[ CAS No. 93-25-4 ] {[proInfo.proName]}

Name: 93-25-4|2-Methoxyphenylacetic acid|97%
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Quality Control of [ 93-25-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 93-25-4 ]

Product Details of [ 93-25-4 ]

CAS No. :	93-25-4	MDL No. :	MFCD00004321
Formula :	C₉H₁₀O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IVEWTCACRDEAOB-UHFFFAOYSA-N
M.W :	166.17	Pubchem ID :	7134
Synonyms :

Calculated chemistry of [ 93-25-4 ]

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 :	1.0
Molar Refractivity :	44.48
TPSA :	46.53 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) :	-6.26 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.56
Log Po/w (XLOGP3) :	1.48
Log Po/w (WLOGP) :	1.32
Log Po/w (MLOGP) :	1.37
Log Po/w (SILICOS-IT) :	1.55
Consensus Log Po/w :	1.46

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.97
Solubility :	1.76 mg/ml ; 0.0106 mol/l
Class :	Very soluble
Log S (Ali) :	-2.06
Solubility :	1.43 mg/ml ; 0.00863 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.29
Solubility :	0.842 mg/ml ; 0.00507 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.37

Safety of [ 93-25-4 ]

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 [ 93-25-4 ]

* 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 [ 93-25-4 ]
Downstream synthetic route of [ 93-25-4 ]

[ 93-25-4 ] Synthesis Path-Upstream 1~9

1
[ 93-25-4 ]
[ 19090-04-1 ]

Reference： [1] Tetrahedron, 1989, vol. 45, # 5, p. 1441 - 1446

2
[ 93-25-4 ]
[ 32940-15-1 ]

Reference： [1] Tetrahedron, 1989, vol. 45, # 5, p. 1441 - 1446

3
[ 93-25-4 ]
[ 7417-18-7 ]

Reference： [1] European Journal of Organic Chemistry, 1999, # 2, p. 463 - 470
[2] Heterocycles, 1998, vol. 49, # 1, p. 105 - 108
[3] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 11, p. 2003 - 2006
[4] Angewandte Chemie - International Edition, 2015, vol. 54, # 36, p. 10596 - 10599[5] Angew. Chem., 2015, vol. 127, p. 10742 - 10745,4
[6] Journal of the American Chemical Society, 1964, vol. 86, p. 2902 - 2909
[7] Bulletin de la Societe Chimique de France, 1973, p. 3433 - 3436
[8] Tetrahedron Letters, 2002, vol. 43, # 43, p. 7777 - 7780
[9] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
[10] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3719 - 3735

4
[ 93-25-4 ]
[ 6342-77-4 ]

Reference： [1] Tetrahedron, 1989, vol. 45, # 5, p. 1441 - 1446

5
[ 93-25-4 ]
[ 36449-75-9 ]

Reference： [1] European Journal of Organic Chemistry, 1999, # 2, p. 463 - 470

6
[ 67-56-1 ]
[ 93-25-4 ]
[ 27798-60-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	at 50℃; for 0.333333 h; Sonication	General procedure: The carboxylic acid (0.271 mmol), TCT (0.050 g, 0.271 mmol), PS-Ph3P (0.009 g, 0.027 mmol, loading 3.0 mmol/g), and Na2CO3 (0.057 g, 0.542 mmol) were added to MeOH (0.5 mL). Then the mixture was sonicated in an ultrasonic bath (Elmasonic S 30H) at 50°C for the specified time. After completion, the crude mixture was filtered through a short pad of silica to obtain the product after solvent evaporation. Whenever necessary, the product was further purified by flash chromatography.
87%	Reflux	General procedure: To an appropriately substituted phenylacetic acid (10 mmol) dissolved in dried methanol (50 mL), concentrated sulfuric acid (0.5 mL) was added dropwise.The mixture was refluxed from 7 to 9 h. Next, the solvent was evaporated, and residue was dissolved in 40 mL of ethyl acetate, washed with 0.5percent NaOH andbrine. Organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to give the products as colorless oils.

Reference： [1] Helvetica Chimica Acta, 2003, vol. 86, # 2, p. 343 - 360
[2] Synlett, 2015, vol. 26, # 14, p. 2006 - 2008
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 2, p. 555 - 559[4] Angew. Chem., 2018, vol. 130, # 2, p. 564 - 568,5
[5] Tetrahedron Letters, 2003, vol. 44, # 2, p. 331 - 334
[6] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 117 - 124
[7] Tetrahedron Letters, 1994, vol. 35, # 40, p. 7307 - 7310
[8] Medicinal Chemistry Research, 1995, vol. 5, # 8, p. 618 - 630
[9] Journal of the Brazilian Chemical Society, 2012, vol. 23, # 5, p. 854 - 860
[10] Chemical Communications, 2012, vol. 48, # 79, p. 9936 - 9938
[11] Medicinal Chemistry Research, 2012, vol. 21, # 11, p. 3885 - 3896
[12] Russian Journal of Bioorganic Chemistry, 2015, vol. 41, # 2, p. 170 - 177
[13] CrystEngComm, 2014, vol. 16, # 2, p. 164 - 174
[14] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3719 - 3735

7
[ 93-25-4 ]
[ 27798-60-3 ]

Reference： [1] Patent: US4695648, 1987, A,

8
[ 186581-53-3 ]
[ 93-25-4 ]
[ 27798-60-3 ]

Reference： [1] Bulletin of the Chemical Society of Japan, 1985, vol. 58, p. 340 - 345
[2] Tetrahedron, 1998, vol. 54, # 12, p. 2763 - 2770

9
[ 93-25-4 ]
[ 22446-37-3 ]

Reference： [1] Journal of the American Chemical Society, 1948, vol. 70, p. 1930

[ 93-25-4 ] Synthesis Path-Downstream 1~57

1
[ 93-25-4 ]
[ 28033-63-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;Inert atmosphere;	To a solution of 2-(2-methoxyphenyl)acetic acid (10 g, 60.2 mmol) in DCM (100 mL) was added oxalyl chloride (15 mL, 180.5 mmol) dropwise followed by DMF (3 drops) and the mixture was stirred at RT under N2 for 2 h. The mixture was concentrated under reduced pressure to give the title compound (11 g, 100%) as a red oil. LCMS-D: Rt 2.28 min; m/z 181.0 [M-CI+MeOH]+.
	With thionyl chloride;	(2-Methoxyphenyl)-acetyl chloride is obtained from a mixture of 2.2 g of (2-methoxyphenyl)-acetic acid and 20 cm3 of thionyl chloride, which is refluxed for 30 minutes. After concentrating to dryness under reduced pressure (2.7 kPa), 2.4 g of a yellow oil, which is used in the crude state in the subsequent syntheses, are obtained.
	With thionyl chloride; urea; for 2h;Inert atmosphere;	EXAMPLE 1; Production of 3-methoxypterocarpan compound (B)Example 1.11-(2,4-dimethoxyphenyl)-2-(2'-methoxyphenyl)-1-ethanone 66 g (0.55 mol) thionyl chloride are prepared under N2-atmosphere and with the addition of 0.4 g urea, 66 g (0.40 mol) 2-methoxyphenyl acetic acid are then added while stirring, in a plurality of portions within 30 min. After 2 h backflow 90 g dichloromethane are added and this solution is metered into a mixture of 69 g (0.50 mol) resorcindimethylether and 67 g (0.50 mol) AlCl3 in 300 g dichloromethane within 1 h at RT (room temperature; about 20 C.). Stirring is continued for 2 h and hydrolysis takes place in 500 g ice water. Rinsing takes place to neutral with water and Na-bicarbonate, the dichloromethane is distilled off and the residue distilled from toluene. Yield: 177 g (60% d.Th.)

	With thionyl chloride; In tetrahydrofuran; for 1.5h;Reflux;	General procedure: 2-Methoxyphenyl acetic acid (465 mg, 2.8 mmol) and thionyl chloride (204 muL, 2.8 mmol) were refluxed in anhydrous THF (1 mL) for 1.5 hours, and the resulting reaction solution was added to a solution containing 9d (200 mg, 0.67 mmol) and DIPEA (210 muL, 1.2 mmol) in THF (0.5 mL). After stirring for 1 day, the reaction mixture was taken up in EtOAc, washed with 1M aqueous HCl, washed with 5% aqueous Na2CO3, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 4:1) to yield an oil (161 mg, 54%). An 81 mg sample was further purified by HPLC (4.8 mg). 1H NMR (300 MHz, CDCl3) delta 11.2 (br s, 1H, NH), 7.31 (m, 2H, Ar-H), 6.95 (m, 2H, Ar-H), 4.53 (s, 2H, 7-CH2), 4.27 (q, J = 7.1 Hz, 2H, CH2CH3), 4.17 (q, J = 7.1 Hz, 2H, CH2CH3), 3.89 (s, 3H, OCH3), 3.82 (s, 2H, CH2Ar), 3.68 (m, 2H, 5-CH2), 2.86 (m, 2H, 4-CH2), 1.30 (t, J = 7.2 Hz, 3H, CH2CH3), 1.30 (t, J = 6.9 Hz, 3H, CH2CH3). ESI-MS m/z 447.3 [M + H]+.
	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4h;	General procedure: To a solution of substituted phenyl acetic acid or naphthylacetic acid (200 mg, 1.1 mmol) in dry DCM (10 ml) was added SOCl2 (128 mg, 1.1 mmol) and DMF (1 drop). The mixture was stirred at room temperature for 4 hours, following which the solvent was removed in vacuo. Dry DCM (10 ml) was added to re-dissolve the residue. After that, the solution was dropwise added into the mixture of 4-methoxybenzyl hydroxylamine (3) (165 mg, 1.1 mmol) and Et3N (223 mg, 2.2 mmol) in DCM (10 ml) and stirred at room temperature for 1h. The reaction mixture was quenched with water (20 ml) and then extracted with DCM (3 x 20ml). The combined organic layers was washed with brine and dried with anhydrous Na2SO4. The solvent was removed in vacuo. The crude product was purified with column chromatography (33% EA/Petroleum ether) to obtain a white solid in yields range from 68 to 88% yield.
	With trichlorophosphate; In 1,2-dichloro-ethane; for 3h;Reflux;	General procedure: Aralkanoic acid chlorides 2a-g were synthesized by the reaction of aralkanoic acid 1a-g (1 mmol) in the presence of 1,2-dichloroethane (12 mL) solvent and phosphorous oxychloride(0.4 mL) chlorinating agent under reflux for 3hours. Then, the resulting solution was cooled to room temperature, and the solvent was removed under reduced pressureto afford aralkanoic acid chloride 2a-g, which was directly used in the next step without further purification. Acid chloride 2a-g was dissolved in acetonitrile (80 mL), addeddropwise to a solution containing hydrazine hydrate(1 mmol), TEA (0.5 mL) and acetonitrile (20 mL) and allowed to reflux for 3 hours with monitoring by TLC. After consumption of the starting material, the reaction mixture was cooled to room temperature. Evaporation of the solvent under reduced pressure yielded crude acid hydrazide 3a-g as a white solid on cooling, which was purified by column chromatography and crystallized in methanol [46].
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere;	General procedure: To an over-dried 100 mL three-necked flask, the carboxylic acid (10 mmol), DMF (5 drops) and DCM (30 mL) were added under a N2 atmosphere. Oxalyl chloride (1.0 mL, 12 mmol) was added dropwise at 0 C resulting in vigorous bubbling. The mixture was stirred for 3 h at room temperature, and the solvent was then removed in vacuo. The resulting acid chloride was used immediately without further purification. To a solution of the acid chloride in DCM (30 mL) ,a solution of 1,1,1,3,3,3-hexamethyldisilazane (30 mmol) in DCM (10 mL) was added dropwise at 0 C, and the solution was then allowed to warm to room temperature. After stirring overnight, the reaction system was quenched with 1 M HCl aq. and saturated aqueous NH4Cl (excess amount) and the organic layer was separated. The aqueous layer was extracted with DCM (2x15 mL). The combined organic layers were washed with saturated aqueous NH4Cl (30 mL) and brine (30 mL), dried over MgSO4, filtered and evaporated in vacuo. The resulting crude material was purified by recrystallization from EtOAc and hexane. The resulting product (5 mmol), 8-bromomethylquinoline (6 mmol), Al2O3 (50 mmol), KOH (25 mmol) and dioxane (30 mL) were added to an over-dried 100 mL three-necked flask. The mixture was stirred for 8 h at 60 C and then was filtered through a celite pad. The filtrate was washed with H2O (30 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtrated and evaporated in vacuo. The resulting crude amide was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1).
	With trichlorophosphate; In 1,2-dichloro-ethane; for 3h;Reflux;	General procedure: The substituted aromatic acid chloride 2 was synthesizedthrough the reaction of substituted aromatic acid 1(1 mmol) in the presence of 1,2-dichloroethane (12 mL)solvent and phosphorous oxychloride (0.4 mL) chlorinatingagent under reflux for 3 h. Then, the resulting solutionwas cooled to room temperature, and the solvent wasremoved under reduced pressure to yield substituted aromaticacid chloride 2, which was directly used in the nextstep without any further purification. The substituted aromaticacid chloride 2 was dissolved in acetonitrile(80 mL), added dropwise to a solution containing hydrazinehydrate (1 mmol), TEA (0.5 mL), and acetonitrile(20 mL), and allowed to reflux for 3 h with monitoring byTLC. After consumption of the starting material, thereaction mixture was cooled to room temperature. Evaporationof the solvent under reduced pressure yielded crudesubstituted aromatic acid hydrazide 3 as a white solid on cooling, which was purified by column chromatography ifneeded and crystallized with methanol.
	With thionyl chloride;	[0081] <strong>[93-25-4]2-Methoxyphenylacetic acid</strong> (75 mg, 0.45 mmol) was treated with thionyl chloride, and thereby made into 2-methoxyphenylacetyl chloride, and the resultant and 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione(95 mg, 0.3 mmol) were heated in pyridine to obtain the title compound (83 mg, yield 60%) as pale yellow crystals.1H NMR (DMSO-d6, 400 MHz) delta: 3.14 (1H, d, J=12Hz), 3.64 (2H, s), 3.69 (1H, d, J=12Hz), 3.77 (3H, s), 6.90 (1H, t,J=7Hz), 6.9-7.0 (2H, m), 7.15 (2H, d, J=8Hz), 7.2-7.3 (2H, m), 7.59 (1H, t, J=8Hz), 7.6-7.7 (4H, m), 7.91 (1H, d, J=8Hz),8.25 (1H, d, J=8Hz), 10.17 (1H, s), 10.86 (1H, s)

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 9206 - 9218
[2]Patent: WO2019/43139,2019,A1 .Location in patent: Page/Page column 74
[3]Monatshefte fur Chemie,1980,vol. 111,p. 81 - 92
[4]Tetrahedron,2000,vol. 56,p. 6279 - 6290
[5]Chemische Berichte,1951,vol. 84,p. 247,252
[6]Journal of the American Chemical Society,1964,vol. 86,p. 2902 - 2909
[7]Journal of the Chemical Society. Perkin transactions I,1991,p. 1453 - 1459
[8]Tetrahedron,1989,vol. 45,p. 1441 - 1446
[9]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 2440 - 2446
[10]Journal of Medicinal Chemistry,1985,vol. 28,p. 1106 - 1109
[11]Journal of Medicinal Chemistry,1997,vol. 40,p. 4053 - 4068
[12]Synlett,1998,p. 153 - 156
[13]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 821 - 823
[14]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 423 - 438
[15]Journal of Medicinal Chemistry,2006,vol. 49,p. 3563 - 3580
[16]Patent: US5463077,1995,A
[17]European Journal of Medicinal Chemistry,2008,vol. 43,p. 792 - 799
[18]Journal of Organic Chemistry,2009,vol. 74,p. 2571 - 2574
[19]Tetrahedron Letters,2010,vol. 51,p. 2888 - 2891
[20]Angewandte Chemie - International Edition,2011,vol. 50,p. 463 - 466
[21]Patent: US2011/34486,2011,A1 .Location in patent: Page/Page column 9-10
[22]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7089 - 7093
[23]Organic and Biomolecular Chemistry,2012,vol. 10,p. 1598 - 1601
[24]Journal of Medicinal Chemistry,2012,vol. 55,p. 9531 - 9540
[25]Chemical Communications,2013,vol. 49,p. 1654 - 1656
[26]Organic Letters,2014,vol. 16,p. 390 - 393
[27]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772
[28]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 607 - 610
[29]Medicinal Chemistry,2014,vol. 10,p. 810 - 823
[30]Chemistry Letters,2015,vol. 44,p. 621 - 623
[31]Journal of the American Chemical Society,2015,vol. 137,p. 11574 - 11577
[32]Archives of Pharmacal Research,2016,vol. 39,p. 161 - 171
[33]Patent: EP3020717,2016,A1 .Location in patent: Paragraph 0081; 0096
[34]ChemMedChem,2017,vol. 12,p. 1512 - 1524
[35]Angewandte Chemie - International Edition,2018,vol. 57,p. 9425 - 9429
Angew. Chem.,2018,vol. 130,p. 9569 - 9573,5
[36]Chemical Science,2019,vol. 10,p. 7399 - 7406
[37]Organic Letters,2019,vol. 21,p. 6909 - 6913
[38]Journal of Enzyme Inhibition and Medicinal Chemistry,2020,vol. 35,p. 404 - 413

2
[ 186581-53-3 ]
[ 93-25-4 ]
[ 27798-60-3 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1985,vol. 58,p. 340 - 345
[2]Tetrahedron,1998,vol. 54,p. 2763 - 2770

3
[ 67-56-1 ]
[ 93-25-4 ]
[ 27798-60-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 1,3,5-trichloro-2,4,6-triazine; sodium carbonate; at 50℃; for 0.333333h;Sonication;	General procedure: The carboxylic acid (0.271 mmol), TCT (0.050 g, 0.271 mmol), PS-Ph3P (0.009 g, 0.027 mmol, loading 3.0 mmol/g), and Na2CO3 (0.057 g, 0.542 mmol) were added to MeOH (0.5 mL). Then the mixture was sonicated in an ultrasonic bath (Elmasonic S 30H) at 50C for the specified time. After completion, the crude mixture was filtered through a short pad of silica to obtain the product after solvent evaporation. Whenever necessary, the product was further purified by flash chromatography.
87%	With sulfuric acid;Reflux;	General procedure: To an appropriately substituted phenylacetic acid (10 mmol) dissolved in dried methanol (50 mL), concentrated sulfuric acid (0.5 mL) was added dropwise.The mixture was refluxed from 7 to 9 h. Next, the solvent was evaporated, and residue was dissolved in 40 mL of ethyl acetate, washed with 0.5% NaOH andbrine. Organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to give the products as colorless oils.
87%	With sulfuric acid; for 8h;Reflux;	(1) First install the three-necked flask on a magnetic stirrer with a heating device, install a temperature controller and a condenser tube, and mix 18g (0.15mol) methoxyphenylacetic acid, 50ml (1.23mol) methanol and 5ml concentrated sulfuric acid Add to a 100ml three-necked flask and reflux for 8h.Then add saturated sodium carbonate to neutralize the excess acid, and then extract with ethyl acetate, add anhydrous sodium sulfate to dry, rotary evaporation to obtain methyl ortho-methoxyphenyl acetate, light yellow liquid, yield 87%.

	With thionyl chloride; at 0 - 20℃; for 3h;	General procedure: 5.1.57.1. Step 1. To a solution of 3-fluorophenylacetic acid (24.85 g,158 mmol) in MeOH (200 mL) was added SOCl2 (4.00 mL,52.2 mmol) at 0 C with silica gel blue tube. After stirring at rtfor 3 h, the reaction mixture was concentrated under reduced pressure.The residue was partitioned between 1 N NaOH (250 mL) andEtOAc (250 mL). The separable organic layer was washed withbrine (100 mL), dried over MgSO4, filtered, concentrated underreduced pressure to obtain methyl (3-fluorophenyl)acetate(25.81 g, 97%) as colorless oil.
	With sulfuric acid; for 8h;Reflux;	General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a)

Reference： [1]Helvetica Chimica Acta,2003,vol. 86,p. 343 - 360
[2]Synlett,2015,vol. 26,p. 2006 - 2008
[3]Angewandte Chemie - International Edition,2018,vol. 57,p. 555 - 559
Angew. Chem.,2018,vol. 130,p. 564 - 568,5
[4]Tetrahedron Letters,2003,vol. 44,p. 331 - 334
[5]European Journal of Medicinal Chemistry,2017,vol. 135,p. 117 - 124
[6]Patent: CN103304441,2016,B .Location in patent: Page/Page column 5-7
[7]Tetrahedron Letters,1994,vol. 35,p. 7307 - 7310
[8]Medicinal Chemistry Research,1995,vol. 5,p. 618 - 630
[9]Journal of the Brazilian Chemical Society,2012,vol. 23,p. 854 - 860
[10]Chemical Communications,2012,vol. 48,p. 9936 - 9938
[11]Medicinal Chemistry Research,2012,vol. 21,p. 3885 - 3896
[12]CrystEngComm,2014,vol. 16,p. 164 - 174
[13]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3719 - 3735
[14]Molecules,2019,vol. 24
[15]Journal of the American Chemical Society,2019,vol. 141,p. 10556 - 10564

4
[ 20780-77-2 ]
[ 93-25-4 ]
[ 124028-90-6 ]

Reference： [1]Journal of Heterocyclic Chemistry,1989,vol. 26,p. 281 - 284

5
[ 7417-18-7 ]
[ 93-25-4 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 2564 - 2566
[2]Organic Syntheses,2005,vol. 81,p. 195 - 203
[3]Tetrahedron Letters,1998,vol. 39,p. 5323 - 5326
[4]Bulletin of the Chemical Society of Japan,1993,vol. 66,p. 1511 - 1515

6
[ 93-25-4 ]
[ 7417-18-7 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 4.5h;Reflux;	General procedure: To a mixture of LiAlH4 (15 mmol) in anhydrous THF (25 mL) in an ice-bath was added dropwise a solution of phenylacetic acids (15 mmol) in THF (8 mL). This mixture was stirred at room temperature for 30 min, and then heated to reflux for 4 h. After it was cooled to room temperature, water (0.5 mL) was added, and then NaOH (15%, 0.5 mL) and water (1.5 mL) were added in sequence. After stirring for another 30 min, the mixture was filtered, dried over anhydrous Na2SO4 and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 50-85% yield by column chromatography. Alternative method: To a solution of phenylacetic acids (15 mmol) in MeOH (30 mL) was added SOCl2 (30 mmol). This mixture was heated to reflux for 3 h before evaporation. The residue was dissolved in DCM (30 mL), washed with aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated to give 100% yield of crude methyl phenylacetates which were used to next step without further purification. To a solution of the methyl phenylacetates in THF (30 mL) was added NaBH4 (60 mmol). When the mixture was heated to gently reflux, MeOH (1.0 mL) was added dropwise from a syringe over 5 min. After refluxing for another 6 h, the mixture was cooled to room temperature and poured into 30 mL ice water, and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 70-85% yield by column chromatography.

Reference： [1]European Journal of Organic Chemistry,1999,p. 463 - 470
[2]Heterocycles,1998,vol. 49,p. 105 - 108
[3]Chemical and Pharmaceutical Bulletin,1993,vol. 41,p. 2003 - 2006
[4]Angewandte Chemie - International Edition,2015,vol. 54,p. 10596 - 10599
Angew. Chem.,2015,vol. 127,p. 10742 - 10745,4
[5]Journal of the American Chemical Society,1964,vol. 86,p. 2902 - 2909
[6]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 131 - 134
[7]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3719 - 3735

7
[ 93-25-4 ]
[ 7017-48-3 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1992,p. 123 - 130

8
[ 27798-60-3 ]
[ 93-25-4 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1982,p. 2575 - 2582

9
[ 93-25-4 ]
[ 33567-59-8 ]

Yield	Reaction Conditions	Operation in experiment
	With borane-THF; Dess-Martin periodane 1.) THF, 4 h, 2.) CH₂Cl₂, 1 h; Yield given; Multistep reaction;
	Multi-step reaction with 3 steps 1: thionyl chloride; N,N-dimethyl-formamide / toluene / 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: zirconocene dichloride; lithium tri-t-butoxyaluminum hydride / tetrahydrofuran / 0.03 h / 20 °C / Inert atmosphere

Reference： [1]Kraus, George A.; Melekhov, Alex [Journal of Organic Chemistry, 1999, vol. 64, # 2-5, p. 1720 - 1722]
[2]Zhao, Yigang; Snieckus, Victor [Organic Letters, 2014, vol. 16, # 2, p. 390 - 393]

10
[ 93-25-4 ]
[ 135-02-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With dipotassium peroxodisulfate; In water; at 90℃; for 12h;Green chemistry;	General procedure: In an oven dried tube containing a mixture of 4-methyl phenyl acetic acid 1a (200 mg, 1.33mmol) and potassium persulfate (360 mg, 2.66 mmol), water (2 mL) was added and heated at 90 °C for 12 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature (24°C) and it was extracted with ethyl acetate (3 x 5 mL). The crude product was purified by column chromatography to furnish compound 2a as colorless liquid (136 mg, 85percent yield).

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 3394 - 3398
[2]Journal of Chemical Research,2011,vol. 35,p. 157 - 160
[3]Oriental Journal of Chemistry,2012,vol. 28,p. 857 - 866,10
[4]Asian Journal of Chemistry,2011,vol. 23,p. 1081 - 1084
[5]Patent: CN110963900,2020,A .Location in patent: Paragraph 0057-0062
[6]Tetrahedron Letters,2006,vol. 47,p. 1965 - 1968
[7]Journal of the Iranian Chemical Society,2011,vol. 8,p. 470 - 476
[8]Chinese Chemical Letters,2019
[9]Tetrahedron Letters,2017,vol. 58,p. 2822 - 2825
[10]Journal of Chemical Research,2004,p. 296 - 297
[11]Journal of Organic Chemistry,2014,vol. 79,p. 1867 - 1871
[12]Photochemical and Photobiological Sciences,2010,vol. 9,p. 1367 - 1377

11
[ 93-25-4 ]
[ 138356-55-5 ]
<i>N</i>-ethyl-2-(2-methoxy-phenyl)-<i>N</i>-(2-pyrrolidin-1-yl-ethyl)-acetamide [ No CAS ]

Reference： [1]European Journal of Pharmacology,2006,vol. 542,p. 61 - 68

12
[ 32566-01-1 ]
[ 93-25-4 ]
[ 677297-15-3 ]

Yield	Reaction Conditions	Operation in experiment
53%		N-[2-(1H-Indol-2-yl)-phenyl]-2-(2-methoxy-phenyl)-acetamide Prepared from 2-(2-aminophenyl) indole and 2-methoxyphenylacetic acid in 53% yield following procedure 1. The product was crystallized from acetonitrile. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=357, 1H NMR (MeOH-d4): 3.45 s (3H, OMe), 3.67 s (2H), 6.17 s (1H), 6.75 d, 8 Hz (1H), 6.83 t, 8 Hz (1H), 7.06 t, 8 Hz (1H), 7.14 t, 8 Hz (1H), 7.17-7.21 m (3H), 7.23-7.36 m (2H), 7.49 t, 8 Hz (2H), 8.13 d, 8 Hz (1H).

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

13
[ 93-25-4 ]
[ 33390-80-6 ]

Yield	Reaction Conditions	Operation in experiment
88%		Unless otherwise specified, carboxylic acid (0.542 mmol), TCT (0.0400 g, 0.216 mmol) and K2CO3 (0.2247 g, 1.626 mmol) were mixed together and hand ground for one minute using porcelain mortar and pestle. After addition of ammonium thiocyanate (0.0495 g, 0.650 mmol), the mixture was ground manually for further five minute. During the grinding, THF (calculated to be less than 1 L/mg of solids) was added to aid homogeneous mixing. The crude material was then purified by short column chromatography (column diameter 1.5 cm, packed with 3-4 g silica gel ) using 40-50percent ethyl acetate/hexane as an eluent.
		Production Example 17 Synthesis of 2-Methoxyphenylacetamide <strong>[93-25-4]2-Methoxyphenylacetic acid</strong> (10.0 g, 60.1 mmol) was dissolved in acetonitrile (15 mL). Subsequently, pyridine (2.84 g, 36.1 mmol) and di-tert-butyl dicarbonate [Boc2O (19.6 g, 90.2 mmol)] were added thereto. The mixture was stirred for 10 minutes at room temperature, and then ammonium hydrogencarbonate (7.1 g, 90.2 mmol) were added. After completion of reaction, the reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the resultant mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and brine. The resultant mixture was subjected to drying over magnesium sulfate and concentration under reduced pressure. The resultant concentrate was used in Production Example 18 without purification.

Reference： [1]Tetrahedron Letters,2018,vol. 59,p. 3571 - 3573
[2]Archiv der Pharmazie,1988,vol. 321,p. 265 - 272
[3]Patent: US2005/101636,2005,A1 .Location in patent: Page/Page column 34
[4]Journal of Medicinal Chemistry,2012,vol. 55,p. 9531 - 9540
[5]Chemistry Letters,2015,vol. 44,p. 621 - 623

14
[ 93-25-4 ]
[ 63909-40-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 98 percent / BF₃*Et₂O / 1 h / 60 - 70 °C 2: 98 percent / methanesulphonyl chloride / dimethylformamide / 1 h / 60 - 70 °C

Reference： [1]Waehaelae, Kristiina; Hase, Tapio A. [Journal of the Chemical Society. Perkin transactions I, 1991, # 12, p. 3005 - 3008]

15
[ 93-25-4 ]
[ 19090-04-1 ]

Reference： [1]Tetrahedron,1989,vol. 45,p. 1441 - 1446

16
[ 93-25-4 ]
[ 6342-77-4 ]

Reference： [1]Tetrahedron,1989,vol. 45,p. 1441 - 1446

17
[ 93-25-4 ]
[ 7569-62-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sulfuryl dichloride; In tetrahydrofuran;	Step A. 5-Chloro-2-methoxy phenylacetic acid A flame dried three-necked 3-L round-bottomed flask, equipped with a septa, stirring bar, argon inlet, thermocouple and addition funnel capped with a septa, was vacuum/argon purged. The flask was charged with commercially available 2-methoxy phenylacetic acid (300 g, 1.81 mol) and anhydrous THF (2 L). The mixture was cooled to approximately -15 C. and stirred until the solution became homogeneous. Neat sulfuryl chloride (205 mL, 2.55 mol) was added dropwise via an additional funnel while stirring over an hour. The internal temperature was maintained below -5 C. (ranging between -15 and -5 C.). Immediately after the complete addition of sulfuryl chloride, HPLC analysis showed the reaction was complete. The reaction mixture was poured into cold water (16 L) with vigorous stirring. The resultant slurry was stirred for 3 hours and the white precipitate was collected by filtration, washed with water (2 L), air dried for about 24 h, and vacuum dried to afford 345.3 g (95% yield, 97% by HPLC) of the title compound as an off-white solid that was used without further purification in the next step.
95%	With sulfuryl dichloride; In tetrahydrofuran; at -15 - -5℃; for 1h;	A flame dried three-necked 3-L round-bottomed flask, equipped with a septa, stirring bar, argon inlet, thermocouple and addition funnel capped with a septa, was vacuum/argon purged. The flask was charged with commercially available 2-methoxy phenylacetic acid (300 g, 1.81 mol) and anhydrous THF (2 L). The mixture was cooled to approximately -15 C and stirred until the solution became homogeneous. Neat sulfuryl chloride (205 mL, 2.55 mol) was added dropwise via an additional funnel while stirring over an hour. The internal temperature was maintained below -5 C (ranging between -15 and -5 C). Immediately after the complete addition of sulfuryl chloride, HPLC analysis showed the reaction was complete. The reaction mixture was poured into cold water (16 L) with vigorous stirring. The resultant slurry was stirred for 3 hours and the white precipitate was collected by filtration, washed with water (2 L), air dried for about 24 h, and vacuum dried to afford 345.3 g (95% yield, 97% by HPLC) of the title compound as an off-white solid that was used without further purification in the next step.
	With sulfuryl dichloride; In tetrahydrofuran; at -10℃; for 1.25h;	To a cooled (-10 00), stirred solution of 2-(2-methoxyphenyl)acetic acid (2.0 g, 12.04 mmol)in THF (34.8 mL) was added dropwise sulfuryl chloride (1.37 mL, 16.85 mmol) over 15mins and stirring continued for 1 hour. The reaction was quenched with ice cold water(34.8 mL) and extracted into EtOAc (3 x 50 mL). The combined organic layers were driedover Na2504 and concentrated in vacuo to afford the titled compound as a pink solid.1H NMR (250 MHz, DMSO-d6) O 12.24 (5, 1H), 7.30 (d, J = 2.7 Hz, 2H), 6.99 (d, J = 8.8Hz, 1H), 3.76 (5, 3H), 3.51 (5, 2H).LC-MS (Method E): Rt 1.01 mins; MS m/z no characteristic mass ion observed

Reference： [1]Patent: US5808095,1998,A
[2]Patent: EP946173,2005,B1 .Location in patent: Page/Page column 9
[3]Journal of Medicinal Chemistry,2008,vol. 51,p. 5085 - 5092
[4]Patent: WO2019/145726,2019,A1 .Location in patent: Page/Page column 101

18
3-(4-bromo-1-methylpyrazole-3-yl)phenylamine [ No CAS ]
[ 93-25-4 ]
[ 94790-37-1 ]
[ 80029-43-2 ]
[ 7087-68-5 ]
N-[3-(4-bromo-1-methylpyrazol-3-yl)phenyl]-2-(2-methoxyphenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	In chloroform;	N-[3-(4-bromo-1-methylpyrazol-3-yl)phenyl]-2-(2-methoxyphenyl)acetamide A mixture of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (30 mg, 0.12 mmol), 2-methoxyphenylacetic acid (20 mg, 0.12 mmol), 1-hydroxybenzotriazole hydrate (16 mg, 0.12 mmol) and <strong>[94790-37-1]2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate</strong> (46 mg, 0.12 mmol) were dissolved in chloroform (1.5 ml). N,N-Diisopropylethylamine (0.02 ml, 0.13 mmol) was added and the mixture stirred at room temperature for 16 h. The reaction mixture was then poured into brine and the organic layer washed with further brine, dried over magnesium sulphate and then concentrated in vacuo. The crude product was purified by column chromatography (chloroform-methanol, 99:1), giving the title compound (18 mg, 38%) as a colourless solid. Rf 0.65 (chloroform-methanol, 98:2). HPLC (Method B): retention time 7.16 min (100%). deltaH (CDCl3) 3.76 (2H, s), 3.83 (3H, s), 3.98 (3H, s), 6.97-7.06 (2H, m), 7.11-7.16 (1H, m), 7.31-7.50 (4H, m), 7.53 (1H, s), 7.57-7.60 (1H, m), 7.91 (1H, br s). MS (AP-): m/z (%)=400 (M-H 81 Br, 90), 398 (M-H 79 Br, 100).

Reference： [1]Patent: US6107324,2000,A

19
SO₂ Cl₂ [ No CAS ]
[ 93-25-4 ]
[ 7569-62-2 ]
[ 584-08-7 ]
[ 26939-01-5 ]

Yield	Reaction Conditions	Operation in experiment
	With dimethyl sulfate In glacial AcOH; water; acetonitrile	Methyl (5-chloro-2-methoxyphenyl)acetate Methyl (5-chloro-2-methoxyphenyl)acetate Neat SO2 Cl2 (30.5 g, 18 mL, 0.225 mol) was added dropwise over 30 minutes to a cold (5° C.) partial solution of (2-methoxyphenyl)acetic acid (25 g, 0.15 mol) in glacial AcOH (500 mL). The mixture was stirred at room temperature for 16 hours and then poured into cold water (2.5 L) with vigorous stirring. The resultant white precipitate was allowed to stand at room temperature for 2-3 hours, then filtered, washed with water and then air dried overnight to afford (5-chloro-2-methoxyphenyl)acetic acid (19.8 g, 66%). A stirred suspension of (5-chloro-2-methoxyphenyl)acetic acid (10 g, 0.05 mol), anhydrous K2 CO3 (8.3 g, 0.06 mol) and dimethyl sulfate (7.6 g, 0.06 mol) in anhydrous CH3 CN (60 mL) was heated to reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and the excess dimethyl sulfate was quenched with Et3 N (1 mL) and then filtered. The filtrate was rotary evaporated and the residue was suspended in water and extracted with ether, washed with satd. NaHCO3, water, brine and then dried (Na2 SO4). Filtration and evaporation of the ether gave a colorless oil which was distilled in vacuo to afford methyl (5-chloro-2methoxyphenyl)acetate (10.1 g, 94%): bp 96°-98° C./0.5 torr; IR (film, cm-1) 1742,1250, 1150, 1028; 1 H NMR (300 MHz, CDCl3)δ 3.56 (2H, s), 3.66 (3H, s), 3.76 (3 H, s), 8.75 (1H, d, J=8.6 Hz), 7.13 (1H, d, J=2.5 Hz), 7.17 (1H, dd, J=8.6 and 2.5 Hz); MS m/e 215 (MH+).
	With dimethyl sulfate In glacial AcOH; water; acetonitrile	Methyl (5-chloro-2-methoxyphenyl)acetate Methyl (5-chloro-2-methoxyphenyl)acetate Neat SO2 Cl2 (30.5 g, 18 mL, 0.225 mol) was added dropwise over 30 minutes to a cold (5° C.) partial solution of (2-methoxyphenyl)acetic acid (25 g, 0.15 mol) in glacial AcOH (500 mL). The mixture was stirred at room temperature for 16 hours and then poured into cold water (2.5 L) with vigorous stirring. The resultant white precipitate was allowed to stand at room temperature for 2-3 hours, then filtered, washed with water and then air dried overnight to afford (5-chloro-2-methoxyphenyl)acetic acid (19.8 g, 66%). A stirred suspension of (5-chloro-2-methoxyphenyl)acetic acid (10 g, 0.05 mol), anhydrous K2 CO3 (8.3 g, 0.06 mol) and dimethyl sulfate (7.6 g, 0.06 mol) in anhydrous CH3 CN (60 mL) was heated to reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and the excess dimethyl sulfate was quenched with Et3 N (1 mL) and then filtered. The filtrate was rotary evaporated and the residue was suspended in water and extracted with ether, washed with satd. NaHCO3, water, brine and then dried (Na2 SO4). Filtration and evaporation of the ether gave a colorless oil which was distilled in vacuo to afford methyl (5-chloro-2-methoxyphenyl)acetate (10.1 g, 94%): bp 96°-98° C./0.5 torr; IR (film, cm-1) 1742, 1250, 1150, 1028; 1 H NMR (300 MHz, CDCl3)δ 3.56 (2 H, s), 3.66 (3 H, s), 3.76 (3 H, s), 8.75 (16 H, d, J=8.6 Hz), 7.13 (1 H, d, J=2.5 Hz), 7.17 (1 H, dd, J=8.6 and 2.5 Hz); MS m/e 215 (MH+).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US5565483, 1996, A
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US5602169, 1997, A

20
[ 93-25-4 ]
[ 37585-16-3 ]
[ 124028-67-7 ]

Yield	Reaction Conditions	Operation in experiment
		7-Chloro-3-(2-methoxyphenyl)-2(1H)-quinolone and 7-Chloro-3-(2-hydroxyphenyl)-2(1H)-quinolone 2-Amino-4-chlorobenzyl alcohol (2 g, 12.86 mmol) and 2-methoxyphenylacetic acid (4.70 g, 28.3mol) were reacted in a similar manner as described in Example 19 to give 7-chloro-3-(2-methoxyphenyl)-2(1H)-quinolone as fine white needles mp 235-236 C. (MeOH). (Found: C, 67.49; H, 4.22; N, 4.93. C16 H12 ClNO2 requires C, 67.26; H, 4.23; N, 4.90%); deltaH (360 MHz, d6 -DMSO) 3.73 (1H, s, CH3) 6.97 (1H, dt, J=0.8 and 7.4 Hz, 5'-H) 7.08 (1H, d, J=8.3 Hz, 3'-H) 7.22 (1H, dd, J=8.4 and 2.1 Hz, 6-H) 2.27 (1H, dd, J=7.5 and 1.7 Hz, 6'-H) 7.34 (1H, d, J=1.8 Hz, 8-H) 7.37 (1H, dt, J=1.7 and 8.2 Hz, 4'-H) 7.70 (1H, d, J=8.4 Hz, 5-H) 7.87 (1H, s, 4-H) 11.87 (1H, br s, NH); m/z (EI+) 285 (M+).

Reference： [1]Patent: US5614532,1997,A

21
[ 93-25-4 ]
[ 74-88-4 ]
[ 81616-80-0 ]

Yield	Reaction Conditions	Operation in experiment
85%		As shown in step 4-i of Scheme 4, to a solution of diisopropylamine (6.70 g, 9.28 mL, 66.2 mmol) in THF (60 mL) at -78 C. under N2 was added n-butyllithium (33.1 mL of 2.0 M in cyclohexane, 66.2 mmol) and the solution was stirred for 40 minutes. A solution of 2-(2-methoxyphenyl)acetic acid (5.00 g, 30.1 mmol) in THF (30 mL) was added dropwise, then the reaction was allowed to warm to room temperature over one hour. The reaction was then cooled to -78 C. and iodomethane (4.27 g, 1.87 mL, 30.1 mmol) was added to the reaction in one portion. The reaction was warmed to room temperature 18 hours, 15 mL of water was added, and the organics were collected and the volatiles removed under reduced pressure. The residue was acidified with 1N HCl and the crude product extracted with Et2O (3*). The combined organics were dried over MgSO4, filtered, concentrated under reduced pressure, and the residue purified by medium pressure chromatography on silica gel (25 to 50% EtOAc in hexanes) to give 2-(2-methoxyphenyl)propanoic acid as a white solid (Compound 2008, 4.86 g, 85% yield): 1H NMR (CDCl3) delta 7.31-7.21 (m, 2H), 7.01-6.84 (m, 2H), 4.09 (q, J=7.2 Hz, 1H), 3.84 (s, 3H), 1.49 (d, J=7.2 Hz, 3H).
71%		General procedure: To 5 mL of a 0.24 M solution of diorganometal 1b or 1c (1.2 mmol), chilled at 0 C, was added a solution of the appropriate arylacetic acid 2 (1.1 mmol) dissolved in 5 mL of dry THF, and the resulting mixture was vigorously stirred for 2 h at 0 C. To the resulting dark brown mixture, chilled at the same temperature, were added 1.7 mmol of the appropriate electrophile. The resulting mixture was vigorously stirred and allowed to reach rt overnight, after which time it was quenched by slow dropwise addition of H2O (15 mL). The organic solvent was evaporated in vacuo and the resulting mixture was extracted with CH2Cl2 (3×10 mL). The aqueous phase was acidified with 1 N HCl, extracted with CH2Cl2 (3×10 mL), and the organic phases were collected, washed with H2O (1×10 mL), brine (10 mL), dried (Na2SO4), and the solvent was evaporated. Crude reaction products were purified and characterized as reported below. The reaction mixture containing crude beta-hydroxyacid 2df was quenched by adding it to 15 mL of 10% HCl containing about 15 g of crushed ice,14 and worked up as described above. After evaporation of the solvent, the resulting crude material was purified and characterized as reported below. Quenching with D2O was realized as described in the above paragraph.
	With n-butyllithium; diisopropylamine; In tetrahydrofuran; water;	A 1.6M solution (20 cc) of n-butyllithium in tetrahydrofuran is added in the course of 20 minutes to a solution of diisopropylamine (45.5 cc) in tetrahydrofuran (250 cc), cooled to +10 C. After stirring for 10 minutes, the mixture is brought to 0 C. and a solution of 2-(2-methoxyphenyl)acetic acid in tetrahydrofuran (100 cc) is added in the course of 20 minutes. After 30 minutes at 35 C., methyl iodide (10 cc) is added and the mixture is stirred for 1 hour at 35 C. Water (150 cc) is added to the reaction mixture and the resulting mixture is diluted with ethyl acetate. The aqueous phase is separated off, acidified with 4N hydrochloric acid and then extracted with ethyl acetate (2*100 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from isopropyl ether (100 cc) and the crystals are drained and dried under reduced pressure (2.7 kPa). (RS)-2-(2-Methoxyphenyl)propionic acid (17.5 g) is obtained in the form of a white solid melting at 108 C.

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 8344 - 8345
[2]Angewandte Chemie - International Edition,2019,vol. 58,p. 11479 - 11482
Angew. Chem.,2019,vol. 131,p. 11603 - 11606,4
[3]Patent: US2013/281431,2013,A1 .Location in patent: Paragraph 0234
[4]Tetrahedron,2011,vol. 67,p. 3470 - 3475
[5]Patent: US5102667,1992,A
[6]Angewandte Chemie - International Edition,2007,vol. 46,p. 8484 - 8487
[7]Organic Letters,2011,vol. 13,p. 1666 - 1669
[8]Journal of the American Chemical Society,2017,vol. 139,p. 15632 - 15635

22
[ 93-25-4 ]
[ 27798-60-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium bicarbonate; sulfuric acid; In methanol;	(a) Methyl 2-methoxy-benzeneacetate 500 g of 2-methoxy-benzeneacetic acid are dissolved in 4 1 of methanol and 150 ml of sulfuric acid (d 1.84). The solution is boiled for 24 hours and poured onto ice water. The aqueous phase is extracted with chloroform which is then shaken against water and a solution of sodium hydrogen carbonate, whereupon the chloroform solution is evaporated.

Reference： [1]Patent: US4695648,1987,A

23
[ 74-96-4 ]
[ 93-25-4 ]
[ 854647-56-6 ]

Yield	Reaction Conditions	Operation in experiment
86.2%		1. To a solution of i-Pr2NH (15.2 g, 150 mmol) in dry THF (100 mL) was added n-BuLi (60 mL, 150 mmol) dropwise at -78 C under N2 and stirred for 30 min. Then a solution of <strong>[93-25-4]2-methoxyphenylacetic acid</strong> (10 g, 60.2 mmol) in dry THF (100 mL) was added dropwise and stirred at this temp for 1 hour. Bromoethane (9.8 g, 90.3 mmol) was added. The resulting solution was stirred at RT overnight. The residue was treated with water and extracted with EA. The organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give Compound 1 (10 g, 86.2 percent). 1HNMR (CDC13, 300 MHz) delta: 0.9-1.0 (t, 3 H), 1.7-1.9 (m, 1 H), 2.0-2.2 (m, 1 H), 3.8-3.9 (s, 1 H), 3.9-4.0 (m, 1 H), 6.8-7.0 (m, 2 H), 7.2-7.4 (m, 2 H).

Reference： [1]Patent: WO2016/77240,2016,A2 .Location in patent: Page/Page column 61
[2]Angewandte Chemie - International Edition,2008,vol. 47,p. 7048 - 7050

24
[ 93-25-4 ]
[ 108-24-7 ]
[ 5211-62-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-methyl-1H-imidazole at 20℃; Inert atmosphere;
	With 1-methyl-1H-imidazole at 20℃; for 12h; Inert atmosphere;

Reference： [1]Chen, Jian; Zhang, Weicheng; Geng, Huiling; Li, Wei; Hou, Guohua; Lei, Aiwen; Zhang, Xumu [Angewandte Chemie - International Edition, 2009, vol. 48, # 4, p. 800 - 802]
[2]Huang, Haizhou; Liu, Xiaoyan; Zhou, Le; Chang, Mingxin; Zhang, Xumu [Angewandte Chemie - International Edition, 2016, vol. 55, # 17, p. 5309 - 5312][Angew. Chem., 2016, vol. 128, # 17, p. 5395 - 5398,4]

25
[ 613-84-3 ]
[ 93-25-4 ]
[ 1190439-39-4 ]

Yield	Reaction Conditions	Operation in experiment
59%	With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃; for 24h;	General procedure: A solution of 2-hydroxy-5-methylbenzaldehyde (7.34mmol) and the corresponding phenylacetic acid (9.18mmol) in dimethyl sulfoxide (15mL) was prepared. N,N?-Dicyclohexylcarbodiimide (11.46mmol) was added, and the mixture was heated in an oil bath at 110°C for 24h. Ice (100mL) and acetic acid (10mL) were added to the reaction mixture. After keeping it at room temperature for 2h, the mixture was extracted with ether (3×25mL). The organic layer was extracted with sodium bicarbonate solution (50mL, 5percent) and then water (20mL). The solvent was evaporated under vacuum, and the dry residue was purified by flash chromatography (hexane/ethyl acetate 9:1). Colorless solids were obtained in a yield of 68percent, 59percent and 53percent, respectively. Suitable crystals for X-ray studies were grown from slow evaporation from acetone/ethanol. 6-Methyl-3-(o-methoxyphenyl)coumarin (2). It was obtained a colorless solid with a yield of 59percent. Mp 177-178 °C. 1H NMR: 2.41 (s, 3H, CH3), 3.82 (s, 1H, OCH3), 7.02 (m, 2H, H-3', H-4'), 7.24-7.41 (m, 5H, H-5, H-7, H-8, H-5' and H-6') 7.69 (s, 1H, H-4). 13C NMR: 20.80 (CH3), 55.81 (OCH3), 111.31 (C-3'), 116.21 (C-8), 119.24 (C-1'), 120.57 (C-5'), 124.20 (C-4a), 126.36 (C-3), 127.58 (C-5), 130.14 (C-4'), 130.80 (C-6'), 132.21 (C-7), 133.89 (C-6), 141.84 (C-4), 151.82 (C-8a), 157.22 (C-2'), 160.55 (C-2). DEPT: 20.80 (CH3), 55.81 (OCH3), 111.31 (C-3'), 116.21 (C-8), 120.57 (C-5'), 127.58 (C-5), 130.14 (C-4'), 130.81 (C-6'), 132.21 (C-7), 141.84 (C-4). EI MS m/z (percent): 267 (22), 266 (M+, 100), 265 (10), 249 (29), 237 (22), 235 (14), 223 (22), 220 (12), 195 (29), 173 (26), 165 (25), 152 (17), 145 (19), 118 (19). Anal. Calcd for C17H14O3: C, 76.68; H, 5.30. Found: C, 76.76; H, 5.22.
	With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃; for 24h;	General procedure: To a solution of the conveniently substituted ortho-hydroxybenzaldehyde (7.34 mmol) and the corresponding phenylacetic acid (9.18 mmol) in dimethyl sulfoxide (15 mL), N,N'-dicyclohexylcarbodiimide (11.46 mmol) was added. The mixture was heated at 110°C for 24 h. Then, ice (100 mL) and acetic acid (10 mL) were added to the reaction mixture. After keeping it at room temperature for 2 h, the mixture was extracted with ether (3*25 mL).The organic layers were combined and washed with sodium bicarbonate solution (50 mL, 5percent) and water (20 mL). Subsequently, the solvent was evaporated under vacuum and the dry residue was purified by flash chromatography (hexane/ethyl acetate 9:1), to give the desired methoxy-3-arylcoumarins.23,28

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5053 - 5055
[2]Journal of Molecular Structure,2013,vol. 1050,p. 185 - 191
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 7127 - 7137
[4]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 3900 - 3906

26
[ 93-25-4 ]
[ 635-93-8 ]
[ 1236360-16-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	With iodine; triethylamine; triphenylphosphine; In dichloromethane; at 0 - 25℃; for 0.166667h;	General procedure: To a solution of Ph3P (0.62 mmol) in CH2Cl2 (4 mL) was added I2 (0.62 mmol) at 0 °C. The resulting solution was sequentially added with aryl acetic acid (0.41 mmol) and hydroxybenzaldehyde (0.45 mmol) at 0 °C, followed by Et3N (2.05 mmol). After that, the solution was allowed to warm up to r.t. and stirred until the completion of reaction. The crude material was purifiedby column chromatography using EtOAc?hexanes as the eluent to afford pure product.
47%	With acetic anhydride; triethylamine; at 120℃; for 8h;	General procedure: A mixture of salicylaldehyde derivative (8 mmol), phenylacetic acid derivative (16 mmol), acetic anhydride (20 mL) and triethylamine (5 mL) were heated at 120 for eight hours. After cooling to room temperature, reaction mixture was slowly poured into ice-water (200 mL) with violent stirring. The precipitated solid was filtered off andrecrystallized from ethyl acetate to give 3-arylcoumarin.

Reference： [1]Synlett,2017,vol. 28,p. 825 - 830
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 5432 - 5434
[3]Molecules,2010,vol. 15,p. 270 - 279
[4]ChemMedChem,2014,vol. 9,p. 1672 - 1676

27
[ 93-25-4 ]
syn-methyl 2-hydroxy-3-phenyl-3-(2,2,2-trifluoroethoxy)propanoate [ No CAS ]
(2SR,3RS)-methyl 2-(2-(2-methoxyphenyl)acetoxy)-3-phenyl-3-(2,2,2-trifluoroethoxy)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h;	General procedure: Alcohol syn-4b (500 mg, 1.797 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv), and DMAP (110 mg, 0.898 mmol, 0.5 equiv) were added to phenylacetic acid (294 mg, 2.16 mmol, 1.2 equiv) in CH2Cl2 (5 mL) at room temperature, under nitrogen. The mixture was stirred at room temperature for 12 h and the solvent was removed under reduced pressure. Et2O was added and the mixture was filtered. The filtrate was washed with sodium acetate buffer (pH=5) and the aqueous layer was extracted with Et2O. The organic layers were combined, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-5percent AcOEt/cyclohexane) to afford compound syn-9b (605 mg, 85percent) as a colorless oil.

Reference： [1]Tetrahedron,2011,vol. 67,p. 2605 - 2611

28
[ 2459-07-6 ]
[ 93-25-4 ]
[ 1283264-85-6 ]