Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:34])[CH3:33])[CH:27]=3)=[O:25])[CH:18]=2)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:15]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:33])[CH3:34])[CH:27]=4)=[O:25])[CH:18]=3)[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: COC(=O)c1cc(N)ccc1Oc1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1c(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)ccc2nc(N)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
Potassium thiocyanate (1.02 g, 10.5 mmol) was suspended in acetic acid (10 mL), and the mixture was stirred at room temperature for 10 min. A solution of methyl 5-amino-2-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]benzoate (1.13 g, 2.62 mmol) in acetic acid (10 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (460 mg, 2.88 mmol) in acetic acid (5 ml) was slowly added dropwise to the obtained solution, and the mixture was stirred at room temperature for 3 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (200 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was is concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (1.15 g, 90%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[CH:28]=[C:29]([CH3:33])[O:30]2)=[CH:25][CH:24]=1>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[CH:28]=[C:29]([CH3:33])[O:30]2)=[CH:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 0.2 ml of trifluoromethansulfonic anhydride was added at 0° C. to 3 ml solution of pyridine with 10 mg of 7-hydroxy-2-methyl-4H-chromen-4-one, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by silicagel chromatography (hexane/ethyl acetate=10/1) to obtain 112 mg of the above compound as a white solid.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].N1C=CC=CC=1.ClCCl.[CH3:23][Si:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][OH:27]>O>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:27][CH2:26][CH2:25][Si:24]([CH3:29])([CH3:28])[CH3:23])=[O:9])(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCO
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 23.9 g of 3-(chlorosulfonyl)benzoyl chloride, 7.9 mL of pyridine, and 100 mL of dichloromethane was added dropwise 14 mL of 2-(trimethylsilyl)ethanol under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with chloroform, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 29.4 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate as a colorless solid.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.ClC(Cl)(Cl)Cl>[I:41][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(O)CC1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOC(=O)N1CCC(I)CC1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
12.5 g of 2-trimethylsilanylethyl 4-hydroxypiperidine-1-carboxylate were dissolved in 136 ml of dichloromethane and 264 ml of tetrachloromethane. The solution was cooled to 0° C. and then 16 g of triphenylphosphine, 4.2 g of imidazole and 15.8 g of iodine were successively added. The mixture was slowly allowed to reach room temperature and was stirred for 14 h. Then 300 ml of a saturated sodium thiosulfate solution were added to the solution. The mixture was stirred until it was colorless. The aqueous phase was then extracted twice with 200 ml of dichloromethane each time. The combined organic phases were washed once with 200 ml of a saturated sodium thiosulfate solution and once with 200 ml of a saturated sodium chloride solution. After drying with MgSO4, the solvents were removed in vacuo, and the residue was purified by chromatography on silica gel.
Reaction SMILES: [N+:1]([N:4]([CH3:7])[CH2:5][OH:6])([O-:3])=[O:2].[C:8](Cl)(=[O:10])[CH3:9]>ClCCl>[C:8]([O:6][CH2:5][N:4]([N+:1]([O-:3])=[O:2])[CH3:7])(=[O:10])[CH3:9]
Reactant: CN(CO)[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)OCN(C)[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a stirred mixture of 10.6 g of 2-nitro-2-azapropanol and 25 ml of dichloromethane under a nitrogen atmosphere was added dropwise and with ice-cooling 12 g of acetyl chloride. The cooling bath was removed and the mixture was slowly heated to reflux. After 3 hours the solution was allowed to cool and was then triturated with 50 ml of ice water. The organic phase was separated, dried (MG SO4), and distilled. The product 2-nitro-2-azapropyl acetate had b.p. 56°-57° C. at 0.07 mm Hg.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](O)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O.S(=O)(=O)(O)O>C(OCC)C>[CH2:7]([OH:25])[CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCO
Yield: 94.2 %

Procedure:
To a suspension of lithium aluminium hydride (50 g) in diethyl ether (1400 ml) under nitrogen was added dropwise with stirring a solution of z,z,z-octadeca-6,9,12-trienoic acid (97%, 200 g) at such a rate that a steady reflux occurred. The mixture was heated under reflux for 4 hours. After cooling to 0°-5° C., water (200 ml) was added cautiously to break down the complex, still maintaining a blanket of nitrogen. To the resulting slurry was added a 10% aqueous solution of sulphuric acid (1500 ml) and a two phase solution occurred. The aqueous layer was separated and the organic layer was washed with water (1000 ml), saturated aqueous sodium bicarbonate (2×1000 ml) and water (2×500 ml). The ether layer was dried (Na2SO4) and evaporated in vacuo to give a yellow oil. Distillation (148°-150° C./0.06 mmHg) gave z,z,z,-octadeca-6,9,12-trienol (179 g, 94% ) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[O:27][CH3:28]>C1COCC1.CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH2:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: COc1cc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)ccc1Cl
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(4-chloro-3-methoxyphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (262.3 mg) in THF (dry) (60 mL) and MeOH (30 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Platinum(IV) oxide (30 mg) was added and the mixture was stirred at room temperature under hydrogen for 4 hr. The insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. MeCN (13 mL) was added and this mixture was purified by preparative HPLC (C18, eluted with water in acetonitrile containing 0.1% TFA). The desired fractions were neutralized with sat.NaHCO3 aq. and the mixture was extracted with EtOAc. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (80.1 mg) as colorless crystals.
Reaction SMILES: [I:1]I.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2)([O-:5])=[O:4]>CN(C)C=O.C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:13]1[CH:14]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[C:8]2[C:12]=1[NH:11][CH2:10][CH2:9]2
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(I)c2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
A mixture of silver sulfate (100 g, 0.32 mol) and iodine (82 g, 0.32 mol) in N,N-dimethylformamide (700 mL) and ethanol (1400 mL) was treated with 5-nitro-2,3-dihydro-1H-indole I (48 g, 0.29 mol). The resulting mixture was stirred at 25° C. for 1.5 h, filtered and the filter pad washed with ethyl acetate. The filtrate was concentrated in vacuo to a volume of approximately 500 mL. This solution was treated with a 1.0N aqueous sodium thiosulfate solution (100 mL) and a saturated aqueous sodium chloride solution (400 mL). The resulting precipitate was collected by filtration, washed with water and petroleum ether, and dried in vacuo to afford 7-iodo-5-nitro-2,3-dihydro-1H-indole II (83.9 g, 98.9%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.18 (d, J=2.20 Hz, 1H), 7.80 (d, J=1.46 Hz, 1H), 7.03 (broad s, 1H) 3.65 (t, J=8.97 Hz, 2H), 3.17 (t, J=8.60 Hz, 2H).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@H:6]1[O:15][C@@H:16]1[C@@H:31]([OH:32])[C@@H:30]([OH:33])[C@@H:29]([CH2:34][O:35][C@@H:36]2[O:43][C@H:42]([CH2:44][OH:45])[C@@H:40]([OH:41])[C@H:38]([OH:39])[C@H:37]2[NH:46][C:47](=[O:49])[CH3:48])[O:28][C@H:17]1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:3])[CH3:2].C1C(=O)NC(=O)NC=1[C@@H]1O[C@H](COP(OP(O[C@H:73]2[O:78][C@H:77]([CH2:79][OH:80])[C@H:76]([OH:81])[C@H:75]([OH:82])[C@H:74]2[OH:83])(O)=O)(O)=O)[C@@H](O)[C@H]1O>[As](C)(C)(=O)[O-].[Na+].[Cl-].[Mn+2].[Cl-]>[C@@H:17]1([O:12][C@@H:9]2[C@@H:8]([CH2:13][OH:14])[O:7][C@@H:6]([O:15][C@@H:16]3[C@@H:31]([OH:32])[C@@H:30]([OH:33])[C@@H:29]([CH2:34][O:35][C@@H:36]4[O:43][C@H:42]([CH2:44][OH:45])[C@@H:40]([O:41][C@@H:73]5[O:78][C@H:77]([CH2:79][OH:80])[C@H:76]([OH:81])[C@H:75]([OH:82])[C@H:74]5[OH:83])[C@H:38]([OH:39])[C@H:37]4[NH:46][C:47](=[O:49])[CH3:48])[O:28][C@H:17]3[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@H:10]2[OH:11])[O:28][C@H:29]([CH2:34][OH:35])[C@H:30]([OH:33])[C@H:31]([OH:32])[C@H:16]1[OH:15]
Reactant: O=c1cc([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)[nH]c(=O)[nH]1
Reactant: COC(=O)CCCCCO[C@@H]1O[C@H](CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Agent: [Mn+2]
Agent: C[As](C)(=O)[O-]
Agent: [Cl-]
Product: COC(=O)CCCCCO[C@@H]1O[C@H](CO[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2NC(C)=O)[C@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1NC(C)=O
Reaction time: 22 h

Procedure:
A solution of compound 17 of Example 17 (72 mg), UDP-galactose, (190 mg), bovine galactosyltransferase (6 U) and bovine serum albumin (3 mg) in 30 mM sodium cacodylate buffer (7 mL, pH 7.0) containing manganese chloride (40 umol) was incubated at 37° C. for 22 h. The reaction mixture was diluted to 20 mL and purified as described in Example 21. Yield of the product was 95 mg. The structural identity of titled compound 23 was unambiguously assigned by 1H- and 13C-n.m.r (see Tables 4 and 5, respectively).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH:21][C:22]([NH:24][C:25]2[N:29]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[N:28]=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)=[O:23])=[CH:13][CH:12]=1.[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46][C:47](Cl)=[O:48]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:37]([C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([O:10][CH2:9][CH2:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:47](=[O:48])[CH2:46][O:45][CH2:44][CH2:43][O:42][CH3:41])=[CH:12][CH:13]=2)[N:29]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[N:28]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccncc3N)c3ccccc23)cc1
Reactant: COCCOCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCOCC(=O)Nc1cnccc1CCOc1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2-c2ccc(C)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.2 %

Procedure:
To 1-(4-(2-(3-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate E) (50 mg, 0.094 mmol) and DMAP (5.71 mg, 0.047 mmol) in DCM (3.0 mL) was added 2-(2-methoxyethoxy)acetyl chloride (30 μl, 0.281 mmol) at 0° C. and the reaction mixture stirred at RT for 1.5 hr. The solvent was removed in vacuo and the residue subjected to SCX capture and release eluting with 1% NH3 in MeOH solution. The residue was purified by column chromatography (4.0 g) gradient elution with 0-8% MeOH in DCM and the product fractions concentrated in vacuo to give N-(4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-3-yl)-2-(2-methoxyethoxy)acetamide (Example 22) as a light purple solid (35 mg, 56%): m/z 651 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.25 (9H, s), 2.40 (3H, s), 3.26 (5H, m), 3.50 (2H, m), 3.70 (2H, m), 4.15 (2H, s), 4.40 (2H, t), 6.35 (1H, s), 6.98 (1H, d), 7.35 (2H, m), 7.42 (2H, m), 7.50 (3H, m), 7.62 (1H, d), 7.87 (1H, d), 8.07 (1H, dd), 8.36 (1H, d), 8.56 (1H. br s), 8.60 (1H, s), 8.76 (1H, br s), 9.55 (1H, br s.).
Reaction SMILES: C([Si](CC)(C(C)C)[O:4][CH:5]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14]([O:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)=[O:21])[CH:13]=[CH:12][CH:11]([CH3:35])[CH:10](/[C:36](/[CH3:61])=[CH:37]/[CH:38]=[CH:39]/[C:40]([OH:60])([CH3:59])[CH2:41][CH:42]2[O:58][CH:43]2[CH:44]([CH3:57])[CH:45]([O:48][Si](CC)(CC)C(C)C)[CH2:46][CH3:47])[O:9][C:7](=[O:8])[CH2:6]1)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:4][CH:5]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14]([O:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)[CH2:24][CH2:23]2)=[O:21])[CH:13]=[CH:12][CH:11]([CH3:35])[CH:10](/[C:36](/[CH3:61])=[CH:37]/[CH:38]=[CH:39]/[C:40]([OH:60])([CH3:59])[CH2:41][CH:42]2[O:58][CH:43]2[CH:44]([CH3:57])[CH:45]([OH:48])[CH2:46][CH3:47])[O:9][C:7](=[O:8])[CH2:6]1
Reactant: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(OC(=O)N2CCN(C3CCN(C)CC3)CC2)C=CC1C
Agent: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)C(OC(=O)N2CCN(C3CCN(C)CC3)CC2)/C=C/C1C
Agent: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(OC(=O)N2CCN(C3CCN(C)CC3)CC2)/C=C/C1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)C(OC(=O)N2CCN(C3CCN(C)CC3)CC2)C=CC1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-16-hydroxy-6,10,12,16,20-pentamethyl-7-((4-(1-methylpiperidin-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide (18.5 mg, 19.2 μmol) in tetrahydrofuran (2 mL) was cooled to 5° C. Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 42.3 μL, 42.3 μmol) was added dropwise to the solution, and the reaction mixture was stirred at room temperature for four hours. The reaction mixture was diluted with ethyl acetate, and then the organic layer was washed with an aqueous solution of sodium hydrogencarbonate. The resulting organic layer was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, filtered concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel plate; methanol-dichloromethane, 1:24) to obtain the title compound (7.6 mg, 56%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].BrBr.Br[O-].[CH2:7]([O:14][C:15]12[CH2:23][CH:19]3[CH2:20][CH:21]([CH2:22]1)[C:17]([C:24](=[O:26])C)([CH2:18]3)[CH2:16]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)=[O:29].CC(O)=O>O1CCOCC1.O>[CH2:7]([O:14][C:15]12[CH2:23][CH:19]3[CH2:20][CH:21]([CH2:22]1)[C:17]([C:24]([OH:29])=[O:26])([CH2:18]3)[CH2:16]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)C12CC3CC1CC(OCc1ccccc1)(C3)C2
Reactant: CC(C)=O
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C12CC3CC1CC(OCc1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.6 %

Procedure:
To a mixture of NaOH (10.8 g, 270 mmol), H2O (72 mL) and 1,4-dioxane (20 mL) at ice bath temperature was added Br2 (5.2 mL, 100.8 mmol) and stirred for 5 minutes. This hypobromite solution was added drop-wise to a solution of the compound obtained from step III (4.84 g, 18 mmol) in 1,4-dioxane (18 mL) kept at ice bath temperature. The reaction mixture was gradually warmed to room temperature and stirred for 1 h, after which it was cooled to ice bath temperature and quenched by adding AcOH (3.9 mL, 65.7 mmol), diluted with water, and extracted in EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-(benzyloxy)tricyclo[3.3.1.03,7]nonane-3-carboxylic acid as a gummy liquid (4.1 g) in 83% yield. m/z (M+1), 273; 1H NMR (CDCl3) 300 MHz δ 7.40-7.20 (m, 5H), 4.52 (s, 2H), 2.78-2.70 (m, 1H), 2.58-2.48 (m, 1H), 2.45-2.37 (m, 1H), 2.18-1.50 (m, 9H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[NH:17]2)[N:11]=1)(C(C)(C)C)(C)C>CO>[OH:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[NH:17]2)[N:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Solvent: CO
Product: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1ncc(CO)n1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (500 mg, 1.12 mmol) in MeOH (15 mL) was added DOWEX-50W-X4 100-200 (1 g, 1.12 mmol) resin. After stirring at rt for 3 h, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (assume quantitative). LCMS: Rt=0.51 min, m/z=332.1 (M+1) Method 2m_acidic.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][CH2:10][C@@H:11]([OH:15])[C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=1)=O.[C:18]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C.C([BH3-])#N.[Na+]>CN1CCCC1=O.COC(OC)OC.CO>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([NH:26][CH2:1][C:3]2[CH:17]=[CH:16][C:6]([C:7]([NH:9][CH2:10][C@@H:11]([OH:15])[C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=2)=[CH:27][CH:28]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=Cc1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(NCc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)cc1
Reaction time: 4 h

Procedure:
The above resin bound (R)-3-(4-formylbenzoylamino)-2-hydroxypropionic acid was treated with a 0.5 M solution of 4-tert-butylaniline (0.25 mmol) in a mixture of N-methyl-2-pyrrolidinone and trimethylorthoformate (1:1, 0.5 mL) and glacial acetic acid (50 μL) for 1 hour at 25° C. Sodium cyanoborohydride (250 μmol, 16 mg) dissolved in a mixture of N-methyl-2-pyrrolidinone and methanol (1:1, 0.25 mL) was added and the mixture was vortexed at 25° C. for 4 hours followed by filtration and washing with a mixture of N-methyl-2-pyrrolidinone and methanol (1:1, 2×1 mL) 3×1 mL N-methyl-2-pyrrolidinone (3×1 mL) and a mixture of 1,2-dichloropropane and diisopropylethylamine (7:1, 2×0.75 mL).
Reaction SMILES: [CH2:1]([P:5]1(=[O:11])[O:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]([CH3:4])=[O:3].[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[C:1]([P:5]1(=[O:11])[O:6][CH2:7][CH2:8][CH2:9][O:10]1)[C:2]([CH3:4])=[O:3])([O-:14])=[O:13]
Reactant: CC(=O)CP1(=O)OCCCO1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)P1(=O)OCCCO1
Yield: 25.8 %

Procedure:
A mixture of 10.0 grams of 2-acetonyl-2-oxo-1,3,2-dioxaphosphorinane and 8.48 grams of m-nitrobenzaldehyde was dissolved in 120 ml of toluene, 1.0 gram of piperidine and 2.0 grams of acetic acid were added as catalysts and the mixture was heated to reflux for 15 hours with a water-remover. After cooled, the crystals separated out were removed by filtration, the filtrate was washed with water, then with aqueous solution of sodium hydroxide, further with 20% sodium acid sulfite solution and finally with water, and the organic solvent layer was dried. The solvent was removed by evaporation in vacuo, the residue was purified by silica gel column chromatography, and 4.5 grams of 2-(1-(3-nitrobenzylidene)acetonyl)-2-oxo-1,3,2-dioxaphosphorinane was obtained as an EZ mixture. Recrystallized from ethyl acetate. M.p. 144°-145.5° C.