Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[CH2:9]N.N([O-])=[O:17].[Na+].C(=O)([O-])O.[Na+]>O>[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[CH2:9][OH:17]
Reactant: O=N[O-]
Reactant: NCc1c(F)cccc1F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: OCc1c(F)cccc1F
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
75 g of 10% aqueous sulfuric acid solution was charged, and 14.3 g of 2,6-difluorobenzylamine obtained in Example 1 was dropwise added thereto under cooling. Then, under cooling, a solution comprising 10.4 g of sodium nitrite and 20 g of water was dropwise added thereto over a period of 30 minutes at a reaction temperature of from 10 to 20° C. After the completion of the dropwise addition, stirring was carried out at the same temperature for 1 hour. After the completion of the reaction, neutralization in an aqueous sodium hydrogencarbonate solution was carried out, and extraction with methylene chloride was carried out. Methylene chloride was recovered, followed by distillation under reduced pressure to obtain 12.4 g of 2,6-difluorobenzyl alcohol (103° C./26 mmHg) (yield: 86.1%, purity: 88.1%).
Reaction SMILES: [Mg].[CH3:2]I.[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=O.O>C(OCC)C>[CH3:2][C:5]1[CH2:6][C:7]2[C:12]([CH:4]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=C1Cc2ccccc2C1
Reactant: CI
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CC1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.7 %

Procedure:
50 ml of diethyl ether was added to 2.5 g of magnesium. A solution of 14.3 g of methyliodide in 50 ml of diethyl ether was added in 1 hour, with cooling with the aid of a water bath. Then the reaction mixture was stirred for 30 minutes at room temperature. A solution of 13.2 g of 2-indanone in 40 ml of diethyl ether was then added to this reaction mixture, followed by 30 minutes' stirring. 100 ml of water was then added. The organic layer was separated from the water layer. This water layer was washed twice, using 50 ml of dichloromethane, after which the combined organic layers were dried over magnesium sulphate. The filtrate obtained after removal of the drying agent through filtration was concentrated through evaporation to yield 14.0 g of residue. This residue was dissolved in 100 ml of toluene, after which 4 drops of concentrated sulphuric acid were added and the resulting reaction mixture was refluxed for 30 minutes. After cooling to room temperature, the mixture was washed once using 50 ml of water. The toluene was removed through evaporation, after which the residue was distilled under a vacuum. Yield: 4.0 g of 2-methylindene (30%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:37][C:36]3[CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=[C:34]([F:33])[CH:35]=3)[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: O=Cc1cc(F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(Cc3cc(F)cc(C(F)(F)F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of a mixture of 4-methyl-2-{5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (40 mg, 0.09 mmol) in 1,2-dichloroethane (2.0 mL) was added 3-fluoro-5-trifluoromethyl-benzaldehyde (19 mg, 0.10 mmol) and sodiumtriacetoxyborohydride (25 mg, 0.12 mmol). The mixture was stirred for 14 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic was washed with saturated aqueous NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture contained 2-{5-[1-(3-fluoro-5-trifluoromethyl-benzyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester and methyl ester. Calcd for C33H34F7NO2 (M+H) 610.62, Found 610.30 (methyl ester) and Calcd for C34H36F7NO2 (M+H) 624.64, Found 624.24 (ethyl ester).
Reaction SMILES: [N:1]([C:4]1[C:9]([CH3:10])=[CH:8][N:7]=[CH:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:9]([CH3:10])=[CH:8][N:7]=[CH:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cncc(C)c1N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cncc(C)c1N
Yield: 98.4 %

Procedure:
0.50 g of material prepared in Step A was dissolved in 15 mL of ethanol. 0.15 g of 10% palladium on carbon was added. The reaction mixture was placed under one atmosphere of hydrogen for 2 hours. The catalyst was removed by filtration. The solvent was removed with a rotary evaporator to afford 0.43 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([C:26](O)=[O:27])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:33][NH2:34]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([C:26]([NH:34][CH3:33])=[O:27])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: Cc1cccc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)O)CC4)nc23)c1
Solvent: O=S(Cl)Cl
Product: CNC(=O)[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4cccc(C)c4)c3n2)CC1

Procedure:
Prepared from compound 134 of Example 1 by reaction with thionyl chloride and methylamine.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].O>O1CCCC1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:16]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:9]([F:8])([F:20])[F:19])[CH:17]=1
Reactant: C[C@@H]1CCC[C@H]1O
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H]1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
Trans-2-Methylcylopentanol (50 mg, 0.5 mmol) was added to a flame dried round bottom flask under nitrogen containing 0.5 mL of dry tetrahydrofuran (“THF”) and cooled to 0° C. A 1.0 M solution of potassium t-butoxide in t-butanol (0.5 mL) was added dropwise and the reaction mixture stirred at 0° C. for 0.5 h. The above solution was then transferred via syringe to a flask containing 2-Trifluoromethyl-4-fluoro-benzonitrile (95 mg, 0.5 mmol) in 0.5 mL of THF at 0° C. The mixture was stirred at 0° C. for 3 h, warmed to room temperature and stirred for 16 h. The reaction mixture was then cooled to 0° C., poured into a seperatory funnel containing 8 mL of water, and extracted with 10 mL of methyl tert-butyl ether. The organic phase was washed with water, brine, dried (MgSO4), concentrated in vacuo, and the residue purified by reverse phase HPLC (Shimadzu) to give 112 mg 4-(trans-2-Methyl-cyclopentyloxy)-2-trifluoromethyl-benzonitrile. GC/MS: 269 (M/Z for C14H14F3NO).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11](C)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].BrC1C=C([F:25])C=CC=1C(OC)=O>>[CH2:1]([C:3]1[CH:12]=[C:11]([F:25])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: CCc1cc(C)ccc1C(=O)OC
Product: CCc1cc(F)ccc1C(=O)OC
Yield: 93 %

Procedure:
The title compound (colorless oil, 14.5 g, 93%) was prepared using a procedure similar to that used for the preparation of compound 48.1 and using of methyl 2-bromo-4-fluorobenzoate (compound 470.1, 20.0 g) in place of methyl 2-bromo-4-methylbenzoate.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH:12]([OH:21])[C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12](=[O:21])[C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C#CC(O)C#Cc2ccccc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)c1ccc(C#CC(=O)C#Cc2ccccc2)cc1
Yield: 92 %

Procedure:
C20H16O, FW=272.34 g/mol. 1-(4-Isopropylphenyl)-5-phenyl-1,4-pentadiyn-3-ol (5.65 g, 20.6 mmol) and manganese dioxide (10.74 g, 124 mmol) were combined in dichloromethane (41 mL) and heated to reflux for 30 minutes. Following completion of the reaction, the reaction mixture is filtered through celite, concentrated and the orange liquid product is isolated in 92% yield. Rf 0.87 (DCM) 1H NMR (500 MHz, CDCl3, ppm) d 7.63 (d, 2H, J=7.0 Hz), 7.57 (d, 2H, J=8.4 Hz), 7.46 (d, 1H, J=7.3 Hz), 7.40 (d, 2H, J=7.7 Hz), 7.29 (Ar, m, 2H) 2.93 (m, 1H), 1.24 (d, 6H, J=7.0 Hz); HR MS (EI) m/z calculated 272.120115, found 272.119612.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CO[CH:11]=[C:12]1[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]1=[O:21]>CC(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:11]=[C:12]2[C:13](=[O:21])[O:14][C:15]([CH3:19])([CH3:20])[O:16][C:17]2=[O:18])=[CH:4][CH:3]=1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: Nc1ccc(Cl)nc1
Solvent: CC(C)O
Product: CC1(C)OC(=O)C(=CNc2ccc(Cl)nc2)C(=O)O1
Yield: 91 %

Procedure:
The mixture of 6-chloropyridin-3-amine (5.0 g, 38.8 mmol) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (7.2 g, 38.8 mmol) in i-PrOH (60 mL) was stirred at reflux for 2 h, and the solvent was removed to afford 5-((6-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as a solid in 91% yield (10.0 g). m/z 283 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[CH:9]([CH:12]=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:30]=[C:28]([NH:27][C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=4)[N:29]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(s1)C(=O)C(C=O)CC2
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc2c(s1)-c1nc(Nc3cccc([N+](=O)[O-])c3)ncc1CC2
Yield: 5.3 %

Procedure:
A mixture of 2-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazole-6-carbaldehyde (200 mg, 1 mmol), meta-nitro-phenyl guanidine nitrate (248 mg, 1), NaOH (41 mg, 1 mmol) and 2-methoxyethanol (2 mL) was heated under reflux for 16 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) gave the title compound as a yellow solid (18 mg, 5%): mp 227-228° C. Anal. RP-HPLC: tR 21.9 min (0-60% MeCN, purity 100%). 1H-NMR (DMSO-d6): δ 10.00 (s, 1H, NH), 8.89 (t, 1H, J 2.3, Ph-H), 8.30 (s, 1H, Py-H), 7.92 (ddd, 1H, J 8.3, 2.3, 0.7, Ph-H), 7.66 (ddd, 1H, J 8.3, 2.3, 0.7, Ph-H), 7.44 (t, 1H, J 8.3, Ph-H), 2.90 (m, 4H, CH2—CH2), 2.66 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 169.16, 159.27, 158.42, 156.05, 155.39, 148.04, 142.02, 129.57, 127.56, 124.22, 117.13, 115.16, 111.91, 24.56, 23.06, 19.48. MS (ESI−): m/z 337.94 (M−H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[CH2:12]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][N:13]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CCN(C(C)C)C(C)C>C(O)(C)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][C:16]3([CH2:12][N:13]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:14][CH2:15]3)[CH2:17][CH2:18]2)[CH:7]=[CH:6][N:5]=1
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccnc(C(F)(F)F)n3)CC2)C1
Yield: 47 %

Procedure:
4-Chloro-2-(trifluoromethyl)pyrimidine (2.72 mmol, 1 eq.) and isopropanol (4 ml) were introduced into a microwave vessel. tert-Butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.72 mmol, 1 eq.) and DIPEA (0.6 ml, 6.8 mmol), 2.5 eq.) were added in succession and the reaction mixture was introduced into a microwave oven at 75° C. for 45 min. After TLC control, the reaction mixture was concentrated on a rotary evaporator. A reddish liquid remained and was diluted with methylene chloride (200 ml). The organic phase was washed with water (2×100 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated. The brown liquid residue was purified by column chromatography (silica gel, ethyl acetate). Yield: 47%
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][C:4](=[O:16])[C:3]=1[C:17]#[N:18].Cl.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:36])=[C:32]([NH:34][NH2:35])[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[NH2:18][C:17]1[N:34]([C:32]2[CH:33]=[C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:29]=[CH:30][C:31]=2[CH3:36])[N:35]=[C:2]2[C:11]3[CH:10]=[C:9]([O:12][CH3:13])[C:8]([O:14][CH3:15])=[CH:7][C:6]=3[NH:5][C:4](=[O:16])[C:3]=12
Reactant: Cc1ccc(OCc2ccccc2)cc1NN
Reactant: COc1cc2[nH]c(=O)c(C#N)c(Cl)c2cc1OC
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2[nH]c(=O)c3c(N)n(-c4cc(OCc5ccccc5)ccc4C)nc3c2cc1OC
Temperature: 80 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (53 mg), 5-benzyloxy-2-methylphenylhydrazine hydrochloride (53 mg), triethylamine (84 μl) and ethanol (5 ml) was stirred at 80° C. for 24 hours. After cooling, 10% citric acid was added thereto, extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography to obtain the target compound (68 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].CS(O[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28]1)(=O)=O>O>[C:37]([O:36][C:34](=[O:35])[NH:33][CH:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[N:11]=3)[CH:6]=[CH:7][C:8]2=[O:12])[CH2:28][CH2:29]1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1ccc2ccc(Cl)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(Cl)nc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of 7-chloro-1,8-naphthyridin-2(1H)-one [J. Org. Chem. 1990, 55, 4744-4750] in dry DMF (20 mL) (540 mg, 3.0 mmol) at 0° C. was treated with sodium hydride (144 mg, 60% in mineral oil, 3.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was cooled using an ice bath. A solution of 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1yl}ethyl methanesulfonate in DMF (Intermediate 6), 0.33 mmol/mL, 10 mL, 3.3 mmol) was then added over 1 hour. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated sodium chloride solution (3×10 mL), dried over sodium sulfate and evaporated. Chromatography on silica gel using methanol in dichloromethane (0-15%) gave the title compound as a brown foam (711 mg, 58%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH3:14]COCC>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: O=C(O)Cc1noc2ccccc12
Reactant: CCOCC
Solvent: CO
Product: COC(=O)Cc1noc2ccccc12

Procedure:
A solution of 1,2-benzisoxazole-3-acetic acid (prepared according to G. Casini et al, J. Het. Chem. 6, 1969, 279) (18 g), ether saturated with dry HCI (150 ml) and methanol (200 ml) was stirred for 2 h at room temperature. Removal of the volatiles in vacuo gave methyl 1,2-benzisoxazole-3-acetate (17 g) as an oil.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:16]=[N+:17]=[N-:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[CH2:9]([N:16]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:18]=[N:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#Cc1ccccc1
Reactant: [N-]=[N+]=NCc1ccccc1
Solvent: ClCCl
Product: c1ccc(Cn2cc(-c3ccccc3)nn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
Phenylacetylene (103 mg, 1.0 mmol, 1.0 eq.) and benzyl azide (133 mg, 1.0 mmol, 1.0 eq.) were dissolved in an air-tight lockable vial with a septum in 10 mL dry dichloromethane. The Cu complex (catalytic or stoichiometric amounts) shown below was added, the vial sealed and the reaction stirred at room temperature for 2 days. For the removal of the catalyst complex the reaction mixture was put in 50 mL methanol and stirred for 20 min. The complex was removed by filtering and the filtrate was concentrated. Removal of the solvent and drying of the product in high vacuum resulted in the compound 1-benzyl-4-phenyl-1H-1,2,3-triazole as light yellow solid with 95% yield (245 mg, 0.95 mmol). The identity of the product was proven by NMR-spectroscopy, infrared spectroscopy and high-resolution mass spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:8][CH2:9]2)=[CH:4][CH:3]=1.C(OCC)(=O)C.CN(C)C.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C>[C:43]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:8][CH2:9]2)=[CH:4][CH:3]=1)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1cc(CN2CCN(C(=O)C3=Cc4ccc(O)cc4CC3)CC2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(CN2CCN(C(=O)C3=Cc4ccc(OC(=O)c5ccccc5)cc4CC3)CC2)cc(OC)c1OC
Reaction time: 7 h
Yield: 60.6 %

Procedure:
A mixture of 1-(7-hydroxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine (0.2 g), ethyl acetate (20 ml), trimethylamine (0.5 g) and benzoyl chloride (0.5 g) is left standing for 7 hours at room temperature. To the mixture is added ethanol (2 ml), and the mixture is left standing overnight. The solvent is distilled off under reduced pressure. To the residue is added ethyl acetate (50 ml), and insolubles are filtered off. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:acetone=1:1-1:2) and crystallized from ethyl ether to afford 1-(7-benzoyloxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine (0.15 g) as colorless prisms, m.p. 117°-119° C.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([CH:16]2[CH2:21][CH2:20][N:19](C(OCC(Cl)(Cl)Cl)=O)[CH2:18][CH2:17]2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2>C(O)(=O)C.[Zn]>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CN1c2ccccc2C(C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2)c2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: CN1c2ccccc2C(C2CCNCC2)c2ccccc21
Temperature: 85 °C

Procedure:
Zinc dust (1.3 g, 20 mmol) is added to a solution of the crude product from step A in 20 mL glacial acetic acid maintained at 85° C. The reaction mixture is filtered after 30 minutes and concentrated in vacuo. The residue is then diluted with water, basified with a 1.0N aqueous NaOH solution, and extracted with CH2Cl2. The extract is dried with Na2SO4, filtered and concentrated in vacuo. The residue is then purified via flash chromatography (MeOH/CH2Cl2) to provide the title compound.
Reaction SMILES: [OH-].[Na+].C(O)C.[NH2:6][C:7]1[N:11]([C:12]2[CH:21]=[CH:20][C:15]3[NH:16][C:17]([CH3:19])=[N:18][C:14]=3[CH:13]=2)[N:10]=[CH:9][C:8]=1[C:22]([C:24]1[N:25](S(C2C=CC=CC=2)(=O)=O)[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23]>O>[NH2:6][C:7]1[N:11]([C:12]2[CH:21]=[CH:20][C:15]3[NH:16][C:17]([CH3:19])=[N:18][C:14]=3[CH:13]=2)[N:10]=[CH:9][C:8]=1[C:22]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23]
Reactant: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccccc5n4S(=O)(=O)c4ccccc4)c3N)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccccc5[nH]4)c3N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
An aqueous solution (1.67 ml) of 4 M sodium hydroxide was added to an ethanol solution (17 ml) of [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1-benzenesulfonyl-1H-indol-2-yl)methanone (87 mg). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water. The resulting solid was collected by filtration, washed with water, and dried to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)methanone (40 mg, 63%).
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([CH2:11][NH2:12])[OH:10]>CCO>[CH:1]1([CH2:7][NH:12][CH2:11][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CCCCC1
Reactant: NCCO
Solvent: CCO
Product: OCCNCC1CCCCC1
Temperature: 75 °C
Yield: 51.3 %

Procedure:
A mixture of cyclohexylmethylbromide (23.2 g, 131 mmol) and ethanolamine (47.9 g, 786 mmol) in EtOH (131 mL) was heated at 75° C. for 2 hours. NMR analysis of an aliquot showed the reaction was complete. The reaction was then concentrated to remove ethanol and the resulting residue was diluted with DCM. The organic layer was washed successively with water (3×100 mL) and brine (100 mL) and then dried over sodium sulfate, filtered, and concentrated to give the title intermediate as a light yellowish oil (10.57 g). (m/z): [M+H]+ calcd for C9H19NO, 158.16. found 158.2. 1H NMR (CDCl3, 300 MHz) δ (ppm): 3.59 (t, J=5.4 Hz, 2H), 2.73 (t, J=5.4 Hz, 2H), 2.42 (d, J=6.6 Hz, 2H), 1.6-1.77 (m, 6H), 1.36-1.6 (m, 1H), 1.10-1.28 (m, 2H), 0.82-0.95 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][C:20](Br)=[O:21].O>ClCCl>[Br:18][CH2:19][C:20]([NH:9][C:6]1[N:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=1)=[O:21]
Reactant: Nc1ccc(C(F)(F)F)nn1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(C(F)(F)F)nn1
Reaction time: 1.5 h

Procedure:
6-Trifluoromethyl-pyridazin-3-ylamine (0.042 g) (prepared by a procedure similar to that described in WO2007048779) was dissolved in dichloromethane (40 mL) and stirred with potassium carbonate (0.214 g). 2-Bromoacetyl bromide (0.12 mL) was added and stirring continued for 1.5 hours. Water (0.24 mL) was added and the reaction mixture was stirred for 1.5 hours after which water (40 mL) was added and the reaction mixture stirred for a further 1.5 hours. The dichloromethane was separated, dried (MgSO4) and evaporated to afford the sub-titled compound as a white solid (0.053 g).