Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.C(Cl)Cl>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)Cl)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 27.0 g of 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid, 19.5 ml of oxalyl chloride and a few drops of N,N-dimethylformamide in 270 ml of methylene chloride was stirred at room temperature for 2 hours. The reaction mixture was evaporated to give 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride. Separately hand, to a suspension of 3.08 g of magnesium and a few drops of carbon tetrachloride in 6.4 ml of absolute ethanol, a solution of 19.2 ml of diethyl malonate in 12 ml of absolute ethanol was added dropwisely at 50° C. and then stirred at room temperature for 1.5 hours. The reaction mixture was evaporated, dissolved in toluene and then, evaporated again. To a solution of this residue in 30 ml of toluene, a solution of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride prepared above in 30 ml of toluene was added dropwise under ice cooling. After 2 hours at room temperature, 100 ml of 5% sulfuric acid was added to the reaction mixture and the resulting solution was extracted with diethyl ether. The combined organic extracts were washed with brine, dried and evaporated to give 47.3 g of the desired compound as brown oil.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[CH2:10]([CH:12]1[C:17](=[O:18])[NH:16][C:15]([CH3:19])=[CH:14][S:13]1)[CH3:11].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:10]([CH:12]1[C:17](=[O:18])[NH:16][C:15]([CH3:19])=[C:14]([CH:23]2[CH:24]=[CH:25][N:20]([C:5]([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])=[O:6])[CH:21]=[CH:22]2)[S:13]1)[CH3:11]
Reactant: CCC1SC=C(C)NC1=O
Reactant: c1ccncc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CCC1SC(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)=C(C)NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,2,2-Trichloroethylchloroformate (1.0 ml) was added dropwise to a solution of 2-ethyl-5-methyl-2H-1,4-thiazin-3(4H)-one (0.94 g) and pyridine (0.96 ml) in acetonitrile (30 ml) under ice-cooling, and the mixture was stirred at 0° C. for 30 minutes. Then the mixture was further stirred at ambient temperature for 18 hours. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate, was washed with water, 2N hydrochloric acid and water in the order named, and was dried over magnesium sulfate. The solvent was removed under reduced pressure to give 2-ethyl-5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (2.0 g) as pale yellow oily product.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH2:11][CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1.[Cl-:20].[NH4+:21]>CO>[ClH:20].[C:14]1([CH:13]=[CH:12][CH2:11][CH:9]2[NH:10][C:3](=[NH:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC1=NC(CC=Cc2ccccc2)CCCCC1
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: Cl
Product: N=C1CCCCCC(CC=Cc2ccccc2)N1

Procedure:
The title product of Example 69 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([S:14]([N:17]2[CH2:21][CH2:20][S:19][C@H:18]2[C:22]([O:24][C@H:25]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]3[CH2:50][CH2:49]3)[CH:37]=2)[CH2:26][C:27]2[C:32]([Cl:33])=[CH:31][N+:30]([O-:34])=[CH:29][C:28]=2[Cl:35])=[O:23])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:7].[CH:51]([C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56](O)=[O:57])=[O:52].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:35][C:28]1[CH:29]=[N+:30]([O-:34])[CH:31]=[C:32]([Cl:33])[C:27]=1[CH2:26][C@@H:25]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)[O:24][C:22]([C@H:18]1[N:17]([S:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6](=[O:7])[NH:5][CH2:4][CH2:3][NH:2][C:56](=[O:57])[C:55]3[CH:59]=[CH:60][CH:61]=[C:53]([CH:51]=[O:52])[CH:54]=3)[CH:9]=2)(=[O:15])=[O:16])[CH2:21][CH2:20][S:19]1)=[O:23]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: NCCNC(=O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=Cc1cccc(C(=O)NCCNC(=O)c2cccc(S(=O)(=O)N3CCS[C@H]3C(=O)O[C@@H](Cc3c(Cl)c[n+]([O-])cc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
4-((S)-2-((S)-3-(3-(2-Aminoethylcarbamoyl)phenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide hydrochloride (195 mg, 0.244 mmol), 3-formylbenzoic acid (110 mg, 0.733 mmol), DMAP (5.97 mg, 0.049 mmol) and EDC (141 mg, 0.733 mmol) were dissolved in DMF. The reaction was stirred at RT overnight to achieve completion. The reaction mixture was diluted with water, and the precipitate was washed with water, dissolved in DCM and extracted with water. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-(2-(3-formylbenzamido)ethylcarbamoyl)-phenylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (100 mg, 0.112 mmol, 45.8% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:33][CH2:32][CH2:31][CH2:30][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7].[CH:37]1([NH:40][CH:41]2[CH2:46][CH2:45][CH:44]([C:47]([O:49]CC)=[O:48])[CH2:43][CH2:42]2)[CH2:39][CH2:38]1>>[ClH:1].[ClH:1].[CH:37]1([N:40]([CH2:2][C:3]2[CH:36]=[CH:35][CH:34]=[C:5]([C:6](=[O:7])[NH:8][C:9]3[S:10][C:11]4[CH2:33][CH2:32][CH2:31][CH2:30][C:12]=4[C:13]=3[C:14](=[O:15])[NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH:4]=2)[CH:41]2[CH2:46][CH2:45][CH:44]([C:47]([OH:49])=[O:48])[CH2:43][CH2:42]2)[CH2:38][CH2:39]1
Reactant: O=C(Nc1sc2c(c1C(=O)Nc1ccc(Cc3ccncc3)cc1)CCCC2)c1cccc(CCl)c1
Reactant: CCOC(=O)C1CCC(NC2CC2)CC1
Product: Cl
Product: O=C(Nc1sc2c(c1C(=O)Nc1ccc(Cc3ccncc3)cc1)CCCC2)c1cccc(CN(C2CCC(C(=O)O)CC2)C2CC2)c1
Yield: 91.5 %

Procedure:
By using 400 mg of 2-{[3-(chloromethyl)benzoyl]amino}-N-[4-(pyridin-4-ylmethyl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide and 819 mg of ethyl 4-(cyclopropylamino)cyclohexanecarboxylate, the alkylation similar to Preparation Example 30 was performed, and then hydrolysis was performed under the conditions similar to Example 5, thereby obtaining 261 mg of 4-(cyclopropyl{3-[(3-{[4-(pyridin-4-ylmethyl)phenyl]carbamoyl}-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)carbamoyl]benzyl}amino)cyclohexane carboxylic acid dihydrochloride.
Reaction SMILES: CN(C=[O:5])C.[Br:6][C:7]1[C:8]([Cl:30])=[CH:9][C:10]([O:26][CH2:27][O:28][CH3:29])=[C:11]([CH:25]=1)[CH:12]([C:15]1[C:20]([O:21][CH2:22][O:23][CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=1)C#N.C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[C:8]([Cl:30])=[CH:9][C:10]([O:26][CH2:27][O:28][CH3:29])=[C:11]([CH:25]=1)[C:12]([C:15]1[C:20]([O:21][CH2:22][O:23][CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:5]
Reactant: COCOc1cc(Cl)c(Br)cc1C(C#N)c1ncccc1OCOC
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCOc1cc(Cl)c(Br)cc1C(=O)c1ncccc1OCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DMF (100 ml) was added to a mixture of 2-(5-bromo-4-chloro-α-cyano-2-methoxymethoxybenzyl)-3-methoxymethoxypyridine (10.1 g) and potassium carbonate (9.84 g). The mixture was stirred at room temperature overnight under oxygen atmosphere. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, dried (anhydrous magnesium sulfate), and concentrated. The concentrate was purified by a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 2-(5-bromo-4-chloro-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine (9.08 g, m.p. 70°-72° C.). The spectrum data are shown as follows:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH:5]=[N:4][CH:3]=[N:2]1.[H][H]>C(O)C.[C].[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(CCCn1cncn1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCCn1cncn1
Yield: 89.1 %

Procedure:
0.5 g of 5% palladium carbon was added to a solution of 11 g of benzyl 4-(1,2,4-triazol-1-yl)butyrate in 150 ml of ethanol. The mixture was stirred at a hydrogen pressure of 1 atm. at room temperature for 1 hour. Thereto was added 100 ml of ethanol. The mixture was heated and made uniform. Palladium carbon was collected by filtration and washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. To the residue was added a small amount of ethanol. The resulting insolubles were collected by filtration to obtain 6.2 g of 4-(1,2,4-triazol-1-yl)butyric acid as a white powder.
Reaction SMILES: [O:1]=[C:2]([NH:5][C:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9]CC)=O)[CH2:3][CH3:4].[H][H]>C(O)(=O)C.[Pt]=O>[O:9]=[C:7]1[C:6]([NH:5][C:2](=[O:1])[CH2:3][CH3:4])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:17][C:18]2=[CH:19][CH:20]=[CH:21][C:22]3=[C:27]2[N:26]1[CH2:25][CH2:24][CH2:23]3
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1cccc2cccnc12)(NC(=O)CC)C(=O)OCC
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)C1(NC(=O)CC)Cc2cccc3c2N(CCC3)C1=O
Yield: 77.8 %

Procedure:
A mixture of diethyl ((1-oxopropyl)amino)(8-quinolinylmethyl)propanedioate (17.47 g, 0.047 mol) and platinum oxide (0.72 g) in glacial acetic acid (150 mL) was hydrogenated (50 1b initial pressure) until hydrogen uptake ceased (1.8 equiv). The mixture was filtered through celite and the solvent removed under reduced pressure. The product was crystallized from ethyl acetate to give 12.08 g of crystals, mp 136°-140° C. A sample was recrystallized from ethyl acetate for analysis; mp 137°-141° C. Anal. Calc'd for C18H22N2O4 : C, 65.44; H, 6.71; N, 8.48. Found: C, 65.66; H, 6.64; N, 8.43.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17].Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: ClCCN1CCOCC1
Reactant: COCCCCOc1cc(O)ccc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COCCCCOc1cc(OCCN2CCOCC2)ccc1C(=O)OC
Yield: 102.4 %

Procedure:
A suspension of 4-hydroxy-2-(4-methoxybutoxy)-benzoic acid methyl ester (2.0 g), 2-chloroethylmorpholine (11.8 g) and caesium carbonate (12.8 g) in acetone (30 ml) is stirred under reflux for 2 hours. Filtration and purification by FC (80 g of silica gel, eluant F and ethyl acetate-conc. ammonia 10:0.1) yield 2-(4-methoxy butoxy)-4-(2-morpholin-4-ylethoxy)-benzoic acid methyl ester (2.96 g), Rf (N)=0.73, in the form of a pale-yellow oil.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:38]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:38].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1
Reactant: Cc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Agent: Cl
Product: Cc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Yield: 54 %

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4′-methylbenzyloxy]azetidine (150) (7.5 mmol) using the procedure described for compound (9). Crystallisation from DIPE-MeOH afforded the product as a white solid (1.39 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13]=[O:14].Cl>CS(C)=O.C[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Methyl 2-(4-chlorophenyl)acetate (36.7 g, 199 mmol) and paraformaldehyde (6.27 g, 209 mmol) were dissolved/suspended in DMSO (400 mL) and treated with NaOMe (537 mg, 9.94 mmol). The mixture was allowed to stir at room temperature for 2 hours to completion by TLC analysis of the crude. The reaction was poured into ice-cold water (700 mL; white emulsion) and neutralized with the addition of 1M HCl solution. The aqueous layer was extracted with ethyl acetate (3×), and the organics were combined. The organic layer was washed with water (2×), brine (1×), separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product as a yellow oil. The residue was loaded onto a large fritted filtered with silica gel and eluted with 9:1 hexanes:ethyl acetate until the starting material/olefin were collected. The plug was then eluted with 1:1 hexanes:ethyl acetate until the pure desired product was eluted completely. The concentrated pure fractions yielded methyl 2-(4-chlorophenyl)-3-hydroxypropanoate as a colorless oil (39.4 g, 92%).
Reaction SMILES: [C:1]([O:14][CH3:15])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:16][N:17]([CH:19](O)[CH2:20]CC)[CH3:18]>>[C:1]([O:14][CH2:15][CH2:20][CH2:19][N:17]([CH3:18])[CH3:16])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC(O)N(C)C
Reactant: CCCCCCCCCCCC(=O)OC
Product: CCCCCCCCCCCC(=O)OCCCN(C)C
Reaction time: 24 h
Yield: 67 %

Procedure:
To a 50-mL conical bottom plastic vial was added methyl laurate (38.5 mmol), dimethylaminobutanol (46.2 mmol, 1.2 eq), and Novozym 435 (400 mg). A syringe was inserted through the cap and two additional holes were punched for gas to exit. Nitrogen was bubbled at a rate sufficient to mix the contents. The vial was placed in a heating block set to 65° C. The reaction was monitored by GC/MS to observe the disappearance of starting material. The reaction was complete after approximately 24 hours. The reaction mixture was allowed to cool. The Novozym 435 was removed by filtration to afford the product as a pale, yellow oil (9.2 g; 67% yield) without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH:13]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:3]=1.C(N(CC)CC)C>CO.[C].[Pd]>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH:13]([C:4]2[CH:3]=[CH:2][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[OH:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:27][CH:26]=1
Reactant: O=C(O)CCCCCC(c1ccc(F)cc1)c1cc(Br)c2ccccc2c1O
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCC(c1ccc(F)cc1)c1ccc2ccccc2c1O
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a solution of 7-(4-bromo-1-hydroxy-2-naphthyl)-7-(4-fluorophenyl)heptanoic acid (1.70 g) in methanol (10 ml) were added 5% palladium-carbon (200 mg) and triethylamine (0.53 ml) and hydrogenation was carried out at room temperature for 1.5 hours. The catalyst was filtered off and the filtrate was distilled off at reduced pressure. The residue was extracted by addition of ethyl acetate and water. The ethyl acetate layer was washed with saturated saline and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by subjecting it to silica gel chromatography and eluting with ethyl acetate/hexane (1:2) to obtain 7-(4-fluorophenyl)-7-(1-hydroxy-2-naphthyl)heptanoic acid (930 mg) (Compound B-3). The physical properties and NMR spectrum data thereof are shown in Table 2.
Reaction SMILES: CN(C)C=O.[NH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([C:35]([F:38])([F:37])[F:36])[O:24][N:23]=[C:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([CH3:34])[CH:26]=3)[CH2:21]2)[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(OCC)(=O)C>CN(C)C(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([C:35]([F:37])([F:36])[F:38])[O:24][N:23]=[C:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:6][N:7]4[CH:11]=[CH:10][CH:9]=[N:8]4)=[O:30])=[C:27]([CH3:34])[CH:26]=3)[CH2:21]2)[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: Nn1cccn1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nn1cccn1

Procedure:
In 4 mL of N,N-dimethylacetamide, 0.23 g of 50% N,N-dimethylformamide solution of 1-aminopyrazole was added, and 0.30 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 2 hours. After the completion of the reaction, 20 mL of ethyl acetate was added in the reaction mixture, washed with water (20 mL×1), and then the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with neutral alumina column chromatography that was eluated with chloroform to obtain 0.22 g of the aimed product as yellow resinous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.ClC1C=C(C=CC=1Cl)CC1C=C(C(N)C(C)C)C=C[N:18]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[NH2:18])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)C(N)c1ccnc(Cc2ccc(Cl)c(Cl)c2)c1
Reactant: COc1cccc(N=C=O)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc(NC(N)=O)c1
Reaction time: 1 h

Procedure:
3-methoxyphenyl isocyanate (37 μl, 0.28 mmol) was added to a solution of provide 1(RS)-[(3,4-dichlorobenzyl)pyridin-4-yl]-2-methylpropylamine (88 mg, 0.28 mmol) in methylene chloride solution (2 ml) at room temperature. After 1 h, the reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution (5 ml). The organic layer was separated and dried over magnesium sulfate, filtered and concentrated to provide 1-{1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-2-methylpropyl)}-3-(3-methoxyphenyl)urea. (104 mg) as a white solid. mp 161.4-161.8° C.
Reaction SMILES: Cl[CH2:2][C:3]([Cl:5])=[O:4].[C:6]([OH:10])(=[O:9])[CH2:7]O.Cl.S(Cl)([Cl:14])=O>>[Cl:14][CH2:7][C:6]([O:10][CH2:2][C:3]([Cl:5])=[O:4])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CO
Reactant: O=C(Cl)CCl
Agent: Cl
Product: O=C(Cl)COC(=O)CCl

Procedure:
The reactant chloroacetoxyacetyl chloride was prepared by the following intermediate step. A solution was made by mixing 127 grams (g) of chloroacetyl chloride and 57 g of glycolic acid. This mixture was refluxed for two hours. When the evolution of hydrogen chloride ceased the mixture was stripped. The residue was then refluxed for two hours with thionyl chloride. The product was distilled under a water aspirator and fractioned between 105° and 115° C. A yield of 48 g (37%) was obtained. The structure was confirmed by IR, NMR, and mass spectrometry.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4ccc(F)cc43)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3ncc4ccc(F)cc43)nc12
Reaction time: 15 h
Yield: 42.1 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-fluoro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (101 mg, 209 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(6-Fluoro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (31 mg, 42%). MS (M+H)+=351; 1H NMR (DMSO-d6) δ: 9.02 (s, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.42 (s, 1H), 8.32 (dd, J=9.4, 2.1 Hz, 1H), 8.02 (dd, J=8.8, 5.3 Hz, 1H), 7.58 (s, 1H), 7.28 (d, J=2.3 Hz, 1H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16])[CH3:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CC(C)=O>[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:12]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCOc1ccccc1N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC(C)=O
Product: CCOc1ccccc1NC(=O)c1ccccc1C
Yield: 94.5 %

Procedure:
A 13.6 g (0.1 mol) portion of o-methylbenzoic acid and 13.7 g of o-ethoxyaniline were dissolved in 200 ml of acetone. A 4.7 g (0.033 mol) amount of phosphorus pentoxide was gradually added to the prepared solution at 30°-40°C. After the addition, the reaction mixture was refluxed for 3 hours with stirring. The acetone was removed and the residual product was poured into water and was extracted with toluene. The toluene layer was dried over anhydrous sodium sulfate and the toluene was removed to obtain 24.1 g (94.5%) of a clear pink liquid, having a boiling point of 148°C/0.04 mm Hg and nD20 of 1.5929.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[F:13][C:14]([F:30])([F:29])[C:15]1([C:18]2[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=2)[C:23](O)=[O:24])[N:17]=[N:16]1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:23](=[O:24])[C:22]2[CH:26]=[C:18]([C:15]3([C:14]([F:30])([F:13])[F:29])[N:17]=[N:16]3)[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])[CH2:7]1
Reactant: COc1ccc(C2(C(F)(F)F)N=N2)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1ccc(C2(C(F)(F)F)N=N2)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-[3-(trifluoromethyl)-3H-diazirin-3-yl]-2-methoxybenzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[NH2:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[F:9][C:6]1[CH:5]=[C:4]([CH2:10][OH:11])[CH:3]=[C:2]([F:1])[C:7]=1[O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][N:21]=[C:20]2[NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1
Reactant: OCc1cc(F)c(F)c(F)c1
Reactant: Cn1ccc(N)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(F)cc(CO)cc4F)cc23)n1

Procedure:
The compound of Example 145 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 3,4,5-trifluoro-benzenemethanol, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.