Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([CH3:17])([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]O)=[CH:9][CH:8]=1)=[O:4].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]([CH3:17])([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][Br:19])=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)C(C)(C)Cc1ccc(CCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of lithium diisopropylamide (0.1 mol/l solution in tetrahydrofuran, 15 ml) was added a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonylpropyl)benzene (0.62 g) in tetrahydrofuran (2 ml) at -78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of iodomethane (0.20 g) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) as an oily liquid. To a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) in tetrahydrofuran (1.5 ml) was added tetra-n-butylammonium fluoride (1 mol/l solution in tetrahydrofuran, 1.34 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride and diethyl ether (7:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) as an oily liquid. To a solution of 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) in methylene chloride (3 ml) were added carbon tetrabromide (0.48 g) and triphenylphosphine (0.38 g), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl bromide (0.323 g) as an oily liquid.
Reaction SMILES: [NH2:1][N:2]1[CH:10]=[C:8]([CH3:9])[C:6](=[O:7])[NH:5][C:3]1=[O:4].[Cl:11][C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[Cl:11][C:12]([NH:1][N:2]1[CH:10]=[C:8]([CH3:9])[C:6](=[O:7])[NH:5][C:3]1=[O:4])=[O:14]
Reactant: Cc1cn(N)c(=O)[nH]c1=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cn(NC(=O)Cl)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-Amino thymine (7, 12.5 g, 0.1 mol) is dissolved in tetrahydrofuran (500 mL) and the solution is cooled to 0° C. and a 2M solution of triphosgene in THF (150 mL) is added and the reaction is stirred for 4 hours. The solution is evaporated to a solid, which is used as is in the next reaction.
Reaction SMILES: [Cu][C:2]#[N:3].[NH2:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8](Br)=[CH:7][CH:6]=1.[C-]#N.[Na+]>CN(C)C=O.O>[NH2:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:2]#[N:3])=[CH:7][CH:6]=1
Reactant: Cc1nc(N)ccc1Br
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N)ccc1C#N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Copper(I) cyanide (12 mmol) is added to 10 mmol of 6-amino-3-bromo-2-methylpyridine dissolved in dimethylformamide. The mixture is refluxed for 10 hours, and then cooled to 80° C. and poured into a solution of sodium cyanide (40 mmol) in water. After stirring for 1 hour at room temperature, the mixture is extracted with ethyl acetate. The organic phase is washed, then dried and evaporated to yield the expected product in the form of an ochre solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.Cl.ClC1C=CC(NC(C2C=CC(C(=N)OCC)=CC=2)=O)=CC=1C1C=CC=CN=1.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:11]=[CH:12][C:13]([C:16](=[NH:17])[N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: Cl
Solvent: CCO
Product: N=C(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1)N1CCOCC1
Temperature: 75 °C
Reaction time: 72 h
Yield: 7.9 %

Procedure:
N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide (300 mg, 0.899 mmol) was slurried in 45 ml ethanol and treated with 10 ml of ethanol saturated with HCl. The reaction was stored at 0° C. for 3 days, then heated to 75° C. for 3.0 hours, and cooled to room temperature for 18 hours. The reaction was cooled in an ice bath, and saturated with HCl gas. After storing at 0° C. for an additional 3 days, N2 gas was bubbled through the solution for 1.0 hour, and the solution was diluted with enough ethanol to make a 0.0155 M solution of ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate. Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (17.5 ml of a 0.0155 M ethanol solution, 0.27 mmol) was treated with morpholine (1.0 ml, 11.4 mmol) for 3 days. The ethanol was evaporated, and the residue purified by reverse phase HPLC to afford 30 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(morpholino)methyl)benzamide. MS (Q1) 421 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21]C(OC(C)(C)C)=O)[CH:16]=2)=[CH:9][N:8]=1)[CH3:2].C(O)(C(F)(F)F)=O.N([O-])=O.[Na+].[N-:42]=[N+:43]=[N-].[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[N+:42]=[N-:43])[CH:16]=2)=[CH:9][N:8]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CSc1ccc(C(=O)Nc2cccc(NC(=O)OC(C)(C)C)c2)cn1
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)CSc1ccc(C(=O)Nc2cccc(N=[N+]=[N-])c2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 118.6 %

Procedure:
To a 0° C. solution of [5-(3-tert-butoxycarbonylaminophenyl-carbamoyl)pyridin-2-ylsulfanyl]-acetic acid ethyl ester (41 mg, 0.10 mmol) in DCM (3 mL) was added TFA (3 mL) followed by stirring for 15 minutes. The mixture was concentrated in vacuo and was taken up in a mixture of acetic acid (3 mL) and water (1 mL), cooled to 0° C., and treated with a solution of sodium nitrite (15 mg, 0.23 mmol) in water (1 mL). After 5 minutes, the mixture was treated with neat sodium azide (15 mg, 0.22 mmol) and the solution was allowed to warm to an ambient temperature over 30 minutes. The mixture was poured into water and was extracted with ethyl acetate (3×25 mL) and the combined extracts were washed with water and brine and dried over magnesium sulfate. Filtration and concentration gave 42.4 mg (100%) of the [5-(3-azido-phenylcarbamoyl)pyridin-2-ylsulfanyl]acetic acid ethyl ester as a solid: 1H NMR (300 MHz, acetone-d6) δ 9.73 (bs, 1H), 8.98 (m, 1H), 8.18 (m, 1H), 7.75 (m, 1H), 7.60 (m, 1H), 7.45 (m, 1H), 7.39 (m, 1H), 6.85 (m, 1H), 4.15 (m, 2H), 4.07 (s, 2H), 1.22 (m, 3H); MS (EI) m/z 356.11 (M−H)−.
Reaction SMILES: O([CH2:9][CH2:10][O:11][CH3:12])S(C(F)(F)F)(=O)=O.COCCO.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:40]2[CH:44]=[C:43]([C:45](=[O:47])[CH3:46])[N:42]=[C:41]2[CH3:48])C=CC=CC=1>C(Cl)Cl>[CH3:12][O:11][CH2:10][CH2:9][N:42]1[C:43]([C:45](=[O:47])[CH3:46])=[CH:44][N:40]=[C:41]1[CH3:48]
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Reactant: COCCOS(=O)(=O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: COCCO
Product: COCCn1c(C(C)=O)cnc1C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A solution of 2-methoxyethyl triflate (prepared on a 6 mmole scale from 2-methoxyethanol and trifluoromethanesulphonic anhydride by the method published in Synthesis 1982 85) in DCM (20 ml) was added dropwise to a solution of 1-(triphenylmethyl)-2-methyl-4-acetylimidazole (Method 34; 1.5 g, 4 mmol) in DCM (5 ml) and the mixture was stirred for 40 hours at ambient temperature. The volatiles were removed by evaporation to give a solid (2.4 g) which was purified by flash chromatography on silica gel eluting with DCM/MeOH (100:0 increasing in polarity to 95:5) to yield the title compound (660 mg, 88%) as a solid NMR (CDCl3) 1.31 (s, 3H), 1.49 (s, 3H), 2.02 (s, 3H), 2.43 (m, 2H), 3.31 (m, 2H), 6.87 (s, 1H); m/z 183.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.OC1C=CC(C([O:19][CH2:20][C:21]2[CH:26]=CC=CC=2)=O)=CC=1.C1(C)C(S(OC[C@@H]2OC2)(=O)=O)=CC=CC=1.C(C1OC1)Br>>[O:19]1[CH2:20][C@@H:21]1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: BrCC1CO1
Agent: Cc1ccccc1S(=O)(=O)OC[C@H]1CO1
Product: COC(=O)c1ccc(OC[C@H]2CO2)cc1
Yield: 90 %

Procedure:
The same procedure of Reference Example 4 was repeated except that methyl 4-hydroxybenzoate was used in lieu of benzyl 4-hydroxybenzoate, and (R)-(-)-glycidyl toluenesulfonate was used in lieu of epibromohydrin to give the title compound (yield 90%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:10](=[O:20])[CH2:9]1)=O)(C)(C)C.[C:21]([N:28]1[CH2:31]C(=O)[CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.ClCCCl.CC(O)=O>[C:24]([O:23][C:21]([N:28]1[CH2:31][CH:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:19]=3)[C:10](=[O:20])[CH2:9]2)[CH2:29]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccn2)C(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(N2CCN(c3ncccn3)C(=O)C2)C1
Yield: 10.5 %

Procedure:
A solution of intermediate 3b (120 mg, 0.43 mmol) in TFA (0.75 mL) and CH2Cl2 (3 mL) was stirred at room temperature for 1.5 h. The solution was concentrated. The resulting residue was stirred with N-Boc-azetidin-3-one 1a (81 mg, 0.47 mmol) and Na(OAc)3BH (100, 0.47 mmol) in 1,2-dichloroethane (4 mL) and HOAc (0.2 mL) at room temperature overnight. The reaction was quenched with aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 3% MeOH/CH2Cl2) gave intermediate 3c as light yellow solid (15 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:10][C@@H:9]2[CH3:14])=[CH:6][CH:7]=1
Reactant: C[C@H]1CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: C[C@H]1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 17.6 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-(S)-methyl-piperazine (0.56 g, 2.6 mmol) in isopropanol (20 mL) was added 2,6-lutidine (0.305 mL, 2.6 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and then treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.64 g, 1.7 mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 20 h. The reaction was concentrated in vacuo and purified by flash chromatography (100% dichloromethane to 2% methanol/dichloromethane) to yield the title compound (0.151 g, 18%). 1H-NMR (CDCl3) δ: 1.0 (3H, d), 1.57 (6H, s), 1.79 (s, 1H), 2.25–2.52 (7H, m), 2.66–2.69 (1H, m), 2.98–3.12 (2H, m), 3.68–3.73 (1H, m), 5.32 (2H, br s), 6.17 (1H, t), 6.82 (3H, d), 7.18–7.31 (4H, m), 7.44 (1H, d), 7.56–7.60 (1H, m), 8.50 (1H, dd). ESI-MS m/z: 504 (M), UV retention time: 1.49 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[C:19]([O:20]COC)=[C:18]([O:24][CH3:25])[CH:17]=[C:16]([O:26]COC)[C:15]=2[O:30][CH3:31])=[C:7]([O:32]COC)[C:6]([O:36][CH3:37])=[C:5]([CH3:38])[C:4]=1[O:39]COC.O1CCCC1.C(O)(C)C.Cl.C(OCC)(=O)C.CCCCCC>O1CCCC1.C(O)(C)C>[CH3:37][O:36][C:6]1[C:7](=[O:32])[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[C:19](=[O:20])[C:18]([O:24][CH3:25])=[CH:17][C:16](=[O:26])[C:15]=2[O:30][CH3:31])=[C:3]([O:2][CH3:1])[C:4](=[O:39])[C:5]=1[CH3:38]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(C)c(OC)c2OCOC)c1OC
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC1=CC(=O)C(OC)=C(CCCCCC2=C(OC)C(=O)C(C)=C(OC)C2=O)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
426 Milligrams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-methyl-6-{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]pentyl}benzene was dissolved in 5 ml of tetrahydrofuran and 5 ml of isopropanol, under nitrogen gas stream conditions, 1 ml of tetrahydrofuran-isopropanol (1:1) solution of 20% hydrogen chloride was added thereto, and the mixture was stirred at room temperature for 12 hours. The solvent was removed by evaporation under reduced pressure to obtain colorless powdery substance. This substance was dissolved, without being purified, in 20 ml of methanol, and a small amount of sodium hydrogen carbonate was added, then the mixture was heated at 60° C., and was stirred for 2 hours under oxygen gas stream condition. The solvent was removed by evaporation under reduced pressure, and the residue obtained was developed on a preparative thin layer chromatography (eluent: 40% ethyl acetate-n-hexane) to obtain 262 mg of 2,5-dimethoxy3-methyl-6-[5-(2,5-dimethoxy-1,4-benzoquinon-3-yl)pentyl]1,4-benzoquinone. Yellow powdery substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([O:14][CH3:15])[C:11]([N+:16]([O-])=O)=[C:10]([NH:19][C:20]([C:22]2[N:23]([CH3:32])[N:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=2[Cl:27])=O)[CH:9]=1.CCOC(C)=O>CC(O)=O.CCOCC.[Fe]>[C:28]([C:25]1[C:26]([Cl:27])=[C:22]([C:20]2[NH:16][C:11]3[C:12]([O:14][CH3:15])=[N:13][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[CH:9][C:10]=3[N:19]=2)[N:23]([CH3:32])[N:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: COc1nc(-c2ccccc2Cl)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1nc(-c2ccccc2Cl)cc2nc(-c3c(Cl)c(C(C)(C)C)nn3C)[nH]c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6-(2-chloro-phenyl)-2-methoxy-3-nitro-pyridin-4-yl]-amide (9.10 g, 32.6 mmol, prepared as described in the previous step above) in AcOH (50 mL) was treated with iron powder (6.80 g, 122 mmol) and heated to 100° C. for 3 h. The resulting mixture was cooled to room temperature and treated with EtOAc (100 mL). The resulting mixture was then filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo. The residue was purified on silica (0:100-100:0 EtOAc/hexane) to yield a white solid. The solid obtained was dissolved in Et2O (200 mL) with heating and sonication. Hexanes (50 mL) were added and the resulting mixture was concentrated until a precipitate started to form. The solution was left at room temperature overnight and the solid formed was collected by suction filtration to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-chloro-phenyl)-4-methoxy-3H-imidazo[4,5-c]pyridine. 1H-NMR (400 MHz, CD3OD) δ: 7.76-7.58 (m, 1H), 7.49 (m, 2H), 7.39 (m, 2H), 4.16 (s, 3H), 4.04 (s, 3H), 1.44 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated for C21H21N5OCl2: 430.1 (M+H). Measured: 430.2.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Cl:23][C:24]1[CH:25]=[C:26]([O:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])[CH:27]=[C:28]([Cl:36])[C:29]=1[CH2:30]OS(C)(=O)=O>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([O:37][S:38]([C:41]([F:43])([F:44])[F:42])(=[O:40])=[O:39])[CH:27]=[C:28]([Cl:36])[C:29]=1[CH2:30][CH:10]1[CH2:11][CH2:12][N:8]([CH:5]2[CH2:4][CH2:3][C:2]([F:1])([F:14])[CH2:7][CH2:6]2)[C:9]1=[O:13]
Reactant: O=C1CCCN1C1CCC(F)(F)CC1
Reactant: CS(=O)(=O)OCc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCC(F)(F)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one (447 mg, 2.2 mmol) in 22 mL dry THF, add 1.76 mL of 2M LDA (1.2 eq.) in THF dropwise at −78° C. Then, add 1.24 g of trifluoro-methanesulfonic acid 3,5-dichloro-4-methanesulfonyloxymethyl-phenyl ester (1.4 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NH4Cl and extract with CH2Cl2. Wash the organic layer with water, then brine, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 376 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23]>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[C:27]1[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: N#Cc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3c(Cl)cc(O)cc23)cc1
Yield: 94 %

Procedure:
This compound was prepared from 45a using 4-cyanophenylboronic acid according to method P. Yellow solid; Yield: 94%; mp 324° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 6.93 (d, J=2.5 Hz, 1H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 7.54 (d, J=2.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 8.03 (s, 1H), 8.04 (dd, J=8.5, 1.6 Hz, 1H), 8.09 (d, J=8.4 Hz, 2H), 8.17 (dd, J=12.9, 2.1 Hz, 1H), 10.32 (s, 2H); 19F-NMR (400 MHz, DMSO-d6) δ −136.43 (dd, J=13.0, 9.7 Hz); MS (ESI) m/z 389/391 ([M−H]−), 391/393 ([M+H]+); Anal. Calcd for C22H12ClFN2O2: C, 67.62; H, 3.09; N, 7.17. Found: C, 67.00; H, 3.74; N, 6.64.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1>CN(C=O)C.C(Cl)Cl>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]2[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: Cn1cccc(CBr)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)c1=O
Reaction time: 8 h
Yield: 50.6 %

Procedure:
3-Iodo-4-nitro-1H-indazole (0.38 g, 1.3 mmol) was reacted with K2CO3 (0.36 g, 2.6 mmol) in DMF (4 mL) for 15 minutes. 3-(Bromomethyl)-1-methylpyridin-2(1H)-one (0.28 g, 1.4 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with CH2Cl2 (30 mL), filtered and concentrated. The residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated. The residue was suspended in EtOAc (8 mL), stirred for 20 minutes and then filtered to provide 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one (0.27 g, 50% yield) as a solid.
Reaction SMILES: Br[CH2:2][C:3]([C@:5]1([OH:27])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:25])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:26])[C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:28]([O-:34])(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32].[Na+]>CC(C)=O>[C:28]([O:34][CH2:2][C:3]([C@:5]1([OH:27])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:25])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:26])[C:8]=2[CH2:7][CH2:6]1)=[O:4])(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C1c2ccccc2C(=O)c2c(O)c3c(c(O)c21)CC[C@](O)(C(=O)CBr)C3
Reactant: CCCCC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCC(=O)OCC(=O)[C@@]1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O

Procedure:
A mixture of 9(R)-bromoacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (1.00 g) obtained in Reference Example 4-(1), sodium valerate (1.44 g) and acetone (50 ml) was stirred under reflux for 2 hours. After removing insoluble matters by filtration, the reaction mixture was concentrated under reduced pressure. The residue was treated with ether (15 ml) and precipitated crystals were collected by filtration to give orange crystals of 9(R)-valeryloxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 149°-152° C.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:28]([S:31]([NH2:34])(=[O:33])=[O:32])([CH3:30])[CH3:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:34][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: CC(C)S(N)(=O)=O
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)C(C)C)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and isopropylsulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (13%); 1H NMR (d6-DMSO) δ 11.60 (br s, 1H), 7.46 (d, J=15.7 Hz, 1H), 7.40–7.09 (m, 12H), 6.86 (d, J=8.1 Hz, 2H), 6.48 (d, J=15.7 Hz, 1H), 3.64 (m, 1H), 2.37 (q, J=7.3 Hz, 2H), 1.23 (d, J=7.0 Hz, 6H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 460 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:14]=[CH:13][S:12][CH:11]=3)[N:7]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:6]=2[CH:22]=1.[CH3:23][O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>>[CH3:23][O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:14]=[CH:13][S:12][CH:11]=3)[N:7]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:6]=2[CH:22]=1
Reactant: COC(=O)CCCCCBr
Reactant: Oc1ccc2nc(-c3ccsc3)n(-c3ccc(F)cc3)c2c1
Product: COC(=O)CCCCCOc1ccc2nc(-c3ccsc3)n(-c3ccc(F)cc3)c2c1

Procedure:
6-Hydroxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole was reacted with 6-bromo-hexanoic acid methyl ester according to general operating instructions 3.