Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:22]=[N:21][CH:20]=[CH:19][C:11]=1[C:12]([NH:14][NH:15][C:16](=[S:18])[NH2:17])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrC(Br)(Br)Br.C(Br)(Br)(Br)Br.C(N(CC)CC)C>CN(C=O)C>[NH2:17][C:16]1[S:18][C:12]([C:11]2[CH:19]=[CH:20][N:21]=[CH:22][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[N:14][N:15]=1
Reactant: NC(=S)NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)s1
Temperature: 50 °C
Yield: 4.7 %

Procedure:
To a solution of 2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}hydrazine carbothioamide (220 mg; 0.51 mmol) in DMF (5.00 mL) were added resin bound triphenylphosphine (401 mg; 1.53 mmol), carbon tetrabromide tetrabromomethane (508 mg; 1.53 mmol), and triethyl amine (180 mg; 1.53 mmol). The mixture was heated at 50° C. for 5 h. Filtered and purified on Agilent Prep. HPLC system to get 10 mg of [4-(5-Amino-[1,3,4]thiadiazol-2-yl)-pyridin-3-yl]-(2-fluoro-4-iodo-phenyl)-amine. MS m/z: 414 M+1
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH2:11].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1
Reactant: Nc1ccc(OCC2CC2)c(Br)c1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
Ethylsulfonyl chloride (233 uL, 2.4 mmol) was added to a stirred solution of 3-bromo-4-(cyclopropylmethoxy)aniline (520 mg, 2.2 mmol) and pyridine (520 uL, 6.5 mmol) in DCM (4 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with 1N HCl (15 mL) and extracted with DCM (3×15 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (10 to 100%) in hexanes to afford the title compound (711 mg, 98%) as a yellow solid. LCMS (M+H)+=335.
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[C:23]([OH:25])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1>[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[C:23]([NH2:3])=[O:25]
Reactant: O=C(O)c1c(O)ccc2ccccc12
Reactant: CCN(CC)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1c(O)ccc2ccccc12
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 345.7 %

Procedure:
Diethylaniline (0.27 μL, 1.7 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (0.8 mg, 1.5 μmol, 1 equiv) in THF (0.2 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 min. 2-Hydroxy-1-naphthoic acid (0.37 mg, 2.0 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.38 mg, 2.0 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.25 mg, 1.8 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 13 h 20 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a white solid, which was purified by flash column chromatography (85% ethyl acetate-hexanes) to give the 2-hydroxy-naphthalene-1-carboxylic acid amide derivative (1.1 mg, 100%) as a white solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11](=[O:27])[N:12]([C@@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17](O)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:41])[CH2:34][CH:35]([NH2:40])[CH:36]([OH:39])[CH2:37][F:38])([CH3:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:28]([O:32][C:33](=[O:41])[CH2:34][CH:35]([NH:40][C:17](=[O:18])[C@@H:16]([N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:11]1=[O:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:36]([OH:39])[CH2:37][F:38])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Reactant: O=C(Nc1cccn([C@@H](Cc2ccccc2)C(=O)O)c1=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(NC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O)C(O)CF
Temperature: 0 °C
Yield: 36.7 %

Procedure:
A stirred mixture of (S)-2-(3-benzoylamino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionic acid (2.20 g, 6.07 mmol), 3(R,S)-Amino-5-fluoro-4(R,S)-hydroxy-pentanoic acid tert-butyl ester (1.39 g, 6.68 mmol), HOBt (902 mg, 6.68 mmol), DMAP (853 mg, 6.98 mmol) and THF (20 mL) was cooled to 0° C. then EDC (1.28 mg, 6.68 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (30-70 to 55-45% ethyl acetate/hexane) to afford the title compound as a white foam (1.23 g, 32%); 1H NMR (400 MHz, CDCl3) δ 0.88-0.93 (3H, m), 1.35-1.42 (9H, 2s), 2.50-2.65 (2H, m), 3.20-3.35 (2H, m), 3.60 (1H, m), 3.98 (1H, m), 4.10-4.32 (3H, m), 5.62-5.70 (1H, m), 6.44 (1H, m), 6.80-6.98 (1H, m), 7.21-7.41 (5H, m), 7.55-7.62 (3H, m), 7.95 (2H, m), 8.58 (1H, t), 9.18 (1H, br s).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:14]=1[OH:15])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH2:25]>C(O)C>[CH3:24][N:25]=[C:1]([C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccc2)cc(O)c(C(=O)c2ccccc2)c1=O
Reactant: CN
Solvent: CCO
Product: CN=C(c1ccccc1)c1c(O)cc(-c2ccccc2)n(C)c1=O

Procedure:
Three grams (0.0098 mole) of 3-benzoyl-4-hydroxy-6-phenyl-1-methyl-2(1H)-pyridone is added to 30 milliliters of ethanol saturated with methylamine. The mixture is refluxed for two hours with a stream of methylamine passing through. The mixture is cooled and the resulting solid filtered and washed with ethanol and then ether to give 3-(α-N-methyliminobenzyl)-4-hydroxy-6-phenyl-1-methyl-2(1H)-pyridone; m.p. 225°-227° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N+:13]([O-:15])=[O:14])[C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].[NH3:16]>C(N)=O>[NH2:16][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=1[CH2:9][CH2:10][OH:11]
Reactant: N
Reactant: O=[N+]([O-])c1cc2c(c([N+](=O)[O-])c1)OCC2
Solvent: NC=O
Product: Nc1c(CCO)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
0.17 Mole (35.7 g) of 2,3-dihydro-5,7-dinitrobenzofuran, prepared according to Chatelus Ann. Chim. [12], 4, 505-547 (1949), is suspended in 350 ml of 20% strength ammonia solution and 220 ml of formamide. After 8 hours' heating at 110° C., a further 100 ml of 20% strength ammonia solution are added. Heating is maintained for 4 hours. When the reaction medium is cooled, the expected product precipitates.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][NH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].CC(=O)CC(=O)C.[Cl:23][C:24]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:25]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:12]([CH3:13])=[N:11][N:10]([CH2:26][C:25]2[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:24]=2[Cl:23])[C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1n[nH]c(C)c1CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)CC(C)=O
Product: Cc1nn(Cc2ccc([N+](=O)[O-])cc2Cl)c(C)c1CC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid tert-butyl ester (2.6 g, 12.4 mmol, preparation according to WO2007/141267 by using 2,4-pentanedione instead of 3,5-heptanedione) and 2-chloro-4-nitrobenzyl bromide (3.11 g, 12.4 mmol) in acetonitrile (30 mL) is added K2CO3 (2.575 g, 18.6 mmol) and the mixture is stirred for 48 hours at room temperature and after that 2 hours at 60° C. The solid is filtered off and the solvent is removed by evaporation. The residue is dissolved in dichloromethane/water. After extraction with dichloromethane the organic layer is dried over MgSO4 and evaporated under reduced pressure to yield 4.4 g of [3,5-dimethyl-1-(2-chloro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+=380). b) To a solution of [3,5-dimethyl-1-(2-chloro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (4.40 g, 11.6 mmol) in methanol (80 mL) is added Raney nickel (440 mg) and the mixture is hydrogenated at 50 psi and room temperature for 12 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 2.4 g of the title compound (ESI mass spectrum: [M+H]+=350; Retention time HPLC: 0.76 min (method D)).
Reaction SMILES: [SH:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CC#N.ClCCl>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:12][S:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[CH3:18]
Reactant: Sc1nc2ccccc2[se]1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)C(=O)CSc1nc2ccccc2[se]1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a suspension of 2-mercaptobenzselenazole (418 mg, 2 mmol) in 4 mL of MeCN and 4 mL of dichloromethane with vigorous stirring was added dropwise, ethyl bromopyruvate (290 mg, 2 mmol). The resulting mixture was stirred for 5 h. It was allowed to settle for 30 min and then filtered. The solid was washed with EtOAc/hexanes (1:1, 2×8 mL) and dried in high vacuum to afford 3-(benzoselenazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester as a white powder (582 mg, 89%). 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 8.14-8.10 (m, 1H), 7.95-7.92 (m, 0.7H), 7.75-7.73 (m, 0.3H), 7.52-7.45 (m, 1H), 7.36-7.30 (m, 1H), 7.07 (s, 0.7H), 4.69 (s, 0.6), 4.37-4.27 (m, 2H), 1.32 (t, J=7 Hz, 3H). MS(ESI) m/z: 330(M+H+, 55), 348 M++H2O, 58 ), 362 (M++MeOH, 100).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[CH3:24][C:25]([CH3:29])([CH3:28])[CH:26]=[CH2:27]>>[CH3:24][C:25]([CH3:29])([CH3:28])[CH2:26][CH2:27][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]2)=[C:9]([OH:8])[CH:14]=1
Reactant: C=CC(C)(C)C
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Product: CC(C)(C)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 3,3-dimethylbut-1-ene analogous to Example 300: (M−1)−=311; HPLC retention time=1.20 min (method A).
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][C:21]=2[CH3:23])[O:16][CH2:15]1>>[CH3:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[O:16][CH2:15][CH:14]([NH2:13])[C:22]=12
Reactant: CON=C1COc2nccc(C)c21
Agent: NC1COc2nnccc21
Product: Cc1ccnc2c1C(N)CO2

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 4-methylfuro[2,3-b]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[S:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[OH:37][C:29]1[CH:28]=[CH:27][C:26]([CH:24]([OH:25])[CH2:23][NH:22][CH:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:13]=[CH:14][C:9]([CH:8]=[C:4]4[S:3][C:2](=[NH:1])[NH:6][C:5]4=[O:7])=[CH:10][CH:11]=3)[CH2:16][CH2:17]2)=[CH:31][C:30]=1[NH:32][S:33]([CH3:36])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: N=C1NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(=N)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidine-4-one (which was obtained in Example 43) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp >210° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-2.00 (m, 2H), 2.50-3.00 (m, 5H), 2.92 (s, 3 H), 3.70-3.90 (m, 2H), 4.47 (dd, J=7.9, 4.4 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.90-7.10 (m, 3 H), 7.18 (d, J=2.0 Hz, 2H), 7.39 (d, J=8.9 Hz, 2H), 7.47 (s, 1H); MS (ES) m/z: 532.0 (MH+); HRMS Calcd. for C24H30N5O5S2 (MH+): 532.1688. Found: 532.1672.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([C:24]2[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH:29]=2)=[N:13][C:14]=1[C:15]1[N:23]=[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]2[N:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:23]1[C:15]([C:14]2[C:9]([NH2:8])=[N:10][CH:11]=[C:12]([C:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=3)[N:13]=2)=[N:16][N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nc4ccccn4n3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 273.4 %

Procedure:
Tert-butyl 4-[5-(bis(tert-butoxycarbonyl)amino)-6-([1,2,4]triazolo[1,5-a]pyridin-2-yl)pyrazin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (77 mg, 0.1297 mmol) was dissolved in DCM (1.6 mL) and treated with TFA (400 μL, 5.192 mmol). The mixture was allowed to stir at ambient temperature for 2 hours and the solvent removed in vacuo. The mixture was azeotroped with DCM (3×) and Ether (3×) and dried under vacuum to furnish the product as a yellow solid (104 mg, quantitative yield). MS (ES+) 294.0
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:29][CH3:30])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:41])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:29]([CH3:30])=[O:41])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CSCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CS(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of N-(4-chlorobenzyl)-1-[(methylsulfanyl)methyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.14 gm) from Example No. 73 in dichloromethane (4 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.06 gm) followed by m-chloroperoxybenzoic acid (˜85%) (0.06 gm). The mixture is stirred for 1 hr. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by recrystallization from methanol-acetonitrile to afford 0.11 gm of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.CO[CH:23](OC)[CH2:24][NH:25][S:26]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:28])=[O:27].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCCl>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][CH2:23][CH2:24][NH:25][S:26]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:27])=[O:28])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: COC(CNS(=O)(=O)NC(=O)OCc1ccccc1)OC
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
A mixture of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (68 mg, 0.20 mmol; from Step D) and benzyl {[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (191 mg, 0.60 mmol, 3.0 equiv.) in 1,2-dichloroethane (3.0 mL) was cooled to 0° C. To this mixture was added trifluoroacetic acid (1.0 mL, 13.0 mmol) and triethylsilane (105 μL, 0.66 mmol, 3.3 equiv.) drop-wise. This reaction mixture was stirred at 0° C. for 2 h. HPLC indicated reaction completion. The reaction mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate to pH ˜8. and the quenched reaction mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was then stirred in a mixture of heptane and diethyl ether overnight. The solids were collected by filtration, washed with heptane and dried in vacuum to give the desired product (125 mg, 99%) as a crude off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.05 (m, 1H), 7.87 (m, 1H), 7.68 (m, 1H), 7.56 (m, 1H), 7.32 (m, 5H), 6.54 (m, 1H), 5.07 (s, 2H), 3.29 (m, 2H), 3.09 (m, 2H); C20H17BrFN7O7S (MW 598.36), LCMS m/e 598/600 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15]N(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.[C:21]([NH2:29])(=[NH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na].[O-]CC>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:28]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(-c3ccccc3)ncc2C1
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step B, 509 mg, 2.0 mmol), benzamidine hydrochloride hydrate (470 mg, 3.0 mmol), and sodium, ethoxide (1 M in ethanol, 6.0 mL, 6.0 mmol) in absolute ethanol (4 mL) was heated to reflux for about 3 d, cooled to room temperature, and concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (Biotagq Flash 40S™, 10→15% ethyl acetate/hexanes) to give 304 mg (49%) of the title compound of Example 101, Step C as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.40-8.38 (c, 2H), 7.50-7.44 (c, 3H), 4.62 (s, 2H), 3.78 (t, 2H) 3.02 (t, 2H), 1.50 (s, 9H); MS (APCI) 312 (MH+).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:12]2=[O:27])[CH2:9][CH2:8][C@@H:7]([NH:28]C(=O)OC(C)(C)C)[CH2:6]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:4][C@@H:5]1[CH2:6][C@H:7]([NH2:28])[CH2:8][CH2:9][C@@H:10]1[N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:12]1=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
To a solution of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (100 g, 0.205 mol) in dichloromethane (400 ml) was added TFA (400 ml) at −20° C. The reaction solution was stirred at room temperature for 2 h. The solvent and most of TFA were removed under reduced pressure, and the residue was diluted with dichloromethane (2 L) and aqueous K2CO3 solution (2 L). The pH was adjusted to 10 with 1N HCl. The aqueous layer was extracted with dichloromethane (3×1 L). The combined organic layer was dried over Na2SO4, and concentrated to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate as an oil (81 g, 100% yield). This amine was used directly in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(CC)CC.[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CCOC(C)=O>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of morpholine (12.04 g, 0.14 mol) and Et3N (13.97 g, 0.14 mol) in EtOAc was added 3,4-difluoronitrobenzene (20.0 g, 0.13 mol) dropwise in an ice bath. The reaction mixture was warmed to rt slowly, stirred at rt overnight, and then filtered. The filter cake was washed with water, dried in vacuo to obtain the 1st crop of product. The organic phase was separated from the filtrate, and the water phase was washed with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the 2nd crop of product. The solids of 1st crop and 2nd crop were combined to give the title compound as a yellow solid (28.0 g, 99%).