Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[NH:8][C:9]3[C:14]([C:4]=2[CH2:3]1)=[CH:13][CH:12]=[CH:11][N:10]=3.[H-].[Na+].CC1C=CC(S(O[CH2:28][CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]([CH2:28][CH2:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)[C:9]3[C:14]([C:4]=2[CH2:3]1)=[CH:13][CH:12]=[CH:11][N:10]=3
Reactant: CN1CCc2[nH]c3ncccc3c2C1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CCn2c3c(c4cccnc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.5 %

Procedure:
To a solution of 6-methyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (200 mg, 1.068 mmol) in DMF (1 mL) was added a suspension of NaH (128.0 mg, 3.24 mmol) in DMF (1 mL). After stirring for 5 min. at RT, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (932 mg, 3.204 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 3 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography eluting with 10% MeOH-DCM to yield 6-methyl-9-(2-(6-methylpyridin-3-yl)ethyl)-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (90 mg) as a free base. The free base was converted into tri-HCl salt by treatment with ethanolic HCl. 1H NMR (CD3OD, Tri-HCl salt) δ (ppm): 8.76 (s, 1H), 8.40 (m, 3H), 7.80 (d, 1H), 7.50 (t, 1H), 4.90-4.70 (m, 3H), 4.42 (m, 1H), 3.95 (m, 1H), 3.66 (m, 1H), 3.42-3.30 (m, 4H), 3.15 (s, 3H), 2.76 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]1([Mg]Br)[CH2:17][CH2:16]1.CO.[BrH:22]>O1CCCC1.C(O)(=O)C>[CH:1]1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:16][CH2:15][CH2:17][Br:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C1CCCCC1)C1CCCCC1
Reactant: Br[Mg]C1CC1
Reactant: Br
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: BrCCC=C(C1CCCCC1)C1CCCCC1

Procedure:
Following the procedures of Example 15, 9.7 g. (0.05 mole) of dicyclohexyl ketone and 14.4 g. (0.1 mole) of cyclopropyl magnesium bromide in dry tetrahydrofuran were reacted and the resulting carbinol dissolved in glacial acetic acid was treated with hydrogen bromide to give 4,4-dicyclohexyl-3-butenyl bromide, b.p. 168°-171° C. (0.1 mm.).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([O:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:21]=2)[NH:18][C:17]([C:29]([NH2:31])=O)=[CH:16]3)=[CH:8][CH:7]=1)(=[O:4])=[O:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][S:2]([CH2:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([O:22][CH:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[CH:21]=2)[NH:18][C:17]([C:29](=[S:41])[NH2:31])=[CH:16]3)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Yield: 72.7 %

Procedure:
To a solution of 5-({6-[(methylsulfonyl)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxamide (3.0 g) in tetrahydrofuran (20 mL) was added a Lawesson's reagent (3.0 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (2.26 g, yield 73%) as a yellow amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:23]=[CH:24][C:25](B(O)O)=[N:26][CH:27]=1.[CH3:31][PH:32](=[O:34])[CH3:33]>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]2[CH:24]=[CH:23][C:22]([P:32]([CH3:33])([CH3:31])=[O:34])=[CH:27][N:26]=2)[CH:3]=1)[CH3:11]
Reactant: C[PH](C)=O
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: OB(O)c1ccc(Br)cn1
Product: CC(Oc1cc(-c2ccc(P(C)(C)=O)cn2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 5-bromo-2-pyridinylboronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 454 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][C@@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:5]([CH2:23][CH:24]=[CH2:25])([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[OH-].[Na+].OO.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:44]>C(OCC)C.O>[OH:44][CH2:25][CH2:24][CH2:23][C:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[CH2:3][CH:2]([CH3:36])[CH3:1]
Reactant: C=CCC(C(=O)OCc1ccccc1)(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CCCO)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.47 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(prop-2-en-1-yl)-1,1,2(R)-pentanetricarboxylate in 5 ml of dry diethyl ether was cooled to 0° and 0.325 ml of monochloroborane-methyl sulphide complex was added. The mixture was stirred at room temperature for 2 hours, then cooled to 0° and 0.5 ml of water, 2.3 ml of 1.5M aqueous sodium hydroxide solution and 2.3 ml of 30% aqueous hydrogen peroxide were added. The mixture was stirred at room temperature for 3 hours and then acidified with 5% aqueous citric acid solution. The product was extracted with diethyl ether and the extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (5:1) for the elution. There were obtained 1.098 g of 1,2-dibenzyl 1-tert.butyl 1-(3-hydroxypropyl)-4-methyl-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil; MS: 513 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si](C(C)(C)C)(C)C)[CH:10]2[N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:22][CH2:23][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:22][CH2:23][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C2C1CCN2C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A solution containing 10 (868 mg, 1.8 mmol) in THF (10 mL) was cooled to 0° C. HF.pyridine reagent (1 mL, 36 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 16 h, the reaction mixture was diluted with EtOAc and washed successively with water, aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 600 mg (90%) of 11. 1H NMR (CDCl3, 300 MHz): δ7.29 (m, 5H), 5.10 (app dd, J=22.7, 12.5 Hz, 2H), 4.32 (m, 4H), 3.71 (m, 2H), 3.58 (m, 1H), 3.38 (m, 1H), 3.17 (m, 1H), 2.14 (m, 1H), 2.02 (m, 1H), 1.42 (s, 9H) ppm. Mass spectrum, m/z [363.2] (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[O:3]1.[CH3:19]O>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([O:15][CH3:19])=[O:14])=[CH:11][CH:10]=2)[O:5]1
Reactant: CO
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Product: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Yield: 83 %

Procedure:
50 g (200 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 1,22 g (10 mmol) of N,N-dimethylpyridine are dissolved in 200 ml of methanol and refluxed for 5 hours. Removal of 150 ml of methanol by distillation gives 43.4 g (165 mmol, 83%) of product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:23]B(O)O.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.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>[CH3:23][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1nc(-c2cc(C)cc(C(F)(F)F)c2)co1
Temperature: 100 °C
Yield: 78 %

Procedure:
A stirred solution of methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 44, 0.150 g, 0.397 mmol), methylboronic acid (0.071 g, 1.19 mmol), and triethylamine (0.402 g, 3.97 mmol) in DMF (10.0 mL) was degassed and then purged with nitrogen. To this reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.0203 mmol) and the resulting reaction mixture was heated at 100° C. for 6 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water and saturated sodium chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 9:1) to provide methyl 3-(4-(3-methyl-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.097 g, 78%) as a viscous yellow oil.
Reaction SMILES: [CH:1]12CC3CC(C[CH:3](C3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26]([OH:28])=O)[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.ON1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:52][CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=1>C(OCC)(=O)C.CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]([CH2:1][CH2:8][CH2:38][CH2:39][CH2:34][CH2:35][CH2:36][CH3:37])[CH3:3])([CH3:29])[C:26](=[O:28])[NH:52][CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)=[CH:18]1
Reactant: NCCc1ccccn1
Reactant: On1nnc2ccccc21
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCC(C)OC(=O)NC(C)(Cc1c[nH]c2ccccc12)C(=O)NCCc1ccccn1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.400 g, 1.01 mmol) in ethyl acetate (6 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added 1-hydroxybenzotriazole (0.138 g, 1.20 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.198 g, 1.03 mmol). This mixture was stirred 2 hours and 2(2-aminoethyl)pyridine (0.16 mL, 1.3 mmol) was added. After stirring an additional 18 hours, the resulting mixture was diluted with ethyl acetate (20 mL), and washed with aqueous 1N citric acid, aqueous saturated sodium bicarbonate, and brine solutions. The organic phase was dried over MgSO4, concentrated, and purified by flash chromatography (SiO2, 230-400 mesh, ethyl acetate eluant). After concentration, the residue was dried under vacuum at 60° C. for 48 hours to provide 0.365 g (72%) of product; 1H NMR (CDCl3) δ 1.40-1.60 (2H, m), 1.56 (3H, s), 1.65-1.95 (12H, m), 2.88 (2H, t, J 6 Hz), 3.39 (2H, d, J 5 Hz), 3.50-3.70 (2H, m), 4.75 (1H, br s), 5.35 (1H, br s), 6.40 (1H, d, J 2 Hz), 7.00-7.20 (4H, m), 7.22-7.35 (2H, m), 7.52-7.60 (2H, m), 8.20 (1H, br s), 8.40-8.45 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[O:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)[CH:3]=1.[Na].O.[CH:23](=O)[CH2:24][CH:25]=O.FC(F)(F)C(O)=O>O1CCOCC1>[CH2:7]([N:6]1[C:2]2=[N:1][CH:23]=[CH:24][CH:25]=[C:3]2[C:4]([C:14]2[O:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[N:5]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cc(-c2ccc(CO)o2)nn1Cc1ccccc1
Reactant: O=CCC=O
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: OCc1ccc(-c2nn(Cc3ccccc3)c3ncccc23)o1

Procedure:
2.69 g (10 mmol) of 5-amino-1-benzyl-3-(5-hydroxymethyl-2-furyl)pyrazole and 1.4 g of malonaldehyde hydrate sodium salt are stirred at 100° C. for 30 min in 100 ml of dioxane and slowly treated with 1.9 ml of trifluoroacetic acid during the course of 5.5 hours. The mixture is evaporated in vacuo, the residue is taken up in ethyl acetate, the mixture is extracted by shaking with K2HPO4 solution, and the organic phase is dried using Na2SO4 and concentrated in vacuo in a rotary evaporator. The residue is chromatographed on silica gel. 200 mg (6.6% of theory) of crystals having a melting point of 104° C. are obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(#N)C>[C:11]1([CH2:10][O:9][C:8]([NH:7][CH2:6][C@@H:2]2[CH2:3][CH2:4][CH2:5][N:1]2[CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=C(NC[C@@H]1CCCN1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)N1CCC[C@H]1CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a mixture of phenylmethyl [(2S)-2-pyrrolidinylmethyl]carbamate (D114, 1.36 g, 5.81 mmol) and K2CO3 (1.6 g, 11.62 mmol) in acetonitrile (20 ml), cooled to 0° C., was added dropwise diethyl bromomalonate (1.37 ml, 6.97 mmol) in a 2-3 mins time. Then the reaction mixture was allowed to warm-up to room temperature and it was stirred for 4 hrs.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[N:4]1)[CH3:2].O1CCCC1.[CH2:26]([Mg]Br)[CH:27]([CH3:29])[CH3:28]>O1CCCC1>[CH2:1]([N:3]1[C:7]([CH:8]([OH:9])[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:6][C:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccc(OC(F)(F)F)cc2)cc1C=O
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CCn1nc(-c2ccc(OC(F)(F)F)cc2)cc1C(O)CC(C)C
Yield: 31 %

Procedure:
1-Ethyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazole-5-carbaldehyde (2.5 g) synthesized in Example 58(2) was dissolved in tetrahydrofuran (20 mL), and 1M isobutylmagnesium bromide tetrahydrofuran solution (12 mL) was added dropwise at 0° C. In the same manner as in Example 1(6), the title object compound (0.9 g, 31%) was obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15]C(=O)OCC1C=CC=CC=1.[H][H]>[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH2:15]
Reactant: O=C(Nc1cc(OC2CCCC2)c(Cl)cc1F)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Yield: 99.6 %

Procedure:
Benzyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (2.00 g, 5.51 mmol) synthesized as described above, 5% Pd/C (100 mg) as a catalyst, and toluene (15 ml) as a solvent were charged into a 50 cc round-bottom flask, and the inside of the flask was replaced sufficiently with a hydrogen gas. Then, in a hydrogen gas atmosphere, the mixture was thoroughly stirred for 3 hours at 50° C. After completion of the reaction, the catalyst was separated by filtration, the resulting filtrate was dried with anhydrous magnesium sulfate. After separating the drying agent by filtration, the solvent was distilled off under reduced pressure from the filtrate to obtain quantitatively 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.26 g) as a pale brown oily substance. The spectral data and the like are shown in Reference Example 1.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:19]2[O:18][CH2:17][CH2:16][N:15]([CH3:20])[C:14](=[O:21])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([O:38][C@@H:39]([CH3:42])[CH2:40][OH:41])[CH:37]=1)[C:26]([NH:28][C:29]1[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=1)=[O:27]>[Pd].C1COCC1.C(O)C>[OH:41][CH2:40][C@H:39]([CH3:42])[O:38][C:36]1[CH:35]=[C:25]([CH:24]=[C:23]([O:22][C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:21])[N:15]([CH3:20])[CH2:16][CH2:17][O:18][C:19]=3[CH:9]=2)[CH:37]=1)[C:26]([NH:28][C:29]1[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=1)=[O:27]
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2Cl)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.5 %

Procedure:
10% Palladium on carbon (30 mg) and triethylamine (2.0 mL) were added to a solution of 3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (160 mg; 0.32 mmol) in dry THF (4 mL) and dry ethanol (4 mL) under argon. The reaction was degassed and placed under a hydrogen balloon and stirred for 24 hours at RT. The mixture was filtered through diatomaceous earth and the filtrate was evaporated. Purification by column chromatography on silica, eluting with 0-5% methanol in DCM, yielded a colourless oil which solidified under vacuum to give the title compound as a white foam (62 mg, 33%). 1H NMR δ (CDCl3): 1.23 (d, 3H), 2.00 (dd, 1H), 3.14 (s, 3H), 3.51 (t, 2H), 3.64-3.71 (m, 2H), 3.73 (s, 3H), 4.34 (t, 2H), 4.46 (dq, 1H), 6.51 (d, 1H), 6.69 (d, 1H), 6.70-6.72 (m, 2H), 7.02 (t, 1H), 7.18 (t, 1H), 7.21 (d, 1H), 7.81 (d, 1H), 8.38 (s, 1H) m/z 467 (M+H)+ 465 (M−H)−
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][CH:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>[Pd].CO>[NH2:1][C:4]1[C:9]2[NH:10][CH:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3cccc([N+](=O)[O-])c3N2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3cccc(N)c3N2)cc1
Yield: 200.4 %

Procedure:
A mixture of toluene-4-sulfonic acid 5-nitro-3,4-dihydro-2H-benzo[1,4]oxazin-3-ylmethyl ester (3.64 g, 10.0 mmole), p-toluenesulfonic acid monohydrate (3.8 g, 20.0 mmole) and 0.50 g of 10% palladium on carbon in 140 mL of methanol was treated with 50 psi of hydrogen on a Parr shaker for 1 hour. The catalyst was filtered and washed with additional methanol. The solvent was evaporated in vacuum to yield 6.7 g of the p-toluenesulfonate salt of the title compound as a pink solid. This compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C.CN(C)C=O.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>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(I)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (950 mg, 2 mmol) and trimethylsilylacetylene (246 mg, 2.5 mmol) were dissolved in triethylamine (2 mL) and N,N-dimethylformamide (4 mL). Tetrakis(triphenylphosphine)palladium(23 mg, 0.02 mmol) and cuprous iodide (4 mg, 0.02 mmol) were added under argon atmosphere, and the mixture was stirred at 40° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (100 mL) and 1 N citric acid (100 mL), stirred, and filtered through celite. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=19:1) to give a light orange solid. This was crystallized by n-hexane to give the title compound (286 mg, 32.1%) as a white crystal.
Reaction SMILES: [CH2:1]=O.[OH:3][C:4]1[C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH2:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:14][CH3:15]>C(#N)C>[OH:3][C:4]1[C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[CH2:1][N:19]1[CH2:20][CH2:21][N:16]([CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]1
Reactant: C=O
Reactant: Oc1cccc2c1OCO2
Reactant: CCCN1CCNCC1
Solvent: CC#N
Product: CCCN1CCN(Cc2ccc3c(c2O)OCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Aqueous formaldehyde (37%; 3.67 g, 45.3 mmol) was added dropwise to a stirred solution of 4-hydroxy-1,3-benzodioxole (5.2 g, 37.8 mmol) and N-propylpiperazine (5.8 g, 45.3 mmol) in acetonitrile (25 ml). The reaction mixture was stirred at room temperature for one hour and evaporated in vacuo. The remaining oil (13.0 g) was purified chromatographically (with ethylacetate/methanol=9/1 (v/v) as an eluent to give 4-hydroxy-5-(4-propylpiperazinylmethyl)-1,3-benzodioxole (5.9 g, 56% yield; compound No. 25), m.p. 115°-117° C.