Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25]C)=[O:24])[C:5]([CH3:22])=[C:6]([CH:21]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[OH-].[Na+]>CO>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][CH:8]([O:7][C:6]2[C:5]([CH3:22])=[C:4]([CH:3]=[C:2]([Cl:1])[CH:21]=2)[C:23]([OH:25])=[O:24])[CH2:13][CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)c1cc(Cl)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(OC2CCN(C(=O)OC(C)(C)C)CC2)cc(Cl)cc1C(=O)O
Temperature: 55 °C
Yield: 74.8 %

Procedure:
To a solution of tert-butyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylate (250 mg, 0.651 mmol) in methanol (1.0 mL) was added 6 N NaOH (2.1 mL, 13.03 mmol). The reaction was heated at 55° C. for 18 h. The reaction was cooled to RT and concentrated in vacuo. The residue was then suspended in water and acidified with 1N HCl solution, filtered, and dried to give 3-((1-(tert -butoxycarbonyl)piperidin-4-yl)oxy)-5-chloro-2-methylbenzoic acid (0.180 g, 0.487 mmol, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.41 (s, 9 H) 1.56 (m, J=12.47, 8.31, 4.14, 4.14 Hz, 2 H) 1.76-1.97 (m, 2 H) 2.23-2.35 (m, 3 H) 3.19-3.31 (m, 2 H) 3.48-3.63 (m, 2 H) 4.70 (dt, J=7.26, 3.82 Hz, 1 H) 7.31 (dd, J=11.37, 2.02 Hz, 2 H) 13.22 (br. s., 1 H). MS(ES) [M+H]+ 370.2.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:11][C:12]1[CH:17]=[C:16]([I:18])[CH:15]=[CH:14][C:13]=1[F:19])C(OCC)=O)C.O.[OH-].[Na+]>CCO>[C:24]([O:23][C:21]([NH:20][CH:5]([CH2:11][C:12]1[CH:17]=[C:16]([I:18])[CH:15]=[CH:14][C:13]=1[F:19])[C:4]([OH:28])=[O:3])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)C(Cc1cc(I)ccc1F)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cc(I)ccc1F)C(=O)O
Temperature: 40 °C

Procedure:
A suspension of 2-tert-butoxycarbonylamino-2-(2-fluoro-5-iodo-benzyl)-malonic acid diethyl ester G-22 in EtOH (113 mL) was heated to 40° C. and water (50 mL) was then added giving an easily stirrable emulsion. 1M aq. NaOH (93 mL) was carefully added and reaction mixture was heated to 100° C. for 16 h. The reaction mixture was cooled to RT and the volatiles were removed in vacuo. The remaining aqueous phase was extracted once with TBME and this extract was discarded. The aqueous layer was acidified with 25% aq. HCl and extracted with TBME (2×). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 25% to 50% EtOAc in hexane) to give the title compound as a white solid. LC-MS B: tR=0.80 min; [M-Me]+=394.95.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)=[C:4]([F:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:4]1[CH:3]=[C:2]([C:21]2[C:20]([NH2:19])=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:6]([F:8])[C:5]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]1
Reactant: Nc1ccccc1B(O)O
Reactant: Fc1cc(Br)cc(F)c1-n1ccc(C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1
Temperature: 85 °C

Procedure:
A mixture of 1-(4-bromo-2,6-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole (i.e. the product of Step C, 1.83 g, 5.6 mmol), B-(2-aminophenyl)-boronic acid (0.90 g, 6.58 mmol), sodium carbonate (2.07 g, 19.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.33 g, 0.76 mmol) in 1,2-dimethoxyethane (46 mL) and water (11 mL) was heated at 85° C. for 16 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes to yield the title compound (1.02 g).
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:12]([N:15]=[C:2]([CH3:4])[C:1](=[O:5])[NH:16]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: CC(=O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2nc(C)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.8 %

Procedure:
Pyruvic acid (60 mL, 868 mmol, 1.2 eq) is added at room temperature to a stirred suspension of 4-methoxy-benzene-1,2-diamine (100 g, 724 mmol, 1.0 eq) in 1.8M sulfuric acid aqueous solution (1000 mL). After 24 hours stirring at room temperature, the reaction mixture is neutralized by the addition of 1N sodium hydroxide aqueous solution. The resulting precipitate is filtered and washed with water to afford 7-methoxy-3-methyl-1H-quinoxalin-2-one as a dark purple solid (125 g, 91% yield).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[OH-].[Na+].[CH3:21][C:22]1[S:23][C:24]([SH:27])=[N:25][N:26]=1.Cl>CC(C)=O.O>[CH3:21][C:22]1[S:23][C:24]([S:27][CH2:5][C:6]2[CH2:15][S:14][CH:9]3[N:8]([C:11](=[O:12])[CH:10]3[NH2:13])[C:7]=2[C:16]([OH:18])=[O:17])=[N:25][N:26]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nnc(S)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)s1

Procedure:
A mixture of 13.6 g. (0.05 M) of 7-aminocephalosporanic acid in 100 ml. of water and 50 ml. of acetone are brought to pH 8 with sodium hydroxide while stirring. 9.8 g. (0.57 M) of 2-methyl-1,3,4-thiadiazole-5-thiol are added and the mixture is heated at 80° for 4 hours. After cooling to 5°, this is acidified to pH 3.5 with dilute hydrochloric acid and stirred for 15 minutes. The precipitated solid is filtered under suction and washed with acetone. This 3 -[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is purified by dissolving in sodium bicarbonate solution and reprecipitating with 2N hydrochloric acid; yield 12.7 g., m.p. 206°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH:8]2[CH2:10][O:9]2)=[CH:5][CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.O>[N:13]([CH2:10][CH:8]([OH:9])[CH2:7][C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N+:14]=[N-:15]
Reactant: COc1ccc(CC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CC(O)CN=[N+]=[N-])cc1
Temperature: 90 °C

Procedure:
To a stirring solution of 2-(4-methoxy-benzyl)-oxirane (2.0 g, 12.2 mmol) in 10 mL DMF was added a solution of sodium azide (0.87 g, 13.4 mmol) in 2 mL water. The solution was heated to 90° C. for 90 min. The solvents were removed under reduced pressure and the resulting solid residue partitioned between ethyl acetate and water. The aqueous phase was washed three times with 10 mL ethyl acetate. The combined organic layers were dried over magnesium sulfate, then purified on 40 g silica eluting with 5-50% ethyl acetate/hexanes to give the product as a clear oil. NMR (CDCl3) d (1H, 1.82 ppm), m (2H, 2.7-2.8 ppm), dd (1H, 3.25 ppm), dd (1H, 3.35 ppm), s (3H, 3.75 ppm), m (1H, 3.9-4.0 ppm), d (2H, 6.85 ppm), d (2H, 7.10 ppm).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH2:11]([N:18]1C(=O)O[C:21](=[O:22])[C:20]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:19]12)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[C:21]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:22])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ccccc12
Reactant: Oc1n[nH]c2ccccc12
Product: O=C(c1ccccc1NCc1ccccc1)n1nc(O)c2ccccc21
Yield: 71.5 %

Procedure:
1H-Indazol-3-ol was reacted with N-benzylisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 71.5% yield; m.p. 163°-165° C.
Reaction SMILES: C(=O)(O)O.[NH:5]([C:7](=[NH:9])[NH2:8])[NH2:6].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15].[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:6][NH:5][C:7](=[NH:8])[NH2:9])=[O:15]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N=C(N)NN
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: N=C(N)NNC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 42.8 %

Procedure:
To a solution of hydrazinecarboximidamide carbonic acid salt (14 g, 241.12 mmol) in pyridine (100 ml) was added 3-chlorobenzoyl chloride (15 g, 85.71 mmol), and the reaction mixture was stirred for 10 h at room temperature. The resulting mixture was concentrated under vacuum to give a residue, which was dissolved in water (30 ml) and adjusted to pH 12 with sodium hydroxide (aq., sat.). The product was precipitated and collected by filtration and dried in an oven under reduced pressure to afford 2-(3-chlorobenzoyl)hydrazinecarboximidamide as a light yellow solid (7.8 g, 43%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([C:11](=[O:26])[NH:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[CH3:14])[CH:3]=1.[CH3:27][NH2:28]>>[CH3:27][NH:28][C:8]([C:6]1[CH:5]=[C:4]([C:11]([NH:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:23])([F:25])[F:24])[CH:16]=2)[CH3:14])=[O:26])[CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:10]
Reactant: CN
Reactant: Cc1cc(C(=O)NC(C)c2cccc(OC(F)(F)F)c2)cc(C(=O)O)n1
Product: CNC(=O)c1cc(C(=O)NC(C)c2cccc(OC(F)(F)F)c2)cc(C)n1

Procedure:
The title compound is prepared from 6-methyl-4-((1-(3-(trifluoromethoxy)phenyl)ethyl)carbamoyl)picolinic acid (20 mg, 0.05 mmol, Step-2, single enantiomer) and methanamine (11 mg, 0.16 mmol) by the similar manner in Example-2.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[O-]S([O-])(=O)=O.[Na+].[Na+].[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)([O-:15])=[O:14].O>ClCCl>[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[S:2]([Cl:1])(=[O:5])=[O:3])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]cc(S(=O)(=O)Cl)c2c1
Yield: 51 %

Procedure:
A solution of chlorosulfonic acid (3 mL, 45 mmol) and Na2SO4 (700 mg, 4.9 mmol) in dichloromethane (30 mL) was treated dropwise with a solution of 5-nitroindole (800 mg, 4.9 mmol) in dichloromethane (20 mL) over 1 hour, stirred for another 30 minures, and decanted to provide a thick brown oil. The oil was slowly treated with water (20 mL), stirred for 10 minutes, filtered, and dried in a vacuum oven to provide 651 mg of the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:18]1([CH:24]([NH2:26])[CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:26][CH:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:25])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: CC(N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(NC1CCC(Nc2ccc3[nH]ncc3c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.1 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and 1-phenylethylamine (61 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (20 mg) and a syn-form compound (15 mg).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][CH3:13])OC1C=CC=CC=1)#[N:2].[NH:14]1[CH2:16][CH2:15]1>>[C:1]([NH:3][C:4]([N:14]1[CH2:16][CH2:15]1)=[N:12][CH3:13])#[N:2]
Reactant: CN=C(NC#N)Oc1ccccc1
Reactant: C1CN1
Product: CN=C(NC#N)N1CC1
Yield: 57.7 %

Procedure:
N-Cyano-N'-methyl-O-phenylisourea (10.0 g, 0.0571 mol) was added in half-gram batches during 6 min to aziridine (7.926 g, 0.184 mol) cooled to 0° and stirred. A solution was formed, from which after 5 min a colourless solid crystallised out. The reaction mixture was stirred at 20° for 90 min. and then cooled to 0° to complete crystallisation. Filtration and washing the residue with cold ether gave crystalline N-cyano-N'-methyl-1-aziridinoamidine (4.09 g, 57%), m.p. 134°-135°, Rf 0.64-0.66 (silica, acetonitrile). Further product (1.78 g) was isolated from the ether washings, giving a total yield of 5.87 g, 82%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH3:21])[C:13](=[O:22])[C:12]2[CH:23]=[N:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:26][C:11]1=2)=[O:9]>C1(C)C=CC=CC=1>[CH3:21][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]([C:8](=[O:9])[CH2:7][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:24]=[CH:23][C:12]=2[C:13]1=[O:22]
Reactant: C1CCNC1
Reactant: CN1C(=O)c2cnc(-c3ccccc3)nc2N(C(=O)CCl)c2ccccc21
Solvent: Cc1ccccc1
Product: CN1C(=O)c2cnc(-c3ccccc3)nc2N(C(=O)CN2CCCC2)c2ccccc21

Procedure:
1.35 g (19 mmol) of pyrrolidine are added slowly at 40° C. to a solution of 3 g (7 mmol) of 11-chloroacetyl-6-methyl-2-phenyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 30 ml of absolute toluene, while stirring. The mixture is stirred for a further 6 hours at 60° C. After filtration the solvent is removed on a rotary evaporator, and the residue is purified by chromatography on neutral silica gel using 99:1 chloroform/methanol as the eluant. After removing the solvent, the residue is stirred with methanol and finally recrystallized from ethanol; yield 1.1 g (34%), m.p. 196° C.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([Cl:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15].Cl>O>[Cl:9][C:6]1[S:5][C:4]([C:1](=[O:3])[CH2:2][C:12]([O:13][CH2:14][CH3:15])=[O:16])=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(Cl)s1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-acetyl-5-chlorothiophene (10.0 g), sodium hydride (60%, oil, 2.49 g) and diethyl carbonate (80 ml) was stirred at 80° C. for 30 min. Water was added to the reaction mixture, and the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(5-chloro-2-thienyl)-3-oxopropionate was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio). A mixture of this oil and N,N-dimethylformamide dimethylacetal (11.1 g) was refluxed for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). To the obtained solution was added hydroxylamine hydrochloride (8.65 g), and the mixture was refluxed for 2 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio) were recrystallized from ethyl acetate-hexane to give ethyl 5-(5-chloro-2-thienyl)isoxazole-4-carboxylate (9.34 g, yield 58%) as a colorless prism. melting point: 74–75° C.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[C:19]1([C:25]2[C:29](B(O)O)=[CH:28][N:27]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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:19]1([C:25]2[C:29]([C:2]3[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=4)[N:3]=3)=[CH:28][N:27]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1Br
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
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: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A mixture of 3-bromo-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (319 mg, 1.0 mmol), (3-phenyl-1-trityl-1H-pyrazol-4-yl)boronic acid (645 mg, 1.5 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), Na2CO3 (318 mg, 3.0 mmol), DME (7.5 mL), and H2O (1.5 mL) was refluxed overnight under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/AcOEt (1/1) and crystallized from MeOH to give the title compound (418 mg, 67% yield) as a white solid: mp 216-218° C.; 1H NMR (300 MHz, CDCl3): δ ppm 6.58 (1H, d, J=7.9 Hz), 7.08 (1H, dd, J=2.3, 7.9 Hz), 7.23-7.39 (20H, m), 7.47-7.54 (3H, m), 8.17 (1H, d, J=7.9 Hz), 8.67 (1H, s). LC-MS (ESI) m/z 625 [M+H]+. Anal. Calcd for C39H27F3N4O: C, 74.99; H, 4.36; N, 8.97. Found: C, 74.84; H, 4.39; N, 9.01.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Cl[CH:26]([C:31]([CH3:33])=[O:32])[C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH:26]([C:27]([O:29][CH3:30])=[O:28])[C:31](=[O:32])[CH3:33])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(C(C)=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 43.8 %

Procedure:
6.6 g (0.02 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are heated at 80° C. with 4.5 g of methyl 2-chloroacetoacetate and 4.2 g of triethylamine in 100 ml of dimethylformamide for 3 hours. The solution is then concentrated in vacuo, the residue is stirred with 50 ml of water and the resulting solid product is washed with methanol and water and recrystallized from glycol monomethyl ether. 3.9 g (44% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-{4-[2-oxo-1-(methoxycarbonyl)-1-propyl]-1-piperazinyl}-3-quinolinecarboxylic acid of decomposition point 224° to 228° C. are isolated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([CH2:29][CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH:25]([CH2:29][CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1
Product: CCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 3-Ethyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 417.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH:17]3[CH2:19][CH2:18]3)[N:11]=2)=[O:9])=[N:3]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:14][CH:13]=[C:12]([CH:17]3[CH2:19][CH2:18]3)[N:11]=2)=[O:9])=[N:3]1
Reactant: Brc1cncnc1
Reactant: Cn1ccc(NC(=O)c2nc(C3CC3)ccc2N)n1
Product: Cn1ccc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-cyclopropyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide and 5-bromopyrimidine in accordance with the general method of example 4 using to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=336.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[C:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13]>CCOC(C)=O.O>[C:12]([N:15]1[CH2:20][CH2:19][N:18]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[Cl:1])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(=O)N1CCNCC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C

Procedure:
2-Chloro-1-fluoro-4-nitrobenzene (10 g, 57 mmol) and 1-acetylpiperazine (14.6 g, 114 mmol) were heated neat at 55° C. for 1 h. Then the reaction mixture was allowed to cool down to room temperature. The viscous orange solution was diluted with EtOAc and water. The organics were washed with water (3 times), brine, dried and evaporation of the solvent gave an orange oil which was triturated with isohexane. After evaporation of solvent the title compound was obtained as a yellow solid which was dried overnight in vac oven at 50° C. (15.68 g, 97%). It was used without further purification. NMR (400 MHz) 2.03 (d, 3H), 3.18 (dt, 4H), 3.62 (m, 4H), 7.30 (d, 1H), 8.17 (dd, 1H), 8.26 (d, 1H); m/z 284-286.