Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.CC([O-])(C)C.[Na+].[Br:26][C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1.C(Cl)(Cl)Cl>O1CCCC1>[Br:26][C:27]1[CH:28]=[N:29][C:30]([O:1][CH2:2][C:3]2[N:4]=[C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)=[N:31][CH:32]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OCc1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3ncc(Br)cn3)co2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
4-Hydroxymethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole (0.538 g, 2.0 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (10 ml) followed by the addition of NaOtBu (0.231 g, 2.4 mmol). After stirring for 15 min at r.t., 5-bromo-2-chloro-pyrimidine (0.426 g, 2.2 mmol) in THF (5 ml) is added slowly over a period of 10 min and stirred for further 30 min at r.t. Chloroform (25 ml) is added; the mixture is washed with 0.5N hydrochloric acid (HCl) and water, dried over MgSO4 and concentrated in vacuo. After flash column chromatography (100% chloroform) 5-bromo-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl-methoxy}-pyrimidine can be isolated as an off-white solid. Yield 0.60 g (71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].C1C(=O)N([Cl:29])C(=O)C1.Cl>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:29])=[CH:16][C:15]=1[Cl:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A mixture of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (2.07 g, 5.50 mmol), NCS (789 mg, 5.91 mmol), and catalytic amount of conc. HCl in DMF (41 mL) was stirred for 1 hour at room temperature. The reaction mixture was diluted with EtOAc, and washed with water (5×). The organic layer was dried over MgSO4, filtered, and concentrated to give the crude material which was purified by silica gel flash column chromatography (3 to 5% EtOAc in hexanes) to afford the desired product (2.02 g, 89%).
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[CH2:29][N:30]2[C@@H:34]([CH3:35])[C@@H:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:32][C:31]2=[O:42])[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=1.[N:44]1[CH:49]=[CH:48][CH:47]=[C:46](B(O)O)[CH:45]=1>>[CH3:35][C@H:34]1[C@@H:33]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:32][C:31](=[O:42])[N:30]1[CH2:29][C:20]1[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=1[C:7]1[C:8]([C:46]2[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=2)=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:43])[CH:6]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1-c1cccnc1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: [2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-6-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and 3-pyridineboronic acid. M+H is 547.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[CH:22]=1)=[O:5]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: COc1cc(N)ccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (25 g, 110.3 mmol) in dichloromethane (125.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8 mL, 330.9 mmol) and dichloromethane (500.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)benzamide (33.6 g, 97.00%) as an off-white solid. ESI-MS m/z calc. 314.07. found 315.2 (M+1)+; Retention time: 1.44 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.12-8.07 (m, 2H), 8.07-7.98 (m, 1H), 7.65 (t, J=9.2 Hz, 1H), 7.24-7.19 (m, 2H), 3.85 (s, 3H) ppm.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)=[O:12])[CH2:10][CH:5]2[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[NH:33]1[CH2:38][CH:37]=[CH:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[N:33]1([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([C:11]([N:9]3[CH2:8][CH2:7][N:6]4[C:2](=[O:1])[O:3][C:4]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:5]4[CH2:10]3)=[O:12])=[CH:14][CH:15]=2)[CH2:34][CH:35]=[CH:36][CH2:37][CH2:38]1
Reactant: C1=CCNCC1
Reactant: O=Cc1ccc(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(CN2CC=CCC2)cc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 27 h
Yield: 40.5 %

Procedure:
To a solution of 4-[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]benzaldehyde (0.15 g, 0.35 mmol) and 1,2,3,6-tetrahydropyridine (44 mg, 0.53 mmol) in tetrahydrofuran (4 mL) was added sodium triacetoxyborohydride (0.11 g, 0.52 mmol), and the mixture was stirred at room temperature for 27 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=4:1) and crystallized from diisopropyl ether to obtain the title compound (70 mg, yield 41%).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][OH:17].[OH-].[K+]>O>[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][O:17][CH2:1][CH2:2][OH:3]
Reactant: CON=C1C(=NO)Oc2ccccc21
Reactant: C1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CON=C1C(=NOCCO)Oc2ccccc21
Temperature: 5 °C
Reaction time: 2.75 h
Yield: 60.5 %

Procedure:
264.3 g (6.0 mol) of ethylene oxide are passed into a solution of 192.2 g (1.0 mol) of benzofuran-2,3-dione 3-(O-methyl oxime) 2-oxime in 2 l of water at 20° C. in the course of 85 minutes. The solution is cooled to 5° C. and 70 g (1.06 mol) of potassium hydroxide lozenges are added, the temperature rising to 10° C. The mixture is stirred for a further 165 minutes without further cooling and the precipitate formed is filtered off with suction, washed with 500 ml of ice-water in portions and dried in a vacuum drying cabinet at 40° C. 143.0 g (61% of theory) of benzofuran-2,3-dione 2-[O-(2hydroxy-ethyl) oxime]-3-(O-methyl oxime) are obtained as a mixture of two stereoisomers.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([O:16][CH3:17])[C:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH2:12]1)=O)C1C=CC=CC=1>CO.[C].[Pd].[H][H]>[C:23]([O:22][C:20]([NH:19][C:13]1([CH3:18])[CH:14]([O:16][CH3:17])[CH2:15][NH:11][CH2:12]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC1CN(C(=O)OCc2ccccc2)CC1(C)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC1CNCC1(C)NC(=O)OC(C)(C)C

Procedure:
To a solution of 1-benzyloxycarbonyl-3-(tert-butoxycarbonylamino)-4-methoxy-3-methylpyrrolidine (fraction α) (0.29 g, 0.8 mmol) in methanol (10 mL), 5% palladium-carbon catalyst (water content, 50%; 0.15 g) was added, and the suspension was stirred at room temperature for 16.5 hours in hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound as a colorless oily product. This product was used in the subsequent reaction with no further purification.
Reaction SMILES: C(O[C@@H:6]1[O:20][C@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@H:7]1[O:8][C:9](=[O:12])[CH2:10][CH3:11])(=O)CC.[C:33]1([OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[C:9]([O:8][C@@H:7]1[C@@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[O:20][C@H:6]1[O:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](OC(=O)CC)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Reactant: Oc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](Oc2ccccc2)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Reaction time: 8 h
Yield: 75.7 %

Procedure:
1,2,3,5,6-Penta-O-propanoyl-β-D-glucofuranose (1.0 g, 2.2 mmol) and phenol (0.41 g, 4.3 mmol) were dissolved in CH2Cl2 (10 mL) and boron trifluoride diethyl etherate (134 μL, 1.1 mmol) was added dropwise. The solution was left at room temperature overnight by which time the reaction was complete by TLC. The reaction mixture was washed with saturated aqueous NaHCO3 (30 mL), water, dried (MgSO4) and concentrated in vacuo. Flash silica chromatography of the residue, eluting with 15% ethyl acetate in petroleum ether, gave phenyl 2,3,5,6-tetra-O-propanoyl-β-D-glucofuranoside as a colourless syrup (0.8 g, 77%); δH (CDCl3) 7.29 (2H, dd, J 7.4 and 8.4, 3′-and 5′-H), 7.02 (1H, t, J 7.4, 4′-H), 7.01 (2H, d, J 8.4, 2′- and 6′-H), 5.63 (1H, s, 1-H), 5.46 (1H, d, J 5.0, 3-H), 5.31 (1H, ddd, J 9.4, 4.6 and 2.4, 5-H), 5.27 (1H, s, 2-H), 4.62 (1H, dd, J 9.4 and 5.0, 4-H), 4.54 (1H, dd, J 12.3 and 2.4, 6a-H), 4.09 (1H, dd, J 12.3 and 4.6, 6b-H), 2.42 (2H, q, J 7.5, CH2), 2.39 (2H, q, J 7.5, CH2), 2.33 (2H, q, J 7.5, CH2), 2.25 (2H, q, J 7.5, CH2), 1.17 (3H, t, J 7.5, CH3), 1.15 (3H, t, J 7.5, CH3), 1.13 (3H, t, J 7.5, CH3), 1.08 (3H, t, J 7.5, CH3); δC (CDCl3) 174.3, 173.3, 173.3, 173.0 (4×C═O), 156.6 (1′-C), 130.0 (3′- and 5′-C), 122.9 (4′-C), 116.9 (2′- and 6′-C), 104.6 (1-C), 80.7 (2-C), 79.7 (4-C), 73.6 (3-C), 68.9 (5-C), 63.2 (6-C), 27.8, 27.8, 27.8, 27.7 (4×CH2), 9.4, 9.2, 9.2, 9.1 (4×CH3).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([O:18]O)(C)(C)C>ClCCl.O.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CCCc2ccc(Br)cc21
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 7-bromo-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene (Compound 15, 1.1 g, 4.62 mmol) in 10 mL of dichloromethane was added chromium (VI) oxide (72 mg, 0.46 mmol) and 5 mL of tert-butyl hydroperoxide solution (TBHP). After stirring at room temperature for 8 h, the mixture was diluted with water (20 mL), extracted with diethyl ether (3×10 mL), washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (90:10 hexane/ethyl acetate) yielded the title compound (920 mg, 79% yield) as a white solid:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH2:26].O1CCOCC1>CC(O)C.Cl.O1CCOCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Clc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Temperature: 80 °C
Yield: 94 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (407.5 g, 1.251 mol) was dissolved in 2-propanol (5.7 L). 3,4-Dichloroaniline (213.8 g, 1.313 mol) and a 4 M solution of gaseous hydrogen chloride in dioxane (17.4 mL, 63 mmol) were added. The mixture was heated to 80° C. for 3 days. The thick suspension was then diluted with additional 2-propanol (1 L), and further 4 M hydrogen chloride in dioxane (695 mL, 2.5 mol) was added. The mixture was again heated to 80° C. for 3 h. The solvent was then removed in vacuo, and the residue was treated with 1 M aqueous sodium hydroxide solution (12 L). The precipitate was collected by suction filtration and washed with water. The product was dried for 2 days at 50° C., then triturated with tert-butyl methyl ether and collected by suction filtration to yield 413 g (92%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH:33](=O)[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+]>ClC(Cl)C.CO>[CH2:33]([N:16]1[CH2:15][CH2:14][N:13]([C:6]2[C:5]([CH3:19])=[C:4]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:26]=3)[C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[N:7]=2)[CH2:18][CH2:17]1)[CH3:34]
Reactant: CC=O
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: CCN1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)CC1
Reaction time: 8 h

Procedure:
The 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)-quinolin-4-amine (50 mg, 0.11 mmol) was dissolved in a mixture of dichloroethane (1.3 mL) and MeOH (0.63 mL). The acetaldehyde (6.4 μL, 0.11 mmol) and sodium triacetoxyborohydride (72 mg, 0.34 mmol) were added and the mixture was stirred overnight. A small amount (50 mg) of sodium cyanoborohydride was added to drive the reaction to completion. The reaction was quenched with satd sodium bicarbonate solution and extracted with EtOAc. The organic layer was then dried over magnesium sulfate and the filtrate was cond. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini™ column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 95% over 20 min to provide 2-(4-ethylpiperazin-1-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. The salt was then free based by eluting through an SCX column with 0 to 2M ammonia in MeOH to give the desired product as the free base. TFA salt: 1H NMR (CDCl3) δ ppm 7.86 (2H, dd, J=4.3, 2.2 Hz), 7.61 (1H, d, J=9.2 Hz), 7.36-7.43 (1H, m), 7.20 (1H, t, J=2.0 Hz), 6.89 (1H, ddd, J=13.4, 8.5, 2.3 Hz), 4.24 (2H, d, J=14.7 Hz), 3.86-3.95 (4H, m), 3.77 (2H, t, J=13.2 Hz), 3.63 (2H, d, J=12.3 Hz), 3.26-3.38 (4H, m), 3.15 (4H, q, J=7.2 Hz), 2.13 (3H, s), 1.39 (3H, t, J=7.3 Hz). Mass Spectrum (ESI) m/e=469.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1)(=[O:34])=[O:33]
Reactant: COc1ccc(C2(CCCO)OCc3cc(C#N)ccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2(CCCOS(C)(=O)=O)OCc3cc(C#N)ccc32)cc1
Reaction time: 1 h
Yield: 96.9 %

Procedure:
15.0 g (48.5 mmol) of the 1-(3-hydroxypropyl)-1-(4-methoxyphenyl)-1,3-dihydro-5-isobenzofurancarbonitrile prepared in step 5 was dissolved in 200 ml of dichloromethane, and 7.4 g (727 mmol) of triethylamine and 6.7 g (58.2 mol) of methanesulfonylchloride were added dropwise at 0° C. The solution was then stirred for 1 hr. The reaction mixture was washed with water and saturated NaCl solution. An organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to afford 18.2 g of the yellow target compound (yield: 79%). The compound thus obtained was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2].[NH2:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:33]=1.N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([NH:31][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:5]3[CH:6]=[N:7][C:8]([O:10][CH2:11][C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[CH:21][C:22]=2[F:30])=[CH:33][C:34]=1[C:40]([F:41])([F:42])[F:43])#[N:37]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a solution of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (1 g, 2.431 mmol) and 4-amino-2-(trifluoromethyl)benzonitrile (0.452 g, 2.431 mmol) in pyridine (3.93 mL, 48.6 mmol) was added T3P® (4.64 g, 7.29 mmol) slowly. The mixture was stirred at rt for 0.5 h. The reaction was quenched with H2O (10 mL) and extracted with DCM (20 mL×5). The combined organic extracts were dried, filtered, and concentrated. Purification by column chromatography (PE/EA=511, Rf=0.6) provided N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (870 mg, 1.351 mmol, 55.6% yield). 1H NMR (400 MHz, CDCl3-d): δ 8.02 (s, 1H), 7.98 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.30-7.45 (m, 5H), 6.93 (d, J=8 Hz, 2H), 6.33 (s, 1H), 5.33 (d, J=8 Hz, 2H), 4.09 (q, J=6.8 Hz, 2H), 3.83 (s, 5H), 1.41 (t, J=6.8 Hz, 3H); LCMS (m/z): 580.0 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]2)[C:14](=[O:21])[C:15]([CH3:20])([CH3:19])[C:16](=[O:18])[CH3:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:30][Mg]Br.Cl>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]2)[C:14](=[O:21])[C:15]([CH3:19])([CH3:20])[C:16]([OH:18])([CH3:30])[CH3:17])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C[Mg]Br
Reactant: CC(=O)C(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCC(N(C(=O)C(C)(C)C(C)(C)O)C2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxobutanoyl)amino]pyrrolidine (100 mg, 0.25 mmol) prepared in Step A of Example C5 in THF was slowly added dropwise methylmagnesium bromide (in diethylether, 3.0M, 0.1 ml, 0.3 mmol) at 0° C., and the solution was stirred at rt for 2 h. After the reaction finished, to the solution was added 1N-HCl at 0° C., and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=1/3) to give the title compound (97 mg, 92%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:8]2[CH:9]3[CH2:12][CH2:13][CH:7]2[C:6]([CH3:14])([C:10]3=[CH2:11])[CH2:5][CH2:4][CH2:3]1.C(O)(=[O:18])C>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:11])[CH:12]2[C:3]3([CH2:14][CH:6]1[CH2:5][CH2:4]3)[C:2]([CH3:15])([CH3:1])[CH2:8][CH2:7][C:13]2=[O:18]
Reactant: CC(=O)O
Reactant: C=C1C2CCC3C2C(C)(C)CCCC13C
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC3(C2)C1C(=O)CCC3(C)C
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A four neck flask of 2 L was charged with 500 g of longifolene and 250 ml of acetic acid, and 250 ml of a boron trifluoride diethyl ether complex was dropwise added thereto in 4 hours while stirring at 20° C. to carry out isomerization reaction. This reaction mixture was washed with ice and water, a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution and refined by distillation, and after refined by distillation, it was mixed with 1800 ml of methylene chloride and 900 ml of a 0.5 mole/L sodium hydrogencarbonate aqueous solution, followed by slowly adding thereto 400 g of 3-chloroperbenzoic acid at 10° C. or lower. After finishing the reaction, the reaction mixture was washed with a 1 mole/L sodium hydroxide aqueous solution and water and concentrated under reduced pressure to obtain a crude product. It was dissolved in 3 L of toluene, and 260 ml of a boron trifluoride diethyl ether complex was slowly dropwise added thereto at 5° C. or lower. After finishing the reaction, the reaction mixture was washed with water and refined by distillation to thereby obtain 270 g of 1,1,5,5-tetramethylhexahydro-2H-2,4a-methano-naphthalene-8-one. This was dropwise added to 640 ml of a 2.1 mole/L methyl lithium/diethyl ether solution at 5° C. or lower to carry out alkylation, and after finishing the reaction, the reaction mixture was washed with a saturated ammonium chloride aqueous solution and water. This reaction product was charged into an autoclave of 1 L together with 30 g of the nickel/diatomaceous earth catalyst for hydrogenation (N-113, manufactured by Nikki Chemical Co., Ltd.) to carry out dehydration hydrogenation (hydrogen pressure: 6 MPa·G, reaction temperature: 250° C., reaction time: 6 hours).