Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].C(N(CC)CC)C.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCOC(CN)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(CNC(=O)c1ccc(Br)cc1)OCC
Reaction time: 6 h
Yield: 66.1 %

Procedure:
To a stirred solution of aminoacetaldehyde diethyl acetal (6.66 g, 50.0 mmol) in CH2Cl2 (100 ml) was added triethylamine (5.06 g, 50.0 mmol), 4-bromobenzoyl chloride (10.97 g, 50.0 mmol), and the mixture was stirred for 6 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate. The solution was washed with 0.5N HCl aqueous solution, water, saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was recystallized with ethyl acetate-bexane to give title compound (10.45 g, 66% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.Cl.Cl.[C:24]1([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][N:41]2[CH2:40][CH2:39][N:38]([CH2:37][CH2:36][CH2:35][CH2:34][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[CH2:43][CH2:42]2)=[CH:5][CH:4]=1
Reactant: c1ccc2c(CCCCN3CCNCC3)cccc2c1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)CN2CCN(CCCCc3cccc4ccccc34)CC2)cc1
Temperature: 25 °C

Procedure:
In 6.0 ml of chloroform was dissolved 0.69 g of 4-methoxyphenacyl bromide, and 3.0 ml of N-ethyldiisopropylamine and 1.20 g of 1-(4-naphthalen-1-yl-butyl)piperazine dihydrochloride were added, followed by reflux with heating for an hour. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. To the residue was added a saturated aqueous sodium bicarbonate solution and, after extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure to give a crude 1-[2-(4-methoxyphenyl)-2-oxoethyl]-4-(4-naphthalen-1-yl-butyl)piperazine.
Reaction SMILES: C1C[O:4]CC1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH3:17])[CH2:15][CH2:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[I:24])[C:11]=2[CH:25]=1.C(=O)(O)[O-].[Na+].BrN1C(=O)CCC1=O>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH3:17])[C:15](=[O:4])[CH2:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[I:24])[C:11]=2[CH:25]=1
Reactant: CN1CCN=C(c2ccccc2I)c2cc(Cl)ccc21
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Product: CN1C(=O)CN=C(c2ccccc2I)c2cc(Cl)ccc21
Reaction time: 0.5 h

Procedure:
A THF solution of 158 mg 7-chloro-2,3-dihydro-5-(2-iodophenyl)-1-methyl-1H-1,4-benzodiazepine and a sodium bicarbonate aqueous solution were simultaneously added by drops to a THF solution of N-bromosuccinimide at room temperature. After the mixture had been stirred at the same temperature for additional 30 minutes, water was poured thereinto and the resulting mixture was extracted with ethyl acetate. Purifying the crude product by silica gel column chromatography gave 140 mg of 2'-iododiazepam.
Reaction SMILES: CN(C=O)C.[CH2:6]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][C:17]=2[C:24]([F:27])([F:26])[F:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:6]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[O:23][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])=[CH:20][CH:19]=[CH:18][C:17]=2[C:24]([F:27])([F:25])[F:26])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Oc1c(Cc2ccccc2)cnc2c(C(F)(F)F)cccc12
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2c(OCCCCCCBr)c(Cc3ccccc3)cnc12
Yield: 85.8 %

Procedure:
A DMF (3 mL) solution of 3-benzyl-8-(trifluoromethyl)quinolin-4-ol (500 mg, 1.65 mmol), 1,6-dibromohexane (3.22 g, 13.20 mmol), and potassium carbonate (455.7 mg, 3.30 mmol) was stirred at room temperature overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane:ethyl acetate), and the title compound (660 mg, yield 86%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:11][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)=[CH:7][CH:6]=2)[N:9]=[C:10]([C:21]([F:26])([F:27])[C:22]([F:23])([F:25])[F:24])[CH2:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2ccc(Br)cc2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CSc1cccc(-c2ccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
1-(4-Bromo-phenyl)-5-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Preparation 15, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (13.0 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (550.0 uL) and 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 90° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 20.0 mg of the titled compound as a white liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[OH:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ncc(-c3cccnc3)cc12
Reaction time: 1 h

Procedure:
To (3-nitro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (P-1399, R═H, 500 mg, 1.44 mmol) in dimethylformamide (26 mL) was added Dess-Martin periodane (674 mg, 1.59 mmol). The reaction was stirred for one hour and the reaction was poured into water. All solids were filtered and purified by silica gel column chromatography eluting with 3% methanol in dichloromethane to give the compound (536, 295 mg, 59%). MS (ESI)[M+H+]+=345.2.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 50 ml sinfle neck round bottom flask, under a nitrogen atmosphere, 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (100 mg, 0.19 mmol) was added to ethyl acetate (4 ml). To this solution was added 10% palladium on activated carbon (100 mg), followed by the addition of a hydrogen balloon. The reaction mixture was stirred for three hours at room temperature, then filtered through a bed of CELITE™. The desired title product was further purified by radial chromatography.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[CH2:10][C:11](=[N:17]O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Ni]>[NH2:17][CH:11]1[CH2:10][CH:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:13]([CH2:14][CH2:15][CH2:16]2)[CH2:12]1
Reactant: ON=C1CC2CCCC(C1)N2Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: NC1CC2CCCC(C1)N2Cc1ccccc1
Yield: 60.9 %

Procedure:
9-Benzyl-9-azabicyclo-(3.3.1)-nonan-3-one oxime (4.0 g; 0.0164 mole), m.p. 134°, was dissolved in ethanol (100 ml) and hydrogenated at 50°-60° at 250 psi in the presence of Raney nickel. The mixture was filtered after 24 hours through kieselguhr and evaporated in vacuo. The resulting oil was dissolved in dilute hydrochloric acid (50 ml) extracted with ethyl acetate (3×150 ml), the aqueous layer was basified and re-extracted with ethyl acetate (3×150 ml). The combined organic extracts were dried (K2CO3), filtered and evaporated in vacuo to yield 3-amino-9-benzyl-9-azabicyclo-[3,3,1]-nonane (2.3 g; 61%), used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N:8]=[CH:7]2)([O-])=O>CO.CCOC(C)=O.[Pd]>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccn2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(cnn2Cc2ccccn2)c1
Reaction time: 1.75 h

Procedure:
To 5-nitro-1-pyridin-2-ylmethyl-1H-indazole (Step 1) (671 mg, 2.63 mmol) in MeOH (15 mL) and EtOAc (5 mL) at RT was added a slurry of 10% Pd/C (150 mg) in MeOH (5 mL). The resulting slurry was stirred under a balloon of H2 for 1.75 h, filtered through Celite®, and rinsed with MeOH and EtOAc. Concentration of the filtrate gave 1-pyridin-2-ylmethyl-1H-indazol-5-ylamine.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:31]=[C:32]([F:40])[C:33]([C:36]([O:38]C)=[O:37])=[N:34][CH:35]=1)[CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1>[Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:31]=[C:32]([F:40])[C:33]([C:36]([OH:38])=[O:37])=[N:34][CH:35]=1)[CH3:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ncc(-c2ccccc2O[C@H](C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1cnc(C(=O)O)c(F)c1
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a tetrahydrofuran solution (96 ml) of methyl 5-(2-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}phenyl)-3-fluoropyridine-2-carboxylate (4.79 g) was added at room temperature an aqueous solution (48 ml) of lithium hydroxide monohydrate (192 mg), followed by stirring for 90 minutes. To the reaction solution was added 1 N hydrochloric acid for neutralization, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 5-(2-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}phenyl)-3-fluoropyridine-2-carboxylic acid (3.27 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:40]=[CH:39][C:29]2=[N:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37](=[O:38])[N:28]2[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:40]=[CH:39][C:29]5=[N:30][C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=6[C:37](=[O:38])[N:28]5[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: O=c1c2ccccc2nc2ccc(Cl)nn12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5nc6ccccc6c(=O)n5n4)cc3CC[C@@H]12
Yield: 59.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-10H-pyridazino[6,1-b]quinazolin-10-one (107 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-10% methanol/ethyl acetate eluent gradient) to give 103 mg (62%) of the title compound as an amorphous foam. mp 110°-114°. FDMS: m/e=456. α[D]589 =+54.77 (c=0.49, chloroform).
Reaction SMILES: [C:1]1([C:7]2([C:12]#N)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C([O:26]CC)C>CCCCCCC>[C:1]1([C:7]2([CH:12]=[O:26])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CCCC1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCCC
Product: O=CC1(c2ccccc2)CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-phenyl-1-cyclopentanecarbonitrile (7.0 g, 41 mmol) in n-heptane (100 ml) cooled to -30° C. was dropwise added a 1M solution of diisobutylaluminium hydride in n-heptane (82 ml, 82 mmol). The mixture was stirred at -30° C. for 1 h and at 0° C. for 1 h. The mixture was diluted with diethylether (100 ml) and silica gel (60 g) was carefully added keeping the temperature below -30° C. The mixture was then allowed to warm to room temperature and then stirred for 20 h. After filtration the filtrate was washed with water (2×100 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 3.45 g of the crude 1-phenyl-1-cyclopentanecarboxaldehyde.
Reaction SMILES: [Br: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.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[C:26]([CH3:30])=[N:27][NH:28][CH:29]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[C:26]([CH3:30])=[N:27][NH:28][CH:29]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1n[nH]cc1-c1ccc2c(c1)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1n[nH]cc1-c1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(3-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: S(O[CH2:6][CH:7]1[O:11][CH2:10][CH2:9][CH2:8]1)(=O)(=O)C.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[O:21][N:20]=2)[C:16]([O:30][CH3:31])=[CH:15][C:14]=1[NH2:32].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:6][CH:7]4[CH2:8][CH2:9][CH2:10][O:11]4)[CH2:28][CH2:29]3)[O:21][N:20]=2)[C:16]([O:30][CH3:31])=[CH:15][C:14]=1[NH2:32]
Reactant: CS(=O)(=O)OCC1CCCO1
Reactant: COc1cc(N)c(Cl)cc1-c1noc(C2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COc1cc(N)c(Cl)cc1-c1noc(C2CCN(CC3CCCO3)CC2)n1
Yield: 39 %

Procedure:
A mixture of tetrahydrofurfuryl mesylate (2.34 g), intermediate 12 (2.7 g) and sodium carbonate (2.8 g) in 4-methyl-2-pentanone (180 ml) was stirred and refluxed for 24 hours. More tetrahydrofurfuryl mesylate (1 g) was added and the reaction mixture was stirred and refluxed for 24 hours. The reaction mixture was cooled, washed with water, dried over MgSO4, filtered and the filtrate evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding of 1.34 g (39%) 2-chloro-5-methoxy-4-[5-[1 -[(tetrahydro-2-furanyl)methyl]-4-piperidinyl]- 1,2,4-oxadiazol-3-yl]-benzenamine (compound 7; mp. 148.5° C.).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([CH2:36][OH:37])=[CH:33][C:32]=2[CH:38]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].N1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([CH2:36][O:37][C:39](=[O:41])[CH3:40])=[CH:33][C:32]=2[CH:38]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(COc2ccc3oc(CO)cc3c2)oc2cccc(OCC3CCCN(Cc4cccnc4)C3)c12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cc2cc(OCc3oc4cccc(OCC5CCCN(Cc6cccnc6)C5)c4c3C)ccc2o1

Procedure:
A solution of [5-[3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-ylmethoxy]-benzofuran-2-yl]-methanol (Example 50, 21 mg), acetic anhydride (100 μl) and pyridine (300 μl) was stirred at room temperature for one hour. The reaction mixture was dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate solution and water. The organic layer was washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give acetic acid 5-[3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-ylmethoxy]-benzofuran-2-ylmethyl ester (22 mg) as a colorless oil. FAB-MS: m/z 555 (MH+); 1H-NMR (CDCl3): δ 1.25-2.23 (7H, m), 2.12 (3H, s), 2.23 (3H, s), 2.78 (1H, m), 2.97 (1H, br d, J=11 Hz), 3.47 (1H, d, J=13 Hz), 3.57 (1H, d, J=13 Hz), 3.86 (1H, dd, J1=9 Hz, J2=7 Hz), 3.94 (1H, dd, J1=9 Hz, J2=5 Hz), 5.09 (2H, s), 5.18 (2H, s), 6.55 (1H, d, J=8 Hz), 6.72 (1H, s), 7.00 (1H, dd, J1=9 Hz, J2=2.5 Hz), 7.04 (1H, d, J=8 Hz), 7.15 (1H, t, J=8 Hz), 7.16 (1H, d, J=2.5 Hz), 7.20 (1H, dd, J1=8 Hz, J2=5 Hz), 7.38 (1H, d, J=9 Hz), 7.66 (1H, br d, J=8 Hz), 8.48 (1H, br d, J=5 Hz), 8.53 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:32])([F:31])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[CH:27]=[N:26][N:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([F:31])([F:32])[F:15])=[CH:20][CH:21]=2)[C:29]1=[O:30])[CH3:13]
Reactant: O=c1[nH]cnn1-c1ccc(OCC(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnn(-c2ccc(OCC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 48.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.971 g of (1S)-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.0 g of 2-[4-(2,2,2-trifluoroethoxy) phenyl]-3(2H,4H)-1,2,4-triazolone, 0.825 g of 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-[4-(2,2,2-trifluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as colorless prisms.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[CH:14]=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1.C1C(=O)N([I:24])C(=O)C1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([I:24])=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1
Reactant: Fc1ccccc1-c1ccc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccccc1-c1ccc2[nH]cc(I)c2n1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution of 5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridine (199 mg, 0.938 mmol) in THF (10 mL) was treated with n-iodosuccinimide (232 mg, 1.031 mmol, Alfa-Aesar). The reaction was stirred at 23° C. under N2. After 45 min, the solution was diluted with EtOAc (75 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 15-30% EtOAc/hexane), affording 5-(2-fluorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (231 mg, 73%). MS (ESI, pos. ion) m/z: 339.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]3[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=3)=[O:44])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]3[CH:23]=[CH:24][C:25]4[NH:26][C:49]([C:48]5[CH:51]=[CH:52][C:45]([C:43](=[O:44])[NH:42][C:39]6[CH:40]=[CH:41][C:36]([N:33]7[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]7)=[CH:37][CH:38]=6)=[CH:46][CH:47]=5)=[N:1][C:4]=4[CH:5]=3)=[O:22])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)cc2)CC1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(C=O)cc3)cc2)CC1
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4nc5cc(NC(=O)c6ccc(N7CCN(C)CC7)cc6)ccc5[nH]4)cc3)cc2)CC1

Procedure:
Compound 196 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-(4-methylpiperazin-1-yl)benzoyl)aniline and 4-(4-(4-methylpiperazin-1-yl)phenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C37H40N8O2: 629.33; found: 629.16.