Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2](O)([C:4]([F:7])([F:6])[F:5])=[O:3].[F:9][CH:10]([F:30])[CH2:11][O:12][CH:13]1[C:18](OC)([O:19]C)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.C(=O)(O)[O-].[Na+]>C1COCC1>[F:30][CH:10]([F:9])[CH2:11][O:12][CH:13]1[C:18](=[O:19])[CH2:17][CH2:16][N:15]([C:2](=[O:3])[C:4]([F:7])([F:6])[F:5])[CH2:14]1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCC(F)F
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCN(C(=O)C(F)(F)F)CC1OCC(F)F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Water (5 mL) and TFA (2 mL) were added to a solution of tert-butyl 3-(2,2-difluoroethoxy)-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (121b) (1.5 g, 4.67 mmol) in THF (30 mL), and the mixture was stirred at 70° C. for one hour. Sodium bicarbonate was added to a pH of about 8, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 1.1 g of the title compound as a light brown oily substance (86%).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:11](=[O:12])[CH2:10][CH2:9][CH:8]1[C:13]#[N:14])=O.[CH2:15]([SH:18])[CH2:16][SH:17].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[S:17]1[CH2:16][CH2:15][S:18][CH:1]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:11](=[O:12])[CH2:10][CH2:9][CH:8]1[C:13]#[N:14]
Reactant: N#CC1CCC(=O)C1CCCCC=O
Reactant: SCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N#CC1CCC(=O)C1CCCCC1SCCS1

Procedure:
17 g [0.063 mol] of 2-(4-formylbutyl)-3-oxo-cyclopentane-carbonitrile were dissolved in 200 ml of toluene and stirred for 30 minutes at room temperature with [0.08 mol]=6.7 ml of 1,2-ethanedithiol and 2 ml of boron trifluoride etherate, washed with water and sodium bicarbonate solution, dried over sodium sulfate and concentrated. 15.6 g of a light color oil were obtained.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH3:6][N:7]=[C:8]=[O:9]>ClCCl>[CH3:6][NH:7][C:8]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:9]
Reactant: CCCCN
Reactant: CN=C=O
Solvent: ClCCl
Product: CCCCNC(=O)NC
Reaction time: 8 h

Procedure:
280.32 Grams (3.84 moles) of butylamine and 300 ml of dichloromethane were charged to a round bottom flask equipped with stirrer, cold bath, thermometer, addition funnel and reflux condenser. 229.8 Grams (4.03 Moles, a 5% excess) of methyl isocyanate were charged to the addition funnel and added to the flask contents over four hours keeping the contents between 0° and 35° C. After an additional hour of stirring the exothermic reaction subsided and the mixture was allowed to stand overnight.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:11][C:12]1[C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH:9]=[CH2:10].Cl[CH2:26][C:27]1[CH:46]=[CH:45][C:30]([O:31][CH2:32][C:33]2[N:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[O:36][C:37]=2[CH3:38])=[C:29]([O:47][CH3:48])[CH:28]=1>C(OCC)(=O)C.CCCCCC>[CH3:38][C:37]1[O:36][C:35]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[N:34][C:33]=1[CH2:32][O:31][C:30]1[CH:45]=[CH:46][C:27]([CH2:26][N:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([O:11][CH2:8][CH:9]=[CH2:10])[C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:28][C:29]=1[O:47][CH3:48]
Reactant: C=CCOc1cccc2[nH]c3ccccc3c12
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.05 g of sodium hydride (60%) was added to N,N-dimethylformamide (170 mL) solution of 35 g of 4-(allyloxy)-9H-carbazole while being cooled in an ice bath, and stirred at room temperature for 1 hour. Thereafter, 49.4 g of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole was added thereto, and stirred for 1 hour. The reaction mixture was diluted with mixture of ethyl acetate:n-hexane=1:1 (340 mL), poured into ice water (680 mL), and stirred for 1 hour. The crystalline precipitate was isolated by filtration, and washed with mixture of ethyl acetate:n-hexane=1:1. The crystalline precipitate was dried under reduced pressure, and 55.4 g the subject compound was prepared as pale yellow crystal.
Reaction SMILES: [NH:1]([C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([S:17][CH3:18])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:21]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[NH:1]([C:8]1[C:13]([C:14]([NH2:21])=[O:15])=[CH:12][N:11]=[C:10]([S:17][CH3:18])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CSc1ncc(C(=O)O)c(Nc2ccccc2)n1
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc(C(N)=O)c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
The compound prepared in Example 92 (2.15 g), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (1.74 g) and 1-hydroxybenzotriazole hydrate (1.39 g) were combined in N,N-dimethylformamide (20 mL). The mixture was stirred for 2 hours at room temperature and then concentrated aqueous ammonium hydroxide (15 mL) was added slowly. The reaction was stirred for one hour and then was diluted with ethyl acetate and sequentially washed with water and brine. The organics were dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (2.06 g) having the following physical data.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl.[CH2:29]([O:31][C:32]([C@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]1)=[O:33])[CH3:30]>C(C(C)=O)C.C(OCC)(=O)C>[CH2:29]([O:31][C:32]([C@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)=[O:33])[CH3:30]
Reactant: CCOC(=O)[C@H]1CCCCN1
Reactant: BrCCC=C1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCOC(=O)[C@H]1CCCCN1CCC=C1c2ccccc2CCc2ccccc21
Temperature: 25 °C

Procedure:
5-(3-Bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.7 g, 8.6 mmol, prepared as described in WO 9518793), potassium carbonate (7.14 g, 52 mmol), potassium iodide (1.4 g 8.6 mmol), and (R)-(+)-2-piperidine-carboxylic acid ethyl ester hydrochloride (3.3 g, 17 mmol) were mixed in methyl ethyl ketone (50 ml) and heated at reflux temperature for 3 days. After cooling to room temperature, ethyl acetate (100 ml) was added and the mixture was washed with water (2×100 ml). The organic phase was dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (600 ml), using a mixture of ethyl acetate and heptane (1:4) as eluent. This afforded 2.62 9 (78%) of (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5-ylidene)-1-propyl)-2-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].F[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10]([NH2:12])=[O:11]>C1COCC1>[CH2:1]([O:3][C:14]1[CH:13]=[C:9]([CH:8]=[CH:7][C:15]=1[N+:16]([O-:18])=[O:17])[C:10]([NH2:12])=[O:11])[CH3:2]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C(N)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethanol (0.8 mL, 13.8 mmol) was added drop wise to a stirred suspension of sodium hydride (60% dispersion in oil, 0.550 g, 13.8 mmol) in anhydrous THF (15 mL) at 0° C. and the resulting solution stirred for 0.5 hours. To this solution was added 3-fluoro-4-nitrobenzamide (2.11 g, 11.5 mmol) drop wise in anhydrous THF (15 mL). After complete addition the solution was stirred at 0° C. for 0.5 hours, before being allowed to warm to ambient temperature. The reaction was stirred at ambient temperature for 18 hours, quenched with water (30 mL) and the aqueous layer extracted with DCM (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The title compound was obtained as a yellow solid (1.694 g, 70% yield) after recrystallisation from MeOH.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[Cl:19].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:19][C:18]1[CH:17]=[CH:16][C:15]([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[CH:14][C:13]=1[NH:12][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(N)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(NC(=O)c3ccc(C#N)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 173.8 %

Procedure:
4-Cyanobenzoyl chloride (0.25 g) was added to a stirred mixture of N-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.39 g), triethylamine (0.51 ml), 4-dimethylaminopyridine (0.01 g) and methylene chloride (25 ml). The mixture was stirred at ambient temperature for 18 hours. The mixture was washed with 2M hydrochloric acid solution and with water. The organic phase was dried (MgSO4)and evaporated. The residue was purified by column chromatography on silica gel using a 49:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.1 1 g);
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:14][C:15]([OH:17])=[O:16])[CH:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cnc2ccccc2c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.006 g (6.4 mmol) of quinoline-3-carbaldehyde were dissolved in 10 ml of pyridine and 0.794 g (7.6 mmol) of malonic acid and 54 mg (0.6 mmol) of piperidine were added. The resulting solution was boiled under reflux for 6 h. The solution was allowed to cool to room temperature and kept for 16 h whereupon the product precipitated. The product was isolated by filtration. Yield: 0.765 g.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C1C2C(=CC=CC=2)C=CC=1S([N:25]=[N+:26]=[N-])(=O)=O.C(N(CC)CC)C.C(OCC)C>C(#N)C>[N+:25](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[N-:26]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc2ccccc2c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])C(=O)OCC
Temperature: 25 °C
Yield: 100 %

Procedure:
To a stirred solution of 24.52 grams (0.15 mole) of diethyl malonate and 34.0 grams (0.15 mole) of 2-naphthalenesulfonyl azide In 100 milliliters of acetonitrile was added 15.49 grams (0.15 mole) of triethylamine, dropwise, with cooling at 0° C.-5° C. On completing the feed the mixture was allowed to warm to room temperature while stirring for an approximate 16-hour period. Volatiles were stripped from the mixture under reduced pressure and the residue was slurried with ethyl ether and the inorganic salt filtered off. The filtrate was evaporated free of ether and purified by silica column chromatography to give 27.03 grams (0.15 mole) of diethyl diazomalonate as a yellow liquid. NMR analysis of the product indicated the following:
Reaction SMILES: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16](C3C=NN(C)C=3)=[C:12]2N=C(C2CCC(CC(OCC)=O)CC2)C=1.[CH3:45][Si:46]([CH3:84])([CH3:83])[CH2:47][CH2:48][O:49][CH2:50][N:51]([CH2:75][O:76][CH2:77][CH2:78][Si:79]([CH3:82])([CH3:81])[CH3:80])[C:52]1[N:57]2[N:58]=[CH:59][C:60](I)=[C:56]2[N:55]=[C:54]([CH:62]2[CH2:67][CH2:66][N:65]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:64][CH2:63]2)[CH:53]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:45][Si:46]([CH3:84])([CH3:83])[CH2:47][CH2:48][O:49][CH2:50][N:51]([CH2:75][O:76][CH2:77][CH2:78][Si:79]([CH3:82])([CH3:81])[CH3:80])[C:52]1[N:57]2[N:58]=[CH:59][C:60]([C:16]3[CH:15]=[N:14][N:13]([CH3:8])[CH:12]=3)=[C:56]2[N:55]=[C:54]([CH:62]2[CH2:67][CH2:66][N:65]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:64][CH2:63]2)[CH:53]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(C)c4)c3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Product: Cn1cc(-c2cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)cc(C4CCN(C(=O)OC(C)(C)C)CC4)nc23)cn1

Procedure:
tert-Butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([O:9][C:10]2C=CC=CC=2)=[O:8])=[CH:3][CH:2]=1.C(=O)(OC)OC.C(=O)(OC1C=CC=CC=1)OC.C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)Oc2ccccc2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: COC(=O)Oc1ccccc1
Solvent: COC(=O)OC
Product: COC(=O)c1ccc(C)cc1
Yield: 33 %

Procedure:
Into an autoclave made of SUS316 having an internal volume of 100 ml were charged the synthesized phenyl p-toluate 30 g (141 mmole), dimethyl carbonate 6.37 g (70.7 mmole) and titanium tetraisopropoxide 0.80 g (2.83 mmole). The pressure was elevated to 20 kg/cm2 with nitrogen, and the contents were then reacted for three hours at 180° C. After completing the reaction, the reaction mixture was analyzed by gas chromatography. As a result, the yield of methyl phenyl carbonate was 18%, and the yield of diphenyl carbonate was 15%. Furthermore, at the same time, methyl p-toluate was produced as a by-product with a yield of 33% (the yield is given in terms of phenyl p-toluate).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH2:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C1COCC1>[CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1)[CH3:2]
Reactant: CCc1cc(N)n(-c2ccccc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a stirred mixture of 3-ethyl-1-phenyl-1H-pyrazol-5-amine (1.00 g, 5.34 mmol) and potassium carbonate (1.48 g, 10.68 mmol) in THF (50 mL) at −5° C., was added phenyl chloroformate (1.00 g, 6.41 mmol) dropwise. After stirring for a further 30 min at −5° C., the reaction mixture it was warmed to rt and stirred for a further 15 h. The mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate, concentrated under reduced pressure, and dried under vacuum to afford an oil. Recrystallization from petroleum ether gave phenyl 3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (1.00 g, 61%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 10.07 (brs, 1H), 6.74-7.59 (m, 10H), 6.30 (s, 1H), 2.60 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H); LC-MS (ESI) m/z 308 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Br[C:10]1[CH:34]=[CH:33][C:13]([CH2:14][C:15]([C:17]2[N:18]([S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:19]=[C:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:21]=2)=[CH2:16])=[CH:12][CH:11]=1.[SnH4]>COCCOC.C(OCC)(=O)C.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>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:20]1[N:21]=[C:17]([C:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=3)=[CH:34][CH:33]=2)=[CH2:16])[N:18]([S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:19]=1
Reactant: C=C(Cc1ccc(Br)cc1)c1nc(CC(C)(C)C)cn1S(=O)(=O)N(C)C
Reactant: Fc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SnH4]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C=C(Cc1ccc(-c2ccc(F)cn2)cc1)c1nc(CC(C)(C)C)cn1S(=O)(=O)N(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Pd(PPh3)4 (196 mg) was added to a solution of 2-bromo-5-fluoropyridine in DME (10 mL) at ambient temperature. After heating at 90° C. overnight the reaction mixture was cooled. 2-[1-(4-bromobenzyl)vinyl]-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (110 mg) was added to the stannane solution followed by Pd(PPh3)4 (100 mg). After stirring at 95° C. overnight, the reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic phase was dried (sodium sulfate) and concentrated. Chromatography of the resulting crude product over silica eluting with 0-50% ethyl acetate/hexanes afforded 4-(2,2-dimethylpropyl)-2-{1-[4-(5-fluoropyridin-2-yl)benzyl]vinyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: IC.[C:3]([O:7][C:8](=[O:19])[NH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([Br:17])=[C:12]([CH3:18])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[C:20](=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C=O)C>[C:3]([O:7][C:8](=[O:19])[N:9]([C:10]1[CH:11]=[C:12]([CH3:18])[C:13]([Br:17])=[C:14]([CH3:16])[CH:15]=1)[CH3:20])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(C)c1Br
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(N(C)C(=O)OC(C)(C)C)cc(C)c1Br
Reaction time: 27 h
Yield: 18.8 %

Procedure:
Iodomethane (20.5 ml, 329 mmol) was added to a solution of (4-bromo-3,5-dimethyl-phenyl)-carbamic acid tert-butyl ester (47.5 g, 158 mmol) and cesium carbonate (80.6 g, 247 mmol) in DMF (165 ml) at room temperature, and the mixture was stirred for 27 hours. Further, cesium carbonate (26.9 g, 82.6 mmol) and iodomethane (20.5 ml, 329 mmol) were added at room temperature, and the mixture was further stirred for three days. An aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (4-bromo-3,5-dimethyl-phenyl)-methyl-carbamic acid tert-butyl ester (9.34 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[O:21][C:22]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][C:20]2[O:21][C:22]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)CCc1oc(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cc2nc(-c3ccccc3)c(CCC(=O)O)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-5-oxazolyl]propionate (1.00 g), lithium hydroxide hydrate (171 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (5.8 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-5-oxazolyl]propionic acid (918 mg, yield 94%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 142–143° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17](OCC)OCC>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:16]=[CH:17][C:4]=2[CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzenethiol (24.7 g) in acetone (100 ml) was added potassium carbonate (18.5 g), then 2-bromo-1,1-diethoxyethane (19.5 ml) was added dropwise thereto, the solution was stirred overnight at room temperature, then acetone was added thereto. The solution was filtered, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system). To a solution of the resulting 1-bromo-4-(2,2-diethoxyethylsulfanyl)benzene (32.5 g) in chlorobenzene (350 ml) was added polyphosphoric acid (60 ml), and then the solution was stirred for 2 hours at 140° C. The reaction mixture was poured into an ice, extracted with ethyl acetate, then sequentially washed with aqueous ammonia, water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, the resulting residue was purified by silica gel column chromatography (hexane) to provide 5-bromobenzo[b]thiophene (13.7 g). By referring to the synthetic method of Tetrahedron Lett., 1993, 34, 1007, to 5-bromobenzo[b]thiophene (13.7 g) was added sodium methoxide (28% solution in methanol) (200 ml). Copper(I) bromide (13.5 g) and ethyl acetate (40 ml) were sequencially added thereto followed by stirring for 4.5 hours at 80° C. Ethyl acetate and water were sequentially added thereto, the solution was stirred, then filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (9.2 g).
Reaction SMILES: [ClH:1].[N:2]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]=[CH:3]1.CS(O[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:32](=[NH:34])[NH2:33])[CH:28]=2)[CH:23]=1)(=O)=O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:1].[ClH:1].[N:2]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([O:14][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:32](=[NH:33])[NH2:34])[CH:28]=4)[CH:23]=3)=[O:13])=[CH:15][CH:16]=2)[CH2:6][CH2:5][N:4]=[CH:3]1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)c1ccc(NN2C=NCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(NN4C=NCC4)cc3)ccc2c1
Yield: 63.6 %

Procedure:
Alternatively, 4 g of 4-(2-imidazolinyl)aminobenzoic acid hydrochloride, 4.67 g of 6-amidino-2-naphthol methanesulfonate and 0.2 g of DMAP were dissolved in 60 ml of anhydrous pyridine, 5.13 g of DCC was added to the solution and then the reaction mixture was treated as described above, via a carbonate salt, to yield 2.35 g of 6-amidino-2-naphthyl 4-(2-imidazolinyl)amino-benzoate dihydrochloride.