Synthetic methods of replacing atoms in organic compounds

Abstract

Compounds and methods for converting oxo moieties of oxo-containing compounds to other moieties, e.g., ethers, thioethers, amines, sulfoxides, sulfones, or other isotopes thereof, are provided. In some embodiments, the methods are performed using a compound of formula I, or a salt or stereoisomer thereof wherein, R20, R21, X, Y, R1, R2, R3, and n are defined herein: (I)

Description

124581.000010 | 25-T-072SYNTHETIC METHODS OF REPLACING ATOMS IN ORGANIC COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit to the priority of U. S. Provisional Patent Application No. 63 / 751,935, filed January 31, 2025, which is incorporated by reference herein.GOVERNMENT RIGHTS

[0002] This invention was made with government support under GM109054 awarded by the National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD

[0003] The present disclosure provides compounds and methods for converting oxo moi eties of oxo-containing compounds to other moi eties, e.g., thioethers, ethers, amines, sulfoxides, sulfones, or other isotopes thereof.BACKGROUND

[0004] Skeletal editing approaches have gained substantial interest in the late-stage isotope labeling and diversification of pharmaceutical compounds. The current skeletal editing methods are primarily based on transforming aromatic rings or π-rich systems. There is an increasing need, however, to develop efficient tools that can directly edit saturated scaffolds.

[0005] Generally, a large number of new compounds need to be prepared during the exploratory drug discovery stage to ensure the successful nomination of one lead compound. Once lead compounds are identified, the lead optimization process for each drug candidate typically needs plenty of time to complete, representing a substantial fraction of the total time required in overall drug development. Thus, methods that allow late-stage diversification of lead compounds can save substantial time and efforts for analogue preparation by avoiding redesigning and re-doing the synthetic route. Despite recent advances in late-stage functionalization techniques, few methods can directly modify saturated carbon skeletons.124581.000010 | 25-T-072

[0006] Isotope-labeled pharmaceuticals play important roles in drug discovery and clinical studies. Among the various approaches to preparing labeled compounds, a late-stage isotope labeling method is highly desired because it not only reduces lead time and cost but can also minimize radioactive waste. Besides hydrogen isotope exchange, however, there are few methods to do so. In addition, most late-stage isotope labelling methods for carbon are reversible reactions, rendering it difficult to reach complete isotope incorporation. Moreover, most methods label at side chains or on the periphery of the molecule, and core labeling remains challenging.

[0007] Saturated heterocycles are found in many approved and clinical stage drugs. While numerous approaches have been reported for their synthesis, preparations of multiply-substituted saturated heterocycles remain a nontrivial issue.SUMMARY

[0008] In some aspects, the disclosure provides compounds of formula I, or a salt or stereoisomer thereof:R21wherein, R20, R21, X, Y, R1, R2, R3, and n are defined herein.

[0009] In other aspects, the disclosure provides methods of transforming an oxo moiety of an oxo-containing compound of formula A to a thioether moiety of a thioether-containing compound of formula B:The methods include combining the compound of formula A with the compound formula I for a time and under conditions sufficient to produce the compound of formula B.124581.000010 | 25-T-072

[0010] In further aspects, the disclosure provides methods of transforming an oxo moiety of an oxo-containing compound of formula A to an ether moiety of an ether-containing compound of formula C:The methods include combining the compound of formula A with a compound of formula I for a time and under conditions sufficient to produce the compound of formula C.

[0011] In yet other aspects, the disclosure provides methods of transforming an oxo moiety of an oxo-containing compound of formula A to a secondary or tertiary amine-containing compound of formula D:The methods include combining the compound of formula A with the compound formula I for a time and under conditions sufficient to produce the compound of formula D.

[0012] In still further aspects, the disclosure provides methods of transforming an oxo moiety of an oxo-containing compound of formula A to a13C-labeled oxo moiety of an oxo-containing compound of formula E:The methods include combining the compound of formula A with a compound of formula I for a time and under conditions sufficient to produce the compound of formula E.124581.000010 | 25-T-072

[0013] In yet other aspects, the disclosure provides methods of transforming an oxo moiety of an oxo-containing compound of formula A to a sulfoxide-containing compound of formula F:The methods include combining the compound of formula A with the compound formula I for a time and under conditions sufficient to produce the compound of formula F.

[0014] In yet other aspects, the disclosure provides methods of transforming an oxo moiety of an oxo-containing compound of formula A to a sulfone-containing compound of formula G:The methods include combining the compound of formula A with the compound formula I for a time and under conditions sufficient to produce the compound of formula G.

[0015] Other aspects and embodiments of the invention will be readily apparent from the following detailed description of the invention.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0016] The disclosure describes the development a suite of “atom-swap” methods based on activation and functionalization of unstrained C-C bonds, which can replace a carbonyl group with a heteroatom or another moiety. These methods and compositions to accomplish them can enable technologies for drug discovery and development. For example, the described methods and compositions are applicable to (a) late-stage isotope labeling, (b) late-stage skeletal diversification of lead compounds, and (c) novel construction of multiply-substituted heterocycles.124581.000010 | 25-T-072

[0017] In the present disclosure the singular forms “a,” “an” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, e.g., a reference to “a material” is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.

[0018] When a value is expressed as an approximation by use of the descriptor “about” or “substantially” it will be understood that the particular value forms another embodiment. In general, use of “about” or “substantially” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about” or “substantially.” In other cases, the gradations used in a series of values may be used to determine the intended range available to “about” or “substantially” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range.

[0019] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0020] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiment s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. Finally,124581.000010 | 25-T-072while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself.

[0021] The term “alkyl” refers to a straight-chain or branched group containing from, for example, from about 1 to about 6 carbon atoms, e.g., from about 1 to about 4 carbon atoms. Examples of alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like. This definition also applies wherever “alkyl” occurs as part of a group. The alkyl can be substituted or unsubstituted, as described herein. Even in instances in which the alkyl is an alkylene chain (e.g., -(CH2)n-), the alkyl group can be substituted or unsubstituted.

[0022] The term “heteroalkyl” refers to an alkyl group comprising 1-3 heteroatoms selected from, e.g., O, S, or N. In some embodiments, the heteroalkyl contains one oxygen atom. In other embodiments, the heteroalkyl contains two oxygen atoms. In further embodiments, the heteroalkyl contains three oxygen atoms. In yet other embodiments, the heteroalkyl contains one sulfur atom. In still further embodiments, the heteroalkyl contains two sulfur atoms. In other embodiments, the heteroalkyl contains one nitrogen atom. M further embodiments, the heteroalkyl contains two nitrogen atom. The heteroalkyl can be substituted or unsubstituted, as described herein. Examples of heteroalkyl include, without limitation, alkoxy ( / .<., alkyloxy), thioalkoxy, alkylthio, or alkylamine.

[0023] The term “halo” refers to a halogen, such as fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0024] The term “alkoxy” or “alkyloxy” as used herein are interchangeable and refer to an alkyl moiety containing an oxygen atom. Examples of alkoxy include methoxy, ethoxy, isopropyloxy, butoxy, and the like. The alkoxy can be substituted or unsubstituted as described herein.

[0025] The term “thioalkoxy” as used herein refers to an alkyl moiety containing a sulfur atom. The alkoxy can be substituted or unsubstituted as described herein.

[0026] The term “alkylamine” as used herein refers to an alkyl moiety containing a nitrogen atom. The alkylamine can be substituted or unsubstituted as described herein. The nitrogen atom may be positioned between two carbon atoms of the alkyl or at the end of the alkyl chain as a NH2 group. The nitrogen atom may be substituted with a group as described herein, e.g., H or Ci-ealkyl.124581.000010 | 25-T-072

[0027] The term “alkylthio” as used herein refers an alkyl moiety containing a sulfur atom. Examples of alkylthio include thio-methoxy, thio-ethoxy, thio-isopropyloxy, thio-butoxy, and the like. The alkylthio can be substituted or unsubstituted as described herein.

[0028] The term “cycloalkyl” as used herein refers to a cyclic alkyl moiety containing from, for example, 3 to 10 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl can be substituted or unsubstituted as described herein.

[0029] The term “aryl” refers to a mono, bi, or tricyclic carbocyclic ring system having one, two, or three aromatic rings. The term “aryl” includes monocyclic and polycyclic aromatics such as, e.g., phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like. An aryl moiety generally contains from, e.g., 6 to 30 carbon atoms (Ce-3o), 6 to 18 carbon atoms (Ce-is), 6 to 14 carbon atoms (Ce-u), or 6 to 10 carbon atoms (Ce-io). The aryl can be substituted or unsubstituted as described herein.

[0030] The term “heteroaryl” refers to aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S, or N) in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. Illustrative examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, imidazolyl, (l,2,3)-triazolyl, (l,2,4)-triazolyl, pyrazinyl, tetrazolyl, furyl, pyrrolyl, thienyl, isothiazolyl, thiazolyl, isoxazolyl, and oxadiazolyl. The heteroaryl can be substituted or unsubstituted as described herein.

[0031] The term “heterocycloalkyl” refers to a saturated or partially unsaturated monocyclic, bicyclic, and spiro ring system containing 3 to 7 ring members of carbon atoms and at least 1 other atom that is nitrogen, sulfur, pr oxygen. In some aspects, the124581.000010 | 25-T-072heterocycloalkyl is a 5, 6, or 7-membered monocyclic ring and contains one, two, or three heteroatoms that are nitrogen, oxygen, or sulfur. The heterocycloalkyl can be attached to the parent structure through a carbon atom or through any heteroatom of the heterocycloalkyl that results in a stable structure. Examples of such heterocycloalkyl rings are aziridinyl, oxiranyl thiiranyl, azetidinyl, oxetanyl thietanyl, pyrrolinyl, oxolanyl, thiolanyl, piperidyl, oxanyl, thianyl, azepanyl, oxepanyl, thiepanyl, pyridazolidinyl, imidazolidinyl, dioxolanyl oxathiolanyl, piperazinyl, di oxanyl, dithianyl, trithianyl, morpholinyl, and thiomorpholinyl. The heterocycloalkyl can be substituted or unsubstituted as described herein.

[0032] Suitable substituents include, e.g., halo, Ci-ealkyl, OH, NO2, CN, NH2, Ci-ealkoxy, Cs-scycloalkyl, aryl, heteroaryl, or heterocycloalkyl.

[0033] In any of the embodiments described herein, whenever a range of the number of atoms in a structure is indicated (e.g., C1-12, C1-8, C1-6, C1-4, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1-8 carbon atoms (Ci-s), 1-6 carbon atoms (Ci-e), 1-4 carbon atoms (C1-4), 1-3 carbon atoms (C1-3), or 2-8 carbon atoms (C2-8) as used with respect to any chemical group (e.g., alkyl, cycloalkyl, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, and / or 8 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, etc., as appropriate).

[0034] Any of the compounds disclosed herein may be converted to a salt. The term “salt” as used herein refers to salt synthesized from the parent compound which contains a basic or acidic moiety prepared by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. For example, an inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid), an organic acid (e.g., oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, or benzylsulfonic acid),124581.000010 | 25-T-072an inorganic base (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or ammonium hydroxide), an organic base (e.g., methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline, or cinchonine), or an amino acid (e.g., lysine, arginine, or alanine) can be used. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p.1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). For example, they can be a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium of salt.

[0035] Moreover, the disclosed compounds may include any stereoisomers thereof. The term “stereoisomers” as used herein refers to compounds having identical chemical constitution, but differing with regard to the arrangement of the atoms or groups in the structures. Stereoisomers include, e.g., enantiomers, diastereomers, or tautomers.CompoundsTo achieve the transformations described herein, the starting oxo-containing compound is combined with a hydrazonamide compound of formula I, or a salt or stereoisomer thereof, as described herein. These hydrazonamide compounds include a series of deacylative reagents that can efficiently condense with alkyl ketones to achieve the described transformations.R21

[0036] According to the disclosure, X is a radical generating moiety. The term “radical-generating moiety” as used herein refers to a chemical group that, when it is removed, leaves an unpaired electron at the carbon-atom to which X is attached. Examples of X include, without limitation, halo, N3, N2+, triflate, tosylate, SO2CI, COOH, B(OH)2, -SC(O)O-N=C(Ph)2, -I+-Ph, or wherein Z is -CH2-, -O-, -NR’- (R’ is H or Ci-124581.000010 | 25-T-072eaiKyi), or -s>-. wnen is cnargea (e.g., x is IN?, i -ijn, or Czl J ), the counteranion may be halo, BFF, NOf, HSOF, PFe’, CFfeCOO’, N(SO2CFs)2-, CF3SO3-, CH3SO3-, CFsCOO', (CH3O)(H)PC>2', or N(CN)2-. In some embodiments, X is halo such as bromo or iodo. In other embodiments, X is N3. In further embodiments, X is N2+. In yet other embodiments, X is triflate. In still further embodiments, X is tosylate. In other embodiments, X is SO2CI. In further embodiments, X COOH. In yet other embodiments, X B(0H)2. In still further embodiments, X -C(O)O-N=C(Ph)2. In other embodiments, X -I+-rn. in runner emoouimems,x isz

[0037] According to the disclosure, Y is C or N. In some embodiments, Y is C. In other embodiments, Y is N.

[0038] According to the disclosure, R1and R2are, independently, absent, H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, or optionally substituted Ci-eheteroalkyl, provided that (i) both R1and R2are not absent and (ii) R1and R2are not absent when Y is C. In some aspects, R1is absent and R2is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, or optionally substituted Ci-eheteroalkyl. In other aspects, R2is absent and R1is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, or optionally substituted Ci-eheteroalkyl. In some embodiments, R1is H. In other embodiments, R1is Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, R1is optionally substituted Cs-scycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl, cyclohexyl. In other aspects, R1is aryl, for example, phenyl. In yet other embodiments, R1is Ci-eheteroalkyl, such as alkyloxy, alkylthio, trifluorom ethyl. In still further embodiments, R2is H. In other embodiments, R2is Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, R2is Cs-scycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl, cyclohexyl. In other aspects, R2is aryl, for example, phenyl. In yet other embodiments, R2is Ci-eheteroalkyl, such as Ci-ealkyloxy, Ci-ealkylthio, or Ci-6trihaloalkyl such as trifluorom ethyl. In some embodiments, R1and R2are the same. In124581.000010 | 25-T-072other embodiments, R1and R2are each methyl. In other embodiments, R1and R2are each hydrogen. In further embodiments, R1and R2are not the same.

[0039] According to the disclosure, R1and R2may be taken together with the carbon atom to which they are attached to form an optionally substituted Cs-scycloalkyl. In some embodiments, R1and R2are taken together with the carbon atom to which they are attached to form Cs-scycloalkyl, such as cyclopropyl, or such as cyclobutyl, or such as cyclopentyl, or such as cyclohexyl, or such as cycloheptyl, or such as cyclooctyl. In further embodiments, R1and R2are taken together with the carbon atom to which they are attached to form optionally substituted heterocycloalkyl. In yet other embodiments, R1and R2are taken together with the carbon atom to which they are attached to form aziridinyl, oxiranyl thiiranyl, azetidinyl, oxetanyl thietanyl, pyrrolinyl, oxolanyl, thiolanyl, piperidyl, oxanyl, thianyl, azepanyl, oxepanyl, thiepanyl, pyridazolidinyl, imidazolidinyl, dioxolanyl oxathiolanyl, piperazinyl, dioxanyl, dithianyl, trithianyl, morpholinyl, or thiomorpholinyl.

[0040] According to the disclosure, R3is optionally substituted Ci-ealkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted Cs-scycloalkyl, or optionally substituted heterocycloalkyl. In some embodiments, R3is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In further embodiments, R3is optionally substituted aryl, such as optionally substituted phenyl. In yet further embodiments, R3is optionally substituted heteroaryl such as optionally substituted pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, imidazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, pyrrolyl, thienyl, isothiazolyl, thiazolyl, isoxazolyl, or oxadiazolyl. In further embodiments, R3is optionally substituted pyridyl. In yet other embodiments, R3is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R3is optionally substituted heterocycloalkyl such as optionally substituted aziridinyl, oxiranyl thiiranyl, azetidinyl, oxetanyl thietanyl, pyrrolinyl, oxolanyl, thiolanyl, piperidyl, oxanyl, thianyl, azepanyl, oxepanyl, thiepanyl, pyridazolidinyl, imidazolidinyl, dioxolanyl oxathiolanyl, piperazinyl, dioxanyl, dithianyl, trithianyl, morpholinyl, or thiomorpholinyl.124581.000010 | 25-T-072

[0041] According to the disclosure, R20and R21are, independently, H or Ci-ealkyl, or R20and R21are taken together with the carbon atoms to which they are attached, form an optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R20and R21are H. In other embodiments, R20and R21are, independently, Ci-ealkyl. In further embodiments, R20is H and R21is Ci-ealkyl. In other embodiments, R20and R21are taken together with the carbon atoms to which they are attached to form an optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R20and R21are taken together with the carbon atoms to which they are attached, to form an optionally substituted heteroaryl.

[0042] According to the disclosure, n is 1 to 3. In some embodiments, n is 1. In other embodiments, n is 2. In further embodiments, n is 3.

[0043] In some embodiments, the compound of formula I is of formula II or is a salt or stereoisomer thereof:In this compound of formula II, R4is H or Ci-ealkyl. In some embodiments, R4is H. In other embodiments, R4is Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. The heteroaryl may be selected by one skilled in the art. In some embodiments, the heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiophenyl, or furanyl. In some embodiments, the heteroaryl is pyridyl. In some embodiments, the heteroaryl is 2-pyridyl.

[0044] In other embodiments, the compound of formula I isor a salt or stereoisomer thereof.124581.000010 | 25-T-072

[0045] In further embodiments, the compound of formula I isNH2or a salt or stereoisomer thereof.Methods

[0046] The inventors developed a novel “atom-swap” method to replace a carbonyl group with a heteroatom or isotopically-labelled carbonyl or heteroatom in an aliphatic system. The methods utilize the compound of formula I described herein which converts a carbonyl group (-C(O)-) to other groups including thioethers (-S-), amines (-NR-), ethers (-0-), sulfoxide (-S(O)-), or sulfone (-S(O)2-). The methods also permit swapping out one carbon isotope in a carbonyl for another carbon isotope (e.g.,12C(O) to13C(O)).

[0047] I. Oxo to Thioether Transformation

[0048] The disclosure provides methods of transforming an oxo moiety of an oxocontaining compound of formula A to a thioether moiety of a thioether-containing compound of formula B. See, Scheme 1.Scheme 1The methods include (i) combining a compound of formula A with the compound of formula I as described herein. The method is performed for a time and under conditions sufficient to produce the compound of formula B. The methods may also include (ii) reacting the product of step (i) with a thiolating agent. In some embodiments, the thiolating agent is P4S10 (Berzelius reagent), pentathiodiphosphorus (V) acid-P, P'-bis(pyridinium betaine) (JBR reagent), 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson’ s reagent), tetraphosphorus decasulfide in pyridine (ThioTOR)), N-(benzylthio)phthalimide, a compound of formula TA-1, or a compound of formula TA-2. In other embodiments, the thiolating agent is Berzelius reagent. In further embodiments, the thiolating agent is JBR reagent. In yet other embodiments, the thiolating agent is Lawesson’ s reagent. In still further124581.000010 | 25-T-072embodiments, the thiolating agent is ThioTOR. In other embodiments, the thiolating agent is N-(benzylthio)phthalimide. In further embodiments, the thiolating agent is a compound of formula TA-1:In formula TA-1, R30is Ci-ealkyl, halo, SH, NH2, aryl, OH, or Ci-eheteroalkyl. The R30group may be attached to any carbon atom of the phenyl ring. In some embodiments, R30is Ci-ealkyl, or such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, such as halo, or such as F, or such as Cl, or such as Br, or such as I. In further embodiments, R30is aryl, such as phenyl. In still other embodiments, R30is OH. In yet further embodiments, R30is Ci-eheteroalkyl such as alkyloxy, alkylthio, trifluoromethyl, C(O)NH2, C(O)N(H)(Ci-ealkyl), or C(O)N(Ci-6alkyl)(Ci-6alkyl). In other embodiments, R30is SH. In further embodiments, R30is NH2. In formula TA-1, R31is benzyl or / -butyl. In some embodiments, R31is benzyl. In other embodiments, R31is t-butyl. In further embodiments, the thiolating agent is a compound of formula TA-2:oo TA-2In formula TA-2, R40and R41are, independently, Ci-ealkyl, halo, SH, NH2, aryl, OH, or Ci-eheteroalkyl, provided that R40and R41are not the same. In some embodiments, R40is Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, R40is halo, such as F, or such as Cl, or such as Br, or such as I. In further embodiments, R40is aryl, such as phenyl. In still other embodiments, R40is OH. In yet further embodiments, R40is Ci-eheteroalkyl such as alkyloxy, alkylthio, trifluoromethyl, C(O)NH2, C(O)N(H)(Ci-ealkyl), or C(O)N(Ci-6alkyl)(Ci-6alkyl). In some embodiments, R41is Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, R41is halo, such as F, or such as Cl, or such as Br, or such as I. In further embodiments, R41is aryl, such as phenyl. In still other embodiments, R41is OH. In yet further embodiments, R41is Ci-eheteroalkyl such as alkyloxy, alkylthio, trifluorom ethyl, C(O)NH2, C(O)N(H)(Ci-ealkyl), or C(O)N(Ci-124581.000010 | 25-T-0726alkyl)(Ci-6alkyl). For example, the thiolating agent is 4-methylbenzenesulfonic thioanhydride.

[0049] The compound of formula A may have the structure of formula III and the compound of formula B may have the structure of formula Ill-a:In these structures, X1is O, S, NR7or CR7R8. In some embodiments, X1is O. In other embodiments, X1is S. In further embodiments, X1is NR7. In yet other embodiments, X1is CR7R8. R5, R6, R7, and R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R5is H. In other embodiments, R5is OC(O)R10. In further embodiments, R5is C(O)R10. In yet other embodiments, R5is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R5is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R5is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5is O-(optionally substituted benzyl). In further embodiments, R5is optionally substituted heterocycloalkyl. In yet other embodiments, R5is optionally substituted heteroaryl. In some embodiments, R6is H. In other embodiments, R6is OC(O)R10. In further embodiments, R6is C(O)R10. In yet other embodiments, R6is optionally substituted Ci-ealkyl. In still further embodiments, R6is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R6is124581.000010 | 25-T-072optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R6is O-(optionally substituted benzyl). In further embodiments, R6is optionally substituted heterocycloalkyl. In yet other embodiments, R6is optionally substituted heteroaryl. In some embodiments, R7is H. In other embodiments, R7is OC(O)R10. In further embodiments, R7is C(O)R10. In yet other embodiments, R7is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R7is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl In other embodiments, R7is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R7is O-(optionally substituted benzyl). In further embodiments, R7is optionally substituted heterocycloalkyl. In yet other embodiments, R7is optionally substituted heteroaryl. In some embodiments, R8is H. In other embodiments, R8is OC(O)R10. In further embodiments, R8is C(O)R10. In yet other embodiments, R8is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R8is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R8is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R8is O-(optionally substituted benzyl). In further embodiments, R8is optionally substituted heterocycloalkyl. In yet other embodiments, R8is optionally substituted heteroaryl. In some embodiments, R5and R6or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In other embodiments, R5and R6are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted124581.000010 | 25-T-072cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In other embodiments, R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In these structures, m is 0 to 6, wherein each X1is independently selected for each m. In some embodiments, m is 0. In other embodiments, m is 1. In further embodiments, m is 2. In yet other embodiments, m is 3. In still further embodiments, m is 4. In other embodiments, m is 5. In further embodiments, m is 6. R10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R10is H. In other embodiments, R10is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In further embodiments, R10is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In yet other embodiments, R10is optionally substituted aryl, such as optionally substituted phenyl. In still further124581.000010 | 25-T-072embodiments, R10is OC(O)R10. In other embodiments, R10is optionally substituted heterocycloalkyl. In further embodiments, R10is optionally substituted heteroaryl.

[0050] In certain embodiments, the thioether moiety comprises32S or34S.In some embodiments, the thioether moiety comprises32S. In other embodiments, the thioether moiety comprises34S.

[0051] In certain embodiments, the compound of formula Illa is of formula Ill-al or III-a2, wherein X1, m, R5and R6are defined herein.In other embodiments, the compound of formula Illa is of formula Ill-al. In further embodiments, the compound of formula Illa is of formula III-a2.

[0052] II. Oxo to Ether Transformations

[0053] The disclosure provides methods of transforming an oxo moiety of an oxocontaining compound of formula A to an ether moiety of an ether-containing compound of formula C. See, Scheme 2.Scheme 2The methods include (i) combining the compound of formula A with a compound of formula I for a time and under conditions sufficient to produce the compound of formula C. The product of (i) may be contacted with LG1-O-LG2, wherein LG1and LG2are, independently, SH2 leaving groups. In some embodiments, LG2is an equal or better SH2 leaving group than LG1. In some embodiments, LG1and LG2may be selected from OtBu, SRA, or SO2RB, wherein RAand RBare, independently, Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. For example, LG1and LG2are, independently, tosylate-O-tosylate, tosylate-O-Ot-Bu, or ^u-O-O^u. The product of (ii) may124581.000010 | 25-T-072then be reacted with a radical initiator such as azobisisobutyronitrile (AIBN) and a hydrogen atom donor such as trimethylsilylsilane.

[0054] In some embodiments, the compound of formula C is of formula IV:In this structure, X2is O, S, NR7or CR7R8. In some embodiments, X2is O. In other embodiments, X2is S. In further embodiments, X2is NR7. In yet other embodiments, X2is CR7R8. R5, R6, R7, and R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R5is H. In other embodiments, R5is OC(O)R10. In further embodiments, R5is C(O)R10. In yet other embodiments, R5is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R5is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R5is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5is O-(optionally substituted benzyl). In further embodiments, R5is optionally substituted heterocycloalkyl. In yet other embodiments, R5is optionally substituted heteroaryl. In some embodiments, R6is H. In other embodiments, R6is OC(O)R10. In further embodiments, R6is C(O)R10. In yet other embodiments, R6is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R6is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted124581.000010 | 25-T-072cyclooctyl. In other embodiments, R6is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R6is O-(optionally substituted benzyl). In further embodiments, R6is optionally substituted heterocycloalkyl. In yet other embodiments, R6is optionally substituted heteroaryl. In some embodiments, R7is H. In other embodiments, R7is OC(O)R10. In further embodiments, R7is C(O)R10. In yet other embodiments, R7is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R7is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R7is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R7is O-(optionally substituted benzyl). In further embodiments, R7is optionally substituted heterocycloalkyl. In yet other embodiments, R7is optionally substituted heteroaryl. In some embodiments, R8is H. In other embodiments, R8is OC(O)R10. In further embodiments, R8is C(O)R10. In yet other embodiments, R8is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R8is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R8is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R8is O-(optionally substituted benzyl). In further embodiments, R8is optionally substituted heterocycloalkyl. In yet other embodiments, R8is optionally substituted heteroaryl. In some embodiments, R5and R6or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In other embodiments, R5and R6are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, such as optionally substituted124581.000010 | 25-T-072cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In other embodiments, R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In the structure for formula IV, m is 0 to 6, wherein each X2is independently selected for each m. In some embodiments, m is 0. In other embodiments, m is 1. In further embodiments, m is 2. In yet other embodiments, m is 3. In still further embodiments, m is 4. In other embodiments, m is 5. In further embodiments, m is 6. R10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R10is H. In other embodiments, R10is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In further embodiments, R10is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In yet other embodiments, R10is optionally substituted aryl, such as optionally substituted phenyl. In still124581.000010 | 25-T-072further embodiments, R10is OC(O)R10. In other embodiments, R10is optionally substituted heterocycloalkyl. In further embodiments, R10is optionally substituted heteroaryl.

[0055] In certain embodiments, the ether moiety comprises16O or18C.In some embodiments, the ether moiety comprises16O. In other embodiments, the ether moiety comprises18O.

[0056] In other embodiments, the compound of formula C is of formula IV-1 or IV- 2, wherein X2, m, R5and R6are defined herein:In further embodiments, the compound of formula C is of formula IV-1. In yet other embodiments, the compound of formula C is of formula IV-2.

[0057] III. Oxo to Amine Transformations

[0058] No straightforward method exists for replacing a carbonyl group with a nitrogen atom via late-stage modification. The challenge is substantial, as it requires efficiently breaking two unstrained C(sp3)-acyl bonds and successively forming two C(sp3)-N bonds, without interfering with various functional groups in complex molecules.

[0059] The disclosure provides methods of transforming an oxo moiety of an oxocontaining compound of formula A to a secondary- or tertiary amine-containing compound of formula D. See, Scheme 3.Scheme 3The methods include (i) combining the compound of formula A with a compound of formula I for a time and under conditions sufficient to produce the compound of formula D.

[0060] In some embodiments, the product of (i) may then be (ii) contacted with an azidation agent. Examples of azidation agents include, without limitation, 1-azido-1λ3-124581.000010 | 25-T-072benzo[d]iodaoxol-3(1H)-one(IBA; ), IB A derivatives (e.g.,), or a compound of formula AA-1:In the structure of formula AA-1, R50is Ci-ealkyl, halo, SH, NH2, aryl, OH, or Ci-eheteroalkyl. In some embodiments, R50is Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, R50is halo, such as F, or such as Cl, or such as Br, or such as I. In further embodiments, R50is aryl, such as phenyl. In still other embodiments, R50is OH. In yet further embodiments, R50is Ci-eheteroalkyl such as alkyloxy, alkylthio, trifluoromethyl, C(O)NH2, C(O)N(H)(Ci-ealkyl), or C(O)N(Ci-6alkyl)(Ci-6alkyl).

[0061] In other embodiments, the product of (i) may then be (ii) contacted with a compound of formula AA-2:V'N / R70AA-2In the structure of formula AA-2, R60and R70are, independently, Ci-ioalkyl, Ci-ioheteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R60is Ci-ioalkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, R70is Ci-ioalkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In further embodiments, R60is optionally substituted aryl, such as phenyl or phenyl substituted with Ci-ealkyl. In further embodiments, R70is optionally substituted aryl, such as phenyl or phenyl substituted with Ci-ealkyl. In yet other embodiments, R60is optionally substituted heteroaryl, such as optionally substituted pyridyl. In still further embodiments, R70is optionally substituted heteroaryl, such as optionally substituted pyridyl. In other embodiments, R60is Ci-ioheteroalkyl. In further embodiments, R70is Ci-ioheteroalkyl.124581.000010 | 25-T-072

[0062] The product of (ii) is then cyclized using skill in the art.

[0063] In some embodiments, the compound of formula D is of formula V,:In this structure, X3is O, S, NR7or CR7R8. In some embodiments, X3is O. In other embodiments, X3is S. In further embodiments, X3is NR7. In yet other embodiments, X3is CR7R8. R5, R6, R7, and R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R5is H. In other embodiments, R5is OC(O)R10. In further embodiments, R5is C(O)R10. In yet other embodiments, R5is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R5is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R5is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5is O-(optionally substituted benzyl). In further embodiments, R5is optionally substituted heterocycloalkyl. In yet other embodiments, R5is optionally substituted heteroaryl. In some embodiments, R6is H. In other embodiments, R6is OC(O)R10. In further embodiments, R6is C(O)R10. In yet other embodiments, R6is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R6is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted124581.000010 | 25-T-072cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R6is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R6is O-(optionally substituted benzyl). In further embodiments, R6is optionally substituted heterocycloalkyl. In yet other embodiments, R6is optionally substituted heteroaryl. In some embodiments, R7is H. In other embodiments, R7is OC(O)R10. In further embodiments, R7is C(O)R10. In yet other embodiments, R7is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R7is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R7is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R7is O-(optionally substituted benzyl). In further embodiments, R7is optionally substituted heterocycloalkyl. In yet other embodiments, R7is optionally substituted heteroaryl. In some embodiments, R8is H. In other embodiments, R8is OC(O)R10. In further embodiments, R8is C(O)R10. In yet other embodiments, R8is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R8is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R8is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R8is O-(optionally substituted benzyl). In further embodiments, R8is optionally substituted heterocycloalkyl. In yet other embodiments, R8is optionally substituted heteroaryl. In some embodiments, R5and R6or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In other embodiments, R5and R6are joined together with the atoms to which they124581.000010 | 25-T-072are attached to form optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In other embodiments, R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In the structure for formula V, m is 0 to 6, wherein each X3is independently selected for each m. In some embodiments, m is 0. In other embodiments, m is 1. In further embodiments, m is 2. In yet other embodiments, m is 3. In still further embodiments, m is 4. In other embodiments, m is 5. In further embodiments, m is 6. R10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R10is H. In other embodiments, R10is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In further embodiments, R10is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In yet other124581.000010 | 25-T-072embodiments, R10is optionally substituted aryl, such as optionally substituted phenyl. In still further embodiments, R10is OC(O)R10. In other embodiments, R10is optionally substituted heterocycloalkyl. In further embodiments, R10is optionally substituted heteroaryl. R9is H or Ci-ealkyl. In some embodiments, R9is H. In other embodiments, R9is Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl.

[0064] In certain embodiments, the secondary- or tertiary amine moiety comprises14N or15N. In some embodiments, the secondary- or tertiary amine moiety comprises14N. In other embodiments, the secondary- or tertiary amine moiety comprises15N.

[0065] In certain embodiments, the compound of formula D is formula V-l or V-2, wherein R5, R6, R9, X3, and m are defined herein:R9In further embodiments, the compound of formula D is formula V-l. In yet other embodiments, the compound of formula D is formula V-2.

[0066] IV.12C oxo to13C oxo Transformations

[0067] The disclosure provides methods of transforming oxo moieties of an oxocontaining compound of formula A to a13C-labeled oxo moiety of an oxo-containing compound of formula E. See, Scheme 4.Scheme 4The methods include (i) combining the compound of formula A with the compound of formula I for a time and under conditions sufficient to produce the compound of formula E.The product of (i) may then be (ii) reacted with LG3-13CN. In some embodiment, LG3is124581.000010 | 25-T-072tosylate, halo, succinate, alkylsulfonyl (e.g., methyl sulfonyl, ethyl sulfonyl, among others) or triflate. The product of (ii) is then reacted with a radical initiator such as azobisisobutyronitrile (AIBN) or di-t-butyldiazene and a hydrogen atom donor such as trimethylsilylsilane or n-BusSnH.

[0068] In certain embodiments, the compound of formula E is of formula VI:In this structure, X4is O, S, NR7or CR7R8. In some embodiments, X4is O. In other embodiments, X4is S. In further embodiments, X4is NR7. In yet other embodiments, X4is CR7R8. R5, R6, R7, and R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R5is H. In other embodiments, R5is OC(O)R10. In further embodiments, R5is C(O)R10. In yet other embodiments, R5is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R5is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R5is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5is O-(optionally substituted benzyl). In further embodiments, R5is optionally substituted heterocycloalkyl. In yet other embodiments, R5is optionally substituted heteroaryl. In some embodiments, R6is H. In other embodiments, R6is OC(O)R10. In further embodiments, R6is C(O)R10. In yet other embodiments, R6is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R6is optionally substituted124581.000010 | 25-T-072Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R6is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R6is O-(optionally substituted benzyl). In further embodiments, R6is optionally substituted heterocycloalkyl. In yet other embodiments, R6is optionally substituted heteroaryl. In some embodiments, R7is H. In other embodiments, R7is OC(O)R10. In further embodiments, R7is C(O)R10. In yet other embodiments, R7is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R7is optionally substituted Cs-scycloalkyl. In other embodiments, R7is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R7is O-(optionally substituted benzyl). In further embodiments, R7is optionally substituted heterocycloalkyl. In yet other embodiments, R7is optionally substituted heteroaryl. In some embodiments, R8is H. In other embodiments, R8is OC(O)R10. In further embodiments, R8is C(O)R10. In yet other embodiments, R8is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R8is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R8is optionally substituted aryl. In yet other embodiments, R8is O-(optionally substituted benzyl). In further embodiments, R8is optionally substituted heterocycloalkyl. In yet other embodiments, R8is optionally substituted heteroaryl. In some embodiments, R5and R6or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In other embodiments, R5and R6are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or124581.000010 | 25-T-072such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In other embodiments, R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In the structure for formula IV, m is 0 to 6, wherein each X4is independently selected for each m. In some embodiments, m is 0. In other embodiments, m is 1. In further embodiments, m is 2. In yet other embodiments, m is 3. In still further embodiments, m is 4. In other embodiments, m is 5. In further embodiments, m is 6. R10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R10is H. In other embodiments, R10is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In further embodiments, R10is optionally substituted C3-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In yet other embodiments, R10is optionally substituted aryl, such as optionally substituted phenyl. In still further embodiments, R10is OC(O)R10. In other embodiments,124581.000010 | 25-T-072R10is optionally substituted heterocycloalkyl. In further embodiments, R10is optionally substituted heteroaryl.

[0069] V. Oxo to Sulfoxide Transformations

[0070] The disclosure provides methods of transforming an oxo moiety of an oxocontaining compound of formula A to a sulfoxide moiety of a sulfoxide-containing compound of formula F. See, Scheme 5.Scheme 5The methods include (i) combining the compound of formula A with the compound formula I for a time and under conditions sufficient to produce the compound of formula F. The methods may also include (ii) reacting the product of step (i) with a thiolating agent. In some embodiments, the thiolating agent is P4S10 (Berzelius reagent), pentathiodiphosphorus (V) acid-P, P'-bis(pyridinium betaine) (JBR reagent), 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson’s reagent), tetraphosphorus decasulfide in pyridine (ThioTOR)), N-(benzylthio)phthalimide, a compound of formula TA-1, or a compound of formula TA-2. In other embodiments, the thiolating agent is Berzelius reagent. In further embodiments, the thiolating agent is JBR reagent. In yet other embodiments, the thiolating agent is Lawesson’s reagent. In still further embodiments, the thiolating agent is ThioTOR. In other embodiments, the thiolating agent is N-(benzylthio)phthalimide. In further embodiments, the thiolating agent is a compound of formula TA-1:In formula TA-1, R30is Ci-ealkyl, halo, SH, NH2, aryl, OH, or Ci-eheteroalkyl. The R30group may be attached to any carbon atom of the phenyl ring. In some embodiments, R30is Ci-ealkyl, or such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, such as halo, or such as F, or such as Cl, or124581.000010 | 25-T-072such as Br, or such as I. In further embodiments, R30is aryl, such as phenyl. In still other embodiments, R30is OH. In yet further embodiments, R30is Ci-eheteroalkyl such as alkyloxy, alkylthio, trifluoromethyl, C(O)NH2, C(O)N(H)(Ci-ealkyl), or C(O)N(Ci-6alkyl)(Ci-ealkyl). In other embodiments, R30is SH. In further embodiments, R30is NH2. In formula TA-1, R31is benzyl or / -butyl. In some embodiments, R31is benzyl. In other embodiments, R31is t-butyl. In further embodiments, the thiolating agent is a compound of formula TA-2:In formula TA-2, R40and R41are, independently, Ci-ealkyl, halo, SH, NH2, aryl, OH, or Ci-eheteroalkyl, provided that R40and R41are not the same. In some embodiments, R40is Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, R40is halo, such as F, or such as Cl, or such as Br, or such as I. In further embodiments, R40is aryl, such as phenyl. In still other embodiments, R40is OH. In yet further embodiments, R40is Ci-eheteroalkyl such as alkyloxy, alkylthio, trifluoromethyl, C(O)NH2, C(O)N(H)(Ci-ealkyl), or C(O)N(Ci-6alkyl)(Ci-6alkyl). In some embodiments, R41is Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, R41is halo, such as F, or such as Cl, or such as Br, or such as I. In further embodiments, R41is aryl, such as phenyl. In still other embodiments, R41is OH. In yet further embodiments, R41is Ci-eheteroalkyl such as alkyloxy, alkylthio, trifluorom ethyl, C(O)NH2, C(O)N(H)(Ci-ealkyl), or C(O)N(Ci-6alkyl)(Ci-6alkyl). For example, the thiolating agent is 4-methylbenzenesulfonic thioanhydride.

[0071] The product of step (ii) is then converted to the sulfoxide. The oxidation may be performed using techniques and reagents known in the art. In some embodiments, the oxidation is performed using an oxidant. In certain embodiments, the oxidant is m-chloroperoxybenzoic acid (CPBA), oxygen, or H2O2. In some embodiments, one equivalent of the oxidant may be used.

[0072] In some embodiments, the compound of formula F is of formula VII:124581.000010 | 25-T-072o

[0073] In this structure, X5is O, S, NR7or CR7R8. In some embodiments, X5is O. In other embodiments, X5is S. In further embodiments, X5is NR7. In yet other embodiments, X5is CR7R8. R5, R6, R7, and R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R5is H. In other embodiments, R5is OC(O)R10. In further embodiments, R5is C(O)R10. In yet other embodiments, R5is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R5is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R5is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5is O-(optionally substituted benzyl). In further embodiments, R5is optionally substituted heterocycloalkyl. In yet other embodiments, R5is optionally substituted heteroaryl. In some embodiments, R6is H. In other embodiments, R6is OC(O)R10. In further embodiments, R6is C(O)R10. In yet other embodiments, R6is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R6is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R6is optionally substituted aryl, such as optionally substituted phenyl. In yet other124581.000010 | 25-T-072embodiments, R6is O-(optionally substituted benzyl). In further embodiments, R6is optionally substituted heterocycloalkyl. In yet other embodiments, R6is optionally substituted heteroaryl. In some embodiments, R7is H. In other embodiments, R7is OC(O)R10. In further embodiments, R7is C(O)R10. In yet other embodiments, R7is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R7is optionally substituted Cs-scycloalkyl. In other embodiments, R7is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R7is O-(optionally substituted benzyl). In further embodiments, R7is optionally substituted heterocycloalkyl. In yet other embodiments, R7is optionally substituted heteroaryl. In some embodiments, R8is H. In other embodiments, R8is OC(O)R10. In further embodiments, R8is C(O)R10. In yet other embodiments, R8is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R8is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R8is optionally substituted aryl. In yet other embodiments, R8is O-(optionally substituted benzyl). In further embodiments, R8is optionally substituted heterocycloalkyl. In yet other embodiments, R8is optionally substituted heteroaryl. In some embodiments, R5and R6or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In other embodiments, R5and R6are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5and R6are joined124581.000010 | 25-T-072together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In other embodiments, R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In the structure for formula IV, m is 0 to 6, wherein each X5is independently selected for each m. In some embodiments, m is 0. In other embodiments, m is 1. In further embodiments, m is 2. In yet other embodiments, m is 3. In still further embodiments, m is 4. In other embodiments, m is 5. In further embodiments, m is 6. R10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R10is H. In other embodiments, R10is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In further embodiments, R10is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In yet other embodiments, R10is optionally substituted aryl, such as optionally substituted phenyl. In still further embodiments, R10is OC(O)R10. In other embodiments, R10is optionally substituted heterocycloalkyl. In further embodiments, R10is optionally substituted heteroaryl.

[0074] In certain embodiments, the sulfoxide moiety comprises32S or34S. In other embodiments, the sulfoxide moiety comprises32S. In further embodiments, the sulfoxide moiety comprises34S.124581.000010 | 25-T-072

[0075] In certain embodiments, the compound of formula VII is of formula VII-1 or VII-2, wherein X5, m, R5and R6are defined herein.o32s, isX5]- m (~" R6,5,5R5VII-2In other embodiments, the compound of formula VII is of formula VII-1. In further embodiments, the compound of formula VII is of formula VII-2.

[0076] VI. Oxo to Sulfone Transformations

[0077] The disclosure provides methods of transforming an oxo moiety of an oxocontaining compound of formula A to a sulfone moiety of a sulfone-containing compound of formula G. See, Scheme 6.Scheme 6The methods include (i) combining the compound of formula A with the compound formula I for a time and under conditions sufficient to produce the compound of formula G. The methods may also include (ii) reacting the product of step (i) with a thiolating agent. In some embodiments, the thiolating agent is P4S10 (Berzelius reagent), pentathiodiphosphorus (V) acid-P, P'-bis(pyridinium betaine) (JBR reagent), 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson’s reagent), tetraphosphorus decasulfide in pyridine (ThioTOR)), N-(benzylthio)phthalimide, a compound of formula TA-1, or a compound of formula TA-2. In other embodiments, the thiolating agent is Berzelius reagent. In further embodiments, the thiolating agent is JBR reagent. In yet other embodiments, the thiolating agent is Lawesson’s reagent. In still further embodiments, the thiolating agent is ThioTOR. In other embodiments, the thiolating agent is N-(benzylthio)phthalimide. In further embodiments, the thiolating agent is a compound of formula TA-1:124581.000010 | 25-T-072In formula TA-1, R30is Ci-ealkyl, halo, SH, NH2, aryl, OH, or Ci-eheteroalkyl. The R30group may be attached to any carbon atom of the phenyl ring. In some embodiments, R30is Ci-ealkyl, or such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, such as halo, or such as F, or such as Cl, or such as Br, or such as I. In further embodiments, R30is aryl, such as phenyl. In still other embodiments, R30is OH. In yet further embodiments, R30is Ci-eheteroalkyl such as alkyloxy, alkylthio, trifluoromethyl, C(O)NH2, C(O)N(H)(Ci-ealkyl), or C(O)N(Ci-6alkyl)(Ci-6alkyl). In other embodiments, R30is SH. In further embodiments, R30is NH2. In formula TA-1, R31is benzyl or / -butyl. In some embodiments, R31is benzyl. In other embodiments, R31is t-butyl. In further embodiments, the thiolating agent is a compound of formula TA-2:o° TA-2In formula TA-2, R40and R41are, independently, Ci-ealkyl, halo, SH, NH2, aryl, OH, or Ci-eheteroalkyl, provided that R40and R41are not the same. In some embodiments, R40is Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, R40is halo, such as F, or such as Cl, or such as Br, or such as I. In further embodiments, R40is aryl, such as phenyl. In still other embodiments, R40is OH. In yet further embodiments, R40is Ci-eheteroalkyl such as alkyloxy, alkylthio, trifluoromethyl, C(O)NH2, C(O)N(H)(Ci-ealkyl), or C(O)N(Ci-6alkyl)(Ci-6alkyl). In some embodiments, R41is Ci-ealkyl, such as methyl, or such as ethyl, or such as propyl, or such as butyl, or such as pentyl, or such as hexyl. In other embodiments, R41is halo, such as F, or such as Cl, or such as Br, or such as I. In further embodiments, R41is aryl, such as phenyl. In still other embodiments, R41is OH. In yet further embodiments, R41is Ci-eheteroalkyl such as alkyloxy, alkylthio, trifluorom ethyl, C(O)NH2, C(O)N(H)(Ci-ealkyl), or C(O)N(Ci-6alkyl)(Ci-6alkyl). For example, the thiolating agent is 4-methylbenzenesulfonicthioanhydride.124581.000010 | 25-T-072

[0078] The product of step (ii) is then converted to the sulfone. The oxidation may be performed using techniques and reagents known in the art. In some embodiments, the oxidation is performed using an oxidant. In certain embodiments, the oxidant is m-chloroperoxybenzoic acid (CPBA), oxygen, or H2O2. In some embodiments, two equivalents of the oxidant may be used.

[0079] In some embodiments, the compound of formula G is of formula VIII:°\ z°|X$~(. R6m \R5Kvni

[0080] In this structure, X6is O, S, NR7or CR7R8. In some embodiments, X6is O. In other embodiments, X6is S. In further embodiments, X6is NR7. In yet other embodiments, X6is CR7R8. R5, R6, R7, and R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R5is H. In other embodiments, R5is OC(O)R10. In further embodiments, R5is C(O)R10. In yet other embodiments, R5is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R5is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R5is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5is O-(optionally substituted benzyl). In further embodiments, R5is optionally substituted heterocycloalkyl. In yet other embodiments, R5is optionally substituted heteroaryl. In some embodiments, R6is H. In other embodiments, R6is OC(O)R10. In further embodiments, R6is C(O)R10. In yet other embodiments, R6is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted124581.000010 | 25-T-072butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R6is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R6is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R6is O-(optionally substituted benzyl). In further embodiments, R6is optionally substituted heterocycloalkyl. In yet other embodiments, R6is optionally substituted heteroaryl. In some embodiments, R7is H. In other embodiments, R7is OC(O)R10. In further embodiments, R7is C(O)R10. In yet other embodiments, R7is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R7is optionally substituted Cs-scycloalkyl. In other embodiments, R7is optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R7is O-(optionally substituted benzyl). In further embodiments, R7is optionally substituted heterocycloalkyl. In yet other embodiments, R7is optionally substituted heteroaryl. In some embodiments, R8is H. In other embodiments, R8is OC(O)R10. In further embodiments, R8is C(O)R10. In yet other embodiments, R8is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In still further embodiments, R8is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In other embodiments, R8is optionally substituted aryl. In yet other embodiments, R8is O-(optionally substituted benzyl). In further embodiments, R8is optionally substituted heterocycloalkyl. In yet other embodiments, R8is optionally substituted heteroaryl. In some embodiments, R5and R6or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In other embodiments, R5and R6are joined together with the atoms to which they124581.000010 | 25-T-072are attached to form an optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R5and R6are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In other embodiments, R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted aryl, such as optionally substituted phenyl. In yet other embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heterocycloalkyl. In still further embodiments, R6and R7are joined together with the atoms to which they are attached to form optionally substituted heteroaryl. In the structure for formula IV, m is 0 to 6, wherein each X6is independently selected for each m. In some embodiments, m is 0. In other embodiments, m is 1. In further embodiments, m is 2. In yet other embodiments, m is 3. In still further embodiments, m is 4. In other embodiments, m is 5. In further embodiments, m is 6. R10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments, R10is H. In other embodiments, R10is optionally substituted Ci-ealkyl, such as optionally substituted methyl, or such as optionally substituted ethyl, or such as optionally substituted propyl, or such as optionally substituted butyl, or such as optionally substituted pentyl, or such as optionally substituted hexyl. In further embodiments, R10is optionally substituted Cs-scycloalkyl, such as optionally substituted cyclopropyl, or such as optionally substituted cyclobutyl, or such as optionally substituted cyclopentyl, or such as optionally substituted cyclohexyl, or such as optionally substituted cycloheptyl, or such as optionally substituted cyclooctyl. In yet other124581.000010 | 25-T-072embodiments, R10is optionally substituted aryl, such as optionally substituted phenyl. In still further embodiments, R10is OC(O)R10. In other embodiments, R10is optionally substituted heterocycloalkyl. In further embodiments, R10is optionally substituted heteroaryl.

[0081] In certain embodiments, the sulfone moiety comprises32S or34S. In other embodiments, the sulfone moiety comprises32S. In further embodiments, the sulfone moiety comprises34S.

[0082] In certain embodiments, the compound of formula VIII is of formula VIII-1 or VIII-2, wherein X6, m, R5and R6are defined herein.In other embodiments, the compound of formula VIII is of formula VIII-1. In further embodiments, the compound of formula VIII is of formula VIII-2.

[0083] VII. Steroid Transformations

[0084] In certain embodiments, the oxo-containing compound of formula A is a steroid. In some embodiments, the compound of formula A is of formula AA-2:In formula AA-2, rings A, B, C, and D are, independently, unsaturated, partially unsaturated, or fully saturated. In some embodiments, ring A is unsaturated. In other embodiments ring A is unsaturated. In further embodiments, ring A is fully saturated. In some embodiments, ring B is unsaturated. In other embodiments ring B is unsaturated. In further embodiments, ring B is fully saturated. In some embodiments, ring C is unsaturated. In other embodiments ring C is unsaturated. In further embodiments, ring C is fully saturated. In some embodiments, ring D is unsaturated. In other embodiments ring D is unsaturated. In further embodiments, ring D is fully saturated. The carbon atoms at positions 1-18 are optionally substituted with one or more substituents. Examples of suitable substituents include, without limitation, alkyl, aryl, heteroalkyl. In some embodiments, the compound of formula l is a124581.000010 | 25-T-072CH, CH,

[0085] For example, the methods disclosed herein may be used to convert oxocontaining steroids to oxo, thioether, amino, sulfoxide, sulfone, or isotope analogs. See, e.g., Scheme 7.Scheme 7In some embodiments, the methods disclosed herein may be used to convert oxo-containing steroids to thioether-containing steroids. In other embodiments, the methods disclosed herein may be used to convert oxo-containing steroids to amino-containing steroids. In further embodiments, the methods disclosed herein may be used to convert oxo-containing steroids to sulfoxide-containing steroids. In still other embodiments, the methods disclosed herein may be used to convert oxo-containing steroids to sulfone-containing steroids. In yet further embodiments, the methods disclosed herein may be used to convert oxo-containing steroids to isotopically-labeled steroid analogs.124581.000010 | 25-T-072

[0086] Compounds described herein can be prepared by any suitable synthetic method. Exemplary methods are set forth in the examples.

[0087] Compounds disclosed herein may exist in one or more enantiomeric or diastereomeric forms. Thus, a reference to a particular compound includes all isomeric forms, including racemic and other mixtures thereof. Such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g., chromatography and / or recrystallisation). Isomers may be prepared using methods known in the art (e.g., asymmetric synthesis). The following examples are provided to illustrate some of the concepts described within this disclosure. While each Example is considered to provide specific individual embodiments of composition, methods of preparation and use, none of the Examples should be considered to limit the more general embodiments described herein.Aspects

[0088] Aspect 1. A compound of formula I:R21wherein:X is a radical generating moiety;Y is C or N;R1and R2are, independently, absent, H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, or optionally substituted Ci-eheteroalkyl, provided that (i) both R1or R2are not absent and (ii) R1and R2are not absent when Y is C;or R1and R2, taken together with the carbon atom to which they are attached, form an optionally substituted Cs-scycloalkyl or optionally substituted heterocycloalkyl;R3is optionally substituted Ci-ealkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted Cs-scycloalkyl, or optionally substituted heterocycloalkyl;124581.000010 | 25-T-072R20and R21are, independently, H or optionally substituted Ci-ealkyl, or, taken together with the carbon atoms to which they are attached, form an optionally substituted aryl or optionally substituted heteroaryl; andn is 1 to 3;or a salt or stereoisomer thereof.

[0089] Aspect 2. The compound of Aspect 1, wherein X is halo, N3, N2+, triflate,tosylate, SO2Cl, COOH, B(OH)2, -C(O)O-N=C(Ph)2, -I+-Ph, oror C Z^I^ J wherein, Z is -CH2-, -O-, -NR’-, or -S- and R’ is H or Ci-ealkyl.

[0090] Aspect 3. The compound of Aspect 1 or 2, wherein X is bromo or iodo.

[0091] Aspect 4. The compound of any one of the preceding Aspects, wherein R1is H.

[0092] Aspect 5. The compound of any one of Aspects 1-3, wherein R1is Ci-ealkyl, such as methyl, such as ethyl, such as propyl, such as butyl, such as pentyl, or such as hexyl.

[0093] Aspect 6. The compound of any one of Aspects 1-3, wherein R1is Ci-eheteroalkyl.

[0094] Aspect 7. The compound of any one of the preceding Aspects, wherein R2is H.

[0095] Aspect 8. The compound of any one of Aspects 1-6, wherein R2is Ci-ealkyl, such as methyl, such as ethyl, such as propyl, such as butyl, such as pentyl, or such as hexyl.

[0096] Aspect 9. The compound of any one of Aspects 1-6, wherein R2is Ci-eheteroalkyl.

[0097] Aspect 10. The compound of any one of Aspects 1-3, wherein R1and R2, taken together with the carbon atom to which they are attached, form an optionally substituted Cs-scycloalkyl.

[0098] Aspect 11. The compound of any one of Aspects 1-3, wherein R1and R2, taken together with the carbon atom to which they are attached, form an optionally substituted heterocycloalkyl.

[0099] Aspect 12. The compound of any one of the preceding Aspects, wherein R3is optionally substituted Ci-ealkyl, such as methyl, such as ethyl, such as propyl, such as butyl, such as pentyl, or such as hexyl.124581.000010 | 25-T-072

[0100] Aspect 13. The compound of any one of Aspects 1-11, wherein R3is optionally substituted aryl, such as phenyl.

[0101] Aspect 14. The compound of any one of Aspects 1-11, wherein R3is optionally substituted heteroaryl, such as pyridyl.

[0102] Aspect 15. The compound of any one of Aspects 1-11, wherein R3is optionally substituted Cs-scycloalkyl, such as cyclopropyl, such as cyclobutyl, such as cyclopentyl, or such as cyclohexyl, or such as cycloheptyl, or such as cyclooctyl.

[0103] Aspect 16. The compound of any one of Aspects 1-11, wherein R3is optionally substituted heterocycloalkyl.

[0104] Aspect 17. The compound of any one of the preceding Aspects, wherein Y is C.

[0105] Aspect 18. The compound of any one of Aspects 1-16, wherein Y is N.

[0106] Aspect 19. The compound of any one of the preceding Aspects, wherein R20and R21are independently H or optionally substituted Ci-ealkyl.

[0107] Aspect 20. The compound of any one of Aspects 1-18, wherein R20and R21are taken together with the carbon atoms to which they are attached, to form an optionally substituted aryl.

[0108] Aspect 21. The compound of any one of Aspects 1-18, wherein R20and R21are taken together with the carbon atoms to which they are attached, to form an optionally substituted heteroaryl.

[0109] Aspect 22. The compound of any one of the preceding Aspects, wherein n is 1.

[0110] Aspect 23. The compound of any one of Aspects 1-21, wherein n is 2.

[0111] Aspect 24. The compound of any one of Aspects 1-21, wherein n is 3.

[0112] Aspect 25. The compound of Aspect 1 that is of formula II:wherein, R4is H or Ci-ealkyl.124581.000010 | 25-T-072

[0113] Aspect 26. The compound of Aspect 1 that is

[0114] Aspect 27. A method of transforming an oxo moiety of an oxo-containing compound of formula A to a thioether moiety of a thioether-containing compound of formula B:comprising combining the compound of formula A with the compound of any one of the preceding Aspects for a time and under conditions sufficient to produce the compound of formula B.

[0115] Aspect 28. The method of Aspect 27, wherein the compound of formula A has the structure of formula III and the compound of formula B has the structure of formula Ill-a:wherein:X1is O, S, NR7or CR7R8;R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally124581.000010 | 25-T-072substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X1is independently selected for each m.

[0116] Aspect 29. The method of Aspect 27 or 28, wherein the thioether moiety comprises32S or34S.

[0117] Aspect 30. A method of transforming an oxo moiety of an oxo-containing compound of formula A to an ether moiety of an ether-containing compound of formula C:comprising combining the compound of formula A with the compound of any one of Aspects 1-26 for a time and under conditions sufficient to produce the compound of formula C.

[0118] Aspect 31. The method of Aspect 30, wherein the compound of formula C is of formula IV:xrmwherein:X2is O, S, NR7or CR7R8;R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally124581.000010 | 25-T-072substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X2is independently selected for each m.

[0119] Aspect 32. The method of Aspect 30 or 31, wherein the ether moiety comprises16O or18O.

[0120] Aspect 33. A method of transforming an oxo moiety of an oxo-containing compound of formula A to a secondary or tertiary amine moiety of a secondary or tertiary amine-containing-containing compound of formula D:A D comprising combining the compound of formula A with the compound of any one of Aspects 1-26 for a time and under conditions sufficient to produce the compound of formula D.

[0121] Aspect 34. The method of Aspect 33, wherein the compound of formula D is of formula V:R9wherein:X3is O, S, NR7or CR7R8;R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;124581.000010 | 25-T-072R9is H or Ci-ealkyl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X3is independently selected for each m.

[0122] Aspect 35. The method of Aspect 33 or 34, wherein the secondary or tertiary amine moiety comprises14N or15N.

[0123] Aspect 36. A method of transforming an oxo moiety of an oxo-containing compound of formula A to a13C-labeled oxo moiety of an oxo-containing compound of formula E:comprising combining the compound of formula A with the compound of any one of Aspects 1-26 for a time and under conditions sufficient to produce the compound of formula E.

[0124] Aspect 37. The method of Aspect 36, wherein the compound of formula E is of formula VI:wherein:X4is O, S, NR7or CR7R8;124581.000010 | 25-T-072R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X4is independently selected for each m.

[0125] Aspect 38. A method of transforming an oxo moiety of an oxo-containing compound of formula A to a sulfoxide moiety of a sulfoxide-containing compound of formula F:o ocomprising combining the compound of formula A with the compound of any one of Aspects 1-26 for a time and under conditions sufficient to produce the compound of formula F.

[0126] Aspect 39. The method of Aspect 38, wherein the compound of formula F is of formula VII:XR5vnwherein:X5is O, S, NR7or CR7R8;124581.000010 | 25-T-072R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X5is independently selected for each m.

[0127] Aspect 40. A method of transforming an oxo moiety of an oxo-containing compound of formula A to a sulfone moiety of a sulfone-containing compound of formula G:comprising combining the compound of formula A with the compound of any one of Aspects 1-26 for a time and under conditions sufficient to produce the compound of formula G.

[0128] Aspect 41. The method of Aspect 40, wherein the compound of formula G is of formula VIII:Ovniwherein:X6is O, S, NR7or CR7R8;R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, ©-(optionally124581.000010 | 25-T-072substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X6is independently selected for each m.

[0129] Aspect 42. The method of Aspect 27, 30, 31, 33, 34, 36, 37, 38, or 40, wherein the oxo-containing compound of formula A is a steroid.Examples

[0130] Example 1: Oxo to Thioether Conversion

[0131] Step 1: Condensation & thiolation.40 mg 4A MS 40 μL PhCF340 μL AcOH - ► 40°C for 12h NAHA ketone 1.1 equiv. 1.0 equiv.2.0 equiv. Cs2CO31stactivation124581.000010 | 25-T-072

[0132] Condensation: A mixture of ketone (0.1 mmol, 1.0 equiv.), NAHA (0.11 mmol, 44.8 mg, 1.1 equiv.) and a stir bar were added to a flame dried 4 mL vial. After the reaction vial was transferred to a nitrogen filled glovebox, 4 Å molecule sieves (40.0 mg, 2.0 equiv.), 40 μL PhCF3 and acetic acid were added to the vial. The vial was sealed, then brought out of the glovebox, and stirred on a pie block under dark at 40 °C for 12 hours.

[0133] Thiolation: The vial from the condensation step was placed under vacuum for 12 hours to totally remove the PhCF3 and acetic acid. The color of the residue changed from red to orange or yellow. The reaction vial was brought to a nitrogen filled glovebox, 1.0 mL PhCF3, Cs2CO3 (0.2 mmol, 65.0 mg, 2.0 equiv.), Bis(trimethylsilyl)acetamide (BSA. 0.1 mmol, 20.3 mg, 1.0 equiv.) and 4-methylbenzenesulfonic thioanhydride (0.3 mmol 102.6 mg, 3.0 equiv.) were added sequentially. The vial was sealed, then brought out of the glovebox, and stirred on a pie block with 1500 rpm stirring rate under dark at 50 °C for 12 hours. After the reaction finished, the residue was purified by column chromatography over silica gel or preparative TLC using hexane / ethyl acetate as eluents to afford the pure 1stactivation thiolation product.1.2 equiv. TMS3SiH 10% AIBN1.0 equiv. 4A MS PhCF3(0.025M) 100°C for 24h

[0134] Step 2: Cyclization.

[0135] The pure product afforded from step 1, TMS3SiH (1.2 equiv.), AIBN (10%), PhCF3 (0.025M) and a stir bar were added to a flame dried 4 mL vial. After the reaction vial was transferred to a nitrogen filled glovebox, 4 A molecule sieves (1.0 equiv.) was added to the reaction vial. The vial was sealed, then brought out of the glovebox, and stirred on a pie block under dark at 100 °C for 24 hours. After the reaction finished, the residue was purified by column chromatography over silica gel or preparative TLC using hexane / ethyl acetate as eluents to afford the pure 2ndactivation thiolation product.

[0136] Example 2: Oxo to Amino Conversion124581.000010 | 25-T-072NAHA* cat. H 4A MS quant.2ndactivation then, TsCI, py 53%2-2 2-3 Scheme 8

[0137] Compound 2-1 may be converted to compound 2-2 or 2-3 as described in Scheme 8.

[0138] Example 3j-z Scheme 9124581.000010 | 25-T-072

[0139] Compound 3-1 may be converted to compound 3-2 as described in Scheme

[0140] Example 4

[0141] This example was performed using the procedures of Example 1 and the starting materials of Table 1 to provide the noted compounds.Table 1Starting CyclicProduct # Product Yield Ketone3i 643j 81cr^3k 8231 OC^0CO 74^g.03m CO 60124581.000010 | 25-T-0723o r^sr jfph 76003p 680 °0Ph Ph3q 74°OX!1O3r 580s" 0s"1Cl' Cl'3s 780j — / (s3t — \ f 643r 0^0° 770 0O'x0oXX|3s 70

[0142] Example 5124581.000010 | 25-T-072

[0143] This example was performed using the procedures of Example 1 and the starting materials of Table 2 to provide the noted compounds.Table 2ProductCompound Starting Cyclic Ketone Product Yield #3a 6JL Ju J i JLHX / - 0Cholesterol to—.. '''(S IH —.'1— V / 4l) Ti—l - 3b H / \1X 46JL 1HJH1O®, / \ SarsasapogeninO03c IJJCLL / JL JIJ A J A ■ JLH 49O ^z* / A**sw / zZ* Epiandrosterone00i JL3dHL / 5JL JL -” J ” i JLHJL / 6'Progesterone124581.000010 | 25-T-0720rM°fHTy / r0HvAJL j7o3eA y i f Xy 45 qKTCholic acid1I JL z '3f 59JC jT J A XHXL / 'ifMifepristoneO HO U. OH 0 HOS^ZXJJK ^ HO \\ OH! XHJL / "3g I XH£ >- 51 f X F J HS X^x^BetamethasoneO3h 56 Lithocholic acid-fructosecomplex

[0144] Example 6

[0145] A. General information

[0146] All commercially available reagents were purchased from Alfa Aesar, Ambeed, Ark Pharm Inc., Combi-Blocks, Fisher Scientific, Oakwood Chemicals, Sigma-Aldrich, TCI America, Ambeed, or Chemscene, and were used as received. Tetrahydrofuran (THF) was distilled freshly over sodium, Trifluorotoluene (PhCF3) was distilled freshly over activated 4Å molecular sieve, acetonitrile (MeCN) was distilled freshly over CaH2. (n-Bu)3SnH was purified by distillation to remove residual BHT. Activated 4A molecular sieve was prepared as described in Zhang, Methyl Ketones as Alkyl Halide Surrogates: A124581.000010 | 25-T-072Deacylative Halogenation Approach for Strategic Functional Group Conversions. J. Am.Chem. Soc. 145, 21096-21103 (2023).. Reactions were monitored by thin-layer chromatography (TLC) carried out on 250 pm EMD silica gel plates (silica gel 60, F254) containing a fluorescent indicator (254 nm). Visualization of the developed TLC plate was performed by irradiation with UV light. Flash column chromatography was performed using Macherey -Nagel Silica 60 M silica gel (60 A pore size, 40 - 63 pm particle size) or a preequipped silica gel column from Biotage.1H NMR spectra were recorded on a Bruker 400 (400 MHz), 500 (500 MHz) or 600 (600 MHz) and are referenced relative to residual CHCI3 (in CDCI3) proton signals at 57.26 ppm. Data for 'H spectra are reported as follows: chemical shift (8 ppm), multiplicity (s =singlet, d = doublet, t = triplet, q = quartet, p = quintet, h = hextet, m = multiplet, br = broad), integration, coupling constant (Hz) and assignment.13C NMR spectra were recorded on a Bruker 400 (101 MHz), 500 (125 MHz) or 600 (151 MHz) and are referenced relative to residual CHCI3 (in CDCI3) at δ 77.16 ppm.Data for13C NMR spectra are reported in terms of chemical shift and multiplicity where appropriate.19F NMR spectra were recorded on a Bruker 500 (471 MHz). Data for19F NMR spectra are reported as chemical shifts and multiplicities, where appropriate. IR spectra were recorded on a Nicolet iS5 FT-IR Spectrometer. Samples were scanned as neat liquids or dissolved in DCM on potassium bromide (KBr) salt plates. High-resolution mass spectra were recorded on an Agilent 6530 TOF LC / MS (Electrospray Ionization ESI or Atmospheric Pressure Chemical Ionization APCI), Agilent 7200B QTOF High Resolution Accurate Mass GC / MS (Electron Impact El) and processed with an Agilent Mass Hunter Operating System.

[0147] B. Synthesis of NAHA-G22.5 equiv. LIHMDS 1.2 equiv. LiAIH41.0 equiv. PBr31.1 equiv. NaCN 2.5 equiv.THF DCM DMSO0 °C for 2 h 0 °C for 0.5 h 100 °C for 0.5 h THF -78 °C to r.t. no purification no purification needs 1.1 equiv. N2H3Boc 2.5 equiv. NaBH3CN toluene: AcOH 5:1 ACOH: H2O 3:1 100 °C for 1 h no purification no purification needs HCI gas 1.1 equiv. Cs2CO31,4-dioxane H2O r.t. for 24 h r.t. for 5 minNAHA-G2Scheme 10: Synthetic procedure of NAHA-G2124581.000010 | 25-T-072

[0148] Synthesis of compound n-2-Br

[0149] An oven dried 1000 mL reaction flask was charged with methyl 2-bromo-6-methylbenzoate (91.6 g, 400.0 mmol), anhydrous THF (500 mL), and a stir bar. The reaction mixture was cooled to 0 °C, and LiAlH4 (14.8 g, 400.0 mmol) was added portion-wise. After stirring at 0 °C for 1 hour, the reaction was gradually warmed to room temperature, then transferred to a water bath at room temperature and stirred overnight. Upon confirmation of reaction completion by TLC, the mixture was filtered through a Celite pad, and the filtrate was quenched by the addition of Na2SO4·10H2O (~20 g). The resulting mixture was stirred for an additional 30 minutes and filtered through a Celite pad. The filtrate was then concentrated under reduced pressure, and the obtained solid was recrystallized from hexane, yielding 61.5 g of crude (2-bromo-6-methylphenyl)methanol as a crystalline white solid, which was used in the next step without further purification.

[0150] An oven dried 500 mL reaction flask was charged with the crude (2-bromo-6-methylphenyl)methanol obtained from the above reaction, a stir bar and DCM (250 mL). After cooling the reaction mixture to 0 °C, PBr3 (25 mL) was added to the reaction mixture dropwise. The reaction was warmed to room temperature and stirred for another 1 hour. After the reaction was finished, the reaction mixture was poured into ice and extracted with DCM (3 x 100 mL). The combined organic extracts were washed with water (2 × 100 mL) and brine, dried over Na2SO4, and filtered through a silica gel pad. The filtrate was concentrated under reduced pressure to yield 78.7 g of crude l-bromo-2-(bromomethyl)-3 -methylbenzene as a pale-yellow solid, which was used in the subsequent step without further purification.

[0151] A 500 mL reaction flask was charged with the crude l-bromo-2-(bromomethyl)-3 -methylbenzene obtained from the above reaction, DMSO (200 mL), and a stir bar. Then NaCN (15.3 g, 312.9 mmol, 1.05 equiv.) was added in portions. The reaction flask was fitted with an air condenser and stirred at 80 °C for 1 hour. Upon completion, as indicated by TLC, the reaction was quenched with water (200 mL). The reaction mixture was extracted with DCM (3 x 200 mL), and the combined organic layers were washed with water (2 x 100 mL) and brine until no DMSO remained. The organic phase was dried over Na2SO4, filtered through a silica gel pad, and concentrated under reduced pressure to yield 54.3 g of 2-(2-bromo-6-methylphenyl)acetonitrile as a white solid, which was used in the next step without further purification.124581.000010 | 25-T-072

[0152] An oven-dried 500 mL reaction flask was charged with HMDS (bis(trimethylsilyl)amine, 135.4 mL, 104.4 g, 646.2 mmol, 2.5 equiv.), THF (200 mL) and a stir bar. The reaction flask was cooled to -78 °C, and n-BuLi (2.5 M in hexane, 258.5 mL, 646.2 mmol, 2.5 equiv.) was added slowly. Upon completion of the addition, the reaction was stirred at -78 °C for an additional 30 minutes, then warmed to 0 °C. In a separate oven-dried 1000 mL reaction flask, the crude 2-(2-bromo-6-methylphenyl)acetonitrile obtained from the above reaction was combined with THF (300 mL) and a stir bar, and the mixture was cooled to -78 °C. The LiHMDS solution from the first flask was then added via cannula. During the addition, the reaction mixture color changed from bright yellow to dark red. Afterward, Mel (40.4 mL, 91.7 g, 646.2 mmol, 2.5 equiv.) was added, and the reaction was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched with saturated NH4Cl solution (100 mL), followed by the addition of water (300 mL). The reaction mixture was extracted with DCM (1 x 300 mL, then 2 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (2 x 50 mL), dried over Na2SO4, and filtered through a silica gel pad. The filtrate was concentrated under reduced pressure to yield 49.3 g 2-(2-bromo-6-methylphenyl)-2 -methylpropanenitrile as a pale-yellow oil, which was used in the next step without further purification. The crude product may contain residual HMDS if it is not dried properly. Column chromatography may be necessary if excessive HMDS remains or if the crude product exhibits a red coloration.

[0153] An oven-dried 500 mL reaction flask was charged with crude 2-(2-iodo-6-methylphenyl)-2 -methylpropanenitrile, DCM (300 mL), and an aqua regia-washed stir bar. The reaction flask was cooled to -78 °C, and a toluene solution of DIBAL-H (25% w / w, ~1.4 M, 170 g, 1.2 equiv.) was added quickly. The reaction mixture was maintained at -78 °C for 1 hour, after which ethyl acetate (50 mL) was added dropwise. The reaction mixture was then poured into 300 mL of a saturated potassium sodium tartrate solution and stirred at room temperature overnight. Once the cloudy aluminum complex had fully dissolved, the organic layer was separated, and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (2 x 50 mL), dried over Na2SO4, and filtered through filter paper. The filtrate was concentrated under reduced pressure to yield a mixture of 2-(2-bromo-6-methylphenyl)-2-methylpropanal and 2-(2-bromo-6-methylphenyl)-2-methylpropan-l -imine as a yellow to orange oil, which was used in the next step without further purification. The crude product typically contains a small124581.000010 | 25-T-072amount of toluene, which does not need to be removed. The presence of toluene does not affect the subsequent reaction.

[0154] An oven-dried 250 mL reaction flask was charged with the crude mixture of 2-(2-bromo-6-methylphenyl)-2-methylpropanal and 2-(2-bromo-6-methylphenyl)-2-methylpropan-1 -imine, toluene (100 mL), tert-butyl hydrazinecarboxylate (200 mmol, 26.4 g, ~1.2 equiv.), AcOH (20 mL) and an aqua regia-washed stir bar. The flask was equipped with a condenser, and the reaction was stirred at 80 °C for 12 hours. Upon completion, the reaction was quenched with water (100 mL). The reaction mixture was then extracted with DCM (1 x 300 mL, then 2 x 100 mL), and the combined organic layers were washed with water (2 x 100 mL) and brine (2 x 50 mL), dried over Na2SO4, and filtered through a silica gel pad. The filtrate was concentrated under reduced pressure to yield tert-butyl (2-(2-bromo-6-methylphenyl)-2-methylpropylidene)hydrazine-l -carboxylate as a pale-yellow solid.

[0155] An oven-dried 500 mL reaction flask was charged with tert-butyl (2-(2-bromo-6-methylphenyl)-2-methylpropylidene)hydrazine-l-carboxylate (50.3 g), a solvent mixture of AcOH and H2O (3:1, 200 mL), and an aqua regia-washed stir bar. After the solid was entirely suspended in the solution, NaBH3CN (30.8 g, 490.8 mmol, 2.5 equiv.) was added portion-wise. The reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, DCM (200 mL) was added, and the mixture was stirred for an additional 30 minutes. The organic layer was separated, and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (5 x 200 mL), dried over Na2SO4, and filtered through filter paper. The filtrate was concentrated under reduced pressure to yield tert-butyl 2-(2-(2-bromo-6-methylphenyl)-2-methylpropyl)hydrazine-l -carboxylate, which was used in the next step without further purification.

[0156] The flask containing tert-butyl 2-(2-(2-bromo-6-methylphenyl)-2-methylpropyl)hydrazine-l -carboxylate from the above reaction was charged with 1,4-dioxane (150 mL) and an aqua regia-washed stir bar. Dry HC1 gas was purged into the reaction flask with vigorous stirring. After 2 hours, the HC1 gas flow was stopped, and stirring was continued for 12 hours. A pale-yellow to off-white solid precipitated during the stirring. Once no additional solid formation was observed, the reaction mixture was concentrated under reduced pressure. Diethyl ether (500 mL) was then added, and the mixture was stirred vigorously. The reaction mixture was filtered, and the solid was collected to obtain 47.9 g (2-124581.000010 | 25-T-072(2-bromo-6-methylphenyl)-2-methylpropyl)hydrazine hydrochloride salt (H NMR analysis indicating that (2-(2-bromo-6-methylphenyl)-2-methylpropyl)hydrazine contains 5 molecules of HC1 when forming the salt. It has a molecular weight of - 440 g / mol).n-2-Br(2-(2-bromo-6-methylphenyl)-2-methylpropyl)hydrazine hydrogen chloride salt (n-2-Br)

[0157] XH NMR (600 MHz, Methanol-d4) 67.56 (dd, J= 7.9, 1.6 Hz, 1H), 7.17 -7.13 (m, 1H), 6.98 (t, J= 7.7 Hz, 1H), 3.68 (s, 2H), 2.65 (s, 3H), 1.77 (s, 6H).13C NMR (151 MHz, MeOD) 8 142.17, 140.55, 134.93, 133.44, 127.42, 123.75, 59.87, 42.16, 29.39, 25.84.N1.1 equiv. Cs2CO3N - — - >■ Br0r.t. for 5 minNAHA-G2

[0158] Synthesis of NAHA-G2

[0159] The synthesis was conducted on a 10 mmol scale. A flame-dried, clean 40 mL vial was charged with methyl picolinimidate (1.36 g, 10.0 mmol, 1.0 equiv.), Cs2CO3(3.57 g, 11.0 mmol, 1.1 equiv.), 30 mL deionized (DI) water, and an aqua regia-washed stir bar. The reaction mixture was stirred at room temperature until all solids were dissolved. Subsequently, (2-(2-bromo-6-methylphenyl)-2-methylpropyl)hydrazine hydrochloride salt (4.4 g, ~10 mmol, ~1.0 equiv.) was added to the vial with vigorous stirring. After 5 minutes, the reaction mixture was extracted with DCM (1 x 50 mL, followed by 2 x 20 mL). The combined organic layers were washed with water (2 x 50 mL) and brine (2 x 20 mL), dried over Na2SO4, and filtered through filter paper. The solvent was removed under reduced pressure, and the residue was purified by column chromatography over silica gel to give NAHA-G2 as a pale yellow, viscous oil (3.2 g, 88% yield).N'-(2-(2-bromo-6-methylphenyl)-2-methylpropyl)picolinohydrazonamide (NAHA-G2)124581.000010 | 25-T-072

[0160] NMR: 1H NMR (500 MHz, Chloroform-d) 68.47 (ddd, J= 4.9, 1.8, 1.0 Hz, 1H), 7.95 (dt, J= 8.1, 1.1 Hz, 1H), 7.64 (ddd, J= 8.0, 7.4, 1.7 Hz, 1H), 7.53 (dd, J= 7.9, 1.7 Hz, 1H), 7.21 (ddd, J= 7.5, 4.9, 1.2 Hz, 1H), 7.05 - 7.02 (m, 1H), 6.88 (t, J= 7.7 Hz, 1H), 5.01 (s, 2H), 4.16 -4.06 (m, 1H), 3.91 (s, 2H), 2.60 (s, 3H), 1.78 (s, 6H).13C NMR (126 MHz, CDCl3) 6 151.03, 148.71, 147.79, 143.58, 140.65, 136.09, 134.92, 133.13, 126.81, 124.39, 123.29, 119.76, 61.44, 44.05, 30.74, 26.99. HRMS: HRMS-ESI& APCI mix mode calcd for C17H22BrN4+ [M+H] 361.1022, found 361.1042. IR: (KBr cm’1): 3437.97, 3337.10, 2964.56, 1688.06, 1632.57, 1587.79, 1563.87, 1472.65, 1433.50, 1379.03, 1145.59, 1123.89, 1090.17, 1057.85, 994.93, 877.06, 813.19, 789.78, 770.18, 744.77, 703.18, 683.90, 669.24, 655.08, 622.55. Rf: 0.43 (Hexane: EA = 2: 1)

[0161] C. Results

[0162] (i) NAHA condensation

[0163] Results for the condensation step using lag and NAHA-G2 as substrates are summarized in Table 3. Owing to the relatively high stability of the NAHA-G2 reagent, the condensation proceeds under mild conditions and affords an almost quantitative yield (entry 1).Table 3. Optimization of the condensation between NAHA-G2 and ketone lai*\ _( \ || 1-AdCO2H Xmol% ' \Z ■ | H T ). CH 1 > \ 20mg 4A MSz\ f J1 1 5 1 / X _ H 1 - ► N'T 1 QHT J QH / NH240 uL PhCF3NJ I H H ' || q = '4— NHO T C forY h f1alNAHA-G2 r=\ PAI-1 al GNEntry Equiv. of NAHA- X T (°C) Y (h) Yield 021 1.0 10 50 °C 12 h 98% 2 1.5 20 50 °C 12 h 96% 3 1.0 50 50 °C 12 h 96% 4 1.0 10 40 °C 12 h 87% 5 1.0 10 60 °C 12 h 93%124581.000010 | 25-T-0726 1.0 10 70 °C 12 h 94% 7 1.0 10 50 °C 1 h 58% 8 1.0 10 50 °C 6 h 89% 9 1.0 10 50 °C 24 h 98% *Unless mentioned otherwise, all reactions were run with lai (0.1 mmol). The yield was determined by 1H NMR using 1,1,2,2-tetrachloroethane as the internal standard. 1-adCO2H: 1-adamantanecarboxylic acid.

[0164] (ii) Radical nitrogenation reaction at 1st C-C bond activation

[0165] Results for the radical nitrogenation, including radical substitution on azo group, imine group and azide group, are summarized.

[0166] (a) The results for the radical substitution on the azo species are summarized in Table 4. Both the base (Cs2CO3) and the additive [BSA (bis(trimethylsilyl)acetamide)] were found to be important for this transformation (entries 8 and 9). Under the conditions, the reaction reached 90% yield when 2.0 equivalents of the azo reagent, 2.0 equivalents of Cs2CO3, and 1.0 equivalent of BSA were stirred with PAI-la in PhCFs at 60 °C for 12 hours (entry 2). The yield decreased to 57% when 1.0 equivalent of the azo reagent was used (entry 1). On the other hand, increasing the loading of the azo reagent to 3.0 equivalents did not further improve the yield (entry 3). The reaction was also found to be sensitive to temperature, as elevated temperatures decreased the yield (entries 6 and 7). Furthermore, azo reagents bearing different aryl groups were also evaluated. In general, aryl groups with electron-withdrawing substituents could facilitate radical addition during both the first and second activation steps. Azo reagents containing 4-CFs phenyl, 3,5-bis(CF3) phenyl, and quinoline moieties were tested. However, these substrates led to low yield (entries 10, 11, and 13).Table 4. Radical substitution on the azo group*124581.000010 | 25-T-072TNM. \ > CBr / ' Ar W:- Additive JAKN-K'TSBASE» N-\[ | Br PhCF3X mL / s^t / L'" N ' — v' T °C for 12 h f| 1 \ —.1* x, NN=N pAMa Azofsfsc& Vsfei? 2a-Ar ArEntry Ar Azo Additive Base X ml, T °C Yield (equiv.)1 1.0 BSA 1.0 Cs2CO32.0 0.5 60 °C 57% equiv. equiv.2 2.0 BSA 1.0 Cs2CO32.0 0.5 60 °C 90% equiv. equiv.3 3.0 BSA 1.0 Cs2CO32.0 0.5 60 °C 91% equiv. equiv.4 2.0 BSA 1.0 Cs2CO32.0 1.0 60 °C 89% equiv. equiv.5 2.0 BSA 1.0 Cs2CO32.0 0.5 40 °C 87% equiv. equiv.6 2.0 BSA 1.0 Cs2CO32.0 0.5 80 °C 74% equiv. equiv.7 2.0 BSA 1.0 Cs2CO32.0 0.5 100 °C 60% equiv. equiv.8 2.0 None Cs2CO32.0 0.5 60 °C 85% equiv.9 2.0 BSA 1.0 None 0.5 60 °C 34% equiv.124581.000010 | 25-T-07210 2.0 BSA 1.0 Cs2CO32.0 0.5 60 °C 21% FSC^IOL, equiv. equiv.11 CF32.0 BSA 1.0 Cs2CO32.0 0.5 60 °C <10% equiv. equiv.12 2.0 BSA 1.0 Cs2CO32.0 0.5 60 °C 88% equiv. equiv.13 2.0 BSA 1.0 Cs2CO32.0 0.5 60 °C 34% equiv. equiv.14 2.0 BSA 1.0 Cs2CO32.0 0.5 60 °C 81% equiv. equiv.15 2.0 BSA 1.0 Cs2CO32.0 0.5 60 °C 73% equiv. equiv.16 2.0 BSA 1.0 Cs2CO32.0 0.5 60 °C 75% equiv. equiv.17 2.0 BSA 1.0 Cs2CO32.0 0.5 60 °C <10%0XX equiv. equiv.18 2.0 BSA 1.0 Cs2CO32.0 0.5 60 °C 74% equiv. equiv.*Unless mentioned otherwise, all reactions were run with PAI-la (0.05 mmol). The yield was determined by 1H NMR using 1,1,2,2-tetrachloroethane as the internal standard. BSA, bis(trimethylsilyl)acetamide.124581.000010 | 25-T-0722-(l-(2-(2-bromo-6-methylphenyl)-2-methylpropyl)-5-(5-(phenyldiazenyl)pentyl)-lH-l,2,4- triazol-3-yl)pyridine (2a)

[0167] NMR: 1H NMR (500 MHz, Chloroform-d) 68.74 (dt, J= 4.7, 1.4 Hz, 1H), 8.07 (dd, J= 7.9, 1.1 Hz, 1H), 7.77 - 7.73 (m, 1H), 7.70 - 7.67 (m, 2H), 7.57 - 7.51 (m, 1H), 7.50 - 7.43 (m, 3H), 7.30 - 7.28 (m, 2H), 7.16 - 7.13 (m, 1H), 7.00 - 6.96 (m, 1H), 6.89 (t, J= 7.7 Hz, 1H), 4.82 (s, 2H), 4.04 (t, J= 7.1 Hz, 2H), 2.38 -2.33 (m, 2H), 2.17 (s, 3H), 1.92 -1.83 (m, 8H), 1.68 - 1.62 (m, 2H), 1.40 (qd, J= 9.5, 8.7, 6.5 Hz, 3H).13C NMR (126 MHz, CDCl3) 6 160.14, 158.21, 152.13, 150.15, 149.94, 141.87, 141.27, 136.54, 135.06, 133.57, 130.38, 129.00, 127.71, 124.92, 123.45, 122.15, 121.40, 69.34, 56.52, 44.67, 31.08, 27.52, 27.51, 27.27, 26.87, 25.61.

[0168] (b) Control experiment:

[0169] The iodide analogue of PAI-la-I also was evaluated in the first activation step. Under the standard conditions, no desired ring-opened product was detected. Spectral analysis revealed a complex mixture, showing that the iodine substituent on the PAI was removed.

[0170] (c) Additional attempts were made using alternative nitrogen-based radical acceptors. Representative examples are summarized below.124581.000010 | 25-T-072BSA (1.0 ec|uiv.) Cs2CO3(2.0 equiv.) PhCF30.5 mL 60 °C for 12 h PAI-1 a “N” 2.0 equiv. 1stscfrVsffeflBSA (1.0 e^uiv.) Cs2CO3(2.0 equiv.) PhCF30.5 mL 60 °C for 12 h PAI -1a “N” 2.0 equiv. 1stacfwaftorsBSA (1.0 e^uiv.) Cs2CO3(2.0 equiv.) PhCF30.5 mL 60 °C for 12 h 1stsctivfiliap.BSA (1.0 e^uiv.) Cs2CO3(2.0 equiv.) PhCF30.5 mL 60 °C for 12 h PAI-1 a “N” 2.0 equiv. 1stSGtivstim124581.000010 | 25-T-072PAI-1a “N” 2.0 equiv.Scheme 11. Additional attempts with other radical nitrogenation reagents

[0171] Unless mentioned otherwise in Scheme 11, all reactions were run with PAI-la (0.05 mmol). The yield was determined by 'H NMR using 1,1,2,2-tetrachloroethane as the internal standard.

[0172] (d) Radical azidation was also explored. Unfortunately, the reaction between PAI and the azide required excess of the azide reagent under neat conditions to achieve an acceptable yield. For example, the azidation afforded the desired azide product 2a-N in 41% yield when 10 equivalents of TsNs were used under neat conditions (entry 4). Dilution of the reaction mixture led to substantial decrease in yield (entries 1-3). Several substituted sulfonyl azide reagents were then also evaluated. The results are summarized in Table 5. The highest yield, up to 85%, was achieved using 2,6-difluorophenyl sulfonyl azide (entry 5).

[0173] In addition, more reactive azidation reagents, such as azide-substituted hypervalent iodides (entries 21-25), were also tested. However, they generally resulted in124581.000010 | 25-T-072(equiv.)1 2.0 none PhCF360 °C trace 0.5 mL2 5.0 none PhCF360 °C 14%0.5 mL3 10.0 none PhCF360 °C 26%0.5 mL4 10.0 none neat 60 °C 41%5 10.0 none neat 60 °C 85%c^c,FF6CIX[Z^^CI10.0 none neat 60 °C 62%Cl7 F^ F 10.0 none neat 60 °C 39%F8 F 10.0 none neat 60 °C 21%Fv^ / k / FF9 0 10.0 none neat 60 °C 45%XoAtX10 10.0 none neat 60 °C 30% °2N'S|^^^124581.000010 | 25-T-07211 10.0 none neat 60 °C 50%12 10.0 none neat 60 °C trace13 3.0 none PhCF360 °C n.d F^F(3 ml)14 10.0 none neat 60 °C 45%15 H 10.0 none 0.5 mL 60 °C 32% o XX t-AmOH16 1 10.0 none neat 60 °C n.d17 10.0 none neat 60 °C n.d H^H18 CF310.0 none neat 60 °C 20%F3CX^x^b>19 / -Pr 10.0 none neat 60 °C 24%^Pr'z^^''^-Pr20 10.0 none neat 60 °C traceChange to hypervalent iodides124581.000010 | 25-T-07221 N31.0 none PhCF360 °C 10% 0.5 mLOQ022 N31.0 TsCl PhCF360 °C trace 1.0 equiv 0.5 mLOQ023 N32.0 none PhCF360 °C 11% 0.5 mLOQ024 N31.0 none PhCF360 °C 13% 0.5 mLQ 1 Q 025 N31.0 TsCl PhCF360 °C 17%1.0 equiv 0.5 mLQ 1 Q 0*Unless mentioned otherwise, all reactions were run with PAI-la (0.05 mmol). The yield was determined by 'HNMR with 1,1,2,2-tetrachloroethane as the internal standard. Ts, tosyl.

[0174] (iii) Radical cyclization during the 2nd C-C bond activation124581.000010 | 25-T-072Entry MH / mol% Initiator / mol% Solvent T Yield 1 (TMS)3SiH 140 AIBN 20 PhCF3(0.025M) 100 °C 17% 2 (TMS)3SiH 140 AIBN 20 PhCF3(0.0125M) 100 °C 11% 3 (TMS)3SiH 140 AIBN 20 PhCF3(0.0083M) 100 °C 5% 4 (TMS)3SiH 120 AIBN 10 PhCF3(0.025M) 100 °C 13% 5 (TMS)3SiH 160 AIBN 10 PhCF3(0.025M) 100 °C 7% 6 (TMS)3SiH 160 AIBN 30 MeCN (0.025M) 100 °C 10% 7 (TMS)3SiH 160 AIBN 30 Benzene 100 °C 8%(0.025M)8 (TMS)3SiH 160 AIBN 30 Heptane (0.025M) 100 °C trace 9 («-Bu)3SnH 120 AIBN 10 MeCN (0.025M) 100 °C 37% 10 («-Bu)3SnH 140 AIBN 20 MeCN (0.025M) 100 °C 40% 11 («-Bu)3SnH 160 AIBN 30 MeCN (0.025M) 100 °C 65% 12 («-Bu)3SnH 220 AIBN 60 MeCN (0.025M) 100 °C 31% 13 («-Bu)3SnH 280 AIBN 90 MeCN (0.025M) 100 °C 28% 14 («-Bu)3SnH 160 AIBN 30 Acetone (0.025M) 100 °C 57% 15 («-Bu)3SnH 160 AIBN 30 Benzene 100 °C 68%(0.025M)16 («-Bu)3SnH 160 AIBN 30 PhCF3(0.025M) 100 °C 47% 17 («-Bu)3SnH 160 AIBN 30 / -BuCN (0.025M) 100 °C messy 18 («-Bu)3SnH 160 AIBN 30 Heptane (0.025M) 100 °C messy 19 («-Bu)3SnH 160 BEt330 Benzene 65 °C n.d.(0.025M)With O220 («-Bu)3SnH 160 BEt330 Benzene 25 °C n.d.(0.025M)With O2124581.000010 | 25-T-07221 EtsSiH 160 AIBN 30 MeCN (0.025M) 100 °C n.d. 22 (z-Pr)3SiH AIBN 30 MeCN (0.025M) 100 °C n.d. 23 EtsSiH 160 BPO 30 MeCN (0.025M) 100 °C n.d. 24 («-Bu)3SnH 160 AIBN 30 MeCN (0.025M) 60 °C 29% 25 («-Bu)3SnH 160 AIBN 30 MeCN (0.025M) 25 °C 17% 26 («-Bu)3SnH 160 AIBN 30 MeCN (0.05M) 100 °C 52% 27 («-Bu)3SnH 160 AIBN 30 MeCN (0. IM) 100 °C 21% *Unless mentioned otherwise, all reactions were run with 2a (0.025 mmol). The yield was determined by 'H NMR with 1,1,2,2-tetrachloroethane as the internal standard. BPO, benzoyl peroxide.N-phenylpiperidin-1-amine (3a)

[0176] NMR:1H NMR (500 MHz, Chloroform^ / ) 67.26 - 7.19 (m, 2H), 6.96 -6.89 (m, 2H), 6.80 (tt, J= 7.3, 1.2 Hz, 1H), 4.38 (s, 1H), 2.68 (s, 4H), 1.72 (p, J= 5.7 Hz, 4H), 1.46 (p, J= 5.9 Hz, 2H).13C NMR (126 MHz, CDCl3) 6 147.80, 129.11, 119.14, 113.56, 57.40, 26.07, 23.73.

[0177] (iii-2) Radical cyclization of the azide intermediate124581.000010 | 25-T-0722 (TMS)3SiH 120 AIBN 10 PhCF3(0.025M) 100 °C 10% 3 (TMS)3SiH 120 AIBN 10 PhCF3(0.0083M) 100 °C 21% 4 (TMS)3SiH 120 AIBN 10 PhCF3(0.0042M) 100 °C 15%* 5 (TMS)3SiH 120 AIBN 10 PhCF3(0.0012M) 100 °C hard to detect 6 («-Bu)3SnH 120 AIBN 10 PhCF3(0.025M) 100 °C 7%7 («-Bu)3SnH 160 AIBN 30 PhCF3(0.025M) 100 °C 8%*Unless mentioned otherwise, all reactions were run with 2a-N (0.025 mmol).r"he yield was determined by 'H NMR using 1,1,2,2-tetrachloroethane as the internal standan 1. *The yield of this reaction was determined by GC-MS.Table 8. Radical cyclization with azide substrate 2e-N*O \i_2<. IniMtiaHtorRi^iiNA-N \ / V -+Nr ' ' Solvent / j +} T °C for 24 h A Sr 'S ^activation R = (TMS)3Si or H2e-N 3e-NEntry MH / mol% Initiator / mol% Solvent T Yield 1 (TMS)3SiH 120 AIBN 10 PhF (0.025M) 100 °C 80% 2 (TMS)3SiH 120 AIBN 10 PhH (0.025M) 100 °C 75% 3 (TMS)3SiH 120 AIBN 10 PhCF3(0.025M) 100 °C 79% 4 (TMS)3SiH 120 AIBN 10 PhCF3(0.016M) 100 °C 83%5 (TMS)3SiH 120 AIBN 10 PhCF3(0.012M) 100 °C 89%*Unless mentioned otherwise, all reactions were run with 2e-N (0.025 mmol). The yield was determined by 'H NMR using 1,1,2,2-tetrachloroethane as the internal standard.124581.000010 | 25-T-072

[0178] Azides performed poorly in the NAHA system for the six-membered-ring formation. In contrast to the five-membered ring closure, the six-membered variant gave low yields unless conducted under highly dilute conditions to suppress intermolecular HAT. Thus, to maximize ring-size tolerance and to achieve better overall efficiency, the azo-based (instead of azide-based) approach was chosen for developing the CO-to-N atom swap transformation.

[0179] D. Reagents and substrates

[0180] (i) Starting material preparation

[0181] Unless otherwise noted, commercially available reagents lb, Ir, Iv, Iw, laa, lag and laj were used without further purification. Substrates 1c, Id, le, If, 1g, Ih, Ij, Ik, 11, Im, Ip, Iq, Is, lu, ly, Iz, lah, lai, lak, lai, lam, lan, lao, lap and Ib-D were synthesized according to the known procedures and their spectroscopic data matched with the124581.000010 | 25-T-072

[0182] Synthesis of 4-oxocyclohexyl 2,2-diphenylacetate (li)EDCI (1.5 equiv.) 4-DMAP (1.5 equiv.) NEt3-3> DCM25 °C for 12 h

[0183] A 100 mL round bottle flask was charged with 2,2-diphenylacetic acid (2.1 g, 10 mmol, 1.0 equiv.), EDCI (2.9 g, 15 mmol, 1.5 equiv.), 4-DMAP (1.8 g, 15 mmol, 1.5 equiv.) and a stir bar. DCM (50 mL) and triethylamine (2 mL) were then added, followed by 4-hydroxycyclohexan-l-one (1.14 g, 10 mmol, 1.0 equiv.). The mixture was stirred at room temperature overnight. After the reaction was complete, 30 mL of water was added to the reaction mixture, which was then extracted with DCM (2 x 100 mL). The combined organic layer was washed sequentially with 0.5 M HC1 (50 mL) and saturated aqueous NaHCCh (100 mL). The separated organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford li as a white solid (2.3 g, 75%). NMR: 1H NMR (500 MHz, Chloroform-d) 87.38 - 7.33 (m, 8H), 7.30 (ddt, J= 7.1, 3.7, 2.1 Hz, 2H), 5.27 (dt, J= 5.8, 2.8 Hz, 1H), 5.09 (s, 1H), 2.37 (ddd, J = 15.7, 10.2, 5.9 Hz, 2H), 2.32 -2.24 (m, 2H), 2.18 - 2.08 (m, 2H), 2.08 - 1.98 (m, 2H).13C NMR (126 MHz, CDCl3) 6209.72, 171.75, 138.46, 128.69, 128.54, 127.43, 69.12, 57.37,124581.000010 | 25-T-07236.96, 30.22. HRMS: HRMS-ESI& APCI mix mode calcd for C15H21O3+[M+H] 249.1485, found 249.1482. IR: (KBr cm-1): 2957.52, 1720.61, 1599.60, 1495.71, 1452.97, 1308.42, 1232.04, 1188.44, 1151.36, 1085.42, 1022.92, 972.53, 743.35, 700.53. Rf: 0.16 (Hexane:EA = 5: 1)

[0184] Synthesis of ethyl 4-(2-(4-oxocyclohexyl)ethoxy)benzoate (In)

[0185] A 250 mL round bottom flask was charged with 2 -(1,4-dioxaspiro[4.5]decan-8-yl)ethan-l-ol (2.0 g, 11 mmol, 1.0 equiv. synthesized as described in Itagaki, Organocatalytic Entry to Chiral Bicyclo[3.n.l]alkanones via Direct Asymmetric Intramolecular Aldolization. Org. Lett. 7, 4185-4188 (2005)., ethyl 4-hydroxybenzoate (2.3 g, 14 mmol, 1.3 equiv.), triphenylphosphine (3.1 g, 12 mmol, 1.1 equiv.), THF (10 mL) and a stir bar. After cooling the reaction mixture to 0°C, diethyl azodi carb oxy late (DEAD, 14 mmol, 6 mL, 40 wt% in toluene, 1.3 equiv.) was added slowly to avoid rapid temperature increases in the reaction system. The reaction mixture was warmed to room temperature and stirred overnight. After the reaction was complete, it was quenched with water and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with water, brine, dried over MgSO4, concentrated under reduced pressure, and the residue was purified by a short silica gel pad to afford crude ethyl 4-(2-(l,4-dioxaspiro[4.5]decan-8-yl)ethoxy)benzoate. The crude residue was transferred into a 20 mL reaction vial, which was then added 2M HC1 (5 mL), THF (10 mL) and a stir bar. The vial was sealed and the reaction was heated to 80 °C for 4 h. After TLC indicated all the ketal had been consumed, the reaction was extracted with DCM (50 mL x 3) and the combined organic layer was washed with saturated aqueous NaHCCh, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, which afforded In as a colorless oil (0.73 g, 23%). NMR: *HNMR (600 MHz, Chloroform-t / ) 6 7.99 (d, J= 8.8 Hz, 2H), 6.91 (d, J= 8.9 Hz, 2H), 4.34 (q, J= 7.2 Hz, 2H), 4.09 (t, J= 6.3124581.000010 | 25-T-072Hz, 2H), 2.45 - 2.31 (m, 4H), 2.12 (dh, J= 11.9, 3.0 Hz, 2H), 2.04 (ddq, J= 11.2, 7.5, 3.7 Hz, 1H), 1.83 (q, = 6.4 Hz, 2H), 1.49 (qd, J= 12.1, 5.4 Hz, 2H), 1.37 (t, J= 7.1 Hz, 3H).13C NMR (151 MHz, CDCI3) 8211.75, 166.37, 162.57, 131.56, 122.96, 113.98, 65.92, 60.65, 40.68, 34.72, 32.96, 32.60, 14.38. HRMS: HRMS-ESI& APCI mix mode calcd for C17H23O4+[M+H] 291.1591, found 291.1593. IR: (KBr cm’1): 3061.86, 3026.57, 2936.87, 2860.82, 1709.31, 1604.27, 1495.61, 1448.72, 1312.74, 1223.27, 1128.32, 1062.72, 1030.11, 754.91, 732.65, 700.19, 560.04. Rf: 0.55 (Hexane: EA = 2: 1)

[0186] Synthesis of 4-oxocyclohexyl 2,2-diphenyl-2-propoxyacetate (lo) EDCI (1.5 equiv.) 4-DMAP (1.5 equiv.) NEt3DCM•OH 25 °C for 12 h o

[0187] Similar to the synthetic procedure for the preparation of li, lo was synthesized using 4-hydroxycyclohexan-l-one (1.80 g, 10 mmol, 1.0 equiv.) and 2,2-diphenyl-2-propoxyacetic acid (2.70 g, 10 mmol, 1.0 equiv., synthesized as described in Salman, Preparation of 3, 6-di substituted azabicyclo[3.1.0]hexane derivatives useful as therapeutic muscarinic receptor antagonists. (2009) as the starting material, lo was obtained as a white solid (1.5 g, 42%).

[0188] NMR: 1H NMR (500 MHz, Chloroform-d) 87.53 - 7.44 (m, 4H), 7.39 -7.29 (m, 6H), 5.27 (tt, J= 5.3, 2.9 Hz, 1H), 3.25 (t, J= 6.6 Hz, 2H), 2.19 (dd, J= 8.3, 5.5 Hz, 4H), 2.12 -2.02 (m, 2H), 1.94 (dtd, J= 15.4, 8.7, 2.9 Hz, 2H), 1.64 (h, J= 7.1 Hz, 2H), 0.94 (t, J= 7.4 Hz, 3H).13C NMR (126 MHz, CDCl3) 6209.71, 171.21, 141.00, 128.45, 128.03, 127.90, 86.58, 69.24, 66.99, 36.71, 30.11, 23.30, 10.74. HRMS: HRMS-ESI& APCI mix mode calcd for C23H26O4Na+[M+Na] 389.1723, found 389.1737. IR: (KBr cm ): 2961.88, 2875.75, 2359.95, 1721.83, 1491.05, 1447.51, 1233.24, 1201.60, 1097.69, 1024.04, 753.82, 726.25, 699.26, 668.78. Rf: 0.29 (Hexane: EA = 2: 1)

[0189] Synthesis of 3-(3-(3-hydroxypropoxy)phenyl)cyclohexan-l-one (It)K2CO3(3.0 equiv.) Br acetone 80 °C for 12 h124581.000010 | 25-T-072

[0190] It was synthesized as described in Guo, Rapid Deoxyfluorination of Alcohols with N-Tosyl-4-chlorobenzenesulfonimidoyl Fluoride (SulfoxFluor) at Room Temperature. Chem. Eur. J. 25, 7259-7264 (2019). A 100 ml round bottle flask was charged with 3-(3-hydroxyphenyl)cyclohexan-l-one (1.9 g, 10 mmol, 1.0 equiv.), 3 -bromopropan- 1-ol (1.4 g, 10 mmol, 1.0 equiv.), K2CO3 (4.2 g, 30 mmol, 3.0 equiv.), acetone (20 mL) and a stir bar. The flask was then equipped with a condenser and heated at 80 °C for 12 h. After the reaction was complete, the flask was cooled to room temperature and quenched with 50 mL of water. The mixture was then extracted with EtOAc (50 mL x 3). The combined organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford the It as a colorless oil (1.6 g, 65%).NMR: 'HNMR (500 MHz, CDCI3) 87.29 - 7.23 (m, 1H), 6.85 - 6.77 (m, 3H), 4.13 (t, J=6.0 Hz, 2H), 3.88 (t, J= 5.9 Hz, 2H), 2.99 (tt, J= 11.8, 3.9 Hz, 1H), 2.63 - 2.32 (m, 4H), 2.23 - 2.11 (m, 1H), 2.11 -2.00 (m, 4H), 1.89 - 1.78 (m, 2H).13C NMR (126 MHz, CDCI3) 6 211.14, 159.06, 146.06, 129.73, 119.13, 113.21, 112.28, 65.64, 60.38, 48.88, 44.75, 41.19, 32.70, 32.03, 25.51. HRMS: HRMS-ESI& APCI mix mode calcd for C15H21O3+[M+H] 249.1485, found 249.1492. IR: (KBr cm’1): 3409.06, 2938.45, 2876.51, 1708.17, 1601.06, 1583.44, 1510.28, 1488.26, 1447.51, 1318.42, 1290.11, 1262.15, 1158.39, 1060.79, 782.26, 698.44, 504.02. Rf: 0.52 (Hexane: EA = 2: 1)

[0191] Synthesis ofN-(4-hexylphenyl)-4-oxocyclohexane-l -carboxamide (lx)EDCI (1.1 equiv.)4-DMAP (1.1 equiv.) D I PEA (4.0 ecjuiv. ) DCMr.t. for 12 h1x

[0192] A 250 mL round bottom flask was charged with 4-oxocyclohexane-l-carboxylic acid (1.2 g, 8.5 mmol, 1.0 equiv.), DCM (100 mL) and a stir bar. After thereaction was cooled to 0 °C, EDCI (1.8 g, 9.4 mmol, 1.1 equiv.), 4-DMAP (1.1 g, 9.4 mmol, 1.1 equiv.) and DIPEA (4.4 g, 5.9 mL, 33.8 mmol, 4.0 equiv.) were added sequentially. After stirring the reaction at 0 °C for another 30 minutes. 4-hexylaniline (1.5 g, 8.5 mmol, 1.0equiv.) was added. The reaction mixture was warmed to room temperature and stirred overnight. After the reaction was complete, it was quenched with saturated aqueous NaHCO3 solution, and the mixture was extracted with DCM (50 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure, and the124581.000010 | 25-T-072residue was purified by silica gel column chromatography to afford the lx as a light brown solid (0.98 g, 39%). NMR: *HNMR (500 MHz, Chloroform^ / ) 87.49 - 7.35 (m, 3H), 7.15 (d, J= 8.1 Hz, 2H), 2.70 (ddt, J= 10.4, 6.5, 3.9 Hz, 1H), 2.65 - 2.51 (m, 4H), 2.45 - 2.33 (m, 2H), 2.25 (dq, J= 14.3, 4.9 Hz, 2H), 2.21 - 2.05 (m, 2H), 1.59 (p, J= 7.4 Hz, 2H), 1.39 -1.25 (m, 6H), 0.95 - 0.86 (m, 3H).13C NMR (126 MHz, CDCl3) 6209.94, 172.20, 139.43, 135.22, 128.94, 120.05, 43.61, 39.83, 35.36, 31.71, 31.47, 29.24, 28.89, 22.61, 14.10.HRMS: HRMS-ESI& APCI mix mode calcd for CC19H28NO2[M+H] 302.2115, found 302.2116. IR: (KBr cm-1): 3308.49, 2929.13, 2856.66, 2361.03, 1717.60, 1654.48, 1603.63, 1533.58, 1412.27, 1326.95, 1259.95, 1162.24, 1127.38, 1077.34, 831.97, 668.69, 504.00. Rf: 0.74 (Hexane: EA = 2: 1)

[0193] Synthesis of (3R,4R)-3-((benzo[d][l,3]dioxol-5-yloxy)methyl)-4-phenylcyclohexan-l-one (lab-A)

[0194] lab-1 was prepared as described in Sun, Benzenesulfonamide compounds, their preparation, and use as voltage-gated sodium channel blockers for therapy. (2013). A 250 mL reaction flask was charged with lab-1 (5 g, 18.7 mmol, 1.0 equiv.), DCM (100 mL) and a stir bar. After the reaction was cooled to 0 °C, Triethylamine (5 mL) and methanesulfonyl chloride (3.2 g, 28 mmol, 1.5 equiv.) were added dropwise. The reaction was stirred at 0 °C for 10 minutes, then warmed to room temperature for another 2 hours.After the reaction was complete, the reaction mixture was poured into ice and extracted with DCM (100 mL x 3). The combined organic layer was washed with 1 M HC1, a saturated NaHCCh solution, and brine, dried over Na2SO4 and concentrated under reduced pressure.The crude methanesulfonate (5.4 g) was used directly for the next step without further purification.

[0195] A 250 mL reaction flask was charged with crude methanesulfonate, sesamol (5.5 g, 40 mmol), DMF (100 mL), K2CO3 (8.3 g, 60 mmol), and a stir bar. The reaction was equipped with an air condenser and vigorously stirred at 100 °C for 48 hours.124581.000010 | 25-T-072After the reaction was complete, it was quenched with saturated K2CO3 solution. The mixture was then extracted by EtOAc (100 mL x 3) and the combined organic layer was washed with saturated K2CO3 solution (100 mL x 10). After TLC indicated that no sesamol remained in the organic layer, the organic layer was dried over Na2SO4, filtered through a silica gel pad and concentrated under reduced pressure to afford crude lab-3 (6.8 g). The crude residue was transferred into a 40 mL reaction vial, which was then added IM HC1 (15 mL), acetone (20 mL) and a stir bar. The vial was sealed and the reaction was heated to 80 °C for 3 h. After TLC indicated that all the ketal was consumed, the reaction was extracted with DCM (50 mL x 3), and the combined organic layer was washed with saturated NaHCCL solution, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, affording lab-A as a pale yellow solid.

[0196] NMR:1H NMR (500 MHz, Chloroform^ / ) 87.23 - 7.13 (m, 2H), 7.06 -6.92 (m, 2H), 6.65 (d, J= 8.4 Hz, 1H), 6.38 (d, J= 2.5 Hz, 1H), 6.16 (dd, J= 8.5, 2.5 Hz, 1H), 5.91 (d, J= 1.6 Hz, 2H), 3.59 - 3.45 (m, 2H), 3.09 (td, J= 11.9, 3.6 Hz, 1H), 2.78 -2.61 (m, 2H), 2.56 (dd, J= 12.1, 5.3 Hz, 2H), 2.37 - 2.25 (m, 1H), 2.22 (ddt, J= 13.7, 7.4, 2.5 Hz, 1H), 2.06 - 1.93 (m, 1H).13C NMR (126 MHz, CDCI3) 6210.56, 162.68, 160.73, 154.15, 148.23, 141.82, 138.46, 138.43, 128.79, 128.73, 115.74, 115.57, 107.90, 105.60, 101.17, 97.99, 70.02, 44.41, 44.10, 43.85, 41.34, 33.74. HRMS: HRMS-ESI& APCI mix mode calcd for C20H20FO4+[M+H] 343.1340, found 343.1350. IR: (KBr cm’1): 2922.89, 1715.62, 1631.83, 1604.88, 1510.28, 1488.46, 1468.79, 1270.33, 1223.10, 1184.94, 1136.29, 1102.65, 1037.88, 980.09, 926.65, 832.53, 786.14, 516.27. Rf: 0.35 (Hexane: EA = 3: 1)

[0197] Synthesis of methyl 2-(4-(4-oxocyclohexyl)phenyl)-2H-indazole-7-carboxylate (lac-A)124581.000010 | 25-T-072

[0198] A 4 mL vial was charged with lac-1 (205 mg, 1.0 mmol, 1.0 equiv. synthesized as described in Zhao, Induction of apoptosis in MDA-MB-231 breast cancer cells by a P ARP 1 -targeting PROT AC small molecule. Chem. Commun. 55, 369-372 (2019), lac-2 (233 mg, 1.0 mmol, 1.0 equiv. synthesized as described in Wang, Preparation of pyrazolopyrimidine compounds as WEE1 kinase inhibitors for treatment and / or prevention of cancer. (2020), AcOH (0.2 mL), DMSO (1.5 mL) and a stir bar. The vial was then sealed and heated to 100 °C for 24 hours. 8 parallel reactions were conducted with the same procedure to give an overall 10 mmol scale reaction (the yield of the cyclization reaction will drop to-10% when it was conducted in 10 mmol scale). After the reaction was complete, 8 small reactions were combined and extracted with DCM (100 mL x 2). The combined organic layer was washed with water (50 mL x 5), brine and dried over Na₂SO₄, then concentrated under reduced pressure to afford the crude ketal. The crude residue was transferred into a 20 mL reaction vial, which was then treated with 2M HC1 (5 mL), a THF -acetone solvent mixture(10 mL, 1: 1 v / v), and a stir bar. The vial was sealed, and the reaction was heated to 80 °C for 4 h. After TLC indicated that all the ketal was consumed, the reaction was extracted with DCM (50 mL x 3) and the combined organic layer was washed with saturated aqueous NaHCCh, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, which afforded lac-A as a brown color solid (1.5 g, 43%). NMR: 1H NMR (500 MHz, Chloroform-d) 88.53 (s, 1H), 8.15 (dd, J = 7.1, 1.1 Hz, 1H), 8.00 - 7.91 (m, 3H), 7.46 - 7.38 (m, 2H), 7.20 (dd, J= 8.4, 7.1 Hz, 1H), 4.06 (s, 3H), 3.13 (tt, J= 12.1, 3.4 Hz, 1H), 2.63 - 2.50 (m, 4H), 2.35 - 2.24 (m, 2H), 2.08 - 1.92 (m, 2H).13C NMR (126 MHz, CDCl3) 6210.66, 166.56, 146.91, 145.16, 138.90,131.67, 127.80, 126.26, 124.37, 121.60, 121.54, 121.24, 119.70, 52.25, 42.34, 41.24, 33.88.HRMS: HRMS-ESI& APCI mix mode calcd for C2iH2iN2O3+[M+H] 349.1547, found 349.1544. IR: (KBr cm’1): 2946.57, 2358.74, 1714.80, 1527.04, 1280.32, 1202.48, 1139.41, 1098.98. Rf: 0.85 (Hexane: EA = 2: 1)

[0199] Synthesis of 4-((l OH-phenothiazin-10-yl) methyl)cyclohexan-l -one (1 ad-A)124581.000010 | 25-T-072

[0200] A 250 mL reaction flask was charged with lOH-phenothi azine (4.0 g, 20 mmol, 2.0 equiv.), (l,4-dioxaspiro[4.5]decan-8-yl)methyl 4-methylbenzenesulfonate (lad-1, 3.3 g, 10 mmol, 1.0 equiv.) K2CO3 (2.7 g, 20 mmol, 2.0 equiv.), DMF (50 mL) and a stir bar. The mixture was stirred at room temperature for 24h until all the starting material lad-1 was fully consumed (heat the reaction mixture to 80 °C if lad-1 remained). After the reaction was complete, 100 mL of water was added to the reaction mixture, and the mixture was then extracted with DCM (100 mL x 3). The combined organic layer was washed with water (200 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was transferred into a 20 mL reaction vial, to which were then added 2M HC1 (5 mL), THF (10 mL) and a stir bar. The vial was sealed, and the reaction was heated to 80 °C for 4 h. After TLC indicated that all the ketal had been consumed, the reaction was extracted with DCM (50 mL x 3) and the combined organic layer was washed with saturated NaHCCL solution, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, affording lad-A as a pale-yellow solid (2.1 g, 68%).NMR:XH NMR (500 MHz, CDCI3) 87.20 (td, J= 7.3, 1.5 Hz, 4H), 6.98 (td, J= 7.5, 1.2 Hz, 2H), 6.96 - 6.88 (m, 2H), 3.85 (d, J= 7.0 Hz, 2H), 2.39 (dtd, J= 11.6, 6.9, 3.2 Hz, 3H), 2.36 - 2.23 (m, 4H), 1.47 (qd, J= 13.2, 6.5 Hz, 2H).13C NMR (126 MHz, CDCI3) 6211.67, 145.49, 127.82, 127.30, 126.06, 122.78, 115.79, 52.21, 40.37, 33.25, 30.37. HRMS: HRMS-ESI& APCI mix mode calcd for C19H20NOS+[M+H] 310.1260, found 310.1266. IR: (KBr cm’1): 2916.67, 2849.26, 2356.95, 2337.84, 1713.53, 1682.52, 1651.52, 1574.45, 1557.45, 1538.81, 1505.03, 1485.53, 1455.55, 1322.19, 1247.45, 1192.11, 1166.31, 1127.18, 1038.04, 751.00. Rf: 0.23 (Hexane: EA = 5: 1)

[0201] Synthesis of N-(4-oxocyclohexyl)-N-phenylpropionamide (lae-A)

[0202] A 200 mL round bottle flask was charged with 4-(phenylamino)cyclohexan-l-one (1.9 g, 10 mmol, 1.0 equiv.), triethyl amine (2.0 g, 20 mmol, 2.0 equiv.), DCM (100 mL) and a stir bar. The reaction was cooled to 0 °C, and propionyl chloride (1.8 g, 20 mmol, 2.0 equiv.) was added dropwise. Upon completion of the addition, the reaction was warmed to room temperature and stirred for another 2 hours. After the reaction was complete, it was quenched with water and the mixture was extracted with DCM124581.000010 | 25-T-072(50 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford the lae-A as a light brown solid (0.78 g, 32%). NMR:1H NMR (500 MHz, Chloroform^ / ) 87.46 - 7.38 (m, 3H), 7.15 - 7.05 (m, 2H), 5.15 (tt, J= 12.2, 3.7 Hz, 1H), 2.54 (td, J= 14.4, 5.9 Hz, 2H), 2.37 (ddt, J= 15.0, 4.8, 2.4 Hz, 2H), 2.15 (ddd, J = 12.5, 6.2, 3.1 Hz, 2H), 1.96 (q, J= 7.4 Hz, 2H), 1.53 (qd, J= 12.8, 4.3 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, CDCl3) 6209.56, 173.71, 138.56, 130.11, 129.51, 128.64, 51.58, 39.97, 30.41, 28.45, 9.58. HRMS: HRMS-ESI& APCI mix mode calcd for C15H20NO2+[M+H] 246.1489, found 246.1512. IR: (KBr cm’1): 2940.03, 2870.94, 2359.94, 2342.07, 1716.37, 1652.41, 1594.98, 1493.17, 1449.03, 1396.32, 1376.06, 1329.84, 1252.87, 1203.28, 706.45. Rf: 0.51 (Hexane: EA = 2: 1)

[0203] Synthesis of 2-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)cyclohexan-l-one (laf-A)1 -Pyrrolidino-1- I SOCI2( 3.0 equiv.) cyclohexene ■ PCM r.t. for 1 h; then1 -pyrrolidino-1 -cyclohexene (1.0 equiv.)1af-11,4-dioxane 1af-A 100 °C for 12 h

[0204] laf-1 was synthesized as described in Johnson, Discovery of PF -04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor. ACS Med. Chem. Lett. 2, 91-96 (2011). A 40 mL reaction vial was charged with laf-1 (2.7 g, 10.0 mmol, 1.0 equiv.), DCM (20 mL), and a stir bar. The mixture was cooled to 0 °C, and thionyl chloride (2.4 mL, 30.0 mmol, 3.0 equiv.) was added dropwise. The reaction mixture was gradually warmed to room temperature and stirred for an additional hour. After completion, the volatiles were removed under reduced pressure (make sure all the thionyl chloride has been removed), and 1 -(cyclohex- l-en-l-yl)pyrrolidine (1.5 g, 10.0 mmol, 1.0 equiv.) and 1,4-dioxane (20 mL) were added. The vial was purged with N2, sealed, and heated to 100 °C for 12 h. The mixture was cooled to ambient temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to afford laf-A as a colorless oil (3.1 g, 89%).

[0205] NMR:1H NMR (500 MHz, Chloroform^ / ) 68.46 (dt, J= 2.7, 1.0 Hz, 1H), 7.91 (dd, J= 8.7, 2.5 Hz, 1H), 7.35 (t, J= 7.8 Hz, 1H), 7.08 (dt, J= 2.2, 1.3 Hz, 1H), 7.05 -124581.000010 | 25-T-0726.95 (m, 3H), 3.27 (dd, J= 14.0, 5.0 Hz, 1H), 2.65 - 2.54 (m, 1H), 2.49 - 2.44 (m, 1H), 2.35 (dd, J= 7.1, 1.8 Hz, 1H), 2.19 -2.02 (m, 2H), 1.94 - 1.79 (m, 2H), 1.74 - 1.61 (m, 2H), 1.43 - 1.32 (m, 1H).13C NMR (126 MHz, CDCI3) 8212.14, 165.86, 153.12, 145.58, 145.55, 145.51, 145.48, 142.69, 136.69, 136.67, 136.64, 136.62, 129.59, 126.35, 124.80, 122.65, 122.10, 121.60, 121.33, 118.95, 111.30, 52.31, 42.18, 35.36, 33.58, 28.03, 27.03, 25.13.19F NMR (470 MHz, Chloroform^ / ) 6 -61.64. HRMS: HRMS-ESI& APCI mix mode calcd for C19H19F3NO2+[M+H] 350.1362, found 350.1371. IR: (KBr cm’1): 3069.73, 2937.87, 2862.35, 1711.27, 1607.98, 1585.48, 1483.87, 1446.86, 1393.76, 1328.13, 1310.39, 1285.80, 1263.25, 1235.99, 1161.09, 1128.40, 1078.02, 1011.86, 957.49, 939.78, 886.25, 837.06, 795.41, 760.69, 697.15, 674.09, 612.11, 514.61. Rf: 0.45 (Hexane: EA = 5: 1)

[0206] (ii) 1,2-carbonyl migration of ketone substrates

[0207] General procedure:OLi OTf LiHMDS Comin's reagent-78 °C 1 h THF-78 °C to r.t.

[0208] Step. A dry 50 mL Schlenk flask charged with a stir bar was purged with nitrogen. Then 2 mL dry THF and bis(trimethylsilyl)amine (0.185 g, 1.15 mmol, 1.15 equiv.) were added. The flask was cooled to -78 °C, and n-BuLi (0.48 mL, 2.5 M in hexanes, 1.2 equiv.) was added over 1 min. After being stirred at this temperature for 30 min, a solution of the ketone substrate (1.0 mmol, 1.0 equiv.) in 1 mL dry THF was added dropwise to the reaction under a nitrogen atmosphere (10 mL syringe over 1 min). The resulting solution was allowed to stir at -78 °C for 1 hour.

[0209] Step 2'. A solution of 0.86 g Comin’s reagent (2.2 mmol, 2.2 equiv.) in 1 mL dry THF was added slowly to the reaction mixture. The crude reaction was then warmed up to room temperature and stirred overnight after quenching with sat. NH4CI solution (5 mL), the reaction mixture was then extracted with Et2O (15 mL x 3). The combined organic layers were washed with brine (5 mL) and dried over MgSCL. The mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to afford the enol triflate.124581.000010 | 25-T-072OTf 1 equiv Pd(COD)CI2(10 mol%) Ph-DavePhos (12 mol%) NaOAc / AcOH 5-CF3-2-pyridone (20 mol%) buffer, r.t., 2 h Cs2CO3(2.0 equiv.)2.2 equiv Toluene / dioxane, 100 °C 12 h

[0210] A flame dried 8 mL vial was charged with Pd(COD)C12 (5.8 mg, 10 mol %), Ph-DavePhos (9.6 mg, 12 mol %), 5-CF3-2-pyridone (6.6 mg, 20 mol %), amidesubstituted NBE (35.4 mg, 0.2 mmol, 1.0 equiv.), the N-0 reagent (107 mg, 0.44 mmol, 2.2 equiv.), the alkenyl triflate substrate (0.2 mmol, 1.0 equiv.) and a stir bar. The reaction vial was then transferred into a glovebox under nitrogen atmosphere, followed by the addition of Cs2CO3(130.4 mg, 0.4 mmol, 2.0 equiv.), 3.1 mL dry toluene and 0.9 mL dry 1,4-dioxane. The reaction vial was sealed and taken out of the glovebox. It was stirred at 100 °C for 12 hours, then diluted with 2 mL THF. After 1 mL acetate buffer (10 g NaOAc, 20 mL AcOH and 20 mL H2O) was added to the reaction, the resulting mixture was stirred for 2 hours at room temperature. The crude reaction mixture was then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with sat. NaHCCh solution (20 mL) and brine (5 mL), then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to afford the ketone product.

[0211] Synthesis of (3R,4R)-4-((benzo[d][l,3]dioxol-5-yloxy)methyl)-3-(4-fluorophenyl)cyclohexan-l -one (1 ab-B)

[0212] Following the general procedure, the reaction was carried out on a 0.2 mmol scale in two parallel runs, affording 40.8 mg of lab-B as a yellow oil. NMR: 1H NMR (500 MHz, Chloroform-d) 67.24 - 7.17 (m, 2H), 7.06 - 6.97 (m, 2H), 6.65 (d, J= 8.5 Hz, 1H), 6.36 (d, J= 2.4 Hz, 1H), 6.15 (dd, J= 8.5, 2.5 Hz, 1H), 5.91 (s, 2H), 3.69 (dd, J= 9.2, 3.0 Hz, 1H),124581.000010 | 25-T-0723.50 (dd, J= 9.2, 6.4 Hz, 1H), 3.04 (ddd, J= 12.4, 11.2, 4.9 Hz, 1H), 2.68 - 2.50 (m, 4H), 2.45 - 2.25 (m, 2H), 1.89 (dtd, J= 13.5, 11.5, 6.9 Hz, 1H).13C NMR (126 MHz, CDCl3) 6209.79, 162.72, 160.77, 154.23, 148.21, 141.72, 138.10, 138.07, 128.60, 128.54, 115.89, 115.72, 107.89, 105.49, 101.14, 97.89, 70.04, 48.80, 45.69, 42.14, 40.71, 29.18.19F NMR (471 MHz, Chloroform-t / ) 6 -115.41 (tt, J= 8.6, 5.3 Hz). HRMS: HRMS-ESI& APCI mix mode calcd for C20H20FO [M+H] 343.1340, found 343.1344. IR: (KBr cm’1): 2916.47, 2357.91, 1715.47, 1603.72, 1510.62, 1488.41, 1470.10, 1222.36, 1185.54, 1135.38, 1102.56, 1037.20, 924.43, 843.95. Rf: 0.33 (Hexane: EA = 3: 1)

[0213] To further confirm the structural assignments of the previously unknown carbonyl-migrated isomer, lab-B was individually synthesized according to the following methods.OAcetone- *- 1.5 equiv. TMSOTf1% NaOH solution NEt32.0 equiv. ^1.2 equiv.80°C for 2h DCM rtfor0.5h Toluene150°C for 12h

[0214] Synthesis of methyl 2-(4-(3-oxocyclohexyl)phenyl)-2H-indazole-7-carboxylate (lac-B)124581.000010 | 25-T-0721ac-A 1ac-B

[0215] Following the general procedure, the reaction was carried out on a 0.2 mmol scale in two parallel runs, affording 71.4 mg of lac-B as a pale-yellow oil. NMR: 1H NMR (500 MHz, Chloroform-d) 68.54 (s, 1H), 8.16 (dd, J= 7.1, 1.1 Hz, 1H), 8.02 - 7.90 (m, 3H), 7.45 - 7.35 (m, 2H), 7.22 (dd, J= 8.4, 7.0 Hz, 1H), 4.07 (s, 3H), 3.13 (tt, J= 11.7, 3.9 Hz, 1H), 2.67 (ddt, J= 14.0, 4.2, 1.9 Hz, 1H), 2.59 (ddd, J= 13.8, 12.4, 1.1 Hz, 1H), 2.52 (dddt, J= 14.4, 4.8, 3.3, 1.7 Hz, 1H), 2.44 (dddd, J= 14.2, 12.4, 6.0, 1.0 Hz, 1H), 2.27 -2.08 (m, 2H), 2.06 - 1.76 (m, 2H).13C NMR (126 MHz, CDCl3) 6210.46, 166.57, 146.94, 144.64, 138.99, 131.71, 127.73, 126.24, 124.38, 121.71, 121.58, 121.24, 119.74, 52.26, 48.77, 44.26, 41.15, 32.70, 25.41. HRMS: HRMS-ESI& APCI mix mode calcd for C2iH2iN2O3+[M+H] 349.1547, found 349.1573. IR: (KBr cm’1): 2949.25, 1710.06, 1554.76, 1526.98, 1434.93, 1381.82, 1346.60, 1313.07, 1270.59, 1203.13, 1141.15, 1047.71, 823.99, 756.50, 734.17. Rf:0.85 (Hexane: EA = 2: 1)

[0216] Synthesis of 3 -((1 OH-phenothiazin-10-yl) methyl)cyclohexan-l -one (1 ad-B)1ad-A 1ad-B

[0217] Following the general procedure, the reaction was carried out on a 0.2 mmol scale in two parallel runs, affording 42.5 mg of lad-B as a yellow oil.

[0218] NMR:1H NMR (500 MHz, Chloroform^ / ) 67.21 - 7.12 (m, 4H), 6.96 (td, J= 7.5, 1.2 Hz, 2H), 6.90 - 6.83 (m, 2H), 3.86 (qd, J= 13.5, 7.0 Hz, 2H), 2.62 (ddt, J= 14.0,124581.000010 | 25-T-0724.1, 1.9 Hz, 1H), 2.45 (ddt, J= 10.9, 7.7, 3.8 Hz, 1H), 2.37 (dtd, J= 11.7, 3.9, 1.8 Hz, 1H), 2.27 (dddd, J= 14.1, 12.4, 6.0, 1.2 Hz, 1H), 2.16 - 2.06 (m, 2H), 2.03 (ddd, J= 13.8, 6.2, 3.9 Hz, 1H), 1.66 - 1.59 (m, 1H), 1.48 - 1.37 (m, 1H).13C NMR (126 MHz, CDCl3) 6210.83, 145.35, 127.80, 127.26, 126.18, 122.81, 115.77, 52.69, 45.58, 41.57, 36.13, 29.00, 24.77.HRMS: HRMS-ESI& APCI mix mode calcd for C19H20NOS+[M+H] 310.1260, found 310.1286. IR: (KBr cm-1): 3061.05, 2936.13, 2863.26, 1709.28, 1678.53, 1592.23, 1570.39, 1485.13, 1456.39, 1331.50, 1285.45, 1251.46, 1232.42, 1202.91, 1162.21, 1127.26, 1107.87, 1038.46, 869.16, 752.09, 699.08, 598.85. Rf: 0.23 (Hexane: EA = 5: 1)

[0219] Synthesis ofN-(3-oxocyclohexyl)-N-phenylpropionamide (lae-B)triflation Pd / NBE [step 1] 45% [step 2] 37%1ae-A

[0220] Following the general procedure, the reaction was carried out on a 0.2 mmol scale in five parallel runs. With slightly modified hydrolysis conditions (avoid retro-Michael addition), affording 26.1 mg of lae-B as a yellow oil.

[0221] As the carbonyl migration reaction did not proceed efficiently for substrates prone to retro-Michael addition, a traditional method for the convenient synthesis of lae-B was employed as described below.

[0222] Similar to the synthesis of lae-A, lae-B was synthesized by using 3-(phenylamino)cyclohexan-l-one (1.9 g, 10 mmol, 1.0 equiv.) and propionyl chloride (1.8 g, 20 mmol, 2.0 equiv.) as the starting material. lae-B can be synthesized as a yellow color oil (1.2 g, 52%). NMR: 'H NMR (500 MHz, Chloroforms / ) 87.54 (d, J= 8.0 Hz, 1H), 7.46 -7.43 (m, 2H), 7.35 - 7.29 (m, 1H), 7.11 - 7.07 (m, 1H), 4.99 -4.86 (m, 1H), 2.57 (ddt, J = 13.6, 4.4, 2.2 Hz, 1H), 2.40 (q, = 7.6 Hz, 1H), 2.35 - 2.29 (m, 1H), 2.24 - 2.16 (m, 1H), 2.12 -2.08 (m, 1H), 2.01 - 1.97 (m, 1H), 1.96 - 1.91 (m, 2H), 1.71 - 1.62 (m, 1H), 1.58 -1.50 (m, 1H), 1.02 (t, J= 7.4 Hz, 3H).13C NMR (126 MHz, CDCI3) 6208.77, 173.44,124581.000010 | 25-T-072130.28, 129.68, 128.75, 53.21, 46.79, 40.39, 29.91, 28.58, 22.10, 9.49. HRMS: HRMS- ESI& APCI mix mode calcd for C15H20NO2+[M+H] 246.1489, found 246.1517. IR: (KBr cm’x): 3317.43, 3060.07, 2939.28, 2875.18, 2360.41, 1711.47, 1657.21, 1596.00, 1541.84, 1493.32, 1461.56, 1441.96, 1396.72, 1375.82, 1309.59, 1258.36, 1220.90, 1192.01, 1092.70, 1073.61, 1050.23, 900.83, 807.57, 781.19, 757.74, 706.23, 657.14, 581.34. Rf: 0.48 (Hexane: EA = 2: 1)

[0223] Synthesis of 4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)cyclohexan-l-one (laf-B) and 3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)cyclohexan-l-one (laf-C)o triflation > Pd / NBE triflation > Pd / NBE CF, [step 1] 60% I 1 JL JJ [step 1] 59%[step 2] 12% CF3[step 2] 43% 1af-A 1af-B | triflation Pd / NBE triflation Pd / NBE [step 1] 59% [step 1] 68%[step 2] trace [step 2] 25%

[0224] To further demonstrate the concept of the nitrogen scanning, a crosssynthetic transformation is presented here, providing a method to interconvert different ketone isomers from a single starting material.

[0225] Following the general procedure, the reaction was carried out on a 0.2 mmol scale in two parallel runs, with laf-B as starting material, affording 35.5 mg of laf-C as a colorless oil.

[0226] Following the general procedure, the reaction was carried out on a 0.2 mmol scale in five parallel runs, with laf-C as starting material, affording 59.1 mg of laf-B as a colorless oil.

[0227] Following the general procedure, the reaction was carried out on a 0.2 mmol scale in five parallel runs, with laf-A as the starting material, affording 25.1 mg of laf-B as a colorless oil.

[0228] 4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)cyclohexan-l -one (laf- B)

[0229] NMR: 1H NMR (500 MHz, Chloroform-d) 68.49 - 8.41 (m, 1H), 7.92 (dd, J= 8.7, 2.5 Hz, 1H), 7.37 (t, J= 7.9 Hz, 1H), 7.09 - 6.97 (m, 3H), 6.95 (t, J= 2.0 Hz, 1H), 2.67 (h, J= 6.6, 6.0 Hz, 2H), 2.48 - 2.36 (m, 2H), 2.29 (ddd, J= 14.2, 12.4, 6.1 Hz, 1H), 2.11 - 2.07 (m, 2H), 1.98 - 1.85 (m, 1H), 1.72 - 1.54 (m, 2H), 1.47 - 1.35 (m, 1H).13CNMR (126124581.000010 | 25-T-072MHz, CDCh) 6211.36, 165.80, 153.21, 145.59, 145.55, 145.52, 145.48, 141.61, 136.73, 136.70, 136.68, 136.65, 129.71, 126.28, 124.79, 122.63, 122.05, 121.67, 121.41, 119.24, 111.34, 47.77, 42.79, 41.38, 40.70, 30.89, 25.06.19F NMR (470 MHz, CDCh) 6 -61.65.HRMS: HRMS-ESI& APCI mix mode calcd for C19H19F3NO2+[M+H] 350.1362, found 350.1368. IR: (KBr cnT1): 2875.16, 1742.30, 1604.37, 1495.45, 1405.82, 1346.31, 1236.91, 1179.48, 1154.52, 956.69, 909.95, 848.93, 804.52, 779.35. Rf: 0.42 (Hexane: EA = 5: 1)

[0230] 3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)cyclohexan-l -one (laf- C)

[0231] NMR:1H NMR (500 MHz, CDCl3) 68.46 (dt, = 2.7, 1.0 Hz, 1H), 7.92 (dd, J = 8.7, 2.6 Hz, 1H), 7.39 (t, J= 7.9 Hz, 1H), 7.09 (dt, J = 7.7, 1.3 Hz, 1H), 7.07 - 6.97 (m, 3H), 2.67 (d, J= 6.8 Hz, 2H), 2.45 - 2.29 (m, 4H), 2.09 - 2.04 (m, 2H), 1.91 - 1.85 (m, 1H), 1.70 - 1.66 (m, 1H), 1.50 - 1.47 (m, 1H).13C NMR (126 MHz, CDCh) 6 211.84, 165.81, 153.21, 145.54, 145.51, 142.54, 136.72, 136.69, 129.69, 126.21, 122.62, 121.97, 121.69, 121.43, 119.14, 111.38, 42.03, 40.72, 38.00, 32.42.19F NMR (471 MHz, Chloroform^ / ) 6 -61.65. HRMS: HRMS-ESI& APCI mix mode calcd for C19H19F3NO2+[M+H] 350.1362, found 350.1367. IR: (KBr cm’1): 2863.58, 1712.20, 1647.15, 1487.88, 1446.91, 1393.86, 1316.47, 1304.81, 1241.35, 1102.19, 997.24, 951.32, 704.21. Rf: 0.42 (Hexane: EA = 5: 1)

[0232] Synthesis of laf-B and laf-C via ketone chain-walking isomerization80% with 2.3: 1.8: 1 ratio (A / B / C)

[0233] As an alternative approach to achieve ketone isomerization, following the procedure in Bragger, Late-Stage Molecular Editing Enabled by Ketone Chain-Walking Isomerization. J. Am. Chem. Soc. 145, 19496-19502 (2023), laf-A can be diversified into additional ketone isomers in a 2.3: 1.8: 1 ratio, obtained in 80% total yield.124581.000010 | 25-T-072

[0234] To further confirm the structural assignments of these previously unknown carbonyl-migrated isomers, laf-B and laf-C were individually synthesized according to the following methods.

[0235] The Ts(N2)Ph reagent was synthesized as described in Dell'Erba, Reactions of arylazosulfones with the conjugate bases of (tert-butoxycarbonyl)methyl and tosylmethyl isocyanide. Synthesis of substituted 1 -arylimidazoles. Tetrahedron 53, 2125-2136 (1997) with slight modifications. A 250 mL round-bottom flask equipped with a stir bar was charged with aniline (9.3 g, 100 mmol, 1.0 equiv.) and water (20 mL). The mixture was cooled to 0 °C, and 40% HBF4 solution (15 mL) was added dropwise. The reaction was stirred at 0 °C for an additional 5 min before a solution of NaNCL (13.8 g, 200 mmol, 2.0 equiv. in 30 mL water) was added dropwise. Caution: rapid addition of the NaNCL solution may result in gas evolution. The mixture was stirred at 0 °C for 30 min, and the resulting suspension was filtered to collect the diazonium salt as a white solid, which was used directly in the next step without further purification.124581.000010 | 25-T-072

[0236] A round-bottom flask equipped with a stir bar was charged with the diazonium salt obtained from the previous step, DCM (150 mL), and TsNa (sodium p-toluenesulfinate, 17.8 g, 100 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature overnight in the dark. Upon completion, the reaction was quenched with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (50 mL), dried over MgSCL, filtered, and concentrated under reduced pressure. The crude residue was recrystallized from Et2O to afford pure 1 -phenyl-2 -tosyldiazene as orange crystals. 1 -phenyl -2 -tosyldiazene is stable only in crystalline form and rapidly decomposes to a black oil or powder when obtained as a fine powder. High purity of this intermediate is critical for reproducibly achieving high yields in the swap reaction; decomposition leads to hydrazone side-product formation and reduced overall efficiency.

[0237] The15N-labeled 1 -phenyl-2 -tosyldiazene was prepared on a 5 mmol scale following the same procedure described above but using Na15NO2instead.(TsNNPh)1 -phenyl-2 -tosyldiazene

[0238] NMR: 1H NMR (500 MHz, Chloroform-d) 67.88 (d, J= 8.0 Hz, 2H), 7.83 (dd, J= 8.1, 1.6 Hz, 2H), 7.66 - 7.56 (m, 1H), 7.51 (t, J= 7.7Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H), 2.49 (s, 3H).13C NMR (126 MHz, CDCl3) 6 149.16, 146.04, 134.82, 130.40, 129.98, 129.91, 129.51, 124.52, 21.83. HRMS: Unstable under MS conditions. IR: (KBr cm-1): 3066.52, 1595.51, 1490.69, 1450.25, 1345.94, 1306.73, 1186.44, 1167.65, 1146.85, 1085.59, 1018.06, 881.99, 813.39, 769.64, 754.29, 702.46, 685.46, 656.11, 606.28, 551.25. Rf: 0.50 (Hexane: EA = 5: 1)(Ts15NNPh)1 -phenyl-2 -tosyldiazene-2-15N

[0239] NMR: 1H NMR (500 MHz, Chloroform-d) 87.88 (d, J= 8.0 Hz, 2H), 7.86 - 7.77 (m, 2H), 7.60 (t, J= 7.4 Hz, 1H), 7.51 (t, J= 7.7 Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H),124581.000010 | 25-T-0722.49 (s, 3H).13C NMR (126 MHz, CDCh) 6 149.19, 149.14, 146.03, 134.81, 130.41, 129.98, 129.91, 129.50, 124.54, 124.51, 21.83. HRMS: Unstable under MS conditions. IR: (KBr cm-1): 3067.40, 1595.23, 1483.01, 1465.15, 1441.76, 1346.88, 1307.29, 1186.21, 1167.18, 1147.32, 1086.45, 1018.68, 877.06, 813.19, 768.17, 744.85, 703.18, 683.90, 669.24, 655.08, 603.85, 551.41. Rf: 0.50 (Hexane: EA = 5: 1)

[0240] The15N NMR of l-phenyl-2-tosyldiazene-2-15N did not show a clear15N signal, possibly due to the absence of a nearby assisting atom. The mass spectrum also failed to provide the molecular weight, likely owing to the inherent instability of this azo compound. Despite the lack of direct characterization evidence of the15N-enriched compound, the13C NMR showed distinct carbon splitting at 149 ppm and 124 ppm, confirming the presence of15N.

[0241] E. 5. CO-to-N swap reaction

[0242] (i) Standard reaction condition1-AdCO2H 20 mol% PhCF30.04 mL 4A MS (20 mg) 50 °C for 12 h NAHA-G2 ketone 1.0 equiv.Phx-JU NTTs (2.0 equiv.)^ BSA, (1.0 equiv.) Cs2CO3, (2.0 equiv.) PhCF3, 60 °C for 12 h1stacfeVatow

[0243] Step 1: condensation and azonation

[0244] Condensation: A mixture of the ketone (0.1 mmol, 1.0 equiv.), NAHA-G2 (36.1 mg, 0.1 mmol, 1.0 equiv.) and a stir bar were added to a flame dried 4 mL vial. After the reaction vial was transferred to a nitrogen filled glovebox, activated 4 A molecule sieves (20.0 mg, 1.0 equiv.), 40 pL PI1CF3 and 1 -adamantanecarboxylic acid (3.6 mg, 20 mmol%) were added to the vial. The vial was sealed, then brought out of the glovebox, and stirred on a pie block at 50°C for 12 hours.

[0245] Azonation: After the reaction vial from the condensation step was transferred into a nitrogen-filled glovebox, PhCFs (1.0 mL), Cs2CO3(65.0 mg, 0.20 mmol,124581.000010 | 25-T-0722.0 equiv.), bis(trimethylsilyl)acetamide (BSA; 20.3 mg, 0.10 mmol, 1.0 equiv.), and 1-phenyl-2 -tosyldiazene (52.0 mg, 0.20 mmol, 2.0 equiv.) were sequentially added. The vial was then sealed and brought out of the glovebox. The reaction mixture was stirred on a pie block at 500 rpm in the dark at 60 °C for 12 h.

[0246] Purification of azo intermediate: Upon completion, the reaction mixture was cooled to room temperature, and the yield of the azonation step was determined by NMR. Water (0.2 mL) was added to the reaction vial, which was then shaken vigorously until all solids were dissolved. The solution was immediately loaded onto a pre-primed 25 g Santai or Biotage prepacked column for purification. The column was first flushed with pure hexane (2 column volumes), followed by 4:1 hexane / ethyl acetate (2 column volumes) to remove solvent and less polar side products. It was then flushed with 3:2 hexane / ethyl acetate (2 column volumes) to remove unreacted l-phenyl-2 -tosyldiazene, continuing until no yellow or orange coloration remained on the column. Finally, the column was eluted with pure ethyl acetate, and all fractions were collected and concentrated under reduced pressure to afford the crude azo, which was used directly in the following step without further purification.

[0247] (1) The azo intermediate is sensitive to acids and amine-type bases, which can promote tautomerization to the corresponding hydrazone and reduce yield. To minimize this risk, the use of less acidic silica gel (e.g., silica gel from Merck, or prepacked columns from Santai Technologies or Biotage, in this case, most of the azo intermediates were purified by a 25 g prepacked column from Santai) is recommended. In general, the crude azo intermediate is considerably more polar than any impurities or starting materials from the azonation step; thus, this rapid purification typically affords the azo intermediate in acceptable purity for the next cyclization step.

[0248] (2) The azo intermediate decomposes under acidic conditions or in solvents that can generate acids upon decomposition. It is therefore important to minimize contact between the azo intermediate and acidic species. Notably, decomposition is accompanied by a distinct deep-red coloration, which can serve as a visual indicator for assessing whether the azo intermediate has degraded.

[0249] (3) The azo intermediate also undergoes slow decomposition upon exposure to light; therefore, all the operations involving this compound have been performed under dark conditions.124581.000010 | 25-T-072(n-Bu)3SnH (1.6 equiv) 30 mol% AIBN Zn, AcOH MeCN (0.025M) r.t. for 6 h 100 °C for 24 hR = NHPh

[0250] Step 2: cyclization and reduction

[0251] Cyclization: In a nitrogen-filled glovebox, a flame-dried 4 mL vial was charged with the crude azo intermediate from step 1, (n-Bu)₃SnH (1.6 equiv., calculated based on the NMR yield), AIBN (30 mol%), MeCN (0.025 M), and a stir bar. The vial was then sealed and brought out of the glovebox. The reaction mixture was stirred on a pie block in the dark at 100 °C for 24 h. Upon completion, the residue was purified by column chromatography on silica gel or by preparative TLC using hexane / ethyl acetate as the eluent to afford the hydrazine product.

[0252] Deprotection: The hydrazine product, Zn powder (5.0 equiv.), acetic acid (0.2 M), and a stir bar were added to a flame-dried 4 mL vial. The vial was purged with nitrogen and sealed. The reaction mixture was stirred on a pie block at room temperature for 6 h. Upon completion, the mixture was filtered through Celite, and the filtrate was basified with 5M NaOH solution. The mixture was extracted with DCM (5 mL x 3), and the combined organic layers were concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel or preparative TLC to afford the amine product. Generally, all the secondary amines have relatively high polarity on silica gel.MeOH is necessary to elute all the products from the silica gel column or preparative TLC.

[0253] (1) (n-Bu)₃SnH and (n-Bu)₃SnBr exhibit poor solubility in MeCN at room temperature but dissolve upon heating.

[0254] (2) If the reaction exhibits low conversion (with residual azo intermediate remaining), purification of (n-Bu)₃SnH by distillation and verification of the purity of AIBN may be required.

[0255] (3) Distilled or BHT-free (n-Bu)₃SnH is unstable at room temperature or upon exposure to air.

[0256] (ii) Glovebox-free reaction procedure

[0257] A glovebox-free procedure was also developed to afford comparable yields while allowing for a more convenient operation.124581.000010 | 25-T-072

[0258] Condensation: A flame-dried 4 mL vial was charged with ketone (0.10 mmol, 1.0 equiv.), NAHA-G2 (36.1 mg, 0.10 mmol, 1.0 equiv.), activated 4 A molecular sieves (40.0 mg, 2.0 equiv.; freshly activated and stored in a 120 °C oven), PhCFs (40 pL), 1-adamantanecarboxylic acid (3.6 mg, 20 mol%), and a stir bar. The vial was purged with N2 gas, sealed, and then stirred on a pie block at 50 °C for 12 h.

[0259] Azonation: To the vial from the condensation step were added PhCFs (1.0 mL), Cs2CO3(65.0 mg, 0.2 mmol, 2.0 equiv.), bis(trimethylsilyl)acetamide (BSA; 20.3 mg, 0.1 mmol, 1.0 equiv.), and l-phenyl-2 -tosyldiazene (52.0 mg, 0.2 mmol, 2.0 equiv.) sequentially. The vial was purged with nitrogen and sealed. The reaction mixture was stirred on a pie block at 500 rpm in the dark at 60°C for 12 h. The purification of the azo intermediate followed the same procedure as the glovebox -involved one.

[0260] Cyclization: The crude azo intermediate from step 1, (n-Bu)3SnH (1.6 equiv., calculated from the NMR yield), AIBN (30 mol%), MeCN (0.025 M), and a stir bar were added to a flame dried 4 mL vial. The vial was purged with nitrogen and sealed. The reaction mixture was stirred on a pie block in the dark at 100 °C for 24 h. Upon completion, the residue was purified by column chromatography on silica gel or by preparative TLC using hexane / ethyl acetate as the eluent to afford the hydrazine product. The purification of the hydrazine product followed the same procedure as the glovebox-involved one.

[0261] (iii) One-pot reaction procedures

[0262] Considering the relative robustness of the cyclization and deprotection steps, the CO-to-N atom swap can be performed in a one-pot process.NAHA-G2(0.1 mmol)ph:ai:.^zx^. O 1-AdCO2H (0.02 mmol) 'N'^'TS (n-Bu)3SnH (0.2 mmol) / x -z[ | benzene 0.04 mL (0.15 mmol) AIBN (0.02 mmol) [ ft(| C 4A MS (20 mg) Cs2CO3, (0.1 mmol) benzene 3 mL total l| J.. 50°C for12 h benzene 2.0 mL, 60 °C for 12 h 100°C for24 h X<^ 1b3b, 45%

[0263] One-pot procedure 1. A flame-dried 4 mL vial was charged with lb (17.4 mg, 0.10 mmol, 1.0 equiv), NAHA-G2 (36.1 mg, 0.10 mmol, 1.0 equiv), activated 4 A molecular sieves (20.0 mg, 2.0 equiv; freshly activated and stored in a 120 °C oven), benzene124581.000010 | 25-T-072(40 pL), 1 -adamantanecarboxylic acid (3.6 mg, 20 mol%), and a stir bar. The vial was purged with N2, sealed, and stirred on a pie block at 50 °C for 12 h. After completion of the condensation, the reaction mixture was supplemented with benzene (1.0 mL), Cs2CO3(33.0 mg, 0.10 mmol, 1.0 equiv), and l-phenyl-2 -tosyldiazene (39.0 mg, 0.15 mmol, 1.5 equiv) sequentially. The vial was purged with N2 again and resealed. The reaction mixture was then stirred on a pie block at 500 rpm in the dark at 60 °C for 12 h.

[0264] Upon completion of the azonation step, the mixture was filtered through a syringe filter to fully remove Cs2CO3. The filtrate was returned to the original 4 mL vial and diluted to a total volume of 3 mL with benzene. (n-Bu)₃SnH (58.2 mg, 0.20 mmol, 2.0 equiv) and AIBN (3.2 mg, 0.02 mmol, 20 mol%) were then added. The vial was purged with N2 and resealed. The reaction mixture was stirred on a pie block in the dark at 100 °C for 24 h. After completion, the residue was purified by silica gel column chromatography or by preparative TLC (hexane / ethyl acetate) to afford 3b (11.4 mg, 45% yield).NAHA-G2(0.1 mmol)1-AdCO2H (0.02 mmol) 'N^Ts

[0265] One-pot procedure 2. The deprotection step was further merged into the one-pot sequence. The reaction was conducted following the same procedure as one-pot procedure 1, except that the reaction mixture was not purified after the cyclization step.Instead, the crude mixture was concentrated under reduced pressure until benzene was removed. The resulting residue was then treated with Zn powder (130.8 mg, 1.0 mmol) and AcOH (0.5 mL). The mixture was stirred at room temperature for 6 h. After completion, the124581.000010 | 25-T-072reaction was worked up and purified according to the standard deprotection procedure, affording 4b as a white solid (6.6 mg, 41% yield).(n-Bu)3SnH (0.16 mmol) Zn (1.0 mmol, AcOH 0.5 mL) AIBN (0.03 mmol) r.t. for 6 h benzene 4 mL 100 °C for 24 h

[0266] One-pot procedure 3. A flame-dried 4 mL vial was charged with 2b (31.0 mg, 0.05 mmol, 1.0 equiv.), («-Bu)sSnH (23.3 mg, 0.08 mmol, 1.6 equiv.), AIBN (2.4 mg, 0.015 mmol, 30 mol%), and benzene (2.0 mL). The vial was purged with N2 and sealed. Two parallel reactions were set up to give a total scale of 0.10 mmol of 2b. The reaction mixtures were stirred on a pie block in the dark at 100 °C for 24 h. After completion, the crude mixtures were concentrated under reduced pressure until benzene was removed. The resulting residues were treated with Zn powder (130.8 mg, 1.0 mmol) and AcOH (0.5 mL) and stirred at room temperature for 6 h. After reaction completion, the mixtures were worked up and purified according to the standard deprotection procedure to afford 4b as a white solid (10.8 mg, 67% yield).

[0267] (iv) Hydrazine productsN,4-diphenylpiperidin-1-amine (3b)

[0268] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 17.4 mg lb as the starting material, giving 3b as a colorless oil (16.4 mg, 92% for step 1, 71% for step 2, 65% overall yield for two steps). NMR: 'H NMR. (500 MHz, Chloroform^ / ) 87.35 (t, J= 7.6 Hz, 2H), 7.29 (d, J= 6.9 Hz, 2H), 7.26 - 7.22 (m, 3H), 7.00 - 6.94 (m, 2H), 6.82 (td, J= 7.3, 1.1 Hz, 1H), 4.43 (s, 1H), 3.36 (dt, J= 11.3, 3.2 Hz, 2H), 2.58 (tt, J= 11.5, 4.5 Hz, 1H), 2.36 (td, J= 11.1, 3.2 Hz, 2H), 2.05 - 1.89 (m, 4H).13C NMR (126 MHz, CDCI3) 6 147.70, 145.85, 129.17, 128.48, 126.85, 126.28, 119.35, 113.66, 57.01, 42.00, 33.53. HRMS: HRMS-ESI& APCI mix mode calcd for C17H21N2+[M+H] 253.1699, found 253.1693. IR: (KBr cm’1): 3025.87, 2933.37, 2871.17, 2785.83, 1735.06,124581.000010 | 25-T-0721602.23, 1495.08, 1452.44, 1375.01, 1330.27, 1307.38, 1253.53, 1166.84, 1068.30, 1027.34, 992.42, 893.11, 828.60, 794.14, 751.70, 697.22, 530.44, 495.75, 464.37, 449.23, 439.64, 428.87, 422.31, 417.18, 411.36, 405.22. Rf: 0.42 (Hexane: EA = 10: 1)N,4-diphenylpiperidin-2,2,6,6-d4-l-amine (3b-D)

[0269] 3b-D was synthesized under the standard reaction conditions with a modified condensation sequence as described in Hirota, Cholinergic regulation of epithelial ion transport in the mammalian intestine. Br. J. Pharmacol. 149, 463-479 (2006). A flame dried 4 mL vial was charged with lb (17.4 mg, 0.1 mmol, 1.0 equiv.) NAHA-G2 (36.1 mg, 0.1 mmol, 1.0 equiv.), pyrrole (2 uL), THF (40 uL) and D2O (100 uL). The mixture was stirred at 60 °C for 6 h. After cooling to room temperature, the volatiles were removed under high vacuum, followed by re-addition of pyrrole (2 pL), THF (40 pL), and D2O (100 pL). The reaction was heated again at 60 °C for 6 h, concentrated under high vacuum, and subsequently treated with activated 4 A molecular sieves (20.0 mg, 1.0 equiv), PhCFs (40 pL), and 1 -adamantanecarboxylic acid (3.6 mg, 20 mol%). The mixture was stirred at 60 °C for an additional 6 h to complete the condensation steps. Following the remaining steps of the standard reaction condition, 3b-D was obtained as a colorless oil (13.3 mg, 80% for step 1, 65% for step 2, 52% overall yield for two steps)

[0270] The reaction could also be conducted with fully deuterated ketone (Ib-D) and NAHA reagent(76), 3b-D can be obtained in overall 55% yield. NMR: 1H NMR (500 MHz, Chloroform-d) 87.34 (t, J= 7.6 Hz, 2H), 7.30 - 7.28 (m, 2H), 7.23 (tq, J= 7.3, 1.8 Hz, 3H), 7.00 - 6.92 (m, 2H), 6.81 (tt, J= 7.3, 1.2 Hz, 1H), 4.44 (s, 1H), 2.57 (td, J= 11.5, 5.6 Hz, 1H), 2.01 - 1.87 (m, 4H).13C NMR (126 MHz, CDCI3) 6 147.73, 145.88, 129.16, 128.47, 126.84, 126.27, 119.32, 113.63, 56.32, 56.14, 41.92, 33.53, 33.42, 33.30. HRMS: HRMS-ESI& APCI mix mode calcd for C17H17D4N2+[M+H] 257.1950, found 257.1952. IR:(KBr cm’1): 3025.62, 2928.79, 2853.81, 2361.41, 1602.46, 1495.15, 1452.80, 1253.26, 985.97, 786.46, 752.64, 696.89, 494.43. Rf: 0.42 (Hexane: EA = 10: 1)124581.000010 | 25-T-072N,4-diphenylpiperidin- 1 -amine (3b-15N)

[0271] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 17.4 mg lb-15N as the starting material, giving 3b-15N as a colorless oil (15.2 mg, 89% for step 1, 67% for step 2, 60% overall yield for two steps). NMR: 'H NMR. (600 MHz, Chloroform^ / ) 67.35 (t, J= 7.6 Hz, 2H), 7.30 - 7.28 (m, 2H), 7.27 - 7.21 (m, 3H), 6.96 (d, J= 7.9 Hz, 2H), 6.82 (t, J= 7.3 Hz, 1H), 4.44 (s, 1H), 3.36 (dt, J= 11.2, 3.3 Hz, 2H), 2.57 (ddt, J= 11.6, 8.7, 4.2 Hz, 1H), 2.36 (td, J= 11.1, 3.0 Hz, 2H), 1.96 (dddd, J = 19.2, 16.2, 11.9, 3.3 Hz, 4H).13C NMR (151 MHz, Chloroform^ / ) 6 147.71 (d, J= 3.4 Hz), 145.86, 129.16, 128.48, 126.85, 126.28, 119.33, 113.64 (d, = 2.5 Hz), 57.00 (d, = 2.6 Hz), 42.01, 33.53 (d, J= 2.0 Hz).15NNMR (61 MHz, Chloroform^ / ) 686.33. HRMS: HRMS-ESI& APCI mix mode calcd for C17H2115NN+[M+H] 254.1670, found 254.1669. IR: (KBr cm’1): 3024.94, 2934.85, 2783.26, 1719.31, 1601.94, 1494.57, 1451.97, 1250.98, 1066.97, 1026.83, 889.80, 825.79, 751.30, 696.48, 505.48, 492.31. Rf: 0.42 (Hexane: EA = 10: 1)NHNN, 3 -diphenylpiperidin- 1 -amine (3c)

[0272] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 17.4 mg 1c as the starting material, giving 3c as a colorless oil (14.8 mg, 87% for step 1, 68% for step 2, 59% overall yield for two steps). NMR: 1H NMR (500 MHz, Chloroform-d) 67.32 (t, J= 7.5 Hz, 2H), 7.27 - 7.25 (m, 2H), 7.24 - 7.21 (m, 2H), 6.97 -6.91 (m, 2H), 6.80 (td, J= 7.2, 1.1 Hz, 1H), 4.46 (s, 1H), 3.43 - 3.21 (m, 2H), 2.99 (tt, J = 11.4, 3.7 Hz, 1H), 2.27 (td, J= 10.6, 7.0 Hz, 2H), 2.02 - 1.93 (m, 1H), 1.87 (tq, J= 10.7, 3.9 Hz, 2H), 1.54 - 1.46 (m, 1H).13C NMR (126 MHz, CDCl3) 6 147.62, 146.20, 129.14, 128.42, 127.16, 126.44, 119.34, 113.63, 63.53, 56.66, 42.97, 31.01, 25.50. HRMS: HRMS-ESI& APCI mix mode calcd for C17H21N2+[M+H] 253.1699, found 253.1693. IR: (KBr cm’x): 2933.39, 2125.77, 1601.76, 1495.20, 1451.02, 1372.33, 1307.59, 1253.43, 1168.50,124581.000010 | 25-T-0721085.77, 897.35, 835.55, 813.65, 750.92, 698.77, 661.47, 594.39, 539.91, 499.29, 436.70, 421.97, 416.85, 403.52. Rf: 0.45 (Hexane: EA = 10: 1)N-phenyl-l,2,4,5-tetrahydro-3H-benzo[d]azepin-3-amine (3d)

[0273] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 16.0 mg Id as the starting material, giving 3d as a colorless oil (12.1 mg, 85% for step 1, 60% for step 2, 51% overall yield for two steps). NMR: *HNMR (500 MHz, Chloroform^ / ) 67.25 (t, J= 8.0 Hz, 2H), 7.16 (dq, J= 9.1, 4.5 Hz, 4H), 6.99 (d, J = 7.9 Hz, 2H), 6.83 (t, J= 7.3 Hz, 1H), 4.73 (s, 1H), 3.15 - 2.75 (m, 8H).13C NMR (126 MHz, CDCl3) 6 147.35, 141.43, 129.22, 129.03, 126.51, 119.41, 113.60, 58.35, 34.89. HRMS: HRMS-ESI& APCI mix mode calcd for C16H19N2+[M+H] 239.1543, found 239.1535. IR: (KBr cm-1): 2956.11, 2926.69, 2854.23, 1732.15, 1603.15, 1494.42, 1455.94, 1302.42, 1252.52, 1152.03, 954.00, 800.86, 751.95, 693.97, 595.32. Rf: 0.39 (Hexane: EA = 10: 1)N,3 -diphenylpyrrolidin- 1 -amine (3e)

[0274] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 16.1 mg le as the starting material, giving 3e as a colorless oil (15.4 mg, 80% for step 1, 81% for step 2, 65% overall yield for two steps). NMR: 1H NMR (500 MHz, Chloroform-d) 67.35 (d, J= 4.3 Hz, 4H), 7.28 - 7.17 (m, 3H), 7.03 - 6.92 (m, 2H), 6.81 (tt, J = 7.3, 1.1 Hz, 1H), 4.41 (s, 1H), 3.45 (dq, J= 9.8, 7.3 Hz, 1H), 3.24 (dd, J= 9.2, 8.0 Hz, 1H), 3.12 - 3.00 (m, 2H), 2.95 (dd, J = 9.2, 6.9 Hz, 1H), 2.47 - 2.35 (m, 1H), 1.97 (ddt, J = 13.0, 8.5, 7.1 Hz, 1H).13C NMR (126 MHz, CDCI3) 6 148.58, 145.41, 129.15, 128.54, 127.18, 126.26, 119.26, 113.29, 63.49, 56.45, 41.61, 31.93. HRMS: HRMS-ESI& APCI mix mode calcd for C16H19N2+[M+H] 249.1543, found 249.1547. IR: (KBr cm-1): 3024.34, 2963.18, 2805.84, 1601.69, 1493.88, 1256.00, 913.17, 747.47, 695.60. Rf: 0.43 (Hexane: EA = 10: 1)2 -benzyl -N-phenylpiperi din- 1 -amine (3f)124581.000010 | 25-T-072

[0275] Following the standard reaction condition, but increasing the condensation temperature to 80 °C and using benzene as the solvent for the cyclization step, the reaction was conducted at 0.1 mmol scale with 18.8 mg If as the starting material, giving 3f as a colorless oil (12.9 mg, 95% for step 1, 52% for step 2, 49% overall yield for two steps)

[0276] NMR:1H NMR (600 MHz, Chloroform^ / ) 87.26 (s, 2H), 7.24 - 7.18 (m, 3H), 7.16 (d, J= 7.6 Hz, 2H), 6.94 (d, J= 7.9 Hz, 2H), 6.83 - 6.75 (m, 1H), 4.30 (s, 1H), 3.42 (d, J= 10.0 Hz, 1H), 3.23 (d, J= 10.4 Hz, 1H), 2.53 - 2.42 (m, 2H), 2.22 (td, J= 10.8, 10.0, 2.8 Hz, 1H), 1.66 (td, J= 7.8, 4.3 Hz, 3H), 1.39 - 1.30 (m, 2H), 1.22 - 1.12 (m, 1H).13C NMR (151 MHz, CDCl3) 6 148.76, 140.19, 129.65, 129.04, 128.06, 125.69, 118.73, 113.29, 67.22, 57.46, 39.81, 30.94, 25.97, 23.91. HRMS: HRMS-ESI& APCI mix mode calcd for C18H23N2+[M+H] 267.1856, found. 267.1861. IR: (KBr cm’1): 2930.75, 2359.67, 1600.32, 1494.49, 1452.61, 1253.35, 748.31, 694.14. Rf: 0.47 (Hexane: EA = 10: 1)N,4,4-triphenylpiperidin-l -amine (3g)

[0277] Following the standard reaction condition, but run the reaction at 80°C / 3h with 3.0 equiv. of TsN2Ph for the azonation step. The reaction was conducted at 0.1 mmol scale with 25.0 mg 1g as the starting material, giving 3g as a colorless oil (20.3 mg, 81% for step 1, 77% for step 2, 62% overall yield for two steps). NMR: 1H NMR (500 MHz, Chloroform-d) 67.33 - 7.31 (m, 6H), 7.26 - 7.17 (m, 6H), 6.89 (d, J= 8.0 Hz, 2H), 6.79 (t, J = 7.4 Hz, 1H), 4.31 (s, 1H), 2.82 (s, 4H), 2.60 (t, J= 5.4 Hz, 4H).13C NMR (126 MHz, CDCI3) 6 147.64, 146.61, 129.13, 128.46, 127.13, 125.85, 119.27, 113.57, 53.14, 44.14, 36.24. HRMS: HRMS-ESI& APCI mix mode calcd for C23H25N2+[M+H] 329.2012, found 329.2017. IR: (KBr cm’1): 2937.46, 2935.92, 2817.29, 2349.83, 1724.73, 1483.95, 1127.80, 1116.43, 826.94, 804.75, 727.46. Rf: 0.51 (Hexane: EA= 10: 1)124581.000010 | 25-T-072phenyl(l-(phenylamino)piperidin-4-yl)methanone (3h)

[0278] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 20.2 mg Ih as the starting material, giving 3h as a colorless oil (12.0 mg, 83% for step 1, 52% for step 2, 43% overall yield for two steps). NMR: 'H NMR. (600 MHz, CDCl3) 68.03 - 7.94 (m, 2H), 7.60 (td, J= 7.3, 1.4 Hz, IH), 7.51 (t, J= 7.8 Hz, 2H), 7.23 (dd, J= 8.6, 7.2 Hz, 2H), 6.97 - 6.92 (m, 2H), 6.82 (td, J= 7.3, 1.3 Hz, IH), 4.45 (s, IH), 3.31 (ddt, J= 14.7, 9.7, 5.5 Hz, 3H), 2.43 (td, J= 11.3, 2.9 Hz, 2H), 2.07 - 1.95 (m, 4H).13C NMR (151 MHz, CDCI3) 5202.51, 147.52, 136.08, 133.07, 129.19, 128.75, 128.25, 119.47, 113.61, 55.79, 42.82, 28.79. HRMS: HRMS-ESI& APCI mix mode calcd for C18H21N2O+[M+H] 281.1648, found 281.1640. IR: (KBr cm-1): 2952.14, 1678.60, 1602.29, 1495.73, 1447.64, 1263.61, 976.62, 752.29, 696.22. Rf: 0.32 (Hexane: EA = 5: 1)l-(phenylamino)piperidin-4-yl 2,2-diphenylacetate (3i)

[0279] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 30.8 mg li as the starting material, giving 3i as a colorless oil (19.7 mg, 83% for step 1, 61% for step 2, 51% overall yield for two steps). NMR: 'H NMR (500 MHz, CDCI3) 67.36 (d, J= 5.8 Hz, 8H), 7.33 - 7.29 (m, 2H), 7.21 (t, J= 7.9 Hz, 2H), 6.89 (d, J = 7.9 Hz, 2H), 6.81 (t, J= 7.3 Hz, IH), 5.06 (s, IH), 4.97 (tt, J= 7.4, 3.8 Hz, IH), 2.83 - 2.55 (m, 4H), 1.99 (ddt, J= 11.9, 7.8, 3.9 Hz, 2H), 1.91 - 1.81 (m, 2H).13C NMR (126 MHz, CDCI3) 6 171.83, 147.43, 138.68, 129.16, 128.68, 128.62, 128.61, 127.29, 119.49, 113.58, 69.57, 57.37, 52.78, 30.48. HRMS: HRMS-ESI& APCI mix mode calcd for C25H27N2O2+[M+H] 387.2067, found 386.2058. IR: (KBr cm-1): 3060.26, 3027.33, 2955.97, 2815.22,124581.000010 | 25-T-0722359.68, 1732.30, 1603.23, 1558.41, 1495.46, 1453.71, 1304.28, 1276.12, 1251.87, 1190.72, 1154.02, 1069.53, 1032.01, 978.31, 882.94, 814.51, 749.79, 695.88, 668.32, 560.78, 497.29, 475.26, 455.64, 446.68, 435.50, 427.65, 417.06, 411.63, 405.18. Rf: 0.16 (Hexane: EA = 10: 1)■NHN3 -( 1 -(phenylamino)piperi din-3 -yl)phenol (3j)

[0280] Following the standard reaction condition, but benzene was used as the solvent for the cyclization step, the reaction was conducted at 0.1 mmol scale with 19.0 mg Ij as the starting material, giving 3j as a colorless oil (11.9 mg, 78% for step 1, 58% for step 2, 45% overall yield for two steps). NMR: 'H NMR (600 MHz, Chloroform -tZ) 67.22 (td, J = 7.2, 3.6 Hz, 2H), 7.18 (td, J= 8.0, 2.1 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.86 - 6.76 (m, 2H), 6.74 (t, J= 2.1 Hz, 1H), 6.69 (dd, J= 8.1, 2.6 Hz, 1H), 4.76 (s, 1H), 3.37 - 3.22 (m, 2H), 2.94 (tt, J= 11.6, 3.5 Hz, 1H), 2.25 (dd, J= 13.0, 8.4 Hz, 2H), 1.99 - 1.91 (m, 1H), 1.85 (dpt, J = 13.3, 9.4, 4.7 Hz, 2H), 1.51 - 1.40 (m, 1H).13C NMR (151 MHz, CDCl3) 6 155.55, 147.58, 145.86, 129.57, 129.15, 119.68, 119.38, 114.14, 113.65, 113.30, 63.39, 56.65, 42.80, 30.92, 25.44. HRMS: HRMS-ESI& APCI mix mode calcd for C17H21N2O+[M+H] 269.1648, found 269.1653. IR: (KBr cnT1): 2930.24, 1601.78, 1495.37, 1456.64, 1251.56, 752.22, 695.84. Rf:0.13 (Hexane: EA= 5: 1)NHNHO4-(4-chlorophenyl)-l -(phenylamino)piperidin-4-ol (3k)

[0281] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 22.4 mg Ik as the starting material, giving 3k as a colorless oil (12.4 mg, 79% for step 1, 52% for step 2, 41% overall yield for two steps). NMR: 1H NMR (500 MHz, Chloroform-d) 87.49 (d, J= 8.1 Hz, 2H), 7.37 (t, J= 8.4 Hz, 2H), 7.23 (t, J= 7.7 Hz, 2H), 6.95 (d, J= 7.9 Hz, 2H), 6.82 (t, J= 7.3 Hz, 1H), 4.52 (s, 1H), 3.14 (dt, J= 11.1, 3.0 Hz, 2H), 2.82 - 2.69 (m, 2H), 2.28 (td, J= 13.2, 4.5 Hz, 2H), 1.83 (dd, J= 14.3, 2.7 Hz, 2H).13C NMR (126 MHz, CDCI3) 6 147.55, 146.51, 133.00, 129.19, 128.51, 126.11, 119.48, 113.67,124581.000010 | 25-T-07270.54, 51.97, 38.67. HRMS: HRMS-ESI& APCI mix mode calcd for C17H20ClN2O+[M+H] 303.1259, found 303.1246. IR: (KBr cm’1): 3305.27, 2953.00, 2825.48, 2359.87, 1732.01, 1602.92, 1494.63, 1254.50, 1133.61, 1095.29, 1042.21, 1012.91, 825.38, 752.88, 694.74, 541.37. Rf: 0.68 (Hexane: EA = 2: 1)l'-(phenylamino)spiro[chromane-2,4'-piperidin]-4-one (31)

[0282] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 23.0 mg 11 as the starting material, giving 31 as a colorless oil (16.3 mg, 85% for step 1, 62% for step 2, 53% overall yield for two steps). NMR: 1H NMR (500 MHz, Chloroform-d) 67.89 (dd, J = 8.1, 1.8 Hz, 1H), 7.52 (ddd, J = 8.7, 7.2, 1.8 Hz, 1H), 7.24 -7.20 (m, 2H), 7.05 - 6.99 (m, 2H), 6.94 - 6.90 (m, 2H), 6.81 (tt, J= 7.2, 1.2 Hz, 1H), 4.51 (s, 1H), 3.00 (dt, J= 11.7, 3.8 Hz, 2H), 2.77 (s, 2H), 2.72 (td, J= 11.4, 2.8 Hz, 2H), 2.16 (dq, J = 14.6, 3.2 Hz, 2H), 1.90 (ddd, J= 13.8, 11.8, 4.5 Hz, 2H).13C NMR (126 MHz, CDCl3) 6 191.81, 147.41, 136.33, 129.20, 126.70, 121.42, 121.16, 120.82, 119.57, 118.33, 113.61, 77.28, 51.23, 39.37, 34.42. HRMS: HRMS-ESI& APCI mix mode calcd for C19H21N2O2+[M+H] 309.1598, found 309.1584. IR: (KBr cm’1): 2933.36, 2841.94, 1689.05, 1604.20, 1495.57, 1463.10, 1307.29, 1230.26, 759.40, 695.10. Rf: 0.23 (Hexane: EA= 5: 1)N-phenyl-3H-spiro[isobenzofuran- 1,4'-piperidin] - 1 '-amine (3m)

[0283] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 20.2 mg Im as the starting material, giving 3m as a colorless oil (15.1 mg, 83% for step 1, 65% for step 2, 54% overall yield for two steps). For the large-scale reaction, the reaction was conducted at 1.0 mmol scale and giving 160 mg 3m as product (57% yield overall). NMR:1H NMR (500 MHz, Chloroform^ / ) 67.35 - 7.30 (m, 2H), 7.27 -7.19 (m, 4H), 7.02 - 6.95 (m, 2H), 6.82 (t, J= 7.3 Hz, 1H), 5.12 (s, 2H), 4.50 (s, 1H), 3.19124581.000010 | 25-T-072(ddd, J= 12.3, 4.3, 1.9 Hz, 2H), 2.70 (ddd, J= 13.2, 10.7, 2.6 Hz, 2H), 2.15 (td, J= 13.2, 4.6 Hz, 2H), 1.87 (dq, J= 14.3, 3.0 Hz, 2H).13C NMR (126 MHz, CDCl3) 6 147.71, 145.31, 138.94, 129.17, 127.71, 127.42, 121.15, 120.73, 119.35, 113.69, 83.99, 70.82, 52.82, 36.88.HRMS: HRMS-ESI& APCI mix mode calcd for C18H20N2O+[M+H] 281.1648, found 281.1645. IR: (KBr cm-1): 3048.16, 2946.22, 2821.65, 2359.91, 1734.00, 1602.94, 1495.69, 1458.52, 1371.65, 1255.06, 1202.45, 1167.38, 1126.89, 1048.65, 1020.63, 943.79, 817.23, 755.91, 720.83, 694.92, 497.36, 456.77, 436.20, 412.90. Rf: 0.16 (Hexane: EA = 10: 1)ethyl 4-(2-(l-(phenylamino)piperidin-4-yl)ethoxy)benzoate (3n)

[0284] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 29.0 mg In as the starting material, giving 3n as a pale-yellow colored oil (17.3 mg, 79% for step 1, 60% for step 2, 47% overall yield for two steps). NMR: 'H NMR (600 MHz, Chloroform^ / ) 68.01 (d, J= 8.5 Hz, 2H), 7.21 (t, J= 7.7 Hz, 2H), 6.92 (t, J = 8.7 Hz, 4H), 6.80 (t, J= 7.3 Hz, 1H), 4.37 (q, J= 7.1 Hz, 3H), 4.09 (t, J= 6.4 Hz, 2H), 3.22 (dt, J= 11.1, 3.4 Hz, 2H), 2.24 (td, J= 11.3, 2.4 Hz, 2H), 1.82 (td, J= 13.2, 12.0, 4.7 Hz, 4H), 1.53 - 1.46 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H).13C NMR (151 MHz, CDCI3) 6 166.43, 162.70, 147.70, 131.56, 129.13, 122.87, 119.27, 114.01, 113.59, 65.91, 60.65, 56.47, 35.33, 32.26, 23.47, 14.40. HRMS: HRMS-ESI& APCI mix mode calcd for C22H29N2O3+[M+H] 369.2173, found 369.2163. IR: (KBr cm ): 2928.37, 1710.08, 1605.53, 1510.35, 1495.70, 1253.56, 1167.87, 1103.29, 1017.73, 770.94, 695.58. Rf: 0.29 (Hexane: EA = 5: 1)1 -(phenylamino)piperidin-4-yl 2,2-diphenyl-2-propoxyacetate (3o)124581.000010 | 25-T-072

[0285] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 36.6 mg lo as the starting material, giving 3o as a colorless oil (25.3 mg, 87% for step 1, 65% for step 2, 57% overall yield for two steps). NMR: 'H NMR (600 MHz, Chloroform^ / ) 67.52 - 7.48 (m, 5H), 7.37 - 7.33 (m, 6H), 7.20 (t, J= 7.7 Hz, 2H), 6.87 (d, J = 7.9 Hz, 2H), 6.80 (t, J= 7.3 Hz, 1H), 4.99 (s, 1H), 3.24 (t, J= 6.6 Hz, 2H), 2.60 (d, J= 30.3 Hz, 4H), 1.93 (ddt, J= 12.4, 7.9, 4.0 Hz, 2H), 1.80 (dq, J= 12.3, 5.7 Hz, 2H), 1.65 (q, J= 7.1 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H).13C NMR (151 MHz, CDCl3) 6 171.24, 147.40, 141.22, 129.15, 128.64, 128.60, 127.86, 127.79, 119.48, 113.56, 86.50, 69.66, 66.97, 52.45, 30.34, 23.32, 10.77. HRMS: HRMS-ESI& APCI mix mode calcd for C28H33N2O3+[M+H] 445.2486, found 445.2476. IR: (KBr cm’1): 2958.16, 1732.25, 1603.61, 1494.60, 1447.46, 1249.32, 1096.53, 1074.59, 1036.57, 752.38, 697.85. Rf: 0.16 (Hexane: EA = 10: 1)oN-methyl-N-phenyl-l-(phenylamino)piperidine-4-carboxamide (3p)

[0286] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 23.1 mg Ip as the starting material, giving 3p as a colorless oil (14.0 mg, 72% for step 1, 63% for step 2, 45% overall yield for two steps). NMR: 'H NMR (600 MHz, Chloroform^ / ) 67.47 (t, J= 7.6 Hz, 2H), 7.40 (t, J= 7.4 Hz, 1H), 7.23 - 7.17 (m, 4H), 6.88 (d, J= 7.9 Hz, 2H), 6.78 (t, J= 7.3 Hz, 1H), 4.23 (d, J= 82.0 Hz, 1H), 3.29 (s, 3H), 3.15 (dt, J= 11.2, 3.3 Hz, 2H), 2.26 - 2.20 (m, 1H), 2.08 - 2.02 (m, 2H), 1.96 (t, J= 11.5 Hz, 2H), 1.67 (dd, J= 11.3, 4.2 Hz, 2H).13C NMR (151 MHz, CDCI3) 6 175.10, 147.52, 144.03, 129.88, 129.12, 127.95, 127.24, 119.34, 113.57, 55.53, 38.73, 37.60, 28.88. HRMS: HRMS-ESI& APCI mix mode calcd for C19H24N3O+[M+H] 310.1914, found 310.1915. IR: (KBr cm’x): 3262.47, 2948.66, 2359.72, 1645.43, 1604.47, 1594.66, 1495.22, 1447.69, 1391.75, 1317.90, 1289.22, 1254.98, 1111.64, 1071.08, 1032.73, 877.01, 806.40, 777.28, 749.18, 699.68, 668.45, 569.93. Rf: 0.55 (Hexane: EA = 2: 1)3 -(3, 5 -dimethyl- 1 H-pyrazol- 1 -yl)-N -phenylpiperidin- 1 -amine (3q)124581.000010 | 25-T-072

[0287] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 19.2 mg Iq as the starting material, giving 3q as a colorless oil (15.1 mg, 87% for step 1, 66% for step 2, 56% overall yield for two steps). NMR: 'H NMR. (600 MHz, Chloroform^ / ) 67.24 - 7.19 (m, 2H), 6.95 - 6.88 (m, 2H), 6.81 (tt, J= 7.3, 1.2 Hz, 1H), 5.78 (s, 1H), 4.54 (s, 1H), 4.22 (tt, J= 11.0, 4.4 Hz, 1H), 3.36 - 3.23 (m, 2H), 2.73 (t, J = 10.5 Hz, 1H), 2.30 (ddd, J= 11.9, 10.5, 2.8 Hz, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 2.04 - 1.96 (m, 2H), 1.95 - 1.89 (m, 1H), 1.82 (dddd, J= 17.4, 13.0, 8.6, 4.6 Hz, 1H).13C NMR (151 MHz, CDCl3) 6 147.38, 147.36, 138.23, 129.16, 119.53, 113.61, 104.82, 61.06, 55.71, 54.37, 29.93, 23.90, 13.60, 10.99. HRMS: HRMS-ESI& APCI mix mode calcd for C16H23N / [M+H] 271.1917, found 271.1914. IR: (KBr cm-1): 2950.73, 1602.55, 1553.29, 1495.51, 1455.99, 1253.53, 1164.21, 1025.14, 837.74, 752.29, 695.37, 501.67. Rf: 0.10 (Hexane: EA = 5: 1)N,4-diphenylpiperazin-l -amine (3r)

[0288] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 17.5 mg Ir as the starting material, giving 3r as a colorless oil (13.1 mg, 80% for step 1, 65% for step 2, 52% overall yield for two steps). NMR: 'H NMR (600 MHz, Chloroform^ / ) 67.34 - 7.29 (m, 2H), 7.27 - 7.22 (m, 2H), 6.98 (tt, J= 7.3, 1.2 Hz, 4H), 6.95 - 6.88 (m, 1H), 6.87 - 6.81 (m, 1H), 4.47 (s, 1H), 3.42 - 3.27 (m, 4H), 2.93 (t, J= 4.9 Hz, 4H).13C NMR (151 MHz, CDCI3) 6 147.29, 129.22, 129.19, 119.96, 119.67, 116.30, 113.75, 55.70, 49.30, 23.47. HRMS: HRMS-ESI& APCI mix mode calcd for C16H20N3+[M+H] 254.1652, found 254.1654. IR: (KBr cm ): 2835.35, 1599.61, 1504.12, 1382.31, 1239.00, 1101.96, 988.99, 924.85, 751.21, 688.64. Rf: 0.13 (Hexane: EA= 10: 1)Hl-(phenylamino)piperidin-4-yl benzoate (3s)

[0289] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 21.8 mg Is as the starting material, giving 3s as a colorless oil (15.7 mg,- Ill -124581.000010 | 25-T-07288% for step 1, 60% for step 2, 53% overall yield for two steps). NMR:1H NMR (600 MHz, Chloroform^ / ) 6 8.14 - 8.04 (m, 2H), 7.63 - 7.58 (m, 1H), 7.49 (t, J= 7.8 Hz, 2H), 7.23 (dd, J= 6.9, 1.6 Hz, 2H), 7.00 - 6.92 (m, 2H), 6.86 - 6.77 (m, 1H), 5.16 (dp, J= 7.6, 3.8 Hz, 1H), 4.51 (s, 1H), 2.99 (s, 2H), 2.78 (s, 2H), 2.14 (ddt, J= 11.7, 7.7, 3.8 Hz, 2H), 2.04 (ddt, J = 13.8, 7.5, 3.7 Hz, 2H).13C NMR (151 MHz, CDCl3) 6 165.90, 147.51, 133.00, 130.57, 129.59, 129.20, 128.40, 119.53, 113.62, 69.31, 53.11, 30.82. HRMS: HRMS-ESI& APCI mix mode calcd for C18H21N2O2+[M+H] 297.1598, found 297.1584. IR: (KBr cm’1):2955.98, 2854.19, 2807.94, 1716.11, 1603.03, 1495.13, 1451.42, 1349.72, 1315.08, 1275.74, 1256.41, 1177.04, 1113.85, 1069.87, 1037.11, 957.48, 883.45, 840.27, 805.96, 752.46, 713.22, 694.97. Rf: 0.13 (Hexane: EA = 10: 1)3 -(3 -( 1 -(phenylamino)piperi din-3 -yl)phenoxy)propan- 1 -ol (3t)

[0290] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 24.8 mg It as the starting material, giving 3t as a colorless oil (13.7 mg, 75% for step 1, 56% for step 2, 42% overall yield for two steps). NMR: 'H NMR (600 MHz, CDCI3) 67.22 (td, J= 7.8, 5.5 Hz, 3H), 6.93 (d, J= 7.9 Hz, 2H), 6.87 - 6.74 (m, 4H), 4.44 (s, 1H), 4.14 (t, J= 5.9 Hz, 2H), 3.89 (t, J= 5.8 Hz, 2H), 3.38 - 3.23 (m, 2H), 2.96 (td, J= 11.6, 5.8 Hz, 1H), 2.31 -2.19 (m, 2H), 2.07 (p, J= 5.9 Hz, 2H), 1.95 (d, J= 13.2 Hz, 1H), 1.86 (tt, J= 11.7, 6.1 Hz, 2H), 1.47 (qd, J= 12.2, 5.1 Hz, 1H).13C NMR(151 MHz, CDCI3) 6 158.83, 147.61, 145.62, 129.40, 129.14, 119.85, 119.35, 113.76, 113.62, 112.05, 65.79, 63.43, 60.69, 56.67, 42.98, 32.02, 31.00, 25.45. HRMS: HRMS-ESI& APCI mix mode calcd for C20H27N2O2+[M+H] 327.2067, found 327.2074. IR: (KBr cm’1): 3310.28, 2955.85, 2926.74, 2854.75, 1602.14, 1495.40, 1455.97, 1377.03, 1251.43, 1177.16, 1073.51, 875.14, 751.20, 695.66, 592.14, 502.97. Rf: 0.39 (Hexane: EA = 2: 1)N,2-diphenylmorpholin-4-amine (3u)124581.000010 | 25-T-072

[0291] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 17.6 mg lu as the starting material, giving 3u as a colorless oil (11.7 mg, 78% for step 1, 59% for step 2, 46% overall yield for two steps). NMR: *HNMR (600 MHz, CDCl3) 67.41 - 7.35 (m, 4H), 7.32 (t, J= 1.6 Hz, 1H), 7.26 - 7.22 (m, 2H), 7.01 -6.94 (m, 2H), 6.86 - 6.83 (m, 1H), 4.70 (dd, J= 10.2, 2.4 Hz, 1H), 4.47 (s, 1H), 4.13 (ddd, J = 11.6, 3.5, 1.6 Hz, 1H), 3.96 (td, J= 11.5, 2.4 Hz, 1H), 3.33 (dt, J= 10.9, 2.1 Hz, 1H), 3.18 (dq, J= 10.9, 1.9 Hz, 1H), 2.54 (td, J= 11.1, 3.4 Hz, 1H), 2.35 (t, J= 10.5 Hz, 1H).13C NMR (151 MHz, CDCI3) 6 147.05, 139.71, 129.24, 128.40, 127.91, 126.09, 119.84, 113.77, 78.33, 66.83, 62.83, 55.74. HRMS: HRMS-ESI& APCI mix mode calcd for C16H19N2O+[M+H] 255.1492, found 255.1494. IR: (KBr cm’1): 2956.67, 1601.99, 1496.22, 753.26, 696.96. Rf:0.16 (Hexane: EA = 10: 1)N-phenyl-l,4-dioxa-8-azaspiro[4.5]decan-8-amine (3v)

[0292] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 15.6 mg Iv as the starting material, giving 3v as a colorless oil (11.9 mg, 84% for step 1, 61% for step 2, 51% overall yield for two steps). NMR: 'H NMR (600 MHz, Chloroform^ / ) 67.22 (t, J= 7.8 Hz, 2H), 6.93 (d, J= 7.9 Hz, 2H), 6.81 (t, J= 7.3 Hz, 1H), 4.42 (s, 1H), 3.99 (d, J= 1.8 Hz, 4H), 2.85 (s, 4H), 1.88 (t, J= 5.8 Hz, 4H).13C NMR (151 MHz, CDCI3) 6 147.61, 129.16, 119.41, 113.61, 106.62, 64.35, 53.79, 34.65. HRMS:HRMS-ESI& APCI mix mode calcd for C13H19N2O2+[M+H] 235.1441, found 235.1437. IR:(KBr cm’1): 2956.92, 2358.41, 1603.78, 1495.52, 1455.97, 1377.03, 1256.29, 1145.96, 1092.78, 1038.13, 946.37, 920.25, 822.87, 752.38, 695.36, 592.14, 502.97. Rf: 0.19 (Hexane: EA = 5: 1)4-(l-(phenylamino)piperidin-4-yl)cyclohexan-l-one (3w)124581.000010 | 25-T-072

[0293] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 19.4 mg Iw as the starting material, giving 3w as a colorless oil (10.7 mg, 71% for step 1, 55% for step 2, 39% overall yield for two steps). NMR: 'H NMR. (500 MHz, CDCl3) 67.25 - 7.16 (m, 2H), 6.94 - 6.87 (m, 2H), 6.84 - 6.74 (m, 1H), 3.27 (dt, J = 10.6, 2.9 Hz, 2H), 2.46 - 2.40 (m, 2H), 2.36 (td, J= 13.7, 5.8 Hz, 2H), 2.23 - 2.15 (m, 2H), 2.11 (ddd, J= 13.1, 6.1, 3.0 Hz, 2H), 1.84 - 1.76 (m, 2H), 1.67 - 1.59 (m, 2H), 1.51 (td, J = 12.6, 4.1 Hz, 4H).13C NMR (126 MHz, CDCI3) 6212.15, 147.66, 129.13, 119.30, 113.59, 56.78, 40.92, 40.79, 39.57, 29.94, 29.71. HRMS: HRMS-ESI& APCI mix mode calcd for C17H25N2O+[M+H] 273.1961, found 273.1956. IR: (KBr cm-1): 2927.50, 1715.81, 1603.16, 1495.55, 751.95. Rf: 0.10 (Hexane: EA = 5: 1)N-(4-hexylphenyl)-l -(phenylamino)piperidine-4-carboxamide (3x)

[0294] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 30.1 mg lx as the starting material, giving 3x as a yellow colored oil (23.9 mg, 90% for step 1, 69% for step 2, 63% overall yield for two steps). NMR: 'H NMR (500 MHz, CDCI3) 67.44 (d, J= 8.1 Hz, 2H), 7.26 - 7.19 (m, 2H), 7.18 - 7.10 (m, 3H), 6.98 - 6.89 (m, 2H), 6.82 (tt, J= 7.3, 1.2 Hz, 1H), 4.43 (s, 1H), 3.35 - 3.24 (m, 2H), 2.59 (t, J = 7.7 Hz, 2H), 2.39 - 2.24 (m, 3H), 2.15 - 1.93 (m, 4H), 1.62 - 1.59 (m, 2H), 1.32 (qq, J= 7.7, 4.3 Hz, 6H), 0.92 - 0.88 (m, 3H).13C NMR (151 MHz, CDCI3) 6 172.67, 147.46, 139.22, 135.34, 129.19, 128.92, 119.92, 119.52, 113.62, 55.64, 43.61, 35.37, 31.73, 31.49, 29.07, 28.90, 22.62, 14.11. HRMS: HRMS-ESI& APCI mix mode calcd for C24H34N3O+[M+H] 380.2696, found 380.2687. IR: (KBr cm ): 3294.28, 2926.77, 2854.48, 1660.84, 1600.61, 1521.03, 1411.61, 1252.56, 751.80. Rf: 0.71 (Hexane: EA = 2: 1)N-phenyl-4-(2-(phenylethynyl)phenyl)piperidin-l -amine (3y)124581.000010 | 25-T-072

[0295] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 27.4 mg ly as the starting material, giving 3y as yellow color oil (12.3 mg, 82% for step 1, 43% for step 2, 35% overall yield for two steps). NMR: 'H NMR. (600 MHz, CDCl3) 67.56 (dd, J= 7.9, 4.0 Hz, 3H), 7.39 (t, J= 7.8 Hz, 3H), 7.36 (d, J= 4.3 Hz, 2H), 7.23 (t, J= 7.8 Hz, 3H), 6.96 (d, J= 8.0 Hz, 2H), 6.82 (t, J= 7.3 Hz, 1H), 4.47 (s, 1H), 3.44 - 3.36 (m, 2H), 3.22 (p, J= 8.0 Hz, 1H), 2.43 (td, J= 10.3, 6.9 Hz, 2H), 2.04 (dt, J = 9.3, 4.4 Hz, 4H).13C NMR (151 MHz, CDCI3) 6 147.71, 147.33, 132.46, 131.44, 129.16, 128.76, 128.47, 128.32, 126.04, 125.58, 123.49, 122.33, 119.33, 113.64, 93.40, 88.00, 57.22, 40.08, 32.39. HRMS: HRMS-ESI& APCI mix mode calcd for C25H25N2+[M+H] 353.2012, found 353.2015. IR: (KBr cm’1): 2956.26, 2146.83, 1601.55, 1495.06, 755.49, 691.95. Rf:0.32 (Hexane: EA = 10: 1)4-(l-(phenylamino)piperidin-4-yl)phenyl trifluorom ethanesulfonate (3z)

[0296] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 32.2 mg Iz as the starting material, giving 3z as a colorless oil (24.0 mg, 85% for step 1, 70% for step 2, 60% overall yield for two steps). NMR: 'H NMR (600 MHz, Chloroform^ / ) 67.35 (d, J= 8.5 Hz, 2H), 7.24 (t, J= 7.5 Hz, 4H), 6.98 - 6.92 (m, 2H), 6.82 (t, J= 7.3 Hz, 1H), 4.44 (s, 1H), 3.40 - 3.32 (m, 2H), 2.62 (dd, J= 10.3, 4.8 Hz, 1H), 2.36 (td, J= 10.5, 5.4 Hz, 2H), 1.94 (td, J= 9.6, 8.2, 3.4 Hz, 4H).13C NMR(151 MHz, CDCI3) 6 147.94, 147.56, 146.34, 129.18, 128.57, 128.56, 121.29, 119.47, 113.64, 56.74, 41.45, 33.47.19F NMR (565 MHz, Chloroform^ / ) 6 -72.88. HRMS: HRMS-ESI& APCI mix mode calcd for C18H20F3SO3N2+[M+H] 401.1141, found 401.1135. IR: (KBr cm’1): 2925.42, 1603.33, 1497.19, 1423.46, 1249.73, 1212.90, 1141.21, 888.93, 840.10, 751.53, 694.79, 608.52. Rf:0.10 (Hexane: EA= 10: 1)F124581.000010 | 25-T-0724-((ls,4s)-4-(3,4-difluorophenyl)cyclohexyl)-N-phenylpiperidin-l-amine (3aa)

[0297] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 29.2 mg laa as the starting material, giving 3aa as a white solid (20.0 mg, 89% for step 1, 60% for step 2, 54% overall yield for two steps). NMR: 'H NMR. (600 MHz, Chloroform^ / ) 67.26 - 7.20 (m, 2H), 7.11 - 7.06 (m, 1H), 7.04 - 6.98 (m, 1H), 6.96 -6.89 (m, 3H), 6.80 (td, J= 7.3, 1.3 Hz, 1H), 4.38 (s, 1H), 3.26 (dt, J= 11.2, 3.3 Hz, 2H), 2.45 (tt, J = 12.3, 3.4 Hz, 1H), 2.23 - 2.15 (m, 2H), 1.94 (td, J = 12.5, 11.7, 3.6 Hz, 4H), 1.78 (dt, J= 13.3, 2.9 Hz, 2H), 1.54 - 1.47 (m, 2H), 1.42 (td, J= 12.6, 3.4 Hz, 2H), 1.26 - 1.10 (m, 4H).13C NMR (151 MHZ, CDCl3) 6 151.05, 150.97, 149.42, 149.33, 147.79, 147.72, 144.68, 144.65, 144.62, 129.12, 122.54, 122.52, 122.50, 122.48, 119.21, 116.87, 116.76, 115.48, 115.37, 113.60, 57.02, 43.73, 41.83, 40.82, 34.38, 30.26, 29.51.19F NMR (565 MHz, Chloroform -tZ) 6 -138.60 (ddd,20.8, 12.0, 8.3 Hz), -142.43 (dddd, J= 22.1, 11.4, 8.1, 4.2 Hz). HRMS: HRMS-ESI& APCI mix mode calcd for C23H29F2N2+[M+H] 371.2293, found 371.2292. IR: (KBr cm’1): 2918.18, 2848.17, 1603.92, 1515.73, 1494.02, 1284.32, 1110.38, 867.89, 759.05, 698.48. Rf: 0.29 (Hexane: EA = 10: 1)Ftrans-3-((benzo[d][l,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-N-phenylpiperidin-l- amine (3ab-A)

[0298] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 34.2 mg lab-A as the starting material, giving 3ab-A as a pale-yellow oil (17.7 mg, 75% for step 1, 56% for step 2, 42% overall yield for two steps). NMR: 'H NMR (600 MHz, CDCI3) 67.26 - 7.19 (m, 4H), 7.01 (t, J= 8.6 Hz, 2H), 6.99 - 6.95 (m, 2H), 6.83 (t, J= 7.3 Hz, 1H), 6.63 (d, J= 8.5 Hz, 1H), 6.34 (d, J= 2.5 Hz, 1H), 6.13 (dd, J= 8.5, 2.5 Hz, 1H), 5.89 (s, 2H), 4.50 (s, 1H), 3.64 - 3.53 (m, 2H), 3.48 (dd, J= 9.3, 5.9 Hz, 1H), 3.36 (dd, J= 10.5, 4.2 Hz, 1H), 2.57 (td, J= 11.5, 4.1 Hz, 1H), 2.36 (dddd, J= 12.2, 9.1, 6.5,124581.000010 | 25-T-0723.7 Hz, 3H), 2.03 (qd, J= 12.4, 3.9 Hz, 1H), 1.92 (dq, J= 13.5, 3.0 Hz, 1H).13C NMR (151 MHz, CDCl3) 6 162.41, 160.79, 154.32, 148.16, 147.54, 141.62, 139.27, 139.25, 129.19, 128.87, 128.82, 121.42, 119.46, 115.55, 115.41, 113.64, 107.84, 105.57, 101.09, 97.96, 69.28, 60.00, 56.85, 43.37, 42.56, 34.18.19F NMR (565 MHz, CDCI3) 6 -116.34 (tt, J= 9.1, 5.3 Hz). HRMS: HRMS-ESI& APCI mix mode calcd for C25H26FN2O3+[M+H] 421.1922, found 421.1913. IR: (KBr cm’1): 2926.47, 2359.28, 1603.96, 1488.30, 1466.12, 1184.90, 1038.42, 832.40, 752.49, 695.36, 468.48. Rf: 0.55 (Hexane: EA= 10: 1)HN1trans-4-((benzo[d][l,3]dioxol-5-yloxy)methyl)-3-(4-fluorophenyl)-N-phenylpiperidin-l- amine (3ab-B)

[0299] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 34.2 mg lab-B as the starting material, giving 3ab-B as a pale yellow oil (19.8 mg, 79% for step 1, 59% for step 2, 47% overall yield for two steps). NMR: 'H NMR. (600 MHz, Chloroform^ / ) 67.21 (dtd, J= 17.5, 6.4, 5.5, 1.9 Hz, 4H), 7.00 (t, J= 8.6 Hz, 2H), 6.96 - 6.92 (m, 2H), 6.81 (t, J= 7.3 Hz, 1H), 6.66 (d, J= 8.5 Hz, 1H), 6.38 (d, J= 2.5 Hz, 1H), 6.18 (dd, J= 8.5, 2.5 Hz, 1H), 5.91 (s, 2H), 4.45 (s, 1H), 3.67 (dd, J= 9.1, 3.1 Hz, 1H), 3.52 (dd, J= 9.1, 7.0 Hz, 1H), 3.43 - 3.37 (m, 1H), 3.30 (ddd, J= 10.7, 4.0, 1.7 Hz, 1H), 2.95 (td, J= 11.3, 3.9 Hz, 1H), 2.42 - 2.31 (m, 2H), 2.14 (dq, J= 13.5, 3.1 Hz, 1H), 1.97 (dtt, J= 10.8, 6.8, 3.4 Hz, 1H), 1.88 (td, J= 12.6, 3.9 Hz, 1H). 13C NMR (151 MHz, CDC13) 6 162.53, 160.90, 154.45, 148.18, 147.47, 141.58, 137.16, 129.18, 129.12, 129.06, 119.52, 115.56, 115.42, 113.67, 107.86, 105.53, 101.10, 97.96, 70.62, 63.52, 56.38, 44.69, 40.95, 29.24.19F NMR (470 MHz, Chloroform^ / ) 6 -115.92 (tt, J= 8.8, 5.3 Hz). HRMS: HRMS-ESI& APCI mix mode calcd for C25H26FN2O3+[M+H] 421.1922, found 421.1917. IR: (KBr cm’1): 2917.74, 1735.03, 1602.92, 1488.18, 1184.99, 831.24, 467.24. Rf: 0.52 (Hexane: EA = 10: 1)124581.000010 | 25-T-072methyl 2-(4-(l-(phenylamino)piperidin-4-yl)phenyl)-2H-indazole-7-carboxylate (3ac-A)

[0300] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 34.8 mg lac-A as the starting material, giving 3ac-A as a pale-yellow oil (23.1 mg, 79% for step 1, 68% for step 2, 54% overall yield for two steps). NMR: 'H NMR. (600 MHz, Chloroform^ / ) 6 8.54 (s, 1H), 8.17 (d, J= 7.0 Hz, 1H), 8.02 - 7.98 (m, 1H), 7.95 - 7.93 (m, 2H), 7.45 - 7.43 (m, 2H), 7.26 - 7.21 (m, 3H), 6.99 - 6.96 (m, 2H), 6.83 (t, J= 7.1 Hz, 1H), 4.08 (s, 3H), 3.39 (d, J= 10.7 Hz, 2H), 2.69 - 2.64 (m, 1H), 2.39 (td, J= 10.9, 4.2 Hz, 2H), 2.09 - 1.96 (m, 4H).13C NMR (151 MHz, CDCl3) 6 166.63, 147.63, 146.89, 146.29, 138.67, 131.63, 129.19, 127.93, 126.25, 124.37, 121.51, 121.49, 121.25, 119.70, 119.42, 113.65, 56.85, 52.28, 41.60, 33.50. HRMS: HRMS-ESI& APCI mix mode cal cd for C26H27N4O2+[M+H] 427.2129, found 427.2107. IR: (KBr cm-1): 2946.52, 1714.90, 1602.54, 1556.61, 1527.34, 1495.51, 1435.01, 1381.48, 1270.48, 1203.15, 1141.33, 754.03, 695.83. Rf: 0.45 (Hexane: EA = 2: 1)methyl 2-(4-(l-(phenylamino)piperi din-3 -yl)phenyl)-2H-indazole-7-carboxylate (3ac-B)

[0301] Following the standard reaction condition, the reaction was conducted at 0.05 mmol scale with 17.4 mg lac-B as the starting material, giving 3ac-B as a pale yellow oil (10.0 mg, 75% for step 1, 63% for step 2, 47% overall yield for two steps). NMR: 'H NMR (600 MHz, CDCI3) 8 8.53 (s, 1H), 8.16 (d, J= 6.9 Hz, 1H), 7.98 (d, J= 8.3 Hz, 1H), 7.95 - 7.90 (m, 2H), 7.43 (d, J= 8.1 Hz, 2H), 7.23 (q, J= 7.7 Hz, 4H), 6.96 (d, J= 8.0 Hz, 2H), 6.82 (t, J= 7.2 Hz, 1H), 4.50 (s, 1H), 4.07 (d, J= 1.6 Hz, 3H), 3.38 (d, J= 9.8 Hz, 1H), 3.32 - 3.26 (m, 1H), 3.12 - 3.05 (m, 1H), 2.38 - 2.29 (m, 2H), 2.01 (d, J= 16.7 Hz, 1H), 1.94 - 1.85 (m, 2H), 1.57 - 1.47 (m, 1H).13C NMR (151 MHz, CDCI3) 6 166.62, 147.54, 146.89, 144.25, 138.78, 131.64, 129.19, 128.27, 126.23, 124.37, 121.50, 121.39, 121.21, 119.72,124581.000010 | 25-T-072119.43, 113.59, 63.24, 56.62, 52.26, 42.53, 31.03, 25.36. HRMS: HRMS-ESI& APCI mix mode calcd for C26H27N4O2+[M+H] 427.2129, found 427.2106. IR: (KBr cm’1): 2934.61, 1713.59, 1602.40, 1526.41, 1494.83, 1381.40, 1280.24, 1202.17, 1141.49, 833.27, 756.54, 696.91, 505.48, 491.45. Rf: 0.55 (Hexane: EA = 2: 1)4-(( 1 OH-phenothiazin- 10-yl)methyl)-N -phenylpiperidin- 1 -amine (3ad- A)

[0302] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 31.0 mg lad-A as the starting material, giving 3ad-A as a pale-yellow oil (19.8 mg, 85% for step 1, 60% for step 2, 51% overall yield for two steps). NMR: 'H NMR (500 MHz, CDCl3) 67.19 (tdd, J= 7.2, 3.5, 2.0 Hz, 6H), 6.96 (td, J= 7.5, 1.2 Hz, 2H), 6.89 (ddd, J= 16.0, 8.4, 1.1 Hz, 4H), 6.78 (tt, J= 7.3, 1.2 Hz, 1H), 3.82 (d, J= 6.6 Hz, 2H), 3.17 (dd, J= 10.4, 4.1 Hz, 2H), 2.23 - 2.09 (m, 2H), 1.97 (dq, J= 13.3, 3.3 Hz, 3H), 1.52 -1.42 (m, 2H).13C NMR (126 MHz, CDCI3) 6 147.64, 145.62, 129.10, 127.71, 127.22, 125.83, 122.58, 119.24, 115.79, 113.54, 56.04, 52.80, 32.37, 30.14. HRMS: HRMS-ESI& APCI mix mode calcd for C24H26N3S+[M+H] 388.1842, found 388.1849. IR: (KBr cm’x): 2925.89, 1732.06, 1602.05, 1572.36, 1494.88, 1456.15, 1331.32, 1284.41, 1249.69, 1214.94, 1137.74, 1104.52, 1038.26, 836.09, 750.50, 694.63. Rf: 0.13 (Hexane: EA = 10: 1)3 -(( 1 OH-phenothiazin- 10-yl)methyl)-N -phenylpiperidin- 1 -amine (3ad-B)

[0303] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 31.0 mg lad-B as the starting material, giving 3ad-B as a pale yellow oil (17.0 mg, 82% for step 1, 54% for step 2, 44% overall yield for two steps). NMR:1H NMR (600 MHz, CDCI3) 67.21 - 7.16 (m, 4H), 7.16 - 7.12 (m, 2H), 6.96 (td, J= 7.5, 1.2 Hz, 2H), 6.92 (dd, J= 8.1, 1.2 Hz, 2H), 6.82 - 6.79 (m, 2H), 6.77 (tt, J= 7.3, 1.2 Hz, 1H), 4.35 (s, 1H), 4.05 - 3.80 (m, 2H), 3.18 - 2.77 (m, 2H), 2.51 - 2.27 (m, 3H), 1.90 - 1.72 (m, 2H), 1.69 - 1.54 (m, 2H).13C NMR (151 MHz, CDCI3) 6 147.47, 145.60, 129.08, 127.70, 127.20,124581.000010 | 25-T-072126.06, 122.57, 119.24, 115.79, 113.53, 60.15, 57.19, 50.10, 33.52, 27.39, 24.09. HRMS: HRMS-ESI& APCI mix mode calcd for C24H26N3S+[M+H] 388.1842, found 388.1836. IR:(KBr cm-1): 2934.24, 1601.35, 1494.70, 1457.21, 1331.07, 1284.81, 1250.37, 1212.49, 749.83, 694.57, 452.01. Rf: 0.16 (Hexane: EA = 10: 1)N-phenyl-N-(l -(phenylamino)piperidin-4-yl)propionamide (3ae-A)

[0304] Following the standard reaction condition, but benzene was used as the solvent for the cyclization step, the reaction was conducted at 0.1 mmol scale with 24.5 mg lae-A as the starting material, giving 3ae-A as a colorless oil (13.8 mg, 75% for step 1, 55% for step 2, 42% overall yield for two steps). NMR: 'HNMR (600 MHz, CDCl3) 67.51 - 7.42 (m, 4H), 7.18 - 7.12 (m, 4H), 6.84 - 6.79 (m, 2H), 6.76 (tt, J= 7.3, 1.2 Hz, 1H), 4.71 (tt, J = 12.2, 3.9 Hz, 1H), 4.35 (s, 1H), 3.25 - 3.18 (m, 2H), 2.41 - 2.36 (m, 2H), 1.95 (q, J= 7.4 Hz, 2H), 1.88 - 1.83 (m, 2H), 1.58 - 1.52 (m, 2H), 1.04 (t, J = 7.5 Hz, 3H).13C NMR (151 MHz, CDCI3) 6 173.65, 147.45, 138.93, 130.31, 129.44, 129.08, 128.44, 119.34, 113.53, 55.68, 51.73, 30.43, 28.53, 9.61. HRMS: HRMS-ESI& APCI mix mode calcd for C20H26N3O+[M+H] 324.2070, found 324.2055. IR: (KBr cm-1): 2936.03, 1645.56, 1595.78, 1495.53, 1398.46, 1256.77, 750.18, 704.89. Rf: 0.39 (Hexane: EA = 2: 1)N-phenyl-N-(l-(phenylamino)piperi din-3 -yl)propionamide (3ae-B)

[0305] Following the standard reaction condition, but benzene was used as the solvent for the cyclization step, the reaction was conducted at 0.1 mmol scale with 24.5 mg lae-B as the starting material, giving 3ae-B as a colorless oil (15.4 mg, 77% for step 1, 62% for step 2, 48% overall yield for two steps). NMR: 'HNMR (600 MHz, Chloroform-t / ) 6 7.43 (d, J= 6.3 Hz, 3H), 7.21 (t, J= 7.7 Hz, 2H), 7.11 (dd, J= 22.0, 14.7 Hz, 2H), 6.90 (d, J124581.000010 | 25-T-072= 7.9 Hz, 2H), 6.80 (t, J= 7.3 Hz, 1H), 4.93 (tt, J= 11.8, 3.9 Hz, 1H), 4.36 (s, 1H), 3.34 (dd, J= 10.4, 3.6 Hz, 1H), 3.11 (d, J= 10.5 Hz, 1H), 1.92 (dq, J= 15.1, 7.7, 7.0 Hz, 5H), 1.84 - 1.77 (m, 1H), 1.72 (dt, J= 13.5, 3.5 Hz, 1H), 1.11 (tt, J = 12.5, 6.3 Hz, 1H), 1.02 (t, J = 7.4 Hz, 3H).13C NMR (151 MHZ, CDCl3) 6 173.47, 147.37, 139.28, 130.19, 129.38, 129.17, 128.40, 119.42, 113.54, 60.10, 55.96, 51.30, 28.66, 28.45, 23.83, 9.55. HRMS: HRMS-ESI& APCI mix mode calcd for C20H26N3O+[M+H] 324.2070, found 324.2061. IR: (KBr cm’x): 2937.12, 1675.28, 1634.85, 1592.17, 1493.22, 1399.80, 1392.84, 1211.56, 751.24, 706.72.Rf: 0.41 (Hexane: EA = 2: 1)CFN-phenyl-2-(3-((5-(trifluoromethyl)pyri din-2 -yl)oxy)benzyl)piperi din- 1 -amine (3af-A)

[0306] Following the standard reaction condition, but increasing the condensation temperature to 80 °C, the reaction was conducted at 0.1 mmol scale with 34.9 mg laf-A as the starting material, giving 3af-A as a colorless oil (19.5 mg, 75% for step 1, 62% for step 2, 46% overall yield for two steps).

[0307] As an alternative method, a ketone mixture derived from ketone chainwalking isomerization was utilized. The CO to N swap reaction was conducted at 0.2 mmol scale with 69.9 mg of the ketone mixture (0.09 mmol P-isomer, 0.07 mmol y-isomer and 0.04 mmol 8-isomer) as the starting material, giving a mixture of 3af-A, 3af-B and 3af-C as a colorless oil. After preparative TLC separation, 3af-A was isolated as a colorless oil (14.2 mg, 37% overall yield, calculated based on 0.09 mmol P-isomer).

[0308] NMR: 'H NMR (600 MHz, CDCI3) 6 8.47 (s, 1H), 7.90 (dd, J= 8.1, 2.4 Hz, 1H), 7.34 (d, J= 7.8 Hz, 1H), 7.19 (t, J= 7.8 Hz, 2H), 7.06 (d, J= 7.7 Hz, 1H), 7.02 -6.94 (m, 3H), 6.90 (d, J= 7.9 Hz, 2H), 6.77 (t, J= 7.3 Hz, 1H), 4.27 (s, 1H), 3.40 (dd, J = 13.3, 3.5 Hz, 1H), 3.23 (d, J= 11.0 Hz, 1H), 2.55 (dd, J= 13.5, 8.8 Hz, 1H), 2.51 -2.43 (m, 1H), 2.21 (td, J= 10.7, 3.8 Hz, 1H), 1.74 - 1.65 (m, 3H), 1.36 (q, J= 11.2 Hz, 2H), 1.20 (d, J = 13.2 Hz, 1H).13C NMR (126 MHz, CDCI3) 6 165.96, 152.97, 148.58, 145.60, 145.57, 142.45, 136.62, 136.58, 129.33, 129.02, 126.90, 124.55, 122.52, 121.56, 121.30, 118.83, 118.66, 113.31, 111.16, 66.93, 57.40, 39.71, 30.99, 25.90, 23.92.19F NMR (470 MHz, Chloroform^ / ) 6 -61.62. HRMS: HRMS-ESI& APCI mix mode calcd for C24H25F3N3O+[M+H] 428.1944, found 428.1957. IR: (KBr cm’1): 3741.92, 3626.30, 2929.27, 2852.89,124581.000010 | 25-T-0722357.59, 2338.03, 1603.35, 1584.44, 1494.56, 1483.31, 1445.12, 1393.01, 1326.85, 1284.45, 1261.84, 1161.33, 1127.97, 1077.44, 1011.50, 751.22, 694.97, 506.99. Rf: 0.21 (Hexane: EA = 10: 1)N-phenyl-3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)piperidin-l-amine (3af-B)

[0309] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 34.9 mg laf-B as the starting material, giving 3af-B as a colorless oil (22.6 mg, 80% for step 1, 66% for step 2, 53% overall yield for two steps).

[0310] As an alternative method, using (0.09 mmol P-isomer, 0.07 mmol y-isomer and 0.04 mmol 6-isomer) as the starting material, 3af-B was isolated as a colorless oil (15.2 mg, 51% overall yield, calculated based on 0.07 mmol y-isomer).

[0311] NMR: 1H NMR (500 MHz, Chloroform-d) 88.48 - 8.41 (m, 1H), 7.88 (dd, J= 8.7, 2.6 Hz, 1H), 7.35 (t, J= 7.8 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.07 (dt, J= 7.7, 1.3 Hz, 1H), 7.03 - 6.93 (m, 3H), 6.93 - 6.84 (m, 2H), 6.78 (tt, J= 7.3, 1.2 Hz, 1H), 4.38 (s, 1H), 3.08 (s, 2H), 2.71 -2.54 (m, 2H), 2.23 (s, 1H), 2.11 - 1.99 (m, 2H), 1.81 - 1.62 (m, 3H), 1.08 - 0.96 (m, 1H).13C NMR (151 MHz, CDCl3) 6 165.91, 153.12, 147.63, 145.60, 145.57, 142.49, 136.66, 136.64, 129.61, 129.11, 126.30, 124.63, 122.02, 121.54, 121.32, 119.23, 118.93, 113.44, 111.17, 62.47, 57.00, 40.47, 38.25, 29.81, 24.81. HRMS: HRMS-ESI& APCI mix mode calcd for C24H25F3N3O+[M+H] 428.1944, found 428.1951. IR: (KBr cm’1): 2359.09, 1604.13, 1494.94, 1326.95, 1284.36, 1128.04, 1077.50, 695.16. Rf: 0.16 (Hexane: EA = 10: 1)N-phenyl-4-(3-((5-(trifluoromethyl)pyri din-2 -yl)oxy)benzyl)piperi din- 1 -amine (3af-C)124581.000010 | 25-T-072

[0312] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 34.9 mg laf-C as the starting material, giving 3af-C as a colorless oil (24.4 mg, 81% for step 1, 70% for step 2, 57% overall yield for two steps).

[0313] As an alternative method, using (0.09 mmol P-isomer, 0.07 mmol y-isomer and 0.04 mmol 6-isomer) as the starting material, 3af-C was isolated as a colorless oil (8.5 mg, 50% overall yield, calculated based on 0.04 mmol 6-isomer).

[0314] NMR: 'H NMR (600 MHz, CDCl3) 6 8.49 - 8.46 (m, 1H), 7.92 (dd, J= 8.7, 2.6 Hz, 1H), 7.37 (t, J= 7.9 Hz, 1H), 7.23 - 7.19 (m, 2H), 7.08 (dt, J= 7.6, 1.3 Hz, 1H), 7.05 - 7.00 (m, 2H), 6.97 (t, J= 2.0 Hz, 1H), 6.92 - 6.87 (m, 2H), 6.79 (tt, J= 7.2, 1.2 Hz, 1H), 4.36 (s, 1H), 3.27 - 3.16 (m, 2H), 2.62 (d, J= 7.1 Hz, 2H), 2.22 - 2.14 (m, 2H), 1.79 -1.69 (m, 3H), 1.51 - 1.44 (m, 2H).13C NMR (151 MHz, CDCI3) 6 165.89, 153.13, 147.71, 145.58, 145.55, 142.89, 136.67, 129.57, 129.12, 126.32, 124.62, 122.83, 122.01, 121.60, 121.38, 119.24, 118.89, 113.56, 111.31, 56.49, 42.69, 37.23, 32.14.19F NMR (470 MHz, CDCI3) 6 -61.63. HRMS: HRMS-ESI& APCI mix mode calcd for C24H25F3N3O+[M+H] 428.1944, found 428.1945. IR: (KBr cm-1): 2925.17, 1605.45, 1482.75, 1326.94, 1284.65, 1262.20, 1129.05, 1077.56, 835.70, 751.52, 694.99. Rf: 0.13 (Hexane: EA = 10: 1)HOmethyl l-(phenylamino)piperidine-4-carboxylate (3ag-A)

[0315] Following the procedure of Milan, Highly Enantioselective Oxidation of Nonactivated Aliphatic C-H Bonds with Hydrogen Peroxide Catalyzed by Manganese Complexes. ACS Cent. Sci. 3, 196-204, 2017, lag was converted into two positional ketone isomers in 1: 1.2 ratio (8: y) with an overall yield of 47% (reported yield, 40% reproduced yield). Following the standard reaction condition, the CO-to-N swap reaction was conducted at 0.2 mmol scale with 31.2 mg ketone mixture (0.091 mmol 6-isomer and 0.11 mmol y-isomer) as the starting material, giving a mixture of 3ag-A and 3ag-B as a pale-yellow oil. After preparative TLC separation, 3ag-A was isolated as a pale-yellow oil (11.1 mg, 52% overall yield, calculated based on 0.091 mmol y-isomer). NMR:1H NMR (500 MHz, Chloroform^ / ) 67.23 - 7.19 (m, 2H), 6.92 - 6.89 (m, 2H), 6.80 (tt, J= 7.3, 1.2 Hz, 1H), 4.41 (s, 1H), 3.72 (s, 3H), 3.16 (d, J= 10.9 Hz, 2H), 2.39 - 2.30 (m, 3H), 1.97 (dtd, J= 20.6, 10.4, 9.2, 3.6 Hz, 4H).13C NMR (126 MHz, CDCI3) 6 175.31, 147.49, 129.16, 119.43, 113.58,124581.000010 | 25-T-07255.52, 51.75, 39.37, 28.38. HRMS: HRMS-ESI& APCI mix mode calcd for C13H19N2O2+[M+H] 235.1441, found 235.1445. IR: (KBr cm-1): 2975.34, 2914.85, 1720.22, 1701.78, 1699.02, 1583.96, 1283.34, 894.73, 873.41, 775.16. Rf: 0.45 (Hexane: EA = 10: 1)methyl l-(phenylamino)piperidine-3 -carboxylate (3ag-B)

[0316] 3ag-B was isolated as a pale-yellow oil (10.1 mg, 40% overall yield, calculated based on 0.11 mmol y-isomer). NMR: 'H NMR (500 MHz, Chloroform -tZ) 67.21 (t, J= 7.6 Hz, 2H), 6.89 (d, J= 8.0 Hz, 2H), 6.85 - 6.77 (m, 1H), 4.45 (s, 1H), 3.70 (s, 3H), 3.25 (d, J= 10.5 Hz, 1H), 3.10 - 2.98 (m, 1H), 2.75 (tt, J= 10.1, 3.9 Hz, 1H), 2.51 (s, 1H), 2.35 (d, J= 10.7 Hz, 1H), 1.98 - 1.80 (m, 2H), 1.79 - 1.66 (m, 1H), 1.61 - 1.47 (m, 1H).13C NMR (126 MHz, CDCl3) 6 173.96, 147.41, 129.13, 119.47, 113.58, 58.02, 56.43, 51.69, 42.00, 26.21, 24.41. HRMS: HRMS-ESI& APCI mix mode calcd for C13H19N2O2+[M+H] 235.1441, found 235.1443. IR: (KBr cm ): 3120.64, 3024.95, 2996.17, 2965.35, 2864.22, 1735.89, 1705.46, 1606.27, 1445.61, 997.53, 925.14, 755.83, 652.01. Rf: 0.40 (Hexane: EA = 10: 1)O(l-(phenylamino)piperidin-4-yl)methyl pivalate (3ah-A)

[0317] Following the procedure of Chen, Combined Effects on Selectivity in Fe-Catalyzed Methylene Oxidation. Science 327, 566-571, 2010, lah was converted into two positional ketone isomers in 1: 2.3 ratio (6: y) with an overall yield of 66% (reported yield, 53% reproduced yield). Following the standard reaction condition, the CO-to-N swap reaction was conducted at 0.4 mmol scale with 84.8 mg ketone mixture (0.12 mmol 6-isomer and 0.28 mmol y-isomer) as the starting material, giving a mixture of 3ah-A and 3ah-B as a pale-yellow oil. After preparative TLC separation, 3ah-A was isolated as a pale-yellow oil (16.6 mg, 47% overall yield, calculated based on 0.12 mmol 6-isomer). NMR:1H NMR (500 MHz, Chloroform^ / ) 67.26 - 7.16 (m, 2H), 6.94 - 6.87 (m, 2H), 6.83 - 6.75 (m, 1H), 4.39 (s, 1H), 3.97 (d, J= 6.5 Hz, 2H), 3.23 (dt, J= 10.8, 3.3 Hz, 2H), 2.23 (td, J= 11.4, 2.5 Hz, 2H), 1.83 - 1.75 (m, 2H), 1.75 - 1.69 (m, 1H), 1.55 - 1.46 (m, 2H), 1.24 (s, 9H).13C NMR124581.000010 | 25-T-072(126 MHz, CDCl3) 6 178.54, 147.62, 129.14, 119.32, 113.55, 68.31, 55.98, 38.88, 34.81, 28.94, 27.25. HRMS: HRMS-ESI& APCI mix mode calcd for C17H27N2O2+[M+H] 291.2067, found 291.2070. IR: (KBr cm-1): 3105.72, 2998.15, 1736.83, 1707.48, 1537.64, 1502.09, 1407.68, 983.01, 675.37. Rf: 0.67 (Hexane: EA = 10: 1)HNli(l-(phenylamino)piperi din-3 -yl)methyl pivalate (3ah-B)

[0318] 3ah-B was isolated as a pale-yellow oil (18.7 mg, 49% overall yield, calculated based on 0.28 mmol y-isomer). NMR: 'H NMR (500 MHz, Chloroform -tZ) 67.21 (t, J= 7.7 Hz, 2H), 6.94 - 6.85 (m, 2H), 6.85 - 6.76 (m, 1H), 4.41 (s, 1H), 4.11 - 3.92 (m, 2H), 3.20 -2.99 (m, 2H), 2.29 (s, 1H), 2.15 (d, J= 10.3 Hz, 2H), 1.80 (tt, J= 7.2, 4.0 Hz, 1H), 1.72 (tdd, J= 13.3, 8.4, 5.5 Hz, 2H), 1.20 (s, 9H), 1.13 (d, J= 11.3 Hz, 1H).13C NMR (126 MHz, CDCI3) 6 178.51, 147.52, 129.14, 119.35, 113.53, 66.50, 59.44, 56.88, 38.84, 36.24, 27.21, 26.47, 24.45. HRMS: HRMS-ESI& APCI mix mode calcd for C17H27N2O2+[M+H] 291.2067, found 291.2075. IR: (KBr cm-1): 3120.85, 3100.71, 1786.49, 1707.51, 1559.46, 1502.17, 1216.35, 975.31, 685.23. Rf: 0.65 (Hexane: EA = 10: 1)4-(6-fluoroquinolin-4-yl)-N-phenylpiperidin-l -amine (3ai-A)

[0319] Following the procedure of Chambers, A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C-H oxidation of carbocyclic N-heterocycles. Proc. Natl. Acad. Sci. U. S. A. 120, e2300315120 (2023), lai was converted into two positional ketone isomers in 1: 1.2 ratio (8: y) with an overall yield of 56% (reported yield, 44% reproduced yield). Following the standard reaction condition, the CO-to-N swap reaction was conducted at 0.2 mmol scale with 48.6 mg of the ketone mixture (0.091 mmol 6-isomer and 0.11 mmol y-isomer) as the starting material, giving a mixture of 3ai-A and 3ai-B as a paleyellow oil. After preparative TLC separation, 3ai-A was isolated as a pale-yellow oil (17.8 mg, 61% overall yield, calculated based on 0.091 mmol 6-isomer). NMR: 1H NMR (500 MHz, Chloroform-d) 6 8.87 (d, J= 4.5 Hz, 1H), 8.16 (dd, J= 9.2, 5.7 Hz, 1H), 7.69 (dd, J = 10.4, 2.8 Hz, 1H), 7.51 (ddd, J= 9.3, 7.9, 2.8 Hz, 1H), 7.39 (d, J= 4.6 Hz, 1H), 7.27 - 7.23124581.000010 | 25-T-072(m, 2H), 7.02 - 6.95 (m, 2H), 6.84 (tt, J= 7.3, 1.2 Hz, 1H), 4.52 (s, 1H), 3.50 - 3.42 (m, 2H), 3.24 (tt, J= 10.4, 5.6 Hz, 1H), 2.52 (td, J= 10.7, 4.6 Hz, 2H), 2.13 - 2.05 (m, 4H).13C NMR (126 MHz, CDCl3) 6 161.63, 159.66, 150.72, 150.68, 149.74, 149.72, 147.50, 145.60, 133.12, 133.05, 129.22, 127.71, 127.63, 119.56, 119.28, 119.08, 118.12, 113.64, 106.55, 106.38, 56.79, 36.82, 32.45.19F NMR (470 MHz, Chloroform^ / ) 6 -112.65 (dt, J= 14.1, 7.1 Hz). HRMS: HRMS-ESI& APCI mix mode calcd for C20H21FN2+[M+H] 322.4069. found 322.4066. IR: (KBr cm-1): 3075.26, 3025.31, 2986.52, 1935.20, 1897.54, 971.54, 865.20, 756.33. Rf: 0.25 (Hexane: EA = 1: 1)3 -(6-fluoroquinolin-4-yl)-N -phenylpiperidin- 1 -ami ne (3ai-B)

[0320] 3ai-A was isolated as a pale-yellow oil (11.6 mg, 33% overall yield, calculated based on 0.11 mmol y-isomer). NMR: 'H NMR (500 MHz, Chloroform -tZ) 6 8.83 (d, J= 4.6 Hz, 1H), 8.14 (dd, J= 9.2, 5.7 Hz, 1H), 7.75 (dd, J= 10.4, 2.8 Hz, 1H), 7.50 (ddd, J= 9.3, 7.9, 2.8 Hz, 1H), 7.38 (d, J= 4.6 Hz, 1H), 7.27 - 7.23 (m, 2H), 7.02 - 6.94 (m, 2H), 6.83 (td, J= 7.3, 1.2 Hz, 1H), 3.67 (tt, J= 10.8, 3.5 Hz, 1H), 3.53 - 3.42 (m, 1H), 3.42 - 3.28 (m, 1H), 2.52 - 2.36 (m, 2H), 2.11 - 2.06 (m, 1H), 1.99 (pd, J= 8.8, 8.1, 4.1 Hz, 2H), 1.70 - 1.58 (m, 1H).13C NMR (126 MHz, CDCI3) 6 161.68, 159.71, 149.47, 149.45, 148.85, 148.81, 147.32, 145.56, 132.95, 132.88, 129.26, 127.75, 127.68, 119.66, 119.39, 119.18, 118.58, 113.62, 106.76, 106.58, 62.08, 56.77, 37.73, 30.33, 25.36.19F NMR (470 MHz, Chloroform-t / ) 6 -112.19 - -112.30 (m). HRMS: HRMS-ESI& APCI mix mode calcd for C20H21FN2+[M+H] 322.4069. found 322.4057. IR: (KBr cm-1): 3037.53, 3036.15, 3000.28, 1957.34, 1622.03, 1598.35, 1577.23, 1520.65, 1470.26, 1463.25, 1270.69, 1144.53, 805.27, 653.79. Rf: 0.27 (Hexane: EA = 1: 1)4-(tert-butyl)-N-phenylpiperidin- 1 -amine (3aj-A)

[0321] Following the procedure of Milan, Highly Enantioselective Oxidation of Nonactivated Aliphatic C-H Bonds with Hydrogen Peroxide Catalyzed by Manganese124581.000010 | 25-T-072Complexes. ACS Cent. Sci. 3, 196-204 (2017), laj was converted into two positional ketone isomers in 1: 1.4 ratio (6: y) with an overall yield of 53% (reported yield, 41% reproduced yield). Following the standard reaction condition, the CO-to-N swap reaction was conducted at 0.2 mmol scale with 30.8 mg of the ketone mixture (0.083 mmol 6-isomer and 0.12 mmol y-isomer) as the starting material, giving a mixture of 3aj-A and 3aj-B as a pale-yellow oil. After preparative TLC separation, 3aj-A was isolated as a colorless oil (8.2 mg, 43% overall yield, calculated based on 0.083 mmol 6-isomer).

[0322] NMR:1H NMR (500 MHz, Chloroform^ / ) 87.25 - 7.17 (m, 2H), 6.95 -6.87 (m, 2H), 6.79 (tt, J= 7.3, 1.2 Hz, 1H), 4.33 (s, 1H), 3.28 (dt, J= 10.4, 2.3 Hz, 2H), 2.20 - 2.06 (m, 2H), 1.73 (dt, J= 13.1, 3.0 Hz, 2H), 1.49 (qd, J= 12.4, 3.7 Hz, 2H), 1.04 (tt, J = 12.1, 3.5 Hz, 1H), 0.91 (s, 9H).13C NMR (126 MHz, CDCI3) 6 147.83, 129.10, 119.13, 113.58, 57.33, 45.99, 32.13, 27.47, 26.96. HRMS: HRMS-ESI& APCI mix mode calcd for C15H25N2+[M+H] 233.2012, found 233.2017. IR: (KBr cm’1): 3071.28, 1574.35, 768.24, 722.01, 628.34. Rf: 0.72 (Hexane: EA = 20: 1)H%3-(tert-butyl)-N-phenylpiperidin-l-amine (3aj-B)

[0323] 3aj-B was isolated as a colorless oil (10.6 mg, 38% overall yield, calculated based on 0.12 mmol y-isomer). NMR: *HNMR (500 MHz, Chloroform-t / ) 67.24 - 7.17 (m, 2H), 6.94 - 6.86 (m, 2H), 6.79 (tt, J= 7.2, 1.1 Hz, 1H), 4.41 (s, 1H), 3.29 (ddt, J= 10.2, 3.5, 1.8 Hz, 1H), 3.24 - 3.14 (m, 1H), 2.03 (ddd, J= 12.9, 10.5, 2.8 Hz, 1H), 1.91 (t, J= 10.7 Hz, 1H), 1.83 - 1.72 (m, 2H), 1.66 (dddd, J= 16.8, 12.8, 8.4, 4.1 Hz, 1H), 1.53 - 1.44 (m, 1H), 0.99 (td, J= 12.4, 3.9 Hz, 1H), 0.90 (s, 9H).13C NMR (126 MHz, CDCl3) 6 147.77, 129.13, 119.06, 113.44, 58.88, 57.03, 46.56, 31.84, 27.69, 25.57, 24.87. HRMS: HRMS-ESI& APCI mix mode calcd for C15H25N2+[M+H] 233.2012, found 233.2015. IR: (KBr cm’1): 3050.12, 1554.37, 735.21, 700.29, 624.39. Rf: 0.65 (Hexane: EA = 20: 1)methyl 3-(4-(l-(phenylamino)piperidin-4-yl)phenyl)quinoline-4-carboxylate (3ak-A)124581.000010 | 25-T-072

[0324] Following the procedure of Chambers, A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C-H oxidation of carbocyclic N-heterocycles. Proc. Natl. Acad. Sci. U. S. A. 120, e2300315120 (2023), lakwas converted into two positional ketone isomers in 1: 1 ratio (y: 8) with an overall yield of 34% (reported yield, 21% reproduced yield). Following the standard reaction condition, the CO-to-N swap reaction was conducted at 0.2 mmol scale with 71.9 mg of the ketone mixture (0.1 mmol y-isomer and 0.1 mmol 6-isomer) as the starting material, giving a mixture of 3ak-A and 3ak-B as a paleyellow oil. After preparative TLC separation, 3ak-A was isolated as a pale-yellow oil (24.9 mg, 57% overall yield, calculated based on 0.1 mmol y-isomer). NMR:1H NMR (500 MHz, Chloroform^ / ) 6 8.76 (dd, J= 8.6, 1.4 Hz, 1H), 8.42 (s, 1H), 8.24 (d, J= 8.4 Hz, 1H), 8.19 (d, J= 8.0 Hz, 2H), 7.80 (ddd, J= 8.4, 6.8, 1.4 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.46 (d, J= 8.1 Hz, 2H), 7.27 - 7.22 (m, 2H), 6.99 - 6.96 (m, 2H), 6.83 (t, J= 7.2 Hz, 1H), 4.46 (s, 1H), 4.11 (s, 3H), 3.42 - 3.34 (m, 2H), 2.68 (tt, J= 11.6, 4.5 Hz, 1H), 2.42 - 2.36 (m, 2H), 2.02 (dtd, J = 26.6, 14.7, 13.9, 4.3 Hz, 4H).13C NMR (126 MHz, CDCI3) 6 166.92, 156.62, 149.31, 147.72, 147.67, 136.97, 135.59, 130.30, 129.90, 129.18, 127.70, 127.62, 127.49, 125.43, 123.93, 120.28, 119.38, 113.65, 56.95, 52.76, 41.89, 33.45. HRMS: HRMS-ESI& APCI mix mode calcd for C28H28N3O2+[M+H] 438.2176, found 438.2180. IR: (KBr cm-1): 3107.54, 2927.88, 1733.06, 1602.28, 1577.46, 1457.29, 1335.74, 1331.20, 1217.56, 1177.24, 1101.25, 834.72, 756.50, 699.47. Rf: 0.37 (Hexane: EA = 5: 1)N«HNmethyl 3-(4-(l-(phenylamino)piperidin-3-yl)phenyl)quinoline-4-carboxylate (3ak-B)

[0325] 3ak-B was isolated as a pale-yellow oil (19.7 mg, 45% overall yield, calculated based on 0.1 mmol 6-isomer). NMR: *HNMR (500 MHz, Chloroform-t / ) 6 8.75 (d, J= 8.5 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J= 8.4 Hz, 1H), 8.16 (d, J= 8.2 Hz, 2H), 7.80 -7.76 (m, 1H), 7.64 (ddd, J= 8.4, 6.8, 1.4 Hz, 1H), 7.44 (d, J= 8.1 Hz, 2H), 7.23 (t, J= 7.7 Hz, 2H), 6.96 (d, J= 7.9 Hz, 2H), 6.81 (t, J= 7.3 Hz, 1H), 4.50 (s, 1H), 4.10 (s, 3H), 3.44 -3.35 (m, 1H), 3.30 (d, J= 10.7 Hz, 1H), 3.09 (ddt, J= 11.3, 7.4, 3.7 Hz, 1H), 2.40 - 2.28 (m, 2H), 2.02 (d, J= 13.8 Hz, 1H), 1.91 (dq, J= 10.7, 6.5, 5.1 Hz, 2H), 1.53 (dd, J= 11.4, 5.6 Hz, 1H).13C NMR (126 MHz, CDCl3) 6 166.91, 156.55, 149.29, 147.59, 145.69, 137.07,124581.000010 | 25-T-072135.59, 130.29, 129.90, 129.18, 127.80, 127.71, 127.55, 125.42, 123.93, 120.26, 119.39, 113.61, 63.23, 56.66, 52.75, 42.83, 31.02, 25.45. HRMS: HRMS-ESI& APCI mix mode calcd for C28H28N3O2+[M+H] 438.2176, found 438.2175. IR: (KBr cm-1): 2933.57, 1735.08, 1607.59, 1457.65, 1337.07, 1484.20, 1213.49, 698.27. Rf: 0.40 (Hexane: EA = 5: 1)(4aR,4bS,6aR,7R,9aS,9bS)-4a,6a-dimethyl-7-((R)-6-methylheptan-2-yl)-N- phenylhexadecahydro-2H-indeno[5,4-f]isoquinolin-2-amine (3al)

[0326] Following the standard reaction condition, except running the reaction at 80°C / 3h with 3.5 equiv. of TsN2Ph reagent for the azonation step, the reaction was conducted at 0.1 mmol scale with 38.6 mg lai as the starting material, giving 3al as a pale-yellow colored oil (17.1 mg, 47% for step 1, 78% for step 2, 37% overall yield for two steps). NMR:'HNMR (500 MHz, CDCl3) 87.23 - 7.19 (m, 2H), 6.90 (d, J= 7.7 Hz, 2H), 6.78 (t, J= 7.3 Hz, 1H), 4.39 (s, 1H), 3.07 (dt, J= 11.2, 3.2 Hz, 1H), 2.80 (ddd, J= 10.6, 3.5, 1.5 Hz, 1H), 2.43 (ddd, J= 13.5, 10.9, 2.8 Hz, 1H), 2.20 (t, J= 11.1 Hz, 1H), 2.00 (dt, J= 12.7, 3.4 Hz, 1H), 1.89 - 1.75 (m, 2H), 1.72 - 1.64 (m, 2H), 1.62 - 1.45 (m, 4H), 1.37 (dtd, J= 17.1, 9.9, 3.9 Hz, 5H), 1.26 (ddd, J= 15.8, 12.7, 6.6 Hz, 3H), 1.21 - 1.11 (m, 6H), 1.08 - 0.97 (m, 3H), 0.93 (d, J= 6.6 Hz, 3H), 0.89 (dd, J= 6.7, 2.3 Hz, 7H), 0.88 (s, 3H), 0.78 - 0.72 (m, 1H), 0.68 (s, 3H).13C NMR (126 MHz, CDCI3) 6 147.88, 129.11, 119.10, 113.51, 67.11, 57.65, 56.42, 56.25, 54.15, 52.65, 45.74, 42.73, 39.95, 39.53, 38.34, 36.19, 35.81, 35.49, 34.11, 31.72, 28.25, 28.03, 25.56, 24.18, 23.84, 22.84, 22.58, 21.04, 18.70, 12.12, 12.08. HRMS:HRMS-ESI& APCI mix mode calcd for C32H52N2+[M+H] 465.4203, found 465.4195. IR: (KBr cm ): 2930.47, 1601.95, 1495.87, 748.47, 692.88, 464.62. Rf: 0.39 (Hexane: EA= 10: 1)124581.000010 | 25-T-0723-(3-(cyclopentyloxy)-4-methoxyphenyl)-N-phenyl-l-oxa-2,8-diazaspiro[4.5]dec-2-en-8- amine (3am)

[0327] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 34.3 mg of lam as the starting material, giving 3am as a pale-yellow colored oil (18.1 mg, 85% for step 1, 51% for step 2, 43% overall yield for two steps). NMR:1H NMR (500 MHz, Chloroform^ / ) 67.40 (d, J=2.0 Hz, 1H), 7.24 - 7.19 (m, 2H), 7.03 (dd, J= 8.3, 2.0 Hz, 1H), 6.96 - 6.91 (m, 2H), 6.87 (d, J= 8.3 Hz, 1H), 6.81 (tt, J= 7.2, 1.1 Hz, 1H), 4.84 (tt, J= 6.5, 3.3 Hz, 1H), 4.48 (s, 1H), 3.90 (s, 3H), 3.12 (s, 2H), 2.90 (d, J= 56.3 Hz, 4H), 2.09 (d, J= 13.2 Hz, 2H), 2.00 (qt, J= 10.9, 9.6, 3.3 Hz, 5H), 1.94 - 1.81 (m, 5H).13C NMR (126 MHz, CDCI3) 6 156.12, 151.77, 147.88, 147.52, 129.17, 122.63, 119.81, 119.47, 113.63, 111.88, 111.10, 83.27, 80.49, 56.04, 52.98, 45.34, 36.17, 32.79, 24.08.HRMS: HRMS-ESI& APCI mix mode calcd for C25H32N3O3+[M+H] 422.2438, found 422.2438. IR: (KBr cm’1): 2954.83, 1602.58, 1513.97, 1255.82, 1175.93, 894.28, 710.84, 628.58, 530.29. Rf: 0.74 (Hexane: EA = 2: 1)N OHN(5R,6aS,7S,9aS,9bS)-5-(4-(dimethylamino)phenyl)-6a-methyl-2-(phenylamino)-7-propyl- 2,3,4,5,6,6a,7,8,9,9a,9b,10,ll,lla-tetradecahydro-lH-indeno[5,4-f]isoquinolin-7-ol (3an)

[0328] Following the standard reaction condition, except running the reaction in benzene, the reaction was conducted at 0.1 mmol scale with 43.5 mg lan as the starting material, giving 3ann as a colorless oil (30.8 mg, 74% for step 1, 81% for step 2, 60% overall yield for two steps). NMR: 1H NMR (500 MHz, Chloroform-d) 67.36 - 7.29 (m, 2H), 7.18 -7.13 (m, 2H), 6.82 (d, J= 7.6 Hz, 2H), 6.75 (dd, J= 8.0, 6.7 Hz, 1H), 6.72 (d, J= 8.4 Hz, 2H), 4.73 (s, 1H), 3.46 (d, J= 4.9 Hz, 1H), 3.26 (s, 1H), 2.97 (s, 6H), 2.90 - 2.86 (m, 1H), 2.73 (td, J= 6.7, 4.6 Hz, 1H), 2.23 - 2.00 (m, 5H), 2.01 - 1.75 (m, 4H), 1.61 (dddd, J= 21.8, 19.5, 15.2, 9.5 Hz, 4H), 1.54 - 1.32 (m, 6H), 1.25 (d, 33.1 Hz, 2H), 1.00 (t, J = 6.9 Hz, 3H), 0.52 (s, 3H).13C NMR (126 MHz, CDCl3) 6 148.16, 147.85, 133.57, 128.98, 128.84, 126.15, 119.03, 113.67, 112.57, 83.96, 58.63, 50.89, 49.09, 47.43, 40.73, 39.72, 39.22, 36.82, 35.92, 34.32, 30.94, 28.18, 27.19, 23.29, 16.95, 16.50, 14.98. HRMS: HRMS-ESI& APCI124581.000010 | 25-T-072mix mode calcd for C34H4sN3O+[M+H] 514.3792, found 514.3799. (This compound is not stable under MS conditions; it will eliminate water and dimerize. The desired molecular weight peak was not the major peak.) IR: (KBr cm-1): 3457.31, 2967.02, 2919.38, 2910.07, 2875.64, 2355.17, 1731.05, 1665.29, 1578.21, 1520.86, 1453.72, 1378.08, 1205.45, 1005.98, 925.84, 917.23, 815.06, 767.18, 705.26. Rf: 0.20 (Hexane: EA = 5: 1)4-methoxy-4-(3-(naphthalen-2-ylmethoxy)phenyl)-N-phenylpiperidin-l -amine (3ao)

[0329] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 36.0 mg lao as the starting material, giving 3ao as a colorless oil (27.2 mg, 88% for step 1, 70% for step 2, 62% overall yield for two steps). NMR: 'H NMR. (500 MHz, Chloroform^ / ) 67.94 - 7.86 (m, 4H), 7.59 (d, J= 8.5 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.33 (t, J= 8.0 Hz, 1H), 7.23 (t, J= 7.7 Hz, 2H), 7.15 (s, 1H), 7.08 - 6.97 (m, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.81 (t, J= 7.3 Hz, 1H), 5.28 (s, 2H), 4.47 (s, 1H), 3.13 - 3.05 (m, 2H), 3.00 (s, 3H), 2.69 (td, J= 10.9, 3.3 Hz, 2H), 2.14 (dtd, J= 15.4, 12.6, 11.9, 5.1 Hz, 4H).13C NMR (126 MHz, CDCl3) 6 159.01, 147.73, 146.16, 134.46, 133.32, 133.10, 129.46, 129.16, 128.42, 127.95, 127.76, 126.46, 126.27, 126.11, 125.38, 119.31, 118.74, 113.62, 113.50, 113.19, 74.95, 70.19, 51.84, 49.74, 34.82. HRMS: HRMS-ESI& APCI mix mode calcd for C29H31N2O2+[M+H] 439.2380, found 439.2367. IR: (KBr cm-1): 2952.63, 1602.45, 1495.40, 1251.68, 1072.95, 816.25, 752.22, 695.96. Rf: 0.29 (Hexane: EA = 5: 1)8-(phenylamino)-2-(4-(trifluoromethoxy)phenyl)-2,8-diazaspiro[4.5]decan-l-one (3ap)

[0330] Following the standard reaction condition, the reaction was conducted at 0.1 mmol scale with 32.7 mg lap as the starting material, giving 3ap as a pale-yellow colored oil (20.1 mg, 69% for step 1, 72% for step 2, 50% overall yield for two steps). NMR:'H NMR (600 MHz, Chloroform^ / ) 67.79 - 7.71 (m, 2H), 7.27 - 7.21 (m, 4H), 6.95 (d, J= 7.9 Hz, 2H), 6.82 (t, J= 7.3 Hz, 1H), 4.48 (s, 1H), 3.82 (t, J= 6.9 Hz, 2H), 3.22 (dt, J= 11.2, 4.2 Hz, 2H), 2.48 (t, J= 11.4 Hz, 2H), 2.23 (ddd, J= 16.1, 11.8, 4.6 Hz, 2H), 2.15 (t, J= 6.9124581.000010 | 25-T-072Hz, 2H), 1.67 (d, J= 13.6 Hz, 2H).13C NMR (151 MHz, CDCl3) 6 177.62, 147.46, 145.38, 138.17, 129.20, 124.13, 121.56, 121.35, 120.72, 119.64, 119.54, 116.79, 113.64, 52.44, 45.07, 43.66, 32.80, 29.36.19F NMR (565 MHz, Chloroform^ / ) 6 -58.09. HRMS: HRMS-ESI& APCI mix mode calcd for C2iH23F3N3O2+[M+H] 406.1737, found 406. 1728. IR: (KBr cm’1): 2936.22, 1693.92, 1603.22, 1510.52, 1393.36, 1258.09, 1222.68, 1162.81, 848.17, 753.56, 696.19. Rf: 0.58 (Hexane: EA = 2: 1)

[0101] (v) 5.4 Free amine productsHin4-phenylpiperidine (4b)

[0331] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.1 mmol scale with 25.2 mg 3b as the starting material (collected from several parallel reactions), giving 4b as a white solid (15.6 mg, 97% yield). NMR: 1H NMR (500 MHz, Chloroform-d) 67.33 (t, J= 7.5 Hz, 2H), 7.27 - 7.19 (m, 3H), 3.22 (dt, J= 12.3, 3.1 Hz, 2H), 2.77 (td, J= 12.2, 2.5 Hz, 2H), 2.64 (tt, J= 12.2, 3.8 Hz, 1H), 1.89 (d, J = 14.6 Hz, 2H), 1.67 (qd, J= 12.5, 4.0 Hz, 2H).13C NMR (126 MHz, CDCI3) 6 146.79, 128.44, 126.82, 126.10, 47.21, 43.11, 34.53.3 -phenylpiperidine (4c)

[0332] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.1 mmol scale with 25.2 mg 3c as the starting material (collected from several parallel reactions), giving 4c as a colorless oil (15.5 mg, 96% yield). NMR: 1H NMR (500 MHz, Chloroform-d) 67.32 (dd, J= 8.6, 6.4 Hz, 2H), 7.26 - 7.20 (m, 3H), 3.24 -3.08 (m, 2H), 2.79 - 2.57 (m, 3H), 2.41 (s, 1H), 2.08 - 1.94 (m, 1H), 1.80 (ddq, J= 10.3, 7.3, 4.2, 3.5 Hz, 1H), 1.71 - 1.56 (m, 2H).13C NMR (126 MHz, CDCI3) 6 144.75, 128.41, 127.10, 126.31, 53.83, 46.51, 44.12, 32.04, 26.93.124581.000010 | 25-T-0722, 3,4, 5 -tetrahydro- 1 H-benzo[d] azepine (4d)

[0333] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.1 mmol scale with 23.8 mg 3d as the starting material (collected from several parallel reactions), giving 4d as a colorless oil (13.2 mg, 90% yield). NMR: 'H NMR (500 MHz, Chloroform ) 67.16 - 7.09 (m, 4H), 3.00 (dd, J= 8.2, 2.4 Hz, 4H), 2.98 -2.94 (m, 4H), 2.86 (q, J= 5.2, 4.6 Hz, 1H).13C NMR (126 MHz, CDCl3) 6 141.97, 129.25, 126.27, 48.36, 39.51.3-phenylpyrrolidine (4e)

[0334] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.1 mmol scale with 23.8 mg 3e as the starting material (collected from several parallel reactions), giving 4e as a colorless oil (13.5 mg, 92% yield). NMR: 1H NMR (500 MHz, Chloroform-d) 67.32 (t, J= 7.6 Hz, 2H), 7.28 - 7.25 (m, 2H), 7.24 - 7.20 (m, 1H), 3.38 (dd, J= 10.8, 7.6 Hz, 1H), 3.28 - 3.20 (m, 1H), 3.18 (ddd, J= 13.3, 7.5, 3.8 Hz, 1H), 3.11 (dt, J= 10.9, 7.5 Hz, 1H), 2.87 (dd, J= 10.8, 8.2 Hz, 1H), 2.26 (dtd, J= 12.8, 8.0, 4.8 Hz, 1H), 2.02 (d, J= 13.0Hz, 1H), 1.88 (dtd, J= 12.6, 8.5, 7.3 Hz, 1H).13C NMR (126 MHz, CDCI3) 6 144.40, 128.45, 127.21, 126.14, 55.38, 47.52, 45.69, 34.59.2-benzylpiperidine (4f)

[0335] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.1 mmol scale with 26.6 mg 3f as the starting material (collected from several parallel reactions), giving 4f as a colorless oil (14.8 mg, 85% yield). NMR: 1H NMR (500 MHz, Chloroform-d) 87.30 (d, J= 7.5 Hz, 2H), 7.25 - 7.19 (m, 3H), 2.99 (ddt, J = 11.6, 4.2, 2.1 Hz, 1H), 2.77 -2.66 (m, 2H), 2.63 - 2.56 (m, 1H), 2.52 (td, J= 11.8, 2.8 Hz, 1H), 1.80 (dtd, J= 12.3, 3.5, 1.8 Hz, 1H), 1.75 - 1.65 (m, 1H), 1.63 - 1.54 (m, 1H), 1.53 -1.40 (m, 1H), 1.38 - 1.19 (m, 2H).13C NMR (126 MHz, CDCI3) 6 139.17, 129.29, 128.45, 126.24, 58.29, 47.07, 43.79, 32.79, 26.08, 24.81.124581.000010 | 25-T-0724,4-diphenylpiperidine (4g)

[0336] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.1 mmol scale with 32.8 mg 3g as the starting material (collected from several parallel reactions), giving 4g as a white solid (21.8 mg, 92% yield). NMR: 1H NMR (500 MHz, Chloroform-d) 67.32 - 7.27 (m, 8H), 7.17 (tt, J= 7.1, 2.0 Hz, 2H), 3.00 -2.93 (m, 4H), 2.43 (dd, J= 6.7, 4.2 Hz, 4H), 1.99 (s, 1H).13C NMR (126 MHz, CDCl3) 6 147.69, 128.42, 128.38, 127.10, 125.73, 45.11, 43.27, 37.45.phenyl(piperidin-4-yl)methanone (4h-amine)

[0337] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.1 mmol scale with 28.0 mg 3h as the starting material (collected from several parallel reactions), giving 4h-amine as a colorless oil (18.0 mg, 95% yield). 4h-amine can be further converted to (l-methylpiperidin-4-yl)(phenyl)methanone (4h) as described in Orjales, Syntheses and Binding Studies of New [(Aryl)(aryloxy)methyl]piperidine Derivatives and Related Compounds as Potential Antidepressant Drugs with High Affinity for Serotonin (5-HT) and Norepinephrine (NE) Transporters. J. Med. Chem. 46, 5512-5532 (2003) with 89% yield. NMR:XH NMR (600 MHz, Chloroform^ / ) 87.98 - 7.93 (m, 2H), 7.59 - 7.55 (m, 1H), 7.48 (t, J= 7.8 Hz, 2H), 3.46 - 3.38 (m, 1H), 3.20 (dt, J= 12.7, 3.5 Hz, 2H), 2.79 (td, J= 12.3, 2.7 Hz, 2H), 1.96 -1.82 (m, 3H), 1.70 (dtd, J= 13.5, 11.6, 4.0 Hz, 2H).13C NMR (151 MHz, CDCI3) 6202.56, 136.02, 132.92, 128.68, 128.29, 46.13, 44.07, 29.77.piperidin-4-yl 2,2-diphenylacetate (4i-amine)124581.000010 | 25-T-072

[0338] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.1 mmol scale with 38.6 mg 3i as the starting material (collected from several parallel reactions), giving 4i-amine as a white solid (28.0 mg, 95% yield). 4i-amine can be further converted to 4-(2,2-diphenylacetoxy)-l,l-dimethylpiperidin-l-ium iodide (4i) as described in Recanatini, Synthesis, muscarinic blocking activity and molecular modeling studies of 4-DAMP -related compounds. Bioorg. Med. Chem. 3, 267-277 (1995) with 80% yield. NMR: *HNMR (500 MHz, Chloroform^ / ) 87.36 - 7.29 (m, 10H), 5.02 (s, 1H), 4.95 - 4.92 (m, 1H), 2.81 (d, J= 9.7 Hz, 2H), 2.75 (s, 2H), 1.87 (d, J= 13.1 Hz, 2H), 1.67 (d, J= 10.6 Hz, 2H).13C NMR (126 MHz, CDCl3) 6 171.54, 138.35, 128.90, 128.69, 128.49, 128.26, 127.44, 126.37, 67.96, 57.16, 40.87, 28.28.HA3 -(piperi din-3 -yl)phenol (4j-amine)

[0339] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.1 mmol scale with 26.8 mg 3j as the starting material (collected from several parallel reactions), giving 4j-amine as a colorless oil (14.5 mg, 82% yield). 4j-amine can be further converted to 3-(l-propylpiperidin-3-yl)phenol (4j) as described in Liu, Decarboxylative Negishi Coupling of Redox -Active Aliphatic Esters by Cobalt Catalysis. Angew. Chem. Int. Ed. 57, 13096-13100 (2018) with 75% yield. NMR:XH NMR (600 MHz, Methanol-t / 4) 67.17 (t, J= 7.8 Hz, 1H), 6.78 - 6.69 (m, 3H), 3.48 - 3.37 (m, 2H), 3.10 - 3.02 (m, 2H), 3.02 - 2.93 (m, 1H), 2.09 - 2.00 (m, 2H), 1.93 (dddd, J= 15.2, 13.3, 9.2, 4.1 Hz, 1H), 1.84 - 1.76 (m, 1H).13C NMR (151 MHz, MeOD) 6 157.56, 142.57, 129.57, 117.74, 114.00, 113.61, 49.04, 43.69, 39.92, 29.48, 22.50.Cl4-phenylpiperidin-4-ol (4k)124581.000010 | 25-T-072

[0340] Following the standard reaction condition (step 2, deprotection), but shorting the reaction time to 30 min, (TLC is needed to determine whether the reaction was complete, longer reaction time will cause the elimination of the alcohol) the reaction was conducted at 0.1 mmol scale with 30.3 mg 3k as the starting material (collected from several parallel reactions), giving 4k as white solid (16.3n mg, 77% yield). NMR: 'H NMR. (500 MHz, Chloroform^ / ) 67.45 (d, J= 8.6 Hz, 2H), 7.33 (d, J= 8.6 Hz, 2H), 3.10 (td, J= 12.3, 2.6 Hz, 2H), 2.96 (dt, J= 12.2, 3.5 Hz, 2H), 1.98 (td, J= 13.0, 4.6 Hz, 4H), 1.71 (dd, J = 14.1, 2.6 Hz, 2H).13C NMR (126 MHz, CDCl3) 6 147.45, 132.72, 128.42, 126.09, 71.42, 42.31, 39.22.Ospiro[chromane-2,4'-piperidin]-4-one (41-amine)

[0341] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.1 mmol scale with 30.8 mg 31 as the starting material (collected from several parallel reactions), giving 41-amine as a pale-yellow solid (21.0 mg, 97% yield).41-amine can be further converted to l'-benzylspiro[chromane-2,4'-piperidin]-4-one (41) as described in Varasi, Discovery, Synthesis, and Pharmacological Evaluation of Spiropiperidine Hydroxamic Acid Based Derivatives as Structurally Novel Histone Deacetylase (HD AC) Inhibitors. J. Med. Chem. 54, 3051-3064 (2011) with 92% yield.NMR: 1H NMR (500 MHz, Chloroform-d) 87.87 (dd, J= 8.0, 1.8 Hz, 1H), 7.50 (ddd, J= 8.8, 7.2, 1.8 Hz, 1H), 7.06 - 6.95 (m, 2H), 3.09 (ddd, J= 12.3, 11.1, 2.9 Hz, 2H), 2.92 (dt, J = 12.7, 4.1 Hz, 3H), 2.74 (s, 2H), 2.05 (dt, J= 12.5, 3.0 Hz, 2H), 1.69 (ddd, J= 14.5, 11.3, 4.5 Hz, 2H).13C NMR (126 MHz, CDCI3) 6 191.92, 159.09, 136.30, 126.57, 121.06, 120.79, 118.35, 78.07, 48.29, 41.52, 34.79.3H-spiro[isobenzofuran-l,4'-piperidine] (4m)124581.000010 | 25-T-072

[0342] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.1 mmol scale with 28.0 mg 3m as the starting material (collected from several parallel reactions), giving 4m as a colorless oil (18.3 mg, 97% yield). NMR: 'H NMR (600 MHz, Chloroform^ / ) 67.34 - 7.25 (m, 2H), 7.25 - 7.21 (m, 1H), 7.20 - 7.11 (m, 1H), 5.09 (s, 2H), 3.16 - 3.02 (m, 4H), 2.67 (s, 2H), 1.92 (td, J= 12.8, 5.2 Hz, 2H), 1.78 (d, J = 13.5 Hz, 2H).13C NMR (151 MHZ, CDCl3) 6 145.79, 138.84, 127.61, 127.38, 121.11, 120.84, 85.01, 70.79, 42.91, 37.00.Oethyl 4-(2-(piperidin-4-yl)ethoxy)benzoate (4n-amine)

[0343] Following the standard reaction condition (step 2, deprotection), the reaction was conducted at 0.05 mmol scale with 18.4 mg 3n as the starting material (collected from several parallel reactions), giving 4n-amine as a white solid (13.7 mg, 99% yield). 4n-amine can be further converted to pirodavir (4n) as described in Stokbroekx, Pyridazine derivatives as antivirals. (1989) with 75% yield. NMR: 'H NMR (500 MHz, Methanol-t / 4) 6 8.03 - 7.90 (m, 2H), 7.07 - 6.92 (m, 2H), 4.34 (q, J= 7.1 Hz, 2H), 4.16 (t, J = 6.1 Hz, 2H), 3.39 (dt, J= 13.0, 3.5 Hz, 2H), 2.99 (td, J= 12.9, 3.0 Hz, 2H), 2.04 - 1.98 (m, 2H), 1.97 - 1.93 (m, 1H), 1.84 (q, J= 6.3 Hz, 2H), 1.56 - 1.45 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H).13C NMR (126 MHz, MeOD) 8 166.58, 162.90, 131.14, 122.49, 113.85, 65.24, 60.44, 53.40, 34.78, 30.96, 28.65, 13.24.piperidin-4-yl 2, 2-diphenyl-2 -propoxyacetate (4o-amine)

[0344] Following the standard reaction condition (step 2, deprotection), except heating the reaction mixture to 70°C, the reaction was conducted at 0.05 mmol scale with 22.2 mg 3o as the starting material, giving 4o-amine as a white solid (16.2 mg, 92% yield).4o-amine can be further converted to propiverine (4o) via reductive amination with 94% yield. NMR:XH NMR (500 MHz, Methanol^) 67.45 (dq, J= 4.5, 3.1, 2.6 Hz, 4H), 7.35 (q, J= 6.2 Hz, 6H), 5.05 (dt, J= 7.2, 3.6 Hz, 1H), 3.21 (t, J= 6.5 Hz, 2H), 2.84 - 2.74 (m, 3H),124581.000010 | 25-T-0721.90 - 1.82 (m, 2H), 1.61 (ddp, J= 11.1, 7.3, 3.9 Hz, 4H), 0.93 (t, = 7.4 Hz, 3H).13C NMR (126 MHz, MeOD) 6 171.07, 140.98, 128.28, 127.69, 127.46, 86.40, 69.90, 66.53, 41.60, 29.43, 22.78, 9.68.

[0345] Example 8: Summary of CO- to -N atom Swap

[0346] C-C bond cleavage of the PAI, formed in situ via condensation of the NAHA reagent with a cyclic ketone, yields an alkyl radical that attacks the diazene moiety to forge a C-N bond (Scheme 12, section A). Subsequent elimination of the sulfonyl radical furnishes an alkyl diazene that can then be intercepted intramolecularly by a distal alkyl radical, generated through the aryl halide-triggered second C-C bond activation. A final hydrogen-atom-transfer (HAT) step quenches the resulting TV-centered radical, completing the conversion of the cyclic ketone to the SNH. PAI-la derived from simple cyclohexanone was employed as the model substrate (Scheme 12, section B). Notably, NAHA-G2 containing an aryl bromide moiety was used, which exhibits better stability and better accessibility than the corresponding iodide-based one. Indeed, the employment of / ?-tosylphenyldiazene (TsN2Ph) as the radical acceptor successfully delivered the corresponding azo-substituted ring-opening product (2a) in 89% yield. Gratifyingly, azo 2a was subsequently converted to the desired piperidine product (3a) in decent yield during the second C-C bond activation event, i.e., treatment with 1.6 equivalents of («-Bu)sSnH and 30 mol% AIBN in CH3CN at 100 °C for 24 hours. Free piperidine moiety (4a) can be revealed in nearly quantitively yield from 3a after a mild reduction. Besides TSN2PI1, other types of nitrogen -based radical acceptors have also been investigated. While the use of the TsNs can afford the azidation product, the following intramolecular radical addition to the azide moiety exhibits poor efficiency. A range of 7V-Ts imines showed low reactivities in both the imine transfer and the radical annulation processes, though it was interesting to note that the more electron-deficient imines promoted the cyclization. Unfortunately, the sulfoximines and sulfilimines were inactive in the first radical addition event. After examining various aryl -substituted -tosyldiazenes, the simple phenyl substituted one, i.e., TSN2PI1, remains optimal. Comparable results were obtained with the tolyl-substituted diazene, whereas the more electron-deficient ones gave much lower yield.

[0347] Control experiments were next conducted to better understand the second C-C activation step. First, both («-Bu)sSnH and AIBN are critical for this transformation (entries 2 and 3). Replacing («-Bu)sSnH with less reactive (TMS)3SiH significantly decreased124581.000010 | 25-T-072the yield (entry 4). Other silane-based hydrides with stronger Si-H bonds were ineffective to deliver the desired product (entries 5-7). Regarding to the choice of solvent, benzene performed slightly better than CH3CN, while the use of PF1CF3 led to diminished reactivity. On the other hand, acetic acid and carbonate base were found detrimental to this reaction, though the exact reason remains unclear (entries 10 and 11). Finally, the annulation process prefers a more diluted condition (entry 12), which is likely to minimize the undesired intermolecular HAT with ( / / -BuhSnH. See, Table 10.Table 10Entry Variations from ‘Standard Condition’ Yield (3a) 1 None 75%2 Without ( / / -Bu)3SnH n.d.3 Without AIBN Trace4 (TMS)3SiH instead of ( / / -BuhSnH 10%5 Et3SiH instead of (n-Bu)3SnH n.d.6 i-Pr3SiH instead of (n-Bu)3SnH n.d.7 Benzene instead of CH3CN 68%8 PhCF3 instead of CH3CN 47%9 1.0 equiv CH3CO2H as an additive Trace10 1.0 equiv Cs2CO3as an additive 25%11 60°C instead 100°C 29%12 CH3CN (0.05 M) 52%124581.000010 | 25-T-072Scheme 12. Developing the carbonyl-to-nitrogen atom swap strategy.

[0348] In Scheme 12, section A shows the reaction design of the CO-to-N atom swap. Section C shows condition optimization using PAI-la as a model substrate. Section D shows the development of one-pot transformations. Unless mentioned otherwise, all reactions were run with PAI-la (0.1 mmol), 2a (0.05 mmol) or 3a (0.1 mmol). The yield was determined by 'H NMR with 1,1,2,2-tetrachloroethane as the internal standard. AIBN, azobisisobutyronitrile. HAT, hydrogen atom transfer. BSA, bis(trimethylsilyl)acetamide. n.d., not detected.

[0349] The PAI formation and the first activation event can be efficiently run in one step (Scheme 12, section C). In addition, the second activation and the piperidine deprotection can also be run in one pot to afford the free amine (4) with comparable yield to the two-step sequence, though the protected piperidines (3) remain the preferred isolates124581.000010 | 25-T-072during the substrate-scope studies due to their ease of purification and characterization (vide infra). Moreover, one-pot protocols of converting the 4-phenylcyclohexanone to the corresponding protected piperidine (3b) and free piperidine (4b) have been realized with good overall efficiency.124581.000010 | 25-T-072<&: 1Scheme 13. Scope of the CO-to-N atom swap strategy.

[0350] In Scheme 13, unless noted otherwise, the yield for the first activation step was determined by 'H NMR. with 1,1,2,2-tetrachloroethane as the internal standard. The124581.000010 | 25-T-072overall yield was determined by isolation. The yields for the second activation step were calculated by the overall yield and the yield of the first activation step. Condition A (deprotection): Zn (5.0 equiv.), acetic acid (0.2 M) at room temperature. Condition B (reductive amination): aldehyde (1.2 equiv.), NaB(OAc)3H (2.0 equiv.) in 30% acetic acid aqueous solution at room temperature. Condition C (alkylation): Mel (5.0 equiv.) in MeOH, reflux. *Biological activity data of compounds 4b-4o is shown herein. fThe yield of a 1.0 mmol scale reaction.

[0351] Substrate scope. The generality and FG tolerance of the CO-to-N atom swap were first examined in the context of synthesizing pharmaceutically relevant SNHs (4b-4o) (Scheme 13). From readily available y- and P-substituted cyclohexanones, the atom swap reaction offers a pair of piperidine positional isomers (3b and 3c), which, upon reductive cleavage of the N-N bond, delivered two known compounds exhibiting complementary biological activities. While piperidines represent one of the most abundant heterocycles in small-molecule drugs (38), the CO-to-N transformation is not limited to forming sixmembered SNHs; seven-membered (azepine 3d) and five-membered (pyrrolidine 3e) rings were also obtained in good yields. Moreover, the reaction tolerates a remarkable range of FGs, including ketones (3h and 3w), esters (3i, 3n,3o and 3s), phenol (3j), free alcohols (3k and 3t), aryl chlorides and fluorides (3k and 3aa), tertiary and secondary amides (3p and 3x), aryl ketones (3h and 31), heteroarenes (3q), ketal (3v), alkyne (3y), and aryl triflate (3z). In most cases, PhNH-protected piperidine products were isolated (instead of free amines) because they are much less polar and easier to be purified. It is noteworthy that the substrate with an a substituent (3f) worked well, and cyclohexanones bearing a C4 quaternary center (1g) are competent substrates. Apart from forming simple piperidines, this strategy is also effective to form spiro-A -heterocycles (31 and 3m), as well as piperazine (3r) and morpholine (3u). For the substrate that contains two symmetrical ketones (3w), it is possible to only replace one with nitrogen. Considering the widespread occurrence of SNHs in pharmaceutical applications, the removal of the NHPh group, sometimes coupled with simple downstream transformations, provides rapid access to a suite of known bioactive compounds that exhibit a wide spectrum of bioactivities (4b-4o), including the drugs pirodavir and propiverine. The intention of these examples is not to suggest that this method surpasses their original synthetic approaches in terms of preparing any specific target molecule; rather, it serves to124581.000010 | 25-T-072underscore the generality and versatility of the CO-to-N strategy in directly preparing a wide range of bioactive compounds from readily accessible ketones.

[0352] Synthetic utilities. Access to positional isomers of piperidine-containing bioactive compounds was first explored through integrating carbonyl 1,2-transposition with the CO-to-N atom swap (Scheme 14). From the readily available ketone precursors, the Pd / NBE-catalyzed method delivered the corresponding translocated ketones with complete site-selectivity, and the subsequent CO-to-N atom swap of the resulting ketone isomers conveniently produced two positional isomers of the cyclic amines in a divergent manner. Using this general strategy, pairs of positional isomers based on the paroxetine structure (3ab-A / B), the niraparib structure (3ac-A / B), and analogues of a caspase-like protein inhibitor (3ad-A / B) and an opiate receptor inhibitor (3ae-A / B), have been successfully obtained, which would otherwise require separate de novo syntheses. In addition, the Bhawal and Morandi’s carbonyl transposition approach allows simultaneous generation of distinct isomers of cycloketones, providing a highly streamlined route to multiple SNH positional variants from a single precursor. For example, ketone laf-A, prepared in two steps from commercially available starting materials, was transformed over three steps into three fully separable positional isomers (3af-A / B / C) of a monoglyceride lipase inhibitor. In total, only five steps were required to obtain all three analogues, whereas synthesis of a single analogue alone via the conventional approach demands five steps.124581.000010 | 25-T-0721ab-B3ad-A, (35%, 63%) 51% CO 1,2- I faseart Nosean tr&nsp&sitsoo w 36%3ad-B, (82%, 54%) 44% 3ae-B, (77%, 52%) 48% COtransposition - 1af-A two steps from commercial for lsf-A / S / 0}3af-A, (75%, 82%) 46%*, 37%+ 3af-B, (80%, 68%) 53%*, 51 %f3af-C, (81%, 70%) 57%*, 50%+&!£ w&£fa 5 Ste&g fa for prior wwfc S steps for synthsis of 3sf-C {Z ~ H) Scheme 14. Nitrogen scanning in sp3-rich scaffolds via merging carbonyl transposition with CO-to-N atom swap.

[0353] In Scheme 14, unless noted otherwise, the yield for the first activation step was determined by 'H NMR. with 1,1,2,2-tetrachloroethane as the internal standard. The overall yield was determined by isolation. The yields for the second activation step were calculated by the overall yield and the yield of the first activation step. *The yield was determined using pure ketone starting materials. fThe reaction was conducted with a mixture124581.000010 | 25-T-072of 3af-(A / B / C) as the starting material, and the yield of each product was determined based on the actual amount of the ketone in the starting material mixture.

[0354] As an alternative strategy for preparing diverse positional variants of SNHs, the CO-to-N atom swap enabled a net “CH2-to-N” transformation (Scheme 15, section A). Given that the C-H oxidation can occur at more than one site on the cycloalkane substrate or across different rings, this approach complements to the carbonyl transposition for accessing ketone isomers. Five representative pairs of examples are shown. Notably, the pair of quinoline-derived piperidines (3ai-A / B) previously required a 10-step synthesis, whereas the present strategy delivers them in only four steps from commercial starting materials.124581.000010 | 25-T-0723ag-A, 52% 3ag-B, 40%3ah-A, 47% 3ah-B, 49% C-H1al81alScheme 15. Further synthetic utilities of the CO-to-N atom swap strategy.

[0355] In Scheme 15, section A shows scanning nitrogen through merging C-H oxidation with CO-to-N atom swap. Section B shows late-stage modification of ketone- containing complex bioactive compounds. Section C shows isotope labelling enabled by CO-to-N atom swap. The yields of 3ag-A / B, 3ah-A / B, 3ai-A / B, 3aj-A / B and 3ak-A / B were determined based on the actual amount of the ketone in the mixture after the C-H oxidation step.124581.000010 | 25-T-072

[0356] To show additional utilities of the CO-to-N method, late-stage modifications of natural products and known bioactive compounds to prepare unusual analogues were explored (Scheme 15, section B). Substrates derived from cholesterol (lai), mifepristone (lan) and ketone-containing various types of inhibitors (lam, lao and lap) all underwent smooth CO-to-N atom swap to afford the corresponding / f-heterocycle analogues that would otherwise be challenging to prepare with the conventional approaches. For example, four-step reduction was realized for preparing the aza-cholesterol (3al) compared to known procedures. In addition, piperidine-based tetracycle 3an contains a previously unprecedented scaffold. Additional FGs, such as oxime ether (3am), electron-rich tertiary amine and tetra-substituted olefin (3an), tertiary alkyl ether (3ao), lactam and trifluoromethyl ether (3ap) were found well compatible. Moreover, the application of this method can be extended to access isotope-labeled amines by taking advantage of the favorable reactivity of ketones (Scheme 15, section C). Owing to facile H / D exchange at the a-position of ketones, in situ deuteration of substrate lb followed by CO-to-N atom swap delivered the tetradeuterated amine product (3b-D) in just two steps, whereas the prior synthesis required 7 steps. On the other hand, the use of the15N-enriched TsN2Ph reagent, conveniently prepared from sodium15N-nitrite, allowed efficient preparation of the previously unknown15N-labelled product 3b-15N with nearly complete isotope incorporation, offering an attractive approach for late-stage15N-labelling.

[0357] In conclusion, an efficient CO-to-N atom-swap strategy that converts ketones into the corresponding cyclic amines was developed. Coupling this transformation with carbonyl 1,2-transposition and C-H oxidation streamlines the preparation of positional isomers of SNH-containing bioactive molecules, enabling rapid nitrogen scanning within sp3-rich scaffolds. Because the CO-to-N conversion proceeds through radical -based deconstruction, the method exhibits exceptional FG tolerance. Given that ketones are abundant native FGs that permit straightforward a- and P-functionalization, this CO-to-N atom-swap strategy also offers a conceptually distinct route to access functionalized SNHs. Altogether, this method further expands the utility of NAHA reagents for late-stage modification of sp3-rich frameworks.

[0358] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, each in its entirety, for all purposes.

Claims

124581.000010 | 25-T-072What is claimed is:

1. A compound of formula I:R21RV^v<aN / VR3' pK / 1XXn R22 H....NH2Jwherein:X is a radical generating moiety;Y is C or N;R1and R2are, independently, absent, H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, or optionally substituted Ci-eheteroalkyl, provided that (i) both R1or R2are not absent and (ii) R1and R2are not absent when Y is C;or R1and R2, taken together with the carbon atom to which they are attached, form an optionally substituted Cs-scycloalkyl or optionally substituted heterocycloalkyl;R3is optionally substituted Ci-ealkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted Cs-scycloalkyl, or optionally substituted heterocycloalkyl;R20and R21are, independently, H or optionally substituted Ci-ealkyl, or, taken together with the carbon atoms to which they are attached, form an optionally substituted aryl or optionally substituted heteroaryl; andn is 1 to 3;or a salt or stereoisomer thereof.

2. The compound of claim 1, wherein X is halo, N3, N2+, triflate, tosylate, SO2CI,coon, D(onj2, -c(ojo-i^=c(imj2, -1 -rn,or e 'zx "'^ J wherein, Z is -CH2-, -O-, -NR’-, or -S- and R’ is H or Ci-ealkyl.

3. The compound of claim 1, wherein X is bromo or iodo.124581.000010 | 25-T-0724. The compound of claim 1, wherein R1is H.

5. The compound of claim 1, wherein R1is Ci-ealkyl, such as methyl, such as ethyl, such as propyl, such as butyl, such as pentyl, or such as hexyl.

6. The compound of claim 1, wherein R1is Ci-eheteroalkyl.

7. The compound of claim 1, wherein R2is H.

8. The compound of claim 1, wherein R2is Ci-ealkyl, such as methyl, such as ethyl, such as propyl, such as butyl, such as pentyl, or such as hexyl.

9. The compound of claim 1, wherein R2is Ci-eheteroalkyl.

10. The compound of claim 1, wherein R1and R2, taken together with the carbon atom to which they are attached, form an optionally substituted Cs-scycloalkyl.

11. The compound of claim 1, wherein R1and R2, taken together with the carbon atom to which they are attached, form an optionally substituted heterocycloalkyl.

12. The compound of claim 1, wherein R3is optionally substituted Ci-ealkyl, such as methyl, such as ethyl, such as propyl, such as butyl, such as pentyl, or such as hexyl.

13. The compound of claim 1, wherein R3is optionally substituted aryl, such as phenyl.

14. The compound of claim 1, wherein R3is optionally substituted heteroaryl, such as pyridyl.

15. The compound of claim 1, wherein R3is optionally substituted Cs-scycloalkyl, such as cyclopropyl, such as cyclobutyl, such as cyclopentyl, or such as cyclohexyl, or such as cycloheptyl, or such as cyclooctyl.

16. The compound of claim 1, wherein R3is optionally substituted heterocycloalkyl.

17. The compound of claim 1, wherein Y is C.

18. The compound of claim 1, wherein Y is N.124581.000010 | 25-T-07219. The compound of claim 1, wherein R20and R21are independently H or optionally substituted Ci-ealkyl.

20. The compound of claim 1, wherein R20and R21are taken together with the carbon atoms to which they are attached, to form an optionally substituted aryl.

21. The compound of claim 1, wherein R20and R21are taken together with the carbon atoms to which they are attached, to form an optionally substituted heteroaryl.

22. The compound of claim 1, wherein n is 1.

23. The compound of claim 1, wherein n is 2.

24. The compound of claim 1, wherein n is 3.

25. The compound of claim 1 that is of formula II:wherein, R4is H or Ci-ealkyl.

27. A method of transforming an oxo moiety of an oxo-containing compound of formula A to a thioether moiety of a thioether-containing compound of formula B:124581.000010 | 25-T-072comprising combining the compound of formula A with the compound of claim 1 for a time and under conditions sufficient to produce the compound of formula B.

28. The method of claim 27, wherein the compound of formula A has the structure of formula III and the compound of formula B has the structure of formula Ill-a:wherein:X1is O, S, NR7or CR7R8;R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X1is independently selected for each m.

29. The method of claim 27, wherein the thioether moiety comprises32S or34S.

30. A method of transforming an oxo moiety of an oxo-containing compound of formula A to an ether moiety of an ether-containing compound of formula C:124581.000010 | 25-T-072oA C comprising combining the compound of formula A with the compound of claim 1for a time and under conditions sufficient to produce the compound of formula C.

31. The method of claim 30, wherein the compound of formula C is of formula IV:wherein:X2is O, S, NR7or CR7R8;R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X2is independently selected for each m.

32. The method of claim 30, wherein the ether moiety comprises16O or18O.

33. A method of transforming an oxo moiety of an oxo-containing compound of formula A to a secondary or tertiary amine moiety of a secondary or tertiary amine-containing- containing compound of formula D:124581.000010 | 25-T-072comprising combining the compound of formula A with the compound of claim 1 for a time and under conditions sufficient to produce the compound of formula D.

34. The method of claim 33, wherein the compound of formula D is of formula V:R9N Iwherein:X3is O, S, NR7or CR7R8;R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;R9is H or Ci-ealkyl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X3is independently selected for each m.

35. The method of claim 33, wherein the secondary or tertiary amine moiety comprises14N or15N.124581.000010 | 25-T-07236. A method of transforming an oxo moiety of an oxo-containing compound of formula A to a13C-labeled oxo moiety of an oxo-containing compound of formula E:o o120^ >A E comprising combining the compound of formula A with the compound of claim 1 for a time and under conditions sufficient to produce the compound of formula E.

37. The method of claim 36, wherein the compound of formula E is of formula VI:wherein:X4is O, S, NR7or CR7R8;R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X4is independently selected for each m.

38. A method of transforming an oxo moiety of an oxo-containing compound of formula A to a sulfoxide moiety of a sulfoxide-containing compound of formula F:124581.000010 | 25-T-072o ocomprising combining the compound of formula A with the compound of claim 1 for a time and under conditions sufficient to produce the compound of formula F.

39. The method of claim 38, wherein the compound of formula F is of formula VII:Owherein:X5is O, S, NR7or CR7R8;R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X5is independently selected for each m.

40. A method of transforming an oxo moiety of an oxo-containing compound of formula A to a sulfone moiety of a sulfone-containing compound of formula G:124581.000010 | 25-T-072oAcomprising combining the compound of formula A with the compound of claim 1 for a time and under conditions sufficient to produce the compound of formula G.

41. The method of claim 40, wherein the compound of formula G is of formula VIII:XbJ- mwherein:X6is O, S, NR7or CR7R8;R5-R8are, independently, H, OC(O)R10, C(O)R10, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, O-(optionally substituted benzyl), optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;or R5and R6, or R6and R7are joined together with the atoms to which they are attached to form an optionally substituted Cs-scycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;m is 0 to 6; andR10is H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted aryl, OC(O)R10, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;wherein each X6is independently selected for each m.

42. The method of claim 27, wherein the oxo-containing compound of formula A is a steroid.

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