Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:3].[CH3:17][N:18]1[C:23]([N:24]2CCCN(C3C=CC=CC=3[N+]([O-])=O)[CH2:26][CH2:25]2)=[CH:22][C:21](=[O:40])[N:20]([CH3:41])[C:19]1=[O:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH3:17][N:18]1[C:23]([NH:24][CH2:25][CH2:26][N:4]([CH2:5][CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:2]([CH3:1])[CH3:3])=[CH:22][C:21](=[O:40])[N:20]([CH3:41])[C:19]1=[O:42]
Reactant: Cn1c(N2CCCN(c3ccccc3[N+](=O)[O-])CC2)cc(=O)n(C)c1=O
Reactant: CC(C)NCCCc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)N(CCCc1ccc([N+](=O)[O-])cc1)CCNc1cc(=O)n(C)c(=O)n1C
Yield: 178.1 %

Procedure:
N-(1-methylethyl)-3-(4-nitrophenyl)propylamine (0.6 g), 0.5 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6) and 50 mg of p-toluenesulfonic acid monohydrate was dissolved in 30 ml acetonitrile, and then the solvent was removed in vacuo. The resultant oil was allowed to react at 80° C. for 3 hours and subjected to silica gel column chromatograph (chloroform/methanol=40:1 (v/v)) for purification. Thus, 1.0 g of 1,3-dimethyl-6-{2-[N-(1-methylethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>C(O)C>[C:12]1([C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccccn1
Solvent: CCO
Product: c1ccc(-c2cn3ccccc3n2)cc1

Procedure:
2-Phenylimidazo[1,2-a]pyridine was prepared by the following procedure. A solution of 2-aminopyridine (9.4 g, 0.1 mol) and bromoacetophenone (19.9 g, 0.1 mol) in ethanol (75 mL) was heated to reflux for 2 h. The ethanol was removed in vacuo and the residue redissolved in 100 mL ethyl acetate. The solution was washed with 1N NaHCO3 (50 mL), followed by a water wash. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Chromatography on silica with dichloromethane/ethyl acetate (90/10) eluent yielded the 2-phenylimidazo[1,2-a]pyridine in 88% yield, mp 134° C. 1H NMR and mass spectra analysis confirmed the structure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:20][N:19]=2)[CH3:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:20][N:19]=2)[CH3:13])=[CH:8][CH:9]=1
Reactant: CN(CCCOc1nsc(-c2ccccc2)n1)CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: CCO
Product: CN(CCCOc1nsc(-c2ccccc2)n1)CCc1ccc(N)cc1
Yield: 56.6 %

Procedure:
2.1 g of 3-(3-[N-(2-(4-nitrophenyl)-ethyl)-N-methylamino]-propyloxy)-5-phenyl-1,2,4-thiadiazole (for) preparation, see Example 8)), were dissolved in a mixture of 75 ml ethanol and 75 ml methanol and reacted with a catalytic quantity of Raney nickel. The reaction mixture was then hydrogenated for 2.5 hours at room temperature with hydrogen at a hydrogen pressure of 5 bars. The catalyst was filtered off and the filtrate concentrated to dryness. The oily crude title compound obtained was purified by medium-pressure chromatography over fine-grained silica gel (Lichroprep Si 60®) using 95:5 ethyl acetate/methanol as the eluent. 1.1 g of the title compound were obtained as an oil.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:22][O:23][C:24]1[N:29]=[N:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>CN(C=O)C.O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:36][CH:33]2[CH2:34][CH2:35][N:30]([C:27]3[N:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH2:31][CH2:32]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N2CCC(N)CC2)nn1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCC(NC3=C(c4ccccc4)S(=O)(=O)N(C(C)(C)C)C3=O)CC2)nn1
Temperature: 120 °C
Yield: 49.2 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.300 g, 1.00 mmol), 1-(6-methoxypyridazin-3-yl)piperidin-4-amine dihydrochloride (0.349 g, 1.24 mmol) and TEA (0.405 g, 4.00 mmol) was dissolved in dry DMF (10 ml) and heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was diluted with water (200 ml) and extracted with EtOAc (200 ml). The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography using a 55:45 mixture of heptane and EtOAc as eluant, to give the title compound (0.232 g, 49%). 1H NMR (500 MHz, CDCl3): δ 7.54-7.49 (m, 2H), 7.46-7.41 (m, 3H), 6.92 (d, 1H), 6.79 (d, 1H), 5.2 (d, 1H), 4.00 (s, 3H), 3.93-3.87 (m, 2H), 3.17-3.08 (m, 1H), 2.53-2.45 (m, 2H), 1.77-1.71 (m, 2H), 1.72 (s, 9H), 1.44-1.35 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 160.1, 159.6, 157.3, 133.8, 131.6, 129.9, 128.7, 125, 119.4, 119.1, 107, 61.6, 54.3, 50.1, 45.1, 31.6, 27.6; Mass Spectrum: M−H+ 472.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[CH3:19][C:20]1[N:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[CH3:15])[C:8]([C:4]1[C:3](=[O:18])[C:24]2[C:23](=[CH:22][CH:21]=[C:20]([CH3:19])[N:25]=2)[NH:26][CH:5]=1)=[O:17]
Reactant: Cc1ccc(N)cn1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc2[nH]cc(C(=O)c3ccc(C)c(C)c3)c(=O)c2n1
Yield: 22 %

Procedure:
Experimental conditions analogous to those described for step 1 of Example 1 were used with 0.50 g (2.01 mmol) 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester, 0.22 g (2.01 mmol) of 6-Methyl-pyridin-3-ylamine, and 15 mL of diphenyl ether to yield 129 mg of 3-(3,4-Dimethyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one as a brown solid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C=O)C>[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4]
Reactant: Nc1ccccc1Br
Reactant: COC(=O)c1ccccc1NC(=O)CBr
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)CNc1ccccc1Br
Temperature: 0 °C
Yield: 30.3 %

Procedure:
A solution of methyl 2-((bromoacetyl)amino)benzoate (2.0 g, 7.35 mmol) and 2-bromoaniline (3.16 g, 18.4 mmol) in anhydrous DMF (30 mL) was heated to 90°-100° C. overnight with stirring under N2. The solution was cooled, poured into 500 mL of ice-water, and then extracted with 3×50 mL of ethyl acetate. The layers were separated and the organic layer was dried (MgSO4), filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (3:1), afforded 0.81 g (30%) of the title compound, mp 89°-91° C.: 1H NMR (DMSO-d6) δ11.19 (s, 1H), 8.52 (dd, J=8.4, J=0.8, 1H), 7.90 (dd, J=8.0, J=1.6, 1H), 7.62 (ddd, J=8.8, J=7.6, J=1.6, 1H), 7.47 (dd, J=8.0, J=1.6, 1H), 7.20-7.14 (m, 2H), 6.60 (ddd, J=8.4, J=8.0, J=1.2, 1H), 6.53 (dd, J=8.4, J=1.6, 1H), 6.06 (bt, J=5.6, 1H), 4.00 (d, J=5.6, 2H), 3.73 (s, 3H); 13C NMR (DMSO-d6) δ169.70, 167.01, 144.53, 139.32, 134.16, 132.36, 130.68, 128.67, 123.21, 120.40, 118.35, 116.66, 111.51, 109.04, 52.26, 48.47; MS (El, m/z) 363 (M+). Anal. Calcd for C16H15N2O3Br: C, 52.91; H, 4.16; N, 7.71. Found: C, 52.22; H, 4.05; N, 7.40.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[OH-].[Na+].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].[Cl-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCNCC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)c1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A mixture of 50.0 g (271 mmol) of cyanuric chloride, 22.0 g of 50% aqueous sodium hydroxide, 22 ml of water, and 150 ml of toluene, cooled to 0° C., is admixed with a solution of 19.8 g (271 mmol) of diethylamine in 25 ml of toluene over a 45 minute interval. The reaction temperature is maintained at 0°-5° C. throughout the addition. After the addition is complete, the reaction mixture is stirred for two hours at ambient temperature. Water is added to the mixture to dissolve the sodium chloride, and the phases are separated. The organic phase is dried over magnesium sulfate and concentrated to give an oil which is crystallized from heptane to give 42.0 g (70% yield) of 2,4-dichloro-6-diethylamino-1,3,5-triazine, a white crystalline material, m.p. 77°-9° C.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])C(=O)CO)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[O-][Bi](=O)=O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C:15]3=[O:25])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: O=[Bi](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)C1=O
Yield: 65.2 %

Procedure:
A solution of 4.7 g (12.0 mmole) of 9-fluoro-16β-methyl-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione in 50% acetic acid (600 ml) was stirred with 18 g of sodium bismuthate at room temperature for 2 hours. The brown suspension was filtered through a bed of deactivated silica powder and washed with 100 ml of 50% acetic acid. The filtrate was concentrated in vacuo to 100 ml, diluted with 100 ml of 20% hydrochloric acid and extracted with chloroform. The chloroform solution was washed with 20% hydrochloric acid and water, dried over anhydrous Na2SO4 and evaporated in vacuo to give a solid. This was dissolved in chloroform and chromatographed on a 30 g silica gel column, eluting successively with chloroform and 1:4 ethyl acetate-chloroform to give 2.6 g of the title compound, melting point 281°-283° C., dec.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=O)[CH3:2].Cl[CH2:16][C:17]([NH2:19])=[O:18].[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]2[CH:8]=[C:16]([C:17]([NH2:19])=[O:18])[O:12][C:6]=2[CH:5]=1)[CH3:2]
Reactant: NC(=O)CCl
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc2cc(C(N)=O)oc2c1
Yield: 68 %

Procedure:
When 4-diethylaminosalicylaldehyde is reacted with chloroacetamide and potassium hydroxide in dimethylformamide at ambient temperature or with potassium carbonate instead of potassium hydroxide at refluxing temperature, the above benzofuran derivative is obtained in a similarly good yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:6]([OH:7])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].O([CH2:28][C:29]([F:32])([F:31])[F:30])S(C(F)(F)F)(=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:11]=[CH:12][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][C:6]=1[O:7][CH2:28][C:29]([F:32])([F:31])[F:30]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
To a mixture of isovanillic acid methyl ester (3.0 g, 0.18 mol) and potassium carbonate (41.4 g, 0.30 mol) in DMF (100 ml) was added a solution of trifluoroethyl triflate [Burdon et al Tetrahedron 21, 1 (1965)] (65.0 g, 0.28 mol) in CH2Cl2. The mixture was stirred at room temperature for 18 h then evaporated to 50 ml, the mixture partitioned between ether and H2O, the organic layer washed with H2O and saturated brine, then dried over MgSO4 and evaporated. The resulting solid was triturated with hexane to give the subtitle compound as an off-white solid (42.55 g, 90%). Rf 0.47 (CH2Cl2). MS m/z 265 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2OS(C(F)(F)F)(=O)=O>N1C(C)=CC=CC=1C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2[O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(OS(=O)(=O)C(F)(F)F)c2cc1OC
Reactant: O=C(Nc1ccc(O)cc1)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: Cc1cccc(C)n1
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 165 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
To a solution of cyclopropane-1,1-dicarboxylic acid (4-fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide (6.98 g, 22.2 mmol) in anhydrous 2,6-lutidine (50 mL) was added trifluoromethanesulfonic acid 6,7-dimethoxy-quinolin-4-yl ester (5 g, 14.8 mmol). The reaction mixture was heated at 165° C. in a sealed pressure tube with stirring for 18 h. The reaction mixture was concentrated on high vacuum to completely remove lutidine. The resulting solid material was dissolved in DCM (250 mL), and washed several times with 1 N sodium hydroxide to remove the excess phenol. The crude mixture was loaded on a silica gel flash column and eluted with 75% EtOAc-hexanes, affording N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (3.2 g, 44%). 1H NMR (400 MHz, d6-DMSO): δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H=502.
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1.C(O)C.[NH2:15]OS(O)(=O)=O>O>[NH2:15][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: NOS(=O)(=O)O
Reactant: c1ccc2[nH]ncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nn1ncc2ccccc21
Temperature: 55 °C
Yield: 47.3 %

Procedure:
To a solution of 2.2 g(55 mmol) of sodium hydroxide in 30 ml of water was added 1.33 g(10 mmol) of 1H-indazole and ethanol was slowly added at 50° C. until the reaction mixture was dissolved thoroughly. The resulting mixture was heated to 55° C. and 2.83 g(25 mmol) of hydroxylamine-O-sulfonic acid was slowly added over 30 min with vigorous stirring followed by further stirring for 30 min. After completion of reaction, the resulting precipitate was filtered off, and the filtrate was extracted with dichloromethane(30 ml×2), dried over anhydrous magnesium sulfate and concetrated under the reduced pressure. The concentrate was chromatographed over silica gel using 10% ethyl acetate/dichloromethane as an eluent. The fractions containing the desired product were concentrated under the reduced pressure and crystallized from benzene/petroleum ether to give 0.63 g of the desired compound(47%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1)#[N:2].[Cl:18][C:19]1[C:24]([C:25]([N:27]=[C:28]=[O:29])=O)=[C:23]([F:30])[C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([F:30])[C:24]=1[C:25]1[NH:27][C:28](=[O:29])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: CC(C)(C)OC(=O)NNc1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C#N)cc3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-cyanophenyl)hydrazinecarboxylate (step-2 of Intermediate 17, 0.060 g, 0.25 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.160 g, 0.51 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.020 g of pure product. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 9H), 4.45 (d, J=5.9 Hz, 2H), 6.19 (m, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 8.19 (d, J=8.4 Hz, 2H), 10.72 (br s, 1H); MS (m/z): 426.27 (M−H−).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:16][CH:15]=1.Cl>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:18][CH:19]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.23 (s, br, 1H), 7.74–6.88 (m, 11H) 5.20–5.12 (m, 1H), 3.68–3.52 (m, br, 2H), 3.02–2.82 (m, br, 2H), 2.82–2.60 (m, 4H), 2.58–2.38 (m, br, 2H), 2.12–2.02 (m, br, 1H), 2.02–1.80 (m, br, 5H), 1.68–1.52 (m, br, 1H), 1.52–1.36 (br, 3H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 603.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27])([O-:15])=[O:14]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:26]([C:17]2[CH:18]=[CH:19][C:20]([C:22]([F:24])([F:25])[F:23])=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:27])=[O:28])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 99.3 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloroquinolin-8-amine (Intermediate 27) (50 mg, 0.28 mmol), 2-nitro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (162 mg, 0.56 mmol) gave the title compound (120 mg, 50%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O)(=O)C>O>[N:22]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCOCC3)cc2c1=O
Temperature: 140 °C

Procedure:
A mixture of 100 mg (0.314 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 0.274 ml (3.14 mmol) of morpholine is heated at 140° C. (oil bath temperature) for 1 hour in a closed vial. After cooling, the residue is dissolved in water, the solution acidified with 2 M acetic acid to pH ˜5 and allowed to stand at room temperature. An orange precipitate forms which is filtered and recrystallized from DMSO/water yielding 81 mg of the title compound as an orange powder, m.p. >260° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][C@H:5]([OH:7])[CH3:6].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.O>CN(C=O)C>[CH3:6][C@@H:5]([O:7][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)[CH2:4][CH2:3][O:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C[C@@H](O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](CCOc1ccc(C#N)cc1)Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Sodium hydride (3.18 g, 133 mmol) was dispersed in 100 ml DMF and added with 1,3-(R)-butanediol (5.03 g, 55.8 mmol) while being cooled with ice. The mixture after being cooled with ice for another one hour was stirred at room temperature for 2 hours and then added with 4-chlorobenzonitrile (16.8 g, 122 mmol) at room temperature, followed by being reacted for 20 hours. After completion of the reaction, the reaction mixture was carefully added with 5 ml water to inactivate excess sodium hydride, followed by distilling out DMF in vacuum. The resulting mixture after being added with 200 ml of water was subjected to processes of extraction of an organic matter with ethyl acetate, washing with a solution of saturated sodium chloride and distillation of the solvent, followed by distillation of the oily residue thus obtained using Kugelloa distilling equipment at a temperature of 275° C. and a pressure of 0.5 mmHg thereby obtaining the intended product (13.3 g, 45.4 mmol, 81%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:11])[CH3:10]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
To a suspension of L-Pro (247 mg, 2.15 mmol) in pyridine (1 ml) was added acetic anhydride (I ml), and the mixture was stirred at room temperature for 5 min. The solvent was removed in vacuo and the resulting oil was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was dried over sodium sulfate, and concentrated, and the resulting solid was recrystallized from ethyl acetate to give N-acetyl-L-proline (167 mg, 44%), a white powder: m.p. 108° C. [lit 115° C. (from CHCl3)99 ]; [α]D25 -171° (c, 0.91, CHCl3) [(lit107 -118° (c, 1, H2O)] Anal. Calcd. for C7H11NO3 : C, 53.49; H, 7.05, N, 8.91. Found: C, 53.57; H, 7.09; N, 8.76.
Reaction SMILES: [N+](=C)=[N-].[OH:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:22](O)(=O)C>C(OCC)C.O1CCOCC1>[CH3:22][O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1Cc2cccc(Oc3ccccc3O)c2O1
Reactant: CC(=O)O
Agent: C=[N+]=[N-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccccc1Oc1cccc2c1OC(=O)C2
Reaction time: 8 h

Procedure:
An excess of a solution of diazomethane in diethyl ether was added to a solution of 7-(2-hydroxyphenoxy)2,3-dihydrobenzofuran-2-one (4.9 g) in a mixture of diethyl ether (50 ml) and dioxane (50 ml), and allowed to stand overnight at room temperature. To the reaction mixture was added acetic acid (1 ml), and the organic solvent was distilled off. The oily residue was purified by column chromatography, and the crude crystals were crystallized from ethyl acetate to give 7-(2-methoxyphenoxy)-2,3-dihydrobenzofuran-2-one (2.3 g). mp 171°-172° C.