Name: 940-64-7|2-(p-Tolyloxy)acetic acid|98%
Brand: Ambeed
SKU: A631383
Price: 6.0 USD
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1
[ 940-64-7 ]
[ 15149-10-7 ]

Reference： [1]Farmaceutisk tidende,1956,vol. 66,p. 49
[2]Chemical Communications,2019,vol. 55,p. 9701 - 9704

2
[ 940-64-7 ]
[ 15516-47-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With thionyl chloride In benzene at 50℃; for 3h;
94%	With thionyl chloride In benzene for 3h; Reflux;	5 p-Tolyloxy-acetyl chloride (SO1 -140) (5a): To a solution of p-tolyoxy-acetic acid (4a) (300 mg, 1 .81 mmol) in 20 ml benzene thionyl chloride (5 mL) was added and the mixture was refluxed for 3h till a clear solution was formed. Excess thionyl chloride and benzene were evaporated to give the pure compound SO1 -140 5a as colorless liquid (313 mg, 94%). 1 H NMR (400 M Hz, CDCI3) δ 7.1 1 (dd, J = 8.7, 0.6 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H), 4.92 (d, J = 3.4 Hz, 1 H), 2.30 (s, 3H).
94%	With thionyl chloride In benzene for 3h; Reflux;

93%	With oxalyl dichloride In dichloromethane at 0 - 20℃;	21a To a 0°C stirring suspension of 4.00 g of the acid (24.07 mmol; 1.0 eqmol) in 40.0 mL of dichloromethane, it was added 2.20 mL of oxalyl chloride (25.27 mmol; 1.05 eqmol) and then 56 uL of dimethylformamide (0.7221 mmol; 0.03 eqmol). The ice bath was removed and the reaction was allowed to stir at room temperature until gas evolution ceased (bubbler monitor).All the volatiles were then evaporated in vacuo. The obtained crude liquid contained some very fine precipitate, so the neat liquid was passed over a Celite pad which was flushed with hexanes. Once again, all the volatiles were then evaporated in vacuo, to obtain a clear liquid which showed only one compound at the 1H-NMR analysis. The obtained 4.129 g (22.36 mmol; 93%) were used in the next step without further purification. 1H NMR (400 MHz; CDCls) δ 2.30 (s, 3H), 4.92 (s, 2H), 6.84 - 6.76 (m, 2H), 7.15 - 7.08 (m, 2H).
93.2%	With thionyl chloride In tetrahydrofuran; N,N-dimethyl-formamide at 50℃; for 5h;	13 Preparation of 4-methylphenoxyacetyl chloride (5a) 2 ml of 4-methylphenoxyacetic acid (4a), 2 ml of sulfuryl sulfoxide, 50 ml of tetrahydrofuran and 0.1 ml of DMF were placed in a reaction flask and reacted at 50C for 5 hours. The reaction was completed and the reaction was dry to obtain 2.07 g of a pale yellow liquid , The yield was 93.2%.
93.2%	With thionyl chloride In tetrahydrofuran at 50℃; for 5h;	15 4Preparation of methylphenoxyacetyl chloride (9a) 2 g of 4-methylphenoxyacetic acid (8a), 2 ml of thionyl chloride, 50 ml of tetrahydrofuran and 0.1 ml of DMF were placed in a reaction flask and reacted at 50 ° C for 5 hours. The reaction was completed and the reaction was dry to obtain a pale yellow liquid 2.07 g, yield 93.2%. m / z (ESI) = 185.5 [M + H] & lt; + & gt ;.
	With thionyl chloride
	With thionyl chloride In ethyl acetate; benzene for 8h; Heating;
	With thionyl chloride for 4h; Heating;
	With thionyl chloride In methanol; ethyl acetate for 7h; Heating;
	With thionyl chloride In methanol; ethyl acetate; benzene for 8h; Heating;
	With thionyl chloride for 8h; Heating;
	With thionyl chloride In chloroform Heating;
	With thionyl chloride In benzene Heating;
	With thionyl chloride; N,N-dimethyl-formamide In chlorobenzene Heating;
	With thionyl chloride for 5h; Heating;
	With dmap; thionyl chloride In dichloromethane for 2h; Reflux;
	With thionyl chloride
	With thionyl chloride for 6h; Reflux;
	With thionyl chloride; N,N-dimethyl-formamide In tetrahydrofuran at 50℃; for 5h;	General procedure for the synthesis of HY-1a-HY-1f General procedure: A mixture of aryloxyl acid (5a-f) (10 mmol), thionyl chloride(15 mmol), tetrahydrofuran (50 ml) and dimethylformamide(1 ml) was stirred at 50 C for 5 h. Then tetrahydrofuran and thionylchloride were removed in vacuo. Yellow liquid (6a-f) obtainedand pyridine (2.5 ml) were then added to a solution of 10 (10 mmolin 25 ml tetrahydrofuran). The solution was stirred at 50 C for 3 h.When the reaction was completed, the solution was poured intohydrochloric acid (1 mol/L) and extracted with CH2Cl2(20 ml 3). The combined organic phase was washed with brine(20 ml 3), dried over Na2SO4, concentrated to afford yellow solid.Purification by silica gel column chromatography (PE:EA = 15:1) yielded the isoflavone amide derivatives HY-1a-HY-1f
	With thionyl chloride for 5h; Reflux;	General procedure for preparation of 5-R-4-R₁-2-nitrobenzoylchlorides 12a-c and 2-phenoxyacetyl chlorides 16a-e General procedure: Substituted benzoyl and phenoxyacetyl chlorides 12a-c and 16a-e were obtained by refluxing for 5 h the appropriate acid derivatives (0.01 mol) with thionyl chloride (7.25 mL). After evaporation under reduced pressure, the crude liquid residue was used for subsequent reactions without purification.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h;	General synthetic procedure for compounds 8-11 and 13-36 General procedure: To a stirred suspension of various carboxylic acid 4a, 4b, 6a and 8a (1.0 equiv) in CH2Cl2 (25 mL) was added oxalyl chloride (3.0 equiv) and a catalytic amount of DMF. After stirring at room temperature for 3 h, the reaction was concentrated under reduced pressure to afford a yellow oil crude acyl chloride. To a solution of methyl 2-(4-amino-2-fluorophenoxy)acetate 3a (1.0 equiv) in CH2Cl2(25 mL) was added Et3N (1.5 equiv), and this mixture was cooled to -5 °C. Subsequently, the crude acyl chloride obtained above was added in dropwise at a rate to ensure that the temperature did not exceed 0 °C. The solution was stirred for another 2 hrs at 25 °C, then washed successively with 10% HCl (2 × 25 mL), 10% NaHCO3 (2 × 25 mL) and brine (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was then evaporated to give the impure amide which was recrystallized from ethanol to give the desired products as colorless crystals. To a solution of the obtained crystals (1.0 equiv)in 2:3:1 THF/MeOH/H2O (18 ml) was added LiOH·H2O (1.5 equiv). After stirring at room temperature for 4 h, the volatiles were removed under reduced pressure. The residue was acidified with 1N hydrochloric acid solution, and then filtered and the filter cake was washed with 5 mL of water, dried in vacuum to afford a white powder. Recrystallization from 75% EtOH gave the desired compounds 8-11 and 13-36 as colorless crystals.
	With thionyl chloride at 65 - 70℃;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere;
	With thionyl chloride Reflux;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 12h;

Reference： [1]Ito, Kazuaki; Takasawa, Toshiro; Ohba, Yoshihiro [Synthetic Communications, 2002, vol. 32, # 24, p. 3839 - 3849]
[2]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2012/129564, 2012, A2 Location in patent: Page/Page column 61-62
[3]Ozcan, Sevil; Kazi, Aslamuzzaman; Marsilio, Frank; Fang, Bin; Guida, Wayne C.; Koomen, John; Lawrence, Harshani R.; Sebti, Saïd M. [Journal of Medicinal Chemistry, 2013, vol. 56, # 10, p. 3783 - 3805]
[4]Current Patent Assignee: Firmenich International SA - WO2012/61698, 2012, A2 Location in patent: Page/Page column 62
[5]Current Patent Assignee: NANJING HUAMAI BIO PHARMACEUTICAL TECH - CN106146450, 2016, A Location in patent: Paragraph 0087; 0088; 0089
[6]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN104672192, 2017, B Location in patent: Paragraph 0093; 0094; 0095
[7]Mameli [Gazzetta Chimica Italiana, 1926, vol. 56, p. 764] Higginbotham; Stephen [Journal of the Chemical Society, 1920, vol. 117, p. 1541]
[8]Jain; Srivastava [Journal of the Indian Chemical Society, 1990, vol. 67, # 9, p. 775 - 776]
[9]Hajela Km.; Sengupta; Shanker; Doval [Archiv der Pharmazie, 1983, vol. 316, # 5, p. 431 - 434]
[10]Purohit; Srivastava [Journal of the Indian Chemical Society, 1991, vol. 68, # 3, p. 163 - 165]
[11]Chaurasia; Srivastava [Journal of the Indian Chemical Society, 1991, vol. 68, # 2, p. 106 - 107]
[12]Chaurasia, Sunita; Srivastava, Savitri D. [Journal of the Indian Chemical Society, 1992, vol. 69, # 1, p. 45 - 46]
[13]Bhatt, P.; Srivastava, S. D.; Mehta, P. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1998, vol. 37, # 5, p. 514 - 516]
[14]Shishoo, Chamanlal J.; Shirsath, Vikas S.; Rathod, Ishwarsinh S.; Yande, Vikas D. [European Journal of Medicinal Chemistry, 2000, vol. 35, # 3, p. 351 - 358]
[15]Vorob'ev; Kurbatov; Krasnikov; Mezheritskii; Usova [Russian Chemical Bulletin, 2006, vol. 55, # 8, p. 1492 - 1497]
[16]Han, Liang; Gao, Jian-Rong; Li, Zheng-Ming; Zhang, Yun; Guo, Wei-Ming [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3231 - 3234]
[17]Location in patent: experimental part Jimenez, Fabiola; Cruz, Maria Del Carmen; Zuniga, Clara; Martinez, Maria A.; Chamorro, German; Diaz, Francisco; Tamariz, Joaquin [Medicinal Chemistry Research, 2010, vol. 19, # 1, p. 33 - 57]
[18]Location in patent: scheme or table He, Hong-Wu; Yuan, Jun-Lin; Peng, Hao; Chen, Ting; Shen, Ping; Wan, Shu-Qing; Lee, Yanjun; Tan, Hong-Liang; He, Ya-Hui; He, Jun-Bo; Li, Yan [Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 9, p. 4801 - 4813]
[19]Location in patent: experimental part Han, Liang; Zhu, Qiong-Yan; Jia, Jian-Hong; Li, Yu-Jin; Gao, Jian-Rong [Asian Journal of Chemistry, 2012, vol. 24, # 3, p. 1223 - 1226]
[20]Wang, Wenbin; He, Yi; Xu, Pei; You, Qidong; Xiao, Hong; Xiang, Hua [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 4428 - 4433]
[21]Raffa, Demetrio; Maggio, Benedetta; Plescia, Fabiana; Cascioferro, Stella; Raimondi, Maria Valeria; Cancemi, Gabriella; D'Anneo, Antonella; Lauricella, Marianna; Cusimano, Maria Grazia; Bai, Ruoli; Hamel, Ernest; Daidone, Giuseppe [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 19, p. 6305 - 6316]
[22]Li, Zheng; Wang, Xuekun; Xu, Xue; Yang, Jianyong; Qiu, Qianqian; Qiang, Hao; Huang, Wenlong; Qian, Hai [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 20, p. 6666 - 6672]
[23]Mo, Wenyan; Shi, Yanxia; He, Junbo; Li, Baoju; Peng, Hao; He, Hongwu [Journal of Heterocyclic Chemistry, 2016, vol. 53, # 1, p. 183 - 187]
[24]Kuznetsov, Dmitry M.; Mukhina, Olga A.; Kutateladze, Andrei G. [Angewandte Chemie - International Edition, 2016, vol. 55, # 24, p. 6988 - 6991][Angew. Chem., 2016, vol. 128, # 24, p. 7102 - 7105,4]
[25]Sheng, Xijun; Zhou, Yuan; Zhang, Shasha; Peng, Hao; He, Hongwu [Journal of Heterocyclic Chemistry, 2017, vol. 54, # 1, p. 165 - 170]
[26]Noncovich, Alain; Priest, Chad; Ung, Jane; Patron, Andrew P.; Servant, Guy; Brust, Paul; Servant, Nicole; Faber, Nathan; Liu, Hanghui; Gonsalves, Nicole S.; Ditschun, Tanya L. [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 16, p. 3931 - 3938]
[27]Lei, Kang; Li, Pan; Yang, Xue-Fang; Wang, Shi-Ben; Wang, Xue-Kun; Hua, Xue-Wen; Sun, Bin; Ji, Lu-Sha; Xu, Xiao-Hua [Journal of Agricultural and Food Chemistry, 2019, vol. 67, # 37, p. 10489 - 10497]

3
[ 106-44-5 ]
[ 79-11-8 ]
[ 940-64-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydroxide In dimethyl sulfoxide at 110℃; for 2h;
82%	Stage #1: chloroacetic acid With sodium hydroxide In water Stage #2: p-cresol With sodium hydroxide In ethanol; water at 105℃; for 5.33333h;
80%	With sodium hydroxide; bentonite In water for 0.0833333h; microwave irradiation;

71%	Stage #1: chloroacetic acid With sodium hydroxide In water Cooling with ice; Stage #2: p-cresol In ethanol; water for 0.333333h; Stage #3: In ethanol; water at 105℃; for 5h;	Synthesis of Phenoxyacetic Acid Derivatives (B1-7) General procedure: Compounds B1-7 were prepared by similar procedures. In atypical synthesis of B1, monochloroacetic acid (0.04 mol,3.78 g) was dissolved in deionized water (15 mL) under thecondition of stirring and an ice bath. Then NaOH (25 %) wasadded dropwise until the pH value was adjusted to 9-10, thena solution of sodium chloroacetate was obtained. To a solutionof NaOH (0.03 mol, 1.20 g), deionized water (15 mL) andethanol (5 mL), phenol (0.04 mol, 3.76 g) was slowly addedunder stirring. After addition, the mixture was stirred for20 min, then the above sodium chloroacetate was addeddropwise, and heated to 105 °C and refluxed for 5 h. Thereaction mixture was cooled to room temperature. The pHvalue of the mixture was acidified to 1-2 with diluted hydrochloricacid. The precipitate was filtered, washed with dilutedhydrochloric acid many times, and recrystallized and dried invacuum, resulting in a white solid product of thephenoxyacetic acid (B1)
71%	Stage #1: chloroacetic acid With sodium hydroxide In water Stage #2: p-cresol With sodium hydroxide In ethanol; water for 5h; Reflux;
70%	Stage #1: chloroacetic acid With sodium hydroxide Stage #2: p-cresol With sodium hydroxide In ethanol; water at 105℃; for 5h;	Synthesis of phenoxyacetic acid derivatives (4a-h) General procedure: A mixture of NaOH (0.04 mol, 1.60 g), deionized water (20 mL) and ethanol (20 mL) were poured into a 150 mL three-necked flask, then phenol (0.04 mol, 3.76 g) was slowly added under stirring. Twenty minutes later, the above sodium chloroacetate was added dropwise. The reaction solution was heated to 105 °C and refluxed for 5 h. After cooling down, the pH value of the mixture was acidified to 1-2 with diluted hydrochloric acid. The precipitate was collected by filtration and washed with diluted hydrochloric acid many times. Recrystallized and dried under a vacuum, resulting in a white solid product of the phenoxyacetic acid (4a).
69%	With potassium hydroxide In water Reflux;	4.1.3. Synthesis of Phenoxy Acetic Acid Derivatives (PAA1-PAA5) General procedure: The phenol derivative (19.2 mmol) was mixed with a solutionof potassium hydroxide (71.4 mmol, 4 g) in 8mL ofwater in a two necked round bottom flask until homogeneoussolution was produced. As the mixture began to boil, 6mL of50% w/v solution (g/ml) of chloroacetic acid was addeddrop-wise using dropping funnel placed in the side arm ofthe flask. The reaction mixture was refluxed until reactionwas completed (monitored by TLC). The solution was transferredto a beaker, cooled to room temperature and acidifiedby drop-wise addition of HCl (monitor using pH paper). Theresultant mixture was cooled in an ice bath, the crude productwas filtered and re-crystallized from boiling water.
	With alkali
	With sodium hydroxide Dampfbad;
	With sodium hydroxide Heating;
	With sodium hydroxide In water Heating;
	With sodium hydroxide Heating;
	With sodium hydroxide In water for 2h;
	With sodium hydroxide
	With sodium hydroxide
	Stage #1: p-cresol; chloroacetic acid With sodium hydroxide In water for 2h; Stage #2: With hydrogenchloride In water	4.1. General procedure for the synthesis of aryloxy acetic acids (7k-s) General procedure: Equimolar quantities of chloroacetic acid (0.05 mol) and appropriate phenol (6k-s) (0.05 mol) were taken in a conical flask, to which aqueous solution of NaOH (0.12 mol in 25 mL water) was slowly added with constant stirring. The solution was stirred for 2 h until the solution turned clear, brown or yellow and then the reaction mixture was evaporated in an evaporating dish until the solid sodium salt was precipitated. The salt was isolated, dried, dissolved in water and acidified by adding con. HCl. The precipitated aryloxy acetic acid was filtered and recrystallized from water or ethanol.
	With sodium hydroxide at 100 - 110℃;
	With sodium hydroxide In water	General procedure for the synthesis of aryloxy acetic/propionicacids (2a-q and 3a-q) General procedure: Equimolar quantities of 2-chloro acetic acid/3-chloro propionicacid (0.05 mol) and appropriate phenol (1a-q) (0.05 mol) were taken in a conical flask, to which aqueous solution of NaOH(0.12 mol in 25 mL water) was slowly added with constant stirring.The solution was stirred for 2 h until the solution turned clear,brown or yellow and then the reaction mixture was evaporatedin a evaporating dish until the solid sodium salt was precipitated. The salt was isolated, dried, dissolved in water and acidified byadding con. HCl. The precipitated aryloxy acetic/propionic acidwas filtered and recrystallized from water or ethanol
	With sodium hydroxide In water at 100 - 110℃;
	With sodium hydroxide
	With sodium hydroxide In water for 15h; Reflux;	2.2.1. Preparation of substituted phenoxyacetic acid General procedure: Solution (A) of substituted phenol (0.25 M) with sodiumhydroxide (NaOH) in water as a solvent medium is preparedand heated up to boiling. In another round bottom flask,solution (B) of chloro-acetic acid in sodium hydroxide is prepared.The solution (B) is dropwise added to the boiling solution(A). The resulting reaction mixture was then refluxed for15 h by keeping the mixture alkaline, throughout the reactionprocess. Dilute hydrochloric acid was added to thisrefluxed solution while warm. Precipitates of substituted phenoxyaceticacid began to separate out by pouring it into theice bath. Residues were collected and recrystallized with hotwater (Takeda et al., 1998).

Reference： [1]Wang, Yanliang; Guo, Xiangguang; Bai, Yan; Sun, Xiaoqi [RSC Advances, 2019, vol. 9, # 58, p. 33922 - 33930]
[2]Wu, Yongqiang; Guo, Tiantong; Shu, Dehua; Zhang, Wu; Luan, Fangfei; Shi, Ling; Guo, Dongcai [Luminescence, 2018, vol. 33, # 5, p. 855 - 862]
[3]Hamid, Hamida M. Abdel; Ramadan, El Sayed; Hagar, Mohamed; El Ashry, El Sayed H. [Synthetic Communications, 2004, vol. 34, # 3, p. 377 - 382]
[4]Yan, Dong; Li, Dong; Cheng, Guang; Yang, Zehui; Shi, Ling; Guo, Dongcai [Journal of Fluorescence, 2015, vol. 25, # 4, p. 849 - 859]
[5]Xiao, Haihua; Jiang, Xi; Li, Dong; Wu, Limin; Zhang, Wu; Guo, Dongcai [Luminescence, 2015, vol. 30, # 5, p. 677 - 685]
[6]Yan, Dong; Xiang, Yu; Li, Kangyun; Chen, Yanwen; Yang, Zehui; Guo, Dongcai [Journal of Molecular Structure, 2014, vol. 1074, p. 487 - 495]
[7]Singh, Gurmeet; Bansal, Yogita; Bansal, Gulshan; Goel, Rajesh Kumar [Medicinal Chemistry, 2014, vol. 10, # 4, p. 418 - 425]
[8]Mameli [Gazzetta Chimica Italiana, 1926, vol. 56, p. 764] Higginbotham; Stephen [Journal of the Chemical Society, 1920, vol. 117, p. 1541] Brueckner [Angewandte Chemie, 1928, vol. 41, p. 1046][Fresenius' Zeitschrift fuer Analytische Chemie, 1928, vol. 75, p. 290]
[9]Koelsch [Journal of the American Chemical Society, 1931, vol. 53, p. 304]
[10]BAKER; LEE; SKINNER; MARTINEZ; TONG [Journal of medicinal and pharmaceutical chemistry, 1960, vol. 2, p. 633 - 657]
[11]Purohit; Srivastava [Journal of the Indian Chemical Society, 1991, vol. 68, # 3, p. 163 - 165]
[12]Purohit; Shah [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1999, vol. 38, # 5, p. 618 - 622]
[13]Shishoo, Chamanlal J.; Shirsath, Vikas S.; Rathod, Ishwarsinh S.; Yande, Vikas D. [European Journal of Medicinal Chemistry, 2000, vol. 35, # 3, p. 351 - 358]
[14]Location in patent: scheme or table Azam, M. Afzal; Suresh, Bhojraj; Kalsi, Sandip S.; Antony, A. Shinesh [South African Journal of Chemistry, 2010, vol. 63, p. 114 - 122]
[15]Location in patent: scheme or table He, Hong-Wu; Yuan, Jun-Lin; Peng, Hao; Chen, Ting; Shen, Ping; Wan, Shu-Qing; Lee, Yanjun; Tan, Hong-Liang; He, Ya-Hui; He, Jun-Bo; Li, Yan [Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 9, p. 4801 - 4813]
[16]More, Uttam A.; Joshi, Shrinivas D.; Aminabhavi, Tejraj M.; Gadad, Andanappa K.; Nadagouda, Mallikarjuna N.; Kulkarni, Venkatrao H. [European Journal of Medicinal Chemistry, 2014, vol. 71, p. 199 - 218]
[17]He, Jun-Bo; Ren, Yan-Liang; Sun, Qiu-Shuang; You, Ge-Yun; Zhang, Li; Zou, Peng; Feng, Ling-Ling; Wan, Jian; He, Hong-Wu [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 12, p. 3180 - 3186]
[18]Joshi, Shrinivas D.; More, Uttam A.; Koli, Deepshikha; Kulkarni, Manoj S.; Nadagouda, Mallikarjuna N.; Aminabhavi, Tejraj M. [Bioorganic Chemistry, 2015, vol. 59, p. 151 - 167]
[19]Mo, Wenyan; Shi, Yanxia; He, Junbo; Li, Baoju; Peng, Hao; He, Hongwu [Journal of Heterocyclic Chemistry, 2016, vol. 53, # 1, p. 183 - 187]
[20]Meng, Defen; Xu, De; Li, Dong; Dai, Ming; Li, Guizhi; Guo, Dongcai [Research on Chemical Intermediates, 2016, vol. 42, # 6, p. 5269 - 5280]
[21]Devi, Vandna; Awasthi, Pamita [Journal of Biomolecular Structure and Dynamics, 2021]

4
[ 67028-40-4 ]
[ 940-64-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With ethanol; potassium hydroxide at 20℃; for 12h;	7 Preparation of 4-methylphenoxyacetic acid (4a) 4 g of methyl 4-methylphenylacetate (3a)Ethanol 20ml, 7.2% potassium hydroxide 5ml, to the reaction flask, room temperature reaction 12 hours, into 1N hydrochloric acid, precipitation of white solid, filter, infrared drying was 1.62g, the yield of 95%.
95%	With potassium hydroxide In ethanol at 20℃; for 12h;	9 4 - methyl phenoxy acetic acid (8 a) preparation of Add 4 - methyl ethyl acetate (7 a) 2 g, ethanol 20 ml, 7.2% potassium hydroxide 5 ml, to the reaction bottle, the reaction at room temperature for 12 hours, poured into 1 N in hydrochloric acid, precipitated white solid, filtered, infrared drying to obtain 1.62 g, yield 95%. MS (ESI): m/z=167 [M + H]+ .
94%	Stage #1: ethyl (4-methylphenoxy)acetate With ethanol; sodium hydroxide Reflux; Stage #2: With hydrogenchloride In water	5 p-Tolyloxy-acetic acid (S01 -136) (4a) : A solution of ethyl 2-(p-tolyloxy)acetate (3a) (0.4 g, 2.4 mmol) an 1 0 ml NaOH (1 M) and 10 ml ethanol was refluxed overnight. Ethanol was evaporated and aqueous solution was acidified with cone. HCI, the product was precipitated, filtered off and washed with water to give the pure compound S01 -136 4a as a white solid (0.34 g, 94%). 1 H NM R (400 M Hz, DMSO) δ 12.94 (s, 1 H), 7.05 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 4.59 (s, 2H), 2.20 (s, 3H).

94%	Stage #1: ethyl (4-methylphenoxy)acetate With sodium hydroxide for 2h; Reflux; Stage #2: With hydrogenchloride In water
93%	With sodium hydroxide In ethanol; water for 8h; Reflux;	4.1.1.2. General synthetic procedure for phenoxy acetic acid derivatives4(a-e). General procedure: The mixture of compounds ( 3a-e , 0.02 mol) was dissolvedin ethanol (15 ml), and sodium hydroxide (0.035 mmol) in water(5 ml) was added. The mixture was refluxed for eight h, and thereaction mixture was cooled and acidified with 3 N hydrochloricacids. The precipitate was filtered, washed with ice water, and finally recrystallized from ethanol to afford the compounds 4(a-e).
81%	With sodium hydroxide In ethanol Reflux;
81%	With sodium hydroxide In ethanol; water Reflux;	9 4.1.2.1 General synthetic procedure for phenoxyacetic acid analogues (4_a-j) General procedure: Compounds (3a-j,0.02mol) were dissolved in ethanol (15mL), sodium hydroxide (0.035mol) in water (5mL) was added, and the mixture was refluxed for 5-9h. The reaction mixture was cooled and acidified with 2N hydrochloric acid. The precipitate was filtered, washed with water, and finally recrystallized from methanol to afford desired compounds (4a-j). Compound (4a) is takenas a representative example to explain physical and characterization data.
81%	With ethanol; sodium hydroxide Reflux;	2.1.2. Synthetic procedure for 2-(p-tolyloxy)acetic acid (4) The phenoxy ester (3, 0.02 mol) was dissolved in ethanol (12 ml), 35% sodium hydroxide solution (2 ml) was added and the mixture was refluxed for 5-9 h. The reaction was monitored by TLC using hexane: ethyl acetate: methanol (6:3:1). The reaction mixture was cooled and quenched with 2 N hydrochloric acid [8]. The precipitate was filtered, washed with water, and finally recrystallized to afford the compound (4).
70%	With tetramethyl ammoniumhydroxide In tetrahydrofuran; water for 24h; Heating;
	With potassium hydroxide
	With lithium hydroxide In tetrahydrofuran; water at 20℃;
	With sodium hydroxide; water In methanol
	With water; lithium hydroxide In tetrahydrofuran
432 mg	Stage #1: ethyl (4-methylphenoxy)acetate With water; sodium hydroxide In methanol at 20℃; for 1h; Inert atmosphere; Stage #2: With hydrogenchloride In water Inert atmosphere;
	With sodium hydroxide In ethanol at 26℃; for 0.5h;	9.2 Step 2: 2-(p-tolyloxy)acetic acid To a solution of ethyl 2-(p-tolyloxy)acetate (200 mg, 1 mmol) in EtOH (10 ml) was added 10% NaOH solution(10 ml) at 26°C. The mixture was stirred for 30 min, concentrated then water (20 mL) added to it before washing with ethyl acetate (2x20 mL). The aqueous layer was acidified with 2N HCL until pH 3 and extracted with EA (2x20 ml) The organic layer was washed with brine (30 mL), dried over Na2S04 and concentrated to give the title compound which was used in next step without further purification.
	Stage #1: ethyl (4-methylphenoxy)acetate With sodium hydroxide In methanol; water for 1h; Stage #2: With hydrogenchloride In water
	With potassium hydroxide In ethanol; water at 20℃; for 1.5h;	General procedure for the synthesis of 5a-f General procedure: A mixture of phenols (0.3 mmol), acetone (10 ml), dimethylformamide(10 ml), ethyl chloroacetate (2.5 ml, 0.26 mmol), potassiumcarbonate (2 g) and potassium iodide (0.15 g) was heated at75 C for 12 h. Afterwards, the solid was filtered and the solventof the filtrate was removed in vacuo. The colorless liquid (4a-f)obtained was dissolved in ethanol (20 ml). A solution of potassiumhydroxide (7.2%, 5 ml) was added and stirred at room temperaturefor 1.5 h. The mixture was poured into hydrochloric acid (1 mol/L)and a white precipitate was formed. Purification by recrystallizationfrom methanol afforded the corresponding aryloxyl acid (5a-f)
	With water; lithium hydroxide
	With ethanol; sodium hydroxide at 26℃; for 0.5h;	9.2 Step 2: 2-(p-tolyloxy)acetic Acid To a solution of 70 ethyl 2-(p-tolyloxy)acetate (200 mg, 1 mmol) in 8 EtOH (10 ml) was added 10% 42 NaOH solution (10 ml) at 26° C. The mixture was stirred for 30 min, concentrated then 43 water (20 mL) added to it before washing with ethyl acetate (2×20 mL). The aqueous layer was acidified with 2N HCL until pH 3 and extracted with EA (2×20 ml). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give the 72 title compound which was used in next step without further purification.
	With sodium hydroxide In ethanol	2.2. Synthesis Synthesis of 2-(phenoxy)-N-(4-(4-chlorophenyl) thiazol-2-yl)acetamide derivatives were implemented as shown in Scheme 1.Initially with the dry acetone as the solvent obtained ethyl 2-phenoxyacetate, which has been hydrolyzed with the solution ofsodium hydroxide to provide 2-phenoxyacetic acid, the esterificationof phenols with ethylchloroacetate are done with anhydrouspotassium carbonate. The final compounds were synthesized byjoining 2-phenoxyacetic acid with 4-(4-chlorophenyl) thiazol-2-amine by using dichloromethane as a solvent and 2,6-lutidine asa base as well as o-(benzotriazol-1-yl)-N,N,N',N'- tetra methyluranium tetra fluoro borate as coupling agent. The reaction wasmonitored by thin layer chromatography. The spectral data for thefinal compounds 6a and 6b are presented in the SupplementaryMaterial (Fig. S1-S8).
	With sodium hydroxide In ethanol

Reference： [1]Current Patent Assignee: NANJING HUAMAI BIO PHARMACEUTICAL TECH - CN106146450, 2016, A Location in patent: Paragraph 0069; 0070; 0071
[2]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN104672192, 2017, B Location in patent: Paragraph 0075; 0076; 0077
[3]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2012/129564, 2012, A2 Location in patent: Page/Page column 56
[4]Ozcan, Sevil; Kazi, Aslamuzzaman; Marsilio, Frank; Fang, Bin; Guida, Wayne C.; Koomen, John; Lawrence, Harshani R.; Sebti, Saïd M. [Journal of Medicinal Chemistry, 2013, vol. 56, # 10, p. 3783 - 3805]
[5]M, Pallavi H; Al-Ostoot, Fares Hezam; Vivek, Hamse Kameshwar; Khanum, Shaukath Ara [Journal of Molecular Structure, 2022, vol. 1247]
[6]Eissa Mohammed, Yasser Hussein; Thirusangu, Prabhu; Zabiulla; Vigneshwaran; B.T, Prabhakar; Khanum, Shaukath Ara [Biomedicine and Pharmacotherapy, 2017, vol. 95, p. 375 - 386]
[7]Mohammed, Yasser Hussein Eissa; Malojirao, Vikas H.; Thirusangu, Prabhu; Al-Ghorbani, Mohammed; Prabhakar; Khanum, Shaukath Ara [European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1826 - 1839]
[8]Sallam, Hamdi Hamid; Mohammed, Yasser Hussien Eissa; Geetha; Al-Ostoot, Fares Hezam; Sridhar; Shaukath, Ara Khanum [Molecular Crystals and Liquid Crystals, 2021, vol. 725, # 1, p. 25 - 44]
[9]Ito, Kazuaki; Takasawa, Toshiro; Ohba, Yoshihiro [Synthetic Communications, 2002, vol. 32, # 24, p. 3839 - 3849]
[10]Vig,O.P. et al. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1979, vol. 18, p. 69 - 70]
[11]Lee, Kyeong; Lee, Jeong Hyung; Boovanahalli, Shanthaveerappa K.; Jin, Yinglan; Lee, Mijeoung; Jin, Xuejun; Kim, Jin Hwan; Hong, Young-Soo; Lee, Jung Joon [Journal of Medicinal Chemistry, 2007, vol. 50, # 7, p. 1675 - 1684]
[12]Location in patent: scheme or table Hidaka, Koushi; Kimura, Tooru; Ruben, Adam J.; Uemura, Tsuyoshi; Kamiya, Mami; Kiso, Aiko; Okamoto, Tetsuya; Tsuchiya, Yumi; Hayashi, Yoshio; Freire, Ernesto; Kiso, Yoshiaki [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 23, p. 10049 - 10060]
[13]Location in patent: scheme or table Shimizu, Kazuki; Maruyama, Minako; Yasui, Yuka; Minegishi, Hidemitsu; Ban, Hyun Seung; Nakamura, Hiroyuki [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 4, p. 1453 - 1456]
[14]Leung, Joe C. T.; Chatalova-Sazepin, Claire; West, Julian G.; Rueda-Becerril, Montserrat; Paquin, Jean-François; Sammis, Glenn M. [Angewandte Chemie - International Edition, 2012, vol. 51, # 43, p. 10804 - 10807][Angewandte Chemie, 2012, vol. 124, # 43, p. 10962 - 10965]
[15]Current Patent Assignee: EPIZYME, INC. - WO2014/100730, 2014, A1 Location in patent: Paragraph 00267
[16]Leung, Joe C. T.; Sammis, Glenn M. [European Journal of Organic Chemistry, 2015, vol. 2015, # 10, p. 2197 - 2204]
[17]Wang, Wenbin; He, Yi; Xu, Pei; You, Qidong; Xiao, Hong; Xiang, Hua [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 4428 - 4433]
[18]Naik, Ravi; Ban, Hyun Seung; Jang, Kyusic; Kim, Inhyub; Xu, Xuezhen; Harmalkar, Dipesh; Shin, Seong-Ah; Kim, Minkyoung; Kim, Bo-Kyung; Park, Jaehyung; Ku, Bonsu; Oh, Sujin; Won, Misun; Lee, Kyeong [Journal of Medicinal Chemistry, 2017, vol. 60, # 20, p. 8631 - 8646]
[19]Current Patent Assignee: EPIZYME, INC. - US2019/83482, 2019, A1 Location in patent: Paragraph 0248-0249
[20]Khamees, Hussien Ahmed; Mohammed, Yasser Hussein Eissa; S, Ananda; Al-Ostoot, Fares Hezam; Y, Sangappa; Alghamdi, Saad; Khanum, Shaukath Ara; Madegowda, Mahendra [Journal of Molecular Structure, 2020, vol. 1199]
[21]Al-Ostoot, Fares Hezam; Khanum, Shaukath Ara; M. A., Sridhar; Mohammed, Yasser Hussien Issa; Sallam, Hamdi Hamid [Journal of Molecular Structure, 2021, vol. 1246]

5
[ 940-64-7 ]
[ 126771-41-3 ]

Yield	Reaction Conditions	Operation in experiment
55%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In chloroform Heating;
	With N-Bromosuccinimide; dibenzoyl peroxide In P₂ O₅; chloroform	1 Preparation of 4-Bromomethylphenoxyacetic acid (b) EXAMPLE 1 Preparation of 4-Bromomethylphenoxyacetic acid (b) To 4-methylphenoxyacetic acid (87.3 g, 0.525 mole) and N-bromosuccinimide (112.2 g. 0.63 mole) was added 900 ml of dry CHCl3 and 100 mg benzoyl peroxide and the mixture was refluxed for 2.5 hours. The mixture was allowed to cool and was stored overnight at 4°. The crystals which had formed were collected by vacuum filtration and were washed twice with 50 ml of ice-cold CHCl3 followed by 50 ml washes with water. After drying in vacuo over P2 O5 to a constant weight, 52.9 g of white product (mp 122°-4° C.) were obtained. To obtain additional product, the organic mother liquor was washed with water (3*150 ml), and 150 ml brine. After drying over Na2 SO4 and filtration, the solvent was removed in vacuo and the residue crystallized from 90 ml boiling CHCl3. The crystals were collected by vacuum filtration, washed three times with 20 ml of CHCl3 /hexanes (1:1) and dried in vacuo to give 17.6 g of additional product (mp 121°-2° C.). Total yield, 70.5 g (55%). The product displayed an Rf =0.33 upon TLC (silica gel 60) developed with 95:5 CHCl3:acetic acid. 1 H NMR (300 MHz, CDCl3, ppm δ relative to tetramethylsilane):4.41 (s,2H), 4.62 (s, 2H), 6.24 (broad s, 1H), 6.82 (d, J=8.7 Hz, 2H), 7.28 (d, J-8.7 Hz, 2H).

Reference： [1]Bernatowicz, Michael S.; Kearney, Thomas; Neves, Richard S.; Koester, Hubert [Tetrahedron Letters, 1989, vol. 30, # 33, p. 4341 - 4344]
[2]Current Patent Assignee: THERMO FISHER SCIENTIFIC INC - US5187270, 1993, A

6
[ 38768-63-7 ]
[ 940-64-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium hydroxide In methanol at 35℃; for 1h;
	With Alkaline; water at 15℃; ΔH(excit.), ΔS(excit.), velocity const., E_A; also at 10 and 20 deg C;
	With sodium hydroxide In methanol

	With water; sodium hydroxide Microwave irradiation;
	With water; lithium hydroxide In methanol at 20℃;
	With lithium hydroxide In methanol; water at 50℃; for 12h;

Reference： [1]Khurana, Jitender M.; Chauhan, Sushma; Bansal, Geeti [Monatshefte fur Chemie, 2004, vol. 135, # 1, p. 83 - 87]
[2]Gurumurthy, R.; Balakrishnan, N. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1982, vol. 21, # 2, p. 154 - 156]
[3]Mimoto, Tsutomu; Kato, Ryohei; Takaku, Haruo; Nojima, Satoshi; Terashima, Keisuke; Misawa, Satoru; Fukazawa, Tominaga; Ueno, Takamasa; Sato, Hideharu; Shintani, Makoto; Kiso, Yoshiaki; Hayashi, Hideya [Journal of Medicinal Chemistry, 1999, vol. 42, # 10, p. 1789 - 1802]
[4]Location in patent: scheme or table Wei, Tai-Bao; Hua, Mao-Tang; Shi, Hai-Xiong; Liu, Yong; Zhang, You-Ming [Journal of Chemical Research, 2010, # 8, p. 452 - 454]
[5]Manley, David W.; Mills, Andrew; O'Rourke, Christopher; Slawin, Alexandra M. Z.; Walton, John C. [Chemistry - A European Journal, 2014, vol. 20, # 18, p. 5492 - 5500]
[6]Lei, Kang; Li, Pan; Yang, Xue-Fang; Wang, Shi-Ben; Wang, Xue-Kun; Hua, Xue-Wen; Sun, Bin; Ji, Lu-Sha; Xu, Xiao-Hua [Journal of Agricultural and Food Chemistry, 2019, vol. 67, # 37, p. 10489 - 10497]

7
[ 940-64-7 ]
[ 95-54-5 ]
[ 3156-25-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride Heating;
	With hydrogenchloride Microwave irradiation;
	With hydrogenchloride In lithium hydroxide monohydrate for 0.25h; Microwave irradiation;

	With hydrogenchloride
	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]Murray, Michael; Ryan, Adrian J.; Little, Peter J. [Journal of Medicinal Chemistry, 1982, vol. 25, # 8, p. 887 - 892]
[2]Location in patent: scheme or table Wei, Tai-Bao; Hua, Mao-Tang; Shi, Hai-Xiong; Liu, Yong; Zhang, You-Ming [Journal of Chemical Research, 2010, # 8, p. 452 - 454]
[3]Wu, Jiacheng; Zhao, Li; Zhao, Changqing; Wang, Zhiyuan; Gu, Haibin; Chen, Wuyong [Journal of the Chemical Society of Pakistan, 2016, vol. 38, # 5, p. 974 - 980]
[4]Zhao, Li; Qiu, Guirong; Wu, Jiacheng; Wang, Zhiyuan; Gu, Haibin [Journal of the Chemical Society of Pakistan, 2017, vol. 39, # 4, p. 628 - 639]
[5]Ersan, Ronak Haj; Kuzu, Burak; Yetkin, Derya; Alagoz, Mehmet Abdullah; Dogen, Aylin; Burmaoglu, Serdar; Algul, Oztekin [Medicinal Chemistry Research, 2022, vol. 31, # 7, p. 1192 - 1208]
[6]Ersan, Ronak Haj; Kuzu, Burak; Yetkin, Derya; Alagoz, Mehmet Abdullah; Dogen, Aylin; Burmaoglu, Serdar; Algul, Oztekin [Medicinal Chemistry Research, 2022, vol. 31, # 7, p. 1192 - 1208]

8
[ 1878-94-0 ]
[ 993-15-7 ]
[ 940-64-7 ]

Reference： [1]Tetrahedron Letters,1995,vol. 36,p. 125 - 128

9
[ 64-17-5 ]
[ 940-64-7 ]
[ 67028-40-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With acetyl chloride at 80℃; for 24h; Cooling with ice;
	With sulfuric acid
	With toluene-4-sulfonic acid for 5h; Heating;

	With hydrogenchloride Reflux;	4.2. General procedure for the synthesis of ethyl aromatic esters (8a-s) General procedure: Each substituted benzoic acid or aroyloxy acetic acid (7a-s) 0.088 mol was refluxed for 2-12 h in 2.4 mol of HCl gas saturated anhydrous ethanol. Then a hot solution was poured into 300 mL of water (no hydrochloride separates) to which solid Na2CO3 was added until the solution turns neutral. Precipitated ester was filtered by suction, dried and recrystallized from ethanol or methanol. In case of liquid esters, the neutralized solution was extracted with chloroform (25 mL x 3), the combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a clear liquid.
	With sulfuric acid for 6h; Reflux;	Synthesis of Substituted Aryloxy hydrazide 5(a-g) General procedure: The substituted acid (0.1 mole) and ethanol (50 ml) were taken with a few drops of concentrated sulfuric acid and it was refluxed for 6 hours.The reaction mixture was concentrated bydistilling of the excess of ethanol under reduced pressure and treated with a saturated solution of sodium bicarbonate. The ester obtained used for the preparation of hydrazide directly. The ester(0.1 mole) was dissolved in appropriate quantity of ethanol and to this hydrazine hydrate (0.1 mole) was added. The reaction mixture was taken in a round bottomed flask and refluxed for a period of 12-18 hours. Excess of ethanol was distilled off under reduced pressure. It was then poured into ice cold water and the solid obtained was filtered. It was crystallized from ethanol.
	With acetyl chloride for 24h; Cooling with ice; Reflux;	Synthesis of Phenoxyacetohydrazide Derivatives (D1-7) General procedure: Compounds D1-7 were prepared by similar procedures. In atypical synthesis of D1, a mixture of phenoxyacetate(10 mmol, 1.80 g), hydrazine hydrate (80 %, 5 mL) and absoluteethanol (30 mL) was added to a 150 mL three-neckflask, then the reaction mixture was refluxed for 5 h. Themixture was cooled to room temperature. The crude productwas collected by filtration and washed several times with ethanol.After drying, white needle crystal was recrystallizedfrom ethanol and dried in vacuum
	With acetyl chloride at 80℃; for 20h;
	With sulfuric acid In water for 3h; Reflux;	General method for the synthesis of substituted esters(2a-c): General procedure: Substituted aromatic acids (1a-c) (1 mmol) weredissolved in 5 mL of ethanol and refluxed for 3 h in the catalyticamount of concentrated sulfuric acid. Reaction completion wasobserved by TLC (toluene:ethyl acetate = 7:3). Ethanol wasevaporated and the resulting mass was neutralized with 5%NaHCO3. The product was extracted into ether, washed withwater and the ether was evaporated to get the product (2a-c),which was taken directly for the second step

Reference： [1]Wu, Yongqiang; Guo, Tiantong; Shu, Dehua; Zhang, Wu; Luan, Fangfei; Shi, Ling; Guo, Dongcai [Luminescence, 2018, vol. 33, # 5, p. 855 - 862]
[2]Osman; Botros; Kandeel; Khalil; Abd El-Latif [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1996, vol. 35, # 5, p. 446 - 455]
[3]Shi; Shi; Wang [Journal of Heterocyclic Chemistry, 2001, vol. 38, # 4, p. 929 - 932]
[4]More, Uttam A.; Joshi, Shrinivas D.; Aminabhavi, Tejraj M.; Gadad, Andanappa K.; Nadagouda, Mallikarjuna N.; Kulkarni, Venkatrao H. [European Journal of Medicinal Chemistry, 2014, vol. 71, p. 199 - 218]
[5]Kumar, P. Sudhir; Sahoo [Oriental Journal of Chemistry, 2014, vol. 30, # 1, p. 211 - 217]
[6]Yan, Dong; Li, Dong; Cheng, Guang; Yang, Zehui; Shi, Ling; Guo, Dongcai [Journal of Fluorescence, 2015, vol. 25, # 4, p. 849 - 859]
[7]Xiao, Haihua; Jiang, Xi; Li, Dong; Wu, Limin; Zhang, Wu; Guo, Dongcai [Luminescence, 2015, vol. 30, # 5, p. 677 - 685]
[8]Gaonkar, Santosh L.; Hakkimane, Sushruta S.; Nayak, Swarnagowri; Shetty, Nitinkumar S.; Swapna, B. [Asian Journal of Chemistry, 2021, vol. 33, # 12, p. 3039 - 3046]

10
[ 940-64-7 ]
[ 158941-63-0 ]
3-[2-hydroxy-4-phenyl-3-(2-p-tolyloxy-acetylamino)-butyryl]-thiazolidine-4-carboxylic acid tert-butylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide

Reference： [1]Mimoto, Tsutomu; Kato, Ryohei; Takaku, Haruo; Nojima, Satoshi; Terashima, Keisuke; Misawa, Satoru; Fukazawa, Tominaga; Ueno, Takamasa; Sato, Hideharu; Shintani, Makoto; Kiso, Yoshiaki; Hayashi, Hideya [Journal of Medicinal Chemistry, 1999, vol. 42, # 10, p. 1789 - 1802]

11
[ 940-64-7 ]
[ 36304-39-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate In methanol for 25h; Heating;
	With sulfuric acid; hydrazine hydrate In ethanol
	Multi-step reaction with 2 steps 1: p-toluenesulfonic acid / 5 h / Heating 2: hydrazine hydrate / ethanol / 3 h / Heating

	Multi-step reaction with 2 steps 1: conc. sulphuric acid 2: hydrazine hydrate
	Multi-step reaction with 2 steps 1: hydrogenchloride / Reflux 2: hydrazine hydrate / Reflux
	Multi-step reaction with 2 steps 1: sulfuric acid / 6 h / Reflux 2: hydrazine hydrate / ethanol / Reflux
	Multi-step reaction with 2 steps 1: acetyl chloride / 24 h / Cooling with ice; Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux
	Multi-step reaction with 2 steps 1: acetyl chloride / 20 h / 80 °C 2: hydrazine hydrate / ethanol / 6 h / 85 °C
	Multi-step reaction with 2 steps 1: acetyl chloride / 24 h / 80 °C / Cooling with ice 2: hydrazine hydrate / ethanol / 85 °C
	Multi-step reaction with 2 steps 1: sulfuric acid / water / 3 h / Reflux 2: hydrazine hydrate / ethanol / Reflux

Reference： [1]Bhat; Bhat; Shenoy [Journal of Pharmacy and Pharmacology, 2001, vol. 53, # 2, p. 267 - 272]
[2]Karthikeyan, Mari Sithambaram; Holla, Bantwal Shivarama; Kumari, Nalilu Suchetha [European Journal of Medicinal Chemistry, 2007, vol. 42, # 1, p. 30 - 36]
[3]Shi; Shi; Wang [Journal of Heterocyclic Chemistry, 2001, vol. 38, # 4, p. 929 - 932]
[4]Osman; Botros; Kandeel; Khalil; Abd El-Latif [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1996, vol. 35, # 5, p. 446 - 455]
[5]More, Uttam A.; Joshi, Shrinivas D.; Aminabhavi, Tejraj M.; Gadad, Andanappa K.; Nadagouda, Mallikarjuna N.; Kulkarni, Venkatrao H. [European Journal of Medicinal Chemistry, 2014, vol. 71, p. 199 - 218]
[6]Kumar, P. Sudhir; Sahoo [Oriental Journal of Chemistry, 2014, vol. 30, # 1, p. 211 - 217]
[7]Yan, Dong; Li, Dong; Cheng, Guang; Yang, Zehui; Shi, Ling; Guo, Dongcai [Journal of Fluorescence, 2015, vol. 25, # 4, p. 849 - 859]
[8]Xiao, Haihua; Jiang, Xi; Li, Dong; Wu, Limin; Zhang, Wu; Guo, Dongcai [Luminescence, 2015, vol. 30, # 5, p. 677 - 685]
[9]Wu, Yongqiang; Guo, Tiantong; Shu, Dehua; Zhang, Wu; Luan, Fangfei; Shi, Ling; Guo, Dongcai [Luminescence, 2018, vol. 33, # 5, p. 855 - 862]
[10]Gaonkar, Santosh L.; Hakkimane, Sushruta S.; Nayak, Swarnagowri; Shetty, Nitinkumar S.; Swapna, B. [Asian Journal of Chemistry, 2021, vol. 33, # 12, p. 3039 - 3046]

12
[ 940-64-7 ]
[ 713517-90-9 ]
5-(2,6-dichloro-benzyl)-9b-phenyl-1-p-tolyloxy-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine In dichloromethane at 0 - 20℃;

Reference： [1]Bolli, Martin H.; Marfurt, Judith; Grisostomi, Corinna; Boss, Christoph; Binkert, Christoph; Hess, Patrick; Treiber, Alexander; Thorin, Eric; Morrison, Keith; Buchmann, Stephan; Bur, Daniel; Ramuz, Henri; Clozel, Martine; Fischli, Walter; Weller, Thomas [Journal of Medicinal Chemistry, 2004, vol. 47, # 11, p. 2776 - 2795]

13
[ 940-64-7 ]
[ 79-19-6 ]
[ 84138-77-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	With poly(ethylene glycol) supported dichlorophosphate at 120℃; for 0.133333h; microwave irradiation;
53%	Stage #1: 2-(4-methylphenoxy)acetic acid; thiosemicarbazide With trichlorophosphate for 0.5h; Reflux; Stage #2: With water for 4h; Reflux;
	With poly(ethylene glycol)-supported dichlorophosphate at 120℃; microwave irradiation;

Stage #1: 2-(4-methylphenoxy)acetic acid; thiosemicarbazide With trichlorophosphate at 75℃; for 0.5h; Stage #2: In water for 4h; Reflux;

General procedure for the preparation of 2-((phenoxy orsubstituted phenoxy)methyl/ethyl)-1,3,4-thiadiazol-5-amines (4a-qand 5a-q) General procedure: A mixture of benzoic acid (50 mmol), N-aminothiourea(50 mmol) and POCl3 (13 mL) was heated at 75 C for 0.5 h. Themixture was cooled to which water (10 mL) was added and thereaction mixture was refluxed for 4 h. The mixture was cooled and pH was adjusted to 8.0 by adding 50% sodium hydroxide solution.The separated solid was filtered and recrystallized from ethanolto give desired compounds.

Reference： [1]Li, Zheng; Yu, Jin-Lan; Yang, Jing-Ya; Shi, Sheng-Yi; Wang, Xi-Cun [Journal of Chemical Research, 2005, # 5, p. 341 - 343]
[2]Location in patent: experimental part Azam, M. Afzal; Suresh, Bhojraj; Kalsi, Sandip S.; Antony, A. Shinesh [South African Journal of Chemistry, 2010, vol. 63, p. 114 - 122]
[3]Li, Zheng; Yu, Jin-Lan; Yang, Jing-Ya; Zhu, Wei; Zhao, Yan-Long; Xing, Yu-Lin; Wang, Xi-Cun [Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 1, p. 183 - 190]
[4]Joshi, Shrinivas D.; More, Uttam A.; Koli, Deepshikha; Kulkarni, Manoj S.; Nadagouda, Mallikarjuna N.; Aminabhavi, Tejraj M. [Bioorganic Chemistry, 2015, vol. 59, p. 151 - 167]

14
[ 5411-58-5 ]
[ 940-64-7 ]
[ 889665-08-1 ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: 2-(4-methylphenoxy)acetic acid With lithium diisopropyl amide In tetrahydrofuran at -72℃; for 0.666667h; Stage #2: ethyl N,N-diethyloxamate With hydrogenchloride In tetrahydrofuran

Reference： [1]Ma, Chicheng; Chen, Yugang; Steinmetz, Mark G. [Journal of Organic Chemistry, 2006, vol. 71, # 11, p. 4206 - 4215]

15
[ 940-64-7 ]
[ 120313-13-5 ]
[ 889665-10-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: 2-(4-methylphenoxy)acetic acid With lithium diisopropyl amide In tetrahydrofuran at -72℃; Stage #2: ethyl 2-(diisopropylamino)-2-oxoacetate With hydrogenchloride In tetrahydrofuran

Reference： [1]Ma, Chicheng; Chen, Yugang; Steinmetz, Mark G. [Journal of Organic Chemistry, 2006, vol. 71, # 11, p. 4206 - 4215]

16
[ 940-64-7 ]
[ 3544-24-9 ]
3-(2-p-tolyloxy-acetyl-amino)-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	<Example 31> 3-(2-p-tolyloxy-acetyl-amino)-benzamideTo a solution of (4-methyl-phenoxy)-acetic acid (100 mg, 0.6 mmol), 3-amino benzamide (163.86 mg, 12' mmol), HOBT (162 mg, 1.2 mmol) and DJJPEA (155 mg, 1.2 mmol) in DMF (6 ml) was added EDC (230.8 mg, 1.2 mmol) at room temperature and the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with a mixture of MeOH : MC (10%), separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified flash chromatography on silica gel (MeOH : MC = 1 :9 ~ 2:8) to afford of 3-[2-(4-tert-buryl- phenoxy)-acetylamino]-benzamide as a colorless solid (133 mg, 78% yield).1H NMR (DMSO-d6, 300 MHz) 10.16(1H, s, CONH), 8.09(1H, s, aromatic), 7.93(1H, s, aromatic), 7.80(1H, d, J=8.1 Hz, aromatic), 7.56(1H, d, J=8.1 Hz, aromatic), 7.37(2H, m, CONH2), 7.10(2H, d, J=8.7 Hz, aromatic), 6.90(2H, d, J =8.4 Hz, aromatic), 4.65(1H, s, OCH2), 2.23(3H, s, CH3).
78%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	To a solution of (4-methyl-phenoxyacetic acid (100 mg, 0.6 mmol), 3-amino benzamide (163.86 mg, 1.2 mmol), HOBT (162 mg, 1.2 mmol) and DIPEA (155 mg, 1.2 mmol) in DMF (6 ml) was added EDC (230.8 mg, 1.2 mmol) at room temperature and the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with a mixture of MeOH:MC (10%), separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified flash chromatography on silica gel (MeOH:MC=1:9~2:8) to afford of 3-[2-(4-tert-butyl-phenoxy)-acetylamino]-benzamide as a colorless solid (133 mg, 78% yield). 1H NMR (DMSO-d6, 300 MHz) 10.16 (1H, s, CONH), 8.09 (1H, s, aromatic), 7.93 (1H, s, aromatic), 7.80 (1H, d, J=8.1 Hz, aromatic), 7.56 (1H, d, J=8.1 Hz, aromatic), 7.37 (2H, m, CONH2), 7.10 (2H, d, J=8.7 Hz, aromatic), 6.90 (2H, d, J=8.4 Hr; aromatic), 4.65 (1H, s, OCH2), 2.23 (3H, s, CH3).

Reference： [1]Patent: WO2008/4798,2008,A1 .Location in patent: Page/Page column 36
[2]Patent: US2009/306078,2009,A1 .Location in patent: Page/Page column 29-30
[3]Journal of Medicinal Chemistry,2007,vol. 50,p. 1675 - 1684

17
[ 106-44-5 ]
[ 940-64-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / dimethylformamide / 20 °C 2: lithium hydroxide monohydrate / tetrahydrofuran; H₂O / 20 °C
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / Reflux 2: sodium hydroxide; ethanol / Reflux
	Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 1 h / 20 °C / Inert atmosphere 2.2: Inert atmosphere

	Multi-step reaction with 2 steps 1.1: potassium carbonate / acetone / 14 h / Reflux 2.1: sodium hydroxide / 2 h / Reflux 2.2: pH 1
	Multi-step reaction with 2 steps 1: potassium carbonate / tetrahydrofuran / 20 - 80 °C 2: lithium hydroxide; water / methanol / 20 °C
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 4 h / 80 °C 2: sodium hydroxide / ethanol / 0.5 h / 26 °C
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 20 °C 2: sodium hydroxide / water; methanol / 1 h
	Multi-step reaction with 2 steps 1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide / 12 h / 75 °C 2: potassium hydroxide / ethanol; water / 1.5 h / 20 °C
	Multi-step reaction with 2 steps 1: sodium hydroxide / water / 8 h / Reflux 2: hydrogenchloride / water / pH 1
	Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / acetone; N,N-dimethyl-formamide / 12 h / Reflux 2: potassium hydroxide; ethanol / 12 h / 20 °C
	Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / acetone / 12 h / Reflux 2: potassium hydroxide / ethanol / 12 h / 20 °C
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 10 h / Reflux 2: sodium hydroxide / ethanol / Reflux
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide 2: water; lithium hydroxide
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / Reflux 2: sodium hydroxide / ethanol; water / Reflux
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 4 h / 80 °C 2: sodium hydroxide; ethanol / 0.5 h / 26 °C
	Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 50 °C 1.2: 12 h / 50 °C 2.1: lithium hydroxide / methanol; water / 12 h / 50 °C
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone 2: sodium hydroxide / ethanol
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone 2: sodium hydroxide / ethanol
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 10 h / Reflux 2: sodium hydroxide / ethanol; water / 8 h / Reflux
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 10 h / 70 °C 2: sodium hydroxide; ethanol / Reflux

Reference： [1]Lee, Kyeong; Lee, Jeong Hyung; Boovanahalli, Shanthaveerappa K.; Jin, Yinglan; Lee, Mijeoung; Jin, Xuejun; Kim, Jin Hwan; Hong, Young-Soo; Lee, Jung Joon [Journal of Medicinal Chemistry, 2007, vol. 50, # 7, p. 1675 - 1684]
[2]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2012/129564, 2012, A2
[3]Leung, Joe C. T.; Chatalova-Sazepin, Claire; West, Julian G.; Rueda-Becerril, Montserrat; Paquin, Jean-François; Sammis, Glenn M. [Angewandte Chemie - International Edition, 2012, vol. 51, # 43, p. 10804 - 10807][Angewandte Chemie, 2012, vol. 124, # 43, p. 10962 - 10965]
[4]Ozcan, Sevil; Kazi, Aslamuzzaman; Marsilio, Frank; Fang, Bin; Guida, Wayne C.; Koomen, John; Lawrence, Harshani R.; Sebti, Saïd M. [Journal of Medicinal Chemistry, 2013, vol. 56, # 10, p. 3783 - 3805]
[5]Manley, David W.; Mills, Andrew; O'Rourke, Christopher; Slawin, Alexandra M. Z.; Walton, John C. [Chemistry - A European Journal, 2014, vol. 20, # 18, p. 5492 - 5500]
[6]Current Patent Assignee: EPIZYME, INC. - WO2014/100730, 2014, A1
[7]Leung, Joe C. T.; Sammis, Glenn M. [European Journal of Organic Chemistry, 2015, vol. 2015, # 10, p. 2197 - 2204]
[8]Wang, Wenbin; He, Yi; Xu, Pei; You, Qidong; Xiao, Hong; Xiang, Hua [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 4428 - 4433]
[9]He, Xingrui; Yu, Zhaonan; Jiang, Shaojie; Zhang, Peizhi; Shang, Zhicai; Lou, Yonggen; Wu, Jun [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5601 - 5603]
[10]Current Patent Assignee: NANJING HUAMAI BIO PHARMACEUTICAL TECH - CN106146450, 2016, A
[11]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN104672192, 2017, B
[12]Eissa Mohammed, Yasser Hussein; Thirusangu, Prabhu; Zabiulla; Vigneshwaran; B.T, Prabhakar; Khanum, Shaukath Ara [Biomedicine and Pharmacotherapy, 2017, vol. 95, p. 375 - 386]
[13]Naik, Ravi; Ban, Hyun Seung; Jang, Kyusic; Kim, Inhyub; Xu, Xuezhen; Harmalkar, Dipesh; Shin, Seong-Ah; Kim, Minkyoung; Kim, Bo-Kyung; Park, Jaehyung; Ku, Bonsu; Oh, Sujin; Won, Misun; Lee, Kyeong [Journal of Medicinal Chemistry, 2017, vol. 60, # 20, p. 8631 - 8646]
[14]Mohammed, Yasser Hussein Eissa; Malojirao, Vikas H.; Thirusangu, Prabhu; Al-Ghorbani, Mohammed; Prabhakar; Khanum, Shaukath Ara [European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1826 - 1839]
[15]Current Patent Assignee: EPIZYME, INC. - US2019/83482, 2019, A1
[16]Lei, Kang; Li, Pan; Yang, Xue-Fang; Wang, Shi-Ben; Wang, Xue-Kun; Hua, Xue-Wen; Sun, Bin; Ji, Lu-Sha; Xu, Xiao-Hua [Journal of Agricultural and Food Chemistry, 2019, vol. 67, # 37, p. 10489 - 10497]
[17]Khamees, Hussien Ahmed; Mohammed, Yasser Hussein Eissa; S, Ananda; Al-Ostoot, Fares Hezam; Y, Sangappa; Alghamdi, Saad; Khanum, Shaukath Ara; Madegowda, Mahendra [Journal of Molecular Structure, 2020, vol. 1199]
[18]Al-Ostoot, Fares Hezam; Khanum, Shaukath Ara; M. A., Sridhar; Mohammed, Yasser Hussien Issa; Sallam, Hamdi Hamid [Journal of Molecular Structure, 2021, vol. 1246]
[19]M, Pallavi H; Al-Ostoot, Fares Hezam; Vivek, Hamse Kameshwar; Khanum, Shaukath Ara [Journal of Molecular Structure, 2022, vol. 1247]
[20]Sallam, Hamdi Hamid; Mohammed, Yasser Hussien Eissa; Geetha; Al-Ostoot, Fares Hezam; Sridhar; Shaukath, Ara Khanum [Molecular Crystals and Liquid Crystals, 2021, vol. 725, # 1, p. 25 - 44]

18
[ 940-64-7 ]
[ 7689-03-4 ]
[ 401478-48-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 20h;	8.A Camptotbecin-20-O-ester of 4-methylphenoxyacetic acid (000518) The mixture of camptothecin (10 mg, 0.029 mmol), 4-methylphenoxyacetic acid (10 mg, 0.63 mmol), EDCI (28 mg, 0.15 mmol), DMAP (2 mg, 0.02 mmol) and dichloromethane (3 ml) was stirred in the room temperature for 20 h, then dichloromethane (20 ml) was added to the solution. Organic layer was washed with water (20 ml), saturated NaHCO3 aqueous solution (10 ml) and brine (20 ml), and then dried over MgSO4. After the solvent was removed under reduced pressure, the resulting solid was separated by column chromatography (eluent: CHCl3:CH3OH 9:1) to afford 12.5 mg camptothecin-20-O-4-methylphenoxyacetate, yield: 88.0%, mp 229-233° C. The chemical structure analysis was performed by 1HNMR (CDCl3, 600 MHz): δ 8.42 (s, 1H, Ar-H), 8.28 (d, 1H, Ar-H), 8.20 (d, 2H. Ar-H), 7.96 (t, 1H, Ar-H), 7.72 (t, 1H, Ar-H), 7.19 (s, 1H, Ar-H), 7.02 (d, 2H, Ar-H), 5.71 (d, 1H, H17), 5.42 (d, 1H, H17), 5.30 (q, 2H, H5), 4.99 (q, 2H, OCH2CO), 3.61 (s, 3H, OCH3), 2.25 (d, 2H, CH2), 0.97 (t, 3H, CH3).

Reference： [1]Current Patent Assignee: CALIFORNIA PACIFIC MEDICAL CENTER - US6350756, 2002, B1 Location in patent: Page column 29-30

19
[ 940-64-7 ]
[ 119-80-2 ]
1-methyl-4-carboxymethoxythioxanthone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.3%	With sulfuric acid at 10 - 40℃; for 4 - 5h;	6 Example 6; Preparation of 1-methyl-4-carboxymethoxythioxanthone Concentrated sulphuric acid (120 mls) and dithiobisbenzoic acid (12.2 g) were charged to a reactor and 4-methylphenoxyacetic acid (19.9 g) was added over 1 to 2 hours at 10° to 15°C with cooling. After stirring for a further 1 hour at 10° to 20°C, then at 30° to 40°C for 2 hours a deep red solution was obtained. This reaction mixture was then quenched onto water (250 mls) whilst allowing the temperature to rise to ∼80°C. The quenched mixture was stirred for a further 25 minutes at ∼80°C then cooled to 30°C. The resulting precipitate was filtered and then washed with water and dried. The resulting crude product was slurried in a mixture of water (60 mls), acetic acid (20 mls), and 2-butanone (30 mls) at reflux for 30 minutes, cooled to ambient temperature and filtered. The damp product cake was washed with a mixture of water and 2-butanone followed by water, then dried. 1-Methyl-4-carboxymethoxythioxanthone (14.0g) was obtained in 58.3% yield. This was a pale yellow powder, melting point 198° to 235°C.
	With sulfuric acid at 20℃; for 2h;

Reference： [1]Current Patent Assignee: LANXESS AG - EP1380580, 2004, A1 Location in patent: Page 6
[2]Turner, Keith [Organic Process Research and Development, 2006, vol. 10, # 3, p. 682 - 682]

20
[ 106-44-5 ]
[ 3926-62-3 ]
[ 940-64-7 ]

Yield	Reaction Conditions	Operation in experiment
87.5%	With sodium hydroxide In ethanol; water for 1h; Reflux;
80%	With sodium hydroxide In water at 20 - 60℃;
74%	Stage #1: p-cresol With sodium hydroxide In ethanol; water at 20℃; for 0.333333h; Stage #2: sodium monochloroacetic acid In ethanol; water at 102℃; for 5h;	Synthesis of phenoxyacetic acid derivative (b^1-7) General procedure: 55mmol monochloroacetic acid was dissolved in 15mL deionized water under the condition of ice water bath, then 30% NaOH solution was used to adjust pH 8-9, sodium chloroacetate solution was obtained. 45mmol NaOH was dissolved in mixed solvent of 15mL deionized water and 5mL ethanol at room temperature with constant stirring, 45mmol phenol was subsequent slowly added. After stirring for another 20min, sodium chloroacetate solution was added. Subsequently, the mixture was refluxed at 102°C for 5h. After the mixture was cooled to room temperature, pH was adjusted to 1-2 with 2.0mol·L-1 HCl, amounts of white precipitations were gained. The precipitations were filtered and washed 3 times with dilute hydrochloric acid, dried at 60°C. White crude product was dispersed in 100mL heated deionized water, pH was adjusted to 8.0 using saturated potassium carbonate solution, then mixture solution was filtered, and filtrate was collected. White precipitated was obtained by adjusting pH of filtrate to 1-2 with 2.0mol·L-1 HCl. After cooled down to room temperature naturally, the mixture was filtered, washed with dilute hydrochloric acid, dried overnight in vacuum, then target product (b1) was obtained. The synthetic procedures of phenoxyacetic acid derivative (b2-7) were similar to that of phenoxyacetic acid (b1).

69%	With sodium hydroxide In ethanol; water at 105℃; for 5h;
	With NaH In tetrahydrofuran; hexane; water; dimethyl sulfoxide	1 4-Methylphenoxyacetic acid STR5 EXAMPLE 1 4-Methylphenoxyacetic acid STR5 Sodium hydride (0.86 g of 60% NaH in oil=0.516 g, 21.5 mmol) in oil dispersion was washed twice with 10 ml of hexane. THF was added (5 ml) and the mixture was cooled to -15° C. A solution of p-methylphenol (1.95 g, 18 mmol) in THF was then added, and the mixture was warmed to 25° C. for 1 hour. The THF was removed by distillation under vacuum and a solution of sodium chloroacetate (2.5 g, 22 mmol) in DMSO (50 ml) was added. The mixture was stirred at room temperature for 20 hours, then diluted with 300 ml. of water. The mixture was extracted twice with 50 ml. of hexane. The aqueous phase was acidified with 4N hydrochloric acid and the product was extracted twice with 100 ml. of ethyl acetate. The combined ethyl acetate layers were washed twice with 100 ml. water, dried over MgSO4, filtered, and the solvent was removed by distillation under reduced pressure to give 2.9 g of product as a white solid. Yield of product=97.6%.

Reference： [1]Location in patent: experimental part Han, Liang; Zhu, Qiong-Yan; Jia, Jian-Hong; Li, Yu-Jin; Gao, Jian-Rong [Asian Journal of Chemistry, 2012, vol. 24, # 3, p. 1223 - 1226]
[2]Location in patent: experimental part Jimenez, Fabiola; Cruz, Maria Del Carmen; Zuniga, Clara; Martinez, Maria A.; Chamorro, German; Diaz, Francisco; Tamariz, Joaquin [Medicinal Chemistry Research, 2010, vol. 19, # 1, p. 33 - 57]
[3]Li, Dewei; Xiong, Suhao; Guo, Tiantong; Shu, Dehua; Xiao, Haihua; Li, Guizhi; Guo, Dongcai [Dyes and Pigments, 2018, vol. 158, p. 28 - 35]
[4]Zhang, Wu; Chai, Yuchao; Li, Kangyun; Chen, Yanwen; Yan, Dong; Guo, Dongcai [Luminescence, 2014, vol. 29, # 8, p. 1113 - 1122]
[5]Current Patent Assignee: PFIZER INC - US4952724, 1990, A

21
[ 79-37-8 ]
[ 940-64-7 ]
[ 15516-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; N,N-dimethyl-formamide	R.20 (S)-4-Benzyl-3-[(4-methylphenoxy)acetyl]oxazolidin-2-one (S)-4-Benzyl-3-[(4-methylphenoxy)acetyl]oxazolidin-2-one Oxalyl chloride (8.83 ml) and N,N-dimethylformamide (3 drops) were added at room temperature to a solution of 4-methylphenoxyacetic acid (6.73 g) in dichloromethane (70 ml), and the reaction mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, then the resulting acidic gas was removed as the toluene azeotrope, and the product was dried under reduced pressure to give 4-methylphenoxyacetyl chloride.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1354602, 2003, A1

22
[ 940-64-7 ]
[ 106-44-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 2-(4-methylphenoxy)acetic acid With triethylamine In N,N-dimethyl-formamide; toluene for 3h; Heating; Stage #2: With potassium hydroxide; glycerol In ethanol; N,N-dimethyl-formamide; toluene for 2h; Heating; Further stages.;

Reference： [1]Spurg, Anke; Waldvogel, Siegfried R. [European Journal of Organic Chemistry, 2008, # 2, p. 337 - 342]

23
[ 10025-74-8 ]
[ 940-64-7 ]
dysprosium(III) 4-methylphenoxyacetate dihydrate [ No CAS ]

Reference： [1]Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical and Analytical,1986,vol. 25,p. 1156 - 1157

24
[ 13538-42-6 ]
[ 940-64-7 ]
2-(2-p-tolyloxy-acetylamino)-isonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.8%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	120 2-(2-p-tolyloxy-acetylamino)isonicotinamide A solution of 4 p-tolyloxy-acetic acid (60.1 mg, 0.36 mmol), 2-amino-isonicotinamide (74.1 mg, 0.54 mmol), DIPEA (0.12 ml, 0.72 mmol) and PyBOP (374.4 mg, 0.72 mmol) in DMF 5.0 mL was stirred, then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by Prep-TLC(CH2Cl2:MeOH=10:1) to give 2-(2-p-tolyloxy-acetylamino)-isonicotinamide as a white solid (68.5 mg, 66.8% yield). 1H-NMR (DMSO-d6, 300 Hz) 10.61 (1H, s, NH), 8.42-8.45 (2H, m, aromatic-H), 8.20 (1H, s, NH2), 7.68 (1H, s, NH2), 7.49-7.51 (1H, m, aromatic-H), 7.10 (2H, d, J=8.7 Hz, aromatic-H), 6.85-6.88 (2H, m, aromatic-H), 4.76 (2H, s, CH2), 2.23 (3H, s, CH3).

Reference： [1]Current Patent Assignee: KOREA RESEARCH INSTITUTE OF BIOSCIENCE AND BIOTECHNOLOGY - US2009/306078, 2009, A1 Location in patent: Page/Page column 53

25
[ 940-64-7 ]
[ 138-14-7 ]
[ 1149568-53-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;

Reference： [1]Location in patent: experimental part Liu, Joe; Obando, Daniel; Schipanski, Liam G.; Groebler, Ludwig K.; Witting, Paul K.; Kalinowski, Danuta S.; Richardson, Des R.; Codd, Rachel [Journal of Medicinal Chemistry, 2010, vol. 53, # 3, p. 1370 - 1382]

26
[ 940-64-7 ]
N-(thiophen-2-ylmethyl)propyl-1-amine [ No CAS ]
[ 1374761-34-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 100℃; for 0.166667h; microwave irradiation; Capped vial;	156 Prepared in a similar manner to example 5 from 2-(p-tolyloxy)acetic acid and N-(thiophen-2- ylmethyl)propan-l -amine. 1H NMR (400 MHz, DMSO-d6) δ 0.89 - 0.75 (m, 3H), 1.53 - 1.31 (m, 2H), 2.17 (s, 3H), 3.66 - 3.52 (m, 2H), 4.30 (br s, 2H), 6.58 (d, J= 8.1 Hz, 2H), 7.00 (d, J= 8.2 Hz, 2H), 7.51 - 7.35 (m, 5H); M+H(304.1).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 100℃; for 0.166667h; Microwave irradiation;

Reference： [1]Current Patent Assignee: Firmenich International SA - WO2012/61698, 2012, A2 Location in patent: Page/Page column 134
[2]Noncovich, Alain; Priest, Chad; Ung, Jane; Patron, Andrew P.; Servant, Guy; Brust, Paul; Servant, Nicole; Faber, Nathan; Liu, Hanghui; Gonsalves, Nicole S.; Ditschun, Tanya L. [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 16, p. 3931 - 3938]

27
[ 940-64-7 ]
[ 622-52-6 ]
[ 1392217-14-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With iron(III) chloride hexahydrate In ethyl acetate at 80℃; for 8h;

Reference： [1]Location in patent: experimental part Li, Zheng; Cai, Hongfang [Journal of Chemical Research, 2012, vol. 36, # 5, p. 290 - 292]

28
[ 940-64-7 ]
[ 103-85-5 ]
[ 1392217-09-2 ]

Yield	Reaction Conditions	Operation in experiment
72%	With iron(III) chloride hexahydrate In ethyl acetate at 80℃; for 8h;

Reference： [1]Location in patent: experimental part Li, Zheng; Cai, Hongfang [Journal of Chemical Research, 2012, vol. 36, # 5, p. 290 - 292]

29
[ 940-64-7 ]
[ 3696-23-9 ]
[ 1392217-20-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With iron(III) chloride hexahydrate In ethyl acetate at 80℃; for 8h;

Reference： [1]Location in patent: experimental part Li, Zheng; Cai, Hongfang [Journal of Chemical Research, 2012, vol. 36, # 5, p. 290 - 292]

30
[ 940-64-7 ]
[ 4244-84-2 ]
[ 1283612-10-1 ]

Yield	Reaction Conditions	Operation in experiment
77.3%	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 16h;	General procedure: trans-Cinnamic acid (1.49, 10.0 mmol) and HOBt (2.263 g, 15 mmol) were dissolved in DMF (50 mL). EDC.HCl (2.865 g, 15 mmol) was added, followed by beta-alanine ethyl ester hydrochloride (1.53 g, 10 mmol) and DIPEA (5.3 mL, 30 mmol) and the solution was stirred at RT for 16 h. The solvent was removed in vacuo and the residual oil was re-dissolved in EtOAc (100 mL), the organic phase was washed with 5percent w/v aqueous sodium hydrogen carbonate solution (2 ×100 mL) then 5percent w/v citric acid solution (2× 30 mL) and brine, before being dried on MgSO4. The solvent was evaporated in vacuo to afford the product (1.48 g, 59.8percent yield).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 6200 - 6204

31
[ 940-64-7 ]
1-(fluoromethoxy)-4-methylbenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With 2,6-di-tert-butyl-pyridine; N-fluorobis(benzenesulfon)imide In acetone for 3h; Inert atmosphere; Irradiation;
34 %Spectr.	Stage #1: 2-(4-methylphenoxy)acetic acid With sodium hydroxide In water for 0.0833333h; Inert atmosphere; Stage #2: With Selectfluor In water for 1h; Inert atmosphere; UV-irradiation;
40 %Spectr.	With triethylamine pentahydrogen fluoride salt; 2,4,6-trimethyl-pyridine In dichloromethane at 20℃; Electrochemical reaction;

Reference： [1]Leung, Joe C. T.; Sammis, Glenn M. [European Journal of Organic Chemistry, 2015, vol. 2015, # 10, p. 2197 - 2204]
[2]Leung, Joe C. T.; Chatalova-Sazepin, Claire; West, Julian G.; Rueda-Becerril, Montserrat; Paquin, Jean-François; Sammis, Glenn M. [Angewandte Chemie - International Edition, 2012, vol. 51, # 43, p. 10804 - 10807][Angewandte Chemie, 2012, vol. 124, # 43, p. 10962 - 10965]
[3]Berger, Michael; De Kruijff, Goswinus H. M.; Herszman, John D.; Kurimoto, Yuji; Ruf, Sven; Schüll, Aaron; Waldvogel, Siegfried R. [Chemical Science, 2020, vol. 11, # 23, p. 6053 - 6057]

32
[ 940-64-7 ]
[ 130-15-4 ]
[ 1449692-25-4 ]

Yield	Reaction Conditions	Operation in experiment
62%	With ammonium peroxydisulfate; silver nitrate In water; acetonitrile at 80℃; for 0.0833333h;

Reference： [1]Claes, Pieter; Jacobs, Jan; Kesteleyn, Bart; Nguyen Van, Tuyen; De Kimpe, Norbert [Journal of Organic Chemistry, 2013, vol. 78, # 17, p. 8330 - 8339]

33
[ 940-64-7 ]
[ 1610785-16-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-(4-methylphenoxy)acetic acid With chloroformic acid ethyl ester; triethylamine In acetone at -5℃; for 0.25h; Stage #2: With sodium azide In water; acetone at -5℃; for 0.583333h;	1 General procedure for preparation of compounds 8a-8e General procedure: To a solution of corresponding substituted phenoxyacetic acid 3or 5 (4 mmol) and Et3N (0.48 g, 4.8 mmol) in acetone (15 mL) was added ethyl chlorocarbonate (0.51 g, 4.8 mmol) in acetone (5 mL) at 5 C. After the addition was complete, the cold mixture was stirred for an additional 15 min. A solution of sodium azide (0.52 g, 8 mmol) in water (2 mL) was added over 5 min while thetemperature was kept at 5 °C. The mixture was stirred for 30 min longer at this temperature, poured into ice water (50 mL), and shaken with toluene (30 mL x 3). The combined toluene extracts were dried over MgSO4. The toluene solution was heated cautiously at 70 °C for 1 h, and then the solution was cooled toroom temperature, which was used for next step directly. To the solution of isocyanate 7 in toluene was added compound 2 (0.21 g, 1.5 mmol) in DMF (2 mL) at 0 °C over 5 min, and then the solution was stirred at room temperature. After 4 h, the toluene was removed under reduced pressure to give a residue. The residue was poured into cold water (30 mL), and the precipitate was collected by filtration and dried to afford the desired compounds 8a-8e

Reference： [1]He, Jun-Bo; Ren, Yan-Liang; Sun, Qiu-Shuang; You, Ge-Yun; Zhang, Li; Zou, Peng; Feng, Ling-Ling; Wan, Jian; He, Hong-Wu [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 12, p. 3180 - 3186]

34
[ 95-02-3 ]
[ 940-64-7 ]
[ 1610784-94-5 ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: 2-(4-methylphenoxy)acetic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -5℃; Stage #2: 5-(aminomethyl)-2-methylpyrimidin-4-amine In tetrahydrofuran; N,N-dimethyl-formamide at -5 - 20℃; for 12h;	5 General procedure for preparation of compounds 6a-6n General procedure: To a solution of corresponding substituted phenoxyacetic acid 3 or 5 (1.5 mmol) and Et3N (0.16 g, 1.6 mmol) in THF (15 mL) was added ethyl chlorocarbonate (0.17g, 1.6 mmol) in THF (2 mL) slowly at -5°C. After the addition was complete, the cold mixture was stirred for an additional 15 min. A solution of 2 (0.22 g, 1.6 mmol) in DMF (2 mL) was added dropwise while the temperature was kept at -5°C. After the addition was complete, the mixture was stirred at room temperature for 12 h. It was poured into water (30mL), and the precipitate was collected by filtration and dried in the atmospheric pressure. Recrystallization with appropriate solvent afforded the desired solid compounds 6a-6n. 5.3.5 N-((4-Amino-2-methylpyrimidin-5-yl)methyl)-2-(p-tolyloxy)acetamide (6e) White solid, yield: 57%, mp 172-174; 1H NMR (CDCl3, 600 MHz): δ 2.29 (s, 3H, CH3), 2.48 (s, 3H, CH3), 4.38 (d, 2H, J = 6.6 Hz, CH2), 4.49 (d, 2H, J = 7.2 Hz, CH2), 5.95 (s, 2H, NH2), 6.78 (d, 1H, J = 8.4 Hz, Ar-H), 7.09 (d, 3H, J = 8.4 Hz, Ar-H + NH), 7.99 (s, 1H, CH); 13C NMR (DMSO-d6, 100 MHz): δ 20.08, 25.14, 36.44, 67.11, 110.66, 114.63, 129.86, 130.11, 154.91, 155.53, 161.57, 165.70, 168.81. EI-MS m/z (%): 286.2 (M+, 3.62). Anal. Calcd for C15H18N4O2: C, 62.92; H, 6.34; N, 19.57. Found: C, 62.81; H, 6.62; N, 19.47.

Reference： [1]He, Jun-Bo; Ren, Yan-Liang; Sun, Qiu-Shuang; You, Ge-Yun; Zhang, Li; Zou, Peng; Feng, Ling-Ling; Wan, Jian; He, Hong-Wu [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 12, p. 3180 - 3186]

35
[ 2963-77-1 ]
[ 940-64-7 ]
[ 900775-74-8 ]

Yield	Reaction Conditions	Operation in experiment
59%		General procedure: The mixture of 0.1mol of phenoxy acetic acid derivative(PAA1-PAA5) and 0.1mol of dicyclohexyl carbodiimide in10 mL dichloromethane was stirred at room temperature.After 30 minutes, a solution of AB or APB in 20 ml of dichloromethaneand 5 ml of pyridine was added. The reactionmixture was stirred initially at 0C for 2 h followed by stirring at room temperature for 12 h. The precipitated dicyclohexylureawas removed by filtration and the solvent wasdistilled at reduced pressure on rotary vacuum evaporator.The dried product was dissolved in ethyl acetate (10 mL) andthe solution was washed with 10% aqueous solution of sodiumbicarbonate followed by distilled water to remove thetraces of residual dicyclohexylurea. The ethyl acetate layerwas dried with anhydrous magnesium sulphate and then solventwas distilled off to obtain the crude product which wasrecrystallized from ethanol-water mixture.

Reference： [1]Medicinal Chemistry,2014,vol. 10,p. 418 - 425

36
[ 934-32-7 ]
[ 940-64-7 ]
[ 1037927-16-4 ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: 2-(4-methylphenoxy)acetic acid With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.5h; Stage #2: 1H-benzimidazol-2-amine With pyridine In dichloromethane at 0 - 20℃; for 14h;	4.1.4.Synthesis of Target Compounds (AB and APB Series) General procedure: The mixture of 0.1mol of phenoxy acetic acid derivative(PAA1-PAA5) and 0.1mol of dicyclohexyl carbodiimide in10 mL dichloromethane was stirred at room temperature.After 30 minutes, a solution of AB or APB in 20 ml of dichloromethaneand 5 ml of pyridine was added. The reactionmixture was stirred initially at 0°C for 2 h followed by stirring at room temperature for 12 h. The precipitated dicyclohexylureawas removed by filtration and the solvent wasdistilled at reduced pressure on rotary vacuum evaporator.The dried product was dissolved in ethyl acetate (10 mL) andthe solution was washed with 10% aqueous solution of sodiumbicarbonate followed by distilled water to remove thetraces of residual dicyclohexylurea. The ethyl acetate layerwas dried with anhydrous magnesium sulphate and then solventwas distilled off to obtain the crude product which wasrecrystallized from ethanol-water mixture.

Reference： [1]Singh, Gurmeet; Bansal, Yogita; Bansal, Gulshan; Goel, Rajesh Kumar [Medicinal Chemistry, 2014, vol. 10, # 4, p. 418 - 425]

37
[ 940-64-7 ]
[ 954279-15-3 ]
[ 1616074-75-9 ]

Yield	Reaction Conditions	Operation in experiment
13.1%	With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h;	3.3 Step 3: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(p-tolyloxy)acetamide A mixture of compound 72 2-(p-tolyloxy)acetic acid (100 mg, 0.60 mmol), 6 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (124 mg, 0.60 mmol), 49 BOP-Cl (183 mg, 0.72 mmol) and 74 DIPEA (1 mL) in 31 DCM (10 mL) was stirred at room temperature for 4 h. The solvent was removed by concentration and the crude product was purified by pre-HPLC to give the 66 title compound (27.8 mg, yield 13.1%). 1H NMR (500 MHz, MeOD): δ 7.32-7.25 (m, 3H), 7.20 (d, J=7.2 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.65-4.52 (br.s, 1H), 4.52 (s, 2H), 4.46-4.30 (br.s, 1H), 4.30-4.24 (m, 1H), 3.85-3.70 (br.s, 1H), 3.43 (d, J=5.6 Hz, 1H), 3.26-3.17 (m, 4H), 2.26 (s, 3H) ppm; ESI-MS (m/z): 355.2 [M+1]+.
27.8 mg	With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 4h;	9.3 Step 3 :N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-2-(p- tolyloxy)acetamide A mixture of compound 2-(p-tolyloxy)acetic acid (100 mg, 0.60 mmol), 1-amino- 3-(3,4-dihydroisoquinolin-2(lH)-yl)propan-2-ol (124 mg, 0.60 mmol), BOP-Cl (183 mg, 0.72 mmol) and DIPEA (1 mL ) in DCM (10 mL) was stirred at room temperature for 4h. The solvent was removed by concentration and the crude product was purified by pre-HPLC to give the title compound (27.8 mg, yield 13.1%). 1H NMR (500 MHz, MeOD): δ 7.32-7.25 (m, 3H), 7.20 (d, J = 1.2 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.65- 4.52 (br.s, 1H), 4.52 (s, 2H), 4.46-4.30 (br.s, 1H), 4.30-4.24 (m, 1H), 3.85-3.70 (br.s, 1H), 3.43 (d, J = 5.6 Hz, 1H), 3.26-3.17 (m, 4H), 2.26 (s, 3H)ppm; ESI-MS (m/z): 355.2 [M+l] +.

Reference： [1]Current Patent Assignee: EPIZYME, INC. - US2019/83482, 2019, A1 Location in patent: Paragraph 0248-0249
[2]Current Patent Assignee: EPIZYME, INC. - WO2014/100730, 2014, A1 Location in patent: Paragraph 00268

38
[ 940-64-7 ]
[ 944727-77-9 ]
[ 1620888-40-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With trichlorophosphate at 106℃; for 7h;	Synthesis of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole derivatives (L1-8) General procedure: Synthetic methods of compounds L1-8 were similar with eachother, we took the synthetic method of the compound L1 for example.A mixture of obtained compound 2 (2 mmol, 0.61 g), phenoxyaceticacid (6 mmol, 0.91 g) and phosphorus oxychloride (15 mL)were added to a 25 mL single-necked flask, then the reaction mixturewas heated to 106 C and refluxed for 7 h. The solvent wasremoved under vacuum distillation and cooled at room temperature.Then the residue was poured into ice-water mixture(400 mL) under stirring. The pH value of the mixture was adjustedto 7-8 with diluted NaOH solution. Then the precipitated solid wasseparated by suction filtration, and washed with water to be neutral.The crude product was dried and added to anhydrous ethanol(100 mL), heated to boiling and separated by suction filtration,purified by washing thoroughly with anhydrous ethanol and driedin vacuum to give the title product L1.
92%	With trichlorophosphate at 106℃; for 7h;

Reference： [1]Yan, Dong; Xiang, Yu; Li, Kangyun; Chen, Yanwen; Yang, Zehui; Guo, Dongcai [Journal of Molecular Structure, 2014, vol. 1074, p. 487 - 495]
[2]Zhang, Wu; Chai, Yuchao; Li, Kangyun; Chen, Yanwen; Yan, Dong; Guo, Dongcai [Luminescence, 2014, vol. 29, # 8, p. 1113 - 1122]

39
[ 940-64-7 ]
[ 80809-38-7 ]
[ 877806-23-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	With trichlorophosphate Reflux;	General procedure for the preparation of1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles3a-h and 4a-f General procedure: A mixture of 2 (182 mg, 1.00 mmol) and a substituted aromatic acid (1.10 mmol) in POCl3 (5 mL) was heated under reflux for 6-7 h. The reaction mixture was slowly poured into crushed ice with stirring and neutralized with solid sodium bicarbonate. The solid product obtained was filtered, washed with cold water, and recrystallized from ethanol to give the desired products

Reference： [1]Khan, Imtiaz; Hameed, Shahid; Al-Masoudi, Najim A.; Abdul-Reda, Nabeel A.; Simpson, Jim [Zeitschrift fur Naturforschung, B: Chemical Sciences, 2015, vol. 70, # 1, p. 47 - 58]

40
[ 179051-29-7 ]
[ 940-64-7 ]
[ 428832-97-7 ]

Yield	Reaction Conditions	Operation in experiment
77.5%	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃;	2 1-(4-(Naphthalen-2-ylsulfonyl)piperazin-1-yl)-2-(p-tolyloxy)ethanone To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.2 g, 0.64 mmol) and 2-(p-tolyloxy)acetic acid (106 mg, 0.64 mmol) in dry DCM (20 mL), DIPEA (495 mg, 3.86 mmol) followed by HATU (486 mg, 1.27 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM and washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.21 g, 77.5%) as an off-white solid. (0246) 1HNMR (DMSO-d6, 500 MHz): 2.16 (s, 3H), 2.95-3.04 (m, 4H), 3.57 (m, 4H), 4.63 (s, 2H), 6.65 (d, 2H), 6.92 (d, 2H), 7.73-7.79 (m, 3H), 8.11 (d, 1H), 8.21 (dd, 2H), 8.42 (s, 1H). MS (ESI): 424.1 (M+1)

Reference： [1]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US9115086, 2015, B2 Location in patent: Page/Page column 42; 43

41
[ 940-64-7 ]
[ 1254707-32-8 ]
[ 1254707-48-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere;	2 3,5-Dimethyl-6-(4-2-(p-tolyloxy)acetyl)piperazin-1-ylsulfonyl)benzo[d]oxazol-2(3H)-one 3,5-Dimethyl-6-(piperazin-1-ylsulfonyl)benzo[d]oxazol-2(3H)-one was dissolved in 25 mL dry DCM and to that di-isopropyl ethyl amine (0.1 mL, 0.64 mmol) and HATU (182 mg, 0.48 mmol) was added at 0° C. under N2 atmosphere. The reaction mixture was stirred for 10 min and 2-(p-tolyloxy)acetic acid (64 mg, 0.384 mmol) was slowly added. The reaction was warmed to room temperature and allowed it to stir for 12 h. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate (2×25 mL). The combined organic phase was washed with bicarbonate solution and brine and dried over sodium sulphate. The solvent was filtered and evaporated on rotavap to obtain a crude compound which was purified by column chromatography to yield pure title compound as a white solid. (0298) 1HNMR (DMSO-d6: 500 MHz): 2.2 (s, 3H), 2.6 (s, 2H), 3.1 (d, 2H), 3.1 (s, 2H), 3.6 (s, 2H), 3.7 (m, 4H), 4.9 (s, 2H), 6.9 (dd, 2H), 7.0 (dd, 2H), 7.4 (s, 1H), 7.6 (s, 1H). MS: (ESI): 460.01 (M+1). HPLC: 93.1%

Reference： [1]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US9115086, 2015, B2 Location in patent: Page/Page column 51

42
[ 2046-82-4 ]
[ 940-64-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In water	2.1 Synthesis of phenoxyacetic acid and ring-substituted phenoxyacetic acids General procedure: General procedure: To a solution of phenol or ring-substituted phenol (20 mmol) in water (20 mL) was added sodium chloroacetate (22 mmol) at rt. The mixture was heated and stirred at reflux for 8 h. The reaction mixture was cooled and the pH was adjusted to a value of 1.0 with 5 N HCl. The solution was filtered and the obtained solid was recrystallized from dehydrated ethanol to afford the pure product. 4-Methylphenoxyacetic acid (1p) Following the general procedure the compound 1p was obtained in 74 % yield as a white solid. m.p. 134-135 °C. 1H NMR (400 MHz, CDCl3) δ10.33(s,1H)7.11 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H),4.66 (s, 2H), 2.30 (s, 3H). MS (ESI) m/z: 165 [M-H]-. (S11)

Reference： [1]He, Xingrui; Yu, Zhaonan; Jiang, Shaojie; Zhang, Peizhi; Shang, Zhicai; Lou, Yonggen; Wu, Jun [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5601 - 5603]

43
[ 940-64-7 ]
[ 1356668-56-8 ]
2-methyl-N-phenyl-2-(p-tolyl)-4-(p-tolyloxy)butanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium persulfate; silver nitrate In water; acetonitrile at 80℃; for 12h;