Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=O.[CH3:17][NH2:18].[BH4-].[Na+].O>CO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([CH:9]([NH:18][CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccn1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(c1ccccn1)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2-Amino-5-bromo-phenyl)-pyridin-2-yl-methanone (500 mg, 1.8 mmol) in MeOH (20 mL) is added Ti(i-OPr)4 (1.0 g, 3.6 mmol) and methylamine (2M in THF, 4.5 mL). Then the mixture is stirred at room temperature for 6 h. Sodium borohydride (137 mg, 3.6 mmol) is added in one portion. The mixture is stirred at room temperature for 2 h. Water (10 mL) is added and the mixture is filtered and washed with EtOAc. The filtrate is washed with brine, the organic layer is concentrated in vacuum to give the desired product as a crude mixture. This is used in next step with no further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:40][S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:40][S:41]([C:44]([F:47])([F:45])[F:46])(=[O:43])=[O:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=3)=[O:24])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NS(=O)(=O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)cc1)NS(=O)(=O)C(F)(F)F
Yield: 65.9 %

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (1.02 g, 3.01 mmol) and ethyl (S)-3-(4-aminophenyl)-2-(trifluoromethylsulfonylamino)propionate (1.03 g, 3.03 mmol) were condensed. The reaction mixture was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1-1/2) to give 1.31 g of ethyl (S)-3-[4-[(5-(benzyloxycarbonylamidino)-2-benzofuranyl]carbonylamino)phenyl]-2-(trifluoromethylsulfonylamino)propionate as a colorless solid (65%). Ethanol (200 ml), 10% palladium-carbon (450 mg) and 1N hydrochloric acid (2 ml) were added to this solid (1.30 g, 1.97 mmol) and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure to quantitatively give 1.11 g of hydrochloride of compound (54) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=3)=[CH:15][C:14]=2[CH3:29])=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:32].C(N(CC)CC)C>C(Cl)Cl>[Cl:32][CH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=3)=[CH:15][C:14]=2[CH3:29])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(C)[n+]([O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(CCl)nc1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of 1.8 g (4.4 mmol) of 6-methyl-3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine-N-oxide in 18 ml of methylene chloride was added dropwise a solution of 0.41 ml (1.13 eq) POCl3 in 4 ml of methylene chloride. After addition of 10% of POCl3 solution, triethylamine (0.54 ml; 1.1 eq) in 4 ml of methylene chloride was added portions. The exothermic mixture was stirred for 30 min, washed with saturated ammonium chloride solution, and the organic layer was separated and dried over sodium sulfate. The organic layer was concentrated in vacuo and purified by flash filtration through silica gel (hexane/ether, 2:1) to afford 0.59 g (31%) of 6-chloromethyl-3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethyl-phenoxy]-propyl]-pyridine (BIL-1991-187), as a pale yellow oil which solidified upon standing, m.p. 79°-81° C.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19]Br)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:3]=[CH:1][O:2][CH:19]=2)=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NC=O
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: c1ccc(COc2ccc(-c3cocn3)cc2)cc1
Yield: 16.6 %

Procedure:
Formamide (1.0ml) was added to 4'-benzyloxy-2-bromoacetophenone (3.0g) and heated at 130° to 135° C. for 1 hour. Water was added to the reaction product, and the mixture was alkalified with aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, treated with activated charcoal, dried with anhydrous sodium sulfate and then concentrated. The residue was purified by column chromatography on silica gel [eluting solvent: ethyl acetate-hexane (1:9)] to give 4-(4-benzyloxyphenyl) oxazole (410 mg, 16.6%). The product was further purified by recrystallization from diethyl etherhexane. m.p. 101°-102° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=[O:19].CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH:18]([C:14]1[N:13]([C:2]2[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:17]=[CH:16][N:15]=1)=[O:19]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc([N+](=O)[O-])cc1-n1ccnc1C=O
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
Into a Round bottom flask, 2-fluoro-4-nitro-benzonitrile (10.4 g, 0.0624 mol), imidazole-2-carboxaldehyde (5.00 g, 0.0520 mol) and dimethyl sulfoxide (200 mL, 3 mol) were added at room temperature. potassium carbonate (7.19 g, 0.0520 mol) was added portion wise to the reaction mixture and heated at 55° C. for 60 minutes. The reaction was cooled at −20° C. overnight. The content was poured over ice and stirred for 30 minutes. The solid was filtered and washed with water. The resulting solid was dissolved with DCM and washed with Brine. The organic was separated, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2-(2-formyl-imidazol-1-yl)-4-nitro-benzonitrile as a yellow solid (10.48 g, 83%). 1H-NMR (DMSO-D6, 400 MHz): δ9.75 (s, 1H), 8.68 (s, 1H), 8.55 (d, 1H), 8.40 (d, 1H), 7.99 (s, 1H), 7.57 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][C:36]=1[Cl:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[Cl:37])[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Cl)c(Cl)c3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,4-dichlorophenol: ESMS m/e: 542.7 (M+H)+.
Reaction SMILES: C(OC(=O)[C:5]([C:31]#[N:32])([N:13]=[N:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(O)(=O)C.Cl.C(=O)(O)[O-].[Na+]>O>[F:23][C:22]([F:24])([F:25])[C:21]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][N:13]=[C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:31]#[N:32])=[CH:20][CH:19]=1)([OH:30])[C:26]([F:27])([F:29])[F:28]
Reactant: CCOC(=O)C(C#N)(Cc1ccccc1)N=Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(Cc1ccccc1)=NNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
A solution of 238 mg. (0.5 mmol) of α-cyano-α-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenylazo]benzenepropanoic acid ethyl ester in 3 ml. of acetic acid and 1 ml. of concentrated hydrochloric acid was stirred at room temperature for 30 minutes, diluted with water, made basic with sodium bicarbonate and extracted with ether. The ether extracts were dried and concentrated. The residue was dissolved in 1:1 benzene-dichloromethane and passed over a little silica gel. The eluate was concentrated and crystallized from hexane to give α-[1-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]hydrazin-2-ylidene]benzenepropanenitrile Isomer A as yellow crystals, m.p. 90°-92°.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH2:16]([O:15][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:20][C:21]1[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=1[CH3:26])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:18])[CH3:17]
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Yield: 64 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-2-phenyl-5-methyl-oxazole, the title compound was obtained in 64% yield as a colourless oil. MS: (M−H)− 403.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[Br:11].Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:15]([CH3:16])[CH3:14])=[CH:6][C:5]=1[Br:11]
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1Br
Temperature: 70 °C
Reaction time: 11 h
Yield: 70 %

Procedure:
To a stirred solution of 5.24 g (22.5 mmol) 2-Bromo-4-fluoro-benzoic acid methyl ester (Rarechemicals) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 11 h at 70° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 7a was obtained in 70% yield (4.08 g, 15.8 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:12][CH3:13])[CH:7]([Cl:8])[CH:6]([O:9][CH3:10])[O:5][C:4]1=O.Cl.[NH3:15]>>[CH3:1][O:2][C:3]1([O:12][CH3:13])[CH:7]([Cl:8])[CH:6]([O:9][CH3:10])[NH:15][C:4]1=[O:5]
Reactant: COC1OC(=O)C(OC)(OC)C1Cl
Reactant: N
Agent: Cl
Product: COC1NC(=O)C(OC)(OC)C1Cl

Procedure:
Concentrated aqueous ammonia (10 ml) was cooled to -10° C. and 3,4-dihydro-3,3,5-trimethoxy-4-chloro-2(5H)-furanone (2 g) was gradually added. The mixture was stirred at 0° C. for about 5 minutes, at the end of which time the excess ammonia was neutralized with HCl-saturated methanol, followed by distillation under reduced pressure. The residue was extracted with chloroform, the chloroform was distilled off, and the residual oil was dissolved in methanol-HCl-saturated methanol (20 ml) and refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography using hexane-acetone (5:3) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give crystals. Recrystallization from benzene yielded 3,3,5-trimethoxy-4-chloro-2-pyrrolidinone as crystals (1.12 g).
Reaction SMILES: [C@:1]12([CH3:30])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][CH:13]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([I:26])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]>C(O)C>[C@:1]12([CH3:30])[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][C@@H:13]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([I:26])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:11]
Reactant: COc1cc(C(OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c([N+](=O)[O-])cc1I
Solvent: CCO
Product: COc1cc([C@H](OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
(R/S)-1-(4-Iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate (3.4 g) was dissolved in boiling ethanol (150 ml), the solution was kept in a warm oil bath and slowly cooled to room temperature and stood overnight. Needle crystals were formed gradually and collected by filtration to yield pure single diastereomer (R)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate (870 mg, 51%). The remaining mother liquor was concentrated in vacuo, and the residue was dissolved again in boiling ethanol (150 ml), and the solution was quickly cooled to room temperature and needle crystals were formed within two hours. The crystals were collected by filtration to yield pure single diastereomer (S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate. The crystallization process was repeated twice to yield additional pure (S)-diastereomer (total 1.07 g, 63%). 1H NMR (400 MHz, CDCl3) for (R)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate: δ 8.48 (s, 1H, Ph-H), 6.94 (s, 1H, Ph-H), 6.84 (s, 1H, Ph-CH), 3.93 (s, 3H, OCH3), 2.42 (m, 1H, CH), 2.11 (m, 1H, CH), 1.92 (m, 1H, CH2), 1.75 (m, 1H, CH2), 1.11 (s, 3H, CH3), 1.05 (s, 3H, CH3), 0.97 (s, 9H, C(CH3)3), 0.86 (s, 3H, CH3). 1H NMR (400 MHz, CDCl3) for (S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate: δ 8.48 (s, 1H, Ph-H), 6.95 (s, 1H, Ph-H), 6.80 (s, 1H, Ph-CH), 3.96 (s, 3H, OCH3), 2.37 (m, 1H, CH), 1.92 (m, 2H, CH2), 1.66 (m, 1H, CH), 1.14 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.06 (s, 3H, CH3), 0.98 (s, 9H, C(CH3)3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]([F:36])([F:35])[C:29]1[S:33][C:32]([NH2:34])=[N:31][N:30]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:34][C:32]3[S:33][C:29]([C:28]([F:36])([F:35])[F:27])=[N:30][N:31]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1nnc(C(F)(F)F)s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1nnc(C(F)(F)F)s1
Yield: 18.7 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine (0.059 g, 0.34 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.025 g of desired product. 1HNMR (DMSO-d6): δ 3.95 (s, 3H), 7.51 (t, J=9.0 Hz, 1H), 7.87-7.76 (m, 3H), 7.78 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 12.86 (br s, 2H); MS (m/z): 514.90 [M]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:15]([CH2:14][CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[N:7]=2)[CH:9]=[N:10]1)[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)#[N:16]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Cl)n2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)cn1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (500.0 mg, 0.001657 mol), p-aminobenzoic acid (341 mg, 0.00248 mol), and p-toluenesulfonic acid (240 mg, 0.0014 mol) in dry 1,4-dioxane (10 mL) was refluxed overnight. The mixture was cooled to room temperature. The resulting solid was filtered, washed with dioxane, and air dried to yield the desired product as a racemic mixture (460 mg, 69%). LCMS (M+H) 403.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:52]1(=[O:58])[NH:56][C:55](=[O:57])[CH:54]=[CH:53]1>C1COCC1.CN(C1C=CN=CC=1)C.CCOCC>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:56]3[C:52](=[O:58])[CH:53]=[CH:54][C:55]3=[O:57])=[O:17])=[CH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(C(OCCCc2ccccc2)(c2ccccc2)c2cccc(OCCO)c2)cc1
Reactant: O=C1C=CC(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1C=CC(=O)N1C(=O)c1ccc(C(OCCCc2ccccc2)(c2ccccc2)c2cccc(OCCO)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of trityl acid 8 (280 mg, 0.42 mM) in dry THF (6 mL) was added dicyclohexyl carbodiimide (DDC, 400 mg, 1.95 mM). The reaction mixture was stirred for 30 min at r.t., maleimide (100 mg, 1.1 mM) and a catalytic amount of DMAP were added and allowed to stir for overnight. The solvent was removed under rotaevaporator and the solid obtained was dissolved in dry ether. The precipitated DCU was filtered and the solvent ether was evaporated. Part of the product was purified by preparative TLC. Yield: 12 mg. 1H-NMR (500 MHz, CDCl3) δ ppm: 1.78 (m, 2H), 1.95 (m 2H), 2.9 (s, 4H), 3.51 (m, 2H), 3.93 (t, 2H), 4.02 (t, 2H), 6.8 (m, 5H), 7.25 (m, 5H), 7.29 (m, 5H), 7.37 (m, 3H), 7.48 (d, 2H), Mass: 561.3 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[CH:3]=1.[OH-:10].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([OH:10])[CH:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(O)nc(Cl)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
To a mixture solution of 6-methyl-2,4-dichloropyrimidine (25 g, 0.153 mol) in tetrahydrofurane(170 ml) was added 1N-NaOH solution(420 ml) and stirred for 48 hours at room temperature. The reaction mixture was washed with ethyl ether to remove impurities, acidified with hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 13.5 g of titled compound as yellow solid form. (Yield: 66.7%)
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30](=O)[CH:31](Br)[CH2:32][CH3:33])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:39][C:40]([C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=1[CH3:52])=[S:41]>CCO>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30]3[N:39]=[C:40]([C:42]4[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=4[CH3:52])[S:41][C:31]=3[CH2:32][CH3:33])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CCC(Br)C(=O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: COC(=O)c1ccc(C(N)=S)c(C)c1
Solvent: CCO
Product: CCc1sc(-c2ccc(C(=O)OC)cc2C)nc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-bromobutanoyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (25 mg, 0.040 mmol) and methyl 4-(aminocarbonothioyl)-3-methylbenzoate (16.87 mg, 0.081 mmol) in EtOH (450 μL) was heated at 70° C. overnight. The reaction was concentrated in vacuo and the residue was purified by preparative TLC (Si, 1000 microns, Hex/EtOAc (80:20)) to afford methyl 4-{4-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-5-ethyl-1,3-thiazol-2-yl}-3-methylbenzoate, as colorless oil. LCMS calc.=731.2; found=731.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H); 7.92 (d, J=8.1 Hz, 1H); 7.86 (d, J=8.0 Hz, 2H); 7.79 (s, 1H); 7.72 (d, J=7.9 Hz, 1H); 7.69 (s, 1H); 7.55 (d, J=7.9 Hz, 1H); 7.29 (s, 1H); 5.59 (d, J=8.0 Hz, 1H); 4.91 (d, J=15.7 Hz, 1H); 4.27 (d, J=15.7 Hz, 1H); 4.04-3.99 (m, 1H); 3.95 (s, 3H); 2.88-2.76 (m, 2H); 2.68 (s, 3H); 1.36 (t, J=7.5 Hz, 3H); 0.57 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]#[CH:15])[C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][OH:5].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:1][N:2]([CH2:13][C:14]#[CH:15])[C@@H:3]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][O:5][S:23]([C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C#CCN(C)[C@H](CO)Cc1ccccc1
Product: C#CCN(C)[C@H](COS(=O)(=O)c1ccc(Br)cc1)Cc1ccccc1
Yield: 47 %

Procedure:
Compound 4c is synthesized by general procedure K from 4b p-bromo-benzene sulfonyl chloride in 47% yield (1.58 g, 1.41 mmol).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:8]2[CH2:9][CH2:10][C:11](=[O:12])[N:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:22])=[CH:16][CH:15]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: O=C1CCNN1c1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C1CCN(C(=S)Nc2ccc(Cl)cc2)N1c1ccccc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture of 2.11 grams (0.013 mole) of 2-phenyl-3-pyrazolidinone, 2.21 grams (0.013 mole) of 4-chlorophenyl isothiocyanate and 0.5 ml of pyridine in 15 ml of toluene was heated at reflux for 9 hours. The reaction mixture was allowed to cool to room temperature forming a crystalline precipitate. The crystalline precipitate was collected by filtration to yield 3.92 grams of 1-(4-chlorophenylthiocarbamoyl)-2-phenyl-3-pyrazolidinone (mp 136°-139° C.).