Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([N:24]([CH2:27][CH3:28])CC)C.CO[CH2:31][CH2:32]O>C(OCC)(=O)C>[C:32]1([C@H:27]([NH:24][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:28])[CH:31]=[CH:9][CH:10]=[CH:3][CH:2]=1
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](Nc1ncnc2sc3c(c12)CCN(C(=O)OC(C)(C)C)C3)c1ccccc1
Temperature: 100 °C
Yield: 75 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (500 mg, 1.54 mmol) was dissolved in 2-methoxyethanol (5 mL), and (R)-methylbenzylamine (223 mg, 1.84 mmol) and triethylamine (621 mg, 6.14 mmol) were added. The mixture was heated to 100° C. for 2 h, then diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to yield 474 mg (75%) of the title compound.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[N+:12]([C:15]1[CH:21]=[CH:20][C:18](N)=[CH:17][CH:16]=1)([O-:14])=[O:13].NC1C=CC=CC=1>CC#N>[CH2:3]([C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[CH:1]=[CH2:2]
Reactant: CC(C)(C)ON=O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: Nc1ccccc1
Solvent: C=CCBr
Product: C=CCc1ccc([N+](=O)[O-])cc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (30 ml), 4-nitroaniline (414 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 34-36° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 35° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 23:2) gave 330 mg of 4-allylnitrobenzene as a light yellow oil containing 15% of 4-bromonitrobenzene. This corresponds to 55% yield of 4-allylnitrobenzene. 1H NMR (CDCl3, 300 MHz) δ 8.16, (m, 2H, J=8.6 Hz), 7.35, (m, 2H, J 8.6 Hz), 6.02-5.88, (m, 1H), 5.19-5.08, (m, 2H), 3.49, (d, 2H, J=6.6 Hz).
Reaction SMILES: [CH3:1][OH:2].N.[Si:4](OC)(OC)(OC)[O:5][CH3:6]>C(O)(C)C>[CH3:6][O-:5].[CH3:1][O-:2].[CH3:6][O-:5].[CH3:6][O-:5].[Si+4:4]
Reactant: CO[Si](OC)(OC)OC
Reactant: CO
Agent: N
Solvent: CC(C)O
Product: C[O-]
Product: [Si+4]
Temperature: 40 °C

Procedure:
The fine particles used were composite inorganic fine particles of silica and titania (average particle diameter: 100 nm). The fine particles were produced in the following manner according to the method disclosed in Production Example and Example of JP-A-7-2520. 140 g of methanol, 260 g of isopropanol and 100 g of aqueous ammonia (25% by weight) were charged in a 4-L glass reactor equipped with stirring blades to prepare a reaction solution, which was stirred while the temperature of the reaction solution was maintained to 40° C. 542 g of silicon tetramethoxide (Si(OMe)4, Methyl Silicate 39, a trade name, produced by Colcoat Co., Ltd.) was charged in a 3-L conical flask, and 195 g of methanol and 28 g of a 0.1% by weight aqueous solution of hydrochloric acid (obtained by diluting 35% hydrochloric acid, produced by Wako Pure Chemical Industries, Ltd. with water to 1/1,000) were added thereto under stirring, followed by further stirring for about 10 minutes. Subsequently, a solution obtained by diluting 300 g of titanium tetraisopropoxide (Ti(O-i-Pr)4, A-1 (TPT), a trade name, produced by Nippon Soda Co., Ltd.) with 634 g of isopropanol was added thereto to obtain a transparent uniform solution (copolycondensate of silicon tetraalkoxide and titanium tetraalkoxide). 1,699 g of the uniform solution and 480 g of aqueous ammonia (25% by weight) were simultaneously added dropwise to the aforementioned reaction solution over 2 hours at a small dropping rate in the initial stage, which was gradually increased toward the final stage. After completing the dropwise addition, the resulting cohydrolyzate was filtered and dried at 50° C. to remove the organic solvents, and it was then dispersed in water to obtain fine particles having a concentration of 10% by weight and a refractive index of 1.56.
Reaction SMILES: COCC[O:5][C:6](=[O:82])[C:7]1[CH:19]=[C:18]([NH:20][S:21]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[C:30]([S:34]([NH:37][C:38]2[CH:39]=[C:40]([C:51]([O:53]CCOC)=[O:52])[CH:41]=[C:42]([CH:50]=2)[C:43]([O:45]CCOC)=[O:44])(=[O:36])=[O:35])=[CH:29][C:28]([S:58]([NH:61][C:62]2[CH:63]=[C:64]([C:75]([O:77]CCOC)=[O:76])[CH:65]=[C:66]([CH:74]=2)[C:67]([O:69]CCOC)=[O:68])(=[O:60])=[O:59])=[CH:27]3)(=[O:23])=[O:22])[CH:17]=[C:9]([C:10]([O:12]CCOC)=[O:11])[CH:8]=1.[OH-].[Na+:84]>>[Na+:84].[Na+:84].[Na+:84].[Na+:84].[Na+:84].[Na+:84].[C:30]1([S:34]([NH:37][C:38]2[CH:39]=[C:40]([C:51]([O-:53])=[O:52])[CH:41]=[C:42]([CH:50]=2)[C:43]([O-:45])=[O:44])(=[O:35])=[O:36])[C:31]2[C:26](=[CH:25][C:24]([S:21]([NH:20][C:18]3[CH:17]=[C:9]([C:10]([O-:12])=[O:11])[CH:8]=[C:7]([CH:19]=3)[C:6]([O-:82])=[O:5])(=[O:22])=[O:23])=[CH:33][CH:32]=2)[CH:27]=[C:28]([S:58]([NH:61][C:62]2[CH:63]=[C:64]([C:75]([O-:77])=[O:76])[CH:65]=[C:66]([CH:74]=2)[C:67]([O-:69])=[O:68])(=[O:59])=[O:60])[CH:29]=1
Reactant: COCCOC(=O)c1cc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4cc(C(=O)OCCOC)cc(C(=O)OCCOC)c4)cc(S(=O)(=O)Nc4cc(C(=O)OCCOC)cc(C(=O)OCCOC)c4)cc3c2)cc(C(=O)OCCOC)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])c1cc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4cc(C(=O)[O-])cc(C(=O)[O-])c4)cc(S(=O)(=O)Nc4cc(C(=O)[O-])cc(C(=O)[O-])c4)cc3c2)cc(C(=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 9.05 g of the product of Example 3 and 45 ml of 2N sodium hydroxide is stirred at room temperature for 45 minutes. The solution is filtered, the filtrate is neutralized with 2.5 ml of glacial acetic acid, and diluted with 250 ml of ethanol. The product formed is collected by filtration, washed with ethanol followed by ether and dried to give 7.85 g of the product of the Example as a yellow powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[Br:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[C:33]([Br:32])[CH:34]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4cccc(Br)c4)c3)c2/C1=C/c1ccc[nH]1
Temperature: -70 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (50 mg, 0.148 mmol) (from Example 5 supra) and Et3N (41 μL , 0.296 mmol) in 3 mL of chloroform was cooled to −70° C. and then treated with 3-bromobenzoyl chloride (21 μL , 0.155 mmol) (Aldrich). The reaction mixture was stirred at −70° C. for 1 hr and then stirred at room temperature for 15 h. The reaction mixture was then concentrated in vacuo. The resulting yellow solid was suspended in water and collected by suction filtration to provide pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-3-bromobenzamide (yield: 70 mg, 98%) as a yellow solid (mp 251-253° C.).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]([F:60])([F:59])[C:14]1[CH:15]=[C:16]([C@H:24]([N:26]([CH3:58])[C:27]([N:29]2[CH2:49][CH2:48][C@:32]3([N:36]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[CH:35]([OH:47])[CH2:34][CH2:33]3)[CH2:31][C@@H:30]2[C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][C:51]=2[CH3:57])=[O:28])[CH3:25])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.O>C(Cl)Cl>[F:60][C:13]([F:12])([F:59])[C:14]1[CH:15]=[C:16]([C@H:24]([N:26]([CH3:58])[C:27]([N:29]2[CH2:49][CH2:48][C@:32]3([N:36]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[C:35](=[O:47])[CH2:34][CH2:33]3)[CH2:31][C@@H:30]2[C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][C:51]=2[CH3:57])=[O:28])[CH3:25])[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@]2(CCC(O)N2C(=O)OCc2ccccc2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CCC(=O)N2C(=O)OCc2ccccc2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a suspension of Pyridinium chlorochromate (PCC) (66.5 mg, 0.307 mmol) in DCM (2 ml) was added a solution of phenylmethyl (5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-hydroxy-1,8-diazaspiro[4.5]decane-1-carboxylate (Intermediate 32, 107 mg) in DCM (2 ml) and the reaction mixture was left stirring at it for 1 hr. Further pyridinium chlorochromate (PCC) (66.5 mg, 0.307 mmol) was added and the reaction mixture was left stirring overnight. To the mixture were added H2O and further DCM. The two phases were separated and the organic one was washed two times with water and filtered through a phase separator tube. The crude obtained after evaporation was purified by Flash Chromatography (20 g cartridge; eluting from 2:1 to 1:1 Cy:EtOAc). Relevant fractions were collected and the solvent removed in vacuo obtaining the title compound (86 mg) as a white solid; UPLC: Rt=0.95 mins, m/z=694 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O.C(Cl)Cl.C(N(CC)CC)C>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:26](=[O:27])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(NC(=O)Cc2ccccc2)n2oc(=O)nc2n1

Procedure:
4.5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 100 ml. of methylene chloride and 10 ml. of triethylamine. 4.8 ml. of phenylacetyl chloride in 30 ml. of methylene chloride are added dropwise while stirring and cooling. The mixture is then stirred at room temperature for 70 minutes, treated with water and adjusted to pH 4 with 3-N hydrochloric acid. The two phases are separated and the aqueous phase is extracted with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}-2-phenyl-acetamide having a melting point of 165°-167° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([Cl:32])=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>>[ClH:32].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:39]3[CH2:40][CH2:41][NH:36][C:37](=[O:42])[CH2:38]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(F)cc2)[C@@H](c2ccc(F)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(F)cc2)[C@@H](c2ccc(F)cc2)N1C(=O)N1CCNC(=O)C1
Product: Cl

Procedure:
4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12a) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 561.4 [(M+H)+]
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][NH:13][CH3:14].C(O)C.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:12][N:13]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:14]
Reactant: CNC
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8.67 h

Procedure:
To 426 mg of the colorless liquid (4-bromobutyl)benzene were added 1.05 ml of 50% dimethylamine aqueous solution and 1 ml of ethanol, and the mixture was stirred at a room temperature for 520 minutes. To the reaction mixture were added 30 ml of ethyl acetate and 10 ml of 5% sodium bicarbonate aqueous solution. The separated organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain a residue. To the residue was added 20 ml of benzene, then was washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain 287 mg of the title compound as colorless liquid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:16]=[CH:15][NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:11][C:12]1[N:16]=[CH:15][N:14]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[N:13]=1
Reactant: Cc1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 70 °C

Procedure:
A mixture of 4-fluoro-1-nitrobenzene (0.28 g, 2.0 mmol), 3-methyl-1H-1,2,4-triazole (0.18 g, 2.2 mmol), K2CO3 (0.55 g, 4.0 mmol) and DMF (2 mL) was heated at 70° C. overnight. The reaction mixture was cooled down to room temperature, diluted with water, extracted with EtOAc (3×). The organic solution was dried over anhydrous MgSO4 and concentrated in vacuo to provide a solid. Purification of this material by column chromatography on silica gel (40% EtOAc/hexane) provided 3-methyl-1-(4-nitrophenyl)-1H-1,2,4-triazole as the major product. 1H NMR (CDCl3, 400 MHz) δ 8.59 (s, 1H), 8.39 (d, 2H), 7.88 (d, 2H), 2.53 (s, 3H). Further elution with 65% EtOAc/hexane provided 5-methyl-1-(4-nitrophenyl)-1H-1,2,4-triazole as the minor product. 1H NMR (CDCl3, 400 MHz) δ 8.34 (d, 2H), 7.93 (s, 1H), 7.66 (d, 2H), 2.59 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=[O:12])[CH2:3]1.S(=O)(=O)(O)O.[CH3:19]O>CCC(O)(C)C>[CH3:19][O:12][C:11]([CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[CH2:3]1)=[O:13]
Reactant: O=C1CC(C(=O)O)c2ccccc21
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCC(C)(C)O
Product: COC(=O)C1CC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 10.0 g of 3-oxo-indan-1-carboxylic acid (56.8 mmol, 1.0 equivalent) and 0.25 mL of concentrated sulfuric acid in 20 mL of methanol was heated to a reflux for 4 hours. The reaction mixture was then cooled to room temperature and diluted with 100 mL of methyl-tert-butyl alcohol. The organic solution was washed twice with 60 mL of a saturated aqueous sodium bicarbonate solution, and once with 50 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The title compound crystallized as a white solid upon concentration, (10.4 g, 96%); mp: 46-47° C.; 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J=7.6 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 4.29 (dd, J=8.0, 3.4 Hz, 1H), 3.76 (s, 3H), 3.13 (dd, J=19.1, 3.4 Hz, 1H), 2.86 (dd, J=19.1, 8.0 Hz, 1H); 13C NMR (100 MHz, CD3OD): δ 204.4, 172.5, 151.3, 136.5, 135.2, 129.1, 126.7, 124.1, 52.9, 43.8, 39.7; IR (neat, cm−1): 2954, 1710, 1602, 1462, 1435, 1403, 1319, 1241, 1206, 1168, 1092, 1044, 1014, 986, 881, 837, 760, 686, 580, 538.
Reaction SMILES: C[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([C:13]([O:15]CC)=[O:14])[C:5]([C:8]([O:10]CC)=[O:9])=[N:6][CH:7]=1.C1(C2C=CN=C(C(OCC)=O)C=2C(OCC)=O)C=CC=CC=1>>[C:18]1([C:3]2[CH:2]=[CH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[C:4]=2[C:13]([OH:15])=[O:14])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ncc(C)c(-c2ccccc2)c1C(=O)OCC
Agent: CCOC(=O)c1nccc(-c2ccccc2)c1C(=O)OCC
Product: O=C(O)c1nccc(-c2ccccc2)c1C(=O)O

Procedure:
In place of diethyl 5-methyl-4-phenyl-2,3-pyridinedicarboxylate in Step 1 in Reference Example 33, diethyl 4-phenyl-2,3-pyridinedicarboxylate (see Japanese Patent Laid-Open No. 62-106081) was reacted and treated in the same manner as in Step 1 in Reference Exaple 33, to obtain 4-phenyl-2,3-pyridinedicarboxylic acid as pale yellow crystals. m.p. 146-148° C. (recrystallized from THF-isopropyl ether) NMR(200 MHz, CDCl3 +DMSO-d6) ppm: 7.3-7.6(6H,m), 8.69(1H,d,J=5.0 Hz)
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:30](=[O:40])[C@H:31]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH2:32])=[O:17])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N[C@@H](Cc1ccccc1)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 22 °C
Yield: 80.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (100 mg, 0.34 mmol, 1.0 eq), L-phenylalanine N-benzylamide (175 mg, 686 umol, 2.0 eq) and dichloromethane (1.0 mL), was cooled to 0° C., and treated with triethylamine (286 uL, 2.0 mmol, 6.0 eq). To this chilled solution was added a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (436 uL, 0.68 mL, 2.0 eq). When TLC indicated the reaction was complete, the solution was allowed to warm to 22° C., washed with satd aq NaHCO3, concentrated in vacuo, and purified by flash chromatography to provide 144 mg (80%) of L-phenylalanine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.O>CN(C=O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1nccc2ccccc12
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc(CN2CCN(c3nccc4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.6 %

Procedure:
A solution of 1-chloroisoquinoline (1.64 g 10 mmol) in dry DMF (5 ml) was added to a stirred solution of 1-benzylpiperazine (1.85 g, 10.5 mmol) and N,N-diisopropylethylamine (2 ml, 1.5 g, 11.5 mmol) in dry DMF (5 ml) under Ar at room temperature. The solution was stirred at room temperature for 17 h. The yellow solution was heated at 110° C. for 7 h, treated with water (100 ml) and extracted with ether (2×50 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (SiO2 ; ethyl acetate) to give the product (1.233 g).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=2)=[CH:7][CH:6]=1.N[C:21](N)=[S:22]>>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]3[NH:18][C:21](=[S:22])[NH:19][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Cc2ccc(N)c(N)c2)cc1
Reactant: NC(N)=S
Agent: Cl
Product: COc1ccc(Cc2ccc3[nH]c(=S)[nH]c3c2)cc1
Reaction time: 2 h

Procedure:
A mixture of 0.35 g (1.16 mmoles) of 4-[(4-methoxyphenyl)-methyl]-o-phenylene-diamine dihydrochloride and 0.286 g (3.76 mmoles) of thiourea are melted in an oil-bath at a temperature of 150°-160° C. and kept at the same temperature for 2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].[Br:26][C:27]1[CH:28]=[C:29]([F:36])[C:30]([CH2:34]Br)=[C:31]([F:33])[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:26][C:27]1[CH:28]=[C:29]([F:36])[C:30]([CH2:34][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:31]([F:33])[CH:32]=1
Reactant: Fc1cc(Br)cc(F)c1CBr
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(Br)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (1.5 g, 4.0 mmol, 1.0 eq), 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.37 g, 4.8 mmol, 1.2 eq) and potassium carbonate (830 mg, 6.0 mmol, 1.5 eq) in acetone (20 mL) was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated and purified by chromatography (silica, 0 to 60% EtOAc/Hex) to provide 2-(4-bromo-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (1.96 g (85%) as a beige solid: 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.27-7.20 (m, 1H), 7.10-7.00 (m, 2H), 6.93-6.82 (m, 2H), 6.51-6.44 (m, 2H), 6.42-6.32 (m, 2H), 4.59 (s, 2H), 3.81-3.76 (m, 3H), 1.55 (d, J=10.3 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([CH2:14][CH2:15][O:16][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC1=CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC2=CCN(Cc3ccccc3)CC2)cc1
Reaction time: 3 h

Procedure:
To a solution of 2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)ethanol (0.822 g, 4.09 mmol) (J. Med. Chem. 1990, 33, 3133) in dichloromethane was added p-toluene sulfonyl chloride (1.71 g, 9.00 mmol) and triethyl amine (2.3 mL, 16.4 mmol) and DMAP (0.050 g, 0.41 mmol) at room temperature and stirring continued at rt for 3 h. The reaction mixture was diluted with dichloromethane and washed with aq NaHCO3 (10% W/V) solution, followed by saturated NaCl solution. The organic layer was dried (Na2SO4), filtered and solvent was evaporated to dryness. The product was flash chromatographed over silica gel using gradient of 0-10% methanol in dichloromethane. 1H NMR (CDCl3) δ 7.77 (d, 8.4 Hz, 2H), 7.34-7.30 (m, 5H), 7.26 (m, 1H), 5.36 (m, 1H), 4.09 (t, J=6.8 Hz, 2H), 3.54 (s, 2H), 2.92-2.88 (m, 2H), 2.50 (t, J=5.6 Hz, 2H), 2.44 (s, 3H), 2.31 (brt, J=6.8 Hz, 2H), 2.20-1.84 (m, 2H).