Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][OH:14].[H-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:14][CH2:13][CH2:12][O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COCCO
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice-cooled solution of 4-bromobenzyl bromide (3.00 g) and 2-methoxyethanol (1.04 ml) in tetrahydrofuran (30 ml) was added sodium hydride (60%) (0.58 g) in a stream of nitrogen. The mixture was stirred at this temperature for 15 minutes and at room temperature for further 4 hours. To the mixture was added water (1 ml) under ice-cooling. The reaction mixture was diluted with ethyl acetate and washed successively with water and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 1-bromo-4-(2-methoxyethoxymethyl)benzene (3.10 g) as a pale yellow oil.
Reaction SMILES: Cl.[C:2]1([C:8]2[C:12]3=[C:13]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]=[N:15][CH:16]=[C:11]3[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([C:31]2[CH:35]=[C:34]([CH:36]=O)[O:33][N:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:2]1([C:8]2[C:12]3=[C:13]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:36][C:34]5[O:33][N:32]=[C:31]([C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=6)[CH:35]=5)[CH2:21][CH2:20]4)[N:14]=[N:15][CH:16]=[C:11]3[O:10][N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(-c2ccccc2)no1
Reactant: c1ccc(-c2noc3cnnc(NCC4CCNCC4)c23)cc1
Agent: Cl
Product: c1ccc(-c2cc(CN3CCC(CNc4nncc5onc(-c6ccccc6)c45)CC3)on2)cc1

Procedure:
According to the same procedure described in Example 35, using the compound obtained in Example 84 instead of the compound obtained in Example 11 and the aldehyde obtained in Example 7 instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: [N:1]1([C:5]([C@@H:7]2[CH2:12][C@H:11]([N:13]([C:18]([C:20]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]4[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:22]=4[N:21]=3)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCCl>[N:1]1([C:5]([C@H:7]2[CH2:8][NH:9][CH2:10][C@@H:11]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([C:20]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]4[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:22]=4[N:21]=3)=[O:19])[CH2:12]2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCC3)CN(C(=O)OC(C)(C)C)C2)nc2cc(F)c(F)cc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCC3)C2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To tert-butyl (3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[{[5,6-difluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (270 mg) in 1,2-dichloroethane (3 ml) was added TFA (5 ml) and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate-water, and neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, fumaric acid (23 mg) was added, and the solvent was evaporated under reduced pressure to give the object product (210 mg).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH2:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH2:14][CH2:13]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(OS(=O)(=O)c2ccccc2)CC1
Reaction time: 0.25 h
Yield: 77 %

Procedure:
Triethylamine (17 ml) was added dropwise to a solution of benzyl 4-hydroxy-1-piperidinecarboxylate (28.83 g) in dichloromethane (100 ml) at 0° C. and stirred for 15 minutes. Benzenesulfonyl chloride (14 ml) was added and the reaction allowed to stir at room temperature for 48 h. The mixture was washed with water (50 ml), saturated sodium bicarbonate solution (50 ml), water (50 ml) and brine (50 ml) then dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by chromatography (SiO2, 20% ethyl acetate in hexane to 30% ethyl acetate in hexane) to give the title compound (31.88 g, 77%) as a white crystalline solid.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Reactant: ClCc1ccccc1
Product: O=c1c2ccccc2nc2n(Cc3ccccc3)c3ccccc3n12

Procedure:
6-Benzylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and benzyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[N:12][N:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:12][N:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCCCCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(CSc2nnc(SCCCCC(=O)O)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
In 2 ml of 90% methanol was dissolved 0.20 g of ethyl 5-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]valerate obtained in Example 9 with heating at 60° C. Further 1.5 ml of a 1N aqueous sodium hydroxide solution was added to the solution followed by stirring at 60° C. for 30 minutes. An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution to fractionate. The aqueous phase was made acidic with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with, in sequence, water, a saturated aqueous sodium chloride solution and then water and, dried over anhydrous magnesium sulfate. The solvent was then distilled off to give 0.18 g of oily 5-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]valeric acid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[C:9]([CH3:14])[N:8]=1>[OH-].[Na+]>[Cl:6][C:7]1[N:8]=[C:9]([CH3:14])[N:10]=[C:11]([OH:2])[CH:12]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(O)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To stirred solution of 13M sulfuric acid (125 mL) at about 0° C., 4,6-dichloro-2-methylpyrimidine (20.0 g, 307 mmol) was added portion wise over about 30 min. The solution was then stirred at about 0° C. for about 1.5 h and the reaction was allowed to warm to ambient temperature over about 1.5 h. The reaction was allowed to stir at RT overnight. The acidic mixture was poured into stirred 6N sodium hydroxide (500 mL) in ice, maintaining the temperature <10° C. and stirred for about 10 min. The white solid was collected and washed with warm water to afford 6-chloro-2-methylpyrimidin-4-ol 40.2 g (91%) 1H NMR (400 MHz, DMSO) δ: 12.85 (brs, 1H), 6.34 (s, 1H), 2.30 (s, 3H). LC/MS (Table 1, Method d) Rt=0.74 min; MS m/z: 145.1 (M+H).
Reaction SMILES: C(C1N(CC2C=CC=CC=2Cl)[C:7](/C=C(\CC2C=CC=CC=2)/C(O)=O)=[C:8]([CH2:10][OH:11])N=1)CCC.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][OH:39])=[CH:36][CH:35]=1>>[C:10]([O:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1)(=[O:11])[CH:8]=[CH2:7]
Reactant: CCCCc1nc(CO)c(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Reactant: COc1ccc(CO)cc1
Product: C=CC(=O)OCc1ccc(OC)cc1

Procedure:
(E)-3-[2-n-Butyl-1-[(2-chlorophenyl)methyl]-4-hydroxymethyl-1H-imidazol-5-yl]-2-benzyl-2-propenoic acid, prepared as in Example 28, is esterified with p-methoxy-benzyl alcohol to give the p-methoxybenzyl propenoate. The 4-hydroxymethyl group is oxidized using Jones reagent in acetone and the ester is hydrolized using 10% sodium hydroxide to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].C([C:14]1(Br)[CH:18]([CH3:19])[O:17][C:15]1=[O:16])C>CN(C)C=O.[Cl-].[NH4+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:14]1[CH2:18][CH2:19][O:17][C:15]1=[O:16]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCC1(Br)C(=O)OC1C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1OCCC1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g of 2,4-Dichlorophenol was dissolved in 10 ml of N,N-dimethylformamide, and 0.27 g of 60% sodium hydride was added thereto under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 0.7 ml of Ethylα-bromo-β-butyrolactone was added to the mixture which was then stirred at room temperature for another 1 hour. The reaction solution was diluted with aqueous ammonium chloride, and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 1 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[N:13]([C:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:15]3[C:21](=[O:22])[N:20]([CH3:23])[C:19](=[O:24])[N:18]([CH3:25])[C:16]3=2)[CH2:12][CH2:11][CH:10]=1.C([O-])=O.[NH4+]>[Pd].CCO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:17]2[N:13]([C:14]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:15]3[C:21](=[O:22])[N:20]([CH3:23])[C:19](=[O:24])[N:18]([CH3:25])[C:16]3=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(c1cccc(F)c1F)=CCC3
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(c1cccc(F)c1F)CCC3
Temperature: 50 °C
Reaction time: 19 h

Procedure:
10-(2,3-Difluorophenyl)-1,3-dimethyl-5-phenyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (step 1,) (40 mg, 0.095 mmol), 10% wt. palladium on activated carbon (10 mg, 9.54 μmol) and ammonium formate (30.1 mg, 0.477 mmol) were suspended in EtOH (5 mL) and the mixture stirred at 50° C. for 19 hours, adding extra 10% wt. palladium on activated carbon (10 mg, 9.54 μmol) after 17 hours. The reaction mixture was cooled to RT and filtered through a Celite® (filter material) cartridge (10 g), rinsing the residues with MeOH. The filtrates were evaporated under reduced pressure. The residue was partitioned between DCM and water and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated under reduced pressure to afford the title product as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[C:14]([O-:16])=O.C(Cl)(=O)C(Cl)=O.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:14](=[O:16])[C:4]2[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=2[O:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(OC)c(C(=O)[O-])c1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC)c(C(=O)Nc2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
1-Ethyl 4-methoxyisophthalate (100 mg) obtained in step D of Example 1-2-1, and 2 μL of N,N-dimethylformamide were dissolved in 5 mL of dichloromethane, and the solution was cooled to 0° C. To this solution, 59 μL of oxalyl chloride was added little by little, and the mixture was stirred for 20 minutes at 0° C., followed by stirring the mixture for 16 hours at room temperature. The reaction mixture was distilled under reduced pressure, and dried to obtain a light yellow solid. This solid was dissolved in 3 mL of dichloromethane, and the solution was added to a solution of 63 mg of 4-chloroaniline and 234 μL of N,N-diisopropylethylamine dissolved in 2 mL of dichloromethane. The mixture was stirred for 3 hours at room temperature, and then dichloromethane was distilled off under reduced pressure. The resulting residue was purified by column chromatography (5 g of silica gel) using a 1:1 mixture of dichloromethane and n-hexane as an elution solvent, thereby obtaining 134 mg (94%) of ethyl N-(4-chlorophenyl)-4-methoxyisophthalamate.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[N:16]1([C:22]2[N:23]=[C:24]3[NH:32][C@H:31]([C:33]([F:36])([F:35])[F:34])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[CH:27]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:32]2[C:24]3=[N:23][C:22]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[CH:27][C:26](=[O:28])[N:25]3[CH2:29][CH2:30][C@H:31]2[C:33]([F:34])([F:35])[F:36])=[CH:10][CH:11]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1ccc(F)cc1
Temperature: 80 °C

Procedure:
0.536 g of caesium carbonate and 0.44 ml of 1-(bromomethyl)-4-fluorobenzene are added, under an argon atmosphere, to a solution of 300 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (Example 1e) in 3 ml of acetonitrile. The resulting mixture is then heated at 80° C. for 2 hours. The reaction mixture is then evaporated under reduced pressure and the residue obtained is then purified by silica chromatography (eluent: CH2Cl2/MeOH 98/02) so as to give 61 mg of (8S)-9-(4-fluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:7]([C:14]([O:16]CC)=[O:15])=[N:8][O:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:7]([C:14]([OH:16])=[O:15])=[N:8][O:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5]
Reactant: CCOC(=O)c1noc(C2CC2)c1C(=O)c1ccc(SC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ccc(C(=O)c2c(C(=O)O)noc2C2CC2)c(Cl)c1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Ethyl 4-(2-chloro-4-methylsulphenylbenzoyl]-5-cyclopropylisoxazole-3-carboxylate (2.4 g) was added to a stirred solution of sodium hydroxide (2.2 g) in ethanol and water while maintaining the temperature below 0° C. The mixture was stirred at below 0° C. for 2 hours. The mixture was carefully acidified to pH1 at 0° C. and the solid was filtered off and dried to give 4-(2-chloro-4-methylsulphenylbenzoyl)-5-cyclopropylisoxazole-3-carboxylic acid (2.1 g) as an off-white solid, m.p. 106°-108° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:38]4[CH:39]=[CH:40][C:35]([C:32]5[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=5)=[CH:36][CH:37]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4ccc(-c5ccccc5)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-biphenyl.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>CO>[ClH:12].[C:25]([NH:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:16]1[CH:10]=[C:11]([Cl:12])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1]1=[NH:2])(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1cccc(CN)c1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)Nc1cccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.70 g) and N-[3-(aminomethyl)phenyl]acetamide hydrochloride (1.20 g) in methanol (10 ml) was added triethylamine (1.66 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (10 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, and the aqueous layer was basified with 1N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.30 g).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[H-].[Na+].C(O[C:13]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1)=O)C>O1CCCC1>[CH:4]([C:3]1[N:7]=[C:13]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:1][N:2]=1)([CH3:6])[CH3:5]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CC(C)C(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1noc(C2CCC(=O)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A mixture of N-hydroxy-isobutyramidine (Intermediate 8; 500 mg, 4.9 mmol) and 4 Å molecular sieves in tetrahydrofuran (15 mL) was stirred for 30 min at room temperature. Sodium hydride (60% dispersion; 204 mg, 5.1 mmol) was added and the mixture was heated to 60° C. for 20 min, and then cooled to room temperature. A solution of 4-oxo-cyclo-hexanecarboxylic acid ethyl ester (TCI America, Portland, Oreg., USA; 1.67 g, 9.8 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was heated at reflux for 1 h and then cooled to room temperature and filtered. The solvent was evaporated and the residue was purified by flash chromatography, eluting with 1% methanol/dichloromethane to give 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexanone (630 mg, 62%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1.[CH3:20][O-:21].[Na+]>CN(C=O)C.CCOCC>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[N:6]=[N:7][C:2]([O:21][CH3:20])=[CH:3][C:4]=1[C:17]([OH:19])=[O:18]
Reactant: C[O-]
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(C(=O)O)c(Nc2ccc(I)cc2F)nn1
Temperature: 135 °C

Procedure:
To solid 6-chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid (34 mg, 0.09 mmol) in DMF was added NaOMe (0.43 mmol, 0.5 M in MeOH). The mixture was heated at 135° C. for 3 h. The mixture was diluted with ether and extracted with NaOH (1N). The aqueous layer was acidified by concentrated HCl. The desired product was precipitated and was collected by vacuum filtration. LC/MS [8.08 min; 390 (M+1)].
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2.O[Li].O>C1COCC1.O>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][NH:21][C:20]=1/[CH:19]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:8]#[C:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])[CH:17]=[CH:16][CH:15]=2
Reactant: COC(=O)CCCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCC(=O)O)c21

Procedure:
Using Method F above, (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynoic acid methyl ester (40 mg, 0.11 mmol) (from Example 7 above) was hydrolyzed with LiOH.H2O (92 mg, 2.19 mmol) in THF (3 mL) and water (3 mL) for 22 h yielding (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynoic acid. (Yield 31 mg, 81%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:19][CH2:20]Cl)[C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16].[NH:22]1[C:26]([NH2:27])=[CH:25][CH:24]=[N:23]1>>[CH3:13][C:11]1([CH3:14])[CH2:10][C:9]2[C:15]([CH3:16])=[C:5]([N:4]3[CH2:19][CH2:20][N:27]([C:26]4[CH:25]=[CH:24][NH:23][N:22]=4)[CH2:2][CH2:3]3)[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]=2[O:12]1
Reactant: Cc1c(C)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Reactant: Nc1ccn[nH]1
Product: Cc1c(C)c(N2CCN(c3cc[nH]n3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 13.5 %

Procedure:
By using N,N-bis(2-chloroethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (165 mg, 0.50 mmol) synthesized in Reference Example 146 and 1H-pyrazole-5-amine (59 mg, 0.60 mmol), the reaction was carried out in the same manner as Example 117 to obtain 23 mg of the title compound as a colorless solid (yield 12%).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18](=[O:19])[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][C:10]=2[CH:20]=1)=O.Cl>C(O)C>[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18](=[O:19])[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][C:10]=2[CH:20]=1
Reactant: CC(C)(C)C(=O)Nc1ccc2c(c1)CCc1ccsc1C2=O
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)CCc1ccsc1C2=O
Yield: 98.8 %

Procedure:
In ethanol (10 ml) was suspended 7-trimethylacetamido-4,5-dihydro-10H-benzo[5,6]cyclohepta[1,2-b]thiophen-10-one obtained in Reference Example 17 (0.40 g, 1.28 mmol), and 6N hydrochloric acid (5 ml) was added thereto, followed by heating under reflux for 6 hours. After the reaction was completed, ethanol was distilled off under reduced pressure, and the resulting mixture was adjusted to pH 10 with an aqueous solution of sodium hydroxide. The mixture was extracted with dichloromethane, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure to give 7-amino-4,5-dihydro-10H-benzo[5,6]cyclohepta[1,2-b]thiophen-10-one (0.29 g, 98.8%).