Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:10][C:22]([NH:21][CH2:19][CH3:20])=[O:23])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN=C=O
Reactant: NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: CCNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 42 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (prepared in Example 13, 103 mg, 0.36 mmol) in toluene (10 mL) was treated with ethyl isocyanate (40 μL, 0.54 mmol). The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea (54 mg, 42%) as a white foam: [α]23589=−41.9° (c=0.031, chloroform); FAB-HRMS m/e calcd for C17H22Cl2N2O2 (M+H)+357.1136, found 357.1137.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13](=[O:28])[CH2:14][C:15]([O:17][C:18]([CH3:27])([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:19]=[CH2:20])=[O:16].[CH3:29]I.Cl>O1CCCC1>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13](=[O:28])[CH:14]([CH3:29])[C:15]([O:17][C:18]([CH3:27])([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:19]=[CH2:20])=[O:16]
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)C(C)C(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (3.92 g, 0.098 mol, 60%) and tetrahydrofuran (100 mL) are placed into a 250 mL three-necked round-bottomed flask fitted with a magnetic stirrer, ice bath, addition funnel, internal thermometer and argon inlet. The contents of the flask are cooled to 0° C. 3,7-Dimethyl-1,6-octadien-3-yl 3-(β-naphthyl)-3-oxo-propionate (15.28 g, 0.044 mol) dissolved in 50 mL of tetrahydrofuran is added dropwise to the flask over 30 min. During addition, the mixture evolves gas. After stirring for 1 h, methyl iodide (10.65 g, 0.075 mol) is added to the reaction mixture. Stirring continues for 2 h at 0° C. and then at room temperature for 18 h. The mixture is neutralized with 20% HCl and extracted with diethyl ether. The organic layers are washed with saturated NaHCO3 solution, water, dried over MgSO4, filtered, concentrated by rotary evaporation and purified by flash chromatography to yield the desired compound. Structure is confirmed my 1H and 13C NMR.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([OH:13])=O)[CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:26]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl.CN(C)C=O>[CH:26]1([CH2:31][NH:32][C:11](=[O:13])[CH2:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)Cc1ccc2cc[nH]c2c1
Reactant: NCC1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccc2cc[nH]c2c1)NCC1CCCC1
Yield: 81 %

Procedure:
A solution of indole-6-acetic acid (0.70 g) and 1,1'-carbonyldiimidazole (0.83 g) in methylene chloride (20 ml) and N,N-dimethylformamide (5 ml) was heated at reflux for 20 min, treated with cyclopentylmethylamine (0.59 g), and heated at reflux for an additional 3 hr. The solution was diluted with methylene chloride; washed successively with 10% v/v hydrochloric acid, water and brine; dried (MgSO4); and evaporated. The residue was purified by flash chromatography, eluting with 1:19 ethyl acetate: hexane, to give N-cyclopentylmethylindole-6-acetamide (0.83, 81%) as a white powder; partial NMR (80 MHz, CDCl3): 3.13(t, 2H, NHCH2), 3.69(s, 2H, ArCH2), 6.55(m, 1H, H3 -indole), 6.98(dd, 1H, H5 -indole), 7.62(d, 1H, H4 -indole).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([NH:11][C:12]([NH:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH:3]=1.[NH2:23][NH2:24].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:9][C:8]1[C:7]2[C:6]([CH3:10])=[N:5][C:4]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:3][C:2]=2[NH:24][N:23]=1
Reactant: NN
Reactant: Cc1nc(NC(=O)N[C@@H](C)c2ccccc2)cc(Cl)c1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
A flask was charged with (S) -1-(4-chloro-5-cyano-6-methylpyridin-2-yl)-3-(1-phenylethyl)urea (920 mg) and ethanol (6989 μl) and hydrazine (183 μl) was added. The reaction was heated to 95° C. for 17 hours. LC/MS showed the reaction was mostly but not entirely complete (˜15% remaining starting material by LC/MS integration). The reaction was heated for 5 additional hours. After cooling, HCl (1N, 14.6 mL) was added and the reaction was stirred for 30 minutes. The reaction was poured into a 500 mL separatory funnel containing 150 mL of concentrated sodium bicarbonate solution. The resulting emulsion was washed 3× with chloroform/IPA (4:1, 100 mL portions). The combined organic washings were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0-10% EtOAc/MeOH+0.1% ammonia) was performed and the active fractions were concentrated to dryness yielding the title compound as a white solid (400 mg, 41.1%). MS ESI calc'd for C16H18N6O [M+H]+ 311. found 311. 1H NMR (ppm500 Mhz, DMSO-d6): δ 9.30 (s, 1H), 8.74 (d, J=0.9 Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.37-7.32 (m, 5H), 7.28-7.21 (m, 1H), 6.60 (s, 2H), 4.88 (p, J=7.0 Hz), 2.47 (s, 3H), 1.42 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:10](Br)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[CH2:22].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH:15]1([C:9]2[C:8]3[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[NH:11][C:10]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:21]=[CH2:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: C=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Temperature: 110 °C
Yield: 83 %

Procedure:
2-bromo-3-cyclohexyl indole-6-carboxylic acid methyl ester (1 eq., prepared as described in WO 2004/087714) was mixed with 2-vinyl benzene boronic acid (1.6 eq.) and bis(triphenylphosphine)palladium dichloride (0.15 eq.) was added. The mixture was degassed and dioxane and 2M aqueous sodium carbonate solution (5 eq.) were added. The mixture was heated under nitrogen atmosphere to 110° C. After 2 h all volatiles were removed in vacuo and the residual material was subjected to flash chromatography (PE:EtOAc, 10:1). After evaporation of the solvent the product was obtained as yellow crystals (83%). MS (ES+): 360.4 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH2:14][O:13][CH2:12][C:11]=12)=[O:5])[CH3:2]>C(O)(=O)C.C(Cl)Cl.[Pt](=O)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH2:12][O:13][CH2:14][C:15](=[O:16])[N:10]2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C2COCC(=O)N2CCC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1CCCN2C(=O)COCC12
Reaction time: 18 h
Yield: 117.9 %

Procedure:
A solution of 65 (225 mg, 1.0 mmol) in 5 ml of acetic acid is hydrogenated over 225 mg of platinum dioxide at RT and normal pressure for 18 hours. Another 225 mg of platinum dioxide is added and hydrogenation continued for 24 hours. The black suspension is diluted with 10 ml of DCM and filtered through a pad of celite. The filtrate is evaporated to give 268 mg of a yellow oil which is purified by chromatography (Biotage 12Si, 1=7.5 cm, ethyl acetate/ethanol 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:31])=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=23)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH:31][C:12](=[O:14])[CH2:11][C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=23)=[CH:18][CH:17]=1
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Product: COc1cc(CC(=O)Nc2nn3cccnc3c2-c2ccc(Cl)cc2)cc(OC)c1
Yield: 8 %

Procedure:
3,5-Dimethoxyphenylacetic acid and the product from Example 99A were processed using the method analogous to that described in example 98 to afford 9 mg (8%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.36-10.57 (bs, 1H), 9.10 (dd, J=6.9, 1.7 Hz, 1H), 8.62 (dd, J=4.1, 1.7 Hz, 1H), 7.66-7.70 (m, 2H), 7.29-7.32 (m, 2H), 7.14 (dd, J=6.9, 4.1 Hz, 1H), 6.47-6.56 (bs, 2H), 6.44 (s, 1H), 3.73 (s, 6H), 3.58 (s, 2H); MS (ESI) m/z 423 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2([CH2:33][CH2:34][OH:35])[O:32][CH2:31][CH2:30][NH:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]>C(#N)C>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([N:29]2[CH2:30][CH2:31][O:32][C:27]([CH2:33][CH2:34][OH:35])([C:22]3[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=3)[CH2:28]2)=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CNCCO1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCOC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)phenylacetic acid (2.0 g, 7.4 mmol) in acetonitrile (20 ml), N,N′-carbonyldiimidazole (1.3 g, 8.1 mmol) was added at room temperature, then 2-[2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol (2.4 g, 8.8 mmol) was further added, and the resulting mixture was stirred at room temperature for one hour. After completion of the reaction, the reaction mixture was evaporated to dryness. To the obtained residue, methylene chloride (20 ml), water (20 ml) and concentrated hydrochloric acid (2 ml) were added, and the resulting mixture was partitioned. The separated organic layer was washed successively with a 5% aqueous solution of sodium hydroxide (25 ml) and water (20 ml) and evaporated to dryness to afford the title compound [2.3 g, yield: 58.6%] as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:20][CH3:21])=[C:8]([CH:10]2[C:16](=[O:17])[CH:15]3[CH2:18][CH:12]([CH2:13][CH2:14]3)[C:11]2=[O:19])[CH:9]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[CH3:38][O:37][C:35](=[O:36])[O:17][C:16]1[CH:15]2[CH2:18][CH:12]([C:11](=[O:19])[C:10]=1[C:8]1[CH:9]=[C:4]([C:3]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=3[Cl:1])[CH:5]=[CH:6][C:7]=1[CH2:20][CH3:21])[CH2:13][CH2:14]2
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C2CCC(C2)C1=O
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1=C(OC(=O)OC)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(2′,4′-dichloro-4-ethylbiphen-3-yl)-bicyclo[3.2.1]octane-2,4-dione (0.133 g, 0.34 mmol) in dichloromethane (2 ml) is added triethylamine (0.24 ml, 1.72 mmol) followed by stirring at room temperature for 5 minutes. To this solution is added methyl chloroformate (0.132 ml, 1.72 mmol) dropwise, then the mixture is left to stand overnight. The reaction mixture is concentrated in vacuo to afford a crude solid which is purified by flash column chromatography on silica gel (100% to 70% hexane/ethyl acetate eluant ratio) to afford carbonic acid 3-(2′,4′-dichloro-4-ethylbiphen-3-yl)-4-oxo-bicyclo[3.2.1]oct-2-en-2-yl ester methyl ester.
Reaction SMILES: CON(C)[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17])=[O:5].C[Li].[C:27](O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)C>[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17])(=[O:5])[CH3:27]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CON(C)C(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 4 h
Yield: 16 %

Procedure:
A solution of N-methoxy-N-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (160 mg) in anhydrous tetrahydrofuran (10 mL) was cooled to −70° C. under nitrogen atmosphere. A solution (1.8 mL) of 1.2M-methyllithium in diethyl ether was added dropwise. The temperature of the solution was gradually raised from −70° C. to 0° C., and the mixture was stirred for 4 hr. The reaction mixture was poured into aqueous citric acid solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-3:7), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (22 mg, yield 16%) as colorless crystals. melting point 241-243° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O1CCC[CH2:12]1.CI.[Br:18][C:19]1[C:27]2[C:22](=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[CH:25][CH:26]=2)[NH:21][CH:20]=1>CN(C)C=O>[Br:18][C:19]1[C:27]2[C:22](=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[CH:25][CH:26]=2)[N:21]([CH3:12])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc2c(Br)c[nH]c2c1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
Method A Add 1M lithium hexamethyldisilazide in tetrahydrofuran (31.2 mL, 31.17 mmol) and methyl iodide (2.6 mL, 41.56 mmol) to a solution of 3-bromo-6-nitro-1H-indole 2 (5.01 g, 20.78 mmol) in N,N-dimethylformamide (100 mL) at 0° C. Warm the reaction mixture to room temperature and allow it to stir for 5 hr. Quench with saturated aqueous ammonium chloride (100 mL), dilute with ethyl acetate (200 mL), and separate the layers. Sequentially, wash the organic layer with 10% aqueous lithium chloride (75 mL), saturated aqueous sodium bicarbonate (75 mL), water (75 mL×2), and brine (75 mL). Dry the resulting organic layer over Na2SO4 and filter. Concentrate the filtrate to provide a residue. Adsorb the residue with the crude product onto silica gel. Chromatograph the residue on a silica gel column eluting with dichloromethane in hexane (5-50 v/v %) to give 4.13 g of the title compound (78%). LRMS (API ES+)=255.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].[OH-].[Na+]>CN(C=O)C.C1COCC1>[CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCNCC5)c4)nc23)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 0° C. solution of (1-methyl-cyclohexyl)-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (24 mg, 0.06 mmol) in DMF (1 ml) was treated with Acetic anhydride (0.01 ml, 0.06 mmol). The reaction mixture was removed from the ice bath and allowed to stir at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc/sat. NaHCO3. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a white solid which was filtered through a Buchner funnel and washed with Et2O and Hexanes to afford a yellow solid. The yellow solid was dissolved in THF (2 ml) and treated with 1N NaOH (0.05 ml, 0.05 mmol). After stirring at room temperature for 16 hours, the reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a light brown oil. The oil was triturated with Et2O providing 4 mg (15%) of 1-(4-{3-[7-(1-methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazin-1-yl)-ethanone as a pale brown solid. M+H=446.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:17]#[N:18].C(OCC)(=O)C>CN1CCCC1=O>[C:17]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7][CH3:8])=[O:6])#[N:18]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(OC(C)C)c(Br)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1

Procedure:
Methyl 3-bromo-4-iso-propoxybenzoate (2.0 g, 7.3 mmol) and copper(I)cyanide in N-methyl pyrrolidone (50 ml) was heated under vigorous reflux for 4 h. Work-up with ethyl acetate gave the title compound (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:23])[CH2:19][CH:18]1[C:20](Cl)=[O:21]>O1CCCC1>[CH3:16][C:17]1([CH3:23])[CH2:19][CH:18]1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:21]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CC1(C)CC1C(=O)Cl
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2CC2(C)C)cc1
Yield: 65.7 %

Procedure:
Using a method similar to that of Example 4, 6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are reacted with 4.7 g (35.4 millimoles) of 2,2-dimethylcyclopropanecarboxylic acid chloride in 150 ml of absolute tetrahydrofuran. The mixture is concentrated to about 70 ml, water is added and the product is filtered off, washed with water and recrystallized twice from dimethylformamide/water, giving 5.8 g (66% of theory) of 4,5-dihydro-6-[p-(2,2-dimethylcyclopropylcarbonylamino)-phenyl]-5-methyl-3(2H)-pyridazinone as colorless crystals, of melting point 222°-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:22][CH2:21]3)=[O:19])=[CH:7][N:8]2[CH2:11][CH2:12]CS(N)(=O)=O)=[CH:4][CH:3]=1.[H-].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:22][CH2:21]3)=[O:19])=[CH:7][N:8]2[CH2:11][CH2:12][N:20]([CH3:21])[C:18](=[O:19])[CH3:6])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)CCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)N(C)CCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl-methanesulfonamide (preparation described herein), was treated with NaH (1.05 eq), MeI (1.05 eq) in dry DMF under argon at RT for 2 h to give after purification by prep. HPLC the title compound.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[CH:26][O:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:20]([NH:38][C:39](=[O:69])[C:40](=[N:66][O:67][CH3:68])[C:41]1[N:42]=[C:43]([NH:46]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:44][CH:45]=1)[C:19]2=[O:70])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>O>[NH2:46][C:43]1[S:44][CH:45]=[C:41]([C:40](=[N:66][O:67][CH3:68])[C:39]([NH:38][CH:20]2[C:19](=[O:70])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH:25]=[CH:26][O:27][S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=2)(=[O:29])=[O:30])=[C:17]3[C:15]([OH:16])=[O:14])=[O:69])[N:42]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Temperature: 50 °C
Yield: 97.7 %

Procedure:
A solution of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetamido]-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene (syn isomer, E-form) (5.93 g) in a mixture of pure formic acid (80 cc) and water (25 cc) is heated at 50° C. for 30 minutes. The mixture is then cooled to 20° C., filtered and concentrated to dryness at 30° C. under 20 mm Hg (2.7 kPa). The residue is taken up in acetone (150 cc), the mixture is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa), the operation is repeated twice more and the residue is then triturated in ether (75 cc) and filtered off. 7-[2-(2-Amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (3.4 g) is obtained in the form of a yellow powder.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:23])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 mg of p-acetoxyphenylacetic acid was dissolved in 5 ml of methylene chloride. To the solution were added, with ice cooling, a catalytic amount of N,N-dimethylformamide and 0.12 ml of oxalyl chloride. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain p-acetoxyphenylacetyl chloride. This compound was dissolved in 5 ml of methylene chloride. To the solution was added 260 mg of a sulfur trioxide-dioxane complex with ice cooling. The mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure to obtain DL-2-(p-acetoxyphenyl)-2-sulfoacetyl chloride. This compound was dissolved in 5 ml of anhydrous tetrahydrofuran.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10]C)=[CH:5][C:4]=1[CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17]>C(#N)C.O>[CH3:9][C:7]1[C:6](=[O:10])[CH:5]=[C:4]([CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])[C:3](=[O:2])[CH:8]=1
Reactant: COc1cc(CCCOC(C)=O)c(OC)cc1C
Solvent: CC#N
Solvent: O
Product: CC(=O)OCCCC1=CC(=O)C(C)=CC1=O
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 5 (1.26 g, 4.99 mmol) in acetonitrile (15 cm3) was added ceric ammonium nitrate (5.50 g, 9.99 mmol) in water (10 cm3) dropwise. The mixture was stirred for 1 hr before the organics were extracted with dichloromethane (3×25 cm3), washed with brine (25 cm3), dried (MgSO4) and concentrated under vacuum to yield the title compound as a brown oil 6 (756 mg, 68%).