Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12](Cl)(=[O:14])=[O:13])[CH:10]=2)[C:5]([Cl:16])=[CH:4][N:3]=1.[NH2:17][C:18]1([C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[NH3:3].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([NH:17][C:18]3([C:25]([O:27][CH3:28])=[O:26])[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)(=[O:14])=[O:13])[CH:10]=2)[C:5]([Cl:16])=[CH:4][N:3]=1
Reactant: COC(=O)C1(N)CCN(C)CC1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCN(C)CC1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
1,4-Dichloro-7-isoquinolinylsulphonyl chloride (1.0 g, 3.37 mmol) was added to a solution of methyl 4-amino-1-methyl-4-piperidinecarboxylate (700 mg, 4.0 mmol) and triethylamine (700 μl, 1.0 mmol) in CH2Cl2 (60 ml), and the reaction stirred at room temperature for 18 h. The mixture was concentrated in vacuo, and the residue purified by column chromatography upon silica gel using an elution gradient of CH2Cl2 -MeOH-0.880 NH3 (97:3:0.3 to 95:5:0.5) to give methyl 4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}-1-methyl-4-piperidinecarboxylate (700 mg, 1.62 mmol) as a white solid.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:22][Si:23]([CH3:33])([CH3:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]O>C(#N)C.C(OCC)C>[CH3:22][Si:23]([CH3:33])([CH3:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][Br:1]
Reactant: C[Si](C)(C)c1ccccc1CO
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: C[Si](C)(C)c1ccccc1CBr
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Bromine (1.07 g, 6.7 mmol) was slowly added to a cooled solution of triphenylphosphine (1.83 g, 7.0 mmol) in acetonitrile to maintain a temperature less than or equal to 5° C. A solution of 2-(trimethylsilyl)benzyl alcohol in acetonitrile (10 mL) was slowly introduced and the resulting mixture was allowed to warm to room temperature and stir. Thin layer chromatography after 20 min indicated no starting material remained. The mixture was diluted with diethyl ether (50 mL) and washed with H2O (two-times with 20 mL), dried (MgSO4) and concentrated under vacuum to yield an opaque oil, 2.5 g. Purification by column chromatography (100 g SiO2 eluting with hexanes) provided the product of Step C as a clear, colorless oil, 1.12 g; (69%); IR (neat): 2954, 1250, 1216, 1110 cm-1 ; 1H NMR (CDCl3); δ7.5-7.3 (m,4H), 4.6 (s,2H), 0.4 (s,9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[CH:15]3[NH:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]3[CH2:19][CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4ccc(F)c(Cl)c4)cc3)C2N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.7 %

Procedure:
A mixture of (3-chloro-4-fluorophenyl)boronic acid (933 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg) and powdered 4A MS (4 g) in MeCN (18 mL) was stirred at room temperature for 3 days. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc-THF/IPE to give (9S)-9-[4-(3-chloro-4-fluorophenoxy)phenyl]-3,4,6,1,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (290.6 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH3:12].[H][H]>CCO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH3:12]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(N)cc1C
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
To the solution of 1-methoxy-2-methyl-4-nitrobenzene (10 g, 60 mmol) in EtOH and EtOAc (250 mL, 3:2) was added 10% Pd/C (2 g). The mixture was stirred for 24 h under one atmosphere of hydrogen. Celite was added and the mixture was stirred for 10 min. The mixture was filtered through a pad of celite. Concentration under reduced pressure gave 4-methoxy-3-methylaniline (8B) (8.2 g). LCMS-ESI+ (m/z): 138.2 (M+H)+.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[CH3:36]>N.CO>[F:29][C:30]1[CH:31]=[C:32]([S:37]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[CH3:36]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.8 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 3-Fluoro-4-methylbenzenesulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.4 mg). MS m/z 361 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:21][OH:22])[NH2:20])[C:3]=1[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].O.[C:31]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]2[N:20]=[CH:31][O:22][N:21]=2)[C:3]=1[S:23]([C:26]([F:28])([F:29])[F:27])(=[O:24])=[O:25]
Reactant: NC(=NO)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Product: Nc1c(S(=O)(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 658.2 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfonyl-3-pyrazolecarboxamide oxime (0.51 g, 1.87 mmol) was dissolved in 12 ml of trimethyl orthoformate and p-toluenesulfonic acid monohydrate (0.05 g) was added, and then the mixture was heated under reflux for 1 hour. Trimethyl orthoformate was distilled off and 80 ml of ethyl acetate was added to the residue. The ethyl acetate layer was washed twice with 50 ml of an aqueous saturated sodium hydrogencarbonate solution, and then washed once with 50 ml of an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a colorless crystal. This crystal was washed with a hexane-chloroform mixed solvent (volume ratio=2:1) to obtain 0.86 g (1.73 mmol) of the title compound as a colorless crystal. Yield 93%.
Reaction SMILES: ClC([O:4][CH2:5][CH3:6])=O.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CNCC1[C:22]([S:32][CH2:33][CH2:34][CH3:35])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31]>C1COCC1.C(Cl)Cl>[CH3:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:24]=1[N:23]=[C:22]([S:32][CH2:33][CH2:34][CH3:35])[C:6]([CH:5]=[O:4])=[CH:31]2
Reactant: CCOC(=O)Cl
Reactant: CCCSc1nc2c(C)cccc2cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCSc1nc2c(C)cccc2cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 229 %

Procedure:
To ethyl chloroformate (0.4 ml, 4.2 mmol) and potassium carbonate (0.875 g, 6.3 mmol) were added to (3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-amine (1.058 g, 2.1 mmol) which was dissolved in anhydrous THF (10 mL). The resulting mixture was stirred at room temperature for overnight. The mixture was diluted with methylene chloride, and was washed one time with water. The organic phase was dried over potassium carbonate and concentrated by rotary evaporation. The resulting sample was dried under vacuum gave a light yellow solid (1.18 g, 97%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[CH:8]2)(=[O:4])=[O:3].[H-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.O>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:10]2[C:11]3[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=3)[CH:8]=[C:9]2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1ccncc1)n2Cc1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
To a solution of the compound obtained in Example 31 (1) (0.4 kg) in N,N-dimethylformamide (160 ml), 60% sodium hydride (0.065 g) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 20 minutes, followed by addition of 4-fluorobenzyl bromide (0.2 ml), and the mixture was stirred at 15 to 30° C. for 15 hours. The reaction solution was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:3) to obtain 0.3882 g of the desired product.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:57][CH2:58][CH3:59])[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:8]=1[C:9]([O:11][CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:10])[CH3:3]>C(O)(=O)C>[OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:57][CH2:58][CH3:59])[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:8]=1[C:9]([O:11][CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])=[O:10])[CH3:3]
Reactant: CCCc1nc(C(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc(C(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 60.8 %

Procedure:
Following a procedure similar to that described in Example 35(c), but using 2.87 g of pivaloyloxymethyl 4-(1-hydroxyethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] and 75% v/v aqueous acetic acid, 1.21 g of the title compound was obtained as a powder.
Reaction SMILES: [I:1]I.N(OC(C)(C)C)=O.N[C:11]1[CH:12]=[C:13]([C:25](=[O:27])[CH3:26])[S:14][C:15]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24]>C(#N)C>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[S:16][C:15]1[S:14][C:13]([C:25](=[O:27])[CH3:26])=[CH:12][C:11]=1[I:1]
Reactant: II
Reactant: CC(=O)c1cc(N)c(Sc2ccc(Cl)cc2Cl)s1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CC(=O)c1cc(I)c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 60 °C
Yield: 99.7 %

Procedure:
To a dark solution of I2 (0.958 g 7.5 mmol) in acetonitrile (20 mL), was added t-butyl nitrite (0.4 g, 3.75 mmol) slowly. The resulting solution was heated to 60° C. for 20 min. To the above solution, was added dropwise of a solution of 1-[4-amino-5-(2,4-dichlorophenyl)sulfanyl-2-thienyl]ethanone (0.8 g, 2.5 mmol) in acetonitrile (20 mL). The resulting mixture was heated at 60° C. for 2 hours. After this time the reaction mixture was quenched with sodium hydroxide aqueous solution (1 M), and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4) and concentrated. The crude solid was purified by silica gel chromatography using a 98:2 mixture of hexane and ethyl acetate as eluent to afford the title product as a yellow solid (1.07 g, 46.2% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.16 (1H, s), 7.82 (1H, dd), 7.47 (1H, dd), 7.05 (1H, dd), 2.54 (3H, s). MS m/z: 428.7 [M+H]+.
Reaction SMILES: [CH2:1]([CH:17]1[CH2:22][C:21](=[O:23])[O:20][C:18]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:24]([C:28]1[CH:29]=[C:30]([CH2:39][CH2:40][C:41]([NH:43][NH2:44])=[O:42])[CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])([CH3:27])([CH3:26])[CH3:25]>>[C:35]([C:32]1[CH:31]=[C:30]([CH2:39][CH2:40][C:41]([NH:43][N:44]2[C:21](=[O:23])[CH2:22][CH:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]2=[O:20])=[O:42])[CH:29]=[C:28]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:33]=1[OH:34])([CH3:36])([CH3:37])[CH3:38]
Reactant: CCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Product: CCCCCCCCCCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 148 °C
Yield: 102.4 %

Procedure:
2-Hexadecylsuccinic anhydride (10.5 g, 31.3 mmol) was heated to about 115° C. under a nitrogen atmosphere. To this stirred melt was added, in portions, 3-(3,5-di-t-butyl-4hydroxyphenyl)propanoic acid hydrazide (9.2 g, 31.3 mmol). Successive additions of hydrazide required raising the melt temperature to facilitate stirring. The final addition of hydrazide was done at a melt temperature of approximately 135° C. After this final portion was blended into the melt, vacuum was applied and the melt temperature was raised to about 148° C. and maintained at that temperature for 20 minutes. The melt was allowed to cool to approximately 115° C. whereupon the vacuum was released and the clear yellow melt was quickly poured into a container. 19.2 g of a yellow viscous liquid was obtained that solidified to a waxy, translucent white solid upon standing for several days at room temperature. The waxy material was recrystallized from acetone to give a white solid having a melting point of 85° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=4)[CH2:13][CH2:12]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1>>[CH3:37][C:32]1[CH:31]=[C:30]([N:1]2[C:9]3[C:4](=[C:5]([CH2:10][N:11]4[CH2:16][CH2:15][CH:14]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=5)[CH2:13][CH2:12]4)[CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:35]=[CH:34][C:33]=1[CH3:36]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Cc1ccc(I)cc1C
Product: Cc1ccc(-n2ccc3c(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)cccc32)cc1C

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-iodo-1,2-dimethylbenzene: ESMS m/e: 480.0 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:17]=[C:18]([C:21]([OH:23])=O)[NH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:21]([C:18]1[NH:19][CH:20]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=1)=[O:23]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccccc2)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 87.59 %

Procedure:
DIPEA (155 mg, 0.2 mL, 1.19 mmol) was added to a stirred solution of 4-Phenyl-1H-pyrrole-2-carboxylic acid (50 mg, 0.26 mmol) in DMF (4 mL). HOBT (40 mg, 0.29 mmol) and EDCI (153 mg, 0.79 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method as described above) (103 mg, 0.29 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and filtered the solid precipitated to afford 113 mg (87.59% yield) of 4-phenyl-1H-pyrrole-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 92.52%. 1H NMR (DMSO-d6): δ 11.6 (s, 1H), 8.2-8.1 (bs, 1H), 7.9-7.72 (m, 2H), 7.7-7.64 (t, 1H), 7.6-7.5 (d, 3H), 7.38-7.28 (t, 3H), 7.24-7.1 (m, 2H), 4.2-4.04 (bd, 2H), 3.82-3.56 (m, 4H), 3.5-3.4 (bs, 2H), 3.2-3.1 (bd, 2H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([NH2:14])=[O:13]>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:11][C:12]([NH2:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: NC(=O)CCl
Solvent: Cc1ccccc1
Product: NC(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.2 %

Procedure:
In the reaction vessel, 4.3 grams (0.09 mole) of a 50% suspension of sodium hydride in mineral oil was washed with two portions of 50 ml each of hexane, then two portions of 50 ml each of toluene. Dry toluene, 75 ml, was added and with stirring a solution of 10.0 grams (0.082 mole) of benzoic acid in 200 ml of dry toluene was added dropwise. The exothermic reaction caused the temperature of the reaction mixture to rise from 27° to 32°. Upon completion of the addition, the reaction mixture was heated under reflux for 1.5 hour. The mixture was cooled to ambient temperature and 8.4 grams (0.09 mole) of 2-chloroacetamide was added in portions. Upon completion of the addition, the reaction mixture was heated under reflux for 18 hours. An additional 150 ml of dry toluene was added and heating under reflux continued an additional 24 hours. The reaction mixture was cooled to ambient temperature and a solid precipitate collected by filtration. The filtrate was extracted with two portions of 200 ml each of water. The milky organic layer was dried twice with sodium sulfate and filtered. the filtrate was evaporated under reduced pressure to a solid residue, which produced bubbling in the presence of aqueous saturated sodium bicarbonate solution, and was concluded to be unreacted benzoic acid. The solid collected by filtration from the original reaction mixture was dissolved in 200 ml of ethyl acetate and washed with two portions of 100 ml each of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to a solid residue. The solid was recrystallized from toluene to give 3.7 grams of (aminocarbonyl)methyl benzoate; mp 118°-120 . The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=S)[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1.O.[NH2:25][NH2:26]>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=[N:25][NH2:26])[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=S
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=NN
Reaction time: 0.67 h

Procedure:
To a solution of tert-butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-thioxopiperidin-3-yl]carbamate (100 mg, 0.29 mmol) in methanol (2.9 mL) was added hydrazine hydrate (55%, 780 μL, 8.76 mmol). The mixture was stirred 40 min, and then concentrated. Water was added, and the mixture was extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound. MS 341.2 (M+1).
Reaction SMILES: C(OC(Cl)=O)C(C)C.[Br:9][C:10]1[C:11]([C:30](O)=O)=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:13]([CH2:19][O:20][CH2:21][CH3:22])[C:14]=1[C:15]([F:18])([F:17])[F:16].C([N:35]([CH2:38]C)CC)C.CN.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:51]2)=CC=1>O1CCCC1.C(OCC)C.O>[Br:9][C:10]1[C:11]([C:30](=[S:51])[NH:35][CH3:38])=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:13]([CH2:19][O:20][CH2:21][CH3:22])[C:14]=1[C:15]([F:18])([F:17])[F:16]
Reactant: CCOCn1c(-c2ccc(Cl)cc2)c(C(=O)O)c(Br)c1C(F)(F)F
Reactant: CCN(CC)CC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C(=S)NC)c(Br)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
Isobutylchloroformate (0.3 mL, 2.3 mmol) is added to a mixture of 4-bromo-2-(p-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)pyrrole-3-carboxylic acid (0.83 g, 2 mmol) and triethylamine (0.33 mL, 2.3 mmol) in tetrahydrofuran at 0° C. The mixture is stirred for 1 hour at 0° C., treated with a 6 wt/wt % methylamine solution (10.6 g, 20 mmol), stirred at room temperature for 2 hours and diluted with a diethyl ether/water mixture. The organic phase is separated, dried over anhydrous Na2SO4, concentrated in vacuo, diluted with toluene and concentrated in vacuo to obtain a liquid. A mixture of the liquid in tetrahydrofuran is treated with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.40 g, 1 mmol), heated at reflux for 2 hours, concentrated in vacuo and chromatographed on silica gel with a 4:1 hexane/ethyl acetate mixture to obtain the title product as a yellow gum (0.3 g) which is identified by 1H and 13C NMR spectral analyses.