[ CAS No. 3939-13-7 ] {[proInfo.proName]}

Name: 3939-13-7|2-Fluoronicotinonitrile|98%
Brand: Ambeed
SKU: A301129
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Quality Control of [ 3939-13-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 3939-13-7 ]

Product Details of [ 3939-13-7 ]

CAS No. :	3939-13-7	MDL No. :	MFCD03095082
Formula :	C₆H₃FN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	USIDQCCXMGJOJM-UHFFFAOYSA-N
M.W :	122.10	Pubchem ID :	2783254
Synonyms :

Calculated chemistry of [ 3939-13-7 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	28.91
TPSA :	36.68 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.33 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.22
Log Po/w (XLOGP3) :	1.0
Log Po/w (WLOGP) :	1.51
Log Po/w (MLOGP) :	0.22
Log Po/w (SILICOS-IT) :	1.76
Consensus Log Po/w :	1.14

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.72
Solubility :	2.32 mg/ml ; 0.019 mol/l
Class :	Very soluble
Log S (Ali) :	-1.36
Solubility :	5.34 mg/ml ; 0.0437 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.34
Solubility :	0.554 mg/ml ; 0.00454 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.63

Safety of [ 3939-13-7 ]

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

Application In Synthesis of [ 3939-13-7 ]

* 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 [ 3939-13-7 ]
Downstream synthetic route of [ 3939-13-7 ]

[ 3939-13-7 ] Synthesis Path-Upstream 1~13

1
[ 3939-13-7 ]
[ 20577-27-9 ]
[ 92914-74-4 ]

Reference： [1] Green Chemistry, 2016, vol. 18, # 18, p. 4941 - 4946
[2] Green Chemistry, 2016, vol. 18, # 18, p. 4941 - 4946

2
[ 3939-13-7 ]
[ 20577-27-9 ]

Reference： [1] Green Chemistry, 2016, vol. 18, # 18, p. 4941 - 4946

3
[ 6602-54-6 ]
[ 3939-13-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With cesium fluoride In dimethyl sulfoxide at 90℃; for 2 h;	General procedure: To a solution of 2,3-dichloropyridine(1.00 g, 6.76 mmol) in DMSO (33.8 ml) was added CsF (2.053 g, 13.51mmol) at room temperature. The mixture was stirred at 110 °C under air for 20h. The mixture was quenched with water at room temperature and extracted withEtOAc. The organic layer was separated, washed with water and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with EtOAc in hexane) togive 3-chloro-2-fluoropyridine (0.639 g, 4.86 mmol, 71.9 percent) as colorlessoil. Thecompound 3B'-8B' were prepared in amanner similar to that described for 2B'.

Reference： [1] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 2, p. 330 - 339
[2] Tetrahedron Letters, 2015, vol. 56, # 44, p. 6043 - 6046
[3] Heterocycles, 1992, vol. 34, # 8, p. 1507 - 1510
[4] Organic Letters, 2015, vol. 17, # 8, p. 1866 - 1869
[5] Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12137 - 12145

4
[ 364-22-7 ]
[ 3939-13-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With resin bound triphenylphosphine In tetrachloromethane; 1,2-dichloro-ethane for 18 h; Heating / reflux	Preparation 51; 2-Fluoro-nicotinonitrile; Add resin bound triphenylphosphine (4.0 g, 12.0 mmol) to a solution of 2-fluoro- nicotinamide (0.6 g, 4.3 mmol) in dichloroethane (20.0 mL) and carbon tetrachloride (20.0 mL). Reflux for 18 hours, cool to RT, filter, and concentrate the filtrate under vacuum. Purify by flash column on silica gel eluting with 10-60percent EtOAc in hexanes to give the title compound (0.34 g, 64percent). MS (ES) 123.1 (M+l) +. 1H NMR (400 MHz, CHC13) 6 8.46 (m, 1H), 8.09 (m, 1H), 7.37 (m, 1H).

Reference： [1] Patent: WO2005/66126, 2005, A1, . Location in patent: Page/Page column 61

5
[ 695-37-4 ]
[ 3939-13-7 ]

Reference： [1] Patent: US6384033, 2002, B1,

6
[ 100-54-9 ]
[ 3939-13-7 ]
[ 69278-08-6 ]

Reference： [1] Synthetic Communications, 1994, vol. 24, # 16, p. 2387 - 2392

7
[ 100-54-9 ]
[ 75-05-8 ]
[ 3939-13-7 ]
[ 69278-08-6 ]

Reference： [1] Synthetic Communications, 1994, vol. 24, # 16, p. 2387 - 2392

8
[ 100-54-9 ]
[ 3939-13-7 ]

Reference： [1] Journal of Organic Chemistry, 1989, vol. 54, # 7, p. 1726 - 1731
[2] Science, 2013, vol. 342, # 6161, p. 956 - 960

9
[ 546-88-3 ]
[ 3939-13-7 ]
[ 92914-74-4 ]

Yield	Reaction Conditions	Operation in experiment
28%	Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: at 50℃; for 5 h;	Synthesis of intermediate VX001: Isoxazolo[5,4-b]pyridin-3-amine 909 mg (8.1 mmol) of KO-t-Bu were added, with vigorous stirring, to a suspension of 668 mg (8.9 mmol) of acethydroxamic acid in DMF (20 ml), and the mixture was stirred for 30 min at RT. 990 mg (8.1 mmol) of 2-fluoro-nicotinonitrile were then added, and stirring was carried out for a further 5 h at 50° C. The mixture was then extracted with EA and the organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 305 mg (2.3 mmol, 28percent) of isoxazolo[5,4-b]pyridin-3-amine.

Reference： [1] Patent: US2010/234419, 2010, A1, . Location in patent: Page/Page column 15

10
[ 3939-13-7 ]
[ 92914-74-4 ]

Reference： [1] Green Chemistry, 2016, vol. 18, # 18, p. 4941 - 4946

11
[ 3939-13-7 ]
[ 20577-27-9 ]
[ 92914-74-4 ]

Reference： [1] Green Chemistry, 2016, vol. 18, # 18, p. 4941 - 4946
[2] Green Chemistry, 2016, vol. 18, # 18, p. 4941 - 4946

12
[ 3939-13-7 ]
[ 205744-16-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogen In ethanol for 3 h;	Example 9: Synthesis of 3-Aminometliyl-2-fluoropyridine19 20[0098] A round bottom flask was charged with 0.3g (2.46mM) of 3-cyano-2- fluoropyridine (19), which was then diluted in 2OmL EtOH. The solution was flushed with argon, and then while under a blanket of argon, 60mg of 10percent Pd/C (20percent by weight), was added. The system was then sealed by septum and put under vacuum. A hydrogen balloon was then added, and the reaction was stirred for three hours (followed by TLC). The reaction was then put under vacuum again, then exposed to air, and filtered (keeping catalyst wet). The resulting solution was dried and evaporated to give 0.28g (90percent) of the title compound, 3-aminomethyl-2-fluoropyridine (20).
90%	With hydrogen In ethanol for 3 h;	Example 9 Synthesis of 3-Aminomethyl-2-fluoropyridine A round bottom flask was charged with 0.3 g (2.46 mM) of 3-cyano-2-fluoropyridine (19), which was then diluted in 20 mL EtOH. The solution was flushed with argon, and then while under a blanket of argon, 60 mg of 10percent Pd/C (20percent by weight), was added. The system was then sealed by septum and put under vacuum. A hydrogen balloon was then added, and the reaction was stirred for three hours (followed by TLC). The reaction was then put under vacuum again, then exposed to air, and filtered (keeping catalyst wet). The resulting solution was dried and evaporated to give 0.28 g (90percent) of the title compound, 3-aminomethyl-2-fluoropyridine (20).
90%	With hydrogen In ethanol for 3 h;	A round bottom flask was charged with 0.3g (2.46mM) of 3-cyano-2- fluoropyridine (19), which was then diluted in 2OmL EtOH. The solution was flushed with argon, and then while under a blanket of argon, 60mg of 10percent Pd/C (20percent by weight), was added. The system was then sealed by septum and put under vacuum. A hydrogen balloon was then added, and the reaction was stirred for three hours (followed by TLC). The reaction was then put under vacuum again, then exposed to air, and filtered (keeping catalyst wet). The resulting solution was dried and evaporated to give 0.28g (90percent) of the title compound, 3-aminomethyl-2-fiuoropyridine (20).

Reference： [1] Patent: WO2006/108103, 2006, A1, . Location in patent: Page/Page column 31
[2] Patent: US2008/119496, 2008, A1, . Location in patent: Page/Page column 10
[3] Patent: WO2008/60301, 2008, A1, . Location in patent: Page/Page column 30

13
[ 3939-13-7 ]
[ 859164-64-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	With hydrogenchloride; hydrogen In methanol; water at 20℃; for 6 h;	Preparation 47; C- (2-Fluoro-pyridin-3-yl)-methylamine hydrochloride; Add concentrated HC1 (0.46 mL) to a suspension 2-fluoro-nicotinonitrile (0.34 g, 2.8 mmol) and 5percent Pd/C (0.5 g) in methanol (10 mL) at RT. Stir suspension under an atmosphere of hydrogen at 1 atm. For 6 hours. Filter reaction mixture and concentrate the filtrate. Add ether to the residue, bubble HC1 gas through the suspension, filter precipitate, and dry to give the title compound (0.37 g, 82percent). MS (ES) 127.1 (M+l) +. lu NMR (400 MHz, DMSO) 8 : 8.65 (brs, 3H), 8.24 (m, 1H), 8.16 (m, 1H), 7.41 (m, 1H), 4.06 (m, 2H).

Reference： [1] Patent: WO2005/66126, 2005, A1, . Location in patent: Page/Page column 59

[ 3939-13-7 ] Synthesis Path-Downstream 1~88

1
[ 100-54-9 ]
[ 75-05-8 ]
[ 3939-13-7 ]
[ 69278-08-6 ]

Reference： [1]Synthetic Communications,1994,vol. 24,p. 2387 - 2392

2
[ 100-54-9 ]
[ 3939-13-7 ]
[ 69278-08-6 ]

Reference： [1]Synthetic Communications,1994,vol. 24,p. 2387 - 2392

3
[ 6602-54-6 ]
[ 3939-13-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With cesium fluoride; In dimethyl sulfoxide; at 90℃; for 2h;	General procedure: To a solution of 2,3-dichloropyridine(1.00 g, 6.76 mmol) in DMSO (33.8 ml) was added CsF (2.053 g, 13.51mmol) at room temperature. The mixture was stirred at 110 C under air for 20h. The mixture was quenched with water at room temperature and extracted withEtOAc. The organic layer was separated, washed with water and brine, dried overNa2SO4 and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with EtOAc in hexane) togive 3-chloro-2-fluoropyridine (0.639 g, 4.86 mmol, 71.9 %) as colorlessoil. Thecompound 3B'-8B' were prepared in amanner similar to that described for 2B'.

Reference： [1]European Journal of Inorganic Chemistry,2017,vol. 2017,p. 330 - 339
[2]Tetrahedron Letters,2015,vol. 56,p. 6043 - 6046
[3]Heterocycles,1992,vol. 34,p. 1507 - 1510
[4]Organic Letters,2015,vol. 17,p. 1866 - 1869
[5]Journal of Organic Chemistry,2015,vol. 80,p. 12137 - 12145

4
C₆H₄FN₂⁽¹⁺⁾*BF₄^(1-) [ No CAS ]
[ 3939-13-7 ]

Reference： [1]Journal of Organic Chemistry,1989,vol. 54,p. 1726 - 1731

5
[ 100-54-9 ]
[ 3939-13-7 ]

Reference： [1]Journal of Organic Chemistry,1989,vol. 54,p. 1726 - 1731
[2]Science,2013,vol. 342,p. 956 - 960

6
[ 3939-13-7 ]
[ 859164-64-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	With hydrogenchloride; hydrogen;5%-palladium/activated carbon; In methanol; water; at 20.0℃; under 760.051 Torr; for 6.0h;	Preparation 47; C- (2-Fluoro-pyridin-3-yl)-methylamine hydrochloride; Add concentrated HC1 (0.46 mL) to a suspension <strong>[3939-13-7]2-fluoro-nicotinonitrile</strong> (0.34 g, 2.8 mmol) and 5% Pd/C (0.5 g) in methanol (10 mL) at RT. Stir suspension under an atmosphere of hydrogen at 1 atm. For 6 hours. Filter reaction mixture and concentrate the filtrate. Add ether to the residue, bubble HC1 gas through the suspension, filter precipitate, and dry to give the title compound (0.37 g, 82%). MS (ES) 127.1 (M+l) +. lu NMR (400 MHz, DMSO) 8 : 8.65 (brs, 3H), 8.24 (m, 1H), 8.16 (m, 1H), 7.41 (m, 1H), 4.06 (m, 2H).

Reference： [1]Patent: WO2005/66126,2005,A1 .Location in patent: Page/Page column 59

7
[ 364-22-7 ]
[ 3939-13-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With resin bound triphenylphosphine; In tetrachloromethane; 1,2-dichloro-ethane; for 18h;Heating / reflux;	Preparation 51; 2-Fluoro-nicotinonitrile; Add resin bound triphenylphosphine (4.0 g, 12.0 mmol) to a solution of 2-fluoro- nicotinamide (0.6 g, 4.3 mmol) in dichloroethane (20.0 mL) and carbon tetrachloride (20.0 mL). Reflux for 18 hours, cool to RT, filter, and concentrate the filtrate under vacuum. Purify by flash column on silica gel eluting with 10-60% EtOAc in hexanes to give the title compound (0.34 g, 64%). MS (ES) 123.1 (M+l) +. 1H NMR (400 MHz, CHC13) 6 8.46 (m, 1H), 8.09 (m, 1H), 7.37 (m, 1H).

Reference： [1]Patent: WO2005/66126,2005,A1 .Location in patent: Page/Page column 61

8
[ 123-75-1 ]
[ 3939-13-7 ]
[ 59025-38-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 0.5h;	EXAMPLE 93A 2-pyrrolidin-1-yl-nicotinonitrile To an oven-dried, N2-purged, 50-mL flask containing a magnetic stir bar were added <strong>[3939-13-7]2-fluoronicotinonitrile</strong> (1.22 g, 10.0 mmol), anhydrous tetrahydrofuran (5 mL), and triethylamine (3.04 g, 4.19 mL, 30.0 mmol). The flask was sealed with a septum and cooled to 0 C. in an ice bath. Neat pyrrolidine (1.04 g, 1.24 mmol, 15.0 mmol) was added via syringe. The mixture was stirred at 0 C. for 30 minutes and then allowed to warm to room temperature overnight. Water (10 mL) was added and the mixture was transferred to a separatory funnel. The mixture was extracted with dichloromethane (3*10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to a brown oil. The product was recrystallized from ethyl acetate/hexanes to give 1.29 g (75%) of the title compound as a tan powder. MS (ESI+) m/z 174.0 (M+H)+; 1H NMR (DMSO-d6) delta 1.91-1.95 (m, 4H), 3.63-3.68 (m, 4H), 6.68 (dd, J=7.6, 4.6 Hz, 1H), 7.91 (dd, J=7.6, 1.9 Hz, 1H), 8.31 (dd, J=4.7, 2.0 Hz, 1H).
75%	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 0.5h;	To an oven-dried, N2-purged, 50-mL flask containing a magnetic stir bar were added 2- fluoronicotinonitrile (1.22 g, 10.0 mmol), anhydrous tetrahydrofuran (5 mL), and triethylamine (3.04 g, 4.19 mL, 30.0 mmol). The flask was sealed with a septum and cooled to 0 C in an ice bath. Neat pyrrolidine (1.04 g, 1.24 mmol, 15.0 mmol) was added via syringe. The mixture was stirred at 0 C for 30 minutes and then allowed to warm to room temperature overnight. Water (10 mL) was added and the mixture was transferred to a separatory funnel. The mixture was extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to a brown oil. The product was recrystallized from ethyl acetate/hexanes to give 1.29 g (75%) of the title compound as a tan powder. MS (ESI+) m/z 174.0 (M+H)+; 1H NMR (DMSO-d6) # 1.91-1.95 (m, 4H), 3.63-3.68 (m, 4H), 6.68 (dd, J = 7.6, 4.6 Hz, 1H), 7.91 (dd, J = 7.6, 1.9 Hz, 1H), 8.31 (dd, J = 4.7, 2.0 Hz, 1H).

Reference： [1]Patent: US2007/105842,2007,A1 .Location in patent: Page/Page column 28
[2]Patent: WO2005/111003,2005,A1 .Location in patent: Page/Page column 197
[3]Organic Letters,2019

9
[ 141-91-3 ]
[ 3939-13-7 ]
[ 870063-72-2 ]

Yield	Reaction Conditions	Operation in experiment
40%	In tetrahydrofuran; at 110℃; for 0.166667h;Microwave;	A solution of <strong>[3939-13-7]2-fluoro-nicotinonitrile</strong> (1.06 g, 8.69 mmol) and 2,6-dimethyl-morpholine (1.0 g, 8.69 mmol) in tetrahydrofuran (10 ml) was heated at 110 C for 10 min in a microwave reactor. The reaction mixture was concentrated and purified by flash column chromatography using hexanes: ethylacetate (2:1 ) to yield 0.37 g (40%) of product. MS (ESI@ m/z 218 (M+H)+

Reference： [1]Patent: WO2005/111003,2005,A1 .Location in patent: Page/Page column 159

10
[ 106-52-5 ]
[ 3939-13-7 ]
[ 870062-46-7 ]

Yield	Reaction Conditions	Operation in experiment
29%	With sodium hydride; In N,N-dimethyl-formamide; at 20℃;	To a mixture of <strong>[3939-13-7]2-fluoro-nicotinonitrile</strong> (400 mg, 3.3 mmol) and 1-methyl-piperidin-4-ol (380 mg, 3.3 mmol) in N, N-dimethylformamide (30 mL) was added NaH (60%) (160 mg, 4.0 mmol) in portions. The reaction was stirred overnight at rt. The mixture was poured into water, and extracted with ethyl acetate (2X). The solvent was removed, and the resulting residue was chromatographed using ethyl acetate/methanol (8:1 ) to give the title compound (210 mg, 29 %). MS (DCI/NH3) m/z 218 (M+1 )+ 'HNMR (400 MHz, DMSO- d6) 8 ppm 1.73 (m, 2 H) 1.96 (m, 2 H) 2.18 (s, 3 H) 2.22 (m, 2 H) 2.59 (m, 2 H) 5.15 (m, 1 H) 7.15 (dd, J=7.67, 5.22 Hz, 1 H) 8.24 (dd, .I--7.67, 2.15 Hz, I H) 8.44 (dd, .J=4.91 , 1 ,84 Hz, 1 H).

Reference： [1]Patent: WO2005/111003,2005,A1 .Location in patent: Page/Page column 118

11
[ 695-37-4 ]
[ 3939-13-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; dimethyl sulfate; In water;	2 N-t-Butyl-3-fluoro-2-pyridinecarboxamide Dimethyl sulfate (1.01 g, 8 mmol) was added to 1-oxido-3-fluoropyridine (0.9 g, 8 mmol) and stirred at 100 C. for 2 hours. The reaction mixture was allowed to cool and concentrated to dryness under a reduced pressure. Water (10 ml) was added to the residue and cooled in an ice-bath. Sodium cyanide (1.18 g, 24 mmol) was added to the mixture and stirred for 30 min. followed by stirring at room temperature for 30 min. Aqueous NaOH (1N) was added thereto and extracted with chloroform. The extract was dried over Na2SO4 and the solvent was evaporated under a reduced pressure to give a mixture of regio-isomers of fluorocyanopyridine (0.9 g).

Reference： [1]Patent: US6384033,2002,B1

12
[ 3939-13-7 ]
[ 205744-16-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogen;palladium 10% on activated carbon; In ethanol; for 3.0h;	Example 9: Synthesis of 3-Aminometliyl-2-fluoropyridine19 20[0098] A round bottom flask was charged with 0.3g (2.46mM) of 3-cyano-2- fluoropyridine (19), which was then diluted in 2OmL EtOH. The solution was flushed with argon, and then while under a blanket of argon, 60mg of 10% Pd/C (20% by weight), was added. The system was then sealed by septum and put under vacuum. A hydrogen balloon was then added, and the reaction was stirred for three hours (followed by TLC). The reaction was then put under vacuum again, then exposed to air, and filtered (keeping catalyst wet). The resulting solution was dried and evaporated to give 0.28g (90%) of the title compound, 3-aminomethyl-2-fluoropyridine (20).
90%	With hydrogen;palladium 10% on activated carbon; In ethanol; for 3.0h;	Example 9 Synthesis of 3-Aminomethyl-2-fluoropyridine A round bottom flask was charged with 0.3 g (2.46 mM) of <strong>[3939-13-7]3-cyano-2-fluoropyridine</strong> (19), which was then diluted in 20 mL EtOH. The solution was flushed with argon, and then while under a blanket of argon, 60 mg of 10% Pd/C (20% by weight), was added. The system was then sealed by septum and put under vacuum. A hydrogen balloon was then added, and the reaction was stirred for three hours (followed by TLC). The reaction was then put under vacuum again, then exposed to air, and filtered (keeping catalyst wet). The resulting solution was dried and evaporated to give 0.28 g (90%) of the title compound, 3-aminomethyl-2-fluoropyridine (20).
90%	With hydrogen;palladium 10% on activated carbon; In ethanol; for 3.0h;	A round bottom flask was charged with 0.3g (2.46mM) of 3-cyano-2- fluoropyridine (19), which was then diluted in 2OmL EtOH. The solution was flushed with argon, and then while under a blanket of argon, 60mg of 10% Pd/C (20% by weight), was added. The system was then sealed by septum and put under vacuum. A hydrogen balloon was then added, and the reaction was stirred for three hours (followed by TLC). The reaction was then put under vacuum again, then exposed to air, and filtered (keeping catalyst wet). The resulting solution was dried and evaporated to give 0.28g (90%) of the title compound, 3-aminomethyl-2-fiuoropyridine (20).

Reference： [1]Patent: WO2006/108103,2006,A1 .Location in patent: Page/Page column 31
[2]Patent: US2008/119496,2008,A1 .Location in patent: Page/Page column 10
[3]Patent: WO2008/60301,2008,A1 .Location in patent: Page/Page column 30

13
[ 3939-13-7 ]
[ 109-85-3 ]
[ 945347-61-5 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In tetrahydrofuran; at 20℃; for 18h;	To a solution of <strong>[3939-13-7]3-cyano-2-fluoropyridine</strong> (15a) (100 mg, 0.82 mmol) in tetrahydrofuran (1.6 mL) was added cesium carbonate (267 mg, 0.82 mmol) and 2-methoxyethylamine (68 mg, 0.9 mmol). The mixture was stirred at room temperature for 18 h, and then concentrated. The residue was taken up in dichloromethane/water, absorbed onto diatomaceous earth, and eluted with dichloromethane. The eluate was concentrated to provide compound 15b.
	With caesium carbonate; In tetrahydrofuran; at 20℃; for 18h;	To a solution of <strong>[3939-13-7]3-cyano-2-fluoropyridine</strong> (15a) (100 mg, 0.82 mmol) in tetrahydrofuran (1.6 ml_) was added cesium carbonate (267 mg, 0.82 mmol) and 2-rnethoxyethylamine (68 mg, 0.9 mmol). The mixture was stirred at room temperature for 18h, and then concentrated. The residue was taken up in dichloromethane/water, absorbed onto diatomaceous earth, and eluted with dichloromethane. The eluate was concentrated to provide compound 15b.
	With caesium carbonate; In tetrahydrofuran; at 20℃; for 18h;	To a solution of <strong>[3939-13-7]3-cyano-2-fluoropyridine</strong> (15a) (100 mg, 0.82 mmol) in tetrahydrofuran (1.6 mL) was added cesium carbonate (267 mg, 0.82 mmol) and 2-methoxyethylamine (68 mg, 0.9 mmol). The mixture was stirred at room temperature for 18 h, and then concentrated. The residue was taken up in dichloromethane/water, absorbed onto diatomaceous earth, and eluted with dichloromethane. The eluate was concentrated to provide compound 15b.

Reference： [1]Patent: US2008/269225,2008,A1 .Location in patent: Page/Page column 38
[2]Patent: WO2007/79214,2007,A2 .Location in patent: Page/Page column 105
[3]Patent: US2011/319400,2011,A1 .Location in patent: Page/Page column 38

14
[ 1075243-16-1 ]
[ 3939-13-7 ]
[ 1075243-19-4 ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine; In acetonitrile; at 60℃; for 24h;	Example 107; N-[(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidene]-l-(3-cyanopyridin-2-yl)pyrrolidine-3- carboxamide; To a 20-mL scintillation vial were added the product from Example 104B (54.2 mg, 0.175 mmol), the 2-fluoronicotin-onitrile (Aldrich, 32.1 mg, 0.263 mmol), and anhydrous acetonitrile (2 mL). Neat triethylamine (53.1 mg, 0.525 mmol) was added. The reaction mixture was heated to 60 0C in a heated shaker block and mixed for 24 hours. After cooling to room temperature, the volatiles were removed by rotary evaporator. The product was purified by flash chromatography (silica gel: 20-65% ethyl acetate in hexanes) to give 54.6 mg (76%) of the title compound. 1H NMR (DMSO-J6) delta ppm 0.88 (t, J = 7.3 Hz, 3H), 1.21- 1.34 (m, 3H), 1.52-1.62 (m, IH), 1.57 (s, 9H), 2.20-2.27 (m, 2H), 2.59-2.64 (m, 2H), 3.35- 3.43 (m, IH), 3.69-3.78 (m, 2H), 3.88-3.95 (m, IH), 4.04-4.09 (m, IH), 6.69 (dd, J = 7.5, 4.8 Hz, IH), 7.93 (dd, J = 7.9, 2.0 Hz, IH), 8.31 (dd, J = 4.8, 2.0 Hz, IH), 8.57 (s, IH). MS (ESI+) m/z 412 (M+H)+.
76%	With triethylamine; In acetonitrile; at 60℃; for 24h;	Example 107; N-r(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidenel-l-(3-cvanopyridin-2-yl)pyrrolidine-3- carboxamide; <n="99"/>To a 20-mL scintillation vial were added the product from Example 104B (54.2 mg, 0.175 mmol), the 2-fluoronicotin-onitrile (Aldrich, 32.1 mg, 0.263 mmol), and anhydrous acetonitrile (2 mL). Neat triethylamine (53.1 mg, 0.525 mmol) was added. The reaction mixture was heated to 60 0C in a heated shaker block and mixed for 24 hours. After cooling to room temperature, the volatiles were removed by rotary evaporator. The product was purified by flash chromatography (silica gel: 20-65% ethyl acetate in hexanes) to give 54.6 mg (76%) of the title compound. 1H NMR (DMSO-J6) delta 0.88 (t, J = 7.3 Hz, 3H), 1.21-1.34 (m, 3H), 1.52-1.62 (m, IH), 1.57 (s, 9H), 2.20-2.27 (m, 2H), 2.59-2.64 (m, 2H), 3.35-3.43 (m, IH), 3.69-3.78 (m, 2H), 3.88-3.95 (m, IH), 4.04-4.09 (m, IH), 6.69 (dd, J = 7.5, 4.8 Hz, IH), 7.93 (dd, J = 7.9, 2.0 Hz, IH), 8.31 (dd, J = 4.8, 2.0 Hz, IH), 8.57 (s, IH). MS (ESI+) m/z 412 (M+H)+.

Reference： [1]Patent: WO2010/54024,2010,A2 .Location in patent: Page/Page column 113-114
[2]Patent: WO2008/130953,2008,A2 .Location in patent: Page/Page column 97-98

15
[ 3939-13-7 ]
[ 5271-27-2 ]
[ 61337-88-0 ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 4502 - 4505

16
(R)-(trans-1-hydroxy-4-adamantyl) 3-aminopyrrolidine-1-carboxylate [ No CAS ]
[ 3939-13-7 ]
(R)-(trans-1-hydroxy-4-adamantyl) 3-(3-cyanopyridin-2-ylamino)pyrrolidine-1-carboxylate trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		A microwave vial was charged with (R)-(trans-1 -hydroxy-4-adamantyl) 3- aminopyrrolidine-1 -carboxylate (10 mg, 0.036 mmol), J-Pr2NEt (0.013 mL, 0.071 <n="98"/>mmol), <strong>[3939-13-7]2-fluoro-3-cyanopyridine</strong> (6.5 mg, 0.054 mmol) and n-PrOH (1 ml.) was heated in the microwave at 160 0C for 4 h. Prep HPLC afforded the title compound (1 1.9 mg, 67%) as its TFA salt. LC-MS Method 1 tR = 1.45 min, m/z = 383; 1H NMR (CD3OD) 1.44 (m, 2H), 1.70-2.20 (12H), 2.28 (m, 1 H), 3.35-3.90 (4H), 4.63 (m, 1 H), 4.78 (s, 1 H), 6.75 (m, 1 H), 6.85 (m, 1 H)1 8.29 (m, 1 H).

Reference： [1]Patent: WO2009/131669,2009,A2 .Location in patent: Page/Page column 96-97

17
[ 127708-09-2 ]
[ 3939-13-7 ]
[ 870062-55-8 ]

Yield	Reaction Conditions	Operation in experiment
51%		The product from Example 88B (1.57 g, 7.9 mmol) in dichloromethane (25 mL) was treated with trifluoroacetic acid (5 mL) for 30 min at rt. The reaction mixture was concentrated to dryness. To the residue was added <strong>[3939-13-7]2-fluoro-nicotinonitrile</strong> (1.0 g, 8.19 mmol) and diisopropyl ethylamine (3.2 mL) in tetrahydrofuran (8 mL). The reaction mixture was heated at 115 C for 10 min under microwave condition. The mixture was concentrated to dryness, and the residue was chromatographed using hexane/ethyl acetate (9:1-6:1) to give the title compound (806 mg, 51 %). MS (DCI/NH3) m/z 202 (M+1)+. 'HNMR (400 MHz, CDC13) 5 ppm 1.98 (s, 2 H) 3.67 (d, J=10.13 Hz, 1 H) 3.91 (dd, J=7.98, 1.53 Hz, 1 H) 3.96 (m, H) 4.69 (s, 1 H) 5.16 (s, 1 H) 6.64 (dd,.J=7.67, 4.91 Hz, 1 H) 7.71 (dd, J=7.36, 1.84 Hz, 1 H) 8.26 (dd, J=4,60, 1 ,84 Hz, 1 H)

Reference： [1]Patent: WO2005/111003,2005,A1 .Location in patent: Page/Page column 121-122

18
[ 1227176-83-1 ]
[ 3939-13-7 ]
[ 1227173-68-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In dimethyl sulfoxide; at 80℃; for 16h;	STEP 3. 2-(4-(1-METHYL-1H-BENZO[D]IMIDAZOL-2-YLAMINO)PHENOXY)NICOTINONITRILE To a solution of 4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenol (120 mg, 0.5 mmol) in DMSO (1 mL) was added cesium carbonate (196 mg, 0.6 mmol) and <strong>[3939-13-7]2-fluoronicotinonitrile</strong> (61 mg, 0.5 mmol). The resulting mixture was heated to 80 C. for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and brine several times to remove DMSO. The aqueous layer was back extracted with EtOAc (3*) and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluding with a gradient of 0% to 5% of MeOH in CH2Cl2, followed by trituration with ether, to provide 2-(4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenoxy)nicotinonitrile as off-white solid. MS (ESI, pos. ion) m/z: 342.2 (M+1). IC50 (uM) +++++.

Reference： [1]Patent: US2010/125062,2010,A1 .Location in patent: Page/Page column 73

19
[ 869224-18-0 ]
[ 3939-13-7 ]
[ 1234337-61-1 ]

Yield	Reaction Conditions	Operation in experiment
62%		To a solution of 5'-(pyrrohdin-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]-2'(r//)-one (85 mg,0,25 mmol) in DMF (3 mL) was added 60% NaH ( 12 mg, 0.3 mmol). After stirring for 10 ininuteb at room temperature, <strong>[3939-13-7]2-fluoronicotinonitrile</strong> (37 mg, 0.3 mmol) was added to the reaction mixture. The resulting solution was stirred at 60 C for 12 hours, l'hc reaction was diluted with EtOLambdac, washed with H2O and brine, then dried (MgSO4), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (CH2Cl2'Et0Ac) to provide 68 rng (62%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): consistent; MS (ES) mh 441.1 (M I II)

Reference： [1]Patent: WO2010/77839,2010,A1 .Location in patent: Page/Page column 132

20
[ 3939-13-7 ]
[ 1269407-34-2 ]

Reference： [1]Patent: WO2011/25799,2011,A1

21
[ 3939-13-7 ]
[ 1269407-35-3 ]

Reference： [1]Patent: WO2011/25799,2011,A1

22
[ 3939-13-7 ]
[ 1269407-36-4 ]

Reference： [1]Patent: WO2011/25799,2011,A1

23
[ 3939-13-7 ]
[ 1269408-52-7 ]

Reference： [1]Patent: WO2011/25799,2011,A1

24
[ 3939-13-7 ]
[ 1269408-53-8 ]

Reference： [1]Patent: WO2011/25799,2011,A1

25
[ 3939-13-7 ]
[ 122536-76-9 ]
[ 1269407-33-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 15h;	To a solution of 1,1-dimethylethyl (35)-3-pyrrolidinylcarbamate (0.763 g, 4.10 mmol) and <strong>[3939-13-7]2-fluoro-3-pyridinecarbonitrile</strong> (0.500 g, 4.10 mmol) in DMF (5.0 mL) was added K2CO3 (1.132 g, 8.19 mmol). The reaction mixture was heated to 80 0C for 15 h. Upon cooling, the reaction mixture was diluted with water (~30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (1.71 g, >100%, contained some residual solvent) as a cream colored solid. LC-MS m/z 289 (M+H)+, 0.91 min (ret time).

Reference： [1]Patent: WO2011/25799,2011,A1 .Location in patent: Page/Page column 73

26
[ 1345961-20-7 ]
[ 3939-13-7 ]
[ 1345960-91-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 0.166667h;Microwave irradiation;	2-[(3-[2,2-difluorocyclopiOpyl]methyl}-2-oxo-2,3-dihydro-l ,3 benzothiazol-6- yr)oxy]pyridine-3-carbonitrile (18-3)To a solution of 3-[(2,2-difluorocyclopropyl)methyl]-6-hydroxy-l,3-benzothiazol- 2(3H)-one (18-2) ( 0.033 g, 0.13 mmol) in anhydrous NMP (1 mL) was added cesium carbonate (0.084 g, 0.26 mmol) and <strong>[3939-13-7]2-fluoronicotinonitrile</strong> (0.024 g, 0.19 mmol). The reaction mixture was then heated under microwave irradiation at 00C for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol and NMP, then filtered and concentrated. Purification of crude reaction mixture by reverse phasechromatography (Waters Sunfire MSC18, 10% acetonitrile / 0.1% trifluoroacetic acid / water? 100% acetonitrile / 0.1% trifluoroacetic acid / water) gave 2-[(3-[2,2- difluorocyclopropyl]methyl}-2-oxo-2,3-dihydro-l 53-benzothiazol-6-yl)oxy]pyridine-3- carbonitrile (18-3) as an off-white solid. HRMS (M+H)?: observed - 360.0623 , calculated = 360.0613.

Reference： [1]Patent: WO2011/137046,2011,A1 .Location in patent: Page/Page column 60-61

27
1-{3-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]phenyl}methanamine hydrochloride [ No CAS ]
[ 3939-13-7 ]
[ 1333263-71-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 0.166667h;Microwave irradiation;	To a microwave vial was added l-{3-[l-(cyclopropylmethyl)-3-methyl-2,2- dioxido- 1 ,3-dihydro-2, 1 ,3-benzothiadiazol-5-yl]phenyl}methanamine hydrochloride (23-2) (0.037 g, 0.097 mmol), <strong>[3939-13-7]2-fluoronicotinonitrile</strong> (0.18 g, 0.15 mmol), NMP (0.7 mL), and finally DIPEA (0.039 mL, 0.22 mmol). The reaction mixture was then heated under microwave irradiation at 100C for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, then filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile / 0.1% trifluoroacetic acid / water- 100% acetonitrile / 0.1% trifluoroacetic acid / water) to give 2-({3-[l-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5- yl]benzyl}amino)nicotinonitrile (24-1) as a tan solid. HRMS (M+H)+: observed = 446.1642, calculated = 446.1645.

Reference： [1]Patent: WO2011/109277,2011,A1 .Location in patent: Page/Page column 66

28
[ 3939-13-7 ]
[ 1044038-49-4 ]

Reference： [1]Patent: US2011/319400,2011,A1

29
[ 3939-13-7 ]
3-(4-fluorobenzyl)-1-(4-methoxybenzyl)-6-[2-(2-methoxyethylamino)pyridin-3-ylmethyl]amino}-1H-[1,3,5]triazine-2,4-dione trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2011/319400,2011,A1

30
[ 3144-09-0 ]
[ 3939-13-7 ]
[ 914095-04-8 ]

Reference： [1]Patent: WO2012/45195,2012,A1 .Location in patent: Page/Page column 78

31
[ 3939-13-7 ]
[ 939791-42-1 ]

Reference： [1]Patent: WO2012/45195,2012,A1
[2]Patent: CN108794453,2018,A
[3]Patent: WO2019/46163,2019,A1
[4]ACS Medicinal Chemistry Letters,2019

32
[ 3939-13-7 ]
[ 1372262-85-5 ]

Reference： [1]Patent: WO2012/45195,2012,A1

33
[ 3939-13-7 ]
[ 1372262-86-6 ]

Reference： [1]Patent: WO2012/45195,2012,A1

34
[ 3939-13-7 ]
[ 1372262-90-2 ]

Reference： [1]Patent: WO2012/45195,2012,A1

35
[ 3939-13-7 ]
[ 1372262-84-4 ]

Reference： [1]Patent: WO2012/45195,2012,A1

36
[ 1184-85-6 ]
[ 3939-13-7 ]
[ 73161-37-2 ]

Yield	Reaction Conditions	Operation in experiment
93%		To N-methylmethanesulfonamide (2.18 g, 20 mmol, 1.0 eq) in 20 mL of DMF, was added t-BuOK (2.24 g, 20 mmol, 1.0 eq.). After stirring at r.t. for 30 min., <strong>[3939-13-7]2-fluoro-3-cyano-pyridine</strong> (2.44 g, 20 mmol, 1.0 eq) was added in one portion, and the resulting mixture was heated to 80 C for 2 hr. (TLC showed the complete reaction). The reaction mixture was poured on ice and extracted with ethyl acetate. The dried organic layer was concentrated, and purified by column chromatography on silica gel with petroleum ether/ethyl acetate (v/v 1/1) as eluent, giving N-(3- cyano-2-pyridyl)- N-methyl-methanesulfonamide (4.0 g, 93%).
	With potassium tert-butylate; In N,N-dimethyl-formamide; for 2h;Reflux;	Example 40N-{3-[({2-[(2-methoxy-4-mo^holm-4-ylphenyl)ammo]-7H-pyiTolo[2,3-d]pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethanesulfonamideExample 40AN-(3-cyanopyridin-2-yl)-N-methylmethanesulfonamide To the N-methylmethanesulfonamide (1.00 g, 9.17 mmol) in N,N- dimethylformamide (20 ml) was added potassium tert-butoxide ( 1.03 g, 9.17 mmol). The mixture was stirred for 20 minutes and <strong>[3939-13-7]2-fluoronicotinonitrile</strong> (1.12 g, 9.17 mmol) was added. The resulting mixture was refluxed for 2 hours. The reaction was cooled and poured into water (100 ml), extracted with dichloromethane, washed with brine, dried (MgS04), filtered, and the solvent was evaporated. The resulting residue was purified by flash chromatography on silica gel, eluting with ethyl acetate/hexane (10-85% ethyl acetate in hexane gradient), to yield the title compound. MS ESI(+) m/z 212.4 [M+H]+.
		Add 2 g of N-methylmethanesulfonamide to a 100 ml round bottom flask,30 ml of anhydrous DMF and 2.1 g of potassium t-butoxide were stirred at room temperature for 20 minutes.2.2 g of <strong>[3939-13-7]2-fluoro-3-cyanopyridine</strong> was added and refluxed for 3 hours.The reaction was quenched with water and extracted with EtOAc.Then, petroleum ether: ethanol = 2:1 was passed through a silica gel column, and crystals were precipitated to obtain 2a.

Reference： [1]Patent: WO2019/46163,2019,A1 .Location in patent: Paragraph 00276
[2]ACS Medicinal Chemistry Letters,2019
[3]Patent: WO2012/45195,2012,A1 .Location in patent: Page/Page column 82-83
[4]Patent: CN108794453,2018,A .Location in patent: Paragraph 0193; 0194; 0195

37
[ 1430747-30-0 ]
[ 3939-13-7 ]
[ 1430745-72-4 ]

Yield	Reaction Conditions	Operation in experiment
44.1%	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 16h;Inert atmosphere;	To a solution of (lR,3s,5S)-tert-butyl 3-((l r,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.061 mmol) in THF (0.615 mL) was added 1M potassium teri-butoxide in THF (73.75 mu?, 73.75 muiotaetaomicron?) was added <strong>[3939-13-7]2-fluoronicotinonitrile</strong> (9.004 mg, 0.074 mmol) at room temperature . After the reaction mixture was stirred for 16 h and then concentrated. The crude was purified twice by TLC (1st: silica gel, 25% EtOAc in hexanes; 2nd: silica gel, 50% DCM in hexanes) to give the title compound (11.6 mg, 0.027 mmol, 44.1 % yield). Exact mass calculated for C24H33N3O4: 427.3, found LCMS m/z = 428.4 [M+H]+; lU NMR (CDCI3 , 400 MHz) 5 ppm 1.42-1.54 (m, 2H), 1.47 (s, 9H), 1.54-1.70 (m, 6H), 1.87-2.03 (m, 6H), 2.08-2.16 (m, 2H), 3.45-3.53 (m, IH), 3.78-3.88 (m, IH), 4.24 (br s, 2H), 5.13-5.23 (m, IH), 6.93 (dd, / = 7.58, 5.05 Hz, IH), 7.84 (dd, / = 7.58, 5.05 Hz, IH), 8.32 (dd, = 5.05, 2.02 Hz, IH).

Reference： [1]Patent: WO2013/55910,2013,A1 .Location in patent: Page/Page column 114

38
[ 1443748-48-8 ]
[ 3939-13-7 ]
[ 1443748-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	In 1-methyl-pyrrolidin-2-one; at 250℃; for 0.166667h;Microwave irradiation;	General procedure: (R)-4-N-Boc-2-methylpiperazine (665 mg, 3.32 mmol), 1-adamantoyl chloride (990 mg, 4.98 mmol), and DIEA (1.15 mL, 6.64 mmol) were dissolved in 2.0 mL of dichloromethane, and the reaction was monitored by LCMS. Upon completion, 5.0 mL of MeOH was added, and the mixture was concentrated in vacuo. The residue was purified by flash chromatography. The purified product was immediately dissolved in 1.0 mL of MeOH and excess 4 N HCl in dioxanes (4.0 mL, 16 mmol). Once the protecting group had cleaved as judged by LCMS, an aqueous solution of saturated sodium bicarbonate was added until the pH was basic. The mixture was extracted with dichloromethane, and the organic layers were concentrated in vacuo to afford 814 mg (94% yield) of adamantan-1-yl((R)-2-methylpiperazin-1-yl)methanone as a white solid. Adamantan-1-yl((R)-2-methylpiperazin-1-yl)methanone (355 mg, 1.35 mmol) and 2-cyano-3-fluoropyridine (1.42 mL, 5.41 mmol) were dissolved in 4.0 mL of NMP in a microwave reaction vial and heated in the microwave for 10 min at 250 C. The reaction mixture was purified via reverse phase chromatography (0.1% TFA in H2O/MeCN). The fractions containing the product were combined and neutralized by the addition of aqueous saturated sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic layers were combined and concentrated in vacuo. The residue was dissolved in 1.0 mL of MeOH and 4 N HCl in dioxanes (3.0 mL, 12 mmol) and stirred for 2 h. The mixture was concentrated in vacuo to afford 212 mgs (39% yield) of the HCl salt as a yellow solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3713 - 3718

39
[ 35691-93-1 ]
[ 3939-13-7 ]
[ 1590406-03-3 ]