Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C([N+]([O-])=O)C=CC=1C=O.C(=O)([O-])[O-].[K+].[K+].S(C[N+]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([C:41]2[O:45][CH:44]=[N:43][CH:42]=2)=[C:37]([Br:46])[CH:36]=1)([O-])=O.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(O)C.C(OCC)(=O)C>[NH2:32][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[O:45][CH:44]=[N:43][CH:42]=2)=[C:37]([Br:46])[CH:36]=1
Reactant: O=[N+]([O-])c1ccc(-c2cnco2)c(Br)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: O=Cc1ccc([N+](=O)[O-])cc1Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2cnco2)c(Br)c1
Temperature: 25 °C

Procedure:
2-Bromo-4nitrotoluene (6.29 g, 29.1 mmol) was dissolved in a mixture of glacial acetic acid 46 mL, and acetic anhydride 46 mL, and cooled in an ice bath. Concentrated sulfuric acid (6.9 mL) was added dropwise. Chromium trioxide (8.08 g, 80.8 mmol) was added portionwise over 1 h. The reaction mixture was stirred for an additional 15 min then poured onto ice. The precipitate was isolated by filtration and dissolved in 16 mL of 1,4-dioxane. Concentrated hydrochloric acid (3 mL) was added and the solution was refluxed for 2 h. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with water, saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and evaporated to yield 1.09 g of 2-bromo-4-nitrobenzaldehyde. The aldehyde was dissolved in methanol (50 mL) and potassium carbonate (0.82 g, 5.96 mmol) and tosylmethyl isocyanide (1.16 g, 5.96 mmol) was added. The reaction mixture was refluxed for 3 h, cooled to room temperature and concentrated. The residue was dissolved in methylene chloride (200 mL) and the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 1.53 g. (96%) of 5-(4-nitro-2-bromophenyl)oxazole. 5-(4-Nitro-2-bromophenyl)oxazole (500 mg, 1.86 mmol) was dissolved in a mixture of 10 mL of ethanol and 20 ml of ethyl acetate. Tin dichloride dihydrate 1.74 g (7.72 mmol) was added and the reaction mixture heated to 80° C. for 0.5 h. The reaction mixture was poured into 400 mL of ice/water and neutralized with sodium carbonate. The suspension was extracted with ethyl acetate (3×100 mL), and the combined organic layer was washed with brine, separated and dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to yield 463 mg of 5-(4-amino-2-bromophenyl)oxazole. 93% pure by HPLC method A. Mass spectrum M+H+=240.95, 1H 400 MHz NMR (CD3OD): 8.09 (s, 1H), 7.40 (s, 1H), 7.34 (d, 1H J=8.5 Hz), 6.89 (d, 1H, J=8.5 Hz), 6.60 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]([CH2:27][O:28]CC3C=CC(OC)=CC=3)=[N:12][C:11]=2[CH:38]([CH3:40])[CH3:39])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N(CC1N(CC)C(C(C)C)=C(SC2C=C(F)C=C(F)C=2)N=1)=[N+]=[N-]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]([CH2:27][OH:28])=[N:12][C:11]=2[CH:38]([CH3:39])[CH3:40])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCCCCCCCCCCn1c(COCc2ccc(OC)cc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: CCn1c(CN=[N+]=[N-])nc(Sc2cc(F)cc(F)c2)c1C(C)C
Product: CCCCCCCCCCCCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1

Procedure:
Compound I-18 was obtained from 5-(3,5-dichlorophenylthio)-1-dodecyl-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17h) by the same synthetic process as that for Compound I-16 in Example 16 (yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH:14]([C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[O:19][C@H:20]([CH2:28][CH3:29])[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:14][C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[O:19][C@H:20]([CH2:28][CH3:29])[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(OCCCN)cc1
Reactant: CCCCOC(=O)[C@@H](CC)Oc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCOC(=O)[C@@H](CC)Oc1cccc(CNCCCOc2ccc(OC)cc2)c1
Temperature: 25 °C

Procedure:
3-(4-Methoxyphenoxy)propylamine (34 mg) was dissolved in methanol (3 mL), and a solution (2 mL) of n-butyl (R)-2-(3-formylphenoxy)butyrate (50 mg) in methanol was added thereto under stirring at room temperature. The mixture was further stirred at 80° C. for 12 hours. Subsequently, an aqueous solution (0.5 mL) of sodium borohydride (7 mg) was added to the solution at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and chloroform was added to the concentrated product. The formed organic layer was washed with water. The washed organic layer was dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby yield 81 mg of a pale yellow, oily substance. The entirety of the substance was employed in the following reaction without any further treatment.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[Cl:14])[CH3:5].[H-].C([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[Cl:14][C:7]1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=1[CH:4]([CH3:5])[CH:3]=[O:2]
Reactant: COC(=O)C(C)c1cc(OC)ccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(Cl)c(C(C)C=O)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
2-(2-Chloro-5-methoxy-phenyl)-propionic acid methyl ester (850 mg) was dissolved in toluene (40 mL) and cooled to −78° C. Diisobutylaluminium hydride (20% in toluene, 3.69 mL) was added over a period of 15 minutes. Stirring was continued for 45 minutes at −78° C. Methanol (2 mL) was added and then 1 N potassium sodium tartrate solution (10 mL). The cooling bath was removed and the mixture was allowed to warm to RT. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The title compound was obtained as a light yellow oil (710 mg) and was used without further purification. 1H-NMR (□, CDCl3): 9.72 (s, 1H), 7.34 (d, 1H), 6.79 (dd, 1H), 6.66 (d, 1H), 4.10 (q, 1H), 3.79 (s, 3H), 1.43 (d, 3H).
Reaction SMILES: Cl.[C:2]1([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]2[N:14]3[CH2:15][CH2:16][C@@H:11]([C@@H:12]([C:17](O)=[O:18])[CH2:13]3)[C:10]2=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:28][N:29]([CH3:30])[C:17]([C@@H:12]1[C@@H:11]2[CH2:16][CH2:15][N:14]([CH:9]([CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]2=[O:20])[CH2:13]1)=[O:18]
Reactant: O=C(O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Reactant: CNC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 46 (2.1 g, 6.6 mmol) and dimethylamine hydrochloride (0.65 g, 8.0 mmol) in DMF (30 ml) was treated with triethylamine (1.3 g, 13 mmol) at room temperature. To this suspension was added diethyl cyanophosphonate (1.2 g, 7.3 mmol) followed by triethylamine (0.67 g, 6.7 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours, poured into NaHCO3 aq (50 ml) and extracted with EtOAc three times. The combined extracts were dried over Na2SO4 and concentrated. This mixture was purified by a column chromatography on silica gel (hexane:EtOAc=1:4) to give 47 as a single isomer at 3-position (1.4 g, 3.9 mmol, 60%)
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].[C:6]1([CH2:12][CH2:13][CH:14]=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N12CCCN=C1CCCCC2>C1COCC1.C(OCC)C.O>[N+:1]([CH:4]([CH3:5])[CH:14]([OH:15])[CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=CCCc1ccccc1
Reactant: CC[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C(O)CCc1ccccc1)[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 1.25 h

Procedure:
Following the procedure of One et al, J. Heterocyclic Chem., 1994, 31, 707-710, which is incorporated by reference, nitroethane (10 mL, 139.2 mmol, 96%) and 3-phenylpropionaldehyde (18.49 mL, 139.9 mmol) were dissolved in THF (70 mL, 2 M). After cooling to −10° C. in a brine bath, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (1.46 mL, 9.74 mmol) was added, and allowed to stir until complete by HPLC (75 min). The reaction was diluted with diethyl ether and H2O, and then the organic was removed and washed with saturated aqueous NaHCO3 and brine. The aqueous layers were back-extracted with diethyl ether, and the combined organics were dried with Na2SO4, filtered, and concentrated to provide 179, which was used without further purification in the next step. HPLC: 9.68 min. (Note: The retention time for the starting materials follow: nitroethane: 6.49 min.; 3-phenylpropionaldehyde: 9.45 min).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]=[C:14]=[O:15])[C:10]([F:16])=[CH:9][C:8]=1[Cl:17])(=[O:5])=[O:4].[OH:18][C@H:19]1[CH2:24][CH2:23][NH:22][C@@H:21]([C:25](OC)=[O:26])[CH2:20]1>ClCCl>[Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:25](=[O:26])[CH:21]3[CH2:20][CH:19]([OH:18])[CH2:24][CH2:23][N:22]3[C:14]2=[O:15])[C:10]([F:16])=[CH:9][C:8]=1[Cl:17])(=[O:4])=[O:5]
Reactant: O=C=Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Reactant: COC(=O)[C@H]1C[C@@H](O)CCN1
Solvent: ClCCl
Product: O=C1C2CC(O)CCN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the title compound of Example 1, Step E (4.54 g, 15.2 mmol) in dichloromethane (20 mL) was added dropwise a solution of methyl cis-4-hydroxy-2-piperidinecarboxylate (2.41 g, 15.2 mmol, prepared as described in J. Org. Chem. (1991), 4084) in dichloromethane (20 mL) at room temperature. The reaction was stirred at room temperature for 20 hours, quenched by the addition of water, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the title compound of Step A, a compound of this invention, was isolated as a foam by flash chromatography (4.98 g). 1H NMR (Me2SO-d6) δ 10.1 (br s, 1H), 7.75 (m, 1H), 7.4 (dd, 1H), 5.1 (m, 1H), 4.9 (s, 2H), 4.1-3.9 (m, 3H), 3.75 (m, 1H), 2.95 (m, 1H), 2.05 (m, 1H), 1.9 (br d, 1H), 1.2 (m, 1H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=O)[CH:17]([CH3:21])[N:16]=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:14]=2[CH:29]=1)(=[O:9])[CH3:8].CI>CC(C)=O>[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH3:18])[C:1](=[O:4])[CH:17]([CH3:21])[N:16]=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:14]=2[CH:29]=1)(=[O:9])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
7.15 g of potassium carbonate are added to a solution of 7.15 g (23.04 mmol) of 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-2H-1,4-benzodiazepin-2-one and 15 ml of methyl iodide in 300 ml of acetone and the mixture is stirred at room temperature for 21 hours. The insoluble material is filtered off and the solution is evaporated in vacuo. The residue is taken up in methylene chloride, washed with water, dried and evaporated. From cyclohexane there is obtained 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 65°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Br:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([Br:17])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Br)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 10 h
Yield: 44.3 %

Procedure:
To a mixture of 1.7 g of 2-amino-5-chlorobenzoic acid and 100 ml of N,N-dimethylformamide was added 1.8 g of N-bromosuccinimide at room temperature, and the mixture was stirred at room temperature for 10 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.1 g of 2-amino-3-bromo-5-chlorobenzoic acid of the formula:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:24](I)[CH3:25]>CS(C)=O>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:25]
Reactant: CCI
Reactant: Cn1cc(-c2ccccc2)c(=O)c(-c2cccc(O)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1cccc(-c2cn(C)cc(-c3ccccc3)c2=O)c1
Temperature: 25 °C

Procedure:
A 3.2 g. portion of the product of Example 145 was added to a suspension of 0.86 g. of sodium hydride in 50 ml. of dimethylsulfoxide. The mixture was stirred at room temperature, and 3.5 g. of ethyl iodide was added. The mixture was stirred for two and one-half hours more, and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and then with water, and dried. The dried extract was then filtered and concentrated to dryness under vacuum. The product was 2.2 g. of 3-(3-ethoxyphenyl)-1-methyl-5-phenyl-4(1H)-pyridone, m.p. 133°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])C)C(O)(C)C.CC(C)([O-])C.[K+].CCOC(C)=O>C1COCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:16]([CH3:18])([CH3:19])[O:15][C:14](=[O:20])[NH:13]1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1F)C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)NC1c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of tert-butyl (1-(2-fluorophenyl)-2-hydroxy-2-methylpropyl)carbamate (400 mg, 1.41 mmol) in THF (8 mL) was added potassium tert-butoxide (316.87 mg, 2.82 mmol) at 0-5° C. The resulting reaction mixture was stirred for 2 hours at ambient temperature. After completion of the reaction (monitored by TLC, TLC system: 50% EtOAc in hexane), the reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic layers were washed with, water, saturated NaCl solution and dried on Na2SO4, filtered, and concentrated under reduced pressure to afford 4-(2-fluorophenyl)-5,5-dimethyloxazolidin-2-one (290 mg, 98.18%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.44-7.35 (m, 2H), 7.30-7.22 (m, 2H), 4.88 (s, 1H), 1.53 (s, 3H), 0.88 (s, 3H). m/z (ESI) 210.1 (M+H)+.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].CO[C:20](=[O:23])[O:21][CH3:22].CC(C)([O-])C.[K+]>COC>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([C:1](=[O:4])[CH:2]([CH3:3])[C:20](=[O:23])[O:21][CH3:22])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)OC
Reactant: CCC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: COC
Agent: [K+]
Product: COC(=O)C(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.51 g (2.1 mmol) of 4-propionyl-1-(tert-butoxycarbonyl)piperidine (from Step A) and 0.35 mL (17.6 mmol) of dimethylcarbonate in 5 mL of tert-butyl, methylether at 0° C. was treated with 0.45 g (4.0 mmol) of potassium tert-butoxide. After 10 minutes at 0° C., the reaction was stirred at rt for 17 hours and refluxed for 3 hours. The reaction was quenched with 1 N HCl and partitioned between 100 mL of Et2O and 100 mL of 1 N HCl. After separating phases, the organic layer was washed with 100 mL of brine, dried over MgSO4 and concentrated. The residue was purified with a 40M Biotage column using 9:1 v/v of hexanes/acetone as the eluant to afford the title compound as a straw colored oil: RF: 0.32 (4:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.35 (d, J=7.1, 3H), 1.42–1.66 (m, 11H), 1.79–1.80 (m, 2H), 2.68–2.79 (m, 3H), 3.71 (q, J=7.1, 1H), 3.73, 3.77 (2s, 3H), 4.12 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(-c4ccccc4)c23)C1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Intermediate 1 (228 mg) obtained in Example 1, Step A is added with phenylboronic acid (122 mg, Aldrich), tetrakis(triphenylphosphine)palladium(0) (116 mg), 1,2-dimethoxyethane (5 ml) and 2 N aqueous sodium carbonate (2 ml), and the mixture is refluxed by heating for 5 hours under a nitrogen gas atmosphere. The reaction mixture is cooled to room temperature, then added with water (25 ml), and extracted 3 times with ethyl acetate (20 ml for each time), and the combined organic layer is washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (158 mg (predictive yield)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]([CH3:36])([C:20]2[N:24]([CH3:25])[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[N:22][N:21]=2)[CH3:19])=[C:6]([C:8]2[O:9][CH:10]=[C:11]([C:13]([O:15]C)=[O:14])[N:12]=2)[CH:7]=1.[Cl:37]N1C(=O)CCC1=O.C(#N)C.[OH-].[Na+]>CO.[Cl-].[Na+].O.O>[Cl:37][C:10]1[O:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:17][C:18]([CH3:19])([C:20]2[N:24]([CH3:25])[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:33])([F:34])[F:35])=[N:22][N:21]=2)[CH3:36])=[N:12][C:11]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1coc(-c2cc(Cl)ccc2OC(C)(C)c2nnc(-c3ccccc3C(F)(F)F)n2C)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1-c1nc(C(=O)O)c(Cl)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
Methyl 2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3-oxazole-4-carboxylate (100 mg) and N-chlorosuccinimide (150 mg) were mixed with acetonitrile (4 ml), followed by heating to reflux for 48 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate. The resulting product was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=2:1 to 1:10). The resulting residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added thereto and the solvent was evaporated under reduced pressure. The resulting solid was washed with ethyl acetate to obtain a white solid. The resulting solid was dissolved in methanol (3 ml) and a 1M aqueous sodium hydroxide solution (1 ml) was added thereto, followed by stirring for 30 minutes. Water and saturated brine were added to the reaction solution, followed by washing with ethyl acetate. 1M hydrochloric acid was added to the aqueous layer, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was washed with ethyl acetate to obtain, as a white solid, 5-chloro-2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3-oxazole-4-carboxylic acid (8.2 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:7]2=[O:23].[C:24]([Zn]C#N)#[N:25]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:8]2[C:7](=[O:23])[C:6]3[C:11](=[C:2]([C:24]#[N:25])[CH:3]=[CH:4][CH:5]=3)[N:10]([CH3:12])[CH:9]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(COc2cn(C)c3c(Br)cccc3c2=O)cc1
Reactant: N#C[Zn]C#N
Agent: [Fe+2]
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(C)c3c(C#N)cccc3c2=O)cc1
Temperature: 110 °C
Yield: 84 %

Procedure:
To a suspension of 8-bromo-3-((4-methoxybenzyl)oxy)-1-methylquinolin-4(1H)-one (2.6 g, 6.95 mmol), DPPF (0.462 g, 0.834 mmol), palladium tetrakis (0.482 g, 0.417 mmol) and Pd2(dba)3 (0.382 g, 0.417 mmol) in N,N-dimethylformamide (30 mL) at room temperature was added dicyanozinc (0.979 g, 8.34 mmol). The mixture was then heated at 110° C. under N2 for 1 h. After cooled to room temperature, the mixture was concentrated in vacuo and then partitioned between EtOAc (80 mL) and conc. NH4Cl (40 mL). The organic phase was separated, washed with brine (40 mL), dried over sodium sulfate, and concentrated. The residue was purified twice by automatic silica gel column chromatography (Combiflash RF), eluting with ethyl acetate/hexanes (0-100%) to afford 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-8-carbonitrile (1.87 g, 5.84 mmol, 84% yield) as a light brown solid. LCMS: (M+H)+: 321.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[Br:15]Br.C(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[Br:15][CH2:13][C:12]([C:4]1[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)=[O:14]
Reactant: BrBr
Reactant: COc1cc(C(C)=O)cc(Cl)c1OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)CBr)cc(Cl)c1OC
Temperature: 25 °C

Procedure:
1-(3-Chloro-4,5-dimethoxyphenyl)-ethanone (31.6 g) was dissolved in chloroform (140 ml) and the solution was stirred at room temperature and treated dropwise with a solution of bromine (7.9 ml) in chloroform (60 ml). After a further 45 min the mixture was neutralised with aqueous potassium bicarbonate solution. The organic layer was separated and washed with sodium chloride solution, dried over sodium sulphate, then filtered and evaporated to dryness. The resultant oil (42.8 g) was crystallized from ether-hexane to give 2-bromo-1-(3-chloro-4,5-di-methoxyphenyl)-ethanone (32.0 g), m.p. 76.5°-78° C.