Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=2)[C@@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20]C=3)[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[C:31]1([C@H:37]([CH2:41][CH3:42])[C:38]([OH:40])=O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CC[N:45]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:10][CH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[CH2:11][N:12]([CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=1)[CH:13]1[C:22]2[N:45]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)[CH2:2][NH:1][C:38](=[O:40])[CH:37]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:41][CH3:42]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC[C@H](C(=O)O)c1ccccc1
Reactant: Cc1cccnc1CN(Cc1ccc(CN)cc1CO)[C@H]1CCCc2ccccc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C(=O)NCc1ccc(CN(Cc2ncccc2C)C2CCCc3cccnc32)c(CO)c1)c1ccccc1
Yield: 21.1 %

Procedure:
Using General Procedure G: To a solution (S)-(5-aminomethyl-2-{[(3-methyl-pyridin-2-ylmethyl)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amino]-methyl}-phenyl)-methanol (128 mg, 0.32 mmol) dissolved in CH2Cl2 (10 mL) was added (S)-2-phenylbutyric acid (74 μl, 0.48 mmol), EDCI (92 mg, 0.48 mmol), HOBT (65 mg, 0.48 mmol), and DIPEA (83 μl, 0.48 mmol). Purification via column chromatography on silica gel (CH2Cl2:MeOH, 97:3, v/v) afforded COMPOUND 439 as a colorless oil (37 mg, 22%). 1H NMR (CDCl3) δ 0.86 (m, 3H), 1.44 (m, 2H), 1.81 (m, 1H), 2.18 (m, 1H), 2.23 (s, 6H), 2.64 (m, 2H), 3.22 (m, 1H), 3.85 (m, 4H), 4.14 (m, 2H), 4.31 (m, 2H), 5.73 (m, 1H), 7.14 (m, 12H), 8.36 (m, 2H); ES-MS m/z 572 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][O:13][C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)=[O:15]>N1C=CC=CC=1>[CH3:12][O:13][C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)=[O:21])=[CH:18][CH:17]=1)=[O:15]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)CC(=O)N3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A mixture of 82.0 mg of 5-amino-2-oxindole and 131.0 mg of 4-methoxycarbonylbenzoyl chloride in pyridine was stirred at room temperature for 3 hr and poured into ice water. The precipitate was filtered, washed with water and dried in a vacuum oven to give 138.0 mg of 5-(4-methoxycarbonylbenzamido)-2-oxindole (81% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:14])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)[CH3:2].[Br:15]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>>[Br:15][CH:1]([C:3]1[C:4](=[O:14])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)[CH3:2]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCc1nc2ccc(F)cc2[nH]c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1nc2ccc(F)cc2[nH]c1=O
Temperature: 80 °C
Reaction time: 20 h
Yield: 133 %

Procedure:
3-Ethyl-7-fluoroquinoxalin-2(1H)-one (20.61 g, 107.2 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (18.77 g, 64.34 mmol) suspended in carbon tetrachloride (1072 ml, 107.2 mmol). To the heterogeneous mixture was added benzoyl peroxide (3.463 g, 10.72 mmol) and the mixture was heated at reflux with stirring (oil bath temperature: 80° C.) for 20 h. After 20 h, the mixture was cooled to rt. After cooling, the mixture was poured into saturated aqueous sodium bicarbonate solution (1 L) with stirring. The precipitate was collected by filtration and washed with water (1 L) to give 3-(1-bromoethyl)-7-fluoroquinoxalin-2(1H)-one (23.19 g, 79.8% yield) as a tan solid:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=3[N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:19](=[O:30])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])OC(C)(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=3[N:13]=2)[C:5]([N:8]([C:19]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[C:19](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ncc(Br)cc1-c1nc2c(F)cccc2o1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1-c1nc2c(F)cccc2o1
Temperature: 25 °C
Reaction time: 45 h
Yield: 89.4 %

Procedure:
N,N-dimethylpyridin-4-amine (0.190 g), was added to a stirred suspension of 5-bromo-3-(4-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (2.4 g) and di-tert-butyl carbonate (4.83 g) in DMF (50 ml) at 25° C. under nitrogen. The resulting suspension was stirred at 25° C. for 45 hours. The DMF was evaporated under reduce pressure. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 0 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford tert-butyl N-[5-bromo-3-(4-fluoro-1,3-benzoxazol-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (3.54 g, 89%) as a pale orange solid. NMR Spectrum: (CDCl3) 1.36 (s, 18H), 7.12 (dd, 1H), 7.38 (ddd, 1H), 7.42 (d, 1H), 8.72 (d, 1H), 8.85 (d, 1H); Mass spectrum: M+H+ 508-510 PdCl2dppf (0.278 g), potassium acetate (2.095 ml) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.923 g) were added over a period of 10 minutes, to a stirred solution tert-butyl N-[5-bromo-3-(4-fluoro-1,3-benzoxazol-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (3.5 g) dissolved in dioxane (30 ml) degazed and under argon. The resulting mixture was stirred at 80° C. for 3 hours. The salts were filtered; The mixture was evaporated under reduce pressure. The crude product was purified by flash chromatography on silica gel eluting with 30 to 40% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl N-tert-butoxycarbonyl-N-[3-(4-fluoro-1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]carbamate (3.26 g) as a pale orange solid. NMR Spectrum: (CDCl3) 1.33 (s, 18H), 1.39 (s, 12H), 7.10 (dd, 1H), 7.34 (ddd, 1H), 7.42 (d, 1H), 8.99 (d, 1H), 9.08 (d, 1H); Mass spectrum: M-(boc+pinacol)+H+ 374
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[C:13]2[C:18]=1[CH:17]=[N:16][CH:15]=[CH:14]2.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:19][C:11]2[CH:12]=[C:13]3[C:18](=[C:9]([Br:8])[CH:10]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1cc(Br)c2cnccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(Br)c3cnccc3c2)cc1
Reaction time: 15 h
Yield: 70.9 %

Procedure:
Triethylamine (0.137 mL) was added to a dichloromethane (5 mL) solution of Intermediate 7 (100 mg) and p-toluenesulfonic acid chloride (66 mg; WAKO) at room temperature and the resulting mixture was stirred as it was for 15 hours. The resulting mixture was diluted with dichloromethane and washed with water, the organic layer was dried, then the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (Yamazen; n-hexane/ethyl acetate) to give the title compound (92.9 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22]CCCCCC)=[CH:16][CH:15]=2)[S:5][C:6]=1[C:7](=[N:9][NH:10][C:11](=[NH:13])[NH2:12])[CH3:8].CO>O>[CH3:1][C:2]1[N:3]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH3:22])=[CH:18][CH:19]=2)[S:5][C:6]=1[C:7](=[N:9][NH:10][C:11](=[NH:12])[NH2:13])[CH3:8]
Reactant: CCCCCCCCCc1ccc(-c2nc(C)c(C(C)=NNC(=N)N)s2)cc1
Solvent: CO
Solvent: O
Product: CCCc1ccc(-c2nc(C)c(C(C)=NNC(=N)N)s2)cc1

Procedure:
2-{1-[4-Methyl-2-(4-nonylphenyl)thiazol-5-yl]ethylidenehydrazinecarboximid-amide (1f). Yellow solid (133 mg, 55%): mp 203-206° C. 1H NMR (DMSO-d6) δ 11.32 (brs, 1 H), 7.79 (d, J=8.1 Hz, 2 H), 7.60 (brs, 3 H), 7.28 (d, J=8.1 Hz, 2 H), 2.58 (m, 5 H), 2.41 (s, 3 H), 1.55 (m, 2 H), 1.22 (m, 12 H), 0.82 (t, J=6.9 Hz, 3 H); 13C NMR (DMSO-d6) δ 165.80, 156.87, 153.45, 147.99, 146.28, 131.19, 131.60, 129.44, 126.25, 36.34, 35.29, 31.60, 30.98, 29.28, 29.19, 28.99, 22.42, 18.46, 18.39, 14.27; ESIMS m/z (rel intensity) 400 (MH+, 100); HRESIMS, m/z 400.2540 MH+, calcd for C22H34N5S 400.2535; HPLC purity (methanol:water, 1:1): 95.40%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH2:16][C:5]3[CH:6]=[CH:7][C:8]([C:9]4[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: COc1cc(CC(=O)O)ccc1-c1ccnc(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CC(=O)Nc2ccc(N3CCN(C(C)=O)CC3)cn2)ccc1-c1ccnc(C)c1
Temperature: 25 °C

Procedure:
To a mixture of 2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)acetic acid 182-3 (26 mg, 0.1 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (22 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (0.6 mL) was added DIEA (52 uL, 0.3 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was diluted into DMSO and purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)acetamide 182. MS m/z 460.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.52 (s, 1H), 8.43 (d, 1H), 8.03 (s, 1H), 7.94 (d, 1H), 7.43-7.30 (m, 3H), 7.15 (s, 1H), 7.04 (d, 1H), 3.79 (s, 2H), 3.72 (b, 2H), 3.57 (b, 2H), 3.14 (b, 2H), 3.07 (b, 2H), 2.49 (s, 3H), 2.04 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7]O.S(Cl)([Cl:11])=O.CCOCC.CO>C(O)C>[ClH:11].[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][Cl:11]
Reactant: CN1CCC[C@H]1CO
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CO
Solvent: CCO
Product: CN1CCC[C@H]1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.99 g (0.052 mol) of (S)-(-)-1-methyl-2-hydroxymethylpyrrolidine in 30 ml of ethanol-free chloroform under nitrogen at 0° was added a solution of 4.75 ml (7.75 g, 0.065 mol) of thionyl chloride in 15 ml of ethanol-free chloroform over 10 min. The resultant clear, brown solution was stirred at room temperature for 30 min. and refluxed for 30 min. After cooling, the dark solution was evaporated to provide a tan-colored, solid residue. The residue was dissolved in absolute ethanol and excess ether was added resulting in the crystallization of a beige-colored solid. The solid was suction-filtered and dried under a nitrogen atmosphere affording 8.02 g (91%): mp 152°-154°; [α]D20 =-6°, c=2.35, methanol.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23](=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH2:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23](=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
To a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (12.0 g, 43.5 mmol) and tert-butyl 4-hydrazinyl-4-oxobutylcarbamate (10.5 g, 47.8 mmol) in CH2Cl2 (360 mL) was added HATU (19.6 g, 52.2 mmol) and DIPEA (16.6 g, 130.5 mmol). The mixture was allowed to warm to rt, was stirred at rt for 12 hrs then diluted with CH2Cl2 (300 mL), washed with water (2×) and saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 50˜80% EtOAc/petroleum ether) to afford tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-4-oxobutylcarbamate (19.3 g, 93%) as a white solid. ESI-MS (EI+, m/z): 476 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.C1(C)C=CC=CC=1>[Pt].C(O)(C)C>[CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15]
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)CNc1c(N)cnc2cccnc12
Temperature: 22 °C

Procedure:
A hydrogenation vessel was charged with N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (7.50 kg, 30.5 mol) and toluene (125.0 kg). A suspension of 3% platinum on carbon (0.44 kg, approximately 33% by weight (w/w) in water) in isopropanol (7.0 kg) was added to the vessel followed by a rinse with toluene (10.0 kg). The reaction mixture was then placed under hydrogen pressure (2.4×105 Pa, 2.4 bars) for six hours while stirring and maintaining the temperature at 22° C. The reaction mixture was then filtered, and the filter cake was washed with toluene (30.0 kg). The filtrate was concentrated under reduced pressure (1×104 Pa, 0.1 bar) at approximately 50° C. to provide a solution of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in toluene (75 L, approximately 10 mL/g).
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1.O[O:19][S:20]([O-:22])=O.[K+].Cl[CH2:25]Cl>>[CH3:25][S:20]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1)(=[O:22])=[O:19]
Reactant: O=S([O-])OO
Reactant: ClCCl
Reactant: CSc1ccc(-c2cc3nccnc3[nH]2)cc1
Agent: [K+]
Product: CS(=O)(=O)c1ccc(-c2cc3nccnc3[nH]2)cc1

Procedure:
A stirred suspension of 6-(4-methylthiophenyl)-5H-pyrrolo[2,3-b]pyrazine [0.125 g, Example 1(ah)] in dichloromethane (15 mL) was treated with TBA oxone (1.35 g). After 4 hours the reaction mixture was evaporated. The residue was subjected to flash chromatography eluting with a mixture of methanol and dichloromethane (1:1, v/v) to give the title compound as a white solid. MS: 274 (MH+). 1H NMR [(CD3)2SO]: δ 12.78 (1H, s); 8.44 (1H, s); 8.28 (3H, m); 8.04 (2H, d, J=8.8 Hz); 7.40 (1H, s); 3.27 (3H, s).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: COc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 17 %

Procedure:
The title compound (34.9 mg) was prepared as in Example 177, Steps C and D, using 299.2 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 329.2 mg of 4-methoxyphenylboronic acid. MS (ESI): exact mass calculated for C19H25N3O, 311.42; found, m/z 312.3 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.26-7.23 (m, 2H), 7.11-7.08 (m, 2H), 4.51 (m, 1H), 3.87 (s, 3H), 3.43-3.40 (m, 2H), 3.20-3.16 (m, 2H), 2.80-2.76 (m, 2H), 2.02-1.86 (m, 6H), 1.64-1.55 (m, 2H).
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(C)nc3C#C[Si](C)(C)C)c2cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), trimethylsilylacetylene (39 mg), and bis(triphenylphosphine)palladium(II) chloride (14 mg) were dissolved in tetrahydrofuran (1 ml) to prepare a solution. Diisopropylethylamine (0.2 ml) and copper iodide (3.8 mg) were added to the solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give the title compound (45 mg, yield 58%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][O:16][C:17]2=[O:20])=[C:13](/[N:21]=[CH:22]/[C:23]2[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=2)[CH:12]=1.[O-:29][CH2:30][CH3:31].[Na+].C(O)C>C(OCC)(=O)CC>[F:10][C:11]1[CH:19]=[C:18]([C:17]([O:16][CH2:15][CH3:14])=[O:20])[C:31]2[C:30](=[O:29])[CH:6]([C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[CH:22]([C:23]3[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=3)[NH:21][C:13]=2[CH:12]=1
Reactant: CC[O-]
Reactant: O=Cc1ccc(F)cc1
Reactant: Cn1ccnc1/C=N/c1cc(F)cc2c1COC2=O
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CCO
Product: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A mixture of 4-fluorobenzaldehyde (248 mg, 2 mmol) and (E)-6-fluoro-4-((1-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one (518 mg, 2 mmol) in ethyl propionate (10 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (184 mg, 8 mmol) in ethanol (5 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 0.5 hr. The mixture was quenched with water (20 mL) and solvents were removed in vacuum. The residues were dissolved in water and extracted with ethyl acetate three times. The combined organic layers were washed with water and brine. After the removal of solvents, the crude product was purified by flash column chromatography to obtain a yellow solid, which was dried in vacuum at 50° C. to give the title compound (200 mg, yield: 24%). LC-MS (ESI) m/z: 412 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH2:15][CH:16]2[CH2:21][CH2:20][C:19]([CH:23]([OH:25])[CH3:24])([OH:22])[CH2:18][CH:17]2[C:26]([O:28]CC2C=CC=CC=2)=O)[CH:4]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C>CN(C)C1C=CN=CC=1.[Pd].N1C=CC=CC=1>[OH:25][CH:23]([C:19]1([OH:22])[CH2:20][CH2:21][CH:16]2[CH:17]([C:26](=[O:28])[C:4]3[C:5]([CH2:15]2)=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=3[O:2][CH3:1])[CH2:18]1)[CH3:24]
Reactant: COc1cc(CC2CCC(O)(C(C)O)CC2C(=O)OCc2ccccc2)c(OC)c2ccccc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1c2c(c(OC)c3ccccc13)C(=O)C1CC(O)(C(C)O)CCC1C2
Yield: 66.1 %

Procedure:
Operating as described in Example 6, 0.44 g of 1-(1,4-dimethoxy-3-naphthylmethyl)-2-benzyloxycarbonyl-4-(1-hydroxyethyl)-4-hydroxy-cyclohexane, prepared as described in Example 11, was treated with acetic anhydride in presence of 4-dimethylamino-pyridine and pyridine. The corresponding acetate was treated with cyclohexone in the presence of 10% by weight palladium-on-carbon in order to remove the benzyl group. The acid was cyclized by treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid at 0° C. Finally the removal of the acetyl 0-protecting groups by treatment with sodium methylate afforded, after purification by chromatography on a silica gel column, 0.225 g of the title compound (overall yield 66%); IR (film): 3450 cm-1 (OH), 1675 cm-1 (C=O, benzylic ketone). PMR (CDCl3): inter alia δ1.3 (d, J=4 Hz, CH3 --CH), 1.6-3.5 (m, 3H), 3.85 (s, OCH3), 3.90 (s, OCH3), 7.2-8.4 (m, four aromatic H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[N+:13]([O-:14])=[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]3=[N:10]2)=[C:4]([F:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:31](Br)[C:32]#[CH:33]>O>[Cl:1][C:2]1[C:7]([O:8][CH2:33][C:32]#[CH:31])=[CH:6][C:5]([N:9]2[N+:13]([O-:14])=[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]3=[N:10]2)=[C:4]([F:19])[CH:3]=1
Reactant: C#CCBr
Reactant: [O-][n+]1c2c(nn1-c1cc(O)c(Cl)cc1F)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-n2nc3c([n+]2[O-])CCCC3)c(F)cc1Cl
Yield: 13.2 %

Procedure:
To a mixture of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1,2,3-benzotriazol-1-oxide (1 g), potassium carbonate (0.3 g) and dimethylformamide (5 ml), propargyl bromide (0.6 g) was added, and the resultant mixture was stirred at 70° to 80° C. for 4 hours. After cooling, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of n-hexane and ethyl acetate as a developing solvent to give 0.15 g of 2-(4-chloro-2-fluoro-5-propargyloxyphenyl)-4,5,6,7-tetrahydro-1,2,3-benzotriazol-1-oxide (Compound No. 12). M.P., 155°-156° C.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21]([O:28][C@@H:29]1[CH2:34][C@@H:33]([CH2:35]I)[O:32][C@@H:31]([O:37][CH3:38])[CH2:30]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[C:3]1([S:9]([CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH2:35][C@H:33]2[O:32][C@@H:31]([O:37][CH3:38])[CH2:30][C@H:29]([O:28][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:34]2)(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cc1ccc(Cl)cc1Cl)c1ccccc1
Reactant: CO[C@H]1C[C@H](OCc2ccccc2)C[C@@H](CI)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H]1C[C@H](OCc2ccccc2)C[C@@H](CC(c2ccc(Cl)cc2Cl)S(=O)(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.5 %

Procedure:
To a stirred suspension of sodium hydride (0.030 g of 50% NaH in mineral oil) in dry DMF (0.5 ml) under nitrogen is added 2,4-dichlorobenzyl phenyl sulfone (0.18 g; 0.6 mmole) as the crystalline solid all at once. The reaction mixture is stirred at room temperature under nitrogen under hydrogen evolution ceases (50 min.) A solution of (2R,4R,6S)-4-benzyloxy-6-iodomethyl-2-methoxy-3,4,5,6-tetrahydro-2H-pyran (0.109 g; 0.3 mmole) in dry DMF (0.4 ml) is added by syringe through a septum. The reaction is stirred for 2.5 hours at room temperature and then partitioned between ether (100 ml) and water (20 ml). The ether layer is extracted with water (4×20 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo to leave 0.24 g of crude product. Flash chromatography of this product on silica gel with a 30 mm×130 mm column, eluting with 2% (by volume) acetone in methylene chloride, gives 40 mg of the major diastereoisomer and 10 mg of the minor diastereoisomer and 60 mg of a mixture of the two with a total of 110 mg of 1-(2,4-dichlorophenyl)-2-(4(R)-benzyloxy-2(R)-methoxy-3,4,5,6-tetra-hydro-2H-pyran-6(S)-yl)ethyl phenyl sulfone.