Technologies useful for oligonucleotide preparation

Abstract

Among other things, the present disclosure provides technologies for preparation of oligonucleotides and intermediates thereof, e.g., nucleosides, phosphoramidites, etc. In some embodiments, such oligonucleotides and intermediates comprise N3U base modification.

Description

Attorney Docket No.: 2010581-1438 TECHNOLOGIES USEFUL FOR OLIGONUCLEOTIDE PREPARATION CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to United States Provisional Application No.63 / 623,750, filed January 22, 2024, the entirety of which is incorporated herein by reference. BACKGROUND

[0002] Oligonucleotides are useful for many purposes, including treating various diseases. Various technologies have been reported for oligonucleotide synthesis. SUMMARY

[0003] Designed oligonucleotides comprising modifications (e.g., modifications to nucleobases sugars, and / or internucleotidic linkages, and patterns thereof) can provide various benefits and advantages. For example, oligonucleotides (N3U) as a nucleobase are useful in nucleic acid editing, e.g., site-directed editing ofin nucleic acids. See, e.g., WO 2021 / 071858, WO 2022 / 099159, etc.

[0004] Among other things, the present disclosure encompasses the recognition of the source of a problem with many technologies for preparation of oligonucleotides and intermediates thereof, e.g., nucleosides, phosphoramidites, etc. In some embodiments, the present disclosure encompasses the recognition that one challenge associated with preparing compounds, e.g., oligonucleotides, phosphoramidites, nucleosides, etc., comprising optionally substituted is that purification can be of high cost and / or low efficiency. For example, many existing methods for nucleosides comprising optionally substituted utilize chromatography for purification. Among other things, the present disclosure recognizes that chromatography purification can suffer from low yields and / or purities and sometimes is unable to purify desired products from impurities due to, e.g., similar properties such as close polarity between desired products and impurities, absorption of products by purification medium, loss of materials during the process such as transfers between different containers, etc. Among other things, the present disclosure recognizes that chromatography purification has limitations in separating stereoisomers (e.g., diastereomers, Z / E isomers, regioisomers, enantiomers, etc.). In some embodiments, 12504599v1Attorney Docket No.: 2010581-1438 an impurity is a byproduct. In some embodiments, an impurity is a stereoisomer (e.g., diastereomers, Z / E isomers, regioisomers, enantiomers, etc.) of a desired product. For example, in some embodiments, a desired is. In many existing methods, utilization of chromatography forgenerates as waste a large amount of solvents, generates a large amount of solid waste (e.g., silica gel, alumina, etc.), requires time-consuming processes for optimizing and priming chromatography conditions, and is not suitable for large scale such as commercial scale synthesis.

[0005] Among other things, the present disclosure provides technologies, e.g., reagents, methods, etc., that can address these challenges and problems. In some embodiments, provided technologies can provide various benefits and advantages, e.g., effective and efficient separation of stereoisomers, improved purities, improved yields, reduced environmental impacts (e.g., by reducing / avoiding use of toxic materials (solvents, silica gel, alumina, etc.), waste, etc.), reduced costs, simplified procedures, improved efficiency, scaled-up production capabilities, etc. when compared a reference technology such as reported chromatography-based purification technologies.

[0006] In some embodiments, the present disclosure encompasses certain surprising findings that trituration can be utilized to obviate various problems associated with previously reported methods, e.g., chromatography purification. In some embodiments, performing trituration on a composition (e.g., a preparation to be purified) enables or improves purification of stereoisomers (e.g., diastereomers, Z / E isomers, regioisomers, enantiomers, etc.). In some embodiments, such stereoisomers are not readily separable or cannot be separated by other methods, e.g., chromatography. In some embodiments, performing trituration on a composition enables or improves purification of diastereomers. In some Page 2 of 71 12504599v1Attorney Docket No.: 2010581-1438 embodiments, performing trituration on a composition or improves purification of Z / E isomers. In some embodiments, performing trituration on a composition or improves purification of regioisomers. In some embodiments, performing trituration on a composition or improves purification of enantiomers. In some embodiments, performing trituration on a composition enables or improves separation of an alpha isomer and a beta isomer of a sugar. In some embodiments, performing trituration on a composition enables or improves separation of alpha isomer and beta isomer of a nucleoside. In some embodiments, performing trituration on a composition enables or improves separation of alpha isomer and beta isomer of a phosphoramidite.

[0007] In some embodiments, performing trituration on a composition circumvents the need of using large amounts of solvents which are required by chromatography purification, simplifies procedures, and is suitable for scaled-up production such as commercial production. In some embodiments, a preparation is a composition of an oligonucleotide, phosphoramidite or nucleoside comprising optionally substituted .In some embodiments, provided technologies can be performed at larger scale with easier operational conditions. In some embodiments, provided technologies provided chiral compounds with higher stereoselectivity. In some embodiments, provided technologies provided chiral compounds with higher stereopurity. In some embodiments, provided technologies provided chiral compounds with higher chemical purity. In some embodiments, a reference technology is chromatography purification.

[0009] In some embodiments, the present disclosure provides a method for preparing a compound or a salt thereof, comprising: performing trituration on a composition with a solvent system, wherein: the composition comprises the compound or a salt thereof and a diastereomer of the compound or a salt thereof; the level of the compound or a salt thereof is increased relative to that of a diastereomer or a salt thereof compared to prior to the trituration; and is −H orPage 3 of 71 12504599v1Attorney Docket No.: 2010581-1438 DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0010] Technologies of the present disclosure may be understood more readily by reference to the following detailed description of certain embodiments. DEFINITIONS

[0011] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0012] As used herein in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising”, “comprise”, “including” (whether used with “not limited to” or not), and “include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least an additional / second one or more; (v) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are included. Unless otherwise clear from context, isomers of compounds are included. As those skilled in the art, compounds may be provided, administered, or delivered in various forms, e.g., salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, esters, prodrugs, tautomers, etc.

[0013] Aliphatic: As used herein, “aliphatic” means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or combinations thereof. In some embodiments, aliphatic groups contain 1-50 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-9 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-7 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups Page 4 of 71 12504599v1Attorney Docket No.: 2010581-1438 contain 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0014] Alkenyl: As used herein, the term “alkenyl” refers to an aliphatic group, as defined herein, having one or more double bonds.

[0015] Alkyl: As used herein, the term “alkyl” is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, alkyl has 1-100 carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C1-C20 for straight chain, C2-C20 for branched chain), and alternatively, about 1-10. In some embodiments, cycloalkyl rings have from about 3-10 carbon atoms in their ring structure where such rings are monocyclic, bicyclic, or polycyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, an alkyl group may be a lower alkyl group, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., C1-C4 for straight chain lower alkyls).

[0016] Alkynyl: As used herein, the term “alkynyl” refers to an aliphatic group, as defined herein, having one or more triple bonds.

[0017] Animal: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development. In certain embodiments, the non- human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate and / or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish and / or worms. In some embodiments, an animal may be a transgenic animal, a genetically-engineered animal and / or a clone.

[0018] Aryl: The term “aryl", as used herein, used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclic or polycyclic ring systems having a total of five to thirty ring members, wherein at least one ring in the system is aromatic. In some embodiments, an aryl group is a monocyclic, bicyclic or polycyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, an aryl group is a biaryl group. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, Page 5 of 71 12504599v1Attorney Docket No.: 2010581-1438 is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and the like.

[0019] Chirally controlled oligonucleotide composition: The terms “chirally controlled oligonucleotide composition”, “chirally controlled nucleic acid composition”, and the like, as used herein, refers to a composition that comprises a plurality of oligonucleotides (or nucleic acids) which share 1) a common base sequence, 2) a common pattern of backbone linkages, and 3) a common pattern of backbone phosphorus modifications, wherein the plurality of oligonucleotides share the same stereochemistry at one or more chiral internucleotidic linkages (chirally controlled internucleotidic linkages), and the level of the plurality of oligonucleotides in the composition is pre-determined. In some embodiments, each chiral internucleotidic linkage is a chiral controlled internucleotidic linkage, and the composition is a completely chirally controlled oligonucleotide composition. In some embodiments, not all chiral internucleotidic linkages are chiral controlled internucleotidic linkages, and the composition is a partially chirally controlled oligonucleotide composition. In some embodiments, a chirally controlled oligonucleotide composition comprises predetermined levels of individual oligonucleotide or nucleic acids types. In some embodiments, oligonucleotides of a plurality share the same constitution and may be optionally in various forms (e.g., acid, basic, salt, etc.).

[0020] Comparable: The term “comparable” is used herein to describe two (or more) sets of conditions or circumstances that are sufficiently similar to one another to permit comparison of results obtained or phenomena observed. In some embodiments, comparable sets of conditions or circumstances are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will appreciate that sets of conditions are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under the different sets of conditions or circumstances are caused by or indicative of the variation in those features that are varied.

[0021] Cycloaliphatic: The term “cycloaliphatic,” “carbocycle,” “carbocyclyl,” “carbocyclic radical,” and “carbocyclic ring,” are used interchangeably, and as used herein, refer to saturated or partially unsaturated, but non-aromatic, cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having, unless otherwise specified, from 3 to 30 ring members. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, a cycloaliphatic group has 3–6 carbons. In some embodiments, a cycloaliphatic group is saturated and is cycloalkyl. The term “cycloaliphatic” may also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or Page 6 of 71 12504599v1Attorney Docket No.: 2010581-1438 tetrahydronaphthyl. In some embodiments, a cycloaliphatic group is bicyclic. In some embodiments, a cycloaliphatic group is tricyclic. In some embodiments, a cycloaliphatic group is polycyclic. In some embodiments, “cycloaliphatic” refers to C3-C6monocyclic hydrocarbon, or C8-C10bicyclic or polycyclic hydrocarbon, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, or a C9-C16polycyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.

[0022] Heteroaliphatic: The term “heteroaliphatic”, as used herein, is given its ordinary meaning in the art and refers to aliphatic groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like). In some embodiments, one or more units selected from C, CH, CH2, and CH3 are independently replaced by one or more heteroatoms (including oxidized and / or substituted forms thereof). In some embodiments, a heteroaliphatic group is heteroalkyl. In some embodiments, a heteroaliphatic group is heteroalkenyl.

[0023] Heteroalkyl: The term “heteroalkyl”, as used herein, is given its ordinary meaning in the art and refers to alkyl groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like). Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly(ethylene glycol)-, alkyl- substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

[0024] Heteroaryl: The terms “heteroaryl” and “heteroar–”, as used herein, used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to monocyclic, bicyclic or polycyclic ring systems having a total of five to thirty ring members, wherein at least one ring in the system is aromatic and at least one aromatic ring atom is a heteroatom. In some embodiments, a heteroaryl group is a group having 5 to 10 ring atoms (i.e., monocyclic, bicyclic or polycyclic), in some embodiments 5, 6, 9, or 10 ring atoms. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, a heteroaryl group has 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. In some embodiments, a heteroaryl is a heterobiaryl group, such as bipyridyl and the like. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, Page 7 of 71 12504599v1Attorney Docket No.: 2010581-1438 quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. A heteroaryl group may be monocyclic, bicyclic or polycyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0025] Heteroatom: The term “heteroatom", as used herein, means an atom that is not carbon or hydrogen. In some embodiments, a heteroatom is boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including oxidized forms of nitrogen, sulfur, phosphorus, or silicon; charged forms of nitrogen (e.g., quaternized forms, forms as in iminium groups, etc.), phosphorus, sulfur, oxygen; etc.). In some embodiments, a heteroatom is silicon, phosphorus, oxygen, sulfur or nitrogen. In some embodiments, a heteroatom is silicon, oxygen, sulfur or nitrogen. In some embodiments, a heteroatom is oxygen, sulfur or nitrogen.

[0026] Heterocycle: As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring", as used herein, are used interchangeably and refer to a monocyclic, bicyclic or polycyclic ring moiety (e.g., 3-30 membered) that is saturated or partially unsaturated and has one or more heteroatom ring atoms. In some embodiments, a heterocyclyl group is a stable 5– to 7–membered monocyclic or 7– to 10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur and nitrogen, the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic, bicyclic or polycyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein Page 8 of 71 12504599v1Attorney Docket No.: 2010581-1438 the alkyl and heterocyclyl portions independently are optionally substituted.

[0027] Optionally Substituted: As described herein, compounds of the disclosure may contain optionally substituted, substituted and / or unsubstituted moieties. In general, the term “substituted,” means that one or more hydrogens of the designated moiety are independently replaced with a substituent. Unless otherwise indicated, an “optionally substituted” group may independently have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with two or more substituents, the substituents may be either the same or different at every position. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. Various substituents are described below.

[0028] Monovalent substituents are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; −O(CH2)0- 4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4Ph, which may be substituted with R°; −(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; – (CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)N(R°)2; −N(R°)C(S)N(R°)2; –(CH2)0–4N(R°)C(O)OR°; –N(R°)N(R°)C(O)R°; −N(R°)N(R°)C(O)N(R°)2; −N(R°)N(R°)C(O)OR°; –(CH2)0– 4C(O)R°; –C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; −(CH2)0–4C(O)OSi(R°)3; –(CH2)0–4OC(O)R°;−SC(S)SR°, -(CH2)0–4OC(O)N(R°)2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; −C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; −S(O)2N(R°)2; -(CH2)0–4S(O)R°; –N(R°)S(O)2N(R°)2; –N(R°)S(O)2R°; –N(OR°)R°; −C(NH)N(R°)2; – Si(R°)3; –OSi(R°)3; −P(R°)2; −P(OR°)2; −OP(R°)2; −OP(OR°)2; −N(R°)P(R°)2; −B(R°)2; −OB(R°)2; −P(O)(R°)2; −OP(O)(R°)2; −N(R°)P(O)(R°)2; –(C1-4straight or branched alkylene)O–N(R°)2; or –(C1-4straight or branched alkylene)C(O)O–N(R°)2; wherein each R° may be independently substituted as defined below and is independently hydrogen, C1-10 (e.g., C1-6, C1-4, etc.) aliphatic, C1-10 (e.g., C1-6, C1-4, etc.) heteroaliphatic having 1-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, C6-10 (e.g., C6, C10, etc.) aryl, 5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, −CH2−(C6-10 (e.g., C6, C10, etc.) aryl), −O(CH2)0-1(C6-10 (e.g., C6, C10, etc.) aryl), −CH2−(5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), −O(CH2)0-1(5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 3-10 (e.g., 3-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, or partially unsaturated ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, Page 9 of 71 12504599v1Attorney Docket No.: 2010581-1438 notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-10 (e.g., 3-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated or aromatic ring (for aromatic ring, 5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered) having, in addition to the intervening atom(s), 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined below.

[0029] Monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2Rl, –(haloRl), –(CH2)0–2OH, –(CH2)0–2ORl, –(CH2)0–2CH(ORl)2; –O(haloRl), –CN, –N3, –(CH2)0–2C(O)Rl, –(CH2)0–2C(O)OH, – (CH2)0–2C(O)ORl, –(CH2)0–2SRl, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHRl, –(CH2)0–2NRl2, –NO2, – SiRl3, –OSiRl3, -C(O)SRl, –(C1–4 straight or branched alkylene)C(O)ORl, or –SSRlwherein each Rlis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3-5, 5-6, etc.)- membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Divalent substituents on a saturated carbon atom of R° are independently =O or =S.

[0030] Divalent substituents are independently the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, −O(C(R*2))2–3O−, or −S(C(R*2))2–3S−, wherein each independent occurrence of R*is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group are independently −O(CR*2)2–3O−, wherein each independent occurrence of R*is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0031] Substituents on the aliphatic group of R*are independently halogen, –Rl, -(haloRl), –OH, −ORl, –O(haloRl), –CN, –C(O)OH, –C(O)ORl, –NH2, –NHRl, –NRl2, or –NO2, wherein each Rlis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0032] Substituents on a substitutable nitrogen are independently –R†, −NR†2, −C(O)R†, –C(O)OR†, Page 10 of 71 12504599v1Attorney Docket No.: 2010581-1438 –C(O)C(O)R†, –C(O)CH2C(O)R†, –S(O)2R†, –S(O)2NR†2, −C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12 (e.g., 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0033] Substituents on the aliphatic group of R†are independently halogen, −Rl, -(haloRl), −OH, – ORl, –O(haloRl), –CN, –C(O)OH, –C(O)ORl, –NH2, –NHRl, –NRl2, or –NO2, wherein each Rlis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0034] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0035] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, an active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0036] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of Page 11 of 71 12504599v1Attorney Docket No.: 2010581-1438 sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0037] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0038] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., 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, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which 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, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, 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, Page 12 of 71 12504599v1Attorney Docket No.: 2010581-1438 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. In some embodiments, a provided compound comprises one or more acidic groups, and a pharmaceutically acceptable salt is an alkali, alkaline earth metal, or ammonium (e.g., an ammonium salt of N(R)3, wherein each R is independently defined and described in the present disclosure) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, a pharmaceutically acceptable salt is a sodium salt. In some embodiments, a pharmaceutically acceptable salt is a potassium salt. In some embodiments, a pharmaceutically acceptable salt is a calcium salt. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. In some embodiments, a provided compound comprises two or more acid groups. In some embodiments, a pharmaceutically acceptable salt, or generally a salt, of such a compound comprises two or more cations, which can be the same or different. In some embodiments, in a pharmaceutically acceptable salt (or generally, a salt), all ionizable hydrogen (e.g., in an aqueous solution with a pKa no more than about 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2; in some embodiments, no more than about 7; in some embodiments, no more than about 6; in some embodiments, no more than about 5; in some embodiments, no more than about 4; in some embodiments, no more than about 3) in the acidic groups are replaced with cations.

[0039] Protecting group: The term “protecting group,” as used herein, is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Also included are those protecting groups specially adapted for nucleoside and nucleotide chemistry described in Current Protocols in Nucleic Acid Chemistry, edited by Serge L. Beaucage et al.06 / 2012, the entirety of Chapter 2 is incorporated herein by reference. Suitable amino–protecting groups include 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– Page 13 of 71 12504599v1Attorney Docket No.: 2010581-1438 dicyclohexylcarboxamido)ethyl carbamate, t–butyl carbamate (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, phenothiazinyl–(10)–carbonyl derivative, N’–p– toluenesulfonylaminocarbonyl derivative, N’–phenylaminothiocarbonyl derivative, t–amyl carbamate, S– benzyl thiocarbamate, p–cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p–decyloxybenzyl carbamate, 2,2– dimethoxycarbonylvinyl carbamate, o–(N,N–dimethylcarboxamido)benzyl carbamate, 1,1–dimethyl–3– (N,N–dimethylcarboxamido)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, 2,4,6– trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3–phenylpropanamide, picolinamide, 3–pyridylcarboxamide, N– benzoylphenylalanyl derivative, benzamide, p–phenylbenzamide, o–nitophenylacetamide, o– nitrophenoxyacetamide, acetoacetamide, (N’–dithiobenzyloxycarbonylamino)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, o– (benzoyloxymethyl)benzamide, 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 Page 14 of 71 12504599v1Attorney Docket No.: 2010581-1438 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–pyrolin–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–ferrocenylmethylamine (Fcm), N–2–picolylamine 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(pentacarbonylchromium– or tungsten)carbonyl]amine, N–copper chelate, N–zinc chelate, N– nitroamine, N–nitrosoamine, amine N–oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o–nitrobenzenesulfenamide (Nps), 2,4– dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2–nitro–4–methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3–nitropyridinesulfenamide (Npys), 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.

[0040] Suitably protected carboxylic acids further include, but are not limited to, silyl–, alkyl–, alkenyl–, aryl–, and arylalkyl–protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, t–butyldimethylsilyl, t–butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p–methoxybenzyl, 3,4–dimethoxybenzyl, trityl, t–butyl, tetrahydropyran–2–yl. Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p–methoxybenzyl (MPM), 3,4– Page 15 of 71 12504599v1Attorney Docket No.: 2010581-1438 dimethoxybenzyl, o–nitrobenzyl, p–nitrobenzyl, p–halobenzyl, 2,6–dichlorobenzyl, p–cyanobenzyl), and 2– and 4–picolyl.

[0041] Suitable hydroxyl protecting groups include 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, 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, phenoxyacetate, 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), alkyl methyl carbonate, 9–fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2–trichloroethyl carbonate (Troc), 2– (trimethylsilyl)ethyl carbonate (TMSEC), 2–(phenylsulfonyl) ethyl carbonate (Psec), 2– (triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl Page 16 of 71 12504599v1Attorney Docket No.: 2010581-1438 carbonate, alkyl p–nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p–methoxybenzyl carbonate, alkyl 3,4–dimethoxybenzyl carbonate, alkyl o–nitrobenzyl carbonate, alkyl p–nitrobenzyl carbonate, alkyl 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–(methoxycarbonyl)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). For protecting 1,2– or 1,3–diols, the protecting groups include methylene acetal, ethylidene acetal, 1–t– butylethylidene ketal, 1–phenylethylidene ketal, (4–methoxyphenyl)ethylidene acetal, 2,2,2– trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p–methoxybenzylidene acetal, 2,4–dimethoxybenzylidene acetal, 3,4– dimethoxybenzylidene acetal, 2–nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1–methoxyethylidene ortho ester, 1–ethoxyethylidine ortho ester, 1,2–dimethoxyethylidene ortho ester, α–methoxybenzylidene ortho ester, 1–(N,N– dimethylamino)ethylidene derivative, α–(N,N’–dimethylamino)benzylidene derivative, 2– oxacyclopentylidene ortho ester, di–t–butylsilylene group (DTBS), 1,3–(1,1,3,3– tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra–t–butoxydisiloxane–1,3–diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

[0042] In some embodiments, a hydroxyl protecting group is acetyl, t-butyl, tbutoxymethyl, methoxymethyl, tetrahydropyranyl, 1 -ethoxyethyl, 1 -(2-chloroethoxy)ethyl, 2- trimethylsilylethyl, p- chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6- dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4,4'-dimethoxytrityl, trimethylsilyl, triethylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifiuoroacetyl, pivaloyl, 9- fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr) and 4,4',4''-trimethoxytrityl (TMTr), 2- cyanoethyl (CE or Cne), 2-(trimethylsilyl)ethyl (TSE), 2-(2-nitrophenyl)ethyl, 2-(4-cyanophenyl)ethyl 2- (4-nitrophenyl)ethyl (NPE), 2-(4-nitrophenylsulfonyl)ethyl, 3,5-dichlorophenyl, 2,4-dimethylphenyl, 2- nitrophenyl, 4-nitrophenyl, 2,4,6-trimethylphenyl, 2-(2-nitrophenyl)ethyl, butylthiocarbonyl, 4,4',4''- tris(benzoyloxy)trityl, diphenylcarbamoyl, levulinyl, 2-(dibromomethyl)benzoyl (Dbmb), 2- (isopropylthiomethoxymethyl)benzoyl (Ptmt), 9-phenylxanthen-9-yl (pixyl) or 9-(p- methoxyphenyl)xanthine-9-y1 (MOX). In some embodiments, each of the hydroxyl protecting groups is, Page 17 of 71 12504599v1Attorney Docket No.: 2010581-1438 independently selected from acetyl, benzyl, t- butyldimethylsilyl, t-butyldiphenylsilyl and 4,4'- dimethoxytrityl. In some embodiments, the hydroxyl protecting group is selected from the group consisting of trityl, monomethoxytrityl and 4,4'-dimethoxytrityl group. In some embodiments a protecting group is 2-cyanoethyl (CE or Cne), 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonylethyl, methyl, benzyl, o-nitrobenzyl, 2-(p-nitrophenyl)ethyl (NPE or Npe), 2-phenylethyl, 3-(N-tert-butylcarboxamido)- 1-propyl, 4-oxopentyl, 4-methylthio-l-butyl, 2-cyano-1,1-dimethylethyl, 4-N-methylaminobutyl, 3-(2- pyridyl)-1-propyl, 2-[N-methyl-N-(2-pyridyl)]aminoethyl, 2-(N-formyl,N-methyl)aminoethyl, or 4-[N- methyl-N-(2,2,2-trifluoroacetyl)amino]butyl.

[0043] Subject: As used herein, the term “subject” or “test subject” refers to any organism to which a compound or composition is administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.) and plants. In some embodiments, a subject is a human. In some embodiments, a subject may be suffering from and / or susceptible to a disease, disorder and / or condition.

[0044] Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological and / or chemical arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and / or chemical phenomena.

[0045] Susceptible to: An individual who is “susceptible to” a disease, disorder and / or condition is one who has a higher risk of developing the disease, disorder and / or condition than does a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition is predisposed to have that disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may not have been diagnosed with the disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may exhibit symptoms of the disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may not exhibit symptoms of the disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0046] Therapeutic agent: As used herein, the term “therapeutic agent” in general refers to any agent that elicits a desired effect (e.g., a desired biological, clinical, or pharmacological effect) when Page 18 of 71 12504599v1Attorney Docket No.: 2010581-1438 administered to a subject. In some embodiments, an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population. In some embodiments, an appropriate population is a population of subjects suffering from and / or susceptible to a disease, disorder or condition. In some embodiments, an appropriate population is a population of model organisms. In some embodiments, an appropriate population may be defined by one or more criterion such as age group, gender, genetic background, preexisting clinical conditions, prior exposure to therapy. In some embodiments, a therapeutic agent is a substance that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms or features of a disease, disorder, and / or condition in a subject when administered to the subject in an effective amount. In some embodiments, a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans. In some embodiments, a therapeutic agent is a provided compound.

[0047] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0048] Treat: As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0049] Unsaturated: The term "unsaturated," as used herein, means that a moiety has one or more Page 19 of 71 12504599v1Attorney Docket No.: 2010581-1438 units of unsaturation.

[0050] As those skilled in the art will appreciate, methods and compositions described herein relating to provided compounds generally also apply to pharmaceutically acceptable salts of such compounds. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0051] Among other things, the present disclosure provides technologies (e.g., compounds, methods, etc.) for preparing oligonucleotides and intermediates thereof (e.g., nucleosides, phosphoramidites, etc.). In some embodiments, provided technologies are particularly useful in preparing oligonucleotides comprising optionally and intermediates thereof, e.g., nucleosides, nucleotides, phosphoramidites, etc. Amongprovided technologies obviates various problems associated with previously reported methods for preparing oligonucleotides, phosphoramidites, nucleotides, nucleosides, etc. comprising optionally substituted . In some embodiments, provided technologies are particularly useful in purifying nucleosides comprising optionally by removing one or more byproducts. In some embodiments, a byproduct is a stereoisomerproduct. In some embodiments, provided technologies enable or improve separation of stereoisomers (e.g., diastereomers, Z / E isomers, regioisomers, enantiomers, etc.) which are not readily separable by previously reported methods, e.g., chromatography purification. In some embodiments, provided technologies enable or improve separation of stereoisomers (e.g., diastereomers, Z / E isomers, regioisomers, enantiomers, etc.) from a crude preparation of nucleosides comprising optionally . In some embodiments, provided technologies improve separation ofdiastereomers. In some embodiments, provided technologies enable or improve separation of Z / E isomers. In some embodiments, provided technologies enable or improve separation of regioisomers. In some embodiments, provided technologies enable or improve separation of enantiomers. In some embodiments, provided technologies enable or improve separation of alpha isomer and beta isomer of a sugar. In some embodiments, provided technologies enable or improve separation of alpha isomer and beta isomer of a nucleoside. In some embodiments, provided technologies enable or improve separation of alpha isomer and beta isomer of a phosphoramidite. Page 20 of 71 12504599v1Attorney Docket No.: 2010581-1438

[0052] In some embodiments, compared to previously reported methods, e.g., chromatography purification, provided technologies improve purify / yield of a product (e.g., nucleosides comprising optionally ), minimize environmental impacts by reducing use of toxic materials (solvents, silica gel,, reduce associated costs, simplify procedures, and / or are suitable for scaling-up.

[0053] In some embodiments, provided technologies can be performed at larger scale with easier operational conditions. In some embodiments, provided technologies provided chiral compounds with higher stereoselectivity. In some embodiments, provided technologies provided chiral compounds with higher stereopurity. In some embodiments, provided technologies provided chiral compounds with higher chemical purity. In some embodiments, provided technologies provided chiral compounds with higher yield.

[0054] In some embodiments, the present disclosure provides a method for preparing a compound or a salt thereof, comprising: performing trituration on a composition with a solvent system, wherein: the composition comprises the compound or a salt thereof and a diastereomer of the compound or a salt thereof; the level of the compound or a salt thereof is increased relative to that of the diastereomer or a salt thereof compared to prior to the trituration; and the compound has the (beta isomer), wherein R1is −H or −F.

[0055] In some embodiments, as described in the Exemplification, a composition is a crude preparation of the compound or a salt thereof that comprises an impurity, e.g., a diastereomer of a nucleoside (whose nucleobase, hydroxyl groups, etc. are optionally substituted and / or protected, e.g., as Page 21 of 71 12504599v1Attorney Docket No.: 2010581-1438 described in the Exemplification) with respect to C1 . Compounds

[0056] isomer),ofDiastereomers Page 22 of 71 12504599v1Attorney Docket No.: 2010581-1438

[0057] In some embodiments, a (beta isomer),is a(alpha isomer). In some embodiments, a diastereomer ofPage 23 of 71 12504599v1Attorney Docket No.: 2010581-1438 (alpha isomer). In some embodiments, the compound is the beta isomer and the diastereomer is the alpha isomer. In some embodiments, the compound is the alpha isomer and the diastereomer is the beta isomer. Solvent System

[0058] In some embodiments, there is a single solvent in a solvent system. In some embodiments, there are two or more solvents in a solvent system. In some embodiments, a solvent system comprises one or more solvents independently selected from water, EtOAc, dichloromethane (DCM), chloroform, acetonitrile, MeOH, EtOH, isopropyl alcohol, hexane, cyclohexane, heptane, pentane, cyclopentane, petroleum ether and a compound having a structure of Ra-O-Rb, wherein Raand Rbare each independently selected from C1-C6 aliphatic and C3-C10 cycloaliphatic, or Raand Rbare taken together to form a 3-10 membered ring having 0-2 additional heteroatoms independently selected from oxygen and nitrogen. In some embodiments, Raand Rbare each independently selected from C1-C6 alkyl and C3-C10 cycloalkyl, or Raand Rbare taken together to form a 3-6 membered ring having 0-1 additional heteroatom selected from oxygen and nitrogen. In some embodiments, Ra-O-Rbis diethyl ether, tetrahydrofuran (THF), or methyl t-butyl ether (MTBE). In some embodiments, a solvent system comprises one or more solvents independently selected from EtOAc and acetonitrile.

[0059] In some embodiments, a solvent system consists of one solvent. In some embodiments, a solvent system consists of water. In some embodiments, a solvent system consists of EtOAc. In some embodiments, a solvent system consists of dichloromethane (DCM). In some embodiments, a solvent system consists of chloroform. In some embodiments, a solvent system consists of acetonitrile. In some embodiments, a solvent system consists of MeOH. In some embodiments, a solvent system consists of EtOH. In some embodiments, a solvent system consists of isopropyl alcohol. In some embodiments, a solvent system consists of hexane. In some embodiments, a solvent system consists of hexanes. In some embodiments, a solvent system consists of cyclohexane. In some embodiments, a solvent system consists of heptane. In some embodiments, a solvent system consists of pentane. In some embodiments, a solvent system consists of cyclopentane. In some embodiments, a solvent system consists of petroleum ether. In some embodiments, a solvent system consists of Ra-O-Rb, wherein Raand Rbare each independently as described herein. In some embodiments, a solvent system consists of diethyl ether. In some embodiments, a solvent system consists of tetrahydrofuran (THF). In some embodiments, a solvent system consists of methyl t-butyl ether (MTBE).

[0060] In some embodiments, a solvent system consists of two solvents. In some embodiments, there are two or more solvents in a solvent system.

[0061] In some embodiments, a solvent system comprises a first solvent and a second solvent. In some embodiments, a solvent system consists of a first solvent and a second solvent. Page 24 of 71 12504599v1Attorney Docket No.: 2010581-1438

[0062] In some embodiments, the ratio of a first solvent : a second solvent is about 1:1. In some embodiments, the ratio of a first solvent : a second solvent is about 2:1. In some embodiments, the ratio of a first solvent : a second solvent is about 3:1. In some embodiments, the ratio of a first solvent : a second solvent is about 4:1. In some embodiments, the ratio of a first solvent : a second solvent is about 5:1. In some embodiments, the ratio of a first solvent : a second solvent is about 10:1. In some embodiments, the ratio of a first solvent : a second solvent is about 15:1. In some embodiments, the ratio of a first solvent : a second solvent is about 20:1. In some embodiments, the ratio of a first solvent : a second solvent is about 25:1. In some embodiments, the ratio of a first solvent : a second solvent is about 30:1. In some embodiments, the ratio of a first solvent : a second solvent is about 50:1. In some embodiments, the ratio of a first solvent : a second solvent is about 100:1. In some embodiments, the ratio of a first solvent : a second solvent is about 200:1. In some embodiments, the ratio of a first solvent : a second solvent is about 500:1. In some embodiments, the ratio of a first solvent : a second solvent is about 1000:1.

[0063] In some embodiments, a solvent system comprises a first solvent which is EtOAc and a second solvent which is acetonitrile. In some embodiments, a solvent system comprises a first solvent which is EtOAc and a second solvent which is petroleum ether. In some embodiments, a solvent system comprises a first solvent which is EtOAc and a second solvent which is hexanes. Temperature

[0064] Titration may be performed at various temperatures, e.g., about 0-80 °C, about 10-80 °C, about 30-80 °C, about 50-80 °C, about 50-70 °C, about 0, 10, 20, 30, 40, 50, 60, 70, 80, 90 °C, etc. In some embodiments, trituration is performed at about 0 °C. In some embodiments, trituration is performed at about 10 °C. In some embodiments, trituration is performed at about 20 °C. In some embodiments, trituration is performed at room temperature. In some embodiments, trituration is performed at an elevated temperature. In some embodiments, trituration is performed at about 30 °C. In some embodiments, trituration is performed at about 40 °C. In some embodiments, trituration is performed at about 50 °C. In some embodiments, trituration is performed at about 60 °C. In some embodiments, trituration is performed at about 65 °C. In some embodiments, trituration is performed at about 70 °C. In some embodiments, trituration is performed at about 80 °C. In some embodiments, trituration is performed at greater than about 80 °C. Purity In some embodiments, a compound, e.g., a product compound prepared from a provided method, has a purity of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, Page 25 of 71 12504599v1Attorney Docket No.: 2010581-1438 99.9%, or more. In some embodiments, a product has a purity of 80% or more. In some embodiments, a compound has a purity of 85% or more. In some embodiments, a compound has a purity of 90% or more. In some embodiments, a compound has a purity of 91% or more. In some embodiments, a compound has a purity of 92% or more. In some embodiments, a compound has a purity of 93% or more. In some embodiments, a compound has a purity of 94% or more. In some embodiments, a compound has a purity of 95% or more. In some embodiments, a compound has a purity of 96% or more. In some embodiments, a compound has a purity of 97% or more. In some embodiments, a compound has a purity of 98% or more. In some embodiments, a compound has a purity of 99% or more. In some embodiments, a compound has a purity of 99.5% or more. In some embodiments, a compound has a purity of 99.9% or more. In some embodiments, an impurity is a stereoisomer of a compound. In some embodiments, an impurity is a diastereomer of a compound. In some embodiments, a purity is weight %. Diastereopurity

[0066] In some embodiments, a composition on which trituration is performed, e.g., a crude a salt thereof) and alphaisomer (e.g., the a salt thereof) of a compound as described herein. In someis about 1:1 to about 50:1. In some embodiments, the ratio of beta:alpha isomers is about 1:1 to about 20:1. In some embodiments, the ratio of beta:alpha isomers is about 1:1 to about 10:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 2:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 3:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than Page 26 of 71 12504599v1Attorney Docket No.: 2010581-1438 about 4:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 5:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 6:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 7:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 8:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 9:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 10:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 20:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 30:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 40:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 50:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 100:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 500:1. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1000:1. In some embodiments, the ratio of beta:alpha isomers is about 1:1 to about 1:50. In some embodiments, the ratio of beta:alpha isomers is about 1:1 to about 1:20. In some embodiments, the ratio of beta:alpha isomers is about 1:1 to about 1:10. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:2. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:3. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:4. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:5. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:6. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:8. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:9. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:10. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:20. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:30. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:40. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:50. In some embodiments, the ratio of beta:alpha isomers is about or no more than about 1:100. the ratio of beta:alpha isomers is about or no more than about 1:500. the ratio of beta:alpha isomers is about or no more than about 1:1000. In some embodiments, the ratio of the beta:alpha isomers is about 2:1 to about 1:2. In some embodiments, the ratio of the beta:alpha isomers is about 3:1 to about 1:3. In some embodiments, the ratio of the beta:alpha isomers is about 4:1 to about 1:4. In some embodiments, the ratio of the beta:alpha isomers is about 5:1 to about 1:5. In some embodiments, the ratio of the beta:alpha isomers is about 6:1 to about 1:6. In some embodiments, the ratio of the beta:alpha isomers is about 7:1 to about 1:7. In some embodiments, the ratio of the beta:alpha isomers is about 8:1 to about 1:8. In some embodiments, the ratio of the beta:alpha isomers is about 9:1 to about 1:9. In some embodiments, the Page 27 of 71 12504599v1Attorney Docket No.: 2010581-1438 ratio of the beta:alpha isomers is about 10:1 to about 1:10. In some embodiments, the ratio of the beta:alpha isomers is about 20:1 to about 1:20. In some embodiments, the ratio of the beta:alpha isomers is about 50:1 to about 1:50. In some embodiments, the ratio of the beta:alpha isomers is about 100:1 to about 1:100. In some embodiments, the ratio of the beta:alpha isomers is about 500:1 to about 1:500. In some embodiments, the ratio of the beta:alpha isomers is about 1000:1 to about 1:1000.

[0067] Among other things, provided technologies can enrich desired compounds, e.g., desired isomers. In some embodiments, provided technologies can enrich a compound by about 2 (e.g., from bata:alpha = 2:1 to beta:alpha = 4:1 when beta isomer is a desired product), 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 100, 200, 500, 1000 fold or more. In some embodiments, an enrichment is about or at least 2 fold. In some embodiments, an enrichment is about or at least 5 fold. In some embodiments, an enrichment is about or at least 10 fold. In some embodiments, an enrichment is about or at least 20 fold. In some embodiments, an enrichment is about or at least 30 fold. In some embodiments, an enrichment is about or at least 40 fold. In some embodiments, an enrichment is about or at least 50 fold. In some embodiments, an enrichment is about or at least 100 fold.

[0068] In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 90:10. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 95:5. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 99:1. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 4:1. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 5:1. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 10:1. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 15:1. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 20:1. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 50:1. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 100:1. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 500:1. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 1000:1. In some embodiments, the ratio of the beta:alpha isomers is improved to about or greater than about 2000:1.

[0069] In some embodiments, the ratio of alpha:beta isomer is improved to about or greater than about 90:10. In some embodiments, the ratio of alpha:beta isomer is improved to about or greater than about 95:5. In some embodiments, the ratio of alpha:beta isomer is improved to about or greater than about 99:1. In some embodiments, the ratio of alpha:beta isomer is improved to about or greater than about 4:1. In some embodiments, the ratio of alpha:beta isomer is improved to about or greater than about 5:1. In some embodiments, the ratio of alpha:beta isomer is improved to about or greater than Page 28 of 71 12504599v1Attorney Docket No.: 2010581-1438 about 10:1. In some embodiments, the ratio of alpha:beta isomer is improved to about or greater than about 15:1. In some embodiments, the ratio of alpha:beta isomer is improved to about or greater than about 20:1. In some embodiments, the ratio of alpha:beta isomer is improved to about or greater than about 50:1. In some embodiments, the ratio of alpha:beta isomer is improved to about or greater than about 100:1. In some embodiments, diastereopurity of a provided compound is about or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, it is about or at least about 90%. In some embodiments, it is about or at least about 95%. In some embodiments, it is about or at least about 98%. In some embodiments, it is about or at least about 99%. Scale

[0070] In some embodiments, the amount of a or a salt thereof in a composition on which trituration is7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, or 1000 mmol. In some embodiments, it is about 1-2000, 50-2000, or 100-2000 mmol. In some embodiments, it is about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, or 1000 mol. In some embodiments, it is about 1- 1000, 1-500, 10-1000 or 1-100 mol.

[0071] In some embodiments, a provided method provides a compound at a scale of about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, or 1000 mmol, or about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, or 1000 mol. In some embodiments, it is about 1-2000, 50-2000, or 100-2000 mmol. In some embodiments, it is about 1-1000, 1-500, 10-1000 or 1-100 mol.

[0072] In some embodiments, a provided method is carried out at a scale of greater than about 10 mmol of the nucleoside product. In some embodiments, a provided method is carried out at a scale of greater than about 20 mmol of the nucleoside product. In some embodiments, a provided method is carried out at a scale of greater than about 50 mmol of the nucleoside product. In some embodiments, a provided method is carried out at a scale of greater than about 100 mmol of the nucleoside product. In some embodiments, a provided method is carried out at a scale of greater than about 150 mmol of the nucleoside product. In some embodiments, a provided method is carried out at a scale of greater than about 200 mmol of the nucleoside product. Page 29 of 71 12504599v1Attorney Docket No.: 2010581-1438

[0073] In some embodiments, a provided method does not involve subjecting the composition to column chromatography. In some embodiments, a provided method does not involve subjecting the composition to prep-HPLC. Preparation of certain compounds

[0074] In some embodiments, the present disclosure provides methods of preparing certain compounds, e.g., phosphoramidites, that comprises a method for preparing, e.g., (beta isomer) or a salt thereof, wherein R1is −H or −F in accordanceembodiments, a method comprises one or more steps described below (e.g., from a compound of formula (5) to a compound of formula (7), from a compound of formula (4) to a compound of formula (5), from a compound of formula (3) to a compound of formula (4), from a compound of formula (1) to a compound of formula (3), etc.), wherein: each of R2, R3, and R4is independently R’, or two or three of R2, R3, and R4are taken together with their intervening atoms to form ; Ring A is an optionallyring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; t is 0-5; each Rsis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −Ls−Rs11, −Ls−ORs11, −Ls−SRs11, −Ls−N(Rs11)2, −O−Ls−ORs11, −O−Ls−SRs11, −O−Ls−N(Rs11)2, −C(Rs11)3 or −Ls−Si(Rs11)3;each Lsis independently L; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; Page 30 of 71 12504599v1Attorney Docket No.: 2010581-1438 each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-10aliphatic, C1-10heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each other variable is independently as described herein (in some embodiments, PG is a protecting group, Halo1 and Halo2 are each independently a halogen).e.g., compounds of formula (7) or salts thereof, comprising one or more or all steps illustrated above as an example, wherein each variable is independently as described herein.

[0076] In some embodiments, a method comprising contacting a compound having the structure of formula (1) with a compound having the structure of formula (2) or a salt thereof provides a compound having the structure of formula (3) or a salt thereof, wherein Halo1 is a leaving group, PG is a protecting group or −C(O)R, and R1is −H or −F. In some embodiments, Halo1 is halogen. In some embodiments, Page 31 of 71 12504599v1Attorney Docket No.: 2010581-1438 Halo1 is Cl. In some embodiments, Halo1 is Br. In some embodiments, Halo1 is I. In some embodiments, PG is a protecting group. In some embodiments, a PG is an acetyl group. In some embodiments, PG is −C(O)R wherein R is as described herein. In some embodiments, a reaction is performed in the presence of a base, e.g., NaH. In some embodiments, a compound having the structure of (3) or a salt thereof is subject to a de-protection condition, e.g., NaOH / NaOMe, to provide a compound having the structure of formula (4) or a salt thereof. In some embodiments, a compound having the structure of (4) or a salt thereof is subject to protection conditions to provide a compound having the structure of (5) or a salt thereof. In some embodiments, a protecting agent is DMTrCl. In some embodiments, contacting a compound having the structure of formula (5) or a salt thereof with a compound having the structure of formula (6) or a salt thereof provides a compound having the structure of formula (7) or a salt thereof. In some , wherein eachR is independently C1-6alkyl or optionally substituted phenyl. In some is, wherein each R is independently C1-6 alkyl or optionally substituted phenyl. In someis, wherein R is optionallysubstituted C1-6 alkyl or optionally substituted phenyl. In some isPage 32 of 71 12504599v1Attorney Docket No.: 2010581-1438 , wherein R is optionally substituted C1-6 alkyl or optionally substituted phenyl. In someembodiments, is.embodiments, the present disclosure provides a method, comprising: reacting a compound having the structure of formula (5): or a salt thereof with a compound(6): to provide a compound having the structure: Page 33 of 71 12504599v1Attorney Docket No.: 2010581-1438 or a salt thereof, wherein each variable herein.

[0078] In some embodiments,a reaction is performed in the presence of a base. In some embodiments, a reaction is performed in the presence of TEA.

[0079] In some embodiments, the present disclosure provides a method, comprising: reacting a compound having the structure of formula (4): or a salt thereof with an agent (e.g.,a leaving group (e.g., −Cl)) to provide a compound having the structure of formula (5): or a salt thereof, wherein each variableherein.

[0080] In some embodiments, a reaction is carried out under a protecting condition. In some embodiments, a reaction is carried out in the presence of DMTrCl. In some embodiments, a reaction is carried out in the presence of a base. In some embodiments, a base is pyridine. In some embodiments, a reaction is carried out in pyridine.

[0081] In some embodiments, the present disclosure provides a method, comprising: reacting a compound having the structure of formula (3): Page 34 of 71 12504599v1Attorney Docket No.: 2010581-1438 or a salt thereof to provide a (4):or a salt thereof, wherein each variable is herein.

[0082] In some embodiments, a a basic condition. In some embodiments, a reaction is carried out in the presence of methoxide. In some embodiments, a reaction is carried out in the presence of NaOMe.

[0083] In some embodiments, the present disclosure provides a method, comprising: reacting a compound having the structure of formula (1): or a salt thereof with a: to provide a compound having the structurePage 35 of 71 12504599v1Attorney Docket No.: 2010581-1438 or a salt thereof, wherein each herein.

[0084] In some embodiments,Halo1 is Br. In some embodiments, Halo1 is I. In some embodiments, reaction is carried out at about 0 °C to about 65 °C. In some embodiments, a crude product comprising stereoisomers of compound of formula (3) or a salt thereof is subject to trituration condition in accordance with the present disclosure to provide beta isomer having the structure of formula (3). In some embodiments, a crude product comprising stereoisomers of compound of formula (3) or a salt thereof wherein R1is −H and is triturated with a mixture of EtOAc and MeCN at, e.g., 60 °C. In some embodiments, a crude product comprising stereoisomers of compound of formula (3) or a salt thereof wherein R1is −F and is triturated with a mixture of EtOAc and petroleum ether at, e.g., 65 °C.

[0085] Certain useful embodiments for various variables are described below as examples. R1

[0086] In some embodiments, R1is −H. In some embodiments, R1is −F. R2

[0087] In some embodiments, R2is R’ as described herein and is not −H. In some embodiments, R2is R as described herein. In some embodiments, R2is optionally substituted C1-6aliphatic. In some embodiments, R2is optionally substituted methyl. In some embodiments, R2is optionally substituted ethyl. In some embodiments, R2is optionally substituted ethyl, wherein the methylene unit boned to the oxygen is optionally monosubstituted, and the methyl is substituted with an electron-withdrawing group, e.g., −CN. Certain electron-withdrawing groups are described in US 10167309, US 11643657, US 11718638, US 11608355 or US 20230089442, the electron-withdrawing groups of each of which are incorporated herein by reference. In some embodiments, R2is −CH2CH2CN. R3In some embodiments, R3is R’ as described herein and is not −H. In some embodiments, R3Page 36 of 71 12504599v1Attorney Docket No.: 2010581-1438 is R as described herein. In some embodiments, R3is not −H. In some embodiments, R3is optionally substituted C1-10aliphatic. In some embodiments, R3is optionally substituted C1-10alkyl. In some embodiments, R3is C1-6aliphatic. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is isopropyl.R4

[0089] In some embodiments, R4is R’ as described herein and is not −H. In some embodiments, R4is R as described herein. In some embodiments, R4is not −H. In some embodiments, R4is optionally substituted C1-10 aliphatic. In some embodiments, R4is optionally substituted C1-10 alkyl. In some embodiments, R4is C1-6 aliphatic. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is isopropyl.

[0090] In some embodiments, R3and R4are the same. In some embodiments, R3and R4are different.

[0091] In some embodiments, −P(OR2)N(R3)(R4) is −P(OCH2CH2CN)N[CH(CH3)2]2.

[0092] In some embodiments, two or three of R2, R3, and R4are taken together with their intervening atoms to form wherein each variable is independently as described herein. In sometaken together with their intervening atoms to form a ring as described herein. In some embodiments, R3and R4are taken together with their intervening atoms to from a ring as described herein. In some embodiments, R2, R3and R4are taken together with their intervening atoms to form a ring as described herein. Ring A

[0093] As defined herein, Ring A is an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having, in addition to the intervening atoms, 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, Ring A is an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, Ring A has no additional heteroatoms. In some embodiments, Ring A has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional heteroatoms.

[0094] In some embodiments, Ring A is not substituted (as appreciated by those skilled in the art, not including Rs). In some embodiments, Ring A is substituted (as appreciated by those skilled in the art, Page 37 of 71 12504599v1Attorney Docket No.: 2010581-1438 not including Rs).

[0095] In some embodiments, Ring A is monocyclic. In some embodiments, Ring A is bicyclic. In some embodiments, Ring A is polycyclic. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur and 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, etc.) carbon atoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 4-10 (e.g., 4, 5, 6, 7, 8, 9, 10, 5-7, 5-6) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur and 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, etc.) carbon atoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-10 membered. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-7 membered. In some embodiments, each monocyclic ring unit is independently an optionally substituted 4-6 membered. In some embodiments, each monocyclic ring unit is independently an optionally substituted 5-6 membered. In some embodiments, each monocyclic ring unit is independently an optionally substituted 5-membered. In some embodiments, a monocyclic ring unit is an optionally substituted saturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted partially unsaturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted aromatic ring. In some embodiments, a monocyclic ring unit is an optionally substituted phenyl ring. In some embodiments, a monocyclic ring unit is an optionally substituted 5-membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6-membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. Each monocyclic ring unit is independently optionally substituted. In some embodiments, a monocyclic ring unit is unsaturated. In some embodiments, a monocyclic ring unit is saturated.

[0096] In some embodiments, a monocyclic ring unit comprising the nitrogen atom to which R2and R3are bond is an optionally substituted saturated 4-10 (e.g., 4-8, 4-6, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having 0-2 heteroatoms in addition to the nitrogen atom independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit comprising the nitrogen atom to which R2and R3are bond is an optionally substituted saturated 4-10 (e.g., 4-8, 4-6, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having no heteroatoms in addition to the nitrogen atom independently selected from nitrogen, oxygen and sulfur. In some embodiments, it is 4-membered. In some embodiments, it is 5- membered. In some embodiments, it is 6-membered. In some embodiments, it is 7-membered. In some embodiments, it is 8-membered. Page 38 of 71 12504599v1Attorney Docket No.: 2010581-1438

[0097] In some embodiments, Ring A is an optionally substituted saturated ring. In some embodiments, Ring A is an optionally substituted partially unsaturated ring. In some embodiments, Ring A is an optionally substituted aromatic ring.

[0098] In some embodiments, Ring A is an optionally substituted monocyclic 3-10 (e.g., 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atom(s), 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is an optionally substituted bicyclic or polycyclic 6-20 (e.g., 6-15, 6-10, 8-20, 8-15, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atom(s), 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is 3-9, 3-8, 3-7, 3-6, 4-10, 4-9, 4-8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10-membered. In some embodiments, Ring A is 3-9 membered. In some embodiments, Ring A is 3-7 membered. In some embodiments, Ring A is 4-10 membered. In some embodiments, Ring A is 4-7 membered. In some embodiments, Ring A is 5-10 membered. In some embodiments, Ring A is 5-7 membered. In some embodiments, Ring A is 3- membered. In some embodiments, Ring A is 4-membered. In some embodiments, Ring A is 5- membered. In some embodiments, Ring A is 6-membered. In some embodiments, Ring A is 7- membered. In some embodiments, Ring A is 8-membered. In some embodiments, Ring A is 9- membered. In some embodiments, Ring A is 10-membered. In some embodiments, Ring A is 11- membered. In some embodiments, Ring A is 12-membered. In some embodiments, Ring A is monocyclic. In some embodiments, Ring A is bicyclic. In some embodiments, Ring A is an optionally substituted bicyclic 7-12 membered ring. In some embodiments, Ring A is an optionally substituted bicyclic 8-10 membered ring. In some embodiments, Ring A is an optionally substituted bicyclic 7- membered ring. In some embodiments, Ring A is an optionally substituted bicyclic 8-membered ring. In some embodiments, Ring A is an optionally substituted bicyclic 9-membered ring. In some embodiments, Ring A is an optionally substituted bicyclic 10-membered ring. In some embodiments, Ring A is polycyclic. In some embodiments, Ring A has no additional heteroatoms. In some embodiments, Ring A has 0-6, e.g., 0, 1-6, 1-5, 1-3, or 1, 2, 3, 4, 5, or 6 additional heteroatoms. In some embodiments, Ring A comprises one or more aromatic ring. In some embodiments, Ring A is bicyclic or polycyclic, and each monocyclic ring unit is independently 3-10 (e.g., 3-9, 3-8, 3-7, 3-6, 4-10, 4-9, 4-8, 4- 7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10) membered, saturated, partially unsaturated or aromatic and having 0-5 (e.g., 0, 1-5, 1-3, 1, 2, 3, 4, or 5) heteroatoms. In some embodiments, a monocyclic ring unit is saturated. In some embodiments, a monocyclic ring unit is partially unsaturated. In some embodiments, a monocyclic ring unit is aromatic. In some embodiments, a monocyclic ring unit is heteroaromatic. Those skilled in the art appreciate that intervening atom(s), e.g., of groups taken Page 39 of 71 12504599v1Attorney Docket No.: 2010581-1438 together to form a ring, are typically atoms on the shortest path connecting such groups if multiple paths exist.

[0099] In some embodiments, a monocyclic ring unit comprising the phosphorus, nitrogen and oxygen atoms is saturated. In some embodiments, a monocyclic ring unit comprising the phosphorus, nitrogen and oxygen atoms is partially saturated. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it is 7- membered. In some embodiments, it has one or more additional heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, the phosphorus, nitrogen and oxygen atoms are the only heteroatoms in that monocyclic ring unit. [000100] In some embodiments, a monocyclic ring unit comprising the nitrogen atom to which R2and R3are bond is an optionally substituted partially unsaturated 4-10 (e.g., 4-8, 4-6, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having 0-2 heteroatoms in addition to the nitrogen atom independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit comprising the nitrogen atom to which R2and R3are bond is an optionally substituted partially unsaturated 4-10 (e.g., 4-8, 4-6, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having no heteroatoms in addition to the nitrogen atom independently selected from nitrogen, oxygen and sulfur. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it is 7- membered. In some embodiments, it is 8-membered. [000101] In some embodiments, Ring A comprises optionally , wherein each Lais independently a covalent bond or a bivalent C1-5 aliphatic group whereinmethylene units of each Laare optionally and independently replaced by −O−, −S−, or −NH. In some embodiments, Ring A is optionally , wherein each Lais independently a covalent bond or a bivalent C1-5 aliphatic groupmore methylene units of each Laare optionally and independently replaced by −O−, −S−, or −NH. In some embodiments, Ring A comprises optionally , wherein each Lais independently a covalent bond or a bivalent C1-5aliphatic group whereinmethylene units of each Laare optionally and independently replaced by −O−, −S−, or −NH. In some embodiments, Ring A is optionally , wherein each Lais independently a covalent bond or a bivalent C1-5aliphatic group whereinmethylene units of each Laare optionally and Page 40 of 71 12504599v1Attorney Docket No.: 2010581-1438 independently replaced by −O−, −S−, or −NH. In some embodiments, Lais a covalent bond. In some embodiments, Lais not a covalent bond. In some embodiments, Lais −CH2−. In some embodiments, Lais –(CH2)2−. In some embodiments, Lais –(CH2)3−. In some embodiments, Lais –(CH2)4−. In some embodiments, Lais –(CH2)5−. In some embodiments, a methylene unit is replaced with −O−. In some embodiments, a methylene unit is replaced with −S−. In some embodiments, aunit is replaced with −NH−.[000102] In some embodiments, Ring A is optionally . In some embodiments,Ring A is optionally substituted . In some embodiments, Ring A is optionally substituted . In some embodimensts, an occurrence of R is bonded to a carbon atom bonded to the oxygen of −P(OR2)N(R3)(R4). In some embodiments, −P(OR2)N(R3)(R4) is , wherein each of Rs1and Rs2is independently Rsas described herein. In some embodiments, −P(OR2)N(R3) . [000104] In some embodiments, one of Rs1and Rs2is −H. In some embodiments,independently not −H. In some embodiments, Rs1is R as described herein. In some embodiments, Rs1is not hydrogen. In some embodiments, Rs1is hydrogen. In some embodiments, Rs1is hydrogen and Rs2is not hydrogen. In some embodiments, Rs1is optionally substituted C1-6aliphatic. In some embodiments, Rs1is methyl. In some embodiments, Rs1is optionally substituted phenyl. In some embodiments, Rs1is phenyl. In some embodiments, Rs2is R as described herein. In some embodiments, Rs2is not hydrogen. In some embodiments, Rs2is hydrogen. In some embodiments, Rs2is optionally substituted C1-6aliphatic. In some embodiments, wherein Rs2is methyl. In some embodiments, Rs2is optionally substituted phenyl. In some embodiments, wherein Rs2is phenyl. [000105] In some embodiments, −P(OR2)N(R3)(R4) wherein each variable isPage 41 of 71 12504599v1Attorney Docket No.: 2010581-1438 independently as described herein. In some is of such a structure thatis a chiral auxiliary, e.g., described in US 10167309, US 11643657, US 11718638, US 11608355 or US 20230089442, the chiral auxiliaries of each of which are incorporated herein by reference. For example, in some embodiments, it . In some embodiments, it is. In some embodiments, it . In some embodiments, it isIn some embodiments, it . In some embodiments, it isIn some embodiments, it . In some embodiments, it . Insome some embodiments, it . In some embodiments, itis . In some embodiments, it . In someembodiments, it is .t [000106] In some embodiments, t is 0. In some embodiments, t is 1-5. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 5. RsIn some embodiments, Rsis −F. In some embodiments, Rsis −Cl. In some embodiments, RsPage 42 of 71 12504599v1Attorney Docket No.: 2010581-1438 is −Br. In some embodiments, Rsis −I. In some embodiments, Rsis −CN. In some embodiments, Rsis −N3. In some embodiments, Rsis −NO. In some embodiments, Rsis −NO2. [000108] In some embodiments, Rsis −Ls−Rs11wherein each of Lsand Rs11is independently as described herein. In some embodiments, Rsis Rs11as described herein. [000109] In some embodiments, Rsis R’ as described herein. For example, in some embodiments, R’ is −C(O)R wherein R is as described herein. In some embodiments, R’ is −CO2R wherein R is as described herein. In some embodiments, R’ is −S(O)2R wherein R is as described herein. In some embodiments, R is C1-6aliphatic. In some embodiments, R is C1-6alkyl. In some embodiments, R is optionally substituted phenyl. In some embodiments, Rsis −S(O)2R wherein R is optionally substituted C1-6 aliphatic. In some embodiments, Rsis −S(O)2Me. In some embodiments, Rsis −S(O)2t-Bu. In some embodiments, Rsis −S(O)2R wherein R is optionally substituted phenyl. In some embodiments, Rsis −S(O)2Ph. [000110] In some embodiments, Rsis R as described herein. For example, in some embodiments, R is not −H. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is optionally substituted C1-6 alkyl. In some embodiments, R is methyl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. [000111] In some embodiments, Rsis −Ls−ORs11wherein each of Lsand Rs11is independently as described herein. In some embodiments, Rsis −ORs11wherein Rs11is as described herein. In some embodiments, Rsis −CH2ORs11wherein Rs11is as described herein. [000112] In some embodiments, Rsis −Ls−SRs11wherein each of Lsand Rs11is independently as described herein. In some embodiments, Rsis −SRs11wherein Rs11is as described herein. In some embodiments, Rsis −CH2SRs11wherein Rs11is as described herein. [000113] In some embodiments, Rsis −Ls−N(Rs11)2 wherein each of Lsand Rs11is independently as described herein. In some embodiments, Rsis −N(Rs11)2 wherein each of Lsand Rs11is independently as described herein. In some embodiments, Rsis −CH2N(Rs11)2 wherein each of Lsand Rs11is independently as described herein. [000114] In some embodiments, Rsis −C(Rs11)3 wherein each Rs11is independently as described herein. In some embodiments, Rsis −CH(Rs11)2 wherein each Rs11is independently as described herein. In some embodiments, two or more Rs11are taken together with the carbon atom to which they are attached to form an optionally substituted 3-20 (e.g., 3-15, 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered ring having 0-10 (e.g., 0, 1-10, 1-5, 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. Page 43 of 71 12504599v1Attorney Docket No.: 2010581-1438 In some embodiments, Rsis optionally . [000115] In some embodiments, Rsis −Ls−Si Rs11is independently as described embodiments, each Rsherein. In some11is as herein and is not −H. In some embodiments, each Rs11is independently R as described herein and is not −H. In some embodiments, at least one Rs11is optionally substituted C1-10aliphatic. In some embodiments, at least one Rs11is optionally substituted C1-10alkyl. In some embodiments, at least one Rs11is methyl. In some embodiments, at least one Rs11is optionally substituted phenyl. In some embodiments, at least one Rs11is phenyl. In some embodiments, each Rs11is independently an optionally substituted group selected from C1-10aliphatic and 6-10 membered aryl. In some embodiments, each Rs11is independently an optionally substituted group selected from C1-10 alkyl and 6-10 membered aryl. In some embodiments, each Rs11is independently an optionally substituted group selected from C1-6 alkyl and 6-10 phenyl. In some embodiments, Rs11is −SiPh2Me. Rs11As used herein, Rs11is R’ as described herein. For example, in some embodiments, R’ is R as described herein. In some embodiments, R’ is −C(O)R wherein R is as described herein. In some embodiments, R’ is −CO2R wherein R is as described herein. In some embodiments, R’ is −S(O)2R wherein R is as described herein. Rs11is −H. In some embodiments, Rs11is not −H. In some embodiments, two or more Rs11on the same atom are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. Certain embodiments of rings are described herein. Ls[000117] As used herein, Lsis L as described herein. For example, in some embodiments, L is a covalent bond. In some embodiments, L is optionally substituted −CH2−. In some embodiments, L is −CH2−. In some embodiments, L is monosubstituted −CH2−. L [000118] Certain embodiments for L are described below. Various variables, e.g., L2s, Ls, etc., can be L, and embodiments for L can also be applied to such variables that can be L. Page 44 of 71 12504599v1Attorney Docket No.: 2010581-1438 [000119] In some embodiments, L is a covalent bond. In some embodiments, L is a bivalent, optionally substituted C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic group wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L is a bivalent, optionallysubstituted C1-6aliphatic group wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L is a bivalent, optionally substituted C1-5 aliphatic group wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, each methylene unit are replaced. In some embodiments, at least one methylene unit is not replaced. In some embodiments, L comprises at least one chain carbon atom. In some embodiments, L is −O−. In some embodiments, L is −S−. In some embodiments, L is −N(R’)−. In some embodiments, L is −C(O)−. [000120] In some embodiments, no methylene unit is replaced. In some embodiments, L is a bivalent, optionally substituted C1-10 (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic group. In some embodiments, L is optionally substituted C1-6 aliphatic group. In some embodiments, L is bivalent, optionally substituted C1-10 (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) alkylene. In some embodiments, L is optionally substituted C1-6 alkylene. In some embodiments, L is linear. In some embodiments, L is branched. In some embodiments, L is substituted. In some embodiments, L is not substituted. [000121] In some embodiments, L is a bivalent, optionally substituted C1-10 heteroaliphatic (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L is a bivalent, optionally substituted C1-6 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L is linear. In some embodiments, L is branched. In some embodiments, L is substituted. In some embodiments, L is not substituted. Page 45 of 71 12504599v1Attorney Docket No.: 2010581-1438 [000122] In some embodiments, a methylene unit is replaced by −Cy− as described herein. −Cy− [000123] As used herein, −Cy− is an optionally substituted bivalent 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, −Cy− is an optionally substituted bivalent 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, −Cy− is monocyclic. In some embodiments, −Cy− is bicyclic. In some embodiments, −Cy− is polycyclic. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 5-8, etc.) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur and 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, etc.) carbon atoms. In some embodiments, a monocyclic ring unit is an optionally substituted saturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted partially unsaturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted aromatic ring. In some embodiments, a monocyclic ring unit is an optionally substituted phenyl ring. In some embodiments, a monocyclic ring unit is an optionally substituted 5-membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6- membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. Each monocyclic ring unit is independently optionally substituted. In some embodiments, a monocyclic ring unit is unsaturated. In some embodiments, a monocyclic ring unit is saturated. In some embodiments, −Cy− is an optionally substituted saturated ring. In some embodiments, −Cy− is an optionally substituted partially unsaturated ring. In some embodiments, −Cy− is an optionally substituted aromatic ring. [000124] In some embodiments, −Cy− is an optionally substituted bivalent 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered monocyclic cycloaliphatic ring. In some embodiments, −Cy− is an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered monocyclic cycloalkyl ring. In some embodiments, −Cy− is an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered monocyclic heteroaliphatic ring having 1-5 heteroatoms. In some embodiments, −Cy− is an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered monocyclic heteroalkyl ring having 1-5 Page 46 of 71 12504599v1Attorney Docket No.: 2010581-1438 heteroatoms. In some embodiments, −Cy− is an optionally substituted bivalent 5-15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered bicyclic or polycyclic cycloaliphatic group. In some embodiments, −Cy− is an optionally substituted bivalent 5-15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered bicyclic or polycyclic cycloalkyl group. In some embodiments, −Cy− is an optionally substituted 5-15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered bicyclic or polycyclic heteroaliphatic ring having 1-5 heteroatoms. In some embodiments, −Cy− is an optionally substituted 5-15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered bicyclic or polycyclic heterocyclyl ring having 1-5 heteroatoms. In some embodiments, a cycloaliphatic, cycloalkyl, heteroaliphatic or heteroalkyl ring is 3-membered. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6- membered. In some embodiments, it is 7-membered. In some embodiments, it is 8-membered. In some embodiments, it is 9-membered. In some embodiments, it is 10-membered. In some embodiments, it is 11-membered. In some embodiments, it is 12-membered. In some embodiments, −Cy− is optionally substituted phenylene. In some embodiments, −Cy− is an optionally substituted bivalent 10-membered bicyclic aryl ring. In some embodiments, −Cy− is an optionally substituted 5-membered heteroaryl ring having 1-4 heteroatoms. In some embodiments, −Cy− is an optionally substituted 6-membered heteroaryl ring having 1-4 heteroatoms. In some embodiments, −Cy− is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-5 heteroatoms. In some embodiments, −Cy− is an optionally substituted 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms. In some embodiments, a heteroaliphatic, heterocyclyl or heteroaryl ring contains no more than 1 heteroatom. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. [000125] In some embodiments, −Cy− is an optionally substituted 4-7 membered ring having 0-3 heteroatoms. In some embodiments, −Cy− is an optionally substituted phenyl ring. In some embodiments, an aryl ring is substituted. In some embodiments, it is substituted with one or more halogen. In some embodiments, it is substituted with one or more −F. In some embodiments, it is not substituted. In some embodiments, −Cy− is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur. R’[000126] Certain embodiments for R’ are described below. Various variables, e.g., R2a, R1, R2, R3, R4, Rs, Rs11, etc., can be R’, and embodiments for R’ can also be applied to such variables that can be R’. [000127] In some embodiments, R’ is R as described herein. In some embodiments, R’ is −H. In some embodiments, R’ is not −H. [000128] In some embodiments, R’ is −C(O)R wherein R is as described herein. In some Page 47 of 71 12504599v1Attorney Docket No.: 2010581-1438 embodiments, R’ is −CO2R wherein R is as described herein. In some embodiments, R’ is −S(O)2R wherein R is as described herein. In some embodiments, as described herein, R is not −H. [000129] In some embodiments, two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 (e.g., 3-15, 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1- 10, 1-5, 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, two or more R’ on the same atom are taken together with the atom to which they are attached to form an optionally substituted 3-20 (e.g., 3-15, 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1-10, 1-5, 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, two R’ on the same atom are taken together with the atom to which they are attached to form an optionally substituted 3-20 (e.g., 3-15, 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1-10, 1-5, 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. [000130] In some embodiments, each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ on the same atom are taken together with the atom to which they are attached to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. Ring [000131] Compounds of the present disclosure may contain various rings. In some embodiments, a variable, e.g., R or a variable that can be R, can be of a ring as described herein. In some embodiments, two variables, e.g., two R’ groups, may be taken together with their intervening atom(s) to form a ring as described herein. In some embodiments, a ring is monovalent. In some embodiments, a ring is bivalent. In some embodiments, a ring structure can be polyvalent. Rings are optionally substituted. In some embodiments, a ring is unsubstituted. In some embodiments, a ring is substituted. [000132] Certain embodiments and features of rings are described below as examples. [000133] In some embodiments, a ring is an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, a ring is an optionally substituted 3-20 Page 48 of 71 12504599v1Attorney Docket No.: 2010581-1438 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, a ring is monocyclic. In some embodiments, a ring is bicyclic. In some embodiments, a ring is polycyclic. [000134] In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 5-8, etc.) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur and 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, etc.) carbon atoms. In some embodiments, a monocyclic ring unit is an optionally substituted saturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted partially unsaturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted aromatic ring. In some embodiments, a monocyclic ring unit is an optionally substituted phenyl ring. In some embodiments, a monocyclic ring unit is an optionally substituted 5- membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6-membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. Each monocyclic ring unit is independently optionally substituted. In some embodiments, a monocyclic ring unit is unsaturated. In some embodiments, a monocyclic ring unit is saturated. [000135] In some embodiments, a ring is an optionally substituted saturated ring. In some embodiments, a ring is an optionally substituted partially unsaturated ring. In some embodiments, a ring is an optionally substituted aromatic ring. [000136] In some embodiments, a ring is an optionally substituted 3-10 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atom(s), 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a ring is 3-9, 3-8, 3-7, 3-6, 4-10, 4-9, 4-8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10-membered. In some embodiments, a ring is 3-9 membered. In some embodiments, a ring is 3-7 membered. In some embodiments, a ring is 4-10 membered. In some embodiments, a ring is 4-7 membered. In some embodiments, a ring is 5-10 membered. In some embodiments, a ring is 5-7 membered. In some embodiments, a ring is 3-membered. In some embodiments, a ring is 4-membered. In some embodiments, a ring is 5-membered. In some embodiments, a ring is 6-membered. In some embodiments, a ring is 7-membered. In some embodiments, a ring is 8-membered. In some embodiments, a ring is 9-membered. In some embodiments, a ring is 10-membered. In some embodiments, a ring is monocyclic. In some embodiments, a ring is bicyclic. In some embodiments, a ring is polycyclic. In some embodiments, a ring has no heteroatoms. In some embodiments, a ring has 1-6, e.g., 1-5, 1-3, or 1, 2, 3, 4, 5, or 6 Page 49 of 71 12504599v1Attorney Docket No.: 2010581-1438 heteroatoms. In some embodiments, a ring formed by two or more groups taken together with their intervening atom(s) has no heteroatoms in addition to the intervening atom(s). In some embodiments, a ring formed by two or more groups taken together with their intervening atom(s) has 1-6, e.g., 1-5, 1-3, or 1, 2, 3, 4, 5, or 6 heteroatoms in addition to the intervening atom(s). In some embodiments, a ring is saturated. In some embodiments, a ring is partially unsaturated. In some embodiments, a ring comprises one or more aromatic ring. In some embodiments, a ring is bicyclic or polycyclic, and each monocyclic ring unit is independently 3-10 (e.g., 3-9, 3-8, 3-7, 3-6, 4-10, 4-9, 4-8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10) membered, saturated, partially unsaturated or aromatic and having 0-5 (e.g., 0, 1- 5, 1-3, 1, 2, 3, 4, or 5) heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is saturated. In some embodiments, a monocyclic ring unit is partially unsaturated. In some embodiments, a monocyclic ring unit is aromatic. In some embodiments, a monocyclic ring unit is heteroaromatic. Those skilled in the art appreciate that intervening atom(s), e.g., of groups taken together to form a ring, are typically atoms on the shortest path connecting such groups if multiple paths exist. [000137] In some embodiments, a ring has one or more heteroatoms. In some embodiments, a ring comprises a nitrogen atom. In some embodiments, a ring comprises an oxygen atom. In some embodiments, a ring comprises a sulfur atom. R [000138] Various variables in the present disclosure can independently be R. Certain embodiments for R are described below as examples. Those skilled in the art reading the present disclosure appreciate that embodiments that are described for a variable that can be R and fall within the definition of R can be embodiments for R as well. Those skilled in the art reading the present disclosure further appreciate that embodiments for R, e.g., those described for R, those described for a variable that can be R and within the definition of R, etc., can be embodiments for a variable that can be R. [000139] In some embodiments, R is −H. In some embodiments, R is not −H. In some embodiments, R is optionally substituted C1-10 (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic. In some embodiments, R is optionally substituted C1-8 aliphatic. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is optionally substituted C1-10 (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) alkyl. In some embodiments, R is optionally substituted C1-8 alkyl. In some embodiments, R is optionally substituted C1-6aliphatic. In some embodiments, R is optionally substituted C1-6alkyl. In some embodiments, R is optionally substituted −CH2−C3-6cycloaliphatic. In some embodiments, R is optionally substituted −CH2−C3-6 cycloaliphatic. In some embodiments, R is optionally substituted −CH2−C3-6cycloalkyl. In some embodiments, R is methyl. In some embodiments, Page 50 of 71 12504599v1Attorney Docket No.: 2010581-1438 R is ethyl. In some embodiments, R is isopropyl. In some embodiments, R is −CF3. In some embodiments, R is −CH2CF3. In some embodiments, R is butyl. In some embodiments, R is t-butyl. [000140] In some embodiments, R is optionally substituted 3-10 membered (e.g., 3-9, 3-8, 3-7, 3-6, 5- 7, 4, 5, 6, 7, 8, 9, 10, etc.) cycloaliphatic. In some embodiments, R is optionally substituted C3-10cycloalkyl. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is optionally substituted cyclohexyl. [000141] In some embodiments, R is optionally substituted C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) heteroaliphatic having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, R is optionally substituted C1-6 (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) heteroaliphatic having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, R is optionally substituted C1-10 (e.g., C1- 6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) heteroaliphatic having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted C1-6 (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) heteroaliphatic having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted C1-6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur C1-6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted C1-6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur C1-6 heteroaliphatic having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is heteroalkyl. [000142] In some embodiments, R is optionally substituted 3-15 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 3-10, 3-7, 4-10, 4-6, etc.) membered heterocyclic ring having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, R is optionally substituted 3-15 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 3-10, 3-7, 4- 10, 4-6, etc.) membered heterocyclic ring having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted 3-10 (e.g., 3-9, 3-8, 3-7, 3-6, 5-7, 4, 5, 6, 7, 8, 9, 10, etc.) membered heterocyclyl having 1-4 (e.g., 1, 2, 3, 4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 3-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 3- membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur. Page 51 of 71 12504599v1Attorney Docket No.: 2010581-1438 In some embodiments, R is optionally substituted 4-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 5-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 6-membered heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 8-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 9-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 10-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, there is one carbon atom in a heterocyclyl ring. In some embodiments, there are two or more (e.g., 2-14, 2-9, 2-6, 2-4, 3-10, 3-5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, etc.) carbon atoms in a heterocyclyl ring. [000143] In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is optionally substituted naphthyl. In some embodiments, R is optionally substituted 1-naphthyl. In some embodiments, R is optionally substituted 2-naphthyl. In some embodiments, R is naphthyl. [000144] In some embodiments, R is optionally substituted 5-14 (e.g., 5, 6, 9, 10, 14, etc.) membered heteroaryl having 1-6 (e.g., 1-5, 1-4, 1, 2, 3, 4, 5, 6, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, R is optionally substituted 5-14 (e.g., 5, 6, 9, 10, 14, etc.) membered heteroaryl having 1-6 (e.g., 1-5, 1-4, 1, 2, 3, 4, 5, 6, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted 5-10 (e.g., 5, 6, 9, 10, etc.) membered heteroaryl having 1-6 (e.g., 1-5, 1-4, 1, 2, 3, 4, 5, 6, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a heteroaryl ring is monocyclic and is 5-membered. In some embodiments, a heteroaryl ring is monocyclic and is 6-membered. In some embodiments, a heteroaryl ring is bicyclic and is 9-membered. In some embodiments, a heteroaryl ring is bicyclic and is 10-membered. In some embodiments, a heteroaryl ring is tricyclic and is 14-membered. In some embodiments, R is optionally substituted 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 5- membered heteroaryl having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 6-membered heteroaryl having 1-4 heteroatoms independently Page 52 of 71 12504599v1Attorney Docket No.: 2010581-1438 selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 6- membered heteroaryl having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 8-10 membered aromatic ring having 1-6 heteroatoms nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 9-membered aromatic ring having 1-6 heteroatoms nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 10-membered aromatic ring having 1-6 heteroatoms nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 9-membered aromatic ring having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 10- membered aromatic ring having 1 heteroatom nitrogen, oxygen and sulfur. In some embodiments, at least one heteroatom is nitrogen. In some embodiments, at least one heteroatom is oxygen. In some embodiments, at least one heteroatom is sulfur. In some embodiments, each heteroatom is the same. In some embodiments, at least one heteroatom is different from another heteroatom. [000145] As described herein, various groups may be optionally substituted. Substituents are routinely utilized in chemistry including in development of various therapeutics. Many substituents can be utilized in accordance with the present disclosure. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. Substituents are preferably those that result in the formation of compounds for a desired property, activity, use, etc., as described herein. In some embodiments, compounds are stable for therapeutic use as described herein. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a substituent is a hydrocarbon group. In some embodiments, a substituent comprises a heteroatom. In some embodiments, a substituent comprises multiple heteroatoms. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, sulfur, phosphorus and silicon. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, and sulfur. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, fluorine, chlorine, bromine, iodine, nitrogen, oxygen, and sulfur. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in a substituent is about or no more than about 1; in some embodiments, it is no more than about 2; in some embodiments, it is no more than about 3; in some embodiments, it is no more than about 4; in some embodiments, it is no more than about 5; in some embodiments, it is no more than about 6; in some embodiments, it is no more than about 7; in some embodiments, it is no more than about 8; in some embodiments, it is no more than about 9; in some embodiments, it is no more than about 10; in some embodiments, it is no more than about 11; in some embodiments, it is no more than about 12; in some embodiments, it is no more than about 13; in some Page 53 of 71 12504599v1Attorney Docket No.: 2010581-1438 embodiments, it is no more than about 14; in some embodiments, it is no more than about 15; in some embodiments, it is no more than about 20. In some embodiments, the total number of carbon and non- halogen heteroatom(s) in each substituent is independently no more than about 20. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 15. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 10. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 6. EXEMPLIFICATION [000146] Non-limiting examples are provided below. A person of ordinary skill in the art appreciates that other technologies, e.g., compounds, compositions, methods, etc., may also be utilized in the present technologies in accordance with the present disclosure. [000147] As described herein, provided technologies can provide a number of advantages, e.g., high efficiency (e.g., fewer steps, higher yield, etc.), improved manufacturing processes (e.g., avoidance or reduction of solvents and solid wastes.), high stereoselectivity, high yield, high product purity, lower cost, etc. Various advantages are demonstrated in Examples below. Example 1: Synthesis of 3-((2R,4S,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4- hydroxytetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (Compound 1)Page 54 of 71 12504599v1Attorney Docket No.: 2010581-1438 [000148] g, beforereaction SM was on vacuum argon pyridine (12 L) at rt. Cool the reaction mixture to 0 ℃ by using ice bath. Add acetic anhydride (6072 mL) dropwise to the reaction mixture by using dropping funnel over a period of 60 min. After addition RM warm to rt and then stir at 130 ℃ for 3 h. TLC (10% MeOH:DCM) show that SM was consumed and new spot was formed. Then, cool the reaction mixture to rt and concentrated under reduced pressure to give a brown color crude. This crude was washed with EtOAC (2 x 4000 mL), filtered through Buckner funnel using whatman filter paper. The solid was dried under reduced pressure to get the Compound 1b (1384 g, 84% yield) as a brown solid.1H NMR (500 MHz, DMSO-d6): δ in ppm = 11.55 (s, 1H), 8.13 (d, 1H, J = 9.0 Hz), 5.80 (d, 1H, J = 8.3 Hz), 2.61 (s, 3H). [000149] Step 2: A clean and dry 300 L glass reactor charge with Compound 1b (1200 g) and dissolved into dry acetonitrile (120 L) under argon atmosphere. Cool the reaction mixture to 0 ℃ by using ice bath. Then, add NaH (468 g) portion wise to the reaction mixture and stir for 30 min at 0 ℃. After that, Compound 1c (4684 g) was added portion wise and stir the reaction mixture for 30 min at 0 ℃ and 65 ℃ for 3 h. TLC (50% EtOAc:hexane) show that SM was consumed and new spots were formed. Then, cool the reaction mixture to rt and filter through Nutsche filter. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (100-200 mesh). The product was eluted with 50% to 80% EtOAc:hexane. Fraction containing product was collected and evaporated to dryness under vacuum to get 1771 g (45% yield) mixture of Compounds 1d (beta isomer) and 1d1 (alpha isomer) as a light brown solid. Trituration: The solid (1771 g) was triturated with ethyl acetate (5700 mL) and MeCN (306 mL) at 60 ℃ for 15 min, filtered and the cake re-triturated for four times, the cake was dried under vacuum to get 1180 g (29% yield) of WV-NU-096d (β isomer) as a white solid. HPLC purity: 99.60%.1HNMR (400MHz, DMSO- d6) δ 11.17 (br s, 1H), 8.02 - 7.88 (m, 4H), 7.61 - 7.56 (m, 2H), 7.55 - 7.50 (m, 2H), 7.46 (d, J = 7.7 Hz, 1H), 6.72 (dd, J = 4.3, 9.0 Hz, 1H), 5.77 (td, J = 5.8, 8.0 Hz, 1H), 5.60 (d, J = 7.5 Hz, 1H), 4.66 - 4.57 (m, 1H), 4.52 - 4.46 (m, 1H), 4.44 - 4.36 (m, 1H), 3.03 (tt, J = 4.2, 8.9 Hz, 1H), 2.48 - 2.40 (m, 1H); MS (ESI), 527.0 [M+Na]+. [000150] Compound 1d (1500 g) was taken into clean and dry 50 L glass reactor. Then Page 55 of 71 12504599v1Attorney Docket No.: 2010581-1438 methanol (21.5 L) was added at 15 ℃ under argon atmosphere. After that, sodium methoxide (401 g) was added portion wise to reaction mixture at 15 ℃ and stir the reaction mixture for 1 h at 15 ℃. TLC (10% MeOH:DCM) show that SM was consumed and new spots were formed. After completion of reaction, pH of reaction mixture was adjusted to neutral by slow addition of ammonium chloride. Then, filter through Nutsche filter. Filter cake was washed with 5 L of methanol. Then, filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (60-120 mesh). The product was eluted with 10% to 12% MeOH:DCM. Fraction containing product was collected and evaporated to dryness under vacuum to get 610 g (90% yield) of Compound 1e as an off white solid.1H NMR (400 MHz, DMSO-d6): δ in ppm = 11.71 (s, 1H), 7.42 (d, 1H, J = 7.6 Hz), 6.54 (dd, 1H, J = 7.6 Hz, and 6.2 Hz), 5.55 (d, 1H, J = 7.9 Hz), 5.08 (brs, 1H), 4.56 (brs, 1H), 4.29 (dt, 1H, J = 8.7 Hz, and J = 3.6 Hz), 3.68-3.65 (m, 1H), 3.58 (dd, 1H, J = 11.4 Hz, and J = 3.8 Hz), 3.44 (q, 1H, J = 5.7 Hz), 2.72-2.67 (m, 1H), 1.94-1.89 (m, 1H). [000151] Step 4. A clean and dry 50 L glass reactor charged with Compound 1e (1000 g, before reaction SM was co-evaporated with pyridine 3 x 7.5 L) and dissolved into dry pyridine (14.7 L) under argon atmosphere. Then, DMTr-Cl (1485 g) was added in portion wise under argon atmosphere at 15 ℃. The resulting mixture was stirred at 15 ℃ for 16 h. TLC (10% MeOH:DCM) indicated SM was consumed and new spots were formed. The reaction mixture was quenched with dropwise addition of DM water (11.5 L) and extracted with ethyl acetate (15 L x 3). The combined organic layers were dried on sodium sulphate, filtered and evaporated to dryness to get crude compound. The crude compound was purified on silica gel column chromatography (230-400 mesh) using hexane / Ethyl acetate = 10:1 to 0:1, with 5% TEA, then DCM: MeOH = 98:2 with 5% TEA) to get 1488 g (64% yield) of Compound 1 as a white solid.1H NMR (500 MHz, DMSO-d6): δ in ppm = 11.04 (br s, 1H), 7.46-7.42 (m, 1H), 7.40-7.38 (m, 1H), 7.27 - 7.19 (m, 7H), 6.86-6.81 (m, 4H), 6.58 (dd, 1H, J = 9.1 Hz and J = 4.3 Hz), 5.55 (dd, 1H, J = 7.6 Hz and J = 1.3 Hz), 5.08 (d, 1H, J = 5.5 Hz), 4.28 - 4.21 (m, 1H), 3.82 (dd, 1H, J = 6.0 Hz, and J = 4.4 Hz), 3.73 (d, 6H, J = 2.2 Hz,), 3.21 (m, 1H, J = 9.6 Hz, and J = 8.0 Hz), 3.05 (dd, 1H, J = 9.8 Hz, and 3.4 Hz), 2.59-2.55 (m, 1H), 2.00 – 1.97 (m, 1H);13C NMR (500 MHz, DMSO-d6): δ in ppm = 163.0, 158.0, 157.9, 150.7, 145.2, 141.2, 135.9, 135.8, 129.7, 127.8, 127.6, 126.5, 113.1, 113.0, 100.2, 85.5, 85.2, 80.4, 71.4, 64.8, 55.0, 54.9, 37.2; HPLC purity: 99.69%; MS: m / z calcd for C30H30N2O7 ([M-H]+), 529.58; found 529.0. Example 2: Synthesis of 3-((2R,4S,5R)-5-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4- (((1S,3S,3aS)-3-((phenylsulfonyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaphosphol-1- yl)oxy)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (Compound 2) Page 56 of 71 12504599v1Attorney Docket No.: 2010581-14382b (17.0 g, 110.3 mmol) in acetonitrile (MeCN) (1700 mL) under argon at 0 ℃ and was stirred at 0°C for 30 minutes. After 1-chloro-3,5-di(4-chlorbenzoyl)-2-deoxy-D-ribose (Compound 2a) (66.0 g, 156.30 mmol) was added to the reaction mixture in a stepwise manner, the reaction mixture was stirred for 30 min at 0°C and at 65°C for 3 hours. The reaction mixture was cooled down to room temperature and filtered. The filtrate was concentrated and purified by flash chromatography over silica gel column chromatography to give a mixture of alpha and beta isomers, which was triturated with EtOAc (66 mL) and MeCN (3.3 mL) at 60°C (4 times) to yield beta isomer Compound 2c (13.5 g, 24%) as a white solid. Proton nuclear magnetic resonance (1HNMR) (400MHz, DMSO-d6) δ 11.17 (br s, 1H), 8.02 - 7.88 (m, 4H), 7.61 - 7.56 (m, 2H), 7.55 - 7.50 (m, 2H), 7.46 (, J = 7.7 Hz, 1H), 6.72 (dd, J = 4.3, 9.0 Hz, 1H), 5.77 (td, J = 5.8, 8.0 Hz, 1H), 5.60 (d, J = 7.5 Hz, 1H), 4.66 - 4.57 (m, 1H), 4.52 - 4.46 (m, 1H), 4.44 - 4.36 (m, 1H), 3.03 (tt, J = 4.2, 8.9 Hz, 1H), 2.48 - 2.40 (m, 1H); electrospray ionization mass spectrometry (MS (ESI)), 527.0 [M+Na]+. [000153] Step 2: Sodium methoxide (NaOMe) (10.82 g, 200.4 mmol) was added slowly to a solution of Compound 2c (40.5 g, 80.15 mmol) in methanol (MeOH) (580 mL) at 15°C and was stirred at room temperature for 1 hour. The reaction mixture was adjusted to neutral by addition of ammonium chloride, filtered, washed with MeOH to give solution. This solution was concentrated and purified by flash chromatography over silica gel eluted with dichloromethane (DCM) / MeOH to yield Compound 2d (17.0 Page 57 of 71 12504599v1Attorney Docket No.: 2010581-1438 g, 93%) as a white solid.1HNMR (400MHz, DMSO-d6) δ 11.07 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.53 (dd, J = 6.4, 8.0 Hz, 1H), 5.54 (d, J = 7.6 Hz, 1H), 5.06 (d, J = 4.1 Hz, 1H), 4.54 (t, J = 5.4 Hz, 1H), 4.29 (dd, J = 3.9, 6.9 Hz, 1H), 3.69 - 3.63 (m, 1H), 3.57 (td, J = 4.0, 11.4 Hz, 1H), 3.48 - 3.40 (m, 1H), 2.74 - 2.62 (m, 1H), 1.91 (ddd, J = 4.5, 8.2, 12.8 Hz, 1H); MS (ESI), 227.1 [M-H]-. [000154] Step 3: Treatment of Compound 2d (17.0 g, 74.50 mmol) in pyridine (250 mL) was added 4,4 -dimethoxytrityl chloride (DMTrCl) (25.24 g, 74.50 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with EtOAc, dried over with magnesium sulfate (Mg2SO4), and concentrated under reduced pressure to give a residue, which was purified by flash chromatography over silica gel (petroleum ether / ethyl acetate = 10:1, 0:1, then DCM: MeOH = 20:1, 5% TEA) to yield Compound 2e (31.0 g, 76%) as a white solid.1HNMR (400MHz, DMSO-d6) δ 11.04 (br s, 1H), 7.48 - 7.35 (m, 3H), 7.30 - 7.15 (m, 7H), 6.92 - 6.77 (m, 4H), 6.59 (dd, J = 4.3, 8.9 Hz, 1H), 5.55 (d, J = 7.6 Hz, 1H), 5.06 (d, J = 5.4 Hz, 1H), 4.31 - 4.19 (m, 1H), 3.86 - 3.77 (m, 1H), 3.73 (d, J = 2.1 Hz, 6H), 3.21 (dd, J = 8.0, 9.6 Hz, 1H), 3.06 (dd, J = 3.4, 9.8 Hz, 1H), 2.59 (ddd, J = 4.3, 8.3, 12.9 Hz, 1H), 2.06 - 2.00 (m, 1H); MS (ESI), 529.2 [M-H]-. [000155] Step 4: Triethylamine (19.57 mL, 140.42 mmol) and (3S,3aS)-1-chloro-3- ((phenylsulfonyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaphosphole (Compound 2f) (0.89 M in tetrahydrofuan (THF)(113.59 mL, 101.1 mmol) was added to a solution of dry Compound 2e (29.8 g, 56.17 mmol) in THF (200 mL). The reaction mixture was stirred at room temperature for 2.5 hours. Thin layer chromatography (TLC) and liquid chromatography mass spectrometry (LCMS) showed that the reaction was complete. The reaction was quenched by water (794 µL) and anhydrous MgSO4 was added. The mixture was filtered through celite, and the filtrate was concentrated to yield the crude product which was purified by normal phase flash chromatography over silica gel eluting with 50-100% EtOAc in hexanes (each mobile phase contained 1% triethylamine) to yield Compound 2 ((40.4 g, 88%) as a white foam.1H NMR (600 MHz, CDCl3) δ 9.28 (bs, 1H), 7.87 (dd, J = 8.3, 1.4 Hz, 2H), 7.63 – 7.57 (m, 1H), 7.53 – 7.44 (m, 4H), 7.37 – 7.33 (m, 4H), 7.23 (t, J = 7.8 Hz, 2H), 7.19 – 7.13 (m, 1H), 6.81 – 6.75 (m, 4H), 6.70 (dd, J = 8.4, 5.1 Hz, 1H), 6.64 (d, J = 7.7 Hz, 1H), 5.53 (d, J = 7.7 Hz, 1H), 4.96 (q, J = 6.1 Hz, 1H), 4.87 (dq, J = 12.8, 5.6 Hz, 1H), 3.93 (td, J = 5.9, 3.9 Hz, 1H), 3.752 (s, 3H), 3.749 (s, 3H), 3.62 (dq, J = 11.7, 6.0 Hz, 1H), 3.44 – 3.25 (m, 5H), 2.94 (qd, J = 10.0, 4.0 Hz, 1H), 2.85 (ddd, J = 13.2, 8.0, 5.2 Hz, 1H), 2.23 (ddd, J = 13.6, 8.6, 5.5 Hz, 1H), 1.85 – 1.79 (m, 1H), 1.76 – 1.69 (m, 1H), 1.65 – 1.59 (m, 1H), 1.12 – 1.02 (m, 1H);31P NMR (243 MHz, CDCl3) δ 149.14; MS (ESI), 812.53 [M-H]-. Example 3: Synthesis of ((2R,3S,5R)-3-((4-Chlorobenzoyl)oxy)-5-(5-fluoro-2,6-dioxo-3,6- dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl 4-chlorobenzoate (Compound 3) Page 58 of 71 12504599v1Attorney Docket No.: 2010581-1438was added NaH (1.5 equiv.) slowly and was stirred at 0 ℃ for 30 minutes. After 1-chloro-3,5-di(4- chlorbenzoyl)-2-deoxy-D-ribose (Compound 3a) (1.0 to 1.39 equiv.) was added to the reaction mixture portion wise, the reaction mixture was stirred for 30 min at 0 ℃ and 65 ℃ for 3 h. The reaction mixture cooled down to room temperature and filtered to give the filtrate. The filtrate was concentrated and purified by flash chromatography over silica gel column chromatography to give a mixture of alpha and beta isomers, which was triturated to give beta isomer Compound 3c as white solid. [000157] Treatment of Compound 3b (18.0 g, 104.6 mmol) and 1-chloro-3,5-di(4-chlorbenzoyl)-2- deoxy-D-ribose (Compound 3a) (62.46 g, 145.37 mmol) in acetonitrile (1800 mL), triturated with Ethyl acetate (200 mL) and Petroleum ether (600 mL) at 65 °C according to general procedure described above afforded 3c (14.0 g, 25.6%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.31 - 11.13 (m, 1H), 7.99 - 7.93 (m, 4H), 7.88 (d, J = 5.4 Hz, 1H), 7.62 - 7.51 (m, 5H), 6.68 (dd, J = 4.1, 8.9 Hz, 1H), 5.80 - 5.71 (m, 1H), 4.61 (dd, J = 4.3, 11.3 Hz, 1H), 4.52 - 4.39 (m, 2H), 3.10 - 3.02 (m, 1H); MS (ESI), 521.2 [M-H]-. [000158] Preparation of Compound 3 from Compound 3c followed similar procedure described in steps 2-4 of Example 2. [000159] Among other things, provided compounds, e.g., nucleosides, phosphoramidites, etc. are useful for manufacturing oligonucleotides. Certain useful technologies for manufacturing oligonucleotides and compositions thereof including chirally controlled oligonucleotide compositions are Page 59 of 71 12504599v1Attorney Docket No.: 2010581-1438 described in WO 2021 / 071858 and WO 2022 / 099159, the entirety of each of which is independently incorporated herein by reference. [000160] Having described some illustrative embodiments of the disclosure, it should be apparent to those skilled in the art that the foregoing is merely illustrative and not limiting, having been presented by way of example only. Numerous modifications and other illustrative embodiments are within the scope of one of ordinary skill in the art in accordance with the present disclosure and are within the scope of the disclosure and claims. In particular, although many of the examples presented herein involve specific combinations of method acts or system elements, it should be understood that those acts and those elements may be combined in other ways to accomplish the same objectives. Acts, elements, and features discussed only in connection with one embodiment are not intended to be excluded from a similar role in other embodiments. Further, for the one or more means-plus-function limitations recited in the following claims, the means are not intended to be limited to the means disclosed herein for performing the recited function, but are intended to cover in scope any means, known now or later developed, for performing the recited function. [000161] Use of ordinal terms such as “first”, “second”, “third”, etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements. Similarly, use of a), b), etc., or i), ii), etc. does not by itself connote any priority, precedence, or order of steps in the claims. Similarly, the use of these terms in the specification does not by itself connote any required priority, precedence, or order. [000162] The foregoing written specification is sufficient to enable one skilled in the art to practice technologies of the present disclosure. The present disclosure is not to be limited in scope by examples provided. Examples are intended as illustrations of one or more aspects of technologies of the present disclosure and other functionally equivalent embodiments are within the scope of the technologies of the present disclosure or claims. Various modifications of the disclosure in addition to those shown and described herein may become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. The advantages and objects of the disclosure are not necessarily encompassed by each embodiment of the disclosure. Page 60 of 71 12504599v1

Claims

Attorney Docket No.: 2010581-1438 Claims 1. A method for preparing a compound or a salt thereof, comprising: performing trituration on a composition with a solvent system, wherein: the composition comprises the compound or a salt thereof and a diastereomer of the compound or a salt thereof; the level of the compound or a salt thereof is increased relative to that of a diastereomer or a salt thereof compared to prior to the trituration; and the compound has the (beta isomer), wherein R1is −H or −F.

2. The method of claim 1, wherein the diastereomer has the structure of .the solvent system comprises one or more solvents.

4. The method of any one of claims 1-2, wherein the solvent system comprises two solvents.

5. The method of any one of claims 1-2, wherein the solvent system consists of two solvents.

6. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 1:

1.

7. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 2:

1.

8. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 3:

1. Page 61 of 71 12504599v1Attorney Docket No.: 2010581-1438 9. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 4:

1.

10. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 5:

1.

11. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 10:

1.

12. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 15:

1.

13. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 20:

1.

14. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 25:

1.

15. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 30:

1.

16. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 50:

1.

17. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 100:

1.

18. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 200:

1.

19. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 500:

1.

20. The method of any one of claims 4-5, wherein the ratio of a first solvent : a second solvent is about 1000:

1.

21. The method of any one of claims 3-20, wherein a solvent is EtOAc.

22. The method of any one of claims 3-20, wherein a solvent is acetonitrile.

23. The method of any one of claims 3-20, wherein each solvent is independently selected from EtOAc and acetonitrile.

24. The method of any one of claims 3-20, wherein the solvent system comprises a first solvent of EtOAc and a second solvent of acetonitrile.

25. The method of any one of claims 3-20, wherein the solvent system comprises a first solvent of EtOAc and a second solvent of petroleum ether.

26. The method of any one of claims 1-2, wherein the solvent system consists of one solvent.

27. The method of any one of claims 1-2, wherein the solvent system consists of EtOAc. Page 62 of 71 12504599v1Attorney Docket No.: 2010581-1438 28. The method of any one of claims 1-27, wherein the trituration is performed at about 0 °C.

29. The method of any one of claims 1-27, wherein the trituration is performed at room temperature.

30. The method of any one of claims 1-27, wherein the trituration is performed at elevated temperature.

31. The method of any one of claims 1-27, wherein the trituration is performed at about 30 °C.

32. The method of any one of claims 1-27, wherein the trituration is performed at about 40 °C.

33. The method of any one of claims 1-27, wherein the trituration is performed at about 50 °C.

34. The method of any one of claims 1-27, wherein the trituration is performed at about 60 °C.

35. The method of any one of claims 1-27, wherein the trituration is performed at about 65 °C.

36. The method of any one of claims 1-27, wherein the trituration is performed at about 70 °C.

37. The method of any one of claims 1-27, wherein the trituration is performed at about 80 °C.

38. The method of any one of claims 1-27, wherein the trituration is performed at greater than about 60 °C.

39. The method of any one of the preceding claims, wherein the composition on which trituration is performed is a crude preparation.

40. The method of any one of claims 1-39, wherein the composition on which trituration is performed comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is between about 3:1 to about 1:

3.

41. The method of any one of claims 1-39, wherein the composition on which trituration is performed comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is between about 2:1 to about 1:

2.

42. The method of any one of claims 1-39, wherein the composition on which trituration is performed comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is 1:

1.

43. The method of any one of claims 1-42, wherein the prepared product has a chemical purity of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more.

44. The method of any one of claims 1-42, wherein the prepared product has a diastereomeric purity of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more.

45. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is or greater than about 90:

10.

46. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is or greater than about 95:

5.

47. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is or greater than about 99:

1. Page 63 of 71 12504599v1Attorney Docket No.: 2010581-1438 48. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is or greater than about 4:

1.

49. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is or greater than about 5:

1.

50. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is or greater than about 10:

1.

51. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is or greater than about 15:

1.

52. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is or greater than about 20:

1.

53. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is or greater than about 50:

1.

54. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the beta:alpha isomer is or greater than about 100:

1.

55. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the alpha:beta isomer is or greater than about 90:

10.

56. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the alpha:beta isomer is or greater than about 95:

5.

57. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the alpha:beta isomer is or greater than about 99:

1.

58. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the alpha:beta isomer is or greater than about 4:

1.

59. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the alpha:beta isomer is or greater than about 5:

1.

60. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the alpha:beta isomer is or greater than about 10:

1.

61. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the alpha:beta isomer is or greater than about 15:

1.

62. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the alpha:beta isomer is or greater than about 20:

1.

63. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the alpha:beta isomer is or greater than about 50:

1.

64. The method of any one of claims 1-42, wherein the prepared product comprises beta isomer and alpha isomer and the ratio of the alpha:beta isomer is or greater than about 100:

1. Page 64 of 71 12504599v1Attorney Docket No.: 2010581-1438 65. The method of any one of claims 1-64, wherein the method is carried out at a scale of greater than about 10 mmol of the product.

66. The method of any one of claims 1-64, wherein the method is carried out at a scale of greater than about 20 mmol of the product.

67. The method of any one of claims 1-64, wherein the method is carried out at a scale of greater than about 50 mmol of the product.

68. The method of any one of claims 1-64, wherein the method is carried out at a scale of greater than about 100 mmol of the product.

69. The method of any one of claims 1-64, wherein the method is carried out at a scale of greater than about 150 mmol of the product.

70. The method of any one of claims 1-64, wherein the method is carried out at a scale of greater than about 200 mmol of the product.

71. The method of any one of claims 1-70, wherein the method does not involve subjecting the composition to column chromatography.

72. The method of any one of claims 1-70, wherein the method does not involve subjecting the composition to prep-HPLC.

73. A method, comprising: reacting a compound having the structure of formula (5): or a salt thereof with a compound(6): to provide a compound having the(7): Page 65 of 71 12504599v1Attorney Docket No.: 2010581-1438 or a salt thereof, wherein: 1R is −H or −F; Halo2 is −Cl, −Br, or −I; each of R2, R3, and R4is independently R’, or two or three of R2, R3, and R4are taken together with their intervening atoms to form ; Ring A is an optionallyring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; t is 0-5; each Rsis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −Ls−Rs11, −Ls−ORs11, −Ls−SRs11, −Ls−N(Rs11)2, −O−Ls−ORs11, −O−Ls−SRs11, −O−Ls−N(Rs11)2, −C(Rs11)3or −Ls−Si(Rs11)3; each Rs11is independently R’; each Lsis independently L; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10aliphatic and C1-10heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, Page 66 of 71 12504599v1Attorney Docket No.: 2010581-1438 oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

74. The method of claim 73, wherein R1is −H.

75. The method of claim 73, wherein R1is −F.

76. The method of any one of claims 73-75, wherein −P(OR2)N(R3)(R4) is −P(OCH2CH2CN)N[CH(CH3)2]2.

77. The method of any one of claims 73-75, wherein −P(OR2)N(R3)(R4) .

78. The method of any one of claims 73-75, .

79. The method of any one of claims 73-75, wherein −P(OR2)N(R3)(R4) .

80. The method of any one of claims 73-75, wherein each R is independently C1-6 alkyl or optionally81. The method of any one of claims 73-75, wherein wherein each R is independently C1-6 alkyl or optionally82. The method of any one of claims 73-75, .

83. The method of any one of claims 73-75, .Page 67 of 71 12504599v1Attorney Docket No.: 2010581-1438 84. The method of any one of claims 73-75, wherein wherein R is optionally substituted C1-6aliphatic.

85. The method of any one of claims 73-75, wherein wherein R is optionally substituted C1-6aliphatic.

86. The method of any one of claims 84-85, wherein87. The method of any one of claims 73-75, wherein wherein R is optionally substituted phenyl.

88. The method of any one of claims 73-75, wherein wherein R is optionally substituted phenyl.

89. The method of any one of claims 73-75, .

90. The method of any one of claims 73-75, .

91. A method, comprising:reacting a compound having the structure of formula (4): or a salt thereof with an agent (e.g.,LG is a leaving group (e.g., −Cl)) to provide a compound having the structure of formula (5): Page 68 of 71 12504599v1Attorney Docket No.: 2010581-1438 or a salt thereof, wherein each other as described in any one of the preceding claims.

92. The method of any one of claims 73-90, comprising a method of claim 91.

93. A method, comprising: reacting a compound having the structure of formula (3): or a salt thereof to provide a formula (4):or a salt thereof, wherein each otheras described in any one of the preceding claims.

94. The method of any one of claims 73-92, comprising a method of claim 93.

95. A method, comprising: reacting a compound having the structure of formula (1): Page 69 of 71 12504599v1Attorney Docket No.: 2010581-1438 or a salt thereof with a (2):wherein PG is a protecting group or having the structure of formula(3): or a salt thereof, wherein eachdescribed in any one of the preceding claims.

96. The method of claim 95, wherein PG is Ac.

97. The method of any one of claims 95-96, wherein the reaction is performed in the presence of a base.

98. The method of claim 96, wherein the base is NaH.

99. The method of any one of claims 95-98, comprising a method of any one of claims 1-72.

100. The method of any one of claims 73-94, comprising a method of any one of claims 95-99. Page 70 of 71 12504599v1