Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[CH:11][NH:12]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:16][O:17][CH3:18]>>[CH3:16][O:17][CH2:18][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:14]=2)[CH:10]=[CH:11]1
Reactant: COCCl
Reactant: c1cc2ccc(N3CCCC3)cc2[nH]1
Product: COCn1ccc2ccc(N3CCCC3)cc21

Procedure:
1-Methoxymethyl-6-pyrrolidin-1-yl-1H-indole was prepared from 6-pyrrolidin-1-yl-1H-indole ( example 12 e) in the same manner as example 1(a) using chloromethyl methylether as the alkylating agent.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:16])[CH:11]=[C:12]([CH3:15])[N:13]=2)[CH:8]=[CH:7][C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].C(Cl)[Cl:34].C(=O)([O-])[O-].[K+].[K+]>O>[ClH:34].[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:16])[CH:11]=[C:12]([CH3:15])[N:13]=2)[CH:8]=[CH:7][C:6]1=[S:20]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cc(C)c2ccc(=O)n(CCN(C)C)c2n1
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C)c2ccc(=S)n(CCN(C)C)c2n1
Product: Cl

Procedure:
A mixture of 1-(2-dimethylaminoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one (2.5 g., 0.01 mole) and phosphorus pentasulfide (2.0 g., 0.009 mole) in 60 ml. of methylene chloride is heated at reflux for 4 hours. The reaction is cooled, water and solid potassium carbonate added, and the organic layer is separated, dried, filtered through charcoal and evaporated to dryness. The residue is dissolved in ether, hydrogen chloride is added and the salt is recrystallized from isopropanol to yield 1-(2-dimethylaminoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-thione hydrochloride m.p. 209°-211° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][CH2:16][CH:17]3[C:21](=[O:22])[N:20]([CH:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25])[C:19](=[O:30])[NH:18]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CN([P+]([O:41][N:42]1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.ON.Cl.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][CH2:16][CH:17]3[C:21](=[O:22])[N:20]([CH:23]([CH:27]([CH3:28])[CH3:29])[C:24]([NH:42][OH:41])=[O:25])[C:19](=[O:30])[NH:18]3)=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(COCc2ccc(-c3cccc(F)c3)cc2)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)NO)N1C(=O)NC(COCc2ccc(-c3cccc(F)c3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of the compound obtained in step c above (20c) (166 mg, 0.401 mmol) in DMF (5 mL) was added BOP reagent (213 mg, 0.481 mmol) at 0° C. After stirring for 30 min, HONH2×HCl (50 mg, 11.38 mmol) and N-methylmorpholine (0.15 mL, 1.34 mmol) were added. The mixture was warmed to room temperature and stirred overnight. The solvent was removed and the residue was partitioned between EtOAc and saturated NH4Cl solution. The aqueous layer was extracted with EtOAc, the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (60 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[C:5]2[CH:16]=[CH:17][N:18]([CH2:19][CH2:20][OH:21])[C:4]=2[N:3]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[CH3:28][S:29]([O:21][CH2:20][CH2:19][N:18]1[C:4]2[N:3]=[C:2]([NH2:1])[N:7]3[N:8]=[C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[C:6]3[C:5]=2[CH:16]=[CH:17]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc2c(ccn2CCO)c2nc(-c3ccco3)nn12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the title C compound, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethanol (15 g, 5.28 mmol) in 45 mL of dry THF is added 75 mL of TEA, 75 mL of pyridine and methanesulfonyl chloride (0.6 mL, 7.75 mmol) at 0° C. The mixture is stirred at RT under N2 for 12 h. The solvent is evaporated in vacuo and the residue is purified by flash chromatography using EtOAc as eluent to give 2-{5-amino-2-(furan-2-yl) -7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate as a white solid: LC/MS (M+1=363.4). 1H NMR (DMSO-d6, 400 MHz) δ 3.07 (s, 3H), 4.47 (t, 2H, J=5.2 Hz), 4.59 (t 2H, J=5.2 Hz), 6.65 (d, 1H, J=3.6 Hz), 6.72 (dd, 1H, J=3.2 Hz and 1.6 Hz), 7.18 (d, 1H, J=3.6 Hz), 7.20 (d, 1H, J=3.2 Hz), 7.60 (s, 2H), 7.92 (d, 1H, J=1.2 Hz).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:26])[CH:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]2OC(=O)C)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:37]1([CH2:43][C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:44](=[O:45])[CH2:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC1CS[C@@H]2C(N)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 7-amino-3-acetoxycepham-4-carboxylic acid diphenylmethyl ester (4) in dichloromethane (7 parts) cooling at -30° to -10° C. are added pyridine (1.7 equivalents) and phenylacetyl chloride (1.1 equivalents). After stirring for 30 minutes, the mixture is neutralized with triethylamine (1 to 9 equivalents), stirred at 0° to 5° C. for 24 hours, and diluted with ice water. The formed organic layer is taken, washed with hydrochloric acid and water, dried, and concentrated. The residue is crystallized from a mixture of ethyl acetate and ether to give 7beta-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (6). Yield: 70.0%. mp. 170°-171° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br.C(OCC)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[F:17])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: Fc1ccccc1CBr
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COc1cc(Br)ccc1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A suspension of 4-bromo-2-(methyloxy)phenol (3.0 g, 14.78 mmol), potassium carbonate (2.99 g, 22.17 mmol) and 2-fluorobenzylbromide (1.78 ml, 14.78 mmol) in acetonitrile (20 ml) was stirred at room temperature overnight. Diethylether was added. The organic phase was then washed was washed with water and 1M NaOH, dried (Na2SO4), filtered and evaporated to afford the title compound (4.388 g, quant.). Rt (HPLC): 6.25 min; 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.5 (m, 1H), 7.4 (m, 1H), 7.2 (m, 2H), 7.1 (s, 1H), 7.0 (m, 2H), 5.1 (s, 2H), 3.7 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:10])[CH2:8][CH3:9].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH2:34][OH:35])[C:30](=[O:33])[O:31][CH3:32])=[C:25]([CH3:36])[CH:24]=1.O>C(Cl)Cl>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH2:34][O:35][C:7](=[O:10])[CH2:8][CH3:9])[C:30](=[O:33])[O:31][CH3:32])=[C:25]([CH3:36])[CH:24]=1
Reactant: CCC(=O)Cl
Reactant: COC(=O)N(CO)c1ccc(OCc2nc3ccccc3s2)cc1C
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCC(=O)OCN(C(=O)OC)c1ccc(OCc2nc3ccccc3s2)cc1C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
0.1 ml of pyridine and 0.1 ml of propionyl chloride were added to a solution of 121 mg of methyl N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N-hydroxymethylcarbamate (prepared as described in Example 19 above) in 2 ml of methylene chloride cooled in an ice-water bath and the resulting mixture was stirred at the same temperature for 10 minutes. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude residue which was purified by column chromatography through silica gel using a 5:1 by volume mixture of hexane and ethyl acetate to give 133 mg (yield 94%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Mg+2].[Cl-].[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[C:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.S(Cl)(Cl)(=O)=O.Cl>C(#N)C.CCOC(C)=O>[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[C:23]1([C:29]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C(O)C1(c2cccc(F)c2F)CCOCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2cccc(F)c2F)CCOCC1
Temperature: 0 °C
Yield: 33 %

Procedure:
A mixture of diethyl malonate (4.2 g, 26 mmol) in 50 mL ACN was stirred at 0° C. and treated with magnesium chloride (2.5 g, 26 mmol) in one portion and TEA (5.9 g, 58 mmol) dropwise. The mixture was stirred at room temperature for 2.5 hours. In a separate flask, a mixture of 4-(2,3-difluorophenyl)-tetrahydro-2H-pyran-4-carboxylic acid (6.4 g, 26 mmol) in sulfuryl dichloride (31 g, 264 mmol) was refluxed for 2 hours, then concentrated in vacuo. This residue was diluted with 30 mL ACN, and added to the malonate/magnesium chloride mixture dropwise. The resulting reaction was stirred at 50° C. for 1.5 hours. The mixture was cooled to room temperature, diluted with 200 mL EtOAc, neutralized to pH=5 with concentrated HCl, washed with H2O (2×50 mL), saturated NaCl (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (10-20% EtOAc/hexane) to give the intermediate 3.3 g as pale yellow oil. MS m/e: (M+H)+ 385.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:21][NH:22][C:23]2=[O:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2CN)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)NCc3ccccc32)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
The obtained 1-(tert-butoxycarbonyl)-4-[(2-aminomethylphenyl)amino]-piperidine (219 mg) was dissolved in toluene (5 ml), added with 1,1′-carbonyldiimidazole (128 mg) and stirred at 100° C. for 1.5 hours. The reaction mixture was added with water (10 ml) and extracted twice with ethyl acetate (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:2→1:3) to obtain 130 mg of the title compound. Yield: 17% (for the three steps).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([CH:9]([C:11]1[O:12][C:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:14][CH:15]=1)O)=[CH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:27]([O-:32])([O-])[O:28][CH2:29][CH3:30].[C:33](O)(=O)CC>>[CH2:29]([O:28][C:27](=[O:32])[CH2:33][CH2:8][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:26])=[CH:9][C:11]1[O:12][C:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:14][CH:15]=1)[CH3:30]
Reactant: C=C(C(=O)OC(C)(C)C)C(O)c1ccc(C(=O)OCc2ccccc2)o1
Reactant: CCOC([O-])[O-]
Reactant: CCC(=O)O
Product: CCOC(=O)CCC(=Cc1ccc(C(=O)OCc2ccccc2)o1)C(=O)OC(C)(C)C
Temperature: 138 °C
Reaction time: 5 h

Procedure:
2-{[5-(Benzyloxycarbonyl)furan-2-yl](hydroxy)methyl}prop-2-enoic acid tert-butyl ester (90 mg, 0.25 mmol) was dissolved in ethyl orthoformate (2.0 mL, 10.9 mmol), propanoic acid (8 mg, 0.10 mmol) was added, and the mixture was stirred at 138° C. for 5 hours. The mixture was purified by silica gel column chromatography to give the title compound.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]([OH:11])(=[S:10])[CH3:9].[N:12]1([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][NH:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34]Cl)[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)(=O)C>[N:12]1([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][NH:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][S:10][C:8](=[O:11])[CH3:9])[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(O)=S
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.50 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to 80 ml of dimethylformamide under an atmosphere of nitrogen gas, and then 10 ml of a dimethylformamide solution containing 0.81 ml of thioacetic acid was added to the resulting mixture. The mixture was then stirred at room temperature for 30 minutes. At the end of this time, 30 ml of a dimethylformamide solution containing 3.79 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was then added to the reaction mixture, which was then washed with a saturated aqueous solution of sodium hydrogencarbonate and water. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 5.04 g (a quantitative yield) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[OH:28]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[OH:28])=[O:9]
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: N[C@H]1CCCC[C@@H]1O
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid and (1S,2S)-2-amino-cyclohexanol as starting materials, MS (ISP) 465.1, 467.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH:12]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)[N:26]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:35][O:36][C:37](=[O:63])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[CH:62])=[CH:57][CH:56]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[CH3:35][O:36][C:37](=[O:63])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:30]3[CH:31]=[CH:32][C:27]([C:25]4[N:26]=[C:22]([CH:12]5[CH2:13][N:14]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:15][CH2:16][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:34])[CH:6]([CH3:8])[CH3:7])[NH:23][CH:24]=4)=[CH:28][CH:29]=3)=[CH:57][CH:56]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41]
Reactant: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
{1-[2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98.7 mg, 0.181 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (71.2 mg, 0.181 mmol) and Pd(PPh3)4 (21.5 mg, 0.018 mmol) under an argon atmosphere. DMF (degassed with Argon) was added followed by triethylamine (181 mg, 1.8 mmol) and copper(I) iodide (3.5 mg, 0.018 mmol). The mixture was heated at 80° C. After 20 minutes, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent EtOAc w MeOH 10%/hexanes) and further purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-(2,2,2-trifluoro-ethyl)-piperazin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (12.4 mg): LCMS-ESI+: calc'd for C44H52F3N9O6: 859.9 (M+). Found: 860.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.91-7.68 (m, 10H), 6.06 (m, 2H), 5.24 (m, 1H), 4.43 (m, 1H), 4.23 (d, J=7.8 Hz, 1H), 4.11 (m, 1H), 3.85 (m, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.49-3.45 (m, 2H), 3.15-3.02 (m, 3H), 2.77 (m, 1H), 2.58 (m, 1H), 2.29-2.01 (m, 5H), 1.07-0.83 (m, 12H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].Cl[C:13]1[N:14]=[N:15][C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:17][CH:18]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][C:13]1[N:14]=[N:15][C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:17][CH:18]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: Clc1ccc(-n2ccnc2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Oc2ccc(-n3ccnc3)nn2)c1
Reaction time: 0.25 h

Procedure:
A mixture of 3 parts of 3,5-dimethylphenol, 1.25 parts of sodium hydride dispersion 50% and 25 parts of N,N-dimethylformamide was stirred for 15 minutes. Then there was added a solution of 4.5 parts of 3-chloro-6-(1H-imidazol-1-yl)pyridazine in 25 parts of N,N-dimethylformamide and the whole was stirred over weekend at 50° C. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanone, yielding 3.5 parts of 3-(3,5-dimethylphenoxy)-6-(1H-imidazol-1-yl)pyridazine; mp. 169.8° C. (compound 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:13])[CH2:10][C:11]#[N:12].[C:14](OC(=O)C)(=O)C.C(OCC)(OCC)OCC.[CH3:31][CH2:32][CH2:33][CH:34]([NH2:38])[CH2:35][CH2:36][CH3:37]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](/[C:10](=[CH:14]/[NH:38][CH:34]([CH2:35][CH2:36][CH3:37])[CH2:33][CH2:32][CH3:31])/[C:11]#[N:12])=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC(N)CCC
Reactant: N#CCC(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(OCC)OCC
Solvent: C1CCOC1
Product: CCCC(CCC)N/C=C(\C#N)C(=O)c1c(Cl)cccc1Cl
Temperature: 150 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
A mixture of 3-(2,6-dichlorophenyl)-3-oxopropanenitrile (0.200 g, 0.93 mmol), acetic anhydride (0.22 g, 2.20 mmol), and triethyl orthoformate (0.21 g, 1.40 mmol) was stirred at 150° C. for 1 hr. The solution was then concentrated and the residue redissolved in ethanol (5 mL). 4-heptylamine (0.16 g, 1.4 mmol) in 1 mL of tetrahydrofuran was added to the reaction mixture at 0° C. The reaction stirred for 30 minutes and was then concentrated. Flash chromatography (20% Ethyl acetate/hexanes) gave the desired compound (0.033 g, 10%).
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH3:6][C:7](=[CH2:15])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].ICI.[Cl-].[NH4+]>CCCCCC>[CH3:15][C:7]1([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][CH2:6]1
Reactant: CC[Zn]CC
Reactant: C=C(C)CCC(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: ICI
Product: CCOC(=O)CCC1(C)CC1
Temperature: 25 °C

Procedure:
Diethylzinc (40 ml. 1.1M solution in toluene) was added dropwise to a solution of ethyl 4-methylpent-4-enoate (1.25 g.) in dry hexane (100 ml.) at -20° under nitrogen After stirring for 10 minutes diiodomethane (23.6 g.) was added dropwise and the mixture maintained at -20° for 6 hours. The mixture was allowed to warm to room temperature, aqueous ammonium chloride solution (60 ml.) added and the two layers separated. The aqueous layer was extracted with diethyl ether (3×50 ml.) and the combined organic extracts washed with sodium thiosulphate solution (50 ml.) and water (50 ml.). The extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. Chromatography on silica, eluting with diethyl ether/hexane mixtures, gave ethyl 3-(1-methylcyclopropyl)propanoate as a colourless oil (1.21 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:22])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1

Procedure:
A solution of (0.025 mole) of 1,3-dihydro-7-chloro-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one in about 500 ml. of pyridine is treated with 5.55 g. (0.025 mole) of phosphorus pentasulfide and heated under reflux in a nitrogen atmosphere for 2 hours. The pyridine is removed in vacuo and the thus-produced residue is poured onto crushed ice. The aqueous phase is extracted with methylene chloride and then discarded. The extract is washed successively with three 200-ml. portions of water and 100 ml. of brine, and dried over anhydrous sodium sulfate. Removal of the solvent gives a solid which is recrystallized from ethanol-water, to give crude material which, after recrystallization from ethanolwater, gives pure 1,3-dihydro-7-chloro-5-(2-chlorophenyl)-2H-1,4-benzodiazepine-2-thione, melting point 251°-253° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([F:18])[C:12]=2[F:19])[N:8]=[C:7]([C:20]([O:22][CH3:23])=[O:21])[C:6]=1[Cl:24])(=O)C.C(Cl)(=O)C>CO>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([F:18])[C:12]=2[F:19])[N:8]=[C:7]([C:20]([O:22][CH3:23])=[O:21])[C:6]=1[Cl:24]
Reactant: COC(=O)c1nc(-c2ccc(Br)c(F)c2F)cc(NC(C)=O)c1Cl
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)c1nc(-c2ccc(Br)c(F)c2F)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
Methyl 4-acetamido-6-(4-bromo-2,3-difluorophenyl)-3-chloropicolinate (0.515 g, 1.227 mmol) was suspended in methanol (20 mL) and acetyl chloride (1.559 mL, 21.93 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature and concentrated under vacuum. The residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate solution. The organic phase was concentrated onto silica gel and purified by flash chromatography (SiO2, eluting with 5-60% ethyl acetate in hexanes) to provide the title compound as a white solid (0.231 g, 55.8%).