Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[NH:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](O)=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:25]([C:21]3[CH:20]=[C:19]4[C:24](=[CH:23][CH:22]=3)[NH:16][CH:17]=[CH:18]4)=[O:26])[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]ccc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a stirred solution of 4-(4-chlorophenoxy)piperidine hydrochloride (300 mg, 1.21 mmol), 1H-indole-5-carboxylic acid (195 mg, 1.21 mmol), and N,N-diisopropylethylamine (0.85 mL, 4.84 mmol) in N,N-dimethylformamide (10 mL) was add HBTU (688 mg, 1.81 mmol) at room temperature. After stirring at 60° C. for 2 hours, the mixture was poured into water (50 mL). This was extracted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (NH-gel, eluting with n-hexane/ethyl acetate=1/1) to give 403 mg (94% yield) of the title compound as a white solid.
Reaction SMILES: [Mg].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=O.C(Cl)(=O)C(Cl)=O.[F:17][C:18]1[C:26]([CH3:27])=[C:25]([N+:28]([O-:30])=[O:29])[C:24]([O:31][CH3:32])=[CH:23][C:19]=1C(O)=O>O1CCCC1.CN(C)C=O.C(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C(O)C>[F:17][C:18]1[C:26]([CH3:27])=[C:25]([N+:28]([O-:30])=[O:29])[C:24]([O:31][CH3:32])=[CH:23][C:19]=1[C:4]([CH2:3][C:2]([O:8][CH2:9][CH3:10])=[O:7])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COc1cc(C(=O)O)c(F)c(C)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Mg]
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cc(OC)c([N+](=O)[O-])c(C)c1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Magnesium (150 mg), ethanol (1 ml) and carbon tetrachloride (0.05 ml) were stirred at room temperature to activate them. A solution of ethyl malonate (1.0 ml) in tetrahydrofuran (6 ml) was added dropwise to the activated mixture, followed by stirring at 80° C. for 4 hours. After the reaction mixture was allowed to cool, it was chilled to -40° C. Oxalyl chloride (0.5 ml) and N,N-dimethylformamide (1 drop) were added to a solution of 2-fluoro-5-methoxy-3-methyl-4-nitrobenzoic acid (1.4 g) in methylene chloride (5 ml). The mixture was stirred at room temperature for 3 hours, and the solvent and the like in the reaction mixture were distilled off. Toluene was added to the residue to conduct azeotropic distillation. The resultant residue was dissolved in tetrahydrofuran (5 ml), and the solution was added dropwise at -40° C. to the reaction mixture obtained previously. After the addition, the temperature of the reaction mixture was given back to room temperature to conduct stirring overnight. The solvent was distilled off, and 12N hydrochloric acid (3 ml) was added to the resultant residue to keep its pH at about 2. The residue was then extracted with chloroform, and the solvent was distilled off. Water (10 ml) and p-toluenesulfonic acid monohydrate (80 mg) were added to the resultant residue, and the mixture was stirred for 5 hours while heating under reflux. After the reaction mixture was allowed to cool, it was extracted with chloroform. An organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant residue was subjected to column chromatography on silica gel to obtain the title compound (240 mg) as a pale yellow oil from a fraction eluted with a 1:10 mixture of ethyl acetate and hexane.
Reaction SMILES: [N+:1]1([O-:10])[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:25]=[C:26]([NH2:32])[C:27]([NH2:31])=[CH:28][C:29]=1[Cl:30]>CN(C)C=O.ClCCl>[NH2:32][C:26]1[CH:25]=[C:24]([Cl:23])[C:29]([Cl:30])=[CH:28][C:27]=1[NH:31][C:7]([C:4]1[CH:3]=[CH:2][N+:1]([O-:10])=[CH:6][CH:5]=1)=[O:9]
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1cc(Cl)c(Cl)cc1NC(=O)c1cc[n+]([O-])cc1
Reaction time: 4 h
Yield: 16.4 %

Procedure:
A suspension of 4-pyridinecarboxylic acid-1-oxide (2.84 g, 20.4 mmol) and 1,1'-carbonyldiimidazole (3.64 g, 22.4 mmol) in dry dimethylformamide (50 ml) was stirred for 4 hours under an air-lock and the resulting solution added dropwise over 1 hour to a stirred solution of 4,5-dichloro-1,2-benzenediamine (7.23 g, 40.8 mmol) in dichloromethane (50 ml) under air lock. After 2.5 days, the mixture was evaporated in vacuo and the residue purified by chromatography [SiO2 ; dichloromethane-methanoltriethylamine (100:3:1)]. Recrystallisation from ethanol-methanol gave the title compound (1.00 g), m.p. >300°. The compound exhibited infra-red spectral bands at 859, 1182, 1260, 1534, 1671, 3253, 3335 and 3417 cm-1. The NMR spectrum of the compound in DMSO-d6 exhibited the following signals: (δ in ppm from TMS) broad 2 proton signal at 5.5; 1 proton singlet at 6.97; 1 proton singlet at 7.42; 2 proton doublet (J7 Hz) at 7.96; 2 proton doublet (J7 Hz) at 8.37 and broad 1 proton singlet at 9.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][S:25]([CH2:28][C:29](O)=[O:30])(=[O:27])=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:24][S:25]([CH2:28][C:29]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1)=[O:30])(=[O:27])=[O:26]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 62.7 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), (methylsulfonyl)acetic acid (67 mg, 0.485 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99 mg, 0.517 mmol), 1-hydroxybenzotriazole (71 mg, 0.522 mmol), triethylamine (0.08 mL, 0.549 mmol) and N,N-dimethylformamide (4.0 mL), and by a reaction in the same manner as in Example 187, the title compound (87 mg, 63%) was obtained as pale-yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:6](CC2C=CC=CC=2)[C:5]2[CH:14]=[C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:16]=[C:17](N)[C:4]=2[N:3]=1.N([O-])=O.[Na+].[Na+].[Br-:30].[OH-].[Na+]>Br.O>[Br:30][C:17]1[C:4]2[N:3]=[C:2]([CH3:1])[NH:6][C:5]=2[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=1
Reactant: [Br-]
Reactant: Cc1nc2c(N)cc(N3CCOCC3)cc2n1Cc1ccccc1
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 57.4 %

Procedure:
To a solution of 2-methyl-6-(4-morpholinyl)-1-(phenylmethyl)-1H-benzimidazol-4-amine (2.3 g, 10 mmol) in aqueous HBr (50 mL) was added a solution of NaNO2 (720 mg, 10.5 mmol) in water (10 mL) dropwise at 0-5° C. After addition the mixture was stirred at 0° C. for 5 minutes, another solution of NaBr (3.1 g, 30 mmol) in aqueous HBr (50 mL) was added dropwise at 60° C. The resulting mixture was then heated to 80° C. for 30 minutes and then cooled to room temperature. It was neutralized with aqueous 2N NaOH and extracted with EtOAc (100 mL×3). The combined organic layers were concentrated in-vacuum and the residue was purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the desired product (1.7 g, 58%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.44 (s, 3H), 3.07 (t, 4H, J=4.8 Hz), 3.74 (t, 4H, J=4.8 Hz), 6.85 (d, 1H, J=1.8 Hz), 7.04 (d, 1H, J=1.8 Hz), 12.20 (br s, 1H); LC-MS: m/e=296 [M+1]+
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=O)[CH2:3]1.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:4]1[CH2:3][C:2]([CH3:1])([CH3:10])[CH2:9][C:7](=[O:8])[CH:6]=1
Reactant: Nc1ccccc1Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Product: CC1(C)CC(=O)C=C(Nc2ccccc2Cl)C1

Procedure:
A mixture of 40 parts of dimedone and 36.4 parts of 2-chloroaniline is heated at 170°-175° C for 45 minutes, followed by cooling. The resulting reaction product is recrystallized to obtain yellow cubes. The crystals are collected by filtration, washed well with isopropyl ether and recrystallized from acetone. The procedure yields colorless prisms of 3-(2-chloroanilino)-5,5-dimethyl-2-cyclohexen-1-one. Melting point: 150°-152° C. By procedures similar to those described in Example 1 (a) and (b), the following compounds are produced.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C:17]2[CH:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[NH:19][N:18]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[NH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([NH:28][CH2:27][CH2:26][NH:25][C:13]([C:11]1[S:12][C:8]([C:5]2[N:4]=[C:3]([NH:16][C:17]3[CH:21]=[C:20]([CH:22]4[CH2:23][CH2:24]4)[NH:19][N:18]=3)[C:2]([Br:1])=[CH:7][N:6]=2)=[CH:9][CH:10]=1)=[O:15])(=[O:31])[CH3:30]
Reactant: CC(=O)NCCN
Reactant: O=C(O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 23 °C
Reaction time: 12 h
Yield: 68.1 %

Procedure:
A 100 mL round bottomed flask was charged with 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxylic acid (332.5 mg, 0.82 mmol, 1 eq), N-(2-aminoethyl)acetamide (125.3 mg, 1.23 mol, 1.5 eq), EDCI (313.0 mg, 1.6 mmol, 2 eq), HOBt (221.1 mg, 1.6 mmol, 2 eq) and DIPEA (635.4 mg, 4.9 mmol, 6 equiv) in DMF (5 mL). The mixture was stirred for 12 h at 23° C. and extracted with THF (3×70 mL). The organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA/MeOH=1:1:0.05 as eluant) to give pale-yellow solid N-(2-acetamidoethyl)-5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxamide (273.8 mg, 68.3%). LC-MS (m/z)=491.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1.C(N(C(C)C)CC)(C)C.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([CH:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(F)c2[nH]c(=O)n(C3CCNCC3)c2c1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
4-Fluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (12.5 mmol, 3.6 g) (D5a) was dissolved in dichloromethane (50 ml), diisopropylethylamine (3 eq., 37.6 mmol, ˜6.4 ml), and tetrahydro-4H-pyran-4-one (4 eq., 50 mmol, ˜5 g) were added in that order at room temperature; sodium triacetoxyborohydride (3 eq., 37.6 mmol, ˜8 g) was added at room temperature and the mixture was stirred at room temperature for one overnight. The reaction mixture was diluted with dichloromethane (100 ml) and quenched with NaHCO3 (saturated aqueous solution); methanol was added to dissolve the solid which developed in the organic layer; the two phases were separated and the aqueous phase was extracted with dichloromethane (2×); the combined organics were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated to afford 3.8 g, 92%. The material was triturated with diethyl ether and filtered to afford 3.6 g title compound. This was dissolved in MeOH/DCM and 2 eq of HCl (1M in Et2O) were added. The mixture was stirred at room temperature for 10 minutes, solvent was evaporated and the solid was triturated with Et2O to afford another batch, 3.8 g, pale grey solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[CH2:25].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:29]1([S:26](/[CH:24]=[CH:25]/[C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]3)=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CN(c2ccc(/C=C/S(=O)(=O)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 120 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (80 mg, 0.18 mmol), ethenesulfonylbenzene (37 mg, 0.22 mmol), Pd(OAc)2 (2 mg) and triethylamine (186 mg, 1.84 mmol) in MeCN (2 mL) is heated at 120° C. in a microwave apparatus for 15 min. The mixture is filtered, poured into EtOAc and is washed with 1N HCl and brine then dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound: (M−1)−=483.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21]4([CH3:29])[CH:23]5[CH2:27][C:26]([CH3:28])([C:20]4([CH3:30])[C:19]=3[CH:31]=2)[CH2:25][CH2:24]5)[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1.[OH-].[Na+].[OH-].[Li+].CO>C1COCC1.O>[CH3:1][C:2]1([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21]4([CH3:29])[CH:23]5[CH2:27][C:26]([CH3:28])([C:20]4([CH3:30])[C:19]=3[CH:31]=2)[CH2:25][CH2:24]5)[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)c1ccc2c(c1)C1(C)C3(C)CCC(C3)C1(C)O2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(c2ccc3c(c2)C2(C)C4(C)CCC(C4)C2(C)O3)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 3-methyl-3-(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofur-8-yl)-2H-1-benzofuran-6-carboxylate (0.41 g, 0.98 mmol), sodium hydroxide (0.1 g, 2.5 mmol), lithium hydroxide (0.1 g, 2.5 mmol), methanol and water in THF is stirred for 48 h at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]=[O:9])=[CH:4][CH:3]=1.[C:12]([OH:17])(=[O:16])[CH:13]([CH3:15])O.B(F)(F)F.CCOCC>CCOCC.O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]2[O:17][C:12](=[O:16])[CH:13]([CH3:15])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=CCOc1ccc(Cl)cc1
Reactant: CC(O)C(=O)O
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1OC(COc2ccc(Cl)cc2)OC1=O
Reaction time: 24 h

Procedure:
To a solution of 17.05g (0.07 mole) of 4-chlorophenoxyacetaldehyde in 100 ml of ether was added 9.0g (0.1 mole) of lactic acid dissolved in 50 ml of tetrahydrofuran. To the clear solution was added 15g (0.105 mole) of boron trifluoride etherate. After 24 hours at ambient temperature, the reaction mixture was washed with aqueous sodium bicarbonate, dried, concentrated, and purified by silica chromatography. The first fraction that emerged from the column was 2-(4-chlorophenoxymethyl)-5-methyl-1,3-dioxolan-4-one, the transisomer, having a melting point of 37°-40°. The second fraction was the cis isomer which melted at 53°-55°.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:81][O:82][C:83](=[O:93])[CH2:84][C:85]1[CH:90]=[CH:89][C:88](Cl)=[CH:87][C:86]=1[F:92]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:81][O:82][C:83](=[O:93])[CH2:84][C:85]1[CH:90]=[CH:89][C:88]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[CH:87][C:86]=1[F:92]
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOCC
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Degassed toluene (0.12 mL) and water (0.012 mL) were added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 16.5 mg, 0.0272 mmol), palladium (II) acetate (0.9 mg, 0.004 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (3.3 mg, 0.0080 mmol) and potassium phosphate (19.0 mg, 0.0895 mmol). After replacement with nitrogen, (4-chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 7.4 mg, 0.037 mmol) was added. After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 96 to 104° C. for one hour. The reaction mixture was diluted with diethyl ether and filtered through cotton plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=50/1) to give the title compound (13.5 mg, 77%).
Reaction SMILES: CO.C([O:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8])(=O)C.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.O1CCCC1>[OH:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)[CH3:8]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OC(C)=O)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Yield: 98.4 %

Procedure:
Into 100 ml of methanol and 50 ml of tetrahydrofuran were dissolved 15 g of the (-)-2-{4-(1-acetoxyethyl)phenyl}-5-decyloxypyrimidine obtained in Preparation Example [starting material compound (VI)] 70, and then 50 ml of 20% aqueous sodium hydroxide solution were added thereto, to subject to reaction at 40° to 45° C. for 4 hours. After completion of the reaction, 4N hydrochloric acid was added to the reaction mixture to adjust it to pH 7 to 8, and then 200 ml of toluene were added to effect extraction and separation. After the organic phase was washed with water, the solvent was distilled off under reduced pressure to obtain 13.2 g (yield: 98.5%) of (-)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23]>C(OCC)(=O)C>[CH3:27][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:8][CH:11]=1)([CH3:26])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(C)(C)OCCCCCCCC(=O)CCl
Reactant: NC(=S)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)OCCCCCCCc1csc(-c2ccccc2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A mixture of 783 mg of thiobenzamide and 1.0 g methyl 2-(9-chloro-8-oxononyloxy)-2-methylpropionate were stirred for 2 hours at 120° C. The reaction solution was cooled and dissolved in ethyl acetate, washed by adding sodium hydrogencarbonate, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=9:1) to provide 963 mg of the objective compound as pale yellow oil.
Reaction SMILES: Cl.[NH2:2]O.[O-:4][CH2:5][CH3:6].[Na+:7].[Na:8].[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13]([O:15]CC)=[O:14].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.[O-]CC>C(O)C>[O-:4][CH2:5][CH3:6].[Na+:7].[Na:8].[F:9][C:10]([F:20])([F:19])[C:11]1[CH:12]=[C:13]([OH:15])[O:14][N:2]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NO
Agent: CC[O-]
Agent: Cl
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Solvent: CCO
Product: Oc1cc(C(F)(F)F)no1
Reaction time: 8 h

Procedure:
To dry ethanol (200 ml) was added 97% hydroxylamine hydrochloride (8.60 g, 0.120 mole), heated and dissolved. While maintaining the mixture below 25° C. to this stirring solution was added a solution of sodium ethoxide in ethanol which was prepared by the addition of sodium metal (2.76 g, 0.120 g-atom) to dry ethanol (56 ml). Ethyl trifluoroacetoacetate (18.4 g, 0.100 mole) was then added and heated under reflux to allow to react for 4 hours. The reaction mixture was cooled with ice and a solution of sodium ethoxide in ethanol which was prepared by the addition of sodium metal (2.30 g, 0.100 g-atom) to ethanol (46 ml) was added and allowed to stand overnight at 0° C. A slight amount of phenolphthalein as an indicator was added and, while cooling with ice, a solution of soidum ethoxide in ethanol was added until the reaction mixture was colored to pale red. The precipitated inorganic crystals were filtered off. The crystals were well washed with dry ethanol (40 ml) and the washings were combined with the above filtrate and ethanol was evaporated under reduced pressure at 40° C. To the resulting residue was added benzene, the solvent was evaporated under reduced pressure, and then the residue was dried under reduced pressure (<1 mmHg) at 100° C. for 1 hour to give 18.06 g of crude 3-trifluoromethyl-5-hydroxyisoxazole sodium salt (crude yield 103.2%, yield calculated as the pure product 79.2%) as a pale pink amorphous material.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[CH3:29])[CH:21]=[CH:22][C:23](O)=O>>[CH3:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[CH3:29])/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: Cc1ccc(C=CC(=O)O)cc1C
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(C)c(C)c3)nc2n(CCC)c1=O

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 5.90 g (26.0 mmol) of 5,6-diamino-1,3-dipropyluracil and 5.5 g (31.3 mmol) of 3,4-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 7.70 g (yield 81l%) of Compound 30 as a white powder.