Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH:2]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[OH-].[K+].O.Cl[C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=1>CC(C)=O>[CH3:24][O:23][C:17]1[N:18]=[C:19]([O:21][CH3:22])[N:20]=[C:15]([S:1][CH:2]([CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:5])=[O:4])[N:16]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: O=C(O)C(S)C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1nc(OC)nc(SC(C(=O)O)C2CCCC2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.1 %

Procedure:
To a mixture solution of 6.0 g of 2-mercapto-2-cyclopentyl acetic acid, 4.2 g of potassium hydroxide and 50 ml of water, a solution of 30 ml of acetone and 6.6 g of 2-chloro-4,6-dimethoxy S-triazine was added at a temperature of from 0° to 5° C. for 20 mimutes. Then, the reaction mixture was stirred at room temperature for 1.5 hours. Acetone was removed by distillation under reduced pressure, and the residue was extracted with ethyl ether. The ethyl ether layer was removed, and the aqueous layer was adjsuted to pH 2 to 3 with a 5% hydrochloric acid aqueous solution and extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried. Then, ethyl acetate was removed by distillation under reduced pressure to obtain a white solid. The solid was recrystallized from isopropyl ether and n-hexane to obtain 4.5 g of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Br[C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH3:41][C:35]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:6]=[C:5]([N:24]2[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]2[CH3:33])[N:4]=3)[CH2:13][CH2:14]1)([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3)n(C)c2n1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)N1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperazin-1-ylmethyl)-9H-purin-6-yl)morpholine was alkylated with ethyl 2-bromo-2-methyl-propionate to give 502. LCMS m/z: 281.7 (2M+H+)
Reaction SMILES: [CH3:1][CH:2]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH2:3][CH2:4][CH3:5].[CH:16]([N:19]=[C:20]=[O:21])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[CH:16]([NH:19][C:20](=[O:21])[O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH:2]([CH2:3][CH2:4][CH3:5])[CH3:1])[CH:7]=[CH:8]2)([CH3:18])[CH3:17]
Reactant: CC(C)N=C=O
Reactant: CCCC(C)n1ccc2cc(O)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(C)n1ccc2cc(OC(=O)NC(C)C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a stirred solution of 1-(pentan-2-yl)-1H-indol-5-ol (9) (2.60 g, 12.8 mmol) in dichloromethane (CH2Cl2, 40 mL) was added isopropyl isocyanate (10) (i-PrNCO, 1.63 g, 19.3 mmol), followed by triethylamine (NEt3, 0.90 mL). The solution was stirred at room temperature overnight, and then concentrated to dryness in vacuo. The resulting oil was purified by silica gel column chromatography (1:3 ethyl acetate/hexanes) to provide 1-(pentan-2-yl)-1H-indol-5-yl isopropylcarbamate (11) (3.6 g, 98%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.35 (d, J=2.0, 1H), 7.32 (d, J=9.0 Hz, 1H), 7.22 (d, J=3.0 Hz, 1H), 6.98 (dd, J=8.5, 2.0, 1H), 6.50 (d, J=3.0 Hz, 1H), 4.86 (d, J=6.5 Hz, 1H), 4.49 (m, 1H), 3.82 (m, 1H), 1.87 (m, 2H), 1.51 (d, J=6.5, 3H), 1.26 (m, 8H), 0.90 (t, J=7.5, 3H).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2N=CC=C3)C=C[CH:2]=1.CC(C)([O-])C.[Na+].CCCCCCCCCCCC.I[C:34]1[CH:35]=[C:36]([CH3:41])[CH:37]=[C:38]([CH3:40])[CH:39]=1.CNC1C=CC=CC=1>[Cu]I.O1CCOCC1>[CH3:40][C:38]1[CH:39]=[C:34]([N:1]([CH3:2])[C:14]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:13]=2)[CH:35]=[C:36]([CH3:41])[CH:37]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCCCCCCCCC
Solvent: CNc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C)cc(N(C)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 469 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (10 mg, 0.0525 mmol, 5.0 mol %), 1,10-phenanthroline (20 mg, 0.111 mmol), sodium tert-butoxide (145 mg, 1.51 mmol), evacuated and backfilled with argon. Dodecane (235 μL), 5-iodo-m-xylene (150 μL, 1.04 mmol), N-methylaniline (135 μL, 1.25 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting brown suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ether 50:1; 10 mL fractions). Fractions 7-11 provided 110 mg (50% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.33−7.27 (m, 2H), 7.05−6.94 (m, 3H), 6.72 (s, 2H), 6.68 (s, 1H), 3.33 (s, 3H), 2.31 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Li+].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.CI.O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([N:16]([CH3:24])[S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)S(=O)NC(c1ccccc1)c1cc(Br)ccc1N
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(c1ccccc1)c1cc(Br)ccc1N)S(=O)C(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of 2-Methyl-propane-2-sulfinic acid [(2-amino-5-bromo-phenyl)-phenyl-methyl]-amide (60 g, 157 mmol) in DMF (700 mL) is cooled to −20° C., then LiHMDS (163 mL, 173 mmol) is added dropwise. After the addition the mixture is stirred at −20° C. for 1 h. Then CH3I (22.3 g, 157 mmol) is added dropwise. After the addition the mixture is warm to r.t. for 2 h. Then H2O is added and is was extracted with MeO(CH3)3, dried over Na2SO4 and concentrated to give product.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]2[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]2)=[CH:10][CH:9]=1)[C:3]#[N:4].N.[H][H]>CO.[Ni]>[CH3:21][C:18]1([CH3:22])[O:17][C@H:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH2:5][CH:2]([NH2:1])[CH2:3][NH2:4])=[CH:9][CH:10]=2)[CH2:20][O:19]1
Reactant: [H][H]
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCC(N)C#N)cc2)O1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC1(C)OC[C@@H](COc2ccc(CCCC(N)CN)cc2)O1

Procedure:
A solution of 2-amino-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-pentanenitrile (1.7 g, 4.28 mmol) in a 2M ammonia in methanol solution (50 ml) is passed through a H-CUBE apparatus fitted with a Raney nickel CatCart at 50° C. and a hydrogen pressure of 50 bar and a flow rate of 1.5 ml/min. After 5 hours of continuous cycling of the solution the reaction mixture is concentrated in vacuo to give 5-[4-((R)-2,2-Dimethyl-[1,3]dioxolane-4-ylmethoxy)-phenyl]-pentane-1,2-diamine as a light-yellow oil; [M+H]+ 309
Reaction SMILES: [C:1]1([CH:11]([P:20]([O:25]CC)(=[O:24])[O:21]CC)[P:12]([O:17]CC)(=[S:16])[O:13]CC)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Si](Br)(C)C>>[C:1]1([CH:11]([P:20]([OH:24])(=[O:21])[OH:25])[P:12]([OH:13])(=[S:16])[OH:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(=O)(OCC)C(c1cccc2ccccc12)P(=S)(OCC)OCC
Agent: C[Si](C)(C)Br
Product: O=P(O)(O)C(c1cccc2ccccc12)P(O)(O)=S
Yield: 82.1 %

Procedure:
Following the same method as described in Example 2, 6.70 g (15 mmol) of tetraethyl 1-naphthylthiomethanediphosphonate was treated with trimethylsilyl bromide, and then hydrolyzed to obtain 3.92 g of the title compound as white crystals. The yield was 78%.
Reaction SMILES: CC1(C)C(C)(C)OB(/[CH:9]=[CH:10]/[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)O1.I[C:26]1[C:34]2[O:33][CH2:32][C:31](=[O:35])[C:30]=2[CH:29]=[CH:28][C:27]=1[O:36][CH3:37].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][O:36][C:27]1[CH:28]=[CH:29][C:30]2[C:31](=[O:35])[CH2:32][O:33][C:34]=2[C:26]=1/[CH:9]=[CH:10]/[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc2c(c1I)OCC2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Yield: 27.2 %

Procedure:
A solution of tert-butyl (E)-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]piperidine-1-carboxylate (0.253 g, 0.750 mmol) in 1,4-dioxane (5 mL) was added with 7-iodo-6-methoxybenzofuran-3(2H)-one (0.198 g, 0.682 mmol) synthesized in Example B46, Step 2, 2 M aqueous sodium carbonate (0.680 mL, 1.36 mmol) and tetrakis(triphenylphosphine)palladium (0.0788 g, 0.0682 mmol), and the mixture was refluxed for 10 hours by heating. The reaction mixture was cooled to room temperature, and then added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was subjected to silica gel column chromatography (chloroform/methanol), and the resulting crude product was further purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (E)-4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)vinyl]piperidine-1-carboxylate (0.0692 g, 27%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1([CH2:11][OH:12])[CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:12][CH2:11][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (25.5 mL) was added dropwise to a solution of cyclopentanemethanol (32.4 mL) and triethylamine (46 mL) in dichloromethane (500 ml) at 0° C. After stirring overnight at room temperature, the mixture was sequentially washed with water, 2% hydrochloric acid, 4% aqueous sodium bicarbonate and water again. Following drying over sodium sulfate, the solvent was removed under vacuum, affording crude cyclopentylmethyl methanesulfonate (ca. 50 g) as a colourless oil. A mixture of this product and sodium iodide in acetone (600 ml) was heated at reflux in the dark for 16 hours. After cooling to room temperature, the reaction mixture was poured into petrol ether/water 2:1 (1.5 L) under stirring. The organic layer was washed twice with water, dried (Na2SO4) and carefully concentrated under reduced pressure (50 mm; temperature of the bath <30° C.). The residue was distilled in vacuo. The title product was obtained as a light yellow oil (39 g), by collecting the fraction boiling at 101-102°/70 mm.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]CO.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:20][Br:24]
Reactant: OCCc1ccccc1Br
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.8 %

Procedure:
Triphenylphosphine (7.83 g, 29.8 mmol) and carbon tetrabromide (12.4 g, 37.3 mmol) were added to a solution of 2-(2-bromophenyl)ethanol (5.00 g, 24.9 mmol) in dichloromethane (123 mL). The mixture was stirred at room temperature for 15 hours, and a saturated aqueous sodium carbonate solution was then added. The organic layer and the aqueous layer were separated, and the organic layer was then concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate:n-hexane (1:4, 200 mL) and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-bromo-2-(2-bromoethyl)benzene as a colorless oil (6.23 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:21])[O:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].CI.[C:26](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:26][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:21])[O:19][CH3:20]
Reactant: COC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 0.5 h

Procedure:
A mixture of 1.27 g of [3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]carbamic acid, methyl ester, 100 ml of dry dimethylformamide and 0.129 g of sodium hydride was stirred under argon, for 30 minutes, then 0.31 ml of methyl iodide was added. This mixture was stirred for 2 hours, then poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extracts were combined, dried and evaporated. The residue was dissolved in dichloromethane:methanol (95:5) and filtered through a short plug of silica gel. The filtrate was concentrated and the resulting solid chromatographed on a column of 500 g of silica gel, eluting with dichloromethane:methanol (97:3). Fractions containing product were combined, evaporated and the solid recrystallized from dichloromethane-hexane, giving 0.92 g of the desired product as off-white crystals, mp 164°-166° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:12]=[N:13][C:14](Cl)=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)[CH:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(COC)OC>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:12]=[N:13][C:14]([C:30]4[CH:29]=[CH:28][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=4)=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)[CH:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: FC(F)(F)c1ccc(-c2cc(Nc3ccc4ncsc4c3)nnc2Cl)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: FC(F)(F)c1ccc(-c2cc(Nc3ccc4ncsc4c3)nnc2-c2ccc3ccccc3c2)cc1
Temperature: 120 °C

Procedure:
(Ph3P)2PdCl2 (0.026 g, 0.038 mmol, Strem) was added to a mixture of benzothiazol-6-yl-[6-chloro-5-(4-trifluoromethylphenyl)pyridazin-3-yl]amine (0.203 g, 0.5 mmol, Example 81(e), 2-naphthaleneboronic acid (0.129 g, 0.75 mmol, Aldrich), Na2CO3 (0.053 g, 0.5 mmol), dimethoxyethane (1.4 mL), EtOH (0.4 mL) and water (0.6 mL). The reaction mixture was heated in a microwave at 120° C. for 15 min with stirring under nitrogen. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with 1N NaOH (20 mL) and water (2×20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/hexane (1:1) to give the title compound as an yellow amorphous solid. MS (ESI, pos. ion) m/z: 499 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.[OH-].[K+]>O1CCOCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ccc(Sc2ccccn2)cc1
Temperature: 60 °C
Yield: 84.7 %

Procedure:
A mixture of 22.7 g of 2-chloropyridine, 25 g of 4-aminothiophenol, 12.4 g of potassium hydroxide and 100 ml of dioxane was heated at 60° C. for about 2 hours to react them, and the product was purified to obtain 34.2 g of 4-(pyridine-2-ylthio) aniline. A mixture of 10 g of 4-(pyridine-2-ylthio) aniline, 5.6 g of triethylamine and 70 ml of chloroform was cooled at lower 5° C. in nitrogen gas atmosphere and 17 g of trifluoromethanesulfonic anhydride was added dropwise to the mixture. After the addition, the mixture was further stirred at 40° to 50° C. for about 1 hour to react them.
Reaction SMILES: [CH:1]([CH:3]([OH:11])[CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)=[CH2:2].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:28]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]>ClCCl.CN(C)C=O>[CH3:31][C:28]([Si:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[O:11][CH:3]([CH:1]=[CH2:2])[CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)([CH3:29])[CH3:30]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=CC(O)CCC1OCCO1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(CCC1OCCO1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
A solution of α-ethenyl-1,3-dioxolane-2-propanol (49.4 g, 315 mmole) in dichloromethane (175 ml) was treated sequentially with dimethylaminopyridine (5.72 g, 47 mmole) and triethylamine (52.8 ml, 380 mmole) followed by (dropwise) a solution of t-butylchlorodiphenylsilane (89.5 g, 332 mmole) in dimethylformamide (150 ml). The reaction was stirred under argon for 48 hours (25° C.), poured into 2.5 L of ice water and extracted with ethyl acetate (1.2 L). The organic extracts were wsashed with water (2×1 L), brine (1 L), dried (sodium sulfate), filtered, and concentrated in vacuo to 130 g of viscous yellow oil. The crude product was dissolved in ether, filtered from a small amount of suspended material, concentrated in vacuo, and chromatographed (Waters, Prep 500 L.C., 10% ethyl acetate:hexane) to afford 106 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:24]2[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=2)=[CH:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][CH:9]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)CCc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.1 %

Procedure:
To a solution of 3-{4-[3,3-bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid ethyl ester (example 5) (1.0 g, 2.0 mmol) in toluene (20 mL) and ethanol (50 mL) was added 1N NaOH (10.0 mL) and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated in vacuo and 1N HCl added. The product was extracted with ethyl acetate (x 3). The organic layers were combined, washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystalised from warm ethanol (100 mL), witch was concentrated to 60 mL, and cooled, to give 600 mg (56%) of the title compound.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:22]3[CH2:24][CH2:23]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH:22]3[CH2:24][CH2:23]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-n2cc(C(O)C3CCCCC3)c(C3CC3)n2)cc1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COc1ccc(-n2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C3CC3)n2)cc1
Yield: 13.7 %

Procedure:
Using cyclohexyl[3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.5 g) synthesized in Example 46(1) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.38 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.11 g, 14%) was obtained as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.B(Br)(Br)Br.ClCCl.CO.C([O-])(O)=O.[Na+]>ClCCl>[CH2:12]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc2c(ccn2CCc2ccccc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)CCN2CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
To a solution of 5-methoxy-1-phenethylindole (95 mg, 0.38 mmol) in 1.9 mL of dry dichloromethane was added boron tribromide-dichloromethane solution (4 M, 0.47 mL, 1.9 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at room temperature for 30 min, methanol (1 mL) was added with additional stirring at room temperature for 5 min. After the reaction mixture was neutralized by saturated NaHCO3 aqueous solution, the solution was extracted with ethyl acetate. The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to obtain the title compound (25.3 mg, 28%).
Reaction SMILES: C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC.[OH:22][C:23]([CH3:44])([CH3:43])/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[CH2:28][C@H:29]([C@H:31]1[CH2:40][CH2:39][CH2:38][C@@H:37]2[C@:32]1([CH3:42])[CH2:33][CH2:34][CH2:35][C@@H:36]2O)[CH3:30]>C(Cl)Cl>[OH:22][C:23]([CH3:43])([CH3:44])/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[CH2:28][C@H:29]([C@H:31]1[CH2:40][CH2:39][CH2:38][C@@H:37]2[C@@:32]1([CH3:42])[CH2:33][CH2:34][CH2:35][CH2:36]2)[CH3:30]
Reactant: C[C@H](C/C=C/C=C/C(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O)CCC[C@]12C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[C@H](C/C=C/C=C/C(C)(C)O)[C@H]1CCC[C@H]2CCCC[C@]21C
Reaction time: 2.5 h
Yield: 50.5 %

Procedure:
459 mg of 4-methylmorpholine N-oxide, 40 mg of tetrapropylammonium perrhutenate, and 2.53 g of molecular sieves (powder, 4Å) were stirred for 0.25 h at ambient temperature. 590 mg of (1S,4aR,5R,8aR)-5-[(3E,5E )-(R)-(7-hydroxy-1,7-dimethyl-octa-3,5-dienyl)]-4a-methyl-decahydro-naphthalen-1-ol, dissolved in 5 ml of CH2Cl2, was added and the mixture kept for 2.5 h at RT. Dilution with ether, filtration over SiO2, evaporation and flash chromatography (SiO2, hexane/AcOEt=7/3) afforded 283 mg of (4aR,5R,8aR)-5-[(3E,5E)-(R)-(7-hydroxy-1,7-dimethyl-octa-3,5-dienyl)]-4a-methyl-octahydro-naphthalen]-1-one besides of 166 mg of a mixture of product and starting alcohol.