GREEN SYNTHESIS OF MEDICINE AND DEVELOPMENT OF INHIBITORS FOR DRUGGABLE PROTEINS OF SARS-COV- 2

As human activity continuously develops, especially after the impact of SARS-CoV-2, medicine-related manufacturing and development of new druggable targets for obscure diseases have become a noteworthy segment of the society. Green synthetic methods, especially step and atom economical methodologies towards sustainable and environmentally friendly medicine synthesis have long been the focus of scientists.
Among the mainstream topics, one of them is methodology towards selective C–N bond
formation. Nitrogen containing molecules serve as a fundamental part of peptide backbone, and amino groups serve as pervasive constructing element of pharmaceutical agents or synthetic intermediates. Thus, introducing amine structure motif into organic molecules with accurate selectivity plays an important role in modern chemistry, especially in medicine synthesis. While classical C(sp3)–H activation provided us many choices in regioselectivity, most of the developed reactions target at activated C–H bonds, possibly due to the reason that unactivated C–H bond own similar C–H activation energy. Also, there are still reactivity beyond the reach of classical C–H activation. Alkenes, as abundant organic resources in reserve, have been standing under the spotlight for its functionalization recently. The concept “metal-walk”, which represents the migration of metal through reversible β-hydride elimination / migratory insertion, provides another pathway towards unactivated C(sp³)–N formation. In Chapter 2, we report a selective C(sp³)–H amidation of alkenes directed by thioether group, with dioxazolones as the amide source, and Ni–H as the catalyst. Due to the preference for five-membered nickelacycle, the Ni–H migration would be terminated at γ-site, selectively and remote from the alkene group. The reaction can be achieved at ideal yields (up to 90% yield) and remarkable selectivity (γ-product : other isomers up to 24:1), with a wide substrate scope (>40 examples reported).
As SARS-CoV-2 emerged in human population in 2019, COVID-19 and its therapeutic treatment quickly dominated human debate in recent years. The disease rapidly spread around the world, with quick generation of new variants. Despite the grievous harm it caused, medication towards SARS-CoV-2 remained largely unexplored. SARS-CoV-2 encodes 16 non-structural proteins (nsps) in total, which serve as the key enzymes in the replication of the virus. Among the enzymes encoded, nsp12, which is RNA dependent RNA polymerase (RdRp) for SARS-CoV-2, attracted the attention of scientists. RdRp is highly conservative, among all the variants and even among other members of coronavirus family. Even “drug repurposing” strategy brought us with several candidate, the proposed RdRp inhibitors still hold some disadvantages such as possibility of mutations, or poor pharmacokinetic (PK) properties, etc. We thus hope to seek for more ideal inhibitors of nsp12 towards more effective oral anti-SARS-CoV-2 candidates. In Chapter 3, we report a series of GS-441524 ester prodrug derivatives as COVID-19 oral drug candidate. We tested their inhibition reactivities towards SARS-CoV-2 RdRp, and their pharmacokinetic properties were also briefly examined. Compound 3-1, the cyclohexyl carboxylic ester prodrug examined, displayed the best inhibition ability, pharmacokinetic property, and oral bioavailability.
The EC₅₀ value of 3-1 is 0.26 μM, lower than that of GS-441524 (EC50 = 1.644 μM). F
value of 3-1 also reached 53.4±3.4%, displaying an ideal oral bioavailability. Cmax of 3-
1 through oral intake was close to that through intravenous injection, demonstrating the potential of 3-1 as oral medicine against COVID-19. We further renamed the compound as SHEN 26, and we went on to optimize its synthetic route and analyzed the quality of industrial produced batch. We achieved a protection-esterification-deprotection 3-step route towards SHEN 26, without protecting the free amine group. We also determined and synthesized potential impurities and analyzed the purity of SHEN 26 from industrial kilogram batch. The purity of SHEN 26 reached 98.8%, with nearly all impurities meeting the acceptance criteria, demonstrating the feasibility of this route in industrial production of SHEN 26.
Apart from RdRp, nsp14 is also a recently heated area. In the replication of SARS-CoV-2, nsp14 is responsible for the methylation (capping) progress of the single-strand RNA. The methylated RNA cap serves as a pivotal instrument, assisting the single-strand RNA with immune escape and further translation. S-Adenosyl methionine (SAM) serves as methyl source, which would give out a methyl group and turns into S-Adenosyl homocysteine
(SAH) during methylation of single-strand RNA molecule. Thus, SAH analogues are considered as potential inhibitors for methyl transferases. Despite its great potential, few examples of SAH analogues as SARS-CoV-2 nsp14 inhibitors were reported, and room for improvements still exists, especially for their selectivity and cellular intake. To further pursue a better inhibitor, meanwhile being highly selective towards SARS-CoV-2 nsp14, we designed and synthesized a series of different SAH analogues in Chapter 3. Their inhibition ability against the SARS-CoV-2 nsp14 was tested with three different testing assays, at fixed concentration and in a dose-response manner. Among all inhibitors synthesized, ester MTI-ZC-007 and amide MTI-ZC-014 displayed the best inhibition ability against SARS-CoV-2 nsp14 ( 100% inhibition of both compounds at 10 μM and 50 μM; IC₅₀ = 1.57 μM and 1.70 μM respectively, IC_50-LCMS = 2.26 μM and 1.65 μM respectively), and we were also glad to see cellular inhibition of both MTI-ZC-007 and MTI-ZC-014 against SARS-CoV-2 virus (EC₅₀ = 21.84 μM and 14.88 μM respectively). A brief docking study was conducted, and structure-activity relationship (SAR) regarding to this series of structure was also briefly discussed.

[(1) Gandeepan, P., et. al. 3d Transition Metals for C–H Activation. Chem. Rev. 2019, 119 (4), 2192-2452.DOI: 10.1021/acs.chemrev.8b00507.(2) Ullmann, F. Ueber eine neue Bildungsweise von Diphenylaminderivaten. 1903, 36 (2), 2382-2384.DOI: https://doi.org/10.1002/cber.190303602174.(3) Goldberg, I. Ueber Phenylirungen bei Gegenwart von Kupfer als Katalysator. Berichte d. D. chem.Gesellschaft. 1906, 39 (2), 1691-1692. DOI: https://doi.org/10.1002/cber.19060390298.(4) Guram, A. S., et. al. Palladium-Catalyzed Aromatic Aminations with in situ GeneratedAminostannanes. J. Am. Chem. Soc. 1994, 116 (17), 7901-7902. DOI: 10.1021/ja00096a059.(5) Paul, F., et. al. Palladium-catalyzed formation of carbon-nitrogen bonds. Reaction intermediates andcatalyst improvements in the hetero cross-coupling of aryl halides and tin amides. J. Am. Chem. Soc.1994, 116 (13), 5969-5970. DOI: 10.1021/ja00092a058.(6) Surry, D. S., et. al. Biaryl Phosphane Ligands in Palladium-Catalyzed Amination. Angew. Chem. Int.Ed. 2008, 47 (34), 6338-6361. DOI: https://doi.org/10.1002/anie.200800497.(7) Hartwig, J. F. Evolution of a Fourth Generation Catalyst for the Amination and Thioetherification ofAryl Halides. Acc. Chem. Res. 2008, 41 (11), 1534-1544. DOI: 10.1021/ar800098p.(8) Kim, H., et. al. Transition-Metal-Mediated Direct C–H Amination of Hydrocarbons with AmineReactants: The Most Desirable but Challenging C–N Bond-Formation Approach. ACS Catal. 2016, 6 (4),2341-2351. DOI: 10.1021/acscatal.6b00293.(9) Wei, Y., et. al. Copper-Catalyzed Direct Alkynylation of Electron-Deficient Polyfluoroarenes withTerminal Alkynes Using O2 as an Oxidant. J. Am. Chem. Soc. 2010, 132 (8), 2522-2523. DOI:10.1021/ja910461e.(10) Wedi, P., et. al. Arene-Limited Nondirected C-H Activation of Arenes. Angew. Chem. Int. Ed. 2018,57 (40), 13016-13027. DOI: https://doi.org/10.1002/anie.201804727.(11) Gu, L., et. al. Gold-Catalyzed Direct Amination of Arenes with Azodicarboxylates. Org. Lett. 2011,13 (7), 1872-1874. DOI: 10.1021/ol200373q.(12) Shrestha, R., et. al. Sterically Controlled, Palladium-Catalyzed Intermolecular Amination of Arenes.J. Am. Chem. Soc. 2013, 135 (23), 8480-8483. DOI: 10.1021/ja4032677.(13) Kuhl, N.; H., e. a. Beyond Directing Groups: Transition-Metal-Catalyzed C-H Activation of SimpleArenes. Angew. Chem. Int. Ed. 2012, 51 (41), 10236-10254. DOI:https://doi.org/10.1002/anie.201203269.(14) Thu, H., et. al. Intermolecular Amidation of Unactivated sp2 and sp3 C−H Bonds via Palladium-Catalyzed Cascade C−H Activation/Nitrene Insertion. J. Am. Chem. Soc. 2006, 128 (28), 9048-9049.DOI: 10.1021/ja062856v.(15) Ng, K., et. al. Pd-Catalyzed Intermolecular ortho-C-H Amidation of Anilides by NNosyloxycarbamate.J. Am. Chem. Soc. 2010, 132 (37), 12862-12864. DOI: 10.1021/ja106364r.(16) Timsina, Y. N., et. al. Palladium-Catalyzed C–H Amination of C(sp2) and C(sp3)–H Bonds:Mechanism and Scope for N-Based Molecule Synthesis. ACS Catal. 2018, 8 (7), 5732-5776. DOI:10.1021/acscatal.8b01168.(17) Xiao, B., et. al. Palladium-Catalyzed Intermolecular Directed C-H Amidation of Aromatic Ketones.J. Am. Chem. Soc. 2011, 133 (5), 1466-1474. DOI: 10.1021/ja108450m.(18) Dick, A. R., et. al. Carbon-Nitrogen Bond-Forming Reactions of Palladacycles with Hypervalent Iodine Reagents. Organometallics 2007, 26 (6), 1365-1370. DOI: 10.1021/om061052l.(19) Ng, K., et. al. A convenient synthesis of anthranilic acids by Pd-catalyzed direct intermolecularortho-C–H amidation of benzoic acids. Chem. Comm. 2012, 48 (95), 11680-11682,10.1039/C2CC36502B. DOI: 10.1039/C2CC36502B.(20) Yoo, E., et. al. Pd-Catalyzed Intermolecular C–H Amination with Alkylamines. J. Am. Chem. Soc.2011, 133 (20), 7652-7655. DOI: 10.1021/ja202563w.(21) Anand, M., et. al. Non-innocent Additives in a Palladium(II)-Catalyzed C–H Bond ActivationReaction: Insights into Multimetallic Active Catalysts. J. Am. Chem. Soc. 2014, 136 (15), 5535-5538.DOI: 10.1021/ja412770h.(22) Anand, M., et. al. Palladium–Silver Cooperativity in an Aryl Amination Reaction through C–HFunctionalization. ACS Catal. 2016, 6 (2), 696-708. DOI: 10.1021/acscatal.5b02639.(23) Zhu, D., et. al. Ligand-Promoted ortho-C-H Amination with Pd Catalysts. Angew. Chem. Int. Ed.2015, 54 (8), 2497-2500. DOI: https://doi.org/10.1002/anie.201408651.(24) Kim, J., et. al. Ruthenium-Catalyzed Direct C-H Amidation of Arenes Including WeaklyCoordinating Aromatic Ketones. Chem. Eur. J. 2013, 19 (23), 7328-7333. DOI:https://doi.org/10.1002/chem.201301025.(25) Shin, Y., et. al. Ru(II)-Catalyzed Selective C–H Amination of Xanthones and Chromones withSulfonyl Azides: Synthesis and Anticancer Evaluation. J. Org. Chem. 2014, 79 (19), 9262-9271. DOI:10.1021/jo501709f.(26) Thirunavukkarasu, V. S., et. al. Expedient C–H Amidations of Heteroaryl Arenes Catalyzed byVersatile Ruthenium(II) Catalysts. Org. Lett. 2013, 15 (13), 3286-3289. DOI: 10.1021/ol401321q.(27) Zhou, X., et. al. Ru-catalyzed direct C–H amidation of 2-arylbenzo[d]thiazoles with sulfonyl azides.Tetrahedron 2014, 70 (38), 6742-6748. DOI: https://doi.org/10.1016/j.tet.2014.07.076.(28) Zhang, L., et. al. Ruthenium-Catalyzed Direct C–H Amidation of Arenes: A Mechanistic Study.Organometallics 2014, 33 (8), 1905-1908. DOI: 10.1021/om500080z.(29) Pan, C., et. al. Ruthenium-Catalyzed C7 Amidation of Indoline C-H Bonds with Sulfonyl Azides.Chem. Eur. J. 2014, 20 (13), 3606-3609. DOI: https://doi.org/10.1002/chem.201304236.(30) Shin, K., et. al. Orthogonal Reactivity of Acyl Azides in C–H Activation: Dichotomy between C–Cand C–N Amidations Based on Catalyst Systems. Org. Lett. 2014, 16 (7), 2022-2025. DOI:10.1021/ol500602b.(31) Shang, M., et. al. Ru(II)-Catalyzed ortho-C–H Amination of Arenes and Heteroarenes at RoomTemperature. Org. Lett. 2013, 15 (20), 5286-5289. DOI: 10.1021/ol402515s.(32) Zhao, H., et. al. Rhodium(III)-Catalyzed Intermolecular N-Chelator-Directed Aromatic C–HAmidation with Amides. Org. Lett. 2013, 15 (19), 5106-5109. DOI: 10.1021/ol4024776.(33) Maiden, T. M. M., et. al. A Mild and Regioselective Route to Functionalized Quinazolines. Chem.Eur. J. 2015, 21 (41), 14342-14346. DOI: https://doi.org/10.1002/chem.201502891.(34) Ng, F., et. al. [RhIII(Cp*)]-Catalyzed ortho-Selective Direct C(sp2)-H Bond Amidation/Aminationof Benzoic Acids by N-Chlorocarbamates and N-Chloromorpholines. A Versatile Synthesis ofFunctionalized Anthranilic Acids. Chem. Eur. J. 2014, 20 (15), 4474-4480. DOI:https://doi.org/10.1002/chem.201304855.(35) Ng, K., et. al. [Cp*RhCl2]2-catalyzed ortho-C–H bond amination of acetophenone o-methyloximeswith primary N-chloroalkylamines: convenient synthesis of N-alkyl-2-acylanilines. Chem. Comm. 2013,49 (63), 7031-7033, 10.1039/C3CC42937G. DOI: 10.1039/C3CC42937G.(36) Grohmann, C., et. al. Rh[III]-Catalyzed C–H Amidation Using Aroyloxycarbamates To Give N-Boc Protected Arylamines. Org. Lett. 2013, 15 (12), 3014-3017. DOI: 10.1021/ol401209f.(37) Shi, J., et. al. Rhodium(III)-catalyzed regioselective C2-amidation of indoles with N-(2,4,6-trichlorobenzoyloxy)amides and its synthetic application to the development of a novel potential PPARγmodulator. Org. Biomol. Chem. 2014, 12 (35), 6831-6836, 10.1039/C4OB00637B. DOI:10.1039/C4OB00637B.(38) Wu, K., et. al. Rh(III)-Catalyzed Intermolecular C–H Amination of 1-Aryl-1H-pyrazol-5(4H)-oneswith Alkylamines. Org. Lett. 2014, 16 (1), 42-45. DOI: 10.1021/ol402965d.(39) Xue, Y., et. al. RhIII-Catalyzed Hydrazine-Directed C(sp2)–H Amination of Phenidones with NAlkyl-O-benzoyl-hydroxylamines. Eur. J. Org. Chem. 2014, 2014 (33), 7481-7488. DOI:https://doi.org/10.1002/ejoc.201402999.(40) Yu, S., et. al. Rhodium(III)-Catalyzed C–H Activation and Amidation of Arenes Using NArenesulfonatedImides as Amidating Reagents. Org. Lett. 2013, 15 (14), 3706-3709. DOI:10.1021/ol401569u.(41) Zhou, B., et. al. Rh(III)-Catalyzed C–H Amidation with N-Hydroxycarbamates: A New Entry to NCarbamate-Protected Arylamines. Organic Letters 2014, 16 (2), 592-595. DOI: 10.1021/ol403477w.(42) Ali, M. A., et. al. [RhCp*Cl2]2-Catalyzed Directed N-Boc Amidation of Arenes “on Water”. OrganicLetters 2015, 17 (6), 1513-1516. DOI: 10.1021/acs.orglett.5b00392.(43) Tang, R., et. al. Rhodium(III)-Catalyzed C(sp2)-H Activation and Electrophilic Amidation with NFluorobenzenesulfonimide.Adv. Synth. Catal. 2013, 355 (5), 869-873. DOI:https://doi.org/10.1002/adsc.201201133.(44) Zhou, B., et. al. Rhodium-Catalyzed Direct Addition of Aryl C–H Bonds to Nitrosobenzenes atRoom Temperature. Org. Lett. 2013, 15 (24), 6302-6305. DOI: 10.1021/ol403187t.(45) Du, J., et. al. Rhodium-Catalyzed Direct Amination of Arenes with Nitrosobenzenes: A New Routeto Diarylamines. Chem. Eur. J. 2014, 20 (19), 5727-5731. DOI: https://doi.org/10.1002/chem.201400221.(46) Kim, J., et. al. Rhodium-Catalyzed Intermolecular Amidation of Arenes with Sulfonyl Azides viaChelation-Assisted C–H Bond Activation. J. Am. Chem. Soc. 2012, 134 (22), 9110-9113. DOI:10.1021/ja303527m.(47) Shi, J., et. al. Rhodium-catalyzed regioselective amidation of indoles with sulfonyl azides via C–Hbond activation. Org. Biomol. Chem. 2012, 10 (45), 8953-8955, 10.1039/C2OB26767E. DOI:10.1039/C2OB26767E.(48) Yu, D., et. al. RhIII/CuII-Cocatalyzed Synthesis of 1H-Indazoles through C–H Amidation and N–NBond Formation. J. Am. Chem. Soc. 2013, 135 (24), 8802-8805. DOI: 10.1021/ja4033555.(49) Wang, H., et. al. Rhodium-Catalyzed Direct ortho C–N Bond Formation of Aromatic AzoCompounds with Azides. J. Org. Chem. 2014, 79 (7), 3279-3288. DOI: 10.1021/jo500412w.(50) Jia, X., et. al. Rhodium-Catalyzed Direct C–H Amidation of Azobenzenes with Sulfonyl Azides: ASynthetic Route to Sterically Hindered ortho-Substituted Aromatic Azo Compounds. J. Org. Chem. 2014,79 (9), 4180-4185. DOI: 10.1021/jo500372d.(51) Ryu, T., et. al. Synthesis of 2-Aryl-2H-benzotrizoles from Azobenzenes and N-Sulfonyl Azidesthrough Sequential Rhodium-Catalyzed Amidation and Oxidation in One Pot. Org. Lett. 2014, 16 (11),2810-2813. DOI: 10.1021/ol501250t.(52) Lian, Y., et. al. Facile Synthesis of Unsymmetrical Acridines and Phenazines by a Rh(III)-CatalyzedAmination/Cyclization/Aromatization Cascade. J. Am. Chem. Soc. 2013, 135 (34), 12548-12551. DOI:10.1021/ja406131a.(53) Yang, W., et. al. Hydroxyamination of aryl C–H bonds with N-hydroxycarbamate by synergistic Rh/Cu catalysis at room temperature. Chem. Comm. 2014, 50 (34), 4420-4422, 10.1039/C3CC49496A.DOI: 10.1039/C3CC49496A.(54) Ryu, J., et. al. Rhodium-Catalyzed Direct C-H Amination of Benzamides with Aryl Azides: ASynthetic Route to Diarylamines. Angew. Chem. Int. Ed. 2012, 51 (39), 9904-9908. DOI:https://doi.org/10.1002/anie.201205723.(55) Shin, K., et. al. Direct C-H Amination of Arenes with Alkyl Azides under Rhodium Catalysis. Angew.Chem. Int. Ed. 2013, 52 (31), 8031-8036. DOI: https://doi.org/10.1002/anie.201302784.(56) Tang, C., et. al. Rh-Catalyzed Diarylamine Synthesis by Intermolecular C–H Amination ofHeteroarylarenes. Eur. J. Org. Chem. 2013, 2013 (33), 7480-7483. DOI:https://doi.org/10.1002/ejoc.201301430.(57) Park, S. H., et. al. Mechanistic Studies of the Rhodium-Catalyzed Direct C–H Amination ReactionUsing Azides as the Nitrogen Source. J. Am. Chem. Soc. 2014, 136 (6), 2492-2502. DOI:10.1021/ja411072a.(58) Park, Y. e. a. Mechanistic Studies on the Rh(III)-Mediated Amido Transfer Process Leading toRobust C–H Amination with a New Type of Amidating Reagent. J. Am. Chem. Soc. 2015, 137 (13), 4534-4542. DOI: 10.1021/jacs.5b01324.(59) Park, Y., et. al. Study of Sustainability and Scalability in the Cp*Rh(III)-Catalyzed Direct C–HAmidation with 1,4,2-Dioxazol-5-ones. Org. Process Res. Dev. 2015, 19 (8), 1024-1029. DOI:10.1021/acs.oprd.5b00164.(60) Kim, H., et. al. Iridium-Catalyzed C–H Amination with Anilines at Room Temperature:Compatibility of Iridacycles with External Oxidants. J. Am. Chem. Soc. 2014, 136 (16), 5904-5907. DOI:10.1021/ja502270y.(61) Lee, D., et. al. Iridium-Catalyzed Direct Arene C–H Bond Amidation with Sulfonyl- and Aryl Azides.J. Org. Chem. 2013, 78 (21), 11102-11109. DOI: 10.1021/jo4019683.(62) Hermann, G. N., et. al. Mechanochemical Iridium(III)-Catalyzed C−H Bond Amidation ofBenzamides with Sulfonyl Azides under Solvent-Free Conditions in a Ball Mill. Angew. Chem. Int. Ed.2016, 55 (11), 3781-3784. DOI: https://doi.org/10.1002/anie.201511689.(63) Hwang, H., et. al. Regioselective Introduction of Heteroatoms at the C-8 Position of Quinoline NOxides:Remote C–H Activation Using N-Oxide as a Stepping Stone. J. Am. Chem. Soc. 2014, 136 (30),10770-10776. DOI: 10.1021/ja5053768.(64) Liu, J. B., et. al. A Computational Mechanistic Study of Amidation of Quinoline N-Oxide: TheRelative Stability of Amido Insertion Intermediates Determines the Regioselectivity. ACS Catal. 2016, 6(4), 2452-2461. DOI: 10.1021/acscatal.5b02938.(65) Kim, J., et. al. Iridium-Catalyzed Direct C-H Amidation with Weakly Coordinating CarbonylDirecting Groups under Mild Conditions. Angew. Chem. Int. Ed. 2014, 53 (8), 2203-2207. DOI:https://doi.org/10.1002/anie.201310544.(66) Lee, D., et. al. Direct C-H Amidation of Benzoic Acids to Introduce meta- and para-Amino Groupsby Tandem Decarboxylation. Chem. Eur. J. 2015, 21 (14), 5364-5368. DOI:https://doi.org/10.1002/chem.201500331.(67) Wei, M. E. Iridium-catalyzed direct ortho-CH amidation of benzoic acids with sulfonylazides.Chinese Chemical Letters 2015, 26 (11), 1336-1340. DOI: https://doi.org/10.1016/j.cclet.2015.08.009.(68) Zhu, B., et. al. Iridium(III)-Catalyzed Direct C-H Sulfonamidation of 2-Aryl-1,2,3-triazole NOxideswith Sulfonyl Azides. Adv. Synth. Catal. 2016, 358 (2), 326-332. DOI:https://doi.org/10.1002/adsc.201501036.(69) Pi, C., et. al. Iridium-Catalyzed Direct C–H Sulfamidation of Aryl Nitrones with Sulfonyl Azides atRoom Temperature. J. Org. Chem. 2015, 80 (15), 7333-7339. DOI: 10.1021/acs.joc.5b01377.(70) Chen, H., et. al. Iridium(III)-Catalyzed Benzylic Amine Directed C-H Sulfonamidation of Areneswith Sulfonyl Azides. ChemCatChem 2015, 7 (5), 743-746. DOI:https://doi.org/10.1002/cctc.201402944.(71) Gwon, D., et. al. Iridium(III)-Catalyzed C-H Amidation of Arylphosphoryls Leading to a PStereogenicCenter. Chem. Eur. J. 2014, 20 (39), 12421-12425. DOI:https://doi.org/10.1002/chem.201404151.(72) Gwon, D., et. al. Dual role of carboxylic acid additive: mechanistic studies and implication for theasymmetric C–H amidation. Tetrahedron 2015, 71 (26), 4504-4511. DOI:https://doi.org/10.1016/j.tet.2015.02.065.(73) Becker, P., et. al. Acylsilanes in Iridium-Catalyzed Directed Amidation Reactions and Formation ofHeterocycles via Siloxycarbenes. Angew. Chem. Int. Ed. 2015, 54 (51), 15493-15496. DOI:https://doi.org/10.1002/anie.201508501.(74) Ryu, J., et. al. Ir(III)-Catalyzed Mild C–H Amidation of Arenes and Alkenes: An Efficient Usage ofAcyl Azides as the Nitrogen Source. J. Am. Chem. Soc. 2013, 135 (34), 12861-12868. DOI:10.1021/ja406383h.(75) Kim, H., et. al. Synthesis of Phosphoramidates: A Facile Approach Based on the C–N BondFormation via Ir-Catalyzed Direct C–H Amidation. Org. Lett. 2014, 16 (20), 5466-5469. DOI:10.1021/ol502722j.(76) Pan, C., et. al. Iridium-Catalyzed Phosphoramidation of Arene C–H Bonds with Phosphoryl Azide.J. Org. Chem. 2014, 79 (19), 9427-9432. DOI: 10.1021/jo5018052.(77) Zhang, T., et. al. Carboxylate-Assisted Iridium-Catalyzed C−H Amination of Arenes withBiologically Relevant Alkyl Azides. Chem. Eur. J. 2016, 22 (9), 2920-2924. DOI:https://doi.org/10.1002/chem.201504880.(78) Shin, K., et. al. Iridium(III)-Catalyzed Direct C-7 Amination of Indolines with Organic Azides. J.Org. Chem. 2014, 79 (24), 12197-12204. DOI: 10.1021/jo5018475.(79) Hou, W., et. al. IrIII-Catalyzed Direct C-7 Amidation of Indolines with Sulfonyl, Acyl, and ArylAzides at Room Temperature. Eur. J. Org. Chem. 2015, 2015 (2), 395-400. DOI:https://doi.org/10.1002/ejoc.201403355.(80) Figg, T. M., et. al. Comparative Investigations of Cp*-Based Group 9 Metal-Catalyzed Direct C–HAmination of Benzamides. Organometallics 2014, 33 (15), 4076-4085. DOI: 10.1021/om5005868.(81) Patel, P., et. al. N-Substituted Hydroxylamines as Synthetically Versatile Amino Sources in theIridium-Catalyzed Mild C–H Amidation Reaction. Org. Lett. 2014, 16 (12), 3328-3331. DOI:10.1021/ol501338h.(82) Sun, B., et. al. Air-Stable Carbonyl(pentamethylcyclopentadienyl)cobalt Diiodide Complex as aPrecursor for Cationic (Pentamethylcyclopentadienyl)cobalt(III) Catalysis: Application for Directed C-2 Selective C-H Amidation of Indoles. Adv. Synth. Catal. 2014, 356 (7), 1491-1495. DOI:https://doi.org/10.1002/adsc.201301110.(83) Patel, P., et. al. Cobalt(III)-Catalyzed C–H Amidation of Arenes using Acetoxycarbamates asConvenient Amino Sources under Mild Conditions. ACS Catal. 2015, 5 (2), 853-858. DOI:10.1021/cs501860b.(84) Park, J., et. al. Comparative Catalytic Activity of Group 9 [Cp*MIII] Complexes: Cobalt-CatalyzedC-H Amidation of Arenes with Dioxazolones as Amidating Reagents. Angew. Chem. Int. Ed. 2015, 54 (47), 14103-14107. DOI: https://doi.org/10.1002/anie.201505820.(85) Liang, Y., et. al. Cationic Cobalt(III)-Catalyzed Aryl and Alkenyl C-H Amidation: A Mild Protocolfor the Modification of Purine Derivatives. Chem. Eur. J. 2015, 21 (46), 16395-16399. DOI:https://doi.org/10.1002/chem.201503533.(86) Mei, R., et. al. Oxazolinyl-Assisted C–H Amidation by Cobalt(III) Catalysis. ACS Catal. 2016, 6(2), 793-797. DOI: 10.1021/acscatal.5b02661.(87) Wang, F., et. al. Co(III)-Catalyzed Synthesis of Quinazolines via C–H Activation of NSulfinyliminesand Benzimidates. Org. Lett. 2016, 18 (6), 1306-1309. DOI: 10.1021/acs.orglett.6b00227.(88) Matsubara, T., et. al. Synthesis of Anthranilic Acid Derivatives through Iron-Catalyzed OrthoAmination of Aromatic Carboxamides with N-Chloroamines. J. Am. Chem. Soc. 2014, 136 (2), 646-649.DOI: 10.1021/ja412521k.(89) Zhang, L. B., et. al. Cobalt(II)-Catalyzed C–H Amination of Arenes with Simple Alkylamines. Org.Lett. 2016, 18 (6), 1318-1321. DOI: 10.1021/acs.orglett.6b00241.(90) Yan, Q., et. al. Nickel-Catalyzed Direct Amination of Arenes with Alkylamines. Org. Lett. 2015, 17(10), 2482-2485. DOI: 10.1021/acs.orglett.5b00990.(91) Peng, J., et. al. Copper-Catalyzed C(sp2)–H Amidation with Azides as Amino Sources. Org. Lett.2014, 16 (18), 4702-4705. DOI: 10.1021/ol502010g.(92) Chen, X., et. al. Cu(II)-Catalyzed Functionalizations of Aryl C−H Bonds Using O2 as an Oxidant.J. Am. Chem. Soc. 2006, 128 (21), 6790-6791. DOI: 10.1021/ja061715q.(93) John, A., et. al. Copper-Catalyzed Amidation of 2-Phenylpyridine with Oxygen as the TerminalOxidant. J. Org. Chem. 2011, 76 (10), 4158-4162. DOI: 10.1021/jo200409h.(94) Xu, H., et. al. Cu-Catalyzed Direct Amidation of Aromatic C–H Bonds: An Access to Arylamines.J. Org. Chem. 2014, 79 (10), 4414-4422. DOI: 10.1021/jo5003592.(95) Li, G., et. al. Copper(I)-Catalyzed Dehydrogenative Amidation of Arenes Using Air as the Oxidant.Adv. Synth. Catal. 2015, 357 (6), 1311-1315. DOI: https://doi.org/10.1002/adsc.201400883.(96) Tran, L. D., et. al. . Directed Amination of Non-Acidic Arene C-H Bonds by a Copper–SilverCatalytic System. Angew. Chem. Int. Ed. 2013, 52 (23), 6043-6046. DOI:https://doi.org/10.1002/anie.201300135.(97) Pumphrey, A. L., et. al. RhII2-Catalyzed Synthesis of α-, β-, or δ-Carbolines from Aryl Azides. Angew.Chem. Int. Ed. 2012, 51 (24), 5920-5923. DOI: https://doi.org/10.1002/anie.201201788.(98) Stokes, B. J., et. al. Rh2(II)-Catalyzed Nitro-Group Migration Reactions: Selective Synthesis of 3-Nitroindoles from β-Nitro Styryl Azides. J. Am. Chem. Soc. 2011, 133 (13), 4702-4705. DOI:10.1021/ja111060q.(99) Stokes, B. J., et. al. Rh2(II)-Catalyzed Synthesis of Carbazoles from Biaryl Azides. J. Org. Chem.2009, 74 (8), 3225-3228. DOI: 10.1021/jo9002536.(100) Chiba, S., et. al. Rh(II)-Catalyzed Isomerization of 2-Aryl-2H-azirines to 2,3-Disubstituted Indoles.ChemInform 2007, 38 (26). DOI: https://doi.org/10.1002/chin.200726104.(101) Shen, M., et. al. Dirhodium(II)-Catalyzed Intramolecular C-H Amination of Aryl Azides. Angew.Chem. Int. Ed. 2008, 47 (27), 5056-5059. DOI: https://doi.org/10.1002/anie.200800689.(102) He, L., et. al. Ruthenium(II) Porphyrin-Catalyzed Amidation of Aromatic Heterocycles. Org. Lett.2004, 6 (14), 2405-2408. DOI: 10.1021/ol049232j.(103) Shou, W. G., et. al. Ruthenium-Catalyzed Intramolecular Amination Reactions of Aryl- andVinylazides. Organometallics 2009, 28 (24), 6847-6854. DOI: 10.1021/om900275j.(104) Wei, J., et. al. Ruthenium porphyrin catalyzed diimination of indoles with aryl azides as the nitrene source. Chem. Comm. 2014, 50 (25), 3373-3376, 10.1039/C3CC49052A. DOI: 10.1039/C3CC49052A.(105) Liang, S., et. al. Half-Sandwich Scorpionates as Nitrene Transfer Catalysts. Organometallics 2012,31 (23), 8055-8058. DOI: 10.1021/om3009102.(106) Liu, Y., et. al. [Fe(F20TPP)Cl]-Catalyzed Amination with Arylamines and{[Fe(F20TPP)(NAr)](PhI=NAr)} Intermediate Assessed by High-Resolution ESI-MS and DFTCalculations. Chem. Asian J. 2015, 10 (1), 100-105. DOI: https://doi.org/10.1002/asia.201402580.(107) Bonnamour, J., et. al. Iron(II) Triflate as a Catalyst for the Synthesis of Indoles by IntramolecularC−H Amination. Org. Lett. 2011, 13 (8), 2012-2014. DOI: 10.1021/ol2004066.(108) John, A., et. al. Copper-catalyzed C(sp2)-H amidation of unactivated arenes by Ntosyloxycarbamates.Chem. Comm. 2013, 49 (93), 10965-10967. DOI: 10.1039/c3cc46412a.(109) Breslow, R., et. al. Intramolecular nitrene carbon-hydrogen insertions mediated by transition-metalcomplexes as nitrogen analogs of cytochrome P-450 reactions. J. Am. Chem. Soc. 1983, 105 (22), 6728-6729. DOI: 10.1021/ja00360a039.(110) Fiori, K. W., et. al. A mechanistic analysis of the Rh-catalyzed intramolecular C–H aminationreaction. Tetrahedron 2009, 65 (16), 3042-3051. DOI: https://doi.org/10.1016/j.tet.2008.11.073.(111) Du Bois, J. Rhodium-Catalyzed C–H Amination. An Enabling Method for Chemical Synthesis.Org. Process Res. Dev. 2011, 15 (4), 758-762. DOI: 10.1021/op200046v.(112) Wehn, P. M., et. al. Stereochemical Models for Rh-Catalyzed Amination Reactions of ChiralSulfamates. Org. Lett. 2003, 5 (25), 4823-4826. DOI: 10.1021/ol035776u.(113) Espino, C. G., et. al. Expanding the Scope of C−H Amination through Catalyst Design. J. Am.Chem. Soc. 2004, 126 (47), 15378-15379. DOI: 10.1021/ja0446294.(114) Grigg, R. D., et. al. Synthesis of Propargylic and Allenic Carbamates via the C–H Amination ofAlkynes. Org. Lett. 2012, 14 (1), 280-283. DOI: 10.1021/ol203055v.(115) Nguyen, Q., et. al. Rh2(II)-Catalyzed Intramolecular Aliphatic C–H Bond Amination ReactionsUsing Aryl Azides as the N-Atom Source. J. Am. Chem. Soc. 2012, 134 (17), 7262-7265. DOI:10.1021/ja301519q.(116) Kurokawa, T., et. al. Synthesis of 1,3-Diamines Through Rhodium-Catalyzed C-H Insertion. Angew.Chem. Int. Ed. 2009, 48 (15), 2777-2779. DOI: https://doi.org/10.1002/anie.200806192.(117) Fiori, K. W., et. al. Catalytic Intermolecular Amination of C−H Bonds: Method Development andMechanistic Insights. J. Am. Chem. Soc. 2007, 129 (3), 562-568. DOI: 10.1021/ja0650450.(118) Roizen, J. L., et. al. Selective Intermolecular Amination of C-H Bonds at Tertiary Carbon Centers.Angew. Chem. Int. Ed. 2013, 52 (43), 11343-11346. DOI: https://doi.org/10.1002/anie.201304238.(119) Bess, E. N., et. al. Analyzing Site Selectivity in Rh2(esp)2-Catalyzed Intermolecular C–HAmination Reactions. J. Am. Chem. Soc. 2014, 136 (15), 5783-5789. DOI: 10.1021/ja5015508.(120) Liang, C., et. al. Efficient Diastereoselective Intermolecular Rhodium-Catalyzed C-H Amination.Angew. Chem. Int. Ed. 2006, 45 (28), 4641-4644. DOI: https://doi.org/10.1002/anie.200601248.(121) Liang, C., et. al. Toward a Synthetically Useful Stereoselective C−H Amination of Hydrocarbons.J. Am. Chem. Soc. 2008, 130 (1), 343-350. DOI: 10.1021/ja076519d.(122) Collet, F. Studies in catalytic C–H amination involving nitrene C–H insertion. Dalton Trans. 2010,39 (43), 10401-10413, 10.1039/C0DT00283F. DOI: 10.1039/C0DT00283F.(123) Buendia, J., et. al. Tandem Catalytic C(sp3)-H Amination/Sila-Sonogashira–Hagihara CouplingReactions with Iodine Reagents. Angew. Chem. Int. Ed. 2015, 54 (19), 5697-5701. DOI:https://doi.org/10.1002/anie.201412364.(124) Reddy, R. P., et. al. Dirhodium Tetracarboxylates Derived from Adamantylglycine as Chiral Catalysts for Enantioselective C−H Aminations. Org. Lett. 2006, 8 (22), 5013-5016. DOI:10.1021/ol061742l.(125) Zalatan, D. N., et. al. A Chiral Rhodium Carboxamidate Catalyst for Enantioselective C−HAmination. J. Am. Chem. Soc. 2008, 130 (29), 9220-9221. DOI: 10.1021/ja8031955.(126) Noda, H., et. al. O-Benzoylhydroxylamines as Alkyl Nitrene Precursors: Synthesis of Saturated NHeterocyclesfrom Primary Amines. Org. Lett. 2020, 22 (22), 8769-8773. DOI:10.1021/acs.orglett.0c02842.(127) Yu, X.-Q., et. al. Amidation of Saturated C−H Bonds Catalyzed by Electron-Deficient Rutheniumand Manganese Porphyrins. A Highly Catalytic Nitrogen Atom Transfer Process. Org. Lett. 2000, 2 (15),2233-2236. DOI: 10.1021/ol000107r.(128) Harvey, M. E., et. al. A Diruthenium Catalyst for Selective, Intramolecular Allylic C–H Amination:Reaction Development and Mechanistic Insight Gained through Experiment and Theory. J. Am. Chem.Soc. 2011, 133 (43), 17207-17216. DOI: 10.1021/ja203576p.(129) Milczek, E., et. al. Enantioselective C-H Amination Using Cationic Ruthenium(II)–pyboxCatalysts. Angew. Chem. Int. Ed. 2008, 47 (36), 6825-6828. DOI:https://doi.org/10.1002/anie.200801445.(130) Nishioka, Y., et. al. Enantio- and Regioselective Intermolecular Benzylic and Allylic C-H BondAmination. Angew. Chem. Int. Ed. 2013, 52 (6), 1739-1742. DOI:https://doi.org/10.1002/anie.201208906.(131) Liu, Y.; Che, C.-M. [FeIII(F20-tpp)Cl] Is an Effective Catalyst for Nitrene Transfer Reactions andAmination of Saturated Hydrocarbons with Sulfonyl and Aryl Azides as Nitrogen Source under Thermaland Microwave-Assisted Conditions. Chemistry – A European Journal 2010, 16 (34), 10494-10501. DOI:https://doi.org/10.1002/chem.201000581.(132) Paradine, S. M., et. al. Iron-Catalyzed Intramolecular Allylic C–H Amination. J. Am. Chem. Soc.2012, 134 (4), 2036-2039. DOI: 10.1021/ja211600g.(133) King, E. R., et. al. Catalytic C−H Bond Amination from High-Spin Iron Imido Complexes. J. Am.Chem. Soc. 2011, 133 (13), 4917-4923. DOI: 10.1021/ja110066j.(134) Prier, C. K., et. al. Enantioselective, intermolecular benzylic C–H amination catalysed by anengineered iron-haem enzyme. Nat. Chem. 2017, 9 (7), 629-634. DOI: 10.1038/nchem.2783.(135) Athavale, S. V., et. al. Enzymatic Nitrogen Insertion into Unactivated C–H Bonds. J. Am. Chem.Soc. 2022, 144 (41), 19097-19105. DOI: 10.1021/jacs.2c08285.(136) Wu, L., et. al. Ligand-Free Iron-Catalyzed Intramolecular Amination of C-H Bond for the Synthesisof Imidazolinones. Chinese Journal of Organic Chemistry 2021, 41 (10), 4083-4087. DOI:10.6023/cjoc202104054.(137) Kweon, J., et. al. Highly Robust Iron Catalyst System for Intramolecular C(sp3)−H AmidationLeading to γ-Lactams. Angew. Chem. Int. Ed. 2021, 60 (6), 2909-2914. DOI:https://doi.org/10.1002/anie.202013499.(138) Paradine, S. M., et. al. A manganese catalyst for highly reactive yet chemoselective intramolecularC(sp3)–H amination. Nature Chem. 2015, 7 (12), 987-994. DOI: 10.1038/nchem.2366.(139) Clark, J. R., et. al. Manganese-catalysed benzylic C(sp3)–H amination for late-stagefunctionalization. Nat. Chem. 2018, 10 (6), 583-591. DOI: 10.1038/s41557-018-0020-0.(140) Ni, Z., et. al. Highly Regioselective Copper-Catalyzed Benzylic C-H Amination by NFluorobenzenesulfonimide.Angew. Chem. Int. Ed. 2012, 51 (5), 1244-1247. DOI:https://doi.org/10.1002/anie.201107427.(141) Kohmura, Y., et. al. Benzylic and Allylic Amination. Synlett 1997, 12 (12), 1456-1458. DOI:10.1055/s-1997-1067.(142) Gephart III, R. T., et. al. Catalytic C-H Amination with Aromatic Amines. Angew. Chem. Int. Ed.2012, 51 (26), 6488-6492. DOI: https://doi.org/10.1002/anie.201201921.(143) Michaudel, Q., et. al. Intermolecular Ritter-Type C–H Amination of Unactivated sp3 Carbons. J.Am. Chem. Soc. 2012, 134 (5), 2547-2550. DOI: 10.1021/ja212020b.(144) Tran, B. L., et. al. Copper-Catalyzed Intermolecular Amidation and Imidation of UnactivatedAlkanes. J. Am. Chem. Soc. 2014, 136 (6), 2555-2563. DOI: 10.1021/ja411912p.(145) Kim, D. S., et. al. Formation of the Tertiary Sulfonamide C(sp3)–N Bond Using Alkyl BoronicEster via Intramolecular and Intermolecular Copper-Catalyzed Oxidative Cross-Coupling. J. Org. Chem.2021, 86 (23), 17380-17394. DOI: 10.1021/acs.joc.1c01759.(146) Lee, J., et. al. Versatile Cp*Co(III)(LX) Catalyst System for Selective Intramolecular C–HAmidation Reactions. J. Am. Chem. Soc. 2020, 142 (28), 12324-12332. DOI: 10.1021/jacs.0c04448.(147) Zhang, Y., et. al. Au(III)-catalyzed intermolecular amidation of benzylic C–H bonds. Org. Biomol.Chem. 2012, 10 (46), 9137-9141, 10.1039/C2OB26857D. DOI: 10.1039/C2OB26857D.(148) Sun, K., et. al. Intramolecular Ir(I)-Catalyzed Benzylic C−H Bond Amination of ortho-SubstitutedAryl Azides. Org. Lett. 2009, 11 (16), 3598-3601. DOI: 10.1021/ol901317j.(149) Ichinose, M., et. al. Enantioselective Intramolecular Benzylic C-H Bond Amination: EfficientSynthesis of Optically Active Benzosultams. Angew. Chem. Int. Ed. 2011, 50 (42), 9884-9887. DOI:https://doi.org/10.1002/anie.201101801.(150) Hong, S. Y., et. al. Selective formation of γ-lactams via C-H amidation enabled by tailored iridiumcatalysts. Science 2018, 359 (6379), 1016-1021. DOI: doi:10.1126/science.aap7503.(151) Dydio, P., et. al. Chemoselective, Enzymatic C–H Bond Amination Catalyzed by a CytochromeP450 Containing an Ir(Me)-PIX Cofactor. J. Am. Chem. Soc. 2017, 139 (5), 1750-1753. DOI:10.1021/jacs.6b11410.(152) Cui, Y., et. al. A Silver-Catalyzed Intramolecular Amidation of Saturated C-H Bonds. Angew. Chem.Int. Ed. 2004, 43 (32), 4210-4212. DOI: https://doi.org/10.1002/anie.200454243.(153) Li, Z., et. al. Silver-Catalyzed Intermolecular Amination of C-H Groups. Angew. Chem. Int. Ed.2007, 46 (27), 5184-5186. DOI: https://doi.org/10.1002/anie.200700760.(154) Alderson, J. M., et. al. Ligand-Controlled, Tunable Silver-Catalyzed C–H Amination. J. Am. Chem.Soc. 2014, 136 (48), 16720-16723. DOI: 10.1021/ja5094309.(155) Hazelard, D., et. al. Catalytic C–H amination at its limits: challenges and solutions. Org. Chem.Front. 2017, 4 (12), 2500-2521, 10.1039/C7QO00547D. DOI: 10.1039/C7QO00547D.(156) Roizen, J. L., et. al. Metal-Catalyzed Nitrogen-Atom Transfer Methods for the Oxidation ofAliphatic C–H Bonds. Acc. Chem. Res. 2012, 45 (6), 911-922. DOI: 10.1021/ar200318q.(157) Darses, B., et. al. Transition metal-catalyzed iodine(III)-mediated nitrene transfer reactions:efficient tools for challenging syntheses. Chem. Comm. 2017, 53 (3), 493-508, 10.1039/C6CC07925C.DOI: 10.1039/C6CC07925C.(158) Chiappini, N. D., et. al. Intermolecular C(sp3)−H Amination of Complex Molecules. Angew. Chem.Int. Ed. 2018, 57 (18), 4956-4959. DOI: https://doi.org/10.1002/anie.201713225.(159) Wang, Y.-C., et. al. Unravelling nitrene chemistry from acyclic precursors: recent advances andchallenges. Org. Chem. Front. 2021, 8 (7), 1677-1693, 10.1039/D0QO01360A. DOI:10.1039/D0QO01360A.(160) Brunard, E., et. al. Catalytic Intermolecular C(sp3)–H Amination: Selective Functionalization of Tertiary C–H Bonds vs Activated Benzylic C–H Bonds. J. Am. Chem. Soc. 2021, 143 (17), 6407-6412.DOI: 10.1021/jacs.1c03872.(161) Brady, P. B., et. al. Recent Applications of Rh- and Pd-Catalyzed C(sp3)–H Functionalization inNatural Product Total Synthesis. Eur. J. Org. Chem. 2017, 2017 (35), 5179-5190. DOI:https://doi.org/10.1002/ejoc.201700641.(162) Abrams, D. J., et. al. Recent applications of C-H functionalization in complex natural productsynthesis. Chem. Soc. Rev. 2018, 47 (23), 8925-8967, 10.1039/C8CS00716K. DOI:10.1039/C8CS00716K.(163) Tsukano, C., et. al. Total Synthesis of Nitrogen-Containing Natural Products Based on Palladium-Catalyzed C-H Functionalization. In Handbook of CH-Functionalization, pp 1-49.(164) Fleming, J. J., et. al. (+)-Saxitoxin: A First and Second Generation Stereoselective Synthesis. J.Am. Chem. Soc. 2007, 129 (32), 9964-9975. DOI: 10.1021/ja071501o.(165) Hinman, A., et. al. A Stereoselective Synthesis of (−)-Tetrodotoxin. J. Am. Chem. Soc. 2003, 125(38), 11510-11511. DOI: 10.1021/ja0368305.(166) Lescot, C., et. al. Intermolecular C–H Amination of Complex Molecules: Insights into the FactorsGoverning the Selectivity. J. Org. Chem. 2012, 77 (17), 7232-7240. DOI: 10.1021/jo301563j.(167) O'Neil, L. G., et. al. Electrophilic Aminating Agents in Total Synthesis. Angew. Chem. Int. Ed.2021, 60 (49), 25640-25666. DOI: https://doi.org/10.1002/anie.202102864.(168) Louillat, M.-L.; P., e. a. Oxidative C–H amination reactions. Chem. Soc. Rev. 2014, 43 (3), 901-910, 10.1039/C3CS60318K. DOI: 10.1039/C3CS60318K.(169) He, J., et. al. Palladium-Catalyzed Transformations of Alkyl C–H Bonds. Chem. Rev. 2017, 117(13), 8754-8786. DOI: 10.1021/acs.chemrev.6b00622.(170) He, G., et. al. Highly Efficient Syntheses of Azetidines, Pyrrolidines, and Indolines via PalladiumCatalyzed Intramolecular Amination of C(sp3)–H and C(sp2)–H Bonds at γ and δ Positions. J. Am. Chem.Soc. 2012, 134 (1), 3-6. DOI: 10.1021/ja210660g.(171) He, G., et. al. Use of a Readily Removable Auxiliary Group for the Synthesis of Pyrrolidones bythe Palladium-Catalyzed Intramolecular Amination of Unactivated γ C(sp3)-H Bonds. Angew. Chem. Int.Ed. 2013, 52 (42), 11124-11128. DOI: https://doi.org/10.1002/anie.201305615.(172) Neumann, J. J., et. al. Palladium-Catalyzed Amidation of Unactivated C(sp3)-H Bonds: fromAnilines to Indolines. Angew. Chem. Int. Ed. 2009, 48 (37), 6892-6895. DOI:https://doi.org/10.1002/anie.200903035.(173) McNally, A., et. al. Palladium-catalysed C–H activation of aliphatic amines to give strainednitrogen heterocycles. Nature 2014, 510 (7503), 129-133. DOI: 10.1038/nature13389.(174) He, J., et. al. Palladium(0)/PAr3-Catalyzed Intermolecular Amination of C(sp3) H Bonds:Synthesis of β-Amino Acids. Angew. Chem. Int. Ed. 2015, 54 (22), 6545-6549. DOI:https://doi.org/10.1002/anie.201502075.(175) Zhang, Q., et. al. Stereoselective Synthesis of Chiral α-Amino-β-Lactams through Palladium(II)-Catalyzed Sequential Monoarylation/Amidation of C(sp3)-H Bonds. Angew. Chem. Int. Ed. 2013, 52 (51),13588-13592. DOI: https://doi.org/10.1002/anie.201306625.(176) Jin, L., et. al. Palladium-catalyzed intermolecular amination of unactivated C(sp3)–H bonds via acleavable directing group. Chem. Comm. 2017, 53 (28), 3986-3989, 10.1039/C7CC00808B. DOI:10.1039/C7CC00808B.(177) Wang, Z., et. al. Copper-Catalyzed Intramolecular C(sp3)-H and C(sp2)-H Amidation by OxidativeCyclization. Angew. Chem. Int. Ed. 2014, 53 (13), 3496-3499. DOI:https://doi.org/10.1002/anie.201311105.(178) Kang, T., et. al. Synthesis of 1,2-amino alcohols via catalytic C–H amidation of sp3 methyl C–Hbonds. Chem. Comm. 2014, 50 (81), 12073-12075, 10.1039/C4CC05655H. DOI: 10.1039/C4CC05655H.(179) Kang, T., et. al. Iridium-Catalyzed Intermolecular Amidation of sp3 C–H Bonds: Late-StageFunctionalization of an Unactivated Methyl Group. J. Am. Chem. Soc. 2014, 136 (11), 4141-4144. DOI:10.1021/ja501014b.(180) Wang, N., et. al. Rhodium(III)-Catalyzed Intermolecular Amidation with Azides via C(sp3)–HFunctionalization. J. Org. Chem. 2014, 79 (11), 5379-5385. DOI: 10.1021/jo5008515.(181) Tang, C., et. al. Rh-Catalyzed Direct Amination of Unactivated C(sp3)−H bond with AnthranilsUnder Mild Conditions. Chem. Eur. J. 2016, 22 (32), 11165-11169. DOI:https://doi.org/10.1002/chem.201602556.(182) Huang, X., et. al. Rhodium(III)-Catalyzed Activation of C-H Bonds and Subsequent IntermolecularAmidation at Room Temperature. Angew. Chem. Int. Ed. 2015, 54 (32), 9404-9408. DOI:https://doi.org/10.1002/anie.201504507.(183) Yu, S., et. al. Anthranil: An Aminating Reagent Leading to Bifunctionality for Both C(sp3)−H andC(sp2)−H under Rhodium(III) Catalysis. Angew. Chem. Int. Ed. 2016, 55 (30), 8696-8700. DOI:https://doi.org/10.1002/anie.201602224.(184) Wang, H., et. al. Rhodium(III)-Catalyzed Amidation of Unactivated C(sp3)-H Bonds. Angew. Chem.Int. Ed. 2015, 54 (44), 13049-13052. DOI: https://doi.org/10.1002/anie.201506323.(185) Liu, B., et. al. Ru(II)-catalyzed amidation reactions of 8-methylquinolines with azides via C(sp3)–H activation. Chem. Comm. 2015, 51 (91), 16334-16337, 10.1039/C5CC06230F. DOI:10.1039/C5CC06230F.(186) Wu, X., et. al. Cobalt-catalysed site-selective intra- and intermolecular dehydrogenative aminationof unactivated sp3 carbons. Nat. Commun. 2015, 6 (1), 6462. DOI: 10.1038/ncomms7462.(187) Cochet, T., et. al. Rhodium(iii)-catalyzed allylic C–H bond amination. Synthesis of cyclic aminesfrom ω-unsaturated N-sulfonylamines. Chem. Comm. 2012, 48 (87), 10745-10747,10.1039/C2CC36067E. DOI: 10.1039/C2CC36067E.(188) Shibata, Y. e. a. Facile Generation and Isolation of π-Allyl Complexes from Aliphatic Alkenes andan Electron-Deficient Rh(III) Complex: Key Intermediates of Allylic C–H Functionalization.Organometallics 2016, 35 (10), 1547-1552. DOI: 10.1021/acs.organomet.6b00143.(189) Burman, J. S., et. al. Regioselective Intermolecular Allylic C−H Amination of Disubstituted Olefinsvia Rhodium/π-Allyl Intermediates. Angew. Chem. Int. Ed. 2017, 56 (44), 13666-13669. DOI:https://doi.org/10.1002/anie.201707021.(190) Farr, C. M. B., et. al. Designing a Planar Chiral Rhodium Indenyl Catalyst for Regio- andEnantioselective Allylic C–H Amidation. J. Am. Chem. Soc. 2020, 142 (32), 13996-14004. DOI:10.1021/jacs.0c07305.(191) Burman, J. S., et. al. Rh(III) and Ir(III)Cp* Complexes Provide Complementary RegioselectivityProfiles in Intermolecular Allylic C–H Amidation Reactions. ACS Catal. 2019, 9 (6), 5474-5479. DOI:10.1021/acscatal.9b01338.(192) Nelson, T. A. F., et. al. Allylic C–H functionalization via group 9 π-allyl intermediates. DaltonTrans. 2020, 49 (40), 13928-13935, 10.1039/D0DT02313B. DOI: 10.1039/D0DT02313B.(193) Sihag, P., et. al. Rh(III)-Catalyzed allylic C–H amidation of unactivated alkenes with in situgenerated iminoiodinanes. Chem. Comm. 2021, 57 (52), 6428-6431, 10.1039/D1CC02283K. DOI:10.1039/D1CC02283K.(194) Wang, F., et. al. Comprehensive Theoretical Study of Cp*IrIII-Catalyzed IntermolecularEnantioselective Allylic C–H Amidation: Reaction Mechanism, Electronic Processes, andRegioselectivity. 2023, 88 (4), 2493-2504. DOI: 10.1021/acs.joc.2c02951.(195) Kazerouni, A. M., et. al. Regioselective Cp*Ir(III)-Catalyzed Allylic C–H Sulfamidation ofAllylbenzene Derivatives. J, Org. Chem 2019, 84 (20), 13179-13185. DOI: 10.1021/acs.joc.9b01816.(196) Sihag, P., et. al. Iridium(III)-Catalyzed Intermolecular Allylic C–H Amidation of Internal Alkeneswith Sulfonamides. J. Org. Chem. 2019, 84 (20), 13053-13064. DOI: 10.1021/acs.joc.9b02047.(197) Lei, H. e. a. A site-selective amination catalyst discriminates between nearly identical C–H bondsof unsymmetrical disubstituted alkenes. Nat. Chem. 2020, 12 (8), 725-731. DOI: 10.1038/s41557-020-0470-z.(198) Knecht, T., et. al. Intermolecular, Branch-Selective, and Redox-Neutral Cp*IrIII-Catalyzed AllylicC−H Amidation. Angew. Chem. Int. Ed. 2019, 58 (21), 7117-7121. DOI:https://doi.org/10.1002/anie.201901733.(199) Huang, F., et. al. Electrostatic repulsion-controlled regioselectivity in nitrene-mediated allylic C–H amidations. Org. Chem. Front. 2021, 8 (21), 6038-6047, 10.1039/D1QO01018B. DOI:10.1039/D1QO01018B.(200) Lei, H., et. al. Ir-Catalyzed Intermolecular Branch-Selective Allylic C–H Amidation of UnactivatedTerminal Olefins. J. Am. Chem. Soc. 2019, 141 (6), 2268-2273. DOI: 10.1021/jacs.9b00237.(201) Duarte, F. J. S., et. al. Mechanistic Study of the Direct Intramolecular Allylic Amination ReactionCatalyzed by Palladium(II). ACS Catal. 2016, 6 (3), 1772-1784. DOI: 10.1021/acscatal.5b02091.(202) Nahra, F., et. al. Striking AcOH Acceleration in Direct Intramolecular Allylic Amination Reactions.2009, 15 (42), 11078-11082. DOI: https://doi.org/10.1002/chem.200901946.(203) Fraunhoffer, K. J., et. al. syn-1,2-Amino Alcohols via Diastereoselective Allylic C−H Amination.Journal of the American Chemical Society 2007, 129 (23), 7274-7276. DOI: 10.1021/ja071905g.(204) Rice, G. T., et. al. Allylic C−H Amination for the Preparation of syn-1,3-Amino Alcohol Motifs. J.Am. Chem. Soc. 2009, 131 (33), 11707-11711. DOI: 10.1021/ja9054959.(205) Jiang, C.; Covell, D. J.; Stepan, A. F.; Plummer, M. S.; White, M. C. Sequential Allylic C–HAmination/Vinylic C–H Arylation: A Strategy for Unnatural Amino Acid Synthesis from α-Olefins.Organic Letters 2012, 14 (6), 1386-1389. DOI: 10.1021/ol300063t.(206) Wu, L., et. al. Brønsted Base-Modulated Regioselective Pd-Catalyzed Intramolecular AerobicOxidative Amination of Alkenes: Formation of Seven-Membered Amides and Evidence for Allylic C−HActivation. Org. Lett. 2009, 11 (12), 2707-2710. DOI: 10.1021/ol900941t.(207) Sharma, A., et. al. Enantioselective Functionalization of Allylic C–H Bonds Following a Strategyof Functionalization and Diversification. J. Am. Chem. Soc. 2013, 135 (47), 17983-17989. DOI:10.1021/ja409995w.(208) Pak S. C., e. a. Asymmetric intermolecular allylic C-H amination of alkenes with aliphatic amines.Science 2022, 378 (6625), 1207-1213. DOI: doi:10.1126/science.abq1274.(209) Wang, J., et. al. Theoretical studies on Mn-catalyzed intermolecular allylic C-H aminations ofinternal olefins: mechanism, chemo- and regioselectivity. Molecular Catalysis 2022, 524, 112278. DOI:https://doi.org/10.1016/j.mcat.2022.112278.(210) Zhou, S., et. al. Direct intermolecular C(sp3)–H amidation with dioxazolones via synergisticdecatungstate anion photocatalysis and nickel catalysis: A combined experimental and computationalstudy. Journal of Catalysis 2022, 415, 142-152. DOI: https://doi.org/10.1016/j.jcat.2022.10.003.(211) Zheng, Y.-W., et. al. Copper(II)-Photocatalyzed N–H Alkylation with Alkanes. ACS Catal. 2020, 10 (15), 8582-8589. DOI: 10.1021/acscatal.0c01924.(212) Wang, Q., et. al. Photoexcited Direct Amination/Amidation of Inert Csp3–H Bonds via Tungsten–Nickel Catalytic Relay. ACS Catal. 2022, 12 (18), 11071-11077. DOI: 10.1021/acscatal.2c03456.(213) Wakikawa, T., et. al. Native Amide-Directed C(sp3)−H Amidation Enabled by Electron-DeficientRhIII Catalyst and Electron-Deficient 2-Pyridone Ligand. Angew. Chem. Int. Ed. 2022, 61 (52),e202213659. DOI: https://doi.org/10.1002/anie.202213659.(214) Thomas, F., et. al. A new generation of terminal copper nitrenes and their application in aromaticC–H amination reactions. Dalton Trans. 2021, 50 (19), 6444-6462, 10.1039/D1DT00832C. DOI:10.1039/D1DT00832C.(215) Bakhoda, A., et. al. Copper-Catalyzed C(sp3)−H Amidation: Sterically Driven Primary andSecondary C−H Site-Selectivity. Angew. Chem. Int. Ed. 2019, 58 (11), 3421-3425. DOI:https://doi.org/10.1002/anie.201810556.(216) Lee, J., et. al. Cobalt-Catalyzed Intermolecular C–H Amidation of Unactivated Alkanes. J. Am.Chem. Soc. 2021, 143 (13), 5191-5200. DOI: 10.1021/jacs.1c01524.(217) Wang, Q., et. al. Visible-light-mediated tungsten-catalyzed C-H amination of unactivated alkaneswith nitroarenes. Science China Chemistry 2022, 65 (4), 678-685. DOI: 10.1007/s11426-021-1170-2.(218) Chen, B., et. al. Overview of lethal human coronaviruses. Sig. Transduct Target Ther. 2020, 5 (1),89. DOI: 10.1038/s41392-020-0190-2.(219) Ramesh, S., et. al. Emerging SARS-CoV-2 Variants: A Review of Its Mutations, Its Implicationsand Vaccine Efficacy. Vaccines 2021, 9 (10). DOI: 10.3390/vaccines9101195.(220) Du, X., et. al. Omicron adopts a different strategy from Delta and other variants to adapt to host.Sig. Transduct Target Ther. 2022, 7 (1), 45. DOI: 10.1038/s41392-022-00903-5.(221) Zhang, Q., et. al. Molecular mechanism of interaction between SARS-CoV-2 and host cells andinterventional therapy. Sig. Transduct Target Ther. 2021, 6 (1), 233. DOI: 10.1038/s41392-021-00653-w.(222) Arya, R., et. al. Structural insights into SARS-CoV-2 proteins. J. Mol. Biol. 2021, 433 (2), 166725.DOI: 10.1016/j.jmb.2020.11.024.(223) Gao, Y., et. al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science2020, 368, 4.(224) Bartlam, M., et. al. Structural proteomics of the SARS coronavirus: a model response to emerginginfectious diseases. J. Struct. Funct. Genomics 2007, 8 (2-3), 85-97. DOI: 10.1007/s10969-007-9024-5.(225) Chu, C. M., et. al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological andclinical findings. Thorax 2004, 59 (3), 252-256. DOI: 10.1136/thorax.2003.012658.(226) Yalcin, N., et. al. COVID-19 and antiepileptic drugs: an approach to guide practices whennirmatrelvir/ritonavir is co-prescribed. Eur. J. Clin. Pharmacol. 2022, 78 (10), 1697-1701. DOI:10.1007/s00228-022-03370-7.(227) Thompson, M. G., et. al. Paxlovid Associated with Decreased Hospitalization Rate Among AdultswithCOVID-19 — United States, April–September 2022. Morb. Mortal Wkly. Rep. 2021, 385 (15), 1355-1371. DOI: 10.1056/NEJMoa2110362 From NLM Medline.(228) Tyndall, J. D. A. S-217622, a 3CL Protease Inhibitor and Clinical Candidate for SARS-CoV-2. J.Med. Chem. 2022, 65 (9), 6496-6498. DOI: 10.1021/acs.jmedchem.2c00624.(229) Xiaoxin, C., et. al. Inhibition mechanism and antiviral activity of an α-ketoamide based SARSCoV-2 main protease inhibitor. bioRxiv 2023, 2023.2003.2009.531862. DOI:10.1101/2023.03.09.531862. (230) Báez-Santos, Y. M., et. al. The SARS-coronavirus papain-like protease: Structure, function andinhibition by designed antiviral compounds. Antiviral Research 2015, 115, 21-38. DOI:https://doi.org/10.1016/j.antiviral.2014.12.015.(231) Walls, A. C., et. al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.Cell 2020, 181 (2), 281-292.e286. DOI: https://doi.org/10.1016/j.cell.2020.02.058.(232) Bégin, P., et. al. Convalescent plasma for hospitalized patients with COVID-19: an open-label,randomized controlled trial. Nat. Med. 2021, 27 (11), 2012-2024. DOI: 10.1038/s41591-021-01488-2.(233) Xiang, R., et. al. Neutralizing monoclonal antibodies against highly pathogenic coronaviruses.Current Opinion in Virology 2022, 53, 101199. DOI: https://doi.org/10.1016/j.coviro.2021.12.015.(234) Xia, S., et. al. Peptide-based pan-CoV fusion inhibitors maintain high potency against SARS-CoV-2 Omicron variant. Cell Research 2022, 32 (4), 404-406. DOI: 10.1038/s41422-022-00617-x.(235) Omrani, A. S., et. al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndromecoronavirus infection: a retrospective cohort study. The Lancet Infectious Dis. 2014, 14 (11), 1090-1095.DOI: https://doi.org/10.1016/S1473-3099(14)70920-X.(236) Rossignol, J.-F. Nitazoxanide: A first-in-class broad-spectrum antiviral agent. Antiviral Research2014, 110, 94-103. DOI: https://doi.org/10.1016/j.antiviral.2014.07.014.(237) Lam, S., et. al. COVID-19: A review of the proposed pharmacological treatments. EuropeanJournal of Pharmacology 2020, 886, 173451. DOI: https://doi.org/10.1016/j.ejphar.2020.173451.(238) Dong, S., et. al. A guideline for homology modeling of the proteins from newly discoveredbetacoronavirus, 2019 novel coronavirus (2019-nCoV). J. Med. Virol. 2020, 92 (9), 1542-1548. DOI:https://doi.org/10.1002/jmv.25768.(239) Gao, Y., et. al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science2020, 368 (6492), 779-782. DOI: doi:10.1126/science.abb7498.(240) Wang, Q., et. al. Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase. Cell 2020,182 (2), 417-428.e413. DOI: https://doi.org/10.1016/j.cell.2020.05.034.(241) Gordon, C. J.; Tchesnokov, E. P.; Schinazi, R. F.; Götte, M. Molnupiravir promotes SARS-CoV-2mutagenesis via the RNA template. J. Biol. Chem. 2021, 297 (1), 100770. DOI:https://doi.org/10.1016/j.jbc.2021.100770.(242) Eastman, R. T., et. al. Remdesivir: A Review of Its Discovery and Development Leading toEmergency Use Authorization for Treatment of COVID-19. ACS Cent. Sci. 2020, 6 (5), 672-683. DOI:10.1021/acscentsci.0c00489.(243) Zhang, J., et. al. Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treatingCOVID-19 patients. Sig. Transduct Target. Ther. 2021, 6 (1), 414. DOI: 10.1038/s41392-021-00835-6.(244) Zhou, S., et. al. β-ᴅ-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But IsAlso Mutagenic To Mammalian Cells. The Journal of Infectious Diseases 2021, 224 (3), 415-419. DOI:10.1093/infdis/jiab247 (acccessed 6/25/2023).(245) Fischer, W. A., et. al. A phase 2a clinical trial of molnupiravir in patients with COVID-19 showsaccelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Science TranslationalMedicine 2022, 14 (628), eabl7430. DOI: doi:10.1126/scitranslmed.abl7430.(246) Warren, T., et. al. Nucleotide Prodrug GS-5734 Is a Broad-Spectrum Filovirus Inhibitor ThatProvides Complete Therapeutic Protection Against the Development of Ebola Virus Disease (EVD) inInfected Non-human Primates. Open Forum Infectious Diseases 2015, 2 (suppl_1). DOI:10.1093/ofid/ofv130.02 (acccessed 5/29/2023).(247) Tchesnokov, E. P.; Feng, J. Y.; Porter, D. P.; Götte, M. Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir. Viruses 2019, 11 (4). DOI: 10.3390/v11040326 FromNLM.(248) Keating, G. M., et. al. Sofosbuvir: First Global Approval. Drugs 2014, 74 (2), 273-282. DOI:10.1007/s40265-014-0179-7.(249) Jácome, R.; Campillo-Balderas, J. A.; Ponce de León, S.; Becerra, A.; Lazcano, A. Sofosbuvir asa potential alternative to treat the SARS-CoV-2 epidemic. Sci. Rep. 2020, 10 (1), 9294. DOI:10.1038/s41598-020-66440-9.(250) Taylor, R., et. al. Activity of Galidesivir in a Hamster Model of SARS-CoV-2. Viruses 2022, 14 (1),8.(251) Julander, J. G., et. al. An update on the progress of galidesivir (BCX4430), a broad-spectrumantiviral. Antiviral Research 2021, 195, 105180. DOI: https://doi.org/10.1016/j.antiviral.2021.105180.(252) Hassanipour, S., et. al. The efficacy and safety of Favipiravir in treatment of COVID-19: asystematic review and meta-analysis of clinical trials. Scientific Reports 2021, 11 (1), 11022. DOI:10.1038/s41598-021-90551-6.(253) Coomes, E. A., et. al. Favipiravir, an antiviral for COVID-19? Journal of AntimicrobialChemotherapy 2020, 75 (7), 2013-2014. DOI: 10.1093/jac/dkaa171 (acccessed 6/28/2023).(254) Tong, S.; Su, Y.; Yu, Y.; Wu, C.; Chen, J.; Wang, S.; Jiang, J. Ribavirin therapy for severe COVID-19: a retrospective cohort study. International Journal of Antimicrobial Agents 2020, 56 (3), 106114.DOI: https://doi.org/10.1016/j.ijantimicag.2020.106114.(255) Steven, S. G., et. al. AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a PotentInhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19.Antimicrob. Agents Chemother. 2021, 65 (4), 10.1128/aac.02479-02420. DOI: doi:10.1128/aac.02479-20.(256) Shannon, A., et. al. A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase. Nat.Comm. 2022, 13 (1), 621. DOI: 10.1038/s41467-022-28113-1.(257) P., V. Atea’s AT-527 fails to meet primary goal of Phase II Covid-19 trial.(258) Ren, Z., et. al. A Randomized, Open-Label, Controlled Clinical Trial of Azvudine Tablets in theTreatment of Mild and Common COVID-19, a Pilot Study. Adv. Sci. 2020, 7 (19), 2001435. DOI:https://doi.org/10.1002/advs.202001435.(259) Xie, Y., et. al. Design and development of an oral remdesivir derivative VV116 against SARSCoV-2. Cell Res. 2021, 31 (11), 1212-1214. DOI: 10.1038/s41422-021-00570-1.(260) Filipowicz, W., et. al. A protein binding the methylated 5'-terminal sequence, m7GpppN, ofeukaryotic messenger RNA. Proc. Natl. Acad. Sci. 1976, 73 (5), 1559-1563. DOI:doi:10.1073/pnas.73.5.1559.(261) Züst, R., et. al. Ribose 2′-O-methylation provides a molecular signature for the distinction of selfand non-self mRNA dependent on the RNA sensor Mda5. Nat. Immunol. 2011, 12 (2), 137-143. DOI:10.1038/ni.1979.(262) Decroly, E., et. al. Conventional and unconventional mechanisms for capping viral mRNA. Nat.Rev. Microbiol. 2012, 10 (1), 51-65. DOI: 10.1038/nrmicro2675.(263) Ogando, N. S., et. al. Structure-function analysis of the nsp14 N7-guanine methyltransferasereveals an essential role in Betacoronavirus replication. PNAS 2021, 118 (49), e2108709118. DOI:doi:10.1073/pnas.2108709118.(264) Devkota, K., et. al. Probing the SAM Binding Site of SARS-CoV-2 Nsp14 In Vitro Using SAMCompetitive Inhibitors Guides Developing Selective Bisubstrate Inhibitors. SLAS Discovery 2021, 26 (9), 1200-1211. DOI: https://doi.org/10.1177/24725552211026261.(265) Zhang, J., et. al. SAM/SAH Analogs as Versatile Tools for SAM-Dependent Methyltransferases.ACS Chem. Biol. 2016, 11 (3), 583-597. DOI: 10.1021/acschembio.5b00812.(266) Anglin, J. L., et. al. Synthesis and Structure–Activity Relationship Investigation of Adenosine-Containing Inhibitors of Histone Methyltransferase DOT1L. J. Am. Chem. Soc. 2012, 55 (18), 8066-8074. DOI: 10.1021/jm300917h.(267) Kim, K. H., et. al. Targeting EZH2 in cancer. Nat. Med. 2016, 22 (2), 128-134. DOI:10.1038/nm.4036.(268) Dowden, J., et. al. Small molecule inhibitors that discriminate between protein arginine NmethyltransferasesPRMT1 and CARM1. Org. Biomol. Chem. 2011, 9 (22), 7814-7821,10.1039/C1OB06100C. DOI: 10.1039/C1OB06100C.(269) McDonald, R. I., et. al. Palladium(II)-Catalyzed Alkene Functionalization via Nucleopalladation:Stereochemical Pathways and Enantioselective Catalytic Applications. Chem. Rev. 2011, 111 (4), 2981-3019. DOI: 10.1021/cr100371y.(270) Lan, X.-W., et. al. Recent Advances in Radical Difunctionalization of Simple Alkenes. Eur. J. Org.Chem. 2017, 2017 (39), 5821-5851. DOI: https://doi.org/10.1002/ejoc.201700678.(271) Coombs, J. R., et. al. Catalytic Enantioselective Functionalization of Unactivated Terminal Alkenes.Angew. Chem. Int. Ed. 2016, 55 (8), 2636-2649. DOI: https://doi.org/10.1002/anie.201507151.(272) Jeon, J., et. al. Regio- and Stereoselective Functionalization Enabled by Bidentate DirectingGroups. Chem. Rec. 2021, 21 (12), 3613-3627. DOI: https://doi.org/10.1002/tcr.202100117.(273) Vasseur, A., et. al. Remote functionalization through alkene isomerization. Nature Chem. 2016, 8(3), 209-219. DOI: 10.1038/nchem.2445.(274) Sommer, H., et. al. Walking Metals for Remote Functionalization. ACS Cent. Sci. 2018, 4 (2), 153-165. DOI: 10.1021/acscentsci.8b00005.(275) Janssen-Müller, D., et. al. Tackling Remote sp3 C−H Functionalization via Ni-Catalyzed “chainwalking”Reactions. Isr. J. Chem. 2020, 60 (3-4), 195-206. DOI: https://doi.org/10.1002/ijch.201900072.(276) Buslov, I., et. al. Chemoselective Alkene Hydrosilylation Catalyzed by Nickel Pincer Complexes.Angew. Chem. Int. Ed. 2015, 54 (48), 14523-14526. DOI: https://doi.org/10.1002/anie.201507829.(277) Buslov, I., et. al. An Easily Accessed Nickel Nanoparticle Catalyst for Alkene Hydrosilylation withTertiary Silanes. Angew. Chem. Int. Ed. 2016, 55 (40), 12295-12299. DOI:https://doi.org/10.1002/anie.201606832.(278) Juliá-Hernández, F., et. al. Remote carboxylation of halogenated aliphatic hydrocarbons withcarbon dioxide. Nature 2017, 545 (7652), 84-88. DOI: 10.1038/nature22316.(279) Sun, S.-Z., et. al. Site-Selective Ni-Catalyzed Reductive Coupling of α-Haloboranes withUnactivated Olefins. J. Am. Chem. Soc. 2018, 140 (40), 12765-12769. DOI: 10.1021/jacs.8b09425.(280) Sun, S.-Z., et. al. Site-Selective Catalytic Deaminative Alkylation of Unactivated Olefins. J. Am.Chem. Soc. 2019, 141 (41), 16197-16201. DOI: 10.1021/jacs.9b07489.(281) He, Y., et. al. Terminal-Selective C(sp3)–H Arylation: NiH-Catalyzed Remote Hydroarylation ofUnactivated Internal Olefins. Organometallics 2021, 40 (14), 2253-2264. DOI:10.1021/acs.organomet.0c00819.(282) Lee, W.-C., et. al. Tandem Isomerization and C–H Activation: Regioselective Hydroheteroarylationof Allylarenes. Org. Lett. 2013, 15 (20), 5358-5361. DOI: 10.1021/ol402644y.(283) He, Y., et. al. Mild and Regioselective Benzylic C–H Functionalization: Ni-Catalyzed ReductiveArylation of Remote and Proximal Olefins. J. Am. Chem. Soc. 2017, 139 (3), 1061-1064. DOI:10.1021/jacs.6b11962.(284) Chen, F., et. al. Remote Migratory Cross-Electrophile Coupling and Olefin HydroarylationReactions Enabled by in Situ Generation of NiH. J. Am. Chem. Soc. 2017, 139 (39), 13929-13935. DOI:10.1021/jacs.7b08064.(285) Xiao, J., et. al. Remote sp3 C–H Amination of Alkenes with Nitroarenes. Chem 2018, 4 (7), 1645-1657. DOI: https://doi.org/10.1016/j.chempr.2018.04.008.(286) Zhang, Y., et. al. Nickel-catalysed selective migratory hydrothiolation of alkenes and alkynes withthiols. Nat. Comm. 2019, 10 (1), 1752. DOI: 10.1038/s41467-019-09783-w.(287) Yulong Z., e. a. Ligand-Enabled NiH-Catalyzed Migratory Hydroamination: Chain Walking as aStrategy for Regiodivergent/Regioconvergent Remote sp3 C-H Amination. CCS Chem. 2021, 3 (9), 2259-2268. DOI: doi:10.31635/ccschem.020.202000490.(288) Liu, J., et. al. Nickel-Catalyzed, Regio- and Enantioselective Benzylic Alkenylation of Olefins withAlkenyl Bromide. Angew. Chem. Int. Ed. 2021, 60 (8), 4060-4064. DOI:https://doi.org/10.1002/anie.202012614.(289) Zhang, Y., et. al. Rapid Access to Highly Functionalized Alkyl Boronates by NiH-CatalyzedRemote Hydroarylation of Boron-Containing Alkenes. Angew. Chem. Int. Ed. 2019, 58 (39), 13860-13864. DOI: https://doi.org/10.1002/anie.201907185.(290) Qian, D., et. al. Ligand-Controlled Regiodivergent Hydroalkylation of Pyrrolines. Angew. Chem.Int. Ed. 2019, 58 (51), 18519-18523. DOI: https://doi.org/10.1002/anie.201912629.(291) Li, W., et. al. Nickel-catalyzed difunctionalization of allyl moieties using organoboronic acids andhalides with divergent regioselectivities. Chem. Sci. 2018, 9 (3), 600-607, 10.1039/C7SC03149A. DOI:10.1039/C7SC03149A.(292) Dhungana, R. K., et. al. Walking metals: catalytic difunctionalization of alkenes at nonclassicalsites. Chem. Sci. 2020, 11 (36), 9757-9774, 10.1039/D0SC03634J. DOI: 10.1039/D0SC03634J.(293) Yu, B., et. al. Azvudine (FNC): a promising clinical candidate for COVID-19 treatment. Sig.Transduct. Target. Ther. 2020, 5 (1), 236. DOI: 10.1038/s41392-020-00351-z.(294) Lipinski, C. A., et. al. Experimental and computational approaches to estimate solubility andpermeability in drug discovery and development settings. Advanced Drug Delivery Reviews 1997, 23 (1),3-25. DOI: https://doi.org/10.1016/S0169-409X(96)00423-1.(295) Bobrovs, R., et. al. Discovery of SARS-CoV-2 Nsp14 and Nsp16 Methyltransferase Inhibitors byHigh-Throughput Virtual Screening. Pharmaceuticals 2021, 14 (12), 1243.(296) Otava, T.; Šála, e. a. The Structure-Based Design of SARS-CoV-2 nsp14 MethyltransferaseLigands Yields Nanomolar Inhibitors. ACS Infect. Dis. 2021, 7 (8), 2214-2220. DOI:10.1021/acsinfecdis.1c00131.(297) Singh, I., et. al. Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase. J. Med. Chem. 2023, 66 (12), 7785-7803. DOI: 10.1021/acs.jmedchem.2c02120.(298) Otava, T., et. al. The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase LigandsYields Nanomolar Inhibitors. ACS Infect. Dis. 2021, 7 (8), 2214-2220. DOI:10.1021/acsinfecdis.1c00131.(299) Bobiļeva, O., et. al. Potent SARS-CoV-2 mRNA Cap Methyltransferase Inhibitors by BioisostericReplacement of Methionine in SAM Cosubstrate. ACS Med. Chem. Lett. 2021, 12 (7), 1102-1107. DOI:10.1021/acsmedchemlett.1c00140.(300) Ahmed-Belkacem, R., et. al. Synthesis of adenine dinucleosides SAM analogs as specific inhibitorsof SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase. European Journal of Medicinal Chemistry 2020, 201, 112557. DOI: https://doi.org/10.1016/j.ejmech.2020.112557.(301) Ahmed-Belkacem, R., et. al. Potent Inhibition of SARS-CoV-2 nsp14 N7-Methyltransferase bySulfonamide-Based Bisubstrate Analogues. J. Med. Chem. 2022, 65 (8), 6231-6249. DOI:10.1021/acs.jmedchem.2c00120.(302) Jung, E., et. al. Bisubstrate Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 Nsp14Methyltransferase. ACS Med. Chem. Lett. 2022, 13 (9), 1477-1484. DOI:10.1021/acsmedchemlett.2c00265.