Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([CH3:23])([CH3:22])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:22][C:10]1([CH3:23])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a stirred mixture solution of 3,3-dimethyl-2-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (230 mg, 0.75 mmol) in methanol (2.5 mL) and tetrahydrofuran (3.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (190 mg, 90%) as a white solid: LC/MS m/e calcd for C18H19NO2 (M+H)+: 282.35, observed: 282.1.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.COCN[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>O1CCCC1>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]
Reactant: COc1ccccc1OC
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: 0 °C

Procedure:
A suitable reactor maintained under nitrogen is charged with veratrole (12.5 kg, 90.0 mol) and about 87 kg of tetrahydrofuran. The solution is cooled and maintained below −10° C. while adding n-butyl lithium (22.9 kg, 83.3 mol, 23.3% solution in hexane). The mixture is warmed to about 0° C. for 1 hour, then to about 25° C. for at least 2 hours. In a separate reactor maintained under nitrogen is charged with 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) as a heptanes wet cake (15.6 kg, 57.3 mol, dry weight basis) and about 66 kg of tetrahydrofuran. The mixture is cooled below −10° C.1 and the lithiated veratrole solution is added at such a rate to maintain the temperature below −10° C. The mixture is warmed to about 25° C. for at least 6 hours.2 When complete, the title compound may be utilized in Scheme H, step a, Example 108 as the reaction solution. 1The solution is sampled and analyzed by GC to determine the amount of 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) present.2The solution is sampled and analyzed by GC to confirm the complete formation of 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7). The reaction is complete if less than 3 area % of 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) is detected.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[C:25]([CH3:37])=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[C:25]([CH3:37])=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Yield: 86.9 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (300 mg) in acetonitrile (20 mL) were added ethyl 3-(3-hydroxy-2-methylphenyl)propanoate (197 mg) and cesium carbonate (511 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (400 mg) as a yellow solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, white solid (108 mg, 96%), MS (ISP) m/z=453.4 [(M+H)+], mp 235.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-fluorobenzoic acid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C@H:10]1[CH3:29])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:18]=2)[C@H:10]1[CH3:29]
Reactant: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1[C@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 4-[(6S,7R)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-(trifluoromethyl)benzonitrile (670 mg) in tetrahydrofuran (12 mL)-methanol (6 mL) was added 6 mol/L hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3) to give the title compound as a colorless solid (yield: 381.9 mg, 78%).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>CCCCCC.C1COCC1>[CH3:3][NH:4][C:5](=[O:9])[CH:6]([C:19](=[O:20])[NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:22])[F:21])=[CH:13][CH:14]=1)[C:7]#[N:8]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CNC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)C(C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 62.4 %

Procedure:
Sodium hydride (0.82 g, 20.4 mmoles), washed with Skellysolve B, was suspended in 20 ml of dry THF and treated at 15° C. with N-methylcyanoacetamide (2.0 g, 20.4 mmoles) [prepared in Step A]. The resultant suspension was further cooled to 5° C. and 4-trifluoromethylphenyl isocyanate (3.80 g, 20.4 mmoles) was added over several minutes. After 18 h at ambient temperature the solvent was removed and the residual syrup was poured into a cold mixture of water and 4 ml of 6N HCl. The precipitate was isolated by filtration and recrystallized from ethanol to give 3.63 g of the title compound, mp 184°-186° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.[C:17](O)([CH3:20])([CH3:19])[CH3:18].N1C=CC=CC=1>ClCCl.C1CCCCC1.C(Cl)(=O)C(Cl)=O.C(OCC)(=O)C>[C:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[Br:1])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)c1ccc(F)cc1Br
Reactant: CC(C)(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(F)cc1Br
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To a suspension of 2-bromo-4-fluoro-benzoic acid (28.5 g, 0.13 mol) in dichloromethane (500 mL) at room temperature was added oxalyl chloride (11.35 mL, 0.26 mmol) followed by DMF (0.05 mL, catalytic, CARE vigorous gas evolution) and the reaction mixture stirred for 3 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in DCM (500 mL) before treatment with a solution of tert-butanol (28.5 g, 0.26 mol) and pyridine (20.5 g, 0.26 mol). The resultant mixture was stirred at room temperature for 3 days before it was diluted with DCM and washed (1M aqueous sodium hydroxide, water, 0.1M aqueous HCl, water) dried (Na2SO4) filtered and concentrated in vacuo to give a yellow oil. The crude oil was subjected to flash chromatography (Si—PPC, gradient 0 to 20% ethyl acetate in cyclohexane) to give the title compound as a colourless oil (15.2 g, 42%). 1H NMR (CDCl3, 400 MHz) 7.76-7.73 (1H, m), 7.37 (1H, dd, J=8.36, 2.53 Hz), 7.05 (1H, ddd, J=8.70, 7.73, 2.53 Hz), 1.60 (9 H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:32]([C:34]1([O:37]C(=O)C)[CH2:36][CH2:35]1)=[O:33]>>[OH:37][C:34]1([C:32]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=5[O:26][CH2:27][CH:28]5[CH2:29][CH2:30]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:33])[CH2:36][CH2:35]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)C5(O)CC5)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A171) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=1.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]3[O:16][C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: O=[N+]([O-])c1cccc(COCCOCCCCCCBr)c1
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc(C3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Reaction time: 0.67 h
Yield: 101.8 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (4.40 g) in anhydrous DMF (75 ml) was treated under nitrogen at 0° with sodium hydride (60% dispersion in mineral oil, 1.04 g) and the mixture stirred for 40 min. A solution of 1-[(2-[(6-bromohexyl)oxy]ethoxy)methyl]-3-nitrobenzene (8.12 g) in DMF (10 ml) was added and the mixture stirred at 20° for 2 h. Phosphate buffer (pH 6.5, 100 ml) and water (100 ml) were added and the product extracted with EtOAc (4×100 ml). The combined organic layer was washed with water (3×100 ml) and dried (Na2SO4). The solvent was removed in vacuo to give a residue that was purified by Biotage. Elution with EtOAc-PE (1:1 then 3:2) followed by solvent evaporation in vacuo gave the title compound (9.50 g). LCMS RT=3.75 min, ES+ve 529 (MH)+.
Reaction SMILES: [ClH:1].Cl.C(OC1C=CC([CH:12]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=CC=1OC(F)(F)F)C.[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][C:38](C(C2(O)CCCCC2)CN2CCN(C(OC(C)(C)C)=O)CC2)=[CH:37][C:36]=1[O:63][C:64]([F:67])([F:66])[F:65])[CH3:33]>>[ClH:1].[ClH:1].[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:13]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH2:12][C:20]2([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:37][C:36]=1[O:63][C:64]([F:65])([F:66])[F:67])[CH3:33]
Reactant: CCOc1ccc(C(CN2CCNCC2)C2(O)CCCCC2)cc1OC(F)(F)F
Reactant: CCOc1ccc(C(CN2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)cc1OC(F)(F)F
Agent: Cl
Product: CCOc1ccc(C(CC2(O)CCCCC2)N2CCNCC2)cc1OC(F)(F)F

Procedure:
In an analogous manner to Example 135, step 4 1-{1-[4-ethoxy-3-(trifluoromethoxy)phenyl]-2-piperazin-1-ylethyl}cyclohexanol dihydrochloride was prepared from tert-butyl 4-[2-[4-(ethoxy)-3-(trifluoromethoxy)phenyl]-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate. MS (ES) m/z 417.1; HRMS: calcd for C21H31F3N2O3+H+, 417.23595; found (ESI, [M+H]+), 417.2354
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]#[N:21]>O1CCCC1>[C:10]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH:8]=[O:9])[CH2:19][C:20]#[N:21])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(C=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of diphenylacetoaldehyde (1 g) in tetrahydrofuran (10 ml) was added a suspension of 60% sodium hydride (0.25 g) in tetrahydrofuran (5 ml) carefully dropwise under ice-cooling and stirring. After completion of dropwise addition, the mixture was further stirred for 20 minutes. Then, bromoacetonitrile (0.41 ml) was added and the mixture was further stirred for 30 minutes. The reaction mixture was poured in ice-water and the oil that had separated out was extracted into ethyl acetate. The organic layer was taken, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The group was purified by silica gel column chromatography to provide the title compound (0.85 g) as colorless oil.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:11]=1[C:12](O)=O>O>[C:10]1([CH3:9])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:11]=1[C:12]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: Nc1ccccc1N
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Solvent: O
Product: Cc1cc(C)c(-c2nc3ccccc3[nH]2)c(C)c1
Temperature: 150 °C

Procedure:
2-Mesitylbenzimidazole was synthesized by dissolving 1.5 g 1,2-phenylene diamine (14 mmol) in 40 g of PPA at 120° C. To this solution, 2.1 g of 2,4,6-trimethylbenzoic acid (13 mmol) was added and the temperature was increased to 150° C. After 16 h the solution was cooled to 60° C. and poured into water forming an off-white precipitate. The precipitate was separated by filtration and washed thoroughly with water, yielding 2.6 g of light brown powder (85% yield).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]([P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[CH:10]=[C:11]([CH3:13])[CH3:12]>CCOCC>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][P:14]([O:15][CH3:16])(=[O:19])[O:17][CH3:18]
Reactant: Oc1cccc(O)c1
Reactant: COP(=O)(CC=C(C)C)OC
Solvent: CCOCC
Product: COP(=O)(CCC(C)(C)c1ccc(O)cc1O)OC

Procedure:
55.0 parts of resorcinol, 17.8 parts of dimethyl prenylphosphonate and 5.0 parts of Fulmont 23 (trademark) are stirred at 125° C. for 18 hours. The cooled reaction mixture is then diluted with ether, filtered free of catalyst, and poured into 500 parts of water. The oil which separated out is then washed by decantation with water and extracted with ether. Following further washes with sodium bicarbonate solution and water, the ether solution after concentration yields dimethyl 3-(2,4-dihydroxyphenyl)-3-methyl-butane-phosphonate, m.p. 142°-3° C., with the following percentage composition by weight.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[N:8]=2)=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:13](=[NH:14])[O:18][CH3:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: N#Cc1cccc(Cc2ccc(Cl)cc2)n1
Agent: [Na+]
Product: COC(=N)c1cccc(Cc2ccc(Cl)cc2)n1
Temperature: 20 °C
Reaction time: 17 h
Yield: 130.9 %

Procedure:
2-p-Chlorobenzyl-6-cyanopyridine (1.69 g, 0.0074 moles) was added to a solution of sodium methoxide [prepared by dissolving sodium metal (0.19 g, 0.0081 gram atoms) in methanol (20 ml)] under nitrogen, and the mixture stirred at 20° C. for 17 hours. The methanol was evaporated, the residue taken up in chloroform, neutralised with acetic acid and the precipitate filtered off on HYFLO. Concentration of the filtrate gave methyl 6-p-chlorobenzyl-2-picoline imidate (1.20 g, 62%) which was used in the next stage without further purification.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=4)[CH2:35][CH2:34]3)=[O:32])[CH2:25][CH2:24]2)=[CH:18][C:17]=1[C:49]([F:52])([F:51])[F:50])([O-:15])=[O:14].C([N-]C(C)C)(C)C.[Li+].CI.[Cl-].[NH4+].Cl>O1CCCC1>[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][CH:30]([CH3:1])[C:31]([N:33]3[CH2:34][CH2:35][N:36]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([F:46])([F:47])[F:48])=[CH:41][CH:40]=4)[CH2:37][CH2:38]3)=[O:32])[CH2:25][CH2:24]2)=[CH:18][C:17]=1[C:49]([F:52])([F:51])[F:50])([O-:15])=[O:14]
Reactant: CC(C)NC(C)C
Reactant: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CI
Product: CC(O[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.28 mL, 2.0 mmol) in dry tetrahydrofuran (3 mL) at 5° C. was added n-butyllithium (2.5 M solution in hexanes, 1 mL, 2.5 mmol). The resulting mixture was allowed to stir for 30 min. Meanwhile, 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (287 mg, 0.5 mmol, prepared in accordance with Example 11) was dissolved in dry tetrahydrofuran (2 mL). The solution was then cooled to −35° C. To the cooled solution was added an aliquot from the freshly prepared lithium diisopropylamide solution (1.8 mL). Stirring was continued for another 30 min. Methyliodide (37 μL, 0.6 mmol) was then added, and the mixture was allowed to attain −10° C. over 1 hr. Saturated ammonium chloride solution was then added (3 mL), and the mixture warmed to room temperature and acidified to a pH of 3 with 1 N HCl. The aqueous solution was then extracted with ethyl acetate (2×15 mL), and the combined organic layers were washed with brine (2×5 mL), dried over magnesium sulfate, and concentrated. Purification by column chromatography (Ethyl acetate/cyclohexanes, 4:1) afforded the desired product as an orange solid (152 mg, 52% yield). The structure was confirmed using Protocol I-B. Calculated mass=589; observed mass=589; HPLC retention time=5.82 min.
Reaction SMILES: [N+](C1C=CC=CC=1C1C=CC(C[N:17]2[C:21]([CH2:22][O:23][CH3:24])=[C:20]([Cl:25])[N:19]=[C:18]2[CH2:26][CH2:27][CH2:28][CH3:29])=CC=1)([O-])=O.C(O)(=O)C>[Fe].CO>[CH2:26]([C:18]1[NH:17][C:21]([CH2:22][O:23][CH3:24])=[C:20]([Cl:25])[N:19]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1nc(Cl)c(COC)[nH]1

Procedure:
A solution of 4.40 g of 1-[(2'-nitrobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole, 2.10 g of iron powder, 4.25 mL of glacial acetic acid, and 200 mL of methanol was refluxed for 5 hours. After cooling, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The precipitated iron salts were removed by filtration through Celite®, and the resulting solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. Column chromatography on silica gel (elution: 10-30% ethyl acetate/benzene) furnished 2.95 g of 1-[2'-aminobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole; NMR (200 MHz, CDCl3); δ 7.43 (d, 2H); 7.19-7.04 (m, 4H); 6.80 (m, 2H); 5.19 (s, 2H); 4.33 (s, 2H); 3.70 (br s, 1H); 3.28 (s, 3H); 2.59 (t, 2H); 1.67 (quint., 2H); 1.34 (sext., 2H); 0.87 (t, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([O:19][CH3:20])=[CH:16]2)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCCCCC>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([O:19][CH3:20])=[CH:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc2ccc(OC)cc2c1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCc1ccc2ccc(OC)cc2c1
Yield: 90 %

Procedure:
Using 7-methoxy-2-naphthyltrifluoromethanesulfonate (30.63 g, 0.10 mol) and 1-octyne (13.78 g, 0.125 mol), 7-octyn-1-yl-2-methoxynaphthalene was synthesized by the same operation as that in the method for synthesizing 7-decyl-2-methoxynaphthalene according to Example 3, and subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain a light yellow oil product of 7-octyn-1-yl-2-methoxynaphthalene (22.9 g, yield of 86%). The obtained 7-octyn-1-yl-2-methoxynaphthalene (total amount) was subjected to catalytic reduction in toluene (213 ml) under a hydrogen atmosphere by adding 10% Pd/C (2.13 g). The obtained product was subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain 7-octyl-2-methoxynaphthalene (compound (3)-10, 24.30 g, yield of 90%).
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11](OC)=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[NH3:16]>>[SH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([NH2:16])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[NH3:5]
Reactant: COC(=O)c1nc2nc(C)cc(S)n2n1
Agent: N
Product: Cc1cc(S)n2nc(C(N)=O)nc2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 2.50 g of methyl 7-mercapto-5-methyl-s-triazolo[1.5-a]pyrimidine-2-carboxylate (Euro. Pat. Publ. 150,507) in 25ml of 25 percent aqueous ammonia was stirred at room temperature for 6 hours. The mixture was filtered and the solid was dried at 50° in a vacuum. There was obtained 7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide as a 1:1:1 adduct with water and ammonia.