[ CAS No. 14062-24-9 ]

Name: 14062-24-9|Ethyl 4-chlorophenylacetate|95%
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Quality Control of [ 14062-24-9 ]

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Product Details of [ 14062-24-9 ]

CAS No. :	14062-24-9	MDL No. :	MFCD00018791
Formula :	C₁₀H₁₁ClO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UTWBWFXECVFDPZ-UHFFFAOYSA-N
M.W :	198.65	Pubchem ID :	84177
Synonyms :

Calculated chemistry of [ 14062-24-9 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	4
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	52.12
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.45 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.31
Log Po/w (XLOGP3) :	2.91
Log Po/w (WLOGP) :	2.45
Log Po/w (MLOGP) :	2.84
Log Po/w (SILICOS-IT) :	3.03
Consensus Log Po/w :	2.71

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.98
Solubility :	0.207 mg/ml ; 0.00104 mol/l
Class :	Soluble
Log S (Ali) :	-3.12
Solubility :	0.15 mg/ml ; 0.000753 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.9
Solubility :	0.0248 mg/ml ; 0.000125 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.64

Safety of [ 14062-24-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 14062-24-9 ]

* 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 [ 14062-24-9 ]
Downstream synthetic route of [ 14062-24-9 ]

[ 14062-24-9 ] Synthesis Path-Upstream 1~7

1
[ 14062-24-9 ]
[ 5445-25-0 ]

Reference： [1] Australian Journal of Chemistry, 1997, vol. 50, # 8, p. 813 - 823
[2] Journal of Medicinal Chemistry, 1981, vol. 24, # 5, p. 481 - 490
[3] Journal of Organic Chemistry, 2011, vol. 76, # 23, p. 9670 - 9677

2
[ 623-73-4 ]
[ 108-90-7 ]
[ 14062-24-9 ]
[ 40061-54-9 ]
[ 14062-29-4 ]

Reference： [1] Organometallics, 2017, vol. 36, # 1, p. 172 - 179

3
[ 19213-72-0 ]
[ 14062-24-9 ]
[ 19677-37-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78 - 20℃;	General procedure: To a stirred solution of phenyl acetic acid ethyl ester 1a (1 g, 6.09 mmol) in THF (10 mL) was added LiHMDS (9.1 ml, 1 M sol. in THF, 7.31 mmol) at -78 °C and the reaction mixture was stirred at this temperature for 30 min. Ethyl-1-imidazole carboxylate 2 (1.2 g, 9.146 mmol) in dry THF (3 ml) was added drop wise to the reaction mixture at -78 °C and stirred at rt for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with water, saturated brine solution, and dried over Na₂SO₄. The solvent was evaporated under reduced pressure and the crude product was chromatographed on a silica gel column. Elution with 4percent ethyl acetate/pet ether gave the pure compound 3a (1.1 g, 81percent yield) as a colorless liquid.

Reference： [1] Tetrahedron Letters, 2012, vol. 53, # 9, p. 1060 - 1062

4
[ 14062-24-9 ]
[ 105-58-8 ]
[ 19677-37-3 ]

Reference： [1] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 6, p. 1415 - 1421
[2] Canadian Journal of Chemistry, 1994, vol. 72, # 11, p. 2312 - 2317
[3] Patent: WO2005/123724, 2005, A1, . Location in patent: Page/Page column 52

5
[ 14062-24-9 ]
[ 623-49-4 ]
[ 19677-37-3 ]

Reference： [1] European Journal of Organic Chemistry, 2010, # 3, p. 484 - 493

6
[ 14062-24-9 ]
[ 74569-27-0 ]
[ 130754-19-7 ]

Reference： [1] Journal of Fluorine Chemistry, 1990, vol. 49, # 1, p. 115 - 126

7
[ 14062-24-9 ]
[ 74569-27-0 ]
[ 188424-98-8 ]
[ 130754-19-7 ]

Reference： [1] Journal of Fluorine Chemistry, 1990, vol. 49, # 1, p. 115 - 126

[ 14062-24-9 ] Synthesis Path-Downstream 1~53

1
[ 1878-66-6 ]
[ 64-17-5 ]
[ 14062-24-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sulfuric acid; In benzene; for 6h;Reflux;	Reference Example-27 Concentrated sulfuric acid (287 mg) and ethanol (10.8 g, 234 mmol) were added to a solution of 2-(4-chlorophenyl)acetic acid (10.0 g, 59.6 mmol) in benzene (10 mL), followed by stirring for 6 hours while heating to reflux. After the reaction was completed, distilled water (100 mL) was added thereto, and the resultant product was extracted with ether (50 mL*3). The mixed organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, whereby ethyl 2-(4-chlorophenyl)acetate (yield: quantitative) was obtained as a colorless oily material. 1H-NMR (400 MHz, CDCl3): delta3.54 (s, 2H), 3.70 (s, 3H), 7.21-7.33 (m, 4H).
99%	sulfuric acid; at 20℃;	The (4-chlorophenyl) -acetic acid (20.0 g, 106 mmol) was dissolved in 220 mL of ethanol at ambient temperature. A catalytic amount of sulfuric acid (10 drops) was added to afford a light yellow solution. The reaction was allowed to stir overnight to completion and was concentrated to 30 mL. The concentrate was partitioned between ethyl acetate and half- saturated NaHC03 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired pure (4-chlorophenyl) -acetic acid ethyl ester as a pale yellow oil (21.0 g, 99%). 1H NMR (CDC13, 400 MHz) 5 7.29 (d, J= 8. 4 Hz, 2H), 7.22 (d, J= 8. 4 Hz, 2H), 4.15 (q, J= 7.2 Hz, 2H), 3.58 (s, 2H), 1.25 (t, J= 7.2 Hz, 3H).
82%	With sulfuric acid; for 4h;Heating / reflux;	(4-Chloro-phenyl)-acetic acid ethyl ester (Intermediate compound): A solution of 4-chlorophenylacetic acid (28.51 g, 167 mmol) in ethanol (99%, 85 ml_) was added cone, sulfuric acid (15 ml_) and refluxed for 4 hours after which the reaction mixture was concentarted to 40 ml_ and poured into water. The aqueous phase was extracted with diethyl ether, dried using MgSO4, filtered and evaporated in vacuo. The crude product was further purified by distillation (approx. 100C/1 Torr) to give 27.2 g (82%) of the title compound.

Example 68; 5-[2-(4-Chlorophenyl)-3-methoxymethoxypropoxy]-quinazoline- 2,4-diamine; [00217] Step 1; 4-Chlorophenyl acetic acid (5.0 g; 29.3 mmol) is dissolved in 50 mL absolute ethanol. With stirring, 100 muL sulfuric acid is added to the solution and the reaction is heated to reflux for 2 hours. The ethanol is removed by rotary evaporation and the resulting oil is dissolved in ethyl acetate. The organics are washed successively with saturated sodium bicarbonate, water, and brine, then dried over magnesium sulfate. After removing the ethyl acetate by rotary evaporation, the resulting oil is dried under vacuum at 35 C for two hours to give 5.60 grams of 4- chlorophenylacetic acid ethyl ester.

Reference： [1]Patent: US2016/24110,2016,A1 .Location in patent: Paragraph 0711; 0712
[2]Patent: WO2005/51304,2005,A2 .Location in patent: Page/Page column 105
[3]Synthetic Communications,2006,vol. 36,p. 7 - 11
[4]Canadian Journal of Chemistry,1994,vol. 72,p. 2312 - 2317
[5]Journal of Organic Chemistry,1995,vol. 60,p. 7072 - 7074
[6]Journal of Organic Chemistry,2016,vol. 81,p. 12116 - 12127
[7]Journal of Medicinal Chemistry,1989,vol. 32,p. 1340 - 1348
[8]Journal of Medicinal Chemistry,2010,vol. 53,p. 3618 - 3625
[9]Patent: WO2007/57447,2007,A1 .Location in patent: Page/Page column 25
[10]Journal fur praktische Chemie (Leipzig 1954),1900,vol. <2> 61,p. 197
[11]Journal of Fluorine Chemistry,1990,vol. 49,p. 115 - 126
[12]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2008,vol. 47,p. 1135 - 1144
[13]Journal of Organic Chemistry,2009,vol. 74,p. 5100 - 5103
[14]European Journal of Medicinal Chemistry,2010,vol. 45,p. 3943 - 3949
[15]Chinese Journal of Chemistry,2010,vol. 28,p. 605 - 612
[16]Medicinal Chemistry Research,2012,vol. 21,p. 3646 - 3655
[17]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 1423 - 1429
[18]Patent: WO2005/123724,2005,A1 .Location in patent: Page/Page column 52

2
[ 14062-24-9 ]
[ 109-94-4 ]
[ 33691-09-7 ]

Yield	Reaction Conditions	Operation in experiment
		(E)-ethyl 3-((fer/-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acrylate. Into a solution of ethyl formate ( 123.9 L. 1538.9 mol) in MTBE ( 189 L) was added ethyl 4- chlorophenylacetate ( 120 kg, 604.1 mol). The mixture was stirred at 15-30 C for 30 min and then a mixture of /-BuOK ( 136.8 kg, 1219.1 mol) in MTBE ( 1215.8 L) was added while maintaining the internal temperature below 5 C. The mixture was stirred between 0-10 C for 1.5 h. The reaction mixture was added to an aqueous solution of hydrochloric acid (35%, 99.8 L in 560 L H20) maintaining the internal temperature below 10 C. The mixture was stirred for 30 min between 0-10 C until a final pH = 2 was observed. The layers were separated and the organic layer was washed with 25% NaCl solution (496 L). The mixture was cooled to -5 C and then isopropylamine ( 107.2 L, 1251.9 mol) and AcOH (70.5L, 1233.3mol) were slowly added maintaining the temperature <10 C. The mixture was stirred for 3 h at 0-10 C and then the organic layer was washed with H20 (760 L), 15% aqueous Na2C03 (424 L) and then 25% aqueous NaCl (650 L). The aqueous layer was separated and DMF (443 L) and DMAP ( 14.4 kg. 1 17.9 mol) were added to the organic solution. The mixture was then heated to 60-65 C followed by slow addition of (Boc)20 (951.6 L, 4142 mol), DMF (228.6 L) and triethylamine (263.0 L, 1821.8 mol) over 24 h. After stirring -6 h, the mixture was cooled to room temperature and MTBE (1434 L), water ( 1010 L) and 10% aqueous citric acid (938 L) were added. The aqueous layer was separated and the mixture was washed by 25% aqueous NaCl (984 L). The organic layer was then concentrated via distillation to a minimum working volume (-240 L) while maintaining the temperature below 50 C. The organic layer was then stirred for 5 h at 0-5 C and filtered. The filter cake was washed with heptane (20.6 L) and dried to afford (E)-ethyl 3-((^/'/-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acrylate ( 148.55 kg, 63% yield over three steps) as a white solid.
	With sodium; In diethyl ether; at 0 - 20℃;	General procedure: To a solution of ester 8 (20 mmol) in anhydrous ethyl ether was added ethyl formate (3.2 mL,40 mmol) at 0oC. Then sodium (0.92 g, 40 mmol) was added slowly. The reaction mixture wasstirred at room temperature. After completion of the reaction, the mixture was poured into icewater and extracted with Et2O (3×30 mL). The aqueous phase was acidified with a solution of 2NHCl to PH 3. Followed an extraction with Et2O (3×30 mL) and the organic layers were combined,dried over Na2SO4, filtered and concentrated in vacuum, leading to aldehyde 9 as a yellow oil which was used in the next step without further purification. Then 9 was dissolved in anhydrousdichloromethane and p-methoxyaniline (2.95 g, 24 mmol) was added, the reaction mixture wasstirred overnight at room temperature, the solvent was evaporated and the residue was subjected tochromatography to afford -enamino ester 1.
		Into a solution of ethyl formate (123.9 L, 1538.9 mol) in MTBE (189 L) was added ethyl 4-chlorophenylacetate (120 kg, 604.1 mol). The mixture was stirred at 15-30 C for 30 mm and then a mixture of t-BuOK (136.8 kg, 1219.1 mol) in MTBE (1215.8 L) was added whilemaintaining the internal temperature below 5 C . The mixture was stirred between 0-10 C for1.5 h. The reaction mixture was added to an aqueous solution of hydrochloric acid (3 5%, 99.8 L in 560 L H20) maintaining the internal temperature below 10 C. The mixture was stirred for 30 mm between 0-10 C until a final pH = 2 was observed. The layers were separated and the organic layer was washed with 25% NaCl solution (496 L).

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 135 - 141
[2]Journal of the Chemical Society,1953,p. 3548,3554
[3]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2709 - 2713
[4]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4735 - 4739
[5]Patent: WO2013/173779,2013,A1 .Location in patent: Paragraph 0086
[6]Synlett,2014,vol. 25,p. 1879 - 1882
[7]Patent: WO2015/73739,2015,A1 .Location in patent: Page/Page column 42

3
[ 14062-24-9 ]
[ 1875-88-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With C30H34Cl2N2P2Ru; potassium methanolate; hydrogen; In tetrahydrofuran; at 100℃; under 38002.6 - 76005.1 Torr; for 5h;Glovebox; Autoclave;	General procedure: In a glove box, add a ruthenium complex Ia (0.3 to 0.7 mg, 0.0002 to 0.001 mmol) to a 300 mL autoclave,Potassium methoxide (35-700 mg, 0.5-10 mmol), tetrahydrofuran (4-60 mL), and ester compounds (10-200 mmol).After sealing the autoclave, take it out of the glove box and fill it with 50 100atm of hydrogen.The reaction kettle was heated and stirred in an oil bath at 100 C for 10 to 336 hours.After the reaction kettle was cooled in an ice-water bath for 1.5 hours, the excess hydrogen was slowly released.The solvent was removed from the reaction solution under reduced pressure, and the residue was purified with a short silica gel column to obtain an alcohol compound. The results are shown in Table 5.
97.75%	With sodium tetrahydroborate; In tetrahydrofuran; isopropyl alcohol; for 28h;Reflux;	490 g of ethyl p-chlorophenylacetate, 1500 ml of THF and 1500 ml of isopropanol were added to a 5000 ml three-necked flask, and after stirring at 200 r/s at reflux temperature, 190.2 g of NaBH4 was added in portions, and the reaction system remained sealed during the reaction. With the addition of NaBH4, gas gradually escapes, the solution changes from transparent to milky white. After the addition is completed, after 28 hours of reaction, the reaction is stopped, cooled to room temperature, acidified to a pH of about neutral, and the layer is allowed to stand, leaving the organic layer. The aqueous layer was extracted with ethyl acetate. The organic layer was combined, and the organic layer and organic phase were combined, and washed three times with saturated brine, and then evaporated under reduced pressure at 60 C. The solvent was evaporated to give a yield of 97.75% and a purity of 99.98%.

Reference： [1]Patent: CN110357923,2019,A .Location in patent: Paragraph 0301-0303; 0305
[2]Patent: CN110128244,2019,A .Location in patent: Paragraph 0016; 0035-0058
[3]Canadian Journal of Chemistry,1974,vol. 52,p. 749 - 760
[4]Journal of the Chemical Society B: Physical Organic,1967,p. 771 - 779
[5]European Journal of Organic Chemistry,2013,p. 2061 - 2065

4
[ 106-39-8 ]
[ 681-94-7 ]
[ 14062-24-9 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1985,vol. 58,p. 3383 - 3384

5
[ 50-00-0 ]
[ 14062-24-9 ]
[ 101492-44-8 ]

Yield	Reaction Conditions	Operation in experiment
	With tetra-(n-butyl)ammonium iodide; potassium carbonate; In toluene; at 60℃;	General procedure: To a solution of ester (20 mmol, 1.0 equiv) in toluene (40 mL) was addedparaformaldehyde (1.80 g, 60 mmol, 3.0 equiv), K2CO3 (8.29 g, 60 mmol, 3.0 equiv),n-Bu4NI (370.0 mg, 1.0 mmol, 0.05 equiv). The reaction mixture was heated to 60 Covernight. After the finish of reaction monitored by TLC, the reaction was cooled toroom temperature, water was added and the aqueous layer was extracted with Et2O(40 mL × 3). The combined organic layer was dried over anhydrous Na2SO4,concentrated in vacuo. The resulting residue was purified by column chromatographyto give the corresponding acrylate intermediate as a colorless oil. Then, a solution ofsubstituted amine (20 mmol, 2.0 equiv)in THF (13.0 mL) at 0C was added a solutionof corresponding acrylate (10 mmol, 1.0 equiv) in THF (7.0 mL) via addition funnel.The reaction mixture was allowed to warm to ambient temperature then stirred atroom temperature for 24h, and concentrated under vacuum. The resulting residue waspurified by column chromatography to give the corresponding intermediate as a oil.Then to a solution of the oil in dichloromethane (20.0 mL) were added di-tert-butyldicarbonate (2.40 g, 11 mmol) and DMAP (122.0 mg, 1 mmol), and the mixture wasstirred at room temperature for 24h. Saturated aq. NH4Cl was added to the mixtureand the resulting mixture was extracted with dichloromethane. The combined organiclayer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo.The resulting residue was purified by column chromatography to give thecorresponding intermediate as a colorless oil. Then to a solution of the resulting oil inTHF/H2O (5 mL/5 mL) was added LiOH (1.20 g, 50 mmol, 5 equiv). The reactionmixture was heated at 60 C overnight. After cooling to room temperature, thereaction was acidified using aqueous HCl (6 M), and the aqueous layer was extractedwith Et2O (20 mL × 3). The combined organic layer was washed with water and brine,dried over Na2SO4, and concentrated in vacuo to give the resulting product 4a-j as acolorless crystal, using for the next step without further purification.

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 1340 - 1348
[2]Organic Letters,2015,vol. 17,p. 1328 - 1331
[3]Organic Letters,2017,vol. 19,p. 5216 - 5219
[4]European Journal of Medicinal Chemistry,2020,vol. 189

6
[ 4360-47-8 ]
[ 14062-24-9 ]
[ 107234-80-0 ]

Reference： [1]European Journal of Medicinal Chemistry,1990,vol. 25,p. 641 - 652

7
[ 14062-24-9 ]
[ 3240-34-4 ]
[ 7138-34-3 ]

Reference： [1]Tetrahedron Letters,1981,vol. 22,p. 2747 - 2750

8
[ 14062-24-9 ]
[ 5445-25-0 ]

Reference： [1]Australian Journal of Chemistry,1997,vol. 50,p. 813 - 823
[2]Journal of Medicinal Chemistry,1981,vol. 24,p. 481 - 490
[3]Journal of Organic Chemistry,2011,vol. 76,p. 9670 - 9677

9
[ 14062-24-9 ]
[ 74569-27-0 ]
(4-Chloro-3-fluoro-phenyl)-acetic acid ethyl ester [ No CAS ]
[ 188424-98-8 ]
[ 130754-19-7 ]

Reference： [1]Journal of Fluorine Chemistry,1990,vol. 49,p. 115 - 126

10
[ 14062-24-9 ]
[ 74569-27-0 ]
[ 130754-19-7 ]

Reference： [1]Journal of Fluorine Chemistry,1990,vol. 49,p. 115 - 126

11
[ 64-17-5 ]
[ 201230-82-2 ]
[ 6258-66-8 ]
[ 14062-24-9 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 147 - 149

12
[ 14062-24-9 ]
[ 109-94-4 ]
[ 95322-54-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium hydride; In diethyl ether; at 20℃;	A solution of (4-chlorophenyl) acetic acid (20.0 g, 0.12 mol) and conc sulfuric acid (2 g) in [ETOH] (150 mL) was heated under reflux for 19 h, cooled, and then concentrated. Diethyl ether (100 mL) was added and the solution was washed with sat'd NaHCO3 solution (40 mL x 2), dried, and the volatiles removed. This provided (4- chlorophenyl) acetic acid ethyl ester as an oil (22.3 g, 96%). Ethyl formate (7.46 g, 0. [101 MOL)] was added dropwise to a stirred ice-cooled suspension of (4-chlorophenyl) acetic acid ethyl ester (20.0 g, 0. [101] mol) and NaH (0.131 mol) in diethyl ether (100 mL). The mixture was then allowed to warm to room temperature overnight. The mixture neutralised (1 M HC1) ; the organic layer was isolated, dried, and the solvent removed to give [2- (4-CHLOROPHENYL)-3-OXO-PROPANOIC] acid ethyl ester as a colourless solid (19.8 g, [87%). 1H NMR (CDCL3)] : [No. ] 12.14 (d, J=12. 8,1 H), 7. [31-7.] 18 (m, 4 H), 4.29 (q, [J=7.] 2,2 H), 1.57 (br, [1] H), 1.29 (t, J=7, 2,3 H).
70%	With sodium hydride; In diethyl ether; mineral oil; at 0 - 20℃; for 12.25h;	General procedure: Sodium hydride (60% in oil, 6.0g, 0.15mol) was added portionwise over a period of 15min to an ice-cold mixture of arylacetate (0.03mol) and ethyl formate (22.2g, 0.30mol) in dry Et2O (150mL). Once addition was complete, cooling bath was removed and the reaction mixture was left at room temperature for 12h and then carefully poured into cold water (200mL). The biphasic mixture was acidified with small portions of conc. aq. HCl until steady pH 2-3 was achieved. Layers were separated, organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to dryness. Hydroxyacrylates 1a30 (yield 81%) and 1b30 (90%) were purified by distillation. Compounds 1c30 (70%) and 1d31 (75%) were washed by decantation with several small portions of cold petroleum ether. Characterization data are given in ESI.
		Ethyl alpha-[[(2-chloro-4-pyridinyl)amino]methylene]-(4-chlorophenyl)acetate. A solution of ethyl (4-chlorophenyl)acetate (10.87 g, 54.72 mmol) in 90 mL of ethyl formate was treated with a 60% suspension of NaH in oil (7.0 g, 175 mmol) added in portions. After stirring overnight, the reaction was added to 130 mL of 10% aq. HCl and 70 mL of water. The resulting mixture was extracted with EtOAc (3×50 mL). The pooled EtOAc layers were washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was treated with solid 4-amino-2-chloropyridine (7.08 g) and 100 mL of EtOH. After 48 h at reflux, the reaction was allowed to cool to room temperature. After standing overnight, the precipitate that formed by isolated and washed with EtOH, affording 8.0 g of the desired product

Reference： [1]Journal of Organic Chemistry,1984,vol. 49,p. 4287 - 4290
[2]Patent: WO2004/31161,2004,A1 .Location in patent: Page 133
[3]Tetrahedron,2017,vol. 73,p. 3939 - 3948
[4]Patent: US2010/190819,2010,A1 .Location in patent: Page/Page column 11

13
[ 14062-24-9 ]
[ 105-58-8 ]
[ 19677-37-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2; Sodium hydride (2.38 g 60%w/w mineral oil; 59.5 mmol) and diethylcarbonate (16.72 gm; 140.9 mmol) are stirred in 80 mL anhydrous THF. To the cold (ice bath) suspension above is added a solution of the previous ester (5.60 g; 28.2 mmol) in 20 mL anhydrous THF over 30 minutes. The reaction is heated to reflux for two hours, and then allowed to room temperature overnight. The reaction is neutralized slowly with saturated ammonium chloride, then extracted with ethyl acetate. The organics are separated and washed with saturated sodium bicarbonate and brine. After drying over magnesium sulfate, the solvent is removed by rotary evaporation, and the resulting oil is purified by column chromatography (5%-20% EtOAc/Hexane). A total of 7.02 grams of 2-(4-chlorophenyl)-malonic acid diethyl ester is isolated.

Reference： [1]Journal of Heterocyclic Chemistry,2012,vol. 49,p. 1415 - 1421
[2]Canadian Journal of Chemistry,1994,vol. 72,p. 2312 - 2317
[3]Patent: WO2005/123724,2005,A1 .Location in patent: Page/Page column 52

14
[ 64-17-5 ]
[ 314765-27-0 ]
[ 14062-24-9 ]

Reference： [1]Organic Letters,2000,vol. 2,p. 3789 - 3791

15
[ 14062-24-9 ]
[ 201230-82-2 ]
[ 71-36-3 ]
n-butyl (4-butoxycarbonylphenyl)acetate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2001,vol. 40,p. 2856 - 2859

16
[ 1679-18-1 ]
[ 105-36-2 ]
[ 14062-24-9 ]

Reference： [1]Tetrahedron,2010,vol. 66,p. 8238 - 8241
[2]Journal of Organic Chemistry,2011,vol. 76,p. 8107 - 8112
[3]Chemical Communications,2002,p. 622 - 623

17
[ 14062-24-9 ]
[ 201230-82-2 ]
[ 71-36-3 ]
[ 501-89-3 ]
n-butyl (4-butoxycarbonylphenyl)acetate [ No CAS ]
(4-butoxycarbonylphenyl)acetic acid [ No CAS ]

Reference： [1]Journal of Organometallic Chemistry,2002,vol. 641,p. 30 - 40

18
[ 14062-24-9 ]
[ 201230-82-2 ]
[ 71-36-3 ]
[ 501-89-3 ]
(4-butoxycarbonylphenyl)acetic acid [ No CAS ]

Reference： [1]Chimia,2001,vol. 55,p. 684 - 687

19
[ 14062-24-9 ]
[ 104503-85-7 ]
[ 849690-63-7 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 2936 - 2943

20
[ 1878-66-6 ]
[ 75-03-6 ]
[ 14062-24-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 4552 - 4564

21
[ 124041-74-3 ]
[ 14062-24-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 95 percent / 2,6-lutidine / CH₂Cl₂ / 0 - 25 °C 2.1: NaOCH₃ / acetonitrile / Heating 2.2: 98 percent / conc. HCl / Heating
	Multi-step reaction with 3 steps 1.1: 95 percent / 2,6-lutidine / CH₂Cl₂ / 0 - 25 °C 2.1: 97 percent / 10percent NaOH / tetrahydrofuran / 0.5 h / 20 °C 3.1: NaOCH₃ / acetonitrile / Heating 3.2: conc. HCl / Heating
	Multi-step reaction with 2 steps 1.1: 95 percent / 2,6-lutidine / CH₂Cl₂ / 0 - 25 °C 2.1: NaOCH₃ / acetonitrile / 20 - 65 °C 2.2: 98 percent / HCl

Multi-step reaction with 3 steps 1.1: 95 percent / 2,6-lutidine / CH₂Cl₂ / 0 - 25 °C 2.1: 97 percent / NaOH / tetrahydrofuran / 0.5 h / 20 °C 3.1: acetonitrile / 2 h / 65 °C 3.2: HCl

Reference： [1]Katritzky; Zhang; Haleem; Hussein; Fang; Steel [Journal of Organic Chemistry, 2001, vol. 66, # 16, p. 5606 - 5612]
[2]Katritzky; Zhang; Haleem; Hussein; Fang; Steel [Journal of Organic Chemistry, 2001, vol. 66, # 16, p. 5606 - 5612]
[3]Katritzky, Alan R.; Zhang, Suoming; Fang, Yunfeng [Organic Letters, 2000, vol. 2, # 24, p. 3789 - 3791]
[4]Katritzky, Alan R.; Zhang, Suoming; Fang, Yunfeng [Organic Letters, 2000, vol. 2, # 24, p. 3789 - 3791]

22
[ 14062-24-9 ]
[ 69308-37-8 ]

Reference： [1]Canadian Journal of Chemistry,1994,vol. 72,p. 2312 - 2317

23
[ 1878-66-6 ]
[ 14062-24-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	sulfuric acid; In ethanol;	EXAMPLE 7 2-(4-Chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of (4-chloro-phenyl)-acetic acid (6.29 g, 0.03 mol) in ethanol (38.4 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 12 h. The reaction was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (4-chloro-phenyl)-acetic acid ethyl ester (6.45 g, 88%) as a pale yellow solid: mp 39-41 C.; EI-HRMS m/e calcd for C10H11C2 (M+) 198.0448, found 198.0452.
88%	sulfuric acid; In ethanol;	EXAMPLE 7 2-(4-Chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of (4-chloro-phenyl)-acetic acid (6.29 g, 0.03 mol) in ethanol (38.4 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 12 h. The reaction was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (4-chloro-phenyl)-acetic acid ethyl ester (6.45 g, 88%) as a pale yellow solid: mp 39-41 C.; EI-HRMS m/e calcd for C10H11ClO2 (M+) 198.0448, found 198.0452.
96.30 g (96.9%)	With sulfuric acid; In ethanol; water; benzene;	PREPARATION 3 Ethyl p-chlorophenylacetate To p-chlorophenylacetic acid (85.30 g, 0.50 mole) was added ethanol (92 g, 2.0 mole), benzene (78.11 g) and conc. sulfuric acid (2.5 g, 0.025 mole) and the azeotropic dehydration reaction was performed for 6 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture, while it was cool and the solution was extracted with diethyl ether. The ether layer was dried with anhydrous sodium sulfate, diethyl ether was distilled off under reduced pressure and the resulting residue was distilled under reduced pressure to give 96.30 g (96.9%) of the title compound as a colorless liquid, b.p. 105-106 C./2.5 mmHg (lit. 130 C./13 mmHg).

96.30 g (96.9%)

With sulfuric acid; In ethanol; water; benzene;

Preparation 3 Ethyl p-chlorophenylacetate To p-chlorophenylacetic acid (85.30 g, 0.50 mole) was added ethanol (92 g, 2.0 mole), benzene (78.11 g) and conc. sulfuric acid (2.5 g, 0.025 mole) and the azeotropic dehydration reaction was performed for 6 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture, while it was cool and the solution was extracted with diethyl ether. The ether layer was dried with anhydrous sodium sulfate, diethyl ether was distilled off under reduced pressure and the resulting residue was distilled under reduced pressure to give 96.30 g (96.9 %) of the title compound as a colorless liquid, b.p. 105-106C/2.5 mmHg (lit. 130C/13 mmHg).

Reference： [1]Patent: US2001/39344,2001,A1
[2]Patent: US6610846,2003,B1
[3]Patent: US5082947,1992,A
[4]Patent: EP220025,1991,B1
[5]Organic Letters,2019,vol. 21,p. 6909 - 6913

24
[ 14062-24-9 ]
[ 27935-87-1 ]
ammonium chloride [ No CAS ]
[ 300355-01-5 ]

Yield	Reaction Conditions	Operation in experiment
90.9%	In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide;	A solution of freshly prepared lithium diisopropylamide (23.0 mL of 0.31M stock solution, 7.13 mmol) cooled to -78 C. was treated with (4-chloro-phenyl)-acetic acid ethyl ester (1.28 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at -78 C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 mg, 7.13 mrmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at -78 C. for 4 h. The reaction was warmed to 25 C. and stirred at 25 C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3*50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.65 g, 90.9%) as a yellow oil: EI-HRMS m/e calcd for C16H21Cl2O2 (M+) 280.1230, found 280.1227.
90.9%	In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide;	A solution of freshly prepared lithium diisopropylamide (23.0 mL of 0.31M stock solution, 7.13 mmol) cooled to -78 C. was treated with (4-chloro-phenyl)-acetic acid ethyl ester (1.28 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at -78 C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 mg, 7.13 mmol) in hexamethylphosphoramide (1 mL). The reaction-mixture was stirred at -78 C. for 4 h. The reaction was warmed to 25 C. and stirred at 25 C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.65 g, 90.9%) as a yellow oil: EI-HRMS m/e calcd for C16H21Cl2O2 (M+) 280.1230, found 280.1227.

Reference： [1]Patent: US2001/39344,2001,A1
[2]Patent: US6610846,2003,B1

25
[ 14062-24-9 ]
ethyl erythro-4-cyano-2-(4-chlorophenyl)-3-phenylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium amide;	EXAMPLE 2 Preparation of ethyl erythro-4-cyano-2-(4-chlorophenyl)-3-phenylbutanoate -2 6.5 g (0.050 mol) of cinnamonitrile dissolved in 10 cm3 of anhydrous ether are placed with stirring in an atmosphere of nitrogen with 2.55 g (0.065 mol) of sodamide in a 100-cm3 reactor maintained at -5 C. by means of an ice/salt bath. 12 g (0.060 mol) of ethyl para-chlorophenylacetate dissolved in 10 cm3 of anhydrous ether are added in the course of 15 min. The reaction is continued at -5 C. for 45 min and then at +5 C. for 30 min. After treatment according to Example 1, 2 is obtained in 69% yield. M.p. 97-98 C. Analysis: C19 H18 Cl NO2:

Reference： [1]Patent: US4785007,1988,A

26
[ 14062-24-9 ]
[ 614-18-6 ]
[ 14062-29-4 ]
[ 40061-24-3 ]

Yield	Reaction Conditions	Operation in experiment
		p-xylyl-(3-pyridyl)-ketone, m.p. 90-91C (from ether), starting from 21.0 g of p-tolylacetic acid ethyl ester and 17.8 g of nicotinic acid ethyl ester; m-chlorobenzyl-(3-pyridyl)-ketone, m.p. 65-67C, starting from 25.0 g of m-chlorophenylacetic acid ethyl ester and 19.0 g of nicotinic acid ethyl ester; p-chlorobenzyl-(3-pyridyl)-ketone (oil), starting from 25.0 g of p-chlorophenylacetic acid ethyl ester and 19.0 g of nicotinic acid ethyl ester; p-methoxybenzyl(4-pyridyl)-ketone, m.p. 130-132C, starting from 25.2 g of p-methoxyphenylacetic acid ethyl ester and 18.9 g of nicotinic acid ethyl ester; m-methoxybenzyl-(3-pyridyl)-ketone, b.p. 160-165C/0.05 Torr, starting from 25.2 g of m-methoxyphenylacetic acid ethyl ester and 19.0 g of nicotinic acid ethyl ester.

Reference： [1]Patent: US3940486,1976,A

27
[ 14062-24-9 ]
[ 68840-62-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; In diethyl ether; ethanol; nitrogen; water;	EXAMPLE 2 2-(alpha-ethoxycarbonyl-4-chlorobenzylidene)-1-methylperhydroazepine Add (drop by drop at 90 in a stream of nitrogen to let the alcohol escape) a solution of 4.6 g of sodium in 100 ml of ethyl alcohol to a mixture of 53.2 g of the title compound of Example 1 and 29.8 g of ethyl 4-chlorophenylacetate. Stir it for a further 4 hours at 90 and then cool it to ambient temperature. Mix the cooled reaction mixture with 100 ml of water and 100 ml of diethyl ether, collect the organic phase and dry the latter over sodium sulfate. Concentrate the dried organic phase and then distil off any excess ethyl 4-chlorophenylacetate under a high vacuum to obtain a crude yield [15.5 g (34% of theory)] of the title compound as yellow oil.

Reference： [1]Patent: US4221788,1980,A

28
[ 14062-24-9 ]
[ 1663-39-4 ]
[ 853680-00-9 ]

Yield	Reaction Conditions	Operation in experiment
57%	With potassium tert-butylate; at -78 - 20℃;	The (4-chlorophenyl) -acetic acid ethyl ester (9.52 g, 47.9 mmol) was dissolved in 80 mL of THF, cooled to 0 C, and treated with potassium tert-butoxide (538 mg, 4.79 mmol). The resulting orange solution was allowed to stir for 15 minutes at 0 C, then cooled to-78 C. The tert-butyl acrylate (7.72 mL, 52.7 mmol) was added in three equal portions over ten minutes. The solution was allowed to stir overnight warming slowly to room temperature. The reaction solution was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated NH4Cl solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 9: 1 hexanes: EtOAc) to afford the 2- (4-chlorophenyl)-pentanedioic acid 5- tert-butyl ester 1-ethyl ester in greater than 80% purity (9.00 g, 57%). IH NMR (CDC13, 400 MHz) 6 7.31-7. 21 (m, 4H), 4.13 (q, J= 7.6 Hz, 2H), 3.58 (t, J= 8.0 Hz, 1H), 2.27 (m, 1H), 2.16 (t, J= 7.2 Hz, 2H), 2.04 (m, 1H), 1.43 (s, 9H), 1.21 (t, J= 7.6 Hz, 3H).

Reference： [1]Patent: WO2005/51304,2005,A2 .Location in patent: Page/Page column 105-106

29
[ 1878-66-6 ]
[ 60-29-7 ]
[ 14062-24-9 ]

Yield	Reaction Conditions	Operation in experiment
96%		A solution of (4-chlorophenyl) acetic acid (20.0 g, 0.12 mol) and conc sulfuric acid (2 g) in [ETOH] (150 mL) was heated under reflux for 19 h, cooled, and then concentrated. Diethyl ether (100 mL) was added and the solution was washed with sat'd NaHCO3 solution (40 mL x 2), dried, and the volatiles removed. This provided (4- chlorophenyl) acetic acid ethyl ester as an oil (22.3 g, 96%). Ethyl formate (7.46 g, 0. [101 MOL)] was added dropwise to a stirred ice-cooled suspension of (4-chlorophenyl) acetic acid ethyl ester (20.0 g, 0. [101] mol) and NaH (0.131 mol) in diethyl ether (100 mL). The mixture was then allowed to warm to room temperature overnight. The mixture neutralised (1 M HC1) ; the organic layer was isolated, dried, and the solvent removed to give [2- (4-CHLOROPHENYL)-3-OXO-PROPANOIC] acid ethyl ester as a colourless solid (19.8 g, [87%). 1H NMR (CDCL3)] : [No. ] 12.14 (d, J=12. 8,1 H), 7. [31-7.] 18 (m, 4 H), 4.29 (q, [J=7.] 2,2 H), 1.57 (br, [1] H), 1.29 (t, J=7, 2,3 H).

Reference： [1]Patent: WO2004/31161,2004,A1 .Location in patent: Page 133

30
[ 14062-24-9 ]
[ 106-96-7 ]
[ 721968-71-4 ]

Yield	Reaction Conditions	Operation in experiment
		500 ml of tetrahydrofuran and 8.7 g of potassium hydride (mixture with liquid paraffin, content 35 %) were mixed. It was cooled to 0 C, and mixed with 15 g of ethyl 4-chlorophenylacetate, then stirred at 0 C for 30 minutes. 5.7 ml of 3-bromopropyn was mixed with it, and mixed at 0C for 30 minutes and at room temperature for 8 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The oil layer was washed successively with 5 % hydrochloric acid, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride, dried by magnesium sulfate, and concentrated under reduced pressure. The obtained residue was was purified by silica gel column to obtain 13 g of ethyl 2-(4-chlorophenyl)-4-pentynic acid. 13 g of ethyl 2-(4-chlorophenyl)-4-pentynic acid, 27 ml of 20 % aqueous solution of caustic soda and about 60 ml of ethanol were mixed at 0 C, and stirred at 70 C for 1 hour. Water was added to the reaction mixture, then adjusted to PH=2 by 5 % hydrochloric acid, and extracted with ethyl acetate. The oil layer was washed successively with buffer solution of PH6.8, saturated aqueous solution of sodium chloride, dried by magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed by hexane to obtain 10 g of 2- (4-chlorophenyl)-4-pentynic acid.1H-NMR (CDCl3, TMS) delta (ppm): 7.20-7.35 (4H, m), 3.80 (1H, t, J=7.6 Hz), 2.90 (1H, ddd, J=17 Hz, 7.6 Hz, 2.7 Hz), 2.64 (1H, ddd, J=17 Hz, 7.6 Hz, 2.7 Hz), 1.97 (1H, t, J=2.7 Hz)

Reference： [1]Patent: EP1577290,2005,A1 .Location in patent: Page/Page column 106

31
[ 14062-24-9 ]
[ 623-49-4 ]
[ 19677-37-3 ]

Reference： [1]European Journal of Organic Chemistry,2010,p. 484 - 493

32
[ 14062-24-9 ]
[ 27935-87-1 ]
[ 300355-01-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: 4-chloro-benzeneacetic acid, ethyl ester With N,N,N,N,N,N-hexamethylphosphoric triamide; lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.75h; Inert atmosphere; Stage #2: cyclopentylmethyl Iodide In tetrahydrofuran at -78 - 25℃; Inert atmosphere;

Reference： [1]Haynes, Nancy-Ellen; Corbett, Wendy L.; Bizzarro, Fred T.; Guertin, Kevin R.; Hilliard, Darryl W.; Holland, George W.; Kester, Robert F.; Mahaney, Paige E.; Qi, Lida; Spence, Cheryl L.; Tengi, John; Dvorozniak, Mark T.; Railkar, Aruna; Matschinsky, Franz M.; Grippo, Joseph F.; Grimsby, Joseph; Sarabu, Ramakanth [Journal of Medicinal Chemistry, 2010, vol. 53, # 9, p. 3618 - 3625]

33
[ 106-39-8 ]
[ 6148-64-7 ]
[ 14062-24-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap; bis(eta3-allyl-mu-chloropalladium(II)); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,3,5-trimethyl-benzene; at 140℃; for 20h;Inert atmosphere;	General procedure: after standard cycles of evacuation and back-filling with dry and pure nitrogen, an oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Pd source (see Table 1, Table 2, Table 3 and Table 4), ligand (see Table 1, Table 2, Table 3 and Table 4), N,N-dimethylpyridin-4-amine (DMAP, see Table 1, Table 2, Table 3 and Table 4), and ethyl potassium malonate (see Table 1, Table 2, Table 3 and Table 4). The tube was evacuated and backfilled with argon (this procedure was repeated three times). Under a counter flow of argon, aryl halide (see Table 1, Table 2, Table 3 and Table 4) and solvent (see Table 1, Table 2, Table 3 and Table 4) were added by syringe. The tube was sealed and stirred at room temperature for 10 min. Then the tube was connected to the Schlenk line, which was full of argon, stirred in a preheated oil bath (140-150 C) for the appointed time (20-25 h). Upon completion of the reaction, the mixture was cooled to room temperature and diluted with diethyl ether, and the yields were determined by gas chromatography using 1,3-dimethoxybenzene as the internal standard.

Reference： [1]Tetrahedron,2012,vol. 68,p. 2113 - 2120

34
[ 19213-72-0 ]
[ 14062-24-9 ]
[ 19677-37-3 ]

Yield	Reaction Conditions	Operation in experiment
78%		General procedure: To a stirred solution of phenyl acetic acid ethyl ester 1a (1 g, 6.09 mmol) in THF (10 mL) was added LiHMDS (9.1 ml, 1 M sol. in THF, 7.31 mmol) at -78 C and the reaction mixture was stirred at this temperature for 30 min. Ethyl-1-imidazole carboxylate 2 (1.2 g, 9.146 mmol) in dry THF (3 ml) was added drop wise to the reaction mixture at -78 C and stirred at rt for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with water, saturated brine solution, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was chromatographed on a silica gel column. Elution with 4% ethyl acetate/pet ether gave the pure compound 3a (1.1 g, 81% yield) as a colorless liquid.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 1060 - 1062

35
[ 64-17-5 ]
[ 201230-82-2 ]
[ 106-43-4 ]
[ 14062-24-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With di-tert-butyl peroxide; dichloro[4,5-bis(diphenylphosphino)-9,9?-dimethylxanthene]palladium(II); at 120℃; under 7600.51 Torr; for 16h;	p-Chlorotoluene (1.89 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 89 mg ethyl p-chlorophenylacetate was obtained by column chromatography, in a yield of 90%. 1HNMR (400 MHz, CDCl3) delta 1.23 (t, J=7.2 Hz, 3H), 3.57 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 7.19-7.23 (m, 2H), 7.27-7.30 (m, 2H); 13CNMR (100 MHz, CDCl3) delta 14.2, 40.7, 61.0, 128.7, 130.7, 132.6, 133.0, 171.2; HRMS (ESI) calcd. for C10H11ClNaO2 [M+Na]: 221.0340. found: 221.0342. The ethyl p-chlorophenylacetate 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, 75 mg product p-chlorophenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 98%.

Reference： [1]Patent: US2013/303798,2013,A1 .Location in patent: Paragraph 0062; 0063
[2]Journal of the American Chemical Society,2012,vol. 134,p. 9902 - 9905

36
[ 14062-24-9 ]
ethyl 2-diazo-2-(4-chlorophenyl)acetate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 1458 - 1462
Angew. Chem.,2019,vol. 131,p. 1472 - 1476,5
[2]Organic and Biomolecular Chemistry,2013,vol. 11,p. 5998 - 6002
[3]Organic Letters,2019,vol. 21,p. 6909 - 6913
[4]Journal of the American Chemical Society,2012,vol. 134,p. 15257 - 15260
[5]Journal of the American Chemical Society,2015,vol. 137,p. 14496 - 14501
[6]Organic Letters,2015,vol. 17,p. 6150 - 6153
[7]Journal of Organic Chemistry,2016,vol. 81,p. 2943 - 2949
[8]Chinese Journal of Chemistry,2016,vol. 34,p. 469 - 472
[9]European Journal of Organic Chemistry,2017,vol. 2017,p. 324 - 331
[10]Organic Letters,2017,vol. 19,p. 846 - 849
[11]Organic Letters,2018,vol. 20,p. 4672 - 4676
[12]Journal of Organic Chemistry,2019,vol. 84,p. 4478 - 4485

37
[ 14062-24-9 ]
[ 41022-54-2 ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium persulfate; N-chloro-succinimide; trifluorormethanesulfonic acid; palladium diacetate In 1,2-dichloro-ethane at 70℃; for 7h; Sealed tube; regioselective reaction;

Reference： [1]Sun, Xiuyun; Shan, Gang; Sun, Yonghui; Rao, Yu [Angewandte Chemie - International Edition, 2013, vol. 52, # 16, p. 4440 - 4444][Angew. Chem., 2013, vol. 125, # 16, p. 4536 - 4540,5]

38
[ 14062-24-9 ]
[ 1878-66-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With water; sodium hydroxide; In 1,4-dioxane; at 60℃; for 2h;pH 10 - 14;	p-Chlorotoluene (1.89 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 89 mg ethyl p-chlorophenylacetate was obtained by column chromatography, in a yield of 90%. 1HNMR (400 MHz, CDCl3) delta 1.23 (t, J=7.2 Hz, 3H), 3.57 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 7.19-7.23 (m, 2H), 7.27-7.30 (m, 2H); 13CNMR (100 MHz, CDCl3) delta 14.2, 40.7, 61.0, 128.7, 130.7, 132.6, 133.0, 171.2; HRMS (ESI) calcd. for C10H11ClNaO2 [M+Na]: 221.0340. found: 221.0342. The ethyl p-chlorophenylacetate 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, 75 mg product p-chlorophenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 98%.

Reference： [1]Patent: US2013/303798,2013,A1 .Location in patent: Paragraph 0018; 0062; 0063

39
[ 14062-24-9 ]
[ 109-94-4 ]
[ 33691-09-7 ]
[ 95322-54-6 ]

Yield	Reaction Conditions	Operation in experiment
		Ethyl 2-(4-chlorophenyI)-3-oxopropanoate. To an oven-dried, round bottom flask purged with nitrogen containing a solution of 4-ethyl 2-(4-chlorophenyl)acetate ( 100 g, 0.51 mol, 1.0 equiv) in MTBE ( 1.0 L, 10 vol), was added the /-BuOK ( 1 13.0 g, 1.0 mol, 2.0 equiv) portionwise at 0 C. The reaction mixture was stirred for 15 min at 0 C and then ethyl formate ( 101.7 mL, 1.3 mol, 2.5 equiv) was added dropwise. Reaction was monitored by HPLC (IPC by LCMS (m/z) [M]+ shows 226.9). The reaction mixture was stirred at 0- 10 C for 3 h then quenched into the cold 2N aqueous HC1. The organic phase was separated and washed with brine (3 x 300 mL). Concentration of the organic phase under reduced pressure afforded the crude product (91 g, 81 % yield) as an unassigned mixture of the isomers (-1 : 1 mixture of ethyl 2-(4-chlorophenyl)-3-oxopropanoate /ethyl 2-(4-chlorophenyl)-3-hydroxyacrylate) and brown oil. The crude product mixture was used directly for next step without further purification.

Reference： [1]Patent: WO2013/173779,2013,A1 .Location in patent: Paragraph 0090

40
[ 14062-24-9 ]
[ 109-94-4 ]
ethyl 3-amino-2-(4-chlorophenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Ethyl 2-(4-chlorophenyI)-3-oxopropanoate. To an oven-dried, round bottom flask purged with nitrogen containing a solution of 4-ethyl 2-(4-chlorophenyl)acetate ( 100 g, 0.51 mol, 1.0 equiv) in MTBE ( 1.0 L, 10 vol), was added the /-BuOK ( 1 13.0 g, 1.0 mol, 2.0 equiv) portionwise at 0 C. The reaction mixture was stirred for 15 min at 0 C and then ethyl formate ( 101.7 mL, 1.3 mol, 2.5 equiv) was added dropwise. Reaction was monitored by HPLC (IPC by LCMS (m/z) [M]+ shows 226.9). The reaction mixture was stirred at 0- 10 C for 3 h then quenched into the cold 2N aqueous HC1. The organic phase was separated and washed with brine (3 x 300 mL). Concentration of the organic phase under reduced pressure afforded the crude product (91 g, 81 % yield) as an unassigned mixture of the isomers (-1 : 1 mixture of ethyl 2-(4-chlorophenyl)-3-oxopropanoate /ethyl 2-(4-chlorophenyl)-3-hydroxyacrylate) and brown oil. The crude product mixture was used directly for next step without further purification.; Ethyl 3-amino-2-(4-chlorophenyl)acrylate. A -1 : 1 mixture of ethyl 2-(4- chlorophenyl)-3-oxopropanoate /ethyl 2-(4-chlorophenyl)-3-hydroxyacrylate (50.0 g, 0.22 mol, 1.0 equiv) and ammonium formate (69.6 g, 1.10 mol, 5.0 equiv) in EtOH (500 mL, 10 vol) was heated at 65 C for 8 h. Reaction was monitored by HPLC (IPC by LCMS (m/z): [M]+ shows 225.9). The reaction mixture was then concentrated under reduced pressure to a minimal working volume. The mixture was partitioned between cold water (200 mL) and EtOAc (200 mL). The organic phase was separated and washed with saturated aqueous NaHC03 ( 100 mL) and brine (3 x 100 mL). The organics were dried over anhydrous Na2S04, filtered and concentrated to give crude product ethyl 3-amino-2-(4-chlorophenyl)acrylate (42 g, 85% yield) as an unassigned mixture of E/Z isomers (-1 : 1 ) and brown oil. The crude product was used directly for next step without further purification

Reference： [1]Patent: WO2013/173779,2013,A1 .Location in patent: Paragraph 0090; 0091

41
[ 14062-24-9 ]
[ 383-63-1 ]
ethyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With sodium; In diethyl ether; for 24h;Reflux;	Ethyl trifluoroacetate (3.57 g, 25.2 mmol) and sodium (580 mg, 25.2 mmol) were added to a solution of ethyl 2-(4-chlorophenyl)acetate (5.0 g, 25.2 mmol) in ether (8 mL), followed by heating to reflux for 24 hours. After the reaction was completed, 2N hydrochloric acid (50 mL) was added thereto, and the resultant product was extracted with ether (20 mL3). The mixed organic layer was washed with water (20 mL3), and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1), whereby ethyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-oxobutanoate (2.42 g, yield: 34%) was obtained as a yellow solid.

Reference： [1]Patent: US2016/24110,2016,A1 .Location in patent: Paragraph 0711; 0713

42
[ 827605-29-8 ]
[ 1071-46-1 ]
[ 14062-24-9 ]

Reference： [1]Journal of the American Chemical Society,2016,vol. 138,p. 13826 - 13829

43
[ 623-73-4 ]
[ 108-90-7 ]
[ 14062-24-9 ]
[ 40061-54-9 ]
[ 14062-29-4 ]

Reference： [1]Organometallics,2017,vol. 36,p. 172 - 179

44
[ 14062-24-9 ]
6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde [ No CAS ]
ethyl (Z)-2-(4-chlorophenyl)-3-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7%	With n-butyllithium; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -10 - 20℃; for 4h;	To a stirred solution of DIPA(211mL, 1.5 mmol, 1.5 eq) in THF (500mL) was added n-BuLi (1mL,1.5 mmol, 1.5 eq) dropwise at -10 C. Ethyl 2-(4-chlorophenyl)acetate(199 mg, 1 mmol, 1 eq) was then added, in solution in THF(400mL) at -10 C. 3a (244 mg, 1 mmol, 1 eq) was then added, insolution in THF (800mL). The reaction was warmed to room temperatureand stirred for 4 h. The reaction was then quenched withNH4Cl aqueous saturated solution (5mL) and the aqueous phasewas extracted thrice with 5 mL of AcOEt. The combined organicphases were dried over MgSO4 and evaporated to dryness. Thecrude mixture was purified by column chromatography on aluminawith a mixture of petroleum ether and AcOEt (5:5?3:7)as eluent. 6 was obtained as a brown oil (32 mg, 7%).1H NMR (300 MHz, CDCl3) d: 8.02 (s, 1H, CHC), 7.45 (m, 2H,Ph-2,6), 7.40 (d, 1H, J = 9.8 Hz, H-8), 7.28-7.23 (m, 3H, H-5 & Ph-3,5), 7.03 (dd, 1H, J = 9.8, 2.2 Hz, H-7), 6.49 (s, 1H, H-3), 4.25 (q,2H, J = 7.1 Hz, OCH2CH3), 3.12-3.05 (m, 4H, 2 CH2 piperazine),2.66 - 2.59 (m, 4H, 2 CH2 piperazine), 2.39 (s, 3H, NCH3), 1.30 (t,3H, J = 7.1 Hz, OCH2CH3). 13C NMR (75 MHz, CDCl3) d: 167.0(CO), 141.9 (C-8a), 140.34 (C-2), 140.29 (C-6), 135.5 (CHC),135.4 (Cl-Ph-4), 134.1 (Cl-Ph-1), 131.0 (Cl-Ph-2,6), 130.9 (CHC),129.4 (Cl-Ph-3,5), 122.3 (C-7), 117.6 (C-8), 113.9 (C-3), 110.9 (C-5), 61.3 (OCH2CH3), 54.7 (2 CH2 piperazine), 50.0 (2 CH2 piperazine),45.9 (NCH3), 14.3 (OCH2CH3). HRMS (ESI): m/z calc. for C23-H25ClN4O2 [M+H]+: 425.17388, found: 425.17222.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 6695 - 6706

45
[ 14062-24-9 ]
[ 98-95-3 ]
[ 7497-60-1 ]