Name: 1078-61-1|3-(3,4-Dihydroxyphenyl)propionic acid|95%
Brand: Ambeed
SKU: A456071
Price: 16.0 USD
Availability: InStock
Rating: 91 (40 reviews)

1
[ 67-56-1 ]
[ 1078-61-1 ]
[ 3598-22-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride at -40 - 20℃; for 24h;
100%	With sulfuric acid for 16h; Heating;
100%	With thionyl chloride for 0.5h; Cooling with acetonitrile-dry ice;	10 Synthesis of DHCA-OMe (26)As shown in FIG. 10, step a, DHCA (18.2 g, 100 mmol), methanol (250 mL), and a magnetic stirring bar were added to a 500 ml flask. The flask was cooled in an acetonitrile/dry ice bath. Thionyl chloride (14.6 mL, 200 mmol) was added. After stirring for 30 min, the cooling bath was removed and the mixture was stirred overnight at room temperature. The volatile materials were removed by rotary evaporation and the resulting yellow residue was dried under vacuum to yield a brown oil, which solidified several days later to produce a dark brown solid (100%).

100%	With thionyl chloride at 20℃; for 24.5h; Cooling with ice;	4 [0098] Synthesis of methyl 3-(3,4-dihydroxyphenyl)propanoate XX. [0098] Synthesis of methyl 3-(3,4-dihydroxyphenyl)propanoate XX. 3,4- dihydroxyhydrocinnamic acid XIX (12.5 g, 68.6 mmol) was dissolved in 100 mL anhydrous MeOH and cooled with ice bath. Thionyl chloride (13.0 mL, 171.5 mmol) was added dropwise with stirring. Ice bath was removed after 30mm and the reaction was stirred at r.t. for 24 h. Solvent was removed by rotary evaporation. Dried under high vacuum gave product as a dark blue viscous oil quantitatively. The oily product became solid after being placed in the freezer. ‘H NMR (500 MHz, CDC13): 2.61 (t, J = 7.70 Hz, 2H), 2.83 (t, J = 7.70Hz, 2H), 3.69 (s, 3H), 5.69 (br. s., 2H), 6.60 (dd, J = 8.07, 1.96 Hz, 1H), 6.71 (d, J = 1.96 Hz, 1H), 6.77 (d, J = 8.07 Hz, 1H). ‘3C NMR (125 MHz, CDC13): 30.25, 35.94, 51.89, 115.43, 120.51, 133.19, 142.12, 143.66,174.38.
97%	With sulfuric acid Reflux;
85%	With acetyl chloride at 68℃; Cooling with ice;	2.2 Step 2: Dissolve S1 in 40 ml of anhydrous methanol and cool with an ice bath, add acetyl chloride dropwise with stirring, remove the ice bath after 30 minutes, and stir the reaction at 68°C overnight, filter and concentrate, pass through a column The crude product was purified by chromatography to give the product S2 as a yellow oil (11.2 g, 85% yield),The oily product turned solid when placed in the refrigerator,
80%	With sulfuric acid for 24h; Reflux;	General procedure for the synthesis of compounds 9-12 and 21-29 General procedure: After dissolving the carboxylic acid in the alcohol, three drops of H2SO4 95% were added to the solution and the mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure and water was added to the crude mixture. The pH of the aqueous layer was adjusted to 7 adding drops of a saturated solution of NaHCO3 and brine was added in the mixture. The aqueous layer was extracted three times with ethyl acetate; the organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure yielding the final compound. Further purification step was made when it was necessary.
26%	With toluene-4-sulfonic acid In benzene Heating;
	With sulfuric acid
	With acetyl chloride at 20℃; for 12h;
	With hydrogenchloride for 4h; Reflux;
	at 20℃; Inert atmosphere;
	With sulfuric acid at 40℃; for 2h;
	With thionyl chloride at 20℃; for 8h;
	With sulfuric acid for 12h; Reflux;
	With Novozyme 435 from C_. antarctica supported on acrylic resin beads at 39.4℃; for 77.5h; Sealed tube; Molecular sieve; Ionic liquid; Enzymatic reaction;

Reference： [1]Dorrestein, Pieter C.; Poole, Keith; Begley, Tadhg P. [Organic Letters, 2003, vol. 5, # 13, p. 2215 - 2217]
[2]Bourne; Golding; McGeary; Meutermans; Jones; Marshall; Alewood; Smythe [Journal of Organic Chemistry, 2001, vol. 66, # 23, p. 7706 - 7713]
[3]Current Patent Assignee: NORTHWESTERN UNIVERSITY (ILLINOIS) - US8227628, 2012, B2 Location in patent: Page/Page column 30
[4]Current Patent Assignee: UNIVERSITY SYSTEM OF OHIO - WO2016/7943, 2016, A1 Location in patent: Paragraph 0097; 0098
[5]Vellaisamy, Kasipandi; Li, Guodong; Ko, Chung-Nga; Zhong, Hai-Jing; Fatima, Sarwat; Kwan, Hiu-Yee; Wong, Chun-Yuen; Kwong, Wai-Jing; Tan, Weihong; Leung, Chung-Hang; Ma, Dik-Lung [Chemical Science, 2018, vol. 9, # 5, p. 1119 - 1125]
[6]Current Patent Assignee: JIANGXI TRADITIONAL CHINESE MEDICINE UNIV - CN114149398, 2022, A Location in patent: Paragraph 0023
[7]Allegretta, Giuseppe; Weidel, Elisabeth; Empting, Martin; Hartmann, Rolf W. [European Journal of Medicinal Chemistry, 2015, vol. 90, p. 351 - 359]
[8]Etzenhouser, Beth; Hansch, Corwin; Kapur, Sanjay; Selassie [Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 1, p. 199 - 209]
[9]Tamura et al. [Nippon Nogeikagaku Kaishi, 1952, vol. 26, p. 413][Chem.Abstr., 1954, p. 2004]
[10]Baranovsky, Alexander; Schmitt, Bettina; Fowler, Daniel J.; Schneider, Bernd [Synthetic Communications, 2003, vol. 33, # 6, p. 1019 - 1045]
[11]Location in patent: experimental part Ketuly, Kamal Aziz; Hadi, A. Hamid A. [Molecules, 2010, vol. 15, # 4, p. 2347 - 2356]
[12]Location in patent: scheme or table Ito, Yumiko; Higashihara, Tomoya; Ueda, Mitsuru [Macromolecules, 2012, vol. 45, # 10, p. 4175 - 4183]
[13]Location in patent: experimental part Fujimoto, Aya; Masuda, Toshiya [Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 20, p. 5142 - 5151]
[14]Yang, Jian; Yang, Jing Xiang; Zhang, Fang; Chen, Gang; Pan, Wei; Yu, Rui; Wu, Shuwen; Tien, Po [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2680 - 2684]
[15]Wang, Li; Yan, Yuping; Wang, Min; Yang, Hong; Zhou, Zhiguo; Peng, Chen; Yang, Shiping [Journal of Materials Chemistry B, 2016, vol. 4, # 10, p. 1908 - 1914]
[16]Gholivand, Somayeh; Lasekan, Ola; Tan, Chin Ping; Abas, Faridah; Wei, Leong Sze [Food Chemistry, 2017, vol. 224, p. 365 - 371]

2
[ 64-17-5 ]
[ 1078-61-1 ]
[ 3967-57-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sulfuric acid for 24h; Reflux;	General procedure for the synthesis of compounds 9-12 and 21-29 General procedure: After dissolving the carboxylic acid in the alcohol, three drops of H2SO4 95% were added to the solution and the mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure and water was added to the crude mixture. The pH of the aqueous layer was adjusted to 7 adding drops of a saturated solution of NaHCO3 and brine was added in the mixture. The aqueous layer was extracted three times with ethyl acetate; the organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure yielding the final compound. Further purification step was made when it was necessary.
38%	With toluene-4-sulfonic acid In benzene Heating;
	With hydrogenchloride

With thionyl chloride at 20℃; for 8h;

Reference： [1]Allegretta, Giuseppe; Weidel, Elisabeth; Empting, Martin; Hartmann, Rolf W. [European Journal of Medicinal Chemistry, 2015, vol. 90, p. 351 - 359]
[2]Etzenhouser, Beth; Hansch, Corwin; Kapur, Sanjay; Selassie [Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 1, p. 199 - 209]
[3]Schoepf; Perrey; Jaeckh [Justus Liebigs Annalen der Chemie, 1932, vol. 497, p. 47,52]
[4]Yang, Jian; Yang, Jing Xiang; Zhang, Fang; Chen, Gang; Pan, Wei; Yu, Rui; Wu, Shuwen; Tien, Po [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2680 - 2684]

3
[ 331-39-5 ]
[ 1078-61-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With palladium on activated charcoal; hydrogen In methanol at 20℃; Inert atmosphere;
95%	With palladium 10% on activated carbon; hydrogen In methanol at 25℃; for 3h;	4.1.20. 3-(3, 4-Dihydroxyphenyl)propanoic acid (32) To a solution of (E)-3-(3, 4-dihydroxyphenyl)acrylic acid (29,0.50 g, 2.78 mmol) in CH3OH (4 mL) was added 10% Pd/C (0.05 g).The mixture was stirred at 25 °C under a 50 psi hydrogen pressurefor 3 h. The reaction mixture was filtered over Celite and washedwith CH3OH. Removal of solvent under reduced pressure, followedby column chromatography on silica gel (12% CH3OH in CH2Cl2 asthe eluent) afforded the corresponding aromatic amine (0.48 g,95%) as pale yellow amorphous solid: 1H NMR (500 MHz, CD3OD) δ 6.67-6.64 (m, 2H, H-20, H-50), 6.52 (d, J 7.0 Hz, 1H, H-60), 2.75 (t,J 7.5 Hz, 2H, H-3a, H-3b), 2.52 (t, J 7.5 Hz, 2H, H-2a, H-2b); 13CNMR (101 MHz, CD3OD) δ 177.0, 146.2, 144.6, 133.8, 120.5, 116.4,116.3, 37.2, 31.5; LC-MS (ESI) [M - H]- m/z 181.4.
92%	With ferrous ammonium sulphate hexahydrate; isopropyl β-D-thiogalactopyranoside In aq. phosphate buffer at 37℃; for 48h;

	With Pd-BaSO₄; ethanol Hydrogenation;
	(catalytic hydrogenation);
	With hydrogen In methanol at 20 - 40℃; for 2h;
	With hydrogen
	With hydrogen In methanol
69 % Chromat.	With ammonium formate; 1-butyl-3-methylimidazolium Tetrafluoroborate at 65℃; for 5h;
	With hydrogen In ethyl acetate at 20℃; for 2h;
	With palladium on activated charcoal; hydrogen In methanol for 3.5h;	1.3 Example 1 1.3 Dihydrocaffeic Acid (Compound 10) In a hydrogenation bottle placed 51.5 mg of 5% Pd/C and a solution of caffeic acid (0.5047 g, 2.8 mmol) in methanol (16 mL). The hydrogenation was performed in a Parr hydrogenation apparatus at 26-35 psi pressure for 3.5 h. The Pd/C was filtered off through a pad of celite and the filtrate was evaporated under reduced pressure. The crude product was recrystallized from water to provide dihydrocaffeic acid as an off-white crystal, mp 138.5-140° C. 1H NMR (300 MHz, CD3OD) δ (ppm) 2.51 (t, J=7.8 Hz, 2H), 2.76 (t, J=7.8 Hz, 2H), 6.52 (dd, J=7.8, 2.2 Hz, 1H), 6.65 (d, J=2.2 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ (ppm) 31.7, 37.4, 116.5, 116.6, 120.6, 133.9, 144.7, 146.3, 177.2.

Reference： [1]Prevost, Marie S.; Delarue-Cochin, Sandrine; Marteaux, Justine; Colas, Claire; Van Renterghem, Catherine; Blondel, Arnaud; Malliavin, Thérèse; Corringer, Pierre-Jean; Joseph, Delphine [Journal of Medicinal Chemistry, 2013, vol. 56, # 11, p. 4619 - 4630]
[2]Zhu, Mei; Shan, Qi; Ma, Ling; Wen, Jiajia; Dong, Biao; Zhang, Guoning; Wang, Minghua; Wang, Juxian; Zhou, Jinming; Cen, Shan; Wang, Yucheng [European Journal of Medicinal Chemistry, 2021, vol. 220]
[3]Sirasani, Gopal; Tong, Liuchuan; Balskus, Emily P. [Angewandte Chemie - International Edition, 2014, vol. 53, # 30, p. 7785 - 7788][Angew. Chem., 2014, vol. 53, # 30, p. 7919 - 7922,4]
[4]Buecking,W. [Diss. <Leipzig 1928> S. 65, 66]
[5]Horner,L.; Geyer,E. [Chemische Berichte, 1965, vol. 98, p. 2016 - 2045]
[6]Nakano, Hidenori; Tahara, Satoshi; Iizuka, Toshihiko; Mizutani, Junya [Agricultural and Biological Chemistry, 1987, vol. 51, # 2, p. 549 - 556]
[7]Burke Jr.; Fesen; Mazumder; Wang; Carothers; Grunberger; Driscoll; Kohn; Pommier [Journal of Medicinal Chemistry, 1995, vol. 38, # 21, p. 4171 - 4178]
[8]Moon, Jae-Hak; Terao, Junji [Journal of Agricultural and Food Chemistry, 1998, vol. 46, # 12, p. 5062 - 5065]
[9]Baán, Zoltán; Finta, Zoltán; Keglevich, György; Hermecz, István [Tetrahedron Letters, 2005, vol. 46, # 37, p. 6203 - 6204]
[10]Russell, Wendy R.; Scobbie, Lorraine; Chesson, Andrew [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 7, p. 2537 - 2546]
[11]Current Patent Assignee: CHANG GUNG UNIVERSITY - US2019/133979, 2019, A1 Location in patent: Paragraph 0135-0137

4
[ 1135-23-5 ]
[ 1078-61-1 ]

Reference： [1]Angewandte Chemie - International Edition,2020,vol. 59,p. 3063 - 3068
Angew. Chem.,2020,vol. 132,p. 3087 - 3092,6
[2]Journal of the Chemical Society,1917,vol. 111,p. 795

5
[ 331-39-5 ]
[ 1078-61-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 2h;
98%	With palladium on activated charcoal; hydrogen In methanol at 35℃;	2.1 Step 1: 3-(3,4-Dihydroxyphenyl)acrylic acid (12 g, 66.6 mmol, 1 equiv) and Pd/C (1.2 g, 0.1 equiv) were dissolved in anhydrous methanol at 35 °C under H2 atmosphere (150ml) overnight, after the reaction, the mixture was evaporated in vacuo to give S1 as a brown solid (11.8g, 98%);
95%	With 10% palladium on activated charcoal; hydrogen In propan-2-one at 20℃; for 3h;	4.6. Preparation of saturated caffeic acid (22) Five percentage palladium on activated carbon (20 mg) was added to caffeic acid (2, 100 mg) in acetone (l mL). The heterogeneous mixture was stirred under a hydrogen atmosphere at room temperature for 3 h. The mixture was filtered through celite which afforded a saturated caffeic acid (22, 95 mg, 95%) as a brown crystal.Saturated caffeic acid (= 3-(3,4-Dihydroxyphenyl)propanoic acid) (22): IR νmax (film) 1715 cm-1; 1H NMR (CD3OD, 500 MHz): δ 6.62 (1H, d, J = 7.6 Hz; H-5'), 6.59 (1H, d, J = 1.5 Hz; H-2'), 6.48 (1H, dd, J = 7.6, 1.5 Hz; H-6'), 2.71 (2H, t, J = 7.6 Hz; H-3), 2.47 (2H, t, J = 7.6 Hz; H-2); EIMS m/z 182 [M]+, 123 (base).

75%	With palladium on activated charcoal; hydrogen In methanol at 20℃;	Synthetic method of Scheme 1 Add 2.5 mmol caffeic acid, a catalytic amount of Pd/C,20 ml anhydrous MeOH to a 100 ml reaction flask, and reactovernight at room temperature in a hydrogen environment.The reaction was monitored by TLC. After the reaction isover, filter with celite, wash with MeOH, collect the filtrateand spin dry. It was extracted with EA (3 × 30 ml) threetimes, dried with anhydrous Na2SO4, and the product waspurified by column chromatography (PE:EA = 5:2).
75%	With palladium on activated charcoal; hydrogen In methanol at 20℃;	Synthetic method of Scheme 1 Add 2.5 mmol caffeic acid, a catalytic amount of Pd/C,20 ml anhydrous MeOH to a 100 ml reaction flask, and reactovernight at room temperature in a hydrogen environment.The reaction was monitored by TLC. After the reaction isover, filter with celite, wash with MeOH, collect the filtrateand spin dry. It was extracted with EA (3 × 30 ml) threetimes, dried with anhydrous Na2SO4, and the product waspurified by column chromatography (PE:EA = 5:2).
	With sodium mercury amalgam; lithium hydroxide monohydrate
	With sodium hydroxide In lithium hydroxide monohydrate; N,N-dimethyl-formamide for 0.333333h; Cooling with ice;	Synthesis of 9 and 10 General procedure: In an ice-bath, 1.60 mmol of the opportune acid has been dissolved in DMF (2 mL) then 0.4 mL of aqueous 0.4 M sodium hydroxyde were added. The mixture was stirred for 20 min and then 2-(bromomethyl)-5-nitrofuran (1.6 mmol) was slowly added. After the addition was complete, the mixture was allowed to reach ambient temperature for 20 h and afterward it was stirred for 2 h at 50 °C. The reaction mixture was treated with H2O and AcOEt (3:1). The ethyl acetate layer was separated and the aqueous layer extracted with ethyl acetate (20 mL). The combined ethyl acetate extracts were washed with water (30 mL), saturated sodium hydrogen carbonate solution (30 mL), water (30 mL) and with saturated sodium chloride solution (30 mL) and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified with column chromatography using silica gel and AcOEt/n-hexane as eluent to give a yellow solid which was crystallized from toluene (yield 40-50%).
	With 5%-palladium/activated carbon; hydrogen In methanol for 3.5h;

Reference： [1]Location in patent: experimental part Takahashi; Miyazawa, Mitsuo [Pharmazie, 2010, vol. 65, # 12, p. 913 - 918]
[2]Current Patent Assignee: JIANGXI TRADITIONAL CHINESE MEDICINE UNIV - CN114149398, 2022, A Location in patent: Paragraph 0023
[3]Location in patent: experimental part Aung, Hnin Thanda; Furukawa, Tadashi; Nikai, Toshiaki; Niwa, Masatake; Takaya, Yoshiaki [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 7, p. 2392 - 2396]
[4]Chen, Hong-geng; Chen, Wei-min; Liu, Wei-liang; Su, Ya-lun; Sun, Ping-hua; Zeng, Shao-gao; Zeng, Yun-feng; Zheng, Jun-xia; Zhou, Hai-bo [Medicinal Chemistry Research, 2022, vol. 31, # 1, p. 177 - 194]
[5]Chen, Hong-geng; Chen, Wei-min; Liu, Wei-liang; Su, Ya-lun; Sun, Ping-hua; Zeng, Shao-gao; Zeng, Yun-feng; Zheng, Jun-xia; Zhou, Hai-bo [Medicinal Chemistry Research, 2022, vol. 31, # 1, p. 177 - 194]
[6]Hlasiwetz [Justus Liebigs Annalen der Chemie, 1867, vol. 142, p. 358]
[7]De Vita, Daniela; Friggeri, Laura; D'Auria, Felicia Diodata; Pandolfi, Fabiana; Piccoli, Francesco; Panella, Simona; Palamara, Anna Teresa; Simonetti, Giovanna; Scipione, Luigi; Di Santo, Roberto; Costi, Roberta; Tortorella, Silvano [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 6, p. 1502 - 1505]
[8]Cheng, Min-Chi; Lu, Yi-Ching; Wu, Jender; Ma, Yunn-Hwa [Colloids and Surfaces B: Biointerfaces, 2019, vol. 179, p. 28 - 36]

6
[ 2107-70-2 ]
[ 1078-61-1 ]

Yield	Reaction Conditions	Operation in experiment
99.2%	With hydrogen bromide In water at 138℃; for 48h; Inert atmosphere;	3-(3,4-Dihydroxyphenyl)propanoic acid (9). To a solution of aqueous hydrobromic acid (8.0 L, 40%) was added3-(3,4-dimethoxyphenyl)propanoic acid 8 (4.0 Kg, 19.02 mol). The temperature waselevated to 138 °C and the mixture was allowed to stir for 2 days, TLC showed thatall the starting materials were consumed (DCM:MeOH = 5:1, UV). Then the reactionwas cooled to ambient temperature and concentrated in vacuum. The residue wasfiltered and washed with petroleum to give the crude acid 9 (3.44 Kg, 99.2% ) , whichwas used for the subsequent step without further purification.
86%	With hydrogenchloride In water at 250℃; for 6h; Autoclave; Inert atmosphere; Green chemistry;
56%	With pyridine hydrochloride at 180 - 200℃; for 1.5h;

	With hydrogen bromide
770 mg	With boron tribromide In dichloromethane at -20 - 20℃;
40 g	With water; hydrogen bromide at 140℃;	1.1.1 EMBODIMENT 1: The Synthesis of Kukoamine B Malate Methods: (1) 50g of compound f1 is dissolved in 100 ml of hydrobromic acid solution (40% concentration), then heated to 140°C to carry out the reaction, and the reaction is monitored via TLC. After reaction is completed, the reaction solution is cooled down and then yellow crystals precipitate out. The yellow crystals are collected by suction filtration and washed with small quantity of petroleum ether, and then 40g of yellow solid compounds f2 are obtained.
40 g	With hydrogen bromide at 140℃;	1.1 1.1 Methods: (1) 50 g of compound fi is dissolved in 100 ml of hydrobromic acid solution (40% concentration), then heated to 140° C. to carry out the reaction, and the reaction is monitored via TLC. Afier the reaction is completed, the reaction solution is cooled down and then yellow crystals precipitate out. The yellow crystals are collected by suction filtration and washed with small quantity of petroleum ether, and then 40 g of yellow solid compounds f2 are obtained. Next, 40 g of compound f2 is dissolved in 120 ml of DMF, added with 116 g of potassium carbonate and 86 ml of benzyl chloride, and then heated to 80° C. to carry out the reaction, and the reaction is monitored via TLC. Afier the reaction is completed, the reaction solution is filtrated, extracted with ethyl acetate, washed sequentially with water and saturated salt water, and dried with anhydrous sodium sulfate, and then compound 13 is collected by suction filtration. Next, 14.4 g of sodium hydroxide is dissolved in 80 ml of water, added with 85 g of compound 13, then added with 80 ml of methanol, and heated to 90° C. to perform reflux reaction, and the reaction is monitored via TLC. After the reaction is completed, the reaction solution is dried by rotary evaporation, then poured into a beaker, added with concentrated hydrochloric acid to make it strongly acidic, and filtrated, and then the filter cake is collected and dried. 60 g of yellow compound f is obtained and the yield is 69%. The reactionequation is expressed as follows:

Reference： [1]Dong, Kai [Synlett, 2018, vol. 29, # 20, p. 2669 - 2672]
[2]Bomon, Jeroen; Bal, Mathias; Achar, Tapas Kumar; Sergeyev, Sergey; Wu, Xian; Wambacq, Ben; Lemière, Filip; Sels, Bert F.; Maes, Bert U. W. [Green Chemistry, 2021, vol. 23, # 5, p. 1995 - 2009]
[3]Zhao, He; Neamati, Nouri; Mazumder, Abhijit; Sunder, Sanjay; Pommier, Yves; Burke Jr., Terrence R. [Journal of Medicinal Chemistry, 1997, vol. 40, # 8, p. 1186 - 1194]
[4]Schoepf; Perrey; Jaeckh [Justus Liebigs Annalen der Chemie, 1932, vol. 497, p. 47,52]
[5]Deng, Lisheng; Sundriyal, Sandeep; Rubio, Valentina; Shi, Zheng-Zheng; Song, Yongcheng [Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6539 - 6542]
[6]Current Patent Assignee: THIRD MILITARY MEDICAL UNIVERSITY; TIANJIN CHASE SUN PHARMACEUTICAL CO LTD - EP2639215, 2013, A1 Location in patent: Paragraph 0036
[7]Current Patent Assignee: THIRD MILITARY MEDICAL UNIVERSITY; TIANJIN CHASE SUN PHARMACEUTICAL CO LTD - US2013/289112, 2013, A1 Location in patent: Paragraph 0062

7
[ 1078-61-1 ]
[ 77-78-1 ]
[ 2107-70-2 ]

Yield	Reaction Conditions	Operation in experiment
85.2%	With potassium carbonate In acetone for 12h; Inert atmosphere; Reflux;
	With potassium hydroxide

Reference： [1]Singh, Harpreet; Tomer, Vijay K.; Jena, Nityasagar; Bala, Indu; Sharma, Nidhi; Nepak, Devadutta; De Sarkar, Abir; Kailasam, Kamalakannan; Pal, Santanu Kumar [Journal of Materials Chemistry A, 2017, vol. 5, # 41, p. 21820 - 21827]
[2]Zetzsche; Huggler [Helvetica Chimica Acta, 1927, vol. 10, p. 472,473]

8
[ 1078-61-1 ]
[ 124702-80-3 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1896 - 1907

9
[ 771-61-9 ]
[ 1078-61-1 ]
[ 169232-24-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With dicyclohexyl-carbodiimide In 1,4-dioxane Ambient temperature;
42%	With dicyclohexyl-carbodiimide In 1,4-dioxane at 20℃; for 4h;

Reference： [1]Burke Jr.; Fesen; Mazumder; Wang; Carothers; Grunberger; Driscoll; Kohn; Pommier [Journal of Medicinal Chemistry, 1995, vol. 38, # 21, p. 4171 - 4178]
[2]Location in patent: experimental part Roleira, Fernanda M.F.; Borges, Fernanda; Andrade, Lourdes C.R.; Paixão, José A.; Almeida, Maria J.M.; Carvalho, Rui A.; Tavares da Silva, Elisiário J. [Journal of Fluorine Chemistry, 2009, vol. 130, # 2, p. 169 - 174]

10
[ 771-61-9 ]
[ 1078-61-1 ]
[ 188662-00-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With dicyclohexyl-carbodiimide In 1,4-dioxane Ambient temperature;

Reference： [1]Zhao, He; Neamati, Nouri; Mazumder, Abhijit; Sunder, Sanjay; Pommier, Yves; Burke Jr., Terrence R. [Journal of Medicinal Chemistry, 1997, vol. 40, # 8, p. 1186 - 1194]

11
[ 1078-61-1 ]
[ 79-22-1 ]
[ 222320-66-3 ]
C₂₆H₂₆O₁₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide at 0℃;
	With sodium hydroxide In water at 0℃;	A A solution of the phenolic acid in 2.2 eq 1N NaOH was cooled to 0° C. and 3.5 eq methyl chloroformate was added drop-wise with stirring. The precipitate was collected by filtration, washed with deionized water, air dried and recrystallized to give the blocked phenolic acid.

Reference： [1]King, Peter J.; Ma, Guoxiang; Miao, Wenfang; Jia, Qi; McDougall, Brenda R.; Reinecke, Manfred G.; Cornell, Chris; Kuan, Jean; Kim, Tracey R.; Robinson Jr., W. Edward [Journal of Medicinal Chemistry, 1999, vol. 42, # 3, p. 497 - 509]
[2]Current Patent Assignee: Robinson JR., W. Edward; King, Peter J.; Reinecke, Manfred G. - US2005/49242, 2005, A1 Location in patent: Page/Page column 8; 10

12
[ 1078-61-1 ]
[ 67-63-0 ]
L 159,084 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With sulfuric acid for 24h; Reflux;	General procedure for the synthesis of compounds 9-12 and 21-29 General procedure: After dissolving the carboxylic acid in the alcohol, three drops of H2SO4 95% were added to the solution and the mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure and water was added to the crude mixture. The pH of the aqueous layer was adjusted to 7 adding drops of a saturated solution of NaHCO3 and brine was added in the mixture. The aqueous layer was extracted three times with ethyl acetate; the organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure yielding the final compound. Further purification step was made when it was necessary.
48%	With toluene-4-sulfonic acid In benzene Heating;
	With thionyl chloride at 20℃; for 8h;

Reference： [1]Allegretta, Giuseppe; Weidel, Elisabeth; Empting, Martin; Hartmann, Rolf W. [European Journal of Medicinal Chemistry, 2015, vol. 90, p. 351 - 359]
[2]Etzenhouser, Beth; Hansch, Corwin; Kapur, Sanjay; Selassie [Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 1, p. 199 - 209]
[3]Yang, Jian; Yang, Jing Xiang; Zhang, Fang; Chen, Gang; Pan, Wei; Yu, Rui; Wu, Shuwen; Tien, Po [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2680 - 2684]

13
[ 1078-61-1 ]
[ 111-27-3 ]
hexyl 3-(3,4-dihydroxyphenyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 24h;
	With Novozyme 435 from C_. antarctica supported on acrylic resin beads at 39.4℃; for 77.5h; Sealed tube; Molecular sieve; Ionic liquid; Enzymatic reaction;

Reference： [1]Location in patent: experimental part Roleira, Fernanda M.F.; Siquet, Christophe; Orr, Elizabeta; Garrido, E. Manuela; Garrido, Jorge; Milhazes, Nuno; Podda, Gianni; Paiva-Martins, Fátima; Reis, Salette; Carvalho, Rui A.; Silva, Elisiário J. Tavares Da; Borges, Fernanda [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 16, p. 5816 - 5825]
[2]Etzenhouser, Beth; Hansch, Corwin; Kapur, Sanjay; Selassie [Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 1, p. 199 - 209]
[3]Gholivand, Somayeh; Lasekan, Ola; Tan, Chin Ping; Abas, Faridah; Wei, Leong Sze [Food Chemistry, 2017, vol. 224, p. 365 - 371]

14
[ 331-39-5 ]
[ 621-54-5 ]
[ 1078-61-1 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 1640 - 1643

15
[ 111-26-2 ]
[ 1078-61-1 ]
3-(6-hexylamino-3,4-dihydroxyphenyl)-propionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With Xylaria polymorpha laccase; 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) diammonium salt In aq. acetate buffer at 20℃; for 6h; Green chemistry; Enzymatic reaction;
75%	With sodium acetate In water at 20℃; for 6h;	Synthesis of 3-[6-(4-carboxyphenyl)amino-3,4-dihydroxyphenyl] propanoic acid (Va), 3-[6-(4-acetophenyl)amino-3,4-dihydroxyphenyl]propanoicacid (Vb), and 3-(6-hexylamino-3,4-dihydroxyphenyl)propanoic acid (Vc) General procedure: The pure enzyme(1.12 IU/mL) was diluted twice with 20 mM sodiumacetate buffer, pH 5.0. 3-(3,4-Dihydroxyphenyl)propionicacid (1 mM) and 4-aminobenzoic acid (1 mM)were added to 2 mL of the solution. The reactionmixture was incubated for 4.15 h at room temperatureupon vigorous stirring. The reaction was monitored byUV-Vis spectrophotometry. The reaction solution wasextracted thrice with ethyl acetate. The ethyl acetate(20 μL) extract was injected in 4.5 × 250 mm column(Waters HPLC Model 600E, spherisorb C18 5 UV),eluent methanol, flow rate 0.5 mL/min. The similarmethod was used for coupling of 3-(3,4-dihydroxyphenyl)propionic acid with 4-aminoacetophenonen-hexylamine, stirring time 4.30 h (IVb) and 6 h (IVc).Yields: 90% (Va), 86% (Va), and 75% (Vc).
60%	In acetate buffer at 30℃; for 6h; Enzymatic reaction;

With laccase In acetate buffer at 30℃; for 6h;

Reference： [1]Chaurasia, Pankaj Kumar; Yadava, Sudha; Bharati, Shashi Lata; Singh, Sunil Kumar [Russian Journal of Bioorganic Chemistry, 2014, vol. 40, # 4, p. 455 - 460]
[2]Chaurasia, Pankaj Kumar; Bharati, Shashi Lata; Singh, Sunil Kumar; Yadava, Sudha [Russian Journal of General Chemistry, 2015, vol. 85, # 1, p. 173 - 175][Zh. Obshch. Khim., 2015, vol. 85, # 1, p. 173 - 175,3][Zhurnal Obshchei Khimii, 2015, vol. 85, # 1, p. 173 - 175,3]
[3]Mikolasch, Annett; Hammer, Elke; Jonas, Ulrike; Popowski, Katrin; Stielow, Anne; Schauer, Frieder [Tetrahedron, 2002, vol. 58, # 38, p. 7589 - 7593]
[4]Mikolasch, Annett; Hammer, Elke; Jonas, Ulrike; Popowski, Katrin; Stielow, Anne; Schauer, Frieder [Tetrahedron, 2002, vol. 58, # 38, p. 7589 - 7593]

16
[ 1078-61-1 ]
[ 150-13-0 ]
3-[6-(4-carboxyphenyl)amino-3,4-dihydroxyphenyl]-propionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium acetate In water at 20℃; for 4.15h;	Synthesis of 3-[6-(4-carboxyphenyl)amino-3,4-dihydroxyphenyl] propanoic acid (Va), 3-[6-(4-acetophenyl)amino-3,4-dihydroxyphenyl]propanoicacid (Vb), and 3-(6-hexylamino-3,4-dihydroxyphenyl)propanoic acid (Vc) The pure enzyme(1.12 IU/mL) was diluted twice with 20 mM sodiumacetate buffer, pH 5.0. 3-(3,4-Dihydroxyphenyl)propionicacid (1 mM) and 4-aminobenzoic acid (1 mM)were added to 2 mL of the solution. The reactionmixture was incubated for 4.15 h at room temperatureupon vigorous stirring. The reaction was monitored byUV-Vis spectrophotometry. The reaction solution wasextracted thrice with ethyl acetate. The ethyl acetate(20 μL) extract was injected in 4.5 × 250 mm column(Waters HPLC Model 600E, spherisorb C18 5 UV),eluent methanol, flow rate 0.5 mL/min. The similarmethod was used for coupling of 3-(3,4-dihydroxyphenyl)propionic acid with 4-aminoacetophenonen-hexylamine, stirring time 4.30 h (IVb) and 6 h (IVc).Yields: 90% (Va), 86% (Va), and 75% (Vc).
89%	With Xylaria polymorpha laccase; 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) diammonium salt In aq. acetate buffer at 20℃; for 3.75h; Green chemistry; Enzymatic reaction;
	In acetate buffer at 30℃; for 3h; Enzymatic reaction;

In acetate buffer at 30℃; for 3h; Enzymatic reaction;

Reference： [1]Chaurasia, Pankaj Kumar; Bharati, Shashi Lata; Singh, Sunil Kumar; Yadava, Sudha [Russian Journal of General Chemistry, 2015, vol. 85, # 1, p. 173 - 175][Zh. Obshch. Khim., 2015, vol. 85, # 1, p. 173 - 175,3][Zhurnal Obshchei Khimii, 2015, vol. 85, # 1, p. 173 - 175,3]
[2]Chaurasia, Pankaj Kumar; Yadava, Sudha; Bharati, Shashi Lata; Singh, Sunil Kumar [Russian Journal of Bioorganic Chemistry, 2014, vol. 40, # 4, p. 455 - 460]
[3]Mikolasch, Annett; Hammer, Elke; Jonas, Ulrike; Popowski, Katrin; Stielow, Anne; Schauer, Frieder [Tetrahedron, 2002, vol. 58, # 38, p. 7589 - 7593]
[4]Mikolasch, Annett; Hammer, Elke; Jonas, Ulrike; Popowski, Katrin; Stielow, Anne; Schauer, Frieder [Tetrahedron, 2002, vol. 58, # 38, p. 7589 - 7593]

17
[ 1078-61-1 ]
[ 2491-20-5 ]
hydrocaffeoyl-L-Ala-OMe [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In acetonitrile at 20℃; for 4h; Cooling with ice;	4.2.1.1 General procedure for the synthesis of the methyl esters of N-phenoyl and N-catechoyl serine, phenylserine and alanine General procedure: To a solution of the phenolic or catecholic acid in acetonitrile (0.0100moldm-3), 1.1 equiv. of HOBt was added, followed by 1.1 equiv. of HBTU, 1.1 equiv. of the methyl ester of the amino acid hydrochloride and 2.2 equiv. of NEt3 in an ice bath. After stirring for 4h at room temperature, the solvent was evaporated at reduced pressure. The residue was dissolved in ethyl acetate (100cm3) and washed with KHSO4 (1moldm-3), NaHCO3 (1moldm-3) and brine (3 times 25cm3 each). The organic layer was dried with MgSO4 and the solvent evaporated at reduced pressure.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane

Reference： [1]Monteiro, Luís S.; Oliveira, Sandra; Paiva-Martins, Fátima; Ferreira, Paula M.T.; Pereira, David M.; Andrade, Paula B.; Valentão, Patrícia [Tetrahedron, 2017, vol. 73, # 43, p. 6199 - 6209]
[2]Lee, Sangku; Lee, Chul-Ho; Oh, Jung-Hoon; Kim, Eun Eai; Choi, Yang-Kyu; Kim, Eun-Hee; Lee, Woo Song; Bok, Song-Hae; Jeong, Tae-Sook [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 16, p. 2681 - 2682]

18
[ 1078-61-1 ]
[ 2886-33-1 ]
(S)-2-[3-(3,4-Dihydroxy-phenyl)-propionylamino]-succinic acid dibenzyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4677 - 4681

19
[ 1078-61-1 ]
[ 150-13-0 ]
5-(2''-carboxyethyl)-N-(4'-carboxyphenyl)-2-hydroxy-1,4-benzoquinoimine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With citrate-phosphate buffer; Myceliophthora thermophila fungal laccase; oxygen at 20℃; Enzymatic reaction;

Reference： [1]Niedermeyer, Timo H. J.; Mikolasch, Annett; Lalk, Michael [Journal of Organic Chemistry, 2005, vol. 70, # 6, p. 2002 - 2008]

20
[ 51-67-2 ]
[ 1078-61-1 ]
N-(3,4-dihydroxyhydrocinnamoyl)tyramine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.8%	With dmap; diisopropyl-carbodiimide In tetrahydrofuran at 0 - 20℃; for 20h;	2 Example 2 50g tyramine, 73g dihydrocaffeic acid, 4.5g N,N'-dimethylaminopyridine dissolved in 300ml anhydrous tetrahydrofuran, cooled to 0, 50.6g diisopropylcarbodiimide dissolved in 200ml anhydrous tetrahydrofuran, 0 Add dropwise to the aforementioned mixture at . After the addition is complete, warm up to room temperature, stir for 20 hours, filter to remove insolubles, concentrate to remove tetrahydrofuran, add 300ml of 1M sodium hydroxide to dissolve the residue, filter to remove insolubles, and acidify the filtrate with 1M hydrochloric acid To pH=1, an off-white solid precipitated, filtered, the filter cake was washed with water until it was neutral, and the solid was dried at 85° C. to obtain 92 g of product, with a yield of 83.8%.
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide for 20h;
	Stage #1: dihydrocaffeic acid With triethylamine In N,N-dimethyl-formamide for 0.25h; Cooling with ice; Stage #2: tyrosamine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;

Reference： [1]Current Patent Assignee: MELALYN - CN111978199, 2020, A Location in patent: Paragraph 0052-0057
[2]Okombi, Sabrina; Rival, Delphine; Bonnet, Sebastien; Mariotte, Anne-Marie; Perrier, Eric; Boumendjel, Ahcene [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 8, p. 2252 - 2255]
[3]Wang, Siyu; Suh, Joon Hyuk; Zheng, Xi; Wang, Yu; Ho, Chi-Tang [Journal of Agricultural and Food Chemistry, 2017, vol. 65, # 2, p. 364 - 372]

21
[ 1078-61-1 ]
[ 7524-50-7 ]
3-(3,4-dihydroxyphenyl)propionic acid (L-phenylalanine methyl ester)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: dihydrocaffeic acid; methyl (2S)-2-amino-3-phenylpropanoate hydrochloride With benzotriazol-1-ol; triethylamine In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; for 18h;

Reference： [1]Park, Eun-Jin; Lee, Sangku; Jeong, Tae-Sook; Bok, Song-Hae; Lee, Mi-Kyung; Park, Yong Bok; Choi, Myung-Sook [Journal of Biochemical and Molecular Toxicology, 2004, vol. 18, # 5, p. 279 - 287]

22
[ 1078-61-1 ]
[ 18162-48-6 ]
[ 116511-71-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: dihydrocaffeic acid; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 48h; Stage #2: With potassium carbonate In tetrahydrofuran; methanol; water at 20℃; for 0.5h;	3-(3,4-Bis((tert-butyldimethylsilyl)oxy)phenyl)propanoic acid (32) After dissolving 17 (1.00 g, 5.48 mmol) in DMF (11 ml), imidazole (3.73 g, 54.80 mmol) and TBDMSCl (3.72 g, 24.66 mmol) were added and the reaction mixture was stirred for 48 h at room temperature. Saturated solution of NH4Cl (40 ml) was added to the reaction and the mixture was extracted three times with ethyl acetate. The organic layers were collected together, washed with brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude extract was dissolved in a mixture of THF/MeOH/H2O 1:3:1 (25 ml), K2CO3 (757 mg, 5.48 mmol) was added in the solution and the system was stirred for 30min at room temperature. The mixture was concentrated under vacuum at room temperature. Water was added to the crude mixture and drops of HCl 1N were added until the pH=7. The aqueous solution was diluted with brine and extracted three times with ethyl acetate. The organic layers were collected together, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude extract was purified by column chromatography (hexane/ethyl acetate 9:1) yielding 2.14 g (95%) of 32 as a white crystalline solid. 1H NMR (500 MHz, acetone-d6): 0.21 (s, 6H), 0.22 (s, 6H), 0.99-1.01 (m, 18H), 2.56 (t, J=7.8, 2H), 2.80 (t, J=7.7, 2H), 6.72 (dd, J=8.1, J=2.3, 1H), 6.79 (d, J=8.1, 1H), 6.81 (d, J=2.1, 1H), 10.53 (ws, 1H). 13C NMR (125 MHz, acetone-d6): -3.86, -3.81, 19.02, 19.04, 26.35, 26.37, 30.8, 36.1, 121.8, 122.1, 122.2, 135.5, 145.8, 147.3, 173.9. MS (ESI) m/z: [M+H]+=410.84. Purity=>99%. Mp=92-93°C. Intermediate 32 was used as is for the synthesis of 33 and 35.
94%	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 48h;
94%	With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 48h;	9 Example 9 Synthesis of Compound of Formula 10 3,4-dihydroxyphenylpropionic acid (900 mg of) was dissolved in 10ml DMF, was added imidazole 1.34g, placed at 0 deg.] C, was slowly added tert-butyldimethylsilyl chloride (1.49 g) at room temperature, the reaction for 2 days, until the end of the reaction 40ml of ether and 10ml of water was added to stop the reaction, saturated ammonium chloride solution and saturated aqueous NaCl solution phase, liquid separation, the combined organic phases, respectively the organic phase after separation was extracted with diethyl ether (40ml × 4) , dried over anhydrous sodium sulfate, filtered, concentrated product was separated by column chromatography (ethyl acetate: petroleum ether = 1: 5), and finally the eluate concentrated to give compound 10 (840mg, 94%) as a yellow oil type.

50%	Stage #1: dihydrocaffeic acid; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere; Stage #2: With potassium carbonate In tetrahydrofuran; methanol; water; N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere;
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
	Stage #1: dihydrocaffeic acid; tert-butyldimethylsilyl chloride With 1H-imidazole at 20℃; for 6h; Stage #2: With water; potassium carbonate In methanol at 20℃; for 1h;

Reference： [1]Allegretta, Giuseppe; Weidel, Elisabeth; Empting, Martin; Hartmann, Rolf W. [European Journal of Medicinal Chemistry, 2015, vol. 90, p. 351 - 359]
[2]Yadav; Kumar, N. Niranjan; Reddy, M. Sridhar; Prasad [Tetrahedron, 2007, vol. 63, # 12, p. 2689 - 2694]
[3]Current Patent Assignee: JIANGXI SCIENCE & TECHNOLOGY NORMAL UNIVERSITY - CN104402852, 2017, B Location in patent: Paragraph 0052; 0053
[4]Agergaard, Asger Holm; Sommerfeldt, Andreas; Pedersen, Steen Uttrup; Birkedal, Henrik; Daasbjerg, Kim [Angewandte Chemie - International Edition, 2021, vol. 60, # 39, p. 21543 - 21549][Angew. Chem., 2021, vol. 133, # 39, p. 21713 - 21719]
[5]Simoni, Elena; Serafini, Melania M.; Caporaso, Roberta; Marchetti, Chiara; Racchi, Marco; Minarini, Anna; Bartolini, Manuela; Lanni, Cristina; Rosini, Michela [ACS Chemical Neuroscience, 2017, vol. 8, # 7, p. 1618 - 1627]
[6]Bian, Linglin; Cao, Shining; Cheng, Lihong; Nakazaki, Atsuo; Nishikawa, Toshio; Qi, Jianhua [ChemMedChem, 2018, vol. 13, # 18, p. 1972 - 1977]

23
[ 1078-61-1 ]
2,3-dihydro-1<i>H</i>-pyrimido[1,2-<i>a</i>]quinoline-8,9-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: 100 percent / thionyl chloride / 24 h / -40 - 20 °C 2.1: 39 percent / NaI; K₂CO₃ / methanol / 5 h / Heating 3.1: AlMe₃ / toluene / 0.25 h / -10 °C 3.2: 98 percent / toluene / 4 h / Heating 4.1: 87 percent / H₂ / 10 percent Pd/C / methanol / 1.25 h 5.1: MnO₂; activated molecular sieves / acetone / 3 h / Heating

Reference： [1]Dorrestein, Pieter C.; Poole, Keith; Begley, Tadhg P. [Organic Letters, 2003, vol. 5, # 13, p. 2215 - 2217]

24
[ 1078-61-1 ]
[ 568584-20-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 100 percent / thionyl chloride / 24 h / -40 - 20 °C 2.1: 39 percent / NaI; K₂CO₃ / methanol / 5 h / Heating 3.1: AlMe₃ / toluene / 0.25 h / -10 °C 3.2: 98 percent / toluene / 4 h / Heating 4.1: 87 percent / H₂ / 10 percent Pd/C / methanol / 1.25 h

Reference： [1]Dorrestein, Pieter C.; Poole, Keith; Begley, Tadhg P. [Organic Letters, 2003, vol. 5, # 13, p. 2215 - 2217]

25
[ 2316-26-9 ]
[ 1078-61-1 ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1186 - 1194

26
[ 1078-61-1 ]
3-(3,5-Dihydroxy-phenyl)-N-[2-(3,5-dihydroxy-phenyl)-ethyl]-propionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 95 percent / dicyclohexylcarbodiimide / dioxane / Ambient temperature 2: 85 percent / Et₃N / CHCl₃; dimethylformamide / 2 h / Ambient temperature 3: 69 percent / H₂ / 10percent Pd/C / ethanol; ethyl acetate / 5 h / 2068.6 Torr / Ambient temperature

Reference： [1]Zhao, He; Neamati, Nouri; Mazumder, Abhijit; Sunder, Sanjay; Pommier, Yves; Burke Jr., Terrence R. [Journal of Medicinal Chemistry, 1997, vol. 40, # 8, p. 1186 - 1194]

27
[ 1078-61-1 ]
N-[2-(3-Benzyloxy-5-hydroxy-phenyl)-ethyl]-3-(3,5-dihydroxy-phenyl)-propionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 95 percent / dicyclohexylcarbodiimide / dioxane / Ambient temperature 2: 85 percent / Et₃N / CHCl₃; dimethylformamide / 2 h / Ambient temperature 3: 13 percent / H₂ / 10percent Pd/C / ethanol; ethyl acetate / 5 h / 2068.6 Torr / Ambient temperature

Reference： [1]Zhao, He; Neamati, Nouri; Mazumder, Abhijit; Sunder, Sanjay; Pommier, Yves; Burke Jr., Terrence R. [Journal of Medicinal Chemistry, 1997, vol. 40, # 8, p. 1186 - 1194]

28
[ 1078-61-1 ]
[ 79622-99-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: dihydrocaffeic acid With sulfuric acid In ethanol at 20℃; for 3h; Heating / reflux; Stage #2: With potassium carbonate; ethyl iodide In DMF (N,N-dimethyl-formamide) at 50℃; for 5h; Stage #3: With sodium hydroxide In tetrahydrofuran for 1h; Heating / reflux;	3.1 3-1) 3-(3,4-Diethoxy)propionic acid 52.3 g of 3-(3,4-dihydroxy)propionic acid was dissolved in 500 ml of ethanol, followed by addition of 5 ml of concentrated sulfuric acid. After heating under reflux for 3 hours, the mixture was left stand to cool to room temperature and evaporated. The resulting residue was extracted with a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate (MgSO4), and evaporated. The resulting residue was dissolved in 320 ml of dimethylformamide (DMF), followed by addition of 103 g of potassium carbonate and 59.7 ml of iodoethane. After stirring at 50°C for 5 hours, the mixture was left stand to cool to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate (MgSO4), and evaporated. The resulting residue was dissolved in 500 ml of THF, followed by addition of 500 ml of a 1 N aqueous solution of sodium hydroxide. After heating under reflux for 1 hour, the mixture was left stand to cool to room temperature, diluted with water and washed with diethyl ether. Further, the aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid, and then the precipitated solid was collected by filtration and dried. The product was recrystallized from ethyl acetate, to give 61.2 g (total yield in the three steps; 90%) of the title compound as white crystals.

Reference： [1]Current Patent Assignee: EISAI CO LTD - EP1468684, 2004, A1 Location in patent: Page/Page column 16

29
[ 1078-61-1 ]
[ 86-52-2 ]
[ 909551-09-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium hydrogencarbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 3h;	1 Synthesis and Identification of DHH105 EXAMPLE 1 Synthesis and Identification of DHH105 3,4-dihydroxyhydrocinnamic acid naphthalene methyl ester was prepared by esterification of 3,4-dihydroxyhydrocinnamic acid with 1-(chloromethyl)naphthalene using NaHCO3 and KI in N,N-dimethylformamide. The detail is given below. 6.0 g (32.9 mmol) of 3,4-Dihydroxyhydrocinnamic acid was dissolved in 30 mL of N,N-dimethylformamide, and 6.0 g (33.9 mmol) of 1-(chloromethyl)naphthalene, 4.2 g (50.0 mmol) of NaHCO3 and 6.0 g (36.1 mmol) of KI were added successively. The reaction mixture was stirred at 80° C. for 3 hours, cooled to room temperature, diluted with 200 mL of water, and extracted with 300 mL of ethyl acetate. The extracts were washed with 200 mL of water and 300 mL of brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (4:1 hexane-EtOAc) to afford 8.2 g (77% yield) of DHH105 as a pale yellow syrup: 1H NMR (CD3OD, 400 MHz) δ (ppm) 7.88 (m, 2H), 7.84 (dd, J=7.2, 2.8 Hz, 1H), 7.51 (m, 2H), 7.43 (d, J=2.0 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H), 6.621 (d, J=2.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.45 (dd, 8.0, 2.0 Hz, 1H), 5.52 (s, 2H), 2.77 (t, J=6.8 Hz, 2H), 2.60 (t, J=6.8 Hz, 2H); 13C NMR (CD3OD, 100 MHz) δ (ppm) 173.5, 145.1, 143.5, 134.0, 132.2, 131.74, 131.68, 129.0, 128.4, 127.2, 126.4, 125.8, 125.1, 123.4, 119.4, 115.3, 115.2, 64.4, 36.1, 30.3.

Reference： [1]Current Patent Assignee: BIONUTRIGEN - US2006/205813, 2006, A1 Location in patent: Page/Page column 3

30
[ 1078-61-1 ]
[ 106-93-4 ]
[ 14939-92-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide In chloroform; water	11 EXAMPLE 11 EXAMPLE 11 3-(3,4-Dihydroxyphenyl)propionic acid (50 g.) was added to a cool solution of 55 g. of potassium hydroxide in 200 ml. of water. To this solution was added 56.4 g. of 1,2-dibromoethane and the resulting mixture was heated under reflux with stirring for 90 minutes. The mixture was cooled, chloroform was added, the aqueous portion was acidified with concentrated hydrochloric acid, and the layers were separated. The chloroform solution was washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtering, the bulk of the chloroform was removed at 40°C. under reduced pressure, with the temperature being raised to 50°C. to remove the last trace of chloroform. A nuclear magnetic resonance spectrum confirmed that the desired 3-(3,4-ethylenedioxyphenyl)propionic acid had been obtained in high purity. The yield was 22 g.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - US3962282, 1976, A

31
[ 1078-61-1 ]
iodosylbenzene diacetate [ No CAS ]
[ 15017-41-1 ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid In water; acetic acid	1 EXAMPLE 1 EXAMPLE 1 7.5 g of hydrocaffeic acid, 13.5 g of iodoso-benzene diacetate and 150 ml of glacial acetic acid are stirred at room temperature (22°C.) under an argon atmosphere. After 2 hours, 0.5 g of p-toluenesulphonic acid is added. The solution thereupon becomes black-red in color and warms to 30°C. After a further 3 hours, the mixture is evaporated at 40°C/12 mmHg and the residue is recrystallized once from ethyl acetate and twice from water. There is obtained 2.5 g of 6,7-dihydroxyhydrocoumarin of melting point 212°C. (decomposition).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; SPARAMEDICA - US3933859, 1976, A

32
[ 106-31-0 ]
[ 1078-61-1 ]
[ 924624-44-2 ]

Yield	Reaction Conditions	Operation in experiment
82%	In diethyl ether at 20℃; for 24.0833h;	2.26 Compound 26. Butyric acid 2-butyryloxy-4-{2-[4-(4-chloro-phenyl)-thiazol-2-ylcarbamoyl]-ethyl}-phenyl ester (B240920) Butyric acid 2-butyryloxy-4-(2-carboxy-ethyl)-phenyl ester (B240908) 3,4-Dihydroxyhydrocinnamic acid (1.0 g, 5.5 mmol) was mixed with butyric acid anhydride (5.5 mL) to form a brown suspension, followed by addition of H2SO4 (0.1 mL). After stirring for 5 min, it became a brown solution. Ether (20 mL) was added to it. The reaction was continued at RT for 24 hours. The mixture was poured into 50 mL, of ice-water. The mixture was extracted with EtOAc (50 mL). The EtOAc solution was dried over Na2SO4. The concentrated oily residue was purified by chromatography (CHCl3-3% MeOH in CHCl3) to afford a semisolid (1.45 g, Y=82%).

Reference： [1]Current Patent Assignee: APOGEE BIOTECHNOLOGY CORPORATION - US2007/32531, 2007, A1 Location in patent: Page/Page column 39

33
[ 18979-61-8 ]
[ 1078-61-1 ]
[ 1020396-02-4 ]

Reference： [1]Journal of Pharmacy and Pharmacology,2008,vol. 60,p. 343 - 348

34
[ 1078-61-1 ]
[ 62571-86-2 ]
C₁₈H₂₃NO₇S [ No CAS ]

Reference： [1]Journal of Agricultural and Food Chemistry,2009,vol. 57,p. 1143 - 1150

35
[ 215872-63-2 ]
[ 1135-24-6 ]
[ 621-54-5 ]
[ 1135-23-5 ]
[ 331-39-5 ]
[ 102-32-9 ]
[ 306-08-1 ]
[ 1078-61-1 ]
[ 23028-17-3 ]
[ 2475-56-1 ]
[ 1081-71-6 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2009,vol. 57,p. 3356 - 3362

36
[ 215872-63-2 ]
[ 1135-24-6 ]
[ 621-54-5 ]
[ 1135-23-5 ]
[ 331-39-5 ]
[ 102-32-9 ]
[ 306-08-1 ]
[ 1078-61-1 ]
[ 1081-71-6 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2009,vol. 57,p. 3356 - 3362

37
[ 1078-61-1 ]
[ 100-39-0 ]
[ 93559-04-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: dihydrocaffeic acid With potassium carbonate In N,N-dimethyl-formamide for 1h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 60℃; for 24h; Stage #3: With water; sodium hydroxide In tetrahydrofuran; methanol at 20℃; for 6h;
69%	Stage #1: dihydrocaffeic acid; benzyl bromide With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 20h; Inert atmosphere; Stage #2: With water; sodium hydroxide In methanol for 1h; Reflux; Stage #3: With hydrogenchloride In water

Reference： [1]Herrmann, Andreas; Li, Bo; Li, Jingjing; Liu, Kai; Ma, Chao; Sun, Jing; Wang, Zili; Xiao, Lingling; Zhang, Hongjie; Zhao, Kelu; Zhou, Yu [Angewandte Chemie - International Edition, 2021, vol. 60, # 44, p. 23687 - 23694][Angew. Chem., 2021, vol. 133, # 44, p. 23880 - 23887]
[2]García, Gonzalo; Rodríguez-Puyol, Manuel; Alajarín, Ramón; Serrano, Isabel; Sánchez-Alonso, Patricia; Griera, Mercedes; Vaquero, Juan J.; Rodríguez-Puyol, Diego; Álvarez-Builla, Julio; Díez-Marqués, María L. [Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7220 - 7227]

38
[ 35231-44-8 ]
[ 1078-61-1 ]
[ 1258525-65-3 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 17490 - 17500

39
[ 149-91-7 ]
[ 1078-61-1 ]
[ 1271320-89-8 ]

Yield	Reaction Conditions	Operation in experiment
21%	With horseradish peroxidase type I; dihydrogen peroxide In acetone aq. buffer; Enzymatic reaction;	4.4. Synthesis of dihydrocrocipodin (6) Gallic acid (3, 1.87 g, 11.0 mmol) and dihydrocaffeic acid (5, 3.01 g, 16.5 mmol) were dissolved in acetone/pH 5.0 phosphate/citrate buffer (1:10 v/v, 50 mL). Then, horseradish peroxidase type I (25 ku) was added in three portions, 4 mg each time. Additionally, every 15 min and four times per period, 3% aq H2O2 (1.2 mL) was added. During the reaction the mixture was shaken occasionally. The precipitate 6 was collected by filtration and dried under high vacuum overnight to yield compound 6 (0.74 g, 21%) as a red solid, mp>290 °C (dec). IR (neat): 3674 (br), 3392 (br), 3220 (w), 1740 (ss), 1646 (s), 1517 (s), 1454 (m), 1401 (m), 1362 (ss), 1290 (ss), 1150 (m), 1089 (m), 972 (ss), 891 (m), 855 (m); 1H NMR (400 MHz, DMSOd6): δ 2.55 (t, J=7.7 Hz, 2H), 3.18 (t, J=7.7 Hz, 2H), 7.43 (s, 1H), 7.61 (d, J=1.3 Hz, 1H), 8.57 (d, J=1.3 Hz, 1H), 9.73 (s, 1H), 10.26 (s, 1H), 12.71 (br, 2H), 14.70 (s, 1H); 13C NMR (100 MHz, DMSOd6): δ=30.3, 35.5, 115.7, 122.2, 123.6, 124.6, 126.1, 132.5, 135.2, 148.5, 150.4, 153.9, 168.3, 173.7, 185.9; HRMS (ESI-) calcd for C15H11O8 [M-H]: 319.0453, found: 319.0456.

Reference： [1]Location in patent: experimental part Kerschensteiner, Lydia; Löbermann, Florian; Steglich, Wolfgang; Trauner, Dirk [Tetrahedron, 2011, vol. 67, # 8, p. 1536 - 1539]

40
[ 1078-61-1 ]
[ 2450-71-7 ]
[ 1260020-82-3 ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: dihydrocaffeic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 30℃; for 0.166667h; Stage #2: Propargylamine In tetrahydrofuran for 4h;

Reference： [1]Location in patent: experimental part Li, Lei; Li, Yan; Luo, Xiaofeng; Deng, Jianping; Yang, Wantai [Reactive and functional polymers, 2010, vol. 70, # 12, p. 938 - 943]

41
[ 1078-61-1 ]
[ 119735-35-2 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride at 60℃; for 4h;
	With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 2h;	1; 2 1) 5 g of 3,4-dihydroxyphenylpropionic acid (DHCA) was dissolved in 25 mL of anhydrous tetrahydrofuran, using N,N-dimethylformamide as a catalyst, adding 3 mL of oxalyl chloride, and stirring at room temperature for 2 hours;2) removing the reaction solvent and unreacted oxalyl chloride by rotary evaporation to obtain an acid chloride form of DHCA
	With thionyl chloride; N,N-dimethyl-formamide In benzene for 1h; Inert atmosphere; Reflux;

With thionyl chloride for 4h; Reflux;

4.1.2 General procedure II General procedure: Substituted cinnamic acid (1 equiv) was dissolved in SOCl2 (10 equiv) and refluxed for 4h. The solvents were removed under reduced pressure to obtain the substituted cinnamoyl chlorides.

Reference： [1]Xi, Pinxian; Cheng, Kai; Sun, Xiaolian; Zeng, Zhengzhi; Sun, Shouheng [Journal of Materials Chemistry, 2011, vol. 21, # 31, p. 11464 - 11467]
[2]Current Patent Assignee: SOUTHWEST UNIVERSITY - CN109042731, 2018, A Location in patent: Paragraph 0032; 0033; 0034; 0035; 0041; 0042; 0043
[3]Hewage, Achala N. D. Punchi; Yao, Huili; Nammalwar, Baskar; Gnanasekaran, Krishna Kumar; Lovell, Scott; Bunce, Richard A.; Eshelman, Kate; Phaniraj, Sahishna M.; Lee, Molly M.; Peterson, Blake R.; Battaile, Kevin P.; Reitz, Allen B.; Rivera, Mario [Journal of the American Chemical Society, 2020, vol. 141, # 20, p. 8171 - 8184]
[4]Feng, Feng; Jiang, Pan; Li, Qi; Liao, Qinghong; Liu, Wenyuan; Qu, Wei; Sun, Haopeng; Yan, Yuhui; Zhao, Yifan [Bioorganic Chemistry, 2020, vol. 99]

42
[ 501-97-3 ]
[ 1078-61-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With Agaricus bisporus; oxygen In aq. phosphate buffer; dichloromethane at 25℃; for 24h;	4.8 Oxidation of phenols and esters derivatives General procedure: The reactions were performed under both homogeneous and heterogeneous conditions in CH2Cl2/buffer. As a general procedure, phenol (0.05mmol), tyrosinase (600IU) and the optimal amount of the Na-phosphate buffer 0.1M, pH 7 (CH2Cl2/buffer ratio ca. 1:0.1) were suspended in CH2Cl2 (2.5mL) at 25°C for 24h, and the mixture stirred under O2 atmosphere. The reactions were monitored by thin layer chromatography (TLC, n-hexane/EtOAc=2.0:1.0). After the disappearance of the substrate, the organic layer was recovered (eventually after filtration for immobilized enzyme), and evaporated under reduced pressure. The crude was treated with Na2S2O4 in equal volume of H2O and THF (2.0mL) with stirring for 5min. The mixture was diluted with EtOAc (4.0mL) and separated from H2O. The organic layer was dried on anhydrous Na2SO4 and evaporated under reduced pressure. When necessary the crude was purified by flash-chromatography. The products were characterized by 1H and 13C NMR, GC-MS (after silylation) and Elemental Analysis. GC-MS analysis was performed on a GC-MS QP5050 Shimadzu apparatus using an SPB column (25m×0.25mm and 0.25mm film thickness) and an isothermal temperature profile of 100°C for 2min, followed by a 10°Cmin-1 temperature gradient to 280°C for 25min. The injector temperature was 280°C. Chromatography-grade helium was used as the carrier gas with a flow of 2.7 mL×min-1. Mass spectra were recorded with an electron beam of 70eV. Quantitative analyses were performed by using dodecane as the internal standard. MS values are referred to full silylated derivatives with the only exception of 3c and 3d.
98%	Stage #1: 3-(4-hydroxyphenyl)propanoic acid With Agaricus bisporus tyrosinase immobilized on polydiallyldimethyl ammonium chloride functionalized oxidized multi-walled carbonanotubes; oxygen In aq. phosphate buffer; dichloromethane at 25℃; for 24h; Enzymatic reaction; Stage #2: With sodium dihydrosulfite In tetrahydrofuran; lithium hydroxide monohydrate at 25℃; for 0.0833333h;	1 5.5. Synthesis of catechol derivatives 3, 3a-d and 4a-d General procedure: MWCNT/Tyr (240 U) was added to a solution of the appropriate substrate (0.05 mmol) in CH2Cl2 (2.5 mL) in PBS (275 μL), and the mixture was stirred at 25 °C under O2. After 24 h, the catalyst was recovered by centrifugation and the organic fraction was concentrated and treated with a solution of sodium dithionite in THF and H2O [1:1 (v/v)]. The mixture was stirred at 25 °C for 5 min to allow the complete reduction of benzoquinones to catechols and extracted twice with ethyl acetate (EtOAc; 2.0 mL2). The collected organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to yield catechol derivatives 3, 3a-d and 4a-d. All experiments were conducted in triplicate. The structure of catechol derivatives was characterized without further purification by comparison with data previously reported in the literature. 5.5.1 (3,4-Dihydroxyphenyl)propanoic acid (3) Oil; 1H NMR (400 MHz, CDCl3): δ H (ppm) = 2.64 (2H, m, CH2), 2.81 (2H, m, CH2), 6.76-6.94 (3H, m, Ph-H); 13C NMR (50 MHz,CDCl3): δC (ppm) = 30.44 (CH2), 35.81 (CH2),115.36 (2 * CH), 119.46 (CH), 132.33 (C), 145.10 (C), 145.93 (C), 174.98 (CO); MS (EI): m/z 398; elemental analysis: calcd C, 59.34; H, 5.53; O, 35.13, found C, 59.30; H, 5.53; O, 35.04.
88%	With Agaricus bisporus tyrosinase; oxygen; L-ascorbic acid In lithium hydroxide monohydrate at 20℃; for 24h; Na-phosphate buffer; Enzymatic reaction;	4.10. Phenols oxidation General procedure: A panel of phenols (Fig. 7) were oxidized, including para-cresol 1, 4-ethyl phenol 2, 4-tert-butyl phenol 3, 4-sec-butyl phenol 4, 2,4-di-tert-butyl phenol 5, meta-cresol 6, 3,4-dimethyl phenol 7, 4-chloro phenol 8, 4-chloro-2-methyl phenol 9, 2-methoxy-4-methyl phenol 10, 2-methoxy phenol 11, 3-(4-hydroxyphenyl)propionic acid 12, 4-hydroxyphenylacetic acid 13, bis(4-hydroxyphenyl)methane 14 and tyrosol 15. As a general procedure phenol (0.05 mmol), tyrosinases (263-526 IU) and AA (1.5 equiv) were placed in 0.1 M Na-phosphate buffer pH 7.0 (5.0 mL) in vigorous stirring at room temperature. For insoluble aqueous phenols 3, 5, 14 substrates were dissolved in CH3CN (1.0 mL) and then added to the buffer solutions. Oxidations were performed using homogeneous and heterogeneous conditions. Reactions were monitored by thin layer chromatography (TLC). After the disappearance of the substrate, the reaction mixture was acidified with a solution of HCl 1.0 N and extracted twice with EtOAc. The organic extracts were treated with a saturated solution of NaCl and dried over anhydrous Na2SO4, then filtered and concentrated under vacuum to yield a colored crude. In the case of immobilized enzyme, biocatalyst was first recovered by filtration and the solution was subjected to the same work up described above. The obtained colored residue was treated with pyridine, HMDS and TMCS (HMDS-TMCS, 2:1 v/v) under vigorous stirring at room temperature for 30 min, then allowed to stand for 5 min.50 All products were identified by 1H NMR, 13C NMR and GC-MS. 1H NMR and 13C NMR were recorded on a Bruker 200 MHz spectrometer using CDCl3 as solvent. All chemical shift are expressed in parts per million (δ scale). GC-MS analysis were performed on a GCMS-QP5050 Shimadzu apparatus using a SPB column (25 m × 0.25 mm and 0.25 mm film thickness) and an isothermal temperature profile of 100 °C for 2 min, followed by a 10 °C/min temperature gradient to 280 °C for 25 min. The injector temperature was 280 °C. Chromatography-grade helium was used as the carrier gas with a flow of 2.7 mL/min. Mass spectra were recorded with an electron beam of 70 eV.

14%	With phosphoric acid monosodium salt at 25℃; for 0.25h; Glovebox;
	With mushroom tyrosinase In N,N-dimethyl-formamide at 25℃; aq. phosphate buffer; Enzymatic reaction;
	With ethylenediaminetetraacetic acid; ammonium iron (II) sulfate; dihydrogen peroxide; L-ascorbic acid In aq. buffer at 30℃; for 0.5h;

Reference： [1]Bozzini, Tiziana; Botta, Giorgia; Delfino, Michela; Onofri, Silvano; Saladino, Raffaele; Amatore, Donatella; Sgarbanti, Rossella; Nencioni, Lucia; Palamara, Anna Teresa [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 24, p. 7699 - 7708]
[2]Botta, Giorgia; Bizzarri, Bruno Mattia; Garozzo, Adriana; Timpanaro, Rossella; Bisignano, Benedetta; Amatore, Donatella; Palamara, Anna Teresa; Nencioni, Lucia; Saladino, Raffaele [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5345 - 5351]
[3]Location in patent: experimental part Guazzaroni, Melissa; Crestini, Claudia; Saladino, Raffaele [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 157 - 166]
[4]Dhammaraj, Taweesak; Phintha, Aisaraphon; Pinthong, Chatchadaporn; Medhanavyn, Dheeradhach; Tinikul, Ruchanok; Chenprakhon, Pirom; Sucharitakul, Jeerus; Vardhanabhuti, Nontima; Jiarpinitnun, Chutima; Chaiyen, Pimchai [ACS Catalysis, 2015, vol. 5, # 8, p. 4492 - 4502]
[5]Location in patent: scheme or table Munoz-Munoz, Jose Luis; Berna, Jose; Garcia-Molina, Maria del Mar; Garcia-Molina, Francisco; Garcia-Ruiz, Pedro Antonio; Varon, Ramon; Rodriguez-Lopez, Jose N.; Garcia-Canovas, Francisco [Biochemical and Biophysical Research Communications, 2012, vol. 424, # 2, p. 228 - 233]
[6]Chen, Chan; Du, Dong; Liu, Wenbin; Ren, Haisheng; Shang, Qi; Su, Yingli; Tang, Weikang; Zhang, Ling [Journal of Inorganic Biochemistry, 2022, vol. 234]

43
[ 119072-55-8 ]
[ 1078-61-1 ]
[ 52988-34-8 ]
[ 75-64-9 ]
[ 1364814-24-3 ]

Yield	Reaction Conditions	Operation in experiment
65%		General procedure: Members of the library were synthesized using an Ugi multi-component reaction1,2 previously reported by our group 3. Briefly, a round bottom flask was charged with amine (1 molar equivalent) and aldehyde (0.5 molar equivalent) in CHCl3 (1 ml) and stirred at room temperature for one hour, followed by the addition of isocyanide (1 molar equivalent) and carboxylic acid (1 molar equivalent) sequentially. The flask was then heated to 75 C and stirred at the same temperature overnight. The entire reaction was then loaded onto silica gel and eluted first with CHCl3 to remove unreacted isocyanide followed by CHCl3:MeOH (20:1) to elute the Ugi product. All products were analyzed by 1H NMR, 13C NMR and high resolution mass spectrometry (HRMS). The synthesis of several compounds that was not described in our previous reports is described below.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2043 - 2045

44
[ 1078-61-1 ]
[ 1038223-66-3 ]
[ 1342283-76-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	Stage #1: dihydrocaffeic acid With triethylamine In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 4-[(hexylamino)methyl]phenol With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h;

Reference： [1]Location in patent: experimental part Aladedunye, Felix; Catel, Yohann; Przybylski, Roman [Food Chemistry, 2012, vol. 130, # 4, p. 945 - 952]

45
[ 1078-61-1 ]
[ 2032-33-9 ]
[ 1342283-63-9 ]

Reference： [1]Food Chemistry,2012,vol. 130,p. 945 - 952

46
[ 1078-61-1 ]
[ 25468-44-4 ]
[ 1342283-65-1 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: dihydrocaffeic acid With triethylamine In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: N-benzylhexylamine With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h;

Reference： [1]Location in patent: experimental part Aladedunye, Felix; Catel, Yohann; Przybylski, Roman [Food Chemistry, 2012, vol. 130, # 4, p. 945 - 952]

47
[ 587-33-7 ]
[ 1078-61-1 ]

Reference： [1]Journal of Natural Products,2012,vol. 75,p. 275 - 279

48
[ 1078-61-1 ]
[ 100-39-0 ]
[ 1375180-02-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h; Inert atmosphere;	Benzyl 3-(3,4-bis(benzyloxy)phenyl)propanoate (2) Benzyl 3-(3,4-bis(benzyloxy)phenyl)propanoate 2 was synthesized from 3-(3,4-dihydroxyphenyl)propanoic acid 1, purchased from Alfa Aesar, according to a previously described procedure with slight modifications. As the carboxylic acid contains potentially air sensitive catechol moieties, after opening, the bottle of carboxylic acid was purged with argon, and the cap tightly wrapped with parafilm until subsequent use. While the previously published procedure was observed to work well on scales <5 grams, adequate stirring became problematic on the scales required for this work, and it is recommended that the procedure be performed with the largest possible football shaped stir bar that can fit into the flask. If stirring is observed to cease during the procedure due to caking of the base, one septa can be briefly removed while under positive Argon flow, and the solidified mass of K2CO3 at the bottom of the flask broken up gently with a dry metal spatula until stirring resumes, whereupon a fresh septa is added to the flask and the vessel stirred until completion on the reaction. A flame dried 500 ml 3-necked round bottom flask was fitted with rubber septa and a large football shaped stir-bar and allowed to cool to ambient temperature under positive argon flow. Subsequently, 20 grams (1 equiv., 109.8 mmol) of 3-(3,4-dihydroxyphenyl)propanoic acid was added, followed by 200 ml of anhydrous DMF with stirring. Once dissolved, 90.9 grams of anhydrous K2CO3 (6 equiv., 658.7 mmol) was added with stirring. Then, 58.678 ml of fresh benzyl bromide (4.5 equiv., 494 mmol) was added via syringe. The solution was placed in an oil bath set to 80° C. and stirred for 1 day at this temperature. After this time, no further reaction was observed by TLC, which also indicated the reaction was incomplete, and contained in addition to the desired product, a mixture of mono- and di-benzylated products. The reaction vessel was allowed to cool to room temperature. The reaction mixture was then poured through a large fritted glass funnel into a 2 L round bottom flask to remove solids, and the reaction vessel was rinsed 3×300 ml EtOAc through the frit. The solvent was then removed under reduced pressure with a rotary evaporator. To assist subsequent extraction, residual DMF was removed by 4 cycles of evaporation with toluene (500 ml). The crude residue was then redissolved in 1.5 L of Et2O and washed 5×100 ml ice cold water, 1×500 ml Brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was then dry-loaded onto silica gel and purified by flash chromatography gradient elution 10-40% Et2O/hexanes in a large (18 inch tall) glass column. Fractions containing the only desired product were identified by TLC at R=0.31 (20:80 Et2O:Hexanes, Stain=UV/Seebach's stain), pooled, and concentrated under reduced pressure to yield 17.42 grams of desired product. Fractions containing the two regioisomeric dibenzylated products, in which the carboxylic acid and either the 3- or 4-hydroxyl was benzylated, were identified by TLC at Rf=0.15 and 0.19 (20:80 Et2O:Hexanes Stain=UV/Seebach's stain), pooled, concentrated under reduced pressure, and then resubjected to the reaction conditions to give an additional 20.56 grams of product, bringing the total amount of product to 37.98 grams in 76% isolated yield. The material was quickly checked for purity by 1H-NMR and then carried on immediately to the next step. If the yield of the initial reaction is not deemed objectionable, after removal of solvent, rather than collecting partially benzylated material and resubjecting it to the reaction conditions, the product can be more rapidly purified by 2 successive filtrations over a 6-8 inch tall pad of basic Al2O3 (Acros, 50-200 μm) eluting with 20% Et2O/Hexanes. 1H NMR (500 MHz, CDCl3) δ (ppm): 7.45-7.41 (m, 4H) 7.38-7.27 (m, 11H), 6.85 (d, J=8.5 Hz, 1H), 6.80 (d, J=2 Hz, 1H), 6.70 (dd, J=2, 8.5 Hz, 1H) 5.12 (s, 2H), 5.10 (s, 2H), 5.09 (s, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H)
	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 20h; Inert atmosphere;	4.1.2. 3-(3,4-Bis-benzyloxy-phenyl)-propan-1-ol (6) A solution of 4 (0.50 g; 2.74 mmol) and benzyl bromide (2.11 g; 12.34 mmol) in anh. DMF (5 mL) was treated with anh. K2CO3 (2.27 g; 16.46 mmol) for 20 h at 60 °C under an argon atmosphere. The reaction mixture was cooled to rt, filtered and evaporated under reduced pressure. The residue was dissolved in AcOEt (10 mL), washed with 1 M HCl (3 × 5 mL), satd. NaCl (5 × 5 mL) and dried (MgSO4). The desiccant was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in anh. Et2O/THF 1:1 (18 mL), added to a slurry of LiAlH4 (0.10 g; 2.71 mmol) in anh. Et2O at 0 °C and the mixture was stirred at room temperature for 2.5 h. 20% HCl was added to give pH = 1 and the mixture was extracted with AcOEt/Et2O 1:1 (4 × 10 mL). The organic phase was washed with satd. NaCl and dried (Na2SO4). The desiccant was filtered off and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using hexane/AcOEt 1:1. Compound 6 (0.68 g; 56%) was obtained as a colourless oil.
	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - US2020/181455, 2020, A1 Location in patent: Paragraph 0138-0141; 0256-0259
[2]Location in patent: experimental part García, Gonzalo; Serrano, Isabel; Sánchez-Alonso, Patricia; Rodríguez-Puyol, Manuel; Alajarín, Ramón; Griera, Mercedes; Vaquero, Juan J.; Rodríguez-Puyol, Diego; Álvarez-Builla, Julio; Díez-Marqués, María L. [European Journal of Medicinal Chemistry, 2012, vol. 50, p. 90 - 101]
[3]Current Patent Assignee: ENVISTA HOLDINGS CORP; ACATECHOL - WO2017/132484, 2017, A1 Location in patent: Paragraph 0080; 0081

49
[ 1078-61-1 ]
[ 35661-40-6 ]
[ 1418498-42-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N-Fmoc L-Phe With 4-O-methylhydroxylaminephenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin; 1-hydroxy-7-aza-benzotriazole; 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 1-methyl-pyrrolidin-2-one at 20℃; for 1.5h; Stage #2: With piperidine In 1-methyl-pyrrolidin-2-one at 20℃; for 0.383333h; Stage #3: dihydrocaffeic acid Further stages;	Solid phase synthesis of HCA-Phe-NHOH and HCA-Pro-NHOH Hydroxylamine hydrochloride (834 mg, 12 mmol) was dissolved in 40 mL of aqueous sodium hydrogen carbonate (2.2 g, 26 mmol), and cooled to 5 °C. N-(9-fluorenylmethoxycarbonyloxy) succinimide (Fmoc-OSu, 4.0 g, 12 mmol) dissolved in 40 mL ethyl acetate was added drop wise to the rapidly stirred hydroxylamine solution in an ice-bath and stirred for 4 h at room temperature. The reaction was monitored by TLC (ethyl acetate/hexane = 1:1, Rf = 0.4). After the water layer was removed, the organic layer was washed with saturated aqueous potassium hydrogen sulfate and brine. This organic extract was concentrated in high vacuum, and then N-Fmoc protected hydroxylamine (Fmoc-NHOH) was obtained as a white crystalline solid after trituration in hexane and stored overnight (80% yield). Its structure was identified by 1H NMR (JNM-LA300 spectrometer, JEOL Ltd, Tokyo, Japan): (δH, CDCl3) 4.21 (1H, t, Fmoc CH), 4.32 (2H, d, Fmoc CH2), 7.28-7.43, 7.68, 7.86 (8H, m, Fmoc Ar. CH), 8.77 (1H, s, NH), 9.75 (1H, br s, OH). Fmoc-NHOH (2 equiv) was coupled to 2-chlorotrityl chloride (CTC) resin (1.43 mmol/g) with N,N’-diisopropylethylamine (DIPEA; 4 equiv) in dichloromethane (DCM) for 48 h. Fmoc-NHOH loaded CTC resin was treated with 10% DIPEA/methanol (v/v) to block the remaining chloride groups. The resulting resin was filtered, and its loading level was 1.0 mmol/g, which was determined by Fmoc titration. After treating with 20% piperidine/N-methyl-2-pyrrolidone (NMP) for 30 min to remove Fmoc groups, Fmoc-l-Pro-OH or Fmoc-l-Phe-OH (2 equiv) was coupled to the resin with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyl uronium hexafluorophosphate methanaminium (HATU), 1-hydroxy-7-azabenzotriazole (HOAt), and DIPEA (4 equiv) for 1.5 h at room temperature. After removing Fmoc groups by 20% piperidine/NMP, HCA (2 equiv) was coupled to the amino acid anchored resin with benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP; 2 equiv), hydroxybenzotriazole (HOBt; 2 equiv) and DIPEA (3 equiv) for 5 h. The final product was cleaved from the resin by 30% trifluoroacetic acid (TFA)/DCM (v/v) for 1 h. The resin was filtered, and the filtrate was concentrated in high vacuum, followed by precipitation with cold diethyl ether. The resulting HCA-Phe-NHOH and HCA-Pro-NHOH were identified by QUATTRO Triple Quardrupole Tandem mass spectrometer (Micromass & Waters, Milford, MA, USA) at National Instrumentation Center for Environmental Management (NICEM): CA-Phe-NHOH (m/z calcd: 343.1 [M+H]+; found: 343.0), CA-Pro-NHOH (m/z calcd: 293.1 [M+H]+; found: 293.1), DHCA-Phe-NHOH (m/z calcd: 345.1 [M+H]+; found: 345.1), DHCA-Pro-NHOH (m/z calcd: 295.1 [M+H]+; found: 295.1), pCoA-Phe-NHOH (m/z calcd: 327.1 [M+H]+; found: 327.1), pCoA-Pro-NHOH (m/z calcd: 277.1 [M+H]+; found: 277.0), FA-Phe-NHOH (m/z calcd: 357.1 [M+H]+; found: 357.1), FA-Pro-NHOH (m/z calcd: 307.1 [M+H]+; found: 307.0), SA-Phe-NHOH (m/z calcd: 387.1 [M+H]+; found: 387.0), SA-Pro-NHOH (m/z calcd: 337.1 [M+H]+; found: 337.1). Their purities were analyzed by RP-HPLC (Thermo Scientific Spectra System AS300; Thermo-Fisher, Waltham, MA, USA) using C18 reverse phase column (120 Å, 5 μm, 4.6 × 250 mm; AAPPTec, Louisville, KY, USA) using the following conditions: gradient elution with A: 0.1% TFA/water, B: 0.1% TFA/acetonitrile; from 10% to 90% over 30 min, a flow rate: 1.0 mL/min; detection: UV, 280 or 326 nm. HCA-Phe-NHOH were purified by a semi-preparative RP-HPLC column using an A to B gradient (A: 0.1% TFA in water, B: 0.1% TFA in acetonitrile; from 10% to 90% B over 30 min, at a flow rate of 4.0 mL/min) and freeze-dried.

Reference： [1]Kwak, Seon-Yeong; Yang, Jin-Kyoung; Choi, Hye-Ryung; Park, Kyung-Chan; Kim, Young-Bu; Lee, Yoon-Sik [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 4, p. 1136 - 1142]

50
[ 1078-61-1 ]
[ 71989-31-6 ]
[ 1418498-46-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Fmoc-Pro-OH With 4-O-methylhydroxylaminephenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin; 1-hydroxy-7-aza-benzotriazole; 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 1-methyl-pyrrolidin-2-one at 20℃; for 1.5h; Stage #2: With piperidine In 1-methyl-pyrrolidin-2-one at 20℃; for 0.383333h; Stage #3: dihydrocaffeic acid Further stages;	Solid phase synthesis of HCA-Phe-NHOH and HCA-Pro-NHOH Hydroxylamine hydrochloride (834 mg, 12 mmol) was dissolved in 40 mL of aqueous sodium hydrogen carbonate (2.2 g, 26 mmol), and cooled to 5 °C. N-(9-fluorenylmethoxycarbonyloxy) succinimide (Fmoc-OSu, 4.0 g, 12 mmol) dissolved in 40 mL ethyl acetate was added drop wise to the rapidly stirred hydroxylamine solution in an ice-bath and stirred for 4 h at room temperature. The reaction was monitored by TLC (ethyl acetate/hexane = 1:1, Rf = 0.4). After the water layer was removed, the organic layer was washed with saturated aqueous potassium hydrogen sulfate and brine. This organic extract was concentrated in high vacuum, and then N-Fmoc protected hydroxylamine (Fmoc-NHOH) was obtained as a white crystalline solid after trituration in hexane and stored overnight (80% yield). Its structure was identified by 1H NMR (JNM-LA300 spectrometer, JEOL Ltd, Tokyo, Japan): (δH, CDCl3) 4.21 (1H, t, Fmoc CH), 4.32 (2H, d, Fmoc CH2), 7.28-7.43, 7.68, 7.86 (8H, m, Fmoc Ar. CH), 8.77 (1H, s, NH), 9.75 (1H, br s, OH). Fmoc-NHOH (2 equiv) was coupled to 2-chlorotrityl chloride (CTC) resin (1.43 mmol/g) with N,N’-diisopropylethylamine (DIPEA; 4 equiv) in dichloromethane (DCM) for 48 h. Fmoc-NHOH loaded CTC resin was treated with 10% DIPEA/methanol (v/v) to block the remaining chloride groups. The resulting resin was filtered, and its loading level was 1.0 mmol/g, which was determined by Fmoc titration. After treating with 20% piperidine/N-methyl-2-pyrrolidone (NMP) for 30 min to remove Fmoc groups, Fmoc-l-Pro-OH or Fmoc-l-Phe-OH (2 equiv) was coupled to the resin with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyl uronium hexafluorophosphate methanaminium (HATU), 1-hydroxy-7-azabenzotriazole (HOAt), and DIPEA (4 equiv) for 1.5 h at room temperature. After removing Fmoc groups by 20% piperidine/NMP, HCA (2 equiv) was coupled to the amino acid anchored resin with benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP; 2 equiv), hydroxybenzotriazole (HOBt; 2 equiv) and DIPEA (3 equiv) for 5 h. The final product was cleaved from the resin by 30% trifluoroacetic acid (TFA)/DCM (v/v) for 1 h. The resin was filtered, and the filtrate was concentrated in high vacuum, followed by precipitation with cold diethyl ether. The resulting HCA-Phe-NHOH and HCA-Pro-NHOH were identified by QUATTRO Triple Quardrupole Tandem mass spectrometer (Micromass & Waters, Milford, MA, USA) at National Instrumentation Center for Environmental Management (NICEM): CA-Phe-NHOH (m/z calcd: 343.1 [M+H]+; found: 343.0), CA-Pro-NHOH (m/z calcd: 293.1 [M+H]+; found: 293.1), DHCA-Phe-NHOH (m/z calcd: 345.1 [M+H]+; found: 345.1), DHCA-Pro-NHOH (m/z calcd: 295.1 [M+H]+; found: 295.1), pCoA-Phe-NHOH (m/z calcd: 327.1 [M+H]+; found: 327.1), pCoA-Pro-NHOH (m/z calcd: 277.1 [M+H]+; found: 277.0), FA-Phe-NHOH (m/z calcd: 357.1 [M+H]+; found: 357.1), FA-Pro-NHOH (m/z calcd: 307.1 [M+H]+; found: 307.0), SA-Phe-NHOH (m/z calcd: 387.1 [M+H]+; found: 387.0), SA-Pro-NHOH (m/z calcd: 337.1 [M+H]+; found: 337.1). Their purities were analyzed by RP-HPLC (Thermo Scientific Spectra System AS300; Thermo-Fisher, Waltham, MA, USA) using C18 reverse phase column (120 Å, 5 μm, 4.6 × 250 mm; AAPPTec, Louisville, KY, USA) using the following conditions: gradient elution with A: 0.1% TFA/water, B: 0.1% TFA/acetonitrile; from 10% to 90% over 30 min, a flow rate: 1.0 mL/min; detection: UV, 280 or 326 nm. HCA-Phe-NHOH were purified by a semi-preparative RP-HPLC column using an A to B gradient (A: 0.1% TFA in water, B: 0.1% TFA in acetonitrile; from 10% to 90% B over 30 min, at a flow rate of 4.0 mL/min) and freeze-dried.

Reference： [1]Kwak, Seon-Yeong; Yang, Jin-Kyoung; Choi, Hye-Ryung; Park, Kyung-Chan; Kim, Young-Bu; Lee, Yoon-Sik [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 4, p. 1136 - 1142]

51
[ 1078-61-1 ]
[ 1450832-96-8 ]
[ 1450833-56-3 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine at 20℃; for 5h;	4.1.4 Typical procedure for the conjugation reaction. 2-(6-Methoxy-2,3-dihydro-1H-inden-1-yl)-N-(4-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)butyl)acetamide (6) General procedure: Compound 4 (30mg, 0.13mmol) was mixed with diisopropyl ethylamine (22.6μL, 0.13mmol), HBTU (49mg, 0.13mmol), and carboxylic acid (26.8mg, 0.13mmol) and the reaction was stirred at rt for 5h. After the mixture was concentrated, the crude sample was directly purified by CC (5-10% NH4OH in propanol, silica gel) to give 6 as a colorless oil (18.2mg, 0.043mmol, 33%)

Reference： [1]Cheng, Wei-Chieh; Weng, Chen-Yi; Yun, Wen-Yi; Chang, Shang-Yu; Lin, Yu-Chun; Tsai, Fuu-Jen; Huang, Fu-Yung; Chen, Yun-Ru [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 17, p. 5021 - 5028]

52
[ 1078-61-1 ]
[ 100-44-7 ]
[ 1375180-02-1 ]

Yield	Reaction Conditions	Operation in experiment
89.2%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 48h; Inert atmosphere;	Benzyl 3-(3,4-bis(benzyloxy)phenyl)propanoate (10). To a solution of acid 9 (3.44 Kg, 18.88 mol) in DMF (3.2 L) was slowly addedpotassium carbonate (8.0 Kg, 58.0 mol) and benzylic chloride (10.0 L, 88.0 mol) at ambient temperature. Then the temperature was elevated to 80 °C and the mixturewas stirred for 48 h, TLC showed that all the starting materials were consumed(Petroleum:EtOAc = 5:1, UV). The mixture was filtered, the filtrate was diluted withbrine (8.0 L) and extracted with EtoAc (16.0 L×3). The organic layers were combined,dried over Na2SO4 and filtered. The solvent was removed in vacuum to give the crudeester 10 (7.62 Kg, 89.2%), which was used for the subsequent step without furtherpurification.
	With potassium carbonate In N,N-dimethyl-formamide at 80℃;	1.1.1 EMBODIMENT 1: The Synthesis of Kukoamine B Malate Next, 40g of compound f2 is dissolved in 120 ml of DMF, added with 116g of potassium carbonate and 86 ml of benzyl chloride, and then heated to 80°C to carry out the reaction, and the reaction is monitored via TLC. After reaction is completed, the reaction solution is filtrated, extracted with ethyl acetate, washed sequentially with water and saturated salt water, and dried with anhydrous sodium sulfate, and then compound f3 is collected by suction filtration
	With potassium carbonate In N,N-dimethyl-formamide at 80℃;	1.1 1.1 Methods: (1) 50 g of compound fi is dissolved in 100 ml of hydrobromic acid solution (40% concentration), then heated to 140° C. to carry out the reaction, and the reaction is monitored via TLC. Afier the reaction is completed, the reaction solution is cooled down and then yellow crystals precipitate out. The yellow crystals are collected by suction filtration and washed with small quantity of petroleum ether, and then 40 g of yellow solid compounds f2 are obtained. Next, 40 g of compound f2 is dissolved in 120 ml of DMF, added with 116 g of potassium carbonate and 86 ml of benzyl chloride, and then heated to 80° C. to carry out the reaction, and the reaction is monitored via TLC. Afier the reaction is completed, the reaction solution is filtrated, extracted with ethyl acetate, washed sequentially with water and saturated salt water, and dried with anhydrous sodium sulfate, and then compound 13 is collected by suction filtration. Next, 14.4 g of sodium hydroxide is dissolved in 80 ml of water, added with 85 g of compound 13, then added with 80 ml of methanol, and heated to 90° C. to perform reflux reaction, and the reaction is monitored via TLC. After the reaction is completed, the reaction solution is dried by rotary evaporation, then poured into a beaker, added with concentrated hydrochloric acid to make it strongly acidic, and filtrated, and then the filter cake is collected and dried. 60 g of yellow compound f is obtained and the yield is 69%. The reactionequation is expressed as follows:

5.6 g

With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 36h;

8.1 Using the procedure described in Example 1,The reaction is carried out under the same scale and conditions,Except that 3,4-dimethoxybenzenepropanoic acid was replaced by 3,4-dihydroxybenzenepropanoic acid (e),And the 3,4-dihydroxybenzenepropanoic acid chlorination reaction was carried out by dissolving 3 g of 3,4-dihydroxybenzenepropanoic acid in 15 ml of N, N-dimethylformamide,8 g of potassium carbonate and 6 ml of benzyl chloride were added,80 ° C for 36 hours,filter,Ethyl acetate extraction,Washed with a saturated saline solution,Dried over anhydrous sodium sulfate,filter,The solvent was dried to give 5.6 g of intermediate e2.5.6 g of intermediate e2 was dissolved in 6 ml of an aqueous solution of sodium hydroxide (concentration 20%),6 ml of methanol was added,90 ° C for 4 hours,Spin drying solvent,10mi concentrated hydrochloric acid was added under ice-cooling to a strong acidity,Precipitation of solid,filter,The filter cake was collected to yield 34.1 g of intermediate e.4.1 g of intermediate e3 was dissolved in 20 ml of dichloromethane,0.1 ml of N, N-dimethylformamide,Followed by addition of 1.5 ml of thionyl chloride,Reaction at 45 ° C for 5 hours,The solvent was dried to give intermediate f.

Reference： [1]Dong, Kai [Synlett, 2018, vol. 29, # 20, p. 2669 - 2672]
[2]Current Patent Assignee: THIRD MILITARY MEDICAL UNIVERSITY; TIANJIN CHASE SUN PHARMACEUTICAL CO LTD - EP2639215, 2013, A1 Location in patent: Paragraph 0036
[3]Current Patent Assignee: THIRD MILITARY MEDICAL UNIVERSITY; TIANJIN CHASE SUN PHARMACEUTICAL CO LTD - US2013/289112, 2013, A1 Location in patent: Paragraph 0062
[4]Current Patent Assignee: CHONGQING ANTIXIN BIOTECHNOLOGY CN - CN105348137, 2016, A Location in patent: Paragraph 0079; 0080

53
[ 1078-61-1 ]
[ 20782-91-6 ]
[ 1580002-54-5 ]

Yield	Reaction Conditions	Operation in experiment
	In water; N,N-dimethyl-formamide; at 20 - 50℃; for 22h;Inert atmosphere;	General procedure: In an ice-bath, 1.60 mmol of the opportune acid has been dissolved in DMF (2 mL) then 0.4 mL of aqueous 0.4 M sodium hydroxyde were added. The mixture was stirred for 20 min and then <strong>[20782-91-6]2-(bromomethyl)-5-nitrofuran</strong> (1.6 mmol) was slowly added. After the addition was complete, the mixture was allowed to reach ambient temperature for 20 h and afterward it was stirred for 2 h at 50 C. The reaction mixture was treated with H2O and AcOEt (3:1). The ethyl acetate layer was separated and the aqueous layer extracted with ethyl acetate (20 mL). The combined ethyl acetate extracts were washed with water (30 mL), saturated sodium hydrogen carbonate solution (30 mL), water (30 mL) and with saturated sodium chloride solution (30 mL) and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified with column chromatography using silica gel and AcOEt/n-hexane as eluent to give a yellow solid which was crystallized from toluene (yield 40-50%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1502 - 1505

54
[ 1078-61-1 ]
[ 62039-92-3 ]
[ 1609175-60-1 ]

Yield	Reaction Conditions	Operation in experiment
48%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃;	1 [00155] Example 1 - Synthesis of Compounds of Formula III [00159] Synthesis ofN-(4-chloro-3-(trifluoromethyl)benzyl)-3-(3,4- dihydroxyphenyl)propanamide (compound C330) [00160] N-(4-chloro-3-(trifluoromethyl)benzyl)-3-(3,4-dihydroxyphenyl)propanamide (compound C330) was synthesized according to General Procedure A. To a 0 °C solution of 3,4-dihydroxyhydro cinnamic acid (205.8 mg, 1.13 mmol), 4-chloro-3-(trifluoromethyl) benzylamine (0.2 mL, 1.36 mmol), N-methylmorpholine (0.12 mL, 1.13 mmol) and ΗΟΒΤ·Η20 (173.0 mg, 1.13 mmol) in 5 mL of dry CH2C12 and 2 mL of DMF, EDC'HCl (216.6 mg, 1.13 mmol) was added in portions. The resulting slurry was allowed to warm to room temperature overnight with stirring. The reaction mixture was concentrated by rotary evaporation, diluted with 30 mL of a 4: 1 solution of EtOAc and hexane, washed with 0.1N HC1 (2x), saturated NaHC03 (2x), and brine (2x). The organic phase was dried with anhydrous MgS04 and concentrated in vacuo. The resultant solid was triturated with chloroform and the solid obtained after filtration was dried in vacuo, which afforded 235 mg (48%) of product as a pale yellow crystalline solid. 1H NMR (DMSO-J6, 400 MHz) δ 8.66 (s, 1H), 8.59 (s, 1H), 8.35 (t, J= 6.0 Hz, 1H), 7.66 (s, 1H), 7.57 (d, J= 8.2 Hz, 1H), 7.31 (d, J= 8.2 Hz, 1H), 6.57 (d, J= 8.2 Hz, 1H), 6.54 (d, J= 1.8 Hz, 1H), 6.39 (dd, J= 1.8, 8.2 Hz, 1H), 4.27 (d, J= 6.0 Hz, 2H), 2.62 (t, J= 7.8 Hz, 2H), 2.33 (t, J= 7.7 Hz, 2H). 13C NMR (DMSO- d6, 100 MHz) δ 172.32, 145.53, 143.89, 140.46, 133.24, 132.45, 131.99, 129.25, 126.99 (q, J= 5.7 Hz), 126.53 (q, J= 30.5 Hz), 125.96, 123.41 (q, J= 270.8 Hz), 119.30, 116.29, 115.92, 41.54, 37.90. HRMS, DART calcd. for CnHisFsNOsCl [M+H]+ 374.07707, found: 374.07880.

Reference： [1]Current Patent Assignee: UNIVERSITY OF MICHIGAN; EASTERN MICHIGAN UNIVERSITY - WO2014/70983, 2014, A1 Location in patent: Paragraph 00155; 00159-00160

55
[ 1078-61-1 ]
[ 619-45-4 ]
C₁₇H₁₇NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With Xylaria polymorpha laccase; 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) diammonium salt In aq. acetate buffer at 20℃; for 3.75h; Green chemistry; Enzymatic reaction;

Reference： [1]Chaurasia, Pankaj Kumar; Yadava, Sudha; Bharati, Shashi Lata; Singh, Sunil Kumar [Russian Journal of Bioorganic Chemistry, 2014, vol. 40, # 4, p. 455 - 460]

56
[ 1078-61-1 ]
[ 99-92-3 ]
[ 1663506-80-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With Xylaria polymorpha laccase; 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) diammonium salt In aq. acetate buffer at 20℃; for 3.75h; Green chemistry; Enzymatic reaction;
86%	With sodium acetate In water at 20℃; for 4.3h;	Synthesis of 3-[6-(4-carboxyphenyl)amino-3,4-dihydroxyphenyl] propanoic acid (Va), 3-[6-(4-acetophenyl)amino-3,4-dihydroxyphenyl]propanoicacid (Vb), and 3-(6-hexylamino-3,4-dihydroxyphenyl)propanoic acid (Vc) The pure enzyme(1.12 IU/mL) was diluted twice with 20 mM sodiumacetate buffer, pH 5.0. 3-(3,4-Dihydroxyphenyl)propionicacid (1 mM) and 4-aminobenzoic acid (1 mM)were added to 2 mL of the solution. The reactionmixture was incubated for 4.15 h at room temperatureupon vigorous stirring. The reaction was monitored byUV-Vis spectrophotometry. The reaction solution wasextracted thrice with ethyl acetate. The ethyl acetate(20 μL) extract was injected in 4.5 × 250 mm column(Waters HPLC Model 600E, spherisorb C18 5 UV),eluent methanol, flow rate 0.5 mL/min. The similarmethod was used for coupling of 3-(3,4-dihydroxyphenyl)propionic acid with 4-aminoacetophenonen-hexylamine, stirring time 4.30 h (IVb) and 6 h (IVc).Yields: 90% (Va), 86% (Va), and 75% (Vc).

Reference： [1]Chaurasia, Pankaj Kumar; Yadava, Sudha; Bharati, Shashi Lata; Singh, Sunil Kumar [Russian Journal of Bioorganic Chemistry, 2014, vol. 40, # 4, p. 455 - 460]
[2]Chaurasia, Pankaj Kumar; Bharati, Shashi Lata; Singh, Sunil Kumar; Yadava, Sudha [Russian Journal of General Chemistry, 2015, vol. 85, # 1, p. 173 - 175][Zh. Obshch. Khim., 2015, vol. 85, # 1, p. 173 - 175,3][Zhurnal Obshchei Khimii, 2015, vol. 85, # 1, p. 173 - 175,3]

57
[ 1078-61-1 ]
dibenzyl 4-(3-(dioctylamino)-3-oxopropyl)-1,2-phenylenediphosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; dicyclohexyl-carbodiimide / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: tetrachloromethane; N-ethyl-N,N-diisopropylamine; dmap / acetonitrile / 0 °C
	Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; dicyclohexyl-carbodiimide / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: tetrachloromethane; dmap; N-ethyl-N,N-diisopropylamine / acetonitrile / 0 °C

Reference： [1]Elumalai, Nagarajan; Berg, Angela; Natarajan, Kalaiselvi; Scharow, Andrej; Berg, Thorsten [Angewandte Chemie - International Edition, 2015, vol. 54, # 16, p. 4758 - 4763][Angew. Chem., 2015, vol. 127, # 16, p. 4840 - 4845,6]
[2]Berg, Angela; Berg, Thorsten; Elumalai, Nagarajan; Natarajan, Kalaiselvi; Scharow, Andrej [Angewandte Chemie - International Edition, 2015, vol. 54, # 16, p. 4758 - 4763][Angew. Chem., 2015, vol. 127, # 16, p. 4840 - 4845,6]

58
[ 1078-61-1 ]
4-(3-(dioctylamino)-3-oxopropyl)-1,2-phenylene bis(dihydrogen phosphate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; dicyclohexyl-carbodiimide / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: tetrachloromethane; N-ethyl-N,N-diisopropylamine; dmap / acetonitrile / 0 °C 3.1: palladium 10% on activated carbon; hydrogen / ethanol
	Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; dicyclohexyl-carbodiimide / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: tetrachloromethane; dmap; N-ethyl-N,N-diisopropylamine / acetonitrile / 0 °C 3.1: palladium 10% on activated carbon; hydrogen / ethanol

Reference： [1]Elumalai, Nagarajan; Berg, Angela; Natarajan, Kalaiselvi; Scharow, Andrej; Berg, Thorsten [Angewandte Chemie - International Edition, 2015, vol. 54, # 16, p. 4758 - 4763][Angew. Chem., 2015, vol. 127, # 16, p. 4840 - 4845,6]
[2]Berg, Angela; Berg, Thorsten; Elumalai, Nagarajan; Natarajan, Kalaiselvi; Scharow, Andrej [Angewandte Chemie - International Edition, 2015, vol. 54, # 16, p. 4758 - 4763][Angew. Chem., 2015, vol. 127, # 16, p. 4840 - 4845,6]

59
[ 1120-48-5 ]
[ 1078-61-1 ]
(3,4-dihydroxyphenyl)-N,N-dioctylpropanamide 3-(3,4-dihydroxyphenyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: dihydrocaffeic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: n-dioctylamine at 0 - 20℃;
57%	Stage #1: dihydrocaffeic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: n-dioctylamine In N,N-dimethyl-formamide at 0 - 20℃;

Reference： [1]Elumalai, Nagarajan; Berg, Angela; Natarajan, Kalaiselvi; Scharow, Andrej; Berg, Thorsten [Angewandte Chemie - International Edition, 2015, vol. 54, # 16, p. 4758 - 4763][Angew. Chem., 2015, vol. 127, # 16, p. 4840 - 4845,6]
[2]Berg, Angela; Berg, Thorsten; Elumalai, Nagarajan; Natarajan, Kalaiselvi; Scharow, Andrej [Angewandte Chemie - International Edition, 2015, vol. 54, # 16, p. 4758 - 4763][Angew. Chem., 2015, vol. 127, # 16, p. 4840 - 4845,6]

60
[ 1078-61-1 ]
[ 9012-76-4 ]
hydrocaffeic acid complex with chitosan [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		HCA-CS conjugates were synthesized using standard EDC chemistryas depicted in Scheme 1. Briefly, <strong>[9012-76-4]chitosan</strong> (0.6 g, 3.0 mM amine groups) was suspended in 60 mL of double distilled water and the pH was adjusted to 2.5 by 0.1 N HCl addition. The suspension was stirred overnight until complete dissolution of <strong>[9012-76-4]chitosan</strong> was achieved. Subsequently, HCA (0.28 g, 1.5 mM) and EDC (0.71 g, 3.7 mM) were dissolved in 30 mL of 1:1 v/v mixture of water and ethanol and were gradually added to the <strong>[9012-76-4]chitosan</strong> solution.The pH of the reaction mixture was adjusted to 5.5 by 0.1 N NaOH and the reaction mixture was continuously stirred for 24 h. The pH of the reaction solution was maintained at 5.5 by the addition of 0.1 N HCl. The reaction mixture was dialyzed (MWCO: 3500, SpectraPor) against pH 4.0 water for 3 days. The HCA-CS conjugates were separated by freeze-drying using a Virtis freeze-dryer (Bench-Top K, VirTis, Canada). 1H NMR spectra of HCA-CS conjugate and unmodified CS solutions in D2O containing 1% v/v DCl (5 mg/mL) were recorded at 25 C using a Varian spectrometer operating at 400 MHz. UV-vis spectroscopy measurements of the conjugate solution in deionized water (3.6 mg/mL) were recorded using a Cary5000UV-Vis-NIR Spectrophotometer (Agilent Technologies). HCA content of the conjugates was calculated by 1H NMR and UV-vis spectroscopy measurements.

Reference： [1]European Journal of Pharmaceutics and Biopharmaceutics,2014,vol. 88,p. 1026 - 1037

61
[ 7188-38-7 ]
[ 1078-61-1 ]
[ 109134-05-6 ]
C₂₃H₂₈N₂O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	In tetrahydrofuran at 40℃; for 48h;	2.5. Synthesis of model compound 2 2.5. Synthesis of model compound 2 3-(3,4-Dihydroxyphenyl) propionic acid (182.18 mg,1 mmol), 5-ethoxy-2-nitro-benzaldehyde (195.17 mg, 1 mmol) and tert-butylisocyanide (99.756 mg,1.2 mmol) were dissolved in THF (1 mL). Thehomogeneous solution was heated to 40 C for 48 h. During thisperiod, the mixture gradually became heterogeneous, indicatingthe formation of the product. Finally, the mixture was poured intodiethyl ether. The precipitated products were collected by ltrationand washed with diethyl ether for three times to get compound 2 asa pale yellow solid in 80% yield. No Tm was detected for thiscompound.

Reference： [1]Wang, Yao-Zong; Li, Lei; Du, Fu-Sheng; Li, Zi-Chen [Polymer, 2015, vol. 68, p. 270 - 278]

62
[ 1078-61-1 ]
[ 40284-59-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium dihydrogenphosphate at 25℃; for 0.25h; Glovebox;

Reference： [1]Dhammaraj, Taweesak; Phintha, Aisaraphon; Pinthong, Chatchadaporn; Medhanavyn, Dheeradhach; Tinikul, Ruchanok; Chenprakhon, Pirom; Sucharitakul, Jeerus; Vardhanabhuti, Nontima; Jiarpinitnun, Chutima; Chaiyen, Pimchai [ACS Catalysis, 2015, vol. 5, # 8, p. 4492 - 4502]

63
[ 1078-61-1 ]
[ 4389-45-1 ]
N-(3,4-dihydroxydihydrocinnamoyl)-3-methylanthranilic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pDRf₁-(4-coumaroyl:CoA ligase 5 from Arabidopsis thaliana)-(hydroxycinnamoyl/benzoyl-CoA:anthranilate N-hydroxycinnamoyl/benzoyltransferase 1 from Dianthus caryophyllus) recombinant yeast In dimethyl sulfoxide at 30℃; for 24h;	Production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates General procedure: An overnight culture from a single colony of the pDRf1-4CL5-HCBT1 recombinant yeast grown on 2X YNB medium without amino acids, supplemented with 6% glucose and 2X CSM-Ura, was used to inoculated 4 mL of fresh minimal medium at an OD600 = 0.15 and shaken at 200 rpm at 30°C. All precursors were prepared in DMSO and added 5 hours post inoculation at the concentrations indicated in S1, S2 and S3 Tables. The anthranilate acceptors were added to the medium at a final concentration of 300 μM (for anthranilate, 3-hydroxyanthranilate, 3-methylanthranilate, and 5-nitroanthranilate) or 50 μM (for 3-chloroanthranilate, 5-methylanthranilate, 3-methoxyanthranilate, 5-fluoroanthranilate, 5-iodoanthranilate, and 5-chloroanthranilate). These concentrations were selected to limit toxicity and growth inhibition due to either the supplied precursors or the metabolites produced. The cultures were shaken at 200 rpm at 30°C for 24 h in the presence of the precursors for the production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates. Yeast colonies harboring the pDRf1-HCBT1 or pDRf1-4CL5 control vectors were grown under similar conditions. For the detection of metabolites, an aliquot of the culture medium was collected and cleared by centrifugation (21,000xg for 5 min at 4°C), mixed with an equal volume of cold methanol:water (1:1, v/v), and filtered using Amicon Ultra centrifugal filters (3,000 Da MW cutoff regenerated cellulose membrane; Millipore, Billerica, MA) prior to LC-TOF MS analysis. The separation and identification of the metabolites were performed using high-performance liquid chromatography (HPLC), electrospray ionization (ESI), and time-of-flight (TOF) mass spectrometry (MS) as previously described [35]. For each compound, the measured masses agreed with the expected theoretical masses within less than 5 ppm mass error. Standard solutions of DHavnD and dianthramide B were prepared in methanol:water (1:1, v/v). Values obtained for the production of DHavnD and dianthramide B are the average of four replicates (n = 4). ESI-MS spectra of other cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates were obtained from single feeding experiments for each combination of precursors.

Reference： [1]Eudes, Aymerick; Benites, Veronica Teixeira; Wang, George; Baidoo, Edward E.K.; Lee, Taek Soon; Keasling, Jay D.; Loqué, Dominique [PLoS ONE, 2015, vol. 10, # 10]

64
[ 1078-61-1 ]
[ 118-92-3 ]
N-(3,4-dihydroxydihydrocinnamoyl)anthranilic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pDRf₁-(4-coumaroyl:CoA ligase 5 from Arabidopsis thaliana)-(hydroxycinnamoyl/benzoyl-CoA:anthranilate N-hydroxycinnamoyl/benzoyltransferase 1 from Dianthus caryophyllus) recombinant yeast In dimethyl sulfoxide at 30℃; for 24h;	Production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates General procedure: An overnight culture from a single colony of the pDRf1-4CL5-HCBT1 recombinant yeast grown on 2X YNB medium without amino acids, supplemented with 6% glucose and 2X CSM-Ura, was used to inoculated 4 mL of fresh minimal medium at an OD600 = 0.15 and shaken at 200 rpm at 30°C. All precursors were prepared in DMSO and added 5 hours post inoculation at the concentrations indicated in S1, S2 and S3 Tables. The anthranilate acceptors were added to the medium at a final concentration of 300 μM (for anthranilate, 3-hydroxyanthranilate, 3-methylanthranilate, and 5-nitroanthranilate) or 50 μM (for 3-chloroanthranilate, 5-methylanthranilate, 3-methoxyanthranilate, 5-fluoroanthranilate, 5-iodoanthranilate, and 5-chloroanthranilate). These concentrations were selected to limit toxicity and growth inhibition due to either the supplied precursors or the metabolites produced. The cultures were shaken at 200 rpm at 30°C for 24 h in the presence of the precursors for the production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates. Yeast colonies harboring the pDRf1-HCBT1 or pDRf1-4CL5 control vectors were grown under similar conditions. For the detection of metabolites, an aliquot of the culture medium was collected and cleared by centrifugation (21,000xg for 5 min at 4°C), mixed with an equal volume of cold methanol:water (1:1, v/v), and filtered using Amicon Ultra centrifugal filters (3,000 Da MW cutoff regenerated cellulose membrane; Millipore, Billerica, MA) prior to LC-TOF MS analysis. The separation and identification of the metabolites were performed using high-performance liquid chromatography (HPLC), electrospray ionization (ESI), and time-of-flight (TOF) mass spectrometry (MS) as previously described [35]. For each compound, the measured masses agreed with the expected theoretical masses within less than 5 ppm mass error. Standard solutions of DHavnD and dianthramide B were prepared in methanol:water (1:1, v/v). Values obtained for the production of DHavnD and dianthramide B are the average of four replicates (n = 4). ESI-MS spectra of other cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates were obtained from single feeding experiments for each combination of precursors.

Reference： [1]Eudes, Aymerick; Benites, Veronica Teixeira; Wang, George; Baidoo, Edward E.K.; Lee, Taek Soon; Keasling, Jay D.; Loqué, Dominique [PLoS ONE, 2015, vol. 10, # 10]

65
[ 52-90-4 ]
[ 1078-61-1 ]
5'-S-cysteinyldihydrocaffeic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With peroxidase from horseradish; dihydrogen peroxide In methanol; water at 25℃; Enzymatic reaction;

Reference： [1]Honda, Sari; Miura, Yukari; Masuda, Toshiya; Masuda, Akiko [Journal of Agricultural and Food Chemistry, 2016, vol. 64, # 4, p. 806 - 811]

66
[ 1078-61-1 ]
[ 67-64-1 ]
[ 1220710-28-0 ]

Yield	Reaction Conditions	Operation in experiment
65%	With phosphorus trichloride at 0℃; for 6h;
60%	With phosphorus trichloride at 0℃; for 6h;	1.1 Example 1 Step one, 1000 mg of 3,4-dihydroxyphenylpropionic acid is dissolved in 20 mL of anhydrous acetone, and 383 μL of phosphorus trichloride is slowly dropped into the above reaction bottle, and reacted at 0 ° C in an ice water bath. After a few hours, the pump spins and evaporates. The crude product was dissolved in a mixture of water and diethyl ether, extracted using a separating funnel, and the organic layer was extracted three times with water. Concentrated and dried to give a white powder of 2,2-dimethyl-1,3-benzodioxol-5-propionic acid. The yield was 60%.
55%	With phosphorus trichloride at 0℃; for 6h; Cooling with ice;

Reference： [1]Du, Chang; Ding, Yue; Qian, Jiwen; Zhang, Rong; Dong, Chang-Ming [Journal of Materials Chemistry B, 2019, vol. 7, # 3, p. 415 - 432]
[2]Current Patent Assignee: SHANGHAI JIAO TONG UNIVERSITY - CN108383765, 2018, A Location in patent: Paragraph 0052-0053
[3]Wei, Qiang; Achazi, Katharina; Liebe, Hendrik; Schulz, Andrea; Noeske, Paul-Ludwig Michael; Grunwald, Ingo; Haag, Rainer [Angewandte Chemie - International Edition, 2014, vol. 53, # 43, p. 11650 - 11655][Angew. Chem., 2014, vol. 126, # 43, p. 11834 - 11840,7]

67
[ 1078-61-1 ]
C₂₁H₃₈N₅O₆Pol [ No CAS ]
C₃₀H₄₆N₅O₉Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h;	General procedure: CA-Aβx-42and DHCA-Aβx-42 (x=38, 40) weresynthesized on a 1.0 mmol scale by standard Fmoc solid phase peptide synthesis(SPPS). Fmoc-Ala-Wang resin (0.72 mmol/g) was swelled with DMF for 30 min,after which the terminal Fmoc group was removed by treatment with 20%piperidine in DMF for 20 min. The resin was washed with DMF for 1 min 5 times.Then, peptide coupling was conducted by treatment with Fmoc-AA-OH (4.0 equiv.),HBTU (4.0 equiv.), HOBt (4.0 equiv.) and DIPEA (8.0 equiv.) in DMF (15 ml) for30 min. After deprotection of the terminal Fmoc group and condensation with theappropriate Fmoc AA-OH, the procedurewas repeated until the peptides wereelongated to the required length. CA or DHCA (4.0 equiv.) was condensed withthe peptide in the same manner. The products were cleaved from the resin bytreatment with TFA/thioanisole/H2O (95/2.5/2.5) for 2 h,and the resinwas washed with CH2Cl2. The cleavage reagent and thewashing solvent were collected. The combined solvent was evaporated to dryness yieldingcrudecompounds. Each compound was purified by RP-HPLC employing an ODS column with agradient of 10-100% acetonitrile (0.1% TFA) for 30 min at flow rate of 10ml/min. Lyophilization resulted inpure compounds.

Reference： [1]Arai, Takuya; Ohno, Akiko; Mori, Kazunori; Kuwata, Hiroshi; Mizuno, Mirei; Imai, Kohei; Hara, Shuntaro; Shibanuma, Motoko; Kurihara, Masaaki; Miyata, Naoki; Nakagawa, Hidehiko; Fukuhara, Kiyoshi [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 22, p. 5468 - 5471]

68
[ 1078-61-1 ]
C₁₄H₂₆N₃O₄Pol [ No CAS ]
C₂₃H₃₄N₃O₇Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h;	General procedure: CA-Aβx-42and DHCA-Aβx-42 (x=38, 40) weresynthesized on a 1.0 mmol scale by standard Fmoc solid phase peptide synthesis(SPPS). Fmoc-Ala-Wang resin (0.72 mmol/g) was swelled with DMF for 30 min,after which the terminal Fmoc group was removed by treatment with 20%piperidine in DMF for 20 min. The resin was washed with DMF for 1 min 5 times.Then, peptide coupling was conducted by treatment with Fmoc-AA-OH (4.0 equiv.),HBTU (4.0 equiv.), HOBt (4.0 equiv.) and DIPEA (8.0 equiv.) in DMF (15 ml) for30 min. After deprotection of the terminal Fmoc group and condensation with theappropriate Fmoc AA-OH, the procedurewas repeated until the peptides wereelongated to the required length. CA or DHCA (4.0 equiv.) was condensed withthe peptide in the same manner. The products were cleaved from the resin bytreatment with TFA/thioanisole/H2O (95/2.5/2.5) for 2 h,and the resinwas washed with CH2Cl2. The cleavage reagent and thewashing solvent were collected. The combined solvent was evaporated to dryness yieldingcrudecompounds. Each compound was purified by RP-HPLC employing an ODS column with agradient of 10-100% acetonitrile (0.1% TFA) for 30 min at flow rate of 10ml/min. Lyophilization resulted inpure compounds.

Reference： [1]Arai, Takuya; Ohno, Akiko; Mori, Kazunori; Kuwata, Hiroshi; Mizuno, Mirei; Imai, Kohei; Hara, Shuntaro; Shibanuma, Motoko; Kurihara, Masaaki; Miyata, Naoki; Nakagawa, Hidehiko; Fukuhara, Kiyoshi [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 22, p. 5468 - 5471]

69
HCl.H-D,L-Phe(β-OH)-OMe [ No CAS ]
[ 1078-61-1 ]
hydrocaffeoyl-D,L-Phe(β-OH)-OMe [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.4%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In acetonitrile at 20℃; for 4h; Cooling with ice;	4.2.1.1 General procedure for the synthesis of the methyl esters of N-phenoyl and N-catechoyl serine, phenylserine and alanine General procedure: To a solution of the phenolic or catecholic acid in acetonitrile (0.0100moldm-3), 1.1 equiv. of HOBt was added, followed by 1.1 equiv. of HBTU, 1.1 equiv. of the methyl ester of the amino acid hydrochloride and 2.2 equiv. of NEt3 in an ice bath. After stirring for 4h at room temperature, the solvent was evaporated at reduced pressure. The residue was dissolved in ethyl acetate (100cm3) and washed with KHSO4 (1moldm-3), NaHCO3 (1moldm-3) and brine (3 times 25cm3 each). The organic layer was dried with MgSO4 and the solvent evaporated at reduced pressure.

Reference： [1]Monteiro, Luís S.; Oliveira, Sandra; Paiva-Martins, Fátima; Ferreira, Paula M.T.; Pereira, David M.; Andrade, Paula B.; Valentão, Patrícia [Tetrahedron, 2017, vol. 73, # 43, p. 6199 - 6209]

70
[ 1078-61-1 ]
1-(chloromethyl)-(5-isopropyl)naphthalene [ No CAS ]
(5-isopropyl)-1-naphthylmethyl dihydrocaffeate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: dihydrocaffeic acid With potassium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 1-(chloromethyl)-(5-isopropyl)naphthalene With sodium iodide In N,N-dimethyl-formamide at 80℃; for 3h;	3 Example 3 Synthesis of dihydrocainic acid-1-naphthalene- (5-isopropyl) -methyl ester (abbreviated PN3 as shown in Formula IV) 1) Weigh 1.10 mmol of dihydrofolic acid,Dissolved in 1.5 mL of DMF,Add 3.3mmol of KHCO3 After stirring at room temperature for 1h,3.3 mmol of sodium iodide and 1.20 mmol of 1- (chloromethyl) - (5-isopropyl) -naphthalene were successively added.The reaction mixture was stirred at 80 ° C for 3h (the reaction was completed by TLC).2) After the reaction was cooled to room temperature,5mL saturated sodium chloride solution and ethyl acetate 5mL,Homogenize after mixing;The aqueous phase was extracted twice with ethyl acetate (3 mL × twice)The combined organic phase,Then washed with saturated copper sulfate solution (4mL × 4 times),And saturated sodium chloride solution (2 mL × 2 times),Dried over anhydrous sodium sulfate,The solvent was removed by rotary evaporation (-0.08 MPa, 45 ° C) to give a solid crude product.3) The crude product was purified by column chromatography,Column chromatography (total volume of solid to crude product mass multiple:Gradient I is 20 times,Gradient II is 10 times,Di-caffeic acid-1-naphthalene- (5-isopropyl) -methyl ester (PN3 180.6 mg, 45% yield) was obtained after 5 times gradient III. Structure identification data as follows:

Reference： [1]Current Patent Assignee: XIAN UNIVERSITY OF SCIENCE & TECHNOLOGY - CN107235842, 2017, A Location in patent: Paragraph 0060; 0061; 0062; 0063; 0064; 0065

71
[ 1078-61-1 ]
[ 2506-41-4 ]
2-naphthylmethyldihydrocaffeate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		1) Weigh 1.10 mmol of dihydrofolic acid,Dissolved in 1.5 mL DMSO,After adding 1.32mmol of Na2CO3 for 0.5h at room temperature,1.10 mmol of potassium iodide and 1.20 mmol of 2- (chloromethyl) naphthalene were sequentially added.The reaction mixture was stirred at 60 C for 6 h (TLC end of the reaction). 2) After the reaction was cooled to room temperature,5mL saturated sodium chloride solution and ethyl acetate 5mL,Homogenize after mixing;The aqueous phase was extracted twice with ethyl acetate (3 mL × twice)The combined organic phase,Then washed with saturated copper sulfate solution (3 mL × 4 times),And saturated sodium chloride solution (2 mL × 2 times),Dried over anhydrous sodium sulfate,The solvent was removed by rotary evaporation (-0.08 MPa, 45 C) to give a solid crude product. 3) The crude product was purified by column chromatography,Column chromatography (total volume of solid to crude product mass multiple:Gradient I is 20 times,Gradient II is 5 times,Gradient III was 5 times) to give 2-naphthyl dicarboxylate (PN 120.4 mg, 65% yield).Structure identification data as follows:

Reference： [1]Patent: CN107235842,2017,A .Location in patent: Paragraph 0050; 0051; 0052; 0053; 0054

72
[ 870-46-2 ]
[ 1078-61-1 ]
t-butyl-2-(3-(3,4-dihydroxyphenyl)propanoyl)hydrazinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: dihydrocaffeic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 25℃; for 4h; Stage #2: t-butoxycarbonylhydrazine In N,N-dimethyl-formamide at 25℃; for 20h;	1.1 Example 1 Preparation of Adriamycin-Dopamine Conjugate Molecules Step one, 455 · 5mg of 3,4-dihydroxyphenylpropionic acid, 405 · 36mg of 1-hydroxybenzotriazole, 619 · 2mg of dicyclohexylcarbodiimide, was dissolved in 20mL of anhydrous dimethyl Amide, after 4 hours reaction at 25 ° C, 396.5 mg of tert-butyl carbazate in dimethylformamide was added dropwise to the above reaction flask. After 20 hours at 25 ° C, dicyclohexylurea was removed by centrifugation and the oil chestnut was rotovapped at 60 ° C. Using petroleum ether column, the eluent was ethyl acetate: petroleum ether (3: 1) mixed solvent, Rf = 0.35. Vacuum oven dry. The product was t-butyl-2- (3- (3,4-dihydroxyphenyl) propanoyl) hydrazinecarboxylate as a white powder solid. Yield 47.3 ~ 61.0%.
	Stage #1: dihydrocaffeic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 25℃; for 4h; Stage #2: t-butoxycarbonylhydrazine at 25℃; for 20h;	1.1 Example 1 Preparation of doxorubicin-dopamine conjugate molecule Step one, 455.5 mg of 3,4-dihydroxyphenylpropionic acid, 405.36 mg of 1-hydroxybenzotriazole, 619.2 mg of dicyclohexylcarbodiimide, dissolved in 20 mL of anhydrous dimethylformamide, After reacting at 25 ° C for 4 hours, 396.5 mg of a solution of t-butyl carbazate in dimethylformamide was dropwise added to the above reaction flask. After reacting at 25 ° C for 20 hours, the dicyclohexylurea was removed by centrifugation, and the oil pump was rotary evaporated at 60 ° C. The column was packed with petroleum ether, and the eluent was a mixed solvent of ethyl acetate: petroleum ether (3:1), Rf = 0.35. Dry in a vacuum oven. The product is a white powder Solid tert-butyl-2-(3-(3,4-dihydroxyphenyl)propanoyl)diamine carboxylate. The yield was 47.3 to 61.0%.

Reference： [1]Current Patent Assignee: SHANGHAI JIAO TONG UNIVERSITY - CN106831905, 2017, A Location in patent: Paragraph 0039
[2]Current Patent Assignee: SHANGHAI JIAO TONG UNIVERSITY - CN108853512, 2018, A Location in patent: Paragraph 0053-0054

73
[ 1078-61-1 ]
[ 34688-34-1 ]
bis(3-(3,4-dihydroxyphenyl)propionic acid) phosphatidylcholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.65 g	Stage #1: dihydrocaffeic acid With 1,1'-carbonyldiimidazole In dimethyl sulfoxide for 0.666667h; Stage #2: glycerolcholine phosphate With 1,8-diazabicyclo[5.4.0]undec-7-ene In dimethyl sulfoxide at 20℃; for 24h;	22 1 g of 3-(3,4-dihydroxyphenyl)propionic acid (dihydrocaffeic acid) was dissolved in 15 mL of DMSO, 0.5 g of CDI was added, activated for 40 minutes, 0.4 g of phosphatidylcholine and 0.5 g of DBU were reacted at room temperature. 24h;The precipitate was precipitated in cold diethyl ether, washed with dilute hydrochloric acid, and the reaction mixture was purified by column chromatography to obtain the product bis(3-(3,4-dihydroxyphenyl)propionic acid) phosphatidylcholine compound 0.65 g;The intermediate product was dissolved in DMSO to prepare a 0.2 M solution, and the same volume of a 0.2 M solution of bortezomib in DMSO was added thereto, allowed to stand at room temperature for 1 hour, and precipitated in diethyl ether to obtain a product bis(bortezomib-dihydrocaffeate)phosphatidylcholine 0.46 g.

Reference： [1]Current Patent Assignee: SOUTHEAST UNIVERSITY - CN105288648, 2018, B Location in patent: Paragraph 0219

74
[ 111-26-2 ]
[ 1078-61-1 ]
[ 125789-30-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 6h;	3.2 General procedure to obtain the hexylamides 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 23 General procedure: Carboxylic acids 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 and 21 (Scheme 1) were dissolved in dimethylformamide (DMF) and triethylamine (TEA). The solution was then cooled in an ice-water bath and hexylamine or diethylamine was added, followed by a solution of (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) in dichloromethane. The mixture was stirred at 0°C for 30min and then at room temperature for specific periods of time. Dichloromethane was removed under reduced pressure and the remaining solution was diluted with water (100mL). The aqueous phase was extracted with ethyl acetate (2x 100mL) and the organic phases were washed with 1N HCl (2x 100mL), water (2x 100mL), NaHCO3 5% (3x 100mL) and water (2x 100mL), dried over anhydrous MgSO4, filtered and concentrated. The obtained residues were purified by silica gel column chromatography or crystallization yielding the corresponding hexylamides 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 23.

Reference： [1]Ribeiro, Daniela; Poença, Carina; Varela; Janela, João; Tavares da Silva, Elisiário J.; Fernandes, Eduarda; Roleira, Fernanda M.F. [Bioorganic Chemistry, 2019, vol. 91]

75
[ 10597-60-1 ]
[ 1078-61-1 ]
2-(3,4-dihydroxyphenyl)ethyl 3-(3,4-dihydroxyphenyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.34%	With 12-molybdosilicic acid hydrate; 1-butyl-3-methylimidazolium Tetrafluoroborate at 25℃; for 8h; Inert atmosphere;	1; 2; 3; 4; 5; 6; 7; 8 Example 7 Preparation of Compound 3,4-dihydroxyphenethyl 3-(3,4-dihydroxyphenyl)propanoate In a 100 mL three-necked flask, 100.2 mg (0.65 mmol) of hydroxytyrosol, 129.3 mg (0.71 mmol) of dihydrocaffeic acid, and 12.0 mg (0.007 mmol) 12-molybdosilicic acid hydrate (H6Mo12O41Si) were dissolved in 50 mL of an ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4])) under nitrogen atmosphere to form a reaction mixture. The reaction mixture was reacted at 25° C. for 8 hours. Thin layer chromatography was used to track the reaction to completion, heating was stopped, and the protective device was removed. The reaction mixture was transferred to a separatory funnel. An ester layer was separated from the ionic liquid layer. The ester layer contained the crude product. The crude product was recrystallized in 50 mL methane to obtain 170.2 mg of purified hydroxytyrosol dihydrocaffeate, a total yield of 82.34%

Reference： [1]Current Patent Assignee: SHAANXI UNIVERSITY OF SCIENCE AND TECHNOLOGY - US10640450, 2020, B1 Location in patent: Page/Page column 3-6

76
8-acryloyloxy-1-octanol [ No CAS ]
[ 1078-61-1 ]
8-((3-(3,4-dihydroxyphenyl)propanoyl)oxy)octyl acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	Stage #1: dihydrocaffeic acid With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: 8-acryloyloxy-1-octanol In tetrahydrofuran at 20℃; for 3h; Inert atmosphere;	3,4-Dihydroxyhydrocinnamic acid (2.75 g, 15.09 mmol, 0.75 equiv), DCC (4.15 g, 20.12 mmol, 1.0 equiv) and DMAP (2.46 g, 20.12 mmol, 1.0 equiv) were agitated in THF (200 ml) at room temperature for 1 hour. Subsequently, the 8-hydroxyoctyl acrylate (4.03 g, 20.12 mmol, 1.0 equiv) added into the reaction mixture, and the reaction continued for 3 hours. The THF solvent was removed using a rotary vacuum evaporator. The crude material was extracted with 150 ml ethyl acetate and the solution washed with 1N HCl. After purification by Biotage Isolera Prime automatic column chromatography (Biotage SNAP 50 g silica column; hexane/ethyl acetate 100:0 to 50:50 gradient; flow rate 40 ml/min), 1.72 g (31% yield) of a white crystal was obtained. 1H NMR (600 MHz, DMSO-d6): =8.64 (q, 1H, Ar-H), 8.27 (d, 2H, Ar-H), 6.58 (d, 1H, -CH2CH-CH2), 6.53 (q, 1H, -CH2CH═CH2), 6.40 (d, 1H, -CH2CH-CH2), 3.98 (t, 2H, -COO-CH2CH2-), 3.55 (m, 4H, -CH2CH2OOC-, -CH2-CH2-OOC-), 2.62 (q, 2H, -ArCH2CH2-), 1.76-0.96 (m, 12H, -CH2CH2CH2CH2CH2CH2CH2CH2-) (FIG. 66). EI-MS, m/z=364.21 [M+Na+].

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - US2020/181455, 2020, A1 Location in patent: Paragraph 0346; 0354-0355

77
[ 1078-61-1 ]
C₂₅H₃₆N₄O₆S [ No CAS ]
(S)-2-(3-(3,4-dihydroxyphenyl)propionamido)-N-((2S,3R)-3-hydroxy-4-((N-isobutyl-4-methoxybenzenesulfonamido))-1-phenylbutan-2-yl)succinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: dihydrocaffeic acid; C₂₅H₃₆N₄O₆S With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 1.16667h; Inert atmosphere; Stage #2: With dmap In N,N-dimethyl-formamide for 2h; Inert atmosphere;	1.4 (4)(S)-2-(3-(3,4-Dihydroxyphenyl)propionamido)-N’-((2S,3R)-3-hydroxy-4-((N-isobutyl-4-methoxy)benzenesulfonamide)-1-phenylbutane-2-yl)succinamide(Compound I-1) Synthesis 3-(3,4-Dihydroxyphenyl)propionic acid (compound 3, 0.10mmol) and amine derivative III-1a (0.10mmol) were dissolved in 2mL of anhydrous DMF,Cool down to 0, slowly add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl, 0.15mmol) under the protection of argonAnd 1-hydroxybenzotriazole (HOBt, 0.11mmol), stirred at 0 for 10min, heated to room temperature and reacted for 1h,4-Dimethylaminopyridine (DMAP, 0.020 mmol) was added, and the reaction was continued for 2 h.After the completion of the reaction, the organic solvent in the reaction system was evaporated under reduced pressure, 4 mL of water was added, and extraction was performed with ethyl acetate (3×4 mL).Combine the organic phases, dry with anhydrous Na2SO4, filter to remove Na2SO4, and concentrate the resulting organic phase.Use silica gel column chromatography to separate and purify the obtained concentrated solution (the eluent is a mixed solvent of ethyl acetate and methanol with a mass ratio of 20:1),Compound I-1 (white powder solid, 0.057 g, yield 83%) was obtained.

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN111205206, 2020, A Location in patent: Paragraph 0184; 0193-0198

78
[ 2518-24-3 ]
[ 1078-61-1 ]
3-(3,4-dihydroxyphenyl)-N-(1,3-dioxoisoindolin-4-yl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	Stage #1: dihydrocaffeic acid With thionyl chloride; N,N-dimethyl-formamide In benzene for 1h; Reflux; Stage #2: 3-aminophthalimide With pyridine for 2h; Reflux;	1 Scheme 3: Synthesis of 3-(3,4-dihydroxyphenyl)-N-(1,3-dioxoisoindolin-4-yl)propanamide: GKK-006-090. [0128] Procedure E2: N-Amidation of amino substituted 4-aminoisoindoline-1,3-dione from the acid. To a stirred solution of the carboxylic acid (1.20 mmol) in benzene was added DMF (2 drops) and SOCb (3.00 mmol). The mixture was heated at reflux for 1 h and cooled to room temperature (23 °C). The solvent and excess SOCI2 were removed under vacuum and the resulting crude acid chloride was dissolved in 10 mL of pyridine. To this solution was added 4-aminoisoindoline-1,3-dione (1.00 mmol) and the mixture was heated at reflux for 2 h. The reaction mixture was allowed to slowly cool to 23 °C, and then further cool in an ice-bath for 15 min. The resulting solid was collected and recrystallized from ethanol/ether (2: 1) to give the corresponding amide. [0141] Procedure E2. Yellow solid (49 mg, yield 15%), mp 235-236 °C; H NMR (DMSO- d): d 11.4 (s, 1H), 9.67 (s, 1H), 8.76 (s, 1H), 8.68 (s, 1H), 8.48 (d, / = 8.4 Hz, 1H), 7.76 (t, / = 7.8 Hz, 1H), 7.49 (d, / = 7.3 Hz, 1H), 6.64 (s, 1H), 6.63 (d, / = 8.4 Hz, 1H), 6.50 (d, / = 8.0 Hz, 1H), 2.77 (t, / = 7.1 Hz, 2H), 2.69 (t, / = 7.1 Hz, 2H) 13C NMR (DMSO-i: d 171.8, 170.8, 169.2, 145.5, 143.9, 136.9, 136.2, 133.3, 131.8, 125.5, 119.3, 118.3, 118.1, 116.2, 115.9, 39.1, 30.4; MS: m/z 326 (C17H14N2O5, M+ ).

Reference： [1]Current Patent Assignee: LOUISIANA STATE UNIVERSITY AND AGRICULTURAL AND MECHANICAL COLLEGE; UNIVERSITY OF KANSAS - WO2020/117832, 2020, A1 Location in patent: Paragraph 0128; 0141

79
[ 1078-61-1 ]
[ 159005-71-7 ]
3-(3,4-dihydroxyphenyl)-N-((2S,3R)-3-hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: dihydrocaffeic acid; N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-methoxybenzenesulfonamide With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With dmap In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere;	4.1.23. (E)-3-(3, 4-dihydroxyphenyl)-N-((2S, 3R)-3-hydroxy-4-((Nisobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)acrylamide (35a) General procedure: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt,0.15 g, 1.1 mmol) were sequentially added in batches to a stirredsolution of (E)-3-(3, 4-dihydroxyphenyl)acrylic acid (29, 0.18 g,1.0 mmol) and N-((2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl)-Nisobutyl-4- methoxybenzenesulfonamide (21, 0.43 g, 1.05 mmol) in3 mL dry DMF at 0 °C under an argon atmosphere. The reactionmixturewas stirred for 10 min at 0 °C and additional 1 h at 25 °C. 4-Dimethylaminopyridine (DMAP, 0.024 g, 0.20 mmol) was addedand the reaction mixture was stirred for another 2 h at 25 °C. Thesolvent was removed under reduced pressure. Water (6 mL) wasadded to the residue and extracted with CH2Cl2 (3 6 mL). Thecombined organic layers were dried over Na2SO4. Removal of solventunder reduced pressure, followed by column chromatographyover silica gel column. Elution with 5% CH3OH in CH2Cl2 gavecompound 35a (0.40 g, 78%) as white amorphous solid:

Reference： [1]Zhu, Mei; Shan, Qi; Ma, Ling; Wen, Jiajia; Dong, Biao; Zhang, Guoning; Wang, Minghua; Wang, Juxian; Zhou, Jinming; Cen, Shan; Wang, Yucheng [European Journal of Medicinal Chemistry, 2021, vol. 220]

80
[ 1078-61-1 ]
[ 169280-56-2 ]
N-((2S,3R)-4-((4-amino-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)-3-(3,4-dihydroxyphenyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: dihydrocaffeic acid; 4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzenesulfonamide With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With dmap In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere;	4.1.23. (E)-3-(3, 4-dihydroxyphenyl)-N-((2S, 3R)-3-hydroxy-4-((Nisobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)acrylamide (35a) General procedure: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt,0.15 g, 1.1 mmol) were sequentially added in batches to a stirredsolution of (E)-3-(3, 4-dihydroxyphenyl)acrylic acid (29, 0.18 g,1.0 mmol) and N-((2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl)-Nisobutyl-4- methoxybenzenesulfonamide (21, 0.43 g, 1.05 mmol) in3 mL dry DMF at 0 °C under an argon atmosphere. The reactionmixturewas stirred for 10 min at 0 °C and additional 1 h at 25 °C. 4-Dimethylaminopyridine (DMAP, 0.024 g, 0.20 mmol) was addedand the reaction mixture was stirred for another 2 h at 25 °C. Thesolvent was removed under reduced pressure. Water (6 mL) wasadded to the residue and extracted with CH2Cl2 (3 6 mL). Thecombined organic layers were dried over Na2SO4. Removal of solventunder reduced pressure, followed by column chromatographyover silica gel column. Elution with 5% CH3OH in CH2Cl2 gavecompound 35a (0.40 g, 78%) as white amorphous solid:

Reference： [1]Zhu, Mei; Shan, Qi; Ma, Ling; Wen, Jiajia; Dong, Biao; Zhang, Guoning; Wang, Minghua; Wang, Juxian; Zhou, Jinming; Cen, Shan; Wang, Yucheng [European Journal of Medicinal Chemistry, 2021, vol. 220]

81
[ 1078-61-1 ]
N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-(methylthio)benzenesulfonamide [ No CAS ]
3-(3,4-dihydroxyphenyl)-N-((2S,3R)-3-hydroxy-4-((N-isobutyl-4-(methylthio)phenyl)sulfonamido)-1-phenylbutan-2-yl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: dihydrocaffeic acid; N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-(methylthio)benzenesulfonamide With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With dmap In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere;	4.1.23. (E)-3-(3, 4-dihydroxyphenyl)-N-((2S, 3R)-3-hydroxy-4-((Nisobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)acrylamide (35a) General procedure: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt,0.15 g, 1.1 mmol) were sequentially added in batches to a stirredsolution of (E)-3-(3, 4-dihydroxyphenyl)acrylic acid (29, 0.18 g,1.0 mmol) and N-((2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl)-Nisobutyl-4- methoxybenzenesulfonamide (21, 0.43 g, 1.05 mmol) in3 mL dry DMF at 0 °C under an argon atmosphere. The reactionmixturewas stirred for 10 min at 0 °C and additional 1 h at 25 °C. 4-Dimethylaminopyridine (DMAP, 0.024 g, 0.20 mmol) was addedand the reaction mixture was stirred for another 2 h at 25 °C. Thesolvent was removed under reduced pressure. Water (6 mL) wasadded to the residue and extracted with CH2Cl2 (3 6 mL). Thecombined organic layers were dried over Na2SO4. Removal of solventunder reduced pressure, followed by column chromatographyover silica gel column. Elution with 5% CH3OH in CH2Cl2 gavecompound 35a (0.40 g, 78%) as white amorphous solid:

Reference： [1]Zhu, Mei; Shan, Qi; Ma, Ling; Wen, Jiajia; Dong, Biao; Zhang, Guoning; Wang, Minghua; Wang, Juxian; Zhou, Jinming; Cen, Shan; Wang, Yucheng [European Journal of Medicinal Chemistry, 2021, vol. 220]

82
[ 1078-61-1 ]
N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-6-methoxypyridine-3-sulfonamide [ No CAS ]
3-(3,4-dihydroxyphenyl)-N-((2S,3R)-3-hydroxy-4-((N-isobutyl-6-methoxypyridine)-3-sulfonamido)-1-phenylbutan-2-yl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: dihydrocaffeic acid; N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-6-methoxypyridine-3-sulfonamide With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With dmap In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere;	4.1.23. (E)-3-(3, 4-dihydroxyphenyl)-N-((2S, 3R)-3-hydroxy-4-((Nisobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)acrylamide (35a) General procedure: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt,0.15 g, 1.1 mmol) were sequentially added in batches to a stirredsolution of (E)-3-(3, 4-dihydroxyphenyl)acrylic acid (29, 0.18 g,1.0 mmol) and N-((2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl)-Nisobutyl-4- methoxybenzenesulfonamide (21, 0.43 g, 1.05 mmol) in3 mL dry DMF at 0 °C under an argon atmosphere. The reactionmixturewas stirred for 10 min at 0 °C and additional 1 h at 25 °C. 4-Dimethylaminopyridine (DMAP, 0.024 g, 0.20 mmol) was addedand the reaction mixture was stirred for another 2 h at 25 °C. Thesolvent was removed under reduced pressure. Water (6 mL) wasadded to the residue and extracted with CH2Cl2 (3 6 mL). Thecombined organic layers were dried over Na2SO4. Removal of solventunder reduced pressure, followed by column chromatographyover silica gel column. Elution with 5% CH3OH in CH2Cl2 gavecompound 35a (0.40 g, 78%) as white amorphous solid:

Reference： [1]Zhu, Mei; Shan, Qi; Ma, Ling; Wen, Jiajia; Dong, Biao; Zhang, Guoning; Wang, Minghua; Wang, Juxian; Zhou, Jinming; Cen, Shan; Wang, Yucheng [European Journal of Medicinal Chemistry, 2021, vol. 220]

83
[ 1078-61-1 ]
N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-4-methoxy-N-propylbenzenesulfonamide [ No CAS ]
3-(3,4-dihydroxyphenyl)-N-((2S,3R)-3-hydroxy-4-((4-methoxy-N-propylphenyl)sulfonamido)-1-phenylbutan-2-yl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: dihydrocaffeic acid; N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-4-methoxy-N-propylbenzenesulfonamide With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With dmap In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere;	4.1.23. (E)-3-(3, 4-dihydroxyphenyl)-N-((2S, 3R)-3-hydroxy-4-((Nisobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)acrylamide (35a) General procedure: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt,0.15 g, 1.1 mmol) were sequentially added in batches to a stirredsolution of (E)-3-(3, 4-dihydroxyphenyl)acrylic acid (29, 0.18 g,1.0 mmol) and N-((2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl)-Nisobutyl-4- methoxybenzenesulfonamide (21, 0.43 g, 1.05 mmol) in3 mL dry DMF at 0 °C under an argon atmosphere. The reactionmixturewas stirred for 10 min at 0 °C and additional 1 h at 25 °C. 4-Dimethylaminopyridine (DMAP, 0.024 g, 0.20 mmol) was addedand the reaction mixture was stirred for another 2 h at 25 °C. Thesolvent was removed under reduced pressure. Water (6 mL) wasadded to the residue and extracted with CH2Cl2 (3 6 mL). Thecombined organic layers were dried over Na2SO4. Removal of solventunder reduced pressure, followed by column chromatographyover silica gel column. Elution with 5% CH3OH in CH2Cl2 gavecompound 35a (0.40 g, 78%) as white amorphous solid:

Reference： [1]Zhu, Mei; Shan, Qi; Ma, Ling; Wen, Jiajia; Dong, Biao; Zhang, Guoning; Wang, Minghua; Wang, Juxian; Zhou, Jinming; Cen, Shan; Wang, Yucheng [European Journal of Medicinal Chemistry, 2021, vol. 220]

84
[ 1078-61-1 ]
N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-cyclopropyl-4-methoxybenzenesulfonamide [ No CAS ]
N-((2S,3R)-4-((N-cyclopropyl-4-methoxyphenyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)-3-(3,4-dihydroxyphenyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: dihydrocaffeic acid; N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-cyclopropyl-4-methoxybenzenesulfonamide With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With dmap In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere;	4.1.23. (E)-3-(3, 4-dihydroxyphenyl)-N-((2S, 3R)-3-hydroxy-4-((Nisobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)acrylamide (35a) General procedure: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt,0.15 g, 1.1 mmol) were sequentially added in batches to a stirredsolution of (E)-3-(3, 4-dihydroxyphenyl)acrylic acid (29, 0.18 g,1.0 mmol) and N-((2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl)-Nisobutyl-4- methoxybenzenesulfonamide (21, 0.43 g, 1.05 mmol) in3 mL dry DMF at 0 °C under an argon atmosphere. The reactionmixturewas stirred for 10 min at 0 °C and additional 1 h at 25 °C. 4-Dimethylaminopyridine (DMAP, 0.024 g, 0.20 mmol) was addedand the reaction mixture was stirred for another 2 h at 25 °C. Thesolvent was removed under reduced pressure. Water (6 mL) wasadded to the residue and extracted with CH2Cl2 (3 6 mL). Thecombined organic layers were dried over Na2SO4. Removal of solventunder reduced pressure, followed by column chromatographyover silica gel column. Elution with 5% CH3OH in CH2Cl2 gavecompound 35a (0.40 g, 78%) as white amorphous solid:

Reference： [1]Zhu, Mei; Shan, Qi; Ma, Ling; Wen, Jiajia; Dong, Biao; Zhang, Guoning; Wang, Minghua; Wang, Juxian; Zhou, Jinming; Cen, Shan; Wang, Yucheng [European Journal of Medicinal Chemistry, 2021, vol. 220]

85
[ 1078-61-1 ]
N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isopropyl-4-methoxybenzenesulfonamide [ No CAS ]
3-(3,4-dihydroxyphenyl)-N-((2S,3R)-3-hydroxy-4-((N-isopropyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: dihydrocaffeic acid; N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isopropyl-4-methoxybenzenesulfonamide With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With dmap In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere;	4.1.23. (E)-3-(3, 4-dihydroxyphenyl)-N-((2S, 3R)-3-hydroxy-4-((Nisobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)acrylamide (35a) General procedure: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt,0.15 g, 1.1 mmol) were sequentially added in batches to a stirredsolution of (E)-3-(3, 4-dihydroxyphenyl)acrylic acid (29, 0.18 g,1.0 mmol) and N-((2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl)-Nisobutyl-4- methoxybenzenesulfonamide (21, 0.43 g, 1.05 mmol) in3 mL dry DMF at 0 °C under an argon atmosphere. The reactionmixturewas stirred for 10 min at 0 °C and additional 1 h at 25 °C. 4-Dimethylaminopyridine (DMAP, 0.024 g, 0.20 mmol) was addedand the reaction mixture was stirred for another 2 h at 25 °C. Thesolvent was removed under reduced pressure. Water (6 mL) wasadded to the residue and extracted with CH2Cl2 (3 6 mL). Thecombined organic layers were dried over Na2SO4. Removal of solventunder reduced pressure, followed by column chromatographyover silica gel column. Elution with 5% CH3OH in CH2Cl2 gavecompound 35a (0.40 g, 78%) as white amorphous solid:

Reference： [1]Zhu, Mei; Shan, Qi; Ma, Ling; Wen, Jiajia; Dong, Biao; Zhang, Guoning; Wang, Minghua; Wang, Juxian; Zhou, Jinming; Cen, Shan; Wang, Yucheng [European Journal of Medicinal Chemistry, 2021, vol. 220]

86
[ 57260-73-8 ]
[ 1078-61-1 ]
C₁₆H₂₄N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 6h;	5.1 (1) Synthesis and characterization of compound 14: Dissolve HOBt (0.75g, 5.5mmol) and HBTU (2.08g, 5.5mmol) in anhydrous DMF (20mL) and add compound 13 (0.92g, 5mmol), and then add compound 12 (0.97g, 6mmol) at room temperature After stirring for 6h, it was quenched with water and extracted with ethyl acetate.The organic layer was washed twice with saturated brine, and then dried with MgSO4.Purification by silica gel column chromatography (petroleum ether:ethyl acetate=1:4) gave compound 14.

Reference： [1]Current Patent Assignee: EAST CHINA UNIVERSITY OF SCIENCE AND TECHNOLOGY - CN113402432, 2021, A Location in patent: Paragraph 0112; 0114; 0115-0117

87
[ 1078-61-1 ]
[ 107-14-2 ]
cyanomethyl 3-(3,4-dihydroxyphenyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With triethylamine In dichloromethane at 25℃; for 16h;	3 General procedure for formation of cvanomethyl ester. General procedure: To a glass vial with a stir bar was added carboxylic acid (1 equiv.), CH2C12 (1.0 M), trimethylamine (1.5 equiv.), and chloroacetonitrile (1.2 equiv.). After stirring for 16 h at 25 °C the reaction mixture was diluted with EtOAc and washed with water or brine. The organic phase was dried and concentrated to provide the crude product. The product was purified by flash column chromatography if necessary; Prepared according to the general procedure using 3-(3,4-dihydroxyphenyl)propanoic acid (60 mg, 0.33 mmol), triethylamine (70 μL, 0.5 mmol), chloroacetonitrile (26.5 μL, 0.4 mmol) and dichloromethane (0.2 mL). The product was obtained as a brown solid (40 mg, 55%). 1H-NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.67 (s, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 1.9 Hz, 1H), 6.46-6.44 (m, 1H), 4.94 (s, 2H), 2.69-2.68 (m, 2H), 2.66-2.64 (m, 2H); 13C NMR (125 MHz, DMSO-d6) ppm 171.9, 145.5, 144.0, 131.3, 119.2, 116.4, 116.1, 115.9, 49.3, 35.2, 29.8; HRMS (El): Exact mass calcd for C11H11N04: [M]+ 221.0688, found 221.0690.

Reference： [1]Current Patent Assignee: UNIVERSITY OF ILLINOIS (SYSTEM); NORTHWESTERN UNIVERSITY (ILLINOIS) - WO2021/221760, 2021, A2 Location in patent: Paragraph 00333-00335; 00344-00345

88
[ 71-44-3 ]
[ 1078-61-1 ]
[ 75288-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3,4-dihydroxyphenylpropionic acid With 4-dimethylaminopyridine; 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 18h; Stage #2: Spermine In tetrahydrofuran for 4h;	Synthesis of kukoamine A The synthesis of kukoamine A was carried out by a modification of the procedure in Piletskaet al. [30]. A solution (2.18 g, 12 mmol) of 3,4-dihydroxyphenylpropionic acid (Sigma-Aldrich,USA)in 20 mL of tetrahydrofuran (THF; Fisher Chemicals, USA) was prepared at ambient temperature. Dicyclohexylcarbodiimide (2.47 g, 12 mmol; Sigma-Aldrich, USA) and4-dimethylaminopyridine (10 mg, 0.08 mmol; Sigma-Aldrich, USA) and then N-hydroxysuccinimide(1.38 g, 12 mmol; Sigma-Aldrich, USA) were then added sequentially. The reactionmixture was stirred for 18 h at ambient temperature then solids were removed by filtrationand washed with THF (2 x 50 mL). This crude reaction product solution was treated with spermine(1.21 g, 6 mmol) in THF (5 mL). After the immediate formation of a white precipitate,the reaction was stirred for 4 h whereupon solids were filtered off and washed with THF (2 x100 mL). Solvents were removed in vacuo and the crude material was purified on an SPE C18prepacked column (Strata x 1g/20 mL Giga 8B-S100-JEG, Phenomenex, USA) conditionedwith 20 mL of methanol (MeOH), then 0.2% formic acid in water (20 mL). A typical sampleloading was 61 mg dissolved in 0.2% formic acid in water (2 mL). The column was eluted successivelywith 0.2% formic in water (2 x 20 mL), then with 20 mL volumes of 0.1% formic acidcontaining successively 10, 20, 30 and 40% MeOH, and finally with 100% MeOH (20 mL). Thefractions containing the product, as analysed by LCMS and by comparison with a commercialstandard (Kukoamine A, TransMIT, Giessen, Germany) were combined, the methanolremoved in vacuo and then freeze-dried. The NMR analysis [22, 31] confirmed the productwas kukoamine A with no kukoamine B detected. The model of NMR spectrometer used wasa Bruker Avance 500. For 1H the operating frequency was 500.13 MHz. 1H NMR (D2O) d 1.63(8H, m), 2.50 (8H, m), 2.76 (4H, tr, J = 7.5 Hz), 2.83 (4H, br, m), 3.13 (4H, tr, J = 6.5 Hz), 6.64(2H, dd, J = 8, 2 Hz), 6.71 (2H, d, J = 2 Hz), 6.79 (2H, d, J = 8 Hz).
	Stage #1: 3,4-dihydroxyphenylpropionic acid With 4-dimethylaminopyridine; 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 18h; Stage #2: Spermine In tetrahydrofuran for 4h;	Synthesis of kukoamine A The synthesis of kukoamine A was carried out by a modification of the procedure in Piletskaet al. [30]. A solution (2.18 g, 12 mmol) of 3,4-dihydroxyphenylpropionic acid (Sigma-Aldrich,USA)in 20 mL of tetrahydrofuran (THF; Fisher Chemicals, USA) was prepared at ambient temperature. Dicyclohexylcarbodiimide (2.47 g, 12 mmol; Sigma-Aldrich, USA) and4-dimethylaminopyridine (10 mg, 0.08 mmol; Sigma-Aldrich, USA) and then N-hydroxysuccinimide(1.38 g, 12 mmol; Sigma-Aldrich, USA) were then added sequentially. The reactionmixture was stirred for 18 h at ambient temperature then solids were removed by filtrationand washed with THF (2 x 50 mL). This crude reaction product solution was treated with spermine(1.21 g, 6 mmol) in THF (5 mL). After the immediate formation of a white precipitate,the reaction was stirred for 4 h whereupon solids were filtered off and washed with THF (2 x100 mL). Solvents were removed in vacuo and the crude material was purified on an SPE C18prepacked column (Strata x 1g/20 mL Giga 8B-S100-JEG, Phenomenex, USA) conditionedwith 20 mL of methanol (MeOH), then 0.2% formic acid in water (20 mL). A typical sampleloading was 61 mg dissolved in 0.2% formic acid in water (2 mL). The column was eluted successivelywith 0.2% formic in water (2 x 20 mL), then with 20 mL volumes of 0.1% formic acidcontaining successively 10, 20, 30 and 40% MeOH, and finally with 100% MeOH (20 mL). Thefractions containing the product, as analysed by LCMS and by comparison with a commercialstandard (Kukoamine A, TransMIT, Giessen, Germany) were combined, the methanolremoved in vacuo and then freeze-dried. The NMR analysis [22, 31] confirmed the productwas kukoamine A with no kukoamine B detected. The model of NMR spectrometer used wasa Bruker Avance 500. For 1H the operating frequency was 500.13 MHz. 1H NMR (D2O) d 1.63(8H, m), 2.50 (8H, m), 2.76 (4H, tr, J = 7.5 Hz), 2.83 (4H, br, m), 3.13 (4H, tr, J = 6.5 Hz), 6.64(2H, dd, J = 8, 2 Hz), 6.71 (2H, d, J = 2 Hz), 6.79 (2H, d, J = 8 Hz).

Reference： [1]Butts, Christine A.; Hedderley, Duncan I.; Martell, Sheridan; Dinnan, Hannah; Middlemiss-Kraak, Susanne; Bunn, Barry J.; McGhie, Tony K.; Lill, Ross E. [PLoS ONE, 2022, vol. 17, # 5 May]
[2]Butts, Christine A.; Hedderley, Duncan I.; Martell, Sheridan; Dinnan, Hannah; Middlemiss-Kraak, Susanne; Bunn, Barry J.; McGhie, Tony K.; Lill, Ross E. [PLoS ONE, 2022, vol. 17, # 5 May]

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	1078-61-1	MDL No. :	MFCD00002776
Formula :	C₉H₁₀O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DZAUWHJDUNRCTF-UHFFFAOYSA-N
M.W :	182.17	Pubchem ID :	348154
Synonyms :	3,4-Dihydroxy-benzenepropanoic acid;3,4-Dihydroxyhydrocinnamic Acid;3,4-Dihydroxyhydrocinnamic Acid, Dihydrocaffeic acid	Chemical Name :	3-(3,4-Dihydroxyphenyl)propionic acid

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	3.0
Molar Refractivity :	46.84
TPSA :	77.76 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.79 cm/s

Log Po/w (iLOGP) :	0.86
Log Po/w (XLOGP3) :	-0.54
Log Po/w (WLOGP) :	1.11
Log Po/w (MLOGP) :	0.79
Log Po/w (SILICOS-IT) :	0.93
Consensus Log Po/w :	0.63

[ CAS No. 1078-61-1 ] {[proInfo.proName]}

Quality Control of [ 1078-61-1 ]

Related Doc. of [ 1078-61-1 ]

Product Details of [ 1078-61-1 ]

Calculated chemistry of [ 1078-61-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1078-61-1 ]

Application In Synthesis of [ 1078-61-1 ]

[ 1078-61-1 ] Synthesis Path-Upstream 1~5

[ 1078-61-1 ] Synthesis Path-Downstream 1~88

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Log S (ESOL) :	-0.77
Solubility :	30.7 mg/ml ; 0.169 mol/l
Class :	Very soluble
Log S (Ali) :	-0.62
Solubility :	43.3 mg/ml ; 0.238 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.43
Solubility :	6.77 mg/ml ; 0.0372 mol/l
Class :	Soluble

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.2

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
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P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
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P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
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P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling