Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[K+].[K+].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[NH:14]1[CH:15]=[CH:16][CH:17]=[C:13]1/[CH:12]=[C:4]1\[C:5](=[O:11])[NH:6][C:7]2[C:3]\1=[C:2]([C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=1)[CH:10]=[CH:9][CH:8]=2
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C1Nc2cccc(-c3cccc(C(F)(F)F)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A suspension of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.089 mmol) (Starting Material 1), K2CO3 (25 mg, 0.180 mmol), (Ph3P)4Pd (5 mg, 0.004 mmol) (Aldrich), and 3-(trifluoromethyl)phenylboronic acid (20 mg, 0.110 mmol) (Aldrich) in 2.5 mL of a 1.5:1 mixture of 1,2-dimethoxyethane:distilled water was heated at reflux under a nitrogen atmosphere for 14 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate-hexanes then 40% ethyl acetate-hexanes elution) to yield pure (Z)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-4-(3-trifluoromethylphenyl)-2H-indol-2-one (yield 18 mg, 56%) as a yellow solid (mp 197-198° C.).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f48) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[C:12](=[CH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.[H][H]>CO.[Pd]>[CH3:23][C:4]1[CH:3]=[CH:2][CH:7]=[C:6]([CH3:8])[C:5]=1[CH:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:11][C:10]1=[O:22]
Reactant: [H][H]
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CC(=CC2CCOCC2)C1=O
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Yield: 49.9 %

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)-4-[1-(tetrahydropyran-4-yl)-methylidene]-cyclopentane-1,3-dione (0.3 g, 0.8 mmol) in methanol (5 ml) is added 10% palladium on carbon (0.06 g), followed by stirring under a 1 bar hydrogen atmosphere for 8 hours. The reaction mixture is then filtered through diatomaceous earth and concentrated to give a crude product which is purified by flash chromatography (hexane/ethyl acetate) to afford 2-(2,6-dimethylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione (0.12 g).
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2].[BH4-].[Na+]>CO>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH2:20][OH:21])[CH:10]=2)[NH2:2]
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)OCC1c2c(O)cc(CO)cc2N2CC3NC3C1(O)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (30 mg) in methanol (3 ml) was added sodium borohydride (40 mg), and the mixture was stirred at room temperature for 1 hour. After evaporation of the solvent, the residue was subjected to column chromatography on non-ionic adsorption resin "Diaion HP-20" (Trade Mark, maker Mitsubishi Chemical Industries Ltd.). Elution was carried out with 50% methanol, and fractions containing the desired compound were collected. The solvent was evaporated off to give 6,9-dihydroxy-4-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate, which was dissolved in pyridine (1 ml). To this solution was added acetic anhydride (0.5 ml), and the resultant solution was allowed to stand at room temperature overnight. Removal of the solvent by using high vacuum pump gave an oil, which was subjected to preparative thin layer chromatography. Development was carried out with a mixture of methanol and chloroform (1:9, v/v) to afford 4-acetoxymethyl-11-acetyl-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (12 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:13][N:12]=1.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.C([O-])(=O)C.[K+]>O.CCO>[F:10][C:11]1[C:16]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=2)=[CH:15][C:14]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:13][N:12]=1
Reactant: Cc1nc(N)nc(Cl)n1
Reactant: CC(c1cnc(F)c(B(O)O)c1)N1CCOCC1
Agent: CC(=O)[O-]
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Product: Cc1nc(N)nc(-c2cc(C(C)N3CCOCC3)cnc2F)n1
Temperature: 100 °C
Yield: 30.3 %

Procedure:
To a 20 mL microwave vial was added 4-chloro-6-methyl-1,3,5-triazin-2-amine (0.300 g, 2.075 mmol), 2-fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid (0.580 g, 2.283 mmol), Amphos (Aldrich) (0.073 g, 0.104 mmol), potassium acetate (Aldrich) (0.611 g, 6.23 mmol), EtOH (9 mL), and water (0.9 mL). The resulting mixture was degassed by bubbling N2 for 5 min then sealed off and microwave heated at 100° C. for 20 min. The reaction mixture was partitioned between 25% IPA in CHCl3 (1% NH4OH) (30 mL) and water (50 mL). The aqueous layer was extracted with more 25% IPA in CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 3% MeOH in DCM) to afford the desired product as a white solid (200 mg). MS (ESI pos. ion) m/z: 319.1. 1H NMR (300 MHz, CDCl3) δ ppm 1.42 (d, J=6.58 Hz, 3H) 2.32-2.47 (m, 2H) 2.49-2.63 (m, 5H) 3.50 (q, J=6.33 Hz, 1H) 3.71 (t, J=4.38 Hz, 4H) 5.49 (br. s., 2H) 8.29 (s, 1H) 8.46 (dd, J=9.13, 2.27 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[S:36][C:16]2=[CH:17][CH:18]=[C:19]3[C:24]([N:23]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([S:32](=[O:35])(=[O:34])[NH2:33])[CH:27]=4)[N:21]=[CH:20]3)=[C:15]2[CH:14]=1)=[O:12])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl.O.C(O)(C(F)(F)F)=O>>[NH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[S:36][C:16]2=[CH:17][CH:18]=[C:19]3[C:24]([N:23]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([S:32](=[O:34])(=[O:35])[NH2:33])[CH:27]=4)[N:21]=[CH:20]3)=[C:15]2[CH:14]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc2c(ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc32)s1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)c1cc2c(ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc32)s1
Reaction time: 8 h
Yield: 95 %

Procedure:
(2-{[2-(3-Sulfamoyl-phenylamino)-thieno[2,3-h]quinazoline-8-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester (138.1 mg, 0.25 mmol) was placed in a 50 mL florentine and cooled in an ice-bath. Premixed TFA/dichloromethane/water (1:4:0.1, 0.5 mL TFA) was added in one portion and the resultant suspension was stirred at 0° C. for 35 minutes. After a further 1.75 hours at room temperature the solution was concentrated under reduced pressure to give a yellow solid. This solid was azeotroped with dichloromethane (3×10 mL), triturated with diethyl ether and isolated by filtration. The solid collected was washed with diethyl ether (3×5 mL) and pentane (3×5 mL) and placed in a drying pistol at 40° C. overnight giving a yellow powder (145.5 mg, 95% yield containing ˜1.5 eq. TFA). MS (ES+) 442. δH (d6 DMSO) 3.0-3.1 (2H, m), 3.5-3.7 (2H, m), 7.3-7.4 (2H, br s), 7.5 (1H, m), 7.6 m), 7.8-8.1 (5H, m), 8.2-8.3 (1H, m), 8.7-8.9 (3H, m), 9.4 (1H, s), 10.5 (1H, s).
Reaction SMILES: C([N:8]1[CH:12]2[CH:13]3[N:17]([CH:18]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:19]4[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=4)[CH:16]([CH:9]1[CH2:10][CH2:11]2)[CH2:15][CH2:14]3)C1C=CC=CC=1.C(N1C2C3N(C(C4C=CC=C(OC)C=4)C4C=CC(C(N(CC)CC)=O)=CC=4)C(CC2)C1CC3)C1C=CC=CC=1>>[CH:13]12[CH2:11][CH2:10][CH:9]3[CH:16]([CH2:15][CH2:14][CH:12]1[NH:8]3)[N:17]2[CH:18]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)[C:19]1[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[O:24])=[CH:21][CH:20]=1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC2C2CCC3N2Cc2ccccc2)cc1
Agent: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC4C2CCC3N4Cc2ccccc2)cc1
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC4NC3CCC42)cc1
Yield: 90 %

Procedure:
The same procedure of Example 5.1 was repeated, but using instead of the compound prepared in Example 4.1 the compound 4-[(7-benzyl-2,7-diazatricyclo[4.4.0.03,8]dec-2-yl)-(3-methoxy-phenyl)methyl]-N,N-diethyl benzamide of Example 4.5. The compound 4-[(2,7-diazatricyclo[4.4.0.03,8]dec-2-yl)-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide was obtained. Yield: 90%. IR (nujol) (λ=cm−1) 1670 (C═O), 3100 (NH); 1H-NMR (CDCl3) δ 1.00-1.40 (m, 6H); 1.90-2.50 (m, 10H); 2.90-3.00 (m, 2H); 3.10-3.30 (m, 2H); 3.40-3.60 (m, 2H); 3.96 (s, 3H); 4.95 (s, 1H); 6.65-6.85 (m, 1H); 7.00-7.40 (m, 5H); 7.48 (d, 2H, J=6.0 Hz). Anal. calc. for C27H35N3O2: C, 74.79; H, 8.14; N, 9.69. Found: C, 74.81; H, 8.11; N, 9.68.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[NH:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9][C:8]([Cl:18])=[CH:7][CH:6]=2.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[Cl:18][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:19])[C:2]([NH:1][C:29]([NH:28][C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[F:20])=[O:30])=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1F)Nc1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A mixture of 3-amino-6-chloro-4-phenyl-2(1H)-quinolone (160 mg), 2,4-difluorophenylisocyanate (0.09 ml) and anhydrous tetrahydrofuran (2 ml) was allowed to stand overnight at room temperature. The precipitated crystals were collected and recrystallized from dimethylformamide containing water to give colorless needles of N-(6-chloro-1,2-dihydro-2-oxo-4-phenyl-3-quinolyl)-N'-(2,4-difluorophenyl)urea (185 mg, 73.4%). mp 222°-224° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccc(C(F)(F)F)cc1
Yield: 61 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 4-(trifluoromethyl)benzoyl chloride to afford the title compound as a brown solid (33 mg, 61%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.93 (d, 1H, Harom, J=7.0 Hz), 7.44 (t, 1H, Harom, J=8.0 Hz), 7.63 (s, 1H, Harom), 7.64-7.68 (m, 1H, Harom), 7.82 (d, 1H, HPy,6, J=6.0 Hz), 7.91 (d, 2H, Harom, J=8.0 Hz), 8.12 (d, 2H, Harom, J=8.0 Hz), 10.55 (s, 1H, NHamide), 11.20 (s, 1H, NHPy3), 11.38 (s, 1H, NHPy2).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:14](=[O:24])[NH:15][C:16]2([C:19]3[N:20]=[CH:21][O:22][CH:23]=3)[CH2:18][CH2:17]2)[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[O:22]1[CH:23]=[C:19]([C:16]2([NH:15][C:14]([C:11]3([NH2:10])[CH2:13][CH2:12]3)=[O:24])[CH2:18][CH2:17]2)[N:20]=[CH:21]1
Reactant: O=C(NC1(C(=O)NC2(c3cocn3)CC2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1(C(=O)NC2(c3cocn3)CC2)CC1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
[1-(1-oxazol-4-yl-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid benzyl ester (70 mg, 0.21 mmol) was dissolved in MeOH (10 ml), followed by the addition of 10% Pd/C (35 mg). The solution mixture was stirred under H2 balloon for 1 h. The reaction mixture was filtered through celite. The solvent was concentrated under high vacuum pump to afford 42 mg of 1-amino-cyclopropanecarboxylic acid (1-oxazol-4-yl-cyclopropyl)-amide as a off-white solid product, m/z 208.8 [M+1]+.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([Br:18])[C:15]([OH:19])=[C:14]([Br:20])[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4].Br[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28]>>[Br:18][C:16]1[CH:17]=[C:12]([C:10]([C:9]2[C:8]3[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=3[O:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[O:11])[CH:13]=[C:14]([Br:20])[C:15]=1[O:19][CH2:26][C:27]([OH:29])=[O:28]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(Br)c(O)c(Br)c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(Br)c(OCC(=O)O)c(Br)c1

Procedure:
This compound was prepared from (2-butyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone and tert-butyl bromoacetate in substantially the same manner, as described in Example 2, and was obtained as an off-white solid, mp 92-94° C.; MS m/e 508 (M+);
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[N:22]([C:23]([CH3:25])=[CH2:24])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=1)(C1C=CC(C)=CC=1)(=O)=O.[SH:30][C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1.C(N(CC)CC)C.O>C(#N)C>[N:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[NH:35][C:31]=1[S:30][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[N:22]([C:23]([CH3:25])=[CH2:24])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: C=C(C)n1c(OCCCCCOS(=O)(=O)c2ccc(C)cc2)nc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: C=C(C)n1c(OCCCCCSc2nc3ccccc3[nH]2)nc2ccccc21
Temperature: 25 °C
Yield: 71.4 %

Procedure:
0.415 g of the compound obtained in Example 14b and 0.15 g of 2-mercaptobenzimidazole were refluxed for 5 hours in 10 ml of acetonitrile solvent containing 0.15 g of triethylamine. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.28 g of the title compound (yield: 71%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]1([CH2:17][CH3:18])[CH3:16])=[O:8].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[C:25]=1[Cl:33]>C1COCC1>[C:19]([C:4]1[S:3][C:2]([NH:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[C:25]=2[Cl:33])=[O:32])=[C:6]([C:7]([N:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]2([CH2:17][CH3:18])[CH3:16])=[O:8])[CH:5]=1)([CH3:21])([CH3:20])[CH3:22]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CCC1(C)C(=O)NCCN1C(=O)c1cc(C(C)(C)C)sc1N
Solvent: C1CCOC1
Product: CCC1(C)C(=O)NCCN1C(=O)c1cc(C(C)(C)C)sc1NC(=O)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To 4-(2-amino-5-tert-butylthiophene-3-carbonyl)-3-ethyl-3-methylpiperazin-2-one (72.0 mg, 0.22 mmol) in THF (2 mL) was added 1,2-dichloro-3-isocyanatobenzene (50.0 mg, 0.27 mmol). The resulting reaction mixture was stirred at room temperature and the reaction progress monitored by SFC-MS. When the reaction was completed, solvent was removed under reduced pressure and the crude product purified by preparative TLC to afford 1-(5-tert-butyl-3-(2-ethyl-2-methyl-3-oxopiperazine-1-carbonyl)thiophen-2-yl)-3-(2,3-dichlorophenyl)urea (50 mg, 44%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 9.93 (s, 1H), 9.52 (s, 1H), 8.10 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.26-7.22 (m, 2H), 6.46 (s, 1H), 3.62-3.58 (m, 1H), 3.40-3.35 (m, 1H), 3.30-3.23 (m, 1H), 3.19-3.13 (m, 1H), 2.65-2.61 (m, 1H), 1.89-1.85 (m, 1H), 1.58 (s, 3H), 1.22 (s, 9H), 0.69 (t, J=7.4 Hz, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([OH:30])=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.[H-].[Na+].I[CH2:37][CH3:38].O>CN(C)C=O>[CH2:37]([O:30][C:20]1[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][N:18]([CH2:17][C:16]2[CH:31]=[CH:32][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:33])=[CH:14][CH:15]=2)[N:19]=1)[CH3:38]
Reactant: CCI
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-hydroxy-1H-pyrazol-4-yl]propionate (452 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 40.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodoethane (0.240 ml) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (348 mg, yield: 73%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([B:18]([OH:21])[OH:19])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COB(OC)OC
Reactant: COc1ccc2ccccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cc2ccccc2cc1B(O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
Under a nitrogen atmosphere, 15.0 g (94.9 mmol) of 2-methoxynaphthalene was dissolved in tetrahydrofuran (300 ml), and the solution was cooled to 0° C. After that, 238 mL (1.6-mol/L solution, 190 mmol) of normal butyllithium were slowly dropped to the solution. After the dropping, the mixture was stirred at 0° C. for 2 hours. After that, the mixture was cooled to −10° C., and 33 mL (340 mmol) of trimethyl borate was dropped over 10 minutes to the mixture. The resultant was heated to room temperature, and was stirred overnight. After that, 0.2N hydrochloric acid was added to the resultant to stop the reaction. Chloroform was added to the resultant to separate an organic layer, and the layer was washed with a saturated aqueous solution of ammonium chloride once and with water four times. After that, the solvent was removed by distillation, and heptane and toluene were added to the resultant residue to purify the residue by recrystallization, whereby 4.81 g of Intermediate Compound 6 were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:51]=[CH:50][CH:49]=[CH:48][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[N:16]([CH:31]=[N:32][NH:33][C:34](=O)[CH2:35][N:36]1[C:44](=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]1=[O:46])C(=O)CN1C(=O)C2C(=CC=CC=2)C1=O)=[O:5].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:51]=[CH:50][CH:49]=[CH:48][C:3]=1[C:4](=[O:5])[C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[N:16]1[CH:31]=[N:32][N:33]=[C:34]1[CH2:35][N:36]1[C:44](=[O:45])[C:43]2=[CH:42][CH:41]=[CH:40][CH:39]=[C:38]2[C:37]1=[O:46]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1Cl)c1cc(C(F)(F)F)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 7, 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-(trifluoromethyl)phenyl]-1,3-dioxo-2-isoindolineacetamido]methylene] hydrazide is heated to 100°-110°C. with trifluoroacetic acid to give 2'-chloro-5-trifluoromethyl-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [Cl:1][CH2:2][CH2:3]/[C:4](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5](/[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C([O-])(=O)C.[Na+]>C(O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][NH:18][C:15]1[CH:14]=[CH:13][C:12](/[C:5](/[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:4](\[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH2:3][CH2:2][Cl:1])=[CH:17][CH:16]=1)[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1

Procedure:
(Z)-4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenylamine (2.0 g, 5.99 mmol), ethanol (30 ml), ethyl bromoacetate (2.5 g, 15 mmol) and sodium acetate (2.4 g, 17.9 mmol) are added to the reaction vessel and refluxed for three hours. Then the solvent is evaporated and the residue is dissolved in water and ethyl acetate. Ethyl acetate phase is dried and evaporated to dryness. Yield 2.9 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]([O:11]C)=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH-].[Na+:14]>CO>[CH3:1][O:2][C:3]1[C:4]([C:9]([O-:11])=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[Na+:14]
Reactant: COC(=O)c1ncccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccnc1C(=O)[O-]
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 3-methoxypyridine-2-carboxylate (Intermediate 95, 0.55 g, 3.3 mmol) in methanol (10 ml) was added dropwise aqueous sodium hydroxide solution (1M, 4 ml, 4 mmol). The mixture was left to stand overnight. The mixture was concentrated under vacuum to give a white solid, which was used without further purification or characterisation.