Name: 61310-53-0|3-Ethoxypropenenitrile|95%
Brand: Ambeed
SKU: A956940
Price: 5.0 USD
Availability: InStock
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1
[ 288-14-2 ]
[ 64-67-5 ]
[ 61310-53-0 ]
[ 2032-34-0 ]

Reference： [1]Journal of Organic Chemistry,1957,vol. 22,p. 192

2
[ 61310-53-0 ]
[ 141-52-6 ]
[ 2032-34-0 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 2660

3
[ 41365-74-6 ]
[ 61310-53-0 ]
[ 2032-34-0 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 2660

4
[ 61310-53-0 ]
[ 57-13-6 ]
[ 71-30-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium butanolate

Reference： [1]Tarsio; Nicholl [Journal of Organic Chemistry, 1957, vol. 22, p. 192]

5
[ 61310-53-0 ]
[ 6192-01-4 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1977,vol. 13,p. 1694 - 1696
Zhurnal Organicheskoi Khimii,1977,vol. 13,p. 1828 - 1830

6
[ 61310-53-0 ]
[ 6162-54-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid

Reference： [1]Movsum-Zade,E.M. et al. [Journal of Organic Chemistry USSR (English Translation), 1977, vol. 13, p. 1694 - 1696][Zhurnal Organicheskoi Khimii, 1977, vol. 13, # 9, p. 1828 - 1830]

7
[ 61310-53-0 ]
[ 2904-62-3 ]
[ 31007-72-4 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran

Reference： [1]Micetich,R.G. [Canadian Journal of Chemistry, 1970, vol. 48, p. 3753 - 3755]

8
[ 110-89-4 ]
[ 61310-53-0 ]
β-piperidinoacrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 80℃; for 1h;
	for 0.0833333h; Microwave irradiation;

Reference： [1]Jiang, Shuiping; Janousek, Zdenek; Viehe, Heinz G. [Bulletin des Societes Chimiques Belges, 1993, vol. 102, # 10, p. 663 - 668]
[2]Salaheldin, Abdellatif M.; Khairou, Khalid S. [Zeitschrift fur Naturforschung, B: Chemical Sciences, 2013, vol. 68, # 2, p. 175 - 181]

9
[ 18922-04-8 ]
[ 61310-53-0 ]
2-[1-Ethoxy-meth-(E)-ylidene]-oct-7-enenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With n-butyllithium 1.) THF-hexane, -110 deg C, 20 min, 2.) -110- -100 deg C, 3 h; -> -50 deg C, 3 h;

Reference： [1]Smirnow, David; Hopkins, Paul B. [Synthetic Communications, 1986, vol. 16, # 10, p. 1187 - 1194]

10
[ 64-17-5 ]
[ 61310-53-0 ]
[ 110596-10-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-Bromosuccinimide for 1.25h; Ambient temperature;
91%	With N-Bromosuccinimide for 2.08333h;
	With N-Bromosuccinimide Inert atmosphere;	6 EXAMPLE 6. SYNTHESIS OF A MOIETIES EXAMPLE 6. SYNTHESIS OF A MOIETIES [0535] Scheme 6-1 : In Step 1 the appropriately substituted nitro species is reduced with palladium as known in the art to afford an amine. In Step 2 the appropriately substituted alkene species is brominated with concurrent addition of ethanol as known in the art to afford the bromide species. In Step 3 the appropriately substituted mixture of tautomers is subjected to the previously prepared bromide species as known in the art to afford the two isomers. The appropriately substituted isomers corresponding to each tautomer may either be separated or used as a mixture in the subsequent reactions with separation at a later step. In Step 4 the appropriately substituted ketal species is deprotected and subsequently cyclized in the presence of acid as known in the art. In Step 5 the appropriately substituted cyano species is subjected to strong acid to afford a primary amide. In Step 6 the appropriately substituted heterocycle is subjected to a bromide species of the appropriate linker to afford the appropriately protected species. Various 5-5 fused bicyclic systems can be appropriately prepared by slight modifications of this synthetic protocol, another non- limiting example is presented in Steps 5 through 12 with the same conditions for formation of a primary amide and installation of linker. In Step 7 the appropriately substituted aryl species is brominated as known in the art. In Step 8 the appropriately substituted ether species is deprotected with palladium as known in the art to afford an alcohol. In Step 9 the appropriately substituted alcohol is oxidized as known in the art to afford an aldehyde. In Step 10 the appropriately substituted aldehyde is subjected to hydrazine to first form a Schiff base and subsequently cyclize to afford a bicyclic system. In Step 11 the appropriately substituted bicyclic system is iodinated as known in the art. In Step 12 the appropriately substituted iodide is subjected to sodium cyanide to afford the cyano species.

	With N-Bromosuccinimide In ethanol	6-1.2 Scheme 6-1: In Step 1 the appropriately substituted nitro species is reduced with palladium as known in the art to afford an amine. In Step 2 the appropriately substituted alkene species is brominated with concurrent addition of ethanol as known in the art to afford the bromidespecies. In Step 3 the appropriately substituted mixture of tautomers is subjected to the previously prepared bromide species as known in the art to afford the two isomers. The appropriately substituted isomers corresponding to each tautomer may either be separated or used as a mixture in the subsequent reactions with separation at a later step. In Step 4 the appropriately substituted ketal species is deprotected and subsequently cyclized in the presence of acid as known in the art. In Step 5 the appropriately substituted cyano species is subjected to strong acid to afford a primary amide. In Step 6 the appropriately substituted heterocycle is subjected to a bromide species of the appropriate linker to afford the appropriately protected species. Various 5-5 fused bicyclic systems can be appropriately prepared by slight modifications of this synthetic protocol, another non- limiting example is presented in Steps 5 through 12 with the same conditions for formation of a primary amide and installation of linker. In Step 7 the appropriately substituted aryl species is brominated as known in the art. In Step 8 the appropriately substituted ether species is deprotected with palladium as known in the art to afford an alcohol. In Step 9 the appropriately substituted alcohol is oxidized as known in the art to afford an aldehyde. In Step 10 the appropriately substituted aldehyde is subjected to hydrazine to first form a Schiff base and subsequently cyclize to afford a bicyclic system. In Step lithe appropriately substituted bicyclic system is iodinated as known in the art. In Step 12 the appropriately substituted iodide is subjected to sodium cyanide to afford the cyano species.
	With N-Bromosuccinimide	6.1.2 EXAMPLE 6. SYNTHESIS OF A MOIETIES Scheme 6-1: In Step 1 the appropriately substituted nitro species is reduced with palladium as known in the art to afford an amine. In Step 2 the appropriately substituted alkene species is brominated with concurrent addition of ethanol as known in the art to afford the bromide species. In Step 3 the appropriately substituted mixture of tautomers is subjected to the previously prepared bromide species as known in the art to afford the two isomers. The appropriately substituted isomers corresponding to each tautomer may either be separated or used as a mixture in the subsequent reactions with separation at a later step. In Step 4 the appropriately substituted ketal species is deprotected and subsequently cyclized in the presence of acid as known in the art. In Step 5 the appropriately substituted cyano species is subjected to strong acid to afford a primary amide. In Step 6 the appropriately substituted heterocycle is subjected to a bromide species of the appropriate linker to afford the appropriately protected species. Various 5-5 fused bicyclic systems can be appropriately prepared by slight modifications of this synthetic protocol, another non- limiting example is presented in Steps 5 through 12 with the same conditions for formation of a primary amide and installation of linker. In Step 7 the appropriately substituted aryl species is brominated as known in the art. In Step 8 the appropriately substituted ether species is deprotected with palladium as known in the art to afford an alcohol. In Step 9 the appropriately substituted alcohol is oxidized as known in the art to afford an aldehyde. In Step 10 the appropriately substituted aldehyde is subjected to hydrazine to first form a Schiff base and subsequently cyclize to afford a bicyclic system. In Step 11 the appropriately substituted bicyclic system is iodinated as known in the art. In Step 12 the appropriately substituted iodide is subjected to sodium cyanide to afford the cyano species.

Reference： [1]Babler, James H. [Synthetic Communications, 1987, vol. 17, # 1, p. 77 - 84]
[2]Welin, Eric R.; Warkentin, Alexander A.; Conrad, Jay C.; MacMillan, David W. C. [Angewandte Chemie - International Edition, 2015, vol. 54, # 33, p. 9668 - 9672][Angew. Chem., 2015, vol. 127, # 33, p. 9804 - 9808,5]
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35413, 2017, A2 Location in patent: Paragraph 0535
[4]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35417, 2017, A1 Location in patent: Paragraph 0613
[5]Current Patent Assignee: ASTRAZENECA PLC - WO2018/160891, 2018, A1 Location in patent: Page/Page column 495-496

11
[ 513-38-2 ]
[ 61310-53-0 ]
2-[1-Ethoxy-meth-(E)-ylidene]-4-methyl-pentanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%	With n-butyllithium 1.) THF-hexane, -110 deg C, 20 min, 2.) -110- -100 deg C, 3 h; -> -50 deg C, 3 h;

Reference： [1]Smirnow, David; Hopkins, Paul B. [Synthetic Communications, 1986, vol. 16, # 10, p. 1187 - 1194]

12
[ 61310-53-0 ]
[ 52943-44-9 ]
[ 141099-94-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate In chloroform for 144h; Ambient temperature;

Reference： [1]Matsuda, Yoshiro; Yamashita, Makoto; Takahashi, Kimitoshi; Ide, Shizuki; Torisu, Katsura; Furuno, Kazuki [Heterocycles, 1992, vol. 33, # 1, p. 295 - 302]

13
[ 61310-53-0 ]
[ 51073-41-7 ]
1-(2-Methylamino-phenyl)-1H-pyrazole-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	With potassium carbonate In ethanol for 168h; Ambient temperature;

Reference： [1]Matsuda; Yamashita; Takahashi; Ide; Itou; Motokawa; Chiyomaru [Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 3, p. 454 - 458]

14
[ 61310-53-0 ]
[ 108-94-1 ]
(Z)-3-Ethoxy-2-(1-hydroxy-cyclohexyl)-acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With n-butyllithium 1.) THF-hexane, -110 deg C, 20 min, 2.) -110- -100 deg C, 3 h; -> -50 deg C, 3 h;

Reference： [1]Smirnow, David; Hopkins, Paul B. [Synthetic Communications, 1986, vol. 16, # 10, p. 1187 - 1194]

15
[ 61310-53-0 ]
[ 100-39-0 ]
[ 76877-59-3 ]

Yield	Reaction Conditions	Operation in experiment
84%	With n-butyllithium 1.) THF-hexane, -110 deg C, 20 min, 2.) -110- -100 deg C, 3 h; -> -50 deg C, 3 h;

Reference： [1]Smirnow, David; Hopkins, Paul B. [Synthetic Communications, 1986, vol. 16, # 10, p. 1187 - 1194]

16
[ 61310-53-0 ]
[ 75-03-6 ]
2-[1-Ethoxy-meth-(E)-ylidene]-butyronitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With n-butyllithium 1.) THF-hexane, -110 deg C, 20 min, 2.) -110- -100 deg C, 3 h; -> -50 deg C, 3 h;

Reference： [1]Smirnow, David; Hopkins, Paul B. [Synthetic Communications, 1986, vol. 16, # 10, p. 1187 - 1194]

17
[ 61310-53-0 ]
[ 106-95-6 ]
3-ethoxyacrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With n-butyllithium 1.) THF-hexane, -110 deg C, 20 min, 2.) -110- -100 deg C, 3 h; -> -50 deg C, 3 h;

Reference： [1]Smirnow, David; Hopkins, Paul B. [Synthetic Communications, 1986, vol. 16, # 10, p. 1187 - 1194]

18
[ 61310-53-0 ]
[ 62-53-3 ]
cis-3-(N-phenylamino)propenenitrile [ No CAS ]
3-phenylaminoacrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide at 100℃; for 4h; Title compound not separated from byproducts;

Reference： [1]Pavlik, James W.; Connors, Robert E.; Burns, Douglas S.; Kurzweil, Edyth M. [Journal of the American Chemical Society, 1993, vol. 115, # 17, p. 7645 - 7652]

19
[ 288-14-2 ]
[ 64-67-5 ]
aq.-ethanolic NaOH [ No CAS ]
[ 61310-53-0 ]
[ 2032-34-0 ]

Reference： [1]Journal of Organic Chemistry,1957,vol. 22,p. 192

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid at 135℃;

21
[ 2032-34-0 ]
[ 7664-93-9 ]
[ 64-17-5 ]
[ 61310-53-0 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 2660

22
[ 110-89-4 ]
[ 61310-53-0 ]
[ 65157-84-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	for 24h; Heating;

Reference： [1]Abdallah, Sanaa O.; Metwally, Nadia H.; Anwar, Hany F.; Elnagdi, Mohamed H. [Journal of Heterocyclic Chemistry, 2005, vol. 42, # 5, p. 781 - 786]

23
[ 61310-53-0 ]
[ 2924-15-4 ]
[ 685094-07-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium ethanolate; In ethanol; at 20 - 82℃; for 30 - 50.5h;	To a suspension of the <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> 1-1 (50 g, JEMCO, Inc.) IN ETOH (300 mL) was added 20 weight % NaOEt in ETOH (292.97 g, Nihon Soda). The ethoxyacrylonitrile 1-2 (53.76 g, Degussa) was then added at ambient temperature. The reaction mixture was warmed to about 82C and aged for 20 to 28 hours. The reaction mixture was cooled to ambient temperature. To the batch was added water (250 mL, 5 volumes) and 6N HC1 to adjust the mixture to a pH between about 2.9-3. 1. The resulting aqueous EtOH solution was stirred at 20C to 25C for 1 to 2 hours. After treatment with 5N NAOH to adjust the solution to a pH of about 6.5 to 8.0, the reaction mixture was concentrated to circa 600 mL (12 volumes), then IPAC (750 mL) was added. The layers were separated and the organic LAYERWASWASHEDWITHL0TAQUEOUSNACL (200ML). ACTIVATEDCARBON (Sirasagi P, 1.75g, 3.5 weigh % to 2-fluorophenylhydrazine HC1) was added to the resulting solution at ambient temperature. After 1 to 20 hours treatment of the activated carbon, the cake was washed with IPAC (4 volumes to a weight % to 2-fluorophenylhydrazine HC1, 200mL). The combined organic layers were concentrated to about 410-510 mL (10-12.5 volumes to assay gram of pyrazole 1-3) to give 1-(2-FLUOROPHENYL)-LH-PYRAZOLE-3-AMINE 1-3. Selected Signals 1H NMR (300 MHz, DMSO-d6) : 8 7.84 (d, J=2.6 Hz, 1H), 7.72 (dd, J=8.2, 1.8 Hz, 1H), 7.34 (ddd, J=11. 1, 7.9, 1.7 Hz, 1H), 7.28-7. 14 (m, 2H), 5.77 (d, J=2.6 Hz, 1H), 5.10 (brs, 2H).To a suspension of the <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> 1-1 (12.5 g, 76.9 mmol, JEMCO) in EtOH (75 mL, 6 volumes) was added 20 weight % NaOEt in ETOH (72.9 g) while keeping the temperature less than 30C. The ethoxyacrylonitrile 1-2 (13.4 g, Degussa) was then added at 25C. The reaction mixture was warmed to about 82C over 30 minutes and then aged for 20 to 28 hours. The reaction mixture was cooled to ambient temperature. Water (62.5 mL, 5 volumes) and 6N HC1, to adjust the mixture to a pH between 2.9 to 3.1, were slowly added to the reaction mixture while keeping the temperature below 30C. The resulting aqueous ethanol solution was stirred at a temperature of about 20C to 25C for 1 to 2 hours, then treated with 5N NAOH, to adjust the pH to between 6.5 to 8.0. The resulting solution was concentrated to 150 mL (12 volumes) in vacuo at 40C, and then extracted with toluene (125 mL) two times. The organic layer was washed with 10% aqueous NaCl (62.5 mL, 5 volumes). Activated carbon (Shirasagi P, 3.5 weight % to 2-FLUOROPHENYLHYDRAZINE HC1, 473. 5 mg) was added to the resulting solution at ambient temperature and stirred for about 15 to 20 hours. The cake (activated carbon) was washed with toluene (4 volumes to assay grams of pyrazole, 40.9 mL). The washings were combined with the filtrate to give 1-(2-FLUOROPHENYL)-LH-PYRAZOLE-3-AMINE 1-3. Selected Signals: 1H NMR (300 MHz, DMSO-d6): 8 7.84 (d, J=2.6 Hz, 1H), 7.72 (dd, J=8.2, 1.8 Hz, 1H), 7.34 (ddd, J=11. 1, 7.9, 1.7 Hz, 1H), 7.28-7. 14 (m, 2H), 5.77 (d, J=2.6 Hz, 1H), 5.10 (brs, 2H).

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 9222 - 9229
[2]Patent: WO2004/37794,2004,A1 .Location in patent: Page 48-49

24
[ 626-55-1 ]
[ 61310-53-0 ]
(E)-3-ethoxy-3-(pyridin-3-yl)acrylonitrile [ No CAS ]
(Z)-3-ethoxy-3-(pyridin-3-yl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

25
[ 5332-24-1 ]
[ 61310-53-0 ]
(E)-3-ethoxy-3-(quinolin-3-yl)acrylonitrile [ No CAS ]
(Z)-3-ethoxy-3-(quinolin-3-yl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

26
[ 108-86-1 ]
[ 61310-53-0 ]
(E)-3-ethoxy-3-phenylacrylonitrile [ No CAS ]
(Z)-3-ethoxy-3-phenylacrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

27
[ 591-50-4 ]
[ 61310-53-0 ]
(E)-3-ethoxy-3-phenylacrylonitrile [ No CAS ]
(Z)-3-ethoxy-3-phenylacrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

28
[ 61310-53-0 ]
[ 3972-65-4 ]
(E)-3-(4-tert-butylphenyl)-3-ethoxyacrylonitrile [ No CAS ]
(Z)-3-(4-tert-butylphenyl)-3-ethoxyacrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

29
[ 61310-53-0 ]
[ 106-38-7 ]
(E)-3-ethoxy-3-(p-tolyl)acrylonitrile [ No CAS ]
[ 260352-22-5 ]

Yield	Reaction Conditions	Operation in experiment
	With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

30
[ 61310-53-0 ]
[ 95-46-5 ]
(E)-3-ethoxy-3-(o-tolyl)acrylonitrile [ No CAS ]
(Z)-3-ethoxy-3-(o-tolyl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

31
[ 61310-53-0 ]
[ 90-11-9 ]
(E)-3-ethoxy-3-(naphthalen-1-yl)acrylonitrile [ No CAS ]
(Z)-3-ethoxy-3-(naphthalen-1-yl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

32
[ 61310-53-0 ]
[ 576-83-0 ]
(E)-3-ethoxy-3-(2,4,6-trimethylphenyl)acrylonitrile [ No CAS ]
(Z)-3-ethoxy-3-(2,4,6-trimethylphenyl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; triphenylphosphine In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

33
[ 61310-53-0 ]
[ 21524-34-5 ]
(E)-3-ethoxy-3-(2,4,6-triisopropylphenyl)acrylonitrile [ No CAS ]
(Z)-3-ethoxy-3-(2,4,6-triisopropylphenyl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

34
[ 61310-53-0 ]
[ 5111-65-9 ]
(E)-3-ethoxy-3-(6-methoxynaphthalen-2-yl)acrylonitrile [ No CAS ]
(Z)-3-ethoxy-3-(6-methoxynaphthalen-2-yl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

35
[ 61310-53-0 ]
[ 460-00-4 ]
(E)-3-ethoxy-3-(4-fluorophenyl)acrylonitrile [ No CAS ]
(Z)-3-ethoxy-3-(4-fluorophenyl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [Tetrahedron Letters, 2006, vol. 47, # 4, p. 459 - 462]
[2]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

36
[ 61310-53-0 ]
[ 36282-26-5 ]
[ 1009036-33-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine In toluene at 100℃; for 24h;	21 Example 21 1-amino-6-fluoro-isoquinoline-4-carbonitrile; Palladium acetate (II) (0.556 g, 2.5 mmol) is added to a degassed solution of 2-bromo-4-fluoro-benzonitrile (10 g, 50 mmol), 3-ethoxyacrylonitrile (10.3 mL, 100 mmol) and triethylamine (14 mL, 100 mmol) in toluene (75 mL). The reaction mixture is stirred in an oil bath at 100° C. for 1 day. The reaction mixture is cooled to RT, filtered through a pad of Celite, and the filter cake is rinsed with EtOAc. After evaporation of the solvent, the residue is purified using a Biotage column eluted with 0-50% EtOAc/hexanes (20 CV) to afford 8.77 g (94%) of 2-(1-cyano-2-ethoxy-vinyl)-4-fluoro-benzonitrile. LC/MS: RT=3.38 min, no ionization.

Reference： [1]Current Patent Assignee: ESANEX INC - US2008/70935, 2008, A1 Location in patent: Page/Page column 51

37
[ 61310-53-0 ]
[ 314084-61-2 ]
(Z)-3-(2,6-diethyl-4-methylphenyl)-3-ethoxyacrylonitrile [ No CAS ]
(E)-3-(2,6-diethyl-4-methylphenyl)-3-ethoxyacrylonitrile [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2007,p. 3122 - 3132

38
[ 61310-53-0 ]
[ 591-17-3 ]
(Z)-3-ethoxy-3-(m-tolyl)acrylonitrile [ No CAS ]
(E)-3-ethoxy-3-(m-tolyl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

39
[ 1072-85-1 ]
[ 61310-53-0 ]
(Z)-3-ethoxy-3-(2-fluorophenyl)acrylonitrile [ No CAS ]
(E)-3-ethoxy-3-(2-fluorophenyl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

40
[ 104-92-7 ]
[ 61310-53-0 ]
(Z)-3-ethoxy-3-(4-methoxyphenyl)acrylonitrile [ No CAS ]
(E)-3-ethoxy-3-(4-methoxyphenyl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h;

Reference： [1]Battace, Ahmed; Feuerstein, Marie; Lemhadri, Mhamed; Zair, Touriya; Doucet, Henri; Santelli, Maurice [European Journal of Organic Chemistry, 2007, # 19, p. 3122 - 3132]

41
[ 61310-53-0 ]
[ 110596-11-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 99 percent / NBS / 1.25 h / Ambient temperature 2: 46 percent / 18-crown-6 / acetonitrile / 168 h / Heating

Reference： [1]Babler, James H. [Synthetic Communications, 1987, vol. 17, # 1, p. 77 - 84]

42
[ 10601-80-6 ]
[ 61310-53-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aqueous NH₃ 2: P₂O₅; triethylamine; benzene

Reference： [1]McElvain; Clarke [Journal of the American Chemical Society, 1947, vol. 69, p. 2660]

43
[ 61310-53-0 ]
[ 59-88-1 ]
[ 1128-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium ethanolate; In ethanol; at 25 - 82℃; for 20.5h;	To a suspension of the phenylhydrazine hydrochloride 3-1 (1.0 g, TCI) in ETOH (5 mL) was added 21 weight % NaOEt in ETOH (7.23 mL) while keeping the temperature less than 30C. The ethoxyacrylonitrile 1-2 (1.33mL, Acros) was then added at 25C. The reaction mixture was warmed to about 82C over 30 minutes and then aged for 20 hours. The reaction mixture was cooled to ambient temperature. Water (10 mL) was slowly added to the reaction mixture while keeping the temperature below 30C. The resulting aqueous ethanol solution was extraced with MTBE (20 mL) then the organic layer was washed with 10% NaCl aqueous solution (5 mL). Activated carbon (Shirasagi P, 5 mg) was added to the resulting solution at ambient temperature and stirred for about 1 hour. Concentration of the filtrate and purification of the resulting residue with flash chromatography (HEPTANE/ETOAC = 2 : 1) gave 1-(2-PHENYL)-LH-PYRAZOLE-3-AMINE 3-2. 1HNMR (500 MHZ, DMSO-D6) : 8 8.12 (d, J=2. 5 HZ, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.38 (dd, J=7.9, 7.9 Hz, 2H), 7.11 (dd, J=7.3, 7.3 Hz, 1H), 5.73 (d, J=2.5 Hz, 1H), 5.06 (brs, 2H)

Reference： [1]Patent: WO2004/37794,2004,A1 .Location in patent: Page 61-62

44
[ 61310-53-0 ]
[ 2042-37-7 ]
[ 697751-83-0 ]

Yield	Reaction Conditions	Operation in experiment
54.5%	Stage #1: 3-ethoxyacrylonitrile; o-cyanobromobenzene With sodium t-butanolate In tetrahydrofuran at 20℃; for 0.5h; Stage #2: In tetrahydrofuran at 70℃; for 0.5h;	1 Example 1; Inden-1,3-dicarbonitrile Example 1; Inden-1,3-dicarbonitrile. In a flame dried three-necked flask, added palladium II acetate (0.175 g, 0.78 MMOL) and tricyclohexylphosphine (0.328 g, 1.17 MMOL). Purged with nitrogen for half a hour, then added 20 ml of anhydrous THF and stirred for an additional 30 minutes. Cooled down to 0°C, then added slowly sodium tert-butoxide (9.41 g, 96.5 MMOL) and stirred for 1 hour at 0°C. Filled the adding funnel with a solution of 2-bromobenzenecyanide (5. 06M1, 39MMOL), 3- ethoxy acrylonitrile (4.01 ML, 30 MMOL) and 5 mi of anhydrous THF. Added very slowly dropwise the solution into the palladium solution. Stirred at room temperature for 30 minutes. Heated up the solution in all oil bath up 70°C. When the solution reach the 45°C, an exothermic reaction occurred. Waited until the ebullition stopped. Continued heating to 70°C. The reaction was complete within 30 minutes. Cooled down to room temperature. Added 75 ml of water and 75 ml of CH2CL2. Separated the organic layer and washed the aqueous one with an additional 25MI of CH2 C12. With an aqueous solution of HCI 5M, lowered the pH of the aqueous layer to 1. Extracted the aqueous layer with 4x 30 ml of EtOAc and washed the combined extraction with brine. Dried with MGS04, filtered through Cellite and concentrated under reduced pressure to give a brown solid (13.8g). Recrystallized from MEOH to give a beige white powder (7.062 g, 54.5%). Anal. CALCD FOR C11H6N2 : C, 79.44 ; H, 3.61 ; N, 16.85. Found C, 79.41 ; 3.61, N 16.60

Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/46077, 2004, A1 Location in patent: Page 7

45
[ 61310-53-0 ]
[ 265324-26-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: cyclopropylcarboxamidine hydrochloride With sodium methylate for 1h; Stage #2: 3-ethoxyacrylonitrile at 20 - 135℃;	2.A Example 2; 3-Chloro-N-(2-cyclopropyl-pyrimidin-4-yl)-2-methyl-benzenesulfonamide; Step A]: 2-Cyclopropyl-pyrimidin-4-ylamine; Cyclopropylcarbamidine hydrochloride (3.0 g) was added to a solution of sodium methoxide (5.4 M, 4.61 mL) and the mixture was allowed to stir for 1 hour. The suspension was filtered in order to remove precipitated NaCl and the filtrate was evaporated in vacuo to give a light brown residue (2.86 g). 3-Ethoxyacrylonitrile (2.55 mL) was added and the mixture was heated at 135° C. for 3 hours and then allowed to stir at RT for another 12 hours. The reaction mixture was directly subjected to flash chromatography (silica gel, ethyl acetate) and the desired product 2-cyclopropyl-pyrimidin-4-ylamine was isolated as a light brown foam (1.53 g). 1H NMR (δ, CDCl3): 8.09 (d, 1H), 6.18 (d, 1H), 4.68 (br s, 2H), 2.04-1.98 (m, 1H), 1.08-1.04 (m, 2H), 0.97-0.92 (m, 2H). MS (ESI): 136.2 (MH+).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2005/288308, 2005, A1 Location in patent: Page/Page column 8-9

46
[ 61310-53-0 ]
2-(2-methyl-thiazol-4-yl)-pyrimidin-4-ylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-methyl-1,3-thiazole-4-carboximidamide hydrochloride With sodium ethanolate for 1h; Stage #2: 3-ethoxyacrylonitrile at 20 - 135℃;	49.A Example 49; 3-Chloro-2-methyl-N-[2-(2-methyl-thiazol-4-yl)-pyrimidin-4-yl]-benzenesulfonamide; Step A] 2-(2-Methyl-thiazol-4-yl)-pyrimidin-4-ylamine; This material was obtained as described in example 2, step A] from 2-ethyl-thiazole-4-carboxamidine hydrochloride (3 g) by treatment with sodium ethoxide (3.13 mL of a 5.4 M solution) and 3-ethoxyacrylonitrile (1.73 mL) to give 2-(2-ethyl-thiazol-4-yl)-pyrimidin-4-ylamine (2.56 g) as a brown solid. MS (ESI): 193.3 (MH+).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2005/288308, 2005, A1 Location in patent: Page/Page column 13

47
[ 61310-53-0 ]
[ 74-88-4 ]
[ 2183-66-6 ]

Yield	Reaction Conditions	Operation in experiment
	With thiourea	P.19.1 Step 1) Synthesis of 4-amino-2-methylthiopyrimidine Step 1) Synthesis of 4-amino-2-methylthiopyrimidine The same procedures described in Preparation Example 2 above were repeated except for using 97.12g of 3-ethoxy acrylonitrile and 76.07g of thiourea to obtain an intermediate. The intermediate thus obtained was treated with 14g of methyl iodide in the presence of tetrahydrofuran and water as a solvent to obtain the title compound.

Reference： [1]Current Patent Assignee: LG CHEM CO.,LTD. - EP584797, 1994, A2

48
[ 61310-53-0 ]
[ 598-52-7 ]
[ 33399-91-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium ethanolate In ethanol	P.2 Preparation Example 2 Preparation Example 2 : Synthesis of 4-amino-1-methyl-2-pyrimidinethione To a solution of 97.12g(1 mole) of 3-ethoxy acrylonitrile dissolved in 200 ml of dry ethanol were added 145g of sodium ethoxide and 90.15g of N-methyl thiourea. The reaction mixture was heated under reflux for 12 hours and cooled to produce precipitates, which were filtered, washed with water and with acetone and dried to obtain 86g of the title compound. m.p.: 98°C NMR(δ, DMSO-d6): 7.86(d, 1H), 7.57(bs, 2H), 6.00(d, 1H), 3.61(s, 3H) MS(EI, M): 141, 126

Reference： [1]Current Patent Assignee: LG CHEM CO.,LTD. - EP584797, 1994, A2

49
[ 61310-53-0 ]
[ 3473-63-0 ]
[ 176799-58-9 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium methylate In isopropyl alcohol at 75℃; for 2h;

Reference： [1]Location in patent: experimental part Linz, Sabine; Mueller, Joerg; Huebner, Harald; Gmeiner, Peter; Troschuetz, Reinhard [Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4448 - 4458]

50
[ 61310-53-0 ]
(4-chloro-2-fluorophenyl)hydrazine hydrochloride [ No CAS ]
[ 1202679-45-5 ]

Yield	Reaction Conditions	Operation in experiment
16%	With sodium ethanolate In ethanol Reflux;	2 Step2; l-(4-Chloro-2-fluoro-phenyl)-lH-pyrazol-3-ylamine: To a round bottom flask was charged (4-chloro-2-fluorophenyl)-hydrazine HCl salt (1.97 g, 10.0 mmol), ethanol (8.00 niL), 2.80 M sodium ethoxide in ethanol (10.0 mL, 28.0 mmol), and 3-ethoxyacrylonitrile (1.85 mL, 18.0 mmol). The reaction mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and then was quenched by pouring into water. The aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (hexane to 50% ethyl acetate in hexane gradient) to provide the desired product as a brown solid (334 mg, 16%). IH NMR CD3OD 6 7.79 (br, IH), 7.72-7.64 (m, IH), 7.32-7.20 (m, 2H), 5.94 (br, IH); MS (ES, m/z) 212 M-I-H+.

Reference： [1]Current Patent Assignee: H. LUNDBECK A/S - WO2010/53861, 2010, A2 Location in patent: Page/Page column 45

51
[ 50-00-0 ]
[ 64-18-6 ]
[ 61310-53-0 ]
[ 10449-07-7 ]
[ 1229380-56-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-ethoxyacrylonitrile; (2-chlorophenyl)hydrazine Stage #2: formaldehyd; formic acid	85 Example 85: compound n°85: (R)-3-benzyl-4-((l-(2-chlorophenyl)-lH-pyrazol-3- yl(methyl)amino)-4-oxobutanoic acid may be synthesized as described in Scheme 12.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2010/66682, 2010, A1 Location in patent: Page/Page column 197; 223

52
[ 61310-53-0 ]
[ 823-85-8 ]
[ 87949-12-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium ethanolate In ethanol for 20h; Reflux;	Intermediate A1.1-(4-Fluorophenyl)-1H-pyrazol-3-amine NaOEt (21% weight in EtOH, 37 mL, 98.17 mmol) and 3-ethoxyacrylonitrile (6.50 mL, 63.10 mmol) were added to a suspension of (4-fluorophenyl)hydrazine hydrochloride (5.70 g, 35.06 mmol) in EtOH (45 mL) and the mixture was heated under reflux for 20 h. The reaction mixture was allowed to reach room temperature and water (35 mL) and HCl (6 N aqueous solution, pH 2) were added, stirring continued for additional 2 h. The reaction was basified with NaOH (40% aqueous solution, pH 8) and was extracted with EtOAc. The combined organic layers were dried over Na2SO4 (anhydrous), filtered and stirred in the presence of charcoal. After 2 h the mixture was filtered through a pad of Celite and the solvent was removed. The crude residue was purified by flash chromatography on SiO2 (40% to 70% EtOAc/hexanes) to afford the title compound (brown solid, 4.94 g, 74% yield). HPLC-MS (Method A): Ret, 7.43 min; ESI+-MS m/z: 178 (M+1).
42%	Stage #1: 4-fluorophenyhydrazine hydrochloride With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; Stage #2: 3-ethoxyacrylonitrile In <i>tert</i>-butyl alcohol for 3h; Reflux;	B.2.1 Example 26-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid [1-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-amideStep 1: 1-(4-Fluoro-phenyl)-1H-pyrazol-3-ylamineTo a hot solution of potassium tert-butoxide (2.54 g, 23 mmol) in tert-butanol (30 ml) was added 4-fluorophenylhydrazine hydrochloride (1.67 g, 10 mmol). After cooling to ambient temperature, a solution of 3-ethoxyacrylonitrile (1.0 g, 10 mmol) in tert-butanol (5 ml) was added and the mixture was refluxed for 3 h. After cooling to ambient temperature, the solvent was evaporated. The residue was dissolved in ethyl acetate and extracted with water. The organic phases were combined, dried and evaporated. Silica gel chromatography using a heptane/ethyl acetate gradient yielded the amine as orange solid (0.78 g, 42%).MS: M=178.3 (M+H)+
42%	With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol for 3h; Reflux;	B.2.1 Example 2: 6-Methyl-3-fpyrimidin-5-ylamino)-pyridine-2-carboxylic acid [l-(4-fluoro- phenyl)-lH-pyrazol-3-yll-amideStep 1: l-(4-Fluoro-phenyl)-lH-pyrazol-3-ylamineTo a hot solution of potassium tert-butoxide (2.54 g, 23 mmol) in tert-butanol (30 ml) was added 4-fluorophenylhydrazine hydrochloride (1.67 g, 10 mmol). After cooling to ambient temperature, a solution of 3-ethoxyacrylonitrile (1.0 g, 10 mmol) in tert-butanol (5 ml) was added and the mixture was refiuxed for 3 h. After cooling to ambient temperature, the solvent was evaporated. The residue was dissolved in ethyl acetate and extracted with water. The organic phases were combined, dried and evaporated. Silica gel chromatography using a heptane/ethyl acetate gradient yielded the amine as orange solid (0.78 g, 42 %).MS: M = 178.3 (M+H)+

16.5%

With sodium ethanolate; sodium hydride In ethanol at 140℃; for 0.5h; Microwave irradiation;

1.1 1-(4-fluorophenyl)-1H-pyrazol-3-amine [300] Sodium hydride (320 mg, 8.0 mmol) was added in portions to ethanol (10 mL) at room temperature. After stirring for 5 minutes, this sodium ethoxide solution was added to a slurry of (4- fluorophenyl)hydrazine (hydrochloride salt; 0.50 g, 3.08 mmol) and 3-ethoxyacrylonitrile (320 L, 3.11 mmol) in ethanol (8.0 mL). The resultant reaction mixture was heated to 140 °C in the microwave for 30 min. After cooling, the reaction mixture was partitioned into ethyl acetate and water. The layers were separated, and the organics were dried (Na2SO4), filtered, and concentrated to an oil. The crude material was purified by silica chromatography (40 g silica column; linear gradient of 0-60% ethyl acetate/heptane) to provide 1-(4-fluorophenyl)-1H-pyrazol-3-amine (90 mg, 16.5% yield) as a yellow solid. ESI-MS m/z calc. 177.07, found 178.01 (M+1).

Reference： [1]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - WO2017/178510, 2017, A1 Location in patent: Page/Page column 227
[2]Current Patent Assignee: ROCHE HOLDING AG - US2011/183979, 2011, A1 Location in patent: Page/Page column 23
[3]Current Patent Assignee: ROCHE HOLDING AG - WO2011/89132, 2011, A1 Location in patent: Page/Page column 57-58
[4]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2018/107056, 2018, A1 Location in patent: Paragraph 300

53
[ 61310-53-0 ]
[ 1334527-89-7 ]
[ 1334527-29-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate In ethanol Reflux;	2.B.4 Carboximidamide 10 was dissolved in an appropriate solvent (xylene, toluene, or pyridine) and charged with vinyl nitrile 11. Reaction is then capped and heated at reflux until > 90% complete by LC/MS analysis. Reaction is then concentrated, taken back up in DCM, and extracted with water. The aqueous portion was then extracted an addition two times with DCM. The organic portions were then combined, dried (Na2S04), filtered, and concentrated. The crude oil was purified by reverse phase, preparative HPLC to give pyrimidine 12, as a (color) solid or liquid, etc. Compound 1-3 was synthesized as a white solid (< 2 % overall yield over 7 steps) using 3-ethoxyacrylonitrile as the vinyl nitrile and ethanol (also added two equiv of sodium methoxide) as solvent in step 4.1H NMR (400 MHz, CDC13) δ 8.30 (d, 1H), 7.29-7.23 (m, 1H), 7.13 (ddd, 1H), 7.09-7.03 (m, 2H) 6.28 (d, 1H), 5.39 (s, 2H), 4.96 (bs, 2H), 2.92-2.88 (m, 2H), 2.52-2.48 (m, 4H) ppm.

Reference： [1]Current Patent Assignee: CYCLERION THERAPEUTICS INC - WO2011/115804, 2011, A1 Location in patent: Page/Page column 91; 92

54
[ 61310-53-0 ]
[ 1378035-62-1 ]
[ 1354043-71-2 ]

Yield	Reaction Conditions	Operation in experiment
17%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 90℃; for 24h;	10 00539] A solution of D4 (from Example 7: General Procedure F) (where Rc = 2-furyl, and (JB)n = 2-fluoro) (811 mg, 1 equiv), 3-ethoxyacrylnitrile (1.39 g, 5 equiv) and DBU (430 μ,, 1 equiv) was stirred at 90 °C in toluene for 24 h. The solvent was removed in vacuo and purification by silica gel chromatography (0 to 40% 7:1 Acetonitrile:methanol indicliloromethane) gave 167 mg (17 %) of the desired compound as off-white solid.1H NMR (400 MHz, CDOD) 8.30 (s, 1H), 7.44-7.42 (m, 1H), 7.27 (s, 1H), 7.23-7.16 (m, 1H), 7.08-7.00 (m, 1H), 6.99-6.94 (m, 1H), 6.84-6.79 (m, 1H), 6.47-6.40 (m, 2H), 6.34 (d, 1H), 5.78 (s, 2H), 5.20 (bs, 2H).

Reference： [1]Current Patent Assignee: CYCLERION THERAPEUTICS INC - WO2012/3405, 2012, A1 Location in patent: Page/Page column 290

55
[ 61310-53-0 ]
[ 1375183-37-1 ]
[ 1375182-80-1 ]

Yield	Reaction Conditions	Operation in experiment
78%	With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 110℃; for 46h;	9.6 Step 6:; To l-(2-fluorobenzyl)-5-(thiazol-2-yl)-lH-l,2,4-triazole-3-carboximidamide (Intermediate- 6, 0.33 mmol) was added a stock solution of 3-ethoxyacrylonitrile (3 equiv) and DBU (1 equiv) in pyridine (3 mL). The reaction was warmed to 110°C and stirred for 46h. The reaction mixture was cone, and purified using S1O2 chromatography and an appropriate gradient (CH3CN/MeOH/CH2Cl2) to afford 2-(l-(2-fluorobenzyl)-5-(thiazol-2-yl)-lH-l,2,4- triazol-3-yl)pyrimidin-4-amine (1-48) as a light tan solid (78% yield).1-48: ¾ NMR (400 MHz, DMSO-d6) δ 8.15 (d, 1H), 8.13 (d, 1H), 8.08 (d, 1H), 7.38 (m, 1H), 7.27-7.14 (m, 3H), 7.13 (br. s, 2H), 6.44 (d, 1H), 6.16 (s, 2H) ppm. MS: [M+H] = 354.

Reference： [1]Current Patent Assignee: CYCLERION THERAPEUTICS INC - WO2012/64559, 2012, A1 Location in patent: Page/Page column 124

56
[ 61310-53-0 ]
[ 1446359-76-7 ]
[ 1446358-98-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With pyridine at 20 - 85℃; for 120h;	1 Compound 15 To a solution of Intermediate-81 (107 mg, 0.33 mmol) in pyridine (2 mL) was added a mixture of E- and Z-3-ethoxyacrylonitrile (97 mg, 0.999 mmol). The solution was stirred at 85 °C for 48 hours, and then for another 3 days at room temperature. The solvent was removed in vacuo and purification by silica gel chromatography (0-8% methanol in dichloromethane) provided product Compound 15 (74 mg, 60% yield) as a tan solid. Compound 15: 1H-NMR (400 MHz, d6-DMSO) δ 9.14 (d, IH), 8.10 (d, IH), 7.58-7.49 (m, IH), 7.42 (s, IH), 7.27 (d, IH), 7.19-7.15 (m, IH), 6.94 (s, 2H), 6.35 (d, IH), 5.94 (s, 2H).

Reference： [1]Current Patent Assignee: CYCLERION THERAPEUTICS INC - WO2013/101830, 2013, A1 Location in patent: Page/Page column 138

57
[ 61310-53-0 ]
[ 1446359-78-9 ]
[ 1446359-02-9 ]

Yield	Reaction Conditions	Operation in experiment
40%	With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 110℃;	1 Compound 37 A mixture 1 -(2,3 -difluorobenzyl)-5-(isoxazol-3 -yl)- 1 H-pyrazole-3 -carboximidamide (Intermediate-8B, 600 mg, 1.64 mmol), 3-ethoxyacrylonitrile (0.850 ml, 8.26 mmol, mixture of E and Z), and DBU (0.498, 3.30 mmol) in pyridine (10 mL) was stirred at 110 °C until the reaction was complete by LC/MS analysis. At this point, the reaction mixture was concentrated in vacuo and purified using column chromatography (0-10% MeOH/DCM) to provide the desired product as an off-white solid (40%). Compound 37: 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, 1H), 8.13 (d, 1H), 7.53 (s, 1H), 7.41-7.33 (m, 1H), 7.25 (d, 1H), 7.16-7.10 (m, 1H), 6.97 (bs, 2H), 6.72-6.68 (m, 1H), 6.37 (d, 1H), 5.93 (s, 2H) ppm.

Reference： [1]Current Patent Assignee: CYCLERION THERAPEUTICS INC - WO2013/101830, 2013, A1 Location in patent: Page/Page column 140-141

58
[ 61310-53-0 ]
[ 1446359-84-7 ]
[ 1446359-24-5 ]

Yield	Reaction Conditions	Operation in experiment
29%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In pyridine at 110℃; for 18h;	1 Compound 71 To a solution of Intermediate 8-N (50 mg, 0.17 mmol) in pyridine (1 mL) was added a mixture of E- and Z-3-ethoxyacrylonitrile (69 mg, 0.82 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (50 mg, 0.33 mmol). The solution was stirred at 110 °C for 18 hours. The contents were diluted with ethyl acetate (25 mL), and washed with saturated ammonium chloride solution (5 mL) and brine (10 mL). The organics were dried over MgS04, filtered, and and the solvent was removed in vacuo. Purification by silica gel chromatography (0-40% 7:l=acetonitrile:methanol in dichloromethane) provided Compound 71 (17 mg, 29% yield) as an off-white solid. Compound 71: 1H-NMR (400 MHz, DMSO) δ 9.10 (d, 1H), 8.13(d, 1H), 7.51 (s, 1H), 7.33- 7.25 (m, 1H), 7.25 (d, 1H), 6.94-7.06 (m, 4H), 6.37 (d, 1H), 5.85 (s, 2H).

Reference： [1]Current Patent Assignee: CYCLERION THERAPEUTICS INC - WO2013/101830, 2013, A1 Location in patent: Page/Page column 156-157

59
[ 61310-53-0 ]
[ 1446359-85-8 ]
[ 1446359-26-7 ]

Yield	Reaction Conditions	Operation in experiment
34%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In pyridine at 110℃; for 20h;	1 Compound 73 To a solution of Intermediate 8-0 (108 mg, 0.36 mmol) in pyridine (1.7 mL) was added a mixture of E- and Z-3-ethoxyacrylonitrile (148 mg, 1.78 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (108 mg, 0.71 mmol). The solution was stirred at 110 °C for 20 hours. The contents were diluted with ethyl acetate (15 mL), and washed with saturated ammonium chloride solution (3 mL) and brine (5 mL). The organics were dried over MgS04, filtered, and and the solvent was removed in vacuo. Purification by silica gel chromatography (0-40% 7:l=acetonitrile:methanol in dichloromethane) provided impure product. Trituration with diethyl ether (2 mL) provided Compound 73 (50 mg, 34 % yield) as a tan solid. Compound 73: 1H-NMR (400 MHz, DMSO-d6) δ 9.10 (d, 1H), 8.13 (d, 1H), 7.52 (s, 1H), 7.31 (td, 1H), 7.26 (d, 1H), 7.23-7.16 (m, 1H), 6.99 (br s, 2H), 6.65 (ddd, 1H), 6.37 (d, 1H), 5.88 (s, 2H).

Reference： [1]Current Patent Assignee: CYCLERION THERAPEUTICS INC - WO2013/101830, 2013, A1 Location in patent: Page/Page column 157-158

60
[ 61310-53-0 ]
[ 1446359-86-9 ]
[ 1446359-28-9 ]

Yield	Reaction Conditions	Operation in experiment
38%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In pyridine at 110℃; for 20h;	1 Compound 78 To a solution of Intermediate Intermediate-8P (100 mg, 0.36 mmol) in pyridine (1.6 mL) was added a mixture of E- and Z-3-ethoxyacrylonitrile (152 mg, 1.56 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (95 mg, 0.63 mmol). The solution was stirred at 110 °C for 20 hours. The contents were diluted with ethyl acetate (10 mL), and washed with saturated ammonium chloride solution (3 mL). The aqueous layer was diluted with water (10 mL) and extracted with ethyl acetate (3x10 mL). The organics were washed with brine (10 mL), dried over MgS04, filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (0-30% 7:l=acetonitrile:methanol in dichloromethane) provided impure product. Trituration with diethyl ether (2 mL) provided Compound 78 (49 mg, 38 % yield) as a tan solid. Compound 78: 1H-NMR (400 MHz, DMSO-d6) δ 9.10 (d, 1H), 8.13 (d, 1H), 7.56 - 7.49 (m, 1H), 7.53 (s, 1H), 7.26 (d, 1H), 7.16 (t, 1H), 6.98 (s, 2H), 6.85 (t, 1H), 6.37 (d, 1H), 5.93 (s, 2H).

Reference： [1]Current Patent Assignee: CYCLERION THERAPEUTICS INC - WO2013/101830, 2013, A1 Location in patent: Page/Page column 159

61
[ 61310-53-0 ]
[ 1445831-18-4 ]
[ 1445831-64-0 ]

Yield	Reaction Conditions	Operation in experiment
58%	With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 110℃; Inert atmosphere;	1-25-1 Preparation of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H- pyrazol-3-yl]pyrimidin-4-amine To a suspension of 10.1 g of 5-cyclopropyl-1-(4-methoxybenzyl)-4-methyl-1H- pyrazole-3-carboximidamide hydrochloride 1 :1 1-3-1 (27.2 mmol, 1.0 eq) in 163 ml_ of dry pyridine and 4.10 ml_ and 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (27.2 mmol, 1.0 eq) 7.94 g 3-Ethoxyacrylsaurenitril (81.7 mmol, 3.30 eq) were added under nitrogen atmosphere. The reaction mixture was stirred over night at 110 *C. After cooling to rt the mixture was purged into water and three times extracted with ethyl acetate. The combined organic layers were dried over Na2S04 and concentrated in vacuo. The residue was taken up in DCM/MeOH 9:1 and the product was precipitated by adding diethyl ether to give 4.20 g of the desired compound 1-25-1. The mother liquor was concentrated in vacuo, the residue was suspended in ethyl acetate. The resulting precipitate was collected by filtration and washed with ethyl acetate to give additionally 1.90 g of the desired compound 1-25-1. In total 6.10 g of the target compound (15.8 mmol, 58%) were obtained. 1H-NMR (300MHz, DMSO-de): δ [ppm] = 0.64 - 0.77 (m, 2 H), 0.96 - 1.07 (m, 2 H), 1.31 (t, 3 H), 1.67 (m, 1 H), 2.24 (s, 3 H), 4.05 (q, 2 H), 5.33 (s, 2 H), 6.26 (d, 1 H), 6.68 - 6.81 (m, 4 H), 8.06 (d, 1 H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2013/92512, 2013, A1 Location in patent: Page/Page column 151; 152

62
[ 5332-25-2 ]
[ 61310-53-0 ]
[ 1491168-42-3 ]

Yield	Reaction Conditions	Operation in experiment
	With bis(tri-t-butylphosphine)palladium⁽⁰⁾; dicyclohexylmethylamine; lithium chloride In 1,4-dioxane at 110℃;

Reference： [1]Kohrt, Jeffrey T.; Conn, Ed; Maguire, Robert; Wright, Stephen W.; Singer, Robert [Tetrahedron Letters, 2013, vol. 54, # 51, p. 7065 - 7068]

63
[ 61310-53-0 ]
[ 1579999-81-7 ]
[ 1579999-86-2 ]

Yield	Reaction Conditions	Operation in experiment
54%	With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 110℃; for 18h;	1 Preparation of compound I-1 To a solution of Intermediate D-1 (50 mg, 0.55 mmol) in pyridine (2.7 mL) was added a mixture of E- and Z-3-ethoxyacrylonitrile (266 mg, 2.74 mmol) and 1 ,8- diazabicyclo[5.4.0]undec-7-ene (167 mg, 1.10 mmol). The solution was stirred at 1 10 °C for 18 hours. The contents were diluted with ethyl acetate (10 mL), and washed with saturated ammonium chloride solution (3 mL). Layers seperated, and aqueous layer was diluted with additional water (10 mL). The aqueous layer was then extracted with dichloromethane (3x 10 mL). Combined organic layers were washed with brine (10 mL). The organics were dried over MgS04, filtered, and and the solvent was removed in vacuo. Purification by silica gel chromatography (0-30% 7: l=acetonitrile:methanol in dichloromethane) provided compound 1-1 (97 mg, 54% yield) as an iridiscent pale brown solid. 1H-NMR (400 MHz, DMSO) δ 9.13-9.07 (m, 1H), 8.12 (d, 1H), 7.49-7.46 (m, 1H), 7.45 (d, 1H), 7.29-7.26 (m, 1H), 7.24-7.21 (m, 1H), 6.99 - 6.92 (m, 3H), 6.36 (dd, 1H), 5.78 (s, 2H)

Reference： [1]Current Patent Assignee: CYCLERION THERAPEUTICS INC - WO2014/47111, 2014, A1 Location in patent: Paragraph 00214; 00215

64
[ 61310-53-0 ]
[ 113696-90-5 ]
[ 1648927-69-8 ]

Yield	Reaction Conditions	Operation in experiment
	at 0 - 50℃; for 5h;	1,000 mL of tetrahydrofuran was added to 50.0 g of cyanuric chloride, 19.0 g of phenylmagnesium bromide (2 mol/L tetrahydrofuran solution) was added dropwise to the obtained solution at 0° C., and the solution after dropwise addition was stirred at 50° C. for 4 hours. Next, 10.0 g of phenylmagnesium bromide was additionally added to the solution after stirring, and the solution was further stirred for 1 hour. This reaction liquid was added to 12% hydrochloric acid, and after the reactant was extracted by toluene, the organic phase was concentrated by an evaporator and the reactant was refined by a silica column to obtain a synthetic intermediate A. 50 mL of tetrahydrofuran was added to 19.0 g of hydrazine monohydrate, 10.0 g of the synthetic intermediate A dissolved in 200 mL of tetrahydrofuran was added dropwise thereto at room temperature and the solution was stirred for 3 hours. 500 mL of water was added thereto at room temperature and a synthetic intermediate B was obtained by filtrating the obtained solid and washing it by water. 100 mL of ethanol was added to 10.0 g of the synthetic intermediate B, 3.7 g of 3-ethoxyacrylonitrile was added dropwise at 0° C., the solution was stirred at 50° C. for 5 hours, 100 mL of water was added at room temperature, and a synthetic intermediate C was obtained by filtrating the obtained solid and washing it by water. 5.0 g of acetic anhydride and 5 mL of pyridine were added to 4.0 g of the synthetic intermediate C and the solution was refluxed for 3 hours. After the reaction liquid was cooled down to room temperature, a compound (1) was obtained by filtrating the obtained solid and washing it by methanol. Mass measured value (M+H)+: 357.15

Reference： [1]Current Patent Assignee: FUJIFILM HOLDINGS CORP. - US2014/213704, 2014, A1 Location in patent: Paragraph 0182

65
3-hydrazinylpyridine dihydrogenchloride [ No CAS ]
[ 61310-53-0 ]
3-(3-amino-1H-pyrazol-1-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: 3-hydrazinylpyridine dihydrogenchloride With sodium ethanolate In ethanol at 23 - 30℃; for 0.25h; Stage #2: 3-ethoxyacrylonitrile In ethanol at 30 - 78℃; for 5h; Inert atmosphere;	16 3-(3-Amino-1H-pyrazol-1-yl)pyridine (8a) Example 16 3-(3-Amino-1H-pyrazol-1-yl)pyridine (8a) To a three-neck round bottomed flask (50 mL) equipped with a reflux condenser was introduced 3-hydrazinopyridine.dihydrochloride (1.82 g, 10.0 mmol) and anhydrous ethanol (10.0 mL). Sodium ethoxide (21 wt % in ethanol, 11.8 mL, 31.5 mmol) was added over 5 minutes and the internal temperature increased from 23° C. to 30° C. The resultant light brown slurry turned light pink after stifling for 10 minutes. 3-Ethoxyacrylonitrile (2.06 mL, 20.0 mmol) was added over 5 minutes and the internal temperature remained at 30° C. The yellow mixture was stirred at 78° C. under nitrogen for 5 hours and was then cooled to 15° C. Hydrochloric acid (4 M in 1,4-dioxane, 2.90 mL) was added slowly to quench any excess base forming a light brown suspension. The mixture was concentrated under reduced pressure to afford a brown solid. The solid was partitioned in water (30 mL) and ethyl acetate (50 mL). The insoluble light brown solid was collected by filtration to afford the first portion of product (0.340 g, >95% pure by 1H NMR). The aqueous layer was extracted with ethyl acetate (3*50 mL). The combined organic extracts were concentrated to afford dark brown wet solid. The mixture was suspended in ethyl acetate (10 mL), filtered, and washed with heptane (20 mL) to afford the second portion of product as a brown solid (1.00 g, >95% pure by 1H NMR). The title compound was obtained as a brown solid (1.34 g, 84%): 1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J=2.4 Hz, 1H), 8.33 (dd, J=4.8, 1.2 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.01 (ddd, J=8.4, 2.8, 1.2 Hz, 1H), 7.42 (dd, J=8.4, 4.8 Hz, 1H), 5.80 (d, J=2.4 Hz, 1H), 5.19 (bs, 2H, -NH2); 13C NMR (100 MHz, DMSO-d6) δ 157.7, 144.7, 138.0, 136.2, 128.3, 123.9, 123.2, 97.1; EIMS m/z 160 ([M]+); HPLC (Zorbax SB-C8 column, P/N: 863954-306; mobile phase: A=water (0.1% formic acid), B=acetonitrile (0.01% formic acid); Gradient from 5 to 100% acetonitrile over 15 minutes; flow: 1.0 mL/minute): tR=1.95 minutes.
84%	Stage #1: 3-hydrazinylpyridine dihydrogenchloride With sodium ethanolate In ethanol at 23 - 30℃; for 0.25h; Stage #2: 3-ethoxyacrylonitrile In ethanol at 30 - 78℃; for 5h; Inert atmosphere;	1 Preparation of 3-(3-arnino-lH-pyrazol-1-yl)pyridine (8a) To a three-neck round bottomed flask (50 mL) equipped with a reflux condenser was introduced 3-hydrazinopyridine.dihydrochloride (1.82 g, 10.0 mmol) and anhydrous ethanol (10.0 mL). Sodium ethoxide (21 wt % in EtOH, 11.8 mL, 31.5 mmol) was added over 5 minutes and the internal temperature increased from 23° C. to 30° C. The resultant light brown slurry turned light pink after stirring for 10 minutes. 3-Ethoxyacrylonitrile (2.06 mL, 20.0 mmol) was added over 5 minutes and the internal temperature remained at 30° C. The yellow mixture was stirred at 78° C. under nitrogen for 5 hours and was then cooled to 15° C. Hydrochloric acid (4 M in 1,4-dioxane, 2.90 mL) was added slowly to quench any excess base forming a light brown suspension. The mixture was concentrated under reduced pressure to afford a brown solid. The solid was partitioned in water (30 mL) and ethyl acetate (50 mL). The insoluble light brown solid was collected by filtration to afford the first portion of product (0.340 g, >95% pure by 1H NMR). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were concentrated to afford dark brown wet solid. The mixture was suspended in ethyl acetate (10 mL), filtered, and washed with heptane (20 mL) to afford the second portion of product as a brown solid (1.00 g, >95% pure by 1H NMR). The title compound was obtained as a brown solid (1.34 g, 84%): 1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J=2.4 Hz, 1H), 8.33 (dd, J=4.8, 1.2 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.01 (ddd, J=8.4, 2.8, 1.2 Hz, 1H), 7.42 (dd, J=8.4, 4.8 Hz, 1H), 5.80 (d, J=2.4 Hz, 1H), 5.19 (bs, 2H, -NH2); 13C NMR (100 MHz, DMSO-d6) δ 157.7, 144.7, 138.0, 136.2, 128.3, 123.9, 123.2, 97.1; EIMS m/z 160 ([M]+); HPLC (Zorbax SB-C8 column, P/N: 863954-306; mobile phase: A=water (0.1% formic acid), B=acetonitrile (0.01% formic acid); Gradient from 5 to 100% acetonitrile over 15 minutes; flow: 1.0 mL/minute): tR=1.95 minutes.
83.8%	Stage #1: 3-hydrazinylpyridine dihydrogenchloride With sodium ethanolate In ethanol at 23 - 30℃; for 0.25h; Inert atmosphere; Stage #2: 3-ethoxyacrylonitrile In ethanol at 30 - 78℃; for 5h; Inert atmosphere;

Reference： [1]Current Patent Assignee: CORTEVA INC - US2015/112078, 2015, A1 Location in patent: Paragraph 0028; 0087; 0088
[2]Current Patent Assignee: CORTEVA INC - US9029555, 2015, B1 Location in patent: Paragraph 0020; 0021
[3]Yang, Qiang; Li, Xiaoyong; Lorsbach, Beth A.; Roth, Gary; Podhorez, David E.; Ross, Ronald; Niyaz, Noormohamed; Buysse, Ann; Knueppel, Daniel; Nissen, Jeffrey [Organic Process Research and Development, 2019, vol. 23, # 10, p. 2122 - 2132]

66
[ 61310-53-0 ]
cyclopropanecarboximidamidine hydrochloride [ No CAS ]
[ 265324-26-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: cyclopropanecarboximidamidine hydrochloride With sodium methylate In methanol at 20℃; for 0.5h; Stage #2: 3-ethoxyacrylonitrile at 135℃; for 3h;	1 2-Cyclopropylpyrimidin-4-amine [00199] A suspension of cyclopropylcarbamidine hydrochloride (1.0 g, 8.3 mmol) in sodium methoxide (0.5 M in MeOH, 16.6 mL, 8.3 mmol) was allowed to stir at ii for 30 mm. The mixture was then filtered and concentrated. Ethoxyacrylonitrile (0.85 mL, 8.3 mmol) was added and the reaction was allowed to stir at 135 °C for 3 h, then allowed to cool toil and stir for another 16 h. The reaction was concentrated and the crude product was purified by column chromatography to provide 2- cyclopropylpyrimidin-4-amine (1.10 g, 85.0%) as a solid. LCMS (FA): m/z 136.2 (M+H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/108861, 2015, A1 Location in patent: Paragraph 00199

67
[ 61310-53-0 ]
[ 618-39-3 ]
[ 33630-25-0 ]

Yield	Reaction Conditions	Operation in experiment
61.8%	at 135℃; for 3.0h;	[00200] A solution of benzamidine (0.655 niL, 5.15 mmol) in 3-ethoxyacrylonitrile (0.500 g, 5.15 mmol) was allowed to stir at 135 °C for 3 hand was then allowed to cool toil and stir for another 16 h. The reaction was concentrated and the crude compound was purified by column chromatography to provide 2-phenylpyrimidin-4-amine (0.545 g, 61.8percent) as a solid. LCMS (FA): m/z 172.4 (M+H).
61.8%	at 20 - 135℃; for 19.0h;	2-Phenylpyrimidin-4-amine A solution of benzamidine (0.655 mL, 5.15 mmol) in 3-ethoxyacrylonitrile (0.500 g, 5.15 mmol) was allowed to stir at 135° C. for 3 h and was then allowed to cool to rt and stir for another 16 h. The reaction was concentrated and the crude compound was purified by column chromatography to provide 2-phenylpyrimidin-4-amine (0.545 g, 61.8percent) as a solid. LCMS (FA): m/z=172.4 (M+H).

Reference： [1]Patent: WO2015/108861,2015,A1 .Location in patent: Paragraph 00200
[2]Patent: US2015/225422,2015,A1 .Location in patent: Paragraph 0266-0267

68
[ 61310-53-0 ]
[ 57297-29-7 ]
[ 265324-26-3 ]

Yield	Reaction Conditions	Operation in experiment
85.0%		2-Cyclopropylpyrimidin-4-amine A suspension of cyclopropylcarbamidine hydrochloride (1.0 g, 8.3 mmol) in sodium methoxide (0.5 M in MeOH, 16.6 mL, 8.3 mmol) was allowed to stir at rt for 30 min. The mixture was then filtered and concentrated. Ethoxyacrylonitrile (0.85 mL, 8.3 mmol) was added and the reaction was allowed to stir at 135° C. for 3 h, then allowed to cool to rt and stir for another 16 h. The reaction was concentrated and the crude product was purified by column chromatography to provide 2-cyclopropylpyrimidin-4-amine (1.10 g, 85.0percent) as a solid. LCMS (FA): m/z=136.2 (M+H).

Reference： [1]Patent: US2015/225422,2015,A1 .Location in patent: Paragraph 0264-0265

69
[ 61310-53-0 ]
2-(diethoxymethyl)-3-formylnonanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / 2.08 h 2: C₁₃H₂₀N₂O₂; tris(bipyridine)ruthenium(II) dichloride hexahydrate; 2,6-dimethylpyridine; 2,6-dimethylpyridinium trifluoromethanesulfonate / dimethyl sulfoxide / 8 h / 23 °C / Inert atmosphere; Sealed tube; Irradiation

Reference： [1]Welin, Eric R.; Warkentin, Alexander A.; Conrad, Jay C.; MacMillan, David W. C. [Angewandte Chemie - International Edition, 2015, vol. 54, # 33, p. 9668 - 9672][Angew. Chem., 2015, vol. 127, # 33, p. 9804 - 9808,5]

70
[ 61310-53-0 ]
(2S,3R)-2-(diethoxymethyl)-3-formylnonanenitrile [ No CAS ]
C₁₅H₂₇NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / 2.08 h 2: tris(bipyridine)ruthenium(II) dichloride hexahydrate; (2R,5S)-(-)-5-tert-butyl-3-methyl-2-(5-methylanfuran-2-yl)-4-imidazolidinone; 2,6-dimethylpyridine; 2,6-dimethylpyridinium trifluoromethanesulfonate / dimethyl sulfoxide / 8 h / 23 °C / Inert atmosphere; Sealed tube; Irradiation

Reference： [1]Welin, Eric R.; Warkentin, Alexander A.; Conrad, Jay C.; MacMillan, David W. C. [Angewandte Chemie - International Edition, 2015, vol. 54, # 33, p. 9668 - 9672][Angew. Chem., 2015, vol. 127, # 33, p. 9804 - 9808,5]

71
[ 61310-53-0 ]
C₁₅H₂₉NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide / 2.08 h 2: C₁₃H₂₀N₂O₂; tris(bipyridine)ruthenium(II) dichloride hexahydrate; 2,6-dimethylpyridine; 2,6-dimethylpyridinium trifluoromethanesulfonate / dimethyl sulfoxide / 8 h / 23 °C / Inert atmosphere; Sealed tube; Irradiation 3: sodium tetrahydroborate / dichloromethane; methanol / 2 h / 0 °C

Reference： [1]Welin, Eric R.; Warkentin, Alexander A.; Conrad, Jay C.; MacMillan, David W. C. [Angewandte Chemie - International Edition, 2015, vol. 54, # 33, p. 9668 - 9672][Angew. Chem., 2015, vol. 127, # 33, p. 9804 - 9808,5]

72
[ 61310-53-0 ]
[ 1354044-23-7 ]
[ 1354041-25-0 ]

Yield	Reaction Conditions	Operation in experiment
49%	With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 110℃; for 16h;

Reference： [1]Nakai, Takashi; Perl, Nicholas R.; Barden, Timothy C.; Carvalho, Andrew; Fretzen, Angelika; Germano, Peter; Im, G-Yoon J.; Jin, Hong; Kim, Charles; Lee, Thomas W.-H.; Long, Kimberly; Moore, Joel; Rohde, Jason M.; Sarno, Renee; Segal, Chrissie; Solberg, Erik O.; Tobin, Jenny; Zimmer, Daniel P.; Currie, Mark G. [ACS Medicinal Chemistry Letters, 2016, vol. 7, # 5, p. 465 - 469]

73
[ 61310-53-0 ]
1-((3-fluoropyridin-2-yl)methyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide [ No CAS ]
[ 76-05-1 ]
(x)C₂HF₃O₂*C₁₆H₁₂FN₇O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17 mg	Stage #1: 3-ethoxyacrylonitrile; 1-((3-fluoropyridin-2-yl)methyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 110℃; for 46h; Stage #2: trifluoroacetic acid In water; acetonitrile	1 Compound 145 A solution of 1 -((3-fluoropyridin-2-yl)methyl)-5-(isoxazol-3-yl)- lH-pyrazole-3-carboximidamide (Intermediate-18) in pyridine was treated with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.0 equiv.) and 3-ethoxyacrylonitrile (2.5 equiv.) and heated at 110 °C for 46 hours. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and partitioned between half-saturated sodium bicarbonate solution and dichloromethane. The organic phases were dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The crude material was purified via silica gel chromatography (10-25% acetonitrile/methanol (7:1) in dichloromethane gradient) followed by preparative HPLC (5-75% acetonitrile/water gradient with 0.1%) trifluoroacetic acid) to afford Compound 1-145 (17 mg, 21%, TFA salt) as a white solid. 'H-NMR (500 MHz, DMSO-de) δ ppm 14.1 (br s, 1H, TFA), 9.11 (s, 1H), 8.78 (br s, 2H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78 (app. t, 1H), 7.61 (s, 1H), 7.42 (m, 1H), 7.28 (s, 1H), 6.63 (d, 1H), 6.11 (s, 2H).

Reference： [1]Current Patent Assignee: CYCLERION THERAPEUTICS INC - WO2016/44447, 2016, A1 Location in patent: Paragraph 00389

74
[ 61310-53-0 ]
[ 100-63-0 ]
[ 1128-56-9 ]

Yield	Reaction Conditions	Operation in experiment
48%	With potassium tert-butylate; In tert-butyl alcohol; at 100℃; for 16h;	Potassium te/ -butoxide (1 1 .9 g, 106.3 mmol) was dissolved in tBuOH (1 OOmL) and the solution was heated to 100 C. Phenyl hydrazine (5 g, 46.2 mmol) and 3-ethoxy acrylonitrile (4.5 g, 46.2 mmol) were sequentially added and heating continued for 16 h. The mixture was concentrated in vacuo. The residue obtained was partitioned between water (500 mL) and ethyl acetate (500 mL). The organic extract was washed with water (250 mL), brine (250 mL), dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 25% EtOAc-hexanes eluent to give 1 - phenyl-1 H-pyrazol-3-amine as a pale brown solid (3.5 g, 48%). 1H NMR (400 MHz, CDCI3): delta = 7.69 (s, 1 H), 7.57 (d, J= 8.0 Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H), 7.2 (t, J = 7.6 Hz, 1 H), 5.85 (s, 1 H), 3.83 (br.s., 2H). LCMS (m/z): 160.3 (M+1 )+.

Reference： [1]Patent: WO2016/131098,2016,A1 .Location in patent: Page/Page column 135; 136

75
[ 61310-53-0 ]
[ 110596-10-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide In ethanol	6 Scheme 6-1: In Step 1 the appropriately substituted nitro species is reduced with palladium as known in the art to afford an amine. In Step 2 the appropriately substituted alkene species is brominated with concurrent addition of ethanol as known in the art to afford the bromide species. In Step 3 the appropriately substituted mixture of tautomers is subjected to the previously prepared bromide species as known in the art to afford the two isomers. The appropriately substituted isomers corresponding to each tautomer may either be separated or used as a mixture in the subsequent reactions with separation at a later step. In Step 4 the appropriately substituted ketal species is deprotected and subsequently cyclized in the presence of acid as known in the art. In Step 5 the appropriately substituted cyano species is subjected to strong acid to afford a primary amide. In Step 6 the appropriately substituted heterocycle is subjected to a bromide species of the appropriate linker to afford the appropriately protected species. Various 5-5 fused bicyclic systems can be appropriately prepared by slight modifications of this synthetic protocol, another non-limiting example is presented in Steps 5 through 12 with the same conditions for formation of a primary amide and installation of linker. In Step 7 the appropriately substituted aryl species is brominated as known in the art. In Step 8 the appropriately substituted ether species is deprotected with palladium as known in the art to afford an alcohol. In Step 9 the appropriately substituted alcohol is oxidized as known in the art to afford an aldehyde. In Step 10 the appropriately substituted aldehyde is subjected to hydrazine to first form a Schiff base and subsequently cyclize to afford a bicyclic system. In Step lithe appropriately substituted bicyclic system is iodinated as known in the art. In Step 12 the appropriately substituted iodide is subjected to sodium cyanide to afford the cyano species.
	With N-Bromosuccinimide In ethanol Inert atmosphere;	6.2 General procedure: Scheme 6-1: In Step 1 the appropriately substituted nitro species is reduced with palladium as known in the art to afford an amine. In Step 2 the appropriately substituted alkene species is brominated with concurrent addition of ethanol as known in the art to afford the bromide species. In Step 3 the appropriately substituted mixture of tautomers is subjected to the previously prepared bromide species as known in the art to afford the two isomers. The appropriately substituted isomers corresponding to each tautomer may either be separated or used as a mixture in the subsequent reactions with separation at a later step. In Step 4 the appropriately substituted ketal species is deprotected and subsequently cyclized in the presence of acid as known in the art. In Step 5 the appropriately substituted cyano species is subjected to strong acid to afford a primary amide. In Step 6 the appropriately substituted heterocycle is subjected to a bromide species of the appropriate linker to afford the appropriately protected species. Various 5-5 fused bicyclic systems can be appropriately prepared by slight modifications of this synthetic protocol, another non- limiting example is presented in Steps 5 through 12 with the same conditions for formation of a primary amide and installation of linker. In Step 7 the appropriately substituted aryl species is brominated as known in the art. In Step 8 the appropriately substituted ether species is deprotected with palladium as known in the art to afford an alcohol. In Step 9 the appropriately substituted alcohol is oxidized as known in the art to afford an aldehyde. In Step 10 the appropriately substituted aldehyde is subjected to hydrazine to first form a Schiff base and subsequently cyclize to afford a bicyclic system. In Step 11 the appropriately substituted bicyclic system is iodinated as known in the art. In Step 12 the appropriately substituted iodide is subjected to sodium cyanide to afford the cyano species.
	With N-Bromosuccinimide In ethanol	6 Scheme 6-1: In Step 1 the appropriately substituted nitro species is reduced with palladium as known in the art to afford an amine. In Step 2 the appropriately substituted alkene species is brominated with concurrent addition of ethanol as known in the art to afford the bromide species.In Step 3 the appropriately substituted mixture of tautomers is subjected to the previously prepared bromide species as known in the art to afford the two isomers. The appropriately substituted isomers corresponding to each tautomer may either be separated or used as a mixture in the subsequent reactions with separation at a later step. In Step 4 the appropriately substituted ketal species is deprotected and subsequently cyclized in the presence of acid as known in the art. InStep 5 the appropriately substituted cyano species is subjected to strong acid to afford a primary amide. In Step 6 the appropriately substituted heterocycle is subjected to a bromide species of the appropriate linker to afford the appropriately protected species. Various 5-5 fused bicyclic systems can be appropriately prepared by slight modifications of this synthetic protocol, another non- limiting example is presented in Steps 5 through 12 with the same conditions for formation of aprimary amide and installation of linker. In Step 7 the appropriately substituted aryl species is brominated as known in the art. In Step 8 the appropriately substituted ether species is deprotected with palladium as known in the art to afford an alcohol. In Step 9 the appropriately substituted alcohol is oxidized as known in the art to afford an aldehyde. In Step 10 the appropriately substituted aldehyde is subjected to hydrazine to first form a Schiff base and subsequently cyclizeto afford a bicyclic system. In Step lithe appropriately substituted bicyclic system is iodinated as known in the art. In Step 12 the appropriately substituted iodide is subjected to sodium cyanide to afford the cyano species.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35411, 2017, A1 Location in patent: Paragraph 0586
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35415, 2017, A1 Location in patent: Paragraph 0566; 0624; 0625
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2018/160889, 2018, A1 Location in patent: Page/Page column 414

76
[ 61310-53-0 ]
C₁₀H₁₅BrN₄O₂ [ No CAS ]
C₁₀H₁₅BrN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / ethanol 2: sodium amide / N,N-dimethyl-formamide / 24 h
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / Inert atmosphere 2: sodium amide / N,N-dimethyl-formamide / 24 h / Inert atmosphere
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / ethanol / Inert atmosphere 2: sodium amide / N,N-dimethyl-formamide / 24 h / Inert atmosphere

	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / ethanol 2: sodium amide / N,N-dimethyl-formamide / 24 h
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide 2: sodium amide / N,N-dimethyl-formamide / 24 h
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / ethanol 2: sodium amide / N,N-dimethyl-formamide / 24 °C

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35411, 2017, A1
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35413, 2017, A2
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35415, 2017, A1
[4]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35417, 2017, A1
[5]Current Patent Assignee: ASTRAZENECA PLC - WO2018/160891, 2018, A1
[6]Current Patent Assignee: ASTRAZENECA PLC - WO2018/160889, 2018, A1

77
[ 446273-59-2 ]
[ 61310-53-0 ]
[ 1220631-46-8 ]

Yield	Reaction Conditions	Operation in experiment
25%		To a solution of 3-ethoxyacrylonitrile (4.94 mL, 48.0 mmol) in dioxane (50 mL) was added water (50 mL). The solution was cooled to -10 C and then N- bromosuccinamide (NBS, 9.39 g, 52.8 mmol) was added. The reaction was stirred at -10 C for 2 hours and then 4-bromo-6-chloropyridazin-3 -amine (10 g, 48.0 mmol) was added. The vessel was sealed and then heated in a 60 C oil bath overnight. The reaction was cooled to room temperature, diluted with dichloromethane and then quenched with saturated (aqueous) sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, concentrated and purified using automated chromatography to give the product (3.1 g, 25%). NMR (400MHz, CHLOROFORM-d) delta 8.28 (s, 1H), 7.63 (s, 1H). LC retention time 0.80 min [J]. MS (E+) m/z: 259 (MH+).

Reference： [1]Patent: WO2017/87590,2017,A1 .Location in patent: Page/Page column 74

78
[ 61310-53-0 ]
1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide [ No CAS ]
2-(1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 110℃; for 48h;	Intermediate 1-13-1 Preparation of 2-(1 -methyl-1 ,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)pyrimidin-4- amine Intermediate 1-13-1 Preparation of 2-(1 -methyl-1 ,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)pyrimidin-4- amine 548 mg 1 -Methyl-1 ,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide 1 -12-1 (3.34 mmol, 1 .0 eq.), 972 mg 3-ethoxyacrylonitrile (10.0 mmol, 3.0 eq.) and 508 mg diazabicyclo(5.4.0)undec-7-en (3.34 mmol, 1 .0 eq.) were dissolved in 30 mL pyridine. The reaction mixture was stirred at 1 10 for 48 h . After cooling, iced water (30 mL) added and the resulting mixture was extracted with methylene chloride (3x30 mL). The combined organic phase was dried by the use of a silicone filter and the solvent was evaporated in vacuo. Purification was achieved via flash-chromatography on silica-gel with methylene chloride/methanol (9/1 ) to yield 474 mg of the targeted compound (65 % yield of theory). 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 2.43 - 2.48 (m, 2H), 2.62 - 2.71 (m, 2H), 2.74 (t, 2H), 3.72 (s, 3H), 6.24 (d, 1 H), 6.69 (s, 2H), 8.05 (d, 1 H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2017/157991, 2017, A1 Location in patent: Page/Page column 105-106

79
[ 61310-53-0 ]
[ 1017391-66-0 ]
4-hydrazino-1-methyl-1H-pyrazole dihydrochloride [ No CAS ]
1-(2-fluorophenyl)-N-(1'-methyl-1'H-[1,4'-bipyrazol]-3-yl)cyclopropane-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	Stage #1: 3-ethoxyacrylonitrile; 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride With sodium ethanolate In ethanol at 160℃; for 0.75h; Microwave irradiation; Sealed tube; Stage #2: 1-(2-fluorophenyl)cyclopropanecarbonyl chloride	1.3.T Method T 1-(2-fluorophenyl)-N-(1'-methyl-1'H-[1,4'-bipyrazol]-3-yl)cyclopropane-1-carboxamide (Compound 390) [380] A mixture of (E/Z)-3-ethoxyprop-2-enenitrile (50 L), 1-methylpyrazol-4-yl)hydrazine [2578] (dihydrochloride salt; 50 mg, 0.27 mmol, 1.0 eq), sodium ethoxide (500 L of 21 %w/v, 1.54 mmol, 5.7 eq), and ethanol (2.0 mL) was sealed and heated to 160 °C in microwave for 45 mins. The mixture was cooled to room temperature, the solvent evaporated, and the crude residue purified by silica gel chromatography (linear gradient of 0-100% ethyl acetate/heptane) to provide 1-(2- fluorophenyl)-N-(1'-methyl-1'H-[1,4'-bipyrazol]-3-yl)cyclopropane-1-carboxamide (24.6 mg, 25% yield).

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2018/107056, 2018, A1 Location in patent: Paragraph 380

80
[ 61310-53-0 ]
[ 2368-80-1 ]
[ 685094-07-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In ethanol; mineral oil at 0 - 70℃; for 2h;	1.1 1-(2-fluorophenyl)-1H-pyrazol-3-amine [299] To a 0 °C solution of (2-fluorophenyl)hydrazine (3.0 g, 23.8 mmol) in ethanol (40 mL) was added 3-ethoxyacrylonitrile (4.6 g, 47.6 mmol, 2.0 eq) and NaH (60% dispersion in oil, 3.8 g, 85.2 mmol, 4.0 eq). The mixture was stirred at 70 °C for 2 h. The reaction mixture was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude residue was purified by silica-gel chromatography (linear gradient of 10-33% ethyl acetate/heptane) to provide 1-(2-fluorophenyl)-1H-pyrazol-3-amine.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2018/107056, 2018, A1 Location in patent: Paragraph 299

81
[ 42166-50-7 ]
[ 61310-53-0 ]
3-(3-amino-1H-pyrazol-1-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With sodium hydride In ethanol; mineral oil at 0 - 70℃; for 2h;	1.1 1-(pyridin-3-yl)-1H-pyrazol-3-amine [301] To a 0 °C solution of 3-hydrazinylpyridine (2.0 g, 18.34 mmol) in ethanol (40mL) was added 3- ethoxyacrylonitrile (3.56 g, 36.70 mmol, 2.0 eq) and NaH (60% dispersion in oil; 2.9 g, 73.4 mmol, 4.0 eq). The mixture was warmed to room temperature and then heated to 70 °C for 2 h. The reaction mixture was partitioned between brine and THF. The layers were separated, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude residue was purified by silica-gel chromatography (linear gradient of 1.0-2.5% methanol/dichloromethane) to provide 1- (pyridin-3-yl)-1H-pyrazol-3-amine (500 mg, 17% yield) as a yellow oil (mixture of products).

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2018/107056, 2018, A1 Location in patent: Paragraph 301

82
[ 61310-53-0 ]
C₁₀H₁₆N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide 2: sodium amide / N,N-dimethyl-formamide / 24 h

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2018/160891, 2018, A1

83
[ 64-67-5 ]
[ 76064-23-8 ]
[ 61310-53-0 ]
[ 2032-34-0 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutylammomium bromide; triethylamine; In acetonitrile; at 40℃; for 10h;	Inject 600.50 grams of sodium methoxide into a 600 ml autoclave.300 grams of acetonitrile, sealed autoclave, ice salt bath for 20 minutes,Inhaled ethyl formate 33.6 g. A nitrogen gas of 1.50 MPa was introduced.The temperature was raised to 110 C with stirring, and the reaction was kept for 15 hours, and the temperature was lowered to room temperature.A white syrupy compound II was obtained which was diluted with 200 g of acetonitrile (CAN).And added to a 1L three-neck bottle, mechanically stirred. Further, 1.50 g of tetrabutylammonium bromide and 63 g of diethyl sulfate were added. Add 6.5 g of triethylamine and warm to 40 C.Stir at this temperature for 10 hours and cool to room temperature. filter,The solid was beaten with 100 g of acetonitrile, filtered, and the mother liquor was spun at 50 C.The mixture I was distilled to give a yield of 98.6% and a purity of 96.3%

Reference： [1]Patent: CN109912454,2019,A .Location in patent: Paragraph 0037; 0038-0048

84
[ 61310-53-0 ]
[ 83-38-5 ]
(Z)-2-((2,6-dichlorophenyl)(hydroxy)methyl)-3-ethoxyacrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 3-ethoxyacrylonitrile With N,N-dimethyl-ethanamine; sodium; diisopropylamine In tetrahydrofuran at -78℃; Flow reactor; Stage #2: 2,6-dichlorobenzaldehyde In tetrahydrofuran at 25℃; Flow reactor; diastereoselective reaction;

Reference： [1]Harenberg, Johannes H.; Weidmann, Niels; Karaghiosoff, Konstantin; Knochel, Paul [Angewandte Chemie - International Edition, 2021, vol. 60, # 2, p. 731 - 735][Angew. Chem., 2021, vol. 133, # 2, p. 742 - 746,5]

85
[ 119-61-9 ]
[ 61310-53-0 ]
(Z)-3-ethoxy-2-(hydroxydiphenylmethyl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: 3-ethoxyacrylonitrile With 2,2,6,6-tetramethyl-piperidine; sodium In tetrahydrofuran; hexane at -78℃; Flow reactor; Stage #2: benzophenone In tetrahydrofuran; hexane at 25℃; for 0.166667h; Flow reactor; diastereoselective reaction;

Reference： [1]Harenberg, Johannes H.; Weidmann, Niels; Karaghiosoff, Konstantin; Knochel, Paul [Angewandte Chemie - International Edition, 2021, vol. 60, # 2, p. 731 - 735][Angew. Chem., 2021, vol. 133, # 2, p. 742 - 746,5]

86
[ 61310-53-0 ]
[ 135-02-4 ]
(Z)-3-ethoxy-2-(hydroxy(2-methoxyphenyl)methyl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 3-ethoxyacrylonitrile With 2,2,6,6-tetramethyl-piperidine; sodium In tetrahydrofuran; hexane at -78℃; Flow reactor; Stage #2: ortho-anisaldehyde In tetrahydrofuran; hexane at 25℃; for 0.166667h; Flow reactor; diastereoselective reaction;

Reference： [1]Harenberg, Johannes H.; Weidmann, Niels; Karaghiosoff, Konstantin; Knochel, Paul [Angewandte Chemie - International Edition, 2021, vol. 60, # 2, p. 731 - 735][Angew. Chem., 2021, vol. 133, # 2, p. 742 - 746,5]

87
[ 61310-53-0 ]
[ 2043-61-0 ]
(Z)-4-cyclohexyl-3-ethoxy-4-hydroxybut-2-enenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: 3-ethoxyacrylonitrile With N,N-dimethyl-ethanamine; sodium; diisopropylamine In tetrahydrofuran at -78℃; Flow reactor; Stage #2: cyclohexanecarbaldehyde In tetrahydrofuran at 25℃; Flow reactor; diastereoselective reaction;

Reference： [1]Harenberg, Johannes H.; Weidmann, Niels; Karaghiosoff, Konstantin; Knochel, Paul [Angewandte Chemie - International Edition, 2021, vol. 60, # 2, p. 731 - 735][Angew. Chem., 2021, vol. 133, # 2, p. 742 - 746,5]

88
[ 61310-53-0 ]
(S)-2-azido-3-O-octadecyl-1,3-propanediol [ No CAS ]
(S)-1-(1-hydroxy-3-(octadecyloxy)propan-2-yl)-1H-1,2,3-triazole-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In toluene at 200℃; for 6h; Microwave irradiation;	Intermediate 81-2: (S)-1-(1-hydroxy-3-(octadecyloxy)propan-2-yl)-1H-1,2,3-triazole-4-carbonitrile A stirred mixture of intermediate 81-1 (60.3 mg, 163 μmol), 3-ethoxyacrylonitrile (200 μL, 1.94 mmol), and toluene (0.4 mL) was heated in a microwave reactor to 200 °C. After 6 h, the resulting mixture was cooled to room temperature and was purified by flash column chromatography on silica gel (0 to 55% ethyl acetate in hexanes) to give intermediate 81-2. LCMS: 421.3.
	In toluene at 200℃; for 6h; Microwave irradiation;	Intermediate 81-2: (S)-1-(1-hydroxy-3-(octadecyloxy)propan-2-yl)-1H-1,2,3-triazole-4-carbonitrile A stirred mixture of intermediate 81-1 (60.3 mg, 163 μmol), 3-ethoxyacrylonitrile (200 μL, 1.94 mmol), and toluene (0.4 mL) was heated in a microwave reactor to 200 °C. After 6 h, the resulting mixture was cooled to room temperature and was purified by flash column chromatography on silica gel (0 to 55% ethyl acetate in hexanes) to give intermediate 81-2. LCMS: 421.3.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0476
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0476

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	61310-53-0	MDL No. :	MFCD00010193
Formula :	C₅H₇NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HUPVIAINOSTNBJ-HWKANZROSA-N
M.W :	97.12	Pubchem ID :	5324714
Synonyms :

Signal Word:	Warning	Class:	N/A
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Hazard Statements:	H302-H315-H319-H227	Packing Group:	N/A
GHS Pictogram:

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Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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

[ CAS No. 61310-53-0 ] {[proInfo.proName]}

Quality Control of [ 61310-53-0 ]

Related Doc. of [ 61310-53-0 ]

Product Details of [ 61310-53-0 ]

Safety of [ 61310-53-0 ]

Application In Synthesis of [ 61310-53-0 ]

[ 61310-53-0 ] Synthesis Path-Upstream 1~3

[ 61310-53-0 ] Synthesis Path-Downstream 1~88

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Yield	Reaction Conditions	Operation in experiment
61.8%	at 135℃; for 3 h;	[00200] A solution of benzamidine (0.655 niL, 5.15 mmol) in 3-ethoxyacrylonitrile (0.500 g, 5.15 mmol) was allowed to stir at 135 °C for 3 hand was then allowed to cool toil and stir for another 16 h. The reaction was concentrated and the crude compound was purified by column chromatography to provide 2-phenylpyrimidin-4-amine (0.545 g, 61.8percent) as a solid. LCMS (FA): m/z 172.4 (M+H).
61.8%	at 20 - 135℃; for 19 h;	2-Phenylpyrimidin-4-amine A solution of benzamidine (0.655 mL, 5.15 mmol) in 3-ethoxyacrylonitrile (0.500 g, 5.15 mmol) was allowed to stir at 135° C. for 3 h and was then allowed to cool to rt and stir for another 16 h. The reaction was concentrated and the crude compound was purified by column chromatography to provide 2-phenylpyrimidin-4-amine (0.545 g, 61.8percent) as a solid. LCMS (FA): m/z=172.4 (M+H).