Reaction SMILES: O([CH2:9][CH2:10][O:11][CH2:12][CH3:13])S(C(F)(F)F)(=O)=O.[CH3:14][C@H:15]1[C@@:54]2([OH:56])[O:55][C@H:18]([CH2:19][C@H:20]([O:77][CH3:78])[C:21]([CH3:76])=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26][C@@H:27]([CH3:75])[CH2:28][C@@H:29]([CH3:74])[C:30]([C@H:32]([O:72][CH3:73])[C@H:33]([OH:71])[C:34]([CH3:70])=[CH:35][C@@H:36]([CH3:69])[C:37]([CH2:39][C@@H:40]([C@@H:57]([CH2:59][C@H:60]3[CH2:65][C@@H:64]([O:66][CH3:67])[C@H:63]([OH:68])[CH2:62][CH2:61]3)[CH3:58])[O:41][C:42]([C@H:44]3[N:49]([C:50]([C:52]2=[O:53])=[O:51])[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:43])=[O:38])=[O:31])[CH2:17][CH2:16]1.N1C(C)=CC=CC=1C.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:9][CH2:10][O:11][CH2:12][CH2:13][O:68][C@H:63]1[C@H:64]([O:66][CH3:67])[CH2:65][CH:60]([CH2:59][C@H:57]([CH:40]2[O:41][C:42](=[O:43])[C@H:44]3[N:49]([CH2:48][CH2:47][CH2:46][CH2:45]3)[C:50](=[O:51])[C:52](=[O:53])[C@:54]3([OH:56])[O:55][C@@H:18]([CH2:17][CH2:16][C@H:15]3[CH3:14])[CH2:19][C@H:20]([O:77][CH3:78])[C:21]([CH3:76])=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26][CH:27]([CH3:75])[CH2:28][C@@H:29]([CH3:74])[C:30](=[O:31])[C@H:32]([O:72][CH3:73])[C@H:33]([OH:71])[C:34]([CH3:70])=[CH:35][C@@H:36]([CH3:69])[C:37](=[O:38])[CH2:39]2)[CH3:58])[CH2:61][CH2:62]1
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Reactant: CCOCCOS(=O)(=O)C(F)(F)F
Agent: CCOCCO[C@@H]1CCC(C[C@@H](C)C2CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)CC(C)/C=C/C=C/C=C(\C)[C@@H](OC)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCCO[C@@H]1CCC(C[C@@H](C)C2CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)CC(C)C=CC=CC=C(C)[C@@H](OC)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Coupling of 2-ethoxyethyl triflate (44.3 equivalents) and rapamycin (1.0 equivalent) in toluene with 2,6-lutidine (49.1 equivalents) was conducted at 55° C. (external water bath temperature) for 90 minutes. In this process (on a 2.0 g scale of, rapamycin), the 2-ethoxyethyl triflate was added to a pre-heated reaction mixture (55° C.) in one portion. After heating for 90 minutes, the external heating was turned off followed by addition of the second portion of 2,6-lutidine (54.9 equivalents). After the addition of the second lutidine portion, the reaction mixture was stirred for an additional 90 minutes at ambient temperature followed by workup to isolate crude BA9. The work-up included: 1. dilution of the reaction mixture with ethyl acetate; 2. quench of the reaction mixture with cold 1 N HCl; and 3. wash of the organic layer with three portions of 20% sodium chloride solution in water. The pH of the water layer after the last sodium chloride wash was ˜6. The crude material was then purified by an isocratic silica gel column chromatography using only one solvent mixture (n-hexane/ethyl acetate in ratio of 4:6 (vol/vol)).