Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NS(=O)(=O)c1ccc(OCCCCl)cc1
Yield: 89.5 %

Procedure:
A mixture of 25 g (0.144 mole) of p-hydroxybenzenesulfonamide, 45.5 g (0.289 mole) of 1-bromo-3-chloropropane and 59.7 g (0.432 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 24 hr. The mixture was cooled, filtered and the filtrate concentrated under vacuum pump pressure at 90° C. to give 32.2 g of tan gum as residue. The gum was purified by column chromatography on 600 g of silica gel. Fractions containing the title compound eluted with 8% acetone in benzene were combined and concentrated under reduced pressure to yield 12.2 g (34%) of white solid, m.p. 106°-107.5° C. on recrystallization from 2-propanol.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][N:6]2[C:11]=1[C:10](=O)[NH:9][CH:8]=[N:7]2)[CH3:2].C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[Cl:28][C:10]1[C:11]2=[C:3]([CH2:1][CH3:2])[C:4]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][N:6]2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1c(C(=O)OC)cn2nc[nH]c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCc1c(C(=O)OC)cn2ncnc(Cl)c12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 112.6 %

Procedure:
A 1 L round bottomed flask was charged with methyl 5-ethyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (25.0 g, 113 mmol), toluene (375 mL) and diisopropylethylamine (11.8 g, 91.6 mmol). Phosphorous oxychloride (20.7 g, 135 mmol) was then added drop-wise at room temperature (exothermic). Once the addition was complete the reaction mixture was heated to 100° C. for 20 hrs. Analysis of an aliquot by HPLC indicated that the starting material had been completely consumed (Rt starting material=10.6 min, Rt product=15.2 min). The reaction was then cooled and slowly poured into a mixture of saturated sodium hydrogen carbonate solution (500 mL), toluene (500 mL) and ice water (350 mL). After stirring for 30 minutes the organic layer was separated and washed with saturated sodium hydrogen carbonate solution (500 mL). Drying over sodium sulfate, filtration and concentration afforded 30.5 g (>100%) of crude methyl 4-chloro-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate. This material was dissolved in acetonitrile (800 mL) and the solution charged to a 2 L round bottomed flask. Sodium hydrogen carbonate (15.1 g, 180 mmol) and 5-amino-1-benzylindazole (27.8 g, 124 mmol) were then added followed by additional acetonitrile (400 mL). The resulting suspension was then stirred at room temperature for 16 h. HPLC analysis after this time indicated that approximately 17% of the starting indazole remained. The mixture was then heated to reflux for 1 hr after which time only 5% of the starting indazole remained. After cooling, the mixture was concentrated and the residue partitioned between methylene chloride (800 mL) and water (300 mL). The lower organic layer was separated and washed further with water (300 mL). Drying over sodium sulfate, filtration and concentration under reduced pressure afforded 51.3 g (100%) of methyl 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][C:46]([Cl:49])=[CH:47][N:48]=1>C(Cl)(Cl)Cl.O>[Cl:49][C:46]1[S:45][C:44]([NH:43][C:32]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[F:23])=[O:34])=[N:48][CH:47]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ncc(Cl)s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ncc(Cl)s4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (3 ml) to prepare a solution. Triethylamine (0.3 ml) and a solution of triphosgene (27 mg) in chloroform (0.2 ml) were then added to the solution, and the mixture was stirred at room temperature for 30 min. Next, a solution of 2-amino-5-chlorothiazole (70 mg) in chloroform (0.6 ml) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The extract was washed with saturated brine and was dried over anhydrous sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 12 mg of the title compound.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[CH3:17][NH:18][S:19]([C:22]1[CH:23]=[C:24]([C:32](Cl)=[O:33])[C:25]2[O:30][CH2:29][CH2:28][O:27][C:26]=2[CH:31]=1)(=[O:21])=[O:20]>C(O)(=O)C.O>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][C:32]([C:24]3[C:25]4[O:30][CH2:29][CH2:28][O:27][C:26]=4[CH:31]=[C:22]([S:19](=[O:21])(=[O:20])[NH:18][CH3:17])[CH:23]=3)=[O:33])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCN(C2CCCCC2)C1
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CNS(=O)(=O)c1cc2c(c(C(=O)NC3CCN(C4CCCCC4)C3)c1)OCCO2
Yield: 61.3 %

Procedure:
84 g of 1-cyclohexyl-3-aminopyrrolidine, 430 ml of chloroform and 146 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were introduced into a balloon flask provided with an agitator and a thermometer. After agitation of the mixture, the base was extracted with methylene chloride and then the solvent was evaporated. The crystals formed were dissolved in boiling absolute alcohol and the resulting solution was filtered on carbon black. The crystals produced after cooling were dissolved in a solution of acetic acid in water and then the solution was filtered over carbon black and the base was reprecipitated by the addition of 20% ammonia. 129.5 g of N-(1-cyclohexyl-3-pyrrolidyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 160°-161° C.; yield: 61.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[CH3:29][NH2:30]>O>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:30][CH3:29])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: CN
Solvent: O
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1CCN2c1ccc(F)cc1C
Temperature: 180 °C

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(700 mg, 1.7 mmol) was dissolved in aqueous solution of methylamine(40%, 5.0 ml) and the reaction mixture was refluxed at 180° C. for 15 hours in the pressure tube. The reaction mixture was dissolved in water, extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:1) to obtain 440 mg of desired compound as solid in 64% of yield.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH2:20](I)[CH2:21][CH3:22]>>[NH2:1][C:2]1[N:7]([CH2:20][CH2:21][CH3:22])[C:6](=[O:8])[C:5]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccncc2)c(=O)[nH]1
Reactant: CCCI
Product: CCCn1c(N)nc(-c2ccco2)c(-c2ccncc2)c1=O

Procedure:
The title compound was synthesized in a manner similar to that described for Example 3 from 2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone and n-propyl iodide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12](B3OC(C)(C)C(C)(C)O3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][C:26]1[C:27]([C:33]([NH:35][CH3:36])=[O:34])=[N:28][C:29](Br)=[CH:30][N:31]=1>>[NH2:25][C:26]1[C:27]([C:33]([NH:35][CH3:36])=[O:34])=[N:28][C:29]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)=[CH:30][N:31]=1
Reactant: CC1(C)OB(c2cccc(NCCc3ccccc3)c2)OC1(C)C
Reactant: CNC(=O)c1nc(Br)cnc1N
Product: CNC(=O)c1nc(-c2cccc(NCCc3ccccc3)c2)cnc1N
Yield: 39 %

Procedure:
3-Amino-N-methyl-6-{3-[(2-phenylethyl)amino]phenyl}pyrazine-2-carboxamide was synthesized according to the procedure described above from N-(2-phenylethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 3-amino-6-bromo-N-methyl-2-pyrazincarboxamide. Yield 39%. 1H NMR (400 MHz, CDCl3): 8.58 (s, 1H), 8.02 (br s, 1H), 7.32 (m, 3H), 7.26 (m, 3H), 7.18 (br d, 1H), 7.02 (br t, 1H), 6.64 (dd, 1H), 3.82 (br s, 1H), 3.51 (t, 2H), 3.02 (d, 3H), 2.94 (t, 2H); MS (EI) for C20H21N5O: 348 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1)=[O:5])[CH3:2].[C:12]([O:16][C:17]([O:19]C(OC(C)(C)C)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].O1CCC[CH2:28]1>CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][O:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])=[N:8][C:7]=1[CH3:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Product: CCOC(=O)c1sc(NOC(=O)OC(C)(C)C)nc1C
Yield: 70 %

Procedure:
A suspension of ethyl-2-amino-thiazole-5-carboxylate (972 mg, 6 mmol, B. Plouvler, C. Bailly, R. Houssin, j-P. Henlchart Heterocyles 32(4), 693–701, 1991 and H. J. Becker, J. de Jonge Rec. Trav. Chim, 61, 463, 1942), di-t-butyldicarbonate (1.94 g, 9 mmol) and 4-dimethylaminopyridine (73 mg, 0.6 mmol) in dry tetrahydrofuran (75 mL) was stirred under nitrogen for 24 h. The solvent was evaporated in vacuo. The residue was suspended in ether (50 mL). The solid was washed with ether (10 mL, 3×), and dried in vacuo to obtain the title compound (1.1 g, 70%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:20]=[C:21]2[C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:25]=3[NH:24][C:23](=[O:31])[N:22]2[CH:32]=1.C(N(CC)CC)C>CN(C=O)C>[C:2]([N:28]1[CH2:29][CH2:30][C:25]2[NH:24][C:23](=[O:31])[N:22]3[CH:32]=[C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[F:12])[N:20]=[C:21]3[C:26]=2[CH2:27]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (57 uL, 0.4 mmol) was added to a solution of 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (124 mg, 0.4 mmol) and triethylamine (74 uL, 0.5 mmol) in DMF (1 mL) at room temperature. The reaction mixture was stirred for 1 hour, then poured into ice water. The precipitate was collected, washed with 95% ethanol and ether, and subsequently dried to give 9-Carbobenzyloxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (Compound 44). Recrystallization from aqueous ethanol afforded Compound 41 as an off-white solid, m.p. 250° C. (d).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[C:6]([C:15]#[N:16])=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[CH2:24][C:25]([NH2:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:15]([C:6]1[C:7]([CH2:12][CH2:13][CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:3][C:2]([O:1][CH2:24][C:25]([NH2:27])=[O:26])=[CH:11][CH:10]=2)#[N:16]
Reactant: CCCc1nc2ccc(O)cc2c(-c2ccccc2)c1C#N
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2)c1C#N
Temperature: 60 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A suspension of 6-hydroxy-4-phenyl-2-propylquinoline-3-carbonitrile (0.98 g, 3.4 mmol), chloroacetamide (0.36 g, 3.8 mmol) and potassium carbonate (0.55 g, 4.0 mmol) in N,N-dimethylformamide (10 ml) was stirred at 60° C. for 18 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 2-[(3-cyano-4-phenyl-2-propylquinolin-6-yl)oxy]acetamide (1.0 g, yield 88%) as pale-yellow crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH2:34])[CH2:24][CH:23]2[OH:35])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].[CH2:36](N(CC)CC)C.[Cl:43][CH2:44][C:45]([CH3:50])([CH3:49])[C:46](Cl)=[O:47].O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][C:46](=[O:47])[C:45]([CH3:50])([CH3:49])[CH:44]([Cl:43])[CH3:36])[CH2:24][CH:23]2[OH:35])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CCN(CC)CC
Reactant: Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(Cl)C(C)(C)C(=O)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexane carbonyl]amino]-1-(2-aminophenyl)piperidin-3-ol (4.0 g) obtained in Step 2 in 30 ml of dichloromethane was cooled to 0° C. 2.2 ml of triethylamine and 2.1 ml of 3-chloropivaloyl chloride were added dropwise to the reaction mixture, which was then stirred for about 2 hours at room temperature. 20 ml of iced water was added to the reaction mixture. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was crystallized with ethyl acetate to give 4.1 g of the titled compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C:12]34[C:15]5[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=5[O:17][CH:11]3[C:10](=O)[CH2:9][CH2:8][CH:7]4[CH2:6]2)[CH2:3][CH2:2]1.[CH2:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C:12]34[C:15]5[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=5[O:17][CH:11]3[CH:10]([CH3:25])[CH2:9][CH2:8][CH:7]4[CH2:6]2)[CH2:3][CH2:2]1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c1OC1C(=O)CCC3CN(CC4CC4)CCC231
Product: COc1cccc2c1OC1C(C)CCC3CN(CC4CC4)CCC231

Procedure:
Oxidation of XI ##STR98## with chromium trioxide gives 3-cyclopropylmethyl-9-methoxy-2,4,4a,5,6,7-hexahydro-1H-benzo[4,5]furo[3,2-e]isoquinolin-7[3H]-one ##STR99## Reaction of this compound with methylenetriphenylphosphorane followed by catalytic hydrogenation of the resulting 7-methylene derivative gives 3-cyclopropylmethyl-9-methoxy-7-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline ##STR100##
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]1[CH2:30][CH2:29][C:16]2([C:21]3=[CH:22][CH:23]=[CH:24][N:20]3[C:19]3[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=3[O:17]2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:34]=[O:35])C>>[CH2:6]([N:13]1[CH2:30][CH2:29][C:16]2([O:17][C:18]3[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=3[N:20]3[C:24]([CH:34]=[O:35])=[CH:23][CH:22]=[C:21]23)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: c1ccc(CN2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
N,N-Dimethylformamide (723 μL, 9.40 mmol), under nitrogen, was cooled to 0° C. and POCl3 (876 μL, 9.40 mmol) was added dropwise. The reaction was stirred for 20 min at 0° C. and a white solid formed. A solution of 1-benzylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (2.07 g, 6.27 mmol) in dry DMF (15.5 mL) was added dropwise and the cooling bath was removed. The reaction mixture was stirred for 2 h at 50° C., then cooled down to room temperature and poured onto ice. Sodium hydroxide (1 M) was added until the pH reached 10, then the solution was acidified to pH 6 with 3 M HCl. The mixture was then extracted with EtOAc. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel: 10-70% EtOAc in hexanes) to give 1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (1.94 g, 86%). ESI-MS m/z calc. 358.4, found 359.3 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 8.17-8.07 (m, 1H), 7.38-7.30 (m, 4H), 7.29-7.24 (m, 1H), 7.20-7.13 (m, 2H), 7.09 (m, 2H), 6.20 (d, J=4.1 Hz, 1H), 3.59 (s, 2H), 2.76 (m, 2H), 2.58-2.45 (m, 2H), 2.10-1.96 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:13][CH:14]=1)[O:7][CH2:8][CH2:9][C:10]2=[O:12]
Reactant: COc1ccc(OCCC(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=O)CCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclisation is carried out on the acid chloride generated starting from the acid. Heating the acid obtained in Step B (500 mg:2.55 mmol) at reflux of toluene (20 ml) for 3 hours in the presence of thionyl chloride (0.56 ml:7.65 mmol:3 eq.) allows easy access to the acid chloride. The solvent and also the excess reagent are removed by concentrating the resulting yellow solution under reduced pressure. The dry residue is then taken up in 20 ml of anhydrous dichloromethane; aluminium chloride (465.9 mg:3.49 mmol:1.5 eq.) is then introduced cautiously. The reaction mixture is hydrolysed in the cold state after 1 hour of stirring at ambient temperature. The product is extracted, washed with water and then purified on a silica column (AcOEt/PE 3/7).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].[BH4-].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:11]1[CH:12]=[C:13]([CH2:14][OH:15])[CH:16]=[CH:17][CH:18]=1
Reactant: CN1CCC(OC(c2cccc(C=O)c2)c2nc3ccccc3[nH]2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(OC(c2cccc(CO)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde (example 505B, 310 mg) in methanol (4 mL) is added portionwise sodium borohydride (50 mg). The reaction mixture is stirred at room temperature for 15 minutes then heated at reflux for 3 h. Methanol is removed under reduced pressure. Water is added and the aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated to give {3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-phenyl}methanol. 1H NMR: 9.85 (sl, 1H), 7.78-7.65 (m, 1H), 7.50-7.12 (m, 7H), 5.87 (s, 1H), 4.64 (s, 2H), 3.62-3.45 (m, 1H), 2.78-2.58 (m, 2H), 2.22 (s, 3H), 2.15-1.50 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6]2.Cl.[CH2:22]([N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C(O)C.CCCCCCC>[CH2:22]([N:29]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:13]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NN(Cc1ccccc1)c1ccccc1
Reactant: CCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Agent: Cl
Solvent: CCCCCCC
Solvent: O
Solvent: CCO
Product: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 10 °C
Yield: 80 %

Procedure:
Generally, a suspension of equimolar amounts of 1-(6-methoxynaphthalen-2-yl)heptan-1-one and N-benzyl-N-phenylhydrazine hydrochloride (BPH) in ethanol is heated under reflux for five hours. Two portions of 0.1 equivalent of BPH in ethanol are added to the suspension at one hour intervals. Alternatively, the solution of BPH in ethanol is added to reaction mixture continuously. The resulting mixture is refluxed for an hour, diluted with heptane, and treated with water at 45° C. The organic and aqueous phases are separated, and the organic phase is washed with water and cooled to 10° C. to initiate crystallization. Upon cooling to −15° C., 80%-85% of crystalline 1-benzyl-2-(6-methoxy-naphthalen-2-yl)-3-pentyl-1H-indole is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[N:6][CH:7]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 5′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,3′]bipyridinyl (example E.24) (0.200 g, 0.5 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.157 g, 0.6 mmol) according to the general procedure VI. Obtained as an off-white solid (0.182 g, 68%). MS (ISP) 526.3 [(M+H)+].
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH2:24]([NH2:26])[CH3:25]>C(O)C>[CH2:24]([NH:26][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1)[CH3:25]
Reactant: CCN
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 9 reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and 33% ethylamine in ethanol (20 ml) yielded the title compound, 0.29 g, m.p. 181°-182° C. (recrystallised from ethanol/water and then from ethanol).