Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:39])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[C:21](=[O:28])[N:20]([CH2:29][C:30]([O:32]CC)=[O:31])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C>Cl.C(OCC)C>[C:30]([CH2:29][N:20]1[C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:17](=[CH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([OH:39])[CH2:13][CH2:12]2)[C:18]2[CH:38]=[CH:37][CH:36]=[CH:35][C:19]1=2)([OH:32])=[O:31]
Reactant: CCOC(=O)CN1C(=O)c2ccccc2C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)CN1C(=O)c2ccccc2C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.4 %

Procedure:
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-ethoxycarbonylmethyl-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol (Example 18) (1.0 g) was solved in 1M hydrogen chloride in diethyl ether and stirred at room temperature for 24 hours. Aqueous sodium hydroxide and ethyl acetate were added to the reaction mixture, the aqueous layer was separated and neutralized with dilute hydrochloric acid. The precipitation was filtered to give the titled compound (250 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]NC(=O)CCC(N)=O>CC(O)=O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([Br:26])=[CH:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:20][CH:21]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CCCCc1ccc(-n2ccc(=O)c(OCc3ccccc3)c2)cc1
Solvent: CC(=O)O
Product: CCCCc1ccc(-n2cc(Br)c(=O)c(OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(benzyloxy)-1-(4-butylphenyl)pyridin-4(1H)-one (705 mg, 2.1 mmol) in AcOH (21 mL) was added N-bromosuccinamide (414 mg, 2.3 mmol) and the reaction mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and purified by flash chromatography (50 g Si02, 0-70% ethyl acetate/hexanes) to provide 3-(benzyloxy)-5-bromo-1-(4-butylphenyl)pyridin-4(1H)-one. LC/MS (M+H)+ 412/414.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15](F)([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].Cl>>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH:35][C:22]([C:21]2[CH:20]=[N:19][N:12]3[C:13]([CH:15]([F:16])[F:17])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[O:23])[CH:32]=[CH:33][CH:34]=1)(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 511.3 [(M+H)+]; mp 262° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([CH2:12][CH3:13])([CH2:7][NH:8][CH:9]([CH3:11])[CH3:10])[CH2:5][CH3:6].[C:15]1(=O)CCC[CH2:16]1>>[CH3:1][O:2][C:3](=[O:14])[C:4]([CH2:7][NH:8][CH:9]1[CH2:10][CH2:16][CH2:15][CH2:11]1)([CH2:12][CH3:13])[CH2:5][CH3:6]
Reactant: O=C1CCCC1
Reactant: CCC(CC)(CNC(C)C)C(=O)OC
Product: CCC(CC)(CNC1CCCC1)C(=O)OC

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 200, on a 50 mmol scale utilising Cyclopentanone (Aldrich; 6.33 g, 75 mmol), and distillation at 50° C. and 0.53 mbar pressure, as a clear oil (7.5 g, 65%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:31]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[N:39]=[C:40]([CH3:43])[S:41][CH:42]=3)[CH2:33][CH2:32]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:30]=[CH:29][C:14]([CH2:15][N:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:31]2[CH2:32][CH2:33][N:34]([CH2:37][C:38]3[N:39]=[C:40]([CH3:43])[S:41][CH:42]=3)[CH2:35][CH2:36]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:30]=[CH:29][C:14]([CH2:15][N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(CN6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)CC2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(CN6CCNCC6)cc5)nc34)CC2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
tert-Butyl 4-(4-(6-chloro-7-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate (0.009 g, 0.036 mmol) was suspended in DCM (1.0 mL) and the mixture cooled in an ice bath. TFA (0.3 mL) was added and the resulting solution was allowed to warm up to room temperature and stirred for 2 h. The mixture was passed through an SCX column (2 g), washed with methanol and further eluted with ammonia (35% solution in water, 0.2M). The filtrate was collected and the solvent removed in vacuo to give the title compound as a solid (0.004 g, 21%); 1H-NMR (500 Mz, DMSO-d6): δ 2.41-2.49 (m, 4H), 2.62-2.70 (m, 7H), 2.87-2.94 (m, 4H), 3.56 (s, 2H, NCH2), 3.64 (s, 2H, NCH2), 3.67-3.74 (m, 4H), 7.32 (s, 1H, thiazole 5-H), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4); LC (Method B)-MS (ESI, m/z) 2.09 min—523/525 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 523.2155, calculated for C26H32ClN8S (M+H)+: 523.2159;
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCI
Reactant: Cc1ncccc1O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1OCCCCl
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxy-2-methylpyridine (2.00 g, 18.3 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.576 g of an 80% dispersion in mineral oil, 19.2 mmol) in DMF (40 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The slurry was cooled to 0-5° C., and 1-chloro-3-iodopropane (4.49 g, 22.0 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 2 h. Cold water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×100 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 3.25 g (96.2%) of an oil.
Reaction SMILES: [H-].[Na+].F[C:4]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:5]=1[NH:6][C@@H:7]([CH3:10])[CH2:8][OH:9]>CN(C=O)C>[F:16][C:13]1[CH:12]=[CH:11][C:5]2[NH:6][C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:14]=1[F:15]
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1COc2c(ccc(F)c2F)N1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To DMF (2 ml) was added sodium hydride (39 mg) and the mixture was heated to 60° C. in an oil bath. Next, a solution of the compound (100 mg) obtained in Example 51 in DMF was dropped thereinto and the obtained mixture was stirred for 1 hour. After treating in a conventional manner, the mixture was subjected to silica gel column chromatography to give 60 mg (66%) of the title compound. The optical purity determined by HPCL was >94% ee. Various spectral data was identical with those of a specimen synthesized separately.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:26]([CH:23]5[CH2:25][CH2:24]5)=[O:27])[CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: Nc1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1)C1CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 170, starting from 3-[6-(4-cyclopropyl-piperazin-1-yl)-pyridazin-3-yl]-phenylamine and cyclopropanecarbonyl chloride. 1H NMR (300 MHz, CD3OD) δ 8.08 (d, 1H), 7.82 (d, 1H), 7.66-7.62 (m, 2H), 7.44-7.39 (m, 1H), 7.33 (d, 1H), 3.69-3.65 (m, 4H), 2.80-2.77 (m, 4H), 1.79-1.71 (m, 2H), 0.97-0.94 (m, 2H), 0.89-0.85 (m, 2H), 0.55-0.49 (m, 4H).
Reaction SMILES: Br[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[C:3](=O)[CH3:4].[NH2:14][C:15](=[S:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CCO>[Br:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][C:2]1[S:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:14][C:3]=1[CH3:4]
Reactant: CCOC(=O)C(N)=S
Reactant: CC(=O)C(Br)Cc1cccc(Br)c1
Solvent: CCO
Product: CCOC(=O)c1nc(C)c(Cc2cccc(Br)c2)s1
Yield: 42 %

Procedure:
A mixture of 3-bromo-4-(3-bromophenyl)butan-2-one (1.8 g, 5.9 mmol) and ethyl 2-amino-2-thioxoacetate (745 mg, 5.6 mmol) in EtOH (20 mL) was refluxed overnight. The solvent was removed and the residue was purified by silica gel column chromatography (EtOAc:Petroleum ether=1:5) to afford ethyl 5-(3-bromobenzyl)-4-methylthiazole-2-carboxylate as a light yellow solid (800 mg, 42.1%). MS (ES+) C14H14BrNO2S requires: 339, 341 found: 340[M+H]+, 342 [M+2+H]+(1:1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1>O1CCOCC1.[OH-].[Na+].O.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:5]([O:4][C:2]([NH:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCc1ccc(N)c(=O)[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (1.8 ml, 12.6 mmol) was added to a solution of 3-amino-6-propyl-2-pyridinone (1.63 g, 10.8 mmol) in a mixture of dioxane (25 ml) and 1N NaOH at 0° C. Within minutes a white precipitate formed. The reaction mixture was stirred at the same temperature for 1 h then at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate then methylene chloride. Each extract was washed with brine then combined and dried over magnesium sulfate. Removal of the solvents in vacuo gave a yellow semi-solid which was a mixture of starting material and product. This was redissolved in a mixture of dioxane (24 ml) and 10% aqueous sodium carbonate (12 ml) and cooled to 0° C. Benzyl chloroformate (1.5 ml, 10.5 mmol) was once again added and after stirring for 0.5 h, the reaction mixture was allowed to stir at room temperature for 3 h. After dilution with water, the precipitate was filtered off and washed thoroughly, first with water and then with ether. Drying gave the title compound as a white powder: 1H NMR (CDCl3) d 0.96 (t, J=7.3 Hz, 3 H), 1.68 (m, 2 H), 2.52 (t, J=7.5 Hz, 2 H), 5.22 (s, 2 H), 6.07 (d, J=7.5 Hz, 1 H), 7.34-7.43 (m, 4 H), 7.68 (s, 1 H), 8.05 (br d, J=5.3 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:4]2[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=3)[CH:7]=[CH:6][CH:5]=2)([CH2:19][F:20])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@](CF)(c2cccc(N)c2)C[C@@H](C(F)(F)F)O1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: NC1=N[C@](CF)(c2cccc(NC(=O)c3ccc(Cl)cn3)c2)C[C@@H](C(F)(F)F)O1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of (4S,6S)-4-(3-aminophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.080 g, 0.275 mmol) and 5-chloro-2-pyridinecarboxylic acid (0.048 g, 0.302 mmol) in THF/MeOH (3/1.2 mL) was stirred at room temperature and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.089 g, 0.302 mmol) was added. The reaction mixture was stirred for 30 min. The reaction was quenched with saturated NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, concentrated. The crude material was purified by column chromatographed on silica gel using 10-50% EtOAc/hexane to afford a white solid as N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)phenyl)-5-chloropicolinamide (0.075 g, 0.174 mmol, 63.4% yield). MS m/z=430.9 [M+H]+. Calculated for C18H15ClF4N4O2: 430.8
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[CH3:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>CN(C=O)C>[CH3:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:35]
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Reactant: Cc1ccccc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccccc1C

Procedure:
1-(2-Methylbenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 2-methylbenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21]OS(C)(=O)=O)[N:19]=2)=[CH:11][CH:10]=1.ClCCl>O1CCCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21][N:3]3[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4]3)[N:19]=2)=[CH:13][CH:14]=1
Reactant: CC1CCCCN1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1
Temperature: 60 °C
Yield: 70.2 %

Procedure:
Add 2-methyl piperidine (0.871 g, 8.77 mmol) to a solution of methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (0.316 g, 0.877 mmol) in tetrahydrofuran (5 mL) in a sealed tube, and heat at 60° C. overnight. Cool to room temperature and add dichloromethane. Wash the crude organic material with saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated methanol in dichloromethane to give (+/−)-1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (0.215 g, 67%): MS (m/e): 363 (M+1).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[Cl:11][C:12]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15]>C(OC(=O)C)C>[Cl:11][C:12]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:13]=1[C:14]([NH:16][C:17]([NH:8][C:5]1[S:6][CH:7]=[C:3]([C:2]([F:10])([F:9])[F:1])[N:4]=1)=[O:18])=[O:15]
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1nc(C(F)(F)F)cs1
Reaction time: 4 h

Procedure:
To a solution of 1.7 g (0.01 mole) of 4-trifluoromethyl-2-aminothiazole in 50 ml of dry ethylacetate was added all at once to a solution of 2.16 g (0.01 mole) of freshly prepared 2,6-dichlorobenzoylisocyanate dissolved in 10 ml of dry ethylacetate. The mixture was allowed to stir at 25° for 4 hours. The solvent was evaporated in vacuo, ether was added to the residue, and the solid was removed by filtration to give 3.7 g of product, m.p. 210°-213°. The infrared and nuclear magnetic resonance spectra were consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].NC1C=CC([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=C(F)C=1>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([Cl:9])[CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1F
Reactant: Nc1ccc(Br)c(Cl)c1
Product: CCOC(=O)C=Cc1ccc(N)cc1Cl
Yield: 99 %

Procedure:
Using 4-bromo-3-chloroaniline (5.0 g), Compound 8a (5.43 g, 99%) was obtained as a yellow solid in the same manner as Compound 2a was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1-c1cccc(F)c1
Solvent: CCOC(C)=O
Product: Cc1ccc[n+]([O-])c1-c1cccc(F)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 81.3 %

Procedure:
To a solution (100 mL) of 2-(3-fluorophenyl)-3-methylpyridine (4.83 g, 25.8 mmol) in ethyl acetate was added 3-chloroperbenzoic acid (7.1 g, 28.4 mmol), and the mixture was stirred at 50° C. for 5 hr. The disappearance of 3-chloroperbenzoic acid was confirmed using potassium iodide starch paper (manufactured by ADVANTEC MFS, INC), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (4.26 g, 81%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:5]1[CH:4]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:8]=[CH:7][C:6]=1[C:9]([F:10])([F:11])[F:12])([O-:17])=[O:16]
Reactant: FC(F)(F)c1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
1,4-Bis(trifluoromethyl)benzene (10.06 g, 47 mmol) in fuming sulfuric acid (20 g) was cooled to 0° C. Fuming nitric acid (8 g) was added cautiously. The mixture was heated to 100° C. and stirred for 1 hour. A mixture of fuming nitric acid (6 g) and fuming sulfuric acid (12 g) was added, and the mixture was heated to 110° C. and stirred for 6 hours. After cooling to r.t., the mixture was poured into ice water (150 g) cautiously, and extracted with chloroform (100 mL×3). The combined organic layers were washed with water (100 mL×2), 10% sodium hydroxide aqueous solution (100 mL×2), and then water (100 mL×2). The resulting organic layers were dried over sodium sulfate, filtered, and concentrated to afford 2-nitro-1,4-bis(trifluoromethyl)benzene as an oil (3.3 g).
Reaction SMILES: [Br:1]Br.[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]3[C:21]([O:35][CH3:36])=[CH:22][C:23]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32]([CH3:34])=[O:33])=[CH:24][C:14]=3[N:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].CCOC(C)=O>C(O)(=O)C>[Br:1][C:24]1[C:14]2[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH:3]([CH3:5])[CH3:4])=[CH:7][CH:8]=3)[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]=2[C:21]([O:35][CH3:36])=[CH:22][C:23]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([CH3:34])=[O:33]
Reactant: BrBr
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3S(C)=O)cc(OC)c21
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3ccccc3S(C)=O)cc(OC)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 501.7 %

Procedure:
53 μl (0.122 mmol) bromine are added to a solution of 496 mg (1.03 mmol) 2-(4-isopropyl-phenyl)-5-(2-methanesulfinyl-benzyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 22 ml glacial acetic acid. The reaction mixture is stirred at room temperature for 10 min. Then 25 ml EtOAc are added and this solution is washed with 4N NaOH (2×), water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:4) to afford 340 mg of the title compound as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].Br.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.BrCC1CCCCO1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, (pyridin-2-ylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: mp 122-123° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.59 (d, J=4.8 Hz, 1H), 7.71 (ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.31-7.15 (m, 4H), 7.03 (dd, J=7.5, 7.5 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 5.24 (d, J=15.9 Hz, 1H), 5.04 (d, J=15.9 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.28-4.20 (m, 1H), 4.14-4.05 (m, 2H), 4.02-3.94 (m, 1H), 2.22-2.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.5, 156.8, 155.4, 153.1, 149.1, 146.3, 142.1, 137.7, 132.2, 129.0, 124.0, 123.7, 123.1, 123.0, 121.9, 116.2, 109.6, 103.6, 80.5, 70.87, 70.85, 58.1, 45.9, 32.2; MS (ES+) m/z 401.0 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:10]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:10][C:9]([C:2]1[CH:3]=[C:4]([C:9]([CH3:10])([CH3:8])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:1]=1[OH:7])([CH3:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: C=C(C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Temperature: 140 °C

Procedure:
This intermediate was made by the general procedure of U.S. Pat. No. 2,714,120 by reacting a mixture of 705.8 grams (7.5 moles) of phenol with 1772.7 grams (15 moles) of α-methylstyrene in the presence of 25.7 grams (0.135 moles) of p-toluenesulfonic acid monohydrate catalyst. This mixture was heated under nitrogen at 140° C. for 2.5 hours. The reaction mixture was cooled to 110° C. and 1125 ml of toluene was added. After washing the resulting solution at 80° C. with 750 ml of an aqueous solution of 37.5 grams of sodium carbonate and 75 grams of sodium chloride, the organic phase was washed thrice with 1000 ml of aqueous sodium chloride solution; then dried over anhydrous sodium sulfate; filtered and vacuum distilled. The above-named product was obtained as the main fraction boiling at 172°-175° C./0.15-0.18 mm Hg in a yield of 1229.8 grams (49.6% of theory). The product melted at 63°-65° C.