Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[C:6]([CH:9]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[C:10](=O)[CH3:11])(=O)[CH3:7].O>C(O)(=O)C>[OH:1][CH2:2][CH2:3][N:4]1[C:10]([CH3:11])=[C:9]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=2)[C:6]([CH3:7])=[N:5]1
Reactant: CC(=O)C(Oc1ccc(C#N)cc1)C(C)=O
Reactant: NNCCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(CCO)c(C)c1Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
A mixture of commercially available 3-chloro-2,4-pentanedione (1.2 ml, 10 mmol), 4-cyanophenol (1.19 g, 10 mmol), caesium carbonate (3.25 g, 10 mmol) and acetone (50 ml) was heated at 60° C. for 4 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting oil was diluted with dichloromethane (25 ml) and washed with 1M hydrochloric acid (30 ml). The aqueous layer, at pH 1, was extracted with dichloromethane (20 ml). The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide 4-(1-acetyl-2-oxopropoxy)benzonitrile (2.06 g, 9.4 mmol) which was used crude in the next step. 2-Hydroxyethyl hydrazine (169 μL, 2.5 mmol) was added to a stirred solution of a portion of the crude 4-(1-acetyl-2-oxopropoxy)benzonitrile (500 mg, 2.3 mmol) in acetic acid (5 ml) at room temperature under nitrogen, and the mixture was stirred at room temperature for 5 hours. Water (20 ml) was then added, and a solid triturated out and filtered off. This was recrystallised from ethyl acetate to provide the title compound (154 mg, 6%).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C.C1(C)C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([CH2:23][O:24][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@@H:20]([O:25][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Sodium hydride (140 mg, 60% oil dispersion, 3.7 mmol) was added portionwise to a stirred solution of benzyl bromide (300 μL, 2.8 mmol) and 1 (200 mg, 0.92 mmol) in DMF (10 mL) at 0° C. On complete addition the resulting suspension was allowed to warm to r.t., diluted with toluene (100 mL), washed with water (50 mL), brine (50 mL), dried (MgSO4), and concentrated in vacuo to afford a syrup. Chromatography afforded 2 (350 mg, 96%) as an oil which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[OH-].[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:11][C:10]1[C:4]2[O:3][C:2]([CH3:12])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)(=[O:17])[CH3:16]
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1cccc2c1OC(C)(C)C2
Yield: 94.6 %

Procedure:
2,3-Dihydro-2,2-dimethyl-7-benzofuranol (16.4 g, 0.1 mol) was dissolved in 100 ml of an aqueous solution of sodium hydroxide (6.0 g, 0.15 mol), and 12.8 g of acetic anhydride was dumped into the solution and thoroughly mixed, whereby a white solid substance was precipitated. This substance was collected by filtration and dried, whereby 19.5 g of 7-acetoxy-2,3-dihydro-2,2-dimethylbenzofuran was obtained. The melting point of this product was 48.5°-49.5° C. This phenol acetate was dissolved in 400 ml of chloroform, and 60 ml of 70% nitric acid was dropwise added at -5° C. Then, the stirring was continued at 10° C. for one hour. The reaction solution was washed with water, then dried over anhydrous sodium sulfate and concentrated. The solid substance thereby obtained was recrystallized from benzene-cyclohexane, whereby 19.6 g of 7-acetoxy-2,3-dihydro-2,2-dimethyl-5-nitrobenzofuran was obtained. The melting point of this product was 141°-142° C. The structure was confirmed by 1H-NMR spectrum and IR spectrum. Then, the product was added to a solution containing 35 g of sodium hydroxide in 200 ml of water and 50 ml of methanol, and heated at 40° C. for 15 minutes to complete hydrolysis. The reaction solution was neutralized by concentrated hydrochloric acid, and then extracted with ether. The extracted solution was washed with water, then dried over anhydrous sodium sulfate and concentrated, whereby 13.0 g of substantially pure 2,3-dihydro-2,2-dimethyl-5-nitro-7-benzofuranol was obtained. The melting point of this product was 97°-97.5° C. The phenol thus obtained, was reacted with O-ethyl-S-n-propyl-thiophosphoryl chloride in the same manner as in Example 1, whereby the compound (No. 4) identified in Table 1 was obtained as oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:23])[CH:21]=[CH2:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C=CC(=O)O
Reactant: Cc1cccc(Nc2ncnc3cc(N)ccc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2c(Nc3cccc(C)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.3 %

Procedure:
To a stirred solution of 7-amino-4-[(3-methylphenyl)amino]quinazoline (123 mg, 0.49 mmol), acrylic acid (0.04 mL, 0.58 mmol), triethylamine (0.15 mL, 1.1 mmol) in DMF (1.5 mL) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123 mg, 0.64 mmol). The resulting light yellow mixture was stirred at 25° C. for 20 hours and quenched with water. The solid was collected and purified by sonication with a mixture of CH2Cl2/EtOAc/MeOH to give the desired product as a yellow solid (75 mg, 49%), mp 269.7-270° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Cn1ccc(N)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cn1ccc(Nc2nc(Cl)ncc2Cl)n1

Procedure:
The mixture 1-methyl-1H-pyrazol-3-amine (48 mg, 0.50 mmol), 2,4,5-trichloropyrimidine (57 μL, 0.5 mmol), and sodium carbonate (53 mg, 0.5 mmol) in 3 mL of EtOH is heated at 40° C. over night. The precipitate is filtered, washed by cold EtOH, and dried in vacuo to afford 2,5-Dichloro-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine; ESMS m/z 244.0 (M+H+).
Reaction SMILES: ClC1C(=O)C2C(C(=[O:13])C=1Cl)=CC=CC=2.[N+]([O-])([O-])=O.[Na+].[N+:20]([C:23]1[C:24](=[O:34])[C:25]2[C:30]([C:31](=[O:33])[CH:32]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)([O-:22])=[O:21]>CO.O>[OH:13][C:32]1[C:31](=[O:33])[C:30]2[C:25]([C:24](=[O:34])[C:23]=1[N+:20]([O-:22])=[O:21])=[CH:26][CH:27]=[CH:28][CH:29]=2
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: O=C1C=C([N+](=O)[O-])C(=O)c2ccccc21
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C(O)=C([N+](=O)[O-])C(=O)c2ccccc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A suspension of 2,3-dichloro-1,4naphthoquinone (6,83g; 0.03 mole) in methanol (40ml) was stirred during the addition of a solution of sodium nitrate (6.9g; 0.1 mole) in water (50ml) and the mixture stirred at 80° C for 3 hrs. Solution was attained after about 1 hr and the nitro naphthoquinone began to separate after 2 hrs. After cooling in ice and the yellow crystalline solid was filtered off, taken up in water (200ml), charcoalised and precipitated the product by addition of one-third the volume of concentrated hydrochloric acid, filtered off, washed well with 5N HCl and dried in vacuo over P2O5 /NaOH to give 5.30 g (81%) of material of m.p. 162°-163° C (d) which was identical to that prepared above.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[C:5]([CH3:17])[CH:4]=1)=O.Cl.[OH:19][NH2:20].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:19][N:20]=[CH:1][C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[C:5]([CH3:17])[CH:4]=1
Reactant: NO
Reactant: Cc1cc(C=O)ccc1C(=O)NCC(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C=NO)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 58.9 %

Procedure:
In a solution of 0.8 g of 4-formyl-2-methyl-N-(2,2,2-trifluoroethyl)benzoic acid amide in 10 ml of ethanol and 5 ml of water, 0.3 g of hydroxyamine hydrochloride and 0.4 g of anhydrous sodium acetate were added with stirring at room temperature, and stirred at the same temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and precipitated crystal was filtered off, washed with water and dried to obtain 0.5 g of the aimed product as white crystal.
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:31][CH3:32])(=O)=O.C(OCC)C>CN(C)C=O>[O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([O:18][CH2:31][CH3:32])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
5.36 g of 3-(4-phenoxybenzoyl)acrylic acid were dissolved in 30 ml of dimethylformamide, and then 1.36 g of potassium carbonate and 3.08 g of diethyl sulfate were added. The mixture was stirred at room temperature for 3 hours. Diethyl ether was added to the reaction mixture, which was then washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. The diethyl ether was removed by evaporation under reduced pressure. The residue was purified first by silica gel column chromatography, eluted with a mixture of hexane and diethyl ether, then by recrystallization from hexane to give 4.36 g of ethyl 3-(4-phenoxybenzoyl)acrylate.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][C:8](OC(C)=O)=[O:9].C([O-])(O)=O.[Na+].Cl>O>[OH:4][CH2:3][C:2]([NH:1][C:8](=[O:9])[CH3:7])([CH3:6])[CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(N)CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-2-methyl-propan-1-ol (2.0 mL, 20.4 mmol), acetanhydride (1.9 mL, 20.4 mmol) and NaHCO3 (2.6 g, 30.6 mmol) in H2O (20 mL) is stirred at RT for 16 h. For workup 1N HCl is added and the mixture is extracted with ethyl acetate. Drying (Na2SO4) of the combined extracts, filtration and evaporation of the solvent yields the title compound as a colorless solid. MS (LC-MS): [M+H]+=132.2. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.38 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[S:47]1[C:56]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51][C:50]=2[NH:49][C:48]1=[O:57]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:53]3[CH2:54][CH2:55][C:56]4[S:47][C:48](=[O:57])[NH:49][C:50]=4[CH2:51][CH2:52]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: O=c1[nH]c2c(s1)CCNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2[nH]c(=O)sc2CC1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 0.25 mmol 6-chloro-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid, 0.30 mmol HATU, 1.52 mmol DIPEA and 0.51 mmol 3,4,5,6,7,8-hexahydro-thiazolo[4,5-d]azepin-2-one in 1 mL DMF. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 20 mg (23% of theory). ESI-MS: m/z=350 (M+H)+.
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33]([CH3:40])[CH:32]=2)=[CH:16][CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33](/[CH:40]=[CH:6]/[N:7]([CH3:9])[CH3:8])[CH:32]=2)=[CH:16][CH:15]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 100.7 %

Procedure:
tert-butoxybis(dimethylamino)methane (0.47 mL, 2.30 mmol) was added to a solution of 3-(4-chlorophenyl)-2-(3-methyl-4-nitrophenyl)quinazolin-4(3H)-one (0.300 g, 0.76 mmol) in DMF (30 mL). After heating at 40° C. for 3.5 hours, concentration in vacuo afforded (E)-3-(4-Chlorophenyl)-2-(3-(2-(dimethylamino)vinyl)-4-nitrophenyl)quinazolin-4(3H)-one (0.342 g, 100%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[CH2:6][CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][C:9]=12.S(=O)(=O)(O)O.[OH-].[NH4+]>>[N+:1]([C:15]1[CH:14]=[CH:13][C:12]2[N:8]3[CH2:7][CH2:6][N:5]=[C:9]3[S:10][C:11]=2[CH:16]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)SC1=NCCN12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)SC1=NCCN12
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 Parts of 2,3-dihydroimidazo[2,1-b]benzothiazole mononitrate are added portionwise to 55.2 parts of concentrated sulfuric acid at 0° C. Upon completion, stirring is continued for 30 minutes at room temperature. The reaction mixture is poured onto crushed ice and the whole is alkalized with ammonium hydroxide at a temperature below 20° C. The product is extracted with a mixture of trichloromethane and methanol (90:10 by volume). The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 160 parts of 1-butanol. The product is filtered off and dried, yielding 8 parts (80%) of 2,3-dihydro-7-nitroimidazol[2,1-b]benzothiazole; mp. 238.9° C.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:14].O1CCCC1.[Na].[CH3:21][SH:22]>O>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:14])[CH:2]([S:22][CH3:21])[CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1)CCC(Br)C2=O
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(SC)C2=O
Reaction time: 3 h
Yield: 64 %

Procedure:
After 20 g of 2-bromo-6-methoxy-1-tetralone [synthesized in accordance with procedures described in W. S. Johnson, et al., J. Am. Chem. Soc., vol.66, p.218 to 220 (1944)] was dissolved into 100 ml of tetrahydrofuran, 36.5 g of a 15% aqueous solution of a sodium salt of methylmercaptan was added dropwise thereto. After the stirring for 3 hours at room temperature, the reaction mixture was poured into 300 ml of cold water. An organic layer was extracted with 200 ml of ether, and the ether layer was sequentially washed with a sodium chloride aqueous solution and water. After the ether layer was dried with magnesium sulfate, the solvent was removed by evaporated under vacuum. The residue was dissolved into 320 ml of a mixed solvent of hexane/ethyl acetate (7/1), and silica gel was added thereto for adsorbing impurities. After the silica gel was removed by filtration, the filtrate was concentrate under vacuum to provide 11.06 g of 6-methoxy-2-(methylthio)-1-tetralone (yield: 64%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[CH3:35][N:36]=[C:37]=[O:38]>O1CCCC1>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][N:16]([C:37](=[O:38])[NH:36][CH3:35])[CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:1][CH3:2])[CH3:5]
Reactant: CN=C=O
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)NC)C3
Temperature: 25 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
A mixture of the compound obtained in Example 5A (1.22 g), methyl isocyanate (0.17 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 5 hours, after which it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane-methanol (20:20:1, v/v) to yield ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-7-methylcarbamoyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below), (0.30 g, 22%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 153 to 155° C. ##STR53##
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:15]=2)[CH2:9][CH2:8]1>O1CCCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:18]2[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:15]=[C:14]2[NH:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][N:4]=[C:1]=[S:3])[CH2:8][CH2:9]2)=[CH:21][CH:22]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: S=C=S
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (below 10° C.) mixture of 5.04 parts of carbon disulfide, 2.06 parts of N,N'-methanetetraylbis[cyclohexanamine] and 45 parts of tetrahydrofuran was added dropwise a solution of 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine in tetrahydrofuran. Upon completion, stirring was continued overnight while the mixture was allowed to reach room temperature. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 4 parts (100%) of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine as a residue (intermediate 141).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:16][CH3:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:6]([O:8]C)=O.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:6]([C:5]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([CH:13]([CH3:15])[CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)([OH:8])[CH2:6][C:5]2[CH:10]=[CH:11][C:12]([CH3:13])=[CH:3][CH:4]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Reactant: Cc1ccc(CBr)cc1
Product: COc1cc(C(O)(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc(OC)c1C(C)C
Yield: 20 %

Procedure:
This material was prepared as a 20% yield from methyl 3,5-dimethoxy-4-i-propylbenzoate and 4-methylbenzyl bromide using the same method as described in example 1 (b). 1HNMR (CDCl3, ppm): δ 1.30 (d, J=7.1 Hz, 6H), 2.31 (s, 6H), 3.02 (d, J=13.5 Hz, 2H), 3.25 (d, J=13.5 Hz, 2H), 3.52 (m, 1H), 3.71 (s, 611), 6.45 (s, 2H), 6.8-7.2 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2=[O:20])=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[OH:20][CH2:9][CH:8]([C:12]1[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=1[OH:10])[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C(CO)c2ccc(Br)cc2)c(O)c1C
Yield: 93 %

Procedure:
Using 3-(4-bromophenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one obtained in Reference Example 229, the title compound was synthesized in the same manner as in Reference Example 8. Yield 93%. Melting point: 114-115° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.CCOC(C)=O>[N+:27]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([NH:39][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([CH2:17][CH2:16][CH2:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:19][CH:20]=2)(=[O:37])=[O:38])=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reaction time: 65 h
Yield: 68.6 %

Procedure:
A mixture of 4-[3-(2-benzyloxyphenyl)propyl)benzoic acid 0.2 g), 4-nitrobenzenesulphonamide (0.12 g), DMAP (0.15 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g) was stirred for 65 hours. The mixture was diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate, to give the title compound (0.21 g) mpt. 112°-113° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([O:32]C)=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:22][CH2:23]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([OH:32])=[O:31])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC(c4ccccn4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC(c4ccccn4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[4-(pyridin-2-yl)piperidin-1-yl]quinoxaline-6-carboxylate (84 mg, 0.19 mmol) in methanol (30 ml) and water (1.0 ml) was added sodium hydroxide (30 mg, 0.75 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 ml), and adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 2-(4-fluorophenyl)-3-[4-(pyridin-2-yl)piperidin-1-yl]quinoxaline-6-carboxylic acid as a light yellow solid (61.1 mg, 75%).