Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:3]=1.C(N(CC)CC)C.C(Cl)Cl>[Pd].CO>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cc1ccc(-c2nc(C)c(C)c(Cl)n2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ncc(C)c(C)n2)cc1
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A mixture of 4,5-dimethyl-6-chloro-2-(4-methylphenyl)pyrimidine (6.2 g), triethylamine (3.2), and palladium on carbon (200 mg) in 100 ml of methanol was stirred overnight under hydrogen. Methylene chloride was added, the solid filtered off through celite, and solvent removed from the filtrate under reduced pressure. Tetrahydrofuran was added to the residue, and triethylamine hydrochloride filtered off. Solvent was removed from the filtrate under reduced pressure, giving 4.4 g of 4,5-dimethyl-2-(4-methylphenyl)pyrimidine, m.p. 114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3Cl)[F:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[F:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(F)c4ccc(Cl)cc4Cl)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCC(F)c1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.5 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(2-(2,4-dichlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylate (0.161 g, 0.284 mmol) in 3:1 THF/ethanol (4 ml) was added sodium hydroxide (0.341 ml, 0.341 mmol), and the reaction was stirred for 3 days at ambient temperature. The reaction was concentrated, taken up in water, acidified with 1M hydrochloric acid, and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 121 mg of the title compound (79.7% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.CS[C:21]1[N:22](C(OCC)=O)[CH2:23][CH2:24][N:25]=1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)C>[NH:25]1[CH2:24][CH2:23][N:22]=[C:21]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCN=C1SC
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCN3)cc2)cs1
Temperature: 65 °C
Reaction time: 6 h
Yield: 48.8 %

Procedure:
A mixture of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (65 mg) prepared in a similar manner according to Step 6 of Production Example 1, ethyl 2-(methylsulfanyl)-4,5-dihydro-1H-imidazole-1-carboxylate (56 mg), acetic acid (0.1 ml), ethanol (0.9 ml) was stirred at 65° C. for 6 hours, and then refluxed for 5 hours. The reaction mixture was poured into ethyl acetate (5 ml) and saturated aqueous sodium bicarbonate. The precipitated solid was filtered, and the solid was dissolved in 50% methanol/chloroform. The insoluble materials were filtered off and the filtrate was concentrated in vacuo. The solid residue was collected and washed with ethyl acetate to give N-(4-{2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-ethyl}-1,3-thiazol-2-yl)acetamide (40 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[CH:13][C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:28].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[CH:13][C:14]([CH:21]=[O:28])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:24][CH:25]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C=Cc1cc(Cl)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-vinylbenzoate (0.12 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00 mL)-water (2.00 mL) were added osmium oxide (fixed catalyst I) (0.04 g) and sodium periodate (0.36 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])[CH:7]([F:9])[F:8]>N1C=CC=CC=1.ClCCCl>[F:5][C:6]([F:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([Cl:3])=[O:15])[CH:7]([F:9])[F:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(Cl)c1cccc(OC(F)(F)C(F)F)c1
Reaction time: 4 h
Yield: 95 %

Procedure:
203 parts by weight of thionyl chloride and 1 drop of pyridine are added to a mixture of 352 part by weight of 3-(1',1',2',2'-tetrafluoroethoxy)-benzoic acid in 900 parts by volume of 1,2-dichloroethane. After stirring the mixture for 4 hours under reflux and concentrating it under reduced pressure, 359 parts by weight (yield: 95% of theory) of 3-(1',1',2',2'-tetrafluoroethoxy)-benzoyl chloride, of nD 25 =1.4660, are obtained. The IR spectrum shows C=O bands at 1770 and 1748 cm-1, and fluoroalkoxy bands at 1225, 1190 and 1125 cm-1.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH2:17][CH2:18][OH:19])[CH2:16][CH2:15][CH2:14][CH:13]=1.N1C=CC=C[CH:21]=1>>[C:3]1([CH3:21])[C:4]([S:7]([O:19][CH2:18][CH2:17][C:12]2[CH2:16][CH2:15][CH2:14][CH:13]=2)(=[O:8])=[O:9])=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Reactant: OCCC1=CCCC1
Product: Cc1ccccc1S(=O)(=O)OCCC1=CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A para-toluenesulfonylchloride (3.81 g, 20 mmol) was added to the pyridine (30 ml) solution of 2-(cyclopent-1-en-1-yl)ethyl alcohol (2.24 g, 20 mmol) and then the reaction mixture was stirred at room temperature for 2 hrs. After the removement of pyridine, the residue was extracted with dichloromethane, washed with 1N HCl, dried, filtered and separated by column chromatography to give a desirable product (2.80 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH:25]=[C:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]=2[CH2:30][O:29][C:28]2[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][N:11]([CH2:23][CH2:24][CH:25]=[C:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[N:36][C:31]=4[CH2:30][O:29][C:28]4[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(C#N)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4-(4-chloro-phenyl)-piperidine-4-carbonitrile (180 mg, 0.8 mmol) in acetonitrile/water (4/1) was added potassium carbonate (221 mg, 1.6 mmol), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. Solvent was evaporated from the combined dried (MgSO4) organic extracts, and the residue was purified by column chromatography on silica gel using hexane-ethyl acetate (6:4) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:10][N:11]3[C:16](O)=[C:15]([CH3:18])[CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:37].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:37][C:16]1[N:11]2[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:12]2[N:13]=[CH:14][C:15]=1[CH3:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1Cl
Temperature: 100 °C
Yield: 96.2 %

Procedure:
To a slurry of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidin-7-ol (I-3A-1c; 119 mg, 0.321 mmol) and diisopropylethylamine (0.084 ml, 0.48 mmol) in toluene (2.2 ml) at room temperature was added POCl3 (0.15 ml, 1.61 mmol), dropwise. The mixture was heated at 100° C. for 22 hours, cooled to room temperature, then slowly added to a stirred mixture of ice, saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo, to afford the crude product (120 mg). Purification on a Biotage™ Flash 12M column using 0–8% ethyl acetate in hexanes as eluant afforded I-3A-1d (102 mg, 82%) as a yellow solid: +ESI MS (M+1) 388.1; 1H NMR (400 MHz, CD2Cl2) δ 8.44 (s, 1H), 7.55–7.37 (m, 6H), 7.27 (d, J=8.7 Hz, 2H), 2.51 (s, 3H).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:13]=O>O.O1CCCC1.CCOCC>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:13]=[N:2][OH:3]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: ON=Cc1ccc(Cl)c(Cl)c1
Temperature: 22 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A solution of hydroxylamine hydrochloride (2.73 g, 39.3 mmol) in water (35 ml) was treated with sodium acetate (2.74 g, 33.4 mmol) followed by a solution of 3,4-dichlorobenzaldehyde (4.0 g, 22.8 mmol) in tetrahydrofuran (15 ml) and the resulting mixture was stirred at 22° C. for 2 h. The reaction mixture was then diluted with ether (250 ml), washed with water, brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent gave 4.3 g of 3,4-dichlorobenzaldehyde oxime as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:26]=4[CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1ccc(C)c(C(=O)Cl)c1
Solvent: ClCCl
Product: Cc1ccc(C)c(C(=O)Nc2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c1
Yield: 64.2 %

Procedure:
As described for Example 9, 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz-[b,e]azepine is reacted with 0.303 g (1.8 mmol) of 2,5-dimethylbenzoyl chloride in 10 ml of dichloromethane. The product is recrystallized from dichloromethane-hexane to give 0.43 g of crystals, m.p. 213°-216° C. Anal. Calc'd for C30H26N2O2 : C,80.7; H,5.9; N,6.3. Found: C,80.0; H,5.9; N,6.1.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:10][CH:9]([N:11]([CH2:13][C@@H:14]2[C@@H:21]3[C@@H:17]([O:18][C:19]([CH3:23])([CH3:22])[O:20]3)[C@H:16]([N:24]3[CH:32]=[N:31][C:30]4[C:25]3=[N:26][CH:27]=[N:28][C:29]=4[NH2:33])[O:15]2)[CH3:12])[CH2:8]1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].O>CN(C=O)C>[N:34]([CH2:6][CH:7]1[CH2:8][CH:9]([N:11]([CH2:13][C@@H:14]2[C@H:21]3[O:20][C:19]([CH3:22])([CH3:23])[O:18][C@H:17]3[C@H:16]([N:24]3[CH:32]=[N:31][C:30]4[C:25]3=[N:26][CH:27]=[N:28][C:29]=4[NH2:33])[O:15]2)[CH3:12])[CH2:10]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(COS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CN=[N+]=[N-])C1
Temperature: 70 °C
Yield: 67.6 %

Procedure:
To a solution of (3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)methyl methane sulfonate (150 mg, 0.31 mmol) in DMF (3 ml) was added NaN3 (81 mg, 1.24 mmol). The mixture was heated at 70° C. for 3 h. Water (30 ml) was added and the mixture was extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by Prep-TLC (DCM:MeOH=30:1) to obtain the title compound (90 mg, Yield 67%). ESI-MS (m/z): 430.2 [M+1]+.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[N:15][C:14]=3[CH:26]=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:28]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:28]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][CH2:26][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[N:17]([CH3:18])[C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)[CH:38]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccccc1-c1nc(C=O)c(CCC23CC4CC(CC(C4)C2)C3)n1C
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccccc1-c1nc(CNc2cccc(C(=O)OCc3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 5-(2-adamantan-1-yl-ethyl)-1-methyl-2-o-tolyl-1H-imidazole-4-carbaldehyde (Example 275, step b) (500 mg, 1.38 mmol) and 3-amino-benzoic acid benzyl ester (313 mg, 1.38 mmol) in 1,2-dichloroethane (5 ml) were added sodium triacetoxyborohydride (409 mg, 1.93 mmol) and then acetic acid (79 μl, 1.38 mmol). The suspension was stirred at room temperature for 2 h, then saturated sodium bicarbonate (40 ml) was added. The product was extracted with ethyl acetate (40 ml), the organic phase was washed with brine (40 ml), dried (MgSO4) and the filtrate was evaporated. The residue was purified by flash column chromatography (silica, hexane/ethyl acetate 1:1) to afford the product (725 mg, 92%). 1H NMR (300 MHz, CDCl3) 7.44-7.23 (12H, m), 6.91 (1H, m), 5.36 (2H, s), 4.50 (1H, br s), 4.24 (2H, s), 3.33 (3H, s), 2.61 (2H, m), 2.20 (3H, s), 2.00 (3H, br s), 1.77-1.57 (12H, m), 1.31 (2H, m).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: COCOc1cc(OC)ccc1B(O)O
Reactant: CCCCn1cnc(C(=O)OCC)c1Br
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCn1cnc(C(=O)OCC)c1-c1ccc(OC)cc1OCOC
Yield: 44.7 %

Procedure:
A mixture of ethyl 5-bromo-1-n-butyl-1H-imidazole-4-carboxylate (0.10 g, 0.37 mmol), 2-methoxymethoxy-4-methoxyphenylboronic acid (0.16 g, 0.73 mmol), sodium carbonate (0.08 g, 0.73 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.04 g) in 12 mL of toluene/ethanol/water (10/1/1) was stirred at reflux for 24 h. After an aqueous work up, extracting with ethyl acetate (3×20 mL), the combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ethyl acetate/hexane) of the residue afforded the title compound as an oil (0.06 g, 46%). 1H NMR (250 MHz, CDCl3)δ 7.53 (s, 1H), 7.09 (d, 1H), 6.75 (d, 1H), 6.60 (dd, 1H), 5.05 (q, 2H), 4.21 (q, 2H), 3.85 (s, 3H) 3.80 (t, 2H), 3.30 (s, 3H) 1.60 (quintet, 2H), 1.30 (m, 5H), 0.80 (t, 3H).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].CCOCC.[N+:17]([O-])([OH:19])=[O:18]>O>[OH:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]=1[N+:17]([O-:19])=[O:18]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1c(O)ccc2c1CCCC2
Reaction time: 1 h
Yield: 32.6 %

Procedure:
5,6,7,8-Tetrahydro-2-naphthol (50 g, 0.337 mol) was mixed with ether (400 ml), and the mixture was added dropwise with 60% nitric acid (28 ml, 0.368 mol) while the reaction temperature was kept below 15° C. , and then stirring was continued at 15° to 20° C. for 1 hour. The reaction mixture was added with water (500 ml) and extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gell C-300: 900 g, eluent: hexane/ethyl acetate=50/1 to 60/1) to give 2-hydroxy-5,6,7,8-tetrahydro-1-nitronaphthalene (21.2 g).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)CC1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].[C:23](=O)([O-])[O-].[Li+].[Li+]>>[F:13][C:14]1[CH:21]=[C:20]([N:6]2[C@H:7]([CH3:23])[CH2:8][C@@:4]([OH:12])([CH3:1])[C@@H:5]2[CH3:9])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(F)cc1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1C[C@](C)(O)[C@H](C)N1c1ccc(C#N)c(F)c1

Procedure:
By an operation in the same manner as in Example 53 and using (2S,3S,5R)-2,3,5-trimethylpyrrolidin-3-ol 0.5 oxalate (93 mg), 2,4-difluorobenzonitrile (120 mg) and lithium carbonate (93 mg), the title compound was obtained as a colorless solid (yield: 76 mg, yield: 57%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([CH:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:40](=[O:53])[CH:41]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH2:42][CH2:43]C(F)(F)F)=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)C(NC(OC)=O)CC[O:60][CH2:61][C:62]([F:65])([F:64])[F:63]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([CH:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:40](=[O:53])[CH:41]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH2:42][CH2:43][O:60][CH2:61][C:62]([F:65])([F:64])[F:63])=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Reactant: COC(=O)NC(CCOCC(F)(F)F)C(=O)OC
Product: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Yield: 74 %

Procedure:
This compound was made in 74% yield by the same procedure as 2-[5-(4′-{2-[1-(5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester, using 2-Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy)-butyric acid methyl ester as the starting material. LCMS-ESI+: calculated for C39H46F3N7O6: 765.35; observed [M+1]+: 766.12.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:8]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1sc(N)c(C#N)c1C
Solvent: C1COCCO1
Product: Cc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (example 4b) (25 g, 164.5 mmol) in 1,4-dioxane (600 mL) was added benzoyl isocyanate (24.2 g, 164.5 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitate was collected by filtration, washed with 1,4-dioxane (20 mL×3), and dried under vacuum at 40° C. for 3 hours to give N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamoyl)benzamide (44.35 g, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.10 (s, 3H), 2.24 (s, 3H), 7.52-7.56 (m, 2H), 7.64-7.69 (m, 1H), 8.01-8.03 (m, 2H), 11.57 (brs, 1H), 12.05 (brs, 1H). MS 300 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][Zn+])#[N:32]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[C:33]([C:31]#[N:32])[CH:34]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: N#Cc1cccc(C[Zn+])c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3cccc(C#N)c3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-cyano-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6): tR=1.23 min; Mass spectrum (ESI+): m/z=508 [M+H]+.