Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]N1C(=O)CCC1=O.O.C(OCC)(=O)C>C(O)(=O)C>[Br:16][C:13]1[CH:14]=[C:9]([O:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:10]([NH2:15])=[N:11][CH:12]=1
Reactant: Nc1ncccc1OCC1CCCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)cc1OCC1CCCCC1
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 2 g of 3-(cyclohexylmethoxy)pyridin-2-amine in 10 ml of acetic acid was added 1.90 g of N-bromosuccinimide over 30 minutes under ice-cooling, followed by stirring for 30 minutes under ice-cooling. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.25 g of 5-bromo-3-(cyclohexylmethoxy)pyridin-2-amine.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:13]([O:14][CH2:15][CH2:16][F:17])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:25]>CN(C)C=O.C(OCC)C.C(Cl)Cl>[F:1][CH2:2][CH2:3][O:4][C:5]1[C:13]([O:14][CH2:15][CH2:16][F:17])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:25])=[O:8]
Reactant: [NH4+]
Reactant: O=C(O)c1cccc(OCCF)c1OCCF
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(OCCF)c1OCCF
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.3 gram (0.0054 mole) of 2,3-di(2-fluoroethoxy)benzoic acid, 1.0 gram (0.0080 mole) of oxalyl chloride, and one drop of N,N-dimethylformamide in 20 ml of diethyl ether was stirred at room temperature for approximately 18 hours. The solvent was evaporated from the reaction mixture leaving a residue. This residue was dissolved in 100 ml of methylene chloride, and the resulting organic solution was added slowly to a stirred, cold (0° C.) aqueous solution of ammonium hydroxide (5 ml of 30% solution). This mixture was allowed to warm to room temperature and stir for approximately 18 hours. The mixture was washed with an aqueous, sodium bicarbonate solution followed by an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a solid residue. Recrystallization of this solid from a mixture of toluene and n-hexane yielded 0.6 gram of 2,3-di(2-fluoroethoxy)benzamide, mp 100°-101° C.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=O)[C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([N:21](CC)CC)C.N.O1CCOCC1>S(Cl)(Cl)(=O)=O.CO>[O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH2:21])=[O:18])[C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)c1cccc2c(=O)c3ccccc3sc12
Reactant: CCN(CC)CC
Agent: N
Solvent: O=S(=O)(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1cccc2c(=O)c3ccccc3sc12
Yield: 23.4 %

Procedure:
A sample of 9-oxo-9H-thioxanthene-4-carboxylic acid 1r (15 g, 58.7 mmol) was heated in sulfonyl chloride (70 mL) for 2 h. Excess sulfonyl chloride was removed via evaporation. The residue was dissolved in tetrahydrofuran (200 mL), and triethylamine (16.4 mL, 117.4 mmol) and a 0.5 M solution of ammonia in dioxane (176 mL, 88.5 mmol) were added. Methanol (20 mL) was added, and the mixture was evaporated. Water and chloroform were added, and a precipitate formed. The precipitate was isolated via filtration, and yielded 3.5 g (25%) of title compound 2r. The organic layer was separated, dried, filtered, and evaporated to yield 11 g of recovered 1r.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].O1CCC[CH2:30]1.[H-].[Na+].IC>C(=O)([O-])O.[Na+]>[CH3:30][O:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: C1CCOC1
Reactant: CC(C)[Si](OCc1ccc(C(O)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC(c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
A solution of 3-[hydroxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile (0.64 g, 1.62 mmol) and tetrahydrofuran (10 mL) is stirred at 0° C. Sodium hydride, 60% in mineral oil, (80 mg, 1.95 mmol) is added and the mixture is stirred at room temperature 10 min. The mixture is cooled to 0° C. and iodomethane (0.12 mL, 1.8 mmol) is added. The resulting mixture is stirred at room temperature 18 hr. The mixture is diluted with aqueous saturated sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer concentrated. The residue is purified via silica chromatography eluting with hexanes to 9:1 hexanes:ethyl acetate to provide 400 mg, 60% the title compound, as a colorless oil. 1H NMR (CDCl3) δ 7.70 (s, 1H), 7.55-7.69 (m, 2H), 7.27-7.46 (m, 5H), 5.27 (s, 1H), 4.88 (s, 2H), 3.41 (s, 3H), 1.05-1.29 (m, 21H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH2:20]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH:21]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:20]2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCN(CCCCc2cccc(OCc3ccccc3)c2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCCCc2cccc(O)c2)C1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
(RS)-4-{1-[4-(3-Benzyloxy-phenyl)-butyl]-pyrrolidine-3-sulfonyl}-phenol (88.4 mg, 0.2 mmol) and Pd/C (40 mg, 10% Pd on charcoal) in MeOH (5 ml) were refluxed for 2 hours under an atmospheric pressure of hydrogen. The reaction mixture was then cooled to room temperature, the catalyst was filtered and the filtrate was concentrated. The residue was chromatographed over silica gel (CH2Cl2—MeOH, 19:1) to provide (RS)-4-{1-[4-(3-hydroxy-phenyl)-butyl]-pyrrolidine-3-sulfonyl}-phenol (53 mg, 69%) as a light beige solid, MS: m/e=376.3 (M+H+).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Agent: Cl
Product: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCN3CCOCC3)cc12
Yield: 62 %

Procedure:
6-(2-Morpholin-4-yl-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime was prepared in 62% yield using the procedure described in example 85A, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 4-(2-chloroethyl)morpholine hydrochloride. The title compound was isolated as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]([CH:12]=[O:13])=[C:10]([Cl:14])[N:9]=[C:8]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[Mg].[CH3:24]I.OS([O-])(=O)=O.[Na+]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH:12]([OH:13])[CH3:24])=[C:10]([Cl:14])[N:9]=[C:8]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:21][CH:22]=1
Reactant: CI
Reactant: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Agent: O=S(=O)([O-])O
Agent: [Mg]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3.8 g of 3-(4-bromobenzyl)-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde are dissolved in 50 ml of THF and a Grignard solution, prepared from 385 mg of magnesium turnings and 990 μl of methyl iodide in 50 ml of diethyl ether, is slowly added by syringe at RT. The mixture is stirred at RT for 3 days, then 200 ml of a 5% aqueous NaHSO4 solution are added und the mixture is extracted twice using 200 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. 3.7 g of a colorless oil are obtained.
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[N:30]=[C:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[CH:27][CH:26]=1.O>CN(C=O)C>[CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=3[F:44])=[C:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[N:30]=2)[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)CN(CC)c1cccc(O)c1
Reactant: COc1ccc(F)c(-c2ccc(CBr)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(CC)c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of ethyl 2-(ethyl(3-hydroxyphenyl)amino)acetate (122 mg) in DMF (5.0 mL) were added potassium carbonate (75 mg) and 6-(bromomethyl)-3-(2-fluoro-5-methoxyphenyl)-2-neopentylpyridine (100 mg), and the mixture was stirred at 80° C. for 1 hr. The mixture was allowed to cool to room temperature, and water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (107 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][OH:14])[CH2:8][CH2:7]1)=S)[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].CCN(CC)CC>CN(C=O)C.Cl[Hg]Cl>[CH2:1]([N:3]1[C:4]([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][OH:14])[CH2:8][CH2:7]2)=[N:17][N:16]=[N:15]1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCNC(=S)N1CCC(CCO)CC1
Agent: Cl[Hg]Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1nnnc1N1CCC(CCO)CC1
Reaction time: 10 h
Yield: 40.6 %

Procedure:
To a mixture of N-Ethyl-4-(2-hydroxyethyl)piperidine-1-carbothioamide (200 mg, 0.93 mmol), HgCl2 (277 mg, 1.02 mmol), and NaN3 (181 mg, 2.78 mmol) in DMF (2.5 mL) was added NEt3 (388 μL, 2.78 mmol) at rt. After stirring for 10 h, the reaction mixture was filtered, and the filter cake was washed with CH2Cl2. The combined filtrates and washings were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo, and the residue was purified by SiO2 chromatograph (60% EtOAc/hexane) to afford the titled compound (85 mg, 41%): 1H NMR (CDCl3) δ 4.18 (q, J=7.2 Hz, 2H), 3.75 (td, J=6.8, 5.2 Hz, 2H), 3.51 (brd, J=12.4, 2H), 3.03 (td, J=12.4, 2.8 Hz, 2H), 1.84 (brd, J=14.4 Hz, 2H), 1.71 (m, 1H), 1.59 (q, J=6.8 Hz, 2H), 1.56 (t, J=7.2 Hz, 3H), 1.48-1.38 (m, 2H)
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12](COS(C2C=CC(C)=CC=2)(=O)=O)[O:11][C@@H:10]1[O:43][CH2:44][CH2:45][CH2:46][OH:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48]([O-])(=[S:50])[CH3:49].[K+].O.[CH3:54]N(C=O)C>>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:49][C:48](=[S:50])[CH3:54])[O:11][C@@H:10]1[O:43][CH2:44][CH2:45][CH2:46][OH:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC([O-])=S
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](OCCCO)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: [K+]
Solvent: O
Product: CC(=S)C[C@H]1O[C@H](OCCCO)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of the compound (6) (28.2 g, 42.5 mmol) in anhydrous DMF (300 ml), added was potassium thioacetate (7.28 g, 1.5 equivalents), and the mixture was stirred at 90° C. for 3 hours. After the sufficient progress of the reaction was confirmed, the reaction liquid was poured to chilled water (900 ml), extracted with ethyl acetate (3×300 ml). The organic layers were combined and washed with saturated saline (2×200 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified with silica gel chromatography (hexane-ethyl acetate, 2:1→3:2→1:1→2:3) to obtain the title compound (7) in the form of light brown oily substance {21.9 g (38.6 mmol), 90.8%}.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](Cl)[N:4]([CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:19]([SH:22])([CH3:21])[CH3:20].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([S:22][CH:19]([CH3:21])[CH3:20])[N:4]([CH3:12])[N:3]=1
Reactant: CC(C)S
Reactant: COC(=O)c1c(Cl)nn(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)nn(C)c1SC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30 g of methyl 3,5-dichloro-1-methylpyrazol-4-ylcarboxylate and 25.5 g of potassium carbonate are suspended in 150 ml of DMSO and to this suspension are slowly added 16.1 ml of isopropylmercaptan at a temperature of 25° to 35° C. After stirring for 3 hours at room temperature, the reaction mixture is poured into 200 ml of ice-water and then 300 ml of ethyl acetate are added. After phase separation, the organic phase is washed with 100 ml of water and 100 ml of a saturated aqueous solution of sodium chloride, dried over MgSO4 and concentrated to dryness under vacuum. Distillation of the residue (113°-114° C., 2×10-3 bar) gives 31.5 g of 3-chloro-4-(methoxycarbonyl)-1-methyl-5-isopropylthiopyrazole in the form of a pale yellow oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[CH:11][C:12](OCC)=O)[CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:23]1CCCC1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]([OH:23])[CH3:12])[CH2:8]2
Reactant: CCOC(=O)C=C1C2CC3CC(C2)CC1C3
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(O)=C1C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
Ethyl adamantylideneacetate (7) (31 g) in tetrahydrofuran (50 cm3) was added dropwise to a suspension of lithium aluminium hydride (5.2 g) in tetrahydrofuran (30 cm3). When the addition was complete, the reaction 0° C., allowed to warm up to room temperature and poured onto crushed ice. Work up gave the alcohol (8) (8.8 g) as a colourless oil which partially crystallised.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[C:13]([O-])(=[O:15])[CH3:14].[Na+]>C(OC(=O)C)(=O)C>[C:13]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1)(=[O:15])[CH3:14]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1cc(C(=O)O)c2ccccc21
Temperature: 110 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
1H-Indole-3-carboxylic acid (400 mg) and sodium acetate (0.96 g) were suspended in acetic anhydride (4.8 ml). The mixture was stirred at 110° C. for 16 hours and extracted with chloroform. The organic phase was washed with 2 N hydrochloric acid, dried over sodium sulfate anhydrous, and concentrated under reduced pressure. The residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 50:1) to give the title compound (170 mg, Y.:34%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[C:23]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:10]2[C:11]3[C@@:12]4([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]4)[C:16]=3[C:17](=[O:18])[N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:33][CH:34]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Cn2c3c(c(=O)n2-c2ccc(F)cc2F)[C@H]2CC[C@]3(C)C2(C)C)cc1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 150 mg, 0.49 mmol), tetrabutylammonium iodide (181 mg, 0.49 mmol) and 4-tert-butylbenzyl bromide (360 μL, 1.96 mmol) in dimethylformamide (3 mL) was heated at 80° C. for 4 days. The solvent was evaporated, dichloromethane (50 mL) was added and the solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 60-70% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give a pale yellow foam. This was dissolved in ethanol and treated with charcoal. The mixture was filtered through Celite, and the filtrate was evaporated and dried under high vacuum to give (4S,7R)-1-(4-tert-butyl-benzyl)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (151 mg, 68%). APCI(+)-MS (M+H) 451.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN1CCCC1=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Nc1cc(Cl)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Temperature: 160 °C
Reaction time: 41 h
Yield: 19.5 %

Procedure:
2-Amino-4-chloropyridine (8.00 g) was dissolved in N-methylpyrrolidone (65 ml), and then 2-fluoro-4-nitrophenol (19.55 g) and N,N-diisopropylethylamine (43.36 ml) were added thereto, followed by stirring at 160° C. for 41 hrs. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate-tetrahydrofuran (1:1) and a 2 N aqueous solution of sodium hydroxide. The organic layer was washed with water and brine in this order. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, then ethyl acetate). Fractions containing the target compound were concentrated to provide a residue, to which ethyl acetate was added to precipitate crystals. The crystals were filtered, and dried under aeration to provide the titled compound (3.02 g, 20%) as opaline crystals.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](O)C.Br[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:13]=1.C(=O)([O-])O.[Na+]>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.O.C(OCC)(=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:14]2[CH:13]=[C:12](/[CH:8]=[CH:7]/[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:24][CH:25]=1
Reactant: Cc1ccccc1
Reactant: CCO
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
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: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a mixed solution of toluene 2.0 mL, ethanol 0.6 mL and water 0.2 mL of methyl 4-bromo-2-(4-fluoroanilino)benzoate 0.20 g were added (E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)styrene 0.21 g, sodium hydrogen carbonate 0.18 g and tetrakis(triphenylphosphine)palladium(0) 40 mg, and it was heated and refluxed under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, tetrakis(triphenylphosphine)palladium(0) 40 mg was added to it, and it was heated and refluxed under nitrogen atmosphere for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid, saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to give methyl 2-(4-fluoroanilino)-4-((E)-2-phenylvinyl)benzoate.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[Br:19][C:20]1[C:21]([NH2:26])=[N:22][O:23][C:24]=1[CH3:25]>O1CCCC1>[Br:19][C:20]1[C:21]([NH:26][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[N:22][O:23][C:24]=1[CH3:25]
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Cc1onc(N)c1Br
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1onc(NC=C2C(=O)Nc3ccccc32)c1Br

Procedure:
The named compound is prepared by substituting 4-bromo-5-methyl-isoxazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2211 gms. 4-bromo-5-methyl-isoxazol-3-ylamine by refluxing in tetrahydrofuran (2.7 mL).
Reaction SMILES: Cl.CN(C)C[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.CO[C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1>O1CCOCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([O:6][CH2:5][O:7][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][CH:17]=1
Reactant: Clc1ccc(I)cc1
Reactant: COc1ccc(O)cc1
Reactant: CN(C)CC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Clc1ccc(OCOc2ccccc2)cc1
Yield: 957.3 %

Procedure:
Following the general procedure for Example 11 (step 1), N,N-dimethylglycine hydrochloride (0.51 g, 3.65 mmol), cesium carbonate (26 g, 79.8 mmol) and Cu(I) iodide (0.29 g, 1.52 mmol) were added to a solution of 4-chloroiodobenzene (6.4 g, 26.8 mmol) and 4-methoxyphenol (5.00 g, 40.3 mmol) in dioxane (10 mL) to afford the title compound (8.2 g, 100%) as a brown oil.