[ CAS No. 28900-10-9 ] {[proInfo.proName]}

Name: 28900-10-9|2-Chloro-6-methylnicotinonitrile|98%
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Quality Control of [ 28900-10-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 28900-10-9 ]

Product Details of [ 28900-10-9 ]

CAS No. :	28900-10-9	MDL No. :	MFCD00082767
Formula :	C₇H₅ClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YSBNBAYNISAUIT-UHFFFAOYSA-N
M.W :	152.58	Pubchem ID :	520400
Synonyms :

Calculated chemistry of [ 28900-10-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.93
TPSA :	36.68 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.86 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.7
Log Po/w (XLOGP3) :	1.93
Log Po/w (WLOGP) :	1.92
Log Po/w (MLOGP) :	0.73
Log Po/w (SILICOS-IT) :	2.4
Consensus Log Po/w :	1.74

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.45
Solubility :	0.547 mg/ml ; 0.00358 mol/l
Class :	Soluble
Log S (Ali) :	-2.32
Solubility :	0.723 mg/ml ; 0.00474 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.1
Solubility :	0.122 mg/ml ; 0.0008 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.73

Safety of [ 28900-10-9 ]

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 [ 28900-10-9 ]

* 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 [ 28900-10-9 ]
Downstream synthetic route of [ 28900-10-9 ]

[ 28900-10-9 ] Synthesis Path-Upstream 1~14

1
[ 28900-10-9 ]
[ 3222-48-8 ]

Reference： [1] Patent: EP104876, 1991, B1,

2
[ 28900-10-9 ]
[ 34107-46-5 ]

Reference： [1] Journal of the American Chemical Society, 1947, vol. 69, p. 2574,2577

3
[ 28900-10-9 ]
[ 56622-54-9 ]

Reference： [1] Journal of the American Chemical Society, 1947, vol. 69, p. 2574,2577

4
[ 4241-27-4 ]
[ 28900-10-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 130℃; for 2 h; Inert atmosphere	Step 1 6-Methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (45.0 g, 335 mmol) was added to phosphorus oxychloride (652 g, 4250 mmol), and stirred for two hours at 130° C. The residue obtained by concentrating the reaction solution was dissolved in methylene chloride, and 4 M sodium hydroxide aqueous solution was added until the pH became 8. The organic layer was separated, washed with (saturated) brine, and then dried with anhydrous sodium sulfate. 2-Chloro-6-methylnicotinonitrile (51.0 g, 99percent) was obtained by distilling off the solvent under reduced pressure. ¹H NMR (400 MHz, CDCl₃) δ 2.65 (s, 3H), 7.24 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H).

Reference： [1] Patent: US2017/145005, 2017, A1, . Location in patent: Paragraph 0149; 0150; 0151; 0152
[2] Heterocycles, 1995, vol. 41, # 6, p. 1307 - 1318
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 2206 - 2210
[4] Polish Journal of Chemistry, 1982, vol. 56, # 2, p. 419 - 423
[5] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2014, vol. 69, # 5, p. 509 - 518

5
[ 4241-27-4 ]
[ 28900-10-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	for 4 h; Reflux	A solution of (I) (1.34 g, 0.01 mol) in phosphorus oxychloride (10 mL) was refluxed for 4 h. The solid obtained afterpouring onto ice water was recrystallized from ethanol togive compound (II). Yield 93percent; mp 114.5°C. IR: 3049(CH arom.), 2929, 2843 (CH aliph.), 2229 (C≡N), 1585 (2C=N), 736 (C–Cl). 1H NMR: 2.4 (s, 3H, CH3),7.6–8.8 (m, 2H, ArH). 13C NMR: 23.0, 108.7, 116.8,121.7, 145.3, 152.6, 161.9. MS, m/z (percent): 152 (M+)(12.4312), 125 (100). Calcd. for C7H5ClN2 (152.58):C, 55.10; H, 3.30; N, 18.36. Found: C, 55.43; H, 3.02;N, 18.71.

Reference： [1] Russian Journal of Bioorganic Chemistry, 2016, vol. 42, # 4, p. 441 - 448
[2] Bulletin de la Societe de Pharmacie de Lille, 1955, p. 60
[3] Journal of the American Chemical Society, 1947, vol. 69, p. 2574,2577
[4] Yakugaku Zasshi, 1944, vol. 64, # 3, p. 145,150[5] Chem.Abstr., 1951, p. 4724
[6] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 101 - 108

6
[ 3222-48-8 ]
[ 28900-10-9 ]

Reference： [1] Australian Journal of Chemistry, 1982, vol. 35, # 7, p. 1451 - 1468

7
[ 40108-12-1 ]
[ 28900-10-9 ]

Reference： [1] Journal of Organic Chemistry, 1942, vol. 7, p. 286,295
[2] Journal of Organic Chemistry, 1942, vol. 7, p. 286,295

8
[ 18619-97-1 ]
[ 28900-10-9 ]

Reference： [1] Journal of Organic Chemistry, 1942, vol. 7, p. 286,295
[2] Journal of Organic Chemistry, 1942, vol. 7, p. 286,295

9
[ 500545-40-4 ]
[ 28900-10-9 ]

Reference： [1] Journal of Organic Chemistry, 1942, vol. 7, p. 286,295

10
[ 31795-59-2 ]
[ 28900-10-9 ]
[ 83640-36-2 ]

Reference： [1] Australian Journal of Chemistry, 1982, vol. 35, # 7, p. 1451 - 1468

11
[ 500546-18-9 ]
[ 28900-10-9 ]

Reference： [1] Journal of Organic Chemistry, 1942, vol. 7, p. 286,295

12
[ 28900-10-9 ]
[ 30529-70-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	at 110℃; for 2 h;	To a solution of 2-chloro-3-cyano-6-methylpyridine (3.05 g) was added 75percent sulfuric acid (10 mL)The mixture was stirred at 110 ° C for 2 hours. The reaction solution was cooled to room temperature,A small amount of successive injection into the ice water. The ice-water was stirred for 10 minutes, and the precipitated crystals were collected by filtration and dried.2.91 g (85percent) of 2-chloro-6-methylnicotinic acid was obtained. To a solution of the resulting 2-chloro-6-methylnicotinic acid (2.91 g)Was added 28percent aqueous ammonia solution (35 mL) and reacted in an autoclave at 170 ° C for 40 hours.The reaction solution was cooled to room temperature, and ammonia was removed under reduced pressure. The precipitated crystals were collected by filtration,Further washed with water and air-dried. Amino-6-methylnicotinic acid 1.91 g (yield 74percent) was obtained.The overall yield is62.9percent.

Reference： [1] Patent: TW2016/509, 2016, A, . Location in patent: Page/Page column 6

13
[ 31795-59-2 ]
[ 28900-10-9 ]
[ 83640-36-2 ]

Reference： [1] Australian Journal of Chemistry, 1982, vol. 35, # 7, p. 1451 - 1468

14
[ 28900-10-9 ]
[ 53234-56-3 ]

Reference： [1] Patent: WO2009/145829, 2009, A1,

[ 28900-10-9 ] Synthesis Path-Downstream 1~69

1
[ 4241-27-4 ]
[ 28900-10-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With trichlorophosphate; for 4h;Reflux;	A solution of (I) (1.34 g, 0.01 mol) in phosphorus oxychloride (10 mL) was refluxed for 4 h. The solid obtained afterpouring onto ice water was recrystallized from ethanol togive compound (II). Yield 93%; mp 114.5C. IR: 3049(CH arom.), 2929, 2843 (CH aliph.), 2229 (C?N), 1585 (2C=N), 736 (C-Cl). 1H NMR: 2.4 (s, 3H, CH3),7.6-8.8 (m, 2H, ArH). 13C NMR: 23.0, 108.7, 116.8,121.7, 145.3, 152.6, 161.9. MS, m/z (%): 152 (M+)(12.4312), 125 (100). Calcd. for C7H5ClN2 (152.58):C, 55.10; H, 3.30; N, 18.36. Found: C, 55.43; H, 3.02;N, 18.71.

Reference： [1]Russian Journal of Bioorganic Chemistry,2016,vol. 42,p. 441 - 448
[2]Bulletin de la Societe de Pharmacie de Lille,1955,p. 60
[3]Journal of the American Chemical Society,1947,vol. 69,p. 2574,2577
[4]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1944,vol. 64,p. 145,150
Chem.Abstr.,1951,p. 4724
[5]European Journal of Medicinal Chemistry,2015,vol. 93,p. 101 - 108

2
[ 28900-10-9 ]
[ 56622-54-9 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 2574,2577

3
[ 28900-10-9 ]
[ 84647-20-1 ]

Yield	Reaction Conditions	Operation in experiment
82%	With ammonia; In ethanol; at 130℃; for 20h;	Example 9; 4-[4-(4-Methoxy-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenol; Example 9A; 2-Amino-6-methyl-nicotinonitrile; [0297] 2-Chloro-6-methyl-nicotinonitrile (25 g, 0.164 mol) and liquid ammonia (250 mL) in 500 mL of ethanol were reacted in a sealed high-pressure vessel at 1300C for 20 hours. The reaction mixture was concentrated under vacuum and the residue washed with water (2 x 50 mL) then dried in a vacuum oven for 24 hours to provide the title compound as a light yellow solid (18 g, 82%). 1H <n="79"/>NMR (300 MHz, DMSO-d6) delta ppm:2.30 (s, 3H), 6.52 (d, J= 7.7 Hz, IH), 6.78 (s, 2H), 7.73 (d, J= 7.7 Hz, IH).
82%	With ammonia; In ethanol; at 130℃; for 20h;	2-Chloro-6-methyl-nicotinonitrile (25 g, 0.164 mol) and liquid ammonia (250 mL) in500 mL of ethanol were reacted in a sealed high-pressure vessel at 1300C for 20 hours. The reaction mixture was concentrated under vacuum and the residue washed with water (2 x 50 mL) then dried in a vacuum oven for 24 hours to provide the title compound as a light yellow solid (18 g, 82%). 1H NMR (300 MHz, DMSOd6) delta ppm:2.30 (s, 3H), 6.52 (d, J= 7.7 Hz, IH), 6.78 (s, 2H), 7.73 (d, J= 7.7 Hz, IH).
70%	With ammonia; In ethanol; at 180℃; for 60h;Autoclave;	1 ) <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (2.00 g, 13.1 mmol) was dispersed in 12 ml of absolute ethanol, saturated with ammonia, and placed in a high-pressure autoclave. The reaction mixture was heated to 180 C for 60 h. Then, after cooling to room temperature, the solvent was evaporated under reduced pressure. The crude product was recrystallized from ethanol obtaining 2-amino-6- methylnicotinonitrile in 70% yield.

70%	With ammonia; In ethanol; at 180℃; for 60h;Autoclave;	1) <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (2.00 g, 13.1 mmol) was dispersed in 12 ml of absolute ethanol, saturated with ammonia, and placed in a high-pressure autoclave. The reaction mixture was heated to 180 C. for 60 h. Then, after cooling to room temperature, the solvent was evaporated under reduced pressure. The crude product was recrystallized from ethanol obtaining 2-amino-6-methylnicotinonitrile in 70% yield.
41%	With ammonia; In ethanol; at 170℃; for 15h;	Ammonia was blown into ethanol (50 mL)A solution of saturated ammonia in ethanol (about 10%) was prepared. 2-Chloro-3-cyano-6-methylpyridine (3.05 g) was added thereto and reacted in an autoclave at 170 C for 15 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (gradient of hexane: ethyl acetate = 9: 1 to 1: 9) to obtain 2-amino-3-cyano-6-methylpyridine 1.10 g (41%).To the resulting 2-amino-3-cyano-6-methylpyridine 1.10 g was added 15% potassium hydroxide (10 mL)The mixture was stirred at 100 C for 3 hours. The reaction solution was cooled to room temperature, and the pH value was adjusted to 4 to 5 by adding 4 N hydrochloric acid dropwise. The precipitated crystals were collected by filtration, washed further with water and air-dried.obtainAmino-6-methylnicotinic acid 1.18 g (94% yield). The overall yield was 38.5%.

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9482 - 9495
[2]Patent: WO2007/76034,2007,A2 .Location in patent: Page/Page column 77-78
[3]Patent: WO2008/133753,2008,A2 .Location in patent: Page/Page column 60
[4]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2206 - 2210
[5]Patent: WO2012/97869,2012,A1 .Location in patent: Page/Page column 10-11
[6]Patent: US2013/289081,2013,A1 .Location in patent: Paragraph 0052
[7]Polish Journal of Chemistry,1982,vol. 56,p. 419 - 423
[8]Patent: TW2016/509,2016,A .Location in patent: Paragraph 6; 7
[9]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1944,vol. 64,p. 145,150
Chem.Abstr.,1951,p. 4724
[10]Patent: WO2019/82140,2019,A1

4
[ 4241-27-4 ]
[ 28900-10-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With trichlorophosphate; at 130℃; for 2h;Inert atmosphere;	Step 1 6-Methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (45.0 g, 335 mmol) was added to phosphorus oxychloride (652 g, 4250 mmol), and stirred for two hours at 130 C. The residue obtained by concentrating the reaction solution was dissolved in methylene chloride, and 4 M sodium hydroxide aqueous solution was added until the pH became 8. The organic layer was separated, washed with (saturated) brine, and then dried with anhydrous sodium sulfate. 2-Chloro-6-methylnicotinonitrile (51.0 g, 99%) was obtained by distilling off the solvent under reduced pressure. 1H NMR (400 MHz, CDCl3) delta 2.65 (s, 3H), 7.24 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H).
77%	With trichlorophosphate; In 1,4-dioxane; at 80℃; for 1h;	General procedure: To a solution of 9a-9h (10 mmol) in 10 mL of 1,4-dioxane, POCl3(2.3 mL, 25 mmol) was added dropwise. The reaction mixture wasstirred at 80 C for 1 h. After cooled to room temperature, themixture was poured to 50 mL of ice water. 20 N NaOH aqueoussolutionwas added to adjust pH = 7. Solid was precipitated, filteredand purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10:1) to provide the title compound. 1H NMR and13C NMR data of selected products are shown as follows.

Reference： [1]Patent: US2017/145005,2017,A1 .Location in patent: Paragraph 0149; 0150; 0151; 0152
[2]Heterocycles,1995,vol. 41,p. 1307 - 1318
[3]European Journal of Medicinal Chemistry,2019,vol. 172,p. 131 - 142
[4]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2206 - 2210
[5]Polish Journal of Chemistry,1982,vol. 56,p. 419 - 423
[6]Zeitschrift fur Naturforschung, B: Chemical Sciences,2014,vol. 69,p. 509 - 518

5
[ 31795-59-2 ]
[ 28900-10-9 ]
[ 83640-36-2 ]

Reference： [1]Australian Journal of Chemistry,1982,vol. 35,p. 1451 - 1468

6
[ 28900-10-9 ]
[ 5798-75-4 ]
[ 296776-90-4 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 5039 - 5042
[2]Tetrahedron,2009,vol. 65,p. 6141 - 6146

7
[ 28900-10-9 ]
[ 619-42-1 ]
4-(3-cyano-6-methyl-pyridin-2-yl)-benzoic acid methyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 5039 - 5042

8
[ 28900-10-9 ]
[ 368426-79-3 ]

Yield	Reaction Conditions	Operation in experiment
30%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 85℃; for 4h;	A solution of <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (42 g, 276 mmol), benzoyl peroxide (6.7 g, 27.6 mmol), and NBS (62 g, 276.3 mmol) in CCI4 (800 mL) was stirred for 4 hours at 85C. The reaction mixture was cooled to 25C, filtered, and concentrated under reduced pressure. The residue was recrystallized from Petroleum Ether:EtOAc (10: 1 ) to afford 6-(bromomethyl)-2-chloronicotinonitrile as a white solid (19 g, 30%). MS (ESI) m/z: 231 [M+H]+.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In benzene; for 48h;Heating / reflux;	A mixture of the 2-chloro-6-methyl-3 -pyridine (6.0 g, 39.4 mmol), N-bromosuccinimide (7.7 g, 43.3 mmol) and AIBNu (0.56 g) in anhydrous benzene (100 ml) were heated at o reflux for 48 hours. The mixture was cooled to room temperature and then chilled in an ice bath for 30 minutes with vigourous stirring. The insoluble material was removed by filtration and the solvent removed in vacuo. The resulting solid was redissolved in acetonitrile (100 ml), triphenylphosphine (10.3 g, 39.4 mmol) was added and the mixture was refluxed for 24 hours. Upon cooling the solid material was collected by suction 5 filtration, washed with acetonitrile and sucked dry to afford the title compound as a white solid (6.7 g, 35%).1H NuMR (400 MHz, DMSO-d6): delta 5.60-5.66 (m, 2H); 7.54 (d, IH, J = 7.8); 7.70 -7.92(m, 15H); 8.42 (d, IH, J = 8.1).

Reference： [1]Patent: WO2015/100609,2015,A1 .Location in patent: Page/Page column 36
[2]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2925 - 2930
[3]Patent: WO2006/65204,2006,A1 .Location in patent: Page/Page column 130
[4]Patent: WO2019/149660,2019,A1 .Location in patent: Page/Page column 82

9
[ 28900-10-9 ]
[ 60787-05-5 ]
[ 929616-26-2 ]

Reference： [1]Synthesis,2007,p. 51 - 54

10
[ 28900-10-9 ]
[ 100-01-6 ]
[ 1016641-72-7 ]

Yield	Reaction Conditions	Operation in experiment
31%	With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 20℃; for 20.5h;Heating / reflux;	Example 22: Scheme H; An oven-dried flask was charged with (rac)-BINAP (0.02 equiv., 1.31 mmol, 0.816 g), palladium(II) acetate (0.02 equiv., 1.31 mmol, 0.294 g) and toluene (400 ml), and then flushed with Ar. The mixture was stirred at room temperature for 30 min. The resulting solution was added to a mixture of 2-chloro-6-methyl-3-pyridinecarbonitrile (H.I) (1 equiv., 65.5 mmol, 10.0 g), 4-nitroaniline (1.2 equiv., 78.6 mmol, 10.9 g) and K2CO3 (20 equiv., 1310 mmol, 181 g). The reaction mixture was heated to reflux under N2 for 20 h. After cooling down, ethyl acetate was added, the reaction mixture was filtered over Celite and the filtrate was partially evaporated under reduced pressure. Upon concentrating, the product precipitated. The precipitate was isolated by filtration, washed with toluene and dried in a vacuum oven to afford compound H.2 (5.1O g, yield = 31 %).

Reference： [1]Patent: WO2008/37784,2008,A1 .Location in patent: Page/Page column 56

11
[ 3222-48-8 ]
[ 28900-10-9 ]

Reference： [1]Australian Journal of Chemistry,1982,vol. 35,p. 1451 - 1468

12
[ 28900-10-9 ]
[ 34107-46-5 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 2574,2577

13
[ 28900-10-9 ]
[ 846021-26-9 ]

Yield	Reaction Conditions	Operation in experiment
82.9%		To a solution of 2-chloro-3-cyano-6-methylpyridine (6.10 g) was added a 28% aqueous ammonia solution (70 mL)The reaction was carried out in an autoclave at 170 C for 7 hours. The reaction solution was cooled to room temperature,The ammonia was removed under reduced pressure Add potassium hydroxide (9.00 g) to the reaction mixture by removal of ammonia, and heated at 100 C under stirring for 3 hours. The reaction mixture was cooled to room temperature, 4N hydrochloric acid was added dropwise and the pH was adjusted to 4-5. The precipitated crystals were collected by filtration, further washed with water and air dried them. To obtain 2-amino-6-methyl nicotinic acid 5.04g (yield 82.9%). With the implementation of purity liquid chromatography analysis showed a high purity of 97.06%.

Reference： [1]Patent: TW2016/509,2016,A .Location in patent: Page/Page column 6
[2]Bulletin de la Societe de Pharmacie de Lille,1955,p. 60
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 9482 - 9495
[4]Patent: TW2016/509,2016,A

14
[ 40108-12-1 ]
[ 28900-10-9 ]

Reference： [1]Journal of Organic Chemistry,1942,vol. 7,p. 286,295
[2]Journal of Organic Chemistry,1942,vol. 7,p. 286,295

15
[ 18619-97-1 ]
[ 28900-10-9 ]

Reference： [1]Journal of Organic Chemistry,1942,vol. 7,p. 286,295
[2]Journal of Organic Chemistry,1942,vol. 7,p. 286,295

16
[ 28900-10-9 ]
para-chlorothiophenol [ No CAS ]
[ 955-63-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃; for 16h;	2-Chloro-3-cyano-6-methylpyridine (1 g, 6.5 mmol), K2CO3 (1.4 g, 10 mmol), and 4-chlorothiophenol (1 g, 7 mmol) were combined in DMF (30 mL) and heated at 50 C. for 16 hours. The mixture was allowed to cool to room temperature, poured into water (100 mL), and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried with MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was treated with hexane and the precipitated solid was filtered to provide the title compound. 1H NMR (300 MHz, DMSO-d6) delta 2.38 (s, 3H), 7.26 (m, 1H), 7.55 (m, 4H), 8.18 (d, J=9 Hz, 1H); MS (DCI/NH3) m/z 261 (M+H)+.

Reference： [1]Patent: US2004/192680,2004,A1 .Location in patent: Page 18

17
[ 28900-10-9 ]
[ 267413-15-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-chloro-succinimide; dibenzoyl peroxide; In benzene;	Step A 2-Chloro-6-chloromethyl-3-cyanopyridine NCS (1.44 g, 10.8 mmol) and benzoyl peroxide (238 mg, 0.98 mmol) were added to a stirred solution of 2-chloro-3-cyano-6-methyl-pyridine (750 mg, 4.92 mmol) in benzene (35 mL) and the mixture was heated to reflux. After 4 h, the mixture was cooled and filtered. The filtrate was diluted with ethyl acetate and was washed with sodium metabisulfite solution, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography on silica (chloroform) to give the title compound: 1H NMR (CDCl3) delta 4.68 (s, 2H), 7.62 (d, J=7.9 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H).

Reference： [1]Patent: US6376499,2002,B1

18
[ 28900-10-9 ]
[ 2365-48-2 ]
[ 193400-52-1 ]

Yield	Reaction Conditions	Operation in experiment
98%		General procedure: Chlorocyanopyridine (0.005 mol), methyl thioglycolate (0.01 mol) and potassium carbonate (0.0075 mol) were mixed in 100 mL of DMF. The mixture was stirred for 24 h at room temperature and then poured into ice-water. The precipitated product was filtered off and dried. It was then cyclized by adding it to 0.005 moles of sodium methanolate in 25 mL of methanol. The mixture was stirred for one hour at room temperature and then poured into ice-water. The precipitated product was filtered off, dried and purified by recrystallization from methanol.
75%	With triethylamine; In methanol; at 80℃;	General procedure: A mixture of 10a-10k (1 mmol), methyl thioglycolate (159 mg,1.5 mmol) and Et3N (152 mg, 1.5 mmol) in 10 mL of methanol was stirred at 80 C for 6-8 h. Methanol was removed under vacuum.The residuewas purified by column chromatography to provide thetitle compound.
63 g (96%)	With triethylamine; In dimethyl sulfoxide;	EXAMPLE I Methyl 3-amino-6-methyl-thieno[2,3-b]pyridine-2-carboxylate STR14 45 g (295 mmol) of 2-chloro-6-methylpyridine-3-carbonitrile are dissolved in 180 ml of DMSO and treated with 90 ml (649 mmol) of triethylamine and 28 ml (310 mmol) of methyl mercaptoacetate, and the mixture is stirred at 80 C. for 18 h. It is allowed to come to room temperature, is tipped onto ice-water, the precipitate is filtered off with suction, and the residue is washed with petroleum ether and dried for 5 h in a recirculating air oven at 60 C. Yield: 63 g (96%) MS: 222 ?M30, 100%! 1 H-NMR (D6 -DMSO, TMS): 8.4 (d, J=9 Hz, 1H); 7.83 (d, J=9 Hz, 1H); 7.26 (s, 2H); 3.8 (s, 3H); 2.58 (s, 3H).

Reference： [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2014,vol. 69,p. 509 - 518
[2]European Journal of Medicinal Chemistry,2019,vol. 172,p. 131 - 142
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 2606 - 2618
[4]Patent: US5827857,1998,A

19
[ 28900-10-9 ]
[ 41038-69-1 ]
[ 108-95-2 ]
6-Methyl-2-[[3-(3-pyridinyl)propyl]amino] 3-pyridinecarbonitrile, dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide	99 6-Methyl-2-[[3-(3-pyridinyl)propyl]amino] 3-pyridinecarbonitrile, dihydrochloride Example 99 6-Methyl-2-[[3-(3-pyridinyl)propyl]amino] 3-pyridinecarbonitrile, dihydrochloride The title compound is prepared by the procedure of Example 9, using 3.1 g of 2-chloro-6-methyl-3-pyridinecarbonitrile, 5.4 g of 3-pyridinepropanamine, 0.10 g potassium iodide and 15 ml of phenol. The product is recrystallized from methanol/diethyl ether to give 2.2 g of tan crystals, mp 188-190oC.

Reference： [1]Current Patent Assignee: PFIZER INC - EP446604, 1991, A2

20
[ 28900-10-9 ]
[ 3222-48-8 ]

Yield	Reaction Conditions	Operation in experiment
		c) 3-Cyano-6-methylpyridine was prepared by hydrogenation of 2-chloro-3-cyano-6-methylpyridine following essentially the same procedure as that described by Bobbitt and Scola (J. Org. Chem. 25 , 560, 1960).

Reference： [1]Patent: EP104876,1991,B1

21
[ 28900-10-9 ]
[ 74-88-4 ]
[ 191220-22-1 ]

Yield	Reaction Conditions	Operation in experiment
46%		Into a 500-mL round-bottom flask was added 2-chloro-6-methylpyridine-3- carbonitrile (8.00 g, 52.4 mmol) and D F (200 mL), The resulting mixture was cooled to 0 C and sodium hydride (60% dispersion in mineral oil; 3.00 g, 125 mmol) was added portion-wise. The reaction mixture was stirred for 10 mill and then iodomethane (29,6 g, 13.0 mL, 209 mmol) was added dropwise with stirring. The resulting solution was stirred for 2 h at RT and then quenched with H2O (500 mL). The reaction mixture was extracted with ethyl acetate (3 x lOOmL), and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by FCC eluting with ethyl acetate / petroleum ether (1 :5) to afford 2-chloro-6- ethylnicotinonitrile as a yellow oil (4 g, 46%). LCMS (ESI, m/z): 168 [M+Hf .

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9482 - 9495
[2]ChemMedChem,2016,p. 1904 - 1914
[3]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00307
[4]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2206 - 2210

22
[ 28900-10-9 ]
[ 617703-01-2 ]
N-(2-aminophenyl)-4-(3-cyano-6-methylpyridin-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 100℃; for 0.5h;Microwave heating;	1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (ii) chloride (32 mg, 0.044 mmol) was added to a mixture of n-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (389 mg, 0.887 mmol; prepared as described in international patent publication number wo03/087057, method 13, page 60), 2-chloro-6-methyl-3-pyridinecarbonitrile (135 mg, 0.887 mmol) and saturated aqueous sodium hydrogen carbonate solution (2 ml) in 1,2-dimethoxyethane (4 ml). the mixture was heated in a microwave at 100 c. for 30 minutes. the mixture was allowed to cool, then partitioned between dichloromethane (30 ml) and water (20 ml). the aqueous layer was extracted with further dichloromethane (2×30 ml). combined organics were dried over magnesium sulfate then evaporated. the residue was purified by flash chromatography (eluting with 99:1?97:3 dichloromethane:methanol) to afford the title compound as a yellow gum which crystallised on trituration (80 mg, 27%).Nmr spectrum: (cdcl3) 2.72 (s, 3h), 3.88 (br s, 2h), 6.86 (m, 2h), 7.11 (m, 1 h), 7.28 (d, 1 h), 7.37 (d, 1 h), 8.05 (m, 6h); mass spectrum: m+h+329.

Reference： [1]Patent: US2008/293687,2008,A1 .Location in patent: Page/Page column 42

23
[ 28900-10-9 ]
[ 623-51-8 ]
[ 52505-51-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium ethanolate; In N,N-dimethyl-formamide; at 20℃; for 1h;	Reference Example 52 ethyl 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylate To a solution of <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (44.0 g, 0.289 mol) and ethyl thioglycolate (35.0 mL, 0.318 mol) in DMF (500 mL) was added sodium ethoxide (21.7 g, 0.318 mol), and the mixture was stirred at room temperature for 30 min. Sodium ethoxide (5.00 g, 73.5 mmol) was added again, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried to give the title compound (66.4 g, yield 97%) as a yellow solid. 1H NMR (CDCl3) delta1.39 (3H, t, J = 7.2 Hz), 2.68 (3H, s), 4.36 (2H, q, J = 7.2 Hz), 5.89 (2H, br), 7.16 (1H, d, J = 8.3 Hz), 7.81 (1H, d, J = 8.3 Hz).
97%	With sodium ethanolate; In N,N-dimethyl-formamide; at 20℃; for 1h;	Reference Example 6 ethyl 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylate [Show Image] To a solution of <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (44.0 g, 0.289 mol) and ethyl thioglycolate (35.0 mL, 0.318 mol) in DMF (500 mL) was added sodium ethoxide (21.7 g, 0.318 mol), and the mixture was stirred at room temperature for 30 min. Further, sodium ethoxide (5.00 g, 73.5 mmol) was added and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the precipitated solid was collected by filtration, washed with water, and dried to give the title compound (66.4 g, yield 97%) as a yellow solid. 1H NMR (CDCl3) delta1.39 (3H, t, J = 7.2 Hz), 2.68 (3H, s), 4.36 (2H, q, J = 7.2 Hz), 5.89 (2H, br), 7.16 (1H, d, J = 8.3 Hz), 7.81 (1H, d, J = 8.3 Hz).
97%		Reference Example 43 ethyl 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylate To a solution of <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (44.0 g, 0.289 mol) and ethyl thioglycolate (35.0 mL, 0.318 mol) in DMF (500 mL) was added sodium methoxide (21.7 g, 0.318 mol), and the mixture was stirred at room temperature for 30 min. Sodium ethoxide (5.00 g, 73.5 mmol) was further added, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the precipitated solid was collected by filtration, washed with water, and dried to give the title compound (66.4 g, yield 97%) as a yellow solid. 1H NMR (CDCl3) delta1.39 (3H, t, J = 7.2 Hz), 2.68 (3H, s), 4.36 (2H, q, J = 7.2 Hz), 5.89 (2H, br), 7.16 (1H, d, J = 8.3 Hz), 7.81 (1H, d, J = 8.3 Hz).

97%	With sodium ethanolate; In N,N-dimethyl-formamide; at 70℃; for 1h;	To a mixture of <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (38b) (44.0g, 289 mmol) and ethyl thioglycolate (35.0 mL, 318 mmol) in DMF (500 mL), NaOEt (21.7 g, 318 mmol) was added and the mixture was stirred for 0.5 h. Then NaOEt (5.00 g, 73.5 mmol) was added and the mixture was stirred for additional 0.5 h. The resulting mixture was diluted with H2O, then precipitate was collected and washed with H2O to afford 39b (66.4 g, 97%). 1H NMR (CDCl3) delta 1.39 (3H, t, J = 7.2 Hz), 2.68 (3H, s), 4.36 (2H, q, J = 7.2 Hz), 5.89 (2H, br), 7.16 (1H, d, J = 8.3 Hz), 7.81 (1H, d, J = 8.3 Hz).
85%	With water; potassium hydroxide; In N,N-dimethyl-formamide; at 0℃; for 1h;	(0688) [00261] To a solution of <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (1.00 g, 6.55 mmol) in DMF (10 ml) was added ethyl 2-mercaptoacetate (0,72 ml, 6.6 mmol) followed by a solution of potassium hydroxide (powder) ( 1.47 g, 26.2 mmol) in 3.0 mL of water at 0 C. The reaction was stirred at 0 C for 1 hour resulting in a precipitate. The precipitate was collected via filtration, washed with water (10 mL) followed by ether (10 mL) and then dried in vacuo to afford ethyl 3-amino- 6-methylthieno[2,3-6]pyridine-2-carboxylate as a yellow powder (1.3 g, 85%). LCMS (ESI, m/z): 237 [M-H] ' .

Reference： [1]Patent: EP2009011,2008,A1 .Location in patent: Page/Page column 41
[2]Patent: EP2123652,2009,A1 .Location in patent: Page/Page column 44-45
[3]Patent: EP2128163,2009,A1 .Location in patent: Page/Page column 57
[4]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3643 - 3647
[5]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00261

24
[ 28900-10-9 ]
[ 5798-75-4 ]
C₁₄H₁₀N₄ [ No CAS ]
[ 296776-90-4 ]

Reference： [1]Angewandte Chemie - International Edition,2008,vol. 47,p. 2089 - 2092

25
[ 28900-10-9 ]
[ 24424-99-5 ]
[ 1104643-35-7 ]

Reference： [1]Tetrahedron,2009,vol. 65,p. 134 - 138

26
[ 28900-10-9 ]
[ 1107620-55-2 ]
6-Methyl-2-[4-[3-(6-bromo-2-pyridyl)prop-2-ynylidene]piperidin-1-yl]nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In ISOPROPYLAMIDE; at 20℃; for 4h;	A well homogenised mixture of Compound 237a (200 mg, 0.86 mmol), 2-bromo-3-nitropyridine (194 mg, 0.95 mmol) and triethylamine (249 muL, 1.74 mmol) in N,N-dimethylacetamide (15 mL) was stirred at r.t. for 4 h. Afterwards, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography eluting with Petroleum Ether-EtOAc 7:3, affording the title product (225 mg) as a yellow oil.MS: [M+H]+=353.40; The title compound was prepared as described for the compound of Example 237 but starting from Compound 305b instead of compound 237a and 2-chloro-6-methyl-3-nitropyridine instead of 2-bromo-3-nitropyridine. An additional equivalent of TEA was used. After the work-up, the residue was purified by automated flash liquid chromatography (Horizon-Biotage) eluting with PE-EtOAc gradient from PE:EtAc 95:5 to 6:4 affording the title product. Yellow oil. Yield: 95%.

Reference： [1]Patent: US2009/42841,2009,A1 .Location in patent: Page/Page column 82

27
[ 28900-10-9 ]
[ 1184-85-6 ]
[ 1073159-99-5 ]

Yield	Reaction Conditions	Operation in experiment
62.5%	With caesium carbonate; In acetonitrile; at 80℃; for 15h;	Step 1. Preparation of N-(3-cyano-6-methyl-pyridin-2-yl)-N-methyl-methanesulfonamide (B14-1): A solution of 2-chloro-6-methyl-nicotinonitrile (20 g, 131.5 mmol) in acetonitrile (300 mL) at 25 C. was treated with HN(CH3)SO2Me (13.1 mL, 124.1 mmol) and Cs2CO3 (60 g, 184.0 mm). The reaction mixture was then stirred at 80 C. for 15 hours. The reaction mixture was allowed to cool to 25 C. and filtered. The resultant filtrate was concentrated and diluted with EtOAc (600 mL). The organic solution was then washed with water (2*250 mL) and brine, and dried over anhydrous sodium sulfate. The organic solution was then concentrated, and the resultant residue was recrystallized with ether to provide B14-1 as an off white solid. Yield: 18.5 g, 62.5%. 1H NMR (CDCl3): delta 7.9 (d, 1H), 7.16-7.26 (m, 1H), 3.28 (s, 3H), 3.24 (s, 3H) and 2.22 (s, 3H). Mass: (M+1) 226 calculated for C9H11N3O2S.

Reference： [1]Patent: US2009/54395,2009,A1 .Location in patent: Page/Page column 42

28
[ 28900-10-9 ]
[ 1312772-66-9 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 216-(4-chlorobenzylthio)-5-cyanopicolinic acid (52) <n="101"/> Step 1Synthesis of 6-chloro-5-cyanopicolinic acid (51) To a solution of 6-chloro-5-cyano-2-picoline 50 (3.0 g, 20 mmol) in COnC-H2SO4 (20 ml) was added CrO3 (4.9 g, 49 mmol) portionwise over 2 hr period while the reaction mixture was kept below 2O 0 C. After stirring overnight at room temperature, the mixture was poured into ice-water and the resulting solid was collected by filtration to give the crude 6-chloro-5-(aminocarbonyl)-2-picolinic acid which was dissolved in POCl3 (15 ml). After heating at reflux for 30 min, the reaction mixture was concentrated in vacuo and the residue was treated with ice water. The precipitate was collected by filtration to afford 2.5 g (71% for 2 steps) of the desired product 51. 1H NMR (600MHz, DMSO-d6) delta 8.65 (delta, IH, theta= 7.8 Hzeta), 8.17 (delta, IH, theta= 7.8 Hzeta)

Reference： [1]Patent: WO2009/145829,2009,A1 .Location in patent: Page/Page column 98-9

29
[ 110-89-4 ]
[ 28900-10-9 ]
[ 89596-01-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 90℃; for 4h;Neat (no solvent);	To 2-chloro-6-methyl-3-pyridine carbonitrile (lg, 6.5 mmol) was added piperidine (2.56 mL, 4 mol eq) and the mixture was heated in neat at 90C for 4 h. The mixture was concentrated, water was added and the mixture was extracted with EtOAc (3x20mL). The recombined organic phases were anhydrified and evaporated to dryness to obtain 32b as pale yellow oil (1.28g, quantitative yield). 'HNMR (DMSO, 200 MHz) delta 1.54 (m, 6H), 2.16 (m, 4H), 3.1 1 (s, 3H), 7.28 (d, 1H, J=8), 7.64 (d, 1H).

Reference： [1]Patent: WO2011/120604,2011,A1 .Location in patent: Page/Page column 72; 73; 138
[2]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3291 - 3294

30
[ 28900-10-9 ]
[ 1239713-64-4 ]
[ 1239713-51-9 ]

Yield	Reaction Conditions	Operation in experiment
29.6%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 160℃; for 0.166667h;Sealed tube; Microwave irradiation;	Example 22; l-(3-cvano-6-methyl-2-pyridyl)-4-[(E)-3-(3-chlorophenyl)-prop-2-enylidene]-piperidine2-Chloro-6-methylnicotinonitrile (77.8 mg, 0.5 mmol) and K2CO3 (105 mg, 0.75 mmol) was weighed in a vial. Afterwards, Compound 3b (130 mg, 0.56 mmol) dissolved in 2 ml of N-methylpyrrolidone was added. The vial was sealed and heated in a microwave oven (CEM DISCOVER)at 1600C for 10 min. After cooling, the reaction mixture was diluted with water, extracted with EtOAc 3 times. The combined extracts were washed with brine, dried over Na2SO4, evaporated to dryness and purified by automated flash chromatography(SPl TM - Biotage; Petroleum Ether - EtOAc from 95 : 5) affording the title product as orange oil. Yield: 29.6 %.MS: [M+H]+ = 350.091H-NMR: (CDCIs1 S): 2.41 - 2.53 (m, 2 H) 2.46 (s, 3 H) 2.68 (t, J=5.50 Hz, 2 H) 3.83 (t,J=5.75 Hz, 4 H) 6.12 (d, J=I 1.00 Hz, 1 H) 6.47 (d, J=15.41 Hz, 1 H) 6.61 (d, J=7.82 Hz, 1 H) 7.06 (dd, J=I 5.41, 11.00 Hz, 1 H) 7.17 - 7.22 (m, 1 H) 7.22 - 7.33 (m, 2 H) 7.41 (s, 1 H) 7.66 (d, J=7.83 Hz, 1 H)

Reference： [1]Patent: WO2010/89119,2010,A1 .Location in patent: Page/Page column 52-53

31
[ 28900-10-9 ]
[ 1222881-74-4 ]

Yield	Reaction Conditions	Operation in experiment
29%	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 35℃;Inert atmosphere;	(0828) [00300] Into a 50-mL round-bottom flask that was purged and maintained under an inert atmosphere of nitrogen was added 2-chloro-6-methylpyridine-3-carbonitrile (0.200 g, 1.31 mmol), /ra-CPBA (0.339 g), and dichioromethane (6 mL). The solution was stirred overnight at (0829) 117 (0830) 144628010 vl 35 C then concentrated in vacuo. The resulting crude product was purified by FCC eluting with petroleum ether ; ethyl acetate (3 : 1) to afford 2-chloro-3-cyario-6-methylpyridine 1 -oxide as a white solid (65 rag, 29%). LCMS (ESI, m/z): 169 [M+H]+.

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 3396 - 3411
[2]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00300

32
[ 28900-10-9 ]
[ 623-50-7 ]
[ 917504-87-1 ]

Yield	Reaction Conditions	Operation in experiment
45%	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 75℃;Inert atmosphere;	To a suspension of 2-chloro-3-cyano-6-methylpyridine, 15 (2.Og, 13.1 mmol, 1eq) and cesium carbonate (12.8g, 39.3mmol, 3eq) in anhydrous NMP (2OmL) was added at rt ethyl glycolate (1.36ml_, 14.4mmol, 1.1eq) under Ar(g). The reaction mixture was heated up at 75C overnight; once cooled down, it was partitioned with H2O (20OmL) and extracted with EtOAc (3 x 7OmL). The combined organics were thoroughly washed with H2O (3 x 75mL), then dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (4:1-1 :3) to yield 16 as a pale yellow solid (1.30 g, 45%).1H NMR (400MHz, CDCI3) deltaH: 7.84 (d, J=8.0Hz, 1 H), 7.12 (d, J=8.0Hz, 1 H), 4.41 (q, J=7.0Hz, 2H), 4.26 (br. s., 2H), 2.66 (s, 3H), 1.42 (t, J=7.0Hz, 3H).MS (ES+) 221.0 (50%, [M+H]+), 243.0 (50%, [M+Na]+).
	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 75℃;	A solution of <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (5 g, 32.77 mmol), ethyl 2- hydroxyacetate (3.36 g, 32.28 mmol), and C52CO3 (32.2 g, 98.83 mmol) in NIVIP (80 mL) was stirred overnight at 75 C. After cooling to room temperature, the mixture was poured into 100 mL of water. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) afforded ethyl 3 -amino-6-methylfuro[2,3 -b]pyridine-2-carboxylate as a pink solid. MS: (ESI, m/z): 221 [M+H]t

Reference： [1]Patent: WO2011/21038,2011,A1 .Location in patent: Page/Page column 46
[2]Patent: WO2019/32863,2019,A1 .Location in patent: Paragraph 00236

33
[ 28900-10-9 ]
[ 41979-39-9 ]
[ 1249826-50-3 ]

Yield	Reaction Conditions	Operation in experiment
7.9%	With potassium carbonate;water; palladium diacetate; tert-butyl alcohol; XPhos; at 110℃; for 8h;Inert atmosphere;	l-(3-cvano-6-methyl-2-pyridyl)-4-oxo-piperidine (Compound 76a)To a mixture of K2C03 (774 mg, 5.6 mmol), 2-chloro-6-methynicotinonitrile (305 mg, 2 mmol) and piperidin-4-one.HCl.H20 (376 mg, 4 mmol) stirred under a nitrogen atmosphere, was added via syringe the pre-activated catalyst obtained from Pd(OAc)2 (4.6 mg, 0.02 mmol) and X-Phos (29.5 mg,0.06 mmol) by adding 4 ml di t-BuOH and 1 ,5 muLambda of degassed water and heating at 1 10C for 1.5 min. The resultant orange suspension was stirred at 1 10C for 2h. Another 2% of preformed catalyst was added and refluxing kept on for 5h. The suspension became yellow. After having added additional 0.8 eq. (251 mg.) of piperidinone.HCl.H20 and 1.6 mmol (221 mg) of K2C03 and refluxed for lh, the reaction mixture was cooled, diluted with EtOAc, washed with water, dried, evaporated to dryness in vacuo and purified by automated flash chromatography (Isolera TM - Biotage) eluting with a gradient PE - EtOAc from 85: 15 to 80:20 affording the title compound as yellowish solid (34 mg). Yield: 7.9%.MS: [M+H]+ = 216.15

Reference： [1]Patent: WO2011/29633,2011,A1 .Location in patent: Page/Page column 93-94

34
[ 28900-10-9 ]
[ 67-63-0 ]
[ 134938-47-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydride; In mineral oil; at 50℃;	The 2-chloro-6-methyl-nicotinonitrile (0.8g, 5.2 mmol) was added in small portion to a mixture of NaH 60% (4 mol eq, 0.8g) in isopropanol (30 mL). The reaction mixture was heated at 50C overnight. The solvent was distilled and water was added to the residue. The aqueous solution was extracted with EtOAc (3x30mL) and the organic phases were evaporated at reduced pressure to give 32a as a pale yellow deliquescent solid (1.25g, quantitative yield). 1HNM (DMSO, 200 MHz) delta 1.24 (s, 3H), 1.32 (s, 3H), 2.25 (s, 3H), 5.02 (m, 1H), 7.31 (d, 1H), 7.69 (m, 1H).

Reference： [1]Patent: WO2011/120604,2011,A1 .Location in patent: Page/Page column 122; 123; 138

35
[ 28900-10-9 ]
10-hydroxy-8-oxa-12-aza-tricyclo[7.3.1.0(2,7)]trideca-2⁽⁷⁾,3,5-triene-12-carboxylic acid methyl ester [ No CAS ]
methyl-3-((3-cyano-6-methylpyridin-2-yl)oxy)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocine-5(6H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74 mg	With copper(l) iodide; 3,4,7,8-Tetramethyl-o-phenanthrolin; caesium carbonate; In toluene; at 115℃; for 29h;Inert atmosphere;	General procedure: Methyl-3-((3-cyano-6-methylpyridin-2-yl)oxy)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5] oxazocine-5(6H)-carboxylate (22). A solution of alcohol 17 (126 mg, 0.38 mmol), CuI (22 mg, 0.11 mmol), Cs2CO3 (494 mg, 1.52 mmol) and 19 (54 mg, 0.23 mmol) in degassed toluene (4.0 mL) was pumped and purged with argon (x3) and sealed in a screwcap reaction vessel. The reaction was heated at 110 oC for 22 h and then cooled to room temperature. 2-Bromo-3-cyano-6-methylpyridine (151 mg, 0.99 mmol) and more CuI (22 mg, 0.11 mmol) were added and the reaction was heated at 115 oC for 29 h. After cooling to room temperature, the mixture was filtered through a plug of Celite and the filter plug was rinsed with multiple portions of CH2Cl2. The combined filtrate and washings were concentrated under reduced pressure and the crude residue was purified via column chromatography (SiO2) eluting with hexanes/EtOAc (100:0; 90:10; 70:30; 60:40) to give 74 mg (53%) of 22 as a light yellow solid: mp 170-172 oC; 1H NMR (400 MHz, CDCl3) (rotamers) delta 7.76 (d, J = 8.0 Hz, 1 H), 7.26-7.11 (comp, 2 H), 6.94 (d, J = 8.4 Hz, 1 H), 6.90-6.84 (comp, 2 H), 5.46-5.42 (m, 0.6 H), 5.32-5.26 (m, 1 H), 5.24-5.22 (m, 0.4 H), 5.04-4.98 (m, 1 H), 4.40-4.33 (m, 0.4 H), 4.26-4.18 (m, 0.6 H), 3.82 (s, 1.3 H), 3.71 (s, 1.7 H), 2.98-2.83 (m, 1 H), 2.50 (s, 3 H), 2.23-2.15 (comp, 2 H); 13C NMR (75 MHz, CDCl3) (rotamers) delta 162.3, 162.2, 155.9, 155.3, 143.6, 130.3, 129.6, 129.2, 120.8, 120.5, 116.9, 116.6, 116.4, 115.4, 94.3, 73.4, 73.0, 69.2, 53.3, 53.1, 45.9, 45.6, 39.9, 39.7, 28.1, 27.7, 25.0; IR (thin film, neat) 3061, 2961, 2231, 1701, 1596, 1458, 1420, 1272, 1229 cm-1; mass spectrum (ESI) m/z 388.1266 [C20H19N3O4Na (M+Na) requires 388.1268.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6855 - 6858

36
[ 28900-10-9 ]
[ 1066-54-2 ]
C₁₂H₁₄N₂Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; tri-tert-butyl phosphine; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In benzene; at 50℃; for 7h;Inert atmosphere;	Example 1186-Methyl-2-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)nicotinonitrile[00325]3-Bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)-one is prepared in close analogy to the procedure descibed for the synthesis of 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (Preparation 1 ) starting with 5-methylcyclohexane-1 ,3-dione.[00326]2-Ethynyl-6-methylnicotinonitrile is prepared in two steps starting from 2-chloro- 6-methylnicotinonitrile (1 .53 g, 10.0 mmol), which is reacted with ethynyltnmethylsilane (1 .473 g, 15.0 mmol), PdCI2[PPh3]2 (351 mg, 0.50 mmol), Cul (192 mg, 1 .00 mmol), P(t- Bu)3 (202 mg, 1 .00 mmol), and TEA (25 mL) in benzene (50 mL) under argon atmosphere at 50 C for 7 h. The reaction mixture is cooled to r.t. and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, DCM/hexane), and the obtained intermediate product is dissolved in THF (15 mL). 1 N TBAF solution in THF (10 mL) is added dropwise at -30 C. The resulting mixture is stirred at 0 C for 20 min, quenched with water (150 mL) at 0 C and extracted with hexane (2x100 mL). The combined organic phases are washed with water, dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give 2-ethynyl-6- methylnicotinonitrile (980 mg, 69% for two steps) as brownish solid.[00327]According to General Procedure 1 , 3-bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)- one (200 mg, 0.83 mmol) is reacted with 2-ethynyl-6-methylnicotinonitrile (1 13 mg, 0.80 mmol) in the presence of PdCI2[dppf] (26 mg, 0.03 mmol), and Cs2C03 (780 mg, 2.40 mmol) in dioxane (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (25 mg, 1 1 %). 1 H NMR (De-DMSO), deltaEta, 1 .20 (d, 3H), 2.34-2.48 (m, 2H), 2.67 (s, 3H), 2.76-2.94 (m, 2H), 3.27 (d, 1 H), 7.25 (d, 1 H), 7.87 (d, 1 H), 8.50 (s, 1 H), 8.94 (s, 1 H).LC/MS (M+H)+ = 302, 343

Reference： [1]Patent: WO2012/52451,2012,A1 .Location in patent: Page/Page column 115

37
[ 28900-10-9 ]
[ 3395-04-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thiourea; In butan-1-ol; at 118℃; for 4h;	A mixture of <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (220 mg, 1 .45 mmol) and thiourea (348 mg, 4.57 mmol) was heated at reflux (1 18 C) in n-butanol for 4 h. After cooling to room temperature, the yellow solution turned to a suspension containing light yellow solids. The solids were collected by filtration, rinsed with n-butanol, and dried in vacuo to give 2-mercapto-6-methylnicotinonitrile (218 mg, 100% yield). C7H6N2S; yellow powder; 1 H NMR (400 MHz, CDCI3) delta 7.97 (1 H, dt, J = 8, 0.8 Hz), 7.79 (1 H, dt, J = 8, 0.8 Hz), 7.70 (1 H, td, J = 8, 1 .2 Hz), 7.46 (1 H, td, J = 8, 1 .2 Hz), 4.64 (2 H, s); 13C NMR (100 MHz, CDCI3) delta 177.39, 154.77, 144.83, 1 17.1 , 1 13.3, 1 12.7, 19.2; ESI-HRMS (negative mode) calcd for C7H5N2S: 149.0173, found: m/z 149.0172 [M - H]-.

Reference： [1]Patent: WO2012/72019,2012,A1 .Location in patent: Page/Page column 63
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 11148 - 11160

38
[ 110-85-0 ]
[ 28900-10-9 ]
[ 622405-21-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	at 110 - 140℃; for 1.5h;Inert atmosphere;	2-Chloro-6-methylpyridine-3-carbonitrile (250 mg, 1.64 mmol) and piperazine (1.4 g,16 mmol) were added to a reaction tube under nitrogen. The tube was sealed and the reaction wasstirred at 110 C for 30 mm, at which point the piperazine had melted to form an orange solution.The reaction mixture was then heated at 140 C for 1 hour. The reaction was diluted with water(30 ml) and extracted with EtOAc (3 x 30m1). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and concentrated in vacuo to give the title compound as a white solid (248 mg, 75%).1H NIVIR (250 IVIFIz, Chloroform-d) 7.63 (d, J = 7.8 Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H), 3.74 -3.65 (m, 4H), 3.04 -2.97 (m, 4H), 2.43 (s, 3H).LCMS Method 8 - Tr = 1.42 mm (ES+) (M+H)+ 203.3
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;	Piperazine (1.13 g) and <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (500 mg) were dissolved in DMF (15 ml), and K2CO3 (1.36 g) was added thereto, followed by stirring at 60 C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 6-methyl-2-piperazin-1-ylnicotinonitrile (628 mg).

Reference： [1]Patent: WO2018/89433,2018,A1 .Location in patent: Paragraph 00252
[2]Patent: US2012/184520,2012,A1 .Location in patent: Page/Page column 18

39
[ 28900-10-9 ]
2-chloro-6-methylpyridine-3-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With diisobutylaluminium hydride; In dichloromethane; at -78 - 20℃;	Example 89.2-(l ,6-Dimethyl-lH-pyrazolo[3,4-b]pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3 -cyano-azetidin- 1 -yl)- 1 -methyl-2-oxo-ethyl]-amideStep 12 -Chloro -6 -methylpyridine-3 -carb aldehyde To a solution of <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (2.0 g, 13.1 mmol) in dichloromethane (40 mL) at -78C was added DIBAL-H (2.92 mL, 16.4 mmol) dropwise. The reaction was stirred at -78C for 5 min then allowed to warm to room temperature and stirred for 6 h. The reaction was carefully quenched with IN HC1 (40 mL) and the mixture was heated at reflux for 30 min. After cooling the reaction was made basic with aqueous 10% NaOH and extracted with EtOAc (3x).The combined organics were washed with brine then dried over MgSC^ and concentrated to afford 1.98 g (97%) of 2-chloro-6-methylpyridine-3-carbaldehyde as a light yellow solid.
42 g	With diisobutylaluminium hydride; In toluene; at -60 - 20℃; for 3h;Inert atmosphere;	Diisobutylaluminum hydride (i M toluene solution, 242 mE, 242 mmol) was added to 300 mE of a toluenesolution of 2-chioro-6-methylnicotinonitrile (35.0 g, 230 mmol) over one hour at -60 C. Afier stirring for 30 minutesat -60 C., the reaction system was stirred for i .5 hour at room temperature. A mixed solution of 350 mE of 2 M sulthric acid aqueous solution and 200 mE of tetrahydrothran was added dropwise over one hour to the reaction solution that had been cooled to -50 C. Afier dropwise addition had been completed, the solution was stirred for i 8 hours at room temperature, and 200 mE of ethyl acetate was added. The separated organic layer was washed with (saturated) brine, dried by sodium sulfate, and a crude product was obtained by distilling off the solvent.10155] Step 3; Step 4 The crude products obtained in step 2 and step 3 together were subjected to silica gel column chromatography (ethyl acetate/petroleum ether), and 2-chloro-6-methylnicotinaldehyde (42.0 g, 78%) was obtained. 1H NMR (400 MHz, CDCl3) delta 2.62 (s, 3H), 7.24 (d, J=8.0 Hz, 1H), 8.1 (d, J=8.0 Hz, 1H), 10.39 (s, 1H).

Reference： [1]Patent: WO2013/30138,2013,A1 .Location in patent: Page/Page column 238; 239
[2]Patent: US2017/145005,2017,A1 .Location in patent: Paragraph 0149; 0153-0159

40
[ 28900-10-9 ]
[ 885269-66-9 ]

Reference： [1]Patent: WO2013/30138,2013,A1
[2]Patent: US2017/145005,2017,A1

41
[ 28900-10-9 ]
1-((2S,3R,4R)-4-amino-6-fIuoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]
2-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-6-methylnicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With Pd(Q-Phos)2; sodium t-butanolate; In toluene; at 50℃; for 17h;Inert atmosphere;	A mixture of I -((2S,3R,4R)-4-am ino-6-fluoro-2,3-dimethyl-3,4-dihydroqu inolin- I (2H)-yl)ethanone (fora preparation see Intermediate 329, 150 mg, 0.635 mmol), sodium tert-butoxide (122 mg, 1.270mmol), Pd(QPhos)2 (24 mg, 0.016 mmol) and <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (145 mg, 0.952 mmol)in anhydrous toluene (2 mL) was evacuated and purged with nitrogen (x3) and stirred under nitrogenat 50 C for 17 h. The reaction mixture was filtered through a 2.5 g celite cartridge and the cartridge then washed with EtOAc (25 mL). The filtrate was evaporated in vacuo and the gum dissolved in DCM (1 mL). The solution was purified by silica gel column chromatography (25 g column, 0-100 % EtOAc in DCM over 10 CV5). The appropriate fractions were combined and the solvent removed byrotary evaporation to give the desired product as an off-white solid (20 mg, 0.057 mmol, 9%). LCMS (2 mm Formic): Rt = 1 .06 mi [MH] = 353.

Reference： [1]Patent: WO2014/140076,2014,A1 .Location in patent: Page/Page column 203

42
[ 28900-10-9 ]
[ 63-74-1 ]
4-(3-Cyano-6-methylpyridin-2-ylamino)benzenesulfonamide [ No CAS ]