Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([C:15]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[O:16])[CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:22]1([N:20]2[CH:21]=[C:17]([C:15]([C:4]3[CH:3]=[C:2]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:14]=[CH:13][C:5]=3[O:6][CH2:7][C:8]([OH:10])=[O:9])=[O:16])[CH:18]=[N:19]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Product: O=C(O)COc1ccc(-c2ccccc2)cc1C(=O)c1cnn(-c2ccccc2)c1

Procedure:
Prepared from ethyl [4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate and phenylboronic acid according to GP4: LC/MS (an 10p8): Rt 1.05 min, m/z 398.6 [M−H]−; 1H NMR (CDCl3): δ 4.86 (s, 2H), 7.17 (d, J=8.6 Hz, 1H), 7.35-7.57 (m, 8H), 7.70-7.75 (m, 2H), 7.78 (dd, J=8.6, 2.3 Hz, 1H), 7.84 (d, J=2.3 Hz, 1H), 8.20 (s, 1H), 8.54 (s, 1H); 13C NMR (CDCl3): δ 67.7, 115.8, 120.1, 124.8, 127.1, 128.0, 128.3, 129.1, 129.3, 129.4, 129.9, 132.3, 136.2, 139.3, 139.3, 143.5, 155.8, 170.4, 189.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)[C:10]([F:13])([F:12])[F:11].Br[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:37][O:36][C:34](=[O:35])[C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(OCCBr)cc1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCCOc2ccc(C(C)C(O)(c3cnc(C)cn3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 1, step 7, 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 1, step 6) was reacted with methyl 4-(2-bromoethoxy)benzenecarboxylate and potassium carbonate to give the title compound as a colorless viscous oil. MS (m/e)=524.9 [M+H+].
Reaction SMILES: [H-].[K+].[Cl:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1.Cl[C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[Cl:3][C:4]1[N:8]([C:15]([O:17][CH3:18])=[O:16])[C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1
Reactant: COC(=O)Cl
Reactant: Cc1cccc2[nH]c(Cl)nc12
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)n1c(Cl)nc2c(C)cccc21
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
Potassium hydride (0.85 g of 35% in oil, washed with ether to remove oil, 7.4 mmol) was added to a stirred solution of 2-chloro-4-methyl-1H-benzimidazole (1.23 g, 7.4 mmol) in THF (25 mL). Methyl chloroformate (0.7 g, 7.4 mmol) was added and the reaction was stirred 10 minutes. The solvent was removed and the material was partitioned between ethyl acetate and water. Evaporation of the organic layer gave 1.68 g of white solid. Crystallization from hexane gave 1.42 g of white crystals, mp 90°-91° C. Anal. Calc'd for C10H9ClN2O2 : C, 53.47; H, 4.04; C1, 15.78; N, 12.47. Found: C, 53.63; H, 4.11; Cl, 15.81; N, 12.45.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([N:14]([CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13].C([O-])([O-])=O.[K+].[K+].[Cl:44][CH2:45][CH2:46][CH2:47]I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([N:14]([CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:47][CH2:46][CH2:45][Cl:44])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13]
Reactant: ClCCCI
Reactant: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccc3n2Cc2ccccc2O)c(Cl)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccc3n2Cc2ccccc2OCCCCl)c(Cl)c1OC
Yield: 99.7 %

Procedure:
A solution of 350 mg (0.67 mmole) of (2-chloro-3,4-dimethoxyphenyl)-N-({l-[(2-hydroxyphenyl)methyl] benzimidazol-2-yl}methyl)-N-(3-methylbutyl) carboxamide and 278 mg (2.01 mmole) of K2CO3 in 2 mL of anhydrous N,N-dimethylformamide is treated with 79.1 μL (0.737 mmole) 1-chloro-3-iodo propane at room temperature for 19 hr. The resulting solution is diluted with 60 mL of ethyl acetate, washed with 3×20 mL water and 1×20 mL of brine, dried over anhydrous Na2SO4 and the solvent is removed in vacuo to afford 400 mg (99%) of (2-chloro-3,4-dimethoxyphenyl)-N-[(1-{[2-(3-chloropropoxy)phenyl]methyl}benzimidazol-2-yl)methyl]-N-(3-methylbutyl) carboxamide.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl-].[Al+3].[Cl-].[Cl-].C1(CC(Cl)=[O:27])C=CC=CC=1>C(=S)=S>[C:9]1([C:1]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:27])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 156.3 %

Procedure:
57.0 g (0.30 mole) of n-octylbenzene are dissolved in 500 ml of carbon disulfide, 45.0 g (0.34 mole) of aluminum chloride are added at 0° C., and a solution of 46.4 g (0.30 mole) of phenylacetyl chloride and 50 ml of carbon disulfide are added dropwise at from 0° to 5° C., while stirring. The reaction mixture is stirred for a further 2 hours at from 0° to 5° C. and then for 15 hours without being cooled, after which it is poured carefully onto 1 l of semiconcentrated ice-cold hydrochloric acid. The phases are separated, the organic phase is extracted by shaking with 300 ml of water, the aqueous phase is extracted with three times 300 ml of methylene chloride, and the combined organic phases are dried over sodium sulfate. The solution is filtered and the solvent is distilled off to give 92 g (=100% of theory) of deoxybenzoin as a colorless crystalline mass, which is shown by thin layer chromatography (silica gel/CH2Cl2 : R≈0.95; toluene: R≈0.61) to be sufficiently pure for the subsequent bromination.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[C:4]([Cl:23])[CH:3]=1.[Br-].[CH2:25]([O:27][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][Zn+])[CH3:26].Cl>O1CCCC1.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>[Cl:23][C:4]1[C:5]([N+:20]([O-:22])=[O:21])=[CH:6][C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[C:2]([CH2:31][CH2:30][CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH:3]=1
Reactant: CCOC(=O)CCC[Zn+]
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-bromo-2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-1-nitrobenzene (2.04 g) in tetrahydrofuran (10 mL) were added 4-ethoxy-4-oxobutylzinc bromide (0.5 mol/L tetrahydrofuran solution, 12 mL) and tetrakis(triphenylphosphine)palladium(0) (0.2 g), and the mixture was stirred at room temperature under an argon atmosphere overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/2) to give ethyl 4-[5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-nitro-phenyl]butyrate (0.72 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution were added methanol (5 mL) and nickel(II) bromide (11 mg). To the mixture was added sodium borohydride (0.12 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/2) to give the title compound (0.41 g).
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.CN(C=O)C.[H-].[Na+].[C:21]([O:24][CH2:25][CH3:26])(=O)C>[NH4+].[Cl-]>[CH3:12][C:2]([O:13][CH2:26][C@@H:25]1[CH2:21][O:24]1)([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(Cn1ccc([N+](=O)[O-])n1)OC[C@@H]1CO1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 43.1 %

Procedure:
A mixture of 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (0.64 g, 3.46 mmol), and DMF (30 mL) was stirred at 0° C. for 5 min, then NaH (60% dispersion in oil, 0.415 g, 17.3 mmol) was added and stirred 20 min at 0° C. S-(+)-glycidyl-3-nitrobenzenesulfonate (1.79 g, 6.92 mmol) was added and stirred at 0° C. for 1 h then warmed to 25° C. for 3 h. The mixture was then diluted with NH4Cl(s), ethyl acetate, the organic phase was separated, washed with NaHCO3(satd) dried with Na2SO4, and filtered. The mixture was then concentrated and purified by column chromatography (40-120 g Analogix column, 80% EtOAc/heptane to yield the product 1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-3-nitro-1H-pyrazole as a white solid (0.36 g, 43.1%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6]Br)=[CH:2]1.[CH3:8][C:9]1[CH:10]=[C:11]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[C:12]([NH:14][CH2:15][C:16]1([N:21]([CH3:23])[CH3:22])[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:13]>>[CH3:28][C:25]1[CH:24]=[C:11]([CH:10]=[C:9]([CH3:8])[C:26]=1[O:27][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:12]([NH:14][CH2:15][C:16]1([N:21]([CH3:23])[CH3:22])[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:13]
Reactant: BrCc1ccsc1
Reactant: Cc1cc(C(=O)NCC2(N(C)C)CCCC2)cc(C)c1O
Product: Cc1cc(C(=O)NCC2(N(C)C)CCCC2)cc(C)c1OCc1ccsc1

Procedure:
Synthesised from 3-thienylmethyl bromide and 3,5-dimethyl-4-hydroxy-N-[(1-dimethylaminocyclopentyl)methyl]benzamide following the procedure as described in Example 10 (b). The crude product was purified by SPE chromatography. 1H NMR (CDCl3) δ: 1.41 (m, 2H), 1.65 (m, 4H), 1.83 (m, 2H), 2.27 (s, 6H), 2.31 (s, 6H), 3.44 (d, 2H, J˜2 Hz), 4.85 (s, 2H), 6.88 (s, 1H), 7.16 (m, 1H), 7.26 (m, 1H), 7.34 (m, 2H), 7.45 (s, 2H). LCMS m/z 387.0 (MH+; 98%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.O1[CH2:22][CH2:21]OCC1>CO>[CH2:2]1[C:2]23[C:21]4[C:22](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:5]([CH2:6][C:10]42[C:9]2[C:4]([CH:3]1[C:16]1[C:11]4=[CH:12][CH:13]=[CH:14][CH:15]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:4]1[C:3]3=[CH:16][CH:11]=[CH:10][CH:9]=1
Reactant: C1COCCO1
Reactant: BrCc1c2ccccc2cc2ccccc12
Solvent: CO
Product: c1ccc2c(c1)C1CC34c5ccccc5C(CC23c2ccccc21)c1ccccc14
Reaction time: 0.5 h
Yield: 18 %

Procedure:
9-(bromomethyl)anthracene (4 gm., 14.8 mmoles) was dissolved in 200 ml. of dioxane at 70° C. under nitrogen. With the addition of powdered stannous chloride dihydrate (3.2 gm., 14 mmoles), the solution turned orange brown. Coloration faded in a few minutes and the reaction mixture was allowed to stand at 70° C. for another half hour and then was diluted with an equal volume of methanol. The crude yellow-green precipitate was filtered and then dissolved in methylene chloride and the methylene chloride solution filtered to remove undissolved material. The solution was decolored and the lepidopterene reprecipitated from the methylene chloride solution by the addition of methanol to obtain 1 gm. (2.6 mmoles) of the colorless, crystalline solid (18% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][NH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:25][N:26]([CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:15]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[N:6][C:7]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1)=[CH:8]2)=[O:17]
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: CNCCN1CCCCC1
Product: Cc1cc(Nc2cc3cc(C(=O)N(C)CCN4CCCCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and Methyl-(2-piperidin-1-yl-ethyl)-amine to give 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid methyl-(2-piperidin-1-yl-ethyl)-amide. LC-MS: m/e 451 (MH+).
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:4]([CH3:3])[C:5](=[O:13])[N:6]=2)[CH:11]=1
Reactant: BrBr
Reactant: CC1C(=O)Nc2ccccc21
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1=c2cc(Br)ccc2=NC1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.7 %

Procedure:
Under an atmosphere of nitrogen, bromine (0.96 g, 6.0 mmol) in acetic acid (5 cm3) was added drop wise to a solution of 3-methyl-2-indolinone (0.8749 g, 6.0 mmol) (Kende, et al, Synth. Commun., 12, 1, 1982) and sodium acetate (0.50 g, 6.0 mmol) in acetic acid (10 cm3). The reaction was stirred at room temperature for 3.5 h. Saturated sodium carbonate was added to quench the reaction. The water layer was extracted with EtOAc (×3), dried (MgSO4), filtered, and evaporated to give the title compound (1.26 g, 93%), Mp=119-120° C.; 1H NMR (DMSO) δ 1.32 (d, 3H, J=7.66 Hz), 3.45 (q, 1H, J=7.62 Hz), 6.77 (d, 1 H, J=8.23 Hz), 7.46 (s, 1H), 7.36-7.33 (m, 1H), 10.4 (s, 1H); IR (KBr) 3200, 1725 cm−; MS (EI) m/z 224/226 (M−H)−; CHN calculated for C9H8BrNO: C, 47.82; H, 3.57; N, 6.20; Found: C, 47.44; H, 3.42; N, 6.04.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=[C:14]2[C:22]2[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:30])[CH:25]=[CH:26][CH:27]=2)=[CH:9][CH:8]=1.C([Si]([O:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][CH2:63][CH:64]2[CH2:66][O:65]2)=[CH:58][CH:57]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:32]([NH:31][C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:14]2[N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][NH:4][CH2:66][CH:64]([OH:65])[CH2:63][O:62][C:59]4[CH:60]=[CH:61][C:56]([OH:55])=[CH:57][CH:58]=4)=[CH:8][CH:9]=3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:23]=1)=[O:30])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCNC(=O)Nc1cccc(-c2nc3cccnc3n2-c2ccc(CCN)cc2)c1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=CO
Product: CCCCCCNC(=O)Nc1cccc(-c2nc3cccnc3n2-c2ccc(CCNCC(O)COc3ccc(O)cc3)cc2)c1
Yield: 40.8 %

Procedure:
N-(3-{3-[4-(2-aminoethyl)phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}phenyl)-N′-hexylurea formate (0.27 g, 0.539 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.217 g, 0.54 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.19 g, 0.22 mmol).
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:15]([Cl:24])[CH:14]=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[Cl:24][C:15]1[CH:14]=[C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][CH2:21][O:22][CH3:23]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: COCCOc1ccc(Br)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (453 mg), methoxyethyl 4-bromo-2-chlorophenyl ether (0.97 g), bis(triphenylphosphine)palladium (II) chloride (105 mg), copper (I) iodide (55 mg), triethylamine (5 ml) and dimethylformamide (10 ml) was stirred at 70° C. under an atmosphere of argon for 2 hours. The triethylamine and dimethylformamide were removed by evaporation. The residue was purified by flash column chromatography on silica gel (Merck Art. No. 9385) using a mixture of 10% methanol in dichloromethane containing 1% ammonia (density, 0.880 g/cm3) as eluent. The residue was crystallised from acetonitrile to give 3-[2-(3-chloro-4-(2-methoxyethoxy)phenyl)ethynyl]quinuclidin-3-ol (0.52 g) as a colourless solid, m.p. 138-139° C.; microanalysis, found: C, 64.1; H, 6.7; N, 4.1%; C18H22ClNO3 requires: C, 63.9; H, 6.6; N, 4.1%; NMR ([CD3 ]2SO): 7.5(1H,d), 7.3(1H,d of d), 7.1(1H,d), 5.5(1H,s), 4.2(2H,m), 3.7(2H,m), 3.3(3H,s), 2.8(2H,m), 2.7(4H,m), 2-1.8(3H,m), 1.6(1H,m) and 1.3(1H,m); m/z 336(M+H).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:15])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[CH2:16](Br)[CH2:17][CH3:18].O>CN(C)C=O>[CH2:16]([CH:12]1[CH2:13][CH2:14][CH:9]([CH:6]2[CH2:5][CH2:4][CH:3]([OH:15])[CH2:8][CH2:7]2)[CH2:10][CH2:11]1)[CH2:17][CH3:18]
Reactant: CCCBr
Reactant: OC1CCC(C2CCCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1CCC(C2CCC(O)CC2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
60% Sodium hydride (1.01 g) was added slowly to a suspension of 4,4′-bicyclohexanol (5 g) in N,N-dimethylformamide (50 ml) at ambient temperature, and the mixture was stirred for 6 hours at 80° C. To the mixture was added dropwise n-propylbromide (2.29 ml) at 0-5° C., and the reaction mixture was stirred for 18.5 hours at 80° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methyl alcohol (50:1) to give 4′-propyl-4-hydroxy-1,1′-bicyclohexane (1.21 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:7]=[C:8]([F:10])[CH:9]=1.N1C=CC=C[C:21]=1C(N)=O.IC>CN(C)C=O.O>[F:10][C:8]1[CH:7]=[C:6]([N:11]([CH3:21])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: O=C(Nc1cc(F)cc(F)c1)c1ccccn1
Reactant: NC(=O)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(C(=O)c1ccccn1)c1cc(F)cc(F)c1
Temperature: 65 °C
Yield: 56 %

Procedure:
To a suspension of 80% sodium hydride (1.22 g, 41 mmol) in anhydrous dimethylformamide (90 mL), was added dropwise a solution of N-(3,5-difluorophenyl)-2-pyridinecarboxamide, prepared by a process of Example 1, difluorophenyl)-2-pyridinecarboxamide, prepared by the process of Example 1, Step 1 (8.71 g, 37 mmol) in dimethylformamide (30 mL). The reaction mixture was warmed to 65° C. for 1 hour and then treated with iodomethane (2.60 mL, 42 mmol) at room temperature. After 2.5 hours the reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with 75% brine, dried, preabsorbed onto silica gel, and flash chromatographed (300 g, elution with 40% ethyl acetate in petroleum ether) to yield pure N-(3,5-difluorophenyl)-N-methyl-2-pyridinecarboxamide (5.16 g, 21 mmol, 56%, m.p. 102°-104° C.), which was reacted with Lawesson's reagent (4.36 g, 11 mmol) in anhydrous toluene (65 mL) at reflux temperature for 1.5 hours. The toluene was evaporated and the residue was dissolved in dichloromethane, preadsorbed onto silica gel, flash chromatographed (300 g, elution with 10% ethyl acetate in petroleum ether), and recrystallized from ethyl acetate in petroleum ether to afford a yellow solid (2.36 g, 24%), m.p. 131°-134° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].Cl[CH2:13][C:14]([OH:16])=[O:15]>>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][O:6][CH2:13][C:14]([OH:16])=[O:15]
Reactant: OCCc1ccc(F)cc1F
Reactant: O=C(O)CCl
Product: O=C(O)COCCc1ccc(F)cc1F
Temperature: 120 °C
Yield: 54.4 %

Procedure:
3.63 g of 2,4-difluorophenethyl alcohol were reacted with 2.17 g of chloroacetic acid in a manner analogous to that described in Example 1(a), except that the reaction mixture was heated at 120° C. for 1 hour, to give 2.7 g (54%) of 2-(2,4-difluorophenyl)ethoxyacetic acid in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH2:13][C:14]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[C:7]1([CH2:13][C:14]2([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CC1(Cc2ccccc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC1(Cc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
To a suspension of 68.8 g (1.81 mole) of LiAlH4 in 1350 ml anhydrous ether, under an atmosphere of nitrogen, there are poured dropwise during 1.5 hour, while keeping the temperature of the reaction mixture between 10° and 20° C., 279.9 g (1.51 mole) of 1-[(phenyl)methyl]cyclopentanecarbonitrile (prepared according to Campaigne E. and Forsh R. A., J. Org. Chem. (1978) 43, 1044-50). After stirring at room temperature during 18 hours, the excess of hydride is destroyed by adding 344 ml water. The organic phase is dried over Na2SO4 and filtered. The filtrate which is concentrated under reduced pressure is distilled to give 273.9 g (yield=95.8%) of a colorless liquid. b.p.2 =122° C.
Reaction SMILES: [Cl:1][C:2]1([Cl:21])[CH2:4][CH:3]1[CH2:5][S:6][C:7]1[CH:20]=[CH:19][C:10]2[NH:11][C:12]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[N:13][C:9]=2[CH:8]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl.CC(O)=O>[Cl:21][C:2]1([Cl:1])[CH2:4][CH:3]1[CH2:5][S:6]([C:7]1[CH:20]=[CH:19][C:10]2[NH:11][C:12]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[N:13][C:9]=2[CH:8]=1)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1nc2cc(SCC3CC3(Cl)Cl)ccc2[nH]1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(S(=O)CC3CC3(Cl)Cl)ccc2[nH]1
Reaction time: 4 h

Procedure:
To a solution of 3.4 g of [5-[(2,2-dichlorocyclopropylmethyl)thio]-1H-benzimidazol-2-yl]carbamic acid, methyl ester in 50 ml of CHCl3 and 50 ml of HOAc at -20° C there is added 2.1 g m-chloroperbenzoic acid in 20 ml of CHCl3. The mixture is allowed to reach room temperature and then is stirred for 4 hours. CHCl3 is removed in vacuo and the solution is neutralized with NaOH. The resulting oil solid is filtered and crystallized from glyme-ethyl ether to give the title compound.