Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:34][C:35]([CH3:43])([CH3:42])[CH2:36]OS([O-])(=O)=O>CN(C)C=O>[NH2:34][C:35]([CH3:43])([CH3:42])[CH2:36][S:1][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=2[N:3]=1
Reactant: CC(C)=CCn1c(S)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Reactant: CC(C)(N)COS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(SCC(C)(C)N)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Reaction time: 0.25 h

Procedure:
30 mg of 8-mercapto-3-methyl-7-(3-methylbut-2-enyl)-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydropurine-2,6-dione were introduced into 2 ml of dimethyl-formamide and, after addition of 37 mg of potassium carbonate, stirred for 15 minutes. Then 13.5 mg of mono(2-amino-2-methylpropyl)sulfate were added, and the mixture was stirred at 80° C. for 29 hours. The volatile fractions were removed in vacuum at 40° C., and the residue was purified by column chromatography (silica gel, mobile phase: methylene chloride: methanol =95:5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=O)[C@@H:12]2[CH2:17][C@H:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:33][C:34]1[CH:38]=[C:37]([Br:39])[S:36][C:35]=1[C:40]([NH2:42])=[O:41]>O1CCCC1.O>[Br:39][C:37]1[S:36][C:35]2[C:40](=[O:41])[NH:42][C:14]([C@@H:13]3[C@@H:12]4[CH2:17][C@@H:9]([CH2:10][CH2:11]4)[N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:33][C:34]=2[CH:38]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1C(=O)O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To a solution (15 mL) of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (0.894 g) and triethylamine (0.541 mL) in tetrahydrofuran was added with stirring isobutyl chloroformate (0.487 mL) under ice-cooling. After stirring at room temperature for 30 min, a solution of 3-amino-5-bromothiophene-2-carboxamide (0.78 g) produced in Example 1, step D, in tetrahydrofuran (3 mL) was added. The reaction system was stirred with heating at 60° C. for 40 hr. Water was poured into the reaction system, and the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. 2M Aqueous sodium hydroxide solution (7.06 mL) and ethanol (14 mL) were added to the residue, and the mixture was stirred with heating at 70° C. for 5 hr. The reaction system was neutralized with 1M hydrochloric acid (4 mL) while stirring under ice-cooling. Insoluble material was removed by filtration. The mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.06 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][C:14]([NH:16][CH3:17])=O)[NH:8][CH:7]=[CH:6]2.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][NH:16][CH3:17])[NH:8][CH:7]=[CH:6]2
Reactant: CNC(=O)CC(c1ccccc1)c1cc2[nH]ccc2cc1OC
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccccc1)c1cc2[nH]ccc2cc1OC

Procedure:
[3-(5-Methoxy-1H-indol-6-yl)-3-phenyl-propyl]-methyl-amine CXXXVI was prepared from 3-(5-Methoxy-1H-indol-6-yl)-N-methyl-3-phenyl-propionamide using the procedure described above for [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=295.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH2:9].C(O[C:13]([SH:15])=[S:14])C.[K]>CN(C=O)C>[SH:15][C:13]1[S:14][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[N:9]=1
Reactant: Cc1ccc(Br)c(N)c1
Reactant: CCOC(=S)S
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ccc2sc(S)nc2c1

Procedure:
The title compound was prepared using the method of example 239, starting with 2-bromo-5-methyl-phenylamine (244) (4.48 g, 24.0 mmol), O-ethylxanthic acid, potassium salt (Lancaster, 8.70 g, 54 mmol) in DMF (35 mL). The mercaptobenzothiazole 245 was obtained as an pale brown solid (2.31 g, 53%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:39][CH:36]3[CH2:38][CH2:37]3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: BrCC1CC1
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(C)N(CC2CC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=554.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and cyclopropyl methyl bromide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[N:14][NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])#[N:2].[H-].[Na+].[C:30](Cl)(=[O:32])[CH3:31]>CCOCC>[C:30]([N:13]([C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[N:14]=[N:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])(=[O:32])[CH3:31]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N
Reaction time: 2 h

Procedure:
A solution of 5.6 g. (0.015 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene in 450 ml. of warm ether is added dropwise to a slurry of 1.20 g. (0.025 mol.) of 50% sodium hydride in 15 ml. of ether. Upon cessation of gas evolution, 1.42 g. (0.018 mol.) of acetyl chloride is gradually added and the reaction mixture is stirred for two hours at 25°. The mixture is filtered to remove excess sodium hydride and the filtrate is concentrated to give 3-acetyl-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene, m.p. 111°-112° (hexane).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N:11]3[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:9]=[CH:10][C:2]=2[OH:1])=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Reactant: O=C(O)c1cc(-n2cccc2)ccc1O
Product: CCOC(=O)c1sc(NC(=O)c2cc(-n3cccc3)ccc2O)nc1-c1ccccc1
Yield: 55 %

Procedure:
Using 2-hydroxy-5-(1-pyrrolyl)benzoic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195(3) gave the title compound.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=3[F:35])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.O>O1CCOCC1.ClCCl>[F:35][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:27]=1[C:17]1[O:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2])[C:11]=2[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3c(F)cccc3OC)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3c(F)cccc3OC)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 42 mg (0.09 mmol) 6-{[6-(2-fluoro-6-methoxyphenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 1.0 ml dioxan and add 0.26 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.26 ml 1 N hydrochloric acid and then 2 ml water and 5 ml dichloromethane. Separate the organic phase, dry over sodium sulphate, filter, and concentrate by evaporation. 39 mg (96% of theor.) of the target compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:20]([NH2:22])=O>CN(C=O)C.C(O)=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[NH:3][C:2]3[N:1]=[CH:20][N:22]=[C:7]([OH:8])[C:6]=3[CH:5]=2)=[CH:13][CH:14]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)[nH]c1N
Solvent: O=CO
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(O)ncnc3[nH]2)cc1

Procedure:
Under a protective gas, 611 mg (2.3 mmol) of 2-amino-3-ethoxycarbonyl-5-(4-methoxy-phenyl)-1H-pyrrole in 5 ml of formamide, 2.5 ml of DMF and 1.25 ml of formic acid are heated at 150° C. overnight. Working-up analogously to Step 8.2 yields the title compound; m.p.>300° C.; FAB-MS: (M+H)+ =242.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:22]=[O:23])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CON=C1CCc2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CON=C1CCc2cc(C=O)ccc21
Temperature: -60 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of the product of Step 1 (112 g, 0.46 mol) in THF (1500 ml) at −60° C. under argon, was added n-BuLi (325 ml, 0.52 mol) over 1 hour. After stirring at −60° C. for 1 hour a solution of DMF (39.7 ml) in THF (50 ml) was added dropwise over 1 hour. The reaction was stirred at −60° C. for 1 hour before being allowed to warm to room temperature. After 1 hour the reaction was quenched with saturated aqueous sodium hydrogen carbonate solution and extracted into ethyl acetate. The organic phase was then dried (Na2SO4), concentrated in vacuo and the residue purified by silica gel chromatography, to give the title compound (57 g, 65%) as a yellow solid; 1H NMR (CDCl3) 10.0 (1H, s), 7.83–7.73 (3H, m), 4.02 (3H, s), 3.10 (2H, m), 2.92 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].[N-:14]=[N+]=[N-].[Na+]>>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:13])[NH:14][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc2c1CCCC2=O
Agent: [Na+]
Product: COc1cccc2c1CCCC(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a solution of 5-methoxy-3,4-dihydronaphthalen-1(2H)-one (8.3 g, 47.15 mmol) in polyphosphoric acid (100 mL) was added sodium azide (3.6 g, 55.4 mmol) in small portions at 0° C. within 30 minutes. Then the mixture was slowly warmed to room temperature and stirred for another 16 hours, and then poured into ice-water. The precipitate was collected and dried to afford the product 6-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one as a white solid (6.8 g, yield 75.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.48 (s, 1H), 7.13-7.17 (t, 1H, J=8.0 Hz), 6.77-6.79 (d, 1H, J=7.6 Hz), 6.58-6.60 (d, 1H, J=7.6 Hz), 3.78 (s, 3H), 2.68-2.72 (t, 2H, J=6.8 Hz), 2.11-2.14 (t, 2H, J=7.2 Hz), 1.99-2.05 (m, 2H).
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=O)[N:16]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].S(O)(O)(=O)=O.[C:27]([NH:30][C:31]([NH2:33])=[O:32])(=[NH:29])[NH2:28]>CO>[NH:30]([C:27]1[N:29]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[N:16]=[C:15]([C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[OH:12])[N:28]=1)[C:31]([NH2:33])=[O:32]
Reactant: N=C(N)NC(N)=O
Reactant: O=c1nc(-c2ccc([N+](=O)[O-])cc2)oc2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Product: NC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)nc(-c2ccccc2O)n1

Procedure:
A solution of 8.9 g (385 millimoles) of sodium in 400 ml of methanol is added dropwise, while stirring, to a suspension of 93.9 g (350 millimoles) of 2-(4-nitrophenyl)-4H-1,3-benzoxazin-4-one and 58.1 g (192.5 millimoles) of guanyl urea sulfate in 1 liter of methanol. Subsequently, the mixture is refluxed for 30 minutes. After cooling of the mixture, the precipitate formed is suction-filtered, washed with water and methanol and dried at 70°C in a vacuum drying oven. The yield is 61.9 g (50.2 % of the theoretical yield). The 4-ureido-2-(2-hydroxyphenyl)-6-(4-nitrophenyl)-s-triazine obtained is a powder having a light yellow color and a melting point of 249°C (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[N:24]4[CH:19]([CH2:20][N:21](C([O-])=O)[CH2:22][CH2:23]4)[CH:18]4[C:28](=[O:33])[N:29]([CH3:32])[C:30](=[O:31])[CH:17]34)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[N:24]4[CH:19]([CH2:20][NH:21][CH2:22][CH2:23]4)[CH:18]4[C:28](=[O:33])[N:29]([CH3:32])[C:30](=[O:31])[CH:17]34)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1C(=O)C2C(C1=O)C1CN(C(=O)[O-])CCN1C2/C=C/c1ccc(-c2cccc(F)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C2C(C1=O)C1CNCCN1C2/C=C/c1ccc(-c2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg of tert-butyl (8-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-2-methyl-1,3-dioxodecahydro-2,5,7a-triazacyclopenta[a]indene-5-carboxylate (from Example 10) are dissolved in 9 ml of dichloromethane, and 3 ml of trifluoroacetic acid are added. The mixture is stirred at RT for 2 h, the solvent is then removed under reduced pressure and the crude product is purified by column chromatography (silica gel, MeOH:DCM).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.COC(OC)(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30]([C:2]4[CH:3]=[CH:4][C:5]5[NH:6][C:7]6[C:12]([C:13]=5[CH:14]=4)=[CH:11][CH:10]=[CH:9][CH:8]=6)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC(C)(O)OC
Solvent: Cc1ccccc1
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1
Yield: 80.8 %

Procedure:
2.5 g of (10 mmol) 3-bromo-9H-carbazole, 2.9 g of (10 mmol) N-phenylcarbazol-3-boronic acid, and 152 mg of (0.50 mmol) tri(ortho-tolyl)phosphine were put into a 200 mL three-neck flask. The air in the flask was replaced with nitrogen. To the mixture were added 50 mL of dimethoxyethanol and 10 mL of an aqueous solution of potassium carbonate (2 mol/L). This mixture was stirred to be degassed while the pressure was reduced. After the degassing, 50 mg (0.2 mmol) of palladium acetate was added to the mixture. This mixture was stirred at 80° C. for 3 hours under a stream of nitrogen. After the stirring, about 50 mL of toluene was added to this mixture. The mixture was stirred for about 30 minutes and then washed with water and a saturated saline solution in this order. After the washing, an organic layer was dried with magnesium sulfate. This mixture was subjected to gravity filtration. The obtained filtrate was condensed to give an oily substance. The obtained oily substance was dissolved in toluene. This solution was subjected to suction filtration through Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), alumina, and celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855). The obtained filtrate was concentrated to give 3.3 g of a white solid, which was the object of the synthesis, at a yield of 80%. A synthesis scheme of Step 1 is shown in (b-1) given below.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].O>C(Cl)Cl>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:29]
Reactant: Nc1ccccc1N1CCc2ccccc21
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1N1CCc2ccccc21)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture, under N2, of 9.86 g of 1-(2-aminophenyl)indoline hydrochloride and 100 ml of dry methylene chloride is treated with 8.09 g of triethylamine. The mixture is cooled to 0°-5° C., and a solution of 6.34 g of o-fluorobenzoyl chloride in 25 ml of CH2Cl2 is added over 1 hour at such a rate as to keep the temperature below 5° C. The mixture is then stirred overnight at ambient temperature. Water is added, the organic layer is separated, washed with 3 N--HCl, with 3 N--NaOH, with H2O, dried and concentrated to a crystalline solid of 1-[2-(2-fluorobenzamido)phenyl]indoline, m.p. 139°-141° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)[CH:12]=2)[C:7](=[O:24])[C:6]([C:25]([O:27]CC)=[O:26])=[CH:5]1.[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)[CH:12]=2)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]1
Reactant: CCOC(=O)c1cn(CCF)c2cc(/C=C/c3nc(C(C)C)cs3)ccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1csc(/C=C/c2ccc3c(=O)c(C(=O)O)cn(CCF)c3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
The ethyl 1-(2-fluoroethyl)-7-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate (254 mg, 0.613 mmol) obtained in (A) was dissolved in a mixed solution of methanol, tetrahydrofuran and water (1:1:1), added with 1 N aqueous sodium hydroxide (1.23 ml, 1.23 mmol), and then the mixture was stirred at room temperature for 8 hours. The reaction mixture was added with 1 N hydrochloric acid (1.23 ml, 1.23 mmol) to neutralize the system, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (174 mg, 73%) as yellow solid.
Reaction SMILES: C([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12]([C:19]#[N:20])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12]([C:19]#[N:20])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c2c1CCCC2
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(O)c2c1CCCC2

Procedure:
4-Benzyloxy-5,6,7,8-tetrahydro-1-naphthonitrile (0.6 g, 2.3 mM) was hydrogenated in ethanol (30 ml) in the presence of 10% palladium on charcoal catalyst (100 mg). After 2 hours the catalyst was filtered off and the filtrate was evaporated to give the phenol (6) a white solid (0.4 g) mpt 133°-134° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([OH:14])=O.Cl.[NH:16]1[CH2:27][CH2:26][CH2:25][C@H:17]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19].C1C2C(=CC=CC=2)CC1CCC(O)=O.Cl.N1CSC[C@H]1C(N1CCCC1)=O>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([N:16]1[CH2:27][CH2:26][CH2:25][C@H:17]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19])=[O:14]
Reactant: O=C(O)C[C@H]1CCc2ccccc2C1
Reactant: O=C([C@@H]1CCCN1)N1CCSC1
Agent: Cl
Agent: O=C(O)CCC1Cc2ccccc2C1
Agent: O=C([C@@H]1CSCN1)N1CCCC1
Product: O=C([C@@H]1CCCN1C(=O)C[C@H]1CCc2ccccc2C1)N1CCSC1
Yield: 63 %

Procedure:
A colorless oil of 3-{1-[(S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-prolyl}thiazolidine was prepared in the same manner as in Example 25, except that (S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and 3-L-prolylthiazolidine hydrochloride were used instead of 3-(indan-2-yl)propionic acid and 1-L-thioprolylpyrrolidine hydrochloride, respectively (yield: 63%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccccc3)s2)c(C)[nH]c1=O

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with benzyl amine as described in Step 5, Example 24 to give the title compound. MS: m/e 389 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[C:9](=[CH:19][N:20]([CH3:22])[CH3:21])[C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)CC(=O)c1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1)C(=O)C(C)(C)C
Yield: 65.5 %

Procedure:
17 g of 1-(4-chlorophenyl)-4,4-dimethyl-1,3-pentanedione and 18 g of dimethylformamide dimethylacetal were added to 200 ml of dry toluene, and the mixture was refluxed under heating for 2 hours, and then the methanol was distilled off over 1 hour. The solvent was distilled off, and the residue was purified by silica gel chromatography (developing solvent: chloroform/hexane=6/4) to obtain 13.7 g of the desired product as a pale yellow solid.