Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[C:7]([O:22][CH3:23])[CH:6]=2.C1C(=O)N([Br:41])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:41][CH2:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[C:7]([O:22][CH3:23])[CH:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.76 g, 3.66 mmol), NBS (0.846 g, 4.75 mmol) and diphenylperoxyanhydride (0.089 g, 0.366 mmol) in carbon tetrachloride (60 mL) was heated to 100° C. and stirred overnight. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to afford methyl 3-(bromomethyl)-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 562.0 (M+H+).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH:11]=[CH:10]1>O.CO>[O:15]=[C:9]1[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][CH:10]1[CH2:11][C:12]([NH2:13])=[O:14]
Reactant: Nc1ccccc1N
Reactant: O=C1C=CC(=O)N1
Solvent: CO
Solvent: O
Product: NC(=O)CC1Nc2ccccc2NC1=O
Temperature: 95 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2-phenylenediamine (21.5 g, 0.2 mol) in water (450 mL) was added dropwise a solution of maleimide, (20.0 g, 0.2 mol) in methanol (180 mL) over 60 min. The mixture was then stirred at 95° C. for 2 hours followed at rt overnight. The precipitate was collected via filtration and was washed with small amount of water for a few times to yield the title compound as a pale gray solid (pure product): 1H NMR (DMSO-d6) δ=10.2 (bs, 1H), 7.37 (bs, 1H) 6.88 (bs, 1H), 6.74–6.68 (m, 3H), 6.31–6.57 (m, 1H), 5.78 (bs, 1H), 4.08–4.04 (m, 1H), 2.63 (dd, 1H, J=3.6, 15.5 Hz), 2.32 (dd, 1H, J=3.3, 15.5 Hz); HPLC (CH3CN—H2O-0.1% TFA): Rf=9.49 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]2[C:8](=[CH:9][C:10]=1Br)[CH2:7][CH:6]([C:12]([OH:14])=[O:13])[CH2:5]2.[C:18](O)(=[O:22])[C:19](O)=[O:20]>C(O)C.O1CCCC1.Cl.[Pd]>[O:20]=[C:19]1[NH:15][C:3]2[C:4]3[CH2:5][CH:6]([C:12]([OH:14])=[O:13])[CH2:7][C:8]=3[CH:9]=[CH:10][C:2]=2[NH:1][C:18]1=[O:22]
Reactant: O=C(O)C(=O)O
Reactant: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(C(=O)O)C2
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 90 °C
Reaction time: 30 h

Procedure:
A mixture of 5-amino-6-bromo-4-nitroindane-2-carboxylic acid (5.5 g, 18 mmol) and 20% Pd/C (0.5 g) in 95% ethanol (250 mL) and tetrahydrofuran (250 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (51 psi) for 30 h. After removing the catalyst, the solvent was evaporated to give a solid. The solid was dissolved in 2N HCl (150 mL) and treated with oxalic acid (4.6 g), and then the mixture was heated at 90° C. for 5 h. After cooling to room temperature, the precipitate was collected by filtration and dried in vacuo (4.0 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)=[N:10][C:6]=2[CH:5]=[C:4]([NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([NH:1][C:2]1[C:7]2[NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)=[N:10][C:6]=2[CH:5]=[C:4]([NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Nc1cc(N)c2[nH]c(-c3ccc(Br)cc3)nc2c1
Solvent: ClCCl
Product: COC(=O)Nc1cc(NC(C)=O)c2[nH]c(-c3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To a solution of 7-amino-5-(methoxycarbonyl)amino-2-(4-bromophenyl)-1H-benzo[d]-imidazole (60 mg, 0.17 mmol) in dichloromethane (5 mL) was added acetic anhydride (18 mg, 0.17 mmol) and the solution was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel using hexane/EtOAc (4/1) as the eluant to afford the desired product (55 mg, 80%) as a pale yellow powder: 1H-NMR (300 MHz, CD3OD) δ 2.24 (s, 3H), 3.74 (s, 3H), 7.65 (m, 3H), 7.67 (bs, 1H), 7.90 (m, 2H); ESI MS m/z 403.0 [M+H]+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([NH:14][CH3:15])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>O1CCCC1>[C:23]([N:11]1[C:12]([NH:14][CH3:15])=[N:13][C:9]([S:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10]1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CNc1nc(SCc2ccccc2)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNc1nc(SCc2ccccc2)nn1C(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Benzylthio-5-methylamino-1,2,4-triazole (11.2 g) was dissolved in tetrahydrofuran (70 ml) and triethylamine (5.7 g) was added. Acetyl chloride (4 ml) in tetrahydrofuran (20 ml) was added, and the mixture was stirred at room temperature for 5 hours. The triethylamine hydrochloride was filtered off, and the filtrate was concentrated to give 13.4 g of the desired crude product.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]=[C:6]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:7]2[S:12][C:11]3[N:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]=[C:16]([CH3:17])[C:10]=3[C:8]=2[N:9]=1)[CH3:2].[OH:30]O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[N:5]=[C:6]([N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)[C:7]2[S:12][C:11]3[N:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]=[C:16]([CH3:17])[C:10]=3[C:8]=2[N:9]=1)=[O:30])[CH3:2]
Reactant: CCSc1nc(N2CCNCC2)c2sc3nc(-c4ccccc4)cc(C)c3c2n1
Reactant: OO
Solvent: CC(=O)O
Product: CCS(=O)c1nc(N2CCNCC2)c2sc3nc(-c4ccccc4)cc(C)c3c2n1

Procedure:
85 mg (0.2 mmol) 2-ethylthio-9-methyl-7-phenyl-4-piperazin-1-yl-pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidine, 3 ml glacial acetic acid and 0.04 ml hydrogen peroxide (60%) are stirred at room temperature for 48 h. Having removed the solvent, the residue is purified by means of flash chromatography (methanol/dichloromethane 1:20-1:3). 50 mg (57%) of the title substance is obtained. ESI-MS [m/z]: 438, melting point: 165-170° C.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[C:8]([C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH2:18])=[CH:12][CH:11]=1)#[N:9]>ClCCl>[C:8]([C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH:18][CH3:2])=[CH:12][CH:11]=1)#[N:9]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1ccc(Oc2cccc(N)c2)cc1
Solvent: ClCCl
Product: CNc1cccc(Oc2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Anhydrous trifluoroacetic acid (20 ml) was added to 20 ml of dichloromethane solution containing 1.53 g of 3-(4-cyanophenoxy)aniline, and the reaction mixture was stirred for 30 minutes at room temperature. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in 40 ml of 2-butanone. Then, 3.14 g of methyl iodide and 2.09 g of potassium carbonate were added thereto. The reaction mixture was heated for 3 hours under reflux, insoluble materials were separated by filtration, and the solvent was evaporated under a reduced pressure. To the thus obtained residue were added 30 ml of methanol, 20 ml of water and 1.10 g of potassium carbonate. The reaction mixture was heated for 2 hours under reflux, diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluant; hexane:ethyl acetate=2:1) to obtain 1.52 g of 3-(4-cyanophenoxy)-N-methylaniline.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:21]1[CH:22]=[CH:23][C:24]2[S:28][CH:27]=[CH:26][C:25]=2[CH:29]=1)[C:9]1[C:17]2[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(=O)=O.ClC1C=CC(C(C2C3C(=C(CSC)C(F)=CC=3)NC=2)CC[C:40]#[N:41])=CC=1>>[S:28]1[C:24]2[CH:23]=[CH:22][C:21]([CH:8]([C:9]3[C:17]4[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=4)[NH:11][CH:10]=3)[CH2:7][CH2:6][C:40]#[N:41])=[CH:29][C:25]=2[CH:26]=[CH:27]1
Reactant: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc4sccc4c3)c[nH]c12
Product: CSCc1cccc2c(C(CCC#N)c3ccc4sccc4c3)c[nH]c12

Procedure:
The title compound was prepared starting from 768 mg (1.72 mmol) of the compound from Example 68A in analogy to the synthesis of the compound from Example 50. 494 mg (76% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][C:8]=1[O:17][CH3:18])(=[O:6])[CH3:5]>C1COCC1>[OH:6][C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][C:8]=1[O:17][CH3:18])([CH3:1])[CH3:5]
Reactant: C[Mg]Cl
Reactant: COc1cc(NC(C)=O)ccc1C(C)=O
Solvent: C1CCOC1
Product: COc1cc(NC(C)=O)ccc1C(C)(C)O
Temperature: 25 °C
Yield: 108 %

Procedure:
Methyl magnesium chloride (49.9 ml, 150 mmol, 3 M solution in THF) in 100 ml THF was cooled to zero degrees C., and N-(4-Acetyl-3-methoxy-phenyl)-acetamide (14.1 g, 68 mmol) in 200 ml THF was added via cannula to over 25 minutes. The reaction mixture was stirred and allowed to warm to room temperature over 2.5 hours. The reaction was quenched by addition of 1 N N4Cl and extracted with EtOAc. The combined organic layers were washed with 1 N ammonium chloride, brine, dried over MgSO4, and concentrated under reduced pressure to afford N-[4-(1-Hydroxy-1-methyl-ethyl)-3-methoxy-phenyl]-acetamide (16.4 g, 100%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].BrC1C=CC=C2C=1[C:27]1([C:38]3=CC4OCOC=4[CH:45]=[C:37]3[O:36][CH2:35]1)C(=O)N2>>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:45][C:37]1[O:36][C:35]([C:2]([F:23])([F:22])[F:1])=[CH:27][CH:38]=1)[C:11]3=[O:19]
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, the title compound was obtained (82%) as a white solid: mp 78-80° C.; 1H NMR (300 MHz, CDCl3) δ 7.33 (td, 1H), 7.21-6.98 (m, 3H), 6.86-6.73 (m, 2H), 6.67 (s, 2H), 6.42 (d, 1H), 5.09 (d, 1H), 5.04 (d, 1H), 4.88 (d, 1H), 4.77 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 176.7, 161.7, 151.9, 150.6, 141.5, 131.7, 129.5, 127.5, 124.2, 124.2, 124.0, 114.1, 112.8, 112.8, 109.6, 109.2, 104.3, 80.7, 57.6, 37.1; MS (ES+) m/z 470 (M+1).
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH:3]1[O:8][CH:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([CH:17]=O)[CH:15]=[CH:16][C:5]=2[O:4]1.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[C:21]1([NH:27][N:28]=[CH:17][C:14]2[CH:15]=[CH:16][C:5]3[O:4][CH:3]([C:2]([Cl:1])([Cl:20])[Cl:19])[O:8][CH:7]([C:9]([Cl:11])([Cl:12])[Cl:10])[C:6]=3[CH:13]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNc1ccccc1
Reactant: O=Cc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Solvent: ClC(Cl)Cl
Product: ClC(Cl)(Cl)C1Oc2ccc(C=NNc3ccccc3)cc2C(C(Cl)(Cl)Cl)O1

Procedure:
A mixture of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxaldehyde (1.0 g.) and phenylhydrazine (0.27 g.) in chloroform (35 ml.) was heated under gentle reflux for 1 hour. The resulting solution was cooled and evaporated to dryness under reduced pressure, and the residue was crystallised from ethanol to give 6-phenylhydrazonomethyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 203°-204° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[F:11][C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[C:16]([F:18])[CH:17]=1>C1C=CC=CC=1.C1COCC1>[F:11][C:12]1[CH:13]=[C:14]([CH:5]2[NH:4][C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[C:7](=[O:8])[CH2:6]2)[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CC1(C)C(=O)C=CNC1=O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC1(C)C(=O)CC(c2cc(F)cc(F)c2)NC1=O

Procedure:
To a solution of 3,3-dimethylpyridine-2,4(1H,3H)-dione (978 mg, 7.03 mmol) [U.S. Pat. No. 2,525,231] in benzene (10 mL) was added 3,5-difluorophenylmagnesium bromide (50 mL of a 0.5 M solution in THF, 25 mmol) and the resulting mixture was heated to reflux for 1.5 h. The mixture was cooled, quenched with 1 N aqueous HCl (10 mL), made basic with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with H2O (50 mL), then brine (50 mL), and dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 60:40, to give the title compound. MS: m/z=254 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:9].N1C=CC=CC=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Br)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(Br)n1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of Example 11A (400 mg, 1.928 mmol) in dichloromethane (20 mL) was added pyridine (0.468 mL, 5.78 mmol) followed by benzoyl chloride (0.325 g, 2.314 mmol) and the mixture was stirred for 2 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with sodium bicarbonate solution, water and brine, and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography (silica gel, 10% ethyl acetate in hexane) afforded the title compound. LCMS: 311 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[C:5]([CH3:14])[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]1=[O:25].[Br:26]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:26][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:25])[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[C:5]=1[CH3:14]
Reactant: Cc1c(-c2ccsc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2ccsc2Br)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
To a solution of 3,6-dimethyl-5-(thiophen-3-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference example 199) (30.7 mg) in acetic acid (1.5 ml) was added N-bromosuccinimide (20.2 mg) and the resulting mixture was stirred at room temperature for three hours. To the reaction mixture were added an aqueous saturated sodium hydrogen carbonate solution (10 ml) and an aqueous saturated sodium thiosulfate solution (10 ml), and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-(2-bromothiophen-3-yl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (17.4 mg).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][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]([CH2:8][CH: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(CC4SC(=N)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-one (which was obtained in Example 45) and N-[5–2-amino-1hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp>90° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.80–2.00 (m, 2 H), 2.50–2.80 (m, 6 H), 2.93 (s, 3 H), 3.25 (dd, J=14.2, 3.9 Hz, 1 H), 3.45–3.60 (m, 2 H), 4.40–4.55 (m, 2 H), 6.81 (d, J=8.3 Hz, 1 H), 6.88 (d, J=8.6 Hz, 2 H), 6.96 (dd, J=8.3, 2.0 Hz, 1 H), 7.04 (d, J=8.6 Hz, 2 H), 7.16 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 267.7 ((M+2H)2+100%), 534.3 (MH+, 45%), 1067.0 (2MH+, 2%); HRMS Calcd. for C24H32N5O5S2 (MH+): 534.1845. Found: 534.1850.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[CH:10]([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][N:7]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20](O)[CH3:21]>>[O:5]=[C:6]1[CH:10]([C:11]([O:13][CH2:20][CH3:21])=[O:12])[CH2:9][CH2:8][N:7]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCO
Reactant: O=C(O)C1CCN(c2ccccc2)C1=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCN(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Thionyl chloride is added at 0° C. (5.8 g) to a solution of 2-oxo-1-phenylpyrrolidine-3-carboxylic acid (5 g) in ethanol, and the batch is stirred at 80° C. for 4 h. When the reaction is complete, the batch is concentrated in vacuo, the residue is taken up in water and extracted with ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over sodium sulfate, giving ethyl 2-oxo-1-phenylpyrrolidine-3-carboxylate (4.5 g, 79%);
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])[N:5]2[C:18](=[O:31])[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:4]2[C:3]1=[O:32].[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[OH:32][CH:3]1[C@@H:4]2[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[N:5]2[CH:6]([C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])=[O:8])[CH:2]1[CH3:1]
Reactant: CC1C(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: ClCCl
Product: CC1C(O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C

Procedure:
By the procedures of Examples 3 and 6, pivaloyloxymethyl 2-methyl-1-oxo-6-(2-phenoxyacetamido)carbapenam-3-carboxylate (102 mg., 0.23 mmole) in 3 ml. of methylene chloride was reduced by the action of tetrabutylammonium borohydride (15 mg., 0.06 mmole) and isolated to yield purified pivaloyloxymethyl 1-hydroxy-2-methyl-6-(2-phenoxyacetamido)carbapenam-3-carboxylate [68 mg.; Rf 0.26 (4:1 chloroform:ethyl acetate; ir (CH2Cl2) 1775, 1750, 1675 cm-1 ].
Reaction SMILES: [NH2:1][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][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.[F:33][C:34]([F:47])([F:46])[O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:42]([C:39]3[CH:40]=[CH:41][C:36]([O:35][C:34]([F:47])([F:46])[F:33])=[CH:37][CH:38]=3)(=[O:44])=[O:43])=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:32])[CH3:30])=[CH:25][CH:24]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(N)ccc2n1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)c1ccc(-c2c(C(=O)O)n(Cc3ccccc3)c3ccc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)cc23)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-3-(4-tert-butylphenyl)-1H-indole-2-carboxylate and 4-trifluoromethoxy-benzenesulfonyl chloride followed the procedure of Example 1 Step 3 as a slight colored solid: 1H NMR (DMSO-d6) δ 1.34 (s, 9H, 5.76 (s, 2H, 7.00 (d, J=1.9 Hz, 1H, 7.07 (d, J=7.8 Hz, 4H, 7.15-7.35 (m, 5H), 7.42 (d, J=8.5 Hz, 2H, 7.54 (d, J=8.8 Hz, 2H, 7.75 (d, J=8.9 Hz, 2H, 9.95 (s, 1H, 12.50 (br s, 1H; MS (ESI) m/z 623 (MH+); MS (ESI) m/z 621 [M-H]−; HRMS calcd for C33H30F3N2O5S: 623.1825; found (ESI+): 623.1813; Anal. calcd for C33H29F3N2O5S.0.25H2O: C, 63.20; H, 4.74; N, 4.47. Found: C, 63.15; H, 4.58; N, 4.58.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=O.I.[NH2:12][NH:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[NH:15].[OH-].[Na+]>C(O)C>[CH2:17]([NH:16][C:14]([NH:13][N:12]=[CH:4][C:3]1[C:2]([CH3:1])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:10])=[NH:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(C)c1C=O
Reactant: N=C(NN)NCc1ccccc1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1C=NNC(=N)NCc1ccccc1

Procedure:
A solution of 1.34 g. of 2,6-dimethylbenzaldehyde [G. Lock and K. Schmidt, J. Prakt. Chem., 140, 229 (1934) and 2.92 g. of 1-amino-3-benzylguanidine hydroiodide in 25 ml. of absolute ethanol is heated at reflux for 18 hours. The solution is evaporated under reduced pressure to give a syrup which is made alkaline with aqueous NaOH. The mixture is extracted with chloroform. The chloroform extract is evaporated under reduced pressure to give a yellow syrup. Trituration of this syrup with diethyl ether and n-hexane, followed by filtration, gives the desired product as light pink crystals, m.p. 125°-126° C.
Reaction SMILES: Cl.O[CH:3]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4]1[CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21].C([OH:30])(C)C>CO.[Pd]>[OH:30][C:7]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4]([CH2:15][CH2:16][NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([NH2:22])=[O:21])[CH2:3][CH2:8]1
Reactant: NC(=O)c1ccccc1NCCN1CCC(c2ccccc2)CC1O
Reactant: CC(C)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)c1ccccc1NCCN1CCC(O)(c2ccccc2)CC1

Procedure:
2-[-(2-[Hydroxy-4-phenylpiperidyl]ethyl)amino]benzamide hydrochloride (12 g.) in 200 ml methanol was hydrogenated at 60 psi using 1.5 g 5% Pd-C catalyst (1.5 g and 1.0 g portions of fresh catalyst were added during the reduction). The catalyst was filtered off and the filtrate concentrated to dryness on the rotovap. The residue was recrystallized from 60 ml isopropanol and then from 300 ml isopropanol to give 6.1 product, m.108-13°. Analysis showed 13.39% isopropanol in the product.