[ CAS No. 622-47-9 ] {[proInfo.proName]}

Name: 622-47-9|2-(p-Tolyl)acetic acid|98%
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Quality Control of [ 622-47-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 622-47-9 ]

Product Details of [ 622-47-9 ]

CAS No. :	622-47-9	MDL No. :	MFCD00004353
Formula :	C₉H₁₀O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	150.17	Pubchem ID :	-
Synonyms :

Calculated chemistry of [ 622-47-9 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	42.95
TPSA :	37.3 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) :	-5.9 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.51
Log Po/w (XLOGP3) :	1.86
Log Po/w (WLOGP) :	1.62
Log Po/w (MLOGP) :	1.98
Log Po/w (SILICOS-IT) :	2.01
Consensus Log Po/w :	1.8

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.21
Solubility :	0.916 mg/ml ; 0.0061 mol/l
Class :	Soluble
Log S (Ali) :	-2.26
Solubility :	0.817 mg/ml ; 0.00544 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.54
Solubility :	0.429 mg/ml ; 0.00286 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.02

Safety of [ 622-47-9 ]

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 [ 622-47-9 ]

* 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 [ 622-47-9 ]
Downstream synthetic route of [ 622-47-9 ]

[ 622-47-9 ] Synthesis Path-Upstream 1~13

1
[ 93-60-7 ]
[ 622-47-9 ]
[ 40061-21-0 ]

Reference： [1] Green Chemistry, 2012, vol. 14, # 3, p. 580 - 585

2
[ 622-47-9 ]
[ 6529-51-7 ]

Reference： [1] Tetrahedron Asymmetry, 1998, vol. 9, # 15, p. 2725 - 2737
[2] Journal of the American Chemical Society, 1977, vol. 99, # 9, p. 3059 - 3067
[3] Helvetica Chimica Acta, 1973, vol. 56, p. 2460 - 2479

3
[ 201230-82-2 ]
[ 589-29-7 ]
[ 106-42-3 ]
[ 7325-46-4 ]
[ 622-47-9 ]

Reference： [1] Bulletin of the Chemical Society of Japan, 1998, vol. 71, # 3, p. 723 - 734

4
[ 201230-82-2 ]
[ 589-29-7 ]
[ 7325-46-4 ]
[ 622-47-9 ]

Reference： [1] Tetrahedron Letters, 1997, vol. 38, # 21, p. 3747 - 3750

5
[ 111-65-9 ]
[ 106-42-3 ]
[ 1822-71-5 ]
[ 7325-46-4 ]
[ 622-47-9 ]
[ 142-62-1 ]

Reference： [1] Journal of the American Chemical Society, 1943, vol. 65, p. 1339,1345

6
[ 622-47-9 ]
[ 66270-97-1 ]

Reference： [1] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 7, p. 2467 - 2472
[2] Journal of Organic Chemistry, 1978, vol. 43, p. 2845 - 2852

7
[ 622-47-9 ]
[ 13737-36-5 ]

Yield	Reaction Conditions	Operation in experiment
91.9%	With N-Bromosuccinimide; dibenzoyl peroxide In chlorobenzene at 85 - 110℃; for 8 h; Irradiation	The raw material p-methylbenzene acetic acid (24 g) was placed in 250 ml of three,75 ml of chlorobenzene was added, 30 g of NBS was added,Benzoyl peroxide 0.5g, with mechanical stirring, heating 85 ,In incandescent light irradiation will automatically raise the temperature to 110 ,The reaction was controlled at 90 to 110 ° C and the reaction was incubated at this temperature range for 8 hours,The TLC plate was monitored and the reaction was complete.After cooling, the solid precipitated, filtered, and washed with water cake, try to filter dry,Then the resulting white solid weighed 33.7 grams after drying,Yield 91.9percentHPLC purity 99.2percent.
57%	With sodium hydroxide In tetrachloromethane; bromine	To a solution of p -tolylacetic acid 239 (47.51 g, 316.7 mmol) in 750 ml of carbon tetrachloride heated to reflux under a flowing steam of nitrogen and irradiated with 150 watt white light in a three-necked round bottom flask was added dropwise bromine (17.13 ml, 332.6 mmol) over 60 min. After addition of the bromine was complete, the solution was irradiated and heated for an additional 60 min during which time the product began to precipitate out of solution. Hydrogen bromide, which was generated during the reaction, was bubbled through an aqueous solution of sodium hydroxide. The heterogeneous solution was cooled to 0°C and filtered. The solid was washed with hexanes and dried affording 41.34 g (57percent yield) of 4-bromomethylbenzeneacetic acid 238 as a white powder.
34.2%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 80℃; Large scale	2-(4-(Bromomethyl)phenyl)acetic acid (B) To a solution of A (4.4 kg, 29.3 mol, 1 eq) in acetonitrile (22 L) was added N-bromosuccinimide (NBS) (5740 g, 32.2 mol, 1.1 eq) and azobisisobutyronitrile (AIBN) (9.2 g, 0.02 eq). The resulting mixture was slowly heated to 80° C. and stirred for 15-30 min. After the starting 1 was consumed as indicated by TLC, the reaction mixture was cooled to -5° C. slowly and kept at -5° C. overnight. The resulting solid was collected by filtration. The filter cake was washed with petroleum ether/EtOAc (1:1) (5 L), petroleum ether (5 L*2), saturated NaHSO3 (aq.) (5 L), water (5 L), and petroleum ether (5 L) to give the title compound (2.3 kg, yield: 34.2percent). HPLC purity: 96.8percent (254 nm); ¹H NMR (300 MHz, DMSO-d₆) δ 12.3 (s, 1H), 7.4 (d, J=8.0 Hz, 2H), 7.2 (d, J=8.0 Hz, 2H), 4.7 (s, 2H), 3.57 (s, 2H).

34.2%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 80℃; Large scale	To a solution of A (4.4 kg, 29.3 mol, 1 eq) in acetonitrile (22 L) was added N-bromosuccinimide (NBS) (5740 g, 32.2 mol, 1.1 eq) and azobisisobutyronitrile (AIBN) (9.2 g, 0.02 eq). The resulting mixture was slowly heated to 80°C and stirred for 15-30 min. After the starting 1 was consumed as indicated by TLC, the reaction mixture was cooled to -5°C slowly and kept at -5°C overnight. The resulting solid was collected by filtration. The filter cake was washed with petroleum ether /EtOAc (1 : 1) (5 L), petroleum ether (5L x 2), saturated NaHS03 (aq.) (5 L), water (5 L), and petroleum ether (5 L) to give the title compound (2.3 kg, yield: 34.2percent). HPLC purity: 96.8percent (254 nm); 1H NMR (300 MHz, DMSO-<) δ 12.3 (s, 1H), 7.4 (d, J = 8.0 Hz, 2H), 7.2 (d, J = 8.0 Hz, 2H), 4.7 (s, 2H), 3.57 (s, 2H).
51 g	With N-Bromosuccinimide In tetrachloromethane for 3 h; Reflux	50 g of compound 1 (4-methylphenylacetic acid) was dissolved in 200 ml of carbon tetrachloride.Heat to reflux,NBS (N-bromosuccinimide) (62 g, 0.35 mol) was added portionwise under heating.After the addition is complete, it will continue to maintain the reflux for 3 hours.There are a lot of solids out,TLC showed that the starting material was completely reacted, and the reaction solution was cooled to room temperature, poured into 500 ml of ice water under stirring, stirring was continued for 20 minutes, filtered, and the filter cake was washed with water three times (300 ml each time) to give a white solid. Drying at 50°C for 10 hours gave 51 g of compound 2 (4-bromomethylphenylacetic acid). Compound 2 was directly subjected to the next reaction without further purification.

Reference： [1] Patent: CN106905135, 2017, A, . Location in patent: Paragraph 0018; 0019; 0020; 0021
[2] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 7, p. 2467 - 2472
[3] European Journal of Organic Chemistry, 2006, # 18, p. 4135 - 4146
[4] Journal of the Chemical Society, Chemical Communications, 1993, # 4, p. 399 - 401
[5] Patent: EP496548, 1992, A1,
[6] Patent: US9643927, 2017, B1, . Location in patent: Page/Page column 33;34
[7] Patent: WO2017/86941, 2017, A1, . Location in patent: Paragraph 00104
[8] Journal of Organic Chemistry, 1978, vol. 43, p. 2845 - 2852
[9] Journal of Organic Chemistry, 1966, vol. 31, p. 3758 - 3764
[10] Patent: US2002/165282, 2002, A1,
[11] Patent: CN107434780, 2017, A, . Location in patent: Paragraph 0055-0058

8
[ 622-47-9 ]
[ 94-36-0 ]
[ 13737-36-5 ]

Yield	Reaction Conditions	Operation in experiment
16.4 mmol, 49.2%	With N-Bromosuccinimide In benzene	p-Bromomethylphenylacetic acid STR955 A mixture (suspension) of p-tolylacetic acid (5.00 g, 33.3 mmol), N-bromosuccinimide (5.93 g, 33.3 mmol) and benzoylperoxide (65 mg, 0.27 mmol) in dry benzene (30 ml) was heated at reflux for 5 h. After cooling it in an ice-bath (ca 10° C.), a white precipitate formed. It was collected and dried yielding 7 g of a white powder. This was triturated with warm water (1*5 ml), filtered and dried to obtain 3.75 g (16.4 mmol, 49.2percent) of p-bromomethylphenylacetic acid as a white powder. This material contained a small amount of succinimide but was used as such in the next step. An analytical sample was obtained by further trituration with warm water: mp 170°-173° C.; ¹ Hmr (DMSO-d₆) δ: 3.57 (2H, s,--CH₂ CO₂), 4.69 (2H, s, --CH₂ Br) and 7.13-3.95-7.33-7.47 ppm (4H, A₂ 'B 2 ', aromatic Hs); ir (nujol) ν_max: 1690 cm^-1 (s,C=O).

Reference： [1] Patent: US4272437, 1981, A,

9
[ 622-47-9 ]
[ 34241-39-9 ]
[ 13737-36-5 ]

Reference： [1] Patent: US6258954, 2001, B1,

10
[ 622-47-9 ]
[ 54941-44-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With nitric acid In dichloromethane	A. 4-Methyl-3-nitrophenylacetic Acid To a solution of 4-methylphenylacetic acid (1.50 g, 10.0 mmol) in dried dichloromethane was added nitric acid (fuming, 1.5 mL) dropwise. The mixture was stirred at room temperature for 2 hours, then quenched with water and extracted with ethyl acetate. The extracts were washed with water twice and brine, dried over magnesium sulfate, filtered, and concentrated to provide the title compound (1.66 g, 85percent yield): ¹H NMR (CDCl₃) 7.91 (d, 1H), 7.42 (dd, 1H), 7.31 (d, 1H), 3.71 (s, 2H), 2.58 (s, 3H); ES-MS m/z 196 [M+H]⁺.
74%	at 0 - 5℃; for 8 h;	p-Tolyl acetic acid (0.6 g, 4.1 mmol) was added H2SO4 (5.5 mL) with cooling in an ice bath. NaN03 (0.35g, 4.1 mmol) was added slowly and mixture was stirred at 0-5 °C for 8h. The solution was carefully poured onto ice and the solids filtered and washed with water to give 3-nitro p-tolylacetic acid (0.59g, 74percent).

Reference： [1] Patent: US6593322, 2003, B1,
[2] Patent: WO2003/90912, 2003, A1, . Location in patent: Page/Page column 117
[3] Journal fuer Praktische Chemie (Leipzig), 1891, vol. <2> 44, p. 85
[4] Patent: WO2014/145022, 2014, A1, . Location in patent: Page/Page column 52

11
[ 622-47-9 ]
[ 7398-42-7 ]

Reference： [1] Journal of Organic Chemistry, 1966, vol. 31, p. 3758 - 3764

12
[ 622-47-9 ]
[ 34841-47-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	With iron(II) acetylacetonate; 1,1,3,3-Tetramethyldisiloxane In water; 1,2-dichloro-ethane at 80℃; for 3 h;	Compound 6:25 ml reaction flask by sequentially adding ferrous acetylacetonate (0.025 mmol), 1, 1, 3, 3 - tetramethyl-siloxane (0.75 mmol), potassium persulphate (0.25 mmol), 1 f (0.25 mmol), 1, 2 - dichloroethane (1 ml), water (1 ml), in the reaction mixture 80 °C lower reaction 3 h. The reaction is finished adding ammonia water (2 ml) to remove the peripheric, add saturated salt water 10 ml, and extraction with ethyl ether (10 ml × 3), the combined organic phase, pressure reducing evaporate the solvent column chromatography separation to obtain yield 70percent

Reference： [1] Patent: CN107216242, 2017, A, . Location in patent: Paragraph 0036; 0037

13
[ 622-47-9 ]
[ 73401-74-8 ]

Reference： [1] Patent: US9643927, 2017, B1,
[2] Patent: WO2017/86941, 2017, A1,
[3] Patent: CN107434780, 2017, A,

[ 622-47-9 ] Synthesis Path-Downstream 1~87

1
[ 622-47-9 ]
[ 699-02-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	With Fe(CO)<SUB>3</SUB>(COD); phenylsilane In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; UV-irradiation; chemoselective reaction;
76%	With dimethylsulfide borane complex In tetrahydrofuran
51%	With lithium aluminium hydride In diethyl ether at 0 - 20℃;

	bei der elektrolytischen Reduktion;
	With lithium aluminium hydride
	bei elektrolytischer Reduktion;
	With lithium aluminium hydride In diethyl ether
	Multi-step reaction with 2 steps 1: H₂SO₄ 2: LiAlH₄ / diethyl ether
	Multi-step reaction with 2 steps 2: LiAlH₄
	With lithium aluminium hydride In tetrahydrofuran for 3h; Heating;
	Multi-step reaction with 2 steps 1: sulfuric acid / 3 h / Reflux 2: diisobutylaluminium hydride / tetrahydrofuran; toluene / 20 °C
	Stage #1: 4-tolylacetic acid With lithium aluminium hydride In tetrahydrofuran at 18 - 26℃; for 2h; Stage #2: With lithium hydroxide monohydrate; ammonia hydrochloride In tetrahydrofuran	4.2. General procedure for the synthesis of aldehydes General procedure: To a suspension of LiAlH4 in dry THF was added the corresponding acid dissolved in dry THF dropwisely at room temperature. Then the mixture was stirred for 2 h and quenched with saturated NH4Cl. The mixture was extracted with chloroform and dried over anhydrous Na2SO4. Then the solvent was evaporated and the product was used without further purification. The crude alcohol was dissolved in dry DCM and DMP (Dess-Martin Periodinane) was added. The resulting mixture was stirred at room temperature for 2 h and quenched with Na2S2O3/NaHCO3 (v/v=1/1). The aqueous phase was extracted with DCM and dried over anhydrous Na2SO4. The solvent was evaporated to afford the corresponding aldehydes.
	bei der elektrolytischen Reduktion;
	Multi-step reaction with 2 steps 1.1: sulfuric acid / 4 h / Reflux 2.1: lithium chloride; diethylzinc(II) / tetrahydrofuran; hexane / 6 h / 20 °C / Inert atmosphere 2.2: 8 h / 20 °C / Inert atmosphere
	With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃;
	With lithium aluminium hydride In tetrahydrofuran at 0℃; for 1h;
	With lithium aluminium hydride In tetrahydrofuran at 0℃; for 4.5h; Reflux;	Preparation of phenylethyl alcohols 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.
	Multi-step reaction with 2 steps 1: thionyl fluoride; N-ethyl-N,N-diisopropylamine / acetonitrile / 1 h / 20 °C / Sealed tube 2: sodium tetrahydridoborate / acetonitrile; N,N-dimethyl acetamide / 1 h / 20 °C

Reference： [1]Misal Castro, Luis C.; Li, Haoquan; Sortais, Jean-Baptiste; Darcel, Christophe [Chemical Communications, 2012, vol. 48, # 85, p. 10514 - 10516,3]
[2]Lanni Jr., Thomas B.; Greene, Keri L.; Kolz, Christine N.; Para, Kimberly S.; Visnick, Melean; Mobley, James L.; Dudley, David T.; Baginski, Theodore J.; Liimatta, Marya B. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 3, p. 756 - 760]
[3]Burke, Christopher P.; Shi, Yian [Organic Letters, 2009, vol. 11, # 22, p. 5150 - 5153]
[4]Kling [Chemisches Zentralblatt, 1908, vol. 79, # II, p. 1863]
[5]Helgeson,R.C.; Cram,D.J. [Journal of the American Chemical Society, 1966, vol. 88, # 3, p. 509 - 515] Schadt,F.L. et al. [Journal of the American Chemical Society, 1978, vol. 100, p. 228 - 246] Pritzkow, Wilhelm; Thomas, Gerda; Willecke, Lothar [Journal fur praktische Chemie (Leipzig 1954), 1985, vol. 327, # 5, p. 847 - 851] Dao, Duc Hai; Okamura, Mutsuo; Akasaka, Takeshi; Kawai, Yasushi; Hida, Kouichi; Ohno, Atsuyoshi [Tetrahedron Asymmetry, 1998, vol. 9, # 15, p. 2725 - 2737]
[6]Kling [Chemisches Zentralblatt, 1908, vol. 79, # II, p. 1863] Kling [Chemisches Zentralblatt, 1908, vol. 79, # I, p. 951]
[7]Weibel,P.A.; Hesse,M. [Helvetica Chimica Acta, 1973, vol. 56, p. 2460 - 2479] Liang, Jiang-Lin; Yuan, Shi-Xue; Huang, Jie-Sheng; Che, Chi-Ming [Journal of Organic Chemistry, 2004, vol. 69, # 11, p. 3610 - 3619]
[8]Dolby,L.J.; Riddle,G.N. [Journal of Organic Chemistry, 1967, vol. 32, p. 3481 - 3485]
[9]Lambert,J.B. et al. [Journal of the American Chemical Society, 1977, vol. 99, # 9, p. 3059 - 3067]
[10]Fristrup, Peter; Kreis, Michael; Palmelund, Anders; Norrby, Per-Ola; Madsen, Robert [Journal of the American Chemical Society, 2008, vol. 130, # 15, p. 5206 - 5215]
[11]Revelant, Germain; Dunand, Sandrine; Hesse, Stephanie; Kirsch, Gilbert [Synthesis, 2011, # 18, p. 2935 - 2940]
[12]Location in patent: experimental part Bu, Xiuli; Hong, Longcheng; Liu, Ruiting; Hong, Jianquan; Zhang, Zhengxing; Zhou, Xigeng [Tetrahedron, 2012, vol. 68, # 38, p. 7960 - 7965]
[13]Kling [Chemisches Zentralblatt, 1908, vol. 79, # I, p. 952]
[14]Kovalenko, Oleksandr O.; Adolfsson, Hans [Chemistry - A European Journal, 2015, vol. 21, # 7, p. 2785 - 2788]
[15]Wang, De; Lei, Yu; Wei, Yin; Shi, Min [Chemistry - A European Journal, 2014, vol. 20, # 47, p. 15325 - 15329]
[16]Lei, Yu; Xing, Jiao-Jiao; Xu, Qin; Shi, Min [European Journal of Organic Chemistry, 2016, vol. 2016, # 21, p. 3486 - 3490]
[17]Xie, Jin; Yang, Fengzhi; Zhang, Man; Lam, Celine; Qiao, Yixue; Xiao, Jia; Zhang, Dongdong; Ge, Yuxuan; Fu, Lei; Xie, Dongsheng [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134]
[18]Bolduc, Trevor G.; Chappell, William P.; Lee, Cayo; Sammis, Glenn M. [Journal of Organic Chemistry, 2022]

2
[ 622-47-9 ]
[ 54941-44-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With nitric acid; In dichloromethane;	A. 4-Methyl-3-nitrophenylacetic Acid To a solution of 4-methylphenylacetic acid (1.50 g, 10.0 mmol) in dried dichloromethane was added nitric acid (fuming, 1.5 mL) dropwise. The mixture was stirred at room temperature for 2 hours, then quenched with water and extracted with ethyl acetate. The extracts were washed with water twice and brine, dried over magnesium sulfate, filtered, and concentrated to provide the title compound (1.66 g, 85% yield): 1H NMR (CDCl3) 7.91 (d, 1H), 7.42 (dd, 1H), 7.31 (d, 1H), 3.71 (s, 2H), 2.58 (s, 3H); ES-MS m/z 196 [M+H]+.
74%	With sodium nitrate; sulfuric acid; at 0 - 5℃; for 8.0h;	p-Tolyl acetic acid (0.6 g, 4.1 mmol) was added H2SO4 (5.5 mL) with cooling in an ice bath. NaN03 (0.35g, 4.1 mmol) was added slowly and mixture was stirred at 0-5 C for 8h. The solution was carefully poured onto ice and the solids filtered and washed with water to give 3-nitro p-tolylacetic acid (0.59g, 74%).

Reference： [1]Patent: US6593322,2003,B1
[2]Patent: WO2003/90912,2003,A1 .Location in patent: Page/Page column 117
[3]Journal fur praktische Chemie (Leipzig 1954),1891,vol. <2> 44,p. 85
[4]Patent: WO2014/145022,2014,A1 .Location in patent: Page/Page column 52

3
[ 14062-19-2 ]
[ 622-47-9 ]

Yield	Reaction Conditions	Operation in experiment
96%	With water; sodium hydroxide; In 1,4-dioxane; at 60℃; for 2h;pH 10 - 14;	p-Xylene (1.59 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120 C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 85 mg ethyl p-methylphenylacetate was obtained by column chromatography, in a yield of 96%. 1HNMR (400 MHz, CDCl3) delta 1.23 (t, J=7.2 Hz, 3H), 2.33 (s, 3H), 3.57 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 7.11-7.18 (m, 4H); 13CNMR (100 MHz, CDCl3) delta 14.2, 21.1, 41.0, 60.8, 129.1, 139.3, 131.1, 136.6, 171.8; HRMS (ESI) calcd. for C11H14NaO2 [M+Na]: 201.0886. found: 201.0882. The ethyl p-methylphenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60 C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 69 mg product p-methylphenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 96%.

Reference： [1]Patent: US2013/303798,2013,A1 .Location in patent: Paragraph 0018; 0046; 0047
[2]Chemische Berichte,1941,vol. 74,p. 315,316

4
[ 64-17-5 ]
[ 622-47-9 ]
[ 14062-19-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	toluene-4-sulfonic acid; In toluene; at 20℃; for 5h;Reflux;	Toluene (100 ml), ethanol (9.20 g, 199.77 mmol) and p-tolylacetic acid (25 g, 166.48 mmol) was added into a 200-mi flask in this order at room temperature and then p-toluenesulfonic acid monohydrate (4.75 g, 24.97 mmol) was charged thereto. The solution was gently heated and subjected to reflux dehydration for 3 to 5 hours. After reflux dehydration, the solution was cooled to around room temperature, added with triethylamine (4.21 g, 41.62 mmol) at room temperature, stirred and then added with silica gel. After stirring for a while, the silica gel was filtered off. After the solvent of the filtrate was removed in vacuum distillation, ethyl p-tolylacetate (28.09 g, 95%) was isolated in distillation.

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 203 - 208
[2]Patent: US2010/324314,2010,A1 .Location in patent: Page/Page column 16
[3]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1586 - 1605
[4]Chemistry - A European Journal,2019,vol. 25,p. 13030 - 13036
[5]Journal of Medicinal Chemistry,1996,vol. 39,p. 3435 - 3450
[6]Journal of the American Chemical Society,1968,vol. 90,p. 2082 - 2096
[7]Journal of Organic Chemistry,1967,vol. 32,p. 3481 - 3485
[8]Chinese Journal of Chemistry,2010,vol. 28,p. 605 - 612

5
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[ 13737-36-5 ]

Yield	Reaction Conditions	Operation in experiment
91.9%	With N-Bromosuccinimide; dibenzoyl peroxide; In chlorobenzene; at 85 - 110℃; for 8h;Irradiation;	The raw material p-methylbenzene acetic acid (24 g) was placed in 250 ml of three,75 ml of chlorobenzene was added, 30 g of NBS was added,Benzoyl peroxide 0.5g, with mechanical stirring, heating 85 ,In incandescent light irradiation will automatically raise the temperature to 110 ,The reaction was controlled at 90 to 110 C and the reaction was incubated at this temperature range for 8 hours,The TLC plate was monitored and the reaction was complete.After cooling, the solid precipitated, filtered, and washed with water cake, try to filter dry,Then the resulting white solid weighed 33.7 grams after drying,Yield 91.9%HPLC purity 99.2%.
57%	With sodium hydroxide; In tetrachloromethane; bromine;	To a solution of p -tolylacetic acid 239 (47.51 g, 316.7 mmol) in 750 ml of carbon tetrachloride heated to reflux under a flowing steam of nitrogen and irradiated with 150 watt white light in a three-necked round bottom flask was added dropwise bromine (17.13 ml, 332.6 mmol) over 60 min. After addition of the bromine was complete, the solution was irradiated and heated for an additional 60 min during which time the product began to precipitate out of solution. Hydrogen bromide, which was generated during the reaction, was bubbled through an aqueous solution of sodium hydroxide. The heterogeneous solution was cooled to 0C and filtered. The solid was washed with hexanes and dried affording 41.34 g (57% yield) of 4-bromomethylbenzeneacetic acid 238 as a white powder.
40.8%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 90℃; for 4h;	p-methylphenylacetic acid (3.88 g, 25.9 mmol), NBS (4.83 g, 27.2 mmol), AIBN (42 mg, 0.26 mmol), and carbon tetrachloride (50 mL) were added to a 100 mL single-mouth bottle, and reacted at 90 C for 4 hours. The mixture was concentrated in vacuo to remove the solvent under a reduced pressure, and was passed through a column (ethyl acetate: petroleum ether= 1:4) to give the product (white solid, 2.28 g), with a yield of 40.8%. 1H NMR (400 MHz, DMSO) delta 12.31 (s, 1H), 7.25 (d, J= 7.6 Hz, 2H), 7.11 (d, J= 7.5 Hz, 2H), 4.56 (s, 2H), 3.44 (s, 2H). MS (ESI) m/z: 228.9 (MH+)

34.2%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In acetonitrile; at 80℃;Large scale;	2-(4-(Bromomethyl)phenyl)acetic acid (B) To a solution of A (4.4 kg, 29.3 mol, 1 eq) in acetonitrile (22 L) was added N-bromosuccinimide (NBS) (5740 g, 32.2 mol, 1.1 eq) and azobisisobutyronitrile (AIBN) (9.2 g, 0.02 eq). The resulting mixture was slowly heated to 80 C. and stirred for 15-30 min. After the starting 1 was consumed as indicated by TLC, the reaction mixture was cooled to -5 C. slowly and kept at -5 C. overnight. The resulting solid was collected by filtration. The filter cake was washed with petroleum ether/EtOAc (1:1) (5 L), petroleum ether (5 L*2), saturated NaHSO3 (aq.) (5 L), water (5 L), and petroleum ether (5 L) to give the title compound (2.3 kg, yield: 34.2%). HPLC purity: 96.8% (254 nm); 1H NMR (300 MHz, DMSO-d6) delta 12.3 (s, 1H), 7.4 (d, J=8.0 Hz, 2H), 7.2 (d, J=8.0 Hz, 2H), 4.7 (s, 2H), 3.57 (s, 2H).
34.2%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In acetonitrile; at 80℃;Large scale;	To a solution of A (4.4 kg, 29.3 mol, 1 eq) in acetonitrile (22 L) was added N-bromosuccinimide (NBS) (5740 g, 32.2 mol, 1.1 eq) and azobisisobutyronitrile (AIBN) (9.2 g, 0.02 eq). The resulting mixture was slowly heated to 80C and stirred for 15-30 min. After the starting 1 was consumed as indicated by TLC, the reaction mixture was cooled to -5C slowly and kept at -5C overnight. The resulting solid was collected by filtration. The filter cake was washed with petroleum ether /EtOAc (1 : 1) (5 L), petroleum ether (5L x 2), saturated NaHS03 (aq.) (5 L), water (5 L), and petroleum ether (5 L) to give the title compound (2.3 kg, yield: 34.2%). HPLC purity: 96.8% (254 nm); 1H NMR (300 MHz, DMSO-<) delta 12.3 (s, 1H), 7.4 (d, J = 8.0 Hz, 2H), 7.2 (d, J = 8.0 Hz, 2H), 4.7 (s, 2H), 3.57 (s, 2H).
	With bromine; In tetrachloromethane; nitrogen; hydrogen bromide;	EXAMPLE 1 (4-Bromomethyl-phenyl)-acetic Acid: To a stirred solution of p-methylphenylacetic acid (0.175 mol, 27.8 g) in tetrachloromethane (250 mL) under a nitrogen atmosphere in a round bottom flask equipped with a reflux condenser and provision for trapping the released HBr was added bromine (0.175 mol, 27.8 g) dissolved in tetrachloromethane. The red/brown mixture was irradiated and brought to reflux with a 250 watt incandescent light source. Over the course of ten minutes, the color was discharged and a crystalline precipitate was formed. The mixture was allowed to cool to room temperature, and the solid was collected by vacuum filtration, and dried in a stream of nitrogen to give (4-bromomethyl-phenyl)-acetic acid as a white solid containing 6.3% by weight p-methylphenylacetic acid as an impurity. (25.1 g, 63%).
51 g	With N-Bromosuccinimide; In tetrachloromethane; for 3h;Reflux;	50 g of compound 1 (4-methylphenylacetic acid) was dissolved in 200 ml of carbon tetrachloride.Heat to reflux,NBS (N-bromosuccinimide) (62 g, 0.35 mol) was added portionwise under heating.After the addition is complete, it will continue to maintain the reflux for 3 hours.There are a lot of solids out,TLC showed that the starting material was completely reacted, and the reaction solution was cooled to room temperature, poured into 500 ml of ice water under stirring, stirring was continued for 20 minutes, filtered, and the filter cake was washed with water three times (300 ml each time) to give a white solid. Drying at 50C for 10 hours gave 51 g of compound 2 (4-bromomethylphenylacetic acid). Compound 2 was directly subjected to the next reaction without further purification.

Reference： [1]Patent: CN106905135,2017,A .Location in patent: Paragraph 0018; 0019; 0020; 0021
[2]Bulletin of the Chemical Society of Japan,1988,vol. 61,p. 2467 - 2472
[3]European Journal of Organic Chemistry,2006,p. 4135 - 4146
[4]Journal of the Chemical Society. Chemical communications,1993,p. 399 - 401
[5]Patent: EP496548,1992,A1
[6]Patent: EP3476829,2019,A1 .Location in patent: Paragraph 0173
[7]Patent: US9643927,2017,B1 .Location in patent: Page/Page column 33;34
[8]Patent: WO2017/86941,2017,A1 .Location in patent: Paragraph 00104
[9]Journal of Organic Chemistry,1978,vol. 43,p. 2845 - 2852
[10]Journal of Organic Chemistry,1966,vol. 31,p. 3758 - 3764
[11]Patent: US2002/165282,2002,A1
[12]Patent: CN107434780,2017,A .Location in patent: Paragraph 0055-0058

6
[ 67-56-1 ]
[ 622-47-9 ]
[ 23786-13-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride for 1h; Heating;
100%	With sulfuric acid at 65℃; for 18h;	196.1 Step 1. Preparation of methyl 2-(p-tolyl)acetate A 500-mL round bottom flask, with stirrer bar, was charged with p-tolylacetic acid (10.0 g, 66.5 mmol) and methanol (240 mL). Concentrated sulfuric acid (0.1 mL) was added at room temperature. The resulting solution was stirred at 65 °C for 18 h. After this time, the mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was washed with saturated sodium chloride (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (11.8 g, 100%) as a colorless oil. MW = 164.20. ]H NMR (CDC13, 300 MHz) δ 7.20-7.10 (m, 4H), 3.68 (s, 3H), 3.59 (s, 2H), 2.33 (s, 3H).
99%	With sulfuric acid

91%	With hydrogenchloride In water monomer for 1h; Reflux;
90%	With sulfuric acid for 3h; Reflux;
87%	With sulfuric acid for 12h; Reflux;	General procedure: To synthesize methyl ester of substituted acyl acid (7-8) (6.0 mmol)was taken and dissolved in 35 mL of dry methanol. Few drops of H2SO4were added into the reaction mixture as a catalyst. The reaction mixturewas refluxed for 12 h. The completion of the reaction was checked byTLC. When the reaction was completed the solvent was evaporated onrotary evaporator. The product so obtained was neutralized with solution of sodium bicarbonate in distilled water and extracted withethyl acetate (3x10 mL). Anhydrous sodium sulphate was used to drythe ethyl acetate layer. The mixture was filtered to remove sodiumsulfate and concentrated on rotary to get methyl ester (10-11)
74%	With sulfuric acid Reflux;	1.1. General procedure of synthesis of esters 3e, 7e-15e 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.
74%	With tert.-butylnitrite at 40℃; for 48h; Green chemistry;
73%	With tert.-butylnitrite at 40℃; for 48h;	27 Add compound 1aa (0.5 mmol, 75.1 mg) and methanol containing 40 mol% tert-butyl nitrite to the reaction tube; then react for 48 hours at 40°C in air; after the reaction, add sodium thiosulfate and stir. After quenching, using a rotary evaporator to remove the solvent, adsorbing on silica gel, and finally performing column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product 3aa with a yield of 73%.
	With sulfuric acid
	With acid Heating;
	With sulfuric acid Heating; Yield given;
	With sulfuric acid for 3h; Reflux;
	With thionyl chloride
	With sulfuric acid for 3h; Reflux;
	With sulfuric acid for 4h; Reflux;
	With sulfuric acid for 5h; Reflux;	Methyl 2-diazo-2-(p-tolyl)acetate (2f) General procedure: (Step 1) A mixture of 4-bromophenylacetic acid (1.08 g, 5.0 mmol) and 95 wt.% sulfonic acid (0.28 mL) inmethanol (5.0 mL) was refluxed for 5 h. The resulting mixture was cooled to room temperature and diluted withsaturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the combinedextracts were washed with brine, dried over sodium sulfate, and concentrated to obtain methyl (4-bromophenyl)acetate (38) (1.13 g, 99% yield) as a colorless oil. The crude product was used without purification. (Step 2)10 A solution of 38 (1.12 g, 4.89 mmol) and p-toluenesulfonyl azide11 (1.16 g, 5.88 mmol) in acetonitrile(9.8 mL) was treated with DBU (1.10 mL, 7.36 mmol) at 0 °C and the mixture was stirred for overnight at roomtemperature. The resulting mixture was quenched with saturated aqueous ammonium chloride and extracted withethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. Theresidue was purified by chromatography on silica gel (n-hexane/ethyl acetate = 10/1 as the eluent) to afford 2a(1.22 g, 98% yield) as an orange solid.
	With thionyl chloride at 65℃;	General Procedure A. Synthesis of aryl diazoacetates by Fischer esterification and diazo transfer. General procedure: To a solution of the aryl acetic acid (12.0 mmol, 1.00 equiv) in methanol (60 mL) was added thionyl chloride (2.63 mL, 36.0 mmol, 3.00 equiv). The solution was heated to reflux. Upon completion (as determined by TLC analysis), the solution was concentrated in vacuo and the crude residue was used without further purification.To a flame-dried round-bottom flask with a magnetic stir bar were added the aryl acetic acid ester (12.0 mmol, 1.00 equiv), p-ABSA (3.46 g, 14.4 mmol, 1.20 equiv), and dry acetonitrile (50 mL). The solution was stirred under nitrogen and cooled to 0 °C using an ice water bath. DBU (1.97 mL, 13.2 mmol, 1.10 equiv) was added by syringe rapidly in one portion, and the reaction mixture was allowed to warm to 23 °C and stir overnight. Upon completion (as determined by TLC analysis) or after 24 hours, whichever came first, the reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ether (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using a mixture of hexanes and ethyl acetate as eluent. The aryl diazoacetates were obtained in 23-70% yield over two steps.
	With sulfuric acid for 6h; Reflux;
	With sulfuric acid for 3h; Reflux;
	With sulfuric acid for 5h; Reflux;
	With sulfuric acid for 8h; Reflux;	4.2.2. General Procedure for Synthesis of the Key Lactone Intermediate II (6a-6k) 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)
	With sulfuric acid for 8h; Reflux; Sealed tube; Inert atmosphere;
	With sulfuric acid for 6h; Reflux;
	With sulfuric acid In methanol for 5h; Reflux;
	With sulfuric acid for 6h; Reflux;
	With sulfuric acid at 20℃; for 3.08333h; Reflux;
	With sulfuric acid at 80℃; for 8h;	In one embodiment, the esterification reaction includes: adding 150 grams (1 mol) of p-toluene acetic acid and 400 mL of methanol into a reaction flask, adding 5.2 grams (0.05 mol) of concentrated sulfuric acid dropwise, and heating at 80°C. The reaction was refluxed for 8 hours, then methanol was distilled off under reduced pressure, 400 mL of water was added to the reactor, 1,2-dichloroethane (200 mL×3 times) was extracted to remove impurities, and the organic layer was washed once with saturated brine (200 mL) Obtain methyl 4-methylphenylacetate, and then directly put into the next reaction.
	With thionyl chloride at 60℃; for 0.5h; Cooling with ice;
	With sulfuric acid for 15h; Reflux; Inert atmosphere;
	With sulfuric acid for 6h; Reflux; Inert atmosphere;
	With thionyl chloride at 0 - 20℃; for 3h;
	With sulfuric acid

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[2]Current Patent Assignee: TETRA DISCOVERY PARTNERS - WO2014/66659, 2014, A1 Location in patent: Paragraph 0841
[3]Location in patent: scheme or table Pietruszka, Joerg; Schoelzel, Melanie [Advanced Synthesis and Catalysis, 2012, vol. 354, # 4, p. 751 - 756]
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7
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[ 69574-07-8 ]
[ 127035-64-7 ]

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 1892 - 1898

8
[ 622-47-9 ]
[ 127-08-2 ]
[ 2216-45-7 ]
[ 14720-70-8 ]
[ 61165-81-9 ]
acetoxy-p-tolyl-acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 8% 2: 11% 3: 8% 4: 56%	With dipotassium peroxodisulfate; copper diacetate In acetic acid for 3h; Heating;

Reference： [1]Giordano, Claudio; Beili, Aldo; Citterio, Attilio; Minisci, Francesco [Journal of the Chemical Society. Perkin transactions I, 1981, p. 1574 - 1576]

9
[ 622-47-9 ]
[ 104-87-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With K₅CoW₁₂O₄₀ In water monomer; acetonitrile for 0.166667h; Microwave irradiation;
95%	With dihydrogen peroxide In water monomer; acetonitrile at 25℃; for 10h; UV-irradiation;
95%	With oxygen; Mn(dtbpy)<SUB>2</SUB>(OTf)<SUB>2</SUB> In acetonitrile at 45℃; for 12h; Irradiation; Schlenk technique;

94%	With 1H-imidazole; C₁₇H₁₆ClMnN₂O₂; tetrabutylammonium (meta)periodate In chloroform at 20℃; for 0.333333h;
88%	With mercury(II) fluoride; oxygen In acetonitrile at 25℃; for 24h; Irradiation;
85%	With potassium peroxodisulfate In water monomer at 90℃; for 12h; Green chemistry;	General Procedure for the preparation of Aldehydes and Ketones from Aryl acetic acids 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, 85% yield). 4-methylbenzaldehyde (2a): IR (neat) cm-1: 2827, 2734, 1689. 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.77 (d, J = 8.1Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 192.1, 145.7,134.3, 129.8, 130.0, 22.0. HRMS (ESI TOF) m/z calcd for C8H8O [M + H]+ 121.0653, found 121.0654.
79%	With ferric(III) chloride; oxygen In N,N-dimethyl-formamide at 110℃;
77%	With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20 - 25℃; for 4h; Irradiation;	5 In a 25mL reaction tube, add photocatalyst 4CzIPN (0.1mol%), DBU (10mol%), solvent acetonitrile 1.5mL, 4-methylphenylacetic acid (0.2mmol), stir in the air at room temperature 25 , react under blue light After 4 hours,Silica gel column chromatography separated the final product, based on the molar amount of arylacetic acid as 100%,The yield of the final product is 77%.
76%	With oxygen; mercuric (II) oxide In methanol; acetonitrile at 25℃; UV-irradiation;
45%	With oxygen; copper (II) acetate In dimethyl sulfoxide at 120℃; for 18h; Sealed tube;
40%	With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; 1,1,3,3-tetramethylguanidine In acetonitrile at 20℃; for 6h; Irradiation;	2.1 Experimental procedure for synthesis of 2a-2q General procedure: To a 25 mL reaction tube, arylacetic acid (0.2 mmol), 4CzIPN (1 mol%), TMG (50 mol%) were dissolved in CH3CN (1.5 mL), and then the tube was stirred in air at room temperature for 6 h with the irradiation of 25 W blue LEDs. After reaction, the mixture was collected, and the residue was purified by column chromatography on silica gel to afford the desired products.
	With pyrimido<5,4-g>pteridine-10-oxide In acetonitrile for 0.666667h; Ambient temperature; Irradiation; Yield given;

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[5]Farhadi, Saeid; Zaringhadam, Parisa; Sahamieh, Reza Zarei [Tetrahedron Letters, 2006, vol. 47, # 12, p. 1965 - 1968]
[6]Mete, Trimbak B.; Khopade, Tushar M.; Bhat, Ramakrishna G. [Tetrahedron Letters, 2017, vol. 58, # 29, p. 2822 - 2825]
[7]Gangadurai, Chinnakuzhanthai; Illa, Giri Teja; Reddy, D. Srinivasa [Organic and Biomolecular Chemistry, 2020, vol. 18, # 41, p. 8459 - 8466]
[8]Current Patent Assignee: HUAIHUA UNIVERSITY - CN110963900, 2020, A Location in patent: Paragraph 0069-0074
[9]Habibi, Mohammad H.; Farhadi, Saeid [Journal of Chemical Research, 2004, # 4, p. 296 - 297]
[10]Feng, Qiang; Song, Qiuling [Journal of Organic Chemistry, 2014, vol. 79, # 4, p. 1867 - 1871]
[11]He, Shuaiqi; Chen, Xiaolan; Zeng, Fanlin; Lu, Peipei; Peng, Yuyu; Qu, Lingbo; Yu, Bing [Chinese Chemical Letters, 2020, vol. 31, # 7, p. 1863 - 1867]
[12]Maki, Yoshifumi; Sako, Magoichi; Oyabu, Iwao; Murase, Toshinobu; Kitade, Yukio; Hirota, Kosaku [Journal of the Chemical Society. Chemical communications, 1989, # 22, p. 1780 - 1782]

10
[ 622-47-9 ]
[ 108-24-7 ]
[ 2216-45-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium 12-tungstocobalt(III)ate; potassium acetate In acetic acid for 2h; Heating; other ammonium 9-molybdonickel(IV)ate;

Reference： [1]Joensson, Lennart [Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry, 1983, vol. 37, # 9, p. 761 - 768]

11
[ 622-47-9 ]
[ 100-66-3 ]
[ 33425-19-3 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 1246 - 1250

12
[ 201230-82-2 ]
[ 104-82-5 ]
[ 622-47-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: carbon monoxide With C₂₈H₂₂CoN₄O₆ In butan-1-ol at 60℃; for 2h; Glovebox; High pressure; Green chemistry; Stage #2: 4-Methylbenzyl chloride With tetra-(n-butyl)ammonium iodide; sodium hydroxide In butan-1-ol at 60℃; for 22h; Glovebox; High pressure; Green chemistry; regioselective reaction;	4.4 Synthesis of 2a-u General procedure: A 100 mL reactor equipped with Teflon-coated magnetic stir bars was charged with n-Butyl alcohol (20 mL) and the catalyst (0.5 mmol). The reactor was then taken out of the glove box and pressured with carbon monoxide (1 atm). The mixture was stirred 2 h at 60 °C, cooled to ambient temperature and slowly vented. After benzyl chloride (10 mmol), NaOH (15 mL, 15%), and TBAI (0.25 mmol) were added, the reactor was sealed and the reaction mixtures were stirred for 22 h at 60 °C under carbon monoxide (1 atm). After the reaction, the water phase was detached and washing the organic phase three times with H2O (3×5 mL), the combined water layer was washed with Et2O, then the resulting solution was cooled to 0 °C and adjusted to pH=1-2 with HCl (6 mol/L). The product was filtered, dried in RT, and then recrystallized.
81%	With bis-triphenylphosphine-palladium(II) chloride; tetraethylammonium chloride; sodium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene at 80℃; for 20h; Autoclave; regioselective reaction;	Catalytic experiments General procedure: The carbonylation reaction was performed in a 150 mL polytetrafluoroethylene(PTFE)-lined autoclave equipped witha magnetic stir bar. In a typical experiment, the substituted benzyl chloride (0.01 mol), Pd(PPh3)2Cl2 (0.13 mmol),TEAC (0.18 mmol), NaOH (4 M, 8 mL) and DMB (10 mL)were placed in the autoclave. The autoclave was purged three times with N2 and three times with CO, and then heated to 80 °C. During the reaction, the CO pressure was maintained at 1.5 MPa. When the reaction was complete,the autoclave was cooled to room temperature in ice water,and the CO was discharged to atmospheric pressure. The mixture was then adjusted to pH 2 with HCl (12 M), and the solid was collected via filtration and air-dried. The crude product was recrystallised in MeOH/H2O (1:1, v/v) to obtain 2,4-DCPA. The remaining commercially available catalysts were evaluated under the same conditions. The percent conversion and yield were quantified by the method reported by Lei et al.
42%	With sodium hydroxide In toluene at 85 - 95℃; for 7h;

Reference： [1]She, Meng-Yao; Xiao, Da-Wei; Yin, Bing; Yang, Zheng; Liu, Ping; Li, Jian-Li; Shi, Zhen [Tetrahedron, 2013, vol. 69, # 35, p. 7264 - 7268]
[2]Li, He; Zhang, Yijun; Liu, Dinghua; Liu, Xiaoqin [Journal of Chemical Research, 2019, vol. 43, # 11-12, p. 548 - 552]
[3]Amer, Ibrahim; Alper, Howard [Journal of the American Chemical Society, 1989, vol. 111, # 3, p. 927 - 930]

13
[ 201230-82-2 ]
[ 104-81-4 ]
[ 622-47-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With cobalt(II) pyridine-2-carboxylate; palladium diacetate; sodium hydroxide In methanol at 150℃; for 6h; Autoclave;	28 312 ml of methanol, 0.55 g of cobalt pyridine-2-carboxylate,1.37 g of palladium acetate was added to the autoclave reactor.The catalyst was dissolved by stirring for 5 minutes, and the air in the kettle was replaced with CO three times, and the temperature was raised to 150 ° C.Rush into the CO until the pressure rises to 1.5 MPa. Within 1 hour,At the same time, 74.0 g (0.4 mol) of p-methylbenzyl bromide and 30% of NaOH 160 g (1.2 mol) were added dropwise to the reaction vessel.After reacting for 5 hours, the temperature was lowered to room temperature, methanol was removed by distillation under reduced pressure, the catalyst was filtered off, and the pH was adjusted to 1 by adding 30% hydrochloric acid, and filtered.Dry to obtain p-methylphenylacetic acid, the purity is:98.95%, the yield is 85%.
80%	With palladium hydroxide, 20 wt% on carbon; tetrabutylammomium bromide; water In tetrahydrofuran at 110℃; for 4h; Sealed tube; Autoclave;
72%	With sodium hydroxide; sodium tetrahydroborate In tetrahydrofuran at 55℃; for 3h;

Reference： [1]Current Patent Assignee: JIANGSU LIANHE CHEMICAL TECH; LIANHETECH YANCHENG; LIANHE CHEMICAL TECH - CN109320413, 2019, A Location in patent: Paragraph 0104; 0105; 0106
[2]Wakuluk-Machado, Anne-Marie; Dewez, Damien F.; Baguia, Hajar; Imbratta, Miguel; Echeverria, Pierre-Georges; Evano, Gwilherm [Organic Process Research and Development, 2020, vol. 24, # 5, p. 713 - 723]
[3]Satyanarayana, N.; Periasamy, M. [Tetrahedron Letters, 1987, vol. 28, # 23, p. 2633 - 2636]

14
[ 140233-83-6 ]
[ 622-47-9 ]
[ 22839-47-0 ]

Reference： [1]Tetrahedron,1992,vol. 48,p. 1115 - 1122

15
[ 622-47-9 ]
[ 100-46-9 ]
[ 82082-45-9 ]

Yield	Reaction Conditions	Operation in experiment
96%	With bis(cyclopentadienyl)titanium dichloride In tetrahydrofuran at 70℃; for 24h; Molecular sieve; Sealed tube; Inert atmosphere;
90%	With triphenylborane In toluene at 110℃;	1 General experimental procedure In 5mL thick wall glass tube (microwave tube) equipped with magnetic stirring bar, first dry toluene 1mL was added then 4-methylphenylacetic acid (1a, 0.50mmol) dissolved into toluene by stirring for 5min. Then benzylamine (2a, 0.55mmol) was added and stirred the reaction mixture for 5min. Finally, catalyst triphenyl borate (4mol%) was added and tube was closed with septum and placed into oil bath and magnetically stirred at 110°C for 3h under air atmosphere. After completion, the reaction mixture was cooled to room temperature. Then reaction mixture was transfer into conical flask and ethyl acetate or dichlormethane (10mL) was added. Then product is purified by acid base extraction using aqueous 1:1 HCl and 10% NaOH and finally washed with brine and water. The organic layer was dried over Na2SO4 and finally organic solvent evaporated on rota-evaporator to afford the pure product 3a. The product was confirmed by 1H and 13C NMR spectroscopic analysis. Same procedure is followed for synthesis of all other amides from 3b to 3q. 4.2.1 N-benzyl-2-(p-tolyl)acetamide (3a) 1H NMR (600 MHz, CHLOROFORM-D) δ 7.29 (dd, J = 10.1, 4.5 Hz, 2H), 7.26-7.22 (m, 2H), 7.17 (d, J = 7.2 Hz, 2H), 7.14 (d, J = 8.7 Hz, 4H), 5.67 (s, 1H), 4.40 (d, J = 5.9 Hz, 2H), 3.59 (s, 2H), 2.33 (s, 3H); 13C NMR (151 MHz, CHLOROFORM-D) δ 152.51, 126.17, 125.31, 120.91, 119.44, 119.12, 118.53, 117.59, 117.53, 50.45, 50.37, 32.48, 15.62.
78%	With bis(cyclopentadienyl)hafnium dichloride; Ethyl 2-phenylethanoate In diethyl ether at 26℃; for 48h; Molecular sieve; chemoselective reaction;

42%

In xylene for 6h; Heating;

Reference： [1]Wang, Hui; Dong, Wei; Hou, Zhipeng; Cheng, Lidan; Li, Xiufen; Huang, Longjiang [Applied Organometallic Chemistry, 2020, vol. 34, # 5]
[2]Ghorpade, Seema A.; Sawant, Dinesh N.; Sekar, Nagaiyan [Tetrahedron, 2018, vol. 74, # 48, p. 6954 - 6958]
[3]Lundberg, Helena; Adolfsson, Hans [ACS Catalysis, 2015, vol. 5, # 6, p. 3271 - 3277]
[4]Agwada, Vincent C. [Journal of Chemical and Engineering Data, 1982, vol. 27, # 4, p. 481 - 483]

16
[ 201230-82-2 ]
[ 589-29-7 ]
[ 7325-46-4 ]
[ 622-47-9 ]

Reference： [1]Tetrahedron Letters,1997,vol. 38,p. 3747 - 3750

17
[ 201230-82-2 ]
[ 589-29-7 ]
[ 106-42-3 ]
[ 7325-46-4 ]
[ 622-47-9 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1998,vol. 71,p. 723 - 734

18
[ 622-47-9 ]
[ 74-88-4 ]
[ 938-94-3 ]

Reference： [1]Journal of the Chemical Society. Perkin Transactions 2 (2001),1998,p. 1767 - 1775
[2]Angewandte Chemie - International Edition,2007,vol. 46,p. 8484 - 8487
[3]Organic Letters,2011,vol. 13,p. 1666 - 1669
[4]Angewandte Chemie - International Edition,2017,vol. 56,p. 13145 - 13149
Angew. Chem.,2017,vol. 129,p. 13325 - 13329,5

19
[ 622-47-9 ]
[ 100-39-0 ]
[ 71989-26-9 ]
[ 102410-65-1 ]
[ 18637-83-7 ]
(S)-1-[(S)-1-(Benzylamino-methyl)-5-(benzyl-methyl-amino)-pentyl]-5-phenyl-4-(2-p-tolyl-ethyl)-piperazine-2,3-dione [ No CAS ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 3319 - 3326

20
[ 622-47-9 ]
[ 951-87-1 ]
N-(2-amino-1,2-diphenyl-ethyl)-2-p-tolyl-acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 435 - 438

21
[ 622-47-9 ]
[ 66270-97-1 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1988,vol. 61,p. 2467 - 2472
[2]Journal of Organic Chemistry,1978,vol. 43,p. 2845 - 2852

22
[ 622-47-9 ]
[ 7398-42-7 ]

Reference： [1]Journal of Organic Chemistry,1966,vol. 31,p. 3758 - 3764

23
[ 622-47-9 ]
[ 611-14-3 ]
[ 699-02-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;	COMPARATIVE EXAMPLE 1 In the same manner as in Example 1 but not using triethylamine, the reaction was carried out to give the following results: conversion of p-methylphenylacetic acid, 99.2%; yield of p-methylphenethyl alcohol, 74.3%; selectivity to p-methylphenethyl alcohol, 74.9%; yield of ethyltoluene, 10.2%.

Reference： [1]Patent: US4317918,1982,A

24
[ 622-47-9 ]
[ 94-36-0 ]
[ 13737-36-5 ]

Yield	Reaction Conditions	Operation in experiment
3.75 g (16.4 mmol, 49.2%)	With N-Bromosuccinimide; In benzene;	p-Bromomethylphenylacetic acid STR955 A mixture (suspension) of p-tolylacetic acid (5.00 g, 33.3 mmol), N-bromosuccinimide (5.93 g, 33.3 mmol) and benzoylperoxide (65 mg, 0.27 mmol) in dry benzene (30 ml) was heated at reflux for 5 h. After cooling it in an ice-bath (ca 10 C.), a white precipitate formed. It was collected and dried yielding 7 g of a white powder. This was triturated with warm water (1*5 ml), filtered and dried to obtain 3.75 g (16.4 mmol, 49.2%) of p-bromomethylphenylacetic acid as a white powder. This material contained a small amount of succinimide but was used as such in the next step. An analytical sample was obtained by further trituration with warm water: mp 170-173 C.; 1 Hmr (DMSO-d6) delta: 3.57 (2H, s,--CH2 CO2), 4.69 (2H, s, --CH2 Br) and 7.13-3.95-7.33-7.47 ppm (4H, A2 'B 2 ', aromatic Hs); ir (nujol) numax: 1690 cm-1 (s,C=O).

Reference： [1]Patent: US4272437,1981,A

25
dirhenium heptoxide [ No CAS ]
[ 622-47-9 ]
[ 611-14-3 ]
[ 699-02-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1,4-dioxane;	EXAMPLE 1 Into a 50 ml volume stainless steel made autoclave equipped with a magnetic stirrer and inserted with a glass tube, p-methylphenylacetic acid (0.6 g), dehydrated dioxane (10 ml), dirhenium heptoxide (60 mg) and triethylamine (4.3 mg) were charged, and the inner atmosphere was replaced by nitrogen gas. Hydrogen gas was pressurized therein up to 100 atm. The reaction was carried out at 162 C. for 5 hours while stirring. After cooling to room temperature, the reaction mixture was subjected to gas chromatographic analysis to give the following results: conversion of p-methylphenylacetic acid, 98.5%; yield of p-methylphenethyl alcohol, 92.4%; selectivity to p-methylphenethyl alcohol, 93.8%; yield of ethyltoluene, 0.5%.

Reference： [1]Patent: US4317918,1982,A

26
[ 622-47-9 ]
[ 14062-19-2 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE II Ethyl 4-tolylacetate STR19 Ethyl 4-tolylacetate is prepared in analogy to the method in Example 1 starting from 4-tolylacetic acid. Rf =0.43 (A)

Reference： [1]Patent: US6114341,2000,A
[2]European Journal of Organic Chemistry,2016,vol. 2016,p. 3930 - 3933

27
[ 622-47-9 ]
[ 34241-39-9 ]
[ 13737-36-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; In tetrachloromethane; water;	(a) 4-bromomethyl Phenyl Acetic Acid A mixture of 50 g (0.33 mol) of 4-methylphenyl acetic acid, 62 g (0.35 mol) of N-bromo-succinimide, 200 ml of carbon tetrachloride and 0.1 g of 2,2-azobis(isobutyronitrile) are placed in a 500 ml flask and heated to reflux with stirring for 4 hours. After the reaction mixture is cooled to room temperature, it is poured into 500 ml of water. The obtained precipitate is filtered off, and then washed with water. After drying under an atmosphere of reduced pressure, 55 g of a white powder are obtained (72%).

Reference： [1]Patent: US6258954,2001,B1

28
[ 622-47-9 ]
[ 137-09-7 ]
[ 959958-62-4 ]

Yield	Reaction Conditions	Operation in experiment
61%	With polyphosphoric acid; at 180℃; for 1.5h;	General procedure: The derivatives were synthesized by heating 2,4-diaminophenoldihydrochloride (1) (0.01 mol) with suitable acid (2a-2l) (0.01 mol) in polyphosphoric acid (PPA) (24 g) and stirring at170-200 Cfor 1.5-2.5 h.At the end of the reaction period, theresidue was poured into an ice-water mixture and neutralizedwith an excess of NaOH (10 %) solution, and the residue wasfiltered and boiled with charcoal (200 mg) in ethanol and filtered.After the evaporation of solvent in vacuo, the crudeproduct was obtained and recrystallized from ethanol-water(1:3) mixture (Yildiz-Oren et al., 2004a; Sener et al., 1987;Wynne et al., 2009).

Reference： [1]Medicinal Chemistry Research,2016,vol. 25,p. 553 - 567
[2]European Journal of Medicinal Chemistry,2008,vol. 43,p. 2568 - 2578
[3]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2016,vol. 55B,p. 240 - 247

29
[ 622-47-9 ]
[ 97986-34-0 ]
[ 629610-52-2 ]

Yield	Reaction Conditions	Operation in experiment
		(2) 1.58M n-BuLi n-hexane solution (17.7 mL) and diisopropylamine (3.1 g) were added to THF (10 mL) at 0C or lower (LDA preparation). Then, p-tolylacetic acid (2 g) dissolved in THF (8 mL) was added, followed by stirring for 1 hour. Then, <strong>[97986-34-0]tetrahydro-2H-pyran-4-yl 4-methylbenzensulfonate</strong> (3.41 g) was added at 0C or lower, followed by stirring at 24C for 6 hours. Water (10 mL) was added to the reaction mixture and the mixture was washed twice with ethyl acetate (12 mL X 2). Then, concentrated hydrochloric acid was added to adjust pH to 4 and the mixture was extracted twice with ethyl acetate (12 mL X 2). The extract was concentrated and ethanol (7 mL) was added to dissolve the residue. Then, water (14 mL) was added to effect crystallization to obtain (4-methylphenyl)(tetrahydro-2H-pyran-4-yl)acetic acid (2.65 g).1H NMR (DMSO)?: 12.32 (s,1H), 7.20-7.12 (q,4H) 3.86-3.14(m,5H), 2.27 (s,3H), 2.08 (m,1H), 1.69-1.00 (m,4H)

Reference： [1]Patent: EP1367058,2003,A1 .Location in patent: Page 25

30
[ 58-27-5 ]
[ 622-47-9 ]
[ 1189393-98-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With ammonium peroxydisulfate; silver nitrate In water; acetonitrile at 85℃; for 2.75h; Reflux;
77%	With ammonium peroxydisulfate In water; acetonitrile at 85℃; Reflux;	1.1.1 EXAMPLE 1; General Procedure for the Silver-catalyzed Coupling Reactions of 1,4-Naphthoquinones with Carboxylic Acids A solution of menadione or plumbagin (5.81 mmol) and a phenylacetic acid derivative (11.58 mmol) in 52.5 mL acetonitrile and 17.5 mL water was heated to 85 0C. AgNO3 (90 mg, 0.58 mmol) was added. (MLi)2S2O8 (1.72 g, 7.54 mmol) in 15 mL acetonitrile and 5 mL water was added dropwise over a period of 45 minutes and then heated at reflux for two hours. The acetonitrile was removed in vacuo. The aqueous phase was extracted with dichloromethane (4 x 10 mL), dried over MgSO4 and purified by flash-chromatography.Example 1.1: 2-Methyl-3-(4-methyl-benzyl)-4a,8a-dihydro- [ 1 ,4] naphthoquinone (P TM21)As starting materials for the coupling reaction menadione and p-tolylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether: ethylacetate = 1 : 1, UV), 2.82 g (10.21 mmol, 77 % yield) of P TM21 were isolated as yellow solid.Melting point: 225 0C decomposition. - 1H-NMR (300 MHz, CDCl3): δ = 8.04 - 8.05 (m, 2H), 7.64 - 7.70 (m, 2H), 7.08 (m, 4H), 3.98 (s, 2H), 2.27 (s, 3H), 2.23 (s, 3H). - 13C-NMR (75 MHz, CDCl3): δ = 185.42 (Cq), 184.66 (C,), 145.53 (Cq), 144.20 (Cq), 135.97 (Cq), 134.94 (Cq), 133.42 (CH), 133.39 (CH), 132.12 (Cq), 132.06 (Cq), 129.31 (CH), 128.46 (CH), 126.44 (CH), 126.21 (CH), 31.99 (CH2), 20.96 (CH3), 13.23 (CH3).- FAB MS (NBA, m/z (%)): 277.2 ([M+H]+, 73), 261.1 (26), 212.1 (24). - IR (KBr): 3437 cm"1 (b, m), 2923 (w), 1660 (vs), 1616 (w), 1595 (m), 1512 (m), 1377 (w), 1332 (w), 1295 (vs), 809 (w), 754 (m), 705 (m). - EA: obs. C, 82.44 %; H, 5.84 %, calcd. C, 82.58 %; H, 5.84 % for Ci9Hi6O2.

Reference： [1]Sidorov, Pavel; Desta, Israel; Chessé, Matthieu; Horvath, Dragos; Marcou, Gilles; Varnek, Alexandre; Davioud-Charvet, Elisabeth; Elhabiri, Mourad [ChemMedChem, 2016, p. 1339 - 1351]
[2]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; HEIDELBERG UNIVERSITY - WO2009/118327, 2009, A1 Location in patent: Page/Page column 22-23

31
[ 7305-71-7 ]
[ 622-47-9 ]
[ 908545-06-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	To a suspension of p-tolylacetic acid (1.00 g, 6.66 mmol) and 2-amino-5-methylthiazole (0.760 g, 6.66 mmol) in dichloromethane (10 mL) was added at 0° C. under a nitrogen atmosphere 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.40 g, 7.32 mmol), 1-hydroxybenzotriazole (90 mg, 0.67 mmol) and N,N-diisopropyl ethyl amine (1.8 mL, 10 mmol). The ice bath was removed and the resulting solution was stirred for 3 h at ambient temperature. The reaction mixture was diluted with dichloromethane (20 mL) and washed with aqueous sodium carbonate (half-concentrated, 20 mL) and water (20 mL). The aqueous layers were extracted with dichloromethane (20 mL) and the combined organic layers were dried over sodium sulfate. The filtrate was concentrated and the residue was suspended in TBME (20 mL) and filtered. Washing with TBME (10 mL) afforded the title compound (1.48 g, 90percent) as a white solid. MS m/e: 247.2 [M+H]+.

Reference： [1]Patent: US2009/312314,2009,A1 .Location in patent: Page/Page column 29-30

32
[ 622-47-9 ]
[ 100-66-3 ]
[ 57297-25-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With trifluoromethylsulfonic anhydride In dichloromethane Cooling with ice;	4.1.1. 1-(2,4-Dimethoxyphenyl)-2-p-tolylethanone (7a) General procedure: Into a 100mL round bottom flask equipped with magnetic stirring was placed 4-tolylacetic acid (0.524g, 3.61mmol) along with 15mL of dry dichloromethane (DCM). To this mixture with ice bath cooling was added 1,3-dimethoxybenzene (0.542g, 3.61mmol) and 4.33mL (4.33mmol) of a 1.00M solution of triflic anhydride in anhydrous DCM. The resulting mixture was stirred overnight, diluted with 20mL of saturated aqueous bicarbonate and extracted with DCM (3×20mL). The DCM solution was dried over anhydrous sodium sulfate, filtered through a fritted glass funnel and the filtrate was then passed through a short plug of silica gel and the plug was then washed with 50mL of ethyl acetate. The combined filtrates were concentrated in vacuo to yield a dark grey solid (0.918g, 94% yield).
80%	Stage #1: 4-tolylacetic acid; methoxybenzene With tetraphosphoric acid In acetonitrile at 20℃; for 0.166667h; Stage #2: With trifluoroacetic anhydride In acetonitrile at 20℃; for 8h;	4.2. A representative synthetic procedure of skeleton 3 is as follows General procedure: PPA (H6P4O13, polyphosphoric acid, 1.7 g, 5.0 mmol) was added to a solution of substituted arenes (3.3 mmol) and phenylacetic acids (3.0 mmol) in MeCN (10 mL) at rt. The reaction mixture was stirred at rt for 10 min. TFAA (trifluoroacetic anhydride, 850 mg, 4.0 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred at rt for 8 h. The solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (320 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc=8/1-4/1) afforded 3.
40%	With phosphoric acid; trifluoroacetic anhydride In water; acetonitrile at 50℃; for 2h;	11 To a solution of 4-methylphenylacetic acid (1.00 g, 6.65 mmol), anisole (2.20 ml, 20.1 mmol), and 85% phosphoric acid (0.45 ml) in acetonitrile (25 ml), a solution of trifluoroacetic anhydride (3.75 ml, 27.0 mmol) in acetonitrile (10 ml) was added dropwise at 50°C. The mixture was stirred at the same temperature for 2 hours, cooled to room temperature, and then poured on ice. After the mixed solution was extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate/n-hexane = 5/1-4/1), and the resulting solid was recrystallized (ethyl acetate/n-hexane = 1/3) to give a title compound (645 mg, 2.68 mmol, 40%) as a white crystal. 1H-NMR (400 MHz, CDCl3) δ: 2.31 (3H, s). 3.86 (3H, s), 4.19 (2H, s), 6.91 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.3 Hz), 7.15 (2H, d, J = 8.3 Hz), 7.99 (2H, d, J = 8.8 Hz).

	With phosphoric acid; trifluoroacetic anhydride at 20℃; for 0.0833333h;	General procedure for the preparation of compounds 5a-d General procedure: To a stirred solution of phenylacetic acid derivative (1mmol), anisole (1.2 mmol) and phosphoric acid (1.2 mmol)was added trifluoroacetic acid anhydride (4 mmol) andstirred for 5 min at room temperature. Then crushed ice wasadded to the reaction mixture while stirring and the precipitatewas filtered and washed with water and then petroleumether respectively. The crude product was used inthe next step without further purification.
	With phosphoric acid; trifluoroacetic anhydride at 20℃; for 0.166667h;	Synthesis of 1,2-Diarylethanones (1a-j) General procedure: To a mixture of arylacetic acid derivatives (1 eq), anisole or thioanisole (1.2 eq) and phosphoric acid (1.2 eq), was added trifluoroacetic anhydride (4 eq) and the resulting mixture was stirred at room temperature for 10 min. Crushed ice was added to the mixture to precipitate the product and then it was filtered and washed with water and petroleum ether. It was used in the next step without further purification. Compounds characterization was previously reported by us in our recent publication (Kucukkilinc et al. 2017; Valipour et al. 2019).

Reference： [1]Gupton, John T.; Shimozono, Alex; Crawford, Evan; Ortolani, Joe; Clark, Evan; Mahoney, Matt; Heese, Campbell; Noble, Jeffrey; Mandry, Carlos Perez; Kanters, Rene; Dominey, Raymond N.; Goldman, Emma W.; Sikorski, James A.; Fisher, Daniel C. [Tetrahedron, 2018, vol. 74, # 21, p. 2650 - 2663]
[2]Chan, Chieh-Kai; Chen, Yi-Chia; Chen, Yeh-Long; Chang, Meng-Yang [Tetrahedron, 2015, vol. 71, # 49, p. 9187 - 9195]
[3]Current Patent Assignee: TORAY INDUSTRIES INC - EP2009006, 2008, A1 Location in patent: Page/Page column 41-42
[4]Tuylu Kucukkilinc, Tuba; Safari Yanghagh, Kamaledin; Ayazgok, Beyza; Ali Roknipour, Mohammad; Homayouni Moghadam, Farshad; Moradi, Alireza; Emami, Saeed; Amini, Mohsen; Irannejad, Hamid [Medicinal Chemistry Research, 2017, vol. 26, # 11, p. 3057 - 3071]
[5]Firouzjaei, Fariba Abedi; Heidarli, Elmira; Ravan, Shabnam; Hosseini, Sayed Masoud; Naderi, Nima; Almasyan, Kiarash; Sarvary, Afshin; Irannejad, Hamid [Medicinal Chemistry Research, 2020, vol. 29, # 8, p. 1520 - 1535]

33
[ 622-47-9 ]
[ 74-88-4 ]
[ 20430-18-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of diisopropylamine (ALDRICH, 15.2 mL, 109 mmol) in 108 mL of anhydrous THF at -20C under N2 was added n-BuLi (55.7 mL, 106 mmol, 1.9M solution in hexane) droDwise via cannula. After stirrina for 2 hours. D-tolvlacetic acid (ALDRICH. 3.99 a. 26.5mmol) was added in 26 mL of THF. The mixture was stirred at -5C for 2 hours and, then, treated with iodomethane (9.9 mL, 159 mmol). The reaction mixture was allowed to gradually warm up to room temperature, stirred at that temperature for 15 hours, and then, quenched by pouring it into 20 mL of HCI (1N). The aqueous layer was extracted with Et20 (3x100 mL). The organic layer was treated with brine and dried over MgS04 and concentrated in vacuo to give 4.86 g of the title compound as a brown oil. 1H NMR (300 MHz, DMSO-d6) 8 ppm: 12.22 (br.s, 1H), 7.21 (m, 2H), 7.12 (m, 2H), 2.25 (s, 3H), 1.43 (s, 6H). No molecular peak is detected by MS.

Reference： [1]Patent: WO2006/27211,2006,A1 .Location in patent: Page/Page column 60-61
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 6129 - 6152

34
[ 622-47-9 ]
[ 7524-50-7 ]
[ 1105566-58-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 24h;	5 DMAP (194 mg, 1 .58 mmol) and DIC (N,N-diisopropylcarbodiimide) (740 μΙ, 4.76 mmol) were added to a solution of L-phenylalanine methyl ester hydrochloride (684 mg, 3.17 mmol) and p-tolylacetic acid (500 mg, 3.33 mmol) in dry DCM (35 ml). After 24h at room temperature the solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (DCM containing 1 % EtOH ) to afford S methyl 2-[2-(4-methylphenyl)acetamido]-3- phenyl-propanoate in quantitative yield. The product was diluted with methanol (78 ml) and then an aqueous solution of NaOH (1 N, 14.2 ml, 14.2 mmol) was added. The reaction mixture was stirred for 1 h at room temperature and concentrated. Then water and HCI 1 N was added until pH 2. The organic product was extracted with DCM (3 x 50 ml), dried with Na2C03 and concentrated under reduced pressure to afford (S)-2-[2-(4-methylphenyl)acetamido]-3-phenyl-propionic acid as a white solid (94 % c.y.)Analytical data:1H-NMR (CDCIs, 400 MHz) δ in ppm: 2.36 (s, 3H, CH3), 3.01 (dd, J= 14.0, 6.8 Hz, 1 H, CHCH2Ph), 3.12 (dd, J= 14.0, 5.4 Hz, 1 H, CHCH2Ph), 3.51 (s, 2H, COCH2), 4.77 (dd, J= 6.8, 5.4 Hz, 1 H, CHCH2Ph), 5.78 (d, J= 7.6 Hz, 1 H, NH), 6.92 (d, J= 7.6 Hz, 2H-Ar), 7.01 (d, J= 8.4 Hz, 2H-Ar), 7.12 (d, J= 7.6 Hz, 2H-Ar), 7.17- 7.23 (m, 3H-Ar); 13C-RMN (CDCI3, 100.4 MHz) δ in ppm: 21 .1 (CH3), 36.8 (CH CH2Ph), 42.9 (CH2CO), 53.2 (CHCH2Ph), 127.1 , 128.6, 129.2, 129.3, 129.8 (CH-Ar), 130.7, 135.3, 137.2 (C-Ar), 172.1 (CO)
	With dmap; diisopropyl-carbodiimide In tetrahydrofuran at 20℃; for 14h; Inert atmosphere;	4.2.16. General procedure for synthesis of (4) General procedure: Procedure A: A solution of a phenylacetic acid (3.7 mmol), DMAP (5.55 mmol) and DCC (5.55 mmol) in THF (40-70 ml) was stirred at room temperature (rt) for 30 min. The hydrochloride salt of the carboxy protected aminoacid (3.7 mmol) was added and the solution was stirred for 48 h at rt. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. The methyl ester (1eq) was dissolved in methanol. A solution of NaOH (1N, 17 ml) was added and the reaction mixture was stirred for 1 h at rt. H2O was added and methanol only was evaporated under reduced pressure. The pH was reduced to 2 using HCl solution 1N. The crude material was extracted with ethyl acetate and the organic phase was dried with Na2SO4 anhydrous. The solvent was removed in vacuo to afford 4 without any further purification. Procedure B: A solution of phenylacetic acid (6 mmol), the hydrochloride salt of the carboxy protected aminoacid (6 mmol), DMAP (3 mmol) and DCI (10 mmol) in (50-80 ml) was stirred at r.t. for 14 h. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. Treatment with NaOH as reported in procedure A.
	Stage #1: 4-tolylacetic acid; methyl (2S)-2-amino-3-phenylpropanoate hydrochloride With triethylamine In dichloromethane at 0℃; for 0.5h; Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h; Inert atmosphere;

Reference： [1]Current Patent Assignee: UNIVERSITY OF LORRAINE; ORESTE PICCOLO STUDIO DI CONSULENZA SCIENTIFICA; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; AIX-MARSEILLE UNIVERSITY; UNIVERSITAT DE BARCELONA - WO2011/36303, 2011, A1 Location in patent: Page/Page column 29; 30
[2]Location in patent: experimental part Furlan, Alessandro; Colombo, Francesco; Kover, Andrea; Issaly, Nathalie; Tintori, Cristina; Angeli, Lucilla; Leroux, Vincent; Letard, Sébastien; Amat, Mercedes; Asses, Yasmine; Maigret, Bernard; Dubreuil, Patrice; Botta, Maurizio; Dono, Rosanna; Bosch, Joan; Piccolo, Oreste; Passarella, Daniele; Maina, Flavio [European Journal of Medicinal Chemistry, 2012, vol. 47, # 1, p. 239 - 254]
[3]Yao, Sen; Wei, Biao; Yu, Mingjun; Meng, Xiaoming; He, Meng; Yao, Risheng [MedChemComm, 2019, vol. 10, # 5, p. 757 - 763]

35
[ 14080-51-4 ]
[ 622-47-9 ]
[ 908551-93-9 ]

Yield	Reaction Conditions	Operation in experiment
26%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	General procedure: A mixture 2-amino-4,5-dimethylthiophene-3-carboxamide (340 mg, 2 mmol), 2-(1-naphthalen-1-yl)acetic acid (372 mg, 2 mol), EDC (458 mg, 2.4 mmol), HOBt (324 mg, 2.4 mmol), DIEA ( 1.1 mL, 6 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into 100 mL of water then extracted with ethyl acetate (150 mL). The organic layer was washed with saturated NaHCO3 solution (3 x 50 mL), brine (3 x 50 mL), water (3 x 50 mL) respectively. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (30 to 40% ethyl acetate in haxane) to afford compound 1 (277 mg, 41%).

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2582 - 2588

36
[ 622-47-9 ]
[ 50413-24-6 ]
[ 959003-56-6 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: 4-tolylacetic acid; 2-bromo-1-(4-methanesulfonylphenyl)ethanone With triethylamine In acetonitrile at 25℃; for 1h; Inert atmosphere; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0℃; for 2h; Inert atmosphere;	3-(para-Tolyl)-4-(4-methanesulfonylphenyl)-5H-furan-2-one (10): Triethyl amine (0.7 mL, 5 mmol) was added dropwise to a mixture of 2-bromo-4'-(methylsulphonyl)acetophenone (8, 0.61 g, 2.25 mmol) and para-tolylacetic acid (9, 0.3 g, 2 mmol) in acetonitrile (8 mL) under argon. The resulting mixture was maintained at 25 °C for 1 hour with stirring prior to cooling to 0 °C. DBU (0.58 mL, 3.88 mmol) was added, the mixture was stirred for 2 h at 0 °C, a solution of 1 N HCl (7 mL) was added, and the mixture was extracted withEtOAc (3 x 50 mL). The organic extract was dried (Na2SO4), the solvent was removed in vacuo, and the residue was purified by elution from a silica gel column using EtOAc-hexane (2:1, v/v) as eluant to furnish 10 (0.41 g, 63%) as a yellow powder:
51.7%	With triethylamine In acetonitrile at 78 - 82℃; for 1h;	2 Example 3 Preparation of 4-(4-methanesulfonylphenyl)-3-(4-methylphenyl)-2,5-dihydrofuran-2-one (Intermediate Iridab in Formula I) body) General procedure: p-Methylphenylacetic acid 13.5gAnd triethylamine 27.3gAdd to 50ml acetonitrile,Heated to 78-82 ° C,A solution prepared by previously adding 32.0 g of α,α-dibromo-4-methanesulfonylacetophenone and 60 ml of acetonitrile was slowly added dropwise, and after refluxing, the reaction was further refluxed for 1 hour, and cooled to 20-25 ° C.Layered with saturated brine. The organic layer is concentrated to dryness.Ethyl acetate and ethanol were added, stirred for 2 h, suction filtered, and the solid was dried to give 27.2 g.The yield was 92.1% and the purity was 98.5%. Basically the same as in Example 3, except that the raw material α,α-dibromo-4-methanesulfonylacetophenone is replaced by α-bromomethylsulfonylacetophenone (as shown in the following formula); The obtained ericoxib intermediate of the formula I was 15.2 g, the yield was 51.7%, and the purity was 96.4%.
	Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 1 h / 20 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 0.25 h / 0 °C

Reference： [1]Location in patent: experimental part Abdellatif, Khaled R.A.; Huang, Zhangjian; Chowdhury, Morshed A.; Kaufman, Susan; Knaus, Edward E. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 13, p. 3951 - 3956]
[2]Current Patent Assignee: JIANGSU MEIDIKE CHEMICAL - CN108864003, 2018, A Location in patent: Paragraph 0051-0053; 0068-0069
[3]Yamakawa, Naoki; Suzuki, Koichiro; Yamashita, Yasunobu; Katsu, Takashi; Hanaya, Kengo; Shoji, Mitsuru; Sugai, Takeshi; Mizushima, Tohru [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 8, p. 2529 - 2534]

37
[ 622-47-9 ]
[ 6638-79-5 ]
[ 130236-78-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 4-tolylacetic acid With 1,1′-carbonyldiimidazole In tetrahydrofuran for 1h; Stage #2: O,N-dimethyl-hydroxylamine hydrochloride With trimethylamine In tetrahydrofuran; acetonitrile for 20h;	N-Methyl-N-methoxy-2-phenylacetamide (1a) General procedure: To a solution of 40.53 g (0.3 mol) of phenylacetic acid in 300 mL of anhydrous THF was added 64.8 g (0.4 mol) of 1,1'-carbonyldiimidazole, and the mixture was stirred for 1 h. At the same time to 48.75 g (0.5 mol) of N-methoxymethanamine hydrochloride in 300 mL of anhydrous acetonitrile was added 52.5 g (0.52 mol) of trimethylamine, and this mixture also was stirred for 1 h. Then both reaction mixtures were combined and stirred for 20 h (TLC monitoring), 600 mL of dichloromethane was added, the obtained solution was washed in succession with water, 7% aqueous HCl, 15% aqueous K23, dried with anhydrous Na2SO4, and concentrated. Yield 97%
95%	Stage #1: 4-tolylacetic acid With 1,1′-carbonyldiimidazole In dichloromethane at 0℃; for 0.5h; Stage #2: O,N-dimethyl-hydroxylamine hydrochloride With triethylamine In dichloromethane at 0 - 20℃;
92%	With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere;

79%	With 4-methyl-morpholine; dicyclohexyl-carbodiimide In dichloromethane at 0℃;
70%	Stage #1: 4-tolylacetic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 4h; Inert atmosphere; Stage #2: O,N-dimethyl-hydroxylamine hydrochloride With triethylamine In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;
	With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 1h; Inert atmosphere;
	With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃;
	With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; Inert atmosphere;
	With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane
	With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 3h;

Reference： [1]Boev; Moskalenko; Belopukhov; Nikonova [Russian Journal of Organic Chemistry, 2017, vol. 53, # 2, p. 169 - 177][Zh. Org. Khim., 2017, vol. 53, # 2, p. 182 - 190,9]
[2]He, Qiaoqiao; Hou, Jun; Wei, Hongbo; Xie, Weiqing; Yan, Jiahang; Zeng, Hongxin; Zhang, Wenting [Organic and Biomolecular Chemistry, 2022, vol. 20, # 12, p. 2387 - 2391]
[3]Tan, Yuqi; Yuan, Wei; Gong, Lei; Meggers, Eric [Angewandte Chemie - International Edition, 2015, vol. 54, # 44, p. 13045 - 13048][Angew. Chem., 2015, vol. 127, # 44, p. 13237 - 13240,4]
[4]Watson, Rebecca B.; Schindler, Corinna S. [Organic Letters, 2018, vol. 20, # 1, p. 68 - 71]
[5]Campano, Teresa E.; Iriarte, Igor; Olaizola, Olatz; Etxabe, Julen; Mielgo, Antonia; Ganboa, Iñaki; Odriozola, José M.; García, Jesús M.; Oiarbide, Mikel; Palomo, Claudio [Chemistry - A European Journal, 2019, vol. 25, # 17, p. 4390 - 4397]
[6]Location in patent: experimental part Kambe, Tohru; Maruyama, Toru; Nakano, Masayuki; Yamaura, Yoshiyuki; Shono, Tomoyuki; Seki, Akiteru; Sakata, Kiyoto; Maruyama, Takayuki; Nakai, Hisao; Toda, Masaaki [Chemical and Pharmaceutical Bulletin, 2011, vol. 59, # 12, p. 1523 - 1534]
[7]Zhang, Di-Han; Knelles, Jakob; Plietker, Bernd [Advanced Synthesis and Catalysis, 2016, vol. 358, # 15, p. 2469 - 2479]
[8]Gong, Jun; Li, Shi-Wu; Qurban, Saira; Kang, Qiang [European Journal of Organic Chemistry, 2017, vol. 2017, # 25, p. 3584 - 3593]
[9]Liu, Wen; Pu, Maoping; He, Jun; Zhang, Tinghui; Dong, Shunxi; Liu, Xiaohua; Wu, Yun-Dong; Feng, Xiaoming [Journal of the American Chemical Society, 2021, vol. 143, # 30, p. 11856 - 11863]
[10]Xiong, Peng; Hemming, Marcel; Ivlev, Sergei I.; Meggers, Eric [Journal of the American Chemical Society, 2022, vol. 144, # 15, p. 6964 - 6971]

38
[ 394-35-4 ]
[ 622-47-9 ]
[ 80749-47-9 ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: methyl 2-fluorobenzoate; 4-tolylacetic acid With sodium hexamethyldisilazane In tetrahydrofuran; pyridine at -10℃; for 3.5h; Inert atmosphere; Stage #2: With hydrazine dihydrochloride; hydrazine In tetrahydrofuran; pyridine at 170℃; for 12h; Inert atmosphere;

Reference： [1]Wu, Guiyong; Yin, Weiyu; Shen, Hong C.; Huang, Yong [Green Chemistry, 2012, vol. 14, # 3, p. 580 - 585]

39
[ 622-47-9 ]
[ 5368-81-0 ]
[ 146767-39-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium hexamethyldisilazane In tetrahydrofuran; N,N-dimethyl-formamide at -10℃; for 3.5h; Inert atmosphere;

Reference： [1]Wu, Guiyong; Yin, Weiyu; Shen, Hong C.; Huang, Yong [Green Chemistry, 2012, vol. 14, # 3, p. 580 - 585]

40
[ 622-47-9 ]
[ 95-54-5 ]
[ 108714-03-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 4-tolylacetic acid; 1,2-diamino-benzene at 190℃; for 2h; Stage #2: With sodium hydroxide In lithium hydroxide monohydrate at 5℃; for 24h;
78%	With Orthoboric acid In 5,5-dimethyl-1,3-cyclohexadiene for 16h; Reflux;	12 General procedure to synthesis of compounds 3a-y and 5 General procedure: To a stirred solution of benzene-1,2-diamine 1 (1.85 mmol)in xylenes (10 mL) were added carboxylic acid 2 (2.77 mmol)and boric acid (0.185 mmol). The resulting solution wasrefluxed for 16 h. After cooling to room temperature, the reactionwas concentrated under reduced pressure and diluted withEtOAc (50 mL). The organic phase was washed with saturatedNaHCO3 solution (2 50 mL), dried over anhydrous Na2SO4and then concentrated under reduced pressure. The residuewas purified by silica gel flash column chromatography (elutingwith 10-15% Ethyl acetate in hexanes) to afford the title compounds3a-y and 5.6.2.12 2-(4-Methylbenzyl)-1H-benzo[d]imidazole (3l) Yield 78%; Off white solid; mp 196-199 °C; IR (KBr) 2854, 2756, 1507, 1451, 1412, 1241, 1183, 1027, 812, 742 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 12.23 (br s, 1H), 7.49-7.55 (m, 1H), 7.37-7.43 (m, 1H), 7.18-7.23 (m, 2H), 7.07-7.15 (m, 4H), 4.11 (s, 2H), 2.26 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 153.9, 143.5, 135.7, 134.7, 134.6, 129.1, 128.8, 121.7, 121.0, 118.3, 111.0, 34.6, 20.6; HRMS calcd for C15H14N2 m/z 222.1225, found 222.1221.
	With hydrogenchloride In lithium hydroxide monohydrate for 6h; Reflux;

	With hydrogenchloride In lithium hydroxide monohydrate	General procedure for the synthesis of targetcompounds (21-35, 41-55, 61-75) General procedure: Compounds 21-35, 41-55, and 61-75 have been prepared following reported procedures. A mixture of 1,2-phenylenediamine derivatives (1 eq) and the corresponding carboxylic acid derivaties (1.1 eq) was refluxed for a periodof 15-27 h in 5M hydrochloric acid. The reaction mixture was poured onto ice water and neutralized by mixing with NaHCO3 till slightly basic pH (8-9) to get the precipitate.The resulting precipitate was filtered off and washed with cold water. Recrystallized with a suitable solvent. The resulting crystalline compounds were filtered and the vacuumed product was dried
	With hydrogenchloride In lithium hydroxide monohydrate	General procedure for the synthesis of targetcompounds (21-35, 41-55, 61-75) General procedure: Compounds 21-35, 41-55, and 61-75 have been prepared following reported procedures. A mixture of 1,2-phenylenediamine derivatives (1 eq) and the corresponding carboxylic acid derivaties (1.1 eq) was refluxed for a periodof 15-27 h in 5M hydrochloric acid. The reaction mixture was poured onto ice water and neutralized by mixing with NaHCO3 till slightly basic pH (8-9) to get the precipitate.The resulting precipitate was filtered off and washed with cold water. Recrystallized with a suitable solvent. The resulting crystalline compounds were filtered and the vacuumed product was dried

Reference： [1]Dos Santos, Aurelie; El Kaim, Laurent; Grimaud, Laurence [Organic and Biomolecular Chemistry, 2013, vol. 11, # 20, p. 3282 - 3287]
[2]Boggu, PullaReddy; Venkateswararao, Eeda; Manickam, Manoj; Kwak, Dajin; Kim, Youngsoo; Jung, Sang-Hun [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 8, p. 1872 - 1878]
[3]Yang, Kai; Luo, Shi-He; Chen, Si-Hong; Cao, Xi-Ying; Zhou, Yong-Jun; Lin, Yan-Lan; Huo, Yan-Ping; Wang, Zhao-Yang [Organic and Biomolecular Chemistry, 2021, vol. 19, # 37, p. 8133 - 8139]
[4]Alagoz, Mehmet Abdullah; Algul, Oztekin; Burmaoglu, Serdar; Dogen, Aylin; Ersan, Ronak Haj; Kuzu, Burak; Yetkin, Derya [Medicinal Chemistry Research, 2022]
[5]Alagoz, Mehmet Abdullah; Algul, Oztekin; Burmaoglu, Serdar; Dogen, Aylin; Ersan, Ronak Haj; Kuzu, Burak; Yetkin, Derya [Medicinal Chemistry Research, 2022]

41
[ 90533-23-6 ]
[ 622-47-9 ]
[ 1440434-95-6 ]

Reference： [1]Medicinal Chemistry Research,2014,vol. 23,p. 259 - 268

42
[ 622-47-9 ]
[ 64987-16-2 ]
[ 1154358-30-1 ]

Reference： [1]Medicinal Chemistry Research,2014,vol. 23,p. 259 - 268

43
[ 622-47-9 ]
[ 619-55-6 ]

Yield	Reaction Conditions	Operation in experiment
78%	With ammonium hydroxide; oxygen In neat (no solvent) at 120℃; for 6h; Sealed tube;	General Procedure for preparation of amides catalyzed by Fe₃O_4SiO₂-SMTU-Cu General procedure: A sealed pressure vessel was charged with phenylacetic acids (68.0 mg, 0.5 mmol), Fe3O4SiO2-SMTU-Cu catalyst (20 mg), and aqueous ammonia solution (28 wt% in H2O; 1.5 mL). The resulting solution was stirred at 120 °C under O2 (monitored by TLC and GC) for 6 hours. Upon completion of the reaction, the catalyst was separated using magnetic stirring bar and ethyl acetate (20 mL) was added, the organic layer was washed with saturate NaHCO3 (20 mL) solution twice, brine (20 mL) once, the combined aqueous layers was extracted with EtOAc (20 mL) twice. The combine organic layers were dried over anhydrous Na2SO4. The solvents were removed via rotary evaporator and the residue was purified with flash chromatography (silica gel, ethyl acetate: petroleum ether=2:1) to give amide products.
60%	With copper oxide (I); ammonium hydroxide; oxygen In lithium hydroxide monohydrate at 110℃; for 32h;

Reference： [1]Riadi, Yassine; M. Kadhim, Mustafa; Jawad Shoja, Sarah; Hussein Ali, Muneam; Fakri Mustafa, Yasser; Sajjadi, Ahmad [Synthetic Communications, 2022, vol. 52, # 6, p. 875 - 887]
[2]Song, Qiuling; Feng, Qiang; Yang, Kai [Organic Letters, 2014, vol. 16, # 2, p. 624 - 627]

44
[ 622-47-9 ]
[ 50413-24-6 ]
[ 1338083-52-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In acetonitrile at 20℃; for 1h;	General procedure for preparation of compounds 21, 7and 8 General procedure: To a stirred solution of phenylacetic acid (13 or 14) and triethylamine in dry CH3CN, phenacyl bromide (15-17) in dry CH3CN was added dropwise at room temperature. The reaction mixture was stirred for 1 h and was concentrated in vacuo. The resulting residue was re-dissolved in AcOEt (50 mL) and washed with 1 M HCl (20 mL). The organic fraction was dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure to give crude product (18-20) that was used in the next step without further purification.
	With sodium carbonate In acetonitrile

Reference： [1]Yamakawa, Naoki; Suzuki, Koichiro; Yamashita, Yasunobu; Katsu, Takashi; Hanaya, Kengo; Shoji, Mitsuru; Sugai, Takeshi; Mizushima, Tohru [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 8, p. 2529 - 2534]
[2]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - CN109553564, 2019, A Location in patent: Paragraph 0031

45
[ 106-25-2 ]
[ 622-47-9 ]
C₁₉H₂₆O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h;	General procedure for the synthesis of esters 1b-i, 2b-j, 3b-e. General procedure: A solution of the appropriate carboxylic acid (0.55 mmol), geraniol or nerol or citronellol (0.50 mmol), EDC (0.90 mmol), and DMAP (0.82 mmol) in dry CH2Cl2 (3 mL) was stirred at room temperature overnight. The mixture was diluted with 2 N HCl and extracted with AcOEt. The organic phase was washed with saturated NaHCO3 and brine, dried (Na2SO4), and evaporated under vacuum. The residue was purified by column chromatography.

Reference： [1]Ortar, Giorgio; Schiano Moriello, Aniello; Morera, Enrico; Nalli, Marianna; Di Marzo, Vincenzo; De Petrocellis, Luciano [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 23, p. 5507 - 5511]

46
[ 622-47-9 ]
[ 88-73-3 ]
[ 16112-21-3 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 976 - 978

47
[ 622-47-9 ]
[ 33425-19-3 ]

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 1575 - 1580

48
[ 3240-34-4 ]
[ 622-47-9 ]
[ 124-38-9 ]
[ 2216-45-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With cobalt(II) chloride hexahydrate In dichloromethane at 100℃; for 8h; Green chemistry; regiospecific reaction;

Reference： [1]Xu, Kun; Wang, Zhiqiang; Zhang, Jinjin; Yu, Lintao; Tan, Jiajing [Organic Letters, 2015, vol. 17, # 18, p. 4476 - 4478]

49
[ 622-47-9 ]
[ 62-53-3 ]
[ 3245-27-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 4-tolylacetic acid With iron(III) chloride; acetic acid In toluene at 50℃; Green chemistry; Stage #2: aniline In toluene at 70 - 75℃; for 5h; Green chemistry;
73%	With triphenylborane In toluene at 110℃;	5 General experimental procedure General procedure: In 5mL thick wall glass tube (microwave tube) equipped with magnetic stirring bar, first dry toluene 1mL was added then 4-methylphenylacetic acid (1a, 0.50mmol) dissolved into toluene by stirring for 5min. Then benzylamine (2a, 0.55mmol) was added and stirred the reaction mixture for 5min. Finally, catalyst triphenyl borate (4mol%) was added and tube was closed with septum and placed into oil bath and magnetically stirred at 110°C for 3h under air atmosphere. After completion, the reaction mixture was cooled to room temperature. Then reaction mixture was transfer into conical flask and ethyl acetate or dichlormethane (10mL) was added. Then product is purified by acid base extraction using aqueous 1:1 HCl and 10% NaOH and finally washed with brine and water. The organic layer was dried over Na2SO4 and finally organic solvent evaporated on rota-evaporator to afford the pure product 3a. The product was confirmed by 1H and 13C NMR spectroscopic analysis. Same procedure is followed for synthesis of all other amides from 3b to 3q.
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	4.2 General procedure for the preparation of 2-phenyl-N-[2-(trifluoromethoxy) phenyl] General procedure: Acetamides (1a-1x, 1ab, 1ac and 1ba-1bc). To a solution of 2-phenylacetic acid (7.0mmol), 2-(trifluoromethoxy)aniline (7.7mmol) in anhydrous CH2Cl2 (25mL) were added EDCI (1.745g, 9.1mmol) and DMAP (256.6mg, 2.1mmol). The reaction mixture was stirred at room temperature overnight, diluted with HCl (1M) aqueous solution, and extracted with CH2Cl2 (3×25mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica gel, petroleum ether: ethyl acetate=50: 1 as eluent) gave the corresponding 2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide compound.

Reference： [1]Basavaprabhu; Muniyappa, Krishnamurthy; Panguluri, Nageswara Rao; Veladi, Panduranga; Sureshbabu, Vommina V. [New Journal of Chemistry, 2015, vol. 39, # 10, p. 7746 - 7749]
[2]Ghorpade, Seema A.; Sawant, Dinesh N.; Sekar, Nagaiyan [Tetrahedron, 2018, vol. 74, # 48, p. 6954 - 6958]
[3]Zhao, Xiao-Jing; Zhao, Jie; Sun, Xin; Liu, Ji-Kai; Wu, Bin [Tetrahedron, 2017, vol. 73, # 25, p. 3463 - 3477]

50
[ 622-47-9 ]
[ 362-75-4 ]
((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-p-tolylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64.5%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; Cooling with ice;	2.21 2.1.1. General procedure for preparation of compounds b General procedure: Triphenylphosphine (1.5 mmol), 20,30-O-isopropylideneadenosine(1.0 mmol), and an appropriately substituted benzeneacetic acids(1.0 mmol) were dissolved in anhydrous THF (20 mL). After thesolution was cooled in an ice bath, diisopropyl azodicarboxylate(DIAD 2.0 mmol) was added dropwise, and the resulted mixturewas stirred at room temperature for several hours (monitored byTLC). Evaporation to dryness and flash chromatography (AcOEt/petroleum ether, from 5:1 to 3:1) afforded compounds b(Scheme 3). 2.1.21 ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-p-tolylacetate (b10) White powder, 64.5%, mp 83-85 °C; 1H NMR (DMSO-d6): 1.32 (s, 3H, CH3); 1.54 (s, 3H, CH3); 2.25 (s, 3H, CH3); 3.54 (d, J = 3.1 Hz, 2H, CH2); 4.16-4.20 (m, 1H, CH); 4.26-4.29 (m, 1H, CH); 4.38 (s, 1H, CH); 5.00 (d, J = 2.9 Hz, 1H, CH); 5.38 (d, J = 4.8 Hz, 1H, CH); 6.17 (d, J = 2.4 Hz, 1H, CH); 7.06 (s, 4H, ArH); 7.38 (s, 2H, NH2); 8.17 (d, J = 5.7 Hz, 1H, CHpurine); 8.27 (d, J = 3.2 Hz, 1H, CHpurine); EIMS m/z 439 (M+). Anal. Calcd for C22H25N5O5: C, 60.13; H, 5.73; N, 15.94; Found: C, 60.32; H, 5.71; N, 15.89.

Reference： [1]Wei, Wei; Shi, Wei-Kang; Wang, Peng-Fei; Zeng, Xiao-Tong; Li, Pan; Zhang, Ji-Rong; Li, Qian; Tang, Zhi-Ping; Peng, Jia; Wu, Lang-Zhou; Xie, Mei-Qun; Liu, Chan; Li, Xian-Hui; Wang, Ying-Chun; Xiao, Zhu-Ping; Zhu, Hai-Liang [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 20, p. 6602 - 6611]

51
[ 622-47-9 ]
[ 7560-50-1 ]
2-(4-methylphenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenyl)acrylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetic anhydride; at 30℃; for 2h;	General procedure: General procedure A Step-a: Synthesis of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl) phenyl) acrylic acid (C). A mixture of 4-fluorophenylacetic acid (2.5 g, 13.2 mmol) and methyl (E)-3-(4-formylphenyl)acrylate (2.03 g, 13.2 mmol) were dissolved under stirring with acetic anhydride (8 ml). To this mixture diisopropylethylamine (DIPEA) (3.4 ml, 19.7 mmol) was added and stirred at 30 C for 2 h. Upon completion (as monitored by TLC using 100% ethyl acetate as eluent), the reaction mixture was poured into water and the pH was adjusted to 1 using dil. HClaq (1:1). The aqueous layer was extracted with ethyl acetate (2 * 150 ml). The combined ethyl acetate layer was washed with water till the washings were neutral and dried over anhydrous Na2SO4. The ethyl acetate layer was evaporated to dryness to obtain a sticky compound, which was triturated with cold dichloromethane (DCM) to furnish a white solid. It was filtered and dried under vacuum to afford the title compound (2 g, 47%).

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 108,p. 274 - 286

52
[ 622-47-9 ]
[ 103261-92-3 ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 15325 - 15329
[2]European Journal of Organic Chemistry,2016,vol. 2016,p. 3486 - 3490

53
[ 622-47-9 ]
[ 2835-77-0 ]
[ 16112-44-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With ammonium acetate; oxygen; copper diacetate In 1-methyl-pyrrolidin-2-one at 120℃; for 20h;
89%	With ammonium acetate; oxygen; copper diacetate In 1-methyl-pyrrolidin-2-one at 120℃; for 20h;	8 Example 8 Adding reaction bottle 1a (2mmol, 394 mg), 2h (4mmol, 600 mg), ammonium acetate (4mmol, 308 mg), copper acetate (20mol %, 80 mg) and NMP (10 ml). Oxygen is then used to replace the three times in the oxygen atmosphere of the reaction system, the 120 °C heating reaction 20 hours. After the reaction is finished first quenching with saturated sodium carbonate solution, then using ethyl acetate extraction, anhydrous sodium sulfate for drying, after decompression turns on lathe does solvent, petroleum ether and ethyl acetate mixed solvent for carrying out simple column chromatography to get product 3ah, the yield is 89%.White solid

Reference： [1]Yan, Yizhe; Shi, Miaomiao; Niu, Bin; Meng, Xiangping; Zhu, Changrui; Liu, Gengyao; Chen, Ting; Liu, Yanqi [RSC Advances, 2016, vol. 6, # 42, p. 36192 - 36197]
[2]Current Patent Assignee: ZHENGZHOU UNIVERSITY OF LIGHT INDUSTRY - CN105384697, 2016, A Location in patent: Page/Page column 7

54
[ 771-61-9 ]
[ 622-47-9 ]
pentafluorophenyl 2-(4-methylphenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 25℃; for 16h;
65%	Stage #1: 4-tolylacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 25℃; for 0.0833333h; Stage #2: 2,3,4,5,6-pentafluorophenol In dichloromethane at 20 - 25℃; for 21h;	General Procedure E: Preparation of activated aryl esters General procedure: The requisite aryl/alkenyl/alkyl acetic acid (2.0 equiv.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, EDCIHCl (1.5 equiv.) were dissolved in CH2Cl2 andallowed to stir at rt for 5 min before the addition of the requisite phenol (1.0 equiv.). Thereaction mixture was stirred at rt for 21 h before being diluted with CH2Cl2 (× 1) and washedwith saturated, aqueous NaHCO3 (× 2). The organic layer was extracted, dried over MgSO4and the filtrate concentrated in vacuo. The crude material was purified by flash silica columnchromatography to give the desired activated aryl ester.
48%	Stage #1: 2,3,4,5,6-pentafluorophenol; 4-tolylacetic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; Stage #2: With hydrogenchloride In dichloromethane; water at -20℃; for 6h; Inert atmosphere;

	With dmap; dicyclohexyl-carbodiimide In dichloromethane
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 12h;

Reference： [1]Zhao, Feng; Shu, Chang; Young, Claire M.; Carpenter-Warren, Cameron; Slawin, Alexandra M. Z.; Smith, Andrew D. [Angewandte Chemie - International Edition, 2021, vol. 60, # 21, p. 11892 - 11900][Angew. Chem., 2021, vol. 133, # 21, p. 11999 - 12007,9]
[2]Arokianathar, Jude N.; Greenhalgh, Mark D.; Hartley, Will C.; McLaughlin, Calum; Ng, Sean; Slawin, Alexandra M. Z.; Smith, Andrew D.; Stead, Darren [Molecules, 2021, vol. 26, # 21]
[3]Schwarz, Kevin J.; Amos, Jessica L.; Klein, J. Cullen; Do, Dung T.; Snaddon, Thomas N. [Journal of the American Chemical Society, 2016, vol. 138, # 16, p. 5214 - 5217]
[4]Jiang, Xingyu; Beiger, Jason J.; Hartwig, John F. [Journal of the American Chemical Society, 2017, vol. 139, # 1, p. 87 - 90]
[5]Kim, Byungjun; Kim, Yongjae; Lee, Sarah Yunmi [Journal of the American Chemical Society, 2021, vol. 143, # 1, p. 73 - 79]

55
[ 622-47-9 ]
[ 133745-75-2 ]
[ 1337913-21-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With copper(l) iodide; 1,10-Phenanthroline In acetonitrile at 80℃; for 2h; Inert atmosphere;	1 Example 1Preparation of compound (1), the specific reaction equation is as follows: The specific preparation process: To a magnetic stirrer with 10mLA round bottom flask with a beaker was charged with acetonitrile (2 mL) as a solvent,4-methylphenylacetic acid (0.46 g, 1 mmol),N-fluorodibenzenesulfonimide (0.097 g, 1.2 mmol),Copper iodide (0.026 ml, 0.3 mmol) and1,10-o-phenanthroline (0.026 ml, 0.3 mmol),After mixing,Put it in a 80 ° C oil bath and continue stirring.TLC detection of substrate disappeared,The reaction is over. The reaction was poured into saturated aqueous sodium chloride (5 mL)Extract with dichloromethane (3 x 6 mL), combine the organic phases, dry over anhydrous magnesium sulfate,After depressurization, the organic solvent was distilled off under reduced pressure,The liquid mixture was obtained and finally subjected to silica gel column chromatography(Eluent V petroleum ether: V ethyl acetate = 10: 1) to give 0.41 g of a light yellow solid which was confirmed as compound (1) by NMR after MS,Based on 4-methylphenylacetic acid, the yield was calculated to be 90%.
54%	With copper(l) iodide; N,N`-dimethylethylenediamine In 1,2-dichloro-ethane at 80℃; for 24h; Sealed tube; Inert atmosphere; regioselective reaction;

Reference： [1]Current Patent Assignee: YANCHENG TEACHERS UNIVERSITY - CN107253925, 2017, A Location in patent: Paragraph 0030; 0031; 0032; 0033; 0034; 0035; 0036; 0037
[2]Fang, Zhongxue; Feng, Yu; Dong, Hai; Li, Dashan; Tang, Tiandi [Chemical Communications, 2016, vol. 52, # 74, p. 11120 - 11123]

56
[ 622-47-9 ]
[ 94790-37-1 ]
C₁₅H₁₃N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere;	General procedure: An oven-dried 50 mL round-bottom flask containing a magnetic stirrer bar was sealed with a septum, charged with Ar and tared on a balance. KH (~0.5 g, 30% mineral oil dispersion) was then added to the flask and the mineral oil removed by trituration under Ar with pet. spirit (2 x 30 mL) using a syringe. The flask containing dry KH was purged with Ar and reweighed to obtain an accurate mass of KH. Dry THF (10 mL) was added to the flask containing KH (0.15 g, 3.7 mmol, under Ar) and the mixture cooled to 0 oC. 3,5-Dimethyl-1H-pyrrole-2-carbaldehyde 5 (0.23 g, 1.9 mmol) was dissolved in dry THF (5 mL) under Ar and added dropwise to the stirring KH solution (Caution - flask requires outlet needle to release evolving H2 gas). After complete addition the mixture was stirred for a further 5 minutes at 0 oC. The phenylacetic acid derivative (1.9 mmoles) was added to a separate dry 50 mL round-bottom flask under Ar along with HBTU (0.71 g, 1.9 mmoles) and dry CH2Cl2 (10 mL). DIPEA (0.65 mL, 3.7 mmoles) was added dropwise to the stirring solution and upon complete addition the mixture was stirred for a further 5 minutes or until the HBTU was completely dissolved. The HBTU solution was then cooled to 0 oC and added in a single portion to the K+ pyrrolate salt solution at 0 oC and the combined mixture allowed to warm slowly to room temperature. A dark red colour observed in each reaction indicated formation of the desired 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one. The reaction was quenched after ~ 2 h with ice-cold water (100 mL) and extracted with Et2O (2 x 50 mL). The combined organic phase was washed with 1 M HCl (2 x 50 mL), saturated NaHCO3 (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous MgSO4 and concentrated. The crude residue was purified by silica gel column chromatography using a gradient from 100% pet. spirit to 1:9 acetone:pet. spirit to afford the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one as a deep red solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 1813 - 1816

57
[ 622-47-9 ]
[ 1535-75-7 ]
2-(p-tolyl)-N-[2-(trifluoromethoxy)phenyl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	General procedure: Acetamides (1a-1x, 1ab, 1ac and 1ba-1bc). To a solution of 2-phenylacetic acid (7.0mmol), <strong>[1535-75-7]2-(trifluoromethoxy)aniline</strong> (7.7mmol) in anhydrous CH2Cl2 (25mL) were added EDCI (1.745g, 9.1mmol) and DMAP (256.6mg, 2.1mmol). The reaction mixture was stirred at room temperature overnight, diluted with HCl (1M) aqueous solution, and extracted with CH2Cl2 (3×25mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica gel, petroleum ether: ethyl acetate=50: 1 as eluent) gave the corresponding 2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide compound.

Reference： [1]Tetrahedron,2017,vol. 73,p. 3463 - 3477

58
[ 622-47-9 ]
[ 2987-53-3 ]
N-[2-(methylthio)phenyl]-2-(p-tolyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	4.2 General procedure for the preparation of 2-phenyl-N-[2-(trifluoromethoxy) phenyl] General procedure: Acetamides (1a-1x, 1ab, 1ac and 1ba-1bc). To a solution of 2-phenylacetic acid (7.0mmol), 2-(trifluoromethoxy)aniline (7.7mmol) in anhydrous CH2Cl2 (25mL) were added EDCI (1.745g, 9.1mmol) and DMAP (256.6mg, 2.1mmol). The reaction mixture was stirred at room temperature overnight, diluted with HCl (1M) aqueous solution, and extracted with CH2Cl2 (3×25mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica gel, petroleum ether: ethyl acetate=50: 1 as eluent) gave the corresponding 2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide compound.

Reference： [1]Zhao, Xiao-Jing; Zhao, Jie; Sun, Xin; Liu, Ji-Kai; Wu, Bin [Tetrahedron, 2017, vol. 73, # 25, p. 3463 - 3477]

59
[ 622-47-9 ]
[ 73401-74-8 ]

Reference： [1]Patent: US9643927,2017,B1
[2]Patent: WO2017/86941,2017,A1
[3]Patent: CN107434780,2017,A

60
[ 622-47-9 ]
[ 155380-11-3 ]

Reference： [1]Patent: US9643927,2017,B1
[2]Patent: WO2017/86941,2017,A1
[3]Patent: CN111217834,2020,A

61
[ 2425-77-6 ]
[ 622-47-9 ]
2-hexyl-1-decyl p-tolylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With p-toluenesulfonic acid monohydrate	2 Preparation of 2-hexyldecyl p-tolylacetate Example 2 Preparation of 2-hexyldecyl p-tolylacetate To a 3-neck 1000 ml round-bottomed flask was added 2-hexyl-1-decanol (200.0 g, 824.93 mmol, 1.0 equiv.), p-tolylacetic acid (154.86 g, 1031.2 mmol, 1.25 equiv.), toluene (240 ml) and p-toluenesulfonic acid monohydrate (1.5692 g, 8.2494 mmol, 0.010 equiv.) at room temperature. The resulting mixture was heated at reflux with stirring in an oil bath at 134° C. under a nitrogen atmosphere for 6 hours. The water produced in the reaction was collected in a Dean-Stark trap. The cooled mixture was diluted with hexanes, washed with dilute aqueous Na2CO3 solution, water, brine, dried (MgSO4), filtered, and concentrated in vacuo to afford a crude product. Excess solvent was further removed by heating the crude product with stirring in an oil bath under high vacuum for 3 hours to afford a light yellow liquid (292.5 g, 94%).

Reference： [1]Current Patent Assignee: EXXON MOBIL CORP - US2017/183595, 2017, A1

62
[ 622-47-9 ]
[ 34841-47-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	With iron(II) acetylacetonate; 1,1,3,3-Tetramethyldisiloxane; In water; 1,2-dichloro-ethane; at 80℃; for 3h;	Compound 6:25 ml reaction flask by sequentially adding ferrous acetylacetonate (0.025 mmol), 1, 1, 3, 3 - tetramethyl-siloxane (0.75 mmol), potassium persulphate (0.25 mmol), 1 f (0.25 mmol), 1, 2 - dichloroethane (1 ml), water (1 ml), in the reaction mixture 80 C lower reaction 3 h. The reaction is finished adding ammonia water (2 ml) to remove the peripheric, add saturated salt water 10 ml, and extraction with ethyl ether (10 ml × 3), the combined organic phase, pressure reducing evaporate the solvent column chromatography separation to obtain yield 70%

Reference： [1]Patent: CN107216242,2017,A .Location in patent: Paragraph 0036; 0037

63
[ 622-47-9 ]
[ 196618-13-0 ]
C₂₅H₃₆N₂O₅ [ No CAS ]

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

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

64
[ 69155-76-6 ]
[ 622-47-9 ]
(E)-6-fluoro-3-(4-methylstyryl)-4H-chromen-4-one [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 5984 - 5987

65
[ 622-47-9 ]
[ 1527-91-9 ]
1,2-diphenyl-4-(p-tolyl)-1H-imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With [2,2]bipyridinyl; nitromethane; copper(II) sulfate; In nitromethane; N,N-dimethyl-formamide; at 130.0℃; for 8.0h;	General procedure: A round-bottom flask was charged with arylacetic acid 1 (1.5 mmol), N-arylbenzamidine 2 or 4 (1.0 mmol), CuSO4 (10 mol%), and 2,2?-bipyridyl (20 mol%). A pre-oxygen degassed solvent system of DMF/nitroalkane (1.5:0.5 mL) was added to above mixture. The resulting mixture was heated at 130 C for 8 h. The reaction progress was monitored by using TLC. After completion of the reaction, water was added to the mixture and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (anhyd Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (230-400 mesh silica gel, EtOAc/n-hexane) to afford imidazoles 3 or 5.

Reference： [1]Synthesis,2018,vol. 50,p. 361 - 370

66
[ 622-47-9 ]
[ 615-43-0 ]
[ 16112-21-3 ]

Yield	Reaction Conditions	Operation in experiment
74%	With copper(II) acetate monohydrate; sulfur; sodium hydroxide; In dimethyl sulfoxide; at 130℃; for 24h;Sealed tube; Inert atmosphere;	General procedure: A mixture of o-iodoaniline (0.5 mmol, 1 equiv), arylacetic acid (0.6 mmol), elemental sulfur (1.5mmol), Cu(OAc)2·H2O (20 mmol%), and NaOH (1.0 mmol) in DMSO (3 mL) was put into a sealed pressure vessel (25 mL) containing a magnetic stirring bar. The tube was purged with nitrogen three times, and then capped and stirred in a preheated oil bath at 130 C for 24 h. The reaction mixture then cooled to room temperature and extracted with ethyl acetate (3x10 mL), the organic layer was washed with saturated NaCl (2x10 mL), dried over anhydrous Na2SO4, evaporated under vacumm and then purified by silica gel column chromatography by using petroleum ether and ethyl acetate (PE:EA=200:1) as eluent.

Reference： [1]Synlett,2018,vol. 29,p. 219 - 224

67
[ 634-36-6 ]
[ 622-47-9 ]
2-(4-methylphenyl)-1-(2,3,4-trimethoxyphenyl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With trifluoromethylsulfonic anhydride In dichloromethane Cooling with ice;	4.1.1. 1-(2,4-Dimethoxyphenyl)-2-p-tolylethanone (7a) General procedure: Into a 100mL round bottom flask equipped with magnetic stirring was placed 4-tolylacetic acid (0.524g, 3.61mmol) along with 15mL of dry dichloromethane (DCM). To this mixture with ice bath cooling was added 1,3-dimethoxybenzene (0.542g, 3.61mmol) and 4.33mL (4.33mmol) of a 1.00M solution of triflic anhydride in anhydrous DCM. The resulting mixture was stirred overnight, diluted with 20mL of saturated aqueous bicarbonate and extracted with DCM (3×20mL). The DCM solution was dried over anhydrous sodium sulfate, filtered through a fritted glass funnel and the filtrate was then passed through a short plug of silica gel and the plug was then washed with 50mL of ethyl acetate. The combined filtrates were concentrated in vacuo to yield a dark grey solid (0.918g, 94% yield).
70%	With phosphoric acid; trifluoroacetic anhydride In dichloromethane at 25℃;	2-(4-Methylphenyl)-1-(2,3,4-trimethoxyphenyl)-ethanone (4). Trifluoroacetic anhydride (71.9 mL,426 mmol) was rapidly added with vigorous stirring at25°C to a mixture of 2-(4-methylphenyl)acetic acid(2, 16 g, 106.5 mmol), 1,2,3-trimethoxybenzene(3, 19.4 mL, 127.8 mmol), and anhydrous methylenechloride (300 mL), and the resulting mixture was stirred overnight at 25°C. After completion of the reaction,the mixture was diluted with 400 ml of a saturatedaqueous solution of sodium hydrogen carbonate andextracted with methylene chloride (3×200 ml). Thecombined extracts were dried with Na2SO4 and filteredthrough silica gel, the sorbent was washed withmethylene chloride, and the combined filtrates were concentrated under reduced pressure. Yield 22.4 g(70%), dark oil. 1H NMR spectrum, δ, ppm: 2.34 s(3H), 3.89 s (3H), 3.91 s (3H), 3.96 s (3H), 4.27 s (2H),6.71 d (1H, J = 9.1 Hz), 7.13 br.s (4H), 7.47 d (1H, J =9.1 Hz). 13C NMR spectrum, δC, ppm: 21.4, 48.9, 56.6,60.9, 61.8, 107.3, 125.9, 126.2, 129.4, 129.6, 132.2,136.2, 142.3, 153.9, 157.5, 196.7. Mass spectrum:m/z 301 [M + H]+.

68
[ 622-47-9 ]
[ 2618-96-4 ]
[ 1337913-21-9 ]

Reference： [1]Chemistry - A European Journal,2018,vol. 24,p. 9254 - 9258

69
[ 123-75-1 ]
[ 622-47-9 ]
[ 512787-27-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With triphenylborane In toluene at 110℃;	6 General experimental procedure General procedure: In 5mL thick wall glass tube (microwave tube) equipped with magnetic stirring bar, first dry toluene 1mL was added then 4-methylphenylacetic acid (1a, 0.50mmol) dissolved into toluene by stirring for 5min. Then benzylamine (2a, 0.55mmol) was added and stirred the reaction mixture for 5min. Finally, catalyst triphenyl borate (4mol%) was added and tube was closed with septum and placed into oil bath and magnetically stirred at 110°C for 3h under air atmosphere. After completion, the reaction mixture was cooled to room temperature. Then reaction mixture was transfer into conical flask and ethyl acetate or dichlormethane (10mL) was added. Then product is purified by acid base extraction using aqueous 1:1 HCl and 10% NaOH and finally washed with brine and water. The organic layer was dried over Na2SO4 and finally organic solvent evaporated on rota-evaporator to afford the pure product 3a. The product was confirmed by 1H and 13C NMR spectroscopic analysis. Same procedure is followed for synthesis of all other amides from 3b to 3q.
84%	Stage #1: 4-tolylacetic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane for 0.0833333h; Stage #2: pyrrolidine In dichloromethane at 20℃;

Reference： [1]Ghorpade, Seema A.; Sawant, Dinesh N.; Sekar, Nagaiyan [Tetrahedron, 2018, vol. 74, # 48, p. 6954 - 6958]
[2]Sandoval, Braddock A.; Clayman, Phillip D.; Oblinsky, Daniel G.; Oh, Seokjoon; Nakano, Yuji; Bird, Matthew; Scholes, Gregory D.; Hyster, Todd K. [Journal of the American Chemical Society, 2021, vol. 143, # 4, p. 1735 - 1739] Sandoval, Braddock A.; Clayman, Phillip D.; Oblinsky, Daniel G.; Oh, Seokjoon; Nakano, Yuji; Bird, Matthew; Scholes, Gregory D.; Hyster, Todd K. [Journal of the American Chemical Society, 2021, vol. 143, # 9, p. 3662 - 3662]

70
[ 622-47-9 ]
[ 39835-11-5 ]
C₁₇H₁₃⁽²⁾H₂NO₃ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 9433 - 9437

71
[ 622-47-9 ]
[ 39835-11-5 ]
2-cyano-5-methoxyphenyl 2-(p-tolyl)acetate [ No CAS ]

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 9433 - 9437

72
[ 644-36-0 ]
[ 622-47-9 ]
1,3-bis(2,4-methylphenyl)acetone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	1-9 Example 1 Take a 100 mL round bottom flask, DCC (1.0320 g, 5 mmol), DMAP (0.1527 g, 1.25 mmol) and4-Methylphenylacetic acid (0.3754 g, 2.5 mmol) was added to 10 mL of dry dichloromethane and stirred at 20 ° C until all dissolved.2-Methylphenylacetic acid (0.3754 g, 2.5 mmol) was dissolved in 20 mL of dry dichloromethane, and then slowly added dropwise to the above solution using a constant pressure dropping funnel.After stirring for 24 h, it was spin-dried and then separated by column chromatography. The eluent was petroleum ether to give the title compound. Characterized as follows:1,3-bis(2,4-methylphenyl)acetone: yield: 65%.

Reference： [1]Current Patent Assignee: DALIAN UNIVERSITY - CN109970528, 2019, A Location in patent: Paragraph 0030-0074

73
[ 622-47-9 ]
[ 621-36-3 ]
1,3-bis(3,4-methylphenyl)acetone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	1-9 Example 1 Take a 100 mL round bottom flask, add DCC (1.0320 g, 5 mmol), DMAP (0.1527 g, 1.25 mmol) and 4-methylphenylacetic acid (0.3754 g, 2.5 mmol) to 10 mL of dry dichloromethane, 20 ° C Stir underneath until all dissolved. 3-Methylphenylacetic acid (0.3754 g, 2.5 mmol) was dissolved in 20 mL of dry dichloromethane, and then slowly added dropwise to the above solution using a constant pressure dropping funnel. Stir for 24 h, spin dry, and then separated by column chromatography.The eluent is petroleum ether to give the target compound.

Reference： [1]Current Patent Assignee: DALIAN UNIVERSITY - CN109970524, 2019, A Location in patent: Paragraph 0030-0074

74
[ 622-47-9 ]
[ 331003-75-9 ]
4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenyl 2-(p-tolyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: o-Tolylacetic acid (0.59 g; 1.0 equiv; 3.77 mmol) and47.0 mg 4-DMAP (10 mol %; 0.38 mmol) were added to a100-mL round flask containing 1 g compound c (3.77 mmol) and stirred in an ice bath for 5 min after the addition of 20 mL methylene chloride. Afterward, 0.80 g DCC (1.0 equiv; 3.77 mmol) was added into the mixture and allowed to react for 3 h at room temperature, until the starting materials (TLC analysis) began to disappear. The resulting DHU was filtered under reduced pressure. The filtrate was extracted using 0.5 M HCl and a saturated solution of NaHCO3 in order. The solvent was removed under reduced pressure after dehydration using anhydrousMgSO4. The purified solid was obtained by recrystallization from ethanol as a light yellow solid. Synthesis of compounds 39-57 is shown in Scheme 1.

Reference： [1]Archives of Pharmacal Research,2019,vol. 42,p. 790 - 814

75
[ 622-47-9 ]
[ 142-71-2 ]
[ 64-19-7 ]
[ 2216-45-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 9-mesityl-2,7-dimethyl-10-phenylacridin-10-ium tetrafluoroborate In acetonitrile at 45℃; for 24h; Molecular sieve; Inert atmosphere; Sealed tube; Irradiation;

Reference： [1]Senaweera, Sameera; Cartwright, Kaitie C.; Tunge, Jon A. [Journal of Organic Chemistry, 2019, vol. 84, # 19, p. 12553 - 12561]

76
[ 100-02-7 ]
[ 622-47-9 ]
[ 1372996-72-9 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 4-tolylacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 25℃; for 0.0833333h; Stage #2: 4-nitro-phenol In dichloromethane at 20 - 25℃; for 21h;	General Procedure E: Preparation of activated aryl esters General procedure: The requisite aryl/alkenyl/alkyl acetic acid (2.0 equiv.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, EDCIHCl (1.5 equiv.) were dissolved in CH2Cl2 andallowed to stir at rt for 5 min before the addition of the requisite phenol (1.0 equiv.). Thereaction mixture was stirred at rt for 21 h before being diluted with CH2Cl2 (× 1) and washedwith saturated, aqueous NaHCO3 (× 2). The organic layer was extracted, dried over MgSO4and the filtrate concentrated in vacuo. The crude material was purified by flash silica columnchromatography to give the desired activated aryl ester.
53%	Stage #1: 4-tolylacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 25℃; for 0.166667h; Inert atmosphere; Stage #2: 4-nitro-phenol In dichloromethane at 20 - 25℃; Inert atmosphere;

Reference： [1]Arokianathar, Jude N.; Greenhalgh, Mark D.; Hartley, Will C.; McLaughlin, Calum; Ng, Sean; Slawin, Alexandra M. Z.; Smith, Andrew D.; Stead, Darren [Molecules, 2021, vol. 26, # 21]
[2]McLaughlin, Calum; Slawin, Alexandra M. Z.; Smith, Andrew D. [Angewandte Chemie - International Edition, 2019, vol. 58, # 42, p. 15111 - 15119][Angew. Chem., 2019, vol. 131, p. 15255 - 15263,9]

77
[ 2587-02-2 ]
[ 622-47-9 ]
N-(2,6-dichloropyridin-4-yl)-2-(p-tolyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 5h;	68.68A 68A. N-(2,6-dichloropyridin-4-yl)-2-(p-tolyl)acetamide To stirred solution of 2-(p-tolyl)acetic acid (1.198 g, 7.98 mmol) in DMF (5 mL) was added DIPEA (5.36 mL, 30.7 mmol), 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphorinane-2, 4, 6-trioxide in ethyl acetate (11.71 g, 18.40 mmol) followed by addition of 2,6-dichloropyridin-4-amine (1 g, 6.13 mmol) and stirred at RT for 5 h. The reaction mixture was diluted with ice-water and stirred for 30 mins. The reaction mixture was extracted with ethyl acetate (2 x 50 mL), combined organics were separated, dried over sodium sulfate, concentrated under reduced pressure to afford 68 A (off white solid, 1.4 g, 4.74 mmol, 77 % yield) as an. The product was carried for next step without further purification. LC-MS Anal.Calc’d for C14H12CI2N2O 294.033, found [M+H] 295.0, Tr =1.10 min (Method O).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO; BIOCON LIMITED - WO2020/23355, 2020, A1 Location in patent: Page/Page column 96

78
[ 622-47-9 ]
methyl (S)-2-amino-3-(4-(2-(4-chloro-3,5-dimethylphenoxy)ethoxy)phenyl)propanoate hydrochloride [ No CAS ]
methyl (S)-3-(4-(2-(4-chloro-3,5-dimethylphenoxy)ethoxy)phenyl)-2-(2-(p-tolyl) acetamido)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With 4-methyl-morpholine; HATU In N,N-dimethyl-formamide at 0 - 20℃;	4.1.50. Methyl (S)-3-(4-(2-(4-chloro-3,5-dimethylphenoxy)ethoxy)phenyl)-2-(2-(p-tolyl) acetamido) propanoate (8a) HATU (1.65 g, 4.35 mmol), NMM (1.0 mL, 8.70 mmol) and 7a(1.20 g, 2.90 mmol) was added to a solution of 2-(p-tolyl)acetic acid(0.48 g, 3.19 mmol) in anhydrous DMF (20 mL) at 0 C. The reactionmixture was stirred at room temperature for overnight. Ethyl acetate was added and the mixture was washed with 5% citric acidsolution and brine, dried over MgSO4, and concentrated. Purificationwith silica gel column chromatography gave 1.20 g (80%) of 8aas white powder. 1H NMR (400 MHz, DMSO-d6) d 8.48 (d, J 7.9 Hz,1H), 7.12e7.09 (m, 2H), 7.04 (d, J 8.0 Hz, 2H), 6.99 (d, J 8.0 Hz,2H), 6.85 (t, J 4.2 Hz, 4H), 4.42 (td, J 8.8, 5.5 Hz, 1H), 4.27 (s, 2H),4.26 (s, 2H), 3.60 (s, 3H), 3.35 (d, J 4.3 Hz, 2H), 2.97 (dd, J 13.7,5.3 Hz, 1H), 2.82 (dd, J 13.8, 9.4 Hz, 1H), 2.29 (s, 6H), 2.24 (s, 3H).

Reference： [1]Fang, Hao; Hou, Xuben; Liu, Lulu; Liu, Renshuai; Yang, Xinying [European Journal of Medicinal Chemistry, 2020, vol. 191]

79
[ 622-47-9 ]
methyl (S)-2-amino-3-(4-(2-(naphthalen-1-yloxy)ethoxy)phenyl)propanoate hydrochloride [ No CAS ]
methyl (S)-3-(4-(2-(naphthalen-1-yloxy)ethoxy)phenyl)-2-(2-(p-tolyl)acetamido) propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With 4-methyl-morpholine; HATU In N,N-dimethyl-formamide at 0 - 20℃;	4.1.50. Methyl (S)-3-(4-(2-(4-chloro-3,5-dimethylphenoxy)ethoxy)phenyl)-2-(2-(p-tolyl) acetamido) propanoate (8a) General procedure: HATU (1.65 g, 4.35 mmol), NMM (1.0 mL, 8.70 mmol) and 7a(1.20 g, 2.90 mmol) was added to a solution of 2-(p-tolyl)acetic acid(0.48 g, 3.19 mmol) in anhydrous DMF (20 mL) at 0 C. The reactionmixture was stirred at room temperature for overnight. Ethyl acetate was added and the mixture was washed with 5% citric acidsolution and brine, dried over MgSO4, and concentrated. Purificationwith silica gel column chromatography gave 1.20 g (80%) of 8aas white powder.

Reference： [1]Fang, Hao; Hou, Xuben; Liu, Lulu; Liu, Renshuai; Yang, Xinying [European Journal of Medicinal Chemistry, 2020, vol. 191]

80
[ 622-47-9 ]
[ 137-07-5 ]
[ 16112-21-3 ]

Reference： [1]New Journal of Chemistry,2021,vol. 45,p. 2643 - 2648

81
[ 622-97-9 ]
[ 13107-39-6 ]
[ 622-47-9 ]
[ 104-09-6 ]
[ 104-87-0 ]
[ 99-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	With oxygen; pivalaldehyde In acetonitrile at 39.84℃; for 3h;	2.3. Catalytic test General procedure: In a typical catalytic reaction procedure, 2.0 mmol of styrene (or styrene derivatives), 5.0 mmol of branched aliphatic aldehyde (PIA or IBA), 5 mL of acetonitrile (solvent), and 25 mg of catalyst were added toa 25 mL two-necked bottle equipped with a stirring bar and a refllux condenser. O2 or air was provided using a balloon filled with specified gas. The mixture was stirred for the required time at a specific temperature.The progress of the reaction was monitored by Shimadzu GC-14C gas chromatograph equipped with a flame ionization detector (FID)using a SE-54 capillary column (30 m ×0.25 mm ×0.25 m). After the reaction, the spent catalyst was isolated by centrifugation and washedwith acetonitrile and methanol repeatedly, dried overnight at 363 Kunder vacuum.

Reference： [1]Hu, Dianwen; Song, Xiaojing; Zhang, Hao; Chang, Xinyu; Zhao, Chen; Jia, Mingjun [Molecular catalysis, 2021, vol. 506]

82
[SbPh₃(O₂CCH₂(C₆H₄CH₃))₂] [ No CAS ]
[ 622-47-9 ]
[ 603-36-1 ]

Yield	Reaction Conditions	Operation in experiment
	With trypanothione trifluoroacetate salt; In dimethylsulfoxide-d6; water-d2; at -80℃;pH 4 - 5;	General procedure: Both complexes were made into 10 mM stocks in 1 mL of d6-DMSO. 100 μL of this solution was placed into an NMR tube and the contents frozen in liquid nitrogen at -80 C. To this frozen tube, 3.5 equivalents of trypanothione, or 7 equivalents of glutathione in 400 μL of 1:1 D2O/DMSO mix was added and the contents frozen once again. For the low pH studies, spectra were recorded one after another for upwards of 1 h, and every 2 h thereafter. For the higher pH glutathione study, spectra were recorded every half hour for Sb and one after the other for upwards of an hour for Bi. The half-life of the Sb complex was then calculated by proton integration ratio of the original complex to the formation of SbPh3. The decomposition graph was obtained using Microsoft excel and the corresponding half-life derived from the logarithmic equation produced.

Reference： [1]Journal of Inorganic Biochemistry,2021,vol. 221

83
[ 622-47-9 ]
[ 33631-01-5 ]
N-(1-methyl-2-oxo-3-pyridyl)-2-(p-tolyl)acetamide [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2021,vol. 19,p. 6244 - 6249

84
[ 622-47-9 ]
[ 349-58-6 ]
3',5'-bis(trifluoromethyl)phenyl 2-(p-tolyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: 4-tolylacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 25℃; for 0.0833333h; Stage #2: 3,5-bis-(trifluoromethyl)phenol In dichloromethane at 20 - 25℃; for 21h;	General Procedure E: Preparation of activated aryl esters General procedure: The requisite aryl/alkenyl/alkyl acetic acid (2.0 equiv.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, EDCIHCl (1.5 equiv.) were dissolved in CH2Cl2 andallowed to stir at rt for 5 min before the addition of the requisite phenol (1.0 equiv.). Thereaction mixture was stirred at rt for 21 h before being diluted with CH2Cl2 (× 1) and washedwith saturated, aqueous NaHCO3 (× 2). The organic layer was extracted, dried over MgSO4and the filtrate concentrated in vacuo. The crude material was purified by flash silica columnchromatography to give the desired activated aryl ester.

85
[ 622-47-9 ]
[ 88-06-2 ]
2',4',6'-trichlorophenyl 2-(p-tolyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: 4-tolylacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 25℃; for 0.0833333h; Stage #2: 2,4,6-Trichlorophenol In dichloromethane at 20 - 25℃; for 21h;	General Procedure E: Preparation of activated aryl esters General procedure: The requisite aryl/alkenyl/alkyl acetic acid (2.0 equiv.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, EDCIHCl (1.5 equiv.) were dissolved in CH2Cl2 andallowed to stir at rt for 5 min before the addition of the requisite phenol (1.0 equiv.). Thereaction mixture was stirred at rt for 21 h before being diluted with CH2Cl2 (× 1) and washedwith saturated, aqueous NaHCO3 (× 2). The organic layer was extracted, dried over MgSO4and the filtrate concentrated in vacuo. The crude material was purified by flash silica columnchromatography to give the desired activated aryl ester.

86
[ 622-47-9 ]
2-(imidazo[1,2-a]pyridin-2-yl)aniline [ No CAS ]
6-(p-tolyl)pyrido[2′,1′:2,3]imidazo[4,5-c]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With iodine In dimethyl sulfoxide at 95℃; for 8h; Inert atmosphere; Green chemistry;	General procedure for the synthesis of 6-phenylpyrido[2’,1’:2,3]imidazo[4,5-c]quinolonederivatives (3a-r) General procedure: Iodine (1.5 eq) was added to a solution of amine (1.0 eq) and phenylacetic acid (1.3 eq)in DMSO (2 mL). The reaction mixture was stirred at 95 C for 8 h under an N2 atmosphere.After completion of the reaction, ice-cold water was added to the reaction massand extracted with ethyl acetate (210 mL). The organic layer was separated andevaporated under a vacuum. The crude reaction mass was purified by column chromatographyin ethyl acetate/hexane to get a pure compound

Reference： [1]Jinkala, Rajesh; Shiva Kumar; Rapolu, Venkateshwarlu; Nikumbh Satish; Jammula, Subba Rao; Vidavalur, Siddaiah; Hindupur, Ramamohan; Tadiparthi, Krishnaji; Raghunadh, Akula [Synthetic Communications, 2022, vol. 52, # 2, p. 258 - 267]

87
[ 622-47-9 ]
2-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline [ No CAS ]
9-methyl-6-(p-tolyl)pyrido[2',1':2,3]imidazo[4,5-c]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With iodine In dimethyl sulfoxide at 95℃; for 8h; Inert atmosphere; Green chemistry;	General procedure for the synthesis of 6-phenylpyrido[2’,1’:2,3]imidazo[4,5-c]quinolonederivatives (3a-r) General procedure: Iodine (1.5 eq) was added to a solution of amine (1.0 eq) and phenylacetic acid (1.3 eq)in DMSO (2 mL). The reaction mixture was stirred at 95 C for 8 h under an N2 atmosphere.After completion of the reaction, ice-cold water was added to the reaction massand extracted with ethyl acetate (210 mL). The organic layer was separated andevaporated under a vacuum. The crude reaction mass was purified by column chromatographyin ethyl acetate/hexane to get a pure compound

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P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 622-47-9 ] {[proInfo.proName]}

Quality Control of [ 622-47-9 ]

Related Doc. of [ 622-47-9 ]

Product Details of [ 622-47-9 ]

Calculated chemistry of [ 622-47-9 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 622-47-9 ]

Application In Synthesis of [ 622-47-9 ]

[ 622-47-9 ] Synthesis Path-Upstream 1~13

[ 622-47-9 ] Synthesis Path-Downstream 1~87

Related Functional Groups of [ 622-47-9 ]

Aryls

Carboxylic Acids

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 622-47-9 ]