Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]([OH:21])[CH2:14]CCCCCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])(=[O:21])[CH3:14]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)OC(=O)[C@@H](N)Cc1ccccc1
Yield: 93.3 %

Procedure:
L-Phenylalanine (5.0 g, 0.03 mol), 1-octanol (3.9 g, 0.03 mol) and p-toluenesulfonic acid monohydrate (6.3 g, 0.038 mol) were suspended in toluene (200 ml) in a flask equipped with a Dean-Stark trap and refluxed for 20 h., resulting in a clear solution. Subsequently, the solvent was removed in vacuo and the remaining white solid was dissolved in CHCl3 (150 ml). This solution was extracted with 10% sodium carbonate, water and brine and dried over MgSO4. Evaporation of the solvent in vacuo yielded a colourless oil (7.7 g, 0.028 mol, 92%). 1H NMR (CDCl3): δ=7.19 (m, 5H), 4.04 (t, 2H, 3J=6.59 Hz), 3.67 (dd, 1H, 3JAB=5.5 Hz, 3JAB=7.7 Hz), 3.03 (dd, 1H, 2JAB=13.6 Hz, 3JAB=5.5 Hz), 2.81 (dd, 1H, 2JAB=13.6 Hz, 3JAB=7.7 Hz), 1.54 (m, 2H), 1.47 (s, 2H), 1.22 (a, 10H), 0.83 (t, 3H, 3J=6.8 Hz); 13C NMR (CDCl3): δ=175.1, 137.15, 129.15, 128.40, 126.65, 65.02, 55.75, 41.06, 31.65, 29.06, 28.41, 25.74, 22.51, 13.97.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[Li]CCCC.C([Cu])#N.[Li+].[Cl-].[C:24](Cl)(=[O:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:24](=[O:26])[CH3:25])=[C:11]([CH3:13])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cn(-c2ccc(F)cc2)nn1
Reactant: CC(=O)Cl
Agent: N#C[Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC(=O)c1c(C)nnn1-c1ccc(F)cc1
Temperature: -35 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a suspension of 1-(4-fluoro-phenyl)-4-methyl-1H-[1,2,3]triazole (4.0 g, 23 mmol) in DME (114 mL) was added n-BuLi (1.6 M in hexane, 17.0 mL, 27 mmol) dropwise at −75° C. The mixture was allowed to warm up to −35° C. and was stirred at −35° C. for 1 h. The reaction mixture was cooled again to −78° C. and a light green suspension of CuCN (2.03 g, 23 mmol) and LiCl (1.92 g, 45 mmol) in THF (32 ml) was added rapidly while stirring at −78° C. After 1 h the mixture was allowed to warm up to −35° C. and acetyl chloride (8.02 mL, 113 mmol) was added dropwise at this temperature. Then the reaction mixture was stirred at room temperature for 2 h and then poured carefully into aqueous saturated sodium carbonate solution (160 mL) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, dichloromethane) afforded the title compound (3.63 g, 69%) as an off white solid. MS: m/e=220.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:32]=[CH:31][C:20]([CH:21]=[CH:22][CH:23]=[C:24]2[O:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:19][CH:18]=1>[C].[Pd].O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH2:22][CH2:23][CH:24]2[O:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:31][CH:32]=1
Reactant: Cc1cccc(-c2nc(CCOc3ccc(C=CC=C4OC(=O)NC4=O)cc3)c(C)o2)c1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1cccc(-c2nc(CCOc3ccc(CCCC4OC(=O)NC4=O)cc3)c(C)o2)c1
Yield: 95.7 %

Procedure:
A mixture of 5-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamylidene]-2,4-oxazolidinedione (0.29 g), palladium-carbon (10%, 0.1 g) and dioxane (50 ml) was subjected to catalytic hydrogenation at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform-methanol (100:3) was obtained 5-[3-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]phenyl]propyl]-2,4-oxazolidinedione (0.28 g, 96%). This product was recrystallized from dichloromethane-methanol to give colorless prisms, m.p.149-150° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:34])[N:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1)([CH3:21])[CH3:22]
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)cn1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: COc1ccc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 62 using (4-isopropylphenyl)[(2-methoxy-5-pyridyl)methyl]amine (0.50 g) and 2,6-diisopropylphenyl isocyanate (0.63 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-[(2-methoxy-5-pyridyl)methyl]urea (0.57 g) was obtained.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:9](=[N:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C>[Pd].C1C=CC=CC=1>[C:23]([C:7]1[CH:8]=[C:9]([CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:27])[NH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C1=CC(=Nc2cccc(OCC(=O)O)c2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(Nc2cccc(OCC(=O)O)c2)cc(C(C)(C)C)c1O
Reaction time: 5 h

Procedure:
A mixture of 5.0 g of 3-(2,6-di-tertiary-butyl-cyclohexadienon-4-ylideneamino)phenoxyacetic acid, 250 ml of ethanol and 10 mg of 5% palladium on charcoal catalyst was placed on a Paar apparatus. Hydrogenation was complete after five hours. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated to give a thick brown oil. The oil was dissolved in 20 ml of benzene, filtered, diluted with 20 ml of cyclohexane and 10 ml of hexane, and chilled to give 1.4 g of light tan crystalline 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)phenoxyacetic acid, m.p. 127°-127.5° C. Analysis: Calculated for C22H29NO4 ; % C, 71.1; % H, 7.9; % N, 3.8; Found: % C, 70.3; H, 7.6; % N, 3.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][NH:6][CH3:7].CCN(C(C)C)C(C)C.[C:20](Cl)(=[O:22])[CH3:21]>CN(C)C1C=CN=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][N:6]([CH3:7])[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CNCc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a DMF (0.1 M) solution of 3-bromo-N-methylbenzylamine (1 eq.), Hunig's base (3 eq) and 4-(dimethylamino)pyridine (5% loading) was added acetyl chloride (1.5 eq). The resulting reaction mixture was stirred at RT for 16 h. After quenching the reaction with sat. aq. NaHCO3, the mixture was extracted with EtOAc. The organic extract was washed with 10% aq. HCl, sat. aq. NaHCO3, and brine. Drying over Na2SO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a yellow oil. Purification by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH2:12])[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=2)=[CH:22][N:21]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=2)=[CH:22][N:21]=1)[CH3:1]
Reactant: COc1ccnc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Reactant: CN(C)Cc1cccc(CSCCN)c1
Solvent: CCO
Product: COc1ccnc(Cc2cnc(NCCSCc3cccc(CN(C)C)c3)[nH]c2=O)c1

Procedure:
Reaction of 2-[3-(dimethylaminomethyl)benzylthio]ethylamine with 2-nitroamino-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone in refluxing ethanol gives 2-[2-(3-(dimethylaminomethyl)benzylthio)ethylamino]-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone which when reacted with boron tribromide gives 2-[2-(3-(dimethylaminomethyl)benzylthio)ethylamino]-5(4-hydroxy-2-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2]>O=[Mn]=O.C(Cl)(Cl)Cl>[C:13]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1)[CH:8]=[O:9])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the crude alcohol from above was added MnO2 and CHCl3 (20 mL). The mixture was stirred overnight at 25° C. and filtered, and the organic solvent was evaporated. The crude residue was purified by flash chromatography on silica gel eluting with 1:6 ethyl acetate-hexane to give 0.3 g of 3,5-di-t-butylbenzaldehyde as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: C1CCNCC1
Product: O=Cc1c(N2CCCCC2)n(-c2ccccc2)c2ccccc12
Yield: 50 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with piperidine as described in Example 2 to give, after flash chromatography, the title compound (50% yield). NMR (CDCl3) 10.23 (1H, s), 8.29 (1H, d), 7.59 (2H, m), 7.50 (1H, m), 7.40 (2H, d), 7.22 (1H, m), 7.11 (1H, t), 6.98 (1H, d), 3.25 (4H, m), 1.53 (2H, m), 1.42 (4H, m).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24](O)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(Cl)Cl>[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24]([F:7])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OC(Cc1ccccc1)CC1CCN(Cc2ccccc2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: FC(Cc1ccccc1)CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 0.27 mL (2.0 mmol) of (Diethylamino)sulfur trifluoride (DAST) in 2 mL of CH2Cl2 was cooled to −78° C. To this was added a solution of 1-benzyl-4-(3-Phenyl-2-hydroxypropyl)piperidine (Example 228, Step 2) in 2 mL of CH2Cl2. The mixture was stirred and warmed to rt. After 20 min, 10 mL of H2O were added and the mixture was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaHCO3 solution and sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 1:1) to give 1-benzyl-4-(3-phenyl-2-fluoropropyl)piperidine. Removal of the benzyl protecting group was achieved under standard conditions.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH:12](O)=O>>[O:11]1[C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=[CH:12]1
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: O=CO
Product: O=C(O)c1ccc2ncoc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Amino-3-hydroxybenzoic acid (2.200 g) and formic acid (20 ml) were heated at 117° C. for 4 h. The reaction mixture was cooled to ambient temperature and the precipitated solid collected by filtration, washed with diethyl ether and dried at reduced pressure. The solid (0.580 g) was heated at reflux with zinc chloride (2.00 g) and c.H2SO4 (2 drops) in xylene (150 ml) under a Dean and Stark for 16 h. On cooling, water was added and the brown solid collected by filtration and washed with water. The resulting solid was washed with methanol and the solvent removed from the filtrate under reduced pressure to give the title compound as a dark brown solid (0.349 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]([CH:17]([OH:28])[CH2:18][N:19]3[N:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20]3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C(N2C(C(OC)=O)=CC(C(O)CN3C(C(F)(F)F)=NN=N3)=N2)=NC=CC=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([CH:17]([OH:28])[CH2:18][N:19]3[N:23]=[N:22][C:21]([C:24]([F:25])([F:27])[F:26])=[N:20]3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(O)Cn2nnc(C(F)(F)F)n2)nn1-c1ncccc1Cl
Agent: COC(=O)c1cc(C(O)Cn2nnnc2C(F)(F)F)nn1-c1ncccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(C(O)Cn2nnc(C(F)(F)F)n2)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
72.5 mg (0.18 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-{1-hydroxy-2-[5-(trifluoromethyl)-2H-tetrazol-2-yl]ethyl}-1H-pyrazole-5-carboxylate and methyl 1-(3-chloropyridin-2-yl)-3-{1-hydroxy-2-[5-(trifluoromethyl)-1H-tetrazol-1-yl]ethyl}-1H-pyrazole-5-carboxylate in a ratio of 66:34 were dissolved in 5.0 ml of ethanol, and 21.0 mg (0.23 mmol) of 45% strength aqueous sodium hydroxide solution were added. After 1 hour of stirring at room temperature, the mixture was diluted with water and acidified with dilute hydrochloric acid. The aqueous phase was extracted repeatedly with ethyl acetate and dried over magnesium sulphate. The solvent was distilled off under reduced pressure, which gave 43 mg (48% of theory) of 1-(3-chloropyridin-2-yl)-3-{1-hydroxy-2-[5-(trifluoromethyl)-2H-tetrazol-2-yl]ethyl}-1H-pyrazole-5-carboxylic acid and 1-(3-chloropyridin-2-yl)-3-{1-hydroxy-2-[5-(trifluoromethyl)-1H-tetrazol-1-yl]ethyl}-1H-pyrazole-5-carboxylic acid in a ratio of 73:27. (logP: 1.68/1.37; MH+: 404.0/404.0
Reaction SMILES: [OH:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].N1C=CN=C1.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].CN(C1C=CC=CN=1)C>O.CN(C)C=O>[C:12]([Si:16]([CH3:18])([CH3:17])[O:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CC(C)(C)O
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To the stirred mixture of 25 g (0.29M) of 3-hydroxy-3-methylbutyne, 50 ml of anhydrous N,N-dimethyl-formamide and 44.5 g (0.65M) imidazole cooled in an ice-bath was added 50 g (0.33M) tert.butyldimethylsilyl chloride. Stirring in the ice-bath was continued for 15 minutes and then at room termperature overnight. After addition of 250 mg of dimethylaminopyridine, the reaction mixture was heated at 70° C. for two hours and then poured into one liter of cold water. It was then extracted with 5×150 ml of ether. The organic extract was washed with brine, dried over MgSO4 and evaporated to dryness. The crude product was purified by vacuum distillation yielding 3-(tert.butyldimethylsilyl)oxy-3-methyl-butyne.
Reaction SMILES: [F:1][As-:2]([F:7])([F:6])([F:5])([F:4])[F:3].C1([I+][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)C=CC=CC=1.[C:21]1([S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1.[Cu]>[F:1][As-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:28]1([S+:27]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: c1ccc([I+]c2ccccc2)cc1
Agent: [Cu+2]
Agent: [Cu]
Agent: F[As-](F)(F)(F)(F)F
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Yield: 97 %

Procedure:
The present invention is based on the discovery that higher yields of aromatic sulfonium salts including substituted derivatives thereof can be obtained at lower reaction temperatures and enhanced reaction rates by employing a copper salt catalyst in combination with the aryl iodonium salt and aryl sulfide or alkyl sulfide. A typical reaction, for example, would be the reaction between diphenyliodonium hexafluoroarsenate and diphenylsulfide in the presence of a copper benzoate catalyst to produce a 97% yield of triphenylsulfonium hexafluoroarsenate at 120° C. for three hours.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:11])=[O:10])[CH:3]=1.[Br:12][C:13]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][C:14]=1[CH:15]=O>>[Br:12][C:13]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][C:14]=1/[CH:15]=[CH:11]/[C:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[OH:8])=[O:10]
Reactant: CC(=O)c1cc(C)ccc1O
Reactant: COc1ccc(C=O)c(Br)c1OC
Product: COc1ccc(/C=C/C(=O)c2cc(C)ccc2O)c(Br)c1OC
Yield: 65.1 %

Procedure:
2-Hydroxy-5-methylacetophenone (85 mg, 0.57 mmol) and 2-bromo-3,4-dimethoxybenzaldehyde (166 mg, 0.68 mmol) were reacted according to the same procedure as Preparation 1 to give 140 mg (Yield 54.6%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.C[O:16][B:17](OC)[O:18]C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([B:17]([OH:18])[OH:16])[CH:3]=1
Reactant: Clc1ccc(Br)cc1I
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Product: OB(O)c1cc(Br)ccc1Cl
Yield: 36 %

Procedure:
Following the method described in Example 81, 4-bromo-1-chloro-2-iodo-benzene, isopropylmagnesium chloride and trimethylborate provided 5-bromo-2-chloro-phenylboronic acid (36% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.Cl.C(=O)([O-])O.[Na+]>CS(C)=O.O>[N:11]1[CH:12]=[CH:13][C:8]([NH:7][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccncc1
Reactant: N#Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Nc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
10 ml of dimethyl sulfoxide was added to the above potassium tert-butoxide, followed by cooling in an ice-water bath. While this mixture was kept at 20° C. or below, 1.882 g of 4-aminopyridine was added thereto, followed by stirring at room temperature for 1 hour. 1.21 g of 4-fluorobenzonitrile was dissolved in 3 ml of dimethyl sulfoxide, and this solution was added dropwise to the above reaction mixture kept at an internal temperature of 30° C. or below, followed by stirring at room temperature for 30 minutes. After water was added to the reaction mixture, the resulting mixture was acidified with dilute hydrochloric acid and then neutralized with a saturated aqueous solution of sodium hydrogen carbonate. The product was extracted with tetrahydrofuran-diethyl ether (1:1), and the organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by silica gel column chromatography (using a 9:1 mixture of chloroform and methanol as the eluent) to obtain 1.85 g of 4-[N-(4-pyridyl)amino]benzonitrile.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C@@:7]([C:17]([O:19][C:20](C)(C)C)=[O:18])([CH3:16])[NH:8]C(OC(C)(C)C)=O)=[CH:3][CH:2]=1>C(Cl)Cl.Cl>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:6]=[CH:5][C:4]([C@@:7]([C:17]([O:19][CH3:20])=[O:18])([CH3:16])[NH2:8])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C(=O)OC(C)(C)C)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@](C)(N)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HCl (7.2 ml, 4M in dioxane) was added dropwise to a solution of 1,1-dimethylethyl 2-(4-biphenylyl)-N-{[(1,1-dimethylethyl)oxy]carbonyl}alaninate (1.14 g, 2.87 mmol) in CH2Cl2 (10 ml) at 0° C. under argon. The resulting mix was stirred at room temperature for 16 h. The reaction mixture was concentrated leaving a white solid which was refluxed in methanolic HCl (30 mL) for 16 h. The reaction mixture was concentrated and the residue was taken into Na2CO3 (10%, 100 ml) and the product was extracted by EtOAc (3×20 ml). The combined extracts were washed by water then brine, dried and concentrated left 830 mg as a clear oil. MS(ES) m/e 256.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([N:21]3[CH2:26][CH2:25]S[CH2:23][CH2:22]3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.O[O:30][S:31]([O-:33])=O.[K+]>CO>[O:30]=[S:31]1(=[O:33])[CH2:25][CH2:26][N:21]([C:12]2[N:11]=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)=[O:9])[C:19]([OH:20])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[CH2:22][CH2:23]1
Reactant: O=S([O-])OO
Reactant: O=C(NCc1ccc(F)cc1)c1nc(N2CCSCC2)c2cccnc2c1O
Agent: [K+]
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc(N2CCS(=O)(=O)CC2)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 28 h

Procedure:
A solution of N-(4-fluorobenzyl)-8-hydroxy-5-thiomorpholin-4-yl-1,6-naphthyridine-7-carboxamide (0.19 g, 0.49 mmol) in methanol (25 mL) was treated with an aqueous solution of Oxone (7.5 mL of a 1M solution, 0.75 mmol) and stirred at room temperature for 28 hr. The solvent was evaporated in vacuo and the residue partitioned between water and CH2Cl2. The organic extracts were purified by reverse phase HPLC. (Vydak C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 30 mL/min over 15 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4(O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([O:30][Si](C)(C)C)=[C:27]([CH3:29])[CH3:28]>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:27]([CH3:29])([CH3:28])[C:26]([O:25][CH3:24])=[O:30])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCCCC1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)C(C)(C)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCCCC1
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
To a solution of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexanol (500 mg, 1.6 mmol) in DCE (20 mL) was added 1-methoxy-2-methyl-1-trimethylsiloxy-propene (935 uL, 4.8 mmol) followed by TiCl4 (1.7 mL of 1.0 M in DCM). Within 10 min, the reaction was complete. The reaction was quenched with MeOH and then extracted from brine containing dilute HCl with EtOAc×4. The organic layers were dried over MgSO4, filtered, concentrated and purified on SiO2 using 25% EtOAc in hexanes to give 635 mg (100%) of methyl 2-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexyl)-2-methylprop-anoate MS found: (M+H)+=395.