Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[CH:23]=[C:22](N)[CH:21]=[CH:20]2)=[O:11].N([O-])=[O:29].[Na+]>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24]([CH:23]=[C:22]([OH:29])[CH:21]=[CH:20]2)=[CH:25][C:14]=1[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(N)ccc3nc2-1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1
Temperature: 0 °C
Yield: 55.8 %

Procedure:
10-Aminocamptothecin (50 mg, 0.138 m-mol) is dissolved in a 10% aqueous solution of sulfuric acid (5 ml). To this solution in a salted ice bath is added dropwise slowly an aqueous solution of sodium nitrite (9.5 mg, 0.138 m-mol) with stirring. After the addition of sodium nitrite, the mixture is further stirred for 10 minutes in a salted ice bath. To the reaction mixture is added conc. sulfuric acid (1 ml), and the whole is boiled under reflux for 2 hours. The reaction mixture is diluted with ice water (200 ml) and chloroform (200 ml) is added. The mixture is shaken in a separating funnel and the resultant emulsion is filtered through celite. The chloroform phase containing camptothecin formed as by-product by side reactions is dried over magnesium sulfate, filtered and evaporated until dryness under reduced pressure whereby camptothecin (8 mg) is recovered. On the other hand, a solid on the celite, which is insoluble in chloroform-water, is taken up in 20% MeOH-CHCl3 (200 ml) and the solution is evaporated until dryness under reduced pressure whereby 28 mg (yield: 66.5% ) of the title compound is obtained as light yellow crystals. M.P. (with decomp.) 270°-272° C. (from pyridine-methanol)
Reaction SMILES: [OH-].[Na+].Br[CH2:4][CH2:5][CH2:6][C:7]#[N:8].[CH3:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1>O.CN(C)C=O>[CH3:9][C:10]1[N:11]([CH:6]([CH2:5][CH3:4])[C:7]#[N:8])[CH:12]=[CH:13][N:14]=1
Reactant: Cc1ncc[nH]1
Reactant: N#CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C#N)n1ccnc1C
Reaction time: 8 h

Procedure:
12.8 g of sodium hydroxide was dissolved in 12 ml of water and diluted with 150 ml of dimethylformamide containing 20.3 g of 2-methylimidazole. A solution of 50.0 g of 4-bromobutyronitrile in 100 ml of dimethylformamide was added slowly maintaining the temperature below 30° C. The resulting mixture was stirred overnight and was concentrated. The residue was taken up in 150 ml of brine and extracted with dichloromethane. The combined organic layers were dried over potassium carbonate and evaporated. The product was distilled. The early fractions were mostly 2-methylimidazole and were discarded. The main fraction 23.2 g, bp 160°-185° C./2.5 mm, was redistilled to give 14.7 g (31%) of (2-methyl-1H-imidazol-1-yl)-butanitrile, bp 140°-147° C./0.5 mm.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])([O:3]CC)=[O:2].Cl>C(O)(=O)C>[C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCC1CCCC1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CCCC1CCCC1=O

Procedure:
In the manner described in Example 2, treatment of 2-carbalkoxy(mixed methyl and ethyl esters )-2-(3-carbethoxypropyl)cyclopentan-1-one (Example 4) with a 20% hydrochloric acid and acetic acid mixture gives a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[CH2:5]2.N1CCCCC1.Cl[C:20]([C@@H:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:20]([CH:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21])[NH:7][C:6](=[O:12])[CH2:5]2
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -40 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
The stirred solution of 5-fluoro-6-amino-1,3-dihydro-indol-2-one (450 mg, 2.71 mmol) in 10 ml of tetrahydrofuran was added with piperidine (0.4 ml). The mixture was cooled to −40° C. in an acetone-dry ice bath and added with (S)-acetic acid 1-chlorocarbonyl-ethyl ester (423 mg, 2.71 mmol) in 10 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester (750 mg, 99%) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[N:25][CH:26]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[N:25][CH:26]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: FC(F)(F)c1cccc(-c2ccc(CCl)cn2)c1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-c2ccc(COc3ccc(CCCCn4ccnn4)cc3)cn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A solution of 100 mg (0.46 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 19 mg (0.48 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 125 mg (0.46 mmol) 5-Chloromethyl-2-(3-trifluoromethyl-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1 and diisopropylether. The residue was dried at 40° C. to give 170 mg (82%) of the title compound as white powder.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[S:16]([OH:19])(=O)=[O:17])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].S(Cl)([Cl:22])=O>N1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[S:16]([Cl:22])(=[O:19])=[O:17])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: O=S(Cl)Cl
Reactant: C=CCCCCOc1cc(OC)ccc1S(=O)(=O)O
Solvent: c1ccncc1
Product: C=CCCCCOc1cc(OC)ccc1S(=O)(=O)Cl
Reaction time: 4 h
Yield: 51 %

Procedure:
To a stirring solution of sulfonic acid 6a (266 mg, 0.9 mmol) in pyridine (2 mL) was added thionyl chloride (0.2 mL, 2.8 mmol) dropwise. The resulting solution was allowed to stir for 4 h and then the reaction mixture concentrated in vacuo. The resulting residue was purified using column chromatography (5:1 hexanes:EtOAc) to give 7a (140 mg, 50%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.63-1.70 (m, 2H), 1.87-1.93 (m, 2H), 2.10-2.16 (m, 2H), 3.88 (s, 3H), 4.14 (t, J=6.2 Hz, 2H), 4.95-5.05 (m, 2H), 5.76-5.86 (m, 1H), 6.51-6.54 (m, 3H), 7.84 (d, J=9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 24.9, 28.1, 33.1, 55.9, 69.2, 99.9, 104.6, 114.7, 124.3, 131.7, 138.3, 158.7, 166.8.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH2:22])[CH2:10]2)=[N:7][CH:8]=1.Cl[C:26]1[O:27][C:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:42])[O:39][CH2:40][CH3:41])[CH:34]=[CH:35][CH:36]=2)=[CH:29][N:30]=1>>[F:24][C:2]([F:1])([F:23])[C:3]1[N:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:26]3[O:27][C:28]([C:31]4[CH:32]=[C:33]([NH:37][C:38](=[O:42])[O:39][CH2:40][CH3:41])[CH:34]=[CH:35][CH:36]=4)=[CH:29][N:30]=3)[CH2:10]2)=[N:7][CH:8]=1
Reactant: CCOC(=O)Nc1cccc(-c2cnc(Cl)o2)c1
Reactant: N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2cnc(C(F)(F)F)cn2)C1
Product: CCOC(=O)Nc1cccc(-c2cnc(N[C@@H]3CCCC[C@H]3N[C@H]3CCCN(c4cnc(C(F)(F)F)cn4)C3)o2)c1
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
Ethyl 3-(2-((1R,2R)-2-((S)-1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-3-ylamino)cyclohexylamino)oxazol-5-yl)phenylcarbamate (7.13 mg, 0.012 mmol, 21% yield) was synthesized as described in General Procedure H using (1R,2R)—N1-((S)-1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-3-yl)cyclohexane-1,2-diamine (19.86 mg, 0.058 mmol) and Intermediate 44, ethyl 3-(2-chlorooxazol-5-yl)phenylcarbamate (15.42 mg, 0.058 mmol). The product was purified via preparative LC/MS with the following conditions: Column. Waters XBridge C18, 19×100 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% ammonium hydroxide; Mobile Phase B: 95:5 acetonitrile:water with 0.1% ammonium hydroxide; Gradient: 35-75% B over 10 minutes, then a 7-minute hold at 75% B; Flow rate: 20 mL/min. Anal. Calcd. for C28H34F3N7O3 m/z 573.3, found: 574.3 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 9.64 (s, 1H), 8.40 (d, J=1.1 Hz, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 7.27-7.18 (m, 3H), 7.15-7.10 (m, 2H), 4.41 (d, J=10.7 Hz, 1H), 4.21 (d, J=12.9 Hz, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.25 (td, J=9.3, 4.0 Hz, 1H), 3.06-2.99 (m, 1H), 2.76-2.69 (m, 1H), 2.66-2.54 (m, 2H), 2.06-1.96 (m, 2H), 1.89-1.82 (m, 1H), 1.75-1.61 (m, 3H), 1.45 (d, J=13.2 Hz, 1H), 1.37-1.28 (m, 2H), 1.28-2.21 (m, 5H), 1.09 (d, J=12.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:14][C:13](=[O:15])[C:12]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[CH:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1

Procedure:
Methanol (3.0 L) was added to a thoroughly dried 7 (427.5 g, 1.42 mol) under argon. To this stirred suspension concentrated sulfuric acid (100 mL) was added and heated at reflux for 20 h under nitrogen. Methanol was evaporated under reduced pressure at 30° C. The residue was taken up in ethyl acetate (3.0 L) and washed with water (2×1.0 L), saturated aqueous Na HCO3 (2×1.0 L), brine (2×1.0 L). The organic layer was dried on anhydrous magnesium sulfate, filtered and the solvent was evaporated. The residue obtained was dried thoroughly under high vacuum as white solid, (433.6 g 97%): mp 106-108° C.; 1HNMR (360 MHz, CDCl3): δ 7.72 (s, 1H), 7.06 (d, J=7.9 Hz, 2H), 6.77 (d, J=7.9 Hz, 2H), 6.33 (t, J=2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 2H), 5.74 (s, 1H), 3.81 (s, 3H), 3.60 (s, 6H); MS (EI) m/z 315[M]+; Anal. (C18H18O5) C, H.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=2[CH:21]=1)=O>>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]2[CH:21]=[C:20]([C:18]#[C:2][C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=3)[CH:29]=[CH:28][C:27]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(C)cc1
Product: Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 55.8 %

Procedure:
Using a process similar to that described in Example 13, 61.4 g (0.22 mole) of diethyl 1-chloro-1-(4-tolyl)-methylphosphonate, 51.1 g (0.22 mole) of 2-formyl5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene and 50 g (0.44 mole) of potassium tert.-butylate were reacted for 1 hour to give 37.1 g (56%) of the title compound of melting point 99° C., the reaction mixture being poured onto water and acidified, and the precipitated solid being filtered off under suction and recrystallized twice from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH:19]([NH:22][OH:23])[CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:24](OC=O)(=[O:26])C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH:19]([N:22]([OH:23])[CH:24]=[O:26])[CH2:20][CH3:21])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCC(CS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)NO
Reactant: CC(=O)OC=O
Solvent: C1CCOC1
Product: CCC(CS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)N(O)C=O
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A solution of Example 75C (0.24 g, 0.72 mmol) in THF (30 mL) cooled to 0° C. was treated with formic acetic anhydride (64 mg, 0.72 mmol), stirred for 2 hours, partitioned between water and dichloromethane, dried (Mg2SO4), filtered, and concentrated to afford 0.25 g of crude product which was recrystallized in ethyl acetate to provide 106 mg (41%) of the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1C=CC=C[CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:21][C:20](=[O:22])[C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:12][CH:11]=1>>[CH2:3]([O:22][C:20]1[C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[N:21]=1)[CH:2]=[CH2:1]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Product: C=CCOc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)OC

Procedure:
Using essentially the same procedure as in Example 1, Step E, but substituting allyl bromide for benzyl bromide, methyl 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (500 mg, 1.47 mmol) from Example 1, Step D afforded the desired higher Rf O-alkylation title compound after purification by flash column chromatography on silica gel (eluted with a gradient of 5 to 10% ethyl acetate in hexanes). HPLC/MS: 380 (M+1); Rt=4.7 min. 1HNMR (CDCl3): δ 3.954 (s, 3H), 5.09 (br d, J=5 Hz, 2H), 5.32 (dd, J=1.5 and 10.5 Hz, 1H), 5.45 (br dd, J=1.6 and 18 Hz, 1H), 6.13-6.23 (m, 1H), 7.16-7.21 (m, 2H), 7.22 (d, J=8.6 Hz, 2H), 7.30-7.36 (m, 3H), 7.37 (d, J=8.6 Hz, 2H), 8.246 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].C(=O)([O-])[O-].[K+].[K+].Br[CH2:58][C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60]>>[CH2:62]([O:61][C:59](=[O:60])[CH2:58][O:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(C)cc2c(c1OCC(=O)OCc1ccccc1)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 52 %

Procedure:
Following General Procedure: Method A using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and benzyl bromoacetate (24 μL, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) to afford (6R,6aS,14aR)-methyl 1-(2-(benzyloxy)-2-oxoethoxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (22 mg, 51%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 14.18 (s, 1H), 8.29 (s, 1H), 7.44-7.31 (m, 5H), 6.88 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 5.87 (s, 1H), 5.40 (d, J=12.2 Hz, 1H), 5.31 (d, J=12.2 Hz, 1H), 5.00 (s, 1H), 4.95 (dd, J=9.9, 7.3 Hz, 1H), 4.68 (d, J=8.7 Hz, 1H), 4.54 (d, J=15.2 Hz, 1H), 4.48 (br s, 1H), 4.45 (br s, 1H), 3.78 (s, 3H), 3.76-3.71 (m, 1H), 3.69 (d, J=1.6 Hz, 1H), 3.60-3.54 (m, 2H), 3.60 (s, 6H), 3.39 (s, 3H), 3.36-3.32 (m, 1H), 3.13 (t, J=9.2 Hz, 1H), 2.47 (d, J=4.5 Hz, 1H), 2.18 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 846 (M+H); HPLC 94.4% (AUC), tR 18.76 min.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][N:34]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>ClCCl>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:35][N:34]=2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N)cn2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (0.67 g, 2.6 mmol), 4-(5-amino-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.76 g, 2.6 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop, 1.45 g, 3.1 mmol), and diisopropylethylamine (0.9 mL, 5.2 mmol) in anhydrous dichloromethane (15 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated and purified by flash chromatography (Merck silica gel 60, 230-400 mesh, eluted with ethyl acetate and hexane) to give 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (0.78 g, 56%) as a white solid. LCMS calcd for C26H28F3N5O4 (m/e) 531, obsd 532 (M+H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[C:10]1([N:9]=[C:1]([Cl:18])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Product: ClC(=Nc1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 100.5 %

Procedure:
5MeO-TPT was prepared by a modified version of the routes described by D. Enders et al. in Synthesis 2003, page 1292, and by K. Potts et al. in J. Org. Chem. 32, page 224. A mixture of 98.6 g (0.5 mol) benzanilide and 75 mL (1.0 mol) thionyl chloride was heated on steam for 20 hours after initial vigorous outgassing. The resulting mixture was then stripped at about 26.67 kPa (20 mmHg) and 60° C. for 3 hours, leaving 108.4 g of N-phenylbenzimidoyl chloride as a low-melting green solid. The solid was dissolved in 250 mL ethyl acetate and stirred at 5° C. while adding a mixture of 54.05 g (0.5 mol) phenylhydrazine and 51.0 g (0.5 mol) triethylamine dropwise, with the temperature of the solution slowly rising to 20° C. The resulting mixture was washed with 1000 mL of 2 weight percent acetic acid. Solid product was present and another 400 mL of ethyl acetate was added to the washed mixture, with some solid still observed. The ethyl acetate portion of the mixture was separated and filtered, yielding 25.1 g of desired product, and the resulting mother liquor was stripped, 150 mL isopropanol and 50 mL water were added, and the resulting solid was filtered and dried to provide 35.9 g initially and 4.4 g as the final crop, for a total yield of 65.4 g (0.227 mol, 46 percent) of N-phenylbenzamide phenylhydrazone as a brown solid.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:38]3[CH:37]=[N:36][C:35]([Cl:34])=[CH:40][CH:39]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)nc1)N1CCC(N2CCCCC2)CC1
Yield: 57 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 2-chloropyridine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (57%).
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8]([CH3:19])([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH3:9])[CH2:4][CH2:3]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([N:2]1[CH2:3][CH:4]=[C:5]([C:8]([CH3:19])([C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH3:9])[CH2:6][CH2:7]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CN1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-1,2,3,6-tetrahydro-pyridine (5.2 g) was dissolved in toluene (100 mL) and ethyl chloroformate (2.4 g). The mixture was heated at reflux for overnight and cooled to RT. The toluene solution was washed with NaHCO3 (aq., sat., 100 mL) then brine (100 mL) and dried over Na2SO4. The organic phase was concentrated in vacuo to give the desired compound which was used without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[C:30](Cl)=[O:31])[CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:29]=3[N:20]=[CH:21][CH:22]=[CH:23]4)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cccc2cccnc12
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccc2cccnc12

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-8-carbonyl chloride were combined to provide N8-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-8-quinolinecarboxamide as a tan powder, m.p. 91.0-93.0° C. 1H NMR (300 MHz, DMSO-d6) δ10.80 (t, J=5.5 Hz, 1H), 8.79 (dd, J=4.3, 1.8 Hz, 1H), 8.55-8.49 (m, 2H), 8.24 (s, 1H), 8.17 (dd, J=8.1, 1.5 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 7.63-7.59 (m, 2H), 7.40 (dt J=7.1, 1.2 Hz, 1H), 7.14 (dt, J=7.1, 1.2 Hz, 1H), 6.57 (broad s, 2H), 4.68 (t, J=7.0 Hz, 2H), 3.51 (m, 2H), 2.02 (m, 2H), 1.69 (m, 2H); MS (EI) m/e 410.1858 (410.1855 calcd for C24H22N6O).