[ CAS No. 94413-64-6 ] {[proInfo.proName]}

Name: 94413-64-6|Methyl 2-cyanoisonicotinate|98%
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Quality Control of [ 94413-64-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 94413-64-6 ]

SDS Specification

Alternatived Products of [ 94413-64-6 ]

Product Details of [ 94413-64-6 ]

CAS No. :	94413-64-6	MDL No. :	MFCD07367894
Formula :	C₈H₆N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ORVHMLCJEKDDAX-UHFFFAOYSA-N
M.W :	162.15	Pubchem ID :	12132796
Synonyms :

Calculated chemistry of [ 94413-64-6 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	40.23
TPSA :	62.98 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.75 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.56
Log Po/w (XLOGP3) :	0.76
Log Po/w (WLOGP) :	0.74
Log Po/w (MLOGP) :	-0.28
Log Po/w (SILICOS-IT) :	1.17
Consensus Log Po/w :	0.79

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.56
Solubility :	4.44 mg/ml ; 0.0274 mol/l
Class :	Very soluble
Log S (Ali) :	-1.66
Solubility :	3.53 mg/ml ; 0.0218 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.18
Solubility :	1.08 mg/ml ; 0.00665 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.82

Safety of [ 94413-64-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 94413-64-6 ]

* 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 [ 94413-64-6 ]
Downstream synthetic route of [ 94413-64-6 ]

[ 94413-64-6 ] Synthesis Path-Upstream 1~12

1
[ 557-21-1 ]
[ 26156-48-9 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In N,N-dimethyl-formamide at 120℃; for 2.5 h; Inert atmosphere	Compound DD (17.4 g, 80.5 mmol) was dissolved in DMF (160 mE), followed by the addition of Zn(CN)2 (5.7 g, 48.53 mmol) in one portion. The mixture was degassed using nitrogen and then Pd(PPh3)4 (4.7 g) was added. The mixture was degassed again and then heated in an oil bath (120° C.). After 2.5 h, the reaction was cooled to ambient temperature and water (200 mE) was added. The mixture was stirred for 30 mm and then filtered through a frit. The solid collected was washed with water (2x1 00 mE) and then dried under vacuum to give compound EE in 84percent yield (11.0 g, 67.9 mmol). EC-MS: [M+H] 163.2 (C8H5N202+H, calc: 162.1). Compound EE was used directly without thrther purification

Reference： [1] Patent: US9139612, 2015, B2, . Location in patent: Page/Page column 153; 154; 159
[2] Patent: US2017/100390, 2017, A1, . Location in patent: Paragraph 1104
[3] Patent: WO2018/170465, 2018, A1, . Location in patent: Paragraph 248

2
[ 773837-37-9 ]
[ 3783-38-8 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
71.6%	With copper(l) iodide; N,N-Dimethylcarbamoyl chloride In acetonitrile at 90℃; for 7 h;	The formula (5) compound methyl isobutyl niacin-N-oxide 1.53g (10mmol), b a carbamic chloride (0.11 ml, 11mmol), sodium cyanide (0.98g, 20mmol), cuprous iodide 0.19g (1mmol) dissolved in 50 ml of acetonitrile, mixtures in 90 °C reaction under 7 hours, detecting reaction TLC (hexane/ethyl acetate = 1 the [...] 1), after the reaction, cooling to room temperature, add 20 ml water to stir reaction 5-30 minutes, removed the organic layer, the aqueous layer extracted with ethyl acetate three times, each 50 ml, combined with the organic layer, anhydrous sodium sulfate for drying, distilling solvent under reduced pressure, to obtain crude products, crude product using normal hexane/ethyl acetate = 4 the [...] 1 column chromatography, to obtain strawcoloured solid 1.16g, yield 71.6percent.

Reference： [1] Patent: CN104151297, 2016, B, . Location in patent: Paragraph 0039; 0040
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 10, p. 3385 - 3396

3
[ 3783-38-8 ]
[ 748101-41-9 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With copper(l) iodide; N,N-Dimethylcarbamoyl chloride In acetonitrile at 80℃; for 5 h;	The formula (5) compound methyl isobutyl niacin-N-oxide 1.53g (10mmol), b a carbamic chloride (0.11 ml, 11mmol), zinc cyanide (1.40g, 12mmol), cuprous iodide 0.19g (1mmol) dissolved in 50 ml of acetonitrile, mixtures in 80 °C reaction under 5 hours, TLC detection reaction (hexane/ethyl acetate = 1 the [...] 1), after the reaction, cooling to room temperature, add 20 ml water to stir reaction 5-30 minutes, removed the organic layer, the aqueous layer extracted with ethyl acetate three times, each 50 ml, combined with the organic layer, anhydrous sodium sulfate for drying, distilling solvent under reduced pressure, to obtain crude products, crude product using normal hexane/ethyl acetate = 4 the [...] 1 column chromatography, to obtain strawcoloured solid 1.53g, yield 94percent, HPLC purity ( unitary method ): 97.7percent ; melting point: 107.5-108.7 °C.

Reference： [1] Patent: CN104151297, 2016, B, . Location in patent: Paragraph 0037; 0038

4
[ 3783-38-8 ]
[ 7677-24-9 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
57%	at 50℃; Inert atmosphere	A mixture of 4-(methoxycarbonyl)pyridine 1-oxide (2 g, 13.06 mmol, 1.00 equiv), N,N-dimethylcarbamoyl chloride (6 g, 55.79 mmol, 4.27 equiv) and trimethylsilanecarbonitrile (6 g, 60.48 mmol, 4.63 equiv) in chloroform (60 g) was stirred overnight under nitrogen at 50 °C. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :20) to give 1.2 g (57percent) of methyl 2-cyanopyridine-4-carboxylate as a light yellow solid. LC MS (Method F, ESI): RT= 1.22 min, m/z = 163.0 [M+H]⁺.
33%	With N,N-Dimethylcarbamoyl chloride In dichloromethane at 20℃; for 12 h;	Trimethylsilyl cyanide (3.8 g, 0.0386 mol) and dimethylcarbamyl chloride (5.0 g, 0.0483 mol) were added to a solution of methylisonicotinate N-oxide (5.0 g, 0.0322 mol) in dry CH₂Cl₂ (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h and then quenched with 10percent K₂CO₃ solution. The organic product was extracted with CH₂Cl₂ and the organic layer was washed with H₂O and brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica 230-400 mesh, eluent 1-2percent MeOH in CH₂Cl₂) to afford methyl 2-cyanoisonicotinate (1.75 g, yield 33percent) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 - 8.95 (d, J = 5.0 Hz, 1 H), 8.41 (m, 1 H), 8.15 - 8.13 (dd, J = 4.8 Hz, 1.6 Hz, 1 H), 3.92 (s, 3H).

Reference： [1] Patent: WO2013/127268, 2013, A1, . Location in patent: Page/Page column 71; 72
[2] Patent: EP2533783, 2015, B1, . Location in patent: Paragraph 0425-0426
[3] Tetrahedron, 2018, vol. 74, # 25, p. 3165 - 3170

5
[ 3783-38-8 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
70.8%	With copper(l) iodide; N,N-Dimethylcarbamoyl chloride In acetonitrile at 90℃; for 8 h;	The compound of formula (5), methyl isonicotinic acid-N-oxide, 1. 53 g (10 mmol), dimethylcarbamoyl chloride (0.1 mmol, 11 mmol), potassium cyanide (1.3 g, 20 mmol) and cuprous iodide 0.19 g (1 mmol) were dissolved in 50 ml of acetonitrile and mixed The reaction was carried out at 90 ° C for 8 hours. The reaction was monitored by TLC (n-hexane / ethyl acetate = 1: 1). After completion of the reaction, The reaction was stirred for 5 - 30 minutes at room temperature, the organic layer was discarded and the aqueous layer was extracted three times with 50 mL each of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was recrystallized from n-hexane / ethyl acetate = 4: 1 Column chromatography to give 1.15 g of a light yellow solid, yield 70.8

Reference： [1] Patent: CN104151297, 2016, B, . Location in patent: Paragraph 0041; 0042

6
[ 557-21-1 ]
[ 3783-38-8 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
65%	With N,N-Dimethylcarbamoyl chloride In toluene for 6 h; Reflux; Inert atmosphere	A reaction mixture of 4-(methoxycarbonyl)pyridine-1-oxide²⁷ (0.20 g, 1.30 mmol), dimethylcarbamoyl chloride (DMCC, 0.12 mL, 1.30 mmol) and Zn(CN)₂ (0.23 g, 1.96 mmol) in toluene (15 mL) was heated to reflux under an argon atmosphere for 6 h. The reaction mixture was cooled to room temperature and deionised H₂O (10 mL) was added, and stirring was continued for 15 min. The organic layer was separated, washed with brine, dried over MgSO₄ and concentrated under reduced pressure to yield an orange solid (0.21 g, 65percent) which required no further purification. m.p. 100-103 °C; ν_max (KBr) 2958, 2852, 2237, 1726, 1441, 1397, 1298, 1209, 1116, 974, 934, 882, 869, 765 cm^-1; δ_H (300 MHz, CDCl₃) 8.90 (1 H, dd, J 4.9, 0.8 Hz, pyr-H), 8.24 (1 H, dd, J 1.5, 0.8 Hz, pyr-H), 8.07 (1 H, dd, J 4.9, 1.5 Hz, pyr-H), 4.01 (3 H, s, OCH₃); δ_C (75 MHz, CDCl₃) 162.6 (C=O), 151.0, 137.7, 133.8, 126.6, 125.0, 115.5 (CN), 52.3 (OCH₃); HRMS (ESI): [M+H]⁺, found 163.0509. C₈H₇N₂O₂ requires 163.0502. NMR data is in agreement with literature data.¹³

Reference： [1] Tetrahedron, 2016, vol. 72, # 51, p. 8470 - 8478

7
[ 3783-38-8 ]
[ 94413-64-6 ]

Reference： [1] Patent: EP1471065, 2004, A1, . Location in patent: Page 7

8
[ 2459-09-8 ]
[ 7677-24-9 ]
[ 94413-64-6 ]

Reference： [1] Chemistry - A European Journal, 2017, vol. 23, # 59, p. 14733 - 14737

9
[ 3783-38-8 ]
[ 7677-24-9 ]
[ 79-44-7 ]
[ 94413-64-6 ]

Reference： [1] Patent: US6509361, 2003, B1,

10
[ 66572-56-3 ]
[ 94413-64-6 ]

Reference： [1] Patent: US9139612, 2015, B2,
[2] Patent: US2017/100390, 2017, A1,
[3] Patent: WO2018/170465, 2018, A1,

11
[ 2459-09-8 ]
[ 94413-64-6 ]

Reference： [1] Patent: WO2013/127268, 2013, A1,
[2] Tetrahedron, 2018, vol. 74, # 25, p. 3165 - 3170

12
[ 94413-64-6 ]
[ 577778-58-6 ]

Reference： [1] Patent: CN107573330, 2018, A,

[ 94413-64-6 ] Synthesis Path-Downstream 1~56

2
[ 94413-64-6 ]
[ 94413-69-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogen; In methanol; at 20℃; under 760.051 Torr; for 0.5h;	ethyl 2-cyanopyridine-4-carboxylate (500 mg, 3.08 mmol, 1 .00 equiv) and Raney Ni (1 .5 g) in MeOH (30 mL) was stirred under 1 atmosphere of hydrogen for 30 min at rt. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to give 0.5 g (98percent) of methyl 2-(aminomethyl)pyridine-4-carboxylate as a light yellow solid. LC MS (Method F, ESI): RT= 0.82 min, m z = 167.0 [M+H]+.
73%	With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In methanol; water; at 20℃; for 2h;	[1139] To a solution of <strong>[94413-64-6]methyl 2-cyanoisonicotinate</strong> (4.22 g, 25.9 mmol) and 10percent palladium on charcoal (2.8 g, 2.6 mmol) in MeOH (400 ml) was added conc. HCl (7.5 ml). The mixture is hydrogenated at rt and balloon pressure, until no more hydrogen is consumed (about 2 h). The reaction mixture is filtered through a pad of celite and the solvent is removed in vacuum to give a yellow solid (4.5 g, 18.8 mmol, 73percent) for methyl 2-(aminomethyl) isonicotinate. This compound is used without further purification. MS (EST+) for C8H10N2O2 m/z 167.2 (M+H)+; HRMS (FAB) calcd for C8H10N2O2+H 167.0820, found 167.0821.
	With hydrogenchloride; 5% palladium on barium sulphate; hydrogen; In 1,4-dioxane; ethanol; under 2844.39 Torr; for 4h;	The crude product of the previous reaction (8.0 g, 49.36 mmol) was dissolved in EtOH (200 mL). Pd/5percent on barium sulfate (2.4 g) and 4N HCl (in 1,4-Dioxane; 20 mL) was added to the reaction mixture. The mixture was hydrogenated at 55 psi for 4 h on a Parr hydrogenator. The mixture was then filtered through a celite pad and then the celite pad was washed with MeOH (3 x 50 mL). The combined filtrate was then concentrated and the residue was partitioned between EtOAc (120 mL) and water (50 mL). The organic layer was washed with 10percent citric acid (20 mL) and brine (20 mL), followed by drying over Na2SO4. Next the mixture was filtered and concentrated to afford compound B in 86percent yield (10.5 g, 40.2 mmol). LC-MS: [M+H] 266.7 (C13H18N2O4+H, calc: 266.1). Compound B was used directly without further purification.

With hydrogenchloride; 20% palladium hydroxide-activated charcoal; In 1,4-dioxane; methanol; water;

Intermediate E (<strong>[94413-64-6]2-cyano-4-carbomethoxypyridine</strong>, 10 g) was dissolved in methanol (100 mL) and transferred to a 250 mL Parr bottle containing 20percent Pd(OH)2?C w/~50percent water (200 mg). Dry HCl (4M in dioxane / 3 eq.) was added. The parr bottle was equipped with a metal safety shield, affixed to a Parr shaker and pressurized to 35 psi with H2. The reaction was shaken for 3h at RT, then vented and removed from the Parr shaker. The reaction was determined to be complete by LC/MS, then filtered through paper filter to remove catalyst. The catalyst and Parr bottle were rinsed with methanol (3x 25 mL). The resulting methanol solution was concentrated under vacuum, to produce Intermediate F (9.2 g) as a white solid after drying under high vacuum for several hours that was used without further purification.

Reference： [1]Patent: WO2013/127268,2013,A1 .Location in patent: Page/Page column 71; 72
[2]Patent: US2003/236264,2003,A1 .Location in patent: Page 51
[3]Patent: US2017/100390,2017,A1 .Location in patent: Paragraph 1102; 1105
[4]Patent: WO2018/170465,2018,A1 .Location in patent: Paragraph 249

3
[ 94413-64-6 ]
[ 135048-32-7 ]

Yield	Reaction Conditions	Operation in experiment
84.3%	With hydrazine hydrate; In ethanol; at -15℃; for 3h;	20 g of <strong>[94413-64-6]2-cyanoisonicotinic acid methyl ester</strong> and 160 ml of ethanol were added to a glass reaction flask, stirred, cooled to -15°C, and 21.6 g of hydrazine hydrate was added dropwise with stirring. The temperature during the dropwise addition was controlled at -15°C. After 30 minutes, the temperature was controlled at -15°C and the reaction was stirred for 2.5 hours. After TLC monitored the end of the reaction, the reaction was stopped. Centrifugal separation was used to collect the filter cake. The filter cake was washed with 50 ml of ethanol and shaken. The cake was added to 50 ml. Add 260 ml of hydrochloric acid solution with 10percent volume concentration under stirring. Stir to dissolve all the solids. Separate the liquid, add 120 ml of ethyl acetate to the aqueous phase, and adjust the pH to 6.5 with KOH while stirring. After stirring for 10 minSeparate the liquid, collect the organic phase, repeat the above extraction operation and extract four times. Combine the organic phases. Add 20 g of anhydrous sodium sulfate to the organic phase, dry for more than 8 hours, and remove sodium sulfate by filtration. The mother liquid is concentrated under reduced pressure at 55° C. (<-0.9 MPa). The resulting solid was transferred to a vacuum drying cabinet and dried under reduced pressure (<-0.9 MPa, 60° C., 8 h) to obtain 16.9 g of an intermediate with a yield of 84.3percent.Among them, the HPLC purity of the intermediate was 98.8percent, the normalized percentage of the peak area of the raw material was 0.8percent, and the normalized percentage of the peak area of the raw material of the side reaction product was 0.4percent.
	With hydrazine hydrate; In ethanol; at 80℃; for 5h;	1.62 g (10 mmol) of the compound of the formula (3) were dissolved in 20 ml of ethanol, stirred at room temperature, 1. 53 g (25 mmol) of 80percent hydrazine hydrate was added and the temperature was raised to 80 ° C. The reaction was incubated for 5 hours and the reaction was monitored by TLC Ethyl acetate: n-hexane = 1: 1). After the reaction, cooling crystallization, a large number of light yellow precipitate, filtration, The cake was recrystallized from absolute ethanol to give 1.35 g of white needles. The yield was 83.3percent / H (DMSO, d6) (1H, s, NC = CH), 8.07 (1H, q, NH2), 8.75 (1H, d, 5-14 (2H, brs, N H 2)
		3) Production of 2-cyanoisonicotinic acid hydrazide 8.44 g of the crystal obtained in 2) was added to 85 ml of methanol, 1.84 g of hydrazine was further added thereto, and the mixture was stirred under argon atmosphere for 2 hours. After the solvent was evaporated under reduced pressure, chloroform was added to the residue, which was stirred at room temperature for one hour. The precipitated crystal was filtered, washed with chloroform and dried with a vacuum pump to yield 4.15 g of a pale yellow powder.1H-NMR(DMSO-d6)deltappm : 4.72 (2 H, s), 8.05(1H, d, J=5.12Hz), 8.31(1H, s), 8.90(1H, d, J=5.12 Hz), 10.23(1H, s)

With hydrazine hydrate; In methanol; at 25 - 35℃; for 6h;

200 g of methanol was sequentially added to a 1000 mL reaction vessel.2-cyano-4-carboxylic acid methyl ester pyridine 31g, stirred;The reaction liquid is controlled to a temperature of 25 ° C to 35 ° C;A methanol solution of hydrazine hydrate (15.4 g hydrazine hydrate + methanol 22 g) was slowly added dropwise.After the addition,The reaction is carried out at 25 ° C to 35 ° C for 6 h, and the reaction is completed;Add 0.1 g of sodium methoxide, 12.2 g of 4-cyanopyridine, and stir;Control the reaction temperature 5 ° C, the reaction 5h;Stop the reaction;Filtration, drying at 40 ° C ~ 50 ° C, -0.095 Mpa, 6 ~ 8h, to obtain a yellow solid 11.45kg, molar yield of about 90.5percent;HPLC purity (normalization method): 99.24percent

Reference： [1]Patent: CN107573330,2018,A .Location in patent: Paragraph 0028; 0029; 0030; 0031; 0047; 0049; 0050-0063
[2]Patent: CN104151297,2016,B .Location in patent: Paragraph 0047; 0048
[3]Patent: EP1471065,2004,A1 .Location in patent: Page 8
[4]Patent: CN107652271,2018,A .Location in patent: Paragraph 0065-0074

4
[ 3783-38-8 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylsilyl cyanide; triethylamine; In acetonitrile; for 16h;reflux;	2) Production of methyl 2-cyanoisonicotinate 11.1 g of the crystal obtained in 1) was dissolved in 170 ml of acetonitrile, 14.6 g of triethylamine and 21.5 g of trimethylsilylnitrile were added thereto, and the mixture was refluxed under argon atmosphere for 16 hours. After the solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography. Chloroform-acetone (95:5) was used as an eluent to yield 8.44 g of a pale yellow powder.1H-NMR(CDCl3) delta ppm: 4.01(3H, s), 8.08(1H, d, J=5.45Hz), 8.24(1H, s), 8.90(1H, d, J=5.45 Hz)

Reference： [1]Patent: EP1471065,2004,A1 .Location in patent: Page 7

5
[ 3783-38-8 ]
[ 7677-24-9 ]
[ 79-44-7 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dichloromethane;	Step 2 Preparation of Methyl 2-Cyanoisonicotinate: To a solution of methyl isonicotinate N-oxide (20.0 g, 0.26 mol) in 200 mL of methylene chloride was added trimethylsilyl cyanide (16.1 g, 0.32 mol), followed by a solution of dimethylcarbamyl chloride (17.82 g, 0.32 mol) in 50 mL of methylene chloride at room temperature. The reaction mixture was stirred overnight (about eighteen hours) and then treated with 500 mL of 10percent potassium carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to 15.2 g of crude product as a brown solid, which was used without further purification.

Reference： [1]Patent: US6509361,2003,B1

6
[ 94413-64-6 ]
1-(2-cyanoisonicotinyl)-1,3-butanedione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium methylate; In tetrahydrofuran; water; acetone;	Step 3 Preparation of 1-(2-Cyanoisonicotinyl)-1,3-butanedione: To a solution of <strong>[94413-64-6]methyl 2-cyanoisonicotinate</strong> (20.0 g, 0.126 mol) in 250 mL THF was added acetone (30.6 mL, 0.42 mol). The solution was warmed to 35° C. and sodium methoxide (7.15 g, 0.132 mol) was added portionwise over 20 minutes. The mixture was heated at reflux for 16 hours. The solvent was removed in vacuo and the residue was dissolved in water, acidified to pH=6 with acetic acid. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 13.0 g (58percent yield) of product as a brown solid, which was used in next step without purification.

Reference： [1]Patent: US6509361,2003,B1

7
[ 773837-37-9 ]
[ 3783-38-8 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
71.6%	With copper(l) iodide; N,N-Dimethylcarbamoyl chloride; In acetonitrile; at 90℃; for 7h;	The formula (5) compound methyl isobutyl niacin-N-oxide 1.53g (10mmol), b a carbamic chloride (0.11 ml, 11mmol), sodium cyanide (0.98g, 20mmol), cuprous iodide 0.19g (1mmol) dissolved in 50 ml of acetonitrile, mixtures in 90 °C reaction under 7 hours, detecting reaction TLC (hexane/ethyl acetate = 1 the [...] 1), after the reaction, cooling to room temperature, add 20 ml water to stir reaction 5-30 minutes, removed the organic layer, the aqueous layer extracted with ethyl acetate three times, each 50 ml, combined with the organic layer, anhydrous sodium sulfate for drying, distilling solvent under reduced pressure, to obtain crude products, crude product using normal hexane/ethyl acetate = 4 the [...] 1 column chromatography, to obtain strawcoloured solid 1.16g, yield 71.6percent.

Reference： [1]Patent: CN104151297,2016,B .Location in patent: Paragraph 0039; 0040
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 3385 - 3396

8
[ 498538-91-3 ]
[ 94413-64-6 ]
[ 1158972-05-4 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 3385 - 3396

9
[ 3783-38-8 ]
[ 7677-24-9 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
57%	In chloroform; at 50℃;Inert atmosphere;	A mixture of 4-(methoxycarbonyl)pyridine 1-oxide (2 g, 13.06 mmol, 1.00 equiv), N,N-dimethylcarbamoyl chloride (6 g, 55.79 mmol, 4.27 equiv) and trimethylsilanecarbonitrile (6 g, 60.48 mmol, 4.63 equiv) in chloroform (60 g) was stirred overnight under nitrogen at 50 °C. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :20) to give 1.2 g (57percent) of methyl 2-cyanopyridine-4-carboxylate as a light yellow solid. LC MS (Method F, ESI): RT= 1.22 min, m/z = 163.0 [M+H]+.
33%	With N,N-Dimethylcarbamoyl chloride; In dichloromethane; at 20℃; for 12h;	Trimethylsilyl cyanide (3.8 g, 0.0386 mol) and dimethylcarbamyl chloride (5.0 g, 0.0483 mol) were added to a solution of methylisonicotinate N-oxide (5.0 g, 0.0322 mol) in dry CH2Cl2 (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h and then quenched with 10percent K2CO3 solution. The organic product was extracted with CH2Cl2 and the organic layer was washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica 230-400 mesh, eluent 1-2percent MeOH in CH2Cl2) to afford methyl 2-cyanoisonicotinate (1.75 g, yield 33percent) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta 8.97 - 8.95 (d, J = 5.0 Hz, 1 H), 8.41 (m, 1 H), 8.15 - 8.13 (dd, J = 4.8 Hz, 1.6 Hz, 1 H), 3.92 (s, 3H).
	With triethylamine; In acetonitrile; at 150℃; under 6000.6 Torr;Flow reactor;	A solution of methyl 4-carboxypyridine (1M in MeCN) and a solution of mCPBA (1M in MeCN) were flowed via a T-mixer into a 10mL flow reactor at 95°C at a rate of 1.0mL per minute (Scheme 3). The solution of methyl 4-carboxypyridine N-oxide exiting the first reactor was combined with TMSCN/NEt3 (1:2.5, 1M in MeCN) via a second T-mixer. This solution was flowed into a 5mL reactor at 150°C at a rate of 0.2mL per minute. The solution exiting the reactor was collected and the solvent evaporated to provide methyl 2-cyanoisonicotinate (4).

Reference： [1]Patent: WO2013/127268,2013,A1 .Location in patent: Page/Page column 71; 72
[2]Patent: EP2533783,2015,B1 .Location in patent: Paragraph 0425-0426
[3]Tetrahedron,2018,vol. 74,p. 3165 - 3170

10
[ 2459-09-8 ]
[ 94413-64-6 ]

Reference： [1]Patent: WO2013/127268,2013,A1
[2]Tetrahedron,2018,vol. 74,p. 3165 - 3170

11
[ 94413-64-6 ]
[ 1454285-26-7 ]

Reference： [1]Patent: WO2013/127268,2013,A1

12
[ 94413-64-6 ]
[ 1377829-50-9 ]

Reference： [1]Patent: WO2013/127268,2013,A1

13
[ 66572-56-3 ]
[ 94413-64-6 ]

Reference： [1]Patent: US9139612,2015,B2
[2]Patent: WO2018/170465,2018,A1

14
[ 557-21-1 ]
[ 26156-48-9 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 2.5h;Inert atmosphere;	Compound DD (17.4 g, 80.5 mmol) was dissolved in DMF (160 mE), followed by the addition of Zn(CN)2 (5.7 g, 48.53 mmol) in one portion. The mixture was degassed using nitrogen and then Pd(PPh3)4 (4.7 g) was added. The mixture was degassed again and then heated in an oil bath (120° C.). After 2.5 h, the reaction was cooled to ambient temperature and water (200 mE) was added. The mixture was stirred for 30 mm and then filtered through a frit. The solid collected was washed with water (2x1 00 mE) and then dried under vacuum to give compound EE in 84percent yield (11.0 g, 67.9 mmol). EC-MS: [M+H] 163.2 (C8H5N202+H, calc: 162.1). Compound EE was used directly without thrther purification
	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 2.5h;Inert atmosphere;	The crude product of the previous reaction was dissolved in DMF (100 mL), followed by the addition of Zn(CN)2 (3.42 g, 29.11 mmol) in one portion. The mixture was degassed using nitrogen and then Pd(PPh3)4 (2.82 g) was added. The mixture was degassed again and then heated in an oil bath (120° C.). After 2.5 h, the reaction was cooled to ambient temperature and water (120 mL) was added. The mixture was stirred for 30 min and then filtered through a frit. The solid collected was washed with water (2×60 mL) and then dried under vacuum to give an off-white solid (5.2 g, 32.6 mmol). LC-MS: [M+H] 163.3 (C8H6N2O2+H, calc: 163.1). The crude product was used directly without further purification.
	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 3h;	Intermediate D (2-bromo-4-carbomethoxypyridine, 20 g) was dissolved in anhydrous DMF (150 mL) followed by the addition of Zn(CN)2 (0.6 eq.) in a single portion. To the resulting slurry was added Pd(PPh3)4 (4.5 g). The mixture was then heated on an oil bath to 120 °C for 3 h. The reaction mixture was allowed to cool to RT and then the reaction mixture was added slowly to a well-stirred flask containing 800 mL of water at room temperature. The resulting thick, off-white precipitate was stirred for ~15 min, then collected via filtration and washed with water (5 x 100 mL). The isolated solid was dried under vacuum to produce Intermediate E (18.8 g) that was used in the next step without further purification.

Reference： [1]Patent: US9139612,2015,B2 .Location in patent: Page/Page column 153; 154; 159
[2]Patent: US2017/100390,2017,A1 .Location in patent: Paragraph 1104
[3]Patent: WO2018/170465,2018,A1 .Location in patent: Paragraph 248

15
[ 94413-64-6 ]
N-(hydrocodone-6-enol-carbonyl)-[(2-methylamino)piperidine-4-carboxylate]-L-arginine-glycine-acetate [ No CAS ]

Reference： [1]Patent: US9139612,2015,B2

16
[ 94413-64-6 ]
C₁₃H₂₄N₂O₄ [ No CAS ]

Reference： [1]Patent: US9139612,2015,B2

17
[ 94413-64-6 ]
C₃₂H₄₃N₃O₈ [ No CAS ]

Reference： [1]Patent: US9139612,2015,B2

18
[ 94413-64-6 ]
C₂₇H₃₅N₃O₆*(x)ClH [ No CAS ]

Reference： [1]Patent: US9139612,2015,B2

19
[ 94413-64-6 ]
C₅₁H₇₁N₇O₁₂S [ No CAS ]

Reference： [1]Patent: US9139612,2015,B2

20
[ 94413-64-6 ]
C₄₆H₆₃N₇O₁₀S*(x)ClH [ No CAS ]

Reference： [1]Patent: US9139612,2015,B2

21
[ 94413-64-6 ]
C₅₀H₆₈N₈O₁₂S [ No CAS ]

Reference： [1]Patent: US9139612,2015,B2

22
[ 94413-64-6 ]
C₄₉H₆₆N₈O₁₂S [ No CAS ]

Reference： [1]Patent: US9139612,2015,B2

23
[ 24424-99-5 ]
[ 94413-64-6 ]
methyl 2-[(tert-butoxycarbonylamino)methyl]pyridine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With 5% palladium on barium sulphate; hydrogen; triethylamine; In isopropyl alcohol; under 2844.39 Torr; for 4h;	Compound EE (20.0 g, 123.4 mmol) was dissolved in IPA (500 mE). Boc2O (37.7 g, 172.8 mmol), Pd/5percent on barium sulfate (6.0 g) and NEt3 (35 mE, 246.9 mmol) were added to the reaction mixture. The mixture was hydrogenated at 55 psi for 4 h on a Parr hydrogenator. The mixture was then filtered through a celite pad and then the celite pad was washed with MeOR (3x80 mE). The combined filtrate was then concentrated and the residue was partitioned between EtOAc (300 mE) and water (100 mE). The organic layer was washed with 10percent citric acid (50 mE) and brine (50 mE), followed by drying over Na2 SO4. Next the mixture was filtered and concentratedto afford compound FF in 86percent yield (28.0 g, 106.8 mmol). EC-MS: [M+H] 267.4 (C13H18N204+H, calc: 266.5). Compound FF was used directly without further purification

Reference： [1]Patent: US9139612,2015,B2 .Location in patent: Page/Page column 155; 156; 159

24
[ 94413-64-6 ]
2-cyanopyridine-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.3%	With water; sodium carbonate; In tetrahydrofuran; isopropyl alcohol; at 20℃; for 2h;	2 - cyano-isonicotinic acid methyl ester 8.1 g (0.05 muM), tetrahydrofuran 50 ml, isopropanol 50 ml, water 30 ml in the form of suspension, stirring at the room temperature in batches under the adding sodium carbonate powder 10.6 g (0.1 muM), canada finishes, room temperature to continue stirring for 2 hours, concentrated hydrochloric acid drop 8.4 ml (0.1 muM), 70 °C filtering to remove the inorganic salt, the filtrate is concentrated, to obtain white solid 7.2 g, yield 97.3percent.
89%	With water; lithium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 1h;	Lithium hydroxide (96 mg, 4.0 mmol) was added to a solution of <strong>[94413-64-6]methyl 2-cyanoisonicotinate</strong> (0.6 g, 3.7 mmol) in THF-H2O (20 mL, 7:3 v/v) at 0 °C. The reaction mixture was allowed to warm up to room temperature and further stirred for 1 h. The reaction mixture was concentrated under reduced pressure and then diluted with water. The aqueous layer was washed with EtOAc. The pH of the aqueous layer was adjusted to ?3 using 1.5N HCl and the organic product was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 2-cyanoisonicotinic acid (490 mg, yield 89percent) as a white solid. 1H NMR (300 MHz, DMSO-d6) delta 14.11 (br s, 1 H), 8.93 - 8.91 (dd, J = 4.9 Hz, 0.8 Hz, 1 H), 8.34 (d, J = 0.9 Hz, 1 H), 8.11 - 8.10 (m, 1 H). MS (ESI) m/z: Calculated for C7H4N2O2: 148.03; found: 147.2 (M-H)-.

Reference： [1]Patent: CN104910068,2017,B .Location in patent: Paragraph 0012; 0013; 0015
[2]Patent: EP2533783,2015,B1 .Location in patent: Paragraph 0427-0428

25
[ 557-21-1 ]
[ 3783-38-8 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
65%	With N,N-Dimethylcarbamoyl chloride; In toluene; for 6h;Reflux; Inert atmosphere;	A reaction mixture of 4-(methoxycarbonyl)pyridine-1-oxide27 (0.20 g, 1.30 mmol), dimethylcarbamoyl chloride (DMCC, 0.12 mL, 1.30 mmol) and Zn(CN)2 (0.23 g, 1.96 mmol) in toluene (15 mL) was heated to reflux under an argon atmosphere for 6 h. The reaction mixture was cooled to room temperature and deionised H2O (10 mL) was added, and stirring was continued for 15 min. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure to yield an orange solid (0.21 g, 65percent) which required no further purification. m.p. 100-103 °C; numax (KBr) 2958, 2852, 2237, 1726, 1441, 1397, 1298, 1209, 1116, 974, 934, 882, 869, 765 cm-1; deltaH (300 MHz, CDCl3) 8.90 (1 H, dd, J 4.9, 0.8 Hz, pyr-H), 8.24 (1 H, dd, J 1.5, 0.8 Hz, pyr-H), 8.07 (1 H, dd, J 4.9, 1.5 Hz, pyr-H), 4.01 (3 H, s, OCH3); deltaC (75 MHz, CDCl3) 162.6 (C=O), 151.0, 137.7, 133.8, 126.6, 125.0, 115.5 (CN), 52.3 (OCH3); HRMS (ESI): [M+H]+, found 163.0509. C8H7N2O2 requires 163.0502. NMR data is in agreement with literature data.13

Reference： [1]Tetrahedron,2016,vol. 72,p. 8470 - 8478

26
[ 94413-64-6 ]
methyl 2-(1H-tetrazol-5-yl)isonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With sodium azide; ammonium chloride; lithium chloride; In N,N-dimethyl-formamide; at 110℃; for 12h;	Compound 1A (0.20 g, 1.25 mmol), NaN3 (0.09 g, 1.38 mmol), NH4Cl (0.07 g, 1.38 mmol) and LiCl (0.03 g, 0.62 mmol) were heated at 110 °C in DMF for 12 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was then taken up in deionised H2O and 1 M HCl was added slowly until precipitation initiated. The mixture was then filtered and the solid dried. Brown solid (0.15 g, 62percent). m.p. 163-166 °C; numax (KBr) 3071, 2922, 1724, 1547, 1438, 1416, 1393, 1336, 1295, 1270, 1247, 1198, 1173, 1054, 1031, 967, 755, 746 cm-1; deltaH (300 MHz, CDCl3) 9.01 (1 H, d, J 4.9 Hz, pyr-H), 8.56 (1 H, s, pyr-H), 8.04 (1 H, d, J 4.9 Hz, pyr-H), 4.03(3 H, s, OCH3); deltaC (75 MHz, CDCl3) 164.3 (C=O), 153.3, 151.4, 144.9, 138.6, 124.5, 121.0, 53.0 (OCH3); HRMS (ESI): [M+H]+, found 206.0677. C8H8N5O2 requires 206.0673.

Reference： [1]Tetrahedron,2016,vol. 72,p. 8470 - 8478

27
[ 100-48-1 ]
[ 94413-64-6 ]
[ 577778-58-6 ]

Yield	Reaction Conditions	Operation in experiment
63%		The 2 - cyano-isonicotinic acid methyl ester by adding (487.1g, 3 muM) soluble in 1L in the ethanol in the reactor, stirring at the room temperature, dropping hydrazine hydrate (187.9g, 3 muM), then heating to 40 C stirring 4h, TLC detection reaction (ethyl acetate: petroleum ether=1:2), the reaction is finished. Then adding sodium methoxide (28g, 0.5 muM), stirring 20min to dissolve, then the compound is added 4 - cyanopyridine (312.33g, 3 muM), 80 C reaction 10h, TLC detection (ethyl acetate: petroleum ether=1:4), after the reaction, cooling the room-temperature crystallization, the separated solid filtering, for 500 ml ethanol after cleaning, vacuum drying to obtain a pale yellow powdery product holds a department he 405.5g, yield 63%.

Reference： [1]Patent: CN106045979,2016,A .Location in patent: Paragraph 0019; 0020

28
[ 3783-38-8 ]
[ 748101-41-9 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With copper(l) iodide; N,N-Dimethylcarbamoyl chloride; In acetonitrile; at 80℃; for 5h;	The formula (5) compound methyl isobutyl niacin-N-oxide 1.53g (10mmol), b a carbamic chloride (0.11 ml, 11mmol), zinc cyanide (1.40g, 12mmol), cuprous iodide 0.19g (1mmol) dissolved in 50 ml of acetonitrile, mixtures in 80 °C reaction under 5 hours, TLC detection reaction (hexane/ethyl acetate = 1 the [...] 1), after the reaction, cooling to room temperature, add 20 ml water to stir reaction 5-30 minutes, removed the organic layer, the aqueous layer extracted with ethyl acetate three times, each 50 ml, combined with the organic layer, anhydrous sodium sulfate for drying, distilling solvent under reduced pressure, to obtain crude products, crude product using normal hexane/ethyl acetate = 4 the [...] 1 column chromatography, to obtain strawcoloured solid 1.53g, yield 94percent, HPLC purity ( unitary method ): 97.7percent ; melting point: 107.5-108.7 °C.

Reference： [1]Patent: CN104151297,2016,B .Location in patent: Paragraph 0037; 0038

29
potassium cyanide [ No CAS ]
[ 3783-38-8 ]
[ 94413-64-6 ]

Yield	Reaction Conditions	Operation in experiment
70.8%	With copper(l) iodide; N,N-Dimethylcarbamoyl chloride; In acetonitrile; at 90℃; for 8h;	The compound of formula (5), methyl isonicotinic acid-N-oxide, 1. 53 g (10 mmol), dimethylcarbamoyl chloride (0.1 mmol, 11 mmol), potassium cyanide (1.3 g, 20 mmol) and cuprous iodide 0.19 g (1 mmol) were dissolved in 50 ml of acetonitrile and mixed The reaction was carried out at 90 ° C for 8 hours. The reaction was monitored by TLC (n-hexane / ethyl acetate = 1: 1). After completion of the reaction, The reaction was stirred for 5 - 30 minutes at room temperature, the organic layer was discarded and the aqueous layer was extracted three times with 50 mL each of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was recrystallized from n-hexane / ethyl acetate = 4: 1 Column chromatography to give 1.15 g of a light yellow solid, yield 70.8

Reference： [1]Patent: CN104151297,2016,B .Location in patent: Paragraph 0041; 0042

30
[ 94413-64-6 ]
C₃₂H₄₆N₆O₈S [ No CAS ]

Reference： [1]Patent: US2017/100390,2017,A1

31
[ 94413-64-6 ]
C₂₇H₃₈N₆O₆S [ No CAS ]

Reference： [1]Patent: US2017/100390,2017,A1

32
[ 94413-64-6 ]
2-(aminomethyl-Arg(Pbf)-Gly-NAc)-4-carbomethoxypyridine [ No CAS ]

Reference： [1]Patent: US2017/100390,2017,A1

33
[ 94413-64-6 ]
C₃₁H₄₉N₇O₈S [ No CAS ]

Reference： [1]Patent: US2017/100390,2017,A1

34
[ 94413-64-6 ]
C₃₆H₅₇N₇O₁₀S [ No CAS ]

Reference： [1]Patent: US2017/100390,2017,A1

35
[ 94413-64-6 ]
2-(aminomethyl-Arg(Pbf)-Gly-NAc)-4-carboxypiperidine [ No CAS ]

Reference： [1]Patent: US2017/100390,2017,A1

36
[ 2459-09-8 ]
[ 7677-24-9 ]
[ 94413-64-6 ]

Reference： [1]Chemistry - A European Journal,2017,vol. 23,p. 14733 - 14737

37
[ 94413-64-6 ]
[ 577778-58-6 ]

Reference： [1]Patent: CN107573330,2018,A

38
[ 94413-64-6 ]
[ 577778-88-2 ]

Reference： [1]Patent: CN107573330,2018,A

39
[ 94413-64-6 ]
MNI-137 [ No CAS ]