Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9]C=2OC)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH:17]1(NN)CCCC1.COC(=C(C#N)C#N)C>>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:15]#[N:16]
Reactant: COc1ccccc1-n1ncc(C#N)c1N
Reactant: NNC1CCCC1
Agent: COC(C)=C(C#N)C#N
Product: Cc1nn(C2CCCC2)c(N)c1C#N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile but substituting 1-cyclopentylhydrazine and 2-(1-methoxyethylidene)malononitrile provided the title compound. 1H NMR (300 MHz, CDCl3): δ 4.24 (m, 3H), 2.24 (s, 3H), 2.01 (m, 4H), 1.90 (m, 2H), 1.67 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][C:7](=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)[CH3:3].[BH4-].[Na+]>CO>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: CC(C)N1CCC(=Nc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CCC(Nc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a stirred and warmed (30°-40° C.) solution of 72 parts of N-[1-(1-methylethyl)-4-piperidinylidene]benzeneamine in 480 parts of methanol are added portionwise 20 parts of sodium borohydride. Upon completion, stirring is continued overnight at at room temperature. The reaction mixture is evaporated and the residue is dissolved in water. The solution is extracted with 4-methyl-2-pentanone. The extract is washed with water and acidified with a diluted hydrochloric acid solution. The aqueous acid phase is alkalized with a diluted sodium hydroxide solution till pH 9 and the product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The residue is distilled (bp. 135°-140° C. at 0.2 mm. pressure) and the distillate is crystallized from petroleumether, yielding 21 parts of 1-(1-methylethyl)-N-phenyl-4-piperidinamine; mp. 69.3° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([NH:17]C=O)[CH:7]=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[O:25].[C:26](=[O:29])([O-])[O-].[K+].[K+].[CH3:32]I>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([NH:17][CH2:32][CH:26]=[O:29])[CH:7]=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[O:25]
Reactant: CI
Reactant: CCOC(=O)c1cn(NC=O)c2cc(-n3cccc3)c(F)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(NCC=O)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 35 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture of 3.47 g (0.01 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-1-formylamino-4-oxo-1,4-dihydroquinoline-3-carboxylate and 3 g (~0.02 mol) of potassium carbonate in 25 ml of dimethylformamide is heated for 10 minutes at 35° C. It is kept at room temperature for 2 hours in a partially precipitated state, 4.3 g (0.03 mol) of methyl iodide are added to this suspension and the mixture is kept at room temperature for 3 hours. It is poured into a water/ice mixture, the precipitate formed is filtered off, washed with water and extracted with chloroform, the mixture is filtered, the solution is evaporated and the residue is recrystallized from an ethanol/water mixture (1:1) to give 1.43 g of a solid melting at 194°-198° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:6](=[N:8]NC(OC)=O)[CH3:7])[CH3:2].[S-:23][C:24]#N.[K+]>Cl>[F:21][C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:22])=[C:6]([CH3:7])[N:8]=[C:24]2[SH:23])=[CH:20][CH:19]=1
Reactant: N#C[S-]
Reactant: CCOC(=O)C(Nc1ccc(F)cc1)C(C)=NNC(=O)OC
Agent: Cl
Agent: [K+]
Product: CCOC(=O)c1c(C)nc(S)n1-c1ccc(F)cc1
Temperature: 70 °C

Procedure:
To a suspension of methyl 2-(4-ethoxy-3-((4-fluorophenyl)amino)-4-oxobutan-2-ylidene)hydrazinecarboxylate (3.1 g, 10 mmol) (this material was synthesized according to the protocol described in J. Org. Chem. Soc. 1978, 43, 3392) in 4N HCl (100 mL) was added potassium thiocyanate (1.5 g, 15 mmol) and the mixture was heated to 70° C. for 2 hours. After cooling to room temperature, the solid was filtered and dried to afford ethyl 1-(4-fluorophenyl)-2-mercapto-4-methyl-1H-imidazole-5-carboxylate (57).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17](=[N:20][S:21]([CH3:24])(=[O:23])=[O:22])SC)[N:11]=1.[CH3:28][NH2:29]>>[F:27][C:2]([F:1])([F:26])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17]([NH:29][CH3:28])=[N:20][S:21]([CH3:24])(=[O:22])=[O:23])[N:11]=1
Reactant: CN
Reactant: CSC(=NS(C)(=O)=O)NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Product: CNC(=NS(C)(=O)=O)NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 64 h

Procedure:
2-[2-(2,2,2-Trifluoroethyl)guanidino]-4-[2-(3-methylsulphonyl-2-methylisothioureido)ethylthiomethyl]thiazole (0.4 g.) was dissolved in ethanolic methylamine (33% w/v 15 ml.) and allowed to stand at room temperature for 64 hours. The solvent was evaporated and the residual gum was purified by preparative thin layer chromatography using chloroform/methanol/ammonia 8:2:0.2 v/v/v as developing solvent. The appropriate zone of the chromatogram was isolated and extracted with methanol/ammonia 10:1 v/v (50 ml.). The solvent was evaporated and the residual gum was dissolved in acetonitrile, filtered and the filtrate evaporated. The residual gum was dissolved in methanol and treated with a solution of excess fumaric acid in methanol. The solvent was evaporated and the residue triturated with acetonitrile to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[2-(2-methylsulphonyl-3-methylguanidino)ethylthiomethyl]thiazole as a cream solid (0.29 g.), m.p. 118°-123° (decomp.), containing 1.5 molar equivalents of fumaric acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7]C(=O)C)[CH2:3][CH2:2]1.[OH-].[K+].Br[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCO>[CH2:18]([O:17][C:15](=[O:16])[C:14]([CH3:21])([S:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH3:20])[CH3:19]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(=O)SC1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC1CCOCC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
A solution of 153 g (0.96 mol) of thioacetic acid S-(tetrahydro-pyran-4-yl) ester in EtOH (3.5 L) is degassed with nitrogen over 0.5 h and 125 g (2.23 mol) of KOH are added. Then a solution of 250 mL (1.68 mol) of ethyl α-bromoisobutyrate in EtOH (1 L) are added over 0.5 h, during which the temperature increased to 40° C. The reaction is stirred for 18 h at RT under a nitrogen atmosphere. The reaction mixture is filtered, the solid is washed with EtOH (0.5 L) and the filtrate is concentrated under reduced pressure. The crude material is dryloaded onto silica and purified by dry-flash column chromatography (silica, eluent: nheptanes, 2-10% EE) to afford 158 g of 2-methyl-2-(tetrahydro-pyran-4-ylsulfanyl)-propionic acid ethyl ester. Yield: 71%; ESI-MS: 233 [M+H]+
Reaction SMILES: [OH:1][CH:2]([CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[CH2:3][O:4][C:5]1[C:10]2[C:11]([CH3:17])=[C:12]([C:14]([OH:16])=O)[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl.[CH2:24]([NH2:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(N(CC)CC)C>[CH2:24]([NH:26][C:14]([C:12]1[O:13][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[C:10]=2[C:11]=1[CH3:17])=[O:16])[CH3:25]
Reactant: CCN
Reactant: Cc1c(C(=O)O)oc2cccc(OCC(O)CNC(C)C)c12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCNC(=O)c1oc2cccc(OCC(O)CNC(C)C)c2c1C
Yield: 36.8 %

Procedure:
A solution of 4-(2-hydroxy-3-isopropylamino-propoxy)-3-methyl-benzofuran-2-carboxylic acid (5 mg), ethylamine hydrochloride (42 mg), water-soluble carbodiimide hydrochloride (10 mg), 1-hydroxybenzotriazole (8 mg) and triethylamine (100 μl) in DMF (1 ml) was stirred at room temperature for five hours. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by preparative thin layer chromatography (using dichloromethane:MeOH:H2O=65:30:5 as a developing solvent) to give 4-(2-hydroxy-3-isopropylamino-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethylamide (2 mg) as a white powder. MALDI-TOF-MS: m/z 335 (MH+); 1H-NMR (CDCl3): δ 1.27 (3H, t, J=7 Hz), 1.34 (6H, d, J=6 Hz), 2.72 (3H, s), 3.13 (1H, dd, J1=12 Hz, J2=9 Hz), 3.32 (2H, m), 3.49 (2H, dq, J1=7 Hz, J2=6 Hz), 4.05 (1H, dd, J1=10 Hz, J2=6 Hz), 4.15 (1H, dd, J1=10 Hz, J2=5 Hz), 4.53 (1H, br s), 6.55 (1H, d, J=8 Hz), 6.56 (1H, m), 7.00 (1H, d, J=8 Hz), 7.22 (1H, t, J=8 Hz).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].C(N(CC)CC)C.[CH2:21]([O:23][P:24]([O-:28])[O:25][CH2:26][CH3:27])[CH3:22]>O1CCCC1>[CH2:21]([O:23][P:24]([CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Br:1])[OH:13])(=[O:28])[O:25][CH2:26][CH3:27])[CH3:22]
Reactant: O=Cc1ccc2ccccc2c1Br
Reactant: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(O)c1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 250.6 %

Procedure:
To a solution of 1-bromo-2-naphthaldehyde (0.740 g, 0.001 mole) in tetrahydrofuran (10 mL) was added triethylamine (0.150 mL, 0.001 mole) followed by diethylphosphite (0.330 mL, 0.002 mole). The reaction mixture was then stirred at room temperature under nitrogen gas for 18 hours. The volatiles then evaporated in vacuo and further dried under vacuum. The resulting solid was triturated with ether and the solid that separated out was collected and dried under vacuum to get 0.935 g of [(1-bromonaphthalene-2-yl)-hydroxymethyl]phosphonic acid diethyl ester B. This material was added to 40 mL of acetone. 20 eq. of manganese dioxide (4.31 g, 0.05 moles) was added and the mixture was stirred at room temperature for one hour. Another 20 eq. of manganese dioxide was added to it and it was stirred for another one hour. The solid manganese dioxide was filtered off on a Celite® pad and washed with hot acetone. Combined filtrates were evaporated to afford 0.6 g of crude (1-bromo-naphthalene-2-carbony)phosphonic acid diethyl ester. Flash chromatography on silica gel using 0-5% ethyl acetate/dichloromethane followed by drying of the product under high vacuum afforded 0.260 g of intermediate. C. To a solution of diethyl (1-bromonaphthalene-2-carbony)phosphonate ester in dichloromethane (2 mL) was added (diethylamino)sulfur trifluoride (1.3 mL, 0.01 mole) at 0° C. and it was allowed to come to room temperature then stirred for another 4 hours. The reaction mixture then was diluted with dichloromethane (50 mL) and washed with cold saturated aqueous sodium bicarbonate (NaHCO3, 25 mL), then dried over magnesium sulfate (MgSO4). Filtration and solvent evaporation provided 0.260 g of product. Flash chromatography on silica gel using 0-5% EtOAc/dichloromethane followed by drying of the product under high vacuum afforded 0.120 g of diethyl [(1-bromo-naphthalene-2-yl)difluoromethylphosphonate ester. Compound 80 was prepared from this corresponding diethyl ester using procedures similar to those of Example 40. 1H NMR: (DMSO-d6, 400 MHz) δ 8.52 (d, 1H, J=8.4 Hz) 8.11 (m, 2H), 7.79 (m, 3H). MS (ion spray): m/z 337.00 (M+H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[C:9]([C:20]#[N:21])[CH:8]=2)=[N:3][CH:2]=1.O.S(=O)(=O)(O)[OH:24].N>C(O)(C(F)(F)F)=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[C:9]([C:20]([NH2:21])=[O:24])[CH:8]=2)=[N:3][CH:2]=1
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccncn2)cc1C#N
Reactant: O=S(=O)(O)O
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccncn2)cc1C(N)=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
To a solution of 5-(pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carbonitrile (85 mg, 0.28 mmol) in TFA (1.0 mL) were sequentially added water (0.15 mL) and 98% sulfuric acid (0.30 mL) under efficient stirring. The mixture was allowed to stir for 5 h at 70° C. and then was diluted by drop wise addition of water (1 mL). The reaction mixture was made basic (pH 10-12) by adding 30% aqueous ammonia (3 mL) under stirring. The precipitated solid was collected by filtration, washed with water and finally dried in a vacuum oven at 50° C. affording the title compound (72 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]2[NH:15][CH2:14][CH2:13][N:10]=2)[CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCC(C#N)c1ccc(F)cc1
Reactant: NCCN
Product: CCC(C1=NCCN1)c1ccc(F)cc1

Procedure:
rac-2-[1-(4-Fluoro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(4-fluoro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 207.0 ((M+H)+.).
Reaction SMILES: [C:1]([CH:18]([OH:46])[C@H:19]([C@H:21]([C@@H:23]([C@@H:25]([CH:27]([C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[OH:28])[OH:26])[OH:24])[OH:22])[OH:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[CH:48]=[C:49](Cl)Cl>N1C=CC=CC=1>[C:1]([CH:18]([OH:46])[C@:19]([C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:48][CH3:49])([C@H:21]([C@@H:23]([C@@:25]([C:19](=[O:20])[CH2:21][CH2:23][CH2:25][CH2:27][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([CH:27]([C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[OH:28])[OH:26])[OH:24])[OH:22])[OH:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)C(=O)CCCCCCCCCCCCCCC
Reactant: ClC=C(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[C@@](O)(C(O)C(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](O)[C@@](O)(C(=O)CCCCCCC/C=C\CCCCCCCC)C(O)C(=O)CCCCCCCCCCCCCCC
Temperature: -18 °C
Reaction time: 4 h

Procedure:
3.3 g of 1,6-dipalmitoyl-D-mannitol and 0.53 of benzene boronic acid anhydride was added to a solution containing 20 ml of pyridine and 20 ml of trichloroethylene, and the mixture was dried with 5 g of molecular sieves. The mixture was cooled at -18° C. and 3.3 g of oleoyl chloride, dissolved in 10 ml of trichloroethylene, was added. The mixture was left standing over night at -18° C. and for four hours at room temperature. The reaction mixture was washed with 120 ml of 2 N hydrochloric acid and with water, and fractionated in a column containing 160 g of Sephadex LH 20 and eluting with a 1:1-mixture of chloroform and ethanol (90%), whereby the boronic acid protection was removed.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)([O-])=O>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccc(Cl)cc2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(Cl)cc2C1=O
Reaction time: 8 h

Procedure:
The solution of 416 g of N-(4-nitro-o-tolyl)-4-chlorophthalimide in 28 lt. of hot ethyl acetate is cooled slightly and transferred under nitrogen to 250 ml (or 460 g) of a suspension of Raney nickel, which has been washed 4 times with anhydrous ethanol and 1 time with ethyl acetate, and 12 lt of ethyl acetate are used for the rinse. The mixture is hydrogenated at 3.4 atm. and 30° for approximately 8 hours, and continued for 2 hours after the hydrogen uptake has ceased. It is filtered, the residue rinsed with 15 lt. of ethyl acetate and the filtrate concentrated to about 14 lt. It is cooled, filtered, and the filtrate reduced to approximately 11/2 lt to yield 2 crops of N-(4-amino-o-tolyl)-4-chlorophthalimide melting at 205°-207°; it is identical (but somewhat purer) than that obtained according to Example 4.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.[CH2:13]([O:15][C:16](=[O:23])[CH2:17][CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:23])[CH2:17][CH:18]([NH:22][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH2:19][CH2:20][CH3:21])[CH3:14]
Reactant: CCCC(N)CC(=O)OCC
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)Nc1cc(C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.2 %

Procedure:
To a solution of 3-Fluoro-4-nitrotoluene (1.0 g, 6.5 mmol) in DMF (5 mL) were: 3-Amino-hexanoic acid ethyl ester hydrochloride (1.3 g, 6.7 mmol) and DIPEA (2.2 mL, 12.9 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated. The resulting residue was purified by Combiflash using hexane and ethyl acetate (10% gradient) as an eluent to afford 1.4 g of the desired product as orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: COc1ccccc1C(=O)Cl
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: COc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 45.7 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (100 mg, 0.315 mmol) obtained in Example 1, (3), and 2-methoxybenzoyl chloride (63 μL, 0.473 mmol), the title compound (65 mg, yield 46%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[S:28]([O:13][CH2:12][CH2:11][CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:30])(=[O:29])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC(CCCO)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CCCOS(C)(=O)=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanol (133 mg, 0.5 mmol) in dichloromethane (8 mL) was added triethylamine (0.140 mL, 1.0 mmol), followed by methanesulfonylchloride (0.057 mL, 0.75 mmol). The solution was then stirred at 0° C. for 15 minutes before being quenched with an aqueous ammonium chloride solution (2 mL). The aqueous and organic layers were then separated, the aqueous layer extracted twice with dichloromethane, and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanol mesylate as a yellow oil, which was used immediately in the next reaction without further purification. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.67-2.00 (m, 4H), 2.95 (s, 3H), 4.18 (t, 2H, J=7.1 Hz), 4.20 (m, 1H), 4.92 (br s, 1H (NH)), 7.21-7.33 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH2:16]([N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][NH2:24])[CH3:17].C1C(=O)N(OP(OC2C=CC=CC=2)(OC2C=CC=CC=2)=O)C(=O)C1.C(N(CC)CC)C>C(#N)C>[CH3:17][CH2:16][N:18]1[CH:19]([CH2:23][NH:24][C:5]([C:4]2[CH:8]=[C:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[O:7])[CH2:20][CH2:21][CH2:22]1
Reactant: CCn1cccc1CN
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Agent: O=C1CCC(=O)N1OP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
A solution of 462 mg (0.002 mol) of 2-methoxy-5-aminosulfonylbenzoic acid and 256 mg (0.002 mol) of N-ethyl-2-aminomethylpyrrole in 10 ml of acetonitrile was admixed with 694 mg (0.002 mol) of SDPP and 202 mg (0.002 mol) of triethylamine, and the admixture was stirred overnight at room temperature. The crystalline material deposited was collected by filtration and washed with acetonitrile and then with ethanol to give sulpiride, that is, 5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl) methyl]-2-methoxybenzamide. mp. 182°~185° C. Yield 24%.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]=2[CH:14]=1
Reactant: c1ccc(C2=NCCNc3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)C(c1ccccc1)=NCCN2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A round-bottomed flask was charged with 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (1.0 g) and tetrahydrofuran. The mixture was treated with N-bromosuccinimide (1.1 equiv.) then stirred at room temperature for 15 min. The reaction was then treated with an excess of sodium sulfite and the mixture was concentrated to dryness. The residue was dissolved in water and then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered and concentrated to an oil. Solids were induced from a methylene chloride/diethyl ether mixture and collected on filter. The solids were washed with diethyl ether then air-dried to provide 7-bromo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (0.60 g). H1 NMR (d6-dmso): 7.38-7.44 (m, 5H), 7.26 (dd, 1H), 6.86 (d, 1H), 6.75 (d, 1H), 6.41 (br t, 1H), 3.89 (m, 2H), 3.55 (m, 2H).