Name: 2905-60-4|2,3-Dichlorobenzoyl chloride|98%
Brand: Ambeed
SKU: A252862
Rating: 90 (22 reviews)

1
[ 50-45-3 ]
[ 2905-60-4 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 80℃; for 2h;	<strong>[50-45-3]2,3-Dichlorobenzoic acid</strong> (200g) is charged into a suitably sized round bottom flask containing thionyl chloride (917g) and heated at 80C for 2hrs. Excess thionyl chloride is removed by distillation under vacuum to obtain 2,3-dichlorobenzoyl chloride (IV) as a viscous liquid. Yield = 210G Purity = 98% (when analyzed by gas chromatography).
	With thionyl chloride; at 80℃; for 1h;	<strong>[50-45-3]2,3-Dichlorobenzoic acid</strong> (500 g, 2.618 moles) was charged into a 2 L four necked round bottom flask containing thionyl chloride (623 g, 5.235 moles) and heated at 80° C. for 1.0 hr to give 2,3-dichlorobenzoyl chloride(C 6 H 3 Cl 2 COCl), after removal of excess of thionyl chloride. Yield = 500 g Purity = 98% (when analysed by Gas Chromatography)
	With oxalyl dichloride;	Example 55:(+)-trans- 2,3-Dichloro-benzoic acid 2-(2-acetoxymethyl-1 -methyl-pyrrolidin-3- yl) -6-acetyl-3,5-dimethoxy-phenyl ester <strong>[50-45-3]2,3-dichloro benzoic acid</strong> (1 .3 g, 6.82 mmol) was converted to its acid chloride using oxalyl chloride (0.76 ml_, 8.87 mmol). Triethylamine (4.04 ml_, 28 mmol) was added to a solution of compound of example 1 (2.0 g, 5.69 mmol) in dry DCM (20 ml_). To this, a solution of the acid chloride dissolved in dry DCM (10 ml.) was added dropwise and the reaction stirred at 25 C for 2 hours. The reaction mixture was poured over crushed ice, basified with saturated sodium carbonate solution (pH 10), extracted with chloroform (3 x 200 ml_), and the solvent removed under reduced pressure to afford the title compound as a viscous oil.Crude yield: 4.35 g

	With thionyl chloride; In toluene; for 3h;Reflux;	General procedure: A solution of thionyl chloride (25 mmol) was addeddropwisely to 1 (20 mmol) in toluene(15 mL). The mixture was heated to reflux for 3 h. Excess thionyl chloride wasremoved in vacuo. The remained mixture was added dropwise to ammonia waterbelow 10 C, then stirred at 10 C for 1 h. The intermediate 3 was obtained as white solid by filtration.
	With thionyl chloride; for 6h;	Add 500g four-necked flask 50g2,3-<strong>[50-45-3]dichlorobenzoic acid</strong>,50g thionyl chloride, the reaction 6h to the end,Vacuum distillation net thionyl chloride,Then add 30g cuprous cyanide,Carefully warmed to 160 , the reaction 6h to the end of the reaction, the solid was filtered to give 2,3-dichlorobenzoyl cyanide solution

Reference： [1]Organic Process Research and Development,2017,vol. 21,p. 1815 - 1821
[2]Bulletin des Societes Chimiques Belges,1968,vol. 77,p. 287 - 293
[3]Journal of the Chemical Society,1903,vol. 83,p. 1213
[4]Journal of Medicinal Chemistry,1988,vol. 31,p. 824 - 830
[5]Pesticide Science,1994,vol. 41,p. 139 - 148
[6]Journal of labelled compounds and radiopharmaceuticals,2002,vol. 45,p. 611 - 618
[7]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 2623 - 2628
[8]Journal of Medicinal Chemistry,2006,vol. 49,p. 4512 - 4516
[9]Journal of Medicinal Chemistry,2007,vol. 50,p. 1365 - 1379
[10]Journal of Medicinal Chemistry,2000,vol. 43,p. 1586 - 1603
[11]Patent: WO2005/3104,2005,A2 .Location in patent: Page 11
[12]Arzneimittel-Forschung/Drug Research,2008,vol. 58,p. 569 - 573
[13]Patent: US6639072,2003,B1 .Location in patent: Page/Page column 8
[14]Patent: WO2011/104584,2011,A1 .Location in patent: Page/Page column 40-41
[15]Bioorganic and medicinal chemistry letters,2012,vol. 22,p. 6974 - 6979,6
[16]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 330 - 335
[17]Journal of Agricultural and Food Chemistry,2013,vol. 61,p. 6792 - 6798
[18]Journal of Heterocyclic Chemistry,2015,vol. 51,p. 1311 - 1321
[19]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2544 - 2546
[20]Patent: CN106083753,2016,A .Location in patent: Paragraph 0031
[21]Journal of Enzyme Inhibition and Medicinal Chemistry,2019,vol. 34,p. 1083 - 1092

2
[ 69687-80-5 ]
[ 2905-60-4 ]
4-(2,3-Dichloro-benzoyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With aluminium trichloride In dichloromethane at 20℃; for 2h; 1.) CH₂Cl₂, -78 deg C, 2.) CH₂Cl₂, 20 deg C, 2 h;

Reference： [1]Baxter; Dixon; Ince; Manners; Teague [Journal of Medicinal Chemistry, 1993, vol. 36, # 19, p. 2739 - 2744]

3
[ 6260-86-2 ]
[ 2905-60-4 ]
1-(2,3-Dichloro-benzoyl)-5-methoxy-2-methyl-1H-indole-3-carbaldehyde [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2263 - 2268

4
[ 2905-60-4 ]
[ 5980-24-5 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide In ethyl acetate
	With ammonium hydroxide at 0 - 10℃; for 1h;	General synthetic procedure for compounds 3a-3t General procedure: A solution of thionyl chloride (25 mmol) was addeddropwisely to 1 (20 mmol) in toluene(15 mL). The mixture was heated to reflux for 3 h. Excess thionyl chloride wasremoved in vacuo. The remained mixture was added dropwise to ammonia waterbelow 10 °C, then stirred at 10 °C for 1 h. The intermediate 3 was obtained as white solid by filtration.

Reference： [1]Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.; Carroll, William A.; Condon, Stephen; Elmore, Steven W.; Kerwin Jr., James F.; Sippy, Kevin B.; Tietje, Karin; Wendt, Michael D.; Hancock, Arthur A.; Brune, Michael E.; Buckner, Steven A.; Drizin, Irene [Journal of Medicinal Chemistry, 2000, vol. 43, # 8, p. 1586 - 1603]
[2]Lei, Peng; Xu, Yan; Du, Juan; Yang, Xin-Ling; Yuan, Hui-Zhu; Xu, Gao-Fei; Ling, Yun [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 10, p. 2544 - 2546]

5
[ 960292-44-8 ]
[ 2905-60-4 ]
[ 960292-38-0 ]

Yield	Reaction Conditions	Operation in experiment
17%	With triethylamine In dichloromethane at 20℃; for 72h;	A21 A21. (3-[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)- 2-methyl-propyl]-[1-(2,3-dichloro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester; A solution of 300 mg (1.0 eq) {3-[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5- clpyrimidin-δ-yl^-methyl-propylaminol-propyll-carbamic acid tert-butyl ester (compound B3), 143 mg (1.2 eq) 2,3-dichloro benzoyl chloride and 249 μl_ (3.0 eq) triethylamine in 7 ml_ dichloromethane is stirred for 3 days at ambient temperature. After addition of 10 ml_ of dichloromethane and 10 ml_ saturated aqueous NaHCO3-solution the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a gradient of n-hexane, ethyl acetate and acetic acid from 39:59:2 to 0:100:0 yielded 67 mg (17%) of the title compound as a colorless solid. Furthermore 164 mg (55%) of the starting material is recovered. M. p.: 109-110 0C. MS: m/z (MH+) = 673.8, 676.0, 677.9.

Reference： [1]Current Patent Assignee: 4 SC AG; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2007/144384, 2007, A1 Location in patent: Page/Page column 62

6
[ 2905-60-4 ]
[ 143-33-9 ]
[ 77668-42-9 ]

Yield	Reaction Conditions	Operation in experiment
>= 80%	With copper(l) iodide; In acetonitrile; at 20℃; for 6 - 9h;	1. Synthesis of 2,3-dichlorobenzoyl cyanide2,3-Dichlorobenzoyl chloride (20.0 g, 100 mmol) and copper(I) iodide (0.90 g, 4.7 mmol) were suspended in acetonitrile (50 mL) and stirred at room temperature until a yellow homogeneous solution formed. Solid sodium cyanide (5.15 g, 1 10 mmol) was charged within 5 to 8 hours. After complete addition the reaction mixture was stirred for one hour, monitoring completion of the reaction by HPLC. The formed inorganic salts (mainly NaCl) were filtered off and washed with acetonitrile (15 mL). The acetonitrile was distilled off at reduced pressure (about 150 mbar). Sodium metabisulfte (Na2S2Os, 0-4 g, 3 mmol) was added to remove traces of iodine. The product was finally isolated by vacuum distillation at 140 0C (jacket temperature), b.p. 115 C (2 mbar).The isolated yield of 2,3-dichlorobenzoyl cyanide (m.p. 60 C) was >80 % with a purity of 100% (according to analytical HPLC).

Reference： [1]Patent: WO2008/19798,2008,A1 .Location in patent: Page/Page column 12

7
[ 959652-66-5 ]
[ 2905-60-4 ]
2,3-dichloro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With triethylamine In tetrahydrofuran at 20℃; for 4h; Heating / reflux;	128 Example 128 2,3-dichloro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide To the product of Example 126A (0.20 g, 1.1 mmol) in 35 mL THF was added Et3N (0.37 mL, 2.7 mmol). This mixture was cooled to 0° C. and 2,3-dichlorobenzoyl chloride (Lancaster, 0.27 g, 1.3 mmol) in 5 mL THF was added dropwise via syringe. This mixture stirred at ambient temperature for 1 hour then was warmed to reflux and was allowed to stir for 3 hours. The mixture was cooled to ambient temperature and was quenched with 5 mL saturated, aqueous NH4Cl and diluted with 10 mL EtOAc. The layers were separated and the aqueous layer was extracted 25 mL EtOAc and 25 mL CH2Cl2. The combined organics were washed 1*5 mL saturated, aqueous NaCl then were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 10% CH3OH:EtOAc). The material was still impure so it was purified again via flash column chromatography (SiO2, 1:1 hexanes:EtOAc) to provide the title compound (0.105 g, 0.29 mmol, 27% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.26 (s, 3 H), 2.28 (s, 3 H), 3.30 (s, 3 H), 3.76 (t, J=4.6 Hz, 2 H), 4.40 (t, J=4.2 Hz, 2 H), 7.23 (t, J=7.7 Hz, 1 H), 7.49 (dd, J=8.0, 1.5 Hz, 1 H), 7.72 (dd, J=7.6, 1.5 Hz, 1 H); MS (DCI/NH3) m/z 359 (M+H)+; Anal. calculated for C15H16Cl2N2O2S: C, 50.15; H, 4.49; N, 7.80. Found; C, 50.17; H, 4.26; N, 7.69
27%	With triethylamine In tetrahydrofuran at 0 - 20℃; for 4h; Heating / reflux;	128 To the product of Example 126A (0.20 g, 1.1 mmol) in 35 mL THF was added Et3N (0.37 mL, 2.7 mmol). This mixture was cooled to 0 0C and 2,3-dichlorobenzoyl chloride (Lancaster, 0.27 g, 1.3 mmol) in 5 mL THF was added dropwise via syringe. This mixture stirred at ambient temperature for 1 hour then was warmed to reflux and was allowed to stir for 3 hours. The mixture was cooled to ambient temperature and was quenched with 5 mL saturated, aqueous NH4Cl and diluted with 10 mL EtOAc. The layers were separated and the aqueous layer was extracted 2 X 5 mL EtOAc and 2 X 5 mL CH2Cl2. The combined organics were washed 1 X 5 mL saturated, aqueous NaCl then were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 10% CH3OH:EtOAc). The material was still impure so it was purified again via flash column chromatography (SiO2, 1: 1 hexanes :EtOAc) to provide the title compound (0.105 g, 0.29 mmol, 27% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.26 (s, 3 H), 2.28 (s, 3 H), 3.30 (s, 3 H), 3.76 (t, J = 4.6 Hz, 2 H), 4.40 (t, J=4.2 Hz, 2 H), 7.23 (t, J=7.7 Hz, 1 H), 7.49 (dd, J=8.0, 1.5 Hz, 1 H), 7.72 (dd, J=I.6, 1.5 Hz, 1 H); MS (DCI/NH3) m/z 359 (M+H)+; Anal, calculated for Ci5Hi6Cl2N2O2S: C, 50.15; H, 4.49; N, 7.80. Found: C, 50.17; H, 4.26; N, 7.69

Reference： [1]Current Patent Assignee: ABBVIE INC - US2008/58335, 2008, A1 Location in patent: Page/Page column 33
[2]Current Patent Assignee: ABBVIE INC - WO2009/67613, 2009, A1 Location in patent: Page/Page column 90

8
3-(2-Methoxy-ethyl)-5-methyl-3H-thiazol-2-ylideneamine [ No CAS ]
[ 2905-60-4 ]
2,3-dichloro-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With triethylamine In tetrahydrofuran at 20℃; for 1h;	140B Example 140B 2,3-dichloro-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide To the product of Example 140A (0.20 g, 1.2 mmol) in 15 mL THF was added Et3N (0.48 mL, 3.5 mmol) followed by a solution of 2,3-dichlorobenzoyl chloride (Lancaster, 0.31 g, 1.5 mmol) in 5 mL THF. This mixture stirred at ambient temperature for 1 hour then was concentrated under reduced pressure, quenched with 5 mL saturated, aqueous NH4Cl and extracted with EtOAc (3*5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting solids were recrystallized from 50% hexanes/EtOAc to afford the title compound (0.27 g, 0.78 mmol, 68% yield) 1H NMR (300 MHz, CDCl3) δ ppm 2.32 (d, J=1.4 Hz, 3 H), 3.34 (s, 3 H), 3.71 (t, J=5.1 Hz, 2 H), 4.34 (t, J=4.8 Hz, 2 H), 6.82-6.86 (m, 1 H), 7.22 (t, J=7.8 Hz, 1 H), 7.49 (dd, J=8.1, 1.7 Hz, 1 H), 7.73 (dd, J=7.5, 1.7 Hz, 1 H); MS (DCI/NH3) m/z 345 (M+H)+; Anal. calculated for C14H14Cl2N2O2S: C, 48.70; H, 4.09; N, 8.11. Found: C, 48.39; H, 3.70; N, 7.94.
68%	With triethylamine In tetrahydrofuran at 20℃; for 1h;	140.B To the product of Example 140A (0.20 g, 1.2 mmol) in 15 mL THF was added Et3N (0.48 mL, 3.5 mmol) followed by a solution of 2,3-dichlorobenzoyl chloride (Lancaster, 0.31 g, 1.5 mmol) in 5 mL THF. This mixture stirred at ambient temperature for 1 hour then was concentrated under reduced pressure, quenched with 5 mL saturated, aqueous NH4Cl and extracted with EtOAc (3 X 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting solids were recrystallized from 50% hexanes/EtOAc to afford the title compound (0.27 g, 0.78 mmol, 68% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.32 (d, J=1.4 Hz, 3 H), 3.34 (s, 3 H), 3.71 (t, J=5.1 Hz, 2 H), 4.34 (t, J=4.8 Hz, 2 H), 6.82-6.86 (m, 1 H), 7.22 (t, J=7.8 Hz, 1 H), 7.49 (dd, J=8.1, 1.7 Hz, 1 H), 7.73 (dd, J=I.5, 1. 7 Hz, 1 H); MS (DCI/NH3) m/z 345 (M+H)+; Anal, calculated for Ci4H14Cl2N2O2S: C, 48.70; H, 4.09; N, 8.11. Found: C, 48.39; H, 3.70; N, 7.94

Reference： [1]Current Patent Assignee: ABBVIE INC - US2008/58335, 2008, A1 Location in patent: Page/Page column 36
[2]Current Patent Assignee: ABBVIE INC - WO2009/67613, 2009, A1 Location in patent: Page/Page column 95

9
[ 959600-56-7 ]
[ 2905-60-4 ]
2,3-dichloro-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 50℃; for 2h;	149B Example 149B 2,3-dichloro-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide To a solution of the product of Example 149A (0.17 g, 0.86 mmol) in 10 mL THF and 1 mL DMF was added Et3N (0.36 mL, 2.6 mmol) followed by 2,3-dichlorobenzoyl chloride (Lancaster, 0.27 g, 1.3 mmol). This mixture was warmed to 50° C. and allowed to stir for 2 hours. The mixture was cooled to ambient temperature, diluted with 10 mL EtOAc, and quenched with 10 mL NH4Cl. The layers were separated and the aqueous layer was extracted 2*5 mL EtOAc. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via column chromatography (SiO2, 20% hexanes/EtOAc) to afford the title compound (0.24 g, 0.64 mmol, 75% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.58-1.68 (m, 1 H), 1.78-1.94 (m, 2 H), 2.00-2.13 (m, 1 H), 2.32 (s, 3 H), 3.72-3.91 (m, 2 H), 4.06-4.15 (m, 1 H), 4.24 (ddd, J=14.0, 7.0, 2.7 Hz, 1 H), 4.47 (dd, J=13.6, 2.7 Hz, 1 H), 6.91-6.95 (m, 1 H), 7.22 (t, J=8.0 Hz, 1 H), 7.49 (dd, J=8.1, 1.7 Hz, 1 H), 7.72 (dd, J=7.5, 1.7 Hz, 1 H); MS (DCI/NH3) m/z 371 (M+H)+; Anal. calculated for C16H16Cl2N2O2S: C, 51.76; H, 4.34; N, 7.55. Found: C, 51.66; H, 4.17; N, 7.46.
75%	In tetrahydrofuran; N,N-dimethyl-formamide at 50℃; for 2h;	149.B To a solution of the product of Example 149A (0.17 g, 0.86 mmol) in 10 mL THF and 1 mL DMF was added Et3N (0.36 mL, 2.6 mmol) followed by 2,3-dichlorobenzoyl chloride (Lancaster, 0.27 g, 1.3 mmol). This mixture was warmed to 50 0C and allowed to stir for 2 hours. The mixture was cooled to ambient temperature, diluted with 10 mL EtOAc, and quenched with 10 mL NH4Cl. The layers were separated and the aqueous layer was extracted 2 X 5 mL EtOAc. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via column chromatography (SiO2, 20% hexanes/EtOAc) to afford the title compound (0.24 g, 0.64 mmol, 75% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.58-1.68 (m, 1 H), 1.78-1.94 (m, 2 H), 2.00-2.13 (m, 1 H), 2.32 (s, 3 H), 3.72-3.91 (m, 2 H), 4.06-4.15 (m, 1 H), 4.24 (ddd, J=14.0, 7.0, 2.7 Hz, 1 H), 4.47 (dd, J=13.6, 2.7 Hz, 1 H), 6.91-6.95 (m, 1 H), 7.22 (t, J=8.0 Hz, 1 H), 7.49 (dd,J=8.1, 1.7 Hz, 1 H), 7.72 (dd, J=I.5, 1.7 Hz, 1 H); MS (DCIZNH3) mZz 371 (M+H)+; Anal, calculated for C16H16Cl2N2O2S: C, 51.76; H, 4.34; N, 7.55. Found: C, 51.66; H, 4.17; N, 7.46

Reference： [1]Current Patent Assignee: ABBVIE INC - US2008/58335, 2008, A1 Location in patent: Page/Page column 37
[2]Current Patent Assignee: ABBVIE INC - WO2009/67613, 2009, A1 Location in patent: Page/Page column 98-99

10
[ 2905-60-4 ]
[ 6574-97-6 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 1586 - 1603

11
[ 6574-97-6 ]
[ 2905-60-4 ]

Reference： [1]Pesticide Science,1994,vol. 41,p. 139 - 148

12
[ 5980-24-5 ]
[ 2905-60-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium peroxide / H₂O / 1 h / 20 °C 2: SOCl₂ / 12 h / Heating

Reference： [1]Oikawa; Nakagawa; Nishimura; Ueno; Fujita [Pesticide Science, 1994, vol. 41, # 2, p. 139 - 148]

13
[ 2905-60-4 ]
[ 77668-42-9 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) cyanide; at 160 - 165℃; for 6h;	Dried copper cyanide (120g) is added to a suitably sized round bottom flask containing 2,3-dichlorobenzoyl chloride (200g). The reaction mixture is heated to 160-165C under nitrogen blanket and the temperature is maintained at 160-165C for 6 hours. The reaction mixture is then cooled to 80C, diluted with 600mL toluene and filtered to remove inorganic salts. The solution is concentrated to dryness under vacuum at 60-70C and the residual oil is crystallized from hexane to obtain pure 2,3-dichlorobenzoyl cyanide (II) as a yellow solid. Yield = 140g Purity = 97% (when analyzed by gas chromatography).

Reference： [1]Patent: WO2005/3104,2005,A2 .Location in patent: Page 11

14
(1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride [ No CAS ]
[ 2905-60-4 ]
2,3-dichloro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium hydrogencarbonate In water; ethyl acetate at 20℃;	50 To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 2,3-dichlorobenzoyl chloride (135 mg, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) and recrystallized from ethyl acetate-hexane to give the title compound (161 mg, 77%). mp 187-188°C IR ν maxKBrcm-1: 1647, 1537, 1514. Anal. Calcd for C23H17C12F4NO2: C, 56.81; H, 3.52; N, 2.88 Found: C, 56.82; H, 3.38; N, 2.85.1H-NMR (CDCl3) δ: 2.80-3.10 (3H, m) , 4.60-4.80 (1H, m) , 5.08 (1H, d, J = 3.8 Hz), 6.06 (1H, d,! J = 8.8 Hz), 6.96-7.38 (6H, m), 7.40-7.62 (5H, m).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1362846, 2003, A1 Location in patent: Page/Page column 58

15
[ 820969-36-6 ]
[ 2905-60-4 ]
tert-butyl (3S)-3-[cyclopentyl(2,3-dichlorobenzoyl)amino]pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.4%	With triethylamine In dichloromethane at 0 - 5℃; for 6h;	2 Preparation 2 tert-Butyl (3S)-3-[cyclopentyl(2,3-dichlorobenzoyl)amino]pyrrolidine-1-carboxylate Triethylamine (24 ml, 170 mmol) was added to a solution of the amine of preparation 1 (36.1 g, 142 mmol) in dichloromethane (350 ml) under nitrogen. The reaction mixture was cooled to 0° C. and 2,3-dichloro-benzoyl chloride (29.8 g, 142 mmol) in dichloromethane was added dropwise keeping the temperature below 5° C. The reaction mixture was then stirred for 6 hours. Water (200 ml) was added and the organic phase collected. The aqueous layer was extracted with dichloromethane (250 ml). The combined organic phases were washed with 2M aqueous sodium hydroxide and 10% citric acid solution, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate:cyclohexane (1:6 to 1:4 to 1:2 to 1:1 by volume) to yield the title product, 50 g (82.4%). 1HNMR(CDCl3, 400 MHz, rotamers) δ: 1.43-1.47(d, 9H), 1.56-1.66(m, 5H), 1.79(m, 0.5H), 1.98(m, 3H), 2.37(m, 1H), 2.92(m, 0.5H), 3.15(m, 0.5H), 3.40(m, 1H), 3.58(m, 1.5H), 3.74(m, 2H), 3.97(m, 1H), 7.10(m, 1H), 7.24(m, 1H), 7.46(d, 1H) MS APCI+ m/z 427 [MH]+ and m/z 327[MH-Boc]+
	With triethylamine at 20℃;

Reference： [1]Current Patent Assignee: PFIZER INC - US2006/111429, 2006, A1 Location in patent: Page/Page column 16
[2]Location in patent: scheme or table Wakenhut, Florian; Allan, Gill A.; Fish, Paul V.; Jonathan Fray; Harrison, Anthony C.; McCoy, Rachel; Phillips, Stephen C.; Stobie, Alan; Westbrook, Dominique; Westbrook, Simon L.; Whitlock, Gavin A. [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 5078 - 5081]

16
tert butyl (3S)-3-[(dicyclopropylmethyl)amino]pyrrolidine-1-carboxylate [ No CAS ]
[ 2905-60-4 ]
[ 891945-15-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	With triethylamine In dichloromethane at 20℃; for 72h;	22 To a solution of the compound of preparation 21 (65mg, 0.232mol) in dichloromethane (1ml) was added triethylamine (0.065ml, 0.464mmol) and 2,3-dichlorobenzoyl chloride (63mg, 0.302mmol), and the EPO reaction mixture was then stirred at room temperature for 72 hours. The solvent was evaporated in vacuo and the residue was redissolved in toluene (1ml). Triethylamine (0.065ml, 0.464mmol) was added and the reaction mixture was heated at 6O0C for 8 hours. The mixture was filtered through a hydrophobic filter and the solvent was evaporated in vacuo. The crude material was purified by column chromatography using an ISCO silica cartridge eluting with 0-35% ethyl acetate: pentane (50mg, 0.11mmol, 47%). 1H-NMR (CDCI3, 400MHz): δ 0.10-0.39 (m, 4H), 0.46 (m, 2H)1 0.60 (m, 2H), 0.69-0.90 (m, 1 H), 0.98 (m, 1 H), 1.47 (s, 9H), 2.09 (m, 1 H), 2.50 (m, 1 H), 2.88-3.02 (m, 1 H), 3.41 (quartet, 1 H), 3.61-3.76 (m, 2H), 3.99 (quintet, 1 H), 4.17 (m, 1 H), 7.08 (t, 1 H), 7.21 (m, 1H), 7.44 (m, 1 H); MS,APCI+ m/z 397 [M-1Bu]+

Reference： [1]Current Patent Assignee: PFIZER INC - WO2006/64332, 2006, A1 Location in patent: Page/Page column 42-43

17
tert-butyl (3S)-3-[(1R,3R,5S)-bicyclo[3.2.0]hept-3-ylamino]pyrrolidine-1-carboxylate [ No CAS ]
[ 2905-60-4 ]
[ 891943-64-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With 4-methyl-morpholine In toluene at 70℃; for 3h;	2 The amine of preparation 1 (500mg, 1.78mmol) was added to a solution of N-methyl morpholine (360mg, 3.56mmol), in toluene (3OmI)1 and the reaction mixture was treated with 2,3-dichloro-benzoyl chloride (450mg, 2.13mmol). The reaction mixture was then heated to 700C and stirred for 3 hours, after which time it was washed with a 10% citric acid solution. The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a gradient of methylene chloride, changing to methylene chloride: methanol (95: 5 by volume) affording the title product as the cis compound, 660mg, (81%).1HNMR (CD3OD, 400MHz, rotamers) δ: 1.42(s, 2.5H), 1.48(s, 6.5H), 1.75-1.80(m, 3H), 1.92-1.96(m, 2H), 2.09(m, 1 H), 2.22(m, 3H), 2.45-2.51 (m, 1.5H), 2.75(m, 2H), 3.47(m, 1 H), 3.64-3.72(m, 2.5H), 3.89(m, 1 H), 4.07(m, 0.5H), 4.31 (m, 0.5H), 7.2(m, 1 H), 7.38(m, 1 H)1 7.59(m, 1 H); MS APCI+ m/z 453 [MH]+ and 353 [(M-BoC)H]+

Reference： [1]Current Patent Assignee: PFIZER INC - WO2006/64332, 2006, A1 Location in patent: Page/Page column 36

18
[ 2905-60-4 ]
[ 544-92-3 ]
[ 77668-42-9 ]

Yield	Reaction Conditions	Operation in experiment
94.2%	at 160 - 165℃; for 7h;	Example 6: Synthesis of 2,3-dichlorobenzoyl cyanide; A reactor was loaded with 350.0 g of 2,3-dichlorobenzoyl chloride (1.67 moles) and 200.0 g of cuprous cyanide. The mixture was heated to 160-165 0C and stirred at this temperature for 7 hours. The mixture was cooled to 85 0C and 1200 ml of toluene was added to the mixture. The mixture was stirred for 1 hour at 60 0C, cooled to 15 0C and the inorganic salts were filtrated. The solvent toluene was distilled from the filtrate at 55 0C under reduced pressure. The crude product was crystallised from petroleum ether giving 323.3 g of 2,3-dichlorobenzoyl cyanide with an assay of 97.4 %. Yield was 94.2 %.
	With potassium iodide; In chlorobenzene; at 132 - 135℃; for 6h;	Copper cyanide (215 g, 2.4 moles), potassium iodide (199 g, 1.2 moles) and monochlorobenzene (1.0 L) were added to a 3 L four necked round bottom flask containing 2,3-dichlorobenzoyl chloride (500g, 2.392 moles). The reaction mixture was heated to reflux under nitrogen blanket and maintained at 132-135° C. for 6 hrs. The reaction mixture was then filtered and monochlorobenzene distilled off to obtain 2,3-dichlorobenzoyl cyanide(C 6 H 3 Cl 6 COCN). Yield = 470 g Purity = 97% (when analysed by Gas Chromatography)

Reference： [1]Patent: WO2007/138075,2007,A1 .Location in patent: Page/Page column 14
[2]Patent: EP1731503,2006,A2 .Location in patent: Page/Page column 7
[3]Patent: US6639072,2003,B1 .Location in patent: Page/Page column 8

19
hydrous magnesium silicate [ No CAS ]
[ 169878-74-4 ]
[ 2905-60-4 ]
N-[4-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)-carbonyl]phenyl]-2,3-dichlorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In hexane; water	153 N-[4-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)-carbonyl]phenyl]-2,3-dichlorobenzamide EXAMPLE 153 N-[4-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)-carbonyl]phenyl]-2,3-dichlorobenzamide A mixture of 301.6 mg of 2,3-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz-[b,e]azepine is added. Stirring is continued for 2 hours. Water is added and the organic layer washed with 1 N HCl, water, 1 M NaHCO3 and water then dried over Na2 SO4. The organic layer is passed through a pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.32 g of the desired product as a crystalline solid, m.p. 225°-230° C.
	With triethylamine In hexane; water	253 N-[4-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2,3-dichlorobenzamide EXAMPLE 253 N-[4-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2,3-dichlorobenzamide A mixture of 301.6 mg of 2,3-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is added. Stirring is continued for 2 hours. Water is added and the organic layer washed with 1N HCl, water, 1M NaHCO3 and water then dried over Na2 SO4. The organic layer is passed through a pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.32 g of the desired product as a crystalline solid, m.p. 225°-230° C.
	With triethylamine In hexane; water	253 N-[4-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2,3-dichlorobenzamide Example 253 N-[4-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2,3-dichlorobenzamide A mixture of 301.6 mg of 2,3-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz-[b,e]azepine is added. Stirring is continued for 2 hours. Water is added and the organic layer washed with 1N HCl, water, 1M NaHCO3 and water then dried over Na2 SO4. The organic layer is passed through a pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.32 g of the desired product as a crystalline solid, m.p. 225°-230° C.

	With triethylamine In hexane; water	253 N-[4-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2,3-dichlorobenzamide EXAMPLE 253 N-[4-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2,3-dichlorobenzamide A mixture of 301.6 mg of 2,3-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz-[b,e]azepine is added. Stirring is continued for 2 hours. Water is added and the organic layer washed with 1N HCl, water, 1M NaHCO3 and water then dried over Na2 SO4. The organic layer is passed through a pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.32 g of the desired product as a crystalline solid, m.p. 225°-230° C.
	With triethylamine In hexane; water	253 N-[4-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2,3-dichlorobenzamide EXAMPLE 253 N-[4-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2,3-dichlorobenzamide A mixture of 301.6 mg of 2,3-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz-[b,e]azepine is added. Stirring is continued for 2 hours. Water is added and the organic layer washed with 1N HCl, water, 1 H NaHCO3 and water then dried over Na2 SO4. The organic layer is passed through a pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.32 g of the desired product as a crystalline solid, m.p. 225°-230° C.

Reference： [1]Current Patent Assignee: CARDIOKINE BIOPHARMA - US5686445, 1997, A
[2]Current Patent Assignee: CARDIOKINE BIOPHARMA - US5736538, 1998, A Current Patent Assignee: CARDIOKINE BIOPHARMA - US5869483, 1999, A
[3]Current Patent Assignee: CARDIOKINE BIOPHARMA - US5693635, 1997, A
[4]Current Patent Assignee: CARDIOKINE BIOPHARMA - US5739128, 1998, A Current Patent Assignee: CARDIOKINE BIOPHARMA - US5760031, 1998, A Current Patent Assignee: CARDIOKINE BIOPHARMA - US5512563, 1996, A
[5]Current Patent Assignee: CARDIOKINE BIOPHARMA - US5747487, 1998, A

20
methyl 3-(4-amino-2-oxohydropyrimidinyl)-2-((tert-butoxy)carbonylamino)propionate [ No CAS ]
[ 2905-60-4 ]
methyl 3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)-2-((tert-butoxy)carbonylamino)propionate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With hydrogenchloride In pyridine; methanol; dichloromethane	3 Methyl 3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)-2-((t-butoxy)carbonylamino) propionate (3) Example 3 Methyl 3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)-2-((t-butoxy)carbonylamino) propionate (3) In 15 ml of pyridine and 10 ml of dichloromethane, 2.96 g (9.48 mmol) of methyl 3-(4-amino-2-oxohydropyrimidinyl)-2-((t-butoxy)carbonylamino) propionate was dissolved, and 2.7 ml (19.0 mmol) of dichlorobenzoyl chloride was added, followed by stirring the resulting mixture at 50ØC for 2 hours. Methanol was added to the reaction solution and the mixture was concentrated. To the residue, 3N hydrochloric acid was added and the resultant was extracted with chloroform. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol = 20:1) to obtain 3.35 g of methyl 3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)-2-((t-butoxy)carbonylamino) propionate (yield: 73%). LR-MS(m/z):484(M+) IR(KBr):3442,3222,2962,1701,1627,1562,1492,1435,1369,1334,1303,1250,1162, 788cm-1 NMR(300MHz,CD3OD, δ ppm):1.38(9H,s),3.77(3H,s),3.83-3.94(1H,m), 4.55-4.63(1H,m), 4.68-4.77(1H,m), 7.41-7.55(4H,m),7.93-7.98(1H,m)

Reference： [1]Current Patent Assignee: TORAY INDUSTRIES INC - EP1323709, 2003, A1

21
[ 2905-60-4 ]
[ 24644-08-4 ]
2,3-Dichloro-N-(2-[tricyclo[3.3.1.13.7]dec-1-yl]ethyl)-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		73 2,3-Dichloro-N-(2-[tricyclo[3.3.1.13,7]dec-1-yl]ethyl)-benzamide EXAMPLE 73 2,3-Dichloro-N-(2-[tricyclo[3.3.1.13,7]dec-1-yl]ethyl)-benzamide Prepared according to the method of Example 1 from 1-adamantaneethylamine hydrochloride (0.102 g) and 2,3-dichlorobenzoyl chloride (0.102 g) to give the title compound as a white solid (0.090 g). Melting point: 158-159° C. MS (APCI+ve) 352/354 (M+H)30 1H NMR (DMSO-d6) δ 8.42 (1H, t), 7.68 (1H, dd), 7.40 (1H, t), 7.34 (1H, dd), 3.22 (2H, m), 1.93 (3H, s), 1.64 (6H, m), 1.51 (6H, d), 1.31 (2H, m).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US6201024, 2001, B1

22
[ 2905-60-4 ]
[ 143-33-9 ]
[ 544-92-3 ]
[ 77668-42-9 ]
[ 252186-80-4 ]

Reference： [1]Patent: EP1731503,2006,A2 .Location in patent: Page/Page column 6

23
[ 2905-60-4 ]
[ 544-92-3 ]
[ 77668-42-9 ]
[ 252186-80-4 ]

Reference： [1]Patent: EP1731503,2006,A2 .Location in patent: Page/Page column 5-6

24
[ 2905-60-4 ]
[ 36725-28-7 ]
2,3-dichloro-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)benzamide [ No CAS ]

Reference： [1]Arzneimittel-Forschung/Drug Research,2008,vol. 58,p. 569 - 573

25
[ 5625-67-2 ]
[ 2905-60-4 ]
[ 1146411-63-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 3h;	15 The 4-[(2,3-dichlorophenyl)carbonyl]-2-piperazinone used in the above procedure was prepared as follows:2-piperazinone (1g, 9.99 mmol) and λ/-ethyl-λ/-(1-methylethyl)-2-propanamine (2.62 ml, 14.98 mmol) were added together in dichloromethane (20 ml) at O0C. Subsequently 2,3-dichlorobenzoyl chloride (2.30 g, 10.99 mmol) was added portionwise. The mixture was left under argon and in an icebath and allowed to return to room temperature whilst being stirred constantly for 3 hours. Dichloromethane and saturated aqueous sodium hydrogen carbonate were added and the mixture was extracted into dichloromethane (x3). The dichloromethane layers were combined and washed with water (x1 ), and then brine(xi ), and dried with magnesium sulphate. The solvent was evaporated in vacuo and the crude product was purified by flash-silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to give 4-[(2,3-dichlorophenyl)carbonyl]-2-piperazinone (1.4 g) as a white solid. LC/MS [M+H]+ = 273, retention time = 1.76 minutes.
	With triethylamine In dichloromethane at 20℃;	10 To a suspension of 2-piperazinone (5.3 g, 52.9 mmol) in dry dichloromethane (DCM) (76 ml) was added triethylamine (16.23 ml, 116 mmol) and finally 2, 3-dichlorobenzoyl chloride (12.20 g, 58.2 mmol) dropwise (exothermic). The mixture was stirred at room temperature. After 1 hour the mixture was diluted with DCM (150 ml.) and sat. NaHCO3 (150 ml), the phases were separated and the aqueous layer extracted with DCM (2x100ml). The combined organic fractions were washed with brine and dried over MgSO4. Evaporation gave 4-[(2,3-dichlorophenyl)carbonyl]-2-piperazinone (12 g)- LC/MS [M+H]+ = 272.93, retention time = 0.69 minutes (2 minute method).
	With triethylamine In dichloromethane at 20℃;	To a suspension of 2-piperazinone (5.3 g, 52.9 mmol, commercially available e.g. from Sigma-Aldrich) in dry Dichloromethane (DCM) (76 ml) was added triethylamine (16.23 ml, 116 mmol) and finally 2,3-dichlorobenzoyl chloride (12.20 g, 58.2 mmol, commercially available e.g. from ABCR, ChemPacific or UkrOrgSynthesis) dropwise (exothermic). The mixture was stirred at room temperature. After 1 hour the mixture was diluted with Dichloromethane (DCM) (150 ml.) and saturated NaHCC>;3 solution(150 ml), the phases were separated and the aqueous layer was extracted with DCM (2x100ml). The combined organic fractions were washed with brine and dried over MgSOφ Evaporation gave 4-[(2,3-dichlorophenyl)carbonyl]-2-piperazinone (12 g).LC/MS [M+H]+ = 272.93, retention time = 0.69 minutes (2 minute method).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/53459, 2009, A1 Location in patent: Page/Page column 44-45
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2010/125101, 2010, A1 Location in patent: Page/Page column 54-55
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2010/125102, 2010, A1 Location in patent: Page/Page column 66

26
[ 780753-89-1 ]
[ 2905-60-4 ]
[ 1146411-57-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	Example 13 4-[(2,3-Dichlorophenyl)carbonyl]-1 -(4-fluorophenyl)-2-piperazinone (E13); 1-(4-Fluorophenyl)-2-piperazinone (150mg, 0.77 mmol, prepared as described above for Example 12) and lambda/-ethyl-lambda/-(1-methylethyl)-2-propanamine (0.20 ml, 1.16 mmol) were added together in dichloromethane (4 ml) at O0C. Subsequently 2,3- dichlorobenzoyl chloride (178 mg, 0.85 mmol) was added portionwise. The mixture was left under argon and in an icebath and allowed to return to room temperature whilst being stirred constantly overnight. Dichloromethane and aqueous 3N citric acid were then added and the mixture was extracted into dichloromethane (x2). The dichloromethane layers were combined and washed sequentially with water (x1 ), saturated aqueous sodium hydrogen carbonate (x1 ), water (x1 ), and brine (x1 ), and then dried over magnesium sulphate. The solvent was evaporated in vacuo to give 4-[(2,3-dichlorophenyl)carbonyl]-<strong>[780753-89-1]1-(4-fluorophenyl)-2-piperazinone</strong> (224 mg) as a white solid. LC/MS [M+H]+ = 367, retention time = 2.62 minutes.

Reference： [1]Patent: WO2009/53459,2009,A1 .Location in patent: Page/Page column 43

27
[ 756818-04-9 ]
[ 2905-60-4 ]
[ 1146411-93-9 ]

Yield	Reaction Conditions	Operation in experiment
44.6%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃;	28 Example 284-[(2,3-dichlorophenyl)carbonyl]-1 -(4-fluoro-2-methylphenyl)-2-piperazinone(E28); In a round-bottomed flask was added 1-(4-fluoro-2-methylphenyl)-2-piperazinone (90 mg, 0.432 mmol) and DIPEA (0.1 13 ml, 0.648 mmol) in dichloromethane (DCM) (4 ml) to give a colorless solution. The reagents were cooled in an ice bath and then 2,3-dichlorobenzoyl chloride (100 mg, 0.475 mmol) was slowly added under an argon atmosphere. The reaction was left to stir overnight. Dichloromethane and aqueous 3N citric acid were added and the product was extracted into dichloromethane. Dichloromethane layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and brine and then dried over magnesium sulafte. Solvent was evaporated in vacuo. Product was purified by MDAP and fractions combined and then the solvent was evaporated in vacuo to give a white solid 4-[(2,3- dichlorophenyl)carbonyl]-1-(4-fluoro-2-methylphenyl)-2-piperazinone (73.5 mg, 0.193 mmol, 44.6 % yield). LC/MS [M+H]+ = 380.9, retention time = 2.72 minutes.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/53459, 2009, A1 Location in patent: Page/Page column 55

28
[ 1146412-95-4 ]
[ 2905-60-4 ]
[ 1146412-93-2 ]

Yield	Reaction Conditions	Operation in experiment
68.5%	With polymer-bound triethylamine In dichloromethane at 20℃;	76 Example 76 i-^-chloro-S^-morpholinylJphenyll^-^.S-dichlorophenylJcarbonyl]^- piperazinone (E76); To 1-[2-chloro-5-(4-morpholinyl)phenyl]-2-piperazinone (250 mg, 0.845 mmol) in dichloromethane (10 ml) was added first the polymer-bound triethylamine (396 mg, 1.268 mmol) and then the 2,3-dichlorobenzoyl chloride (0.131 ml, 0.972 mmol), and the reaction stirred at room temperature overnight. Saturated sodium hydrogen carbonate solution was added, stirred for 10 minutes and the organic layer was seperated through a hydrophobic frit and reduced under vacuum. The residue was purified by SP4 silica gel chromatography with a 10-100% ethyl acetate/isohexane gradient, eluting in 100% ethylacetate, to leave a white solid. 1-[2-chloro-5-(4-morpholinyl)phenyl]-4-[(2,3-dichlorophenyl)carbonyl]-2-piperazinone (277 mg, 0.579 mmol, 68.5 % yield) LC/MS [M+H]+ = 468.02, retention time = 2.53 minutes

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/53459, 2009, A1 Location in patent: Page/Page column 85

29
[ 907972-32-1 ]
[ 2905-60-4 ]
[ 1146411-73-5 ]

Yield	Reaction Conditions	Operation in experiment
59.2%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 3h;	22 Example 224-[(2,3-dichlorophenyl)carbonyl]-1 -(1 -naphthalenyl)-2-piperazinone (E22); In a round-bottomed flask was added 1-(1-naphthalenyl)-2-piperazinone (100 mg, 0.442 mmol) and DIPEA (0.1 16 ml, 0.663 mmol) in Dichloromethane (DCM) (4 ml) to give a colorless solution. The reagents were cooled in an ice bath and 2,3- dichlorobenzoyl chloride (102 mg, 0.486 mmol) was slowly added under an argon atmosphere. Once the 2,3-dichlorobenzoyl chloride had been added the reaction was stirred for one hour at O0C and then at ambient temperature for 2 hours. Dichloromethane and aqueous 3N citric acid were added and the product was extracted into dichloromethane. The dichloromethane layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and brine and then dried over magnesium sulphate. The solvent was evaporated in vacuo. The product was triturated with methanol and then dried on the high vacuum and placed in the oven overnight to give 4-[(2,3-dichlorophenyl)carbonyl]-1-(1-naphthalenyl)-2-piperazinone (110 mg, 0.262 mmol, 59.2 % yield) as a pale orange solid. LC/MS [M+H]+ = 399, retention time = 2.89 minutes.The 1-(1-naphthalenyl)-2-piperazinone used in the above reaction was prepared in a manner analogous to that described in Example 4 for the preparation of 1-(2- methylphenyl)-2-piperazinone but using 1-naphthylamine in the place of o-toluidine.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/53459, 2009, A1 Location in patent: Page/Page column 50

30
[ 1146411-87-1 ]
[ 2905-60-4 ]
[ 1146411-90-6 ]

Yield	Reaction Conditions	Operation in experiment
22.32%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃;	27 Example 274-[(2,3-dichlorophenyl)carbonyl]-1 -[2-(1 -methylethyl)phenyl]-2-piperazinone(E27); In a round-bottomed flask was added 1-[2-(1-methylethyl)phenyl]-2-piperazinone (100 mg, 0.458 mmol, prepared in an analogous manner to that described in Example 25) and DIPEA (0.120 ml, 0.687 mmol) in dichloromethane (DCM) (4 ml) to give a colorless solution. The reagents were cooled in an ice bath and then 2,3- dichlorobenzoyl chloride (106 mg, 0.504 mmol) was slowly added under an argon atmosphere. The reaction was left to stir overnight. Dichloromethane and aqueous 3N citric acid were added and the product was extracted into dichloromethane. Dichloromethane layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and brine and then dried over magnesium sulfate. Solvent was evaporated in vacuo. The product was purified by column chromatography on silica gel eluting with a gradient of 0% to 50% ethyl acetate in iso-hexane. Fractions were collected and solvent was evaporated in vacuo. The product was purified again by MDAP and fractions combined and then the solvent was evaporated in vacuo to give a white solid 4-[(2,3-dichlorophenyl)carbonyl]-1-[2-(1-methylethyl)phenyl]-2- piperazinone (40 mg, 0.102 mmol, 22.32 % yield). LC/MS [M+H]+ = 390.9, retention time = 2.95 minutes.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/53459, 2009, A1 Location in patent: Page/Page column 54-55

31
[ 1146412-05-6 ]
[ 2905-60-4 ]
[ 1146412-04-5 ]

Yield	Reaction Conditions	Operation in experiment
31%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	38 Example 382-{4-[(2,3-dichlorophenyl)carbonyl]-2-oxo-1 -piperazinyl}-5-fluorobenzonitrile(E38); To a suspension of 5-fluoro-2-(2-oxo-1-piperazinyl)benzonitrile.HCI (90 mg, 0.352 mmol) in dichloromethane (DCM) (7 ml) at O0C under argon was added the DIPEA (0.154 ml, 0.880 mmol) and then, portionwise, the 2,3-dichlorobenzoyl chloride (81 mg, 0.387 mmol). The reaction mixture was allowed to warm to RT and left to stir atRT under argon overnight.Dichloromethane (15ml) and aqueous 3N citric acid (15ml) were added and the product extracted into dichloromethane (x2). The dichloromethane layers were combined and washed sequentially with water (15ml) (x1 ), saturated aqueous sodium hydrogen carbonate (15ml) (x1 ), water (15ml) (x1 ), and brine (15ml) (x1 ), and the dried over magnesium sulphate. The solvent was evaporated in vacuo to give a brown oil.The crude product was purified by flash-silica gel chromatography, eluting with 0- 10% MeOH / EtOAc. Product-containing fractions were concentrated under vacuum to give an orange solid, 2-{4-[(2,3-dichlorophenyl)carbonyl]-2-oxo-1-piperazinyl}-5- fluorobenzonitrile (45mg, 0.109 mmol, 31.0 % yield), LC/MS [M+H]+ = 392.0, retention time = 2.28 minutes.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/53459, 2009, A1 Location in patent: Page/Page column 59-60

32
[ 2905-60-4 ]
[ 438197-19-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1368 - 1372

33
[ 1129401-20-2 ]
[ 2905-60-4 ]
[ 1129401-45-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	In toluene at 20℃; for 20h;	12 Methyl 2-amino-5-(4-(4-butoxyphenylsulfonamido)-3-(methoxycarbonyl)benzoyl)benzoate (0.11 g, 0.198 mmol), prepared by procedure G, was mixed with aroyl chloride (0.218 mmol), dissolved in toluene and stirred at rt for 20 h. After concentration, MeOH was added and the precipitate was collected and purified by chromatography. The hydrolysis was performed according to the general procedure H affording the pure di-acid in yields depicted in table 3.

Reference： [1]Current Patent Assignee: OREXO AB - US2010/286215, 2010, A1 Location in patent: Page/Page column 24; 25

34
[ 21909-49-9 ]
[ 2905-60-4 ]
[ 1164275-30-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: ethyl (2-methylindol-3-yl)acetate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; Stage #2: 2,3-dichlorobenzoyl chloride In N,N-dimethyl-formamide; mineral oil at 20℃;	[1-(2,3-Dichloro-benzoyl)-2-methyl-1H-indol-3-yl]-acetic acid ethyl ester 31; Indole 30 (5 g, 23.0 mmol, 1 eq) was dissolved in DMF (50 ml) and was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 1.01 g, 25.31 mmol, 1.1 eq) was added and the mixture was stirred for 30 min. 2, 3-dichlorobenzoyl chloride (5.06 g, 24.16 mmol, 1.05 eq) was dissolved in DMF (25 ml) and this solution was added to the reaction over 2 min and the mixture was stirred overnight at ambient temperature. The mixture was poured into water (100 ml) and DCM (100 ml) and the organic layer was poured off. The aqueous layer was then extracted with DCM (2×50 ml) and the combined organic layers were washed with water (2×100 ml), were washed with brine (50 ml), were dried over Na2SO4, filtered and the solvent was removed in vacuo. The product was purified via column chromatography eluted with a gradient from 4:1 to 1:1 CyH:EtOAc (Rf product=0.4, Rf SM=0.27, UV, CAM). This gave 7.224 g (80%) of a yellow-green oil. 1H-NMR (CDCl3) 500 MHz: δ (ppm)=1.24 (3H, t, J=7.1 Hz, CH2CH3), 2.26 (3H, s, CH3), 3.66 (2H, s, CCH2CO), 4.14 (2H, quart, J=7.1 Hz, CH2CH3), 7.13 (1H, t, J=7.3 Hz NCCHCHCHCHC), 7.24 (1H, t, J=7.6 Hz NCCHCHCHCHC), 7.32 (1H, d, J=8.3 Hz, NCCHCHCHCHC), 7.37 (1H, dd, J=7.6 Hz, J=7.6 Hz, CCHCHCHCCl), 7.39 (1H, dd, J=2.0 Hz, J=7.6 Hz, CCHCHCHCCl), 7.50 (1H, d, J=7.8 Hz NCCHCHCHCHC), 7.60 (1H, dd, J=2.0 Hz, J=7.6 Hz, CCHCHCHCCl). 13C-NMR (CDCl3) 125 MHz: δ (ppm)=13.5 (CH3), 14.2 (CH3), 30.3 (CH2), 61.0 (CH2), 114.3 (C), 114.6 (CH), 118.4 (CH), 123.8 (CH), 124.3 (CH), 127.2 (CH), 128.1 (CH), 130.2 (C), 130.3 (C), 132.5 (CH), 134.3 (C), 134.4 (C), 135.8 (C), 138.4 (C), 165.8 (CO), 170.6 (CO). IR Spectrum; evaporated film: v(cm-1)=3068, 2980, 2931, 1734, 1687, 1456, 1358, 1320, 1160. MS-ES (positive): 390.1 (M+H+), 392.1 (M+H+).

Reference： [1]Current Patent Assignee: GIULIANI S.P.A. - US2011/39808, 2011, A1 Location in patent: Page/Page column 53-54

35
[ 1426214-91-6 ]
[ 2905-60-4 ]
[ 76-05-1 ]
2,3-dichloro-N-[6-[4-[(2-fluoro-5-methylphenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide trifluoroacetate salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5 mg	Stage #1: N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide; 2,3-dichlorobenzoyl chloride With pyridine at 20 - 25℃; for 16h; Stage #2: trifluoroacetic acid In water; acetonitrile	24.ii 2,3-Dichloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]- 1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide To a solution of 70 mg of N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide in 0.5 ml pyridine, 13 mg of 2,3-dichloro- benzoyl chloride were added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and filtered through a chem elut cartridge by eluting with EtOAc. After removal of the solvents under reduced pressure the crude product was purified by preparative HPLC (018 reversed phase column, elution with a water/MeCN gradient with 0.1% TEA). The fractions containing the product were lyophilized to yield the title compound in the form of its salt with trifluoroacetic acid. Yield: 5mg. 1H-NMR (DMSO-d6): δ (ppm) = 2.33 (s, 3H), 7.29 (d, J = 8.8 Hz, 2H), 7.32 (m, 1 H), 7.48 (m, 1 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.73 (m, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 2H), 9.29 (s, 1 H), 10.95 (s, 1 H), 12.40 (br, 1 H). MS (ES+): m/e = 571 .3 (M+H), chloro pattern.
5 mg	Stage #1: N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide; 2,3-dichlorobenzoyl chloride With pyridine at 20 - 25℃; for 16h; Stage #2: trifluoroacetic acid In water; acetonitrile	24.ii (ii) 2,3-Dichloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1 H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide To a solution of 70 mg of N-[4-(3-amino-1 H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2- fluoro-5-methyl-benzenesulfonamide in 0.5 ml pyridine, 13 mg of 2,3-dichloro- benzoyl chloride were added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and filtered through a chem elut cartridge by eluting with EtOAc. After removal of the solvents under reduced pressure the crude product was purified by preparative HPLC (C18 reversed phase column, elution with a water/MeCN gradient with 0.1 % TFA). The fractions containing the product were lyophilized to yield the title compound in the form of its salt with trifluoroacetic acid. Yield: 5 mg.H-NMR (DMSO-de): δ (ppm) = 2.33 (s, 3H), 7.29 (d, J = 8.8 Hz, 2H), 7.32 (m, 1 H), 7.48 (m, 1 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.73 (m, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 2H), 9.29 (s, 1 H), 10.95 (s, 1 H), 12.40 (br, 1 H).MS (ES+): m/e = 571.3 (M+H), chloro pattern.
5 mg	Stage #1: N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide; 2,3-dichlorobenzoyl chloride With pyridine at 20 - 25℃; for 16h; Stage #2: trifluoroacetic acid	24.ii (ii) (ii) 2,3-Dichloro-N-[6-[4-[(2-fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide To a solution of 70 mg of N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide in 0.5 ml pyridine, 13 mg of 2,3-dichloro-benzoyl chloride were added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and filtered through a chem Elut cartridge by eluting with EtOAc. After removal of the solvents under reduced pressure the crude product was purified by preparative HPLC (C18 reversed phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the title compound in the form of its salt with trifluoroacetic acid. Yield: 5 mg. 1H-NMR (DMSO-d6): δ (ppm)=2.33 (s, 3H), 7.29 (d, J=8.8 Hz, 2H), 7.32 (m, 1H), 7.48 (m, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.73 (m, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H), 9.29 (s, 1H), 10.95 (s, 1H), 12.40 (br, 1H). MS (ES+): m/e=571.3 (M+H), chloro pattern.

5 mg	Stage #1: N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide; 2,3-dichlorobenzoyl chloride With pyridine at 20 - 25℃; for 16h; Stage #2: trifluoroacetic acid In water; acetonitrile	24.ii (ii) 2,3-dichloro-N-[6-[4-[(2-fluoro-5-methylphenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide In 0.5 ml of pyridine in 70mg N-[ 4 - (3-amino -1H-pyrazolo [3,4-b] pyrazin-6-yl) phenyl] - 2-fluoro-5-methyl-benzene sulfonamide adding 13mg2,3-dichloro-benzoyl chloride, the reaction mixture stirring at room temperature 16h. Furthermore, the reaction mixture is diluted with water, filtering through chem Column (chem Cartridge), eluting with EtOAc. After removing the solvent under reduced pressure, the crude product by preparative HPLC (C18 reverse phase column, containing 0.1% TFA water/MeCN gradient elution) purification. Fractions containing product of freeze-drying to obtain trifluoroacetic acid salt forms of title compound. Yield: 5 mg.
5 mg	Stage #1: N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-2-fluoro-5-methyl-benzenesulfonamide; 2,3-dichlorobenzoyl chloride With pyridine at 20℃; for 16h; Stage #2: trifluoroacetic acid	24.II 2,3-dichloro-N-[6-[4-[(2-fluoro-5-methylphenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-b]pyrazin-3-yl]benzamide To a solution of 70 mg of N- [4- (3-amino-1H-pyrazolo [3,4-b] pyridin-6-yl) phenyl] -2-fluoro-5-methyl-benzenesulfonamide in 0.5 ml of pyridine 13 mg of 2,3-dichloro-benzoyl chloride was added and the reaction mixture was stirred at room temperature for 16 hours, then the reaction mixture was diluted with water and then dissolved with EtOAc The crude product was purified by preparative HPLC (C18 reverse phase column, eluting with a water / MeCN gradient with 0.1% TFA) to remove the solvent under reduced pressure, The fractions containing the product were lyophilized to give the title compound in the form of its salt with trifluoroacetic acid Yield: 5 mg.

Reference： [1]Current Patent Assignee: SANOFI - WO2013/41502, 2013, A1 Location in patent: Page/Page column 105
[2]Current Patent Assignee: SANOFI - WO2013/41119, 2013, A1 Location in patent: Page/Page column 104
[3]Current Patent Assignee: SANOFI - US2013/72493, 2013, A1 Location in patent: Paragraph 0387; 0388; 0389
[4]Current Patent Assignee: SANOFI - CN103012407, 2016, B Location in patent: Paragraph 0425; 0426; 0429; 0430
[5]Current Patent Assignee: SANOFI - JP5827849, 2015, B2 Location in patent: Paragraph 0157;0159

36
[ 2905-60-4 ]
[ 150-86-7 ]
1-O-(2,3-dichlorobenzoyl)phyto [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With pyridine; dmap at 30 - 35℃; for 14h;
	With pyridine; dmap at 30 - 35℃; for 14h;	General procedure for synthesizing phytol (PhY)derivatives 1-10 General procedure: Phytol (592 mg, 2 mmol) was dissolved in dry pyridine, andthe respective acyl/aryl chloride (3 mmol) was added. Afteradding a catalytic amount of 4-dimethylaminopyridine(DMAP), the reaction mixture was stirred at 30-35 °C for14 h. After completion of the reaction, crushed ice wasadded, and the reaction mixture was extracted withchloroform (3 × 25 mL). The combined chloroform extractwas washed with 6% aqueous HCl solution to remove thepyridine. Finally, the combined CHCl3 extract was washedwith distilled water and dried over anhydrous Na2SO4, andthe solvent was removed under vacuum. The resulting crudeproducts were separately purified by column chromatography(silica gel, 60-120 mesh, 24 g, column diameter2 × 30 cm) to afford the respective derivatives, 1-10, in highpurity (>95%).

Reference： [1]Upadhyay, Harish C.; Dwivedi, Gaurav R.; Roy, Sudeep; Sharma, Ashok; Darokar, Mahendra P.; Srivastava, Santosh K. [ChemMedChem, 2014, vol. 9, # 8, p. 1860 - 1868]
[2]Saxena, Archana; Upadhyay, Harish C.; Cheema, Harveer S.; Srivastava, Santosh K.; Darokar, Mahendra P.; Bawankule, Dnyaneshwar U. [Medicinal Chemistry Research, 2018, vol. 27, # 5, p. 1345 - 1354]

37
[ 5248-20-4 ]
[ 2905-60-4 ]
4,7-dimethyl-2-oxo-2H-chromen-6-yl 2,3-dichlorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate In neat (no solvent) at 20℃; for 0.25h; Milling;	General Procedure for the Synthesis of the Title Compounds (3a-ss) General procedure: 6-Hydroxycoumarin (2a-b) (1 mmol), anhydrous K2CO3 (0.17 g, 1.2 mmol), and aryl chloride (1.1 mmol) were mixed in a 5 mL stainless steel container and milled in a ball mill at 30 Hz with one stainless steel ball of 0.5 cm diameter for 15 min at room temperature. The reaction was monitored by TLC analysis. The crude reaction mixture was washed by water, and filtered; the product was recrystallized from EtOH to yield the title compounds (3a-ss).

Reference： [1]Xie, Ying; Lei, Zheng-Lin; Luo, Yan-Ping [Letters in drug design and discovery, 2014, vol. 11, # 9, p. 1124 - 1132]

38
[ 2905-60-4 ]
(S)-3-(6-fluoro-2-pyridyl)-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine [ No CAS ]
(S)-(2,3-dichlorophenyl)(3-(6-fluoropyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With triethylamine In dichloromethane at 0 - 20℃; for 1h;	54 (S)-(2,3-dichlorophenyl)(3-(6-fluoropyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone To a solution of (S)-3-(6-fluoro-2-pyridyl)-6-methyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-ajpyrazine (110 mg, 0.41 mmol) (prepared as described in Example 54, Intermediate 54B, replacing 4-methoxy-pyridine-2-carboxylic acid hydrazide with 6-fluoro-pyridine-2-carboxylic acid hydrazide in step for intermediate 54A) and triethylamine (0.283 mL, 2.04 mmol) in CH2CI2 (3 mL) was added 2,3-dichlorobenzoyl chloride (128.1 mg, 0.61 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with ((. The organic layers were separated, dried (Na2S04), filtered and the solvent concentrated in vacuo. The crude compound was purified by column chromatography (silica, MeOH in EtOAC 0: 100 to 10:90), the desired fractiones were collected, the solvent evaporated to give (S)-(2,3-dichlorophenyl)(3-(6-fluoropyridin-2-yl)-6-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (100 mg, 60 %) as a white foam
	With triethylamine In dichloromethane for 1h;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - JP2017/527588, 2017, A Location in patent: Paragraph 0428-0430
[2]Rudolph, Dale A.; Alcazar, Jesus; Ameriks, Michael K.; Anton, Ana Belen; Ao, Hong; Bonaventure, Pascal; Carruthers, Nicholas I.; Chrovian, Christa C.; De Angelis, Meri; Lord, Brian; Rech, Jason C.; Wang, Qi; Bhattacharya, Anindya; Andres, Jose Ignacio; Letavic, Michael A. [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 16, p. 3157 - 3163]

39
[ 2905-60-4 ]
(S)-3-(4-methoxy-2-pyridyl)-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine [ No CAS ]
(S)-(2,3-dichlorophenyl)(3-(4-methoxypyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39.3%	With triethylamine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere;	55 (S)-(2,3-dichlorophenyl)(3-(4-methoxypyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 2,3-Dichlorobenzoyl chloride (103.3 mg, 0.49 mmol) was added to a stirred solution of (S)-3-(4-methoxy-2-pyridyl)-6-methyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine (121 mg, 0.49 mmol) and triethylamine (0.171 mL, 1.23 mmol) in CH2CI2 under nitrogen at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for lh. The reaction mixture was quenched with water and extracted with CH2CI2 (1.5 mL). The organic layers were separated, dried ( a2S04), filtered and the solvent concentrated in vacuo. The crude product was purified by column chromatography (silica, MeOH in EtOAc 0: 100 to 10:90) and the desired fractions were collected and the solvent evaporated. The residue was further purified by column chromatography (silica, CH3CN in CH2CI2 0/100 to 100/0). The desired fractions were collected and the solvent evaporated. The residue was triturated with diisopropyl ether to yield (S)-(2,3-dichlorophenyl)(3-(4-methoxypyridin-2-yl)-6-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (81 mg, 39.3 %) as an off-white solid
	With triethylamine In dichloromethane for 1h;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - JP2017/527588, 2017, A Location in patent: Paragraph 0431-0432; 0435
[2]Rudolph, Dale A.; Alcazar, Jesus; Ameriks, Michael K.; Anton, Ana Belen; Ao, Hong; Bonaventure, Pascal; Carruthers, Nicholas I.; Chrovian, Christa C.; De Angelis, Meri; Lord, Brian; Rech, Jason C.; Wang, Qi; Bhattacharya, Anindya; Andres, Jose Ignacio; Letavic, Michael A. [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 16, p. 3157 - 3163]

40
[ 2905-60-4 ]
(S)-3-(5-fluoro-2-pyridyl)-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine [ No CAS ]
(S)-(2,3-dichlorophenyl)(3-(5-fluoropyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.4%	With triethylamine In dichloromethane at 20℃; for 0.5h; Inert atmosphere;	69 (S)-(2,3-dichlorophenyl)(3-(5-fluoropyridin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 2,3-Dichlorobenzoyl chloride (94.3 mg, 0.45 mmol) was added to a stirred solution of (S)-3-(5-fluoro-2-pyridyl)-6-methyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.30 mmol) (prepared as described in Example 54, Intermediate 54B, replacing 4-methoxy-pyridine-2-carboxylic acid hydrazide with 5-fluoro-pyridine-2-carboxylic acid hydrazide in step for intermediate 54A) and triethylamine (0.21 mL, 1.50 mmol) in CH2CI2 (2 mL) under nitrogen at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 30 additional min. The reaction mixture was quenched with water and extracted with CH2CI2. The organic layers were separated, dried ( a2S04), filtered and the solvent concentrated in vacuo. The crude product was purified by column chromatography (silica, MeOH in EtOAc 0: 100 to 10:90), the desired fractions were collected and the solvent evaporated in vacuo to yield the desired compound with some impurities. This was purified by RP HPLC on (C18 Sunfire 30 x 100 5um). Mobile phase (Gradient from 50% 0.1% NH4C02CH3 solution in Water, 40% CH3CN to 40% 0.1% NH4C02CH3 solution in Water, 50% CH3CN), yielding (S)-(2,3-dichlorophenyl)(3-(5-fluoropyridin-2-yl)-6-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (31.3 mg, 24.4%).
	With triethylamine In dichloromethane for 1h;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - JP2017/527588, 2017, A Location in patent: Paragraph 0471-0473
[2]Rudolph, Dale A.; Alcazar, Jesus; Ameriks, Michael K.; Anton, Ana Belen; Ao, Hong; Bonaventure, Pascal; Carruthers, Nicholas I.; Chrovian, Christa C.; De Angelis, Meri; Lord, Brian; Rech, Jason C.; Wang, Qi; Bhattacharya, Anindya; Andres, Jose Ignacio; Letavic, Michael A. [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 16, p. 3157 - 3163]

41
[ 2905-60-4 ]
(S)-3-(5-fluoropyrimidin-2-yl)-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine [ No CAS ]
(S)-(2,3-dichlorophenyl)(3-(5-fluoropyrimidin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38.5%	With triethylamine In dichloromethane at 20℃; for 1h; Inert atmosphere;	73 (S)-(2,3-dichlorophenyl)(3-(5-fluoropyrimidin-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 2,3 -Dichlorobenzoyl chloride (60 mg, 0.29 mmol) was added to a stirred solution of (S)-3-(5-fluoropyrimidin-2-yl)-6-methyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine (67 mg, 0.29 mmol) (prepared as described in Example 54, Intermediate 54B, replacing 4-methoxy-pyridine-2-carboxylic acid hydrazide with 5-fluoropyrimidine-2-carboxylic acid hydrazide in step for intermediate 54A) and triethylamine (0.20 mL, 1.43 mmol) in CH2CI2 (15 mL) under nitrogen at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for lh. The reaction mixture was quenched with water and extracted with CH2CI2. The organic layers were separated, dried (Na2S04), filtered and the solvent concentrated in vacuo. The crude product was purified by column chromatography (silica, MeOH in EtOAc 0: 100 to 10:90), and the desired fractions were collected and the solvent evaporated in vacuo to yield (S)-(2,3-dichlorophenyl)(3-(5-fluoropyrimidin-2-yl)-6-methyl-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (45 mg, 38.5 %).
	With triethylamine In dichloromethane for 1h;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - JP2017/527588, 2017, A Location in patent: Paragraph 0483-0485
[2]Rudolph, Dale A.; Alcazar, Jesus; Ameriks, Michael K.; Anton, Ana Belen; Ao, Hong; Bonaventure, Pascal; Carruthers, Nicholas I.; Chrovian, Christa C.; De Angelis, Meri; Lord, Brian; Rech, Jason C.; Wang, Qi; Bhattacharya, Anindya; Andres, Jose Ignacio; Letavic, Michael A. [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 16, p. 3157 - 3163]

42
[ 2905-60-4 ]
[ 108-94-1 ]
(2,3-dichlorophenyl)-(2-hydroxycyclohex-1-enyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: cyclohexanone With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: 2,3-dichlorobenzoyl chloride In tetrahydrofuran at -78 - 20℃; for 18h; Inert atmosphere;	4.2 (2,3-Dichloro-phenyl)-(2-hydroxy-cyclohex-1-enyl)methanone (7a) Diisopropylamine (2.7mL, 19.3mmol) in THF (10mL) was cooled to -78°C and n-BuLi (2.5M in hexane, 7.6mL, 19.1mmol) was added. The solution was stirred for 5min before adding cyclohexanone (2.0mL, 19.3mmol). The solution was stirred at -78°C for 1h before addition of 2,3-dichlorobenzoyl chloride (1.3mL, 9.30mmol). The solution was then allowed to warm to room temperature and stirred at room temperature for 18h. HCl (2M, 15mL) was added and the product was extracted with EtOAc (3×50mL) then the combined organic layers dried (MgSO4). Removal of the solvent and purification by column chromatography (35% EtOAc in petroleum ether) gave 7a as a white solid (2.12g, 84%). Mp 101-102°C; IR (film) 2935, 1557, 1410, 1316, 1153, 900, 795cm-1; δH (400MHz, CDCl3) 15.70 (1H, s, enol), 7.50 (1H, dd, J=1.5, 7.8Hz, ArH), 7.27 (1H, t, J=7.8Hz, ArH), 7.13 (1H, dd, J=1.5, 7.8Hz, ArH), 2.48 (2H, t, J=6.5Hz, CH2), 2.05 (2H, br s, CH2), 1.78-1.70 (2H, m, CH2), 1.64-1.57 (2H, m, CH2); δC (100MHz, CDCl3) 191.5 (C), 187.3 (C), 139.3 (C), 133.6 (C), 130.9 (CH), 128.7 (C), 127.8 (CH), 125.6 (CH), 107.7 (C), 32.0 (CH2), 24.3 (CH2), 22.8 (CH2), 21.5 (CH2); MS (ES+) m/z 271 [MH+, 35Cl, 35Cl], 273 [MH+, 35Cl, 37Cl], 275 [MH+, 37Cl, 37Cl]; HRMS (ES+) calcd for C13H12Cl2NaO2 [MNa+, 35Cl, 35Cl]: 293.0107; found 293.0106.

Reference： [1]Turner, Penelope A.; Samiullah; Geden, Joanna V.; White, Alexander; Clarkson, Guy J.; Shipman, Michael [Tetrahedron, 2015, vol. 71, # 50, p. 9433 - 9438]

43
[ 2905-60-4 ]
[ 141-78-6 ]
[ 672323-07-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: ethyl acetate With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: 2,3-dichlorobenzoyl chloride In tetrahydrofuran; hexane at -70 - -65℃; for 0.5h;	57.1 57.1 Ethyl 3 -(2,3 -dichlorophenyl)-3 -oxopropanoate To a stirred solution of di-iso-propylamine (8.7 g, 0.086 mol) in THF (100 mL) cooled to-78°C was added n-BuLi (49.2 mL of a 1.6 M solution in hexanes, 0.079 mol). Stirring was continued for 30 minutes after which time, freshly distilled ethyl acetate (6.94 g, 0.079 mol) was added drop wise at -78°C. The resulting solution was stirred for 30 minutes whereupon 2,3 dichloro benzoyl chloride(15 g, 0.072 mol) was added as a solution in THF (150 mL). The reaction mixture was stirred at -65 to-70°C for 30 minutes and then terminated by the addition of 1 N HC1 solution (until acidic). Theresulting bi-phasic mixture was allowed to warm to a temperature of about 25°C before being diluted with ethyl acetate (250 mL) and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (2 x 150 mL) and the organic layers were combined, washed with brine (30 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure to provide the beta-keto ester which was used directly in the next step.

Reference： [1]Current Patent Assignee: THE JOHNS HOPKINS UNIVERSITY; BRISTOL-MYERS SQUIBB CO - WO2015/183839, 2015, A1 Location in patent: Page/Page column 264

44
[ 2905-60-4 ]
[ 118-93-4 ]
2-acetylphenyl 2,3-dichlorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	In pyridine at 20℃; for 2h; Inert atmosphere;	General Synthetic Procedure for Compound 11 General procedure: A mixture of 2'-hydroxyacetophenone (10.0 mmol) and 2-chlorobenzoyl chloride (15.0 mmol) were stirred in dry pyridine(10 mL) at room temperature for 2 h. The reaction mixture was then poured into a mixture of crushed ice (15 mL) and concentrated HCl (5 mL), extracted twice with dichloromethane, washed thrice with aqueous K2CO3, and then washed thrice with water. The solvent was removed under reduced pressure. The residue was recrystallized from ethanol to give 2-acetylphenyl 2-chlorobenzoate (11-1). The remaining compounds were prepared using a similar procedure to that used for preparing 11-1.

Reference： [1]Lei, Kang; Sun, Dong-Wei; Tao, Yuan-Yuan; Xu, Xiao-Hua [Australian Journal of Chemistry, 2016, vol. 69, # 1, p. 98 - 106]

45
[ 6973-60-0 ]
[ 2905-60-4 ]
4-(2,3-dichlorobenzoyl)-1-methyl-1H-pyrrole-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With aluminum (III) chloride; In 1,2-dichloro-ethane; at 20℃; for 3h;Inert atmosphere;	Aluminium chloride (8.51 g, 63.8 mmol) was added to asolution of 2,3-dichlorobenzoyl chloride (6.68 g, 31.9 mmol) in 1,2-dichloroethane (100 mL) under an ice-cooled condition in anitrogen atmosphere. Then, 1-methylpyrrole-2-carboxylic acid(3.99 g, 31.9 mmol) in 1,2-dichloroethane (59.0 mL) was addedunder ice-cooled condition. The mixture was stirred at room temperaturefor 3 h. Then the reaction mixture was poured into theiced water (200 mL) and the resulting precipitated solid was collectedby filtration. The solid was washed with water and MeOH,and dried to give 8.32 g (27.9 mmol, 88%) of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxylic acid as a gray-white solid.1H NMR (DMSO-D6) d: 12.82 (1H, s), 7.79 (1H, dd, J = 7.9,1.8 Hz), 7.61 (1H, d, J = 1.8 Hz), 7.51-7.42 (2H, m), 7.04 (1H, d,J = 1.8 Hz), 3.87 (3H, s); MS m/z 298 (M)+.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3540 - 3546

46
[ 2905-60-4 ]
[ 14165-18-5 ]
N-[2-(N-benzyl-N-methylamino)ethyl]-2,3-dichlorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With triethylamine In dichloromethane at 0 - 20℃; for 12h;	35 5.1.3.18 General procedure E1 General procedure: A solution of N,N-disubstitutedalkyldiamine 5a-f or commercially available amine (1 eq), and triethylamine (3 eq) in 10mL of DCM was cooled at 0°C. A solution of substituted benzoylchloride (1 eq) in 5mL of DCM was added slowly. The resulting mixture was stirred at room temperature overnight. The solution was evaporated under reduced pressure. An aqueous solution of 3% sodium hydroxide (20mL) was added and the mixture was stirred for 1h. The solution was extracted with DCM. The organic layer was dried over magnesium sulphate and concentrated to give an oily product. The residue was purified by thick layer chromatography (DCM:MeOH(NH3), 9:1 (v/v)) or column chromatography (DCM:MeOH(NH3), 9:1 (v/v)).

Reference： [1]Donnier-Maréchal, Marion; Carato, Pascal; Larchanché, Paul-Emmanuel; Ravez, Séverine; Boulahjar, Rajaa; Barczyk, Amélie; Oxombre, Bénédicte; Vermersch, Patrick; Melnyk, Patricia [European Journal of Medicinal Chemistry, 2017, vol. 138, p. 964 - 978]

47
[ 2905-60-4 ]
[ 13910-49-1 ]
N-[3-(N-benzyl-N-methylamino)propyl]-2,3-dichlorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With triethylamine In dichloromethane at 0 - 20℃; for 12h;	34 5.1.3.18 General procedure E1 General procedure: A solution of N,N-disubstitutedalkyldiamine 5a-f or commercially available amine (1 eq), and triethylamine (3 eq) in 10mL of DCM was cooled at 0°C. A solution of substituted benzoylchloride (1 eq) in 5mL of DCM was added slowly. The resulting mixture was stirred at room temperature overnight. The solution was evaporated under reduced pressure. An aqueous solution of 3% sodium hydroxide (20mL) was added and the mixture was stirred for 1h. The solution was extracted with DCM. The organic layer was dried over magnesium sulphate and concentrated to give an oily product. The residue was purified by thick layer chromatography (DCM:MeOH(NH3), 9:1 (v/v)) or column chromatography (DCM:MeOH(NH3), 9:1 (v/v)).

Reference： [1]Donnier-Maréchal, Marion; Carato, Pascal; Larchanché, Paul-Emmanuel; Ravez, Séverine; Boulahjar, Rajaa; Barczyk, Amélie; Oxombre, Bénédicte; Vermersch, Patrick; Melnyk, Patricia [European Journal of Medicinal Chemistry, 2017, vol. 138, p. 964 - 978]

48
verbenone (E)-oxime [ No CAS ]
[ 2905-60-4 ]
(Z)-verbenone O-(2',3'-dichlorobenzoyl) oxime [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.5%	With triethylamine In dichloromethane Cooling with ice;	3.4. General Procedure for the Synthesis of (Z)- and (E)-verbenone Oxime Esters 4 Under an anhydrous atmosphere, acyl chloride (1.1 mmol) was added slowly to a stirred solutionof (Z)- or (E)-verbenone oxime (3, 0.17 g, 1.00 mmol) in dichloromethane (5 mL) and ten drops oftriethylamine in an ice-water bath. The reaction process was monitored by TLC. Upon completion,5 mL deionized water was added to destroy the unreacted acyl chloride. Then, the organic layer wasseparated, washed with deionized water three times, and concentrated in vacuum. The crude productwas further purified by silica gel chromatography to afford the target compounds (Z)- and (E)-4a-4n.

Reference： [1]Hu, Qiong; Lin, Gui-Shan; Duan, Wen-Gui; Huang, Min; Lei, Fu-Hou [Molecules, 2017, vol. 22, # 10]

49
verbenone (Z)-oxime [ No CAS ]
[ 2905-60-4 ]
(E)-verbenone O-(2',3'-dichlorobenzoyl) oxime [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.5%	With triethylamine In dichloromethane Cooling with ice;	3.4. General Procedure for the Synthesis of (Z)- and (E)-verbenone Oxime Esters 4 Under an anhydrous atmosphere, acyl chloride (1.1 mmol) was added slowly to a stirred solutionof (Z)- or (E)-verbenone oxime (3, 0.17 g, 1.00 mmol) in dichloromethane (5 mL) and ten drops oftriethylamine in an ice-water bath. The reaction process was monitored by TLC. Upon completion,5 mL deionized water was added to destroy the unreacted acyl chloride. Then, the organic layer wasseparated, washed with deionized water three times, and concentrated in vacuum. The crude productwas further purified by silica gel chromatography to afford the target compounds (Z)- and (E)-4a-4n.

Reference： [1]Hu, Qiong; Lin, Gui-Shan; Duan, Wen-Gui; Huang, Min; Lei, Fu-Hou [Molecules, 2017, vol. 22, # 10]

50
[ 2905-60-4 ]
copper(l) cyanide [ No CAS ]
[ 77668-42-9 ]

Yield	Reaction Conditions	Operation in experiment
	at 160℃; for 6h;	Add 500g four-necked flask 50g2,3-dichlorobenzoic acid,50g thionyl chloride, the reaction 6h to the end,Vacuum distillation net thionyl chloride,Then add 30g cuprous cyanide,Carefully warmed to 160 , the reaction 6h to the end of the reaction, the solid was filtered to give 2,3-dichlorobenzoyl cyanide solution

Reference： [1]Organic Process Research and Development,2017,vol. 21,p. 1815 - 1821
[2]Organic Process Research and Development,2017,vol. 21,p. 1815 - 1821
[3]Patent: CN106083753,2016,A .Location in patent: Paragraph 0031

51
[ 773837-37-9 ]
[ 2905-60-4 ]
[ 77668-42-9 ]
[ 252186-80-4 ]
[ 50-45-3 ]
C₁₆H₆Cl₄N₂O₂ [ No CAS ]

Reference： [1]Organic Process Research and Development,2017,vol. 21,p. 1815 - 1821

52
[ 2905-60-4 ]
[ 84057-84-1 ]

Reference： [1]Patent: CN106083753,2016,A

53
[ 2905-60-4 ]
5-(4-bromothiophen-2-yl)pyridin-3-amine [ No CAS ]
N-(5-(4-bromothiophen-2-yl)pyridin-3-yl)-2,3-dichlorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine In acetone at 20℃; for 2h;	4.1.1.2 Procedure B, general procedure for amide synthesis (4a, 6a-34a) General procedure: A solution of 0.18gm (0.7mmol) of compound D dissolved in acetone was treated with 0.84mmol of the appropriate acid chloride followed by the addition of 0.12gm (1.05mmol) of TEA. The reaction mixture was left to stir at room temperature for 2h which was followed by evaporation of solvent in vacuo and the product was purified by CC.

Reference： [1]Darwish, Sarah S.; Abdel-Halim, Mohammad; Salah, Mohamed; Abadi, Ashraf H.; Becker, Walter; Engel, Matthias [European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1031 - 1050]

54
[ 2905-60-4 ]
2,2,2-trifluoro-N-(4-(3-(trifluoromethyl)phenyl)thiophen-2-yl)acetamide [ No CAS ]
N-(5-(2,3-dichlorobenzoyl)-4-(3-(trifluoromethyl)phenyl)thiophen-2-yl)-2,2,2-trifluoroacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With tin(IV) chloride In dichloromethane; 1,2-dichloro-ethane at 40℃;	Step 1: To a solution of 2,2,2-trifluoro-N-(4-(3-(trifluoromethyl)phenyl)thiophen-2-yl)acetamide 55 (50 mg, 0.15 mmol) in 1.5 mL of anhydrous DCE were added 2,3-dichlorobenzoyl chloride (62 mg, 0.29 mmol) and SnCl4 1M in DCM (295 µL, 0.29 mmol). The reaction was stirred at 40°C overnight. Upon completion (monitored by HPLC), the solvent was removed and the crude product was purified by Combiflash silica gel chromatography (0-30% of EtOAc in hexane), which provided 60 mg (79%) of the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ=10.23 (br. s., 1H), 7.67 (d, J=7.1 Hz, 1H), 7.63 - 7.50 (m, 2H), 7.44 - 7.31 (m, 2H), 7.31 - 7.21 (m, 1H), 7.09 (d, J=7.6 Hz, 1H), 7.04 - 6.99 (m, 1H), 6.97 (s, 1H); MS (ESI+) m/z: 415.9 [M+H+].

Reference： [1]Doebelin, Christelle; Patouret, Rémi; Garcia-Ordonez, Ruben D.; Chang, Mi Ra; Dharmarajan, Venkatasubramanian; Novick, Scott; Ciesla, Anthony; Campbell, Sean; Solt, Laura A.; Griffin, Patrick R.; Kamenecka, Theodore M. [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 19, p. 3210 - 3215]

55
[ 438197-19-4 ]
[ 2905-60-4 ]
2,3-dichloro-N'-(2′,3′-dichlorobenzoyl)benzohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With pyridine; for 36.0h;Reflux;	General procedure: N-benzoyl/nicotinoyl aryl benzohydrazides were obtained by treating different hydrazides with various derivatives of benzoyl chlorides in pyridine and the reaction mixture was refluxed for 36 h.The progress of reaction was monitored by TLC, after completion, the reaction mixture was poured onto 19% HCl, precipitates formed were filtered further washed with hot water and hexane. The solid product was crystallized from ethanol. The compounds thus obtained were characterized via EI-MS and H1-NMR. Among all synthetic derivatives,compounds 19, 37, and 40 are new while rest of the compounds are reported in the literature [25-37]

Reference： [1]Bioorganic Chemistry,2019,vol. 82,p. 163 - 177

56
[ 70010-33-2 ]
[ 2905-60-4 ]
(2,3-dichlorophenyl)(3-hydroxyindazol-1-yl)ketone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With pyridine at 0 - 20℃; for 16h;	4.1.23. General procedure for the synthesis of 3-hydroxyindazolylketone derivatives (23-34) General procedure: To a solution of the 1H-3-indazolol in pyridine at 0 °C, the . Theprecipitated solid is recovered by filtration, washed with water anddried correspondingacyl chloride is added dropwise. The mixture is stirredand allowed to warm to room temperature. At the end of reaction,the crude is poured on water and acidified with acetic acidto obtain the expected product.

Reference： [1]González-Naranjo, Pedro; Pérez-Macias, Natalia; Pérez, Concepción; Roca, Carlos; Vaca, Gabriela; Girón, Rocio; Sánchez-Robles, Eva; Martín-Fontelles, María Isabel; de Ceballos, María L.; Martin-Requero, Angeles; Campillo, Nuria E.; Páez, Juan A. [European Journal of Medicinal Chemistry, 2019, vol. 166, p. 90 - 107]

57
[ 261179-38-8 ]
[ 2905-60-4 ]
methyl (2R,3R)-2-[4-(2,3-dichlorobenzoyl)oxy-3-methoxyphenyl]-7-methoxy-5-[(E)-3-methoxy-3-oxoprop-1-enyl]-2,3-dihydrobenzofuran-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With pyridine In dichloromethane at 15 - 20℃; for 24h;	Diversification of methyl (2R, 3R)-2-(4-hydroxy-3-methoxy-phenyl)-7-methoxy-5-[(E)-3-methoxy-3-oxo-prop-1-enyl]-2,3-dihydrobenzofuran-3-carboxylate [C] to its ester derivatives General procedure: Compounds (1-9) were synthesized by following general method.These were prepared by following general methodas depicted below.To a stirred solution of methyl (2R,3R)-2-(4-hydroxy-3-methoxy-phenyl)-7-methoxy-5-[(E)-3-methoxy-3-oxo-prop-1-enyl]-2,3-dihydrobenzofuran-3-carboxylate [C] (1eq) in dichloromethane (30 ml) was added pyridine [E] (2.5 eq) and cooled the reaction inice bath at 150. Clear solution of reaction mixture was obtained. To this, was added benzoyl chloride/substituted benzoyl chloride/acetyl chloride/substituted acetyl chloride [D] (2eq) at 15-200 and stirred, allowed to attain room temp and stirring was continued for next 24hr (TLC). The organic layer was concentrated under reduced pressure to minimum to yield crude mass which was preadsorbed on silicagel and purified by column chromatography (SiO2, 100-200 mesh) with increase in concentration of ethylacetate in petroleum ether to yield pure compound.The purified compounds were unambiguously characterized by 1H NMR, Mass and IR spectroscopy.The general yields of these reactions ranged between 60-80%.

Reference： [1]Vakharia, Jyot; Gangan, Vijay D.; Chakraborty, Chaitaly T.; Bhawe, Vijay G.; Bhalekar, Satish M. [Indian Journal of Heterocyclic Chemistry, 2014, vol. 23, # 3, p. 315 - 320]

58
[ 2905-60-4 ]
[ 79-19-6 ]
N₂-(2,3-dichlorobenzoyl)thiosemicarbazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	In acetone at 80℃; for 0.0166667h; Irradiation; Sonication;	Synthesis of 2,3-dichlorophenyl thiosemicarbazide (2) To a solution of 2,3-dichlorobenzoyl chloride 1 (10 mmol)in acetone (100 ml) was added thiosemicarbazide (10 mmol) in a closed vessel. Thereaction was irradiated for 1min at 80C using a sonication bath. The reaction mixturewas processed as described above to give compound 2 in 98% yield

Reference： [1]Al-blewi, Fawzia F. [Organic Preparations and Procedures International, 2019, vol. 51, # 3, p. 240 - 254]

59
[ 2905-60-4 ]
[ 153-18-4 ]
C₅₀H₂₀Cl₁₀O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.4%	With piperidine In N,N-dimethyl-formamide at 78℃; for 4h;	12 Synthesis of quercetin penta(2,3-dichlorobenzoic acid) ester (12) Weigh 610 mg (1 mmol) of rutin and dissolve it in 20 ml of dimethylformamide (DMF).Add 5 ml of 2,3-dichlorobenzoyl chloride and stir with a magnetic stirrer for 0.5 h.After fully dissolving, 15 drops of piperidine were added, the temperature was controlled at 78 ° C, and refluxed for 4 h. The reaction was monitored by TLC plate to ensure the reaction was completed. 80 ml of distilled water was added and stirred for 2 hours, and a large amount of solid precipitated. The solid was precipitated and the water became clear and the water layer was clarified. The precipitate was washed with water until neutral, dissolved in 70 mL of ethyl acetate, and passed through a silica gel column, methyl acetate: dichloromethane (2:3), and the eluent was evaporated. Recrystallization from chloroform / methanol, white solid, yield 52.4%

Reference： [1]Current Patent Assignee: ZHENGZHOU UNIVERSITY OF INDUSTRY TECHNOLOGY - CN109678832, 2019, A Location in patent: Paragraph 0062-0064

60
[ 2905-60-4 ]
2‐hydroxyethyl adamantane‐1‐carboxylate [ No CAS ]
2-(2,3-dichlorobenzoyloxy)ethyl adamantane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.6%	With triethylamine In tetrahydrofuran at 20℃; for 3h; Cooling with ice;	11 Example 11 Synthesis of the derivative Ik (R (n) = 2,3-dichloro): The intermediate 2-hydroxyethyl adamantane-1-carboxylate(0.336 g, 1.5 mmol),Tetrahydrofuran (14.6 mL) and acid binding agent triethylamine (3.0 mmol) were mixed and dissolved by stirring, Slowly dropwise add a solution of 2,3-dichlorobenzoyl chloride (2.0 mmol) in tetrahydrofuran (7.5 mL) dropwise under ice bath conditions.After the dropwise addition, the reaction was performed at room temperature for 3 h, and then the triethylamine hydrochloride formed by the reaction was removed by filtration.The filtrate obtained by filtration was subjected to rotary evaporation to remove the solvent tetrahydrofuran.The obtained rotary distillation residue was separated by column chromatography (eluent was a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1: 4) to obtain a white waxy solid.That is 2- (2,3-dichlorobenzoyloxy) ethyl adamantane-1-carboxylate, and the yield is calculated to be 66.6%.
66.6%	With triethylamine In tetrahydrofuran at 20℃; for 3h; Cooling with ice;	11 Example 11Synthesis of compound Ik (R (n) = 2,3-dichloro): The intermediate 2-hydroxyethyl-1-adamantane formate (0.336 g, 1.5 mmol),Tetrahydrofuran (14.6 mL) and acid binding agent triethylamine (3.0 mmol) were mixed,The solution was stirred to dissolve, and a solution of 2,3-dichlorobenzoyl chloride (2.0 mmol) in tetrahydrofuran (7.5 mL) was slowly added dropwise under an ice bath.After the dropwise addition, the reaction was performed at room temperature for 3 hours.Subsequently, the hydrochloride of triethylamine formed by the reaction was removed by filtration, and the filtrate was subjected to rotary evaporation to remove the solvent tetrahydrofuran.The obtained rotary distillation residue was separated by column chromatography (eluent was a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1: 4) to obtain a white waxy solid.Which is 2- (2,3-dichlorobenzoyloxy) ethyl 1-adamantanoate,The calculated yield was 66.6%.

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN110463704, 2019, A Location in patent: Paragraph 0038-0039
[2]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN110483284, 2019, A Location in patent: Paragraph 0067-0071

61
[ 2905-60-4 ]
[ 78743-65-4 ]
2,3-dichlorobenzoic acid 2-(1-adamantanecarboxamido)ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50.5%	With triethylamine In tetrahydrofuran at 20℃; for 4h; Cooling with ice;	14 Example 14 Synthesis of compound In (R = 2,3-dichlorophenyl): The intermediate N-2-hydroxyethyl-1-adamantanecarboxamide (0.335 g, 1.5 mmol) and tetrahydrofuran (14.6 mL) and the acid binding agent triethylamine (3.0 mmol) were mixed, dissolved and stirred, and the solution was ice-cooled. A solution (7.5 mL) of 2,3-dichlorobenzoyl chloride (2.0 mmol) in tetrahydrofuran was slowly added dropwise. After the dropwise addition, the reaction was carried out at room temperature for 4 hours, and then the triethylamine hydrochloride formed by the reaction was filtered off. The filtrate was subjected to rotary evaporation to remove the solvent tetrahydrofuran. The obtained rotary distillation residue was separated by column chromatography to obtain a white solid (eluent was a volume A mixed solution of ethyl acetate and petroleum ether with a ratio of 1: 4) is 2,3-dichlorobenzoic acid-2- (1-adamantanecarboxamido) ethyl ester, and the yield is calculated to be 50.5%
	With triethylamine In tetrahydrofuran at 20℃; for 4h; Cooling with ice;	14 Example 14 Synthesis of compound In (R = 2,3-dichlorophenyl): The intermediate N-2-hydroxyethyl-1-adamantanecarboxamide (0.335 g, 1.5 mmol),Tetrahydrofuran (14.6mL) and acid binding agent triethylamine (3.0mmol) were mixed, dissolved by stirring,A tetrahydrofuran solution (7.5 mL) of 2,3-dichlorobenzoyl chloride (2.0 mmol) was slowly added dropwise dropwise under ice bath conditions.After the dropwise addition, the reaction was carried out at room temperature for 4 hours, and then the triethylamine hydrochloride formed by the reaction was filtered off.The obtained rotary distillation residue was separated by column chromatography (eluent was a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1: 4) to obtain a white solid.That is, 2,3-dichlorobenzoic acid-2- (1-adamantanecarboxamido) ethyl ester, and the yield was calculated to be 50.5%.

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN110423216, 2019, A Location in patent: Paragraph 0080-0083
[2]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN110476977, 2019, A Location in patent: Paragraph 0079-0082

62
[ 2905-60-4 ]
C₁₀H₁₄N₆ [ No CAS ]
(4-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)piperidin-1-yl)(2,3-dichlorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3h;	4.2.3. General procedure synthesis of compounds 5a-j General procedure: To a solution of intermediate 4a (1 mmol) and DIEA (1.1 mmol)in dichloromethane (10 ml), a solution of R1COCl (1.1 eq) in dichloromethane (2 ml) was added dropwise at room temperaturefor 3 h. The mixture was washed with water, saturated aqueoussodium bicarbonate and brine, and then dried over anhydrous sodiumsulfate. After removing the solvent under reduced pressure,the crude product was purified by flash chromatography on silicagel, eluting with dichloromethane/methanol (10e20%), yield70e90%.

Reference： [1]He, Zhendan; Pan, Dabo; Tang, Pan; Yao, Dahong; Zhang, Jin; Zou, Ling [European Journal of Medicinal Chemistry, 2020, vol. 194]

63
1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-ylamine [ No CAS ]
[ 2905-60-4 ]
N-(1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-2,3-dichlorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3h;	4.2.7. General procedure synthesis of compounds 7a-j To a solution of intermediate 4b (1 mmol) and DIEA (1.1 mmol)in dichloromethane (10 ml), a solution of R1COCl (1.1 eq) indichloromethane (2 ml) was added dropwise at room temperaturefor 3 h. The mixture was washed with water, saturated aqueoussodium bicarbonate and brine, and then dried over anhydrous sodiumsulfate. After removing the solvent under reduced pressure,the crude product was purified by flash chromatography on silicagel, eluting with dichloromethane/methanol (10e20%), yield70e90%.

Reference： [1]He, Zhendan; Pan, Dabo; Tang, Pan; Yao, Dahong; Zhang, Jin; Zou, Ling [European Journal of Medicinal Chemistry, 2020, vol. 194]

64
[ 1001020-08-1 ]
[ 2905-60-4 ]
[ 333-20-0 ]
tert-butyl 3-carbamoyl-2-(3-(2,3-dichlorobenzoyl)thioureido)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2020,vol. 35,p. 1524 - 1538

65
[ 2905-60-4 ]
[ 10338-51-9 ]
4-(2-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl 2,3-dichlorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With tetrabutylammomium bromide; sodium carbonate In water; ethyl acetate at 5℃;	4.1.2. Synthesis of phenolic hydroxyl-modified derivatives ofsalidroside General procedure: Compounds 1a, 1b, 1c, 1d, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m, 1n, 1o, 2a, 2d, 2f, 2g and 2h were synthesized by mixing 10 mmol salidrosidewith 10 mmol sodium carbonate and 0.15 mmol tetrabutylammoniumin 10 mL water. The mixture was stirred in an ice bath untilthe solid was completely dissolved, and the temperature of mixturewas cooled at 5 C. 10 mmol of the corresponding acyl chloride (seeFig. 1), dissolved in 10 mL of ethyl acetate, was added. The mixturewas maintained at 5 C by stirring. Reactions were monitored bythin-layer chromatography (CHCl3:CH3OH 3:1) and spots werevisualized under the UV light (l 254 nm). The reaction wasstopped when the starting material was completely consumed. Thewater layerwas extracted with ethyl acetate (3 5mLwashes). Theethyl acetate layer was separated and washed with brine, driedover anhydrous Na2SO4 and evaporated under reduced pressure togive a residue which was then purified by flash column chromatographyon silica gel (the ratio of eluent CH2Cl2: CH3OH from 0:1 to1:3).

Reference： [1]Yang, Zelin; Huang, Xin; Lai, Wenfang; Tang, Yuheng; Liu, Junjie; Wang, Yingzheng; Chu, Kedan; Brown, John; Hong, Guizhu [European Journal of Medicinal Chemistry, 2021, vol. 209]

66
[ 1073435-85-4 ]
[ 2905-60-4 ]
C₁₆H₁₃Br₂Cl₂N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.54%	Stage #1: (3,5-dibromo-pyrazin-2-yl)-carbamic acid tert-butyl ester With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 2,3-dichlorobenzoyl chloride In tetrahydrofuran at 0 - 20℃; for 8h; Inert atmosphere;	1.2 Step 2 :Under N2 protection, LiHMDS (1M, 29.74mL, 29.74mmol, 1.5eq) was added to compound 2a (7g, 19.83mmol) in THF (100mL) at 0°C, and then the reaction solution was stirred at room temperature for 0.5 hours, and then cooled At 0°C, compound 3 (6.23 g, 29.74 mmol, 1.5 eq) was added, and the reaction solution was stirred at room temperature for 8 hours. The reaction was quenched by adding saturated ammonium chloride, and then extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine in turn, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. Then the crude product was purified by column chromatography (petroleum ether/ethyl acetate=0-20%) to obtain compound 4a (8.87 g, yield: 85.54%) as a colorless oil.

Reference： [1]Current Patent Assignee: SUZHOU JINGCHI MEDICAL TECH; SUZHOU LONGMAB BIOSCIENCES - CN111825700, 2020, A Location in patent: Paragraph 0063-0064; 0067-0070

67
[ 2905-60-4 ]
[ 108-18-9 ]
2,3-dichloro-N,N-diisopropylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In dichloromethane at 0 - 20℃; for 12h;

Reference： [1]Chattopadhyay, Buddhadeb; Hassan, Mirja Md Mahamudul; Hoque, Md Emdadul [Journal of the American Chemical Society, 2021, vol. 143, # 13, p. 5022 - 5037]

68
[ 2905-60-4 ]
[ 97-52-9 ]
N-(2-methoxy-4-nitrophenyl)-2,3-dichlorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.3%	With triethylamine In tetrahydrofuran at 0℃; Reflux;	17 Synthesis of N-(2-Methoxy-4-nitrophenyl)-2,3-dichlorobenzamide (17A) Dissolve 2-methoxy-4-nitroaniline (0.51g, 3.03mmol) and triethylamine (0.60g, 5.94mmol) in anhydrous tetrahydrofuran (18mL), slowly add dropwise 2,3 at 0 -Dichlorobenzoyl chloride (0.69g, 3.34mmol) in anhydrous tetrahydrofuran solution (2mL), reflux and stir overnight, cool, concentrate under reduced pressure, add anhydrous ether and stir for 10min, filter with suction, wash with water, and dry to obtain a yellow solid 0.62g, yield 70.3%

Reference： [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY; NANJING ZHONGAO CONVERSION MEDICINE RES INSTITUTE - CN113061098, 2021, A Location in patent: Paragraph 0195-0198

69
[ 2905-60-4 ]
7-methyl-2-propyl-1H-benzo[d]imidazole-5-carbohydrazide [ No CAS ]
N'-(2,3-dichlorobenzoyl)-7-methyl-2-propyl-1H-benzo[d]imidazole-5-carbohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine In dichloromethane at 10 - 20℃;	3.2.2. General procedure for the synthesis of N'-benzoyl-7-methyl-2-propyl-1H-benzo[d]imidazole-5-carbohydrazides(5a-f) General procedure: Compound 3 (1.0 mmol) was dissolved in dichloromethane and cooled to 10-15 °C in ice-bath and triethylamine(2.0 mmol) was added drop wise. After the addition of triethylamine,aromatic acid chloride (1.2 mmol) in dichloromethane was added drop wise at 10-15 °C, and the reaction mixture brought to room temperature and stirred for another 2-3 hours. Reaction progress was monitored by TLC (10%methanol in dichloromethane). The separated solid was filtered under vacuum and the obtained crude product was takenin methanol and heated to 70 °C to dissolve the crude solid. Half of the methanol was distilled off and stirred at room temperature. The white solid separated was filtered, washed with cold methanol and dried.N'-Benzoyl-7-methyl-2-propyl-1H-benzo[d]imidazole-5-carbohydrazides.

Reference： [1]Katikireddy, Ramamurthy; Kakkerla, Ramu; Murali Krishna; Durgaiah, Gandamalla; Reddy [Letters in Organic Chemistry, 2020, vol. 17, # 12, p. 959 - 968]

70
[ 2905-60-4 ]
[ 65234-09-5 ]
C₂₀H₁₄Cl₃NO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;	4.1.2 Syntheses of 4-arylthiophene-3-carboxylic acid derivatives General procedure: Taking 2-(1-naphthamido)-4-(4-chlorophenyl) thiophene-3-carboxylic acid (6) as an example. Step a: 18.55g (120mmol) 4-chloroacetophenone, 16.29g (144mmol) ethyl cyanoacetate, 7.12g (120mmol) acetic acid, 23.00g (264mmol) morpholine, and 500mL ethanol were added into a round bottom flask and stirred for 3h under an argon atmosphere at 70°C. Then 4.91g (144mmol) sulfur was added and stirred for 48h. The solution was evaporated, and the residue was purified by column chromatography to afford 2-aminothiophene-3-carboxylate acid ethyl ester (yield 21%). Step b: 0.195g (0.73mmol) 2-aminothiophene-3-carboxylate acid ethyl ester was dissolved in 10mL DCM and 0.125g (0.66mmol) 1-naphthyl chloride which was dissolved in 10mL DCM was dropped it into the solution at 0°C. Stirred for 8h at room temperature, followed by evaporation and recrystallization using DCM/petroleum ether. White powder intermediate Ethyl 2-(1-naphthamido)-4-(4-chlorophenyl)thiophene-3-carboxylate 0.227g (0.54mmol) was obtained (yield 75%) as white powder. Step c: 0.143g (0.34mmol) ethyl 2-(1-naphthamido)-4-(4-chlorophenyl)thiophene-3-carboxylate and 0.068g (1.7mmol) NaOH were dissolved in THF/methanol/water solution and stirred for 8h at room temperature. Adjusted pH to neutral by acetic acid and precipitated by adding water. 0.094g (0.23mmol) colorless crystal compound 6 was obtained
	With triethylamine In dichloromethane at 20℃;	4.1.2 Syntheses of 4-arylthiophene-3-carboxylic acid derivatives General procedure: Taking 2-(1-naphthamido)-4-(4-chlorophenyl) thiophene-3-carboxylic acid (6) as an example. Step a: 18.55g (120mmol) 4-chloroacetophenone, 16.29g (144mmol) ethyl cyanoacetate, 7.12g (120mmol) acetic acid, 23.00g (264mmol) morpholine, and 500mL ethanol were added into a round bottom flask and stirred for 3h under an argon atmosphere at 70°C. Then 4.91g (144mmol) sulfur was added and stirred for 48h. The solution was evaporated, and the residue was purified by column chromatography to afford 2-aminothiophene-3-carboxylate acid ethyl ester (yield 21%). Step b: 0.195g (0.73mmol) 2-aminothiophene-3-carboxylate acid ethyl ester was dissolved in 10mL DCM and 0.125g (0.66mmol) 1-naphthyl chloride which was dissolved in 10mL DCM was dropped it into the solution at 0°C. Stirred for 8h at room temperature, followed by evaporation and recrystallization using DCM/petroleum ether. White powder intermediate Ethyl 2-(1-naphthamido)-4-(4-chlorophenyl)thiophene-3-carboxylate 0.227g (0.54mmol) was obtained (yield 75%) as white powder. Step c: 0.143g (0.34mmol) ethyl 2-(1-naphthamido)-4-(4-chlorophenyl)thiophene-3-carboxylate and 0.068g (1.7mmol) NaOH were dissolved in THF/methanol/water solution and stirred for 8h at room temperature. Adjusted pH to neutral by acetic acid and precipitated by adding water. 0.094g (0.23mmol) colorless crystal compound 6 was obtained

Reference： [1]Gao, Jian; Guo, Yi; Hu, Xiaoyue; Huang, Han; Jin, Zefang; Li, Zhongtang; Liu, Zhenming; Wang, Kewei; Wang, Yuxi; Zhang, Liangren; Zhong, Yi; Zong, Xiaolin [European Journal of Medicinal Chemistry, 2022, vol. 237]
[2]Gao, Jian; Guo, Yi; Hu, Xiaoyue; Huang, Han; Jin, Zefang; Li, Zhongtang; Liu, Zhenming; Wang, Kewei; Wang, Yuxi; Zhang, Liangren; Zhong, Yi; Zong, Xiaolin [European Journal of Medicinal Chemistry, 2022, vol. 237]

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CAS No. :	2905-60-4	MDL No. :	MFCD00035937
Formula :	C₇H₃Cl₃O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YBONBWJSFMTXLE-UHFFFAOYSA-N
M.W :	209.46	Pubchem ID :	17944
Synonyms :

Signal Word:	Danger	Class:	8
Precautionary Statements:	P273-P280-P305+P351+P338-P310-P501	UN#:	3261
Hazard Statements:	H302-H314-H410	Packing Group:	Ⅱ
GHS Pictogram:

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[ CAS No. 2905-60-4 ] {[proInfo.proName]}

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[ 2905-60-4 ] Synthesis Path-Upstream 1~9

[ 2905-60-4 ] Synthesis Path-Downstream 1~70

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