Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][C:60]1[CH:61]=[CH:62][C:63]([F:74])=[C:64]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][OH:73])[CH:67]=2)[CH:65]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([NH:58][CH2:59][C:60]4[CH:65]=[C:64]([C:66]5[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][OH:73])[CH:67]=5)[C:63]([F:74])=[CH:62][CH:61]=4)=[O:27])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NCc1ccc(F)c(-c2cccc(CO)c2)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Reaction time: 72 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-amino)carbonyl]benzoic acid (0.045 g, 0.1 mmol) in CH2Cl2 (2 mL) was stirred under argon at room temperature. HBTU (0.038 g, 0.1 mmol) was added followed by [5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol (0.0231 g, 0.1 mmol) and triethylamine (28 μL, 0.2 mmol). The resulting mixture was stirred for three days. The solvents were pumped off and the residue was purified on the CombiFlash (12 g silica gel column) eluted with 70-100% EtOAc/hexane) to afford the title compound. LC-MS m/z 664.8 (M+H)+, 1.75 min (ret time).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[CH:16]([NH:18]C(=O)OC(C)(C)C)[CH3:17].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[CH:16]([NH2:18])[CH3:17]
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2ncccc2n1-c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1nc2ncccc2n1-c1ccccn1
Reaction time: 0.83 h

Procedure:
To a mixture of tert-butyl 1-(1-(pyridin-2-yl)-1H-imidazo[4,5-b]pyridin-2-yl)ethylcarbamate (0.516 g, 1.520 mmol) in DCM (10.14 mL) was added TFA (10.14 mL, 132 mmol) dropwise at rt with stirring. After 50 min, the mixture was concentrated in vacuo and co-evaporated with triethylamine and MeOH. The neutralized crude mixture was purified by chromatography through a Redi-Sep™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% DCM:MeOH:NH4OH (89:9:1) in DCM, to provide 1-(1-(pyridin-2-yl)-1H-imidazo[4,5-b]pyridin-2-yl)ethanamine as brown syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68-8.76 (1H, m), 8.49 (1H, dd, J=4.7, 1.6 Hz), 8.19 (1H, td, J=7.7, 2.0 Hz), 7.79-7.92 (2H, m), 7.63 (1H, ddd, J=7.6, 4.8, 0.9 Hz), 7.32 (1H, dd, J=8.1, 4.8 Hz), 4.47 (1H, q, J=6.7 Hz), 1.45 (3H, d, J=6.8 Hz); LC-MS (ESI) m/z 240.1 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
A 1 M solution of borane-tetrahydrofuran complex (30 ml) was added dropwise to a stirred solution of 2-phenoxybenzoic acid (5.35 g) in dry THF (50 ml), cooled to 0° C. (effervescence). Following the addition, the mixture was stirred at 0° C. for 15 minutes, then at room temperature for 1.5 hours. It was poured into water and extracted with ether. The extracts were washed successively with water, aqueous sodium bicarbonate, aqueous sodium carbonate, then dried and concentrated under reduced pressure to give 2-phenoxybenzyl alcohol (4.83 g, 97%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][C:12]1[C:13]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:25]1[CH2:24][CH2:23][CH:22]([O:21][C:13]2[C:12]([CH3:11])=[CH:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][N:14]=2)[CH2:27][CH2:26]1)=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cc([N+](=O)[O-])cnc1OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cnc1OC1CCN(C(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add 2-fluoro-benzoyl chloride (1.74 g, 11.0 mmol) dropwise to a solution of 3-methyl-5-nitro-2-(piperidin-4-yloxy)-pyridine in dichloromethane (50 mL) and triethylamine (1.21 g, 12 mmol) and stir under N2 at room temperature for 2 hours. Wash the reaction mixture with distilled water (3×20 mL) followed by saturated aq. sodium chloride solution (1×20 mL). Dry the organic phase over sodium sulfate and concentrate to give (2-fluoro-phenyl)-[4-(3-methyl-5-nitro-pyridin-2-yloxy)-piperidin-1-yl]-methanone as a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].N1C=CC=CC=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29].[NH2:40][CH2:41][CH2:42][CH2:43][OH:44]>ClCCl.C(OCC)C>[CH3:20][O:19][CH:3]1[CH:2]([O:1][C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:29])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:10]1([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]1.[OH:44][CH2:43][CH2:42][CH2:41][NH:40][C:28]([O:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20])=[O:29]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: NCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC1C(OC(=O)NCCCO)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Product: COC1C(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reaction time: 3 h
Yield: 139.3 %

Procedure:
To a mixture of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (423 mg) and pyridine (474 mg) in dichloromethane (9 ml) was added portionwise 4-nitrophenyl chloroformate (1.2 g) at ambient temperature. After stirring for 3 hours, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-(4-nitrophenoxycarbonyloxy)-1-oxaspiro[2,5]octane was prepared in the reaction mixture. To the mixture 3-amino-1-propanol (2.25 g) was added in one portion. The mixture was stirred for 2 hours at ambient temperature and then diluted with diethyl ether (20 ml). The solution was washed with brine, 1N aqueous hydrochloric acid, 1N agueous sodium hydroxide, and brine successively. The solvent was dried and evaporated in vacuo to give a crude oil, which was purified by column chromatography on silica gel eluted by ethyl acetate to yield 6-(3-hydroxypropylcarbamoyloxy)-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (400 mg) as crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1F)[C:5]([O:7][CH3:8])=[O:6].[CH2:25]([NH2:28])[CH:26]=[CH2:27].CO.O>C1COCC1>[CH2:25]([NH:28][C:11]1[C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:2]=1[F:1])[CH:26]=[CH2:27]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C=CCN
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCNc1c([N+](=O)[O-])cc(C(=O)OC)c(Nc2ccc(I)cc2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyl 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-nitrobenzoate (3.9 g, 8.62 mmoles) and allylamine (3.5 ml, 43 mmoles) in a mixture of THF (10 ml), MeOH (10 ml) and H2O (2.5 ml) is stirred at room temperature for 30 min. The yellow suspension is filtered and washed with hexane to remove the excess of allylamine. The resulting solid is dried under vacuum to obtain the title compound.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=O)[CH:3]([CH2:4]2)[CH2:2]1.C(O[CH:14]([N:18]([CH3:20])C)[N:15](C)C)(C)(C)C.Cl.[NH2:22]C(N)=N.[Na]>>[CH2:1]1[CH:5]2[C:6]3[C:7]([CH:3]([CH2:4]2)[CH2:2]1)=[N:22][C:14]([NH2:15])=[N:18][CH:20]=3
Reactant: N=C(N)N
Reactant: O=C1CC2CCC1C2
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Agent: [Na]
Product: Nc1ncc2c(n1)C1CCC2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Norcamphor (6.11 g, 55.5 mMol) was heated with t-butoxy bis(dimethylamino)methane (Bredereck's reagent, 9.7 g, 55.5 mmol) at 100° C. overnight. The solvent was removed under vacuum and the crude residue was taken up in anhydrous ethanol (120 mL). Guanidine hydrochloride (10.6 g, 110 mmol, 2 eq.) and sodium metal (2.5 g, 110 mmol) were added. After the sodium dissolved, the mixture was heated to reflux for 48 h. After cooling to ambient temperature, sodium metal (0.47 g) and guanidine hydrochloride (2.0 g) were added and heating was resumed for another 24 h. The reaction mixture was concentrated under vacuum and then partitioned between chloroform and water. The aqueous layer was extracted once with chloroform. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 2-amino-5,8-methano-5,6,7,8-tetrahydroquinazoline as a pale yellow solid; 1H NMR (CDCl3, 300 MHz) 7.89 (s, 1H), 5.07 (br s, 2H), 3.31 (s, 1H), 3.16 (s, 1H), 1.93 (m, 2H), 1.74 (d, 1H), 1.53 (d, 1H), 1.25 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz) 179.44, 147.43 (2C), 128.79, 47.51, 45.41, 39.85, 27.81, 25.42; MS(ES) 162 (M+H). The aniline, 2-amino-5,8-methano-5,6,7,8-tetrahydroquinazoline, can be used to make the corresponding hydrazine as outlined below, or alternatively, can be used as an aniline (B) as outlined in Reaction Scheme 1 above.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc(C)c1-c1cccc(C=O)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethyl-3-biphenylcarbaldehyde (2.26 g, 10.0 mmol) and benzyl bromide (3.42 g, 20.0 mmol) in N,N-dimethylformamide. (10 mL) was added potassium carbonate (2.76 g, 20.0 mmol), and the mixture was stirred at 70° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-10% ethyl acetate/hexane) to give the title compound (2.90 g, yield 92%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(=[O:22])C.OO.[OH2:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)(=[O:22])=[O:26])=[CH:4][CH:3]=1
Reactant: O
Reactant: COC(=O)Cc1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: CC(=O)O
Agent: OO
Product: COC(=O)Cc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 14.62 g of methyl [p-(p-chlorophenylthio)phenyl]acetate, 100 ml of glacial acetic acid and 62.5 ml of 30% hydrogen peroxide is heated to 70° C and kept at 70° C for 3 hours. After cooling, the mixture is poured into 500 ml of water and extracted with three 100 ml portions of chloroform. The combined extracts are washed with three 100 ml portions of water, 100 ml of saturated NaHCO3, saturated brine and dried over MgSO4. Evaporation of the solvent affords an oil which crystallizes on standing to give 14.9 g of product as white crystals (from petroleum ether) mp 78°-80° C.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:39]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:39]1([NH:44][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)(=[O:28])=[O:29])=[CH:38][CH:37]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: O=C(NC1CCCC1)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 95.4 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 57 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 598 [M+H]+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.[CH3:16][C:17]([S:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[N:22][S:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21]
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=Cc1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of commercially available dibenzo[b,d]furan-2-carbaldehyde (1.992 g; 10.20 mmol), titanium(IV) ethoxide Ti(OEt)4 (3.98 ml; 19.00 mmol), and 2-methylpropane-2-sulfinamide (1.150 g; 9.49 mmol) in anh. THF (18 ml) was stirred at rt, under nitrogen, for 4 h. AcOEt and brine were added, and the organic layer was further washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM) afforded N-(dibenzo[b,d]furan-2-ylmethylene)-2-methylpropane-2-sulfinamide as a pale yellow solid. LC-MS (conditions A): tR=0.96 min.; [M+H]+: 300.33 g/mol.
Reaction SMILES: Cl.[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)#[CH:3].[OH-].[Na+].[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N:22]2[N:26]=[CH:25][CH:24]=[N:23]2)=[C:17]([CH:21]=1)[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:18]([C:17]1[CH:21]=[C:13]([CH3:12])[CH:14]=[CH:15][C:16]=1[N:22]1[N:26]=[CH:25][CH:24]=[N:23]1)=[O:19])#[CH:3]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)Cl)c1
Reactant: C#CC1CCCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C#CC1CCCCN1C(=O)c1cc(C)ccc1-n1nccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a rapidly-stirred mixture of 2-ethynylpiperidine hydrochloride (329 mg, 2.26 mmol), toluene (5 mL), and 1N NaOH (4.7 mL), cooled at 0° C., was added a solution of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (500 mg, 2.26 mmol) in toluene (8 mL) dropwise over 20 mins. The mixture was stirred at 0° C. for 20 mins, then allowed to warm to ambient temperature. After 1 h, the solution was diluted with EtOAc and the layers separated. Brine was added to the aqueous layer and it was extracted with EtOAc. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-60% EtOAc in hexanes to provide (2-ethynylpiperidin-1-yl)[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone as a collapsing white foam. The compound gave a high resolution mass spectrum (ES+) m/z of 259.1553, calculated for M+H+ [C17H18N4O: 295.1553]. 1H NMR δ (ppm) (CDCl3): 7.75-7.86 (3H, m), 7.30-7.34 (1 H, m), 7.18-7.20 (1H, m), 5.76 (1H, d, J=33.6 Hz), 4.50-4.67 (1H, m), 3.20-3.31 (1H, m), 2.91-3.08 (1H, m), 2.43 (3H, s), 2.04-2.36 (1H, m), 1.64-1.91 (2H, m), 1.42-1.61 (1H, m), 1.30-1.37 (1H, m).
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[CH:11]=[C:12]([CH2:14][CH3:15])[S:13][C:7]=3[NH:6][C:5]2=[O:16])[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:35]=[C:34](C(Cl)(Cl)Cl)[O:33][N:32]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-:41].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[CH:11]=[C:12]([CH2:14][CH3:15])[S:13][C:7]=3[N:6]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:41])[O:33][N:32]=4)=[CH:21][CH:20]=3)[C:5]2=[O:16])[CH2:3][CH2:2]1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(=O)n(C3CC3)c(=O)[nH]c2s1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(C3CC3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
A mixture of 3-cyclopropyl-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.55 g), potassium carbonate (0.18 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.3 g, 56%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>N1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][N:11]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1ccc(-c2ccccc2)cn1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(-c3ccccc3)cn2)cc1OC
Temperature: 25 °C
Reaction time: 19 h
Yield: 69 %

Procedure:
To a solution of 5-phenylpyridin-2-amine (340 mg, 2 mmol) in 10 mL of dry pyridine was added 3,4-dimethoxybenzenesulfonyl chloride (529 mg, 2.23 mmol). The solution was stirred at room temperature under Argon. After 19 h, the pyridine was removed in vacuo and flashed off with toluene, the solid residue was partitioned between EtOAc and 1M NaOH. The alkaline phase was made acidic and the solid was collected by filtration and dried in vacuo to give 511 mg of a solid. This was taken up in 5 mL of HOAc, diluted with 3 mL of water; crystallization took place to give 447 mg of a white crystalline product with mp 202-204° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24](O)=[O:25])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:33][CH:34]=1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([N:38]2[CH2:39][CH2:40][N:35]([C:32]4[CH:31]=[CH:30][C:29]([C:28]([F:42])([F:27])[F:41])=[CH:34][N:33]=4)[CH2:36][CH2:37]2)=[O:25])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.134 mmol) with 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine in the presence of triethylamine (34 mg, 0.337 mmol) in dichloromethane (5 mL) gave 46 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.25-0.29 (m, 2H), 0.52-0.58 (m, 2H), 1.25-1.28 (m, 1H), 3.72-3.74 (m, 4H), 3.78-3.82 (m, 6H), 3.83 (s, 3H), 6.61 (d, J=9.0 Hz, 1H), 6.79-6.82 (m, 1H), 6.87-6.88 (m, 1H), 7.00 (t, J=7.8 Hz, 1H), 7.09-7.12 (m, 1H), 7.19-7.22 (m, 1H), 7.61-7.63 (m, 1H), 7.74 (d, J=3.9 Hz, 1H), 7.80 (d, J=15.9 Hz, 1H), 8.36 (br s, 1H); ESI-MS (m/z) 584.35 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[N:6][OH:7].ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:22]=[C:23]([C:28]([C:30]([F:33])([F:32])[F:31])=[CH2:29])[CH:24]=[C:25]([Cl:27])[CH:26]=1.C(=O)([O-])O.[K+]>COCCOC.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:29][C:28]([C:23]3[CH:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[CH:22]=3)([C:30]([F:31])([F:33])[F:32])[O:7][N:6]=2)[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1ccc(C=NO)cc1Cl
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
In a solution of 10.6 g of 3-chloro-4-methylbenzaldoxime in 60 mL of 1,2-dimethoxyethane, 9.2 g of N-chlorosuccinimide was added, and stirred at 70° C. for 2 hours. Then, the reaction mixture was left and cooled to room temperature, 11.3 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 1, 15.6 g of potassium hydrogen carbonate and 10 mL of water were added, and continued to stir at room temperature further for 20 hours. After the completion of the reaction, the reaction mixture was diluted with 70 mL of ethyl acetate, washed with water (50 mL×1), and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and then the solvent was distilled off under reduced pressure. The residual solid was washed with diisopropyl ether to obtain 13.8 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8](=[O:18])[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13]C(=O)C)[O:4][N:3]=1.C(N(CC)CC)C.Cl>C(O)C>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=2[CH3:13])[O:4][N:3]=1
Reactant: CC(=O)CCCC(=O)CC(=O)Cc1cc(C)no1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1=C(c2cc(C)no2)C(=O)CCC1
Temperature: 0 °C
Yield: 39.4 %

Procedure:
1.2 g of 3-methylisooxazol-5-yl-2,4,8-nonanetrione obtained in Example 6 was dissolved in 15 ml of ethanol, and 0.53 g of triethylamine was added to it to stir at reflux for 8 hours. After cooling, the reaction solution was poured into ice water, acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl-acetate layer was washed with water, dehydrated over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified on silica gel column chromatography to give 0.36 g of the title compound as white crystals. Melting point: 104-105° C.