Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([C:28]#[N:29])=[C:8]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:21][CH:22]=2)[C:9]([O:15][CH3:16])=[C:10]([CH:12](O)[CH3:13])[CH:11]=1.C(Cl)[Cl:31]>CN(C)C=O>[Cl:5][C:6]1[C:7]([C:28]#[N:29])=[C:8]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:21][CH:22]=2)[C:9]([O:15][CH3:16])=[C:10]([CH:12]([Cl:31])[CH3:13])[CH:11]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 5 h
Yield: 80 %

Procedure:
Thionyl chloride (800 μL, 10 mmol) was added dropwise to a solution of 5-[3-chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]N,N-dimethylpyridine-2-carboxamide (2 g, 6 mmol), methylene chloride (100 mL) and N,N-dimethylformamide (100 μL) at room temperature. The reaction was stirred for 5 hrs and was complete by LC/MS. The reaction mixture was partitioned between EtOAc and water. The combined organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give crude 5-[3-chloro-5-(1-chloroethyl)-2-cyano-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide as an oil (1.8 g, 80%). LCMS calculated for C18H18Cl2N3O2(M+H)+: m/z=378.1; found: 378.1.
Reaction SMILES: F[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(N2CCOCC2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 105 °C
Yield: 91.3 %

Procedure:
A mixture containing 4-(4-fluorobenzoyl)-nitrobenzene (1.96 9, 8 mmol), morpholine (0.84 g, 9.6 mmol), and potassium carbonate (1.33 g, 9.6 mmol) in dimethyl sulfoxide (15 mL) was heated to 100-110° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with cold water, and filtered. The crude product was washed several times with water and dried to give 4-(4-morpholinobenzoyl)-nitrobenzene (2.28 g, 91%), m.p. 173-175° C., and was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:27](=[O:33])[C:28]([O:30]CC)=[O:29])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:27](=[O:33])[C:28]([OH:30])=[O:29])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(C(C)(C)C)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)c(C(=O)C(=O)O)cn3Cc2ccccc2)cc1
Yield: 62.5 %

Procedure:
{1-Benzyl-5-[4-(tert-butyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-[4-(tert-butyl)phenyl]-1H-indol-3-yl}(oxo)acetate (0.669 g, 1.52 mmol), potassium hydroxide (0.30 g, 5.3 mmol) in THF (15 mL) and water (15 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from acetonitrile and drying at 90° C. furnished the title compound as a light yellow solid (0.391 g, 63%), mp: 210-211° C. (dec.). Mass spectrum (+APCI, [M+H]+) m/z 412; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.7 (s, 1H), 8.4 (d, 1H, J=1.7 Hz), 7.65 (d, 1H, J=8.5 Hz), 7.55-7.6 (m, 3H), 7.5 (dd, 2H, J=6.5 Hz and 1.8 Hz), 7.3-7.35 (m, 5H), 5.6 (s, 2H), and 1.3 ppm (s, 9H). Elemental Analysis for C27H25NO3.0.1 H2O: Calculated: C, 78.46; H, 6.15; N, 3.39. Found: C, 78.34; H, 5.94; N, 3.35.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22]([OH:24])=O)(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[N:26]1([CH2:31][CH2:32][O:33][C:34]2([C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)[CH:30]=[N:29][CH:28]=[N:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22]([N:37]2[CH2:38][CH2:39][C:34]([C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)([O:33][CH2:32][CH2:31][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[CH2:35][CH2:36]2)=[O:24])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCn2cncn2)(c2cccnc2)CC1
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCn3cncn3)(c3cccnc3)CC2)c(C)c1
Yield: 24 %

Procedure:
The desired target compound was synthesized under reaction conditions analogously to the process described for Example 61 (see below) from (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] and tert-butyl 4-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-4-(pyridin-3-yl)piperidine-1-carboxylate [amine G]. Yield: 24%. MS, Rt=3.3 min, m/z=627.4 [MH]+
Reaction SMILES: [F:1][C@@H:2]1[C@@H:7](OS(C)(=O)=O)[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.[CH:20]1([O:24][C:25]2[C:34]([C:35]3[CH:36]=[N:37][NH:38][CH:39]=3)=[CH:33][CH:32]=[C:31]3[C:26]=2[CH2:27][CH2:28][C@H:29]([CH3:44])[N:30]3[C:40]([O:42][CH3:43])=[O:41])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:16]([O:15][C:13]([N:4]1[CH2:5][CH2:6][C@@H:7]([N:37]2[CH:36]=[C:35]([C:34]3[C:25]([O:24][CH:20]4[CH2:21][CH2:22][CH2:23]4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:40]([O:42][CH3:43])=[O:41])[C@@H:29]([CH3:44])[CH2:28][CH2:27]4)[CH:39]=[N:38]2)[C@@H:2]([F:1])[CH2:3]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@@H](F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N1c2ccc(-c3cnn([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@@H]4F)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 56 %

Procedure:
(3S,4S)-tert-Butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (96 mg, 0.322 mmol) was added to a solution of (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (100 mg, 0.293 mmol) and cesium carbonate (153 mg, 0.469 mmol) in DMF (1.0 mL), and the reaction mixture was heated at 100° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford methyl (S)-6-(1-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (89 mg, 56%) as a colorless oil. MS (ESI, pos. ion) m/z 543 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH:27]=[N:26][C:25]([NH2:28])=[N:24]1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH:27]=[N:26][C:25]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:24]1
Reactant: Nc1ncn(-c2ccccc2Cl)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(-c4ccccc4Cl)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(2-chloro-phenyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless solid (Yield=27%). MS ISP (m/e): 374.3 (100) [(M+H)+].
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[C:8]([CH3:22])=[N:9][N:10]3[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=23)=[C:4]([Cl:23])[CH:3]=1.C([Mg]Cl)C.[CH2:28]([O:30][C:31](C#N)=[O:32])[CH3:29]>C1COCC1>[CH2:28]([O:30][C:31]([C:2]1[S:6][C:5]([C:7]2[C:8]([CH3:22])=[N:9][N:10]3[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=23)=[C:4]([Cl:23])[CH:3]=1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C#N
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)cc3Cl)c(C)nn12
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Cl)c(-c2c(C)nn3c(C(CC)CC)cc(C)nc23)s1
Temperature: 0 °C
Yield: 18.7 %

Procedure:
Chill to 0° C. a mixture of 3-(5-bromo-3-chloro-thiophene-2-yl)-7-(1-ethyl-propyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (0.62 g, 1.5 mmol) in anhydrous THF (5 mL) under an inert atmosphere and add ethyl magnesium chloride (2 M THF solution, 0.83 mL, 1.65 mmol). Stir the reaction 5 min, warm to room temperature, and stir an additional 15 min before lowering the reaction temperature to 0° C. Add ethylcyanoformate (0.16 mL, 1.58 mmol) diluted in anhydrous THF (1 mL). Warm the reaction to room temperature and stir 1 h. Quench the reaction with saturated sodium bicarbonate (20 mL) and extract with ether (2×75 mL). Combine the organic portions, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify using flash chromatography, eluting with 100% hexane/0% (20% ethyl acetate/hexane) to 0% hexane/100% (20% ethyl acetate/hexane) in a step gradient of 10% increments. Dry the resulting material under vacuum to provide a white solid (0.114 g, 19%). ES/MS m/z (35Cl) 406.3 (M+1)+.
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH2:15])[CH2:9]2.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>CN(C=O)C.CCOC(C)=O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([N:15]1[C:19](=[O:20])[C:18]3[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]1=[O:21])[CH2:9]2
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc2c(c1)CC(N)C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC(N1C(=O)c3ccccc3C1=O)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a suspension of 60% NaH (8 g; 0.240 mol) in DMF (250 mL), cooled to 0° C., is added 5-methoxyindan-2-ylamine hydrochloride (40.0 g; 0.2 mol) and the suspension stirred for 1 h at RT. Phthalic anhydride (30 g; 0.2 mol) is added in 1-portion and the suspension stirred for an additional 1-1.5 h at RT followed by stirring at 120° C. for 96 h. The reaction is cooled and diluted with EtOAc. The organic phase is washed with H2O, the resultant precipitate filtered, washed with EtOAc, MeOH and dried under vacuo to afford 25.2 g (43%) of 2-(5-methoxyindan-2-yl)isoindole-1,3-dione as a white solid. The organic phase is washed with H2O, evaporated under reduced pressure and the solid is triturated with MeOH, filtered, and dried to afford an additional 19.7 (33%) g of 2-(5-methoxyindan-2-yl)isoindole-1,3-dione as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]3[CH2:13][CH2:14]3)[C:23](=[O:25])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C(O)c1cc(Cl)ccc1NC1CC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1oc(=O)n(C2CC2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 270.3 %

Procedure:
A solution of 5-chloro-2-(cyclopropylamino)benzoic acid (4.70 g) and triethylamine (3.12 mL, 1 eq) in DCM (111 mL) was cooled to 0° C. and treated with triphosgene (2.31 g, 0.35 eq) in small portions. Dimethylaminopyridine (271 mg, 0.1 eq) was then added and the reaction was stirred at room temperature overnight. The crude was washed with cold 1 N HCl, and the organic portion was dried over sodium sulfate, and concentrated, then held under vacuum for 18 h delivering product (5.00 g, 95% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.88 (m, 2H), 7.68 (d, 1H), 2.90 (m, 1H), 1.16 (m, 2H), 0.80 (m, 2H). MS (ES+) m/z 260.0 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=O)[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:18][C:26]([C:27]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])=[C:15]([CH3:16])[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: O=C(CBr)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(OCc3ccccc3)cc12
Temperature: 60 °C
Reaction time: 15 h
Yield: 42.4 %

Procedure:
To a solution (500 mL) of 1-[5-(benzyloxy)-2-hydroxyphenyl]ethanone (29.5 g) synthesized in the above-mentioned (1) in N,N-dimethylformamide were added potassium carbonate (41.4 g) and 2-bromo-1-cyclohexylethanone (25.0 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a solid. The obtained solid was washed with ethanol-isopropyl ether to give the title object compound (18.0 g, 43%) as a pale-yellow solid.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:24]=[O:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH:26]([Mg]Cl)([CH3:28])[CH3:27]>C1COCC1>[CH3:27][CH:26]([CH3:28])[CH:24]([C:22]1[CH:21]=[N:20][CH:19]=[C:18]([C:14]2[CH:15]=[N:16][C:17]3[NH:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:23]=1)[OH:25]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(C=O)c3)cnc21
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(O)c1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of 6-(5-formyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (125 mg, 0.37 mmol) in THF (1 mL) is added a solution of isopropylmagnesium chloride in THF (1.3M, 850 μL, 1.1 mmol). The resultant mixture is stirred warming to room temperature for 3 h. The reaction is quenched with saturated aqueous ammonium chloride solution and is extracted with EtOAc. The combined organic extracts are washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue is taken up in MeOH (1 mL) and 4N HCl in 1,4-dioxane (1 mL) is added. The reaction is stirred at room temperature for 16 h then is concentrated to provide 2-methyl-1-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-propan-1-ol (124 mg) as the dihydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C@H:6]1[CH2:11][CH2:10][N:9](C)[CH2:8][C@H:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30].ClC([O-])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C@H:6]1[CH2:11][CH2:10][N:9]([C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30])[CH2:8][C@H:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1CC[C@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 2.48 g of the free base cis-4-(3-chlorophenoxy)-1-methyl-3-phenylpiperidine, of Example 36, 1.14 g of anhydrous potassium carbonate and 30 ml of dry benzene is treated with 1.42 ml of 2,2,2-trichloroethyl chloroformate. After 30 minutes at room temperature the mixture is refluxed 18 hours. Another 0.36 ml of chloroformate is added, and the mixture is refluxed another 4 hours. The mixture is then cooled and partitioned between 100 ml of ether and 50 ml of water. The aqueous phase is extracted with 50 ml of ether, and the combined organic extracts are washed with 2 N HCl solution, saturated aqueous NaCl solution, and dried over Na2SO4. Concentration in vacuo affords a mixture of a solid and an oil which is triturated with 25 ml of ether and then diluted with hexane to a volume of about 125 ml. After refrigeration for 18 hours the mixture is filtered, the solid is washed with hexane, and the filtrate is washed successively with 10% aqueous NaOH solution, water, and saturated aqueous NaCl solution. After drying over Na2SO4 the solution is concentrated in vacuo to a gum. Chromatography of this material on silica gel affords a colorless gum of cis-4-(3-chlorophenoxy)-3-phenyl-1-(2,2,2-trichloroethoxycabonyl) piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: ClCc1ccc2ccccc2c1
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2Cc2ccc3ccccc3c2)cc1

Procedure:
5,6-dichloro2-(4-formylphenyl)-1-(2-naphtylmethyl)benzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and 2-chloromethylnaphthalene by following General Procedure 3.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:18]=2[N:19]=1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCCC3
Reactant: NCCc1ccc2c(c1)OCO2
Product: Clc1nc(NCCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine yields 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([S:21][C@H:22]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]3)=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](S)C1
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(Br)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S[C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 130 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
A mixture of 2-(5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 1, 1.93 g, 5.69 mmol), (S)-tert-butyl 3-mercaptopyrrolidine-1-carboxylate (STEP C, 7.42 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (165 mg, 0.285 mmol), tris(dibenzylideneacetone)dipalladium(0) (130 mg, 0.142 mmol) and N,N-diisopropylethylamine (1.10 g, 8.54 mmol) in 1,4-dioxane (25 mL) was stirred at 130° C. for 18 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (pre-treatment with triethylamine, hexane-ethyl acetate, gradient) to give the title compound (1.83 g, 70%) as a brown oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: Brc1nccs1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1csc(-c2nccs2)c1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
2-Bromothiazole (15.0 g) and 2-thiopheneboronic acid (14.0 g) were dissolved in dimethoxyethane (150 ml). To the mixture was added bis(triphenyl)phosphine palladium(II)dichloride (3.2 g) and 2M sodium carbonate (137 ml), and the mixture was refluxed under argon atmosphere for 2 hours. The mixture was cooled to room temperature, and the reaction solution was diluted with ethyl acetate, and washed with water. The organic layer was collected, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=96:4) to give 2-(2-thienyl)thiazole (9.87 g) as oil. APCI-Mass m/z 168 (M+H) (2) The above compound (3.17 g) was treated in a manner similar to Reference Example 121 to give 5-fluoro-2-(2-thienyl)thiazole (1.58 g) as oil. APCI-Mass m/z 186 (M+H) (3) The above compound (1.58 g) was dissolved in chloroform (16 ml), cooled to 0° C., and thereto was added dropwise a solution of bromine (1.43 g) in chloroform (15 ml). The mixture was stirred at the same temperature for one hour, warmed, and further stirred at room temperature for one hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The extract was washed with 10% aqueous sodium thiosulfate solution, brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3) to give 2-(5-bromo-2-thienyl)-5-fluorothiazole (1.81 g) as a pale yellow solid. (4) The above compound (300 mg) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were used and treated in a manner similar to Reference Example 7 to give the desired 5-bromo-2-chloro-1-(5-(5-fluorothiazol-2-yl)-2-thienylmethyl)benzene (199 mg) as a pale yellow powder.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1(O)[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2.[C:28]1([CH2:34][O:35][NH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:8][C:9]1([NH:36][O:35][CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: NOCc1ccccc1
Reactant: CC1(O)CCCc2nc(OCc3ccccc3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(NOCc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
Trifluoroacetic acid (17.4 g) was added in one portion to a solution of 5,6,7,8-tetrahydro-5-methyl-2-(phenylmethoxy)-quinolin-5-ol (41 g), phenylmethoxyamine (47 g), and toluene (770 ml) at room temperature. The solution was stirred at room temperature for 24 hrs, and then quenched with concentrated ammonium hydroxide solution. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over potassium carbonate, filtered, and the filtrate was concentrated. Purification by high performance liquid chromatography (silica gel, elution with ethyl acetate-hexanes) gave 44.2 g (77%) of 5,6,7,8-tetrahydro-5-methyl-N,2-bis(phenylmethoxy)-5-quinolinamine.