Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[NH:10][C:11]2[C:17]([CH3:18])=[C:16]([N+:19]([O-])=O)[C:15]([CH3:22])=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C>[NH2:19][C:16]1[C:15]([CH3:22])=[CH:14][C:12]2[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[NH:10][C:11]=2[C:17]=1[CH3:18]
Reactant: [H][H]
Reactant: Cc1cc2nc(NC(=O)OC(C)(C)C)[nH]c2c(C)c1[N+](=O)[O-]
Solvent: CCO
Product: Cc1cc2nc(NC(=O)OC(C)(C)C)[nH]c2c(C)c1N
Yield: 88.7 %

Procedure:
A suspension of 2-(t-butoxycarbonyl)amino-4,6-dimethyl-5-nitrobenzimidazole (0.625 g, 2.04 mmol) in ethanol (70 mL) is treated with hydrogen at 45 psi for 15 hours. The mixture is filtered on Celite and the filtrate is rotary evaporated to afford 5-amino-2-(t-butoxycarbonyl)amino-4,6-dimethylbenzimidazole (0.5 g).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:5][C:4]=1[NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]1)[CH3:2].ClC(Cl)C.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:37]([N:22]1[CH2:21][CH2:20][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:6]3[C:7]([C:9]([NH2:11])=[O:10])=[N:8][C:3]([CH2:1][CH3:2])=[C:4]([NH:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]4)[N:5]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)(=[O:39])[CH3:38]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(C3CCNCC3)cc2)nc1N[C@H]1CC[C@H](O)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCc1nc(C(N)=O)c(Nc2ccc(C3CCN(C(C)=O)CC3)cc2)nc1N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(4-piperidin-4-ylphenyl)amino]pyrazine-2-carboxamide (Example 358) (43 mg) and dichloroethane (1 mL), pyridine (0.01 mL) and acetic anhydride (0.01 mL) were added under ice cooling and stirred at room temperature for 20 minutes. After addition of saturated aqueous sodium hydrogen carbonate, the reaction liquid was partitioned using chloroform and saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the organic layer was concentrated, and the resulting residue was solidified with ethyl acetate-hexane to give 3-{[4-(1-acetylpiperidin-4-yl)phenyl]amino}-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide (26 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:29])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([CH:27]=[O:28])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:30]([F:33])([F:32])[F:31])=[N:10]2)=[CH:5][CH:4]=1.[Zn](C)[CH3:35]>CCOCC.Cl[Ti](Cl)(Cl)Cl>[OH:28][CH:27]([C:24]1([C:21]2[CH:22]=[CH:23][C:18]([N:15]3[CH2:16][CH2:17][C:12]4[C:11]([C:30]([F:33])([F:31])[F:32])=[N:10][N:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[C:13]=4[C:14]3=[O:29])=[CH:19][CH:20]=2)[CH2:25][CH2:26]1)[CH3:35]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C=O)CC4)cc2)CC3)cc1
Reactant: C[Zn]C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C(C)O)CC4)cc2)CC3)cc1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
1-{4-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-phenyl}-cyclopropanecarbaldehyde (93 mg, 0.21 mmol) was stirred in Et2O (2 mL) at −78° C. ZnMe2 (2M in toluene, 0.16 mL, 1.5 eq) was added followed by the addition of TiCl4 (1 M in CH2Cl2, 0.3 mL). The resulting mixture was stirred for 1 h. The reaction was quenched by addition of NH4Cl, extracted with EtOAc, washed with H2O and brine, dried over MgSO4, filter, and concentrated. The residue was purified by silica gel column to yield the pure desired product (62 mg, yield: 64.5%). LC/MS (ESI+) 472.6 (M+H)+, tR=2.44 min (35–95% CH3CN/H2O in a 6-min run).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[F:39][C:40]([I+]C1C=CC=CC=1)([F:48])[C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43]>ClCCl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:40]([F:48])([F:39])[C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: FC(F)(F)C(F)(F)C(F)(F)[I+]c1ccccc1
Reactant: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.3 %

Procedure:
2.1 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 60 mL of dichloromethane, and 0.51 g of pyridine was added. To the obtained solution, 3.0 g of (perfluoro-n-propyl)phenyliodonium trifluoromethanesulfonate was slowly added, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, a saturated salt solution was added, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.10 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2,3,3,3-heptafluoropropoxy)pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].Cl.C1C(O)=CC=CC=1C.[CH3:19][NH:20][C:21]#[N:22].[OH-].[Na+]>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:21]([NH:20][CH3:19])=[NH:22]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CNC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: CCOCC
Product: CNC(=N)Nc1c(Cl)cccc1Cl

Procedure:
To 51 g (0.315 mole) of 2,6-dichloroaniline is added 0.4 mole of ethereal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 17.7 g (0.315 mole) of methyl cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2 × 1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dichlorophenyl)-3-methylguanidine hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][N:27]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:26]=1.[CH3:44]N(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:29]([CH2:30][CH:31]4[S:35][C:34](=[O:36])[N:33]([CH3:44])[C:32]4=[O:37])=[CH:28][N:27]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: O=C1NC(=O)C(Cc2cn(-c3ccccc3)nc2O)S1
Reactant: CN(C)C=O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC2SC(=O)N(C)C2=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.40 g), 5-[(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)methyl]-1,3-thiazolidine-2,4-dione (0.30 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature. The mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 5-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methyl)-3-methyl-1,3-thiazolidine-2,4-dione as pale-yellow crystals (0.22 g, yield 37%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 111-112° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[C:5]([O:15][CH3:16])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>C(O)CC(C)C>[ClH:1].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[C:5]([O:15][CH3:16])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=3)[N:3]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: COc1ccc2c(N)nc(Cl)nc2c1OC
Reactant: O=C(c1ccco1)N1CCNCC1
Solvent: CC(C)CCO
Product: COc1ccc2c(N)nc(N3CCN(C(=O)c4ccco4)CC3)nc2c1OC
Product: Cl
Yield: 79 %

Procedure:
A mixture of 2-chloro-4-amino-7,8-dimethoxyquinazoline (3.00 g., 12.5 mmoles) and 1-(2-furoyl)piperazine (2.71 g., 15.0 mmoles) was refluxed in 80 ml. isoamyl alcohol for two hours and then cooled in an ice-bath. The resulting white product was collected by filtration and recrystallized from methanol/ether to yield 4.53 g. (79%) of pure final product, M.P. 251° C. The water solubility was found to be 20 mg./ml.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH3:26])[C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH3:26])[C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CN(C(=O)CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1)c1nccs1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)N(C)c5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-methyl-N-(thiazol-2-yl)acetamide (0.035 g, 0.08 mmol), ethanol (3.5 ml), and 4-dimethylaminobenzaldehyde (0.016 g, 0.11 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.32 ml, 0.32 mmol). The reaction mixture was heated at 70° C. for 3 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 30% to 60% ethyl acetate in dichloromethane. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.006 g, 14%); 1H-NMR (500 MHz, DMSO-d6) 2.76 (br s, 4H, piperazine N(CH2)2), 2.99 (s, 6H, N(CH3)2), 3.66 (br s, 6H, piperazine N(CH2)2 and NCH2CO), 3.75 (s, 3H, N—CH3), 6.81 (d, J=9.2 Hz, 2H) and 8.01 (d, J=9.7 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.31 (d, J=3.5 Hz, 1H, thiazole 5-H), 7.55 (d, J=3.9 Hz, 1H, thiazole-H), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.19 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C@@H:12]([C:14]1[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=1)[CH3:13])=[CH:7]2.CI.[CH2:31](Cl)Cl>C1COCC1.[Cl-].[Na+].O>[CH3:31][N:3]1[C:11]2[C:6](=[CH:7][C:8]([C@@H:12]([C:14]3[N:18]4[N:19]=[C:20]([C:23]5[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=5)[CH:21]=[CH:22][C:17]4=[N:16][CH:15]=3)[CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: ClCCl
Reactant: C[C@@H](c1ccc2n[nH]cc2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc2c(cnn2C)c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of NaH (4.8 mg, 0.1 mmol) in THF (0.5 mL) cooled to 0° C. was added (3-[(S)-1-(2H-indazol-5-yl)-ethyl]-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 195, 34.3 mg, 0.10 mmol). The RM was allowed to warm up to rt and stirred 15 min. Then it was cooled down again and methyliodide (21.3 mg, 0.150 mmol) was added dropwise. The RM was allowed to warm up to rt and stirred for 5 h. It was then taken into DCM and brine, extracted, and the organics were joined dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in EtOAc) to afford the title compound after evaporation of the solvent and drying of the material under vacuum (tR 3.72 min (conditions 3), MH+=358, 1H-NMR in DMSO-d6: 8.35 (s, 1H); 8.03 (d, 1H); 8.00 (s, 1H); 7.94 (s, 1H); 7.73 (s, 1H); 7.70 (s, 1H); 7.52 (d, 1H); 7.45 (d, 1H); 7.43 (d, 1H); 4.73 (q, 1H); 4.74 (s, 3H); 3.89 (s, 3H); 1.77 (d, 3H)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([F:30])([F:29])[F:18])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: COC(=O)c1c(O)c2cc(-c3ccccc3C(F)(F)F)ccc2sc1=O

Procedure:
4-Hydroxy-2-oxo-6-(2-trifluoromethyl-phenyl)-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 2-trifluoromethyl-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.572 (s, 1H), 7.838-7.676 (m, 4H), 7.487-7.354 (m, 2H), 4.028 (s, 3H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[I:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]>CN(C=O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:7]([I:6])=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1I
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(N)ccc1I
Temperature: 50 °C
Reaction time: 1 h

Procedure:
15.1 g (67 mmol) of tin(II) chloride dihydrate are added to a solution of 4.9 g (16.8 mmol) of the compound from Example 3A in 200 ml of DMF. The reaction mixture is stirred at 50° C. for one hour, and then the DMF is removed in vacuo. The residue is partitioned between 1 l of ethyl acetate and water, the phases are separated, and the organic phase is discarded. The aqueous phase is basified with 10% strength sodium hydroxide solution and again extracted with 500 ml of ethyl acetate. The product is dried over magnesium sulfate, filtered with suction and concentrated in vacuo. 3.95 g (90% of theory) of the title compound are obtained and are reacted without further purification in the next stage.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[CH:11]2.[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:21][O:22][C:18]=2[CH:17]=1.C([O-])([O-])=O.[K+].[K+].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C(OCC)(=O)C.O.C(#N)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([CH:23]3[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:14]=4[NH:13][CH:12]=[CH:11]5)[CH2:27][CH2:28]3)=[N:21][O:22][C:18]=2[CH:17]=1.[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([CH:23]3[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:14]=4[NH:13][CH:12]=[CH:11]5)[CH2:27][CH2:28]3)=[N:21][O:22][C:18]=2[CH:17]=1
Reactant: ClCCCOc1cccc2cc[nH]c12
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Fc1ccc2c(C3CCN(CCCOc4cccc5cc[nH]c45)CC3)noc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
A stirred mixture of 7-(3-chloropropoxy)-1H-indole (3.5 g, 17 mmol), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 17 mmol), K2CO3 (2.3 g) and acetonitrile (60 ml) was refluxed for 11 hour The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4), and the solvent was concentrated to afford a dark oil. The oil was flash chromatographed on silica gel. Upon concentration of the appropriate fractions, 3.0 g of a white, foamy substance was obtained. The substance was dissolved in ethyl acetate (75 ml) and fumaric acid (0.97 g, 83 mmol) was added. The mixture was briefly heated to reflux, and then stirred at ambient temperature for 1.5 hours. The resultant insoluble white fumarate salt was collected and afforded 4.2 g of product. Recrystallization of the salt from dimethylformamide yielded 3.1 g (36%) of 6-fluoro-3-[1-[3-1(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole hemifumarate as a white solid, m.p.=213-215° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=2)[N:5]=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][N:3]12.Cl.[NH2:21][OH:22].C(NC(C)C)(C)C.C(O)(=O)C>CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:21][OH:22])=[O:13])[CH:10]=2)[N:5]=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][N:3]12
Reactant: COC(=O)c1ccc2nc3ccccn3c(=O)c2c1
Reactant: NO
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(NO)c1ccc2nc3ccccn3c(=O)c2c1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
5.9 gm of 11-oxo-11-H-pyrido[2,1-b]quinazoline-2-carboxylic acid chloride (see Example 12) were introduced into a solution of 2.08 gm of hydroxylamine hydrochloride and 9.8 ml of diisopropylamine in 100 ml of dimethylformamide, and the mixture was stirred at 20° C for 5 hours. Thereafter, the reaction mixture was acidified with dilute acetic acid and suction-filtered, yielding as the filter cake the semihyrate of the formula ##STR25##
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=[C:11]([CH:14]=2)[C:12]#[N:13])[CH:6]=1.N.[OH:20]O.O>CN1C(=O)CCC1>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[C:11]([CH:10]=[C:9]([C:15]([F:18])([F:16])[F:17])[CH:8]=2)[C:12]([NH2:13])=[O:20])[CH:6]=1
Reactant: OO
Reactant: Cc1cn(-c2cc(C#N)cc(C(F)(F)F)c2)cn1
Agent: N
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(-c2cc(C(N)=O)cc(C(F)(F)F)c2)cn1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
A solution of 5-(4-methyl-imidazol-1-yl)-3-trifluoromethyl-benzonitrile (3.5 g, 13.93 mmol) in NMP (28 mL) is treated with aqueous ammonia (9.8 mL, 25%) and aqueous hydrogen peroxide (3.5 mL, 30%). The resulting mixture is stirred for 1 hour at 20-25° C. and then poured into chilled water (420 mL). The resulting suspension is filtered and the filter cake is washed with water (50 mL), and dried in vacuo at 50° C. to give 3.2 g of the title compound (XXIII) (85.4%) as white crystals (98% area by HPLC).
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[CH:11]=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]2)=[O:19])[CH:11]=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cnc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3OC)CC2)cnc1C
Yield: 80 %

Procedure:
Phenyl-N-(5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.[CH3:18][NH:19][O:20][CH3:21].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:10][CH:11]=1)=[O:16]
Reactant: O=C(Cl)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: CNOC
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2′,4′-Dichloro-biphenyl-4-carbonyl chloride was dissolved in chloroform (10 mL) and added dropwise to a chilled solution of N,O-dimethyl hydroxylamine (2.5 g) and triethylamine (7 mL) in chloroform (40 mL). Following addition, the mixture was allowed to warm to room temperature and stirred for a further 30 minutes. The mixture was poured into water and the organic phase separated, washed with water, and dried. Evaporation gave an oil, which was purified by column chromatography (petrol/ethyl acetate) to give a pale yellow oil which slowly crystallised upon standing to give the title compound as a white solid. 13C NMR (CDCl3): δ 33.8, 61.2, 127.3, 128.2, 129.1, 129.9, 132.0, 133.2, 133.5, 134.2, 138.3, 140.5 and 169.5. 1H NMR (CDCl3): δ 3.39 (3H, s), 3.58 (3H, s), 7.26 (2H, m), 7.45 (2H, d, J=8.5 Hz), 7.54 (1H, s) and 8.08 (2H, d, J=8.5 Hz).
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[CH2:31]([N:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O)[CH3:32].[C:40]([BH3-])#[N:41].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:41]([CH2:40][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:38][C:34]3[N:33]([CH2:31][CH3:32])[CH:37]=[CH:36][N:35]=3)[CH2:21][C:22]3[NH:26][CH:25]=[CH:24][N:23]=3)=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: CCn1ccnc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3nccn3CC)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (120 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and then added with the compound (58.0 mg) obtained in Example 90-1 and sodium cyanoborohydride (18.0 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 2 days. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (107 mg) of the subject compound as a white solid.