Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[CH:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]=2[CH2:12][CH2:13]\1)[CH3:3].[CH3:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2C(N)=[CH:31][CH:30]=[N:29]2)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>O>[CH3:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[C:3]3[N:2]=[CH:4][C:5]4[CH2:13][CH2:12][C:11]5[N:10]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)[N:9]=[CH:8][C:7]=5[C:6]=4[C:31]=3[CH:30]=[N:29]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: CN(C)/C=C1/CCc2c(cnn2-c2ccccc2)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2ncc3c4c(cnc32)CCc2c-4cnn2-c2ccccc2)cc1
Temperature: 100 °C
Yield: 52.5 %

Procedure:
To a mixture of (Z)-5-((dimethylamino)methylene)-1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one (1 g, 3.74 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (3.5 g, 17.2 mmol) was added trifluoroacetic acid (0.8 mL, 10.3 mmol). The reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was then poured into ice-cooled water (100 mL) and extracted with dichloromethane (3×75 mL). The combined organic extracts were dried using sodium sulfate and concentrated under reduced pressure to give a dark residue. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to a residue, which was further purified by crystallization from methanol and isopropanol to give the pure desired product (0.8 g, 15%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.33 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.55-7.49 (m, 4H), 7.41-7.39 (m, 1H), 7.38 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 5.66 (s, 2H), 3.75 (s, 3H), 3.14-3.09 (m, 4H); LCMS [M+H]: 408.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>C1(C)C=CC=CC=1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][NH:13][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:16]=1
Reactant: NCc1cccnc1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: O=C(NCc1cccnc1)Nc1ccc([N+](=O)[O-])cc1
Yield: 98 %

Procedure:
A solution of 415 g. of crude p-nitrophenyl isocyanate in 4.5 l. of toluene was stirred at room temperature. The mixture was filtered and 35 g. of insoluble impurity removed. The material in solution was 380 g. (2.32 mol) of purified p-nitrophenyl isocyanate. The solution was stirred under dry nitrogen, and 3-(aminomethyl)pyridine (250 g., 2.32 mol) was added dropwise. An exotherm to 40° C. was noted. The resulting thick suspension was stirred overnight and then vacuum filtered. The product was washed with hexane and dried in a vacuum oven at 60° C. overnight to give 610.7 g. melting at 220°-221.5° C. The product was a 98% yield of 1-(3-pyridylmethyl)-3-(4-nitrophenyl)urea. This product after recrystallization from 2-methoxyethanol melted with decomposition at 223°-225° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([NH2:28])=[CH:23][CH:24]=3)[CH2:19]2)[CH2:16][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>CCOC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:16][CH3:17])[CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([NH:28][C:37](=[O:38])[C:36]4[CH:35]=[CH:34][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:41][CH:40]=4)=[CH:23][CH:24]=3)[CH2:19]2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(N)cc2C1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a solution of 4-{[(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.87 mmol) in EtOAc (50 mL) and 20% aq. potassium carbonate (50 mL) was added 4-methanesulfonyl-benzoyl chloride (760 mg, 4.1 mmol) dropwise in EtOAc (75 mL). The reaction was stirred at room temperature overnight and the layers separated. The EtOAc layer was concentrated onto silica gel and placed on top of a flash column. The column was eluted with 35% acetone in hexanes. Product containing fractions were pooled and concentrated to afford 4-({ethyl-[7-(4-methanesulfonyl-benzoylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a light pink solid (1.33 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][CH2:17][C:18]2[O:19]C=CC=2)[N:14]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:33].C(Cl)Cl>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][CH2:17][C:18]([OH:33])=[O:19])[N:14]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C:13]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@H]1CCc1ccco1
Reactant: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@H]1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of (±)-t-butyl 2-[cis-3-benzyloxycarbonylamino-4-(2-(2-furyl)ethyl)-2-oxoazetidin-1-yl]acetate (100 mg) and sudan red 7B (0.2 mg) in 6 mL of methanol-methylene chloride (1:1) was cooled to -78° C. Ozone/oxygen was bubbled in to the solution up to the endpoint of sudan red. The solution was allowed to warm to ambient temperature when 0.25N NaOH (1.87 mL) and 30% hydrogen peroxide (0.25 mL) were added. The solution was stirred for 2 hrs and was then diluted with H2O. The organic solvents were removed, and the aqueous solution was washed with ethyl acetate. The aqueous solution was layered with ethyl acetate and the pH of the mixture lowered to 3.7 with dilute hydrochloric acid. The ethyl acetate layer was washed (saturated NaCl), dried (NaSO4), and concentrated. The residue was crystallized from diethyl ether to provide the title compound (44 mg, 46% yield), mp 118°-120° C. Recrystallization from ethyl acetate-hexane provided colorless crystals of the analytical sample.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:11][C:12]([CH3:20])([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH3:13])C(=O)OC(C)(C)C>O1CCOCC1.CCOCC>[ClH:1].[CH3:2][NH:3][CH2:11][C:12]([CH3:20])([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[CH3:13]
Reactant: CN(CC(C)(C)N1CCOCC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNCC(C)(C)N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4 M HCl in dioxane (0.890 mL, 3.5 mmol) was added dropwise to a solution of tert-butyl methyl(2-methyl-2-morpholinopropyl)carbamate (970 mg, max. 2.98 mmol) in dry dioxane (5 mL) under a N2 atmosphere. The mixture was stirred at room temperature for 6 h. The mixture was evaporated to dryness and the residue was stirred in Et2O overnight. The solids were filtered off, rinsed with Et2O and dried on air to yield a white solid. The solids were dissolved in dry dioxane (2 mL) and 4 M HCl in dioxane (0.890 mL, 3.5 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with Et2O and the solids were filtered off, which resulted in AMN-39 (453 mg, 73% over 2 steps).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH:4]([C:9](=[O:12])[NH:10][CH3:11])[CH2:5][C:6]([OH:8])=[O:7].[F:14][C:15]1[C:20](O)=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25].C(Cl)CCl>ClCCl>[F:14][C:15]1[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=1[O:7][C:6](=[O:8])[CH2:5][CH:4]([C:9](=[O:12])[NH:10][CH3:11])[CH2:3][CH:2]([CH3:13])[CH3:1]
Reactant: CNC(=O)C(CC(=O)O)CC(C)C
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: ClCCl
Product: CNC(=O)C(CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To an ice-cooled solution of 5-methyl-3-methylcarbamoyl-hexanoic acid (0.40 g, 2.13 mmol) in dichloromethane (10 ml) was added pentafluorophenol (0.43 g, 2.35 mmol) and EDC (0.45 g, 2.35 mmol). The mixture was stirred at room temperature for 2 h, diluted with more dichloromethane and washed successively with 1 M Na2CO3 solution, 1M HCl and brine. The organic phase was dried (anhydrous MgSO4), filtered and evaporated to leave the title compound as an oil (0.38 g, 56%), which was used in Step D without further purification. 1H-NMR; δ (CDCl3), 5.77 (1H, m), 3.10 (1H, m), 2.83 (3H, d, J=4.7 Hz), 2.75 (2H, m), 1.70 (1H, m), 1.59 (1H, m), 1.31 (1H, m), 0.95 (3H, d, J=4.9 Hz) and 0.93 (3H, d, J=4.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH2:26])=[O:25]>CN(C)C=O.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH2:26])=[O:25])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: NC(=O)c1ccccc1N
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1ccccc1C(N)=O)C(F)(F)F
Yield: 61 %

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (500 mg) and 2-aminobenzamide (1.17 g) in dimethylformamide (2.5 mL) was heated at 140° C. for 19.5 hours. The resulting mixture was diluted with diethyl ether, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 15 to 30% ethyl acetate-hexanes) to give 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]benzamide as a white foam (447 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([NH:15][C@H:16]([C:19](O)=[O:20])[CH2:17][OH:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:11]([O:10][C:8](=[O:9])[NH:15][C@@H:16]([CH2:19][OH:20])[C:17]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC(O)CC1

Procedure:
4-Hydroxypiperidine (6.7 mmol) and Boc-L-serine (6.4 mmol) were coupled according to Procedure A (60 hour reaction time) with the following workup: the reaction mixture was concentrated, the residue dissolved in chloroform and 1N NaOH (6 mL), and the resulting solution extracted repeatedly (ten or mor times) with chloroform. The chloroform extracts were concentrated and the residue purified by chromatography on silica gel eluted with 1-16% ethanol in dichloromethane. Yield 751 mg, 41%; HPLC (40/60) 2.72 minutes (96%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:28]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:28][C:8]1[C:7](=[O:12])[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH3:11]
Reactant: CCCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 4′-[(2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.8 g) in acetic acid (40 mL) was added bromine (0.77 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was allowed to cool to room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.96 g, 88%) as a colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=O)[CH:12]=[C:7]12.O=P(Cl)(Cl)Cl.[CH2:24]([C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)[CH3:25]>ClCCCl>[CH2:24]([C:26]1[N:27]=[CH:28][N:29]([C:13]2[CH:12]=[C:7]3[C:8]4[C:3]([CH2:4][CH2:5][N:6]3[C:16](=[O:17])[CH2:15][N:14]=2)=[C:2]([I:1])[CH:11]=[CH:10][CH:9]=4)[CH:30]=1)[CH3:25]
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Reactant: CCc1c[nH]cn1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cn(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)cn1
Temperature: 100 °C
Yield: 97.6 %

Procedure:
111-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (440 mg, 1.24 mmol) in dry DCE (10 mL) was treated with POCl3 (0.23 mL, 2.49 mmol) and heated to 100° C. for 1 h. The mixture was allowed to cool to RT and then poured onto H2O and extracted with DCM. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was taken up in DCE (10 mL) and 4-ethyl-1H-imidazole (597 mg, 6.21 mmol) was added. The mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto H2O, extracted with DCM and the combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1) to give the title compound (523 mg) as a brown oil. UPLC-MS: MS 433.1 (M+H+); UPLC rt 0.93 min.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:34])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[N:23]=[C:22]([CH3:34])[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(F)cc2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
36 mg (0.89 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 185 mg (0.85 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.85 mmol) 3-chloromethyl-6-(4-fluoro-phenyl)-2-methyl-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. The residue was dried at 40° C. in vacuum to give 295 mg (83%) of the title compound as white powder.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[CH:10][C:11]([F:15])=[C:12]([OH:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[C:23]([Si:27]([CH3:29])([CH3:28])[O:14][C:12]1[CH:13]=[C:8]([C:7]([CH3:17])([CH3:16])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=[CH:10][C:11]=1[F:15])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
To a solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol (4.60 g, 17.9 mmol, 1.0 equiv) in anhydrous DMF (20 mL) at 0° C. under Ar was added imidazole (1.34 g, 19.7 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane (2.97 g, 19.7 mmol, 1.1 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 18 h at rt. The reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with a sat. solution of Na2CO3 (2×100 mL) and NaCl (2×100 mL). The organic phase was dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 4.50 g (68%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s, 9H), 0.92 (s, 9H), 4.55 (s, 2H), 6.71-6.74 (m, 1H), 6.80-6.83 (m, 1H), 6.87-6.92 (m, 1H). MS (EI): 370.2 [M]+.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:27]#[N:28])[CH:21]=3)[NH:16]2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1>ClCCl>[C:27]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]([C:11]1[CH:10]=[C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH:14]=[CH:13][CH:12]=1)[CH2:24][C:23]2([CH3:26])[CH3:25])#[N:28]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C#N)ccc3N2)c1
Reaction time: 168 h
Yield: 46.8 %

Procedure:
Propane-2-sulfonyl chloride (231 mg, 1.62 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (342 mg, 4.32 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir for 7 days. The reaction mixture was washed by water, dried over magnesium sulfate. Filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford propane-2-sulfonic acid [3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (97 mg, yield: 46.8%). MS (ESI+APCI) M+1=384.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14].[OH-].[K+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl>CS(C)=O.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:1]([CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[F:18])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14]
Reactant: Fc1ccccc1CCl
Reactant: CC(=O)c1c(C)nc2ccccc2c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1c(C)nc2ccccc2c1N(Cc1ccccc1F)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-amino-2-methyl-3-quinolinyl)-ethanone in dimethylsulfoxide (150 ml) was added to a stirred slurry of pulverized 85% potassium hydroxide (7 g) in dimethylsulfoxide (40 ml). This mixture was stirred at ambient temperature for twenty minutes, and thereafter a solution of o-fluorobenzylchloride (15.2 g) in dimethylsulfoxide (40 ml) was added dropwise. The mixture was stirred for two hours and allowed to stand overnight at room temperature. Thereafter, it was then poured onto ice and diluted with water to form a tacky lump. This was allowed to stand for fifteen minutes, and the aqueous dimethylsulfoxide was decanted. The tacky precipitate was dissolved in dichloromethane, washed with water (3x) and saturated sodium chloride solution, and dried over sodium sulfate. Removal of the sodium sulfate by filtration and the solvent by evaporation gave 26.5 g of viscous oil.
Reaction SMILES: BrBr.[F:3][C:4]([F:14])([F:13])[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[S-:15][C:16]#[N:17].[K+].N>C(O)(=O)C.O>[NH2:17][C:16]1[S:15][C:11]2[CH:12]=[C:6]([O:5][C:4]([F:13])([F:14])[F:3])[CH:7]=[CH:8][C:9]=2[N:10]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: N
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of 77 g of bromine in 220 ml of acetic acid is added drop by drop, in a period of one hour, to a solution of 84 g of 4-trifluoromethoxy-aniline and 187 g of potassium thiocyanate in 500 ml of acetic acid. The mixture is stirred overnight at the ambient temperature. The reaction mixture is then poured into 2 liters of water. The resulting mixture is cooled in an icebath and neutralized by addition of ammonia. The insoluble material is separated by filtration, washed with water, then recrystallized in an ethanol-water mixture (50--50). 77 g of 2-amino-6-trifluoromethoxy-benzothiazole, which melts at 119° C., are thus obtained.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:39][O:38][C:32]1[CH:31]=[C:30]([CH:35]=[C:34]([O:36][CH3:37])[CH:33]=1)[CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: COc1cc(CNC(=O)C(C)C(=O)O)cc(OC)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: COc1cc(CNC(=O)C(C)C(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc(OC)c1

Procedure:
The title compound, MS: m/e=515.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3,5-dimethoxy-benzyl)-malonamic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:12]([N:14]([CH2:15][CH3:16])[C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=1)[CH3:13]
Reactant: CCNCC
Reactant: COc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methoxybenzoic acid (6 g, 39 mmol) was treated with diethylamine (4.45 mL, 43 mmol), TBTU (15 g, 46.8 mmol), disopropylethylamine (10.2 mL, 58.5 mmol) in DMF (40 mL). The mixture was stirred at ambient temperature overnight. The reaction was poured into ice water and the resulting mixture extracted several times with ethyl acetate. The organic layer was washed with a solution of saturated sodium bicarbonate, water and then brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 30 to 70% ethyl acetate in hexanes to obtain a brown oil. Yield=7.8 g. MS (M+H)+ 208.