Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])[C:10]=1[CH3:27].CC(C)([O-])C.[Na+].[CH3:34][C@H:35]1[C@H:39]([CH3:40])OS(=O)(=O)[O:36]1.Cl>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([C@H:39]([CH3:40])[C@@H:35]([OH:36])[CH3:34])[CH:12]=[C:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])[C:10]=1[CH3:27]
Reactant: C[C@@H]1OS(=O)(=O)O[C@H]1C
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccc(F)cc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cn([C@H](C)[C@H](C)O)c1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a solution of 5-(2-chloro-4-fluorophenyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxamide (0.50 g, 1.2 mmol) in anhydrous DMA (8.0 ml) was added sodium tert-butoxide (0.27 g, 2.8 mmol) and stirred at room temperature for 30 min under N2. (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (0.28 g, 1.8 mmol) in anhydrous DMA (2.0 ml) was added to the solution and stirred at 70° C. for 2.0 h. The reaction mixture was cooled to room temperature and added 2N HCl (2.0 ml) and concentrated on a rotary evaporator. To this residue was added anhydrous THF (4.0 ml) and 5N HCl (5.0 ml) and stirred at 60° C. for 80 min. The mixture was diluted with ethyl acetate and washed with water, satd NaHCO3 and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (3:7 to 2:8 hexane:ethyl acetate) to give an atropisomeric mixture of the title compound (0.29 g, 50%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH:19](=O)[CH2:20][CH3:21]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:13]([CH2:19][CH2:20][CH3:21])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCCCC1
Reactant: CCC=O
Solvent: O
Product: CCCN1CCCCC(C(=O)OC)=Cc2cc(Br)ccc21
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of methyl 9-bromo-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.0 g) in 1,27-dichloroethane (20 ml) were added propion aldehyde (1.87 g) and triacetoxy sodium borohydride (4.11 g) and the mixture was stirred overnight. Water was added and the mixture was extracted with ethyl acetate, after which it was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give methyl 9-bromo-1-propyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.15 g) as a yellow oily material.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:13])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(=O)([O-])O.[Na+]>O1CCCC1>[OH:12][C:11]1[C:3]([NH:2][C:21](=[O:23])[CH3:22])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1O)C(=O)CC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1O)C(=O)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
6-Amino-7-hydroxyindan-1-one hydrobromide (800 mg, 3.28 mmol) was suspended in tetrahydrofuran (20 mL), triethylamine (571 μL, 4.10 mmol) and acetic anhydride (387 μL, 4.10 mmol) were added, and the mixture was stirred at room temperature for 1.5 hr. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=60/40→100/0) to give the title compound (481 mg, yield 71%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[C:5]([CH3:27])[NH:4][C:3]=1[CH3:28].[H-].[Na+].[P:31](Cl)([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C>[P:31]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])([O:8][C:7]1[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[C:5]([CH3:27])[N:4]=[C:3]([CH3:28])[C:2]=1[Br:1])=[O:32]
Reactant: Cc1[nH]c(C)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(=O)c1Br
Reactant: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)Oc1c(Br)c(C)nc(C)c1-c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-Bromo-5-(4-(4-trifluoromethoxyphenoxy)phenyl)-2,6-dimethyl pyridin-4(1H)-one (4.44 g) in dry DMF (30 ml) under nitrogen was added sodium hydride (0.39 g of a 60% dispersion in mineral oil). After stirring at rt for 30 min diethyl chlorophosphate (2.1 ml) was added dropwise. The mixture was stirred at rt for 48 hr then filtered. The filtrate was diluted with toluene (200 ml), washed with 2M sodium carbonate, dried over magnesium sulphate and concentrated in vacuo. The residue was chromatographed on silica, eluting with 1:4 ethyl acetate:dichloromethane to afford the title compound (1.22 g), m.p. 80°-81°, NMR δH (CDCl3) 7.35-7.0 (8H, m), 4-3.8 (4H, m), 2.7 (3H, s), 2.25 (3H, s), 1.25-1.15 (6H, 2×t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH:11]2[CH2:13][CH2:12]2)=[N:9]/[OH:10])=[CH:4][CH:3]=1.[O-]CC.[Na+].Cl[CH2:19][C:20]1[C:21]([CH3:32])=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1>C(O)C>[CH3:32][C:21]1[C:20]([CH2:19][O:10]/[N:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)\[CH:11]2[CH2:12][CH2:13]2)=[CH:25][CH:24]=[CH:23][C:22]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O/N=C(/c1ccc(Cl)cc1)C1CC1
Reactant: Cc1c(CCl)cccc1-c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(CO/N=C(/c2ccc(Cl)cc2)C2CC2)cccc1-c1ccccc1

Procedure:
In a manner similar to General Procedure F of European Patent Publication No. 4,754, published Oct. 17, 1979, 1.96 g (0.01 mole) of (E)-(4-chlorophenyl)(cyclopropyl)methanone oxime was treated with 0.23 g (0.01 mole) of sodium ethoxide in 10 ml of ethanol, and the mixture was evaporated to dryness. The residue was dissolved in a minimum amount of solvent consisting of N,N-dimethylformamide and t-butanol (9:1 ratio) and treated with 2.16 g (0.01 mole) of 3-chloromethyl-2-methyl[1,1'-biphenyl] to yield, after purification by column chromatography, 0.83 g of (E)-(4-chlorophenyl)(cyclopropyl)methanone O-[(2-methyl[1,1'-biphenyl]-3-yl)methyl]oxime as an oil.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH:6]=[C:5]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([F:18])[CH:11]=3)[C:4]=2[CH:3]=[N:2]1.[H][H]>CO>[F:18][C:12]1[CH:11]=[C:10]([CH:5]2[CH2:6][CH2:7][CH2:8][C:9]3[NH:1][N:2]=[CH:3][C:4]2=3)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccc(C2=CCCc3[nH]ncc32)cc1F
Reactant: [H][H]
Solvent: CO
Product: N#Cc1ccc(C2CCCc3[nH]ncc32)cc1F
Yield: 20.2 %

Procedure:
4-(6,7-Dihydro-1H-indazol-4-yl)-2-fluoro-benzonitrile (0.102 g, 0.43 mmol) 5% Pd/C wt/wt % (0.04 g) is added to MeOH (5.0 mL) and the mixture is stirred under 45-35 psi of hydrogen for 3 hours. The mixture is filtered through a plug of diatomaceous earth and concentrated to dryness. The residue is purified by silica gel chromatography eluting with 1:1 hexanes/ethyl acetate to give the title compound (0.021 g, 18%). ES/MS m/z 242 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[CH:11]=[N:12][N:13]=[C:6]2[C:5]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1)[CH2:2][CH3:3]>C(O)=O>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:13]2[N:12]=[CH:11][N:7]=[C:6]2[C:5]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)n2cnnc2c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: O=CO
Product: CCCc1nc(C)n2ncnc2c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 75 %

Procedure:
10 g of 7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[4,3-c]pyrimidine, prepared in Example 69, are heated to reflux for 4 hours in 150 ml of formic acid. The mixture is evaporated to dryness under vacuum, and the residue, taken up with ether and pentane, crystallises to give 7.5 g of 7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidine in the form of crystals of melting point 112° C.
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([CH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cccc(OCc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ncc(COc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)methoxy)phenyl)propanoate (143 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (129 mg) as a white amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=S)[NH:11][NH2:12])=[C:4]([CH3:14])[CH:3]=1.Cl[CH:16]([C:22]([CH3:24])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:22]([CH3:24])[NH:12][N:11]=2)=[C:4]([CH3:14])[CH:3]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Cc1cc(Br)cc(C)c1NC(=S)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2c(C)cc(Br)cc2C)n[nH]c1C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
A mixture of 14.6 g (0.06 mole) of 4-(4-bromo-2,6-dimethylphenyl)-3-thiosemicarbazide and 9.93 g (0.06 mole) of ethyl 2-chloroacetoacetate in 60 mL of absolute ethanol was stirred under nitrogen atmosphere for 2 hr, treated with 30 mL of 2N ethanolic hydrogen chloride and heated at reflux until the reaction mixture cleared (3 hr). The reaction mixture was filtered hot then concentrated in vacuo to give an orange solid which, when triturated with warm benzene/ligroin (50:50) and filtered gave 10.8 g of slightly orange crystalline product. The filtrate upon standing for ~16 hr gave an additional 4.4 g of yellow crystals which became white when washed with warm acetone. The 2 fractions were combined and recrystallized from benzene/ligroin to give 10.35 g of fine white crystalline rods, mp 171°-199° C. (with degassing). An NMR analysis showed the solid to be a salt with some solvent present; mass spectra confirmed the presence of hydrogen chloride. After drying at 82° C. under high vacuum, there was left 9.56 g, mp 168°-196° C. A broad melting point range suggested that it may be a mixture of free base and salt; therefore, it was dissolved in methanol/water along with other reaction mixture material, made basic with 3N sodium hydroxide and extracted with 5×60 mL of methylene chloride. The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo to give a dark yellow solid. Recrystallization from benzene/ligroin then from benzene gave 10.7 g of white granular powder, mp 184°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:25])[CH2:10][NH:11][S:12]([C:15]1[C:16]2[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:17]=2[S:18][CH:19]=1)(=[O:14])=[O:13].[C:26](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:25])[CH2:10][N:11]([CH3:26])[S:12]([C:15]1[C:16]2[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:17]=2[S:18][CH:19]=1)(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCc2c(S(=O)(=O)NCC(O)c3ccc(F)cc3F)csc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(CC(O)c1ccc(F)cc1F)S(=O)(=O)c1csc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid[2-(2,4-difluorophenyl)-2-hydroxy-ethyl]-amide (the compound of Preparation Example 51) (197 mg) in N,N-dimethylformamide (3 mL) was added potassium carbonate (140 mg) and methyl iodide (0.1 mL). After stirring at room temperature for 1 hour, ethyl acetate was added, and the precipitate was removed by filtration. The solvent was evaporated at reduced pressure. Purification was carried out by silica gel column chromatography (hexane/ethyl acetate), and the title compound (190 mg) was obtained as a colorless candy-like substance.
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[CH:5]/[CH:6]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:7]1=[CH2:8])=[O:3].Cl.NO.C([O-])(=[O:20])C.[Na+]>C(O)C.O>[CH2:8]=[C:7]1[CH2:9][CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[CH:6]1[C:5](=[O:20])[CH2:4][C:2](=[O:3])[CH3:1]
Reactant: CC(=O)[O-]
Reactant: C=C1CCCC(C)(C)C1/C=C/C(C)=O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=C1CCCC(C)(C)C1C(=O)CC(C)=O
Reaction time: 0.08 h
Yield: 96 %

Procedure:
A solution of 30 g of γ-ionone in 75 ml of ethanol was added to a solution of hydroxylamine hydrochloride (12 g) and sodium acetate (21.6 g) in 30 ml of water. The addition was completed within 5 minutes. The reaction was slightly exothermic, the reaction mixture was stirred for 30 minutes, then it was concentrated under reduced pressure. Thereafter 30 ml of water and 30 ml of ether were added to the said mixture, and it was extracted with petroleum-ether. After drying and concentration, the combined organic extracts yielded a thick oil (31.2 g). An aliquot was distilled in a small distillation tube at a temperature of 180° and a pressure of 0.001 Torr. There was thus obtained a pure product which, as shown by vapour phase chromatography, constituted a mixture of the γ-ionone oxime in the form of the two syn- and anti-isomers in a ratio of 20:80.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:5]([NH2:7])[CH3:6].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:5]([NH:7][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])[CH3:6]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc1ccccc1[N+](=O)[O-]
Yield: 78.1 %

Procedure:
A suspension (2S,3S)-3-amino-2-tert-butoxycarbonylamino-butyric acid methyl ester (6.0 g, 20.7 mmol) (prepared according to WO 2010031750), 1-fluoro-2-nitrobenzene (4.37 g, 31.0 mmol) and sodium hydrogen carbonate (5.21 g, 62 mmol) in N,N-dimethylformamide (60 ml) was heated to 85° C. for 24 h. The reaction was cooled, concentrated in vacuo and the residue was diluted with water (100 ml) and extracted with ethyl acetate (2×150 ml). The organic layers were combined, washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 5 to 60% v/v ethyl acetate hexanes to give (2S,3S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenylamino)-butyric acid methyl ester (5.71 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][CH:17]1[CH2:22]CN(C(OC(C)(C)C)=O)[CH2:19][CH2:18]1.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrC[C@H]1CCC[N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][C@H:17]1[CH2:18][CH2:19][CH2:59][N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CBr)C1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(C[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 13 from 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt and 1,1-dimethylethyl (3S)-3-(bromomethyl)-1-piperidinecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH:13]=[CH2:14]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:13]=[CH2:12]
Reactant: Oc1ccc(F)cc1
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
To a solution of 4-fluorophenol (22.4 g, 200 mmol) in DCM (200 mL) was added 50% NaOH (aq) (100 mL), 3-bromoprop-1-ene (26.0 mL, 300.0 mmol) and tetra-n-butylammonium bromide (1.90 g, 6.0 mmol). The suspension was stirred at room temperature for 24 h. The layers were separated and washed with water (2×100 mL), brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-20% EtOAc in hexanes) to provide the desired 1-(allyloxy)-4-fluorobenzene (852) (29.7 g, 97.8%) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH:5]=[CH2:6].[CH3:7][O:8][SiH:9]([O:12][CH3:13])[O:10][CH3:11]>[Pt]>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][Si:9]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:7]
Reactant: C=COCCCl
Reactant: CO[SiH](OC)OC
Agent: [Pt]
Product: CO[Si](CCOCCCl)(OC)OC
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A 50 ml two-necked recovery flask equipped with a thermometer and a calcium chloride tube was charged with 4.26 g (40 mmol) of 2-chloroethylvinyl ether (manufactured by Tokyo Kasei Kogyo Co., Ltd.) and 0.2 g of a platinum catalyst (“BY 24-835” manufactured by Toray-Dow Corning Co.). Then, 4.89 g (40 mmol) of trimethoxysilane (manufactured by Tokyo Kasei Kogyo Co., Ltd.) was slowly added with stiffing while controlling the temperature at 50° C. or less. After then, more 0.2 g of the platinum catalyst was added and the mixture was stirred at room temperature (20° C.) for 6 hours. The reaction mixture was distilled under reduced pressure to obtain 7.32 g of the target 2-(2-chloroethoxy)ethyltrimethoxysilane.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:16](=[O:20])[C:17]([O-:19])=[O:18])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:16](=[O:20])[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-:3])=[O:2]
Reactant: O=C([O-])C(=O)c1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)C(=O)c1ccc(C2CCCCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of 0.66 moles of 3-nitro-4-cyclohexylphenylglyoxylate is stirred in 1.5 l. of boiling 10% sodium carbonate solution for 16 hours. The mixture is slowly filtered through charcoal into 1.1 l. of ice-cold 3-N-hydrochloric acid. The precipitate of crude material is collected on a filter, the recrystallized from benzene to give 3-nitro-4-cyclohexylphenylglyoxylic acid.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:22]([CH3:33])[CH:21]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:22]([CH3:33])[CH:21]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(C)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cncc(-c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of ethyl [4-({butyl[6-(4-methylphenyl)pyrazin-2-yl]amino}methyl)-2-methylphenoxy]acetate (39 mg, 0.087 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL), was added 2M sodium hydroxide (1 mL). After shaking for 1 h at room temperature the solvent was evaporated and the residue was then acidified with 2M HCl and extracted CH2Cl2 (2×10 mL). The organic solution separated by hydrophobic frit and the solvents removed in vacuo to afford the title compound as a bright yellow solid (34 mg).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][CH2:17][N:18]([CH3:21])[CH:19]=O)[C:14]2[N:13]([CH3:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:21][N:18]([CH3:19])[CH2:17][CH2:16][C:2]1([CH3:1])[C:14]2[N:13]([CH3:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CN(C=O)CCC1(C)CCCc2c1n(C)c1ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCC1(C)CCCc2c1n(C)c1ccccc21
Reaction time: 2 h

Procedure:
A solution of N-[2-(1,2,3,4-tetrahydro-1,9-dimethylcarbazol-1-yl)ethyl]-N-methylformamide (5.0 g, 0.017 mole), described in Example 225, in anhydrous THF (100 ml) is added dropwise to a stirred suspension of lithium aluminium hydride (0.50 g, 0.015 mole) in anhydrous THF (50 ml) under nitrogen. Stirring is continued for 2 hr at 25° C. The excess hydride is destroyed by dropwise addition of water to the cooled mixture. Saturated sodium chloride solution is added and the compound is extracted with ether. The ether solution is dried (MgSO4) and concentraed to yield the title compound, nmr (CDCl3) δ 1.4 (s, 3H), 2.19 (s, 6H), 3.8 (s, 3H), 7.0-7.6 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:8]=2)([O:3][CH3:4])=[O:2].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[SH:26].C1C=CC(I(OC(C(F)(F)F)=O)OC(C(F)(F)F)=O)=CC=1>FC(F)(F)C(O)C(F)(F)F>[CH3:4][O:3][C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[S:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[F:18])=[CH:11][CH:10]=[C:9]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:8]=2)=[O:2]
Reactant: Fc1ccc(S)c(F)c1
Reactant: COC(=O)c1cc2ccc(S(C)(=O)=O)cc2[nH]1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: COC(=O)c1[nH]c2cc(S(C)(=O)=O)ccc2c1Sc1ccc(F)cc1F
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 2-carbomethoxy-6-methylsulfonylindole (750 mg, 2.8 mmol), in 10 mL hexafluoroisopropanol was treated with 2,4-difluorothiophenol (7.5 mmol) followed by addition of PIFA (5.6 mmol). The dark colored solution was stirred overnight then partitioned between methylene chloride and water. After concentration of the methylene chloride layer to 20 mL the product was precipitated by addition of 30 mL hexane. An 88% yield of 3-(2,4-difluoro-phenylsulfanyl)-6-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester was obtained.