Copper-catalyzed bimodal dehydrogenation and lactonization of c(SP3)-h bonds

Abstract

This application discloses methods of copper-catalyzed bimodal dehydrogenation and lactonization of N-methoxyamides via γ-C-H radical abstraction.

Description

TSRI 2216.1PC COPPER-CATALYZED BIMODAL DEHYDROGENATION AND LACTONIZATION OF C(SP3)-H BONDS CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. provisional patent application No. 63 / 605,065, which was filed on December 1, 2023, and which is hereby incorporated by reference in its entirety. GOVERNMENT SUPPORT

[0002] This invention was made with government support under GM084019 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION

[0003] This application discloses methods of copper-catalyzed bimodal dehydrogenation and lactonization of N-methoxyamides via γ-C−H radical abstraction.

[0004] This application claims priority to U.S. provisional patent application No. 63 / 605,065, which was filed on December 1, 2023, and which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION

[0005] Olefins and carbon-oxygen bonds are ubiquitous and highly important in organic synthesis1. A particularly attractive strategy for constructing such moieties is the direct oxidation of inert C−H bonds. The generation of a C−O bond at the expense of a C−H bond leads to increased complexities and enables the direct synthesis of the target of interest from a simple hydrocarbon fragments2,3. From the perspective of downstream diversification, the desaturation of aliphatic chains by C−H dehydrogenation can be even more versatile than the direct conversion of C−H to C−O bonds. Nature has evolved various enzymes to catalyze the direct oxidation of hydrocarbon skeletons with great precision4, resulting in a large array of oxidative diversity. In some cases, a single enzyme was found to simultaneously catalyze different types of reactions5,6. In 1987, a landmark discovery by Baillie and coworkers showcased that a type of hepatic cytochrome P450, normally considered a hydroxylase, couldTSRI 2216.1PC also act as a desaturase5. When catalyzing the oxidation of the antiepileptic drug valproic acid (VPA), it produces a mixture of the hydroxylated product and the dehydrogenated product Δ4-VPA, a potent hepatotoxin. It is believed that a common carbon-centered radical intermediate is responsible for this mixed hydroxylase / desaturase activity (Fig.1a). The recombination of carbon radical-perferric hydroxide radical pairs accounts for the formation of 4-OH-VPA, and a loss of a second hydrogen atom affords Δ4-VPA. Inspired by this remarkable enzymatic chemistry, it was envisioned that the possibility of accessing remote bimodal C−H dehydrogenation / oxygenation reaction with metal catalysts through radical abstraction. Such a reaction could be useful for direct oxidation state elevation of hydrocarbon frameworks2,3, and it would be a valuable tool for late-stage modifications and diversifications of natural products and drug molecules7-9. Although biomimetic dehydrogenation and oxygenation reactions based on the hydrogen atom abstraction strategy have been reported starting with the pioneering work of Breslow10,11and Groves12,13et al., dual desaturation / oxygenation reaction remains a grand challenge. The few early examples suffered from limited scope (only for benzylic C−H)14,15and / or overoxidation15,16. Moreover, these methods require exogenous stoichiometric oxidants, most of which give mixed dehydrogenated / hydroxylated products and cannot be tuned to produce a single major product. Therefore, the development of a controllable bimodal dehydrogenation / oxygenation reaction would be highly desirable. Therefore, there exists a need in the field for the highly desirable yet challenging development of a controllable bimodal dehydrogenation / oxygenation reaction. BRIEF DESCRIPTION OF THE FIGURES

[0006] Figure 1. (a) Nature’s approach: hepatic P450-mediated bimodal oxidation of valproic acid. (b) Our design of Cu-catalyzed bimodal oxidation of N-methoxyamides. (c) Synthetic approach: dual desaturation / lactonization reactivity enables rapid diversification of carboxylic acid derivatives.

[0007] Figure.2. Substrate scope for the dehydrogenation reaction.1-25, substrates with secondary γ-C−H; 27-38, substrates with tertiary γ-C−H; 39-65, substrates from amino acids, natural products and drugs. Reaction conditions: A (0.1 mmol), CuF2(10 mol%), acid (8 eq. AcOH or 0.5 eq. CSA, see Experimental section for details), dioxane or DCE (0.50 mL), at 125 °C for 1-20 h. Isolated yields are reported. *135 °C. †The acid is TsOH•H2O (0.5 eq.). L (20 mol%) was added. [(MeCN)4Cu]BF4 (10 mol%) was used instead of CuF2.TSRI 2216.1PC

[0008] Figure.3. Substrate scope for the lactonization reaction.1-19, representative examples of bimodal dehydrogenation / lactonization, see Fig.2 for the corresponding dehydrogenated product from the same substrate.20-25, substrates with primary γ-C−H; 26- 42, substrates with secondary γ-C−H; 43-44, substrates with tertiary γ-C−H; 45-54, substrates from natural products and drugs. Reaction conditions: A (0.1 mmol), CuF2(10 mol%) or [(CH3CN)4Cu]BF4(10 mol%), acid (5 eq. TFA or 0.5 eq. CSA, see SI for details), dioxane or AcOH (0.50 mL), at 125 °C for 1-20 h. Isolated yields are reported. ¶The solvent is dioxane / MeNO2(0.25 mL / 0.25 mL). *The acid is TsOH•H2O (0.5 eq.). 0.2 eq. CSA was used. §0.25 eq. TFA was used.

[0009] Figure.4. Experiments using a low loading of copper and mechanistic studies. (a) Reaction conditions for dehydrogenation: A (0.1 mmol), catalyst (0.5-1 mol%), CSA (0.5 eq), dioxane (0.50 mL), 125 °C. Reaction conditions for lactonization: A (0.1 mmol), catalyst (0.5-1 mol%), TFA (5 eq), dioxane or AcOH (0.50 mL), 125 °C. ± [(CH3CN)4Cu]BF4(0.5 mol%). #CuF2(1 mol%). *AcOH (0.5 mL). Isolated yields are reported. (b) Investigation of Cu(I) generated in situ. (c) Radical clock experiment. (d) Inverted regioselectivity of a cationic intermediate. (e) Plausible mechanism based on the mechanistic studies and literature precedents. SUMMARY OF THE INVENTION

[0010] In summary, a bimodal Cu-catalyzed dehydrogenation / lactonization of N- methoxyamides has been achieved. This redox-neutral process led to two controllable reaction pathways for synthesizing γ,δ-unsaturated primary amides and γ-lactones from various carboxylic acids (as the precursors of N-methoxyamides).

[0011] The application provides a method of copper-catalyzed bimodal dehydrogenation of N-methoxyamides via radical abstraction of γ-aliphatic C−H bonds.

[0012] The application further provides the above method, wherein the dehydrogenation occurs according to the following scheme: NH2TSRI 2216.1PC wherein: Ra, Rb, and Rcare independently H, -(C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, -NPhth, -OAc, or Ph; Rdand Reare independently H, (C1-C6) alkyl, -OAc, -OC(=O)(CH2)2NHC(=O)CH2NPhth, - CH2OPhMe2, or -NPhth; Rfand Rgare independently H, (C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, Ph, -NPhth, or -OAc; or Reand Rgtogether form a bond; or Rfand Rgtogether form -(C2-C6) alkenyl.

[0013] The application further provides the above method, wherein the dehydrogenation alternatively occurs according to the following scheme: NH2wherein: Ra, Rb, and Rcare independently H, -(C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, -NPhth, -OAc, or Ph; Rdand Reare independently H, -(C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, -NPhth, -OAc, or Ph; or Rdand Retogether form -(C2-C6) alkenyl.

[0014] The application further provides the above method, wherein the dehydrogenation alternatively occurs according to the following scheme: NH2wherein: Q’ is a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated (C3-C16) heterocycloalkyl, -(C6-C10) aryl, or -(C5-C10) heteroaryl;TSRI 2216.1PC each R1is independently -OH, -(C1-C6) alkyl, oxo, -OAc, -O-(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, saturated or partially unsaturated (C3-C16) cycloalkyl, -NPhth, or -CH2NPhth; each R2is independently R2aor R2b; each R2ais independently -OH, -CN, halo, or oxo; each R2bis independently -(C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) heterocycloalkyl; or one R1and one R2together form -(C6-C10) aryl, saturated or partially unsaturated (C3-C14) cycloalkyl, or saturated or partially unsaturated (C3-C16) heterocycloalkyl, or -(C5- C10) heteroaryl, each optionally substituted with one or more -(C1-C10) alkyl, -OAc, or - PhOMe; each R3is independently H, -(C1-C6) alkyl, saturated or partially unsaturated (C3-C16) cycloalkyl, -NPhth, or -(C6-C10) aryl; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0015] The application further provides the above method, wherein the dehydrogenation alternatively occurs according to the following scheme: NH2R5wherein: Q is saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated (C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, or -(C6-C10) aryl; R1is H, halo, oxo, or -OAc; or R1and R5together form partially unsaturated (C3-C16) cycloalkyl or saturated or partially unsaturated (C3-C14) heterocycloalkyl, optionally substituted with one or more R1’;R1’is -OH, -CN, halo, oxo, (C1-C6) alkyl, -OAc, or -(C2-C6) alkenyl; R2is R2aor R2b; R2ais -OH, -CN, halo, or oxo; R2bis -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, saturated or partially unsaturated -(C3-C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl,TSRI 2216.1PC -O-(C1-C6) alkyl, -(C5-C10) heteroaryl, -S-PhMe, -O-PhMe2, or 1,3,2-dioxaborolanyl, each optionally substituted with one or more -OH, -CN, halo, oxo, -(C1-C6) alkyl, or -PhOMe; R4is H or -(C1-C6) alkyl; R5is H or (C1-C6) alkyl; or R4and R5together form saturated or partially unsaturated (C3-C16) cycloalkyl or saturated or partially unsaturated (C3-C14) heterocycloalkyl, each optionally substituted with one or more -OH, -CN, halo, oxo, -(C1-C6) alkyl, or -PhOMe; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, or 3.

[0016] The application additionally provides a method of copper-catalyzed bimodal lactonization of N-methoxyamides via radical abstraction of the γ -aliphatic C−H bonds.

[0017] The application additionally provides the above method, wherein the lactonization occurs according to the following scheme: O RfRewherein: Raand Rbare independently H, -NPhth, -OAc, -C≡C-Ph, -C≡C-(C2-C6) alkenyl, or -(C1-C6) alkyl, -(C2-C14) alkenyl, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O-(C1-C6) alkyl, a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3- C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C6-C10) aryl, or -(C2-C6) alkenyl (C6-C10) aryl, each optionally substituted with one or more halo, -NHTs, NO2, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -OAc, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C1-C6) alkyl (C6-C10) aryl, or -(C2-C6) alkenyl (C6-C10) aryl; Rcand Rdare independently H, (C1-C6) alkyl, -OAc, saturated or partially unsaturated (C3- C16) cycloalkyl, -CH=CH-C(=O)-NPhth, or -CH2NPhth; Reand Rfare independently H, -OAc, or (C1-C6) alkyl, -NPhth, NHC(=O)CH2NHC(=O)Ph, - OC(=O)(CH2)2NHC(=O)(C1-C6) alkyl , or -CH2NPhth, each optionally substituted with one or more halo;TSRI 2216.1PC or Rdand Retogether form a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C1-C6) alkyl-(C3-C7) heterocycloalkyl, or -(C6-C10) aryl, each optionally substituted with one or more halo, oxo, -NHTs, -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C3-C7) cycloalkyl, -OAc, - OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, or -O-(C1-C6) alkyl, each optionally substituted with one or more halo, oxo, or -(C1-C6) alkyl; or Rband Retogether form-CH2-CH2-; or Raand Rbtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl; or Rcand Rdtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl; or Reand Rftogether form -(C2-C6) alkenyl.

[0018] The application additionally provides the above method, wherein the lactonization occurs according to the following scheme: [(MeCN (1)40C mu]oBl%F4), O RfRe125 °C, 1-20 wherein: Raand Rbare independently H, -NPhth, -OAc, or -C≡C-Ph, -C≡C-(C2-C6) alkenyl, - (C1-C6) alkyl, -(C2-C14) alkenyl, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O- (C1-C6) alkyl, a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C6-C10) aryl, or -(C2-C6) alkenyl (C6-C10) aryl, each optionally substituted with one or more -OH, - CN, halo, -NHTs, NO2, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -OAc, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C1-C6) alkyl (C6-C10) aryl, or -(C2- C6) alkenyl (C6-C10) aryl; or Raand Rbtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl;TSRI 2216.1PC Rcand Rdare independently H, (C1-C6) alkyl, -OAc, saturated or partially unsaturated (C3-C16) cycloalkyl, -CH=CH-C(=O)-NPhth, -CH2OPhMe2, -NPhth, or -CH2NPhth; or Rband Rctogether form saturated or partially unsaturated -(C3-C14) cycloalkyl, saturated or partially unsaturated (C3-C16) heterocycloalkyl, -(C5-C10) heteroaryl, or -(C6-C10) aryl, each optionally substituted with one or more -OH, -CN, halo, -NHTs, NO2, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C3-C7) cycloalkyl, or -OAc; or Rcand Rdtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl; Reand Rfare independently H, -OAc, or (C1-C6) alkyl, saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C6-C10) aryl, -NPhth, - OC(=O)(CH2)2NHC(=O)CH2NPhth, -NHC(=O)CH2NHC(=O)Ph, - OC(=O)(CH2)2NHC(=O)(C1-C6) alkyl, or -CH2NPhth, each optionally substituted with one or more halo, -OH, -CN, (C1-C6) alkyl, -NHTs, NO2, oxo, or -OAc; or Rband Retogether form-CH2-CH2-; or Rdand Retogether form a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C1-C6) alkyl-(C3-C7) heterocycloalkyl, or -(C6-C10) aryl, each optionally substituted with one or more halo, oxo, -NHTs, -CH2NHTs, -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C3-C7) cycloalkyl, -OAc, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, or -O-(C1-C6) alkyl, each optionally substituted with one or more halo, oxo, OAc, or - (C1-C6) alkyl; or Reand Rftogether form -(C2-C6) alkenyl. DETAILED DESCRIPTION OF THE INVENTION

[0019] N-methoxyamides have become a major class of practically useful substrates in Pd(II)- and Rh(III)-catalyzed C−H activation reactions17since their first introduction18. They can be readily prepared in large quantities from carboxylic acids in a single step and are bench-stable for long-term storage. It was hoped to achieve a reductive cleavage of the N−O bond to generate the amidyl radical. Despite advances in the field of amidyl radicalTSRI 2216.1PC generation via N−O cleavage19,20, specifically the use of photocatalysis to generate amidyl radicals from activated O-acyl and O-aryl hydroxamides21-23, the simple N-methoxyamide substrates have not been shown to be compatible with these chemistry via N−O bond cleavage, presumably due to its relatively high reduction potential24. Notably, developing C−H functionalization reactions based on such radical abstraction require external traps20or photocatalysis of highly redox-active groups25to close the redox catalytic cycle (Fig.1b). Inspired by previously reported Cu(I)-mediated formation of iminyl radicals from active oxime esters and subsequent cyclization with tethered olefins26, it was wondered whether Cu(I) could reduce N-methoxyamides to form amidyl radicals (the efforts to overcome the relatively high BDE of N−O bond of N-methoxyamide are summarized in the Experimental section). If successful, this reductive method would essentially use the methoxy group as the green internal oxidant, thus omitting the photoredox catalysts, and external oxidants which often lead to overoxidation of the formed double bond. This amidyl radical I can then perform 1,5-H atom abstraction to form the γ-carbon-centered radical IV (see Fig.1c). It was envisioned that the combination of this alkyl radical with Cu(II) species could either favor oxidative elimination to afford dehydrogenation products (V to II, path A) or undergo oxidative substitution leading to the formation of lactone III via intramolecular trapping of carbocationic intermediate VI (path B)27-29. In both pathways, Cu(I) would be regenerated, closing this redox-neutral catalytic cycle. The only by-product of the dehydrogenation reaction is MeOH (or MeOH and ammonium salt for the lactonization). Herein, a redox- neutral Cu-catalyzed bimodal dehydrogenation / lactonization reaction of N-methoxyamides without using highly reactive redox-active groups which require additional installation steps (Fig.1d) is reported. This platform would allow the rapid diversification of widely available carboxylic acids into valuable lactones and dehydrogenated primary amides, where the amides could be further diversified by transformations of the amide, functionalization of the alkene and a cyclization between the amide and the double bond.

[0020] The realization of the dehydrogenation was enabled by using CuF2(10 mol%) as the catalyst, 8-methoxyquinoline (20 mol%) as the ligand, and AcOH as the additive in 1,4- dioxane (Fig.2; the details of the reaction optimization are discussed in the Experimental section, see Figure S1-S6). Under these reaction conditions, N-methoxyamide A27 gave dehydrogenated product B27 in 70% yield.

[0021] With the optimized reaction conditions in hand, the substrate scope of the dehydrogenation (Fig.2) were then explored. Both unactivated (A1-A8) and benzylic (A9- A25) γ-C−H bonds reacted to form the corresponding olefins in good yields with both acyclicTSRI 2216.1PC and cyclic substrates. β,γ-olefins can also be obtained as the major product when the δ- position was blocked (B4 and B5). A particularly striking example is the formation of γ,δ- unsaturated skipped diene B2 rather than the conjugated β,γ-olefin. Although studies from Kochi have demonstrated that tertiary radicals are more prone to oxidative substitution than dehydrogenation29, it was found that N-methoxyamides bearing γ-methines were also competent substrates, affording the desired olefins (B26-B38). Although small amounts of β,γ-unsaturated isomers were formed in some cases (B33-B36), the reaction generally exhibited a strong preference for the formation of γ,δ- rather than β,γ-olefins. The reaction was also found to tolerate a wide range of functionality, including alkyl acetates (B3, B6, and B28), pre-existing olefins (B2, B20, and B26), alkynes (B21), (thio)ethers (B10, B22, B24, and B25), carbamates (B19), heterocycles (B11, B22, and B23), and potential cross coupling partners for downstream elaborations such as aryl halides (B13, B14, and B18) and boronic esters (B15). Moreover, pre-existing stereocenters at the α- and β-positions remained intact (B3, B27, and B28). The exceptional ability of this oxidative catalytic system to tolerate a wide range of oxidatively sensitive functionality demonstrates the unique advantage of using amide substrate as the mild internal oxidant rather than using harsh exogenous oxidants.

[0022] Next examined was the reaction in a range of more complex settings. A variety of α-, β-, and γ-amino acid derivatives were subjected to the reaction, affording the corresponding dehydrogenated products in synthetically useful yields (B39-B50). Although E / Z selectivity was poor for product B43, the reaction remained highly, or in the case of cyclic products B44-B46 and B49, exclusively, selective for γ,δ-olefin formation with substrates possessing δ-C−H bonds. N-Methoxyamide derivatives of natural products and pharmaceuticals also proved amenable to dehydrogenation (B51-B65). The exclusive formation of mono-desaturation product B52 from valproic acid derivative A52 offers a particularly notable example, as our internal oxidant strategy, unlike the use of external oxidant, prevents further dehydrogenation. Site-selectivity became somewhat more complicated with polycyclic substrates. Betulinic acid derivative B62 offers a particularly informative example wherein high yields of a single product were obtained despite the presence of four competing γ-C−H bonds. Notably, the major product was formed by HAT at an unactivated methine rather than the allylic γ-methine, indicating that geometric factors can outweigh the intrinsic reactivity of the competing C−H bonds. As with the examples discussed above, the reaction displayed a remarkable tolerance for sensitive functionality such as the conjugated triene system formed in B59, though migration of the pre-existing double bond was observed in B64 and B65. Considering that abietane-type structures areTSRI 2216.1PC widely found in nature and are also precursors of many complex terpenes, it was decided to test a large-scale reaction on the derivative of dehydroabietic acid. Treatment of 1.65 gram of A58 with CuF2(5 mol%) and CSA (0.5 equiv.) gave B58 in 72% yield after refluxing for 20 hours.

[0023] Amidyl radicals can in principle be utilized to synthesize γ-lactones via derivations of the classical Hofmann-Löffler-Freytag reaction30-34, but both the multiple-step reaction conditions involving external oxidants and narrowed substrate scope remain to be substantially improved (see Scheme S7 in the Experimental section for a detailed comparison). Nevertheless, these early studies prompted us to investigate if our catalytic system involving a similar radical intermediate can be engineered to switch from dehydrogenation to γ-C−H lactonization, thereby realizing bimodal catalysis using a copper catalyst. When performing dehydrogenation of substrate A29 under our standard reaction conditions, the formation of a trace amount of lactone C29 was observed. Hence, a series of experiments were conducted to favor the lactonization reaction pathway. In particular, DCE suppressed the formation of lactone, while replacing the AcOH additive with a stronger acid such as TFA increased the yield of lactone. To our delight, when dioxane was used as the solvent and TFA was included as an additive, C29 was formed in 78% yield with no B29 detected. For substrates with unactivated γ-methylene C−H bonds, a combination of dioxane / nitromethane as solvent with [(CH3CN)4Cu]BF4was found to be optimal for lactonization. Representative examples of this condition-based switch in reactivity from dehydrogenation to lactonization are given in Fig.3a (see Tables S8-S9 and Scheme S10 in the Experimental section for the details of switching from dehydrogenation to lactonization and a summary of this bimodal reactivity). Selectivity for lactonization over dehydrogenation can be perfectly controlled for substrates bearing tertiary or benzylic γ-C−H bonds (e.g., C27- C29, C35, C37, C38, C47, C48). Lactonization of long-chain fatty acids and amino acids with unactivated γ-methylene were also feasible via this method (e.g., C43 and C51), though competing dehydrogenation was observed with these starting materials. Owing to the large differences between these two products, the rapid diversification of carboxylic acids could be envisioned because of this dual dehydrogenation / lactonization reactivity, which is valuable from the perspective of chemical space expansion.

[0024] A variety of additional substrates were prepared to test the generality of the lactonization reaction (Fig.3, C68-C101). Activated benzylic, allylic, and propargylic γ-C–H bonds generally underwent efficient lactonization regardless of whether the position was primary (C68-C73), secondary (C74-C83, C87-C90) or tertiary (C91), with little sensitivityTSRI 2216.1PC to the electronic nature of the (hetero)arene (compare between C68-C73 and between C74, C78-C80, and C82, though reduced yield was obtained with C76. As noted above, substrates with unactivated secondary (B84-C86) and tertiary (C92) γ-C−H bonds also performed well in the reaction. In the case of C84, although a more reactive δ-benzylic site is present, γ- lactone is still exclusively formed via 1,5-H atom abstraction. As expected, the method displayed favorable functional group compatibility with synthetically valuable aryl halides (C69 and C78) and oxidatively sensitive groups such as olefins (C81, C83, and C88), alkynes (C87 and C88), and highly electron rich arenes (C74), which are unlikely to be tolerated by conventional approaches that rely on strong external oxidants.

[0025] The reliability and synthetic utility of the reaction by examining the lactonization of several derivatives of natural products and pharmaceuticals (C93-C102) was next investigated. As with the dehydrogenation, the γ-lactonization tolerated structural and functional complexity of these compounds well and formed the corresponding lactone products in moderate to good yields when the site of HAT was tertiary or allylic. Notably, when the γ position is blocked, the amidyl radical can instead abstract a δ-hydrogen, for example, affording rearranged product C95 in 41% yield. Additionally, C97 was formed without undergoing the C-20 methyl rearrangement known to occur to related carbocations, suggesting that the trapping by the amide is relatively rapid. Interestingly, treatment of the derivative of estrone with the standard conditions gave the lactam as the main product (C102) with lactone C101 as the minor product. This suggests that the reaction may proceed through a alkyl Cu(III) intermediate that undergoes C−N and C−O bond formation to avoid the unfavorable formation of an unstabilized primary carbocation. This pathway to construct lactams from N-methoxyamides is currently being exploited.

[0026] It is noteworthy that our reactions were also efficient using low loading of catalyst with prolonged reaction time (Fig.4a). Both dehydrogenation and lactonization proceeded smoothly with as low as 0.5 mol% of copper under an argon atmosphere, and the products were obtained in almost the same yields as when 10 mol% catalyst was used. A series of experiments were conducted to investigate the mechanism of the dehydrogenation and lactonization reactions. While screening the reaction conditions, it was found that when 2,2’- biquinoline was added as a ligand, the reaction mixture turned an intense purple color rather than the usual blue or green (Fig.4b). This is a characteristic of the formation of Cu(I)- biquinoline complex35,26and suggests that Cu(I) produced by disproportionation of the CuF2precatalyst is present in solution as a potential active catalyst36. A radical clock experiment was performed to investigate the radical intermediacy. When compound A66 was subjectedTSRI 2216.1PC to the standard conditions, diene B66 was obtained in 43% yield (Fig.4c). Presumably, the carbon-centered radical Int-1 formed by 1,5-H-abstraction rearranged via an opening of the adjacent cyclopropane, forming the primary allylic radical Int-2, which can subsequently undergo oxidative elimination to afford diene B66. Taken together, these results support a mechanism initiated by Cu(I)-catalyzed oxidation of the N-methoxyamide to afford an amidyl radical, which then rearranges to a carbon-centered radical at the γ-position via 1,5-HAT.

[0027] Based on Kochi’s mechanistic studies on radical pathways with copper29, two plausible pathways of the elimination: 1) a Cu(II)-induced oxidation of the alkyl radical to a carbocation followed by a subsequent β-deprotonation; 2) a recombination of the alkyl radical and Cu(II) to form an alkylcopper(III) intermediate followed by a β-oxidative elimination were envisioned. If the elimination proceeds through β-deprotonation, the more acidic β-H should be preferentially eliminated, which is contrary to the regioselectivity that was observed (e.g., B34 vs. B49, B39 vs. B52). Furthermore, alkyl chloride A67 was treated with AgBF4for in-situ carbocation generation (Fig.4d). Contrary to the regioselectivity of our reaction, this reaction afforded the β,γ- and γ,δ-olefins in a 10:1 mixture. Thus, our copper- catalyzed dehydrogenation unlikely proceeds via a cation intermediate, and the second pathway involving organocopper(III) species is more plausible37,38. Additionally, the nearly exclusive γ,δ-selectivity may be attributed to the coordination of the amide to the copper to form a metallocycle, favoring the elimination of an exocyclic δ-H rather than an endocyclic β-H39. Kochi and coworkers revealed that the ratio of elimination to substitution of organocopper(III) intermediates was found to be largely controlled by nature of the substrate (with substrates that can form more stable carbocations typically favoring substitution), but also exhibited sensitivity to the reaction conditions29, particularly copper sources and solvents (more polar solvents favor oxidative substitution). These findings are in line with our experimental data. Of note, C68-C73, C85, and C101 rule out the possibility that the lactone is formed via a cyclization of the dehydrogenated amide under acidic conditions.

[0028] Based on our experimental results and literature precedents, a proposed mechanism for this bimodal dehydrogenation / lactonization reaction is outlined in Fig.4e. An in-situ generation of Cu(I) initiates the reaction by promoting the reductive cleavage of the N−O bond of N-methoxyamide I to form amidyl radical II and a Cu(II) species. Once formed, II undergoes 1,5-H atom abstraction to afford alkyl radical III, which could recombine with Cu(II) to form alkylcopper(III) intermediate IV, analogous to the Kharasch allylic oxidation40. From this point forward, the reaction diverges into two paths. On the one hand, alkylcopper(III) species have significant carbocationic character. Hence, they canTSRI 2216.1PC undergo oxidative elimination to generate alkene V. On the other hand, in a more polar environment (with more polar solvent and a more acidic additive), the elimination may be suppressed, and instead, carbocation intermediate VI can form via an inner-sphere oxidation. Intramolecular trapping of cation VI and subsequent iminium hydrolysis provides lactone VII. Remarkably, for substrates where the carbocationic intermediate VI is relatively stabilized (e.g., when the γ position is benzylic, tertiary, or allylic), the selectivity between the two pathways can be perfectly controlled.

[0029] In conclusion, a method of bimodal Cu-catalyzed dehydrogenation / lactonization of synthetically common N-methoxyamides has been developed as herein disclosed. This redox-neutral process led to two controllable reaction pathways for synthesizing γ,δ- unsaturated primary amides and γ-lactones from various carboxylic acids (as the precursors of N-methoxyamides). Both the dehydrogenation and the lactonization could serve as strategies for the diversifications of a variety of drug molecules and natural products. References: 1. Larock, R. C. Comprehensive Organic Transformation (Wiley, 2018). 2. Ishihara, Y. & Baran, P. S. Two-phase terpene total synthesis: historical perspective and application to the Taxol®problem. Synlett 12, 1733−1745 (2010). 3. Qiu, Y. & Gao, S. Trends in applying C−H oxidation to the total synthesis of natural products. Nat. Prod. Rep.33, 562−581 (2016). 4. Buist, P. H. Fatty acid desaturases: selecting the dehydrogenation channel. Nat. Prod. Rep.21, 249−262 (2004). 5. Rettie, A. E., Rettenmeier, A. W., Howald, W. N. & Baillie, T. A. Cytochrome P-450- catalyzed formation of Δ4-VPA, a toxic metabolite of valproic acid. Science 235, 890−893 (1987). 6. Zhou, J. et al. Spectroscopic studies of substrate interactions with clavaminate synthase 2, a multifunctional a-KG-dependent non-heme iron enzyme: correlation with mechanisms and reactivities. J. Am. Chem. Soc.123, 7388−7398 (2001). 7. Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P. & Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev.45, 546−576 (2016).TSRI 2216.1PC 8. Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem.10, 383−394 (2018). 9. Hong, B.; Luo, T. & Lei, X. Late-stage diversification of natural products. ACS Cent. Sci.6, 622−635 (2020). 10. Breslow, R. & Baldwin, S. W. Conversion of cholestanol to 12-oxocholestanol and to cholest-14-enol and-8(14)-enol by remote oxidation. J. Am. Chem. Soc.92, 732−734 (1970). 11. Breslow, R. Biomimetic chemistry and artificial enzymes: catalysis by design. Acc. Chem. Res.28, 146−153 (1995). 12. Groves, J. T.; Nemo, T. E. & Myers, R. S. Hydroxylation and epoxidation catalyzed by iron-porphine complexes. Oxygen transfer from iodosylbenzene. J. Am. Chem. Soc.101, 1032−1033 (1979). 13. Huang, X. & Groves, J. T. Beyond ferryl-mediated hydroxylation: 40 years of the rebound mechanism and C−H activation. J. Biol. Inorg. Chem.22, 185−207 (2017). 14. Kim, C.; Dong, Y. & Que, L. Jr. Modeling nonheme diiron enzymes: hydrocarbon hydroxylation and desaturation by a high-valent Fe2O2diamond core. J. Am. Chem. Soc.119, 3635−3636 (1997). 15. Hull, J. F. et al. Manganese catalysts for C−H activation: an experimental / theoretical study identifies the stereoelectronic factor that controls the switch between hydroxylation and desaturation pathways. J. Am. Chem. Soc.132, 7605−7616 (2010). 16. Bigi, M. A.; Reed, S. A. & White, M. C. Diverting non-haem iron catalyzed aliphatic C−H hydroxylations towards desaturations. Nat. Chem.3, 216−222 (2011). 17. Zhu, R.-Y.; Farmer, M. E., Chen, Y.-Q. & Yu, J.-Q. A simple and versatile amide directing group for C−H functionalizations. Angew. Chem. Int. Ed.55, 10578−10599 (2016). 18. Wang, D.-H.; Wasa, M. Giri, R. & Yu, J.-Q. Pd(II)-catalyzed cross-coupling of sp3C−H bonds with sp2and sp3boronic acids using air as the oxidant. J. Am. Chem. Soc. 130, 7190−7191 (2008).TSRI 2216.1PC 19. Zard, S. Z. Recent progress in the generation and use of nitrogen-centred radicals. Chem. Soc. Rev.37, 1603 (2008). 20. Fazekas, T. J.; Alty, J. W.; Neidhart, E. K.; Miller, A. S.; Leibfarth, F. A. & Alexanian, E. J. Diversification of aliphatic C−H bonds in small molecules and polyolefins through radical chain transfer. Science 375, 545−550 (2022). 21. Davies, J.; Svejstrup, T. D.; Fernandez Reina, D. F.; Sheikh, N. S. & Leonori, D. Visible-light-mediated synthesis of amidyl radicals: transition-metal-free hydroamination and N-arylation reactions. J. Am. Chem. Soc.138, 8092−8095 (2016). 22. Davies, J.; Morcillo, S. P.; Douglas, J. J. & Leonori, D. Hydroxylamine derivatives as nitrogen-radical precursors in visible-light photochemistry. Chem. - Eur. J.24, 12154−12163 (2018). 23. Kwon, K.; Simons, R. T.; Nandakumar, M. & Roizen, J. L. Strategies to generate nitrogen-centered radicals that may rely on photoredox catalysis: development in reaction methodology and applications in organic synthesis. Chem. Rev.122, 2353−2428 (2022). 24. Bach, R. D. & Schlegel, H. B. The bond dissociation energy of the N−O bond. J. Phys. Chem. A 125, 5014−5021 (2021). 25. Stateman, L. M.; Dare, R. M.; Paneque, A. N. & Nagib, D. A. Aza-heterocycles via copper-catalyzed, remote C−H desaturation of amines. Chem 8, 210−224 (2022). 26. Faulkner, A.; Race, N. J.; Scottb, J. S. & Bower, J. F. Copper catalyzed Heck-like cyclizations of oxime esters. Chem. Sci.5, 2416−2421 (2014). 27. Kochi, J. K. The decomposition of peroxides catalyzed by copper compounds and the oxidation of alkyl radicals by cupric salts. J. Am. Chem. Soc.85, 1958−1968 (1963). 28. Kochi, J. K. Mechanisms of organic oxidation and reduction by metal complexes: electron and ligand transfer processes form the basis for redox reactions of radicals and metal species. Science, 155, 415−424 (1967). 29. Kochi, J. K.; Bemis, A. & Jenkins, C. L. Mechanism of electron transfer oxidation of alkyl radicals by copper(II) complexes. J. Am. Chem. Soc.90, 4616−4625 (1968).TSRI 2216.1PC 30. Barton, D. H. R.; Beckwith, A. L. J. & Goosen, A. Photochemical transformations. Part XVI. A novel synthesis of lactones. J. Chem. Soc.181−190 (1965). 31. Neale, R. S.; Marcus, N. L. & Schepers, R. G. The chemistry of nitrogen radicals. IV. The rearrangement of N-halamides and the synthesis of iminolactones1. J. Am. Chem. Soc.88, 3051−3058 (1966). 32. Chen, K.; Richter, J. M. & Baran, P. S.1,3-Diol synthesis via controlled, radical- mediated C−H functionalization. J. Am. Chem. Soc.130, 7247−7249 (2008). 33. Chen, K. & Baran, P. S. Total synthesis of eudesmane terpenes by site-selective C−H oxidations. Nature, 459, 824−828 (2009). 34. Richers, J.; Heilmann, M.; Drees, M. & Tiefenbacher, K. Synthesis of lactones via C−H functionalization of nonactivated C(sp3)−H bonds. Org. Lett.18, 6472−6475 (2016). 35. Hoste, J. On a new copper specific group. Anal. Chim. Acta, 4, 23−27 (1950). 36. Ribas, X. et al. Aryl C−H activation by CuIIto form an organometallic aryl-CuIIIspecies: a novel twist on copper disproportionation, Angew. Chem. Int. Ed.41, 2991−2994 (2002). 37. Xu, J. et al. Copper-catalyzed trifluoromethylation of terminal alkenes through allylic C−H bond activation. J. Am. Chem. Soc.133, 15300−15303 (2011). 38. Beniazza, R. et al. Copper(I)-photocatalyzed trifluoromethylation of alkenes. Chem. Commun.51, 9571−9574 (2015). 39. Wu, X.; Riedel, J. & Dong, V. M. Transforming olefins into γ,δ-unsaturated nitriles through copper catalysis. Angew. Chem. Int. Ed.56, 11589−11593 (2017). 40. Beckwith, A. L. J. & Zavitsas, A. A. Allylic oxidations by peroxy esters catalyzed by copper salts. The potential for stereoselective syntheses. J. Am. Chem. Soc.108, 8230−8234 (1986). Embodiments

[0030] Embodiment 1. A method of copper-catalyzed bimodal dehydrogenation of N- methoxyamides via radical abstraction of γ-aliphatic C−H bonds.TSRI 2216.1PC

[0031] Embodiment 2. A method of copper-catalyzed bimodal lactonization of N- methoxyamides via radical abstraction of the γ-aliphatic C−H bonds.

[0032] Embodiment 3. The method of either Embodiment 1 or Embodiment 2, wherein the copper catalyst is a Cu(I) catalyst.

[0033] Embodiment 4. The method of Embodiment 3, wherein the Cu(I) catalyst is [Cu(MeCN)4]BF4.

[0034] Embodiment 5. The method of Embodiment 3, wherein the Cu(I) catalyst is [(CH3CN)4Cu]PF6.

[0035] Embodiment 6. The method of Embodiment 3, wherein the Cu(I) catalyst is CuBr.

[0036] Embodiment 7. The method of Embodiment 1, wherein the copper catalyst is a Cu(II) catalyst.

[0037] Embodiment 8. The method of any one of Embodiments 1-7, wherein the Cu(II) catalyst is CuF2.

[0038] Embodiment 9. The method of any one of Embodiments 1-7, wherein the Cu(II) catalyst is Cu(OTFA)2•H2O.

[0039] Embodiment 10. The method of Embodiment 1, wherein the dehydrogenation occurs according to the following scheme: NH2wherein: Ra, Rb, and Rcare independently H, -(C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, -NPhth, -OAc, or Ph; Rdand Reare independently H, (C1-C6) alkyl, -OAc, -OC(=O)(CH2)2NHC(=O)CH2NPhth, - CH2OPhMe2, or -NPhth; Rfand Rgare independently H, (C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, Ph, -NPhth, or -OAc; or Reand Rgtogether form a bond; or Rfand Rgtogether form -(C2-C6) alkenyl.TSRI 2216.1PC

[0040] Embodiment 11. The method of Embodiment 1, wherein the dehydrogenation occurs according to the following scheme: NH2wherein: Ra, Rb, and Rcare independently H, -(C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, -NPhth, -OAc, or Ph; Rdand Reare independently H, -(C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, -NPhth, -OAc, or Ph; or Rdand Retogether form -(C2-C6) alkenyl.

[0041] Embodiment 12. The method of Embodiment 1, wherein the dehydrogenation occurs according to the following scheme: NH2wherein: Q’ is a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated (C3-C16) heterocycloalkyl, -(C6-C10) aryl, or -(C5-C10) heteroaryl; each R1is independently -OH, -(C1-C6) alkyl, oxo, -OAc, -O-(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, saturated or partially unsaturated (C3-C16) cycloalkyl, -NPhth, or -CH2NPhth; each R2is independently R2aor R2b; each R2ais independently -OH, -CN, halo, or oxo; each R2bis independently -(C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) heterocycloalkyl; or one R1and one R2together form -(C6-C10) aryl, saturated or partially unsaturated (C3-C14) cycloalkyl, or saturated or partially unsaturated (C3-C16) heterocycloalkyl, or -(C5-TSRI 2216.1PC C10) heteroaryl, each optionally substituted with one or more -(C1-C10) alkyl, -OAc, or - PhOMe; each R3is independently H, -(C1-C6) alkyl, saturated or partially unsaturated (C3-C16) cycloalkyl, -NPhth, or -(C6-C10) aryl; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0042] Embodiment 13. The method of Embodiment 1, wherein the dehydrogenation occurs according to the following scheme: NH2R5wherein: Q is saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated (C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, or -(C6-C10) aryl; R1is H, halo, oxo, or -OAc; or R1and R5together form partially unsaturated (C3-C16) cycloalkyl or saturated or partially unsaturated (C3-C14) heterocycloalkyl, optionally substituted with one or more R1’;R1’is -OH, -CN, halo, oxo, (C1-C6) alkyl, -OAc, or -(C2-C6) alkenyl; R2is R2aor R2b; R2ais -OH, -CN, halo, or oxo; R2bis -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, saturated or partially unsaturated -(C3-C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -O-(C1-C6) alkyl, -(C5-C10) heteroaryl, -S-PhMe, -O-PhMe2, or 1,3,2- dioxaborolanyl, each optionally substituted with one or more -OH, -CN, halo, oxo, -(C1-C6) alkyl, or -PhOMe;TSRI 2216.1PC R4is H or -(C1-C6) alkyl; R5is H or (C1-C6) alkyl; or R4and R5together form saturated or partially unsaturated (C3-C16) cycloalkyl or saturated or partially unsaturated (C3-C14) heterocycloalkyl, each optionally substituted with one or more -OH, -CN, halo, oxo, -(C1-C6) alkyl, or -PhOMe; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, or 3.

[0043] Embodiment 14. The method of any one of Embodiments 10-13, wherein the Cu(II) catalyst is CuF2.

[0044] Embodiment 15. The method of any one of Embodiments 10-13, wherein the Cu(II) catalyst is Cu(OTFA)2•H2O.

[0045] Embodiment 16. The method of any one of Embodiments 10-15, wherein the solvent is dioxane.

[0046] Embodiment 17. The method of any one of Embodiments 10-15, wherein the solvent is dioxane / MeNO2.

[0047] Embodiment 18. The method of any one of Embodiments 10-15, wherein the solvent is MeNO2.

[0048] Embodiment 19. The method of any one of Embodiments 10-15, wherein the solvent is DCE.

[0049] Embodiment 20. The method of any one of Embodiments 10-15, wherein the solvent is PhMe.

[0050] Embodiment 21. The method of any one of Embodiments 10-15, wherein the solvent is AcOH.

[0051] Embodiment 22. The method of any one of Embodiments 10-15, wherein the solvent is THF.

[0052] Embodiment 23. The method of any one of Embodiments 10-22, wherein the solvent is approximately 0.2M.

[0053] Embodiment 24. The method of any one of Embodiments 10-23, wherein the Cu catalyst is added at approximately 10 mol%.

[0054] Embodiment 25. The method of any one of Embodiments 10-24, further comprising addition of the Ligand (L).TSRI 2216.1PC

[0055] Embodiment 26. The method of Embodiment 25, wherein Ligand (L) is selected from the group consisting of: N .L

[0056] Embodiment 27. The method of Embodiment 26, wherein Ligand (L) is 8- methoxyquinoline.

[0057] Embodiment 28. The method of any one of Embodiments 10-27, wherein the Ligand (L) is added at approximately 20 mol%.

[0058] Embodiment 29. The method of any one of Embodiments 10-28, wherein the AcOH is added at approximately 8 equivalents.

[0059] Embodiment 30. The method of any one of Embodiments 10-29, wherein the reaction temperature is approximately 125 °C.

[0060] Embodiment 31. The method of any one of Embodiments 10-30, wherein the reaction time is approximately 2-20 h.

[0061] Embodiment 32. The method of Embodiment 1, wherein the dehydrogenation occurs according to the following scheme: CuF (10 mol%) 2 RaRdReO Ligand (L) (20 mol%)Ra d eAcOH (8 equiv.)R RO RbRbNH ,c g2RRf R125 °C, 2-20 h .

[0062] Embodiment 33. The method of Embodiment 32, wherein Ligand (L) is 8- methoxyquinoline.

[0063] Embodiment 34. The method of Embodiment 32, wherein Ligand (L) is absent.

[0064] Embodiment 35. The method of Embodiment 10, wherein the dehydrogenation occurs according to the following scheme: NH2g, (0.1 mmol).

[0065] Embodiment 36. The method of Embodiment 35, wherein the solvent is dioxane.

[0066] Embodiment 37. The method of Embodiment 35, wherein the solvent is DCE.TSRI 2216.1PC

[0067] Embodiment 38. The method of any one of Embodiments 35-37, wherein the acid is AcOH (8 equiv.).

[0068] Embodiment 39. The method of any one of Embodiments 35-37, wherein the acid is CSA (0.5 equiv.).

[0069] Embodiment 40. The method of any one of Embodiments 35-37, wherein the acid is TsOH•H2O (0.5 eq.).

[0070] Embodiment 41. The method of any one of Embodiments 35-40, wherein the product is selected from the group consisting of: OO NH2NH2O 57% ONH2.69%

[0071] Embodiment 42. The method of any one of Embodiments 35-40, wherein the product is selected from the group consisting of: n= 3, 68%rr n = 4, 67% rr H2, , . 4:1 rr, 7:3 E / Z from gabapentin

[0072] Embodiment 43. The method of any one of Embodiments 35-40, wherein the product is selected from the group consisting of:TSRI 2216.1PC C Me O OMeMeONH2MeCONH273% O OMe NH Me CONH2Me . acid

[0073] Embodiment 44. The method of Embodiment 2, wherein the lactonization occurs according to the following scheme: OORfRewherein: Raand Rbare independently H, -NPhth, -OAc, -C≡C-Ph, -C≡C-(C2-C6) alkenyl, or -(C1-C6) alkyl, -(C2-C14) alkenyl, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O-(C1-C6) alkyl, a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3- C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C6-C10) aryl, or -(C2-C6) alkenyl (C6-C10) aryl, each optionally substituted with one or more halo, -NHTs, NO2, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -OAc, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C1-C6) alkyl (C6-C10) aryl, or -(C2-C6) alkenyl (C6-C10) aryl; Rcand Rdare independently H, (C1-C6) alkyl, -OAc, saturated or partially unsaturated (C3- C16) cycloalkyl, -CH=CH-C(=O)-NPhth, or -CH2NPhth; Reand Rfare independently H, -OAc, or (C1-C6) alkyl, -NPhth, NHC(=O)CH2NHC(=O)Ph, - OC(=O)(CH2)2NHC(=O)(C1-C6) alkyl , or -CH2NPhth, each optionally substituted with one or more halo;TSRI 2216.1PC or Rdand Retogether form a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C1-C6) alkyl-(C3-C7) heterocycloalkyl, or -(C6-C10) aryl, each optionally substituted with one or more halo, oxo, -NHTs, -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C3-C7) cycloalkyl, -OAc, - OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, or -O-(C1-C6) alkyl, each optionally substituted with one or more halo, oxo, or -(C1-C6) alkyl; or Rband Retogether form-CH2-CH2-; or Raand Rbtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl; or Rcand Rdtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl; or Reand Rftogether form -(C2-C6) alkenyl.

[0074] Embodiment 45. The method of Embodiment 44, wherein the solvent is dioxane.

[0075] Embodiment 46. The method of Embodiment 44, wherein the solvent is approximately (1:1) dioxane / MeNO2.

[0076] Embodiment 47. The method of Embodiment 44, wherein the solvent is AcOH.

[0077] Embodiment 48. The method of Embodiment 44, wherein the solvent is MeNO2.

[0078] Embodiment 49. The method of any one of embodiments 44-48, wherein the solvent is approximately 0.2M.

[0079] Embodiment 50. The method of any one of embodiments 44-49, wherein the Cu catalyst is [Cu(MeCN)4]BF4.

[0080] Embodiment 51. The method of any one of embodiments 44-49, wherein the Cu catalyst is CuF2.

[0081] Embodiment 52. The method of any one of embodiments 44-51, wherein the Cu catalyst is approximately 10 mol%.

[0082] Embodiment 53. The method of any one of embodiments 44-52, wherein the acid additive is CSA.

[0083] Embodiment 54. The method of any one of embodiments 44-52, wherein the acid additive is TFA.

[0084] Embodiment 55. The method of any one of embodiments 44-52, wherein the acid additive is TSOH.TSRI 2216.1PC

[0085] Embodiment 56. The method of any one of embodiments 42-52, wherein the acid additive is AcOH.

[0086] Embodiment 57. The method of any one of embodiments 44-52, wherein the acid additive is added at approximately 0.5-5 equivalents.

[0087] Embodiment 58. The method of any one of embodiments 44-57, wherein the reaction temperature is approximately 125 °C.

[0088] Embodiment 59. The method of any one of embodiments 44-58, wherein the reaction time is approximately 2-20 h.

[0089] Embodiment 60. The method of any one of embodiments 44-58, wherein the reaction time is approximately 3-5 h.

[0090] Embodiment 61. The method of Embodiment 2, wherein the lactonization occurs according to the following scheme: [(MeCN(1)40Cmu]oBl%F4), O RfRe125 °C, 1-20 wherein: Raand Rbare independently H, -NPhth, -OAc, or -C≡C-Ph, -C≡C-(C2-C6) alkenyl, -(C1-C6) alkyl, -(C2-C14) alkenyl, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O-(C1-C6) alkyl, a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3- C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C6-C10) aryl, or -(C2-C6) alkenyl (C6-C10) aryl, each optionally substituted with one or more -OH, -CN, halo, -NHTs, NO2, -(C1-C6) alkyl, - (C3-C7) cycloalkyl, -OAc, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O-(C1-C6) alkyl, - (C1-C6) alkyl (C6-C10) aryl, or -(C2-C6) alkenyl (C6-C10) aryl; or Raand Rbtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl; Rcand Rdare independently H, (C1-C6) alkyl, -OAc, saturated or partially unsaturated (C3- C16) cycloalkyl, -CH=CH-C(=O)-NPhth, -CH2OPhMe2, -NPhth, or -CH2NPhth; or Rband Rctogether form saturated or partially unsaturated -(C3-C14) cycloalkyl, saturated or partially unsaturated (C3-C16) heterocycloalkyl, -(C5-C10) heteroaryl, or -(C6-C10)TSRI 2216.1PC aryl, each optionally substituted with one or more -OH, -CN, halo, -NHTs, NO2, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C3-C7) cycloalkyl, or -OAc; or Rcand Rdtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl; Reand Rfare independently H, -OAc, or (C1-C6) alkyl, saturated or partially unsaturated (C3- C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C6-C10) aryl, -NPhth, -OC(=O)(CH2)2NHC(=O)CH2NPhth, - NHC(=O)CH2NHC(=O)Ph, -OC(=O)(CH2)2NHC(=O)(C1-C6) alkyl, or -CH2NPhth, each optionally substituted with one or more halo, -OH, -CN, (C1-C6) alkyl, -NHTs, NO2, oxo, or - OAc; or Rband Retogether form-CH2-CH2-; or Rdand Retogether form a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C1-C6) alkyl-(C3-C7) heterocycloalkyl, or -(C6-C10) aryl, each optionally substituted with one or more halo, oxo, -NHTs, -CH2NHTs, -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C3-C7) cycloalkyl, - OAc, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, or -O-(C1-C6) alkyl, each optionally substituted with one or more halo, oxo, OAc, or -(C1-C6) alkyl; or Reand Rftogether form -(C2-C6) alkenyl.

[0091] Embodiment 62. The method of Embodiment 61, wherein the solvent is dioxane.

[0092] Embodiment 63. The method of Embodiment 61, wherein the solvent is AcOH.

[0093] Embodiment 64. The method of any one of Embodiments 61-63, wherein the Cu catalyst is [Cu(MeCN)4]BF4.

[0094] Embodiment 65. The method of any one of Embodiments 61-63, wherein the Cu catalyst is CuF2.

[0095] Embodiment 66. The method of any one of Embodiments 61-65, wherein the acid additive is CSA (0.2-0.5 equiv.).

[0096] Embodiment 67. The method of any one of Embodiments 61-65, wherein the acid additive is TFA (0.25-0.5 equiv.).

[0097] Embodiment 68. The method of any one of Embodiments 61-65, wherein the acid additive is TsOH•H2O (0.5 equiv.).TSRI 2216.1PC

[0098] Embodiment 69. The method of any one of Embodiments 61-68, wherein the product is selected from the group consisting of: O O D.ONPhth d.r.4:5 O O 23%.

[0099] Embodiment 70. The method of any one of Embodiments 61-68, wherein the product is selected from the group consisting of: O O 64% , 78% 60% O O 53%

[0100] Embodiment 71. The method of Embodiment 61, wherein the product is selected from the group consisting of:TSRI 2216.1PC O O 64% 78%60% O O

[0101] Embodiment 72. The method of Embodiment 61, wherein the product is selected from the group consisting of XOH56%

[0102] Embodiment 73. The method of Embodiment 61, wherein the product is selected from the group consisting of:TSRI 2216.1PC O56%,.

[0103] Embodiment 74. The method of Embodiment 1, wherein the dehydrogenation occurs on a gram scale according to the following scheme: , Me ,Me,A58, 1.65g, 5.0 mmol.

[0104] Embodiment 75. Any method disclosed in the instant application. Definitions

[0105] The phrase “a” or “an” entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

[0106] The phrase "as defined herein above" refers to the broadest definition for each group as provided in the Summary of the Invention, the Detailed Description of the Invention, the Experimentals, or the broadest claim. In all other embodiments provided below, substituents which can be present in each embodiment and which are not explicitly defined retain the broadest definition provided in the Summary of the Invention.

[0107] As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open- ended meaning. That is, the terms are to be interpreted synonymously with the phrasesTSRI 2216.1PC "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

[0108] As used herein, unless specifically indicated otherwise, the word "or" is used in the "inclusive" sense of "and / or" and not the "exclusive" sense of "either / or".

[0109] The term "independently" is used herein to indicate that a variable is applied in any one instance without regard to the presence or absence of a variable having that same or a different definition within the same compound. Thus, in a compound in which “R” appears twice and is defined as "independently selected from” means that each instance of that R group is separately identified as one member of the set which follows in the definition of that R group. For example, “each R1and R2is independently selected from carbon and nitrogen" means that both R1and R2can be carbon, both R1and R2can be nitrogen, or R1or R2can be carbon and the other nitrogen or vice versa.

[0110] When any variable occurs more than one time in any moiety or formula depicting and describing compounds employed or claimed in the present invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such compounds result in stable compounds.

[0111] The symbols "*" at the end of a bond or a line drawn through a bond or “~~~~” drawn through a bond each refer to the point of attachment of a functional group or other chemical moiety to the rest of the molecule of which it is a part.

[0112] A bond drawn into ring system (as opposed to connected at a distinct vertex) indicates that the bond may be attached to any of the suitable ring atoms.

[0113] The term “optional” or “optionally” as used herein means that a subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted” means that the “optionally substituted” moiety may incorporate a hydrogen or a substituent.

[0114] The phrase “optional bond” means that the bond may or may not be present, and that the description includes single, double, or triple bonds. If a substituent is designated to be a "bond" or "absent", the atoms linked to the substituents are then directly connected.TSRI 2216.1PC

[0115] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20%.

[0116] Certain compounds disclosed herein may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates. Common prototropic tautomers include keto / enol (-C(=O)-CH- ^ -C(-OH)=CH-), amide / imidic acid (-C(=O)-NH- ^ -C(-OH)=N-) and amidine (-C(=NR)-NH- ^ -C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings and the present invention encompasses all tautomeric forms of the compounds.

[0117] In this disclosure, a “pharmaceutically acceptable salt” is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound described herein. Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3- naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A pharmaceutically acceptable salt can have more than one charged atom in its structure. In this instance the pharmaceutically acceptable salt can have multiple counterions. Thus, aTSRI 2216.1PC pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.

[0118] Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art. Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10thEd., McGraw Hill Companies Inc., New York (2001). Any suitable materials and / or methods known to those of skill can be utilized in carrying out the present invention. However, preferred materials and methods are described. Materials, reagents and the like to which reference are made in the following description and examples are obtainable from commercial sources, unless otherwise noted.

[0119] The definitions described herein may be appended to form chemically-relevant combinations, such as “heteroalkylaryl,” “haloalkylheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,” “alkoxyalkyl,” and the like. When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group. Thus, for example, “phenylalkyl” refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl. An “alkylaminoalkyl” is an alkyl group having one to two alkylamino substituents. “Hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2- methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth. Accordingly, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups defined below. The term -(ar)alkyl refers to either an unsubstituted alkyl or an aralkyl group. The term (hetero)aryl or (het)aryl refers to either an aryl or a heteroaryl group.

[0120] The term “acyl” as used herein denotes a group of formula -C(=O)R wherein R is hydrogen or lower alkyl as defined herein. The term or "alkylcarbonyl" as used herein denotes a group of formula C(=O)R wherein R is alkyl as defined herein. The term C1-6acyl refers to a group -C(=O)R contain 6 carbon atoms. The term "arylcarbonyl" as used herein means a group of formula C(=O)R wherein R is an aryl group; the term "benzoyl" as used herein an "arylcarbonyl" group wherein R is phenyl.

[0121] The term “alkyl” as used herein denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 12 carbon atoms. The termTSRI 2216.1PC “lower alkyl” or “C1-C6alkyl” as used herein denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. "C1-12alkyl" as used herein refers to an alkyl composed of 1 to 12 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

[0122] When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically- named group. Thus, for example, “phenylalkyl” denotes the radical R'R"-, wherein R' is a phenyl radical, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The terms “arylalkyl” or "aralkyl" are interpreted similarly except R' is an aryl radical. The terms "(het)arylalkyl" or "(het)aralkyl" are interpreted similarly except R' is optionally an aryl or a heteroaryl radical.

[0123] When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C1–6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0124] “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 15 carbon atoms (“C1–15alkyl”). In some embodiments, an alkyl group has 1 to 14 carbon atoms (“C1–14alkyl”). In some embodiments, an alkyl group has 1 to 13 carbon atoms (“C1–13alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12alkyl”). In some embodiments, an alkyl group has 1 to 11 carbon atoms (“C1–11alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 toTSRI 2216.1PC 6 carbon atoms (“C2–6alkyl”). Examples of C1–6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n– pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6). Additional examples of alkyl groups include n–heptyl (C7), n– octyl (C8) and the like.

[0125] “Alkenyl” or “olefin” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds (“C2–10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C2–4alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0126] “Alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2–10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2–7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2–6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2–5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2–4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2–3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2–4alkynyl groups include, without limitation, ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. Examples of C2–6alkenylTSRI 2216.1PC groups include the aforementioned C2–4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.

[0127] The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refers to a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms wherein one or more carbon atoms are substituted with one or more halogen atoms.

[0128] The term "alkylene" or "alkylenyl" as used herein denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH2)n)or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g., -CHMe- or -CH2CH(i-Pr)CH2-), unless otherwise indicated. Except in the case of methylene, the open valences of an alkylene group are not attached to the same atom. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2-ethylbutylene.

[0129] The term "alkoxy" as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t- butyloxy, pentyloxy, hexyloxy, including their isomers. "Lower alkoxy" as used herein denotes an alkoxy group with a "lower alkyl" group as previously defined. "C1-10alkoxy" as used herein refers to an-O-alkyl wherein alkyl is C1-10.

[0130] The term "hydroxyalkyl" as used herein denotes an alkyl radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is / are replaced by hydroxyl groups.

[0131] The terms "alkylsulfonyl" and "arylsulfonyl" as used herein refers to a group of formula -S(=O)2R wherein R is alkyl or aryl respectively and alkyl and aryl are as defined herein. The term “heteroalkylsulfonyl” as used herein refers herein denotes a group of formula -S(=O)2R wherein R is “heteroalkyl” as defined herein.

[0132] The terms "alkylsulfonylamino" and "arylsulfonylamino"as used herein refers to a group of formula -NR'S(=O)2R wherein R is alkyl or aryl respectively, R' is hydrogen or C1-3alkyl, and alkyl and aryl are as defined herein.

[0133] The term “cycloalkyl” as used herein refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C3-7cycloalkyl" as used herein refers to an cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring.

[0134] The term carboxy-alkyl as used herein refers to an alkyl moiety wherein one, hydrogen atom has been replaced with a carboxyl with the understanding that the point ofTSRI 2216.1PC attachment of the heteroalkyl radical is through a carbon atom. The term “carboxy” or “carboxyl” refers to a –CO2H moiety.

[0135] The term "heteroaryl” or "heteroaromatic" as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing four to eight atoms per ring, incorporating one or more N, O, or S heteroatoms, the remaining ring atoms being carbon, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. As well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazol, isoxazole, thiazole, isothiazole, triazoline, thiadiazole and oxadiaxoline which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino,dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole and benzisothiazole. Bicyclic moieties can be optionally substituted on either ring; however the point of attachment is on a ring containing a heteroatom.

[0136] The term "heterocyclyl", “heterocycloalkyl” or "heterocycle" as used herein denotes a monovalent saturated cyclic radical, consisting of one or more rings, preferably one to two rings, including spirocyclic ring systems, of three to eight atoms per ring, incorporating one or more ring heteroatoms (chosen from N,O or S(O)0-2), and which can optionally be independently substituted with one or more, preferably one or two substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated. Examples of heterocyclic radicals include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl.TSRI 2216.1PC

[0137] “Heterocyclyl” or “heterocyclic” refers to a group or radical of a 3– to 14– membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon– carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

[0138] In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0139] Exemplary 3–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,TSRI 2216.1PC dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione. Exemplary 5– membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro–1,8–naphthyridinyl, octahydropyrrolo[3,2–b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H–benzo[e][1,4]diazepinyl, 1,4,5,7–tetrahydropyrano[3,4–b]pyrrolyl, 5,6–dihydro–4H–furo[3,2–b]pyrrolyl, 6,7–dihydro– 5H–furo[3,2–b]pyranyl, 5,7–dihydro–4H–thieno[2,3–c]pyranyl, 2,3–dihydro–1H– pyrrolo[2,3–b]pyridinyl, 2,3–dihydrofuro[2,3–b]pyridinyl, 4,5,6,7–tetrahydro–1H–pyrrolo- [2,3–b]pyridinyl, 4,5,6,7–tetrahydrofuro[3,2–c]pyridinyl, 4,5,6,7–tetrahydrothieno[3,2– b]pyridinyl, 1,2,3,4–tetrahydro–1,6–naphthyridinyl, and the like.

[0140] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl (α-naphthyl) and 2–naphthyl (β-naphthyl)). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.TSRI 2216.1PC

[0141] “Heteroaryl” refers to a radical of a 5–14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).

[0142] In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0143] Exemplary 5–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroarylTSRI 2216.1PC groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6– bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0144] “Saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.

[0145] Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted. In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a non-hydrogen substituent, and which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or non-hydrogen substituents which satisfy the valencies of the heteroatoms and results in the formation of a stable compound.

[0146] Exemplary non-hydrogen substituents wherein a moiety is “optionally substituted” as used herein means the moiety may be substituted with any additional moiety selected from, but not limited to, the group consisting of halogen, –CN, –NO2, –N3, –SO2H, –SO3H, – OH, –ORaa, –N(Rbb)2, –N(ORcc)Rbb, –SH, –SRaa, –C(=O)Raa, –CO2H, –CHO, –CO2Raa, – OC(=O)Raa, –OCO2Raa, –C(=O)N(Rbb)2, –OC(=O)N(Rbb)2, –NRbbC(=O)Raa, –NRbbCO2Raa, –TSRI 2216.1PC NRbbC(=O)N(Rbb)2, –C(=NRbb)Raa, –C(=NRbb)ORaa, –OC(=NRbb)Raa, –OC(=NRbb)ORaa, – C(=NRbb)N(Rbb)2, –OC(=NRbb)N(Rbb)2, –NRbbC(=NRbb)N(Rbb)2, –C(=O)NRbbSO2Raa, – NRbbSO2Raa, –SO2N(Rbb)2, –SO2Raa, –S(=O)Raa, –OS(=O)Raa, -B(ORcc)2, C1–10alkyl, C2–10alkenyl, C2–10alkynyl, C3–14carbocyclyl, 3– to 14- membered heterocyclyl, C6–14aryl, and 5– to 14- membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, or two geminal hydrogens on a carbon atom are replaced with the group =O; each instance of Raais, independently, selected from the group consisting of C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–14carbocyclyl, 3– to 14- membered heterocyclyl, C6–14aryl, and 5– to 14- membered heteroaryl, or two Raagroups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from the group consisting of hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, –C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, –SO2Raa, – SO2N(Rcc)2, –SORaa, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–14carbocyclyl, 3– to 14- membered heterocyclyl, C6–14aryl, and 5– to 14- membered heteroaryl, or two Rbbgroups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from the group consisting of hydrogen, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–14carbocyclyl, 3– to 14- membered heterocyclyl, C6–14aryl, and 5– to 14- membered heteroaryl, or two Rccgroups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; and each instance of Rddis, independently, selected from the group consisting of halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, – OC1–6alkyl, –ON(C1–6alkyl)2, –N(C1–6alkyl)2, –N(OC1–6alkyl)(C1–6alkyl), –N(OH)(C1–6alkyl), –NH(OH), –SH, –SC1–6alkyl, –C(=O)(C1–6alkyl), –CO2H, –CO2(C1–6alkyl), – OC(=O)(C1–6alkyl), –OCO2(C1–6alkyl), –C(=O)NH2, –C(=O)N(C1–6alkyl)2, – OC(=O)NH(C1–6alkyl), –NHC(=O)( C1–6alkyl), –N(C1–6alkyl)C(=O)( C1–6alkyl), – NHCO2(C1–6alkyl), –NHC(=O)N(C1–6alkyl)2, –NHC(=O)NH(C1–6alkyl), –NHC(=O)NH2, –C(=NH)O(C1–6alkyl),–OC(=NH)(C1–6alkyl), –OC(=NH)OC1–6alkyl, –C(=NH)N(C1–6alkyl)2, –C(=NH)NH(C1–6alkyl), –C(=NH)NH2, –OC(=NH)N(C1–6alkyl)2, – OC(NH)NH(C1–6alkyl), –OC(NH)NH2, –NHC(NH)N(C1–6alkyl)2, –NHC(=NH)NH2, –TSRI 2216.1PC NHSO2(C1–6alkyl), –SO2N(C1–6alkyl)2, –SO2NH(C1–6alkyl), –SO2NH2,–SO2C1–6alkyl, - B(OH)2, -B(OC1–6alkyl)2,C1–6alkyl, C1–6perhaloalkyl, C2–6alkenyl, C2–6alkynyl, C3–10carbocyclyl, C6–10aryl, 3–to 10- membered heterocyclyl, and 5- to 10- membered heteroaryl; or two geminal Rddsubstituents on a carbon atom may be joined to form =O.

[0147] “Halo” or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, –Br), or iodine (iodo, –I).

[0148] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combination of the specified ingredients.

[0149] “Salt” includes any and all salts. “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts include those derived from inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium,TSRI 2216.1PC quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0150] Unless otherwise indicated, compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC). Compounds described herein can be in the form of individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0151] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, replacement of a carbon by a13C- or14C- enriched carbon, and / or replacement of an oxygen atom with18O, are within the scope of the disclosure. Other examples of isotopes include15N,18O,17O,31P,32P,35S,18F,36Cl and123I. Compounds with such isotopically enriched atoms are useful, for example, as analytical tools or probes in biological assays.

[0152] Certain isotopically-labelled compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability.

[0153] Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes, for example, those labeled with positron-emitting isotopes like11C or18F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like123I can be useful for application in Single Photon Emission Computed Tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and hence, may be preferred in some circumstances. Additionally, isotopic substitution at a siteTSRI 2216.1PC where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time. Isotopically labeled compounds of Formula (I), in particular those containing isotopes with longer half- lives (t1 / 2>1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.

[0154] If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. In some cases, however, where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry. Those skilled in the art of organic synthesis will know if the compounds are prepared as single enantiomers from the methods used to prepare them. EXAMPLES Abbreviations

[0155] Commonly used abbreviations include: acetyl (Ac), azo-bis-isobutyrylnitrile (AIBN), atmospheres (Atm), 9-borabicyclo[3.3.1]nonane (9-BBN or BBN), tert- butoxycarbonyl (Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), Chemical Abstracts Registration Number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), 1,4-diazabicyclo[2.2.2]octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N'-dicyclohexylcarbodiimide (DCC), 1,2- dichloroethane (DCE), dichloromethane (DCM), diethyl azodicarboxylate (DEAD), di-iso- propylazodicarboxylate (DIAD), di-iso-butylaluminumhydride (DIBAL or DIBAL-H), 1,3- Diisopropylcarbodiimide (DIC), di-iso-propylethylamine (DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,1'-bis-(diphenylphosphino)ethane (dppe), 1,1'-bis- (diphenylphosphino)ferrocene (dppf), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H- quinoline-1-carboxylic acid ethyl ester (EEDQ), diethyl ether (Et2O), O-(7-azabenzotriazole- 1-yl)-N, N,N’N’-tetramethyluronium hexafluorophosphate acetic acid (HATU), acetic acidTSRI 2216.1PC (HOAc), 1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), iso-propanol (IPA), lithium hexamethyl disilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2- (mesyl or Ms), , methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrum (ms), methyl t-butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), iso-propyl (i-Pr), pounds per square inch (psi), pyridine (pyr), room temperature (rt or RT), tert-butyldimethylsilyl or t-BuMe2Si (TBDMS), triethylamine (TEA or Et3N), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF3SO2- (Tf), trifluoroacetic acid (TFA), 1,1'-bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me3Si (TMS), p- toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H4SO2- or tosyl (Ts), N- urethane-N-carboxyanhydride (UNCA),. Conventional nomenclature including the prefixes normal (n), iso (i-), secondary (sec-), tertiary (tert-) and neo have their customary meaning when used with an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.). General Information

[0156] CuF2and [(CH3CN)4Cu]BF4were purchased from Alfa-Aesar and Sigma-Aldrich. Solvents were obtained from Sigma-Aldrich, Alfa-Aesar, and Acros, and used directly without further purification. Other reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254 using UV light for visualization and aqueous ammonium cerium nitrate / ammonium molybdate or basic aqueous potassium permanganate as developing agent.1H NMR spectra were recorded on Bruker AMX-400, Bruker AV-500, or Bruker DRX-600 instruments.13C NMR spectra were recorded on Bruker AV-500, or Bruker DRX-600 and were fully decoupled by broad band proton decoupling. The spectra were calibrated by using residual undeuterated solvents (for1H NMR) and deuterated solvents (for13C NMR) as internal references: undeuterated chloroform (δH= 7.26 ppm) and CDCl3(δC= 77.16 ppm); undeuterated methanol (δH= 3.31 ppm) and methanol-d4(δC= 49.00 ppm); undeuterated acetone (δH= 2.05 ppm) and acetone- d6(δC= 29.84 ppm); undeuterated DMSO (δH= 2.50 ppm) and DMSO-d6(δC= 39.50 ppm). The following abbreviations (or combinations thereof) were used to explain multiplicities: s =TSRI 2216.1PC singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling constants, J, were reported in Hertz unit (Hz). Column chromatography was performed using E. Merck silica (60, particle size 0.043–0.063 mm), and pTLC was performed on Miles Scientific silica plates (UV254, 1000 micron). High-resolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer using ESI-TOF (electrospray ionization time-of-flight). Visible light absorption measurements were recorded on a Cary 100 UV-vis spectrophotometer. The single crystal X-ray diffraction studies were carried out on a Bruker SMART APEX II diffractometer equipped with Cu Kαradiation (λ = 1.54178 Å). Melting points (m.p.) were recorded on a Stuart SMP50 automatic digital melting point apparatus. Optimization of ConditionsTable S1. Investigation of Cu(I) salts for γ-dehydrogenation. Reaction conditions: catalyst (10 mol%), AcOH (0.2 M), 125 °C, 12 h. Isolated yields are reported. *Under protection of Ar. Note: The use of acetic acid as the solvent was initially motivated by two considerations: the first was to facilitate the dissolution of copper salts to obtain a homogeneous reaction system. The second, and more important, was to promote N−O bond cleavage. As mentioned in the main text, N-methoxyamides have not been shown to be the precursor of amidyl radicals via N−O bond cleavage, presumably due to its relatively high N−O BDE. To overcome this, it was envisioned that in an acidic environment, the reversibleTSRI 2216.1PC protonation of the amide on oxygen occurs to give the conjugate acid B of the amide (this resonance also accounts for the hydrolysis of substrates in some cases):

[0157] The BDE of N−O bond of B would be lower and therefore the cleavage would be easier. The acid additive also has an important role in regulating the reaction path in our bimodal reaction system.

[0158] For these reasons, although better solvents were later found, the acid additive is still necessary.Scheme S2. Investigation of ligands for γ-dehydrogenation in AcOH. Reactionconditions:[(CH3CN)4Cu]BF4(10 mol%), ligand (10 mol%), AcOH (0.2 M), 125 °C, 12h.Note: The addition of a ligand is to improve the reducing ability of the copper catalyst, which contributes to the cleavage of N−O bond. For more ligand screening in dioxane, see Scheme S5.TSRI 2216.1PC entry Catalyst (10 mol%) Yield of B27 (%) 1 Cu(OAc)2 0 2 CuCl20 3 CuBr2 0 4 Cu(OTFA)2•xH2O 12 5 Cu(OTf)20 6 CuSO4 0 7 Cu3(PO4)20 8 Cu(NO3)2•xH2O 0 9 CuF228Table S3. Investigation of Cu(II) salts for γ-dehydrogenation. Reaction conditions: catalyst (10 mol%), AcOH (0.2 M), 125 °C, 12 h. Isolated yields are reported. *Under protection of Ar. entry Solvent / AcOH (0.2 M) Yield of B27 (%) 1 MeOH 0 2 MeCN 0 3 PhMe 22 4 THF 7 5 1,4-Dioxane 49±6 HFIP 0 7 DCE 43±8 DMSO 0 9 DMF 0 10 tAmyl-OH 0 11 1,4-Dioxane 60* 12 DCE 52* Table S4. Investigation of solvents for γ-dehydrogenation. Reaction conditions: CuF2(10mol%), solvent (0.2 M), AcOH (8.0 eq.), 125 °C, 12 h. Isolated yields are reported.±The starting material could be partially recovered. *Reaction time was 24 h. Note: The starting material (S.M.) was not completely consumed at 12 hours (entry 5 and 7) and when the reaction time was extended to 24 h (entry 11 and 12), the S.M. was fully consumed. To improve the conversion, introduction of a ligand was tried.TSRI 2216.1PCScheme S5. Investigation of ligands for γ-dehydrogenation. Reaction conditions: CuF2(10mol%), ligand (10 mol%), AcOH (8.0 eq.), dioxane (0.2 M), 125 °C, 10 h.aIsolatedyields are reported. *20 mol% ligand was added. Note: ligands L1-L4, which are commonly used in copper-catalyzed reactions, were first tried but no desired product was obtained. Next, the library of ligands available in our lab for Pd-catalyzed reactions (L5-L15) were screened, and L8 was found to increase the catalytic efficiency the most. It was speculated that L8 may be able to enhance the reducing ability of the Cu center, promoting the N−O bond reductive cleavage. A later screen of ligands bearing similar structures as L8 revealed that the simplified L16 achieved a similar result, and the best yield (70%) was obtained when L18 was used, which has the methoxyTSRI 2216.1PC substituent moved to the 8- position of the quinoline. Of note, the reaction time was reduced to 10 h (see entry 11, in Table S4 for comparison).

[0159] Although the ligand can improve the conversion, it is not necessary for every substrate as it may also lead to less optimal regioselectivity in some cases. Conditions with and without the ligand are usually tested to determine the best conditions, and the labeled substrates are those that require the ligand, see Fig.2.Table S6. Some additional conditions screened for γ-dehydrogenation. Standard reactionconditions: CuF2(10 mol%), L18 (20 mol%), AcOH (8.0 eq.), dioxane (0.2 M),125 °C, 10 h.Isolated yields are reported. *The substrate could be partially recovered.TSRI 2216.1PCScheme S7. Comparison of lactone syntheses from amides. (a) The principle of lactone synthesis based on the Hofmann-Löffler-Freytag reaction: multiple steps and strong external oxidants needed, leading to very limited scope and poor atom economy; (b) An example utilizing strategy a by the Baran group; (c) Our redox-neutral lactonization of one step synthesis with no external oxidants that gives good atom economy and good functional group tolerance.TSRI 2216.1PCTable S8. Investigation of the bimodal oxidation: switching from dehydrogenation to lactonization. Reaction conditions for dehydrogenation of A29: CuF2 (10 mol%), AcOH (8.0 eq.), dioxane (0.2 M), 125 °C. Isolated yields are reported. Note: 1) The optimized conditions for lactonization of tertiary, allylic, and benzylic γ-C−H: CuF2 (10 mol%) or [(MeCN)4Cu]BF4 (10 mol%), TFA (5 eq.), dioxane (0.2 M), 125 °C. AcOH is a complementary solvent for such substrates (entry 8) but may cause the hydrolysis of some substrates. 2) A stronger acid additive (TFA) is crucial for the lactonization. 3) Using CuF2 and [(MeCN)4Cu]BF4 affords product of similar yields. Usually both were tested and the better one is reported. 4) The ligand is unnecessary for this lactonization.TSRI 2216.1PCTable S9. Investigation of lactonization of unactivated γ-methylene. Standard conditions for lactonization of tertiary γ-C−H: CuF2 (10 mol%) or [(MeCN)4Cu]BF4 (10 mol%), TFA (5 eq.), dioxane (0.2 M), 125 °C, 5 h. Isolated yields are reported. Note: 1) The optimized conditions for lactonization of unactivated γ-methylene: [(MeCN)4Cu]BF4 (10 mol%), CSA (0.5 eq.), dioxane / MeNO2 (1:1, 0.2 M), 125 °C. 2)A more polar solvent combination (dioxane / MeNO2) is crucial for a better lactone / alkeneratio. 3)[(MeCN)4Cu]BF4 gave better yields than CuF2 for lactonization of unactivated γ-methylene (see entry 9 and entry 11). 4) The ligand is unnecessary for this lactonization.TSRI 2216.1PCTSRI 2216.1PC Scheme S10-1. Representative examples of bimodal oxidation. Isolated yields are reported. * The solvent is dioxane.Scheme S10-2. Representative examples of bimodal oxidation. Isolated yields are reported.TSRI 2216.1PC Note: 1) For a given substrate, a few different conditions are usually tried, and reported herein are the best conditions. Therefore, the reaction conditions may be slightly different, even for the same type of substrate. ) In general, for a given substrate, a more polar solvent and a stronger acid additive, or a combination of the two would favor lactonization, and conversely, the elimination. The catalyst does not affect the yield as much as the solvent and acid do. ) Toluene is a complementary solvent (or can be a cosolvent with dioxane) for the lactonization. The yields in toluene are generally lower than those when dioxane is the solvent, but entry 2 (C28) is an exception. ) TsOH•H2O is a complementary acid additive for lactonization, especially for benzylic C−H (eg. entry 11) but may cause the hydrolysis of some substrates. ) The combination of CuF2 (10 mol%) and AcOH (0.2 M) is an alternative for some substrates that require higher reaction temperatures. (entry 14 and 17). Synthesis of Carboxylic Acids Note: all reactions for the synthesis of substrates are unoptimized. CO2H

[0160] A 25 mL round-bottom flask was charged with 1-hydroxycyclohexanecarboxylic acid (433 mg, 3.0 mmol, 1.0 equiv) in acetyl chloride (5.0 mL). The mixture was allowed to stir at 22 ℃ for 12 h before the excess of acetyl chloride was removed under vacuum to give carboxylic acid SA9, which was directly used in the next step without further purification. 2Me

[0161] To a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (1.23 g, 3.59 mmol, 1.2 equiv) in THF (20 mL) was added LiHMDS (3.60 mL, 1.0 M in THF, 3.60 mmol, 1.2 equiv) at 0 °C. The mixture was allowed to stir at that temperature for 30 minTSRI 2216.1PC before a solution of methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate (589 mg, 3.00 mmol, 1.0 equiv) in THF (5.0 mL) was added. The mixture was then heated at 80 °C for 2 h before it was cooled to 22 °C, then saturated aq. NaHCO3(30 mL) was added. The resultant aqueous solution was extracted with EtOAc (3 × 40 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the crude enol ether. To a stirred solution of above enol ether in acetone (7.5 mL) was added TsOH•H2O (285 mg, 1.50 mmol, 0.5 equiv) at 22 °C. The mixture was allowed to stir at that temperature for 16 h before saturated aq. NaHCO3(10 mL) was added. The excess of acetone was removed under vacuum, and the resultant aqueous solution was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / EA (5:1) as eluent to give aldehyde SA10-1 (463mg, 73%).

[0162] To a stirred solution of SA10-1 (463 mg, 2.2 mmol, 1.0 equiv) in tBuOH / H2O (3:1, 10 mL) were sequentially added 2-methyl-2-butene (993 mg, 1.50 mL, 14.2 mmol, 6.5 equiv), NaH2PO4(528 mg, 4.40 mmol, 2.0 equiv), and NaClO2(373 mg, 80 wt%, 3.30 mmol, 1.5 equiv) at 0 ℃. The mixture was allowed to warm to 22 °C and stir at that temperature for 1 h before saturated aq. NH4Cl (10 mL) was added. The excess of tBuOH and 2-methyl-2- butene was removed under vacuum before the aqueous solution was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and dried under vacuum to give crude carboxylic acid SA10, which was directly used in the next step without further purification.

[0163] To a stirred solution of SA13-1 (1) (365 mg, 2.0 mmol, 1.0 equiv) in CH2Cl2(10 mL) was sequentially added pyridine (393 mg, 0.40 mL, 5.0 mmol, 2.5 equiv) and triflic anhydride (1.18 g, 0.7 mL, 4.2 mmol, 2.1 equiv) at 0 ℃. The mixture was allowed to stir at that temperature for 1 h before saturated aq. NaHCO3(10 mL) was added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (60 mL), dried over Na2SO4, filtered, andTSRI 2216.1PC concentrated under vacuum to give SA13-2, which was directly used in the next step without further purification.

[0164] A flame-dried 50 mL round-bottom flask was charged with SA13-2 (472 mg, 1.5 mmol, 1.0 equiv), Pd(OAc)2(16.8 mg, 0.075 mmol, 0.05 equiv), 1,1’- bis(diphenylphosphino)ferrocene (166 mg, 0.3 mmol, 0.2 equiv), and KOAc (883 mg, 9.0 mmol, 6.0 equiv). The flask was capped with a septum stopper, then dry DMF (7.5 mL) was added. The flask was purged with carbon monoxide (CO balloon) for 5 min. The reaction mixture was allowed to stir at 60 ℃ for 16 h under carbon monoxide atmosphere (CO balloon) before it was cooled to room temperature. Saturated aq. NH4Cl (30 mL) was added, and the resultant mixture was extracted with EtOAc (3 × 40 mL). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give carboxylic acid SA13.

[0165] Carboxylic acid SA14 was prepared from 4-bromo-5,6,7,8-tetrahydro-1- naphthalenol following the method used to obtain SA13.

[0166] The title compound was synthesized according to a published procedure (2) with minor alteration. To a stirred solution of 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (3.52g, 20.0 mmol, 1.0 equiv) in trifluoroacetic acid (60 mL) was added NIS (N- iodosuccinimide) (4.95 g, 22.0 mmol, 1.1 equiv) in small portions at 22 ℃. After NIS was fully dissolved, concentrated H2SO4(1.0 mL, 18.0 mmol, 0.9 equiv) was added dropwise to the mixture. The mixture was allowed to stir at 22 ℃ for 4 h before the excess of TFA was removed under vacuum. To the residue so obtained was added cold 10% aq. Na2SO3solution (100 mL) at 0 ℃, the mixture was extracted with DCM (3 × 150 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by recrystallization (DCM / hexane) to give carboxylic acid SA18 as an off-white powder.TSRI 2216.1PC

[0167] A Schlenk tube was charged with SA18 (604 mg, 2.0 mmol, 1.0 equiv), PdCl2(dppe) (115 mg, 0.2 mmol.0.1 equiv), KOAc (589 mg, 6.0 mmol, 3.0 equiv), and bis(pinacolato)diboron (609 mg, 2.4 mmol, 1.2 equiv) in dry dimethylformamide (10 mL). The tube was evacuated and refilled with argon three times and sealed. The mixture was allowed to stir at 95 ℃ for 16 h before cooled down to room temperature. Saturated aq. NH4Cl (40 mL) was added to quench the reaction, and it was extracted with EtOAc (3 × 40 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (4:1) as eluent to give carboxylic acid SA15.

[0168] A Schlenk tube was charged with carboxylic acid SA18 (604 mg, 2.0 mmol, 1.0 equiv), CuI (38.1 mg, 0.2 mmol, 0.1 equiv), 8-hydroxyquinoline (58.1 mg, 0.4 mmol, 0.2 equiv) and aq. KOH (4 M, 2 mL) in dimethyl sulfoxide (2 mL). The tube was evacuated and refilled with argon three times and sealed. The mixture was allowed to stir at 100 ℃ for 16 h before cooled down to room temperature. It was then acidified with aq. HCl (2 M) to pH = 3‒4 and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give carboxylic acid SA16, which was used directly in the next step without further purification. 2H

[0169] A Schlenk tube was charged with carboxylic acid SA18 (604 mg, 2.0 mmol, 1.0 equiv) and CuCN (215 mg, 2.4 mmol, 1.2 equiv) in dry dimethylformamide (4 mL). The tube was evacuated and refilled with argon three times and sealed. The mixture was allowed to stirTSRI 2216.1PC at 140 ℃ for 16 h before cooled down to room temperature. It was then acidified with aq. HCl (2 M) to pH = 3‒4 and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give SA17. 1,2-

[0170] A Schlenk tube was charged with carboxylic acid SA18 (604 mg, 2.0 mmol, 1.0 equiv), CuI (38.1 mg, 0.2 mmol, 0.1 equiv), trans-1,2-diaminocyclohexane (22.8 mg, 24.0 ^^^^L, 0.2 mmol, 0.1 equiv), K2CO3(829 mg, 6.0 mmol, 3.0 equiv), and 2-oxazolidinone (261 mg, 3.0 mmol, 1.5 equiv). The tube was evacuated and refilled with argon three times before 1,4-dioxane (8 mL) was added. The sealed mixture was allowed to stir at 110 ℃ for 16 h before cooled down to room temperature. It was then acidified with aq. HCl (2 M) to pH = 3‒ 4, and the excess of 1,4-dioxane was removed under vacuum. The resultant aqueous solution was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give SA19.

[0171] A Schlenk tube was charged with SA18 (604 mg, 2.0 mmol, 1.0 equiv), PdCl2(dppe) (115 mg, 0.2 mmol.0.1 equiv), and potassium vinyltrifluoroborate (402 mg, 3.0 mmol, 1.5 equiv). The tube was evacuated and refilled with argon three times before a solution of Et3N (654 mg, 0.9 ml, 6.45 mmol, 3.23 equiv) in dry methanol (8 mL) was added. The sealed mixture was allowed to stir at 90 ℃ for 16 h and cooled down to room temperature before saturated aq. NH4Cl (30 mL) was added. The excess of methanol was removed under vacuum, and the resultant aqueous solution was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected toTSRI 2216.1PC flash column chromatography for purification using hexane / acetone (2:1) as eluent to give SA20.

[0172] A Schlenk tube was charged with carboxylic acid SA18 (604 mg, 2.0 mmol, 1.0 equiv), 1-ethynyl-4-methoxybenzene (396 mg, 3.0 mmol, 1.5 equiv), (PPh3)2PdCl2(70 mg, 0.1 mmol, 0.05 equiv), and CuI (38 mg, 0.2 mmol, 0.1 equiv). The tube was evacuated and refilled with argon three times before a solution of Et3N (102 mg, 1.4 mL, 10 mmol, 5.0 equiv) in dry tetrahydrofuran (10 mL) was added at 22 ℃. The reaction was allowed to stir at that temperature for 16 h before saturated aq. NH4Cl (30 mL) was added. The excess of tetrahydrofuran was removed under vacuum, and the resultant aqueous solution was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give SA21. proline

[0173] A Schlenk tube was charged with carboxylic acid SA18 (604 mg, 2.0 mmol, 1.0 equiv), CuI (76.2 mg, 0.4 mmol, 0.2 equiv), L-proline (46.0 mg, 0.4 mmol, 0.2 equiv), and K3PO4(1.27 g, 6.0 mmol, 3.0 equiv). The tube was evacuated and refilled with argon three times before a solution of morpholine (303 mg, 0.3 mL, 3.47 mmol, 1.16 equiv) in dry dimethylformamide (8 mL) was added. The sealed mixture was allowed to stir at 90 ℃ for 16 h and cooled down to room temperature before saturated aq. NH4Cl (50 mL) was added. The resultant mixture was extracted with EtOAc (3 × 40 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give SA22.TSRI 2216.1PC 1,2-

[0174] A Schlenk tube was charged with carboxylic acid SA18 (604 mg, 2.0 mmol, 1.0 equiv), CuI (19.1 mg, 0.1 mmol, 0.05 equiv), trans-1,2-diaminocyclohexane (22.8 mg, 24.0 ^^^^L, 0.2 mmol, 0.1 equiv), K3PO4(1.06 g, 5.0 mmol, 2.5 equiv), and 7-azaindole (260 mg, 2.2 mmol, 1.1 equiv). The tube was evacuated and refilled with argon three times before dry 1,4-dionaxe (8 mL) was added. The mixture was allowed to stir at 110 ℃ for 16 h before cooled down to room temperature. It was quenched with saturated aq. NH4Cl (40 mL), and the excess of 1,4-dioxane was removed under vacuum. The resultant aqueous solution was extracted with EtOAc (3 × 40 mL). The combined organic phases were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (4:1) as eluent to give SA23.

[0175] A Schlenk tube was charged with carboxylic acid SA18 (604 mg, 2.0 mmol, 1.0 equiv), copper powder (38.1 mg, 0.6 mmol, 0.3 equiv), KOH (337 mg, 6.0 mmol, 3.0 equiv), and 4-methylthiophenol (877 mg, 6.0 mmol, 3.0 equiv) in H2O (8 mL). The tube was evacuated and refilled with argon three times and sealed. The mixture was then allowed to stir at 110 ℃ for 16 h before cooled down to room temperature. It was acidified with aq. HCl (2 M) to pH = 3‒4 and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (4:1) as eluent to give SA24.= N,N-dimethylglycineTSRI 2216.1PC

[0176] A Schlenk tube was charged with carboxylic acid SA18 (604 mg, 2.0 mmol, 1.0 equiv), CuI (76.2 mg, 0.4 mmol, 0.2 equiv), N,N-dimethylglycine (82.5 mg, 0.8 mmol, 0.4 equiv), 3,5-dimethylphenol(489 mg, 4.0 mmol, 2.0 equiv), and Cs2CO3(1.95 g, 6.0 mmol, 3.0 equiv) in dry dimethylformamide (8 mL). The tube was evacuated and refilled with argon three times and sealed. The mixture was then allowed to stir at 110 ℃ for 16 h before cooled down to room temperature. It was acidified with aq. HCl (2 M) to pH = 3‒4 and extracted with EtOAc (3 × 20 ml). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / EtOAc (2:1) as eluent to give SA25. CO2H

[0177] Carboxylic acid SA28 was prepared from L-leucic acid following the method used to prepare SA9. O OH

[0178] To a stirred solution of cyclododecanecarboxaldehyde (589 mg, 3.0 mmol, 1.0 equiv) in toluene (30 mL) was added benzyl(triphenylphosphoranylidene)acetate (1.35 g, 3.3 mmol, 1.1 equiv) at 22 ℃. The mixture was then refluxed at 125 ℃ for 16 h before cooled down to room temperature. The mixture was quenched with saturated aq. NH4Cl (30 mL) and extracted with EtOAc (3 × 50 ml). The combined organic phases were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / Et2O (2:1) as eluent to give intermediate SA38-1.

[0179] A 50 mL round-bottom flask was charged with SA38-1 (657 mg, 2.0 mmol, 1.0 equiv) and palladium on carbon (131 mg, 10 wt%) in methanol (10 mL) at 22 ℃. The flask was purged with hydrogen (H2balloon) for 5 min. The reaction mixture was allowed to stir at 22 ℃ for 16 h under H2atmosphere (H2balloon) before it was filtered through Celite®. The filtrate was concentrated under vacuum to give carboxylic acid SA38, which was used directly in the next step without further purification.TSRI 2216.1PC CO2H

[0180] Carboxylic acid SA35 was prepared from cycloheptanecarbaldehyde following the method used to prepare SA38. CO2H

[0181] Carboxylic acid A36 was prepared from cyclooctanecarboxaldehyde following the method used to to prepare SA38. CO2H

[0182] Carboxylic acid SA37 was prepared from cyclohexylketone following the method used to prepare SA38. 2H

[0183] To a stirred solution of norvaline (315 mg, 3.0 mmol, 1.0 equiv) and Na2CO3(350 mg, 3.3 mmol, 1.1 equiv) in water (20 mL) was added N-ethoxycarbonylphthalimide (723 mg, 3.3 mmol, 1.1 equiv) at 22 ℃. The mixture was allowed to stir at that temperature for 3 h before it was acidified with aq. HCl (2 M) to pH = 3‒4. The resultant mixture was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give SA39. Me CO2H22SA40TSRI 2216.1PC

[0184] Carboxylic acid SA40 was prepared from 3-aminopentanoic acid following the procedure used to obtain SA39. O OH

[0185] Carboxylic acid SA41 was prepared from pregabalin following the method used to obtain SA39. O OH

[0186] Carboxylic acid SA42 was prepared from homophenyalanine following the method used to obtain SA39. CO2H

[0187] Carboxylic acid SA43 was prepared from norleucine following the procedure used to obtain SA39. CO2H

[0188] To a stirred solution of 1-aminocyclopentanecarboxylic acid (649 mg, 5.0 mmol, 1.0 equiv) and phthalic anhydride (741 mg, 5.0 mmol, 1.0 equiv) in toluene (25 mL) was added Et3N (72.6 mg, 0.10 ml, 0.72 mmol, 0.72 equiv) at 22 ℃. The mixture was allowed to reflux at 125 ℃ for 16 h before cooled down to room temperature. The resultant mixture was acidified with aq. HCl (2 M) to pH = 3‒4. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give carboxylic acid SA45.TSRI 2216.1PC Et3N phthalicCO2H toluene, 125CO2HSA44

[0189] Carboxylic acid SA44 was prepared from 1-aminocyclohexanecarboxylic acid following the method used to obtain SA45. CO2H

[0190] Carboxylic acid SA46 was prepared from gabapentin following the method used to obtain SA39. OHO

[0191] Carboxylic acid SA47 was prepared from 3-amino-4-methylpentanoic acid following the procedure used to obtain SA39. Et3N CO2H phthalic CO2Htoluene, 125NPhth SA49

[0192] Carboxylic acid SA49 was prepared from L-cyclohexylalanine following the method used to prepare SA45. O O

[0193] To a stirred solution of SA50-1 (414 mg, 1.5 mmol, 1.0 equiv) and SA50-2 (367 mg, 1.65 mmol, 1.1 equiv) in THF (10 mL) were sequentially added DMAP (18.3 mg, 0.15 mmol, 0.1 equiv), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) (431 mg, 2.25 mmol, 1.5 equiv), HOBt (hydroxybenzotriazole) (380 mg, 80 wt%, 2.25 mmol, 1.5 equiv), and DIPEA (594 mg, 0.8 ml, 4.59 mmol, 3.1 equiv) at 0 ℃. The mixture was thenTSRI 2216.1PC warmed to 22 ℃ and allowed to stir at that temperature for 16 h before saturated aq. NH4Cl (30 mL) was added. The resultant mixture was extracted with EtOAc (3 × 40 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / EtOAc (2:1) as eluent to give the corresponding benzyl ester intermediate SA50-3.

[0194] A 50 ml round-bottom flask was charged with SA50-3 (481 mg, 1.0 mmol, 1.0 equiv) and palladium on carbon (48.1 mg, 10 wt%) in methanol (10 mL) at 22 ℃. The flask was purged with hydrogen (H2 balloon) for 5 min. The reaction mixture was allowed to stir at 22 ℃ for 16 h under H2atmosphere (H2balloon) before it was filtered through Celite®. The filtrate was concentrated under vacuum to give carboxylic acid SA50, which was used directly in the next step without further purification. OMeCHO SA53 SA53-4

[0195] Compound SA53-1 was prepared from 3-methyl (1S, 3R)-1,2,2-trimethyl-1,3- cyclopentanedicarboxylate following a reported method (3). To a stirred suspension of SA53- 1 (500 mg, 2.5 mmol, 1.0 equiv) and Celite®(1.5 g) in DCM (30 mL) was added PCC (pyridium chlorochromate) (593 mg, 2.75 mmol, 1.1 equiv) in small portions at 0 ℃. The mixture was allowed to stir at 22 ℃ for 2 h before filtered through Celite®. The resultant filtrate was concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / EtOAc (10:1) as eluent to give aldehyde SA53-2, which was transformed to SA53 following the method used in the synthesis of SA10.TSRI 2216.1PC 1)MeOPPh3CO2H

[0196] SA54 was prepared from SA54-1 following the method used in the synthesis of SA10. COOH

[0197] To a stirred solution of (+)-manoyl oxide (581 mg, 2.0 mmol, 1.0 equiv) in THF (10 mL) at 0 °C was added 9-BBN (4.4 mL, 0.5 M in THF, 2.2 mmol, 1.1 equiv), and the reaction mixture was warmed to 22 °C and stirred for 12 h. The reaction mixture was then cooled to 0 °C and quenched by the slow addition of 2.0 M aq. NaOH (5.0 mL) and 35% aq. H2O2(2.0 mL). The biphasic mixture was stirred vigorously at 0 °C for 30 min before it was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated aqueous Na2S2O3(10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / EtOAc (4:1) as eluent to give alcohol SA60-1.

[0198] To a stirred solution of SA60-1 (309 mg, 1.0 mmol, 1.0 equiv) in CH2Cl2(10 mL) was added DMP (467 mg, 1.10 mmol, 1.1 equiv) at 0 ℃. The mixture was allowed to stir at that temperature for 30 min before saturated aq. NaHCO3(15 mL) and aq. Na2S2O3(5 mL) were sequentially added, the resultant mixture was allowed to warm to 22 ℃ and stir at that temperature for 15 min. The organic layer was then separated, and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the crude aldehyde, which was transformed to SA60 via a Pinnick oxidation following the method used in the synthesis of SA10.TSRI 2216.1PC Me °CMe

[0199] SA61-2 was synthesized according to a published procedure (6) with minor alteration. A 100 mL round-bottom flask was charged with (+)-cholest-4-en-3-one (1.15g, 3.0 mmol, 1.0 equiv) in CH2Cl2(20 mL) and sealed. A solution of m-CPBA (m-chloroperbenzoic acid, 75%) (2.76 g, 12 mmol, 4.0 equiv) in CH2Cl2(20 mL) was slowly added to the mixture at 22 ℃. The mixture was allowed to stir at that temperature for 8 h before saturated aq. Na2S2O3(20 mL) was added to quench the excess of m-CPBA. The mixture was then washed with saturated aq. NaHCO3(40 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 40 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / EtOAc (2:1) as eluent to give intermediate SA61-1.

[0200] To a stirred solution of SA61-1 (1.11g, 2.7 mmol, 1.0 equiv) in MeOH (30 mL) was added aq. NaOH (2 M, 6.5 mL) at 0 ℃. The mixture was allowed to slowly raise to 22 ℃ while stirred for 16 h before it was acidified with aq. HCl (2 M) to pH = 3‒4. The excess of MeOH was removed under vacuum, and the resultant aqueous solution was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / Et2O (1:1) as eluent to give intermediate SA61-2.

[0201] Carboxylic acid SA61 was prepared from intermediate SA61-2 via a Pinnick oxidation following the method used in the synthesis of SA10.TSRI 2216.1PC OH O

[0202] Compound SA64-1 was prepared from olenolic acid according to a reported method (7). A flame-dried 250 mL round-bottom flask was charged with methyltriphenylphosphonium bromide (5.36 g, 15 mmol, 3 equiv) in dry THF (75 mL) at 0 ℃ before tBuOK (1.68 g, 15 mmol, 3 equiv) was slowly added. The sealed mixture was warmed to 22 ℃ and allowed to stir at that temperature for 30 min before a solution of SA64- 1 (2.36 g, 5.0 mmol, 1.0 equiv) in dry THF (6 mL) was slowly added to the mixture. The resultant mixture was allowed to reflux at 90 ℃ for 3 h before it was cooled to ambient temperature and acidified with aq. HCl (2 M) to pH = 3‒4. The excess of THF was removed under vacuum, and the resultant aqueous solution was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / EtOAc (4:1) as eluent to give the alkene. To a stirred solution of above alkene (1.41 g, 3.0 mmol, 1.0 equiv) in pyridine (9 mL) was sequentially added DMAP (73.3 mg, 0.6 mmol, 0.2 equiv) and acetic anhydride (972 mg, 0.90 mL, 9.52 mmol, 3.2 equiv) at 22 ℃. The mixture was allowed to stir at that temperature for 2 h before the excess of acetic anhydride and pyridine was removed under vacuum. The remaining mixture was acidified with aq. HCl (2 M) to pH = 3‒4, and the resultant aqueous mixture was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give carboxylic acid SA63, which was directly used in the next step without further purification.

[0203] To a stirred solution of 5-phenyl-1-pentanol (329 mg, 2.0 mmol, 1.0 equiv) and Et3N (218 mg, 0.30 mL, 2.20 mmol, 1.1 equiv) in DCM (10 mL) was added 4- chloropentanoyl chloride (310 mg, 2.0 mmol, 1.0 equiv) in DCM (2.0 mL) at 22 ℃. The mixture was allowed to stir at that temperature for 1 h before saturated aq. NaHCO3(20 mL)TSRI 2216.1PC was added. The resultant mixture was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / Et2O (4:1) as eluent to give A67 (508 mg, 90%) as a colorless oil. Me NHTs

[0204] To a stirred solution of 3-amino-2-methylbenzoic acid (302 mg, 2.0 mmol, 1.0 equiv) and 4-toluenesulfonyl chloride (381 mg, 2.0 mmol, 1.0 equiv) in H2O (8 mL) at 22 ℃ was slowly added Na2CO3to pH = 8. The mixture was allowed to stir at that temperature for 2 h before it was acidified with aq. HCl (2 M) to pH = 3‒4. The resultant mixture was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give carboxylic acid SA68.

[0205] Carboxylic acid SA73 was prepared from 1,4-dimethyl-2- naphthalenecarboxaldehyde via a Pinnick oxidation following the method used in the synthesis of SA10. O OH Ph

[0206] A flame-dried 50 mL round-bottom flask was charged with 1,3-diethyl 2-(2- phenylethyl)propanedioate (1.32 g, 5.0 mmol, 1.0 equiv) in dry dimethylformamide (5 mL) at 0 ℃. Sodium hydride (60% dispersion in mineral oil) (240 mg, 6.0 mmol, 1.2 equiv) was then slowly added. The mixture was allowed to stir at that temperature for 30 min before 1- iodopropane (1.25 g, 720 ^^^^L, 1.5 equiv) was added. The mixture was warmed to 22 ℃ and allowed to stir at that temperature for 3 h. The mixture was then quenched with saturated aq.TSRI 2216.1PC NH4Cl (40 mL) and extracted with EtOAc (3 × 40 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / EtOAc (10:1) as eluent to give intermediate SA77-1.

[0207] To a stirred solution of SA77-1 (919 mg, 3.0 mmol, 1.0 equiv) in EtOH (10 mL) was added NaOH (120 mg, 3.0 mmol, 1.0 equiv) at 22 ℃. The mixture was allowed to stir at that temperature for 16 h before it was acidified with aq. HCl (2 M) to pH = 3‒4. The excess of EtOH was removed under vacuum, and the resultant aqueous solution was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give carboxylic acid SA77, which was used directly in the next step without further purification. CO2H

[0208] A flame-dried 250 mL round-bottom flask was charged with methyltriphenylphosphonium bromide (5.36 g, 15 mmol, 5.0 equiv) in dry THF (75 mL) at 0 ℃ before tBuOK (1.68 g, 15 mmol, 5.0 equiv) was slowly added. The sealed mixture was warmed to 22 ℃ and allowed to stir at that temperature for 30 min before a solution of α- oxobenzenebutanoic acid (534 mg, 3.0 mmol, 1.0 equiv) in dry THF (6 mL) was slowly added to the mixture. The resultant mixture was allowed to stir at 22 ℃ for 3 h before it was acidified with aq. HCl (2 M) to pH = 3‒4. The excess of THF was removed under vacuum, and the resultant aqueous solution was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give carboxylic acid SA81. CO2H

[0209] Carboxylic acid SA83 was prepared from δ-oxobenzenepentanoic acid via a Wittig reaction following the method used to obtain SA81.TSRI 2216.1PC OHO

[0210] SA86 is prepared from (αS)-α-aminocyclopentaneacetic acid following the method used to obtain SA45. OMe

[0211] To a stirred solution of 2,2-dimethlglutaric anhydride (711mg, 5.0 mmol, 1.0 equiv) and 2,7-dimethoxynaphthalene (1.13 g, 6.0 mmol, 1.2 equiv) in DCM (25 mL) was added AlCl3(1.33g, 10 mmol, 2.0 equiv) at 0 ℃. The mixture was warmed to 22 ℃ and allowed to stir at that temperature for 4 h before saturated aq. NH4Cl (50 mL) was added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give intermediate SA89-1. Carboxylic acid SA89 was prepared from SA89-1 via a Wittig reaction following the method used to obtain SA81.

[0212] A flame-dried 100 mL round-bottom flask was charged with glutaric anhydride (570 mg, 5.0 mmol, 1.0 equiv) in THF (25 mL) under argon at 0 ℃. Decylmagnesium bromide (6.0 mL, 1.0 M in Et2O, 6.0 mmol, 1.2 equiv) was then slowly added. The mixture was warmed to 22 ℃ and allowed to stir at that temperature for 4 h before saturated aq. NH4Cl (30 mL) was added. The resultant aqueous solution was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / Et2O (2:1) as eluent to give intermediateTSRI 2216.1PC SA90-1. Carboxylic acid SA90 was prepared from SA90-1 via a Wittig reaction following the method used to obtain SA81. CO2H

[0213] Carboxylic acid SA94 was prepared from citronellal following the method used to obtain SA10. CO2H

[0214] A 50 mL round-bottom flask was charged with mycophenolic acid (641 mg, 2.0 mmol, 1.0 equiv) and palladium on carbon (64.1 mg, 10 wt%) in MeOH (10 mL) at 22 ℃. The flask was purged with hydrogen (H2balloon) for 5 min. The reaction mixture was allowed to stir at 22 ℃ for 16 h under H2atmosphere (H2balloon) before it was filtered through Celite®. The filtrate was concentrated under vacuum to give intermediate SA96-1, which was used directly in the next step without further purification.

[0215] To a stirred solution of SA96-1 (322 mg, 1.0 mmol, 1.0 equiv) in pyridine (5 mL) was sequentially added DMAP (12.2 mg, 0.1 mmol, 0.1 equiv) and acetic anhydride (151 mg, 140 ^^^^L, 1.48 mmol, 1.5 equiv) at 0 ℃. The reaction was allowed to stir at that temperature for 2 h before the excess of acetic anhydride and pyridine was removed under vacuum. It was then acidified with aq. HCl (2 M) to pH = 3‒4 and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and dried under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give carboxylic acid SA96. iPrTSRI 2216.1PC

[0216] Compound SA97-1 was prepared from dehydroabietic acid following a reported method (12). Carboxylic acid SA97 was prepared from intermediate SA97-1 following the method used in the synthesis of SA10. OH O OH CHO

[0217] To a stirred solution of androsterone acetate (665 mg, 2.0 mmol, 1.0 equiv) in CH2Cl2(10 mL) were sequentially added Et3N (290 mg, 0.40 mL, 2.87 mmol, 1.4 equiv) and TMSOTf (490 mg, 0.40 mL, 2.2 mmol, 1.1 equiv) at 0 °C. The mixture was allowed to stir at that temperature for 1 h before saturated aq. NaHCO3(30 mL) was added. The resultant mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in CH2Cl2(10 mL). To the stirred solution were sequentially added NaHCO3(252 mg, 3.0 mmol, 1.5 equiv) and 3-chloroperbenzoic acid (493 mg, 77 wt%, 2.2 mmol, 1.1 equiv) at 0 °C. The mixture was allowed to warm to 22 ℃ and stir at that temperature for 15 h before saturated aq. NaHCO3(30 mL) and aq. Na2S2O3(10 mL) were sequentially added. The resultant mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / EtOAc (4:1 → 2:1) as eluent to give SA99-1 (460 mg, 66%) as a white foam.

[0218] To a stirred solution of SA99-1 (460 mg, 1.32 mmol, 1.0 equiv) in THF / H2O (4.0 mL / 6.0 mL) was added NaIO4(424 mg, 1.98 mmol, 1.5 equiv) at 22 ℃. The mixture was allowed to stir at that temperature for 10 h before saturated aq. NaHCO3(30 mL) and aq. Na2S2O3(10 mL) were sequentially added. The resultant mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected toTSRI 2216.1PC flash column chromatography for purification using hexane / EtOAc (2:1 → 1:1) as eluent to give SA99-2 (337 mg, 70%) as a white powder.

[0219] To a stirred suspension of methyltriphenylphosphonium chloride (863 mg, 2.76 mmol, 3.0 equiv) in THF (5 mL) was added LiHMDS (2.80 mL, 1.0 M in THF, 2.80 mmol, 3.0 equiv) at 0 °C. The mixture was allowed to stir at that temperature for 30 min before a solution of SA99-2 (335 mg, 0.92 mmol, 1.0 equiv) in THF (5.0 mL) was added. The mixture was allowed to warm to 22 ℃ and stir at that temperature for 1 h before saturated aq. NH4Cl (30 mL) was added. The resultant aqueous mixture was extracted with EtOAc (3 × 40 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / EtOAc (2:1 → 1:1) as eluent to give SA99 (296 mg, 89%) as a white powder. O OH

[0220] SA100 was prepared following the method used in the synthesis of SA9 from deoxycholic acid. CO2H

[0221] Compound SA101-1 was prepared from estrone 3-methyl ether following a reported method (14), which was transformed to SA101 following the method used in the synthesis of SA60. Preparation and Characterization Data of N-MethoxyamidesTSRI 2216.1PC

[0222] General Procedure A: To a stirred solution of carboxylic acid SA (2.0 mmol, 1.0 equiv) in CH2Cl2(10 mL) were sequentially added DMAP (4-dimethylaminopyridine) (24.4 mg, 0.20 mmol, 0.1 equiv), H2NOMe•HCl (200 mg, 2.4 mmol, 1.2 equiv), EDC (1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride) (460 mg, 2.4 mmol, 1.2 equiv), and Et3N (290 mg, 0.40 mL, 2.9 mmol, 1.45 equiv) at 0 °C. The mixture was allowed to stir at 22 °C for 2 h before saturated aq. NH4Cl (30 mL) was added. The resultant mixture was extracted with CH2Cl2(3 × 40 mL). The combined organic phases were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration and removal of the volatiles under vacuum, the residue was purified by flash column chromatography with hexane / acetone (2:1) to give N-methoxyamide A. 1) (COCl)2, cat. DMF, CH2Cl2

[0223] General Procedure B: To a stirred solution of carboxylic acid SA (2.0 mmol, 1.0 equiv) in CH2Cl2(10 mL) were sequentially added oxalyl chloride (450 mg, 0.30 mL, 3.60 mmol, 1.8 equiv) and a drop of DMF at 22 °C. The mixture was allowed to stir at that temperature for 3 h before the excess of oxalyl chloride and CH2Cl2were removed under vacuum. The crude acid chloride in CH2Cl2(5 mL) was added slowly to a vigorously stirring solution of H2NOMe•HCl (200 mg, 2.4 mmol, 1.2 equiv) and NaHCO3(403 mg, 4.8 mmol, 2.4 equiv) in CH2Cl2(5 mL) and water (5 mL) at 0 °C. The mixture was stirred at 22 °C for 3 h before water (20 mL) was added. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2(3 × 30 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane / acetone (2:1) as eluent to give N-methoxyamide A.

[0224] The title compound was prepared according to general procedure A from 3,3- dimethylpentanoic acid. Purification by flash column chromatography afforded A1 (462 mg, 83%, 3.5 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 9.79 (br s, 1H), 3.70 (s, 3H), 1.95 (s, 2H), 1.33 (q, J = 6.6 Hz, 2H), 0.98 – 0.94 (m, 6H), 0.85 – 0.78 (m, 3H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 169.88, 64.02, 44.21, 34.94, 33.57, 26.70, 8.51 ppm. HRMS (m / z): [M+H]+calcd for C8H18NO2+160.1338, found 160.1334.

[0225] The title compound was prepared according to general procedure A from propylacrylic acid. Purification by flash column chromatography afforded A2 (246 mg, 86%, 2.0 mmol scale) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 8.70 (br s, 1H), 5.57 (s, 1H), 5.28 (s, 1H), 3.81 (s, 3H), 2.26 (t, J = 7.6 Hz, 2H), 1.47 (h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.53, 142.75, 118.54, 64.25, 34.24, 21.18, 13.70 ppm. HRMS (m / z): [M+H]+calcd for C7H14NO2+144.1019, found 144.1019. O

[0226] The title compound was prepared according to general procedure A from (2S,3S)- 2-(Acetyloxy)-3-methylpentanoic acid. Purification by flash column chromatography afforded A3 (339 mg, 83%, 2.0 mmol scale) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 9.16 (br s, 1H), 4.91 (d, J = 6.0 Hz, 1H), 3.74 (s, 3H), 2.11 (s, 3H), 2.05 – 1.97 (m, 1H), 1.59 – 1.49 (m, 1H), 1.25 – 1.15 (m, 1H), 0.91 (d, J = 6.9 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.34, 167.06, 76.33, 64.45, 36.65, 24.37, 20.84, 14.80, 11.29 ppm. HRMS (m / z): [M+Na]+calcd for C9H17NO4Na+226.1055, found 226.1055.TSRI 2216.1PC

[0227] The title compound was prepared according to general procedure A from 5,5- dimethylhexanoic acid. Purification by flash column chromatography afforded A5 (305 mg, 88%, 2.0 mmol scale) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ = 10.07 (br s, 1H), 3.70 (s, 3H), 2.05 (t, J = 7.7 Hz, 2H), 1.62 – 1.52 (m, 2H), 1.18 – 1.11 (m, 2H), 0.82 (s, 9H) ppm. 13C NMR (126 MHz, CDCl3): δ = 171.31, 64.03, 43.66, 33.84, 30.33, 29.30, 20.83 ppm. HRMS (m / z): [M+H]+calcd for C9H20NO2+174.1494, found 174.1496.

[0228] The title compound was prepared according to general procedure A from 4-(1- adamantyl)butanoic acid. Purification by flash column chromatography afforded A4 (262 mg, 61%, 1.7 mmol scale) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 8.21 (br s, 1H), 3.76 (s, 3H), 2.02 (br s, 1H), 1.93 (br s, 3H), 1.73 – 1.67 (m, 3H), 1.65 – 1.55 (m, 6H), 1.46 (br s, 6H), 1.10 – 1.01 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.37, 64.44, 44.26, 42.46, 37.28, 34.18, 32.34, 28.78, 18.90 ppm. HRMS (m / z): [M+H]+calcd for C15H26NO2+252.1964, found 252.1966. Me

[0229] The title compound was prepared according to general procedure A from 2- ethylbenzoic acid. All characterization data are consistent with reported data (15). Me OMe

[0230] The title compound was prepared according to general procedure A from 2-ethyl- 3-methoxybenzoic acid. Purification by flash column chromatography afforded A7 (326 mg, 78%, 2.0 mmol scale) as a white powder.TSRI 2216.1PC 1H NMR (400 MHz, CDCl3): δ = 9.46 (br s, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 2.59 (q, J = 7.4 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ = 167.60, 157.59, 133.80, 131.48, 126.54, 119.27, 112.21, 64.00, 55.51z, 20.32, 14.69 ppm. HRMS (m / z): [M+H]+calcd for C11H16NO3+210.1130, found 210.1131.

[0231] The title compound was prepared according to general procedure A from 3-ethyl- 2-thiophencarboxylic acid. Purification by flash column chromatography afforded A8 (334 mg, 90%, 2.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.34 (br s, 1H), 7.32 (d, J = 5.0 Hz, 1H), 6.99 (d, J = 5.0 Hz, 1H), 3.86 (s, 3H), 2.97 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 163.04, 150.62, 130.34, 127.75, 125.43, 64.89, 23.07, 15.05 ppm. HRMS (m / z): [M+H]+ calcd for C8H12NO2S+186.0589, found 186.0590.

[0232] The title compound was prepared according to general procedure A from SA9. Purification by flash column chromatography afforded A9 (228 mg, 59%, 1.8 mmol scale) as a white powder. 1H NMR (500 MHz, CDCl3): δ = 8.63 (s, 1H), 3.73 (s, 3H), 2.23 – 2.15 (m, 2H), 2.10 (s, 3H), 1.73 (td, J = 13.2, 4.1 Hz, 2H), 1.66 – 1.59 (m, 3H), 1.50 (qt, J = 13.2, 3.9 Hz, 2H), 1.28 (ddt, J = 21.0, 12.8, 3.9 Hz, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 171.20, 170.23, 80.99, 64.27, 32.27, 25.10, 21.49, 21.32 ppm. HRMS (m / z): [M+Na]+calcd for C10H17NO4Na+238.1049, found 238.1051.TSRI 2216.1PC

[0233] The title compound was prepared according to general procedure A from SA10. Purification by flash column chromatography afforded A10 (383 mg, 75%, 2.0 mmol scale) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 8.20 (br s, 1H), 3.76 (s, 3H), 3.63 (s, 3H), 1.86 (br s, 2H), 1.83 – 1.74 (m, 6H), 1.67 – 1.63 (m, 1H), 1.59 – 1.54 (m, 5H) ppm. 13C NMR (151 MHz, CDCl3): δ = 178.34, 169.01, 64.71, 51.82, 44.55, 38.73, 31.10, 30.73, 28.49, 27.86 ppm. HRMS (m / z): [M+H]+calcd for C13H22NO4+256.1549, found 256,1551.

[0234] The title compound was prepared according to general procedure A from bicyclo[2.2.1]heptane-2-carboxylic acid. Purification by flash column chromatography afforded A9 (274 mg, 81%, endo / exo > 9:1, 2.0 mmol scale) as a white powder. 1H NMR (400 MHz, (CD3)2SO): δ = 10.88 – 10.74 (m, 1H), 3.49 (s, 2.73H), 3.48 (s, 0.27H), 2.47 – 2.41 (m, 1H) 2.41 – 2.31 (m, 1H), 2.31 – 2.24 (m, 1H), 2.15 – 2.07 (m, 1H), 1.49 – 1.31 (m, 3H), 1.31 – 1.14 (m, 3H), 1.15 – 1.05 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 174.25, 172.57, 64.14, 44.14, 43.69, 43.65, 41.77, 41.29, 40.67, 37.00, 36.56, 35.90, 34.11, 31.13, 29.87, 29.13, 28.57, 24.24 ppm. HRMS (m / z): [M+H]+calcd for C9H16NO2+170.1181, found 170.1178.A12

[0235] The title compound was prepared according to general procedure A from 5,6,7,8- Tetrahydro-1-naphthalenecarboxylic acid. All characterization data are consistent with reported data (16).TSRI 2216.1PC

[0236] The title compound was prepared according to general procedure A from SA13. Purification by flash column chromatography afforded A13 (216 mg, 82%, 1.1 mmol scale) as a pale yellow oil. 1H NMR (600 MHz, CD3OD): δ = 7.23 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 3.77 (s, 1H), 2.80 (t, J = 6.2 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H), 1.84 – 1.77 (m, 4H) ppm. 13C NMR (151 MHz, CD3OD): δ = 168.94, 139.06, 137.91, 137.01, 133.36, 127.36, 126.70, 64.46, 28.65, 28.18, 23.51, 23.31 ppm. HRMS (m / z): [M+H]+calcd for C12H15ClNO2+240.0791, found 2400793.

[0237] The title compound was prepared according to general procedure A from SA14. Purification by flash column chromatography afforded A14 (406 mg, 84%, 1.7 mmol scale) as a pale yellow powder. 1H NMR (400 MHz, CDCl3): δ = 8.29 (br s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 3.89 (s, 3H), 2.88 (t, J = 6.2 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 1.87 – 1.69 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.43, 138.58, 138.00, 132.18, 129.72, 128.77, 125.43, 64.83, 30.88, 27.47, 22.83, 22.38 ppm. HRMS (m / z): [M+H]+calcd for C12H15BrNO2+284.0286, found 284.0298.TSRI 2216.1PC

[0238] The title compound was prepared according to general procedure A from SA15. Purification by flash column chromatography afforded A15 (233 mg, 88%, 0.8 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.42 (br s, 1H), 7.59 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 3.89 (s, 3H), 2.92 – 2.86 (m, 2H), 2.81 – 2.76 (m, 2H), 1.80 – 1.73 (m, 4H), 1.33 (s, 12H) ppm. 13C NMR (151 MHz, CDCl3): δ = 168.18, 139.63, 138.30, 138.04, 132.40, 130.41, 84.12, 64.84, 29.76, 26.91, 24.95, 24.71, 22.87, 22.71 ppm. HRMS (m / z): [M+H]+calcd for C18H27BNO4+331.2069, found 331.2067.

[0239] The title compound was prepared according to general procedure A from SA16. Purification by flash column chromatography afforded A16 (263 mg, 85%, 1.4 mmol scale) as a light brown powder. 1H NMR (600 MHz, (CD3)2CO): δ = 10.33 (br s, 1H), 8.30 (s, 1H), 6.63 (d, J = 2.7 Hz, 1H), 6.61 (d, J = 2.7 Hz, 1H), 3.79 (s, 3H), 2.77 – 2.61 (m, 4H), 1.76 – 1.67 (m, 4H) ppm. 13C NMR (151 MHz, (CD3)2CO): δ = 167.59, 155.40, 139.86, 135.83, 126.53, 117.89, 113.12, 64.01, 30.50, 26.39, 23.93, 23.54 ppm. HMRS (m / z): [M+H]+calcd for C12H16NO3+222.1130, found 222.1131.

[0240] The title compound was prepared according to general procedure A from SA17. Purification by flash column chromatography afforded A17 (225 mg, 89%, 1.1 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.68 (br s, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 3.89 (s, 3H), 2.93 – 2.86 (m, 2H), 2.83 – 2.76 (m, 2H), 1.83 – 1.75 (m, 4H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3) δ =165.97, 142.06, 140.33, 134.88, 134.10, 127.77, 118.35, 109.29, 64.95, 29.68, 26.95, 22.28, 22.07 ppm. HRMS (m / z): [M+H]+calcd for C13H15N2O2+231.1134, found 231.1136.

[0241] The title compound was prepared according to general procedure A from SA18. Purification by flash column chromatography afforded A18 (596 mg, 90%, 2.0 mmol scale) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 8.85 (br s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 3.84 (s, 3H), 2.77 – 2.67 (m, 4H), 1.79 – 1.66 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 166.33, 141.03, 140.21, 135.65, 134.79, 133.05, 89.82, 64.73, 29.56, 26.28, 22.59, 22.34 ppm. HRMS (m / z): [M+H]+calcd forC12H15INO2+332.0147, found 332.0144.

[0242] The title compound was prepared according to general procedure A from SA19. Purification by flash column chromatography afforded A19 (376 mg, 81%, 1.6 mmol scale) as a pale yellow powder. 1H NMR (600 MHz, CD3OD): δ = 7.42 (d, J = 2.6 Hz, 1H), 7.34 (d, J = 2.7 Hz, 1H), 4.51 – 4.46 (m, 2H), 4.11 – 4.06 (m, 2H), 3.82 (s, 3H), 2.85 – 2.75 (m, 4H), 1.84 – 1.76 (m, 4H) ppm. 13C NMR (151 MHz, CD3OD): δ = 169.23, 157.79, 140.38, 137.17, 134.98, 122.06, 116.47, 64.48, 63.28, 46.56, 30.96, 27.02, 24.00, 23.78 ppm. HRMS (m / z): [M+H]+calcd for C15H19N2O4+291.1345, found 291.1343.TSRI 2216.1PC

[0243] The title compound was prepared according to general procedure A from SA20. Purification by flash column chromatography afforded A20 (216 mg, 85%, 1.1 mmol scale) as a pale yellow powder. 1H NMR (600 MHz, CDCl3): δ = 8.39 (br s, 1H), 7.19 – 7.14 (m, 2H), 6.61 (dd, J = 17.6, 10.9 Hz, 1H), 5.70 (d, J = 17.6 Hz, 1H), 5.23 (d, J = 10.9 Hz, 1H), 3.89 (s, 3H), 2.84 (t, J = 6.3 Hz, 2H), 2.77 (t, J = 6.3 Hz, 2H), 1.81 – 1.73 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.93, 138.42, 135.35, 134.55, 133.07, 129.10, 122.40, 113.90, 64.47, 29.87, 26.38, 22.86, 22.64 ppm. HRMS (m / z): [M+H]+calcd for C14H18NO2+232.1338, found 232.1336. O

[0244] The title compound was prepared according to general procedure A from SA21. Purification by flash column chromatography afforded A21 (269 mg, 89%, 0.9 mmol scale) as a pale yellow powder. 1H NMR (400 MHz, CDCl3): δ = 8.48 (br s, 1H), 7.43 (d, J = 9.0 Hz, 2H), 7.29 (s, 1H), 7.27 (s, 1H), 6.87 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 2.85 (d, J = 6.5 Hz, 2H), 2.77 (d, J = 6.4 Hz, 2H), 1.86 – 1.73 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.46, 159.85, 138.93, 136.15, 134.37, 133.18, 128.92, 127.38, 120.73, 115.25, 114.18, 89.70, 87.30, 64.90, 55.46, 29.78, 26.64, 22.81, 22.56 ppm. HMRS (m / z): [M+H]+calcd for C21H22NO3+336.1600, found 336.1597.TSRI 2216.1PC

[0245] The title compound was prepared according to general procedure A from SA22. Purification by flash column chromatography afforded A22 (309 mg, 82%, 1.3 mmol scale) as a light brown powder. 1H NMR (400 MHz, CDCl3) δ = 8.49 (br s, 1H), 6.70 (d, J = 2.9 Hz, 1H), 6.68 (d, J = 3.0 Hz, 1H), 3.86 (s, 3H), 3.85 – 3.77 (m, 4H), 3.12 – 3.04 (m, 4H), 2.74 (d, J = 9.4 Hz, 4H), 1.79 – 1.69 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3) δ = 168.31, 148.80, 139.35, 133.66, 127.13, 118.54, 112.84, 66.93, 64.79, 49.63, 30.38, 25.93, 23.20, 22.89 ppm. HRMS (m / z): [M+H]+calcd for C16H23N2O3+291.1709, found 291.1705.

[0246] The title compound was prepared according to general procedure A from SA23. Purification by flash column chromatography afforded A23 (273 mg, 85%, 1.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 9.64 (br s, 1H), 8.27 – 8.22 (m, 1H), 7.96 (ddd, J = 7.8, 3.3, 1.7 Hz, 1H), 7.48 (d, J = 12.7 Hz, 1H), 7.41 – 7.36 (m, 2H), 7.11 (dt, J = 7.8, 4.8 Hz, 1H), 6.59 (dd, J = 6.3, 3.2 Hz, 1H), 3.88 (s, 3H), 2.91 (d, J = 5.9 Hz, 2H), 2.85 – 2.69 (m, 2H), 1.90 – 1.67 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.15, 147.20, 143.20, 139.98, 135.31, 134.73, 133.86, 129.67, 128.20, 126.80, 121.83, 121.02, 116.82, 101.84, 64.65, 30.15, 26.39, 22.88, 22.56 ppm. HRMS (m / z): [M+H]+calcd for C19H20N3O2+322.1556, found 322.1555.A24

[0247] The title compound was prepared according to general procedure A from SA24. Purification by flash column chromatography afforded A24 (524 mg, 89%, 1.8 mmol scale) as a white powder.TSRI 2216.1PC 1H NMR (400 MHz, CDCl3): δ = 8.33 (br s, 1H), 7.27 – 7.19 (m, 2H), 7.13 – 7.08 (m, 3H), 7.04 (d, J = 2.0 Hz, 1H), 3.84 (s, 3H), 2.86 – 2.77 (m, 2H), 2.74 – 2.66 (m, 2H), 2.33 (s, 3H), 1.81 – 1.70 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3) δ =167.42, 139.73, 137.72, 134.76, 133.76, 133.43, 131.83, 131.78, 131.41, 130.25, 126.36, 64.87, 29.87, 26.36, 22.84, 22.55, 21.25 ppm. HRMS (m / z): [M+H]+calcd for C19H22NO2S+328.1371, found 328.1367.

[0248] The title compound was prepared according to general procedure A from SA25. Purification by flash column chromatography afforded A25 (392 mg, 86%, 1.4 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.24 (br s, 1H), 6.79 (d, J = 3.7 Hz, 2H), 6.74 (s, 1H), 6.58 (s, 2H), 3.87 (s, 3H), 2.84 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.28 (s, 6H), 1.82 – 1.74 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.59, 157.19, 154.71, 140.57, 139.83, 133.93, 130.58, 125.30, 121.73, 116.53, 115.44, 64.93, 30.14, 26.19, 23.04, 22.62, 21.46 ppm. HRMS (m / z): [M+H]+calcd for C20H24NO3+326.1756, found 326.1758.

[0249] The title compound was prepared according to general procedure A from SA26. Purification by flash column chromatography afforded A26 (297 mg, 80%, 2.0 mmol scale) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 8.12 (br s, 1H), 5.44 (br s, 1H), 3.90 (hept, J = 6.9 Hz, 1H), 3.77 (s, 3H), 2.52 (hept, J = 6.7 Hz, 1H), 1.06 (d, J = 6.9 Hz, 12H) ppm. 13C NMR (151 MHz, CDCl3): δ = 172.87, 166.85, 110.88, 64.70, 30.37, 28.90, 24.46, 20.67 ppm.TSRI 2216.1PC HRMS (m / z): [M+H]+calcd for C10H20NO2+186.1494, found 186.1494. MeMeA27

[0250] The title compound was prepared according to general procedure A from (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxylic acid. Purification by flash column chromatography afforded A27 (779 mg, 55%, 6.6 mmol scale) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 8.45 (br s, 1H), 3.76 (s, 3H), 1.95 – 1.81 (m, 1H), 1.80 – 1.65 (m, 4H), 1.64 – 1.53 (m, 1H), 1.41 – 1.18 (m, 2H), 1.09 – 0.82 (m, 8H), 0.77 (d, J = 6.9 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 173.73, 64.50, 45.95, 43.93, 39.05, 34.55, 32.42, 28.72, 24.03, 22.40, 21.45, 16.21 ppm. HRMS (m / z): [M+H]+calcd for C12H24NO2+214.1807, found 214.1808.

[0251] The title compound was prepared according to general procedure A from SA28. Purification by flash column chromatography afforded A28 (285 mg, 70%, 2.0 mmol scale) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 10.36 (br s, 1H), 4.96 (dd, J = 9.6, 4.2 Hz, 1H), 3.58 (s, 3H), 1.97 (s, 3H), 1.69 – 1.62 (m, 1H), 1.61 – 1.44 (m, 2H), 0.79 (d, J = 6.6 Hz, 3H), 0.77 (d, J = 6.6 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.29, 167.95, 70.84, 63.73, 40.38, 24.21, 22.82, 21.44, 20.51 ppm. HRMS (m / z): [M+Na]+calcd for C9H17NO4Na+226.1066, found 226.1060. iPrTSRI 2216.1PC

[0252] The title compound was prepared according to general procedure A from 2- isopropylbenzoic acid. All characterization data are consistent with reported data (15). iPr

[0253] The title compound was prepared according to general procedure B from 2,4,6- triisopropylbenzoyl chloride. Purification by flash column chromatography afforded A30 (458 mg, 33%, 5.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.22 (br s, 1H), 7.00 (s, 2H), 3.92 (s, 3H), 3.01 (hept, J = 6.9 Hz, 2H), 2.88 (hept, J = 6.9 Hz, 1H), 1.25 (d, J = 6.8 Hz, 12H), 1.23 (d, J = 7.1 Hz, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 168.34, 151.04, 146.30, 129.08, 121.21, 64.64, 34.59, 31.60, 31.08, 24.78, 24.51, 24.06 ppm. HRMS (m / z): [M+H]+calcd for C17H28NO2+278.2120, found 278.2124.

[0254] The title compound was prepared according to general procedure A from 2,3- dihydro-1H-indene-2-propanoic acid. Purification by flash column chromatography afforded A31 (373 mg, 85%, 2.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 9.51 (br s, 1H), 7.22 – 7.14 (m, 2H), 7.13 – 7.09 (m, 2H), 3.75 (s, 3H), 3.08 – 3.01 (m, 2H), 2.64 – 2.57 (m, 2H), 2.51 – 2.40 (m, 1H), 2.25 – 2.14 (m, 2H), 1.90 – 1.84 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.11, 143.08, 126.26, 124.45, 64.27, 39.76, 39.03, 32.06, 31.24 ppm. HRMS (m / z): [M+H]+calcd for C13H18NO2+220.1338, found 220.1339.TSRI 2216.1PC

[0255] The title compound was prepared according to general procedure A from 2- cyclohexylbenzoic acid. All characterization data are consistent with reported data (15).

[0256] The title compound was prepared according to general procedure A from 3- cyclopentylpropanoic acid. Purification by flash column chromatography afforded A33 (308 mg, 90%, 2.0 mmol scale) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 10.12 (br s, 1H), 3.69 (s, 3H), 2.15 – 2.00 (m, 2H), 1.80 – 1.65 (m, 3H), 1.64 – 1.57 (m, 2H), 1.56 – 1.49 (m, 2H), 1.48 – 1.39 (m, 2H), 1.10 – 0.99 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.45, 63.94, 39.78, 32.43, 31.73, 30.47, 25.14 ppm. HRMS (m / z): [M+H]+calcd for C9H18NO2+172.1338, found 172.1337.

[0257] The title compound was prepared according to general procedure A from 3- cyclohexylpropanoic acid. Purification by flash column chromatography afforded A34 (1.59 g, 86%, 10 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 10.42 (br s, 1H), 3.66 (s, 3H), 2.12 – 2.03 (m, 2H), 1.65 – 1.52 (m, 5H), 1.49 – 1.42 (m, 2H), 1.21 – 1.00 (m, 4H), 0.86 – 0.76 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.63, 63.78, 37.34, 32.97, 32.89, 30.60, 26.47, 26.18 ppm. HRMS (m / z): [M+H]+calcd for C10H20NO2+186.1494, found 186.1494.

[0258] The title compound was prepared according to general procedure A from SA35. Purification by flash column chromatography afforded A35 (240 mg, 80%, 1.5 mmol scale) as a colorless oil.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 8.18 (br s, 1H), 3.76 (s, 3H), 2.52 – 1.98 (m, 2H), 1.70 – 1.52 (m, 8H), 1.52 – 1.35 (m, 5H), 1.23 – 1.10 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.36, 64.46, 60.55, 39.00, 34.35, 33.51, 31.43, 28.57, 26.45, 21.17, 14.30 ppm. HRMS (m / z): [M+H]+calcd for C11H22NO2+200.1651, found 200.1653.

[0259] The title compound was prepared according to general procedure A from SA36. Purification by flash column chromatography afforded A36 (495 mg, 86%, 2.7 mmol scale) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 8.40 (br s, 1H), 3.75 (s, 3H), 2.19 – 1.98 (m, 2H), 1.68 – 1.35 (m, 15H), 1.33 – 1.19 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3): δ = 171.56, 64.64, 37.09, 33.55, 32.20, 31.60, 27.33, 26.40, 25.53 ppm. HRMS (m / z): [M+H]+calcd for C12H24NO2+214.1807, found 214.1807.

[0260] The title compound was prepared according to general procedure A from SA37. Purification by flash column chromatography afforded A37 (300 mg, 80%, 1.4 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.14 (br s, 1H), 3.75 (s, 3H), 1.99 (br, 1H), 1.76 – 1.67 (m, 5H), 1.67 – 1.56 (m, 7H), 1.44 – 1.35 (m, 2H), 1.27 – 1.15 (m, 4H), 1.11 (tt, J = 12.7, 3.5 Hz, 2H), 1.04 (qd, J = 12.5, 3.5 Hz, 2H), 0.94 (qd, J = 12.4, 3.6 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3): δ = 172.15, 63.98, 44.88, 39.58, 32.34, 31.75, 29.72, 26.99, 26.83, 26.74 ppm. HRMS (m / z): [M+H]+calcd for C16H30NO2+268.2277, found 268.2280.TSRI 2216.1PC

[0261] The title compound was prepared according to general procedure A from SA38. Purification by flash column chromatography afforded A38 (386 mg, 95%, 1.5 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.03 (br s, 1H), 3.76 (s, 3H), 2.12 – 2.04 (m, 1H), 1.61 – 1.57 (m, 1H), 1.56 – 1.54 (m, 1H), 1.47 – 1.15 (m, 24H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.56, 64.69, 33.94, 31.53, 30.50, 28.92, 24.89, 24.27, 23.46, 23.39, 21.74 ppm. HRMS (m / z): [M+H]+calcd for C16H32NO2+270.2428, found 270.2427. NHOMe O NPhth A39

[0262] The title compound was prepared according to general procedure B from SA39. Purification by flash column chromatography afforded A39 (345 mg, 42%, 3.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 9.25 (br s, 1H), 7.89 – 7.84 (m, 2H), 7.77 – 7.73 (m, 2H), 5.02 – 4.72 (m, 2H), 3.75 (s, 5H), 2.33 – 2.17 (m, 2H), 2.11 – 2.02 (m, 2H), 1.30 (q, J = 7.5 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 168.26, 167.37, 134.64, 131.61, 123.86, 64.64, 53.63, 30.97, 19.60, 13.49 ppm. HRMS (m / z): [M+H]+calcd for C14H17N2O4+277.1188, found 277.1193.PhthN O A40

[0263] The title compound was prepared according to general procedure A from SA40. Purification by flash column chromatography afforded A40 (720 mg, 93%, 2.8 mmol scale) as a white powder.TSRI 2216.1PC 1H NMR (400 MHz, CD3OD): δ = 7.91 – 7.77 (m, 4H), 4.66 – 4.51 (m, 1H), 3.56 (s, 3H), 2.88 (dd, J = 14.4, 9.7 Hz, 1H), 2.63 (dd, J = 14.4, 5.5 Hz, 1H), 2.18 – 2.02 (m, 1H), 1.92 – 1.74 (m, 1H), 0.96 – 0.87 (m, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 168.56, 168.00, 134.02, 131.69, 123.21, 123.19, 63.98, 50.13, 35.53, 25.58, 10.83 ppm. HRMS (m / z): [M+H]+calcd for C14H17N2O4+277.1188, found 277.1185. O Me Me

[0264] The title compound was prepared according to general procedure A from SA41. Purification by flash column chromatography afforded A41 (510 mg, 80%, 2.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3) δ = 9.93 (br s, 1H), 7.72 – 7.65 (m, 2H), 7.64 – 7.57 (m, 2H), 3.66 – 3.52 (m, 4H), 3.49 (dd, J = 13.9, 8.2 Hz, 1H), 2.38 – 2.27 (m, 1H), 2.09 – 1.92 (m, 2H), 1.70 – 1.61 (m, 1H), 1.97 (dd, J = 14.6, 6.4 Hz, 1H), 1.15 – 1.07 (m, 2H), 0.82 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 169.37, 168.73, 133.97, 131.70, 123.09, 63.82, 41.65, 41.19, 36.17, 33.04, 25.06, 22.63, 22.36 ppm. HRMS (m / z): [M+H]+calcd for C17H23N2O4+319.1652, found 319.1656.

[0265] The title compound was prepared according to general procedure A from SA42. Purification by flash column chromatography afforded A42 (761 mg, 90%, 2.5 mmol scale) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 9.27 (br s, 1H), 7.84 – 7.76 (m, 2H), 7.74 – 7.69 (m, 2H), 7.15 (t, J = 7.6 Hz, 2H), 7.09 (d, J = 7.3 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H), 4.94 – 4.75 (m, 1H), 3.72 (s, 3H), 2.74 – 2.55 (m, 1H), 2.48 – 2.39 (m, 1H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 168.07, 166.97, 139.82, 134.43, 131.44, 128.46, 128.32, 126.13, 123.65, 64.54, 53.54, 32.75, 29.99 ppm. HRMS (m / z): [M+H]+calcd for C19H19N2O4+339.1340, found 339.1348. O

[0266] The title compound was prepared according to general procedure B from SA43. Purification by flash column chromatography afforded A43 (332 mg, 54%, 2.1 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 9.55 (br s, 1H), 7.85 – 7.78 (m, 2H), 7.76 – 7.69 (m, 2H), 4.84 – 4.66 (m, 1H), 3.71 (s, 3H), 2.29 – 2.12 (m, 1H), 2.11 – 2.01 (m, 1H), 1.37 – 1.14 (m, 4H), 0.82 (t, J = 7.3 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ = 168.16, 167.22, 134.50, 131.60, 123.72, 64.44, 53.49, 28.51, 28.37, 22.09.13.89 ppm. HRMS (m / z): [M+H]+calcd for C15H19N2O4+291.1340, found 291.1332.

[0267] The title compound was prepared according to general procedure A from SA44. Purification by flash column chromatography afforded A44 (181 mg, 60%, 1.0 mmol scale) as a white powder. 1H NMR (500 MHz, CDCl3): δ = 8.79 (s, 1H), 7.82 – 7.76 (m, 2H), 7.73 – 7.67 (m, 2H), 3.73 (s, 3H), 2.97 – 2.89 (m, 2H), 2.03 – 1.94 (m, 2H), 1.75 – 1.66 (m, 2H), 1.58 – 1.42 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.93, 169.35, 134.35, 131.81, 123.25, 77.36, 65.38, 64.30, 32.25, 25.07, 22.71 ppm. HRMS (m / z): [M+Na]+calcd for C16H18N2O4Na+325.1164, found 325.1161.TSRI 2216.1PC PhthN NHOMe O A45

[0268] The title compound was prepared according to general procedure A from SA45. Purification by flash column chromatography afforded A45 (868 mg, 86%, 3.5 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 9.40 (br s, 1H), 7.68 – 7.61 (m, 2H), 7.68 – 7.61 (m, 2H), 3.62 (s, 3H), 2.48 – 2.35 (m, 4H), 1.76 – 1.66 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.25, 168.75, 134.17, 131.72, 123.23, 123.14, 69.73, 63.97, 63.96, 35.43, 23.62 ppm. HRMS (m / z): [M+Na]+calcd for C15H16N2O4Na+310.1008, found 310.1001.CONHOMe NPhth A46

[0269] The title compound was prepared according to general procedure A from SA46. Purification by flash column chromatography afforded A46 (702 mg, 85%, 2.5 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 10.38 (s, 1H), 7.86 – 7.83 (m, 4H), 7.77 – 7.73 (m, 4H), 3.82 (s, 3H), 3.67 (s, 2H), 2.18 (s, 2H), 1.65 – 1.48 (m, 7H), 1.41 – 1.34 (m, 2H), 1.33 – 1.26 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.11, 168.34, 134.58, 131.74, 123.67, 64.42, 47.08, 38.39, 34.19, 25.83, 21.52 ppm. HRMS (m / z): [M+H]+calcd for C18H23N2O4+331.1658, found 331.1659.A47

[0270] The title compound was prepared according to general procedure A from SA47. Purification by flash column chromatography afforded A47 (470 mg, 90%, 1.8 mmol scale) as a white powder.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 8.39 (br s, 1H), 7.82 – 7.78 (m, 2H), 7.72 – 7.66 (m, 2H), 4.39 (ddd, J = 11.3, 9.4, 4.2 Hz, 2H), 3.53 (s, 3H), 3.05 – 2.94 (m, 1H), 2.70 – 2.66 (m, 1H), 2.44 – 2.24 (m, 1H), 1.03 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 168.82, 168.36, 134.19, 131.74, 123.44, 64.37, 54.76, 33.80, 31.14, 20.09, 19.91 ppm. HRMS (m / z): [M+H]+calcd for C15H19N2O4+291.1340, found 291.1329. NHOMeO Me NPhth A48

[0271] The title compound was prepared according to general procedure B from N- Phthaloyl-leucine. Purification by flash column chromatography afforded A48 (460 mg, 79%, 2.0 mmol scale) as a white powder. 1H NMR (500 MHz, CDCl3): δ = 9.77 (br s, 1H), 7.82 – 7.76 (m, 2H), 7.72 – 7.66 (m, 2H), 4.82 (br s, 1H), 3.67 (s, 3H), 2.35 – 2.17 (m, 1H), 1.83 – 1.71 (m, 1H), 1.38 (br s, 1H), 0.95 – 0.73 (m, 6H) ppm. 13C NMR (126 MHz, CDCl3): δ = 168.09, 167.33, 134.39, 131.58, 123.58, 64.24, 51.48, 37.21, 25.04, 23.07, 21.15 ppm. HRMS (m / z): [M+H]+calcd for C15H19N2O4+291.1345, found 291.1341. O

[0272] The title compound was prepared according to general procedure A from SA49. Purification by flash column chromatography afforded A49 (803 mg, 90%, 2.7 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 9.72 (br s, 1H), 7.74 – 7.66 (m, 2H), 7.74 – 7.66 (m, 2H), 4.85 (s, 1H), 3.67 (s, 3H), 2.32 – 2.13 (m, 1H), 1.92 – 1.70 (m, 2H), 1.65 – 1.45 (m, 4H), 1.11 – 1.01 (m, 4H), 0.95 – 0.76 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 168.10, 167.41, 134.38, 131.57, 123.61, 64.24, 50.81, 35.95, 34.31, 33.55, 31.83, 26.29, 26.06, 25.84 ppm.TSRI 2216.1PC HRMS (m / z): [M+H]+calcd for C18H23N2O4+331.1658, found 331.1659.

[0273] The title compound was prepared according to general procedure A from SA50. Purification by flash column chromatography afforded A50 (360 mg, 78%, 1.1 mmol scale) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 9.40 (br s, 1H), 7.95 – 7.80 (m, 2H), 7.81 – 7.67 (m, 2H), 6.78 (s, 1H), 5.38 – 5.06 (m, 1H), 4.38 (d, J = 16.1 Hz, 1H), 4.31 (d, J = 16.1 Hz, 1H), 3.92 – 3.60 (m, 4H), 3.51 (br, 1H), 2.78 – 2.48 (m, 2H), 1.79 (q, J = 9.1 Hz, 1H), 1.73 – 1.61 (m, 2H), 0.95 (d, J = 6.2 Hz, 3H), 0.92 (d, J = 5.9 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.65, 168.13, 167.99, 166.86, 134.42, 132.14, 123.77, 71.95, 64.40, 40.90, 40.72, 35.62, 34.51, 24.61, 23.17, 21.85 ppm. HRMS (m / z): [M+H]+calcd for C20H26N3O7+4201771, found 420.1764.

[0274] The title compound was prepared according to general procedure A from stearic acid. Purification by flash column chromatography afforded A51 (564 mg, 90%, 2.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.63 (br s, 1H), 3.75 (s, 3H), 2.57 – 1.92 (m, 2H), 1.63 (p, J = 7.6 Hz, 2H), 1.37 – 1.19 (m, 29H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ = 171.24, 64.53, 33.42, 32.05, 29.82, 29.81, 29.78, 29.74, 29.61, 29.49, 29.44, 29.36, 25.51, 22.82, 14.24 ppm. HRMS (m / z): [M+H]+calcd for C19H40NO2+314.3059, found 314.3066.TSRI 2216.1PC

[0275] The title compound was prepared according to general procedure A from valproic acid. Purification by flash column chromatography afforded A52 (312 mg, 90%, 2.0 mmol scale) as a white powder.

[0276] The title compound was prepared according to general procedure A from SA53. Purification by flash column chromatography afforded A53 (362 mg, 64%, 2.2 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 9.38 (br s, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 2.77 (dd, J = 10.2, 8.4 Hz, 1H), 2.16 – 2.04 (m, 2H), 1.98 – 1.88 (m, 2H), 1.82 – 1.74 (m, 1H), 1.70 – 1.62 (m, 1H), 0.99 (s, 3H), 0.96 (s, 3H), 0.70 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 175.56, 170.14, 64.19, 52.77, 51.53, 47.59, 46.87, 39.92, 35.93, 23.25, 22.79, 21.43, 20.34 ppm. HRMS (m / z): [M+H]+cald for C13H24NO4+258.1705, found 258.1700.

[0277] The title compound was prepared according to general procedure A from SA54. Purification by flash column chromatography afforded A54 (288 mg, 88%, 1.1 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.10 (br s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.66 (dd, J = 7.6, 2.0 Hz, 1H), 6.62 (s, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.76 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H), 1.99 (s, 2H), 1.83 – 1.75 (m, 2H), 1.55 – 1.49 (m, 2H), 1.06 (s, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 169.56, 157.10, 136.64, 130.44, 123.71, 120.87, 112.26, 68.47, 64.60, 44.92, 38.71, 33.42, 27.40, 24.54, 21.54, 15.93 ppm. HRMS (m / z): [M+H]+calcd for C17H28NO3+294.2069, found 294.2066.TSRI 2216.1PC Me

[0278] The title compound was prepared according to general procedure A from SA55 (4). Purification by flash column chromatography afforded A55 (376 mg, 91%, 1.5 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.50 (br s, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 3.89 (s, 3H), 3.06 (t, J = 7.2 Hz, 2H), 1.94 (t, J = 7.2 Hz, 2H), 1.32 (s, 9H), 1.25 (s, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.97, 154.25, 150.48, 139.11, 128.20, 122.34, 122.29, 64.80, 43.97, 41.55, 34.91, 31.60, 29.68, 28.74 ppm. HRMS (m / z): [M+H]+calcd for C17H26NO2+276.1964, found 276.1968.

[0279] The title compound was prepared according to general procedure A from SA56 (5). Purification by flash column chromatography afforded A56 (942 mg, 44%, 6.7 mmol scale) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 9.74 (br s, 1H), 6.64 (s, 1H), 3.71 (s, 3H), 2.76 – 2.58 (m, 2H), 2.52 – 2.39 (m, 1H), 2.33 – 2.22 (m, 4H), 2.13 (s, 3H), 2.06 – 1.95 (m, 2H), 1.94 – 1.82 (m, 4H), 1.35 – 1.22 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 173.64, 169.99, 146.55, 135.89, 134.55, 132.76, 125.31, 120.17, 63.95, 42.15, 36.65, 32.01, 26.55, 25.46, 20.84, 19.40, 14.88, 11.65 ppm. HRMS (m / z): [M+H]+calcd for C18H26NO4+320.1862, found 320.1863. MeTSRI 2216.1PC

[0280] The title compound was prepared according to general procedure A isolongifolic acid. Purification by flash column chromatography afforded A57 (203 mg, 85%, 0.90 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.93 (br s, 1H), 3.76 (s, 3H), 2.52 (br s, 1H), 2.34 – 2.31 (m, 1H), 2.27 (br s, 1H), 2.03 (d, J = 4.0 Hz, 1H), 1.77 – 1.66 (m, 2H), 1.59 – 1.50 (m, 4H), 1.48 – 1.45 (m, 1H), 1.41 – 1.29 (m, 3H), 1.02 (s, 3H), 1.01 (s, 3H), 0.95 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 172.42, 64.63, 62.59, 50.80, 45.70, 43.88, 42.20, 42.07, 39.89, 33.36, 32.91, 29.57, 25.70, 25.50, 22.58, 21.62 ppm. HRMS (m / z): [M+H]+calcd for C16H28NO2+266.2120, found 266.2125. Me Me

[0281] The title compound was prepared according to general procedure B from dehydroabietic acid. Purification by flash column chromatography afforded A58 (2.00 g, 70%, 8.7 mmol scale) as a white powder. 1H NMR (500 MHz, CDCl3): δ = 8.52 (br s, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.99 (dd, J = 8.1, 2.3 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 3.75 (s, 3H), 2.96 – 2.85 (m, 2H), 2.84 – 2.76 (m, 1H), 2.30 (dt, J = 12.9, 3.8 Hz, 1H), 2.18 (dd, J = 12.6, 2.3 Hz, 1H), 1.89 – 1.67 (m, 4H), 1.63 – 1.47 (m, 3H), 1.25 (s, 3H), 1.23 – 1.20 (m, 9H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.57, 146.86, 145.91, 134.68, 126.99, 124.16, 124.05, 64.28, 46.80, 45.27, 37.94, 37.16, 37.05, 33.58, 30.02, 25.40, 24.10, 21.24, 18.56, 15.91 ppm. HRMS (m / z): [M+H]+calcd for C21H32NO2+330.2433, found 330.2441. Me MeTSRI 2216.1PC

[0282] The title compound was prepared according to general procedure A (24 h) from abietic acid. Purification by flash column chromatography afforded A59 (525 mg, 80%, 2.0 mmol scale) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 8.53 (br s, 1H), 5.74 (s, 1H), 5.32 (d, J = 4.8 Hz, 1H), 3.72 (s, 3H), 2.20 (p, J = 6.8 Hz, 1H), 2.11 – 1.90 (m, 5H), 2.89 – 1.72 (m, 4H), 1.62 – 1.50 (m, 3H), 1.27 – 1.10 (m, 5H), 1.00 (d, J = 3.3 Hz, 3H), 0.98 (d, J = 3.3 Hz, 3H), 0.81 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ =176.41, 145.44, 135.70, 122.46, 120.31, 64.25, 50.97, 45.91, 45.52, 38.22, 37.35, 34.99, 34.75, 27.51, 25.38, 22.55, 21.53, 20.97, 18.07, 16.36, 14.32 ppm. HRMS (m / z): [M+H]+calcd for C21H34NO2+332.2590, found 332.2589.

[0283] The title compound was prepared according to general procedure A from SA60. Purification by flash column chromatography afforded A60 (207 mg, 49%, 1.2 mmol scale) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 9.32 (br s, 1H), 3.70 (s, 3H), 2.26 (d, J = 14.2 Hz, 1H), 2.19 (d, J = 14.3 Hz, 1H), 1.79 – 1.72 (m, 1H), 1.67 – 1.60 (m, 2H), 1.59 – 1.32 (m, 6H), 1.29 (d, J = 8.5 Hz, 2H), 1.26 – 1.20 (m, 7H), 1.14 – 1.07 (m, 2H), 0.87 (d, J = 11.7 Hz, 1H), 0.82 – 0.76 (m, 4H), 0.74 (s, 3H), 0.71 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 169.84, 76.45, 72.24, 64.25, 58.14, 56.51, 50.38, 43.18, 42.04, 39.01, 36.91, 33.29, 27.13, 24.64, 21.26, 19.82, 18.51, 15.79, 15.14 ppm. HRMS (m / z): [M+H]+calcd for C21H38NO3+352.2852, found 352.2839. MeA61TSRI 2216.1PC

[0284] The title compound was prepared according to general procedure B from SA61. Purification by flash column chromatography afforded A61 (416 mg, 75%, 1.2 mmol scale, d.r.5.6:1) as a white powder. 1H NMR (500 MHz, CDCl3): δ = 9.22 (s, 1H), 3.72 (s, 3H), 2.70 – 2.54 (m, 2H), 2.46 – 2.38 (m, 1H), 2.01 – 1.04 (m, 25H), 1.00 (s, 3H), 0.88 (d, J = 6.7 Hz, 3H), 0.86 – 0.82 (m, 6H), 0.65 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ = 172.01, 170.57, 87.07, 64.23, 56.14, 55.42, 45.79, 42.88, 39.80, 39.64, 39.59, 36.23, 35.89, 34.53, 31.74, 28.44, 28.31, 28.09, 27.51, 26.28, 24.13, 23.97, 22.92, 21.72, 18.74, 14.79, 12.19 ppm. HMRS (m / z): [M+H]+calcd for C28H48NO4+462.3583, found 462,3583.

[0285] The title compound was prepared from betulinic acid according to a published method with minor alteration (20). Et3N and DMAP were added in the second step, and the reaction time was extended to 48 h. Purification by flash column chromatography afforded A62 (359 mg, 37%, 2.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.36 (br s, 1H), 4.73 (d, J = 2.5 Hz, 1H), 4.59 (dt, J = 2.8, 1.4 Hz, 1H), 3.76 (s, 3H), 3.17 (dd, J = 11.5, 4.8 Hz, 1H), 3.13 – 3.08 (m, 1H), 2.41 (ddd, J = 13.1, 11.6, 3.7 Hz, 1H), 2.05 – 1.95 (m, 1H), 1.92 – 1.85 (m, 1H), 1.76 (dd, J = 12.0, 7.6 Hz, 1H), 1.71 – 1.68 (m, 1H), 1.65 (t, J = 3.6 Hz, 1H), 1.62 – 1.48 (m, 7H), 1.45 – 1.33 (m, 6H), 1.30 – 1.21 (m, 2H), 1.19 – 1.15 (m, 1H), 1.07 – 0.85 (m, 12H), 0.81 (s, 3H), 0.75 (s, 3H), 0.70 – 0.63 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 150.71, 109.71, 79.13, 64.29, 55.52, 54.72, 50.73, 50.67, 46.86, 42.54, 40.94, 39.00, 38.87, 38.23, 37.94, 37.34, 34.51, 33.22, 30.92, 29.83, 29.57, 28.12, 27.55, 25.72, 21.02, 19.60, 18.43, 16.27, 16.25, 15.49, 14.84 ppm. HRMS (m / z): [M+H]+calcd for C31H52NO3+486.3942, found 486.3939.TSRI 2216.1PC

[0286] The title compound was prepared according to general procedure A from 18β- glycyrrhetinic acid. Purification by flash column chromatography afforded A63 (769 mg, 77%, 2.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.47 (s, 1H), 5.68 (s, 1H), 3.76 (s, 3iH), 3.22 (dd, J = 11.0, 5.3 Hz, 1H), 2.79 (dt, J = 13.5, 3.7 Hz, 1H), 2.23 – 2.16 (m, 1H), 2.06 – 1.98 (m, 1H), 1.92 (dd, J = 13.7, 3.4 Hz, 1H), 1.84 (td, J = 13.5, 4.6 Hz, 1H), 1.78 – 1.73 (m, 1H), 1.72 (d, J = 13.2 Hz, 1H), 1.69 – 1.56 (m, 5H), 1.50 – 1.38 (m, 5H), 1.37 – 1.32 (m, 4H), 1.21 – 1.17 (m, 1H), 1.16 (s, 3H), 1.13 (s, 3H), 1.12 (s, 3H), 1.07 – 0.91 (m, 5H), 0.83 (s, 3H), 0.80 (s, 3H), 0.69 (dd, J = 11.8, 1.9 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 200.28, 174.01, 169.01, 128.78, 78.95, 64.50, 62.00, 55.12, 48.18, 45.52, 43.34, 42.96, 41.58, 39.33, 39.29, 37.48, 37.25, 32.92, 32.00, 31.44, 29.57, 28.59, 28.25, 27.45, 26.59, 26.54, 23.52, 18.83, 17.63, 16.51, 15.71 ppm. HRMS (m / z): [M+H]+calcd for C31H50NO4+500.3740, found 500.3740.

[0287] The title compound was prepared according to general procedure B from SA64 (double-bond migration took place). Purification by flash column chromatography afforded A64 (462 mg, 35%, 2.4 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.61 (s, 1H), 5.32 (s, 1H), 4.48 (dd, J = 11.0, 5.5 Hz, 1H), 3.76 (s, 3H), 2.76 – 2.71 (m, 1H), 2.21 – 2.17 (m, 1H), 2.09 – 2.02 (m, 1H), 2.04 (s, 3H), 1.90 – 1.80 (m, 2H), 1.74 (s, 1H), 1.72 (s, 3H), 1.68 – 1.63 (m, 2H), 1.59 – 1.46 (m, 3H), 1.43 – 1.34 (m, 3H), 1.33 – 1.11 (m, 6H), 1.04 – 0.99 (m, 2H), 0.93 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.83 (s, 6H), 0.83 (s, 3H), 0.72 (s, 3H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 176.23, 171.20, 135.73, 123.45, 81.04, 64.32, 54.91, 52.56, 47.13, 43.60, 41.20, 39.32, 38.09, 37.95, 37.79, 36.61, 34.90, 34.52, 33.69, 33.45, 30.97, 30.44, 27.88, 26.98, 23.66, 23.54, 23.01, 21.44, 21.03, 18.87, 18.38, 17.08, 16.82, 16.26 ppm. HRMS (m / z): [M+H]+calcd for C34H56NO4+542.4209, found 542.4208.

[0288] The title compound was prepared according to general procedure A from 11- deoxoglycyrrhetinic acid. Purification by flash column chromatography afforded A65 (345 mg, 71%, 1.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.38 (s, 1H), 5.29 (t, J = 3.7 Hz, 1H), 3.77 (s, 3H), 3.22 (dd, J = 11.4, 4.8 Hz, 1H), 2.00 – 1.82 (m, 5H), 1.81 – 1.71 (m, 2H), 1.70 – 1.60 (m, 4H), 1.59 – 1.48 (m, 4H), 1.44 – 1.31 (m, 6H), 1.14 (s, 3H), 1.13 (s, 3H), 1.01 – 0.86 (m, 4H), 0.96 (s, 3H), 0.94 (s, 3H), 0.89 (ddt, J = 13.2, 4.4, 2.3 Hz, 1H), 0.80 (s, 3H), 0.79 (s, 3H), 0.73 (dd, J = 11.8, 2.0 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 174.71, 144.37, 123.04, 79.17, 64.44, 55.35, 48.19, 47.80, 43.27, 43.23, 41.67, 39.94, 38.93, 38.80, 38.07, 37.08, 32.80, 32.15, 31.47, 29.89, 28.26, 28.22, 27.38, 27.01, 26.24, 26.09, 23.66, 18.49, 16.92, 15.72, 15.65 ppm. HRMS (m / z): [M+H]+calcd for C31H52NO3+486.3947, found 486.3952.

[0289] The title compound was prepared according to general procedure A from spiro[2.5]octane-6-carboxylic acid. Purification by flash column chromatography afforded A66 (270 mg, 92%, 1.6 mmol scale) as a white powder.TSRI 2216.1PC 1H NMR (400 MHz, CDCl3): δ = 8.57 (s, 1H), 3.76 (s, 3H), 2.11 – 1.95 (m, 1H), 1.83 – 1.61 (m, 6H), 0.99 – 0.87 (m, 2H), 0.31 – 0.26 (m, 2H), 0.25 – 0.17 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 174.09, 64.48, 42.29, 34.70, 28.48, 18.31, 12.48, 11.95 ppm. HRMS (m / z): [M+H]+calcd for C10H18NO2+184.1338, found 184.1337. Me Cl

[0290] The title compound was prepared according to general procedure B from 4- chloropentanoyl chloride and 5-phenyl-1-pentanol. Purification by flash column chromatography afforded A67 (509 mg, 90%, 2.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.30 – 7.26 (m, 2H), 7.20 – 7.16 (m, 3H), 4.12 – 4.04 (m, 3H), 2.65 – 2.60 (m, 2H), 2.58 – 2.44 (m, 2H), 2.12 – 2.05 (m, 1H), 1.98 – 1.89 (m, 1H), 1.69 – 1.63 (m, 4H), 1.53 (d, J = 6.6 Hz, 3H), 1.45 – 1.36 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 173.11, 142.50, 128.52, 128.43, 125.86, 64.71, 57.88, 35.90, 35.25, 31.48, 31.16, 28.60, 25.66, 25.47 ppm. HRMS (m / z): [M+H]+calcd for C16H24ClO2+283.1459, found 283.1459. OMe

[0291] The title compound was prepared according to general procedure A from 3- methoxy-2-methylbenzoic acid. Purification by flash column chromatography afforded A68 (532 mg, 91%, 3.0 mmol scale) as a light brown powder. 1H NMR (400 MHz, CDCl3): δ = 8.37 (br s, 1H), 7.20 – 7.12 (m, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 3.5 Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3) δ = 167.82, 158.20, 134.22, 126.78, 125.69, 119.16, 112.20, 64.81, 55.79, 12.61 ppm. HRMS (m / z): [M+H]+calcd for C10H14NO3+196.0974, found 196.0973.TSRI 2216.1PC Me I

[0292] The title compound was prepared according to general procedure A from 3-iodo- 2-methylbenzoic acid. Purification by flash column chromatography afforded A69 (271 mg, 93%, 1.0 mmol scale) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 8.36 (br s, 1H), 7.92 (dd, J = 7.9, 1.4 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 6.90 (t, J = 7.9 Hz, 1H), 3.91 (s, 3H), 2.51 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.26, 141.57, 139.66, 133.99, 127.42, 127.20, 103.57, 64.90, 25.58 ppm. HRMS (m / z): [M+H]+calcd for C9H11INO2+291.9834, found 291.9832. Me NHTs

[0293] The title compound was prepared according to general procedure A from SA70. Purification by flash column chromatography afforded A70 (602 mg, 90%, 2.0 mmol scale) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 8.85 (br s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.31 – 7.26 (m, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.11 – 7.03 (m, 2H), 6.87 (s, 1H), 3.81 (s, 3H), 2.38 (s, 3H), 2.04 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.25, 144.28, 136.64, 135.72, 134.51, 130.52, 129.92, 127.22, 126.65, 126.36, 125.17, 64.67, 21.68, 14.28 ppm. HRMS (m / z): [M+H]+calcd for C16H19N2O4S+335.1066, found 335.1058.

[0294] The title compound was prepared according to general procedure A from 4- cyclopropyl-2-methylbenzoic acid. Purification by flash column chromatography afforded A71 (361 mg, 88%, 2.0 mmol scale) as a white powder.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 8.52 (br s, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 2.2 Hz, 1H), 6.84 (dd, J = 7.8, 2.1 Hz, 1H), 3.84 (s, 3H), 2.39 (s, 3H), 1.85 (tt, J = 8.3, 5.0 Hz, 1H), 1.02 – 0.94 (m, 2H), 0.72 – 0.66 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 168.19, 147.22, 137.16, 129.55, 128.52, 127.37, 122.76, 64.65, 19.82, 15.38, 9.78 ppm. HRMS (m / z): [M+H]+calcd for C12H16NO2+206.1181, found 206.1181. OMe

[0295] The title compound was prepared according to general procedure A from 4- Methyl 2-methyl-1,4-benzenedicarboxylate. Purification by flash column chromatography afforded A72 (390 mg, 87%, 2.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.47 (br s, 1H), 7.90 (s, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 3.98 – 3.84 (m, 6H), 2.48 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.11, 166.54, 137.42, 136.86, 132.15, 131.94, 127.32, 127.03, 64.88, 52.50, 19.53 ppm. HRMS (m / z): [M+H]+calcd for C11H14NO4+224.0923, found 224.0926.

[0296] The title compound was prepared according to general procedure A from SA73. Purification by flash column chromatography afforded A73 (794 mg, 77%, 4.5 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.50 (br s, 1H), 8.09 – 8.04 (m, 1H), 8.02 – 7.95 (m, 1H), 7.61 – 7.54 (m, 2H), 7.20 (s, 1H), 3.94 (s, 3H), 2.69 (s, 3H), 2.63 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 168.74, 133.34, 133.07, 132.75, 131.41, 129.84, 126.87, 126.48, 125.40, 124.77, 124.47, 64.85, 19.37, 15.74 ppm. HRMS (m / z): [M+H]+calcd for C14H16NO2+230.1181, found 230.1182.TSRI 2216.1PC OMe OMe

[0297] The title compound was prepared according to general procedure A from SA74 (8). Purification by flash column chromatography afforded A74 (560 mg, 90%, 2.2 mmol scale) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 8.85 (br s, 1H), 6.37 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.72 (s, 3H), 2.57 (t, J = 8.0 Hz, 2H), 2.12 – 2.03 (m, 2H), 1.98 – 1.90 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.82, 153.16, 137.24, 136.19, 105.42, 64.40, 60.90, 56.12, 35.54, 32.34, 26.85 ppm. HRMS (m / z): [M+H]+calcd for C14H22NO5+284.1498, found 284.1486.

[0298] The title compound was prepared according to general procedure A from 2-ethyl- 3-pyridinecarboxylic acid. Purification by flash column chromatography afforded A75 (106 mg, 29%, 2.0 mmol scale) as a pale yellow powder. 1H NMR (600 MHz, CDCl3): δ = 9.78 (br s, 1H), 8.45 (d, J = 5.3 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.08 (dd, J = 7.7, 5.0 Hz, 1H), 3.82 (s, 3H), 2.83 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ = 166.50, 161.77, 150.67, 135.43, 128.25, 120.71, 64.54, 29.04, 14.09 ppm. HRMS (m / z): [M+H]+calcd for C9H13N2O2+181.0977, found 181.0978.

[0299] The title compound was prepared according to general procedure A from 2- pyridinebutanoic acid. Purification by flash column chromatography afforded A76 (512 mg, 87%, 3.0 mmol scale) as a pale yellow foam.TSRI 2216.1PC 1H NMR (400 MHz, CDCl3): δ = 10.24 (br s, 1H), 8.50 (dd, J = 5.0, 2.9 Hz, 1H), 7.63 (td, J = 7.7, 1.9 Hz, 1H), 7.21 – 7.11 (m, 2H), 3.79 (s, 3H), 2.85 (t, J = 7.0 Hz, 2H), 2.30 – 1.84 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.86, 161.00, 148.58, 136.92, 123.22, 121.39, 64.00, 36.47, 32.08, 25.75 ppm. HRMS (m / z): [M+H]+calcd for C10H15N2O2+195.1134, found 195.1133.

[0300] The title compound was prepared according to general procedure A from SA77. Purification by flash column chromatography afforded A77 (615 mg, 80%, 2.5 mmol scale) as a white powder. 1H NMR (500 MHz, CDCl3): δ = 10.69 (br s, 1H), 7.28 – 7.22 (m, 2H), 7.19 – 7.10 (m, 3H), 4.22 – 4.10 (m, 2H), 3.81 (s, 3H), 2.63 – 2.55 (m, 1H), 2.42 – 2.30 (m, 2H), 2.12 – 1.99 (m, 2H), 1.83 – 1.70 (m, 1H), 1.35 – 1.21 (m, 4H), 1.18 – 1.05 (m, 1H), 0.88 (t, J = 7.3 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3); δ = 174.92, 168.84, 141.08, 128.48, 126.17, 64.27, 61.73, 58.19, 40.40, 39.52, 31.85, 18.66, 14.17, 14.15 ppm. HRMS (m / z): [M+H]+calcd for C17H26NO4+308.1862, found 308.1863.

[0301] The title compound was prepared according to general procedure A from 4-(4- bromophenyl)butanoic acid. Purification by flash column chromatography afforded A78 (490 mg, 90%, 2.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.26 (br s, 1H), 7.42 – 7.37 (m, 2H), 7.05 (d, J = 8.3 Hz, 2H), 3.75 (s, 3H), 2.65 – 2.59 (m, 2H), 2.18 – 2.00 (m, 2H), 1.99 – 1.92 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.65, 140.27, 131.61, 130.37, 119.93, 64.70, 34.55, 32.26, 26.55 ppm.TSRI 2216.1PC HRMS (m / z): [M+H]+calcd for C11H15BrNO2+272.0286, found 272.0286.

[0302] The title compound was prepared according to general procedure A from 4-(4- netrophenyl)butanoic acid. Purification by flash column chromatography afforded A79 (405 mg, 85%, 2.0 mmol scale) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 9.10 (br s, 1H), 8.10 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 3.73 (s, 3H), 2.75 (t, J = 7.6 Hz, 2H), 2.20 – 1.92 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.32, 149.40, 146.50, 129.38, 123.75¸64.45, 34.97, 32.07, 26.30 ppm. HRMS (m / z): [M+H]+calcd for C11H15N2O4+239.1032, found 239.1031.

[0303] The title compound was prepared according to general procedure A from 4-(4- methylphenyl)butanoic acid. Purification by flash column chromatography afforded A80 (361 mg, 87%, 2.0 mmol scale) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ = 8.94 (br s, 1H), 7.14 – 6.96 (m, 4H), 3.73 (s, 3H), 2.61 (t, J = 7.6 Hz, 2H), 2.31 (s, 3H), 2.08 (br, 2H), 2.01 – 1.91 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.94, 138.26, 135.54, 129.17, 128.43, 64.40, 34.74, 32.48, 26.95, 21.07 ppm. HRMS (m / z): [M+H]+calcd for C12H18NO2+208.1138, found 208.1137.

[0304] The title compound was prepared according to general procedure A from SA81. Purification by flash column chromatography afforded A81 (378 mg, 80%, 2.3 mmol scale) as colorless oil.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 8.29 (br s, 1H), 7.28 (t, J = 7.6 Hz, 2H), 7.22 – 7.16 (m, 3H), 5.53 (s, 1H), 5.29 (s, 1H), 3.78 (s, 3H), 2.80 (t, J = 7.8 Hz, 2H), 2.64 (t, J = 7.8 Hz, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.54, 142.41, 141.03, 128.62, 128.56, 126.27, 119.23, 64.64, 34.40, 34.12 ppm. HRMS (m / z): [M+H]+calcd for C12H16NO2+206.1181, found 206.1180.

[0305] The title compound was prepared according to general procedure A from SA82 (9). Purification by flash column chromatography afforded A82 (253 mg, 92%, 1.0 mmol scale) as a light brown powder. 1H NMR (400 MHz, CDCl3): δ = 9.98 (br s, 1H), 7.40 – 7.19 (m, 6H), 5.46 (s, 2H), 3.73 (s, 3H), 2.71 (t, J = 7.2 Hz, 2H), 2.23 – 2.08 (m, 2H), 2.02 – 1.88 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.80, 147.62, 134.73, 129.20, 128.82, 128.12, 121.35, 64.30, 54.21, 32.08, 25.42, 24.22 ppm. HRMS (m / z): [M+H]+calcd for C14H19N4O2+275.1508, found 275.1506.

[0306] The title compound was prepared according to general procedure A from SA83. Purification by flash column chromatography afforded A83 (339 mg, 91%, 1.7 mmol scale) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 8.58 (br s, 1H), 7.39 (d, J = 7.4 Hz, 2H), 7.35 – 7.29 (m, 2H), 7.28 – 7.23 (m, 1H), 5.30 (s, 1H), 5.07 (s, 1H), 3.73 (s, 3H), 2.66 – 2.48 (m, 2H), 2.18 – 2.00 (m, 2H), 1.85 – 1.77 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.34, 147.03, 140.30, 131.63, 131.57, 127.92, 127.06, 125.65, 112.61, 63.96, 34.06, 31.87, 23.26 ppm. HRMS (m / z): [M+H]+calcd for C13H18NO2+220.1338, found 220.1341.TSRI 2216.1PC

[0307] The title compound was prepared according to general procedure B from 4- phenylbutanoic acid. Purification by flash column chromatography afforded A84 (1.00 g, 97%, 5.0 mmol scale) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 8.81 (br s, 1H), 7.29 – 7.22 (m, 3H), 7.21 – 7.12 (m, 2H), 3.73 (s, 3H), 2.62 (t, J = 7.4 Hz, 2H), 2.25 – 2.00 (m, 2H), 1.74 – 1.62 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.04, 142.18, 128.48, 128.43, 125.90, 64.46, 35.70, 33.15, 31.05, 25.09 ppm. HRMS (m / z): [M+H]+calcd for C12H18NO2+208.1332, found 208.1329. O NHOMe A85

[0308] The title compound was prepared according to general procedure A from 2- adamantylacetic acid. Purification by flash column chromatography afforded A85 (375 mg, 84%, 2.0 mmol scale) as a white powder. 1H NMR (500 MHz, CDCl3): δ = 8.86 (br s, 1H), 3.75 (s, 3H), 1.95 (br, 3H), 1.84 (br, 2H), 1.73 – 1.53 (m, 12H) ppm. 13C NMR (126 MHz, CDCl3): δ = 169.04, 64.45, 47.72, 42.63, 36.80, 32.92, 28.71 ppm. HRMS (m / z): [M+H]+calcd for C13H22NO2+224.1651, found 224.1649.

[0309] The title compound was prepared according to general procedure A from SA86. Purification by flash column chromatography afforded A86 (332 mg, 69%, 1.6 mmol scale) as a white powder.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 9.60 (br s, 1H), 1.78 – 1.68 (m, 2H), 1.78 – 1.68 (m, 2H), 4.52 (d, J = 11.6 Hz, 1H), 3.76 (s, 3H), 3.08 – 2.91 (m, 1H), 2.01 – 1.88 (m, 1H), 1.78 – 1.68 (m, 2H), 1.67 – 1.57 (m, 2H), 1.56 – 1.40 (m, 2H), 1.17 – 1.03 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 168.46, 166.84, 134.69, 131.46, 123.90, 64.55, 59.53, 39.15, 30.46, 30.23, 25.50, 24.84 ppm. HRMS (m / z): [M+H]+calcd for C16H19N2O4+303.1340, found 303.1349. O

[0310] The title compound was prepared according to general procedure A from 6- phenyl-5-hexynoic acid. Purification by flash column chromatography afforded A87 (554 mg, 91%, 2.8 mmol scale) as pale yellow oil. 1H NMR (600 MHz, CDCl3): δ = 8.85 (br s, 1H), 7.41 – 7.35 (m, 2H), 7.31 – 7.25 (m, 3H), 3.75 (s, 3H), 2.48 (t, J = 7.1 Hz, 2H), 2.27 (br, 2H), 2.00 – 1.87 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.58, 131.62, 128.35, 127.86, 123.73, 88.87, 81.71, 64.51, 31.98, 24.24, 18.92 ppm. HRMS (m / z): [M+H]+calcd for C13H16NO2+218.1181, found 218.1183.

[0311] The title compound was prepared according to general procedure A from 6- phenyl-5-hexynoic acid. Purification by flash column chromatography afforded A88 (347 mg, 87%, 2.2 mmol scale) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 8.47 (br s, 1H), 5.88 – 5.74 (m, 1H), 5.29 (dq, J = 17.0, 1.9 Hz, 1H), 5.09 (dq, J = 10.0, 1.7 Hz, 1H), 3.75 (s, 3H), 2.97 – 2.89 (m, 2H), 2.37 – 2.10 (m, 4H), 1.91 – 1.78 (m, 2H) ppm.13C NMR (126 MHz, CDCl3): δ = 170.71, 133.23, 115.76, 81.45, 77.77, 64.28, 31.96, 24.58, 23.12, 18.32 ppm. HRMS (m / z): [M+H]+calcd for C10H16NO2+182.1181, found 182.1182.TSRI 2216.1PCA89

[0312] The title compound was prepared according to general procedure A from SA89. Purification by flash column chromatography afforded A89 (414 mg, 96%, 1.2 mmol scale) as a light brown foam. 1H NMR (600 MHz, CDCl3): δ = 8.23 (br s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 2.5 Hz, 1H), 7.12 (d, J = 8.9 Hz, 1H), 7.00 (dd, J = 8.9, 2.6 Hz, 1H), 5.51 (d, J = 1.8 Hz, 1H), 5.04 (d, J = 1.9 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.66 (s, 3H), 2.49 – 2.37 (m, 2H), 1.78 – 1.59 (m, 2H), 1.14 (s, 3H), 1.12 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 175.47, 158.25, 153.72, 145.16, 134.23, 129.63, 128.47, 125.23, 124.81, 116.37, 116.07, 110.90, 103.53, 64.34, 56.66, 55.41, 41.42, 38.96, 32.57, 25.29, 25.19 ppm. HRMS (m / z): [M+H]+calcd for C21H28NO4+358.2018, found 358.2011.

[0313] The title compound was prepared according to general procedure A from SA90. Purification by flash column chromatography afforded A90 (210 mg, 44%, 1.7 mmol scale) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ = 8.10 (br s, 1H), 4.74 (s, 1H), 4.71 (s, 1H), 3.76 (s, 3H), 2.13 – 2.04 (m, 3H), 1.99 (t, J = 7.9 Hz, 2H), 1.85 – 1,75 (m, 2H), 1.44 – 1.35 (m, 2H), 1.33 – 1.19 (m, 15H), 0.92 – 0.84 (m, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.09, 149.01, 109.77, 64.76, 35.90, 35.40, 32.71, 32.06, 29.79, 29.77, 29.70, 29.57, 29.49, 27.90, 23.20, 22.83, 14.27 ppm. HRMS (m / z): [M+H]+calcd for C17H34NO2+284.2590, found 284.2589.TSRI 2216.1PC

[0314] The title compound was prepared according to general procedure A from γ- methylbenzenebutanoic acid. Purification by flash column chromatography afforded C91 (945 mg, 93%, 4.9 mmol scale) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.86 (br s, 1H), 7.34 – 7.27 (m, 2H), 7.24 – 7.14 (m, 3H), 3.72 (s, 3H), 2.80 – 2.62 (m, 1H), 2.52 – 1.62 (m, 4H), 1.27 (d, J = 7.0 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.02, 146.25, 128.66, 127.17, 126.40, 64.57, 39.62, 33.37, 31.45, 22.60 ppm. HRMS (m / z): [M+H]+calcd for C12H18NO2+208.1338, found 208.1341.

[0315] The title compound was prepared according to general procedure A from 4- methylnonanoic acid. Purification by flash column chromatography afforded A92 (537 mg, 89%, 3.0 mmol scale) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 8.52 (br s, 1H), 3.75 (s, 3H), 2.51 – 1.92 (m, 2H), 1.74 – 1.60 (m, 1H), 1.52 – 1.37 (m, 2H), 1.35 – 1.17 (m, 7H), 1.17 – 0.98 (m, 1H), 0.92 – 0.82 (m, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.49, 64.57, 36.78, 32.67, 32.47, 32.26, 31.16, 26.73, 22.80, 19.44, 14.22 ppm. HRMS (m / z): [M+H]+calcd for C11H24NO2+202.1807, found 202.1811. Me

[0316] The title compound was prepared according to general procedure A from SA93 (10). Purification by flash column chromatography afforded A93 (300 mg, 82%, 0.94 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 10.14 (br s, 1H) 7.65 (t, J = 5.4 Hz, 1H), 7.54 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.33 – 7.29 (m, 2H), 4.48 – 4.41 (m, 1H), 4.25 (dd, J = 16.7, 5.7 Hz, 1H), 4.12 (dd, J = 16.9, 5.2 Hz, 1H), 3.81 (d, J = 6.9 Hz, 1H), 3.70 (s, 3H), 1.86 (s, 1H), 1.70 – 1.55 (m, 3H), 0.92 (d, J = 6.3 Hz, 3H), 0.90 (d, J = 6.0 Hz, 3H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 169.46, 169.17, 166.02, 135.76, 133.25, 131.59, 131.53, 129.98, 129.38, 64.30, 49.64, 43.69, 40.81, 24.81, 22.83, 22.20, 19.11. ppm. HRMS (m / z): [M+H]+calcd for C16H22Cl2N3O4+390.0982, found 390.0969. O

[0317] The title compound was prepared according to general procedure A from SA94. Purification by flash column chromatography afforded A94 (516 mg, 78%, 3.1 mmol scale) as colorless oil. 1H NMR (600 MHz, CDCl3): δ = 8.14 (br s, 1H), 5.11 – 5.05 (m, 1H), 3.76 (s, 3H), 2.59 – 1.85 (m, 4H), 1.72 – 1.64 (m, 4H), 1.60 (s, 3H), 1.52 – 1.42 (m, 2H), 1.38 – 1.28 (m, 1H), 1.21 – 1.12 (m, 1H), 0.89 (d, J = 6.5 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.56, 131.51, 124.72, 64.61, 36.86, 32.40, 32.29, 31.17, 25.84, 25.55, 19.32, 17.79 ppm. HRMS (m / z): [M+H]+calcd for C12H24NO2+214.1807, found 214.1806. Me

[0318] The title compound was prepared according to general procedure A from SA95 (11). Purification by flash column chromatography afforded A95 (547 mg, 89%, 3.0 mmol scale) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 9.19 (br s, 1H), 3.75 (s, 3H), 2.63 (d, J = 17.5 Hz, 1H), 2.35 – 2.20 (m, 2H), 2.19 (s, 3H), 1.99 – 1.90 (m, 1H), 1.09 (s, 3H), 0.98 – 0.89 (m, 5H) ppm. 13C NMR (151 MHz, CDCl3) δ 210.16, 170.34, 64.33, 39.06, 30.10, 29.88, 28.50, 21.90, 21.73, 17.15, 15.21 ppm. HRMS (m / z): [M+H]+calcd for C11H20NO3+214.1443, found 214.1446.TSRI 2216.1PC

[0319] The title compound was prepared according to general procedure A from SA96. Purification by flash column chromatography afforded A96 (152 mg, 88%, 0.44 mmol scale) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 8.27 (br s, 1H), 5.14 (s, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 2.68 – 2.53 (m, 2H), 2.43 (s, 3H), 2.22 (s, 3H), 2.12 – 1.97 (m, 1H), 1.75 – 1.60 (m, 2H), 1.58 – 1.28 (m, 4H), 0.98 (d, J = 6.4 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.09, 169.67, 168.55, 162.96, 146.25, 145.75, 130.57, 123.06, 113.44, 68.53, 64.47, 61.41, 36.50, 32.23, 32.01, 30.80, 21.96, 20.70, 19.44, 11.99 ppm. HRMS (m / z): [M+H]+calcd for C20H28NO7+394.1866, found 394.1862. iPr

[0320] The title compound was prepared according to general procedure A from SA97. Purification by flash column chromatography afforded A97 (866 mg, 90%, 2.8 mmol scale) as a white powder. 1H NMR (500 MHz, CDCl3): δ = 9.37 (br s, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 3.71 (s, 3H), 2.98 – 2.76 (m, 3H), 2.26 (d, J = 12.6 Hz, 1H), 2.19 (d, J = 13.6 Hz, 1H), 1.94 (d, J = 13.6 Hz, 1H), 1.83 (d, J = 15.0 Hz, 1H), 1.79 – 1.57 (m, 4H), 1.56 – 1.46 (m, 2H), 1.41 – 1.31 (m, 1H), 1.22 (d, J = 7.2 Hz, 6H), 1.20 (s, 3H), 1.09 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ = 169.71, 147.32, 145.59, 134.65, 126.84, 124.26, 123.91, 64.22, 48.95, 46.94, 38.43, 37.82, 37.18, 33.51, 30.35, 25.45, 24.08, 20.18, 19.47, 18.92 ppm. HRMS (m / z): [M+H]+calcd for C22H34NO2+344.2590, found 344.2593.TSRI 2216.1PC

[0321] The title compound was prepared according to general procedure A from SA98 (13). Purification by flash column chromatography afforded A98 (238 mg, 81%, 1.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.07 (br s, 1H), 4.84 (s, 1H), 4.49 (s, 1H), 3.76 (s, 3H), 2.38 (ddd, J = 12.8, 4.4, 2.5 Hz, 1H), 2.02 – 1.85 (m, 3H), 1.77 (d, J = 12.5 Hz, 1H), 1.72 (dp, J = 13.1, 2.8 Hz, 1H), 1.68 – 1.58 (m, 3H), 1.54 (tt, J = 13.4, 3.4 Hz, 1H), 1.48 (dp, J = 14.1, 3.6 Hz, 1H), 1.40 – 1.36 (m, 1H), 1.32 (qd, J = 13.0, 4.4 Hz, 1H), 1.17 (td, J = 13.4, 4.2 Hz, 1H), 1.11 – 1.03 (m, 2H), 0.86 (s, 3H), 0.79 (s, 3H), 0.68 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.62, 148.34, 106.59, 64.72, 56.21, 55.61, 42.21, 39.91, 39.07, 38.41, 33.74, 33.71, 32.02, 29.84, 24.59, 21.83, 19.46, 14.50 ppm. HRMS (m / z): [M+H]+calcd for C18H32NO2+294.2433, found 294.2433.

[0322] The title compound was prepared according to general procedure A from SA99. Purification by flash column chromatography afforded A99 (253 mg, 81%, 0.80 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.35 (br s, 1H), 5.82 (ddt, J = 17.0, 10.1, 7.0 Hz, 1H), 4.98 (dq, J = 17.2, 1.8 Hz, 1H), 4.94 – 4.88 (m, 1H), 4.68 (tt, J = 11.3, 4.8 Hz, 1H), 3.74 (s, 3H), 2.08 (dt, J = 15.4, 6.3 Hz, 1H), 2.01 (s, 3H), 1.99 – 1.90 (m, 2H), 1.84 – 1.77 (m, 2H), 1.76 – 1.71 (m, 2H), 1.63 – 1.59 (m, 1H), 1.58 – 1.55 (m, 1H), 1.53 – 1.42 (m, 1H), 1.41 – 1.28 (m, 3H), 1.26 – 1.13 (m, 4H), 1.10 (s, 3H), 1.01 (td, J = 13.6, 4.0 Hz, 1H), 0.94 (td, J = 12.3, 4.5 Hz, 1H), 0.91 – 0.81 (m, 2H), 0.79 (s, 3H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 176.72, 170.71, 139.12, 115.11, 73.52, 64.07, 52.95, 46.60, 46.29, 44.04, 38.14, 37.11, 36.57, 35.74, 35.58, 33.80, 31.72, 28.53, 27.33, 21.46, 19.95, 14.65, 12.15 ppm. HRMS (m / z): [M+H]+calcd for C23H38NO4+392.2801, found 392.2800.

[0323] The title compound was prepared according to general procedure A from SA100. Purification by flash column chromatography afforded A100 (738 mg, 73%, 2.0 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.33 (br s, 1H), 5.07 (t, J = 2.8 Hz, 1H), 4.69 (tt, J = 11.3, 4.7 Hz, 1H), 3.74 (s, 3H), 2.09 (s, 3H), 2.02 (s, 3H), 1.96 – 1.74 (m, 5H), 1.73 – 1.50 (m, 9H), 1.50 – 1.15 (m, 9H), 1.15 – 1.04 (m, 2H), 1.00 (td, J = 14.3, 3.4 Hz, 1H), 0.89 (s, 3H), 0.85 – 0.76 (m, 3H), 0.71 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3) δ 173.75, 170.74, 170.64, 76.05, 74.34, 64.60, 49.55, 47.88, 45.17, 41.94, 35.79, 34.98, 34.84, 34.52, 34.16, 32.38, 31.03, 27.49, 27.00, 26.76, 25.98, 25.78, 23.55, 23.19, 21.60, 21.52, 17.72, 17.65, 12.56 ppm. HRMS (m / z): [M+Na]+calcd for C29H47NO6Na+528.3301, found 528.3382.

[0324] The title compound was prepared according to general procedure A from SA101. Purification by flash column chromatography afforded A101 (326 mg, 79%, 1.2 mmol scale) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 8.00 (br s, 1H), 7.19 (dd, J = 8.7, 1.2 Hz, 1H), 6.71 (dd, J = 8.5, 2.9 Hz, 1H), 6.63 (d, J = 2.7 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 2.93 – 2.77 (m, 2H), 2.35 – 2.30 (m, 1H), 2.29 – 2.19 (m, 2H), 2.14 – 1.99 (m, 2H), 1.93 – 1.87 (m, 1H), 1.86 – 1.76 (m, 2H), 1.57 – 1.49 (m, 1H), 1.47 – 1.25 (m, 5H), 0.77 (s, 3H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 170.56, 157.06, 137.46, 131.84, 125.78, 113.35, 111.08, 64.21, 54.83, 54.76, 53.58, 43.88, 43.31, 38.31, 38.10, 29.35, 27.29, 26.07, 23.73, 22.88, 12.82 ppm. HRMS (m / z): [M+H]+calcd for C21H30NO3+344.2226, found 344.2230. Dehydrogenation / Lactonization of N-Methoxyamides and Characterization Data of Products General Procedures for the Copper-Catalyzed Dehydrogenation of N- Methoxyamides Method A (10 mol%), NL

[0325] A reaction tube (16 mL) with a magnetic stir bar was charged with N- methoxyamide A (0.1 mmol), CuF2(1.0 mg, 0.01 mmol), and 8-methoxyquinoline L (3.2 mg, 0.02 mmol). Dioxane (0.5 mL) and AcOH (45 μL, 47.2 mg, 0.78 mmol) were added to the tube and the tube was sealed with a screw cap. The reaction mixture was heated at 125 °C until complete consumption of the substrate (2-20 hours) was observed (by TLC). Then the reaction was cooled to room temperature, the solvents were removed under reduced pressure and the residue was purified by flash column chromatography or preparative TLC to afford the desired product B. Method B (10 mol%), CuF2R O acid (0.5-8 equiv.), O H NHOMe H solvent (0.2 M),NH2A125 °C, 1-20 hB

[0326] A reaction tube (16 mL) with a magnetic stir bar was charged with N- methoxyamide A (0.1 mmol), CuF2(1.0 mg, 0.01 mmol). Dioxane or DCE (0.5 mL) and the acidic additive (0.5-8 equiv.) were added to the tube and the tube was sealed with a screw cap. The reaction mixture was heated at 125 °C until complete consumption of the substrateTSRI 2216.1PC (2-20 hours) was observed (by TLC). Then the reaction was cooled to room temperature, the solvents were removed under reduced pressure and the residue was purified by flash column chromatography or preparative TLC to afford the desired product B. Gram-scale synthesis Me Me

[0327] A flask (100 mL) with a magnetic stir bar was charged with N-methoxyamide A58 (1.65 g, 5.0 mmol), CuF2(50 mg, 0.5 mmol). Dioxane (25 mL) and (±)-camphorsulfonic acid (581 mg, 2.5 mmol) were added to the mixture and the reaction mixture was refluxed at 125 °C for 20 hours under the protection of nitrogen. Then the reaction was cooled to room temperature, the solvents were removed under reduced pressure and the residue was purified by flash column chromatography (hexane / EA 2:1 to hexane / acetone 2:1, gradient elution) to afford B58 (1.07 g, 72%) as a white powder. General Procedures for the Copper-Catalyzed Lactonization of N-Methoxyamides Method C OOC

[0328] A reaction tube (16 mL) with a magnetic stir bar was charged with N- methoxyamide A (0.1 mmol), CuF2 (1.0 mg, 0.01 mmol) or [Cu(MeCN)4]BF4 (3.2 mg, 0.01 mmol). Dioxane or AcOH (0.5 mL) and the acidic additive (0.5-5 equiv.) were added to the tube and the tube was sealed with a screw cap. The reaction mixture was heated at 125 °C until complete consumption of the substrate (1-20 hours) was observed (by TLC). Then the reaction was cooled to room temperature, the solvents were removed under reduced pressure and the residue was purified by flash column chromatography or preparative TLC to afford the desired product C.TSRI 2216.1PC Method D (10 mol%) OOC

[0329] A reaction tube (16 mL) with a magnetic stir bar was charged with N- methoxyamide A (0.1 mmol), [Cu(MeCN)4]BF4(3.2 mg, 0.01 mmol). Dioxane / MeNO2(0.25 mL / 0.25 mL) and (±)-camphorsulfonic acid (0.5 equiv.) were added to the tube and the tube was sealed with a screw cap. The reaction mixture was heated at 125 °C until complete consumption of the substrate (2-20 hours) was observed (by TLC). Then the reaction was cooled to room temperature, the solvents were removed under reduced pressure and the residue was purified by flash column chromatography or preparative TLC to afford the desired product C. General Procedures for the Reactions with Low Catalyst Loading.

[0330] Reactions were conducted following Method B-D in Schlenk tubes under the protection of argon. The reaction mixture was degassed by two successive freeze-pump-thaw operations before heating. Preparation of solutions of copper:

[0331] Solution 1: A mixture of [Cu(MeCN)4]BF4(3.2 mg, 0.010 mmol) and DCE (0.50 mL) was stirred at 22 ˚C for 5 min. (0.02 M)

[0332] Solution 2: A mixture of CuF2(2.0 mg, 0.020 mmol), CSA (23.2 mg, 0.10 mmol) and dioxane (10.0 mL) was heated at 80 ˚C for 30 min. (0.002 M)

[0333] Solution 3: A mixture of CuF2(2.0 mg, 0.020 mmol) and AcOH (10.0 mL) was heated at 80 ˚C for 5 min. (0.002 M)

[0334] Solution 4: A mixture of CuF2(2.0 mg, 0.020 mmol) and TFA (0.80 mL) was heated at 80 ˚C for 5 min. (0.025 M)

[0335] Note: For Solution 1, [Cu(MeCN)4]BF4shows relatively good solubility in DCE. Although we found that DCE could suppress the formation of lactone (Table S8, entry 2 and entry 10), when it was used as a cosolvent with dioxane (<1 / 10, v / v), the yield of lactone did not decrease, as shown by the low catalyst loading experiment that yields C29. Characterization Data of ProductsTSRI 2216.1PC O NH2

[0336] The compound was prepared following the general procedure (Method A, 4 h) and was purified by flash column chromatography (CH2Cl2 / acetone 8:1 to hexane / acetone 2:1, gradient elution) to give B1 (10.2 mg, 80%) as a white foam, along with 8% inseparable reduction product. 1H NMR (600 MHz, CDCl3): δ = 5.92 (dd, J = 17.5, 10.7 Hz, 1H), 5.74 (br s, 1H), 5.53 (br s, 1H), 5.07 – 5.00 (m, 2H), 2.22 (s, 2H), 1.14 (s, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 173.82, 147.33, 112.00, 49.16, 36.23, 27.04 ppm. HRMS (m / z): [M+H]+calcd for C7H14NO+128.1070, found 128.1068. *Note: The reduction by-product may arise by H-abstraction from the solvent, which is a common side reaction in radical chemistry21,22, 12 examples suffered this issue. The yields of the two products were determined by1H NMR integration. O NH2B2

[0337] The compound was prepared following the general procedure (Method A, 4 h) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B2 (6.2 mg, 56%) as a white foam. 1H NMR (400 MHz, CDCl3): δ = 5.94 – 5.79 (m, 1H), 5.83 (s, 1H), 5.75 (br s, 1H), 5.42 (s, 1H), 5.20 – 5.10 (m, 2H), 3.11 – 3.06 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.03, 142.08, 135.30, 121.05, 117.48, 36.63 ppm. HRMS (m / z): [M+H]+calcd for C6H10NO+112.0757, found 112.0758. NH2O OAc

[0338] The compound was prepared following the general procedure (Method B, 8 h, 0.5 mL DCE and 45 μL AcOH) and was purified by flash column chromatography usingTSRI 2216.1PC hexane / acetone (2:1) as eluent to give B3 (11.8 mg, 69%) as a colorless oil, along with 7% inseparable reduction product. 1H NMR (600 MHz, CDCl3): δ = 5.89 (br s, 1H), 5.77 (ddd, J = 17.2, 10.3, 7.8 Hz, 1H), 5.55 (br s, 1H), 5.16 (d, J = 4.5 Hz, 1H), 5.13 (dt, J = 17.2, 1.4 Hz, 1H), 5.10 (ddd, J = 10.3, 1.6, 0.9 Hz, 1H), 2.87 – 2.80 (m, 1H), 2.16 (s, 3H), 1.10 (d, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ = 171.30, 169.81, 137.60, 116.87, 76.95, 40.10, 20.98, 16.21 ppm. HRMS (m / z): [M+H]+calcd for C8H14NO3+172.0974, found 172.0978. NH2

[0339] The compound was prepared following the general procedure (Method B, 2 h, 0.5 mL dioxane and 45 μL AcOH) and was purified by flash column chromatography using hexane / ethyl acetate (1:1) as eluent to give B4 (9.6 mg, 68%) as a white foam, along with 11% inseparable reduction product. 1H NMR (600 MHz, CDCl3): δ = 6.01 (br s, 1H), 5.66 (d, J = 15.5 Hz, 1H), 5.65 (br s, 1H), 5.45 (dt, J = 15.5, 7.1 Hz, 1H), 2.94 (dd, J = 7.1, 1.4 Hz, 2H), 1.01 (s, 9H) ppm. 13C NMR (151 MHz, CDCl3): δ = 174.68, 147.52, 117.46, 40.18, 33.33, 29.57 ppm. HRMS (m / z): [M+H]+calcd for C8H16NO+142.1227, found 142.1227. NH2

[0340] The compound was prepared following the general procedure (Method B, 4 h, 0.5 mL dioxane and 45 μL AcOH) and was purified by pTLC (hexane / acetone 4:1) to give B5 (15.4 mg, 70%) as a white foam, along with 7% inseparable reduction product. 1H NMR (400 MHz, CDCl3): δ = 5.57 (br s, 1H), 5.52 (d, J = 15.8 Hz, 1H), 5.44 – 5.33 (m, 1H), 5.40 (br s, 1H), 2.95 (d, J = 7.0 Hz, 2H), 2.02 – 1.96 (m, 3H), 1.76 – 1.69 (m, 3H), 1.68 – 1.61 (m, 3H), 1.60 – 1.56 (m, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 174.21, 147.95, 117.65, 42.30, 40.36, 36.92, 35.19, 28.49 ppm.TSRI 2216.1PC HRMS (m / z): [M+H]+calcd for C14H22NO+222.1701, found 222.1701. NH2

[0341] The compound was prepared following the general procedure (Method B, 5 h, with 0.5 mL dioxane and 45 μL AcOH) and was purified by pTLC (CH2Cl2 / acetone 3:1) to give B6 (10.4 mg, 71%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.60 – 7.57 (m, 1H), 7.55 (dd, J = 7.6, 1.5 Hz, 1H), 7.46 – 7.40 (m, 1H), 7.32 (td, J = 7.6, 1.3 Hz, 1H), 7.15 (dd, J = 17.5, 10.9 Hz, 1H), 5.99 (br s, 1H), 5.82 (br s, 1H), 5.74 (dd, J = 17.5, 1.2 Hz, 1H), 5.38 (dd, J = 11.0, 1.1 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.33, 136.36, 134.81, 134.18, 130.81, 127.91, 127.78, 126.72, 117.22 ppm. HRMS (m / z): [M+H]+calcd for C9H10NO+148.0762, found 148.0763. OMe

[0342] The compound was prepared following the general procedure (Method B, 4 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by pTLC (CH2Cl2 / acetone 3:1) to give B7 (10.6 mg, 60%) as a white powder. 1H NMR (500 MHz, CDCl3): δ = 7.28 – 7.23 (m, 1H), 7.11 (dd, J = 7.7, 1.2 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.89 (dd, J = 17.9, 11.7 Hz, 1H), 5.90 (br s, 1H), 5.82 (dd, J = 17.9, 1.8 Hz, 1H), 5.78 (br s, 1H), 5.52 (dd, J = 11.7, 1.8 Hz, 1H), 3.86 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.97, 157.71, 136.65, 130.38, 128.51, 124.77, 120.98, 120.04, 112.53, 55.91 ppm. HRMS (m / z): [M+H]+calcd for C10H12NO2+178.0868, found 178.0871. O NH2TSRI 2216.1PC

[0343] The compound was prepared following the general procedure (Method B, 2 h, 0.5 mL DCE and 11.6 mg CSA) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B8 (12.1 mg, 79%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 7.42 – 7.30 (m, 2H), 7.27 – 7.23 (m, 1H), 5.72 (br s, 2H), 5.72 (dd, J = 17.7, 1.2 Hz, 1H), 5.46 (dd, J = 11.0, 1.2 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 164.34, 142.94, 130.85, 130.14, 127.88, 127.38, 118.60 ppm. HRMS (m / z): [M+H]+calcd for C7H8NOS+154.0327, found 154.0328. NH2

[0344] The compound was prepared following the general procedure (Method B, 10 h, 0.5 mL dioxane and 45 μL AcOH) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B9 (10.4 mg, 57%) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 5.81 (br s, 1H), 5.79 – 5.73 (m, 1H), 5.66 – 5.60 (m, 1H), 5.52 (br s, 1H), 2.85 – 2.77 (m, 1H), 2.49 – 2.42 (m, 1H), 2.33 – 2.27 (m, 1H), 2.17 – 2.12 (m, 2H), 2.10 (s, 3H), 2.04 – 1.82 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 174.49, 170.21, 126.86, 123.03, 80.02, 33.38, 28.80, 22.14, 21.49 ppm. HRMS (m / z): [M+H]+calcd for C9H14NO3+184.0974, found 184.0970.

[0345] The compound was prepared following the general procedure (Method B, 4 h, 0.5 mL dioxane and 45 μL AcOH) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B10 (17.9 mg, 80%) as a white foam. 1H NMR (400 MHz, CDCl3): δ = 6.46 (d, J = 8.5 Hz, 1H), 6.32 (d, J = 8.2 Hz, 1H), 5.43 (br s, 2H), 3.74 (s, 3H), 2.38 (s, 2H), 1.94 – 1.84 (m, 2H), 1.59 – 1.46 (m, 4H), 1.42 – 1.33 (m, 2H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 176.86, 173.18, 136.02, 132.37, 52.12, 44.83, 44.53, 36.61, 31.63, 30.26 ppm. HRMS (m / z): [M+H]+calcd for C12H18NO3+224.1287, found 224.1279. OB11

[0346] The compound was prepared following the general procedure (Method A, 4 h) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B11 (11.2 mg, 82%) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 6.26 (dd, J = 5.7, 3.1 Hz, 1H), 6.03 (dd, J = 5.7, 2.8 Hz, 1H), 5.32 (br s, 1H), 3.15 (br s, 1H), 2.94 (br s, 1H), 2.92 – 2.88 (m, 1H), 1.99 – 1.93 (m, 1H), 1.52 – 1.45 (m, 1H), 1.37 – 1.29 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.82, 138.12, 132.36, 50.26, 46.36, 44.60, 42.88, 30.10 ppm. HRMS (m / z): [M+H]+calcd for C8H12NO+138.0914, found 138.0915. NH2

[0347] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 40 μL TFA) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give B12 (14.3 mg, 83%) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 7.32 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 9.9 Hz, 1H), 6.21 – 6.15 (m, 1H), 6.14 (br s, 1H), 5.81 (br s, 1H), 2.80 (t, J = 8.2 Hz, 2H), 2.33 – 2.27 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.90, 137.06, 132.07, 131.89, 130.99, 129.86, 126.62, 125.45, 124.83, 28.10, 22.64 ppm. HRMS (m / z): [M+H]+calcd for C11H12NO+174.0919, found 174.0919.TSRI 2216.1PC NH2

[0348] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 40 μL TFA) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give B13 (12.4 mg, 60%) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 7.25 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.92 – 6.87 (m, 1H), 6.25 – 6.18 (m, 1H), 6.12 (br s, 1H), 5.79 (br s, 1H), 2.93 (t, J = 8.3 Hz, 2H), 2.37 – 2.30 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.97, 135.46, 134.50, 133.78, 131.71, 131.06, 127.67, 126.12, 124.46, 24.37, 22.06 ppm. HRMS (m / z): [M+H]+calcd for C11H11ClNO+208.0529, found 208.0523. NH2

[0349] The compound was prepared following the general procedure (Method A, 4 h) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give B14 (17.2 mg, 68%) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 7.40 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 9.8 Hz, 1H), 6.21 (dt, J = 9.1, 4.5 Hz, 1H), 5.73 (br s, 2H), 2.94 (t, J = 8.3 Hz, 2H), 2.37 – 2.32 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.76, 136.35, 133.92, 131.80, 131.46, 130.95, 126.48, 126.42, 124.54, 27.48, 22.36 ppm. HRMS (m / z): [M+H]+calcd for C11H11BrNO+252.0024, found 252.0017. NH2TSRI 2216.1PC

[0350] The compound was prepared following the general procedure (Method B, 2 h, 0.5 mL dioxane and 40 μL TFA) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B15 (19.4 mg, 65%) as a white foam. 1H NMR (400 MHz, CDCl3): δ = 7.76 (s, 1H), 7.62 (s, 1H), 6.99 (d, J = 9.8 Hz, 1H), 6.27 – 6.18 (m, 1H), 5.83 (br s, 1H), 5.78 (br s, 1H), 2.81 (t, J = 8.4 Hz, 2H), 2.35 – 2.25 (m, 2H), 1.34 (s, 12H) ppm. 13C NMR (126 MHz, CDCl3): δ = 171.62, 136.20, 135.98, 134.85, 132.44, 131.81, 131.26, 125.07, 84.14, 27.85, 24.96, 22.79 ppm. HRMS (m / z): [M+H]+calcd for C17H23BNO3+, 299.1807, found 299.1808. NH2

[0351] The compound was prepared following the general procedure (Method A, 2 h) and was purified by flash column chromatography using hexane / acetone (2:1 to 1:1) as eluent to give B16 (12.2 mg, 65%) as a white powder. 1H NMR (600 MHz, CD3COCD3): δ = 8.44 (s, 1H), 6.96 (br s, 1H), 6.82 (d, J = 9.9 Hz, 1H), 6.73 (d, J = 2.6 Hz, 1H), 6.64 (d, J = 3.3 Hz, 1H), 6.60 (br s, 1H), 5.88 – 5.83 (m, 1H), 2.66 (t, J = 8.1 Hz, 2H), 2.18 – 2.13 (m, 2H) ppm. 13C NMR (151 MHz, CD3COCD3): δ = 171.46, 156.64, 139.31, 135.91, 126.66, 126.01, 124.43, 117.09, 112.76, 29.13, 23.25 ppm. HRMS (m / z): [M+H]+calcd for C11H12NO2+, 190.0868, found 190.0865. NH2

[0352] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 40 μL TFA) and was purified by pTLC (hexane / acetone 2:1) as eluent to give B17 (14.0 mg, 71%) as a pale yellow foam, along with 8% inseparable reduction product.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 7.63 – 7.60 (m, 1H), 7.45 – 7.44 (m, 1H), 6.96 – 6.92 (m, 1H), 6.39 – 6.35 (m, 1H), 2.85 (t, J = 8.3 Hz, 2H), 2.39 – 2.34 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 169.33, 138.22, 136.27, 135.19, 132.68, 132.52, 129.42, 124.14, 118.48, 109.97, 27.61, 22.36 ppm. HRMS (m / z): [M+H]+calcd for C12H11N2O+, 199.0871, found 199.0867. NH2

[0353] The compound was prepared following the general procedure (Method B, 2 h, 0.5 mL dioxane and 40 μL TFA) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give B18 (24.6 mg, 82%) as a pale yellow powder. 1H NMR (500 MHz, CDCl3): δ = 7.65 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 6.86 (dt, J = 9.9, 2.3 Hz, 1H), 6.20 (dt, J = 9.9, 4.4 Hz, 1H), 5.88 (br s, 1H), 5.75 (br s, 1H), 2.76 (t, J = 8.2 Hz, 2H), 2.32 – 2.24 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3): δ = 169.82, 139.24, 138.50, 134.13, 133.69, 131.80, 131.47, 124.30, 91.13, 27.66, 22.48 ppm. HRMS (m / z): [M+H]+cald for C11H11INO+299.9885, found 299.9882. NH2

[0354] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 40 μL TFA) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B19 (19.5 mg, 75%) as a pale yellow powder. 1H NMR (600 MHz, CD3OD): δ = 7.50 – 7.45 (m, 2H), 6.80 (dt, J = 9.9, 2.0 Hz, 1H), 6.12 (dt, J = 9.9, 4.4 Hz, 1H), 4.53 – 4.46 (m, 1H), 4.15 – 4.06 (m, 1H), 2.83 (t, J = 8.2 Hz, 1H), 2.32 – 2.27 (m, 2H) ppm. 13C NMR (151 MHz, CD3OD): δ = 174.53, 157.73, 139.10, 137.96, 134.63, 130.54, 128.66, 125.32, 120.50, 116.38, 63.30, 46.57, 29.26, 23.59 ppm.TSRI 2216.1PC HRMS (m / z): [M+H]+calcd for C14H15N2O3+, 259.1083, found 259.1081. NH2

[0355] The compound was prepared following the general procedure (Method B, 2 h, 0.5 mL dioxane and 40 μL TFA) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B20 (14.0 mg, 70%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.35 (d, J = 2.1 Hz, 1H), 7.28 – 7.23 (m, 1H), 6.93 – 6.90 (m, 1H), 6.65 (dd, J = 17.6, 10.9 Hz, 1H), 6.21 – 6.14 (m, 1H), 6.00 (br s, 1H), 5.80 (br s, 1H), 5.75 (d, J = 18.4 Hz, 1H), 5.26 (d, J = 11.7 Hz, 1H), 2.80 (t, J = 8.2 Hz, 2H), 2.33 – 2.28 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.63, 137.30, 136.01, 135.96, 132.32, 131.44, 131.13, 127.31, 124.70, 123.56, 114.41, 28.22, 22.73 ppm. HRMS (m / z): [M+H]+calcd for C13H14NO+, 200.1075, found 200.1076. NH2

[0356] The compound was prepared following the general procedure (Method B, 2 h, 0.5 mL dioxane and 40 μL TFA) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B21 (20.0 mg, 66%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.49 (s, 1H), 7.45 (d, J = 9.0 Hz, 2H), 7.33 (s, 1H), 6.94 (d, J = 9.9 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 6.25 – 6.18 (m, 1H), 5.84 (br s, 1H), 5.81 (br s, 1H), 3.83 (s, 3H), 2.80 (t, J = 8.2 Hz, 2H), 2.35 – 2.29 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.89, 159.90, 137.23, 133.21, 132.40, 132.01, 131.90, 131.71, 128.46, 124.63, 121.78, 115.25, 114.21, 90.50, 87.69, 55.47, 27.95, 22.64 ppm. HRMS (m / z): [M+H]+calcd for C20H18NO2+, 304.1338, found 304.1341.TSRI 2216.1PC NH2

[0357] The compound was prepared following the general procedure (Method A, 3 h) and was purified by pTLC (hexane / acetone 2:1) to give B22 (17.3 mg, 67%) as a white powder, along with 10% inseparable reduction product. 1H NMR (400 MHz, CDCl3): δ = 6.85 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 6.77 (s, 1H), 6.10 – 5.98 (m, 2H), 5.77 (br s, 1H), 3.84 (t, J = 4.9 Hz, 4H), 3.16 (t, J = 4.9 Hz, 3.5H), 3.10 (t, J = 4.9 Hz, 0.5H), 2.76 (t, J = 8.1 Hz, 2H), 2.34 – 2.19 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.90, 149.66, 138.44, 132.99, 128.15, 124.37, 123.95, 117.36, 112.11, 66.90, 49.19, 28.96, 22.74 ppm. HRMS (m / z): [M+H]+calcd for C15H19N2O2+, 259.1447, found 259.1444. NH2

[0358] The compound was prepared following the general procedure (Method B, 3 h, 10 mg CuF2, 0.5 mL dioxane and 45 μL AcOH) and was purified by pTLC (CH2Cl2 / acetone 5:1) to give B23 (15.1 mg, 52%) as a pale yellow powder, along with along with 10% inseparable reduction product. 1H NMR (600 MHz, CDCl3): δ = 8.34 (dd, J = 4.7, 1.6 Hz, 1H), 7.98 (dd, J = 7.8, 1.7 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 2.2, 0.9 Hz, 1H), 7.49 (d, J = 3.6 Hz, 1H), 7.14 (dd, J = 7.8, 4.6 Hz, 1H), 7.00 – 6.96 (m, 1H), 6.63 (d, J = 3.7 Hz, 1H), 6.26 – 6.18 (m, 2H), 5.80 (br s, 1H), 2.91 (t, J = 8.2 Hz, 2H), 2.39 – 2.32 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.91, 147.57, 143.63, 138.60, 136.52, 132.81, 131.07, 130.25, 129.46, 127.83, 125.28, 124.44, 121.82, 121.08, 116.98, 102.12, 28.40, 22.55 ppm. HRMS (m / z): [M+H]+calcd for C18H16N3O+, 290.1293, found 290.1299.TSRI 2216.1PC NH2

[0359] The compound was prepared following the general procedure (Method B, 2 h, 0.5 mL dioxane and 40 μL TFA) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B24 (14.5 mg, 49%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 7.8 Hz, 2H), 7.21 (s, 1H), 7.14 (d, J = 7.7 Hz, 2H), 7.09 (s, 1H), 6.87 (d, J = 9.3 Hz, 1H), 6.19 – 6.11 (m, 1H), 5.89 (br s, 1H), 5.71 (br s, 1H), 2.73 (t, J = 8.2 Hz, 2H), 2.35 (s, 3H), 2.31 – 2.22 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.99, 138.07, 138.06, 135.46, 132.67, 132.45, 131.04, 130.90, 130.80, 130.43, 130.34, 126.42, 124.46, 28.13, 22.59, 21.30, 21.26 ppm. HRMS (m / z): [M+H]+calcd for C18H18NOS+, 296.1109, found 296.1110. NH2B25

[0360] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 40 μL TFA) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B25 (20.3 mg, 69%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 6.94 (d, J = 2.6 Hz, 1H), 6.91 – 6.83 (m, 1H), 6.76 (s, 2H), 6.11 (dt, J = 9.8, 4.6 Hz, 1H), 5.94 (br s, 1H), 5.75 (br s, 1H), 2.76 (t, J = 8.2 Hz, 2H), 2.31 – 2.26 (m, 8H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.05, 156.82, 155.95, 139.88, 139.37, 133.19, 129.45, 127.11, 125.57, 124.34, 120.35, 116.93, 115.22, 28.46, 22.48, 21.46 ppm. HRMS (m / z): [M+H]+calcd for C19H20NO2+, 294.1494, found 294.1497. NH2TSRI 2216.1PC

[0361] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 9.5 mg TsOH·H2O) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B26 (9.3 mg, 60%) as a pale yellow foam, along with 9% inseparable reduction product. 1H NMR (600 MHz, CDCl3): δ = 5.59 (s, 1H), 5.42 (br s, 2H), 4.93 – 4.91 (m, 1H), 4.83 – 4.81 (m, 1H), 3.87 (hept, J = 7.0 Hz, 1H), 1.89 (s, 3H), 1.12 (d, J = 7.0 Hz, 6H) ppm. 13C NMR (151 MHz, CDCl3) δ 168.90, 165.42, 145.60, 117.31, 114.61, 28.77, 24.32, 21.46 ppm. HRMS (m / z): [M+H]+calcd for C9H16NO+, 154.1227, found 154.1227. OMe

[0362] The compound was prepared following the general procedure (Method A, 10 h) and was purified by flash column chromatography using hexane / acetone (3:1) as eluent to give B27 (12.7 mg, 70%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 5.47 (br s, 1H), 5.43 (br s, 1H), 4.76 (s, 2H), 2.28 – 2.11 (m, 2H), 1.96 – 1.86 (m, 1H), 1.81 – 1.68 (m, 2H), 1.71 (s, 3H), 1.49 – 1.37 (m, 1H), 1.33 – 1.19 (m, 2H), 1.08 – 0.95 (m, 1H), 0.91 (d, J = 6.6 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.80, 148.42, 110.97, 49.29, 47.56, 38.90, 34.71, 32.16, 32.00, 22.43, 20.67 ppm. HRMS (m / z): [M+H]+calcd for C11H20NO+, 182.1545, found 182.1548. NH2O OAc

[0363] The compound was prepared following the general procedure (Method B, 8 h, 0.5 mL DCE and 45 μL AcOH) and was purified by flash column chromatography using CH2Cl2 / acetone 8:1 as eluent to give B28 (11.2 mg, 65%) as a pale yellow powder, along with along with 9% inseparable reduction product.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 6.10 (br s, 1H), 5.95 (br s, 1H), 5.33 (dd, J = 8.9, 4.1 Hz, 1H), 4.84 – 4.82 (m, 1H), 4.77 – 4.74 (m, 1H), 2.63 (dd, J = 14.4, 4.2 Hz, 1H), 2.49 (dd, J = 14.4, 8.9 Hz, 1H), 2.13 (s, 3H), 1.77 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 172.19, 169.62, 140.49, 114.57, 71.93, 40.35, 22.39, 21.00 ppm. HRMS (m / z): [M+H]+calcd for C8H14NO3+, 172.0968, found 172.0962. O Me

[0364] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 45 μL AcOH) and was purified by flash column chromatography using hexane / acetone (3:1) as eluent to give B29 (9.2 mg, 57%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 7.5 Hz, 1H), 7.44 – 7.39 (m, 1H), 7.37 – 7.31 (m, 1H),, 7.22 (d, J = 7.5 Hz, 1H), 6.31 (br s, 1H), 6.04 (br s, 1H), 5.26 – 5.23 (m,1H), 5.10 (s, 1H), 2.12 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.11, 146.99, 142.36, 132.89, 130.98, 129.13, 129.00, 127.66, 116.13, 24.54 ppm. HRMS (m / z): [M+H]+calcd for C10H12NO+, 162.0919, found 162.0917. Me

[0365] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL DCE and 11.6 mg CSA) and was purified by pTLC (CH2Cl2 / acetone 10:1) to give B30 (16.2 mg, 66%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.11 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 5.86 (br s, 1H), 5.63 (br s, 1H), 5.17 – 5.14 (m, 1H), 5.05 – 5.02 (m, 1H), 3.23 (p, J = 6.8 Hz, 1H), 2.89 (p, J = 6.9 Hz, 1H), 2.12 – 2.10 (m, 3H), 1.27 (d, J = 6.9 Hz, 6H), 1.25 (d, J = 6.9 Hz, 6H).TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 172.55, 149.91, 145.97, 145.47, 141.01, 131.61, 123.75, 122.73, 115.82, 34.32, 30.64, 24.62, 24.57, 24.02 ppm. HRMS (m / z): [M+H]+calcd for C16H24NO+, 246.1858, found 246.1859. O NH2

[0366] The compound was prepared following the general procedure (Method A, 3 h) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B31 (16.9 mg, 85%) as a white powder, along with 7% inseparable reduction product. 1H NMR (600 MHz, CDCl3): δ = 7.38 (dd, J = 7.4, 1.0 Hz, 1H), 7.27 (d, J = 7.4 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.12 (td, J = 7.4, 1.2 Hz, 1H), 6.56 (s, 1H), 5.43 (br s, 2H), 3.35 (s, 2H), 2.85 (t, J = 7.6 Hz, 2H), 2.55 (dd, J = 8.3, 7.0 Hz, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 174.48, 148.59, 145.30, 143.09, 127.05, 126.49, 124.15, 123.61, 120.31, 41.32, 35.14, 26.85 ppm. HRMS (m / z): [M+H]+calcd for C12H14NO+, 188.1070, found 188.1067.

[0367] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 45 μL AcOH) and was purified by flash column chromatography using hexane / acetone (3:1) as eluent to give B32 (10.3 mg, 51%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.7 Hz, 1H), 7.43 – 7.37 (m, 1H), 7.35 – 7.29 (m, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.36 (br s, 1H), 5.85 – 5.80 (m, 1H), 5.75 (br s, 1H), 2.32 – 2.24 (m, 2H), 2.23 – 2.16 (m, 2H), 1.79 – 1.72 (m, 2H), 1.71 – 1.64 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.18, 143.02, 140.22, 132.78, 131.03, 129.54, 129.26, 127.58, 127.28, 30.63, 25.76, 23.35, 21.91 ppm. HRMS (m / z): [M+H]+calcd for C13H16NO+, 202.1232, found 202.1237. O NH2TSRI 2216.1PC

[0368] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by flash column chromatography using hexane / acetone (3:1) as eluent to give B33 (10.7 mg, 77%, r.r. > 18:1) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 5.52 (br s, 2H), 5.39 (s, 1H), 2.40 (s, 4H), 2.33 – 2.28 (m, 2H), 2.27 – 2.23 (m, 2H), 1.90 – 1.82 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 175.34, 143.24, 124.42, 35.22, 34.29, 32.59, 26.94, 23.49 ppm. HRMS (m / z): [M+H]+calcd for C8H14NO+, 140.1070, found 140.1063. O NH2

[0369] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by flash column chromatography using hexane / acetone (3:1) as eluent to give B34 (10.8 mg, 70%, r.r. > 20:1) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 5.64 – 5.42 (m, 3H), 2.40 – 2.31 (m, 2H), 2.28 – 24 (m, 2H), 2.01 – 1.95 (m, 2H), 1.98 – 1.88 (m, 2H), 1.65 – 1.59 (m, 2H), 1.59 – 1.51 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 175.54, 136.40, 122.09, 34.28, 33.57, 28.34, 25.32, 22.99, 22.52 ppm. HRMS (m / z): [M+H]+calcd for C9H16NO+, 154.1127, found 154.1120. O NH2

[0370] The compound was prepared following the general procedure (Method A, 5 h) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give B35 (11.5 mg, 68%, r.r. >14:1) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 5.76 – 5.40 (m, 3H), 2.35 – 2.18 (m, 4H), 2.13 – 2.03 (m, 3H), 1.76 – 1.67 (m, 2H), 1.65 – 1.53 (m, 1H), 1.51 – 1.40 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 175.52, 143.24, 127.22, 35.76, 34.67, 32.71, 32.66, 28.36, 27.30, 26.91 ppm.TSRI 2216.1PC HRMS (m / z): [M+H]+calcd for C10H18NO+, 168.1388, found 168.1381. O NH2

[0371] The compound was prepared following the general procedure (Method A, 5 h) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give B36 (12.2 mg, 67%, r.r. =20:1) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 5.57 (br s, 1H), 5.53 (br s, 1H), 5.39 (t, J = 8.1 Hz, 1H), 2.38 – 2.29 (m, 4H), 2.19 – 2.12 (m, 2H), 2.11 – 2.04 (m, 2H), 1.54 – 1.49 (m, 2H), 1.49 – 1.42 (m, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 175.46, 139.37, 124.85, 34.56, 32.87, 30.03, 28.96, 28.87, 26.64, 26.45, 26.34 ppm. HRMS (m / z): [M+H]+calcd for C11H20NO+, 182.1545, found 182.1543. NH2O

[0372] The compound was prepared following the general procedure (Method A, 18 h) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give B37 (18.9 mg, 80%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 5.52 (br s, 1H), 5.47 (s, 1H), 5.42 (br s, 1H), 2.45 (dd, J = 14.2, 3.9 Hz, 1H), 2.17 (dd, J = 14.2, 10.7 Hz, 1H), 2.13 – 2.03 (m, 1H), 2.04 – 1.95 (m, 2H), 1.93 – 1.68 (m, 5H), 1.66 – 1.51 (m, 6H), 1.28 – 1.10 (m, 4H), 0.95 – 0.77 (m, 2H). 13C NMR (151 MHz, CDCl3): δ = 175.63, 138.30, 124.36, 50.47, 40.15, 37.79, 31.64, 31.03, 26.69, 26.64, 25.93, 25.41, 23.12, 22.79 ppm. HRMS (m / z): [M+H]+calcd for C15H26NO+, 236.2014, found 236.2014. NH2TSRI 2216.1PC

[0373] The compound was prepared following the general procedure (Method B, 2 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give B38 (15.9 mg, 67%, E / Z = 7:3, r.r. > 12:1) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 5.47 (br s, 2H), 5.38 (t, J = 7.7 Hz, 0.7H), 5.17 (t, J = 7.8 Hz, 0.3H), 2.42 – 2.24 (m, 3H), 2.14 – 2.03 (m, 4H), 1.53 – 1.18 (m, 18H). 13C NMR (151 MHz, CDCl3): δ = 175.54, 175.38, 137.73, 136.15, 129.86, 127.07, 35.29, 34.74, 34.68, 31.77, 27.52, 27.39, 26.94, 26.64, 26.05, 25.85, 25.51, 25.19, 25.10, 24.90, 24.86, 24.67, 24.59, 24.52, 24.48, 24.46, 24.18, 23.95, 22.59, 22.46 ppm. HRMS (m / z): [M+H]+calcd for C15H28NO+, 238.2166, found 238.2169. NH2O NPhth

[0374] The compound was prepared following the general procedure (Method A, 20 h) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B39 (16.9 mg, 69%) as a white powder, along with 9% inseparable reduction product. 1H NMR (400 MHz, CDCl3): δ = 7.89 – 7.83 (m, 2H), 7.80 – 7.71 (m, 2H), 6.18 (br s, 1H), 5.80 – 5.65 (m, 1H), 5.55 (br s, 1H), 5.13 – 5.07 (m, 1H), 5.04 – 4.99 (m, 1H), 4.93 – 4.87 (m, 1H), 3.08 – 2.90 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.66, 168.13, 134.56, 133.46, 131.69, 123.82, 119.42, 53.87, 33.66 ppm. HRMS (m / z): [M+H]+calcd for C13H13N2O3+, 245.0926, found 245.0917. NH2O

[0375] The compound was prepared following the general procedure (Method B, 8 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B40 (13.0 mg, 53%) as a white powder, along with 9% inseparable reduction product. 1H NMR (600 MHz, CDCl3): δ = 7.87 – 7.82 (m, 2 H), 7.76 – 7.71 (m, 2 H), 6.16 – 6.09 (m, 1 H), 5.62 (br s, 1 H), 5.45 (br s, 1 H), 5.35 – 5.29 (m, 1 H), 5.30 (d, J = 7.2 Hz, 1 H),TSRI 2216.1PC 5.23 (d, J = 10.3 Hz, 1 H), 3.22 (dd, J = 15.1, 9.6 Hz, 1 H), 2.86 (dd, J = 15.0, 6.2 Hz, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.56, 168.12, 134.39, 134.22, 131.96, 123.51, 117.99, 50.42, 38.04 ppm. HRMS (m / z): [M+H]+calcd for C13H13N2O3+, 245.0921, found 245.0913. O NH2

[0376] The compound was prepared following the general procedure (Method B, heated at 135 ˚C for 10 h, 0.5 mL AcOH) and was purified by flash column chromatography using hexane / acetone (1:1) as eluent to give B41 (15.8 mg, 55%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.85 – 7.81 (m, 2H), 7.74 – 7.70 (m, 2H), 5.75 (br s, 1H), 5.36 (br s, 1H), 4.97 – 4.93 (m, 1H), 3.67 (dd, J = 13.7, 7.7 Hz, 1H), 3.61 (dd, J = 13.7, 7.1 Hz, 1H), 3.37 – 3.24 (m, 1H), 2.34 (dd, J = 14.6, 5.8 Hz, 1H), 2.20 (dd, J = 14.6, 8.0 Hz, 1H), 1.65 (d, J = 1.5 Hz, 3H), 1.61 (d, J = 1.5 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 173.52, 168.71, 136.48, 134.18, 132.08, 123.90, 123.41, 42.11, 39.79, 35.04, 25.96, 18.24 ppm. HRMS (m / z): [M+H]+calcd for C16H19N2O3+, 287.1390, found 287.1395. O NH2

[0377] The compound was prepared following the general procedure (Method B, 0.5 mL DCE and 45 μL AcOH) and was purified by pTLC (hexane / acetone 2:1) to give B42 (17.2 mg, 56%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.89 – 7.84 (m, 2H), 7.75 – 7.70 (m, 2H), 7.46 – 7.41 (m, 2H), 7.38 – 7.32 (m, 2H), 7.32 – 7.28 (m, 1H), 6.86 (d, J = 15.9 Hz, 1H), 6.79 (dd, J = 15.9, 9.1 Hz, 1H), 6.08 (br s, 1H), 5.77 (br s, 1H), 5.49 (d, J = 9.1 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3) δ 169.09, 167.50, 138.17, 135.10, 134.22, 131.98, 128.96, 128.81, 126.93, 123.64, 121.05, 55.99 ppm.TSRI 2216.1PC HRMS (m / z): [M+H]+calcd for C18H15N2O3+, 307.1077, found 307.1071. NH2O NPhth

[0378] The compound was prepared following the general procedure (Method A, 20 h) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B43 (16.1 mg, 62%, E / Z = 3:2) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.92 – 7.87 (m, 1H), 7.80 – 7.75 (m, 1H), 6.23 (br s, 1H), 5.61 – 5.52 (m, 1H), 5.41 – 5.30 (m, 1H),4.92 – 4.82 (m, 1H), 3.14 – 3.06 (m, 0.4H), 2.98 – 2.91 (m, 1.6H), 1.59 (d, J = 7.4 Hz, 1.2H), 1.55 (d, J = 6.6 Hz, 1.8H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.91, 168.20, 168.15, 134.52, 134.49, 131.76, 131.74, 130.22, 128.95, 125.90, 124.89, 123.77, 123.76, 54.33, 54.05, 32.69, 27.20, 18.01, 13.03 ppm. HRMS (m / z): [M+H]+calcd for C14H15N2O3+259.1083, found 259.1076. NH2

[0379] The compound was prepared following the general procedure (Method B, 8 h, 0.5 mL dioxane and 45 μL AcOH) and was purified by flash column chromatography using hexane / acetone (3:1) as eluent to give B44 (16.2 mg, 60%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.85 – 7.77 (m, 1H), 7.73 – 7.69 (m, 1H), 5.99 (br s, 1H), 5.82 – 5.76 (m, 1H), 5.53 (br s, 1H), 3.13 (d, J = 17.5 Hz, 1H), 3.05 (dt, J = 12.5, 6.2 Hz, 1H), 2.86 (d, J = 18.9 Hz, 1H), 2.36 – 2.29 (m, 1H), 2.24 – 2.09 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 174.40, 169.05, 134.27, 131.84, 127.24, 124.55, 123.31, 63.82, 32.93, 28.18, 22.81 ppm. HRMS (m / z): [M+H]+calcd for C15H15N2O3+271.1083, found 271.1076. NH2TSRI 2216.1PC

[0380] The compound was prepared following the general procedure (Method A, 10 h) and was purified by flash column chromatography using CH2Cl2 / acetone (15:1 → 10:1) as eluent to give B45 (13.3 mg, 52%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 7.86 – 7.78 (m, 2H), 7.75 – 7.67 (m, 2H), 6.16 – 5.78 (m, 3H), 5.43 (br s, 1H), 3.53 (d, J = 15.5 Hz, 2H), 3.39 (d, J = 15.5 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3): δ = 174.15, 169.44, 134.21, 132.20, 129.92, 123.42, 68.18, 43.23 ppm. HRMS (m / z): [M+H]+calcd for C14H13N2O3+257.0921, found 257.0926.

[0381] The compound was prepared following the general procedure (Method B, heated at 135 ˚C for 8 h, 0.5 mL AcOH) and was purified by flash column chromatography using hexane / acetone (1:1) as eluent to give B46 (12.6 mg, 42%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 7.88 – 7.82 (m, 2H), 7.79 – 7.71 (m, 2H), 6.90 (br s, 1H), 5.87 (dt, J = 10.1, 3.8 Hz, 1H), 5.54 – 5.46 (m, 2H), 3.83 – 3.74 (m, 2H), 2.32 – 2.27 (m, 2H), 2.09 – 1.99 (m, 2H), 1.73 – 1.59 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 172.93, 169.63, 134.43, 131.93, 130.32, 130.18, 123.62, 45.83, 45.29, 38.99, 31.45, 25.01, 18.58 ppm. HRMS (m / z): [M+H]+calcd for C17H19N2O3+, 299.1396, found 299.1395. NH2O

[0382] The compound was prepared following the general procedure (Method B, 4 h, 0.5 mL DCE and 11.6 mg CSA) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B47 (17.3 mg, 67%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.86 – 7.79 (m, 2H), 7.74 – 7.68 (m, 2H), 5.57 (br s, 1H), 5.35 (br s, 1H), 5.24 (dd, J = 10.7, 5.3 Hz, 1H), 5.02 (s, 1H), 4.99 (s, 1H), 3.39 (dd, J = 15.0, 10.6 Hz, 1H), 2.90 (dd, J = 15.0, 5.3 Hz, 1H), 1.79 (s, 3H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3) δ 172.01, 168.49, 141.68, 134.22, 131.88, 123.51, 113.51, 52.51, 36.11, 20.66 ppm. HRMS (m / z): [M+H]+calcd for C14H15N2O3+, 259.1077, found 259.1077. NH2O NPhth

[0383] The compound was prepared following the general procedure (Method B, 8 h, 0.5 mL DCE and 45 μL AcOH) and was purified by flash column chromatography using hexane / acetone (3:1) as eluent to give B48 (17.0 mg, 66%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.85 (dd, J = 5.3, 3.1 Hz, 2H), 7.74 (dd, J = 5.6, 3.0 Hz, 2H), 6.29 (br s, 1H), 5.79 (br s, 1H), 5.03 (dd, J = 11.2, 5.1 Hz, 1H), 4.71 (s, 1H), 4.68 (s, 1H), 3.06 (dd, J = 14.3, 11.2 Hz, 1H), 2.80 (dd, J = 13.9, 4.8 Hz, 1H), 1.75 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.20, 168.12, 141.18, 134.49, 131.69, 123.75, 114.85, 52.51, 37.41, 21.62 ppm. HRMS (m / z): [M+H]+calcd for C14H15N2O3+, 259.1083, found 259.1086. NH2O

[0384] The compound was prepared following the general procedure (Method A, 10 h) and was purified by flash column chromatography using CH2Cl2 / acetone (15:1 → 10:1) as eluent to give B49 (18.9 mg, 63%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 7.90 – 7.82 (m, 2H), 7.79 – 7.70 (m, 2H), 6.31 (br s, 1H), 5.55 (br s, 1H), 5.38 (s, 1H), 4.99 (dd, J = 10.7, 5.6 Hz, 1H), 2.94 – 2.85 (m, 1H), 2.74 (dd, J = 14.0, 5.8 Hz, 1H), 2.12 – 1.97 (m, 1H), 1.96 – 1.80 (m, 2H), 1.69 – 1.30 (m, 5H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.36, 168.21, 134.48, 133.53, 131.75, 126.34, 123.68, 52.80, 37.87, 27.56, 25.39, 22.77, 22.14 ppm. HRMS (m / z): [M+H]+calcd for C17H19N2O3+, 299.1396, found 299.1404.TSRI 2216.1PC O NH2Me

[0385] The compound was prepared following the general procedure (Method A, 12 h) and was purified by flash column chromatography using hexane / acetone (1:1) as eluent to give B50 (27.9 mg, 72%) as a white powder. 1H NMR (600 MHz, CD3COCD3): δ = 7.92 – 7.84 (m, 4H), 7.78 (br s, 1H), 7.14 (br s, 1H), 6.54 (br s, 1H), 5.23 (dd, J = 9.4, 3.8 Hz, 1H), 4.84 – 4.80 (m, 1H), 4.79 – 4.76 (m, 1H), 4.31 (s, 2H), 3.58 – 3.43 (m, 2H), 2.68 – 2.46 (m, 4H), 1.76 (s, 3H) ppm. 13C NMR (151 MHz, CD3COCD3): δ = 172.49, 171.62, 168.47, 167.20, 142.01, 135.23, 133.33, 124.01, 114.22, 72.78, 41.12, 40.89, 36.09, 35.09, 22.48 ppm. HRMS (m / z): [M+H]+calcd for C19H22N3O6+, 388.1509, found 388.1513. NH2O

[0386] The compound was prepared following the general procedure (Method B, 4 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by by flash column chromatography using hexane / EA (4:1) as eluent to give B51 (17.5 mg, 62%, r.r. > 14:1, a mixture of E / Z isomers) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 5.70 – 5.30 (m, 4H), 2.41 – 2.19 (m, 4H), 2.10 – 1.93 (m, 2H), 1.42 – 1.18 (m, 22H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ = 175.17, 175.13, 136.91, 132.39, 132.06, 128.13, 127.54, 122.43, 40.14, 36.09, 35.99, 35.98, 32.66, 32.06, 29.84, 29.82, 29.81, 29.80, 29.78, 29.75, 29.70, 29.65, 29.62, 29.59, 29.50, 29.48, 29.38, 29.35, 29.32, 28.52, 27.41, 25.68, 23.36, 22.83, 14.26.ppm. HRMS (m / z): [M+H]+calcd for C18H36NO+, 282.2791, found 282.2799. O NH2MeTSRI 2216.1PC

[0387] The compound was prepared following the general procedure (Method B, 5 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by flash column chromatography using hexane / acetone (3:1) as eluent to give B52 (10.4 mg, 74%) as a white foam, r.r. = 6:1, E / Z = 5:1. 1H NMR (600 MHz, CDCl3): δ = 6.11 (br s, 1H), 5.83 – 5.74 (m, 1H), 5.68 – 5.57 (m, 1H), 5.66 (br s, 1H), 5.15 – 5.00 (m, 2H), 2.40 – 2.30 (m, 1H), 2.27 – 2.18 (m, 2H), 1.50 – 1.28 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ = 178.02, 135.87, 116.94, 46.84, 37.15, 34.62, 20.73, 14.17 ppm. HRMS (m / z): [M+H]+calcd for C8H16NO+142.1227, found 142.1227.

[0388] The compound was prepared following the general procedure (Method B, 12 h, 0.5 mL dioxane and 45 μL AcOH) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B53 (16.0 mg, 71%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 6.02 (d, J = 5.9 Hz, 1H), 5.70 (d, J = 6.0 Hz, 1H), 5.58 (br s, 1H), 5.38 (br s, 1H), 3.70 (s, 3H), 3.31 – 3.29 (m, 1H), 2.42 (d, J = 12.7 Hz, 1H), 1.99 (d, J = 12.6 Hz, 1H), 1.14 (s, 3H), 1.08 (s, 3H), 0.87 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 174.67, 174.45, 141.09, 126.44, 60.45, 51.74, 50.97, 48.37, 42.95, 24.88, 20.40, 20.12 ppm. HRMS (m / z): [M+H]+calcd for C12H20NO3+, 226.1443, found 226.1433.

[0389] The compound was prepared following the general procedure (Method B, 5 h, 10 mg CuF2, 0.5 mL dioxane and 45 μL AcOH) and was purified by pTLC (hexane / acetone 2:1) to give B54 (13.3 mg, 51%) as a white powder.TSRI 2216.1PC 1H NMR (400 MHz, CDCl3): δ = 7.01 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 6.64 (s, 1H), 5.92 (d, J = 15.7 Hz, 1H), 5.72 (dt, J = 15.5, 5.6 Hz, 1H), 5.31 (br s, 1H), 5.24 (br s, 1H), 4.53 (d, J = 5.3 Hz, 2H), 2.30 (s, 3H), 2.24 (s, 2H), 2.18 (s, 3H), 1.19 (s, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 173.33, 156.64, 142.57, 136.61, 130.64, 124.04, 123.24, 121.28, 112.91, 68.68, 49.39, 35.59, 27.36, 21.53, 16.04 ppm. HRMS (m / z): [M+H]+calcd for C16H24NO2+, 262.1807, found 262.1811. Me

[0390] The compound was prepared following the general procedure (Method B, 6 h, 0.5 mL dioxane and 40 μL TFA) and was purified by pTLC (hexane / acetone 2:1) to give B55 (15.6 mg, 64%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 7.53 (s, 1H), 7.45 (s, 1H), 7.09 (d, J = 5.6 Hz, 1H), 6.47 (d, J = 5.6 Hz, 1H), 5.96 (br s, 2H), 1.36 (s, 9H), 1.32 (s, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.16, 154.71, 149.31, 148.71, 139.11, 126.92, 126.57, 122.46, 121.29, 49.65, 35.01, 31.72, 24.49 ppm. HRMS (m / z): [M+H]+calcd for C16H22NO+, 244.1701, found 244.1702. Me

[0391] The compound was prepared following the general procedure (Method B, 2 h, with 0.5 mL dioxane and 40 μL TFA) and was purified by flash column chromatography using hexane / acetone 2:1 as eluent to give B56 (21.0 mg, 73%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 6.68 (s, 1H), 6.59 (s, 1H), 5.75 (br s, 2H), 3.25 (q, J = 7.0 Hz, 1H), 2.80 – 2.59 (m, 2H), 2.31 (s, 3H), 2.28 – 2.22 (m, 2H), 2.22 (s, 3H), 2.10 (s, 3H), 1.36 (d, J = 7.1 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.12, 169.88, 147.40, 141.57, 133.41, 133.38, 131.25, 122.91, 121.95, 121.77, 48.33, 24.77, 24.14, 20.92, 19.43, 15.09, 11.68 ppm.TSRI 2216.1PC HRMS (m / z): [M+H]+calcd for C17H22NO3+, 288.1600, found 288.1602. Me Me

[0392] The compound was prepared following the general procedure (Method A, 20 h) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give B57 (18.2 mg, 78%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 6.44 (dd, J = 5.8, 3.2 Hz, 1H), 6.33 (dd, J = 5.9, 3.3 Hz, 1H), 5.55 (br s, 1H), 5.32 (s, 1H), 2.98 (d, J = 3.2 Hz, 1H), 2.91 (s, 1H), 2.55 (s, 1H), 1.92 – 1.85 (m, 1H), 1.74 – 1.67 (m, 1H), 1.67 – 1.57 (m, 4H), 1.31 (dd, J = 14.5, 8.1 Hz, 1H), 0.94 (s, 3H), 0.90 (s, 3H), 0.86 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.39, 140.14, 137.01, 72.21, 54.45, 51.57, 47.86, 46.96, 41.32, 38.89, 33.45, 32.80, 28.54, 26.97, 21.73 ppm. HRMS (m / z): [M+H]+calcd for C15H24NO+, 234.1858, found 234.1863. Me Me

[0393] The compound was prepared following the general procedure (Method B, 4 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by pTLC (hexane / acetone 2:1) to give B58 (21.7 mg, 73%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 7.12 – 7.03 (m, 2H), 6.91 (s, 1H), 6.55 (dd, J = 9.5, 3.0 Hz, 1H), 5.79 (dd, J = 9.4, 2.9 Hz, 1H), 5.72 (br s, 1H), 5.44 (br s, 1H), 2.89 – 2.81 (m, 1H), 2.80 – 2.77 (m, 1H), 2.22 (d, J = 12.5 Hz, 1H), 1.84 – 1.77 (m, 2H), 1.76 – 1.70 (m, 3H), 1.24 (d, J =6.9 Hz, 6H), 1.10 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 180.66, 146.59, 145.26, 132.61, 129.37, 129.03, 126.03, 124.94, 121.77, 47.28, 46.27, 37.53, 36.97, 35.57, 33.72, 24.12, 20.96, 18.72, 18.11 ppm. HRMS (m / z): [M+H]+calcd for C20H28NO+, 298.2171, found 298.2178.TSRI 2216.1PC Me Me

[0394] The compound was prepared following the general procedure (Method B, 2 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by flash column chromatography using hexane / EA 3:1 as eluent to give B59 (12.0 mg, 40%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 6.04 (br s, 1H), 5.98 (d, J = 5.8 Hz, 1H), 5.96 (s, 1H), 5.71 (d, J = 3.1 Hz, 1H), 5.25 (br s, 1H), 2.32 – 2.27 (m, 1H), 2.26 – 2.20 (m, 1H), 2.14 – 1.99 (m, 2H), 1.86 – 1.80 (m, 2H), 1.80 – 1.75 (m, 1H), 1.71 – 1.55 (m, 3H), 1.50 – 1.42 (m, 1H), 1.38 (s, 3H), 1.35 – 1.29 (m, 1H), 1.08 – 1.01 (m, 6H), 0.94 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 180.50, 149.25, 148.76, 137.24, 122.01, 121.73, 117.76, 48.11, 47.59, 36.43, 35.44, 32.36, 31.95, 28.06, 26.96, 23.27, 21.38, 20.90, 16.96, 16.70 ppm. HRMS (m / z): [M+H]+calcd for C20H30NO+, 300.2327, found 300.2319.

[0395] The compound was prepared following the general procedure (Method B, heated at 135 ˚C for 12 h, 0.5 mL dioxane and 45 μL AcOH) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give B60 (24.7 mg, 77%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 6.84 (br s, 1H), 5.84 (dd, J = 10.3, 2.6 Hz, 1H), 5.66 (dd, J = 10.3, 3.1 Hz, 1H), 5.37 (br s, 1H), 2.39 (dd, J = 14.3, 0.8 Hz, 1H), 2.33 (dd, J = 14.3, 1.7 Hz, 1H), 2.00 – 1.97 (m, 1H), 1.92 – 1.88 (m, 1H), 1.75 – 1.69 (m, 2H), 1.66 – 1.59 (m, 2H), 1.49 – 1.38 (m, 4H), 1.34 (s, 3H), 1.22 (s, 3H), 1.19 – 1.12 (m, 1H), 0.96 (dd, J = 12.2, 2.6 Hz, 1H), 0.87 (s, 3H), 0.80 (s, 3H), 0.78 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 173.63, 132.85, 125.10, 75.63, 73.00, 56.12, 55.40, 50.30, 42.21, 41.50, 38.81, 36.21, 33.34, 33.30, 26.75, 23.75, 21.23, 19.95, 18.39, 16.35 ppm. HRMS (m / z): [M+H]+calcd for C20H34NO2+, 320.2584, found 320.2586.TSRI 2216.1PC Me

[0396] The compound was prepared following the general procedure (Method B, 0.5 mL dioxane and 11.6 mg CSA, 3 h) and was purified by flash column chromatography using CH2Cl2 / acetone (5:1) as eluent to give B61 (30.5 mg, 71%) as a white foam.

[0397] Low catalyst loading experiment: The compound was prepared following the general procedure (Method B, 0.5 mL solution 2 and 10.0 mg CSA, 24 h) and was purified by flash column chromatography using CH2Cl2 / acetone (5:1) as eluent to give B61 (30.0 mg, 70%) as a white foam. 1H NMR (400 MHz, CDCl3): δ = 6.10 (br s, 1H), 5.34 (br s, 1H), 5.30 (d, J = 5.5 Hz, 1H), 2.76 – 2.67 (m, 2H), 2.27 – 2.04 (m, 5H), 1.94 – 1.68 (m, 5H), 1.56 – 1.47 (m, 1H), 1.44 – 1.10 (m, 11H), 1.19 (s, 3H), 0.91 (d, J = 6.4 Hz, 3H), 0.88 – 0.84 (m, 1H), 0.86 (d, J = 6.5 Hz, 6H), 0.62 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 173.56, 171.48, 141.98, 118.88, 87.77, 56.22, 52.75, 41.69, 41.38, 40.31, 39.61, 36.21, 35.75, 35.05, 30.66, 28.43, 28.13, 27.73, 27.44, 26.87, 25.16, 23.96, 22.94, 22.69, 22.39, 18.45, 12.04 ppm. HRMS (m / z): [M+H]+calcd for C27H44NO3+, 430.3321, found 430.3319.

[0398] The compound was prepared following the general procedure (Method B, 1 h, 3.2 mg [Cu(MeCN)4]BF4, 0.5 mL dioxane and 11.6 mg CSA) and was purified by flash column chromatography using hexane / acetone (5:1) as eluent to give B62 (35.9 mg, 79%) as a white foam.

[0399] Low catalyst loading experiment: The compound was prepared following the general procedure (Method B, 0.5 mL dioxane, 25 μL solution 1 and 11.6 mg CSA, 20 h) andTSRI 2216.1PC was purified by flash column chromatography using hexane / acetone (5:1) as eluent to give B62 (32.5 mg, 72%) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 6.36 (br s, 1H), 5.59 (br s, 1H), 5.49 – 5.46 (m, 1H), 4.71 (s, 2H), 3.22 (dd, J = 11.3, 4.9 Hz, 1H), 2.89 (td, J = 11.2, 5.5 Hz, 1H), 2.51 (dd, J = 11.2, 2.6 Hz, 1H), 2.32 – 2.28 (m, 1H), 2.23 (dt, J = 13.0, 3.5 Hz, 1H), 2.02 – 1.97 (m, 1H), 1.94 – 1.88 (m, 2H), 1.80 – 1.35 (m, 14H), 1.67 (s, 3H), 1.26 – 1.21 (m, 2H), 1.20 (s, 3H), 1.00 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H), 0.79 (s, 3H), 0.76 – 0.73 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 179.19, 147.98, 141.96, 120.52, 110.24, 79.04, 56.79, 55.39, 49.60, 47.44, 44.95, 44.28, 39.13, 38.99, 38.93, 37.07, 34.20, 33.89, 29.39, 28.71, 28.26, 27.38, 23.46, 23.06, 19.46, 18.36, 17.36, 16.04, 15.78 ppm. HRMS (m / z): [M+H]+calcd for C30H48NO2+, 454.3680, found 454.3689.

[0400] The compound was prepared following the general procedure (Method B, 2 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by by flash column chromatography using CH2Cl2 / acetone (5:1) as eluent to give B63 (32.8 mg, 70%) as a white foam. 1H NMR (400 MHz, CDCl3): δ = 5.74 – 5.71 (m, 2H), 5.50 (br s, 1H), 5.31 (br s, 1H), 3.22 (dd, J = 11.4, 4.9 Hz, 1H), 2.69 (dt, J = 13.5, 3.8 Hz, 1H), 2.29 (s, 1H), 2.15 – 1.94 (m, 2H), 1.72 – 1.37 (m, 11H), 1.35 – 1.32 (m, 1H), 1.31 (s, 3H), 1.25 (s, 1H), 1.21 (s, 3H), 1.19 (s, 6H), 1.00 (s, 3H), 0.99 (s, 3H), 0.95 (dd, J = 12.8, 4.5 Hz, 1H), 0.81 (s, 3H), 0.69 (d, J = 12.0 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 200.16, 178.81, 162.99, 145.89, 129.66, 124.28, 78.90, 61.11, 55.27, 45.61, 44.98, 43.77, 39.25, 39.24, 37.15, 35.91, 35.62, 35.30, 34.12, 30.31, 28.25, 27.41, 26.20, 25.06, 24.77, 19.92, 18.59, 17.71, 16.89, 15.82 ppm. HRMS (m / z): [M+H]+calcd for C30H46NO3+, 468.3478, found 468.3473.TSRI 2216.1PC

[0401] The compound was prepared following the general procedure (Method B, 1.5 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by pTLC (hexane / ethyl acetate 2:1) to give B64 (33.6 mg, 66%) as a white solid.

[0402] Low catalyst loading experiment: The compound was prepared following the general procedure (Method B, 0.5 mL solution 2 and 10.0 mg CSA, 24 h) and was purified by pTLC (hexane / ethyl acetate 2:1) to give B64 (33.1 mg, 65%) as a white solid. 1H NMR (600 MHz, CDCl3): δ = 5.76 (br s, 1H), 5.56 (br s, 1H), 5.45 (s, 1H), 4.51 (dd, J = 11.7, 4.8 Hz, 1H), 2.99 (dd, J = 13.0, 2.4 Hz, 1H), 2.05 (s, 3H), 2.02 – 1.95 (m, 2H), 1.79 – 1.66 (m, 5H), 1.72 (s, 3H), 1.65 – 1.56 (m, 3H), 1.56– 1.51 (m, 1H), 1.49 – 1.36 (m, 3H), 1.31 – 1.27 (m, 1H), 1.26 – 1.22 (m, 2H), 1.20 (s, 3H), 1.13 – 1.07 (m, 1H), 0.98 (s, 3H), 0.98 (s, 3H), 0.97 (s, 3H), 0.91 (s, 3H), 0.95 – 0.91 (m, 1H), 0.89 (s, 3H), 0.87 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 181.54, 171.18, 155.30, 136.36, 125.13, 120.95, 80.60, 51.12, 45.90, 42.38, 42.04, 41.08, 38.63, 38.00, 36.79, 35.98, 34.30, 32.98, 32.77, 32.18, 30.83, 28.26, 27.05, 25.50, 24.31, 23.98, 23.26, 22.26, 21.46, 20.00, 18.26, 16.89, 16.83 ppm. HRMS (m / z): [M+H]+calcd for C33H52NO3+, 510.3947, found 510.3946. m.p. = 230-233 ˚C (from MeCN). Me

[0403] The compound was prepared following the general procedure (Method B, 2 h, with 0.5 mL dioxane and 11.6 mg CSA) and was purified by by flash column chromatography using CH2Cl2 / acetone (5:1) as eluent B65 (29.5 mg, 65%) as a white foam. 1H NMR (600 MHz, (CD3)2SO): δ = 7.10 (br s, 1H), 6.74 (br s, 1H), 6.41 (dd, J = 10.7, 3.1 Hz, 1H), 5.59 – 5.54 (m, 1H), 4.33 (d, J = 5.3 Hz, 1H), 3.05 – 3.00 (m, 1H), 2.60 (d, J =TSRI 2216.1PC 14.8 Hz, 1H), 2.01 (d, J = 14.1 Hz, 1H), 1.87 (s, 1H), 1.85 – 1.77 (m, 2H), 1.65 – 1.57 (m, 1H), 1.58 – 1.49 (m, 4H), 1.45 – 1.34 (m, 5H), 1.34 – 1.27 (m, 2H), 1.03 (s, 3H), 1.01 – 0.93 (m, 2H), 0.92 (s, 3H), 0.91 (s, 3H), 0.90 (s, 3H), 0.82 (s, 3H), 0.8 – 0.75 (m, 1H), 0.67 (s, 3H), 0.66 (s, 3H) ppm. 13C NMR (151 MHz, (CD3)2SO): δ = 179.86, 136.09, 134.26, 125.90, 125.35, 76.81, 54.33, 53.72, 43.04, 41.99, 38.52, 37.59, 37.55, 36.22, 35.40, 34.28, 32.13, 31.86, 29.77, 27.93, 26.86, 25.05, 23.89, 20.06, 19.90, 19.89, 18.03, 17.81, 16.34, 15.47 ppm. HRMS (m / z): [M+H]+calcd for C30H48NO2+, 454.3685, found 454.3699.B66

[0404] The compound was prepared following the general procedure (Method A, 6 h) and was purified by flash column chromatography using CH2Cl2 / acetone (8:1) as eluent to give B66 (6.5 mg, 43%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 6.35 (dd, J = 17.5, 10.8 Hz, 2H), 5.78 – 5.74 (m, 1H), 5.50 (br s, 2H), 5.09 (d, J = 17.5 Hz, 1H), 4.95 (d, J = 10.8 Hz, 2H), 2.46 – 2.32 (m, 4H), 2.21 – 2.13 (m, 1H), 2.09 – 2.03 (m, 1H), 1.80 – 1.73 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.90, 139.34, 135.90, 127.36, 110.96, 40.84, 28.81, 25.78, 23.40 ppm. HRMS (m / z): [M+H]+calcd for C9H14NO+, 152.1070, found 152.1064.

[0405] A reaction tube (16 mL) with a magnetic stir bar was charged with A67 (0.1 mmol), AgBF4(30 mg, 0.2 mmol). DCE (0.5 mL) was added to the tube and the tube was sealed with a screw cap. The reaction mixture was heated at 125 °C for 30 min. Then the reaction was cooled to room temperature before it was filtered through Celite®. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography using hexane / EA 10:1 as eluent to give the mixture of B67 and B67’ (5.5 mg, 22%) as a colorless oil.TSRI 2216.1PC B67 (Z / E mixture):1H NMR (600 MHz, CDCl3): δ = 7.29 – 7.26 (m, 2H), 7.20 – 7.16 (m, 3H), 5.69 – 5.49 (m, 2H), 4.10 – 4.05 (m, 2H), 3.10 – 3.05 (m, 0.6 H), 3.03 – 2.98 (m, 1H), 2.62 (t, J = 7.7 Hz, 2H), 2.42 – 2.35 (m, 0.4 H), 1.73 – 1.61 (m, 7H), 1.43 – 1.36 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 172.45, 172.27, 142.55, 142.54, 129.47, 128.52, 128.43, 127.60, 125.85, 122.96, 115.58, 64.79, 64.73, 64.53, 38.26, 35.92, 32.88, 31.18, 28.64, 28.61, 28.60, 25.68, 18.07, 13.09 ppm. HRMS (m / z): [M+H]+calcd for C16H23O2+, 247.1693, found 247.1687. Me Me

[0406] The compound was prepared following the general procedure (Method C, 0.5 mL AcOH and 40 μL TFA, 5 h) and was purified by flash column chromatography using hexane / ethyl acetate (8:1) as eluent to give C1 (13.9 mg, 76%) as a white solid. 1H NMR (600 MHz, CDCl3): δ = 2.26 – 2.19 (m, 1H), 2.17 – 2.11 (m, 1H), 1.88 – 1.82 (m, 1H), 1.82 – 1.76 (m, 1H), 1.70 – 1.63 (m, 1H), 1.48 – 1.40 (m, 1H), 1.43 (s, 3H), 1.31 – 1.20 (m, 1H), 1.26 (s, 3H), 1.03 – 0.94 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.66, 85.69, 52.43, 44.31, 34.41, 33.86, 32.78, 27.47, 25.82, 22.05, 20.85 ppm. HRMS (m / z): [M+H]+calcd for C11H19O2+, 183.1380, found 183.1373. m.p. = 69-74 ˚C (from hexane). OO

[0407] The compound was prepared following the general procedure (Method C, 0.5 mL AcOH and 40 μL TFA, 20 h) and was purified by flash column chromatography using hexane / ethyl acetate (10:1) as eluent to give C2 (12.3 mg, 73%) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 2.56 (t, J = 8.2 Hz, 2H), 2.02 (t, J = 8.1 Hz, 2H), 1.95 (ddd, J = 14.4, 9.2, 1.8 Hz, 2H), 1.76 (ddd, J = 14.4, 9.6, 1.8 Hz, 2H), 1.72 – 1.62 (m, 4H), 1.58 – 1.50 (m, 2H), 1.49 – 1.40 (m, 2H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 177.03, 90.48, 40.16, 34.37, 29.24, 28.87, 22.40 ppm. HRMS (m / z): [M+H]+calcd for C10H17O2+, 169.1229, found 169.1225. Me Me

[0408] The compound was prepared following the general procedure (Method C, 3.2 mg [Cu(MeCN)4]BF4, 0.5 mL dioxane and 40 μL TFA, 8 h) and was purified by flash column chromatography using hexane / EA (5:1) as eluent to give C3 (12.6 mg, 78%) as a colorless oil.

[0409] Low catalyst loading experiment: The compound was prepared following the general procedure (Method C, 0.5 mL dioxane, 25 μL solution 1 and 40 μL TFA, 24 h) and was purified by flash column chromatography using hexane / EA (5:1) as eluent to give C3 (12.3 mg, 76%) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 7.87 (dt, J = 7.6, 1.0 Hz, 1H), 7.66 (td, J = 7.6, 1.2 Hz, 1H), 7.51 (td, J = 7.6, 1.0 Hz, 1H), 7.40 (dt, J = 7.7, 0.9 Hz, 1H), 1.66 (s, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 169.95, 155.14, 134.23, 129.06, 125.94, 125.48, 120.78, 85.55, 27.50 ppm. HRMS (m / z): [M+H]+calcd for C10H11O2+, 163.0754, found 163.0751. MeO OMe NPhth C4

[0410] The compound was prepared following the general procedure (Method C, 3.2 mg [Cu(MeCN)4]BF4, 0.5 mL dioxane and 40 μL TFA, 5 h) and was purified by pTLC (CH2Cl2 / ethyl acetate 10:1) to give C4 (16.1 mg, 62%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.89 – 7.85 (m, 2H), 7.78 – 7.74 (m, 2H), 5.23 (dd, J = 11.5, 9.6 Hz, 1H), 2.62 – 2.57 (m, 1H), 2.44 (dd, J = 12.4, 9.6 Hz, 1H), 1.64 (s, 3H), 1.51 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.58, 167.10, 134.61, 131.85, 123.88, 82.55, 48.73, 38.66, 29.08, 27.69 ppm. HRMS (m / z): [M+H]+calcd for C14H14NO4+, 260.0923, found 260.0924.TSRI 2216.1PC O OAc

[0411] The compound was prepared following the general procedure (Method C, 3.2 mg [Cu(MeCN)4]BF4, 0.5 mL toluene and 40 μL TFA, 6 h) and was purified by flash column chromatography using hexane / ethyl acetate (4:1) as eluent to give C5 (10.0 mg, 58%) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 5.57 (dd, J = 9.6, 8.8 Hz, 1H), 2.59 (dd, J = 12.9, 8.8 Hz, 1H), 2.16 (s, 3H), 2.06 (dd, J = 12.8, 9.6 Hz, 1H), 1.52 (s, 3H), 1.45 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 172.21, 169.95, 82.32, 69.30, 41.27, 29.19, 27.99, 20.79 ppm. HRMS (m / z): [M+H]+calcd for C8H12O4+, 173.0809, found 173.0821. O O

[0412] The compound was prepared following the general procedure (Method C, 0.5 mL AcOH and 40 μL TFA, 20 h) and was purified by flash column chromatography using hexane / EA (10:1) as eluent to give C6 (9.8 mg, 41%) as white powder. 1H NMR (400 MHz, CDCl3): δ = 2.57 (t, J = 8.3 Hz, 2H), 1.99 (t, J = 8.3 Hz, 2H), 1.88 – 1.76 (m, 2H), 1.61 – 1.56 (m, 1H), 1.55 – 1.44 (m, 2H), 1.41 – 1.19 (m, 17H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.03, 90.05, 33.57, 32.71, 28.89, 26.30, 26.01, 22.62, 22.23, 19.54 ppm. HRMS (m / z): [M+H]+calcd for C15H27O2+, 239.2006, found 239.2014. OO

[0413] The compound was prepared following the general procedure (Method C, 3.2 mg [Cu(MeCN)4]BF4, 0.5 mL dioxane and 40 μL TFA, 6 h) and was purified by pTLC (CH2Cl2 / ethyl acetate 10:1) to give C7 (16.1 mg, 62%) as a white powder.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 7.91 – 7.84 (m, 2H), 7.81 – 7.74 (m, 2H), 4.82 – 4.78 (m, 1H), 3.18 – 3.06 (m, 2H), 1.54 (s, 3H), 1.30 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 173.81, 168.07, 134.77, 131.42, 123.95, 85.88, 54.47, 32.95, 27.98, 22.77 ppm. HRMS (m / z): [M+H]+calcd for C14H14NO4+, 260.0918, 260.0913. OO

[0414] The compound was prepared following the general procedure (Method C, 0.5 mL AcOH and 40 μL TFA, 12 h) and was purified by flash column chromatography using hexane / EA (10:1) as eluent to give C8 (17.3 mg, 73%) as a colorless oil. Low catalyst loading experiment: The compound was prepared following the general procedure (Method C, 0.5 mL solution 3 and 40 μL TFA, 24 h) and was purified by flash column chromatography using hexane / EA (10:1) as eluent to give C8 (19.0 mg, 80%) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 2.56 (dd, J = 17.4, 8.4 Hz, 1H), 2.32 (dd, J = 17.5, 11.6 Hz, 1H), 1.89 (dt, J = 11.6, 8.7 Hz, 1H), 1.84 – 1.78 (m, 1H), 1.76 – 1.56 (m, 12H), 1.49 (ddd, J = 13.6, 11.7, 5.2 Hz, 1H), 1.44 – 1.36 (m, 1H), 1.29 – 1.10 (m, 4H), 1.04 – 0.89 (m, 2H). 13C NMR (151 MHz, CDCl3): δ = 176.05, 88.57, 51.34, 38.31, 38.03, 33.90, 32.66, 31.87, 30.64, 26.22, 26.15, 26.09, 25.47, 22.88, 21.72 ppm. HRMS (m / z): [M+H]+calcd for C15H25O2+, 237.1855, found 237.1859. O O Me

[0415] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 9.5 mg TsOH·H2O, 12 h) and was purified by flash column chromatography using hexane / acetone (2:1) as eluent to give C9 (26.8 mg, 69%) as white powder.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 7.88 – 7.84 (m, 2H), 7.75 – 7.71 (m, 2H), 6.66 – 6.60 (m, 1H), 5.68 (dd, J = 10.1, 8.9 Hz, 1H), 4.33 (s, 2H), 3.67 – 3.53 (m, 2H), 2.67 – 2.63 (m, 2H), 2.57 (dd, J = 12.7, 8.9 Hz, 1H), 2.19 (dd, J = 13.0, 10.4 Hz, 1H), 1.56 (s, 3H), 1.46 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 172.69, 171.28, 167.93, 166.49, 134.30, 132.24, 123.73, 82.87, 69.48, 40.83, 40.64, 35.60, 34.23, 29.14, 27.89 ppm. HRMS (m / z): [M+H]+calcd for C19H21N2O7+, 389.1349, found 389.1346. MeOMe C10

[0416] The compound was prepared following the general procedure (Method C, 3.2 mg [Cu(MeCN)4]BF4, 0.5 mL dioxane and 40 μL TFA, 5 h) and was purified by flash column chromatography using hexane / ethyl acetate (8:1) as eluent to give C10 (13.0 mg, 71%) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 7.50 – 7.44 (m, 2H), 7.12 – 7.06 (m, 1H), 5.55 (q, J = 6.7 Hz, 1H), 3.91 (s, 3H), 1.65 (d, J = 6.7 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.63, 154.45, 139.19, 130.98, 127.82, 117.32, 115.06, 77.16, 55.73, 19.16 ppm. HRMS (m / z): [M+H]+calcd for C10H11O3+, 179.0708, found 179.0707. O NPhth

[0417] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 9.5 mg TsOH·H2O, 2 h)) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give C11 (18.8 mg, 61%, d.r. = 3:2) as white powder. 1H NMR (600 MHz, CDCl3): δ = 7.92 – 7.86 (m, 2H), 7.79 – 7.74 (m, 2H), 7.55 – 7.51 (m, 1H), 7.48 – 7.42 (m, 2H), 7.41 – 7.33 (m, 2H), 5.93 (dd, J = 8.7, 3.3 Hz, 0.4H), 5.50 (dd, J = 10.7, 6.1 Hz, 0.6H), 5.30 (dd, J = 12.0, 9.2 Hz, 0.6H), 5.18 – 5.14 (m, 0.4H), 3.15 – 3.08 (m, 0.4H), 2.95 – 2.88 (m, 0.6H), 2.86 – 2.79 (m, 0.6H), 2.67 – 2.62 (m, 0.4H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 172.38, 171.65, 167.08, 167.06, 139.13, 138.10, 134.70, 131.83, 131.80, 129.37, 129.20, 129.08, 128.81, 126.53, 125.12, 123.98, 123.96, 79.17, 78.72, 49.05, 46.61, 35.45, 34.32 ppm. HRMS (m / z): [M+H]+calcd for C18H14NO4+, 308.0918, found 308.0929. O OMe

[0418] The compound was prepared following the general procedure (Method C, 3.2 mg [Cu(MeCN)4]BF4, 0.5 mL dioxane and 40 μL TFA, 12 h) and was purified by pTLC (hexane / acetone 3:1) to give C12 (7.1 mg, 48%) as a white powder and the dehydrogenated product (4.4 mg, 29%). 1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 4.7 Hz, 1H), 7.01 (d, J = 5.0 Hz, 1H), 5.51 (q, J = 6.8 Hz, 1H), 1.62 (d, J = 6.7 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 165.03, 164.77, 140.36, 129.70, 119.87, 76.91, 20.28 ppm. HRMS (m / z): M+calcd for C7H6SO2+, 154.0, found 154.0. Me

[0419] The compound was prepared following the general procedure (Method D, 11.6 mg CSA, 3 h) and was purified by flash column chromatography using hexane / acetone (5:1 → 2:1) as eluent to give C13 (5.0 mg, 35%, d.r. =3:2) as a colorless oil and the dehydrogenated product (5.5 mg, 39%). 1H NMR (600 MHz, CDCl3): δ = 4.70 – 4.63 (m, 0.6H), 4.51 – 4.45 (m, 0.4H), 2.67 – 2.58 (m, 1H), 2.47 (ddd, J = 12.5, 8.5, 5.5 Hz, 0.4H), 2.11 – 2.05 (m, 0.6H), 2.01 (ddd, J = 12.8, 9.1, 5.1 Hz, 0.6H), 1.93 – 1.86 (m, 0.4H), 1.85 – 1.78 (m, 0.4H), 1.52 – 1.36 (m, 7H), 0.97 – 0.93 (m, 3H), 0.91 – 0.86 (m, 0.4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 179.73, 179.38, 75.31, 75.16, 41.45, 39.28, 37.15, 35.21, 32.92, 32.57, 21.39, 21.15, 20.73, 20.72, 13.95, 13.93 ppm. HRMS (m / z): [M+H]+calcd for C8H15O2+, 143.1067, found 143.1073TSRI 2216.1PC OO C14

[0420] The compound was prepared following the general procedure (Method D, 11.6 mg CSA, 7 h) and was purified by flash column chromatography using hexane / acetone (5:1 → 2:1) as eluent to give C14 (12.0 mg, 46%) as a white powder and the dehydrogenated product (5.9 mg, 23%). 1H NMR (600 MHz, CDCl3): δ = 7.88 – 7.83 (m, 2H), 7.77 – 7.72 (m, 2H), 4.99 (s, 1H), 3.45 – 3.41 (m, 1H), 2.81 – 2.75 (m, 1H), 2.71 – 2.64 (m, 1H), 2.14 – 2.09 (m, 2H), 2.07 – 2.03 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 173.23, 168.16, 134.51, 131.83, 123.61, 78.33, 64.35, 42.91, 28.54, 26.30 ppm. HRMS (m / z): [M+H]+calcd for C14H12NO4+, 258.0761, found 258.0770. O NPhth

[0421] The compound was prepared following the general procedure (Method D, 11.6 mg CSA, 2 h) and was purified by flash column chromatography using hexane / acetone (5:1 → 2:1) as eluent to give C15 (11.9 mg, 48%, d.r. = 4:5) as a white powder and the dehydrogenated product (6.8 mg, 28%). 1H NMR (400 MHz, CDCl3): δ = 7.91 – 7.85 (m, 2H), 7.79 – 7.73 (m, 2H), 5.20 – 5.12 (m, 1H), 5.08 – 4.96 (m, 0.45H), 4.73 – 4.63 (m, 0.55H), 2.84 – 2.75 (m, 0.45H), 2.69 – 2.61 (m, 0.55H), 2.49 – 2.39 (m, 0.55H), 2.32 – 2.23 (m, 0.45H), 1.59 (d, J = 6.1 Hz, 1.65H), 1.50 (d, J = 6.6 Hz, 1.35H) ppm. 13C NMR (151 MHz, CDCl3): δ = 172.31, 171.88, 167.07, 167.04, 134.62, 134.61, 131.82, 131.81, 123.90, 123.87, 75.09, 74.63, 49.08, 46.93, 34.33, 33.08, 21.65, 21.11 ppm. HRMS (m / z): [M+H]+calcd for C13H12NO4+, 246.0761, found 246.0761. O EtTSRI 2216.1PC

[0422] The compound was prepared following the general procedure (Method D, 11.6 mg CSA, 3 h) and was purified by flash column chromatography using hexane / acetone (5:1 → 2:1) as eluent to give C16 (9.3 mg, 33%) as a white powder and the dehydrogenated product (11.8 mg, 42%). 1H NMR (600 MHz, CDCl3): δ = 4.51 – 4.45 (m, 1H), 2.55 – 2.50 (m, 2H), 2.35 – 2.28 (m, 1H), 1.89 – 1.80 (m, 1H), 1.77 – 1.70 (m, 1H), 1.63 – 1.56 (m, 1H), 1.50 – 1.41 (m, 1H), 1.40 – 1.21 (m, 23H), 0.88 (t, J = 6.9 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.43, 81.21, 35.75, 32.07, 29.84, 29.82, 29.80, 29.77, 29.67, 29.61, 29.51, 29.49, 29.02, 28.17, 25.38, 22.84, 14.27 ppm. HRMS (m / z): [M+H]+calcd for C18H35O2+, 283.2632, found 283.2620. ONPhth

[0423] The compound was prepared following the general procedure (Method D, 11.6 mg CSA, 2 h) and was purified by flash column chromatography using hexane / acetone (4:1 → 2:1) as eluent to give C17 (13.5 mg, 52%, d.r. = 1:1) as a white powder and the dehydrogenated product (7.5 mg, 29%). 1H NMR (400 MHz, CDCl3): δ = 7.91 – 7.84 (m, 2H), 7.79 – 7.72 (m, 2H), 5.20 – 5.07 (m, 1H), 4.84 – 4.76 (m, 0.5H), 4.55 – 4.44 (m, 0.5H), 2.77 – 2.67 (m, 0.5H), 2.65 – 2.56 (m, 0.5H), 2.52 – 2.41 (m, 0.5H), 2.37 – 2.28 (m, 0.5H), 2.01 – 1.90 (m, 0.5H), 1.90 – 1.79 (m, 1H), 1.79 – 1.68 (m, 0.5H), 1.12 – 1.02 (m, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 172.45, 171.91, 167.07, 167.05, 134.62, 134.60, 131.84, 131.82, 123.90, 123.86, 80.01, 79.34, 48.79, 46.94, 32.18, 31.25, 28.87, 28.41, 9.58, 9.22 ppm. HRMS (m / z): [M+H]+calcd for C14H14NO4+, 260.0918, found 260.0929. O O

[0424] The compound was prepared following the general procedure (Method D, 11.6 mg CSA, 3 h) and was purified by pTLC (hexane / acetone 2:1) to give C18 (7.2 mg, 25%, d.r.TSRI 2216.1PC =3:2) as a white powder, C18’ (6.3 mg, 22%), and the dehydrogenated product (8.0 mg, 28%). 1H NMR (600 MHz, CDCl3): δ = 7.90 – 7.84 (m, 2H), 7.79 – 7.73 (m, 2H), 4.14 – 4.11 (m, 0.6H), 4.09 (dd, J = 9.9, 5.3 Hz, 0.4H), 3.84 – 3.68 (m, 2H), 3.02 – 2.95 (m, 0.4H), 2.82 – 2.75 (m, 0.6H), 2.67 (dd, J = 18.1, 9.5 Hz, 0.6H), 2.60 – 2.53 (m, 0.4H), 2.52 – 2.44 (m, 1H), 2.09 – 2.00 (m, 0.4H), 1.92 – 1.84 (m, 0.6H), 1.15 (d, J = 6.4 Hz, 1.2H), 1.12 (d, J = 6.6 Hz, 1.2H), 1.00 (d, J = 6.8 Hz, 1.8H), 0.97 (d, J = 6.8 Hz, 1.8H) ppm. 13C NMR (151 MHz, CDCl3): δ = 175.68, 175.54, 168.51, 168.46, 134.57, 134.46, 131.92, 131.79, 123.77, 123.68, 87.73, 87.50, 40.97, 37.30, 37.19, 36.26, 34.68, 33.22, 32.34, 28.65, 20.25, 18.32, 18.29, 17.25 ppm. HRMS (m / z): [M+H]+calcd for C16H18NO4+, 288.1231, found 288.1232. O OWhite powder. d.r. > 10:1 1H NMR (600 MHz, CDCl3): δ = 7.92 – 7.87 (m, 2H), 7.82 – 7.77 (m, 2H), 6.01 (d, J = 4.2 Hz, 1H), 3.28 (dd, J = 18.0, 9.6 Hz, 1H), 3.12 – 3.06 (m, 1H), 2.33 (dd, J = 18.0, 5.7 Hz, 1H), 1.68 – 1.61 (m, 1H), 1.56 – 1.51 (m, 1H), 1.50 – 1.44 (m, 1H), 0.92 – 0.87 (m, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 175.28, 166.89, 134.97, 131.60, 124.15, 84.12, 43.77, 36.60, 35.09, 26.00, 22.66, 22.39 ppm. HRMS (m / z): [M+H]+calcd for C16H18NO4+, 288.1231, found 288.1242. O O

[0425] The compound was prepared following the general procedure (Method D, 11.6 mg CSA, 3 h) and was purified by pTLC (hexane / acetone 2:1) to give C19 (8.1 mg, 27%) as a white powder, C19’ (5.7 mg, 19%), and the dehydrogenated product (6.8 mg, 23%).TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 7.90 – 7.85 (m, 2H), 7.79 – 7.74 (m, 2H), 4.32 – 4.30 (m, 1H), 3.84 – 3.77 (m, 2H), 2.68 (d, J = 17.0 Hz, 1H), 2.25 (d, J = 17.0 Hz, 1H), 2.11 – 2.03 (m, 1H), 1.95 – 1.86 (m, 1H), 1.67 – 1.57 (m, 4H), 1.56 – 1.43 (m, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 175.79, 168.88, 134.60, 131.82, 123.80, 80.47, 43.35, 42.26, 41.18, 30.44, 25.64, 20.85, 19.58 ppm. HRMS (m / z): [M+H]+calcd for C17H18NO4+, 300.1231, found 300.1246. O OWhite powder. 1H NMR (500 MHz, CDCl3): δ = 7.94 – 7.88 (m, 1H), 7.84 – 7.78 (m, 1H), 6.09 (s, 1H), 3.07 (d, J = 17.8 Hz, 1H), 2.56 (d, J = 17.8 Hz, 1H), 1.80 – 1.71 (m, 3H) 1.57 – 1.31 (m, 7H) ppm. 13C NMR (151 MHz, CDCl3): δ = 175.93, 167.48, 134.90, 131.61, 124.08, 87.22, 42.94, 39.66, 37.20, 31.89, 25.30, 23.33, 22.31 ppm. HRMS (m / z): [M+H]+calcd for C17H18NO4+, 300.1231, found 300.1238. OMe

[0426] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 19 mg TsOH·H2O, 3 h)) and was purified by flash column chromatography using hexane / EtOAc (1:1) as eluent to give C20 (12.8 mg, 78%) as white powder. 1H NMR (400 MHz, CDCl3): δ = 7.53 – 7.44 (m, 2H), 7.15 – 7.06 (m, 1H), 5.27 (s, 2H), 3.92 (s, 3H);13C NMR (151 MHz, CDCl3): δ = 171.32, 154.39, 135.11, 130.95, 127.55, 117.44, 114.84, 68.27, 55.74 ppm. HRMS (m / z): [M+H]+calcd for C9H9O3+, 165.0552, found 165.0548. ITSRI 2216.1PC

[0427] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 9.5 mg TsOH·H2O, 2 h)) and was purified by flash column chromatography using hexane / EtOAc (1:1) as eluent to give C21 (17.9 mg, 69%) as light brown powder. 1H NMR (400 MHz, CDCl3): δ = 8.05 (dd, J = 7.7, 0.9 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 5.13 (s, 2H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.50, 151.05, 142.88, 131.00, 127.91, 125.55, 88.40, 72.84 ppm. HRMS (m / z): [M+H]+calcd for C8H6IO2+, 260.9412, found 260.9413. NHTs

[0428] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 9.5 mg TsOH·H2O, 4 h)) and was purified by flash column chromatography using hexane / EtOAc (1:1) as eluent to give C22 (24.3 mg, 80%) as white powder. 1H NMR (600 MHz, CDCl3): δ = 7.78 (dd, J = 7.6, 0.9 Hz, 1H), 7.64 – 7.59 (m, 2H), 7.44 – 7.40 (m, 1H), 7.27 (dd, J = 8.6, 0.8 Hz, 2H), 7.23 (dd, J = 7.8, 1.0 Hz, 1H), 6.81 (s, 1H), 5.27 (s, 2H), 2.42 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.48, 145.00, 142.18, 135.50, 131.24, 130.51, 130.17, 129.90, 127.94, 127.37, 124.24, 68.81, 21.78 ppm. HRMS (m / z): [M+H]+calcd for C15H14NO4S+, 304.0644, found 304.0641. O O

[0429] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 19 mg TsOH·H2O, 2 h)) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give C23 (15.7 mg, 90%) as white powder. 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.9 Hz, 1H), 7.20 (dd, J = 8.0, 0.9 Hz, 1H), 7.13 (s, 1H), 5.25 (s, 2H), 2.06 – 1.98 (m, 1H), 1.15 – 1.08 (m, 2H), 0.83 – 0.77 (m, 2H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 171.27, 152.08, 147.28, 126.86, 125.67, 123.14, 118.75, 69.53, 16.28, 10.89 ppm. HRMS (m / z): [M+H]+calcd for C11H11O2+, 175.0759, found 175.0758. O O

[0430] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and, 19 mg TsOH·H2O, 2 h) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give C24 (17.3 mg, 90%) as light brown powder. 1H NMR (400 MHz, CDCl3): δ = 8.24 – 8.15 (m, 2H), 7.99 (d, J = 8.0 Hz, 1H), 5.38 (s, 2H), 3.98 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.14, 165.91, 146.55, 135.52, 130.51, 129.57, 125.99, 123.68, 69.75, 52.93 ppm. HRMS (m / z): [M+H]+calcd for C10H9O4+, 193.0501, found 193.0500.

[0431] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 μL TFA, 2 h) and was purified by flash column chromatography using hexane / EtOAc (1:1) as eluent to give C25 (14.1 mg, 71%) as white powder.

[0432] Low catalyst loading experiment: The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 μL solution 4, 24 h) and was purified by flash column chromatography using hexane / EtOAc (1:1) as eluent to give C25 (14.5 mg, 73%) as white powder. 1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.79 – 7.72 (m, 1H), 7.72 – 7.64 (m, 2H), 5.62 (s, 2H), 2.77 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 172.10, 145.48, 137.14, 135.47, 129.31, 127.58, 127.13, 125.79, 124.19, 122.88, 120.75, 69.22, 19.97 ppm. HRMS (m / z): [M+H]+calcd for C13H11O2+, 199.0759, found 199.0760.TSRI 2216.1PC OMe

[0433] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 19 mg TsOH·H2O, 4 h) and was purified by flash column chromatography using hexane / acetone (4:1) as eluent to give C26 (15.1 mg, 60%) as brown powder. 1H NMR (400 MHz, CDCl3): δ = 6.53 (s, 2H), 5.45 (dd, J = 8.3, 5.8 Hz, 1H), 3.87 (s, 6H), 3.84 (s, 3H), 2.72 – 2.59 (m, 3H), 2.27 – 2.12 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.93, 153.73, 138.09, 135.13, 102.32, 81.40, 61.02, 56.38, 31.28, 29.20 ppm. HRMS (m / z): [M+H]+calcd for C13H17O5+, 253.1076, found 253.1078. O O Me

[0434] The compound was prepared following the general procedure (Method C, 2.0 mg CuF2, 0.5 mL dioxane and 11.6 mg CSA, 4 h) and was purified by pTLC (hexane / acetone 2:1) to give C27 (6.9 mg, 46%) as a pale yellow powder. 1H NMR (600 MHz, CDCl3): δ = 8.86 (dd, J = 4.8, 1.6 Hz, 1H), 8.19 (dd, J = 7.7, 1.5 Hz, 1H), 7.48 (dd, J = 7.7, 4.9 Hz, 1H), 5.56 (q, J = 6.7 Hz, 1H), 1.71 (d, J = 6.7 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3) δ 170.08, 168.57, 155.36, 134.28, 124.14, 119.63, 78.95, 18.85 ppm. HRMS (m / z): [M+H]+calcd for C8H8NO2+, 150.0555, found 150.0552. O O

[0435] The compound was prepared following the general procedure (Method C, 2.0 mg CuF2, 0.5 mL dioxane and 11.6 mg CSA, 4 h) and was purified by pTLC (hexane / acetone 2:1) to give C28 (5.1 mg, 31%) as a pale yellow oil.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 8.60 (d, J = 4.4 Hz, 1H), 7.73 (td, J = 7.7, 1.7 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.28 – 7.23 (m, 1H), 5.60 – 5.55 (m, 1H), 2.74 (dddd, J = 12.5, 9.6, 7.5, 6.0 Hz, 1H), 2.70 – 2.59 (m, 2H), 2.42 (dddd, J = 12.5, 9.0, 7.6, 6.4 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.20, 158.71, 149.69, 137.20, 123.38, 120.31, 81.15, 28.73, 28.35 ppm. HRMS (m / z): [M+H]+calcd for C9H10NO2+, 164.0712, found 164.0709. O OPh

[0436] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ^^^^L TFA, 8 h) and was purified by flash column chromatography using hexane / EtOAc (4:1) as eluent to give C29 (18.2 mg, 66%, d.r. = 3:2) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.43 – 7.31 (m, 5H), 5.56 – 5.43 (m, 1H), 4.36 – 4.22 (m, 1.2H), 4.20 – 4.11 (m, 0.8H), 3.10 (dd, J = 13.2, 6.1 Hz, 0.6H), 2.83 (dd, J = 13.5, 8.0 Hz, 0.4H), 2.66 (dd, J = 13.4, 7.4 Hz, 0.4H), 2.21 – 1.91 (m, 2H), 1.79 (ddd, J = 13.8, 12.0, 4.8 Hz, 0.6H), 1.55 – 1.20 (m, 5H), 1.04 – 0.92 (m, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 174.77, 174.18, 170.07, 169.57, 139.24, 138.95, 128.95, 128.88, 128.78, 128.71, 125.66, 125.58, 79.42, 78.63, 62.53, 62.22, 56.79, 55.56, 40.84, 40.15, 36.74, 36.24, 18.42, 18.35, 14.33, 14.27, 14.24, 14.05 ppm. HRMS (m / z): [M+H]+calcd for C16H21O4+, 277.1440, found 277.1440. O O

[0437] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ^^^^L TFA, 6 h) and was purified by flash column chromatography using hexane / EtOAc (2:1) as eluent to give C30 (15.4 mg, 64%) as white powder. 1H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 5.46 (dd, J = 8.2, 6.1 Hz, 1H), 2.73 – 2.60 (m, 3H), 2.20 – 2.06 (m, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 176.64, 138.58, 132.09, 127.09, 122.56, 80.57, 31.07, 28.98 ppm.TSRI 2216.1PC HRMS (m / z): [M+H]+calcd for C10H10BrO2+, 240.9864, found 240.9859. O O

[0438] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ^^^^L TFA, 4.5 h) and was purified by flash column chromatography using hexane / EtOAc (2:1) as eluent to give C31 (16.2 mg, 78%) as light brown powder. 1H NMR (600 MHz, CDCl3): δ = 8.29 – 8.23 (m, 2H), 7.55 – 7.49 (m, 2H), 5.60 (dd, J = 8.3, 6.9 Hz, 1H), 2.81 – 2.63 (m, 3H), 2.20 – 2.12 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.09, 148.02, 146.73, 126.08, 124.26, 79.75, 31.05, 28.76 ppm. HRMS (m / z): [M]+calcd for C10H9NO4+, 207.0532, found 207.0. O O

[0439] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ^^^^L TFA, 3 h) and was purified by flash column chromatography using hexane / EtOAc (2:1) as eluent to give C32 (10.6 mg, 60%) as light brown powder. 1H NMR (600 MHz, CDCl3): δ = 7.24 – 7.21 (m, 2H), 7.21 – 7.18 (m, 2H), 5.51 – 5.46 (m, 1H), 2.68 – 2.59 (m, 3H), 2.36 (s, 3H), 2.25 – 2.15 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.11, 138.49, 136.47, 129.56, 125.48, 81.48, 31.11, 29.19, 21.29 ppm. HRMS (m / z): [M+H]+calcd for C11H13O2+, 177.0916, found 177.0910. O O

[0440] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 9.5 mg TsOH·H2O, 8 h) and was purified by flash column chromatography using hexane / EtOAc (5:1) as eluent to give C33 (7.2 mg, 41%) as a colorless oil.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 7.43 – 7.37 (m, 2H), 7.36 – 7.30 (m, 3H), 6.32 (t, J = 2.8 Hz, 1H), 5.69 (t, J = 2.5 Hz, 1H), 5.53 (dd, J = 8.1, 6.4 Hz, 1H), 3.41 (ddt, J = 17.0, 8.0, 2.4 Hz, 1H), 2.92 (ddt, J = 17.0, 6.4, 2.8 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 170.29, 139.97, 134.35, 129.00, 128.73, 125.54, 122.62, 78.11, 36.45 ppm. HRMS (m / z): [M+H]+calcd for C11H11O2+, 175.0759, found 175.0759. OO

[0441] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ^^^^L TFA, 3 h) and was purified by flash column chromatography using hexane / EtOAc (2:1) as eluent to give C34 (17.5 mg, 72%) as a pale yellow powder. 1H NMR (600 MHz, CDCl3): δ = 7.49 (s, 1H), 7.42 – 7.34 (m, 3H), 7.30 – 7.26 (m, 2H), 5.64 (t, J = 6.4 Hz, 1H), 5.54 (d, J = 14.8 Hz, 1H), 5.51 (d, J = 14.8 Hz, 1H), 2.73 – 2.58 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.74, 146.78, 134.22, 129.39, 129.15, 128.39, 122.00, 74.36, 54.53, 28.44, 27.96 ppm. HRMS (m / z): [M+H]+calcd for C13H14N3O2+, 244.1086, found 244.1086. O O

[0442] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ^^^^L TFA, 3 h) and was purified by flash column chromatography using hexane / EtOAc (5:1) as eluent to give C35 (12.0 mg, 59%) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 7.41 – 7.30 (m, 5H), 5.45 (t, J = 7.0 Hz, 1H), 5.42 (s, 1H), 5.41 (s, 1H), 2.56 – 2.50 (m, 2H), 2.46 – 2.39 (m, 1H), 2.03 – 1.94 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.11, 146.38, 138.03, 128.81, 128.39, 126.90, 113.64, 80.50, 28.15, 27.99 ppm. HRMS (m / z): [M+H]+calcd for C12H13O2+, 189.0916, found 189.0909.TSRI 2216.1PC O O

[0443] The compound was prepared following the general procedure (Method D, 11.6 mg CSA, 20 h) and was purified by pTLC (hexane / EA 4:1) to give C36 (8.9 mg, 50%) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 7.34 – 7.30 (m, 2H), 7.28 – 7.22 (m, 3H), 4.77 – 4.71 (m, 1H), 3.08 (dd, J = 14.1, 6.1 Hz, 1H), 2.93 (dd, J = 14.0, 6.3 Hz, 1H), 2.50 – 2.42 (m, 1H), 2.38 (ddd, J = 17.7, 9.4, 4.7 Hz, 1H), 2.29 – 2.22 (m, 1H), 2.00 – 1.92 (m, 1H). 13C NMR (151 MHz, CDCl3): δ = 177.14, 136.02, 129.60, 128.81, 127.14, 80.92, 41.48, 28.79, 27.28 ppm. HRMS (m / z): [M+H]+calcd for C11H13O2+, 177.0910, found 177.0915. O O

[0444] The compound was prepared following the general procedure (Method C, 101 mg CuF2, 0.5 mL dioxane and 40 ^^^^L TFA, 24 h) and was purified by flash column chromatography using hexane / EtOAc (4:1) as eluent to give C37 (14.0 mg, 73%) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 4.11 (d, J = 3.5 Hz, 1H), 2.36 – 2.32 (m, 1H), 2.23 (d, J = 16.0 Hz, 1H), 2.13 (d, J = 16.0 Hz, 1H), 2.05 – 2.01 (m, 1H), 1.98 –1.84 (m, 4H), 1.78 – 1.59 (m, 6H), 1.52 (dt, J = 12.7, 3.1 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.30, 87.22, 44.62, 39.42, 39.09, 36.99, 36.61, 36.28, 29.88, 29.41, 28.76, 27.13 ppm. HRMS (m / z): [M+H]+calcd for C12H17O2+, 193.1229, found 193.1231. H O OTSRI 2216.1PC

[0445] The compound was prepared following the general procedure (Method D, 11.6 mg CSA, 3 h) and was purified by by flash column chromatography using hexane / EA (2:1) as eluent to give C38 (15.3 mg, 56%) as a white solid. 1H NMR (600 MHz, CDCl3): δ = 7.90 – 7.86 (m, 2H), 7.78 – 7.74 (m, 2H), 5.33 – 5.29 (m, 1H), 4.71 (d, J = 5.5 Hz, 1H), 3.03 – 2.98 (m, 1H), 2.15 – 2.09 (m, 1H), 1.93 – 1.74 (m, 5H) ppm. 13C NMR (151 MHz, CDCl3): δ = 173.34, 167.00, 134.61, 131.86, 123.91, 85.25, 54.19, 44.25, 33.27, 32.69, 23.50 ppm. HRMS (m / z): [M+H]+calcd for C15H14NO4+, 272.0918, found 272.0920. m.p. = 152-155 ˚C (from MeCN). OO

[0446] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 20 μL TFA, 3 h) and was purified by flash column chromatography using hexane / EA (10:1) as eluent to give C39 (14.3 mg, 77%) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 7.46 – 7.43 (m, 2H), 7.38 – 7.31 (m, 3H), 5.37 (dd, J = 7.4, 5.6 Hz, 1H), 2.77 – 2.71 (m, 1H), 2.65 – 2.54 (m, 2H), 2.45 – 2.39 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.20, 131.96, 129.25, 128.55, 121.70, 87.55, 85.10, 69.76, 30.04, 28.04 ppm. HRMS (m / z): [M+H]+calcd for C12H11O2+, 187.0759, found 187.0755. O O

[0447] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 20 μL TFA, 3 h) and was purified by flash column chromatography using hexane / EA (10:1) as eluent to give C40 (8.0 mg, 53%) as a pale yellow oil.TSRI 2216.1PC 1H NMR (600 MHz, CDCl3): δ = 5.83 – 5.75 (m, 1H), 5.33 – 5.26 (m, 1H), 5.19 – 5.10 (m, 2H), 3.03 – 3.00 (m, 2H), 2.72 – 2.61 (m, 1H), 2.58 – 2.46 (m, 2H), 2.33 – 2.23 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3) δ 176.29, 131.61, 116.80, 85.35, 78.95, 69.64, 30.17, 28.03, 23.10 ppm. HRMS (m / z): [M+H]+calcd for C9H11O2+, 151.0759, found 151.0753. OMe

[0448] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ^^^^L TFA, 5 h) and was purified by flash column chromatography using hexane / EtOAc (2:1) as eluent to give C41 (25.8 mg, 79%, mixture of rotamers 5:4) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 7.76 (d, J = 9.0 Hz, 1H), 7.69 (dd, J = 8.8, 3.4 Hz, 1H), 7.30 (d, J = 2.6 Hz, 0.55H), 7.13 (t, J = 8.8 Hz, 1H), 7.09 (d, J = 2.6 Hz, 0.42H), 7.02 (dt, J = 8.8, 2.1 Hz, 1H), 5.95 (s, 0.56H), 5.92 (s, 0.44H), 5.43 (dd, J = 9.2, 6.9 Hz, 0.56H), 5.26 (s, 0.53H), 5.25 (s, 0.42H), 5.05 (t, J = 7.8 Hz, 0.43H), 3.92 (s, 1.70H), 3.90 (s, 1.23H), 3.88 (s, 1.23H), 3.86 (s, 1.71H), 2.23 (dd, J = 12.8, 8.7 Hz, 0.46H), 2.12 (dd, J = 12.8, 6.7 Hz, 0.48H), 1.99 (dd, J = 12.8, 6.8 Hz, 0.56H), 1.85 (dd, J = 12.8, 9.4 Hz, 0.61H), 1.33 (s, 1.32H), 1.24 (s, 1.70H), 1.22 (s, 1.71H), 1.21 (s, 1.32H) ppm. 13C NMR (151 MHz, CDCl3): δ = 182.30, 182.02, 158.72, 158.63, 154.72, 154.53, 142.93, 142.67, 134.71, 134.41, 129.82, 129.63, 129.52, 124.90, 124.61, 120.87, 120.31, 116.78, 116.63, 116.51, 116.48, 110.77, 110.47, 103.28, 102.62, 77.88, 77.57, 56.54, 56.47, 55.47, 55.41, 42.98, 42.36, 40.55, 40.40, 25.59, 25.39, 24.72, 24.67 ppm. HRMS (m / z): [M+H]+calcd for C20H23O4+, 327.1596, found 327.1593. 8CH3TSRI 2216.1PC

[0449] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ^^^^L TFA, 5 h) and was purified by flash column chromatography using hexane / EtOAc (5:1) as eluent to give C42 (19.9 mg, 79%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ = 5.10 (s, 1H), 4.94 (s, 1H), 4.90 (t, J = 7.3 Hz, 1H), 2.64 – 2.46 (m, 2H), 2.45 – 2.32 (m, 1H), 2.13 – 1.93 (m, 3H), 1.53 – 1.43 (m, 2H), 1.35 – 1.24 (m, 14H), 0.92 – 0.82 (m, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.17, 146.67, 110.58, 82.12, 32.05, 31.52, 29.75, 29.74, 29.63, 29.56, 29.47, 28.65, 27.80, 27.61, 22.83, 14.27 ppm. HRMS (m / z): [M+H]+calcd for C16H29O2+, 253.2168, found 253.2168. O O

[0450] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ^^^^L TFA, 5 h) and was purified by flash column chromatography using hexane / EtOAc (4:1) as eluent to give C43 (7.8 mg, 44%) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 7.41 – 7.34 (m, 3H), 7.33 – 7.28 (m, 1H), 2.68 – 2.59 (m, 1H), 2.54 – 2.46 (m, 2H), 2.45 – 2.38 (m, 1H), 1.73 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3) δ 176.66, 144.44, 128.76, 127.78, 124.24, 87.14, 36.34, 29.59, 29.12 ppm. HRMS (m / z): [M+H]+calcd for C11H13O2+, 177.0916, found 177.0912. O O

[0451] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ^^^^L TFA, 2.5 h) and was purified by flash column chromatography using hexane / EtOAc (5:1) as eluent to give C44 (7.8 mg, 46%) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ = 2.68 – 2.52 (m, 2H), 2.09 (ddd, J = 12.8, 9.5, 7.9 Hz, 1H), 1.97 (ddd, J = 12.8, 9.5, 6.5 Hz, 1H), 1.72 – 1.58 (m, 2H), 1.43 – 1.23 (m, 6H), 1.38 (s, 3H), 0.89 (t, J = 7.0 Hz, 3H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3): δ = 177.01, 87.11, 41.11, 33.10, 32.15, 29.35, 25.80, 23.67, 22.67, 14.12 ppm. HRMS (m / z): [M]+calcd for C10H18O2+, 170.1307, found 170.1. Me Me

[0452] The compound was prepared following the general procedure (Method C, 3.2 mg [Cu(MeCN)4]BF4, 0.5 mL dioxane and 40 μL TFA, 1 h) and was purified by pTLC (hexane / acetone 4:1) to give C45 (17.6 mg, 49%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 7.68 – 7.66 (m, 1H), 7.36 – 7.35 (m, 2H), 7.16 – 7.10 (m, 1H), 6.84 – 6.79 (m, 1H), 4.80 (ddd, J = 11.6, 8.8, 6.5 Hz, 1H), 4.25 (dd, J = 16.8, 5.4 Hz, 1H), 4.17 (dd, J = 16.8, 5.3 Hz, 1H), 2.68 (dd, J = 12.6, 8.9 Hz, 1H), 2.04 – 1.98 (m, 1H), 1.52 (s, 3H), 1.45 (s, 3H). 13C NMR (151 MHz, CDCl3): δ = 174.23, 168.83, 165.72, 135.28, 133.52, 131.93, 131.71, 130.43, 129.30, 83.11, 50.56, 43.71, 41.98, 29.05, 27.15 ppm. HRMS (m / z): [M+H]+calcd for C15H17Cl2N2O4+, 359.0560, found 359.0568. O O Me

[0453] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 μL TFA, 3 h) and was purified by flash column chromatography using hexane / EA (20:1 → 10:1) as eluent to give D46 (10.0 mg, 55%) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 5.11 – 5.05 (m, 1H), 2.67 – 2.53 (m, 2H), 2.15 – 2.02 (m, 3H), 1.98 (ddd, J = 12.9, 9.7, 6.3 Hz, 1H), 1.72 – 1.64 (m, 5H), 1.60 (s, 3H), 1.39 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.94, 132.59, 123.28, 86.85, 41.03, 33.13, 29.29, 25.79, 25.72, 22.72, 17.80 ppm. HRMS (m / z): [M+H]+calcd for C11H19O2+, 183.1385, found 183.1382.TSRI 2216.1PC e O H

[0454] The compound was prepared following the general procedure (Method C, 2.0 mg CuF2, 0.5 mL AcOH and 40 μL TFA, 1 h) and was purified by pTLC (hexane / EA 2:1) to give C47 (7.5 mg, 41%) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 6.65 (dd, J = 15.8, 8.3 Hz, 1H), 6.20 (dd, J = 15.7, 1.2 Hz, 1H), 3.07 – 3.01 (m, 1H), 2.73 (dd, J = 17.4, 8.2 Hz, 1H), 2.64 (dd, J = 17.5, 10.9 Hz, 1H), 2.29 (s, 3H), 1.50 (s, 3H), 1.29 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 197.24, 174.16, 141.46, 133.24, 86.17, 48.85, 34.47, 28.03, 27.41, 23.05 ppm. HRMS (m / z): [M+H]+calcd for C10H15O3+, 183.1385, found 183.1386. Me O O

[0455] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 μL TFA, 12 h) and was purified by flash column chromatography using hexane / EA (2:1) as eluent to give C48 (21.5 mg, 59%) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 5.15 (s, 2H), 3.84 (s, 3H), 2.77 – 2.68 (m, 2H), 2.68 – 2.60 (m, 2H), 2.43 (s, 13H), 2.23 (s, 3H), 2.13 – 2.03 (m, 2H), 1.86 – 1.78 (m, 2H), 1.48 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3) δ 176.61, 169.43, 168.33, 162.79, 146.64, 145.89, 129.37, 123.18, 113.77, 86.05, 68.50, 61.51, 40.71, 33.41, 29.15, 25.34, 20.66, 19.19, 11.99 ppm. HRMS (m / z): [M+Na]+calcd for C19H22O7Na+, 385.1263, found 385.1255.TSRI 2216.1PC Me Me

[0456] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 μL TFA, 3 h) and was purified by flash column chromatography using hexane / EA (8:1) as eluent to give C49 (15.9 mg, 51%) as a white foam. 1H NMR (600 MHz, CDCl3): δ = 7.09 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 8.1, 2.0 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 3.10 – 3.01 (m, 1H), 2.95 (dd, J = 17.6, 8.0 Hz, 1H), 2.85 – 2.78 (m, 1H), 2.71 (d, J = 17.0 Hz, 1H), 2.30 – 2.22 (m, 1H), 2.18 (d, J = 17.0 Hz, 1H), 2.15 – 2.09 (m, 1H), 1.96 (dd, J = 14.1, 8.0 Hz, 1H), 1.92 – 1.85 (m, 1H), 1.84 – 1.73 (m, 1H), 1.73 – 1.65 (m, 1H), 1.60 – 1.51 (m, 1H), 1.30 (s, 3H), 1.29 (s, 3H), 1.21 (d, J = 6.9 Hz, 6H) ppm. HRMS (m / z): [M+H]+calcd for C21H29O2+, 313.2168, found 313.2163. O O

[0457] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 μL TFA, 3 h) and was purified by flash column chromatography using hexane / EA (10:1) as eluent to give C50 (16.3 mg, 62%, d.r.1:1) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 4.98 – 4.97 (m, 1H),, 4.91 – 4.90 (m, 1H), 4.84 (s, 1H), 4.69 – 4.78 (m, 1H), 2.59 – 2.40 (m, 7H), 2.34 – 2.24 (m, 2H), 2.23 – 2.10 (m, 2H), 2.03 – 1.94 (m, 1H), 1.80 – 1.72 (m, 2H), 1.67 – 1.59 (m, 2H), 1.56 – 1.50 (m, 2H), 1.49 – 1.40 (m, 5H), 1.38 – 1.28 (m, 3H), 1.26 – 1.13 (m, 4H), 1.00 (s, 3H), 0.91 (s, 3H), 0.90 (s, 3H), 0.86 (s, 3H), 0.82 (s, 3H), 0.81 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.04, 176.80, 147.63, 146.23, 110.18, 107.47, 93.86, 93.72, 48.03, 47.04, 42.82, 42.44, 42.13, 41.42, 33.82, 33.77, 33.42, 33.41, 33.07, 32.43, 31.97, 31.74, 29.76, 28.85, 26.86, 23.34, 22.66, 22.59, 22.14, 22.04, 18.95, 18.55, 15.83 ppm. HRMS (m / z): [M+H]+calcd for C17H27O2+, 263.2011, found 263.2020.TSRI 2216.1PC O O

[0458] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 4.6 mg CSA, 2 h) and was purified by flash column chromatography using hexane / EA (5:1) as eluent to give C51 (18.7 mg, 52%, d.r. = 25:2) as a white powder. 1H NMR (600 MHz, CDCl3): δ = 5.82 (ddd, J = 16.9, 10.2, 7.7 Hz, 1H), 5.46 (d, J = 17.0 Hz, 1H), 5.31 (d, J = 10.3 Hz, 1H), 4.73 – 4.61 (m, 2H), 2.02 (s, 3H), 1.90 (ddd, J = 12.8, 4.5, 2.5 Hz, 1H), 1.82 – 1.68 (m, 4H), 1.64 – 1.57 (m, 2H), 1.53 – 1.45 (m, 2H), 1.42 – 1.32 (m, 2H), 1.32 – 1.17 (m, 4H), 1.16 (s, 3H), 1.08 – 1.01 (m, 1H), 1.00 – 0.91 (m, 1H), 0.85 (s, 3H), 0.82 – 0.75 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 180.28, 170.80, 136.18, 120.48, 82.86, 73.37, 56.79, 53.96, 44.53, 43.07, 36.77, 35.82, 33.94, 33.40, 32.20, 31.79, 28.12, 27.47, 21.56, 20.21, 15.38, 12.28 ppm. HRMS (m / z): [M+H]+calcd for C22H33O4+, 361.2379, found 361.2379. O O H

[0459] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 20 μL TFA, 12 h) and was purified by flash column chromatography using hexane / EA (5:1) as eluent to give C52 (21.5 mg, 45%, d.r.5:4) as a white powder. 1H NMR (400 MHz, CDCl3): δ = 5.20 – 5.16 (m, 0.55H), 5.10 – 5.06 (m, 0.44H), 4.72 (d, J = 11.4 Hz, 1H), 2.75 – 2.23 (m, 3H), 2.20 – 2.07 (m, 4H), 2.03 (s, 3H), 1.91 – 1.78 (m, 3H), 1.77 – 1.52 (m, 10H), 1.52 – 1.42 (m, 3H), 1.36 (s, 3H), 1.31 – 1.09 (m, 4H), 1.08 – 0.97 (m, 1H), 0.93 – 0.79 (m, 6H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.45, 176.16, 170.71, 170.67, 170.44, 170.43, 89.39, 87.93, 75.91, 75.34, 74.29, 74.24, 50.83, 50.05, 49.67, 49.64, 45.57, 45.44, 41.90, 35.29, 35.22, 34.84, 34.57, 34.47, 34.20, 34.19, 34.13, 32.42, 32.40, 31.72, 29.25, 28.11, 26.97,TSRI 2216.1PC 26.80, 26.76, 26.44, 25.90, 25.88, 25.82, 25.43, 25.37, 23.22, 23.20, 23.14, 23.03, 22.16, 21.61, 21.53, 14.43, 13.89 ppm. HRMS (m / z): [M+H]+calcd for C28H43O6+, 475.3060, found 475.3051. OOH

[0460] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 11.6 mg CSA, 5 h) and was purified by flash column chromatography using hexane / acetone (5:1 → 2:1) as eluent to give C53 (4.7 mg, 15%) as a white solid and C54 (17.5 mg, 56%). 1H NMR (600 MHz, CDCl3): δ = 7.19 (d, J = 8.5 Hz, 1H), 6.72 (dd, J = 8.7, 2.9 Hz, 1H), 6.63 (d, J = 3.0 Hz, 1H), 4.08 (d, J = 9.8 Hz, 1H), 3.99 (dd, J = 9.6, 2.0 Hz, 1H), 3.78 (s, 3H), 2.90 – 2.83 (m, 2H), 2.57 (dd, J = 12.0, 3.3 Hz, 1H), 2.54 – 2.49 (m, 1H), 2.33 – 2.27 (m, 1H), 2.23 – 2.15 (m, 2H), 2.08 – 2.01 (m, 1H), 1.99 – 1.92 (m, 2H), 1.65 – 1.58 (m, 2H), 1.53 – 1.44 (m, 2H), 1.44 – 1.35 (m, 1H), 1.17 – 1.09 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3) δ 180.80, 157.85, 137.74, 131.49, 126.50, 114.03, 111.89, 72.61, 55.37, 54.24, 51.82, 48.93, 42.81, 39.98, 34.79, 30.02, 29.74, 28.00, 27.41, 26.60 ppm. HRMS (m / z): [M+H]+calcd for C20H25O3+, 313.1804, found 313.1802. m.p. = 176-179 ˚C (from MeCN). H NOHWhite solid. 1H NMR (600 MHz, CDCl3): δ = 7.10 (d, J = 8.7 Hz, 1H), 6.62 (dd, J = 8.6, 2.8 Hz, 1H), 6.53 (d, J = 2.8 Hz, 1H), 6.09 (br s, 1H), 3.67 (s, 3H), 2.99 (d, J = 10.1 Hz, 1H), 2.94 (d, J = 10.1 Hz, 1H), 2.82 – 2.72 (m, 2H), 2.40 – 2.33 (m, 1H), 2.24 (dd, J = 11.4, 3.0 Hz, 1H), 2.22 – 2.15 (m, 1H), 2.08 – 2.01 (m, 1H), 2.01 – 1.94 (m, 1H), 1.91 – 1.82 (m, 2H), 1.81 – 1.75 (m, 1H), 1.50 – 1.24 (m, 5H), 1.13 – 1.04 (m, 1H) ppm.TSRI 2216.1PC 13C NMR (151 MHz, CDCl3) δ 181.32, 157.73, 137.88, 131.98, 126.49, 113.97, 111.79, 55.34, 54.57, 51.28, 51.14, 47.49, 43.03, 39.56, 35.92, 30.49, 29.82, 27.97, 27.47, 26.91 ppm. HRMS (m / z): [M+H]+calcd for C20H26NO2+, 312.1964, found 312.1964. m.p. = 283-286 ˚C (from MeCN).

[0461] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which suc...

Claims

TSRI 2216.1PC WHAT IS CLAIMED IS:

1. A method of copper-catalyzed bimodal dehydrogenation of N-methoxyamides via radical abstraction of γ-aliphatic C−H bonds.

2. A method of copper-catalyzed bimodal lactonization of N-methoxyamides via radical abstraction of the γ-aliphatic C−H bonds.

3. The method of either Claim 1 or Claim 2, wherein the copper catalyst is a Cu(I) catalyst.

4. The method of Claim 3, wherein the Cu(I) catalyst is [Cu(MeCN)4]BF4.

5. The method of Claim 3, wherein the Cu(I) catalyst is [(CH3CN)4Cu]PF6.

6. The method of Claim 3, wherein the Cu(I) catalyst is CuBr.

7. The method of Claim 1, wherein the copper catalyst is a Cu(II) catalyst.

8. The method of any one of Claims 1-7, wherein the Cu(II) catalyst is CuF2.

9. The method of any one of Claims 1-7, wherein the Cu(II) catalyst is Cu(OTFA)2•H2O.

10. The method of Claim 1, wherein the dehydrogenation occurs according to the following scheme: NH2wherein: Ra, Rb, and Rcare independently H, -(C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, -NPhth, -OAc, or Ph; Rdand Reare independently H, (C1-C6) alkyl, -OAc, -OC(=O)(CH2)2NHC(=O)CH2NPhth, - CH2OPhMe2, or -NPhth; Rfand Rgare independently H, (C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, Ph, -NPhth, or -OAc; or Reand Rgtogether form a bond; orTSRI 2216.1PC Rfand Rgtogether form -(C2-C6) alkenyl.

11. The method of Claim 1, wherein the dehydrogenation occurs according to the following scheme: NH2wherein: Ra, Rb, and Rcare independently H, -(C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, -NPhth, -OAc, or Ph; Rdand Reare independently H, -(C1-C6) alkyl, -(C3-C14) cycloalkyl, -(C3-C14) heterocycloalkyl, -NPhth, -OAc, or Ph; or Rdand Retogether form -(C2-C6) alkenyl.

12. The method of Claim 1, wherein the dehydrogenation occurs according to the following scheme: NH2wherein: Q’ is a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated (C3-C16) heterocycloalkyl, -(C6-C10) aryl, or -(C5-C10) heteroaryl; each R1is independently -OH, -(C1-C6) alkyl, oxo, -OAc, -O-(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, saturated or partially unsaturated (C3-C16) cycloalkyl, -NPhth, or -CH2NPhth; each R2is independently R2aor R2b; each R2ais independently -OH, -CN, halo, or oxo; each R2bis independently -(C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) heterocycloalkyl;TSRI 2216.1PC or one R1and one R2together form -(C6-C10) aryl, saturated or partially unsaturated (C3-C14) cycloalkyl, or saturated or partially unsaturated (C3-C16) heterocycloalkyl, or -(C5- C10) heteroaryl, each optionally substituted with one or more -(C1-C10) alkyl, -OAc, or - PhOMe; each R3is independently H, -(C1-C6) alkyl, saturated or partially unsaturated (C3-C16) cycloalkyl, -NPhth, or -(C6-C10) aryl; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2; and p is 0, 1, 2, or 3.

13. The method of Claim 1, wherein the dehydrogenation occurs according to the following scheme: NH2R5wherein: Q is saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated (C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, or -(C6-C10) aryl; R1is H, halo, oxo, or -OAc; or R1and R5together form partially unsaturated (C3-C16) cycloalkyl or saturated or partially unsaturated (C3-C14) heterocycloalkyl, optionally substituted with one or more R1’;R1’is -OH, -CN, halo, oxo, (C1-C6) alkyl, -OAc, or -(C2-C6) alkenyl; R2is R2aor R2b; R2ais -OH, -CN, halo, or oxo; R2bis -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, saturated or partially unsaturated -(C3-C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -O-(C1-C6) alkyl, -(C5-C10) heteroaryl, -S-PhMe, -O-PhMe2, or 1,3,2-TSRI 2216.1PC dioxaborolanyl, each optionally substituted with one or more -OH, -CN, halo, oxo, -(C1-C6) alkyl, or -PhOMe; R4is H or -(C1-C6) alkyl; R5is H or (C1-C6) alkyl; or R4and R5together form saturated or partially unsaturated (C3-C16) cycloalkyl or saturated or partially unsaturated (C3-C14) heterocycloalkyl, each optionally substituted with one or more -OH, -CN, halo, oxo, -(C1-C6) alkyl, or -PhOMe; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, or 3.

14. The method of any one of Claims 10-13, wherein the Cu(II) catalyst is CuF2.

15. The method of any one of Claims 10-13, wherein the Cu(II) catalyst is Cu(OTFA)2•H2O.

16. The method of any one of Claims 10-15, wherein the solvent is dioxane.

17. The method of any one of Claims 10-15, wherein the solvent is dioxane / MeNO2.

18. The method of any one of Claims 10-15, wherein the solvent is MeNO2.

19. The method of any one of Claims 10-15, wherein the solvent is DCE.

20. The method of any one of Claims 10-15, wherein the solvent is PhMe.

21. The method of any one of Claims 10-15, wherein the solvent is AcOH.

22. The method of any one of Claims 10-15, wherein the solvent is THF.

23. The method of any one of Claims 10-22, wherein the solvent is approximately 0.2M.

24. The method of any one of Claims 10-23, wherein the Cu catalyst is added at approximately 10 mol%.

25. The method of any one of Claims 10-24, further comprising addition of the Ligand (L).

26. The method of Claim 25, wherein Ligand (L) is selected from the group consisting of:TSRI 2216.1PC N .L 27. The method of Claim 26, wherein Ligand (L) is 8-methoxyquinoline.

28. The method of any one of Claims 10-27, wherein the Ligand (L) is added at approximately 20 mol%.

29. The method of any one of Claims 10-28, wherein the AcOH is added at approximately 8 equivalents.

30. The method of any one of Claims 10-29, wherein the reaction temperature is approximately 125 °C.

31. The method of any one of Claims 10-30, wherein the reaction time is approximately 2-20 h.

32. The method of Claim 1, wherein the dehydrogenation occurs according to the following scheme: CuF (10 mol%) 2 RaRd ReO Ligand (L) (20 mol%)a eAcOH (8 equiv.)RRd RO RbRbNH ,c g2RRf R125 °C, 2-20 h .

33. The method of Claim 32, wherein Ligand (L) is 8-methoxyquinoline.

34. The method of Claim 32, wherein Ligand (L) is absent.

35. The method of Claim 10, wherein the dehydrogenation occurs according to the following scheme: g NH2- (0.1 mmol).

36. The method of Claim 35, wherein the solvent is dioxane.TSRI 2216.1PC 37. The method of Claim 35, wherein the solvent is DCE.

38. The method of any one of Claims 35-37, wherein the acid is AcOH (8 equiv.).

39. The method of any one of Claims 35-37, wherein the acid is CSA (0.5 equiv.).

40. The method of any one of Claims 35-37, wherein the acid is TsOH•H2O (0.5 eq.).

41. The method of any one of Claims 35-40, wherein the product is selected from the group consisting of: ONH O NH2NH2O 57% ONH2., 69%42 The method of any one of Claims 35-40, wherein the product is selected from the group consisting of: n = 3, 68% rr n = 4, 67% rr, , . from gabapentin 43 The method of any one of Claims 35-40, wherein the product is selected from the group consisting of:TSRI 2216.1PC Me O Me CONH2MeCONH2O OMe NH Me CONH2Me .acid44 The method of Claim 2, wherein the lactonization occurs according to the following scheme: O RfRewherein: Raand Rbare independently H, -NPhth, -OAc, -C≡C-Ph, -C≡C-(C2-C6) alkenyl, or -(C1-C6) alkyl -(C2-C14) alkenyl, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O-(C1-C6) alkyl, a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3- C14heterocycloalkyl, -(C5-C10) heteroaryl, -(C6-C10) aryl, or -(C2-C6) alkenyl (C6-C10) aryl, each optionally substituted with one or more halo, -NHTs, NO2, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -OAc, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C1-C6) alkyl (C6-C10) aryl, or -(C2-C6) alkenyl (C6-C10) aryl; Rcand Rdare independently H, (C1-C6) alkyl, -OAc, saturated or partially unsaturated (C3- C16 cycloalkyl, -CH=CH-C(=O)-NPhth, or -CH2NPhth; Reand Rfare independently H, -OAc, or (C1-C6) alkyl, -NPhth, NHC(=O)CH2NHC(=O)Ph, - OC(=O (CH2)2NHC(=O)(C1-C6) alkyl , or -CH2NPhth, each optionally substituted with one or more halo;TSRI 2216.1PC or Rdand Retogether form a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C1-C6) alkyl-(C3-C7) heterocycloalkyl, or -(C6-C10) aryl, each optionally substituted with one or more halo, oxo, -NHTs, -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C3-C7) cycloalkyl, -OAc, - OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, or -O-(C1-C6) alkyl, each optionally substituted with one or more halo, oxo, or -(C1-C6) alkyl; or Rband Retogether form-CH2-CH2-; or Raand Rbtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl; or Rcand Rdtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl; or Reand Rftogether form -(C2-C6) alkenyl.

45. The method of Claim 44, wherein the solvent is dioxane.

46. The method of Claim 44, wherein the solvent is approximately (1:1) dioxane / MeNO2.

47. The method of Claim 44, wherein the solvent is AcOH.

48. The method of Claim 44, wherein the solvent is MeNO2.

49. The method of any one of claims 44-48, wherein the solvent is approximately 0.2M.

50. The method of any one of claims 44-49, wherein the Cu catalyst is [Cu(MeCN)4]BF4.

51. The method of any one of claims 44-49, wherein the Cu catalyst is CuF2< / sub>.

52. The method of any one of claims 44-51, wherein the Cu catalyst is approximately 10 mol%.

53. The method of any one of claims 44-52, wherein the acid additive is CSA.

54. The method of any one of claims 44-52, wherein the acid additive is TFA.

55. The method of any one of claims 44-52, wherein the acid additive is TSOH.TSRI 2216.1PC 56. The method of any one of claims 42-52, wherein the acid additive is AcOH.

57. The method of any one of claims 44-52, wherein the acid additive is added at approximately 0.5-5 equivalents.

58. The method of any one of claims 44-57, wherein the reaction temperature is approximately 125 °C.

59. The method of any one of claims 44-58, wherein the reaction time is approximately 2-20 h.

60. The method of any one of claims 44-58, wherein the reaction time is approximately 3-5 h.

61. The method of Claim 2, wherein the lactonization occurs according to the following scheme: [(MeCN (1)40C mu]oBl%F4), O RfRe125 °C, 1-20 wherein: Raand Rbare independently H, -NPhth, -OAc, or -C≡C-Ph, -C≡C-(C2-C6) alkenyl, -(C1-C6) alkyl, -(C2-C14) alkenyl, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O-(C1-C6) alkyl, a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3- C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C6-C10) aryl, or -(C2-C6) alkenyl (C6-C10) aryl, each optionally substituted with one or more -OH, -CN, halo, -NHTs, NO2, -(C1-C6) alkyl, - (C3-C7) cycloalkyl, -OAc, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, -O-(C1-C6) alkyl, - (C1-C6) alkyl (C6-C10) aryl, or -(C2-C6) alkenyl (C6-C10) aryl; or Raand Rbtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl; Rcand Rdare independently H, (C1-C6) alkyl, -OAc, saturated or partially unsaturated (C3- C16) cycloalkyl, -CH=CH-C(=O)-NPhth, -CH2OPhMe2, -NPhth, or -CH2NPhth; or Rband Rctogether form saturated or partially unsaturated -(C3-C14) cycloalkyl, saturated or partially unsaturated (C3-C16) heterocycloalkyl, -(C5-C10) heteroaryl, or -(C6-C10)TSRI 2216.1PC aryl, each optionally substituted with one or more -OH, -CN, halo, -NHTs, NO2, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -(C3-C7) cycloalkyl, or -OAc; or Rcand Rdtogether form a saturated or partially unsaturated spiro (C3-C16) cycloalkyl; Reand Rfare independently H, -OAc, or (C1-C6) alkyl, saturated or partially unsaturated (C3- C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C6-C10) aryl, -NPhth, -OC(=O)(CH2)2NHC(=O)CH2NPhth, - NHC(=O)CH2NHC(=O)Ph, -OC(=O)(CH2)2NHC(=O)(C1-C6) alkyl, or -CH2NPhth, each optionally substituted with one or more halo, -OH, -CN, (C1-C6) alkyl, -NHTs, NO2, oxo, or - OAc; or Rband Retogether form-CH2-CH2-; or Rdand Retogether form a saturated or partially unsaturated (C3-C16) cycloalkyl, saturated or partially unsaturated -(C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, -(C1-C6) alkyl-(C3-C7) heterocycloalkyl, or -(C6-C10) aryl, each optionally substituted with one or more halo, oxo, -NHTs, -CH2NHTs, -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C3-C7) cycloalkyl, - OAc, -OC(=O)(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, or -O-(C1-C6) alkyl, each optionally substituted with one or more halo, oxo, OAc, or -(C1-C6) alkyl; or Reand Rftogether form -(C2-C6) alkenyl.

62. The method of Claim 61, wherein the solvent is dioxane.

63. The method of Claim 61, wherein the solvent is AcOH.

64. The method of any one of Claims 61-63, wherein the Cu catalyst is [Cu(MeCN)4]BF<sub>4.

65. The method of any one of Claims 61-63, wherein the Cu catalyst is CuF<sub>2.

66. The method of any one of Claims 61-65, wherein the acid additive is CSA (0.2- 0.5 equiv.).

67. The method of any one of Claims 61-65, wherein the acid additive is TFA (0.25- 0.5 equiv.).

68. The method of any one of Claims 61-65, wherein the acid additive is TsOH•H2O (0.5 equiv.).TSRI 2216.1PC 69. The method of any one of Claims 61-68, wherein the product is selected from the group consisting of: O O 4:5OO 23%.<img src='' class="img-anchor img-center" img-id="IMGF000191_0001" / >70. The method of any one of Claims 61-68, wherein the product is selected from the group consisting of: O O 78% 60%O O<img src='' class="img-anchor img-center" img-id="IMGF000191_0002" / >71 The method of Claim 61, wherein the product is selected from the group consisting of:TSRI 2216.1PC O O OMe O O O O O O E R OOtO O O 64% 78%60%O O 53%<img src='' class="img-anchor img-center" img-id="IMGF000192_0001" / >72. The method of any one of Claims 61-68, wherein the product is selected from the group consisting of: XOH<img src='' class="img-anchor img-center" img-id="IMGF000192_0002" / >56%73. The method of any one of Claims 61-68, wherein the product is selected from the group consisting of:TSRI 2216.1PC O56%,.<img src='' class="img-anchor img-center" img-id="IMGF000193_0001" / >74. The method of Claim 1, wherein the dehydrogenation occurs on a gram scale according to the following scheme: , Me ,Me,<img src='' class="img-anchor img-center" img-id="IMGF000193_0002" / >A58, 1.65g, 5.0 mmol<img src='' class="img-anchor img-center" img-id="IMGF000193_0003" / >.

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