Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2.Cl.N1C=CC=CC=1.[OH-].[NH4+]>O>[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([OH:2])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc2cnccc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc2cnccc2c1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
Heat a mixture of 6-methoxy-isoquinoline (2.1 g, 13.2 mmol) and pyridine hydrochloride (30 g) in a heavy walled screw cap sealed tube at 160° C. overnight. Cool to room temperature, add water and concentrated ammonium hydroxide to bring the pH of the mixture to 10-11, extract with ethyl acetate (4 times), wash the combined organic extracts with water (4 times), and concentrate under reduced pressure. Purification by medium pressure liquid chromatography eluting with 0-3% of 2N NH3/MeOH in dichloromethane afford the title compound (520 mg, 27%): δH (DMSO-d6, 400 MHz): 7.09 (s, 1H), 7.19 (dd, 1H, J=9, 2 Hz), 7.56 (d, 1H, J=6 Hz), 7.94 (d, 1H, J=9 Hz), 8.29 (d, 1H, J=6 Hz), 9.05 (s, 1H), 10.36 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:33]=[CH:32][CH:31]=[CH:30][C:8]=1[C:9]([NH:11][CH2:12][C@H:13]([CH:27]([CH3:29])[CH3:28])[CH2:14][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:16]1[CH2:18][O:17]1)=[O:10].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+]>CO>[N:34]([CH2:18][C@@H:16]([C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:14][C@H:13]([CH2:12][NH:11][C:9](=[O:10])[C:8]1[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:27]([CH3:29])[CH3:28])[OH:17])=[N+:35]=[N-:36]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CO1)C(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN=[N+]=[N-])C(C)C

Procedure:
The solution of 0.600 g of tert-butyl (3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}-4-methyl-1(S)—(R)-oxiranylpentyl)carbamate (Example 1b) in 12 ml of methanol is admixed with 0.208 g of sodium azide and 0.123 g of ammonium chloride, and stirred at reflux over 6 hours. The reaction solution is cooled, poured onto ice-water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.37 (2:1 EtOAc-heptane); Rt=18.95 (gradient II).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][S:8][C:4]=2[CH:3]=1.[F:17][C:18]([F:24])([F:23])[CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:17][C:18]([F:24])([F:23])[CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([NH:9][C:10](=[O:11])[O:12][CH2:13][CH3:14])=[CH:7][S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)Nc1csc2cc(O)ccc12
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Nc1csc2cc(OCCCC(F)(F)F)ccc12
Yield: 90.8 %

Procedure:
A mixture of 2.0 g (8.4 mmol) of ethyl 6-hydroxybenzothiophene-3-carbamate (obtained in Stage 13.5. of Example 13), 2.4 g (12.6 mmol) of 4,4,4-trifluoro-1-bromobutane and 2.3 g (16.8 mmol) of potassium carbonate in 30 ml of acetonitrile is heated at reflux for 90 min. The mixture is evaporated under reduced pressure and the residue is triturated in petroleum ether. 2.65 g of product are obtained.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4].[C:9]([N:13]=[N:14][C:15](Cl)([CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:16])([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+].[Cl-].[K+]>O>[C:9]([N:13]=[N:14][C:15]([O:8][O:7][C:3]([CH3:6])([CH3:5])[CH3:4])([CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:16])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)CC(C)(Cl)N=NC(C)(C)C
Reactant: CC(C)(C)OO
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(C)CC(C)(N=NC(C)(C)C)OOC(C)(C)C
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
To a solution of 36.2 grams (0.55 moles) of 85% potassium hydroxide in 75 ml. of water, cooled to 15° C in a 2 liter jacketed reactor was added 70 grams (0.70 moles) of 90% t-butylhydroperoxide slowly and with rapid stirring. The temperature was held at 20°-25° C by the rate of addition and by circulating 15° C water through the reactor jacket. After the addition was complete, the reaction was stirred for 20 minutes at 15° C and then 102 grams (0.5 moles) of 2-t-butylazo-2-chloro-4-methylpentane was added dropwise over a 40 minute period holding the temperature at 18°-20° C. After the addition was complete the reaction was stirred for 15 minutes at 20° C. It was then cooled to 0°-5° C and stirred for 45 minutes. A 0.2 mole (16 grams) portion of 50% NaOH was then added and the reaction stirred for 15 minutes. Ice water was then added until the potassium chloride dissolved. The mixture was extracted with 200ml. of pentane, the pentane extract washed with ice cold water, saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure at 10° C to leave 114.2 grams (89% yield) of crude 2-t-butylazo-2-(t-butylperoxy)-4-methylpentane. The crude azo-peroxide assayed 82% when compared with an analytical standard obtained by low temperature recrystallization using an infrared analysis technique.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[C:8]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:38])[C:30]([CH2:36][CH3:37])=[C:31]([C:34]#[N:35])[C:32]=1I)=[O:27])[CH3:24]>[Pd].C(O)C>[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:38])[C:30]([CH2:36][CH3:37])=[C:31]([C:34]#[N:35])[C:32]=1[C:11]1[CH:12]=[CH:13][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][CH:10]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3)cc2)c(C#N)c(CC)n1C
Temperature: 80 °C
Yield: 88.7 %

Procedure:
Charge deionized water (0.50 L), potassium carbonate (66.3 grams, 0.48 mol), and 4-biphenyl boronic acid (62.4 grams, 0.315 mol) and ethanol (1.4 L) to a 3 L 3-neck reaction flask equipped with a mechanical stirrer, condenser, heating mantle, thermocouple, and nitrogen inlet. Stir the mixture to dissolve the solids. Add 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (Preparation 38), additional ethanol (0.90 L) and stir the mixture while the flask is inerted with nitrogen. Add palladium black to the reaction mixture and heat the mixture to reflux at 80° C. Stir the reaction mixture at reflux for 70 minutes. Add ethyl acetate (0.50 L) and filter the mixture through Whatman® GF/F to remove palladium black. Concentrate the filtrate to about 0.6 L by distillation and filter the resulting suspension to collect the precipitate. Rinse the filter cake with ethanol (0.441 L) and vacuum-dry to afford 95.6 grams of the title compound in 88.7% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][SH:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(Cl)Cl>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][S:31][C:2]2[N:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: Fc1ccc(CS)cc1
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(-n2cnc(SCc3ccc(F)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A mixture of 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one Part A of procedure 11 (20 mg, 0.06 mmol), (4-fluorophenyl)methanethiol (26 mg, 0.18 mmol), and potassium carbonate (25.5 mg, 0.185 mmol) in THF (0.5 mL) was stirred at 70° C. overnight. The reaction was diluted with CH2Cl2, filtered, and concentrated. The crude product was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product 6-(4-fluorobenzylthio)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one H-3 (17.25 mg, 0.038 mmol, 61.8% yield) as off-white solid. LC/MS 431 (M+H)+, tR 0.91 min (method 5). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.14 (1H, s), 7.35-7.45 (2H, m), 6.95-7.09 (3H, m), 6.80-6.90 (2H, m), 6.49 (1H, s), 4.28 (2H, s), 3.88 (5H, s), 1.39 (6H, s)
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].Cl.[C:18]([C:22]1[CH:26]=[C:25]([NH2:27])[N:24]([CH:28]([CH3:30])[CH3:29])[N:23]=1)([CH3:21])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:18]([C:22]1[CH:26]=[C:25]([NH:27][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:24]([CH:28]([CH3:30])[CH3:29])[N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)n1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a mixture of phenyl chloroformate (170 mg, 1.1 mmol) and potassium carbonate (210 mg, 1.5 mmol) in DCM (3 mL) at 0° C., was added dropwise a solution of 3-tert-butyl-1-isopropyl-1H-pyrazol-5-amine hydrochloride (220 mg, 1 mmol) in N,N-diisopropylethylamine (130 mg, 1 mmol) and the reaction mixture was stirred at 0° C. for 3 h. The mixture was filtrated, concentrated under reduced pressure, and the residue dissolved in dichloromethane. The organic phase was washed water, brine and concentrated under reduced pressure to give the crude product which was purified via recrystallization from diethyl ether to afford phenyl 3-tert-butyl-1-isopropyl-1H-pyrazol-5-ylcarbamate (300 mg, 100%) as a colorless solid. LC-MS (ESI) m/z 302 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:9]=2[CH3:20])[CH:5]=[CH:4][N:3]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N:21]1([C:2]2[CH:7]=[C:6]([C:8]3[S:12][C:11]([NH:13][C:14]4[CH:19]=[N:18][CH:17]=[CH:16][N:15]=4)=[N:10][C:9]=3[CH3:20])[CH:5]=[CH:4][N:3]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Cc1nc(Nc2cnccn2)sc1-c1ccnc(Cl)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(Nc2cnccn2)sc1-c1ccnc(-n2ccnc2)c1
Temperature: 140 °C

Procedure:
A stirred solution of [5-(2-Chloro-pyridin-4-yl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine (Ex. 2b, 0.4 g, 1.32 mmol) in DMSO (10 ml) is treated with imidazole (0.18 g, 2.64 mmol) followed by caesium carbonate (0.86 g, 2.64 mmol). The reaction mixture is heated to 140° C. for 48 hours and then allowed to cool to room temperature. The mixture is diluted with water (100 ml) and extracted with ethyl acetate (4×100 ml). The organics are combined, dried over MgSO4 and the solvent removed in vacuo to yield the crude product as a yellow oil. Purification by chromatography on silica, eluting with ethyl acetate-methanol (9:1) affords the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH:20]=[CH:19][N:18]=[N:17]3)[CH:10]=2)[N:3]=1.[Cl:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C([O-])([O-])=O.[K+].[K+]>C(C#N)(C)=O.CO.C(Cl)Cl>[Cl:21][C:22]1[N:26]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]4[CH:20]=[CH:19][N:18]=[N:17]4)[CH:10]=3)[N:3]=2)[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1
Reactant: Clc1ncnc(Nc2cccc(Cn3ccnn3)c2)n1
Reactant: Clc1nc2ccccc2[nH]1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: Clc1nc2ccccc2n1-c1ncnc(Nc2cccc(Cn3ccnn3)c2)n1
Temperature: 70 °C

Procedure:
(4-Chloro-[1,3,5]triazin-2-yl)-(3-[1,2,3]triazol-1-ylmethyl-phenyl)-amine (552.7 mg, 1.921 mmol) is combined with 2-chlorobenzimidazole (381 mg, 2.497 mmol) and K2CO3 (372 mg, 2.689 mmol) in AcCN (10 ml) and heated at 65-75° C. for 2 to 20 h. The reaction mix is cooled to RT and diluted with MeOH and CH2Cl2. The inorganic salts are filtered off and the organic solution is concentrated under reduced pressure. The crude is treated with AcCN (5-8 ml), forming a precipitate. The precipitate is filtered and dried, giving [4-(2-chloro-benzoimidazol-1-yl)-[1,3,5]triazin-2-yl]-(3-[1,2,3]triazol-1-ylmethyl-phenyl)-amine.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[O:16]C.Cl.N1C=CC=CC=1>Cl>[OH:16][C:3]1[CH:4]=[C:5]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: CCCC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
10.2 g of 4'-hydroxy-3'-methoxy-5'-nitrobutyrophenone are treated with 80 g of pyridine hydrochloride and stirred at 200° for 40 minutes. After cooling the reaction mixture is poured into 500 ml of ice-water. The mixture is treated with 30 ml of 3N hydrochloric acid and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The crude product obtained is chromatographed with methylene chloride on 150 g of silica gel. The material obtained is recrystallized from methylene chloride/n-hexane. There is obtained 3',4'-dihydroxy-5'-nitrobutyrophenone in the form of yellow crystals of m.p. 88°-90°.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][CH2:29][C:30](O)=[O:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:29](=[O:28])[CH2:30][OH:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)CO
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (52 mg, 84%), MS (ISP) m/z=389.4 [(M+H)+], mp 246° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) 2-hydroxy-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[CH:21]([O-])([O-])OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:21]=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCOC([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2

Procedure:
To a solution of 2.0 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and 7.4 parts of ethyl orthoformate in 80 parts by volume of chloroform is added 2 parts of concentrated sulfuric acid with stirring. The mixture is stirred at room temperature for further 30 minutes, and neutralized with a saturated aqueous sodium bicarbonate solution. Chloroform layer is washed with water and dried over sodium sulfate, followed by distillation of the solvent. Recrystallization of the residue from acetone-n-hexane yields 8-chloro-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine as colorless flakes melting at 226°-227° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:18].[OH-].[Na+].CN(C)C=O.Cl[CH:27]([F:29])[F:28]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:28][CH:27]([F:29])[O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][C:8](=[O:18])[N:7]2[CH2:6][CH:2]2[O:1][CH2:5][CH2:4][O:3]2)=[N:12][CH:13]=1
Reactant: O=c1ccc2ncc(O)cc2n1CC1OCCO1
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2ncc(OC(F)F)cc2n1CC1OCCO1
Reaction time: 0.83 h

Procedure:
To a suspension of 0.15 g of 1-(1,3-dioxolan-2-ylmethyl)-7-hydroxy-1,5-naphthyridin-2(1H)-one in 1.5 mL of toluene, 1 mL of a 40% aqueous sodium hydroxide solution, 97 mg of tetrabutylammonium bromide and 0.25 mL of an N,N-dimethylformamide solution of 10 mol/L chloro(difluoro)methane were added, the mixture was stirred for 50 minutes, then, thereto was added 1 mL of an N,N-dimethylformamide solution of 10 mol/L chloro(difluoro)methane, and the mixture was stirred for 3 hours 40 minutes. Water and toluene were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with toluene. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 95 mg of 7-(difluoromethoxy)-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one as a light brown solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[CH2:17][C:18]([O-:20])=[O:19].[Na+].Cl>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:17][C:18]([OH:20])=[O:19])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
17.94 g of sodium hydride with 61% purity and 350 ml of dried dimethyl sulfoxide were added to a well dried 1-litre 4-necked flask and suspended at room temperature. 99.00 g of methyl 3,4-dichlorophenylacetate was added dropwise thereto under cooling with ice water, the solution being continuously stirred at room temperature even after the end of the dropwise addition. Then 50.38 g of sodium chloroacetate was added under cooling with ice water and the solution was stirred at room temperature. The produced red suspension was poured into a mixture of 500 ml of 1N hydrochloric acid and 300 ml of ice water, and the solution was stirred vigorously. The reaction mixture was extracted with 800 ml of ether, and the organic layer was washed with 500 ml of water (three times) and 500 ml of a saturated saline solution (once). The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled away to obtain 123.94 g of an oily substance. This oily substance was crystallized by treating it with about 400 ml of an ethyl acetate/hexane (1/20) mixture. The precipitated crystals were filtered out, washed with a small quantity of ethyl acetate/hexane (1/20) and then dried to give 93.46 g of the primary crystals of the title substance. Meanwhile, the filtrate was concentrated and crystallized from ethyl acetate/hexane, and the precipitated crystals were filtered out and dried to obtain 9.29 g of the secondary crystals (102.75 g with the primary and secondary crystals put together, 81.0% yield) of the title substance.
Reaction SMILES: [F-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:17][CH:16]2[CH:12]([CH2:13][C:14]3[C:20]([Br:21])=[C:19](I)[S:18][C:15]=32)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[F:23][C:24]([Si](C)(C)C)([F:26])[F:25]>CN(C=O)C.CN1CCCC1=O.[Cu]I>[C:3]([O:7][C:8]([N:10]1[CH2:17][CH:16]2[CH:12]([CH2:13][C:14]3[C:20]([Br:21])=[C:19]([C:24]([F:26])([F:25])[F:23])[S:18][C:15]=32)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2Cc3c(sc(I)c3Br)C2C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC2Cc3c(sc(C(F)(F)F)c3Br)C2C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Dipyridyl (31 mg, 0.20 mmol), CuI (34 mg, 0.18 mmol) and KF (10 mg, 0.18 mmol) were added to a solution of the product from step b) (78 mg, 0.17 mmol) in 1.6 mL of 1:1 DMF/1-methyl-2-pyrollidinone. The reaction mixture was stirred for 1 hour at 80° C. and then cooled to room temperature. Next, trifluoromethyl trimethylsilane (118 mg, 0.83 mmol) was added and the reaction mixture was heated to 80° C. for 12 hours. The reaction was cooled to room temperature and filtered through a silica plug eluting with CH2Cl2 (10 ml). The organic mixture was washed with brine (2×3 mL), dried with MgSO4, and was concentrated to a dark oil that was purified by preparative LC/MS to give the subtitle compound. MS calculated for C15H17BrF3NO2S +H: 412, observed: 413.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[C:47]([CH3:57])=[N:48][O:49][C:50]=3[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:41]2=[O:58])[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[C:47]([CH3:57])=[N:48][O:49][C:50]=3[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:41]2=[O:58])[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3c(C)noc3-c3ccccc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3c(C)noc3-c3ccccc3)C2=O)sc1C(=O)O
Yield: 88 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 4-methyl-2-(3-((3-methyl-5-phenylisoxazol-4-yl)methyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 88% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.64-7.61 (m, 2H), 7.49-7.47 (m, 3H), 4.40 (s, 2H), 3.87-3.82 (m, 2H), 3.28-3.23 (m, 2H), 2.48 (s, 6H); MS (ES+) m/z 399.1 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH:17]([NH2:24])[C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[Cl:25][C:26]1[C:27]([O:45][CH3:46])=[C:28]([C:42](O)=[O:43])[CH:29]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH:31]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C@@H:17]([NH:24][C:42]([C:28]3[CH:29]=[C:30]([C:32]4[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=4)[CH:31]=[C:26]([Cl:25])[C:27]=3[O:45][CH3:46])=[O:43])[C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Cc1noc(C(N)Cc2cccc(-c3ccc(F)c(Cl)c3)c2)n1
Reactant: COc1c(Cl)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Agent: Cl
Product: COc1c(Cl)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1cccc(-c2ccc(F)c(Cl)c2)c1)c1nc(C)no1

Procedure:
5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.087) was prepared using the general procedure A, from 2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride salt (0.077 g, 0.21 mmol, prepared from [2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butylester following general procedure N) and 5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.07 g, 0.21 mmol).