Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Yield: 133.9 %

Procedure:
The procedure described in Example 4.1. is repeated. Starting from 2.5 g (11.6 mmol) of 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidine-carboxylate and 8.13 g (46.4 mmol) of 1-bromo-4-fluorobenzene gives 5.75 g of crude product in oil form.
Reaction SMILES: CN(C)[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5](OCC)=[O:6].[CH2:14]([O:21][CH2:22][C:23](=[NH:25])[NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O(C)[Na].Cl>CO>[CH2:14]([O:21][CH2:22][C:23]1[N:24]=[C:5]([OH:6])[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][N:25]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=CN(C)C)[N+](=O)[O-]
Reactant: N=C(N)COCc1ccccc1
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1cnc(COCc2ccccc2)nc1O

Procedure:
To a mixture of step A product, 3-c, (24 g, 127 mmol) and 2-(benzyloxy)acetimidamide (25.9 g, 127 mmol) in CH3OH (30 mL) was added with NaOCH3 (14.2 g, 254 mmol) and 30° C. overnight. The pH of reaction mixture was adjusted to 7 by addition of concentrated HCl. The solids were filtered to afford the crude product, 3-d, (25 g). LC-MS (M+H)+ 262.1
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([N:6]=[C:7]=[S:8])=[O:5].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[N:10]1([C:7]([NH:6][C:4](=[O:5])[CH:3]=[C:2]([CH3:9])[CH3:1])=[S:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)=CC(=O)N=C=S
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: CC(C)=CC(=O)NC(=S)N1CCCCC1
Reaction time: 2 h
Yield: 103.3 %

Procedure:
To a solution of 3-methylbut-2-enoyl isothiocyanate (2 g, 14.2 mmol, Eq: 1.00) in benzene (40.0 ml) was added a solution of piperidine (1.21 g, 1.4 ml, 14.2 mmol, Eq: 1.00) in benzene (20.0 ml). The mixture was stirred for 2 hours. The mixture was evaporated affording 3-methyl-but-2-enoic acid (piperidine-1-carbothioyl)-amide (3.32 g, 104%) as a yellow oil. MS: m/z=227.2 (M+H+)
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]([NH:17][CH2:18][CH2:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=1)=[O:16].[NH2:32][OH:33].[OH-].[Na+].Cl>CO>[OH:33][NH:32][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([O:20][CH2:19][CH2:18][NH:17][C:15]([C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH2:5][O:4][CH2:3][C:2]([F:31])([F:30])[F:1])=[O:16])=[CH:22][CH:23]=1
Reactant: NO
Reactant: O=C([O-])c1ccc(OCCNC(=O)c2oc3ccccc3c2COCC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NO)c1ccc(OCCNC(=O)c2oc3ccccc3c2COCC(F)(F)F)cc1
Reaction time: 8 h

Procedure:
4-{2-[3-(2,2,2-Trifluoroethoxymethyl)benzofuran-2-yl-carbonylamino]-ethoxy}-benzoate was dissolved in MeOH and excess aqueous hydroxylamine solution and NaOH(aq) were added to give pH 10-11. After stirring overnight, the reaction mixture was neutralized reaction to pH 7-8 with aqueous hydrochloric acid. The reaction mixture was concentrated in vacuo to give a solid which was collected and washed with water, then dissolved in acetonitrile and water and purified with prep HPLC to give the title compound (35 mg). 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.95 (t, J=5.6 Hz,1H), 8.89 (s,1H), 7.81 (d, J=7.6 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.00 (d, J=9.2 Hz, 2H), 5.25 (s, 2H), 4.18 (m, 4H), 3.67 (m, 2H). EM (calc.): 452.1; MS (ESI) m/e (M+1H)+: 453.0, (M−1H)−: 451.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:15][NH2:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[CH:15][NH2:16]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CN
Product: COc1cc(C=CN)cc(OC)c1OC
Yield: 95 %

Procedure:
3,4,5-Trimethoxybenzaldehyde (7.81-40.0 mmol) and a 40% aqueous solution of methylamine (20 mL) were stirred at room temperature for 2.5 h. The mixture was extracted with ether (4×75 mL), the ether layers were combined, and the solution washed with saturated aqueous sodium chloride (75 mL), dried (MgSO4), and concentrated under reduced pressure to give a colorless oil (7.94 g, 95%): IR (neat) 2940, 2840, 1646, 1576, 1500, 1453, 1407, 1369, 1323, 1230, 1115, 1013 cm−1; 1H NMR (CDCl3, 300 MHz) δ8.18 (d, 1H, J=1.3 Hz), 6.95 (s, 2H), 3.89 (s, 6H), 3.87 (s, 3H), 3.50 (d, 3H, J=1.3 Hz); CIMS m/z (relative intensity) 210 (MH+, 100). Anal. Calcd for C11H15NO3: C, H, N.
Reaction SMILES: [Br-:1].[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:17][N+:12]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[Br-:1].[C:18]([O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:17][N+:12]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccccc1-c1cc2cccc[n+]2o1
Agent: [Br-]
Product: CC(=O)Oc1ccccc1-c1cc2cccc[n+]2o1
Yield: 73 %

Procedure:
2-(2-Hydroxyphenyl)isoxazolo[2,3-a]pyridinium bromide from Example 1 (5.0 g) is refluxed in acetic anhydride (40 ml) under nitrogen for 60-90 minutes. The solution is cooled, and the solvent is evaporated. The oily residue is diluted with ethyl acetate to crystallize the product. Recrystallization from isopropanol gives gray-white crystals (4.16 g, 73%), m.p. 198°-201° C.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:8]([CH3:7])[C:9](=[O:10])[CH2:11][CH2:12]2)=[O:4]
Reactant: CN1C(=O)CCc2ccccc21
Reactant: CC(Br)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)c1ccc2c(c1)CCC(=O)N2C
Temperature: 25 °C

Procedure:
2-Bromopropionyl chloride (41.1 g) is added dropwise to a suspension of the N-methyl product obtained in Step 1. above (18.6 g) and AlCl3 (37.4 g) in chloroform (350 ml). The stirred reaction mixture is refluxed for 4 hours, cooled to RT and stirred with an ice/water mixture for 45 minutes. The reaction mixture is separated, extracted with methylene chloride and the combined extracts are washed with H2O, 5% aq. bicarbonate, H2O, dried, filtered and concentrated in vacuo, yielding a viscous oil, which is crystallized from ethyl acetate affording the desired product, M.P.=86°-88° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([OH:16])=O.[CH2:17]=O.S(Cl)(Cl)=O.[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:17][CH2:1][C:2]3[CH:6]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[S:4][C:3]=3[C:14]2=[O:16])=[CH:30][CH:29]=1
Reactant: C=O
Reactant: Cc1ccc(-c2cc(C)c(C(=O)O)s2)cc1
Reactant: CN(C)CCOc1ccc(N)cc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(OCCN(C)C)cc2)CC3)cc1

Procedure:
Firstly 3-methyl-5-p-tolylthiophene-2-carboxylic acid was reacted with paraformaldehyde by method C1, and then the product was treated with thionyl chloride by method B. The resulting dichloride was finally reacted with 4-(2-dimethylaminoethoxy)phenylamine by method A. The product with the molecular weight of 406.55 (C24H26N2O2S) was obtained in this way; MS (ESI): 407 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([NH2:16])([C:13]([OH:15])=[O:14])[CH2:8]2)[CH3:2].C(N(CC)CC)C.[C:24](=O)([O:40]N1C(=O)CCC1=O)[O:25][CH2:26][CH:27]1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>C(#N)C.O>[C:24]([CH:8]1[C:9]2[C:4](=[C:3]([CH2:1][CH3:2])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1([NH2:16])[C:13]([OH:15])=[O:14])([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40]
Reactant: CCc1cccc2c1CCC(N)(C(=O)O)C2
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.4 %

Procedure:
A mixture of racemic 5-ethyl-2-aminotetraline-2-carboxylic acid (765 mg, 3.49 mmole), triethylamine (1.0 ml, 7.17 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 1.79 g, 5.31 mmole) in acetonitrile (40 ml) and water (40 ml) was stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH˜3 with 10% aqueous citric acid solution, and the white emulsion extracted twice with methylene chloride, twice with ethyl acetate. The methylene chloride extracts were washed with water, brine and dried over magnesium sulfate. The ethyl acetate extracts were washed with water, brine and dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 2→5→8% methanol/methylene chloride) to give racemic Fmoc-5-ethyl-2-aminotetraline-2-carboxylic acid (330 mg, 21% yield) as a white solid. HRMS (FAB): C28H28NO4 (M+H) calc. 442.2018; observed: 442.2010.
Reaction SMILES: Br[C:2](Br)([F:4])[F:3].CN(P(N(C)C)N(C)C)C.O=[C:17]([CH3:25])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(OCC)C>O1CCCC1>[F:3][C:2]([F:4])=[C:17]([CH3:25])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: FC(F)(Br)Br
Reactant: COC(=O)CCCC(C)=O
Agent: CN(C)P(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CCCC(C)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Reaction was carried out under nitrogen atmosphere. To 650 ml of tetrahydrofuran, 80 g (0.38 mol) of dibromodifluoromethane was dissolved, followed by drop-wisely adding 121 g (0.74 mol) of tris(dimethylamino)phosphine at −10° C. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature for 1 hour, followed by further drop-wisely adding 24.9 g (0.17 mol) of methyl 5-oxohexanoate dissolved in 250 ml of tetrahydrofuran, at −20° C. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature overnight. To this mixture, diethyl ether was added, followed by washing with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (diethyl ether:hexane=1:4) to obtain 27 g (yield: 88%) of methyl 6,6-difluoro-5-methyl-5-hexenoate.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[NH2:27][C:28]1[CH:36]=[CH:35][C:31]2[NH:32][N:33]=[N:34][C:30]=2[CH:29]=1.C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C=O>[NH:32]1[C:31]2[CH:35]=[CH:36][C:28]([NH:27][C:12](=[O:14])[CH2:11][O:10][C:9]3[CH:8]=[CH:7][C:6]([NH:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:16][CH:15]=3)=[CH:29][C:30]=2[N:34]=[N:33]1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: CC(=O)NNc1ccc(OCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NNc1ccc(OCC(=O)Nc2ccc3[nH]nnc3c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-(2-acetylhydrazino)phenoxyacetic acid (1.1 g), N-hydroxybenzotriazole (1.0 g) and 5-aminobenzotriazole (0.67 g, 0.005 mole) in dry dimethylformamide (10 ml) was stirred at 0° under dry nitrogen. Dicyclohexylcarbodiimide (1.1 g) in dry dimethylformamide (5 ml) was added dropwise over 15 minutes and the reaction mixture was stirred for 1 hour at 0° and 4 hours at room temperature. The dicyclohexylurea which precipitated was filtered and dried (0.7 g) and the filtrate was stirred at 60° overnight, under nitrogen. The reaction mixture was cooled and an additional precipitate of dicyclohexylurea was filtered off (0.3 g). The filtrate was evaporated, the residue was triturated with boiling methanol (50 ml) and the solid which precipitated was filtered off and dried (0.7 g). The filtrate was cooled at 5° overnight and the solid which crystallized out was filtered off and dried (0.6 g). The two precipitates, which were identical by IR, were combined and recrystallized from methanol:acetonitrile to give the product was a beige-colored powder (1.0 g). NMR analysis indicates the presence of ca 0.3 mole of H2O.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[OH:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)COCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)COCCO
Yield: 84.4 %

Procedure:
A mixture of methyl [2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate (1.07 g) and pyridinium p-toluenesulfonate (24.6 mg) in MeOH (10 mL) was heated under reflux for 2 hours. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (10:1-1:3) to give methyl (2-hydroxyethoxy)acetate as colorless oil (555 mg).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1C
Reactant: c1nc[nH]n1
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:18]([C:32]#[N:33])[C:17]1=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([N:26]2[CH2:31][CH2:30][N:29]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:28][CH2:27]2)=[C:18]([C:32]#[N:33])[C:17]1=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(N2CCNCC2)c2cccnc2n(Cc2ccccc2)c1=O
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
2-Thiophene carbonyl chloride (0.16 mL, 1.5 mmol) was added to a stirred solution of 1-benzyl-2-oxo-4-piperazin-1-yl-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (9) (345 mg, 1 mmol) in pyridine at 0° C. The solution was allowed to come at room temperature and further stirred overnight at room temperature. The solution was poured into ice water and the solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with linear gradients of 0-3% MeOH in CH2Cl2 to yield 273 mg (45%) of 1-benzyl-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (10) as white solids. MP: 263° C.; 1H-NMR (DMSO-d6): δ 3.75 (m, 4H), 3.94 (m, 4H), 5.58 (s, 2H), 7.15 (dd, J=3.5, 4.8 Hz, 1H), 7.19-7.29 (m, 5H), 7.40 (dd, J=4.8, 8.0 Hz, 1H), 7.52 (dd, J=4.0, 5.2 Hz, 1H), 8.35 (dd, J=1.6, 8.0 Hz, 1H), 8.72 (dd, J=1.6, 8.0 Hz, 1H); EIMS: 456 (M+1). Anal. C25H21N5O2S (C,H,N).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:39])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:35])([CH3:34])[C:31](=[O:33])[CH3:32])=[CH:26][C:25]=3[O:36][CH2:37][CH3:38])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:42][S:43]([CH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)(=[O:45])=[O:44]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:39])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:52]3[CH2:53][CH2:54][N:49]([CH2:48][CH2:47][CH2:46][S:43]([CH3:42])(=[O:44])=[O:45])[CH2:50][CH2:51]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:35])([CH3:34])[C:31](=[O:33])[CH3:32])=[CH:26][C:25]=3[O:36][CH2:37][CH3:38])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title product as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C39H49N4O5SCl2 [(M+H)+] 775.2795, observed 775.2795.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](O)=[O:24])=[CH:15]1>>[CH2:4]1[CH:5]2[N:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:11][CH2:12][CH:3]1[CH2:2][O:1][C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]([CH3:13])[CH:15]=1)=[O:24]
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: OCC1CCN2CCCCC2C1
Product: Cn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-2-Hydroxymethylquinolizidine (N. J. Leonard et al, J. Org. Chem., 1957, 22, 1445) was reacted with the acid chloride of 1-methylindole-3-carboxylic acid using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate. The resulting pale yellow oil was crystallised from n-pentane to afford the title compound (E15) as a white crystalline solid mp 115°-116° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:5][CH:4]=1)#[N:2].C([BH3-])#N.[Na+].Cl>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)CCCc2c[nH]cn2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(C2CCCc3cncn32)cc1
Reaction time: 2 h

Procedure:
A solution of 0.24 g of 1-(p-cyanophenyl)-4-(4-imidazolyl)-1-butanone in 20 ml of methanol at room temperature is treated with 0.2 g of sodium cyanoborohydride. The pH is adjusted and maintained at 5.5-6.0 by addition of concentrated hydrochloric acid. The reaction mixture is stirred for 2 h, adjusted to pH 2, and evaporated to dryness. The residue is taken up in methylene chloride and washed with saturated sodium bicarbonate. The organic layer is dried over sodium sulfate and evaporated to yield 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH2:21])=[NH:20])[N:9]=2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C.[OH-].[Na+]>C(#N)C.CN(C1C=CN=CC=1)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:21][S:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)(=[O:31])=[O:30])=[NH:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(N)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N=C(NS(=O)(=O)c1ccc(F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
Part B: To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (0.50 gram, 1.68 mmol) and 4-fluorophenylsulfonyl chloride (0.34 gram, 1.75 mmol) in acetonitrile (10 ml) was added N,N-dimethyl-4-aminopyridine (0.020 gram, 0.175 mmol) and triethylamine (1 ml). The resulting solution was stirred at room temperature for 30 minutes. After addition of a 2 N sodium hydroxide solution and extraction with ethylacetate (400 ml), the ethylacetate layer was concentrated in vacuo. The resulting crude residue was further purified by means of flash chromatography (petroleum ether/diethyl ether=1/1 (v/v), followed by ethylacetate). Subsequent concentration in vacuo afforded solid 3-(4-chlorophenyl)-4,5-dihydro-N-((4-fluorophenyl)sulfonyl)-4-phenyl-1H-pyrazole-1-carboxamidine (0.55 gram, 72% yield). Melting point: 214-215° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C(O[C:14]([S-])=[S:15])C.[K+]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[N:9]=[C:14]([SH:15])[NH:10][C:4]=2[CH:3]=1
Reactant: CCOC(=S)[S-]
Reactant: Cc1cc(N)c(N)cc1C
Agent: [K+]
Product: Cc1cc2nc(S)[nH]c2cc1C

Procedure:
Reaction of 30 g (0.22 mole) of 4,5-dimethyl-1,2-phenylenediamine with potassium ethylxanthate using the method described in Example 86 yielded 19 g of 5,6-dimethyl-2-mercaptobenzimidazole, as confirmed by the nmr and infrared spectra and by elemental analysis. The title compound (3.0 g) was prepared by the method of Example 84 using 3.5 g of 5,6-dimethyl-2-mercaptobenzimidazole instead of 2-mercaptobenzimidazole. Structure assignment was supported by the nmr spectrum.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:24]([CH3:25])=[C:23]2[NH:26][C:4]=1[CH:5]=[C:6]1[N:10]=[C:9]([C:11]([CH:38]=[O:39])=[C:12]3[N:16]=[C:15]([CH:17]=[C:18]4[NH:27][C:21](=[CH:22]2)[C:20]([CH:28]=[CH2:29])=[C:19]4[CH3:30])[C@@H:14]([CH3:31])[C@@H:13]3[CH2:32][CH2:33][C:34]([O:36]C)=[O:35])[C:8]([C:40]([O:42]C)=[O:41])=[C:7]1[CH3:44].Cl>CC(C)=O>[CH3:1][CH2:2][C:3]1[C:24]([CH3:25])=[C:23]2[NH:26][C:4]=1[CH:5]=[C:6]1[N:10]=[C:9]([C:11]([CH:38]=[O:39])=[C:12]3[N:16]=[C:15]([CH:17]=[C:18]4[NH:27][C:21](=[CH:22]2)[C:20]([CH:28]=[CH2:29])=[C:19]4[CH3:30])[C@@H:14]([CH3:31])[C@@H:13]3[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:8]([C:40]([OH:42])=[O:41])=[C:7]1[CH3:44]
Reactant: C=Cc1c(C)c2cc3nc(c(C=O)c4nc(cc5[nH]c(cc1[nH]2)c(C)c5CC)C(C)=C4C(=O)OC)[C@@H](CCC(=O)OC)[C@@H]3C
Agent: Cl
Solvent: CC(C)=O
Product: C=Cc1c(C)c2cc3nc(c(C=O)c4nc(cc5[nH]c(cc1[nH]2)c(C)c5CC)C(C)=C4C(=O)O)[C@@H](CCC(=O)O)[C@@H]3C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Purpurin 5 dimethyl ester is dissolved in acetone and concentrated hydrochloric acid (37%) is added in the ratio 1:2. The mixture is stirred for 2 hours at 25° C., neutralised, purpurin 5 is filtered out, washed with water, dissolved in 10% N-methyl-D-glucamine solution and gel filtrated on a Sephadex G10 column with the use of 1% N-methyl-D-glucamine solution as an eluent, the second fraction is collected, neutralised, a precipitate is filtered out, washed with water, dried over phosphorus pentoxide till the weight becomes constant to give purpurin 5 (5,2% calculating to the dry reaction mass taken for esterification).