Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][C:14](=N)[C:13]=2[C:27]#[N:28])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C([O-])(O)=[O:30].[Na+]>C1COCC1.O.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][C:14](=[O:30])[C:13]=2[C:27]#[N:28])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(-c2c(C#N)c(=N)oc3c2ccc2c3ccn2C)cc(Br)c1OC
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2c(C#N)c(=O)oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 18 %

Procedure:
To a solution of 4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-7-methyl-2H-pyrrolo[2,3-h]chromene (100 mg, 0.216 mmol) in THF:water (10:2) was added a ZnCl2 solution (1 mL, 1.0 M in CH2Cl2). The solution was stirred at room temperature for approximately 7 h. The reaction mixture was made basic with saturated NaHCO3 (10 mL), and extracted with EtOAc (2×25 mL). The EtOAc extracts were washed with brine (10 mL), dried over MgSO4, and evaporated to yield a yellow solid. The solid was purified by flash column chromatography (silica gel, EtOAc:hexanes 30-70% EtOAc) to yield 17 mg (18%) of the product as a yellow solid. 1H NMR (acetone-d6): 7.51-7.48 (m, 2H), 7.42 (d, J=1.8 Hz, 1H), 7.34 (d, J=2.1 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 6.91 (dd, J=0.6, 3.3 Hz, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][O:11][CH2:12]Cl.[Br:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=[O:21]>ClCCl>[Br:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([O:23][CH2:10][O:11][CH3:12])=[C:19]([CH:22]=1)[CH:20]=[O:21]
Reactant: COc1cc(Br)cc(C=O)c1O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(C=O)cc(Br)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
Ethyldiisopropylamine (3.01 ml, 17.1 mmol) and methoxymethylchloride (1.5 ml, 15.7 mmol) were added to a dichloromethane solution (30 ml) of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (3.3 g, 14.3 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→11:9). The purified product was concentrated to dryness under reduced pressure to obtain 5-bromo-3-methoxy-2-methoxymethoxybenzaldehyde (4.2 g) as light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:16][CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH3:22]>C(C(C)=O)C>[ClH:16].[NH:1]=[C:2]1[N:6]([CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH3:22])[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3]1
Reactant: CCCSCCCl
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: CCC(C)=O
Product: CCCSCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Product: Cl
Yield: 38.8 %

Procedure:
A mixture of 2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and 1-chloro-2-propylthioethane (6.1 g) in methyl ethyl ketone (30 cc) is heated for 72 hours to boiling. The precipitate formed is filtered off, washed with methyl ethyl ketone (2×20 cc) and recrystallized in 2-propanol (30 cc). 2-Imino-3-(2-propylthioethyl)-6-trifluoromethoxybenzothiazoline hydrochloride (5.8 g), m.p. 187° C., is obtained.
Reaction SMILES: C(C1C=C(NC2N=C(NC3C=CC=C(C(O)=O)C=3)C(F)=CN=2)C=CC=1)(O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:40][C:41]2[N:46]=[C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([O:56]C)=[O:55])=[C:50]([O:58][CH3:59])[CH:49]=3)[C:44]([F:60])=[CH:43][N:42]=2)[CH:33]=[CH:34][C:35]=1[C:36]([O:38]C)=[O:37].[OH-].[Na+]>>[C:36]([C:35]1[CH:34]=[CH:33][C:32]([NH:40][C:41]2[N:46]=[C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([OH:56])=[O:55])=[C:50]([O:58][CH3:59])[CH:49]=3)[C:44]([F:60])=[CH:43][N:42]=2)=[CH:31][C:30]=1[O:29][CH3:28])([OH:38])=[O:37]
Reactant: COC(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)OC)c(OC)c3)n2)cc1OC
Agent: O=C(O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)O)c3)n2)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(Nc2ncc(F)c(Nc3ccc(C(=O)O)c(OC)c3)n2)ccc1C(=O)O
Yield: 70 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (30 mg, 0.06 mmol) and NaOH (200 mg, 5 mmol) gave N2,N4-bis(4-carboxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (18 mg, 64%) as a white solid. 1H NMR (DMSO-d6): δ 3.66 (s, 3H), 3.73 (s, 3H), 7.37 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.49 (s, 1H), 7.61-7.71 (m, 3H), 8.25 (d, J=3.6 Hz, 1H), 9.65 (s, 1H, NH), 9.70 (s, 1H, NH); 19F NMR (282 MHz, DMSO-d6): δ −162.11; LCMS: ret. time: 17.25 min.; purity: 100%; MS (m/e): 429.04 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([C:12]1[N:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([S:33]([CH3:36])(=[O:35])=[O:34])[C:30]([CH2:37][OH:38])=[C:29]([F:39])[CH:28]=3)=[CH:23][C:22]=2[F:40])[CH:14]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[N:16]=1)([CH3:11])[CH3:10].C(N(C(C)C)[P:45]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])(C)C.N1C=NN=N1.[OH:64]O>>[P:45]([O:38][CH2:37][C:30]1[C:31]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:32][C:27]([C:24]2[CH:25]=[CH:26][C:21]([N:13]3[CH:14]=[C:15]([C:17]([OH:20])([CH3:18])[CH3:19])[N:16]=[C:12]3[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])([CH3:10])[CH3:11])=[C:22]([F:40])[CH:23]=2)=[CH:28][C:29]=1[F:39])([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:64]
Reactant: CC(C)(O)c1cn(-c2ccc(-c3cc(F)c(CO)c(S(C)(=O)=O)c3)cc2F)c(C(C)(C)c2c(Cl)cccc2Cl)n1
Reactant: OO
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Agent: c1nnn[nH]1
Product: CC(C)(C)OP(=O)(OCc1c(F)cc(-c2ccc(-n3cc(C(C)(C)O)nc3C(C)(C)c3c(Cl)cccc3Cl)c(F)c2)cc1S(C)(=O)=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
To a solution of 2-(2-(1-(2,6-dichlorophenyl)-1-methylethyl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)-4-biphenylyl)-1H-imidazol-4-yl)-2-propanol (prepared in the manner described in PCT Publication No. WO 2010/138598, 1.98 g, 3.25 mmol) and di-tert-butyl diisopropylphosphoramidite (1.35 g, 4.87 mmol) in CH2CH2 (10 mL) was added tetrazole (0.569 g, 8.13 mmol). The resulting suspension was stirred at rt for about 16 hours. After this time, hydrogen peroxide (30%, 8.13 mmol) was added drop-wise and the resulting mixture was stirred for 2 hours. At the conclusion of this period, the reaction mixture was diluted with CH2CH2 (10 mL), washed with brine, dried and then concentrated to yield the crude product. The crude product was purified by column chromatography (hexane and acetone gradient; 9:1 to 1:1) to afford di-tert-butyl (4′-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)-3,3′-difluoro-5-(methylsulfonyl)biphenyl-4-yl)methyl phosphate (0.960 g, 1.20 mmol, 37% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(OC(C)(C)C)=O)[N:17]=[C:16]3[NH:29][C:30](=[O:33])[CH2:31]Br)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:37]([CH:40]([CH3:42])[CH3:41])CC)(C)C.C1(N)CC1.Cl>C(#N)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[NH:29][C:30](=[O:33])[CH2:31][NH:37][CH:40]2[CH2:42][CH2:41]2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)CBr)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Agent: Cl
Agent: NC1CC1
Solvent: CC#N
Product: O=C(CNC1CC1)Nc1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of Example 305A (100 mg, 0.196 mmol) and diisopropylethylamine (0.034 mL, 0.19 mmol) in acetonitrile (1 mL) was added cyclopropanamine (11 mg, 0.19 mmol) and the reaction mixture was heated at about 60° C. for about 1 hour. The reaction mixture was cooled to ambient temperature and hydrochloric acid (4 N in dioxane, 1 mL) was added. The reaction mixture was stirred at ambient temperature for about 16 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (s, 1H), 8.28 (s, 1H), 8.56 (s, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.30-7.45 (m, 5H), 5.64 (s, 2H), 3.45 (s, 2H), 2.18-2.26 (m, 1H), 1.89 (s, 3H), 0.37-0.45 (m, 2H), 0.29-0.37 (m, 2H). MS (ESI+) m/z 388 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](O)=[O:21])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][C@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:21])[N:24]([CH3:23])[CH:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][CH2:26]3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)n2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester (150 mg, 0.49 mmol), methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amine (0.079 g, 0.49 mmol), and diisopropylethylamine (0.50 mL, 0.49 mmol) in DMF (10 mL) was added dropwise BOP (238 mg, 0.49 mmol) at RT. After stirring overnight at RT, the reaction mixture was poured on water (10 mL) and extracted with ethylacetate (20 mL). The aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with aq. sat. sodium bicarbonate solution (30 mL), 1M HCl solution (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/hexane 4:1) to give 6-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamoyl]-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (215 mg, 97%). 1H-NMR (400 MHz, CDCl3): δ=1.47 (s, 9H), 1.64-2.05 (m, 8H), 2.18-2.22 (m, 1H), 2.72-2.81 (m, 4H), 2.82 (s, 3H), 4.15-4.25 (m, 2H), 5.15-5.20 (m, 1H), 7.18-7.25 (m, 5H), 7.53-7.71 (m, 1H), 7.73-7.74 (m, 1H).
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([CH2:30][C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].Cl>CCOCC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([CH2:30][C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[C:27]([N:6]2[CH2:5][CH2:4][N:3]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:8][CH2:7]2)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=C(O)C(Cc1c[nH]cn1)c1ccc(Cl)c(Cl)c1
Reactant: c1nc(N2CCNCC2)c2cc[nH]c2n1
Agent: Cl
Solvent: CCOCC
Product: O=C(C(Cc1c[nH]cn1)c1ccc(Cl)c(Cl)c1)N1CCN(c2ncnc3[nH]ccc23)CC1

Procedure:
2-(3,4-Dichlorophenyl)-3-(1H-imidazol-4-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one was prepared by substituting 5-piperazin-1-yl-1H-indazole with 4-Piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride and substituting (D)-Boc-4-chlorophenylalanine with 2-(3,4-Dichlorophenyl)-3-(1H-imidazol-4-yl)-propionic acid in Example B-1, Step 2. The free amine was converted to HCl salt by treatment with HCl in Ether. 1H NMR (CD3OD, 400 MHz) δ 8.76 (s, 1H), 8.32 (s, 1H), 7.52 (m, 2H), 7.38 (s, 1H), 7.29 (m, 2H), 6.92 (s, 1H), 4.58 (m, 1H), 3.70-4.20 (m, 7H), 3.63 (m, 1H), 3.43 (m, 1H), 3.16 (m, 1H). LCMS (APCI+) m/z 470, 472, 474 [M+H]+; Rt=2.15 min.
Reaction SMILES: [O-2:1].[Mg+2:2].[C:3](=[O:5])=[O:4]>O>[C:3](=[O:1])([OH:5])[O-:4].[Mg+2:2].[C:3](=[O:1])([OH:5])[O-:4]
Reactant: [O-2]
Reactant: O=C=O
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])O

Procedure:
Magnesium oxide is hydrated for 0.5 hours at 95° C. The weight ratio of water to magnesium oxide is 2:1. Then water is added into the mixture to prepare slurry at a weight ratio of water to magnesium oxide of 50:1. After that, carbon dioxide (85 vt %) is introduced into the slurry to react for 3.5 hours at 18° C. Subsequently, a pure magnesium bicarbonate solution (MgO: 17.2 g/L, Fe: 3.5 ppm, Al: 2.2 ppm) is obtained after clarification and filtration.
Reaction SMILES: [C:1]1(C(Cl)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:19]([O:18][C:14]([C:15]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)=[CH2:16])=[O:17])[CH3:20]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: C=C(C(=O)OCC)c1cccc2ccccc12

Procedure:
0.2244 g (10-3 mols) of palladium acetate, 15.05 g (0.1 mol) of naphthalene-1-carboxylic acid chloride, 13.54 ml (0.125 mol) of ethyl acrylate and 23.95 ml (0.1 mol) of tri-n-butylamine, in 200 ml of p-xylene, are stirred for 1 hour at 120° C. The crude product is distilled in vacuo. 15.6 g (69% of theory) of a colourless liquid (which distils at 143°-147° C./106 Pa) are obtained. Analysis for C15H14O2 : calculated C 79.62%, H 6.24%, O 14.14%; found C 79.24%, H 6.39%, O 14.27%.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]1[C:24]2([CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:23][CH2:22][NH:21]1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:21]3[CH2:22][CH2:23][C:24]4([CH2:28][CH2:27][NH:26][CH2:25]4)[CH2:20]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: C1CC2(CCNC2)CN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4(CCNC4)C3)c(F)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.3 %

Procedure:
A suspension of 0.81 g (3.0 mmol) 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 40 ml acetonitrile was treated with 0.80 g (6.3 mmol) 2,7-diazaspiro[4.4]nonane [J. Org. Chem. 46, 2757 (1981)]and the mixture stirred two days at room temperature, refluxed 1.5 hours, cooled, and filtered to afford 1.17 g of the title compound, mp 234°-240° C. (dec). Analysis calculated for C19H21N3F2O3 ; C, 60.47; H, 5.61; N, 11.13. Found: C, 60.17; H, 5.46; N, 11.11.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([S:10][CH3:11])=[CH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[N:6]1)[CH2:2][CH2:3][CH3:4].OO.[OH2:18].C(O)(=[O:21])C>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH2:1]([N:5]1[C:9]([S:10]([CH3:11])(=[O:21])=[O:18])=[CH:8][C:7]([C:12]([F:14])([F:13])[F:15])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCCn1nc(C(F)(F)F)cc1SC
Reactant: CC(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CCCCn1nc(C(F)(F)F)cc1S(C)(=O)=O

Procedure:
4.40 g of Compound (15) was dissolved in 20 ml of acetic acid. While stirring, 6.36 g of a 30% hydrogen peroxide solution and 0.62 g of sodium tungstate dihydrate were added sequentially. The mixture was stirred at room temperature for 4 hours, then poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to produce 5.00 g of 1-butyl-5-methanesulfonyl-3-(trifluoromethyl)pyrazole (2-2).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]1C=CCC[C:4]1([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(O)(=O)C.O.[OH-].[Na+]>C1CCCCC1>[CH3:20][N:2]([CH3:1])[CH2:3][CH:4]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1(c2ccccc2)CCC=CC1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(CN(C)C)c1ccccc1

Procedure:
13.7 g (0.05 mol) of ethyl 2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate (mixture of cis and trans isomers) [ethyl 3-dimethylamino-2-phenylpropionate content (HPLC): 1%], dissolved in 40 ml of cyclohexane, was refluxed with 3.0 g (0.05 mol) of acetic acid for 2 hours. After cooling, 30 ml of water were added. The two-phase mixture was made alkaline with sodium hydroxide solution. The aqueous phase was then separated off. The organic phase was washed with 30 ml of water and concentrated. 13.4 g (98%) of ethyl 2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate isomer mixture of unchanged composition in respect of the cis/trans ratio were obtained with an ethyl 3-dimethylamino-2-phenyl-propionate content of 0.05% (HPLC).
Reaction SMILES: [N+]1([O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([C:10]1C=C[CH:13]=[CH:12][CH:11]=1)=O.CCCCCC.C([OH:25])(C)C>C(#N)C>[O:25]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:6][C:5]=2[CH:4]=[CH:3][CH2:2]1
Reactant: [O-][n+]1ccccc1
Reactant: O=Ic1ccccc1
Reactant: CC(C)O
Solvent: CC#N
Solvent: CCCCCC
Product: C1=Cc2ccccc2OC1
Temperature: 0 °C
Yield: 98 %

Procedure:
26.2 mg of compound [IV-1] (0.10 mmol) and 2.6 mg of the compound [I-1] (2.5 μmol) were dissolved in 1.25 mL of an acetonitrile solution of pyridine-N-oxide (0.02M, 0,025 mmol), followed by cooling to 0° C. To the resulting solution was added 44.0 mg of iodosylbenzene (0.20 mmol) all at once under a nitrogen atmosphere, followed by stirring at 0° C. for twenty four hours. Insoluble matters were filtered out through Celite, the filtrate was concentrated, and the residues were purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:2-4:6) to obtain the intended compound. (epoxide yield: 20. 1 mg (72%)) (asymmetric yield: 98% e.e.) (Daicel Chiralcel OJ, hexane-isopropanol=1:1, flow rate: 0.5 mL/min.)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:18])[NH:11][NH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28]([O:36][C@@H:37]3[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:59])[CH3:58])[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@H:38]3[O:39][C:40](=[O:42])[CH3:41])=[N:29][NH:30][C:31]=2[C:32]([F:35])([F:34])[F:33])=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28]([O:36][C@@H:37]3[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:59])[CH3:58])[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@H:38]3[O:39][C:40](=[O:42])[CH3:41])=[N:29][NH:30][C:31]=2[C:32]([F:35])([F:34])[F:33])=[CH:22][CH:21]=1.[C@@H:37]1([O:18][C:10]2[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[C:13]([C:14]([F:17])([F:16])[F:15])[NH:12][N:11]=2)[O:54][C@H:53]([CH2:55][OH:56])[C@@H:48]([OH:49])[C@H:43]([OH:44])[C@H:38]1[OH:39]
Reactant: Cc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(F)(F)F)cc1

Procedure:
4-[(4-Methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in Reference Example 28 using 1,2-dihydro-4-[(4-methylphenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one instead of 1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one. Then, the title compound was prepared in a similar manner to that described in Reference Example 37 using 4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole instead of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.
Reaction SMILES: [CH2:1]([C:4]1([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH2:1]([C:4]1([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1ccc(F)cc1
Reactant: C=CCC1(c2cccs2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: C=CCC1(c2cccs2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1

Procedure:
The two diastereomers of the title compound were prepared separately from the diastereomers of 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 111 using 4-fluorophenylboronic acid. The diastereomers were separated.
Reaction SMILES: [H-].[Na+].[CH2:3]([S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][SH:11])[CH3:4].I[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[C:17]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][S:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][S:5][CH2:3][CH3:4]
Reactant: CCSCCCCCS
Reactant: CCOC(=O)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCSCCCCCSCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
NaH (0.4 g, 8.4 mmol) was washed with hexanes and then suspended in dry THF (55 mL). 5-Ethylthiopentanethiol (8 mmol, 73% pure by GC analysis, contaminated by 1,5-bis(ethylthio)pentane, 1.80 g of mixture) in THF (8 mL) was added and stirred for 1 h at room temperature. Ethyl 5-iodovalerate (2.1 g, 8 mmol) in THF (8 mL) was added and the mixture refluxed for 8 h. The solvent was evaporated in vacuo, the residue was dissolved in EtOAc (150 mL ), washed with water (2×50 mL), brine (50 mL), dried (Na2SO4), chromatographed (silica gel, EtOAc/hexanes 1:10) and distilled (Kugelrohr) to yield the title compound (1.86 g, 80%) as a colorless oil (bp 147°-149° C./0.2 torr). IR (neat): 1740 cm-1. 1H-NMR: 1 25 (t, 6H); 1.50 (quintet, 2H); 1.54-1.67 (m, 6H); 1.73 quintet, 2H); 2.32 (t, 2H); 2.46-2.57 (m, 8H); and 4.12 (q, 2H). Anal. Calcd for C14H28S2O2 : C, 57.49; H, 9.65%. Found: C, 57.36; H, 9.59%.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=2[NH:11][C:10]1=[O:19])(=O)=O.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:6][CH2:7][CH2:8][N:9]3[C:13]4[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=4[NH:11][C:10]3=[O:19])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2CCCOS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
A mixture of 5.68 parts of 3-(2,3-dihydro-5-methyl-2-oxo-1H-benzimidazol-1-yl)propyl methanesulfonate, 4.8 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 3.7 parts of sodium carbonate and 45 parts of N,N-dimethylformamide is stirred for 1 hour at 50°-60° C. The reaction mixture is cooled to room temperature and poured onto water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized twice from 4-methyl-2-pentanone, yielding 0.5 parts (6.5%) of 1-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-2H-benzimidazol-2-one; mp. 149° C.