[ CAS No. 85331-33-5 ] {[proInfo.proName]}

Name: 85331-33-5|3,5-Dichloropicolinonitrile|97%
Brand: Ambeed
SKU: A408326
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Quality Control of [ 85331-33-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 85331-33-5 ]

SDS Specification

Alternatived Products of [ 85331-33-5 ]

Product Details of [ 85331-33-5 ]

CAS No. :	85331-33-5	MDL No. :	MFCD03788758
Formula :	C₆H₂Cl₂N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ATUOLSDAAPMVJJ-UHFFFAOYSA-N
M.W :	173.00	Pubchem ID :	2769699
Synonyms :

Calculated chemistry of [ 85331-33-5 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.97
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) :	-5.79 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.65
Log Po/w (XLOGP3) :	2.2
Log Po/w (WLOGP) :	2.26
Log Po/w (MLOGP) :	1.0
Log Po/w (SILICOS-IT) :	2.61
Consensus Log Po/w :	1.94

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.74
Solubility :	0.313 mg/ml ; 0.00181 mol/l
Class :	Soluble
Log S (Ali) :	-2.6
Solubility :	0.43 mg/ml ; 0.00249 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.34
Solubility :	0.0793 mg/ml ; 0.000458 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.95

Safety of [ 85331-33-5 ]

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

Application In Synthesis of [ 85331-33-5 ]

* 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 [ 85331-33-5 ]
Downstream synthetic route of [ 85331-33-5 ]

[ 85331-33-5 ] Synthesis Path-Upstream 1~8

1
[ 85331-33-5 ]
[ 81719-53-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	at 115℃;	3,5-Dichloro-pyridine-2-carbonitrile (10 g, 57 8 mmol) was dissolved in 100 mL of 95percent concentrated sulfuric acid and this mixture was heated to 115 °C overnight The reaction mixture was then cooled, poured over ice with strong stirring The resulting solid was filtered, washed with water and dried at 40 °C under reduced pressure to give 94g (85percent) of pure product as a white solid

Reference： [1] Patent: WO2009/89263, 2009, A2, . Location in patent: Page/Page column 117

2
[ 15177-57-8 ]
[ 7677-24-9 ]
[ 85331-33-5 ]

Yield	Reaction Conditions	Operation in experiment
40.2%	With N,N-Dimethylcarbamoyl chloride In dichloromethane at 20℃; for 48 h;	[0166] 21.8 ml (0.174 mmol) of trimethylsilyl cyanide and 14.6 ml (0.158 mmol) of dimethylcarbamoyl chloride are added successively to a solution of 26 g (0.158 mol) of 3,5-dichloropyridine 1-oxide (Johnson et al., J. Chem. Soc. B, 1967, 1211) in 80 ml of dichloromethane and stirred at room temperature for 48 hours. 100 ml of a 10percent strength aqueous NaHCO3 solution are added, and the mixture is vigorously stirred for 10 minutes. Separation of the phases is followed by extraction once with dichloromethane; the combined organic phases are dried and concentrated. The residue is chromatographed on silica gel with dichloromethane and recrystallized from a little methanol. [0167] 11 g (40.2percent) of 2-cyano-3,5-dichloropyridine (melting point: 102° C.) are obtained.

Reference： [1] Patent: US2003/232842, 2003, A1, . Location in patent: Page 8

3
[ 16063-70-0 ]
[ 85331-33-5 ]

Yield	Reaction Conditions	Operation in experiment
40%	With copper(I) cyanide; tetraphenylphosphonium bromide; potassium iodide In diethylene glycol dimethyl ether for 113 h; Heating / reflux	[0169] In analogy to Troschuetz, R. et al., J. Heterocycl. Chem. 33, 1815-1821 (1996), 150 ml of diethylene glycol dimethyl ether, 47.68 g (0.261 mol) of 2,3,5-trichloro-pyridine, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) of finely powdered potassium iodide and 75.0 g (0.838 mol) of copper(I) cyanide are mixed under nitrogen and stirred under reflux for 24 hours. Then a further 100 ml of diethylene glycol dimethyl ether, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) of finely powdered potassium iodide and 75 g (0.838 mol) of copper(I) cyanide are added, and the mixture is stirred at reflux temperature for a further 89 hours. Cooling to room temperature is followed by filtration with suction, and the filtrate is distilled to remove most of the diethylene glycol dimethyl ether. The residue is taken up in toluene and washed with an aqueous solution of Mohr's salt and then with aqueous NaHCO3 solution (peroxide test). It is then washed with water to remove diethylene glycol dimethyl ether. After filtration through cellit, the filtrate is dried over magnesium sulfate, and the solution is concentrated. [0170] 18.0 g (40.0percent) of 2-cyano-3,5-dichloropyridine are obtained.

Reference： [1] Patent: US2003/232842, 2003, A1, . Location in patent: Page 8

4
[ 15177-57-8 ]
[ 85331-33-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine In acetonitrile	EXAMPLE 27A 2-Cyano-3,5-dichloropyridine 3,5-Dichloropyridine-N-oxide (10.0 g, 61 mmol), trimethysilylcyanide (25 mL, 183 mmol) and triethylamine (17 mL, 122 mmol) combined in acetonitrile (60 mL) and heated to reflux for 6 hr. The solvent was evaporated and the residue was partitioned between diethyl ether and 5percent aq. NaHCO₃. The organic phase was dried (MgSO₄), evaporated, and the product purified by chromatography over silica gel to yield 10.0 g (97percent) of the title compound: ¹ H NMR (300 MHz, CDCl₃) δ 7.92 (d, 1H), 8.58 (d, 1H).

Reference： [1] Patent: US6046207, 2000, A,
[2] Patent: US5891882, 1999, A,

5
[ 2457-47-8 ]
[ 85331-33-5 ]

Reference： [1] Patent: US5716971, 1998, A,

6
[ 85331-33-5 ]
[ 1000025-07-9 ]

Reference： [1] Patent: US2012/309977, 2012, A1,
[2] Patent: WO2016/153996, 2016, A1,

7
[ 85331-33-5 ]
[ 298709-29-2 ]

Reference： [1] Patent: US2003/232842, 2003, A1, . Location in patent: Page 8

8
[ 85331-33-5 ]
[ 1415226-40-2 ]

Reference： [1] Patent: US2012/309977, 2012, A1,
[2] Patent: WO2016/153996, 2016, A1,

[ 85331-33-5 ] Synthesis Path-Downstream 1~51

1
[ 74-93-1 ]
[ 85331-33-5 ]
[ 91164-63-5 ]

Reference： [1]Journal of Heterocyclic Chemistry,1984,vol. 21,p. 97 - 101

2
[ 85331-33-5 ]
[ 100-51-6 ]
[ 1000025-92-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium hydride; In tetrahydrofuran; at 0 - 190℃; for 5h;microwave;	To an 80 mL microwave pressure vessel is charged dry THF (30 mL) and benzyl alcohol (6.32 mL, 61.1 mmol). The solution is cooled to 0 C. and sodium hydride (2.44 g of a 60% dispersion in mineral oil, 61.1 mmol) is added in portions. The reaction mixture is gradually allowed to warm to room temperature with efficient stirring until the evolution of hydrogen gas ceases. The solution is re-cooled to 0 C. and <strong>[85331-33-5]3,5-dichloro-2-cyanopyridine</strong> (5.00 g, 29.1 mmol) is added, and the solution is transferred to an unfocussed Mars 5 CEM microwave reactor to 190 C., 300 W and held for 5 hours. The reaction mixture is quenched with H2concentrated under reduced pressure, diluted with EtOAc and washed with 2M Na2CO3, H2O and saturated aqueous NaCl. The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to give a brown solid. The crude solid is purified over silica (EtOAc:heptane, gradient 1:1 to 1:0) to afford 8.6 g (94% yield) of the desired compound as an orange solid. 1H NMR (400 MHz, CDCl3) delta ppm 7.96 (1H, d, J=2.2 Hz), 7.25-7.37 (10H, m), 6.78 (1H, d, J=2.2 Hz), 5.10 (2H, s), 5.03 (2H, s). HPLC-MS: m/z 317 [M+H]+.
		Synthesis of 3,5-bis(benzyloxy)picolinonitrile (2) (0549) To a solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1, 65.0 g, 377.2 mmol) in tetrahydrofuran (500 mL) under nitrogen, sodium hydride (27.2 g, 1.13 mol) was added at 0 C. The suspension was stirred at room temperature for 30 minutes. Benzyl alcohol (81.37 mL, 755 mmol) was added and the reaction was stirred for another 3 h. After completion, the reaction mass was treated with saturated ammonium chloride solution at 0 C. The residue was dissolved in ethyl acetate (1000 mL), separated the organic layer and washed with water (2×200 mL) then with brine (100 mL). The organics were separated and dried over anhydrous sodium sulfate before concentration to dryness and triturated with pentane. The precipitated solid was filtered and dried under vacuum to afford 3,5-bis(benzyloxy)picolinonitrile (2) as an off-white solid. Yield: 130.0 g, crude; MS (ESI) m/z 317.21[M+1]+.

Reference： [1]Patent: US2007/299086,2007,A1 .Location in patent: Page/Page column 9
[2]Patent: US2017/145026,2017,A1 .Location in patent: Paragraph 0548; 0549
[3]Journal of Medicinal Chemistry,2020

3
[ 15177-57-8 ]
[ 7677-24-9 ]
[ 85331-33-5 ]

Yield	Reaction Conditions	Operation in experiment
40.2%	With N,N-Dimethylcarbamoyl chloride; In dichloromethane; at 20℃; for 48h;	[0166] 21.8 ml (0.174 mmol) of trimethylsilyl cyanide and 14.6 ml (0.158 mmol) of dimethylcarbamoyl chloride are added successively to a solution of 26 g (0.158 mol) of 3,5-dichloropyridine 1-oxide (Johnson et al., J. Chem. Soc. B, 1967, 1211) in 80 ml of dichloromethane and stirred at room temperature for 48 hours. 100 ml of a 10% strength aqueous NaHCO3 solution are added, and the mixture is vigorously stirred for 10 minutes. Separation of the phases is followed by extraction once with dichloromethane; the combined organic phases are dried and concentrated. The residue is chromatographed on silica gel with dichloromethane and recrystallized from a little methanol. [0167] 11 g (40.2%) of 2-cyano-3,5-dichloropyridine (melting point: 102 C.) are obtained.

Reference： [1]Patent: US2003/232842,2003,A1 .Location in patent: Page 8

4
[ 16063-70-0 ]
[ 85331-33-5 ]

Yield	Reaction Conditions	Operation in experiment
40%	With copper(I) cyanide; tetraphenylphosphonium bromide; potassium iodide; In diethylene glycol dimethyl ether; for 113h;Heating / reflux;	[0169] In analogy to Troschuetz, R. et al., J. Heterocycl. Chem. 33, 1815-1821 (1996), 150 ml of diethylene glycol dimethyl ether, 47.68 g (0.261 mol) of <strong>[16063-70-0]2,3,5-trichloro-pyridine</strong>, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) of finely powdered potassium iodide and 75.0 g (0.838 mol) of copper(I) cyanide are mixed under nitrogen and stirred under reflux for 24 hours. Then a further 100 ml of diethylene glycol dimethyl ether, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) of finely powdered potassium iodide and 75 g (0.838 mol) of copper(I) cyanide are added, and the mixture is stirred at reflux temperature for a further 89 hours. Cooling to room temperature is followed by filtration with suction, and the filtrate is distilled to remove most of the diethylene glycol dimethyl ether. The residue is taken up in toluene and washed with an aqueous solution of Mohr's salt and then with aqueous NaHCO3 solution (peroxide test). It is then washed with water to remove diethylene glycol dimethyl ether. After filtration through cellit, the filtrate is dried over magnesium sulfate, and the solution is concentrated. [0170] 18.0 g (40.0%) of 2-cyano-3,5-dichloropyridine are obtained.

Reference： [1]Patent: US2003/232842,2003,A1 .Location in patent: Page 8

5
[ 85331-33-5 ]
[ 298709-32-7 ]

Yield	Reaction Conditions	Operation in experiment
39.1%	With trimethylaluminum; ammonium chloride; In hexane; toluene; at 0 - 80℃;	[0175] 328 ml of trimethylaluminum (2 M in hexane, 0.624 mol) are added dropwise to a suspension, cooled to 0 to 5 C., of 33.4 g (0.624 mol) of ammonium chloride in 1 l of toluene; the mixture is stirred at room temperature until methane evolution has ceased. The solution of <strong>[85331-33-5]2-cyano-3,5-dichloropyridine</strong> from Example V in toluene is then added dropwise, and the mixture is subsequently stirred at 80 C. overnight. After cooling to 0 to -5 C., methanol is added dropwise until gas evolution ceases, and the salts are filtered off with suction and washed twice with a little methanol. The solvent is stripped off, the residue is dissolved in 500 ml of dichloromethane/methanol (9:1) and again filtered with suction to remove inorganic salts. 23.6 g (39.1%) of 3,5-difluoro-2-pyridinecarboximidamide hydrochloride (melting point: 183 C.) remain after the solvent has been stripped off. [0176] 1H-NMR (DMSO-D6): 8.3-8.45 (m, 1H) ppm; 8.8 (d, J=2 Hz, 1H) ppm; 9.7 (s, broad, 4H) ppm.

Reference： [1]Patent: US2003/232842,2003,A1 .Location in patent: Page 8-9

6
[ 85331-33-5 ]
[ 298709-29-2 ]

Yield	Reaction Conditions	Operation in experiment
	With polyethylene glycol 8000; potassium fluoride; In dimethyl sulfoxide; at 160℃; for 0.5h;	[0172] 50 g (0.29 mol) of 2-cyano-3,5-dichloropyridine from Example IV, 33.6 g (0.58 mol) of potassium fluoride and 10 g of polyethylene glycol 8000 are mixed with 125 ml of DMSO and heated at 160° C. for 30 minutes. After cooling, the product is distilled out together with the DMSO under high vacuum, the distillate is added to water and, after extraction with toluene, dried over sodium sulfate. The product is reacted further as solution in toluene. [0173] Rf: 0.43 (cyclohexane/ethyl acetate=7:3)

Reference： [1]Patent: US2003/232842,2003,A1 .Location in patent: Page 8

7
trimethysilylcyanide [ No CAS ]
[ 15177-57-8 ]
[ 85331-33-5 ]

Yield	Reaction Conditions	Operation in experiment
10.0 g (97%)	With triethylamine; In acetonitrile;	EXAMPLE 27A 2-Cyano-3,5-dichloropyridine 3,5-Dichloropyridine-N-oxide (10.0 g, 61 mmol), trimethysilylcyanide (25 mL, 183 mmol) and triethylamine (17 mL, 122 mmol) combined in acetonitrile (60 mL) and heated to reflux for 6 hr. The solvent was evaporated and the residue was partitioned between diethyl ether and 5% aq. NaHCO3. The organic phase was dried (MgSO4), evaporated, and the product purified by chromatography over silica gel to yield 10.0 g (97%) of the title compound: 1 H NMR (300 MHz, CDCl3) delta 7.92 (d, 1H), 8.58 (d, 1H).

Reference： [1]Patent: US6046207,2000,A

8
[ 85331-33-5 ]
[ 2365-48-2 ]
methyl 3-amino-6-chloro-thieno[3,2-b]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.23 g (25%)	With sodium methylate; In tetrahydrofuran; sodium hydrogencarbonate;	EXAMPLE 38A Methyl 3-amino-6-chloro-thieno[3,2-b]pyridine-2-carboxylate The product from Example 27A (3.46 g, 20 mmol) and methyl thioglycolate (1.8 mL, 20 mmol) were combined in 40 mL THF. To the solution was added 1.08 g NaOMe (20 mmol) After 1.5 h, and additional 1.08 g NaOMe was added, and then after an additional 2 h, the reaction was quenched in 5% aq. NaHCO3 and extracted with diethyl ether. The organic extracts were dried (MgSO4), evaporated, and the product was purified by silica gel column chromatography to yield 1.23 g (25%) of the title compound: 1 H NMR (300 MHz, CDCl3) delta 3.92 (s, 3H), 6.20 (br s, 2H), 8.04 (d, 1H), 8.54 (d, 1H).
1.23 g (25%)	With sodium methylate; In tetrahydrofuran; sodium hydrogencarbonate;	EXAMPLE 38A Methyl 3-amino-6-chloro-thieno[3,2-b]pyridine-2-carboxylate The product from Example 27A (3,46 g, 20 mmol) and methyl thioglycolate (1.8 mL, 20 mmol) were combined in 40 mL THF. To the solution was added 1.08 g NaOMe (20 mmol) After 1.5 h, and additional 1.08 g NaOMe was added, and then after an additional 2 h, the reaction was quenched in 5% aq. NaHCO3 and extracted with diethyl ether. The organic extracts were dried (MgSO4), evaporated, and the product was purified by silica gel colmun chromatography to yield 1.23 g (25%) of the title compound: 1 H NMR (300 MHz, CDCl3) delta 3.92 (s, 3H), 6.20 (br s, 2H), 8.04 (d, 1H), 8.54 (d, 1H).

Reference： [1]Patent: US5891882,1999,A
[2]Patent: US6046207,2000,A

9
[ 85331-33-5 ]
3-chloro-5-methoxypyridine-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.27 g (32%, second eluding component)	With sodium methylate; In tetrahydrofuran; sodium hydrogencarbonate;	EXAMPLE 27B 3-Chloro-2-cyano-5-methoxypyridine The product from Example 27A (0.865 g, 5.0 mmol) was dissolved in THF (10 mL) and 0.27 g NaOMe was added. After 3 h and 25 C., the reaction was quenched in 5% aq. NaHCO3 solution and extracted with diethyl ether. The organic phase was dried, evaporated, and the residue purified by column chromatography, eluding with 70:30 hexanes:ethyl acetate to yield 0.27 g (32%, second eluding component) of the title compound: 1 H NMR (300 MHz, CDCl3) delta 3.95 (s, 3H), 7.29 (d, 1H), 8.28 (d, 1H).

Reference： [1]Patent: US6046207,2000,A

10
[ 85331-33-5 ]
[ 81719-53-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid; water; at 115℃;	3,5-Dichloro-pyridine-2-carbonitrile (10 g, 57 8 mmol) was dissolved in 100 mL of 95% concentrated sulfuric acid and this mixture was heated to 115 C overnight The reaction mixture was then cooled, poured over ice with strong stirring The resulting solid was filtered, washed with water and dried at 40 C under reduced pressure to give 94g (85%) of pure product as a white solid

Reference： [1]Patent: WO2009/89263,2009,A2 .Location in patent: Page/Page column 117

11
[ 85331-33-5 ]
[ 79887-14-2 ]
[ 1186637-62-6 ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	To a round bottom flask capped with septa was added <strong>[79887-14-2]1-ethoxy-4-ethynylbenzene</strong> (1.1 eq), 3,5-dichloropicolinonitrile (1 eq.), triethylamine (5 eq.), and anhydrous DMF (0.2 M). Vacuumed and nitrogen flushed for three times. CuI (0.05 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.05 eq) were added. The septum was replaced with a refluxing condenser and the flask was heated at 60 C. overnight under nitrogen atmosphere. Upon completion of the reaction as monitored by TLC, the content of the flask was loaded onto a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes:EtOAc (1:4%)) afforded the product 3-chloro-5-((4-ethoxyphenyl)ethynyl)picolinonitrile.
	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	To a round bottom flask capped with septa was added l-ethoxy-4-ethynylbenzene (1 1 eq), 3,5-dichloropicolinonitrile (1 eq.), tnethylamine (5 eq.), and anhydrous DMF (0.2 M). Vacuumed and nitrogen flushed for three times. CuI (0.05 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.05 eq) were added. The septum was replaced with a refluxing condenser and the flask was heated at 60 0C overnight under nitrogen atmosphere. Upon completion of the reaction as monitored by TLC, the content of the flask was loaded onto a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes:EtOAc (1:4%)) afforded the product 3-chloro-5-((4-ethoxyphenyl)ethynyl)picolinonitrile.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 88
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 196

12
[ 39604-97-2 ]
[ 85331-33-5 ]
[ 1186638-12-9 ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 50℃; for 3h;	A solution of 3,5-dichloropicolinonitrile (1.0 eq.), <strong>[39604-97-2]1-ethynyl-4-propoxybenzene</strong> (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50 C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-10% ethyl acetate in hexane to give 3-chloro-5-((4-propoxyphenyl)ethynyl)picolinonitrile as a white solid.
	With triethylamine;copper(l) iodide; trans-dichlorobis(triphenylphosphine)platinum(II); In N,N-dimethyl-formamide; at 50℃; for 3h;	A solution of 3,5-dichloropicolinonitrile (1.0 eq.), l-ethynyl-4-propoxybenzene(commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol%), copper (I) iodide (20 mol%), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 500C for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-10% ethyl acetate in hexane to give3-chloro-5-((4-propoxyphenyl)ethynyl)picolinonitrile as a white solid.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 114
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 223

13
[ 124-41-4 ]
[ 85331-33-5 ]
3-chloro-5-methoxypyridine-2-carbonitrile [ No CAS ]
5-chloro-2-cyano-3-methoxypyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 0 - 20℃; for 0.583333h;	To a solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (22.5 g, 130 mmol) in DMF (500 mL) at 0 C. was added sodium methoxide (6.67 g, 124 mmol) slowly. The reaction was stirred for 5 minutes at 0 C., then allowed to warm to RT and stir for 30 minutes. The solution was partitioned between water and EtOAc. The organic layer was washed with water and concentrated. The crude product was purified via silica gel chromatography, eluting with 0-75% ethyl acetate in heptanes, to afford a 1:1 ratio of the desired isomer 3-chloro-5-methoxypicolinonitrile and 5-chloro-3-methoxypicolinonitrile (7.0 g, 41.5 mmol). The material was used without further purification. MS m/z=169 (M+H).
	In N,N-dimethyl-formamide; at 0 - 20℃; for 0.583333h;	To a solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (22.5 g, 130 mmol) in DMF (500 mL) at 0 C was added sodium methoxide (6.67 g, 124 mmol) slowly. The reaction was stirred for 5 minutes at 0 C, then it was allowed to warm to RT and stir for 30 minutes. The solution was partitioned between water and EtOAc. The organic layer was washed with water and concentrated. The crude product was purified via silica gel A-1813-WO-PCT - 138 - chromatography, eluting with 0-75 % ethyl acetate in heptanes, to afford a 1 : 1 ratio of the desired isomer 3-chloro-5-methoxypicolinonitrile and 5-chloro-3- methoxypicolinonitrile (7.0 g, 41.5 mmol). The material was used without further purification. MS m/z = 169 (M+H)
	In N,N-dimethyl-formamide; at 0 - 20℃; for 0.583333h;	To a solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (22.5 g, 130 mmol) in DMF (500 mL) at 0 C. was added sodium methoxide (6.67 g, 124 mmol) slowly. The reaction was stirred for 5 minutes at 0 C., then allowed to warm to RT and stir for 30 minutes. The solution was partitioned between water and EtOAc. The organic layer was washed with water and concentrated. The crude product was purified via silica gel chromatography, eluting with 0-75% ethyl acetate in heptanes, to afford a 1:1 ratio of the desired isomer 3-chloro-5-methoxypicolinonitrile and 5-chloro-3-methoxypicolinonitrile (7.0 g, 41.5 mmol). The material was used without further purification. MS m/z=169 (M+H).

	In N,N-dimethyl-formamide; at 0 - 20℃; for 0.583333h;	To a solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (22.5 g, 130 mmol) in DMF (500 mL) at 0 C was added sodium methoxide (6.67 g, 124 mmol) slowly. The reaction was stirred for 5 min at 0 C then stirred at RT for 30 min. The solution was partitioned between water and EtOAc. The organic layer was washed with water and concentrated. The crude product was purified via silica gel chromatography, eluting with 0-75% EtOAc in heptane, to afford a 1 : 1 ratio of the desired isomer 3-chloro-5-methoxypicolinonitrile and 5-chloro-3-methoxypicolinonitrile (7.0 g, 41.5 mmol). The material was used without further purification. MS m/z = 169 (M+H). A sealed vessel was charged with bis(acetonitrile)palladium (II) chloride (0.154 g, 0.593 mmol), dicyclohexyl(2',4',6'- triisopropyl-[1 ,1 '-biphenyl]-2-yl)phosphine (0.848 g, 1.780 mmol), cesium carbonate (25.1 g, 77 mmol), the mixture (1 : 1 ratio) of 3-chloro-5-methoxypicolinonitrile and 5- chloro-3-methoxypicolinonitrile (5 g, 29.7 mmol), and ACN (60 mL). The vessel was flushed with argon, and stirred at RT for 25 min. To the reaction was added triethyl(ethynyl)silane (5.41 g, 38.6 mmol), and the vessel was resealed and stirred at 90 C for 3 h. The solution was concentrated, and the residue was purified via silica gel chromatography, eluting with 0-50% EtOAc in heptane, to afford the title compound (3.8 g, 13.9 mmol). MS m/z = 273 (M+H) +.
	In N,N-dimethyl-formamide; at 75℃; for 14h;	To a solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.) in dimethyl formamide (DMF) (0.5M) was added sodium methoxide (1.5 eq.) and heated to 75C. After stirring for 14 hours, the reaction was diluted with ethyl acetate and water. The organic layer was washed with saturated aqueous NaHCO3 three times, water twice, dried over anhydrous MgSO4, and concentrated en vacuo. The crude residue was purified by a COMBIFLASH system (ISCO) using 15% ethyl acetate in hexane to give a mixture of two methoxy regioisomers, one of which was the desired product. The mixture was carried onto the next step without further purification.

Reference： [1]Patent: US2014/213581,2014,A1 .Location in patent: Paragraph 0610
[2]Patent: WO2014/138484,2014,A1 .Location in patent: Page/Page column 137; 138
[3]Patent: US2015/38497,2015,A1 .Location in patent: Paragraph 0774
[4]Patent: WO2016/22724,2016,A1 .Location in patent: Page/Page column 256; 257
[5]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 182

14
[ 10602-03-6 ]
[ 85331-33-5 ]
[ 1186638-02-7 ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 50℃; for 3h;	A solution of 3,5-dichloropicolinonitrile (commercially available) (1.0 eq.), <strong>[10602-03-6]ethyl 4-ethynylbenzoate</strong> (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50 C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH, system (ISCO) using 0-20% ethyl acetate in hexane to give ethyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)benzoate as a white solid.
	With triethylamine;copper(l) iodide; trans-dichlorobis(triphenylphosphine)platinum(II); In N,N-dimethyl-formamide; at 50℃; for 3h;	A solution of S.S-dichloropicolinonitrile (commercially available) (1.0 eq.), ethyl 4- ethynylbenzoate (commercially available) (1.0 eq.), trans- dichlororbis(triphenylphosphine)palladium (II) (10 mol%), copper (I) iodide (20 mol%), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 5O0C for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-20% ethyl acetate in hexane to give ethyl 4-((5-chloro- 6-cyanopyridin-3-yl)ethynyl)benzoate as a white solid .

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 106; 107
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 215

15
[ 85331-33-5 ]
[ 165059-42-7 ]
[ 1186637-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80 - 100℃; for 6h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 100 C. for 2 hours, then 80 C. for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacua. The crude product was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give (E)-3-chloro-5-(3-methoxyprop-1-enyl)picolinonitrile as a white solid.
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80 - 100℃; for 6h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), (E)-2-(3-methoxyprop-l-enyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1 0 eq.), tetrakis(tnphenyl-phosphme)palladium (5 mol%), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 1000C for 2 hours, then 800C for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give (E)-3-chloro-5-(3-methoxyprop-l-enyl)picolinonitrile as a white solid.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 79
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 187

16
[ 85331-33-5 ]
[ 75927-49-0 ]
[ 1186637-47-7 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 95℃;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 95 C. overnight. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid.
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 95℃;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), 4,4,5,5-tetramethyl-2-vinyl-1.3.2- dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol%), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 950C overnight. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 76
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 184

17
[ 24388-23-6 ]
[ 85331-33-5 ]
[ 1186637-48-8 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80 - 100℃; for 6h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 100 C. for 2 hours, then 80 C. for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid.
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80 - 100℃; for 6h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), 4,4,5,5-tetramethyl-2-phenyl-l,3,2- dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol%), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 1000C for 2 hours, then 800C for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 77
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 185

18
[ 85331-33-5 ]
[ 83947-56-2 ]
[ 1186637-49-9 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80 - 100℃; for 6h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 100 C. for 2 hours, then 80 C. for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid.
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80 - 100℃; for 6h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol%), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 1000C for 2 hours, then 800C for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 78
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 186

19
[ 889108-48-9 ]
[ 85331-33-5 ]
[ 1186637-60-4 ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	To a round bottom flask capped with septa was added 5-ethynyl-1H-indole (from the previous step) (1.1 eq), <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1 eq.), triethylamine (5 eq.), and anhydrous DMF (0.2 M). Vacuumed and nitrogen flushed for three times. CuI (0.05 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.05 eq) were added. The septum was replaced with a refluxing condenser and the flask was heated at 60 C. overnight under nitrogen atmosphere. Upon completion of the reaction as monitored by TLC, the content of the flask was loaded onto a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes:EtOAc (1:4%)) afforded the product 5-((1H-indol-5-yl)ethynyl)-3-chloropicolinonitrile.
	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	To a round bottom flask capped with septa was added 5-ethynyl-lH-indole (from the previous step) (1.1 eq), <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1 eq.), tnethylamine (5 eq.), and anhydrous DMF (0.2 M) Vacuumed and nitrogen flushed for three times. CuI (0.05 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.05 eq) were added. The septum was replaced with a refluxing condenser and the flask was heated at 60 0C overnight under nitrogen atmosphere. Upon completion of the reaction as monitored by TLC, the content of the flask was loaded onto a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes: EtOAc (1:4%)) afforded the product 5-((lH-indol-5-yl)ethynyl)-3-chloropicolinonitrile.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 87
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 195

20
[ 85331-33-5 ]
[ 766-97-2 ]
[ 1186638-04-9 ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 50℃; for 3h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (commercially available) (1.0 eq.), 1-ethynyl-4-methylbenzene (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50 C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by stirring in hot ether/hexane mixtures and filtered to give 3-chloro-5-(p-tolylethynyl)picolinonitrile.
	With triethylamine;copper(l) iodide; trans-dichlorobis(triphenylphosphine)platinum(II); In N,N-dimethyl-formamide; at 50℃; for 3h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (commercially available) (1.0 eq.), l-ethynyl-4- methylbenzene (commercially available) (1.0 eq.), trans- dichlororbis(triphenylphosphine)palladium (II) (10 mol%), copper (I) iodide (20 mol%), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 5O0C for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by stirring in hot ether/hexane mixtures and filtered to give 3-chloro-5-(p-tolylethynyl)picolinonitrile.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 108
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 216

21
[ 85331-33-5 ]
[ 126726-62-3 ]
[ 1186637-51-3 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 80 - 100℃; for 6h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 100 C. for 2 hours, then 80 C. for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give 3-chloro-5-(prop-1-en-2-yl)picolinonitrile as a white solid.
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80 - 100℃; for 6h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), 4,4,5,5-tetramethyl-2-(prop-l-en-2- yl)-l,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol%), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 1000C for 2 hours, then 8O0C for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to <n="191"/>give 3-chloro-5-(prop-l-en-2-yl)picolinonitrile as a white solid.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 81
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 188-189

22
[ 85331-33-5 ]
[ 83947-58-4 ]
[ 1186637-58-0 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 95℃;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), (E)-4,4,5,5-tetramethyl-2-(prop-1-enyl)-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 95 C. overnight. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid (E)-3-chloro-5-(prop-1-enyl)picolinonitrile.
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 95℃;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), (E)-4,4,5,5-tetramethyl-2-(prop-l- enyl)-l,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol%), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 95C overnight. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash <n="196"/>chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid (E)-3-chloro-5-(prop-l-enyl)picolinonitrile.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 85
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 193-194

23
[ 1186638-07-2 ]
[ 85331-33-5 ]
[ 1186638-08-3 ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 50℃; for 3h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), ethyl 4-ethynyl-3-methylbenzoate (from the previous step) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (1) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50 C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-10% ethyl acetate in hexane to give ethyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate as a white solid.
	With triethylamine;copper(l) iodide; trans-dichlorobis(triphenylphosphine)platinum(II); In N,N-dimethyl-formamide; at 50℃; for 3h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), ethyl 4-ethynyl-3-methylbenzoate (from the previous step) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol%), copper (I) iodide (20 mol%), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 500C for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-10% ethyl acetate in hexane to give ethyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate as a white solid.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 110
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 219

24
[ 769-26-6 ]
[ 85331-33-5 ]
[ 1186638-10-7 ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 50℃; for 3h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), 2-ethynyl-1,3,5-trimethylbenzene (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50 C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-10% ethyl acetate in hexane to give 3-chloro-5-(mesitylethynyl)picolinonitrile a as white solid.
	With triethylamine;copper(l) iodide; trans-dichlorobis(triphenylphosphine)platinum(II); In N,N-dimethyl-formamide; at 50℃; for 3h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), 2-ethynyl-l,3,5-trimethylbenzene(commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol%), copper (I) iodide (20 mol%), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 500C for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-10% ethyl acetate in hexane to give3-chloro-5-(mesitylethynyl)picolinonitrile a as white solid.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 112; 113
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 221

25
[ 85331-33-5 ]
[ 74331-69-4 ]
[ 1186637-69-3 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; at 60℃;	To a round bottom flask capped with septa was added l-ethynyl-4-methoxy-2- methylbenzene (commercially available) (1.1 eq), <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1 eq.), triethylamine (5 eq.), and anhydrous DMF (0.2 M). Vacuumed and nitrogen flushed for three times. CuI (0.05 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.05 eq) were added. The septum was replaced with a refluxing condenser and the flask was heated at 60 0C overnight under nitrogen atmosphere. Upon completion of the reaction as monitored by TLC, the content of the flask was loaded onto a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes :EtO Ac (1:4%)) afforded the product 3-Chloro-5-((4- methoxy-2-methylphenyl)ethynyl)picolinonitrile.
	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	Preparation of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (B-4)Step B-1: 3-chloro-5-((4-methoxy-2-methylphenyl)ethynyl)picolinonitrile (B-1)To a round bottom flask capped with septa was added 1-ethynyl-4-methoxy-2-methylbenzene (1.1 eq), <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1 eq.), triethylamine (5 eq.), and anhydrous DMF (0.2 M). The mixture was degassed (vacuum) and nitrogen flushed three times. CuI (0.05 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.05 eq) were added and the septum was replaced with a refluxing condenser and the flask was heated at 60 C. overnight under nitrogen atmosphere. Upon completion of the reaction as monitored by TLC, the content of the flask was loaded onto a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes:EtOAc (1:4%)) afforded the product 3-chloro-5-((4-methoxy-2-methylphenyl)ethynyl)picolinonitrile (B-1).
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	To a round bottom flask capped with septa was added 1-ethynyl-4-methoxy-2-methylbenzene (1.1 eq), <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1 eq.), triethylamine (5 eq.), and anhydrous DMF (0.2 M). The mixture was degassed (vacuum) and nitrogen flushed three times. CuI (0.05 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.05 eq) were added and the septum was replaced with a refluxing condenser and the flask was heated at 60 C. overnight under nitrogen atmosphere. Upon completion of the reaction as monitored by TLC, the content of the flask was loaded onto a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes:EtOAc (1:4%)) afforded the product 3-chloro-5-((4-methoxy-2-methylphenyl)ethynyl)picolinonitrile (B-1).

Reference： [1]Patent: WO2010/48582,2010,A1 .Location in patent: Page/Page column 192
[2]Patent: US2011/53893,2011,A1 .Location in patent: Page/Page column 50-51
[3]Patent: US9950062,2018,B2 .Location in patent: Page/Page column 96; 97; 99

26
[ 1258595-03-7 ]
[ 85331-33-5 ]
[ 1258595-04-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	Step 7: 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (6-10)A solution of 1-ethynyl-4-(methoxymethoxy)-2-methylbenzene (6-8) (1.0 equiv.), <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (6-9) (0.90 equiv.), CuI (0.10 equiv.), and Pd(PPh3)2Cl2 (0.10 equiv.), and triethylamine (5.0 equiv.) in DMF (0.25 M) was degassed and flushed with nitrogen. The reaction mixture was then heated to 60 C. and stirred overnight. After cooling to room temperature, water was added. The mixture was extracted with EA (2×). The combined organic layers were washed with 10% aq NH4OH (2×), brine, and concentrated. The crude material was filtered through a pad of silica (wetted with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated. The resulting solids were washed in hot ether and filtered to give a yellow solid, which was used in the next step without further purification. The filtrate was concentrated and purified by Combiflash using 0-10% EtOAc in Hexanes to give 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (6-10) as a yellow solid.
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	Step 7: 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (10) A solution of l-ethynyl-4-(methoxymethoxy)-2-methylbenzene (8) (l.Oequiv.), <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (9) (0.90 equiv.), Cul (O.lOequiv.), and Pd(PPh3)2Cl2 (O.lOequiv.), and triethylamine (5.0equiv.) in DMF (0.25M) was degassed and flushed with nitrogen. The reaction mixture was then heated to 60C and stirred overnight. After cooling to room temperature, water was added. The mixture was extracted with EA (2x). The combined organic layers were washed with 10% aq NH4OH (2x), brine, and concentrated. The crude material was filtered through a pad of silica (wetted with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated. The resulting solids were washed in hot ether and filtered to give a yellow solid, which was used in the next step without further purification. The filtrate was concentrated and purified by Combiflash using 0-10% EtOAc in Hexanes to give 3-chloro-5-((4- (methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (10) as a yellow solid.
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 20 - 60℃;Inert atmosphere;	A solution of 1-ethynyl-4-(methoxymethoxy)-2-methylbenzene (6-8) (1.0 equiv.), <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (6-9) (0.90 equiv.), CuI (0.10 equiv.), and Pd(PPh3)2Cl2 (0.10 equiv.), and triethylamine (5.0 equiv.) in DMF (0.25 M) was degassed and flushed with nitrogen. The reaction mixture was then heated to 60 C. and stirred overnight. After cooling to room temperature, water was added. The mixture was extracted with EA (2). The combined organic layers were washed with 10% aq NH4OH (2), brine, and concentrated. The crude material was filtered through a pad of silica (wetted with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated. The resulting solids were washed in hot ether and filtered to give a yellow solid, which was used in the next step without further purification. The filtrate was concentrated and purified by Combiflash using 0-10% EtOAc in Hexanes to give 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (6-10) as a yellow solid.

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 5868 - 5878
[2]Patent: US2011/53893,2011,A1 .Location in patent: Page/Page column 67
[3]Patent: WO2013/131985,2013,A1 .Location in patent: Page/Page column 21; 23
[4]Patent: US9950062,2018,B2 .Location in patent: Page/Page column 124; 125; 126; 129

27
[ 85331-33-5 ]
[ 471909-65-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	With diisobutylaluminium hydride; In tetrahydrofuran; at -20℃; for 4h;Inert atmosphere; Reflux;	<strong>[85331-33-5]2-Cyano-3,5-dichloropyridine</strong> (432 mg, 2.5 mmol) was dissolved in THF (20 mL) under N 2 atmosphere, and DIBAL-H (1.0 M) was added dropwise at -20 C. Toluene solution (2.5 mL, 2.5 mmol). The mixture was stirred at -20 C for 4 h. Methanol was added to quench the reaction and 1N HCl was added to adjust the pH to 4-5. The reaction mixture was diluted with ethyl acetate and washed two times After that, the organic layer was dried over anhydrous sodium sulfate. Concentration by filtration and column chromatography of the residue provided the title compound as a yellow solid (300 mg, 70% yield).

Reference： [1]Organic and Biomolecular Chemistry,2012,vol. 10,p. 1239 - 1245
[2]Patent: CN103570683,2018,B .Location in patent: Paragraph 0801; 0805-0807

28
[ 63503-60-6 ]
[ 85331-33-5 ]
[ 1415226-38-8 ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 50℃; for 25.5h;Inert atmosphere;Product distribution / selectivity;	A 20 L reactor equipped with a mechanical stirrer, dip tube, thermometer and nitrogen inlet was charged with (3-chlorophenyl)boronic acid (550 g, 3.52 mol), <strong>[85331-33-5]3,5-dichloro-2-cyanopyridine</strong> (639 g, 3.69 mol), K2CO3 (5.5 g, 40 mmol), [1,1'-bis(diphenyphosphino)ferrocene]dichloro-palladium(II) [PdCl2(dppf)] (11.5 g, 140 mmol), and dimethylformamide (3894 g, 4.125 L). The reaction solution was agitated and purged with nitrogen through the dip-tube for 30 minutes. Degassed water (413 g) was then charged to the reaction mixture while maintaining a temperature of less than 50 C. 25 hours. The reaction was determined to be complete due to the disappearance of <strong>[85331-33-5]3,5-dichloro-2-cyanopyridine</strong> as measured by TLC analysis using ethyl acetate/methanol (4:1) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction solution was then cooled to 5 C. and charged with heptane (940 g, 1.375 L) and agitated for 30 minutes. Water (5.5 L) was charged and the mixture was further agitated for 1 hour as the temperature was allowed to rise to 15 C. The solid product was isolated by filtration and washed with water (5.5 L) followed by heptane (18881 g, 2750 ML). The resulting cake was air dried under vacuum for 18 hours and then triturated with a mixture of 2-propanol (6908 g, 8800 mL0 and heptane (1 g, 2200 mL0 at 50 C. for 4 hours, cooled to ambient temperature and then agitated at ambient temperature for 1 hour. The product was then isolated by filtration and washed with cold 2-propanol (3450 g, 4395 mL) followed by heptane (3010 g, 4400 mL). The resulting solid was dried under high vacuum at 40 C. for 64 hours to afford 565.9 g (65% yield) of the desired product as a beige solid. Purity by HPLC was 98.3. 1H NMR (DMSO-d6) delta 9.12 (d, 1H), 8.70 (d, 1H), 8.03 (t, 1H) 7.88 (m, 1H), and 7.58 (m, 2H).
65%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 50℃; for 25h;Inert atmosphere;	A 20 L reactor equipped with a mechanical stirrer, dip tube, thermometer and nitrogen inlet was charged with (3-chlorophenyl)boronic acid (550 g, 3.52 mol), 3,5-dichloro-2- cyanopyridine (639 g, 3.69 mol), K2CO3 (5.5 g, 40 mmol), [1,1?- bis(diphenyphosphino)ferrocene]dichloro-palladium(II) [PdCl2(dppf)] (11.5 g, 140 mmol), and dimethylformamide (3894 g, 4.125 L). The reaction solution was agitated and purged with nitrogen through the dip-tube for 30 minutes. Degassed water (413 g) was then charged to the reaction mixture while maintaining a temperature of less than 50 C 25 hours. The reaction was determined to be complete due to the disappearance of <strong>[85331-33-5]3,5-dichloro-2-cyanopyridine</strong> as measured by TLC analysis using ethyl acetate/methanol (4:1) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction solution was then cooled to 5 C and charged with heptane (940 g, 1.375 L) and agitated for 30 minutes. Water (5.5 L) was charged and the mixture was further agitated for 1 hour as the temperature was allowed to rise to 15 C. The solid product was isolated by filtration and washed with water (5.5 L) followed by heptane (18881 g, 2750 ML). The resulting cake was air dried under vacuum for 18 hours and then triturated with a mixture of 2-propanol (6908 g, 8800 mL and heptane (1 g, 2200mL at 50 C for 4 hours, cooled to ambient temperature and then agitated at ambient temperature for 1 hour. The product was then isolated by filtration and washed with cold 2-propanol (3450 g, 4395 mL) followed by heptane (3010 g, 4400mL). The resulting solid was dried under high vacuum at 40 C for 64 hours to afford 565.9 g (65% yield) of the desired product as a beige solid. Purity by HPLC was 98.3%. NMR (DMSO-rie) d 9.12 (d, 1H), 8.70 (d, 1H), 8.03 (t, 1H) 7.88 (m, 1H), and 7.58 (m, 2H).
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 45℃; for 18h;Inert atmosphere;	To a 100-mL round bottom flask adapted for magnetic stirring and equipped with a nitrogen inlet is charged (3-chlorophenyl)boronic acid, 3,5-dichloro- 2-cyanopyridine, K2C03, PdCl2(dppf), dimethylformide, and water. The reaction solution is agitated and heated to 45 C, and held at that temperature for 18 hours after which the reaction is determined to be complete due to the disappearance of <strong>[85331-33-5]3,5-dichloro-2-cyanopyridine</strong> as measured by TLC analysis. The reaction solution is cooled to room temperature and the contents partitioned between ethyl acetate (250 mL) and saturated aqueous NaCl (100 mL). The organic phase is isolated and washed a second time with saturated aqueous NaCl (100 mL). The organic phase is dried over MgS04, filtered, and the solvent is concentrated in vacuo. The residue that remained is then slurried in methanol (50 mL) at room temperature for 20 hours. The resulting solid is collected by filtration and washed with cold methanol (50 mL) then hexanes (60 mL) and dried to afford compound C as an admixture containing a 96:4 ratio of the desired regioisomer.

Reference： [1]Patent: US2012/309977,2012,A1 .Location in patent: Page/Page column 19; 21
[2]Patent: WO2019/217550,2019,A1 .Location in patent: Paragraph 0066
[3]Patent: WO2016/153996,2016,A1 .Location in patent: Paragraph 00128

29
[ 85331-33-5 ]
[ 1415226-39-9 ]

Reference： [1]Patent: US2012/309977,2012,A1
[2]Patent: WO2016/153996,2016,A1
[3]Patent: WO2019/217550,2019,A1

30
[ 85331-33-5 ]
[ 1415226-40-2 ]

Reference： [1]Patent: US2012/309977,2012,A1
[2]Patent: WO2016/153996,2016,A1
[3]Patent: WO2019/217550,2019,A1

31
[ 85331-33-5 ]
[ 1000025-07-9 ]

Reference： [1]Patent: US2012/309977,2012,A1
[2]Patent: WO2016/153996,2016,A1
[3]Patent: WO2019/217550,2019,A1

32
[ 768-35-4 ]
[ 85331-33-5 ]
[ 1415796-65-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 20 - 53℃;Inert atmosphere; Large scale;	6.5.1 Prepar enyl)-3-chloro-2-cyanopyri Potassium carbonate (1785 g, 1.49 eq), 3,5-dic-hloro-2-cyanopyridine (1500 g, 1.0 eq), (3-fluorophenyl)boronic acid (1069.5 g, 1.0 eq), dichloro[l, l '-bis(diphenylphosphino) ferrocene] palladium (II) (DCM adduct PdCl2(dppf)) (30 g, 0.004 eq) and dimethylformamide (10.6 kg) were charged to a 30L reactor equipped with an over-head agitator, condenser, thermocouple and nitrogen sparger. The mixture was agitated and sparged with nitrogen gas through the dip-tube for ca. 30 minutes. Degassed water (969 g) was slowly charged to the mixture while maintaining a temperature of less than 45 C'C. The reaction mixture was agitated at 20 to 45 C and sparged with nitrogen gas through the dip-tube for 30 minutes, followed by agitation at 50 C (between 47 to 53 C) for 2 to 24 hours until the reaction was determined to be complete due to the disappearance of compound 2 as measured by HPLC. The reaction mixture was cooled to 22 C (between 19 to 25 C). n-Heptane (2.2 kg) and water (12.9 kg) were charged to the reaction mixture while keeping the temperature at no more than 45 C. After the mixture was agitated at 22 C (between 9 to 25 C) for 1 to 2 hours, crude 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was isolated as a solid by filtration. The crude 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was transferred into an empty reactor with water (12.9 kg). The mixture was agitated at 22 C'C (between 19 to 25 C) for 2 hours. Crude 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was isolated as a solid by filtration and washed with water (3 kg). The crude 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was transferred into an empty reactor with 2-propanol (14.25 kg). The mixture was agitated at reflux at 82 C for 1 to 2 hours. After cooling to 22 C (19 to 25 C), the mixture was agitated at 22 C (19 to 25 C) for 2 to 3 hours. 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was isolated as a solid by filtration and rinsed with 2-propanol (2.36 kg). After being dried under vacuum at 50 C until the water content was less than 1.5% (-16 hours), 1736.9 g 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was obtained as a brown solid (yield 86%). Figure 77 depicts the NMR spectrum of 5-(3~fluorophenyl)-3- chloro-2-cyanopyridine (4).
86%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 20 - 53℃;Inert atmosphere; Large scale;	Potassium carbonate (1785 g, 1.49 eq), 3,5- dichloro-2-cyanopyridine (1500 g, 1.0 eq), (3-fluorophenyl) boronic acid (1069.5 g, 1.0 eq), dichloro[1,1?-bis(diphenylphosphino) ferrocene]palladium (II) (DCM adduct PdCl2 (dppf)) (30 g, 0.004 eq) and dimethylformamide (10.6 kg) were charged to a 30 L reactor equipped with an over-head agitator, condenser, thermocouple and nitrogen sparger. The mixture was agitated and sparged with nitrogen gas through the dip-tube for ca. 30 minutes. Degassed water (969 g) was slowly charged to the mixture while maintaining a temperature of less than 45 C.10628] The reaction mixture was agitated at 20 to 45 C. and sparged with nitrogen gas through the dip-tube for 30 minutes, followed by agitation at 50 C. (between 47 to 53 C.) for 12 to 24 hours until the reaction was determined to be complete due to the disappearance of compound 2 as measured by HPLC.10629] The reaction mixture was cooled to 22 C. (between19 to 25 C.). n-Heptane (2.2 kg) and water (12.9 kg) werecharged to the reaction mixture while keeping the temperature at no more than 45 C. After the mixture was agitated at22 C. (between 19 to 25 C.) for ito 2 hours, crude 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was isolated as asolid by filtration.10630] The crude 5-(3-fluorophenyl)-3-chloro-2-cyanopy- ridine (4) was transferred into an empty reactor with water (12.9 kg). The mixture was agitated at 22 C. (between 19 to 25 C.) for 2 hours. Crude 5-(3-fluorophenyl)-3-chioro-2- cyanopyridine (4) was isolated as a solid by filtration and washed with water (3 kg).10631] The crude 5-(3-fluorophenyl)-3-chloro-2-cyanopy- ridine (4) was transferred into an empty reactor with 2-pro- panol (14.25 kg). The mixture was agitated at reflux at 82 C. for ito 2 hours. Afier cooling to 22 C. (19 to 25 C.), the mixture was agitated at 22 C. (19 to 25 C.) for 2 to 3 hours. 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was isolated as a solid by filtration and rinsed with 2-propanol (2.36 kg).10632] After being dried under vacuum at 50 C. until thewater content was less than 1.5% (.-16 hours), 1736.9 g 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was obtained asa brown solid (yield 86%). FIG. 77 depicts the ?H NMRspectrum of 5-(3-fluorophenyl)-3-chioro-2-cyanopyridine(4).
	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 45℃; for 18h;Inert atmosphere;	To a 100 mL round bottom flask that is adapted for magnetic stirring and equipped with a nitrogen inlet is charged (3-fluorophenyl)boronic acid (4.48 g, 32 mmol), <strong>[85331-33-5]3,5-dichloro-2-cyanopyridine</strong> (5.8 g, 34 mmol), K2CO3 (5.5 g, 40 mmol), [1,1'-bis(diphenyphosphino)ferrocene]dichloro-palladium(II) [PdCl2(dppf)] (0.1 g, 0.13 mmol), dimethylformamide (50 mL) and water (5 mL). The reaction solution is agitated and heated to 45 C. and held at that temperature for 18 hours after which the completeness of the reaction can be determined by the absence of the starting material <strong>[85331-33-5]3,5-dichloro-2-cyanopyridine</strong> via TLC using ethyl acetate/methanol (4:1) as the mobile phase and UV 435 nm to visualize any remaining starting material. The reaction solution is then cooled to room temperature and the contents partitioned between ethyl acetate (250 mL) and saturated aqueous NaCl (100 mL). The organic phase is isolated and washed a second time with saturated aqueous NaCl (100 mL). The organic phase is dried for 4 hours over MgSO4, the MgSO4 is removed by filtration and the solvent is removed under reduced pressure. The residue that remains is then slurried in methanol (50 mL) at room temperature for 20 hours. The resulting solid is collected by filtration and washed with cold methanol (50 mL) then hexanes (60 mL) and dried to afford desired product.

With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 45℃; for 18h;Inert atmosphere;

To a 100 mL round bottom flask that is adapted for magnetic stirring and equipped with a nitrogen inlet is charged (3-fluorophenyl)boronic acid (4.48 g, 32 mmol), <strong>[85331-33-5]3,5-dichloro-2-cyanopyridine</strong> (5.8 g, 34 mmol), K2CO3 (5.5 g, 40 mmol), [l, l '-bis(diphenyphosphino)ferrocene]dichloro-palladium(II) [PdCi2(dppf)] (0.1 g, 0.13 mmol), dimethylformamide (50 mL) and water (5mL). The reaction solution is agitated and heated to 45 C and held at that temperature for 18 hours after which the completeness of the reaction can be determined by the absence of the starting material 3,5- dichloro-2-cyanopyridine via TLC using ethyl acetate/methanol (4: 1) as the mobile phase and UV 435 nm to visualize any remaining starting material. The reaction solution is then cooled to room temperature and the contents partitioned between ethyl acetate (250 mL) and saturated aqueous NaCl (100 mL). The organic phase is isolated and washed a second time with saturated aqueous NaCl (100 mL). The organic phase is dried for 4 hours over MgS04, the MgS04 is removed by filtration and the solvent is removed under reduced pressure. The residue that remains is then slurried in methanol (50 mL) at room temperature for 20 hours. The resulting solid is collected by filtration and washed with cold methanol (50 mL) then hexanes (60 mL) and dried to afford desired product.

Reference： [1]Patent: WO2016/118858,2016,A1 .Location in patent: Paragraph 00599-00604
[2]Patent: US2016/214939,2016,A1 .Location in patent: Paragraph 0626-0632
[3]Patent: US2012/316204,2012,A1 .Location in patent: Page/Page column 9-10
[4]Patent: WO2015/23967,2015,A2 .Location in patent: Paragraph 0179; 0185

33
[ 85331-33-5 ]
[ 1415796-67-6 ]

Reference： [1]Patent: US2012/316204,2012,A1
[2]Patent: WO2015/23967,2015,A2
[3]Patent: WO2016/118858,2016,A1
[4]Patent: US2016/214939,2016,A1

34
[ 85331-33-5 ]
[ 1415796-69-8 ]

Reference： [1]Patent: US2012/316204,2012,A1
[2]Patent: WO2015/23967,2015,A2
[3]Patent: WO2016/118858,2016,A1
[4]Patent: US2016/214939,2016,A1

35
[ 1777-03-3 ]
[ 124-41-4 ]
[ 85331-33-5 ]
[ 1600511-76-9 ]

Yield	Reaction Conditions	Operation in experiment
3.8 g		A sealed vessel was charged with bis(acetonitrile)palladium (II) chloride (0.154 g, 0.593 mmol), dicyclohexyl(2',4',6'-triisopropyl-[l,l'-biphenyl]-2-yl)phosphine (0.848 g, 1.780 mmol), cesium carbonate (25.1 g, 77 mmol), the product of Intermediate 1, step 1 (5 g, 29.7 mmol), and ACN (60 mL). The vessel was flushed with argon, sealed, and stirred at RT for 25 minutes. To the reaction was added triethyl(ethynyl)silane (5.41 g, 38.6 mmol), and the vessel was resealed and stirred at 90 C for 3 hours. The solution was concentrated, and the residue was purified via silica gel chromatography, eluting with 0-50 % ethyl acetate in heptanes, to afford the title compound (3.8 g, 13.9 mmol). MS m/z = 273 (M+H)+
3.8 g		To a solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (22.5 g, 130 mmol) in DMF (500 mL) at 0 C was added sodium methoxide (6.67 g, 124 mmol) slowly. The reaction was stirred for 5 min at 0 C then stirred at RT for 30 min. The solution was partitioned between water and EtOAc. The organic layer was washed with water and concentrated. The crude product was purified via silica gel chromatography, eluting with 0-75% EtOAc in heptane, to afford a 1 : 1 ratio of the desired isomer 3-chloro-5-methoxypicolinonitrile and 5-chloro-3-methoxypicolinonitrile (7.0 g, 41.5 mmol). The material was used without further purification. MS m/z = 169 (M+H). A sealed vessel was charged with bis(acetonitrile)palladium (II) chloride (0.154 g, 0.593 mmol), dicyclohexyl(2',4',6'- triisopropyl-[1 ,1 '-biphenyl]-2-yl)phosphine (0.848 g, 1.780 mmol), cesium carbonate (25.1 g, 77 mmol), the mixture (1 : 1 ratio) of 3-chloro-5-methoxypicolinonitrile and 5- chloro-3-methoxypicolinonitrile (5 g, 29.7 mmol), and ACN (60 mL). The vessel was flushed with argon, and stirred at RT for 25 min. To the reaction was added triethyl(ethynyl)silane (5.41 g, 38.6 mmol), and the vessel was resealed and stirred at 90 C for 3 h. The solution was concentrated, and the residue was purified via silica gel chromatography, eluting with 0-50% EtOAc in heptane, to afford the title compound (3.8 g, 13.9 mmol). MS m/z = 273 (M+H) +.

Reference： [1]Patent: WO2014/138484,2014,A1 .Location in patent: Page/Page column 138
[2]Patent: WO2016/22724,2016,A1 .Location in patent: Page/Page column 256; 257

36
[ 925-90-6 ]
[ 85331-33-5 ]
1-(3,5-dichloropyridin-2-yl)-1-propanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4.4 g	With hydrogenchloride; In tetrahydrofuran; at 20℃; for 1h;Cooling with ice;	To 5.0 g of 3,5-dichloropyridin-2-carbonitrile in 50 ml of tetrahydrofuran, 38 ml of 13% ethylmagnesium bromide in tetrahydrofuran was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was added dropwise to 55 ml of 1 N aqueous hydrochloric acid with stirring under cooling with ice, and extracted with ethyl acetate (50 mlx2). The resulting organic layers were combined, washed with water (50 ml*1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of 5:95 to 15:85) as the eluent to obtain 4.4 g of the desired product as pale yellow crystals. 1H NMR (CDCl3, Me4Si, 300MHz) delta8.48 (d, J=2.1Hz, 1H), 7.81 (d, J=2.1Hz, 1H), 3.10 (q, J=7.2Hz, 2H), 1.20 (t, J=7.2Hz, 3H).
4.4 g	In tetrahydrofuran; at 20℃; for 1h;Cooling with ice;	To 5.0 g of 3,5-dichloropyridin-2-carbonitrile in 50 ml of tetrahydrofuran, 38 ml of 13% ethylmagnesium bromide in tetrahydrofuran was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was added dropwise to 55 ml of 1N aqueous hydrochloric acid with stirring under cooling with ice, and extracted with ethyl acetate (50 ml×2). The resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of 5:95 to 15:85) as the eluent to obtain 4.4 g of the desired product as pale yellow crystals

Reference： [1]Patent: EP2873658,2015,A1 .Location in patent: Paragraph 0430
[2]Patent: JP2016/11286,2016,A .Location in patent: Paragraph 0467

37
[ 75-16-1 ]
[ 85331-33-5 ]
1-(3,5-dichloropyridin-2-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.8%		A solution of 40 g of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> in 200 g of toluene is cooled to 0 C.,85 ml of a diethyl ether solution (3 mol / L) of methylmagnesium bromide was dropped in 23 minutes.The reaction solution was stirred at 0 C. for 10 minutes, and then added dropwise to a 12 mass% aqueous hydrochloric acid solution cooled to 5 C.The reaction solution was stirred at 0 C. for 1 hour.The reaction solution was separated, and the aqueous layer was extracted with 40 g of toluene.The organic layers were combined, washed with 200 g of water, and then 50 g of saturated brine,It was then dried over anhydrous sodium sulfate.The obtained organic layer was evaporated under reduced pressure.The residue obtained is chromatographed on silica gel [ethyl acetate: hexane = 1: 9(By volume, the same applies hereinafter)],24.51 g of the desired product was obtained as a colorless oil (yield 55.8%).
17.16 g		To 20 g of <strong>[85331-33-5]3,5-dichloropyridine-2-carbonitrile</strong> in 150 ml of tetrahydrofuran, 139 ml of a 1 M tetrahydrofuran solution of methylmagnesium bromide was added dropwise with stirring under cooling with ice, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was mixed with 15 ml of concentrated hydrochloric acid and 100 ml of water and extracted with ethyl acetate (100 ml2), the resulting organic layers were combined, washed with water (100 ml1) and dried over saturated aqueous solution chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in 40 ml of ethyl acetate and 10 ml of hexane, 20 g of silica gel was added, the mixture was stirred at room temperature for 1 hour and then subjected to filtration, and the solvent was evaporated under reduced pressure. The precipitated solid was washed with 50 ml of hexane to obtain 17.16 g of the desired product as pale yellow crystals. 1H NMR (CDCl3, Me4Si, 300MHz) delta8.50 (d, J=2.1 Hz, 1 H), 7.82 (d, J=2.1 Hz, 1 H), 2.68 (s, 3H).
17.16 g		Step 1; 1-in (3,5-dichloro-2-yl) ethanone tetrahydrofuran 150ml solution of manufacturing 3,5-dichloro-2-carbonitrile 20g of, under ice-cooling and stirring, 1M tetrahydrofuran solution of methyl magnesium bromide It was added dropwise to 139ml, and stirred for 1 hour at the same temperature.After completion of the reaction, extraction with the added ethyl acetate concentrated hydrochloric acid 15ml and 100ml of water to the reaction mixture (100mlx2), washed with water and the combined organic layer (100mlx1), dehydrated and dried in the order of the saturated brine then anhydrous sodium sulfate, It and the solvent was evaporated under reduced pressure.The residue was added to dissolve silica gel 20g of ethyl acetate and hexane 40ml 10ml, filtered after stirring one hour at room temperature, and the solvent was distilled off under reduced pressure.The precipitated solid was washed with hexane 50ml, and the intended product was obtained 17.16g as pale yellow crystals

17.6 g

In tetrahydrofuran; for 1h;Cooling with ice;

3,5-Dichloropyridine-2-carbonitrile 20 gIn 150 ml of tetrahydrofuran was added under ice cooling and stirring,139 ml of a 1 M tetrahydrofuran solution of methyl magnesium bromide was added dropwise,And the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, 15 ml of concentrated hydrochloric acid and 100 ml of water were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml × 2). The organic layer was combined, washed with water (100 ml × 1), dehydrated and dried in the order of saturated saline and then anhydrous sodium sulfate, The solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (40 ml) and hexane (10 ml), 20 g of silica gel was added and the mixture was stirred at room temperature for 1 hour, then filtered and the solvent was distilled off under reduced pressure. The precipitated solid was washed with hexane 50Ml to obtain 17.16 g of the objective compound as pale yellow crystals.

Reference： [1]Patent: JP2019/34892,2019,A .Location in patent: Paragraph 0169
[2]Patent: EP2873658,2015,A1 .Location in patent: Paragraph 0404
[3]Patent: JP2016/11286,2016,A .Location in patent: Paragraph 0436
[4]Patent: JP2015/155399,2015,A .Location in patent: Paragraph 0279

38
[ 112245-13-3 ]
[ 85331-33-5 ]
(S)-4-tert-butyl-2-(3,5-dichloropyridin-2-yl)-4,5-dihydrooxazole [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 2010 - 2018

39
[ 35447-83-7 ]
[ 85331-33-5 ]
N-(4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)phenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 4h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), N-(4-ethynylphenyl)acetamide (from the previous step) (1.0 eq.), bis(triphenyl-phosphine)palladium chloride (10 mol %), copper iodide (10 mol %), and triethylamine (5.0 eq.) in DMF (0.04 M) was stirred at 60 C. for 4 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated. The organic layer was washed twice with water, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give N-(4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)phenyl)acetamide as a white solid.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 135; 136

40
methyl 4-ethynyl-3-methylbenzoate [ No CAS ]
[ 85331-33-5 ]
methyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 4h;	A solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.), methyl 4-ethynyl-3-methylbenzoate (from the previous step) (1.0 eq.), bis(triphenyl-phosphine)palladium chloride (10 mol %), copper iodide (10 mol %), and triethylamine (5.0 eq.) in DMF (0.04 M) was stirred at 60 C. for 4 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated. The organic layer was washed twice with water, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give methyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate as a white solid.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 137

41
[ 85331-33-5 ]
3-chloro-5-mercaptopicolinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium sulfide; In N,N-dimethyl-formamide;	To a solution of <strong>[85331-33-5]3,5-dichloropyridine-2-carbonitrile</strong> (50 mg, 0.29 mmol) in DMF (2 mL) was added Na2S (33.83 mg, 0.43 mmol). After completion of the reaction the mixture was added NaHS04 (aq) to adjust pH 4-5 followed by DCM(10 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulphate. Removal of solvent gave the desired product (30 mg, crude). m/z calcd for [C6H3C1 2S]" [M-H]": 169.0; found: 169.0.

Reference： [1]Patent: WO2016/120403,2016,A1 .Location in patent: Page/Page column 156; 157

42
4-ethynyl-N,N,3-trimethylaniline [ No CAS ]
[ 85331-33-5 ]
3-chloro-5-((4-(dimethylamino)-2-methylphenyl)ethynyl)picolinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 20℃;	To a solution of 4-ethynyl-N,N-3-trimethylaniline (from the previous step) (1 eq) <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.2 eq), dichlorobis(triphenylphosphine)-palladium (II) (10 mol %), copper iodide (10 mol %) and DMF: triethylamine (0.28 M) was stirred at ambient temperature overnight. The reaction mixture was then diluted with ethyl acetate and ammonium chloride solution. The two phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-100% ethyl acetate in hexane and 3-chloro-5-((4-(dimethylamino)-2-methylphenyl)ethynyl)picolinonitrile was isolated as a off-yellow solid.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 177

43
[ 42472-69-5 ]
[ 85331-33-5 ]
5-((4-acetylphenyl)ethynyl)-3-chloropicolinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 20℃;	To a solution of 1-(4-ethynylphenyl)ethanone (commercially available) (1 eq) <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1 eq), dichlorobis(triphenylphosphine)-palladium (II) (20 mol %), copper iodide (10 mol %) and DMF:Triethylamine (10:1) (0.13 M) was stirred at ambient temperature overnight. The reaction mixture was then diluted with ethyl acetate and sodium bicarbonate solution. The two phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-100% ethyl acetate in hexane and 5-((4-acetylphenyl)ethynyl)-3-chloropicolinonitrile was isolated as a yellow solid

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 165

44
[ 124-41-4 ]
[ 85331-33-5 ]
3-chloro-5-methoxypyridine-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 75℃; for 14h;	To a solution of <strong>[85331-33-5]3,5-dichloropicolinonitrile</strong> (1.0 eq.) in dimethyl formamide (DMF) (0.5 M) was added sodium methoxide (1.5 eq.) and heated to 75 C. After stirring for 14 hours, the reaction was diluted with ethyl acetate and water. The organic layer was washed with saturated aqueous NaHCO3 three times, water twice, dried over anhydrous MgSO4, and concentrated en vacuo. The crude residue was purified by a COMBIFLASH system (ISCO) using 15% ethyl acetate in hexane to give a mixture of two methoxy regioisomers, one of which was the desired product. The mixture was carried onto the next step without further purification.

Reference： [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 74

45
[ 6746-94-7 ]
[ 85331-33-5 ]
3-chloro-5-(cyclopropylethynyl)pyridine-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18.40 g	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	3,5-dichloro-2-carbonitrile 17.37g of N, N-dimethylformamide ATriethylamine 50.60g, cyclopropyl acetylene 7.90g to bromide 200ml solution,Copper iodide (I) 2.20g and dichlorobis (triphenylphosphine) palladium (II) 2.10Was added g, under a nitrogen atmosphere, the mixture was stirred overnight at room temperature. After completion of the reaction, water 500m to the reaction mixturel extracted with added ethyl acetate (250mlx2), washed with water and the combined organic layer (500mlx1), Saturated saline and then dehydrated and dried in this order over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.The residue was ethyl acetate - hexane (1: 9) silica gel column chromatography eluting withWas purified by chromatography, the desired product was obtained 18.40g as a brown solid.
18.4 g	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	To a solution of 17.37 g of <strong>[85331-33-5]3,5-dichloropyridine-2-carbonitrile</strong> in 200 ml of N, N-dimethylformamide were added 50.60 g of triethylamine, 7.90 g of cyclopropylacetylene,2.20 g of copper (I) iodideAnd dichlorobis (triphenylphosphine) palladium (II)2.10 g was added,And the mixture was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, 500 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (250 ml × 2). The organic layer was combined (500 ml × 1), washed with saturated brine and dried over anhydrous sodium sulfate in this order, The solvent was distilled off. The residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1: 9) to obtain 18.40 g of the desired product as a brown solid.
18.40 g	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	Step 1: Production of 3-chloro-5-(cyclopropylethynyl)pyridine-2-carbonitrile To a 200 ml solution of 17.37 g of <strong>[85331-33-5]3,5-dichloropyridine-2-carbonitrile</strong> in N,N-dimethylformamide, 50.60 g of triethylamine, 7.90 g of cyclopropyl acetylene, 2.20 g of copper(I) iodide and 2.10 g of dichlorobis(triphenylphosphine)palladium(II), were added. After completion of the addition, the mixture was stirred under a nitrogen atmosphere overnight at room temperature. After completion of the reaction, 500 ml of water was added to the reaction mixture, followed by extraction with ethyl acetate (250 ml2). The obtained organic layers were put together and washed with water (500 ml1). Thereafter, using in the order of saturated aqueous sodium chloride and then anhydrous sodium sulfate, dehydration and drying were carried out, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography by eluting it with ethyl acetate-hexane [1:9 (volume ratio, the same applies hereinafter)], to obtain 18.40 g of the desired product as a brown solid. 1H NMR (CDCl3, Me4Si, 300 MHz) delta 8.50 (d, J=1.7 Hz, 1H), 7.77 (d, J=1.7 Hz, 1H), 1.45-1.55 (m, 1H), 0.8-1.05 (m, 4H).

Reference： [1]Patent: JP2016/11286,2016,A .Location in patent: Paragraph 0557
[2]Patent: JP2015/155399,2015,A .Location in patent: Paragraph 0288
[3]Patent: US2017/188580,2017,A1 .Location in patent: Paragraph 0145; 0146

46
[ 16466-97-0 ]
[ 85331-33-5 ]
3-chloro-5-(1-propynyl)pyridine-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.50 g		Zinc bromide under a nitrogen atmosphere (tetrahydrofuran 120 ml solution of II)10.87g in ice cold stirring, 1-propinilmagnesiumbromide 0.5 M tetrahydrofuran solution 92 ml, after stirring for ten minutes at this temperature. Followed by this reaction mixture in 3, 5 - dichloropyridine, which-2 - ketones with 5.00 g and Dichloro [1, 1 '-bis (diphenylphosphino) Ferrocene, palladium (continuous stirring two hours at 50 C, and the addition of the II)0.94g. After the reaction is complete, the reaction mixture and added 40 ml of water and cool to room temperature and extracted in ethyl acetate (20mlx2), the organic layer along with water (40mlx1) and then eating saturated salt followed by sodium sulfate anhydrous pressure dewatering and drying, under the distilled solvent. And then purified by silica gel column chromatography in hexane leaching residue, to 5.50 g got as pale yellow solid.
5.50 g		Step 1: Production of 3-chloro-5-(1-propynyl)pyridine-2-carbonitrile Under a nitrogen atmosphere, 92 ml of a 0.5 M tetrahydrofuran solution of 1-propynyl magnesium bromide was added dropwisely to a 120 ml solution of 10.87 g of zinc(II) bromide in tetrahydrofuran, with stirring under cooling with ice. After completion of the dropwise addition, the reaction mixture was stirred at the same temperature for 10 minutes. After completion of the stirring, to the reaction mixture, 5.00 g of <strong>[85331-33-5]3,5-dichloropyridine-2-carbonitrile</strong> and 0.94 g of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) were added. After completion of the addition, the reaction mixture was continuously stirred at 50 C. for 2 hours. After completion of the reaction, the reaction mixture was left to cool to room temperature, then, 40 ml of water was added, followed by extraction with ethyl acetate (20 ml2). The obtained organic layers were put together, washed with water (40 ml1) and then dehydrated and dried by using saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography by eluting it with hexane, to obtain 5.50 g of the desired product as a pale yellow solid. 1H NMR (CDCl3, Me4Si, 300 MHz) delta 8.54 (d, J=1.8 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 2.13 (s, 3H).

Reference： [1]Patent: JP2016/11286,2016,A .Location in patent: Paragraph 0566
[2]Patent: US2017/188580,2017,A1 .Location in patent: Paragraph 0162; 0163

47
[ 85331-33-5 ]
[ 100-58-3 ]
phenyl(3,5-dichloropyridin-2-yl)methanimine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	In toluene; at -40 - 20℃; for 12h;	PhMgBr (3.69 mmol, 1.0 eq) was slowly added dropwise at -40 C to a solution of 3,5-difluoropyridine-2-carbonitrile (517 mg, 3.69 mmol) in 10 mL of toluene.The mixture was gradually warmed to room temperature and then stirred at room temperature for 12 hours.After injecting 20 mL of NH4Cl / H2O aqueous solution, the organic solvent was extracted and the water was removed with Na2SO4.A yellow oil was obtained through a silica gel column at a yield of 519 mg, 60%

Reference： [1]Patent: KR2017/110400,2017,A .Location in patent: Paragraph 0179-0181

48
[ 14482-51-0 ]
copper(l) cyanide [ No CAS ]
[ 85331-33-5 ]

Yield	Reaction Conditions	Operation in experiment
68.2%	With 2-methylimidazole; In N,N-dimethyl acetamide; at 105 - 110℃;Inert atmosphere;	Raw material selection: 17.5 g of <strong>[14482-51-0]2-bromo-3,5-dichloropyridine</strong>, 34.54 g of cuprous cyanide (CuCN), 12.6 g of 2-methylimidazole,The reaction organic solvent dimethylacetamide (DMSO) 105 ml; purified organic solvent n-heptane 100 ml.In the process of extracting and washing the organic solvent (or ethyl acetate or toluene or cyclohexane or petroleum ether) after the completion of the reaction, the amount of the organic solvent and the amount of water are conventional and not limited; the following specific process is toluene Extraction is an example.Reaction step: 17.5 g of <strong>[14482-51-0]2-bromo-3,5-dichloropyridine</strong> prepared above, 34.54 g of cuprous cyanide (CuCN), 12.6 g of 2-methylimidazole were added to a dry 250 ml reaction flask, and an organic solvent was added. 105 ml of dimethylacetamide was heated to 105-110 ° C under the protection of nitrogen, and the reaction was completely cooled to room temperature.Add 150 ml of toluene in an organic solvent, stir for about 10 minutes, add 100 ml of water, filter the solid, separate the organic phase from the filtrate, and wash the residue twice with toluene (50 ml/time).The washing liquid continues to extract the aqueous phase, and the liquid phase is separated, and the organic phase is combined, washed once with 100 ml of water, and evaporated to dryness under reduced pressure at 60 ° C in a water bath.Producing a crude solid of 3,5-dichloro-2-cyanopyridine;The crude solid of 3,5-dichloro-2-cyanopyridine obtained is recrystallized from purified organic solvent n-heptane: 100 ml of n-heptane is added and heated to 90 ° C to dissolve, and then slowly cooled to about 10 ° C to precipitate a solid, and the product is obtained by filtration. ,Drying at 40-60 ° C under vacuum gave 9.1 g of 3,5-dichloro-2-cyanopyridine, the yield was 68.2percent, the product purity was 99.2percent, and the total reaction yield was 64.4percent.

Reference： [1]Patent: CN109020882,2018,A .Location in patent: Paragraph 0031; 0038-0042; 0043; 0048-0052; 0053; 0058; 0059

49
potassium cyanide [ No CAS ]
[ 823-56-3 ]
[ 85331-33-5 ]

Yield	Reaction Conditions	Operation in experiment
86.1%	With tetrabutylammomium bromide; at 120 - 125℃; for 10h;	To the <strong>[823-56-3]3,5-dichloro-2-fluoropyridine</strong> solution obtained in step (1) was added 1.0 g of catalyst tetrabutylammonium bromide,35.5g of powdery solid potassium cyanide (99% by mass, 0.55mol),Heat to 120-125 C for cyanation reaction.Sampling during the reaction to detect changes in the content of intermediates and products,Incubate until the intermediate content is less than 2.0% (about 10h), stop the reaction, cool to room temperature, filter, and wash the obtained solid three times with sulfolane (10mL each time).The filtrate and washing solution were combined, and concentrated under reduced pressure (temperature less than 150 C, vacuum greater than -0.095 MPa) to recover the solvent sulfolane,500 mL of cyclohexane was added to the residue, heated to 40-45 C, washed with water, and the phases were separated.The organic phase is cooled to 0-5 C and crystallized, and filtered (fast filter paper can be used, pore size 80-120 microns),Drying under reduced pressure (temperature below 60 C) to obtain 75.5 g of the product (98.6% product content, less than 0.1% moisture),Yield: 86.1% (based on 2,3,5-trichloropyridine).

Reference： [1]Patent: CN110498767,2019,A .Location in patent: Paragraph 0041; 0045-0047; 0051-0053; 0057-0058

50
[ 85331-33-5 ]
[ 1000024-87-2 ]
[ 1000025-07-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / N,N-dimethyl-formamide; water / 4 h / 45 °C / Inert atmosphere; Large scale 2.1: methanol / 6 h / Reflux; Inert atmosphere; Large scale 3.1: sodium hydroxide; water / methanol / 6 h / Reflux 4.1: 1,1'-carbonyldiimidazole / dichloromethane / 2 h / 20 °C 4.2: 1 h / 20 °C 5.1: aluminum (III) chloride / N,N-dimethyl acetamide / 14 h / 85 °C

Reference： [1]Lin, Biyue; Kou, Jingping; Wu, Shuming; Cai, Xuerong; Xiao, Qingbo; Li, Yinglong; Hu, Jian; Li, Jianbing; Wang, Zhongqing [Organic Process Research and Development, 2021, vol. 25, # 4, p. 960 - 968]

51
[ 85331-33-5 ]
[ 1000025-93-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 20 °C / Cooling with ice 2: sodium hydroxide / lithium hydroxide monohydrate; ethanol / 90 °C

Reference： [1]Current Patent Assignee: JIANGSU SUZHONG PHARMACEUTICAL RES INSTITUTE; JIANGSU SUZHONG PHARMA GROUP CO., LTD. - WO2022/78428, 2022, A1

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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

[ CAS No. 85331-33-5 ] {[proInfo.proName]}

Quality Control of [ 85331-33-5 ]

Related Doc. of [ 85331-33-5 ]

Product Details of [ 85331-33-5 ]

Calculated chemistry of [ 85331-33-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 85331-33-5 ]

Application In Synthesis of [ 85331-33-5 ]

[ 85331-33-5 ] Synthesis Path-Upstream 1~8

[ 85331-33-5 ] Synthesis Path-Downstream 1~51

Related Functional Groups of [ 85331-33-5 ]

Chlorides

Nitriles

Related Parent Nucleus of [ 85331-33-5 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 85331-33-5 ]

Related Parent Nucleus of
[ 85331-33-5 ]