[ CAS No. 501-97-3 ] {[proInfo.proName]}

Name: 501-97-3|3-(4-Hydroxyphenyl)propionic acid|98%
Brand: Ambeed
SKU: A187271
Price: 5.0 USD
Availability: InStock
Rating: 97 (32 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 501-97-3

Structure of 501-97-3 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 501-97-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 501-97-3 ]

SDS Specification

Alternatived Products of [ 501-97-3 ]

Product Details of [ 501-97-3 ]

CAS No. :	501-97-3	MDL No. :	MFCD00002778
Formula :	C₉H₁₀O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NMHMNPHRMNGLLB-UHFFFAOYSA-N
M.W :	166.17	Pubchem ID :	10394
Synonyms :	Desaminotyrosine;3-(4-Hydroxyphenyl)propionic acid;NSC 40949;3-(4-Hydroxyphenyl)propanoic acid;Phloretate;Hydro-p-coumaric acid;Phloretic acid	Chemical Name :	3-(4-Hydroxyphenyl)propionic acid

Calculated chemistry of [ 501-97-3 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	44.82
TPSA :	57.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.49 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.19
Log Po/w (XLOGP3) :	1.16
Log Po/w (WLOGP) :	1.41
Log Po/w (MLOGP) :	1.37
Log Po/w (SILICOS-IT) :	1.4
Consensus Log Po/w :	1.31

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.77
Solubility :	2.8 mg/ml ; 0.0169 mol/l
Class :	Very soluble
Log S (Ali) :	-1.96
Solubility :	1.81 mg/ml ; 0.0109 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.0
Solubility :	1.67 mg/ml ; 0.0101 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.0

Safety of [ 501-97-3 ]

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:

Application In Synthesis of [ 501-97-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 501-97-3 ]
Downstream synthetic route of [ 501-97-3 ]

[ 501-97-3 ] Synthesis Path-Upstream 1~17

1
[ 108-73-6 ]
[ 501-97-3 ]
[ 60-82-2 ]

Reference： [1] Tetrahedron, 2006, vol. 62, # 5, p. 841 - 846

2
[ 501-97-3 ]
[ 524-14-1 ]
[ 60-82-2 ]
[ 920318-17-8 ]

Reference： [1] Journal of Molecular Catalysis B: Enzymatic, 2010, vol. 66, # 3-4, p. 257 - 263

3
[ 501-97-3 ]
[ 60-82-2 ]

Reference： [1] Chemische Berichte, 1917, vol. 50, p. 618[2] Chem. Zentralbl., 1916, vol. 87, # II, p. 1025

4
[ 501-97-3 ]
[ 74-88-4 ]
[ 1929-29-9 ]

Reference： [1] Tetrahedron Asymmetry, 2001, vol. 12, # 4, p. 585 - 596
[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1900, vol. 131, p. 43[3] Annales de Chimie (Cachan, France), 1902, vol. <7> 25, p. 507,537

5
[ 501-97-3 ]
[ 77-78-1 ]
[ 1929-29-9 ]

Reference： [1] Bulletin of the Chemical Society of Japan, 1936, vol. 11, p. 781,784

6
[ 64-17-5 ]
[ 501-97-3 ]
[ 23795-02-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 25℃; for 24 h;	General procedure: To a suspension of 3(4-hydroxyphenyl)propanoic acid 1 (0.05 mmol) in TMCS (0.1 mmol), the appropriate alcohol (1.0 mL) was added and the reaction mixture was stirred at 25°C. After 24 h, the reaction was stopped and evaporated under reduced pressure to afford 1a–d in quantitative yield without the need of purification: 3-(4-Hydroxyphenyl)propionic ethyl ester (1b) Oil; ¹HNMR (400 MHz, CDCl₃): δH (ppm) = 1.13 (3H, m, CH₃), 2.82 (2H, m, CH₂), 2.88 (2H, m, CH₂), 4.00 (2H, m, OCH₂), 6.75 (2H, m,Ph-H), 7.06 (2H, m, Ph-H); ¹³C NMR (50 MHz, CDCl₃): δC (ppm) = 14.20 (CH₃), 30.12 (CH₂), 35.10 (CH₂), 60.10 (CH₂), 115.45 (2 CH), 129.48 (2 CH), 131.75 (C), 155.43 (C), 172.10 (CO); MS (EI): m/z 266; Elemental analysis: calcd C, 68.02;H, 7.27; O, 24.71, found C, 68.0; H, 7.26; O, 24.68.
94%	at 20℃; for 3 h;	To a stirred solution of acid 9 (3 g, 18 mmol) in 30 mL of ethanol, under ice-cooling, was addedthionyl chloride (1.1 eq, 1.44 mL, 19 mmol) dropwise over 20 min. After stirring the reaction mixturefor 3 h at room temperature, methanol is distilled out and 25 mL of water is added. The separatedester is extracted with ethyl acetate and washed with 10 mL of saturated sodium bicarbonate solution.Evaporation of the ethyl acetate gave the ester in pure form. Yield 94percent, yellow liquid; 1H-NMR (CDCl3) δ : 1.22 (d, 3H, CH3), 2.59 (t, 2H, CH2), 2.87 (t, 2H, CH2), 4.12, q, 2H, CH2), 6.74 (d, 2H, 2.09, 6.48,H-3A-H-5A), 7.03 (d, 2H, 6.54, H-2A, H-6A). 13C-NMR (CDCl3) : 14.2 (CH3), 30.2 (CH2), 36.3 (CH2),60.6 (CH2), 115.4 (C-3A, C-5A), 129.4 (C-2A, C-6A), 154.3 (C-4A), 173.6 (C=O). MS/EI: m/z (percent int. rel).194 (M+) 49percent, 142 (M - 74) 100percent.
90%	at 145℃;	Alternative Synthesis Route for Compound 4'3-(4 Hydroxy-phenyl)-propionic acid ethyl ester (4'-1)4 drops of concentrated HCl are added, under stirring, to a solution of commercial 3-(4 Hydroxy-phenyl)-propionic acid (13.08 g; 78.79 mmol) in 100 mL of ethanol. The reaction medium is heated to reflux in a bath at 145° C. overnight. The ethanol is evaporated off and ethyl acetate is added. The organic phase is washed with a saturated NaHCO₃solution and with a NaCl solution. After drying over MgSO₄and evaporation, an oil is obtained. This latter is distilled by Kugelrohr (150-175° C.; 1.2 mmbar). A transparent oil which crystallizes is obtained in order to produce the expected compound 4'-1 (13.8 g; 71.1 mmol; 90percent) in the form of a white solid. C₁₁H₁₄O₃M=194 g.mol^-1R_f=0.31 (1:4 ethyl acetate/cyclohexane)UV: 278, 224, 199 nm.IR ν_max(film, cm^-1): 3391, 2983, 1709, 1615, 1517, 1447, 1374, 1225, 1036.¹H NMR (400 MHz, CDCl₃): δ=1.22 (t, J=7.2 Hz, 3H, -OCH₂CH₃), 2.59 (t, J=7.9 Hz, 2H, 2.x.H3), 2.86 (t, J=7.9 Hz, 2H, 2.x.H2), 4.12 (q, J=7.2 Hz, 2H, -OCH₂CH₃), 6.75 (d, J=8.5 Hz, 2H, 2.x.H2'), 7.01 (d, J=8.5 Hz, 2H, 2.x.H3').¹³C NMR (100 MHz, CDCl₃): δ=14.2 (-OCH₂CH₃), 30.21 (C3), 36.5 (C2), 60.9 (-OCH₂CH₃), 115.5 (2.x.C2'), 129.4 (2.x.C3'), 132.1 (C1'), 154.5 (C4'), 174.2 (C1).LRMS (ESI+): m/z (percent) 217 (26) [M+Na]⁺, 107 (100).

Reference： [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5345 - 5351
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 7, p. 1495 - 1503
[3] Tetrahedron Letters, 2010, vol. 51, # 44, p. 5753 - 5756
[4] Molecules, 2018, vol. 23, # 2,
[5] Patent: US2010/298422, 2010, A1, . Location in patent: Page/Page column 18
[6] Journal of Organic Chemistry, 1995, vol. 60, # 21, p. 7072 - 7074
[7] Chemische Berichte, 1917, vol. 50, p. 618[8] Chem. Zentralbl., 1916, vol. 87, # II, p. 1025
[9] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 5, p. 1328 - 1334
[10] Journal of Medicinal Chemistry, 1982, vol. 25, # 12, p. 1408 - 1412
[11] Journal of Labelled Compounds and Radiopharmaceuticals, 2005, vol. 48, # 12, p. 855 - 871
[12] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 13, p. 4279 - 4290
[13] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 24, p. 7699 - 7708
[14] Patent: WO2015/66290, 2015, A1, . Location in patent: Page/Page column 113
[15] Patent: CN107721836, 2018, A, . Location in patent: Paragraph 0060-0062
[16] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 1231

7
[ 501-97-3 ]
[ 23795-02-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride In ethanol	1) To an ice-cooled solution of 3-(p-hydroxyphenyl)-propionic acid (8.3 g, 50.0 mmol) in ethanol (100 mL) was dropwise added thionyl chloride (3.7 mL, 50.7 mmol). The mixture was stirred at room temperature over night, concentrated in vacuo and the residue purified by kugelrohr distillation, to give 9.6 g (99percent) of 3-(4-hydroxy-phenyl)-propionic acid ethyl ester as a colourless oil. ¹H NMR (CDCL₃): δ 1.21 (3H, t), 2.58 (2H, t), 2.86 (2H, t), 4.12 (2H, q), 6.75 (2H, d), 6.90 (1H, bs), 7.01 (2H, d).

Reference： [1] Patent: US2003/139473, 2003, A1,
[2] Patent: US2006/278851, 2006, A1,

8
[ 67-56-1 ]
[ 501-97-3 ]
[ 5597-50-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 25℃; for 24 h;	General procedure: To a suspension of 3(4-hydroxyphenyl)propanoic acid 1 (0.05 mmol) in TMCS (0.1 mmol), the appropriate alcohol (1.0 mL) was added and the reaction mixture was stirred at 25°C. After 24 h, the reaction was stopped and evaporated under reduced pressure to afford 1a–d in quantitative yield without the need of purification: 3-(4-Hydroxyphenyl)propionic acid methyl ester(1a) Oil; ¹HNMR (400 MHz, CDCl₃): δ H (ppm) = 2.66 (2H, m, CH₂),3.05 (2H, m, CH₂),3.65 (3H, m, OCH₃), 6.73 (2H, m, Ph-H), 7.04(2H, m, Ph-H); 13C NMR (50 MHz, CDCl₃): δ C (ppm) = 30.19 (CH₂),35.23 (CH₂), 50.99 (CH₃),115.57 (2 CH), 129.54 (2 CH),131.59 (C), 155.71 (C), 172.74 (CO); MS (EI): m/z 252; Elemental analysis: calcd C, 66.65; H, 6.71; O, 26.64, found C, 66.64; H, 6.71;O, 26.63.
100%	With acetyl chloride In methanol at 0℃; for 1.5 h;	To a solution of3-(4-hydroxyphenyl)propanoic acid (2.50g, 15.04 mmol) in methanol(40 mL) were added dropwise 5.35 mL acetyl chloride (5.0eq,75.20 mmol) at 0 °C. The reaction mixture was stirred over 1.5 h at0 °C. After completion of the reaction, the mixture was concentratedin vacuo and ethyl acetate was added. The organic layer waswashed with NaHCO3 (3 x 50 mL) and concentrated in vacuo to givemethyl 3-(4-hydroxyphenyl)propanoate 38 (2.70 g, 100percent) as acolorless oil. UPLC-MS: 1.62 min, 100percent. 1H NMR (300 MHz, CD3OD) δ (ppm) 7.08-6.94 (m, 2H), 6.80-6.64 (m, 2H), 3.69-3.49 (m, 3H),2.87-2.70 (m, 2H), 2.60-2.45 (m, 2H). 13C NMR (75 MHz, CD3OD) δ (ppm) 174.4, 155.8, 131.8, 129.3, 115.3, 51.1, 36.1, 30.2. MS (ES) m/z181.7 (M + H)+. HRMS calculated for C10H12O3: 203.0679; found:203.0679 (M + Na)+.
99%	With hydrogenchloride In 1,4-dioxane at 20℃; for 3 h;	[355] Preparation Example 4: 3-(4-hydroxy-phenyl)-propionic acid methyl ester[356] After 3-(4-hydroxy-phenyl)propionic acid (3 g, 18 mmol) was added with MeOH(6 mL), 4M HCl/dioxane solution (18 mL, 72 mmol) was added thereto, and themixture was stirred at room temperature for 3 hours. The reactant wasconcentrated, added with EtOAc, and then washed with NaCl aqueous solution. Theorganic layer was separated, dried with MgSO₄, and filtered toobtain the title compound (3.26 g, 99percent). [357] ¹H-NMR (CDCl₃) δ 7.06(2H, m), 6.75(2H, m),4.79(1H, brs, OH), 3.66(3H, s), 2.88(2H, t), 2.59(2H, t)

98%	at 70℃; for 3 h;	4.61 g p-hydroxyphenpropionic acid, 50 ml methanol and 0.5 ml concentrated H₂SO₄ were refluxed at 70°C for 3 hours and cooled. Excessive acid was neutralized with saturated NaHCO₃ solution. The neutralized solution was extracted with ethyl acetate for three times. The extract was dried, filtrated, evaporated and purified by column chromatograph (petroleum ether: ethyl acetate=2:1) to obtain 4.9 g white solid, yield 98percent. ¹H-NMR (400MHz, DMSO-d₆, δ ppm) δ 2.5(2H, m), 2.7(2H, t), 3.567(3H, s), 6.6(2H, d, J=6.4Hz), 7.0(2H, d, J=8.4Hz), 9.0(1H, s).
98%	at 70℃; for 3 h;	Intermediate 10: Methyl p-hydroxyphenpropionate 4.61 g p-hydroxyphenpropionic acid, 50 ml methanol and 0.5 ml concentrated H₂SO₄ were refluxed at 70° C. for 3 hours and cooled. Excessive acid was neutralized with saturated NaHCO₃ solution. The neutralized solution was extracted with ethyl acetate for three times. The extract was dried, filtrated, evaporated and purified by column chromatograph (petroleum ether:ethyl acetate=2:1) to obtain 4.9 g white solid, yield 98percent. ¹H-NMR (400 MHz, DMSO-d₆, δ ppm) δ 2.5 (2H, m), 2.7 (2H, t), 3.567 (3H, s), 6.6 (2H, d, J=6.4 Hz), 7.0 (2H, d, J=8.4 Hz), 9.0 (1H, s).
98%	for 16 h; Reflux	General procedure: According to a literature protocol.[1] Propanoic acid derivative (10 g) was dissolved inmethanol (80 ml) and H2SO4 (700μl, 6 mmol) added. The resulting solution was refluxed for16 h and then allowed to cool to room temperature. The reaction mixture was reduced todryness and re-dissolved in ethyl acetate (20 ml). The organic phase was washed withsaturated aqueous sodium hydrogen carbonate (10 ml), brine (10 ml) and dried over MgSO4.Removal of the solvent gave the desired methyl ester. (Note: column chromatography is oftennot required for the methyl ester starting materials). Methyl 3-(4-hydroxyphenyl)propanoate (1a) Synthesized according to general procedure A (98percent); 1H NMR (500 MHz, d4-MeOH): δ 6.98(d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 3.60 (s, 3H), 2.78 (t, J = 7.6 Hz, 2H), 2.53 (t, J= 7.6 Hz, 2H); 13C NMR (125 MHz, d4-MeOH): 172.8, 155.6, 130.6, 129.1, 115.1, 51.2, 35.4,29.5; HRMS (EI) calculated for C10H12O3 [M]+: 180.078643; found: 180.078803.
98.2%	for 10 h; Reflux	20 g of p-hydroxyphenylpropionic acid was added to 300 ml of anhydrous methanol and2 ml of concentrated sulfuric acid, heated to reflux for 10 h, the solvent was evaporated under reduced pressure, then dissolved with ethyl acetate and washed sequentially with sodium hydrogen carbonate and water.Polyester, organic layer dried over anhydrous magnesium sulfate,The solvent was evaporated to give 21.2 g (yield: 98.2percent).
92%	at 20℃; for 16 h;	15 g (0.09 mol, 1 eq) of 3-(4-hydroxyphenyl)propanoic acid are dissolved in 50 ml of methanol and 4 drops of sulfuric acid are added. The reaction mixture is stirred for 16 hours at room temperature. The reaction is stopped by addition of 50 mL of saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 14.9 g of methyl 3-(4-hydroxyphenyl)propanoate are obtained. Yield = 92 percent
84%	at 20℃; for 8 h;	To a solution of 3-(4-hydroxyphenyl)propanoic acid (3 g, 18.1 mmol) in 50 mL MeOH was added ΒΡ₃·Ε₂0 (0.3 mL). The mixture was stirred at rt for 8 h. The mixture was concentrated, and the residue was purified by flash chromatography (FC) (ethyl acetate (EtOAc) /hexane = 2/8) to give 2.72 g white solid A (yield: 84percent): ¹HNMR(400 MHz, CDC1₃) δ: 7.07(d, 2H, J= 8.4 Hz), 6.76(d, 2H, J= 8.4 Hz), 4.72(s, 1H), 3.68(s, 3H), 2.89(t, 2H, J= 7.6 Hz), 2.60(t, 2H, J= 7.6 Hz). HRMS (ESI) calculated for C10H13O3 (M+H⁺), 181.0865; found, 181.0889
68%	for 12 h; Heating / reflux	0. 8g 4-hydroxy cinnamic acid in 40 ml methanol and 10 drops HCl were refluxed for 12 hours. Workup as above gave 0.6g oil, 68percent yield. NMR CDC13 7.02, 6.75 (4H, Abq, J=8.6 Hz), 3.66 (3H, s), 2.86 (2H, t, J=7.4 Hz), 2.60 (2H, t, J=7. 4 Hz).
68%	for 12 h; Heating / reflux	AV 32 [ CNHISNOG] Mol. Wt.: 209.24 A. 0.8 gr 4-hydroxy cinnamic acid in 40 [ML METHANOL] and 10 drops HCI were [REFLUXED] for 12 hours. Workup as above gave 0.6 gr oil, 68percent yield. NMR CDCl3 7.02, 6.75 (4H, Abq, J=8.6 Hz), 3.66 (3H, s), 2.86 (2H, t, J=7.4 [HZ),] 2.60 (2H, t, J=7. 4 Hz). B. 0.6 gr, 3.3 mM, ester from step A and 0.26 gr, 4.2 mM, ethanol amine were heated at 100 for 3 hours in an open vessel. Chromatography gave 0.3 gr recovered ester followed by amide. The viscous oil was triturated with acetone-methylene chloride and filtered to give 160 mg white solid, 23percent yield, mp-102. NMR acetone d6 8.10 (1H, s, OH), 7. [03,] 6.74 (4H, Abq, J=8. [8 HZ),] 3.90 (1H, t, J=5.2 Hz, NH), 3.54 (2H, q, J=7.1 Hz), 3.28 (2H, t, J=7.1 [HZ),] 2.80 (2H, t, J=8.2 Hz), 2.41 (2H, t, J=8.2 Hz).
68%	for 12 h; Heating / reflux	0. 8g 4-hydroxy cinnamic acid in 40 ml methanol and 10 drops HCl were refluxed for 12 hours. Workup as above gave 0.6g oil, 68percent yield. NMR CDC13 7.02, 6.75 (4H, Abq, J=8.6 Hz), 3.66 (3H, s), 2.86 (2H, t, J=7.4 Hz), 2.60 (2H, t, J=7. 4 Hz).
62%	for 24 h; Reflux	General procedure: After dissolving the carboxylic acid in the alcohol, three drops of H₂SO₄ 95percent 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.
21.2 g	at 0℃; Inert atmosphere	To a solution of 3-(4-hydroxyphenyl)propionic acid (20 mg, 120 mmol) in MeOH (300 mL) was added SOCl₂ (28.6 g, 240 mmol) at 0° C. under nitrogen. The resulting mixture was stirred overnight then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NaHCO₃ (2*50 mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo to yield Compound 1 as a red oil (21.2 g). A solution of Compound 1 (19 g, 106 mmol) in dry THF (200 mL) was slowly added to a suspension of LAH (6 g, 158 mmol) in dry THF (200 mL) at 0° C. under nitrogen. The mixture was allowed to reach room temperature and was then stirred for 2 hours. Then water (6 mL) and 15percent aqueous NaOH (24 mL) were added. Additional water (6 mL) was added to quench the reaction. The solids were filtered and the filter cake was washed with EtOAc several times. The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (hexanes:EtOAc 8:1˜5:1˜2:1) to yield Compound 2 as a yellow oil (10 g).
365.8 g	for 7 h; Reflux	2L three-mouth bottle, is provided with a stirring, thermometer and a condenser. Adding 340.0g the hydroxy phenylpropanoic acid, 3.4g concentrated sulfuric acid and 1500 ml methanol, heating reflux for 7 hours. Cooling to room temperature, using NaHCO ₃ solution to neutral, rotary evaporimeter desolventizing, by adding 600 ml of water and 600 ml toluene, liquid separation, the organic phase washed to neutral, and to obtain the product solvent 365.8g, GC purity: 98.4percent.

Reference： [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 21, p. 3351 - 3354
[2] Journal of Organic Chemistry, 2009, vol. 74, # 11, p. 4236 - 4241
[3] Organic Letters, 2013, vol. 15, # 23, p. 6058 - 6061
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5345 - 5351
[5] Organic Letters, 2016, vol. 18, # 11, p. 2600 - 2603
[6] European Journal of Medicinal Chemistry, 2017, vol. 129, p. 110 - 123
[7] Synlett, 2018, vol. 29, # 9, p. 1239 - 1243
[8] Tetrahedron Asymmetry, 1993, vol. 4, # 2, p. 261 - 272
[9] Patent: WO2014/69963, 2014, A1, . Location in patent: Paragraph 355-357
[10] Patent: EP2952517, 2015, A1, . Location in patent: Paragraph 0217
[11] Patent: EP2184277, 2010, A1, . Location in patent: Page/Page column 13
[12] Patent: US2011/9427, 2011, A1, . Location in patent: Page/Page column 8
[13] Tetrahedron Letters, 2013, vol. 54, # 25, p. 3294 - 3297
[14] Patent: CN108640834, 2018, A, . Location in patent: Paragraph 0020; 0028; 0029; 0034
[15] Organic Letters, 2003, vol. 5, # 13, p. 2215 - 2217
[16] Tetrahedron, 2005, vol. 61, # 30, p. 7144 - 7152
[17] Chemistry - An Asian Journal, 2011, vol. 6, # 8, p. 2034 - 2039
[18] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 4, p. 428 - 432
[19] Organic and Biomolecular Chemistry, 2003, vol. 1, # 9, p. 1486 - 1497
[20] Nucleosides, Nucleotides and Nucleic Acids, 2004, vol. 23, # 1-2, p. 89 - 115
[21] Tetrahedron, 1990, vol. 46, # 20, p. 7105 - 7118
[22] Analytical Chemistry, 2002, vol. 74, # 2, p. 468 - 478
[23] Patent: WO2006/18326, 2006, A1, . Location in patent: Page/Page column 22
[24] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 17, p. 9476 - 9482
[25] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1993, # 11, p. 1225 - 1234
[26] Organic and Biomolecular Chemistry, 2015, vol. 13, # 22, p. 6225 - 6241
[27] European Journal of Medicinal Chemistry, 2009, vol. 44, # 1, p. 332 - 344
[28] Patent: WO2017/116994, 2017, A1, . Location in patent: Paragraph 0072
[29] Bioconjugate Chemistry, 2016, vol. 27, # 5, p. 1314 - 1323
[30] Synthetic Communications, 2012, vol. 42, # 5, p. 722 - 726
[31] Patent: WO2005/92305, 2005, A2, . Location in patent: Page/Page column 25
[32] Patent: WO2004/31129, 2004, A2, . Location in patent: Example 1
[33] Patent: WO2005/92305, 2005, A2, . Location in patent: Page/Page column 25
[34] Bulletin of the Polish Academy of Sciences, Chemistry, 1986, vol. 34, # 3-4, p. 115 - 122
[35] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 351 - 359
[36] Chemische Berichte, 1917, vol. 50, p. 618[37] Chem. Zentralbl., 1916, vol. 87, # II, p. 1025
[38] Tetrahedron, 1966, vol. 22, p. 861 - 866
[39] Collection of Czechoslovak Chemical Communications, 1981, vol. 46, # 5, p. 1173 - 1187
[40] Journal of Medicinal Chemistry, 1982, vol. 25, # 12, p. 1408 - 1412
[41] Gazzetta Chimica Italiana, 1996, vol. 126, # 2, p. 121 - 125
[42] Tetrahedron, 1997, vol. 53, # 12, p. 4387 - 4410
[43] Synthetic Communications, 1998, vol. 28, # 4, p. 747 - 751
[44] Journal of Agricultural and Food Chemistry, 1998, vol. 46, # 4, p. 1670 - 1676
[45] Patent: WO2005/16862, 2005, A1, . Location in patent: Page/Page column 411
[46] Patent: WO2004/74270, 2004, A2, . Location in patent: Page 316
[47] Patent: US2005/176701, 2005, A1, . Location in patent: Page/Page column 152
[48] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1939 - 1944
[49] Patent: US2004/44258, 2004, A1, . Location in patent: Page 57
[50] Patent: WO2003/95441, 2003, A1, . Location in patent: Page/Page column 15
[51] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 7, p. 345 - 349
[52] Journal of Materials Chemistry A, 2013, vol. 1, # 6, p. 2256 - 2266
[53] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 24, p. 7699 - 7708
[54] Patent: US2013/323271, 2013, A1, . Location in patent: Paragraph 0387; 0388
[55] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6874 - 6878
[56] Patent: CN103539640, 2016, B, . Location in patent: Paragraph 0070; 0082; 0083
[57] Patent: CN107721836, 2018, A, . Location in patent: Paragraph 0043; 0044-0046

9
[ 501-97-3 ]
[ 74-88-4 ]
[ 5597-50-2 ]

Yield	Reaction Conditions	Operation in experiment
95.9%	Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: at 0 - 20℃; for 3 h;	Intermediate 2: Methyl 3-(4-hydroxyphenyl) propanoateTo a 1000 mL RB flask fitted with magnetic stirrer was charged 250 mL of DMF, 3-(4- Hydroxy-phenyl)-propanoic acid (25.0 g, 150.43 mmol) and K₂C0₃ (41.58 g, 300.87 mmol). The resulting mixture was stirred at RT for 30 minutes. Methyl Iodide (25.627 g, 180.51 mmol) was added to the resulting mixture which was precooled to 0 3/4. The resulting mixture was stirred at RT for 3 h. After completion of the reaction (reaction monitored by TLC), the solvent was removed under reduced pressure and the crude mass was dissolved in ethyl acetate (250 mL). The organic layer was washed with water (250 mL), saturated sodium bicarbonate solution (250 mL X 2), and saturated brine solution (250 mL). The organic layer was dried over anhydrous Na₂S0₄ and the solvent was removed under reduced pressure. The product was obtained as yellow color oil (26 g, Yield: 95.9 percent): MS (ESI, 120 eV) : m/z = 178.9 (M- H)⁺; ¹H NMR (300MHz, CDCI₃): δ 6.97-7.00(d, 2H), 6.66-6.69(d, 2H), 4.94(s, 1 H), 3.59(s, 3H), 2.78-2.83(t, 2H), 2.50-2.55(t, 2H).

Reference： [1] Synthetic Communications, 2005, vol. 35, # 1, p. 145 - 152
[2] Patent: WO2012/11125, 2012, A1, . Location in patent: Page/Page column 59; 60
[3] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 6, p. 1462 - 1469

10
[ 501-97-3 ]
[ 5597-50-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sulfuric acid In methanol; silica gel; toluene	(a) Methyl 3-(4-Hydroxyphenyl)propionate A solution of 17 gm (0.1 mole) of 3-(4-hydroxyphenyl)propionic acid in 500 ml methanol and 2 ml concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3 A molecular sieves. The solution was heated to reflux for 72 hours and the sieves were exchanged at 24 hours intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 ml toluene and extracted with 3*100 ml water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 15 gm (80percent) of a clear oil. The NMR spectrum was consistent with the assigned structure and this material was utilized directly in the next reaction step.
80%	With sulfuric acid In methanol; silica gel; toluene	Methyl 3-(4-Hydroxyphenyl)propionate A solution of 17 gm (0.1 mole) of 3-(4-hydroxyphenyl)propionic acid in 500 mL methanol and 2 mL concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3 A molecular sieves. The solution was refluxed for 72 hours and the sieves were exchanged at 24 hour intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 mL toluene and extracted with 3*100 mL water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 15 gm (80percent) of a clear oil. The NMR spectrum was consistent with the assigned structure and this material was utilized directly in the next reaction step.

Reference： [1] Patent: US4623652, 1986, A,
[2] Patent: US4387103, 1983, A,

11
[ 501-97-3 ]
[ 616-38-6 ]
[ 5597-50-2 ]

Reference： [1] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11606 - 11611

12
[ 501-97-3 ]
[ 77-78-1 ]
[ 5597-50-2 ]

Reference： [1] Journal of Organic Chemistry, 2001, vol. 66, # 10, p. 3606 - 3609

13
[ 501-97-3 ]
[ 5597-50-2 ]

Reference： [1] Patent: US4450173, 1984, A,

14
[ 501-97-3 ]
[ 149-73-5 ]
[ 5597-50-2 ]

Reference： [1] Journal of Polymer Science, Part A: Polymer Chemistry, 2013, vol. 51, # 22, p. 4894 - 4903

15
[ 186581-53-3 ]
[ 501-97-3 ]
[ 5597-50-2 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1963, vol. 663, p. 74 - 82

16
[ 501-97-3 ]
[ 24807-40-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 14, p. 3359 - 3368
[2] Tetrahedron, 2005, vol. 61, # 30, p. 7144 - 7152
[3] Bulletin of the Polish Academy of Sciences, Chemistry, 1986, vol. 34, # 3-4, p. 115 - 122
[4] Tetrahedron, 1990, vol. 46, # 20, p. 7105 - 7118
[5] Patent: EP2952517, 2015, A1,

17
[ 501-97-3 ]
[ 81161-17-3 ]

Reference： [1] Synthetic Communications, 2012, vol. 42, # 5, p. 722 - 726

[ 501-97-3 ] Synthesis Path-Downstream 1~88

1
[ 67-56-1 ]
[ 501-97-3 ]
[ 5597-50-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride In 1,4-dioxane at 20℃; for 2h;
100%	With sulfuric acid for 2h; Inert atmosphere; Reflux;
100%	With thionyl chloride at 0 - 20℃;

100%	With chloro-trimethyl-silane at 25℃; for 24h;	SI 4. General procedure for the preparation of esters 1a-d General procedure: To a suspension of 3(4-hydroxyphenyl)propanoic acid 1 (0.05 mmol) in TMCS (0.1 mmol), the appropriate alcohol (1.0 mL) was added and the reaction mixture was stirred at 25°C. After 24 h, the reaction was stopped and evaporated under reduced pressure to afford 1a-d in quantitative yield without the need of purification: 3-(4-Hydroxyphenyl)propionic acid methyl ester(1a) Oil; 1HNMR (400 MHz, CDCl3): δ H (ppm) = 2.66 (2H, m, CH2),3.05 (2H, m, CH2),3.65 (3H, m, OCH3), 6.73 (2H, m, Ph-H), 7.04(2H, m, Ph-H); 13C NMR (50 MHz, CDCl3): δ C (ppm) = 30.19 (CH2),35.23 (CH2), 50.99 (CH3),115.57 (2 CH), 129.54 (2 CH),131.59 (C), 155.71 (C), 172.74 (CO); MS (EI): m/z 252; Elemental analysis: calcd C, 66.65; H, 6.71; O, 26.64, found C, 66.64; H, 6.71;O, 26.63.
100%	With sulfuric acid for 2h; Reflux;
100%	With acetyl chloride In methanol at 0℃; for 1.5h;	Methyl 3-(4-hydroxyphenyl)propanoate (38) To a solution of3-(4-hydroxyphenyl)propanoic acid (2.50g, 15.04 mmol) in methanol(40 mL) were added dropwise 5.35 mL acetyl chloride (5.0eq,75.20 mmol) at 0 °C. The reaction mixture was stirred over 1.5 h at0 °C. After completion of the reaction, the mixture was concentratedin vacuo and ethyl acetate was added. The organic layer waswashed with NaHCO3 (3 x 50 mL) and concentrated in vacuo to givemethyl 3-(4-hydroxyphenyl)propanoate 38 (2.70 g, 100%) as acolorless oil. UPLC-MS: 1.62 min, 100%. 1H NMR (300 MHz, CD3OD) δ (ppm) 7.08-6.94 (m, 2H), 6.80-6.64 (m, 2H), 3.69-3.49 (m, 3H),2.87-2.70 (m, 2H), 2.60-2.45 (m, 2H). 13C NMR (75 MHz, CD3OD) δ (ppm) 174.4, 155.8, 131.8, 129.3, 115.3, 51.1, 36.1, 30.2. MS (ES) m/z181.7 (M + H)+. HRMS calculated for C10H12O3: 203.0679; found:203.0679 (M + Na)+.
100%	With sulfuric acid for 2h; Reflux;
100%	With sulfuric acid for 6h; Reflux;
99%	With hydrogen cation esterification;
99%	With hydrogenchloride In 1,4-dioxane at 20℃; for 3h;	4 [355] Preparation Example 4: 3-(4-hydroxy-phenyl)-propionic acid methyl ester [355] Preparation Example 4: 3-(4-hydroxy-phenyl)-propionic acid methyl ester[356] After 3-(4-hydroxy-phenyl)propionic acid (3 g, 18 mmol) was added with MeOH(6 mL), 4M HCl/dioxane solution (18 mL, 72 mmol) was added thereto, and themixture was stirred at room temperature for 3 hours. The reactant wasconcentrated, added with EtOAc, and then washed with NaCl aqueous solution. Theorganic layer was separated, dried with MgSO4, and filtered toobtain the title compound (3.26 g, 99%). [357] 1H-NMR (CDCl3) δ 7.06(2H, m), 6.75(2H, m),4.79(1H, brs, OH), 3.66(3H, s), 2.88(2H, t), 2.59(2H, t)
99%	With sulfuric acid In dichloromethane for 41h; Reflux;
99.6%	Stage #1: methanol With thionyl chloride at 5℃; for 0.5h; Stage #2: 4-hydroxyphenylpropionic acid at 35℃;	1.1 Add 70.00g methanol into the reaction flask, stir and cool to 5°C, add 15.00g (0.126mol) thionyl chloride dropwise at 5°C, and finish the dropwise addition at 0.5h, and react at 5°C for 0.5h.Add 20.00g (0.120mol) p-hydroxyphenylpropionic acid (II), raise the temperature to 35, control the temperature at 35 to react for 0.5-1.0h, TLC will detect the reaction is complete, control the temperature at 30-40 and distill under reduced pressure to obtain a light yellow oil 21.62g, purity 99.9%, 21.60g converted to methyl p-hydroxyphenylpropionate (III), molar yield 99.6%
98%	With sulfuric acid at 70℃; for 3h;	4.61 g p-hydroxyphenpropionic acid, 50 ml methanol and 0.5 ml concentrated H2SO4 were refluxed at 70°C for 3 hours and cooled. Excessive acid was neutralized with saturated NaHCO3 solution. The neutralized solution was extracted with ethyl acetate for three times. The extract was dried, filtrated, evaporated and purified by column chromatograph (petroleum ether: ethyl acetate=2:1) to obtain 4.9 g white solid, yield 98%. 1H-NMR (400MHz, DMSO-d6, δ ppm) δ 2.5(2H, m), 2.7(2H, t), 3.567(3H, s), 6.6(2H, d, J=6.4Hz), 7.0(2H, d, J=8.4Hz), 9.0(1H, s).
98%	With sulfuric acid at 70℃; for 3h;	Intermediate 10: Methyl p-hydroxyphenpropionate 4.61 g p-hydroxyphenpropionic acid, 50 ml methanol and 0.5 ml concentrated H2SO4 were refluxed at 70° C. for 3 hours and cooled. Excessive acid was neutralized with saturated NaHCO3 solution. The neutralized solution was extracted with ethyl acetate for three times. The extract was dried, filtrated, evaporated and purified by column chromatograph (petroleum ether:ethyl acetate=2:1) to obtain 4.9 g white solid, yield 98%. 1H-NMR (400 MHz, DMSO-d6, δ ppm) δ 2.5 (2H, m), 2.7 (2H, t), 3.567 (3H, s), 6.6 (2H, d, J=6.4 Hz), 7.0 (2H, d, J=8.4 Hz), 9.0 (1H, s).
98%	With sulfuric acid for 16h; Reflux;	Typical procedure for synthesis of methyl esters General procedure: According to a literature protocol.[1] Propanoic acid derivative (10 g) was dissolved inmethanol (80 ml) and H2SO4 (700μl, 6 mmol) added. The resulting solution was refluxed for16 h and then allowed to cool to room temperature. The reaction mixture was reduced todryness and re-dissolved in ethyl acetate (20 ml). The organic phase was washed withsaturated aqueous sodium hydrogen carbonate (10 ml), brine (10 ml) and dried over MgSO4.Removal of the solvent gave the desired methyl ester. (Note: column chromatography is oftennot required for the methyl ester starting materials). Methyl 3-(4-hydroxyphenyl)propanoate (1a) Synthesized according to general procedure A (98%); 1H NMR (500 MHz, d4-MeOH): δ 6.98(d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 3.60 (s, 3H), 2.78 (t, J = 7.6 Hz, 2H), 2.53 (t, J= 7.6 Hz, 2H); 13C NMR (125 MHz, d4-MeOH): 172.8, 155.6, 130.6, 129.1, 115.1, 51.2, 35.4,29.5; HRMS (EI) calculated for C10H12O3 [M]+: 180.078643; found: 180.078803.
98.2%	With sulfuric acid for 10h; Reflux;	2.5 5) Preparation of methyl 3-(4-hydroxyphenyl)propanoate: 20 g of p-hydroxyphenylpropionic acid was added to 300 ml of anhydrous methanol and2 ml of concentrated sulfuric acid, heated to reflux for 10 h, the solvent was evaporated under reduced pressure, then dissolved with ethyl acetate and washed sequentially with sodium hydrogen carbonate and water.Polyester, organic layer dried over anhydrous magnesium sulfate,The solvent was evaporated to give 21.2 g (yield: 98.2%).
97%	With sulfuric acid Reflux;
97%	With sulfuric acid
96%	With thionyl chloride at 20℃; for 24h;
95%	With hydrogenchloride at 20℃; for 3h;
95%	With thionyl chloride at -40 - 20℃; for 12h; Cooling with acetonitrile-dry ice;
95%	With sulfuric acid at 60℃; for 6h;
95%	With sulfuric acid at 35℃; for 4h;
95.3%	With sulfuric acid for 6h; Reflux;	1.1 1. Preparation of methylparaben: 150g of p-hydroxyphenylacetic acid, 400g of anhydrous methanol, 0.2ml of concentrated sulfuric acid, heated to reflux for 6 hours, after the reaction was completed, 3.0g of sodium carbonate was added to neutralize the sulfuric acid, then the methanol was evaporated under reduced pressure, 400g of toluene was added, and 500g of purified water was extracted and layered Then, an organic phase was obtained, and the organic phase was concentrated under reduced pressure to obtain 154.4 g of methylparaben, the purity detected by HPLC was 99.0%, and the yield was 95.3%.
94%	With sulfuric acid for 3h; Heating;
93%	With sulfuric acid In dichloromethane for 5h; Heating;
92.7%	With hydrogenchloride Heating;
92%	at 20℃; for 12h;
92%	With sulfuric acid at 20℃; for 16h;	4.b 15 g (0.09 mol, 1 eq) of 3-(4-hydroxyphenyl)propanoic acid are dissolved in 50 ml of methanol and 4 drops of sulfuric acid are added. The reaction mixture is stirred for 16 hours at room temperature. The reaction is stopped by addition of 50 mL of saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 14.9 g of methyl 3-(4-hydroxyphenyl)propanoate are obtained. Yield = 92 %
92%	With sulfuric acid for 24h; Reflux;
89%	With acetyl chloride Heating;
88%	With sulfuric acid at 65℃; for 16h; Sealed tube;
86%	With toluene-4-sulfonic acid for 14h; Reflux;
86%	With thionyl chloride at 20℃; for 2h;	Methyl 3-(4-hydroxyphenyl)propanoate (2). 3-(4-hydroxyphenyl)propanoic acid (1, 3.0 g, 18.1 mmol) was dissolved in methanol (50 mL), and SOCl2 (1.5 mL) was added. The solution was stirred at room temperature for 2 h. Then, the reaction mixture was concentrated in vacuo to afford 3.2 g (17.8 mmol) of crude product 2 as oil. The obtained crude product 2 was purified by silica gel column chromatography (dichloromethane). The process was monitored by TLC on silica gel plates (dichloromethane:ethyl acetate,4:1, Rf 0,79) with compound detection accomplished in an iodine chamber. The eluate was evaporated on a rotary evaporator to give compound 2 (2.8 g, 15.5 mmol, 86%) as an oil and with purity >98% (HPLC, method A, UV 220 nm).
85%	With sulfuric acid for 24h; Reflux;
84%	With boron trifluoride diethyl etherate at 20℃; for 8h;	1 Methyl 3-(4-hydroxyphenyl)propanoate (A). To a solution of 3-(4-hydroxyphenyl)propanoic acid (3 g, 18.1 mmol) in 50 mL MeOH was added ΒΡ3·Ε20 (0.3 mL). The mixture was stirred at rt for 8 h. The mixture was concentrated, and the residue was purified by flash chromatography (FC) (ethyl acetate (EtOAc) /hexane = 2/8) to give 2.72 g white solid A (yield: 84%): 1HNMR(400 MHz, CDC13) δ: 7.07(d, 2H, J= 8.4 Hz), 6.76(d, 2H, J= 8.4 Hz), 4.72(s, 1H), 3.68(s, 3H), 2.89(t, 2H, J= 7.6 Hz), 2.60(t, 2H, J= 7.6 Hz). HRMS (ESI) calculated for C10H13O3 (M+H+), 181.0865; found, 181.0889
84%	With boron trifluoride diethyl etherate at 20℃; for 6h;	1.1 Synthesis of compound 3 (methyl 3-(4-hydroxyphenyl)propionate): Adding p-hydroxyphenylpropionic acid to a round bottom flask(3g, 18.1mmol) and 50mL of methanol,Subsequently, boron trifluoride diethyl ether (0.3 mL) was added dropwise to the mixed solution.After stirring at room temperature for 6 hours,The organic phase in the filtrate was removed under reduced pressure using a rotary evaporator using n-hexane/ethyl acetate (v/v, 2/8)Through the silica gel column separation,Collect target components,The solvent was removed under reduced pressure.2.72 g of a white solid were obtained (yield: 84%);
83.5%	With boron trifluoride diethyl etherate at 20℃; for 6h;
70%	Acidic conditions; Reflux;
68%	With hydrogenchloride for 12h; Heating / reflux;	1.AV 32.A EXAMPLES EXAMPLE 1: Synthesis of compounds AV 32 AV 32 [ CNHISNOG] Mol. Wt.: 209.24 A. 0.8 gr 4-hydroxy cinnamic acid in 40 [ML METHANOL] and 10 drops HCI were [REFLUXED] for 12 hours. Workup as above gave 0.6 gr oil, 68% yield. NMR CDCl3 7.02, 6.75 (4H, Abq, J=8.6 Hz), 3.66 (3H, s), 2.86 (2H, t, J=7.4 [HZ),] 2.60 (2H, t, J=7. 4 Hz). B. 0.6 gr, 3.3 mM, ester from step A and 0.26 gr, 4.2 mM, ethanol amine were heated at 100 for 3 hours in an open vessel. Chromatography gave 0.3 gr recovered ester followed by amide. The viscous oil was triturated with acetone-methylene chloride and filtered to give 160 mg white solid, 23% yield, mp-102. NMR acetone d6 8.10 (1H, s, OH), 7. [03,] 6.74 (4H, Abq, J=8. [8 HZ),] 3.90 (1H, t, J=5.2 Hz, NH), 3.54 (2H, q, J=7.1 Hz), 3.28 (2H, t, J=7.1 [HZ),] 2.80 (2H, t, J=8.2 Hz), 2.41 (2H, t, J=8.2 Hz).
68%	With hydrogenchloride for 12h; Heating / reflux;	1.A 0. 8g 4-hydroxy cinnamic acid in 40 ml methanol and 10 drops HCl were refluxed for 12 hours. Workup as above gave 0.6g oil, 68% yield. NMR CDC13 7.02, 6.75 (4H, Abq, J=8.6 Hz), 3.66 (3H, s), 2.86 (2H, t, J=7.4 Hz), 2.60 (2H, t, J=7. 4 Hz).
65%	With hydrogen cation
62%	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.
	With sulfuric acid at 80℃; unter Druck;
	With sulfuric acid In 1,2-dichloro-ethane Heating;
	With hydrogenchloride Heating;
	With 3 A molecular sieve; sulfuric acid for 72h; Heating;
	With boron trifluoride for 0.0333333h; Heating;
	With Amberlyst 15 for 8h; Heating;
	With sulfuric acid Yield given;
	With thionyl chloride at 0 - 20℃; for 2h;	A-1 [Example A-1]; Synthesis of methyl 3- (4-HYDROXYPHENYL) propionate (Intermediate 1); A solution obtained beforehand by adding thionyl chloride (18.3 ml, WAKO) dropwise to methanol (250 ml) and mixing the mixture under ice cooling was added dropwise with a solution of 3- (4-HYDROXYPHENYL) propionic acid (16. 6g, TCI) in methanol (50 ml) under ice cooling, stirred for 30 minutes, warmed to room temperature, and further stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then extracted with diethyl ether (200 ml). The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 1,17. 95 g).
	With hydrogenchloride In 1,4-dioxane	B.67.1 Step 1: 3- (4-Hydroxyphenyl) propionic acid methyl ester. A solution of HCI in dioxane (4.0 M, 7.4 mL) was added to a solution of 4- hydroxyphenylpropionic acid (15.0 g, 90.3 mmol) in MeOH (500 mL). The reaction mixture was stirred overnight and then evaporated. The residue was evaporated from benzene (2 x 50 mL) to provide the product as an oil, which was used without further purification.
	With hydrogenchloride In 1,4-dioxane	B.67.1 A solution of HCl in dioxane (4.0 M, 7.4 mL) was added to a solution of 4-hydroxyphenylpropionic acid (15.0 g, 90.3 mmol) in MeOH (500 mL). The reaction mixture was stirred overnight and then evaporated. The residue was evaporated from benzene (2×50 mL) to provide the product as an oil, which was used without further purification.
	With sulfuric acid at 25℃;
	With thionyl chloride at 0 - 20℃; for 2h;	1.c Reference Example 1; Synthesis of methyl 3-(4-hydroxyphenyl)Propionate (Intermediate 1) (Step c) Reference Example 1 Synthesis of methyl 3-(4-hydroxyphenyl)Propionate (Intermediate 1) (Step c) A solution obtained beforehand by adding thionyl chloride (18.3 ml, WAKO) dropwise to methanol (250 ml) under ice cooling was added dropwise with a solution of 3-(4-hydroxyphenyl)propionic acid (16.6 g, TCI) in methanol (50 ml) under ice cooling, stirred for 30 minutes, then warmed to room temperature and further stirred for 1.5 hours.The reaction mixture was concentrated under reduced pressure and then extracted with diethyl ether (200 ml).The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine.The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 1, 17.95 g).
	With hydrogenchloride In 1,4-dioxane	1.1 A solution of HCl in dioxane (4.0 M, 7.4 mL) was added to a solution of 4- hydroxyphenylpropionic acid (15.0 g, 90.3 mmol) in MeOH (500 mL). The reaction mixture was stirred overnight and then evaporated. The residue was evaporated from benzene (2 x 50 mL) to provide the product as an oil, which was used without further purification.
	With hydrogenchloride
	With sulfuric acid
	With chloro-trimethyl-silane at 25℃; for 24h;	4.6 General procedure for the preparation of esters 2a-l General procedure: To a suspension of acidic phenols 1a-d (0.05mmol) in TMCS (0.1mmol), the alcohol (1.0mL) was added and the reaction mixture was stirred at 25°C. After 24h, the reaction was stopped and evaporated under reduced pressure to afford 2a-l in quantitative yield without the need of purification:
21.2 g	With thionyl chloride at 0℃; Inert atmosphere;	2 To a solution of 3-(4-hydroxyphenyl)propionic acid (20 mg, 120 mmol) in MeOH (300 mL) was added SOCl2 (28.6 g, 240 mmol) at 0° C. under nitrogen. The resulting mixture was stirred overnight then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (2*50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to yield Compound 1 as a red oil (21.2 g). A solution of Compound 1 (19 g, 106 mmol) in dry THF (200 mL) was slowly added to a suspension of LAH (6 g, 158 mmol) in dry THF (200 mL) at 0° C. under nitrogen. The mixture was allowed to reach room temperature and was then stirred for 2 hours. Then water (6 mL) and 15% aqueous NaOH (24 mL) were added. Additional water (6 mL) was added to quench the reaction. The solids were filtered and the filter cake was washed with EtOAc several times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexanes:EtOAc 8:1˜5:1˜2:1) to yield Compound 2 as a yellow oil (10 g).
	With sulfuric acid for 10h; Reflux; Inert atmosphere;	Concentrated H2SO4 (40 μl, 0.83 mmol)was added to a solution of 3-(4-hydroxyphenyl)propionic acid (11) (2.76 g, 16.6 mmol) in MeOH (30mL), the resulting solution was heated to reflux and stirred for 10 h. The mixture was cooled to roomtemperature by removal of the oil bath, and the residual solvent was removed under reduced pressure.The crude residue was dissolved in EtOAc (40 mL), washed with saturated aqueous NaHCO3 (1 x 40mL) and the layers were separated. The organic layer was dried (MgSO4) and concentrated underreduced pressure to provide a clear, colorless oil that was dissolved in CH2Cl2 (55 mL) and cooled to 0°C. Imidazole (1.70 g, 24.9 mmol) was added, the solution stirred for 10 min, followed by a portion-wiseaddition of TBSCl (2.76 g, 18.3 mmol). The cooling bath was removed and the resulting heterogeneousmixture was stirred for 10 h. The mixture was diluted with H2O (50 mL), the layers were separated, andthe aqueous phase extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were washed withsaturated aqueous NaCl (50 mL), dried (MgSO4), and concentrated under reduced pressure to provide4.39 g of methyl 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)propanoate as a clear, colorless crude oil.This crude residue was dissolved in CH2Cl2 ( 75 mL), cooled to -90 °C, and a solution of DIBAL-H (1.0M in hexanes, 16.6 mmol, 15 mL) was then added dropwise while ensuring that the internal reactiontemperature remained below -80 °C. The mixture was stirred for 1 h, then excess DIBAL-H wasquenched by the slow addition of MeOH (15 mL), while again being careful to ensure that the internaltemperature of the solution did not rise above -80 °C. The mixture was allowed to warm to roomtemperature by removal of the cooling bath, diluted with saturated aqueous Rochelle’s salt (70 mL), andstirred vigorously for 10 h. The layers were separated and the aqueous phase was extracted with CH2Cl2(3 x 50 mL). The combined organic extracts were washed with saturated aqueous NaCl (50 mL), dried(MgSO4), and concentrated under reduced pressure. The crude residue was purified by flash columnchromatography eluting with hexanes/EtOAc (7:1) to provide 12 in 76% yield (16.6 mmol scale, 3.36mg) over three steps as a clear colorless oil. 1H and 13C NMR data for 12 was consistent with literature reported values.
365.8 g	With sulfuric acid for 7h; Reflux;	1.1 4-hydroxy-phenylpropionic acid methyl ester preparation 2L three-mouth bottle, is provided with a stirring, thermometer and a condenser. Adding 340.0g the hydroxy phenylpropanoic acid, 3.4g concentrated sulfuric acid and 1500 ml methanol, heating reflux for 7 hours. Cooling to room temperature, using NaHCO 3 solution to neutral, rotary evaporimeter desolventizing, by adding 600 ml of water and 600 ml toluene, liquid separation, the organic phase washed to neutral, and to obtain the product solvent 365.8g, GC purity: 98.4%.
	With sulfuric acid at 35℃; for 4h;	1.1 Preparation of methyl 3-(4-hydroxyphenyl)propanoate 3-(4-Hydroxyphenyl)propionic acid (8 g, 48.14 mmol) was dissolved in methanol (40 mL),catalyzed by thedropwise addition of concentrated sulfuric acid (0.4 mL), reacted at 35° C. for 4 h, and concentrated under reduced pressure to remove some of the methanol. was added 10mL of water, adjusted to pH 6 with saturated sodium bicarbonate,with 20mL ethyl acetate three times, washed three times with 20mL saturated brine, dried over anhydrous sodium sulfate under reduced pressure to remove acetic acidethyl ester to give 3- (4- Hydroxyphenyl)propionic acid methyl ester.
11 g	With sulfuric acid for 16h; Reflux;

Reference： [1]Xue; He; Corbett; Roderick; Wasserman; Liu; Jaffee; Covington; Qian; Trzaskos; Newton; Magolda; Wexler; Decicco [Journal of Medicinal Chemistry, 2001, vol. 44, # 21, p. 3351 - 3354]
[2]Rauniyar, Vivek; Hall, Dennis G. [Journal of Organic Chemistry, 2009, vol. 74, # 11, p. 4236 - 4241]
[3]Taylor, James E.; Daniels, David S. B.; Smith, Andrew D. [Organic Letters, 2013, vol. 15, # 23, p. 6058 - 6061]
[4]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]
[5]Tung, Chun Ling; Wong, Clarence T. T.; Fung, Eva Yi Man; Li, Xuechen [Organic Letters, 2016, vol. 18, # 11, p. 2600 - 2603]
[6]St-Georges, Catherine; Désilets, Antoine; Béliveau, François; Ghinet, Mariana; Dion, Sébastien P.; Colombo, Éloic; Boudreault, Pierre-Luc; Najmanovich, Rafael J.; Leduc, Richard; Marsault, Éric [European Journal of Medicinal Chemistry, 2017, vol. 129, p. 110 - 123]
[7]Makarem, Ata; Konrad, Moritz; Liolios, Christos; Kopka, Klaus [Synlett, 2018, vol. 29, # 9, p. 1239 - 1243]
[8]Horn, Jessica; Locklin, Jason; Ring, John; White, Evan M.; Winfield, Demichael [Green Chemistry, 2021, vol. 23, # 23, p. 9658 - 9668]
[9]Jones; Heaton [Tetrahedron Asymmetry, 1993, vol. 4, # 2, p. 261 - 272]
[10]Current Patent Assignee: LG CHEM CO.,LTD. - WO2014/69963, 2014, A1 Location in patent: Paragraph 355-357
[11]Current Patent Assignee: TOHOKU UNIVERSITY; THE UNIVERSITY OF TOKYO - EP2952517, 2015, A1 Location in patent: Paragraph 0217
[12]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN113480438, 2021, A Location in patent: Paragraph 0053-0055; 0074
[13]Current Patent Assignee: ACADEMY OF MILITARY MEDICAL SCIENCES - EP2184277, 2010, A1 Location in patent: Page/Page column 13
[14]Current Patent Assignee: ACADEMY OF MILITARY MEDICAL SCIENCES - US2011/9427, 2011, A1 Location in patent: Page/Page column 8
[15]Jones, Kevin M.; Hillringhaus, Tim; Klussmann, Martin [Tetrahedron Letters, 2013, vol. 54, # 25, p. 3294 - 3297]
[16]Current Patent Assignee: HUBEI GUANGCHEN PHARMACEUTICAL; HUBEI UNIVERSITY; WUHAN INSTITUTE OF TECHNOLOGY - CN108640834, 2018, A Location in patent: Paragraph 0020; 0028; 0029; 0034
[17]António, João P. M.; Faustino, Hélio; Gois, Pedro M. P. [Organic and Biomolecular Chemistry, 2021, vol. 19, # 28, p. 6221 - 6226]
[18]Aguiar, Sandra I.; André, Ana S.; António, João P. M.; Bernardes, Gonçalo J. L.; Carvalho, Joana Inês; Dias, Joana N. R.; Faustino, Hélio; Gois, Pedro M. P.; Lopes, Ricardo M. R. M.; Veiros, Luis F.; da Silva, Frederico A. [Angewandte Chemie - International Edition, 2021, vol. 60, # 49, p. 25914 - 25921][Angew. Chem., 2021, vol. 133, # 49, p. 26118 - 26125]
[19]Dorrestein, Pieter C.; Poole, Keith; Begley, Tadhg P. [Organic Letters, 2003, vol. 5, # 13, p. 2215 - 2217]
[20]Lewin, Anita H.; Szewczyk, Jerzy; Wilson, Joseph W.; Carroll, F. Ivy [Tetrahedron, 2005, vol. 61, # 30, p. 7144 - 7152]
[21]Location in patent: experimental part Oh, Dong Ju; Kim, Kyung Mi; Ahn, Kyo Han [Chemistry - An Asian Journal, 2011, vol. 6, # 8, p. 2034 - 2039]
[22]Liu, Jiaxiang; Tian, Chengsen; Jiang, Tianyu; Gao, Yuqi; Zhou, Yubin; Li, Minyong; Du, Lupei [ACS Medicinal Chemistry Letters, 2017, vol. 8, # 4, p. 428 - 432]
[23]Hong, Jing; Meng, Lin; Qin, Feng; Yu, Peipei; Yu, Zhiguo; Zhang, Zhaoyan; Zhao, Yunli; Zhou, Ceng [RSC Advances, 2020, vol. 10, # 46, p. 27794 - 27804]
[24]Current Patent Assignee: TIANJIN CHASE SUN PHARMACEUTICAL CO LTD - CN113651706, 2021, A Location in patent: Paragraph 0031
[25]Clough, John M.; Jones, Ray V.H.; McCann, Hannah; Morris, David J.; Wills, Martin [Organic and Biomolecular Chemistry, 2003, vol. 1, # 9, p. 1486 - 1497]
[26]Meier, Chris; Ruppel, Manuel F. H.; Vukadinovic, Dalibor; Balzarini, Jan [Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 89 - 115]
[27]Herbert, Richard B.; Kattah, Abdullah E. [Tetrahedron, 1990, vol. 46, # 20, p. 7105 - 7118]
[28]Galve, Roger; Nichkova, Mikaela; Camps, Francisco; Sanchez-Baeza, Francisco; Marco, M.-Pilar [Analytical Chemistry, 2002, vol. 74, # 2, p. 468 - 478]
[29]Current Patent Assignee: Galderma (in: EQT Partners); Eqt Partners AB - WO2006/18326, 2006, A1 Location in patent: Page/Page column 22
[30]Location in patent: experimental part Meepagala, Kumudini M.; Schrader, Kevin K.; Burandt, Charles L.; Wedge, David E.; Duke, Stephen O. [Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 17, p. 9476 - 9482]
[31]Ricca, Jean-Marc; Crout, David H. G. [Journal of the Chemical Society. Perkin transactions I, 1993, # 11, p. 1225 - 1234]
[32]Hickey, Shane M.; Ashton, Trent D.; Khosa, Simren K.; Robson, Ryan N.; White, Jonathan M.; Li, Jian; Nation, Roger L.; Yu, Heidi Y.; Elliott, Alysha G.; Butler, Mark S.; Huang, Johnny X.; Cooper, Matthew A.; Pfeffer, Frederick M. [Organic and Biomolecular Chemistry, 2015, vol. 13, # 22, p. 6225 - 6241]
[33]Location in patent: experimental part Junek, Richard; Kverka, Miloslav; Jandera, Antonin; Panajotova, Vladimira; Satinsky, Dalibor; Machacek, Milos; Kuchar, Miroslav [European Journal of Medicinal Chemistry, 2009, vol. 44, # 1, p. 332 - 344]
[34]Jerzyk; Kludkiewicz; Pijarowska-Kruszyna; Jaron; Maurin; Sikora; Kordowski; Garnuszek [Tetrahedron, 2021, vol. 84]
[35]Hefke, Lena; Hiesinger, Kerstin; Kramer, Jan S.; Proschak, Ewgenij; Zhu, W. Felix [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 6, p. 1244 - 1249]
[36]Current Patent Assignee: FIVE ELEVEN PHARMA INC - WO2017/116994, 2017, A1 Location in patent: Paragraph 0072
[37]Current Patent Assignee: BEIJING JIUJIE CONTAMINATION CONTROL TECH - CN109438517, 2019, A Location in patent: Paragraph 0071; 0073; 0074; 0075; 0076; 0077
[38]Zha, Zhihao; Song, Jin; Choi, Seok Rye; Wu, Zehui; Ploessl, Karl; Smith, Megan; Kung, Hank [Bioconjugate Chemistry, 2016, vol. 27, # 5, p. 1314 - 1323]
[39]Location in patent: scheme or table Zhang, Cunyu A.; Erhardt, Paul W. [Synthetic Communications, 2012, vol. 42, # 5, p. 722 - 726]
[40]Current Patent Assignee: NOVAREMED AG - WO2004/31129, 2004, A2 Location in patent: Example 1
[41]Current Patent Assignee: NOVAREMED AG - WO2005/92305, 2005, A2 Location in patent: Page/Page column 25
[42]Krawczyk, Andrzej R.; Lipkowska, Ewa; Wrobel, Jerzy T. [Bulletin of the Polish Academy of Sciences: Chemistry, 1986, vol. 34, # 3-4, p. 115 - 122]
[43]Allegretta, Giuseppe; Weidel, Elisabeth; Empting, Martin; Hartmann, Rolf W. [European Journal of Medicinal Chemistry, 2015, vol. 90, p. 351 - 359]
[44]Fischer,E.; Nouri [Chemische Berichte, 1917, vol. 50, p. 618][Chemisches Zentralblatt, 1916, vol. 87, # II, p. 1025]
[45]Marvell,E.N. et al. [Tetrahedron, 1966, vol. 22, p. 861 - 866]
[46]Kuchar, Miroslav; Brunova, Bohumila; Rejholec, Vaclav; Roubal, Zdenek; Nemecek, Oldrich [Collection of Czechoslovak Chemical Communications, 1981, vol. 46, # 5, p. 1173 - 1187]
[47]Erhardt, Paul W.; Woo, Chi M.; Anderson, William G.; Gorczynski, Richard J. [Journal of Medicinal Chemistry, 1982, vol. 25, # 12, p. 1408 - 1412]
[48]Casella, Luigi; Monzani, Enrico; Gullotti, Michele; Santelli, Eugenio; Poli, Sonia; Beringhelli, Tiziana [Gazzetta chimica Italiana, 1996, vol. 126, # 2, p. 121 - 125]
[49]Mitchell, Anthony S.; Russell, Richard A. [Tetrahedron, 1997, vol. 53, # 12, p. 4387 - 4410]
[50]Lee, Thomas B.K.; Tebben, Andrew J.; Weiberth, Franz J.; Wong, George S.K. [Synthetic Communications, 1998, vol. 28, # 4, p. 747 - 751]
[51]Queffelec, Anne-Laurence; Nodet, Patrice; Haelters, Jean-Pierre; Thouvenot, Daniel; Corbel, Bernard [Journal of Agricultural and Food Chemistry, 1998, vol. 46, # 4, p. 1670 - 1676]
[52]Current Patent Assignee: ASAHI KASEI CORPORATION - WO2005/16862, 2005, A1 Location in patent: Page/Page column 411
[53]Current Patent Assignee: PFIZER INC - WO2004/74270, 2004, A2 Location in patent: Page 316
[54]Current Patent Assignee: PFIZER INC - US2005/176701, 2005, A1 Location in patent: Page/Page column 152
[55]Wang, Wei; Devasthale, Pratik; Farrelly, Dennis; Gu, Liqun; Harrity, Thomas; Cap, Michael; Chu, Cuixia; Kunselman, Lori; Morgan, Nathan; Ponticiello, Randy; Zebo, Rachel; Zhang, Litao; Locke, Kenneth; Lippy, Jonathan; O'Malley, Kevin; Hosagrahara, Vinayak; Zhang, Lisa; Kadiyala, Pathanjali; Chang, Chiehying; Muckelbauer, Jodi; Doweyko, Arthur M.; Zahler, Robert; Ryono, Denis; Hariharan, Narayanan; Cheng, Peter T.W. [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1939 - 1944]
[56]Current Patent Assignee: ASAHI KASEI CORPORATION - US2004/44258, 2004, A1 Location in patent: Page 57
[57]Current Patent Assignee: PFIZER INC - WO2003/95441, 2003, A1 Location in patent: Page/Page column 15
[58]Location in patent: scheme or table Christiansen, Elisabeth; Due-Hansen, Maria E.; Urban, Christian; Merten, Nicole; Pfleiderer, Michael; Karlsen, Kasper K.; Rasmussen, Sanne S.; Steensgaard, Mette; Hamacher, Alexandra; Schmidt, Johannes; Drewke, Christel; Petersen, Rasmus Koefoed; Kristiansen, Karsten; Ullrich, Susanne; Kostenis, Evi; Kassack, Matthias U.; Ulven, Trond [ACS Medicinal Chemistry Letters, 2010, vol. 1, # 7, p. 345 - 349]
[59]Balamurugan; Reddy; Jayakannan [Journal of Materials Chemistry A, 2013, vol. 1, # 6, p. 2256 - 2266]
[60]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]
[61]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/323271, 2013, A1 Location in patent: Paragraph 0387; 0388
[62]Campos, Catherine A.; Gianino, Joseph B.; Bailey, Barbara J.; Baluyut, Mary E.; Wiek, Constanze; Hanenberg, Helmut; Shannon, Harlan E.; Pollok, Karen E.; Ashfeld, Brandon L. [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6874 - 6878]
[63]Current Patent Assignee: VALIANT CO., LTD. - CN103539640, 2016, B Location in patent: Paragraph 0070; 0082; 0083
[64]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN107721836, 2018, A Location in patent: Paragraph 0043; 0044-0046
[65]Liu, Caiping; Han, Jingxuan; Marcelina, Olivia; Nugrahaningrum, Dyah Ari; Huang, Song; Zou, Meijuan; Wang, Guixue; Miyagishi, Makoto; He, Yun; Wu, Shourong; Kasim, Vivi [Journal of Medicinal Chemistry, 2022, vol. 65, # 1, p. 135 - 162]

2
[ 74-96-4 ]
[ 501-97-3 ]
[ 4919-34-0 ]

Reference： [1]Chemische Berichte,1874,vol. 7,p. 1736
Gazzetta Chimica Italiana,1875,vol. 5,p. 6

3
[ 64-17-5 ]
[ 501-97-3 ]
[ 23795-02-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With chloro-trimethyl-silane; at 25℃; for 24h;	General procedure: To a suspension of 3(4-hydroxyphenyl)propanoic acid 1 (0.05 mmol) in TMCS (0.1 mmol), the appropriate alcohol (1.0 mL) was added and the reaction mixture was stirred at 25C. After 24 h, the reaction was stopped and evaporated under reduced pressure to afford 1a-d in quantitative yield without the need of purification: 3-(4-Hydroxyphenyl)propionic ethyl ester (1b) Oil; 1HNMR (400 MHz, CDCl3): deltaH (ppm) = 1.13 (3H, m, CH3), 2.82 (2H, m, CH2), 2.88 (2H, m, CH2), 4.00 (2H, m, OCH2), 6.75 (2H, m,Ph-H), 7.06 (2H, m, Ph-H); 13C NMR (50 MHz, CDCl3): deltaC (ppm) = 14.20 (CH3), 30.12 (CH2), 35.10 (CH2), 60.10 (CH2), 115.45 (2 CH), 129.48 (2 CH), 131.75 (C), 155.43 (C), 172.10 (CO); MS (EI): m/z 266; Elemental analysis: calcd C, 68.02;H, 7.27; O, 24.71, found C, 68.0; H, 7.26; O, 24.68.
94%	With thionyl chloride; at 20℃; for 3h;	To a stirred solution of acid 9 (3 g, 18 mmol) in 30 mL of ethanol, under ice-cooling, was addedthionyl chloride (1.1 eq, 1.44 mL, 19 mmol) dropwise over 20 min. After stirring the reaction mixturefor 3 h at room temperature, methanol is distilled out and 25 mL of water is added. The separatedester is extracted with ethyl acetate and washed with 10 mL of saturated sodium bicarbonate solution.Evaporation of the ethyl acetate gave the ester in pure form. Yield 94%, yellow liquid; 1H-NMR (CDCl3) delta : 1.22 (d, 3H, CH3), 2.59 (t, 2H, CH2), 2.87 (t, 2H, CH2), 4.12, q, 2H, CH2), 6.74 (d, 2H, 2.09, 6.48,H-3A-H-5A), 7.03 (d, 2H, 6.54, H-2A, H-6A). 13C-NMR (CDCl3) : 14.2 (CH3), 30.2 (CH2), 36.3 (CH2),60.6 (CH2), 115.4 (C-3A, C-5A), 129.4 (C-2A, C-6A), 154.3 (C-4A), 173.6 (C=O). MS/EI: m/z (% int. rel).194 (M+) 49%, 142 (M - 74) 100%.
90%	hydrogenchloride; at 145℃;	Alternative Synthesis Route for Compound 4'3-(4 Hydroxy-phenyl)-propionic acid ethyl ester (4'-1)4 drops of concentrated HCl are added, under stirring, to a solution of commercial 3-(4 Hydroxy-phenyl)-propionic acid (13.08 g; 78.79 mmol) in 100 mL of ethanol. The reaction medium is heated to reflux in a bath at 145 C. overnight. The ethanol is evaporated off and ethyl acetate is added. The organic phase is washed with a saturated NaHCO3 solution and with a NaCl solution. After drying over MgSO4 and evaporation, an oil is obtained. This latter is distilled by Kugelrohr (150-175 C.; 1.2 mmbar). A transparent oil which crystallizes is obtained in order to produce the expected compound 4'-1 (13.8 g; 71.1 mmol; 90%) in the form of a white solid. C11H14O3 M=194 g.mol-1 Rf=0.31 (1:4 ethyl acetate/cyclohexane)UV: 278, 224, 199 nm.IR numax (film, cm-1): 3391, 2983, 1709, 1615, 1517, 1447, 1374, 1225, 1036.1H NMR (400 MHz, CDCl3): delta=1.22 (t, J=7.2 Hz, 3H, -OCH2CH3), 2.59 (t, J=7.9 Hz, 2H, 2×H3), 2.86 (t, J=7.9 Hz, 2H, 2×H2), 4.12 (q, J=7.2 Hz, 2H, -OCH2CH3), 6.75 (d, J=8.5 Hz, 2H, 2×H2'), 7.01 (d, J=8.5 Hz, 2H, 2×H3').13C NMR (100 MHz, CDCl3): delta=14.2 (-OCH2CH3), 30.21 (C3), 36.5 (C2), 60.9 (-OCH2CH3), 115.5 (2×C2'), 129.4 (2×C3'), 132.1 (C1'), 154.5 (C4'), 174.2 (C1).LRMS (ESI+): m/z (%) 217 (26) [M+Na]+, 107 (100).

	With chloro-trimethyl-silane; at 25℃; for 24h;	General procedure: To a suspension of acidic phenols 1a-d (0.05mmol) in TMCS (0.1mmol), the alcohol (1.0mL) was added and the reaction mixture was stirred at 25C. After 24h, the reaction was stopped and evaporated under reduced pressure to afford 2a-l in quantitative yield without the need of purification:
	With sulfuric acid;Reflux;	As outlined in Scheme 7d, a novel methodology was applied to synthesis TG42 in fair yield ~ 40% by reacting the phenolic compound 1 with 2-bromoacetic acid under basic conditions for 6 h to yield compound 2. Vilsmeier formylation using phosphorous oxychloride and DMF was conducted on 2 for 5h followed by basic workup to form the decarboxylated bis- aldehyde 3. Compound 3 was allowed to react with the quaternary salt using sodium acetate in boiling ethanol for around 3-5 h to afford the desired compound.As such, in another aspect, the invention provides a method of preparing a compound, the method comprising reacting a decarboxylated bis-aldehyde with a quarternary salt to produce the compound.
	With sulfuric acid; at 35℃; for 4h;	3-(4-Hydroxyphenyl)propionic acid (8 g, 48.14 mmol) was dissolved in ethanol (40 mL),catalyzed by thedropwise addition of concentrated sulfuric acid (0.4 mL), reacted at 35 C. for 4 h, and concentrated under reduced pressure to remove some of the methanol. was added 10mL of water, adjusted to pH 6 with saturated sodium bicarbonate,with 20mL ethyl acetate three times, washed three times with 20mL saturated brine, dried over anhydrous sodium sulfate under reduced pressure to remove acetic acidethyl ester to give 3- (4- Ethyl hydroxyphenyl) propionate.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5345 - 5351
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 1495 - 1503
[3]Tetrahedron Letters,2010,vol. 51,p. 5753 - 5756
[4]Molecules,2018,vol. 23
[5]Patent: US2010/298422,2010,A1 .Location in patent: Page/Page column 18
[6]Journal of Organic Chemistry,1995,vol. 60,p. 7072 - 7074
[7]Chemische Berichte,1917,vol. 50,p. 618
Chemisches Zentralblatt,1916,vol. 87,p. 1025
[8]Bulletin of the Chemical Society of Japan,1990,vol. 63,p. 1328 - 1334
[9]Journal of Medicinal Chemistry,1982,vol. 25,p. 1408 - 1412
[10]Journal of labelled compounds and radiopharmaceuticals,2005,vol. 48,p. 855 - 871
[11]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 4279 - 4290
[12]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7699 - 7708
[13]Patent: WO2015/66290,2015,A1 .Location in patent: Page/Page column 113
[14]Patent: CN107721836,2018,A .Location in patent: Paragraph 0060-0062
[15]Patent: DE233551,
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 10,p. 1231

4
[ 60-82-2 ]
[ 108-73-6 ]
[ 501-97-3 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1868,vol. <1> 104,p. 390
Zeitschrift fuer Chemie,1868,p. 727

5
[ 7400-08-0 ]
[ 501-97-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen In methanol Ambient temperature;
100%	With hydrogen In methanol
99%	With hydrogen In ethyl acetate at 20℃;

99%	With palladium 10% on activated carbon; hydrogen In ethanol for 0.5h;	3.5. Synthesis of 3-(4-Hydroxyphenyl)propanoic Acid (9) A mixture of acid 8 (0.2 g, 1.20 mmol) and Pd/C 10% (0.02 g) in ethanol (40 mL) was hidrogenatedat 60 lb/in2 in a hydrogenation apparatus for 30 min. After filtration and evaporation of the solventuder reduce pressure a yellow oil was obtained. After cooling, a solid compound was obtained whichpurificated by recrystallyzation in ethanol. Yield 99%, yellow crystals m.p. 129-131 °C; 1H-NMR(DMSO-d6) δ :2.45 (t, 2H, CH2), 2.72 (t, 2H, CH2), 6.65 (d, 2H, H-3', H-5', J = 8.01 Hz), 7.05 (d, 2H, H-2',H-6', J = 8.02 Hz), 9.54 (bs, 2H, OH, COOH) ppm.13C-NMR (DMSO-d6) : 30.1 (CH2), 36.9 (CH2), 115.5(C-3', C-5'), 129.5 (C-2', C-6'), 131.8 (C-1'), 155.5 (C-4'), 175.1 (C=O) ppm. MS/EI: m/z (% int. rel).166 (M+).
99.6%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 12h;	Synthesis of substrates and reference material. 3-(4-Hydroxyphenyl)propanoic acid (6): To a 10 mL round-bottom flask containing 5 (2.46 g, 15 mmol) was added MeOH (45 mL), Pd/C (10%, 750 mg). The mixture was stirred at room temperature for 12 h under H2 atmosphere. Pd/C was filtered and washed with MeOH. The filtrate was concentrated in vaccum to provide compound 6 as white solid (2.48 mg, 99.6%). 1H NMR (400 MHz, MeOD) δ 7.03 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 2.81 (t, J = 7.6 Hz, 2H), 2.54 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, MeOD) δ 177.0, 156.7, 132.9, 130.2, 116.2, 37.1, 31.2.
99%	With hydrogen In ethyl acetate at 20℃;	1 Example 1: l-Oxo-l-[5-(2-pyridyl)oxazol-2-yl]-3-(4-(benzyloxy)phenyl)propane(Ha). 3-(4-(Benzyloxy)phenyl)propanoic acid. 4-Hydroxycinnamic acid (700 mg, 4.26 mmol) was dissolved in EtOAc (15 niL) and 10% Pd/C (51 mg, 0.479 mmol) was added. The reaction mixture was stirred under an atmosphere of H2 overnight at room temperature before it was filtered through diatomaceous earth and concentrated in vacuo. No further purification was needed to yield 3-(4- hydroxyphenyl)propanoic acid (700 mg, 99%).
93%	With sodium hydroxide; sodium-lead alloy In water at 20℃; for 3h;
93%	With 10% Pd/C; cyclohexa-1,4-diene In ethyl acetate at 100℃; for 0.0833333h; Microwave irradiation;
90%	With ferrous ammonium sulphate hexahydrate; isopropyl β-D-thiogalactopyranoside In aq. phosphate buffer at 37℃; for 48h;
	With sodium amalgam; water
	With tetrahydrofuran; platinum Hydrogenation;
	With 1,4-dioxane; palladium Hydrogenation;
	With hydrogen In methanol for 0.5h; Ambient temperature;
	With hydrogen for 3h;
	With hydrogen In ethyl acetate at 20℃; for 2h;

Reference： [1]Krawczyk, Andrzej R.; Lipkowska, Ewa; Wrobel, Jerzy T. [Bulletin of the Polish Academy of Sciences: Chemistry, 1986, vol. 34, # 3-4, p. 115 - 122]
[2]Nagano, Hideharu; Kato, Eisuke; Yamamura, Shosuke; Ueda, Minoru [Organic and biomolecular chemistry, 2003, vol. 1, # 18, p. 3186 - 3192]
[3]Hardouin, Christophe; Kelso, Michael J.; Romero, F. Anthony; Rayl, Thomas J.; Leung, Donmienne; Hwang, Inkyu; Cravatt, Benjamin F.; Boger, Dale L. [Journal of Medicinal Chemistry, 2007, vol. 50, # 14, p. 3359 - 3368]
[4]Colín-Lozano, Blanca; Estrada-Soto, Samuel; Chávez-Silva, Fabiola; Gutiérrez-Hernández, Abraham; Cerón-Romero, Litzia; Giacoman-Martínez, Abraham; Almanza-Pérez, Julio Cesar; Hernández-Núñez, Emanuel; Wang, Zhilong; Xie, Xin; Cappiello, Mario; Balestri, Francesco; Mura, Umberto; Navarrete-Vazquez, Gabriel [Molecules, 2018, vol. 23, # 2]
[5]Peng, Chang; Liu, Yuxue; Guo, Xiaojia; Liu, Wujun; Li, Qing; Zhao, Zongbao K. [Tetrahedron Letters, 2018, vol. 59, # 42, p. 3810 - 3815]
[6]Current Patent Assignee: SCRIPPS RESEARCH - WO2008/147553, 2008, A1 Location in patent: Page/Page column 25
[7]Galve, Roger; Nichkova, Mikaela; Camps, Francisco; Sanchez-Baeza, Francisco; Marco, M.-Pilar [Analytical Chemistry, 2002, vol. 74, # 2, p. 468 - 478]
[8]Location in patent: scheme or table Quinn, John F.; Razzano, Dana A.; Golden, Kathryn C.; Gregg, Brian T. [Tetrahedron Letters, 2008, vol. 49, # 42, p. 6137 - 6140]
[9]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]
[10]Hlasiwetz [Justus Liebigs Annalen der Chemie, 1867, vol. 142, p. 358]
[11]Pearl [Journal of Organic Chemistry, 1959, vol. 24, p. 736,738]
[12]Schmir et al. [Journal of the American Chemical Society, 1959, vol. 81, p. 2228,2232]
[13]Lam, Thi Bach Tuyet; Iiyama, Kenji; Stone, Bruce A. [Phytochemistry, 1992, vol. 31, # 4, p. 1179 - 1184]
[14]Niwa, Toshio; Dpi, Umeyuki; Kato, Yoji; Osawa, Toshihiko [Journal of Agricultural and Food Chemistry, 2001, vol. 49, # 1, p. 177 - 182]
[15]Russell, Wendy R.; Scobbie, Lorraine; Chesson, Andrew [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 7, p. 2537 - 2546]

6
[ 2393-17-1 ]
[ 501-97-3 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1884,vol. 225,p. 75,80, 82
[2]Journal of Biological Chemistry,1922,vol. 50,p. 245

7
[ 501-97-3 ]
[ 38196-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	With nitric acid; acetic acid; at 15.0℃; for 1.5h;	A mixture of 60% HNO3 (9.83 mL, 0.144 mmol) and acetic acid (20 mL) was added drop-wise into a solution of 3-(4-hydroxyphenyl)propanoic acid (1) (20.0 g, 0.120 mmol) in acetic acid (150 mL) at 15 C over 1.0 h. The resulting mixture was stirred for 30 min, and then it was poured into cool 300 mL water. The water layer was extracted with 200 mL CH2Cl2. The organic layer was washed with brine and dried with anhydrous Na2SO4. The solvent was removed in vacuum to give a yellow solid 24.6 g. The crude yellow solid was dissolved in a mixture of MeOH (300 mL)/H2SO4 (30 mL), and the mixture was heated at reflux for 12 h. The reaction was cooled to room temperature, and the solvent was removed. The residue was poured into ice-water and then extracted with ether (300 mL). The ether layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed to give a solid residue, which was filtered through a short silica gel column eluting with petroleum ether/ethyl acetate (3:1) to give compound 2 (22.8 g, 84%) as a bright yellow solid;
	With nitric acid; In acetic acid; at 15.0℃; for 1.5h;	A mixture of 60% HNO3 (9.8mL, 0.2mmol) and acetic acid (20mL) was added drop-wise into a solution of 3-(4-hydroxyphenyl)propanoic acid 3 (20.0g, 0.1mmol) in acetic acid (150mL) at 15C over 1h. The resulting mixture was stirred for 30min, and then it was poured into 300mL cool water. The water layer was extracted with 200mL CH2Cl2. The organic layer was washed with brine and dried with anhydrous Na2SO4. The solvent was removed in vacuo to give a yellow solid 4 (24.6g). The crude yellow solid 4 was dissolved in a mixture of EtOH (300mL)/ H2SO4 (30mL), and the mixture was heated at reflux for 12h. The reaction was cooled to room temperature, the solvent was then removed, and the residue was poured into ice-water and then extracted with ether (300mL). The ether layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed to give a solid residue, which was filtered through a short silica column eluting with petroleum ether/ethyl acetate (3:1) to give compound 5 (22.5g, 83%) as a bright yellow solid.

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 1057 - 1061
Angew. Chem.,2014,vol. 126,p. 1075 - 1079
[2]Journal of the American Chemical Society,2014,vol. 136,p. 9572 - 9579
[3]Journal of the American Chemical Society,2014,vol. 136,p. 12600 - 12606
[4]Journal of Agricultural and Food Chemistry,2001,vol. 49,p. 1486 - 1492
[5]Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1900,vol. 131,p. 43
Annales de Chimie (Cachan, France),1902,vol. <7> 25,p. 507,537
[6]Journal of Heterocyclic Chemistry,1972,vol. 9,p. 681 - 682
[7]Chemistry - A European Journal,2006,vol. 12,p. 749 - 757
[8]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3639 - 3650
[9]European Journal of Medicinal Chemistry,2017,vol. 126,p. 7 - 14

8
[ 22767-72-2 ]
[ 501-97-3 ]

Reference： [1]Journal of the American Chemical Society,1941,vol. 63,p. 3052,3055

9
[ 501-97-3 ]
[ 100-39-0 ]
[ 50463-48-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydroxide; water; tetra(n-butyl)ammonium hydrogensulfate In tetrahydrofuran at 20 - 80℃;
99%	With sodium carbonate In tetrahydrofuran; water at 20 - 80℃;	I 3-(4-benzyloxyphenyl)propionic acid (2)A solution of 3-(4-hydroxyphenyl)propionic acid (20.0 g, 0.12 mol) and benzyl bromide (21.5 mL, 0.18 mol) in 155 mL of THF is added, at ambient temperature to a 1N aqueous solution of soda (301 mL). The phase transfer catalyst, Bu4NHSO4 (155 mg, 0.45 mmol), is finally added. The reaction medium is stirred overnight before being heated for 1 h at 80° C. After cooling down, 150 mL of a 1N aqueous solution of HCl is added slowly. After extraction with CH2Cl2, the organic phases are dried over MgSO4, filtered and concentrated under vacuum. Purification is carried out on silica gel (CH2Cl2 up to CH2Cl2/MeOH 95:5) in order to produce compound 2 (30.4 g, 0.12 mol, 99%) in the form of a white solid. C16H16O3 M=256.3 g.mol-1 NMR 1H (400 MHz, CDCl3): δ=2.63 (t, J=7.7 Hz, 2H); 2.88 (t, J=7.7 Hz, 2H); 5.02 (s, 2H); 6.90 (d, J=8.6 Hz, 2H); 7.11 (d, J=8.6 Hz, 2H); 7.28-7.44 (m, 5H).NMR 13C (100 MHz, CDCl3): δ=29.9; 36.1; 70.2; 115.1; 127.7; 128.1; 128.8; 129.4; 132.7; 137.2; 157.5; 179.6.HRMS (ESI+): m/z calculated for C16H16O3Na 279.0997, found 279.0999.
98%	Stage #1: 4-hydroxyphenylpropionic acid; benzyl bromide With potassium carbonate In acetone Reflux; Stage #2: With sodium hydroxide In methanol; water Reflux;

77%	With sodium hydroxide In ethanol
72%	Stage #1: 4-hydroxyphenylpropionic acid With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; Further stages.;
72%	Stage #1: 4-hydroxyphenylpropionic acid With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃;	1 A solution of 3-(4- hydroxyphenyl)propanoic acid (700 mg, 4.21 mmol) in anhydrous DMF (16 tnL) at 0 °C was treated with a solution of 60% NaH (450 mg, 18.75 mmol) in DMF dropwise. The reaction mixture was stirred for 10 min before benzyl bromide (0.675 mL, 5.68 mmol) was added. The reaction mixture was stirred overnight at room temperature, quenched with aqueous 1 N HCl and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NH4Cl, saturated aqueous NaCl and dried over Na2SO4. Column chromatography (SiO2, 4 x 9 cm, 20-40% EtOAc-hexanes gradient) afforded 3-(4-(benzyloxy)phenyl)propanoic acid (780 mg, 72%) as a white solid: 1H NMR (CDCl3, 500 MHz) 7.44 (d, 2H, J= 7.4 Hz), 7.40 (t, 2H, J= 7.4 Hz), 7.35-7.32 (m, IH), 7.14 (d, 2H, J= 8.8 Hz), 6.92 (d, 2H, J= 8.4 Hz), 5.06 (s, 2H), 2.92 (t, 2H, J= 7.7 Hz), 2.66 (t, 2H, J= 7.7 Hz); 13C NMR (CDCl3, 125 MHz) 179.0, 157.3, 137.0, 132.5, 129.2, 128.5, 127.9, 127.4, 114.9, 70.0, 35.8, 29.7. (See: Xue, C-B.; He, X.; et al. J Med Chem. 2001, 44, 3351-3354) l
70%	Stage #1: 4-hydroxyphenylpropionic acid; benzyl bromide With sodium hydride In N,N-dimethyl-formamide Stage #2: With sodium hydroxide In methanol
	With sodium hydroxide
	With potassium hydroxide In ethanol; water Heating;
44g	With tetrabutylammomium bromide; potassium iodide; sodium hydroxide In ethanol; water at 50 - 70℃; for 3h;	Charged with a stirrer, a condenser and a thermometer, 3-(p-hydroxyphenyl)propionic acid in a reaction vessel equipped with 20g (120 mmol), potassium iodide 2g, 0.5g tetrabutyl ammonium bromide, and 400ml of ethanol was stirred at room temperature.It was added dropwise a 25% aqueous solution of sodium hydroxide, 12g slowly.After the addition, maintaining the reaction vessel at 50 , and 25g was added dropwise benzyl bromide (144 mmol) slowly.After the addition was completed, the reaction vessel also by heating to 70 by further reaction for 3 hours.After completion of the reaction, neutralized with 10% hydrochloric acid and subjected to extraction with ethyl acetate and dried over sodium sulfate, the solvent was concentrated to 44g of the compound synthesized as shown in equation (20).

Reference： [1]Peuchmaur, Marine; Saïdani, Nadia; Botté, Cyrille; Maréchal, Eric; Vial, Henri; Wong, Yung-Sing [Journal of Medicinal Chemistry, 2008, vol. 51, # 16, p. 4870 - 4873]
[2]Current Patent Assignee: JOSEPH FOURIER UNIVERSITY - US2010/298422, 2010, A1 Location in patent: Page/Page column 17
[3]Location in patent: scheme or table Jones, Raymond C.F.; Yau, Sze Chak; Iley, James N.; Smith, Janet E.; Dickson, James; Elsegood, Mark R.J.; McKee, Vickie; Coles, Simon J. [Organic Letters, 2009, vol. 11, # 7, p. 1519 - 1522]
[4]Wasikiewicz; Rokicki; Kielkiewicz; Paulus; Boehmer [Monatshefte fur Chemie, 1997, vol. 128, # 8-9, p. 863 - 879]
[5]Hardouin, Christophe; Kelso, Michael J.; Romero, F. Anthony; Rayl, Thomas J.; Leung, Donmienne; Hwang, Inkyu; Cravatt, Benjamin F.; Boger, Dale L. [Journal of Medicinal Chemistry, 2007, vol. 50, # 14, p. 3359 - 3368]
[6]Current Patent Assignee: SCRIPPS RESEARCH - WO2008/147553, 2008, A1 Location in patent: Page/Page column 25
[7]Chu, Lin; Hutchins, Jennifer E.; Weber, Ann E.; Lo, Jane-Ling; Yang, Yi-Tien; Cheng, Kang; Smith, Roy G.; Fisher, Michael H.; Wyvratt, Matthew J.; Goulet, Mark T. [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 509 - 513]
[8]Doherty [Journal of the American Chemical Society, 1955, vol. 77, p. 4887,4891]
[9]Neubert, M. E.; Leung, K.; Jirousek, M. R.; Ezenylimba, M. C.; Sabol-Keast, S.; et al. [Molecular Crystals and Liquid Crystals (1969-1991), 1991, vol. 197, p. 21 - 41]
[10]Current Patent Assignee: DIC CORP. - KR101523330, 2015, B1 Location in patent: Paragraph 0185; 0186

10
[ 501-97-3 ]
[ 74-88-4 ]
[ 15823-04-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate In N,N-dimethyl-formamide	67.1 (1) (1) Ethyl (S)-3-(4-aminophenyl)-2-[3-(4-methoxyphenyl)propionylamino]propionate 3-(4-Hydroxyphenyl)propionic acid (1.36 g, 8.18 mmol) and methyl iodide (1.20 ml, 19.3 mmol) were dissolved in N,N-dimethylformamide (20 ml) and potassium carbonate (3.40 g, 24.6 mmol) was added. The mixture was stirred at 50°-60° C. for 4 hours and at room temperature for 14 hours. The reaction mixture was filtrated and the filtrate was added to saturated brine (1 00 ml) and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give 1.35 g of methyl 3-(4-methoxyphenyl)propionate as a colorless solid (85%).
	With methanol; sodium hydroxide at 120℃; im Druckrohr;
	With potassium carbonate Inert atmosphere;

12 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	1 Step 1: Synthesis of 3-(4-Methoxy-phenyl)-propionic acid methyl ester (2) Step 1: Synthesis of 3-(4-Methoxy-phenyl)-propionic acid methyl ester (2)To a suspension of 1 (10.0 g, 60 mmol) and K2003 (21.0 g, 150 mmol) in DMF was added CH3I (26 g, 180 mmol ). The mixture was stirred at rt for overnight. EA (500 m) was added. The mixture was washed with water (150 ml x 2) and brine (100 ml). The organic layer was dried over Na2504, filtered and concentrated to afford 2 as a light yellow oil (12.0 g).
12 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	1 Step 1 : Synthesis of 3-(4-Methoxy-phenyl)-propionic acid methyl ester (2) Step 1 : Synthesis of 3-(4-Methoxy-phenyl)-propionic acid methyl ester (2) To a suspension of 1 (10.0 g, 60 mmol) and K2CO3 (21 .0 g, 150 mmol) in DMF was added CH3I (26 g, 180 mmol ). The mixture was stirred at rt for overnight. EA (500 m) was added. The mixture was washed with water (150 ml x 2) and brine (100 ml). The organic layer was dried over Na2SO4, filtered and concentrated to afford 2 as a light yellow oil (12.0 g).

Reference： [1]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - US5635527, 1997, A
[2]Eigel [Chemische Berichte, 1887, vol. 20, p. 2537] Koerner; Corbetta [Chemische Berichte, 1874, vol. 7, p. 1736][Gazzetta Chimica Italiana, 1875, vol. 5, p. 6] Bougault [Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1900, vol. 131, p. 43][Annales de Chimie (Cachan, France), 1902, vol. <7> 25, p. 507,537]
[3]Ugele, Markus; Maier, Martin E. [Tetrahedron, 2010, vol. 66, # 14, p. 2633 - 2641]
[4]Current Patent Assignee: SANOFI - WO2014/154727, 2014, A1 Location in patent: Page/Page column 92
[5]Current Patent Assignee: SANOFI - WO2014/154726, 2014, A1 Location in patent: Page/Page column 100

11
[ 71-23-8 ]
[ 501-97-3 ]
[ 83281-52-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With chloro-trimethyl-silane at 25℃; for 24h;	SI 4. General procedure for the preparation of esters 1a-d General procedure: To a suspension of 3(4-hydroxyphenyl)propanoic acid 1 (0.05 mmol) in TMCS (0.1 mmol), the appropriate alcohol (1.0 mL) was added and the reaction mixture was stirred at 25°C. After 24 h, the reaction was stopped and evaporated under reduced pressure to afford 1a-d in quantitative yield without the need of purification: 3-(4-Hydroxyphenyl)propionic acid propyl ester(1c) Oil; 1H NMR (400 MHz, CDCl3): δH (ppm) = 1.4-1.5 (5H, m, CH2+CH3), 2.59 (2H, m, CH2), 2.89 (2H, m, CH2), 5.0-5.5 (2H, m, OCH2), 7.02 (2H, m, Ph-H), 7.28 (2H, m, Ph-H); 13C NMR (50 MHz,CDCl3): δC (ppm) = 20.10 (CH3), 30.0 (CH2), 38.10 (2 CH2), 68.15 (CH2), 118.11 (2 CH), 129.31 (2 CH), 132.08 (C), 154.28 (C), 172.15 (CO); MS (EI): m/z 280; Elemental analysis: calcd C, 69.21; H, 7.74; O, 23.05, found C, 69.23; H, 7.74; O, 23.0.
	With 3 A molecular sieve; sulfuric acid for 72h; Heating;
	With hydrogenchloride Heating;

With chloro-trimethyl-silane at 25℃; for 24h;

4.6 General procedure for the preparation of esters 2a-l General procedure: To a suspension of acidic phenols 1a-d (0.05mmol) in TMCS (0.1mmol), the alcohol (1.0mL) was added and the reaction mixture was stirred at 25°C. After 24h, the reaction was stopped and evaporated under reduced pressure to afford 2a-l in quantitative yield without the need of purification:

Reference： [1]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]
[2]Erhardt, Paul W.; Woo, Chi M.; Anderson, William G.; Gorczynski, Richard J. [Journal of Medicinal Chemistry, 1982, vol. 25, # 12, p. 1408 - 1412]
[3]Stout, David M.; Black, Lawrence A.; Barcelon-Yang, Cynthia; Matier, W. L.; Brown, Barry S.; et al. [Journal of Medicinal Chemistry, 1989, vol. 32, # 8, p. 1910 - 1913]
[4]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]

12
[ 51-67-2 ]
[ 501-97-3 ]
[ 118798-93-9 ]

Yield	Reaction Conditions	Operation in experiment
48%	With dicyclohexyl-carbodiimide In chloroform for 6h; Ambient temperature;
23%	Stage #1: 4-hydroxyphenylpropionic acid With thionyl chloride In cyclohexane for 1.5h; Heating / reflux; Stage #2: tyrosamine With triethylamine In dichloromethane at 20℃; for 2h;	1 0.22g 1. 3mM, 4-hydroxy hydrocinnamic acid and 2 ml thionyl chloride in 30 ml cyclohexane were refluxed for 1.5 hours. Evaporation gave light yellow solid to which were added 0.2g 1.5 mM, tyramine, 30 ml dichloromethane and 0.3 ml triethyl amine. After stirring for 2 hours at room temperature, water and KOH were added to neutral pH and the reaction was extracted with dichloromethane. Evaporation gave a viscous oil which was recrystallized with ethanol to give 85 mg white solid, 23%. NMR acetone d6 7. 36 (4H, ABq, J=8. 8 Hz), 7.20 (4H, Abq, J=8.6 Hz), 3.48 (2H, q, J=7.1 Hz), 3.05 (2H, t, J=7.1 Hz), 2.88 (2H, t, J=7.1 Hz), 2.52 (2H, t, J=7.1 Hz).
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide for 20h;

	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane; N,N-dimethyl-formamide at 4 - 20℃; for 20.5h;	16 N-dihydrocoumaroyltyramine A solution of 3-(4-hydroxyphenyl)propionic acid or p-dihydrocoumaric acid (1 g; 6.02 mmol) and of triethylamine (1.5 eq; 9.03 mmol) in DMF (10 mL) is cooled to 4° C. using an ice bath. An amine, tyramine (1 eq; 6.02 mmol) is added to the medium, followed by addition of a solution of BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1 eq; 6.02 mmol) in dichloromethane (10 mL); the mixture is stirred for about thirty minutes in the ice bath and then for 20 hours at room temperature. Stirring is then stopped and the dichloromethane is evaporated off under vacuum. 100 mL of water are added to the remaining solution and the mixture obtained is extracted with ethyl acetate (3*75 mL). The organic phase is successively washed with 100 mL of 1N HCl solution, 100 mL of water and 100 mL of 1M sodium bicarbonate (NaHCO3) solution. It is then dried over sodium sulfate and evaporated to dryness. The product is obtained in the form of a white precipitate after purification by chromatography on a column of silica gel.
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; trimethylamine In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;	5 General procedure for cinnamic acid amides (1-1d) General procedure: BOP (Castro's reagent [29], 0.25 mmol) was added to a mixture solution of acid (0.20 mmol) and amine (0.20 mmol) in dry DMF (20 ml) under a nitrogen atmosphere at room temperature. To this mixture, trimethylamine (0.40 mmol) was added drop wise with vigorous stirring. The stirring was continued for 12 h. The reaction mixture was quenched with water (100 ml) and then extracted with ethylacetate (3 50 ml). Organic layer was wished with brine and dried over anhydrous Na2SO4. The solvent was evaporated and residue was subjected to silica gel chromatography using CHCl3/CH3OH (10:1) as eluent to give corresponding amides (1-1d) as 30-80% yield.

Reference： [1]Herbert, Richard B.; Kattah, Abdullah E. [Tetrahedron, 1990, vol. 46, # 20, p. 7105 - 7118]
[2]Current Patent Assignee: NOVAREMED AG - WO2005/92305, 2005, A2 Location in patent: Page/Page column 25
[3]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]
[4]Current Patent Assignee: BASF SE; JOSEPH FOURIER UNIVERSITY - US2007/183996, 2007, A1 Location in patent: Page/Page column 8
[5]Song, Yeong Hun; Kim, Dae Wook; Curtis-Long, Marcus J.; Park, Chanin; Son, Minky; Kim, Jeong Yoon; Yuk, Heung Joo; Lee, Keun Woo; Park, Ki Hun [European Journal of Medicinal Chemistry, 2016, vol. 114, p. 201 - 208]

13
[ 60-82-2 ]
[ 10210-17-0 ]
[ 501-97-3 ]
[ 108-46-3 ]

Reference： [1]Agricultural and Biological Chemistry,1989,vol. 53,p. 3087 - 3090

14
[ 7400-08-0 ]
[ 501-97-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 5% Pd(II)/C(eggshell); hydrogen In methanol; water for 3h;
99%	Stage #1: para-coumaric acid With palladium diacetate; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In ethyl acetate at 25℃; for 12h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride In water	4 Replace the gas environment in the Shrek tube with a nitrogen environment, add 4-hydroxycinnamic acid 0.25 mmol, palladium acetate 0.0025 mmol, ethyl acetate 0.5 mL, add pinacol borane 0.275 mmol under stirring, and react at room temperature for 12 h. After the completion of the reaction, the reaction liquid obtained was diluted with 10 mL of ethyl acetate, 10 mL of saturated sodium bicarbonate was added, extracted three times with ethyl acetate, the pH value of the aqueous phase was adjusted to acidic with concentrated hydrochloric acid, and then extracted with ethyl acetate, and the organic phase was vacuumed Concentrate below to obtain the target product in a yield of> 99% as a white solid.
99%	With palladium diacetate; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In ethyl acetate at 25℃; for 12h; Sealed tube; Inert atmosphere; chemoselective reaction;

96%	With hydrazine hydrate In ethanol for 5.5h; Reflux;
71.1%	With tetralin for 2h; Heating;
	Multi-step reaction with 3 steps 1: potassium carbonate, potassium iodide / acetonitrile / 1 h / Heating 2: 86 percent / hydrogen / 10percent palladium on carbon / ethanol / 3 h / 760 Torr 3: 98 percent / hydrogen / 10percent palladium on carbon / ethanol / 15 h / 3040 Torr
	Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / 2 h / Reflux 2: sodium tetrahydroborate; copper(l) chloride / methanol / 0.5 h / 0 °C 3: water / Alkaline conditions
	With formic acid; Pd/C; triethylamine In ethanol at 30℃; for 1.5h;

Reference： [1]Fumeaux, Rene; Menozzi-Smarrito, Candice; Stalmach, Angelique; Munari, Caroline; Kraehenbuehl, Karin; Steiling, Heike; Crozier, Alan; Williamson, Gary; Barron, Denis [Organic and Biomolecular Chemistry, 2010, vol. 8, # 22, p. 5199 - 5211]
[2]Current Patent Assignee: ZHENGZHOU UNIVERSITY - CN111099986, 2020, A Location in patent: Paragraph 0034; 0057-0060
[3]Wang, Yong; Cao, Xinyi; Zhao, Leyao; Pi, Chao; Ji, Jingfei; Cui, Xiuling; Wu, Yangjie [Advanced Synthesis and Catalysis, 2020, vol. 362, # 19, p. 4119 - 4129]
[4]Chen, Hao; Wang, Jianmin; Hong, Xuechuan; Zhou, Hai-Bing; Dong, Chune [Canadian Journal of Chemistry, 2012, vol. 90, # 9, p. 758 - 761]
[5]Neubert, M. E.; Leung, K.; Jirousek, M. R.; Ezenylimba, M. C.; Sabol-Keast, S.; et al. [Molecular Crystals and Liquid Crystals (1969-1991), 1991, vol. 197, p. 21 - 41]
[6]Davis, Roman; Muchowski, Joseph M. [Synthesis, 1982, # 11, p. 987 - 988]
[7]Takahashi; Miyazawa, Mitsuo [Pharmazie, 2010, vol. 65, # 12, p. 913 - 918]
[8]Yakukhnov, Sergey A.; Pentsak, Evgeniy O.; Galkin, Konstantin I.; Mironenko, Roman M.; Drozdov, Vladimir A.; Likholobov, Vladimir A.; Ananikov, Valentine P. [ChemCatChem, 2018, vol. 10, # 8, p. 1869 - 1873]

16
[ 501-97-3 ]
[ 100-39-0 ]
[ 58608-97-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium hydride In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide for 15h; Heating;
97%	Stage #1: 4-hydroxyphenylpropionic acid With potassium carbonate In N,N-dimethyl-formamide at 20℃; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 80℃;
91%	With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; for 4h;	Benzyl 3-[4-(benzyloxy)phenyl]propanoate (15b) Commercial molecule 15a6 (2.0 g, 12.04 mmol, 1.0 equivalent) and K2CO3 (6.6 g, 47.78 mmol, 3.97 equivalents) were dissolved in N,N-dimethylformamide (DMF, 11.7 mL, 1.03 M) in a 250 mL round-bottom flask with a magnetic stir bar at room temperature (RT). CAUTION (caustic smell hazard): Benzyl bromide (9.4 mL, 78.47 mmol, 6.52 equivalents) was then added dropwise at RT. The flask was then warmed to 80 °C and heated for 4.0 hours. Once complete (TLC), the mixture was cooled to RT and quenched with H2O (20 mL). The vessel was then cooled to 0 °C in an ice bath, and the mixture was gradually brought to pH <4.0 by slow addition of 1N HCl. At this point, the suspension was transferred to a separatory funnel, where the layers were mixed and separated. The aqueous layer was then extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4, concentrated, and purified by column chromatography (8% EtOAc/hexanes). This procedure yielded 3.82 g (91%) of the ester product as a light-yellow oil. Data are: TLC Rf = 0.40 (10% EtOAc/hexanes); 1H NMR (CDCl3, 500 MHz) δ 7.37-7.34 (m, 10H), 7.14 (d, J=5Hz, 2H), 6.93 (d, J=5Hz, 2H), 5.15 (s, 2H), 5.07 (s, 2H), 2.96 (t, J=10Hz, 2H), 2.69 (t, J=10 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 172.8, 157.4, 137.2, 136.0, 132.8, 129.3, 128.6, 128.5, 128.3, 128.2, 127.9, 127.5, 114.9, 70.1, 66.3, 36.2, 30.2; GCMS found 346 [M]+, calcd 346.16 for [C23H22O3].

	With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium hydride 1.) THF, 3 h; 2.) THF, reflux, 15 h; Yield given. Multistep reaction;
	With potassium carbonate In acetone for 18h; Heating;
	With potassium carbonate In acetonitrile Reflux;	2.a Synthesis of:2-((4-(3-(Cyclopropylmethoxy)propyl)phenoxy)methyloxirane (2.6). Reagents and conditions: (a) Benzyl Bromide, K2C03, CH3CN reflux; (b) AILiH4 THF 0°C or LiBH4 THF 50°C; (c) Cyclopropylmethyl Bromide, tBuOK, DMA 0°C; (d) Pd/C EtOH RT; (e) NaOH, epichlorohydrin (7eq.), MW100°C or Dry DMF, 0°C, NaH, (S) or (R) glycidyl-3-nitrobenzenesulfonate
	With potassium carbonate In N,N-dimethyl-formamide at 80℃;

Reference： [1]Guedin-Vuong, D.; Nakatani, Y.; Luu, B.; Ourisson, G. [Tetrahedron Letters, 1985, vol. 26, # 48, p. 5959 - 5962]
[2]Location in patent: experimental part Rogano, Frank; Rueedi, Peter [Helvetica Chimica Acta, 2010, vol. 93, # 7, p. 1281 - 1298]
[3]Mangum, Cathy L.; Munford, Mica B.; Sam, Alyssa B.; Young, Sandra K.; Beales, Jeremy T.; Subedi, Yagya Prasad; Mangum, Chad D.; Allen, Tanner J.; Liddell, Miranda S.; Merrell, Andrew I.; Saavedra, Diana I.; Williams, Becky L.; Evans, Nicole; Beales, Joseph L.; Christiansen, Michael A. [Tetrahedron Letters, 2020, vol. 61, # 1]
[4]Guedin-Vuong, Denis; Nakatani, Yoichi [Bulletin de la Societe Chimique de France, 1986, # 2, p. 245 - 252]
[5]Vara Prasad; Boyer, Frederick E.; Domagala, John M.; Ellsworth, Edmund L.; Gajda, Christopher; Hamilton, Harriet W.; Hagen, Susan E.; Markoski, Larry J.; Steinbaugh, Bruce A.; Tait, Bradley D.; Humblet, Christine; Lunney, Elizabeth A.; Pavlovsky, Alexander; Rubin, John R.; Ferguson, Donna; Graham, Neil; Holler, Tod; Hupe, Donald; Nouhan, Carolyn; Tummino, Peter J.; Urumov; Zeikus, Eric; Zeikus, Greg; Gracheck, Stephen J.; Saunders, James M.; Vanderroest, Steven; Brodfuehrer, Joanne; Iyer; Sinz; Gulnik, Sergei V.; Erickson, John W. [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 12, p. 2775 - 2800]
[6]Current Patent Assignee: UNIVERSITY OF NOTTINGHAM - WO2012/104659, 2012, A1 Location in patent: Page/Page column 30
[7]Pandey, Ganesh; Laha, Ramkrishna; Mondal, Pradip Kumar [Chemical Communications, 2019, vol. 55, # 65, p. 9689 - 9692]

17
[ 501-97-3 ]
[ 23735-43-5 ]
[ 144256-11-1 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1992,vol. 40,p. 1462 - 1469

18
[ 501-97-3 ]
[ 75-65-0 ]
[ 51458-31-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	With N,N-dimethylformamide dineopentyl acetal In toluene Heating;
69%	With N,N-dimethylformamide dineopentyl acetal In toluene Reflux;
65%	Stage #1: 4-hydroxyphenylpropionic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 40℃; for 48h; Stage #2: <i>tert</i>-butyl alcohol With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 65℃; for 2h; Further stages.;

60%	Stage #1: 4-hydroxyphenylpropionic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 40℃; for 2h; Inert atmosphere; Stage #2: <i>tert</i>-butyl alcohol With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran for 48h; Inert atmosphere; Reflux;	Synthesis of tert-Butyl 3-(4-Hydroxyphenyl)propanoate To a solution of 3-(4-hydroxyphenyl)propanoic acid (8 g, 48.14 mmol, 1 eq) in absolute tetrahydrofuran(100 ml) under inert gas atmosphere was added 1,1'-carbonyldiimidazole (10.15 g, 62.59 mmol, 1.3 eq),and the reaction mixture was stirred at 40 °C. After 2 h, dry tert-butanol (10.70 g, 144.42 mmol, 3 eq) anddry DBU (14.67 g, 96.34 mmol, 2 eq) were added. The reaction mixture stirred under inert gas atmosphereand reflux conditions for 48 h. Then, it was cooled to room temperature and the volatiles were removedunder reduced pressure. The residue was dissolved in chloroform (100 ml) and washed with sodiumbicarbonate solution (0.5 M, 100 ml x 1). The organic fraction was dried over sodium sulfate, filtered,concentrated under reduced pressure and isolated by flash column chromatography (ethyl acetate- hexane,1:3) to give ester product 7 as a clear colorless oil (yield: 6.42 g, 28.88 mmol, 60%).
	With 2-tert-butyl-1,3-diisopropylisourea Ambient temperature;
	With N,N-dimethylformamide dineopentyl acetal In toluene for 5h; Heating;
	Stage #1: 4-hydroxyphenylpropionic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 40℃; for 2h; Stage #2: <i>tert</i>-butyl alcohol With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 65℃; for 48h;	AK.1 3-(4-Methoxycarbonylmethoxy-phenyl)-propionic acid To a solution of 3-(4-hydroxyphenyl)propanoic acid (3.32 g, 20 mmol) in dry DMF (20 ml) is carefully added 1,1'-carbonyldiimidazole (3.24 g, 20 mmol) portionwise. The reaction mixture is stirred at 40° C. for 2 hours after which time DBU (6.02 ml, 40 mmol) and tert-butanol (4.78 ml, 50 mmol) are added and the reaction mixture is now stirred at 65° C. for 2 days. The reaction mixture is allowed to cool to room temperature and poured into water (50 ml) and the product is extracted with diethyl ether (3*30 ml). The organics are combined, dried (MgSO4) and the solvent removed in vacuo to give a yellow oil. Purification by flash chromatography (SiO2, EtOAc/iso-hexane) yields 3-(4-Hydroxy-phenyl)-propionic acid tert-butyl ester as a colorless oil. 1H NMR (DMSO-d6) 9.1 (1H, s), 7.0 (2H, d, J=8.45), 6.65 (2H, d, J=8.45), 2.7 (2H, t, J=7.28), 2.4 (2H, t, J=7.28), 1.4 (9H, s).
	Stage #1: 4-hydroxyphenylpropionic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 40℃; for 2h; Stage #2: <i>tert</i>-butyl alcohol With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 65℃; for 48h;	15 Synthesis of 3-(4-Hydroxyphenyl)-propionic acid t-butyl ester (24): To a solution of 3-(4-Hydroxyphenyl)-propionic acid in dimethylformamide was carefully added carbonyl diimidazole. The reaction mixture was stirred at 40° C. for 2 hours. DBU and t-butanol were then added and the reaction mixture was stirred at 65° C. for 2 days after which time TLC indicated that the starting material had been consumed. The reaction mixture was cooled to room temperature, water (40 mL) added and the product extracted with MTBE. The organic fraction was dried, concentrated under reduced pressure and the product isolated by flash column chromatography to give the product as a colorless oil.

Reference： [1]Meier, Chris; Ruppel, Manuel F. H.; Vukadinovic, Dalibor; Balzarini, Jan [Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 89 - 115]
[2]Location in patent: body text Jessen, Henning J.; Balzarini, Jan; Meier, Chris [Journal of Medicinal Chemistry, 2008, vol. 51, # 20, p. 6592 - 6598]
[3]Clough, John M.; Jones, Ray V.H.; McCann, Hannah; Morris, David J.; Wills, Martin [Organic and Biomolecular Chemistry, 2003, vol. 1, # 9, p. 1486 - 1497]
[4]Makarem, Ata; Konrad, Moritz; Liolios, Christos; Kopka, Klaus [Synlett, 2018, vol. 29, # 9, p. 1239 - 1243]
[5]Hagmann; Kissinger; Shah; Finke; Dorn; Brause; Ashe; Weston; Maycock; Knight; Dellea; Fletcher; Hand; Osinga; Davies; Doherty [Journal of Medicinal Chemistry, 1993, vol. 36, # 6, p. 771 - 777]
[6]Meier, Chris; Ducho, Christian; Jessen, Henning; Vukadinovic-Tenter, Dalibor; Balzarini, Jan [European Journal of Organic Chemistry, 2006, # 1, p. 197 - 206]
[7]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2015/231142, 2015, A1 Location in patent: Paragraph 2556
[8]Current Patent Assignee: TERUMO CORPORATION - US2018/85487, 2018, A1 Location in patent: Paragraph 0168-0169

19
[ 501-97-3 ]
[ 74-88-4 ]
[ 5597-50-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium hydrogencarbonate In N,N-dimethyl-formamide at 40℃;
95.9%	Stage #1: 4-hydroxyphenylpropionic acid With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 0 - 20℃; for 3h;	1 Intermediate 2: Methyl 3-(4-hydroxyphenyl) propanoateTo a 1000 mL RB flask fitted with magnetic stirrer was charged 250 mL of DMF, 3-(4- Hydroxy-phenyl)-propanoic acid (25.0 g, 150.43 mmol) and K2C03 (41.58 g, 300.87 mmol). The resulting mixture was stirred at RT for 30 minutes. Methyl Iodide (25.627 g, 180.51 mmol) was added to the resulting mixture which was precooled to 0 ¾. The resulting mixture was stirred at RT for 3 h. After completion of the reaction (reaction monitored by TLC), the solvent was removed under reduced pressure and the crude mass was dissolved in ethyl acetate (250 mL). The organic layer was washed with water (250 mL), saturated sodium bicarbonate solution (250 mL X 2), and saturated brine solution (250 mL). The organic layer was dried over anhydrous Na2S04 and the solvent was removed under reduced pressure. The product was obtained as yellow color oil (26 g, Yield: 95.9 %): MS (ESI, 120 eV) : m/z = 178.9 (M- H)+; 1H NMR (300MHz, CDCI3): δ 6.97-7.00(d, 2H), 6.66-6.69(d, 2H), 4.94(s, 1 H), 3.59(s, 3H), 2.78-2.83(t, 2H), 2.50-2.55(t, 2H).
	With potassium hydroxide In dimethyl sulfoxide at 40℃;

Reference： [1]Guo, Wei; Li, Junfei; Fan, Ningjuan; Wu, Weiwei; Zhou, Peiwen; Xia, Chizhong [Synthetic Communications, 2005, vol. 35, # 1, p. 145 - 152]
[2]Current Patent Assignee: CONNEXIOS LIFE SCIENCES PVT - WO2012/11125, 2012, A1 Location in patent: Page/Page column 59; 60
[3]Iguchi; Iwamura; Nishizaki; Hayashi; Senokuchi; Kobayashi; Sakaki; Hachiya; Ichioka; Kawamura [Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 6, p. 1462 - 1469]

20
[ 501-97-3 ]
[ 108-24-7 ]
[ 7249-16-3 ]

Yield	Reaction Conditions	Operation in experiment
97.1%	With sodium hydroxide In water at 0 - 20℃;
96%	Stage #1: 4-hydroxyphenylpropionic acid; acetic anhydride With potassium hydroxide In water for 16h; Stage #2: With hydrogenchloride In water
96%	With sodium hydroxide In water at -5 - 20℃; for 14h;	1.1; 2.1 (1) Preparation of p-acetoxyphenylpropionic acid In a 5L reactor, 100.8 g (2.52 mol) of sodium hydroxide was added, 320 mL of water was stirred to dissolve, and 166 g (1 mol) of p-hydroxyphenylpropionic acid was added and stirred to dissolve. 214.4g of acetic anhydride (2.1mol) was added dropwise under ice bath (-5-0°C). During the addition, the solution became a milky white suspension, and the solution was stirred at room temperature for 14h. The pH of the solution was adjusted to 4.3 with hydrochloric acid, extracted with ethyl acetate, washed with water, and dried to obtain 203.5 g of crude p-acetoxyphenylpropionic acid.Add the above crude p-acetoxyphenylpropionic acid to 150mL toluene to dissolve, connect to a water separator, azeotropically distill for 2h, distill 115mL of toluene to recover, and dry to obtain 199.7g p-acetoxyphenylpropionic acid with a yield of 96.0%

80%	With sodium hydroxide In water at 0℃;
80%	Stage #1: 4-hydroxyphenylpropionic acid With sodium hydroxide for 0.5h; Stage #2: acetic anhydride at 0 - 20℃; for 17h; Further stages.;
67%	With dmap In pyridine at 20℃; for 5h;
40%	With pyridine
	With sodium hydroxide Yield given;
	With pyridine
	With sodium hydroxide In water for 0.333333h;
	With pyridine
	With pyridine; dmap at 20℃;
59.2 g	With sodium hydroxide In water at 20℃; for 1h;	1.1 1. Synthesis of p-acetoxyphenylpropionic acid 50g of p-hydroxyphenylpropionic acid, add 150ml of acetonitrile and stir until it is completely dissolved, 22.5g of sodium hydroxide is dissolved in 150ml of water, added to the reaction solution, 46.5g of acetic anhydride is added dropwise to the reaction solution, the addition is complete, stirring at room temperature for 1h, TLC monitors the completion of the reaction, adds 6M hydrochloric acid acidified solution pH=1 to the reaction solution, adds 150ml ethyl acetate to extract the layers, wash the organic phase with water until neutral, and concentrate the organic phase to dryness to obtain 59.2g white solid product.

Reference： [1]Ohkata, Katsuo; Tamura, Yukiko; Shetuni, Brandon B.; Takagi, Ryukichi; Miyanaga, Wataru; Kojima, Satoshi; Paquette, Leo A. [Journal of the American Chemical Society, 2004, vol. 126, # 51, p. 16783 - 16792]
[2]Location in patent: scheme or table Parker, Gregory D.; Seden, Peter T.; Willis, Christine L. [Tetrahedron Letters, 2009, vol. 50, # 26, p. 3686 - 3689]
[3]Current Patent Assignee: SHANGHAI YIMING CHEMICAL TECH; ZHENGZHOU UNIVERSITY OF LIGHT INDUSTRY; GUANGZHOU HOPESN FINE CHEMICAL - CN112939803, 2021, A Location in patent: Paragraph 0045-0052; 0065-0069
[4]Adlington, Robert M.; Baldwin, Jack E.; Chen, Beining; Cooper, Stephen L.; McCoull, William; Pritchard, Gareth J.; Howe, Trevor J.; Becker, Gerald W.; Hermann, Robert B.; McNulty, Ann M.; Neubauer, Blake L. [Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 13, p. 1689 - 1694]
[5]Adlington; Baldwin; Becker; Chen; Cheng; Cooper; Hermann; Howe; McCoull; McNulty; Neubauer; Pritchard [Journal of Medicinal Chemistry, 2001, vol. 44, # 10, p. 1491 - 1508]
[6]Yang, Dan; Wong, Man-Kin; Yan, Zheng [Journal of Organic Chemistry, 2000, vol. 65, # 13, p. 4179 - 4184]
[7]Safi, Rmi; Rodriguez, Frderic; Hilal, Georges; Diab-Assaf, Mona; Diab, Youssef; El-Sabban, Marwan; Najjar, Fadia; Delfourne, Evelyne [Chemical Biology and Drug Design, 2016, vol. 87, # 3, p. 382 - 397]
[8]Braun, Norbert A.; Ciufolini, Marco A.; Peters, Karl; Peters, Eva-Maria [Tetrahedron Letters, 1998, vol. 39, # 26, p. 4667 - 4670]
[9]Lu, Fachuang; Ralph, John [Journal of Agricultural and Food Chemistry, 1999, vol. 47, # 5, p. 1988 - 1992]
[10]Braun, Norbert A.; Ousmer, Malika; Bray, Jonathan D.; Bouchu, Denis; Peters, Karl; Peters, Eva-Maria; Ciufolini, Marco A. [Journal of Organic Chemistry, 2000, vol. 65, # 14, p. 4397 - 4408]
[11]Gu, Xianfeng; Wang, Yuehao; Kumar, Anil; Ye, Guofeng; Parang, Keykavous; Sun, Gongqin [Journal of Medicinal Chemistry, 2006, vol. 49, # 25, p. 7532 - 7539]
[12]Kiviranta, Paeivi H.; Salo, Heikki S.; Leppaenen, Jukka; Rinne, Valtteri M.; Kyrylenko, Sergiy; Kuusisto, Erkki; Suuronen, Tiina; Salminen, Antero; Poso, Antti; Lahtela-Kakkonen, Maija; Wallen, Erik A.A. [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 17, p. 8054 - 8062]
[13]Current Patent Assignee: MELALYN - CN111978199, 2020, A Location in patent: Paragraph 0039-0042

21
[ 501-97-3 ]
[ 10210-17-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With borane-THF; Trimethyl borate In tetrahydrofuran at 0℃; for 4h; Inert atmosphere;	4-(3-hydroxypropyl)phenol(9a) 3-(4-Hydroxyphenyl)propionicacid (1.66 g, 10.0 mmol) was dissolved in dry THF (10 mL) under argonand trimethyl borate (3.35 mL, 30.0 mmol) was added. Separately,BH3.THFcomplex solution (20.0 mL, 20.0 mmol, 1.0 M solution in THF) wascooled to 0°C. The acid solution was added dropwise to theBH3.THFcomplex solution and the reaction mixture was stirred at 0°C for4 h. The reaction mixture was quenched with H2O(10 mL) and extracted with EtOAc (3 x 30 mL). The organic extractswere combined, dried over anhydrous MgSO4,filtered, and concentrated invacuoto obtain 4-(3-hydroxypropyl)phenol as a yellow oil (1.51 g, 9.9mmol, 99%) that was used without further purification. 1HNMR (500 MHz, CDCl3)δ 7.07-7.05 (d, J= 8.5 Hz,2H), 6.76-6.74 (d, J= 8.5 Hz,2H), 3.68-3.65 (t, J= 6.5 Hz,2H), 2.65-2.62 (t, J= 7.5 Hz,2H), 1.88-1.82 (p, J= 6.5 Hz,2H); 13CNMR: (125 MHz, CDCl3)δ 153.9, 133.8, 129.6, 115.3, 62.4, 34.4, 31.2.
98%	With sodium tetrahydroborate; Trimethyl borate; dimethyl sulfate In tetrahydrofuran at 20℃; for 1.5h;
98%	With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃;	4.1 Preparation of trans-4-{3-[ethyl-(4-phenylcyclohexyl)amino]propyl}phenol EXAMPLE 4 [0184] Preparation of trans-4-{3-[ethyl-(4-phenylcyclohexyl)amino]propyl}phenol [CHEMMOL-00016] [0185] Step 1: To an ice-cold, stirred solution of 3-(4-hydroxyphenyl)propionic acid 7 (5.43 g, 32.7 mmol) in anhydrous THF (60 mL) was added BH3SMe2 (3.6 mL of a 1 M solution in THF, 3.6 mmol). The reaction was allowed to warm to room temperature overnight and then quenched with MeOH (100 mL). Concentration under reduced pressure gave alcohol 12 (4.96 g, 98%) as a white solid: 1H NMR (500 MHz, CDCl3) ? 7.04 (d, J=8 Hz, 2H), 6.75 (d, J=8 Hz, 2H), 3.67 (m, 2), 2.63 (t, J=7 Hz, 2H), 1.86 (m, 2H).

91%	With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
88%	With lithium aluminium tetrahydride In tetrahydrofuran at 60℃; for 2h;
50.6%	With lithium aluminium tetrahydride In tetrahydrofuran for 6h; Heating;
	Multi-step reaction with 2 steps 1: H₂SO₄ / 1.5 h / Heating 2: 13.5 g / LiAlH₄ / tetrahydrofuran / 12 h / 55 °C
	Multi-step reaction with 3 steps 1: 97.1 percent / NaOH / H₂O / 0 - 20 °C 2: 100 percent / K₂CO₃ / dimethylformamide / 23 h / 20 °C 3: 95.5 percent / LiBH₄ / tetrahydrofuran / 22 h / 70 °C

Reference： [1]McLane, Richard D.; Le Cozannet-Laidin, Léon; Boyle, Maxwell S.; Lanzillotta, Lindsey; Taylor, Zachary L.; Anthony, Sarah R.; Tranter, Michael; Onorato, Amber J. [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 3, p. 334 - 338]
[2]Zhou, Yuhan; Gao, Guchao; Li, Hui; Qu, Jingping [Tetrahedron Letters, 2008, vol. 49, # 20, p. 3260 - 3263]
[3]Current Patent Assignee: PFIZER INC - US2003/225164, 2003, A1 Location in patent: Page 11-12
[4]Liang, Huan; Ciufolini, Marco A. [Chemistry - A European Journal, 2010, vol. 16, # 44, p. 13262 - 13270]
[5]Hori, Manabu; Janda, Kim D. [Journal of Organic Chemistry, 1998, vol. 63, # 3, p. 889 - 894]
[6]González, Antonio G.; Silva, Margarita Hernández; Padrón, Juan I.; León, Francisco; Reyes, Eduardo; Álvarez-Mon, Melchor; Pivel, Juan P.; Quintana, José; Estévez, Francisco; Bermejo, Jaime [Journal of Medicinal Chemistry, 2002, vol. 45, # 12, p. 2358 - 2361]
[7]Ghirmai, Senait; Mume, Eskender; Lundqvist, Hans; Tolmachev, Vladimir; Sjoeberg, Stefan [Journal of labelled compounds and radiopharmaceuticals, 2005, vol. 48, # 12, p. 855 - 871]
[8]Ohkata, Katsuo; Tamura, Yukiko; Shetuni, Brandon B.; Takagi, Ryukichi; Miyanaga, Wataru; Kojima, Satoshi; Paquette, Leo A. [Journal of the American Chemical Society, 2004, vol. 126, # 51, p. 16783 - 16792]

22
[ 501-97-3 ]
[ 56414-96-1 ]
3-(4-hydroxy-phenyl)-<i>N</i>-(2-morpholin-4-yl-2-oxo-ethyl)-propionamide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,1999,vol. 34,p. 1023 - 1034

23
[ 60-82-2 ]
[ 7722-84-1 ]
aqueous Na₂CO₃ [ No CAS ]
[ 501-97-3 ]

Reference： [1]Journal of the Chemical Society,1930,p. 767
Chemisches Zentralblatt,1929,vol. 100,p. 432

24
[ 60-82-2 ]
KOH-solution [ No CAS ]
[ 108-73-6 ]
[ 501-97-3 ]

Reference： [1]Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften,1855,p. 702

25
[ 501-97-3 ]
EtX [ No CAS ]
[ 23795-02-0 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 2540 - 2544

26
[ 60211-57-6 ]
[ 29022-11-5 ]
[ 501-97-3 ]
resin-bound phenol [ No CAS ]
{3-[4-(3,5-dichloro-benzyloxy)-phenyl]-propionylamino}-acetic acid [ No CAS ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 3763 - 3767

27
[ 29022-11-5 ]
[ 501-97-3 ]
[ 50438-75-0 ]
resin-bound phenol [ No CAS ]
(3-{4-[2-(4-dimethylamino-phenyl)-ethoxy]-phenyl}-propionylamino)-acetic acid [ No CAS ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 3763 - 3767

28
[ 501-97-3 ]
[ 100-39-0 ]
[ 31770-76-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium hydrogencarbonate In acetone for 18h; Reflux;
94%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;	83.a a) To a solution of 3-(4-hydroxyphenyl)propionic acid (1.49 g, 8.96 mmol) in dimethylformamide (21.5 mL) were added potassium carbonate (1.30 g, 9.41 mmol) and benzyl bromide (1.69 g, 9.86 mmol), and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with toluene and water to separate the phases. The residue obtained by concentrating the organic layer under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 5:1→3:1) to give 2.16 g of benzyl 3-(4-hydroxyphenyl)propionate as oil (yield: 94%).
91%	With potassium hydrogencarbonate In N,N-dimethyl-formamide at 40℃;

88%	With potassium carbonate In N,N-dimethyl-formamide for 15h;	4.1 Step 1: Benzyl 3-(4-hydroxyphenyl)propanoate Benzyl bromide (5.7 g, 33.09 mmol) was added to a suspension of 3-(4-hydroxyphenyl)propanoic acid (5.0 g, 30.08 mmol) and anhydrous potassium carbonate (8.31 g, 60.17 mmol) in anhydrous DMF (60 ml), and the mixture was stirred for 15 hr. The reaction mixture was diluted with water and was extracted with ethyl acetate, and the organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate = 8:2) to give the title compound as an oil (6.8 g, yield 88%). 1H-NMR (400 MHz, CDCl3): δ (ppm) 7.38-7.28 (m, 5H), 7.03 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 9.2 Hz, 2H), 5.10 (s, 2H), 4.90 (s, 1H), 2.89 (t, J = 7.2 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H).
765 mg	With potassium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 12h;

Reference： [1]Cons, Benjamin D.; Bunt, Adam J.; Bailey, Christopher D.; Willis, Christine L. [Organic Letters, 2013, vol. 15, # 8, p. 2046 - 2049]
[2]Current Patent Assignee: MEIJI HOLDINGS CO., LTD - US2008/90825, 2008, A1 Location in patent: Page/Page column 30; 31
[3]Guo, Wei; Li, Junfei; Fan, Ningjuan; Wu, Weiwei; Zhou, Peiwen; Xia, Chizhong [Synthetic Communications, 2005, vol. 35, # 1, p. 145 - 152]
[4]Current Patent Assignee: MEIJI HOLDINGS CO., LTD - EP2737900, 2014, A1 Location in patent: Paragraph 0124-0126
[5]Akai, Shoji; Kajihara, Yasuhiro; Nagashima, Yasuhiko; Kamei, Masugu; Arai, Junko; Bito, Masami; Sato, Ken-Ichi [Journal of Carbohydrate Chemistry, 2001, vol. 20, # 2, p. 121 - 143]

29
[ 108-73-6 ]
[ 501-97-3 ]
[ 60-82-2 ]

Yield	Reaction Conditions	Operation in experiment
60%	With boron trifluoride diethyl etherate; at 85℃; for 4h;Inert atmosphere;	General procedure: A mixture of S1 (40 mmol), S2 (40 mmol), and BF3·Et2O (26 mL, 204 mmol) was stirred at 85 C for 4h under N2. The reaction mixture was poured into 10% aqueous NaOAc solution (200 mL) and allowed to stand for 4h, then the solution wa sextracted with EtOAc (3 × 200 mL). The combined EtOAc layer was washed with water (200 mL), brine (200 mL) and dried over Na2SO4. The residue obtained after evaporation of the solvent was chromatographed over silica gel column using petroleum ether-EtOAc mixtures as eluent to give Sa-h.

Reference： [1]Carbohydrate Research,2019,vol. 484
[2]Tetrahedron,2006,vol. 62,p. 841 - 846

30
[ 501-97-3 ]
[ 1080-06-4 ]
[ 240418-72-8 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 6h;	23 3-(4-Hydroxy-phenyl)-2-[3-(4-hydroxy-phenyl)-propionylamino]-propionic acid methyl ester A solution of 3(4-hydroxy phenyl) propionic acid (10 grams, 60.17 mmol) and Example 1 (11.7 grams, 60.00 mmol) in anhydrous dichloro methane (100 mL) under a nitrogen atmosphere at 0° C. is added dropwise to a solution of 1,3-dicyclohexyl carbodiimide(31 grams, 150.24 mmol) in dichloro methane (75 mL). The mixture is stirred at room temperature for 6 hours. The resulting solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 23, which can be purified in appropriate solvent.

Reference： [1]Current Patent Assignee: BEZWADA BIOMEDICAL LLC; BEZWADA BIOMEDICAL - US2007/135355, 2007, A1 Location in patent: Page/Page column 26

31
[ 32566-01-1 ]
[ 501-97-3 ]
[ 677297-20-0 ]

Yield	Reaction Conditions	Operation in experiment
55%		3-(4-Hydroxy-phenyl)-N-[2-(1H-indol-2-yl)-phenyl]-propionamide Prepared from 2-(2-aminophenyl) indole and 3-(4-hydroxyphenyl) propionic acid in 55% yield following procedure 1. The product was chromatographed on silica and crystallized from acetonitrile. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=357, 1H NMR (MeOH-d4): 2.61 t, 7.4 Hz (1H), 2.89 t, 7.4 Hz (1H), 6.37 s (1H), 6.72 d, 8 Hz (2H), 7.00-7.06 m (3H), 7.11 t, 7 Hz (1H), 7.27-7.35 m (2H), 7.38 d, 8 Hz (1H), 7.54 d, 7 Hz (1H), 7.58 dd, 7,1 Hz (1H), 7.67 d, 8 Hz (1H).

Reference： [1]Patent: US2005/282814,2005,A1

32
[ 501-97-3 ]
[ 24807-40-7 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3359 - 3368
[2]Tetrahedron,2005,vol. 61,p. 7144 - 7152
[3]Bulletin of the Polish Academy of Sciences: Chemistry,1986,vol. 34,p. 115 - 122
[4]Tetrahedron,1990,vol. 46,p. 7105 - 7118
[5]Patent: EP2952517,2015,A1

33
[ 501-97-3 ]
potash [ No CAS ]
[ 24807-40-7 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 3351 - 3354

34
[ 501-97-3 ]
potash [ No CAS ]
[ 4654-08-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 509 - 513

35
[ 501-97-3 ]
potash [ No CAS ]
[ 37827-68-2 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 5353 - 5361

36
[ 501-97-3 ]
EtX [ No CAS ]
[ 117896-99-8 ]

Reference： [1]Journal of Organic Chemistry,2000,vol. 65,p. 4179 - 4184
[2]Journal of Organic Chemistry,2000,vol. 65,p. 4179 - 4184

37
[ 501-97-3 ]
[ 23838-70-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: 4-hydroxyphenylpropionic acid With thionyl chloride In methanol Stage #2: With ammonium hydroxide In acetonitrile at 0℃;	1 Synthesis of 3-(4-hydroxyphenyl)propionamide 15 mL of thionyl chloride was added to 2 g of p-hydroxybenzene propionamide, stirred to clarify, sample, add a small amount of methanol, PE: EA = 5: 1 odr, about 1-1.5 h.Then spin off the thionyl chloride, add a small amount of acetonitrile dissolved slowly into the 0mL 20mL 25-28% ammonia water, stirring 15-30min, sampling, acidification, DCM: MeOH = 10: 1 point plate.After completion of the reaction, the solvent was removed and a small amount of concentrated hydrochloric acid was added to the resulting solid. The solid was yellowened from yellow, spin off hydrochloric acid, dried and excess ethyl acetate. The mixture was heated to reflux to dissolve the solid. , Spin off most of the ethyl acetate, into the ice, precipitation of solid.The yield of 3- (4-hydroxyphenyl) propionamide was 84%.
	Multi-step reaction with 2 steps 1: concentrated sulfuric acid / 80 °C / unter Druck 2: methanol; ammonia / 100 °C / im Autoklaven
	Stage #1: 4-hydroxyphenylpropionic acid With 1-methyl-pyrrolidin-2-one; benzotriazol-1-ol; diisopropyl-carbodiimide Stage #2: With trifluoroacetic acid In water

Multi-step reaction with 2 steps 1: sulfuric acid 2: ammonia / 120 °C

Reference： [1]Current Patent Assignee: CHANGZHOU UNIVERSITY - CN104030941, 2016, B Location in patent: Paragraph 0028 - 0032
[2]Fischer,E.; Nouri [Chemische Berichte, 1917, vol. 50, p. 618][Chemisches Zentralblatt, 1916, vol. 87, # II, p. 1025]
[3]Location in patent: experimental part Agerbirk, Niels; Warwick, Suzanne I.; Hansen, Paul R.; Olsen, Carl E. [Phytochemistry, 2008, vol. 69, # 17, p. 2937 - 2949]
[4]Current Patent Assignee: Bayer & Co. - DE233551, 1800, C [Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 1231][Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 1231]

38
[ 501-97-3 ]
[ 60-82-2 ]

Reference： [1]Chemische Berichte,1917,vol. 50,p. 618
Chemisches Zentralblatt,1916,vol. 87,p. 1025

39
[ 91-21-4 ]
[ 501-97-3 ]
[ 637358-60-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 0 - 20℃;	12.a Example 12; a) 4-[3-(3,4-Dihydroisoquinolin-2(lH)-yl)-3-oxopropyl]phenol [3- (4-HYDROXYPHENYL)] propionic acid (202 mg, 1.216 mmol) in DMF (3 ml) was cooled in an ice-bath. 1,2, 3, [4-TETRAHYDROISOQUINOLINE] (170 mg, 1.276 mmol) was added and then TBTU (410 mg, 1.276 mmol) followed by DIPEA (330 mg, 2.553 mmol). The mixture was stirred at room temperature overnight. Sodium hydrogencarbonate aqueous solution (sat. ) was added. The mixture was extracted with ethyl acetate (x2). The extracts were combined and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column [(ISOLUTE (E)] SI, 2g/6 [ML)] using DCM and then MeOH/DCM (1: 99) as eluant gave 303 mg the desired product, yield 89%. ['H] NMR (rotamers, 400 MHz, CDC13) : 8 2.72-2. 77 [(M,] 2H), 2.83-2. 90 [(M,] 2H), 2.95-3. 01 [(M,] 2H), 3.63, 3. [88] (t, t, 2H), 4.57, 4.79 (s, s, 2H), 6.85-6. 90 [(M,] 2H) and 7.07-7. 26 [(M,] 6H).
78.3%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	4.1.1 General procedure for the preparation of cinnamic acid hyrbids 4a-4p and 5a-5p) General procedure: The starting materials 1a-1q (1mmol) were dissolved in anhydrous dichloromethane (8mL), respectively. EDCI) (1.5mmol) and HOBt (1.5mmol) were added to the solution as condensating agent. Finally, the excessive amounts of 1,2,3,4-tetrahydroisoquinoline (a) and 4-benzylpiperidine (b) (1~2mmol) was added to the aforementioned solution, respectively. The reaction mixture was stirred under room temperature for 6~8h monitored by TLC. After reaction finished, the mixture was diluted with water and extracted with CH2Cl2. The organic phases were combined, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by silica gel chromatography with dichloromethane/acetone=50:1 as eluent to give the target compounds 4a-4p and 5a-5p.

Reference： [1]Current Patent Assignee: ASTRAZENECA AB; ASTRAZENECA UK LIMITED - WO2004/295, 2003, A1 Location in patent: Page 43
[2]Wang, Keren; Shi, Jian; Zhou, Yi; He, Ying; Mi, Jing; Yang, Jing; Liu, Shuang; Tang, Xiangcheng; Liu, Wenmin; Tan, Zhenghuai; Sang, Zhipei [Bioorganic Chemistry, 2021, vol. 112]

40
[ 501-97-3 ]
[ 39590-27-7 ]
[ 637358-84-0 ]

Yield	Reaction Conditions	Operation in experiment
93.9%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 0 - 20℃;	21.a Example 21 a) 2- (2-Ethoxyphenyl) ethanamine (0.55 g, 3.33 mmol) and [3- (4-HYDROXYPHENYL)] propanoic acid [(0. 50] g, 3.00 mmol) was dissolved in dimethyl formamide (5 [ML)] and cooled o [0° C.] [N-[(1H-1,] 2, 3-benzotriazol-1-yloxy) (dimethylamino) methylene]-N-methyhnethanaminium tetrafluoroborate (1.18 g, 3.66 mmol) and [DIISOPROPYLETHYLAMINE] (0.90 g, 7.0 mmol) were added and the solution was warmed to room temperature and stirred overnight.. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 [ML).] The organic phase was dried [(MGS04)] and EtOAc was removed by evaporation to give 0.98 gram of N [2- (2-ethoxyphenyl) ethyl]-3- (4- hydroxyphenyl) [PROPANAMIDE] (yield 93.9%). [1HNMR] (Rotamers, 500 MHz, CDC13) : 5 1.42 (t, 3H), 2.42 (t, 2H), 2.8-2. 92 [(M,] 4H), 3.55 (q, [2H),] 4.05 (q, 2H), 6.08 [(M,] 1H), 6.82-6. 93 [(M,] 4H), 6.96-7. 1 [(M,] 3H), 7.22 (t, [1H).]

Reference： [1]Current Patent Assignee: ASTRAZENECA AB; ASTRAZENECA UK LIMITED - WO2004/295, 2003, A1 Location in patent: Page 61, 62

41
[ 3490-06-0 ]
[ 501-97-3 ]
[ 637358-42-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 0 - 20℃;	5.a Example 5; a) N-[2-(3,4-dimethoxyphenyl)ethyl]-3-(4-hydroxyphenyl)-N-methylpropanamide [3- (4-HYDROXYPHENYL)] propionic acid (166.2 mg, 1 mmol) was dissolved in DMF (4 [ML).] 2- (3, [4-DIMETHOXYPHENYL)-N-METHYLETHYLAMINE] (211 mg, 1.05 mmol) was added. The mixture was cooled in an ice-bath TBTU (337 mg, 1.05 mmol) was added, followed by DIPEA (0.37 ml, 2.1 [MMOL).] The mixture was stirred overnight and the temperature was allowed up to room temperature. Ethyl acetate and sodium hydrogencarbonate aqueous solution (sat. ) were added and then the two phases were separated. The water phase was extracted with ethyl acetate. The organic phases were combined and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column [(ISOLUTES)] SI, 5g/15 [ML)] using DCM and then MeOH/DCM (1: 99) as eluant gave 333 mg the desired product, yield 97%. [1H] NMR (rotamers, 500 MHz, [CDC1S)] : 8 2.35, 2.59 (t, t, 2H), 2.71-2. 80,2. 90 (m, t, [4H),] 2.84, 2.97 (s, s, 3H), 3.45, 3.58 (t, t, 2H), 3.84-3. 86 [(M,] 6H), 6.61-6. 83 [(M,] 4H), 6.95 (d, 1H), 7.05 (d, [1H)] and 7.50, 7.56 (s, s, 1H).

Reference： [1]Current Patent Assignee: ASTRAZENECA AB; ASTRAZENECA UK LIMITED - WO2004/295, 2003, A1 Location in patent: Page 34

42
[ 6304-26-3 ]
[ 501-97-3 ]
[ 637358-87-3 ]

Yield	Reaction Conditions	Operation in experiment
91.9%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 0 - 20℃;	22.a Example 22 a) [N-ETHYL-N-(2-PYRIDIN-2-YLETHYL) AMINE] (0.5 g, 3.32 mmol) and [3- (4-HYDROXYPHENYL)-] propanoic acid (0.50 g, 3.00 mmol) was dissolved in dimethylformamide (5 ml) and cooled [O] [0° C. N-[(LH-1,] 2, [3-BENZOTRIAZOL-1-YLOXY)] (dimethylamino) methylene]-N- [METHYLMETHANAMINIUM TETRAFLUOROBORATE] (1.18 g, 3.66 mmol) and diisopropylethylamine (0.90 g, 7.0 mmol) were added and the solution was warmed to room temperature and stirred overnight. EtOAc (15 [ML)] was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). The organic phase was dried [(MGS04)] and EtOAc was removed by evaporation to give 0.913 gram of N-ethyl-3- (4- hydroxyphenyl)-N-(2-pyridin-2-ylethyl) propanamide (yield 91.9%). [1HNMR] (Rotamers, 500 MHz, [CDC13)] : 8 0.97, 1.05 (t, t, 3H), 2.41, 2.52 (t, t, 2H), 2.75- 3.0 [(M,] 4H), 3.09, 3.33 (q, q, 2H), 3.54, 3.61 (t, t, 2H), 6. [74-6. 82 (M,] 2H), 6.93-7. [2 (M,] 4H), 7. [58 (M, 1H),] 8. [48 (M, 1H).]

Reference： [1]Current Patent Assignee: ASTRAZENECA AB; ASTRAZENECA UK LIMITED - WO2004/295, 2003, A1 Location in patent: Page 63, 64

43
[ 637014-99-4 ]
[ 501-97-3 ]
[ 637015-08-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 0 - 20℃;	5.a Example 5; a) [N (2, 4-DIFLUOROBENZYL)-N-HEPTYL-3- (4-HYDROXYPHENYL)] propanamide [3- (4-HYDROXYPHENYL)] propionic acid [(108] mg, 0.650 mmol) was dissolved in [DMF.] [N-(2,] 4- [DIFLUOROBENZYL)-N-HEPTYLAMINE] (164.7 mg, 0.682 mmol) was added. The mixture was cooled in an ice-bath. TBTU (219 mg, 0.682 mmol) was added and followed by [D1PEA] (0.238 ml, 1.365 mmol). The mixture was stirred overnight and the temperature was allowed up to room temperature. Ethyl acetate and sodium hydrogencarbonate aqueous solution (sat. ) were added and then the two phases were separated. The water phase was extracted with ethyl acetate. The organic phases were combined and dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE SI, 5g/15 ml) using DCM and then [MEOH/DCM] (1: 99) as eluant gave 223 mg desired product, yield [88%.] [1H] NMR (rotamers, 500 MHz, CDC13) : [8] 0.86-0. 90 (m, 3H), 1. [21-1. 31] (m, 8H), 1.47-1. 53 (m, [2H),] 2.60, 2.67 (t, t, 2H), 2.85-2. 96 (m, [2H),] 3.15, 3.32 (t, t, [2H),] 4.41, 4.60 (s, s, 2H), 6.75-6. 85 (m, [4H),] 6.90-6. 96,7. 12-7.18 (m, m, 1H) and 7.00, 7.04 (d, d, 2H).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2004/790, 2003, A1 Location in patent: Page 31

44
[ 64248-58-4 ]
[ 501-97-3 ]
[ 643746-95-6 ]

Yield	Reaction Conditions	Operation in experiment
32%	With 1-methyl-pyrrolidin-2-one; potassium carbonate;copper(I) bromide; at 20 - 140℃; for 12h;	In a 50- mL RB-flask was added [3- (4-HYDROXYPHENYL)] propionic acid (1.66 g, [10.] 0 mmol), <strong>[64248-58-4]3,4-difluoroiodobenzene</strong> (2.40 g, 10.0 mmol), copper (I) bromide (0.100 g), potassium carbonate (2.76 g, 20.0 [MMOL),] and [N-METHYL-2-PYRROLIDONE] (20 [ML)] as solvent. The mixture was stirred for 5 min at room temperature and then heated to [140 C] (oil bath). After being stirred for 12 hours at [140 C,] the reaction mixture was cooled to room temperature and diluted with [ETOAC] (100 mL). The diluted mixture was washed with citric acid (aq, 30 mL), water (3 x 50 mL, brine and dried over [MGS04. THE] removal of solvent in vacuo afforded crude which was purified by chromatography (0.901 g, [32%)] : [1H] NMR (400 MHz, CDCl3) 8 11.44-11. 06 (br, 1H), 7.24-7. 14 (m, 2H), 7.14-7. 00 (m, [1H),] 7.00-6. 86 (m, 2H), 6.86-6. 75 (m, 1H), 6.75-6. 61 (m, 1H), 2.94 (t, 2H, J = 7.6 Hz), 2.68 (t, 2H, [J = 7.] 6 Hz); ESMS [M/E] : 277.2 (M-H+).

Reference： [1]Patent: WO2004/5257,2004,A1 .Location in patent: Page 78-79

45
[ 57260-73-8 ]
[ 501-97-3 ]
[ 852714-54-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 18h;	1 EXAMPLE 1 SYNTHESIS OF N-(2-{2-[2-CHLORO-4-(6-OXO-1,4,5,6-TETRAHYDROPYRIDAZIN-3-YL)- PHENOXY]-ACETYLAMINO}-ETHYL)-2-(4-((S)-2-HYDROXY-3- ISOPROPYLAMINOPROPOXY)-PHENYL] -ACETAMIDE (7)N-(2-{2-[2-Chloro-4-(6-oxo-1 ,4,5,6-tetrahydropyridazin-3-yl)- phenoxy]-acetylamino}-ethyl)-2-(4-((S)-2-hydroxy-3-isopropylaminopropoxy)- phenyl]-acetamide (7) was synthesized according to Scheme I.Scheme I EPO resn DMF Synthesis of (2-[2-(4-Hvdroxy-phenyl)-propionylamino1-ethyl}-carbamic acid tert butyl ester (2) To a round bottom flask containing 4-hydroxyphenyl propanoic acid (1) (1.66 g, 10 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (EDC HCI, 2.15 g, 11 mmol), [1 ,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt, 0.556 g, 4 mmol) and Λ/-(tertbutyloxycarbonyl)ethylene diamine (1.76 g, 11 mmol) was added Λ/,Λ/-dimethylformamide (10 ml_). The mixture was stirred at ambient temperature for 18 h then poured onto 50% saturated NH4CI (aq.) (60 ml). The mixture was then extracted with ethyl acetate (4 x 20 ml) and the organic extracts were combined and washed with 1M aqueous citric acid solution (2 x 40 ml), 1M NaHCO3 (40 ml), water (2 x 40 ml) and saturated brine (50 ml). The solution was then dried (Na2SO4) and concentrated under reduced pressure to give a colorless foam (2.79 g, 90% yield), 97% pure by LC- MS and >90% pure by 1H-nmr.

Reference： [1]Current Patent Assignee: NORDIC CAPITAL PARTNERS II AS - WO2006/60127, 2006, A2 Location in patent: Page/Page column 27-28

46
[ 19235-89-3 ]
[ 501-97-3 ]
[ 900254-54-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 72h;	11.1 To a suspension of 4-chloropyridine-2-carbonitrile (2.3 g, 16.6 mmol) in DMF (100 mL) was added cesium carbonate (16.3 g, 50.0 mmol) and 3-(4-hydroxy-phenyl)propanoic acid (3.03 g, 18.3 mmol). The reaction was heated to 50° C. for 3 days. The mixture was cooled to rt, concentrated, and then taken up in 300 mL of water. The pH was adjusted to 3 by the dropwise addition of oxalic acid and a precipitate formed. The precipitate was filtered to give the title compound as a cream solid (4.17 g, 95%). LCMS: Method FA, Rt=1.49 min, [MH+=269].

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2006/160803, 2006, A1 Location in patent: Page/Page column 147

47
[ 501-97-3 ]
[ 220000-87-3 ]
[ 900254-52-6 ]

Yield	Reaction Conditions	Operation in experiment
37%	With caesium carbonate In N,N-dimethyl-formamide at 100℃;	8.1 A mixture of 3-(4-hydroxyphenyl)propanoic acid (10.7 g, 64.5 mmol), 4-chloro-N-methylpicolinamide (10.0 g, 58.6 mmol) and cesium carbonate (57.3 g, 175.8 mmol) was stirred in DMF and heated at 100° C. overnight. After cooling to rt, the mixture was filtered and washed with EtOAc to remove cesium carbonate. The remaining solid was dissolved in a minimal amount of water and the pH of the solution was adjusted to 4 by the dropwise addition of a sat. oxalic acid solution. The solution was extracted with DCM, the organic solutions washed with water and brine, dried over MgSO4, filtered, and concentrated. The resulting solid was recrystallized from EtOAc to give the desired product as a pale cream solid (5.07 g, 37%). 1H NMR (400 MHz, d6-DMSO) δ: 12.13 (s, 1H), 8.70-8.78 (m, 1H), 8.49 (d, J=5.6 Hz, 1H), 7.34-7.39 (m, 3H), 7.11-7.14 (m, 3H), 2.87 (br t, J=7.6 Hz, 2H), 2.77 (d, J=4.8 Hz, 3H), and 2.57 (br t, J=7.6 Hz, 2H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2006/160803, 2006, A1 Location in patent: Page/Page column 144

48
[ 501-97-3 ]
[ 23795-02-0 ]

Yield	Reaction Conditions	Operation in experiment
9.6 g (99%)	With thionyl chloride; In ethanol;	1) To an ice-cooled solution of 3-(p-hydroxyphenyl)-propionic acid (8.3 g, 50.0 mmol) in ethanol (100 mL) was dropwise added thionyl chloride (3.7 mL, 50.7 mmol). The mixture was stirred at room temperature over night, concentrated in vacuo and the residue purified by kugelrohr distillation, to give 9.6 g (99%) of 3-(4-hydroxy-phenyl)-propionic acid ethyl ester as a colourless oil. 1H NMR (CDCL3): delta 1.21 (3H, t), 2.58 (2H, t), 2.86 (2H, t), 4.12 (2H, q), 6.75 (2H, d), 6.90 (1H, bs), 7.01 (2H, d).
	With sulfuric acid; sodium carbonate; In ethanol; ethyl acetate;	Step 1: Sulfuric acid (230 g) was dropped under stirring for 10 minutes to an ethanol solution (1500 mL) of 3-(4-hydroxyphenyl) propionic acid (1150 g), and refluxed successively for 5 hours. The reaction mixture was concentrated and the obtained concentrated solution was poured into water (1,000 mL) and stirred with addition of ethyl acetate. After separation of the solution, an ethyl acetate layer was neutralized with an aqueous solution of a saturated sodium carbonate, washed with a small amount of water and then dried over anhydrous magnesium sulfate. Ethyl acetate and unreacted ingredients were distilled off from the ethyl acetate layer to obtain concentrates (1,400 g). The concentrates were purified by distillation under a reduced pressure to obtain ethyl 3-(4-hydroxyphenyl) propionate (1,144 g). The boiling point was 160 C./4.0 hPa.

Reference： [1]Patent: US2003/139473,2003,A1
[2]Patent: US2006/278851,2006,A1

49
[ 20170-32-5 ]
[ 501-97-3 ]

Reference： [1]Russian Chemical Bulletin,2007,vol. 56,p. 1119 - 1124

50
[ 6386-38-5 ]
[ 501-97-3 ]

Reference： [1]Russian Chemical Bulletin,2007,vol. 56,p. 1119 - 1124

51
[ 501-97-3 ]
[ 524-14-1 ]
[ 60-82-2 ]
[ 920318-17-8 ]

Reference： [1]Journal of Molecular Catalysis B: Enzymatic,2010,vol. 66,p. 257 - 263

52
[ 811442-84-9 ]
[ 501-97-3 ]
[ 1262963-04-1 ]

Reference： [1]Organic and Biomolecular Chemistry,2010,vol. 8,p. 5568 - 5575

53
[ 501-97-3 ]
[ 88829-82-7 ]
[ 1262963-03-0 ]

Reference： [1]Organic and Biomolecular Chemistry,2010,vol. 8,p. 5568 - 5575

54
[ 35231-44-8 ]
[ 501-97-3 ]
[ 1258525-62-0 ]

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

55
[ 501-97-3 ]
[ 81161-17-3 ]

Reference： [1]Synthetic Communications,2012,vol. 42,p. 722 - 726

56
[ 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]

57
[ 501-97-3 ]
[ 10210-17-0 ]
[ 1379072-68-0 ]

Yield	Reaction Conditions	Operation in experiment
1: 48% 2: 23%	With samarium diiodide; water; triethylamine In tetrahydrofuran at 20℃; for 3h; Inert atmosphere;

Reference： [1]Szostak, Michal; Spain, Malcolm; Procter, David J. [Organic Letters, 2012, vol. 14, # 3, p. 840 - 843]

58
[ 501-94-0 ]
[ 501-97-3 ]
[ 956024-94-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 48h; Schlenk technique; Inert atmosphere;	Synthesis of Target Compounds 3g-3p General procedure: Tyrosol (1, 0.4 mmol, 1.0 equiv), organic acids 2g-2p (0.4 mmol, 1.0 equiv),and TPP (0.4 mmol, 1.0 equiv) were placed in a dry standard Schlenk tube under N2. Dry THF (1.0 mL) was added, followedby the addition of DIAD (0.4 mmol, 1.0 equiv) at 0 ° C. The reaction mixture was stirred at room temperature for 48 h, and thereaction was monitored with TLC. The crude reaction mixture was purified by column chromatography on Sephadex LH-20 toafford the corresponding product.
65%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 48h; Inert atmosphere;	10 The reactor was continuously purged with nitrogen to protect the reaction, and 5 mmol of tyrosol was added in sequence.6mmol triphenylphosphine and 5mmol 4-hydroxyphenylpropionic acid, then added 12mL tetrahydrofuran,6 mmol of diisopropyl azodicarboxylate was added dropwise at a temperature of 0 ° C. After the dropwise addition was completed, the ice bath was removed, and the mixture was warmed to room temperature, and the reaction was stirred for 48 hours.After the reaction is completed, the reaction solution is evaporated and dried.Dissolve in 180 mL of ethyl acetate and wash 4 times with 180 mL of saturated sodium bicarbonate solution.Then, it was washed 4 times with 180 mL of a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate.Desalting by suction filtration, concentration to obtain a concentrate; the concentrate is in dichloromethane,Column chromatography is carried out using a mixture of methanol in a 1:1 volume ratio as a solvent.4-hydroxyphenylpropionic acid 4-hydroxyphenethyl ester is isolated,The yield is 65%.
	With toluene-4-sulfonic acid In 1,2-dichloro-ethane for 0.4h; Dean-Stark; Reflux;	1 Synthesis of 4-hydroxyphenethyl 3-(4-hydroxyphenyl)propanoate (DTy) into a 500 mL round bottomed flask fitted with an overhead stirrer, and a modified Dean-stark trap for solvents heavier than water were added 10 g (72 mmol) of tyrosol, 13 g (78 mmol) of desaminotyrosine (DAT), 0.65 g (3.4 mmol) of 4-toluenesulfonic acid monohydrate, and 200 mL of 1,2-dichloroethane (DCE). A water-cooled reflux condenser was placed on top of the modified Dean-stark trap and the contents of the flask were heated to reflux while being stirred. The reaction was continued until approximately 1.4 mL of water collected in the modified Dean-stark trap above the DCE and the water collection essentially stopped (about 4 hours of reflux). The reaction mixture was cooled to room temperature when the crude product precipitated as off-white crystalline solid, which was dissolved in 100 mL of ethyl acetate and washed twice with 100 mL portions of 5% sodium bicarbonate solution. After drying over magnesium sulfate the organic layer was concentrated and precipitated with hexane. The resulting white crystalline solid was collected by filtration and dried in a vacuum oven at 25° C. The product was characterized by elemental analysis, HPLC, and 1H NMR.

Reference： [1]Zang, Hao; Shen, Peng; Xu, Qian; Zhang, Luyun; Xia, Guangqing; Sun, Jiaming; Zhu, Junyi; Yang, Xiaohong [Chemistry of Natural Compounds, 2019, vol. 55, # 6, p. 1043 - 1049][Khim. Prir. Soedin., 2019, # 6, p. 899 - 904,6]
[2]Current Patent Assignee: UNIV TONGHUA NORMAL - CN109232255, 2019, A Location in patent: Paragraph 0050; 0051; 0052
[3]Current Patent Assignee: RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY - US2013/203713, 2013, A1 Location in patent: Paragraph 0214

59
[ 501-97-3 ]
[ 6305-38-0 ]
C₁₃H₁₅NO₄ [ No CAS ]

Reference： [1]ChemBioChem,2014,vol. 15,p. 87 - 93

60
[ 68858-20-8 ]
[ 35661-60-0 ]
[ 501-97-3 ]
[ 35661-39-3 ]
C₂₇H₂₃N₂O₃Pol [ No CAS ]
[ 35661-40-6 ]
[ 71989-14-5 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 71989-35-0 ]
[ 35661-38-2 ]
[ 132388-59-1 ]
[ 132327-80-1 ]
[ 109425-55-0 ]
[ 77284-32-3 ]
[ 111061-56-4 ]
[ 135112-27-5 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
Fmoc-AspfOBuVOH [ No CAS ]
Dat-D-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Orn-Val-Leu-Abu-Gln-Leu-Ser-Ala-Arg-Orn-Leu-Leu-Gln-Asp-Ile-Nle-Asp-Arg-NH-CH₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19 mg		Example 3 Dat1-D-Ala2-Asp3-Ala4-Ile5-Phe6-Thr7-Asn8-Ser9-Tyr10-Arg11-Orn12-Val13-Leu14-Abu15-Gln16-Leu17-Ser18-Ala19-Arg20-Orn21-Leu22-Leu23-Gln24-Asp25-Ile26-Nle27-Asp28-Arg29-NH-CH3 (Peptide 27400). [Dat1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH-CH3 The synthesis is conducted in a stepwise manner using manual solid phase peptide synthesis equipment. Briefly, [3-[(Methyl-Fmoc-amino)methyl]-indol-1-yl]-acetyl AM resin (Nova Biochem, La Jolla, Calif.) (750 mg, 0.50 mmol) is deprotected with 20% piperidine in DMF for 5 and 15 minutes and washed according to the protocol described in Table 3. The solution of Fmoc-Arg(Pbf)-OH (975 mg, 1.5 mmol) in DMF is shaken with the washed resin and DIC (235 muL, 1.5 mmol) in a manual solid phase peptide synthesis apparatus for 1 hour. After washing the resin three times with DMF, the coupling reaction was repeated as described above. After the repeated coupling and after the completion of the reaction is proved by negative ninhydrin test, the deprotection and neutralization protocols described in Table 3 are performed in order to remove the Fmoc protecting group and prepare the peptide-resin for coupling of the next amino acid. The synthesis is continued and the peptide chain is built stepwise by coupling the following protected amino acids in the indicated order on the resin to obtain the desired peptide sequence: Fmoc-Asp(OBut)-OH, Fmoc-Nle-OH, Fmoc-Ile-OH, Fmoc-AspfOBuVOH, Fmoc-Gln(Trt)-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Orn(Boc)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Ala-OH, Fmoc-Ser(Trt)-OH, Fmoc-Leu-OH, Fmoc-Gln(Trt)-OH, Fmoc-Abu-OH, Fmoc-Leu-OH, Fmoc-Val-OH, Fmoc-Orn(Boc)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Ile-OH, Fmoc-Ala-OH, Fmoc-AspBu1)-OH, Fmoc-D-Ala-OH, Dat-OH. These protected amino acid residues (also commonly available from Novabiochem, Advanced Chemtech, Bachem, and Peptides International) are represented above according to a well accepted convention. The suitable protecting group for the side chain functional group of particular amino acids appears in parentheses. The OH groups in the above formulae indicate that the carboxyl terminus of each residue is free. The protected amino acids (1.5 mmol each) are coupled with DIC (235 muL, 1.5 mmol) with the exceptions of Fmoc-Asn(Trt)-OH and Fmoc-Gln(Trt)-OH which are coupled with HBTU reagent. In order to cleave the peptide from the resin and deprotect it, a portion of 250 mg of the dried peptide resin is stirred with 2.5 mL cleavage cocktail (94% TFA, 3% H2O, 1.5% m-cresol, and 1.5% phenol) at room temperature for 3 hours. To induce peptide precipitation, the cleavage mixture is added dropwise to cold (preferably -20 C.) ether. The precipitated material is collected by filtration or centrifugation and is washed three times with cold ether. The cleaved and deprotected peptide is dissolved in 50% acetic acid and separated from the resin by filtration. After dilution with water and lyophilization, 118 mg crude product is obtained. The crude peptide is checked by analytical HPLC using a Hewlett-Packard Model HP-1090 liquid chromatograph equipped with a Supelco Discovery HS C18 reversed-phase column (2.1 mm×5 cm, packed with C18 silica gel, 300 pore size, 3 mum particle size) (Supelco, Bellefonte, Pa.). Linear gradient elution (e.g., 40-70% B) is used with a solvent system consisting of (A) 0.1% aqueous TFA and (B) 0.1% TFA in 70% aqueous MeCN, and the flow rate is 0.2 mL/min. Purification is performed on a Beckman System Gold HPLC system (Beckman Coulter, Inc., Brea, Calif.) equipped with 127P solvent Module; UV-VIS Detector, model 166P; Computer workstation with CPU Monitor and printer, and 32-Karat software, version 3.0. 118 mg of crude peptide is dissolved in AcOH/H2O, stirred, filtered and applied on an XBridge Prep OBD reversed phase column (4.6×250 mm, packed with C18 silica gel, 300 A pore size, 5 mum particle size) (Waters Co., Milford, Mass.). The column is eluted with a solvent system described above in a linear gradient mode (e.g., 40-60% B in 120 min); flow rate 12 mL/min. The eluent is monitored at 220 nm, and fractions are examined by analytical HPLC. Fractions with purity higher than 95% are pooled and lyophilized to give 19 mg pure product. The analytical HPLC is carried out on a Supelco Discovery C18 reversed-phase column described above using isocratic elution with a solvent system described above with a flow rate of 0.2 mL/min. The peaks are monitored at 220 and 280 nm. The product is judged to be substantially (>95%) pure by analytical HPLC. Molecular mass is checked by electrospray mass spectrometry, and the expected amino acid composition is confirmed by amino acid analysis.

Reference： [1]Patent: US2014/179604,2014,A1 .Location in patent: Paragraph 0192; 0331-0335

61
[ 936571-71-0 ]
[ 501-97-3 ]
[ 1791-13-5 ]
[ 1427752-38-2 ]

Yield	Reaction Conditions	Operation in experiment
4.7 mg		Example A1 To a solution of di-tert-butyl L-aspartate hydrochloride (40 mumoL) were added 0.5 mL of a solution of 3-(4-hydroxyphenyl)propionic acid (299 mg) and 4-dimethylaminopyridine (220 mg) in N,N-dimethylformamide (30 mL), and 0.5 mL of a solution of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (518 mg) in N,N-dimethylformamide (30 mL), followed by stirring at room temperature overnight. After concentrating under reduced pressure, 1.0 mL of a solution of 4-[N',N'-bis(tert-butoxycarbonyl)carbamimidamido]benzoic acid (911 mg) in dichloromethane (60 mL) and 0.5 mL of a solution of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (518 mg) in dichloromethane (30 mL) were added thereto, followed by stirring at room temperature overnight. Trifluoroacetic acid (0.5 mL) was added thereto, followed by stirring further at room temperature overnight. After concentrating under reduced pressure, the product was preparatively purified with LC (aqueous formic acid solution/methanol) by means of an MS trigger, and then concentrated under reduced pressure to obtain N-(3-{4-[(4-carbamimidamidobenzoyl)oxy]phenyl}propanoyl)-L-aspartic acid (4.7 mg).

Reference： [1]Patent: EP2757093,2014,A1 .Location in patent: Paragraph 0219

Yield	Reaction Conditions	Operation in experiment
		General procedure: FIGURES 8A-8C are illustrations of the hydroxylation of arenes mediated by 4,5-dichlorophthaloyl peroxide. To examine the scope of the hydroxylation reaction mediated by 4,5-dichlorophthaloyl peroxide (2), two general sets of reaction conditions were developed. The oxidations are carried out using either 1.3 equivalents of 4,5-dichlorophthaloyl peroxide (2) at 50 C or 2.5 equivalents heated to 75 C. Operationally the reaction proceeds without the need for special exclusion of air and the use of commercial grade HFIP is sufficient. Thermogravimetric analysis indicates that 4,5-dichlorophthaloyl peroxide has a point of decomposition at 135 C. Therefore, all reactions reported are conducted at or below 75 C. While we have not encountered exothermic reactions, appropriate precautions must be used similar to those for all experiments using peroxides. Isolated yields are given below each entry. The yield in parentheses refers to the starting material recovered. The minor regioisomeric positions are labeled with the respective carbon atom number and, after the major isomer, listed sequentially. Reaction conducted at 0C. Prior to the addition of 4,5-dichlorophthaloyl peroxide (2) p-toluenesulfonic acid monohydrate (1.0 equiv.) was added to the solution of 3(y).

63
[ 501-52-0 ]
[ 495-78-3 ]
[ 501-97-3 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 8084 - 8095

64
[ 56-41-7 ]
[ 68858-20-8 ]
[ 501-97-3 ]
[ 112883-29-1 ]
[ 71989-31-6 ]
[ 136083-57-3 ]
[ 73724-45-5 ]
C₄₆H₆₂N₈O₁₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: All linear peptides were assembled using standard Fmoc peptide synthesisprotocol with the Rink amide resin on 433A Peptide Synthesizer (Applied Biosystems).For each coupling reaction, 10 equiv of Fmoc-amino acid, 0.45 Msolution of HOBt/HBTU (9 equiv) in DMF, 2 M solution of DIEA in NMP wereused. The coupling reaction was allowed to proceed for 9 min. Fmoc deprotectionwas performed by treating the resin-bound peptide with 20% piperidinein DMF for 10 min. The peptide was cleaved from the resin by treating the resin with a cleavage cocktail containing 94% TFA, 2% water, 2% triisopropylsilane,2% phenol for 3 hr. All protecting groups were also removedduring this cleavage reaction. TFA was removed under reduced pressureand the peptides were precipitated in diethyl ether, centrifuged, and washedwith diethyl ether before drying in high vacuum. The crude peptides werepurified by preparative reverse phase high-performance liquid chromatography(HPLC). The final compound was characterized by NMR and MALDIMS.All compounds were > 95% purity. The synthetic approaches for123B9-L2-PTX and the scrambled XDP-L2-PTX are similar to what we haverecently reported

Reference： [1]Chemistry and Biology,2015,vol. 22,p. 876 - 887

65
[ 501-97-3 ]
[ 98-59-9 ]
3-(4-(tosyloxy)phenyl)propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydroxide In water at 0 - 20℃; for 24h;	. 3-(4-(tosyloxy)phenyl)propanoic acid (20) To a stirred solution of 19 (0.996 g, 6.00 mmol) in water (100 mL) was added NaOH (0.600 g,15.00 mmol) and TsCl (1.425 g, 7.50 mmol) at 0 oC. It was stirredfor 24 h at room temperature. The reaction mixture was acidified by addinghydrochloric acid solution (2 M) to give white solid. The solid product wasfiltered and air dried to give pure product 20 (1.766 g, 92 % yield). 1H NMR (Acetone-d6)δ 10.58 (br s, 1H), 7.74 (d, J = 8.35, 2H), 7.47 (d, J = 8.35, 2H), 7.26 (d, J= 8.55, 2H), 6.95 (d, J = 8.55, 2H), 2.90 (t, J = 7.62, 2H), 2.60 (t, J = 7.62,2H), 2.74 (s, 3H); 13C NMR (Acetone-d6) 173.6, 148.9,146.6, 141.3, 133.5, 130.8, 130.5, 129.2, 122.9, 33.6, 30.7, 21.6; MS: for C16H16O5Scalcd 320.36, found 343.3 (M+Na)+
45.9%	With sodium hydroxide In water at 20 - 30℃; Inert atmosphere;	60 example 60 100 ml round bottom flask is added to sodium hydroxide (4g), water (50 ml) to dissolve, cooling to room temperature, add 60A (4.0g, 24 . 1mmol), stirring to dissolve, then added in batches 60B (5.05g, 26 . 5mmol), stirring the mixture at room temperature for overnight. Reaction solution is an aqueous solution of hydrochloric acid (2mol/L) adjusted to pH 4, separating solid, filtering, washing, collecting filter cake, the filter cake with an aqueous sodium hydroxide solution (2mol/L) dissolving, filtering the insoluble matter, the filtrate of aqueous solution of hydrochloric acid (2mol/L) adjusted to pH 4, separating solid, filtering, washing, drying to obtain white solid 60C (3.54g, yield 45.9%).

Reference： [1]Taj, Rafiq; Sorensen, John L. [Tetrahedron Letters, 2015, vol. 56, # 51, p. 7108 - 7111]
[2]Current Patent Assignee: CHENGDU BEISIKAIRUI BIOTECHNOLOGY - CN105777632, 2016, A Location in patent: Paragraph 0502; 0503; 0504

66
[ 501-97-3 ]
[ 4389-45-1 ]
N-(4-hydroxydihydrocinnamoyl)-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]

67
[ 68858-20-8 ]
[ 35661-60-0 ]
[ 501-97-3 ]
[ 35661-39-3 ]
C₃₄H₃₀N₃O₃Pol [ No CAS ]
[ 35661-40-6 ]
[ 71989-14-5 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 71989-35-0 ]
[ 35661-38-2 ]
[ 132388-59-1 ]
[ 132327-80-1 ]
[ 109425-55-0 ]
[ 77284-32-3 ]
[ 111061-56-4 ]
[ 135112-27-5 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
[Dat¹, D-Ala², Orn¹², Abu¹⁵, Orn²¹, Nle²⁷, Asp²⁸]hGH-RH(1-29)NH—CH₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[Dat1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGH-RH(1-29)NH-CH3 The synthesis is conducted in a stepwise manner using manual solid phase peptide synthesis equipment. Briefly, [3-[(Methyl-Fmoc-amino)methyl]-indol-1-yl]-acetyl AM resin (Nova Biochem, La Jolla, Calif.) (750 mg, 0.50 mmol) is deprotected with 20% piperidine in DMF for 5 and 15 minutes and washed according to the protocol described in Table 3. The solution of Fmoc-Arg(Pbf)-OH (975 mg, 1.5 mmol) in DMF is shaken with the washed resin and DIC (235 muL, 1.5 mmol) in a manual solid phase peptide synthesis apparatus for 1 hour. After washing the resin three times with DMF, the coupling reaction was repeated as described above. After the repeated coupling and after the completion of the reaction is proved by negative ninhydrin test, the deprotection and neutralization protocols described in Table 3 are performed in order to remove the Fmoc protecting group and prepare the peptide-resin for coupling of the next amino acid. The synthesis is continued and the peptide chain is built stepwise by coupling the following protected amino acids in the indicated order on the resin to obtain the desired peptide sequence: Fmoc-Asp(OBut)-OH, Fmoc-Nle-OH, Fmoc-Ile-OH, Fmoc-Asp(OBut)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Orn(Boc)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Ala-OH, Fmoc-Ser(Trt)-OH, Fmoc-Leu-OH, Fmoc-Gln(Trt)-OH, Fmoc-Abu-OH, Fmoc-Leu-OH, Fmoc-Val-OH, Fmoc-Orn(Boc)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Ile-OH, Fmoc-Ala-OH, Fmoc-Asp(OBut)-OH, Fmoc-D-Ala-OH, Dat-OH. (0249) These protected amino acid residues (also commonly available from Novabiochem, Advanced Chemtech, Bachem, and Peptides International) are represented above according to a well accepted convention. The suitable protecting group for the side chain functional group of particular amino acids appears in parentheses. The OH groups in the above formulae indicate that the carboxyl terminus of each residue is free. (0250) The protected amino acids (1.5 mmol each) are coupled with DIC (235 muL, 1.5 mmol) with the exceptions of Fmoc-Asn(Trt)-OH and Fmoc-Gln(Trt)-OH which are coupled with HBTU reagent. (0251) In order to cleave the peptide from the resin and deprotect it, a portion of 250 mg of the dried peptide resin is stirred with 2.5 mL cleavage cocktail (94% TFA, 3% H2O, 1.5% m-cresol, and 1.5% phenol) at room temperature for 3 hours. To induce peptide precipitation, the cleavage mixture is added dropwise to cold (preferably -20 C.) ether. The precipitated material is collected by filtration or centrifugation and is washed three times with cold ether. The cleaved and deprotected peptide is dissolved in 50% acetic acid and separated from the resin by filtration. After dilution with water and lyophilization, 118 mg crude product is obtained. (0252) The crude peptide is checked by analytical HPLC using a Hewlett-Packard Model HP-1090 liquid chromatograph equipped with a Supelco Discovery HS C18 reversed-phase column (2.1 mm×5 cm, packed with C18 silica gel, 300 pore size, 3 mum particle size) (Supeico, Bellefonte, Pa.). Linear gradient elution (e.g., 40-70% B) is used with a solvent system consisting of (A) 0.1% aqueous TFA and (B) 0.1% TFA in 70% aqueous MeCN, and the flow rate is 0.2 mL/min. Purification is performed on a Beckman System Gold HPLC system (Beckman Coulter, Inc., Brea, Calif.) equipped with 127P solvent Module; UV-VIS Detector, model 166P; Computer workstation with CPU Monitor and printer, and 32-Karat software, version 3.0. 118 mg of crude peptide is dissolved in AcOH/H2O, stirred, filtered and applied on an XBridge Prep OBD reversed phase column (4.6×250 mm, packed with C18 silica gel, 300 pore size, 5 mum particle size) (Waters Co., Milford, Mass.). The column is eluted with a solvent system described above in a linear gradient mode (e.g., 40-60% B in 120 min); flow rate 12 mL/min. The eluent is monitored at 220 nm, and fractions are examined by analytical HPLC. Fractions with purity higher than 95% are pooled and lyophilized to give 19 mg pure product. The analytical HPLC is carried out on a Supelco Discovery C18 reversed-phase column described above using isocratic elution with a solvent system described above with a flow rate of 0.2 mL/min. The peaks are monitored at 220 and 280 nm. The product is judged to be substantially (>95%) pure by analytical HPLC. Molecular mass is checked by electrospray mass spectrometry, and the expected amino acid composition is confirmed by amino acid analysis.

Reference： [1]Patent: US2015/274798,2015,A1 .Location in patent: Paragraph 0107; 0248-0252

68
[ 501-97-3 ]
[ 6638-79-5 ]
[ 827331-49-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at 20℃; for 1h; Inert atmosphere;	3.1 4.2 General procedure A: preparation of Weinreb amides General procedure: To a stirred solution of acid (1.00mmol), MeNH(OMe)·HCl (107mg, 1.10mmol) and DIPEA (0.52mL, 3.00mmol) in CH2Cl2 (2.5mL) was added T3P 50% in EtOAc (955mg, 1.50mmol). The solution was stirred at RT until completion was observed by TLC. The reaction mixture was poured into water (20mL) and acidified using 10% aq. HCl (5mL). The organics were collected and the aqueous extracted with EtOAc (3×30mL). The organics were combined, washed with aq. 2 M NaOH (20mL), brine (20mL), dried over MgSO4 and concentrated in vacuo to afford the Weinreb amide product.
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane Inert atmosphere;

Reference： [1]Clarke, Aimee K.; Unsworth, William P.; Taylor, Richard J.K. [Tetrahedron, 2018, vol. 74, # 38, p. 5374 - 5382]
[2]Yongsheng, Zheng; Ghazvini Zadeh, Ebrahim H.; Yuan, Yu [European Journal of Organic Chemistry, 2016, vol. 2016, # 12, p. 2115 - 2119]

69
[ 501-97-3 ]
[ 304-20-1 ]
C₁₇H₁₄N₄O [ No CAS ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 1078 - 1089

70
[ 501-97-3 ]
[ 999-97-3 ]
trimethylsilyl 3-(4-((trimethylsilyl)oxy)phenyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With iodine In neat (no solvent) at 20℃; for 20h; Green chemistry;	47 Representative procedure of I₂-catalyzed functionalization of carboxylic acids with HMDS General procedure: To a mixture of decanoic acid 1b (1.72 g, 10 mmol) and HMDS (1.61 g, 10 mmol), iodine (0.15 g, 0.6 mmol) was added, and the mixture was stirred at room temperature until the complete conversion of 1b. The initial heterogeneous reaction mixture became homogeneous, and 1H NMR analysis confirmed full conversion. A brown reaction mixture was diluted with a few drops of TBME, and anhydrous sodium thiosulfate was added in small portions during stirring at room temperature. After some time of stirring, the reaction mixture decolorized (the color of iodine disappeared). In some cases, the color of iodine persisted for hours, and then small portions of sodium thiosulfate pentahydrate were added. Further stirring reduced iodine, and the brown color disappeared. In a few cases, iodine disappeared during the reaction, and its removal was not needed. The reaction mixture was diluted with a small volume of TBME and filtered. The filtrate was concentrated under reduced pressure, and the thus-obtained reaction mixture was subjected to a vacuum distillation. After removal of excess of HMDS, the distillation of crude product gave trimethylsilyl decanoate 2b (1.18 g, 48%) as a slightly yellow oil. The distilled excess of HMDS could be reused.

Reference： [1]Jereb, Marjan; Lakner, Janja [Tetrahedron, 2016, vol. 72, # 37, p. 5713 - 5723]

71
[ 501-97-3 ]
[ 51762-67-5 ]
3-[4-(2-carboxyethyl)phenoxy]phthalonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate In dimethyl sulfoxide at 20 - 45℃;	1.1 With 3-nitrophthalonitrile (10 mmol) and p-hydroxyphenylpropionic acid (10-40 mmol, preferably 20 mmol) as the reactants, dimethyl sulfoxide (DMSO) (20-100 mL, preferably 30 mL) is the solvent, in the presence of potassium carbonate (30-90 mmol, preferably 50 mmol) and under the protection of nitrogen, the reaction is stirred at 20-45 (preferably 45 ) for 17-24 hours, and the end of the reaction is monitored by thin layer chromatography.After the reaction, the reaction solution was added to 300 mL of ice water, and 1 M HCl was added to make a large amount of brownish-yellow precipitate precipitate. The bush funnel was suction filtered, washed with a large amount of deionized water until the filtrate was neutral, and the crude product was collected.After drying, add a small amount of acetone to dissolve the crude product, then add deionized water for recrystallization, suction filtration, washing with water, and drying to obtain the product with a yield of 85%.
70%	With potassium carbonate In dimethyl sulfoxide at 20℃; for 30h; Inert atmosphere;	3.1 (3) Preparation of the following structural formula 3-[4-(2-carboxyethyl)phenoxy]phthalonitrile In p-hydroxyphenyl propionic acid (15mmol) and 3-nitro phthalonitrile (15mmol) as reactants, anhydrous DMSO as solvent (30ml), potassium carbonate (45mmol) the presence and under nitrogen, stirred at room temperature The reaction 30 hours, by thin layer chromatography to monitor the end of reaction.The reaction mixture was diluted with sand core funnel filtration, the filtrate was collected, and the filtrate was added to 500ml of ice water mixture, adjusted with 1M hydrochloric acid solution until the solution was acidic precipitation heavy precipitate, was allowed to stand, an organic microporous membrane, repeated washing more times until the solution was neutral, the solid was collected and lyophilized to give a white solid, further use DMF- water purified by recrystallization to give a white desired product, a yield of about 70%.
	With potassium carbonate In dimethyl sulfoxide at 20℃; Inert atmosphere;

Reference： [1]Current Patent Assignee: FUZHOU UNIVERSITY - CN113603698, 2021, A Location in patent: Paragraph 0023
[2]Current Patent Assignee: FUZHOU UNIVERSITY - CN105622682, 2016, A Location in patent: Paragraph 0032; 0033
[3]Biyiklioglu, Mack [Journal of Porphyrins and Phthalocyanines, 2020]

72
[ 207399-07-3 ]
[ 501-97-3 ]
C₄₅H₅₃N₂O₃⁽¹⁺⁾*I^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 5h;	500 mg (0.92 mmol, 1 eq) of the compound prepared in Step 2 of Preparation Example 3 was dissolved in 2.5 mL of DMF, 255.6 mg (1.85 mmol, 2 eq) of potassium carbonate and307.4 mg (1.85 mmol, 2 eq) of 3- (4-hydroxyphenyl) propionic acid was added and the mixture was stirred at 40 C for 5 hours. After completion of the reaction, 120 mL of ethyl acetate was added to form crystals, followed by filtration and drying under reduced pressure. Purification by silica gel column chromatography with chloroform: methyl alcohol (6: 1) yielded pure compound 7-3. (62.0 mg, 10%).

Reference： [1]Patent: KR2015/49824,2015,A .Location in patent: Paragraph 0231; 0240-0242

73
[ 31643-49-9 ]
[ 501-97-3 ]
4-(4-carboxyethylphenoxy)phthalonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: 4-Nitrophthalonitrile; 3-(4-hydroxyphenyl)propanoic acid In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 36h; Inert atmosphere;	4.1 2.4.1 3(4-Phenoxy)-propanoic acid) phthalonitrile (1) 3-(4-Hydroxyphenyl)-propionic acid (1.44 g, 8.66 mmol) and 4-nitrophthalonitrile (1.5 g, 8.66 mmol) were dissolved in DMF (20 mL) under nitrogen atmosphere and the mixture was stirred at room temperature for 15 min. Finely ground K2CO3 (2.11 g,15.31 mmol) was added thereafter, and the reaction mixture was left to stir for a further 36 h at room temperature. The mixture was then added to ice water (150 mL). The resulting precipitate was filtered off, thoroughly washed with water, dried and recrystallized from ethanol to give complex 1. Yield: 2.24 g (89%). IR [cm-1]: 3300 (COOH) 2890-3030 (C-H), 2230 (C≡N), 1668-1583 (C=C), 1437-1387 (C-O), 1322-1275 (C-O), 1228 (Ar-O-Ar). 1H NMR (DMSO-d6): δ, ppm 7.89 (d, J = 7.52 Hz, 1H, Ar-H), 7.56 (d, J = 7.35 Hz, 1H, Ar-H), 7.37-7.32 (m, 3H, Ar-H), 7.12 (m, 2H, Ar-H), 3.48 (s, 1H, OH), 2.85 (t, J = 5.17 Hz, 2H, CH2), 2.55 (t, J = 6.54 Hz, 2H, CH2). Anal. Calc. for (C17H12N2O3): C, 69. 86; H, 4.14; N, 9.58. Found: C, 68.69: H, 3.89; N, 9.87.
87%	With potassium carbonate In N,N-dimethyl-formamide at 75℃;

Reference： [1]Dube, Edith; Nwaji, Njemuwa; Oluwole, David O.; Mack, John; Nyokong, Tebello [Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 349, p. 148 - 161]
[2]Hışır, Arif; Karakuş, Mücella Özbay; Karaoğlan, Gülnur Keser; Koca, Atıf; Maden, Yaren Erdağ [Dyes and Pigments, 2022]

74
[ 501-97-3 ]
[ 1481-92-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With borane-THF; Trimethyl borate In tetrahydrofuran at 0℃; for 4h; Inert atmosphere;	2-(3-hydroxypropyl)phenol(9b) 3-(4-Hydroxyphenyl)propionicacid (1.66 g, 10.0 mmol) was dissolved in dry THF (10 mL) under argonand trimethyl borate (3.35 mL, 30.0 mmol) was added. Separately,BH3.THFcomplex solution (20.0 mL, 20.0 mmol, 1.0 M solution in THF) wascooled to 0°C. The acid solution was added dropwise to theBH3.THFcomplex solution and the reaction mixture was stirred at 0°C for4 h. The reaction mixture was quenched with H2O(10 mL) and extracted with EtOAc (3 x 30 mL). The organic extractswere combined, dried over anhydrous MgSO4,filtered, and concentrated invacuoto obtain 2-(3-hydroxypropyl)phenol as a yellow oil (1.51 g, 9.9mmol, 99%) that was used without further purification. 1HNMR: (500 MHz, CDCl3):δ 7.12-7.09 (m, 2H), 6.88-6.84 (m, 2H), 3.66-3.64 (t,J = 6.0 Hz,2H), 2.79-2.76 (t, J= 6.5 Hz, 2H),1.91-1.86 (p, J= 6.0 Hz, 2H);13CNMR: (125 MHz, CDCl3):δ 154.7, 130.7, 127.7, 127.2, 120.9, 116.3, 60.9, 32.3, 25.2

75
[ 501-97-3 ]
[ 85-61-0 ]
[ 95456-56-7 ]

Yield	Reaction Conditions	Operation in experiment
	With recombinant Selaginella moellendorffii 4-coumarate:coenzyme A ligase 2; ATP; magnesium chloride; In aq. buffer; at 30℃; for 0.5h;pH 7.5;Enzymatic reaction;Kinetics;	General procedure: We performed Sm4CLs enzyme assays to detect the formation of the <strong>[85-61-0]CoA</strong> esters of variouscinnamic acid derivatives. Each 200 muL assay contained 10 mug purified protein, 200 muMsubstrate, 5mMATP, 300 muM<strong>[85-61-0]CoA</strong>, and 5mMMgCl2, made up in 200mMTris-HCl buffer (pH 7.5). Enzymatic reactionswere incubated for 30 min at 30 C, and the reaction products were analyzed using a HPLC device(1260 Infinity Binary LC system, Agilent, Santa Clara, CA, USA), equipped with a multi wavelengthdetector. The samples were separated through a 5-mum reverse-phase XDB-C18 column with a flow rateof 1 mL/min. A linear gradient of solvent A (1% H3PO4 in H2O) and solvent B (CH3CN) were appliedas follows: 0-5 min, 5% B isocratic; 5-35 min, 5-25% B linear; 35-36 min, 25-100% B linear. Standardsolutions of reference compounds were used for calibration.The effects of pH and temperature on the enzyme activity were examined using p-coumaricacid as substrate. To determine optimal pH, enzymatic activity was assessed in 200 mM Tris-HClbuffer (pH 5.0, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, and 9.0), while the optimal temperature was determined bymeasuring enzymatic activity at 10, 20, 30, 40, 50, and 60 C. All experiments were performed intriplicate. Kinetic parameters were determined using different substrate concentrations. We performedthis experiment in triplicate, with 3 mug purified enzyme in a final volume of 200 muL of 200 mM Tris-HClbuffer at the optimal pH and temperature for 10 min. The level of UV absorption was recorded at1 min intervals. Relevant wavelengths were 311 nm (cinnamoyl <strong>[85-61-0]CoA</strong>), 333 nm (p-coumaroyl <strong>[85-61-0]CoA</strong>),346 nm (caffeoyl <strong>[85-61-0]CoA</strong>), 346 nm (feruloyl <strong>[85-61-0]CoA</strong>), and 352 nm (sinapoyl <strong>[85-61-0]CoA</strong>) [37,41,42]. For determiningkinetic properties with dihydro-p-coumaric acid, reactions were incubated at optimal temperature for10 min and analyzed using HPLC, and then the quantity of the reaction product present was estimatedfrom a standard calibration curve.

Reference： [1]Advanced Synthesis and Catalysis,2019,vol. 361,p. 5346 - 5350
[2]Molecules,2018,vol. 23

76
[ 501-97-3 ]
[ 298-14-6 ]
[ 105650-32-6 ]

Yield	Reaction Conditions	Operation in experiment
24.1%	With 5-carboxyvanilate decarboxylase from Sphingmonas paucimobilis SYK-6 species, protein 2; In aq. phosphate buffer; dimethyl sulfoxide; at 30℃; for 24h;pH 8.5;Enzymatic reaction;	General procedure: lyophilized whole cells (1g) were resuspended in phosphate buffer (30mL, pH 5.5, 100mM) and were rehydrated for 30min. The substrate was added as 600muL stock solution (DMSO) to yield a final concentration of 50mM, followed by addition of KHCO3 (3M, 9g, final pH 8.5). The mixture was shaken at 30C and 200rpm. After 24h the reaction mixture was centrifuged (13,000rpm, 15min). The aqueous phase was acidified with 5M HCl and extracted with EtOAc. The organic phase were combined and subjected to silica gel column chromatography to yield the compound 2P as white solid

Reference： [1]Tetrahedron Letters,2018,vol. 59,p. 3810 - 3815

77
[ 501-97-3 ]
[ 58479-61-1 ]
C₄₁H₄₆O₃Si₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 1h;	1 Ph-C3-phenol-2-TG (Int-67) DBU (108 tL, 1.08 mmol) and t-butyldiphenylsilyl chloride (TBDPSC1, 338 tL, 1.30 mmol) were added to a solution of (4-hydroxyphenyl)propionic acid (Int-63; commercially available) (120 mg, 0.722 mmol) in DMF (4 mL) and the mixture stirred at room temperature for one hour. The reaction was diluted with ethyl acetate (15 mL) and organic phase washed with water and brine (15 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4.5% ethyl acetate/hexanes) gave silyl ester Int-64 (165 mg, 36%) as a colorless oil. ‘H NIVIR (400 MHz, CDC13): 7.75 - 7.70 (m, 4H), 7.63 - 7.58 (m, 4H), 7.46 -7.31 (m, 12H), 6.97 -6.91 (m, 2H), 6.71 -6.67 (m, 2H), 2.87 (t, J= 7.6 Hz, 2H), 2.72 (t, J 7.6 Hz, 2H), 1.11 (s, 9H), 1.07 (s, 9H); ‘3C NIVIR (101 IVIFIz, CDC13): 172.3 (C), 154.1 (C), 135.7 (4C; CH), 135.4 (4C; CH), 133.2 (2C; C), 133.0 (C), 132.0 (2C; C), 130.1 (2C; CH), 130.0 (2C; CH), 129.2 (2C; CH), 127.9 (4C; CH), 127.8 (4C; CH), 119.7 (2C; CH), 37.9 (CH2),30.4 (CH2), 27.0 (3C; CH3), 26.7 (3C; CH3), 19.6 (C), 19.2 (C).
36%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 1h;	1 DBU (108 µL, 1.08 mmol) and t-butyldiphenylsilyl chloride (TBDPSCl, 338 µL, 1.30 mmol) were added to a solution of (4-hydroxyphenyl)propionic acid (Int-63; commercially available) (120 mg, 0.722 mmol) in DMF (4 mL) and the mixture stirred at room temperature for one hour. The reaction was diluted with ethyl acetate (15 mL) and organic phase washed with water and brine (15 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4.5% ethyl acetate/hexanes) gave silyl ester Int-64 (165 mg, 36%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d 7.75- 7.70 (m, 4H), 7.63- 7.58 (m, 4H), 7.46- 7.31 (m, 12H), 6.97- 6.91 (m, 2H), 6.71- 6.67 (m, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.11 (s, 9H), 1.07 (s, 9H); 13C NMR (101 MHz, CDCl3): d 172.3 (C), 154.1 (C), 135.7 (4C; CH), 135.4 (4C; CH), 133.2 (2C; C), 133.0 (C), 132.0 (2C; C), 130.1 (2C; CH), 130.0 (2C; CH), 129.2 (2C; CH), 127.9 (4C; CH), 127.8 (4C; CH), 119.7 (2C; CH), 37.9 (CH2), 30.4 (CH2), 27.0 (3C; CH3), 26.7 (3C; CH3), 19.6 (C), 19.2 (C).
36%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 1h;	1 DBU (108 µL, 1.08 mmol) and t-butyldiphenylsilyl chloride (TBDPSCl, 338 µL, 1.30 mmol) were added to a solution of (4-hydroxyphenyl)propionic acid (Int-63; commercially available) (120 mg, 0.722 mmol) in DMF (4 mL) and the mixture stirred at room temperature for one hour. The reaction was diluted with ethyl acetate (15 mL) and organic phase washed with water and brine (15 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4.5% ethyl acetate/hexanes) gave silyl ester Int-64 (165 mg, 36%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d 7.75- 7.70 (m, 4H), 7.63- 7.58 (m, 4H), 7.46- 7.31 (m, 12H), 6.97- 6.91 (m, 2H), 6.71- 6.67 (m, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.11 (s, 9H), 1.07 (s, 9H); 13C NMR (101 MHz, CDCl3): d 172.3 (C), 154.1 (C), 135.7 (4C; CH), 135.4 (4C; CH), 133.2 (2C; C), 133.0 (C), 132.0 (2C; C), 130.1 (2C; CH), 130.0 (2C; CH), 129.2 (2C; CH), 127.9 (4C; CH), 127.8 (4C; CH), 119.7 (2C; CH), 37.9 (CH2), 30.4 (CH2), 27.0 (3C; CH3), 26.7 (3C; CH3), 19.6 (C), 19.2 (C).

36%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 1h;	1 DBU (108 pL, 1.08 mmol) and t-butyldiphenylsilyl chloride (TBDPSCI, 338 pL, 1.30 mmol) were added to a solution of (4-hydroxyphenyl)propionic acid (lnt-63; commercially available) (120 mg, 0.722 mmol) in DMF (4 mL) and the mixture stirred at room temperature for one hour. The reaction was diluted with ethyl acetate (15 mL) and organic phase washed with water and brine (15 mL each), dried (MgSCL) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4.5% ethyl acetate/hexanes) gave silyl ester Int-64 (165 mg, 36%) as a colorless oil. NMR (400 MHz, CDCh): d 7.75 - 7.70 (m, 4H), 7.63 - 7.58 (m, 4H), 7.46 - 7.31 (m, 12H), 6.97 - 6.91 (m, 2H), 6.71 - 6.67 (m, 2H), 2.87 (t, J= 7.6 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.11 (s, 9H), 1.07 (s, 9H); 13C NMR (101 MHz, CDCh): d 172.3 (C), 154.1 (C), 135.7 (4C; CH), 135.4 (4C; CH), 133.2 (2C; C), 133.0 (C), 132.0 (2C; C), 130.1 (2C; CH), 130.0 (2C; CH), 129.2 (2C; CH), 127.9 (4C; CH), 127.8 (4C; CH), 119.7 (2C; CH), 37.9 (CH2), 30.4 (CH2), 27.0 (3C; C), 26.7 (3C; C), 19.6 (C), 19.2 (C).
36%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 1h;	[00519] DBU (108 pL, 1.08 mmol) and t-butyldiphenylsilyl chloride (TBDPSCI, 338 pL, 1.30 mmol) were added to a solution of (4-hydroxyphenyl)propionic acid (lnt-63; commercially available) (120 mg, 0.722 mmol) in DMF (4 mL) and the mixture stirred at room temperature for one hour. The reaction was diluted with ethyl acetate (15 mL) and organic phase washed with water and brine (15 mL each), dried (MgSCL) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4.5% ethyl acetate/hexanes) gave silyl ester Int-64 (165 mg, 36%) as a colorless oil. NMR (400 MHz, CDCh): d 7.75 - 7.70 (m, 4H), 7.63 - 7.58 (m, 4H), 7.46 - 7.31 (m, 12H), 6.97 - 6.91 (m, 2H), 6.71 - 6.67 (m, 2H), 2.87 (t, J= 7.6 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.11 (s, 9H), 1.07 (s, 9H); 13C NMR (101 MHz, CDCh): d 172.3 (C), 154.1 (C), 135.7 (4C; CH), 135.4 (4C; CH), 133.2 (2C; C), 133.0 (C), 132.0 (2C; C), 130.1 (2C; CH), 130.0 (2C; CH), 129.2 (2C; CH), 127.9 (4C; CH), 127.8 (4C; CH), 119.7 (2C; CH), 37.9 (CH2), 30.4 (CH2), 27.0 (3C; C), 26.7 (3C; C), 19.6 (C), 19.2 (C).
36%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 1h;	1 Ph-C3-phenol-2-TG (Int-67): [00458] DBU (108 L, 1.08 mmol) and t-butyldiphenylsilyl chloride (TBDPSCl, 338 L, 1.30 mmol) were added to a solution of (4-hydroxyphenyl)propionic acid (Int-63; commercially available) (120 mg, 0.722 mmol) in DMF (4 mL) and the mixture stirred at room temperature for one hour. The reaction was diluted with ethyl acetate (15 mL) and organic phase washed with water and brine (15 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4.5% ethyl acetate/hexanes) gave silyl ester Int-64 (165 mg, 36%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.75 - 7.70 (m, 4H), 7.63 - 7.58 (m, 4H), 7.46 - 7.31 (m, 12H), 6.97 - 6.91 (m, 2H), 6.71 - 6.67 (m, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.11 (s, 9H), 1.07 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 172.3 (C), 154.1 (C), 135.7 (4C; CH), 135.4 (4C; CH), 133.2 (2C; C), 133.0 (C), 132.0 (2C; C), 130.1 (2C; CH), 130.0 (2C; CH), 129.2 (2C; CH), 127.9 (4C; CH), 127.8 (4C; CH), 119.7 (2C; CH), 37.9 (CH2), 30.4 (CH2), 27.0 (3C; CH3), 26.7 (3C; CH3), 19.6 (C), 19.2 (C).
36%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 1h;	1 Ph-C3-phenol-2-TG (Int-67): [00458] DBU (108 L, 1.08 mmol) and t-butyldiphenylsilyl chloride (TBDPSCl, 338 L, 1.30 mmol) were added to a solution of (4-hydroxyphenyl)propionic acid (Int-63; commercially available) (120 mg, 0.722 mmol) in DMF (4 mL) and the mixture stirred at room temperature for one hour. The reaction was diluted with ethyl acetate (15 mL) and organic phase washed with water and brine (15 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4.5% ethyl acetate/hexanes) gave silyl ester Int-64 (165 mg, 36%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.75 - 7.70 (m, 4H), 7.63 - 7.58 (m, 4H), 7.46 - 7.31 (m, 12H), 6.97 - 6.91 (m, 2H), 6.71 - 6.67 (m, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.11 (s, 9H), 1.07 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 172.3 (C), 154.1 (C), 135.7 (4C; CH), 135.4 (4C; CH), 133.2 (2C; C), 133.0 (C), 132.0 (2C; C), 130.1 (2C; CH), 130.0 (2C; CH), 129.2 (2C; CH), 127.9 (4C; CH), 127.8 (4C; CH), 119.7 (2C; CH), 37.9 (CH2), 30.4 (CH2), 27.0 (3C; CH3), 26.7 (3C; CH3), 19.6 (C), 19.2 (C).

Reference： [1]Current Patent Assignee: PURETECH HEALTH PLC; MONASH UNIVERSITY - WO2019/46491, 2019, A1 Location in patent: Paragraph 00494; 00495
[2]Current Patent Assignee: PURETECH HEALTH PLC - WO2020/28787, 2020, A1 Location in patent: Paragraph 00365; 00366
[3]Current Patent Assignee: PURETECH HEALTH PLC - WO2020/176859, 2020, A1 Location in patent: Paragraph 00525-00526
[4]Current Patent Assignee: PURETECH HEALTH PLC; MONASH UNIVERSITY - WO2020/176868, 2020, A1 Location in patent: Paragraph 00405; 00535
[5]Current Patent Assignee: MONASH UNIVERSITY; PURETECH HEALTH PLC - WO2020/176856, 2020, A1 Location in patent: Paragraph 00519
[6]Current Patent Assignee: MONASH UNIVERSITY; PURETECH HEALTH PLC - WO2021/159021, 2021, A1 Location in patent: Paragraph 00458
[7]Current Patent Assignee: MONASH UNIVERSITY; PURETECH HEALTH PLC - WO2021/159021, 2021, A1 Location in patent: Paragraph 00458

78
[ 124-38-9 ]
[ 14140-15-9 ]
[ 938-96-5 ]
[ 501-97-3 ]

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 9001 - 9005

79
[ 1643-29-4 ]
[ 501-97-3 ]

Yield	Reaction Conditions	Operation in experiment
79%	With copper(I) oxide; 1D-1-O-Methyl-muco-inostol; sodium hydroxide; In water; at 100℃; for 6h;	In the l00mL hydrothermal synthesis reactor,Add sodium hydroxide (3 mmol), water (5 mL), stir and dissolve,Adding iodinePhenylpropionic acid(0.5 mmol), cuprous oxide (0.05 mmol),White lignan (0.05 mmol), the reaction was stirred at 100 C for 6 hours.After cooling, the pH was adjusted to 2 with dilute hydrochloric acid and extracted with ethyl acetate.The extract was concentrated and subjected to column chromatography to obtain p-hydroxyphenylpropionic acid, 65.6 mg.The yield was 79%.

Reference： [1]Patent: CN109970542,2019,A .Location in patent: Paragraph 0060-0062

80
[ 107-13-1 ]
[ 108-95-2 ]
[ 501-97-3 ]

Yield	Reaction Conditions	Operation in experiment
87.5%	With hydrogenchloride; aluminum (III) chloride at 180 - 200℃;	1; 2; 3; 4; 5 Example 5 The first storage part of the tubular reactor system was charged with 1.27 kg of acrylonitrile, 2.10 kg of phenol, and slightly heated to dissolve it.Solution; the second reserve of the tubular reactor system was charged with 1.27 kg of acrylonitrile.2.58 kg of aluminum trichloride, and slightly heated to dissolve it;The reaction materials of the first reserve portion and the second reserve portion of the reaction system are sent to the opposite side through the connecting pipe of the tubular reactorThe product is reacted to obtain the product p-hydroxyphenylpropionic acid.The flow rate of the reactant inside the connecting pipe is 8-10 L/min, and the temperature is 180-200 ° C,The pressure is from 7 bar to 10 bar, and the reaction time of the reactants in the reaction portion is from 25 minutes to 30 minutes; the product is hydrolyzed by washing with ice water, acidified by hydrochloric acid, and the organic layer is dried with saturated sodium chloride and anhydrous magnesium sulfate.After removal under reduced pressure, a white solid was obtained.That is, the target product p-hydroxyphenylpropionic acid is 1.75 kg.The yield was 87.5%.

Reference： [1]Current Patent Assignee: LIAONING BOMEI PHARMACEUTICAL TECH - CN109836325, 2019, A Location in patent: Paragraph 0023; 0026-0030

81
[ 50-00-0 ]
[ 501-97-3 ]
[ 124-30-1 ]
C₂₉H₄₉NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	In toluene at 119.84℃; for 16h;	Preparation of 3-octadecyl-3-(3-phenyl-3,4-dihydro-2H-1,3-benzoxazine-6-yl) propanoic acid(PA-sa) A mixture of stearylamine (6 mmol), phloretic acid(6 mmol) and paraformaldehyde (18 mmol) in toluene(50 mL) was refluxed at 393 K for 16 h. The resulting lightyellow solution was cooled, filtered and concentrated under educed pressure, resulting in a yellow powder. Product was washed with cold diethyl ether several times and was dried in vacuum. The monomer thus obtained has been designatedas PA-sa. (Yield ~ 80%) FT-IR: 2916 cm-1, 2852 cm-1,2535 cm-1, 1716 cm-1, 1369 cm-1, 1234 cm-1, 1141 cm-1,1004 cm-1, 957 cm-1. 1H-NMR (400 MHz, CDCl3):0.9 ppm(3H, t, CH2CH3),1.3 ppm (30H, m, -CH2-), 1.5 ppm(2H, m, CH2CH3), 2.6 ppm (2H, t, CH2Ar), 2.7 ppm(2H, t, CH2COOH), 2.8 ppm (2H, t, CH2N-), 4.0 ppm(2H, s, NCH2Ar), 4.8 ppm (2H, s, OCH2N), 6.7-6.9 ppm(6H, ArH), 13C-NMR (CDCl3): 14 ppm (-CH3), 22 ppm(CH2CH3), 27 ppm (-CH2-), 28 ppm (-CH2-), 30 ppm(-CH2-), 33 ppm (-CH2-), 36 ppm (-CH2-), 49 ppm(-NCH2-), 51 ppm (-ArCH2N-), 82 ppm (-OCH2N-),115-153 ppm (aromatic carbons), 179 (COOH).

Reference： [1]Kirubakaran, Ramachandran; Sharma, Pratibha; Manisekaran, Ahilan; Bijwe, Jayashree; Nebhani, Leena [Journal of Thermal Analysis and Calorimetry, 2020, vol. 142, # 3, p. 1233 - 1242]

82
[ 501-97-3 ]
[ 62-53-3 ]
[ 58608-95-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With ammonium cerium (IV) nitrate In neat (no solvent) at 160 - 165℃; for 2h; Microwave irradiation; Green chemistry;	General procedure General procedure: Amine (4.2 mmol), carboxylic acid (2 mmol), and catalyst (ceric ammonium nitrate) (2 mol%)were added to an empty flask equipped with a reflux condenser, at atmospheric pressure, placed ina microwave set to maintain a constant temperature in the range of 160-165 °C for a given time period(microwave power set up to 480 W but was smoothly and automatically controlled by the softwareto keep the target temperature constant). After 2 h, the reaction mixture was allowed to cool to roomtemperature, and subsequently, 25 mL of ethyl acetate were added. The organic phase was washedwith 3 x 15 mL of 2 M aqueous HCl, 3 x 15 mL saturated aqueous NaHCO3, and 3 x 15 mL of saturatedaqueous NaCl; dried over Na2SO4; filtered; and the solvent was removed under reduced pressure toobtain the pure product. The resulting products were characterized by 1H NMR, 13C NMR, andHRMS.