Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:3]1=[O:35].Cl>O1CCCC1.CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:3]1=[O:35]
Reactant: COC(=O)CCCSc1c2c(=O)n(C)c(=O)n(CC(C)C)c2cn1Cc1cccc2ccccc12
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(=O)O)n(Cc3cccc4ccccc34)cc21
Reaction time: 1.5 h

Procedure:
The compound of Example 2, methyl 4-[(2,3,4,6-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]-pyrimidin-5-yl)thio]butanoate (400 mg), was dissolved in 3:1:1 tetrahydrofuran/methanol/1M lithium hydroxide and stirred for 1.5 h before being acidified by dropwise addition of concentrated hydrochloric acid (HCl). The mixture was then extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate (MgSO4) and evaporated to dryness in vacuo. The resultant yellow oil was chromatographed (silica), eluting with 200:10:1 dichloromethane/methanol/glacial acetic acid. The resultant red oil was dissolved in toluene and then evaporated, then similarly with trichloromethane to yield a pink foam. The foam was recrystallised from ethyl acetate/hexane to yield 129 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[C:11]([C@H:19]([CH3:23])[C:20](Cl)=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[C:11]([C@H:19]([CH3:23])[C:20]([N:9]1[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]1=[O:10])=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CC1CCC(=O)N1
Reactant: C[C@H](C(=O)Cl)C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@@H](C)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 45 %

Procedure:
To 60% sodium hydride (336 mg, 10.0 mmol) in toluene (20 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (1.0 mg, 9.0 mmol) in toluene (10 mL) over a 10 min period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete generation of the anion. To the anion at 25° C. was added dropwise a solution of (2S)-2-benzoylpropanoyl chloride (21, 2.7 g, 12.6 mmol) in toluene (10 mL) over a 10 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and t-butyl methyl ether, 1:1). Water (50 mL) as added to the reaction mixture and the phases were separated. The aqueous phase was extracted with diethyl ether (2×40 mL). The combined organic phases were washed with a saturated aqeous sodium bicarbonate solution (1×100 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 6.5 cm diameter×20 cm length) using hexane and t-butyl methyl ether (10:1) afforded 1.1 g (42%) of (5S)-N-((2S)-2-benzoylpropanoyl)-5-ethenylpyrrolidin-2-one (24a) as a thick oil: 1H NMR (CDCl3) δ1.44-1.46 (d, J=6.5 Hz ,3 H), 1.64-1.80 (m, 1 H), 2.12-2.20 (m, 1 H), 2.42-2.84 (m, 2 H), 4.12-4.21 (q, J=6.4 Hz, 1 H), 4.38-4.47 (m, 1 H), 4.58-4.67 (m, 1 H), 4.89-4.91 (m, 1 H), 5.06-5.19 (m, 2 H), 5.77-5.85 (m, 1 H), 7.28-7.40 (m, 5 H); 13C NMR (CDCl3) δ174.8, 173.5, 137.7, 135.3, 128.0, 127.7, 127.4, 115.1, 74.6, 71.6, 31.3, 24.0, 18.1; IR (neat) 3066 (w), 3033 (w), 2939 (w), 1740 (vs), 1708 (vs), 1455 (s), 1370 (s), 1277 (s), 1148 (s), 1113 (s), 739 (s) cm-1.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])=[CH:10][CH:9]=1.[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(OCC)(=O)C>CN(C)C=O>[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])=[CH:10][CH:9]=2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CC(C)(O[Si](C)(C)C)c1ccc(Br)cc1
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2ccc(C(C)(C)O[Si](C)(C)C)cc2)c(C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 47.8 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M sodium carbonate solution (0.1 mL, 0.2 mmol) and [1-(4-bromo-phenyl)-1-methyl-ethoxy]-trimethylsilane (Example 15-(1); 26.25 mg, 0.091 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1, developed three times) to give the title compound (16.7 mg, 47.9%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][NH:13][C:12](=[O:15])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:1][C:2]2[CH:3]=[C:4]([CH:10]3[CH2:14][NH:13][C:12](=[O:15])[CH2:11]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])=[CH:19][CH:18]=1
Reactant: COc1ccc(C2CNC(=O)C2)cc1O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2CNC(=O)C2)cc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.3 %

Procedure:
A mixture of 4-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidone (63 mg, 0.3 mmol), 4-chlorophenylboronic acid (61 mg, 0.45 mmol), copper (II) acetate (54 mg, 0.3 mmol), triethylamine (152 mg, 1.5 mmol), dichloromethane (3 ml) and small amount of molecular sieves is allowed to stir at ambient temperature. After 18 hours, the mixture is filtered over celite and the filtrate is concentrated under vacuum. The resulting residue is dissolved in 30 ml of ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. Purification by flash column chromatography (ethyl acetate/hexane 1:1 to methanol/dichloromethane 3:97) gives 26 mg (27%) of 4-(3-(4-chlorophenyloxy)-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J=9.2 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.87 (s, 1H), 6.83 (d, J=9.2 Hz, 2H), 5.83 (b, 1H), 3.80 (s, 3H), 3.72 (t, J=8.4 Hz, 1H), 3.65-3.62 (m, 1H), 3.34 (t, J=8.4 Hz, 1H), 2.68 (dd, J=16.8, 8.8 Hz, 1H), 2.41 (dd, J=16.8, 9.2 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].[CH3:16][O-:17].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[S:6][C:7]=1[O:17][CH3:16])#[N:2]
Reactant: C[O-]
Reactant: COC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C#N)c(OC)s1
Yield: 73 %

Procedure:
Methyl 4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (2 g, 8 mmol) was refluxed with 0.5 M sodium methoxide in methanol (16 mL) for 15 minutes. The solution was cooled, the crystallized solid collected on a Buchner funnel and washed with methanol (50 mL) to give methyl 4-cyano-5-methoxythiophene-2-carboxylate (1.145 g, 73%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.87 (s, 1H) 4.19 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH:24]=1)[C:19](O)=[O:20].N1C=CC=CC=1.[NH2:37][C:38]1[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=1>C(Cl)Cl>[Cl:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([C:19]([NH:37][C:38]2[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=2)=[O:20])[CH:22]=[C:23]([O:25][C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH:24]=1
Reactant: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)O)c3)c2Cl)C1=O
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)Nc4ccn(C(=O)OC(C)(C)C)n4)c3)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 52.5 %

Procedure:
1-Chloro-N,N-2-trimethylpropenylamine (0.09 mL, 0.37 mmol) was added to a solution of 3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (145 mg, 0.34 mmol) in DCM (5 mL) and the reaction stirred at RT for 30-40 minutes. Pyridine (0.055 mL, 0.67 mmol) and 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (123 mg, 0.67 mmol) were added and the reaction stirred for 2 hours at RT. The reaction mixture was evaporated in vacuo and water (20 mL) added. The mixture was extracted with ethyl acetate (3×20 mL), washed with 1N hydrochloric acid (20 mL), a saturated solution of sodium hydrogen carbonate (20 mL), brine (20 mL), dried (MgSO4) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound as a pale yellow oil (107 mg). m/z 611 (M−H)−
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH:19]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=3)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:13][C:12]=2[CH3:33])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[NH2:53][CH2:54][C:55]#[N:56]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:33])=[CH:13][C:14]([O:18][CH:19]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:56][CH2:55][C:54]#[N:53])=[O:30])=[CH:31][CH:32]=3)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][C:16]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#CCN
Reactant: Cc1cc(OC(CC(C)C)c2ccc(C(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(OC(CC(C)C)c2ccc(C(=O)NCC#N)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
4-[1-(4′-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid (1.00 g, 2.25 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (593 mg, 3.38 mmol) is stirred in THF (25 mL) under nitrogen. N-Methyl morpholine (0.37 mL, 3.38 mmol) is added followed by addition of aminoacetonitrile hydrochloride (229 mg, 2.48 mmol) and the mixture stirred at room temperature for 24 h. The reaction is filtered and the resulting filtrate concentrated and purified by silica gel chromatography, eluting with hexanes using a gradient of 0-100% ethyl acetate to provide 806 mg (74%) of the titled compound as a white solid. 1H NMR.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:17]C2C=CC(C(OC)=O)=CC=2)[C:12]=1[S:13][CH2:14][CH2:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C1C=NN(C[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([O:50][CH3:51])=[O:49])[CH:43]=2)C=1Cl)=O)(C)(C)C>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:17][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([O:50][CH3:51])=[O:49])[CH:43]=2)[C:12]=1[S:13][CH2:14][CH2:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCSc1c(C(=O)OC(C)(C)C)cnn1Cc1ccc(C(=O)OC)cc1
Reactant: COC(=O)c1cccc(Cn2ncc(C(=O)OC(C)(C)C)c2Cl)c1
Product: CCCSc1c(C(=O)OC(C)(C)C)cnn1Cc1cccc(C(=O)OC)c1

Procedure:
Compound prepared in an analogous manner to Intermediate #46, replacing 5-Chloro-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester with 5-Chloro-1-(3-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.Br.Br.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[OH:31])[N:24]=[C:23]2[CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[OH:31])[N:24]=[C:23]2[CH2:32][CH:33]2[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=3)[CH2:37][CH2:38]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CCCl)cc1
Reactant: Oc1ncnc2nc(CC3CCNCC3)n(Cc3ccc(F)cc3)c12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CCN2CCC(Cc3nc4ncnc(O)c4n3Cc3ccc(F)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of 1.9 parts of 1-(2-chloroethyl)-4-methoxybenzene, 5 parts of 7-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-7H-purin-6-ol dihydrobromide, 4 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 70° C. After cooling, the reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.2 parts (46%) of 7-[(4-fluorophenyl)methyl]-8-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methyl]-7H-purin-6-ol; mp. 122.2° C. (compound 62).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[N:17]([CH:18]2[CH2:24][C@H:23]3[N:25]([CH2:26][CH2:27][C:28]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[C@H:20]([CH2:21][CH2:22]3)[CH2:19]2)[C:16]2[CH:40]=[CH:41][CH:42]=[CH:43][C:15]=2[N:14]=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:31]2[CH2:30][CH2:29][C:28]([CH2:27][CH2:26][N:25]3[C@H:20]4[CH2:21][CH2:22][C@@H:23]3[CH2:24][CH:18]([N:17]3[C:16]5[CH:40]=[CH:41][CH:42]=[CH:43][C:15]=5[N:14]=[C:13]3[CH3:12])[CH2:19]4)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:33][CH2:32]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCNCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(S(=O)(=O)c2cccc(Cl)c2)CC1
Yield: 20.8 %

Procedure:
3-Chlorobenzenesulfonyl chloride (31.6 mg, 0.122 mmol) was added to a solution of 2-methyl-1-{(1R,5S)-8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (50.0 mg, 0.117 mmol) and diisopropyletheylamine (44.9 mg, 0.348 mmol) in DCM. The reactions were quenched with sat. NaHCO3 and separated with a hydrophobic frit. Flash chromatography on silica 0 to 10% MeOH in EtOAc afforded 1-[(1R,5S)-8-(2-{1-[(3-chlorophenyl)sulfonyl]-4-phenyl-4-piperidinyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole 14.7 mg (20% yield). MS ES+ 603 (M+H). 1H NMR (300 MHz, chloroform-d) δ ppm 1.6 (m, 2H), 1.7 (m, 4H), 1.9 (m, 8H), 2.4 (m, 4H), 2.6 (s, 3H), 2.8 (m, 2H), 3.4 (m, 2H), 4.6 (m, 1H), 7.2 (m, 5H), 7.3 (m, 3H), 7.4 (t, J=7.9 Hz, 1H), 7.5 (m, 1H), 7.6 (d, J=7.8 Hz, 1H), 7.7 (m, 1H), 7.7 (m, J=1.8, 1.8 Hz, 1H).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN([CH:26]=[O:27])C.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Si:5]([O:8][C:9]1[C:10]([F:17])=[C:11]([CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)[CH:26]=[O:27])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CN(C)C=O
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 12.7 g of t-butyl-(5-ethyl-2-fluorophenoxy)dimethylsilane and 7.5 g of N,N,N′N′-tetramethylethylenediamine in 250 ml of THF was cooled to −75° C. under a nitrogen atmosphere, and then 55.6 ml of s-butyllithium (0.99 M, cyclohexane solution) was added and the mixture was stirred for 2 hours. After adding 7.74 ml of DMF and stirring at −75° C. for 1 hour, the temperature was raised to room temperature. Next, 500 ml of diethyl ether and 500 ml of a 5% aqueous ammonium chloride were added to the reaction mixture, the organic layer was washed twice with 500 ml of water and once with 500 ml of saturated aqueous sodium chloride in that order, and the aqueous layer was extracted with 100 ml of diethyl ether. The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (12.6 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O.[NH2:18][C:19]1[C:20](Cl)=[N:21][CH:22]=[CH:23][CH:24]=1>C(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[C:3]3[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=3[NH:1][C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)=[CH:7][CH:8]=1
Reactant: Nc1cccnc1Cl
Reactant: COc1ccc(C(=O)c2ccccc2N)cc1
Solvent: ClCCl
Product: COc1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Temperature: 180 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 20.0 g (0.088 mole) of 2-amino-4'-methoxybenzophenone and 13.0 g (0.097 mole) of 3-amino-2-chloropyridine (96%) was heated at 180° C. under a nitrogen atmosphere for 2.0 hr. The reaction mixture was cooled to approximately 70° C. and 100 ml of methylene chloride was added slowly. After the mixture had cooled to room temperature, another 50 ml of methylene chloride was added and the mixture was stirred overnight. The suspended solid was collected by filtration, air dried, dissolved in methanol and basified with 3N sodium hydroxide. The suspension was diluted with 500 ml water and extracted with three 250 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. Analysis by mass spectra (EI and CI) indicated the residue was a mixture of [2-[(3-amino-2-pyridyl)amino]phenyl](4-methoxyphenyl)methanone and the title compound. The residue-mixture was dissolved in 250 ml toluene with a catalytic amount of para toluene sulfonic acid and the solution was refluxed overnight under a nitrogen atmosphere while separating water in a Dean-Stark trap. The reaction mixture was filtered while hot. The product precipitated as the filtrate cooled to room temperature and was collected by filtration. After recrystallization from benzene the product weighed 1.8 g, m.p. 198.5°-200-5° C. (d).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14](O)=[CH:15][C:16](=[O:18])[CH3:17])=[CH:7]2.C([O-])(=O)C.[Na+].O.O.O.C([O-])(=O)C.[Na+]>O.[Pd].CO>[CH3:13][O:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:5]=[CH:4]2
Reactant: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(CCC(C)=O)ccc2c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
24.72 Grams (0.077 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one, 4.57 g of anhydrous sodium acetate and 2.58 g of sodium acetate trihydrate, equivalent to 0.075 moles of sodium acetate, 2 g of a 50% suspension in water of 5% palladium on carbon, equivalent to 0.00047 moles of palladium, and 200 ml of methanol are put in a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of three atmospheres. The reaction temperature is kept at 40° C. for a period of time of 6 hours, then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered in order to eliminate the catalyst. The solution is brought to pH 6 with a 5% aqueous solution of sodium hydroxide and concentrated under vacuum. The oily residue is treated with 150 ml of toluene and 50 ml of water and after stirring for 15 minutes the two layers are separated. The aqueous phase is discarded while the organic phase is evaporated under vacuum at 70° C. obtaining an oil that is dissolved in 50 ml of methanol. The solution is kept for 2 hours at 0° C. and the precipitated solid is filtered, washed with 10 ml of methanol cooled to 0° C. and dried in oven under vacuum. The methanolic filtrates from crystallization and washing are concentrated under vacuum at half volume so obtaining, after cooling to 0° C., the crystallization of other product that is dried in oven under vacuum. 14 Grams of product are obtained in totality with an overall yield equal to 79.7%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:6][CH2:7]Br.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][CH2:31][NH:32][CH3:33].N1C2C=CC=CC=2NC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:6][CH2:7][N:32]([CH2:31][CH2:30][CH2:29][C:21]1[NH:20][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)[CH3:33]
Reactant: COC(=O)C(CCCBr)(c1ccc(Br)cc1)C(C)C
Reactant: CNCCCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc2[nH]cnc2c1
Solvent: CCO
Product: COC(=O)C(CCCN(C)CCCc1nc2ccccc2[nH]1)(c1ccc(Br)cc1)C(C)C

Procedure:
After the 5-bromo-2-(4-bromophenyl)-2-isopropylpentanoic acid methyl ester (1 g, 1 eq) was dissolved in ethanol, [3-(1H-benzimidazole-2-yl)propyl]methylamine (0.66 g, 1 eq) as a benzimidazole derivative, and potassium carbonate (0.58 g, 1.2 eq) were added into the solution and heated and refluxed for 3 hours. When the reaction was completed, the precipitate was filtrated and the solvent was removed at low pressures. The target compound 5-{[3-(1H-benzimidazole-2-yl)propyl]methylamino}-2-(4-bromophenyl)-2-isopropyl pentanoic acid methyl ester was obtained by separation and purification of the mixture using a column chromatography (ethyl acetate:methanol=10:1) (635 mg, 36%).