Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[N:6]=1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>CN1C(=O)CCC1>[CH2:17]([NH:19][C:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=2)[N:6]=1)=[O:21])[CH3:18]
Reactant: COC(=O)c1ccc(-c2csc(N)n2)cc1
Reactant: CCN=C=O
Solvent: CN1CCCC1=O
Product: CCNC(=O)Nc1nc(-c2ccc(C(=O)OC)cc2)cs1
Temperature: 110 °C
Yield: 40.4 %

Procedure:
To a solution of methyl 4-(2-amino-1,3-thiazol-4-yl)benzoate (Intermediate 11; 150 mg, 0.64 mmol) in NMP (3 mL), ethyl isocyanate (90 μl, 1.14 mmol) was added. The solution was heated at 110° C. for one hour in a microwave. The crude was partitioned between water and EtOAc. The organic layer was washed with NaHCO3 solution, water and brine. It was dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (2% MeOH in DCM) to give the desired product (79 mg). MS (ESP): 306 (M+H+) for C14H15N3O3S; NMR: 1.06 (t, 3H), 3.12-3.16 (m, 2H), 3.85 (s, 3H), 6.48 (s, 1H), 7.66 (s, 1H), 7.98 (s, 4H), 10.65 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](O)([CH3:13])([CH3:12])[CH3:11].S(=O)(=O)(O)O.ClCCl>C(O)(=O)C>[C:10]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH3:9])=[CH:4][C:5]=1[OH:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)O
Reactant: Cc1cc(O)ccc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(O)c(C(C)(C)C)cc1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
The starting compound 2-tert-butyl-4-chloro-5-methyl-phenol was prepared by t-butylation in the following manner: 4-chloro-3-methyl-phenol (10.0 g, 70 mmol) was dissolved in glacial acetic acid (30 mL) at ambient temperature. tert-Butanol (10.1 mL, 1.5 equivalents) was added, and subsequently 95% sulfuric acid (3.75 mL, 1 equiv.). The reaction vessel was closed with a drying tube and heated at 50° C. After 1 d, additional amounts of tert-butanol (5 mL) and sulfuric acid (1.8 mL) were added and heating was continued. After 3 d, dichlormethane (150 mL) was added, and the solution was washed three times with saturated aqueous sodium chloride (150 mL). Drying and evaporation of the solution provided 14.9 g of a pale yellow oil. Pure 2-tert-butyl-4-chloro-5-methyl-phenol was obtained by flash chromatography (silica/toluene-heptane 7:3) as a colourless oil, 1H NMR (CDCl3): δ 7.19 (s, 1H), 6.52 (s, 1H), 4.70 (s, 1H), 2.26 (s, 3H), 1.37 (s, 9H); TLC (silica/toluene-heptane 7:3) Rf=0.45.
Reaction SMILES: [Na].[CH3:2][SH:3].C[O-].[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[NH:19][N:20]=[C:21]([CH2:24]Cl)[CH:22]=[O:23]>CO>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[NH:19][N:20]=[C:21]([CH2:24][S:3][CH3:2])[CH:22]=[O:23]
Reactant: O=CC(CCl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CS
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CSCC(C=O)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 40 °C
Reaction time: 1 h

Procedure:
9.2 g of sodium was dissolved in 900 ml of methanol. 21.3 g of methanethiol was introduced into the sodium methylate solution thus obtained. Then 110.0 g of 3-chloropyruvaldehyde-1-[2,6-dichloro-4-(trifluoromethyl)-phenyl]hydrazone (produced according to Example 1) was added in portions at 30° to 40° C. The reaction mixture was stirred for 1 hour at 40° C. and then the methanol was distilled off in a water jet vacuum. The residue was mixed with 500 ml of water and extracted three times with 250 ml of dichloromethane each. The combined dichloromethane extracts were dried on sodium sulfate and concentrated by evaporation. The residue was suspended in 200 ml of n-hexane, filtered off and dried in a water jet vacuum. The yield of the product was 92.2 g [content (GC): 94.7 percent]. The melting point of the product was 88° to 90° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[CH:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[C:5]=1[N+:9]([O-:11])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1c(O)cc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(F)cc(F)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 72.7 %

Procedure:
To a solution of 4,6-difluoro-2-hydroxynitrobenzene (12.5 g, 71.1 mmol) in DMF (150 ml) was added sodium hydride (60% in oil, 3.70 g, 92.4 mmol) under stirring at 0° C., and the reaction mixture was stirred for 15 minutes. Benzyl bromide (11.0 ml, 92.4 mmol) was added dropwise at 0° C. After completion of the dropwise addition, the reaction mixture was stirred at 80° C. for 18 hours. After cooling to room temperature, the mixture was poured in ice-1N HCl to neutralize therewith, followed by extraction with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate/hexane (1/5) eluate fractions, 2-benzyloxy-4,6-difluoronitrobenzene (13.7 g, 73%) was obtained as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C1COCC1>[C:14]([O:13][C:11](=[O:12])[CH2:10][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C1CCCN1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCCC1=O
Yield: 97 %

Procedure:
A mixture of 2-pyrrolidone (2.66 ml, 34 mmol) and NaH (60% in oil, 1.25 g, 31.3 mmol) in THF (75 ml) was stirred until gas evolution ceased (30 min). tert-Butyl 2-bromoacetate (4.45 ml, 30 mmol) was added and stirred at r.t. overnight then partitioned between water (200 ml) and ethyl acetate (200 ml) to give intermediate 2-(oxo-pyrrolidin-1-yl)-acetic acid tert-butyl ester (5.8 g). It was dissolved in acetic acid (40 ml) and cone. aq. HCl (6 ml) with gas evolution observed. After stirring at r.t. for 2 hours it was evaporated and recrystallized from toluene/ethanol to give 2.58 g of the title compound (60% yield). 1H NMR (500 MHz, DMSO-d6): 1.95 (quintet, J=7.7 Hz, 2H), 2.24 (t, J=8.1 Hz, 2H), 3.38 (m, overalapping with H2O (3.35 ppm), 2H), 3.91 (s, 2H), 12.77 (br., 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:19]([O:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)COc1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)COc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 5 h
Yield: 99.5 %

Procedure:
To a solution of 4.00 g (20.4 mmol) of the product of Step A dissolved in 30 mL of CH2Cl2 was added 5.00 g (40.8 mmol) of 4-dimethylaminopyridine and 3.69 g (24.5 mmol) of tert-butyldimethylchlorosilane and the mixture was stirred under N2 for 5 hours. The reaction mixture was then filtered and the filtrate was diluted with ethyl acetate. The solution was washed with water, 1N HCl, saturated NaHCO3, dried (MgSO4), filtered and evaporated. Drying in vacuo afforded 6.30 g (99%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCn4ccnn4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14.9 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (18 mg, 15%).
Reaction SMILES: CC([S@@]([NH:7][C@:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[CH:9]([F:11])[F:10])=O)(C)C.Cl>CO>[NH2:7][C@@:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])([CH:9]([F:11])[F:10])[CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15]
Reactant: CC(C)(C)[S@](=O)N[C@@](C[C@H](O)C(F)(F)F)(c1ccccc1F)C(F)F
Agent: Cl
Solvent: CO
Product: N[C@@](C[C@H](O)C(F)(F)F)(c1ccccc1F)C(F)F
Yield: 87.7 %

Procedure:
Intermediate XVIII-1: Under an inert atmosphere a solution of (S)-2-methyl-N-((2S,4S)-1,1,5,5,5-pentafluoro-2-(2-fluorophenyl)-4-hydroxypentan-2-yl)propane-2-sulfinamide (XVII-2) (261 mg, 0.667 mmol) and hydrochloric acid (4 M in dioxane, 0.667 ml, 2.67 mmol) in MeOH (5 ml) was stirred at 25° C. After 4 h the solvent was removed at reduced pressure. The residue was treated with a half-saturated solution of Na2CO3 and extracted three times with AcOEt. The combined organic layers were dried over MgSO4 and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel (eluent: heptane/AcOEt 10:1) to yield the (2S,4S)-4-amino-1,1,1,5,5-pentafluoro-4-(2-fluorophenyl)pentan-2-ol (XVIII-1) (168 mg, 87.7%) as a light yellow solid. MS: m/z=288.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[C:18]([F:22])=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24]([CH3:25])=[O:37])[C:18]([F:22])=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg (0.80 mmol) of the compound from Example 50 were introduced into 55 ml of dichloromethane at 0° C., 198 mg (0.80 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the mixture was extracted with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The phases were separated, and the solvents were removed from the organic phase in vacuo. The crude product was purified initially by preparative HPLC (mobile phase: acetonitrile/water gradient) and then by flash chromatography of the resulting, slightly impure product on silica gel (mobile phase: ethyl acetate). 197 mg (63% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Br:11].CC(C)([O-])C.[K+].[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:21].Cl>CN(C=O)C.C1COCC1>[Br:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[O:21][CH2:20][C:19]([F:26])([F:18])[C:22]([F:25])([F:24])[F:23]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Br)c(OCC(F)(F)C(F)(F)F)n1
Temperature: 140 °C
Reaction time: 96 h
Yield: 21.8 %

Procedure:
To a solution of 6-chloro-5-bromo-pyridine-2-carboxylic acid (CAN 959958-25-9, 1.7 g, 7.19 mmol) in DMF (90 mL) and THF (30 mL) was added potassium tert-butoxide (2.02 g, 18.0 mmol) and 2,2,3,3,3-pentafluoropropan-1-ol (5.73 mL, 57.5 mmol). The mixture was stirred at 140° C. for 4 days, cooled and poured into ice-water (100 mL). 2 M Hydrochloric acid (15 mL) was added to adjust the pH to 2-3 and the mixture was extracted with TBME, organic layers were washed twice with water, pooled, dried with Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient) to give the title compound (548 mg, 22%) as light-brown solid; LC-MS (UV peak area, ESI) 100%, 347.9306 [M−H−].
Reaction SMILES: C(OC([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[N:13][C:14]([CH3:20])=[N:15][C:16]=32)[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:20][C:14]1[N:13]=[CH:12][C:11]2[CH:10]3[CH2:19][CH:17]([CH2:18][NH:8][CH2:9]3)[C:16]=2[N:15]=1
Reactant: Cc1ncc2c(n1)C1CC2CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: Cc1ncc2c(n1)C1CNCC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 4-methyl-3,5,10-triaza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (0.1 mmol) in methanol (2 ml) was added a solution of 1N HCl in methanol (2 mL). The reaction mixture was stirred for 3 h at room temperature and the solvents were removed to leave a solid (0.1 mmol). 1H NMR (CD3OD, 400 MHz) δ 8.40 (s, 1H), 4.20–3.80 (m, 2H), 3.40–3.00 (m, 4H), 2.60 (s, 3H), 2.10 (m, 1H), 0.80 (br s, 1H); APCl MS m/z 176.2 (M+H)+.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:22]([N:12]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)[CH:9]1[CH2:10][CH2:11][N:6]([CH3:4])[CH2:7][CH2:8]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)N1CCC(N(Cc2ccccc2)c2ccc3[nH]ccc3c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(N(Cc2ccccc2)c2ccc3[nH]ccc3c2)CC1
Yield: 64.1 %

Procedure:
A mixture of 4-[benzyl-(1H-indol-5-yl)-amino]-piperidine-1-carboxylic acid ethyl ester (100 mg, 0.265 mmol) and lithium aluminum hydride (1.0 M in THF, 1.06 mL) in THF (5.0 mL) was heated under nitrogen atmosphere to reflux. After 2.5 hours the reaction mixture was cooled and quenched by addition of Na2SO4.10H2O. The resulting mixture was filtered and the inorganic salts were washed with a mixture of MeOH and DCM. The filtrate was evaporated under reduced pressure and the crude residue was purified by flash chromatography to give 54.3 mg (64% yield) of benzyl-(1H-indol-5-yl)-(1-methyl-piperidin-4-yl)-amine, MS=320 [M+H]+.
Reaction SMILES: [CH:1]1([B-](F)(F)F)[CH2:3][CH2:2]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:16]1[CH:17]=[CH:18][C:19]([C:28]([OH:30])=[O:29])=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>CC([O-])=O.CC([O-])=O.[Pd+2].C(PC12CC3CC(CC(C3)C1)C2)CCC>[CH:1]1([C:16]2[CH:17]=[CH:18][C:19]([C:28]([OH:30])=[O:29])=[N:20][C:21]=2[O:22][CH2:23][C:24]([F:26])([F:27])[F:25])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)F)n1
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCPC12CC3CC(CC(C3)C1)C2
Product: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)F)n1
Temperature: 120 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
In a 150 ml round-bottom-flask, Pd(OAc)2 (15.7 mg, 70.0 μmol), butyl-1-adamantylphosphin (37.6 mg, 105 μmol), potassium cyclopropyltrifluoroborate (523 mg, 3.53 mmol), cesium carbonate (3.42 g, 10.5 mmol) and 5-bromo-6-(2,2,2-trifluoroethoxy)picolinic acid (Example 282a) (1.05 g, 3.5 mmol) were combined. The flask was evacuated in vacuo and flushed with argon three times, followed by addition of a mixture toluene (25 ml)/H2O (3 ml) through a septum cap. The reaction mixture was heated to 120° C., stirred for 20 h and then cooled to ambient temperature. Evaporation of volatiles in vacuo and the residue was redissolved in ethyl acetate and extracted with 1M HCl (12.5 ml). The aqueous phase was back-extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 5% MeOH in DCM) to give the title compound (530 mg, 58%). MS (EI): m/e=262.2[M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[C:18]([F:19])([F:21])[F:20]
Reactant: COCCO
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
2-Methoxyethanol (219 mg, 2.88 mmol) was dissolved in THF (6 mL), and sodium hydride (60%, 39 mg, 0.96 mmol) was added thereto. The mixture was stirred at room temperature for 10 minutes, and 2-fluoro-5-nitrobenzotrifluoride (200 mg, 0.96 mmol) was added thereto. The resulting mixture was heated at 60° C. for 5 hours. The reaction solution was poured in a saturated sodium bicarbonate solution and extracted with ethyl acetate and washed with saturated brine. To the organic layer, 10% palladium carbon (20 mg) and methanol (2 mL) were added. The resulting mixture was stirred under hydrogen atmosphere at atmospheric pressure at room temperature for 16 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=5:1) to give the desired material (170 mg, yield: 76%) as a yellow oil.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[C:8]1(C)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH3:11][C:10]1[CH:9]=[CH:8][CH:13]=[CH:12][C:2]=1[C:3]([OH:5])=[O:4]
Reactant: Cc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccccc1C(=O)O
Temperature: 53 °C
Reaction time: 16 h

Procedure:
A mixture of K2S2O8 (1.35 g), trifluoroacetic acid (5 mL), 0.083 mL of a catalyst solution as prepared in Example 3(a) above, and toluene (5 mL) was stirred under CO (1 atm) at 53° C. (oil bath) for 16 hours. After the reaction was quenched with water, the unreacted toluene was removed with an air flow over the liquid phase. Ether (20 mL) and chlorobenzene (internal standard; 0.15 mL) were added. After vigorously stirring the mixture for 5-10 minutes, the ethereal phase was analyzed by GC-MS. The GC yield of toluic acid was 260 mg (TON=58, assuming that the Rh oxide used to prepare the catalyst contained 5 molecules of water per each Rh2O3 unit). The ether layer was separated, and the aqueous layer was extracted with ether. The combined ether solutions were evaporated to dryness to give solid toluic acid which was purified by vacuum sublimation. The yield of the purified toluic acid (1H NMR: 95% p-isomer) was 222 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([B:8]2[O:9][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:10]2)[CH:7]=1
Reactant: OB(O)c1cc(F)ccc1O
Reactant: CC(C)(O)C(C)(C)O
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2cc(F)ccc2O)OC1(C)C
Yield: 92 %

Procedure:
To a suspension of (5-fluoro-2-hydroxyphenyl)boronic acid (1.000 g, 0.00641 mol) in toluene (3.0 ml) was added pinacol (0.875 g, 0.007404 mol). This was heated to reflux using a Dean-Stark apparatus for 24 hours before concentrating in vacuo. The residue was suspended in tert-butyl-methyl ether (10.0 ml) and organic layer was washed with saturated aqueous sodium chloride solution (2×10.0 ml), dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound as a translucent oil, 1.4 g, 92% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH3-]C#N.[Na+]>CO>[CH2:14]([N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc(C2CCCNC2)cc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(C2CCCN(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 3-(4-chlorophenyl)piperidine in MeOH (0.2 M), benzaldehyde (2.1 eq.) was added and the reaction mixture was stirred at RT for 1 h. Then, it was cooled to 0° C. and NaBH3CN (3 eq.) was added. The mixture was allowed to warm to RT and stirred for 1 h. Evaporation of the solvent gave a residue that was partitioned between sat. aq. NaHCO3 and EtOAc and the organic phase was separated and dried (Na2SO4). Evaporation of the solvent gave a crude that was purified by flash chromatography column on silica (Petroleum ether to EtOAc/Petroleum ether 1:19) yielding (62%) the title compound as a yellow powder. 1H NMR (300 MHz, DMSO-d6, 300K) δ 7.36-7.17 (9H, m), 3.48 (2H, s), 2.87-2.68 (3H, m), 2.05-1.91 (2H, m), 1.86-1.75 (1H, m), 1.74-1.50 (2H, m), 1.48-1.3 (1H, m). MS (ES+) C18H20ClN required: 285, found: 286 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1C.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:21]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)[CH:7]=3)[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N2CCN(CCCSc3ccnc(CSc4ccncc4)c3)CC2)cc1
Yield: 79 %

Procedure:
According to the procedure indicated in Example 7, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 1-phenylpiperazine and potassium carbonate and subsequent chromatography on silica gel gives, after crystallization from diisopropyl ether, the title compound; m.p. from 210° C. (dec.); yield 79% of theory.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[CH2:15]([O:17][CH2:18][CH2:19]Br)[CH3:16]>>[CH2:15]([O:17][CH2:18][CH2:19][N:6]1[CH2:5][CH2:4][C:3]([C:1]#[N:2])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)[CH3:16]
Reactant: CCOCCBr
Reactant: N#CC1(c2ccccc2)CCNCC1
Product: CCOCCN1CCC(C#N)(c2ccccc2)CC1

Procedure:
The title compound was prepared as described in Example I 2 from 4-cyano-4-phenylpiperidine and 2-bromoethyl ethyl ether excluding KI: Reaction time under reflux 6 hours. The compound boiled at 130°-135°/0.005 mm Hg.
Reaction SMILES: C[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[CH:11](O)/[C:12](/[CH3:15])=[CH:13]/[CH3:14].OS(O)(=O)=O>CCCCCC>[CH3:14][CH:13]1[C:2]2[C:3](=[C:4]([CH3:10])[C:5]([CH3:9])=[CH:6][C:7]=2[CH3:8])[CH:11]=[C:12]1[CH3:15]
Reactant: C/C=C(\C)C(O)c1c(C)c(C)cc(C)c1C
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: CC1=Cc2c(C)c(C)cc(C)c2C1C
Temperature: 25 °C
Yield: 89.2 %

Procedure:
Preparation of E-1-(2,3,5,6-tetramethylphenyl)-2-methyl-2-buten-1-ol (1.50 g, 0.00734 moles) in hexane (20 mL) was added dropwise to concentrated H2SO4 (20 mL) at 0° C. The resulting red solution was then allowed to warm to room temperature and then quenched by adding the solution dropwise to a solution of Na2CO3 (300 mL of 1.89 M solution) at 0° C. The organic layer was then separated and the aqueous layer extracted with pentane (3×100 mL). The organic layers were then combined and dried over MgSO4 followed by filtration and solvent removal resulting in the isolation of the desired product (1.22 g, 89.7 percent).