Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Cl.[NH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)[CH2:29][CH2:28]1.Cl[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[N:50]=1.CC(C)([O-])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1(/C=C/C(=O)/C=C/C2C=CC=CC=2)C=CC=CC=1.[Pd].C1(C)C=CC=CC=1>[CH3:55][C:51]1[N:50]=[C:49]([N:27]2[CH2:28][CH2:29][CH:30]([CH2:33][CH2:34][CH:35]3[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]3)[CH2:31][CH2:32]2)[CH:54]=[CH:53][CH:52]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC2CCNCC2)CC1
Reactant: Cc1cccc(Cl)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCC(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
2-(Dicyclohexylphosphino)biphenyl (71 mg) and (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one-palladium (93 mg) were added to a toluene (10 ml) suspension of tert-butyl 4-(2-piperidin-4-ylethyl)piperidine-1-carboxylate hydrochloride (1.13 g), 2-chloro-6-methylpyridine (431 mg) and sodium tert-butoxide (487 mg), followed by stirring at 120° C. for 1 hour. The reaction liquid was left cooled, then an aqueous saturated sodium carbonate solution was added thereto, followed by extraction with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl 4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidine-1-carboxylate (660 mg) as a red oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:16][CH2:15][N:14]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C([O-])(O)=O.[Na+]>>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]([N:14]1[CH2:13][CH2:12][C:11]([CH2:10][CH2:9][OH:8])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:16][CH2:15]1)=[O:22]
Reactant: CC(C)(C)C(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(c2ccccc2)OC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1CCC(CCO)(c2ccccc2)OC1

Procedure:
6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinane (4.07 g, 10.03 mmol) was stirred in a 1M solution of tetrabutylammonium fluoride in THF (40 mL, 40 mmol) for 2 h at room temperature. Saturated aqueous NaHCO3 was added, and the reaction mixture was extracted with CHCl3. The organic layers were dried (Na2SO4), concentrated and the residue was filtered through a silica plug flushing with 1:1 hex:EtOAc to afford 2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethanol in quantitative yield as a clear oil that was used without further purification. 1H NMR (400 MHz, CDCl3): δ 37.45-7.37 (m, 4H), 7.31 (m, 1H), 5.51 (dd, 1H, J=10.9, 2.1 Hz), 4.69 (d, 1H, J=11.0 Hz), 4.30 (m, 1H), 3.58 (m, 2H), 2.99 (m, 1H), 2.31 (dt, 1H, J=14.1, 3.4 Hz), 2.16 (ddd, 1H, J=14.1, 11.7, 4.4 Hz), 2.04 (ddd, 1H, J=14.5, 7.0, 4.7 Hz), 1.92 (ddd, 1H, J=14.6, 6.9, 4.7 Hz), 1.28 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[N:17]1([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([O:35][CH3:36])[C:29](N(OC)C)=[O:30])=[CH:24][CH:23]=2)[CH:21]=[N:20][CH:19]=[N:18]1>>[N:17]1([C:22]2[CH:23]=[CH:24][C:25]([CH:28]([O:35][CH3:36])[C:29]([C:12]3[O:11][C:10]([C:5]4[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:15][CH3:16])[CH:4]=4)=[CH:14][CH:13]=3)=[O:30])=[CH:26][CH:27]=2)[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-n2cncn2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-n4cncn4)cc3)o2)cc(OC)c1Br
Yield: 11 %

Procedure:
2-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) followed by another purification (40% acetone-hexanes) gave 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanone as a pale yellow solid (0.078 g, 11% yield). MS: ink 498.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)[N:9]2C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc(-c3cncnc3)n(C(=O)OC(C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(-c3cncnc3)[nH]c2c1
Yield: 91.1 %

Procedure:
tert-Butyl 6-methoxy-2-pyrimidin-5-yl-1H-indole-1-carboxylate (295 mg) in tetrahydrofuran (2.27 mL) was added tetrabutylammonium fluoride (about 1.0 mol/L tetrahydrofuran solution, 3.63 mL) at room temperature, and the mixture was heated under reflux for 30 hours. The reaction mixture was left to be cooled, diluted with ethyl acetate, and then washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (186 mg). 1H-NMR (CDCl3) δ ppm: 3.88 (3H, s), 6.84 (1H, dd, J=2.3, 8.8 Hz), 6.88-6.95 (2H, m), 7.54 (1H, d, J=8.8 Hz), 8.20-8.52 (1H, br), 8.99 (2H, s), 9.11 (1H, s). ESI-MS (m/z): 226 (M+H)+
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH:11]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.N1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH:11]1([N:19]2[C:1](=[O:9])[C:2]3[CH2:3][CH2:4][CH2:5][C:6]=3[O:7][C:20]2=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C=NC1CCCCCCC1
Reactant: O=C(Cl)CCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: O=c1oc2c(c(=O)n1C1CCCCCCC1)CCC2

Procedure:
With stirring and reflux cooling, 183 g (1 mole) of adipic acid chloride were added to a solution, kept at 120°C., of 168.6 g (1.1 moles) of cyclooctylisocyanate and 162 ml (2 moles) of pyridine in 500 ml of xylene. After 3 hours' reaction time, cooling was effected, followed by filtering off from the separated pyridine hydrochloride. The filtrate was first freed from solvent under reduced pressure and, finally, was distilled in a high vacuum. 158.2 g (60% of the theory) of 3-cyclooctyl-2,3,4,5,6,7-hexahydrocyclopenta[e]-1,3-oxazine-2,4-dione of the boiling point 172°-174°C/0.3 mm Hg were obtained when solidified to give a colorless crystal mass of the melting point 48°-51°C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Br-].CC1(C)N([O])C(C)(C)CCC1.[O-]Cl.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O.O.C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=CCCCCc1ccccc1

Procedure:
To a solution of 5-phenylpentanol (5 g, 30.4 mmol), NaBr (3.2 g, 31.3 mmol), and TEMPO® (48 mg, 0.3 mmol) in EtOAc (60 mL), toluene (60 mL), and water (9 mL), cooled to 0° C., is added portionwise (50 mL) over 30 minutes a solution containing NaOCl (0.35 M in H2O, 287 mL, 100.4 mmol) and NaHCO3 (22.2 g, 264.8 mmol). The reaction is quenched by the addition of EtOH (10 mL). The biphasic mixture is separated and the organic phase is washed with aqueous Na2S2O3 (2×100 mL), brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated to afford crude 5-phenylpentanal which is homogeneous by TLC analysis [hexane/EtOAc, 4:1, Rf (5-phenylpentanol)=0.30; Rf (5-phenylpentanal)=0.65] and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)=O.CN(C)C1C=CC=CC=1>CCOC(C)=O>[CH3:11][O:10][C:8]1[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:7]=1[CH:13]=[C:14]([C:16]1[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[NH:6]2
Reactant: COc1cc(OC)cc(C(=O)CBr)c1
Reactant: COc1cc(N)cc(OC)c1
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(-c2cc3c(OC)cc(OC)cc3[nH]2)c1
Reaction time: 0.17 h

Procedure:
0.32 g (2.1 mmoles) of 3,5-dimethoxyaniline, 0.26 g (1.0 mmol) of 2-bromo-1-(3,5-dimethoxyphenyl)ethanone and 0.42 ml (3.3 mmol) of N,N-dimethylaniline were placed in a vial. The vial was placed inside a monomode microwave reactor and was radiated at a power of 100 W, at a temperature of 150° C. for 10 minutes. After cooling the reaction vial, the mixture was dissolved in AcOEt, was washed with an aqueous HCl 2N solution, was dried on anhydrous Na2SO4 and was evaporated at low pressure. The crude portion was purified by means of pressure column chromatography (Eluent: AcOEt/hexanes) obtaining 4,6-dimethoxy-2-(3,5-dimethoxyphenyl)-1H-indole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12]Cl)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N:16]1([C:21]2[NH:22][C:23]3[C:28]([C:29]=2[CH3:30])=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:19][N:18]=[CH:17]1.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]([CH3:30])=[C:21]2[N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(OCCCl)cc1
Reactant: Cc1c(-n2ccnc2)[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1ccc(OCCn2c(-n3ccnc3)c(C)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
2-(p-Ethoxycarbonylphenoxy)-1-chloroethane is added in one portion to a mixture of 2-(1-imidazolyl)-3-methylindole (1.97 g), potassium hydroxide (0.62 g) and tetrabutylammonium bromide (0.32 g) in acetonitrile (250 ml) while stirring under nitrogen at room temperature. After stirring at room temperature for 65 hours an additional 0.64 g of tetrabutylammonium bromide is added and the mixture is refluxed for 41 hours. The reaction mixture is cooled to room temperature and filtered. The filtrate is concentrated in vacuo and the oil obtained dissolved in ethyl acetate and extracted with 1N hydrochlorid acid. The aqueous extract is made basic to pH 10 with 3N sodium hydroxide and extracted with ethyl acetate (3×100 ml). This extract is dried over magnesium sulfate, filtered, and concentrated in vacuo to give a crude oil which is purified by flash chromatography on silica gel. The product is eluted with 3% methanol in methylene chloride to give 1-[2-(p-ethoxycarbonylphenoxy)-ethyl]-2-(1-imidazolyl)-3-methylindole; NMR (CDCl3): δ 8.02 (d, 2H), 7.87-7.13 (m, 7H), 6.80 (d, 2H), 4.50-4.00 (m, 6H), 2.20 (s, 3H), 1.37 (t, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[N:1]1([CH2:7][CH2:8][O:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCN1CCCCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 0.573 g (4 mmole) of 2-piperidin-1-yl-ethanol and 8 mL of pyridine at 0 degrees was added 0.763 g (4 mmole) of p-toluenesulphonyl chloride. The mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure and 10 mL of water was added. The mixture was extracted twice with 10 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give toluene-4-sulfonic acid 2-piperidin-1-yl-ethyl ester as a purple oil, which was carried to next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:13][CH3:14])[C:11]=1[OH:12])[C:6]([OH:8])=[O:7])[CH3:2].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:7][C:6](=[O:8])[C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:11]([OH:12])=[C:10]([CH2:13][CH3:14])[CH:9]=1
Reactant: CCc1cc(C(=O)O)cc(CC)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1cc(C(=O)OC)cc(CC)c1O

Procedure:
A solution of 27.2 g. (0.14 mol.) of 3,5-diethyl-4-hydroxybenzoic acid in 200 ml. of methanol containing 2 ml. of sulfuric acid is refluxed for 12 hours. After cooling, excess methanol is evaporated, water is added to the residue and it is made basic with 10% aqueous sodium hydroxide. The precipitate is collected, washed with water and dried in vacuo to give 3,5-diethyl-4-hydroxybenzoic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].F[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C#N)cc3)ccc2C1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
Combine in a round bottom flask equipped with a Dean Stark trap 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.59 g, 6.36 mmol), toluene, dimethylacetamide (10 mL and 30 mL respectively), K2CO3 (1.25 g, 9.04 mmol), and 4-fluorobenzonitrile (0.72 g, 6.04 mmol). Reflux the reaction under a nitrogen atmosphere for 4 hours then cool to room temperature. Add water to the reaction mixture and extract the product from the water layer using ethyl acetate. The product, a white solid, precipitates out from the ethyl acetate to afford 1.93 g, 5.5 mmol (87% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.5 (9H, s), 2.75-2.85 (2H, m), 3.6-3.7 (2H, m), 4.5 (2H, s), 6.8-6.9 (2H, m), 6.9-7.0 (2H, m), 7.1-7.2 (1H, m), 7.5-7.6 (2H, m); MS m/z 249 (M−CO2t-Bu).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([CH3:20])=[C:8]([CH:13]=[CH:14][C:15]=2[S:16]([CH3:19])(=[O:18])=[O:17])[C:9]([O:11]C)=[O:10])=[N:2]1.[OH-].[Na+].Cl>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([CH3:20])=[C:8]([CH:13]=[CH:14][C:15]=2[S:16]([CH3:19])(=[O:18])=[O:17])[C:9]([OH:11])=[O:10])=[N:2]1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(-c2ccon2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1-c1ccon1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.5 %

Procedure:
To 0.80 g of methyl 3-(isoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoate were added 8 ml of ethanol and 8 ml of a 1N sodium hydroxide solution to stir at room temperature for 2 days. The reaction solution was poured into ice water, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure to give 0.56 g of the title compound as white crystals. m.p. 150-151° C.
Reaction SMILES: [Br:1]C1CC2C(=CC=C(OCC(F)(F)F)C=2)C1=O.C(N)(=S)C.Br.[CH3:23][C:24]1[S:25][CH:26]2[CH2:35][C:34]3[CH:33]=[C:32]([O:36][CH2:37][C:38]([F:41])([F:40])[F:39])[CH:31]=[CH:30][C:29]=3[C:27]2(O)[N:28]=1>CC(C)=O>[BrH:1].[CH3:23][CH:24]1[N:28]=[C:27]2[C:29]3[CH:30]=[CH:31][C:32]([O:36][CH2:37][C:38]([F:41])([F:39])[F:40])=[CH:33][C:34]=3[CH:35]=[C:26]2[S:25]1
Reactant: CC1=NC2(O)c3ccc(OCC(F)(F)F)cc3CC2S1
Reactant: O=C1c2ccc(OCC(F)(F)F)cc2CC1Br
Agent: Br
Agent: CC(N)=S
Solvent: CC(C)=O
Product: CC1N=C2C(=Cc3cc(OCC(F)(F)F)ccc32)S1

Procedure:
2-Bromo-5-(2,2,2-trifluoroethoxy)indan-1-one is stirred with an equivalent amount of thioacetamide in acetone at room temperature for 5 h. The precipitate consisting of 2-methyl-6-(2,2,2-trifluoroethoxy)-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol hydrobromide is removed and boiled in 15 ml of glacial acetic acid. The solvent is removed by distillation under reduced pressure, and the residue is induced to crystallize under diisopropyl ether. Colorless crystals, melting point 220-224° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8](I)=[CH:7][C:6]=1[OH:14])([CH3:3])[CH3:2].[Si:15]([C:22]#[C:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:15]([CH:22]1[C:23](=[CH:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[C:6]=2[O:14]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)C#CCO[Si](C)(C)C(C)(C)C
Reactant: COc1cc(I)cc(O)c1OC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1OC(C)C)OC([Si](C)(C)C(C)(C)C)C2=CO[Si](C)(C)C(C)(C)C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
A suspension of 2-isopropoxy-3-methoxy-5-iodophenol (4.41 mmol), 1-(tert-butyldimethylsilyl)-3-(tert-butyldimethylsilyloxy)propyne (1.5 g, 5.28 mmol), lithium chloride (189 mg, 4.45 mmol) and sodium carbonate (2.34 g, 22.08 mmol) in dry dimethylformamide (5 mL) at 100° C. was deoxygenated 4 times by evacuation and backfilling with nitrogen. Palladium acetate (135 mg, 0.60 mmol) was added and the reaction vessel was degassed twice with nitrogen. The reaction mixture was then stirred at this temperature for 4 hours (tic) and the solvent was removed by distillation under vacuum. The residue was dissolved in ethyl acetate (75 mL), stirred well, filtered and treated with triethylamine (5 mL). The solution was concentrated onto silica gel (10 g) and purified by flash chromatography (silica gel, eluent=hexane/diethyl ether/triethylamine; 95:5:1%) to afforded the title compound as a yellow oil (1.45 g, 96%); 1H NMR (300 MHz, CDCl3) δ 7.24(d, 1H, J=8.45 Hz), 6.88(d, 1H, J=8.47 Hz), 4.80(s, 2H, CH2), 4.73(m, 1H), 3.88(s, 3H, OMe), 1.36(d, 6H, J=6.17 Hz), 0.94(s, 9H), 0.92(s, 9H), 0.35(s, 6H), 0.12(s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[O:15])[CH2:9]2)=[CH:4][C:3]=1[O:23][CH3:24].COC1C=C(N2CCC[C@@H](C(N3CCN(C)CC3)=O)C2)C=CC=1[N+]([O-])=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[O:15])[CH2:9]2)=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Agent: COc1cc(N2CCC[C@@H](C(=O)N3CCN(C)CC3)C2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC[C@@H](C(=O)N3CCN(C)CC3)C2)ccc1N

Procedure:
[(R)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with [(R)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone. (390 mg, 98%). LC/MS (E/I+) 333.20 (M+H).
Reaction SMILES: II.Br[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[F:15].[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>CCOCC>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([CH2:4][C:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=2[F:15])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1ccc(C(F)(F)F)cc1CBr
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(Cc2cc(C(F)(F)F)ccc2F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a stirring suspension of Mg strips (308 mg) in Et2O (5 mL) was added a crystal of iodine followed by 0.3 mL of 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene under argon. The reaction was initiated with a high intensity heat gun, then 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (2.5 g, 9.73 mmol) in Et2O (5 mL) was added slowly (maintaining reflux). After addition was completed the reaction mixture was refluxed for 50 min, cooled to room temperature. A solution of 1-benzylpiperidin-4-one (1.84 g, 9.73 mmol) in Et2O (10 mL) was added slowly with vigorous stirring. After addition was completed, the reaction mixture was left at room temperature for 50 min, saturated aqueous NH4Cl solution was added and stirred at room temperature untill hydrolysis was finished, extracted with ethyl acetate. The combined organic layer was washed with water, dtied over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane, 0.2% NH4OH) to give the subtitled compound (720 mg).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][C:19]([CH3:26])=[C:20]([C:22](OC)=[O:23])[N:21]=3)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:18][C:19]([CH3:26])=[C:20]([CH2:22][OH:23])[N:21]=3)=[CH:15][CH:16]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1nc(-c2ccc(Cn3cnc4ccccc43)cc2)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Cn3cnc4ccccc43)cc2)nc1CO
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of methyl {2-{4-[(1H-benzimidazol-1-yl)methyl]phenyl}-5-methyl-1,3-oxazol-4-yl}carboxylate (0.093 g, 0.27 mmol) in dry THF was treated portionwise with LiAlH4 (0.020 g, 0.5 mmol) at 0° C., stirred for 1 h, quenched with ethyl acetate (0.5 mL) and water (0.2 mL), stirred for 30 min and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica, CH2Cl2:MeOH 95:5) to give the title compound as a white solid in 52% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 320 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH:5]2[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[OH-].[Na+].OO>C1COCC1.C(O)C.O>[CH3:1][C:2]1([C@@H:5]2[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]2)[CH2:3][CH2:4]1
Reactant: CC1(C2CCC(=O)CC2)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1([C@H]2CC[C@@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4.0 g (26.3 mmol) of 4-(1-methylcyclopropyl)cyclohexanone in 30 ml of THF was added dropwise at -78° C. to 5.5 g (29.0 mmol) of L-Selectride (1M in THF) and the mixture was subsequently stirred for 3 hours. It was then heated to room temperature, and 4 ml of H2O, 15 ml of ethanol, 11 ml of 6N NaOH and 13 ml of 35% strength H2O2 solution were added in succession to the reaction solution. This solution was left to stand overnight and then subjected to aqueous workup. Extraction was carried out with methylene chloride, and the extract was dried and concentrated. 3.4 g (86% of theory) were obtained of a colorless crystal powder, m.p.: 56° to 57° C.