Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:21][O:20][C:19]3[CH:22]=[C:23]4[C:27](=[CH:28][C:18]1=3)[CH2:26][CH2:25][O:24]4)[C:5](=[O:17])[N:6]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][O:13]1.O.[CH3:30][N:31]([CH3:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[CH3:30][N:31]([CH3:41])[C:32]1[N:33]=[CH:34][C:35]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:21][O:20][C:19]4[CH:22]=[C:23]5[C:27](=[CH:28][C:18]2=4)[CH2:26][CH2:25][O:24]5)[C:5](=[O:17])[N:6]3[CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)=[CH:36][CH:37]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: O=C1N(C[C@H]2CCCO2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
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: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2cccc3c2C2(COc4cc5c(cc42)CCO5)C(=O)N3C[C@H]2CCCO2)cn1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
A stirred solution of 4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.125 g, 0.3 mmol), 2-(dimethylamino)pyridine 5-boronic acid hydrate (0.08 g, 0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.03 mmol), 2 M sodium carbonate (1 mL) in N,N-dimethylformamide (4 mL) was heated with stirring at 150° C. for 15 min in a microwave reactor. The solution was poured into distilled water (15 mL) and washed with ethyl acetate (75 mL). The ethyl acetate layer was washed with brine (3×25 mL), dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (gradient: 30% to 60%) to afford 4′-[6-(dimethylamino)pyridin-3-yl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.11 g, 73%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.53 (d, J=2.4 Hz, 1H), 7.33 (dd, J=7.8 Hz, 1H), 7.18 (dd, J=7.4, 4.7 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 6.71 (ddd, J=8.8, 2.4, 0.9 Hz, 1H), 6.51 (d, J=5.6 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 6.12 (d, J=0.9 Hz, 1H), 4.59-4.41 (m, 3H), 4.33 (dd, J=9.4, 3.1 Hz, 1H), 4.23-4.08 (m, 1H), 3.89-3.55 (m, 4H), 3.09-2.86 (m, 2H), 2.95 (s, 6H), 2.05-1.69 (m, 3H), 1.67-1.51 (m, 1H); MS (ES+) m/z 484.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][CH3:10])=[N:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[CH2:23]([N:25](CC)CC)[CH3:24].C(Cl)(=O)C>C1C=CC=CC=1>[CH2:9]([N:8]1[C:7]2=[N:6][C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=[C:2]2[N:25]=[C:23]1[CH3:24])[CH3:10]
Reactant: CCN(CC)CC
Reactant: CCNc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Solvent: c1ccccc1
Solvent: CC(=O)Cl
Product: CCn1c(C)nc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 15 °C

Procedure:
2-Chloro-3-ethylamino-5,6-diphenylpyrazine, (3.10 g, 0.01 moles) is dissolved in benzene (50 ml) and then triethylamine (1.29 g, 0.013 moles) and acetyl chloride (1.00 g, 0.013 moles) are added. The solution is refluxed 41/2 hours, cooled to 15°C and filtered. The filtrate is diluted with ethanol (3ml), warmed briefly at 50°C and then all volatile materials evaporated. The resultant brown oil is treated with liquid ammonia (17 g) in ethanol (60 ml) in a bomb at 165°C for 12 hours. The solution is diluted with water (200 ml), cooled and the yellow precipitate filtered off. The solid is triturated with boiling 50% aqueous methanol, filtered, and the filtrate chilled. The product is collected by filtration. Yield 0.45 g (14%). It is recrystallized from benzene-heptane, m.p. 178.5°-180°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccno3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:16][NH2:17]>CO.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:16][NH2:17])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CSc1nncc(-c2ccc(F)cc2)n1
Solvent: CO
Solvent: C1CCOC1
Product: NNc1nncc(-c2ccc(F)cc2)n1

Procedure:
To a solution of 11.9 g. of 5-(p-fluorophenyl)-3-(methylthio)-1,2,4-triazine in 50 ml. of 1:1 methanol-tetrahydrofuran is added 2.1 ml. of 95% hydrazine. The mixture is refluxed for 12 hours and then cooled. The solid which forms is collected by filtration and washed with hexane, giving 5-(p-fluorophenyl)-3-hydrazino-1,2,4-triazine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:29]([NH2:34])([CH2:32][CH3:33])([CH3:31])[CH3:30]>C(Cl)(Cl)Cl>[C:29]([NH:34][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])([CH2:32][CH3:33])([CH3:31])[CH3:30]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCC(C)(C)N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(C)(C)NC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 54 %

Procedure:
A mixture containing 8.16 g (0.04 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 ml (0.044 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 4 ml (0.042 mol) of ethyl chloroformate in 20 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -17° C. during 15 minutes. After stirring for 5 minutes, 3.84 g (0.044 mol) of tert.-pentylamine dissolved in 40 ml of chloroform are dropped to the above solution at the same temperature during 15 minutes. The reaction mixture is stirred for 1 hour at about -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 50 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 50 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. The residue slowly becomes crystalline to give 5.9 g (54%) of the named compound, m.p.: 87°-89° C. after recrystallization from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].CS(O[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])(=O)=O.C([O-])(O)=O.[Na+].O>C(#N)C>[CH2:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)[CH2:17][CH2:16][CH2:15][CH2:19][CH2:20][CH3:21]
Reactant: Cc1cc(N)ccc1F
Reactant: CCCC(CCC)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCCCCCNc1ccc(F)c(C)c1
Yield: 349.5 %

Procedure:
To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline in 30 mL of acetonitrile was added 7.64 g (3.93 mmol) of 4-methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of NaHCO3(s). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of H2O and extracted with diethyl ether (2×30 mL). The combined ether layers were back extracted with brine (1×30 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 97.5:2.5 hexanes:ethyl acetate, to give 2.56 g (35%) of a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([OH:13])[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)[CH3:2].C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>CC(CC(C)C)=O>[C:21]([O:13][C:3]1([CH2:1][CH3:2])[CH:4]2[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]1[CH2:9]3)[CH2:5]2)(=[O:24])[CH:22]=[CH2:23]
Reactant: CCC1(O)C2CC3CC(C2)CC1C3
Reactant: C=CC(=O)Cl
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1(CC)C2CC3CC(C2)CC1C3
Temperature: 40 °C
Yield: 80 %

Procedure:
180 g of 2-Ethyl-2-adamantanol, 303 g of triethylamine and 500 g of methylisobutyl ketone were mixed by stirring at 40° C. While stirring, 136 g of acrylic acid chloride was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred for three more hours. Then, extraction and distillation were conducted to obtain 2-ethyl-2-adamantyl acrylate at the yield of 80%.
Reaction SMILES: C(Cl)[Cl:2].O[CH:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][N:7]1[C:15]2[C:10](=[C:11]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C(N(CC)CC)C.CS(Cl)(=O)=O>C(OCC)(=O)C>[Cl:2][CH:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][N:7]1[C:15]2[C:10](=[C:11]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: ClCCl
Reactant: O=C1NC(=O)C(Cc2cccc3c2ccn3CC(O)c2ccccc2)S1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(Cc2cccc3c2ccn3CC(Cl)c2ccccc2)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 10 ml of methylene chloride, there were dissolved 150 mg of 5-[1-(2-hydroxy-2-phenylethyl)indol-4-yl]methyl-2,4-thiazolidinedione prepared in Example 323 and 45 mg of triethylamine under an argon gas atmosphere and then 51 mg of methanesulfonyl chloride was added to the solution under ice-cooling. After stirring at room temperature for 30 minutes, 30 ml of ethyl acetate was added to the solution, the mixture was in order washed with a 10% citric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated common salt solution, dried over anhydrous sodium sulfate and then the solvent was removed by evaporation under reduced pressure. The resulting residue was dissolved in 10 ml of dimethylformamide, followed by addition of 21 mg of lithium chloride and heating to 70° C. with stirring for 20 hours. The solution was poured into a 10% ammonium chloride aqueous solution and extracted with ethyl acetate (20 ml×3). The resulting extract was in order washed with a 10% citric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated common salt solution, dried over anhydrous sodium sulfate and the solvent was removed through evaporation under reduced pressure to give a crude product. The product was purified by preparatory silica gel thin layer chromatography (hexane:ethyl acetate=10:1) to give 35 mg of 5-[1-(2-chloro-2-phenylethyl)indol-4-yl]methyl-2,4-thiazolidinedione as a yellow amorphous substance. The yield thereof was found to be 22%.
Reaction SMILES: [CH3:1]CN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:24]1([N:28]2[CH2:33][CH2:32][N:31]([C:34]([C@@H:36]3[CH2:38][C@H:37]3[C:39]3[CH:47]=[CH:46][C:42]([C:43]([NH2:45])=[O:44])=[CH:41][CH:40]=3)=[O:35])[CH2:30][C@H:29]2[CH3:48])[CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[CH:24]1([N:28]2[CH2:33][CH2:32][N:31]([C:34]([C@@H:36]3[CH2:38][C@H:37]3[C:39]3[CH:40]=[CH:41][C:42]([C:43]([NH2:45])=[O:44])=[CH:46][CH:47]=3)=[O:35])[CH2:30][C:29]2([CH3:1])[CH3:48])[CH2:25][CH2:26][CH2:27]1
Reactant: C[C@@H]1CN(C(=O)[C@@H]2C[C@H]2c2ccc(C(N)=O)cc2)CCN1C1CCC1
Reactant: CCN(C(C)C)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)[C@@H]2C[C@H]2c2ccc(C(N)=O)cc2)CCN1C1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
Intermediate 14 (282 mg, 1.38 mmol) was dissolved in DMF (15 mL). DIPEA (1.201 mL, 6.88 mmol) was added, followed by HOBT (279 mg, 2.06 mmol), EDC (395 mg, 2.06 mmol) and Intermediate 2 (278 mg, 1.65 mmol). The reaction mixture was stirred at rt for 2 h and concentrated under reduced pressure. The residue was redissolved in DCM, washed with sat NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure to give 632 mg of crude as an orange oil. The crude material was purified on preparative HPLC UV using the long high pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v, B: CH3CN, 30 min run) on XBridge Prep C18 OBD, 50×250 mm, 10μ, Waters reverse phase column, providing 151 mg title compound (30.9%) as a solid (enantiomeric mixture). 1H NMR (400 MHz, CD3OD) δ ppm 1.01 (s, 2H) 1.08 (s, 4H) 1.34-1.43 (m, 1H) 1.55-1.70 (m, 4H) 1.96-2.12 (m, 5H) 2.25-2.37 (m, 1H) 2.40-2.48 (m, 1H) 2.61 (br. s., 2H) 3.45 (br. s., 2H) 3.75 (br. s., 1H) 7.26 (dd, J=8.20, 5.08 Hz, 2H) 7.80 (dd, J=8.40, 2.93 Hz, 2H); HRMS m/z calcd for C21H30N3O2 356.23325 [M+H]+, found 356.23286.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
4-(4-Nitro-benzyl)-piperazin-1-yl carboxylic acid tert-butyl ester (769 mg, 2.4 mmol) and tin chloride dihydrate (2.70 g, 12 mmol) are suspended in ethyl acetate (20 mL) and stirred at room temperature overnight. Then, saturated aqueous solution of sodium bicarbonate (20 mL) is added and vigorously stirred for 1 hour. Solids are removed by filtration and the organic layer of the filtrate is separated and washed with water (20 mL). The organic phase is dried over anhydrous magnesium sulfate and concentrated to give a white solid (620 mg, 89% yield, ES+(m/z) 293 [M+H]).
Reaction SMILES: O=S(Cl)[Cl:3].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH2:13][Cl:3])[CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccn1
Solvent: ClC(Cl)Cl
Product: COc1cc(CCl)ccn1
Reaction time: 16 h

Procedure:
1.57 ml (21.6 mmol) of SOCl2 are added dropwise, whilst cooling with ice and under a N2 atmosphere, to a solution of 1.5 g (10.8 mmol) of 2-methoxy-4-(hydroxymethyl)-pyridine [for preparation see J. Org. Chem. 54 (1989), 5580] in 13 ml of chloroform. After 16 h at RT, the mixture is concentrated by evaporation, water and 2N sodium hydroxide solution are added to the residue, and extraction immediately takes place 3 times with chloroform. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation to form 2-methoxy-pyridin-4-yl-methylchloride; 1H NMR (CDCl3) δ8.15 (d, 1H), 6.90 (d, 1H), 6.76 (s, 1H), 4.49 (s, 2H), 3.94 (s, H3C).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NC1CCOCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Br)cc1NC1CCOCC1
Temperature: 60 °C

Procedure:
To a solution of N-(5-bromo-2-nitrophenyl)tetrahydro-2H-pyran-4-amine (2.5 g, 8.333 mmol) in EtOH/H2O (1:1) (50 mL) was added iron powder (2.8 g, 50 mmol) and NH4Cl (2.65 g, 50 mmol). The reaction mixture was heated at 60° C. for 12 h. After filtering the reaction mixture, the resulting filtrate was extracted with DCM with the separated organic layer dried over sodium sulfate, filtered and concentrated to obtain crude product which was used in next step without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=[O:20])=[CH:17][CH:16]=1>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:22][NH:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: COc1ccc(C(=O)NN)cc1
Solvent: CCO
Product: COc1ccc(C(=O)NN=Cc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A mixture of 3.14 gm (0.02 mole) of 2-quinolinecarboxaldehyde, 3.32 gm (0.02 mole) of 4-methoxybenzhydrazide and 100 ml of ethanol is refluxed for 9 hrs. The hot solution is filtered and cooled slowly to room temperature. The mixture is chilled. The crystals which separate are collected. The crude mixture is crystallized from ethyl acetate and recrystallized from tetrahydrofuran to yield 3.0 gm (49%) of title compound, having a melting point of 220°-222° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].N[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].[OH-].[Na+].O1CCCC1>O>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(S(=O)(=O)CCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
2.5 g of 4-diethylaminobenzenesulphonyl chloride are added to a solution comprising 1.17 g of 5-aminovaleric acid and 1.2 g of sodium hydroxide dissolved in 12 cm3 of water, followed by the addition of 12 cm3 of tetrahydrofuran in order to obtain a solution. The mixture is kept stirring for 2 hours at room temperature, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid and extracted with chloroform, the organic phase is dried and the solvents are removed under reduced pressure. 2.2 g of expected product are obtained. M.p. 106°-108° C. After crystallization in an isopropanol/water mixture (1:1), the product, melting point 109°-110° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[N:19]=2)[N:3]=1.N1C=CC=CC=1.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([N:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)(=[O:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=3)[N:19]=2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(S(=O)(=O)N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzene-1-sulfonyl chloride (50 mg, 0.1 mmol) in DCM (5 mL) were added pyridine (0.05 ml) and 1-methylpiperazine (20 mg, 0.2 mmol). The mixture was stirred at RT for 1 h, then diluted with DCM and washed with H2O (100 mL). The aqueous layer was separated and extracted with DCM (2×100 mL), the combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC (Mobile phase: A=0.1% formic acid/H2O, B=MeCN; Gradient: B=36%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to give the title compound as a white solid; MS (ES+) C21H19F3N6O4S requires: 508. found: 509 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.28 (d, J=8 Hz, 2H), 7.86 (bs, 1H), 7.84 (m, 1H), 7.64 (m, 2H), 7.50 (d, J=7.5 Hz, 2H), 5.67 (s, 2H), 3.98 (m, 2H), 3.61 (m, 2H), 3.26 (m, 2H), 2.90 (s, 3H), 2.74 (m, 2H), 2.69 (s, 3H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[CH:4]=1.BrBr.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)=O>O1CCCC1>[Br:23][C:19]1[CH:18]=[C:17]([C:15]([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[CH:4]=2)=[CH2:14])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(Br)cc1C
Reactant: CC(=O)c1cccc(Br)c1
Agent: BrBr
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc(OC)c(C)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
Tetrahydrofuran (5 mL) was added to magnesium turnings (330 mg, 13.56 mmol) in a dried apparatus consisting of 250 mL 3-necked flask, addition funnel and reflux condenser. Then 5 mL of a solution of 4-bromo-2-methylanisole (2.5 g, 12.43 mmol) in tetrahydrofuran (15 mL) was added, followed by a drop of bromine. The exothermic reaction started instantaneously, and the 4-bromo-2-methylanisole solution was added at such a rate to maintain gentle reflux of the reaction mixture (25 min). After complete addition, the light-brown hazy Grignard solution was stirred for another 2 h at 40° C. The mixture was then cooled to 0° C. and a solution of 3-bromoacetophenone (1.42 mL, 11.3 mmol) in tetrahydrofuran (15 mL) was added dropwise over 30 min. After the addition was complete, the mixture was stirred overnight, followed by cooling in an ice bath and careful quenching with 0.5 N cold HCl. After further dilution with ethyl acetate (100 mL) and water (100 mL), the layers were separated and the aqueous layer extracted once more with ethyl acetate (50 mL). The organic layer was dried (magnesium sulfate), filtered and evaporated under reduced pressure. The residual material (tertiary alcohol) was dissolved in a mixture of acetic acid/sulfuric acid (4 mL of acetic acid, 0.12 mL of sulfuric acid) and the reaction mixture was stirred for 3 h at room temperature; then it was examined by LC-MS which showed the complete formation of desired product. The solution was quenched with ice and dichloromethane (20 mL) was added. The two phases formed and were separated. The organic layer was washed with a saturated solution of sodium bicarbonate and brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Crude was purified by flash chromatography eluting with cyclohexane. 1.9 g of desired product was obtained as colorless oil (Yield: 55%).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([NH2:9])=[O:8])[C:5]1([CH3:11])[CH3:10].ClC(Cl)=CC1C(C(O)=O)C1(C)C.C(Cl)(=O)C(Cl)=O.N.[O:32]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7](=[NH:9])[O:8][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:40]=2)[C:5]1([CH3:10])[CH3:11]
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(N)=O
Agent: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Product: CC1(C)C(C=C(Cl)Cl)C1C(=N)OCc1cccc(Oc2ccccc2)c1

Procedure:
Following the method of Example 1, 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropaneamide, from 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid, oxalyl chloride and ammonia, is reacted with 3-phenoxybenzyl bromide to give 3-phenoxybenzyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanimidate.