Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C(=O)([O-])[O-].[Ag+2]>[CH2:12]([O:11][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=[C:6]([CH3:10])[N:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(C)c(C#N)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-cyano-4,6-dimethyl-1H-pyridin-2-one (4.6 g) in dichloromethane (150 mL) were added benzyl bromide (5.6 mL) and silver carbonate (26 g), and the mixture was stirred under shading for 3 hours at 50° C. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=7/1) to give 2-benzyloxy-3-cyano-4,6-dimethylpyridine (7.1 g). To diisobutylaluminum hydride (1.5 mol/L solution in toluene, 8.7 mL) was added a solution of 2-benzyloxy-3-cyano-4,6-dimethylpyridine (2.4 g) in tetrahydrofuran (4.3 mL) at 0° C., and the mixture was stirred for 4 hours at 0° C. The reaction mixture was poured into 1 mol/L hydrochloric acid solution (40 mL), and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=50/1-20/1-10/1) to give 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.90 g). To a solution of 4-ethylbromobenzene (0.044 g) in tetrahydrofuran (1.2 mL) was added tert-butyllithium (1.5 mol/L solution in hexane, 0.17 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. A solution of 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.048 g) in tetrahydrofuran (1.3 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes for 0° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethylether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=5/1) to give 2-benzyloxy-4,6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.066 g). To a solution of the obtained 2-benzyloxy-4,6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.061 g) in ethanol (3.5 mL) was added 10% palladium carbon powder (0.037 g), and the mixture was stirred for 12 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloro-methane/methanol=10/1) to give 3-(4-ethylbenzyl)-4,6-dimethyl-1H-pyridin-2-one (0.039 g).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH2:9]O)[CH:6]=[CH:7][CH:8]=1.[CH3:12][C:13]1([CH3:25])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)[O:14]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][N:23]2[CH:24]=[C:20]([B:15]3[O:14][C:13]([CH3:25])([CH3:12])[C:17]([CH3:19])([CH3:18])[O:16]3)[CH:21]=[N:22]2)[CH:4]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN(C)c1cccc(CO)c1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CN(C)c1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Reaction time: 8 h

Procedure:
To a solution of (3-(dimethylamino)phenyl)methanol (0.100 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.167 g) and cyanomethylenetributylphosphorane (0.208 g) were added and stirred together in toluene (1 mL) at room temperature. After stirring overnight the reaction was loaded directly onto silica gel and eluted using a gradient of 5% to 35% ethyl acetate/hexanes to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].C(Cl)Cl>C(O)C.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9])[NH2:10]
Reactant: CCc1ccc([N+](=O)[O-])cc1Br
Agent: [Ni]
Solvent: CCO
Solvent: ClCCl
Product: CCc1ccc(N)cc1Br

Procedure:
Hydrogenation of 4.45 g (19 mmol) of 3-bromo-4-ethyl-nitrobenzene (for preparation see Macromolecules 1995, 28, 5618) in 100 ml of ethanol in the presence of 1 g of Raney nickel, followed by filtration, concentration by evaporation and chromatography (SiO2; methylenechloride), yields 3-bromo-4-ethyl-aniline; 1H NMR (CDCl3) δ 6.94 (d, 1H), 6.82 (s, 1H), 6.50 (d, 1H), 3.50 (s, H2N), 2.57 (q, 2H), 1.10 (t, 3H).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([CH:28]2[NH:27][C@H:26]([C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([O:16][C:15]4[CH:39]=[CH:40][C:12]([F:11])=[CH:13][CH:14]=4)=[CH:22][CH:21]=3)=[O:25])[CH2:30][C@H:29]2[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: Cc1ccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)cc1
Agent: Cl
Product: Cc1ccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)NC2C(=O)Cn2cncn2)cc1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide, gave Compound 4, (2S,4R)-5-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): σ 9.02 (br s, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.40 (m, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 7.03-6.98 (m, 2H), 6.94-6.87 (m, 4H), 4.98 (dd, 2H), 4.78 (d, 1H), 3.62 (m, 1H), 3.23 (t, 1H), 3.02-2.87 (m, 2H), 2.65-2.60 (m, 2H), 2.34 (s, 3H), 1.74-1.66 (m, 1H); MS (EI) for C29H28FN5O3. found 514.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=1)=[C:10]=[O:11]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:11])[NH:9][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: Nc1ccccc1F
Reactant: COC(=O)Cc1ccc(N=C=O)cc1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2F)cc1

Procedure:
4-(2-Fluorophenyl)ureidophenylacetic acid was prepared using procedure C with 2-fluoroaniline and KCl: 1H NMR (CD3SOCD3, 300 MHz, ppm) 9.00 (s, 1H), 8.51 (d, 2.4 Hz, 1H), 8.14 (dd, 8.3 Hz, 1.5 Hz, 1H), 7.37 (d, 8.5 Hz, 2H), 7.07-7.25 (m, 4H), 6.99 (m, 1H), 3.48 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:4].[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:34].C(S(O)(=O)=O)(F)(F)F>ClCCl>[F:16][C:2]([F:1])([F:15])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[I:34])=[O:4]
Reactant: O=C(NCCc1ccc(Cl)cc1)C(F)(F)F
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCc1ccc(Cl)cc1I)C(F)(F)F
Reaction time: 8 h
Yield: 38.9 %

Procedure:
A solution of N-trifluoroacetyl-4-chlorophenethylamine (1.6 g, 6.4 mmol) in dichloromethane (20 mL) was treated with bis(pyridine)iodonium(I)tetrafluoroborate (2.6 g, 7.0 mmol), CF3SO3H (2.1 g, 14.1 mmol) and stirred overnight at 20 C. The product mixture was concentrated, dissolved in EtOAc (100 mL), washed twice with 5% aqueous sodium bisulfite (50 mL), twice with saturated aqueous NaHCO3, (50 mL) once to with brine (50 mL), dried with Na2SO4 and concentrated to give 0.94 g of a clear oil. MS calculated for C10H8ClF3INO+H: 378, observed: 378.
Reaction SMILES: [Na].[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][OH:7])[CH3:3].[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][O:7][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:24][CH2:23]1)=[O:26])[CH3:3]
Reactant: O=C(NC1CCN(C(=O)Cl)CC1)c1ccccc1
Reactant: CCN(CC)CCO
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CCOC(=O)N1CCC(NC(=O)c2ccccc2)CC1
Yield: 59.8 %

Procedure:
Sodium (0.432 g., 0.0188 mole) was added to β-diethylaminoethanol (2.23 g., 0.0190 mole) in dry toluene (80 ml) and the mixture was refluxed to give a complete solution. 4-Benzamidopiperidine-1-carbonyl chloride (4.2 g., 0.01575 mole) in suspension in dry toluene (150 ml.) was added in portions and the mixture refluxed for 21/2 hours. Water was added to the mixture, the toluene layer was collected, dried and evaporated to give the title compound (3.27 g. 37%), melting point 78°-82° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8](CC)=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].Br[C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:39]=2[NH:38][CH:37]=[CH:36]3)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: Brc1cccc2cc[nH]c12
Reactant: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(CC)n1C
Product: CCOC(=O)c1c(-c2ccc(-c3cccc4cc[nH]c34)cc2)c(C#N)cn1C

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-222 using 4-cyano-5-ethyl-1-methyl-3-(4-trifluoromethanesulfonyloxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-97a or 97b) and 7-bromo-indole. Purify the material by silica gel chromatography eluting with hexanes/ethyl acetate 4:1 to provide the title compound as a white solid. Mass spectrum (m/e): 398.25 (M*+1).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH:12](I)([CH3:14])[CH3:13].[OH:16][C:17]1[C:26]([OH:27])=[C:25]2[C:20]([C:21](=[O:30])[CH2:22][C:23]([CH3:29])([CH3:28])[O:24]2)=[CH:19][CH:18]=1>COCCOCCOC>[CH:12]([O:16][C:17]1[C:26]([OH:27])=[C:25]2[C:20]([C:21](=[O:30])[CH2:22][C:23]([CH3:28])([CH3:29])[O:24]2)=[CH:19][CH:18]=1)([CH3:14])[CH3:13]
Reactant: CC1(C)CC(=O)c2ccc(O)c(O)c2O1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COCCOCCOC
Product: CC(C)Oc1ccc2c(c1O)OC(C)(C)CC2=O
Temperature: 140 °C
Yield: 90 %

Procedure:
In 50 ml of N,N-dimethyl formamide 4.2 g (20 millimoles) of 7.8-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 5 ml of diethylene glycol dimethylether, 3.0 g (22 millimoles) of potassium carbonate and 4.2 g (2.5 ml, 25 millimoles) of isopropyl iodide are added. The reaction mixture is heated at 140° C. for 4 hours and worked up according to Example 19. Thus 4.5 g of the desired compound are obtained, yield 90%, mp.: 114°-116° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][C@@H:4]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:18][C:19]([F:40])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:40][C:19]([F:18])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[C:10]2/[C:6]([NH:5][C@H:4]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:3][N:2]([CH3:17])[CH3:1])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:25][CH2:24]1
Reactant: CN(C)C[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
To a solution of 3-(dimethylamino)-N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-alaninamide (775 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) in 2-propanol (10 mL) was added piperidinium acetate (436 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (593 mg)
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:40])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([O:24][CH2:25][C:26]([N:28]2[CH2:32][CH2:31][CH2:30][C@@H:29]2[C:33]([O:35]C(C)(C)C)=[O:34])=[O:27])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:33]([C@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26](=[O:27])[CH2:25][O:24][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]#[N:23])[CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:40])([OH:35])=[O:34]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cc(C#N)cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h
Yield: 125.7 %

Procedure:
A solution of 280 mg (0.5 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-cyano-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml trifluoroacetic acid was stirred for 18 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 280 mg (72%) of the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@@H:15]1[CH2:20][C@@H:19]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:18]([CH2:32][C:33]#[N:34])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[C:33]([CH2:32][C@H:18]1[CH2:17][CH2:16][C@H:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:20][C@H:19]1[NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:34]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N#CC[C@H]1CC[C@H](N)C[C@H]1NC(=O)OCc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)C[C@H]1NC(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (22.0 mg, 0.102 mmol), benzyl [(1R,2R,5S)-5-amino-2-(cyanomethyl)cyclohexyl]carbamate (32 mg, 0.11 mmol) and triethylamine (35.7 μL, 0.256 mmol) in isopropyl alcohol (0.4 mL) was stirred at 90° C. for 2 h. The mixture was cooled and purified on silica gel, eluted with 10-90% EtOAc in hexanes to give 28 mg (59%) of the desired product. LCMS calculated for C23H24N5O4S (M+H)+: m/z=466.2. Found: 466.1.
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[C:12]([CH2:17]O)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:21])=O>>[CH:1]1([C:7]2[C:16]3[C:11](=[C:12]([CH2:17][Cl:21])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCc1cccc2c(C3CCCCC3)nccc12
Product: ClCc1cccc2c(C3CCCCC3)nccc12

Procedure:
1-Cyclohexyl-5-hydroxymethylisoquinoline and phosphorus oxychloride were reacted in the same way as in step (g) of Example 13 to afford 1-cyclohexyl-5-chloromethylisoquinoline having a melting point of 88.4° to 89.4° C.
Reaction SMILES: [NH2:1]CC(O)=O.[CH3:6][O:7][C:8](=[O:20])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH3:19])[CH:12]=1.N([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[CH2:17]([C:13]1[CH:12]=[C:11]([N:10]([CH2:9][C:8]([O:7][CH3:6])=[O:20])[NH2:1])[CH:16]=[CH:15][CH:14]=1)[CH2:18][CH3:19]
Reactant: NCC(=O)O
Reactant: CCCc1cccc(NCC(=O)OC)c1
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCCc1cccc(N(N)CC(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Glycine (Intermediate 32, 10 g, 48 mmol) was dissolved in acetic acid (50 ml) and water (5 ml). The solution was cooled to 0° C. and sodium nitrite (3.67 g, 53 mmol) in water (10 ml) was added such that the temperature did not rise above 5° C. The yellow solution turned red then brown, and was stirred at 0° C. for 1 h. The mixture was cooled to -5° C. and zinc powder (12.6 g, 193 mmol) was added very slowly such that the temperature did not rise above 0° C. The mixture was stirred at 0° C. for 5 h then poured into water (400 ml) and extracted with ethyl acetate (3×150 ml). The combined, dried (Na2SO4) organic extracts were concentrated in vacuo to give a dark yellow oil. The crude material was purified by chromatography on silica (500 g) eluted with chloroform-ethanol 98:2 to give the title compound (Intermediate 33, 1.4 g, 13%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ClC(OCC(C)C)=O.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:25]=1[CH2:26][NH2:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:27][CH2:26][C:25]1[C:28]([O:32][CH3:33])=[CH:29][CH:30]=[CH:31][C:24]=1[O:23][CH3:22])=[O:9]
Reactant: COc1cccc(OC)c1CN
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(OC)c1CNC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
5-Chloro-2-nitrobenzoic acid (25.0 g, 201.6 mmol) was placed in 250 mL dichloromethane and stirred for 5 minutes. After 17.0 mL triethylamine had been added at 25° C., the yellow suspension dissolved gradually. After storing for 10 minutes, the mixture was cooled to 5° C. Isobutyl chloroformate (16.25 mL, 122.8 mmol) was added by drops without dilution within 15 minutes. The reaction mixture was allowed to reach room temperature while stirring and stirring was continued for 1.5 hours. A light yellow precipitate was formed. The mixture was again cooled to 5° C. and 2,6-dimethoxybenzylamine (20.5 g, 122.8 mmol) was added by portions over a period of 20 minutes. For dilution, another 250 mL dichloromethane was added and the mixture was stirred for 15 minutes at 5° C. and then for 65 hours at room temperature. The reaction was monitored by thin layer chromatography, revealing traces of the starting materials. The batch was mixed with 5% citric acid, whereupon a precipitate formed and was filtered out. Product was still detected in the organic phase, so the organic phase was extracted again with 5% citric acid (1×), washed until neutral with sodium bicarbonate solution (1×) and extracted with sodium chloride solution. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo. The solid yellow residue was suspended in diethyl ether/pentane as solvents, then filtered out and washed with diethyl ether. The two crystal products were combined and a pure 5-chloro-N-(2,6-dimethoxybenzyl)-2-nitrobenzamide was isolated. Yield: 31.3 g (89.2 mmol, 73%).
Reaction SMILES: CO.[F:3][C:4]1[CH:36]=[CH:35][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[C:25]([C:27]([O:29]C)=[O:28])[N:26]=4)=[CH:18][C:17]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:14])=[O:13])=[C:10]([CH3:11])[C:6]=2[CH:5]=1.[OH-].[Na+]>O>[F:3][C:4]1[CH:36]=[CH:35][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=4)=[CH:18][C:17]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:13])=[O:14])=[C:10]([CH3:11])[C:6]=2[CH:5]=1
Reactant: COC(=O)c1coc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(C(=O)O)co3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
Into 150 mL of methanol was dissolved 7.85 g of Compound 23, and 15 mL of 10% aqueous sodium hydroxide solution and 15 mL of water were added thereto at room temperature, followed by 15 minutes of stirring. The precipitated crystals were dissolved by adding 90 mL of water, and the solution was stirred at the same temperature for 17 hours. After the solvent was removed by evaporation, 45 mL of 1 mol/L hydrochloric acid was added to the residue, the precipitated crystals were collected by filtration and washed with water, and 100 mL of DMF was added to the resulting crude crystals, followed by heating under refluxing. After filtration at a hot state, 70 mL of ethanol was added and recrystallization was carried out. The resulting crystals were collected by filtration, washed several times with ethanol and water alternatively, and dried over diphosphorus pentoxide under reduced pressure to obtain 5.78 g of the title compound as colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[CH:29][CH:28]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=4)=[S:35])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccc(Br)cc5)c4c(c23)C1=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of acetonitrile. 128 μl (2 molar equivalents) of 4-bromophenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 147 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=90%) which was characterized as follows:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5]=2[N:4]=[C:3]1/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl[S:28]([OH:31])(=[O:30])=[O:29]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5]=2[N:4]=[C:3]1/[CH:19]=[CH:20]/[C:21]1[CH:22]=[CH:23][C:24]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:25][CH:26]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccccc3)n2C)n(CCC)c1=O
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(S(=O)(=O)O)cc3)n2C)n(CCC)c1=O
Temperature: 0 °C
Yield: 39.1 %

Procedure:
(E)-7-Methyl-1,3-dipropyl-8-styrylxanthine (WO92/06976) (500 mg, 1.42 mmol) was dissolved in chloroform (5 ml), and chlorosulfonic acid (0.28 ml, 4.26 mmol) was added dropwise thereto at 0° C. The resulting solution was heated under reflux for 3 hours and then poured into 20 ml of ice-water. The chloroform layer was separated and the aqueous layer was extracted 5 times with tetrahydrofuran. The combined organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 240 mg (yield 39%) of Compound 31 as a pale yellow powder.