Name: 196618-13-0|(3R,4R,5S)-Ethyl 4-acetamido-5-amino-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate|97%
Brand: Ambeed
SKU: A348556
Rating: 93 (35 reviews)

1
[ 24424-99-5 ]
[ 196618-13-0 ]
[ 367252-68-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With 1-methyl-1H-imidazole In toluene at 20℃; for 1h; Inert atmosphere;
90%	With triethylamine In methanol at 20℃; for 4h; Inert atmosphere;	3 EXAMPLE 3 - OSELTAMIVIR DERIVATIVES; Oseltamivir Boc-Amide; To a room temperature stirring solution of oseltamivir (1.5 g, 4,81 mrnoi) in anhydrous methanol (50 mL) under inert atmosphere was added di-terf-butyl dicarbonate (1.15 g, 1.1 eq.) and triethylamine (2 mL). After four hours, the crude mixture was concentrated under reduced pressure and subjected to flash coiumn chromatography (30 % methanol/ dichloromethane) to afford the product as a white solid (1.6 g, 90 %).1H NMR1 400MHz (CDCI3) δ 6.80 (1 H, s), 5.72 (1 H, dr J = 9.2), 5.07 (1H, d, J - 9.1), 4.21 (2H, dq, J = 6.7, 1.7), 4.08 (1 Hf q, J = 9.1), 3.95 (1 H, m), 3.80 (1 H1 m), 3.35 (1H, m), 2.74 (1H, dd: J = 17.8, 5.1), 2.29 (1 Hr m), 1.99 (3H1 s), 1.51 (4H, m), 1.42 (9H1 s), 1.29 (3H, t, J = 7.2) and 0.89 (6H, d, J = 7.4).
86%	With triethylamine In methanol at 20℃; for 18h;	21 Tamiflu (3.12 g, 10 mmol) was taken up in 50 mL of CH3OH and triethylamine (3.03 g, 30 mmol) was added slowly at 0° C. Di(tert-butyl) carbonate (2.40 g, 11 mmol) was then added. The resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with CH2Cl2 (50 mL) and washed with saturated aq. NH4Cl (3×50 mL) and brine (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 3.56 g of (3R,4R,5S)-ethyl 4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (86%). A solution of (3R,4R,5S)-ethyl 4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (3.56 g, 8.64 mmol) in 50 mL of THF was treated with 25 mL of aq. NaOH (5N). The resulting reaction mixture was stirred at room temperature for 2 h. Then the solution was acidified to pH=2 with 6 N HCl. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 3.17 g of (3R,4R,5S)-4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic acid (95%).

80%	With triethylamine In dichloromethane at 20℃; for 6h;	Synthesis of (3R, 4R, 5S)-4-acetamido-5-(tert-butoxycarbonyl)amino-3-(1-ethyl-propoxy)-1-cyclohexene-1-carboxylic acid ethyl ester (1) To a solution of oseltamivir (0.718 g, 2.297 mmol) in CH2Cl2 (50 mL) was added (Boc)2O (0.792 mL) and TEA (637 μL) at room temperature and the mixture was stirred for 6h. Subsequently, the reaction mixture was evaporated under vacuum to afford compound 1 (0.734 g, 80% yield) as Yellow oil.
78%	With triethylamine In methanol; water at 20℃;	12.1 To a solution of (3R,4R,5S)-ethyl 4-acetamido-5-amino-3 -(pentan-3 - yloxy)cyclohex-1-enecarboxylate (9-1) (Oseltamivir phosphate, 2.5 g, 6.09 mmol) in water (20 mL) and methanol (20 mL) was added triethylamine (2.46 mL, 17.67 mmol) at room temperature followed by di-tert-butyl carbonate(Boc anhydride, 2.87 g, 16.45 mmol). The reaction mixture was stirred at room temperature overnight. The solid product obtained was collected by filtration, washed with water, dried under vacuum to furnish (3R,4R,5S)- ethyl 4-acetamido-5 -((tert-butoxycarbonyl)amino)-3 -(pentan-3 -yloxy)cyclohex- 1 - enecarboxylate (9-2) (1.95 g, 4.73 mmol, 78 % yield) as a white solid; 1HNMR (300 MHz, DMSO-+) 413.22 (M+l, 435.20 (M+Na), 847.44 (2M+Na); (ES-) 410.64 (M-l), 446.71(M+C1); Elemental analysis calculated for C21H36N2O6: C, 61.14; H, 8.80; N, 6.79. Found: C, 61.11; H, 8.90; N, 6.75.
	With triethylamine In tetrahydrofuran at 0 - 20℃; for 0.666667h;
1 g	With sodium hydrogencarbonate In tetrahydrofuran; water at 25℃; for 2h;	2 4.4.2 Ethyl 4-acetamido-5-(tert-butoxycarbonyl)amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (5) To a mixture of oseltamivir (0.75g, 2.4mmol) and NaHCO3 (0.77g, 9.14mmol) in THF/ H2O (10 mL/10mL) was added (Boc)2O (0.52g, 2.38mmol). The mixture was stirred for 2h at room temperature, and concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The aqueous phase was extracted with CH2Cl2 (3×). The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give compound 5 (1.0g, 2.4mmol). C21H36N2O6; colorless solid, mp 142-144°C; TLC (EtOAc/hexane, 1:3) Rf=0.16; 1H NMR (400MHz, CDCl3) δ 6.77 (1H, s), 5.82 (1H, d, J=8.8Hz), 5.10 (1H, d, J=9.2Hz), 4.23-4.15 (2H, m), 4.08-4.01 (1H, m), 4.06-3.95 (1H, m), 3.82-3.73 (1H, m), 3.36-3.31 (1H, m), 2.96 (1H, dd, J=1.8, 4.8Hz), 2.31-2.24 (1H, m), 1.97 (3H, s), 1.57-1.45 (4H, m), 1.41 (9H, s), 1.28 (3H, t, J=7.2Hz), 0.91-0.85 (6H, m); 13C NMR (100MHz, CDCl3) δ 170.1, 165.2, 155.7, 137.2, 128.8, 82.1, 79.5, 75.8, 61.0, 54.6, 49.3, 31.2, 28.6 (3×), 26.5, 26.0, 23.7, 14.6, 10.0, 9.7; HRMS calcd for C21H37N2O6: 413.2652, found: m/z 413.2658 [M+H]+.
0.49 g	With triethylamine In dichloromethane at 20℃; for 4h; Inert atmosphere;	7 4.1.7 Ethyl (3R,4R,5S)-4-acetamido-5-[(tert-butoxycarbonyl)-amino]-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (7) To a solution of oseltamivir free base 3 (0.38 g, 1.21 mmol) in DCM (3 mL) was added triethylamine (0.61 g, 6.08 mmol) followed by addition of di-tert-butyl dicarbonate (0.53 g, 2.42 mmol) and then the reaction mixture was stirred for 4 h at room temperature. The mixture was diluted with water (10 mL) and then extracted with DCM (3 * 10 mL). The combined organic phase was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent DCM to DCM/MeOH, 20:1) to afford the protected amine (0.49 g, 98% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 6.78 (s, 1H), 5.80 (d, J = 8.2 Hz, 1H), 5.11 (d, J = 9.0 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.13-4.00 (m, 1H), 3.97 (s, 1H), 3.79 (dd, J = 9.7, 5.1 Hz, 1H), 3.52-3.28 (m, 1H), 2.74 (dd, J = 18.1, 4.9 Hz, 1H), 2.29 (dd, J = 17.7, 9.6 Hz, 1H), 1.98 (s, 3H), 1.51 (dd, J = 5.5, 4.1 Hz, 4H), 1.42 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H), 0.88 (dd, J = 13.6, 7.3 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 170.9, 166.1, 156.4, 137.7, 129.5, 82.3, 79.8, 76.0, 61.1, 54.5, 49.2, 31.1, 28.5, 26.3, 25.8, 23.5, 14.3, 9.6, 9.4. HR-ESI-MS calculated for C21H37O6N2 (M + H)+ 413.2646, found 413.2648.
	With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 5h; Inert atmosphere;	4.3.8. Ethyl 4-acetamido-5-(2-(tert-butoxycarbonyl)-3-octanoyl) guanidino-3-(pentyl-3-oxy)cyclohex-1-ene-1-carboxylate (16a) To a suspension of Tamiflu capsule (985 mg, 2.40 mmol) and NaHCO3 (1007 mg, 11.99 mmol) in THF/H2O (10 mL/10 mL) was added (Boc)2O (720 mL, 3.13 mmol). The mixture was stirred at room temperature for 5 h. The organic layer was collected, and the aqueous layer was washed with EtOAc. All organic phase was combined, dried over MgSO4, filtered, and purified by silica gel chromatography (EtOAc/hexane 3:7 to 4:6) to afford the Bocprotecting oseltamivir 15 (907 mg, 92%) [31]. To a solution of compound 15 (128 mg, 0.31 mmol) in CH2Cl2 (2 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1 h, and then concentrated under reduced pressure to give the corresponding amine. The amine product was dissolved in CH2Cl2 (4 mL), and compound 12a (98 mg, 0.31 mmol), HgCl2 (92 mg, 0.34 mmol), and Et3N (216 mL, 1.55 mmol) were added. The mixture was stirred at room temperature under argon for 6 h, filtered through Celite, and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with 1 M HCl(aq), saturated NaHCO3(aq), and brine. The organic phase was dried over MgSO4, filtered, and purified by silica gel chromatography (EtOAc/hexane 2:3 to 1:1) to afford the coupling product 16a (141 mg, 77%). C30H52N4O7; white foam; TLC (EtOAc/hexane 1:1) Rf 0.48; [a]D 24 65.1 (c 1.0, CH2Cl2); IR ymax (neat) 3280, 2929, 1722, 1614 cm1 ; 1 H NMR (CDCl3, 400 MHz, two tautomers (4:1)) d 12.18 (0.8H, s), 12.12 (0.2H, s), 9.19 (0.8H, d, J 8.4 Hz), 8.65 (0.2H, d, J 7.6 Hz), 6.75 (0.2H, s), 6.71 (0.8H, s), 6.42e6.31 (1H, m), 4.39e4.25 (1H, m), 4.14e3.89 (4H, m), 3.27 (1H, quin, J 5.6 Hz), 2.71 (1H, dd, J 17.6, 5.2 Hz), 2.32e2.19 (3H, m), 1.82 (0.6H, s), 1.80 (2.4H, s), 1.61e1.48 (2H, m), 1.48e1.31 (13H, m), 1.27e1.10 (11H, m), 0.84e0.69 (9H, m); 13C NMR (CDCl3, 100 MHz, two tautomers (4:1)) d 187.6, 174.3, 170.2, 170.1, 165.8, 165.7, 163.2, 156.4, 155.9, 152.5, 137.6, 137.1, 128.8, 128.5, 82.9, 82.6, 82.2, 79.4, 75.3, 75.2, 60.69, 60.66, 53.6, 53.0, 47.9, 41.2, 37.6, 31.5, 31.3, 30.0, 29.5, 29.1, 29.0, 28.62, 28.59, 28.0, 27.9, 27.7, 25.88, 25.85, 25.5, 24.3, 23.0, 22.9, 22.4, 22.3, 13.9, 13.82, 13.77, 9.4, 9.3, 9.14, 9.08; HRMS (ESI) calcd for C30H53N4O7: 581.3914, found: m/z 581.3912 [M H].
0.734 g	With triethylamine In dichloromethane at 20℃; for 2h;	1 Synthesis of (3R,4R,5S)-4-acetylamino-5-(tert-butoxycarbonylamino)-3-(1-ethylpropoxy)-1-cyclohexene-1-ethyl ester (II) Add in a 100mL round bottom flask0.718 g (2.297 mmol) of oseltamivir,0.792 mL (3.447 mmol) (Boc)2O,637 μL (4.595 mmol) of triethylamine,The mixture was stirred at room temperature for 2 h with 50 mL of dichloromethane.Evaporate the solvent under reduced pressure to give 0.734 g (1.844 mmol)(3R,4R,5S)-4-Acetylamino-5-(tert-butoxycarbonylaminoamino)-3-(1-ethylpropoxy)-1-cyclohexene-1-ethyl ester (II) Crude.The resulting crude product was used directly in the next step without treatment.

Reference： [1]Saito, Kenta; Kanai, Motomu [Heterocycles, 2012, vol. 86, # 2, p. 1565 - 1574]
[2]Current Patent Assignee: REDX PHARMA GB - WO2010/131054, 2010, A1 Location in patent: Page/Page column 52
[3]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - US2016/129122, 2016, A1 Location in patent: Paragraph 0733; 0734
[4]Wang, Boyu; Wang, Kuanglei; Meng, Peipei; Hu, Yaping; Yang, Fei; Liu, Kemin; Lei, Zaiqiang; Chen, Binfeng; Tian, Yongshou [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 21, p. 3477 - 3482]
[5]Current Patent Assignee: BIOCRYST PHARMACEUTICALS INC - WO2014/186465, 2014, A1 Location in patent: Paragraph 00339; 00340; 00341
[6]Kim, Choung U.; Lew, Willard; Williams, Matthew A.; Wu, Huiwei; Zhang, Lijun; Chen, Xiaowu; Escarpe, Paul A.; Mendel, Dirk B.; Laver, W. Graeme; Stevens, Raymond C. [Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2451 - 2460]
[7]Chen, Chun-Lin; Lin, Tzu-Chen; Wang, Shi-Yun; Shie, Jiun-Jie; Tsai, Keng-Chang; Cheng, Yih-Shyun E.; Jan, Jia-Tsrong; Lin, Chun-Jung; Fang, Jim-Min; Wong, Chi-Huey [European Journal of Medicinal Chemistry, 2014, vol. 81, p. 106 - 118]
[8]Albinaña, Carlos Berenguer; MacHara, Aleš; Rezacov, Pavlína; Pachl, Petr; Konvalinka, Jan; Kozísek, Milan [European Journal of Medicinal Chemistry, 2016, vol. 121, p. 100 - 109]
[9]Hsu, Peng-Hao; Chiu, Din-Chi; Wu, Kuan-Lin; Lee, Pei-Shan; Jan, Jia-Tsrong; Cheng, Yih-Shyun E.; Tsai, Keng-Chang; Cheng, Ting-Jen; Fang, Jim-Min [European Journal of Medicinal Chemistry, 2018, vol. 154, p. 314 - 323]
[10]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN108101804, 2018, A Location in patent: Paragraph 0036-0038

2
[ 196618-13-0 ]
oseltamivir carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydroxide In ethanol at 90℃; for 2h;
88%	Stage #1: (3R,4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester With potassium hydroxide; water monomer In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: With Amberlite IR-120 In tetrahydrofuran	14 A solution of azide 11a (110 mg, 0.3 mmol) in ethanol (15 mL) was treated with Lindlar's catalyst (70 mg) under an atmosphere of hydrogen for 16 h at room temperature. The reaction mixture was filtered through Celite, and rinsed with ethanol. The filtrate was evaporated under reduced pressure to give colorless foam (95 mg), which was dissolved in THF (10 mL) and treated with aqueous KOH solution (1 M, 0.5 mL, 0.5 mmol) at o° C. The reaction mixture was warmed to room temperature and stirred for 1 h. After which, the mixture was acidified to pH 5 with Amberlite IR-120, filtered and rinsed with aqueous ethanol (95%). The filtrate was concentrated under reduced pressure. The residue was purified on a C18 column (CH3CN/H2O, 1:19) to afford 2 (75 mg, 88% yield). White solid, mp 185-1870C; [α]D20 =-143.2 (c = 0.4, H2O); IR (neat) 3525, 2991, 1751, 1611, 1050 cm-i; 1H NMR (600 MHz, D2O) δ 6.50 (1 H, s), 4.28 (1 H, d, J = 8.4 Hz), 4.05 (1 H, dd, J = 9.6, 4.8 Hz), 3-57-3-52 (2 H, m), 2.89 (1 H, dd, J = 17.4, 5.4 Hz), 2.48 (1 H, dd, J = 17.4, 10.8 Hz), 2.09 (3 H, s), 1.61-1.52 (3 H, m), 1.50-1.43 (1 H, m), 0.90 (3 H, t, J = 7-5 Hz), 0.87 (3 H, t, J = 7.5 Hz); «C NMR (150 MHz, D2O) δ 175.1, 173.8, 133.0, 132.4, 84.2, 75.6, 52.9, 49.7, 29.5, 25.4, 25.1, 22.3, 8.54, 8.45; HRMS calcd for Ci4H24N2NaO4 (M+ + Na): 307.1634, found: m/z 307.1633. Anal. Calcd for Ci4H24N2O4: C, 59.13; H, 8.51; N, 9.85. Found: C, 59.04; H, 8.58;N, 9.79.
79%	Stage #1: (3R,4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester With potassium hydroxide In methanol; water monomer Stage #2: In methanol; water monomer for 0.0833333h;

16%	With sodium hydroxide In tetrahydrofuran; water monomer at 0 - 65℃; for 1h;
	With potassium hydroxide In tetrahydrofuran for 0.666667h; Ambient temperature; Yield given;
75 mg	With potassium hydroxide In tetrahydrofuran at 0 - 20℃;
	Stage #1: (3R,4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester With water monomer; lithium hydroxide monohydrate In tetrahydrofuran at 25℃; for 3h; Stage #2: In tetrahydrofuran; water monomer
	With potassium dihydrogen orthophosphate; anhydrous trisodium citrate; 2-amino-2-(hydroxymethyl)propane-1,3-diol; magnesium(II) chloride at 37℃; for 1h;

Reference： [1]Konno, Fujiko; Arai, Takuya; Zhang, Ming-Rong; Hatori, Akiko; Yanamoto, Kazuhiko; Ogawa, Masanao; Ito, Gukuto; Odawara, Chika; Yamasaki, Tomoteru; Kato, Koichi; Suzuki, Kazutoshi [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1260 - 1263]
[2]Current Patent Assignee: ACADEMIA SINICA - WO2009/29888, 2009, A2 Location in patent: Page/Page column 57
[3]Mooney, Caitlin A.; Johnson, Stuart A.; 'T Hart, Peter; Quarles Van Ufford, Linda; De Haan, Cornelis A. M.; Moret, Ed E.; Martin, Nathaniel I. [Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 3154 - 3160]
[4]Hajzer, Viktória; Fišera, Roman; Latika, Attila; Durmis, Július; Kollár, Jakub; Frecer, Vladimír; Tučeková, Zuzana; Miertuš, Stanislav; Kostolanský, František; Varečková, Eva; Šebesta, Radovan [Organic and Biomolecular Chemistry, 2017, vol. 15, # 8, p. 1828 - 1841]
[5]Kim, Choung U.; Lew, Willard; Williams, Matthew A.; Wu, Huiwei; Zhang, Lijun; Chen, Xiaowu; Escarpe, Paul A.; Mendel, Dirk B.; Laver, W. Graeme; Stevens, Raymond C. [Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2451 - 2460]
[6]Shie, Jiun-Jie; Fang, Jim-Min; Wang, Shi-Yun; Tsai, Keng-Chang; Cheng, Yih-Shyun E.; Yang, An-Suei; Hsiao, Shih-Chia; Su, Ching-Yao; Wong, Chi-Huey [Journal of the American Chemical Society, 2007, vol. 129, # 39, p. 11892 - 11893]
[7]Ma, Jimei; Zhao, Yanying; Ng, Simon; Zhang, Jing; Zeng, Jing; Than, Aung; Chen, Peng; Liu, Xue-Wei [Chemistry - A European Journal, 2010, vol. 16, # 15, p. 4533 - 4540]
[8]Johnson, Joshua L.; Huang, Jiansheng; Rooney, Michael; Gu, Chungang [Xenobiotica, 2022, vol. 52, # 2, p. 105 - 112]

3
[ 204255-06-1 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	With hydrogen at 20℃; for 3h;	3 Example 3 In a 100 ml reaction flask by adding (3R, 4R, 5S) - 4-acetamido-5-azido-3 - (1-ethyl-propoxy) - 1-cyclohexene-1-carboxylic acid ethyl ester 150 mg, 7 . 5mgLindlar catalyst, adding hydrogen, pressure is 0.5atm, reaction at room temperature to 3h. After the reaction is ended, filtering the reaction solution, the solvent in the filtrate to dryness, to obtain 136.4 mg product, yield of 98.5%. With the verification method of the embodiment 1.
97%	With tributylphosphine; acetic acid In ethanol; water at 5 - 25℃; for 5.5 - 9h;	8 Step 8-Preparation of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)cyclohex-1-enecarboxylic acid ethyl ester (32) To a solution of 50.0 g (0.147 mol ) of 30, 300 mL of EtOH, 50 mL of water and 0.09 g of acetic acid in a nitrogen-purged 1000 mL glass reactor fitted with a mechanical stirrer, a condenser, and a 250 mL dropping funnel was added a solution of 31.4 g (0.155 mol) of tributylphosphine in 150 mL EtOH at a temperature of 5 C. (+-5 C.) over a period of 30-90 min. The reaction temperature was maintained at this temperature by slight cooling of the jacket (ca. 3 C.). The funnel was rinsed with 20 mL of EtOH. The clear reaction mixture was stirred for additional 90 min at 5 C. (+-5 C.) under slight jacket cooling. Subsequently the temperature was raised within 30-60 min to 20-25 C. and the solution was stirred for another 3 h (nitrogen evolution). After the reaction was finished (HPLC assay) 0.18 g of acetic acid were added to the clear solution and the mixture was concentrated to near dryness under reduced pressure (300 to 50 mbar) at a maximum temperature of 60 C. and a maximum jacket temperature of 75 C. The oily residue (80-100 mL) was diluted with 160 mL of EtOH, the resulting solution was then again concentrated following the method described above. The oily residue was dissolved in EtOH up to a volume of 250 mL. The water content of this solution was determined by KF (Karl Fischer) titration to be less than 1.0% wt. %. Yield: 44.4 g (97% area by HPLC) of 32 in EtOH solution. IR (NJL) 3279, 1720, 1639, 1554, 1252, 1128 cm-1. MS (ion spray) MH+ 313.1, MNa+ 335.3
96%	With triphenylphosphine In tetrahydrofuran; water at 50℃; for 10h;	116 The three benzene phosphine (342 mg, 1 . 30mmol) to a time 261 of (272g, 0.80mmol) THF (17 ml)/ water (1.6 ml) solution. Then the reaction mixture to the 50 °C heating 10 hours, vacuum concentration after cooling to obtain the plain-colored solid. The crude solid by silica gel (50% methanol/ethyl acetate) to obtain rapid chromatographic purification 242 mg (96%) light-coloured solid amino ethyl ester 262. The its dissolved in 3NHCl in, freeze-drying to obtain the corresponding water-soluble HCl salt.

96%	With sodium tetrahydroborate; ethanol; cobalt(II) chloride In water at 20℃; for 0.00138889h; Sonication;	8 Reaction 8: Continuous flow synthesis of Oseltamivir 33 A 0.8 ml PTFE coil reactor (0.8 mm ID, 1 .6 m tube length) under sonication (Scheme 17) was used to optimise the azide 32 reduction to afford Oseltamivir using NaBH4 and C0CI2. A mixture of azide 32 (0.15 M) with C0CI2 (0.1 equiv.) in ethanol and NaBH4 (0.30 M, 2 equiv.) in water (pH = 8) was pumped through the continuous flow system to afford Oseltamivir 33. The samples collected were first filtered through a PTFE syringe filter (0.45 mI pore size) to remove the cobalt boride precipitates formed in the reaction, and then analysed using HPLC method A. (0196) Oseltamivir 33 was synthesised from C0CI2 catalysed NaBH4 reduction of azide 32 in a continuous flow system under sonication because the formation of a black precipitate (cobalt boride) was observed in preliminary batch-type investigations. However, it is possible that the formation of this precipitate may not be problematic when the method is performed using industrial scale equipment. (0197) A mixture of azide 32 (0.15 M) with C0CI2 (0.1 equiv.) in ethanol was treated with NaBH4 (0.3 M, 2 equiv.) in buffered water (pH = 8) in a 0.8 ml PTFE coil reactor system (0.8 mm ID, 1 .6 m tube length) under sonication to afford oseltamivir 33. The results of these experiments are shown in Figure 19. Conversion towards Oseltamivir 33 increased with increase in residence time. Conversion towards oseltamivir 33 was unexpectedly found to be 81 % and 96 % at residence times of only 1 s and 5 s respectively. The preferred conditions were found to be about room temperature and a residence time of about 5 s to afford Oseltamivir 33 (96 %). (0198) We also conducted experiments to investigate the use of ethanol and methanol for NaBFk These experiments were done at room temperature for 1 .5 s residence time in a sonicated continuous flow system. Although ethanol and methanol are known to react with NaBFk it appears that the azide reduction reaction, in the presence of a catalytic amount of C0CI2, is so fast that it overshadows the competing reactions by these solvents. Therefore, although water at ph > 7 is preferred, it is anticipated that several other solvents will also be suitable. (0199) In other experiments, as suggested in known batch methods, a phosphine based reaction was attempted in flow by treating azide 32 (0.15 M) in THF with Phi3P (0.18 M, 1 .2 equiv.) in THF/water (10:1 ) in continuous flow system at 50 °C to afford Oseltamivir 33. The conversion of azide 32 towards Oseltamivir 33 was 25 % and 78 % at 5 min and 60 min residence time respectively, which is much lower than that obtained in the preferred reaction with C0CI2 and NaBFk
90%	With water; triphenylphosphine In tetrahydrofuran at 20℃; for 3h; Heating / reflux;	PPh3 was added to a solution of azide 14B (23 mg, 0.068 mmol) in THF/water (0.25 mL, 4:1 v/v) at room temperature. The mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (CH2Cl2ZMeOH = 5:1) on silica gel to give amine 1 (19 mg, 90 %) as colorless oil. 1H NMR (CDCl3, 400 MHz): δ 6.76 (s, IH), 5.95 (d, J= 8.0 Hz, IH), 4.18 (q, J = 6.8 Hz, 3H), 3.52 (dd, J= 8.6 Hz, J= 18.4 Hz, IH), 3.34-3.29 (m, IH), 3.19 (dt, Ji)2 = 5.4 Hz, J1>3 = 10.0 Hz, IH), 2.73 (dd, Jlj2 = 5.0 Hz, J1;3 = 17.7 Hz, IH) 2.16-2.09 (m, IH), 2.02 (s, IH), 1.51-1.46 (m, 4H), 1.26 (t, J= 7.1 Hz, 3H), 0.90-0.85 (m, 6H), 13C NMR (CDCl3, 100 MHz): δ 171.0, 166.3, 137.6, 129.4, 81.6, 74.8, 60.8, 58.8, 49.1, 33.5, 26.2, 25.6, 23.6, 14.1, 9.5, 9.3; HR/MS (ESI) calculated for C16H29N2O4 [M+H+], 313.2127, found 313.2126.
90%	With water; triphenylphosphine In tetrahydrofuran for 3h; Reflux;
88%	With hydrogen In ethanol for 10h;	16 4.1.16. Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(1-ethylpropoxy) cyclohex-1-ene-1-carboxylate (13) To a solution of 12 (55 mg) in EtOH (10 mL) was treated with Lindlar catalyst (55 mg) and the resulting suspension was stirred under atmosphere of hydrogen gas for 10 h. The mixture was then filtered and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (silica gel, CH2Cl2:MeOH, 4:1) to give 13 (45 mg, 88%) as a colourless oil.
82%	Stage #1: oseltamivir With triphenylphosphine In tetrahydrofuran at 20℃; for 4h; Stage #2: With water; triethylamine In tetrahydrofuran at 20℃; for 24h;	Oseltamivir free base^{S3, S6, S9-13} Triphenyl phosphine (53 mg, 0.2 mmol) was added into the solution of 19 (34 mg, 0.1 mmol) in THF (2 mL) and stirred for 4 h at room temperature. Water (0.2 mL) and triethylamine (0.04 mL, 0.30 mmol) were added into the reaction mixture and stirred at room temperature for 24 h. The mixture was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography on siliga gel (CH2Cl2/MeOH : 17/3) to give oseltamivir free base (25.7 mg, 82 %) as a pale yellow solid.
	With water; triphenylphosphine In tetrahydrofuran at 50℃; for 10h;
	With hydrogen In ethanol at 20℃; for 16h;
	With Lindlar's catalyst; hydrogen
	With hydrogen In ethanol at 20℃; for 16h;	13; 14; 16 A solution of azide 11a (170 mg, 0.5 mmol) in ethanol (20 niL) was treated with Lindlar's catalyst (100 mg) under an atmosphere of hydrogen for 16 h at room temperature. The reaction mixture was filtered through Celite, and rinsed with ethanol. The filtrate was evaporated under reduced pressure to give colorless foam (155 mg), which was dissolved in ethanol (3 mL) and added slowly in portions to a hot (550 C) solution of phosphoric acid (85%, 115 mg, 0.6 mmol) in ethanol (5 mL). Crystallization commenced within minutes. After cooling to o° C, the precipitates were collected by filtration and rinsed with cold acetone (2 x) to afford 1 (187 mg, 91% yield). White crystal, mp 189-1910 C [lit. (Fukuta et al., J. Am. Chem. Soc. 2006,128, 6312-6313) mp 184-1860 C]; [α]D20 = -35.8 (c = 1, H2O) [lit.(Rohloff et al., . J. Org. Chem. 1998, 63, 4545-4550.) [α] = -39.9 (c = 1, H2O); or lit. (Fukuta et al., 2006) [α]D22 = -30.5 (c = 0.480, H2O)]; IR (neat) 3501, 1734, 1612, 1150 cm-i; 1H NMR (600 MHz, D2O) δ 6.91 (1 H, s), 4.39 (1 H, d, J =8.0 Hz), 4.32-4.30 (2 H, m), 4.11 (1 H, dd, J = 10.5, 5.7 Hz), 3-67"3-59 (2 H, m),3.01 (1 H, dd, J = 17.4, 5.4 Hz), 2.60-2.56 (1 H, m), 2.14 (3 H, s), 1.61-1.50 (4 H, m), 1.34 (3 H, t, J = 7.1 Hz), 0.94 (3 H, t, J = 7.3 Hz), 0.89 (3 H, t, J = 7.3 Hz); «C NMR (150 MHz, D2O) δ 178.1, 170.3, 140.7, 130.4, 87.2, 77.9, 65.2, 55.4, 52.0, 30.9, 28.3, 27.9, 25.2, 16.1, 11.36, 11.30; 3φ NMR (162 MHz, D2O) δ 0.43; HRMS calcd for CiOH29N2O4 (M+- H3PO4 + H): 313.2127, found: m/z 313.2123. Anal. Calcd for CiH3iN2θ8P: C, 46.83; H, 7.61; N, 6.83. Found: C, 46.70; H, 7.69; N, 6.74.; A solution of azide 11a (110 mg, 0.3 mmol) in ethanol (15 mL) was treated with Lindlar's catalyst (70 mg) under an atmosphere of hydrogen for 16 h at room temperature. The reaction mixture was filtered through Celite, and rinsed with ethanol. The filtrate was evaporated under reduced pressure to give colorless foam (95 mg), which was dissolved in THF (10 mL) and treated with aqueous KOH solution (1 M, 0.5 mL, 0.5 mmol) at o° C. The reaction mixture was warmed to room temperature and stirred for 1 h. After which, the mixture was acidified to pH 5 with Amberlite IR-120, filtered and rinsed with aqueous ethanol (95%). The filtrate was concentrated under reduced pressure. The residue was purified on a C18 column (CH3CN/H2O, 1:19) to afford 2 (75 mg, 88% yield). White solid, mp 185-1870C; [α]D20 =-143.2 (c = 0.4, H2O); IR (neat) 3525, 2991, 1751, 1611, 1050 cm-i; 1H NMR (600 MHz, D2O) δ 6.50 (1 H, s), 4.28 (1 H, d, J = 8.4 Hz), 4.05 (1 H, dd, J = 9.6, 4.8 Hz), 3-57-3-52 (2 H, m), 2.89 (1 H, dd, J = 17.4, 5.4 Hz), 2.48 (1 H, dd, J = 17.4, 10.8 Hz), 2.09 (3 H, s), 1.61-1.52 (3 H, m), 1.50-1.43 (1 H, m), 0.90 (3 H, t, J = 7-5 Hz), 0.87 (3 H, t, J = 7.5 Hz); «C NMR (150 MHz, D2O) δ 175.1, 173.8, 133.0, 132.4, 84.2, 75.6, 52.9, 49.7, 29.5, 25.4, 25.1, 22.3, 8.54, 8.45; HRMS calcd for Ci4H24N2NaO4 (M+ + Na): 307.1634, found: m/z 307.1633. Anal. Calcd for Ci4H24N2O4: C, 59.13; H, 8.51; N, 9.85. Found: C, 59.04; H, 8.58;N, 9.79; A solution of azide lia (150 mg, 0.41 mmol) in ethanol (20 mL) was treated with Lindlar's catalyst (80 mg) under an atmosphere of hydrogen for 16 h at room temperature. The reaction mixture was filtered through Celite, and rinsed with ethanol. The filtrate was evaporated under reduced pressure to give colorless foam (110 mg), which was dissolved in anhydrous DMF (20 mL) and treated with AT,AT-bis(ferf-butoxycarbonyl)thiourea (148 mg, 0.51 mmol) and Et3N (148 μL, 1.03 mmol). The mixture was cooled to o° C and HgCL (138 mg, 0.51 mmol) was added slowly. The suspension was warmed to room temperature and stirred for 10 h. After which, the reaction was diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated and purified by flash column chromatography (EtOAc/hexane, 3:7) to afford guanidine 12a (177 mg, 78% yield). Colorless foam; TLC (EtOAc/hexane, 1:1) Rf= 0.4; [α]D20 = -81.6 o (c = 1.0, CHCl3); IR (neat) 3302, 1724, 1635, 1612, 1120 cm-i; 1H NMR (600 MHz, CDCl3) δ 11.36 (1 H, s), 8.60 (1 H, d, J = 8.1 Hz), 6.78 (1 H, s), 6.21 (1 H, d, J = 9.0 Hz), 4.37-4.34 (1 H, m), 4.17 (2 H, q, J = 7.1 Hz), 4.14-4.08 (lH, m), 3.98 (1 H, dd, J = 4.3, 1.3 Hz), 3-32-3-30 (1 H, m), 2.74 (1 H, dd, J = 17.8, 5.3 Hz), 2.35 (1 H, dd, J = 17.8, 9.4 Hz), 1.87 (3 H, s), 1.50-1.44 (22 H, m), 1.24 (3 H, t, J = 7.1 Hz), 0.86 (3 H, t, J = 7.4 Hz), 0.83 (3 H, t, J = 7.4 Hz); ^C NMR (150 MHz, CDCl3) δ 170.2, 165.9, 163-1, 156.8, 152.5, 137.9, 128.6, 83.4, 82.6, 79.5, 76.1, 60.9, 54.3, 48.0, 30.4, 28.3 (3χ), 28.0 (3 x), 26.0, 25.7, 23.2, 14.1, 9.5, 9.3; HRMS calcd for C27H47N4Os (M+ + H): 555-3394, found: m/z 555-3398.
	With triphenylphosphine In tetrahydrofuran; water for 5h; Heating / reflux;	1.II Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (8.5 gm) was dissolved in tetrahydrofuran (130 ml) and then triphenyl phosphine (10.5 gm) and water (50 ml) are added. The contents were heated to reflux, refluxed for 5 hours and then distilled off the solvent under vacuum. To the reaction mass added ethyl acetate (80 ml), washed with 30% sodium chloride solution (50 ml) and distilled off the solvent completely under vacuum. Acetone (130 ml) was added to the residue, heated to reflux, under reflux the mixture of H3PO4 (3 gm) and ethyl acetate (50 ml) was slowly added during 1 hour and then refluxed for 1 hour. The reaction mass was cooled to 25° C. and stirred for 2 hours at 20-25° C. Filtered the solid, washed with acetone (10 ml) and dried at 60-65° C. for 4 hours to yield 6.5 gm of oseltamivir phosphate (HPLC Purity: 99.6%).
	With pyridine; hydrogen sulfide at 25 - 35℃; for 8h;	2 Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohex-ene-1-carboxylate (8.5 gm) was added to pyridine (200 ml) and then bubbled H2S gas for 3 hours at 25-35° C. Stopped the bubbling of H2S gas and then the reaction mixture was stirred for 5 hours at 25-35° C. The reaction mass was flushed with N2 gas for 20-30 minutes and distilled off the solvent completely under reduced pressure keeping the bath temperature below 50° C. To the residue added ethyl acetate (100 ml) and washed with 30% sodium chloride solution (50 ml). Distilled off the ethyl acetate completely under reduced pressure. Acetone (100 ml) was added to the residue, heated to reflux, under reflux the mixture of H3PO4 (3.2 gm) and ethanol (25 ml) was slowly added during 1 hour 30 minutes and then refluxed for 2 hours. The reaction mass was cooled to 25° C. and then stirred for 2 hours at 20-25° C. Filtered the solid, washed with acetone (10 ml) and dried at 60-65° C. for 4 hours to give 6.9 gm of oseltamivir phosphate (HPLC purity: 99.8%).
	With tributylphosphine In ethanol at 20℃; for 5h; Inert atmosphere;
	With water; triphenylphosphine In tetrahydrofuran for 8h; Reflux;	4.8. Oseltamivir phosphate 1 Compound 9 (0.90 g, 2.66 mmol) was dissolved in aqueous tetrahydrofuran (20 mL, THF/H2O = 10:1). Triphenylphosphine (0.77 g, 2.94 mmol) was added in portions at room temperature. After the mixture was heated at reflux and stirring was continued for 8 h. Solvents were removed by vacuum distillation, and the residue was cooled down to room temperature. The residue was then dissolved in a mixed solvent of ethyl acetate (3.5 mL) and ethanol (1.5 mL). After aqueous phosphoric acid (368 mg, 85% w/w, 3.19 mmol) was added, the mixture was warmed to 50 °C, and stirring was continued for 2 h at 50 °C. The reaction mixture was cooled down to room temperature and stirred for a further 8 h. White crystals were formed and precipitated. After suction and twice rinsing with ethyl acetate, the white crystals were dried under vacuum at 50 °C overnight to furnish the title compound oseltamivir phosphate 1 (997 mg, 2.43 mmol) in 91% yield. The characterization data of compound 1 were identical with those of the sample obtained in our previous articles.31,32
	Multi-step reaction with 2 steps 1.1: dichloromethane; toluene / 2 h / 20 °C 2.1: hydrogenchloride; water / dichloromethane; toluene / 4 h / 20 °C 2.2: pH 10
	With hydrogen In ethanol at 20℃;
	With hydrogen In ethanol at 20℃; for 6h;	12.3 Example 12: (-)-oseltamivir free base(l Compound 17 (312 mg, 1 mmol) and triethylamine (303 mg, 3 mmol) were dissolved in dry CH2C12 (15 mL), and the solution was cooled to 0°C. Methane sulfonyl chloride (229.2 mg, 2 mmol) was added, and the resulting solution was stirred at 0°C for 1 h. After TLC indicated completion of reaction, further CH2CI2 (20 mL) was added. The organic phase was washed with brine and then dried over anhydrous Na2S04. After the solvent was removed by a rotavaporator, the crude product was dissolved in DMF and NaN3 (390 mg, 6 mmol) was added. The reaction mixture was stirred at 80°C for 3 h. After completion of reaction (monitored by TLC), the reaction mixture was partitioned between EtOAc and brine. The organic layer was further washed with brine, dried over anhydrous Na2S04. Removal of solvent under reduced pressure gave crude product which on chromatographic purification with petroleum ether/ethyl acetate (4:6 v/v) gave the corresponding cyclic azide (this reaction is already known in literature) and the next reaction was done without the purification of cyclic azide. The cyclic azide was dissolved in EtOH and Lindlar's catalyst (20 mg) added. The reaction mixture was stirred for 6 h under a balloon of H2 at room temperature and filtered through a celite pad. The filtrate was concentrated and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (7:3 v/v) as eluent to give (-)- oseltamivir free base as gum. Yield: 64%; [ct]D25 -47.8 (c 0.5, CHC13) {lit.4a [a]D25 -54.2 (c 0.48, CHC13)}; IR (CHC13, cm- 1): 1068, 1127, 1255, 1374, 1456, 1568, 1644, 1714, 2977, 3289 cm-1; 1H NMR (200 MHz, CDC13): 0.90 (m, 6H), 1.31 (t, J = 7.1 Hz, 3H), 1.42 (m, 4H), 2.03 (s, 3H), 2.23 (m, 1H), 2.76 (m, 1H), 3.30 (m, 1H), 3.46 (m, 1H), 4.15 (m, 3H), 5.78 (m, 1H), 6.79 (s, IH); 13C NMR (50 MHz, CDC13): δ 10.1, 10.2, 14.8, 24.5, 26.3, 26.7, 34.3, 49.8, 59.5, 61.3, 75.7, 82.3, 129.9, 138.0, 167.1, 171.8; Anal. Calcd for C16H28N204 requires C, 61.51; H, 9.03; N, 8.97; Found: C, 61.47; H, 8.98; N, 8.88%.
	With acetic acid; triphenylphosphine In tetrahydrofuran; water at 45℃; for 16h;
	With hydrogen In ethanol for 18h;	[0101] The compound expressed by the Structural Formula (I) can be obtained in the following manner. Specifically, a mixture of the compound of formula 115 and Lindlar catalyst in absolute ethanol is stirred for 18 hours while hydrogen (1 atm) is bubbled through the mixture. Filtration through Celite and concentration of the filtratein in vacuo afford the compound expressed by the Structural Formula (I) as a foam. Notably, this foam will be solidified when left to stand.
	With 5% Pd-CaCO3; hydrogen In ethanol at 20℃; for 16h;
	With Lindlar's catalyst; hydrogen In ethanol at 20℃; for 6h;	12 Example 12 (-)-oseltamivir free base (1) Example 12 (-)-oseltamivir free base (1) [0124] 17 (312 mg, 1 mmol) and triethylamine (303 mg, 3 mmol) were dissolved in dry CH2Cl2 (15 mL), and the solution was cooled to 0° C. Methane sulfonyl chloride (229.2 mg, 2 mmol) was added, and the resulting solution was stirred at 0° C. for 1 h. After TLC indicated completion of reaction, further CH2Cl2 (20 mL) was added. The organic phase was washed with brine and then dried over anhydrous Na2SO4. After the solvent was removed by a rotavaporator, the crude product was dissolved in DMF and NaN3 (390 mg, 6 mmol) was added. The reaction mixture was stirred at 80° C. for 3 h. After completion of reaction (monitored by TLC), the reaction mixture was partitioned between EtOAc and brine. The organic layer was further washed with brine, dried over anhydrous Na2SO4. Removal of solvent under reduced pressure gave crude product which on chromatographic purification with petroleum ether/ethyl acetate (4:6 v/v) gave the corresponding cyclic azide (this reaction is already known in literature) and the next reaction was done without the purification of cyclic azide. The cyclic azide was dissolved in EtOH and Lindlar's catalyst (20 mg) added. The reaction mixture was stirred for 6 h under a balloon of H2 at room temperature and filtered through a celite pad. The filtrate was concentrated and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (7:3 v/v) as eluent to give (-)-oseltamivir free base as gum. [0126] Yield: 64%; [α]D25 -47.8 (c 0.5, CHCl3) {lit. 4a [α]D25 -54.2 (c 0.48, CHCl3)}; IR (CHCl3, cm-1): 1068, 1127, 1255, 1374, 1456, 1568, 1644, 1714, 2977, 3289 cm-1; 1H NMR (200 MHz, CDCl3): 0.90 (m, 6H), 1.31 (t, J=7.1 Hz, 3H), 1.42 (m, 4H), 2.03 (s, 3H), 2.23 (m, 1H), 2.76 (m, 1H), 3.30 (m, 1H), 3.46 (m, 1H), 4.15 (m, 3H), 5.78 (m, 1H), 6.79 (s, 1H); 13C NMR (50 MHz, CDCl3): δ 10.1, 10.2, 14.8, 24.5, 26.3, 26.7, 34.3, 49.8, 59.5, 61.3, 75.7, 82.3, 129.9, 138.0, 167.1, 171.8; Anal. Calcd for C16H28N2O4 requires C, 61.51; H, 9.03; N, 8.97. Found: C, 61.47; H, 8.98; N, 8.88%.

Reference： [1]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN105439884, 2016, A Location in patent: Paragraph 0037; 0038
[2]Current Patent Assignee: ROCHE HOLDING AG - US2009/76296, 2009, A1 Location in patent: Page/Page column 9
[3]Current Patent Assignee: GILEAD SCIENCES INC - CN103772231, 2016, B Location in patent: Paragraph 2414-2426
[4]Current Patent Assignee: NELSON MANDELA UNIVERSITY - WO2020/183281, 2020, A1 Location in patent: Page/Page column 7; 32-33
[5]Current Patent Assignee: NANYANG TECHNOLOGICAL UNIVERSITY - WO2009/78813, 2009, A1 Location in patent: Page/Page column 42-43
[6]Ma, Jimei; Zhao, Yanying; Ng, Simon; Zhang, Jing; Zeng, Jing; Than, Aung; Chen, Peng; Liu, Xue-Wei [Chemistry - A European Journal, 2010, vol. 16, # 15, p. 4533 - 4540]
[7]Kongkathip, Boonsong; Akkarasamiyo, Sunisa; Kongkathip, Ngampong [Tetrahedron, 2015, vol. 71, # 16, p. 2393 - 2399]
[8]Chuanopparat, Nutthawat; Kongkathip, Ngampong; Kongkathip, Boonsong [Tetrahedron Letters, 2012, vol. 53, # 46, p. 6209 - 6211,3]
[9]Kim, Choung U.; Lew, Willard; Williams, Matthew A.; Wu, Huiwei; Zhang, Lijun; Chen, Xiaowu; Escarpe, Paul A.; Mendel, Dirk B.; Laver, W. Graeme; Stevens, Raymond C. [Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2451 - 2460]
[10]Shie, Jiun-Jie; Fang, Jim-Min; Wang, Shi-Yun; Tsai, Keng-Chang; Cheng, Yih-Shyun E.; Yang, An-Suei; Hsiao, Shih-Chia; Su, Ching-Yao; Wong, Chi-Huey [Journal of the American Chemical Society, 2007, vol. 129, # 39, p. 11892 - 11893]
[11]Location in patent: scheme or table Shie, Jiun-Jie; Fang, Jim-Min; Wong, Chi-Huey [Angewandte Chemie - International Edition, 2008, vol. 47, # 31, p. 5788 - 5791]
[12]Current Patent Assignee: ACADEMIA SINICA - WO2009/29888, 2009, A2 Location in patent: Page/Page column 56; 57; 59
[13]Current Patent Assignee: HETERO DRUGS LIMITED - US2009/54682, 2009, A1 Location in patent: Page/Page column 3
[14]Current Patent Assignee: HETERO DRUGS LIMITED - US2009/54682, 2009, A1 Location in patent: Page/Page column 3
[15]Location in patent: scheme or table Karpf, Martin; Trussardi, Rene [Angewandte Chemie - International Edition, 2009, vol. 48, p. 5760 - 5762][Angew. Chem., Int. Ed., 2009, vol. 121, p. 5871 - 5873]
[16]Location in patent: experimental part Nie, Liang-Deng; Shi, Xiao-Xin; Quan, Na; Wang, Fei-Feng; Lu, Xia [Tetrahedron Asymmetry, 2011, vol. 22, # 16-17, p. 1692 - 1699]
[17]Kongkamnerd, Jarinrat; Cappelletti, Luca; Prandi, Adolfo; Seneci, Pierfausto; Rungrotmongkol, Thanyada; Jongaroonngamsang, Nutthapon; Rojsitthisak, Pornchai; Frecer, Vladimir; Milani, Adelaide; Cattoli, Giovanni; Terregino, Calogero; Capua, Ilaria; Beneduce, Luca; Gallotta, Andrea; Pengo, Paolo; Fassina, Giorgio; Miertus, Stanislav; De-Eknamkul, Wanchai [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 6, p. 2152 - 2157]
[18]Rawat, Varun; Dey, Soumen; Sudalai, Arumugam [Organic and Biomolecular Chemistry, 2012, vol. 10, # 20, p. 3988 - 3990]
[19]Current Patent Assignee: COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (IN) - WO2013/61340, 2013, A1 Location in patent: Page/Page column 29
[20]Kalashnikov; Sysolyatin; Sakovich; Sonina; Shchurova [Russian Chemical Bulletin, 2013, vol. 62, # 1, p. 163 - 170][Izv. Akad. Nauk, Ser. Khim., 2013, vol. 62, # 1, p. 165 - 171,7]
[21]Current Patent Assignee: TOHO UNIVERSITY - US2014/51756, 2014, A1 Location in patent: Paragraph 0101
[22]Mooney, Caitlin A.; Johnson, Stuart A.; 'T Hart, Peter; Quarles Van Ufford, Linda; De Haan, Cornelis A. M.; Moret, Ed E.; Martin, Nathaniel I. [Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 3154 - 3160]
[23]Current Patent Assignee: COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (IN) - US2014/243537, 2014, A1 Location in patent: Paragraph 0124-0126

4
[ 312904-18-0 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	With ethanolamine In ethanol at 20℃; for 3h; Heating / reflux;	1.f In a 114-necked round bottom flask equipped with a thermometer, a mechanical stirrer, a reflux condenser and an inert gas supply 176.2 g of (3R,4R,5S)-4-acetylamino-5-allylamino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester obtained according to (d) and 30.0 ml of ethanolamine (d=1.015, 0.54 mol) were dissolved at room temperature in 880 ml of ethanol and treated with 17.6 g of 10% palladium on charcoal. The black suspension was heated to reflux for 3 h, cooled to room temperature and filtered. The filter cake was washed with 100 ml of ethanol and the combined filtrates were evaporated in a rotary evaporator at 50° C./<20 mbar. The brown, oily residue (207.3 g) was treated with 600 ml of 2N hydrochloric acid and the brown solution was distilled in a rotary evaporator at 50° C./75 mbar for 5 min. The solution was cooled to room temperature, washed with 600 ml of tert.-butyl methyl ether and treated with stirring and cooling with about 110 ml of 25% aqueous ammonia keeping the temperature below room temperature until pH=9-10 was reached and a brown emulsion formed. The emulsion was extracted three times with 600 ml, in total with 1800 ml of ethyl acetate. The combined extracts were dried over about 200 g of sodium sulfate and filtered. The filter cake was washed with about 200 ml of ethyl acetate and the combined filtrates were evaporated in a rotary evaporator at 50° C./<20 mbar to yield 158.6 g of a brown oil which was dissolved in 650 ml ethanol. The brown solution was added in the course of 1 min with stirring to a hot solution (50° C.) of 57.60 g of 85% ortho-phosphoric acid (d=1.71, 0.50 mol) in 2500 ml of ethanol. The resulting solution was cooled in the course of 1 h to 22° C. At 40° C. seed crystals of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester (about 10 mg) were added whereby crystallization started. The beige suspension was cooled in the course of 2 h to -20° C. to -25° C. and stirred at this temperature for 5 h. The suspension was filtered over a pre-cooled (-20° C.) glass filter funnel for 2 h. The filter cake was first washed with 200 ml of ethanol pre-cooled to -25° C., then twice with 850 ml, in total with 1700 ml acetone, then twice with 1000 ml, in total with 2000 ml of n-hexane, then dried at 50° C./20 mbar for 3 h to yield 124.9 g (70%) of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-ene carboxylic acid ethyl ester as white crystals; m.p. 205-207° C., decomposition.
	With palladium on activated charcoal; ethanolamine In ethanol for 3h; Heating;
	With ethanolamine In ethanol for 3h; Heating;

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2006/47002, 2006, A1 Location in patent: Page/Page column 7
[2]Abrecht, Stefan; Harrington, Peter; Iding, Hans; Karpf, Martin; Trussardi, René; Wirz, Beat; Zutter, Ulrich [Chimia, 2004, vol. 58, # 9, p. 621 - 629]
[3]Karpf; Trussardi [Journal of Organic Chemistry, 2001, vol. 66, # 6, p. 2044 - 2051]

5
ethyl (3R,4R,5S)-4-N-acetylamino-5-N,N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate [ No CAS ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
88.7%	With 1,3-dimethylbarbituric acid In tetrahydrofuran at 50℃; for 2.21667h;	1.f A 50 mL airlessware flask (N2-vacuum line on sidearm) equipped with a septum and a magnetic stir bar is charged with 1.874 g of 1,3-Dimethylbarbituric Acid (NDMBA) (12.00 mmol). The flask is sealed and the atmosphere is changed to dry nitrogen (10 nitrogen-vacuum cycles). The flask is transferred to a glove bag and 50.0 mg (0.0433 mmol) of tetrakis (triphenylphosphine) palladium is charged. [0197] A solution of 3.925 g (10.00 mmol) of the ethyl (3R,4R,5S)-4-N-Acetylamino-5-N,N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate prepared as in (e) in 5 mL of dry THF is prepared in a 15 mL 1-necked flask capped with a septum (10 nitrogen-vacuum cycles prior to adding THF). This solution is then transferred to the reaction flask using a 20-gauge stainless steel cannula. The transfer is completed using 2 mL of fresh dry THF. The resulting yellow suspension is heated at 50° C. for 133 min. [0198] The suspension is cooled to 25° C. and 10 mL toluene and 8 mL 1.5 M HCl are added. The layers are separated (aqueous pH=1). The aqueous layer is washed with 10 mL of toluene three times. A solution of 0.52 g (13 mmol) NaOH in 1.5 mL H20 is slowly added to the aqueous layer (aqueous pH=12). 5 mL of brine are then added. The resulting suspension is extracted with 10 mL of isopropyl acetate three times. The combined extracts are concentrated in vacuo (rotary evaporator at 30-35° C. and 60 mm Hg, hexanes trituration, then vacuum pump at 25° C. and 1 mm Hg for 16 h) to yield 2.770 g (Theoretical 3.124 g, 88.7% yield) of ethyl (3R,4R,5S)-4-N-Acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate as a colorless solid.
83.69%	Stage #1: ethyl (3R,4R,5S)-4-N-acetylamino-5-N,N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate With 1,3-dimethylbarbituric acid; palladium diacetate; triphenylphosphine In ethanol at 35℃; for 2h; Inert atmosphere; Stage #2: With phosphoric acid In acetone for 2h;	1 At room temperature, add 4.0g OSTW-M1, 2.4g NDMBA, 0.28g Ph3P, 0.04g Pd(AcO)2, 40ml absolute ethanol into a 100ml three-necked flask. Replace with nitrogen three times, raise the temperature to 35°C, and react for 2 hours. After the reaction is completed, filter, and add 40 ml of acetone to the filtrate. 1.2 g of 85% phosphoric acid was added dropwise. The reaction solution was stirred for 2 hours, filtered, and dried to obtain a solid, namely 3.5 g crude oseltamivir, with a purity of 99.9% and a yield of 83.69%.
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; 1,3-dimethylbarbituric acid

	With 1,3-dimethylbarbituric acid In ethanol at 36℃; for 2h;	2.f 31.78 g (0.08096 mol) of crude ethyl (3R,4R,5S)-4-N-Acetylamino-5-N,N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate, as prepared from (e), are dissolved in 77 mL of EtOH and charged to a 500 mL 3-necked round-bottomed jacketed flask equipped with an overhead (paddle) stirrer, a nitrogen inlet and a septum with thermocouple. 56 mL of Ethanol are used to rinse the transfer vessel to the reactor. 15.17 g of Dimethylbarbituric acid (0.09715 mol) are charged to the reactor flask followed by 0.8493 g of triphenylphosphine (0.003238 mol). A nitrogen sweep is placed on the reactor for 5 min and palladium acetate (0.1817 g, 0.0008096 mol) and ethanol (58 mL) are added and the jacket temperature set to 36° C. The reaction mixture is stirred for 2 h with agitation (284 RPM) under an atmosphere of nitrogen. The reaction is sampled for LC analysis and is completed. The jacket temperature is set to 10° C. for an overnight hold.
	With 1,3-dimethylbarbituric acid; palladium diacetate; triphenylphosphine In ethanol at 35℃; for 2h; Sealed tube; Inert atmosphere;
	With 1,3-dimethylbarbituric acid; palladium diacetate; triphenylphosphine In ethanol at 20 - 25℃; for 2h; Inert atmosphere;	1 Under nitrogen protection, in a 2000ml reaction bottle,The compound of the formula (V) obtained above is added in that order,Anhydrous ethanol 800g,N,N-dimethylbarbituric acid(85.0g, 0.54mol),Palladium acetate (1.01 g, 0.0045 mol),Triphenylphosphine (4.73 g, 0.018 mol),After the addition, the temperature was controlled at 20-25 ° C, and the reaction was stirred for 2 h.Cool down to 10-15 ° C, keep warm for 30 min, suction filtration,The filtrate was concentrated to obtain a crude oseltamivir free base of the formula (II) in a yield of 88% and a purity of 96.9%.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2004/180933, 2004, A1 Location in patent: Page/Page column 9-10
[2]Current Patent Assignee: GOOD DOCTOR PHARMACEUTICAL GROUP CO LTD - CN111978195, 2020, A Location in patent: Paragraph 0047; 0050-0052
[3]Abrecht, Stefan; Harrington, Peter; Iding, Hans; Karpf, Martin; Trussardi, René; Wirz, Beat; Zutter, Ulrich [Chimia, 2004, vol. 58, # 9, p. 621 - 629]
[4]Current Patent Assignee: ROCHE HOLDING AG - US2004/180933, 2004, A1 Location in patent: Page/Page column 11
[5]Harrington, Peter J.; Brown, Jack D.; Foderaro, Tommaso; Hughes, Robert C. [Organic Process Research and Development, 2004, vol. 8, # 1, p. 86 - 91]
[6]Current Patent Assignee: BRIGHTGENE BIO MEDICAL TECHNOLOGY CO LTD - CN109627180, 2019, A Location in patent: Paragraph 0020; 0024

6
[ 891831-22-4 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: tert-butyl [(1S,5R,6R)-6-acetylamino-3-cyano-5-(1-ethylpropoxy)cyclohex-3-en-1-yl]carbamate With hydrogenchloride In ethanol at 60℃; for 4h; Stage #2: With water In ethanol at 4℃; for 3h;

Reference： [1]Fukuta, Yuhei; Mita, Tsuyoshi; Fukuda, Nobuhisa; Kanai, Motomu; Shibasaki, Masakatsu [Journal of the American Chemical Society, 2006, vol. 128, # 19, p. 6312 - 6313]

7
[ 927395-63-9 ]
[ 64-17-5 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: (3R,4R,5S)-4-acetylamino-5-benzyloxycarbonylamino-1-cyano-3-(1-ethylpropoxy)cyclohexene; ethanol With hydrogenchloride at 20℃; for 24h; Stage #2: With water In ethanol at 20℃; for 2h; Stage #3: With ammonium hydroxide In ethanol at 20℃; for 10h;

Reference： [1]Mita, Tsuyoshi; Fukuda, Nobuhisa; Roca, Francesc X.; Kanai, Motomu; Shibasaki, Masakatsu [Organic Letters, 2007, vol. 9, # 2, p. 259 - 262]

8
[ 145013-05-4 ]
[ 196618-13-0 ]
ethyl (3R,4R,5S)-4-acetamido-5-[N²,N³-bis(tert-butoxycarbonyl)guanidino]-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine; mercury dichloride In N,N-dimethyl-formamide at 0℃;
89%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃;	117 Qian in accordance with the Kim, "TetrahedronLett." 34:7677 (1993) for the step of processing. The HgCl 2 (69 mg, 0 . 25mmol) to a time 0 °C amine 262 (72 mg, 0 . 23mmol), b-Boc thiourea (66 mg, 0 . 24mmol) and Et 3 N (108 μ L) anhydrous DMF (600 μ L) solution. The non-homogeneous reaction mixture to the 0 °C stirring 1 hour, stirring the mixture at room temperature for 15 minutes, then diluted with EtOAc, for filtering diatomaceous earth pad. After concentrating under vacuum, the residue on silica gel (20% hexanes/ethyl acetate) the rapid chromatographic separation to give 113 mg (89%) colorless foam 263.
177 mg	With triethylamine; mercury dichloride In N,N-dimethyl-formamide at 20℃; for 10h;

	With triethylamine; mercury dichloride In N,N-dimethyl-formamide at 0 - 20℃; for 10h;	16 A solution of azide lia (150 mg, 0.41 mmol) in ethanol (20 mL) was treated with Lindlar's catalyst (80 mg) under an atmosphere of hydrogen for 16 h at room temperature. The reaction mixture was filtered through Celite, and rinsed with ethanol. The filtrate was evaporated under reduced pressure to give colorless foam (110 mg), which was dissolved in anhydrous DMF (20 mL) and treated with AT,AT-bis(ferf-butoxycarbonyl)thiourea (148 mg, 0.51 mmol) and Et3N (148 μL, 1.03 mmol). The mixture was cooled to o° C and HgCL (138 mg, 0.51 mmol) was added slowly. The suspension was warmed to room temperature and stirred for 10 h. After which, the reaction was diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated and purified by flash column chromatography (EtOAc/hexane, 3:7) to afford guanidine 12a (177 mg, 78% yield). Colorless foam; TLC (EtOAc/hexane, 1:1) Rf= 0.4; [α]D20 = -81.6 o (c = 1.0, CHCl3); IR (neat) 3302, 1724, 1635, 1612, 1120 cm-i; 1H NMR (600 MHz, CDCl3) δ 11.36 (1 H, s), 8.60 (1 H, d, J = 8.1 Hz), 6.78 (1 H, s), 6.21 (1 H, d, J = 9.0 Hz), 4.37-4.34 (1 H, m), 4.17 (2 H, q, J = 7.1 Hz), 4.14-4.08 (lH, m), 3.98 (1 H, dd, J = 4.3, 1.3 Hz), 3-32-3-30 (1 H, m), 2.74 (1 H, dd, J = 17.8, 5.3 Hz), 2.35 (1 H, dd, J = 17.8, 9.4 Hz), 1.87 (3 H, s), 1.50-1.44 (22 H, m), 1.24 (3 H, t, J = 7.1 Hz), 0.86 (3 H, t, J = 7.4 Hz), 0.83 (3 H, t, J = 7.4 Hz); ^C NMR (150 MHz, CDCl3) δ 170.2, 165.9, 163-1, 156.8, 152.5, 137.9, 128.6, 83.4, 82.6, 79.5, 76.1, 60.9, 54.3, 48.0, 30.4, 28.3 (3χ), 28.0 (3 x), 26.0, 25.7, 23.2, 14.1, 9.5, 9.3; HRMS calcd for C27H47N4Os (M+ + H): 555-3394, found: m/z 555-3398.
	With triethylamine; mercury dichloride In N,N-dimethyl-formamide
0.16 g	With triethylamine; mercury dichloride In N,N-dimethyl-formamide at 0 - 20℃; for 24h; Inert atmosphere;	4 4.1.4 Ethyl (3R,4R,5S)-4-acetamido-5-[N²,N³-bis(tert-butoxycarbonyl)guanidino]-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (4) Mercury(II) chloride (0.11 g, 0.406 mmol) was added portionwise to a solution of oseltamivir base 3 (0.10 g, 0.320 mmol), N,N'-di-(tert-butoxycarbonyl)thiourea (0.11 g, 0.400 mmol) and triethylamine (0.11 mL, 0.800 mmol) in DMF (15 mL) at 0 °C. The reaction mixture was stirred for 24 h at room temperature. The mixture was diluted with EtOAc (10 mL), filtered through a pad of Celite and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (3 * 10 mL). The combined organic phase was washed with water, brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography (eluent Hexanes/EtOAc, 2:1) to afford the Boc-protected guanidine derivative 4 (0.16 g, 89%). TLC (Hexanes/EtOAc 1:1) Rf = 0.4. 1H NMR (300 MHz, CDCl3) δ 11.33 (s, 1H), 8.57 (d, J = 8.1 Hz, 1H), 6.76 (s, 1H), 6.16 (d, J = 8.9 Hz, 1H), 4.43-4.23 (m, 1H), 4.20-4.01 (m, 3H), 3.96 (d, J = 7.7 Hz, 1H), 3.36-3.21 (m, 1H), 2.72 (dd, J = 17.6, 5.3 Hz, 1H), 2.42-2.23 (m, 1H), 1.85 (s, 3H), 1.55-1.49 (m, 22H), 1.22 (dd, J = 12.6, 5.5 Hz, 3H), 0.82 (dt, J = 10.3, 7.4 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 170.3, 166.0, 163.3, 157.0, 152.7, 138.1, 128.7, 83.6, 82.8, 79.6, 76.3, 61.1, 54.5, 48.2, 30.6, 28.41, 28.2, 26.2, 25.9, 23.4, 14.3, 9.7, 9.4. HR-ESI-MS calculated for C27H47O8N4 (M + H)+ 555.3388, found 555.3389.

Reference： [1]Gupta, Deepak; Varghese Gupta, Sheeba; Dahan, Arik; Tsume, Yasuhiro; Hilfinger, John; Lee, Kyung-Dall; Amidon, Gordon L. [Molecular Pharmaceutics, 2013, vol. 10, # 2, p. 512 - 522]
[2]Current Patent Assignee: GILEAD SCIENCES INC - CN103772231, 2016, B Location in patent: Paragraph 2427-2444
[3]Shie, Jiun-Jie; Fang, Jim-Min; Wang, Shi-Yun; Tsai, Keng-Chang; Cheng, Yih-Shyun E.; Yang, An-Suei; Hsiao, Shih-Chia; Su, Ching-Yao; Wong, Chi-Huey [Journal of the American Chemical Society, 2007, vol. 129, # 39, p. 11892 - 11893]
[4]Current Patent Assignee: ACADEMIA SINICA - WO2009/29888, 2009, A2 Location in patent: Page/Page column 59
[5]Current Patent Assignee: SINEVIR THERAPEUTICS - US9181281, 2015, B2 Location in patent: Page/Page column 15; 16
[6]Albinaña, Carlos Berenguer; MacHara, Aleš; Rezacov, Pavlína; Pachl, Petr; Konvalinka, Jan; Kozísek, Milan [European Journal of Medicinal Chemistry, 2016, vol. 121, p. 100 - 109]

9
(3S,4S,5S)-4-acetamido-5-allyloxycarbonylamino-1-ethoxycarbonyl-3-(3-pentyloxy)cyclohex-2-ene [ No CAS ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
95.1%	With pyrrolidine In ethanol for 0.5h;	12 Example 12; [Show Image] As shown in the chemical equation 19, after the 1-cyclohexene-1-carboxylic acid derivative (25a) (25.2 mg, 63.6 µmol) and tetrakis(triphenylphosphine)palladium (16.8 mg, 14.5 µmol) were dissolved in ethanol (1 ml) in an argon atmosphere, pyrrolidine (12 µl, 140 µmol) was added, and stirring was then performed for 30 minutes. After this reaction liquid was condensed under reduced pressure, was then dissolved in ethyl acetate, and was further extracted twice with hydrochloric acid (1 mol/l), an obtained aqueous layer was saturated by sodium bicarbonate and was then extracted three times with dichloromethane. An obtained organic layer was washed with saturated aqueous sodium chloride. The aqueous layer was extracted with dichloromethane, and a collected organic layer was dried by sodium sulfate and was then condensed under reduced pressure, so that a 1-cyclohexene-1-carboxylic acid derivative (26a) (18.9 mg, 60.5 µmol, Y. 95.1%) having a free amino group at the 5-position was obtained. The spectrum data of this 1-cyclohexene-1-carboxylic acid derivative (26a) is as follows. 1H NMR (CDCl3):δ(ppm) 6.79 (s, 1H), 5.70 (brd, J = 7.3 Hz, 1H), 4.21 (q, J = 7.3 Hz, 2H), 4.20(m, 1H), 3.55 (m, 1H), 3.34 (quintet, J = 6.0 Hz, 1H), 3.24 (m, 1H), 2.76 (dd, J = 17.4, 4.6 Hz, 1H), 2.16 (m, 1H), 2.05 (s, 3H), 1.51 (m, 4H), 1.29 (t, J = 7.3Hz, 3H), 0.90(dt, J = 7.3, 4.6 Hz, 6H).
	With 1,3-dimethylbarbituric acid; triphenylphosphine In ethanol; water at 80℃; for 1h;

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF TOKYO - EP2050752, 2009, A1 Location in patent: Page/Page column 18
[2]Satoh, Nobuhiro; Akiba, Takahiro; Yokoshima, Satoshi; Fukuyama, Tohru [Angewandte Chemie - International Edition, 2007, vol. 46, # 30, p. 5734 - 5736]

10
[ 204254-96-6 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: 97 percent / MgBr₂*OEt₂ / acetonitrile; various solvent(s) / 16 h / 55 °C 2.1: ethanolamine; Pd/C / ethanol / 3 h / Heating 2.2: 77 percent / H₂SO₄ 3.1: various solvent(s) 4.1: Et₃N / various solvent(s) 5.1: various solvent(s) / 15 h / 111 - 112 °C / 2625.21 - 3375.27 Torr 6.1: AcOH; MeSO₃H / various solvent(s) / 15 h / 20 °C 7.1: NH₂CH₂CH₂OH; Pd/C / ethanol / 3 h / Heating
	Multi-step reaction with 7 steps 1.1: MgBr₂*OEt₂ / acetonitrile; various solvent(s) / Heating 1.2: H₂NCH₂CH₂OH / Pd/C / ethanol / 3 h / Heating 2.1: 6 h / 100 °C / 750.08 - 3750.38 Torr 3.1: Et₃N / ethyl acetate / 0 - 20 °C 4.1: MeSO₃H / ethanol / 2.67 h / Heating 5.1: ethyl acetate / 6 h / 112 °C / 750.08 - 4500.45 Torr 6.1: AcOH; MeSO₃H / various solvent(s) / 0 - 20 °C 7.1: H₂NCH₂CH₂OH / Pd/C / ethanol / 3 h / Heating
	Multi-step reaction with 7 steps 1.1: MgBr₂*OEt₂ / acetonitrile; various solvent(s) / Heating 1.2: H₂NCH₂CH₂OH / Pd/C / ethanol / 3 h / Heating 2.1: 6 h / 100 °C / 750.08 - 3750.38 Torr 3.1: Et₃N / ethyl acetate / 0 - 20 °C 4.1: MeSO₃H / ethanol / 2.67 h / Heating 5.1: ethyl acetate / 6 h / 112 °C / 750.08 - 4500.45 Torr 6.1: AcOH; MeSO₃H / various solvent(s) / 0 - 20 °C 7.1: HOCH₂CH₂OH / Pd/C / ethanol / Heating

	Multi-step reaction with 7 steps 1.1: MgBr₂*OEt₂ / acetonitrile; various solvent(s) / Heating 1.2: HOCH₂CH₂OH / Pd/C / ethanol / Heating 2.1: 6 h / 100 °C / 750.08 - 3750.38 Torr 3.1: Et₃N / ethyl acetate / 0 - 20 °C 4.1: MeSO₃H / ethanol / 2.67 h / Heating 5.1: ethyl acetate / 6 h / 112 °C / 750.08 - 4500.45 Torr 6.1: AcOH; MeSO₃H / various solvent(s) / 0 - 20 °C 7.1: H₂NCH₂CH₂OH / Pd/C / ethanol / 3 h / Heating
	Multi-step reaction with 7 steps 1.1: MgBr₂*OEt₂ / acetonitrile; various solvent(s) / Heating 1.2: HOCH₂CH₂OH / Pd/C / ethanol / Heating 2.1: 6 h / 100 °C / 750.08 - 3750.38 Torr 3.1: Et₃N / ethyl acetate / 0 - 20 °C 4.1: MeSO₃H / ethanol / 2.67 h / Heating 5.1: ethyl acetate / 6 h / 112 °C / 750.08 - 4500.45 Torr 6.1: AcOH; MeSO₃H / various solvent(s) / 0 - 20 °C 7.1: HOCH₂CH₂OH / Pd/C / ethanol / Heating
	Multi-step reaction with 6 steps 1.1: lithium hydroxide monohydrate; ammonia hydrochloride / ethanol / 0.33 h 1.2: 14 h / 68 °C 2.1: trimethylphosphine / tetrahydrofuran; acetonitrile / 2.17 h / 20 °C / Inert atmosphere 3.1: Caswell No_. 744A; ammonia hydrochloride / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: 4-methyl-morpholine / dichloromethane / 0 - 20 °C 5.1: dichloromethane; toluene / 2 h / 20 °C 6.1: hydrogenchloride; lithium hydroxide monohydrate / dichloromethane; toluene / 4 h / 20 °C 6.2: pH 10
	Multi-step reaction with 5 steps 1.1: boron trifluoride diethyl ether complex / 1.17 h / 0 °C 1.2: 4 h / 0 - 20 °C 1.3: 36 h / 20 °C 2.1: triethylamine; 4-dimethylaminopyridine / 1 h / 0 °C 3.1: sodium hydride / dichloromethane; dimethyl sulfoxide; mineral oil / 8 h / 20 °C 4.1: boron trifluoride diethyl ether complex / dichloromethane / 0.37 h / -15 °C 5.1: Cs₂CO₃ / dimethyl sulfoxide / 0.25 h / 80 °C 5.2: 0.33 h / 80 °C
	Multi-step reaction with 4 steps 1.1: Caswell No_. 744A; ammonia hydrochloride / lithium hydroxide monohydrate; ethanol / 8 h / 70 - 75 °C 1.2: 6 h / Reflux 2.1: Caswell No_. 744A; ammonia hydrochloride / N,N-dimethyl-formamide / 5 h / 8 - 85 °C 3.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; dichloromethane / 1 h / 20 °C 4.1: hydrogen / ethanol / 18 h / 760.05 Torr
	Multi-step reaction with 8 steps 1.1: anhydrous zinc chloride / tetrahydrofuran / 1 h 1.2: 24 h / 50 °C 2.1: hydrogen; palladium on activated charcoal / isopropanol; acetonitrile / 6 h / 60 °C / 760.05 Torr 3.1: acetonitrile / 1 h / 35 °C 4.1: pyridine / chloroform / 3 h / -5 °C 5.1: pyridine / tert-butyl methyl ether / 10 h / 80 °C 6.1: hydrogen; palladium on activated charcoal / ethanol / 8 h / 35 °C / 760.05 Torr 7.1: tert-butyl methyl ether / 2 h / 40 °C 8.1: trifluoroacetic acid / isopropanol / 7 h / 0 - 30 °C
	Multi-step reaction with 5 steps 1.1: magnesium(II) chloride / toluene / 2 h / 20 - 30 °C 1.2: 16 h / 50 - 60 °C 2.1: benzenesulfonyl chloride / toluene / 0.5 h / 0 - 10 °C 2.2: 4.5 h / 0 - 75 °C 3.1: benzoic acid / toluene / 3 h / 115 - 120 °C 4.1: anhydrous Sodium acetate / toluene / 3 h / 110 - 115 °C 5.1: palladium on activated charcoal; hydrogen; glacial acetic acid / ethyl acetate / 16 h / 50 - 60 °C / 2250.23 - 3750.38 Torr
	Multi-step reaction with 6 steps 1.1: magnesium(II) chloride / toluene / 3 h / 20 °C 1.2: 5 h / 50 - 60 °C 2.1: methanesulfonyl chloride / toluene / 2.5 h / 0 - 5 °C 2.2: 3 h 3.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / dichloromethane; lithium hydroxide monohydrate / 3 h / 20 °C 3.2: 0.25 h 4.1: anhydrous Sodium acetate / 5 h / 80 °C 5.1: toluene-4-sulfonic acid / toluene / 8 h / 115 - 120 °C 6.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / dichloromethane; lithium hydroxide monohydrate / 3 h / 20 °C 6.2: 0.25 h

Reference： [1]Abrecht, Stefan; Harrington, Peter; Iding, Hans; Karpf, Martin; Trussardi, René; Wirz, Beat; Zutter, Ulrich [Chimia, 2004, vol. 58, # 9, p. 621 - 629]
[2]Karpf; Trussardi [Journal of Organic Chemistry, 2001, vol. 66, # 6, p. 2044 - 2051]
[3]Karpf; Trussardi [Journal of Organic Chemistry, 2001, vol. 66, # 6, p. 2044 - 2051]
[4]Karpf; Trussardi [Journal of Organic Chemistry, 2001, vol. 66, # 6, p. 2044 - 2051]
[5]Karpf; Trussardi [Journal of Organic Chemistry, 2001, vol. 66, # 6, p. 2044 - 2051]
[6]Kongkamnerd, Jarinrat; Cappelletti, Luca; Prandi, Adolfo; Seneci, Pierfausto; Rungrotmongkol, Thanyada; Jongaroonngamsang, Nutthapon; Rojsitthisak, Pornchai; Frecer, Vladimir; Milani, Adelaide; Cattoli, Giovanni; Terregino, Calogero; Capua, Ilaria; Beneduce, Luca; Gallotta, Andrea; Pengo, Paolo; Fassina, Giorgio; Miertus, Stanislav; De-Eknamkul, Wanchai [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 6, p. 2152 - 2157]
[7]Nie, Liang-Deng; Wang, Fei-Feng; Ding, Wei; Shi, Xiao-Xin; Lu, Xia [Tetrahedron Asymmetry, 2013, vol. 24, # 11, p. 638 - 642]
[8]Current Patent Assignee: TOHO UNIVERSITY - US2014/51756, 2014, A1
[9]Current Patent Assignee: HUNAN OUYA PHARMACEUTICAL - CN111499536, 2020, A
[10]Current Patent Assignee: SHANGHAI AOBO PHARMTECH; ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. - CN113024396, 2021, A
[11]Current Patent Assignee: UNIV ZHEJIANG TECHNOLOGY - CN114539088, 2022, A

11
[ 312904-12-4 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: various solvent(s) 2: Et₃N / various solvent(s) 3: various solvent(s) / 15 h / 111 - 112 °C / 2625.21 - 3375.27 Torr 4: AcOH; MeSO₃H / various solvent(s) / 15 h / 20 °C 5: NH₂CH₂CH₂OH; Pd/C / ethanol / 3 h / Heating
	Multi-step reaction with 6 steps 1: 6 h / 100 °C / 750.08 - 3750.38 Torr 2: Et₃N / ethyl acetate / 0 - 20 °C 3: MeSO₃H / ethanol / 2.67 h / Heating 4: ethyl acetate / 6 h / 112 °C / 750.08 - 4500.45 Torr 5: AcOH; MeSO₃H / various solvent(s) / 0 - 20 °C 6: H₂NCH₂CH₂OH / Pd/C / ethanol / 3 h / Heating
	Multi-step reaction with 6 steps 1: 6 h / 100 °C / 750.08 - 3750.38 Torr 2: Et₃N / ethyl acetate / 0 - 20 °C 3: MeSO₃H / ethanol / 2.67 h / Heating 4: ethyl acetate / 6 h / 112 °C / 750.08 - 4500.45 Torr 5: AcOH; MeSO₃H / various solvent(s) / 0 - 20 °C 6: HOCH₂CH₂OH / Pd/C / ethanol / Heating

Multi-step reaction with 6 steps 1: acetonitrile / 1 h / 35 °C 2: pyridine / chloroform / 3 h / -5 °C 3: pyridine / tert-butyl methyl ether / 10 h / 80 °C 4: hydrogen; palladium on activated charcoal / ethanol / 8 h / 35 °C / 760.05 Torr 5: tert-butyl methyl ether / 2 h / 40 °C 6: trifluoroacetic acid / isopropyl alcohol / 7 h / 0 - 30 °C

Reference： [1]Abrecht, Stefan; Harrington, Peter; Iding, Hans; Karpf, Martin; Trussardi, René; Wirz, Beat; Zutter, Ulrich [Chimia, 2004, vol. 58, # 9, p. 621 - 629]
[2]Karpf; Trussardi [Journal of Organic Chemistry, 2001, vol. 66, # 6, p. 2044 - 2051]
[3]Karpf; Trussardi [Journal of Organic Chemistry, 2001, vol. 66, # 6, p. 2044 - 2051]
[4]Current Patent Assignee: HUNAN OUYA PHARMACEUTICAL - CN111499536, 2020, A

12
[ 584-02-1 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: BF₃*Et₂O / 2 h / 70 - 75 °C 2: pyridine, (dimethylamino)pyridine / 18 h / Ambient temperature 3: Ph₃P, H₂O / tetrahydrofuran / 10 h / 50 °C
	Multi-step reaction with 4 steps 1: boron trifluoride diethyl etherate / 75 °C / Inert atmosphere 2: pyridine; dmap / 1 h / 150 °C / Inert atmosphere; Microwave irradiation 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C / Inert atmosphere 4: hydrazine / ethanol / 10 h / 68 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: boron trifluoride diethyl etherate / 75 °C / Inert atmosphere 2: pyridine; dmap / 1 h / 150 °C / Inert atmosphere; Microwave irradiation 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C / Inert atmosphere 4: hydrazine / ethanol / 10 h / 68 °C / Inert atmosphere

	Multi-step reaction with 6 steps 1: boron trifluoride diethyl etherate / 75 °C / Inert atmosphere 2: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 40 °C / Inert atmosphere 3: boron trifluoride diethyl etherate / 75 °C / Inert atmosphere 4: pyridine; dmap / 1 h / 150 °C / Inert atmosphere; Microwave irradiation 5: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C / Inert atmosphere 6: hydrazine / ethanol / 10 h / 68 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1: boron trifluoride diethyl etherate / 75 °C / Inert atmosphere 2: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 40 °C / Inert atmosphere 3: boron trifluoride diethyl etherate / 75 °C / Inert atmosphere 4: pyridine; dmap / 1 h / 150 °C / Inert atmosphere; Microwave irradiation 5: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C / Inert atmosphere 6: hydrazine / ethanol / 10 h / 68 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: diisobutylaluminium hydride / dichloromethane; toluene / 2.5 h / Inert atmosphere; Cooling 1.2: 72.5 h / 20 °C / Inert atmosphere 2.1: sodium periodate; silica gel / dichloromethane; water / 3.58 h 3.1: (2S)-2-{diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine; chloroacetic acid / dimethyl sulfoxide / 20 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride / acetonitrile / 70 °C / Inert atmosphere 5.1: acetic acid; zinc / 34 h / 20 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: diisobutylaluminium hydride / dichloromethane; toluene / 2.5 h / Inert atmosphere; Cooling 1.2: 72.5 h / 20 °C / Inert atmosphere 2.1: sodium periodate; silica gel / dichloromethane; water / 3.58 h 3.1: (2S)-2-{diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine; chloroacetic acid / chloroform; water / 5 h / 0 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride / acetonitrile / 70 °C / Inert atmosphere 5.1: acetic acid; zinc / 34 h / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: diisobutylaluminium hydride / dichloromethane; toluene / 2.5 h / Inert atmosphere; Cooling 1.2: 72.5 h / 20 °C / Inert atmosphere 2.1: sodium periodate; silica gel / dichloromethane; water / 3.58 h 3.1: (2S)-2-{diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine; chloroacetic acid / dimethyl sulfoxide / 20 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride / acetonitrile / 70 °C / Inert atmosphere 5.1: potassium carbonate 6.1: acetic acid; zinc / 34 h / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: diisobutylaluminium hydride / dichloromethane; toluene / 2.5 h / Inert atmosphere; Cooling 1.2: 72.5 h / 20 °C / Inert atmosphere 2.1: sodium periodate; silica gel / dichloromethane; water / 3.58 h 3.1: (2S)-2-{diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine; chloroacetic acid / chloroform; water / 5 h / 0 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride / acetonitrile / 70 °C / Inert atmosphere 5.1: potassium carbonate 6.1: acetic acid; zinc / 34 h / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide / water / 0.17 h / 0 °C / Inert atmosphere 1.2: 15 h / 0 - 20 °C / Inert atmosphere 2.1: periodic acid / diethyl ether / 4.5 h / 0 - 20 °C / Inert atmosphere 3.1: 1,3-bis(3,5-bis(trifluoro-ethyl)phenyl)thiourea; formic acid; (-)-(S)-α,α-diphenylpyrrolidine-2-methanol methyl(diphenyl)silyl ether / chlorobenzene / 0.5 h / 20 °C / Inert atmosphere 4.1: potassium <i>tert</i>-butylate / ethanol / 0.33 h / 0 °C / Inert atmosphere 5.1: chloro-trimethyl-silane / -40 °C / Inert atmosphere 6.1: hydrogenchloride / water / 1 h / 50 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: diisobutylaluminium hydride / dichloromethane; hexane / 1.17 h / 0 - 20 °C 1.2: 96 h / 20 °C 2.1: silica gel; sodium periodate / water; dichloromethane / 3 h / 20 °C 3.1: MANDELIC ACID; (2S)-2-{diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine / water; dichloromethane / 2 h / 0 °C 4.1: 18-crown-6 ether; potassium carbonate / water; dichloromethane / 2 h / 70 °C / Microwave irradiation 5.1: zinc; acetic acid; chloro-trimethyl-silane / diethyl ether / 8 h / Reflux
	Multi-step reaction with 5 steps 1: boron trifluoride diethyl etherate / acetonitrile / 0 h / 100 °C / 7500.75 Torr 2: sulfuric acid / acetonitrile / 0 h / 170 °C / 7500.75 Torr 3: sodium hydroxide / acetonitrile / 0.01 h / 20 °C 4: sodium azide / water; N,N-dimethyl-formamide / 0.01 h / 190 °C / 7500.75 Torr 5: sodium tetrahydroborate; cobalt(II) chloride; ethanol / water / 0 h / 20 °C / pH 8 / Sonication
	Multi-step reaction with 3 steps 1.1: sodium hydride / diethyl ether / 0.33 h / 20 °C / Inert atmosphere 1.2: 0.04 h / 5 - 20 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid / dichloromethane / 8.5 h / 50 °C / Inert atmosphere 2.2: 24 h / 50 °C / Inert atmosphere 2.3: 8 h / -10 - 20 °C / Schlenk technique; Inert atmosphere 3.1: hydrazine / ethanol / 11 h / 68 °C / Schlenk technique; Inert atmosphere

Reference： [1]Kim, Choung U.; Lew, Willard; Williams, Matthew A.; Wu, Huiwei; Zhang, Lijun; Chen, Xiaowu; Escarpe, Paul A.; Mendel, Dirk B.; Laver, W. Graeme; Stevens, Raymond C. [Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2451 - 2460]
[2]Trost, Barry M.; Zhang, Ting [Chemistry - A European Journal, 2011, vol. 17, # 13, p. 3630 - 3643]
[3]Trost, Barry M.; Zhang, Ting [Chemistry - A European Journal, 2011, vol. 17, # 13, p. 3630 - 3643]
[4]Trost, Barry M.; Zhang, Ting [Chemistry - A European Journal, 2011, vol. 17, # 13, p. 3630 - 3643]
[5]Trost, Barry M.; Zhang, Ting [Chemistry - A European Journal, 2011, vol. 17, # 13, p. 3630 - 3643]
[6]Rehak, Juraj; Huka, Martin; Latika, Attila; Brath, Henrich; Almassy, Ambroz; Hajzer, Viktoria; Durmis, Julius; Toma, Stefan; Sebesta, Radovan [Synthesis, 2012, vol. 44, # 15, p. 2424 - 2430]
[7]Rehak, Juraj; Huka, Martin; Latika, Attila; Brath, Henrich; Almassy, Ambroz; Hajzer, Viktoria; Durmis, Julius; Toma, Stefan; Sebesta, Radovan [Synthesis, 2012, vol. 44, # 15, p. 2424 - 2430]
[8]Rehak, Juraj; Huka, Martin; Latika, Attila; Brath, Henrich; Almassy, Ambroz; Hajzer, Viktoria; Durmis, Julius; Toma, Stefan; Sebesta, Radovan [Synthesis, 2012, vol. 44, # 15, p. 2424 - 2430]
[9]Rehak, Juraj; Huka, Martin; Latika, Attila; Brath, Henrich; Almassy, Ambroz; Hajzer, Viktoria; Durmis, Julius; Toma, Stefan; Sebesta, Radovan [Synthesis, 2012, vol. 44, # 15, p. 2424 - 2430]
[10]Hayashi, Yujiro; Ogasawara, Shin [Organic Letters, 2016, vol. 18, # 14, p. 3426 - 3429]
[11]Hajzer, Viktória; Fišera, Roman; Latika, Attila; Durmis, Július; Kollár, Jakub; Frecer, Vladimír; Tučeková, Zuzana; Miertuš, Stanislav; Kostolanský, František; Varečková, Eva; Šebesta, Radovan [Organic and Biomolecular Chemistry, 2017, vol. 15, # 8, p. 1828 - 1841]
[12]Current Patent Assignee: NELSON MANDELA UNIVERSITY - WO2020/183281, 2020, A1
[13]Current Patent Assignee: SHANDONG UNIVERSITY - CN112812033, 2021, A

13
[ 196618-13-0 ]
[ 204255-11-8 ]

Yield	Reaction Conditions	Operation in experiment
89.9%	With phosphoric acid; In ethanol; at -18.8℃; for 17h;	(g) Preparation of ethyl (3R,4R,5S)-4-N-Acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate [1:1] A 500 ML 3-necked round-bottomed jacketed flask equipped with an overhead (paddle) stirrer, an addition funnel with nitrogen inlet and a septum with thermocouple, is charged with a solution of 9.40 g (0.08153 mol) of 85% phosphoric acid, followed by 120 ML of absolute EtOH. The solution is heated to 52 C. The crude ethyl (3R,4R,5S)-4-N-Acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate solution from (f) is warmed to 25 C., then approximately 2/3 of the solution is rapidly added to the crystallization vessel.The crystallization mixture is seeded with 102 mg of oseltamivir phosphate and crystallization occurs immediately.The slurry is aged 30 minutes before the remainder of the aminoacetamide solution is added over 30 minutes.The slurry is cooled to -18.8 C (-20 C. jacket) over 15 h and aged 2 h.A 600 ML jacketed, fritted funnel with a N2 sweep (set point of -17 C.) is used for the isolation.The slurry is poured into the funnel and as soon as the solvent front reaches the top of the cake, the crystallization vessel is rinsed with acetone (50 ML) and poured on top of the cake.The wet cake is washed with acetone (450 ML) followed by heptane (350 ML).The product is dried in vacuo (45 C. and ~20 mm Hg with a N2 sweep for 18 h) to yield 29.86 g (89.9% yield) of ethyl (3R,4R,5S)-4-N-Acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate [1:1] as a colorless solid.
88.6%	With phosphoric acid; In ethanol; at 50 - 55℃;	EXAMPLE 2; Preparation of Crystalline Form B of the Compound of Formula I16.9 g of phosphoric acid were mixed with 700 mL ethanol in a nitrogen purged 1000 mL glass reactor fitted with a mechanic stirrer and heated to 50 to 55 C. A solution of 45.8 g of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester in 250 mL of ethanol was added to the phosphoric acid solution within 3 to 5 minutes under stirring. The result clear solution was cooled to -40 C. within 1 hour without seeding. The obtained crystal suspension was slowly stirred at -40 C. over night. The suspension was filtered and washed with 240 mL of acetone and 300 mL of n-heptane. The crystal was then dried in vacuum under maximal temperature of 50 C. 53 g of fine white crystal form B was obtained, correspond to a yield of 88.6%.
85%	With phosphoric acid; In ethanol; at 60℃; for 3h;	A solution of amine 1 (19 mg, 0.061 mmol) in ethanol (1 mL) was added slowly to a hot (60 C) solution of phosphoric acid (85 %, 11.5 mg, 0.061 mmol) in ethanol (0.2 mL). The resulting mixture was stirred for 3h. After cooling to 0 C, the precipitates were collected by filtration and rinsed with cold acetone (2 x 5 mL) to give tamiflu as a white crystal (21 mg, 85 %).1H NMR (CDCl3, 400 MHz): delta 6.86 (s, IH), 4.34 (d, J= 8.9 Hz, IH), 4.25 (dq, J= 1.5 Hz, J = 7.2 Hz, 2H), 4.07 (dd, J= 9.0 Hz, J = 11.7 Hz, IH), 3.74 (t, J = 6.5 Hz, IH), 3.63-3.54 (m, IH), 2.97 (dd, J1)2 = 5.4 Hz, J1)3 = 17.3 Hz, IH) 2.56-2.49 (m, IH), 2.01 (s, IH), 1.58-1.47 (m, 4H), 1.29 (t, J= 7.1 Hz, 3H), 0.87 (dt, Jlj2 = 7.4 Hz, J1)4 = 17.6 Hz, 6H), 13C NMR (D2O, 100 MHz): delta 175.2, 167.4, 137.8, 127.6, 84.3, 75.1, 62.4, 52.6, 49.1, 28.1, 25.4, 25.0, 22.3, 13.3, 8.5, 8.4; 31P NMR (162 MHz, D2O) delta 0.65; HR/MS (ESI) calculated for C16H29N2O4 [M+H+], 313.2127, found 313.2122.

82%	With phosphoric acid; In ethanol; at 0 - 50℃;	20% H3PO4 in EtOH (0.02 mL) was added in the solution of oseltamivir free base (25 mg, 0.08 mmol) in EtOH (0.5 mL). The mixture was stirred and heated to 50 ?C for 30 min and then cooled to 0 ?C. The solvent was removed and the residue was purified by short column chromatography eluted with MeOH to gave oseltamivir phosphate as a white solid (27 mg, 82%).
70%	With phosphoric acid; In ethanol; at 60℃; for 3h;	To a solution of 13 (10 mg) in ethanol (1 mL) and added a hot (60 C) solution of phosphoric acid (3 mg) in ethanol (1 mL). The reaction mixture was heated and stirred at 60 C for 3 h. After cooling to 0 C, the precipitates were collected by filtration and rinsed with cold acetone (2*1 mL) to afford oseltamivir phosphate (1) (9 mg, 70%) as a white crystal.
7.6%	With phosphoric acid; In ethanol;	Example 13; [Show Image] As shown in the chemical equation 20, after the 1-cyclohexene-1-carboxylic acid derivative (26a) (18.9 mg, 60.5 mumol) was dissolved in ethanol (450 ml), phosphoric acid (ethanol 1 M solution, 60.5 ml) was added, and condensation was performed under reduced pressure, so that a crystal was obtained. This crystal was washed with ethyl acetate and was then recrystallized from ethanol. The obtained crystal was washed twice with acetone, so that a phosphate (27a) (3.3 mg, 8.0 mumol, Y. 7.6%) was obtained in the form of a white crystal. The spectrum data of this phosphate (27a) is as shown below and coincided with the spectrum data of an authentic sample of oseltamivir. In addition, the spectrum data of the compounds (25a) and (26a) coincided with that obtained from a compound derived from the authentic sample of oseltamivir. Furthermore, since the optical rotation of the compound (25a) coincided with that of a compound having an allyl carbamate group derived from the amino group at the 5-position of the authentic sample of oseltamivir, the absolute configuration represented by each chemical formula was confirmed. 1H NMR (D2O):delta(ppm) 6.91 (s, 1H), 4.38 (brd, J = 8.3 Hz, 1H), 4.31 (m, 2H), 4.11 (dd, J = 11.9, 9.5 Hz, 1H), 3.62 (m, 2H),3.02(dd, J = 17.2, 5.8 Hz, 1H), 2.58 (m, 1H), 2.14 (s, 3H), 1.70-1.45 (m, 4H), 1.34 (t, J = 7.0 Hz, 3H), 0.94 (t, J = 7.8 Hz, 3H), 0.90 (t, J = 7.8 Hz, 3H).
	With phosphoric acid; In ethanol; at 55℃;Product distribution / selectivity;	A solution of azide 11a (170 mg, 0.5 mmol) in ethanol (20 niL) was treated with Lindlar's catalyst (100 mg) under an atmosphere of hydrogen for 16 h at room temperature. The reaction mixture was filtered through Celite, and rinsed with ethanol. The filtrate was evaporated under reduced pressure to give colorless foam (155 mg), which was dissolved in ethanol (3 mL) and added slowly in portions to a hot (550 C) solution of phosphoric acid (85%, 115 mg, 0.6 mmol) in ethanol (5 mL). Crystallization commenced within minutes. After cooling to o C, the precipitates were collected by filtration and rinsed with cold acetone (2 x) to afford 1 (187 mg, 91% yield). White crystal, mp 189-1910 C [lit. (Fukuta et al., J. Am. Chem. Soc. 2006,128, 6312-6313) mp 184-1860 C]; [alpha]D20 = -35.8 (c = 1, H2O) [lit.(Rohloff et al., . J. Org. Chem. 1998, 63, 4545-4550.) [alpha] = -39.9 (c = 1, H2O); or lit. (Fukuta et al., 2006) [alpha]D22 = -30.5 (c = 0.480, H2O)]; IR (neat) 3501, 1734, 1612, 1150 cm-i; 1H NMR (600 MHz, D2O) delta 6.91 (1 H, s), 4.39 (1 H, d, J =8.0 Hz), 4.32-4.30 (2 H, m), 4.11 (1 H, dd, J = 10.5, 5.7 Hz), 3-67"3-59 (2 H, m),3.01 (1 H, dd, J = 17.4, 5.4 Hz), 2.60-2.56 (1 H, m), 2.14 (3 H, s), 1.61-1.50 (4 H, m), 1.34 (3 H, t, J = 7.1 Hz), 0.94 (3 H, t, J = 7.3 Hz), 0.89 (3 H, t, J = 7.3 Hz); «C NMR (150 MHz, D2O) delta 178.1, 170.3, 140.7, 130.4, 87.2, 77.9, 65.2, 55.4, 52.0, 30.9, 28.3, 27.9, 25.2, 16.1, 11.36, 11.30; 3phi NMR (162 MHz, D2O) delta 0.43; HRMS calcd for CiOH29N2O4 (M+- H3PO4 + H): 313.2127, found: m/z 313.2123. Anal. Calcd for CiH3iN2theta8P: C, 46.83; H, 7.61; N, 6.83. Found: C, 46.70; H, 7.69; N, 6.74.
	With phosphoric acid; In ethyl acetate; acetone; at 20℃; for 4h;Heating / reflux;Product distribution / selectivity;	Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (8.5 gm) was dissolved in tetrahydrofuran (130 ml) and then triphenyl phosphine (10.5 gm) and water (50 ml) are added. The contents were heated to reflux, refluxed for 5 hours and then distilled off the solvent under vacuum. To the reaction mass added ethyl acetate (80 ml), washed with 30% sodium chloride solution (50 ml) and distilled off the solvent completely under vacuum. Acetone (130 ml) was added to the residue, heated to reflux, under reflux the mixture of H3PO4 (3 gm) and ethyl acetate (50 ml) was slowly added during 1 hour and then refluxed for 1 hour. The reaction mass was cooled to 25 C. and stirred for 2 hours at 20-25 C. Filtered the solid, washed with acetone (10 ml) and dried at 60-65 C. for 4 hours to yield 6.5 gm of oseltamivir phosphate (HPLC Purity: 99.6%).
	With phosphoric acid; In ethanol; acetone; at 20℃; for 5.5h;Heating / reflux;Product distribution / selectivity;	Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohex-ene-1-carboxylate (8.5 gm) was added to pyridine (200 ml) and then bubbled H2S gas for 3 hours at 25-35 C. Stopped the bubbling of H2S gas and then the reaction mixture was stirred for 5 hours at 25-35 C. The reaction mass was flushed with N2 gas for 20-30 minutes and distilled off the solvent completely under reduced pressure keeping the bath temperature below 50 C. To the residue added ethyl acetate (100 ml) and washed with 30% sodium chloride solution (50 ml). Distilled off the ethyl acetate completely under reduced pressure. Acetone (100 ml) was added to the residue, heated to reflux, under reflux the mixture of H3PO4 (3.2 gm) and ethanol (25 ml) was slowly added during 1 hour 30 minutes and then refluxed for 2 hours. The reaction mass was cooled to 25 C. and then stirred for 2 hours at 20-25 C. Filtered the solid, washed with acetone (10 ml) and dried at 60-65 C. for 4 hours to give 6.9 gm of oseltamivir phosphate (HPLC purity: 99.8%).
997 mg	With phosphoric acid; In ethanol; water; ethyl acetate; at 20 - 50℃;	Compound 9 (0.90 g, 2.66 mmol) was dissolved in aqueous tetrahydrofuran (20 mL, THF/H2O = 10:1). Triphenylphosphine (0.77 g, 2.94 mmol) was added in portions at room temperature. After the mixture was heated at reflux and stirring was continued for 8 h. Solvents were removed by vacuum distillation, and the residue was cooled down to room temperature. The residue was then dissolved in a mixed solvent of ethyl acetate (3.5 mL) and ethanol (1.5 mL). After aqueous phosphoric acid (368 mg, 85% w/w, 3.19 mmol) was added, the mixture was warmed to 50 C, and stirring was continued for 2 h at 50 C. The reaction mixture was cooled down to room temperature and stirred for a further 8 h. White crystals were formed and precipitated. After suction and twice rinsing with ethyl acetate, the white crystals were dried under vacuum at 50 C overnight to furnish the title compound oseltamivir phosphate 1 (997 mg, 2.43 mmol) in 91% yield. The characterization data of compound 1 were identical with those of the sample obtained in our previous articles.31,32
0.34 g	With phosphoric acid; In ethanol; ethyl acetate; at 50℃; for 2h;	A solution of compound 8 (460.0mg, 1.005mmol) in DMSO (8mL) was heated to 80C. Fine powdered Cs2CO3 (815.0mg, 2.501mmol) was added quickly, and the mixture was stirred at 80C for 15min. An aqueous solution of acetic acid (50% w/w, 3mL) was added, and stirring was continued at 80C for 20min. After the mixture was cooled down to room temperature, ethyl acetate (30mL) and an aqueous solution of K2CO3 (20% w/w, 15mL) were added. After the mixture was vigorously stirred for 10min, the two phases were separated, and the aqueous phase was extracted twice with ethyl acetate (2×20mL). The organic extracts were combined and dried over anhydrous MgSO4. Evaporation of the solvent under vacuum gave a pale yellow oily residue, which was dissolved in a mixed solvent of ethyl acetate (4mL) and ethanol (4mL). Phosphoric acid (85%, 130.0mg, 1.128mmol) was then added, and the resulting suspension was heated and stirred at 50C for 2h. The suspension was cooled down to room temperature, and then allowed to stand overnight. White crystals were collected on a Buchner funnel by suction and washed twice with ethyl acetate (2×1mL). After being dried overnight in warm air, oseltamivir phosphate 1 (0.340g, 0.828mmol) was obtained in 82% yield. The characterization data of compound 1 were identical with those of the sample obtained in our previous report.(a), (b), (c)and(d)
	With phosphoric acid; In ethanol; acetone;Reflux;	[0102] A phosphoric acid salt of the compound expressed by the Structural Formula (I) can be obtained in the following manner. Specifically, a solution of the compound expressed by the Structural Formula (I) in acetone is refluxed and treated with phosphoric acid in absolute ethanol. Crystallization commences immediately and after cooling to 0 C. for 12 hours the precipitate is collected by filtration to afford the phosphoric acid salt of the compound expressed by the Structural Formula (I) as colorless needles.
	With phosphoric acid; In ethanol; at 45 - 50℃; for 0.75h;	The above formula (II) is dissolved in 240 ml of absolute ethanol at room temperature, and the temperature is raised to 45 to 50 C, and the addition is completed over 60 minutes.Dissolve a mixed solution of 13.4 g of 85% phosphoric acid in 150 ml of absolute ethanol, and stir at 45 to 50 C for 45 minutes; slowly cool down,4.0h was lowered to 0 C, stirred at -5 to 0 C for 60 minutes, suction filtered, and the filter cake was rinsed with 60 ml of absolute ethanol and drained. Vacuum drying Drying (45 ~ 50 C) for 6 h, obtained a white solid (I) crude. The crude product of formula (I) is dissolved in 180 ml of absolute ethanol + 30 ml of pure at room temperature. In a mixed solvent of water, the temperature is raised to 45 to 50 C, the temperature is maintained for 60 minutes, and the mixture is rapidly filtered while the mother liquor is at 45. Concentrated to a solid precipitate at C; add 180 ml of absolute ethanol, continue to concentrate at 45 C to a paste; add 180 ml of absolute ethanol, Warm up, maintain 45 ~ 50 C and continue to stir for 60 minutes; adjust the stirring speed to 75 rev / min, slowly cool down, 2.5 h will drop the temperature The mixture was stirred at -0 to 0 C for 120 minutes to 0 C; filtered, and the filter cake was rinsed with 60 ml of anhydrous ethanol and drained. Dry at 45~50C vacuum After drying for 6 hours, the white solid (I) oseltamivir phosphate was obtained.The total yield was 65.8% and the purity was 99.8%.

Reference： [1]Patent: US2004/180933,2004,A1 .Location in patent: Page/Page column 11
[2]Patent: US2009/176886,2009,A1 .Location in patent: Page/Page column 4
[3]Patent: WO2009/78813,2009,A1 .Location in patent: Page/Page column 43
[4]Chemistry - A European Journal,2010,vol. 16,p. 4533 - 4540
[5]Tetrahedron Letters,2012,vol. 53,p. 6209 - 6211,3
[6]Tetrahedron,2015,vol. 71,p. 2393 - 2399
[7]Patent: EP2050752,2009,A1 .Location in patent: Page/Page column 18-19
[8]Angewandte Chemie - International Edition,2008,vol. 47,p. 5788 - 5791
[9]Patent: WO2009/29888,2009,A2 .Location in patent: Page/Page column 56
[10]Patent: US2009/54682,2009,A1 .Location in patent: Page/Page column 3
[11]Patent: US2009/54682,2009,A1 .Location in patent: Page/Page column 3
[12]Angewandte Chemie - International Edition,2009,vol. 48,p. 5760 - 5762
Angew. Chem., Int. Ed.,2009,vol. 121,p. 5871 - 5873
[13]Tetrahedron Letters,2010,vol. 51,p. 3208 - 3210
[14]Tetrahedron Asymmetry,2011,vol. 22,p. 1692 - 1699
[15]Tetrahedron Asymmetry,2013,vol. 24,p. 638 - 642
[16]Organic Process Research and Development,2004,vol. 8,p. 86 - 91
[17]Russian Chemical Bulletin,2013,vol. 62,p. 163 - 170
Izv. Akad. Nauk, Ser. Khim.,2013,vol. 62,p. 165 - 171,7
[18]Patent: US2014/51756,2014,A1 .Location in patent: Paragraph 0102
[19]Patent: CN109627180,2019,A .Location in patent: Paragraph 0020; 0025; 0026; 0030; 0034; 0035 0039; 0043

14
[ 204255-11-8 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium hydrogencarbonate In water at 20℃; for 0.0833333h; Inert atmosphere;	3 4.1.3 Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (3) To a solution of oseltamivir phosphate (1.0 g, 2.43 mmol) in water (30 mL) was added a saturated solution of sodium bicarbonate (10 mL). The reaction mixture was stirred for 5 min at room temperature. The mixture was extracted with DCM/MeOH mixture (3:1; 4 * 10 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish the free base of oseltamivir (0.75 g, 98% yield). The product was used without further purification. 1H NMR (300 MHz, CDCl3) δ 6.78 (t, J = 2.1 Hz, 1H), 6.26 (d, J = 8.3 Hz, 1H), 4.34-4.10 (m, 3H), 3.55 (dt, J = 10.3, 8.4 Hz, 1H), 3.37 (dd, J = 17.7, 12.0 Hz, 1H), 3.26-3.08 (m, 1H), 2.76 (dd, J = 17.7, 5.1 Hz, 1H), 2.26-2.08 (m, 1H), 2.04 (s, 3H), 1.58 (s, 2H), 1.55-1.44 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H), 0.90 (td, J = 7.4, 3.8 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 171.1, 166.4, 137.8, 129.5, 81.7, 77.6, 77.2, 76.7, 75.0, 60.8, 58.9, 49.3, 33.7, 26.2, 25.7, 23.6, 14.2, 9.6, 9.3. HR-ESI-MS calculated for C16H29O4N2 (M + H)+ 313.2122, found 313.2122.
	Stage #1: oseltamivir phosphate In dichloromethane; water at 25 - 30℃; for 0.166667h; Stage #2: With ammonia In dichloromethane; water Stage #3: In n-heptane at 25 - 30℃; for 1h;	1.a; 1.b Example 1; Step-(a); :Oseltamivir phosphate (20 gm, HPLC purity: 97%) is stirred with water (100 ml) and methylene chloride (100 ml) for 10 minutes at 25 - 300C and then pH of the mass is adjusted to 9 - 10 with liquor ammonia. Separated the layers, the organic layer is subjected to carbon treatment and filtered on hiflo bed. Washed the hiflo bed with methylene chloride (20 ml) and then distilled the organic layer under vacuum at 400C to give 16.5 gm of oseltamivir free base as a residue. Step-(b):To the residue obtained in step-(a) is added n-heptane (100 ml) and stirred for 1 hour at 25 - 300C. Filtered the solid and dried to give 13 gm of pure oseltamivir free base (HPLC Purity: 99.2%, Melting Range: 102.5 - 103.90C).
	Stage #1: oseltamivir phosphate In dichloromethane; water at 25 - 30℃; for 0.166667h; Stage #2: With ammonia In dichloromethane; water Stage #3: In n-heptane; toluene at 20 - 30℃; for 3.5h;	2 Example 2; The residue (5 gm, obtained as per the process described in step-(a) of example 1) is dissolved in toluene (10 ml), n-heptane (70 ml) is slowly added to the solution for 30 minutes to 1 hour at 20 - 300C and then stirred for 2 hours at 20 - 300C. Filtered the solid, washed with n-heptane (20 ml) and dried to yield pure oseltamivir free base (HPLC Purity: 99.3%).

In dichloromethane; water at 20℃; for 0.75h;

9 A stirred solution of oseltamivir phosphonate 100 mg, in 50 mL DCM was treated with 50 mL water, Na2CO3 (60 mg). The white solution was stirred over a period of 45 minutes at room temperature. The combined aqueous and organic layers were extracted with dichloro methane (100 mL) and the organic phase was dried over Na2SO4 and the combined organic phase was evaporated in a rotary evaporator to yield the product oseltamivir as a liquid. This oseltamivir was used without further purification in the next step. Oseltamivir amine was coupled with Fmoc-PEG-acid (16 atoms) in the presence of EDC, HOBt and DIPEA in DCM. The solution was stirred over a period of 16 h at room temperature. The crude product was purified by silica column chromatography using a 8:2 mixture of DCM and hexane. The combined fractions were evaporated and dried on a rotary evaporator to obtain the product as a yellow oil. A solution of 20% piperidine in dichloromethane was added to the above a yellow oil and stirred for 30 min. The crude product was purified by preparative RP-HPLC using aqueous CH3CN, then freeze-dried to yield the desired compound as a pale yellow resin.

Reference： [1]Albinaña, Carlos Berenguer; MacHara, Aleš; Rezacov, Pavlína; Pachl, Petr; Konvalinka, Jan; Kozísek, Milan [European Journal of Medicinal Chemistry, 2016, vol. 121, p. 100 - 109]
[2]Current Patent Assignee: HETERO DRUGS LIMITED - WO2007/77570, 2007, A1 Location in patent: Page/Page column 4
[3]Current Patent Assignee: HETERO DRUGS LIMITED - WO2007/77570, 2007, A1 Location in patent: Page/Page column 4
[4]Current Patent Assignee: PURDUE UNIVERSITY SYSTEM - US9250238, 2016, B2 Location in patent: Page/Page column 84; 85; 86

15
[ 367252-68-4 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	With trifluoroacetic acid In dichloromethane at 20℃; for 4h; Inert atmosphere;	38 Embodiment 38 The reactant was dissolved in dichloromethane (1 mL), TFA (50 mmol) was added under the protection of argon at room temperature. The reaction mixture was stirred for 4 h at room temperature and then pH value of the mixture was adjusted to 12 by aqueous ammonia. The mixture was extracted by chloroform for three times, the organic phase was washed by brine, dried by anhydrous magnesium sulfate. The solvent was removed by vacuum evaporation and the product was given. Yield: 92%. Spectral analysis data is according to embodiment 19.
90%	Stage #1: (3R,4R,5S)-ethyl 4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate With hydrogenchloride; water In ethanol at 50℃; for 1h; Stage #2: With sodium hydrogencarbonate In water
13.8 mg	With hydrogenchloride In tetrahydrofuran; ethyl acetate for 0.05h;

	With hydrogen bromide In acetic acid at 20℃; for 20h;
	With trifluoroacetic acid In dichloromethane at 20℃; for 1h; Inert atmosphere;
	With trifluoroacetic acid In dichloromethane at 20℃; for 1h;

Reference： [1]Current Patent Assignee: LIANHE CHEMICAL TECHNOLOGY CO., LTD. - US2014/221662, 2014, A1 Location in patent: Paragraph 0167-0168
[2]Location in patent: experimental part Arai, Takuya; Konno, Fujiko; Ogawa, Masanao; Zhang, Ming-Rong; Suzuki, Kazutoshi [Journal of labelled compounds and radiopharmaceuticals, 2009, vol. 52, # 9, p. 350 - 354]
[3]Morita, Masataka; Sone, Toshihiko; Yamatsugu, Kenzo; Sohtome, Yoshihiro; Matsunaga, Shigeki; Kanai, Motomu; Watanabe, Yasuyoshi; Shibasaki, Masakatsu [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 2, p. 600 - 602]
[4]Zutter, Ulrich; Iding, Hans; Spurr, Paul; Wirz, Beat [Journal of Organic Chemistry, 2008, vol. 73, # 13, p. 4895 - 4902]
[5]Yamatsugu, Kenzo; Yin, Liang; Kamijo, Shin; Kimura, Yasuaki; Kanai, Motomu; Shibasaki, Masakatsu [Angewandte Chemie - International Edition, 2009, vol. 48, # 6, p. 1070 - 1076]
[6]Wichienukul, Pawinee; Akkarasamiyo, Sunisa; Kongkathip, Ngampong; Kongkathip, Boonsong [Tetrahedron Letters, 2010, vol. 51, # 24, p. 3208 - 3210]

16
[ 1041262-68-3 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrazine In ethanol at 68℃; for 10h;
100%	With hydrazine In ethanol at 68℃; for 10h; Inert atmosphere;
86%	With hydrazine In ethanol at 68℃; for 11h; Schlenk technique; Inert atmosphere;	1.5 (5)(3R,4R,5S)-4-acetylamino-5-(1,3-dioxoisoindol-2-yl)-3-(pentyl-3-yloxy)cyclohexyl-1 -Ethyl ene-1-carboxylate () was prepared by deprotection reaction to prepare oseltamivir. 10mL dried Shrek tube was added to (3R, 4R, 5S)-4-acetamido-5-(1,3- Dioxyisoindol-2-yl)-3-(pentyl-3-yloxy)cyclohex-1-ene-1-carboxylic acid ethyl ester () (22.0mg, 0.05mmol), evacuated Argon, add 1mL of absolute ethanol, add 1mol/L of hydrazine in ethanol solution (250uL, 0.25mmol), react at 68 for 11 hours, after the reaction is completed, add 10mL of ether to the solution to precipitate the precipitate, and filter with suction to obtain the filtrate The precipitate was discarded, the solvent was removed from the filtrate, and the resulting product was purified by silica gel column chromatography to obtain a yellow oil (13.0 mg, 86%), which was oseltamivir; the silica gel used for silica gel column chromatography was 200-300 Mesh silica gel, the eluent is a mixed solvent with a volume ratio of dichloromethane: methanol = 5:1.

Reference： [1]Trost, Barry M.; Zhang, Ting [Angewandte Chemie - International Edition, 2008, vol. 47, # 20, p. 3759 - 3761]
[2]Trost, Barry M.; Zhang, Ting [Chemistry - A European Journal, 2011, vol. 17, # 13, p. 3630 - 3643]
[3]Current Patent Assignee: SHANDONG UNIVERSITY - CN112812033, 2021, A Location in patent: Paragraph 0130; 0165-0170

17
phosphoric acid [ No CAS ]
[ 196618-13-0 ]
[ 204255-11-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	In ethanol; water at 50 - 55℃; for 1.5 - 2h;	Preparation of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)cyclohex-1-enecarboxylic acid ethyl ester (I) phosphate (1:1)To a solution of 17.0 g of ortho phosphoric acid (85% in water) and 400 mL of EtOH was warmed to 50-55 C. in a dry and nitrogen purged 1000 mL glass reactor fitted with a mechanical stirrer, a condenser, and a 500 mL dropping funnel was added a solution 0.147 mol of ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (I) and 250 mL of EtOH with stirring. After fast addition (10-15 min) of two thirds (ca. 160 mL) of the total volume of this solution, the addition was stopped and the supersaturated clear solution was seeded with 0.2 g of previously obtained ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (1:1). Immediately crystallization commenced. The resulting thick suspension was stirred for 45-60 min at 5-55 C. The remaining amine solution was slowly added (45-60 min) to the suspension at 50-55 C. The feeder was rinsed with 20 mL of EtOH. Subsequently the thick suspension was continuously cooled to 12-20 C. in about 4 h (cooling speed=10 C./h). To complete the crystallization stirring was continued at 12-20 C. for additional 2+-1 h. Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (1:1) was isolated by pressure filtration (0.3 bar nitrogen overpressure, Dacron filter cloth). The crystalline product was washed twice with 240 mL of acetone and twice with 300 mL of n-heptane at RT. Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (1:1) was dried in vacuo (ca. 20 mbar) at a maximum temperature of 50 C. until constant weight. Yield: 54-55 g (88-91%) of the title product in the form of colorless needles with an assay of=99 wt. % (sum of impurities <0.5 wt. %, single impurities ?0.1 wt. %). IR (NJL) 3352, 3164, 2923, 2854, 1724, 1663, 1551, 1463, 1263, 1132 cm-1. MS (ion spray) MH+ 313.1, MNa+ 335.3

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2009/76296, 2009, A1 Location in patent: Page/Page column 9

18
(1S,2R,3S,4R,5S)-ethyl 4-acetamido-5-amino-3-(pentan-3-yloxy)-2-(p-tolylthio)cyclohexanecarboxylate [ No CAS ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate In ethanol at 23℃; for 4h;
91%	With potassium carbonate In ethanol at 23℃; for 4h;	25 <Reaction Example 25; Preparation of (-)-Oseltamivir> Potassium carbonate (195.4 mg, 1.4 mmol) was added to a solution of the compound 18 (8.8 mg, 0.02 mmol) in ethanol (2 mL) at 23°C. The reaction mixture was stirred for 4 hrs before filtration. After removing excess ethanol under reduced pressure, 2 N hydrochloric acid was added to the residue at 0°C. The aqueous layer was washed with ethyl acetate followed by adjustment to pH of 11 with 28% ammonium hydroxide in water. The aqueous layer was extracted three times with 10% methanol-trichloromethane. The combined organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to afford (-)-oseltamivir (compound 1, 5.7 mg, yield 91%). All spectral data were identical with reported data. 1H NMR (400 MHz, CDCl3) δ 6.78 (t, J = 2.0 Hz, 1H), 5.62 (d, J = 7.6 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.15-4.20 (m, 1H), 3.52 (q, J = 8.0 Hz, 1H), 3.34 (quintet, J = 5.6 Hz, 1H), 3.24 (dt, J = 5.2, 10.0 Hz, 1H), 2.75 (dd, J = 17.6, 5.2 Hz, 1H), 2.15 (ddt, J = 17.6, 10.0, 2.8 Hz, 1H), 2.04 (s, 3H), 1.40-1.60 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H), -NH2 undetected; 13C NMR (100 MHz, CDCl3) δ 170.9, 166.3, 137.5, 129.6, 81.7, 74.8, 60.8, 59.0, 49.2, 33.6, 26.3, 25.8, 23.7, 14.2, 9.5, 9.3; IR (film) νmax 3276, 3077, 2965, 2936, 2877, 1715, 1655, 1558, 1464, 1374, 1303, 1244, 1195, 1127, 1064, 1031, 944, 861, 778, 736 cm-1; HRMS (ESI) [M+Na]+ calculated for [C16H28N2NaO4]+: 335.1941, found: 335.1934; [α]23D -54.9 (c 0.68, CHCl3).
45.2 mg	Stage #1: (1S,2R,3S,4R,5S)-ethyl 4-acetamido-5-amino-3-(pentan-3-yloxy)-2-(p-tolylthio)cyclohexanecarboxylate With ammonia In ethanol at 0℃; for 0.166667h; Inert atmosphere; Stage #2: With potassium carbonate In ethanol at 23℃; for 6h; Inert atmosphere;

80.5 mg	Stage #1: (1S,2R,3S,4R,5S)-ethyl 4-acetamido-5-amino-3-(pentan-3-yloxy)-2-(p-tolylthio)cyclohexanecarboxylate With ammonia In ethanol at 0℃; for 0.25h; Inert atmosphere; Stage #2: With potassium carbonate In ethanol at 20℃; for 6h; Inert atmosphere;
1.49 g	With potassium carbonate at 20℃;
34 mg	With ammonia; potassium carbonate at 20℃; for 14h;
	Stage #1: (1S,2R,3S,4R,5S)-ethyl 4-acetamido-5-amino-3-(pentan-3-yloxy)-2-(p-tolylthio)cyclohexanecarboxylate With ammonia In ethanol at -20℃; for 0.0833333h; Stage #2: With potassium carbonate In ethanol at 20℃; for 6h;	19 Embodiment 19 The reactant (1 mmol) was dissolved in ethanol, zinc powder (50 mmol) and trimethylchlorosilane (30 mmol) were added under the protection of argon at room temperature. The reaction mixture was stirred for 4 h at 70° C. and then was cooled to -20° C. After NH3 gas was bubbled for 5 min at -20° C., the reaction temperature was raised to room temperature and then potassium carbonate (20 mmol) was added. And the reaction mixture was stirred for 6 h. The solvent was removed by vacuum evaporation, and 1N hydrochloric acid solution was added to dissolve. The solution was washed by ethyl acetate, and the pH value was adjusted to 12 by ammonia, extracted by chloroform for three times. The organic phase was washed by brine, dried by anhydrous magnesium sulfate, and after removing the solvent the product was given by vacuum evaporation. Yield: 92%. NMR analysis: NMR (400 MHz, CDCl3) δ 6.78 (t, J=2.0 Hz, 1H), 5.62 (d, J=7.6 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.15-4.20 (m, 1H), 3.52 (q, J=8.0 Hz, 1H), 3.34 (quintet, J=5.6 Hz, 1H), 3.24 (dt, J=5.2, 10.0 Hz, 1H), 2.75 (dd, J=17.6, 5.2 Hz, 1H), 2.15 (ddt, J=17.6, 10.0, 2.8 Hz, 1H), 2.04 (s, 3H), 1.40-1.60 (m, 4H), 1.29 (t, J=7.2 Hz, 3H), 0.90 (t, J=7.2 Hz, 3H), 0.89 (t, J=7.2 Hz, 3H); mass spectrometry: MS (m/z) 312.4 (M+); specific rotation: [α]D22=-54.9 (c 1.40, CHCl3).

Reference： [1]Ishikawa, Hayato; Suzuki, Takaki; Orita, Hideo; Uchimaru, Tadafumi; Hayashi, Yujiro [Chemistry - A European Journal, 2010, vol. 16, # 42, p. 12616 - 12626]
[2]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - EP2301911, 2011, A1 Location in patent: Page/Page column 41
[3]Ishikawa, Hayato; Suzuki, Takaki; Hayashi, Yujiro [Angewandte Chemie - International Edition, 2009, vol. 48, # 7, p. 1304 - 1307]
[4]Weng, Jiang; Li, Yong-Bo; Wang, Rui-Bin; Li, Feng-Quan; Liu, Can; Chan, Albert S. C.; Lu, Gui [Journal of Organic Chemistry, 2010, vol. 75, # 9, p. 3125 - 3128]
[5]Location in patent: scheme or table Vaxelaire, Carine; Winter, Philipp; Christmann, Mathias [Angewandte Chemie - International Edition, 2011, vol. 50, # 16, p. 3605 - 3607]
[6]Mukaiyama, Takasuke; Ishikawa, Hayato; Koshino, Hiroyuki; Hayashi, Yujiro [Chemistry - A European Journal, 2013, vol. 19, # 52, p. 17789 - 17800]
[7]Current Patent Assignee: LIANHE CHEMICAL TECHNOLOGY CO., LTD. - US2014/221662, 2014, A1 Location in patent: Paragraph 0123-0124

19
[ 1196490-17-1 ]
[ 1196490-21-7 ]
[ 1052063-39-4 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate In tetrahydrofuran; ethanol at -30 - 20℃;	9 Example 9: major product minor productsCompound 16 (32 mg, 0.07 mmol) was dissolved in 0.5 mL ethanol and 0.1 mL THF and cooled to - 30 0C. Sodium borohydride (14 mg, 0.37 mmol) was added in small portions. The reaction was stirred for 5 h at - 30 0C and slowly warmed to room temperature before it was stirred for another 12 h, concentrated at reduced pressure, and partitioned between CH2CI2 and water. The organic phase was dried over MgSO4, filtered and evaporated. Purification by flash column chromatography (CH2CI2ZMeOH 96:4 to 4:1) afforded compound 17 as the major product and a mixture of oseltamivir isomers 4a and 4b. 4a and 4b mixture: Rf 0.40 (CH2CI2/MeOH 8:2); 1H NMR (600 MHz, CDCI3) δ = 7.14 ((J1 J = 5.1 Hz, 1 H), 6.83 (d, J = 5.1 Hz, 1 H), 5.45 (bs, N-H), 4.15 (q, J = 7.2 Hz, 2 H), 3.83 (m, 1 H), 3.68 (m, 1 H), 3.39 (quint, J = 5.7 Hz, 1 H), 2.87 (dd, J = 5.1 Hz, J = 17.1 Hz, 1 H)1 2.25 (m, 1 H), 1.96 (s, 3 H), 1.40 (m, 4 H), 1.19 (t, J = 7.2 Hz, 3 H), 0.76 (t, J = 7.2 Hz1 3 H), 0.75 (t, J = 7.2 Hz1 3 H) ppm.

Reference： [1]Current Patent Assignee: BROCK UNIVERSITY - WO2009/137916, 2009, A1 Location in patent: Page/Page column 60

20
(1S,2R,3S,4R,5S)-4-acetylamino-3-(1-ethylpropoxy)-5-nitro-2-p-tolylsulfanylcyclohexanecarboxylic acid ethyl ester [ No CAS ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: (1S,2R,3S,4R,5S)-4-acetylamino-3-(1-ethylpropoxy)-5-nitro-2-p-tolylsulfanylcyclohexanecarboxylic acid ethyl ester With chloro-trimethyl-silane; zinc In ethanol at 23 - 70℃; for 2h; Inert atmosphere; Stage #2: With ammonia In ethanol at 0℃; for 0.166667h; Stage #3: With potassium carbonate In ethanol at 23℃; for 6h;
81%	Stage #1: (1S,2R,3S,4R,5S)-4-acetylamino-3-(1-ethylpropoxy)-5-nitro-2-p-tolylsulfanylcyclohexanecarboxylic acid ethyl ester With chloro-trimethyl-silane; zinc In ethanol at 70℃; for 2h; Inert atmosphere; Stage #2: With ammonia In ethanol at 0℃; for 0.166667h; Inert atmosphere; Stage #3: With potassium carbonate In ethanol at 23℃; for 9h; Inert atmosphere;
80%	Stage #1: (1S,2R,3S,4R,5S)-4-acetylamino-3-(1-ethylpropoxy)-5-nitro-2-p-tolylsulfanylcyclohexanecarboxylic acid ethyl ester With chloro-trimethyl-silane; zinc In ethanol at 70℃; for 2h; Stage #2: With ammonia; potassium carbonate In ethanol at 20℃; for 6h;	1.2 (2) Synthesis of oseltamivir: To a solution of C in ethanol (5 mL) was added trimethylchlorosilane (1.14 mL, 37.2 mmol) at room temperature and active zinc dust (0.975 g, 15 mmol) was carefully added. The mixture was stirred at 70 ° C for 2 hours, then ammonia gas was bubbled at 0 ° C for 15 minutes followed by potassium carbonate (0.826 g, 6.02 mmol) and the resulting mixture was stirred at room temperature for 6 hours. The ethanol was removed under reduced pressure at 0 ° C Two equivalents of hydrochloric acid (10 mL) was added. The reaction mixture was poured into ethyl acetate (25 mL) and neutralized with 28% liquid ammonia. The aqueous phase was extracted three times with 10% methanol in chloroform (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the final product oseltamivir (0.075 g, 96% ee, 80% yield).

	Multi-step reaction with 2 steps 1: hydrogenchloride; zinc / ethanol; water / 3 h / 23 °C / Inert atmosphere 2: potassium carbonate / ethanol / 4 h / 23 °C
	Multi-step reaction with 2 steps 1.1: chloro-trimethyl-silane; zinc / ethanol / 70 °C 1.2: 0 °C 2.1: potassium carbonate / 20 °C
	Multi-step reaction with 2 steps 1: chloro-trimethyl-silane; zinc / 2 h / -15 - 70 °C 2: ammonia; potassium carbonate / 14 h / 20 °C
	Multi-step reaction with 2 steps 1.1: zinc; chloro-trimethyl-silane / ethanol / 4 h / 70 °C / Inert atmosphere 2.1: ammonia / ethanol / 0.08 h / -20 °C 2.2: 6 h / 20 °C

Reference： [1]Zhu, Shaolin; Yu, Shouyun; Wang, You; Ma, Dawei [Angewandte Chemie - International Edition, 2010, vol. 49, # 27, p. 4656 - 4660]
[2]Location in patent: experimental part Ishikawa, Hayato; Bondzic, Bojan P.; Hayashi, Yujiro [European Journal of Organic Chemistry, 2011, # 30, p. 6020 - 6031]
[3]Current Patent Assignee: HANGZHOU NORMAL UNIVERSITY - CN107304171, 2017, A Location in patent: Paragraph 0044-0046; 0051; 0052; 0056; 0057; 0061; 0062
[4]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - EP2301911, 2011, A1
[5]Vaxelaire, Carine; Winter, Philipp; Christmann, Mathias [Angewandte Chemie - International Edition, 2011, vol. 50, # 16, p. 3605 - 3607]
[6]Mukaiyama, Takasuke; Ishikawa, Hayato; Koshino, Hiroyuki; Hayashi, Yujiro [Chemistry - A European Journal, 2013, vol. 19, # 52, p. 17789 - 17800]
[7]Current Patent Assignee: LIANHE CHEMICAL TECHNOLOGY CO., LTD. - US2014/221662, 2014, A1

21
[ 949164-64-1 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With acetic acid; zinc at 20℃; for 34h; Inert atmosphere;
71%	Stage #1: ethyl (3R,4R,5S)-4-acetamido-5-nitro-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate With acetic acid; zinc In ethanol at 70℃; Inert atmosphere; Reflux; Stage #2: With ammonium hydroxide In ethanol; water at 20℃; Inert atmosphere;
	With hydrogenchloride In water at 50℃; for 1h; Inert atmosphere;

With chloro-trimethyl-silane; acetic acid; zinc In diethyl ether for 8h; Reflux;

Reference： [1]Location in patent: experimental part Rehak, Juraj; Huka, Martin; Latika, Attila; Brath, Henrich; Almassy, Ambroz; Hajzer, Viktoria; Durmis, Julius; Toma, Stefan; Sebesta, Radovan [Synthesis, 2012, vol. 44, # 15, p. 2424 - 2430]
[2]Weng, Jiang; Li, Yong-Bo; Wang, Rui-Bin; Li, Feng-Quan; Liu, Can; Chan, Albert S. C.; Lu, Gui [Journal of Organic Chemistry, 2010, vol. 75, # 9, p. 3125 - 3128]
[3]Hayashi, Yujiro; Ogasawara, Shin [Organic Letters, 2016, vol. 18, # 14, p. 3426 - 3429]
[4]Hajzer, Viktória; Fišera, Roman; Latika, Attila; Durmis, Július; Kollár, Jakub; Frecer, Vladimír; Tučeková, Zuzana; Miertuš, Stanislav; Kostolanský, František; Varečková, Eva; Šebesta, Radovan [Organic and Biomolecular Chemistry, 2017, vol. 15, # 8, p. 1828 - 1841]

22
[ 196618-13-0 ]
(aS)-2'-methoxy-1,1'-binaphthalene-8-carboxaldehyde [ No CAS ]
C₃₈H₄₂N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With aluminum oxide In dichloromethane at 20℃; for 42h; Inert atmosphere;

Reference： [1]Fukui, Hiroki; Fukushi, Yukiharu [Organic Letters, 2010, vol. 12, # 12, p. 2856 - 2859]

23
[ 196618-13-0 ]
(aR)-2'-methoxy-1,1'-binaphthalene-8-carboxaldehyde [ No CAS ]
C₃₈H₄₂N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With aluminum oxide In dichloromethane at 20℃; for 42h; Inert atmosphere;

Reference： [1]Fukui, Hiroki; Fukushi, Yukiharu [Organic Letters, 2010, vol. 12, # 12, p. 2856 - 2859]

24
[ 1197396-47-6 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: (3R,4R,5S)-ethyl-4-(N-acetylacetamide)-5-(1,3-dioxoisoindolin-2-yl)-3-(3-pentyloxy)cyclohex-1-ene carboxylate With hydrazine hydrate In ethanol at 50℃; for 14h; Inert atmosphere; Stage #2: With hydrogenchloride; water In ethanol Stage #3: With ammonium hydroxide In water	12 <Reaction Example 12; Preparation of (-)-Oseltamivir (Compound 1) > Hydrazine monohydrate (15 μL, 0.31 mmol) was added to a solution of the compound 10 (30 mg, 0.062 mmol) in ethanol (0.5 mL) at 23°C under argon atmosphere. The reaction mixture was stirred for 14 hrs at 50°C before being quenched with 1 N hydrochloric acid (3 mL). The water phase was washed with ethyl acetate followed by an adjustment to pH 11 with 28% ammonium hydroxide in water. The organic phase was extracted with 10% methanol/trichloromethane, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to afford (-)-oseltamivir (compound 1, 18.5 mg, 96%). 1H NMR (400 MHz, CDCl3) δ 6.78 (t, J = 2.0 Hz, 1H), 5.62 (d, J = 7.6 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.15-4.20 (m, 1H), 3.52 (q, J = 8.0 Hz, 1H), 3.34 (quintet, J = 5.6 Hz, 1H), 3.24 (dt, J = 5.2, 10.0 Hz, 1H), 2.75 (dd, J = 17.6, 5.2 Hz, 1H), 2.15 (ddt, J = 17.6, 10.0, 2.8 Hz, 1H), 2.04 (s, 3H), 1.40-1.60 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H), -NH2 undetected; 13C NMR (100 MHz, CDCl3) δ 170.9, 166.3, 137.5, 129.6, 81.7, 74.8, 60.8, 59.0, 49.2, 33.6, 26.3, 25.8, 23.7, 14.2, 9.5, 9.3; IR (film) νmax 3276, 3077, 2965, 2936, 2877, 1715, 1655, 1558, 1464, 1374, 1303, 1244, 1195, 1127, 1064, 1031, 944, 861, 778, 736 cm-1; HRMS (ESI) [M+Na]+ calculated for [C16H28N2NaO4]+. 335.1941, found: 335.1934; [α] 23D -54.9 (c 0.68, CHCl3).

Reference： [1]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - EP2301911, 2011, A1 Location in patent: Page/Page column 32-33

25
[ 1362750-80-8 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
53.2 mg	Stage #1: C₁₉H₃₅N₂O₄P With hydrogenchloride; water In dichloromethane; toluene at 20℃; for 4h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water; toluene	A 1M solution of trimethylphosphine in toluene (640 μl, 0.64 mmol) was added dropwise to a solution of azido derivative 17 (144 mg, 0.46 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 2 hours. The iminophosphorane 20 was formed according to LC-MS (MW: 358.42, found: m/z 359.1 [M++H]). A 1M solution of hydrochloric acid in water (10 ml) was then added. The reaction mixture was vigorously stirred at room temperature for 4 hours and the pH was adjusted to 10 by using saturated NaHCO3 solution. The mixture was extracted by dichloromethane (2x40 ml). The water layer was washed by ethyl acetate (3x40 ml) and 5% methanol in dichloromethane (50 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Oseltamivir ethyl ester 21 was obtained (53.2 mg, yield 40.3%) as a brown viscous liquid.

Reference： [1]Kongkamnerd, Jarinrat; Cappelletti, Luca; Prandi, Adolfo; Seneci, Pierfausto; Rungrotmongkol, Thanyada; Jongaroonngamsang, Nutthapon; Rojsitthisak, Pornchai; Frecer, Vladimir; Milani, Adelaide; Cattoli, Giovanni; Terregino, Calogero; Capua, Ilaria; Beneduce, Luca; Gallotta, Andrea; Pengo, Paolo; Fassina, Giorgio; Miertus, Stanislav; De-Eknamkul, Wanchai [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 6, p. 2152 - 2157]

26
[ 196618-13-0 ]
[ 1363339-68-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide In 1,4-dioxane; water at 20℃; for 4h;	The reaction was performed on a small scale (6.3 mg of amino ester 8) in a small vial for further lyophilization and delivery to biological testing. An aqueous KOH solution (1M, 0.0527 mL, 0.0527 mmol, 3 equivalents), immediately followed by dioxane (0.527 mL) was added to compound 21, at room temperature, and an HPLC-MS chromatogram was recorded at t=0. The reaction mixture was then stirred at room temperature, and its progress was checked periodically by HPLC-MS, after 4 hours the reaction was complete (HPLC-MS). The reaction mixture was then lyophilized to get compound PMC 34 (4, oseltamivir) as a potassium salt; the excess of KOH was not removed, as biological testing was to be performed in a buffer solution.

Reference： [1]Kongkamnerd, Jarinrat; Cappelletti, Luca; Prandi, Adolfo; Seneci, Pierfausto; Rungrotmongkol, Thanyada; Jongaroonngamsang, Nutthapon; Rojsitthisak, Pornchai; Frecer, Vladimir; Milani, Adelaide; Cattoli, Giovanni; Terregino, Calogero; Capua, Ilaria; Beneduce, Luca; Gallotta, Andrea; Pengo, Paolo; Fassina, Giorgio; Miertus, Stanislav; De-Eknamkul, Wanchai [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 6, p. 2152 - 2157]

27
[ 1443055-49-9 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3R,4R,5S)-ethyl 4-acetylamino-3-(pentan-3-yloxy)-5-(2,2,2-trichloroacetamido)cyclohex-1-enecarboxylate With caesium carbonate In dimethyl sulfoxide at 80℃; for 0.25h; Stage #2: With acetic acid In water; dimethyl sulfoxide at 80℃; for 0.333333h;	4.8. Oseltamivir phosphate 1 A solution of compound 8 (460.0mg, 1.005mmol) in DMSO (8mL) was heated to 80°C. Fine powdered Cs2CO3 (815.0mg, 2.501mmol) was added quickly, and the mixture was stirred at 80°C for 15min. An aqueous solution of acetic acid (50% w/w, 3mL) was added, and stirring was continued at 80°C for 20min. After the mixture was cooled down to room temperature, ethyl acetate (30mL) and an aqueous solution of K2CO3 (20% w/w, 15mL) were added. After the mixture was vigorously stirred for 10min, the two phases were separated, and the aqueous phase was extracted twice with ethyl acetate (2×20mL). The organic extracts were combined and dried over anhydrous MgSO4. Evaporation of the solvent under vacuum gave a pale yellow oily residue, which was dissolved in a mixed solvent of ethyl acetate (4mL) and ethanol (4mL). Phosphoric acid (85%, 130.0mg, 1.128mmol) was then added, and the resulting suspension was heated and stirred at 50°C for 2h. The suspension was cooled down to room temperature, and then allowed to stand overnight. White crystals were collected on a Buchner funnel by suction and washed twice with ethyl acetate (2×1mL). After being dried overnight in warm air, oseltamivir phosphate 1 (0.340g, 0.828mmol) was obtained in 82% yield. The characterization data of compound 1 were identical with those of the sample obtained in our previous report.(a), (b), (c)and(d)

Reference： [1]Nie, Liang-Deng; Wang, Fei-Feng; Ding, Wei; Shi, Xiao-Xin; Lu, Xia [Tetrahedron Asymmetry, 2013, vol. 24, # 11, p. 638 - 642]

28
[ 6217-54-5 ]
[ 196618-13-0 ]
(3R,4R,5S)-ethyl 4-acetamido-5-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42.8%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	17 Example 17Preparation of (3R,4R,5S)-ethyl 4-acetamido-5-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa- -hexaenamido)-3-(pentaii-3-yloxy)cyclohex-l-enecarboxylate (IV-1): (4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid (197 mg, 0.64 mmol) was taken up in 10 mL of CH2CI2along with HOBt (95 mg, 0.70 mmol), EDCI (135 mg, 70 mmol), tamiflu (200 mg, 0.64 mmol) and TEA (194 mg, 1.92 mmol). The resulting reaction mixture was stirred at room temperature overnight. It was then diluted with CH2CI2(10 mL) and washed with saturated aq. NH4CI (3 x 10 mL) and brine (3 x 10 mL). The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The resulting residue was purified by HLPC to afford 160 mg of (3R,4R,5S)-ethyl 4-acetamido-5- ((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19-hexaenamido)-3-(pentan-3-yloxy)cyclohex- 1 -enecarboxylate (Yield: 42.8%).MS calculated for C38H58N205: 622.88; Found: 623.50 [M+H]+. H NMR (400 MHz, CDC13) δ 0.87-0.99 (m, 9 H), 1.25-1.31 (t, j=7.2 Hz, 3 H), 1.49-1.56 (m, 4 H), 1.98 (s, 3 H), 2.06-2.10 (m, 2 H),.2.17-2.22 (m, 2 H), 2.33-2.38 (m, 2 H), 2.73-2.86 (m, 11 H), 3.35-3.39 (m, 1 H), 3.99-4.13 (m, 3 H), 4.12-4.23 (m, 2 H),5.30-5.42 (m, 12 H), 5.63-5.66 (d, J = 8 Hz, 1 H),6.36-6.39 (d, J = 8 Hz, 1 H), 6.80 (s,l H).
42.8%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	18 Preparation of (3R,4R,5S)-ethyl 4-acetamido-5-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (IV-1) Example 18 Preparation of (3R,4R,5S)-ethyl 4-acetamido-5-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (IV-1) (4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid (197 mg, 0.64 mmol) was taken up in 10 mL of CH2Cl2 along with HOBt (95 mg, 0.70 mmol), EDCI (135 mg, 70 mmol), tamiflu (200 mg, 0.64 mmol) and TEA (194 mg, 1.92 mmol). The resulting reaction mixture was stirred at room temperature overnight. It was then diluted with CH2Cl2 (10 mL) and washed with saturated aq. NH4Cl (310 mL) and brine (310 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by HLPC to afford 160 mg of (3R,4R,5S)-ethyl 4-acetamido-5-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (Yield: 42.8%). MS calculated for C38H58N2O5: 622.88. Found: 623.50 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.87-0.99 (m, 9H), 1.25-1.31 (t, J=7.2 Hz, 3H), 1.49-1.56 (m, 4H), 1.98 (s, 3H), 2.06-2.10 (m, 2H), 2.17-2.22 (m, 2H), 2.33-2.38 (m, 2H), 2.73-2.86 (m, 11H), 3.35-3.39 (m, 1H), 3.99-4.13 (m, 3H), 4.12-4.23 (m, 2H), 5.30-5.42 (m, 12H), 5.63-5.66 (d, J=8 Hz, 1H), 6.36-6.39 (d, J=8 Hz, 1H), 6.80 (s, 1H).
42.8%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	17 Preparation of (3R,4R,5S)-ethyl 4-acetamido-5-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (IV-1) (4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid (197 mg, 0.64 mmol) was taken up in 10 mL of CH2Cl2 along with HOBt (95 mg, 0.70 mmol), EDCI (135 mg, 70 mmol), tamiflu (200 mg, 0.64 mmol) and TEA (194 mg, 1.92 mmol). The resulting reaction mixture was stirred at room temperature overnight. It was then diluted with CH2Cl2 (10 mL) and washed with saturated aq. NH4Cl (3×10 mL) and brine (3×10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by HLPC to afford 160 mg of (3R,4R,5S)-ethyl 4-acetamido-5-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (Yield: 42.8%). MS calculated for C38H58N2O5: 622.88. Found: 623.50 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.87-0.99 (m, 9H), 1.25-1.31 (t, J=7.2 Hz, 3H), 1.49-1.56 (m, 4H), 1.98 (s, 3H), 2.06-2.10 (m, 2H), 2.17-2.22 (m, 2H), 2.33-2.38 (m, 2H), 2.73-2.86 (m, 11H), 3.35-3.39 (m, 1H), 3.99-4.13 (m, 3H), 4.12-4.23 (m, 2H), 5.30-5.42 (m, 12H), 5.63-5.66 (d, J=8 Hz, 1H), 6.36-6.39 (d, J=8 Hz, 1H), 6.80 (s, 1H).

Reference： [1]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - WO2013/90420, 2013, A2 Location in patent: Paragraph 00167
[2]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - US2014/288025, 2014, A1 Location in patent: Paragraph 0842; 0843; 0844; 0845
[3]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - US2016/129122, 2016, A1 Location in patent: Paragraph 0717-0720

29
[ 136897-53-5 ]
[ 196618-13-0 ]
(3R,4R,5S)-ethyl 4-acetamido-5-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)acetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	19 Example 19Preparation of (3R,4R,5S)-ethyl 4-acetamido-5-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa- 4,7,10,13,16,19-hexaenamido)acetamido)-3-(peiitaii-3-yloxy)cyclohex-l-enecarboxylate (IV- 3): 2-((4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenamido)acetic acid (580 mg, 1.5 mmol) was taken up in 30 mL of CH2C12along with HOBt (220 mg, 1.7 mmol), EDCI (330 mg, 1.7 mmol), tamiflu (500 mg, 1.6 mmol) and Et3N (450 mg, 4.5 mmol). The resulting reaction mixture was stirred at room temperature overnight. It was then diluted with CH2C12(30 mL) and washed with saturated aq.NELCl (3 x 30 mL) and brine (3 x 30 mL). The organic layer was dried over anhydrous a2S04and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 370 mg of (3R,4R,5S)-ethyl 4-acetamido-5-(2- ((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19-hexaenamido)acetamido)-3-(pentan-3- yloxy)cyclohex-l-enecarboxylate (36 %).MS calculated for C4oH6iN306:679.9; Found: 680.6 [M+H]+.1H MR (400 MHz, CDC13) δ 0.87-1.01 (m, 9 H), 1.27-1.32 (t, J = 9.6 Hz, 3 H), 1.49-1.55 (m, 4 H),1.99 (s, 3 H),2.08-2.11 (m, 2 H), 2.32-2.45 (m, 5 H),.2.78-2.85 (m, 1 1 H), 3.36-3.40 (m, 1 H), 3.86-3.92 (m, 2 H), 4.04-4.08 (m, 3 H), 4.17-4.24 (m, 2 H), 5.31-5.43 (m, 12 H), 5.92-5.94 (d, J=9.6 Hz,l H), 6.29 (s, 1 H), 6.80 (s, 1 H), 7.11-7.13 (d, J = 9.6, 1 H).
36%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	20 Preparation of (3R,4R,5S)-ethyl 4-acetamido-5-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)acetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (IV-3) 2-((4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenamido)acetic acid (580 mg, 1.5 mmol) was taken up in 30 mL of CH2Cl2 along with HOBt (220 mg, 1.7 mmol), EDCI (330 mg, 1.7 mmol), tamiflu (500 mg, 1.6 mmol) and Et3N (450 mg, 4.5 mmol). The resulting reaction mixture was stirred at room temperature overnight. It was then diluted with CH2Cl2 (30 mL) and washed with saturated aq. NH4Cl (330 mL) and brine (330 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 370 mg of (3R,4R,5S)-ethyl 4-acetamido-5-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)acetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (36%). MS calculated for C40H61N3O6: 679.9. Found: 680.6 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.87-1.01 (m, 9H), 1.27-1.32 (t, J=9.6 Hz, 3H), 1.49-1.55 (m, 4H), 1.99 (s, 3H), 2.08-2.11 (m, 2H), 2.32-2.45 (m, 5H), 2.78-2.85 (m, 11H), 3.36-3.40 (m, 1H), 3.86-3.92 (m, 2H), 4.04-4.08 (m, 3H), 4.17-4.24 (m, 2H), 5.31-5.43 (m, 12H), 5.92-5.94 (d, J=9.6 Hz, 1H), 6.29 (s, 1H), 6.80 (s, 1H), 7.11-7.13 (d, J=9.6, 1H).
36%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	19 Preparation of (3R,4R,5S)-ethyl 4-acetamido-5-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)acetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate To a suspension of glycine methyl ester hydrochloride (4 g, 44.9 mmol), EDC (9.47 g, 49.4 mmol), HOBt (6.67 g, 49.4 mmol) and Et3N (13.6 g, 0.135 mol) in 100 mL of CH2Cl2 was added DHA (14 g, 42.7 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was washed with saturated aq. NH4Cl (3×200 mL) and brine (3×200 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 9.8 g of methyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)acetate (55%). To the solution of methyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)acetate (3 g, 7.52 mmol) in 50 mL of THF was added 20 mL of aq. NaOH (5N). The resulting reaction mixture was stirred at room temperature for 2 h and then acidified to pH=2 with 6 N HCl. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 2.54 g of 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)acetic acid (88%). 2-((4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenamido)acetic acid (580 mg, 1.5 mmol) was taken up in 30 mL of CH2Cl2 along with HOBt (220 mg, 1.7 mmol), EDCI (330 mg, 1.7 mmol), tamiflu (500 mg, 1.6 mmol) and Et3N (450 mg, 4.5 mmol). The resulting reaction mixture was stirred at room temperature overnight. It was then diluted with CH2Cl2 (30 mL) and washed with saturated aq. NH4Cl (3×30 mL) and brine (3×30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 370 mg of (3R,4R,5S)-ethyl 4-acetamido-5-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)acetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (36%). MS calculated for C40H61N3O6:679.9. Found: 680.6 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.87-1.01 (m, 9H), 1.27-1.32 (t, J=9.6 Hz, 3H), 1.49-1.55 (m, 4H), 1.99 (s, 3H), 2.08-2.11 (m, 2H), 2.32-2.45 (m, 5H), 2.78-2.85 (m, 11H), 3.36-3.40 (m, 1H), 3.86-3.92 (m, 2H), 4.04-4.08 (m, 3H), 4.17-4.24 (m, 2H), 5.31-5.43 (m, 12H), 5.92-5.94 (d, J=9.6 Hz, 1H), 6.29 (s, 1H), 6.80 (s, 1H), 7.11-7.13 (d, J=9.6, 1H).

Reference： [1]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - WO2013/90420, 2013, A2 Location in patent: Paragraph 00169
[2]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - US2014/288025, 2014, A1 Location in patent: Paragraph 0850; 0851; 0852; 0853
[3]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - US2016/129122, 2016, A1 Location in patent: Paragraph 0725-0728

30
[ 34619-03-9 ]
[ 196618-13-0 ]
[ 367252-68-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In methanol at 0 - 20℃; for 18h;	21 Example 21Preparation of (3R,4R,5S)-4-acetamido-5-amino-N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa- 4,7,10,13,16,19-hexaenamido)ethyl)-3-(pentaii-3-yloxy)cyclohex-l-enecarboxamide (IV-7): Tamiflu (3.12 g, 10 mmol) was taken up in 50 mL of CH3OH and triethylamine (3.03 g, 30 mmol) was added slowly at 0 °C. Di(ieri-butyl) carbonate (2.40 g, 1 1 mmol) was then added. The resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with CH2CI2(50 mL) and washed with saturated aq.NELCl (3 x 50 mL) and brine (3 x 50 mL). The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 3.56g of (3R,4R,5S)-ethyl 4- acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-l -enecarboxylate (86%).
86%	With triethylamine In methanol at 0 - 20℃; for 18h;	22 Example 22 Preparation of (3R,4R,5S)-4-acetamido-5-amino-N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethyl)-3-(pentan-3-yloxy)cyclohex-1-enecarboxamide (IV-7) Tamiflu (3.12 g, 10 mmol) was taken up in 50 mL of CH3OH and triethylamine (3.03 g, 30 mmol) was added slowly at 0° C. Di(tert-butyl) carbonate (2.40 g, 11 mmol) was then added. The resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with CH2Cl2 (50 mL) and washed with saturated aq. NH4Cl (350 mL) and brine (350 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 3.56 g of (3R,4R,5S)-ethyl 4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (86%).

Reference： [1]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - WO2013/90420, 2013, A2 Location in patent: Paragraph 00171
[2]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - US2014/288025, 2014, A1 Location in patent: Paragraph 0858; 0859

31
[ 651324-07-1 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: hydrogenchloride / water; ethanol / 13 - 25 °C 2: trifluoroacetic acid / 1.5 h / 50 °C 3: 1,3-dimethylbarbituric acid; triphenylphosphine; palladium diacetate / ethanol / 2 h / 35 °C / Sealed tube; Inert atmosphere
	Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 1 h / 50 °C 2: 1,3-dimethylbarbituric acid; palladium diacetate; triphenylphosphine / ethanol / 2 h / 20 - 25 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: 1,3-dimethylbarbituric acid; palladium diacetate; triphenylphosphine / ethanol / 2 h / 20 - 25 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 2 h / 35 - 40 °C

With 1,3-dimethylbarbituric acid; palladium diacetate; triphenylphosphine In ethanol; water at 50℃;

1 The crude intermediate of formula (IX), N,N-dimethylbarbituric acid (1.56g, 0.01mol), palladium acetate (22.5mg, 0.1mmol), triphenylphosphine (0.87g,) were added to 25mL without In the water and ethanol, nitrogen is replaced three times to drive off excess air. The system was heated to 50°C to react for 2-3 hours, and the reaction was completed as monitored by TLC. Suction filtration, and the filtrate is dissolved to obtain the intermediate of formula (II).

Reference： [1]Harrington, Peter J.; Brown, Jack D.; Foderaro, Tommaso; Hughes, Robert C. [Organic Process Research and Development, 2004, vol. 8, # 1, p. 86 - 91]
[2]Current Patent Assignee: BRIGHTGENE BIO MEDICAL TECHNOLOGY CO LTD - CN109627180, 2019, A
[3]Current Patent Assignee: BRIGHTGENE BIO MEDICAL TECHNOLOGY CO LTD - CN109627180, 2019, A
[4]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN111747861, 2020, A Location in patent: Paragraph 0061-0073; 0075

32
[ 196618-13-0 ]
oseltamivir hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In ethanol; acetone	[0103] A hydrochloric acid salt of the compound expressed by the Structural Formula (I) can be obtained in the following manner. Specifically, an absolute ethanol solution of a solution of the compound expressed by the Structural Formula (I) in acetone is treated with hydrogen chloride in ethanol. Most of the ethanol is evaporated in vacuo and the oily residue is stirred with ethyl acetate until solid forms. Hexanes are gradually added to the stirred mixture. After one hour at ambient temperature, the solid is collected by filtration, washed with diethyl ether and dried in vacuo, to afford the hydrochloric acid salt of the compound expressed by the Structural Formula (I) as an off-white solid.

Reference： [1]Current Patent Assignee: TOHO UNIVERSITY - US2014/51756, 2014, A1 Location in patent: Paragraph 0103

33
S-(2-naphthylmethyl)thioacetimidate hydrobromide [ No CAS ]
[ 196618-13-0 ]
[ 1431974-59-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	In ethanol at 0 - 20℃; for 1h;
71%	In ethanol at 0 - 20℃; for 1h;	(3R,4R,5S)-4-acetamido-5-(N-acetimidamido)-3-(1-ethylpropoxy)cyclohex-1-en-1-carboxylic acid ethyl ester hydrobromide (2) 1 g of oseltamivir (3.2 mmol) is dissolved in 10 ml of ethanol and the mixture is cooled to 0° C. 1.04 g of S-(naphthylmethyl)acetimidobromid (1.1 equivalents) are added to this solution and then stirred for one hour at room temperature. The mixture is concentrated subsequently in vacuo and taken up in about 80 ml water. This solution is washed with a little diethyl ether and concentrated in vacuo. The product (85%) contains at this point still small amounts of the parent compound, which could be removed by column chromatography (DCM/MeOH, 5-10%) only. Yield: 960 mg (71%) of a white solid. [0108] DC: Rf=0.65 (DCM/MeOH, 9:1) [0109] 1H-NMR (DMSO-d6, 300 MHz): δ/ppm=0.79 (t, 3J=7.4 Hz, 3H), 0.85 (t, 3J=7.4 Hz, 3H), 1.23 (t, 3J=7.1 Hz, 3H), 1.44 (mc, 4H), 1.83 (s, 3H), 2.11 (s, 3H), 2.33 (mc, 1H), 2.67 (dd, 2J=17.6 Hz, 3J=4.7 Hz, 1H), 3.42 (quin, 3J=5.6 Hz, 1H), 3.82 (mc, 1H), 4.05 (mc, 1H), 4.17 (q, 3J=7.1 Hz, 2H), 4.35, (mc, 1H), 6.69 (mc, 1H), 8.04 (br d, 3J=9.0 Hz, 1H), 8.63 (br s, 1H), 9.25, 9.35 (2×br s, 1H). [0110] MS (ESI): m/z=354 [M+H]+

Reference： [1]Schade, Dennis; Kotthaus, Joscha; Riebling, Lukas; Kotthaus, Jürke; Müller-Fielitz, Helge; Raasch, Walter; Koch, Oliver; Seidel, Nora; Schmidtke, Michaela; Clement, Bernd [Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 759 - 769]
[2]Current Patent Assignee: KIEL UNIVERSITY - US2014/288312, 2014, A1 Location in patent: Paragraph 0107-0110

34
[ 683-58-9 ]
[ 196618-13-0 ]
[ 1431974-61-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 4h;
70%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 4h;	(3R,4R,5S)-4-acetamido-5-[N-(N′-hydroxy)acetimidamido]-3-(1-ethylpropoxy)cyclohex-1-en-1-carboxylic acid ethyl ester (4) 465 mg of oseltamivir (1.49 mmol), 290 mg of DIPEA (389 μl, 1.5 equiv) are dissolved in 5 ml of dichloromethane, and cooled to 0° C. Freshly prepared acethydroximoyl chloride (209 mg, 1.5 equiv) is added slowly (dropwise) to this solution. The mixture is stirred for four hours at room temperature, mixed with 15 ml of water, stirred for an additional hour and then separated in a separating funnel. In order to increase the yield of the desired amidoxime, the aqueous phase is extracted four times with dichloromethane. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (DCM/MeOH, 9:1). [0120] Yield: 70% of colorless, crystalline solid [0121] DC: Rf=0.29 (DCM/MeOH, 9:1) [0122] 1H-NMR (DMSO-d6, 300 MHz): [0123] δ/ppm=0.80 (t, 3J=7.4 Hz, 3H), 0.85 (t, 3J=7.4 Hz, 3H), 1.23 (t, 3J=7.1 Hz, 3H), 1.43 (mc, 4H), 1.80 (s, 3H), 1.95 (s, 3H), 2.38 (mc, 1H), 2.62 (dd, 2J=17.4 Hz, 3J=5.0 Hz, 1H), 3.40 (quin, 3J=5.6 Hz, 1H), 3.65 (mc, 1H) 3.78 (dd, 2J=17.4 Hz, 3J=8.7 Hz, 1H), 4.15 (q, 3J=7.1 Hz, 2H), 4.19 (mc, 1H), 6.67, (mc,1H), 6.81 (br d, 1H, 3J=9.1 Hz), 7.99 (d, 1H, 3J=8.6 Hz), 9.73 (br s, 1H). [0124] MS (ESI): m/z=392 [M+Na]+, 370 [M+H]+, 354 [M-OH+H]+. [0125] HRMS (ESI): m/z calcd. for C18H31N3O5 [M+H]+: 370.23365. found: 370.23379.

Reference： [1]Schade, Dennis; Kotthaus, Joscha; Riebling, Lukas; Kotthaus, Jürke; Müller-Fielitz, Helge; Raasch, Walter; Koch, Oliver; Seidel, Nora; Schmidtke, Michaela; Clement, Bernd [Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 759 - 769]
[2]Current Patent Assignee: KIEL UNIVERSITY - US2014/288312, 2014, A1 Location in patent: Paragraph 0119-0125

35
[ 506-68-3 ]
[ 196618-13-0 ]
[ 1431974-62-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium acetate In ethanol at 20℃; for 4h;
93%	With sodium acetate In ethanol at 20℃; for 2h;

Reference： [1]Schade, Dennis; Kotthaus, Joscha; Riebling, Lukas; Kotthaus, Jürke; Müller-Fielitz, Helge; Raasch, Walter; Koch, Oliver; Seidel, Nora; Schmidtke, Michaela; Clement, Bernd [Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 759 - 769]
[2]Current Patent Assignee: KIEL UNIVERSITY - US2014/288312, 2014, A1 Location in patent: Paragraph 0046

36
[ 1135-24-6 ]
[ 196618-13-0 ]
C₂₆H₃₆N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (E)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0℃; for 0.166667h; Inert atmosphere; Stage #2: oseltamivir With 4-methyl-morpholine In tetrahydrofuran at 0 - 20℃; for 25h; Inert atmosphere;	General procedure for the preparation of N-hydroxycinnamoylamides General procedure: In a typical preparation, to a solution of substituted cinnamic acid (3.2 mmol), EDC(0.61 g, 3.2 mmol) and 1-hydroxybenzotriazole (0.43 g, 3.2 mmol) in 10 mL THF, after 10min stirring at 0 °C, the antiviral compound (3.2 mmol) and NMM (0.35 mL, 3.2 mmol),dissolved in 7 mL THF were added. The resultant reaction mixture was stirred for 1 h at 0 °Cand then for 24 h at room temperature, under a nitrogen atmosphere. After completion of thereaction (TLC control - CH2Cl2/CH3OH (3:0.2; 3:0.3); CH2Cl2/EtOAc/CH3OH (3:0.1:0.1)),the THF was evaporated in vacuo, and the residue was diluted with EtOAc and then was successivelywashed with 5 % NaHSO4, NaHCO3 and brine, dried over anhydrous Na2SO4 andevaporated in vacuo. The residue was purified by column chromatography or preparative TLCon silica gel (CH2Cl2/CH3OH) to give the desired compound.

Reference： [1]Chochkova, Maya G.; Georgieva, Assya P.; Ivanova, Galya I.; Nikolova, Nadya; Mukova, Luchia; Nikolaeva-Glomb, Lubomira; Milkova, Tsenka S. [Journal of the Serbian Chemical Society, 2014, vol. 79, # 5, p. 517 - 526]

37
[ 331-39-5 ]
[ 196618-13-0 ]
[ 1656283-98-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: caffeic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0℃; for 0.166667h; Inert atmosphere; Stage #2: oseltamivir With 4-methyl-morpholine In tetrahydrofuran at 0 - 20℃; for 25h; Inert atmosphere;	General procedure for the preparation of N-hydroxycinnamoylamides General procedure: In a typical preparation, to a solution of substituted cinnamic acid (3.2 mmol), EDC(0.61 g, 3.2 mmol) and 1-hydroxybenzotriazole (0.43 g, 3.2 mmol) in 10 mL THF, after 10min stirring at 0 °C, the antiviral compound (3.2 mmol) and NMM (0.35 mL, 3.2 mmol),dissolved in 7 mL THF were added. The resultant reaction mixture was stirred for 1 h at 0 °Cand then for 24 h at room temperature, under a nitrogen atmosphere. After completion of thereaction (TLC control - CH2Cl2/CH3OH (3:0.2; 3:0.3); CH2Cl2/EtOAc/CH3OH (3:0.1:0.1)),the THF was evaporated in vacuo, and the residue was diluted with EtOAc and then was successivelywashed with 5 % NaHSO4, NaHCO3 and brine, dried over anhydrous Na2SO4 andevaporated in vacuo. The residue was purified by column chromatography or preparative TLCon silica gel (CH2Cl2/CH3OH) to give the desired compound.

Reference： [1]Chochkova, Maya G.; Georgieva, Assya P.; Ivanova, Galya I.; Nikolova, Nadya; Mukova, Luchia; Nikolaeva-Glomb, Lubomira; Milkova, Tsenka S. [Journal of the Serbian Chemical Society, 2014, vol. 79, # 5, p. 517 - 526]

38
[ 530-59-6 ]
[ 196618-13-0 ]
C₂₇H₃₈N₂O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: trans-3,5-dimethoxy-4-hydroxycinnamic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0℃; for 0.166667h; Inert atmosphere; Stage #2: oseltamivir With 4-methyl-morpholine In tetrahydrofuran at 0 - 20℃; for 25h; Inert atmosphere;	General procedure for the preparation of N-hydroxycinnamoylamides General procedure: In a typical preparation, to a solution of substituted cinnamic acid (3.2 mmol), EDC(0.61 g, 3.2 mmol) and 1-hydroxybenzotriazole (0.43 g, 3.2 mmol) in 10 mL THF, after 10min stirring at 0 °C, the antiviral compound (3.2 mmol) and NMM (0.35 mL, 3.2 mmol),dissolved in 7 mL THF were added. The resultant reaction mixture was stirred for 1 h at 0 °Cand then for 24 h at room temperature, under a nitrogen atmosphere. After completion of thereaction (TLC control - CH2Cl2/CH3OH (3:0.2; 3:0.3); CH2Cl2/EtOAc/CH3OH (3:0.1:0.1)),the THF was evaporated in vacuo, and the residue was diluted with EtOAc and then was successivelywashed with 5 % NaHSO4, NaHCO3 and brine, dried over anhydrous Na2SO4 andevaporated in vacuo. The residue was purified by column chromatography or preparative TLCon silica gel (CH2Cl2/CH3OH) to give the desired compound.

Reference： [1]Chochkova, Maya G.; Georgieva, Assya P.; Ivanova, Galya I.; Nikolova, Nadya; Mukova, Luchia; Nikolaeva-Glomb, Lubomira; Milkova, Tsenka S. [Journal of the Serbian Chemical Society, 2014, vol. 79, # 5, p. 517 - 526]

39
hexyloxycarbonyl isothiocyanate [ No CAS ]
[ 196618-13-0 ]
(3R,4R,5S)-4-acetamido-5-[N-(N′-n-hexyloxycarbonyl)thioureido]-3-(1-ethylpropoxy)-cyclohex-1-en-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In dichloromethane at 20℃; for 2h;	(3R,4R,5S)-4-acetamido-5-[N-(N′-n-hexyloxycarbonyl)thioureido]-3-(1-ethylpropoxy)-cyclohex-1-en-1-carboxylic acid ethyl ester (7) 500 mg of oseltamivir (1.6 mmol) are dissolved in 50 ml of dry dichloromethane and equimolar amounts of hexyloxycarbonyl isothiocyanate (from an approximately 0.5 M solution in dichloromethane) are slowly added dropwise. After stirring for 2 hours at room temperature it is washed with 1% HCl, water, NaCl solution. The organic phase is dried over Na2SO4 and concentrated on a rotary evaporator. The crude product can be triturated or washed with cyclohexane and is sufficiently pure for the next reaction by this. For elemental analysis, the compound was further purified by silica gel column chromatography (Cy/EtOAc, 6:4). [0137] Yield: 600 mg (75%) of a white-yellowish solid [0138] DC: Rf=0.20 (Cy/EtOAc, 6:4) [0139] 1H-NMR (DMSO-d6, 300 MHz): [0140] δ/ppm=0.79 (t, 3J=7.4 Hz, 3H), 0.84 (t, 3J=7.3 Hz, 3H), 0.87 (t, 3J=6.8 Hz, 3H), 1.23 (t, 3J=7.2 Hz, 3H), 1.30 (mc, 6H), 1.45 (mc, 4H), 1.57 (mc, 2H) 1.80 (s, 3H), 2.30 (dd, 1H, 2J=17.8 Hz, 3J=6.8 Hz), 2.90 (dd, 1H, 2J=17.8 Hz, 3J=5.0 Hz), 3.43 (quin, 1H, 3J=5.4 Hz), 4.07 (mc, 4H), 4.16 (q, 2H, 3J=7.1 Hz), 4.55 (mc, 1H), 6.74 (br s, 1H), 7.91 (br d, 1H, 3J=8.0 Hz), 9.98 (d, 1H, 3J=7.6 Hz), 10.90 (s, 1H). [0141] MS (ESI): [0142] m/z=500 [M+H]+, 483, 412

Reference： [1]Current Patent Assignee: KIEL UNIVERSITY - US2014/288312, 2014, A1 Location in patent: Paragraph 0136-0142

40
[ 196618-13-0 ]
15–(9–fluorenylmethyloxycarbonyl)amino–4,7,10,13–tetraoxa–pentadecanoic acid [ No CAS ]
C₄₂H₅₉N₃O₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h;	9 A stirred solution of oseltamivir phosphonate 100 mg, in 50 mL DCM was treated with 50 mL water, Na2CO3 (60 mg). The white solution was stirred over a period of 45 minutes at room temperature. The combined aqueous and organic layers were extracted with dichloro methane (100 mL) and the organic phase was dried over Na2SO4 and the combined organic phase was evaporated in a rotary evaporator to yield the product oseltamivir as a liquid. This oseltamivir was used without further purification in the next step. Oseltamivir amine was coupled with Fmoc-PEG-acid (16 atoms) in the presence of EDC, HOBt and DIPEA in DCM. The solution was stirred over a period of 16 h at room temperature. The crude product was purified by silica column chromatography using a 8:2 mixture of DCM and hexane. The combined fractions were evaporated and dried on a rotary evaporator to obtain the product as a yellow oil. A solution of 20% piperidine in dichloromethane was added to the above a yellow oil and stirred for 30 min. The crude product was purified by preparative RP-HPLC using aqueous CH3CN, then freeze-dried to yield the desired compound as a pale yellow resin.

Reference： [1]Current Patent Assignee: PURDUE UNIVERSITY SYSTEM - US9250238, 2016, B2 Location in patent: Page/Page column 84; 85; 86

41
[ 108-30-5 ]
C₄₆H₃₉O₅PolS [ No CAS ]
[ 71989-14-5 ]
[ 181954-34-7 ]
[ 196618-13-0 ]
C₃₀H₄₈N₆O₁₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A oseltamivir-PEG-Succinyl-Diaminopropionyl-Asp-Cys-conjugate (a novel water soluble neuraminidase inhibitor for the detection of influenza viruses) has been synthesized for direct attachment to inorganic surfaces. This conjugate was prepared from Fmoc-Cys(4-methoxytrityl)-Wang resin, swollen with CH2Cl2 followed by DMF. A solution of 20% piperidine in DMF was added to the resin, and argon was bubbled for 5 minutes. The resin was washed with DMF and isopropyl alcohol. Formation of free amine was assessed by the Kaiser test. After swelling the resin in DMF, a solution of Fmoc-Asp-(OtBu)-OH, Diaminopropionic acid, succinic anhydride, oseltamivir-amine, and HBTU, HOBt plus DIPEA in DMF was added. Argon was bubbled for 2 hours, and resin was washed with DMF and i-PrOH. The coupling efficiency was assessed by the Kaiser Test. The above sequence was repeated for the 4 required sequential coupling steps. The final compound was cleaved from the resin using a TFA/H2O/iPr3SiH/ethanedithiol cocktail (37:1:1:1) and concentrated under vacuum. The concentrated product was precipitated in diethyl ether and dried under vacuum. The crude product was purified by preparative RP-HPLC using aqueous CH3CN and then freeze-dried to yield the desired compound as a white solid.

Reference： [1]Patent: US9250238,2016,B2 .Location in patent: Page/Page column 129; 130; 131; 132; 133; 134

42
[ 4712-55-4 ]
[ 196618-13-0 ]
C₂₈H₃₇N₂O₇P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With triethylamine In tetrachloromethane at 0℃; for 1h;	7 At 0°C, diphenyl phosphite (234 mg, 1 mmol) was dissolved in carbon tetrachloride (3 mL). After 10 min, a mixture of triethylamine (1 mL) and commercially available oseltamivir drug F (82 mg, 0.2 mmol) was slowly added. Maintain 0°C reaction for 1h. The reaction is basically complete. Column chromatography gave compound G in 48% yield. Compound G was dissolved in a mixed solution of 2 N NaOH (1 mL) and MeOH (1 mL). Stir at room temperature for 12h. After the completion of the reaction, the pH value of the solution was adjusted to a weak acidity by adding a cation exchange resin. The resin was removed by filtration. Solvent was removed. Column chromatography gave compound 2-8 in 45% yield.

Reference： [1]Current Patent Assignee: Sun Yat-sen University; Lu, Gui; Liu, Jinbiao; Nie, Lin - 2016 Location in patent: Paragraph 0082; 0083

43
[ 762-04-9 ]
[ 196618-13-0 ]
C₂₀H₃₇N₂O₇P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With triethylamine In tetrachloromethane at 0℃; for 1h;	9 At 0°C, diethyl phosphite (138 mg, 1 mmol) was dissolved in carbon tetrachloride (3 mL). After 10 min, a mixture of triethylamine (1 mL) and commercially available oseltamivir drug F (82 mg, 0.2 mmol) was slowly added. Maintain 0°C reaction for 1h. The reaction is basically complete. Column chromatography gave compound H in 56% yield. Compound H was dissolved in a mixed solution of 1 N NaOH (1 mL) and THF (1 mL). Stir at room temperature for 12h. After the completion of the reaction, the pH value of the solution was adjusted to a weak acidity by adding a cation exchange resin. The resin was removed by filtration. Solvent was removed. Column chromatography gave compound 2-7 in 83% yield.

Reference： [1]Current Patent Assignee: Sun Yat-sen University; Lu, Gui; Liu, Jinbiao; Nie, Lin - 2016 Location in patent: Paragraph 0088; 0089

44
(3R,4R)-ethyl 4-acetamido-5-nitro-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate [ No CAS ]
[ 1402431-91-7 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
10 % de	With chloro-trimethyl-silane; ethanol; zinc In tetrahydrofuran; toluene at 70℃; for 2h; Flow reactor;	Flow unit 5: Zn reduction All flow units, the same as the previous used, were connected. For the Zn reduction, we conducted as follows. SNAP Empty cartridge 10 g was used. Celite 545 (8 g) and an activated Zn powder (5 g) were charged into the column. After a EtOH solution of TMSCl (0.6 M) was injected to the next micormixer (Comet-X-01) by using the seventh syringe pump at a flow rate of 0.04 mL/min and united with the reaction mixture, the solution was introduced into the column from the bottom to the top, which was heated at 70 °C. The reaction mixture was allowed to flow for 2 hours through the column. This package of column was replaced every 5 h because zinc activity was gradually decreasing. After stabilization, the exiting solution was collected in one-hour fraction, three-hour fraction and five-hour fraction. The fractions were monitored by TLC (CHCl3 : MeOH =4 : 1, compounds were visualized by UV, KMnO4) and checked by 1H NMR analysis after quenched with 28% NH4OH, extracted with MeOH/CHCl3 and concentrated. The yields of the obtained crude products were determined by 1H NMR analysis using 1,3,6-trimethoxybenzene as an internal standard. The result was that desired compound 1 was obtained in 18% yield. There is not much difference between the first one-hour fraction, three-hour fraction and the five-hour fraction. When 3 columns were demonstrated in the same method, the flow systems were continuously operated in 15 h. After stabilization, the exiting solution was collected. Several fractions (column-1; 1 h, 3 h, 5 h, column-2; 6 h, 8 h, 10 h, column-3; 11 h, 13 h,15 h) were monitored and showed almost same data. All fractions were concentrated invacuo. 1N HCl was added to the residue at 0 °C. The aqueous layer was washed with AcOEt. To the aqueous layer was added 28% NH4OH to adjust pH 11. The aqueous layer was extracted three times with 10% MeOH/CHCl3. The combined organic layer was concentrated in vacuo. The residue was dissolved in 10% MeOH/AcOEt, and washed with 10% NaCl in H2O to remove TBAF, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (CHCl3/MeOH = 10/1) to afford the (-)-Oseltamivir (1) (58 mg / 15 h), 13% yield; pale yellow oil, Rf=0.3 (CHCl3/MeOH = 4/1). Spectroscopic data are identified with the publish data (Hayashi, Y.; Ogasawara, S. Org. Lett, 2016, 18, 3426). the details were shown ;1) A column packed with activated Zn and celite (it takes 2 hours to fill with the reaction solution in inside of the column). The column-1 was attached to the flow system. 2) The exiting solution from the column-1 was collected in 3 hours before the column-1was replaced for column-2. At this time, the column-1 was filled with the reaction solution and the column-2 did not contain the solution. 3) It took 2 hours to fill with the reaction solution in the column-2. In this time of waiting, the solution was extruded from the column-1 at 70 °C with co-solvent of toluene and ethanol. As a result, the exiting solution from the column-1 was collected in 5 hours (3 hours + 2 hours). 4) The exiting solution from the column-2 was collected in 3 hours before the column-2 was replaced for column-3. 5) While the column-3 was filled with the reaction solution, the solution was extruded from the column-2 same as the above operation. The exiting solution from the column-2 was collected in 5 hours. 6) The column-3 was continuously demonstrated in 5 hours. Though the reaction solution was remained in the inside of the column-3 after 5 hours, we did not collect the solution in this time.

Reference： [1]Ogasawara, Shin; Hayashi, Yujiro [Synthesis, 2017, vol. 49, # 2, p. 424 - 428]

45
[ 64-19-7 ]
[ 196618-13-0 ]
[ 1191921-01-3 ]

Yield	Reaction Conditions	Operation in experiment
74.5%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate at 20℃;	1 Example 1 (3R,4R,5S)-4-acetylamino-5-acetylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester (II-1) To a 50 mL round bottom flask was added 130 mg (0.417 mmol) of oseltamivir, 238 mg of HATU (0.625 mmol), 182 μL of DIPEA (1.04 mmol) of 30 mg of glacial acetic acid (0.50 mmol), and the reaction was stirred at room temperature. Washed with 1N HCl solution, saturated sodium carbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, purified by column chromatographyThe solid was 110 mg and the yield was 74.5%.
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN106748872, 2017, A Location in patent: Paragraph 0031; 0032; 0033
[2]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

46
(Z)-N'-(([1,1'-biphenyl]-4-yl) methyl)-S-methylisothiourea-N-formate tert-butyl ester [ No CAS ]
[ 196618-13-0 ]
(3R,4R,5S)-5-((Z)-2-([1,1'biphenyl]-4-yl)guanidino)-4-acetamido-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (Z)-N'-(([1,1'-biphenyl]-4-yl) methyl)-S-methylisothiourea-N-formate tert-butyl ester; oseltamivir With triethylamine In acetonitrile at 30℃; for 16h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 6h;	16 (3R, 4R, 5S) -5 - ((Z) -2 - ([1,1'-biphenyl] -4-ylmethyl) guanidino) -4-acetamido-3- (pentane -3-oxo) cyclohexene-1-ene-1-carboxylate (16) WeighedOseltamivir(0.62 g, 2 mmol),(Z) -N '- ([1,1'-biphenyl] -4-yl) methyl) -S-methylisothiourea (0.71 g, 2 mmol)In 30 mL of dry acetonitrile and 5 mL of triethylamine,30 ° C for 16 h (TLC detection reaction finished developing agent: ethyl acetate). The solvent was evaporated, 30 mL of water was added, extracted three times with 30 mL of ethyl acetate, washed with dilute hydrochloric acid and dried over anhydrous magnesium sulfate. The solvent was evaporated and the solvent was evaporated to give a pale yellow oil which was used directly in the next step.

Reference： [1]Current Patent Assignee: SHANDONG UNIVERSITY - CN107056636, 2017, A Location in patent: Paragraph 0256; 0257; 0258; 0259; 0260

47
[ 64-18-6 ]
[ 196618-13-0 ]
C₁₇H₂₈N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

48
[ 144-49-0 ]
[ 196618-13-0 ]
(3R,4R,5S)-4-acetylamino-5-fluoroacetylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

49
[ 381-73-7 ]
[ 196618-13-0 ]
(3R,4R,5S)-4-acetylamino-5-difluoroacetylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

50
[ 76-05-1 ]
[ 196618-13-0 ]
(3R,4R,5S)-4-acetylamino-5-trifluoroacetylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

51
[ 802294-64-0 ]
[ 196618-13-0 ]
(3R,4R,5S)-ethyl 4-acetamido-5-(propionamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

52
[ 79-10-7 ]
[ 196618-13-0 ]
C₁₉H₃₀N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

53
[ 196618-13-0 ]
[ 107-92-6 ]
C₂₀H₃₄N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

54
[ 79-31-2 ]
[ 196618-13-0 ]
C₂₀H₃₄N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

55
[ 196618-13-0 ]
[ 109-52-4 ]
C₂₁H₃₆N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

56
[ 142-62-1 ]
[ 196618-13-0 ]
(3R,4R,5S)-4-acetylamino-5-n-hexanoylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

57
[ 1118-68-9 ]
[ 196618-13-0 ]
C₂₀H₃₅N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

58
[ 622-47-9 ]
[ 196618-13-0 ]
C₂₅H₃₆N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

59
[ 87-51-4 ]
[ 196618-13-0 ]
C₂₆H₃₅N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

60
[ 196618-13-0 ]
[ 501-52-0 ]
(3R,4R,5S)-ethyl 4-acetamido-5-(3-phenylpropionamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

61
[ 140-10-3 ]
[ 196618-13-0 ]
C₂₅H₃₄N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

62
[ 1821-12-1 ]
[ 196618-13-0 ]
(3R,4R,5S)-4-acetylamino-5-(4-phenylbutylamino)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

63
[ 29678-81-7 ]
[ 196618-13-0 ]
(3R,4R,5S)-4-acetamido-5-(R-2-hydroxyl-4-phenylbutylamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic acid [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 141,p. 648 - 656

64
[ 29678-81-7 ]
[ 196618-13-0 ]
C₂₆H₃₈N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃;	General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 141,p. 648 - 656

65
[ 4530-20-5 ]
[ 196618-13-0 ]
C₂₃H₃₉N₃O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

66
Boc-(R)-Ala [ No CAS ]
[ 196618-13-0 ]
C₂₄H₄₁N₃O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;	2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11.

Reference： [1]Wang, Kuanglei; Yang, Fei; Wang, Lihui; Liu, Kemin; Sun, Lu; Lin, Bin; Hu, Yaping; Wang, Boyu; Cheng, Maosheng; Tian, Yongshou [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 648 - 656]

67
tert-butyl (benzamido(methylthio)methylene)carbamate [ No CAS ]
[ 196618-13-0 ]
C₂₉H₄₂N₄O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; mercury dichloride In N,N-dimethyl-formamide at 20℃; Cooling with ice;	1 Synthesis of Intermediate 3: Oseltamivide phosphate (200 mg, 0.82 mmol),Intermediate 2 (241 mg, 0.82 mmol)Triethylamine (274 mg, 2.71 mmol)Dissolved in 3mLDMF solution,Stirred at room temperature, 10min, mercuric chloride (268mg, 0.98mmol) was added in an ice bath,After 5min precipitated, stirred at room temperature overnight,Until the reaction is complete, stop the reaction, cooled to room temperature,Add water, dilute the reaction solution with ethyl acetate, filter through celite, remove the solid precipitate, extract the filtrate twice with ethyl acetate,Washed twice with saturated saline, dried over anhydrous sodium sulfate, concentrated to dryness,Flash column chromatography (PE: EA = 3: 2) gave Intermediate 3.

Reference： [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN106905193, 2017, A Location in patent: Paragraph 0052

68
[ 530-62-1 ]
[ 196618-13-0 ]
ethyl (3R,4R,5S)-4-acetamido-5-(1-(imidazolyl)-aminocarboxamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	In dichloromethane at 0 - 20℃;	4.1.1.1 General procedure for synthesis of intermediates (13) Oseltamivir was dissolved in dichloromethane, then reaction mixture was cooled to 0°C. N, N′-carbonyldiimidazole (1.1 equivalents) was added in batches. After half an hour, the reaction mixture was stirred at room temperature. After reaction completed (judged by TLC), the mixture was washed by saturated ammonium chloride solution and brine successively, dried by sodium sulfate (Na2SO4), filtrate, concentrated in vacuum to get crude product. It was purified by column chromatography to obtain target compound (13). ethyl(3R,4R,5S)-4-acetamido-5-(1H-imidazole-1-carboxamido)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (13). Column chromatography (methanol: dichloromethane=1:40). White powder, 93.0% yield, 1H NMR (600MHz, CDCl3) δ 8.17 (s, 1H), 7.96 (d, J=7.2Hz, 1H), 7.38 (s, 1H), 7.03 (s, 1H), 6.80 (s, 1H), 6.34 (d, J=7.6Hz, 1H), 4.25-4.08 (m, 5H), 3.39 (p, J=5.6Hz, 1H), 2.95 (dd, J=17.9, 5.0Hz, 1H), 2.53-2.43 (m, 1H), 1.97 (s, 3H), 1.57-1.46 (m, 4H), 1.28 (t, J=7.1Hz, 3H), 0.89 (td, J=7.4, 4.1Hz, 6H). LC-MS (ESI): [M+H]+ found 407.1; [M+Na]+ found 429.2; [M-H]- found 404.9.
	In dichloromethane Cooling with ice;	2 Implementation example 2 (3R,4R,5S)-4-acetamido-5-(1-(imidazolyl)-aminocarboxamido)-3-(1-ethylpropoxy)-1-cyclohexene-1- Ethyl carboxylate(II) 500 mg (1.60 mmol) of oseltamivir was added to a 100 mL round bottom flask.Add 30mL of dichloromethane to dissolve, under ice water bath,260 mg (1.60 mmol) of carbonyldiimidazole was added in portions and stirred.After the reaction, the organic phase is washed with a saturated ammonium chloride solution and a saturated sodium chloride solution.Dry over anhydrous sodium sulfate and concentrate to give 530 mg of crude material.The next reaction was directly carried out without purification.
	In dichloromethane at 0 - 20℃;	4.1.1.1 General procedure for synthesis of intermediates (21 and 25) General procedure: Oseltamivir was dissolved in dichloromethane, then reaction mixture was cooled to 0°C. 1,1′-thiocarbonyldiimidazole (or N, N′-carbonyldiimidazole, 1.1 equivalent) was added in batches. After half an hour, the reaction mixture was stirred at room temperature. After reaction completed, the mixture was washed by saturated ammonium chloride solution and brine successively, dried by sodium sulfate, filtrate, concentrated in vacuum to get crude product. It was purified by column chromatography to obtain target compound (21 or 25).

Reference： [1]Zhao, Hongqian; Jiang, Siyuan; Ye, Zhifan; Zhu, Hongxi; Hu, Baichun; Meng, Peipei; Hu, Yanmei; Zhang, Huicong; Wang, Kuanglei; Wang, Jun; Tian, Yongshou [European Journal of Medicinal Chemistry, 2021, vol. 221]
[2]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN109553554, 2019, A Location in patent: Paragraph 0038; 0039; 0040
[3]Chen, Binfeng; Lei, Zaiqiang; Liu, Kemin; Tian, Yongshou; Wang, Jian; Wang, Kuanglei; Yang, Fei; Zhang, Huicong; Zhang, Kun; Zhao, Hongqian; Zhao, Xiaodi; Zhu, Hongxi [European Journal of Medicinal Chemistry, 2020, vol. 200]

69
C₂₀H₃₆N₂O₄ [ No CAS ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid In dichloromethane at 35 - 40℃; for 2h;	2; 3; 4; 5; 6 The crude product of the above formula (III) was dissolved in 45 ml of dichloromethane and added dropwise to 200 ml of trifluoroacetic acid.The temperature was controlled at 35-40 ° C for 2 h.The reaction temperature is ≤50 °C,Concentrate the solvent under reduced pressure.Add toluene to dry three times.The concentrate was added to 200 ml of toluene.200ml purified water,Stir vigorously for 30 minutes,The layers were stood at rest, and the organic layer was washed with 100 ml × 2 purified water, and the aqueous layer was combined. The aqueous layer was quenched with 50 mL x 2 toluene. Add 200ml of dichloromethane to the water layerThe pH was adjusted to 9.0 with a saturated aqueous solution of Na 2CO 3. Let stand layering. The aqueous layer was extracted with 100 ml × 3 dichloromethane.The methylene chloride layer was combined and dried over anhydrous sodium sulfate.Filtration and concentration to obtain 30.3 g of crude oseltamivir free base of formula (II).The yield is 97.0%.The purity is 96.8%.
	With trifluoroacetic acid In dichloromethane at 50℃; for 2h;	1.4; 3; 1; 2 Step (4): The crude intermediate of formula (VI) was dissolved in 100 mL of dichloromethane, added dropwise to trifluoroacetic acid (18.24 g, 0.16 mol), and heated to 50° C. for reaction for 2 hours. After the reaction is completed, it is concentrated on a rotary evaporator, and toluene is added to dry the excess trifluoroacetic acid. The concentrated solution was added with 100 mL of toluene and 100 mL of water, stirred vigorously for 30 min, and allowed to stand for layering. The organic phase was washed with water (100 mL×3), and the organic phase was concentrated under reduced pressure to obtain a crude oily intermediate of formula (II).

Reference： [1]Current Patent Assignee: BRIGHTGENE BIO MEDICAL TECHNOLOGY CO LTD - CN109627180, 2019, A Location in patent: Paragraph 0030; 0033; 0039; 0042; 0048; 0052; 0053
[2]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN111747861, 2020, A Location in patent: Page/Page column 7-12

70
[ 124-63-0 ]
[ 196618-13-0 ]
C₁₇H₃₀N₂O₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine In dichloromethane at 20℃; for 2h;	1 (3R,4R,5S)-4-acetamido-5-methanesulfonamido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (I-1) In a 50 mL round bottom flask, 300 mg (0.960 mmol) of oseltamivir, 89 μL (1.150 mmol) of methanesulfonyl chloride, and 267 μL (1.921 mmol) of triethylamine were added.The mixture was stirred at room temperature for 2 h with 10 mL of dichloromethane. After the reaction,The organic phase is washed with a 1N hydrochloric acid solution, a saturated sodium carbonate solution and a saturated sodium chloride solution.Concentrated and purified by column chromatography to give 300 mg.The yield was 80%.
	With triethylamine In dichloromethane at 0℃;	General Procedure for the Preparation of Compounds 4a-4k and 6i-6k General procedure: Oseltamivir (2, 312.4 mg, 1.0 mmol), TEA (208 µL, 1.5 mmol) and 10 mL CH2Cl2 were charged in a 50 mL round bottom ask, then the corresponding sulfonyl chloride (1.2 mmol) was added dropwise. The mixture was stirred at 0°C until oseltamivir was completely consumed, as indicated by TLC analysis. The organic layer was washed successively with 1N HCl aqueous solution, saturated aq.Na2CO3, and brine. The organic layer was concentrated in vacuo. The crude product was puried by column chromatography to obtain one of the intermediates (3a-3k).

Reference： [1]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN110015979, 2019, A Location in patent: Paragraph 0033-0035
[2]Hu, Yaping; Chen, Binfeng; Lei, Zaiqiang; Zhao, Hongqian; Zhu, Hongxi; Quan, Peng; Tian, Yongshou [Molecules, 2019, vol. 24, # 11]

71
[ 594-44-5 ]
[ 196618-13-0 ]
C₁₈H₃₂N₂O₆S [ No CAS ]