), or salt thereof.

[0314] In some embodiments, a reaction temperature associated with the addition of the compound of Formula (XII), or salt thereof, to the reaction mixture is referred to as a “third reaction temperature.”

[0315] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises a third reaction temperature of about 0 ℃ to about 50 ℃, or about 25 ℃. In certain embodiments, the third reaction temperature is about 0 ℃ to about 50 ℃. In certain embodiments, the third reaction temperature is about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, or about 50 ℃. In certain embodiments, the third reaction temperature is about 20 ℃. In certain embodiments, the third reaction temperature is about 21 ℃. In certain embodiments, the third reaction temperature is about 22 ℃. In certain embodiments, the third reaction temperature is about 23 ℃. In certain embodiments, the third reaction temperature is about 24 ℃. In certain embodiments, the third reaction temperature is about 25 ℃.

[0316] In certain embodiments, combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises dichloromethane. In certain embodiments, the solvent is or comprises pentane. In certain embodiments, the solvent is or comprises pentane and dichloromethane. In certain embodiments, the solvent is or comprises diethyl ether. In certain embodiments, the solvent is or comprises tetrahydrofuran. In certain embodiments, the solvent is or comprises 2-methyltetrahydrofuran. In certain embodiments, the solvent is or comprises chloroform. In certain embodiments, the solvent is or comprises 1,2-dichloroethane.

[0317] In certain embodiments, the methods further comprise quenching the reaction. In certain embodiments, quenching the reaction comprises addition of sodium carbonate decahydrate to theH0824.70449WO00 103 / 250 #14309532v1reaction mixture. In certain embodiments, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 4.0, 4.5, or 5.0 molar equivalents of sodium carbonate decahydrate are used relative to the compound of Formula (XI), or salt thereof. In certain embodiments, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5 molar equivalents of sodium carbonate decahydrate are used relative to the compound of Formula (XI), or salt thereof. In certain embodiments, 3.0 molar equivalents of sodium carbonate decahydrate are used relative to the compound of Formula (XI), or salt thereof.

[0318] In certain embodiments, the methods further comprise purifying the compound of Formula (IX), or salt thereof. In certain embodiments, purifying the compound of Formula (IX), or salt thereof, comprises recrystallization. In certain embodiments, purifying the compound of Formula (IX), or salt thereof, comprises flash column chromatography. Embodiments of Formula (X)

[0319] As generally described herein, the compound of Formula (X):or salt thereof, is prepared by methods described in Example 2, wherein: Y′ is =C(R9)2, =CHR9, or =CH2; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; each instance of R14is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl; p is 0, 1, 2, 3, or 4; and each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted orH0824.70449WO00 104 / 250 #14309532v1unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0320] In certain embodiments, the compound of Formula (X) is of Formula (X-a) or (X-b):or a salt thereof.

[0321] In certain embodiments, the compound of Formula (X) is of Formula (X-a), or a salt thereof. In certain embodiments, the compound of Formula (X) is of Formula (X-b), or a salt thereof.

[0322] In some embodiments of Formula (X-a) or (X-b), or salt thereof, R9is –CH3, –CH2CH3, –CH2CH2CH3, –CH2CH2CH2CH3, –CH(CH3)2, –CH2CH(CH3)2, –CH2C(CH3)3, or –C(CH3)3. In some embodiments of Formula (X-a) or (X-b), or salt thereof, R9is –CH2CH(CH3)2.

[0323] In certain embodiments, the compound of Formula (X) is of Formula (X-c) or (X-d):or a salt thereof.

[0324] In certain embodiments, the compound of Formula (X) is of Formula (X-c), or a salt thereof. In certain embodiments, the compound of Formula (X) is of Formula (X-d), or a salt thereof.

[0325] In certain embodiments, the compound of Formula (X) is of formula:, or a salt thereof. Embodiments of Formula (XI)

[0326] As generally described herein, the compound of Formula (XI):, or salt thereof, is prepared by methods described in Example 2, wherein: each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted orH0824.70449WO00 105 / 250 #14309532v1unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0327] In some embodiments of Formula (XI), or salt thereof, two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring. In some embodiments of Formula (XI), or salt thereof, two instances of R13are joined to form a substituted heterocyclyl ring. In some embodiments of Formula (XI), or salt thereof, two instances of R13are joined to form a substituted 5-6 membered heterocyclyl ring. In some embodiments of Formula (XI), or salt thereof, two instances of R13are joined to form a substituted heterocyclyl ring containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments of Formula (XI), or salt thereof, two instances of R13are joined to form a substituted 5-6 membered heterocyclyl ring containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments of Formula (XI), or salt thereof, two instances of R13are joined to form a substituted 5-6 membered heterocyclyl ring containing 2 ring heteroatoms selected from O and N. In some embodiments of Formula (XI), or salt thereof, two instances of R13are joined to form a substituted 5 membered heterocyclyl ring containing 2 ring heteroatoms selected from O and N. In some embodiments of Formula (XI), or salt thereof, two instances of R13are joined to form a substituted oxazolidinonyl.

[0328] In certain embodiments, the compound of Formula (XI) is of Formula (XI-a):or a salt thereof, wherein R13ais substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or substituted or unsubstituted heteroaliphatic.

[0329] In certain embodiments, the compound of Formula (XI) is of Formula (XI-a-1) or (XI-a-2): (XI-a-1) or (XI-a-2), or a salt thereof.

[0330] In certain embodiments, the compound of Formula (XI) is of Formula (XI-a-1), or a salt thereof. In certain embodiments, the compound of Formula (XI) is of Formula (XI-a-2), or a salt thereof.H0824.70449WO00 106 / 250 #14309532v1

[0331] In some embodiments of Formula (XI-a), (XI-a-1), or (XI-a-2), or salt thereof, R13ais substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. In some embodiments of Formula (XI-a), (XI-a-1), or (XI-a-2), or salt thereof, R13ais substituted or unsubstituted C1-6alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted C1-6 aralkyl. In some embodiments of Formula (XI-a), (XI-a-1), or (XI-a-2), or salt thereof, R13ais substituted or unsubstituted C1-3alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted C1-3aralkyl. In some embodiments of Formula (XI-a), (XI-a-1), or (XI-a- 2), or salt thereof, R13ais unsubstituted C1-6 alkyl, unsubstituted phenyl, or unsubstituted C1-6 aralkyl. In some embodiments of Formula (XI-a), (XI-a-1), or (XI-a-2), or salt thereof, R13ais unsubstituted C1-3 alkyl, unsubstituted phenyl, or unsubstituted C1-3 aralkyl. In some embodiments of Formula (XI- a), (XI-a-1), or (XI-a-2), or salt thereof, R13ais –CH(CH3)2, phenyl, or benzyl. In some embodiments of Formula (XI-a), (XI-a-1), or (XI-a-2), or salt thereof, R13ais –CH(CH3)2. In some embodiments of Formula (XI-a), (XI-a-1), or (XI-a-2), or salt thereof, R13ais phenyl. In some embodiments of Formula (XI-a), (XI-a-1), or (XI-a-2), or salt thereof, R13ais benzyl.

[0332] In certain embodiments, the compound of Formula (XI) is of formula:, or a salt thereof.

[0333] In certain embodiments, the compound of Formula (XI) is of formula:, or a salt thereof. Embodiments of Formula (XII)

[0334] As generally described herein, the compound of Formula (XII):or salt thereof, is prepared by methods described in Example 2, wherein: X′ is =O, =S, or =NR9; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitutedH0824.70449WO00 107 / 250 #14309532v1aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and each instance of ROis independently hydrogen or an oxygen protecting group; and each instance of RNis independently hydrogen or a nitrogen protecting group; or an ROgroup and an RNgroup are joined to form a substituted or unsubstituted heterocyclyl ring.

[0335] In certain embodiments, the compound of Formula (XII) is of Formula (XII-a):, or a salt thereof.

[0336] In certain embodiments, the compound of Formula (XII) is of Formula (XII-b):or a salt thereof, wherein each instance of R12is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaliphatic.H0824.70449WO00 108 / 250 #14309532v1

[0337] In certain embodiments, the compound of Formula (XII-b) is of Formula (XII-b-1):, or a salt thereof.

[0338] In some embodiments of Formula (XII-b) or (XII-b-1), or salt thereof, each instance of R12is independently substituted or unsubstituted alkyl. In some embodiments of Formula (XII-b) or (XII-b- 1), or salt thereof, each instance of R12is independently substituted or unsubstituted C1-6 alkyl. In some embodiments of Formula (XII-b) or (XII-b-1), or salt thereof, each instance of R12is independently unsubstituted C1-4 alkyl. In some embodiments of Formula (XII-b) or (XII-b-1), or salt thereof, each instance of R12is independently –CH3.

[0339] In certain embodiments, the compound of Formula (XII) is of formula:, or a salt thereof.

[0340] In certain embodiments, the compound of Formula (XII) is of formula:, or a salt thereof. Embodiments of Formula (XIII) and Preparation Thereof

[0341] As generally described herein, a compound of Formula (XIII):,H0824.70449WO00 109 / 250 #14309532v1or pharmaceutically acceptable salt thereof, is prepared by: oxidizing a compound of Formula (II):or a salt thereof, under suitable conditions to provide a compound of Formula (I):or a salt thereof; and coupling the compound of Formula (I), or salt thereof, with a compound of Formula (XIV):, or a salt thereof, to provide the compound of Formula (XIII), or pharmaceutically acceptable salt thereof, wherein: A1is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, or –SRA; A2is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or A1and A2are optionally joined to form Ring A, which is represented by “- - -” and is a substituted or unsubstituted heterocyclic ring; or A2and R7are joined to form a substituted or unsubstituted heterocyclic ring; X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; each instance of R′ is independently hydrogen or an oxygen protecting group;H0824.70449WO00 110 / 250 #14309532v1R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and represents a single or double bond.H0824.70449WO00 111 / 250 #14309532v1

[0342] In certain embodiments, the compound of Formula (XIII) is of Formula (XIII-a), (XIII-b), (XIII-c), or (XIII-d):, or a pharmaceutically acceptable salt thereof.

[0343] In certain embodiments, the compound of Formula (XIII) is of Formula (XIII-a), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII) is of Formula (XIII-b), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII) is of Formula (XIII-c), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII) is of Formula (XIII-d), or a pharmaceutically acceptable salt thereof.H0824.70449WO00 112 / 250 #14309532v1

[0344] In certain embodiments, the compound of Formula (XIII-b) is of Formula (XIII-b-1):, or a pharmaceutically acceptable salt thereof.

[0345] In certain embodiments, the compound of Formula (XIII-c) is of Formula (XIII-c-1) or (XIII-c-2):or a pharmaceutically acceptable salt thereof.

[0346] In certain embodiments, the compound of Formula (XIII-c) is of Formula (XIII-c-1), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII-c) is of Formula (XIII-c-2), or a pharmaceutically acceptable salt thereof.H0824.70449WO00 113 / 250 #14309532v1

[0347] In certain embodiments, the compound of Formula (XIII-d) is of Formula (XIII-d-1) or (XIII-d-2):or a pharmaceutically acceptable salt thereof.

[0348] In certain embodiments, the compound of Formula (XIII-d) is of Formula (XIII-d-1), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII-d) is of Formula (XIII-d-2), or a pharmaceutically acceptable salt thereof.

[0349] In certain embodiments, the compound of Formula (XIII) is of Formula (XIII-a), (XIII-b), (XIII-c), or (XIII-d), or pharmaceutically acceptable salt thereof, and the compound of Formula (XIV) is of Formula (XIV-a), or salt thereof.

[0350] In certain embodiments, the compound of Formula (XIII) is of Formula (XIII′):or a pharmaceutically acceptable salt thereof, wherein: A1is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, or –SRA;H0824.70449WO00 114 / 250 #14309532v1A2is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and X, Y, R8, R9, n, and p are as defined for Formula (XIII).

[0351] In certain embodiments, the compound of Formula (XIII′) is of Formula (XIII′-a), (XIII′-b), (XIII′-c), or (XIII′-d):, or a pharmaceutically acceptable salt thereof.

[0352] In certain embodiments, the compound of Formula (XIII′) is of Formula (XIII′-a), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′) is of Formula (XIII′-b), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′) is of Formula (XIII′-c), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′) is of Formula (XIII′-d), or a pharmaceutically acceptable salt thereof.

[0353] In certain embodiments, the compound of Formula (XIII′-b) is of Formula (XIII′-b-1):or a pharmaceutically acceptable salt thereof.H0824.70449WO00 115 / 250 #14309532v1

[0354] In certain embodiments, the compound of Formula (XIII′-c) is of Formula (XIII′-c-1) or (XIII′-c-2):or a pharmaceutically acceptable salt thereof.

[0355] In certain embodiments, the compound of Formula (XIII′-c) is of Formula (XIII′-c-1), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′-c) is of Formula (XIII′-c-2), or a pharmaceutically acceptable salt thereof.

[0356] In certain embodiments, the compound of Formula (XIII′-d) is of Formula (XIII′-d-1) or (XIII′-d-2):or a pharmaceutically acceptable salt thereof.

[0357] In certain embodiments, the compound of Formula (XIII′-d) is of Formula (XIII′-d-1), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′-d) is of Formula (XIII′-d-2), or a pharmaceutically acceptable salt thereof.

[0358] In certain embodiments, the compound of Formula (XIII′) is of Formula (XIII′-a), (XIII′-b), (XIII′-c), or (XIII′-d), or pharmaceutically acceptable salt thereof, and the compound of Formula (XIV) is of Formula (XIV′-a), or salt thereof.H0824.70449WO00 116 / 250 #14309532v1

[0359] In certain embodiments, the compound of Formula (XIII) is of Formula (XIII′′):, or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each instance of R2is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen-S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; q is 3, 4, 5, or 6; and X, Y, R8, R9, n, and p are as defined for Formula (XIII).

[0360] In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-a), (XIII′′- b), (XIII′′-c), or (XIII′′-d),H0824.70449WO00 117 / 250 #14309532v1or a pharmaceutically acceptable salt thereof.

[0361] In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-a), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-b), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-c), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-d), or a pharmaceutically acceptable salt thereof.

[0362] In certain embodiments, the compound of Formula (XIII′′-b) is of Formula (XIII′′-b-1):or a pharmaceutically acceptable salt thereof.

[0363] In certain embodiments, the compound of Formula (XIII′′-c) is of Formula (XIII′′-c-1) or (XIII′′-c-2):, or a pharmaceutically acceptable salt thereof.

[0364] In certain embodiments, the compound of Formula (XIII′′-c) is of Formula (XIII′′-c-1), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′′- c) is of Formula (XIII′′-c-2), or a pharmaceutically acceptable salt thereof.H0824.70449WO00 118 / 250 #14309532v1

[0365] In certain embodiments, the compound of Formula (XIII′′-d) is of Formula (XIII′′-d-1) or (XIII′′-d-2):, or a pharmaceutically acceptable salt thereof.

[0366] In certain embodiments, the compound of Formula (XIII′′-d) is of Formula (XIII′′-d-1), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′′- d) is of Formula (XIII′′-d-2), or a pharmaceutically acceptable salt thereof.

[0367] In certain embodiments, the compound of Formula (XIII) is of Formula (XIII′′), or pharmaceutically acceptable salt thereof, and the compound of Formula (XIV) is of Formula (XIV′′), or salt thereof.

[0368] In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-a), (XIII′′- b), (XIII′′-c), or (XIII′′-d), or pharmaceutically acceptable salt thereof, and the compound of Formula (XIV′′) is of Formula (XIV′′-a), or salt thereof.

[0369] In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-e-1),H0824.70449WO00 119 / 250 #14309532v1, or a pharmaceutically acceptable salt thereof.

[0370] In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-e-1), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-e-2), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-e-3), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-e-4), or a pharmaceutically acceptable salt thereof.

[0371] In certain embodiments of Formula (XIII′′-e-1), (XIII′′-e-2), (XIII′′-e-3), or (XIII′′-e-4), or pharmaceutically acceptable salt thereof, R2is hydrogen or –CH3. In certain embodiments of Formula (XIII′′-e-1), (XIII′′-e-2), (XIII′′-e-3), or (XIII′′-e-4), or pharmaceutically acceptable salt thereof, each instance of R′ is independently H. In certain embodiments of Formula (XIII′′-e-1), (XIII′′-e-2), (XIII′′-e-3), or (XIII′′-e-4), or pharmaceutically acceptable salt thereof, R2is –CH3, and each instance of R′ is independently H.

[0372] In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-f-1), (XIII′′-f-2), (XIII′′-f-3), or (XIII′′-f-4):H0824.70449WO00 120 / 250 #14309532v1or a pharmaceutically acceptable salt thereof.

[0373] In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-f-1), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-f-2), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-f-3), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIII′′) is of Formula (XIII′′-f-4), or a pharmaceutically acceptable salt thereof.

[0374] In certain embodiments of Formula (XIII′′-f-1), (XIII′′-f-2), (XIII′′-f-3), or (XIII′′-f-4), or pharmaceutically acceptable salt thereof, at least one instance of R2is fluoro. In certain embodiments of Formula (XIII′′-f-1), (XIII′′-f-2), (XIII′′-f-3), or (XIII′′-f-4), or pharmaceutically acceptable salt thereof, each instance of R′ is independently H. In certain embodiments of Formula (XIII′′-f-1), (XIII′′-f-2), (XIII′′-f-3), or (XIII′′-f-4), or pharmaceutically acceptable salt thereof, at least one instance of R2is fluoro, and each instance of R′ is independently H.

[0375] In certain embodiments, the compound of Formula (XIII) is:H0824.70449WO00 121 / 250 #14309532v1H0824.70449WO00 122 / 250 #14309532v1H0824.70449WO00 123 / 250 #14309532v1H0824.70449WO00 124 / 250 #14309532v1H0824.70449WO00 125 / 250 #14309532v1H0824.70449WO00 126 / 250 #14309532v1or pharmaceutically acceptable salt thereof.H0824.70449WO00 127 / 250 #14309532v1

[0376] In certain embodiments, the compound of Formula (XIII) is:, or pharmaceutically acceptable salt thereof.

[0377] In certain embodiments, the compound of Formula (XIII) is:, or pharmaceutically acceptable salt thereof.

[0378] In certain embodiments, the compound of Formula (XIII) is:, or pharmaceutically acceptable salt thereof.H0824.70449WO00 128 / 250 #14309532v1

[0379] In certain embodiments, the compound of Formula (XIII) is:, or pharmaceutically acceptable salt thereof.

[0380] In certain embodiments, coupling the compound of Formula (XIV), or salt thereof, with the compound of Formula (I), or salt thereof, comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.40, 1.50, 1.60, 1.70, 1.80, 1.90, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the compound of Formula (I), or salt thereof, relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, coupling the compound of Formula (XIV), or salt thereof, with the compound of Formula (I), or salt thereof, comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, or 1.25 molar equivalents of the compound of Formula (I), or salt thereof, relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, or 1.25 molar equivalents of the compound of Formula (I), or salt thereof, relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.00 molar equivalents of the compound of Formula (I), or salt thereof, relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.05 molar equivalents of the compound of Formula (I), or salt thereof, relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.10 molar equivalents of the compound of Formula (I), or salt thereof, relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.15 molar equivalents of the compound of Formula (I), or salt thereof, relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.20 molar equivalents of the compound of Formula (I), or salt thereof, relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.25 molar equivalents of the compound of Formula (I), or salt thereof, relative to the compound of Formula (XIV), or salt thereof.

[0381] In certain embodiments, coupling the compound of Formula (XIV), or salt thereof, with the compound of Formula (I), or salt thereof, comprises exposure to a coupling reagent. In certain embodiments, coupling the compound of Formula (XIV), or salt thereof, with the compound ofH0824.70449WO00 129 / 250 #14309532v1Formula (I), or salt thereof, comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.40, 1.50, 1.60, 1.70, 1.80, 1.90, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the coupling reagent relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, coupling the compound of Formula (XIV), or salt thereof, with the compound of Formula (I), or salt thereof, comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, or 1.25 molar equivalents of the coupling reagent relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, or 1.25 molar equivalents of the coupling reagent relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.00 molar equivalents of the coupling reagent relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.05 molar equivalents of the coupling reagent relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.10 molar equivalents of the coupling reagent relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.15 molar equivalents of the coupling reagent relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.20 molar equivalents of the coupling reagent relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises exposure to 1.25 molar equivalents of the coupling reagent relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the coupling reagent is O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)- N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)- N,N,N′,N′-tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HCTU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′N′- tetramethyluronium tetrafluoroborate (TOTU), (1-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), 1,3- dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), hydroxybenzotriazole (HOBt), propanephosphonic acid anhydride (T3P), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7- azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOP-Cl), O-(N-succinimidyl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TSTU), O-(5-norbornene-2,3-dicarboximido)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TNTU), O-(1,2-dihydro-2-oxo-1-pyridyl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TPTU), 3-(diethylphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), orH0824.70449WO00 130 / 250 #14309532v1carbonyldiimidazole (CDI), or a combination thereof. In certain embodiments, the coupling reagent is O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU).

[0382] In certain embodiments, coupling the compound of Formula (XIV), or salt thereof, with the compound of Formula (I), or salt thereof, comprises addition of an amine base. In certain embodiments, coupling the compound of Formula (XIV), or salt thereof, with the compound of Formula (I), or salt thereof, comprises addition of 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the amine base relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises addition of 1.0 molar equivalent of the amine base relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises addition of 1.5 molar equivalents of the amine base relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises addition of 2.0 molar equivalents of the amine base relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises addition of 2.5 molar equivalents of the amine base relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the method comprises addition of 3.0 molar equivalents of the amine base relative to the compound of Formula (XIV), or salt thereof. In certain embodiments, the amine base is N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), tributylamine, or benzyldimethylamine. In certain embodiments, the amine base is N,N- diisopropylethylamine (DIPEA). In certain embodiments, the amine base is triethylamine (TEA). In certain embodiments, the amine base is tributylamine. In certain embodiments, the amine base is benzyldimethylamine.

[0383] In certain embodiments, coupling the compound of Formula (XIV), or salt thereof, with the compound of Formula (I), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises a polar aprotic solvent. In certain embodiments, the solvent is or comprises N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), ethyl acetate (EA), dimethylsulfoxide (DMSO), tert-butyl methyl ether (TBME), cyclopentylmethyl ether (CPME), or dimethylcarbonate (DMC). In certain embodiments, the solvent is or comprises N,N-dimethylformamide (DMF). In certain embodiments, the solvent is or comprises N,N-dimethylacetamide (DMA). In certain embodiments, the solvent is or comprises dichloromethane (DCM). In certain embodiments, the solvent is or comprises tetrahydrofuran (THF). In certain embodiments, the solvent is or comprises 2- methyltetrahydrofuran (2-MeTHF). In certain embodiments, the solvent is or comprises ethyl acetate (EA). In certain embodiments, the solvent is or comprises dimethylsulfoxide (DMSO). In certain embodiments, the solvent is or comprises tert-butyl methyl ether (TBME). In certain embodiments, the solvent is or comprises cyclopentylmethyl ether (CPME). In certain embodiments, the solvent is or comprises dimethylcarbonate (DMC).

[0384] In certain embodiments, coupling the compound of Formula (XIV), or salt thereof, with the compound of Formula (I), or salt thereof, comprises a reaction temperature of about 20 ℃, about 21H0824.70449WO00 131 / 250 #14309532v1℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, about 80 ℃, or about 85 ℃. In certain embodiments, the reaction temperature is about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, or about 25 ℃. In certain embodiments, the reaction temperature is about 20 ℃. In certain embodiments, the reaction temperature is about 21 ℃. In certain embodiments, the reaction temperature is about 22 ℃. In certain embodiments, the reaction temperature is about 23 ℃. In certain embodiments, the reaction temperature is about 24 ℃. In certain embodiments, the reaction temperature is about 25 ℃.

[0385] In certain embodiments, the methods further comprise purifying the compound of Formula (XIII), or pharmaceutically acceptable salt thereof. In certain embodiments, purifying the compound of Formula (XIII), or pharmaceutically acceptable salt thereof, comprises flash column chromatography. In certain embodiments, purifying the compound of Formula (XIII), or pharmaceutically acceptable salt thereof, comprises preparative HPLC.

[0386] In certain embodiments, the compound of Formula (XIII), or pharmaceutically acceptable salt thereof, is isolated as an oil. In certain embodiments, the compound of Formula (XIII), or pharmaceutically acceptable salt thereof, is isolated as a solid. In certain embodiments, the compound of Formula (XIII), or pharmaceutically acceptable salt thereof, is isolated as a foam.

[0387] In certain embodiments, the compound of Formula (XIII) is isolated as a pharmaceutically acceptable salt. In certain embodiments, the compound of Formula (XIII) is isolated as an acetate salt. Embodiments of Formula (XIV)

[0388] As generally described herein, a compound of Formula (XIV):or a salt thereof, is prepared by developed synthetic methods, wherein: A1is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, or –SRA;H0824.70449WO00 132 / 250 #14309532v1A2is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or A1and A2are optionally joined to form Ring A, which is represented by “- - -” and is a substituted or unsubstituted heterocyclic ring; or A2and R7are joined to form a substituted or unsubstituted heterocyclic ring; each instance of R′ is independently hydrogen or an oxygen protecting group; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group; and each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0389] In certain embodiments, the compound of Formula (XIV) is of Formula (XIV-a):or a salt thereof.

[0390] In certain embodiments, the compound of Formula (XIV) is of Formula (XIV′):, or a salt thereof, wherein: A1is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted orH0824.70449WO00 133 / 250 #14309532v1unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, or –SRA; A2is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and R′, R7, and RAare as defined for Formula (XIV).

[0391] In certain embodiments, the compound of Formula (XIV) is of Formula (XIV′-a):, or a salt thereof.

[0392] In certain embodiments, the compound of Formula (XIV) is of Formula (XIV′′):or a salt thereof, wherein: each instance of R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each instance of R2is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, -ORA, -N(RA)2, -SRA, -CN, -SCN, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)N(RA)2, -C(=O)RA, -C(=O)ORA, -C(=O)N(RA)2, -NO2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)N(RA)2, -NRAC(=NRA)N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)N(RA)2, -NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; q is 3, 4, 5, or 6; and R′, R7, and RAare as defined for Formula (XIV).H0824.70449WO00 134 / 250 #14309532v1

[0393] In certain embodiments, the compound of Formula (XIV′′) is of Formula (XIV′′-a):or a salt thereof.

[0394] It is understood that the embodiments described herein for groups R8, R9, X, Y, n, p, R11, R12, R13, R13a, R14, R′, R′′, RA1, RO, RO1, RO2, RN, RN1, X′, Y′, A1, A2, Ring A, R7, and RAapply to any of the compounds or methods described herein, and that any of the embodiments described herein can be combined, where applicable, with any other embodiment described in the present disclosure. Groups R8, R9, X, Y, n, and p

[0395] As generally described herein, R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group.

[0396] In certain embodiments, R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, –C(=O)RA, –C(=O)ORA, or a nitrogen protecting group. In certain embodiments, R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, –C(=O)RA, –C(=O)ORA, or a nitrogen protecting group. In certain embodiments, R8is hydrogen, substituted or unsubstituted alkyl, –C(=O)RA, –C(=O)ORA, or a nitrogen protecting group. In certain embodiments, R8is hydrogen, –C(=O)RA, –C(=O)ORA, or a nitrogen protecting group. In certain embodiments, R8is hydrogen, –C(=O)RA, or –C(=O)ORA. In certain embodiments, R8is hydrogen, –C(=O)ORA, or a nitrogen protecting group. In certain embodiments, R8is hydrogen, –C(=O)RA, or a nitrogen protecting group. In certain embodiments, R8is hydrogen or –C(=O)RA. In certain embodiments, R8is hydrogen or –C(=O)ORA. In certain embodiments, R8is hydrogen or a nitrogen protecting group. In certain embodiments, R8is hydrogen, –CH3, –C(=O)OC(CH3)3, or –C(=O)OCH2C6H5. In certain embodiments, R8is hydrogen, –C(=O)OC(CH3)3, or –C(=O)OCH2C6H5. In certain embodiments, R8is hydrogen or –C(=O)OC(CH3)3. In certain embodiments, R8is hydrogen or –C(=O)OCH2C6H5.

[0397] In certain embodiments, R8is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R8is hydrogen or unsubstituted alkyl. In certain embodiments, R8is hydrogen or unsubstituted C1-6alkyl. In certain embodiments, R8is hydrogen or unsubstituted C1-4alkyl. In certain embodiments, R8is hydrogen or unsubstituted C1-3alkyl. In certain embodiments, R8is hydrogen orH0824.70449WO00 135 / 250 #14309532v1unsubstituted C1-2alkyl. In certain embodiments, R8is hydrogen or –CH2CH3. In certain embodiments, R8is hydrogen or –CH3. In certain embodiments, R8is hydrogen.

[0398] In certain embodiments, R8is substituted or unsubstituted alkyl. In certain embodiments, R8is substituted or unsubstituted C1-6alkyl. In certain embodiments, R8is unsubstituted C1-6alkyl. In certain embodiments, R8is unsubstituted C1-4 alkyl. In certain embodiments, R8is unsubstituted C1-3 alkyl. In certain embodiments, R8is unsubstituted C1-2alkyl. In certain embodiments, R8is –CH2CH3. In certain embodiments, R8is –CH3.

[0399] In certain embodiments, R8is substituted or unsubstituted alkenyl. In certain embodiments, R8is substituted or unsubstituted C2-6 alkenyl. In certain embodiments, R8is substituted or unsubstituted alkynyl. In certain embodiments, R8is substituted or unsubstituted C2-6 alkynyl. In certain embodiments, R8is substituted or unsubstituted carbocyclyl. In certain embodiments, R8is substituted or unsubstituted C3-6 carbocyclyl. In certain embodiments, R8is substituted or unsubstituted heterocyclyl. In certain embodiments, R8is substituted or unsubstituted 3-6 membered heterocyclyl. In certain embodiments, R8is substituted or unsubstituted heteroaliphatic. In certain embodiments, R8is substituted or unsubstituted C1-6 heteroaliphatic.

[0400] In certain embodiments, R8is –C(=NRA)RA. In certain embodiments, R8is –C(=NRA)ORA. In certain embodiments, R8is –C(=NRA)N(RA)2. In certain embodiments, R8is –C(=O)N(RA)2.

[0401] In certain embodiments, R8is –C(=O)RA. In certain embodiments, R8is –C(=O)RA, wherein RAis substituted or unsubstituted alkyl. In certain embodiments, R8is –C(=O)RA, wherein RAis substituted or unsubstituted C1-6 alkyl. In certain embodiments, R8is –C(=O)RA, wherein RAis unsubstituted C1-6 alkyl. In certain embodiments, R8is –C(=O)RA, wherein RAis unsubstituted C1-4 alkyl.

[0402] In certain embodiments, R8is –C(=O)ORA. In certain embodiments, R8is –C(=O)ORA, wherein RAis substituted or unsubstituted alkyl. In certain embodiments, R8is –C(=O)ORA, wherein RAis substituted or unsubstituted C1-6 alkyl. In certain embodiments, R8is –C(=O)ORA, wherein RAis unsubstituted C1-6 alkyl. In certain embodiments, R8is –C(=O)ORA, wherein RAis unsubstituted C1-4 alkyl. In certain embodiments, R8is –C(=O)OC(CH3)3 (i.e., t-butyloxycarbonyl (Boc)).

[0403] In certain embodiments, R8is –C(=O)ORA, wherein RAis substituted or unsubstituted aralkyl. In certain embodiments, R8is –C(=O)ORA, wherein RAis substituted or unsubstituted C1-6aralkyl. In certain embodiments, R8is –C(=O)ORA, wherein RAis substituted or unsubstituted C1-3aralkyl. In certain embodiments, R8is –C(=O)ORA, wherein RAis unsubstituted C1-6aralkyl. In certain embodiments, R8is –C(=O)ORA, wherein RAis unsubstituted C1-3aralkyl. In certain embodiments, R8is –C(=O)OCH2C6H5(i.e., carboxybenzyl (Cbz)).

[0404] In certain embodiments, R8is –S(O)2RA. In certain embodiments, R8is –S(O)2RA, wherein RAis substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In certain embodiments, R8is –S(O)2RA, wherein RAis substituted or unsubstituted C1-6alkyl or substituted or unsubstituted phenyl.H0824.70449WO00 136 / 250 #14309532v1In certain embodiments, R8is –S(O)2RA, wherein RAis substituted or unsubstituted C1-3alkyl or substituted or unsubstituted phenyl.

[0405] In certain embodiments, R8is a nitrogen protecting group.

[0406] As generally described herein, each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA,–S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring. In certain embodiments, the R9substituent is the (S) stereocenter (i.e., the carbon to which it is attached is of the (S) configuration). In certain embodiments, the R9substituent is the (R) stereocenter (i.e., the carbon to which it is attached is of the (R) configuration).

[0407] In certain embodiments, at least one instance of R9is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, –ORA, or –N(RA)2; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring.

[0408] In certain embodiments, at least one instance of R9is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, –C(=O)ORA, –C(=O)N(RA)2, –C(=NRA)N(RA)2, –ORA, or –N(RA)2; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring.

[0409] In certain embodiments, at least one instance of R9is halogen, substituted or unsubstituted alkenyl, substituted alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; or two R9groups are joined to form a substituted or unsubstituted carbocyclyl ring.

[0410] In certain embodiments, at least one instance of R9is halogen, unsubstituted ethenyl, substituted or unsubstituted phenethynyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted phenethyl; or two R9groups are joined to form an unsubstituted cycloalkyl ring.

[0411] In certain embodiments, at least one instance of R9is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. In certain embodiments, atH0824.70449WO00 137 / 250 #14309532v1least one instance of R9is substituted or unsubstituted aryl or substituted or unsubstituted aralkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted phenyl or substituted or unsubstituted phenethyl.

[0412] In certain embodiments, at least one instance of R9is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, or unsubstituted heteroalkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted carbocyclyl.

[0413] In certain embodiments, at least one instance of R9is halogen.

[0414] In certain embodiments, at least one instance of R9is substituted or unsubstituted alkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of R9is substituted C1-6 alkyl. In certain embodiments, at least one instance of R9is C1-6 alkyl substituted with halogen, alkenyl, C3-6 cycloalkyl, or –ORA. In certain embodiments, at least one instance of R9is C1-6 alkyl substituted with halogen, alkenyl, C3-6 cycloalkyl, heterocyclyl, –N(RA)2, –SO2RA, or –ORA. In certain embodiments, at least one instance of R9is –CH2CH=CH2. In certain embodiments, at least one instance of R9is –CH2CH2F. In certain embodiments, at least one instance of R9is –CH2CHF2. In certain embodiments, at least one instance of R9is –CH2CH2CH2F. In certain embodiments, at least one instance of R9is –CH2CH2CF2H. In certain embodiments, at least one instance of R9is –CH2CH2CH2Cl. In certain embodiments, at least one instance of R9is. In certain embodiments, at least one instance of R9is –CH2CH2CH2OCH3. In certain embodiments, at least one instance of R9is –CH2CH2CH2OH. In certain embodiments, at least one instance of R9is –CH2CH2CH2SO2CH3. In certain embodiments, at least one instance of R9is. In certain embodiments, at least one instance of R9is –CH2CH2CH2NH2. In certain embodiments, at least one instance of R9is –CH2CH2CH2N(CH3)2. In certain embodiments, at least one instance of R9is –CH2C(CH3)2OH. In certain embodiments, at least one instance of R9is –CH2CF2CH3. In certain embodiments, at least one instance of R9isH0824.70449WO00 138 / 250 #14309532v1.

[0415] In certain embodiments, at least one instance of R9is unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of R9is –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2CH(CH3)2, or –C(CH3)3. In certain embodiments, at least one instance of R9is –CH3, –CH2CH3, –CH2CH2CH3, –CH2CH2CH2CH3, –CH(CH3)2, –CH2CH(CH3)2, –CH2C(CH3)3, or –C(CH3)3. In certain embodiments, at least one instance of R9is –CH3. In certain embodiments, at least one instance of R9is –CH2CH3. In certain embodiments, at least one instance of R9is –CH2CH2CH3. In certain embodiments, at least one instance of R9is –CH(CH3)2. In certain embodiments, at least one instance of R9is –C(CH3)3. In certain embodiments, at least one instance of R9is –CH2CH(CH3)2.

[0416] In certain embodiments, at least one instance of R9is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R9is unsubstituted alkenyl. In certain embodiments, at least one instance of R9is –CH=CH2.

[0417] In certain embodiments, at least one instance of R9is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R9is substituted alkynyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted phenethynyl.

[0418] In certain embodiments, at least one instance of R9is substituted or unsubstituted carbocyclyl. In certain embodiments, at least one instance of R9is unsubstituted carbocyclyl. In certain embodiments, at least one instance of R9is unsubstituted C3-6cycloalkyl. In certain embodiments, at least one instance of R9is unsubstituted C5-6cycloalkyl. In certain embodiments, at least one instance of R9is unsubstituted cyclopentyl. In certain embodiments, at least one instance of R9is unsubstituted cyclohexyl.

[0419] In certain embodiments, at least one instance of R9is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R9is substituted or unsubstituted phenyl.

[0420] In certain embodiments, at least one instance of R9is substituted or unsubstituted aralkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted C1-6aralkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted benzyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted phenethyl.

[0421] In certain embodiments, at least one instance of R9is substituted or unsubstituted heterocyclyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R9is substituted or unsubstituted heteroaralkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted heteroaliphatic. In certain embodiments, at least one instance of R9is –ORA. In certain embodiments, at least one instance of R9is –N(RA)2. In certain embodiments, at least one instance of R9is –SRA. In certain embodiments, at least one instance of R9is –CN. In certain embodiments, at least one instanceH0824.70449WO00 139 / 250 #14309532v1of R9is –SCN. In certain embodiments, at least one instance of R9is –C(=NRA)RA. In certain embodiments, at least one instance of R9is –C(=NRA)ORA. In certain embodiments, at least one instance of R9is –C(=NRA)N(RA)2. In certain embodiments, at least one instance of R9is –C(=O)RA. In certain embodiments, at least one instance of R9is –C(=O)ORA. In certain embodiments, at least one instance of R9is –C(=O)N(RA)2. In certain embodiments, at least one instance of R9is –NO2. In certain embodiments, at least one instance of R9is –NRAC(=O)RA. In certain embodiments, at least one instance of R9is –NRAC(=O)ORA. In certain embodiments, at least one instance of R9is –NRAC(=O)N(RA)2. In certain embodiments, at least one instance of R9is –NRAC(=NRA)N(RA)2. In certain embodiments, at least one instance ...

Claims

1. CLAIMS What is claimed is:

1. A method of preparing a compound of Formula (I): , or a salt thereof, comprising oxidizing a compound of Formula (II): , or a salt thereof, under suitable conditions to provide the compound of Formula (I), or a salt thereof, wherein: X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,H0824.70449WO00 188 / 250 #14309532v1substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and represents a single or double bond.

2. A method of preparing a compound of Formula (XIII):, or a pharmaceutically acceptable salt thereof, the method comprising: oxidizing a compound of Formula (II):, or a salt thereof, under suitable conditions to provide a compound of Formula (I):, or a salt thereof; andH0824.70449WO00 189 / 250 #14309532v1coupling the compound of Formula (I), or salt thereof, with a compound of Formula (XIV):, or a salt thereof, to provide the compound of Formula (XIII), or pharmaceutically acceptable salt thereof, wherein: A1is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, or –SRA; A2is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or A1and A2are optionally joined to form Ring A, which is represented by “- - -” and is a substituted or unsubstituted heterocyclic ring; or A2and R7are joined to form a substituted or unsubstituted heterocyclic ring; X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; each instance of R′ is independently hydrogen or an oxygen protecting group; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA,H0824.70449WO00 190 / 250 #14309532v1–NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and represents a single or double bond.

3. The method of claim 1 or 2, wherein the compound of Formula (I) is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), or (I-g):, or a salt thereof.

4. The method of claim 3, wherein the compound of Formula (I) is of Formula (I-e-2) or (I-f-2):or a salt thereof.H0824.70449WO00 191 / 250 #14309532v15. The method of any one of claims 1-4, wherein the compound of Formula (I) is of formula:, or a salt thereof.

6. The method of any one of claims 1-5, wherein oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises exposing the compound of Formula (II), or salt thereof, to a nitroxyl radical, a chlorite salt, and / or a hypochlorite salt.

7. The method of claim 6, wherein the nitroxyl radical is 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO).

8. The method of claim 6 or 7, wherein the chlorite salt is sodium chlorite.

9. The method of any one of claims 6-8, wherein the hypochlorite salt is sodium hypochlorite.

10. The method of any one of claims 1-9, wherein oxidizing the compound of Formula (II), or salt thereof, under suitable conditions to provide the compound of Formula (I), or the salt thereof, comprises a reaction temperature of greater than ambient temperature, about 25 ℃ to about 60 ℃, or about 35 ℃.

11. A method of preparing a compound of Formula (II):, or a salt thereof, comprising cyclizing a compound of Formula (III):,H0824.70449WO00 192 / 250 #14309532v1or a salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, wherein: X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.H0824.70449WO00 193 / 250 #14309532v112. The method of any one of claims 1-10 further comprising cyclizing a compound of Formula (III):or a salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, wherein: R11is a leaving group; and RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group.

13. The method of any one of claims 1-12, wherein the compound of Formula (II) is of Formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), or (II-g):or a salt thereof.

14. The method of claim 13, wherein the compound of Formula (II) is of Formula (II-e-2) or (II-H0824.70449WO00 194 / 250 #14309532v1f-2):or a salt thereof.

15. The method of any one of claims 1-14, wherein the compound of Formula (II) is of formula:, or a salt thereof.

16. The method of any one of claims 11-15, wherein cyclizing the compound of Formula (III), or salt thereof, under suitable conditions to provide the compound of Formula (II), or the salt thereof, comprises exposing the compound of Formula (III), or salt thereof, to a base.

17. The method of claim 16 , wherein the base is a hydroxide salt.

18. The method of claim 16 or 17, wherein the base is sodium hydroxide.

19. The method of any one of claims 11-18, wherein cyclizing the compound of Formula (III), or salt thereof, under suitable conditions to provide the compound of Formula (II), or the salt thereof, comprises exposing the compound of Formula (III), or salt thereof, to a phase transfer catalyst.

20. The method of claim 19, wherein the phase transfer catalyst is tetrabutylammonium hydrogen sulfate.

21. The method of any one of claims 11-20, wherein cyclizing the compound of Formula (III), or salt thereof, under suitable conditions to provide the compound of Formula (II), or the salt thereof, comprises a reaction temperature of about 0 ℃ to about 40 ℃, or about 25 ℃.H0824.70449WO00 195 / 250 #14309532v122. A method of preparing a compound of Formula (III):or a salt thereof, comprising deprotecting a compound of Formula (IV):, or a salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted orH0824.70449WO00 196 / 250 #14309532v1unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

23. The method of any one of claims 11-21 further comprising deprotecting a compound of Formula (IV):, or a salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, wherein X is –O–, –S–, or –NR9–; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; and RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group.

24. The method of any one of claims 11-23, wherein the compound of Formula (III) is ofH0824.70449WO00 197 / 250 #14309532v1Formula (III-a), (III-b), (III-c), or (III-d):.

25. The method of claim 24, wherein the compound of Formula (III) is of Formula (III-c-1) or (III-d-1):, or a salt thereof.

26. The method of any one of claims 11-25, wherein the compound of Formula (III) is of formula:, or a salt thereof.

27. The method of any one of claims 22-26, wherein deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, comprises exposing the compound of Formula (IV), or salt thereof, to an acid.

28. The method of claim 27, wherein the acid is (±)-camphor-10-sulfonic acid.H0824.70449WO00 198 / 250 #14309532v129. The method of any one of claims 22-28, wherein deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (III), or salt thereof, comprises a reaction temperature of about 0 ℃ to about 40 ℃, or about 25 ℃.

30. A method of preparing a compound of Formula (IV):or a salt thereof, comprising hydrofunctionalization of a compound of Formula (V):, or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4;H0824.70449WO00 199 / 250 #14309532v1each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

31. The method of any one of claims 22-29 further comprising hydrofunctionalization of a compound of Formula (V):or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof.

32. The method of any one of claims 22-31, wherein the compound of Formula (IV) is of Formula (IV-a), (IV-b), or (IV-c):,H0824.70449WO00 200 / 250 #14309532v1or a salt thereof, wherein each instance of R12is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaliphatic.

33. The method of claim 32, wherein the compound of Formula (IV) is of Formula (IV-b-1) or (IV-c-1):or a salt thereof.

34. The method of any one of claims 22-33, wherein the compound of Formula (IV) is of formula:, or a salt thereof.

35. The method of any one of claims 30-34, wherein hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises hydroboration of the compound of Formula (V) by exposing the compound of Formula (V), or salt thereof, to a borane.

36. The method of claim 35, wherein the borane is dicyclohexylborane.

37. The method of any one of claims 30-34, wherein hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises hydroboration of the compound of Formula (V) by exposing the compound of Formula (V), or salt thereof, to an organozirconium compound.H0824.70449WO00 201 / 250 #14309532v138. The method of claim 37, wherein the organozirconium compound is Schwartz's reagent (Cp2ZrHCl).

39. The method of any one of claims 30-38, wherein hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises a first reaction temperature of about -20 ℃ to about 30 ℃, or about 0 ℃.

40. The method of any one of claims 30-39, further comprising addition of an oxidant.

41. The method of claim 40, wherein the oxidant comprises iodine.

42. The method of claim 40 or 41, wherein the oxidant comprises sodium acetate and iodine.

43. The method of any one of claims 30-42, wherein hydrofunctionalization of the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises a second reaction temperature of about -20 ℃ to about 50 ℃, about 0 ℃, or about 25 ℃.

44. A method of preparing a compound of Formula (V):or a salt thereof, comprising protecting a compound of Formula (VI):or a salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group;H0824.70449WO00 202 / 250 #14309532v1each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

45. The method of any one of claims 30-43 further comprising protecting a compound of Formula (VI):H0824.70449WO00 203 / 250 #14309532v1or a salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof.

46. The method of any one of claims 30-45, wherein the compound of Formula (V) is of Formula (V-a), (V-b), or (V-c):, or a salt thereof, wherein each instance of R12is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaliphatic.

47. The method of claim 46, wherein the compound of Formula (V) is of Formula (V-b-1) or (V- c-1):, or a salt thereof.

48. The method of any one of claims 30-47, wherein the compound of Formula (V) is of formula:, or a salt thereof.H0824.70449WO00 204 / 250 #14309532v149. The method of any one of claims 44-48, wherein protecting the compound of Formula (VI), or salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, comprises exposing the compound of Formula (VI), or salt thereof, to a base, catalyst, and protecting group reagent.

50. The method of claim 49, wherein the base is a hydroxide salt.

51. The method of claim 49 or 50, wherein the base is sodium hydroxide.

52. The method of any one of claims 49-51, wherein the catalyst is 4-(dimethylamino)pyridine.

53. The method of any one of claims 49-52, wherein the protecting group reagent is Boc2O.

54. The method of any one of claims 44-53, wherein protecting the compound of Formula (VI), or salt thereof, under suitable conditions to provide the compound of Formula (V), or salt thereof, comprises a reaction temperature of about 0 ℃ to about 50 ℃, or about 25 ℃.

55. A method of preparing a compound of Formula (VI):or a salt thereof, comprising reducing a compound of Formula (VII):, or a salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group;H0824.70449WO00 205 / 250 #14309532v1each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

56. The method of any one of claims 44-54 further comprising reducing a compound of FormulaH0824.70449WO00 206 / 250 #14309532v1(VII):or a salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof.

57. The method of any one of claims 44-56, wherein the compound of Formula (VI) is of Formula (VI-a), (VI-b), or (VI-c):, or a salt thereof, wherein each instance of R12is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaliphatic.

58. The method of claim 57, wherein the compound of Formula (VI) is of Formula (VI-b-1) or (VI-c-1):, or a salt thereof.

59. The method of any one of claims 44-58, wherein the compound of Formula (VI) is ofH0824.70449WO00 207 / 250 #14309532v1formula:, or a salt thereof.

60. The method of any one of claims 55-59, wherein reducing the compound of Formula (VII), or salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, comprises exposing the compound of Formula (VII), or salt thereof, to a metal hydride.

61. The method of claim 60, wherein the metal hydride is lithium aluminum hydride.

62. The method of any one of claims 55-61, wherein reducing the compound of Formula (VII), or salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, comprises a first reaction temperature of about -20 ℃ to about 25 ℃, or about 0 ℃.

63. The method of any one of claims 55-62, wherein reducing the compound of Formula (VII), or salt thereof, under suitable conditions to provide the compound of Formula (VI), or salt thereof, comprises a second reaction temperature of greater than ambient temperature, about 25 ℃ to about 100 ℃, or about 70 ℃.

64. A method of preparing a compound of Formula (VII):or a salt thereof, comprising protecting a compound of Formula (VIII):or a salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, wherein:H0824.70449WO00 208 / 250 #14309532v1X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.H0824.70449WO00 209 / 250 #14309532v165. The method of any one of claims 55-63 further comprising protecting a compound of Formula (VIII):or a salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof.

66. The method of any one of claims 55-65, wherein the compound of Formula (VII) is of Formula (VII-a), (VII-b), (VII-c), or (VII-d):or a salt thereof, wherein each instance of R12is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaliphatic.

67. The method of claim 66, wherein the compound of Formula (VII) is of Formula (VII-c-1) or (VII-d-1):, or a salt thereof.H0824.70449WO00 210 / 250 #14309532v168. The method of any one of claims 55-67, wherein the compound of Formula (VII) is of formula:, or a salt thereof.

69. The method of any one of claims 64-68, wherein protecting the compound of Formula (VIII), or salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to 2,2-dimethoxypropane and / or acetone.

70. The method of any one of claims 64-69, wherein protecting the compound of Formula (VIII), or salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to an acid.

71. The method of claim 70, wherein the acid is (±)-10-camphorsulfonic acid.

72. The method of any one of claims 64-71, wherein protecting the compound of Formula (VIII), or salt thereof, under suitable conditions to provide the compound of Formula (VII), or salt thereof, comprises a reaction temperature of about 0 ℃ to about 40 ℃, or about 25 ℃.

73. A method of preparing a compound of Formula (VIII):or a salt thereof, comprising cyclizing a compound of Formula (IX):H0824.70449WO00 211 / 250 #14309532v1or a salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;H0824.70449WO00 212 / 250 #14309532v1each instance of ROis independently hydrogen or an oxygen protecting group; and each instance of RNis independently hydrogen or a nitrogen protecting group; or an ROgroup and an RNgroup are joined to form a substituted or unsubstituted heterocyclyl ring; and represents a single or double bond.

74. The method of any one of claims 64-72 further comprising cyclizing a compound of Formula (IX):, or a salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, wherein: each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and each instance of ROis independently hydrogen or an oxygen protecting group; and each instance of RNis independently hydrogen or a nitrogen protecting group; or an ROgroup and an RNgroup are joined to form a substituted or unsubstituted heterocyclyl ring.

75. The method of any one of claims 64-74, wherein the compound of Formula (VIII) is of Formula (VIII-a) or (VIII-b):or a salt thereof.H0824.70449WO00 213 / 250 #14309532v176. The method of claim 75, wherein the compound of Formula (VIII) is of Formula (VIII-b-1):or a salt thereof.

77. The method of any one of claims 64-76, wherein the compound of Formula (VIII) is of formula:, or a salt thereof.

78. The method of any one of claims 73-77, wherein cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises exposing the compound of Formula (IX), or salt thereof, to an acid, thereby forming a reaction mixture.

79. The method of claim 78, wherein the acid is HCl.

80. The method of any one of claims 73-79, wherein cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises a first reaction temperature of about 0 ℃ to about 40 ℃, or about 25 ℃.

81. The method of any one of claims 73-80, wherein cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, further comprises addition of a base to the reaction mixture.

82. The method of claim 81, wherein the base is ammonia.H0824.70449WO00 214 / 250 #14309532v183. The method of any one of claims 73-82, wherein cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises a second reaction temperature of about 0 ℃ to about 40 ℃, or about 25 ℃.

84. A method of preparing a compound of Formula (IX):or a salt thereof, comprising combining a compound of Formula (X):or a salt thereof, with a compound of Formula (XI):, or a salt thereof, and a compound of Formula (XII):, or a salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; X′ is =O, =S, or =NR9; Y′ is =C(R9)2, =CHR9, or =CH2; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA,H0824.70449WO00 215 / 250 #14309532v1–NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; each instance of R14is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; each instance of ROis independently hydrogen or an oxygen protecting group; and each instance of RNis independently hydrogen or a nitrogen protecting group; or an ROgroup and an RNgroup are joined to form a substituted or unsubstituted heterocyclyl ring; and represents a single or double bond.

85. The method of any one of claims 73-83 further comprising combining a compound of Formula (X):or a salt thereof, with a compound of Formula (XI):,H0824.70449WO00 216 / 250 #14309532v1or a salt thereof, and a compound of Formula (XII):or a salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, wherein: X′ is =O, =S, or =NR9; Y′ is =C(R9)2, =CHR9, or =CH2; each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and each instance of R14is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl.

86. The method of any one of claims 73-85, wherein the compound of Formula (IX) is of Formula (IX-a), (IX-b), or (IX-c):or a salt thereof, wherein R13ais substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or substituted or unsubstituted heteroaliphatic.

87. The method of claim 86, wherein the compound of Formula (IX) is of Formula (IX-b-1) orH0824.70449WO00 217 / 250 #14309532v1(IX-c-1):, or a salt thereof.

88. The method of any one of claims 73-87, wherein the compound of Formula (IX) is of formula:, or a salt thereof.

89. The method of any one of claims 73-88, wherein cyclizing the compound of Formula (IX), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises deprotecting the compound of Formula (IX), or salt thereof, under suitable conditions to provide a compound of Formula (IX′):, or a salt thereof.

90. The method of claim 89, wherein the compound of Formula (IX′) is of Formula (IX′-a) orH0824.70449WO00 218 / 250 #14309532v1(IX′-b):or a salt thereof, wherein R13ais substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or substituted or unsubstituted heteroaliphatic.

91. The method of claim 90, wherein the compound of Formula (IX′) is of Formula (IX′-a-1), (IX′-b-1), or (IX′-b-2):or a salt thereof.

92. The method of any one of claims 89-91, wherein the compound of Formula (IX′) is of formula:, or a salt thereof.

93. The method of any one of claims 84-92, wherein the compound of Formula (X) is of Formula (X-a) or (X-b):H0824.70449WO00 219 / 250 #14309532v1or a salt thereof.

94. The method of any one of claims 84-93, wherein the compound of Formula (X) is of formula:, or a salt thereof.

95. The method of any one of claims 84-94, wherein the compound of Formula (XI) is of Formula (XI-a):or a salt thereof, wherein R13ais substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or substituted or unsubstituted heteroaliphatic.

96. The method of any one of claims 84-95, wherein the compound of Formula (XI) is of Formula (XI-a-1):or a salt thereof.

97. The method of any one of claims 84-96, wherein the compound of Formula (XI) is of formula:, or a salt thereof.H0824.70449WO00 220 / 250 #14309532v198. The method of any one of claims 84-97, wherein the compound of Formula (XII) is of Formula (XII-a) or (XII-b):or a salt thereof, wherein each instance of R12is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaliphatic.

99. The method of claim 98, wherein the compound of Formula (XII) is of Formula (XII-b-1):or a salt thereof.

100. The method of any one of claims 84-99, wherein the compound of Formula (XII) is of formula:, or a salt thereof.

101. The method of any one of claims 84-100, wherein combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to a Lewis acid, thereby forming a reaction mixture.

102. The method of claim 101, wherein the Lewis acid is TiCl4.

103. The method of claim 101, wherein the Lewis acid is dibutylboron trifluoromethanesulfonate.H0824.70449WO00 221 / 250 #14309532v1104. The method of any one of claims 84-103, wherein combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises a first reaction temperature of about -78 ℃ to about 0 ℃, or about -78 ℃.

105. The method of any one of claims 101-104, wherein combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises addition of the compoud of Formula (X), or salt thereof, to the reaction mixture.

106. The method of any one of claims 101-105, wherein combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises addition of an amine base to the reaction mixture.

107. The method of claim 106, wherein the amine base is tetramethylethylenediamine (TMEDA).

108. The method of any one of claims 84-107, wherein combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises a second reaction temperature of about -78 ℃ to about 0 ℃, or about 0 ℃.

109. The method of any one of claims 101-108, wherein combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises addition of the compound of Formula (XII), or salt thereof, to the reaction mixture.

110. The method of any one of claims 84-109, wherein combining the compound of Formula (X), or salt thereof, with the compound of Formula (XI), or salt thereof, and the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (IX), or salt thereof, comprises a third reaction temperature of about 0 ℃ to about 50 ℃, or about 25 ℃.

111. The method of any one of claims 1-110, wherein R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, –C(=O)RA, or –C(=O)ORA.

112. The method of any one of claims 1-111, wherein R8is hydrogen, substituted or unsubstituted alkyl, or –C(=O)ORA.H0824.70449WO00 222 / 250 #14309532v1113. The method of any one of claims 1-112, wherein R8is hydrogen, –CH3, or –C(=O)OC(CH3)3.

114. The method of any one of claims 1-113, wherein R8is hydrogen.

115. The method of any one of claims 1-113, wherein R8is –C(=O)OC(CH3)3.

116. The method of any one of claims 1-115, wherein at least one instance of R9is substituted or unsubstituted alkyl.

117. The method of any one of claims 1-116, wherein at least one instance of R9is substituted or unsubstituted C1-6 alkyl.

118. The method of any one of claims 1-117, wherein at least one instance of R9is –CH3, –CH2CH3, –CH2CH2CH3, –CH2CH2CH2CH3, –CH(CH3)2, –CH2CH(CH3)2, or –CH(CH3)3.

119. The method of any one of claims 1-118, wherein at least one instance of R9is –CH2CH(CH3)2.

120. The method of any one of claims 11-25, 27-33, and 35-43, wherein R11is halogen.

121. The method of any one of claims 11-25, 27-33, 35-43, and 120, wherein R11is –I.

122. The method of any one of claims 32, 33, 46, 47, 57, 58, 66, 67, 98, and 99, wherein each instance of R12is independently substituted or unsubstituted C1-6 alkyl.

123. The method of any one of claims 32, 33, 46, 47, 57, 58, 66, 67, 98, 99, and 122, wherein each instance of R12is independently –CH3.

124. The method of any one of claims 73, 74, 84-87, 89-91, 95, and 96, wherein the moiety–N(R13)2 is of Formula (xiii-a): (xiii-a), wherein R13a is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted orH0824.70449WO00 223 / 250 #14309532v1unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or substituted or unsubstituted heteroaliphatic.

125. The method of any one of claims 73, 74, 84-87, 89-91, 95, 96, and 124, wherein the moiety–N(R13)2 is of Formula (xiii-b(xiii-b), wherein R13a is substituted or unsubstituted alkyl,substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl.

126. The method of any one of claims 73, 74, 84-87, 89-91, 95, 96, 124, and 125, wherein the moiety –N(R13)2 is of Formula:.

127. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-126, wherein the compound of Formula (XIII) is of Formula (XIII-a), (XIII-b), (XIII-c), or (XIII-d):,H0824.70449WO00 224 / 250 #14309532v1, or a pharmaceutically acceptable salt thereof, and the compound of Formula (XIV) is of Formula (XIV-a):or a salt thereof.

128. The method of claim 127, wherein the compound of Formula (XIII) is of Formula (XIII-c-1) or (XIII-d-1):, or a pharmaceutically acceptable salt thereof.H0824.70449WO00 225 / 250 #14309532v1129. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-128, wherein the compound of Formula (XIII) is of Formula (XIII′):or a pharmaceutically acceptable salt thereof, and the compound of Formula (XIV) is of Formula (XIV′):, or a salt thereof, wherein: A1is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, or –SRA; and A2is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

130. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-129, wherein the compound of Formula (XIII) is of Formula (XIII′-a), (XIII′-b), (XIII′-c), or (XIII′-d):,H0824.70449WO00 226 / 250 #14309532v1or a pharmaceutically acceptable salt thereof, and the compound of Formula (XIV) is of Formula (XIV′-a):or a salt thereof.

131. The method of claim 130, wherein the compound of Formula (XIII) is of Formula (XIII′-c-1) or (XIII′-d-1):, or a pharmaceutically acceptable salt thereof.

132. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-131, wherein A1is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, or –SRA.

133. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-132, wherein A1is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or – SRA.H0824.70449WO00 227 / 250 #14309532v1134. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-133, wherein A1is –SRA, and RAis unsubstituted C1-4alkyl.

135. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-134, wherein A1is –SCH3.

136. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-135, wherein A2is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,are joined to form a substituted or unsubstituted heterocyclic ring, wherein: R3ais halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, –ORA, –N3, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA,R3bis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic; R4is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic; R5is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic; R6a, R6b, and R6care each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, or substituted or unsubstituted acyl.H0824.70449WO00 228 / 250 #14309532v1137. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-136, wherein A2is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,138. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-137, wherein.

139. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-128, wherein A1and A2are joined to form a substituted or unsubstituted 8-14 membered heterocyclic ring.

140. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, 85- 128, and 139, wherein the compound of Formula (XIII) is of Formula (XIII′′):, or a pharmaceutically acceptable salt thereof; and the compound of Formula (XIV) is of Formula (XIV′′):, or a salt thereof, wherein: each instance of R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–;H0824.70449WO00 229 / 250 #14309532v1each instance of R2is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen-S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and q is 3, 4, 5, or 6.

141. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, 85- 128, 139, and 140, wherein the compound of Formula (XIII) is of Formula (XIII′′-a), (XIII′′-b), (XIII′′-c), or (XIII′′-d):or a pharmaceutically acceptable salt thereof, and the compound of Formula (XIV) is of FormulaH0824.70449WO00 230 / 250 #14309532v1(XIV′′-a):or a salt thereof.

142. The method of claim 141, wherein the compound of Formula (XIII) is of Formula (XIII′′-c- 1) or (XIII′′-d-1):, or a pharmaceutically acceptable salt thereof.

143. The method of any one of claims 2-10, 12-21, 23-29, 31-43, 45-54, 56-63, 65-72, 74-83, and 85-142, wherein R7is hydrogen.

144. The method of claim 2, wherein the compound of Formula (XIII) is:H0824.70449WO00 231 / 250 #14309532v1H0824.70449WO00 232 / 250 #14309532v1H0824.70449WO00 233 / 250 #14309532v1H0824.70449WO00 234 / 250 #14309532v1H0824.70449WO00 235 / 250 #14309532v1H0824.70449WO00 236 / 250 #14309532v1or pharmaceutically acceptable salt thereof.H0824.70449WO00 237 / 250 #14309532v1145. A compound of Formula (II):, or a salt thereof, wherein: X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and represents a single or double bond.H0824.70449WO00 238 / 250 #14309532v1146. The compound of claim 145, wherein the compound of Formula (II) is of formula:, or a salt thereof.

147. A compound of Formula (III):, or a salt thereof, wherein: X is –O–, –S–, –NR9–, or –C(R9)2–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted orH0824.70449WO00 239 / 250 #14309532v1unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

148. The compound of claim 147, wherein the compound of Formula (III) is of formula:, or a salt thereof.

149. A compound of Formula (IV):or a salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, =N–, –N=, –NR9–, –C(R9)2–, =CR9–, –CR9=, –CHR9–, –CH2–, =CH–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group;H0824.70449WO00 240 / 250 #14309532v1each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; R11is a leaving group; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.H0824.70449WO00 241 / 250 #14309532v1150. The compound of claim 149, wherein the compound of Formula (IV) is of formula:, or a salt thereof.

151. A compound of Formula (V):, or a salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstitutedH0824.70449WO00 242 / 250 #14309532v1aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

152. The compound of claim 151, wherein the compound of Formula (V) is of formula:, or a salt thereof.

153. A compound of Formula (VI):or a salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitutedH0824.70449WO00 243 / 250 #14309532v1aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring; RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

154. The compound of claim 153, wherein the compound of Formula (VI) is of formula:, or a salt thereof.H0824.70449WO00 244 / 250 #14309532v1155. A compound of Formula (VII):, or a salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R′′ is an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or R′′ is joined with RA1to form a substituted or unsubstituted heterocyclyl ring;H0824.70449WO00 245 / 250 #14309532v1RA1is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group; and represents a single or double bond.

156. The compound of claim 155, wherein the compound of Formula (VII) is of formula:, or a salt thereof.

157. A compound of Formula (VIII):, or a salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,H0824.70449WO00 246 / 250 #14309532v1–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and represents a single or double bond.

158. The compound of claim 157, wherein the compound of Formula (VIII) is of formula:, or a salt thereof.

159. A compound of Formula (IX):or a salt thereof, wherein: X is –O–, –S–, or –NR9–; Y is –O–, –S–, –N=, –NR9–, –C(R9)2–, –CR9=, –CHR9–, –CH2–, or –CH=; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group;H0824.70449WO00 247 / 250 #14309532v1each instance of R9is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; each instance of R13is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or a nitrogen protecting group, or two instances of R13are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; n is 0 or 1; p is 0, 1, 2, 3, or 4; each instance of RAis independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; each instance of ROis independently hydrogen or an oxygen protecting group; and each instance of RNis independently hydrogen or a nitrogen protecting group; or an ROgroup and an RNgroup are joined to form a substituted or unsubstituted heterocyclyl ring; and represents a single or double bond.H0824.70449WO00 248 / 250 #14309532v1160. The compound of claim 159, wherein the compound of Formula (IX) is of formula:, or a salt thereof.H0824.70449WO00 249 / 250 #14309532v1

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