Name: 5123-55-7|N-Pht-Phe-OH|98%
Brand: Ambeed
SKU: A724312
Price: 5.0 USD
Availability: InStock
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1
[ 85-44-9 ]
[ 63-91-2 ]
[ 5123-55-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	In water monomer for 0.5h; microwave irradiation;
97%	at 135 - 140℃; for 2.5h;	(S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoicacid, [(S)-1] General procedure: Compound (S)-1 was prepared according to the reported protocolwith slight modifications [27]. A 250mL round bottomed flask containing a magnetic stirrer and equippedwith a reflux condenser was charged with L-phenylalanine(6.7 g, 40.6 mmol) and phthalic anhydride (6.0 g,40.6 mmol). The resulting mixture was heated to135-140 °C for 2.5 h and after the completion of the reaction,the reaction mixture was allowed to cool down to roomtemperature. The crude product was purified by recrystallizationfrom EtOH/H2O (2:1). This product was obtainedas a white solid; yield 11.1 g (97%); enantiomeric excess93.0%; HPLC retention time 19.8 min; mp 181-183 °C (lit.mp 184-186 °C [27]); 1H NMR (Methanol-d4, 400 MHz) δ7.75 (4H, m, H-Ar), 7.13 (4H, m, H-Ar), 7.07 (1H, m, HAr),5.14 (1H, dd, J = 11.5, 5.3 Hz, CH), 3.50 (2H, m,CHHPh diastereotopic proton); 13C NMR (Methanol-d4,101 MHz) δ 172.1 (C, HO=O), 168.9 (2 C, NC=O), 138.6(C, benzyl), 135.6 (2 CH, Phth), 132.7 (2C, Phth), 129.9(2CHortho, benzyl), 129.5 (2CHmeta, benzyl), 127.8 (CHpara, benzyl), 124.2 (2CH, Phth), 54.5 (CH, CHCO2H), 35.5(CH2, CH2Ph); HRMS (ESI+) m/z calculated forC17H14NO4 296.09228, found 296.09226 (M+ H+).
97%	at 135 - 140℃; for 2.5h;	(S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoicacid, [(S)-1] General procedure: Compound (S)-1 was prepared according to the reported protocolwith slight modifications [27]. A 250mL round bottomed flask containing a magnetic stirrer and equippedwith a reflux condenser was charged with L-phenylalanine(6.7 g, 40.6 mmol) and phthalic anhydride (6.0 g,40.6 mmol). The resulting mixture was heated to135-140 °C for 2.5 h and after the completion of the reaction,the reaction mixture was allowed to cool down to roomtemperature. The crude product was purified by recrystallizationfrom EtOH/H2O (2:1). This product was obtainedas a white solid; yield 11.1 g (97%); enantiomeric excess93.0%; HPLC retention time 19.8 min; mp 181-183 °C (lit.mp 184-186 °C [27]); 1H NMR (Methanol-d4, 400 MHz) δ7.75 (4H, m, H-Ar), 7.13 (4H, m, H-Ar), 7.07 (1H, m, HAr),5.14 (1H, dd, J = 11.5, 5.3 Hz, CH), 3.50 (2H, m,CHHPh diastereotopic proton); 13C NMR (Methanol-d4,101 MHz) δ 172.1 (C, HO=O), 168.9 (2 C, NC=O), 138.6(C, benzyl), 135.6 (2 CH, Phth), 132.7 (2C, Phth), 129.9(2CHortho, benzyl), 129.5 (2CHmeta, benzyl), 127.8 (CHpara, benzyl), 124.2 (2CH, Phth), 54.5 (CH, CHCO2H), 35.5(CH2, CH2Ph); HRMS (ESI+) m/z calculated forC17H14NO4 296.09228, found 296.09226 (M+ H+).

96%	at 140℃; for 0.166667h;
96%	With glacial acetic acid for 4h; Reflux;	31.1 Step 1 To a 1 -necked round-bottom flask (500 mL) equipped with a condenser was charged with L- phenylalanine (25.0 g, 151.3 mmol), phthalic anhydride (22.2 g, 151.3 mmol), and glacial acetic acid (300 mL) in that order. The resulting mixture was refluxed for 4 hrs. The solvent was completely removed in vacuo, and the residue was precipitated from a mixture of ethyl acetate and hexanes to give (S)-2-(l,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (42.8 g, 96%) as a white solid.
95%	With pyridine for 12h; Heating;
93.9%	In toluene at 20℃; for 17.5h; Reflux;
92.6%	With triethylamine In toluene Heating / reflux;	1 Example 1 Preparation of N-phthaloyl (S)-phenvlalanine chloride (X) A 1-L round-bottom flask was charged with 50.19 g of (S)-phenylalanine, 47.3 g of phthalic anhydride, 0.5 mL of triethylamine, and 500 mL of toluene. The mixture was heated to reflux with stirring, and the water removed using a Dean Stark trap. After the water removal was complete, the mixture was cooled to ambient temperature, chilled in an ice bath, and the solid isolated by filtration to give a 103.4 g wet-cake of (IX) (80.3% solids, 83.0 g dry weight basis, 92.6% yield). A 60.47-g portion of the wet-cake was charged to a 1-L flask with 250 mL of toluene and 1 mL of N,N-dimethylformamide. To the slurry was added dropwise 19 mL of oxalyl chloride. After stirring overnight at ambient temperature, the solvent was evaporated to give a 139.7 g residue. The residue was dissolved in 200 g of ethyl acetate to give a 15 wt% solution of the acid chloride (X) in ethyl acetate.
91%	With 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate at 130℃; for 0.0833333h;
91%	at 145℃; for 1h;	1.2.14 Synthesis of Phth-Phe-OH To a 250 L round bottom flask, L-phenylalanine (7.72 g, 46.7 mmol) and phthalic anhydride (6.92 g, 46.7 mmol) were added. The solids were then carefully heated up to 145°C (not above to avoid racemization) and mechanically stirred. Upon heating, the solids started to melt and a brown solid was formed after 1 h indicating completion. The residue was dissolved in hot MeOH (70 mL) stirred and filtered. Cold water (50 mL) was then slowly added to allow crystallization. Pure Phth-Phe-OH was obtained as white crystals after filtration and drying (12.54 g, 91 %). (0436) Formula: C17H13N04; MW: 295.29 g/mol; TLC: Rf = 0.43 (CH2CI2/MeOH 95:5 + 1 % AcOH); HPLC: tR = 2.5 min; LC-MS (ES+): [M-COOH]+ = 249.91 Da, [M+H]+ = 295.90 Da; 1 H NMR: (500 MHz, 298 K, CDCI3): d (ppm) 7.75 (m, 2H, arom. H Phth), 7.70 (m, 2H, arom. H Phth), 7.13 (m, 5H, arom. H Phe), 5.22 (t, 1 H, Ha, J= 8.1 1 ), 3.61 (dd, 2H, CHP, J= 8.60 Hz, J= 1 .21 Hz).
90%	at 150 - 160℃; for 0.166667h;
90%	at 143℃; for 0.5h;
90%	Stage #1: phthalic anhydride; L-phenylalanine With pyridine for 1h; Reflux; Stage #2: With hydrogenchloride In water monomer	42.D 42D. Preparation of (S)-2-(l,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid [0172] A mixture of isobenzofuran-l,3-dione ( 9.0 g , 6.1 mmol, 1.0 eq) and (S)-2- amino-3-phenylpropanoic acid (10.0 g, 6.1 mmol, 1.0 eq) in pyridine (30 ml) was refluxed for lh. The reaction mixture was added to ice-cooled HCl (150 mL H20 and 50 mL cone. HCl). The solid precipitate that formed was collected by filtration, washed with water (3x30 mL), and dried to give (5)-2-(l,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (16.5 g, yield: 90%); LC/MS: m/z (M++l) = 296.
89%	In toluene for 4h; Reflux; Dean-Stark; Inert atmosphere;
87.4%	In N,N-dimethyl-formamide for 0.0333333h; Microwave irradiation;
85%	With triethylamine In toluene at 120℃; for 1h; Molecular sieve; Microwave irradiation;
82%	With N,N-dimethyl-formamide for 0.0125h; microwave irradiation;
74%	In neat (no solvent) at 132℃; for 2h;
72%	at 160℃; for 2h;
64%	at 140℃; for 0.5h;
	With triethylamine; toluene auf Siedetemperatur und Entfernen des entstehenden Wassers;
	at 150℃;
	at 150 - 180℃; for 0.5h;
	With triethylamine In toluene Heating;
	In N,N-dimethyl-formamide at 100℃; for 12h;
	In toluene for 20h; Heating;
	With triethylamine In toluene Reflux;
	at 140 - 150℃; for 0.5h;
	With triethylamine In toluene Heating;
	With triethylamine In toluene for 2h; Reflux;
	In glacial acetic acid at 50℃;
	With glacial acetic acid Reflux; Schlenk technique;
	at 135℃; for 0.5h;
	With glacial acetic acid Schlenk technique; Reflux;
	With glacial acetic acid Reflux; Schlenk technique; Inert atmosphere;
	With glacial acetic acid for 4h; Reflux;	1.1.1 General procedure for preparation of compounds Q1-Q18 General procedure: Phenylalanine or alanine (10 mmol) and anhydride (10 mmol) were heatedand refluxed in 20 mL of acetic acid for 4 h and monitored by TLC. Aftercompletion of the reaction, the solution was stirred and poured into 500 mL ofice water. When the precipitate was appeared, filtering it and then dry it in vacuumdrying oven. Next, the carboxylic acid (5 mmol) which was obtained in theprevious step and podophyllotoxin (6 mmol) were dissolved in dichloromethane(25mL) and stirred for 12 h with DCC (10 mmol) as dehydrator and DMAP (1 mmol) ascatalyst at room temperature. Adding proper amount of silica gel and condensingsolvent by vacuum concentration. Then, collecting target compounds by columnchromatography (V (dichloromethane):V (acetone) =1:50).
	With triethylamine In toluene for 4h; Dean-Stark; Reflux;	13 General Peptide Synthesis Procedures: N-Protection with Phthalimide General procedure: Amino acid (13.5 mmol, 1.0 equiv), phthalic anhydride (13.5 mmol, 1.0 equiv), and triethylamine (1.35 mmol, 0.1 equiv) were dissolved in toluene (70 mL) in an oven dried round bottom flask equipped with a stir bar and a Dean-Stark apparatus. The reaction mixture was heated to reflux for 4 h. Upon cooling, the reaction mixture was concentrated. The residue was dissolved in EtOAc, transferred to a separatory funnel, and washed with 1 M HCl. The organic layer was dried with MgSO4, filtered through Celite, and concentrated. The products were purified via column chromatography on silica gel eluting with hexanes/EtOAc.
	With glacial acetic acid at 50℃;
	With triethylamine In toluene Reflux; Inert atmosphere;
	With triethylamine In toluene Reflux; Inert atmosphere; Dean-Stark;
	With triethylamine In toluene Reflux;
	at 160℃;	Reaction condition a: If the compound of formula If is added in a molar ratio of 1: 2,The reaction at 180 degrees and agitated conditions is ‘abdominal drunk:
	With glacial acetic acid at 70℃; for 12h;
	at 140℃; for 2h;	General Procedure II for the preparation of 1e: A mixture of L-phenylalanine s-e (10 mmol, 1 equiv) and phthalic anhydride (11 mmol,1.1 equiv) was heated at 140 °C for 2 h. After cooling to room temperature, the resulting water and the unreacted phthalic anhydride were washed off by acetone (2 mL) and DCM (2 mL), the resulting solid mixture was then dissolved in anhydrous CH2Cl2 (20 mL), SOCl2 (13 mmol, 1.3 eq) was added and stirred at 55 °C overnight. After the reaction, CH2Cl2 and excess of thionyl chloride were removed in vacuo. The crude acyl chloride was diluted with CH2Cl2 (20 mL), amine (9.2 mmol, 0.92 equiv) and Et3N (13mmol, 1.3 equiv) were added and stirred at room temperature overnight. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the desired amide product 1e.

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[2]Andrade-Jorge, Erik; Rivera-Sánchez, Fernando; Rodríguez, Jessica E.; Lagos-Cruz, Jesús A.; Reyes-Vallejo, Natalia; Villalobos-Molina, Rafael; Gallardo-Ortíz, Itzell A.; Reyes-Ramírez, Adelfo [Medicinal Chemistry Research, 2022, vol. 31, # 6, p. 851 - 866]
[3]Andrade-Jorge, Erik; Rivera-Sánchez, Fernando; Rodríguez, Jessica E.; Lagos-Cruz, Jesús A.; Reyes-Vallejo, Natalia; Villalobos-Molina, Rafael; Gallardo-Ortíz, Itzell A.; Reyes-Ramírez, Adelfo [Medicinal Chemistry Research, 2022, vol. 31, # 6, p. 851 - 866]
[4]Griesbeck, Axel G.; Mauder, Harald; Mueller, Ingrid [Chemische Berichte, 1992, vol. 125, # 11, p. 2467 - 2476]
[5]Current Patent Assignee: THE ROSKAMP INST - WO2020/154420, 2020, A2 Location in patent: Page/Page column 49-50
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[8]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2005/110986, 2005, A1 Location in patent: Page/Page column 8
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[11]Beck; Hoelzl; Schoenenberger [Arzneimittel-Forschung/Drug Research, 1981, vol. 31, # 10, p. 1726 - 1731]
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[29]Location in patent: scheme or table Gondal, Humaira Y.; Mashooda; Ali, Muhammad [Journal of the Korean Chemical Society, 2011, vol. 55, # 4, p. 650 - 655]
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2
[ 623-33-6 ]
[ 5123-55-7 ]
[ 1742-81-0 ]

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 In dichloromethane at 20℃;	Ethyl (S)-(2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl)glycinate (2) To a solution of compound 1 (5 g, 16.9 mmol) in DCM (80 mL), HATU (7.07 g, 18.6 mmol), Gly-OEt·HCl (2.6 g, 18.6 mmol) and DIPEA (8.83 mL, 50.7 mmol) were added, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was washed with 1N HCl solution (80 mL × 3), saturated NaHCO3 solution (80 mL × 3), water (80 mL × 3) and saturated NaCl solution (80 mL × 3). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was crystallized from a minimum amount of hot ether to afford 4.81 g (74.5%) of compound 2. HR-ESI-MS m/z 381.1445 [M+H]+, 403.1264 [M+Na]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.8 Hz, 1H), 7.81-7.79 (m, 4H), 7.19-6.87 (m, 5H), 5.02 (dd, J = 12.0, 4.6 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.92 (dd, J = 17.2, 5.8 Hz, 1H), 3.77 (dd, J = 17.2, 5.8 Hz, 1H), 3.53 (dd, J = 13.9, 4.6 Hz, 1H), 3.36 (dd, J = 13.9, 12.0 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H).
	With dichloromethane; dicyclohexyl-carbodiimide
	With 1,4-dioxane; 1-cyclohexyl-3-(2-morpholino-ethyl)-carbodiimide

	With 1,4-dioxane; 1-cyclohexyl-3-(4-diethyl-aminocyclohexyl)carbodiimide
	With phosphorodichloridous acid ethyl ester; phosphorous acid trimethyl ester
	With 1-chloro-1-ethoxy-ethene; ethyl acetate

Reference： [1]Li, Jing; Zhang, Tao; Sun, Jialin; Ren, Fengxia; Jia, Hongxin; Yu, Zixing; Cheng, Jingchao; Shi, Weiguo [Chinese Chemical Letters, 2022, vol. 33, # 8, p. 4107 - 4110]
[2]Sheehan; Hess [Journal of the American Chemical Society, 1955, vol. 77, p. 1067]
[3]Sheehan; Hlavka [Journal of Organic Chemistry, 1956, vol. 21, p. 439]
[4]Sheehan; Hlavka [Journal of Organic Chemistry, 1956, vol. 21, p. 439]
[5]Young et al. [Journal of the American Chemical Society, 1956, vol. 78, p. 2126,2128]
[6]Heslinga; Arens [Recueil des Travaux Chimiques des Pays-Bas, 1957, vol. 76, p. 982,992]

3
[ 62-53-3 ]
[ 5123-55-7 ]
[ 1195342-68-7 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus trichloride; benzene
	Stage #1: Nα-phthaloyl-L-phenylalanine With oxalyl dichloride In dichloromethane at 0 - 20℃; for 6h; Stage #2: aniline With triethylamine at 20℃; for 0.5h;	4.2. Synthesis: general procedure for compounds 8a-8u General procedure: Compound 3 (1 mmol) added to dry CH2Cl2 (15 mL) and stirredat 0 °C. After that, oxalyl chloride (1.5 mmol) was dripped into themixture and stirred at room temperature for 6 h. After the reaction,the solvent and excess oxalyl chloride was evaporated underreduced pressure. Aromatic primary amines (1 mmol) and triethylamine(0.5 mmol) were added to the mixture and stirred atroom temperature for 0.5 h. After the reaction, the solvent wasevaporated under reduced pressure, and the crude product waspurified by chromatography on silica gel eluted with petroleumether/ethylacetate (V:V 6:1) to offer compound 4. Compound 4(1 mmol) and hydrazine hydrate (3 mmol) were added to ethanol(15 mL) and the mixture was stirred at room temperature for 8 h.After the reaction was completed, the solvent was evaporated underreduced pressure, and the crude product was purified bychromatography on silica gel eluted with petroleum ether/ethylacetate (V: V 3: 1) to obtain compounds 5. Compounds 6(1 mmol) added to dry H2Cl2 (15 mL) was stirred at 0 °C and oxalylchloride (2.0 mmol) was dripped into the mixture and stirred atroom temperature for 6 h. After the reaction, the solvent and excessoxalyl chloride was evaporated under reduced pressure. Compounds5 (2 mmol) and triethylamine (1 mmol) were added to themixture and stirred at room temperature for 18 h. After the reaction,the solvent was evaporated under reduced pressure, and thecrude product was purified by chromatography on silica gel elutedwith petroleum ether/ethyl acetate (V: V 6:1) to offer compounds8a-8u. The structures were confirmed by 1H NMR,13C NMR and HRMS(see Supporting information).

Reference： [1]Bose [Journal of the Indian Chemical Society, 1954, vol. 31, p. 108]
[2]Huang, Ri-Zhen; Liang, Gui-Bin; Huang, Xiao-Chao; Zhang, Bin; Zhou, Mei-Mei; Liao, Zhi-Xin; Wang, Heng-Shan [European Journal of Medicinal Chemistry, 2017, vol. 138, p. 979 - 992]

4
[ 5123-55-7 ]
[ 32150-91-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With thionyl chloride for 1h; Ambient temperature;
93%	With thionyl chloride In toluene at 0℃; for 24h; Inert atmosphere; Reflux;
91%	With thionyl chloride at 45℃; for 2h;	42.E 42E. Preparation of (S)-2-(l,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride [0173] A solution of (S)-2-(l,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (7 g, 2.4 mmol, 1.0 eq) in thionyl chloride (15 ml) was stirred at 45 °C for 2 hours, then the reaction mixture was evaporated to give (S)-2-(l ,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (7 g, yield: 91%).

88%	With thionyl chloride In dichloromethane for 5h; Heating;
87%	With oxalyl dichloride; N,N-dimethyl-formamide In hexane; benzene at 20℃;
80%	With thionyl chloride In dichloromethane for 12h; Heating;
	With phosphorus pentachloride; benzene
	With phosphorus pentachloride In benzene for 1h;
	With thionyl chloride for 0.666667h; Heating;
	With phosphorus pentachloride In 1,2-dichloro-ethane 1.) 30 min, 0 deg C, 2.) 16 h, r. t.;
	With phosphorus pentachloride In benzene at 50℃; for 15h;
	With oxalyl dichloride In N,N-dimethyl-formamide
	With oxalyl dichloride In N,N-dimethyl-formamide; benzene for 1h; Ambient temperature; Yield given;
	With thionyl chloride at 60℃; for 0.833333h;
	With oxalyl dichloride
	With phosphorus pentachloride In toluene at 60℃; for 2h;
	With thionyl chloride In benzene Heating;
	With pyridine; thionyl chloride In tetrachloromethane for 2h; Heating;
	With Dichloromethyl methyl ether Heating;
	With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 20℃;	1 Example 1 Preparation of N-phthaloyl (S)-phenvlalanine chloride (X) A 1-L round-bottom flask was charged with 50.19 g of (S)-phenylalanine, 47.3 g of phthalic anhydride, 0.5 mL of triethylamine, and 500 mL of toluene. The mixture was heated to reflux with stirring, and the water removed using a Dean Stark trap. After the water removal was complete, the mixture was cooled to ambient temperature, chilled in an ice bath, and the solid isolated by filtration to give a 103.4 g wet-cake of (IX) (80.3% solids, 83.0 g dry weight basis, 92.6% yield). A 60.47-g portion of the wet-cake was charged to a 1-L flask with 250 mL of toluene and 1 mL of N,N-dimethylformamide. To the slurry was added dropwise 19 mL of oxalyl chloride. After stirring overnight at ambient temperature, the solvent was evaporated to give a 139.7 g residue. The residue was dissolved in 200 g of ethyl acetate to give a 15 wt% solution of the acid chloride (X) in ethyl acetate.
	With thionyl chloride
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1h;
	With oxalyl dichloride In dichloromethane at 0℃; Inert atmosphere;	7 N-Protected-L-phenylalanine (5.0 mmol) was put under an argon atmosphere and anhydrous CH2C12 (25 mL) and DMF (2 drops) were added to dissolve the solid. The solution was cooled to 0°C and oxalyl chloride (0.48 mL, 5.5 mmol) was slowly added to the solution over 15 minutes. The solution was allowed to stir at 0°C overnight. Tnmethylsilyldiazomethane (5.0 mL of a 2 M solution in hexanes, 10 mmol) was slowly added to the reaction mixture over 1 hour. The solution was allowed to stir at 0°C under argon for 24 hours. At this time HCI (5.0 mL of a 2 M solution in diethyl ether, 10 mmol) was added. After 1 hour, the solution was allowed to warm to room temperature and the reaction was opened to the atmosphere. After 3 hours, the organic layer was washed with saturated NaHC03 and then with brine. The solvent was removed via rotary evaporation resulting in a yellow solid. The crude material was decolorized with charcoal in CH3CN.[0070] N-Phthaloyl-(3S)-3-amino-l-chloro-4-phenyl-2-butanone (7). The decolorized material was recrystallized in a 9: 1 mixture of hexanes/EtOAc. Compound 7 was isolated as a white solid (1.2 g, 3.7 mmol, 73%): mp 1 17-1 18°C (lit mp 1 19-120°C); NMR δ 3.30 (br m, 2H), 4.80 (br q, 2H), 5.33 (q, 1H), 7.10 (m, 5H), 7.81 (s, 4H); 13C NMR δ 32.9, 47.7, 57.9, 123.4, 126.7, 128.3, 128.8, 130.9, 134.8, 136.7, 167.1, 196.9; HRMS (FAB+) calcd for C18Hi4N03Cl 327.0662, found 328.0731 (M+H); Elemental analysis calcd for Ci8H14N03Cl: C 65.96, H 4.31 , N 4.27; found: C 65.90, H 4.20, N 4.21.
	With phosphorus pentachloride In benzene at 50℃; for 2h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere;
	With oxalyl dichloride In hexane; N,N-dimethyl-formamide; benzene at 20℃;
	With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 15 - 20℃; for 16h;
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 4h; Reflux;
	With oxalyl dichloride In dichloromethane at 0 - 20℃; for 6h;	Compound 2 (1 mmol) added to dry CH2Cl2 (15 mL) was stirred at 0 °C and oxalyl chloride (1.5 mmol) was dripped into the mixture and stirred at room temperature for 6 h. After the reaction, the solvent and excess oxalyl chloride was evaporated under reduced pressure. Aromatic primary amines (1 mmol) and triethylamine (0.5 mmol) were added to the mixture and stirred at room temperature for 0.5 h. After the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by chromatography on silica gel eluted with petroleum ether/ethyl acetate (V:V=6:1) to offer compound 4. Compound 4 (1 mmol) and hydrazine hydrate (3 mmol) were added to ethanol (15 mL) and the mixture was stirred at room temperature for 8 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was purified by chromatography on silica gel eluted with petroleum ether/ethyl acetate (V:V=3:1) to obtain compounds 5. DHA (1 mmol) added to dry CH2Cl2 (15 mL) was stirred at 0 °C and oxalyl chloride (1.5 mmol) was dripped into the mixture and stirred at room temperature for 6 h. After the reaction, the solvent and excess oxalyl chloride was evaporated under reduced pressure. Compounds 5 (1 mmol) and triethylamine (0.5 mmol) were added to the mixture and stirred at room temperature for 0.5 h. After the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by chromatography on silica gel eluted with petroleum ether/ethyl acetate (V:V=6:1) to offer compounds 7a-7s.
	With thionyl chloride In toluene Reflux; Schlenk technique;
	With thionyl chloride; N,N-dimethyl-formamide at 40 - 90℃; for 2h;
	With thionyl chloride; N,N-dimethyl-formamide at 90℃; for 2h;	2.4 (S)-2-(1-(4-Benzylpiperidin-1-yl)-4-methyl-1-oxopentan-2-yl)isoindoline-1,3-dione (13) General procedure: N-phthaloyl-l-leucine, 1 (1 g, 3.83 mmol), DMF (0.05 mL, 0.65 mmol) and freshly distilled thionyl chloride (0.5 mL, slow addition) were mixed together and the contents were heated at 90 °C for 2 h. The reaction mixture was cooled to room temperature and kept in an ice bath. 4-Benzylpiperidine (1.0 mL, 5.7 mmol, dissolved in 20 mL of ethylacetate) and triethylamine (1.0 mL) were added subsequently to the reaction mixture and the contents were stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and extracted into ethylacetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (9:1-6:4 petroleum ether/ethylacetate gradient) to afford the title compound (1.1 g, 2.6 mmol, 69%). Mp: 78-80 °C; [α]D25 -12.4; 1H NMR (400 MHz, CDCl3): δ 7.77-7.64 (m, 4H, Ar-H), 7.19-6.99 (m, 5H, Ar-H), 5.08 (m, 1H, NCH), 4.46 (m, 1H, benzylic CH2), 3.70 (m, 1H, benzylic CH2), 3.0 (m, 1H, CH2), 2.58-2.42 (m, 4H, 2 * NCH2), 1.69-1.46 (m, 6H), 1.18-1.04 (m, 1H, CH), 0.87 (d, 6H, J = 4.12 Hz, 2 * CH3), 13C NMR (100 MHz, CDCl3): δ 168.3 (C=O), 167.6 (C=O), 139.8 (Ar-C), 134.0 (Ar-C), 131.7 (Ar-C), 128.9 (Ar-C), 128.2 (Ar-C), 126.0 (Ar-C), 123.3 (Ar-C), 50.3 (CH), 42.7 (CH2), 31.7 (CH2), 25.3 (CH), 23.1 (CH3), 21.1 (CH3); IR (KBr) νmax (cm-1) = 3025, 2930, 2869, 1715 (C=O), 1655 (C=O), 1448, 1381, 1076, 720; HRMS m/z calculated [M+H]+ for C26H31N2O3+: 419.2329; found: 419.1951.
	With thionyl chloride In toluene Schlenk technique; Reflux;
	With thionyl chloride In neat (no solvent) at 60℃; for 1h;
	With thionyl chloride In toluene Reflux; Schlenk technique; Inert atmosphere;
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 55℃; for 3h;
	With oxalyl dichloride In dichloromethane at 0 - 20℃; for 6h;
	With thionyl chloride In dichloromethane at 55℃;	General Procedure II for the preparation of 1e: A mixture of L-phenylalanine s-e (10 mmol, 1 equiv) and phthalic anhydride (11 mmol,1.1 equiv) was heated at 140 °C for 2 h. After cooling to room temperature, the resulting water and the unreacted phthalic anhydride were washed off by acetone (2 mL) and DCM (2 mL), the resulting solid mixture was then dissolved in anhydrous CH2Cl2 (20 mL), SOCl2 (13 mmol, 1.3 eq) was added and stirred at 55 °C overnight. After the reaction, CH2Cl2 and excess of thionyl chloride were removed in vacuo. The crude acyl chloride was diluted with CH2Cl2 (20 mL), amine (9.2 mmol, 0.92 equiv) and Et3N (13mmol, 1.3 equiv) were added and stirred at room temperature overnight. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the desired amide product 1e.
	With phosphorus pentachloride In dichloromethane at 20℃; for 3h;	31.2; 61.1 Step 2 To a solution (S)-2-(l,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (42.3 g, 142.0 mmol) in anhydrous DCM (550 mL) was added PC15 (32.8 g, 157.0 mmol) in portions. The reaction mixture was stirred for 3 hrs at rt. All volatiles were completely removed via rotovap to give (S)- (0390) 2-(l,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride as a crude was used in next step without further purification.
	With thionyl chloride
	With thionyl chloride at 20℃; for 5h;

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5
[ 67-56-1 ]
[ 5123-55-7 ]
[ 14380-85-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With hydrogenchloride at 10℃; for 4h;
93%	With sulfuric acid for 3h; Reflux;	Methyl (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoate, [(S)-2] General procedure: A 100 mL round-bottomed flask containing a magneticstirrer and equipped with a reflux condenser was chargedwith (S)-1 (12.0 g, 40.6 mmol, 93.0% ee) and was dissolvedin methanol (50 mL) prior to the addition of H2SO4(0.9 mL). The reaction mixture was heated to reflux for 3 hand then allowed to cool to room temperature. The solventwas removed at reduced pressure before the addition ofwater (100 mL) and the acid-reaction mixture was neutralizedwith K2CO3 powder. The residue was dissolved inwater (200 mL) and EtOAc (100 mL), and the aqueouslayer was extracted with EtOAc (3 × 30 mL). The combinedorganic layers were washed with brine (30 mL),dried over anhydrous Na2SO4, and concentrated underreduced pressure. This was obtained as a white solid; yield10.9 g (93%); enantiomeric excess 97.2%; HPLC retentiontime 14.7 min; mp 124-126 °C (lit. mp 124.8-126.8 °C [29]); TLC: Rf (hexane/AcOEt, 7:3) = 0.53; 1HNMR (CDCl3, 400MHz) δ 7.77 (2H, dd, J = 5.5, 3.1 Hz,H-Ar), 7.68 (2H, dd, J = 5.5, 3.0 Hz, H-Ar), 7.17 (4H, m,H-Ar), 7.12 (1H, m, H-Ar), 5.16 (1H, dd, J = 11.2, 5.4 Hz,CH), 3.78 (3H, s, OCH3), 3.55 (2H, m, CHHPh diastereotopicproton); 13C NMR (CDCl3, 101MHz) δ 169.3 (C,O=O), 167.4 (2 C, NC=O), 136.7 (C, benzyl), 134.1(2 CH, Phth), 131.5 (2C, Phth), 128.8 (2CHortho, benzyl),128.5 (2CHmeta, benzyl), 126.8 (CHpara, benzyl), 123.4(2CH, Phth), 53.2 (CH, CHCO2CH3), 52.8 (CH3, 34.6 (CH2, CH2Ph); HRMS (ESI+) m/z calculated forC18H16NO4 310.10793, found 310.10670 (M+ H+).OCH3),
93%	With sulfuric acid for 3h; Reflux;	Methyl (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoate, [(S)-2] General procedure: A 100 mL round-bottomed flask containing a magneticstirrer and equipped with a reflux condenser was chargedwith (S)-1 (12.0 g, 40.6 mmol, 93.0% ee) and was dissolvedin methanol (50 mL) prior to the addition of H2SO4(0.9 mL). The reaction mixture was heated to reflux for 3 hand then allowed to cool to room temperature. The solventwas removed at reduced pressure before the addition ofwater (100 mL) and the acid-reaction mixture was neutralizedwith K2CO3 powder. The residue was dissolved inwater (200 mL) and EtOAc (100 mL), and the aqueouslayer was extracted with EtOAc (3 × 30 mL). The combinedorganic layers were washed with brine (30 mL),dried over anhydrous Na2SO4, and concentrated underreduced pressure. This was obtained as a white solid; yield10.9 g (93%); enantiomeric excess 97.2%; HPLC retentiontime 14.7 min; mp 124-126 °C (lit. mp 124.8-126.8 °C [29]); TLC: Rf (hexane/AcOEt, 7:3) = 0.53; 1HNMR (CDCl3, 400MHz) δ 7.77 (2H, dd, J = 5.5, 3.1 Hz,H-Ar), 7.68 (2H, dd, J = 5.5, 3.0 Hz, H-Ar), 7.17 (4H, m,H-Ar), 7.12 (1H, m, H-Ar), 5.16 (1H, dd, J = 11.2, 5.4 Hz,CH), 3.78 (3H, s, OCH3), 3.55 (2H, m, CHHPh diastereotopicproton); 13C NMR (CDCl3, 101MHz) δ 169.3 (C,O=O), 167.4 (2 C, NC=O), 136.7 (C, benzyl), 134.1(2 CH, Phth), 131.5 (2C, Phth), 128.8 (2CHortho, benzyl),128.5 (2CHmeta, benzyl), 126.8 (CHpara, benzyl), 123.4(2CH, Phth), 53.2 (CH, CHCO2CH3), 52.8 (CH3, 34.6 (CH2, CH2Ph); HRMS (ESI+) m/z calculated forC18H16NO4 310.10793, found 310.10670 (M+ H+).OCH3),

90%	With thionyl chloride at 0 - 20℃; for 18h;	F F . Auxiliary Cleavage The mono-arylated product Compound 2 (153 mg, 0.3 mmol) was dissolved in the mixed solvents (3 mL, AcOH/Ac20 = 1/2), and then cooled to 0 °C. NaN02 (414 mg, 6 mmol) was slowly added into the reaction mixture in portions. The reaction mixture was first stirred at 0 °C for 3 hours and then at room temperature for 17 hours. Upon completion, the solvents were removed under reduced pressure, and the mixture was neutralized by slow addition of saturated aHC03 solution to pH 8. The aqueous phase was extracted with ether (4 χ 10 mL) , and then carefully acidified with cold HC1 solution (I N) to pH 2, and then extracted with ether (4 χ 20 mL) . The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo to afford the desired product Compound 4 (84.5 mg, 95%) (31) . NMR (400 MHz, CDC13) δ 8.11 (br s, 1H) , 7.80-7.75 (m, 2H) , 7.70-7.65 (m, 2H) , 7.21-7.11 (m, 5H) , 5.22 (dd, Ji = 7.6 Hz, J2 = 8.8 Hz, 1H) , 3.60- 3.58 (m, 2H) . To a solution of Compound 4 (29.5 mg, 0.1 mmol) in anhydrous methanol (5 mL) was added thionyl chloride (44 L, 0.6 mmol) dropwise at 0 °C. The solution was stirred overnight (about 18 hours) at room temperature. After concentration, the mixture was purified by column chromatography using hexane/EtOAc (5/1) as the eluent, and the product Compound 16 was obtained as white solid (27.8 mg, 90%, 97% ee) [Fu et al., Bioorg. Med. Chem. Lett. 17:1102-1106 (2007)]. The ee value was determined by HPLC analysis on a Chiralcel OJ column (25% isopropanol/hexanes, 0.5 mL/min) with tr = 28.1 min (major), 43.3 min (minor) . XH NMR (400 MHz, CDC13) δ 7.80-7.76 (m, 2H) , 7.71-7.66 (m, 2H) , 7.21-7.11 (m, 5H) , 5.16 (dd, Ji = 5.2 Hz, J2 = 11.2 Hz, 1H) , 3.78 (s, 3H) , 3.60 (ABqd, Ji = 5.2 Hz, J2 = 14.4 Hz, 1H) , 3.54 (ABqd, Ji = 11.2 Hz, J2 = 14.4 Hz, 1H) .
26.3 mg	Stage #1: (S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-phenylpropionic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h; Stage #2: methanol In dichloromethane for 1h;

Reference： [1]Griesbeck, Axel G.; Mauder, Harald; Mueller, Ingrid [Chemische Berichte, 1992, vol. 125, # 11, p. 2467 - 2476]
[2]Andrade-Jorge, Erik; Rivera-Sánchez, Fernando; Rodríguez, Jessica E.; Lagos-Cruz, Jesús A.; Reyes-Vallejo, Natalia; Villalobos-Molina, Rafael; Gallardo-Ortíz, Itzell A.; Reyes-Ramírez, Adelfo [Medicinal Chemistry Research, 2022, vol. 31, # 6, p. 851 - 866]
[3]Andrade-Jorge, Erik; Rivera-Sánchez, Fernando; Rodríguez, Jessica E.; Lagos-Cruz, Jesús A.; Reyes-Vallejo, Natalia; Villalobos-Molina, Rafael; Gallardo-Ortíz, Itzell A.; Reyes-Ramírez, Adelfo [Medicinal Chemistry Research, 2022, vol. 31, # 6, p. 851 - 866]
[4]Current Patent Assignee: SCRIPPS RESEARCH - WO2015/131100, 2015, A1 Location in patent: Page/Page column 130; 131
[5]Chen, Gang; Zhuang, Zhe; Li, Gen-Cheng; Saint-Denis, Tyler G.; Hsiao, Yi; Joe, Candice L.; Yu, Jin-Quan [Angewandte Chemie - International Edition, 2017, vol. 56, # 6, p. 1506 - 1509][Angew. Chem., 2017, vol. 129, # 6, p. 1528 - 1531]

6
[ 6066-82-6 ]
[ 5123-55-7 ]
[ 122237-11-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	With dicyclohexyl-carbodiimide In tetrahydrofuran 1.) -20 deg C, overnight, 2.) RT, 3 h;

Reference： [1]Carpino, Louis A.; Chao, Hann Guang; Tien, Jien-Heh [Journal of Organic Chemistry, 1989, vol. 54, # 18, p. 4302 - 4313]

7
[ 2491-20-5 ]
[ 5123-55-7 ]
[ 108061-10-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; triethylamine In tetrahydrofuran 1.) -5 deg C, overnight, 2.) RT, 4 h;

Reference： [1]Carpino, Louis A.; Chao, Hann Guang; Tien, Jien-Heh [Journal of Organic Chemistry, 1989, vol. 54, # 18, p. 4302 - 4313]

8
[ 67-68-5 ]
[ 5123-55-7 ]
[ 79756-16-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With t-butyl bromide; sodium hydrogencarbonate at 25 - 30℃; for 24h;

Reference： [1]Dossena, Arnaldo; Marchelli, Rosangela; Casnati, Guiseppe [Journal of the Chemical Society. Perkin transactions I, 1981, p. 2737 - 2739]

9
[ 111581-86-3 ]
[ 5123-55-7 ]
(S)-N-(2-Chloro-cyclohex-2-enyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In dichloromethane

Reference： [1]Flynn, Gary A.; Giroux, Eugene L.; Dage, Richard C. [Journal of the American Chemical Society, 1987, vol. 109, # 25, p. 7914 - 7915]

10
[ 63-91-2 ]
[ 22509-74-6 ]
[ 5123-55-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium carbonate In water at 20℃; for 2h;
40%	With sodium carbonate In ethyl acetate
	With sodium carbonate In water at 20℃; for 5h;

Reference： [1]Ling, Peng-Xiang; Fang, Sheng-Long; Yin, Xue-Song; Zhang, Qi; Chen, Kai; Shi, Bing-Feng [Chemical Communications, 2017, vol. 53, # 47, p. 6351 - 6354]
[2]Aitken, R. Alan; Cooper, Harris R.; Mehrotra, Amit P. [Journal of the Chemical Society. Perkin transactions I, 1996, # 5, p. 475 - 483]
[3]Chen, Zhongxiang; Fan, Hongjun; Yang, Shiwei; Bian, Guangling; Song, Ling [Organic and Biomolecular Chemistry, 2018, vol. 16, # 37, p. 6933 - 6939]

11
[ 6973-51-9 ]
[ 5123-55-7 ]
(S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(4-nitro-benzothiazol-2-yl)-3-phenyl-propionamide [ No CAS ]

Reference： [1]Pakistan Journal of Scientific and Industrial Research,1995,vol. 38,p. 246 - 248

12
[ 63-91-2 ]
[ 17858-14-9 ]
[ 5123-55-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine In water; acetonitrile for 0.166667h; Ambient temperature;

Reference： [1]Kehler, Jan; Breuer, Eli [Synthesis, 1998, # 10, p. 1419 - 1420]

13
[ 5123-55-7 ]
Sodium tris[(S)-N,N-phthaloylphenylalanine]borohydride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium tetrahydroborate In tetrahydrofuran at 20℃; for 10h;

Reference： [1]Hajipour; Hantehzadeh [Journal of Organic Chemistry, 1999, vol. 64, # 23, p. 8475 - 8478]

14
[ 5123-55-7 ]
[ 103169-13-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,4-dioxane; 1-cyclohexyl-3-(4-diethyl-aminocyclohexyl)carbodiimide
	With 4-<2-(cyclohexylimino-methylenamino)-ethyl>-4-methyl-morpholinium-<t; triethylamine; acetonitrile Reagens 3:oluol-4-sulfonat>;
	With tetrahydrofuran; dicyclohexyl-carbodiimide

With tetrahydrofuran; diphenylketene-N-p-tolylimine

Reference： [1]Sheehan; Hlavka [Journal of Organic Chemistry, 1956, vol. 21, p. 439]
[2]Sheehan; Hlavka [Journal of Organic Chemistry, 1956, vol. 21, p. 439]
[3]Sheehan; Hess [Journal of the American Chemical Society, 1955, vol. 77, p. 1067]
[4]Current Patent Assignee: PFIZER INC - US2820781, 1956, A

15
[ 17585-69-2 ]
[ 438470-19-0 ]
[ 5123-55-7 ]

Reference： [1]Journal of Organic Chemistry,2002,vol. 67,p. 3764 - 3768

16
[ 124491-96-9 ]
[ 5123-55-7 ]
(S)-N-((R)-1-Dimethylcarbamoyl-ethyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;

Reference： [1]Hill, Roger R.; Birch, David; Jeffs, Graham E.; North, Michael [Organic and Biomolecular Chemistry, 2003, vol. 1, # 6, p. 965 - 972]

17
[ 3705-50-8 ]
[ 5123-55-7 ]
(S)-N-((R)-1-Dimethylcarbamoyl-2-phenyl-ethyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;

Reference： [1]Hill, Roger R.; Birch, David; Jeffs, Graham E.; North, Michael [Organic and Biomolecular Chemistry, 2003, vol. 1, # 6, p. 965 - 972]

18
[ 230643-41-1 ]
[ 5123-55-7 ]
2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionylamino]-3,<i>N</i>,<i>N</i>-trimethyl-butyramide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;

Reference： [1]Hill, Roger R.; Birch, David; Jeffs, Graham E.; North, Michael [Organic and Biomolecular Chemistry, 2003, vol. 1, # 6, p. 965 - 972]

19
[ 5123-55-7 ]
proline-N,N-dimethylamide [ No CAS ]
(R)-1-[(S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionyl]-pyrrolidine-2-carboxylic acid dimethylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;

Reference： [1]Hill, Roger R.; Birch, David; Jeffs, Graham E.; North, Michael [Organic and Biomolecular Chemistry, 2003, vol. 1, # 6, p. 965 - 972]

20
[ 74-89-5 ]
[ 5123-55-7 ]
[ 98654-98-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran; water at -20℃; for 1h;

Reference： [1]Shendage, Deepak M.; Froehlich, Roland; Haufe, Guenter [Organic Letters, 2004, vol. 6, # 21, p. 3675 - 3678]

21
[ 5123-55-7 ]
[ 828253-37-8 ]
2-{(S)-1-Benzyl-2-[(4R,6R)-6-((R)-5,5-dimethyl-2-oxo-tetrahydro-furan-3-yloxy)-2-oxo-4-phenyl-[1,3]oxazinan-3-yl]-2-oxo-ethyl}-isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With 4-methyl-morpholine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 16h;

Reference： [1]Yin, Biaolin; Dhal, Robert; Maisonneuve, Vincent; Dujardin, Gilles [European Journal of Organic Chemistry, 2006, # 15, p. 3309 - 3313]

22
[ 613-89-8 ]
[ 5123-55-7 ]
[ 872017-63-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In pyridine at 20℃; for 12h;	48.A N-Phthaloyl-L-phenylalanine (290 mg, 1 mmol) and 2-aminoacetophenone (171 mg, 1 .mmol) were dissolved -in 10 mL of pyridine. Bop reagent (470 mg, 1.1 mmol) was added The mixture was stirred at rt under N2 for 12 h. The solvent was removed. The residue was dissolved in EtOAc and washed with water and sat. NaHC03. The organic layer was dried over Na2S04, filtered, and concentrated to yield 412 mg of the product (100% yield). MS 413.2 (M+H)+.
100%	With pyridine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate at 20℃; for 16h; Inert atmosphere;

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2005/123050, 2005, A2 Location in patent: Page/Page column 130
[2]Hangeland, Jon J.; Friends, Todd J.; Rossi, Karen A.; Smallheer, Joanne M.; Wang, Cailan; Sun, Zhong; Corte, James R.; Fang, Tianan; Wong, Pancras C.; Rendina, Alan R.; Barbera, Frank A.; Bozarth, Jeffrey M.; Luettgen, Joseph M.; Watson, Carol A.; Zhang, Ge; Wei, Anzhi; Ramamurthy, Vidhyashankar; Morin, Paul E.; Bisacchi, Gregory S.; Subramaniam, Srinath; Arunachalam, Piramanayagam; Mathur, Arvind; Seiffert, Dietmar A.; Wexler, Ruth R.; Quan, Mimi L. [Journal of Medicinal Chemistry, 2014, vol. 57, # 23, p. 9915 - 9932]

23
[ 5123-55-7 ]
[ 21946-94-1 ]

Yield	Reaction Conditions	Operation in experiment
59.05%	With 1H-imidazole In tetrahydrofuran at 60℃; for 4h;
	Multi-step reaction with 2 steps 1: ethyl chloroformate 2: 21 percent / nickel peroxide / benzene / Heating

Reference： [1]Coêlho, Lucas Cunha Duarte; De Oliveira Cardoso, Marcos Veríssimo; Moreira, Diogo Rodrigo Magalhães; De Moraes Gomes, Paulo André Teixeira; Cavalcanti, Suellen Melo Tibúrcio; Oliveira, Arsenio Rodrigues; De Oliveira Filho, Gevanio Bezerra; Pessoa De Siqueira, Lucianna Rabelo; De Oliveira Barbosa, Miria; De Oliveira Borba, Elizabeth Fernanda; Da Silva, Teresinha Gonçalves; Kaskow, Belinda; Karimi, Mahdad; Abraham, Lawrence J.; Leite, Ana Cristina Lima [MedChemComm, 2014, vol. 5, # 6, p. 758 - 765]
[2]Easton, Christopher J.; Eichinger, Sharon K.; Pitt, Michael J. [Tetrahedron, 1997, vol. 53, # 15, p. 5609 - 5616]

24
[ 5123-55-7 ]
[ 721-90-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: benzene; phosphorus (V)-chloride 2: triethylamine; dichloromethane / -45 °C 3: water; acetone; hydrochloric acid 4: ethanol; N₂H₄+H₂O

Reference： [1]Sheehan; Bloom [Journal of the American Chemical Society, 1952, vol. 74, p. 3825,3827]

25
[ 106-88-7 ]
sodium metabisulfite [ No CAS ]
[ 79-37-8 ]
argon [ No CAS ]
[ 5123-55-7 ]
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-2-hydroxy-4-phenylbutyronitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With NaCN In water; N,N-dimethyl-formamide; toluene	23 (III→VI via IV, V) EXAMPLE 23 (III→VI via IV, V) A suspension of 100 g of 3-phenyl-2(S)-phthalimido-propionic acid in 810 ml of toluene was combined with stirring at 22° C. with 0.34 ml of DMF and 45.1 g of oxalyl chloride. The mixture was stirred for 3 hours at 22° C. Argon was passed into the solution. The solution was then combined with 59 ml of 1,2-butylene oxide. The mixture was then degassed and treated with a suspension of 15.9 g of Pd/C in 100 ml of toluene. The suspension was hydrogenated for 16 hours with stirring, then degassed and the suspension filtered under argon. The residue was washed with toluene. The filtrate was combined with stirring at 22° C. with a solution of 32.2 g of sodium pyrosulphite and 320 ml of water. After 7 hours, the mixture was combined with a solution of 13 g of NaCN in 130 ml of water. After 30 minutes, the aqueous layer was separated and extracted with toluene. The toluene layers were washed with water and the combined layers evaporated. The resultant suspension was diluted with hexane with stirring and then filtered. The residue was washed with hexane/toluene (10/1). 80.9 g (78%) of 3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-2-hydroxy-4-phenylbutyronitrile were obtained as a 73.6:26.4 mixture of the (2S,3S) and (2R,3S) isomers, melting point 128°-132° C., [α]D20: -151.4° (1% in methylene chloride)

Reference： [1]Current Patent Assignee: EVONIK INDUSTRIES AG - US5859248, 1999, A

26
[ 870-08-6 ]
[ 5123-55-7 ]
2C₈H₄O₂NCH(CH₂C₆H₅)COO^(1-)*4(CH₂)7CH₃^(1-)*2Sn⁽⁴⁺⁾*O^(2-)=((C₈H₄O₂NCH(CH₂C₆H₅)COO)Sn(CH₃CH₂CH₂CH₂CH₂CH₂CH₂CH₂)2)2O [ No CAS ]

Reference： [1]Journal of Organometallic Chemistry,1985,vol. 279,p. 373 - 384

27
[ 870-08-6 ]
[ 5123-55-7 ]
(C₈H₄O₂NCH(CH₂C₆H₅)COO)2Sn(CH₃CH₂CH₂CH₂CH₂CH₂CH₂CH₂)2*4H₂O [ No CAS ]

Reference： [1]Journal of Organometallic Chemistry,1985,vol. 279,p. 373 - 384

28
[ 69320-89-4 ]
[ 5123-55-7 ]
[ 1098701-21-3 ]

Reference： [1]Tetrahedron,2009,vol. 65,p. 206 - 211

29
[ 141-30-0 ]
[ 5123-55-7 ]
[ 1187648-11-8 ]

Yield	Reaction Conditions	Operation in experiment
22.7%	With ammonium peroxydisulfate; silver nitrate; trifluoroacetic acid In water at 70℃; for 0.833333h;	1.1A Example 1; (+/-)-(E)-MethyI 4-(6-chloro-5-(l-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamido)- 2-phenylethyl)pyridazin-3-yl)phenylcarbamate; IA. 2-(l-(3,6-dichloropyridazin-4-yl)-2-phenylethyl)isoindoline-l,3-dione: To a mixture of 3,6-dichloropyridazine (5g, 33.6 mmol), (S)-2-(1,3-dioxoisoindolin- 2-yl)-3-phenylpropanoic acid (16.85 g, 57.1 mmol), and silver nitrate (0.570 g, 3.36 mmol) in water (50 mL) was added TFA (0.517 mL, 6.71 mmol). The reaction mixture was warmed up to 70 °C and then a solution of ammonium persulfate (13.79 g, 60.4 mmol) in water (20 mL) was added dropwise over 20 min. The reaction was stirred at 70 °C for an additional 30 min. EtOAc (50 mL) was added and the reaction was cooled to rt. Ammonium hydroxide was added to adjust the pH to ~9. The layers were separated and the organic layer was washed with IM HCl (1 x 25 mL), saturated NaCl (1 x 25 mL), dried over Na2SC>4, filtered and concentrated. Purification by normal phase chromatography gave IA (3.03 g, 22.7 % yield) as a tan solid. MS (ESI) m/z: 398.1/400.1 (M+H)+.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2009/114677, 2009, A1 Location in patent: Page/Page column 118-119

30
[ 4299-70-1 ]
[ 5123-55-7 ]
[ 1194630-03-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; triethylamine; HATU In N,N-dimethyl-formamide at 0℃;

Reference： [1]Luzung, Michael R.; Lewis, Chad A.; Baran, Phil S. [Angewandte Chemie - International Edition, 2009, vol. 48, # 38, p. 7025 - 7029][Angewandte Chemie, 2009, vol. 121, # 38, p. 7159 - 7163]

31
[ 148763-83-1 ]
[ 5123-55-7 ]
[ 1092575-91-1 ]

Yield	Reaction Conditions	Operation in experiment
1.572 g	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃;

Reference： [1]Zhang, Bin; Nikolovska-Coleska, Zaneta; Zhang, Yan; Bai, Longchuan; Qiu, Su; Yang, Chao-Yie; Sun, Haiying; Wang, Shaomeng; Wu, Yikang [Journal of Medicinal Chemistry, 2008, vol. 51, # 23, p. 7352 - 7355]

32
[ 167304-90-7 ]
[ 5123-55-7 ]
[ 116330-74-6 ]

Yield	Reaction Conditions	Operation in experiment
353 mg	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃;

Reference： [1]Zhang, Bin; Nikolovska-Coleska, Zaneta; Zhang, Yan; Bai, Longchuan; Qiu, Su; Yang, Chao-Yie; Sun, Haiying; Wang, Shaomeng; Wu, Yikang [Journal of Medicinal Chemistry, 2008, vol. 51, # 23, p. 7352 - 7355]

33
[ 16509-61-8 ]
[ 5123-55-7 ]
[ 142589-42-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: (R)-2-amino-6-hydroxy-hexanoic acid With hydrogenchloride In methanol at 20℃; for 2h; Stage #2: Nα-phthaloyl-L-phenylalanine With 4-methyl-morpholine; benzotriazol-1-ol In DMF (N,N-dimethyl-formamide); dichloromethane at 0 - 20℃; for 1.33333h;	5.A EXAMPLE 5 A solution of L-hydroxynorleucine (2.0 g, 13.6 mmoles) in dry methanol (70 ml) was saturated with HCl gas until a clear yellow solution was obtained. The reaction mixture was cooled to room temperature, stirred for 2.0 hours, evaporated to dryness, evaporating the syrup once from toluene (100 ml) then evaporated in vacuo to give the ester as a yellow oil. The crude ester was dissolved in dry CH2Cl2 (50 ml) and dry DMF (15 ml), treated with NMM (2.5 ml, 22.7 mmoles) and cooled to 0° C. (ice-salt bath). The mixture was treated with N-phthaloyl-L-phenyl-alanine (4.0 g, 13.6 mmoles), HOBt.H2O (1.89 g, 13.99 mmoles) and EDAC (2.87 g, 14.98 mmoles), stirred at 0° C. for 25 minutes and at room temperature for 2.0 hours. [00200] The reaction mixture was partitioned between EtOAc (2×200 ml) and H2O (60 ml) and the combined organic extracts were washed sequentially with 0.5 N HCl (60 ml), H2O (60 ml), ½ saturated NaHCO3 (60 ml) and brine (60 ml), dried (anhydrous Na2SO4), filtered, evaporated to dryness and dried in vacuo. The crude product mixture was chromatographed on a silica gel column (Merck, 200 g), eluting the column with EtOAc to give the desired product as a syrup (4.0 g). An additional 321 mg was obtained on re-chromatography of the impure fractions to give title compound (4.32 g, 73%) with consistent 1H-NMR and 13C-NMR spectral data. [00201] TLC: Rf 0.43 (Silica gel; EtOAc; UV).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6777550, 2004, B1 Location in patent: Page column 32

34
[ 947139-63-1 ]
[ 5123-55-7 ]
[ 947139-64-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triphenyl phosphite; 3-methyl-1-propylimidazolium bromide at 110℃; for 2.5h;

Reference： [1]Location in patent: experimental part Zahmatkesh, Saeed [Amino Acids, 2011, vol. 40, # 2, p. 533 - 542]

35
[ 67-56-1 ]
[ 1161-13-3 ]
[ 5123-55-7 ]
[ 828253-37-8 ]
[ 1360566-07-9 ]

Yield	Reaction Conditions	Operation in experiment
115 mg	Stage #1: methanol; (4R,6R)-6-[(3R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yloxy]-4-phenyl-1,3-oxazinan-2-one With toluene-4-sulfonic acid Stage #2: Nα-phthaloyl-L-phenylalanine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; Stage #3: N-Cbz-L-Phe Further stages;	4.1.9. (1-{1-[3-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3-yloxy)-3-methoxy-1-phenyl-propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-phenyl-ethyl)-carbamic acid benzyl ester 13 To a solution of 10a (210 mg, 0.369 mmol) in 10 mL of methanol was added a solution of hydrazine monohydrate (36.9 mg, 0.737 mmol) in 2 mL of methanol. The mixture was refluxed for 2.5 h until the disappearance of starting material according to TLC. The solvent was removed under reduced pressure and the residue was submitted to the next step without further purification. To the mixture of l-CBz-phenylalanine 9c (156.6 mg, 0.523 mmol) in 5 mL of dry dichloromethane was added EDCI·HCl (105.7 mg, 0.551 mmol), HOBt (49 mg, 0.363 mmol), NMM (55 mg, 0.544 mmol) at 0 °C. The mixture was stirred at the same temperature for 15 min. Then the compound obtained from the previous step in 5 mL of dry dichloromethane was added slowly to the reaction. The reaction was stirred at 0 °C for 1 h then at room temperature overnight. H2O (10 mL) was added to quench the reaction. The solution was extracted with ethyl acetate (10 mL×3). The combined organic extracts were dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography using ethyl acetate/cyclohexane (1:1) as eluent affording a gum (115 mg, 43%), which was a 89:11 mixture (1H NMR) of the two diastereoisomeric mixed acetal 13. Rf=0.53 (eluant: PE/EA 1/1, UV detection). 1H NMR (400 MHz, acetone-d6) major mixed acetal δ 7.80 (1H,d, J=7.9 Hz), 7.60 (1H, d, J=7.6 Hz), 7.4-7.1 (20H, m), 6.58 (1H, d, J=7.5 Hz), 5.17 (1H, q, J=6.9 Hz), 5.03, 4.92 (2H, 2d, JAB=12.5 Hz), 4.72 (1H, q, J=7.0 Hz), 4.48 (1H, m), 4.44 (1H, t, J=4.9 Hz), 4.06 (1H, s), 3.78 (3H, s), 3.55 (1H, d, J=11.2 Hz), 3.41 (1H, d, J=11.2 Hz), 3.13 (1H, dd, J=6.9, 13.7 Hz), 3.04 (1H, dd, J=7.4, 13.7 Hz), 3.08 (1H, m), 2.88 (1H, m), 2.13 (1H, m), 2.04 (1H, m), 1.05 (3H, s), 0.91 (3H, s). Characteristic signals of minor mixed acetal δ 7.87 (d, J=7.9 Hz), 6.70 (d, J=7.1 Hz), 5.28 (m), 4.59 (m), 4.12 (s), 3.58, 3.47 (d, J=11.2 Hz), 3.08, 2.99 (dd, J=5.3, 13.9 Hz). 13C NMR (100 MHz, acetone-d6) major mixed acetal δ 171.9, 170.3, 169.9, 157.1, 143.4, 138.5, 138.4, 138.0, 130.4, 130.2, 129.3, 129.2, 129.2, 129.1, 128.6, 128.5, 127.8, 127.4, 127.3, 127.3, 100.3, 83.6, 78.0, 66.9, 57.4, 55.6, 52.0, 50.3, 41.4, 38.8, 38.6, 33.5, 21.9, 19.9. Characteristic signals of minor mixed acetal δ 172.2, 83.8, 66.9, 57.9, 55.4, 50.0, 41.6, 33.4, 20.1. IR (neat, cm-1): 3295, 3063, 3030, 2955, 1705, 1645, 1533, 1231, 699. HRMS (FD) [M]+ (C42H47N3O8) calcd: 721.3363, found: 721.3394

Reference： [1]Location in patent: experimental part Shpak-Kraievskyi, Pavlo; Yin, Biaolin; Martel, Arnaud; Dhal, Robert; Dujardin, Gilles; Laurent, Mathieu Y. [Tetrahedron, 2012, vol. 68, # 9, p. 2179 - 2188]

36
[ 67-56-1 ]
[ 5123-55-7 ]
[ 828253-37-8 ]
[ 1360566-06-8 ]
[ 1360566-05-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methanol; (4R,6R)-6-[(3R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yloxy]-4-phenyl-1,3-oxazinan-2-one With toluene-4-sulfonic acid Stage #2: Nα-phthaloyl-L-phenylalanine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃;	4.1.5. (2S)-N-[(1R,3RS)-3-((3R)-4,4-Dimethyl-2-oxo-tetrahydro-furan-3-yloxy)-3-methoxy-1-phenyl-propyl]-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionamide 10a To the mixture of l-phthalyl-phenylalanine 9a (222 mg, 1.753 mmol) in 5 mL of dry dichloromethane was added EDCI·HCl (144 mg, 0.753 mmol), HOBt (67 mg, 0.502 mmol) at 0 °C. The mixture was stirred at the same temperature for 15 min. Then crude mixture of 7 and 8 (150 mg, 0.502 mmol) in 5 mL of dry dichloromethane was slowly added to the reaction. The reaction was stirred at 0 °C for 1 h then at room temperature overnight. H2O (10 mL) was added to quench the reaction. The solution was extracted with ethyl acetate (10 mL×3). The combined organic extracts were dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography using ethyl acetate/cyclohexane (1:3) as eluent affording 10a as a gum (62 mg, 43%). Rf=0.63 (eluant: PE/EA 1/1, UV detection). 1H NMR (400 MHz, CDCl3) major mixed acetal δ 7.73 (2H, m), 7.62 (2H, m), 7.53 (1H,d, J=7.3 Hz), 7.32-7.08 (10H, m), 5.26 (1H, q, J=6.4 Hz), 5.16 (1H, dd, J=7, 10 Hz), 4.41 (1H, t, J=5.2 Hz), 3.91 (1H, s), 3.69 (3H, s), 3.64 (2H, m), 3.44 (1H, d, J=11.4 Hz), 3.33 (1H, d, J=11.4 Hz), 2.20 (2H, m), 1.01 (3H,s), 0.88 (3H, s). Characteristic signals of dimethyl acetal δ 7.77 (m), 7.67 (m), 7.34 (d, J=7.4 Hz), 4.14 (t), 3.58 (m), 3.18, 3.06 (2s), 2.03 (m). 13C NMR (100 MHz, CDCl3) major mixed acetal δ 169.2, 168.1, 167.6, 141.2, 137.1, 134.0, 131.8, 129.0, 128.6, 128.5, 127.1, 126.8, 126.0, 123.3, 100.0, 82.9, 77.5, 55.9, 51.9, 50.6, 40.0, 34.8, 32.9, 21.8, 19.4. Characteristic signals of dimethyl acetal δ 167.9, 167.5, 141.1, 136.9, 134.3, 131.4, 128.8, 128.7, 127.2, 126.9, 123.5, 102.4, 53.5, 52.7, 50.8, 38.5, 34.6. IR (neat, cm-1): 3385, 3064, 2958, 2873, 1776, 1713, 1666, 1525, 1385. HRMS (DCI, NH3) [M+H]+ (C33H35N2O7): calcd: 571.2444, found: 571.2444.

Reference： [1]Location in patent: experimental part Shpak-Kraievskyi, Pavlo; Yin, Biaolin; Martel, Arnaud; Dhal, Robert; Dujardin, Gilles; Laurent, Mathieu Y. [Tetrahedron, 2012, vol. 68, # 9, p. 2179 - 2188]

37
[ 1360566-10-4 ]
[ 5123-55-7 ]
C₂₈H₂₆N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Nα-phthaloyl-L-phenylalanine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: (1R)-2-[1,3]dioxolan-2-yl-1-phenylethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;	4.3. General procedure for the three-step synthesis of dipeptide aldehydes 12 General procedure: To the mixture of 6 (1 equiv) in dry dichloromethane (20 mL/mmol of 6) was added 1.5 equiv of para-toluenesulfonic acid and 3 equiv of diol. The mixture was heated to 35 °C and stirred during 48 h. After completion of the reaction (disappearance of starting material monitored by TLC), saturated aqueous NaHCO3 (1.7 mL/mmol of 6) was added. The aqueous layer was extracted with dichloromethane three times. The organic layers were combined, dried over MgSO4, and concentrated under vacuum affording crude symmetric acetal 16 in mixture with pantolactone. In a second step, to the N-protected amino acid 9 (1.2 equiv) in solution in dry dichloromethane (9 mL/mmol of 6) under nitrogen atmosphere was added EDCI (1.2 equiv) and HOBt (0.8 equiv) at 0 °C. After 15 min, the preformed aminoacetal 16 was added in solution in dichloromethane (7 mL/mmol of 6). The solution was warmed up to room temperature and stirred overnight. Water (15 mL/mmol of 6) was added and the reaction mixture was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated under vacuum to give crude product. Finally, acetal was deprotected by dissolving crude mixture in acetonitrile (12 mL/mmol of 6) and HCl 5 N (12 mL/mmol of 6) and by stirring at room temperature overnight. The reaction mixture is then treated with a solution of NaOH 2 N (30 mL/mmol of 6) and with a saturated solution of NaHCO3 to complete neutralization.

Reference： [1]Location in patent: experimental part Shpak-Kraievskyi, Pavlo; Yin, Biaolin; Martel, Arnaud; Dhal, Robert; Dujardin, Gilles; Laurent, Mathieu Y. [Tetrahedron, 2012, vol. 68, # 9, p. 2179 - 2188]

38
[ 5123-55-7 ]
[ 828253-37-8 ]
(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-N-[(1R)-3-oxo-1-phenylpropyl]-3-phenylpropionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	Stage #1: (4R,6R)-6-[(3R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yloxy]-4-phenyl-1,3-oxazinan-2-one With methanol; toluene-4-sulfonic acid Stage #2: Nα-phthaloyl-L-phenylalanine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; Stage #3: With hydrogenchloride; water In acetonitrile at 20℃;	4.1.7. (2S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-[(1R)-3-oxo-1-phenyl-propyl]-3-phenyl-propionamide 12a To the mixture of crude 10a (170 mg, 0.250 mmol) in 5 mL of acetonitrile was added 5 mL of 5 N HCl, the reaction was stirred at room temperature overnight. The reaction mixture is then treated with a solution of NaOH 2 N (12 mL/mmol of 6a) and with a saturated solution of NaHCO3. Then the mixture was extracted with ethyl acetate (15 mL×3). The combined organic extracts were washed with H2O to remove the pantolactone, dried (MgSO4), and filtered. The solvent was removed under reduced pressure. Flash chromatography on silica gel (cyclohexane/acetone 80:20, then cyclohexane/acetone 50:50) afforded 26 mg of 12a as a white solid (24% for three steps). 1H NMR (400 MHz, CDCl3) δ 9.61 (1H, dd, J=1.2, 2.1 Hz), 7.69 (2H, m), 7.60 (2H, m), 7.30-7.00 (10H, m), 6.90 (1H, d, J=8.2 Hz), 5.43 (1H, q, J=6.9 Hz), 5.03 (1H, dd, J=6.0, 10.6 Hz), 3.50 (1H, dd, J=6.0, 14.1 Hz), 3.40 (1H, dd, J=10.6, 14.1 Hz), 2.96 (1H, ddd, J=2.1, 6.5, 17.0 Hz), 2.86 (1H, ddd, J=1.2, 6.1, 17.0 Hz).

Reference： [1]Location in patent: experimental part Shpak-Kraievskyi, Pavlo; Yin, Biaolin; Martel, Arnaud; Dhal, Robert; Dujardin, Gilles; Laurent, Mathieu Y. [Tetrahedron, 2012, vol. 68, # 9, p. 2179 - 2188]

39
[ 108-98-5 ]
[ 5123-55-7 ]
N-phthaloy-Phe-SPh [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; Inert atmosphere;

Reference： [1]Garcia-Reynaga, Pablo; Carrillo, Angela K.; Vannieuwenhze, Michael S. [Organic Letters, 2012, vol. 14, # 4, p. 1030 - 1033]

40
[ 1417710-91-8 ]
[ 5123-55-7 ]
[ 1417710-93-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With trichlorophosphate for 16h; Reflux;	Experimental General procedure: A mixture of amino triazole 1a-b (2 mmol), N-phethaloyl-l-amino acid 2a-d (2 mmol) in POCl3 (10 mL) was refluxed for 16 h. The reaction mixture slowly was poured into crashed ice with stirring and neutralized with solid potassium carbonate. The mixture was allowed to stand overnight and the solid separated out was filtered and washed with cold water. The compound so obtained was dried and giving the pure products 3a-h.

Reference： [1]Ebrahimi, Sattar; Sayadi, Masoomeh; Darvishi, Ghasem [Chinese Chemical Letters, 2012, vol. 23, # 12, p. 1335 - 1338]

41
[ 4413-43-8 ]
[ 5123-55-7 ]
[ 1417710-97-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With trichlorophosphate for 16h; Reflux;	Experimental General procedure: A mixture of amino triazole 1a-b (2 mmol), N-phethaloyl-l-amino acid 2a-d (2 mmol) in POCl3 (10 mL) was refluxed for 16 h. The reaction mixture slowly was poured into crashed ice with stirring and neutralized with solid potassium carbonate. The mixture was allowed to stand overnight and the solid separated out was filtered and washed with cold water. The compound so obtained was dried and giving the pure products 3a-h.

Reference： [1]Ebrahimi, Sattar; Sayadi, Masoomeh; Darvishi, Ghasem [Chinese Chemical Letters, 2012, vol. 23, # 12, p. 1335 - 1338]

42
[ 1071-46-1 ]
[ 5123-55-7 ]
ethyl (S)-4-(1,3-dioxoisoindolin-2-yl)-3-oxo-5-phenylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: Nα-phthaloyl-L-phenylalanine With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 16h; Inert atmosphere; Stage #2: hydrogen ethyl malonate With triethylamine; magnesium chloride In tetrahydrofuran at 0 - 20℃; for 4.5h;	Synthesis of β-ketoesters 7 General procedure: The appropiate N-phthaloyl-amino acid 6 (1 equiv.) was dissolved in 100-200 mL of dry THF.N,N’-carbonyldiimidazole (1.1 equiv.) was added in portions, and the mixture was stirred for 16h under argon at room temperature. In a separate flask purged with argon and cooled in an icebath, a solution of malonic acid monoethyl ester (1.1 equiv.) in dry THF (100-200 mL) wasprepared. To the stirred solution were added anhydrous MgCl2 (0.6 equiv.) and triethylamine(1.2 equiv., gradual addition so as to keep the temperature below 10 oC), and the formed whiteslurry was stirred for 1 h at 0 °C. The ice bath was removed and the two mixtures were combinedand stirred for 3.5 h at room temperature. Most of the solvent (90%) was evaporated, and diethylether and water (60-100 mL each) were added. The phases were separated, and the water phasewas extracted with three portions (3 × 15-20 mL) of ether. The combined organic phases wereextracted with three portions of water (3 × 15-20 mL) and once with brine. After drying withNa2SO4, the solvent was removed, and the crude product was purified by columnchromatography. The eluent was evaporated, and the product was dried at 25 °C/10-3 bar

Reference： [1]Enssle, Marc; Buck, Stefan; Werz, Roland; Maas, Gerhard [ARKIVOC, 2012, vol. 2012, # 3, p. 149 - 171]

43
C₂₄H₃₆N₄O₂*2C₂HF₃O₂ [ No CAS ]
[ 5123-55-7 ]
C₅₈H₅₈N₆O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 25h;	4.2. Synthesis of hydroxyethylamine based small molecules Synthesis of compound I was performed following literature procedure.20 N-Phthaloyl-l-phenylalanine was synthesized by following literature method26 and recrystallisation with 10% (v/v) ethanol water solution gave the pure product. Boc-protected epoxide (1.5 mmol, 400 mg) was refluxed with piperazine (0.76 mmol, 65.4 mg) in 50 mL of isopropanol for 12 h. The reaction mixture was cooled to room temperature and the solvent was evaporated to afford II as white solid in 89% yield. For the deprotection, compound II was stirred with 20% trifluoroacetic acid in dichloromethane at room temperature for 2 h. Further, coupling with N-phthaloyl-l-phenylalanine (1.75 mmol, 516 mg) was carried out at room temperature in the presence of coupling reagents, EDC·HCl (2.0 mmol, 390 mg) and HOBT (2.0 mmol, 270 mg) in DCM (40 mL) with excess of triethylamine (7.2 mmol, 727 mg) for 24 h. The reaction mixture thus obtained was evaporated under reduced pressure. The resultant was extracted with ethyl acetate and water. The organic layer was dried over anhydrous sodium sulphate. Viscous compound was then purified by silica gel chromatography (Methanol/Chloroform; 95:5) to afford III in 72% yield.

Reference： [1]Rathi, Brijesh; Singh, Anil K.; Kishan, Ram; Singh, Neelu; Latha; Srinivasan; Pandey, Kailash C.; Tiwari, Hemandra K.; Singh, Brajendra K. [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 17, p. 5503 - 5509]

44
[ 38330-80-2 ]
[ 5123-55-7 ]
[ 1224928-27-1 ]

Yield	Reaction Conditions	Operation in experiment
88%		General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.

Reference： [1]Tetrahedron,2013,vol. 69,p. 11092 - 11108

45
(S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenyl-N-(2-(pyridin-2-yl)propan-2-yl)propanamide [ No CAS ]
[ 5123-55-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenyl-N-(2-(pyridin-2-yl)propan-2-yl)propanamide With acetic acid; sodium nitrite In acetic anhydride at -15℃; for 48.5h; Stage #2: With lithium hydroxide monohydrate; dihydrogen peroxide In tetrahydrofuran; water; acetic anhydride at -15℃; for 2h; Stage #3: In tetrahydrofuran; water; acetic anhydride at 0℃; for 2h;

Reference： [1]Zhang, Qi; Chen, Kai; Rao, Weihao; Zhang, Yuejun; Chen, Fa-Jie; Shi, Bing-Feng [Angewandte Chemie - International Edition, 2013, vol. 52, # 51, p. 13588 - 13592][Angew. Chem., 2013, vol. 125, # 51, p. 13833 - 13837,5]

46
[ 1582806-47-0 ]
[ 5123-55-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With acetic anhydride; acetic acid; sodium nitrite at 0 - 20℃; for 20h;
95%	With acetic anhydride; sodium nitrite In acetic acid at 0 - 20℃; for 20h;	F F . Auxiliary Cleavage The mono-arylated product Compound 2 (153 mg, 0.3 mmol) was dissolved in the mixed solvents (3 mL, AcOH/Ac20 = 1/2), and then cooled to 0 °C. NaN02 (414 mg, 6 mmol) was slowly added into the reaction mixture in portions. The reaction mixture was first stirred at 0 °C for 3 hours and then at room temperature for 17 hours. Upon completion, the solvents were removed under reduced pressure, and the mixture was neutralized by slow addition of saturated aHC03 solution to pH 8. The aqueous phase was extracted with ether (4 χ 10 mL) , and then carefully acidified with cold HC1 solution (I N) to pH 2, and then extracted with ether (4 χ 20 mL) . The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo to afford the desired product Compound 4 (84.5 mg, 95%) (31) . NMR (400 MHz, CDC13) δ 8.11 (br s, 1H) , 7.80-7.75 (m, 2H) , 7.70-7.65 (m, 2H) , 7.21-7.11 (m, 5H) , 5.22 (dd, Ji = 7.6 Hz, J2 = 8.8 Hz, 1H) , 3.60- 3.58 (m, 2H) .

Reference： [1]He, Jian; Li, Suhua; Deng, Youqian; Fu, Haiyan; Laforteza, Brian N.; Spangler, Jillian E.; Homs, Anna; Yu, Jin-Quan [Science, 2014, vol. 343, # 6176, p. 1216 - 1220]
[2]Current Patent Assignee: SCRIPPS RESEARCH - WO2015/131100, 2015, A1 Location in patent: Page/Page column 130; 131

47
[ 77897-23-5 ]
[ 5123-55-7 ]
[ 1643770-69-7 ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 7228 - 7231

48
[ 1643771-07-6 ]
[ 5123-55-7 ]
[ 1643771-03-2 ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: Nα-phthaloyl-L-phenylalanine With diisopropyl-carbodiimide In tetrahydrofuran at 0℃; for 0.333333h; Inert atmosphere; Stage #2: 3-hydroxy-2,2-dimethyl-1-(2-phenylacetyl)imidazolidin-4-one In tetrahydrofuran at 20℃; Inert atmosphere;

Reference： [1]Hsieh, Sheng-Ying; Wanner, Benedikt; Wheeler, Philip; Beauchemin, Andre M.; Rovis, Tomislav; Bode, Jeffrey W. [Chemistry - A European Journal, 2014, vol. 20, # 24, p. 7228 - 7231]

49
[ 481038-59-9 ]
[ 5123-55-7 ]
[ 1643770-75-5 ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 7228 - 7231

50
[ 1415097-58-3 ]
[ 5123-55-7 ]
N-phthaloyl-L-phenylalaninyl-N-acetylglycine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With silver carbonate In dichloromethane at 20℃; for 2h;

Reference： [1]Pourvali, Aysa; Cochrane, James R.; Hutton, Craig A. [Chemical Communications, 2014, vol. 50, # 100, p. 15963 - 15966]

51
[ 116287-43-5 ]
[ 5123-55-7 ]
N-phthaloyl-L-phenylalaninyl-N-acetyl-L-alanine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With silver carbonate In dichloromethane at 20℃; for 2h;

Reference： [1]Pourvali, Aysa; Cochrane, James R.; Hutton, Craig A. [Chemical Communications, 2014, vol. 50, # 100, p. 15963 - 15966]

52
N-thioacetyl-L-phenylalanine methyl ester [ No CAS ]
[ 5123-55-7 ]
N-phthaloyl-L-phenylalaninyl-N-acetyl-L-phenylalanine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With silver carbonate In dichloromethane at 20℃; for 2h;

Reference： [1]Pourvali, Aysa; Cochrane, James R.; Hutton, Craig A. [Chemical Communications, 2014, vol. 50, # 100, p. 15963 - 15966]

53
[ 105740-12-3 ]
[ 5123-55-7 ]
N-phthaloyl-L-phenylalaninyl-N-acetyl-L-valine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With silver carbonate In dichloromethane at 20℃; for 2h;

Reference： [1]Pourvali, Aysa; Cochrane, James R.; Hutton, Craig A. [Chemical Communications, 2014, vol. 50, # 100, p. 15963 - 15966]

54
N-thioacetyl-L-leucine methyl ester [ No CAS ]
[ 5123-55-7 ]
N-phthaloyl-L-phenylalaninyl-N-acetyl-L-leucine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With silver carbonate In dichloromethane at 20℃; for 2h;

Reference： [1]Pourvali, Aysa; Cochrane, James R.; Hutton, Craig A. [Chemical Communications, 2014, vol. 50, # 100, p. 15963 - 15966]

55
[ 517-89-5 ]
[ 5123-55-7 ]
(2S)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-3-yl)-4-methylpent-3-en-1-yl-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: Nα-phthaloyl-L-phenylalanine With dicyclohexyl-carbodiimide In dichloromethane for 0.25h; Inert atmosphere; Cooling with ice; Stage #2: shikonin With dmap In dichloromethane for 12h; Cooling with ice;

Reference： [1]Baloch, Shahla Karim; Ma, Lin; Wang, Xue-Liang; Shi, Jing; Zhu, Yu; Wu, Feng-Yao; Pang, Yan-Jun; Lu, Gui-Hua; Qi, Jin-Liang; Wang, Xiao-Ming; Gu, Hong-Wei; Yang, Yong-Hua [RSC Advances, 2015, vol. 5, # 40, p. 31759 - 31767]

56
C₁₅H₂₅N₃O [ No CAS ]
[ 5123-55-7 ]
C₃₂H₃₆N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Nα-phthaloyl-L-phenylalanine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 1h; Stage #2: C₁₅H₂₅N₃O In dichloromethane at 0 - 20℃; for 24.5h;	General procedure for deprotection and coupling reaction with N-phthaloyl-L-aminoacids to afford 6a-6u. General procedure: A solution of Boc-protected hydroxyethylamines, 5a (101 mg, 0.28mmol) in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the oily substance obtained was used for further reactions without purification. In another round bottomed flask, N-phthaloyl-L-leucine (88 mg, 0.34 mmol) in dichloromethane (20 mL) along with triethylamine (TEA) (1 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCHCl) (97 mg, 0.51 mmol) and anhydrous 1-hydroxybenzotriazole (HOBt) (69 mg, 0.51mmol) were stirred at 0°C for 1 h followed by addition of Boc-deprotected hydroxyethylamine diluted with dichloromethane (3 mL). This procedure was followed to prepare compounds 6aq. The reaction mixture was stirred at 0°C for another 30 minutes and then at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The semi-solid material obtained was diluted with 25 mL of ethyl acetate and washed three times with distilled water. The organic layer obtained was dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The obtained compounds were purified by column chromatography using silica gel as stationary phase and chloroform-methanol (96:4) as eluent that afforded a white solid (6a-q) in fair to good yield (Table 2). The spectroscopic details are furnished in supporting information.To obtain 6r, 6t and 6u, a solution of Boc-protected bis-hydroxyethylpiperazine, 5f (171mg, 0.28 mmol) in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the oily substance obtained was used for further reactions without purification. In another round bottomed flask, N-phthaloyl-L-amino acid (161 mg, 0.62 mmol) in dichloromethane (20 mL) along with triethylamine (TEA) (1 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC•HCl) (177 mg, 0.93 mmol) and anhydrous 1-hydroxybenzotriazole (HOBt) (125 mg, 0.93 mmol) were stirred at 0°C for 1 h followed by addition of Boc-deprotected hydroxyethyl piperazine diluted with dichloromethane (3 mL). The reaction mixture was stirred at 0°C for another 30 minutes and then at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The semi-solid material obtained was diluted with 25 mL of ethyl acetate and washed three times with distilled water. The organic layer obtained was dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The obtained compounds were purified by column chromatography using silica gel as stationary phase and chloroform-methanol (96:4) as eluent that afforded a white solid (6r-u) in fair to good yield (Table 3). The spectroscopic details are furnished in supporting information. Compound 6s was prepared following literature procedure [30].

Reference： [1]Singh, Anil K.; Rathore, Sumit; Tang, Yan; Goldfarb, Nathan E.; Dunn, Ben M.; Rajendran, Vinoth; Ghosh, Prahlad C.; Singh, Neelu; Latha; Singh, Brajendra K.; Rawat, Manmeet; Rathi, Brijesh [PLoS ONE, 2015, vol. 10, # 10]

57
C₁₆H₂₇N₃O [ No CAS ]
[ 5123-55-7 ]
C₃₃H₃₈N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Nα-phthaloyl-L-phenylalanine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 1h; Stage #2: C₁₆H₂₇N₃O In dichloromethane at 0 - 20℃; for 24.5h;	General procedure for deprotection and coupling reaction with N-phthaloyl-L-aminoacids to afford 6a-6u. General procedure: A solution of Boc-protected hydroxyethylamines, 5a (101 mg, 0.28mmol) in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the oily substance obtained was used for further reactions without purification. In another round bottomed flask, N-phthaloyl-L-leucine (88 mg, 0.34 mmol) in dichloromethane (20 mL) along with triethylamine (TEA) (1 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCHCl) (97 mg, 0.51 mmol) and anhydrous 1-hydroxybenzotriazole (HOBt) (69 mg, 0.51mmol) were stirred at 0°C for 1 h followed by addition of Boc-deprotected hydroxyethylamine diluted with dichloromethane (3 mL). This procedure was followed to prepare compounds 6aq. The reaction mixture was stirred at 0°C for another 30 minutes and then at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The semi-solid material obtained was diluted with 25 mL of ethyl acetate and washed three times with distilled water. The organic layer obtained was dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The obtained compounds were purified by column chromatography using silica gel as stationary phase and chloroform-methanol (96:4) as eluent that afforded a white solid (6a-q) in fair to good yield (Table 2). The spectroscopic details are furnished in supporting information.To obtain 6r, 6t and 6u, a solution of Boc-protected bis-hydroxyethylpiperazine, 5f (171mg, 0.28 mmol) in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the oily substance obtained was used for further reactions without purification. In another round bottomed flask, N-phthaloyl-L-amino acid (161 mg, 0.62 mmol) in dichloromethane (20 mL) along with triethylamine (TEA) (1 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC•HCl) (177 mg, 0.93 mmol) and anhydrous 1-hydroxybenzotriazole (HOBt) (125 mg, 0.93 mmol) were stirred at 0°C for 1 h followed by addition of Boc-deprotected hydroxyethyl piperazine diluted with dichloromethane (3 mL). The reaction mixture was stirred at 0°C for another 30 minutes and then at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The semi-solid material obtained was diluted with 25 mL of ethyl acetate and washed three times with distilled water. The organic layer obtained was dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The obtained compounds were purified by column chromatography using silica gel as stationary phase and chloroform-methanol (96:4) as eluent that afforded a white solid (6r-u) in fair to good yield (Table 3). The spectroscopic details are furnished in supporting information. Compound 6s was prepared following literature procedure [30].

Reference： [1]Singh, Anil K.; Rathore, Sumit; Tang, Yan; Goldfarb, Nathan E.; Dunn, Ben M.; Rajendran, Vinoth; Ghosh, Prahlad C.; Singh, Neelu; Latha; Singh, Brajendra K.; Rawat, Manmeet; Rathi, Brijesh [PLoS ONE, 2015, vol. 10, # 10]

58
C₂₁H₂₈FN₃O [ No CAS ]
[ 5123-55-7 ]
C₃₈H₃₉FN₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Nα-phthaloyl-L-phenylalanine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 1h; Stage #2: C₂₁H₂₈FN₃O In dichloromethane at 0 - 20℃; for 24.5h;	General procedure for deprotection and coupling reaction with N-phthaloyl-L-aminoacids to afford 6a-6u. General procedure: A solution of Boc-protected hydroxyethylamines, 5a (101 mg, 0.28mmol) in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the oily substance obtained was used for further reactions without purification. In another round bottomed flask, N-phthaloyl-L-leucine (88 mg, 0.34 mmol) in dichloromethane (20 mL) along with triethylamine (TEA) (1 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCHCl) (97 mg, 0.51 mmol) and anhydrous 1-hydroxybenzotriazole (HOBt) (69 mg, 0.51mmol) were stirred at 0°C for 1 h followed by addition of Boc-deprotected hydroxyethylamine diluted with dichloromethane (3 mL). This procedure was followed to prepare compounds 6aq. The reaction mixture was stirred at 0°C for another 30 minutes and then at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The semi-solid material obtained was diluted with 25 mL of ethyl acetate and washed three times with distilled water. The organic layer obtained was dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The obtained compounds were purified by column chromatography using silica gel as stationary phase and chloroform-methanol (96:4) as eluent that afforded a white solid (6a-q) in fair to good yield (Table 2). The spectroscopic details are furnished in supporting information.To obtain 6r, 6t and 6u, a solution of Boc-protected bis-hydroxyethylpiperazine, 5f (171mg, 0.28 mmol) in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the oily substance obtained was used for further reactions without purification. In another round bottomed flask, N-phthaloyl-L-amino acid (161 mg, 0.62 mmol) in dichloromethane (20 mL) along with triethylamine (TEA) (1 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC•HCl) (177 mg, 0.93 mmol) and anhydrous 1-hydroxybenzotriazole (HOBt) (125 mg, 0.93 mmol) were stirred at 0°C for 1 h followed by addition of Boc-deprotected hydroxyethyl piperazine diluted with dichloromethane (3 mL). The reaction mixture was stirred at 0°C for another 30 minutes and then at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The semi-solid material obtained was diluted with 25 mL of ethyl acetate and washed three times with distilled water. The organic layer obtained was dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The obtained compounds were purified by column chromatography using silica gel as stationary phase and chloroform-methanol (96:4) as eluent that afforded a white solid (6r-u) in fair to good yield (Table 3). The spectroscopic details are furnished in supporting information. Compound 6s was prepared following literature procedure [30].

Reference： [1]Singh, Anil K.; Rathore, Sumit; Tang, Yan; Goldfarb, Nathan E.; Dunn, Ben M.; Rajendran, Vinoth; Ghosh, Prahlad C.; Singh, Neelu; Latha; Singh, Brajendra K.; Rawat, Manmeet; Rathi, Brijesh [PLoS ONE, 2015, vol. 10, # 10]

59
C₂₁H₂₈BrN₃O [ No CAS ]
[ 5123-55-7 ]
C₃₈H₃₉BrN₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Nα-phthaloyl-L-phenylalanine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 1h; Stage #2: C₂₁H₂₈BrN₃O In dichloromethane at 0 - 20℃; for 24.5h;	General procedure for deprotection and coupling reaction with N-phthaloyl-L-aminoacids to afford 6a-6u. General procedure: A solution of Boc-protected hydroxyethylamines, 5a (101 mg, 0.28mmol) in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the oily substance obtained was used for further reactions without purification. In another round bottomed flask, N-phthaloyl-L-leucine (88 mg, 0.34 mmol) in dichloromethane (20 mL) along with triethylamine (TEA) (1 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCHCl) (97 mg, 0.51 mmol) and anhydrous 1-hydroxybenzotriazole (HOBt) (69 mg, 0.51mmol) were stirred at 0°C for 1 h followed by addition of Boc-deprotected hydroxyethylamine diluted with dichloromethane (3 mL). This procedure was followed to prepare compounds 6aq. The reaction mixture was stirred at 0°C for another 30 minutes and then at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The semi-solid material obtained was diluted with 25 mL of ethyl acetate and washed three times with distilled water. The organic layer obtained was dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The obtained compounds were purified by column chromatography using silica gel as stationary phase and chloroform-methanol (96:4) as eluent that afforded a white solid (6a-q) in fair to good yield (Table 2). The spectroscopic details are furnished in supporting information.To obtain 6r, 6t and 6u, a solution of Boc-protected bis-hydroxyethylpiperazine, 5f (171mg, 0.28 mmol) in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the oily substance obtained was used for further reactions without purification. In another round bottomed flask, N-phthaloyl-L-amino acid (161 mg, 0.62 mmol) in dichloromethane (20 mL) along with triethylamine (TEA) (1 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC•HCl) (177 mg, 0.93 mmol) and anhydrous 1-hydroxybenzotriazole (HOBt) (125 mg, 0.93 mmol) were stirred at 0°C for 1 h followed by addition of Boc-deprotected hydroxyethyl piperazine diluted with dichloromethane (3 mL). The reaction mixture was stirred at 0°C for another 30 minutes and then at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The semi-solid material obtained was diluted with 25 mL of ethyl acetate and washed three times with distilled water. The organic layer obtained was dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The obtained compounds were purified by column chromatography using silica gel as stationary phase and chloroform-methanol (96:4) as eluent that afforded a white solid (6r-u) in fair to good yield (Table 3). The spectroscopic details are furnished in supporting information. Compound 6s was prepared following literature procedure [30].

Reference： [1]Singh, Anil K.; Rathore, Sumit; Tang, Yan; Goldfarb, Nathan E.; Dunn, Ben M.; Rajendran, Vinoth; Ghosh, Prahlad C.; Singh, Neelu; Latha; Singh, Brajendra K.; Rawat, Manmeet; Rathi, Brijesh [PLoS ONE, 2015, vol. 10, # 10]

60
C₂₀H₃₃N₃O [ No CAS ]
[ 5123-55-7 ]
C₃₇H₄₄N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Nα-phthaloyl-L-phenylalanine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 1h; Stage #2: C₂₀H₃₃N₃O In dichloromethane at 0 - 20℃; for 24.5h;	General procedure for deprotection and coupling reaction with N-phthaloyl-L-aminoacids to afford 6a-6u. General procedure: A solution of Boc-protected hydroxyethylamines, 5a (101 mg, 0.28mmol) in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the oily substance obtained was used for further reactions without purification. In another round bottomed flask, N-phthaloyl-L-leucine (88 mg, 0.34 mmol) in dichloromethane (20 mL) along with triethylamine (TEA) (1 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCHCl) (97 mg, 0.51 mmol) and anhydrous 1-hydroxybenzotriazole (HOBt) (69 mg, 0.51mmol) were stirred at 0°C for 1 h followed by addition of Boc-deprotected hydroxyethylamine diluted with dichloromethane (3 mL). This procedure was followed to prepare compounds 6aq. The reaction mixture was stirred at 0°C for another 30 minutes and then at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The semi-solid material obtained was diluted with 25 mL of ethyl acetate and washed three times with distilled water. The organic layer obtained was dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The obtained compounds were purified by column chromatography using silica gel as stationary phase and chloroform-methanol (96:4) as eluent that afforded a white solid (6a-q) in fair to good yield (Table 2). The spectroscopic details are furnished in supporting information.To obtain 6r, 6t and 6u, a solution of Boc-protected bis-hydroxyethylpiperazine, 5f (171mg, 0.28 mmol) in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the oily substance obtained was used for further reactions without purification. In another round bottomed flask, N-phthaloyl-L-amino acid (161 mg, 0.62 mmol) in dichloromethane (20 mL) along with triethylamine (TEA) (1 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC•HCl) (177 mg, 0.93 mmol) and anhydrous 1-hydroxybenzotriazole (HOBt) (125 mg, 0.93 mmol) were stirred at 0°C for 1 h followed by addition of Boc-deprotected hydroxyethyl piperazine diluted with dichloromethane (3 mL). The reaction mixture was stirred at 0°C for another 30 minutes and then at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The semi-solid material obtained was diluted with 25 mL of ethyl acetate and washed three times with distilled water. The organic layer obtained was dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The obtained compounds were purified by column chromatography using silica gel as stationary phase and chloroform-methanol (96:4) as eluent that afforded a white solid (6r-u) in fair to good yield (Table 3). The spectroscopic details are furnished in supporting information. Compound 6s was prepared following literature procedure [30].

Reference： [1]Singh, Anil K.; Rathore, Sumit; Tang, Yan; Goldfarb, Nathan E.; Dunn, Ben M.; Rajendran, Vinoth; Ghosh, Prahlad C.; Singh, Neelu; Latha; Singh, Brajendra K.; Rawat, Manmeet; Rathi, Brijesh [PLoS ONE, 2015, vol. 10, # 10]

61
[ 100-01-6 ]
[ 5123-55-7 ]
Nphth-L-phenylalanyl-p-nitroanilide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-nitro-aniline; Nα-phthaloyl-L-phenylalanine In ethyl acetate Stage #2: With dicyclohexyl-carbodiimide In ethyl acetate at 20℃;	2.4. Synthesis of the substrate Z-l-phenylalanine-p-nitroanilide(Z-l-Phe-PNA) General procedure: The substrate Z-l-Phe-PNA was synthesized by dissolving2.99 mg (0.01 mol) Z-l-phenylalanine and 1.38 mg (0.01 mol) p-nitroaniline in 30 mL ethyl acetate and the solution was stirred ona magnetic stirrer in an ice-water bath for half an hour. A solu-tion of 2.06 mg (0.01 mol) DCC in 30 mL ethyl acetate was addeddrop wise and the reaction mixture was stirred for 30 min in theice water bath and the stirring was continued for further 3 h atroom temperature. The DCU formed was filtered off and the filtratewas evaporated in vacuum. The residue obtained was recrystal-lized from hot ethanol containing 1% acetic acid. The substrates,t-Boc/Nphth/Fmoc-l-phenylalanyl-p-nitroanilide and Z-l-alanyl-p-nitroanilide were also prepared following the same procedure.

Reference： [1]Mathew, Divya; Thomas, Benny; Devaky [Journal of Molecular Catalysis A: Chemical, 2016, vol. 415, p. 65 - 73]

62
Nphth-L-phenylalanyl-p-nitroanilide [ No CAS ]
[ 5123-55-7 ]

Yield	Reaction Conditions	Operation in experiment
	With phenyl-1-(N-benzyloxycarbonylamino)-2-(phenyl)ethylphosphonate In acetonitrile at 45℃; Enzymatic reaction;	General procedure: A suspension of 10 mg chymotrypsin mimic C1 (0.00647 mmol)was suspended in 5 mL acetonitrile-Tris HCl buffer (1:9 by volume,pH 7.75) in a reagent bottle and 271 mg, 0.647 mmol of the sub-strate Z-Phe-PNA in 50 mL acetonitrile was added. The reactionmixture was placed in a water bath shaker at 45C and shakengently. Amidolysis of Z-Phe-PNA was followed by monitoring theabsorbance of released p-nitroaniline spectrophotometrically at374 nm in the framework of Michaelis-Menten kinetics and thereaction was monitored for two days. A blank reaction was also car-ried out in the absence of the enzyme mimic. From the absorbancedata, the rate constants and percentage amidolysis were evaluated.Amidase activity of the mimics C2-C7 was evaluated in a similarmanner.

Reference： [1]Mathew, Divya; Thomas, Benny; Devaky [Journal of Molecular Catalysis A: Chemical, 2016, vol. 415, p. 65 - 73]

63
[ 5123-55-7 ]
[ 518-28-5 ]
(5aR,8aR)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl (2S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 12h;	1.1.1 General procedure for preparation of compounds Q1-Q18 General procedure: Phenylalanine or alanine (10 mmol) and anhydride (10 mmol) were heatedand refluxed in 20 mL of acetic acid for 4 h and monitored by TLC. Aftercompletion of the reaction, the solution was stirred and poured into 500 mL ofice water. When the precipitate was appeared, filtering it and then dry it in vacuumdrying oven. Next, the carboxylic acid (5 mmol) which was obtained in theprevious step and podophyllotoxin (6 mmol) were dissolved in dichloromethane(25mL) and stirred for 12 h with DCC (10 mmol) as dehydrator and DMAP (1 mmol) ascatalyst at room temperature. Adding proper amount of silica gel and condensingsolvent by vacuum concentration. Then, collecting target compounds by columnchromatography (V (dichloromethane):V (acetone) =1:50).

Reference： [1]Han, Hong-Wei; Qiu, Han-Yue; Hu, Cui; Sun, Wen-Xue; Yang, Rong-Wu; Qi, Jin-Liang; Wang, Xiao-Ming; Lu, Gui-Hua; Yang, Yong-Hua [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 14, p. 3237 - 3242]

64
[ 17609-47-1 ]
[ 5123-55-7 ]
C₂₄H₂₆N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The N-protected amino acid (12.0 mmol, 1.0 equiv) and HOBt (12.0 mmol, 1.0 equiv), were dissolved in EtOAc (90 mL)in a round bottom flask equipped with a stir bar. The reaction mixture was cooled to 0 C. DCC (13.2 mmol, 1.1 equiv) was added, and the reaction mixture was stirred for 30 min at 0 C. The reaction mixture was then warmed to room temperature, and the C-protected amino acid hydrochloride (12.0 mmol, 1.0 equiv) and triethylamine (12.0 mmol, 1.0 equiv) were added. The reaction mixture was stirred for an additional 2 h. Hexanes (25 mL) were added, and the reaction mixture was stored in a freezer overnight. It was then filtered through Celite to remove in soluble byproducts. The filtrate was transferred to separatory funnel, washed with 0.5 M HCl, saturated NaHCO3, and then brine. The combined organic layers were dried with MgSO4, filtered through Celite, and concentrated. Products were purified via recrystallization using Et2O/EtOAc.

Reference： [1]Tetrahedron,2016,vol. 72,p. 6031 - 6036

65
[ 2743-40-0 ]
[ 5123-55-7 ]
[ 103169-13-7 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The N-protected amino acid (12.0 mmol, 1.0 equiv) and HOBt (12.0 mmol, 1.0 equiv), were dissolved in EtOAc (90 mL)in a round bottom flask equipped with a stir bar. The reaction mixture was cooled to 0 C. DCC (13.2 mmol, 1.1 equiv) was added, and the reaction mixture was stirred for 30 min at 0 C. The reaction mixture was then warmed to room temperature, and the C-protected amino acid hydrochloride (12.0 mmol, 1.0 equiv) and triethylamine (12.0 mmol, 1.0 equiv) were added. The reaction mixture was stirred for an additional 2 h. Hexanes (25 mL) were added, and the reaction mixture was stored in a freezer overnight. It was then filtered through Celite to remove in soluble byproducts. The filtrate was transferred to separatory funnel, washed with 0.5 M HCl, saturated NaHCO3, and then brine. The combined organic layers were dried with MgSO4, filtered through Celite, and concentrated. Products were purified via recrystallization using Et2O/EtOAc.

Reference： [1]Tetrahedron,2016,vol. 72,p. 6031 - 6036

66
[ 5123-55-7 ]
(2R)-2-(1,3-dioxoisoindolin-2-yl)-3-fluoro-3-phenylpropanoic acid [ No CAS ]
(2R)-2-(1,3-dioxoisoindolin-2-yl)-3-fluoro-3-phenylpropanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Selectfluor; dibenzosuberenon In acetonitrile for 16h; Sealed tube; Irradiation; Overall yield = 80 %; Optical yield = 9.091 %de;	2 4.1. General procedure for photochemical fluorination of peptides General procedure: The substrate (0.25 mmol), Selectfluor (177 mg, 0.5 mmol), dibenzosuberenone (3.0 mg, 0.01 mmol), and anhydrous MeCN (3 mL) were added to an oven-dried microwave vial equipped with a stir bar under ambient air; the vial was then sealed with a septum to prevent solvent evaporation. The reaction mixture was stirred and irradiated with visible light (14-Watt CFL) for 16 h. At this time, 0.3 mL aliquots were taken for 19F NMR analysis, while the remainder of the reaction mixture was diluted with Et2O, filtered through Celite, and concentrated. Products were purified as individual diastereomers (compounds 2, 4, 7, 8, and 9) or as mixtures of diastereomers via gradient column chromatography using a CombiFlash Rf+Lumen either on silica gel eluting with 100:0 hexanes:EtOAc to 0:100 hexanes:EtOAc or on C18 eluting with 10:90 MeCN:H2O to 100:0 MeCN:H2O.

Reference： [1]Bume, Desta Doro; Pitts, Cody Ross; Jokhai, Rayyan Trebonias; Lectka, Thomas [Tetrahedron, 2016, vol. 72, # 40, p. 6031 - 6036]

67
[ 5123-55-7 ]
(2R)-2-(1,3-Dioxoisoindolin-2-yl)-3-fluoro-3-phenylprop-anoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With Selectfluor; dibenzosuberenon In acetonitrile for 16h; Sealed tube; Irradiation;	13 4.1. General procedure for photochemical fluorination of peptides General procedure: The substrate (0.25 mmol), Selectfluor (177 mg, 0.5 mmol), dibenzosuberenone (3.0 mg, 0.01 mmol), and anhydrous MeCN (3 mL) were added to an oven-dried microwave vial equipped with a stir bar under ambient air; the vial was then sealed with a septum to prevent solvent evaporation. The reaction mixture was stirred and irradiated with visible light (14-Watt CFL) for 16 h. At this time, 0.3 mL aliquots were taken for 19F NMR analysis, while the remainder of the reaction mixture was diluted with Et2O, filtered through Celite, and concentrated. Products were purified as individual diastereomers (compounds 2, 4, 7, 8, and 9) or as mixtures of diastereomers via gradient column chromatography using a CombiFlash Rf+Lumen either on silica gel eluting with 100:0 hexanes:EtOAc to 0:100 hexanes:EtOAc or on C18 eluting with 10:90 MeCN:H2O to 100:0 MeCN:H2O.

Reference： [1]Bume, Desta Doro; Pitts, Cody Ross; Jokhai, Rayyan Trebonias; Lectka, Thomas [Tetrahedron, 2016, vol. 72, # 40, p. 6031 - 6036]

68
[ 91345-62-9 ]
[ 5123-55-7 ]
(S)-2-(1-(4-(4-bromobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: Nα-phthaloyl-L-phenylalanine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 0.25h; Stage #2: With benzotriazol-1-ol In dichloromethane at 0℃; for 0.25h; Stage #3: 1-(4-bromobenzyl)piperazine In dichloromethane at 20℃; for 24h;	2.1b General procedure for synthesis of phthalimides (3a-t): General procedure: To the solution of N-phthaloyl-L-amino acid (0.4 mmol) in dichloromethane (20 mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, EDC·HCl (0.6 mmol) and triethylamine, TEA (1.6 mmol) were added and the contents were stirred at 0C for 15 min to secure homogenous reaction mixture. Subsequently, HOBt (0.6 mmol) was added to the reaction mixture and stirring was continued for another 15 min atthe same temperature. N-substituted piperazine derivative (0.48 mmol) was added and reaction mixture was stirred for 24 h at room temperature. The solvent was evaporated under reduced pressure and the reaction contents were extracted with ethyl acetate and water. The organic layer was collected separately, concentrated under reduced pressure and purified by column chromatography(ethylacetate/petroleum ether, 4:6). Phthalimides(3a, 3e, 3g, 3i and 3m) have been previously prepared by our team and their structural aspects were investigated for nonlinear optical property.37 All the compounds were characterized by spectroscopic tools and the corresponding spectroscopic data are described in supporting information.

Reference： [1]Singh, Anil K; Bhardwaj, Jitender K; Olival, Ana; Kumar, Yogesh; Podder, Avijit; Maheshwari, Ankur; Agrawal, Renuka; Latha; Singh, Brajendra K; Tomás, Helena; Rodrigues, João; Kishan, Ram; Rupini; Rathi, Brijesh [Journal of Chemical Sciences, 2016, vol. 128, # 8, p. 1245 - 1263]

69
[ 70931-28-1 ]
[ 5123-55-7 ]
(S)-2-(1-(4-(4-fluorobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: Nα-phthaloyl-L-phenylalanine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 0.25h; Stage #2: With benzotriazol-1-ol In dichloromethane at 0℃; for 0.25h; Stage #3: 1-(4-fluorophenylmethyl)piperazine In dichloromethane at 20℃; for 24h;	2.1b General procedure for synthesis of phthalimides (3a-t): General procedure: To the solution of N-phthaloyl-L-amino acid (0.4 mmol) in dichloromethane (20 mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, EDC·HCl (0.6 mmol) and triethylamine, TEA (1.6 mmol) were added and the contents were stirred at 0C for 15 min to secure homogenous reaction mixture. Subsequently, HOBt (0.6 mmol) was added to the reaction mixture and stirring was continued for another 15 min atthe same temperature. N-substituted piperazine derivative (0.48 mmol) was added and reaction mixture was stirred for 24 h at room temperature. The solvent was evaporated under reduced pressure and the reaction contents were extracted with ethyl acetate and water. The organic layer was collected separately, concentrated under reduced pressure and purified by column chromatography(ethylacetate/petroleum ether, 4:6). Phthalimides(3a, 3e, 3g, 3i and 3m) have been previously prepared by our team and their structural aspects were investigated for nonlinear optical property.37 All the compounds were characterized by spectroscopic tools and the corresponding spectroscopic data are described in supporting information.

Reference： [1]Singh, Anil K; Bhardwaj, Jitender K; Olival, Ana; Kumar, Yogesh; Podder, Avijit; Maheshwari, Ankur; Agrawal, Renuka; Latha; Singh, Brajendra K; Tomás, Helena; Rodrigues, João; Kishan, Ram; Rupini; Rathi, Brijesh [Journal of Chemical Sciences, 2016, vol. 128, # 8, p. 1245 - 1263]

70
[ 107890-32-4 ]
[ 5123-55-7 ]
(S)-2-(1-oxo-3-phenyl-1-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)propan-2-yl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: Nα-phthaloyl-L-phenylalanine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 0.25h; Stage #2: With benzotriazol-1-ol In dichloromethane at 0℃; for 0.25h; Stage #3: 1-(4-trifluoromethylbenzyl)piperazine In dichloromethane at 20℃; for 24h;	2.1b General procedure for synthesis of phthalimides (3a-t): General procedure: To the solution of N-phthaloyl-L-amino acid (0.4 mmol) in dichloromethane (20 mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, EDC·HCl (0.6 mmol) and triethylamine, TEA (1.6 mmol) were added and the contents were stirred at 0C for 15 min to secure homogenous reaction mixture. Subsequently, HOBt (0.6 mmol) was added to the reaction mixture and stirring was continued for another 15 min atthe same temperature. N-substituted piperazine derivative (0.48 mmol) was added and reaction mixture was stirred for 24 h at room temperature. The solvent was evaporated under reduced pressure and the reaction contents were extracted with ethyl acetate and water. The organic layer was collected separately, concentrated under reduced pressure and purified by column chromatography(ethylacetate/petroleum ether, 4:6). Phthalimides(3a, 3e, 3g, 3i and 3m) have been previously prepared by our team and their structural aspects were investigated for nonlinear optical property.37 All the compounds were characterized by spectroscopic tools and the corresponding spectroscopic data are described in supporting information.

Reference： [1]Singh, Anil K; Bhardwaj, Jitender K; Olival, Ana; Kumar, Yogesh; Podder, Avijit; Maheshwari, Ankur; Agrawal, Renuka; Latha; Singh, Brajendra K; Tomás, Helena; Rodrigues, João; Kishan, Ram; Rupini; Rathi, Brijesh [Journal of Chemical Sciences, 2016, vol. 128, # 8, p. 1245 - 1263]

71
[ 956-61-6 ]
[ 5123-55-7 ]
(S)-2-(1-(4-(4-(tert-butyl)benzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: Nα-phthaloyl-L-phenylalanine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 0.25h; Stage #2: With benzotriazol-1-ol In dichloromethane at 0℃; for 0.25h; Stage #3: 1-(4-tert-butylbenzyl)piperazine In dichloromethane at 20℃; for 24h;	2.1b General procedure for synthesis of phthalimides (3a-t): General procedure: To the solution of N-phthaloyl-L-amino acid (0.4 mmol) in dichloromethane (20 mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, EDC·HCl (0.6 mmol) and triethylamine, TEA (1.6 mmol) were added and the contents were stirred at 0C for 15 min to secure homogenous reaction mixture. Subsequently, HOBt (0.6 mmol) was added to the reaction mixture and stirring was continued for another 15 min atthe same temperature. N-substituted piperazine derivative (0.48 mmol) was added and reaction mixture was stirred for 24 h at room temperature. The solvent was evaporated under reduced pressure and the reaction contents were extracted with ethyl acetate and water. The organic layer was collected separately, concentrated under reduced pressure and purified by column chromatography(ethylacetate/petroleum ether, 4:6). Phthalimides(3a, 3e, 3g, 3i and 3m) have been previously prepared by our team and their structural aspects were investigated for nonlinear optical property.37 All the compounds were characterized by spectroscopic tools and the corresponding spectroscopic data are described in supporting information.

Reference： [1]Singh, Anil K; Bhardwaj, Jitender K; Olival, Ana; Kumar, Yogesh; Podder, Avijit; Maheshwari, Ankur; Agrawal, Renuka; Latha; Singh, Brajendra K; Tomás, Helena; Rodrigues, João; Kishan, Ram; Rupini; Rathi, Brijesh [Journal of Chemical Sciences, 2016, vol. 128, # 8, p. 1245 - 1263]

72
[ 5321-49-3 ]
[ 5123-55-7 ]
(S)-2-(1-oxo-1-(4-phenethylpiperazin-1-yl)-3-phenylpropan-2-yl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: Nα-phthaloyl-L-phenylalanine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; for 0.25h; Stage #2: With benzotriazol-1-ol In dichloromethane at 0℃; for 0.25h; Stage #3: 4-(phenethyl)piperazine In dichloromethane at 20℃; for 24h;	2.1b General procedure for synthesis of phthalimides (3a-t): General procedure: To the solution of N-phthaloyl-L-amino acid (0.4 mmol) in dichloromethane (20 mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, EDC·HCl (0.6 mmol) and triethylamine, TEA (1.6 mmol) were added and the contents were stirred at 0C for 15 min to secure homogenous reaction mixture. Subsequently, HOBt (0.6 mmol) was added to the reaction mixture and stirring was continued for another 15 min atthe same temperature. N-substituted piperazine derivative (0.48 mmol) was added and reaction mixture was stirred for 24 h at room temperature. The solvent was evaporated under reduced pressure and the reaction contents were extracted with ethyl acetate and water. The organic layer was collected separately, concentrated under reduced pressure and purified by column chromatography(ethylacetate/petroleum ether, 4:6). Phthalimides(3a, 3e, 3g, 3i and 3m) have been previously prepared by our team and their structural aspects were investigated for nonlinear optical property.37 All the compounds were characterized by spectroscopic tools and the corresponding spectroscopic data are described in supporting information.

Reference： [1]Singh, Anil K; Bhardwaj, Jitender K; Olival, Ana; Kumar, Yogesh; Podder, Avijit; Maheshwari, Ankur; Agrawal, Renuka; Latha; Singh, Brajendra K; Tomás, Helena; Rodrigues, João; Kishan, Ram; Rupini; Rathi, Brijesh [Journal of Chemical Sciences, 2016, vol. 128, # 8, p. 1245 - 1263]

73
α-Isocyan-β,β-diphenylacrylsaeure-ethylester [ No CAS ]
[ 5123-55-7 ]
ethyl 4-phenyl-1-((1,3-dioxisoindolin-2-yl)-2-phenylethyl)isoquinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium phosphate; dipotassium peroxodisulfate; silver carbonate In water; acetonitrile at 70℃; for 4h; Inert atmosphere;

Reference： [1]Yao, Qian; Zhou, Xin; Zhang, Xiuli; Wang, Cong; Wang, Peng; Li, Ming [Organic and Biomolecular Chemistry, 2017, vol. 15, # 4, p. 957 - 971]

74
[ 125485-57-6 ]
[ 5123-55-7 ]
ethyl 7-fluoro-4-phenyl-1-((1,3-dioxisoindolin-2-yl)-2-phenylethyl)isoquinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium phosphate; dipotassium peroxodisulfate; silver carbonate In water; acetonitrile at 70℃; for 4h; Inert atmosphere;

Reference： [1]Yao, Qian; Zhou, Xin; Zhang, Xiuli; Wang, Cong; Wang, Peng; Li, Ming [Organic and Biomolecular Chemistry, 2017, vol. 15, # 4, p. 957 - 971]

75
C₂₀H₁₉NO₄ [ No CAS ]
[ 5123-55-7 ]
ethyl 7-methoxy-4-(4-methoxyphenyl)-1-((1,3-dioxiso-indolin-2-yl)phenylethyl)isoquinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium phosphate; dipotassium peroxodisulfate; silver carbonate In water; acetonitrile at 70℃; for 4h; Inert atmosphere;

Reference： [1]Yao, Qian; Zhou, Xin; Zhang, Xiuli; Wang, Cong; Wang, Peng; Li, Ming [Organic and Biomolecular Chemistry, 2017, vol. 15, # 4, p. 957 - 971]

76
[ 1428264-89-4 ]
[ 5123-55-7 ]
2-methyl-6-((1,3-dioxisoindolin-2-yl)-2-phenylethyl)phenanthridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium phosphate; dipotassium peroxodisulfate; silver carbonate In water; acetonitrile at 70℃; for 4h; Inert atmosphere;

Reference： [1]Yao, Qian; Zhou, Xin; Zhang, Xiuli; Wang, Cong; Wang, Peng; Li, Ming [Organic and Biomolecular Chemistry, 2017, vol. 15, # 4, p. 957 - 971]

77
[ 763-32-6 ]
[ 5123-55-7 ]
3-methylbut-3-en-1-yl (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 24℃; for 2h; Inert atmosphere;

Reference： [1]Ma, Xiaoshen; Dang, Hester; Rose, John A.; Rablen, Paul; Herzon, Seth B. [Journal of the American Chemical Society, 2017, vol. 139, # 16, p. 5998 - 6007]

78
[ 536-90-3 ]
[ 5123-55-7 ]
C₂₄H₂₀N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Nα-phthaloyl-L-phenylalanine With oxalyl dichloride In dichloromethane at 0 - 20℃; for 6h; Stage #2: m-Anisidine With triethylamine at 20℃; for 0.5h;	4.2. Synthesis: general procedure for compounds 8a-8u General procedure: Compound 3 (1 mmol) added to dry CH2Cl2 (15 mL) and stirredat 0 °C. After that, oxalyl chloride (1.5 mmol) was dripped into themixture and stirred at room temperature for 6 h. After the reaction,the solvent and excess oxalyl chloride was evaporated underreduced pressure. Aromatic primary amines (1 mmol) and triethylamine(0.5 mmol) were added to the mixture and stirred atroom temperature for 0.5 h. After the reaction, the solvent wasevaporated under reduced pressure, and the crude product waspurified by chromatography on silica gel eluted with petroleumether/ethylacetate (V:V 6:1) to offer compound 4. Compound 4(1 mmol) and hydrazine hydrate (3 mmol) were added to ethanol(15 mL) and the mixture was stirred at room temperature for 8 h.After the reaction was completed, the solvent was evaporated underreduced pressure, and the crude product was purified bychromatography on silica gel eluted with petroleum ether/ethylacetate (V: V 3: 1) to obtain compounds 5. Compounds 6(1 mmol) added to dry H2Cl2 (15 mL) was stirred at 0 °C and oxalylchloride (2.0 mmol) was dripped into the mixture and stirred atroom temperature for 6 h. After the reaction, the solvent and excessoxalyl chloride was evaporated under reduced pressure. Compounds5 (2 mmol) and triethylamine (1 mmol) were added to themixture and stirred at room temperature for 18 h. After the reaction,the solvent was evaporated under reduced pressure, and thecrude product was purified by chromatography on silica gel elutedwith petroleum ether/ethyl acetate (V: V 6:1) to offer compounds8a-8u. The structures were confirmed by 1H NMR,13C NMR and HRMS(see Supporting information).