Name: 4640-66-8|4-Chlorophenacylcyanide|97%
Brand: Ambeed
SKU: A430835
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1
[ 4640-66-8 ]
[ 33866-48-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With hydroxylamine hydrochloride; sodium acetate In methanol at 20℃; Inert atmosphere;
80%	With hydroxylamine hydrochloride; sodium acetate In methanol
75%	With hydroxylamine hydrochloride; sodium hydroxide In water at 100℃;	General procedure: Step 2: To a stirred solution of nitrile compound 9 (10.14mmol) and NaOH (20.80mmol) in water (20mL), hydroxylamine hydrochloride (11.16mmol) was added. The resulting mixture was heated at 100°C for 3h. After cooling to rt, the precipitated compound was filtered and washed with water and dried under vacuum to afford the title compound 10. Those which did not obtain precipitation, the mixture was diluted with EtOAc and the organic layer was separated. The aqueous layer was further extracted with EtOAc (2x times), the combined organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure to afford the title compound 10

	With hydroxylamine hydrochloride; sodium acetate In ethanol
1.8 g	With hydroxylamine hydrochloride; sodium hydroxide In water at 0 - 100℃;	34.a Step a To a solution of 3-(4-chlorophenyl)-3-oxopropanenitrile (CAS Number 4640- 66-8; 3.000 g, 16.70 mmol) and NH2OH.HCI (1.390 g, 20.00 mmol) in water (45ml) was added NaOH (1 .330g, 33.41 mmol) portion wise at 0°C. The reaction mixture was heated to 100°C for 3 h. The resulting reaction mixture was cooled to rt and poured into water (250 ml) thenextracted with EtOAc (4 x 50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (32% EtOAc in hexane) yielding 3-(4-chlorophenyl)isoxazol-5-amine (1 .800 g, 9.277 mmol). LCMS: Method C, 1 .777 min, MS: ES+ 195.19; 1H NMR (400 MHz, DMSO) δ ppm 7.75 (d, J =8.8, 2 H), 7.51 (d, J = 8.8, 2 H), 6.83 (s, 2 H), 5.42 (s, 1 H).
	With hydroxylamine hydrochloride; sodium acetate In methanol at 20℃;

Reference： [1]Ge, Yun; Sun, Wangbin; Pei, Bingbing; Ding, Jia; Jiang, Yaojia; Loh, Teck-Peng [Organic Letters, 2018, vol. 20, # 9, p. 2774 - 2777]
[2]Ge, Yun; Sun, Wangbin; Chen, Yang; Huang, Yulin; Liu, Zhuang; Jiang, Yaojia; Loh, Teck-Peng [Journal of Organic Chemistry, 2019, vol. 84, # 5, p. 2676 - 2688]
[3]Boggu, Pulla Reddy; Venkateswararao, Eeda; Manickam, Manoj; Sharma, Niti; Kang, Jong Seong; Jung, Sang-Hun [Bioorganic and Medicinal Chemistry, 2020, vol. 28, # 22]
[4]Nishiwaki,T.; Saito,T. [Journal of the Chemical Society C: Organic, 1971, p. 3021 - 3026]
[5]Current Patent Assignee: MISSION THERAPEUTICS LIMITED - WO2018/60689, 2018, A1 Location in patent: Page/Page column 71
[6]Liu, Hui; Yan, Yingkun; Li, Min; Zhang, Xiaomei [Organic and Biomolecular Chemistry, 2021, vol. 19, # 17, p. 3820 - 3824]

2
[ 20174-68-9 ]
[ 4640-66-8 ]
2-<5-amino-3-(4-chlorophenyl)pyrazol-1-yl>-4-methylbenzothiazole [ No CAS ]

Reference： [1]Pharmazie,1994,vol. 49,p. 452 - 453

3
[ 7335-27-5 ]
[ 75-05-8 ]
[ 4640-66-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: ethyl 4-chlorobenzoate With potassium <i>tert</i>-butylate In tetrahydrofuran; water Stage #2: acetonitrile In tetrahydrofuran; water at 20℃; for 0.5h;	4.5 Typical procedure for reaction of esters with cyanides to β-ketonitriles 9 under the optimized conditions General procedure: Ethyl ester 1 (6.65 mmol, 1 equiv) was dissolved in THF (30 mL, technical grade involving 0.2% water) with stirring (about 230rpm) at ambient temperature for 5min. Potassium tert-butoxide (1.57 g, 14.0 mmol, 95%, 2 equiv) was added immediately to the above THF solution. After stirring enough the flask, the corresponding cyanide 8 (6.65mmol, 1equiv) was then added. The resulting mixture was stirred at ambient temperature. The reaction mixture was quenched by addition of water (50mL) and then stirred for 5min. After adding ethyl acetate (40 mL) and then HCl solution (1 mL, 12 M), the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was applied to the top of an open-bed silica gel column (for 9a-e, 9g-j: 3×15cm, n-hexane/ethyl acetate (3:1, v/v); for 9f: 3.5×8 cm, CH2Cl2). Fractions containing the product were combined and evaporated under reduced pressure to give the corresponding β-ketonitriles.
67.5%	With sodium hydride In toluene at 90℃; for 24h;
	With sodium hydride In tetrahydrofuran at 20℃;

	With potassium <i>tert</i>-butylate In tetrahydrofuran at 17 - 19℃; for 0.583333h;
	Stage #1: acetonitrile With sodium hydride In toluene at 0℃; for 0.5h; Stage #2: ethyl 4-chlorobenzoate In toluene at 100℃; for 12h;	9 Synthesis of XL: To a stirred solution of acetonitrile (10 mL) in toluene (100 mL) was added sodium hydride(3.26 g; 81 mmol) at 0°C. The stirring was continued for 30 minutes and then ethyl 4-chlorobenzoate (XXXIX; 5 g; 27 mmol) was added. The reaction mixture was stirred at 100°Cfor 12 hours. The reaction mixture was cooled, concentrated at reduced pressure and dilutedwith ice cold water. The reaction mixture was acidified using iN hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound 3-(4-chlorophenyl)-3-oxopropanenitrile as a crude light yellow solid (XL; 3 g,61%yield).
	With sodium hydride In tetrahydrofuran; mineral oil at 70℃; for 5h;	5.1.2. General Procedure for the Preparation of 6a-c General procedure: To a stirred suspension of sodium hydride (60% dispersionin mineral oil, 50 mmol) in THF (25 mL) was added a mixture of ethyl benzoate (5a-c, 33 mmol) and acetonitrile(50 mmol). The resulting pale yellow suspension was heated at 70 °C for 5h, monitoring by TLC. After cooling to rt, the reaction mixture was poured into water (150 mL), acidified to pH2 with aqueous 2M HCl and the resulting solution was extracted with diethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure to afford the title ketonitriles which were used without further purification.
	With sodium hydride In tetrahydrofuran for 1h; Reflux;	2.5 General procedure for synthesis of starting Materials 1a-p[1]-[3] General procedure: To a stirred solution of carboxylic acid (1.0 eq.) in ethanol (2 M) was added thionyl chloride (2.0 eq.) dropwise at room temperature, and then refluxed for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give crude product, which was chromatographed on silica gel column using 1:30 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product esters in 80% - 95% yields. Esters (1.0 eq.) were added dropwise to a stirred solution of acetonitrile (2.0 eq.) and NaH (3.0 eq.) in THF (2 M) at room temperature, and then refluxed for 1h . After it was cooled to room temperature, Water was added dropwise to the reaction mixture under ice bath until no gas bubbles generated, and employing dilute hydrochloric acid neutralization to neutral, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:4 to 1:2 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product β-ketonitriles, white or light yellow solid compounds in 50% - 85% yields. Finally, stirred in concentrated sulfuric acid (3 M) at room temperature for 5 to 10 hours. The reaction mixture was neutralized to neutral by ammonia water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:1 to 2:1 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product β-ketoamides 1a-p, white solid compounds in 45% - 85% yields.
	With sodium hydride In tetrahydrofuran at 20℃;
	With sodium hydride In N,N-dimethyl-formamide; benzene for 4h; Reflux;
	With sodium hydride In N,N-dimethyl-formamide; benzene for 4h; Reflux;
	With sodium hydride In toluene for 2h;
	With sodium hydride In tetrahydrofuran; mineral oil at 50℃;	6.1.8 General procedure for the preparation of 10 General procedure: Step 1: A stirred suspension of NaH (15.6mmol, 60% dispersion in mineral oil) in THF was heated to 50°C. To this was added a mixture of ester 8 (10.40mmol) and acetonitrile (15.60mmol) dropwise over the course of 15min. The resulting suspension was heated at reflux temperature for a further 16h. After cooling to rt, the reaction mixture was poured into H2O and then the resulting solution was washed with diethyl ether (2x times) (ether extract discarded). The aqueous layer was separated, acidified to pH~2 with aqueous 2M HCl, and extracted with EtOAc (2x times). The combined EtOAc layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure to afford the title compounds 9, which is used for the next step without further purification.

Reference： [1]Kim, Bo Ram; Lee, Hyung-Geun; Kang, Seung-Beom; Jung, Kwang-Ju; Sung, Gi Hyeon; Kim, Jeum-Jong; Lee, Sang-Gyeong; Yoon, Yong-Jin [Tetrahedron, 2013, vol. 69, # 48, p. 10331 - 10336]
[2]Seneci; Nicola; Inglesi; Vanotti; Resnati [Synthetic Communications, 1999, vol. 29, # 2, p. 311 - 341]
[3]Location in patent: scheme or table Kim, Ikyon; Song, Jong Hwan; Park, Chang Min; Jeong, Joon Won; Kim, Hyung Rae; Ha, Jin Ryul; No, Zaesung; Hyun, Young-Lan; Cho, Young Sik; Sook Kang, Nam; Jeon, Dong Ju [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 922 - 926]
[4]Kim, Bo Ram; Sung, Gi Hyeon; Ryu, Ki Eun; Lee, Sang-Gyeong; Yoon, Hyo Jae; Shin, Dong-Soo; Yoon, Yong-Jin [Chemical Communications, 2015, vol. 51, # 44, p. 9201 - 9204]
[5]Current Patent Assignee: NORGINE BV - WO2015/97122, 2015, A1 Location in patent: Page/Page column 94; 95
[6]Tabrizi, Mojgan Aghazadeh; Baraldi, Pier Giovanni; Baraldi, Stefania; Prencipe, Filippo; Preti, Delia; Saponaro, Giulia; Romagnoli, Romeo; Gessi, Stefania; Merighi, Stefania; Stefanelli, Angela; Fazzi, Debora; Borea, Pier Andrea; Maia, Rodolfo Couto; Romeiro, Nelilma C.; Fraga, Carlos A.M.; Barreiro, Eliezer J. [Medicinal Chemistry, 2015, vol. 11, # 4, p. 342 - 353]
[7]Zheng, Congke; Zhang, Xiaohui; Ijaz Hussain, Muhammad; Huang, Mingming; Liu, Qing; Xiong, Yan; Zhu, Xiangming [Tetrahedron Letters, 2017, vol. 58, # 6, p. 574 - 577]
[8]Goud; Rao; Hemasri; Thirupathi [Russian Journal of General Chemistry, 2016, vol. 86, # 12, p. 2732 - 2736][Zh. Obshch. Khim., 2016, vol. 86, # 12, p. 2732 - 2736,5]
[9]Eldehna, Wagdy M.; El-Naggar, Dina H.; Hamed, Ahmed R.; Ibrahim, Hany S.; Ghabbour, Hazem A.; Abdel-Aziz, Hatem A. [Journal of Enzyme Inhibition and Medicinal Chemistry, 2018, vol. 33, # 1, p. 309 - 318]
[10]Al-Rashood, Sara T.; Hamed, Ahmed R.; Hassan, Ghada S.; Alkahtani, Hamad M.; Almehizia, Abdulrahman A.; Alharbi, Amal; Al-Sanea, Mohammad M.; Eldehna, Wagdy M. [Journal of Enzyme Inhibition and Medicinal Chemistry, 2020, vol. 35, # 1, p. 831 - 839] Abdel-Aziz, Hatem A.; Barghash, Reham F.; Eldehna, Wagdy M.; Kovalová, Markéta; Kryštof, Vladimír; Vojáčková, Veronika [European Journal of Medicinal Chemistry, 2022, vol. 227]
[11]Guo, Ming; Jia, Fang; Jiang, Nan; Lei, Hongrui; Li, Changtao; Yang, Yu; Zhai, Xin; Zhu, Minglin [European Journal of Medicinal Chemistry, 2020, vol. 201]
[12]Boggu, Pulla Reddy; Venkateswararao, Eeda; Manickam, Manoj; Sharma, Niti; Kang, Jong Seong; Jung, Sang-Hun [Bioorganic and Medicinal Chemistry, 2020, vol. 28, # 22]

4
[ 108-94-1 ]
[ 4640-66-8 ]
[ 40312-34-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With pyrrolidine; sulfur In N,N-dimethyl-formamide at 50℃; for 0.5h; Microwave irradiation;	General procedure: A mixture of 1 (1 mmol), 2 (1.1 mmol), sulfur (1.1 mmol), corresponding base (1 mmol) and solvent (3mL) was put into a 5 mL microwave reaction vial. The vial was irradiated in the microwave reactor at50 °C for 30 min with the absorbance set to “very high”. After cooling, the reaction mixture was extractedwith EtOAc (3 × 20 mL). The combined organic phase was dried over Na2SO4 and concentrated underreduced pressure and the crude residue purified by flash chromatography on silica gel to give the products3a-3m and 4a-4r.
46%	With sulfur; diethylamine In ethanol at 50℃; for 2h;
44.2%	With morpholine; sulfur In ethanol at 70℃; for 12h; Inert atmosphere;

With sulfur In ethanol at 50℃; for 4h;

Reference： [1]Ruan, Bankang; Zhang, Zhiyan; Huang, Lei; Xu, Chao; Li, Luolan [Heterocycles, 2021, vol. 102, # 10, p. 2007 - 2018]
[2]Van Der Klein, Pieter A. M.; Kourounakis, Angeliki P.; IJzerman, Ad P. [Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3629 - 3635]
[3]Zhang, Chong-Jing; Tan, Chelsea Y. J.; Ge, Jingyan; Na, Zhenkun; Chen, Grace Y. J.; Uttamchandani, Mahesh; Sun, Hongyan; Yao, Shao Q. [Angewandte Chemie - International Edition, 2013, vol. 52, # 52, p. 14060 - 14064][Angew. Chem., 2013, vol. 125, # 52, p. 14310 - 14314,5]
[4]Tranberg, C. Elisabet; Zickgraf, Andrea; Giunta, Brian N.; Luetjens, Henning; Figler, Heidi; Murphree, Lauren J.; Falke, Ruediger; Fleischer, Holger; Linden, Joel; Scammells, Peter J.; Olsson, Ray A. [Journal of Medicinal Chemistry, 2002, vol. 45, # 2, p. 382 - 389]

5
[ 78-93-3 ]
[ 4640-66-8 ]
[ 50508-66-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With morpholine; sulfur; In ethanol; at 23 - 70℃; for 12h;	Sulfur (220 mg, 6.9 mmol, 1.00 equiv) was added as a solid to a solution of 4- chlorobenzoyl acetonitrile SI (1.24 g, 6.9 mmol, 1 equiv), 2-butanone (0.62 ml, 6.9 mmol, 1.00 equiv), and morpholine (0.60 ml, 6.9 mmol, 1.00 equiv) in ethanol (20 ml, 0.35 M) at 23C 21. The mixture was then heated to 70 C. After 12 hours, the reaction mixture was cooled to 23 C and poured into brine (100 ml). The aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine (50 ml), were dried over anhydrous sodium sulphate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash RF system, 40 gram silica gel, gradient 0 to 100 % ethyl acetate-hexanes) to afford S2 (1.28 g, 70 %) as a yellow solid.
70%	With morpholine; sulfur; In ethanol; at 25℃; for 12h;	Compound 3 (1.24 g, 6.9 mmol, 1 equiv), butanone (0.62 mL, 6.9 mmol, 1.00Equiv) and morpholine (0.6 mL, 6.9 mmol, 1.00 equiv) were dissolved in ethanol at room temperature, Solid sulfur (220 mg, 6.9 mmol, 1.00 equiv) was then added to the mixed solution. After 12 hours, the mixed solution was cooled to 23C, poured into saturated brine, and the aqueous layer was extracted three times with ethyl acetate (3 * 50 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the mixture was subjected to column chromatography to give compound 5 (1.28 g, 70% yield).
51%	With morpholine; sulfur; In ethanol; for 18h;Reflux;	Step 2: Preparation of (2-amino-4, 5-dimethylthiophen-3 -yl)(4-chlorophenyl)methanone (Intermediate 43) To a solution of 3-(4-chlorophenyl)-3-oxopropanenitrile (12.0 g, 66.8 mmol),2-butanone (5.98 mL, 66.8 mmol) and morpholine (5.82 mL, 66.8 mmol) in EtCH(191 mL) was added sulfur (2.14 g, 66.8 mmol) at room temperature. The reaction mixture was refluxed for 18 hours, cooled to room temperature and poured into water. The mixture was extracted with EtOAc twice. The combined organic layers weredried over Na2504, filtered and concentrated in vacuo. The residue was purified by column chromatography on Si02 (Hex:EtOAc = 1:1) to obtain the title compound (8.97 g, 51%) as a yellow solid.1H-NMR (400 MHz, CDC13): oe 7.47 (d, J= 8.4 Hz, 2H), 7.38 (d, J 8.4Hz,2H), 6.43 (brs, 2H), 2.14 (s, 3H), 1.56 (s, 3H).

51%	With morpholine; sulfur; In ethanol; at 85℃;	Into a 2-L 3-necked round-bottom flask were placed 3-(4-chlorophenyl)-3- oxopropanenitrile (60 g, 334.07 mmol, 1.00 equiv), ethanol (600 mL), butan-2-one (26.5 g, 367.52 mmol, 1.10 equiv), sulfur (12 g, 374.3 mmoles of elemental sulfur), and morpholine (32.3 g, 370.75 mmol, 1.11 equiv). The solution was stirred overnight at 85C and then concentrated under vacuum. The resulting solution was extracted with 3x400 mL of ethyl acetate and the organic layers were combined. The mixture was washed with 2x300 mL of H20, 1x200 mL of saturated sodium chloride (aq), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 45 g (169.33 mmoles, 51%) of 3-[(4-chlorophenyl)carbonyl]-4,5-dimethylthiophen-2- amine (1) as a yellow solid.?H-NMR (CDCh, 400MHz): d 7.48-7.46 (d, J=8.4Hz, 2H), 7.40-7.38 (d, J=8.4Hz, 2H), 2.14 (s, 3H), 1.56 (s, 3H).
45.9%	With morpholine; sulfur; In ethanol; at 70℃; for 12h;	To a stirred solution of Compound B (50 g, 280 mmol) in ethanol (300 mL) were added sulfur (8.9 g, 280 mmol), morpholine (24.3 g, 280 mmol) and butan-2-one (20 g, 280 mmol), and the reaction liquid was heated to reflux for 12 hours. The progress of the reaction was monitored by TLC. After the reaction completed, the solvent was distilled off under reduced pressure. The reaction liquid was diluted with water and extracted with ethyl acetate (4 times). The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to obtain a crude product. The crude product was triturated with IPA and n-pentane to purify the same to obtain pure Compound 1. The remaining crude compound was purified by column chromatography with silica gel of 100-200 mesh using 20% ethyl acetate-hexane to obtain Compound 1 (0.51 g, 45.9%). The same batch was repeated with the scales of 100 g and 600 g. 1H NMR (400 MHz, DMSO-d6): delta 7.93 (d, 2H), 7.56-7.42 (m, 2H), 7.4 -7.38 (m, 2H), 2.04 (s, 3H), 1.42 (s, 3H); LCMS: 266.05 (M+1).
	With morpholine; sulfur; In ethanol; at 18 - 30℃; for 1h;	A. (2-Amino-4,6-dimethylthiophen-3-yl)(4-chlorophenyl)methanone A 12 L, 3 neck round bottom flask equipped with a mechanical stirrer and a thermometer is charged with 3-(4-chlorophenyl)-3-oxopropanenitrile (800 g, 4.46 mol), absolute EtOH (4 L), sulphur (321 g, 4.46 mol) and ethylmethylketone (321 g, 4.46 mol). Morpholine (388 g, 4.46 mol) is added and the reaction mixture thickens, and the temperature increases from 18 C. to 30 C. The reaction mixture is stirred for 1 h at ambient temperature, heated at reflux overnight, then cooled to ambient temperature and concentrated in vacuo. The residue is combined with a previous batch of crude material from a 500 g reaction. The combined residues are taken up in EtOAc (12 L), washed with water (6 L), 10% NaHSO4 (3 L) and brine (2 L), dried over anhydrous NaSO4 and filtered through Celite. The filtrate is concentrated in vacuo to give a gummy solid. The solids are collected by filtration, washed with hexanes and air dried to yield (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone as a tan coloured solid (680 g).
		with morpholine This substance has been prepared using morpholine as the activating partner (eg. WO 2015/156601, WO 2015/131113, Angewandte Chemie, International Edition (2013), 52, 14060-14064, Journal of Biological Chemistry (2012), 287, 28840-28851, WO2011/143660, Nature (2010), 468, 1067-1073 & US 6323214) or with diethylamine (WO 2009/063301). In all reports, the product was purified by chromatography followed by recrystallization and no mention of the ethyl-isomer as side product has been recorded ever anywhere.Purification via oxalate saltCrude aminothiophene (5.0 g, 19 mmol) and oxalic acid (1.7 g, 1 eq.) were taken up in methanol (50 ml). The light orange suspension was heated to reflux creating a dark red solution which then was cooled to ambient temperature. The brown suspension that formed was evaporated on a rotovap at 45 C/250-25 mb and the crude oxalate salt dried for 4 h at 45 C/25 mbar providing a yellow-orange crystalline solid (6.2 g, GC: 87% product, 13% ethyl isomer). a) The oxalate salt (3.0 g) was taken up in acetonitrile (30 ml, lOx v/w) and the brown suspension was heated to reflux. The red solution produced was cooled and stirred at 25 C/1 h. A brown suspension arose which was filtered and the purified product was washed with dichloromethane (4 ml). The salt recovered was dried at 45 C/25 mb for 3 h and the filtrate evaporated.Yield: 1.4 g yellow solid GC (area): 99% product, 1% ethyl isomer

Reference： [1]Patent: WO2011/143657,2011,A1 .Location in patent: Page/Page column 78
[2]Patent: ,2016, .Location in patent: Paragraph 0075; 0076; 0077; 0078; 0079; 0080
[3]Patent: WO2015/156601,2015,A1 .Location in patent: Page/Page column 67; 68; 69
[4]Patent: WO2019/238557,2019,A1 .Location in patent: Paragraph 000118
[5]Patent: EP3640253,2020,A1 .Location in patent: Paragraph 0090; 0093; 0330-0332
[6]Angewandte Chemie - International Edition,2013,vol. 52,p. 14060 - 14064
Angew. Chem.,2013,vol. 125,p. 14310 - 14314,5
[7]Journal of Medicinal Chemistry,1999,vol. 42,p. 3629 - 3635
[8]Patent: US2008/119460,2008,A1 .Location in patent: Page/Page column 37
[9]Journal of Medicinal Chemistry,2012,vol. 55,p. 7719 - 7735
[10]Patent: WO2018/109053,2018,A1 .Location in patent: Page/Page column 16; 17
[11]Patent: EP3686204,2020,A1 .Location in patent: Paragraph 0063-0066

6
[ 120-92-3 ]
[ 4640-66-8 ]
(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-chlorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With pyrrolidine; sulfur In N,N-dimethyl-formamide at 50℃; for 0.5h; Microwave irradiation;	General procedure: A mixture of 1 (1 mmol), 2 (1.1 mmol), sulfur (1.1 mmol), corresponding base (1 mmol) and solvent (3mL) was put into a 5 mL microwave reaction vial. The vial was irradiated in the microwave reactor at50 °C for 30 min with the absorbance set to “very high”. After cooling, the reaction mixture was extractedwith EtOAc (3 × 20 mL). The combined organic phase was dried over Na2SO4 and concentrated underreduced pressure and the crude residue purified by flash chromatography on silica gel to give the products3a-3m and 4a-4r.
45%	With morpholine; sulfur In ethanol at 70℃; for 1h;
	With sulfur In ethanol at 50℃; for 4h;

Reference： [1]Ruan, Bankang; Zhang, Zhiyan; Huang, Lei; Xu, Chao; Li, Luolan [Heterocycles, 2021, vol. 102, # 10, p. 2007 - 2018]
[2]Baraldi, Pier Giovanni; Zaid, Abdel Naser; Lampronti, Ilaria; Fruttarolo, Francesca; Pavani, Maria Giovanna; Tabrizi, Mojgan Aghazadhe; Shryock, John C.; Leung, Edward; Romagnoli, Romeo [Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 17, p. 1953 - 1957]
[3]Tranberg, C. Elisabet; Zickgraf, Andrea; Giunta, Brian N.; Luetjens, Henning; Figler, Heidi; Murphree, Lauren J.; Falke, Ruediger; Fleischer, Holger; Linden, Joel; Scammells, Peter J.; Olsson, Ray A. [Journal of Medicinal Chemistry, 2002, vol. 45, # 2, p. 382 - 389]

7
[ 40018-26-6 ]
[ 4640-66-8 ]
[ 55865-51-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 1,4-dithiane-2,5-diol; p-chlorobenzoylacetonitrile In ethanol at 20℃; for 0.166667h; Stage #2: With N-methylpiperazine-functionalized Polyacrylonitrile Fiber In ethanol for 5h; Reflux;
68%	With diethylamine In ethanol at 50℃;
58%	With diethylamine In ethanol at 50℃; for 6h;	1 Step-1: Synthesis of (2-aminothiophen-3-yl)(4-chlorophenyl)methanone (Intermediate 1) To a solution of SM-1 (1 g, 5.58 mmol) in ethanol (5 mL) were added diethylamine (0.6 mL) and SM-2 (424 mg, 2.79 mmol), and the mixture was stirred at 50°C for 6 hours. After the reaction completed, yellow precipitates were filtered, washed with ethanol and dried under highly reduced pressure to obtain Intermediate 1 (750 mg). Yield: 58%, 1H NMR (400 MHz, DMSO-d6) δ 6.28 (d, J=5.87 Hz, 1H), 6.73 (d, J=5.87 Hz, 1H), 7.52-7.57 (m, 2H), 7.59-7.63 (m, 2H), 8.37 (brs, 2H) and LC-MS (M+1): 238.03

With diethylamine In ethanol at 50℃; for 4h;

Reference： [1]Ma, Lichao; Yuan, Liwei; Xu, Changzhu; Li, Guowei; Tao, Minli; Zhang, Wenqin [Synthesis, 2013, vol. 45, # 1, p. 45 - 52]
[2]Location in patent: experimental part Aurelio, Luigi; Valant, Celine; Flynn, Bernard L.; Sexton, Patrick M.; White, Jonathan M.; Christopoulos, Arthur; Scammells, Peter J. [Journal of Medicinal Chemistry, 2010, vol. 53, # 18, p. 6550 - 6559]
[3]Current Patent Assignee: BLACKSTONE PARTNERS LLC - EP3640253, 2020, A1 Location in patent: Paragraph 0226-0228
[4]Tranberg, C. Elisabet; Zickgraf, Andrea; Giunta, Brian N.; Luetjens, Henning; Figler, Heidi; Murphree, Lauren J.; Falke, Ruediger; Fleischer, Holger; Linden, Joel; Scammells, Peter J.; Olsson, Ray A. [Journal of Medicinal Chemistry, 2002, vol. 45, # 2, p. 382 - 389]

8
[ 4640-66-8 ]
[ 78583-81-0 ]

Yield	Reaction Conditions	Operation in experiment
53.2%	With hydrazine hydrate; In ethanol; for 3h;Reflux;	A mixture of 60.66 g (337 mmol) of 3-(4-chlorophenyl)-3-oxopropanenitrile, 43.46 ml of hydrazine hydrate in 1660 ml of ethanol.was refluxed for 3 h. The reaction mixture was cooled and diluted with water (300 mL). The ethanol was evaporated under reduced pressure. The precipitated crystals were filtered off and washed with water to yield 34,84 g (53,2 %) of the title compound, Mp. : 168-173 C.
49%	With hydrazine hydrate; In methanol; at 150℃; for 0.0833333h;Microwave irradiation;	General procedure: A microwave tube was charged with ketonitrile (2.0 mmol), methanol (1 mL), and hydrazine monohydrate (2.6 mmol) and subjected to microwave irradiation (100 W, 150 C) for 5 minutes. Volatiles were subsequently removed under reduced pressure. The residue was purified by either trituration with cold methanol or cyclohexane, or by using column chromatography to give the final product.
1 g	With hydrazine hydrate; In ethanol; for 12h;Reflux;	To a stirred solution of 3-(4-chlorophenyl)-3-oxopropanenitrile (XL; 1.5 g; 8.3 mmol) in ethanol (75 mL) was added hydrazine hydrate (0.8g; 16.7 mmol). The reaction mixture was heated to a reflux for 12 hours. The reaction mixture was cooled and concentrated underreduced pressure and then diluted with water. The aqueous layer was extracted using ethyl acetate (3 x 2OmL) and triturated with hexane to afford 3-(4-chlorophenyl)-1H-pyrazol-5- amine as a yellow solid (XLI; 1 g, 60% yield). ‘H NMR (400 MHz, CDC13): ö 11.81 (bs, 1H),7.67-7.65 (d, J = 8.4 Hz, 2H), 7.42-7.40 (d, J = 8.4 Hz, 2H), 5.74 (s, 1H), 4.85 (bs, 2H). MS (M-1): 192.27.

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7501 - 7511
[2]Organic Preparations and Procedures International,2004,vol. 36,p. 494 - 498
[3]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 3072 - 3079
[4]Patent: WO2018/167629,2018,A1 .Location in patent: Page/Page column 31
[5]Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 122 - 1228
[6]Pharmaceuticals,2021,vol. 14
[7]Heterocyclic Communications,2004,vol. 10,p. 163 - 166
[8]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 922 - 926
[9]Tetrahedron Letters,2014,vol. 55,p. 5159 - 5163
[10]Chemical Communications,2015,vol. 51,p. 9201 - 9204
[11]Patent: WO2015/97122,2015,A1 .Location in patent: Page/Page column 94; 95
[12]ACS Combinatorial Science,2017,vol. 19,p. 437 - 446

9
[ 4640-66-8 ]
p-chlorobenzoylmethylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With Rhodococcus rhodochrous IFO 15564 In phosphate buffer; ethanol at 28℃; for 1.83333h;
	With sulfuric acid In water at 20℃;	2.5 General procedure for synthesis of starting Materials 1a-p[1]-[3] General procedure: To a stirred solution of carboxylic acid (1.0 eq.) in ethanol (2 M) was added thionyl chloride (2.0 eq.) dropwise at room temperature, and then refluxed for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give crude product, which was chromatographed on silica gel column using 1:30 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product esters in 80% - 95% yields. Esters (1.0 eq.) were added dropwise to a stirred solution of acetonitrile (2.0 eq.) and NaH (3.0 eq.) in THF (2 M) at room temperature, and then refluxed for 1h . After it was cooled to room temperature, Water was added dropwise to the reaction mixture under ice bath until no gas bubbles generated, and employing dilute hydrochloric acid neutralization to neutral, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:4 to 1:2 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product β-ketonitriles, white or light yellow solid compounds in 50% - 85% yields. Finally, stirred in concentrated sulfuric acid (3 M) at room temperature for 5 to 10 hours. The reaction mixture was neutralized to neutral by ammonia water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:1 to 2:1 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product β-ketoamides 1a-p, white solid compounds in 45% - 85% yields.
	Stage #1: p-chlorobenzoylacetonitrile With sulfuric acid at 20℃; for 4h; Stage #2: With water for 0.5h; Cooling with ice;	2 Step 2; The crude 3-(4-chloro-phenyl)-3-oxo-propionitrile obtained above was stirred with 100 mL of sulfuric acid at room temperature for 4 hours. The mixture was poured into 500 mL of ice-water and stirred for 30 minutes. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give 5.73 g of 3-(4-chloro-phenyl)-3-oxo-propionamide as a brown solid which was used in next step without further purification.

Reference： [1]Gotor, Vicente; Liz, Ramón; Testera, Ana Ma [Tetrahedron, 2004, vol. 60, # 3, p. 607 - 618]
[2]Zheng, Congke; Zhang, Xiaohui; Ijaz Hussain, Muhammad; Huang, Mingming; Liu, Qing; Xiong, Yan; Zhu, Xiangming [Tetrahedron Letters, 2017, vol. 58, # 6, p. 574 - 577]
[3]Current Patent Assignee: ROCHE HOLDING AG - US2010/160308, 2010, A1 Location in patent: Page/Page column 8

10
[ 100-63-0 ]
[ 4640-66-8 ]
[ 19652-14-3 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: phenylhydrazine; p-chlorobenzoylacetonitrile With hydrogenchloride In water at 150℃; for 0.166667h; Sealed tube; Microwave irradiation; Green chemistry; Stage #2: With sodium hydroxide In water Green chemistry;	General Procedure 2: Synthesis of 1H-pyrazole-5-amines from α-cyanoketones and phenylhydrazine In a 2-5 mL microwave vial containing a stir bar, 3-oxo-3-phenylpropanenitrile (290 mg, 2 mmol) and 5mL of 1M HCl were combined with stirring to give a 0.4 M solution of starting material. Next, phenylhydrazine (216 mg, 2mmol) was added to the solution. The microwave vial was then sealed with an aluminum cap and irradiated in the microwave reactor at 150 °C for 10 m with the absorbance set to “very high.” After cooling, the resulting solution was basified with 10% NaOH and was sonicated for 5 min. to produce a visible solid precipitate. The precipitate was filtered, washed twice with D.I. water, and then dried to yield the product as a light brown solid (365 mg, 78% yield).
53%	In ethanol for 8h; Reflux; Green chemistry;
50%	In ethanol for 8h; Reflux;

	In isopropyl alcohol Heating;
	With hydrogenchloride In ethanol; water at 100℃; for 4h;	5.1.3. General Procedure for the Preparation of 7d-r General procedure: To a mixture of appropriate β-ketonitrile (6a-c, 5.5mmol) and substituted hydrazine or hydrazine hydrochloride(6 mmol) in 20 mL of ethanol was added aqueous 2 M HCl(0.8 mL). The resulting solution was heated at 100 °C for 4h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was poured into ice water and basified with aqueous 10% NaOH. The resulting suspension was extracted with diethyl acetate (3 x20 mL). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure to afford the title aminopyrazoles, which were purified by crystallization from ethanol.
	In water at 100℃; for 2h;	1 In a 5 mL round bottom flask4-Chlorobenzoylacetonitrile (1 mmol, 179 mg) was added,Phenylhydrazine (1 mmol, 108 mg),Water (2 mL),Stir,Heated to reflux (100 ° C)After 2 hours,Benzaldehyde (1 mmol, 106 mg) was added successively,Methic acid (1 mmol, 144 mg),Stirring at 100 ° C,After one hour,Stop the reaction,Ethyl acetate (3 x 5 mL) was added and the organic phase was combined,After removal of the solvent by rotary evaporation,Column chromatography separation and purification.(3-chlorophenyl) -4,5-dihydro-1,4-diphenyl-1H-pyrazolo [3,4-b] pyridin-6 (7H) -one, 3- (4-chlorophenyl) Dihydro-1,4-diphenyl-1H-pyrazole [3,4-b] pyridine-6 (7-hydro)Yield 61%As a white solid.
	In neat (no solvent) at 120℃; for 2h;	3-{1,3,5-Triphenyl-1,6-dihydropyrrolo[2,3-c]pyrazol-4-yl}indolin-2-one (5a); Typical Procedure General procedure: Benzoylacetonitrile (1a, 0.25 mmol) and phenylhydrazine (2a,0.25 mmol) were mixed in neat conditions and heated at 120 °Cfor 2.0 h. After completion of the reaction, the reaction mixturewas cooled to room temperature. Then, 3-(2-aryl-2-oxoethylidene)indolin-2-one (4a, 0.25 mmol) PTSA·H2O (0.05 mmol)and EtOH (2.5 mL) were added to the reaction mixture. Afterwards,the mixture was stirred for 6 h under reflux conditions.Upon the completion of the reaction (monitored by TLC), thereaction mixture was cooled to room temperature. The precipitatewas collected by filtration and washed with cold ethanol togive the pure product 5a (93 mg, yield 80%).
	In water at 100℃; for 2h;	5 Add 4-chlorobenzoylacetonitrile (1mmol, 179mg), phenylhydrazine (1mmol, 108mg) and 2mL of water into the round bottom reaction flask, stir, heat to 100°C and reflux for 2 hours to obtain 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-5amine.

Reference： [1]Everson, Nikalet; Yniguez, Kenya; Loop, Lauren; Lazaro, Horacio; Belanger, Briana; Koch, Grant; Bach, Jordan; Manjunath, Aashrita; Schioldager, Ryan; Law, Jarvis; Grabenauer, Megan; Eagon, Scott [Tetrahedron Letters, 2019, vol. 60, # 1, p. 72 - 74]
[2]Zeng, Li-Yan; Liu, Teng; Yang, Jie; Yang, Yueli; Cai, Chun; Liu, Shuwen [ACS Combinatorial Science, 2017, vol. 19, # 7, p. 437 - 446]
[3]Abdel-Aziz, Hatem A.; Farahat, Aya A.; Samir, Eman M.; Serya, Rabah A. T.; Zaki, Mayssoune Y. [Archiv der Pharmazie, 2022, vol. 355, # 2]
[4]Reddy, G. Jagath; Manjula; Rao, K. Srinivasa; Khalilullah; Latha; Thirupathaiah [Heterocyclic Communications, 2006, vol. 12, # 1, p. 19 - 24]
[5]Tabrizi, Mojgan Aghazadeh; Baraldi, Pier Giovanni; Baraldi, Stefania; Prencipe, Filippo; Preti, Delia; Saponaro, Giulia; Romagnoli, Romeo; Gessi, Stefania; Merighi, Stefania; Stefanelli, Angela; Fazzi, Debora; Borea, Pier Andrea; Maia, Rodolfo Couto; Romeiro, Nelilma C.; Fraga, Carlos A.M.; Barreiro, Eliezer J. [Medicinal Chemistry, 2015, vol. 11, # 4, p. 342 - 353]
[6]Current Patent Assignee: SOUTHERN MEDICAL UNIVERSITY CHINA - CN106432230, 2017, A Location in patent: Paragraph 0017; 0039
[7]Farhid, Hassan; Javanbakht, Siamak; Nazeri, Mohammad Taghi; Notash, Behrouz; Shaabani, Ahmad [Synlett, 2020, vol. 31, # 10, p. 965 - 971]
[8]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Shanghai Institute of Materia Medica (in: CAS) - CN110746355, 2020, A Location in patent: Paragraph 0520-0522

11
[ 1003-04-9 ]
[ 4640-66-8 ]
(2-amino-4,5-dihydrothieno[2,3-b]thiophen-3-yl)-(4-chlorophenyl)methanone [ No CAS ]

Reference： [1]Medicinal Chemistry Research,2005,vol. 14,p. 125 - 142

12
[ 1072-72-6 ]
[ 4640-66-8 ]
(2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)-(4-chlorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With sulfur; triethylamine In DMF (N,N-dimethyl-formamide) at 65℃; for 2h;	5.a a) Preparation of 12 To 4-chlorobenzoylacetonitrile (2,3. 6 g, 20 mmol) and sulfur (0.65 g) in DMF (6 mL), triethylamine (2.0 mL) is added under stirring. To this solution tetrahydrothiopyran-4-one (11,2. 32 g, 20 mmol) is added dropwise. The mixture is heated to [65°C] for 2 hours and it is poured into water (60 mL), which is extracted with diethyl ether (50 mL). The ethereal solution is dried with sodium sulfate and concentrated to give the desired compound as a brown solid (5.07 g, 82% yield). Physical characteristics: MS [(ES+)] for m/z [310.]
66%	With morpholine; sulfur In ethanol for 21h;

Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/35591, 2004, A1 Location in patent: Page 25
[2]Romagnoli, Romeo; Baraldi, Pier Giovanni; Pavani, Maria Giovanna; Tabrizi, Mojgan Aghazadeh; Iaconinoto, Maria Antonietta; Carrion, Maria Dora; Lopez Cara, Carlota; Shryock, John C.; Leung, Edward; Moorman, Allan R.; Gessi, Stefania; Merighi, Stefania; Borea, Pier Andrea [Medicinal Chemistry Research, 2005, vol. 14, # 3, p. 125 - 142]

13
[ 4640-66-8 ]
[ 84466-38-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium tetrahydroborate; ethanol for 2h; Cooling with ice;	89 PREPARATION 885-(Chloromethyl)-3-[2-(4-ch Iorophenoxy)ethyl]-1 ,2,4-oxadiazole Synthesized from the crude title compound of PREPARATION 87 and chloroacetic anhydride following the method of PREPARATION 76. The title compound was first partially purified by normal-phase chromatography and then purified by reverse-phasechromatography using the Isolera Purification system. Yield: 50% over two steps. Purity 100%.1H NMR (400 MHz, Chloroform-d) ppm 7.24 - 7.18 (m, 2H), 6.88 - 6.76 (m, 2H),4.67 (s, 2H), 4.34 (t, J = 6.5 Hz, 2H), 3.24 (t, J = 6.5 Hz, 2H).UPLC/MS (3 mm) retention time 1 .82 mm.LRMS: m/z 273 (M+1, 2xCl).
87%	With sodium tetrahydroborate In ethanol at 0 - 20℃;
79%	With sodium tetrahydroborate In ethanol at 0℃; for 1h;

52%

With sodium tetrahydroborate In ethanol at 0 - 25℃;

Reference： [1]Current Patent Assignee: ALMIRALL SA - WO2017/60488, 2017, A1 Location in patent: Page/Page column 92
[2]Kamila, Sukanta; Zhu, Dunming; Biehl, Edward R.; Hua, Ling [Organic Letters, 2006, vol. 8, # 20, p. 4429 - 4431]
[3]Schenkel, Laurie B.; Olivieri, Philip R.; Boezio, Alessandro A.; Deak, Holly L.; Emkey, Renee; Graceffa, Russell F.; Gunaydin, Hakan; Guzman-Perez, Angel; Lee, Josie H.; Teffera, Yohannes; Wang, Weiya; Youngblood, Beth D.; Yu, Violeta L.; Zhang, Maosheng; Gavva, Narender R.; Lehto, Sonya G.; Geuns-Meyer, Stephanie [Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2794 - 2809]
[4]Coady, Tracey M.; Coffey, Lee V.; O'Reilly, Catherine; Lennon, Claire M. [European Journal of Organic Chemistry, 2015, vol. 2015, # 5, p. 1108 - 1116]

14
[ 1126-46-1 ]
[ 75-05-8 ]
[ 4640-66-8 ]

Yield	Reaction Conditions	Operation in experiment
97.6%	With sodium methylate for 6h; Inert atmosphere; Reflux;	a 3-(4-chlorophenyl)-3-oxopropanenitrile To a solution of 59.0 g (346 mmol) of methyl 4-chlorobenzoate in 690 mL of acetonitrile 37.37 g ( 692 mmol) sodium methyiate was added in nitrogen athmosphere and the mixture was refluxed for 6 h. The reaction mixture was cooled and poured into 500 mL of water. The pH of the mixture was adjusted to 3 by the addition of 2M hydrochloric acid. The precipitated product was filtered off and washed with water to yield 60.66 g (97.6 %) of the title compound. Mp. : 130-143 °C.
74%	Stage #1: acetonitrile With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 1h; Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran; n-heptane; ethylbenzene at -78 - 20℃;
70%	With sodium methylate for 6h; Reflux; Inert atmosphere;

64%	Stage #1: acetonitrile With lithium hexamethyldisilazane In tetrahydrofuran; toluene at -78 - -60℃; for 1h; Inert atmosphere; Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran; toluene at -78 - 20℃; for 16h; Inert atmosphere;
62%	With sodium hydride In toluene at 100℃; for 15h;	Synthesis of 3-(4-Chlorophenyl)-3-oxopropanenitrile To a stirred solution of methyl 4-chlorobenzoate (5 g, 29.41 mmol) in toluene (50 mL), ACN (4.6 mL, 88.23 mmol) and NaH (60%, 3.3 g, 88.23 mmol) were added and stirred at 100 °C for 15 h. Progress of the reaction was monitored by TLC. Upon completion the reaction mixture was diluted with ice cold water, quenched with 2N HC1 up to pH=2 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure resulting in a crude compound which was purified by column chromatography to afford the title compound (3.2 g, 62%)
53%	With potassium <i>tert</i>-butylate; isopropyl alcohol In 2-methyltetrahydrofuran at 20℃; for 1h; Inert atmosphere;	General procedure for the synthesis of the β-ketonitriles General procedure: To a solution of methyl/ethyl ester (1.0 equiv) in 20 mL 2-MeTHF under N2 was added IPA (0.2 equiv),CH3CN (1.0 equiv), followed by KOt-Bu (1.0 equiv). The reaction mixture was stirred at room temperaturefor an hour under N2 atmosphere, then dosed-up with an additional 1.0 mol equiv of CH3CN and KOt-Bu,respectively. The reaction mixture was stirred for another hour, quenched with 200 mL of saturated NH4Cl solution and the layers separated. The aqueous layer was extracted with 200 mL DCM. The combinedorganic layer was dried over Na2SO4, filtered and the solvents removed in vacuo by roto-evaporation. Theresulting residue was purified by SiO2 gel column chromatography using EtOAc/hexane mixtures as mobilephases.
43%	With sodium methylate for 2h; Reflux; Inert atmosphere;
20%	With sodium methylate at 20 - 100℃; for 19h;	12 3-(4-Chlorophenyl)-3-oxopropanenitrile; Methyl 4-chlorobenzoate (3.40 g, 20 mmol) was dissolved in toluene (16 niL). Acetonitrile (1.32 mL, 25 mmol) and NaOCH3 (1.08 g, 20 mmol) were added and the reaction was stirred at room temperature under argon for 18h. The reaction was heated to 1000C for Ih, and the reaction mixture was cooled to ambient temperature and the volatiles were removed by rotary evaporation leaving a residue. The residue was dissolved in water (10 mL) and washed with diether (3 times). The aqueous layer was then acidified to pH 6.4 with citric acid. The resulting precipitate was collected on fritted glass, washed with water, saturated aqueous NaHCO3, and water. The solid on the filter was dried under high vacuum over night to provide the beta-ketonitrile (692 mg, 20% yield).
	With sodium hydride In toluene; mineral oil for 24h;
0.7 g	Stage #1: acetonitrile With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran at -78℃; for 0.5h;	B Step-B: Synthesis of 3-(4-chlorophenyl)-3-oxopropanenitrile (Compound B) To a stirred solution of dry CH3CN (14.5 g, 35 mmol) and dry tetrahydrofuran (300 mL) was added lithium diisopropylamide (220 mL, 441 mmol, 2M solution, in tetrahydrofuran) at -78°C, and the mixture was stirred at the same temperature for 1 hour under nitrogen atmosphere. Compound A (50 g, 29.4 mmol) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Next, the reaction mixture was allowed to cool at room temperature, and quenched with an ammonium chloride solution. The precipitated solid was filtered, washed with water, ether and pentane, and dried to obtain Compound B (0.7 g, 63.1%). The same batch was repeated with the scales of 50 g x 20. 1H-NMR (400 MHz, CDCl3): δ7.89 (d, 2H), 7.45 (d, 1H), 4.02 (s, 2H); LCMS: 180.1 (M+1).
	Stage #1: acetonitrile With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran at 66℃; for 12h;
	With sodium hydride In toluene for 4h; Reflux;
	With sodium hydride In tetrahydrofuran for 5h; Reflux; Inert atmosphere;

Reference： [1]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - WO2018/167629, 2018, A1 Location in patent: Page/Page column 31
[2]Takahashi, Toshiyuki; Sakuraba, Aya; Hirohashi, Tomoko; Shibata, Takunobu; Hirose, Masaaki; Haga, Yuji; Nonoshita, Katsumasa; Kanno, Tetsuya; Ito, Junko; Iwaasa, Hisashi; Kanatani, Akio; Fukami, Takehiro; Sato, Nagaaki [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 22, p. 7501 - 7511]
[3]Ma, Lichao; Yuan, Liwei; Xu, Changzhu; Li, Guowei; Tao, Minli; Zhang, Wenqin [Synthesis, 2013, vol. 45, # 1, p. 45 - 52]
[4]Location in patent: experimental part Cleghorn, Laura A.T.; Woodland, Andrew; Collie, Iain T.; Torrie, Leah S.; Norcross, Neil; Luksch, Torsten; Mpamhanga, Chido; Walker, Roderick G.; Mottram, Jeremy C.; Brenk, Ruth; Frearson, Julie A.; Gilbert, Ian H.; Wyatt, Paul G. [ChemMedChem, 2011, vol. 6, # 12, p. 2214 - 2224]
[5]Current Patent Assignee: EPIZYME, INC. - WO2016/44666, 2016, A1 Location in patent: Paragraph 0349; 0351
[6]Pienaar, Daniel P.; Butsi, Kamogelo R.; Rousseau, Amanda L.; Brady, Dean [Beilstein Journal of Organic Chemistry, 2019, vol. 15, p. 2930 - 2935]
[7]Location in patent: experimental part Moe, Scott T.; Thompson, Andrew B.; Smith, Genessa M.; Fredenburg, Ross A.; Stein, Ross L.; Jacobson, Alan R. [Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 8, p. 3072 - 3079]
[8]Current Patent Assignee: ROLFES HOLDINGS LIMITED - WO2009/45761, 2009, A1 Location in patent: Page/Page column 64
[9]Zhou, Jie; Zhu, Xinhai; Huang, Manna; Wan, Yiqian [European Journal of Organic Chemistry, 2017, vol. 2017, # 16, p. 2317 - 2321]
[10]Current Patent Assignee: BLACKSTONE PARTNERS LLC - EP3640253, 2020, A1 Location in patent: Paragraph 0090; 0092
[11]Qin, Qiaohua; Wu, Tianxiao; Yin, Wenbo; Sun, Yixiang; Zhang, Xiangyu; Wang, Ruifeng; Guo, Jing; Zhao, Dongmei; Cheng, Maosheng [Archiv der Pharmazie, 2020, vol. 353, # 10]
[12]Hassan, Ghaneya S.; Georgey, Hanan H.; Mohammed, Esraa Z.; George, Riham F.; Mahmoud, Walaa R.; Omar, Farghaly A. [European Journal of Medicinal Chemistry, 2021, vol. 218]
[13]Liu, Chong; Yuan, Jing; Zhang, Zhenfeng; Gridnev, Ilya D.; Zhang, Wanbin [Angewandte Chemie - International Edition, 2021, vol. 60, # 16, p. 8997 - 9002][Angew. Chem., 2021, vol. 133, # 16, p. 9079 - 9084,6]

15
[ 4640-66-8 ]
(R)-3-hydroxy-3-(4’-chlorophenyl)-propanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With D-glucose; D-glucose dehydrogenase; NADPH In phosphate buffer; dimethyl sulfoxide at 20℃; for 24h;
84%	With β-D-glucose In aq. phosphate buffer; toluene at 25℃; for 6h; Enzymatic reaction;

Reference： [1]Zhu, Dunming; Ankati, Haribabu; Mukherjee, Chandrani; Yang, Van; Biehl, Edward R.; Hua, Ling [Organic Letters, 2007, vol. 9, # 13, p. 2560 - 2563]
[2]Xu, Guo-Chao; Yu, Hui-Lei; Zhang, Zhi-Jun; Xu, Jian-He [Organic Letters, 2013, vol. 15, # 21, p. 5408 - 5411]

16
[ 368-78-5 ]
[ 4640-66-8 ]
[ 601487-17-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With acetic acid In ethanol at 120℃; for 2h;	P7.1 Example P7; Preparation of 3-(4-chlorophenvl)-1-(3-trifluoromethylphenyl)-5-vinyl-1 H- pyrazol (20); Step 1; Preparation of 5- (4-chlorophenyl)-2- (3-trifluoromethylphenyl)-2H-pyrazol-3-yl- amine (18); A solution of 7.93 g of 3-trifluoromethylphenylhydrazine and 7.69 g of 4-chlorobenzoyl- acetonitrile in 40 mi of glacial acetic acid and 40 ml of ethanol is heated at 120°C for two hours until the reaction is complete (TLC monitoring). The reaction mixture is completely concentrated and the residue is caused to crystallise by azeotropic treatment with toluene (4x 20 ml) and diethyl ether (3x 20ml). 14.0 g (97% of theory) of the aminopyrazole (18) are obtained in the form of a solid having a melting point of 128-130°C, which is used in the next reaction without further purification.

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2003/76409, 2003, A1 Location in patent: Page/Page column 28

17
[ 4640-66-8 ]
[ 324574-51-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: With (p-cymene)ruthenium(II) chloride; triethylamine; N-[(1S,2S)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide In dichloromethane at 35℃; for 1h; Stage #2: p-chlorobenzoylacetonitrile With tetra-(n-butyl)ammonium iodide In water; sodium formate at 40℃; for 4h; Ultrasonic irradiation; optical yield given as %ee;
85%	With β-D-glucose In aq. phosphate buffer; toluene at 25℃; for 6h; Enzymatic reaction;
81%	With D-glucose; D-glucose dehydrogenase; alcohol dehydrogenase YMR₂₂₆c from Saccharomyces cerevisiae; NADPH In dimethyl sulfoxide at 20℃; for 24h; potassium phosphate buffer; Enzymatic reaction; optical yield given as %ee; enantioselective reaction;

91 %Chromat.	With enzyme YOL₁₅₁w for 12h; Enzymatic reaction; optical yield given as %ee;	Whole-cell screening procedure General procedure: LB medium supplemented with 30 μg/mL kanamycin was inoculated with a single colony of E. coli (containing the appropriate overexpressed gene) and shaken 15 h at 37 °C. This preculture was diluted 1:100 into 30 mL of the same medium and shaken 2.5 h at 37 °C with a stir rate of 220 rpm. Upon reaching an O.D.600 = 0.5 the cell culture was cooled to 20 °C, and isopropylthio-β-D-galactoside was added to a final concentration of 100 μM and shaken for 2 h. The β-keto nitrile substrate was added to a final concentration of 2 mM using a concentrated acetonitrile solution. (Ethanol and methanol solutions were avoided due to an increase in alkylation). This reaction was allowed to shake at 220 rpm for 12 h. The reaction was then gently extracted with methylene chloride (2 mL) and analyzed by chiral GCMS.
	With chloro([(S,2S)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium (II); formic acid/triethylamine complex 5:2 In acetonitrile at 19 - 24℃; for 3h; Inert atmosphere;	(3S)-3-(4-chlorophenyl)-3-hydroxypropanenitrile 10.0 g (55.7 mmol) 4-Chlorobenzoylacetonitrile are added to 100 mL ACN under inert atmosphere. 142 mg (0.23 mmol) Chloro([(S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium (II) (CAS 174813-81-1) are added before 8.30 mL (19.8 mmol) formic acid triethylamine complex (5:2) are added dropwise. After stirring at RT for 3 h the solvent is removed in vacuo. To the remaining crude mixture is added water and this mixture is extracted two times with EtOAc. The organic layers are combined, dried over MgSO4 and the solvent is removed in vacuo. (0119) C9H8ClNO (M=181.6 g/mol) (0120) ESI-MS: 226 [M+HCOO]- (0121) Rt(HPLC): 0.81 min (method B)
96 % ee	With tris(2,2'-bipyridyl)ruthenium dichloride; D-glucose; NAD; Bacillusa myloliquefaciens flavin-dependent nitroreductase BaNTR₁ In dimethyl sulfoxide for 16h; Irradiation; Enzymatic reaction; enantioselective reaction;

Reference： [1]Location in patent: experimental part Wang, Weiwei; Li, Zhiming; Mu, Wenbo; Su, Ling; Wang, Quanrui [Catalysis Communications, 2010, vol. 11, # 5, p. 480 - 483]
[2]Xu, Guo-Chao; Yu, Hui-Lei; Zhang, Zhi-Jun; Xu, Jian-He [Organic Letters, 2013, vol. 15, # 21, p. 5408 - 5411]
[3]Ankati, Haribabu; Zhu, Dunming; Yang, Yan; Biehl, Edward R.; Hua, Ling [Journal of Organic Chemistry, 2009, vol. 74, # 4, p. 1658 - 1662]
[4]Nowill, Randall W.; Patel, Trisha J.; Beasley, David L.; Alvarez, Jose A.; Jackson III, Elizah; Hizer, Todd J.; Ghiviriga, Ion; Mateer, Scott C.; Feske, Brent D. [Tetrahedron Letters, 2011, vol. 52, # 19, p. 2440 - 2442]
[5]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2021/107918, 2021, A1 Location in patent: Paragraph 0117-0121
[6]Prats Luján, Alejandro; Bhat, Mohammad Faizan; Saravanan, Thangavelu; Poelarends, Gerrit J. [ChemCatChem, 2022, vol. 14, # 8]

18
[ 33906-30-8 ]
[ 4640-66-8 ]
2-(4-chlorophenyl)pyrazolo[1,5-a]quinazolin-5(4H)-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4196 - 4200

19
[ 555-96-4 ]
[ 4640-66-8 ]
[ 309732-91-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	In ethanol at 100℃; for 1h;	12 l-Benzyl-3-(4-chlorophenyl)-lH-pyrazol-5 -amine; The beta-ketonitrile, prepared above, 3-(4-chlorophenyl)-3-oxopropanenitrile (177 mg, 1 mmol), was dissolved in abs. ethanol (1 mL). To this solution was added benzyl hydrazine (146, 1.2 mmol, prepared by free basing commercial benzylhydrazine hydrochloride). The reaction mixture was heated in a sealed tube to 1000C for Ih, and the reaction was cooled to room temperature. Water (2 mL) was added dropwise to precipitate the heterocyclic product as a solid. This material was collected on a fritted glass funnel, washed with water, then dried overnight under high vacuum to provide 238.8 mg, 85% yield of a fluffy powder.
	With hydrogenchloride In ethanol; water at 100℃; for 4h;	5.1.3. General Procedure for the Preparation of 7d-r General procedure: To a mixture of appropriate β-ketonitrile (6a-c, 5.5mmol) and substituted hydrazine or hydrazine hydrochloride(6 mmol) in 20 mL of ethanol was added aqueous 2 M HCl(0.8 mL). The resulting solution was heated at 100 °C for 4h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was poured into ice water and basified with aqueous 10% NaOH. The resulting suspension was extracted with diethyl acetate (3 x20 mL). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure to afford the title aminopyrazoles, which were purified by crystallization from ethanol.

Reference： [1]Current Patent Assignee: ROLFES HOLDINGS LIMITED - WO2009/45761, 2009, A1 Location in patent: Page/Page column 64
[2]Tabrizi, Mojgan Aghazadeh; Baraldi, Pier Giovanni; Baraldi, Stefania; Prencipe, Filippo; Preti, Delia; Saponaro, Giulia; Romagnoli, Romeo; Gessi, Stefania; Merighi, Stefania; Stefanelli, Angela; Fazzi, Debora; Borea, Pier Andrea; Maia, Rodolfo Couto; Romeiro, Nelilma C.; Fraga, Carlos A.M.; Barreiro, Eliezer J. [Medicinal Chemistry, 2015, vol. 11, # 4, p. 342 - 353]

20
[ 68755-37-3 ]
[ 4640-66-8 ]
[ 1245739-95-0 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 6550 - 6559

21
[ 68755-42-0 ]
[ 4640-66-8 ]
[ 1245739-93-8 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 6550 - 6559

22
[ 122-01-0 ]
[ 372-09-8 ]
[ 4640-66-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: cyanoacetic acid With [2,2]bipyridinyl; n-butyllithium; magnesium sulfate In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: 4-chloro-benzoyl chloride In tetrahydrofuran; methanol; hexane at -78 - 20℃; Inert atmosphere; Stage #3: With hydrogenchloride In tetrahydrofuran; methanol; hexane; water	Synthesis of β-keto nitriles General procedure: Cyanoacetic acid (1.7 g, 20 mmol, 2 equiv), 0.2 mg MgSO4, and ~1 mg 2,2'-bipyridyl was dissolved in tetrahydrofuran (100 mL) and placed in a 500 mL three-neck flask fitted with two dropping funnels and a mechanical stirrer. The system was flushed with nitrogen and cooled to -78 C with a dry ice/ acetone bath. An n-butyl lithium solution (25 mL, 1.6 M in hexanes; 40 mmol, 4 equiv) was added via a dropping funnel with stirring. Once the solution turned slightly purple it was stirred (30 min) after which the acid chloride (10 mmol, 1 equiv) in 5 mL of methanol was added drop-wise with stirring. During this process, the cloudy solution took on a yellow color. The solution was stirred at -78 C for one hour, then the bath was removed and the reaction was allowed to return to room temperature for one hour. An HCl solution (50 mL, 1M) was added drop-wise. At this point, the reaction became clear, while remaining yellow. Water (25 mL) and CH3Cl (50 mL) were added. The aqueous layer was extracted three times with the same volume of CH3Cl. The combined organic layers were washed with two portions (50 mL) of saturated sodium bicarbonate solution and dried over magnesium sulfate, filtered, and reduced on a rotoevaporator. Samples were purified by flash chromatography 6 Hex : 1 EtOAc resulting in percent yields from 50-80%.

Reference： [1]Nowill, Randall W.; Patel, Trisha J.; Beasley, David L.; Alvarez, Jose A.; Jackson III, Elizah; Hizer, Todd J.; Ghiviriga, Ion; Mateer, Scott C.; Feske, Brent D. [Tetrahedron Letters, 2011, vol. 52, # 19, p. 2440 - 2442]

23
[ 4640-66-8 ]
[ 1268524-70-4 ]

Reference： [1]Patent: WO2011/143657,2011,A1
[2]Patent: WO2011/143657,2011,A1
[3]Patent: ,2016,
[4]Patent: WO2018/109053,2018,A1
[5]Patent: WO2018/109053,2018,A1
[6]Patent: WO2018/109053,2018,A1
[7]Patent: WO2018/109053,2018,A1

24
[ 4640-66-8 ]
3-amino-5-(4-chlorophenyl)pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With hydrazine hydrate In ethanol for 24h; Reflux; Inert atmosphere;
51.01%	With hydrazine hydrate In ethanol at 80℃; Inert atmosphere;	1 Scheme 4 Dissolve 6mmol of raw material-substituted benzoylacetonitrile in 20mL of ethanol, add 1mL of 80% hydrazine hydrate aqueous solution, replace the air in the reaction flask with nitrogen, and heat the reaction solution at 80°C for 3-8h. The solvent was distilled off under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol, gradient 0-5%) to obtain the target product in two tautomeric forms.
	With hydrazine hydrate

With hydrazine In methanol at 65℃; for 3h;

Reference： [1]Location in patent: experimental part Cleghorn, Laura A.T.; Woodland, Andrew; Collie, Iain T.; Torrie, Leah S.; Norcross, Neil; Luksch, Torsten; Mpamhanga, Chido; Walker, Roderick G.; Mottram, Jeremy C.; Brenk, Ruth; Frearson, Julie A.; Gilbert, Ian H.; Wyatt, Paul G. [ChemMedChem, 2011, vol. 6, # 12, p. 2214 - 2224]
[2]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN112876482, 2021, A Location in patent: Paragraph 0035-0037; 0053; 0057-0058
[3]Ali, Korany A.; Ragab, Eman A.; Mloston, Grzegorz; Celeda, Malgorzata; Linden, Anthony; Heimgartner, Heinz [Helvetica Chimica Acta, 2013, vol. 96, # 4, p. 633 - 643]
[4]Qin, Qiaohua; Wu, Tianxiao; Yin, Wenbo; Sun, Yixiang; Zhang, Xiangyu; Wang, Ruifeng; Guo, Jing; Zhao, Dongmei; Cheng, Maosheng [Archiv der Pharmazie, 2020, vol. 353, # 10]

25
[ 98-03-3 ]
[ 4640-66-8 ]
[ 1370042-79-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With piperidine In (+/-)-2-pentanol at 120℃; for 0.25h; Microwave irradiation;	General Knoevenagel Condensation Procedure General procedure: To a 0.5-2.0ml vial with 1 mmol ketone (1 eq) issolved in 2-pentanol (1.66 M) was added 1.1 eq of aromatic aldehyde and catalytic piperidine (0.08 eq), stirring vigorously. After heating under μWave for 15min at 120 °C, the reaction was cooled to r.t. and precipitate was vacuum filtered and washed with minimal, cold hexanes. After drying under vacuum, solid was analyzed via NMR, IR, and mp.

Reference： [1]Deshpande, Shyam J.; Leger, Paul R.; Sieck, Stephen R. [Tetrahedron Letters, 2012, vol. 53, # 14, p. 1772 - 1775]

26
[ 104-87-0 ]
[ 4640-66-8 ]
[ 1370042-80-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	With piperidine In (+/-)-2-pentanol at 120℃; for 0.25h; Microwave irradiation;	General Knoevenagel Condensation Procedure General procedure: To a 0.5-2.0ml vial with 1 mmol ketone (1 eq) issolved in 2-pentanol (1.66 M) was added 1.1 eq of aromatic aldehyde and catalytic piperidine (0.08 eq), stirring vigorously. After heating under μWave for 15min at 120 °C, the reaction was cooled to r.t. and precipitate was vacuum filtered and washed with minimal, cold hexanes. After drying under vacuum, solid was analyzed via NMR, IR, and mp.

Reference： [1]Deshpande, Shyam J.; Leger, Paul R.; Sieck, Stephen R. [Tetrahedron Letters, 2012, vol. 53, # 14, p. 1772 - 1775]

27
[ 104-88-1 ]
[ 4640-66-8 ]
(E)-2-(4-chlorobenzoyl)-3-(4-chlorophenyl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With piperidine In (+/-)-2-pentanol at 120℃; for 0.25h; Microwave irradiation;	General Knoevenagel Condensation Procedure General procedure: To a 0.5-2.0ml vial with 1 mmol ketone (1 eq) issolved in 2-pentanol (1.66 M) was added 1.1 eq of aromatic aldehyde and catalytic piperidine (0.08 eq), stirring vigorously. After heating under μWave for 15min at 120 °C, the reaction was cooled to r.t. and precipitate was vacuum filtered and washed with minimal, cold hexanes. After drying under vacuum, solid was analyzed via NMR, IR, and mp.

Reference： [1]Deshpande, Shyam J.; Leger, Paul R.; Sieck, Stephen R. [Tetrahedron Letters, 2012, vol. 53, # 14, p. 1772 - 1775]

28
[ 555-16-8 ]
[ 4640-66-8 ]
[ 1370042-82-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With piperidine In (+/-)-2-pentanol at 120℃; for 0.25h; Microwave irradiation;	General Knoevenagel Condensation Procedure General procedure: To a 0.5-2.0ml vial with 1 mmol ketone (1 eq) issolved in 2-pentanol (1.66 M) was added 1.1 eq of aromatic aldehyde and catalytic piperidine (0.08 eq), stirring vigorously. After heating under μWave for 15min at 120 °C, the reaction was cooled to r.t. and precipitate was vacuum filtered and washed with minimal, cold hexanes. After drying under vacuum, solid was analyzed via NMR, IR, and mp.

Reference： [1]Deshpande, Shyam J.; Leger, Paul R.; Sieck, Stephen R. [Tetrahedron Letters, 2012, vol. 53, # 14, p. 1772 - 1775]

29
[ 100-10-7 ]
[ 4640-66-8 ]
[ 1370042-78-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With piperidine In (+/-)-2-pentanol at 120℃; for 0.25h; Microwave irradiation;	General Knoevenagel Condensation Procedure General procedure: To a 0.5-2.0ml vial with 1 mmol ketone (1 eq) issolved in 2-pentanol (1.66 M) was added 1.1 eq of aromatic aldehyde and catalytic piperidine (0.08 eq), stirring vigorously. After heating under μWave for 15min at 120 °C, the reaction was cooled to r.t. and precipitate was vacuum filtered and washed with minimal, cold hexanes. After drying under vacuum, solid was analyzed via NMR, IR, and mp.

Reference： [1]Deshpande, Shyam J.; Leger, Paul R.; Sieck, Stephen R. [Tetrahedron Letters, 2012, vol. 53, # 14, p. 1772 - 1775]

30
[ 367-57-7 ]
[ 615-21-4 ]
[ 4640-66-8 ]
[ 1384952-42-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 1,3-benzothiazol-2-ylhydrazine; p-chlorobenzoylacetonitrile With toluene-4-sulfonic acid for 0.0833333h; Heating; Neat (no solvent); Stage #2: 1,1,1-Trifluoro-2,4-pentanedione at 80 - 90℃; for 0.25h; Neat (no solvent); regiospecific reaction;	4.1. General procedure for three-component solvent-free synthesis of 1-(benzothiazol-2'-yl)-3-aryl-4-substituted-6-trifluoromethyl-1Hpyrazolo[3,4-b]pyridines 4a-h. General procedure: Equimolar amounts of appropriate 2-hydrazinobenzothiazole1a-b, α-cyanoacetophenone 2a-c, and PTSA were mixed thoroughly in pestle mortar and heated on water bath for 4-5 min and then equimolar amount of appropriate trifluoromethyl β-diketones 3a-d was added to it and mixed thoroughly. The reaction mixture was again heated 80-90 ° C for 15 min on water bath. The solid was obtained by addition of aq. ethanol, filtered and crystallized from the mixture of ethanol and chloroform to give pure 4.

Reference： [1]Location in patent: experimental part Aggarwal, Ranjana; Kumar, Virender; Bansal, Anshul; Sanz, Dionisia; Claramunt, Rosa M. [Journal of Fluorine Chemistry, 2012, vol. 140, p. 31 - 37]

31
[ 50329-91-4 ]
[ 4640-66-8 ]
[ 1395098-23-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium azide; triethylamine In N,N-dimethyl-formamide at 50 - 60℃; for 3.5h;	Representative procedure for the synthesis of tetrazolo[4′,5′:1,6]pyrido[2,3-c]coumarins 5/7/9: General procedure: 4-Chloro-3-formyl coumarin 2 (1 mmol, 208 mg), sodium azide 3 (1.25 mmol, 80 mg) and cyanoacetamide 4a (1.5 mmol, 126 mg) were taken in a round bottom flask. To this were added DMF (5 ml) and one drop of triethylamine. The reaction mixture was stirred with a magnetic stirrer at 50-60 °C for 3 h. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and then poured into water (10 mL) with stirring. A brown coloured solid product appears. The mixture was kept in a refrigerator for 3 h. The solid product was filtered and purified by column chromatography using petroleum ether and ethyl acetate (7:3) as eluent. The structure of the compound was ascertained as 5a from the spectroscopic data and elemental analysis. Yield = 0.203 g (72.24%).

Reference： [1]Borah, Pallabi; Seetham Naidu, P.; Bhuyan, Pulak J. [Tetrahedron Letters, 2012, vol. 53, # 37, p. 5034 - 5037,4]

32
[ 18498-59-4 ]
[ 4640-66-8 ]
2-(4-chlorobenzoyl)hept-6-ynenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; <i>L</i>-proline In ethanol at 25℃; for 16h;

Reference： [1]Wong, Ying-Chieh; Kao, Tzu-Ting; Yeh, Yu-Cheng; Hsieh, Bing-Siou; Shia, Kak-Shan [Advanced Synthesis and Catalysis, 2013, vol. 355, # 7, p. 1323 - 1337]

33
[ 4640-66-8 ]
[ 84-58-2 ]
[ 1476782-00-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	In ethyl acetate at 25℃;	General procedure: DDQ (341 mg, 1.5 mmol) was added to -cyanoketone (0.5 mmol) in ethyl acetate (2 mL). Theresulting reaction mixture was stirred overnight during which time a yellow solid precipitated.Ethyl acetate (30 mL) was added and the resultant mixture was subsequently washed with coldaqueous 5% NaHCO3 (10 mL×3) and brine. Silica gel (0.5 g) was added and the mixture rotaryevaporated. The resulting powder was added to the top of a short silica-gel column and purifiedusing petroleum ether/ethyl acetate in a 10:1~7:1 ratio (volume ratio) as the eluent to afford thedesired product.

Reference： [1]Li, Jiang-Sheng; Xue, Yuan; Li, Zhi-Wei; Liu, Wei-Dong; Lu, Cui-Hong; Zhao, Pei-Xia [Synlett, 2013, vol. 24, # 15, p. 2003 - 2005]

34
[ 1449412-24-1 ]
[ 4640-66-8 ]
[ 1449412-29-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With piperidine In ethanol at 130℃; for 0.333333h; Microwave irradiation;	4.3.1. Method (A) General procedure: To a solution of 2 (0.49 g, 1.7 mmol) in ethanol (20 ml) and piperidine (0.5 ml) as a catalyst was added substituted β-ketonitriles 3a-d (1.7 mmol). The reaction mixture was heated under reflux for (8-10) h and the progress of the reaction was monitored by TLC using benzene/acetone (2:1) as eluent. The solvent was evaporated under reduced pressure; the oil residue was treated with petroleum ether 40-60°C (3 x 10 ml) and recrystallized from ethanol to give (4a-d).

Reference： [1]El-Borai, Mohamed A.; Rizk, Hala F.; Beltagy, Doha M.; El-Deeb, Ibrahim Y. [European Journal of Medicinal Chemistry, 2013, vol. 66, p. 415 - 422]

35
[ 23906-13-0 ]
[ 4640-66-8 ]
[ 1154566-92-3 ]

Reference： [1]Medicinal Chemistry Research,2014,vol. 23,p. 1454 - 1464

36
[ 873-76-7 ]
[ 75-05-8 ]
[ 4640-66-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With oxygen; potassium hydroxide; copper dichloride In N,N-dimethyl acetamide at 20℃; for 12h; Green chemistry;
82%	With oxygen; potassium hydroxide; copper dichloride In N,N-dimethyl acetamide at 25℃; for 12h;	1.1-1 Example 1-1 Compound 1 (2.85 g, 20 mmol) was weighed out in 20 mL of N, N-dimethylacetamide, 10 mL of acetonitrile, 0.1 g of cupric chloride, and 3 g of potassium hydroxide were sequentially added to the reaction mixture under an oxygen atmosphere at room temperature (25 ° C) Should be 12h. After completion of the reaction, 1 mol / L hydrochloric acid was slowly added dropwise, the pH was adjusted to 7, and the mixture was filtered through celite, The filtrate was washed with water three times and then three times with saturated brine, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness.Column chromatography gave the title compound 3 (2.92 g, 82% yield) as a yellow solid.

Reference： [1]Shen, Jiaxuan; Yang, Dejun; Liu, Yuxiao; Qin, Shuangshuang; Zhang, Jingwu; Sun, Jiangkai; Liu, Chunhui; Liu, Chaoyang; Zhao, Xiaomei; Chu, Changhu; Liu, Renhua [Organic Letters, 2014, vol. 16, # 2, p. 350 - 353]
[2]Current Patent Assignee: Southeast University; Cai, Lin; Chen, Guoqing; Ji, Min; Li, Yong; Guo, Minliang; Xu, Hua; Liu, Wenjing - 2016 Location in patent: Paragraph 0067; 0068; 0069; 0070; 0071; 0072

37
[ 64-17-5 ]
[ 4640-66-8 ]
[ 34966-48-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With oxygen; In tetrahydrofuran; at 20℃; for 24h;Irradiation;	General procedure: alcohols0.6 mmolbenzoylacetonitrile0.4 mmolTHF2 mLwere added to grass tube. The reaction mixture was irradiated byone halogen tungsten lamp (500W) for 24 h accompanied with a fan beingsufficient to allow reaction temperature down to room temperature. After thereaction was completed (monitored by TLC), the reaction liquid was purifiedby chromatography on silica gel (20:1 petroleum ether/EtOAc) to give theproduct 3a-3s.
75%	With [bis(acetoxy)iodo]benzene; In dichloromethane; for 0.5h;Reflux;	General procedure: beta-Oxo-benzenepropanenitrile 1(1.0 mmol),PIDA (2.2 mmol) were dissolved in EtOH (8 mL) and stirred under refluxing for 0.5h. After the reaction was completed (monitored by TLC), thereaction mixture was concentrated under vacuum. The residue was purified by chromatographyon silica gel (20:1 petroleum ether/EtOAc) to give the product 3a-o .Thesolvent for the synthesis of 3o was MeOH.

Reference： [1]Synlett,2018,vol. 29,p. 1065 - 1070
[2]Tetrahedron Letters,2015,vol. 56,p. 3793 - 3795

38
[ 7391-28-8 ]
[ 4640-66-8 ]
2-p-chlorophenyl-5-p-tolylpyrazolo[1,5-a]pyrimidin-7-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: p-chlorobenzoylacetonitrile With hydrazine hydrate In ethanol; toluene for 0.5h; Reflux; Stage #2: p-tolueneacetonitrile With toluene-4-sulfonic acid In ethanol; toluene for 4h; Reflux;	1 6.2. General procedure for synthesis 2,5-diarylpyrazolo[1,5-a]pyrimidin-7-amines (4aek) General procedure: To the 1 mol eq. of 3-aryl-3-oxopropanonitrile (2) was added1 mol eq. of hydrazine hydrate (1) in Toluene/EtOH (9:1) and thereaction mixture was refluxed for 30 min then another 1 mol eq. ofdifferent 3-aryl-3-oxopropanonitrile (2) and catalytic amount ofPTSA (0.01 mol eq.) was added. Again reaction mixture wasrefluxed up to 4 h. On completion of the reaction, excess solvent was distilled off. The solid so obtained was filtered and washedwith cold ethanol. Solid was neutralised with aq. sodium bicarbonatesolution and again filtered. Compound thus obtained wasair dried and recrystallized from ethanol.

Reference： [1]Aggarwal, Ranjana; Singh, Gulshan; Kaushik, Pawan; Kaushik, Dhirender; Paliwal, Deepika; Kumar, Ajay [European Journal of Medicinal Chemistry, 2015, vol. 101, p. 326 - 333]

39
[ 7391-28-8 ]
[ 4640-66-8 ]
2-p-tolyl-5-p-chlorophenylpyrazolo[1,5-a]pyrimidin-7-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: p-tolueneacetonitrile With hydrazine hydrate In ethanol; toluene for 0.5h; Reflux; Stage #2: p-chlorobenzoylacetonitrile With toluene-4-sulfonic acid In ethanol; toluene for 4h; Reflux;	1 6.2. General procedure for synthesis 2,5-diarylpyrazolo[1,5-a]pyrimidin-7-amines (4aek) General procedure: To the 1 mol eq. of 3-aryl-3-oxopropanonitrile (2) was added1 mol eq. of hydrazine hydrate (1) in Toluene/EtOH (9:1) and thereaction mixture was refluxed for 30 min then another 1 mol eq. ofdifferent 3-aryl-3-oxopropanonitrile (2) and catalytic amount ofPTSA (0.01 mol eq.) was added. Again reaction mixture wasrefluxed up to 4 h. On completion of the reaction, excess solvent was distilled off. The solid so obtained was filtered and washedwith cold ethanol. Solid was neutralised with aq. sodium bicarbonatesolution and again filtered. Compound thus obtained wasair dried and recrystallized from ethanol.

Reference： [1]Aggarwal, Ranjana; Singh, Gulshan; Kaushik, Pawan; Kaushik, Dhirender; Paliwal, Deepika; Kumar, Ajay [European Journal of Medicinal Chemistry, 2015, vol. 101, p. 326 - 333]

40
[ 4640-66-8 ]
[ 4592-94-3 ]
2-p-chlorophenyl-5-p-bromophenylpyrazolo[1,5-a]pyrimidin-7-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%		General procedure: To the 1 mol eq. of 3-aryl-3-oxopropanonitrile (2) was added1 mol eq. of hydrazine hydrate (1) in Toluene/EtOH (9:1) and thereaction mixture was refluxed for 30 min then another 1 mol eq. ofdifferent 3-aryl-3-oxopropanonitrile (2) and catalytic amount ofPTSA (0.01 mol eq.) was added. Again reaction mixture wasrefluxed up to 4 h. On completion of the reaction, excess solvent was distilled off. The solid so obtained was filtered and washedwith cold ethanol. Solid was neutralised with aq. sodium bicarbonatesolution and again filtered. Compound thus obtained wasair dried and recrystallized from ethanol.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 101,p. 326 - 333

41
[ 4640-66-8 ]
[ 4592-94-3 ]
2-p-bromophenyl-5-p-chlorophenylpyrazolo[1,5-a]pyrimidin-7-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		General procedure: To the 1 mol eq. of 3-aryl-3-oxopropanonitrile (2) was added1 mol eq. of hydrazine hydrate (1) in Toluene/EtOH (9:1) and thereaction mixture was refluxed for 30 min then another 1 mol eq. ofdifferent 3-aryl-3-oxopropanonitrile (2) and catalytic amount ofPTSA (0.01 mol eq.) was added. Again reaction mixture wasrefluxed up to 4 h. On completion of the reaction, excess solvent was distilled off. The solid so obtained was filtered and washedwith cold ethanol. Solid was neutralised with aq. sodium bicarbonatesolution and again filtered. Compound thus obtained wasair dried and recrystallized from ethanol.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 101,p. 326 - 333

42
[ 948-65-2 ]
[ 33513-42-7 ]
[ 4640-66-8 ]
(E)-2-(4-chlorobenzoyl)-3-(2-phenyl-1H-indol-3-yl)prop-2-enenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 2-phenyl-indole; N,N-dimethyl-formamide With benzoyl chloride at 0℃; Stage #2: p-chlorobenzoylacetonitrile With triethylamine In N,N-dimethyl-formamide at 90℃; for 0.75h; stereoselective reaction;	General one-pot procedure for the preparation of compounds 2-8 General procedure: To a stirred solution of the suitable indole 11-17 (10 mmol) in dry DMF (5 mL), benzoyl chloride (1.41 g, 10 mmol) was added in a single portion. After stirring at rt for 1 h, the reaction mixture was allowed to stand at 0 °C for 18-48 h. Then, a solution of the suitable active methylene reagent (11 mmol) and triethylamine (1.21 g, 12 mmol) in dry DMF (8 mL) pre-warmed at 80 °C, were added in a single portion. The reaction mixture was stirred for 45 min at 90 °C (for 5b and 5u: 1.5 h at 105 °C; for 5v: 1.5 h at 120 °C). After cooling to rt, Et3N·HCl precipitated and the resulting suspension was treated with water (50 mL). Then, work-ups 1-4 were carried out, as follows: Work-up 1 (for 2a, c-g, 3b, 4a, b, 5a-h, j, l-p, r, s, u, x, z, 6a, b, 7a, b, 8a, b): the precipitate obtained was filtered off, dried and crystallized from the suitable solvent or solvent mixture. Work-up 2 (for 4d, 5i, w, y): the precipitate was filtered off and dissolved in CH2Cl2. The organic layer was washed with water (3 * 20 mL), dried over anhydrous Na2SO4 and filtered through a pad of Florisil. After evaporation of the solvent, the crude product was purified by crystallization from ethanol. Work-up 3 (for 4c, 5k, q, t): the precipitate was filtered off, air dried, purified by chromatography (eluents: petroleum ether/ethyl acetate) and then crystallized from the suitable solvent or solvent mixture. Work-up 4 (for 2b, 3a, 5v, aa-ac): the reaction mixture was extracted with ethyl acetate (2b, 3a, 5ac) or CH2Cl2 (5v, aa, ab) (3 * 35 mL). The combined organic extracts were washed with water (5 * 30 mL), dried over anhydrous Na2SO4 and filtered through a pad of Florisil. After evaporation of the filtrate, the crude products 3a and 5v, ac were crystallized from the proper solvent(s). Conversely, the crude products of 2b and 5z, aa were purified by chromatography (eluent: petroleum ether/ethyl acetate) and then crystallized from the proper solvent mix.

Reference： [1]Spallarossa, Andrea; Caneva, Chiara; Caviglia, Matteo; Alfei, Silvana; Butini, Stefania; Campiani, Giuseppe; Gemma, Sandra; Brindisi, Margherita; Zisterer, Daniela M.; Bright, Sandra A.; Williams, Clive D.; Crespan, Emmanuele; Maga, Giovanni; Sanna, Giuseppina; Delogu, Ilenia; Collu, Gabriella; Loddo, Roberta [European Journal of Medicinal Chemistry, 2015, vol. 102, p. 648 - 660]

43
potassium cyanide [ No CAS ]
[ 937-20-2 ]
[ 4640-66-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	In ethanol; water at 20℃; for 4h;	15.1 Step 1: Preparation of 3-(4-chlorophenyl)-3-oxopropanenitrile (Intermediate 42) To a solution of 2-chloro-1-(4-chlorophenyl)ethanone (15.5 g, 66.4 mmol) in EtOH (101 mL) was added a solution of KCN (10.8 g, 166 mmol) in water (10 mL). The reaction mixture was stirred at room temperature for 4 hours, then diluted with5 water and DCM. The mixture was treated with acetic acid (20 mL). The separated organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (11.8 g, 99%) as a yellow solid.‘H-NMR (400 MHz, CDC13): ö 7.88 (d, J= 8.4 Hz, 2H), 7.52 (d, J= 8.4 Hz, 2H), 4.06 (s, 2H).

Reference： [1]Current Patent Assignee: KAINOS MEDICINE INC - WO2015/156601, 2015, A1 Location in patent: Paragraph 67; 68

44
[ 105-36-2 ]
[ 4640-66-8 ]
[ 114957-79-8 ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: ethyl bromoacetate; p-chlorobenzoylacetonitrile With chloro-trimethyl-silane; zinc In tetrahydrofuran for 4h; Inert atmosphere; Reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 30℃; for 0.5h; Inert atmosphere; regioselective reaction;	3,5-Dioxopentanoates 9a-m and 3-Amino-5-oxopent-3-enoates 10a-f; General Procedure General procedure: A solution of TMSCl (10 mol%) in THF (1 mL) was added to a suspensionof Zn powder (1.2 mmol, 3 equiv) in THF (8 mL), andthe mixture was refluxed with vigorous stirring for 25 min. Asolution of the appropriate α-cyano ketone 8 (0.4 mmol, 1equiv) in THF (2 mL) and a solution of the α-bromo ester (0.8mmol) in THF (2 mL) were simultaneously added dropwise over30 min by using two syringes. After the addition, the pale-greenmixture was refluxed until all the α-cyano ketone was consumed(TLC; 3-6 h), by which time the color had changed tobrown. The mixture was then cooled to r.t. and centrifuged at700 rpm. The upper solution was collected, and the residualsolid was washed with THF (2 × 2 mL) and the solvent was collectedafter centrifugation. Method A: 3,5-Diketo Esters 9a-mThe pH of the combined THF solutions was adjusted to 2 with 3M HCl (~2 mL) and the mixture was stirred for 30 min at r.t. TheTHF was removed on a rotary evaporator under reduced pressure,and the residue was diluted with CH2Cl2 (20 mL) and H2O(20 mL). The organic layer was separated, washed sequentiallywith H2O (2 × 20 mL) and brine (10 mL), dried (Na2SO4), filtered,and concentrated under reduced pressure to give the crude 3,5-diketo ester, which was purified by column chromatography[silica gel (100-200 mesh), 10% EtOAc-hexane].Ethyl 5-(4-Chlorophenyl)-3,5-dioxopentanoate (9c) Prepared by the general procedure (Method A) from 3-(4-chlorophenyl)-3-oxopropanenitrile (8c; 503 mg, 2.79 mmol) andethyl bromoacetate (2; 932 mg, 5.58 mmol) in the presence ofZn powder (544 mg, 8.38 mmol) and TMSCl (30 mg, 10 mol %)in THF (10 mL) for 4 h followed by hydrolysis with 3 N HCl (2mL) as a pale-yellow liquid; yield: 553 mg (74%); Rf = 0.5 (10%EtOAc). IR: 2983, 2934, 1741, 1719, 1607, 1318, 1267, 1038, 817cm-1. 1H NMR (400 MHz, CDCl3 + CCl4, 1:1): δ = 15.73 (s, 1 H),7.82 (d, J = 8.6 Hz, 2 H), 7.42 (d, J = 8.6 Hz, 2 H), 6.24 (s, 1 H), 4.22(q, J = 7.2, 2 H), 3.47 (s, 2 H), 1.30 (t, J = 7.1 Hz, 3 H). 13C NMR(100 MHz, CDCl3 + CCl4, 1:1): δ = 189.3, 181.4, 167.3, 139.1,132.8, 129.1, 128.6, 96.6, 61.6, 45.9, 14.3. HRMS (ESI): m/z [M +H] calcd for C13H14ClO4: 269.0581; found: 269.0580.

Reference： [1]Rao, H. Surya Prakash; Muthanna, Nandurka [Synlett, 2016, vol. 27, # 13, p. 2014 - 2018]

45
[ 105-36-2 ]
[ 4640-66-8 ]
ethyl (Z)-3-amino-5-(4-chlorophenyl)-5-oxopent-3-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: ethyl bromoacetate; p-chlorobenzoylacetonitrile With chloro-trimethyl-silane; zinc In tetrahydrofuran for 4h; Inert atmosphere; Reflux; Stage #2: With potassium carbonate In dichloromethane; water at 0 - 30℃; for 0.25h; Inert atmosphere; regioselective reaction;	3,5-Dioxopentanoates 9a-m and 3-Amino-5-oxopent-3-enoates 10a-f; General Procedure General procedure: A solution of TMSCl (10 mol%) in THF (1 mL) was added to a suspensionof Zn powder (1.2 mmol, 3 equiv) in THF (8 mL), andthe mixture was refluxed with vigorous stirring for 25 min. Asolution of the appropriate α-cyano ketone 8 (0.4 mmol, 1equiv) in THF (2 mL) and a solution of the α-bromo ester (0.8mmol) in THF (2 mL) were simultaneously added dropwise over30 min by using two syringes. After the addition, the pale-greenmixture was refluxed until all the α-cyano ketone was consumed(TLC; 3-6 h), by which time the color had changed tobrown. The mixture was then cooled to r.t. and centrifuged at700 rpm. The upper solution was collected, and the residualsolid was washed with THF (2 × 2 mL) and the solvent was collectedafter centrifugation. Method B: (3Z)-3-Amino-5-oxo-5-pent-3-enoates 10a-f The solvent was removed from the combined THF solutions under reduced pressure, the residue was diluted with CH2Cl2(20 mL), and the resulting solution was stirred with 50% aqK2CO3 (5 mL) for 15 min. The organic layer was separated,washed sequentially with H2O (2 × 20 mL) and brine (10 mL),dried (Na2SO4), filtered, and concentrated under reduced pressureto give the crude (3Z)-3-amino-5-oxo-5-pent-3-enoate,which was purified by column chromatography [silica gel (100-200 mesh), 15% EtOAc-hexane].

Reference： [1]Rao, H. Surya Prakash; Muthanna, Nandurka [Synlett, 2016, vol. 27, # 13, p. 2014 - 2018]

46
[ 4640-66-8 ]
[ 99839-00-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With [RuCl₂(η⁶-p-cymene)(P(4-C₆H₄F)₂Cl)]; water; sodium formate at 100℃; for 24h; Inert atmosphere; Sealed tube;
88%	With [RuCl₂(η⁶-p-cymene)(P(4-C₆H₄F)₂Cl)]; sodium formate In water at 100℃; for 24h; Inert atmosphere; Sealed tube;	2.3. General procedure for the catalytic conversion of β-ketonitrilesinto β-hydroxyamides General procedure: Under argon atmosphere, the corresponding β-ketonitrile 2(1 mmol), water (3 mL), the ruthenium(II) complex 1 (0.028 g,0.05 mmol; 5 mol%) and NaO2CH (1.360 g, 20 mmol) were introducedinto a Teflon-capped sealed tube, and the reaction mixturestirred at 100 C for 24e48 h. The solvent was then removed undervacuum and the resulting solid residue purified by flash columnchromatography over silica gel using, unless otherwise stated, amixture of MeOH/EtOAc (1:10) as eluent. Characterization data forthe isolated β-hydroxyamides are as follows:

Reference： [1]González-Fernández, Rebeca; Crochet, Pascale; Cadierno, Victorio [Organic Letters, 2016, vol. 18, # 23, p. 6164 - 6167]
[2]González-Fernández, Rebeca; Crochet, Pascale; Cadierno, Victorio [Journal of Organometallic Chemistry, 2019, vol. 896, p. 90 - 101]

47
[ 4640-66-8 ]
[ 59843-58-2 ]

Reference： [1]Organic Letters,2016,vol. 18,p. 6388 - 6391

48
[ 105-56-6 ]
[ 4640-66-8 ]
ethyl 2,4-diamino-5-(4-chlorobenzoyl)thiophene-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With sulfur; triethylamine In ethanol for 3h; Reflux;	General procedure for preparation of the thiophenederivatives 3a-f General procedure: To a solution of any of the 3-oxo-3-phenylpropanenitrile(1a) (1.45 g, 0.01 mol), 3-oxo-3-(4chlorophenyl)propanenitrile(1b) (1.75 g, 0.01 mol) or 3-oxo-3-(4-methylphenyl)propanenitrile (1c) (1.59 g, 0.01 mol) in ethanol (40 mL)containing (0.01 mol) triethylamine either malononitrile(0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g, 0.01 mol)and elemental sulfur (0.32 g, 0.01 mol) were added. Thewhole reaction mixture, in each case, was heated underreflux for 3 h then poured onto ice/water containing fewdrops of hydrochloric acid and the formed solid product, ineach case was collected by filtration

Reference： [1]Mohareb, Rafat M.; Ibrahim, Rehab A. [Medicinal Chemistry Research, 2017, vol. 26, # 3, p. 587 - 602]

49
C₁₅H₁₆O₄ [ No CAS ]
[ 4640-66-8 ]
C₂₂H₁₈ClNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With C₃₃H₂₈F₅N₃O₂; potassium carbonate In toluene at 0℃; for 48h; enantioselective reaction;	4.2 General procedure General procedure: To a 25 mL flask was added catalysts 5g (0.04 mmol, 23.7 mg), K2CO3 (0.24 mmol, 33.2 mg), 3 or 6 or 8 (0.24 mmol) and toluene (1.5 mL). After the mixture was stirred at 0 °C for 5 min, a solution of 2 (0.20 mmol) in toluene (1.5 mL) was slowly added. The reaction was stirred at 0 °C for 48 h. After that, the solvent was removed and the residue was directly subjected to silica gel column chromatography (petroleum ether/ethyl acetate as eluent) to give (3+3) annulation product.

Reference： [1]Ni, Chunjie; Zhou, Weiping; Tong, Xiaofeng [Tetrahedron, 2017, vol. 73, # 24, p. 3347 - 3354]

50
[ 874-05-5 ]
[ 123-08-0 ]
[ 4640-66-8 ]
2-(4-chlorophenyl)-4-(4-hydroxyphenyl)pyrimido[1,2-b]indazole-3-carbonitrile [ No CAS ]