Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][C:16](Cl)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[N:9]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>ClCCl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([N:9]2[CH:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:40][CH2:39][C:38]4[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=4)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[CH2:11][CH2:12][CH:8]2[C:5]2[CH:6]=[CH:7][C:2]([NH:40][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)=[C:3]([N+:30]([O-:32])=[O:31])[CH:4]=2)=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1cc(C2CCC(c3ccc(Cl)c([N+](=O)[O-])c3)N2c2ccc(F)cc2)ccc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Product: COc1ccc(CNc2ccc(C3CCC(c4ccc(NCc5ccc(OC)cc5)c([N+](=O)[O-])c4)N3c3ccc(F)cc3)cc2[N+](=O)[O-])cc1
Temperature: 145 °C
Yield: 62.7 %

Procedure:
2,5-Bis(4-chloro-3-nitrophenyl)-1-(4-fluorophenyl)pyrrolidine (0.88 g, 1.86 mmol) was combined with 4-methoxy benzylamine (3.64 mL, 28.0 mmol) and heated at 145° C. for 1 hour in a microwave reactor. The mixture was diluted with dichloromethane and filtered. The filtrate was concentrated and purified by chromatography on silica gel with a 330 g column, eluting with 0-60% ethyl acetate/hexanes to give 0.79 g (62%) of an orange foam solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[C:10]([C:12]3[C:26]([F:27])=[CH:25][C:15]4[C:16]([C:19]5[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=5)=[N:17][O:18][C:14]=4[CH:13]=3)[C:9]([CH3:28])=[C:8]([F:29])[CH:7]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.CCOCC>C(Cl)(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[C:10]([C:12]3[C:26]([F:27])=[CH:25][C:15]4[C:16]([C:19]5[CH:20]=[CH:21][N+:22]([O-:39])=[CH:23][CH:24]=5)=[N:17][O:18][C:14]=4[CH:13]=3)[C:9]([CH3:28])=[C:8]([F:29])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1cc2onc(-c3ccncc3)c2cc1F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1cc2onc(-c3cc[n+]([O-])cc3)c2cc1F
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 72.2 %

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-[5-fluoro-3-(4-pyridinyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide (Example 3, 12 mg) in chloroform (1 ml) under nitrogen was treated with M-CPBA (10 mg) and the mixture was stirred at 60° C. for 40 min. Further m-CPBA (10 mg) was added and stirring was continued for 1 h. The solution was applied to an Isolute amino cartridge (1 g) which was eluted with chloroform/methanol (100:0 to 90:10) to give a glass. Trituration using a small quantity of ether gave the title compound as a white powder (9 mg).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]SC1SCC(=O)N=1.[OH-].[Na+]>CN(C=O)C>[Cl:11][C:12]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCCCCSc2nc3ccccc3[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Stir at room temperature for four days 2.5 gms. 2-mercapto-benzimidazole, 2 gms. of the iodide prepared in Examples 2 and 3, 25 ml. DMF and 0.71 gm. sodium hydroxide in a reaction flask. Remove the solvent and partition with water/methylene chloride. Elute on a silica column with 100% methylene chloride then 50/50 ethylacetate/methylene chloride to obtain the title compound. MS: m/z 391 (M+) H1 -NMR-200 mHz-δH (CDCl3), 1.5-1.6 (4H,m), 1.7-1.9 (4H,m), 3.35 (2H,t,J 7Hz), 3.75 (3H,s) 3.95 (2H,t,J 6Hz), 6.7-7.0 (3H,m), 7.2-7.4 (4H,m), 7.65-7.75 (1H,m).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1>>[CH3:23][N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:9]([C:5]2[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=2[CH3:8])=[O:11])[CH2:18][CH2:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CN1CCN(CCCN)CC1
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN1CCN(C)CC1
Yield: 23 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1.0 g, 6 mmol) was reacted with 1-(3-aminopropyl)-4-methylpiperazine (1.06 mL) to give 0.38 g (23% yield) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide using General Amidation Procedure 1. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.8 (br s, 1H, NH), 9.52 (s, 1H, CHO), 7.52 (m, 1H, CONH), 3.2 (m, 2H, CH2), 2.8 (m, 2H, CH2), 2.5 (m, 8H, 4×CH2), 2.34 (s, 3H, CH3), 2.29 (s, 3H, CH3), 1.68 (m, 2H, CH2). MS m/z 307 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][N:14]([C:34](=[O:43])[C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=4[Cl:42])[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:44]I.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([CH3:44])[S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][N:14]([C:34](=[O:43])[C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=4[Cl:42])[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCCS(=O)(=O)N(C)c1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C

Procedure:
Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (0.5 g, 0.8 mmol) were dissolved in 1 ml dimethylformamide 0.1 g sodium carbonate was added under stirring at room temperature. Methyl iodide (70 μl, 0.16 g, 1.1 mmol) was added dropwise under vigorous stirring at room temperature by a syringe. The reaction mixture was stirred at room temperature overnight. Water was added to the stirred suspension, and the mixture was stirred for 1 hour. The reaction mixture was extracted with ethyl acetate twice (2×20 ml). The organic layer was dried over sodium sulfate. After drying of the organic layer, the solvent was evaporated under reduced pressure at 46° C. The brownish remaining crude product was used for the further synthesis without purification.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].C[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18]C)=[CH:10][C:9]=1[CH2:20][O:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:25][NH:24][CH2:23]1>O.C(#N)C>[CH2:38]([O:37][CH2:36][CH2:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH:27]2[CH2:26][CH2:25][NH:24][CH2:23][CH:22]2[O:21][CH2:20][C:9]2[C:8](=[O:7])[C:17]3[C:12]([C:11](=[O:18])[CH:10]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:33][CH:32]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cc(COC2CNCCC2c2ccc(OCCOCCc3ccccc3)cc2)c(OC)c2ccccc12
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1C=C(COC2CNCCC2c2ccc(OCCOCCc3ccccc3)cc2)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
A solution of 240 mg of Cer(IV) ammonium nitrate in 1 ml of water was added dropwise at room temperature to a solution of 118 mg of (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine in 10 ml of acetonitrile. The reaction solution was stirred at room temperature for 15 minutes and subsequently evaporated under reduced pressure. The residue was partitioned between methylene chloride and water, the organic phase was dried and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 9:1 mixture of methylene chloride and methanol as the eluent. There were obtained 95 mg (85% of theory) of (3RS,4RS)-2-[4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidin-3-yloxymethyl]-[1,4]naphthoquinone as a red solid; MS: 512 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.Br[CH2:15][C:16]([NH2:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:15][C:16](=[O:17])[NH2:18])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: NC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NCC(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-amino-1-N-Boc pyrrolidine (0.5 g, 2.68 mmol) and 2-bromo acetamide (0.44 g, 3.21 mmol) in DMF (6.0 mL) was added potassium carbonate (1.11 g, 8.04 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and re-dissolved in dichloromethane. Potassium carbonate was filtered off and filtrate was concentrated and purified using ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 1.50 (9H, s), 1.60–1.80 (2H, m), 2.10 (1H, m), 3.10–3.60 (6H, m), 5.65 (1H, br, s), 6.90 (1H, br, s). ESI-MS m/z: 367(M+1), UV retention time: 0.61 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:19](Cl)([Cl:21])=[S:20]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:19]([Cl:21])=[S:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCCN1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)N1CCCCN1C(=S)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
With the temperature maintained at 30° or below, a mixture of N-ethoxycarbonylhexahydropyridazine (1.5 g, 9.49 mmol) and triethylamine (1.0 g, 9.49 mmol) in 8 ml of benzene is added dropwise to a stirring solution of thiophosgene (1.1 g, 9.49 mmol) in 10 ml of benzene. The reaction is stirred at RT for 4 hours, and is then diluted with benzene to 50 ml, quickly washed with water and with brine, dried and stripped to give N-ethoxycarbonyl-N'-chlorothiocarbonylhexahydropyridazine.
Reaction SMILES: [OH:1][C:2]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].S(OC)(O[CH3:22])(=O)=O>[OH-].[K+]>[CH3:22][O:1][C:2]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(Sc2ccccc2Cl)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Product: COc1c(C=O)cccc1Sc1ccccc1Cl
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A mixture of 2-hydroxy-3-(2-chlorophenylthio)benzaldehyde (19.3 g) and dimethyl sulfate (18.4 g) was stirred at room temperature. To the mixture was added dropwise an aqueous solution (50 ml) of potassium hydroxide (12.5 g) at temperature below 60° C., and then the mixture was stirred for an hour. The reaction mixture was cooled to the ambient temperature and insoluble substance was filtered off. The filtrate was extracted with diethyl ether, and the extract was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure to give oily 2-methoxy-3-(2-chlorophenylthio)benzaldehyde (9.2 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (48.0 g) in dichloromethane (250 ml) was added triethylamine (26.4 ml) and methanesulfonyl chloride (14.3 ml) under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was washed in turn with water (100 ml) and saturated aqueous sodium chloride (100 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-methanesulfonyloxymethylpyrrolidine (48.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:12]
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
2-(2-chloro-4-fluorophenyl)acetamide (400 mg, 2.13 mmol) was diluted with THF (2 mL), placed under nitrogen and cooled to 0° C. LAH (4264 μL, 4.26 mmol) was added dropwise and the reaction was refluxed for 3 hours. The reaction was cooled to 0° C. and quenched with 160 μL of water, 160 μL of 15% NaOH, and 530 μL of water. After stirring for 30 minutes the reaction was filtered and concentrated. The material was purified using a biotage 25 column eluting with 2% NH4OH/10% methanol/DCM to yield 2-(2-chloro-4-fluorophenyl)ethanamine (60 mg, 0.346 mmol, 16.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2cccc(CCCNC(C)=O)c2c1
Product: COc1ccc2cc(C(=O)c3ccccc3)cc(CCCNC(C)=O)c2c1

Procedure:
By reacting N-[3-(7-methoxy-1-naphthyl)propyl]acetamide obtained in Example 1 with benzoyl chloride, the compound of the title is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.OS(O)(=O)=O.[CH3:19]O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([O:13][CH3:19])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ncc(Br)cc12
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVIII) (1.6 Kg, 6.6 mol) in anhydrous MeOH (32 L) was added H2SO4 (160 mL) The reaction was slowly heated to 70° C. and stirred for 20 hours. The solution was concentrated under vacuum to a volume of 1.6 L. The residue was partitioned between DCM (120 L) and aqueous 10% NaHCO3 (32 L). The organic phase was separated and washed with aqueous 25% NaCl (32 L), dried over Na2SO4 and concentrated to a volume of 4.8 L. The product was crystallized by charging the solution with 3×n-heptane (8 L) while concentrating the volume to 4.8 L after each addition of n-heptane. The solid was filtered and dried under vacuum at 50° C. to produce methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) (1.53 Kg, 6.0 mol, 80.6% purity, 90.4% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 3.95 (s, 3H), 8.62 (d, J=2 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H), 14.78 (brs, 1H); ESIMS found C8H6BrN3O2 m/z 256.0 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([OH:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>CC(=O)CC>[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22][O:17][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:19]
Reactant: CCN(CC)C(=O)CCl
Reactant: Oc1nc(-c2ccccc2)cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN(CC)C(=O)COc1nc(-c2ccccc2)cc2ccccc12

Procedure:
The procedure is as in Example 47, starting with 3-phenyl-1-isoquinolinol (5.1 g), N,N-diethylchloroacetamide (3.8 g), sodium carbonate (4.8 g) and cuprous iodide (1.15 g) in 2-butanone (100 cc). After 2 chromatographic separations on silica gel with chloroform as eluant and crystallization of the product in petroleum ether, N,N-diethyl-(3-phenyl-1-isoquinolyl)oxyacetamide (0.5 ), m.p. 102° C., is obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:18][CH:17]=3)[CH2:11][CH2:12][C:13](=[N:14]O)[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].CO>[CH2:1]([C:5]1[N:9]2[CH:10]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:20][CH:21]=3)[CH2:11][CH2:12][CH:13]([NH2:14])[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=NO
Agent: [Pd]
Solvent: CO
Product: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2N

Procedure:
Alternatively, the title compound of Example 1468 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, the title compound of Example 1466) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under 50 psi of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1468.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[C:12](=[O:42])[C:13](=[CH:16][C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:21]=3[CH3:22])[CH2:14][CH2:15][C:4]=12)[CH3:2].C([O-])=O.[NH4+]>[Pd].C(O)(=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[C:12](=[O:42])[CH:13]([CH2:16][C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[CH2:14][CH2:15][C:4]=12)[CH3:2]
Reactant: CCc1c2n(c3ccccc13)C(=O)C(=Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCc1c2n(c3ccccc13)C(=O)C(Cc1nc[nH]c1C)CC2
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 56.8 %

Procedure:
A mixture of 10-ethyl-8,9-dihydro-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (1.0 g), 10% palladium on carbon (0.25 g), and ammonium formate (0.5 g) in acetic acid (14 ml) was stirred at 90° C. for 1 hour and 45 minutes and cooled to room temperature. After filtration of the catalyst, the filtrate was evaporated in vacuo and the residue was suspended in 0.5N hydrochloric acid. The aqueous layer was washed twice with toluene, made basic with aqueous sodium bicarbonate solution, and extracted three times with chloroform. The chloroform layer was washed with water twice and brine, dried over anhydrous magnesium sulfate, and evaporated to give crystals. Recrystallization from chloroform-methanol gave 10-ethyl-8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)-methyl]pyrido[1,2-a]indol-6(7H)-one (0.319 g).
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O-:21])=[O:20])(=[O:3])[CH3:2].[Na+].[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>O1CCCC1.C1OCCOCCOCCOCCOC1>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)[O-])N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N/C=C/SC1=C(C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.3 %

Procedure:
Sodium (5R,6S)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e64) (50 mg, 50% pure material) in dry tetrahydrofuran (THF) (5 ml) containing 15-crown-5 crown ether (2 drops) and 3 A molecular sieves was treated with tert-butylchlorodiphenylsilane (80 mg). After stirring at r.t. for 20 hr., the THF was evaporated in vacuo and the mixture loaded onto a silica gel column (10 g) and the column eluted with chloroform (10 ml) followed by a chloroform/ethanol mixture (4:1). The fractions containing the ester were combined and evaporated to give tert-Butyldiphenylsilyl (5R,6S)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e65) as an oil (20 mg), νmax (CH2Cl2) 1785, 1700, 1685, 1625 cm-1. δ(CDCl3) 1.13 (9H,s,C(CH3)3), 1.27 (3H,d,J 6 Hz, CH3CH), 1.77 (3H,s,CH3CO), 2.7-3.2 (2H,m, 4--CH2), 3.22 (1H, m, sharpens to dd on D2O exchange, J1 approx. 5 Hz, J2 approx. 3 Hz, 6--CH), 3.6 (1H, broad, exchanges D2O, OH), 3.9-4.3 (2H,m, 5--CH, 8--CH), 5.60 (1H,d,J 14 Hz, S CH=), 7.02 (1H,dd,J1 14 Hz, J2 10 Hz,d,J 14 Hz on D2O exchange, CH=CH NH), 7.3-7.8 (10H, Ar--H), 8.34 (1H, broad d, exchange D2O, NH) p.p.m. The UV spectrum showed a maximum at about 328 nm.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH2:5](N)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:16]([NH:1][C:2]([NH2:4])=[O:3])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5]
Reactant: NC(N)=O
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC(N)=O

Procedure:
250 g of urea were continuously introduced into a decomposer in the course of 2 hours. The pyrolysis gases were introduced into a melt of 1200 g of dodecylamine at a temperature of 80 to 90° C. After completion of the reaction, the excess dodecylamine was distilled off in vacuo and the residue was recrystallized from chloroform. 598.9 g, i.e. 63% of theory, of dodecylurea having a melting point of 105 to 107° C were obtained in this way.