Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[NH:7][C:8](=[O:21])[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[N:7]([CH3:26])[C:8](=[O:21])[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c2c1C
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)n(C)c(=O)c2c1C
Yield: 58 %

Procedure:
A mixture of 100 mg of ethyl 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, 40 mg of potassium carbonate, 10 mL of acetonitrile and 40 mg of methyl iodide was heated under reflux for 1.5 hours. After condensing the reaction mixture under reduced pressure, the residue was purified on silica gel column chromatography (ethyl acetate:hexane=1:1) to provide 60 mg (58%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[CH3:14][Mg]Br>C1COCC1>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:6](=[O:7])[CH3:14])=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1ccc(F)nc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a cold solution (−78° C.) of 6-fluoro-N-methoxy-N-methylnicotinamide (Method 38, 7.2 g, 39 mmol) in THF (130 ml), was added methyl magnesium bromide (20 ml, 59 mmol, 3M solution in ether) dropwise. The cooling bath was removed and reaction mixture was allowed to warm to room temperature and stir for 2 hours. The reaction was quenched with 3N HCl solution, layers were cut, and organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford 3.8 g (70% yield) of the title compound. 1H NMR (CDCl3) δ 8.80 (s, 1H) 8.29-8.43 (m, 1H) 6.98-7.06 (m, 1H) 2.62 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:19]3[C:18]([O:20][CH3:21])=[CH:17][CH:16]=[C:15]([C:22](O)=[O:23])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.CN(C=O)C>[N:35]1[CH:36]=[CH:37][C:32]([NH:31][C:22]([C:15]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]([CH2:6][C:5]4[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=4)[C:19]=3[C:18]([O:20][CH3:21])=[CH:17][CH:16]=2)=[O:23])=[CH:33][CH:34]=1
Reactant: COc1ccc(C(=O)O)c2c3ccccc3n(Cc3ccc(F)cc3)c12
Reactant: Nc1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccncc2)c2c3ccccc3n(Cc3ccc(F)cc3)c12
Reaction time: 2 h
Yield: 37 %

Procedure:
To a suspension of 9-(4-fluoro benzyl)-1-methoxy 9H-4-carbazole carboxylicacid (100 mg, 0.286 mmoles) in dry chloroform (15 ml), thionyl chloride (0.063 ml, 0.86 mmoles) was added followed by 2 drops of dry DMF and the reaction mixture was sired under nitrogen atmosphere for two hours. Solvent and the excess thionyl chloride were evaporated from the reaction mixture and dried under vacuum. To this residue, dry chloroform (15 ml) was added followed by 4-aminopyridine (27 mg, 0.286 mmoles) and triethylamine (0.06 ml, 0.43 mmoles) were added and the reaction mixture was stirred under nitrogen atmosphere for 17 hours. The reaction mixture was diluted with chloroform (30 ml) and washed with water (2×10 ml). The organic layer was washed with brine (20 ml), dried over Na2SO4 and concentrated to give 45 mg of the title product as pale yellow solid, m.p: 230-232° C.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])[CH3:3].C(N(CC)C1C=CC=CC=1)C.[C:37]([C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([F:47])[CH:46]=1)[NH:42][CH3:43])#[CH:38]>CN(C=O)C>[C:37]([C:39]1[CH:40]=[C:41]([N:42]([CH3:43])[CH:2]([C:4]2[CH:5]=[C:6]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][C:9]3=[O:20])[CH3:3])[CH:44]=[C:45]([F:47])[CH:46]=1)#[CH:38]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: C#Cc1cc(F)cc(NC)c1
Solvent: CCN(CC)c1ccccc1
Solvent: CN(C)C=O
Product: C#Cc1cc(F)cc(N(C)C(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 34 %

Procedure:
8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (185 mg, 0.37 mmol), N,N-diethylaniline (174 μl, 1.10 mmol) and 3-ethynyl-5-fluoro-N-methylaniline (60 mg, 0.40 mmol) in DMF (1043 μl) were stirred at 50° C. for 2 days. Purification was done using an analogous procedure to the one described in Example 3.03 to give 8-(1-((3-ethynyl-5-fluorophenyl)(methyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (60 mg, 34%) as a white solid. Mass Spectrum: M+H+ 478. NMR Spectrum (DMSOd6): 1.55 (d, 3H), 2.62 (s, 3H), 2.92 (bs, 3H), 3.01 (bs, 3H), 3.18-3.27 (m, 2H), 3.28-3.33 (m partially hidden by H2O, 2H), 3.40-3.48 (m, 2H), 3.48-3.57 (m, 2H), 4.21 (s, 1H), 5.54 (q, 1H), 5.62 (s, 1H), 6.52 (d, 1H), 6.73 (d, 1H), 6.80 (s, 1H), 7.72 (d, 1H), 7.89 (d, 1H).
Reaction SMILES: [O:1]1[C:19]([CH3:24])([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:2]1[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1.[H][H]>[Pt]=O.C(OCC)(=O)C>[O:1]1[C:19]([CH3:24])([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:2]1[CH2:3][CH2:4][CH:5]([CH3:18])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1
Reactant: [H][H]
Reactant: CC(=CCOc1ccc2c(c1)OCO2)CCC1OC1(C)CC(C)C
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)CC1(C)OC1CCC(C)CCOc1ccc2c(c1)OCO2

Procedure:
1.66 g. of 4-[(6,7-epoxy-3,7,9-trimethyl-2-decenyl)-oxy]-1,2-(methylenedioxy)-benzene are dissolved in 30 ml. of ethyl acetate and hydrogenated by passing hydrogen gas in the presence of 50 mg. of platinum oxide until uptake of the theoretical amount of hydrogen. The catalyst is then filtered off and the filtrate evaporated. By chromatography on slica gel in hexane/ether (9:1 parts by volume) there is obtained pure 4-[(6,7-epoxy-3,7,9-trimethyldecyl)-oxy]-1,2-(methylenedioxy)-benzene of boiling point (bulb tube) 128° C./0.03 mm Hg; nD23 = 1.5027.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[Br:19][C:20]1[CH:21]=[CH:22][C:23](=O)[NH:24][CH:25]=1.N1C(C)=CC=CC=1C.O>ClCCl>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[N:24][CH:25]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](Oc1ccc(Br)cn1)(C(C)C)C(C)C
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (65.4 g) was added dropwise to a solution of 5-bromo-2(1H)-pyridinone (33.8 g) and 2,6-lutidine (31.1 g) in 775 ml of dichloromethane at 0° C. The resulting solution was stirred for 15 minutes, and then it was poured into water and the layers were separated. The aqueous phase was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to give a liquid. The product was slurried with silica gel and hexanes. Filtration gave 64.6 g of oil.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6]CC)=O.[CH2:13]([N:15]1[C:20]2[N:21]=[CH:22][CH:23]=[CH:24][C:19]=2C(=O)[O:17][C:16]1=O)[CH3:14].Cl>O.C(O)C>[CH2:13]([N:15]1[C:20]2[C:19](=[CH:24][CH:23]=[CH:22][N:21]=2)[C:4]([OH:6])=[C:3]([C:2]([O:10][CH2:11][CH3:12])=[O:9])[C:16]1=[O:17])[CH3:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCn1c(=O)oc(=O)c2cccnc21
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cccnc2n(CC)c1=O
Reaction time: 0.08 h

Procedure:
To a solution of 0.115 g. (0.005 g. atom) of sodium in 20 ml. of ethanol was added 1.6 g. (0.01 mole) of diethyl malonate. After stirring for 5 minutes the solution was evaporated in a rotary evaporator. The residue was dissolved in 15 ml. of N,N-dimethylformamide and 0.96 g. (0.005 mole) of 1-ethyl-2H-pyrido[2,3-d]-[1,3]oxazine-2,4[1H]dione was added. The mixture was heated under reflux for 1.5 hours. The mixture was cooled, diluted with a little water and was acidified with concentrated hydrochloric acid. The precipitate which formed was collected, air dried and was recrystallized from heptane to give 0.2 g. of the title product, m.p. 120°-2° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[NH:15][C:14](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:13][N:12]=2)=[CH:6][CH:5]=1.Br[CH2:33][CH2:34][CH2:35][CH2:36]Br.[Cl-].[NH4+]>CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11]3[N:12]([N:13]=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]5)=[C:20]([O:30][CH3:31])[CH:19]=4)[N:15]=3)[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:8][CH:9]=1
Reactant: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Reactant: BrCCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(/C=C/c2nc3n(n2)CCCCN3c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
60% sodium hydride (10 mg) was added to a solution of (4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}amine synthesized in Example 162 (47.5 mg) in DMF (3 mL) at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. 1,4-Dibromobutane (0.02 mL) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for two hours. 60% sodium hydride (5 mg) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for two hours. A saturated ammonium chloride solution was added to the reaction solution at 0° C., followed by extraction with ethyl acetate. The resulting extract was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system), silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) and CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain 14 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:13](O)(=[O:16])[CH2:14][CH3:15]>>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: N[C@@H]1CCCc2c(Br)cncc21
Reactant: CCC(=O)O
Product: CCC(=O)N[C@@H]1CCCc2c(Br)cncc21
Yield: 97 %

Procedure:
In analogy to the procedure described for the preparation of intermediate A-4 [D], (+)-(R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate A-11) and propionic acid gave the title compound as white solid in 97% yield. MS: 283.5 (M+H+, 1 Br).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[CH:23]=[CH:24][C:25]2[N:26]([N:28]=[CH:29][N:30]=2)[N:27]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:22]3[CH:23]=[CH:24][C:25]4[N:26]([N:28]=[CH:29][N:30]=4)[N:27]=3)[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(C(OC2CCN(c3ccc4ncnn4n3)CC2)c2ccccc2)cc1
Yield: 54.4 %

Procedure:
4-(Diphenylmethoxy)piperidine (1.12 g) and 6-chloro[1,2,4]triazolo[1,5-b]pyridazine (558 mg) were dissolved in 1-butanol (25 ml), followed by addition of N-ethyldiisopropylamine (700 mg). The mixture was refluxed under heating for 17 hours. After being cooled, the mixture was concentrated under reduced pressure. Ice-water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of hexane and ethyl acetate (1:3). Fractions containing the objective compound were collected and recrystallized from ethanol to yield the title compound (757 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:35]=[CH:34][C:13]3=[N:14][N:15]([C:17]4[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=4[OH:29])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:16]=[C:12]3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][N:37]1[C:42]([CH3:44])([CH3:43])[CH2:41]C(O)[CH2:39][C:38]1([CH3:47])[CH3:46].C([Sn](=O)CCCCCCCC)CCCCCCC>>[C:1]1([S:7]([C:10]2[CH:35]=[CH:34][C:13]3=[N:14][N:15]([C:17]4[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:32])([CH3:31])[CH3:33])[C:28]=4[OH:29])[CH2:20][CH2:21][C:22]([O:24][CH:25]4[CH2:41][C:42]([CH3:44])([CH3:43])[N:37]([CH3:36])[C:38]([CH3:47])([CH3:46])[CH2:39]4)=[O:23])[N:16]=[C:12]3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1cc(-n2nc3ccc(S(=O)(=O)c4ccccc4)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: CCCCCCCC[Sn](=O)CCCCCCCC
Product: CN1C(C)(C)CC(OC(=O)CCc2cc(-n3nc4ccc(S(=O)(=O)c5ccccc5)cc4n3)c(O)c(C(C)(C)C)c2)CC1(C)C
Temperature: 160 °C
Yield: 70 %

Procedure:
Methyl 3-(5-phenylsulfonylbenzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate (5 g, 0.01 mol), xylenes (18 g, 0.17 mol), 1,2,2,6,6-pentamethyl-4-hydroxypiperidine (2.1 g, 0.012 mol) and dioctyltin oxide (0.5 g, 0.0014 mol) are charged to a reactor and heated to 160° C. while being vigorously stirred. At the end of six hours, any remaining xylene is removed by distillation under vacuum. The crude yellow oil obtained is chromatographed through a pad of silica gel using ethyl aetate as the eluent. The title compound is obtained in a 70% yield as a low melting yellow solid, melting at 45-52° C., whose structure is consistent with 1Hnmr and mass spectrometry.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=1)([O-:23])=[O:22]>>[CH2:1]([C:5]1[N:6]([CH2:36][C:33]2[CH:32]=[CH:31][C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N+:21]([O-:23])=[O:22])=[CH:35][CH:34]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Yield: 91 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2,4-dihydro-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step A) was alkylated with (2'-nitrobiphenyl-4-yl)methyl bromide (from Step B). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) gave a 91% yield of the title compound as a sticky foam; satisfactory purity by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 497 (M+1)+.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:19])/[C:13](/I)=[CH:14]\[CH:15]([CH3:17])[CH3:16].[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)(=[O:23])=[O:22].[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][O:11][C:12](=[O:19])/[C:13](/[C:27]1[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=1)=[CH:14]/[CH:15]([CH3:17])[CH3:16]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: COC(=O)/C(I)=C\C(C)C
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC(=O)/C(=C/C(C)C)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
A mixture of zinc dust (1.71 g, 26 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (2 mL) under argon was treated with 1,2-dibromoethane (0.28 g, 1.5 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (163 mg, 1.5 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-2-iodo-4-methyl-pentenoic acid methyl ester (2.22 g, 8.7 mmol) in dry tetrahydrofuran (3 mL) over 2 min. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (8 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (81 mg, 0.15 mmol) and triphenylphosphine (156 mg, 0.6 mmol) in dry tetrahydrofuran (15 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (1.64 g, 7 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. for 24 h. The reaction mixture was then cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (100 mL), and the organic compound was extracted into ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/2 hexanes/ethyl acetate) afforded (E)-2-(4-(methanesulfonyl)-phenyl)-4-methyl-pentenoic acid methyl ester (1.876 g, 95%) as a viscous yellow oil: EI-HRMS m/e calcd for C14H18O4S (M+) 282.0926, found 282.0933.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[CH:12]([C:14]1[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)=O.[OH-].[K+]>CCO>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])/[CH:10]=[CH:12]/[C:14]2[CH:15]=[CH:16][C:17](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(CO)cc1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(/C=C/C(=O)c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A mixture of 1-(4-hydroxymethyl-phenyl)-ethanone (1 g, 6.67 mmol), 4-formylcinnamic acid (1.17 g, 6.67 mmol) and 1.7 M KOH (5.89 ml) in EtOH (60 ml) was stirred at room temperature overnight. The resulting precipitate was filtered and washed with EtOH to give 1.39 g of (E)-3-{4-[(E)-3-(4-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid as its potassium salt.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][CH2:22][S:23][CH2:24][CH2:25][OH:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][CH2:22][S:23][CH2:24][CH2:25][O:26][C:28](=[O:30])[CH3:29])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: CC(=O)OCCSCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 87 %

Procedure:
Following a procedure similar to that described in Example 2, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-3-(2-hydroxyethylthio)propionamide (prepared as described in Example 11) and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 87% yield.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6](=[O:33])[CH2:7][CH:8]1[N:14]([C:15](=O)[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:13][C:12]2[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=2[N:10]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:9]1=[O:32].Br.BrCC1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6](=[O:33])[CH2:7][CH:8]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:13][C:12]2[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=2[N:10]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:9]1=[O:32]
Reactant: CC(C)(C)CN1C(=O)C(CC(=O)NCc2ccccc2F)N(C(=O)c2ccncc2)Cc2ccccc21
Agent: Br
Agent: BrCc1ccncc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)CN1C(=O)C(CC(=O)NCc2ccccc2F)N(Cc2ccncc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.9 %

Procedure:
To a solution of the compound (0.36 g) obtained in Example 1B (1) in dimethylformamide (15 ml) were added 4-(bromomethyl)pyridine hydrobromide (0.92 g) and potassium carbonate (0.87 g), and the mixture was stirred at room temperature for 20 hrs. Ethyl acetate was added, and the mixture was washed with water and dried over anhydrous MgSO4. The solvent was evaporated, and the residue was purified by silica gel column chromatography and recrystallized from hexane-chloroform to give the title compound (0.15 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[C:12](I)[S:11][C:10]=1I)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)CCC.Cl>CN(C=O)C.[Cu]>[CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:10]2[S:11][CH:12]=[CH:13][CH:9]=2)[S:11][C:10]=1[C:31]1[S:30][CH:29]=[CH:33][CH:32]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOP(=O)(OCC)c1c(I)sc(I)c1P(=O)(OCC)OCC
Agent: [Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1c(-c2cccs2)sc(-c2cccs2)c1P(=O)(OCC)OCC
Temperature: 80 °C
Reaction time: 12 h

Procedure:
3,4-bis(diethoxyphosphoryl)-2,5-diiodothiophene obtained in Example 7, and different types of copper reagents (2.2 equivalents, commercial products) indicated in Table 9 were dissolved in DMF, to which 2-tributylstannylthiophene (2.2 equivalents) was added at room temperature. Thereafter, the reaction mixture was heated to 80° C. and stirred for 11 to 13 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a 0.6 M hydrochloric acid aqueous solution was added, followed by extraction of the resulting product with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting product was purified with a silica gel column (ethyl acetate:methanol=15:1) to obtain the specified substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH:16]1([NH2:19])[CH2:18][CH2:17]1.C(N(CC)CC)C>>[CH:16]1([NH:19][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: NC1CC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CC2)c1Cl
Yield: 77.3 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.39 g, 4.78 mmol), cyclopropylamine (273 mg, 4.78 mmol) and triethylamine(1.0 mL, 7.17 mmol) were reacted to form the desired product (1.15 g, 77%). 1H NMR (MeOD-d4): δ 7.72 (d, 1H), 7.65 (d, 1H), 2.34 (m, 1H), 0.75 (m, 4H).