A METHOD FOR FLUORINATED RING-OPENING OF A SUBSTRATE

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of ET.S. Provisional Application No. 62/679,463, filed

June 1, 2018, which is incorporated herein by reference in its entirety and for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with government support under GM084906 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

[0003] The ubiquity of carbon-carbon (C-C) bonds in organic compounds places a premium on methods that construct C-C bonds. In general, these bond constructions lead to an increase in structural complexity. However, in certain cases, the cleavage of C-C bonds may lead to more synthetically complex products that cannot be prepared efficiently in any other way. Historically, the full benefit of C-C bond cleavage (deconstructive strategies) is often realized by coupling this process with value-added bond constructions such as C-C bond formation (e.g., in olefin metathesis processes) (7, 2) or C-0 bond formation (e.g., in ozonolysis) (3) (FIG. 1 A). While the benefits of these Csp ² -Csp ² double bond cleavage/functionalization processes are well established, the value of deconstructive processes become even more apparent when Csp ³ -Csp ³ single bond cleavage/functionalization is considered, especially in the context of late-stage skeletal diversification to access novel chemical space ( 4 ) (FIG. 1B). In our view, particularly significant would be the development of deconstructive functionalizations of cyclic amines given the continued importance of nitrogen in pharmaceuticals and agrochemicals (5,6). [0004] In this context, Csp ³ -F bond forming reactions are valued bond constructions because of the influence of fluorine substitution on the properties of pharmaceuticals, agrochemicals, and organic materials (7 10). For example, installment of fluorine may lead to increased metabolic stability, altered physicochemical properties such as increased lipophilicity, reduced basicity of nearby nitrogen atoms, and conformational tuning. As a consequence, work continues on site- selective Csp ³ -F bond forming reactions (77, 12). Nevertheless, the development of novel Csp ³ - F bond forming methods that facilitate the preparation of a variety of fluorine-containing building blocks from easily available starting materials remains a prominent goal. Disclosed herein, inter alia , are solutions to these and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

[0005] In an aspect is provided a method of making a fluoroalkyl amine including reacting a protected cyclic amine with a fluorinating agent in the presence of an oxidizing agent and a metal source. [0006] In an aspect is provided a method of making an a-oxygenated cyclic amine including reacting a protected cyclic amine with a fluorinating agent in the presence of an oxidizing agent and a metal source.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 A-1D. Development of a deconstructive fluorination of cyclic amines. (FIG. 1 A) deconstructive functionalization. (FIG. 1B) An elusive deconstructive functionalization. (FIG. 1C) A blueprint for deconstructive fluorination of cyclic amines. (FIG. 1D) Optimization of Ag- mediated deconstructive fluorination of N-Bz piperidine la.

[0008] FIG 2. Interaction of AgBF ₄ with la. To a 4 ml vial containing la (18.9 mg, 0.100 mmol) and AgBF ₄ (l9.4 mg, 0.100 mmol) was added 1 :9 (v/v) Acetone-<7 ₆ /D ₂ 0 (1.0 ml). The contents of the reaction vial were then transferred into a NMR tube and spectroscopic data was collected right after. The same procedure was followed with varying amounts of AgBF _4. The residual signal of acetone was used as internal reference.

[0009] FIG 3. Interaction of AgBF ₄ with Selectfluor ^® . To a 4 ml vial containing Selectfluor ^® (35.4 mg, 0.100 mmol) and AgBF ₄ (19.4 mg, 0.100 mmol) was added 1 :9 (v/v) Acetone-i/d/DiO (1.0 ml). The resulting solution was allowed to stir at 40 °C for 1 h. The contents of the reaction vial were then transferred into a NMR tube and an NMR spectrum was taken directly afterwards to measure consumption of Selectfluor ^® . [0010] FIG 4. Cyclic voltammograms of la (lmM) and Ar background in 0.10 M NBu ₄ PF ₆ in acetonitrile. Data was collected with a scan rate of lOOmV/s.

DETAILED DESCRIPTION

I. Definitions

[0011] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0012] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0013] The term“alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.

[0014] The term“alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A“lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term“alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0015] The term“heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH ₂ - CH2-O-CH3, -CH2-CH2-NH-CH3, -CH ₂ -CH ₂ -N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-

CH ₃ , -CH ₂ -CH ₂ -S(0) ₂ -CH3, -CH=CH-0-CH ₃ , -Si(CH ₃ ) ₃ , -CH ₂ -CH=N-OCH ₃ , -CH=CH-N(CH ₃ )- CH ₃ , -O-CH ₃ , -O-CH ₂ -CH ₃ , and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-0-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term“heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds. The term“heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.

[0016] Similarly, the term“heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy,

alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0) ₂ R'- represents both -C(0) ₂ R'- and -R'C(0) ₂ -. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as - C(0)R', -C(0)NR', -NR'R", -OR', -SR', and/or -SO2R. Where“heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term“heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.

[0017] The terms“cycloalkyl” and“heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of“alkyl” and“heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for

heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, l-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1 -(1,2, 5, 6- tetrahydropyridyl), l-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1- piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and

heterocycloalkyl, respectively.

[0018] In embodiments, the term“cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH ₂ ) _W , where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3. l. l]heptane, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3. l]nonane, and bicyclo[4.2. l]nonane. In embodiments, fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In

embodiments, the multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic cycloalkyl groups include, but are not limited to tetradecahydrophenanthrenyl,

perhydrophenothiazin-l-yl, and perhydrophenoxazin-l-yl. [0019] In embodiments, a cycloalkyl is a cycloalkenyl. The term“cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH ₂ ) _w , where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbomenyl and bicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. [0020] In embodiments, a heterocycloalkyl is a heterocyclyl. The term“heterocyclyl” as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3- dioxanyl, l,3-dioxolanyl, l,3-dithiolanyl, l,3-dithianyl, imidazolinyl, imidazolidinyl,

isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, l,l-dioxidothiomorpholinyl

(thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.

Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3- dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-l-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-lH- indolyl, and octahydrobenzofuranyl. In embodiments, heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic heterocyclyl groups include, but are not limited to lOH-phenothiazin-lO-yl, 9,l0-dihydroacridin-9-yl, 9,10- dihydroacridin-lO-yl, lOH-phenoxazin-lO-yl, 10,1 l-dihydro-5H-dibenzo[b,f azepin-5-yl, l,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, l2H-benzo[b]phenoxazin-l2-yl, and

dodecahydro-lH-carbazol-9-yl.

[0021] The term“cyclic amine” means, unless otherwise stated, a heterocycloalkyl group including one ring nitrogen atom. Examples of cyclic amines include, but are not limited to, aziridine, azetidine, pyrrolidine, 2,3-dihydro- liT-pyrrole, piperidine, l,2,3,4-tetrahydropyridine, azepane, 2,3,4,5-tetrahydro-liT-azepine, azocane, (Z)-l,2,3,4,5,6-hexahydroazocine, azonane, azecane, azacycloundecane, azacyclododecane, and the like.

[0022] The term“cyclic amine” means a monocyclic or a multicyclic (e.g., bicyclic) heterocycloalkyl ring system including one ring nitrogen, wherein the base ring of the multicyclic system is the cyclic amine. In embodiments, a monocyclic amine is a cyclic hydrocarbon group including from 3 to 8 carbon atoms and only one nitrogen atom, where such group can be saturated or unsaturated, but not aromatic. In embodiments, cyclic amine groups are fully saturated. Examples of monocyclic cyclic amines include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, azonane, azecane,

azacycloundecane, and azacyclododecane. Bicyclic cyclic amine ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, fused bicyclic heterocycloalkyl ring systems contain a monocyclic heterocycloalkyl ring fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl. In embodiments, the bridged or fused bicyclic heterocycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic heterocycloalkyl ring. In embodiments, heterocycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the fused bicyclic cyclic amine is a C ₃ -C ₆ monocyclic cyclic amine ring fused to either a C ₅ -C ₆ monocyclic cycloalkyl, a C ₅ -C ₆ monocyclic cycloalkenyl, or a C ₄ -C ₆ monocyclic heterocyclyl, wherein the fused bicyclic cyclic amine is optionally substituted by one or two groups which are independently oxo or thia.

[0023] The term“protected cyclic amine,” by itself or as part of another substituent, means, unless otherwise state, a“cyclic amine” wherein the nitrogen of the amine is bonded to an amine protecting group. An amine protecting group is a protecting group that is attached to the nitrogen of an amine. Examples of amine protecting groups for a cyclic amine include, but are not limited to, carbobenzyloxy (Cbz), /er/-butyloxy carbonyl (BOC), 9- fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p- methoxybenzyl ether (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), pivaloyl (Piv), and tosyl (Ts). For additional examples of amine protecting groups, See Greene, T.W.; Wuts, P. G. M. Protective Groups in Organic Synthesis. 3 ^rd Edition. John Wiley and Sons Chapter 7, pp 494-615.

[0024] The term“a-oxygentated cyclic amine” is a cyclic amine, wherein the carbon atom adjacent to the nitrogen atom in the ring (the“a-carbon atom”) is substituted with an oxo group. Examples of a-oxygentated cyclic amines include, but are not limited to, azetidin-2-one, pyrrolidin-2-one, piperidin-2-one, and azepan-2-one.

[0025] The terms“halo” or“halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(Ci-C ₄ )alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. In embodiments, the term “fluoroalkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, fluoropropyl, fluorobutyl, fluoropenytl, and the like.

[0026] A“fluoroalkyl amine” is a compound that includes a fluoroalkyl amine moiety attached to the remainder of the compound. A fluoroalkyl amine moiety is an alkyl (e.g. C1-C20 alkyl, C3- Cx alkyl, etc.) substituted with one or more fluorine atoms, a substituted or unsubstituted amine (e.g. -NR R ) and optionally substituted with additional chemical moieties (e.g. a substituent, size-limited substituent or lower substituent). The fluoroalkyl amine moiety may be fully saturated, mono- or polyunsaturated.

[0027] The term“acyl” means, unless otherwise stated, -C(0)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0028] The term“aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. Thus, the term“heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A

5.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a

6.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1- naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrol yl, 2-pyrrolyl, 3 -pyrrol yl, 3-pyrazolyl, 2-imidazolyl, 4- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2- benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5 -quinoxalinyl, 3- quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An“arylene” and a“heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0029] A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring

heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring

heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein.

[0030] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different.

Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl ene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

[0031] The symbol denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0032] The term“oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0033] The term“ alkyl sulfonyl,” as used herein, means a moiety having the formula -S(0 ₂ )-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specified number of carbons (e.g.,“Ci-C ₄ alkylsulfonyl”).

[0034] The term“alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:

[0035] An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, -N ₃ , -CF ₃ , - CCl ₃ , -CBr ₃ , -CI3, -CN, -C(0)H, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₂ CH ₃ -SO3H, -OSO3H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0036] Each of the above terms (e.g.,“alkyl,”“heteroalkyl,”“cycloalkyl,”“hete rocycloalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0037] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkyl ene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR, =0, =NR', =N-OR’, -NR'R", -SR, halogen, -SiRR"R'", -OC(0)R', - C(0)R', -C(0)OR', -C(0)NR'R", -OC(0)NR'R", -NR"C(0)R', -NR'-C(0)NR"R", -NR"C(0) ₂ R, - NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(0)R, -S(0) ₂ R, -S(0) ₂ NR'R", -NRS0 ₂ R, -NR'NR"R'", -ONR'R", -NR'C(0)NR"NR"'R"", -CN, -N0 ₂ , -NR'S0 ₂ R", -NR'C(0)R", - NR'C(0)-OR", -NR'OR", in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R, R, R", R'", and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or

unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, l-pyrrolidinyl and 4-morpholinyl. From the above discussion of

substituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g, -CFs and -CH ₂ CF ₃ ) and acyl (e g, -C(0)CH ₃ , -C(0)CF ₃ , -C(0)CH ₂ 0CH ₃ , and the like).

[0038] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R", -SR, halogen, - SiR'R'R'", -0C(0)R, -C(0)R, -C0 ₂ R, -CONR'R", -0C(0)NR'R", -NR"C(0)R', -NR'- C(0)NR"R"', -NR"C(0) ₂ R, -NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(0)R', -S(0) ₂ R, -

S(0) ₂ NR'R", -NRSOzR', -NR'NR"R'", ONR'R", -NR'C(0)NR"NR"'R"", -CN, -N0 ₂ , -R, -N ₃ , -

CH(Ph) ₂ , fluoro(Ci-C ₄ )alkoxy, and fluoro(Ci-C ₄ )alkyl, -NR'SOzR", -NR'C(0)R", -NR'C(O)- OR", -NR'OR", in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R'", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R"" groups when more than one of these groups is present.

[0039] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroaryl ene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency. [0040] In embodiments, when there are multiple substituents connected to an atom, it is understood that the substituents bond to the atom according to the standard rules of chemical valency known in the chemical arts. For example, for a compound having the structure , wherein each R ^a may independently be a substituent selected from the group halogen or oxo, it is understood that both R ^a may each independently be a halogen substituent, , or both R ^a together form an oxo substituent,cr In embodiments, for a compound having the structure , wherein each R ^a may independently be a substituent selected from the group halogen or oxo, it is understood that each R ^a may independently be halogen, or one R ^a may independently be an oxo and the other R ^a will be absent,

O

Thus, in embodiments, both R ^a , together with the atom they are connected to, form

[0041] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring forming substituents are attached to non-adjacent members of the base structure.

[0042] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR') _q -U-, wherein T and U are independently -NR-, -O-, - CRR-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH ₂ ) _r -B-, wherein A and B are independently -CRR-, -O-, -NR-, -S-, -S(O) -, - S(0) ₂ -, -S(0) ₂ NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') _s -X'- (C"R"R"') _d -, where s and d are independently integers of from 0 to 3, and X' is -0-, -NR'-, -S-, -S(O)-, -S(0) ₂ -, or -S(0) ₂ NR'-. The substituents R, R', R", and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0043] As used herein, the terms“heteroatom” or“ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0044] A“substituent group,” as used herein, means a group selected from the following moieties:

(A) oxo,

halogen, -CC1 ₃ , -CBr ₃ , -CF ₃ , -CI ₃ ,-CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S O ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO ₂ H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCl ₃ , -OCF ₃ , -OCBr ₃ , -OCI ₃ ,-OCHCl ₂ , -OCHBr ₂ , -OCHI ₂ , -OCHF ₂ , unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and

(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:

(i) oxo,

halogen, -CC1 ₃ , -CBr ₃ , -CF ₃ , -CI ₃ ,-CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -

SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ ,

-NHC(0)NHNH ₂ ,-NHC(0)NH ₂ , -NHSO ₂ H,

-NHC(0)H, -NHC(0)OH, -NHOH, -OCCl ₃ , -OCF ₃ , -OCBr ₃ , -OCI ₃ ,-OCHCl ₂ , -OCHBr 2, -OCHI ₂ , -OCHF ₂ , unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and

(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:

(a) oxo,

halogen, -CCb, -CBr ₃ , -CF ₃ , -CI ₃ ,-CN, -OH, -NH ₂ , -C(0)0H, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,-NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCCb, -OCF ₃ , -OCBr ₃ , -OCI ₃ ,-OCH Cl ₂ , -OCHBr ₂ , -OCHI ₂ , -OCHF ₂ , unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-C ₆ alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C ₆ - C10 aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and

(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo,

halogen, -CCb, -CBr ₃ , -CF ₃ , -Cb,-CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, - S0 ₃ H,

-SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO ₂ H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCCb, -OCF ₃ , -OCBr ₃ , -OCb,-OCHCb, -OCHBr

2,

-OCHI ₂ , -OCHF ₂ , unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-C ₆ alkyl, or C ₁ -C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0045] A“size-limited substituent” or“ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C ₁ -C ₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C ₆ -Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0046] A“lower substituent” or“ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C ₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C ₃ -C ₇ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C ₆ -Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0047] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0048] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C ₁ -C ₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C ₆ -Cio aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C ₁ -C ₂₀ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C ₆ -Cio arylene, and/or each substituted or unsubstituted heteroaryl ene is a substituted or unsubstituted 5 to 10 membered heteroaryl ene.

[0049] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C ₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C ₆ -Cio aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-C ₈ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C ₆ -Cio arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0050] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted

heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively).

[0051] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.

[0052] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkyl ene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.

[0053] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkyl ene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.

[0054] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkyl ene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size- limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different. [0055] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute

stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active ( R )- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefmic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0056] As used herein, the term“isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. [0057] The term“tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0058] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. [0059] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0060] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this disclosure. [0061] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (¾), iodine-l25 ( ¹²⁵ I), or carbon-l4 ( ¹⁴ C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0062] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

[0063] As used herein, the term“bioconjugate” refers to the resulting association between atoms or molecules of bioconjugate reactive groups. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., -NH ₂ , -C(0)OH, - N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g. a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g. electrostatic interactions (e.g. ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g. dipole-dipole, dipole- induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e. the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC

CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et ak, MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g. a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g. a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g. a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., -N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g. an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g. a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., -sulfo-N- hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g. an amine).

[0064] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example:

(a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztri azole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters;

(b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.

(c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom;

(d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups;

(e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition;

(f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides;

(h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc;

(j) epoxides, which can react with, for example, amines and hydroxyl compounds;

(k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (1) metal silicon oxide bonding; and

(m) metal bonding to reactive phosphorus groups (e.g. phosphines) to form, for example, phosphate diester bonds.

(n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry.

(o) biotin conjugate can react with avidin or strepavidin to form an avidin-biotin complex or streptavi din-biotin complex.

[0065] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.

[0066] “Analog,” or“analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0067] The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0068] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as“R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R ¹³ substituents are present, each R ¹³ substituent may be distinguished as R ^13A , R ^13B , R ^13C , R ^13D , etc., wherein each of R ^13A , R ^13B , R ^13C , R ^13D , etc. is defined within the scope of the definition of R ¹³ and optionally differently.

[0069] “Oxidizing agent” is used in accordance with its ordinary plain meaning within

Chemistry and Biology and refers to a substance that has the ability to oxidize other substances. The term“oxidizing agent” is a substance that, in the course of a chemical reaction, removes one or more electrons from another substrate or gains one or more electrons from another substrate. In embodiments, an“oxidizing agent” is a chemical species that transfers electronegative atoms to another substrate. In embodiments, the term“oxidizing agent” is analogous to the term “electron acceptor”. Non-limiting examples of oxidizing agents include oxygen (O2), ozone (O3), hydrogen peroxide (H2O2), nitric acid (HNO3), sulfuric acid (H2SO4), hexavalent chromium, pyridinium chlorochromate (PCC), A-methyl morphol i ne-A-oxi de (NMO), chromium trioxide (Cr0 ₃ , Jones reagent), potassium permanganate (K^MnO^, potassium nitrate (KNO3), Dess- Martin periodinane (DMP), 2-iodoxybenzoic acid (IBX), 2,2,6,6-tetramethylpiperidinyloxy (TEMPO), and Selectfluor ^® (F-TEDA-BF4, chloromethyl-4-fluoro-l,4- di azoni abi cy cl o [2.2.2] octane bi s(tetrafluorob orate) . [0070] “Fluorinating agent” is used in accordance with its ordinary plain meaning within Chemistry and Biology and refers to a substance (e.g., compound or composition) that has the ability to incorporate one or more fluorine atoms (e.g. fluorination, difluorination, trifluorination, etc.) into another substance (e.g., compound or composition). Fluorinating agents may be divided into two classes: nucleophilic fluorinating agents and electrophilic fluorinating agents. Nucleophilic fluorinating agents are nucleophilic sources of fluorine which can be combined with a carbon-centered electrophile to afford organofluorine compounds. Electrophilic fluorinating agents are electrophilic sources of fluorine which can be combined with a carbon- centered nucleophile to afford organofluorine compounds. Non-limiting examples of

nucleophilic fluorinating agents include (diethylamino)sulfur trifluoride (DAST), bis(2- methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor ^® ), 4-/tv7-butyl -2, 6-dim ethyl phenyl sulfur trifluoride (Fluolead™), difluoro(morpholino)sulfonium tetrafluorob orate (XtalFluor ^® -M), (diethylamino)difluorosulfonium tetrafluorob orate (XtalFluor ^® -E), and hydrogen fluoride pyridine (HF-pyridine, Olah’s reagent). Non-limiting examples of electrophilic fluorinating agents include SelectFluor ^® (F-TEDA, l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)), SelectFluor ^® PF ₆ (F-TEDA-PF ₆ ),

SelectFluor ^® II (l-fluoro-4-methyl-l,4-diazoniabicyclo[2.2.2]octanebis(tetra fluoroborate), N- fluorobenzenesulfonimide (NFSI), (3aS,6R aR)- \ -fluoro-8,8-dimethylhexahydro- l //-3a,6- methanobenzo[c]isothiazole 2,2-dioxide, A-fluoro-o-benzenedisulfonimide (NFOBS), 2-fluoro- 3 ,3 -dimethyl-2,3 -dihydro- 1 ,2-benzisothiazole 1 , 1 -dioxide, 1 -fluoropyridinium

trifluoromethanesulfonate, 6-dichloro-l -fluoropyridinium triflate, 2,6-dichloro-l- fluoropyridinium triflate, l-fluoro-2,4,6-trimethylpyridinium triflate, l-fluoro-2,4,6- trimethylpyridinium tetrafluorob orate, 4-iodotoluene difluoride, and xenon difluoride.

[0071] A“metal source” is used in accordance with its ordinary plain meaning within

Chemistry and Biology and refers to a compound, salt or complex that includes a transition metal (e.g., as found in the periodic table of the elements). This compound or complex can contain one of many transition metals. In one embodiment, the metal source can be a“silver source”, wherin the transition metal is silver. Non-limiting examples of a silver source include silver(I) tetrafluorob orate (AgBF ₄ ), silver(I) nitrate (AgNCh), silver(II) fluoride (AgF ₂ ), silver(I) fluoride (AgF), silver trifluoromethanesulfonate (AgOTf), silver bis(trifluoromethanesulfonyl)imide (AgNTf2), silver carbonate (Ag ₂ CC> ₃ ), silver(I) oxide (Ag ₂ 0), silver(I) acetate (AgOAc), silver(I) sulfate (Ag ₂ S0 ₄ ), silver methanesulfonate (AgOMs), silver hexafluoroantimonate(V) (AgSbF ₆ ), silver 2-toluenesulfonate (AgOTs), silver(I) trifluoromethanethiolate (AgSCF3), and silver(I) bromide (AgBr). In one embodiment, the metal source can be a“copper source”, wherin the transition metal is copper. Non-limiting examples of a copper source include copper(II) sulfate (CuS0 ₄ ). In one embodiment, the metal source can be an“iron source”, wherin the transition metal is iron. Non-limiting examples of an iron source include iron(III) chloride (FeCh) and iron(I) nitrate (FeNCh) In one embodiment, the metal source can be a“manganese source”, wherin the transition metal is manganese. Non-limiting examples of a manganese source include manganese(II) chloride (MnCb), manganese(III) acetate (Mn(OAc) ₃ ), manganese(III) acetyl acetonate (Mn(acac) ₃ ), and manganese(III) 2-pyridinecarboxylate (Mn(pic) ₃ ). See, Chem. Lett. 2017, 46, 1692.

[0072] A“detectable agent” or“detectable moiety” is a substance (e.g., compound) or composition detectable by appropriate means such as spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, useful detectable agents include ¹⁸ F, ³² P, ³³ P, ⁴⁵ Ti, ⁴⁷ Sc, ⁵² Fe, ⁵⁹ Fe, ⁶² Cu, ⁶⁴ Cu, ⁶⁷ Cu,

Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, ³² P, fluorophore (e.g. fluorescent dyes), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall

superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates,

monocrystalline iron oxide nanoparticles, monocrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g. carbon-l l, nitrogen-l3, oxygen-l 5, fluorine-l 8, rubidium-82), fluorodeoxyglucose (e.g. fluorine-l 8 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g. including microbubble shells including albumin, galactose, lipid, and/or polymers; microbubble gas core including air, heavy gas(es), perfluorocarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g. iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. A detectable moiety is a monovalent detectable agent or a detectable agent capable of forming a bond with another composition.

[0073] Radioactive substances (e.g., radioisotopes) that may be used as imaging and/or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to, ¹⁸ F, ³² P, ³³ P, ⁴⁵ Ti, ⁴⁷ Sc, ⁵² Fe, ⁵⁹ Fe, ⁶² Cu, ⁶⁴ Cu, ⁶⁷ Cu, ⁶⁷ Ga, ⁶⁸ Ga, ⁷⁷ As, ⁸⁶ Y, ⁹⁰ Y. ⁸⁹ Sr, ⁸⁹ Zr, ⁹⁴ Tc, ⁹⁴ Tc, ^99m Tc, "Mo, ¹⁰⁵ Pd, ¹⁰⁵ Rh, ^lu Ag, ^U1 ln, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ¹⁴² Pr, ¹⁴³ Pr, ¹⁴⁹ Pm, ¹⁵³ Sm, ^{154 1581} Gd, ¹⁶¹ Tb, ¹⁶⁶ Dy, ¹⁶⁶ HO, ¹⁶⁹ Er, ¹⁷⁵ Lu, ¹⁷⁷ Lu, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁸⁹ Re, ¹⁹⁴ Ir, ¹⁹⁸ Au, ¹⁹⁹ Au, ²¹¹ At,

²¹¹ Pb, ²¹² Bi, ²¹² Pb, ²¹³ Bi, ²²³ Ra and ²²⁵ Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g. metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.

[0074] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0075] The term“leaving group” is used in accordance with its ordinary meaning in chemistry and refers to a moiety (e.g., atom, functional group, molecule) that separates from the molecule following a chemical reaction (e.g., bond formation, reductive elimination, condensation, cross- coupling reaction) involving an atom or chemical moiety to which the leaving group is attached, also referred to herein as the“leaving group reactive moiety”, and a complementary reactive moiety (i.e. a chemical moiety that reacts with the leaving group reactive moiety) to form a new bond between the remnants of the leaving groups reactive moiety and the complementary reactive moiety. Thus, the leaving group reactive moiety and the complementary reactive moiety form a complementary reactive group pair. Non limiting examples of leaving groups include hydrogen, hydroxide, organotin moieties (e.g., organotin heteroalkyl), halogen (e.g., Br), perfluoroalkyl sulfonates (e.g. triflate), tosylates, mesylates, water, alcohols, nitrate, phosphate, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, boronic acid, boronate esters, and alkoxides. In embodiments, two molecules with leaving groups are allowed to contact, and upon a reaction and/or bond formation (e.g., acyloin condensation, aldol condensation, Claisen condensation, Stille reaction) the leaving groups separates from their respective molecule. In embodiments, a leaving group is a bioconjugate reactive moiety. In embodiments, at least two leaving groups (e.g., R ¹ and R ¹³ ) are allowed to contact such that the leaving groups are sufficiently proximal to react, interact or physically touch. In embodiments, the leaving group is designed to facilitate the reaction.

[0076] The term“protecting group” is used in accordance with its ordinary meaning in organic chemistry and refers to a moiety covalently bound to a heteroatom to prevent reactivity of the heteroatom during one or more chemical reactions performed prior to removal of the protecting group. In embodiments, the protecting group is covalently bound to a heteroatom that is part of a heteroalkyl, heterocycloalkyl or heteroaryl moiety. Typically a protecting group is bound to a heteroatom (e.g., O) during a part of a multistep synthesis wherein it is not desired to have the heteroatom react (e.g., a chemical reduction) with a reagent. Following protection the protecting group may be removed (e.g., by modulating the pH). In embodiments the protecting group is an alcohol protecting group. Non-limiting examples of alcohol protecting groups include acetyl, benzoyl, benzyl, methoxymethyl ether (MOM), tetrahydropyranyl (THP), and silyl ether (e.g., trimethyl silyl (TMS), /c/7-butyl dimethylsilyl (TBS)). In embodiments the protecting group is an amine protecting group. Non-limiting examples of amine protecting groups include

carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), /er/-butyloxy carbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl ether (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), pivaloyl (Piv), tosyl (Ts), and phthalimide.

[0077] A person of ordinary skill in the art will understand when a variable (e.g., moiety or linker) of a compound or of a compound genus (e.g., a genus described herein) is described by a name or formula of a standalone compound with all valencies filled, the unfilled valence(s) of the variable will be dictated by the context in which the variable is used. For example, when a variable of a compound as described herein is connected (e.g., bonded) to the remainder of the compound through a single bond, that variable is understood to represent a monovalent form (i.e., capable of forming a single bond due to an unfilled valence) of a standalone compound (e.g., if the variable is named“methane” in an embodiment but the variable is known to be attached by a single bond to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is actually a monovalent form of methane, i.e., methyl or - CFb). Likewise, for a linker variable (e.g., L ¹ , L ² , or L ³ as described herein), a person of ordinary skill in the art will understand that the variable is the divalent form of a standalone compound (e.g., if the variable is assigned to“PEG” or“polyethylene glycol” in an embodiment but the variable is connected by two separate bonds to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is a divalent (i.e., capable of forming two bonds through two unfilled valences) form of PEG instead of the standalone compound PEG).

[0078] The term“exogenous” refers to a molecule or substance (e.g., a compound, nucleic acid or protein) that originates from outside a given cell or organism. For example, an "exogenous promoter" as referred to herein is a promoter that does not originate from the plant it is expressed by. Conversely, the term "endogenous" or "endogenous promoter" refers to a molecule or substance that is native to, or originates within, a given cell or organism.

[0079] The term“lipid moiety” is used in accordance with its ordinary meaning in chemistry and refers to a hydrophobic molecule which is typically characterized by an aliphatic

hydrocarbon chain. In embodiments, the lipid moiety includes a carbon chain of 3 to 100 carbons. In embodiments, the lipid moiety includes a carbon chain of 5 to 50 carbons. In embodiments, the lipid moiety includes a carbon chain of 5 to 25 carbons. In embodiments, the lipid moiety includes a carbon chain of 8 to 25 carbons. Lipid moieties may include saturated or unsaturated carbon chains, and may be optionally substituted. In embodiments, the lipid moiety is optionally substituted with a charged moiety at the terminal end. In embodiments, the lipid moiety is an alkyl or heteroalkyl optionally substituted with a carboxylic acid moiety at the terminal end. [0080] A charged moiety refers to a functional group possessing an abundance of electron density (i.e. electronegative) or is deficient in electron density (i.e. electropositive). Non-limiting examples of a charged moiety includes carboxylic acid, alcohol, phosphate, aldehyde, and sulfonamide. In embodiments, a charged moiety is capable of forming hydrogen bonds.

[0081] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g ., hydroxyproline, g-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g. , homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g, norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms“non-naturally occurring amino acid” and“unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0082] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical

Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0083] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may In embodiments be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.

[0084] As may be used herein, the terms“nucleic acid,”“nucleic acid molecule,”“nucleic acid oligomer,”“oligonucleotide,”“nucleic acid sequence,”“nucleic acid fragment” and

“polynucleotide” are used interchangeably and are intended to include, but are not limited to, a polymeric form of nucleotides covalently linked together that may have various lengths, either deoxyribonucleotides or ribonucleotides, or analogs, derivatives or modifications thereof.

Different polynucleotides may have different three-dimensional structures, and may perform various functions, known or unknown. Non-limiting examples of polynucleotides include a gene, a gene fragment, an exon, an intron, intergenic DNA (including, without limitation, heterochromatic DNA), messenger RNA (mRNA), transfer RNA, ribosomal RNA, a ribozyme, cDNA, a recombinant polynucleotide, a branched polynucleotide, a plasmid, a vector, isolated DNA of a sequence, isolated RNA of a sequence, a nucleic acid probe, and a primer.

Polynucleotides useful in the methods of the disclosure may include natural nucleic acid sequences and variants thereof, artificial nucleic acid sequences, or a combination of such sequences.

[0085] A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when the polynucleotide is RNA). Thus, the term“polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and/or modified nucleotides.

[0086] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including

biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.

[0087] The term“contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.

II. Methods of making compounds

[0088] In an aspect is provided a method of making a fluoroalkyl amine including reacting a protected cyclic amine with a fluorinating agent in the presence of an oxidizing agent and a metal source.

[0089] In embodiments the protected cyclic amine has the structure of formula (I):

independently -L'-R ¹ or R ³ , wherein each R ⁵ is optionally different. L ¹ is independently a bond, -S(0) ₂ -, -S(O)- , -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(

O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. R ⁸ is independently hydrogen, halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -OCX ⁸ ₃ , -CN, -SO _n8 R ^8D , -SO _v8 NR ^8A R ^8B , -NHC(0)NR ^8A R ^8B , -N(0) _m8 , -NR ^{8 A} R ^8B , -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , -NR ^8A S0 ₂ R ^8D , -NR ^8A C(0)R ^8C , -NR ^8A C(0) OR ^8C , -NR ^8A OR ^8C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ¹ is independently hydrogen, halogen, -CX -CHX ¹ !, -CH ₂ X\ -OCX , -OCH2X ¹ , -OCHX ,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted amino acid moiety, a substituted or unsubstituted peptide moiety, a substituted or unsubstituted nucleoside, a substituted or unsubstituted nucleotide, a substituted or unsubstituted nucleic acid moiety, a bioconjugate moiety, or a lipid moiety. Two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl. Two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , R ^1D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently hydrogen, -CX3, -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I. The symbol nl and n8 are independently an integer from 0 to 4. The symbols ml, vl, m8 and v8 are

independently 1 or 2. The symbol z2 is an integer from 0 to 18. R ² is an amine protecting group. R ³ is independently -OH, -C(0)OH, or -C(0)H.

[0090] In embodiments the protected cyclic amine has the structure of formula (Iz): wherein R ² and z2 are as described herein, including in embodiments. R ⁵³ , R ^{5 2} , R ⁵ R ^{5 4} and R5 ⁵ .5 ⁵ are each independently a value of R ⁵ (e.g., embodiments of R ⁵ ).

[0091] In embodiments the fluoroalkyl amine has the structure of formula (II):

independently -I^-R ¹ , or -F, wherein each R ⁶ is optionally different. L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(

O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. R ⁸ is independently hydrogen, halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -

OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -OCX ⁸ ₃ , -CN, -SOn ₈ R ^8D , -SO _v8 NR ^8A R ^8B , -NHC(0)NR ^8A R ^8B , -N(0)me, -NR ^{8 A} R ^8B , -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , -NR ^8A S0 ₂ R ^8D , -NR ^8A C(0)R ^8C , -NR ^8A C(0) OR ^8C , -NR ^8A OR ^8C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ¹ is independently hydrogen, halogen, -CX , -CHX , -CH ₂ X\ -OCX , -OCHzX ¹ , -OCHX ,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted amino acid moiety, a substituted or unsubstituted peptide moiety, a substituted or unsubstituted nucleoside, a substituted or unsubstituted nucleotide, a substituted or unsubstituted nucleic acid moiety, a bioconjugate moiety, or a lipid moiety. Two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl. Two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , R ^1D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I. The symbol nl and n8 are independently an integer from 0 to 4. The symbols ml, vl, m8, and v8 are

independently 1 or 2. The symbol z2 is an integer from 0 to 18. R ² is an amine protecting group. R ⁴ is hydrogen or -C(0)H.

[0092] In embodiments the fluoroalkyl amine has the structure of formula (IIz):

wherein R ² , R ⁴ and z2 are as described herein, including in embodiments. R ^6·1 , R ⁶ , R ⁶ _, R ^{6 4} and R ^{6 5} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0093] In embodiments the protected cyclic amine has the structure of formula (I):

independently -L'-R ¹ or R ³ , wherein each R ⁵ is optionally different. L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(

O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. R ⁸ is independently hydrogen, halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -

OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -OCX ⁸ ₃ , -CN, -SOn ₈ R ^8D , -SO _v8 NR ^8A R ^8B , -NHC(0)NR ^8A R ^8B , -N(0)me, -NR ^{8 A} R ^8B , -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , -NR ^8A S0 ₂ R ^8D , -NR ^8A C(0)R ^8C , -NR ^8A C(0) OR ^8C , -NR ^8A OR ^8C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ¹ is independently hydrogen, halogen, -CX , -CHX , -CH ₂ X\ -OCX , -OCHzX ¹ , -OCHX ,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl. Two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl. Two -L' -R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl. X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , R ^1D , independently

hydrogen, -CX3, -CHX2, -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I. The symbol nl and n8 are independently an integer from 0 to 4. The symbols ml, vl, m8 and v8 are independently 1 or 2. The symbol z2 is an integer from 0 to 18. R ² is an amine protecting group. R ³ is independently -OH, -C(0)0H, or -C(0)H. [0094] In embodiments the protected cyclic amine has the structure of formula (Iz):

wherein R ² and z2 are as described herein, including in

embodiments R ⁵³ , R ^{5 2} , R ⁵ R ^{5 4} _, and R ^{5 5} are each independently a value of R ⁵ (e.g.,

embodiments of R ⁵ ).

[0095] In embodiments the fluoroalkyl amine has the structure of formula (II):

independently -L'-R ¹ , or -F, wherein each R ⁶ is optionally different. L ¹ is independently a bond, -S(0) ₂ -, -S(O)-, -NR ⁸ -,

, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -0C(0)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. R ⁸ is independently hydrogen, halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -

OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -OCX ⁸ ₃ , -CN, -SOn ₈ R ^8D , -SO _v8 NR ^8A R ^8B , -NHC(0)NR ^8A R ^8B , -N(0)me, -NR ^{8 A} R ^8B , -C(0)R ^8C , -C(0)-0R ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , -NR ^8A S0 ₂ R ^8D , -NR ^8A C(0)R ^8C , -NR ^8A C(0) OR ^8C , -NR ^8A OR ^8C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ¹ is independently hydrogen, halogen, -CX , -CHX , -CH ₂ X\ -OCX , -OCHzX ¹ , -OCHX ,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl. Two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl. Two -L' -R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl. X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , R ^1D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I. The symbol nl and n8 are independently an integer from 0 to 4. The symbols ml, vl, m8, and v8 are independently 1 or 2. The symbol z2 is an integer from 0 to 18. R ² is an amine protecting group. R ⁴ is hydrogen or -C(0)H. In embodiments, when R ⁵ is -

C(0)0H in a compound of formula (la) as shown (la), becomes a

compound of formula (Ila) as shown (Ila). In embodiments, when

R ⁵ is -C(0)0H in a compound of formula (lb) as shown (lb), becomes

a compound of formula (lib) as shown (lib).

[0096] In embodiments the fluoroalkyl amine has the structure of formula (IIz):

wherein R ² , R ⁴ and z2 are as described herein, including in embodiments R ^6·1 , R ⁶ , R ⁶ _, R ^{6 4} _, and R ^{6 5} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0097] In embodiments, when R ⁵ is -C(0)0H in a compound of formula (Iaz) as shown

ein. R ⁵³ , R ^{5 2} , R ⁵ and R ^{5 4} are each independently a value of R ⁵ (e.g., embodiments of R ⁵ ). R ^{6 1} , R ^{6 2} , R ^{6 3} _, and R ^{6 4} _, are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0098] In embodiments, when R ⁵ is -C(0)OH in a compound of formula (Ibz) as shown

becomes a compound of formula (Ilbz) as shown (Ilbz), wherein R ² has any of the values disclosed herein. R ^{5 J} , R ^{5 2} ,

R ⁵ and R ^{5 4} are each independently a value of R ⁵ (e.g., embodiments of R ⁵ ). R ^6·1 , R ^{6 2} , R ⁶³ and R ^{6 4} _, are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0099] In embodiments the protected cyclic amine has the structure of formula (III):

independently -L'-R ¹ or -R ³ , wherein each R ⁵ is optionally different. L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(

O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -

OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ¹ is independently hydrogen, halogen, -CX' ₃ , -CHX , - CH ₂ X\ -OCX , -OCIfcX ¹ , -OCHX ,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Two -L' -R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl. Two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl. X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , R ^1D , independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. Each X is independently -F, -Cl, -Br, or -I. The symbol nl is independently an integer from 0 to 4. The symbols ml and vl are independently 1 or 2. The symbol z2 is an integer from 0 to 18. R ² is an amine protecting group. R ³ is independently -OH, -C(0)0H, or -C(0)H.

[0100] In embodiments the protected cyclic amine has the structure of formula (IIIz):

wherein R ² and z2 are as described herein, including in embodiments re each independently a value of R (e.g., embodiments of R ).

[0101] In embodiments, the fluoroalkyl amine has the structure of formula (IV): independently -L'-R ¹ , or -F, wherein each R ⁶ is optionally different.. L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(

O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -

OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-0R ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ¹ is independently hydrogen, halogen, -CX , -CHX , - CH ₂ X\ -OCX , -OCIBX ¹ , -OCHX ,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl. Two -L' -R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl. Two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl. X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , R ^1D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. Each X is independently -F, -Cl, -Br, or -I. The symbol nl is independently an integer from 0 to 4. The symbols ml and vl are independently 1 or 2. The symbol z2 is an integer from 0 to 18. R ² is an amine protecting group. R ⁴ is hydrogen or -C(0)H.

[0102] In embodiments, the fluoroalkyl amine has the structure of formula (IVz):

wherein R ² , R ⁴ and z2 are as described herein, including in embodiments R ⁶ · ¹ , R ^{6 2} , R ⁶ and R ⁶⁴ are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0103] In an aspect is a method of making an a-oxygenated cyclic amine including reacting a protected cyclic amine with a fluorinating agent in the presence of an oxidizing agent and a metal source.

[0104] In embodiments the protected cyclic amine has the structure of formula (V):

independently oxo or -L -R , wherein each R is optionally different. L is independently a bond, -S(0) ₂ -, -S(O)- , -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC( O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -

OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-0R ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ¹ is independently hydrogen, halogen, -CX' ₃ , -CHX ¹ ?, - CH ₂ X\ -OCX , -OCIBX ¹ , -OCHX ,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl. Two -L' -R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl. Two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl. X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , R ^1D ,

R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I. The symbol nl is independently an integer from 0 to 4. The symbols ml and vl are independently 1 or 2. The symbol z2 is an integer from 1 to 18. R ² is an amine protecting group. In embodiments, two R ⁷ substituents on the same carbon collectively form one oxo substituent. In embodiments, when an R ⁷ directly bonded to the carbon adjacent to the ring nitrogen is independently oxo, the cyclic amine of formula (Va) has the following

structure:

[0105] In embodiments the protected cyclic amine has the structure of formula (Vz):

wherein R ² and z2 are as described herein, including in

embodiments R ⁷³ , R ^{7 2} , R ⁷ R ^{7 4} _, and R ^{7 5} are each independently a value of R ⁷ (e.g.,

embodiments of R ⁷ ).

[0106] In embodiments, when an R ^{7 1} and R ^{7 2} directly bonded to the carbon adjacent to the ring nitrogen are independently oxo, the cyclic amine of formula (Vaz) has the following

structure: , wherein R ² and z2 are as described herein, including in embodiments

R ⁷³ R ^{7 4} _anc] R ^{7 5} _{are eac} independently a value of R ⁷ (e.g., embodiments of R ⁷ ).

[0107] In embodiments, the a-oxygenated cyclic amine has the structure of formula (VI):

independently oxo or -I^-R ¹ , wherein each R ⁷ is optionally different. L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC(

O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , -

OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-0R ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ¹ is independently hydrogen, halogen, -CX' ₃ , -CHX , - CH ₂ X\ -OCX , -OCIBX ¹ , -OCHX ,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl. Two -L' -R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl. Two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl. X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I. R ^1A , R ^1B , R ^1C , R ^1D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I. The symbol nl is independently an integer from 0 to 4. The symbols ml and vl are independently 1 or 2. The symbol z2 is an integer from 1 to 18. R ² is an amine protecting group. In embodiments, two R ⁷ substituents on the same carbon collectively form an oxo substituent. In embodiments, when an R ⁷ directly bonded to the carbon adjacent to the ring nitrogen is independently oxo, the a-oxygenated amine of formula (Via) has the

following structure:

[0108] In embodiments, the a-oxygenated cyclic amine has the structure of formula (Viz):

wherein R ² and z2 are as described herein, including in embodiments R ⁷³ , R ^{7 2} , R ⁷ R ^{7 4} _, and R ^{7 5} are each independently a value of R ⁷ (e.g.,

embodiments of R ⁷ ).

[0109] In embodiments, when an R ⁷ directly bonded to the carbon adjacent to the ring nitrogen is independently oxo, the a-oxygenated amine of formula (VIaz) has the following structure:

, wherein R ² and z2 are as described herein, including in embodiments

R ⁷³ , R 7 ⁴ ^ ^7.5 _anc j j^ ^7.6 _{are eacj1} independently a value of R ⁷ (e.g., embodiments of R ⁷ ).

[0110] In embodiments the protected cyclic amine has the structure of formula (I):

embodiments R ⁵ , R ⁵ , R ⁵³ _, and R ^{5 5} are each independently a value of R ⁵ (e.g., embodiments of R ⁵ ).

[0112] In embodiments the fluoroalkyl amine has the structure of formula (II):

wherein R ⁶ , R ² , R ⁴ , and z2 have any of the values disclosed herein. [0113] In embodiments the fluoroalkyl amine has the structure of formula (IIz):

wherein R , R , and z2 are as described herein, including in embodiments R ^{6 1} , R ^{6 2} , R ⁶ R ⁶³ and R ^{6 5} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0114] In embodiments the protected cyclic amine has the structure of formula (III):

wherein R ⁵ , R ² and z2 have any of the values disclosed herein.

[0115] In embodiments the protected cyclic amine has the structure of formula (IIIz):

[0117] In embodiments, the fluoroalkyl amine has the structure of formula (IVz):

wherein R ² , R ⁴ , and z2 are as described herein, including in embodiments R ^6·1 , R ^{6 2} , R ⁶ and R ^{6 4} are each independently a value of R ⁶ (e.g., embodiments of R ⁶ ).

[0118] In embodiments the protected cyclic amine has the structure of formula (V):

embodiments R ⁷³ , R ^{7 2} , R ⁷ R ^{7 4} _, and R ^{7 5} are each independently a value of R ⁷ (e.g., embodiments of R ⁷ ).

[0120] In embodiments, the a-oxygenated cyclic amine has the structure of formula (VI):

wherein R , R , and z2 have any of the values disclosed herein.

[0121] In embodiments, the a-oxygenated cyclic amine has the structure of formula (Viz): wherein R ² and z2 are as described herein, including in embodiments R ⁷³ , R ^{7 2} , R ⁷ R ^{7 4} _, and R ^{7 5} are each independently a value of R ⁷ (e.g.,

embodiments of R ⁷ ).

[0122] In embodiments, R ⁵ is independently -L'-R ¹ or R ³ , wherein each R ⁵ is optionally different.

[0123] In embodiments, R ⁶ is independently -iS-R ¹ , or -F, wherein each R ⁶ is optionally different.

[0124] In embodiments, L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC( O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene.

[0125] In embodiments, R ⁸ is independently hydrogen, halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , - CH ₂ X ⁸ , -OCX ⁸ 3, - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -OCX ⁸ 3, -CN, -SOn ₈ R ^8D , -SO _v8 NR ^8A R ^8B , -NHC(0)NR ^8A R ^8B , -N(0) _m8 , -NR ^{8 A} R ^8B , -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , -NR ^8A S0 ₂ R ^8D , -NR ^8A C(0)R ^8C , -NR ^8A C(0) OR ^8C , -NR ^8A OR ^8C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0126] In embodiments, R ¹ is independently hydrogen, halogen, -CX , -CHX , -

CH ₂ X\ -OCX , -OCftX ¹ , -OCHX ,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N _S , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted amino acid moiety, a substituted or unsubstituted peptide moiety, a substituted or unsubstituted nucleoside, a substituted or unsubstituted nucleotide, a substituted or unsubstituted nucleic acid moiety, a bioconjugate moiety, or a lipid moiety.

[0127] In embodiments, R ¹ is independently hydrogen, halogen, -CX^, -CHX ¹ _! , - CH2X ¹ , -OCX , -

OCH2X ¹ , -OCHXS, -CN, -SOniR ^1D , -SOviNR ^1A R ^1B , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C( 0)R ^1C , -C(0)-0R ^lc , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -N R ^1A 0R ^1C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted amino acid moiety, a substituted or unsubstituted peptide moiety, a substituted or unsubstituted nucleoside, a substituted or unsubstituted nucleotide, a substituted or unsubstituted nucleic acid moiety, a bioconjugate moiety, or a lipid moiety.

[0128] In embodiments, R ¹ is independently hydrogen, halogen, -CX^, -CHX ¹ _! , - CH ₂ X\ -OCX , -

OCHiX ¹ , -OCHXS, -CN, -SO _ni R ^1D , -SO _vi NR ^1A R ^1B , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C( 0)R ^1C , -C(0)-OR ^lc , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -N R ^1A OR ^lc , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0129] In embodiments, two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl. Two -L' -R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0130] In embodiments, X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I. [0131] In embodiments, R ^1A , R ^1B , R ^1C , R ^1D , R ^8A , R ^8B , R ^8C , and R ^8D , are independently hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0132] In embodiments, R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0133] In embodiments, X is independently -F, -Cl, -Br, or -I.

[0134] In embodiments, the symbol nl and n8 are independently an integer from 0 to 4.

[0135] In embodiments, the symbols ml, vl, m8 and v8 are independently 1 or 2.

[0136] In embodiments, the symbol z2 is an integer from 0 to 18.

[0137] In embodiments, R ² is an amine protecting group.

[0138] In embodiments, R ³ is independently -OH, -C(0)OH, or -C(0)H.

[0139] In embodiments, R ⁴ is hydrogen or -C(0)H.

[0140] In embodiments, z2 is an integer from 0 to 8.

[0141] In embodiments, z2 is an integer from 0 to 4.

[0142] In embodiments, R ¹ is independently hydrogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , - OCH ₂ F, -OCHF ₂ ,

oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^lc , or unsubstituted C _3-8 alkyl.

[0143] In embodiments, L ¹ is independently a

bond, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or R ²² -substituted or unsubstituted alkylene. [0144] In embodiments, L ¹ is independently a

bond, -C(0)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or unsubstituted Ci-Cx alkyl ene.

[0145] In embodiments, two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted Cx-Cx cycloalkyl or a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.

[0146] In embodiments, two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted Cx-Cx cycloalkyl, a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, a substituted or unsubstituted C ₆ -Cio aryl or a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0147] In embodiments, R ⁸ is hydrogen.

[0148] In embodiments, R ⁴ is hydrogen.

[0149] In embodiments, R ² is substituted or unsubstituted alkyl, CBz, Moz, BOC, FMOC, Ac, Bz, Bn, carbamate, PMB, DMPM, PMP, PIV, or Ts.

[0150] In embodiments, the fluorinating agent is an oxidizing agent.

[0151] In embodiments, R ¹ is independently hydrogen, halogen, -CX , -CHX , - CH2X ¹ , -OCX , -OCH2X ¹ , -OCHX ,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-C ₆ alkyl, or C1-C4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., Cx-Cx cycloalkyl, C3- C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, C10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0152] In embodiments, R ¹ is independently hydrogen,

halogen, -CX , -CHX , -CH2X ¹ , -OCX , -OCHX , -OCH2X ¹ ,

oxo, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)OCH ₃ , -C(0)H, -C(0)NH ₂ , -NO2, substituted or unsubstituted Ci-C ₈ alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered

heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is independently halogen, -CX , oxo, -CN, -

OH, -C(0)OH, -C(0)OCH ₃ , -C(0)H, -C(0)NH ₂ , unsubstituted C1-C4 alkyl, or unsubstituted 2 to

4 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted butyl. In embodiments, R ¹ is independently unsubstituted methyl. In embodiments, R ¹ is independently unsubstituted ethyl.

In embodiments, R ¹ is independently unsubstituted propyl. In embodiments, R ¹ is independently unsubstituted n-propyl. In embodiments, R ¹ is independently unsubstituted isopropyl. In embodiments, R ¹ is independently unsubstituted butyl. In embodiments, R ¹ is independently unsubstituted n-butyl. In embodiments, R ¹ is independently unsubstituted isobutyl. In embodiments, R ¹ is independently unsubstituted tert-butyl. In embodiments, R ¹ is independently unsubstituted pentyl. In embodiments, R ¹ is independently unsubstituted hexyl. In

embodiments, R ¹ is independently halogen. In embodiments, R ¹ is independently -F. In embodiments, R ¹ is independently -Cl. In embodiments, R ¹ is independently -Br. In

embodiments, R ¹ is independently -I. In embodiments, R ¹ is independently unsubstituted methoxy. In embodiments, R ¹ is independently unsubstituted ethoxy. In embodiments, R ¹ is independently -CF ₃ . In embodiments, R ¹ is independently -CCl ₃ .

[0153] In embodiments, R ¹ is independently hydrogen. In embodiments, R ¹ is independently halogen. In embodiments, R ¹ is independently -CX . In embodiments, R ¹ is independently - CHX . In embodiments, R ¹ is independently -CH2X ¹ . In embodiments, R ¹ is

independently -OCX . In embodiments, R ¹ is independently -OCH2X ¹ . In embodiments, R ¹ is independently -OCHX In embodiments, R ¹ is independently oxo. In embodiments, R ¹ is independently -CN. In embodiments, R ¹ is independently -NHC(0)NR ^1A R ^1B . In embodiments, R ¹ is independently -N(0) _mi . In embodiments, R ¹ is independently -NR ^1A R ^1B . In embodiments, R ¹ is independently -C(0)R ^lc . In embodiments, R ¹ is independently -C(0)-OR ^lc . In embodiments, R ¹ is independently -C(0)NR ^1A R ^1B . In embodiments, R ¹ is independently -OR ^1D . In embodiments, R ¹ is independently -NR ^1A S0 ₂ R ^1D . In embodiments, R ¹ is

independently -NR ^1A C(0)R ^lc . In embodiments, R ¹ is independently -NR ^1A C(0)0R ^lc . In embodiments, R ¹ is independently -OH. In embodiments, R ¹ is independently -NH ₂ . In embodiments, R ¹ is independently -C(0)0H. In embodiments, R ¹ is independently -C(0)0CH ₃ . In embodiments, R ¹ is independently -C(0)H. In embodiments, R ¹ is independently -C(0)NH ₂ . In embodiments, R ¹ is independently -N0 ₂ . In embodiments, R ¹ is independently -SH.

[0154] In embodiments, R ¹ is independently oxo.

[0155] In embodiments, R ¹ is independently a substituted or unsubstituted amino acid moiety. In embodiments, R ¹ is independently a substituted or unsubstituted peptide moiety. In

embodiments, R ¹ is independently a substituted or unsubstituted nucleoside. In embodiments, R ¹ is independently a substituted or unsubstituted nucleotide. In embodiments, R ¹ is independently a substituted or unsubstituted nucleic acid moiety. In embodiments, R ¹ is independently a bioconjugate moiety. In embodiments, R ¹ is independently a substituted or unsubstituted lipid moiety.

[0156] In embodiments, R ¹ is independently an unsubstituted amino acid moiety. In embodiments, R ¹ is independently an unsubstituted peptide moiety. In embodiments, R ¹ is independently an unsubstituted nucleoside. In embodiments, R ¹ is independently an

unsubstituted nucleotide. In embodiments, R ¹ is independently an unsubstituted nucleic acid moiety. In embodiments, R ¹ is independently a bioconjugate moiety. In embodiments, R ¹ is independently an unsubstituted lipid moiety.

[0157] In embodiments, R ¹ is independently -C(0)NR ^1A R ^1B . In embodiments, R ^1A and R ^1B are independently hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R ^1A and R ^1B are independently hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, or substituted or unsubstituted alkyl. In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X is independently -F, -Cl, -Br, or -I. [0158] In embodiments, R ¹ is independently substituted or unsubstituted alkyl. In embodiments, R ¹ is independently substituted or unsubstituted heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted cycloalkyl. In embodiments, R ¹ is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted aryl. In embodiments, R ¹ is independently substituted or unsubstituted heteroaryl. In embodiments, R ¹ is independently substituted alkyl. In embodiments, R ¹ is independently substituted heteroalkyl. In embodiments, R ¹ is independently substituted cycloalkyl. In embodiments, R ¹ is independently, substituted heterocycloalkyl. In embodiments, R ¹ is independently substituted aryl. In embodiments, R ¹ is independently substituted heteroaryl. In embodiments, R ¹ is independently unsubstituted alkyl. In embodiments, R ¹ is independently unsubstituted heteroalkyl. In embodiments, R ¹ is independently unsubstituted cycloalkyl. In embodiments, R ¹ is independently, unsubstituted heterocycloalkyl. In embodiments, R ¹ is independently unsubstituted aryl. In embodiments, R ¹ is independently unsubstituted heteroaryl. In embodiments, R ¹ is independently substituted or unsubstituted Ci-C ₈ alkyl. In embodiments, R ¹ is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted C ₃ -C ₈ cycloalkyl. In embodiments, R ¹ is independently, substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted C ₆ -Cio aryl. In embodiments, R ¹ is

independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ¹ is independently substituted Ci-C ₈ alkyl. In embodiments, R ¹ is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R ¹ is independently substituted C3-C8 cycloalkyl. In embodiments, R ¹ is independently, substituted 3 to 8 membered heterocycloalkyl. In

embodiments, R ¹ is independently substituted C ₆ -Cio aryl. In embodiments, R ¹ is independently substituted 5 to 10 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted Ci- C ₈ alkyl. In embodiments, R ¹ is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted C3-C8 cycloalkyl. In embodiments, R ¹ is independently, unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R ¹ is independently unsubstituted C ₆ -Cio aryl. In embodiments, R ¹ is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ¹ is independently substituted or unsubstituted Ci- C ₄ alkyl. In embodiments, R ¹ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted C3-C6 cycloalkyl. In embodiments, R ¹ is independently, substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted phenyl. In embodiments, R ¹ is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is independently substituted Ci-C ₄ alkyl. In embodiments, R ¹ is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently substituted C ₃ -C ₆ cycloalkyl. In embodiments, R ¹ is independently, substituted 3 to 6 membered heterocycloalkyl. In embodiments, R ¹ is independently substituted phenyl. In embodiments, R ¹ is independently substituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted Ci- C ₄ alkyl. In embodiments, R ¹ is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R ¹ is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R ¹ is independently unsubstituted phenyl. In embodiments, R ¹ is independently unsubstituted 5 to 6 membered heteroaryl.

[0159] In embodiments, R ¹ is independently hydrogen,

halogen, -CXS, -CHXS, -CH2X ¹ , -OCX , -OCH2X ¹ , -OCHXS,

oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^1c , -NR ^1A OR ^1c , -N ₃ , R ²⁰ -substituted or unsubstituted alkyl, R ²⁰ -substituted or unsubstituted heteroalkyl, R ²⁰ - substituted or unsubstituted cycloalkyl, R ²⁰ -substituted or unsubstituted heterocycloalkyl, R ²⁰ - substituted or unsubstituted aryl, or R ²⁰ -substituted or unsubstituted heteroaryl. In embodiments, R ¹ is independently hydrogen, halogen, -CXS, -CHXS, -CH2X ¹ ,

oxo, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -NO2, -SH, -SO3H, -S0 ₄ H, -SO2NH2, -NHNH ₂ , -ONH2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCXS, -OCH2X ¹ , -OCHXS, -OCXS, R ²⁰ -substituted or unsubstituted alkyl (e.g., Ci- Cx alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁰ - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁰ - substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, C10 aryl, or phenyl), or R ²⁰ - substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ¹ is independently hydrogen,

halogen, -CX^, -CHX ¹ _! , -CH2X ¹ ,

oxo, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCX , -OCHiX ¹ , -OCHX , -OCXS, unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X ¹ is -F, -Cl, -Br, or -I. In embodiments, R ¹ is independently hydrogen. In embodiments, R ¹ is independently methyl. In embodiments, R ¹ is independently ethyl. In embodiments, R ¹ is independently oxo. In embodiments, R ¹ is independently -OH. In embodiments, R ¹ is independently -C(0)OH. In embodiments, R ¹ is independently -C(0)OCH ₃ . In embodiments, R ¹ is independently -C(0)H. In embodiments, R ¹ is independently -C(0)NH ₂ .

[0160] R ²⁰ is independently oxo, halogen, -CX ²⁰ ₃ , -CHX ²⁰ ₂ , -

CH ₂ X ²⁰ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ ,

-NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ²⁰ 3, -OCHX ²⁰ 2, -OCH ₂ X ²⁰ , R ²¹ - substituted or unsubstituted alkyl, R ²¹ - substituted or unsubstituted heteroalkyl, R ²¹ - substituted or unsubstituted cycloalkyl, R ²¹ -substituted or unsubstituted heterocycloalkyl, R ²¹ -substituted or unsubstituted aryl, or R ²¹ -substituted or unsubstituted heteroaryl. X ²⁰ is -F, -Cl, -Br, or -I. In embodiments, R ²⁰ is independently oxo, halogen, -CX ²⁰ ₃ , -CHX ²⁰ ₂ , -

CH ₂ X ²⁰ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ ,

-NHNHi, -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ²⁰ 3, -OCHX ²⁰ 2, -OCH ₂ X ²⁰ , R ²¹ - substituted or unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), R ²¹ - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²¹ - substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C3-C6 cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²¹ - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²¹ - substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, C10 aryl, or phenyl), or R ²¹ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ²⁰ is independently oxo, halogen, -CX ²⁰ ₃ , -CHX ²⁰ ₂ , - CH ₂ X ²⁰ , -CN, -OH, -NH ₂ , -C(0)0H, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -SO ₂ NH ₂ ,

-NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCX ²⁰ 3, -OCHX ²⁰ 2, -OCH ₂ X ²⁰ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0161] In embodiments, R ²⁰ is independently oxo, halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ ,

-ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF _I , or -OCH ₂ F.

[0162] In embodiments, R ²⁰ is oxo, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -C(0)OH, -C(0)NH ₂ , - NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH, -OCF ₃ , -OCHF ₂ , or - OCH ₂ F.

[0163] R ²¹ is independently oxo,

halogen, -CX ²¹ ₃ , -CHX ²¹ ₂ , -CH ₂ X ²¹ ,-CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₃ H, - S0 ₄ H, -S0 ₂ NH ₂ , -NHNHi, -ONH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ²¹ ₃ , -OCHX ²¹ ₂ , -OCH ₂ X ²¹ , unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X ²¹ is -F, -Cl, -Br, or -I. [0164] In embodiments, R ¹ is independently hydrogen, halogen, -CX , -CHX ¹ _! , - CH2X ¹ , -OCX , -OCH2X ¹ , -OCHX ,

oxo, -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0R ^lc , -C(0)NR ^1A R ^1B , -OR ^1D , -N R ^1A C(0)R ^lc , -NR ^1A C(0)0R ^1c , -NR ^1A 0R ^1C , -N ₃ , R ²⁰ -substituted or unsubstituted alkyl, R ²⁰ - substituted or unsubstituted heteroalkyl, R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ - substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ - substituted or unsubstituted heteroaryl. In embodiments, R ²⁰ is independently oxo,

halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)0H, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)0H, -NHOH, -0CF3, -OCHF ₂ , or -OCH ₂ F.

[0165] In embodiments, R ¹ is independently hydrogen, -CF3, -CHF ₂ , -CH ₂ F, -OCF3, - OCH ₂ F, -OCHF _I ,

oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^lc , -N3, or R ²⁰ -substituted or unsubstituted C3-8 alkyl. In embodiments, R ²⁰ is independently oxo, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -C(0)OH, -C(0)NH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH, -OCF3, -OCHF ₂ , or -OCH ₂ F.

[0166] In embodiments, L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC( O)-, substituted or unsubstituted alkylene (e.g., Ci-Cx alkylene, Ci-C ₆ alkylene, or C1-C4 alkylene), substituted or unsubstituted heteroalkyl ene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C ₅ -C ₆ cycloalkylene), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), substituted or unsubstituted arylene (e.g., C ₆ -Cio arylene, C10 arylene, or phenylene), or substituted or unsubstituted heteroaryl ene (e.g., 5 to 10 membered heteroaryl ene, 5 to 9 membered

heteroaryl ene, or 5 to 6 membered heteroaryl ene). [0167] In embodiments, L ¹ is independently a

bond, -NH-, -0-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O) -, substituted or unsubstituted Ci-Cx alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted Cx-Cx cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C ₆ -Cio arylene, or substituted or unsubstituted 5 to 10 membered heteroaryl ene. In embodiments, L ¹ is independently a bond, -NH-, -0-, -C(O)-, -C(0)NH-, -NHC(O)-, -C(0)0-, -OC(O)-, unsubstituted Ci-C ₄ alkylene, unsubstituted 2 to 4 membered heteroalkylene, unsubstituted C ₃ -C ₆ cycloalkylene, unsubstituted 3 to 6 membered heterocycloalkylene, unsubstituted phenylene, or unsubstituted 5 to 6 membered heteroaryl ene. In embodiments, L ¹ is independently unsubstituted methylene, unsubstituted ethylene, unsubstituted propylene, or unsubstituted butylene. In embodiments, L ¹ is independently unsubstituted methylene. In embodiments, L ¹ is independently unsubstituted ethylene. In embodiments, L ¹ is independently unsubstituted propylene. In embodiments, L ¹ is independently unsubstituted n-propylene. In embodiments, L ¹ is independently unsubstituted isopropylene. In embodiments, L ¹ is independently unsubstituted butylene. In embodiments, L ¹ is independently unsubstituted n-butylene. In embodiments, L ¹ is independently unsubstituted isobutylene.

[0168] In embodiments, L ¹ is independently a bond, -NH- or -0-. In embodiments, L ¹ is independently -C(O)-, -C(0)NH-, -NHC(O)-, -C(0)0- or -OC(O)-. In embodiments, L ¹ is independently a bond, -C(O)-, -C(0)NH-, -NHC(O)-, -C(0)0-, -OC(O)-, or substituted or unsubstituted Ci-C ₈ alkylene. In embodiments, L ¹ is independently a

bond, -C(O)-, -C(0)NH-, -C(0)0-, or substituted or unsubstituted Ci-C ₆ alkylene. In embodiments, L ¹ is independently a bond. In embodiments, L ¹ is independently -NH-. In embodiments, L ¹ is independently -0-. In embodiments, L ¹ is independently -C(O)-. In embodiments, L ¹ is independently -C(0)NH-. In embodiments, L ¹ is independently -NHC(O)-. In embodiments, L ¹ is independently -C(0)0-. In embodiments, L ¹ is independently -OC(O)-.

[0169] In embodiments, L ¹ is independently substituted or unsubstituted alkyl. In

embodiments, L ¹ is independently substituted or unsubstituted heteroalkyl. In embodiments, L ¹ is independently substituted or unsubstituted cycloalkyl. In embodiments, L ¹ is independently, substituted or unsubstituted heterocycloalkyl. In embodiments, L ¹ is independently substituted or unsubstituted aryl. In embodiments, L ¹ is independently substituted or unsubstituted heteroaryl. In embodiments, L ¹ is independently substituted alkyl. In embodiments, L ¹ is independently substituted heteroalkyl. In embodiments, L ¹ is independently substituted cycloalkyl. In embodiments, L ¹ is independently, substituted heterocycloalkyl. In embodiments, L ¹ is independently substituted aryl. In embodiments, L ¹ is independently substituted heteroaryl. In embodiments, L ¹ is independently unsubstituted alkyl. In embodiments, L ¹ is independently unsubstituted heteroalkyl. In embodiments, L ¹ is independently unsubstituted cycloalkyl. In embodiments, L ¹ is independently, unsubstituted heterocycloalkyl. In embodiments, L ¹ is independently unsubstituted aryl. In embodiments, L ¹ is independently unsubstituted heteroaryl. In embodiments, L ¹ is independently substituted or unsubstituted Ci-C ₈ alkyl. In embodiments, L ¹ is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, L ¹ is independently substituted Ci-C ₈ alkyl. In embodiments, L ¹ is independently substituted 2 to 8 membered heteroalkyl. In embodiments, L ¹ is independently unsubstituted Ci-C ₈ alkyl. In embodiments, L ¹ is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, L ¹ is independently substituted or unsubstituted Ci-C ₄ alkyl. In embodiments, L ¹ is

independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, L ¹ is independently substituted Ci-C ₄ alkyl. In embodiments, L ¹ is independently substituted 2 to 4 membered heteroalkyl. In embodiments, L ¹ is independently unsubstituted Ci-C ₄ alkyl. In embodiments, L ¹ is independently unsubstituted 2 to 4 membered heteroalkyl.

[0170] In embodiments L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC( O)-, R ²² -substituted or unsubstituted alkylene, R ²² -substituted or unsubstituted heteroalkyl ene, R ²² -substituted or unsubstituted cycloalkylene, R ²² -substituted or unsubstituted

heterocycloalkylene, R ²² -substituted or unsubstituted arylene, or R ²² -substituted or unsubstituted heteroaryl ene. In embodiments, L ¹ is independently a

bond, -S(0) ₂ -, -NH-, -O-, -S-, -C(0)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0 )0-, -OC(O)-, R ²² -substituted or unsubstituted alkylene (e.g., Ci-C ₈ alkylene, Ci-C ₆ alkylene, or Ci-C ₄ alkylene), R ²² -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R ²² - substituted or unsubstituted cycloalkylene (e.g., C ₃ -C ₈ cycloalkylene, C3-C6 cycloalkylene, or C -Cf, cycloalkylene), R ²² -substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), R ²² -substituted or unsubstituted arylene (e.g., C ₆ -Cio arylene, Cio arylene, or phenyl ene), or R ²² -substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroaryl ene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L ¹ is independently a

bond, -S(0) ₂ -, -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0 )0-, -OC(O)-, unsubstituted alkylene (e.g., Ci-C ₈ alkylene, Ci-C ₆ alkylene, or Ci-C ₄ alkylene), unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), unsubstituted cycloalkylene (e.g., C ₃ -C ₈ cycloalkylene, C3-C6 cycloalkylene, or C ₅ -C ₆ cycloalkylene), unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), unsubstituted arylene (e.g., C ₆ -Cio arylene, Cio arylene, or phenylene), or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).

[0171] R ²² is independently oxo, halogen, -CX ²² ₃ , -CHX ²² ₂ , -

CH ₂ X ²² , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -SO ₂ NH ₂ ,

-NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ²² 3, -OCHX ²² 2, -OCH ₂ X ²² , R ²³ - substituted or unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), R ²³ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²³ - substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²³ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered

heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²³ - substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or R ²³ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). R ²² is independently oxo, halogen, -CX ²² ₃ , -CHX ²² ₂ , - CH ₂ X ²² , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ ,

-NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ²² 3, -OCHX ²² 2, -OCH ₂ X ²² , unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X ²² is - F, -Cl, -Br, or -I.

[0172] In embodiments, R ²² is independently oxo, halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ ,

-ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0173] In embodiments, R ²² is independently oxo, halogen, -CF ₃ , -CHF ₂ , - CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHC(0)H, -NHC(0)OH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0174] R ²³ is independently oxo, halogen, -CX ²³ ₃ , -CHX ²³ ₂ , - CH ₂ X ²³ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ ,

-NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHSO _Z H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ²³ ₃ , -OCHX ²³ ₂ , -OCH ₂ X ²³ , unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or C ₁ -C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X ²³ is -F, -Cl, -Br, or -I.

[0175] In embodiments, L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)- , R ²² -substituted or unsubstituted alkyl ene, R ²² -substituted or unsubstituted heteroalkylene, R ²² - substituted or unsubstituted cycloalkylene, R ²² -substituted or unsubstituted heterocycloalkylene, R ²² -substituted or unsubstituted arylene, or R ²² -substituted or unsubstituted heteroaryl ene. In embodiments, R ²² is independently oxo, halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)0H, -C(0)NH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0176] In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted aryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted aryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted aryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted C ₃ -Cx cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted C ₆ -Cio aryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted C ₃ -Cx cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted 3 to 8 membered heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted C ₆ -Cio aryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted 5 to 10 membered heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an

unsubstituted C ₃ -C ₈ cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted 3 to 8 membered heterocycloalkyl. In

embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an

unsubstituted C ₆ -Cio aryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted 5 to 10 membered heteroaryl. In embodiments, two adjacent -L ¹ - R ¹ substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted phenyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted C3-C6 cycloalkyl. In embodiments, two adjacent - LkR ¹ substituents may optionally be joined to form a substituted 3 to 6 membered

heterocycloalkyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted phenyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a substituted 5 to 6 membered heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted C3-C6 cycloalkyl. In

embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an

unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, two adjacent -L'-R ¹

substituents may optionally be joined to form an unsubstituted phenyl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form an unsubstituted 5 to 6 membered heteroaryl.

[0177] In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ -substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ -substituted or unsubstituted heteroaryl. In embodiments, two adjacent -L'-R ¹ substituents may optionally be joined to form a R ²⁰ - substituted or unsubstituted C3-C8 cycloalkyl, R ²⁰ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R ²⁰ -substituted or unsubstituted phenyl, or R ²⁰ -substituted or unsubstituted 5 to 6 membered heteroaryl.

[0178] In embodiments, R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-0R ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or Cs-O, cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0179] In embodiments, R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)CH ₃ , -C(0)-OH, -C(0)H, -C(0)NH ₂ , -OH, substituted or unsubstituted Ci-C ₈ alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C ₃ -Cx cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , - CH ₂ X ⁸ , -CN, -C(0)CH ₃ , -C(0)-OH, -C(0)H, -C(0)NH ₂ , -OH, unsubstituted Ci-C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0180] In embodiments, R ⁸ is independently hydrogen. In embodiments, R ⁸ is

independently -CF ₃ . In embodiments, R ⁸ is independently -CHF ₂ . In embodiments, R ⁸ is independently -CH ₂ F. In embodiments, R ⁸ is independently -C(0)CH ₃ . In embodiments, R ⁸ is independently -C(0)NH ₂ . In embodiments, R ⁸ is independently -OH. In embodiments, R ⁸ is independently Ci-C ₄ alkyl. In embodiments, R ⁸ is independently methyl. In embodiments, R ⁸ is independently ethyl. In embodiments, R ⁸ is independently propyl. In embodiments, R ⁸ is independently butyl.

[0181] In embodiments, R ⁸ is independently hydrogen, halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , - CH ₂ X ⁸ , -OCX ⁸ ₃ , - OCH2X ⁸ , -OCHX ⁸ 2, -CN, -SO _n8 R ^8D , -SO _v8 NR ^8A R ^8B , -NHC(0)NR ^8A R ^8B , -N(0) _m8 , -NR ^8A R ^8B , -C( 0)R ^8C , -C(0)-0R ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , -NR ^8A S0 ₂ R ^8D , -NR ^8A C(0)R ^8C , -NR ^8A C(0)0R ^8C , -N R ^8A OR ^8C , R ²⁴ -substituted or unsubstituted alkyl, R ²⁴ -substituted or unsubstituted heteroalkyl, R ²⁴ -substituted or unsubstituted cycloalkyl, R ²⁴ -substituted or unsubstituted heterocycloalkyl, R ²⁴ -substituted or unsubstituted aryl, or R ²⁴ -substituted or unsubstituted heteroaryl. In embodiments, R ⁸ is independently hydrogen,

halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -CN, -OH, -NH ₂ , -C(0)0H, -C(0)NH ₂ , -NO2, -SH, -SO3H, -S 0 ₄ H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH ₂ , -

NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCX ⁸ ₃ , -OCH ₂ X ⁸ , -OCHX ⁸ ₂ , R ²⁴ - substituted or unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or C1-C4 alkyl), R ²⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁴ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁴ -substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, C10 aryl, or phenyl), or R ²⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ⁸ is independently hydrogen, halogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -CN, -OH, -NH ₂ , -C(0)0H, -C(0)NH ₂ , -NO2, -SH, -S0 ₃ H, -S 0 ₄ H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH ₂ , -

NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCX ⁸ ₃ , -OCH ₂ X ⁸ , -OCHX ⁸ ₂ , unsubstituted alkyl (e.g., Ci-C ₈ alkyl, Ci-C ₆ alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), nsubstituted aryl (e.g., C ₆ -Cio aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X ⁸ is -F, -Cl, -Br, or -I. In embodiments, R ⁸ is independently hydrogen. In embodiments, R ⁸ is independently methyl. In embodiments, R ⁸ is independently ethyl. [0182] R ²⁴ is independently oxo, halogen, -CX ²⁴ ₃ , -CHX ²⁴ ₂ , -

CH ₂ X ²⁴ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,

-NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ²⁴ ₃ , -OCHX ²⁴ ₂ , -OCH ₂ X ²⁴ , R ²⁵ - substituted or unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), R ²⁵ - substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R ²⁵ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁵ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁵ -substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or R ²⁵ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ²⁴ is independently oxo, halogen, -CX ²⁴ ₃ , -CHX ²⁴ ₂ , -

CH ₂ X ²⁴ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ ,

-NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ²⁴ ₃ , -OCHX ²⁴ ₂ , -OCH ₂ X ²⁴ , unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X ²⁴ is -F, -Cl, -Br, or -I.

[0183] R ²⁵ is independently oxo, halogen, -CX ²⁵ ₃ , -CHX ²⁵ ₂ , -

CH ₂ X ²⁵ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S0 ₃ H, -S0 ₄ H, -S0 ₂ NH ₂ ,

-NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ ,

-NHC(0)NH ₂ , -NHSO _Z H, -NHC(0)H, -NHC(0)OH, -NHOH, -OCX ²⁵ ₃ , -OCHX ²⁵ ₂ , -OCH ₂ X ²⁵ , unsubstituted alkyl (e.g., Ci-Cx alkyl, Ci-C ₆ alkyl, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X ²⁵ is -F, -Cl, -Br, or -I.

[0184] In embodiments, X ¹ is independently -F. In embodiments, X ¹ is independently -Cl. In embodiments, X ¹ is independently -Br. In embodiments, X ¹ is independently -I.

[0185] In embodiments, X ⁸ is independently -F. In embodiments, X ⁸ is independently -Cl. In embodiments, X ⁸ is independently -Br. In embodiments, X ⁸ is independently -I.

[0186] In embodiments, R ^1A , R ^1B , R ^1C , R ^1D , R ^8A , R ^8B , R ^8C , and R ^8D are independently hydrogen, -CX ₃ , -CHX ₂ , -CFhX, -CN, -C(0)OH, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0187] In embodiments, R ^1A is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁰ -substituted or unsubstituted alkyl (e.g. C i-Cx alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered

heteroalkyl), R ²⁰ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), R ²⁰ -substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^1A is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cx alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ - Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^1A is independently unsubstituted methyl. In embodiments, R ^1A is independently unsubstituted ethyl. In

embodiments, R ^1A is independently unsubstituted propyl. In embodiments, R ^1A is independently unsubstituted isopropyl. In embodiments, R ^1A is independently unsubstituted tert-butyl.

[0188] In embodiments, R ^1B is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁰ -substituted or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered

heteroalkyl), R ²⁰ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), R ²⁰ -substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^1B is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cx alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ - Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^1B is independently unsubstituted methyl. In embodiments, R ^1B is independently unsubstituted ethyl. In

embodiments, R ^1B is independently unsubstituted propyl. In embodiments, R ^1B is independently unsubstituted isopropyl. In embodiments, R ^1B is independently unsubstituted tert-butyl. [0189] In embodiments, R ^1C is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , R ²⁰ -substituted or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered

heteroalkyl), R ²⁰ -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), R ²⁰ -substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, C10 aryl, or phenyl), or R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^1C is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cx alkyl, Ci-C ₆ alkyl _, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3- Cx cycloalkyl, C3-C6 cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^1C is independently unsubstituted methyl. In embodiments, R ^1C is independently unsubstituted ethyl. In

embodiments, R ^1C is independently unsubstituted propyl. In embodiments, R ^1C is independently unsubstituted isopropyl. In embodiments, R ^1C is independently unsubstituted tert-butyl.

[0190] In embodiments, R ^1D is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁰ -substituted or unsubstituted alkyl (e.g. Ci-Cs alkyl, Ci-C ₆ alkyl _, or C ₁ -C ₄ alkyl), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered

heteroalkyl), R ²⁰ -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), R ²⁰ -substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, C ₁₀ aryl, or phenyl), or R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^1D is independently hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cx alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ - Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is independently -F, -Cl, -Br, or -I. In embodiments, R ^1D is independently unsubstituted methyl. In embodiments, R ^1D is independently unsubstituted ethyl. In

embodiments, R ^1D is independently unsubstituted propyl. In embodiments, R ^1D is independently unsubstituted isopropyl. In embodiments, R ^1D is independently unsubstituted tert-butyl.

[0191] In embodiments, R ^8A is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁴ -substituted or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), R ²⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered

heteroalkyl), R ²⁴ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), R ²⁴ -substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or R ²⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8A is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cx alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ - Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8A is independently unsubstituted methyl. In embodiments, R ^8A is independently unsubstituted ethyl. In embodiments, R ^8A is independently unsubstituted propyl. In embodiments, R ^8A is independently unsubstituted isopropyl. In embodiments, R ^8A is independently unsubstituted tert-butyl. X is independently -F, -Cl, -Br, or -I.

[0192] In embodiments, R ^8B is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁴ -substituted or unsubstituted alkyl (e.g. Ci-Cx alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), R ²⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered

heteroalkyl), R ²⁴ -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), R ²⁴ -substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, C ₁₀ aryl, or phenyl), or R ²⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8B is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cx alkyl, Ci-C ₆ alkyl _, or C ₁ -C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), nsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8B is independently unsubstituted methyl. In embodiments, R ^8B is independently unsubstituted ethyl. In embodiments, R ^8B is independently unsubstituted propyl. In embodiments, R ^8B is independently unsubstituted isopropyl. In embodiments, R ^8B is independently unsubstituted tert-butyl. X is independently -F, -Cl, -Br, or -I.

[0193] In embodiments, R ^8C is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁴ -substituted or unsubstituted alkyl (e.g. Ci-Cx alkyl, Ci-C ₆ alkyl _, or C ₁ -C ₄ alkyl), R ²⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered

heteroalkyl), R ²⁴ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R ²⁴ -substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or R ²⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8C is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cx alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ - Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), nsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8C is independently unsubstituted methyl. In embodiments, R ^8C is independently unsubstituted ethyl. In embodiments, R ^8C is independently unsubstituted propyl. In embodiments, R ^8C is independently unsubstituted isopropyl. In embodiments, R ^8C is independently unsubstituted tert-butyl. X is independently -F, -Cl, -Br, or -I.

[0194] In embodiments, R ^8D is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , R ²⁴ -substituted or unsubstituted alkyl (e.g. Ci-C ₈ alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), R ²⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered

heteroalkyl), R ²⁴ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), R ²⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered

heterocycloalkyl), R ²⁴ -substituted or unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or R ²⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8D is independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)OH, -C(0)NH ₂ , unsubstituted alkyl (e.g. Ci-Cx alkyl, Ci-C ₆ alkyl _, or Ci-C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ - Cx cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -Cio aryl, Cio aryl, or phenyl), or or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R ^8D is independently unsubstituted methyl. In embodiments, R ^8D is independently unsubstituted ethyl. In embodiments, R ^8D is independently unsubstituted propyl. In embodiments, R ^8D is independently unsubstituted isopropyl. In embodiments, R ^8D is independently unsubstituted tert-butyl. X is independently -F, -Cl, -Br, or -I.

[0195] In embodiments, X is -F. In embodiments, X is -Cl. In embodiments, X is -Br. In embodiments, X is -I.

[0196] In embodiments, z2 is an integer from 0 to 18. In embodiments, z2 is an integer from 0 to 12. In embodiments, z2 is an integer from 0 to 8. In embodiments, z2 is an integer from 0 to 4. In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5. In embodiments, z2 is 6.

[0197] In embodiments, R ² is substituted or unsubstituted alkyl, CBz, Moz, BOC, FMOC, Ac, Bz, Bn, carbamate, PMB, DMPM, PMP, PIV, or Ts. In embodiments, R ² is substituted or unsubstituted alkyl. In embodiments, R ² is CBz. In embodiments, R ² is BOC. In embodiments, R ² is Ac. In embodiments, R ² is Bz. In embodiments, R ² is Bn. In embodiments, R ² is PMB. In embodiments, R ² is PIV. In embodiments, R ² is Ts. In embodiments, R ² is substituted or unsubstituted Ci-Cx alky. In embodiments, R ² is substituted or unsubstituted Ci-C ₆ alky. In embodiments, R ² is substituted or unsubstituted Ci-C ₄ alky. In embodiments, R ² is

independently unsubstituted methyl. In embodiments, R ² is independently unsubstituted ethyl.

In embodiments, R ² is independently unsubstituted propyl. In embodiments, R ² is independently unsubstituted isopropyl. In embodiments, R ² is independently unsubstituted tert-butyl.

[0198] In embodiments, R ³ is independently -OH, -C(0)OH, or -C(0)H. In embodiments, R ³ is independently -OH. In embodiments, R ³ is independently -C(0)OH, or -C(0)H. In

embodiments, R ³ is independently -C(0)OH. In embodiments, R ³ is independently -C(0)H.

[0199] In embodiments, R ⁴ is hydrogen or -C(0)H. In embodiments, R ⁴ is hydrogen. In embodiments, R ⁴ is -C(0)H. [0200] In embodiments, R ⁵ is independently -I^-R ¹ , or -R ³ , wherein each R ⁵ is optionally different. In embodiments, R ⁵ is independently -I^-R ¹ . In embodiments, R ⁵ is independently - I^-R ¹ , wherein -R ¹ is hydrogen. In embodiments, R ⁵ is independently - L ¹ - R ¹ , wherein -L ¹ is a bond and -R ¹ is hydrogen. In embodiments, R ⁵ is independently -R ³ . [0201] In embodiments, R ⁶ is independently -I^-R ¹ , or -F, wherein each R ⁶ is optionally different. In embodiments, R ⁶ is independently -I^-R ¹ . In embodiments, R ⁶ is independently - I^-R ¹ , wherein -R ¹ is hydrogen. In embodiments, R ⁶ is independently - L ¹ - R ¹ , wherein -L ¹ is a bond and -R ¹ is hydrogen. In embodiments, R ⁶ is independently -F.

[0202] In embodiments, R ⁷ is independently oxo or -I^-R ¹ , wherein each R ⁷ is optionally different. In embodiments, R ⁷ is independently -I^-R ¹ . In embodiments, R ⁷ is independently - I^-R ¹ , wherein -R ¹ is hydrogen. In embodiments, R ⁷ is independently -L'-R ¹ , wherein -L ¹ is a bond and -R ¹ is hydrogen. In embodiments, R ⁷ is independently oxo.

[0203] In embodiments, two R ⁷ substituents on the same carbon atom collectively form an oxo substituent. In embodiments, the carbon atom adjacent to the amine in formula (V) and the two R ⁷ substituents directly bonded to the carbon atom form a single oxo substituent, as shown in the

following protected cyclic amine of formula (Vb): wherein R ⁷ , R ² , and z2 have any of the values described herein. In embodiments, the carbon atom adjacent to the amine in formula (VI) and the two R ⁷ substituents directly bonded to the carbon form a single oxo substituent, as shown in the following a-oxygenated cyclic amine of formula (VIb):

wherein R ⁷ , R ² , and z2 have any of the values described herein.

[0204] In embodiments, the carbon atom adjacent to the amine in formula (V) and the two R ⁷ substituents directly bonded to the carbon atom form a single oxo substituent, as shown in the following protected cyclic amine of formula (Vbz): wherein R ² and z2 are as described herein, including embodiments. R ^{7 3} , R ⁷⁴ , and R ^{7 5} are each independently a value of R ⁷ (e.g., embodiments of R ⁷ ).

[0205] In embodiments, the carbon atom adjacent to the amine in formula (VI) and the two R ⁷ substituents directly bonded to the carbon form a single oxo substituent, as shown in the

following a-oxygenated cyclic amine of formula ( , wherein R ² and z2 are as described herein, including embodiments. R ^{7 3} , R ^{7 4} , and R ^{7 5} are each

independently a value of R ⁷ (e.g., embodiments of R ⁷ ).

[0206] In embodiments, the cyclic amine is part of a substituted or unsubstituted amino acid. In embodiments, the cyclic amine is part of a substituted or unsubstituted peptide. In

embodiments, the cyclic amine is part of a substituted or unsubstituted nucleic acid. In embodiments, the cyclic amine is part of a bioconjugate. In embodiments, the cyclic amine is part of a lipid.

[0207] In embodiments, the cyclic amine is part of a polypeptide. In embodiments, the cyclic amine is part of a peptide containing 2 to 20 amino acids. In embodiments, the cyclic amine is part of a peptide containing 2 to 10 amino acids. In embodiments, the cyclic amine is part of a peptide containing 2 to 5 amino acids. In embodiments, the cyclic amine is part of a peptide containing 2 to 3 amino acids. In embodiments, the cyclic amine is part of a pentapeptide. In embodiments, the cyclic amine is part of a tetrapeptide. In embodiments, the cyclic amine is part of a tripeptide. In embodiments, the cyclic amine is part of a dipeptide. In embodiments, at least one of the amino acids of the peptide is proline. In embodiments, at least one of the amino acids of the peptide is pipecolic acid. In embodiments, at least one of the amino acids of the peptide is alanine. In embodiments, at least one of the amino acids of the peptide is valine.

[0208] In embodiments, the metal source is a silver source. In embodiments, the metal source is a silver(I) source. In embodiments, the metal source is a silver (II) source. In embodiments, the metal source is a copper source. In embodiments, the metal source is a copper(II) source. In embodiments, the metal source is an iron source. In embodiments, the metal source is an iron(I) source. In embodiments, the metal source is an iron(III) source. In embodiments, the metal source is a manganese source. In embodiments, the metal source is a manganese(II) source. In embodiments, the metal source is a manganese(III) source.

[0209] In embodiments, the metal source is silver(I) tetrafluorob orate (AgBF ₄ ), silver(I) nitrate (AgNCh), silver(II) fluoride (AgF ₂ ), silver(I) fluoride (AgF), silver trifluoromethanesulfonate (AgOTf), silver bis(trifluoromethanesulfonyl)imide (AgNTfz), silver carbonate (Ag ₂ C0 ₃ ), silver(I) oxide (Ag ₂ 0), silver(I) acetate (AgOAc), silver(I) sulfate (Ag ₂ S0 ₄ ), silver

methanesulfonate (AgOMs), silver hexafluoroantimonate(V) (AgSbF ₆ ), silver / oluenesulfonate (AgOTs), silver(I) trifluoromethanethiolate (AgSCF ₃ ), or silver(I) bromide (AgBr). In embodiments, the metal source is silver(I) tetrafluoroborate (AgBF ₄ ). In embodiments, the metal source is copper(II) sulfate (CuS0 ₄ ). In embodiments, the metal source is iron(III) chloride (FeCh). In embodiments, the metal source is iron(I) nitrate (FeNCh). In embodiments, the metal source is manganese(II) chloride (MnCl ₂ ). In embodiments, the metal source is manganese(III) acetate (Mn(OAc) ₃ ). In embodiments, the metal source is manganese(III) acetyl acetonate (Mn(acac) ₃ ). In embodiments, the metal source is manganese(III) 2-pyridinecarboxylate

(Mn(pic) ₃ ).

[0210] In embodiments, an excess (e.g. a greater amount than necessary to react completely with the limiting reactant) of the metal source is used in the reaction. In embodiments, 1.1 to 10 equivalents (e.g. as compared to the amount of the limiting reactant, wherein the limiting reactant may be the cyclic amine) of the metal source are used in the reaction. In embodiments, 2 to 8 equivalents of the metal source are used in the reaction. In embodiments, 3 to 5 equivalents of the metal source are used in the reaction. In embodiments, 4 equivalents of the metal source are used in the reaction. In embodiments, sub-stoichiometric amounts of the metal source are used in the reaction. In embodiments, 0.1 to 0.9 equivalents of the metal source are used in the reaction. In embodiments, 0.4 to 0.6 equivalents of the metal source are used in the reaction. In embodiments, 0 equivalents of the metal source are used in the reaction. In embodiments, an excess of the silver source is used in the reaction. In embodiments, 1.1 to 10 equivalents of the silver source are used in the reaction. In embodiments, 2 to 8 equivalents of the silver source are used in the reaction. In embodiments, 3 to 5 equivalents of the silver source are used in the reaction. In embodiments, 4 equivalents of the silver source are used in the reaction. In embodiments, sub-stoichiometric amounts of the silver source are used in the reaction. In embodiments, 0.1 to 0.9 equivalents of the silver source are used in the reaction. In

embodiments, 0.4 to 0.6 equivalents of the silver source are used in the reaction. In

embodiments, an excess of AgBF ₄ is used in the reaction. In embodiments, 1.1 to 10 equivalents of AgBF ₄ are used in the reaction. In embodiments, 2 to 8 equivalents of AgBF ₄ are used in the reaction. In embodiments, 3 to 5 equivalents of AgBF ₄ are used in the reaction. In embodiments, 4 equivalents of AgBF ₄ are used in the reaction. In embodiments, sub-stoichiometric amounts of AgBF ₄ are used in the reaction. In embodiments, 0.1 to 0.9 equivalents of AgBF ₄ are used in the reaction. In embodiments, 0.4 to 0.6 equivalents of AgBF ₄ are used in the reaction. In

embodiments, an excess of AgNCh is used in the reaction. In embodiments, 1.1 to 10 equivalents of AgNCh are used in the reaction. In embodiments, 2 to 8 equivalents of AgNCh are used in the reaction. In embodiments, 3 to 5 equivalents of AgNCh are used in the reaction. In embodiments, 4 equivalents of AgNCh are used in the reaction. In embodiments, at least 0.1 equivalents of the silver source are used in the reaction. In embodiments, at least 0.5 equivalents of the silver source are used in the reaction.

[0211] In embodiments, the fluorinating agent is a nucleophilic fluorinating agent or an electrophilic fluorinating agent. In embodiments, the fluorinating agent is a nucleophilic fluorinating agent. In embodiments, the nucleophilic fluorinating agent is (diethylamino)sulfur trifluoride (DAST), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor ^® ), 4-/tvV-butyl -2,6- dim ethyl phenyl sulfur trifluoride (Fluolead™), difluoro(morpholino)sulfonium tetrafluorob orate (XtalFluor ^® -M), (diethylamino)difluorosulfonium tetrafluorob orate (XtalFluor ^® -E), and hydrogen fluoride pyridine (HF-pyridine, Olah’s reagent). In embodiments, the electrophilic fluorinating agent is SelectFluor ^® (F-TEDA, l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)), SelectFluor ^® PF ₆ (F-TEDA-PF ₆ ), SelectFluor ^® II (l-fluoro-4-methyl-l,4-diazoniabicyclo[2.2.2]octanebis(tetra fluoroborate), N- fluorobenzenesulfonimide (NFSI), (3aS,6R aR)- \ -fluoro-8,8-dimethylhexahydro- l //-3a,6- methanobenzo[c]isothiazole 2,2-dioxide, /V-fluoro-o-benzenedisulfonimide (NFOBS), 2-fluoro- 3 ,3 -dimethyl-2,3 -dihydro- 1 ,2-benzisothiazole 1 , 1 -dioxide, 1 -fluoropyridinium

trifluoromethanesulfonate, 6-dichloro-l -fluoropyridinium triflate, 2,6-dichloro-l- fluoropyridinium triflate, l-fluoro-2,4,6-trimethylpyridinium triflate, l-fluoro-2,4,6- trimethylpyridinium tetrafluorob orate, 4-iodotoluene difluoride, or xenon difluoride. In embodiments, the electrophilic fluorinating agent is SelectFluor ^® (F-TEDA, l-chloromethyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)), SelectFluor ^® PF ₆ (F-TEDA-PF ₆ ), or SelectFluor ^® II (l-fluoro-4-methyl-l,4-diazoniabicyclo[2.2.2]octanebis(tetra fluoroborate).

[0212] In embodiments, the solvent for the reaction is a mixture of FhO and an organic solvent. In embodiments, the solvent for the reaction is a mixture of FhO and acetone, acetonitrile, toluene, ethyl acetate, dimethyl sulfoxide (DMSO), N,N-d\ m ethyl form am i de (DMF), methanol, ethanol, 2-propanol, dichloromethane, benzene, tetrahydrofuran, 2- methyltetrahydrofuran (2-Me-THF), chloroform, diethylether, or dioxane. In embodiments, the solvent for the reaction is a mixture of H ₂ 0/organic solvent ranging from a 10: 1 (v/v) mixture to 1 : 1 (v/v) mixture. In embodiments, the solvent for the reaction is a mixture of FhO/organic solvent ranging from a 10: 1 (v/v) mixture to 4: 1 (v/v) mixture. In embodiments, the solvent for the reaction is a 9: 1 (v/v) mixture of FhO/organic solvent. In embodiments, the solvent for the reaction is a 4: 1 (v/v) mixture of FhO/organic solvent. In embodiments, the solvent for the reaction is a 7:3 (v/v) mixture of FhO/organic solvent. In embodiments, the solvent for the reaction is a 3 :2 (v/v) mixture of FhO/organic solvent. In embodiments, the solvent for the reaction is a 1 : 1 (v/v) mixture of FhO/organic solvent. In embodiments, the solvent for the reaction is a mixture of FhO and acetone. In embodiments, the solvent for the reaction is a mixture of FhO and acetonitrile. In embodiments, the solvent for the reaction is a mixture of FhO and dichloromethane. In embodiments, the solvent for the reaction is a 9: 1 (v/v) mixture of FhO/acetone. In embodiments, the solvent for the reaction is a 4: 1 (v/v) mixture of FhO/acetone. In embodiments, the solvent for the reaction is a 7:3 (v/v) mixture of FhO/acetone. In

embodiments, the solvent for the reaction is a 3 :2 (v/v) mixture of FhO/acetone. In

embodiments, the solvent for the reaction is a 1 : 1 (v/v) mixture of FhO/acetone. In embodiments, the solvent for the reaction is a 9: 1 (v/v) mixture of H ₂ 0/acetonitrile. In embodiments, the solvent for the reaction is H ₂ 0. In embodiments, the solvent for the reaction is acetone. In embodiments, the solvent for the reaction is acetonitrile. In embodiments, the solvent for the reaction includes at least 10% (v/v) of H ₂ 0. In embodiments, the solvent for the reaction includes at least 50% (v/v) of H ₂ 0.

[0213] In embodiments, the temperature for the reaction ranges from room temperature to 80°C. In embodiments, the temperature for the reaction ranges from room temperature to 60°C.

In embodiments, the temperature for the reaction ranges from room temperature to 40°C. In embodiments, the temperature for the reaction ranges from 30 °C to 80°C. In embodiments, the temperature for the reaction ranges from 30 °C to 50°C. In embodiments, the temperature for the reaction is 40 °C.

[0214] In embodiments, the yield for the reaction ranges from 0 to 100%. In embodiments, the yield for the reaction ranges from 1 to 100%. In embodiments, the yield for the reaction ranges from 20 to 100%. In embodiments, the yield for the reaction ranges from 40 to 95%. In embodiments, the yield for the reaction ranges from 60 to 90%. In embodiments, the yield for the reaction ranges from 50 to 85%. In embodiments, the yield for the reaction is 80 to 90%. In embodiments, the yield for the reaction ranges from 1 to 10%. In embodiments, the yield for the reaction ranges from 10 to 20%. In embodiments, the yield for the reaction ranges from 20 to 30%. In embodiments, the yield for the reaction ranges from 30 to 40%. In embodiments, the yield for the reaction ranges from 40 to 50%. In embodiments, the yield for the reaction ranges from 50 to 60%. In embodiments, the yield for the reaction ranges from 60 to 70%. In embodiments, the yield for the reaction ranges from 70 to 80%. In embodiments, the yield for the reaction ranges from 80 to 90%. In embodiments, the yield for the reaction ranges from 90 to 100%.

[0215] In embodiments, the cyclic amine contains a pipecolic acid moiety and the fluoroalkyl amine contains a 2-amino-5-fluoropentanoic acid moiety. In embodiments, the cyclic amine contains a proline moiety and the fluoroalkyl amine contains a 5-oxopyrrolidine-2-carboxylic acid moiety. III. Embodiments

[0216] Embodiment Pl . A method of making a fluoroalkyl amine comprising reacting a protected cyclic amine with a fluorinating agent in the presence of an oxidizing agent and a metal source. [0217] Embodiment P2. A method of embodiment Pl, wherein said protected cyclic amine has the structure of formula (I):

and said fluoroalkyl amine has the structure of formula (II):

wherein,

R ⁵ is independently -L' -R ¹ or -R ³ , wherein each R ⁵ is optionally different;

L ¹ is independently a bond, -S(0) ₂ -,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC( O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkyl ene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , - OCX , - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-0R ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R ¹ is independently hydrogen, halogen, -CX^, -CHX^, -CFhX ¹ , -OCX , -OCFhX ¹ , -OCHX , oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl;

X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2; z2 is an integer from 0 to 18;

R ² is an amine protecting group;

R ³ is -OH, -C(0)0H, or -C(0)H;

R ⁴ is hydrogen or -C(0)H; and R ⁶ is independently -I^-R ¹ , or -F, wherein each R ⁶ is optionally different.

[0218] Embodiment P3. A method of embodiment Pl, wherein said protected cyclic amine has the structure of formula (III):

and said fluoroalkyl amine has the structure of formula (IV):

wherein,

R ⁵ is independently -L' -R ¹ or -R ³ , wherein each R ⁵ is optionally different;

L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC( O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-0R ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R ¹ is independently hydrogen, halogen, -CX^, -CHX^, -CFhX ¹ , -OCX , -OCFhX ¹ , -OCHX , oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl;

X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2; z2 is an integer from 0 to 18;

R ² is an amine protecting group; R ³ is -OH, -C(0)0H, or -C(0)H;

R ⁴ is hydrogen or -C(0)H; and

R ⁶ is independently -I^-R ¹ , or -F, wherein each R ⁶ is optionally different

[0219] Embodiment P4. A method of making an a-oxygenated cyclic amine comprising reacting a protected cyclic amine with a fluorinating agent in the presence of an oxidizing agent and a metal source.

[0220] Embodiment P5. A method of embodiment P4, wherein said protected cyclic amine has the structure of formula (V):

and said a-oxygenated cyclic amine has the structure of formula (VI):

wherein,

R ⁷ is independently oxo or -L'-R ¹ , wherein each R ⁷ is optionally different;

L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC( O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-0R ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R ¹ is independently hydrogen, halogen, -CX^, -CHX^, -CFhX ¹ , -OCX , -OCFhX ¹ , -OCHX , oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl;

X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2; z2 is an integer from 0 to 18; and

R ² is an amine protecting group.

[0221] Embodiment P6. The compound of one of embodiments P2, P3, and P5, wherein z2 is an integer from 0 to 8.

[0222] Embodiment P7. The compound of one of embodiments P2, P3, and P5, wherein z2 is an integer from 0 to 4.

[0223] Embodiment P8. The compound of one of embodiments P2, P3, and P5-P7, wherein each R ¹ is independently hydrogen, halogen, -CX , -CHX , -CEhX ¹ , -OCX , - OCH2X ¹ , -OCHXS,

oxo, -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-OR ^lc , -C(0)NR ^1A R ^1B , -OR ^1D , -N R ^1A C(0)R ^lc , -NR ^1A C(0)OR ^lc , -NR ^1A OR ^lc , -N ₃ , R ²⁰ -substituted or unsubstituted alkyl, R ²⁰ - substituted or unsubstituted heteroalkyl, R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ - substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ - substituted or unsubstituted heteroaryl; and

R ²⁰ is independently oxo, halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0224] Embodiment P9. The compound of one of embodiments P2, P3, and P5-P7, wherein each R ¹ is independently hydrogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCH ₂ F, -OCHF ₂ , oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-0R ^1c , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^lc , -N ₃ , or R ²⁰ -substituted or unsubstituted C3-8alkyl; and

R ²⁰ is independently oxo, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -C(0)0H, -C(0)NH ₂ , - NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)0H, -OCF3, -OCHF ₂ , or - OCH ₂ F.

[0225] Embodiment P10. The compound of one of embodiments P2, P3, and P5-P7, wherein each R ¹ is independently hydrogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCH ₂ F, -OCHF ₂ ,

oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-0R ^1c , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^lc , or unsubstituted C3-8alkyl.

[0226] Embodiment Pl 1. The compound of one of embodiments P2, P3, and P5-P10, wherein each L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)- , R ²² -substituted or unsubstituted alkyl ene, R ²² -substituted or unsubstituted heteroalkylene, R ²² - substituted or unsubstituted cycloalkylene, R ²² -substituted or unsubstituted heterocycloalkylene, R ²² -substituted or unsubstituted arylene, or R ²² -substituted or unsubstituted heteroaryl ene; and

R ²² is independently oxo, halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0227] Embodiment P12. The compound of one of embodiments P2, P3, and P5-P10, wherein each L ¹ is independently a

bond, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or R ²² -substituted or unsubstituted alkylene; and

R ²² is independently oxo, halogen, -CF3, -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.. [0228] Embodiment P13. The compound of one of embodiments P2, P3, and P5-P10, wherein each L ¹ is independently a

bond, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or unsubstituted Ci-Cx alkyl ene.

[0229] Embodiment P14. The compound of one of embodiments P2, P3, and P5-P10, wherein two -L' -R ¹ substituents attached to the same carbon atom are independently joined to form a substituted or unsubstituted Cx-Cx cycloalkyl or a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.

[0230] Embodiment P15. The compound of one of embodiments P2, P3, and P5-P10, wherein two -L' -R ¹ substituents attached to adjacent carbon atoms are independently joined to form a substituted or unsubstituted Cx-Cx cycloalkyl, a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, a substituted or unsubstituted C ₆ -Cio aryl or a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0231] Embodiment P16. The compound of one of embodiments P2, P3, and P5-P15, wherein each R ⁸ is hydrogen.

[0232] Embodiment P17. The compound of one of embodiments P2, P3, and P6-P15, wherein each R ⁴ is hydrogen.

[0233] Embodiment P18. The compound of one of embodiments P2, P3, and P5-P17, wherein R ² is substituted or unsubstituted alkyl, CBz, Moz, BOC, FMOC, Ac, Bz, Bn, carbamate, PMB, DMPM, PMP, PIV, or Ts.

IV. Additional Embodiments

[0234] Embodiment 1. A method of making a fluoroalkyl amine comprising reacting a protected cyclic amine with a fluorinating agent in the presence of an oxidizing agent and a metal source.

[0235] Embodiment 2. The method of embodiment 1, wherein said protected cyclic amine has the structure of formula (I):

and said fluoroalkyl amine has the structure of formula (II):

wherein, R ⁵ is independently -L' -R ¹ or -R ³ , wherein each R ⁵ is optionally different;

L ¹ is independently a bond, -S(0) ₂ -,-S(0)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC( O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroaryl ene;

R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-0R ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or sub stituted or unsub stituted heteroaryl ;

R ¹ is independently hydrogen, halogen, -CX , -CHX , -CffcX ¹ , -OCX , -OCffcX ¹ , -OCHX , oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl;

X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2; z2 is an integer from 0 to 18;

R ² is an amine protecting group;

R ³ is -OH, -C(0)0H, or -C(0)H;

R ⁴ is hydrogen or -C(0)H; and

R ⁶ is independently -I^-R ¹ , or -F, wherein each R ⁶ is optionally different. [0236] Embodiment 3. The method of embodiment 1, wherein said protected cyclic amine has the structure of formula (III):

and said fluoroalkyl amine has the structure of formula (IV):

wherein,

R ⁵ is independently -L' -R ¹ or -R ³ , wherein each R ⁵ is optionally different;

L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC( O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , -OCX ⁸ ₃ , - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-OR ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ¹ is independently hydrogen, halogen, -CX^, -CHX^, -CH2X ¹ , -OCX , -OCH2X ¹ , -OCHX , oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl;

X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX3, -CHX2, -CFhX, -CN, -C(0)0H, -CjOjNFh, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2; z2 is an integer from 0 to 18;

R ² is an amine protecting group;

R ³ is -OH, -C(0)0H, or -C(0)H;

R ⁴ is hydrogen or -C(0)H; and R ⁶ is independently -L'-R ¹ , or -F, wherein each R ⁶ is optionally different

[0237] Embodiment 4. A method of making an a-oxygenated cyclic amine comprising reacting a protected cyclic amine with a fluorinating agent in the presence of an oxidizing agent and a metal source. [0238] Embodiment 5. The method of embodiment 4, wherein said protected cyclic amine has the structure of formula (V):

and said a-oxygenated cyclic amine has the structure of formula (VI):

wherein,

R ⁷ is independently oxo or -L^R ¹ , wherein each R ⁷ is optionally different;

L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NR ⁸ -, -0-, -S-, -C(O)-, -C(0)NR ⁸ -, -NR ⁸ C(0)-, -NR ⁸ C(0)NH-, -NHC(0)NR ⁸ -, -C(0)0-, -OC( O)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkyl ene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R ⁸ is independently hydrogen, -CX ⁸ ₃ , -CHX ⁸ ₂ , -CH ₂ X ⁸ , - OCX , - OCH ₂ X ⁸ , -OCHX ⁸ ₂ , -CN, -C(0)R ^8C , -C(0)-0R ^8C , -C(0)NR ^8A R ^8B , -OR ^8D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R ¹ is independently hydrogen, halogen, -CX^, -CHX^, -CFhX ¹ , -OCX , -OCFhX ¹ , -OCHX , oxo, -CN, -SOniR ^1D , -SO _VI NR ^1A R ^1b , -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-0 R ^1C , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A S0 ₂ R ^1D , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^1c , -NR ^1A OR ^1c , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two -L'-R ¹ substituents attached to the same carbon atom may be joined to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; two -L'-R ¹ substituents attached to adjacent carbon atoms may be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or

unsubstituted heteroaryl;

X ¹ and X ⁸ are independently -F, -Cl, -Br, or -I;

R ^1A , R ^1b , R ^1C , R ^1d , R ^8A , R ^8B , R ^8C , and R ^8D , are independently

hydrogen, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -C(0)0H, -C(0)NH ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^8A and R ^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X is independently -F, -Cl, -Br, or -I; nl is independently an integer from 0 to 4; ml and vl are independently 1 or 2; z2 is an integer from 0 to 18; and R ² is an amine protecting group.

[0239] Embodiment 6. The method of one of embodiments 2, 3, and 5, wherein z2 is an integer from 0 to 8.

[0240] Embodiment 7. The method of one of embodiments 2, 3, and 5, wherein z2 is an integer from 0 to 4.

[0241] Embodiment 8. The method of one of embodiments 2, 3, and 5-7, wherein each R ¹ is independently hydrogen, halogen, -CX , -CHX , -CEhX ¹ , -OCX , -OCEhX ¹ , -OCHX , oxo, -NHC(0)NR ^1A R ^1B , -N(0) _mi , -NR ^1A R ^1B , -C(0)R ^lc , -C(0)-OR ^lc , -C(0)NR ^1A R ^1B , -OR ^1D , -N R ^1A C(0)R ^lc , -NR ^1A C(0)OR ^lc , -NR ^1A OR ^lc , -N ₃ , R ²⁰ -substituted or unsubstituted alkyl, R ²⁰ - substituted or unsubstituted heteroalkyl, R ²⁰ -substituted or unsubstituted cycloalkyl, R ²⁰ - substituted or unsubstituted heterocycloalkyl, R ²⁰ -substituted or unsubstituted aryl, or R ²⁰ - substituted or unsubstituted heteroaryl; and

R ²⁰ is independently oxo, halogen, -CF ₃ , -CHF2, -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0242] Embodiment 9. The method of one of embodiments 2, 3, and 5-7, wherein each R ¹ is independently hydrogen, -CF3, -CHF ₂ , -CH ₂ F, -OCF3, -OCH ₂ F, -OCHF ₂ ,

oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-OR ^lc , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)OR ^lc , -N3, or R ²⁰ -substituted or unsubstituted Cx-xalkyl; and

R ²⁰ is independently oxo, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -C(0)OH, -C(0)NH ₂ , - NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH, -OCF3, -OCHF ₂ , or - OCH ₂ F.

[0243] Embodiment 10. The method of one of embodiments 2, 3, and 5-7, wherein each R ¹ is independently hydrogen, -CF3, -CHF ₂ , -CH ₂ F, -OCF3, -OCH ₂ F, -OCHF ₂ , oxo, -NHC(0)NR ^1A R ^1B , -C(0)R ^1c , -C(0)-0R ^1c , -C(0)NR ^1A R ^1B , -OR ^1d , -NR ^1A C(0)R ^1c , -NR ^1A C(0)0R ^lc , or unsubstituted C3-8alkyl.

[0244] Embodiment 11. The method of one of embodiments 2, 3, and 5-10, wherein each

L ¹ is independently a bond, -S(0) ₂ -, -S(O)-

, -NH-, -0-, -S-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)- , R ²² -substituted or unsubstituted alkyl ene, R ²² -substituted or unsubstituted heteroalkylene, R ²² - substituted or unsubstituted cycloalkylene, R ²² -substituted or unsubstituted heterocycloalkylene, R ²² -substituted or unsubstituted arylene, or R ²² -substituted or unsubstituted heteroaryl ene; and

R ²² is independently oxo, halogen, -CF ₃ , -CHF2, -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -SO4H, -SO ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F.

[0245] Embodiment 12. The method of one of embodiments 2, 3, and 5-10, wherein each

L ¹ is independently a

bond, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or R ²² -substituted or unsubstituted alkylene; and

R ²² is independently oxo, halogen, -CF ₃ , -CHF ₂ , -

CH ₂ F, -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -SO3H, -S0 ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO _I H, -NHC(0)H, -NHC(0)OH,

-NHOH, -OCF ₃ , -OCHF ₂ , or -OCH ₂ F..

[0246] Embodiment 13. The method of one of embodiments 2, 3, and 5-10, wherein each

L ¹ is independently a

bond, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(0)NH-, -C(0)0-, -OC(O)-, or unsubstituted Ci-Cx alkylene.

[0247] Embodiment 14. The method of one of embodiments 2, 3, and 5-10, wherein two -

LkR ¹ substituents attached to the same carbon atom are independently joined to form a substituted or unsubstituted C3-C8 cycloalkyl or a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. [0248] Embodiment 15. The method of one of embodiments 2, 3, and 5-10, wherein two - L'-R ¹ substituents attached to adjacent carbon atoms are independently joined to form a substituted or unsubstituted C ₃ -C ₈ cycloalkyl, a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, a substituted or unsubstituted C ₆ -Cio aryl or a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0249] Embodiment 16. The method of one of embodiments 2, 3, and 5-15, wherein each R ⁸ is hydrogen.

[0250] Embodiment 17. The method of one of embodiments 2, 3, and 6-15, wherein each R ⁴ is hydrogen. [0251] Embodiment 18. The method of one of embodiments 2, 3, and 5-17, wherein R ² is substituted or unsubstituted alkyl, CBz, Moz, BOC, FMOC, Ac, Bz, Bn, carbamate, PMB, DMPM, PMP, PIV, or Ts.

EXAMPLES

Example 1. Development of a Deconstructive Fluorination of Cyclic Amines

[0252] Our strategy for deconstructive fluorination of cyclic amine derivatives is based on two discrete stages, each mediated by the same transition metal (denoted as TM in FIG. 1C). In the first stage, we envisioned that under an appropriate set of oxidative conditions, a saturated cyclic amine would be oxidized to the corresponding iminium ion (A, FIG. 1C), which is trapped by FhO to form hemi-aminal B (FIG. 1C) (13). In the second stage, the resulting hemi-aminal (B, FIG. 1C) could undergo radical ring opening upon engaging a transition metal species to yield primary radical C (FIG. 1C) (14). A subsequent fluorine atom transfer would deliver the desired fluorinated product. On this basis, cyclic amines can now be viewed as synthons for amino alkyl radicals, which have conventionally only been shown to arise from the corresponding halide, alcohol, or carboxylic acid derivatives (75). The challenge in achieving our envisioned overall transformation lies in discovering a transition metal and fluorinating reagent combination that would act in synergy to selectively cleave the desired C-C bond. Several recent investigations support the feasibility of the second stage (16 19). Specifically, Loh and co-workers have demonstrated a Ag-mediated radical ring-opening fluorination of unstrained cycloalkanols such as cyclopentanol and cyclohexanol using Selectfluor® as a fluorinating reagent (17). In light of this, we selected the combination of Ag(I) and Selectfluor® as the reagent combination for our planned transformation. We began our investigation by establishing the conditions for the overall transformation using N-Bz piperidine la as the substrate (FIG. 1D). After extensive screening of various conditions, we identified the optimized conditions shown in entry 1 which employs cheap and commercially available AgBF ₄ in a 9: 1 (v/v) mixture of FhO/acetone at 40 °C. Other Ag(I) sources led to lower yields, with AgN0 ₃ providing the highest yield among them (entry 2). A control experiment established that a Ag salt is essential to obtaining the desired fluorinated product (entry 3). Increasing the amount of acetone in the mixture led to decreased yields and none of the target compound was obtained when only acetone was used as the solvent (entry 4). A 9: 1 (v/v) mixture of MeCN/FhO gave a diminished yield (51%) of 2a (entry 5), pointing to the superiority of acetone as the co-solvent. The overall transformation can be conducted with sub- stoichiometric amounts of AgBF ₄ to provide 2a, albeit in modest yield (entry 6).

Example 2. Deconstructive Fluorination: Cyclic Amine Scope

[0253] With the optimized conditions in hand, we proceeded to investigate the scope of the deconstructive fluorination process. As shown in FIG. 2, several structurally and electronically distinct N-substituted piperidine derivatives are fluorinated effectively, including those bearing acetyl (Ac: lb), ter /-butoxy carbonyl (Boc: lc) and pivaloyl (Piv: Id) groups. This inexpensive method has provided the majority of the fluorinated alkyl amine products for the first time. Even in the cases where they are known, (e.g., 4-fluorobutane-l -amine) they are prohibitively expensive (871 USD/gram from Enamine Building Blocks) highlighting the practicality of our method. This method is not limited to piperidine derivatives; a range of A-benzoylated saturated azacycles including azetidine le, pyrrolidine If, azepane lg, and azocane lh are all viable in the deconstructive fluorination reaction. It is of note that fluorinated products 2e, 2f were obtained in the deformylated form. We have found that deformylation can occur under the reaction conditions ( vide infra). The variation of the cyclic amine substrate ring size leads to fluoroamine derivatives bearing varying carbon chain lengths. A variety of substitution patterns on the piperidine ring are also well tolerated and the corresponding acyclic fluorinated amines were obtained in moderate to good yields (50-85%). For example, 2-substituted piperidines lj and lk afforded the corresponding fluoroamines (2j and 2k), respectively, with complete positional selectivity. The observed selectivity for cleavage away from the substituents may be attributed to the steric hindrance imparted by these groups at the alpha-position of the cyclic amines. 3- Substituted piperidines are also good substrates as evidenced by 11 undergoing ring- opening/fluorination to provide 21 in 50% yield, demonstrating that secondary alkyl fluorides can be accessed by this method. Fused piperidines such as lm underwent deconstructive fluorination to provide 2m in 43% yield. This example demonstrates that polycyclic molecules can be functionalized as well, paving the way for late-stage skeletal diversification of complex molecules. Moreover, L-pipecolic acid derivative In gave 5-fluoro-L-norvaline derivative 2n in 68% yield (3 steps from L-pipecolic acid), considerably shortening the synthesis of 5-fluoro-L- norvaline (previously prepared in 7 steps from L-glutamic acid) (20). We have found that L- proline methyl ester derivative lo is converted to pyrrolidinone derivative 2o presumably by over-oxidation of an intermediate 5-hydroxyproline derivative. Similarly, N-methyl-2- piperidinone (lp) and N-methyl-2-pyrrolidinone (lq) are oxygenated under the reaction conditions to give N-methyl imides 2p and 2q, respectively. These oxygenation reactions are important in their own right because methods for the direct a-oxygenation of cyclic amides offer a strategy for amino-acid diversification and yet only few complementary methods exist for this purpose (13). Interestingly, N-Piv-2 -pyrrolidinone lr afforded fluorinated product 2r under the same conditions. Notably, piperidines containing carboxylic acid groups undergo dual functionalization to provide difluorinated amines through decarboxylative (21) and

deconstructive fluorination. For example, N-Bz piperidine Is and It underwent dual fluorination to provide 3, 5 -difluorinated amine 2s and 4, 5 -difluorinated amine 2t, respectively.

[0254] Table 1. Deconstructive fluorination: cyclic amine scope. Reaction conditions: 1 (0.1 mmol), AgBF ₄ (4 equiv), Selectfluor® (4 equiv), acetone: FLO (1 :9), 40 °C, 1 h. ^a obtained as a deformylated form.

Example 3. Diversification of Pipecolic Acid and Proline Residues in peptides

[0255] As a demonstration of the utility of this method, we were drawn to its application to functionalizing synthetic peptides, which continue to see widespread use (22-24) and attract new methods for their late-stage diversification. Deconstructive functionalization of peptides can provide orthogonal and complementary skeletal diversification and add profitably to the current toolbox of available methods (25). When dipeptide 3a, which possesses a valine residue, was subjected to our reaction conditions, the fluorination proceeded readily to afford the fluorinated dipeptide (4a) in 50% yield (66% yield BRSM) as shown in FIG. 3. Internal peptides such as 3b also undergo deconstructive fluorination to provide 4b in 38% yield (63% BRSM). Likewise, tripeptide 3c served as a substrate and 4c was formed in 39% yield (52% BRSM). In this way, this novel fluorinated amino acid, which is related to ornithine, can be installed at a late-stage in peptides. This methodology can also be applied to the selective C5-oxygenation of L-proline containing peptides. For example, peptide 3d was oxygenated in 76% yield to provide 4d. N- Benzoyl imide-containing peptide 4d serves as a versatile intermediate for further

functionalization.

[0256] Scheme 1. Diversification of pipecolic acid and proline residues in peptides. Reaction conditions: 3 (0.1 mmol), AgBF ₄ (4 equiv), Selectfluor® (4 equiv), acetone: H ₂ 0 (1 :9), RT, 15 h.

Example 4. Experiments to Elucidate Reaction Mechanism

[0257] A number of additional experiments were performed in order to elucidate the reaction mechanism. We began by investigating using NMR the interaction of Ag(I) and Selectfluor®. Surprisingly, a ¹⁹ F NMR spectrum of an equimolar mixture of Selectfluor® and AgBF ₄ in a 1 :9 (v/v) mixture of Acetone-r/ _f /DiO, taken after stirring at 40 °C for 1 h, displayed no consumption of Selectfluor® (Selectfluor® is reported to react with AgNCh in acetone-r/ADiO (26)).

However, in the presence of an equivalent of la, consumption of Selectfluor® was observed, which suggests that the N-protected cyclic amine substrates play an important role in initiating the ring-opening/fluorination process. In addition, line broadening in the 'H NMR spectrum was observed, which suggests the formation of a paramagnetic Ag(II) complex. Furthermore, downfield shifts of NMR resonances of la were observed in the ¾ NMR spectra upon addition of AgBF ₄ , suggesting the binding of Ag(I) to the amide moiety of la (27, 28). On the basis of these NMR experiments, we propose a mechanism which involves initial coordination of Ag(I) to la, followed by single-electron oxidation by Selectfluor® to form Ag(II) and radical dication 5 (Eq 1 in Scheme 2A) (26). The resulting Ag(II) is sufficiently oxidizing [E° (Ag ²⁺ /Ag ⁺ ) =

+1.98 V vs saturated calomel electrode (SCE)] and undergoes single-electron transfer with la [ E _pa = +1.13 V vs SCE] (29). Subsequent hydrogen atom abstraction by 5 (30) would deliver iminium ion A followed by trapping by H ₂ 0 to give hemi-aminal B (Eq 2 in Scheme 2A). From hemiaminal B, an alkoxy Ag(II) intermediate may form (not shown). Opening of this

intermediate to primary radical C would achieve the desired Csp ³ -Csp ³ bond cleavage and attendant fluorination of the radical by Selectfluor® would yield 2a (Path A in Scheme 2B). However, we recognize that an alternative pathway could be operable based on the fact that deformylated products were obtained in some cases. In this alternate pathway, opening of the hemiaminal to linear aldehyde D and subsequent oxidation to the corresponding carboxylic acid will then set the stage for a decarboxylative fluorination - in line with the precedent of Li (Path B in Scheme 2B) (21). In a series of experiments to support or refute either mechanism (Scheme 2C), aldehyde D, which likely exists in equilibrium with hemiaminal B, was subjected to our reaction conditions and gave fluoro-amine 2a in 55% yield, which can only be accessed through Pathway A. In addition, when the reaction is conducted over a prolonged period, the benzoyl amide product 6 is obtained as the major product, indicating the conversion of 2a to 6 likely occurs through a deformylation process. However, the successful fluorination of N-phthaloyl aldehyde 7 demonstrates that fluorination can proceed from the aldehyde, which cannot form the hemiaminal. Notably, subjecting carboxylic acid 9 to the optimized conditions resulted in 23% yield of fluorinated product 6. On the basis of these experiments, we cannot rule out the possibility that Pathway B is operative for substrates which gave, exclusively, deformylated products. Finally, on the basis of our mechanistic proposal, we sought to explore the reactivity of enamides under our optimized reaction conditions. We envisioned enamides 10 undergoing electrophilic fluorination followed by trapping of the resulting carbocation with water to yield 11 (31). An alkoxy Ag(II)F intermediate would follow, leading to Csp ³ -Csp ³ cleavage and fluorination to yield gem-difluorinated protected amine 12. As shown in Scheme 2D, a variety of enamides related to 10 underwent the desired deconstructive difluorination to yield 12a-c in 54- 76 % yield using catalytic amounts of silver salts. In support of Pathway A (Scheme 2A), the formyl imide products were isolated as the major product under the optimized reaction conditions. These results are significant given the established importance of difluoromethyl groups (32, 33). For example, the difluoromethyl moiety serves as a lipophilic hydrogen bond donor that acts as a bioisostere for thiol and hydroxyl groups.

[0258] Scheme 2. (A) Proposed mechanism for la oxidation. (B) Possible mechanisms for fluorination of B. (C) Mechanistic studies. Reaction conditions: a) starting material (0.1 mmol), AgBF ₄ (4 equiv), Selectfluor® (4 equiv), acetone: H ₂ 0 (1 :9), 40 °C, 1 h, b) la (0.5 mmol),

AgBF ₄ (4 equiv), Selectfluor® (4 equiv), acetone: FhO (1 :9), rt, 16 h. (D) Mechanistically driven gem-fluorination of eneamides 10. Reaction conditions: 10 (0.1 mmol), AgBF ₄ (0.25 equiv), Selectfluor® (4 equiv), acetone: FhO (1 : 1), rt, 15 h.

Example 5. Experimental Procedures for Preparation of Starting Materials: Preparation of /V-Protected Cyclic Amines

[0259] Solvents and Reagents: Tetrahydrofuran (THF) and triethylamine (Et ₃ N) were sparged with argon and dried by passing through alumina columns using argon in a Glass Contour solvent purification system. Dichloromethane (CH2CI2) was freshly distilled over calcium hydride under a N2 atmosphere prior to each use. N-Boc-piperidine (lc), N-methyl-2- pyrrolidinone (lp) and N-methyl-2-piperidinone (In) were obtained from commercial vendors and used as received. Reagents for the fluorination reaction were purchased from commercial vendors as follows: Silver tetrafluorob orate (AgBF ₄ , 99%) was purchased from Oakwood

Chemicals and stored in a glovebox. Selectfluor ^® was purchased from Matrix Scientific. Acetone (HPLC) was purchased from Fisher Scientific. Water (HPLC) was purchased from Fisher Scientific.

[0260] Experimental Procedures: ETnless otherwise noted in the experimental procedures, reactions were carried out in flame or oven-dried glassware under a positive pressure of N2 in anhydrous solvents using standard Schlenk techniques. However, in general, the deconstructive fluorination reactions can be run without the strict exclusion of air or without the use of degassed solvents. Reaction temperatures above room temperature (22-23 °C) were controlled by an IKA® temperature modulator and monitored using liquid-in-glass thermometers. Reaction progress was monitored using a combination of LC/MS analysis (via a Shimadzu LCMS-2020 (UFLC) equipped with the LC-20AD solvent delivery system, a SPD-20AV prominence UV/Vis detector (SPD-M20A Photo Diode Array), and a Thermo Scientific Hypersil GOLD HPLC column (5 pm particle size, 4.6 x 50 mm)), and thin-layer chromatography (TLC) on SiliCycle Siliaplates (glass backed, extra hard layer, 60 A, 250 pm thickness, F254 indicator). Flash column chromatography was performed with either glass columns using Silicycle silica gel (40- 63 pm particle size) or with a Yamazen Smart Flash EPCLC W-Prep 2XY (dual channel) automated flash chromatography system on prefilled, premium, universal columns using ACS grade solvents. Preparative thin layer chromatography was performed on SiliCycle Siliaplates (glass backed, extra hard layer, 60 A, 250 pm thickness, F254 indicator). [0261] Analytical Instrumentation: 'H NMR and ¹³ C NMR data were recorded on Bruker AVQ-400, AVB-400, RDX-500, AV-600 and AV-700 spectrometers using CDCb as solvents, typically at 20-23 °C. Chemical shifts (d) are reported in ppm relative to the residual solvent signal (d 7.26 for ¾ NMR, d 77.16 for ¹³ C NMR in CDCh, d 3.31 for ¾ NMR, d 49.00 for ¹³ C NMR in CD ₃ OD). The ¹⁹ F NMR spectra were acquired on an AVQ-400 spectrometer and internally referenced to CFCh (d 0.00). Data for ¾, ¹³ C and ¹⁹ F NMR spectroscopy are reported as follows; chemical shift (d ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, hept = heptet, m = multiplet, br = broad), coupling constant (Hz), integration. Melting points were determined using a MEL-TEMP™ apparatus and are uncorrected. Optical rotations were measured on a Perkin-Elmer 241 polarimeter. High-resolution mass spectra (HRMS) were obtained from the Catalysis Facility of the Lawrence Berkeley National

Laboratory (supported by the Director, Office of Science, of the ETS Department of Energy under contract no. DE-AC02-05CH11231) using a PerkinElmer AxION 2 TOF-MS.

[0262] Phenyl(piperidin-l-yl)methanone (la) was prepared according to a published procedure. Spectral data were in full agreement with the reported literature values (36).

[0263] l-(Piperidin-l-yl)ethan-l-one (lb) was prepared according to a published procedure. Spectral data were in full agreement with the reported literature values (37).

Piv

[0264] 2,2-Dimethyl-l-(piperidin-l-yl)propan-l-one (Id) was prepared according to a published procedure. Spectral data were in full agreement with the reported literature values (35).

[0265] Azetidin-l-yl(phenyl)methanone (le) was prepared according to a published procedure. Spectral data were in full agreement with the reported literature values (36).

[0266] Phenyl(pyrrolidin-l-yl)methanone (If) was prepared according to a published procedure. Spectral data were in full agreement with the reported literature values (36).

[0267] Azepan-l-yl(phenyl)methanone (lg) was prepared according to a published procedure. Spectral data were in full agreement with the reported literature values (39).

[0268] Azocan-l-yl(phenyl)methanone ( round-bottomed flask was charged with a solution of azocane (300 mg, 3.02 mmol) and Et ₃ N (0.57 mL, 4.1 mmol) in CH2CI2 (5.0 mL) and cooled to 0 °C. Benzoyl chloride (0.320 mL, 2.75 mmol) was added dropwise over 5 min and the resulting mixture was warmed to room temperature. After 24 h, the reaction mixture was quenched with 1 M HC1 aq. (5.0 mL) and the phases were separated. The aqueous phase was extracted with CH2CI2 (10 mL ^c 3). The combined organic layers were washed with brine (2.0 mL), dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (S1O2, 50% EtO Ac/hexanes) to provide the title compound (400 mg, 66%) as a yellow oil. Ή NMR (400 MHz, CDCb): d 7.41-7.34 (m, 5H), 3.62 (t, J = 6.1 Hz, 2H), 3.31 (br, 2H), 1.86 (br, 2H), 1.61-1.59 (m, 8H); ¹³ C NMR (101 MHz, CDCb) d 171.5, 137.7, 129.0, 128.5, 126.4, 51.2, 46.7, 27.0, 26.5, 26.4, 25.6, 24.2; HRMS (ESI): Calc’d for C14H20NO [M+H] ⁺ : 218.1539, found: 218.1535.

[0269] (4-Methylpiperidin-l-yl)(phenyl)methanone (li) was prepared from 4- methylpiperidine using a procedure analogous to that for the preparation of lh. Spectral data were in full agreement with the reported literature values (40).

[0270] (2-Methylpiperidin-l-yl)(phenyl)methanone (lj) was prepared according to a published procedure. Spectral data were in full agreement with the reported literature values (41).

[0271] (2-Ethylpiperidin-l-yl)(phenyl)methanone (lk) was prepared from 2-ethylpiperidine using a procedure analogous to that used for the synthesis of lh. The title compound was obtained as a colorless oil (525 mg, 81%). ¹ H NMR (600 MHz, CDCh, ca. 1 : 1 mixture of rotamers): d 7.38-7.33 (m, 5H), 4.81 (br, 0.5H), 4.57 (br, 0.5H), 3.67 (br, 0.5H), 3.49 (br, 0.5H), 3.02 (br, 0.5H), 2.78 (br, 0.5H), 1.81-1.76 (m, 1H), 1.74-1.31 (m, 7H), 0.95 (br, 1.5H), 0.73 (br, 1.5H); ¹³ C NMR (151 MHz, CDCh, mixture of rotamers): 5 170.9, 137.3, 129.1, 128.5, 126.6,

56.1, 49.8, 43.3, 37.0, 28.8, 28.0, 26.4, 25.9, 22.8, 19.2, 10.8 (One ¹³ C signal is overlapping with others due to amide rotation ); HRMS (ESI): Calc’d for C14H20NO [M+H] ⁺ : 218.1538, found: 218.1540.

[0272] (3,5-Dimethylpiperidin-l-yl)(phenyl)methanone (11) was prepared from 3,5- dimethylpiperidine (mixture of cis and trans) using a procedure analogous to that for the preparation of lh. Spectral data were in full agreement with the literature values (42).

[0273] (Octahydroquinolin-l(2Ef)-yl)(phenyl)methanone (lm) was prepared from trans- decahydroquinoline using a procedure analogous to that used for the synthesis of lh. The title compound was obtained as a yellow oil (276 mg, 53%). ¹ H NMR (400 MHz, CDCh): d 7.36 (br, 5H), 3.50 (td, J= 10.7, 3.2 Hz, 1H), 2.43-2.28 (m, 2H), 2.29-2.24 (m, 1H), 1.79-1.52 (m, 7H), 1.49-1.16 (m, 4H), 1.13-1.03 (m, 1H); ¹³ C NMR (101 MHz, CDCh): 171.6, 137.8, 129.3, 128.4, 126.9, 61.3, 42.4, 38.2, 33.2, 30.5, 26.7, 26.3, 25.6, 23.7; HRMS (ESI): Calc’d for

CieHiiNO [M+H] ⁺ : 244.1696, found: 244.1697.

[0274] Methyl (N)-l-Benzoylpiperidine-2-carboxylate (In) was prepared from L-pipecolic acid methyl ester hydrochloride using a procedure analogous to that used for the preparation of lh. Spectral data were in full agreement with the reported literature values (43).

[0275] Methyl Benzoyl-L-prolinate (lo) was prepared from L-proline methyl ester hydrochloride using a procedure analogous to that used for the synthesis of lh. Spectral data were in full agreement with the reported literature values (44).

Piv

[0276] l-Pivaloylpiperidin-2-one (lr) was prepared from 2-piperidinone and pivaloyl chloride using a procedure analogous to that used for the synthesis of lh. The title compound was obtained as a colorless oil (456 mg, 83%). *H NMR (500 MHz, CDCh): d 3.50 (br s, 2H), 2.46 (t, 5.8 Hz, 2H), 1.85-1.84 (m, 4H), 1.28 (s, 9H); ¹³ C NMR (126 MHz, CDCh): d 190.0,

173.2, 47.2, 43.7, 34.0, 27.7, 22.7, 21.5; HRMS (ESI): Calc’d for C _IO H _I8 N0 ₂ [M+H] ⁺ :

184.1332, found: 184.1333.

[0277] l-Benzoylpiperidine-3-carboxylic acid (Is) was prepared according to a published procedure. Spectral data were in full agreement with the reported literature values (45).

[0278] l-Benzoylpiperidine-4-carboxylic acid (It) was prepared according to a published procedure. Spectral data were in full agreement with the reported literature values (46).

Example 6. Experimental Procedures for Preparation of Starting Materials:

Preparation of Peptides

[0279] Representative Procedure for Methyl Ester Hydrolysis

1 p S1

[0280] A 100 mL round-bottom flask was charged with a solution of lp (1.24 g, 5.00 mmol) in 3: 1 THF: H ₂ 0 (10 mL) and cooled to 0 °C. LiOH ^» H ₂ 0 (210 mg, 25.0 mmol) was added and the resulting mixture was warmed to room temperature. After 13 h, the reaction mixture was cooled to 0 °C and acidified with 1 M HC1 aq. (10 mL) to pH <2. The solution was then diluted with EtOAc (10 mL) and the aqueous layer was extracted with EtOAc (10 mL ^c 3). The combined organic layers were washed with brine (5.0 mL), dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford SI, which was used in the next step without further purification. [0281] Representative Procedure for Condensation Reaction

3a

[0282] Methyl (fV)-l -Benzoyl pi peri dine-2-carbonyl)-/.-valinate (3a): A 100 mL round- bottomed flask was charged with a solution of Z-valine methyl ester hydrochloride (922 mg, 5.50 mmol) in CH2CI2 (45 mL) and cooled to 0 °C. zP^NEt (0.96 mL, 5.5 mmol) was added dropwise over 5 min and the resulting mixture was stirred at 0 °C for 10 min. To this solution were added the crude Sl, hydroxybenzotri azole (HOBt: 676 mg, 5.00 mmol) followed by l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC: 1.05 g, 5.50 mmol) and the resulting mixture was warmed to room temperature. After 19 h, the reaction mixture was cooled to 0 °C and quenched with 1 M HC1 aq. (10 mL). The phases were separated and the aqueous phase was extracted with CH2CI2 (10 mL ^c 3). The combined organic layers were washed with brine (10 mL), dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (S1O2, 25% to 50% EtOAc/ hexanes) to provide the title compound (1.23 g, 71% over 2 steps) as a white amorphous solid. Optical Rotation:

[a] ²² o = -100 (c 0.770, CHCb); *H NMR (600 MHz, CDCb _, cor. 3: 1 mixture of rotamers): d 7.44

(br s, 5H), 7.10 (d, J= 6.6 Hz, 0.75H), 6.60 (br, 0.25H), 5.29 (s, 0.75H), 4.79 (br, 0.25H), 4.64 (br, 0.25H), 4.52 (s, 0.75H), 4.42 (br, 0.25H), 3.76 (s, 3H), 3.72 (s, 0.75H), 3.04 (t, J= 12.4 Hz, 0.75H), 2.86 (br, 0.25H), 2.35-2.30 (m, 1H), 2.27-2.20 (m, 1H), 1.93-1.84 (m, 0.75H), 1.76-

1.74 (m, 1.25H), 1.68-1.47 (m, 3H), 0.93 (d, J= 6.9 Hz, 6H); ¹³ C NMR (151 MHz, CDCb, peaks of major rotamer are listed): d 172.5, 172.0, 170.9, 135.2, 130.2, 128.6, 127.1, 57.1, 52.6, 52.1, 46.1, 30.9, 25.5, 25.3, 20.5, 19.2, 17.7; HRMS (ESI): Calc’ d for C19H27N2O4 [M+H] ⁺ : 347.1965, found: 347.1959.

[0283] Methyl (L')-1 -(Benzoyl -T-alanyl)pi peri dine-2-carboxyl ate (3b) was prepared from methyl fV)-piperidine-2-carboxyl ate (47) and A -b enzoy 1 -A-al an i n e according to the

representative procedure. The title compound was obtained as a colorless foam (1.37 g, 86% over 2 steps). Optical Rotation: [a] ²² _D = -54 ( c 1.7, CHCh); ¹ H NMR (600 MHz, CDCh, ca. 4:4: 1 : 1 mixture of rotamers): d 7.78 (d, J= 7.5 Hz, 2H), 7.45 (t, J= 7.5 Hz, 1H), 7.42-7.41 (m, 1H), 7.38 (t, J= 7.5 Hz, 2H), 5.35 (d, J= 5.3 Hz, 0.4H), 5.29 (d, J= 5.3 Hz, 0.4H), 5.14 (quint, J = 6.8 Hz, 0.4H), 5.10 (quint, J= 6.8 Hz, 0.4H), 5.04 (quint, J= 6.8 Hz, 0.1H), 4.94 (quint, J =

6.8 Hz, 0.1H), 4.87 (d, J= 4.0 Hz, 0.1H), 4.62 (d, J= 4.9 Hz, 0.1H), 4.54 (d, J= 12.8 Hz, 0.1H), 4.48 (d, J= 13.9 Hz, 0.1H), 3.86 (d, J= 12.8 Hz, 0.4H), 3.80 (d, J= 13.3 Hz, 0.4H), 3.75 (s,

0.3H), 3.70 (s, 1.2H), 3.68 (s, 1.2H), 3.59 (s, 0.3H), 3.28-3.21 (m, 0.8H), 2.77-2.69 (m, 0.2H), 2.33 (d, J= 13.6 Hz, 0.1H), 2.27-2.23 (m, 0.9H), 1.72-1.71 (m, 2H), 1.65-1.59 (m, 1H), 1.51- 1.28 (m, 3H), 1.42 (d, J= 6.8 Hz, 1.5H), 1.41 (d, J= 6.8 Hz, 1.5H); ¹³ C NMR (151 MHz,

CDCh, peaks of 2 maj or rotamers are listed): d 172.6, 172.4, 171.3, 171.2, 166.3, 166.2, 134.2, 134.2, 131.5, 128.5, 128.5, 127.1, 127.0, 52.5, 52.4, 52.3, 52.3, 46.0, 45.8, 43.5, 43.4, 26.6, 26.4,

25.2, 25.1, 20.9, 19.6, 18.2 ( Two ¹³ C signals are overlapping with others ) HRMS (ESI): Calc’d for Ci ₇ H ₂₂ N ₂ 0 ₄ Na [M+Na] ⁺ : 341.1472, found: 341.1471.

[0284] Methyl (fV)- l -Benzoyl pi peri dine-2-carbonyl)-/.-valyl-/.-alaninate (3c) was prepared from 3a and /.-alanine methyl ester hydrochloride according to the representative procedure. The title compound was obtained as a white amorphous solid (864 mg, 69% over 2 steps). Optical Rotation: [a] ²² _D = -105 (c 2.01, CHCh); Ή NMR (600 MHz, CDCh, ca. 4:1 mixture of rotamers): d 7.43 (br s, 5H), 7.17 (d, J= 7.3 Hz, 0.8H), 6.79 (br, 0.2H), 6.62 (d, J= 5.0 Hz, 0.8H), 6.46 (br, 0.2H), 5.29 (s, 0.8H), 4.79 (br, 0.2H), 4.58 (quint, J= 7.2 Hz, 1H), 4.35 (br, 0.2H), 4.33-4.30 (m, 1H), 3.74 (s, 3H), 3.71 (br, 0.8H), 3.05 (t, J= 12.8 Hz, 0.8H), 2.88 (br, 0.2H), 2.32-2.12 (m, 2H), 1.85-1.52 (m, 5H), 1.41 (d, J= 7.2 Hz, 3H), 0.95 (d, J= 6.7 Hz, 6H);

¹³ C NMR (151 MHz, CDCh, peaks of major rotamer are listed): d 173.2, 172.7, 171.3, 170.5, 135.2, 130.4, 128.7, 127.3, 58.4, 53.0, 52.5, 48.2, 46.2, 30.8, 25.7, 25.5, 20.8, 19.5, 18.2, 17.9; HRMS (ESI): Calc’d for CiiHsiNsOsNa [M+Na] ⁺ : 440.2156, found: 440.2151.

[0285] Methyl Benzoyl-L-prolyl-L-valinate (3d) was prepared from A-benzoyl -/.-proline

(48) and /.-valine methyl ester hydrochloride according to the representative procedure. The title compound was obtained as a white solid (538 mg, 81%). Melting Point: 104-106 °C; Optical Rotation: [a] ²² _D = -142 (c 0.960, CHCh); ³ H NMR (600 MHz, CDCh): d 7.45-7.38 (m, 5H), 7.33 (br, 1H), 4.80 (s, 1H), 4.49 (t, j= 6.4 Hz, 1H), 3.71 (s, 3H), 3.51 (s, 1H), 3.44 (s, 1H), 2.43 (s, 1H), 2.18-2.16 (m, 1H), 2.02 (s, 2H), 1.81 (s, 1H), 0.92 (d, j= 6.4 Hz, 3H), 0.89 (d, j= 6.4

Hz, 3H); ¹³ C NMR (151 MHz, CDCh): d 172.2, 171.1, 171.0, 136.4, 130.3, 128.5, 127.0, 59.8, 57.6, 52.1, 50.4, 31.1, 27.1, 25.5, 19.2, 17.8; HRMS (ESI): Calc’d for Ci ₈ H ₂₄ N ₂ 0 ₄ Na [M+Na] ⁺ : 355.1628, found: 355.1627.

Example 7. Experimental Procedures for Preparation of Starting Materials:

Preparation of Enamides

[0286] (3,4-Dihydropyridin-l(2Ef)-yl)(phenyl)methanone (10a) was prepared according to a published procedure. Spectral data were in full agreement with the reported literature values (49).

S2

[0287] A 100 mL round-bottomed flask was charged with a solution of /er/-butyl 4-methyl-2- oxopiperidine-l-carboxylate (50) (2.00 g, 9.38 mmol) in dioxane (40 mL) and cooled to 0 °C. HC1 (4.0 M solution in dioxane, 7.00 mL, 28.1 mmol) was added and the resulting mixture was warmed to room temperature. After 16 h, the reaction mixture was concentrated under reduced pressure to afford a white solid, which was used in the next step without further purification. The solid was dissolved in MeCN (30 mL) and the resulting solution was cooled to 0 °C. To this solution was added Et ₃ N (3.92 mL, 28.1 mmol), DMAP (115 mg, 0.938 mmol) and BzCl (1.31 mL, 11.3 mmol) and the reaction mixture was heated to 70 °C. After 12 h, H ₂ 0 (1.0 mL) was added and the reaction mixture was allowed to continue to stir at 70 °C for an additional 1 h. The solution was then allowed to cool to room temperature, poured into a separatory funnel, and washed with sat. NaHCCh aq. (20 mL). The aqueous phase was extracted with EtOAc (10 mL ^c 2). The combined organic layers were washed with 1 M HC1 (10 mL) and brine (10 mL), dried over MgSCL, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (Si0 ₂ , 5% to 15% EtOAc/ hexanes) to provide S2 (1.47 g, 73% over 2 steps) as a white solid. Melting Point: 74-77 °C; Ή NMR (500 MHz, CDCh): d 7.54 (d, J = 7.4 Hz, 2H), 7.46 (t, J= 7.4 Hz, 1H), 7.38 (t, J= 7.4 Hz, 2H), 3.95 (dt, J= 12.9, 4.3 Hz, 1H),

3.64 (ddd, J= 12.9, 11.5, 4.0 Hz, 1H), 2.59 (ddd, j= 16.4, 4.6, 1.9 Hz, 1H), 2.23 (dd, 7= 16.4, 10.9 Hz, 1H), 2.13-2.05 (m, 2H), 1.65-1.57 (m, 1H), 1.10 (d, J= 6.4 Hz, 3H); ¹³ C NMR (126 MHz, CDCh): d 174.8, 173.4, 136.2, 131.6, 128.2, 128.0, 45.4, 42.9, 30.9, 28.8, 21.3; HRMS (ESI): Calc’d for C _I3 H _I6 N0 ₂ [M+H] ⁺ : 218.1176, found: 218.1183.

[0288] (4-Methyl -3, 4-dihydropyridin-l (2//)-yl)(phenyl)methanone (lOb) was prepared from S2 according to a published procedure (57). The title compound was obtained as a colorless oil (323 mg, 74%). ³ H NMR (500 MHz, CDCh, ca. 3 : 1 mixture of conformers): d 7.45-7.35 (m, 5H), 7.22 (br, 0.25H), 6.37 (d, J= 7.9 Hz, 0.75H), 5.08 (br, 0.25H), 4.68 (d, J= 7.9 Hz, 0.75H), 4.03 (br, 0.75H), 3.59-3.55 (m, 1H), 3.47 (br, 0.25H), 2.34 (br, 1H), 2.02 (br, 0.75H), 1.83 (br, 0.25H), 1.55 (br, 0.75H), 1.40 (br, 0.25H), 1.02 (d, J= 7.0 Hz, 3H); ¹³ C NMR (126 MHz, CDCh, peaks of major conform er are listed): d 169.3, 135.1, 130.2, 128.4, 128.2, 126.3, 113.8, 39.9, 30.0, 27.4, 21.3; HRMS (ESI): Calc’d for C _I3 H _I6 NO [M+H] ⁺ : 202.1226, found: 202.1226

[0289] Phenyl(2,3,4,5-tetrahydro-l77-azepin-l-yl)methanone (lOc) was prepared according to a published procedure. Spectral data were in full agreement with the reported literature values (57).

Example 8. Experimental Procedures for Silver-Mediated Fluorination:

Representative Procedure for the Silver-Mediated Monofluorination of Cyclic Amines

AgBF ₄ (4 equiv)

Selectfluor (4 equiv)

- ►

acetone:H ₂ 0 (1 :9)

Bz

40 °C, 1 h

1a 2a

[0290] To a l-dram vial was added sequentially la (18.9 mg, 0.100 mmol), AgBF ₄ (77.9 mg, 0.400 mmol), Selectfluor ^® (142 mg, 0.400 mmol) and 1 :9 acetone: H ₂ 0 (0.5 mL) The resulting mixture was heated to 40 °C and held at this temperature. After 1 h, the reaction mixture was partitioned with EtOAc (0.5 mL) and H ₂ 0 (0.5 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (1.5 mL ^c 3) and the combined organic layers were

concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (50% EtO Ac/hexanes) to provide A-(4-fl uorobutyl )- A'-form yl benzam i de (2a) (18.0 mg, 81%) as a pale yellow oil. Ή NMR (600 MHz, CDCh): d 8.93 (s, 1H), 7.57 (t, J= 7.2 Hz, 1H), 7.53-7.48 (m, 4H), 4.48 (dt, J= 47.6, 5.6 Hz, 2H), 3.92 (t, J= 7.1 Hz, 2H), 1.82-1.72 (m, 4H); ¹³ C NMR (151 MHz, CDCh): 172.5, 164.3, 133.7, 132.3, 129.1, 128.9, 83.6 (d, J = 165.2 Hz), 40.2, 28.0 (d, J= 20.2 Hz), 24.2 (d, J= 5.0 Hz); ¹⁹ F NMR (376 MHz, CDCh): d -217.5 - -217.9 (m, 1F);

HRMS (ESI): Calc’d for Ci ₂ Hi ₄ FN0 ₂ Na [M+Na] ⁺ : 246.0906, found: 246.0906. [0291] /V-(4-Fluorobutyl)-/V-formylacetamide (2b): The title compound was prepared according to the representative procedure using lb. Purification by preparative thin-layer chromatography (25% EtO Ac/hexanes) provided the title compound (7.2 mg, 45%) as a colorless oil. ¾ NMR (600 MHz, CDCh): d 9.16 (s, 1H), 4.45 (dt, J= 47.0, 5.7 Hz, 2H), 3.73 (t, J= 7.3 Hz, 2H), 2.41 (s, 3H), 1.74-1.62 (m, 4H); ¹³ C NMR (151 MHz, CDCh): d 171.2, 162.8, 83.6 (d, J= 165.3 Hz), 39.6, 27.9 (d, J= 20.0 Hz), 24.3 (d, J= 4.3 Hz), 23.0; ¹⁹ F NMR (376 MHz, CDCh): d -217.8 (tt, j= 47.9, 24.4 Hz, 1F); HRMS (El): Calc’d for C ₇ Hi ₃ FN0 ₂ [M+H] ⁺ : 162.0925, found: 162.0933.

Boc

[0292] tert- Butyl (4-Fluorobutyl)(formyl)carbamate (2c): The title compound was prepared according to the representative procedure using lc. Purification by preparative thin-layer chromatography (25% EtOAc/hexanes) provided the title compound (8.6 mg, 39%) as a colorless oil. ¾ NMR (600 MHz, CDCh): d 9.17 (s, 1H), 4.45 (dt, J= 47.0, 5.7 Hz, 2H), 3.63 (t, J= 7.1 Hz, 2H), 1.73-1.63 (m, 4H), 1.54 (s, 9H); ¹³ C NMR (151 MHz, CDCh): d 163.2, 152.6, 84.2, 83.6 (d, J= 165.2 Hz), 40.2, 28.2, 27.8 (d, J= 20.0 Hz), 24.4 (d, J= 5.0 Hz); ¹⁹ F NMR (376 MHz, CDCh): d -217.9 (tt, j= 48.1, 25.7 Hz, 1F); HRMS (ESI): Calc’d for C10H19FNO3

[M+H] ⁺ : 220.1343, found: 220.1351.

[0293] /V-(4-Fluorobutyl)pivalamide (2d): The title compound was prepared according to the representative procedure using Id. Purification by preparative thin-layer chromatography (25% EtO Ac/hexanes) provided the title compound (12.3 mg, 70%) as a white solid. Melting Point: 67-69 °C; Ή NMR (600 MHz, CDCh): d 5.70 (br, 1H), 4.47 (dt, J= 47.2, 5.8 Hz, 2H), 3.29 (t, J= 6.8 Hz, 2H), 1.76-1.61 (m, 4H), 1.19 (s, 9H); ¹³ C NMR (151 MHz, CDCh): d 178.6, 83.9 (d, J= 164.6 Hz), 39.1, 38.8, 27.9 (d, J= 19.9 Hz), 27.7, 25.9 (d, J= 4.4 Hz); ¹⁹ F NMR (376 MHz, CDCh): d -219.0 (tt, j= 47.4, 25.8 Hz, 1F); HRMS (ESI): Calc’d for C9H19FNO

[M+H] ⁺ : 176.1445, found: 176.1442.

[0294] /V-(2-Fluoroethyl) benzamide (2e): The title compound was prepared according to the representative procedure using le. Purification by preparative thin-layer chromatography (50% EtO Ac/hexanes) provided the title compound (6.7 mg, 40%) as a colorless oil. ³ H NMR (400 MHz, CDCh): d 7.80 (d, J= 7.5 Hz, 2H), 7.51 (t, J= 7.5 Hz, 1H), 7.43 (t, J= 7.5 Hz, 2H), 6.63 (br, 1H), 4.60 (dt, J= 47.4, 4.9 Hz, 2H), 3.77 (dq, J= 28.3, 4.9 Hz, 2H); ¹³ C NMR (101 MHz, CDCh): d 167.8, 134.2, 131.8, 128.7, 127.1, 83.0 (d, J= 166.4 Hz), 40.6 (d, J= 19.7 Hz); ¹⁹ F NMR (376 MHz, CDCh): d -223.0 - -223.5 (m, 1F); HRMS (ESI): Calc’d for C ₉ H ₁₁ FNO [M+H] ⁺ : 168.0819, found: 168.0825.

[0295] /V-(3-Fluoropropyl) benzamide (2f): The title compound was prepared according to the representative procedure using If. Purification by preparative thin-layer chromatography (50% EtOAc/hexanes) provided the title compound (6.0 mg, 33%) as a pale yellow waxy solid. ³ H NMR (400 MHz, CDCh): d 7.76 (d, J= 6.9 Hz, 2H), 7.51 (t, J= 6.9 Hz, 1H), 7.43 (t, J= 6.9 Hz, 2H), 6.44 (br, 1H), 4.61 (dt, j= 47.3, 6.0 Hz, 2H), 3.63 (q, j= 6.0 Hz, 2H), 2.04 (dquint, J = 28.2, 6.0 Hz, 2H); ¹³ C NMR (101 MHz, CDCh): d 167.8, 134.6, 131.6, 128.7, 127.0, 83.0 (d, J = 163.9 Hz), 37.4 (d, 7= 4.1 Hz), 30.3 (d, J= 19.2 Hz); ¹⁹ F NMR (376 MHz, CDCh): d -218.9 - -219.3 (m, 1F); HRMS (ESI): Calc’d for C10H13FNO [M+H] ⁺ : 182.0976, found: 182.0976. [0296] /V-(5-Fluoropentyl)-/V-formylbenzamide (2g): The title compound was prepared according to the representative procedure using lg. Purification by preparative thin-layer chromatography (50% EtO Ac/hexanes) provided the title compound (15.6 mg, 67%) as a colorless oil. ³ H NMR (700 MHz, CDCh): d 8.92 (s, 1H), 7.57 (t, J= 7.5 Hz, 1H), 7.53 (d, J = 7.5 Hz, 2H), 7.49 (t, J= 7.5 Hz, 2H), 4.45 (dt, J= 47.3, 6.1 Hz, 2H), 3.88 (t, J= 7.5 Hz, 2H), d 1.81-1.68 (m, 4H), 1.49 (quint, J = 7.5 Hz, 2H); ¹³ C NMR (176 MHz, CDCh): d 172.5, 164.4, 133.7, 132.3, 129.1, 128.9, 83.9 (d, J= 164.7 Hz), 40.5, 30.1 (d, J= 19.8 Hz), 27.7, 22.8 (d, J = 5.3 Hz); ¹⁹ F NMR (376 MHz, CDCh): d -217.9 (tt, J= 47.3, 25.5 Hz, 1F); HRMS (ESI): Calc’d for C13H17FNO2 [M+H] ⁺ : 238.1238, found: 238.1238.

[0297] /V-(6-Fluorohexyl)-N-formylbenzamide (2h): The title compound was prepared according to the representative procedure using lh. Purification by preparative thin-layer chromatography (50% EtOAc/hexanes) provided the title compound (12.4 mg, 49%) as a colorless oil. Ή NMR (700 MHz, CDCh) d 8.92 (s, 1H), 7.60 (t, J= 7.2 Hz, 1H), 7.53-7.48 (m, 4H), 4.47 (dt, J= 47.3, 6.0 Hz, 2H), 3.87 (t, J= 7.4 Hz, 2H), 1.73-1.63 (m, 4H), 1.47-1.41 (m, 4H); ¹³ C NMR (176 MHz, CDCh) d 172.5, 164.4, 133.8, 132.3, 129.1, 128.9, 84.2 (d, J= 164.4 Hz), 40.6, 30.4 (d, J= 19.7 Hz), 28.0, 26.7, 25.0 (d, J= 5.2 Hz); ¹⁹ F NMR (376 MHz, CDCh): d -217.5 (tt, j= 48.9, 24.5 Hz, 1F); HRMS (ESI): Calc’d for Ci ₄ H ₁₈ FN0 ₂ Na [M+Na] ⁺ : 274.1214, found: 274.1216.

[0298] /V-(4-Fluoro-3-methylbutyl)-/V-formylbenzamide (2i): The title compound was prepared according to the representative procedure using li. Purification by preparative thin- layer chromatography (50% EtOAc/hexanes) provided the title compound (14.0 mg, 59%) as a colorless oil. Ή NMR (400 MHz, CDCh): d 8.92 (s, 1H), 7.60-7.47 (m, 5H), 4.32 (ddd, J = 47.5, 8.9, 5.7 Hz, 1H), 4.29 (ddd, J= 47.5, 8.9, 5.9 Hz, 1H), 3.94 (t, J= 7.6 Hz, 2H), 1.98-1.77 (m, 2H), 1.58-1.47 (m, 1H), 1.05 (dd, J= 6.7, 0.9 Hz, 3H); ¹³ C NMR (101 MHz, CDCh): d 172.4, 164.3, 133.7, 132.4, 129.1, 128.9, 88.0 (d, J= 169.7 Hz), 38.8, 32.4 (d, J= 18.5 Hz), 31.1

(d, J= 5.1 Hz), 15.8 (d, J= 6.8 Hz); ¹⁹ F NMR (376 MHz, CDCb): d -221.2 (td, J= 47.4, 19.4 Hz, 1F); HRMS (ESI): Calc’d for Ci ₂ H ₁₆ FNONa [M-CO+Na] ⁺ : 232.1108, found: 232.1107. [0299] /V-(5-Fluoropentan-2-yl)benzamide (2j): The title compound was prepared according to the representative procedure using lj. Purification by preparative thin-layer chromatography (50% EtOAc/hexanes) provided the title compound (17.0 mg, 81%) as a colorless oil. Ή NMR (400 MHz, CDCb): d 7.75 (d, J= 7.3 Hz, 2H), 7.49 (t, J= 7.3 Hz, 1H), 7.42 (d, J= 7.3 Hz, 2H), 5.96 (br, 1H), 4.47 (dddd, J= 47.2, 9.0, 6.4, 3.7 Hz, 2H), 4.26 (hept, J= 6.6 Hz, 1H), 1.86-1.60 (m, 4H), 1.27 (d, J= 6.6 Hz, 3H); ¹³ C NMR (101 MHz, CDCb): d 167.1, 134.9, 131.5, 128.7,

126.9, 83.9 (d, J= 164.8 Hz), 45.5, 33.0 (d, J= 4.3 Hz), 27.3 (d, J= 19.9 Hz), 21.3; ¹⁹ F NMR (376 MHz, CDCb): d -217.6 - -218.0 (m, 1F); HRMS (ESI): Calc’d for Ci ₂ H ₁₆ FNONa

[M+Na] ⁺ : 232.1108, found: 232.1111. [0300] /V-(6-Fluorohexan-3-yl) benzamide (2k): The title compound was prepared according to the representative procedure using lk. Purification by preparative thin-layer chromatography (50% EtOAc/hexanes) provided the title compound (19.0 mg, 85%) as a colorless oil. ³ H NMR (700 MHz, CDCb): d 7.75 (d, J= 7.4 Hz, 2H), 7.49 (t, J= 7.4 Hz, 1H), 7.42 (t, J= 7.4 Hz, 2H), 5.92 (br, 1H), 4.53-4.41 (m, 2H), 4.11 (ddq, J= 13.6, 8.9, 4.9 Hz, 1H), 1.85-1.72 (m, 3H), 1.70- 1.64 (m, 1H), 1.60-1.49 (m, 2H), 0.97 (t, J= 7.4 Hz, 3H); ¹³ C NMR (151 MHz, CDCb): d

167.6, 134.9, 131.5, 128.7, 126.9, 84.0 (d, J= 164.7 Hz), 50.8, 30.9 (d, J= 4.4 Hz), 28.4, 27.2 (d, J= 19.8 Hz), 10.5; ¹⁹ F NMR (376 MHz, CDCb): d -217.8 - -218.2 (m, 1F); HRMS (ESI): Calc’d for C13H19FNO [M+H] ⁺ : 224.1445, found: 224.1450. [0301] /V-(4-Fluoro-2-methylpentyl)-/V-formylbenzamide (21): The title compound was prepared according to the representative procedure using 11. Purification by preparative thin- layer chromatography (50% EtOAc/hexanes) provided the title compound (12.6 mg, 50%) as a colorless oil as a 1 : 1 mixture of diastereomers. ¹ H NMR (400 MHz, CDCh): (400 MHz, 1H), 8.95 (s, 1H), 7.59-7.47 (m, 10H), 4.91-4.68 (m, 2H), 3.88-3.74 (m, 4H), 2.25- 2.10 (m, 2H),

1.80-1.49 (m, 3H), 1.42-1.26 (m, 1H), 1.34 (dd, 7= 23.7, 6.1 Hz, 3H), 1.33 (dd, 7= 23.7, 6.1 Hz, 3H), 1.00 (d, J= 6.6 Hz, 3H), 0.99 (d, J= 6.6 Hz, 3H); ¹³ C NMR (101 MHz, CDCh): d 172.7 (2C), 164.7, 164.6, 133.84, 133.79, 132.4, 132.3, 129.14, 129.13, 128.94, 128.92, 89.6 (d, J= 164.6 Hz), 88.7 (d, J= 165.0 Hz), 46.0, 45.8, 41.90 (d, J= 20.7 Hz), 41.86 (d, J= 20.6 Hz), 29.7 (d, J= 4.0 Hz), 29.1 (d, J= 2.9 Hz), 21.8 (d, J= 22.6 Hz), 21.4 (d, J= 22.8 Hz), 18.3, 17.6;

¹⁹ F NMR (376 MHz, CDCh): d -169.8 - -170.3 (m, 1F), -172.6 - -173.1 (m, 1F); HRMS (ESI): Calc’d for Ci ₄ Hi ₈ FN0 ₂ Na [M+Na] ⁺ : 274.1214, found: 274.1212.

[0302] t/Yi/f.v-/V-(2-(2-Fluoroethyl)cyclohexyl)benzamide (2m): The title compound was prepared according to the representative procedure using lm. Purification by preparative thin- layer chromatography (50% EtOAc/hexanes) provided the title compound (10.7 mg, 43%) as a colorless oil. ³ H NMR (400 MHz, CDCh): d 7.76 (d, J= 7.3 Hz, 2H), 7.50 (t, J= 7.3 Hz, 1H), 7.44 (t, J= 7.3 Hz, 2H), 5.92 (br, 1H), 4.52 (ddd, J= 47.4, 7.2, 3.7 Hz, 2H), 3.83 (dq, j= 10.6, 3.9 Hz, 1H), 2.16-2.05 (m, 2H), 2.00-1.96 (m, 1H), 1.81-1.74 (m, 2H), 1.63-1.09 (m, 6H); ¹³ C NMR (151 MHz, CDCh): d 167.2, 135.0, 131.5, 128.7, 127.0, 82.4 (d, J= 163.6 Hz), 53.0, 40.1 (d, J= 3.3 Hz), 34.2, 33.8 (d, J= 19.5 Hz), 31.6, 25.7, 25.4; ¹⁹ F NMR (400 MHz, CDCh): d -217.5 - -217.9 (m, 1F); HRMS (ESI): Calc’d for C15H21FNO [M+H] ⁺ : 250.1602, found: 250.1595.

[0303] Methyl (N)-2-Benzamido-5-fluoropentanoate (2n): The title compound was prepared according to the representative procedure using In. Purification by preparative thin-layer chromatography (25% EtO Ac/hexanes) provided the title compound (17.2 mg, 68%) as a white solid. Melting Point: 63-65 °C; Optical Rotation: [a] ²² _D = +17 (c 0.67, CHCb); *H NMR (600 MHz, CDCh): d 7.80 (d, J= 7.4 Hz, 2H), 7.52 (t, J= 7.4 Hz, 1H), 7.44 (t, J= 7.4 Hz, 2H),

6.78 (d, J= 7.4 Hz, 1H), 4.87 (dt, J= 7.4, 5.3 Hz, 1H), 4.54-4.41 (m, 2H), 3.79 (s, 3H), 2.16- 2.10 (m, 1H), 1.95-1.89 (m, 1H), 1.88-1.72 (m, 2H); ¹³ C NMR (151 MHz, CDCh): d 172.9, 167.2, 133.9, 132.0, 128.8, 127.2, 83.4 (d, J= 165.5 Hz), 52.7, 52.2, 28.9 (d, J= 4.7 Hz), 26.6 (d, J= 20.2 Hz); ¹⁹ F NMR (376 MHz, CDCh): d -218.4 (tt, J= 47.3, 25.7 Hz, 1F); HRMS (ESI): Calc’d for C13H17FNO3 [M+H] ⁺ : 254.1187, found: 254.1185.

[0304] Methyl (/ _>' )-! -Benzoyl -5-oxopyrrolidine-2-carboxyl ate (lo): The title compound was prepared according to the representative procedure using lo. Purification by preparative thin- layer chromatography (50% EtO Ac/hexanes) provided the title compound (11.4 mg, 46% yield). Spectroscopic data is fully consistent with previously reported data (52).

[0305] l-Methylpyrrolidine-2,5-dione (lp): The title compound was prepared according to the representative procedure using lp. Purification by preparative thin-layer chromatography (50% EtO Ac/hexanes) provided the title compound (9.2 mg, 81% yield). Spectroscopic data is fully consistent with previously reported data (55).

[0306] l-Methylpiperidine-2,6-dione (lq): The title compound was prepared according to the representative procedure using lp. Purification by preparative thin-layer chromatography (50% EtO Ac/hexanes) provided the title compound (7.1 mg, 56% yield). Spectroscopic data is fully consistent with previously reported data (55).

[0307] 4-Fluoro-/V-pivaloylbutanamidebenzamide (2r): The title compound was prepared according to the representative procedure using lr. Purification by preparative thin-layer chromatography (30% EtO Ac/hexanes) provided the title compound (8.1 mg, 43% yield) as a white solid. Melting Point: 63-65 °C; ¾ NMR (600 MHz, CDCh): d 8.07 (br, 1H), 4.51 (dt, J = 47.2, 5.9 Hz, 2H), 3.01 (t, j= 7.2 Hz, 2H), 2.05 (ddd, j= 25.8, 7.2, 5.9 Hz, 2H), 1.25 (s, 9H); ¹³ C NMR (151 MHz, CDCh): d 177.2 , 175.3, 83.2 (d, J= 165.1 Hz), 40.2, 33.4 (d, J= 5.2 Hz), 27.2, 25.0 (d, J= 20.3 Hz); ¹⁹ F NMR (376 MHz, CDCh): d -219.1 (tt, J= 47.2, 25.8 Hz, 1F); HRMS (ESI): Calc’d for C9H17FNO2 [M+H] ⁺ : 190.1238, found: 190.1245.

[0308] /V-(2,4-Difluorobutyl)benzamide (2s): The title compound was prepared according to the representative procedure using Is. Purification by preparative thin-layer chromatography (50% EtO Ac/hexanes) provided the title compound (6.0 mg, 28% yield) as a waxy white solid. Ή NMR (400 MHz, CDCh): d 7.79 (d, J= 7.3 Hz, 2H), 7.52 (t, J= 7.3 Hz, 1H), 7.45 (t, J= 7.3 Hz, 2H), 6.52 (br, 1H), 4.90 (dtt, J= 48.4, 7.2, 3.6 Hz, 1H), 4.62 (dt, J= 47.3, 5.9 Hz, 2H), 3.89 (dddd, J= 28.2, 14.7, 6.6, 3.0 Hz, 1H), 3.66-3.54 (m, 1H), 2.20-1.93 (m, 2H); ¹³ C NMR (101 MHz, CDCh): d167.8, 134.1, 131.9, 128.8, 127.1, 89.8 (dd, = 169.6, 3.6 Hz), 79.7 (dd, = 165.6, 5.1 Hz), 43.6 (d, J= 20.1 Hz), 33.5 (t, J= 20.1 Hz); ¹⁹ F NMR (376 MHz, CDCh): d -188.7 - -189.1 (m, 1F), -220.3 - -220.7 (m, 1F); HRMS (ESI): Calc’d for CnH ₁₄ F ₂ NO

[M+H] ⁺ : 214.1038, found: 214.1038. [0309] /V-(3,4-Difluorobutyl)benzamide (2t): The title compound was prepared according to the representative procedure using It. Purification by preparative thin-layer chromatography (50% EtO Ac/hexanes) provided the title compound (4.7 mg, 22% yield) as a waxy white solid. ³ H NMR (700 MHz, CDCb) 7.78 (d, J= 7.4 Hz, 2H), 7.52 (t, J= 7.4 Hz, 1H), 7.46-7.41 (m, 2H), 6.45 (br, 1H), 4.98-4.74 (m, 1H), 4.69-4.41 (m, 2H), 3.73-3.62 (m, 2H), 2.14-1.98 (m,

2H); ¹³ C NMR (176 MHz, CDCb) d 167.9, 134.4, 131.8, 128.8, 127.0, 90.8 (dd, J= 172.6, 19.7 Hz), 84.0 (dd, J= 174.5, 22.4 Hz), 36.5 (d, J= 4.3 Hz), 36.5 (dd, J= 20.2, 6.0 Hz); ¹⁹ F NMR (376 MHz, CDCb): d -189.5 - -190.0 (m, 1F), -229.4 - -229.8 (m, 1F); HRMS (ESI): Calc’d for C ₁₁ H ₁₄ F ₂ NO [M+H] ⁺ : 214.1038, found: 214.1038.

[0310] Methyl ((ri)-2-Benzamido-5-fluoropentanoyl)-Z-valinate (4a): The title compound was prepared according to the representative procedure using 3a with the following modifications: reaction time of 15 h at room temperature. Purification by preparative thin-layer chromatography (20% to 50% EtO Ac/hexanes) provided the title compound (17.5 mg, 50% yield) as a white amorphous solid along with recovered 3a (8.7 mg, 25%). Optical Rotation: [a] ²² _D = -13 (c 0.47, CHCh); ¾ NMR (600 MHz, CDCb): d 7.80 (d, J= 7.4 Hz, 2H), 7.50 (t, J= 7.4 Hz, 1H), 7.80 (t, J= 7.4 Hz, 2H), 7.04 (d, J= 8.3 Hz, 1H), 6.89 (d, J= 8.5 Hz, 1H), 4.84 (q, J= 8.5 Hz, 1H), 4.51 (dd, J= 8.3, 5.0 Hz, 1H), 4.50 (dt, J= 47.4, 5.7 Hz, 2H), 3.75 (s, 3H), 2.21-2.14 (m, 1H), 2.09 (ddt, J= 13.4, 9.4, 6.1 Hz, 1H), 1.97-1.76 (m, 3H), 0.90 (d, J= 6.9 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H); ¹³ C NMR (151 MHz, CDCh): d 172.1, 171.6, 167.5, 133.8, 132.0, 128.7, 127.2,

83.9 (d, 7= 164.8 Hz), 57.6, 53.0, 52.3, 31.1, 29.1 (d, 7= 4.1 Hz), 26.6 (d, J= 20.0 Hz), 19.1, 17.8; ¹⁹ F NMR (376 MHz, CDCb): d -217.1 - -217.5 (m, 1F); HRMS (ESI): Calc’d for Ci ₈ H ₂₅ FN ₂ 0 ₄ Na [M+Na] ⁺ : 375.1691, found: 375.1692.

[0311] Methyl fY)-2-(fV)-2-Benzamidopropanamido)-5-fluoropentanoate (4b): The title compound was prepared according to the representative procedure using 3b with the following modifications: reaction time of 15 h at room temperature. Purification by preparative thin-layer chromatography (20% to 50% EtOAc/hexanes) provided the title compound (12.3 mg, 38% yield) as a white amorphous solid along with recovered 3b (12.7 mg, 40%). Optical Rotation:

[a] ²² _D = +7.1 (c 0.63, CHCb); Ή NMR (600 MHz, CDCb, ca. 1 : 1 mixture of rotamers): d 7.81— 7.79 (m, 2H), 7.52-7.49 (m, 1H), 7.45-7.40 (m, 2H), 7.33 (d, j = 7.9 Hz, 0.5H), 7.23 (d, J= 7.9 Hz, 0.5H), 7.09 (d, J= 7.3 Hz, 1H), 4.83 (dq, J= 14.3, 7.3 Hz, 1H), 4.63-4.59 (m, 1H), 4.49- 4.47 (m, 0.5H), 4.42-4.39 (m, 1H), 4.34-4.32 (m, 0.5H), 3.75 (s, 1.5H), 3.68 (s, 1.5H), 2.03- 1.98 (m, 1H), 1.86-1.66 (m, 3H), 1.495 (d, J= 7.0 Hz, 1.5H), 1.491 (d, J= 7.0 Hz, 1.5H); ¹³ C NMR (151 MHz, CDCb, mixture of rotamers): d 172.6, 172.5, 172.4, 172.3, 167.5, 167.4, 133.9 (2C), 131.9 (2C), 128.7 (2C), 127.23, 127.20, 82.23 (d, J= 165.7 Hz), 82.20 (d, J= 165.7 Hz), 52.61, 52.58, 52.1, 52.0, 49.29, 49.26, 28.33 (d, J = 4.7 Hz), 28.30 (d, J= 4.7 Hz), 26.61 (d, J = 20.2 Hz), 26.55 (d, J= 20.2 Hz), 18.7, 18.6; ¹⁹ F NMR (376 MHz, CDCb): d -218.4 - -218.9 (m, 1F); HRMS (ESI): Calc’d for Ci ₆ H _2i FN ₂ 0 ₄ Na [M+Na] ⁺ : 347.1378, found: 347.1379.

[0312] Methyl ((ri)-2-Benzamido-5-fluoropentanoyl)-Z-valyl-Z-alaninate (4c): The title compound was prepared according to the representative procedure using 3c with the following modifications: reaction time of 15 h at room temperature. Purification by preparative thin-layer chromatography (5% MeOH/CFbCb) provided the title compound (16.5 mg, 39% yield) as a white amorphous solid along with recovered 3c (10.4 mg, 25%). Optical Rotation: [a] ²² _D = -41 (c 0.39, MeOH); ³ H NMR (700 MHz, CD ₃ OD): d 7.85-7.84 (m, 2H), 7.55-7.53 (m, 1H), 7.47- 7.45 (m, 2H), 4.64 (dt, J= 8.8, 4.7 Hz, 1H), 4.47 (d, J= 47.6 Hz, 2H), 4.39 (dt, J= 13.5, 6.7 Hz, 1H), 4.24 (dd, j= 6.6, 4.2 Hz, 1H), 3.69 (s, 3H), 2.08 (dt, j= 12.1, 5.5 Hz, 1H), 2.01 (tt, j =

10.4, 5.3 Hz, 1H), 1.90-1.77 (m, 3H), 1.39 (br s, 3H), 0.99 (br s, 9H); ¹³ C NMR (176 MHz, CD ₃ OD): d 174.4, 174.2, 173.3, 170.5, 135.2, 132.9, 129.6, 128.5, 84.4 (d, J= 164.3 Hz), 59.8, 55.0, 52.6, 49.4, 32.3, 28.9 (d, J= 5.3 Hz), 28.3 (d, J= 20.0 Hz), 19.6, 18.6, 17.3; ¹⁹ F NMR (376 MHz, CD3OD): d -219.7 (tt, j= 47.7, 24.8 Hz, 1F); HRMS (ESI): Calc’d for C _2i H ₃ oFN ₃ 0 ₅ Na [M+Na] ⁺ : 446.2062, found: 446.2060.

[0313] Methyl (fV)- l -Benzoyl -5 -ox opyrrolidine-2-carbonyl)-T-valinate (4d): The title compound was prepared according to the representative procedure using 3d with the following modifications: 0.2 mmol scale with a reaction time of 15 h at room temperature. Purification by preparative thin-layer chromatography (20% to 50% EtO Ac/hexanes) provided the title compound (52.6 mg, 76% yield) as a white solid. Melting Point: 155-158 °C; Optical

Rotation: [a] ²² _D = -256 (c 0.46, CHCh); Ή NMR (600 MHz, CDCh): d 7.62-7.61 (m, 2H), 7.52-7.48 (m, 1H), 7.40 (t, J= 7.8 Hz, 2H), 4.83 (dd, J= 8.3, 3.6 Hz, 1H), 4.57 (dd, J= 8.9, 4.8 Hz, 1H), 3.75 (s, 3H), 2.89-2.83 (m, 1H), 2.53 (ddd, J= 17.8, 9.1, 4.3 Hz, 1H), 2.36-2.25 (m, 2H), 2.23-2.17 (m, 1H), 0.95 (d, J= 6.9 Hz, 3H), 0.93 (d, J= 6.9 Hz, 3H); ¹³ C NMR (151 MHz, CDCh): d 174.1, 172.4, 170.9, 170.4, 134.0, 132.2, 129.0, 128.0, 60.0, 57.5, 52.4, 32.1, 31.4, 22.2, 19.0, 17.8; HRMS (ESI): Calc’d for Ci ₈ H ₂₃ N ₂ 0 ₅ [M+H] ⁺ : 347.1601, found: 347.1599.

Example 9. Experimental Procedures for Silver-Mediated Fluorination:

Representative Procedure for the Silver-Mediated Difluorination of Enamides

RT, 15 h

10a 12a

[0314] To a l-dram vial containing a solution of 10a (18.7 mg, 0.100 mmol) in 1 : 1 acetone: H ₂ 0 (0.5 mL) was added Selectfluor ^® (142 mg, 0.400 mmol) followed by AgBF ₄ (4.9 mg, 0.025 mmol). The resulting mixture was stirred at room temperature. After 15 h, the reaction mixture was partitioned with EtOAc (0.5 mL) and H ₂ 0 (0.5 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (1.5 mL ^c 3) and the combined organic layers were concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (25% EtO Ac/hexanes) to provide /V-(4,4-difluorobutyl)-/V-formylbenzamide (12a) (18.7 mg, 78%) as a colorless oil. *H NMR (600 MHz, CDCh): d 8.93 (s, 1H), 7.59 (d, J = 7.1 Hz, 1H), 7.54-7.49 (m, 4H), 5.87 (tt, J= 56.5, 4.2 Hz, 1H), 3.93 (t, J= 7.2 Hz, 2H), 1.96- 1.82 (m, 4H); ¹³ C NMR (151 MHz, CDCb): d 178.6, 83.9 (d, J= 164.6 Hz), 39.1, 38.8, 27.9 (d, J= 19.9 Hz), 27.7, 25.9 (d, J= 4.4 Hz) ¹³ C NMR (151 MHz, CDCb) d 172.4, 164.3, 133.5, 132.5, 129.2, 128.9, 116.8 (t, J= 239.2 Hz), 39.9, 31.8 (t, 7= 21.5 Hz), 20.9 (t, j= 5.5 Hz); ¹⁹ F NMR (376 MHz, CDCb): d -115.3 (dt, J= 56.5, 16.9 Hz, 2F); HRMS (ESI): Calc’d for C11H14F2NO [M-CO+H] ⁺ : 214.1038, found: 214.1038.

[0315] /V-(4,4-Difluoro-3-methylbutyl)-/V-formylbenzamide (l2b): The title compound was prepared according to the representative procedure using lOb. Purification by preparative thin- layer chromatography (20% EtOAc/hexanes) provided the title compound (13.9 mg, 54%) as a colorless oil. Ή NMR (500 MHz, CDCb): d 8.93 (s, 1H), 7.58 (t, J= 6.9 Hz, 1H), 7.54-7.48 (m, 4H), 5.68 (td, J= 56.7, 3.5 Hz, 1H), 3.94 (t, J= 7.5 Hz, 2H), 2.01-1.90 (m, 2H), 1.59-1.53 (m, 1H), 1.11 (d, J= 6.9 Hz, 3H); ¹³ C NMR (126 MHz, CDCb): d 172.4, 164.3, 133.5, 132.5, 129.2, 128.9, 118.8 (t, 7= 242.5 Hz), 38.4, 35.7 (t, J= 19.9 Hz), 28.3 (t, J= 4.4 Hz), 12.6 (t, J = 5.2 Hz); ¹⁹ F NMR (376 MHz, CDCb): d -122.4 (ddd, J= 56.6, 29.6, 14.7 Hz, 2F); HRMS (ESI): Calc’d for C13H16F2NO [M-CO+H] ⁺ : 256.1144, found: 256.1143.

[0316] /V-(5,5-Difluoropentyl)-/V-formylbenzamide (l2c): The title compound was prepared according to the representative procedure using 10c. Purification by preparative thin-layer chromatography (20% EtOAc/hexanes) provided the title compound (15.6 mg, 61%) as a colorless oil. ³ H NMR (500 MHz, CDCb): d 8.92 (s, 1H), 7.59-7.56 (m, 1H), 7.53-7.48 (m, 4H), 5.82 (tt, J= 56.8, 4.4 Hz, 1H), 3.88 (t, J= 7.4 Hz, 2H), 1.95-1.83 (m, 2H), 1.72 (quint, J = 7.4 Hz, 2H), 1.53 (quint, J= 7.4 Hz, 2H); ¹³ C NMR (126 MHz, CDCb): d 172.5, 164.4, 133.6, 132.4, 129.1, 128.9, 117.1 (t, J= 238.8 Hz), 40.2, 33.7 (t, J= 21.0 Hz), 27.5, 19.6 (t, J= 5.6 Hz); ¹⁹ F NMR (376 MHz, CDCb): d -115.3 (dt, J= 56.7, 17.5 Hz, 2F); HRMS (El): Calc’d for C13H15F2NO2 [M] ⁺ : 255.1065, found: 255.1070. Example 10. Mechanistic Studies

0 AgBF ₄ (4 equiv) 0

I acetone:H ₂ 0 (1 :9)

H 40 °C, 1 h Bz

_D (55% NMR yield) 2a

[0317] According to the representative procedure, aldehyde D (54) was used as a starting material. Triphenylmethane was used as an internal standard and 'H NMR analysis showed the formation of 2a in 55% yield.

AgBF ₄ (4 equiv)

Selectfluor (4 equiv)

acetone:H ₂ 0 (1 :9)

RT, 16 h

(54% yield)

6

[0318] To a l-dram vial containing la (94.5 mg, 0.5 mmol), AgBF ₄ (390 mg, 2.00 mmol) and Selectfluor ^® (710 mg, 2.00 mmol) was added 1 :9 acetone: H ₂ 0 (2.5 mL), and the resulting mixture was stirred at room temperature. After 16 h, the reaction mixture was partitioned with EtOAc (2.5 mL) and H ₂ 0 (0.5 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (5.0 mL ^c 3) and the combined organic layers were concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (50% EtO Ac/hexanes) to provide /V-(4-fluorobutyl)benzamide (6) (52.7 mg, 54%) as a waxy white solid. ³ H NMR (700 MHz, CDCh): d 7.76 (d, J= 7.5 Hz, 2H), 7.49 (t, J= 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 6.31 (br, 1H), 4.50 (dt, J= 46.9, 5.6 Hz, 2H), 3.51 (q, 7= 6.5 Hz, 2H), 1.86-1.72

(m, 4H); ¹³ C NMR (176 MHz, CDCh): d 167.6, 134.6, 131.4, 128.5, 126.8, 83.7 (d, J= 164.7 Hz), 39.5, 27.8 (d, J= 19.9 Hz), 25.7 (d, J= 4.4 Hz); ¹⁹ F NMR (376 MHz, CDCh): d -217.4 (tt, J= 47.5, 26.2 Hz, 1F); HRMS (ESI): Calc’d for CnH _l4 FNONa [M+Na] ⁺ : 218.0952, found: 218.0952.

[0319] According to the representative procedure, aldehyde 7 (55) was used as a starting material. Triphenylmethane was used as an internal standard and 'H NMR analysis showed theformation of 8 (56) in 70% yield.

AgBF ₄ (4 equiv)

Selectfluor (4 equiv)

-►

acetone: H ₂ 0 (1 :9)

40 °C, 1 h

(23% NMR yield)

[0320] According to the representative procedure, carboxylic acid 9 (55) was used as a starting material. Triphenylmethane was used as an internal standard and ¾NMK analysis showed the formation of 6 in 23% yield.

Example 11. NMR Studies: Interaction of AgBF ₄ with la.

[0321] Procedure: To a 4 ml vial containing la (18.9 mg, 0.100 mmol) and AgBF ₄ (19.4 mg, 0.100 mmol) was added 1 :9 (v/v) Acetone-r/^/DiO (1.0 ml). The contents of the reaction vial were then transferred into a NMR tube and spectroscopic data was collected right after. The same procedure was followed with varying amounts of AgBF _4. The residual signal of acetone was used as internal reference.

Example 12. NMR Studies: Interaction of AgBF ₄ with Selectfluor ^® .

[0322] Procedure: To a 4 ml vial containing Selectfluor ^® (35.4 mg, 0.100 mmol) and AgBF ₄ (19.4 mg, 0.100 mmol) was added 1 :9 (v/v) Acetone-i/d/EhO (1.0 ml). The resulting solution was allowed to stir at 40 °C for 1 h. The contents of the reaction vial were then transferred into a NMR tube and an NMR spectrum was taken directly afterwards to measure consumption of Selectfluor ^® .

Example 13. Electrochemical Measurement.

[0323] Non-aqueous electrochemical experiments were conducted under an Ar atmosphere in 0.1 M NBu ₄ PF ₆ electrolyte in acetonitrile. Cyclic voltammetry experiments were performed using an Epsilon potentiostat from Bioanalytical Systems, Inc. The working electrode was a 3.0 mm diameter glassy carbon disk (from Bioanalytical Systems, Inc.) and was polished between every scan with 0.05-micron alumina powder on a felt pad. The counter electrode was a platinum wire. A silver wire in porous Vycor tip glass tube filled with 0.1 M NBu ₄ PF ₆ in acetonitrile was used as a pseudo-reference electrode. At the conclusion of the series of experiments, the pseudo- reference potentials were referenced against ferrocene/ferrocenium as an external standard. The scan rate for all cyclic voltammograms was 100 mV/sec unless otherwise noted. All scans were compensated for internal resistance. Data measured with respect to Fc/Fc ⁺ and reported to SCE. REFERENCES

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[0324] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.