Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](N)=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]1[Cl:24].[CH3:25][S:26]SC.C(ON=O)(C)(C)C>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([S:26][CH3:25])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]1[Cl:24]
Reactant: CSSC
Reactant: Nc1c(SC(F)(F)F)nc(Cl)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CSc1c(SC(F)(F)F)nc(Cl)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
To a solution of 700 mg (1.77 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-amino-2-chloro-4-trifluoromethylsulfenylimidazole in 8 ml of chloroform was added 0.26 ml (2.54 mmole) of dimethyl disulfide and 0.32 ml (0.89 mmole) of t-butylnitrite at 0° C. The resulting mixture was stirred at 0° C. for 15 min. and then at RT for 45 min. The mixture was diluted with 75 ml of methylene chloride and partitioned between water and methylene chloride. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by preparative TLC using 5% ethyl acetate in hexane to give 480 mg (58.74% yield) of the desired product. 1H NMR (CDCl3): δ2.26 (s, 3H), 7.82 (s, 2H).
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=O>ClCCl>[CH2:15]([O:14][C:10](=[O:13])[CH:11]=[N:9][C@H:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:1])[CH3:16]
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)C=O
Solvent: ClCCl
Product: CCOC(=O)C=N[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Treat a solution of neat (S)-α-methylbenzylamine (7.5 mL, 59 mmol) in dichloromethane (300 mL) at 0° C. with ethyl glyoxalate solution (50% in toluene, 11.5 mL). Add 4Å molecular sieves (20 g) to the above solution. Stir the reaction mixture at 0° C. for 2 h. Filter the solids off, concentrate and purify (silica gel chromatography, eluting with 20:80 to 70:30 ethyl acetate:hexanes) to give the title compound (11.1 g, 97%)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([NH2:22])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1>>[O:21]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:16][NH:22][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: NCc1ccco1
Product: OC(c1ccccc1)C(NCc1ccco1)c1ccccc1
Temperature: 140 °C
Reaction time: 14 h
Yield: 78.4 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and furfurylamine (3.00 g, 0.030 mol) was heated at 140° C. for 6 hours, and then allowed to stand at ambient temperature for 14 hours. The solidified reaction mixture was triturated with petroleum ether and the crude solid collected by filtration. Recrystallization from toluene-isooctane gave 2.3 g (78%) of the product; mp 141°-144° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[CH:30]=4)=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Reactant: Cc1cccc(B(O)O)c1
Product: CCOC(=O)c1cc2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1-(4-methylbenzyl)-1H-indole-2-carboxylate (step 1 of Example 1) and 3-methylphenylboronic acid in substantially the same manner, as described in step 2 of Example 1. The product was obtained as a solid. Mass spectrum (ESI, [M+H]+) m/z 384. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.63 (d, 1H, J=7.70 Hz), 7.60 (d, 1H, J=8.47 Hz), 7.48 (s, 1H), 7.44 (d, 1H, J=7.95 Hz), 7.39 (s, 1H), 7.33 (t, 1H, J=7.63 Hz), 7.14 (d, 1H, J=7.49 Hz), 7.07 (d, 2H, J=7.94 Hz), 6.93 (d, 2H, J=7.94 Hz), 5.82 (s, 2H), 4.29 (q, 2H, J=7.17 Hz), 2.37 (s, 3H), 2.21 (s, 3H), and 1.30 ppm (t, 3H, J=7.18 Hz).
Reaction SMILES: I[C:2]1[O:3][C:4]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:18]([O-:23])([N+]([O-])=O)=[O:19].O>C(O)(=O)C>[CH3:17][C:16]1[C:4]2[O:3][C:2]([N+:18]([O-:23])=[O:19])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: Cc1cccc2c(-c3ccccc3)c(I)oc12
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reaction time: 1 h

Procedure:
To a stirred solution of 5.0 g (0.015 mole) of 2-iodo-7-methyl-3-phenylbenzofuran from Example 9 in 100 ml of acetic acid is added dropwise 2.0 g (0.022 mole) of dinitrogen tetroxide in 10 ml of acetic acid. After stirring one hour the mixture is poured into cold water, then extracted with diethyl ether. The ether extracts are washed with water, 10% sodium bisulfite solution, water and saturated sodium chloride solution and dried. Concentration gives a tan powder which is recrystallized from aqueous ethanol to give yellow crystals of 7-methyl-2-nitro-3-phenylbenzofuran, m.p. 123°-126° C. This product is identical to the product of Example 2 according to comparative infrared spectral analysis.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[SH:34]>>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[S:34][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1
Reactant: COC(=O)c1cccnc1S
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: COC(=O)c1cccnc1Sc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 25 %

Procedure:
2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-nicotinic acid methyl ester (124 mg, 25%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-mercapto-nicotinic acid methyl ester (340 mg, 2 mmol) following the general procedure O.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[N:24]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:15]2=[N:16][CH:17]=[C:18]3[CH:22]=[N:21][N:20]([CH3:23])[C:19]3=[C:14]2[CH:13]=1.[H-].[Na+].Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH:7]=[C:6]2[C:12]1[N:24]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:15]2=[N:16][CH:17]=[C:18]3[CH:22]=[N:21][N:20]([CH3:23])[C:19]3=[C:14]2[CH:13]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc2[nH]cc(-c3cc4c5c(cnc4n3S(=O)(=O)c3ccc(C)cc3)cnn5C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
7-(5-Methoxy-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.100 g, 0.212 mmol; Preparation #P.1.1) and 60 wt % NaH (0.009 g, 0.212 mmol) were suspended in DMF (3 mL). After about 10 min, 2-chloro-N,N-dimethylacetamide (0.052 g, 0.424 mmol, Pfaltz-Bauer) was added and mixture was stirred at rt. After about 1 h additional 60 wt % NaH (0.005 g, 0.212 mmol) was added and the mixture was heated to about 40° C. for about 16 h. The mixture was concentrated in vacuo and purified on a 4 g silica column eluting with EtOAc to provide 2-(5-methoxy-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-1-yl)-N,N-dimethylacetamide (0.097 g, 82%): LC/MS (Table 2, Method c) Rt=1.46 min; MS m/z 557 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([O:40][CH3:41])[C:8]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:9]=2[CH2:10][N:11]([CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[C:12]2[N:13]=[N:14][NH:15][N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47].C(=O)([O-])[O-].[Na+].[Na+]>CC1OCCC1.CN(C=O)C>[CH:1]1([CH:7]([O:40][CH3:41])[C:8]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:9]=2[CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]([C:28]([F:29])([F:31])[F:30])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=2)[C:12]2[N:13]=[N:14][N:15]([CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1)C1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO[Si](C)(C)C(C)(C)C)n1)C1CCCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a mixture of N-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine (40.4 mg, 0.068 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (25 mg, 22 μL, 0.10 mmol) in 2-MeTHF/DMF was added sodium carbonate (29.1 mg, 0.275 mmol). The slurry was stirred at 60° C. overnight. The reaction was diluted and filtered. The filtrate was concentrated and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-20% ethyl acetate in heptane) to afford the title compound (39.3 mg, 77%). 1H NMR (400 MHz, CDCl3) δ ppm 0.08 (s, 6H) 0.80 (s, 9H) 0.92-1.12 (m, 5H) 1.15-1.21 (m, 1H) 1.42-1.52 (m, 1H) 1.57-1.62 (m, 2H) 1.68-1.72 (m, J=2.90 Hz, 1H) 1.89 (d, J=12.44 Hz, 1H) 3.03 (s, 3H) 4.05-4.09 (m, 3H) 4.54 (t, J=5.60 Hz, 2H) 4.64-4.76 (m, 3H) 4.89 (d, J=16.17 Hz, 1H) 7.35 (s, 1H) 7.47 (d, J=7.88 Hz, 1H) 7.54 (d, J=9.12 Hz, 1H) 7.65 (s, 2H) 7.75 (s, 1H). MS (ES+) Calc: 753.3, Found: 754.6 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25](I)=[N:24][N:23]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[C:18]=3[N:19]=[C:20]([Cl:22])[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25]([CH:33]=[CH2:34])=[N:24][N:23]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[C:18]=3[N:19]=[C:20]([Cl:22])[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)nc3c2c(I)nn3C2CCCCO2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 80 °C
Yield: 69.8 %

Procedure:
In a 1 L single necked flask were charged 4-[6-chloro-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (21.3 g, 37 mmol), anhydrous tetrahydrofuran (370 ml), and tributyl(vinyl)stannane (11.9 ml, 40.7 mmol). The mixture was degassed for 15 minutes using argon, dichlorobis(triphenylphosphine)palladium (1.3 g, 1.8 mmol) was then added. The resulting solution was heated at 80° C. overnight under argon, then evaporated under reduced pressure. Ethyl acetate and a 5% aqueous potassium fluoride solution were added to the residue, the resulting precipitate was filtered. The filtrate was recovered and the two layers separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on a silica gel column chromatography using a gradient of ethyl acetate (0-40%) in cyclohexane to afford the title compound as a brown foam (12.3 g, 70%).
Reaction SMILES: [Na].[OH:2][C:3]1(C2C=CC=CC=2)[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[C:11]1([C:4]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:3](=[O:2])[NH:7][C:6]([S:8][CH:4]([CH3:3])[CH2:5][CH3:6])=[C:5]2[C:9]#[N:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CC1=C(c2ccccc2)C(O)(c2ccccc2)NC1=S
Agent: [Na]
Solvent: CCO
Product: CCC(C)SC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.8 g. Sodium is dissolved in 150 ml. absolute ethanol, 10.0 g. 5-hydroxy-4,5-diphenyl-2-thioxo-3-pyrroline-3-carbonitrile are added thereto and the reaction mixture is boiled for 30 minutes. The solvent is thereafter removed on a rotary evaporator and the residue is taken up in 100 ml. dimethylformamide. 5.1 g. sec.-Butyl bromide are added thereto, the reaction mixture is stirred for 24 hours at ambient temperature, a further 3.0 g. of the alkylating agent are again added thereto and stirring is continued for 24 hours. Thereafter, the solvent is distilled off under wafter pump vacuum and the residue is triturated with water. The precipitate is filtered off with suction, washed with water and crystallised from ethanol. There are obtained 7.0 g. of the desired product in the form of colourless crystals; m.p. 155°-156° C.
Reaction SMILES: [F:1][C:2]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[N:14]([N:25]=[CH:26][C:27]=3[C:28](O)=[O:29])[C:15]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])=[O:9])[CH2:4][CH2:3]1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:3][CH2:4][N:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[N:14]([N:25]=[CH:26][C:27]=3[C:28]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:29])[C:15]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])=[O:9])[CH2:6][CH2:7]1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(F)(c3ccc(F)cc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(F)(c4ccc(F)cc4)CC3)cnc12
Yield: 30 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-[4-fluoro-4-(4-fluorophenyl)piperidine-1-carbonyl]-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (26 mg, 0.05 mmol) obtained in step 4 and ethanesulfonamide (27 mg, 0.26 mmol), the title compound (9 mg, 30%) was obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:60][CH:61]([C:69]1[CH:74]=[CH:73][C:72]([Cl:75])=[CH:71][CH:70]=1)[CH2:62][CH2:63][NH:64][S:65]([CH3:68])(=[O:67])=[O:66]>CN1C(=O)CCC1>[Cl:75][C:72]1[CH:71]=[CH:70][C:69]([CH:61]([NH:60][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:38][CH2:37][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:35][CH2:34]2)=[O:49])[CH2:62][CH2:63][NH:64][S:65]([CH3:68])(=[O:67])=[O:66])=[CH:74][CH:73]=1
Reactant: CS(=O)(=O)NCCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCNS(C)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (245 mg, 0.65 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (155 mg, 0.43 mmol) and N,N-diisopropylethylamine (0.213 mL, 1.29 mmol) in NMP (2 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. N-(3-amino-3-(4-chlorophenyl)propyl)methanesulfonamide (Intermediate 116) (113 mg, 0.43 mmol) in NMP (2 mL) was then added to the reaction and stirred for 18 hours. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(1-(4-chlorophenyl)-3-(methylsulfonamido)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (261 mg, 100%).
Reaction SMILES: [CH2:1]([N:5]([CH:11]([CH3:13])[CH3:12])[C:6](=[O:10])[O:7][CH2:8]Cl)[CH:2]([CH3:4])[CH3:3].[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O-:36])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16].[Na+]>>[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O:36][CH2:8][O:7][C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:11]([CH3:13])[CH3:12])=[O:10])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: CC(C)CN(C(=O)OCCl)C(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(C)CN(C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C(C)C
Yield: 67.9 %

Procedure:
In the same manner as in step b) in Example 125, 279 mg of the title compound was prepared from 177 mg of chloromethyl N-isobutyl-N-isopropylcarbamate and 300 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethyl-thiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: C([CH:6]([O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])[CH2:7][CH2:8][CH3:9])(=O)C(C)C.ClC1[CH:27]=[C:28]([CH:33]=CC=1)[C:29]([O:31]O)=[O:30].C([O-])(O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:29]([O:31][CH:6]([O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:12])[CH2:7][CH2:8][CH3:9])(=[O:30])[CH:28]([CH3:33])[CH3:27]
Reactant: CCCC(OC(=O)NCC1(CC(=O)O)CCCCC1)C(=O)C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.6 %

Procedure:
To a solution of (104) (780 mg, 2.3 mmol) in dichloromethane (20 mL) was added m-chloroperoxybenzoic acid (1.03 g, 4.6 mmol) and NaHCO3 (386 mg, 4.6 mmol). After stirring for 16 h at room temperature, another batch of m-chloroperoxybenzoic acid (791 mg, 4.6 mmol) and NaHCO3 (386 mg, 4.6 mmol) was added. The resulting mixture was stirred for another 8 h and then treated with 10% citric acid. After filtration, the organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by reverse phase preparative HPLC to afford 79 mg (11%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 0.94 (t, J=7.2 Hz, 3H), 1.153 (d, J=7.2 Hz, 3H), 1.150 (d, J=7.2 Hz, 3H), 1.32–1.58 (m, 12H), 1.74 (m, 2H), 2.28 (s, 2H), 2.56 (m, 1H), 3.23 (m, 2H), 5.27 (t, J=6.8 Hz, 1H, NH), 6.71 (t, J=5.6 Hz, 1H). MS (ESI) m/z 358.30 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:42]=[CH:41][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:29]=C4/C(=O)N(CC(O)=O)C(=O)S/4)=[C:25]([F:28])[CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:43]([F:46])([F:45])[F:44])[CH:15]=1>>[Cl:13][C:14]1[CH:42]=[CH:41][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:29]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[C:25]([F:28])[CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:43]([F:46])([F:45])[F:44])[CH:15]=1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Reactant: O=C(O)CN1C(=O)S/C(=C\c2cc3cnn(Cc4ccc(Cl)cc4C(F)(F)F)c3cc2F)C1=O
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2cc3cnn(Cc4ccc(Cl)cc4C(F)(F)F)c3cc2F)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-6-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and [4-chloro-2-(trifluoromethyl)benzyl]-6-fluoro-1H-indazol-5-carbaldehyde (from Example 348) following General Procedure E.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:17][C:11]1([CH3:16])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:18][C:10]1=2
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: C1COCCN1
Product: CC1(C)c2cc(N3CCOCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and morpholine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH2:16][CH:15]([NH:17]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:14][O:13]1)=[O:11].C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CO>C(#N)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH2:16][CH:15]([NH2:17])[CH2:14][O:13]1)=[O:11]
Reactant: COC(=O)c1ccccc1C(=O)N1CC(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CO1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1ccccc1C(=O)N1CC(N)CO1
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A solution of 2-[4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carbonyl]-benzoic acid methyl ester (200 mg, 0.46 mmol) and PhSH (0.035 ml, 1.1 equiv) in acetonitrile (2.3 ml) under argon at rt was treated with K2CO3 (95 mg, 1.5 equiv). The reaction mixture turned bright yellow. The reaction was left to stir overnight. As TLC indicated complete consumption of starting material, volatiles were removed in vacuo. Flash column chromatography eluting with dichloromethane:methanol (9/1) afforded 85 mg of the expected amine (0.34 mmol, 74%). LCMS (Method E) 0.55 and 1.41 min, M+H 251. 1H-NMR (CDCl3, 400 MHz): 7.95 (d, 1H), 7.63-7.52 (m, 1H), 7.51-7.36 (m, 2H), 4.17-3.92 (m, 3H), 3.87 (s, 3H), 3.80-3.55 (m, 2H), 2.04-1.75 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:8]([Cl:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:8]([Cl:11])=[CH:9][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 3-acetamido-6-chlorobenzotrifluoride (908 mg, 3.82 mmol) in concentrated H2SO4 (4 mL) at 0° C. was added dropwise 70% HNO3 (0.5 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature 3 h, and it was poured into ice water (15 g). The precipitate was collected by filtration, affording 990 mg (91%) of crude 3-acetamido-6-chloro-4-nitrobenzofluoride. It was crystallized. from EtOH/H2O to give 770 mg of pure compound as yellow needles. 1H NMR (CDCl3): δ2.326 (s, 3H), 8.345 (s, 1H), 9.293 (s, 1H), 10.222 (s, 1H).