Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[H][H].[C:11]([N:15]=[N:16][C:17](Cl)([CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:18])([CH3:14])([CH3:13])[CH3:12]>O1CCOCC1>[C:11]([N:15]=[N:16][C:17]([CH3:18])([O:7][CH2:6][CH2:5][CH2:4][CH2:3][O:8][C:17]([CH3:18])([N:16]=[N:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)CC(C)(Cl)N=NC(C)(C)C
Reactant: OCCCCO
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)CC(C)(N=NC(C)(C)C)OCCCCOC(C)(CC(C)C)N=NC(C)(C)C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a slurry of 1.98 grams (.047 moles) of sodium hydride in 50 ml. dioxane in a 100 ml. reaction flask equipped with a magnetic stirrer, thermometer, addition funnel, and gas bubbler, was added 2.11 grams (.0235 moles) of 1,4-butanediol. The reaction was followed by hydrogen evolution and it required over 8 hours to complete so the reaction was stirred overnight. The next morning, 9.59 grams (.047 moles) of 2-t-butylazo-2-chloro-4-methylpentane was added dropwise at room temperature to the stirred salt solution. After the addition was complete, the reaction was stirred 4 hours and then checked by gas chromatography. Gas chromatography indicated there was a small amount of unreacted 2-t-butylazo-2-chloro-4-methylpentane left so the reaction was allowed to stir overnight. The next day, the reaction mixture was poured into 200 mls. of cold water and extracted with pentane. The pentane solution was washed with H2O, dried over anhydrous sodium sulfate, filtered and the pentane evaporated to leave 9.3 grams (93% yield) of a straw yellow liquid. The crude product was purified by column chromatography over alumina, using pentane as the eluent. The infrared spectrum of the purified material was in agreement with the structure of the desired product.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13](=[O:16])([O-])[O-].[K+].[K+].[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22]>>[F:19][C:20]([F:24])([F:23])[CH2:21][O:22][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:16][CH2:13][C:20]([F:24])([F:23])[F:19])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: OCC(F)(F)F
Agent: [K+]
Product: Cc1cc(OCC(F)(F)F)c([N+](=O)[O-])c(OCC(F)(F)F)n1
Yield: 94 %

Procedure:
2,4-Dichloro-6-methyl-3-nitropyridine (30 g, 144.9 mmol) was dissolved in 2,2,2-trifluoroethanol (250 mL), followed by the addition of potassium carbonate (50 g, 361.8 mmol). The mixture was subjected to heating under reflux for 21 hours. The reaction mixture was extracted with chloroform-water. The organic layer was washed with a saturated aqueous solution of sodium chloride (brine), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (45.40 g, 94%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[C:28]([CH2:29]O)=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:17][CH:16]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[C:28]([CH2:29][C:31]#[N:33])=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CO)cn1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC#N)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a mixture of [2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]-3-pyridyl]methanol (2.55 g), triethylamine (1.27 g) and ethyl acetate (200 mL) was dropwise added methanesulfonyl chloride (1.44 g) under ice-cooling and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (30 mL) was added an aqueous solution (3 mL) of sodium cyanide (0.77 g) at room temperature and the mixture was stirred at room temperature for 15 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.85 g, 71%) of 2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 110-111° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:57])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:56])[CH:48]([NH2:55])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.[C:67](Cl)(=[O:70])[CH2:68][CH3:69]>C1COCC1>[CH3:1][O:2][C:3](=[O:57])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:56])[CH:48]([C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)[NH:55][C:67](=[O:70])[CH2:68][CH3:69])=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: CCC(=O)Cl
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(N)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
[1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.05 g, 0.057 mmol) was suspended in THF (0.572 mL). Upon addition of DIPEA (0.050 mL, 0.286 mmol), the slurry partially clarified. Propionyl chloride (0.005 mL, 0.057 mmol) was added at room temperature and the reaction was allowed to stir at room temperature overnight. Upon completion, the reaction was quenched with a small amount of formic acid and purified by reverse phase HPLC (10-45% acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving [2-Methyl-1-(2-{5-[6-(4-{2-[1-(2-phenyl-2-propionylamino-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.008 g, 17%) as a white solid. LCMS-ESI+: calc'd for C48H52N8O5: 820.41 (M+); Found: 821.51 (M+H+).
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[C:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])[CH3:13]>CO>[O:11]=[C:6]([CH2:13][C:12](=[O:14])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.7 %

Procedure:
Sodium methoxide (5.4 g, 100 mmol) and dimethyloxalate (11.8 g, 100 mmol) were dissolved in anhydrous methanol (700 mL) and stirred at room temperature under nitrogen until a suspension was formed. To this mixture, 3-acetylpyridine (5.5 mL, 50 mmol) was added and the stirring was continued for 3 days at room temperature. The reaction was quenched with enough 5% aqueous KHSO4 until all solids have dissolved. The methanol was removed under reduced pressure, and the residue was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (2×200 mL), brine and dried (NaSO4) followed by the removal of solvent under reduced pressure to give the title compound (8.67 g, 84% yield) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 9.21-9.20 (m, 1H), 8.84-8.82 (m, 1H), 8.30-8.26 (m, 1H), 7.50-7.45 (m, 1H), 7.08 (s, 1H), 3.96 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 188.5, 170.4, 162.2, 153.9, 149.0, 135.2, 130.5, 123.8, 98.0, 53.3. mass spectrum (APIMS) m/z 208 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][C:16]=1[N+:24]([O-:26])=[O:25]>CN(C)C=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:17][C:16]=1[N+:24]([O-:26])=[O:25]
Reactant: O=C=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(F)c([N+](=O)[O-])c2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate. 5.5 g of 4-fluoro-3-nitrophenyl isocyanate and 30 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)[P:54]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)C.N1C=NN=N1.ClC1C=CC=C(C(OO)=[O:86])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.ClCCl>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][P:54]([O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)([O:63][CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)=[O:86])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Reactant: CCN(CC)P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](OP(=O)(OCc2ccccc2)OCc2ccccc2)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: -45 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A solution of the compound of Example 1 (6.0 g, 8.32 mmol), dibenzyl diethylphosphoramidite (3.96 g), and 1H-tetrazole (2.63 g) in THF (100 mL) was stirred at room temperature for 4 hours. The mixture was cooled to −45° C., followed by dropwise addition of a solution of m-chlorperbenzoic acid (7.2 g) in dichloromethane (100 mL). The mixture was warmed to room temperature and stirred for 1 hour. A 10% solution of Na2S2O3 (100 mL) was added and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate and washed with 10% Na2S2O3 and saturated NaHCO3. The organic phase was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel, eluting with 2% methanol in dichloromethane containing 0.05% NH4OH, to give the title compound (6.2 g, 76% yield).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][C@H:35]([CH2:40][OH:41])[CH2:36][CH:37]([CH3:39])[CH3:38]>O1CCCC1.CC(C)=O>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:34][C@H:35]([CH2:40][OH:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)CO
Agent: CC(C)COC(=O)Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 58 %

Procedure:
A solution containing 2.49 g (10 mmol) N-carbobenzoxy-L-proline and 1.01 g (10 mmol) N-methylmorpholine in approximately 100 ml tetrahydrofuran (THF) was cooled to -20° under nitrogen, and 1.37 g (10 mmol) isobutyl chloroformate was added with magnetic stirring. After five minutes, a solution of 1.17 g (10 mmol) L-leucinol in 5 mL THF was added, and the resulting reaction mixture was stirred for 30 minutes at 0°. THF evaporated under vacuum, and 30 mL water and 100 mL ethyl acetate were added to the resulting residue. After separation of aqueous and organic layers, the organic layer was decanted and retained. The aqueous layer was extracted with a second aliquot (100 mL) of ethyl acetate, and the resulting organic phase was separated. The combined organic layers were washed with 50 mL of ice-cold, 5% aqueous citric acid, followed by 50 mL of an ice-cold, 5% sodium bicarbonate solution. An organic phase was separated, dried over anhydrous magnesium sulfate, and the ethyl acetate was evaporated to provide 3.25 g of crude product. Recrystallization from a mixture of 40 mL ethyl acetate and 25 mL n-hexane gave 2.03 g (5.8 mmol; 58%) of colorless N-carbobenzoxy-L-prolyl-L-leucinol, m.p. 95°-95.5°, α25D-72°, (C=1.03 g/100 mL acetone).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[OH:18][C@@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[S:28][C:29]([CH3:32])=[CH:30][N:31]=2)=[O:25])[CH2:20]1.ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[NH:13][N:14]=2)[N:3]=[C:2]([N:22]2[CH2:23][C@@H:19]([OH:18])[CH2:20][C@H:21]2[C:24]([NH:26][C:27]2[S:28][C:29]([CH3:32])=[CH:30][N:31]=2)=[O:25])[N:7]=1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: Cc1cnc(NC(=O)[C@@H]2C[C@H](O)CN2)s1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: Cc1cnc(NC(=O)[C@@H]2C[C@H](O)CN2c2nc(Cl)nc(Nc3cc(C4CC4)[nH]n3)n2)s1

Procedure:
96C was prepared from 1A and 96B as described for 1C. LC/MS [M+H]+: 462; Ret time (Method F): 2.53 min.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: Nc1cc([N+](=O)[O-])c(Br)cc1F
Temperature: 0 °C
Yield: 22.6 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (58.6 g) in conc. sulfuric acid (100 ml), there was dropwise added a mixture of conc. nitric acid (25.3 g) and conc. sulfuric acid (15 ml) at a temperature of 0° to -5° C. The resultant mixture was stirred at 0°-5° C. for 1 hour, poured into ice-water and extracted with toluene. The toluene layer was washed with water and an aqueous sodium hydrogen carbonate solution and concentrated. The residue was purified by silica gel chromatography to give 16.4 g of 4-bromo-2-fluoro-5-nitroaniline. M.P., 90°-92° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[C:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:34])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: CC(=O)c1ccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-acetylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]#N)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:23].Cl.[OH-:25].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[OH2:42]>O1CCOCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:23])[CH:4]=2)([C:21]([OH:42])=[O:25])[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: [OH-]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)c(F)c2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 43.96 %

Procedure:
Tert-butyl 4-(4-chloro-3-fluorophenyl)-4-cyanopiperidine-1-carboxylate (1.96 g, 5.785 mmol) was dissolved in concentrated HCl (48.21 mL, 578.5 mmol), heated to reflux, and then stirred over the weekend (approximately 60 hours). The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and washed with ether. The aqueous layer was concentrated on a rotary evaporator and dried on a high vacuum line. The resulting solids were dissolved in 10% NaOH (9.255 g, 23.14 mmol), dioxane (40 mL) was added, followed by a Boc2O addition (1.326 g, 6.074 mmol). The reaction mixture was stirred at room temperature overnight (16 hours). The reaction mixture was then diluted with H2O and washed with ether. The aqueous layer was acidified with solid KHSO4, and then extracted with DCM. The combined extracts were dried (Na2SO4), filtered, concentrated and dried on a high vacuum line to give 1-(tert-butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid (0.910 g, 43.96% yield) as a foam. LC/MS (APCI−) m/z 713 [2M−H]−.
Reaction SMILES: [CH:1]1([NH:7][CH:8](O)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17]([Cl:19])=[O:18].C(OCC)(=[O:29])C>>[ClH:19].[CH3:9][CH2:8][N:7]([C:15]1[C:14]([O:13][CH3:12])=[C:22]([O:23][CH3:24])[C:21]([O:25][CH3:26])=[CH:20][C:16]=1[C:17]([OH:29])=[O:18])[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)NC1CCCCC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CCOC(C)=O
Agent: Cl
Product: CCN(c1c(C(=O)O)cc(OC)c(OC)c1OC)C1CCCCC1
Reaction time: 8 h

Procedure:
2.86 g. of cyclohexylamino-ethanol are dissolved in 50 ml. of anhydrous ethyl acetate, whereupon gaseous hydrochloric acid is introduced until a pH value of 1 is reached. 4.61 g. of 3,4,5-trimethoxy-benzoyl chloride are added and the reaction mixture is refluxed under stirring for 8 hours. After cooling the precipitated crystalline mass is filtered by suction. 6.9 g. of N-2-ethyl-cyclohexylamino-3,4,5-trimethoxy-benzoate-hydrochloride are obtained. Mp.: 206°-208° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:24]([O:34][CH3:35])[CH:23]=3)[N:13]3[CH2:18][CH2:17][NH:16][C:15](=[O:19])[C:14]=23)=[CH:6][CH:5]=1.CI.O.[C:39](=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:24]([O:34][CH3:35])[CH:23]=3)[N:13]3[CH2:18][CH2:17][N:16]([CH3:39])[C:15](=[O:19])[C:14]=23)=[CH:8][CH:9]=1
Reactant: O=C([O-])O
Reactant: COc1cc(/C=C/c2nc(-c3ccc(F)cc3)c3n2CCNC3=O)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: COc1cc(/C=C/c2nc(-c3ccc(F)cc3)c3n2CCN(C)C3=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (containing mineral oil at 60%, 8 mg) was added to a solution of 1-(4-fluorophenyl)-3-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-6,7-dihydro-5H-imidazo[1,5-a]pyrazin-8-one (42 mg) in THE (3 mL), and the reaction solution was stirred at room temperature for 20 minutes. Methyl iodide (20 mg) was added to the reaction solution, and the reaction solution was stirred at room temperature for two hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 10 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([CH2:9]O)[CH:6]=[CH:7][CH:8]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.[CH3:17][C:18]1(C)[C:22](C)(C)OB(C2C=NNC=2)O1>>[CH3:17][C:18]1([CH3:22])[C@@H:4]2[CH2:3][C@H:8]1[CH2:7][CH2:6][C@H:5]2[CH2:9][N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: c1cn[nH]c1
Reactant: CN(C)c1cccc(CO)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC1(C)[C@@H]2CC[C@@H](Cn3cccn3)[C@H]1C2

Procedure:
The title compound was prepared by substituting ((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol for (3-(dimethylamino)phenyl)methanol and pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: [CH:1]1([NH:7][NH:8]C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[C:22]([C:23]([N:25]=[C:26]=[O:27])=O)=[C:21]([F:28])[C:20]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:21]([F:28])[C:22]=1[C:23]1[NH:25][C:26](=[O:27])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]=1
Reactant: CC(C)(C)OC(=O)NNC1CCCCC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(C3CCCCC3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(cyclohexyl)hydrazinecarboxylate (Intermediate-64, 0.050 g, 0.23 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.225 g, 0.70 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.015 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 1.13 (s, 9H), 1.22-1.23 (m, 2H), 1.30-1.37 (m, 2H), 1.62-1.64 (m, 2H), 1.78-1.81 (m, 4H), 3.90-3.92 (m, 1H), 4.27-4.28 (d, J=4.8 Hz, 2H), 7.37-7.41 (t, 1H), 7.46-7.48 (d, 1H), 8.17 (br s, 1H); MS (m/z): 409.36 (M+H+).