Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1.[OH-].[K+]>C(O)C>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
A mixture of ethyl 2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (4.6 g), aqueous potassium hydroxide (1.07 g in 200 ml water) and ethanol (92 ml) was refluxed for 6 hours. After allowing to cool to ambient temperature, the reaction mixture was washed with ethyl acetate (150 ml×2). The separated aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid. To this mixture was added acetic acid (40 ml) and stirred for 30 minutes under ice cooling. The resulting precipitates were collected by filtration, washed with water and dried in vacuo to give 2-methyl-4-(3-nitrophenyl)-6-phenyl-3pyridinecarboxylic acid (1.98 g).
Reaction SMILES: [CH3:1][N:2]([S:26]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27])[C:3]1[CH:4]=[C:5]([O:21][C:22]([F:25])([F:24])[F:23])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C[N:36](C)CCCN=C=NCC.CN(C)C=O>O>[CH3:1][N:2]([S:26]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27])[C:3]1[CH:4]=[C:5]([O:21][C:22]([F:24])([F:25])[F:23])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:36])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
A mixture of {2-[7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (210 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (90 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (120 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. 1H-1,2,3-Benzotriazol-1-ol-ammonia complex (150 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (190 mg) were added to the reaction mixture, and the mixture was further stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was purified by preparative HPLC to give the title compound (90 mg, yield 43%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give pale-yellow prism crystals. melting point 186-187° C. MS: 519 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.Br[CH2:37][CH2:38][CH2:39][N:40]1[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]2[C:41]1=[O:50].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:41]1(=[O:50])[N:40]([CH2:39][CH2:38][CH2:37][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][N:14]=3)[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:10]([NH:20][C:21]([NH:23][C:24]3[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=3[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]2=[O:19])[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCN3C(=O)c4ccccc4C3=O)c3ncccc23)c1
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (200 mg, 0.43 mmol) and N-(3-bromopropyl)phthalimide (133 mg, 0.50 mmol) in DMF (10 ml) was added potassium carbonate (114 mg, 0.83 mmol), and the mixture was stirred at 50°-60° C. for one hour. After allowed to stand for cooling, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, purified by silica gel column chromatography (1-3% methanol in chloroform), and crystallized from hexane to give the title compound (229 mg, 0.35 mmol).
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([B:22]4[O:26]C(C)(C)C(C)(C)[O:23]4)=[C:18]([CH:31]=O)[CH:17]=3)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CO>[CH:1]1([O:6][C:7]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]4[B:22]([OH:26])[O:23][CH2:31][C:18]=4[CH:17]=3)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(OC4CCCC4)n3)cc2C=O)OC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2-cyclopentyloxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (2.0 g, 4.60 mmol) in methanol (15 mL) at 0° C. was added sodium borohydride (0.26 g, 6.90 mmol). After 1 h at rt, 2 M HCl was added to it at 0° C. until pH reached to 3-4. The resulting mixture was stirred at 0° C. for 30 min and then sonicated to give white solid which was filtered and lyophilized to yield D100 (0.85 g, 56%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.27 (d, J=1.2 Hz, 1H), 7.18 (dd, J=8.2, 1.9 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 4.97 (br. s., 3H), 1.75-1.54 (m, 6H), 1.52-1.33 (m, 2H); MS (ES) m/z: 337 (M+1)+; HPLC purity 99.36% (Maxplot), 99.35% (220 nm); Elemental analysis for C18H17BN2O4.0.25 H2O: Calculated C=63.46%, H=5.18%, N=8.22%. Found C=63.34%, H=5.17%, N=8.34%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11](=O)[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)CCC(=O)c1c(C)[nH]c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCc1c(C)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of methyl 4-(2-methylindol-3-yl)-4-oxobutyrate (2.0 g) in tetrahydrofuran (50 ml) was added a 1M solution of boran in tetrahydrofuran (16.5 ml) at 0° C. After stirred at 0° C. for 30 minutes, the mixture was poured into a mixture of ethyl acetate and brine. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was purified by column chromatography on silica gel (50 g) eluting with chloroform to give methyl 4-(2-methylindol-3-yl)butyrate (1.67 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]([F:8])(Br)[C:3]([F:6])([F:5])[Br:4].Cl[C:10](F)(Cl)C(F)(F)Cl.C(Cl)(Cl)=C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH:33]([O-:35])=[O:34].[Na+]>CN(C=O)C>[Br:4][C:3]([F:6])([F:5])[C:2]([Cl:1])([F:8])[CH2:10][C:33]([OH:35])=[O:34]
Reactant: FC(F)(Br)C(F)(Cl)Br
Reactant: O=C[O-]
Reactant: FC(F)(Cl)C(F)(Cl)Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C=C(Cl)Cl
Product: O=C(O)CC(F)(Cl)C(F)(F)Br

Procedure:
A one pot reaction of 1-chloro-1,2-dibromotrifluoroethane (VI) or 1,1,2-trichlorotrifluoroethane (X) with vinylidene chloride in the presence of ammonium persulfate/sodium formate/air in DMF to give 4-bromo-3-chloro-3,4,4-trifluorobutanoic acid (VIII) or 3,4-dichloro-3,4,4-trifluorobutanoic add (XI).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20](Cl)=[O:21].[Si]([O:39][C:40]([O:42][CH3:43])=[CH2:41])(C(C)(C)C)(C)C>>[CH3:43][O:42][C:40](=[O:39])[CH2:41][CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[N:6]1[C:20](=[O:21])[C:19]1[CH:18]=[C:17]([C:16]([F:31])([F:30])[F:15])[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=1
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: COC(=O)CC1c2ccccc2-c2ccccc2N1C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
[5-(3,5-Bis-trifluoromethyl-benzoyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid methyl ester was prepared from phenanthridine, 3,5-bis(trifluoromethyl)benzoyl chloride, and 1-(tert-butyldimethylsilyloxy)-1-methoxyethene according to GP 2. Yield, 49%. 1H-NMR (DMSO-d6): δ=2.46 (dd, J=14.5 Hz, J=7.0 Hz, 1H), 2.57 (dd, J=14.5 Hz, J=7.8 Hz, 1H), 3.57 (s, 3H), 6.03 (s, br., 1H), 6.80 (s, br., 1H), 7.12 (s, br., 1H), 7.31 (t, J=7.6 Hz, 1H), 7.36-7.44 (m, 2H), 7.46-7.53 (m, 1H), 7.80 (s, br., 2H), 8.03 (dd, J=7.9 Hz, J=1.1 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 8.20 (s, br., 1H); (+)-ESI-MS: m/z=494 [M+H]+.
Reaction SMILES: O.NN.[C:4]([O:8][C:9](=[O:28])[CH2:10][O:11][C@H:12]1[CH2:16][C@H:15]([N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:14]=[CH:13]1)([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9](=[O:28])[CH2:10][O:11][CH:12]1[CH2:16][CH:15]([NH2:17])[CH:14]=[CH:13]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)CO[C@@H]1C=C[C@@H](N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)COC1C=CC(N)C1

Procedure:
Add 22 μl (0.545 mmol) of hydrazine monohydrate to 120 mg (0.349 mmol) of trans-{[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclopent-2-en-1-yl]oxy}acetic acid tert-butyl ester in 0.3 ml of ethanol. Heat the mixture under reflux for 15 min. This forms a voluminous precipitate. After cooling, remove it by filtration and wash it with a little ethanol. Concentrate the filtrate under reduced pressure and use the resulting product (74 mg) without further purification.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(CC)CC.[C:40]([NH:47][C@:48]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:50](O)=[O:51])[CH3:49])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CN(C=O)C>[C:56]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:55]=[CH:54][C:53]([C:48]([NH:47][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:49])[C:50](=[O:51])[N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:58][CH:57]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C(=O)O)c1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C)(C(=O)N1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
BOP (880 mg, 2.0 mmol) was added to a mixture containing pyrrolidine (142 mg, 2.0 mmol), Et3N (279 ul, 2.0 mmol) and N-Boc-2-phenylalanine (570 mg, 1.67 mmol) in DMF (10 ml) and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was taken up in EtOAc and washed with brine, dried and concentrated. The crude product was purified by column chromatography (48 g silica gel 60, 230-400 mesh, 20% EtOAc in hexane as eluent) to give 581 mg (75%) of the title compound as a white solid. MS (ES) m/e 395.6 [M+H]+
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:17]2[C:16](=[O:18])[N:15]([C:19]3[CH:20]=[C:21]([C:25]4[O:29][C:28](=[O:30])[N:27]([CH3:31])[N:26]=4)[CH:22]=[CH:23][CH:24]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:7]=[C:6](S(C)(=O)=O)[N:5]=1)[CH3:2].[CH2:36]([NH2:38])[CH3:37].C1COCC1>C1COCC1>[CH2:1]([NH:3][C:4]1[C:17]2[C:16](=[O:18])[N:15]([C:19]3[CH:20]=[C:21]([C:25]4[O:29][C:28](=[O:30])[N:27]([CH3:31])[N:26]=4)[CH:22]=[CH:23][CH:24]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:7]=[C:6]([NH:38][CH2:36][CH3:37])[N:5]=1)[CH3:2]
Reactant: CCNc1nc(S(C)(=O)=O)nc2c1C(=O)N(c1cccc(-c3nn(C)c(=O)o3)c1)C[C@@H]1CCCN21
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc(NCC)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
(S)-5-[3-(7-Ethylamino-9-methanesulfonyl-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (23.6 mg, 0.0472 mmol) obtained in Step 1 was dissolved in THF (2.0 mL), and the mixture was stirred at 90° C. for 30 minutes under microwave (CEM; Discover; 250 watts) irradiation after adding a 2.0 mol/L ethylamine/THF solution (1.0 mL, 2.00 mmol). The mixture was further stirred at 90° C. for 30 minutes under microwave (CEM; Discover; 250 watts) irradiation after adding a 2.0 mol/L ethylamine/THF solution (0.049 mL, 0.0981 mmol). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (Compound 158) (20.8 mg, 88%).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@:11]([OH:27])([CH3:26])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C.O>CN(C=O)C>[CH3:26][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:27][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reaction time: 2 h
Yield: 70.9 %

Procedure:
Tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-piperazine-1-carboxylate prepared in Example 365 (10.25 g, 25.4 mmol) was dissolved in DMF (30 ml). To the solution, sodium hydride (1.12 g, 27.9 mmol) was added followed by stirring for 2 hours with cooling on ice-bath. To the reaction mixture, ethyl acetate (10 ml) and water (70 ml) were added. The precipitates were filtered off, and washed with water. The crude solids were recrystallized from ethyl acetate (70 ml) to afford tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (6.62 g, yield 71%) as a light yellow powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[O:22]=[C:20]1[C:19]2[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:27])[N:21]1[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Agent: [K]
Solvent: CN(C)C=O
Product: CN1CC(CCN2C(=O)c3ccccc3C2=O)Oc2ncccc2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
To a solution of 4.92 g (0.02 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5-(4H)one in 35 ml of dimethylformamide was added 7.55 g (0.041 mole) of potassium phthalimide. The mixture was stirred for 5 hr at 100° C. and left standing at room temperature overnight. Dimethylformamide was removed by rotary evaporation (80° C. vacuum pump). The residue was taken up in 100 ml of chloroform and washed with water (2×30 ml) and 2M potassium hydroxide (2×3 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70° C., water aspirator). The 6.26 g of crude product was recrystallized from isopropyl alcohol to give 2.60 g (36%) white crystalline powder, m.p. 146°-47° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[N:26]=2)=[CH:21][CH:20]=1)=[C:17]=[S:18]>>[OH:4][CH2:3][CH:2]([NH:1][C:17]([NH:16][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:38])[F:39])=[CH:32][CH:31]=3)[N:26]=2)=[CH:23][CH:24]=1)=[S:18])[C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:9][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccc(OC(F)(F)F)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-(trifluoromethoxy)phenyl)ethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an white solid (1.42 g, 87%) 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.35-8.22 (m, 2H), 7.94 (s, 1H), 7.88-7.71 (m, 2H), 7.51-7.11 (m, 9H), 7.05 (d, J=7.9 Hz, 1H), 5.75 (s, 1H), 4.06 (dd, J=11.2, 3.9 Hz, 1H), 3.94 (dd, J=11.2, 4.7 Hz, 1H); ESIMS m/z 584 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc(N)c2ncccc2c1
Agent: CN(C)c1ccncc1
Product: COc1cc(NS(=O)(=O)c2ccccc2)c2ncccc2c1
Yield: 63.6 %

Procedure:
In the similar fashion using route 14 general procedure 27, 6-methoxyquinolin-8-amine (Intermediate 23) (250 mg, 1.43 mmol), benzenesulfonyl chloride (220 μl, 1.3 mmol) and DMAP (cat.) gave the title compound (260 mg, 57%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH:27]([NH2:29])[CH3:28])[C:26]2[C:20]([CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].C(Cl)[Cl:47]>>[ClH:47].[C:17]1([CH:27]([NH:29][CH2:15][CH2:14][CH2:13][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:12]=2)[CH3:28])[C:26]2[C:20]([CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:19][CH:18]=1
Reactant: ClCCl
Reactant: O=CCCc1cccc(-c2ccccc2)n1
Reactant: CC(N)c1ccc2cccccc1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(NCCCc1cccc(-c2ccccc2)n1)c1ccc2cccccc1-2
Product: Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dehydrated methylene chloride (2 mL) was added with 3-(6-phenylpyridin-2-yl)propane aldehyde (52.5 mg), [1-(azulen-1-yl)ethyl]amine (63.3 mg), and sodium triacetoxyborohydride (158.9 mg, Aldrich), and stirred at room temperature for 72 hours. The reaction mixture was added with 2 N sodium hydroxide, and extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 63.2 mg of the title compound in the free form. This compound was dissolved in chloroform, and added with 0.1 N solution of hydrochloric acid in methanol (1.7 mL), and the solvent was evaporated under reduced pressure to obtain 69.3 mg of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(Cl)Cl.[CH:14]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH:20]=[CH:19][C:18]=2[N:17]=[CH:16][CH:15]=1.[C-:28]#[N:29].[K+]>C(Cl)Cl.O>[C:28]([CH:16]1[CH:15]=[CH:14][C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH:20]=[CH:19][C:18]=2[N:17]1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:29]
Reactant: O=C(Cl)c1ccccc1
Reactant: [C-]#N
Reactant: c1ccc2c(c1)ccc1ncccc12
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CC1C=Cc2c(ccc3ccccc23)N1C(=O)c1ccccc1
Reaction time: 6 h

Procedure:
648 μl (5.58 mmol) benzoyl chloride was added to a two phase system of water/methylene chloride over a period of two hours. These two layers contain 500 mg (2.79 mmol) of benzo(f)chinolin in the methylene chloride layer and 545 mg (8.37 mmol) KCN in water. Stirring was continued for 6 hours. The organic phase was separated and washed with water, 5% hydrochloric acid, water, 5% NaOH solution, and again with water. After drying over magnesium sulfate, the solution was evaporated to dryness.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:14])(=O)=O>>[Cl:14][CH:3]([C:2](=[O:1])[CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)CC
Reactant: O=S(=O)(Cl)Cl
Product: CCOC(=O)C(Cl)C(=O)CC
Reaction time: 16 h

Procedure:
Ethyl 3-oxopentanoate, 20.0 grams (0.175 mole), was stirred at ambient temperature, and 23.6 grams (0.175 mole) of sulfuryl chloride was added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture was stirred for about 16 hours. The reaction mixture was then distilled under reduced pressure, yielding 23.3 grams of ethyl 2-chloro-3-oxopentanoate; bp 100°-103° C. at 21mm.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([F:17])=[CH:9][CH:8]=1.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C1COCC1.O.CCOC(C)=O>[F:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Fc1ccc(Br)c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccc(F)c2ccccc12
Temperature: -20 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
A solution of n-butyllithium (2.5 M in THF, 20 mL, 50 mmol) was cooled to −78° C., and a solution of 1-bromo-4-fluoronaphthalene (11.25 g, 50 mmol) in THF (40 mL) was added slowly and the mixture was stirred for 1 hour. The reaction mixture was warmed to −20° C., then added to a solution of diethyl oxalate (29.2 g, 200 mmol) in THF (40 mL) at −78° C. After slowly warming-up to room temperature, EtOAc (100 mL), 10% HCl (50 mL) and water (50 mL) were added and the phases were separated. The aqueous layer was extracted with EtOAc (2×100 mL), and the organic layers were combined, washed with brine (50 mL), and dried over Na2SO4. After evaporating the solvent and the excess diethyl oxalate under high vacuum, the residue was purified by flash column chromatography (1:1 DCM:hexane) to give the title compound (9.4 g, 76% yield) as a white solid. 1H—NMR (400 MHz, CDCl3) δ (9.13 (d, J=8.6 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.01 (dd, J=8.2, 5.4 Hz, 1H), 7.76 (t, J=7.2 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.21 (t, J=8.5 Hz, 1H), 4.49 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).