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].[Cl:51]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:51][C:15]1[C:16](=[O:29])[C:17]2[C:18]([OH:28])=[C:19]3[C:10](=[CH:11][C:12]=2[C:13](=[O:43])[C:14]=1[NH:30][C@@H:31]1[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]1)[C:9](=[O:44])[C@:8]1([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]([C:47]([O:49][CH3:50])=[O:48])=[C:2]([OH:1])[C:7]=21)[C:20]3=[O:27]
Reactant: O=C1CCC(=O)N1Cl
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
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: 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(Cl)=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Temperature: 75 °C
Yield: 13 %

Procedure:
To a solution of (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 (100 mg, 0.14 mmol) in chloroform (2 mL) was added N-chlorosuccinimide (28 mg, 0.21 mmol) followed by benzoyl peroxide (1-2 mg). The reaction mixture was refluxed at 75° C. for 12 h, and then N-chlorosuccinimide (19 mg, 0.14 mmol) was refilled and the reaction mixture was refluxed for another 5 h. After cooled to room temperature, the reaction mixture was diluted with chloroform (10 mL) and washed with saturated sodium bicarbonate (5 mL). The aqueous layer was further extracted with chloroform (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative TLC (silica gel, 95:5 chloroform/methanol) and semi-preparative HPLC to afford (6R,6aS,14aR)-methyl 10-chloro-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 (13.3 mg, 14%) as a red solid: 1H NMR (500 MHz, CDCl3) δ 13.72 (s, 1H), 12.11 (s, 1H), 8.22 (s, 1H), 7.11 (br s, 1H), 6.54 (s, 1H), 5.73 (s, 1H), 5.20 (s, 1H), 4.95 (s, 1H), 4.60 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.73 (s, 2H), 3.60 (s, 3H), 3.59-3.52 (m, 1H), 3.41 (s, 3H), 3.38-3.31 (m, 1H), 3.34 (d, J=19.5 Hz, 1H), 3.11 (t, J=9.5 Hz, 1H), 2.48 (br s, 1H), 2.41 (s, 3H), 1.36 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 732 (M+H); HPLC 95.1% (AUC), tR 14.34 min; and (6R,6aS,14aR)-methyl 4,10-dichloro-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 (3.6 mg, 3%) as a dark blue solid: 1H NMR (500 MHz, CDCl3) δ 13.72 (s, 1H), 11.70 (br s, 1H), 8.20 (s, 1H), 7.11 (br s, 1H), 5.71 (s, 1H), 5.26 (s, 1H), 5.00 (s, 1H), 4.71 (s, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.73 (s, 2H), 3.60 (s, 3H), 3.59-3.52 (m, 1H), 3.50-3.41 (m, 2H), 3.41 (s, 3H), 3.11 (t, J=9.0 Hz, 1H), 2.54 (s, 3H), 2.46 (s, 1H), 1.34 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 766 (M+H); HPLC 92.8% (AUC), tR 15.63 min.