Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[Cl:12][CH2:13][C:14](Cl)=[O:15]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:14](=[O:15])[CH2:13][Cl:12]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Product: Cc1cccc(C(=O)O)c1NC(=O)CCl
Yield: 73.4 %

Procedure:
3-Methylanthranilic acid 10 g (0.07 mol) was dissolved in dried benzene 100 ml. To this solution, chloroacetylchloride 5.81 ml (0.07 mol) was added dropwise at room temperature and heated under reflux for two hours. After cooling, deposited crystals were collected by filtration and recrystallized from benzene-toluene to obtain 3-methyl-N(chloroacetyl)anthranilic acid 11.7 g (yield: 79%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30](=[O:33])[NH:31][CH3:32])[C:20]([C:34]([F:37])([F:36])[F:35])=[CH:19][N:18]=2)=[C:12]([O:38][CH3:39])[CH:11]=1)(=[O:8])[O:5]CC)[CH3:2]>Cl>[CH3:39][O:38][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30](=[O:33])[NH:31][CH3:32])[C:20]([C:34]([F:36])([F:35])[F:37])=[CH:19][N:18]=1)[CH2:9][P:4](=[O:5])([OH:8])[O:3][CH2:1][CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1)OCC
Agent: Cl
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1

Procedure:
A solution of diethyl (3-methoxy-4-{[4-{[2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 53, 44.3 mg, 0.0781 mmol) in 37% HCl (1 mL) was heated at 80° C. for a total of 3.5 h. The reaction was concentrated in vacuo. The residue was dissolved in DMSO and submitted for mass-directed purification (under basic conditions; ammonium bicarbonate buffer, pH 9). The fractions containing product were combined and concentrated in vacuo, giving the title material as a white solid, 11.6 mg (27%). 1H NMR (400 MHz, MeOD) δ ppm: 8.33 (d, J=8.3 Hz, 1H), 8.29 (s, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.62 (dd, J=7.8, 1.3 Hz, 1H), 7.49 (ddd, J=8.5, 7.4, 1.5 Hz, 1H), 7.18 (td, J=7.6, 1.0 Hz, 1H), 7.05 (t, J=1.8 Hz, 1H), 6.79 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 3.89 (s, 3H), 3.79-3.88 (m, 2H), 2.96 (d, J=20.2 Hz, 2H), 2.89 (s, 3H), 1.19 (t, J=6.9 Hz, 3H). MS (ES+): m/z 540.14 (100) [MH+]. HPLC: tR=2.63 min (ZQ3, polar—5 min).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:19])[CH:13]=1.[C:21]([O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Br)([CH3:24])([CH3:23])[CH3:22]>CC(C)=O>[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:29][CH2:28][CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:31])=[C:14]([CH3:19])[CH:13]=1
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCC(=O)OC(C)(C)C)c(C)c1
Yield: 76 %

Procedure:
Potassium carbonate (580 mg, 4.20 mmol) and potassium iodide (72 mg, 0.43 mmol) were added to a solution of 4-hydroxy-3-methyl-benzoic acid methyl ester from Example E29 (293 mg, 1.76 mmol) and 4-bromo-butyric acid tert-butyl ester from Example E42.1 (397 mg, 1.78 mmol) in acetone (50 ml). The mixture was heated at reflux for 18 h then the solid was filtered off and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc, washed with water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% pet. ether) to yield the title compound (414 mg, 76%).
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].C(Cl)(Cl)Cl.C(=O)=O.[Br:12][C@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15].S(=O)(=O)(O)O>ClCCl>[C:2]([O:16][C:14](=[O:15])[C@H:13]([Br:12])[CH2:17][CH:18]([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)C[C@@H](Br)C(=O)O
Reactant: C=C(C)C
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)C[C@@H](Br)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Into dichloromethane (80 mL) was condensed isobutene to double the volume (at -50° C. CHCl3 /dry ice). To this solution was added (2R)-2-bromo-4-methylpentanoic acid (28 g, 143.6 mmol) and maintaining the temperature between -40° and -50° C. concentrated sulphuric acid (1 mL) was added dropwise. The reaction was then allowed to warm to room temperature over 20 hours. The solution was then concentrated before adding additional methylene chloride (300 mL) which was subsequently washed with saturated NaHCO3 (2×100 mL) followed by water (2×100 mL). After drying over Na2SO4, the organic layer was filtered and concentrated to give a yellow oil. The material was distilled to give 23 g of (2R)-2-bromo-4-methylpentanoic acid t-butyl ester as a clear colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C([Cl:16])(=O)C.P(Cl)(Cl)(Cl)(Cl)Cl>CCOCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:16])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(=O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(Cl)c1cc2ccccc2[nH]1
Yield: 73.3 %

Procedure:
To a mixture of 1H-Indole-2-carboxylic acid (2.50 g, 15.5 mmol) and acetyl chloride (31 mL, 0.43 mol) in Et2O (31.5 mL) was added phosphorus pentachloride (3.55 g, 17.1 mmol) in portions, and the mixture was then heated under reflux for 1.5 hours. The cooled reaction mixture was concentrated under reduced pressure, and the crude product obtained thus was recrystallized from heptanes to give 1H-indole-2-carbonyl chloride (2.04 g, 73%) as yellow needles.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH:24][CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1.[F:35][C:36]1[CH:41]=[C:40]([C:42]([NH:44]O)=[NH:43])[CH:39]=[CH:38][C:37]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O.CN(C)C=O>[F:35][C:36]1[CH:41]=[C:40]([C:42]2[N:43]=[C:30]([C:29]3[CH:28]=[CH:27][C:26]([CH2:25][OH:24])=[CH:34][CH:33]=3)[O:32][N:44]=2)[CH:39]=[CH:38][C:37]=1[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: N=C(NO)c1ccc(-c2ccccc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(-c2nc(-c3ccc(-c4ccccc4)c(F)c3)no2)cc1
Temperature: 135 °C

Procedure:
1-Hydroxybenzotriazole hydrate (1.35 g, 0.01 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (1.95 g, 0.01 mol) are added to a stirred N,N-dimethylformamide solution (20 mL) of 4-hydroxymethylbenzoic acid (1.52 g, 0.01 mol). 2-Fluoro-N-hydroxybiphenyl-4-carboxamidine (2.3 g, 0.01 mol) is added to the reaction mixture which is then heated at 130-140° C. for 4 hrs. The reaction mixture is cooled to room temperature, Demineralized water (60 mL) is added and the aqueous layer is extracted with ethyl acetate (3×20 mL). Combined organic layers are washed with demineralized water (2×10 mL) followed by brine (1×20 mL) and finally dried over sodium sulphate. Removal of ethyl acetate under reduced pressure gives a crude liquid which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane 30:70) to furnish {4-[3-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazol-5-yl]phenyl}methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1OC)[CH:5]=[O:6].[H-].[CH2:13]1COCC1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[CH3:13]
Reactant: COc1ccc(C=O)cc1F
Reactant: C1CCOC1
Agent: [H-]
Product: Cc1ccc(CO)cc1F
Reaction time: 0.5 h

Procedure:
3-fluoro-p-anisaldehyde (12.5 g, 81.1 mmol) was dissolved in 100 ml THF. Under N2 a solution of diisobutylalumium hydride (100 ml, 1M in THF) was added at 0° C. over 30 min. The reaction was stirred for 30 min and quenched with 250 ml 1N HCl solution. The resulting mixture was stirred for 15 min and filtered through a short column of Celite®. The product was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried with MgSO4, and concentrated to give a viscous oil in 11.6 g. This product was used without further purification. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:35]([F:38])([F:37])[F:36])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([C:31]([F:34])([F:33])[F:32])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C)C=O.[H-].[Na+].FC(F)(F)S(O[CH2:52][C:53]([F:56])([F:55])[F:54])(=O)=O>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:35]([F:36])([F:37])[F:38])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:52][C:53]([F:56])([F:55])[F:54])[CH2:26]4)=[O:24])=[C:19]([C:31]([F:33])([F:34])[F:32])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1CC(F)(F)F
Reaction time: 1 h

Procedure:
Into a 50-mL round bottom flask, was placed 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]imidazolidin-4-one (50 mg, 0.09 mmol, 1.00 equiv), N,N-dimethylformamide (1 mL), sodium hydride (7 mg, 0.17 mmol, 2.00 equiv, 60%), The resulting solution was stirred for 20 min at 25° C. Added 2,2,2-trifluoroethyl trifluoromethanesulfonate (40 mg, 0.17 mmol, 1.98 equiv). The resulting solution was allowed to react, with stirring, for an additional 1 h at r t. The reaction was then quenched by the addition of 10 ml of water. The resulting solution was extracted with 2×10 ml of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with PE/EA (2/1). This resulted in 23.7 mg (37%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]-3-(2,2,2-trifluoroethyl)imidazolidin-4-one as yellow oil. ES, m/z): [M+CH3CN]+697.0; 1H NMR (300 MHz, CDCl3): δ8.12-8.22 (m, 2H), 7.98 (s, 1H), 7.86 (d, J=7.8 Hz, 2H), 7.73 (d, J=7.8 Hz, 1H), 5.17 (s, 1H), 4.79 (s, 1H), 4.44 (d, J=18.0 Hz, 1H), 4.01-4.31 (m, 4H), 3.93 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20](=O)[CH3:21]>CN(C)C=O>[CH3:21][C:20]1[C:13]2[C:14](=[O:16])[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=3)[CH2:11][C:12]=2[O:17][CH:19]=1
Reactant: Cc1ccc(C2CC(=O)CC(=O)C2)cc1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C2CC(=O)c3c(C)coc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
In dimethylformamide (10 ml) was suspended 60% sodium hydride (0.44 g, washed with hexane thrice), and to the suspension were added 5-(4-methylphenyl)cyclohexane-1,3-dione (2.0 g) and chloroacetone (0.92 g). The mixture was stirred at room temperature for 1 hour and then at 150° C. for 13 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane), and the resulting crystals were recrystallized from hexane to give colorless crystals of 3-methyl-6-(4-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.51 g).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([O:4][CH2:5][C:6](O)=[O:7])[CH3:3].C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([O:4][CH2:5][C:6]([Cl:13])=[O:7])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OCC(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OCC(=O)Cl
Yield: 52.9 %

Procedure:
To a 3-neck 500 ml round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added (1,1-dimethylethoxy)acetic acid (24.00 g, 0.182 moles) and 300 ml of toluene under nitrogen. Oxalyl chloride (46.10 g, 0.363 moles) was then added dropwise and to this mixture was added N,N-dimethylformamide (0.25 g, 0.003 moles). This solution was heated at 30°-40° C. for 5 hours and then concentrated in vacuo to give 14.5 g of the product as a brown oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15](O)=[O:16])[CH:8]=[CH:7]2.C(Cl)(=O)C(Cl)=O.[NH3:25]>C1C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15]([NH2:25])=[O:16])[CH:8]=[CH:7]2
Reactant: CC(C(=O)O)c1ccc2cc(F)ccc2c1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C(N)=O)c1ccc2cc(F)ccc2c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A suspension of 2.4 g. of sodium hydride and 50 ml. of benzene is added to a mixture of 23 g. of 6-fluoro-2-naphthyl-α-methylacetic acid and 450 ml. of benzene. The resulting mixture is stirred for four hours. The mixture is cooled to 0° C and 19 g. of oxalyl chloride are added; after the addition, the mixture is allowed to stand for four hours. The resulting mixture is then saturated with ammonia and allowed to stand for 8 hours. This mixture is then evaporated under reduced pressure. The residue is taken up in methylene chloride, washed with water to neutrality, dried, filtered, and evaporated to give 6-fluoro-2-naphthyl-α-methylacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=[CH2:31])[C@H:10]([N:26]=[N+:27]=[N-:28])[C:11](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C1COCC1.[Li+].[BH4-]>CO>[N:26]([C@@H:10]([C@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:29][CH:30]=[CH2:31])[CH2:11][OH:12])=[N+:27]=[N-:28]
Reactant: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)[C@@H](CO)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 3-(3(S)-(3,4-dichlorophenyl)-2(S)-azido-1-oxo-5-hexenyl)-4(S)-benzyl-2-oxazolidinone (890 mg, 1.94 mmol) and THF (25 mL) at 0° C. was added MeOH (126 mL, 3.1 mmoL), followed by LiBH4 (68 mg, 3.1 mmol). The mixture was allowed to stir for 2 h, and was then quenched by addition of sat. aq. Rochelle salts (50 mL) and was allowed to warm to room temp and stirred vigorously for 2 h. The mixture was diluted with H2O (150 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel 60, 10-40% EtOAc/hexanes) to afford the alcohol (452 mg, 82%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[C:9]([Br:12])[C:5]2=[N:6][S:7][N:8]=[C:4]2[C:3]=1[Br:13].[CH3:14][C:15](=O)[C:16](=O)[CH3:17].O>C(O)(=O)C>[Br:13][C:3]1[C:4]2[C:5](=[N:6][S:7][N:8]=2)[C:9]([Br:12])=[C:10]2[C:2]=1[N:1]=[C:16]([CH3:17])[C:15]([CH3:14])=[N:11]2
Reactant: CC(=O)C(C)=O
Reactant: Nc1c(N)c(Br)c2nsnc2c1Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c(Br)c3nsnc3c(Br)c2nc1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5,6-Diamino-4,7-dibromobenzo[c][1,2,5]thiadiazole (0.257 g, 7.93×10−4 mol) was dissolved in acetic acid (30 ml). 2,3-Butanedione (0.30 ml, 3.4×10−3 mol) was added, and the reaction mixture was stirred for 19 h at room temperature under N2. Water (50 ml) was added, and the resulting precipitate was filtered, dissolved in CH2Cl2, washed with water, and dried over Na2SO4. After the solvent was evaporated, the residue was chromatographed on silica gel with CHCl3. Yield=0.256 g (86% based on 0.257 g of 5,6-diamino-4,7-dibromobenzo[c][1,2,5]thiadiazole). 1H NMR (360 MHz, CDCl3): δ 2.88 (s, 6H, —CH3). Chemical Ionization MS m/z: 371.8675 (M+) (calcd 371.868).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>ClCCCl>[C:24]([N:10]1[C:9](=[O:14])[CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:15][CH3:16])[O:12][C:11]1=[O:13])(=[O:26])[CH3:25]
Reactant: COc1ccc(Cl)cc1C1OC(=O)NC1=O
Reactant: CC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C1OC(=O)N(C(C)=O)C1=O
Reaction time: 0.02 h
Yield: 64.2 %

Procedure:
At room temperature, 5-(5-chloro-2-methoxyphenyl)oxazolidine-2,4-dione (1.21 g., 5 mmoles) was suspended in 25 ml. of 1,2-dichloroethane. Triethylamine (505 mg., 0.7 ml., 5 mmoles) was added and the mixture stirred for 1 minute to achieve solution. Acetyl chloride (393 mg., 0.36 ml., 5 mmoles) was added and the mixture stirred for 1 hour. The reaction mixture was concentrated to 5 ml., and solids precipitated by the addition of about 25 ml. of ether. The isolated solids were distributed between chloroform and saturated sodium bicarbonate. The organic phase was separated, washed with fresh bicarbonate and then with brine, dried over anhydrous magnesium sulfate and evaporated to yield 3-acetyl-5-(5-chloro-2-methoxyphenyl)oxazolidine-2,4-dione [910 mg., 64%; m.p. 161°-164° C.; pnmr/DMSO-d6 /delta 2.5 (s, 3H), 3.9 (s, 3H), 6.0 (s, 1H), 7.4 (m, 3H)].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=3)=[CH:14][CH:15]=2)[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[N:7]=1)=[O:5])C.[OH-].[Na+].CO>CCOC(C)=O>[CH3:25][S:22]([C:18]1[CH:17]=[C:16]([C:13]2[S:12][C:11]([C:9]3[N:8]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:33])([F:34])[F:35])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=3)=[CH:15][CH:14]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2C(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(=O)O)nn3-c3ccccc3C(F)(F)F)s2)c1
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To a 100 mL round bottom flask attached with condenser was added 5-[5-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-1-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (2.52 g, 4.98 mmol), 1N aq NaOH (30 mL), and MeOH (25 mL). The reaction solution was stared at 55° C. for 1.5 hr prior to TLC analysis. The reaction solution was diluted with EtOAc (200 mL), poured into a separately funnel and the organic phase was partitioned. The aqueous phase was neutralized by the addition of aq 1 N HCl and extracted with EtOAc (70 mL×2). The combined organic phase was dried over Na2SO4, filtered into a round bottom flask and concentrated on the Rotavapor. The crude residue was chromatographed thru a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 85% EtOAc to afford 1.35 g (55% yield) title compound. MS (ES) 493.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:9]=[O:10])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][C:21]([C:23]([NH:25][C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Reactant: O=C=Nc1cccc(Cl)c1
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(Cl)c3)cc2)o1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 1, using 1-chloro-3-isocyanatobenzene (0.533 mmol) and intermediate 1. 1H NMR (DMSO-d6, 300 MHz): δ 9.056 (s, 1H), 9.013-8.986 (d, 2H), 7.820 (s, 1H), 7.799-7.770 (d, J=8.7 Hz, 2H), 7.728-7.704 (m, 1H), 7.631-7.601 (d, J=9 Hz, 2H), 7.347-7.268 (m, 2H), 7.059-7.024 (m, 1H), 4.328-4.277 (m, 1H), 3.680 (s, 3H), 2.286-2.218 (m, 1H), 0.980-0.958 (d, J=6.6 Hz, 6H); MS (ESI) m/z 469 (M−H), 470 (M+H)+.
Reaction SMILES: Cl[C:2]([F:12])([C:9]([OH:11])=[O:10])[C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5]>O1CCOCC1.[Zn]>[F:7][C:3]([F:8])([CH:2]([F:12])[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C(F)(F)C(F)(Cl)C(=O)O
Agent: [Zn]
Solvent: C1COCCO1
Product: O=C(O)C(F)C(F)(F)C(=O)O
Temperature: 25 °C
Reaction time: 10 h
Yield: 40.7 %

Procedure:
To a stirring solution of the chlorotrifluorosuccinic acid (part b) (24.5 g) in 200 ml dioxane was added portionwise zinc metal (85 g) and the mixture was stirred at ambient temperature for 10 hours to yield a viscous liquid which was decanted from the unreacted zinc. Most of the dioxane was evaporated in vacuo. The residue was dissolved in 100 ml H2O and a solution of 7.7 ml of concentrated H2SO4 in 25 ml of water was added. The solution was extracted with ether (3×100 ml) and dried over anhydrous MgSO4. The organic layer was stripped to yield 8.3 g (32%) of the product as a crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.O=[C:18]([CH3:31])[CH2:19][C:20]([O:22][C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:21].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C.C(OCC)C>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([CH3:31])[C:19]([C:20]([O:22][C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:21])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)O[C@H](C)c1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOCC
Solvent: CCO
Product: Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
To a solution of (2-amino-5-chlorophenyl)(phenyl)methanone (1.16 g, 5.0 mmol) in ethanol (20 ml) was added (R)-1-phenylethyl 3-oxobutanoate (1.3 g, 6.5 mmol) followed by ytterbium triflate (294 mg, 0.5 mmol). The mixture was stirred at room temperature for 12 hours, then the ethanol was removed under reduced pressure, and the residual viscous oil dissolved in ethyl acetate. The organic phase was poured into a separatory funnel and washed with 1M aqueous hydrochloric acid, water, then brine. The organic phase was seoarated, and the solvent was removed under reduced pressure to provide a viscous oil. This was dissolved in a small amount of diethyl ether, and the solution allowed to stand at room temperature overnight. The white precipitate formed was filtered, washed with cold diethyl ether, and dried under reduced pressure, to provide (R)-1-phenylethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate (1.33 g, 67%) as a white powder. Rf=0.26 using 80:20 hexanes:ethyl acetate eluent on glass backed silica gel plates. 1H NMR (CDCl3, 400 MHz) δ 8.98 (d, 1H, J=8.9 Hz); 7.96 (d, 1H, J=7.4 Hz); 7.72 (d, 1H, J=1.95 Hz); 7.6-7.1 (m, 10H); 5.88 (q, 1H, J=6.6 Hz); 3.05 (s, 3H); 1.3 (d, 3H, J=6.6 Hz). LC MS (CI) shows M+H 402.