Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][C:18]([F:24])([F:23])[CH2:19][CH:20]1[CH2:22][CH2:21]1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[ClH:25]>O1CCOCC1>[ClH:25].[NH2:11][C@@H:12]([CH2:17][C:18]([F:23])([F:24])[CH2:19][CH:20]1[CH2:22][CH2:21]1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CC(F)(F)CC1CC1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CC(F)(F)CC1CC1
Yield: 98.8 %

Procedure:
A solution of (S)-methyl 2-(benzyloxycarbonylamino)-5-cyclopropyl-4,4-difluoropentanoate (570 mg, 1.87 mmol) in dioxane/4N-HCl (9 mL, 37 mmol) was stirred at RT for two hr, after which the solvent was removed by rotoevaporation to give 450 mg of (S)-methyl 2-amino-5-cyclopropyl-4,4-difluoropentanoate hydrochloride as a beige solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](OC)=O)=[C:11]([O:19][CH3:20])[CH:10]=1)#[N:2].[BH4-].[Li+].[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24].[Cl-].[NH4+]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:24]([C:11](=[O:19])[CH2:10][CH2:9][CH3:4])[C:23]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([O:19][CH3:20])[CH:10]=1)#[N:2]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(-c2ccccc2C#N)cc1OC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a solution of methyl 2′-cyano-3-methoxybiphenyl-4-carboxylate (1.86 g) in tetrahydrofuran (40 mL) was added lithium borohydride (0.67 g) at 0° C., and the mixture was stirred at room temperature for 12 hr. To the reaction mixture were added ethyl acetate and saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in toluene (30 mL), phosphorus tribromide (0.33 mL) was added, and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. This was dissolved in tetrahydrofuran (10 mL), the mixture was added dropwise to a solution of ethyl 3-oxohexanoate (1.7 g) and 60% sodium hydride (0.28 g) in tetrahydrofuran (15 mL) at 0° C., and the mixture was stirred at room temperature for 15 hr. To the reaction mixture were added ethyl acetate and saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.8 g, 89%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)([CH3:19])[CH3:18])[CH2:16][O:15]2)=[CH:10][CH:9]=1>C(O)CC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:15])([C:17]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)([CH3:18])[CH3:19])[CH2:16][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:10][CH:9]=1
Reactant: CC(C)(n1cncn1)C1(c2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCCO
Product: CC(C)(n1cncn1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 24.2 %

Procedure:
3.6 g (0.052 mole) of 1,2,4-triazole are added to a solution of 0.11 g (0.047 mole) of sodium in 30 ml of n-propanol at room temperature, while stirring. The mixture is heated to the reflux temperature and a solution of 2-(4-chlorophenyl)-2-[2-(1,2,4-triazol-1-yl)prop-2-yl]-oxirane in 20 ml of n-propanol is added. The reaction mixture is heated under reflux for 15 hours and then cooled and poured onto water. The mixture is extracted with methylene chloride and the organic phase is dried over sodium sulphate and concentrated. The residue is purified by column chromatography (silica gel; chloroform:methanol=9:1). 3.7 g (24.2% of theory) of 2-(4-chlorophenyl)-1,3-di-(1,2,4-triazol-1-yl)-3-methyl-2-butanol of melting point 114° C. are obtained.
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.O=O.C1CC2C(=CC=CC=2)C(O)C1>[OH-].[Cu+2].[OH-].O>[CH2:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1CCCc2ccccc21
Agent: [Cu+2]
Agent: O=O
Agent: OC1CCCc2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCCC2
Temperature: 80 °C

Procedure:
Tetralone (132 g), toluene (131 g), and 0.5 g of copper hydroxide suspension (37.5% Cu(OH)2), were mixed into a 500 ml round bottom with temperature control, gas dispersion tube, water-cooled condenser and a magnetic stirrer. The reaction was maintained at 80° C. for 9.8 hr. with a 300 ml/minute oxygen flow at atmospheric pressure. GC analysis (area %) indicates 3% 1-tetralol, 5.2% 1-tetralone and 15% 1-tetralin hydroperoxide.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C@@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[OH:12])[CH:3]=[N:2]1>CCCCCC.C(O)C>[NH:1]1[CH:5]=[C:4]([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:12])[CH:3]=[N:2]1
Reactant: O[C@@H]1CCCC[C@H]1c1cn[nH]c1
Solvent: CCCCCC
Solvent: CCO
Product: O[C@H]1CCCC[C@@H]1c1cn[nH]c1

Procedure:
The (1R*,2S*)-2-(1H-pyrazol-4-yl)cyclohexanol prepared in Example 169a was optically resolved with CHIRALPAK AD-H (Daicel Corp.; hexane/ethanol=8:2) to yield the title compound as a colorless solid.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH:5]1([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH:5]1([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH3:4])[CH2:30][CH2:29]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1
Reactant: CCCI
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCCNCC3)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCN1CCCN(c2ccc3ncn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Iodopropane (0.039 ml) was added to a stirred mixture of N-cyclopropyl-3-[6-(1,4-diazepan-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzamide (0.150 g) and potassium carbonate (0.199 g) in DMA (0.50 ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20 ml), the resulting solid was filtered and dried (magnesium sulphate) under vacuum at 40° C. There was thus obtained the title compound (0.098 g); NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.68 (m, 2H), 0.80 (t, 3H), 1.39 (m, 2H), 1.87 (m, 2H), 2.11 (s, 3H), 2.36 (t, 2H), 2.49 (m, 2H), 2.72 (m, 2H), 2.84 (m, 1H), 3.56 (m, 4H), 7.23 (d, 1H), 7.36 (d, 1H), 7.50 (d, 1H), 7.58 (d, 1H), 7.79 (s, 1H), 7.87 (d, 1H), 7.95 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[C:14](O)=[O:15])=[CH:7][CH:6]=1)=[O:4].[Cl-].[NH4+]>C1COCC1.O.C(OCC)(=O)C>[OH:15][CH2:14][CH:13]([CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(CCC(CCc2ccc(C(=O)OC)cc2)C(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC(CO)CCc2ccc(C(=O)OC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
At −10° C., 54.1 ml (54.1 mmol) of a 1 M borane/THF complex solution are added dropwise to a solution of 10.4 g (27.1 mmol) of 4-[4-(methoxycarbonyl)phenyl]-2-{2-[4-(methoxy-carbonyl)phenyl]ethyl}butanoic acid in 260 ml of THF. The reaction mixture is then warmed to 0° C. and stirred at this temperature for 4 h. After the reaction has gone to completion, saturated ammonium chloride solution is added, the reaction mixture is diluted with water and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and freed from the solvent under reduced pressure. This gives 8.73 g (23.56 mmol, 87% of theory) of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[N:4]([CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[N:8](C(=O)C(F)(F)F)[C@@H:7]([CH:25]2[CH2:27][CH2:26]2)[CH2:6]1.O1CCCC1.[OH-].[Li+].O>CO>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:41])([F:42])[F:40])[CH:32]=1)[CH2:28][N:4]([C:3]([O:2][CH3:1])=[O:43])[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[NH:8][C@@H:7]([CH:25]2[CH2:27][CH2:26]2)[CH2:6]1
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)C(F)(F)F)c2ccc(C(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)Nc2ccc(C(F)(F)F)cc21
Reaction time: 2 h
Yield: 97.1 %

Procedure:
cis-(3,5-Bis-trifluoromethyl-benzyl)-(2-cyclopropyl-1-trifluoroacetyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid methyl ester (Example 47) (900 mg, 1.41 mmol) was dissolved in 20 mL of methanol and 60 mL of tetrahydrofuran before adding lithium hydroxide (1.6 mL of 1.0M aqueous solution, 1.6 mmol) to the solution. After 2 h at room temperature, 100 mL of water was added and the mixture extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with 50 mL of brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title product (740 mg) as a colorless solid which was used without further purification. MS m/z 542 (M+2)+; 1H NMR (CDCl3) δ 0.2 (m, 2H), 0.55 (m, 2H), 0.8 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4]([NH:12][CH2:13][C:14]([O:16]CC)=[O:15])[N:3]=1.[OH-].[Na+]>O1CCOCC1>[CH3:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[N:3]=[C:4]([NH:12][CH2:13][C:14]([OH:16])=[O:15])[N:5]=1
Reactant: CCOC(=O)CNc1nc(C)c([N+](=O)[O-])c(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(NCC(=O)O)nc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
Compound 10 (80 mg) was suspended in 1,4-dioxane (1.5 mL) and a 2N aqueous sodium hydroxide solution (1.5 mL) was added at room temperature (20 to 30° C.). The mixture was stirred at room temperature (20 to 30° C.) for 8 hours. Subsequently, the mixture was washed with diethyl ether. While the reaction mixture was cooled, a 2N aqueous HCl solution was added portionwise to neutralize the mixture to a pH of 3. The mixture was extracted twice with chloroform and the organic layer was concentrated under reduced pressure to give 52 mg (75% yield) of the desired product as a pale yellow amorphous.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]=[CH:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]1
Reactant: [H][H]
Reactant: CCCC1CCC(C=Cc2c(C)cc(OCC)c(F)c2F)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCC1CCC(CCc2c(C)cc(OCC)c(F)c2F)CC1

Procedure:
0.1 g of Pd/C was added to the compound 1-1-3-17 having been dissolved in 20 mL of toluene and 20 mL of Solmix, and under a hydrogen atmosphere, the mixture was stirred at room temperature until hydrogen was not absorbed. Pd/C was removed, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallization to obtain 2.01 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-propylcyclohexyl)ethane (Compound 1-2-3-4) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[NH2:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:6]
Reactant: NCC(O)CO
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)NCC(O)CO
Yield: 85.9 %

Procedure:
The same procedure as in Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 1.9 g of 3-amino-1,2-propanediol were used as the starting materials. 6.5 g (86%) of the title compound was obtained as a white wax.
Reaction SMILES: C([Li])CCC.[CH3:6][C@@H:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:18])[NH:8]1.[Br:19][CH2:20][C:21](Cl)=[O:22].[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1>[Br:19][CH2:20][C:21]([N:8]1[C@H:7]([CH3:6])[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9]1=[O:18])=[O:22]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: O=C(Cl)CBr
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CBr
Temperature: -70 °C
Reaction time: 1.75 h
Yield: 68.7 %

Procedure:
117 ml of a 1.6 molar solution of butyllithium in hexane is added to a solution of 30.1 g of (4R,5S)-4-methyl-5-phenyloxazolidin-2-one in 500 ml of tetrahydrofuran within 30 minutes at −70° C. under nitrogen. Then, a solution of 26.8 g of bromoacetyl chloride in 250 ml of tetrahydrofuran is added in drops in such a way that the temperature does not exceed −65° C. After 1.75 hours of stirring at −70° C., a saturated ammonium chloride solution is added, followed by 60 ml of a saturated sodium bicarbonate solution, and it is allowed to come to 25° C. After the phases are separated, the aqueous phase is extracted twice with 100 ml of ether each. The combined organic phases are washed with semiconcentrated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum after filtration. The residue that is thus obtained is purified by chromatography on silica gel. With hexane/0-50% ether, 34.8 g of the title compound is obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:29]3[C:30]([CH:33]=[O:34])=[CH:31][CH:32]=[C:28]3[C:8]3([CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH3:26])[CH:16]=4)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:35]=1.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:29]3[C:30]([CH2:33][OH:34])=[CH:31][CH:32]=[C:28]3[C:8]3([CH2:13][CH2:12][N:11]([C:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[C:17]([O:25][CH3:26])[CH:16]=4)=[O:27])[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:35]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2c(C=O)ccc23)ccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2c(CO)ccc23)ccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-Chloro-1′-(3-methoxy-4-(trifluoromethyl)benzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (50 mg, 0.10 mmol) dissolved in dry THF (3 mL) was cooled to 0° C. NaBH4 (3.9 mg, 0.10 mmol) was added and stirring was continued for 30 min. The mixture was filtered through Celite, evaporated and purified by column chromatography (5-30% AcOEt in dichloromethane) to yield (7-chloro-1-(hydroxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-methoxy-4-(trifluoromethyl)phenyl)methanone. ESI-MS m/z calc. 506.9. found 507.0 (M+1)+; Retention time: 1.96 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:27])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52])=[CH:46][CH:45]=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)=[S:55])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:8]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)CC1
Reaction time: 0.08 h
Yield: 36.8 %

Procedure:
After dissolving 3-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (70.3 mg) in ethanol (2 ml) under a nitrogen atmosphere, D-10-camphorsulfonic acid (43.7 mg) was added and the mixture was stirred for 5 minutes. A 0.24 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (1.02 ml) was added thereto, and the mixture was stirred for 17.5 hours. Then, a 0.24 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.3 ml) was further added to the reaction mixture, and stirring was continued for 30 minutes. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition. The organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:8), and then fractions containing the target compound were concentrated under reduced pressure. Diethyl ether (1 ml) and hexane (2 ml) were added to the resultant residue to produce a suspension. After filtering the solid, it was subjected to aeration drying to provide the title compound (39.4 mg, 36.8%) as pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36](/B(O)O)=[CH:37]\[CH2:38][CH2:39][CH3:40]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH:36]=[CH:37][CH2:38][CH2:39][CH3:40])=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: CCC/C=C/B(O)O
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: CCCC=Cc1ccc(Cc2nc(-c3ccc(Cl)cc3Cl)cn2-c2cccc(N3CC(=O)NS3(=O)=O)c2)cc1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using trans-1-penten-1-ylboronic acid (34 mg, 0.3 mmol) to give 5-{3-[4-(2,4-dichloro-phenyl)-2-(4-pent-1-enyl-benzyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Na:1].[CH2:2]1[O:4][CH2:3]1.[C:5]([OH:10])(=[O:9])[C:6]([CH3:8])=[CH2:7].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=[CH2:21].[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])[CH:26]=[CH2:27].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O>[CH:11]([CH2:7][C:6](=[CH2:8])[C:5]([O-:10])=[O:9])=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])[CH:26]=[CH2:27].[Na:1].[CH2:3]1[O:4][CH2:2]1.[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)O
Agent: C=CC(=O)OCCCC
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Solvent: C1CO1
Product: C=C(CC=Cc1ccccc1)C(=O)[O-]
Temperature: 75 °C
Reaction time: 0.33 h

Procedure:
Into a reaction vessel equipped with a stirring rod and a thermometer, 683 parts by mass of water, 11 parts by mass of sodium salt of methacrylic acid ethylene oxide adduct sulfate ester (ELEMINOL RS-30, manufactured by Sanyo Chemical Industries, Ltd.), 10 parts by mass of polylactic acid, 60 parts by mass of styrene, 100 parts by mass of methacrylic acid, 70 parts by mass of butyl acrylate, and 1 part by mass of ammonium persulfate were charged and then stirred at 1,500 rpm for 20 minutes, to thereby obtain a white emulsion. Then, the temperature of the reaction system was raised to 75° C. by heating and reacted for 3 hours. Further, 30 parts by mass of a 1% by mass aqueous ammonium persulfate solution was added to the reaction system and aged at 65° C. for 12 hours, to thereby obtain an aqueous dispersion liquid of a vinyl resin (a copolymer of styrene-methacrylate-butyl acrylate-sodium salt of methacrylic acid ethylene oxide adduct sulfate ester), i.e., Fine Particle Dispersion Liquid 6. The volume average particle diameter of Fine Particle Dispersion Liquid 6 was 720 nm as measured with a particle size distribution measurement device (LA-920, manufactured by HORIBA, Ltd.). A part of Fine Particle Dispersion Liquid 6 was dried so that the resin part was isolated therefrom. The resin part had Tg of 57° C., and a weight average molecular weight of 120,000.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[F:21])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21

Procedure:
The procedure of Preparation Example 1 (6) was repeated using 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylic acid ethyl ester, potassium pentafluoropropionate, cuprous iodide, toluene and N,N-dimethylformamide to give 6-pentafluoroethyl-2,2-bisfluoromethyl-2H-1-benzopyran-4-carboxylic acid ethyl ester as an oil;
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:28]#[CH:29])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[OH:30]S(O)(=O)=O>CC(C)=O.S([O-])([O-])(=O)=O.[Hg+2]>[C:28]([C:9]1[CH:10]=[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][CH:8]=1)(=[O:30])[CH3:29]
Reactant: O=S(=O)(O)O
Reactant: C#Cc1cnc(OCCCC)c(-c2nc3c(CC)n(CCOC)nc3c(=O)[nH]2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: CC(C)=O
Product: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1

Procedure:
The title compound of Example 15 (2.4 g, 6 mmol) and mercury sulfate (100 mg, 0.34 mmol) were stirred together in a mixture of 1N H2SO4 (5 mL) and acetone (35 mL). After 2 h a further portion of mercury sulfate (100 mg) was added and a third portion (100 mg in 5 mL 1N H2SO4) was added 2 h later. The crude reaction mixture was concentrated and the black residue partitioned between dichloromethane and water. The organic phase was separated and washed with saturated sodium bicarbonate solution and brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (gradient elution from 30% ethyl acetate: pentane to 100% ethyl acetate) gave 780 mg product.