[ CAS No. 1572-98-1 ]

Name: 1572-98-1|Ethyl 2-Cyano-2-methylpropionate|98%
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CAS No. :	1572-98-1	MDL No. :	MFCD00034667
Formula :	C₇H₁₁NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FYGRPGOHQCPZCV-UHFFFAOYSA-N
M.W :	141.17 g/mol	Pubchem ID :	344887
Synonyms :

Safety of [ 1572-98-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P501-P261-P270-P210-P271-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330-P302+P352+P312-P304+P340+P312-P403+P235	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H227	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1572-98-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 1572-98-1 ]
Downstream synthetic route of [ 1572-98-1 ]

[ 1572-98-1 ] Synthesis Path-Upstream 1~7

1
[ 1572-98-1 ]
[ 26734-09-8 ]

Reference： [1] Journal of Organic Chemistry, 1981, vol. 46, # 24, p. 4907 - 4911
[2] Chemistry - A European Journal, 2012, vol. 18, # 5, p. 1383 - 1400
[3] Journal of Heterocyclic Chemistry, 1971, vol. 8, p. 961 - 966
[4] Advanced Synthesis and Catalysis, 2014, vol. 356, # 5, p. 1113 - 1118
[5] Russian Chemical Bulletin, 2014, vol. 63, # 2, p. 409 - 415[6] Izvestiya Akademii Nauk. Seriya Khimicheskaya, 2014, vol. 2, p. 409 - 415,7

2
[ 1572-98-1 ]
[ 19295-57-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: With sodium tetrahydroborate In tetrahydrofuran; water at 20℃; for 3 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran	1) 3-hydroxy-2,2-dimethylpropanenitrile To a mixture of ethyl 2-cyano-2-methylpropionate (5.0 g, 35.4 mmol), tetrahydrofuran (40 ml) and water (100 ml), sodium borohydride (4.47 g, 106 mmol) was slowly added, and the mixture was stirred at room temperature for 3 hr. 6N hydrochloric acid was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, passed through a small amount of silica gel and concentrated under reduced pressure to give the title compound (3.4 g, yield 97percent) as an oil. ¹H-NMR (CDCl₃): δ 1.36 (6H, s), 3.58 (2H, s).
97%	Stage #1: With sodium tetrahydroborate In tetrahydrofuran; water at 20℃; for 3 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water	To a mixture of ethyl 2-cyano-2-methylpropionate (5.0 g, 35.4 mmol), tetrahydrofuran (40 ml) and water (100 ml), sodium borohydride (4.47 g, 106 mmol) was slowly added, and the mixture was stirred at room temperature for 3 hr. 6N hydrochloric acid was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, passed through a small amount of silica gel and concentrated under reduced pressure to give the title compound (3.4 g, yield 97percent) as an oil.
63%	Stage #1: With lithium borohydride In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water	Under an atmosphere of nitrogen, a tetrahydrofuran (200 ml) solution of 28.2 g (0.20 mol) of cyano-dimethylacetic acid ethyl ester (1-70) was added dropwise to a tetrahydrofuran (500 ml) solution of 4.8 g (0.22 mol) of lithium borohydride spending 30 minutes, and then the mixture was stirred overnight at room temperature. By adding 6 N hydrochloric acid to the reaction solution, separation of layers was effected, the aqueous layer was extracted with ethyl acetate, combined with the first organic layer, washed with brine and then dried over magnesium sulfate. The solvent was evaporated, ether was added to the resulting residue, the insoluble material was removed by filtration, and then the solvent of the filtrate was evaporated. The thus obtained residue was applied to a silica gel column chromatography, and 12.5 g (63percent) of the title compound was obtained as a colorless oily substance from a n-hexane-ethyl acetate (2:1 v/v) eluate. ¹H-NMR (CDCl₃)δ: 1.36 (6H, s), 2.26 (1H, brs), 3.58 (2H, s).

55.09%	With sodium tetrahydroborate In methanol at 0 - 20℃;	To a solution of ethyl 2-cyano-2-methylpropanoate (10.34 g, 73.25 mmol) in methanol(200 mL) were added NaBH4 (5.54 g, 146 mmol) in portions at 0 °C. Then the mixture wasstirred at room temperature overnight. The mixture was adjusted to pH = 7~8 with saturatedNH4Cl aqueous solution, and then extracted with EtOAc (100mL x 3). The combined organiclayers were washed with brine (150mL), dried over Na2S04, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =20/1 to 10/1)to give the title compound as colorless oil (4.0 g, yield 55.09percent).1HNMR (400 MHz, CDCb) 8 (ppm): 3.44 (d, J= 6.3 Hz, 2H), 1.23 (s, 6H).
55.09%	at 20℃;	0 ° C,To 2-cyano-2-methylpropionic acidEthyl ester (10.34 g, 73.25 mmol)In methanol (200 mL) was added NaBH4 (5.54 g, 146 mmol) in portions.The reaction was stirred overnight at room temperature.After the reaction,The reaction solution was adjusted to pH = 7 to 8 with saturated aqueous ammonium chloride solution,Then extracted with EtOAc (100 mL x 3).The combined organic phases were washed with saturated brine (150 mL)Dried over anhydrous sodium sulfate,Filtered and concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1 to 10/1)The title compound was obtained as a colorless oil (4.0 g, yield 55.09percent).
1 g	With sodium tetrahydroborate; water In tetrahydrofuran at 20℃; for 6 h;	Description 933-llydroxy-2,2-dimethylpropanenitrile (D93)To a mixture of ethyl 2-cyano-2-methylpropanoate (2.5 g) in THF (20 mL) and water (50 mL) was added NaBH4 (3.35 g) portionwise. After addition the mixture was stirred at RT for 6 hours. Hydrochloric acid (6 M) was added to quench the reaction mixture, and then extracted with EtOAc(50 mL). The extract was washed with water (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (1 g). 1H NMR (400 MHz, MeOD-d4): 5.45 (s, 1H), 3.36 (s, 2H), 1.21 (s, 6H).Description 94

Reference： [1] Patent: US2009/156582, 2009, A1, . Location in patent: Page/Page column 35
[2] Patent: EP1847531, 2007, A1, . Location in patent: Page/Page column 51
[3] Patent: EP1717238, 2006, A1, . Location in patent: Page/Page column 61
[4] Patent: WO2017/48675, 2017, A1, . Location in patent: Paragraph 0434
[5] Patent: CN106478651, 2017, A, . Location in patent: Paragraph 0900; 0901; 0902
[6] Patent: US2007/299111, 2007, A1, . Location in patent: Page/Page column 33
[7] Patent: WO2007/28051, 2007, A2, . Location in patent: Page/Page column 49-50
[8] Patent: WO2015/180612, 2015, A1, . Location in patent: Page/Page column 68

3
[ 1572-98-1 ]
[ 324763-51-1 ]

Reference： [1] Patent: WO2011/148392, 2011, A1,
[2] Patent: WO2012/21446, 2012, A2,
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 957 - 971

4
[ 1572-98-1 ]
[ 22426-30-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: at 20℃; for 1 h;	Preparation Example A4-3: 2-cyano-2-methylpropanoyl chloride; [536] To a solution of commercially available ethyl-2-cyano-2-methylpropanoate (3.5g, 24.8mmol) in methanol (10 ml) was added LiOH (900mg, 37.2mmol) and water (0.5ml), and reacted at rt for 1 h. After the reaction finished, the solvent was con- <n="32"/>centrated in vacuo, IN-HCl (50ml) was added, and extracted with EtOAc. The extracted organic layer was dried over MgSO 4 , concentrated in vacuo to give2-cyano-2-methylpropionic acid (2.67g, 95percent). This compound (2.5g, 22mmol) was dissolved in DCM (7 ml), and reacted according to the procedure described in Step B of Preparation Example A4-1 to give the title compound (2.5g, 86.3percent).
73%	With potassium hydroxide In water at 40℃; for 2 h;	To a vial was added ethyl 2-cyano-2-methylpropanoate (1.0 g, 7.08 mmol), water (5 mL) and KOH (795 mg, 14.1 mmol). The mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated to remove methanol, acidified to pH 5 with 1 N HCl and extracted with ethyl acetate (50 ml*2). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give 2-cyano-2-methyl-propanoic acid (600 mg, 73percent yield) as a pale-yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.59 (br, 1H), 1.52 (s, 6H).

Reference： [1] Patent: WO2008/7930, 2008, A1, . Location in patent: Page/Page column 30-31
[2] Synthesis, 2005, # 4, p. 569 - 574
[3] Patent: US2018/282328, 2018, A1, . Location in patent: Paragraph 0832; 0833
[4] Chemische Berichte, 1932, vol. 65, p. 432,441
[5] Journal of the American Chemical Society, 1916, vol. 38, p. 911

5
[ 105-56-6 ]
[ 77-78-1 ]
[ 1572-98-1 ]
[ 72291-30-6 ]

Reference： [1] Patent: WO2012/21446, 2012, A2, . Location in patent: Page/Page column 29

6
[ 105-56-6 ]
[ 74-88-4 ]
[ 1572-98-1 ]
[ 72291-30-6 ]

Reference： [1] Patent: EP1717238, 2006, A1, . Location in patent: Page/Page column 60

7
[ 1572-98-1 ]
[ 180181-02-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 11, p. 1171 - 1173

[ 1572-98-1 ] Synthesis Path-Downstream 1~59

1
[ 1572-98-1 ]
[ 22426-30-8 ]

Yield	Reaction Conditions	Operation in experiment
95%		Preparation Example A4-3: 2-cyano-2-methylpropanoyl chloride; [536] To a solution of commercially available ethyl-2-cyano-2-methylpropanoate (3.5g, 24.8mmol) in methanol (10 ml) was added LiOH (900mg, 37.2mmol) and water (0.5ml), and reacted at rt for 1 h. After the reaction finished, the solvent was con- <n="32"/>centrated in vacuo, IN-HCl (50ml) was added, and extracted with EtOAc. The extracted organic layer was dried over MgSO 4 , concentrated in vacuo to give2-cyano-2-methylpropionic acid (2.67g, 95%). This compound (2.5g, 22mmol) was dissolved in DCM (7 ml), and reacted according to the procedure described in Step B of Preparation Example A4-1 to give the title compound (2.5g, 86.3%).
73%	With potassium hydroxide; In water; at 40℃; for 2h;	To a vial was added ethyl 2-cyano-2-methylpropanoate (1.0 g, 7.08 mmol), water (5 mL) and KOH (795 mg, 14.1 mmol). The mixture was stirred at 40 C. for 2 hours. The reaction mixture was concentrated to remove methanol, acidified to pH 5 with 1 N HCl and extracted with ethyl acetate (50 ml*2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 2-cyano-2-methyl-propanoic acid (600 mg, 73% yield) as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 13.59 (br, 1H), 1.52 (s, 6H).

Reference： [1]Patent: WO2008/7930,2008,A1 .Location in patent: Page/Page column 30-31
[2]Synthesis,2005,p. 569 - 574
[3]Patent: US2018/282328,2018,A1 .Location in patent: Paragraph 0832; 0833
[4]Chemische Berichte,1932,vol. 65,p. 432,441
[5]Journal of the American Chemical Society,1916,vol. 38,p. 911

2
[ 1572-98-1 ]
[ 59193-77-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonia; hydrogen In ethanol at 20℃; for 40h;	85 Ethyl 3-amino-2,2-dimethylpropanoate; A solution of ethyl 2-cyano-2- methylpropanoate (12 g, 85 mmol) in 1% ammonia in ethanol (200 mL) was hydrogenated with 5% rhodium on alumina (3 g) for 20 h, after which, another 3 g of rhodium on alumina was added and the mixture was again hydrogenated for 20 h. When the reaction was done, the reaction mixture was filtered through celite. The filtrate was concentrated and dried to give the product, ethyl 3-amino-2,2-dimethylpropanoate (12.4 g, quantitative yield) as light yellow liquid. 1H NMR (400 MHz, CHLOROFORM-^) δ 1.12 (s, 6 H) 1.20 (t, J=IA Hz, 3 H) 2.69 (s, 2 H) 4.10 (q, J=7.1 Hz, 2 H).
80%	With hydrogen In methanol; ethanol for 24h;	152 152A: Ethyl 3 -amino-2,2-dimethylpropanoate Raney nickel (1.214 g, 14.17 mmol) was rinsed with MeOH (2 mL) and added to 2-cyano-2-methylpropionic acid ethyl ester (2.066 mL, 14.17 mmol) in ethanol (50 mL). The reaction mixture was put on a Parr shaker under 50 psi H2 for 24 h. The reaction mixture was filtered and concentratedto yield a crude product. The crude product was dissolved in CH2C12 (90 mL) and washed with water (15 mL), brine (15 mL) and dried over Na2SO4. The mixture was filtered and concentrated in vacuo to yield 152A (1.65 g, 80% yield). ‘H NMR (400 MHz, CDC13) ö 4.16 (q, J=7.1 Hz, 2H), 2.76 (s, 2H), 1.28 (t, J7.1 Hz, 3H), 1.18 (s, 6H).
70%	With ammonium hydroxide; hydrogen In ethanol at 20℃; for 16h;	80 Example 80: ethyl 3-amino-2,2-dimethylpropanoater.t, 1 6 hY: 70%To a solution of ethyl 2-cyano-2-methylpropanoate (0.6 g, 4.2 mmol, 1.0 equiv) in 6 mL of ethanol/ammonium hydroxide (10:1) was added Ra/Ni (20%, 0.12 g). The resulting mixture was stirred under hydrogen at r.t. for 16 h. The catalyst was filtered off, and the filtrate was concentrated to give ethyl 3-amino-2,2-dimethylpropanoate (0.43 g, yield: 70%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 4.15 (q, 2H), 2.77 (s, 2H), 1.76 (s, 2H), 1.26 (t, 3H), 1.18 (s, 6H).

67%	With ammonia; hydrogen In methanol; ethanol at 45℃; for 11h;
	With hydrogen
	With platinum(IV) oxide; hydrogen In acetic acid
	With hydrogen In methanol at 18 - 25℃; for 3h;	10.B Step B 2The mixture of compound 2' (0.5 g, 3.54 mmol) and Ra-Ni (0.1 g) in MeOH was stirred at r.t. under H2 atmosphere for 3 hour. The reaction mixture was filtered and concentrated to give the crude product (484 mg) without further purification.
	With hydrogen In methanol at 18 - 25℃; for 3h;	10.B The mixture of compound V (0.5 g, 3.54 mmol) and Ra-Ni (0.1 g) in MeOH was stirred at r.t. under H2 atnosphere for 3 hour. The reaction mixture was filtered and concentrated to give the crude product (484 mg) without further purification
4.5 g	With hydrogen In ethanol at 20℃; for 20h;	38.a Ethyl 3-amino-2,2-dimethylpropanoate To a slurry of Raney-Ni (1.6 g, 50% in H20, rinsed 3 times with EtOH before use) in EtOH (78 mL) was added ethyl 2-cyano-2-methylpropanoate (5 g, 35 mmol). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 20 hours. The liquid was then carefully decanted into another flask and the metal was washed twice with EtOH. The combined EtOH solution was concentrated in vacuo to give the title compound in 4.5 g, which was used in the subsequent step without further purification. lH NMR (CDC13, 200 MHz): δ = 4.13 (q, 2H, J= 7.0 Hz), 2.74 (s, 2H), 1.26 (t, 3H, J= 7.0 Hz), 1.17 (s, 6H).
1.4 g	With hydrogen In methanol at 20℃; for 3h; Inert atmosphere;	III-18 Intermediate III-18. 5,5-dimethylpiperidine-2,4-dione Ethyl 2-cyano-2,2-dimethylacetate (2.0g, 14.18 mmol) was dissolved in methanol (20 ml) and Raney Nickel (0.4 g) was added. The system was purged with N2-gas and evacuated. The reaction assembly was made saturated with H2-gas and stirred at RT for 3 hours under hydrogen atmos- phere. After reaction was completed, the mixture was filtered through celite pad. The filtrate was collected and concentrated under reduced pressure. The yield of ethyl 3-amino-2,2-dimethylpropanoate was 1 .4 g.
	With nickel; decalin at 130 - 150℃; Hydrogenation;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2009/67547, 2009, A1 Location in patent: Page/Page column 207; 208
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/100166, 2016, A1 Location in patent: Page/Page column 110; 111
[3]Current Patent Assignee: BIOGEN IDEC INC. - WO2011/17561, 2011, A1 Location in patent: Page/Page column 61
[4]Maibaum, Jürgen; Stutz, Stefan; Göschke, Richard; Rigollier, Pascal; Yamaguchi, Yasuchika; Cumin, Frédéric; Rahuel, Joseph; Baum, Hans-Peter; Cohen, Nissim-Claude; Schnell, Christian R.; Fuhrer, Walter; Gruetter, Markus G.; Schilling, Walter; Wood, Jeanette M. [Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4832 - 4844]
[5]Fotouhi, Nader; Joshi, Pramod; Fry, David; Cook, Charles; Tilley, Jefferson W.; Kaplan, Gerry; Hanglow, Angela; Rowan, Karen; Schwinge, Virginia; Wolitzky, Barry [Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 11, p. 1171 - 1173]
[6]Location in patent: scheme or table Nair, Latha G.; Bogen, Stephane; Doll, Ronald J.; Shih; Njoroge, F. George [Tetrahedron Letters, 2010, vol. 51, # 9, p. 1276 - 1279]
[7]Current Patent Assignee: MERCK & CO INC - WO2011/103715, 2011, A1 Location in patent: Page/Page column 53
[8]Current Patent Assignee: MERCK & CO INC - WO2011/106276, 2011, A1 Location in patent: Page/Page column 52
[9]Current Patent Assignee: FIBROGEN, INC. - WO2013/134660, 2013, A1 Location in patent: Paragraph 0258
[10]Current Patent Assignee: ARANDA PHARMA - WO2014/191632, 2014, A1 Location in patent: Page/Page column 64
[11]Current Patent Assignee: MERCK KGAA - DE606349, 1933, C [Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 21, p. 622][Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 21, p. 622] Current Patent Assignee: MERCK & CO INC - US2370015, 1935, A Current Patent Assignee: MERCK KGAA - DE629054, 1934, C [Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 23, p. 584,588][Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 23, p. 584,588]

3
[ 1572-98-1 ]
[ 81891-82-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; ethanol at 0℃;
	With sulfuric acid
	Stage #1: 2-cyano-2-methyl-propionic acid ethyl ester With sulfuric acid; water In ethanol at 20℃; for 16h; Stage #2: With sodium hydrogencarbonate In ethanol; water	115.A Intermediate 115; 2-Methyl-2- [4- (4-trifluoromethyl-phenyl) oxazol-2-yl] -propan-1-ol; Step A; Cyano-dimethyl-acetic acid ethyl ester (3 g, 21.2 mmol) is dissolved in EtOH (5 mL) , then concentrated H2SO4 (20 mL) is added and the mixture is stirred at rt for 16 h. The reaction is poured into water (100 mL) and NaHCO3 is added portionwise to neutral pH. Then the mixture is extracted with EtOAc (3 x 60 mli) . The organic layers are combined and washed with brine, dried (MgSO4) , filtered and evaporated to afford 2 , 2-dimethyl-malonamic acid ethyl ester 113 as a clear oil. 1H-NMR (400MHz, CDCl3) 4.11 (q, J = 7.2 Hz, 2H), 1.38 (S, 6H) , 1.20 (t, J" = 7.2 Hz, 3H) .

Reference： [1]Lin; Li [Journal of the Chinese Chemical Society, 1938, vol. 6, p. 88][Chem.Abstr., 1941, p. 5096]
[2]Lin; Li [Journal of the Chinese Chemical Society, 1938, vol. 6, p. 88][Chem.Abstr., 1941, p. 5096]
[3]Current Patent Assignee: IRM LLC - WO2007/56366, 2007, A2 Location in patent: Page/Page column 74-75

4
[ 1572-98-1 ]
[ 26734-09-8 ]

Yield	Reaction Conditions	Operation in experiment
78.2%	With lithium aluminium tetrahydride In tetrahydrofuran for 48h; Heating;
77%	With lithium aluminium tetrahydride In tetrahydrofuran for 48h; Inert atmosphere; Reflux;
	With lithium aluminium tetrahydride In diethyl ether

	With lithium aluminium tetrahydride In tetrahydrofuran for 48h; Reflux;
12.7 g	With lithium aluminium tetrahydride In tetrahydrofuran for 1h; Reflux;

Reference： [1]Thompson, Hugh W.; Swistok, Joseph [Journal of Organic Chemistry, 1981, vol. 46, # 24, p. 4907 - 4911]
[2]Pignataro, Luca; Boghi, Michele; Civera, Monica; Carboni, Stefano; Piarulli, Umberto; Gennari, Cesare [Chemistry - A European Journal, 2012, vol. 18, # 5, p. 1383 - 1400]
[3]Higgins,R.H. et al. [Journal of Heterocyclic Chemistry, 1971, vol. 8, p. 961 - 966]
[4]He, Tian; Gao, Wen-Chao; Wang, Wei-Kun; Zhang, Chi [Advanced Synthesis and Catalysis, 2014, vol. 356, # 5, p. 1113 - 1118]
[5]Gvozdev; Shavrin; Nefedov [Russian Chemical Bulletin, 2014, vol. 63, # 2, p. 409 - 415][Izvestiya Akademii Nauk. Seriya Khimicheskaya, 2014, vol. 2, p. 409 - 415,7]

5
[ 1572-98-1 ]
[ 17969-52-7 ]

Yield	Reaction Conditions	Operation in experiment
14%	With diphenylphosphinodithioic acid In isopropyl alcohol Reflux;	308.A; 309.A Example 308 and Example 309; 2-[5-(2-Amino-4-pyrimidinyl)-4-(3-[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-2-methylpropanoic acid and 2-[5-(2-Amino-4-pyrimidinyl)-4-(3-[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-2-methylpropanamide; Step A: 3-Hydroxy-2,2-dimethylpropanethioamide; ethyl 2-cyano-2-methylpropanoate (2.5 g, 17.71 mmol) and diphenylphosphinodithioic acid (8.86 g, 35.4 mmol) in isopropanol (150 mL) were heated to reflux overnight, then cooled to ambient temperature. The mixture was transferred in a freezer for 50 minutes then filtered rapidly (white deposit produced during freezer storage was left behind). The filtrate was evaporated, residue dissolved in DCM (250 mL) and the solution washed sequentially with 100 mL each of water, 1N-NaOH and sat. aq. sodium bicarbonate. After drying (MgSO4), the solution was filtered and filtrate evaporated to give clear liquid which was flash chromatographed on silica gel to afford the title compound as a yellow liquid (0.43 g, 14%). 1H NMR (400 MHz, DMSO-d6) d ppm 9.73 (br s, 1H) 8.82 (br s, 1H) 3.96-4.15 (q, J=7.07 Hz, 2H) 1.40 (s, 6H) 1.16 (t, J=7.07 Hz, 3H), MS (ESI) 175.0 [M+H]+.
	With pyridine; hydrogen sulfide; triethylamine

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2009/298815, 2009, A1 Location in patent: Page/Page column 193
[2]Pechenyuk,V.A. et al. [Journal of Organic Chemistry USSR (English Translation), 1978, vol. 14, p. 688 - 690][Zhurnal Organicheskoi Khimii, 1978, vol. 14, p. 745 - 747]

6
[ 1572-98-1 ]
[ 64-17-5 ]
[ 103910-33-4 ]

Yield	Reaction Conditions	Operation in experiment
67%	With hydrogenchloride at 0℃;	General procedure for the preparation of carboximidates 3a-f*HCl General procedure: A solution of -cyanocarboxylate 2a-f (2 mol) in EtOH (200 mL) was cooled with an ice water bath, saturated with anhydrous HCl and the resulting mixture was left at 0C overnight. Then it was diluted with Et2O (1.5 L), the formed precipitate was filtered, and dried to constant weight at reduced pressure at rt to give the title compound 3a-f as colorless crystals.
39%	With hydrogenchloride In diethyl ether at 0℃; for 120h;

Reference： [1]Khomenko, Dmytro M.; Doroshchuk, Roman O.; Ivanova, Hanna V.; Zakharchenko, Borys V.; Raspertova, Ilona V.; Vaschenko, Oleksandr V.; Shova, Sergiu; Dobrydnev, Alexey V.; Moroz, Yurii S.; Grygorenko, Oleksandr O.; Lampeka, Rostyslav D. [Tetrahedron Letters, 2021, vol. 69]
[2]Chiba; Takahashi; Sakaki; Kaneko [Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 7, p. 3046 - 3049]

7
[ 1572-98-1 ]
[ 106544-20-1 ]
[ 121994-21-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	In N,N-dimethyl-formamide at 50℃; for 28h; Reaction under normal pressure, at 80 deg C in toluene. Investigation of other nitriles.;
75%	In N,N-dimethyl-formamide at 50℃; for 28h;

Reference： [1]Hermkens, Pedro H.H.; Maarseveen, Jan H. v.; Kruse, Chris G.; Scheeren, Hans W. [Tetrahedron, 1988, vol. 44, # 20, p. 6491 - 6504]
[2]Hermkens, Pedro H.H.; Maarseveen, Jan H. v.; Kruse, Chris G.; Scheeren, Hans W. [Tetrahedron, 1988, vol. 44, # 20, p. 6491 - 6504]

8
[ 109539-54-0 ]
[ 1572-98-1 ]
[ 22584-00-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 1.7% 2: 79%	With Perbenzoic acid; APC<C2Lys(C5N(1+))2C14>4; tri-n-butyl-tin hydride In dichloromethane; water at 10℃; dark;

Reference： [1]Murakami, Yukito; Hisaeda, Yoshio; Kikuchi, Jun-ichi; Ohno, Teruhisa; Suzuki, Masashi; et al. [Journal of the Chemical Society. Perkin transactions II, 1988, p. 1237 - 1246]

9
[ 109539-54-0 ]
[ 1572-98-1 ]
[ 22584-00-5 ]
[ 109539-56-2 ]

Yield	Reaction Conditions	Operation in experiment
1: 60% 2: 12%	With cobalt complex of 2,10-diethyl-3,9-dipropyl-1,4,8,11-tetraazaundeca-1,3,8,10-tetraene-1,11-diol electrolytic process;
1: 20% 2: 5%	With tetrabutylammonium tetrafluoroborate In N,N-dimethyl-formamide by electrolysis; Yields of byproduct given;
1: 5% 2: 20%	With tetrabutylammonium tetrafluoroborate In N,N-dimethyl-formamide by electrolysis;

32 % Chromat.	With tetrabutylammonium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 8h; electrolysis with Pt electrodes, in the dark; other catalysts;
	With 1H-imidazole; Co(III)<(C23C3)(DO)(DOH)pn>Br2>; tetrabutyl ammonium fluoride In N,N-dimethyl-formamide at 20℃; electrochemical reduction; Yield given. Yields of byproduct given;
20 % Chromat.	With tetrabutylammonium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 3h; electrolysis with Pt electrodes, in the dark; other catalysts; Title compound not separated from byproducts;
20 % Chromat.	With tetrabutylammonium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 3h; electrolysis with Pt electrodes, in the dark; other catalysts; Yield given. Title compound not separated from byproducts;
	With tetrabutylammonium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 8h; electrolysis with Pt electrodes, other catalysts and reaction time;
	With tetrabutyl ammonium fluoride In N,N-dimethyl-formamide at 20℃; for 20h; electrolysis with Pt electrodes, with or without CH₃COOH additive, irradiation, various time, and potential;

Reference： [1]Murakami, Yukito; Hisaeda, Yoshio; Fan, Sheng-Di; Matsuda, Yoshihisa [Chemistry Letters, 1988, # 5, p. 835 - 838]
[2]Murakami, Yukito; Hisaeda, Yoshio; Ozaki, Toshiaki; Matsuda, Yoshihisa [Journal of the Chemical Society. Chemical communications, 1989, # 16, p. 1094 - 1096]
[3]Murakami, Yukito; Hisaeda, Yoshio; Ozaki, Toshiaki; Matsuda, Yoshihisa [Journal of the Chemical Society. Chemical communications, 1989, # 16, p. 1094 - 1096]
[4]Murakami, Yukito; Hisaeda, Yoshio; Ozaki, Toshiaki; Matsuda, Yoshihisa [Chemistry Letters, 1988, p. 469 - 472]
[5]Murakami, Yukito; Hisaeda, Yoshio; Fan, Sheng-Di; Matsuda, Yoshihisa [Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 7, p. 2219 - 2228]
[6]Murakami, Yukito; Hisaeda, Yoshio; Ozaki, Toshiaki; Matsuda, Yoshihisa [Chemistry Letters, 1988, p. 469 - 472]
[7]Murakami, Yukito; Hisaeda, Yoshio; Ozaki, Toshiaki; Matsuda, Yoshihisa [Chemistry Letters, 1988, p. 469 - 472]
[8]Murakami, Yukito; Hisaeda, Yoshio; Ozaki, Toshiaki; Matsuda, Yoshihisa [Chemistry Letters, 1988, p. 469 - 472]
[9]Murakami, Yukito; Hisaeda, Yoshio; Ozaki, Toshiaki; Tashiro, Takako; Ohno, Teruhisa; et al. [Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 1, p. 311 - 324]

10
[ 105-56-6 ]
[ 74-88-4 ]
[ 1572-98-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: ethyl 2-cyanoacetate With sodium hydride In tetrahydrofuran at 20℃; Cooling with ice; Stage #2: methyl iodide In tetrahydrofuran at 20℃; for 3h;	79 Example 79: ethyl 2-cyano-2-methylpropanoateO CH3l (3eq.),NaH (4eq.) QNC^0^ NC>Aθ^° THF, r.t, 3 h /85%A solution of ethyl 2-cyanoacetate (3 g, 0.026 mol, 1.0 equiv) in tetrahydrofuran (80 rnL) was cooled at ice-salt bath, followed by the addition of sodium hydride (2.6 g, 0.104 mol, 4.0 equiv) in several portions. The suspension was stirred at r.t.. Then iodomethane (11 g, 0.078 mmol, 3.0 equiv) was added and the reaction mixture was stirred at r.t for 3 h before quenched with water. The mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4 and concentrated to obtain crude product ethyl 2-cyano-2-methylpropanoate (3.2 g, yield: 85%) as a dark green oil. 1H NMR (400 MHz, CDCl3) δ: All (q, 2H), 1.62 (s, 6H), 1.34 (t, 3H).
82%	With potassium carbonate In dimethyl sulfoxide at 0 - 20℃; for 3h;	70 Cyano-dimethylacetic acid ethyl ester (I-70) A 242 g (1.75 mol) portion of potassium carbonate was added to a dimethyl sulfoxide (200 ml) solution of 56.6 g (0.50 mol) of ethyl cyanoacetate, 109 ml (1.75 mol) of methyl iodide was added dropwise thereto spending 1 hour under ice-cooling, and then this was further stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was mixed with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The thus obtained residue was applied to a silica gel column chromatography, and 57.6 g (82%) of the title compound was obtained as a colorless oily substance from a n-hexane-ethyl acetate (9:1 v/v) eluate. 1H-NMR (CDCl3)δ: 1.33 (3H, t, J= 7.2 Hz), 1.61 (6H, s), 4.27 (2H, q, J= 7.2 Hz).
75%	With potassium carbonate In acetone Reflux;

68.71%	Stage #1: ethyl 2-cyanoacetate With potassium carbonate In water; N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: methyl iodide In water; N,N-dimethyl-formamide at 20℃;	26.1 To a suspension of ethyl 2-cyanoacetate (20 g, 176.82 mmol) in DMF (200 mL) andwater (10 mL) was added K2C03 (101.83 g, 442.07 mmol) in portions at 0 °C. Then the reactionmixture was stirred at this temperature for 30 min, iodomethane (62.75 g, 442.1 mmol) wasadded dropwise to the mixture for 1 h and the resulting mixture was stirred at rt for overnight.The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (500 mL x3). The combined organic layers were washed with brine (600mL), dried over Na2S04, filteredand concentrated in vacuo. The residue was purified by flash silica gel column chromatography(PE/EtOAc (v/v) = 10/1) to give the title product as light yellow oil (17.15 g, yield 68.71 %).1H NMR (600 MHz, CDCb) 8 (ppm): 4.24 (q, J = 7.1 Hz, 2H), 1.58 (s, 6H), 1.30 (t, J = 7.2 Hz,3H).
68.71%	Stage #1: ethyl 2-cyanoacetate With potassium carbonate In water; N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: methyl iodide In water; N,N-dimethyl-formamide at 20℃;	26.1 step 1) ethyl 2-cyano-2-methylpropionate 2-cyanoacetic acidEthyl ester (20 g, 176.82 mmol) was suspended in a mixed solvent of DMF (200 mL) and water (10 mL)0 ° C,To this was added K2CO3 (101.83 g, 442.07 mmol) in portions.The reaction was stirred at this temperature for 30 minutes,then,To this was added methyl iodide (62.75 g, 442.1 mmol)1 hour drop finished,The resulting mixture was stirred overnight at room temperature.After the reaction,Add water (500mL) quenching reaction,And extracted with EtOAc (500 mL x 3).The combined organic phases were washed with saturated brine (600 mL)Dried over anhydrous sodium sulfate,Filtered and concentrated under reduced pressure.The resulting residue was purified by flash silica gel column chromatography (PE / EtOAc (v / v) = 10/1)The title compound was obtained as a pale yellow oil (17.15 g, yield 68.71%).
64.1%	With sodium hydride In tetrahydrofuran at 25℃;
61%	With potassium carbonate In acetone at 0 - 20℃; for 2h;
49%	With sodium hydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
	With potassium hydroxide In ethanol at 0℃; for 4h;
	With sodium hydride 1.) THF, -10 deg C, 10 min, 2.) THF, from -10 deg C to 20 deg C, 2 h 45 min; Yield given. Multistep reaction;
	With sodium hydride In tetrahydrofuran at 0℃;
	In tetrahydrofuran	27.a (a) (a) Ethyl 2,2-dimethylcyanoacetate A solution of ethyl cyanoacetate (20 g; 0.17 moles) in tetrahydrofuran (350 mL) was cooled to -10° C. followed by the addition of sodium hydride (7.25 g; 0.17 moles) in several portions. The suspension was stirred for 10 minutes at -10° C. before adding iodomethane (23.3 g; 0.17 moles). The ice bath was removed and the solution gradually warmed to 20° C. for over 45 minutes. The solution was then recooled to -10° C. and a second equivalent of sodium hydride (7.25 g; 0.17 moles) was added, again, in small portions. Soon after, iodomethane (23.3 g; 0.17 moles) was added, the ice bath removed, and the solution stirred at room temperature for 2 hours before being quenched with H2 O. The product was extracted with ethyl ether (500 mL) and washed with brine, dried over MgSO4, and the solution concentrated in vacuo, leaving a crude product that was purified by distillation. Yield: 16.9 g, b.p. 82°-85° C.; 15 mm Hg.
	With potassium carbonate In N,N-dimethyl-formamide at 20 - 30℃;	2 COMPARATIVE EXAMPLE 2Preparation of ethyl 2-cyano-2-methylpropanoateMethyl iodide (49,6 ml, 50 % access) was slowly added into the stirring mixture of ethyl cyanoacetate (30 g), potassium carbonate (73,4 g) in 80 ml of DMF keeping temperature below 30 0C. The mixture was stirred for further 20 h at room temperature, salts were filtered, washed by fresh MTBE. The filtered solution was washed by 120 ml of 0.1 N HCI, 120 ml of brine and evaporated to give 35 g of solid title product which contained 8 area % of monomethylated impurity measured by GC.
16.9 g	With sodium hydride In tetrahydrofuran at -10 - 20℃;
	Stage #1: ethyl 2-cyanoacetate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at 0 - 25℃;	10.A Step ATo a solution of NaH (31 g, 0.795 mol) in THF (200 mL), was added compound 1' (30 g, 0.265 mol) was added dropwise at 0°C under N2. The solution was stirred at this temperature for 30 minutes, then iodomethane (94.11 g, 0.663 mol) was added into the mixture and stirring was continued as the solution warmed slowly to room temperature overnight. Water (300 mL) was added and the aqueous layer was extracted with EA (200 mL) twice. The organic layer was washed with an aqueous solution of NaC1 (150 mL) and dried over Na2S04. The organic layer was concentrated under reduced pressure to give compound 2' (32.1 g) as slight yellow liquid.
	With potassium carbonate In N,N-dimethyl-formamide at 0 - 5℃; for 9h;	38 376 grams of methyl iodide was added to a mixture of 244 grams of potassium carbonate, 300 ml of Ν,Ν-dimethylformamide and cooled the reaction mixture to 0-5°C.100 grams of ethyl 2-cyano acetate compound of formula-24 was added to the reaction mixture at 0-5°C and stirred for 9 hours at the same temperature. After completion of the reaction, the reaction mixture was filtered and washed with methyl tert-butyl ether. Aqueous hydrochloric acid was added to the obtained filtrate. Separated the both organic and aqueous layers. Extracted the aqueous layer with methyl tert-butyl ether. Both the organic layers were combined, washed with brine solution and followed by sodium thio sulphate solution. Distilled off the solvent completely from organic layer under reduced pressure to get the title compound. Yield: 106 grams.
	Stage #1: ethyl 2-cyanoacetate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at 0 - 25℃;	10.A To a solution of NaH (31 g, 0.795 mol) in THF (200 mL), was added compound 1' (30 g, 0.265 mol) was added dropwise at 0°C under N2. The solution was stirred at this temperature for 30 minutes, then iodomethane (94.11 g, 0.663 mol) was added into the mixture and stirring was continued as the solution warmed slowly to room temperature overnight. Water (300 mL) was added and the aqueous layer was extracted with EA (200 mL) twice. The organic layer was washed with an aqueous solution of NaCl ( 50 mL) and dried over Na2SC> . The organic layer was concentrated under reduced pressure to give compound V (32.1 g) as slight yellow liquid.
2.5 g	Stage #1: ethyl 2-cyanoacetate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: methyl iodide In tetrahydrofuran; mineral oil at 0 - 20℃;	III-18 Intermediate III-18. 5,5-dimethylpiperidine-2,4-dione Ethyl 2-cyanoacetate (4.7 ml, 44.24 mmol) was added slowly to the stirred mixture of 60% NaH (5.3 g, 132 mmol) in dry THF at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. Methyl iodide (6.89 ml, 1 10.61 mmol) was slowly added at 0° and the reaction mixture was allowed to warm up to RT. Stirring was continued at RT for 18 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. Organic phase was separated, dried over sodium sulphate and concentrated under reduced pressure. The yield of ethyl 2-cyano-2,2-dimethylacetate was 2.5 g.
	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; Cooling with ice;
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 0 - 20℃; for 20h; Inert atmosphere;

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2011/17561, 2011, A1 Location in patent: Page/Page column 61
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1717238, 2006, A1 Location in patent: Page/Page column 60-61
[3]Gvozdev; Shavrin; Nefedov [Russian Chemical Bulletin, 2014, vol. 63, # 2, p. 409 - 415][Izvestiya Akademii Nauk. Seriya Khimicheskaya, 2014, vol. 2, p. 409 - 415,7]
[4]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2017/48675, 2017, A1 Location in patent: Paragraph 0433
[5]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN106478651, 2017, A Location in patent: Paragraph 0897; 0898; 0899
[6]Thompson, Hugh W.; Swistok, Joseph [Journal of Organic Chemistry, 1981, vol. 46, # 24, p. 4907 - 4911]
[7]He, Tian; Gao, Wen-Chao; Wang, Wei-Kun; Zhang, Chi [Advanced Synthesis and Catalysis, 2014, vol. 356, # 5, p. 1113 - 1118]
[8]Pignataro, Luca; Boghi, Michele; Civera, Monica; Carboni, Stefano; Piarulli, Umberto; Gennari, Cesare [Chemistry - A European Journal, 2012, vol. 18, # 5, p. 1383 - 1400]
[9]Chiba; Takahashi; Sakaki; Kaneko [Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 7, p. 3046 - 3049]
[10]O'Brien; Sliskovic; Picard; Lee; Purchase II; Roth; White; Anderson; Mueller; Bocan; Bousley; Hamelehle; Homan; Lee; Krause; Reindel; Stanfield; Turluck [Journal of Medicinal Chemistry, 1996, vol. 39, # 12, p. 2354 - 2366]
[11]Fotouhi, Nader; Joshi, Pramod; Fry, David; Cook, Charles; Tilley, Jefferson W.; Kaplan, Gerry; Hanglow, Angela; Rowan, Karen; Schwinge, Virginia; Wolitzky, Barry [Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 11, p. 1171 - 1173]
[12]Current Patent Assignee: PFIZER INC - US5366987, 1994, A
[13]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2010/112482, 2010, A1 Location in patent: Page/Page column 29
[14]Current Patent Assignee: PFIZER INC - EP1203767, 2002, A1 Location in patent: Example 27
[15]Current Patent Assignee: MERCK & CO INC - WO2011/103715, 2011, A1 Location in patent: Page/Page column 52
[16]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/148392, 2011, A1 Location in patent: Page/Page column 63-64
[17]Current Patent Assignee: MERCK & CO INC - WO2011/106276, 2011, A1 Location in patent: Page/Page column 52
[18]Current Patent Assignee: ARANDA PHARMA - WO2014/191632, 2014, A1 Location in patent: Page/Page column 64
[19]Patrick, Donald A.; Gillespie, J. Robert; McQueen, Joshua; Hulverson, Matthew A.; Ranade, Ranae M.; Creason, Sharon A.; Herbst, Zackary M.; Gelb, Michael H.; Buckner, Frederick S.; Tidwell, Richard R. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 957 - 971]
[20]Shang, Rui; Huang, Zheng; Xiao, Xiao; Lu, Xi; Fu, Yao; Liu, Lei [Advanced synthesis and catalysis, 2012, vol. 354, # 13, p. 2465 - 2472,8]

11
[ 1572-99-2 ]
[ 74-88-4 ]
[ 1572-98-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	With sodium hydride In N,N-dimethyl-formamide; benzene Ambient temperature;
	Stage #1: ethyl 2-cyanopropionate With sodium hydride In N,N-dimethyl-formamide for 0.25h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 0 - 20℃;	85 Compound 85: 4-(9-Cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4,5-b][l,4]diazepin-2-ylamino)-3-methoxybenzoic acid; [0400] Ethyl l-cyano-l-methylpropanoate; To a stirred suspension of 4.2 g of NaH(60% dispersion in oil, 105 mmol) in 100 rnL of dry DMF was added a solution of ethyl 2- cyanopropinate (12.7 g, 100 mmol). The mixture was stirred for 15 min., then cooled to 0 0C, methyl iodide (6.5 mL, 105 mmol) was added drop wise. The reaction mixture was stirred at 0 0C for 3 h and then rt. over night. It was then quenched with saturated ammonium chloride, diluted to ethyl acetate. The organic layer was washed with brine and water, dried over Na2SO4 and concentrated in vacuo to obtain ethyl 2-cyano-2- methylpropanoate (14 g, quantitative yield) as light yellow liquid. 1H NMR (400 MHz, CHLOROFORM-J) δ 1.32 (t, J=7.1 Hz, 3 H) 1.60 (s, 6 H) 4.26 (q, J=7.2 Hz, 2 H).

Reference： [1]Murakami, Yukito; Hisaeda, Yoshio; Ozaki, Toshiaki; Tashiro, Takako; Ohno, Teruhisa; et al. [Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 1, p. 311 - 324]
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2009/67547, 2009, A1 Location in patent: Page/Page column 207-208

12
[ 1572-98-1 ]
[ 149476-35-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With trimethylsilylazide; di(n-butyl)tin oxide In toluene Inert atmosphere;
55%	With tri-n-butyltin azide In 1,4-dioxane Heating;

Reference： [1]Location in patent: scheme or table Kazmierski, Wieslaw M.; Anderson, Don L.; Aquino, Christopher; Chauder, Brian A.; Duan, Maosheng; Ferris, Robert; Kenakin, Terrence; Koble, Cecilia S.; Lang, Dan G.; Mcintyre, Maggie S; Peckham, Jennifer; Watson, Christian; Wheelan, Pat; Spaltenstein, Andrew; Wire, Mary B.; Svolto, Angilique; Youngman, Michael [Journal of Medicinal Chemistry, 2011, vol. 54, # 11, p. 3756 - 3767]
[2]O'Brien; Sliskovic; Picard; Lee; Purchase II; Roth; White; Anderson; Mueller; Bocan; Bousley; Hamelehle; Homan; Lee; Krause; Reindel; Stanfield; Turluck [Journal of Medicinal Chemistry, 1996, vol. 39, # 12, p. 2354 - 2366]

13
[ 1572-98-1 ]
[ 925-90-6 ]
ethyl 2-(1-aminocyclopropyl)-2-methylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	Stage #1: 2-cyano-2-methyl-propionic acid ethyl ester With titanium(IV) isopropylate In diethyl ether at 20℃; for 0.166667h; Inert atmosphere; Stage #2: ethylmagnesium bromide In diethyl ether at -5 - 0℃; for 1.08333h;	Synthesis of fragment C3: ethyl 2-(1-aminocvclopropyl)-2,2-dimethylpropanoate Under argon, to a solution of ethyl 2-cyano-2-methylpropionate (CAS number [1572-98-1], 2 g, 13.88 mmol) in Et20 (48 mL) was added titanium (IV) isopropoxide (4.63 g, 15.97 mmol). The reaction mixture was stirred 10 min at RT then cooled at -5°C. A solution of ethylmagnesium bromide 3M in Et20 (9.72 mL, 29.16 mmol) was added dropwise at -5°C-0°C in 25 min, the reaction mixture was then stirred 40 min without the cooling bath. At this time, a TLC showed than the reaction was complete. The reaction medium was cooled at 0°C and boron trifluoride diethyl etherate (3M in Et20, 3.6 mL, 29.16 mmol) was added dropwise at 0°C. The reaction mixture was stirred 30 min without the cooling bath. After this time, 1 N HCI was added at 0°C until pH 1-2 (8 mL) then 2N NaOH until pH 8 (28 mL), the reaction mixure was extracted with EtOAc (3 x 150 mL). The combined organic phases were dried over MgS04, filtered and concentrated in vacuo to give 2.4 g of a crude yellow oil that was purified by flash chromatography on 70 g of silica gel (gradient elution DCM/MeOH) to give 915 mg of fragment C3 as a pale yellow oil (39%). RMN 1H (400 MHz, δ in ppm, CDC3-d1): 0.52 (m, 2 H); 0.70 (m, 2 H); 1.1 1 (s, 6 H); 1.27 (t, J = 7.2 Hz, 3 H); 1.64 (broad s, 2 H); 4.18 (q, J = 7.2 Hz, 2 H).
35%	Stage #1: 2-cyano-2-methyl-propionic acid ethyl ester; ethylmagnesium bromide With titanium(IV) isopropylate In diethyl ether at 20℃; Stage #2: With boron trifluoride diethyl etherate In diethyl ether at 20℃;

Reference： [1]Current Patent Assignee: SANOFI - WO2017/76998, 2017, A1 Location in patent: Page/Page column 162-163
[2]Bertus, Philippe; Szymoniak, Jan [Synlett, 2003, # 2, p. 265 - 267]

14
[ 1572-98-1 ]
[ 180181-02-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1171 - 1173

15
[ 1572-98-1 ]
[ 149476-37-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 55 percent / tri-n-butyltin azide / dioxane / Heating 2: 59 percent / Et₃N / acetonitrile / 16 h / Heating 3: 69 percent / NaOH / ethanol / 16 h / Ambient temperature

Reference： [1]O'Brien; Sliskovic; Picard; Lee; Purchase II; Roth; White; Anderson; Mueller; Bocan; Bousley; Hamelehle; Homan; Lee; Krause; Reindel; Stanfield; Turluck [Journal of Medicinal Chemistry, 1996, vol. 39, # 12, p. 2354 - 2366]

16
[ 1572-98-1 ]
2-(1-Dodecyl-1H-tetrazol-5-yl)-2-methyl-propionic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 55 percent / tri-n-butyltin azide / dioxane / Heating 2: Et₃N / acetonitrile / 16 h / Heating

17
[ 1572-98-1 ]
[ 149476-36-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 55 percent / tri-n-butyltin azide / dioxane / Heating 2: 59 percent / Et₃N / acetonitrile / 16 h / Heating

18
[ 1572-98-1 ]
2-dodecyl-α,α'-dimethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 55 percent / tri-n-butyltin azide / dioxane / Heating 2: 59 percent / Et₃N / acetonitrile / 16 h / Heating 3: 69 percent / NaOH / ethanol / 16 h / Ambient temperature 4: 1.) carbonyldiimidazole / 1.) THF, RT, 1 h, 2.) THF, RT, 5 d

19
[ 1572-99-2 ]
[ 1572-98-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 68 percent / NaH / dimethylformamide; benzene / 2 h / Ambient temperature 2: TBAF / 1ester>ClO₄ / dimethylformamide / 20 h / 20 °C / electrolysis with Pt electrodes, with or without CH₃COOH additive, irradiation, various time, and potential

Reference： [1]Murakami, Yukito; Hisaeda, Yoshio; Ozaki, Toshiaki; Tashiro, Takako; Ohno, Teruhisa; et al. [Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 1, p. 311 - 324]

20
[ 105-56-6 ]
[ 1572-98-1 ]

Yield	Reaction Conditions	Operation in experiment
86.7%	With acetic acid; dimethyl sulfate In tetrahydrofuran; water	R.1 Synthesis of Ethyl 2,2-dimethylcyanoacetate REFERENCE EXAMPLE 1 Synthesis of Ethyl 2,2-dimethylcyanoacetate In a 2 L four-necked flask, ethyl cyanoacetate (250.0 g, 2.210 mol) and dimethyl sulfate (613.3 g, 4.862 mol) were simultaneously added dropwise to a solution of 60% sodium hydride (203.3 g, NaH=5.083 mol) in THF (1050 mL) at 35-45° C. over 4 hr 55 min. After the completion of the reaction, the reaction mixture was added to an aqueous acetic acid solution containing acetic acid (79.7 g, 1.3 mol) and water (545 mL), and the mixture was maintained at 65-70° C. for 2 hr to decompose remaining dimethyl sulfate. The reaction mixture was cooled to room temperature and adjusted to pH 6.80-7.50 with 20.5% NaOH (172.6 g). The THF layer was separated and THF was evaporated under somewhat reduced pressure (20-26.6 kPa) and then distilled under reduced pressure of 1.3-1.6 kPa. As a result, ethyl 2,2-dimethylcyanoacetate (270.4 g) was obtained as a fraction at 62-69° C. The yield was 86.7% relative to ethyl cyanoacetate.

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2003/144533, 2003, A1

21
heptane-THF [ No CAS ]
[ 540-88-5 ]
[ 1572-98-1 ]
[ 507468-86-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; lithium diisopropyl amide In tetrahydrofuran	1 Synthesis of tert-butyl 4-cyano-4-methyl-3-oxopentanoate EXAMPLE 1 Synthesis of tert-butyl 4-cyano-4-methyl-3-oxopentanoate In a 500 mL four-necked flask under a nitrogen atmosphere, were charged dry THF (150 mL), ethyl 2,2-dimethylcyanoacetate (141 g, 1.0 mol) and tert-butyl acetate (141.5 g, 1.05 mol), and the mixture was cooled to -70° C. Thereto was dropwise added 2 M lithium diisopropylamide (1.00 mol)/heptane-THF solution (500 mL) over 6 hr while maintaining the mixture at -80° C. to -60° C. After the completion of the dropwise addition, the reaction mixture was stirred at the same temperature for about 1 hr. The reaction mixture was warmed to room temperature (10-30° C.) and 2 M aqueous hydrochloric acid solution (608 g) was added dropwise thereto to adjust the pH to 7-7.5. By partitioning, the organic layer was obtained, which was concentrated under reduced pressure to give tert-butyl 4-cyano-4-methyl-3-oxopentanoate as an orange-brown oil (211 g). The yield was 100% relative to ethyl 2,2-dimethylcyanoacetate.

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2003/144533, 2003, A1

22
[ 1572-98-1 ]
[ 20487-40-5 ]
[ 507468-94-2 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; magnesium sulfate; acetic acid; diisopropylamine In tetrahydrofuran; toluene	12 Synthesis of tert-butyl 4-cyano-2,4-dimethyl-3-oxopentanoate EXAMPLE 12 Synthesis of tert-butyl 4-cyano-2,4-dimethyl-3-oxopentanoate A mixed solution of tert-butyl propionate (2.60 g, 20 mmol) and ethyl 2,2-dimethylcyanoacetate (2.82 g, 20 mmol) in dry THF (50 mL) was cooled to -70° C. and LDA (22 mmol) was dropwise added to this solution over 1 hr in such a manner that the internal temperature does not exceed -65° C. As the LDA, used was one prepared by diluting diisopropylamine (3.08 mL, 22 mmol) with dry THF (50 mL), cooling the solution to -50° C., dropwise adding n-BuLi (15% hexane solution) (9.365 g, 22 mmol), gradually raising the temperature to 0° C. and stirring for 30 min. After dropwise addition of LDA, the mixture was stirred at -70° C. to -65° C. for 1 hr, after which it was gradually warmed to 0° C. over 0.5 hr. 1N Aqueous acetic acid solution (53 mL) was added to adjust pH to around 7 and the mixture was further stirred for 30 min. The mixture was heated to 23° C. and toluene (50 mL) was added and stirred for 10 min. Partitioning gave an organic layer. This organic layer was washed with saturated brine (50 mL) and anhydrous magnesium sulfate (5 g) was added for drying. Magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to give tert-butyl 4-cyano-2,4-dimethyl-3-oxopentanoate (4.17 g, 18.51 mmol, yield: 92.5%). 1H-NMR(CDCl3)(δppm): 1.39-1.41 (d, J=17 Hz, 3H), 1.47 (s, 9H), 1.51 (s, 3H), 1.59(s, 3H), 4.05-4.10 (q, J=17 Hz, 1H).

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2003/144533, 2003, A1

23
[ 17846-68-3 ]
[ 1572-98-1 ]
[ 149476-35-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In 1,4-dioxane; diethyl ether	27.b (b) (b) α,α'-Dimethyltetrazole-5-acetic acid, ethyl ester Ethyl-2,2-dimethylcyanoacetate (a) (11.6 g; 0.082 moles) was dissolved in dioxane (240 mL) and treated with tri-n-butyltin azide (76.3 g; 0.23 moles) in one portion. The solution was refluxed for overnight, cooled to room temperature, and then concentrated in vacuo. The resulting liquid was dissolved in ethyl ether (500 mL) and treated with gaseous HCl continuously for 15 minutes. The ether was concentrated in vacuo, leaving a viscous liquid which gradually solidified on standing. Yield: 8.4 g. 1 H NMR (CDCl3) δ12.2 (bs, 1H), 4.2 (q, 2H), 1.8 (s, 6H), 1.3 (5, 3H) ppm.

Reference： [1]Current Patent Assignee: PFIZER INC - US5366987, 1994, A

24
[ 1572-98-1 ]
[ 19295-57-9 ]

Yield	Reaction Conditions	Operation in experiment
97%		1) 3-hydroxy-2,2-dimethylpropanenitrile To a mixture of ethyl 2-cyano-2-methylpropionate (5.0 g, 35.4 mmol), tetrahydrofuran (40 ml) and water (100 ml), sodium borohydride (4.47 g, 106 mmol) was slowly added, and the mixture was stirred at room temperature for 3 hr. 6N hydrochloric acid was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, passed through a small amount of silica gel and concentrated under reduced pressure to give the title compound (3.4 g, yield 97%) as an oil. 1H-NMR (CDCl3): delta 1.36 (6H, s), 3.58 (2H, s).
97%		To a mixture of ethyl 2-cyano-2-methylpropionate (5.0 g, 35.4 mmol), tetrahydrofuran (40 ml) and water (100 ml), sodium borohydride (4.47 g, 106 mmol) was slowly added, and the mixture was stirred at room temperature for 3 hr. 6N hydrochloric acid was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, passed through a small amount of silica gel and concentrated under reduced pressure to give the title compound (3.4 g, yield 97%) as an oil.
63%		Under an atmosphere of nitrogen, a tetrahydrofuran (200 ml) solution of 28.2 g (0.20 mol) of cyano-dimethylacetic acid ethyl ester (1-70) was added dropwise to a tetrahydrofuran (500 ml) solution of 4.8 g (0.22 mol) of lithium borohydride spending 30 minutes, and then the mixture was stirred overnight at room temperature. By adding 6 N hydrochloric acid to the reaction solution, separation of layers was effected, the aqueous layer was extracted with ethyl acetate, combined with the first organic layer, washed with brine and then dried over magnesium sulfate. The solvent was evaporated, ether was added to the resulting residue, the insoluble material was removed by filtration, and then the solvent of the filtrate was evaporated. The thus obtained residue was applied to a silica gel column chromatography, and 12.5 g (63%) of the title compound was obtained as a colorless oily substance from a n-hexane-ethyl acetate (2:1 v/v) eluate. 1H-NMR (CDCl3)delta: 1.36 (6H, s), 2.26 (1H, brs), 3.58 (2H, s).

55.09%	With sodium tetrahydroborate; In methanol; at 0 - 20℃;	To a solution of ethyl 2-cyano-2-methylpropanoate (10.34 g, 73.25 mmol) in methanol(200 mL) were added NaBH4 (5.54 g, 146 mmol) in portions at 0 C. Then the mixture wasstirred at room temperature overnight. The mixture was adjusted to pH = 7~8 with saturatedNH4Cl aqueous solution, and then extracted with EtOAc (100mL x 3). The combined organiclayers were washed with brine (150mL), dried over Na2S04, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =20/1 to 10/1)to give the title compound as colorless oil (4.0 g, yield 55.09%).1HNMR (400 MHz, CDCb) 8 (ppm): 3.44 (d, J= 6.3 Hz, 2H), 1.23 (s, 6H).
55.09%	With methanol; sodium tetrahydroborate; at 20℃;	0 C,To 2-cyano-2-methylpropionic acidEthyl ester (10.34 g, 73.25 mmol)In methanol (200 mL) was added NaBH4 (5.54 g, 146 mmol) in portions.The reaction was stirred overnight at room temperature.After the reaction,The reaction solution was adjusted to pH = 7 to 8 with saturated aqueous ammonium chloride solution,Then extracted with EtOAc (100 mL x 3).The combined organic phases were washed with saturated brine (150 mL)Dried over anhydrous sodium sulfate,Filtered and concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1 to 10/1)The title compound was obtained as a colorless oil (4.0 g, yield 55.09%).
		To a solution of cyano-dimethyl-acetic acid ethyl ester (7.00 g, 49.6 mmol, 1.0 equiv.) which was prepared as described in the reference (P. M. O'Brien et al., J. Med. Chem. 1996, 39, 2354-2366) in 1,2-dimethoxyethane/MeOH (10/1, 100 mL) was added NaBH4 (3.77 g, 99.2 mmol, 2.0 equiv.) slowly at 0 C. After being stirred for 16 h at 25 C., the reaction was quenched (saturated aqueous NH4Cl) cautiously and the resulting solution was stirred at 25 C. for additional 1 h. The reaction mixture was then diluted (EtOAc) and washed (1×H2O and 1×brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to provide the product as a colorless liquid.
		Preparation No.6: 3-Methoxy-2,2-dimethylpropylamine HCl; To a mixture of sodium tetrahydroborate (7.4 g, 200 mmol) in EtOH (100 mL) at about 0 0C was added cyanodimethylacetic acid ethyl ester (TCI, 10.0 g, 70.8 mmol) in EtOH (100 mL) over about EPO <DP n="51"/>45 min. The mixture was allowed to warm to ambient temperature over about 30 min. After about 60 h, the solvents were removed in vacuo. The resulting material was treated with saturated aqueous NH4Cl (150 mL) and extracted using DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4 and concentrated to yield the crude 3-hydroxy-2,2-dimethylpropionitrile (8.61 g). A mixture of crude 3-hydroxy-2,2-dimethyl-propionitrile (1.0 g, 10 mmol) in DCM (40 mL) was treated with tetrafluoroboric acid (1.4 g, 10 mmol) followed by 2 M trimethylsilyldiazomethane in heptane (5.0 mL, 10 mmol) at about 0 0C over about 10 min. The mixture was treated with additional 2 M trimethylsilyldiazomethane in heptane (2 mL, 4.0 mmol) after about 20 min, followed by additions of 2 M trimethylsilyldiazomethane in heptane (1.3 mL, 2.6 mmol) and 2 M trimethylsilyldiazomethane in heptane (1.3 mL, 2.6 mmol) after about 20 min intervals sequentially. The mixture was allowed to stir at about 0 0C for about 50 min before it was poured slowly over water. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, dried over Na2SO4, and concentrated to yield the crude 3- methoxy-2,2-dimethylpropionitrile as a yellow oil (1.2 g). Into a Parr shaker vessel was added crude 3-methoxy-2,2-dimethylpropionitrile (1.0 g, 8.8 mmol), 33% aqueous ammonium hydroxide (75 mL), MeOH (10 mL), and 8.0 M Raney nickel in water (1 mL, 8.0 mmol). The materials were charged with hydrogen and shaken at ambient temperature. After about 16 h, the mixture was filtered over Celite and treated with 5 M sodium hydroxide in water (2 mL), di-tert- butyldicarbonate (2.3 g, 11 mmol), and EtOAc (75 mL). After about 5 h, the layers were separated and the aqueous layer was washed with DCM. The combined organic layers were washed with water then dried over Na2SO4 and concentrated in vacuo. The residue was purified via FCC using EtO Ac/heptane (1:4). The fractions containing product, as visualized on TLC with ninhydrin stain, were concentrated in vacuo to yield (3-methoxy-2,2-dimethylpropyl)-carbamic acid tert-butyl ester, which was treated with 1.25 M HCl in methanol (1 mL) at ambient temperature. After about 2 h, the mixture was concentrated in vacuo to give methoxy-2,2-dimethylpropylamine HCl: (0.090 g): 1H NMR (DMSO-d6, 400 MHz) 6 3.85-3.75 (2H), 3.26 (3H), 3.13 (2H), 2.65-2.70 (2H), 0.91 (6H); TLC (acetone/MeOH 95:5) Rf = 0.2.
1 g	With sodium tetrahydroborate; water; In tetrahydrofuran; at 20℃; for 6h;	Description 933-llydroxy-2,2-dimethylpropanenitrile (D93)To a mixture of ethyl 2-cyano-2-methylpropanoate (2.5 g) in THF (20 mL) and water (50 mL) was added NaBH4 (3.35 g) portionwise. After addition the mixture was stirred at RT for 6 hours. Hydrochloric acid (6 M) was added to quench the reaction mixture, and then extracted with EtOAc(50 mL). The extract was washed with water (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (1 g). 1H NMR (400 MHz, MeOD-d4): 5.45 (s, 1H), 3.36 (s, 2H), 1.21 (s, 6H).Description 94

Reference： [1]Patent: US2009/156582,2009,A1 .Location in patent: Page/Page column 35
[2]Patent: EP1847531,2007,A1 .Location in patent: Page/Page column 51
[3]Patent: EP1717238,2006,A1 .Location in patent: Page/Page column 61
[4]Patent: WO2017/48675,2017,A1 .Location in patent: Paragraph 0434
[5]Patent: CN106478651,2017,A .Location in patent: Paragraph 0900; 0901; 0902
[6]Patent: US2007/299111,2007,A1 .Location in patent: Page/Page column 33
[7]Patent: WO2007/28051,2007,A2 .Location in patent: Page/Page column 49-50
[8]Patent: WO2015/180612,2015,A1 .Location in patent: Page/Page column 68

25
[ 1572-98-1 ]
[ 64-17-5 ]
[ 72291-30-6 ]
C₇H₁₃NO₃*ClH [ No CAS ]
[ 863399-80-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In tetrahydrofuran; diethyl ether; at -10℃; for 6h;	At -10C, hydrogen chloride gas was bubbled into an ethanol (50 ml) solution of 8.00 g of the mixture of cyano-dimethylacetic acid ethyl ester and cyano-dimethylacetic acid methyl ester (I-69), while stirring for 6 hours. After concentration of the reaction solution, ether was added to the thus obtained residue and stirred for 30 minutes, and the precipitated crystals were collected by filtration and dried to obtain 8.2 g of the title compound as a colorless solid. This was directly used in the subsequent reaction.

Reference： [1]Patent: EP1717238,2006,A1 .Location in patent: Page/Page column 61

26
[ 1572-98-1 ]
[ 7486-91-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-cyano-2-methyl-propionic acid ethyl ester With hydrogen In ethanol for 48h; Stage #2: With lithium hexamethyldisilazane In diethyl ether at 0℃; for 2h;	78.a A 250 ml. Parr glass vessel is charged with Rh/AI2O3 (2.33 g, 1.13 mmol) and ethyl 2,2- dimethylcyanoacetate (2.0 g) dissolved in ethanol (90 ml_). The flask is evacuated and filled with hydrogen (50 psi) and the mixture is shaken under 50 psi of hydrogen. After 48 h, the mixture is filtered and concentrated in vacuo (50 Torr, 35 0C, 30 min) to give a crude mixture which is dissolved in anhydrous ether (60 ml_) under nitrogen and cooled to 0 0C. LHMDS (1.0M in THF, 10 ml_, 10 mmol) is added dropwise and the cooling bath is removed. After 2 h, the mixture is cooled to 0 0C and quenched with 1M aqueous sodium bisulfate and diluted with ether. The organic phase is washed with 1M aqueous sodium bisulfate and brine. The pH of the combined aqueous phase is adjusted to 14 with 4M aqueous sodium hydroxide and the aqueous phase is repeatedly extracted with dichloromethane. The dichloromethane phase is dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue which is purified by silica gel flash chromatography (ethyl acetate) to give 3,3-dimethyl-azetidin-2-one as a colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 1.34 (s, 6 H), 3.13 (s, 2 H).

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2009/156462, 2009, A2 Location in patent: Page/Page column 117-118

27
[ 74-87-3 ]
[ 105-56-6 ]
[ 1572-98-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 15 - 30℃;	3 EXAMPLE 3 (according to the invention)Preparation of ethyl 2-cyano-2-methylpropanoate (in DMF as the aprotic polar solvent)Methyl chloride was slowly added into the stirring mixture of ethyl cyanoacetate (1 13 g), potassium carbonate (303.6 g) in 500 ml of DMF at temperature 15 - 30 0C. Kinetics was followed by GC. After about 195 g of methyl chloride was added (approx. 5 h) there was still 23 % of monomethyl derivative. Stirring and adding methyl chloride (with reduced flow) at 15- 30 0C was continued until GC showed monomethyl derivative dropped below 0.1 % area (usually there was no more detectable monomethyl derivative). The total consumption of methyl chloride was 220 g.Reaction mixture was then bubbled by nitrogen, solid material was filtered and the filter cake was washed with 750 ml of MTBE. Filtrates were then washed with 400 ml of water. Water phase was again extracted with 250 ml of MTBE. The combined organic phase was washed twice with 250 ml of 5% NaCI and evaporated to obtain 108.0 g (85 %) of crude ethyl 2- cyano-2-methylpropanoate in the form of brown - yellow oil which was used in next step without purification.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2010/112482, 2010, A1 Location in patent: Page/Page column 28

28
[ 75-93-4 ]
[ 105-56-6 ]
[ 1572-98-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 10 - 35℃;	1 COMPARATIVE EXAMPLE 1Preparation of ethyl 2-cyano-2-methylpropanoateMixture of ethyl cyanoacetate (5.65 g), potassium carbonate (13.8 g) in 50 ml of DMF was cooled to 10 0C, and then 15.75 g of methyl sulphate was slowly added within 0.5 h while temperature was maintained below 35 0C. Stirring was continued for 18 h at room temperature and the resulting suspension was filtered, washed with 70 ml of MTBE. Combined filtrate were then washed with water (50 ml), water phase was again extracted with 30 ml of MTBE, organic phase was added to first crops of extracts and the combined fractions were finally washed twice with 30 ml of 5% NaCI and evaporated to obtain 5.2 g of product in a form of brown oil which showed 32.5% (GC, area) of monomethyl derivative and some amounts (6%) of unidentified impurities.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2010/112482, 2010, A1 Location in patent: Page/Page column 28

29
[ 105-56-6 ]
[ 74-88-4 ]
[ 1572-98-1 ]
[ 72291-30-6 ]

Yield	Reaction Conditions	Operation in experiment
		Under ice-cooling, 8.8 g (0.22 mol) of sodium hydride was added to an N,N-dimethylformamide (250 ml) solution of 11.3 g (0.10 mol) of ethyl cyanoacetate and stirred at the same temperature for 30 minutes. A tetrahydrofuran (15 ml) solution of 15.6 ml (0.25 mol) of methyl iodide was added dropwise thereto spending 45 minutes, and then this was stirred at room temperature for 71 hours. This was mixed with brine and extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and the solvent was evaporated. The thus obtained residue was applied to a silica gel column chromatography, and 8.27 g of the title compound was obtained as a colorless oily substance from a n-hexane-ethyl acetate (5:1 v/v) eluate. This was used in the subsequent reaction as such.

Reference： [1]Patent: EP1717238,2006,A1 .Location in patent: Page/Page column 60

30
[ 1572-98-1 ]
[ 1314974-56-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: hydrogen / Rh/Al₂O₃ / ethanol / 48 h / 2585.81 Torr 1.2: 2 h / 0 °C 2.1: potassium carbonate / water / 20 - 75 °C 3.1: thionyl chloride / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2009/156462, 2009, A2

31
[ 1572-98-1 ]
[ 1202551-88-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: hydrogen / Rh/Al₂O₃ / ethanol / 48 h / 2585.81 Torr 1.2: 2 h / 0 °C 2.1: potassium carbonate / water / 20 - 75 °C

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2009/156462, 2009, A2

32
[ 1572-98-1 ]
[ 1202549-88-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: hydrogen / Rh/Al₂O₃ / ethanol / 48 h / 2585.81 Torr 1.2: 2 h / 0 °C 2.1: potassium carbonate / water / 20 - 75 °C 3.1: thionyl chloride / dichloromethane / 20 °C 4.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 4.2: 1 h

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2009/156462, 2009, A2

33
[ 1572-98-1 ]
[ 851233-80-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium <i>tert</i>-butylate In ethanol; water Inert atmosphere; Heating;
92%	With potassium <i>tert</i>-butylate In ethanol; water at 60℃; for 0.5h; Schlenk technique; Inert atmosphere;
56%	With potassium <i>tert</i>-butylate In ethanol; water at 60℃; for 0.5h;	288 Synthesis of 288.4: To a stirred solution of 288.3 (3 g, 21.2 mmol) in EtOH (40 mL) and water (401 mg, 22.2 mmol) at RT was added a solution of potassium tert-butoxide (2.4 g, 21.2 mmol) in EtOH (20 mL) at 60 °C over a period of 30 minutes. After stirring for 2 h at 60 °C, the reaction mixture was concentrated under reduced pressure. The residue was triturated with a mixture of diethyl ether and EtOH to afford 288.4 (1.8 g, 56%) as a solid. (1053) NMR (500 MHz, DMSO-rie): 1.29 (s, 6H).

39.4%	With potassium <i>tert</i>-butylate In ethanol at 20℃; for 2h;	1.1 (1) Synthesis of Intermediate 1 Add ethyl 2-cyano-2-methylpropionate (17.8g, 126mmol) and ethanol (EtOH, 125mL) into a 500mL round bottom flask,After stirring to dissolve, potassium tert-butoxide (tBuOK, 14.1g, 126mmol) was added dropwise to it at room temperatureethanol solution (125mL),After the dropwise addition is completed, keep it at this temperature for 2 hours, then spin off most of the ethanol, then add methyl tert-butyl ether (100mL), filter, collect the solid, and drain to obtain the product intermediate 1 (7.5g , The yield is 39.4%).
4.7 g	With potassium <i>tert</i>-butylate In ethanol; water at 60℃; for 4h;	34 Reference Production Example 34 5 mL of ethyl 2-cyano-2-methylpropionate, 3.85 g of potassium tert-butoxide,10 mL of water, and 20 mL of ethanol was stirred at 60 ° C. for 4 hours.The reaction mixture was cooled to room temperature and concentrated under reduced pressure.The precipitated solid was washed with MTBE to obtain 4.7 g of Intermediate 4-1 shown below.
4.7 g	With potassium <i>tert</i>-butylate; water In ethanol at 60℃; for 4h;	34 Reference Production Example 34 A mixture of 5 mL of ethyl 2-cyano-2-methylpropionate, 3.85 g of potassium tert-butoxide, 10 mL of water and 20 mL of ethanol was stirred at 60 ° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The precipitated solid is washed with MTBE andThere were obtained 4.7 g of Intermediate 4-1 shown below.
4.7 g	With potassium <i>tert</i>-butylate In ethanol; water at 60℃; for 4h;	34 Reference Preparation Example 34 A mixture of 5 mL of ethyl 2-cyano-2-methylpropionate, 3.85 g of potassium tert-butoxide, 10 mL of water, and 20 mL of ethanol was stirred at 60° C. for 4 hours. The reaction mixtures were cooled to room temperature, and concentrated under reduced pressure. The precipitated solids were washed with MTBE to obtain the intermediate compound 4-1 below 4.7 g. (1637) Intermediate compound 4-1: 1H-NMR (CDCl3) δ: 1.51 (6H, s).
	With potassium <i>tert</i>-butylate; water In ethanol at 20℃; Inert atmosphere;
	With potassium <i>tert</i>-butylate In ethanol; water at 60℃; for 3h;	1.2.41 Illustrative synthesis of Int 170 [0440] To a solution of ethyl 2-cyano-2-methyl-propanoate (CASNo. 1572-98-1; 25 g, 177 mmol, 1 eq.) in EtOH (354 mL) are added water (3.5 mL) and t-BuOK (CASNo. 865-47-4; 20 g, 177 mmol, 1 eq.). The reaction mixture is stirred at 60 °C for 3 h then concentrated under reduced pressure and the resulting solid is filtered and dried under vacuum for 18 h to afford the desired intermediate.

Reference： [1]Shang, Rui; Ji, Dong-Sheng; Chu, Ling; Fu, Yao; Liu, Lei [Angewandte Chemie - International Edition, 2011, vol. 50, # 19, p. 4470 - 4474]
[2]Feng, Yi-Si; Xu, Zhong-Qiu; Mao, Long; Zhang, Feng-Feng; Xu, Hua-Jian [Organic Letters, 2013, vol. 15, # 7, p. 1472 - 1475]
[3]Current Patent Assignee: FLATLEY DISCOVERY LAB LLC - WO2020/160010, 2020, A1 Location in patent: Page/Page column 217-218
[4]Current Patent Assignee: BEIJING SUMMER SPROUT TECHNOLOGY CO LTD - CN113321685, 2021, A Location in patent: Paragraph 0167; 0171-0173
[5]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - JP2018/76354, 2018, A Location in patent: Paragraph 0559
[6]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - JP2019/94335, 2019, A Location in patent: Paragraph 0325
[7]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2019/327970, 2019, A1 Location in patent: Paragraph 1636-1637
[8]Shang, Rui; Huang, Zheng; Xiao, Xiao; Lu, Xi; Fu, Yao; Liu, Lei [Advanced synthesis and catalysis, 2012, vol. 354, # 13, p. 2465 - 2472,8]
[9]Current Patent Assignee: GALAPAGOS - WO2020/239658, 2020, A1 Location in patent: Paragraph 0440

34
[ 1572-98-1 ]
[ 1073723-10-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: hydrogen / Ra-Ni / methanol / 3 h / 18 - 25 °C 2.1: triethylamine / ethanol / 3 h / 80 °C 3.1: acetic acid / methanol / 0.5 h / Reflux 3.2: 3 h / 0 - 25 °C 4.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 - 25 °C
	Multi-step reaction with 4 steps 1.1: hydrogen / Raney-Ni / methanol / 3 h / 18 - 25 °C 2.1: triethylamine / ethanol / 3 h / 80 °C 3.1: acetic acid / methanol / 0.5 h / Reflux 3.2: 0 - 25 °C 4.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 - 25 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2011/103715, 2011, A1
[2]Current Patent Assignee: MERCK & CO INC - WO2011/106276, 2011, A1

35
[ 1572-98-1 ]
[ 1195298-57-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrogen / Ra-Ni / methanol / 3 h / 18 - 25 °C 2: triethylamine / ethanol / 3 h / 80 °C
	Multi-step reaction with 2 steps 1: hydrogen / Raney-Ni / methanol / 3 h / 18 - 25 °C 2: triethylamine / ethanol / 3 h / 80 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2011/103715, 2011, A1
[2]Current Patent Assignee: MERCK & CO INC - WO2011/106276, 2011, A1

36
[ 1572-98-1 ]
[ 1332455-38-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: hydrogen / Ra-Ni / methanol / 3 h / 18 - 25 °C 2.1: triethylamine / ethanol / 3 h / 80 °C 3.1: acetic acid / methanol / 0.5 h / Reflux 3.2: 3 h / 0 - 25 °C
	Multi-step reaction with 3 steps 1.1: hydrogen / Raney-Ni / methanol / 3 h / 18 - 25 °C 2.1: triethylamine / ethanol / 3 h / 80 °C 3.1: acetic acid / methanol / 0.5 h / Reflux 3.2: 0 - 25 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2011/103715, 2011, A1
[2]Current Patent Assignee: MERCK & CO INC - WO2011/106276, 2011, A1

37
[ 1572-98-1 ]
[ 324763-51-1 ]

Reference： [1]Patent: WO2011/148392,2011,A1
[2]Patent: WO2012/21446,2012,A2
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 957 - 971

38
[ 1572-98-1 ]
[ 173334-57-1 ]

Reference： [1]Patent: WO2011/148392,2011,A1
[2]Patent: WO2011/148392,2011,A1
[3]Patent: WO2012/21446,2012,A2

39
[ 1572-98-1 ]
[ 324763-47-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: ammonia / methanol / 12 h / 25 - 30 °C 2: hydrogen; ammonia / raney nickel / methanol / 14 h / 40 - 45 °C / 2942.29 Torr 3: triethylamine; 2-hydroxypyridin / 16 h / 85 - 90 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/148392, 2011, A1

40
[ 1572-98-1 ]
[ 7505-93-3 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia In methanol at 25 - 30℃; for 12h;	39 1000 ml of methanolic ammonia was added to 100 grams of ethyl 2-cyano-2- methylpropanoate compound of formula-25 and stirred the reaction mixture for 12 hours at 25-30°C. After the reaction was completed, the reaction mixture was distilled off completely under reduced pressure. Cyclohexane was added to the reaction mixture and stirred for 1 hour at 25-30°C. The reaction mixture was filtered, washed with cyclohexane and then dried to get the title compound. Yield: 67.5 grams.
	With ammonia In methanol at 25 - 35℃;	1.2 To a 10% solution of ammonia in methanol (72.3 g, 0.42 mol) was charged ethyl 2-cyano-2-methylpropanoate (20 g) at 25-35°C and stirred for 12-14 hours at same temperature 25-35°C. After reaction completion, the reaction mass was 3Q evaporated at below 50°C under vacuum and the resulting crude material was triturated with hexane (40 mL) at 25-35°C for 2-3 hours. The solid obtained, was isolated by filtration, washed with hexane (20 mL) at 25-35 ° C, and then dried by suction for 10-15 min. The wet solid obtained was dried at 35-40°C for 6-8 hours to obtain 14.69 grams of desired compound. Alternatively, the resulting crude material can be triturated in ethyl acetate (23.8 mL) at 0-5°C for 2-3 hours to obtain very pure material of compound of present interest. The yield obtained is 14.56 g. The present purification can be selectively opted to enhance the purity of present intermediate. Purity details by GC: 2-cyano-2-methylpropanamide: >99%; ethyl 2-cyano-2-methylpropanoate: not detected (starting material).
	With ammonia In methanol at 35℃; for 96h; Sealed tube; Cooling with ice;

With ammonia In methanol at 30℃;

1 Step 1: 2-cyano-2-methylpropanamide A solution of ethyl 2-cyano-2-methylpropanoate (2.5 g, 17.7 mmol) in ammonia-methanol solution (30 mL, 1 M) was stirred at 30°C overnight. The mixture was concentrated to dryness to give 2-cyano-2-methylpropanamide (1.90 g) as a white solid. The crude product was used in next step without further purification. XH NMR (400 MHz, CDCI3) δ 6.28-6.20 (d, J = 32 Hz, 2H), 1.54 (d, 6H).

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/148392, 2011, A1 Location in patent: Page/Page column 64
[2]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2012/21446, 2012, A2 Location in patent: Page/Page column 29-30
[3]Patrick, Donald A.; Gillespie, J. Robert; McQueen, Joshua; Hulverson, Matthew A.; Ranade, Ranae M.; Creason, Sharon A.; Herbst, Zackary M.; Gelb, Michael H.; Buckner, Frederick S.; Tidwell, Richard R. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 957 - 971]
[4]Current Patent Assignee: LARIMAR THERAPEUTICS INC - WO2018/31877, 2018, A1 Location in patent: Paragraph 00239

41
[ 105-56-6 ]
[ 77-78-1 ]
[ 1572-98-1 ]
[ 72291-30-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide;tetrabutylammomium bromide; In dichloromethane; at 10 - 40℃;	To a mixture of sodium hydroxide (22.12 g, 0.55 mol) in dichloromethane (250 mL) was charged tetrabutyl ammonium bromide (7.12 g, 0.022 mol) at 25- 35C and then cooled to -10 to -5C. To the resulting heterogeneous reaction mass was added another solution containing ethyl 2-cyano acetate (Formula IMA) (25 gm, 0.223 mol) and dimethyl sulfate (64.1 g, 0.5 mol) at below 10C over a period of 2-3 hours. The resulting reaction mass was heated to 35-40C and stirred at same temperature for 2-3 hours. After reaction completion, reaction mass was cooled to 0-5C and then quenched using water (125 mL) at below 10C. The resulting aqueous and organic layers were separated, the aqueous layer was extracted twice with dichloromethane (2 x 50 mL). The organic layers were combined and washed twice with water (2 x 125 mL) at 25-35C. The final organic layer was subjected to evaporation at 45C under atmospheric pressure and finally under applied vacuum to remove the traces of dichloromethane left over in the crude compound. The resulting crude compound was purified via high vacuum distillation at 140C under vacuum to obtain about 20 grams pure compound of ethyl 2-cyano-2-methylpropanoate. Purity details by GC: ethyl 2- cyano-2-methylpropanoate: 76.3%; Methyl 2-cyano-2-methylpropanoate: 22.9 (trans esterified product); mono methyl impurity: 0.03%

Reference： [1]Patent: WO2012/21446,2012,A2 .Location in patent: Page/Page column 29

42
[ 1572-98-1 ]
[ 173338-07-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: ammonia / methanol / 25 - 35 °C 2.1: ammonia / Raney nickel / methanol / 25 - 35 °C / Autoclave 2.2: 10 h / 60 - 65 °C / 5149.01 - 5884.58 Torr 3.1: triethylamine; 2-hydroxypyridin

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2012/21446, 2012, A2

43
[ 1572-98-1 ]
[ 75-05-8 ]
[ 1012879-83-2 ]

Yield	Reaction Conditions	Operation in experiment
48%	With sodium hydride In tetrahydrofuran; mineral oil at 70 - 75℃; for 15.75h;
44%	Stage #1: acetonitrile With n-butyllithium In tetrahydrofuran at -10℃; for 1h; Inert atmosphere; Stage #2: 2-cyano-2-methyl-propionic acid ethyl ester In tetrahydrofuran for 3h;	11.1 Procedure for Synthesis of 2,2-dimethyl-3-oxo-pentanedinitrile (Step 1) Procedure for Synthesis of 2,2-dimethyl-3-oxo-pentanedinitrile (Step 1) Acetonitrile (5.55 ml, 106.25 mmol) was added drop wise to a solution of n-butyl lithium (1.2 equiv., 85 mmol) in tetrahydrofuran (150 ml) at -10° C. under nitrogen atmosphere. After 1 hour, solution of ethyl 2-cyano-2-methyl-propanoate (10 g, 70.83 mmol) in tetrahydrofuran (20 ml) was added drop wise to the reaction mixture. The reaction mixture was stirred for 3 hours and then acidified with dilute acetic acid. The reaction mixture was extracted with ethyl acetate (100 ml*3), combined organic layers were dried over sodium sulphate and concentrated under vacuum to give a crude mass. The crude mass was purified using silica gel column chromatography to give the desired compound (4.2 g, 44% yield) 1H NMR (CDCl3): 3.98 (s, 2H), 1.59 (s, 6H).
44%	Stage #1: acetonitrile With n-butyllithium In tetrahydrofuran at -10℃; for 1h; Inert atmosphere; Stage #2: 2-cyano-2-methyl-propionic acid ethyl ester In tetrahydrofuran for 3h; Inert atmosphere;	4.1 Procedure for synthesis of 2,2-dimethyl-3-oxo-pentanedinitrile (Step 1) Procedure for synthesis of 2,2-dimethyl-3-oxo-pentanedinitrile (Step 1) Acetonitrile (5.55 ml, 106.25 mmol) was added drop wise to a solution of n-butyl lithium (1.2 equiv., 85 mmol) in tetrahydrofuran (150 ml) at -10° C. under nitrogen atmosphere. After 1 hour, solution of ethyl 2-cyano-2-methyl-propanoate (10 g, 70.83 mmol) in tetrahydrofuran (20 mL) was added drop wise to the reaction mixture. The reaction mixture was stirred for 3 hours and then acidified with dilute acetic acid. The reaction mixture was extracted with ethyl acetate (100 mL*3), combined organic layers were dried over sodium sulphate and concentrated under vacuum to give a crude mass. The crude mass was purified using silica gel column chromatography to give the desired compound (4.2 g, 44% yield). 1H NMR (CDCl3): 3.98(s, 2H), 1.59 (s, 6H).

With sodium hydride In tetrahydrofuran at 70 - 75℃; for 15h;

A-5 2,2-dimethyl-3-oxopentanedinitrile A stirred suspension of NaH (1.3 g, 31.88 mmol, 60% purity) in THF (25 mL) was heated to 75 °C. To this was added a mixture of 2,2-dimethyl-2-cyanoacetic acid ethyl ester (3 g, 21,25 mmol) and CH3CN (1 ,7 mL, 31.88 mmol) in THF (20 ml.) dropwise over a period of 45 min. The resulting pale yellow suspension was heated at 70 °C for a further 15 h. The reaction mixture was poured into water (150 mL) and the resulting solution was extracted with EtOAc (2 x 100 mL). The aqueous layer was separated, acidified to pH 2 with aqueous 1 M HC1, and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2S04 and then concentrated under reduced pressure to afford 2,2-diraethyl-3-oxopentanedinitrile as yellow oil . LCMS: RT 0.213 min, m/z = 137.1 [M+H]

Reference： [1]Location in patent: experimental part Rowbottom, Martin W.; Faraoni, Raffaella; Chao, Qi; Campbell, Brian T.; Lai, Andiliy G.; Setti, Eduardo; Ezawa, Maiko; Sprankle, Kelly G.; Abraham, Sunny; Tran, Lan; Struss, Brian; Gibney, Michael; Armstrong, Robert C.; Gunawardane, Ruwanthi N.; Nepomuceno, Ronald R.; Valenta, Ianina; Hua, Helen; Gardner, Michael F.; Cramer, Merryl D.; Gitnick, Dana; Insko, Darren E.; Apuy, Julius L.; Jones-Bolin, Susan; Ghose, Arup K.; Herbertz, Torsten; Ator, Mark A.; Dorsey, Bruce D.; Ruggeri, Bruce; Williams, Michael; Bhagwat, Shripad; James, Joyce; Holladay, Mark W. [Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1082 - 1105]
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - US2016/66574, 2016, A1 Location in patent: Paragraph 0292; 0293; 0294
[3]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - US2017/318810, 2017, A1 Location in patent: Paragraph 0230; 0231; 0232
[4]Current Patent Assignee: DENALI THERAPEUTICS INC - WO2017/87905, 2017, A1 Location in patent: Page/Page column 108; 109

44
[ 1572-98-1 ]
[ 1015-38-9 ]
[ 17969-52-7 ]

Yield	Reaction Conditions	Operation in experiment
46.32%	In isopropyl alcohol for 4h; Reflux;	91 Intermediate 91: ethyl 3-amino-2,2-dimethyl-3-thioxopropanoate A mixture of diphenyldithiophosphonic acid (ALFAAESAR, 1.42 g, 5.67 mmol) and 2-cyano-2-methylpropionic acid ethyl ester (ABCR, 0.412 mL, 2.83 mmol) in isopropanol (30 mL) was heated under reflux for 4 h. Reaction mixture was cooled to room temperature and a precipitate was formed. Reaction flask was placed in the freezer for 1 h. Reaction mixture was filtered and filtrate was concentrated. Residue was taken up in DCM (100 mL) and washed with water (20 mL), 1N NaOH (20 mL), saturated NaHCO3 (20 mL) and dried over sodium sulfate and concentrated. The resulting oil was loaded on a 25 g silica cartridge and eluted with linear gradient 0-50% hexane-ethyl acetate to yield the title compound (110 mg, 0.628 mmol, 22.2% yield). Another impure batch was loaded on a 10 g silica cartridge and eluted with linear gradient 0-50% hexane-ethyl acetate to recover the title compound (120 mg, 0.685 mmol, 24.17% yield). Total yield: (230 mg, 1.313 mmol, 46.32%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.70 (br s, 1H), 8.86 (br s, 1H), 4.05 (q, 2H), 1.39 (s, 6H), 1.15 (t, 3H). [ES+MS] m/z 176 (MH+).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/95064, 2012, A1 Location in patent: Page/Page column 36

45
[ 1572-98-1 ]
α-Cyano-2-methylpropionic acid Na salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With water; sodium t-butanolate In ethanol at 20℃; Inert atmosphere;

Reference： [1]Shang, Rui; Huang, Zheng; Xiao, Xiao; Lu, Xi; Fu, Yao; Liu, Lei [Advanced synthesis and catalysis, 2012, vol. 354, # 13, p. 2465 - 2472,8]

46
[ 1572-98-1 ]
lithium 2-cyano-2-methylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With water; lithium tert-butoxide In ethanol at 20℃; Inert atmosphere;

Reference： [1]Shang, Rui; Huang, Zheng; Xiao, Xiao; Lu, Xi; Fu, Yao; Liu, Lei [Advanced synthesis and catalysis, 2012, vol. 354, # 13, p. 2465 - 2472,8]

47
[ 1572-98-1 ]
[ 1426841-19-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / ethanol; water / 0.5 h / 60 °C / Schlenk technique; Inert atmosphere 2: copper(I) bromide; 8-quinolinol; silver carbonate / N,N-dimethyl acetamide / 16 h / 130 °C / Schlenk technique; Inert atmosphere

Reference： [1]Feng, Yi-Si; Xu, Zhong-Qiu; Mao, Long; Zhang, Feng-Feng; Xu, Hua-Jian [Organic Letters, 2013, vol. 15, # 7, p. 1472 - 1475]

48
[ 1572-98-1 ]
[ 24424-99-5 ]
tert-butyl N-(4-ethoxy-2,2-dimethyl-3-oxobutyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.45 g	With hydrogen In methanol at 20℃; for 24h; Inert atmosphere;	III-19 Intermediate III-19. 1-ethyl-5,5-dimethylpiperidine-2,4-dione Ethyl 2-cyano-2,2-dimethylacetate (1 .0 g, 7.09 mmol) was dissolved in methanol (10 ml) and Pd on C (0.1 g) and Boc-anhydride (1 .85 g, 8.59 mmol) was added. The system was purged with N2-gas and evacuated. The reaction assembly was made saturated with H2-gas and stirred at RT for 24 hours under hydrogen atmosphere. After reaction was completed, the mixture was filtered through celite pad. The filtrate was collected and concentrated under reduced pressure. The yield of tert-butyl N-(4-ethoxy-2,2-dimethyl-3-oxobutyl)- carbamate after flash chromatography (100-200 mesh size silica gel, 10% ethyl acetate in hexane) was 0.45 g.

Reference： [1]Current Patent Assignee: ARANDA PHARMA - WO2014/191632, 2014, A1 Location in patent: Page/Page column 65

49
[ 1572-98-1 ]
[ 1591-31-7 ]
[ 2920-38-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With copper(I) oxide; oxygen; silver nitrate; triphenylphosphine In 1-methyl-pyrrolidin-2-one at 130℃; Schlenk technique;

Reference： [1]Zhang, Song-Lin; Huang, Lu [Organic and Biomolecular Chemistry, 2015, vol. 13, # 39, p. 9963 - 9968]

50
[ 1572-98-1 ]
[ 108-00-9 ]
C₉H₁₇N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	In neat (no solvent) at 90℃; Sealed tube;

Reference： [1]López-Andarias, Javier; Frontera, Antonio; Matile, Stefan [Journal of the American Chemical Society, 2017, vol. 139, # 38, p. 13296 - 13299]

51
[ 1572-98-1 ]
[ 5122-94-1 ]
[ 2920-38-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 4-biphenylboronic acid With copper(l) iodide; oxygen; triphenylphosphine In 1-methyl-pyrrolidin-2-one Schlenk technique; Sealed tube; Stage #2: 2-cyano-2-methyl-propionic acid ethyl ester With tert.-butylhydroperoxide; acetic acid In 1-methyl-pyrrolidin-2-one at 130℃; for 18h; Schlenk technique; Sealed tube;

Reference： [1]Wang, Xian-Jin; Zhang, Song-Lin [New Journal of Chemistry, 2017, vol. 41, # 24, p. 14826 - 14830]

52
[ 1572-98-1 ]
C₃₇H₄₈N₈O₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; ethanol / 1,2-dimethoxyethane / 17 h / 0 - 20 °C 2.1: lithium / pentane / Reflux 2.2: 3 h / -78 - 20 °C / Inert atmosphere 2.3: 15 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 30 h / 20 °C / 760.05 Torr 4.1: ammonium cerium (IV) nitrate / aq. buffer / 1 h / 37 °C / pH 6

Reference： [1]Ishiyama, Takashi; Kanai, Motomu; Maruyama, Katsuya; Oisaki, Kounosuke; Sakai, Kentaro; Seki, Yohei; Togo, Takaya [Journal of the American Chemical Society, 2021, vol. 143, # 47, p. 19844 - 19855]

53
[ 1572-98-1 ]
C₃₇H₄₇N₉O₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium tetrahydroborate; ethanol / 1,2-dimethoxyethane / 17 h / 0 - 20 °C 2.1: lithium / pentane / Reflux 2.2: 3 h / -78 - 20 °C / Inert atmosphere 2.3: 15 h / 20 °C 3.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 0.17 h / -78 °C / Inert atmosphere 3.2: 2 h / -78 - 20 °C 4.1: 2-methyl-but-2-ene; sodium dihydrogenphosphate; sodium chlorite / water; <i>tert</i>-butyl alcohol / 5 h / 20 °C 5.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 5.2: 18 h / 0 - 20 °C 6.1: palladium 10% on activated carbon; hydrogen / methanol / 0.5 h / 20 °C / 760.05 Torr 7.1: ammonium cerium (IV) nitrate / aq. buffer / 1 h / 37 °C / pH 6

54
[ 1572-98-1 ]
C₁₅H₂₃NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate; ethanol / 1,2-dimethoxyethane / 17 h / 0 - 20 °C 2.1: lithium / pentane / Reflux 2.2: 3 h / -78 - 20 °C / Inert atmosphere 2.3: 15 h / 20 °C

55
[ 1572-98-1 ]
C₈H₁₇NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; ethanol / 1,2-dimethoxyethane / 17 h / 0 - 20 °C 2.1: lithium / pentane / Reflux 2.2: 3 h / -78 - 20 °C / Inert atmosphere 2.3: 15 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 30 h / 20 °C / 760.05 Torr

56
[ 1572-98-1 ]
C₁₅H₂₁NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; ethanol / 1,2-dimethoxyethane / 17 h / 0 - 20 °C 2.1: lithium / pentane / Reflux 2.2: 3 h / -78 - 20 °C / Inert atmosphere 2.3: 15 h / 20 °C 3.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 0.17 h / -78 °C / Inert atmosphere 3.2: 2 h / -78 - 20 °C

57
[ 1572-98-1 ]
C₁₅H₂₁NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; ethanol / 1,2-dimethoxyethane / 17 h / 0 - 20 °C 2.1: lithium / pentane / Reflux 2.2: 3 h / -78 - 20 °C / Inert atmosphere 2.3: 15 h / 20 °C 3.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 0.17 h / -78 °C / Inert atmosphere 3.2: 2 h / -78 - 20 °C 4.1: 2-methyl-but-2-ene; sodium dihydrogenphosphate; sodium chlorite / water; <i>tert</i>-butyl alcohol / 5 h / 20 °C

58
[ 1572-98-1 ]
C₁₅H₂₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium tetrahydroborate; ethanol / 1,2-dimethoxyethane / 17 h / 0 - 20 °C 2.1: lithium / pentane / Reflux 2.2: 3 h / -78 - 20 °C / Inert atmosphere 2.3: 15 h / 20 °C 3.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 0.17 h / -78 °C / Inert atmosphere 3.2: 2 h / -78 - 20 °C 4.1: 2-methyl-but-2-ene; sodium dihydrogenphosphate; sodium chlorite / water; <i>tert</i>-butyl alcohol / 5 h / 20 °C 5.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 5.2: 18 h / 0 - 20 °C

59
[ 1572-98-1 ]
C₈H₁₆N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium tetrahydroborate; ethanol / 1,2-dimethoxyethane / 17 h / 0 - 20 °C 2.1: lithium / pentane / Reflux 2.2: 3 h / -78 - 20 °C / Inert atmosphere 2.3: 15 h / 20 °C 3.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 0.17 h / -78 °C / Inert atmosphere 3.2: 2 h / -78 - 20 °C 4.1: 2-methyl-but-2-ene; sodium dihydrogenphosphate; sodium chlorite / water; <i>tert</i>-butyl alcohol / 5 h / 20 °C 5.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 5.2: 18 h / 0 - 20 °C 6.1: palladium 10% on activated carbon; hydrogen / methanol / 0.5 h / 20 °C / 760.05 Torr

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P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
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. 1572-98-1 ]

Quality Control of [ 1572-98-1 ]

Related Doc. of [ 1572-98-1 ]

Product Details of [ 1572-98-1 ]

Safety of [ 1572-98-1 ]

Application In Synthesis of [ 1572-98-1 ]

[ 1572-98-1 ] Synthesis Path-Upstream 1~7

[ 1572-98-1 ] Synthesis Path-Downstream 1~59

Related Functional Groups of [ 1572-98-1 ]

Aliphatic Chain Hydrocarbons

Esters

Nitriles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1572-98-1 ]