Reaction SMILES: [CH3:1][C@H:2]1[C:40](=[CH2:41])[C@@H:39]2[O:42][C@@H:4]([CH2:5][CH2:6][C@@H:7]3[O:12][C@@H:11]([CH2:13][CH2:14][C@@:15]45[O:24][C@H:23]6[C@H:25]7[O:31][C@@H:30]([CH2:32][C:33]([CH2:35][C@@H:36]8[C@@H:45]([O:46][CH3:47])[C@@H:44]([CH2:48][C@H:49]([OH:52])[CH2:50]O)[O:43][C@H:37]8[CH2:38]2)=[O:34])[CH2:29][CH2:28][C@@H:26]7[O:27][CH:20]2[C@H:21]6[O:22][C@H:17]([C@@H:18]2[O:19]4)[CH2:16]5)[CH2:10][C:8]3=[CH2:9])[CH2:3]1.[F-].[K+].[N:55]1C(C)=CC(C)=CC=1C.N1C=CC=CC=1.O(S(C1C=CC(C)=CC=1)(=O)=O)S(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.ClCCl.O>[CH3:1][C@H:2]1[C:40](=[CH2:41])[C@@H:39]2[O:42][C@@H:4]([CH2:5][CH2:6][C@@H:7]3[O:12][C@@H:11]([CH2:13][CH2:14][C@@:15]45[O:24][C@H:23]6[C@H:25]7[O:31][C@@H:30]([CH2:32][C:33]([CH2:35][C@@H:36]8[C@@H:45]([O:46][CH3:47])[C@@H:44]([CH2:48][C@H:49]([OH:52])[CH2:50][NH2:55])[O:43][C@H:37]8[CH2:38]2)=[O:34])[CH2:29][CH2:28][C@@H:26]7[O:27][C@@H:20]2[C@H:21]6[O:22][C@@H:17]([C@@H:18]2[O:19]4)[CH2:16]5)[CH2:10][C:8]3=[CH2:9])[CH2:3]1
Reactant: C=C1C[C@@H]2CC[C@@]34C[C@@H]5O[C@@H]6C(O[C@H]7CC[C@H](CC(=O)C[C@@H]8[C@@H](OC)[C@@H](C[C@H](O)CO)O[C@H]8C[C@H]8O[C@@H](CC[C@@H]1O2)C[C@@H](C)C8=C)O[C@@H]7[C@@H]6O3)[C@H]5O4
Reactant: Cc1cc(C)nc(C)c1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C1C[C@@H]2CC[C@@]34C[C@H]5O[C@H]6[C@@H](O3)[C@H]3O[C@H](CC[C@@H]3O[C@H]6[C@H]5O4)CC(=O)C[C@@H]3[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]3C[C@H]3O[C@@H](CC[C@@H]1O2)C[C@@H](C)C3=C
Yield: 75 %

Procedure:
ER-076349 (0.259 kg, 0.354 mol, 1 eq) was dissolved in toluene (4.7 kg) and azeotroped in vacuo at <25° C. The residue was diluted with toluene (4.5 kg) to give a toluene solution for monitoring of water content. Water content was measured by Karl-Fischer (KF) titration method. If the KF value was >125 ppm, the solution was azeotroped in vacuo at <25° C. and diluted with toluene (4.5 kg) until the water content came down to 125 ppm. If the KF value reached the target value, the solution was concentrated and dissolved in anhydrous dichloromethane (6.5 kg). 2,4,6-collidine (0.172 kg, 1.27 mol, 4 eq) and pyridine (0.0014 g, 0.018 mol, 0.05 eq) in anhydrous dichloromethane (84.1 g) were added, and the mixture was cooled. A solution of Ts2O (0.124 kg, 0.380 mol, 1.07 eq) in anhydrous dichloromethane (3.4 kg) was added to the reaction mixture at a rate to maintain the reaction temperature at ≦−10° C., and the mixture was stirred at ≦−10° C. When the residual amount of ER-076349 was <3% or the generation of corresponding bis-tosylate was more than 4%, the reaction mixture was quenched by the addition of water (1.0 kg). The mixture was warmed up, and then isopropyl alcohol (IPA) (20.5 kg) and ammonium hydroxide (NH4OH; 25.7 kg) were added consecutively at 10-30° C. Upon complete consumption of the epoxide (target≦0.85%; add extra NH4OH if necessary), the reaction mixture was concentrated in vacuo at <30° C. To the residue, dichloromethane (20.7 kg) and a sufficient amount of buffer solution of NaHCO3/Na2CO3/water (9/9/182 w/w/w; not more than 5.166 kg) were added and extracted. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (8.6 kg). The organic layer was separated and combined with the first extract. The combined organic layers were concentrated in vacuo at <30° C. The concentrate was diluted with acetonitrile (4.0 kg) and then loaded onto silica gel column which was preequilibrated with acetonitrile (200 L). The column was eluted sequentially with: (1) acetonitrile (100 L), (2) 90.0/7.5/2.5 v/v/v acetonitrile/water/200 mM aqueous NH4OAc (152.4 L), (3) 85.8/11.7/2.5 v/v/v acetonitrile/water/200 mM aqueous NH4OAc (152.4 L), (4) 83.5/14.0/2.5 v/v/v acetonitrile/water/200 mM aqueous NH4OAc (152.6 L), and (5) 80.0/17.6/2.4 v/v/v acetonitrile/water/200 mM aqueous NH4OAc (>100.2 L). Desired fractions were combined and concentrated in vacuo at ≦40° C. while maintaining the internal pH at 5.5-9.0 by adding NH4OH. To the residue, dichloromethane (13.9 kg) and a sufficient amount of buffer solution of NaHCO3/Na2CO3/water (9/9/182 w/w/w; not more than 15.51 kg) were added and extracted. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (8.7 kg). The organic layer was separated and combined with the first extract. The combined organic layers were concentrated in vacuo at <30° C. The residue was dissolved in 75% v/v anhydrous dichloromethane in n-pentane (6.12 kg) and filtered. The filtrate was concentrated in vacuo at <30° C., diluted with acetonitrile (2.1 kg), and concentrated in vacuo at 35° C. to give eribulin (75-95% yield).