Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1([CH3:28])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][CH3:20])[CH:14]=3)[NH:9][C:8]=2[CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)[NH:6]1)=[O:4].[Br:29][CH2:30][CH2:31][N:32]=[C:33]=[O:34]>CC(=O)CC>[Br:29][CH2:30][CH2:31][N:32]1[C:33](=[O:34])[N:6]2[CH:7]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[CH2:17][C:5]2([CH3:28])[C:3]1=[O:4])=[CH:14][C:13]([O:18][CH2:19][CH3:20])=[CH:12][CH:11]=4
Reactant: O=C=NCCBr
Reactant: CCOc1ccc2[nH]c3c(c2c1)CC(C)(C(=O)OC)NC3c1cccc(O)c1
Solvent: CCC(C)=O
Product: CCOc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Yield: 39.8 %

Procedure:
To a solution of 500 mg (1.31 mmol) (1RS,3SR)-6-Ethoxy-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester in 25 ml 2-butanon are added 120 μl (1.31 mmol) bromoethyl isocyanate. The mixture is heated to reflux for 24 h. The solvent is removed under reduced pressure. The crude product is purified by column chromatography (silica gel; toluene, ethyl acetate 6:1). 260 mg (40%) of the title compound are obtained as a colorless solid. m.p.: 250-252° C., MS: m/z (MH+)=498.1/500.0
Reaction SMILES: [C:1]([C:5]1[CH:52]=[CH:51][C:8]2[NH:9][C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([N:17]([CH2:19][C@@H:20]4[C@H:24]5[O:25]C(C)(C)[O:27][C@H:23]5[C@H:22]([N:30]5[C:34]6[N:35]=[CH:36][N:37]=[C:38]([NH:39]CC7C=CC(OC)=CC=7OC)[C:33]=6[CH:32]=[CH:31]5)[O:21]4)[CH3:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O.O>[NH2:39][C:38]1[C:33]2[CH:32]=[CH:31][N:30]([C@H:22]3[C@H:23]([OH:27])[C@H:24]([OH:25])[C@@H:20]([CH2:19][N:17]([CH:15]4[CH2:14][CH:13]([CH2:12][C:10]5[NH:9][C:8]6[CH:51]=[CH:52][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=6[N:11]=5)[CH2:16]4)[CH3:18])[O:21]3)[C:34]=2[N:35]=[CH:36][N:37]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(Cc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@H]1O[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(Cc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
7-((3aR,4R,6R,6aR)-6-(((3-((5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)methyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (170 mg, 0.24 mmol) was dissolved in a mixture of trifluoroacetic acid (5.0 mL) and water (0.5 mL) which had been precooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, and warmed to room temperature. After 5 h at room temperature, the now very pink reaction mixture was concentrated. The residue was taken up in 10 mL MeOH and concentrated. This procedure was repeated twice and the residue placed on high vac for 1 h. The material was taken up in 7 mL MeOH and was treated with 130 mg K2CO3 and five drops of water. The mixture was allowed to stir for 1 hr, during which time the solution was found to be basic. The mixture was filtered through a fine frit, the solids were washed with 10 mL MeOH and the filtrate was concentrated to yield a nearly colorless solid. The crude material was purified by flash chromatography (30 g silica gel; 12% 7N NH3 in CH3OH/CH2Cl2) to yield Compound 6 (81 mg, 65%) as a colorless glass/stiff foam: MS (ESI+) for C28H37N7O3 m/z 520.4 (M+H)+; MS (ESI−) for C28H37N7O3 m/z 518.5 (M−H)−; HPLC purity >95% (ret. time, 2.51 min); 1H NMR (400 MHz, d4-MeOH) δH ppm 8.08 (s, 1H), 7.48 (br. s., 1H), 7.39 (d, J=8.50 Hz, 1H), 7.29 (dd, J=8.40, 4.87 Hz, 1H), 6.63 (m, 1H), 6.12 (d, J=4.15 Hz, 1H), 4.40 (m, 1H), 4.09 (m, 2H), 3.15 (m, 0.5H), 3.02 (d, J=8.09 Hz, 1H), 2.92 (d, J=7.26 Hz, 1H), 2.84 (m, 0.5H), 2.65 (m, 2H), 2.43 (m, 1H), 2.29 (m, 1H), 2.20 (d, J=5.80 Hz, 3H), 2.13 (m, 1H), 1.99 (br. s., 1H), 1.67 (m, 1H), 1.37 (d, J=3.94 Hz, 9H), 1.30 (dd, J=13.99, 4.66 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:25]4[CH2:26][CH2:27][N:22]([C:28]5[N:29]=[CH:30][CH:31]=[CH:32][N:33]=5)[CH2:23][CH2:24]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ncccn2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-piperazin-1-yl-pyrimidine in ethanol, essentially as described above in Example 70. Purity by LC/MS=-100%, [M+H]+=450.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][N:6]=1>CO.O>[Cl:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([O:2][CH3:1])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ncc(Cl)cc1[N+](=O)[O-]
Reaction time: 7 h
Yield: 96.9 %

Procedure:
A solution of sodium methoxide (0.84 g, 16.6 mmol) in methanol (4 mL) was added dropwise to a solution of 2,5-dichloro-3-nitropyridine (1.00 g, 5.2 mmol) in methanol (10 mL) and the mixture was stirred and heated to reflux. After 7 hours, the mixture was cooled and diluted with water and the precipitate was filtered and washed with water to give the title compound (0.95 g, 97%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[S:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])=O.[CH2:31]([Mg]Br)[CH3:32]>CCCCCC.C(OCC)(=O)C>[CH:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:8]2[C:7]3[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:4]([CH3:30])=[C:3]([CH2:1][CH2:31][CH3:32])[C:11]=3[S:10][CH2:9]2)=[CH:13][CH:14]=1)([CH3:20])[CH3:19]
Reactant: CC[Mg]Br
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CS2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Yield: 22 %

Procedure:
Using N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide obtained in Example 163 and ethylmagnesium bromide, the title compound was synthesized in the same manner as in Example 164. Yield: 22%. Melting point: 159-160° C. (hexane-ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=3)[S:17][C:10]=12.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=3)[S:17][C:10]=12
Reactant: Cn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C=NC(=O)Cc1ccccc1
Product: Cn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 306 (99mg, 0.29 mmol) and 2-phenylacetyl isocyanate (97 mg, 0.60 mmoL) [A. J. Hill, et al. JACS, 62, 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and gradient eluted with EtOAc, to MeOH/EtOAc (10:90) to afford the title compound 307 (42% yield) as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.11(s, 1H), 10.68(s, 1H, J=5.5 Hz), 8.49(d), 7.85(s, 1H), 7.82(dd, 1H, J1=12.9 Hz, J2=2.4Hz), 7.76(s, 1H), 7.43(m, 2H), 7.40(s, 1H), 7.32(m, 4H), 7.28(m, 1H), 6.61(d, 1H, J=5.5 Hz), 3.89(s, 3H), 3.74(s, 2H). MS (m/z):502.4 (M+H) (found).
Reaction SMILES: [F:1][CH2:2][CH:3]([CH2:16][F:17])[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:8]#[N:9].O.O.[Sn](Cl)Cl.C(O)C>O>[NH2:13][C:12]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:4][CH:3]([CH2:2][F:1])[CH2:16][F:17]
Reactant: N#Cc1ccc([N+](=O)[O-])c(OC(CF)CF)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(N)c(OC(CF)CF)c1

Procedure:
3-(2-Fluoro-1-fluoromethyl-ethoxy)-4-nitro-benzonitrile (1.45 g), tin(II) chloride dihydrate (4.00 g) and ethanol (60 ml) were stirred at 100° C. for 2 hours. The mixture was poured in water and extracted with DCM. The organic layer was washed with water, dried and concentrated.
Reaction SMILES: CO[C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1.[CH3:32][O:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[CH3:32][O:33][CH2:34][CH2:35][CH2:36][NH:37][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(N3CCCCC3)n(-c3ccccc3)c2c1
Reactant: COCCCN
Product: COCCCNC(=O)CCCCCOc1ccc2nc(N3CCCCC3)n(-c3ccccc3)c2c1

Procedure:
100 mg of 6-[[2-(piperidin-1-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with 3-methoxypropylamine according to general operating instructions 4. 47 mg was obtained.
Reaction SMILES: [C-]#N.[Na+].[Cu][C:5]#[N:6].Br[C:8]1[N:9]=[C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])[C:11]([NH2:15])=[N:12][C:13]=1[NH2:14]>CN(C)C=O>[C:5]([C:8]1[N:9]=[C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])[C:11]([NH2:15])=[N:12][C:13]=1[NH2:14])#[N:6]
Reactant: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1Br
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(-c2cc(Cl)cc(Cl)c2Cl)c(N)nc1N
Temperature: 130 °C

Procedure:
A mixture of 97% sodium cyanide (0.064 g, 1.306×10−3 mole) and 90% copper(I) cyanide (0.135 g, 1.306×10−3 mole) in dry dimethylformamide (5 ml) was stirred and heated to 130° C. To the resulting clear solution was added 5-Bromo-2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine (0.35 g, 0.95×10−3 mole) in small portions, and the solution was maintained at 140-150° C. for 16 hrs. The reaction mixture was cooled and evaporated in vacuo. The residue was extracted with ethyl acetate (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was purified by ‘flash chromatography’ using 5-17% ethyl acetate in cyclohexane as the eluent. Yield 0.152 g (51 %), M.p. 277-279° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:12]([O:14]CC)=[O:13])[CH3:11])=[CH:4][C:3]=1[N:17]1[C:21](=[O:22])[C:20]2[CH2:23][CH2:24][CH2:25][CH2:26][C:19]=2[C:18]1=[O:27].CS(O)(=O)=O.C(O)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:12]([OH:14])=[O:13])[CH3:11])=[CH:4][C:3]=1[N:17]1[C:21](=[O:22])[C:20]2[CH2:23][CH2:24][CH2:25][CH2:26][C:19]=2[C:18]1=[O:27]
Reactant: CCOC(=O)C(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl
Agent: CS(=O)(=O)O
Solvent: O=CO
Solvent: O
Product: CC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 14.4 g. of N-[2,4-dichloro-5-(1-ethoxycarbonylethyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide, 3.40 g. of methanesulfonic acid and 35 ml. of 86% formic acid was refluxed with stirring for 15 hours and the reaction mixture was cooled to room temperature and water was added and the product was extracted with ethyl acetate. The extract was concentrated under a reduced pressure and the oily product was admixed with n-hexane and was triturated to obtain the crystals. The product was recrystallized from benzene-cyclohexane to obtain 8.7 g. of Compound No. 11 shown in Table 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][C:3]=1[SH:13].[C:14](Cl)(=O)[CH2:15][CH3:16].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH2:15]([C:16]1[S:13][C:3]2[CH:4]=[C:5]([N:8]3[N:9]=[CH:10][CH:11]=[N:12]3)[CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:14]
Reactant: Nc1ccc(-n2nccn2)cc1S
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1nc2ccc(-n3nccn3)cc2s1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
The 2-amino-5-(1,2,3-triazol-2-yl)-thiophenol (2.3 g) was dissolved in N-methylpyrrolidone (8 ml), and propionyl chloride (0.472 ml) was added to the solution, followed by heating and stirring at 70° C. for 5 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, and subjected to extraction with dichloromethane. The resultant organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then purified through a silica gel column (hexane-ethyl acetate=4:1→1:1), thereby obtaining the intended compound, 2-ethyl-6-(1,2,3-triazol-2-yl)benzothiazole (940 mg). Physical properties of this product are described below.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:43]=[CH:42][C:15]([CH2:16][C@H:17]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:18][C@@H:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:14][C:13]=1[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])C1C=CC=CC=1>CO.[Pd].[H][H]>[C:24]([O:23][C:21]([NH:20][C@H:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:18][C@H:17]([CH2:16][C:15]1[CH:42]=[CH:43][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH:14]=1)[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCOCc2ccccc2)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCO)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 340 mg (0.506 mmol) di-tert-butyl (4S)-4-{4-[2-(benzyloxy)ethoxy]-3-tert-butoxybenzyl}-N-(tert-butoxycarbonyl)-L-glutamate in 5 ml methanol was added a little amount of palladium on carbon. The solution is stirred in hydrogen atmosphere for 4 hours. The reaction mixture is filtrated. The filtrate is concentrated. The crude product is concentrated in vacuo. The crude product (310 mg) was used in the following reaction without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH2:35][CH3:36])=[O:27])[N:23]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([F:18])[F:17])C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:18][CH:16]([F:17])[O:15][C:14]1[CH:13]=[CH:12][C:11]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH2:35][CH3:36])=[O:27])[N:23]=2)=[CH:10][C:9]=1[OH:8]
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(OCc3ccccc3)c2)n1
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 75 mg quantity of 3-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one obtained in Example 228 was dissolved in 1 ml of ethanol. A 7 mg quantity of 10% palladium-carbon powder was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature for 45 minutes. The catalyst was removed by filtration, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane:ethanol=100:1) to give 32 mg of white powdery 3-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:55][CH3:56])=[C:15]([C:17]2([N:44]3[CH2:53][C@H:52]([OH:54])[CH2:51][C@H:45]3[C:46]([N:48]([CH3:50])[CH3:49])=[O:47])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=3[O:38][C:39]([F:42])([F:41])[F:40])(=[O:29])=[O:28])[C:18]2=[O:43])[CH:16]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.O>C1COCC1>[Cl:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][C:39]([F:40])([F:42])[F:41])(=[O:28])=[O:29])[C:18](=[O:43])[C:17]2([N:44]1[CH2:53][C@H:52]([OH:54])[CH2:51][C@H:45]1[C:46]([N:48]([CH3:49])[CH3:50])=[O:47])[C:15]1[CH:16]=[C:11]([CH2:10][CH2:9][OH:8])[CH:12]=[CH:13][C:14]=1[O:55][CH3:56]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCO[Si](C)(C)C(C)(C)C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCO)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 500 mg of the compound obtained in Step 216-6 in THF (5.0 ml) was added dropwise a solution of 1 mol/L TBAF/THF (2.6 ml) under ice cooling. The solution was stirred at room temperature for two hours. Water was added to the reaction solution and the resulting mixture was extracted with EtOAc. The extract was dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=8/1; v/v) to obtain 320 mg of the title compound (light yellow solid).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:49]=[C:50]([C@@H:54]([NH2:56])[CH3:55])[CH:51]=[CH:52][CH:53]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:56][C@H:54]([C:50]4[CH:51]=[CH:52][CH:53]=[C:48]([F:47])[CH:49]=4)[CH3:55])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C[C@H](N)c1cccc(F)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@@H](C)c2cccc(F)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (S)-1-(3-fluorophenyl)ethylamine (Synquest) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]1[CH:11]=[C:10]2[C:12]([C:14]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[C:15]=3[C:16](=[O:17])[C:9]2=[CH:8][CH:7]=1)=[O:13]>[O-2].[O-2].[Mn+4].O>[CH:6]1[CH:7]=[CH:8][C:9]2[C:16](=[O:17])[C:15]3[C:18]([OH:23])=[C:19]([OH:22])[CH:20]=[C:21]([OH:2])[C:14]=3[C:12](=[O:13])[C:10]=2[CH:11]=1
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(O)c2O
Reactant: O=S(=O)(O)O
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c(O)c(O)cc(O)c21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A suspension of 17.5 g of manganese dioxide/40 g of concentrated sulfuric acid, that had been prepared by putting 9.0 g of water and 130 g of 96% sulfuric acid into 30 g of alizarin (manufactured by Sigma-Aldrich Corporation), followed by ice-cooling, was added over 1 hour to a reaction liquid while maintaining it at 10° C. or lower. After 2 hours, the reaction liquid was poured into 1 L of water, with the inside of the container being washed with 400 mL of water, and filtered. The crystal collected by filtration was washed with 300 mL of methanol and dried to obtain 32.4 g of purpurin.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[N:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5]1.[CH2:13]([CH:16]([C:19]#[N:20])[C:17]#[N:18])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([C:16]([CH2:3][N:4]1[CH:8]=[N:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5]1)([C:19]#[N:20])[C:17]#[N:18])[CH:14]=[CH2:15]
Reactant: CC(C)(C)c1ncn(CCl)n1
Reactant: C=CCC(C#N)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(C#N)Cn1cnc(C(C)(C)C)n1
Yield: 10.8 %

Procedure:
1.28 g of 1-(chloromethyl)-3-t-butyl-1H-1,2,4-triazole hydrochloride and 0.77 g of allyl malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 1.01 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.16 g of allyl [(3-t-butyl-1H-1,2,4-triazole-1-yl)methyl]malononitrile (referred as the compound of the present invention (31), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]([NH:21]C(=O)C)=[C:4]([F:25])[CH:3]=1>CO>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]([NH2:21])=[C:4]([F:25])[CH:3]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Solvent: CO
Product: COC(=O)COc1ncccc1Oc1cc(N)c(F)cc1Cl
Reaction time: 3 h
Yield: 94.4 %

Procedure:
First, 20 ml of a methanol solution of a boron trifluoride methanol complex was mixed with 1.04 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]acetamide, and the mixture was stirred at 60° C. to 70° C. for 3 hours and then concentrated. The residue was diluted with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to column chromatography to give 0.87 g of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline.