Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]C)=[O:34])[CH2:24][CH:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:24][CH:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCCCCN1CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)C(c2cccc(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(CCCCCC(=O)O)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of 180 mg of methyl 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]hexanoate in 2.0 mL of methanol was added 1.00 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring for 1 hour. It was neutralized by addition of 1.00 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 168 mg of 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]hexanoic acid. ESI+: 577
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:15]([OH:17])=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:19]([CH2:23][C@@H:24]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[NH2:25])([CH3:22])([CH3:21])[CH3:20].CN1CCOCC1>>[CH2:29]([O:28][C:26](=[O:27])[C@H:24]([CH2:23][C:19]([CH3:21])([CH3:20])[CH3:22])[NH:25][C:15](=[O:17])[C@@H:9]([CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Product: CC(C)(C)C[C@H](NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 97 %

Procedure:
N-(tert-Butoxycarbonyl)-3-tert-butyl-D-alanine (3.28 g, 13.4 mmol) and benzyl 3-tert-butyl-L-alaninate hydrochloride (4.0 g, 14.7 mmol; J. X. He, W. L. Cody, A. M. Doherty, J. Org. Chem. 1995, 60, 8262-8266) are reacted by general procedure 6 (in this case 5 equivalents of N-methylmorpholine). Aqueous workup results in 6.0 g of product (97% of theory). The product can be finally purified by preparative HPLC (method 16).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:26][C:25](C)([CH3:27])[CH2:24][C:23](C)(C)[CH2:22]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](OC)=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CC1[C:36](B(O)O)=[C:35](C)[O:34][N:33]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[C:21]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([CH3:17])=[N:33][O:34][C:35]=3[CH3:36])=[CH:11][CH:10]=2)[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:26][CH2:25][CH2:27][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1-c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 114.7 %

Procedure:
The procedure described for 202 was followed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.100 g, 0.28 mmol), PdCl2(PPh3)2, (0.020 g, 0.028 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (0.079 g, 0.56 mmol), Na2CO3 (0.060 g, 0.56 mmol), and THF/H2O (5 mL, 4:1). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 0.120 g (78%) of the title compound 206 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 9.28 (s, 1H), 7.28 (d, J=6.00 Hz, 2H), 7.18 (d, J=6.0 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.67 (d, J=6.3 Hz, 2H), 2.37 (s, 3H), 2.23-2.22 (br, m, s, 4H), 1.52 (br s, 8H). LCMS (ESI): m/z 372 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:38][CH2:37][C:11]2[N:12]=[C:13]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]3)[N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[Cl:25])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:38][CH2:37][C:11]2[N:12]=[C:13]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]3)[N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[Cl:25])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(c2nc3c(c(NCc4ccc(F)cc4Cl)n2)CN(C(=O)OC(C)(C)C)CC3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(N3CCC(C(=O)O)CC3)nc(NCc3ccc(F)cc3Cl)c2C1
Temperature: 65 °C
Yield: 62 %

Procedure:
Ethyl 1-[6-tert-butoxycarbonyl-4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]piperidine-4-carboxylate (9.16 g, 16.1 mmol) prepared according to Process Step 3 was dissolved in ethanol (300 mL), and the solution was mixed with an aqueous sodium hydroxide solution (1 mol/L, 32 mL), followed by stirring at 65° C. for sixteen hours. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was mixed with water and washed with diethyl ether. The aqueous layer was neutralized with diluted hydrochloric acid (1 mol/L, 35 mL), the precipitated crystals were collected by filtration and thereby yielded 1-[6-tert-butoxycarbonyl-4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]piperidine-4-carboxylic acid (3.94 g). The filtrate was extracted with dichloromethane, the organic layer was washed with brine, was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was mixed with diethyl ether for crystallization. The precipitated crystals were collected by filtration and thereby yielded crystals of the target compound (1.07 g, 5.01 g in total with the above-mentioned crystals, in a yield of 62%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](Cl)(Cl)[Cl:4].[C:9]([O:13]C=C)(C)(C)[CH3:10]>[Hg]>[Cl:4][C:3]([C:2]([F:8])([F:7])[F:1])=[CH:10][CH:9]=[O:13]
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Reactant: C=COC(C)(C)C
Agent: [Hg]
Product: O=CC=C(Cl)C(F)(F)F
Temperature: 40 °C
Yield: 60 %

Procedure:
A mixture of 1,1,1-trifluoro-2,2,2-trichloroethane and tert-butylvinyl ether in a 3:1 molar ratio is introduced to a jacketed photochemical reaction vessel. The mixture is irradiated using a medium-pressure mercury UV lamp so as to maintain the temperature of the mixture at about 35-45° C. for about 2 hours. The resultant reaction mixture is concentrated to remove volatiles and distilled to produce 3-chloro-4,4,4-trifluorobut-2-enal in a 60% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>C1C2C(CCCC2)CCC1.O>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccnc2)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])OS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCC2CCCCC2C1
Product: C1=C(c2cccnc2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A dispersion of 4.52 g (16.8 mmol) of 1'-benzyl-2',3',5',6'-tetrahydro-1'H-[3,4']bipyridinyl-4'-ol and 18 g (71 mmol) of potassium disulphate in 35 ml of decalin was stirred at 190° C. for 30 minutes. After cooling to room temperature the reaction mixure was dissolved in water and extracted twice with 50 ml of toluene each time. Subsequently, the aqueous phase was made alkaline with sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate phase was thereafter dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 98:2:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained 4.03 g (61% of theory) of 1'-benzyl-1',2',3',6'-tetrahydro-3,4'-bipyridine as a yellowish oil; MS: 250 (M)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C@@H:8]([C:16](N1[C@H](C)[C@H](C2C=CC=CC=2)OC1=O)=[O:17])[CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[OH:32]O>C1COCC1.O>[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:16]([OH:17])=[O:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reactant: OO
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ester 138 (2.65 g, 6.14 mmol) in 20 mL THF at 0° C. was added a precooled (0° C.) solution of LiOH monohydrate (1.0 g, 23.8 mmol) and hydrogen peroxide (30 wt % aqueous solution, 5.0 mL) in 10 mL H2O. The mixture was stirred vigorously for 90 minutes, then warmed to ambient temperature and stirred 90 minutes. The reaction was quenched at 0° C. by addition of 100 mL 10% NaHSO3 (aq), then extracted with Et2O. The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. The crude acid 139 was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:12][S:11][C:10](=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]2[CH3:20])=[CH:4][C:3]=1[S:22]([N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)(=[O:24])=[O:23]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:20])[C:10](=[N:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22]([N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)(=[O:24])=[O:23]
Reactant: CN1CCN(S(=O)(=O)c2cc(C3(O)CSC(=Nc4ccccc4)N3C)ccc2Cl)CC1
Solvent: CC(=O)O
Product: CN1CCN(S(=O)(=O)c2cc(-c3csc(=Nc4ccccc4)n3C)ccc2Cl)CC1

Procedure:
Obtained by a procedure analogous to that indicated in Example 2(b), from 4-[4-chloro-3-(1-methyl-4-piperazinylsulfonyl)-phenyl]-3-methyl-2-phenyliminothiazolidin-4-ol, by boiling with glacial acetic acid and subsequently distilling off the solvent. Water is added to the residue and the pH is adjusted to 13 with 2 N NaOH. The crystals are filtered off and recrystallized from isopropanol. Melting point 156°-158° C.
Reaction SMILES: [C:1]([CH:9]1[C:13](=O)[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[C:10]1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:13]1[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[C:10]([CH3:21])[C:9]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CC1=NN(c2ccccc2)C(=O)C1C(=O)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nn(-c2ccccc2)c(Cl)c1C(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution containing 2.0 g of 4-benzoyl-3-methyl-1-phenyl-2-pyrazolin-5-one (commercially available e.g. Aldrich 15,660-4) in 4 ml of phosphorus oxychloride was stirred under nitrogen at 100° C. for 30 min. The mixture was poured into 40 ml of saturated sodium hydrogen carbonate solution and extracted three times with 30 ml of dichloromethane. Combined extracts were dried over magnesium sulphate, filtered and evaporated to give 2.0 g of (5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-phenyl-methanone as a yellow oil which was used without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.[C:17](Cl)(=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[CH3:15][C:14]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:4][NH:3][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Cc1c(CN)[nH]c2ccccc2c1=O
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCC(=O)NCc1[nH]c2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 69 %

Procedure:
To an ice-cold solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (160 mg) in pyridine (5 mL) was added heptanoic acid chloride (110 mg), and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure, and then water (40 mL) was added to the residue. The resulting solid was collected by filtration, washed with water, and dried. This solid was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]heptanamide (127 mg).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[N:9]=1)[C:2]([NH2:4])=[NH:3].Cl.[CH2:17]([OH:19])[CH3:18]>C(Cl)(Cl)Cl>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:15])[O:19][CH2:17][CH3:18])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N#CCCCCc1csc(NC(=N)N)n1
Reactant: CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)CCCCc1csc(NC(=N)N)n1
Reaction time: 2 h

Procedure:
2 g of 2-guanidino-4-(4-cyanobutyl)thiazole was suspended in a mixture of 15 ml of ethanol and 25 ml of chloroform, and hydrogen chloride gas was passed through the solution under stirring at -5° to 5° C. for 2 hours. The resulting solution was allowed to stand at 5° C. for 4 days and the solvent was distilled away under reduced pressure. The residue was suspended in ethanol, and the suspension was poured into ice water containing 15 g of potasium carbonate. The precipitated crystals were collected by filtration washed with water and ether to provide 2.1 g of ethyl 5-(2-guanidinothiazol-4-yl)pentanoimidate having a melting point of 138°-139° C. ##STR64##
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[N:10]=[CH:9][CH:8]=[N:7][C:6]=2[C:5](=[O:12])[CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:3]1=[O:23].N1C=CC=CC=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>ClCCl>[CH3:1][C:2]1([CH3:24])[C:11]2[N:10]=[CH:9][CH:8]=[N:7][C:6]=2[C:5]([O:12][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:3]1=[O:23]
Reactant: CC1(C)C(=O)C(c2ccccc2C(F)(F)F)C(=O)c2nccnc21
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)OC1=C(c2ccccc2C(F)(F)F)C(=O)C(C)(C)c2nccnc21
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a stirred solution of crude 8,8-dimethyl-6-(2-trifluoromethyl-phenyl)-8H-quinoxaline-5,7-dione (0.190 g) in dichloromethane (2.0 ml) at ambient temperature was added pyridine (0.054 g) followed by isobutryl chloride (isopropyl-C(O)—Cl, 0.064 g) and the reaction mixture stirred for 1 hour. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane) to give isobutyric acid 8,8-dimethyl-7-oxo-6-(2-trifluoromethyl-phenyl)-7,8-dihydro-quinoxalin-5-yl ester (compound F1 of Table F) (0.162 g).
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2].C1C(=O)N([Br:23])C(=O)C1>C1COCC1>[Br:23][C:7]1[CH:8]=[CH:9][N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a -78° C. solution under nitrogen of 1-triisopropylsilylpyrrole (2.8 g, 12.6 mmol) in THF (30 ml) was added NBS (2.23 g, 12.6 mmol) via a solid addition funnel. The reaction mixture was stirred at -78° C. for 1 hour and then was warmed to ambient temperature over 1 hour. The reaction mixture was concentrated, carbon tetrachloride was added to precipitate the succinimide and the solid was filtered and washed with carbon tetrachloride. The filtrate was concentrated, and the crude product was purified by flash chromatography (hexanes) to afford 3-bromo-1-triisopropylsilylpyrrole (3.18 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Cl)=[CH:39][CH:38]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:41][C:40]2[CH:43]=[CH:44][C:37]([F:36])=[CH:38][CH:39]=2)[CH:24]=1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: COc1ccc(N(Cc2cnn(Cc3ccc(F)cc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.56 g) and 4-fluorobenzyl chloride (0.172 mL) as starting materials, 5-benzyloxy-N-{[1-(4-fluorobenzyl)pyrazol-4-yl]methyl}-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.60 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 133, N-{[1-(4-fluorobenzyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) was obtained.
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[CH:40]=[CH:39][C:18]([CH2:19][O:20][C:21]2[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:22]=2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:40]=[CH:39][C:18]([CH2:19][O:20][C:21]2[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:23]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:22]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cc(CCC(=O)O)n(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of ethyl 3-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (950 mg), 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (4 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionic acid (770 mg, yield 81%), which was then recrystallized from acetone-hexane. melting point: 154–155° C.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23]>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([NH:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23])=[O:5]
Reactant: NC(=O)c1ccc(F)cc1N
Reactant: O=C(O)C(Br)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1ccc(F)cc1NC(=O)C(Br)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-2-(4-fluorophenyl)acetic acid (425 mg, 1.82 mmol) in DCM (5 mL) and DMF (0.05 mL) was added oxalyl chloride (0.17 mL, 1.91 mmol) and the solution was stirred for 0.75 h. The solution was then cooled to 0° C. and a solution of 2-amino-4-fluorobenzamide (267 mg, 1.73 mmol) in pyridine (1 mL) was added. The solution was stirred at rt for 1 h and then evaporated. The crude residue was partitioned between EtOAc and 2 N HCl. The EtOAc layer was evaporated to give 2-(2-bromo-2-(4-fluorophenyl)acetamido)-4-fluorobenzamide as a crude oil which was used without further purification. (420 mg, 62%). LC-MS (ESI) m/z 369 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O[C:14](=[C:21]1[S:25][C:24](=[O:26])[NH:23][C:22]1=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1NC(=O)C(=C(O)c2ccccc2)S1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)Oc1ccccc1C=C1SC(=O)NC1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
3,4-Dichlorophenylacetic acid was dissolved in SO2Cl2 followed by addition of a few drops of DMF. This resulting mixture was heated to 80 ° C for 15-30 min. followed by concentration of the reaction mixture under reduced pressure. The residue was dissolved in THF and slowly added to a solution of 5-(hydroxybenzylidene)thiazolidine-2,4-dione (1.5 eq.) and TEA (1.5 eq.) in THF. The resulting reaction was stirred for 1-2 h at which time the solid was filtered off and filtrate was concentrated under reduced pressure to yield light yellow solid. The solid was dissolved in EtOAc followed by washing with sat. aq. K2CO3. The organic phase was separated, and dried over Na2SO4 followed by concentration under reduced pressure to yield pure compound.
Reaction SMILES: C(OC(=O)C(OCC)CC1C=CC(O)=CC=1C)C.[CH2:19]([O:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29]1[O:30]C(C)=C(CCO)N=1)[CH3:20].C(I)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([O:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH:29]=[O:30])[CH3:20]
Reactant: CCOc1cc(F)ccc1-c1nc(CCO)c(C)o1
Agent: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOc1cc(F)ccc1C=O

Procedure:
In analogy to the procedure described in example 7 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 34 b]) was reacted with 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (prepared from 4-fluoro-2-hydroxy-benzaldehyde [J. Chem. Soc., Perkin Trans. 1 (1994), (13), 1823-31] by i) treatment with ethyl iodide, potassium carbonate in N,N-dimethylformamide to give 2-ethoxy-4-fluoro-benzaldehyde; ii) conversion of 2-ethoxy-4-fluoro-benzaldehyde into 4-chloromethyl-2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazole in analogy to the procedures described in examples 2 a] and b]; iii) conversion of 4-chloromethyl-2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazole into 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol by treatment with sodium cyanide in DMSO followed by hydrolysis of the nitrile function with sodium hydroxide in ethanol/water at reflux and reduction of the acid formed with BH3xTHF in tetrahydrofuran at room temperature) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid ethyl ester as light yellow liquid.