Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])=[O:24]>C(#N)C.O>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[C:23](=[O:24])[CH2:22][NH:1][C:2]1[CH:3]=[C:4]([N:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(N2CC(=O)NS2(=O)=O)c1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CN(c2cccc(NCC(=O)c3ccc(Cl)cc3Cl)c2)S(=O)(=O)N1
Temperature: 35 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
To a solution of 5-(3-amino-phenyl)-1,1-dioxo-[1,2,5]thiadiazolidin-3-one (5 g, 22 mmol) in 37.5 mL of 9:1 v/v acetonitrile-water was added NaHCO3 (4.62 g, 55 mmol). The mixture was stirred at 25° C. while 2-bromo-1-(2,4-dichloro-phenyl)-ethanone (7.1 g, 26.4 mmol) was added. The mixture was stirred for 12-16 hours at 35° C. The mixture was cooled on an ice bath to further precipitate the product, which was then collected by filtration. The filtrate was concentrated under reduced pressure and a second crop of crude product was collected. The combined crude product washed once with 25 mL water and dried, then washed once with 10 mL methyl tert-butyl ether and dried, to provide 6.36 g (70% yield) of 5-{3-[2-(2,4-dichloro-phenyl)-2-oxo-ethylamino]-phenyl}-1,1-dioxo-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: S(C1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=O)=O.CC([O-])(C)C.[K+].O.[CH3:19][CH2:20][O:21][C:22]([CH3:24])=O>C1COCC1>[CH:10]([C:8]1[C:9]2[CH2:19][CH2:20][O:21][C:22]=2[CH:24]=[CH:6][CH:7]=1)=[CH2:11]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cccc2c1CCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
The Part C tosylate (100 g, 314 mmol) was dissolved in THF (1200 mL) in a 2000 mL three-neck round bottomed flask equipped with a mechanical stirrer, a digital thermometer, and a pressure equalizing addition funnel at room temperature. The reaction mixture was cooled to 0° C. by an ice-water bath. To this was added a solution of t-BuOK (1 M, 345.5 mL) in THF dropwise at 0° C. over a period of 110 min. The reaction mixture was warmed to ambient temperature and stirred for additional 2 hr. Water (350 mL) and EtOAc (600 mL) were added and the two layers were separated. The aqueous layer was further extracted with EtOAc (2×150 mL). The combined EtOAc layers were washed with brine (2×150 mL) dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give 46 g of the title styrene in 100% yield.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=1[CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>C(O)C.C1(C)C=CC=CC=1>[CH2:29]([O:28][P:24]([CH2:23][C:22]1[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=1[CH2:20][CH2:19][CH2:18][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O:25][CH2:26][CH3:27])=[O:31])[CH3:30]
Reactant: CCOP(=O)(Cc1ccccc1CCCBr)OCC
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(CCCc1ccccc1CP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 42 %

Procedure:
To 0.48 g (21 mmol) of sodium in 50 mL of dry ethanol was added 4.56 g (21 mmol) of solid diethyl acetamidomalonate portionwise. This solution was stirred at reflux under nitrogen for 2 h. After cooling to room temperature the solvent was removed under reduced pressure yielding a tan solid. This solid was dried under vacuum about 2 h. The sodium salt of diethyl acetamidomalonate was then suspended in 50 mL of dry toluene and 9.0 g (21 mmol) of diethyl 2-(3-bromopropyl)benzylphosphonate in 25 mL of dry toluene was added dropwise. This solution was stirred at reflux under nitrogen for 20 h. After cooling to room temperature the solid which precipitated was removed by filtration and washed with toluene. The combined toluene solutions were concentrated under reduced pressure to yield a dark oil. This oil was chromatographed on a column of silica gel with ethyl acetate as eluant. The combined fractions were concentrated under reduced pressure yielding 4.2 g (42%) of the product as a yellow viscous oil which solidified upon standing, mp 76°-79° C. IR(neat) 1745.9, 1680 cm-1 (C=O). 1H NMR(CDCl3) δ 1.0-1.4 (m, 12H); 2.0 (s, 3H); 2.2-3.3 (m, 6H); 3.7-4.4 (m, 8H); 6.8 (5, 1H); 7.0-7.3 (m, 4H). Anal. Calcd. for C23H36NO8P: C, 56.90; H, 7.48; N, 2.89. Found: C, 56.27; H, 7.51; N, 2.86.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(NC(=O)C(C)(C)C)cn3)cc2)CC1
Reaction time: 15 h

Procedure:
To a mixture of {4-[4-(5-amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (100 mg, 0.3 mmol) in methylene chloride (10 ml) was added triethylamine (43 ul, 0.3 mmol) and trimethylacetyl chloride (40 ul, 0.3 mmol). After 15 hours at room temperature, the reaction was diluted with hexanes to afford a precipitate which was collected by filtration: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (dd, J=12.69, 1.71 Hz, 2H) 1.26 (s, 10H) 1.42-1.56 (m, 1H) 1.50 (d, J=9.85 Hz, 1H) 1.82 (d, J=11.37 Hz, 5H) 2.26 (d, J=6.69 Hz, 2H) 3.61 (s, 3H) 7.32 (d, J=8.34 Hz, 2H) 7.87 (d, J=8.72 Hz, 1H) 7.95 (d, J=8.34 Hz, 2H) 8.15 (dd, J=8.72, 2.53 Hz, 1H) 8.88 (d, J=2.53 Hz, 1H) 9.53 (s, 1H); (M+H)+409.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].Cl.[NH2:13][C:14]1[O:15][C:16]2[CH:22]=[C:21]([CH2:23]Cl)[CH:20]=[CH:19][C:17]=2[N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([NH:4][C:5]1[C:10]([O:11][CH2:23][C:21]2[CH:20]=[CH:19][C:17]3[N:18]=[C:14]([NH2:13])[O:15][C:16]=3[CH:22]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: Nc1nc2ccc(CCl)cc2o1
Reactant: CC(=O)Nc1ncccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncccc1OCc1ccc2nc(N)oc2c1
Temperature: 40 °C
Reaction time: 4.3 h
Yield: 40.6 %

Procedure:
A mixture of 2-acetamido-3-hydroxypyridine (1.3 g), 2-amino-6-chloromethylbenzoxazolehydrochloride (1.5 g) and potassium carbonate (2.8 g) in N,N-dimethylformamide (20 ml) was stirred for 4.3 hours at 40° C. The reaction mixture was added to water and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was crystallized from ethyl acetate to give 6-(2-acetamido-pyridin-3-yloxymethyl}-2-aminobenzoxazole (0.83 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>ClCCl.C(N(CC)CC)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCNCC1
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a stirred solution of piperazine (10.8 g) in dry dichloromethane (160 ml) and triethylamine (20 ml) at 0° C. was added slowly a solution of 4-bromobenzenesulphonyl chloride (16 g) in dichloromethane (80 ml) and stirred for 24 hours. The reaction was then quenched by removal of the dichloromethane solvent by evaporation, taken up in water and extracted with ethyl acetate. The organic extracts were washed with aqueous sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and then evaporated to give a white crystalline solid which was recrystallised from ethyl acetate/isohexane to afford 1-(4-bromophenylsulphonyl)piperazine (14.1 g) as a solid, m.p. 102-104° C.; microanalysis found: C, 39.5; H, 4.4; N, 9.1%: C10H13BrN2O2S requires: C, 39.4; H, 4.3; N, 9.2%; NMR (CDCl3): 1.52(s,1H), 2.97(dt,8H), 7.61(d,2H), 7.69(d,2H): MS m/z 305 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.[C:18]([C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[CH2:25]Br)([CH3:21])([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:25][C:24]1[CH:23]=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=1)[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Product: CC(C)C1=CCC(C)(C)c2cc(OCc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c(Br)cc21
Yield: 72 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.14 g, 0.48 mmol) was reacted with 3,5-di-t-butylbenzylbromide to afford 0.074 g (72%) of the title compound as a yellow solid. PNMR (300 MHz, CDCl3) δ 1.20 (m, 12H), 1.37 (s, 18H), 2.15 (d, 2H, J=4.8 Hz), 2.85 (m, 1H), 5.20 (s, 2H), 5.72 (m, 3H), 6.95 (s, 1H), 7.40 (m, 3H), 7.55 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](I)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:20](B(O)O)=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)(O)[O-].[Na+]>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>[CH2:1]([N:8]1[CH:12]=[C:11]([C:20]2[C:15]([Cl:14])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cnn(Cc2ccccc2)c1
Reactant: OB(O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ncccc1-c1cnn(Cc2ccccc2)c1
Temperature: 85 °C

Procedure:
1-Benzyl-4-iodo-1H-pyrazole (1.35 g, 4.77 mmol), 2-chloropyridin-3-ylboronic acid (1.50 g, 9.53 mmol), sodium bicarbonate (1.20 g, 14.3 mmol) and Pd(PPh3)4 (276 mg, 0.239 mmol) were combined in an argon-purged sealed tube. Dimethoxyethane (8 mL) and water (5 mL) were added and the mixture was heated to 85° C. for 16 hours. The reaction was cooled to rt, diluted with water and extracted into EtOAc. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. This residue was purified by silica gel chromatography (50-75% EtOAc/hexanes) to yield 3-(1-benzyl-1H-pyrazol-4-yl)-2-chloropyridine as a light yellow oil after concentration. MS m/z=270 [M+1]+. Calc'd for C15H12FN3: 269.74.
Reaction SMILES: O=[C:2]([CH2:8]CC)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[CH3:7][C:6]1([CH:11]=[CH2:12])[O:5][C:3](=[O:4])[CH2:2][CH2:8]1
Reactant: C=C[Mg]Br
Reactant: CCCC(=O)C(=O)OCC
Solvent: C1CCOC1
Product: C=CC1(C)CCC(=O)O1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of ethyl 2-ketopentanoate (10 mL, 71 mmol) in 100 mL of THF at −78° C. was added dropwise a solution of 1.0 M vinyl magnesium bromide (80 mL, 80 mmol). After completion of the addition, the mixture was stirred for two more hours, the cooling bath was removed and the mixture was gradually warmed to ambient temperature. After the removal of the most of the solvent, the residue was poured to 2N HCl aqueous solution, extracted with ethyl acetate and dried over MgSO4 Purification by lash column chromatography on silica gel with DCM as elute afforded 4.80 grams of 5-methyl-5-vinyl-dihydro-furan-2-one. 1H-NMR (300 MHz, CDCl3) δ (ppm): 5.824-5.917 (dd, 1H); 5.29 (d, 1H); 5.13 (d, 1H); 2.50-2.56 m, (2H); 2.07-2.18 (m, 2H); 1.48 (s, 3H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][OH:35].C(N)C>O1CCCC1.CN(C)C=O>[OH:35][NH:34][C:18]([CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:12]=1)=[O:20]
Reactant: O=C(O)CCc1ccc(NC(=O)c2ccccc2)cc1
Reactant: NO
Agent: CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(CCc1ccc(NC(=O)c2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
(Method H7) To a solution of 3-(4-benzoylamino-phenyl)-propionic acid (6b) (1.04 g, 3.86 mmol) in tetrahydrofuran (30 ml) under argon atmosphere 1,1′-carbonyldiimidazole (0.814 g, 5.0 mmol) was added and the mixture was stirred at room temperature for 1 hour. In an another vessel, a solution of hydroxylamine hydrochloride (0.805 g, 11.6 mmol) in dimethylformamide (10 ml) was treated with ethyl amine (1.62 ml, 11.6 mmol), the precipitate was filtered off and both solutions were mixed together. The resultant mixture was stirred at ambient temperature for 24 hours, concentrated under reduced pressure and diluted with 3% hydrochloric acid (15 ml). The resulting precipitate was filtered, washed with water (3×20 ml), and crystallized from acetonitrile to give the title compound as a white solid (0.790 g, 72%). M.p. 189-191° C. 1H NMR (DMSO-d6, HMDSO) δ: 2.26 (t, 2H, J=7.5 Hz); 2.79 (t, 2H, J=7.5 Hz); 7.17 (d, 2H, J=8.4 Hz); 7.45-7.60 (m, 3H); 7.67 (d, 2H, J=8.4 Hz); 7.88-8.02 (m, 2H); 8.73 (s, 1H); 10.18 (s, 1H); 10.38 ppm (s, 1H). HPLC analysis on Symmetry C18 column: impurities 1.8% (column size 3.9×150 mm; mobile phase acetonitrile −0.1M phosphate buffer (pH 2.5), 28:72; sample concentration 0.25 mg/ml; detector UV 220 nm). Anal. Calcd for C16H16N2O3, %: C, 67.59; H, 5.67; N, 9.85. Found, %: C, 67.46; H, 5.61; N, 9.87.
Reaction SMILES: [OH:1][CH:2]([CH2:30][OH:31])[CH2:3][O:4][C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:8][CH:7]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(Cl)(Cl)Cl>O>[C:32]([N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:9]1[CH:10]=[CH:11][C:6]([C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:30][OH:31])=[O:29])=[CH:7][CH:8]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 3.26 g. of 2,3-dihydroxypropyl-4-(n-hexadecylamino)benzoate and 0.85 ml. of acetic anhydride in 50 ml. of chloroform is heated to reflux for 1 hour and then cooled. The mixture is washed with 90 ml. of water and solid at the interface filtered. The chloroform layer on concentration in vacuo gives a residue which on trituration with methylene chloride yields a white solid (starting material) after filtration. The filtrate on concentration in vacuo yields a pale yellow oil. The oil is stirred overnight with water, extracted with chloroform and azeotroped free of acetic acid with benzene. The pale yellow oil obtained by evaporation in high vacuum is then chromatographed to remove a trace of N,O-diacetylated material. The liquid product is characterized by elemental analyses, infrared spectrum and nuclear magnetic resonance.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C)C=O>[Si:21]([O:20][CH2:19][CH2:18][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.5 %

Procedure:
5.00 g (24.8 mmol) of tert-butyl 4-hydroxy-1-piperidine carboxylate was dissolved in 100 mL of dimethylformamide and 1.08 g (24.8 mmol) of sodium hydride (55% or more, oily) was added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 4 hours. Thereafter, 20 mL of a solution of 6.54 g (27.3 mmol) of (2-bromoethoxy)-tert-butyldimethylsilane in dimethylformamide was added dropwise to the reaction mixture under ice-cooling and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate, followed by washing successively with water and a saturated NaCl solution and drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography (eluting solvent: hexane/ethyl acetate=100/0-90/10) to obtain 1.65 g (yield: 18%) of the title compound as a colourless oil.
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[NH3:18]>C(Cl)Cl.C(OCC)(=O)C>[NH2:18][S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3]
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Reactant: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](CS(N)(=O)=O)C(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 1.22 g of benzyl 3-chlorosulfonyl-2(R)-methylpropionate in 15 mL CH2Cl2 and cooled to −78° C. To this solution was added to 10 mL of liquid ammonia at −78° C. After 20 minutes the reaction was warmed to room temperature, concentrated in vacuo to afford a white solid. The solid was slurried in ethyl acetate, filtered to remove inorganic salts and concentrated in vacuo to afford 1.08 g of benzyl 3-aminosulfonyl-2(R)-methylpropionate as a clear yellow oil. The crude product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([NH:11][C:12](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=1[O:26][CH2:27][C@H:28]([NH:41][C:42](=[O:56])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]2[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH:44]=1)[CH2:29][CH2:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[CH3:9].Cl.Cl[C:59]([NH2:61])=[NH:60].CS(C)(=O)=O>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([NH:11][C:12](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=1[O:26][CH2:27][C@H:28]([NH:41][C:42](=[O:56])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]2[CH:54]=[CH:53][C:52]([NH:55][C:59]([NH2:61])=[NH:60])=[CH:51][CH:50]=2)[CH:44]=1)[CH2:29][CH2:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[CH3:9]
Reactant: N=C(N)Cl
Reactant: COC(=O)C(=Cc1ccc(C#N)cc1OC[C@@H](CCC(=O)OCc1ccccc1)NC(=O)c1cccc(-c2ccc(N)cc2)c1)NC(C)=O
Agent: CS(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(=Cc1ccc(C#N)cc1OC[C@@H](CCC(=O)OCc1ccccc1)NC(=O)c1cccc(-c2ccc(NC(=N)N)cc2)c1)NC(C)=O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 340 mg (0.52 mmol) of methyl 2-acetamido-3-[2-[(2R)-2-[[3-(4-aminophenyl)benzoyl]amino]-4-benzyloxycarbonylbutoxy]-4-cyanophenyl]acrylate trifluoroacetate, 430 mg (3.74 mmol) of chloroformamidine hydrochloride and 2.0 g of dimethyl sulfone was stirred at 120° C. for 2 hours. Water was added to the reaction mixture. After washing with ethyl acetate, the aqueous layer was freeze-dried and purified by the reversed phase HPLC in the same manner as that in step 5 in Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([C:19]([OH:58])([CH:38]([OH:57])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:59][N:60]([CH3:68])[CH2:61][CH2:62][CH2:63][CH2:64][C:65](O)=[O:66].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:59][N:60]([CH3:68])[CH2:61][CH2:62][CH2:63][CH2:64][C:65]([O:57][CH:38]([C:19]([OH:58])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:66]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)C(O)(CCCCCCCC/C=C\C/C=C\CCCCC)CCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN(C)CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(OC(=O)CCCCN(C)C)C(O)(CCCCCCCC/C=C\C/C=C\CCCCC)CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution of (6Z,9Z,29Z,32Z)-19-((9Z,12Z)-octadeca-9,12-dienyl)octatriaconta-6,9,29,32-tetraene-19,20-diol (0.75 g, 0.98 mmol), 5-(dimethylamino)pentanoic acid (285 mg, 2.0 mmol), EDC hydrochloride (378 mg, 2.0 mmol), and 4-(N,N-dimethylamino)pyridine (5 mg) in anhydrous dichloromethane (10 mL) was added DIPEA (0.68 mL, 3.9 mmol). The reaction was stirred for 16 hours at room temperature under nitrogen. TLC (1:1 hexanes/ethyl acetate) indicated that the reaction had stalled, so additional 5-(dimethylamino)pentanoic acid (70 mg, 0.5 mmol) and fresh EDC hydrochloride (300 mg, 1.6 mmol) were added. The reaction was stirred for an additional 24 hours under nitrogen at room temperature. The solution was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate (50 mL), water (50 mL), and brine (50 mL). The combined aqueous layers were back extracted once with dichloromethane (50 mL). The combined dichloromethane extracts were dried on magnesium sulfate, filtered, and concentrated in vacuo to dryness. The resulting orange oil was purified by column chromatography on silica gel 60 (eluted with a gradient of 25%→50% ethyl acetate in hexanes) to afford (6Z,9Z,29Z,32Z)-20-hydroxy-20-((9Z,12Z)-octadeca-9,12-dienyl)octatriaconta-6,9,29,32-tetraen-19-yl 5-(dimethylamino)pentanoate as a pale yellow oil (560 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 5.43-5.29 (m, 12H), 4.95 (dd, 1H, J=10.1, 2.7 Hz), 2.78 (t, 6H, J=6.5 Hz), 2.38 (t, 2H, J=7.5 Hz), 2.28 (t, 2H, J=7.5 Hz), 2.22 (s, 6H), 2.09-2.02 (m, 12H), 1.72-1.42 (m, 13H), 1.41-1.19 (m, 56H), 0.90 (t, 9H, J=6.7 Hz).