Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([C:16]2[N:17]=[CH:18][C:13]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(-c2ccc(Cl)cn2)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (18.0 ml, 353.7 mmol) is slowly added to a soln. of 2-amino-5-chloropyridine (15.0 g, 116.7 mmol) in 47% aq. HBr (75.0 ml) at −10° C. An aq. soln. of NaNO2 (28.1 g, 407.3 mmol) is slowly added. The mixture is stirred for 1 h at −10 to −5° C., then for 1 h at 5° C. The mixture is neutralised with 5M aq. NaOH soln. maintaining the temperature below 25° C. The precipitate is filtered and recrystallized from pentane to give 2-bromo-5-chloropyridine. 2-Bromo-5-chloropyridine (5.0 g, 26.0 mmol), p-tolylboronic acid (4.0 g, 29.4 mmol) and tetrakis(triphenylphosphine)palladium (1.44 g, 1.2 mmol) are dissolved in toluene:EtOH 9:1 (1375 ml). A 2M aq. Na2CO3 soln. (62.5 ml) is added to the reaction mixture. The mixture is stirred at 90° C. for 24 h, cooled to rt and filtered over celite. The toluene layer is separated and washed with brine. The aq. layers are extracted with AcOEt. The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown solid which is purified by FC (silica gel, eluent toluene) to give 5-chloro-2-p-tolyl-pyridine. (R)-3-Quinuclidinol (2.97 g, 23.4 mmol) is added to a suspension of NaH (0.96 g of a 60% dispersion in mineral oil, 22.8 mmol) in DMF (90 ml). The mixture is stirred for 1 h at rt. 5-Chloro-2-p-tolyl-pyridine (4.00 g, 19.6 mmol) is added and the mixture is heated for 135 h at 135° C. The reaction mixture is diluted with toluene and washed with 1M aq. NaOH soln. and brine. The aq. layers are re-extracted with toluene (3×). The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown oil which is purified by FC (silica gel, eluents: AcOEt, then AcOEt/MeOH/NEt3 87:10:3) and recrystallized from CH3CN to give (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane; mp° C.: 110-112; [α]Drt=+21.2° (0.50, MeOH), M+H+ 295.2.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10]Br)=[CH:4][CH:3]=1.[C-:18]#[N:19].[K+]>C(O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][C:18]#[N:19])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: BrCc1ccccc1CCc1ccc(Br)cc1
Agent: [K+]
Solvent: CCO
Product: N#CCc1ccccc1CCc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
2-(4-Bromophenethyl)-benzyl bromide, 27.0 g. (0.0764 mole) and 6.2 g. (0.0954 mole) of potassium cyanide are suspended in 180 ml. of 95% ethanol and the mixture is stirred at reflux for 2 hours. Ethanol, 70 ml. of 95%, is added and stirring at reflux is continued for 2 hours. The precipitate is removed by filtration and the ethanolic filtrate evaporated under reduced pressure. The residual brown oil is dissolved in benzene and the solution is washed thoroughly with water and dried over anhydrous sodium sulfate. Evaporation of the benzene under reduced pressure leaves the product as the residual dark yellow oil that slowly solidifies to an oily solid. Recrystallization from cyclohexane-petroleum ether gives purified material, m.p. 59°-60.5° C. Vapor phase chromatography indicates a purity of approximately 99%.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:47][O:46][C:40]1[CH:39]=[C:38]([CH:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:28][CH:27]=2)[C:23]2[NH:22][C:21](=[O:20])[N:10]([C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([OH:2])=[O:4])[N:11]=2)[CH:43]=[CH:42][C:41]=1[O:44][CH3:45]
Reactant: COC(=O)c1sccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OC)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
After adding 30 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 25 μl of triethylamine to a solution of 80 mg of {2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (36d)) in 3 ml of DMF, the mixture was stirred at 85° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2 ml of methanol and 2 ml of THF. After adding 35 μl of acetic acid and 56 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 15 hours. Next, 2 ml of an aqueous 1N sodium hydroxide solution was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. After adding 2 ml of 1N hydrochloric acid to the reaction mixture, extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 70 mg of 3-(3-{(3,4-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][C:21]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C1COCC1>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:14][CH2:13][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[CH:11][CH:10]=2)[C:15]([F:16])([F:17])[F:18])=[CH:22][C:21]=1[NH:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Fc1ccc(CBr)cc1Nc1ccccc1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(COCc2ccc(F)c(Nc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 120 mg of sodium hydride (60% oil dispersion) was added to 10 ml of dry THF. A solution of 0.69 of 2-(4-ethoxyphenyl)-3,3,3-trifluoropropanol and 0.82 g or 4-fluoro-3-anilinobenzyl bromide in 20 ml of dry THF was then added with ice-cooling, and the reaction solution was stirred with ice-cooling for 1 hour and at room temperature for 46 hours. Thereafter, the reaction mixture was poured into ice water and adjusted to pH 6 with dilute HCl and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (25:1) mixture] to obtain 368 mg of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14]([CH3:16])=[O:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.FC1C=C(N[C:44]([NH:46][C:47](=[O:55])[CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[S:45])C=CC=1OC1C2SC(SC)=CC=2N=CN=1>>[F:1][C:2]1[CH:20]=[C:19]([NH:21][C:44]([NH:46][C:47](=[O:55])[CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[S:45])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14]([CH3:16])=[O:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CSc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reactant: CS(=O)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Product: CS(=O)c1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Yield: 36 %

Procedure:
Starting from the compound 285 and following the procedure described above for the synthesis of compound 283 (scheme 64, step 4, example 225), title compound 286 was obtained in 36% yield as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 12.45 (s, 1H), 11.83 (s, 1H), 8.80 (s, 1H), 8.13 (s, 1H), 7.93(dd, 1H, J1=2.3 Hz, J2=10.9 Hz), 7.55 (t, 1H, J=8.6 Hz), 7.48 (m, 1H), 7.34-7.31 (m, 4H), 7.28-7.25 (m, 1H), 3.81 (s, 2H), 3.08 (s, 3H). MS (m/z): 501.0 (M+H) (found).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[I:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[O:29])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccc(I)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(c1ccc(I)cc1)c1ccc(OC[C@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 2 (25 mg, 0.05 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. The resulting solid was filtered out and dried under vacuo to yield the title product (16 mg, 80%); LCMS; 100% ESI+ Calcd: 407.3, found m/z: 408.5 (M+1); 1H NMR (500 MHz, DMSO-d6); δ 1.71-1.80 (m, 1H), 1.82-2.06 (m, 2H), 2.10-2.20 (m, 1H), 3.16-3.30 (m, 2H), 3.90-4.00 (m, 1H), 4.23-4.27 (m, 1H), 4.38 (dd, J1=10.0 Hz, J2=2.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 2H), 7.46 (d, J=7.5 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.95 (d, J=8.0 Hz, 2H):
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(S([C:19]1[S:20][C:21]([C:26]#[N:27])=[CH:22][C:23]=1[C:24]#[N:25])=O)C>C(#N)C>[C:1]1([S:7][C:19]2[S:20][C:21]([C:26]#[N:27])=[CH:22][C:23]=2[C:24]#[N:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: CCS(=O)c1sc(C#N)cc1C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cc(C#N)c(Sc2ccccc2)s1
Reaction time: 8 h

Procedure:
4.4 ml of thiophenol and 5.0 ml of triethylamine are added, while stirring, to a solution of 8.9 g of 2-ethylsulphinyl-3,5-dicyanothiophene, obtained according to Example I, in 100 ml of acetonitrile. After leaving to stand overnight, the reaction mixture is refluxed for 8 hours. After evaporating the solvent, the residue is taken up in methylene chloride and chromatographed over a 1 l dry silica gel column. The desired product is obtained in a yield of 9.07 g; melting-point 68°-71° C. Optionally, any 2-alkylsulphinyl compound may be used as the starting substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](Cl)=[O:28].O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)=[O:28])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)c1ccccn1
Yield: 31.6 %

Procedure:
A solution of amine 8 (0.145 g, 0.57 mmol) and picolinoyl chloride hydrochloride (0.180 g, 1.01 mmol) in dry pyridine (5 ml) was stirred at room temperature overnight. After addition of water the brown solid was filtered and passed through a SiO2 gel, eluting with CH2Cl2: MeOH (100:5) affording the desired product 21 (0.065 g, 31%).
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](#[N:16])[CH2:13][C:14]#[N:15].C([O-])(=O)C.[NH4+].C(O)C>O.Cl>[C:2]1([C:1]([CH2:9][C:10]#[N:11])=[C:13]([C:12]#[N:16])[C:14]#[N:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#CCC(=C(C#N)C#N)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of benzoylacetonitrile (9.94 g, 0.0685 mole), malononitrile (11.3 g, 0.17 mole), ammonium acetate (5.4 g, 0.07 mole) and ethanol (100 mL) was heated at reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and concentrated hydrochloric acid (7.5 mL) was added dropwise over 5 minutes. The resulting precipitate was collected by filtration and washed with water and ligroin. The yield was 10.0 g (76%), m.p. 92°-98° C.
Reaction SMILES: [Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])(O)[C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[CH:14][CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[CH:3]=1
Reactant: CN(C)CCCC1(O)c2ccccc2C=C(Br)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN(C)CCC=C1c2ccccc2C=C(Br)c2ccccc21
Reaction time: 2 h

Procedure:
10-Bromo-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene (14.75 g., 0.0396 mole) is dissolved in 100 ml. of trifluoroacetic acid. Trifluoroacetic anhydride, 50 ml., is added and the solution heated to refluxing with stirring for 11/2 hours. The excess trifluoroacetic anhydride and the trifluoroacetic acid are distilled, the residue suspended in water and the mixture rendered alkaline with sodium hydroxide solution. The base is extracted into ether. After washing the extract with water, the ether is distilled, leaving the oily product as the residue in a yield of 13.75 g. (98%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C([Li])(C)(C)C.S(C)C.C1C[O:22]CC1>CCCCC>[OH:22][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: C1CCOC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CSC
Product: Cc1cc(C#N)ccc1O
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (7.07 g, 36.1 mmol) in 225 mL of THF at -78° C. is added a 1.7 M solution of tert-butyl lithium (45.6 mL, 77.6 mmol) in pentane. After 5 minutes, CuBr.SMe2 (15.9 g, 77.6 mmol) is added. The resulting solution is stirred for 10 minutes, then O2 is slowly bubbled through the reaction mixture for 30 minutes. After this time, the solution is allowed to warm to ambient temperatures. The solution is stirred for 16 hours. The solution is then poured into 100 mL of H2O. The solution is diluted with EtOAc. The layers are separated. The organic layer is washed with saturated (NH4)2SO4 solution. The organic layer is then extracted with 10 N NaOH. The collected aqueous basic layers are acidified to pH=6 with 6N HCl. The solution is then extracted with EtOAc. The combined organic layers are dried over MgSO4, filtered and concentrated. The title compound is obtained as a solid.
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([OH:27])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH3:32][N:33]([CH3:42])P(N(C)C)(N(C)C)=O>O1CCCC1>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:33]([CH3:42])[CH3:32])=[O:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1ccccc1C(=O)O)c1ccccc1Oc1ccccc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(=O)N(Cc1ccccc1C(=O)N(C)C)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a mixture of 10 ml of tetrahydrofuran and 0.1 ml of hexamethylphosphoramide was dissolved 0.50 g of N-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline, and 0.2 ml of thionyl chloride was added, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, the residue was dissolved in 10 ml of tetrahydrofuran, and 2 ml of 50% aqueous dimethylamine solution was added dropwise with stirring. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:3) to give 0.49 g of N-acetyl-N-(2-dimethylaminocarbonylbenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:9])([F:8])[S:4](Cl)(=[O:6])=[O:5].C(=O)([O-])O.[Na+].[OH:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].O>C(#N)C>[F:8][C:3]([F:9])([S:4]([O:15][N:16]1[C:20](=[O:21])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]1=[O:26])(=[O:6])=[O:5])[CH2:2][OH:1]
Reactant: O=S(=O)(Cl)C(F)(F)CO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)C(F)(F)CO
Temperature: 0 °C
Yield: 54.7 %

Procedure:
In 100 mL of acetonitrile, 25.5 g of a liquid of 2-hydroxy-1,1-difluoroethanesulfonyl chloride (purity: 98%, equivalent to 0.138 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 14.0 g (0.166 mol) of sodium hydrogencarbonate and 24.8 g (0.152 mol) of N-hydroxyphthalimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water and subjected to concentration. The concentration residue was admixed with 75 mL of ethyl acetate, followed by heating the solution at 60° C. to dissolve the solid substance. Then, 150 mL of heptane was dropped into the solution. The solution was gradually cooled to 0° C. to precipitate a crystalline out of the solution. The crystalline precipitate was filtered out and dried. With this, 23.2 g of the target compound was obtained as a white solid (yield: 53%, purity: 97%, pure content: 22.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[OH:31].ClC[CH2:34][C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[O:31][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)CCCl
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(O)c3)nc2-c2ccc3ncccc3c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1cc(Cc2nc(-c3ccc4ncccc4c3)c(-c3cccc(C)n3)[nH]2)ccc1F
Temperature: 60 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a stirred solution of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol (Example 81) (100 mg, 0.244 mmol) in acetone (5 mL) were added methyl 3-chloropropanoate (32 uL, 0.366 mmol) and K2CO3 (67 mg, 0.488 mmol) and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL), and extracted with CH2Cl2 (5 mL, 3 times). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=1:50 (v/v)) to afford the title compound (88.4 mg, 75%). (300 MHz, CDCl3) δ 2.50 (3H, s), 3.74 (3H, s), 4.16 (2H, s), 4.71 (2H, s), 6.91-6.97 (3H, m), 7.06 (1H, td), 7.24 (1H, s), 7.37 (1H, d), 7.42 (1H, dd), 7.97 (1H, d), 8.10-8.18 (3H, m), 8.92 (1H, dd), 10.35 (1H, bs). MS (ESI) m/z 483 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[F:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH:43][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccccc1F
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1ccccc1CNCCCOc1cccc(-c2noc3ccsc23)c1
Temperature: 80 °C
Yield: 94.1 %

Procedure:
Combine a mixture (1 mmol total) of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole with 2-fluorobenzylamine (0.63 g, 5.0 mmol), potassium carbonate (0.41 g, 3.0 mmol) and a mixture of acetonitrile:water (80:20) and heat (80° C.) for 30 hours. Cool the reaction mixture and concentrate to give a residue. Purify the residue by column (silica) chromatography (ethyl acetate). Combine the appropriate fractions and concentrate to give the title compound (0.36 g, 94% Yield) as an oil. Purity by LC/MS (APCI)=100% area, [M+H]+=383 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:6]([N:8]1[CH:14]2[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7].[Cl-:22].[NH4+]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[Cl:22][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[NH:8][C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]#[CH:21])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: C#CCOc1ccc(C(=O)N2C3CCCCC32)cc1OC
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: C#CCOc1ccc(C(=O)NC2CCCCC2Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2 ml of chloroform and 224 mg of zinc (II) chloride was stirred at room temperature for 5 minutes. Then, a mixture of 235 mg of 7-[3-methoxy-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane and 2 ml of chloroform was added dropwise thereto at room temperature, and the resulting mixture was stirred at room temperature for 5 hours. Then, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and this was extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to obtain 0.25 g of N-(2-chlorocyclohexyl)-3-methoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 108 of the present invention) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([N:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]1[Cl:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccccc2)n(Cc2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution (7 M) of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate in DMF at 0° C. was treated with NaH (1.2 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 30 min then it was treated with benzyl bromide (1.2 eq.). The reaction mixture was stirred at RT for 90 min then poured into water and extracted with AcOEt. The combined organic phase was washed with water and dried. Evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (1:8 AcOEt/petroleum ether) to afford the title compound (71%) as a solid.