Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([S:32](Cl)(=[O:34])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:32]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])=[N:7][CH:6]=2)[CH2:13][CH2:12]1)=[O:15]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Reactant: CCCCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCS(=O)(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Temperature: 60 °C
Yield: 7.6 %

Procedure:
To a solution of [4-(6-aminopyridin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.035 g, 0.10 mmol) in pyridine (3 mL) was added hexanesulfonyl chloride (0.022 mL, 0.12 mmol). After heating at 60° C. for 20 h, the mixture was diluted with ethyl acetate (100 mL), washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. Purification by preparative thin layer chromatography afforded the title compound as a white solid (3.8 mg, 8% yield). 1H NMR (300 MHz, CDCl3) δ 7.66, 7.29, 4.08, 3.91, 3.38, 3.27, 3.08, 1.84, 1.35, 1.27, 0.87. MS (ES+) m/z 499.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:4](=[O:16])[C:3]=1[Br:17].C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29].[OH-].[Na+]>CN(C)C1C=CN=CC=1.C(#N)C>[Br:17][C:3]1[C:4](=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[C:26]([F:25])=[CH:34][CH:33]=[CH:32][C:31]=1[F:35]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
4-amino-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one (from step 3) (0.30 g, 1.01 mmol) and 4-dimethylaminopyridine (0.002 g, 0.01 mmol) were suspended in acetonitrile (5 mL) followed by dropwise addition of triethylamine (0.2 mL, 1.41 mmol). This reaction mixture was stirred for 10 minutes at room temperature before being cooled to 0° C. 2,6-difluorobenzoyl chloride (0.37 g, 2.12 mmol) was added dropwise and the reaction was heated at reflux overnight. The reaction was cooled to room temperature and 1N NaOH (10 mL) was added. The reaction was then stirred for 45 minutes at room temperature. The reaction mixture was extracted with ethyl acetate (3×25 mL) and the organic layer washed with 1N NaOH (2×25 mL), H2O (until pH neutral), brine (50 mL), dried over MgSO4, concentrated, and subjected to chromatography (on C-18, acetonitrile/H2O with 0.1% trifluoracetic acid) to afford a white solid (0.19 g, 43%). 1H NMR (400 MHz, CDCl3) δ 8.42 (br s, 1H), 7.67 (d, J=7.65 Hz, 1H), 7.49 (app tt, J=6.31, 8.60 Hz, 1H), 7.33-28 (m, 2H), 7.10-6.97 (m, 5H), 5.17 (s, 2H). ES-HRMS m/z 437.0083 (M+H C19H12BrF3N2O2 requires 437.0107).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH3:15])=[CH:10][CH:9]=1.[CH:17]1[C:22]([O:23][C:24](Cl)=[O:25])=[CH:21][CH:20]=[C:19]([Cl:27])[CH:18]=1>O1CCOCC1.C([O-])(O)=O.[Na+]>[Cl:27][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24](=[O:25])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]#[C:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:16])[CH3:1])=[CH:9][CH:10]=2)[CH3:15])=[CH:17][CH:18]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CNc1ccc(C#CCCCN(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CCCC#Cc1ccc(N(C)C(=O)Oc2ccc(Cl)cc2)cc1
Yield: 54.9 %

Procedure:
A solution of 59 mg (0.27 mmol) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-amine in 0.3 ml dioxane was treated with 0.07 ml (0.55 mmol; 2 equivalents) Hünigsbase and dropwise with a solution of 0.05 ml (0.27 mmol) 4-chlorophenylchloroformate in 0.45 ml dioxane. The mixture was then immediately dissolved in aqueous saturated NaHCO3 IEt2O (3×). The organic phase was dried over Na2SO4 and evaporated. Flash column chromatography on silica gel with CH2Cl2/MeOH (95:5) yielded 55 mg (54%) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester, MS: 371 (MH+, 1Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13])=[CH:5][CH:4]=1.[CH2:16]([NH2:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:16]([N:28]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COc1ccc(C(=O)CCC(C)=O)cc1
Reactant: CCCCCCCCCCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCn1c(C)ccc1-c1ccc(OC)cc1
Yield: 78 %

Procedure:
A solution of 1-(4-methoxyphenyl)-1,4-pentanedione (3.00 g, 14.5 mol), dodecylamine (3.24 g, 17.5 mmol) and p-toluenesulfonic acid (150 mg, 0.871 mmol) in toluene (100 ml) was refluxed for 10 hours under heating using Dean-Stark's apparatus. The insoluble matter was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the object compound as an oily substance. 4.01 g (yield: 78%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>O1CCOCC1.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[CH:6]=[N:5]2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1cnc2cc(Br)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CO
Product: C=C(OCC)c1cnc2cc(Br)ccc2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Dichlorobis(triphenylphosphine)-palladium(II) (17.30 mg, 0.025 mmol) was added to a solution of 6-bromo-2-chloroquinoxaline (60 mg, 0.246 mmol) and tributyl(1-ethoxyvinyl)stannane (107 mg, 0.296 mmol) in dioxane (1.5 mL) and the mixture was stirred at 110° C. for 2 h. The reaction was diluted with MeOH, and purified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer) to yield 6-bromo-2-(1-ethoxyvinyl)quinoxaline (36 mg, 0.129 mmol, 52.3% yield) as white solid. LC-MS retention time 2.76 min; m/z 279 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: Br[C:2]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[N:4][C:3]=1[C:10]1[CH:17]=[CH:16][C:13](C=O)=[CH:12][CH:11]=1.C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)CCC.[O:36]1CCOC[CH2:37]1>C(Cl)Cl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[C:2]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[N:4][C:3]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:16][C:17]=1[CH:37]=[O:36]
Reactant: O=Cc1ccc(-c2nc3sccn3c2Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccccc1-c1nc2sccn2c1-c1nccs1
Temperature: 25 °C

Procedure:
4-(5-Bromo-imidazo[2,1-b]thiazol-6-yl)-benzaldehyde 0.09 g (0.37 mM) is dissolved in 5 mL of 1,4 dioxane and 0.5 eq of Pd(PPh3)4 is added followed by the addition of 2-(tributylstannyl)-1,3-thiazole (1.1 eq) and the reaction mixture is heated to reflux for 24 h. The reaction mixture is cooled down to room temperature and diluted with 10 mL of methylene chloride and 15 mL of water. The separated organic layer is washed with water and dried over Na2SO4. The crude reaction mixture is used for next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.[N:17]1[CH:22]=[C:21](B(O)O)[CH:20]=[N:19][CH:18]=1.C([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#N>>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:33]=[CH:32][C:31]([C:21]5[CH:22]=[N:17][CH:18]=[N:19][CH:20]=5)=[CH:30][CH:29]=4)=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:15]1
Reactant: OB(O)c1cncnc1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Product: CN1C[C@H]2CCN(c3ccc(-c4ccc(-c5cncnc5)cc4)cc3)[C@H]2C1

Procedure:
The title compound was prepared according to the procedure described in Example 7D, substituting the product of Example 41A for the product of Example 7C and substituting pyrimidine-5-boronic acid for 4-cyanophenylboronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 9.19 (s, 1H) 8.99 (s, 2H) 7.62-7.74 (m, 4H) 7.52-7.58 (m, 2H) 6.63-6.70 (m, 2H) 4.20-4.31 (m, 1H) 3.55-3.67 (m, 1H) 3.30-3.42 (m, 1H) 2.99-3.14 (m, 1H) 2.60-2.84 (m, 4H) 2.42 (s, 3H) 2.16-2.26 (m, 1H) 1.95-2.05 (m, 1H); MS (M+H)+=357.
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13](=O)[CH2:14]Cl)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:4])[CH3:3].[NH2:17][C:18]([NH2:20])=[S:19].C(O)C>O>[NH2:20][C:18]1[S:19][CH:14]=[C:13]([C:7](=[N:6][O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:17]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCC(C)C)C(=O)CCl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOCC(C)C)c1csc(N)n1
Yield: 50.8 %

Procedure:
Ethyl 2-iso-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 31.9 g.), thiourea (9.72 g.), sodium acetate 3-hydrate (17.4 g.), ethanol (120 ml.) and water (80 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetate (syn isomer, 17.6 g.), mp 122° to 124° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:18])[CH2:14]C(O)=O)[CH3:11].N1CCCCC1>N1C=CC=CC=1>[CH2:10]([O:12][C:13](=[O:18])[CH:14]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[CH3:11]
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccc(C)cc1
Yield: 79 %

Procedure:
Application of the previously unused Knoevenagel condensation (Silva, N. M. et al, Eur. J. Pled. Chem. 2002, 37, 163-170; Díaz, J. L. et al., Chem. Mater. 2002, 14, 2240-2251; Ren, X. et al., Tetrahedron: Asymmetry 2002, 13, 1799-1804) of p-tolualdehyde with malonic acid monoethyl ester (Breslow, D. S. et al., J. Am. Chem. Soc. 1944, 66, 1286-1288) in pyridine containing a catalytic amount of piperidine gave the known α,β-unsaturated ethyl cinnamate 5 (Tsuge, O. et al, J. Org. Chem. 1982, 47, 5171-5177; Colas, C; Goeldner, M. Eur. J. Org. Chem. 1999, 1357-1366; Chuzel, O.; Piva, O., Synth. Commun. 2003, 33, 393-402) in 79% yield. Reaction of 5 with (p-tolylsulfonyl)methyl isocyanide (TosMIC) afforded β-substituted pyrrole 6 (a known compound with incomplete data (Di Santo, R. et al, Med. Chem. Res. 1997, 7, 98-108)) in 74% yield. Removal of the ethoxycarbonyl group of pyrrole 6 by treatment with NaOH in ethylene glycol at 160° C. gave the known β-substituted pyrrole 7 (Sakai, K. et al., Chem. Pharm. Bull. 1980, 28, 2384-2393; Campi, E. M. et al., Aust. J. Chem. 1992, 45, 1167-1178; Pavri, N, P.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649-2651) in 71% yield. Vilsmeier-Haack formylation of 7 yielded a mixture of regioisomers owing to substitution at the 2- or 5-position. After column chromatography, the two regioisomers were determined to be present in ˜13:1 ratio by 1H NMR integration of the methyl unit of the p-tolyl group. Selective precipitation readily afforded the major regioisomer 8 in 64% yield (Scheme 3).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:43][CH:44]([CH3:55])[CH2:45][C@H:46]([NH:53][CH3:54])[CH2:47][N:48]1[CH2:51][CH:50]([OH:52])[CH2:49]1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([N:53]([C@@H:46]([CH2:45][CH:44]([CH3:55])[CH3:43])[CH2:47][N:48]1[CH2:49][CH:50]([OH:52])[CH2:51]1)[CH3:54])=[O:16]
Reactant: CN[C@@H](CC(C)C)CN1CC(O)C1
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(F)c(F)c1
Reaction time: 0.05 h
Yield: 65.1 %

Procedure:
DIPEA (0.252 mL, 1.45 mmol) was added to a stirred suspension of 3,4-difluorobenzoic acid (76 mg, 0.48 mmol) and TBTU (155 mg, 0.48 mmol) in DCM (2 mL) at rt. The suspension was stirred for 3 min. A solution of (S)-1-(4-methyl-2-(methylamino)pentyl)azetidin-3-ol (Compound G2.4) (100 mg, 0.48 mmol) in DCM (1 mL) was added and the reaction was stirred at rt overnight. The reaction was washed with an 8% aq. solution of NaHCO3 (1.5 mL). The organic layer was concentrated and purified by preparative HPLC affording the title compound (102 mg, 65%). Mixture of rotamers:
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:11])C.CC1(C)N([O])C(C)(C)CCC1.[OH-].[Na+]>C(#N)C.O>[CH2:1]([C:3]1([C:7]([OH:11])=[O:8])[CH2:6][O:5][CH2:4]1)[CH3:2]
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: CCC1(CO)COC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCC1(C(=O)O)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
(3-Ethyloxetan-3-yl)methanol (0.58 g, 5.00 mmol) was dissolved in 10 mL of a 1:1 ACN-water mixture, and bis-acetoxyiodobenzene (BAIB, 3.54 g, 11.0 mmol) was added. The mixture was cooled in an ice bath, and TEMPO (0.156 g, 1.00 mmol) was added under argon flow. The mixture was stirred at room temperature for 1 hr, and then treated with 1 M aqueous sodium hydroxide (20 mL). The solution was washed twice with EtOAc and then acidified to pH 2. The aqueous solution was extract six times with EtOAc and these combined extracts were dried over sodium sulfate and concentrated to afford 0.37 g (57%) of Intermediate 55 as oil, which was used without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].Cl[CH2:58][O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:58][O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: ClCOCc1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCOCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg in 2 ml methylene chloride) was added disopropylethylamine (99.4 μl) followed by benzyl chloromethyl ether (34.2 μl neat) and the mixture stirred at room temperature. After 24 hours, the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (92 mg).