[ CAS No. 39891-04-8 ] {[proInfo.proName]}

Name: 39891-04-8|5-Fluoronicotinaldehyde|97%
Brand: Ambeed
SKU: A120690
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Quality Control of [ 39891-04-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 39891-04-8 ]

CAS No. :	39891-04-8	MDL No. :	MFCD07778429
Formula :	C₆H₄FNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FEPXZFGQVDIXMZ-UHFFFAOYSA-N
M.W :	125.10	Pubchem ID :	14141159
Synonyms :

Calculated chemistry of [ 39891-04-8 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	29.58
TPSA :	29.96 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) :	-6.77 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.03
Log Po/w (XLOGP3) :	0.41
Log Po/w (WLOGP) :	1.45
Log Po/w (MLOGP) :	0.22
Log Po/w (SILICOS-IT) :	1.94
Consensus Log Po/w :	1.01

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.3
Solubility :	6.25 mg/ml ; 0.05 mol/l
Class :	Very soluble
Log S (Ali) :	-0.61
Solubility :	31.0 mg/ml ; 0.248 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.21
Solubility :	0.773 mg/ml ; 0.00618 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.22

Safety of [ 39891-04-8 ]

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

Application In Synthesis of [ 39891-04-8 ]

* 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 [ 39891-04-8 ]
Downstream synthetic route of [ 39891-04-8 ]

[ 39891-04-8 ] Synthesis Path-Upstream 1~13

1
[ 22620-29-7 ]
[ 39891-04-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1989, vol. 32, # 3, p. 583 - 593
[2] Patent: WO2004/9552, 2004, A1, . Location in patent: Page 59

2
[ 107756-01-4 ]
[ 39891-04-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1989, vol. 32, # 3, p. 583 - 593

3
[ 701-40-6 ]
[ 39891-04-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1989, vol. 32, # 3, p. 583 - 593

4
[ 591-22-0 ]
[ 39891-04-8 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521

5
[ 407-21-6 ]
[ 39891-04-8 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521

6
[ 3430-19-1 ]
[ 39891-04-8 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521

7
[ 3222-49-9 ]
[ 39891-04-8 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521

8
[ 402-66-4 ]
[ 39891-04-8 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521

9
[ 455-70-9 ]
[ 39891-04-8 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521

10
[ 70-57-5 ]
[ 39891-04-8 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521

11
[ 884494-95-5 ]
[ 39891-04-8 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521

12
[ 22620-32-2 ]
[ 39891-04-8 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521

13
[ 39891-04-8 ]
[ 22620-32-2 ]

Reference： [1] Patent: WO2010/132999, 2010, A1, . Location in patent: Page/Page column 103

[ 39891-04-8 ] Synthesis Path-Downstream 1~88

1
[ 39891-04-8 ]
[ 141-82-2 ]
[ 118419-96-8 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 583 - 593

2
[ 39891-04-8 ]
[ 114995-48-1 ]
[ 114995-63-0 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 3513 - 3521

3
[ 22620-32-2 ]
[ 39891-04-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 3513 - 3521

4
[ 107756-01-4 ]
[ 39891-04-8 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 583 - 593

5
[ 39891-04-8 ]
[ 118420-35-2 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 583 - 593

6
[ 701-40-6 ]
[ 39891-04-8 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 583 - 593

7
[ 22620-29-7 ]
[ 39891-04-8 ]

Yield	Reaction Conditions	Operation in experiment
	With diisobutylaluminium hydride; In toluene; at -78℃; for 3h;	To a mixture of 3.5 g of ethyl 5-fluoronicotinate (21 mmol) in [80] [ML] of dry toluene at -78C under nitrogen was added 42 [ML] of [1.] OM DIBAL in toluene dropwise with stirring. The mixture was [STIRRED] at-78C for [3H] and the excess DIBAL was quenched by adding 0.5 mL of EtOAc. The mixture was allowed to warm to room temperature and 100 mL of water was added. The mixture was filtered through celite and the filter cake washed with [3 X 10] mL of toluene. The layers were separated and the organic phase was washed with brine, dried [(MGS04)] and loaded onto a [COLUMN] (silica gel). The product was purified by eluting with 20%-35% EtOAc in hexanes to give 700 mg [OF 5-FLUORO-3-PYRIDINECARBOXALDELIYDE] and 2.0 g of un-reacted starting material.

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 583 - 593
[2]Patent: WO2004/9552,2004,A1 .Location in patent: Page 59

8
[ 591-22-0 ]
[ 39891-04-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 3513 - 3521

9
[ 407-21-6 ]
[ 39891-04-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 3513 - 3521

10
[ 3430-19-1 ]
[ 39891-04-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 3513 - 3521

11
[ 3222-49-9 ]
[ 39891-04-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 3513 - 3521

12
[ 402-66-4 ]
[ 39891-04-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 3513 - 3521

13
[ 455-70-9 ]
[ 39891-04-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 3513 - 3521

14
[ 39891-04-8 ]
[ 114995-43-6 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 3513 - 3521

15
[ 70-57-5 ]
[ 39891-04-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 3513 - 3521

16
[ 884494-95-5 ]
[ 39891-04-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 3513 - 3521

Yield	Reaction Conditions	Operation in experiment
		To a stirred mixture of 5.1 g of the hydrazide in 40 ml of pyridine, 6.9 g of p-toluenesulfonyl chloride is added slowly. After the mixture becomes a clear solution, the remaining pyridine is distilled off under reduced pressure, and 30 ml of water is added. The resulting precipitate is collected and hashed with water to give 6.6 g of the crude p-toluenesulfonyl derivative. The product is added to 40 ml of ethylene glycol at 120C, and to the mixture is added with stirring 6.5 g of anhydrous sodium carbonate. The reaction mixture is stirred at 160C for 10 minutes and cooled, and 50 ml of water is added. The mixture is extracted with three 100-ml portions of diethyl ether. The combined extracts are dried over magnesium sulfate and concentrated to give 1.1 g of crude 5-fluoro-3-pyridinecarbaldehyde.

18
[ 110-89-4 ]
[ 39891-04-8 ]
[ 118419-96-8 ]
[ 118419-97-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; malonic acid; In water;	A mixture of 1.1 g of the crude <strong>[39891-04-8]5-fluoro-3-pyridinecarbaldehyde</strong>, 1.8 g of malonic acid, 0.15 ml of piperidine, and 7 ml of pyridine is stirred at 110C for 2 hours. The reaction mixture is concentrated, and 20 ml of water is added. The resulting precipitate is collected and washed with cold water to give 0.5 g of the title compound. The following compounds are prepared in substantially the same manner as in Reference Example 2, using the corresponding starting materials: 3-(5-bromo-3-pyridyl)acrylic acid, and 3-(5-chloro-3-pyridyl)acrylic acid.

Reference： [1]Patent: EP210782,1991,B1

19
[ 39891-04-8 ]
[ 1029052-69-4 ]
[ 1029052-71-8 ]

Yield	Reaction Conditions	Operation in experiment
48%		Step 1 - Synthesis of [5-(l-benzemsulfupsilonnyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4- chloro-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (595):; [0239] To 5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro- thiazol-2-ylamine (592, 50,0 mg, 0.11 mmol, prepared as described in Example 27, Scheme 183) in ethanol (1.60 mL) and acetic acid (0.08 niL) were added <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (594, 43 mg, 0.34 mmol) and silica supported cyanoborohydride (1,21 mmol/g, 0.180 g). The reaction was irradiated with microwave on 300 watts, 1000C for 7 minutes. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the desired compound (595, 0.030 g. 48%).

Reference： [1]Patent: WO2008/63888,2008,A2 .Location in patent: Page/Page column 110

20
[ 39891-04-8 ]
[ 1029052-74-1 ]
[ 1029052-76-3 ]

Yield	Reaction Conditions	Operation in experiment
59%	With acetic acid; In ethanol; at 100℃; for 0.166667h;Microwave irradiation;	Step 1 - Synthesis of [5-(l-benzenesulfonyl-5-chlupsilonro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl]~-(5~fluoro-pyridin-3-ylmethyl)~amine (601); [0248] To 5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2- ylamine (599, 80.0 mg, 0.20 mmol, prepared as described in Example 29, Scheme 185) in etha?ol (2.0 mL) and acetic acid (0.10 mL, 0.0018 mol) were added <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (594, 62.7 mg, 0.50 mmol) and sodium cyanoborohydride on silica gel (1.200 mmol/g loading; 0.251 g, 0.30 mmol). The reaction was irradiated with microwave on 300 watts, 100 0C for 10 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (601, 0.060 g, 59%).

Reference： [1]Patent: WO2008/63888,2008,A2 .Location in patent: Page/Page column 113

21
[ 39891-04-8 ]
[ 1062204-25-4 ]
[ 1062205-01-9 ]

Yield	Reaction Conditions	Operation in experiment
25%	With sodium cyanoborohydride; zinc(II) chloride; In methanol; at 20℃; for 24h;	A mixture of [3-(6-morpholin-4-yl-9-piperidin-4-yl-9H-purin-2-yl)phenyl]methanol (30 mg, 0.076 mmol), NaCNBH3 (25 mg, 0.40 mmol), zinc chloride (20 mg, 0.183 mmol) and 5-fluoronicotinoylaldehyde (14 mg, 0.11 mmol) in methanol is stirred for 24 hours at room temperature. The mixture is then filtered, dissolved in DMSO (1 mL) and purified by chromatography by HPLC to give 10 mg (25% yield) of the title product (MS (ESI) m/z 504.6).

Reference： [1]Patent: US2008/233127,2008,A1 .Location in patent: Page/Page column 34

22
[ 39891-04-8 ]
[ 57260-71-6 ]
[ 1095380-85-0 ]

Yield	Reaction Conditions	Operation in experiment
95%		Example 3 te/t-Butyl3-Fluoro-5-formyl pyridine (0.50 g, 4.0 mmol, 1 eq) was dissolved in a mixture of EtOH (9.9 mL) and AcOH (1.1 mL). N-Boc piperazine (1.86 g, 10.0 mmol, 2.5 eq) was added in one portion and the mixture was stirred and cooled in a water-ice bath for 10 minutes before the portionwise addition of NaBH3CN (0.24 g, 3.8 mmol, 0.95 eq). The mixture was allowed to warm up to rt and stirred for 17h. The solvents were removed in vacuo and the crude material was purified purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1 :1 ) to give the title compound (1.12 g, 95%); 1H-NMR (500 MHz, CDCI3): delta 1.46 (s, 9H, C(CH3J3), 2.40 <n="13"/>(t, 4H, J = 4.8 Hz, piperazine N(CH2)2), 3.44 (t, 4H, J = 5.0 Hz, piperazine N(CH2)2). 3.54 (s, 2H, NCH2), 7.42-7.47 (m, 1 H, py 4-H), 8.34-8.37 (m, 1H, py 2-H), 8.38 (d, 1 H1 J = 2.5 Hz, py 6-H); 13C-NMR (125 MHz, CDCI3): delta 28.4, 52.9, 59.4, 79.7, 123.0 (d, 2J0F = 18 Hz), 135.6 (d, 4JCF = 3 Hz), 137.1 (d, 2JCF = 23 Hz), 145.9 (d, 2JCF = 3 Hz), 159.7 (d, 1JcF = 255 Hz); LC(Method B) - MS (ESI, m/z): Rt = 2.30 min - 196 [(M- Boc+H)+, 100%].

Reference： [1]Patent: WO2009/1021,2008,A1 .Location in patent: Page/Page column 11-12

23
[ 39891-04-8 ]
[ 1198353-49-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; sodium acetate; In ethanol; at 20℃; for 12h;	The titled compound was prepared according to Method OB using <strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (Aldrich). 1H NMR (300 MHz, MeOH-d4) delta 7.85 (dt, J=9.5, 2.2 Hz, 1H), 8.16 (s, 1H), 8.43 (d, J=2.7 Hz, 1H), 8.57 (s, 1H) ppm; MS (DCI/NH3) m/z 141 (M+H)+.; Method OB: To a solution of aryl aldehyde or heteroaryl aldehyde (10.0 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (Aldrich, 0.96 g, 15.0 mmol) and sodium acetate (Aldrich, 1.14 g, 15.0. mmol). The mixture was stirred at ambient temperature for 12 hours. Then the reaction mixture was diluted with EtOAc (100 mL) and washed with water (2×10 mL) and brine (2×10 mL). The organic solution was dried over anhydrous Na2SO4 for 1 hour. The drying agent was removed by filtration, and the organic solution was concentrated to give the title product.

Reference： [1]Patent: US2009/306096,2009,A1 .Location in patent: Page/Page column 9; 13

24
[ 39891-04-8 ]
[ 22620-32-2 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; sodium tetrahydroborate; at 20℃; for 3.0h;	To a 0C solution of 5-fluoropyridine-3-carbaldehyde (500 mg, 4.0 mmol) in anhydrous methanol (20 niL) was added sodium borohydride (150 mg, 4.0 mmol). The reaction mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution (20 mL) was added. The resultant mixture was extracted with EtOAc (3 x 20 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (5-fluoropyridin-3- yl)methanol (430 mg, 85% yield). The product was used without further purification.

Reference： [1]Patent: WO2010/132999,2010,A1 .Location in patent: Page/Page column 103

25
[ 33955-17-8 ]
[ 39891-04-8 ]
4-((5-fluoro-3-pyridinyl)methylene)-2-(2-thienyl)-5(4H)-oxazolone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium acetate; acetic anhydride; In water;	Example 3 4-((5-Fluoro-3-pyridinyl)methylene)-2-(2-thienyl)-5(4H)-oxazolone To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), <strong>[39891-04-8]5-fluoro-3-pyridinecarboxaldehyde</strong> (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90 C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 56 mg of the above-captioned compound. 1H-NMR (400 MHz, DMSO-d6, delta). 9.13 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.20 (d, J=4.8 Hz, 1H), 8.06 (d, J=3.8 Hz, 1H), 7.37 (dd, J=4.8, 3.8 Hz, 1H), 7.33 (s, 1H). ESI-MS m/z 275 (M+H)+.

Reference： [1]Patent: US2011/294857,2011,A1

26
[ 39891-04-8 ]
[ 1356483-94-7 ]
[ 1356483-27-6 ]

Yield	Reaction Conditions	Operation in experiment
	With Oxone; In water; N,N-dimethyl-formamide; at 20℃; for 3h;Cooling;	Step C. 2-[5.6-difluoro-2-(5-fiuoropyridin-3-yl)-lHr-benzimidazol-l-yl]ethanol:To a stirred solution of l-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5-difluorobenzene-l;2- diamine (38; 0.09 g, 0.0003 mol) in the mixture of DMF (3 ml) and water (0.3 ml) was added OmicronChiOmicronNuEpsilonPhi (0.218 g, 0.0004 mol) and followed by <strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (0.041 g, 0.0003 mol) was added portion wise under cooling condition with constant stirring. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was concentrated and diluted with cold water (10 ml) and extracted with ethyl acetate (3 15 ml). The combined organic layers were washed with brine dried over Na2S04 and concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product 2-[5,6-difluoro-2-(5- fluoropyridin-3-yl)-lH-benzimidazol-l-yl]ethanol as an off white solid. 1H NMR (400 MHz, DMSO-d6), delta: 8.93 (s, 1H), 8.77 (m, 1H)> 8.33 (m, 1H), 7.96 (m, 1H), 7.81 (m, 1H), 5.09-5.11 (t, J = 5.2 Hz, 1H)5 4.35-4.38 (t, J - 5.0 Hz, 2H), 3.75-3.76 (m, 2H). LCMS (ES) m/e MS(M+l=294) Purity 99.33%.

Reference： [1]Patent: WO2012/12478,2012,A1 .Location in patent: Page/Page column 98

27
[ 39891-04-8 ]
{cis-3-piperazin-1-yl-1-[ 4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile [ No CAS ]
C₃₁H₄₀FN₉OSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane;	Example 23a. {cis-3-{4-[(5-fluoropyridin-3-yl)methyl]piperazin-l-yl}-l-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclobutyl}acetonitrile{cis-3-Piperazin-l -yl- 1 -[4-(7- [2-(trimethylsilyl)ethoxy]methyl} -7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclobutyl}acetonitrile (0.030 g, 0.061 mmol, prepared as in Example la, Step 9) and <strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (0.011 g, 0.085 mmol) were combined in methylene chloride (1 mL) and after 10 minutes, sodium triacetoxyborohydride (0.0516 g, 0.244 mmol) was added. The reaction was continued overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous portion was extracted a further two times with ethyl acetate. The combined extracts were washed with water, then brine, dried over sodium sulfate, decanted and concentrated. The crude product was deprotected by first stirring the residue in a 1 : 1 mix of TFA:DCM (4 mL) for 2 hours, followed by removal of the solvents in vacuo and then stirring with 0.2 mL ethylenediamine in 2 mL methanol overnight. The solution was filtered and the product was purified via preparative HPLC-MS (CI 8, eluting with a gradient of H20/MeCN containing 0.15% NH4OH). The eluent containing the desired mass was frozen and lyophilized to afford product as the free base (0.01 g, 30%>). 1H NMR (400 MHz, CDC13): delta 10.13 (br s, 1H), 8.82 (s, 1H), 8.37 (d, 1H), 8.35 (dd, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.43 (ddd, 1H), 7.37 (dd, 1H), 6.76 (dd, 1H), 3.54 (s, 2H), 3.13 (s, 2H), 2.89 (tt, 1H), 2.84-2.76 (m, 2H), 2.75-2.67 (m, 2H), 2.64-2.27 (br, 8H); 19F NMR (376 MHz, dg-dmso): delta -128.43 (dd, IF); LCMS (M+H)+: 472.5.

Reference： [1]Patent: WO2012/68450,2012,A1 .Location in patent: Page/Page column 115-116

28
[ 39891-04-8 ]
[ 490-78-8 ]
[ 1426899-73-1 ]

Reference： [1]Patent: EP2567958,2013,A1
[2]Patent: US2013/65859,2013,A1
[3]Patent: CN102993195,2017,B
[4]Patent: WO2013/37388,2013,A1

29
[ 39891-04-8 ]
[ 490-78-8 ]
(E)-1-(2,5-dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)propenone [ No CAS ]
[ 1426899-73-1 ]

Yield	Reaction Conditions	Operation in experiment
42%; 39%	With ammonium acetate; acetic acid; for 8h;Reflux;	Example A[0137] (E)-1-(2,5-Dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone and 2-(5-fluoro-pyridin-3-yl)-6-hydroxy-chroman-4-one <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (3.1 g, 24.6 mmol, 1.1 eq) and ammonium acetate (2.2 g, 29.1 mmol, 1.3 eq) were suspended in acetic acid (100%, 70 ml) and heated to reflux for 8 h. The solution was allowed to reach room temperature. The volume of the resulting suspension was reduced to half of the volume under reduced pressure. The mixture was poured on ice water and neutralized with caution using sodium carbonate. The aqueous layer was washed with ethyl acetate and the remaining precipitate filtered. Solid (E)-1-(2,5-dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone (2.4 g, 42%) was obtained as a brownish solid and used in the cyclization reaction without further purification. The remaining aqueous solution was extracted with ethyl acetate and the combined organic layers dried with sodium sulfate, filtered, the solvent removed under reduced pressure and the resulting solid digested with few dichloromethane. 2-(5-Fluoro-pyridin-3-yl)-6-hydroxy-chroman-4-one was obtained as a brown solid (2.3 g, 39%) and used in the next step without further purification.

Reference： [1]Patent: EP2567958,2013,A1 .Location in patent: Paragraph 0137

30
[ 39891-04-8 ]
[ 490-78-8 ]
[ 1426899-73-1 ]
[ 1426899-72-0 ]

Yield	Reaction Conditions	Operation in experiment
39%; 42%	With ammonium acetate; acetic acid; for 8h;Reflux;	Example A (E)-1-(2,5-Dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone and 2-(5-fluoro-pyridin-3-yl)-6-hydroxy-chroman-4-one 2,5-Dihydroxy-acetophenone (3.4 g, 22.4 mmol), <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (3.1 g, 24.6 mmol, 1.1 eq) and ammonium acetate (2.2 g, 29.1 mmol, 1.3 eq) were suspended in acetic acid (100%, 70 ml) and heated to reflux for 8 h. The solution was allowed to reach room temperature. The volume of the resulting suspension was reduced to half of the volume under reduced pressure. The mixture was poured on ice water and neutralized with caution using sodium carbonate. The aqueous layer was washed with ethyl acetate and the remaining precipitate filtered. Solid (E)-1-(2,5-dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone (2.4 g, 42%) was obtained as a brownish solid and used in the cyclization reaction without further purification. The remaining aqueous solution was extracted with ethyl acetate and the combined organic layers dried with sodium sulfate, filtered, the solvent removed under reduced pressure and the resulting solid digested with few dichloromethane. 2-(5-Fluoro-pyridin-3-yl)-6-hydroxy-chroman-4-one was obtained as a brown solid (2.3 g, 39%) and used in the next step without further purification.

Reference： [1]Patent: US2013/65859,2013,A1 .Location in patent: Paragraph 0211; 0212

31
[ 39891-04-8 ]
[ 490-78-8 ]
[ 1426899-73-1 ]
(E)-1-(2,5-dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium acetate; acetic acid; for 8h;Reflux;	Example A(E)-1 -(2,5-Dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone and 2-(5-fluoro- pyridin-3-yl)-6-hydroxy-chroman-4-one2,5-Dihydroxy-acetophenone (3.4 g, 22.4 mmol), <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (3.1 g, 24.6 mmol, 1 .1 eq) and ammonium acetate (2.2 g, 29.1 mmol, 1 .3 eq) were suspended in acetic acid (100%, 70 ml) and heated to reflux for 8 h. The solution was allowed to reach room temperature. The volume of the resulting suspension was reduced to half of the volume under reduced pressure. The mixture was poured on ice water and neutralized with caution using sodium carbonate. The aqueous layer was washed with ethyl acetate and the remaining precipitate filtered. Solid (E)-1 -(2,5- dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone (2.4 g, 42%) was obtained as a brownish solid and used in the cyclization reaction without further purification. The remaining aqueous solution was extracted with ethyl acetate and the combined organic layers dried with sodium sulfate, filtered, the solvent removed under reduced pressure and the resulting solid digested with few dichloromethane. 2-(5-Fluoro- pyridin-3-yl)-6-hydroxy-chroman-4-one was obtained as a brown solid (2.3 g, 39%) and used in the next step without further purification

Reference： [1]Patent: WO2013/37388,2013,A1 .Location in patent: Page/Page column 98; 99

32
[ 39891-04-8 ]
[ 1441160-19-5 ]
[ 1441157-14-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol; at 60℃; for 0.5h;	EXAMPLE 1 1 : 6-(5,5-dimethyl-4H-isoxazol-3-yl)-4-[(E)-(5-fluoro-3-pyridyl)methyleneamino1-2,5- dihvdro-1 ,2,4-triazin-3-one (Compound 3.002) To a solution of 4-amino-6-(5,5-dimethyl-4H-isoxazol-3-yl)-2,5-dihydro-1 ,2,4-triazin-3-one (238 mg, 1 .01 mmol) in EtOH at 60 C was added pydridine-3-carbaldehyde (0.141 mL, 1 .50 mmol), followed by addition of 1 droplet cone. HCI . The mixture stirred at this temperature for 30 min . After cooling to room temperature, the formed precipitate was filtered, washed with ether and dried to give the desired product as a white solid. LCMS (Method I) RT 1 .39 min. [M+H]+ 319. M.p. 260 C (decomp.).

Reference： [1]Patent: WO2013/79350,2013,A1 .Location in patent: Page/Page column 132

33
[ 39891-04-8 ]
[ 1250695-64-7 ]
[ 1440251-69-3 ]

Yield	Reaction Conditions	Operation in experiment
19%		General procedure: To each reaction tube in a 24-position Bohdan MiniBlock XT was added the appropriate aldehyde (5.0 equiv, 1.15 mmol), which was dissolved in MeCN (1 mL). A solution of 2-(benzo[d][1,3]dioxol-5- yl)pyrimidin-4-amine (8) in MeCN (0.13 M, 1.8 mL, 0.23 mmol, 1.0 equiv) was then dispensed into each tube. ClTi(Oi-Pr)3 (95%, 0.35 mL, 1.38 mmol, 6.0 equiv) was added to each tube, followed by AcOH (3 drops). The reactions were shaken at 450 rpm for 5 minutes, and then solid NaBH(OAc)3 (95%, 257 mg, 1.15 mmol, 5.0 equiv) was added to each tube. The reactions were shaken at 450 rpm for an additional 1.5 hours, and then a solution of 15% aqueous NH4OH (2 mL) and CH2Cl2 (2 mL) were added to each tube causing white solids to precipitate. Shaking was continued for 30 minutes at 450 rpm. Using stackable 24-position Bohdan MiniBlock XTs, the liquid portions of the crude reaction mixtures were passed into phase separators, to which H2O (2 mL) was added. The biphasic mixtures were mixed by hand using pipettes, and then the heavier organic layers were passed from the phase separators into new reaction tubes. The white solids in the original reaction tubes were washed with CH2Cl2 (2 mL) and the washings were passed into the closed phase separators. The biphasic mixtures were again mixed by hand using pipettes and the heavier organic layers were passed into the reaction tubes containing the organic layers from the first separation. The crude reaction mixtures were then placed on a sample concentrator to remove the solvents. TFA/MeOH (1:19, 3 mL) was added to each crude reaction mixture, and the samples were then shaken at 450 rpm for 1 hour. The solutions were then passed onto columns of Dowex 50WX4-400 ion exchange resin (2.0 g, pre-washed with TFA/MeOH (1:99, 5 mL)). Each reaction tube was washed with MeOH (2 mL) and the washings were allowed to pass onto the Dowex columns. The columns were washed with MeOH (3 mL) and the washings discarded. The products were then eluted into collection tubes using a mixture of Et3N/MeOH (1:9, 10 mL). Solvents were removed using a sample concentrator and the products were subjected to reverse-phase preparative HPLC purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3654 - 3661

34
[ 39891-04-8 ]
[ 1448520-28-2 ]
[ 1448520-29-3 ]

Yield	Reaction Conditions	Operation in experiment
105 mg		Step 1: A solution of 1-[1-(4-isopropoxy-3-methylbenzoyl)-4-piperidylidene]propan-2-one (130 mg, 0.41 mmol) in dichloromethane (1.7 mL) was treated with diisopropylethylamine (93 mu,, 0.53 mmol) at 0 C followed by the addition of (tert-butyl(dimethyl)silyl) trifluoromethanesulfonate (114 mg, 99 mu, 0.43 mmol). The mixture was stirred at 0 C for 30 min. Step 2: A solution of <strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (51 mg, 0.41 mmol) in dichloromethane (1.7 mL) was cooled to -78 C and boron trifluoride diethyl etherate (164 ih, 0.82 mmol) was added. The mixture was stirred at -78 C for 5 min. The solution from step 1 was added. The mixture was stirred at -78 C for 5 min, quenched with a buffer solution of pH=7. The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified on silica gel utilizing a gradient of 60-100% ethyl acetate in hexanes to afford 4-(5-fluoro-3-pyridyl)-4-hydroxy-1-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]butan-2-one (105 mg). 1H NMR (400 MHz, CDCl3) delta 8.46 - 8.31 (m, 2H), 7.53 - 7.49 (m, 1H), 7.24-7.22 (m, 2H), 6.83 (d, J= 8.1 Hz, 1H), 6.09 (s, 1H), 5.26 (dd, J= 8.9, 5.9 Hz, 1H), 4.62-4.53 (m, 1H), 4.13-4.12 (m, 1H), 3.69 (br d, 4H), 3.00 (br s, 2H), 2.88 (d, J= 6.2 Hz, 2H), 2.37 (br s, 2H), 2.21 (s, 3H), 1.36 (d, J= 6.0 Hz, 6H). ESI-MS m/z calc. 440.21, found 441.4 (M+1)+; Retention time: 1.65 minutes (3 min run).

Reference： [1]Patent: WO2013/109521,2013,A1 .Location in patent: Paragraph 00237-00239

35
[ 39891-04-8 ]
[ 75-16-1 ]
[ 1249603-25-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	In tetrahydrofuran; diethyl ether; at 0℃; for 1h;	Example A46: l-(l-(5-fluoropyridin-3-yl)ethyl)-lH-pyrazol-4-amine To an ice water cooled solution of methylmagnesium bromide (3.0 M in THF, 3.0 equiv, 24 mmol, 8.0 mL) in 20 mL of diethyl ether was added slowly dropwise a solution of 5- fluoropyridine-3-carbaldehyde (1.00 g, 8.00 mmol) in 10 mL of diethyl ether. The reaction mixture was stirred at cooled temp (0 C) for 1 hour, then a saturated ammonium chloride solution was added, followed by extraction with EtOAc. The organic extracts were dried (Na2S04) and concentrated in vacuo to provide l-(5-fluoropyridin-3-yl)ethanol (800 mg, 74% yield) of sufficient purity to be used directly. The title compound was then prepared in an analogous manner to l-(3-(dimethylamino)- l-phenylpropyl)-lH-pyrazol-4-amine (Example A3), replacing 3-(dimethylamino)-l-phenyl- propan-l-ol with l-(5-fluoropyridin-3-yl)ethanol.

Reference： [1]Patent: WO2014/23258,2014,A1 .Location in patent: Page/Page column 74

36
[ 39891-04-8 ]
[ 536-90-3 ]
N-((5-fluoropyridin-3-yl)methylene)-3-methoxyaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 60℃; for 6h;	General procedure: EXAMPLE 4: PREPARATION OF 2-(5-fluoropyridin-3-yl)-2-((3-methoxyphenyl)amino)-1 -(1 - methyl-4-phenyl-1 H-pyrazol-3-yl)ethanone Step 1 : A solution of A/-((5-fluoropyridin-3-yl)methylene)-3-methoxyaniline in ethanol was prepared according to general procedure C from a mixture of <strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (0.062 g; 0.504 mmol) and m-anidisine (0.056 mL; 0.500 mmol) in ethanol (0.5 mL), heated at 60 C for 6 h. General procedure C: A mixture of an aldehyde and an amine in ethanol was heated at 60 - 70 C for 5 - 20 h. The formation of the imine was quantitative and the solution of the imine in ethanol was used in the next step without further purification.

Reference： [1]Patent: WO2014/154682,2014,A1 .Location in patent: Page/Page column 128; 130

37
[ 39891-04-8 ]
[ 19718-49-1 ]
2-(5-fluoro-3-pyridinyl)-6-benzothiazolecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.66 g	With sulfur; 1,10-Phenanthroline; copper(II) choride dihydrate; water; potassium carbonate; for 16h;Reflux;	Methyl 4-amino-3-iodobenzoate (1.93 g, 6.96 mmol) was combined with K2C03 (1.92g), 8 (668 mg), CuC12-2H20 (119 mg), 1,10-phenanthroline (125 mg) and <strong>[39891-04-8]5-fluoro-3-pyridinecarboxaldehyde</strong> (957 mg) in H20 (30 mL), and the reaction mixture was heated at reflux 16 hours. The cooled reaction mixture was filtered, and the filtrate was treated with NH4C1 (1.49 g). The reaction mixture was stirred at ambient temperature for 10 minutes, filtered, and the solid was dried in vacuo to yield a gray solid. The solid was suspended in dioxane, the suspension was heated to reflux, cooled, and filtered to isolate a solid. Thesolid was rinsed with ethyl ether to give the title compound (0.66 g). ?H NMR (DMSO-d6) oe: 9.15 (s, 1H), 8.80 (d, J=2.7 Hz, 1H), 8.65 (s, 1H), 8.39 (dt, J=9.5, 2.2 Hz, 1H), 8.10 (d, 1H), 8.05 (d, 1H), 8.0-6.5 (br s).
0.66 g	With sulfur; 1,10-Phenanthroline; copper(II) choride dihydrate; potassium carbonate; In water; for 16h;Reflux;	Methyl 4-amino-3-iodobenzoate (1.93 g, 6.96 mmol) was combined with K2C03 (1.92g), 8 (668 mg), CuC12-2H20 (119 mg), 1,10-phenanthroline (125 mg) and 5-fluoro-3- pyridinecarboxaldehyde (957 mg) in H20 (30 mL), and the reaction mixture was heated at reflux 16 hours. The cooled reaction mixture was filtered, and the filtrate was treated with NH4C1 (1.49 g). The reaction mixture was stirred at ambient temperature for 10 minutes, filtered, and the solid was dried in vacuo to yield a gray solid. The solid was suspended indioxane, the suspension was heated to reflux, cooled, and filtered to isolate a solid. The solid was rinsed with ethyl ether to give the title compound (0.66 g). ?H NMR (DMSO-d6) oe: 9.15 (s, 1H), 8.80 (d, J=2.7 Hz, 1H), 8.65 (s, 1H), 8.39 (dt, J=9.5, 2.2 Hz, 1H), 8.10 (d, 1H), 8.05 (d, 1H), 8.0-6.5 (br s).

Reference： [1]Patent: WO2015/38503,2015,A1 .Location in patent: Page/Page column 44
[2]Patent: WO2016/144351,2016,A1 .Location in patent: Page/Page column 44

38
[ 39891-04-8 ]
2-(5-fluoro-3-pyridinyl)-N-(2,2,2-trifluoroethyl)-6-benzothiazolecarboxamide [ No CAS ]

Reference： [1]Patent: WO2015/38503,2015,A1
[2]Patent: WO2016/144351,2016,A1

39
[ 39891-04-8 ]
C₁₃H₆ClFN₂OS [ No CAS ]

Reference： [1]Patent: WO2015/38503,2015,A1
[2]Patent: WO2016/144351,2016,A1

40
[ 39891-04-8 ]
(R)-dimethyl (2-oxo-2-(2-oxo-4-phenyloxazolidin-3-yl)ethyl)-phosphonate [ No CAS ]
(R,E)-3-(3-(5-fluoropyridin-3-yl)acryloyl)-4-phenyloxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%		To a stirred solution of (R)-dimethyl (2-oxo-2-(2-oxo-5-phenyloxazolidin-3- yl)ethyl)phosphonate (43.5 g, 132 mmol) in THF (100 mL) was added potassium tert-butoxide (132 mL, 1M in THF, 132 mmol) and mixture was stirred at room temperature for 20 mm. Asolution of 3-fluoroisonicotinaldehyde (15.0 g, 120 mmol) in THF (30.0 mL) was added drop- wise and reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with H20 (75.0 mL), extracted with EtOAc (2 x 300 mL). The organic layer was washed with brine (300 mL), dried (Na2504), filtered and concentrated under reduced pressure. The residue was purified by 40 g 5i02 column using a gradient elution of 0-50% EtOAc inhexanes. Fractions containing product were combined and the solvents were removed in vacuo to provide the product (32.5 g, 87%) as a white solid.

Reference： [1]Patent: WO2015/95265,2015,A1 .Location in patent: Page/Page column 85

41
[ 39891-04-8 ]
benzyl 2-((3-benzyl-5-phenylpyrazin-2-yl)amino)-2-(diethoxyphosphoryl)acetate [ No CAS ]
C₂₅H₁₇FN₄O [ No CAS ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 10369 - 10375

42
[ 39891-04-8 ]
[ 131341-58-7 ]
[ 1426899-73-1 ]
[ 1426899-72-0 ]

Yield	Reaction Conditions	Operation in experiment
39%; 42%	With ammonium acetate; acetic acid; for 8h;Reflux;	2,5-Dihydroxy-acetophenone (3.4 g, 22.4 mmol), <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (3.1 g, 24.6 mmol, 1 .1 eq) and ammonium acetate (2.2 g, 29.1 mmol, 1 .3 eq) were suspended in acetic acid (100%, 70 ml) and heated to reflux for 8 h. The solution was allowed to reach room temperature. The volume of the resulting suspension was reduced to half of the volume under reduced pressure. The mixture was poured on ice water and neutralized with caution using sodium carbonate. The aqueous layer was washed with ethyl acetate and the remaining precipitate filtered. Solid (E)-1 -(2,5- dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone (2.4 g, 42%) was obtained as a brownish solid and used in the cyclization reaction without further purification. The remaining aqueous solution was extracted with ethyl acetate and the combined organic layers dried with sodium sulfate, filtered, the solvent removed under reduced pressure and the resulting solid digested with few dichloromethane. 2-(5-Fluoro- pyridin-3-yl)-6-hydroxy-chroman-4-one was obtained as a brown solid (2.3 g, 39%) and used in the next step without further purification

Reference： [1]Patent: JP5941637,2016,B2 .Location in patent: Paragraph 0175

43
[ 39891-04-8 ]
[ 131341-58-7 ]
[ 1426899-73-1 ]

Reference： [1]Patent: JP5941637,2016,B2

44
[ 39891-04-8 ]
[ 56553-60-7 ]
[ 1003-03-8 ]
N-[(3-fluoropyridin-4-yl)methyl]cyclopentanamine acetate [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 257 - 270

45
[ 39891-04-8 ]
[ 1003-03-8 ]
N-[(5-luoropyridin-3-yl)methyl]cyclopentanamine [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 257 - 270

46
[ 39891-04-8 ]
4-{cyclopentyl[(5-fluoropyridin-3-yl)methyl]amino}-6-(morpholin-4-yl)-1,3,5-triazine-2-carbonitrile [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 257 - 270

47
[ 39891-04-8 ]
4-{cyclopentyl[(3-fluoropyridin-4-yl)methyl]amino}-6-(morpholin-4-yl)-1,3,5-triazine-2-carbonitrile [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 257 - 270

48
[ 39891-04-8 ]
N-[(3-fluoropyridin-4-yl)methyl]cyclopentanamine [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 257 - 270

49
[ 39891-04-8 ]
4-chloro-N-cyclopentyl-N-[(5-fluoropyridin-3-yl)methyl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 257 - 270

50
[ 39891-04-8 ]
4-chloro-N-cyclopentyl-N-[(3-fluoropyridin-4-yl)methyl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 257 - 270

51
[ 39891-04-8 ]
6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride [ No CAS ]
4-(6-(4-((5-fluoropyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%		A room temperature mixture of 6-( i-methyl-i H-pyrazol-4-yl)-4-(6-(piperazin- 1- yl)pyridin-3 -yl)pyrazolo[ 1,5 -a]pyridine-3 -carbonitrile dihydrochloride (Example 2; 30.00 mg, 78.04 mmol) and <strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (14.64 mg, 117.06 mmol) in DMF (1.00 mL) was treated with TEA (32.45 mL, 234.12 mmol). The mixture was acidified to pH 6 with acetic acid, and then stirred for 2 h at 25 C. NaBH3CN (9.808 mg, 156.08 mmol) was added to the reaction mixture. The resulting mixture was stirred at 25 C for 10 h. The reaction mixture was filtered to remove particulates, and the filtrate was purified by preparative HPLC (10 mM NH4(HCO3)/ACN) to afford the title compound (14.8 mg, 38% yield). MS (apci) m/z = 494.1 (M+H), 516.1 (M+Na).

Reference： [1]Patent: WO2017/11776,2017,A1 .Location in patent: Paragraph 001428; 001429; 001430

52
[ 685086-10-6 ]
[ 39891-04-8 ]
6-fluoro-2-((5-fluoropyridin-3-yl)methyl)-1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.5%		General procedure: To a solution of amine (1.0 equiv) in 1,2-dichloroethane (0.1 M) were added aldehyde (1.2 equiv) and acetic acid (0.5 mL), the reaction mixture stirred at rt for 10 min, followed the addition of sodium triacetoxyborohydride (2.0 equiv). The reaction was stirred at rt under nitrogen for 18 h and concentrated. Sat. NaHCO3 (30 mL) was added and extracted with dichloromethane (20 mL x 3) and the combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography on silica gel eluting with 0-10% methanol/dichloromethane to give the desired product.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 132,p. 157 - 172

53
[ 39891-04-8 ]
[ 490-78-8 ]
[ 1426899-72-0 ]

Yield	Reaction Conditions	Operation in experiment
42%	With ammonium acetate; acetic acid; for 8h;Reflux;	2,5-Dihydroxy-acetophenone (3.4 g, 22.4 mmol), <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (3.1 g, 24.6 mmol, 1.1 eq) and ammonium acetate (2.2 g, 29.1 mmol, 1.3 eq) were suspended in acetic acid (100%, 70 ml) and heated to reflux for 8 h. The solution was allowed to reach room temperature. The volume of the resulting suspension was reduced to half of the volume under reduced pressure. The mixture was poured on ice water and neutralized with caution using sodium carbonate. The aqueous layer was washed with ethyl acetate and the remaining precipitate filtered. Solid (E)-1-(2,5-dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone (2.4 g, 42%) was obtained as a brownish solid and used in the cyclization reaction without further purification.

Reference： [1]Patent: CN102993195,2017,B .Location in patent: Paragraph 0356-0359

54
[ 39891-04-8 ]
[ 20099-89-2 ]
[ 1366060-25-4 ]
[ 57-13-6 ]
[ 1426388-99-9 ]

Yield	Reaction Conditions	Operation in experiment
64%		General procedure: Reaction mixtures of ketal-protected thioamide 3 (50 mg,0.246 mmol, 1 equiv) and a-bromoketones 4 (0.246 mmol) wereprepared in 0.6 mL of DMF and heated to 150 C for 5 min in sealedvials. After cooling, aldehydes 5 (0.295 mmol, 1.2 equiv) and ureas6 (0.295 mmol, 1.2 equiv) were added and the reaction mixturesheated to 200 C for an additional 10 min. Once cooled, the crudereaction mixtures were purified using reverse-phase preparativeHPLC, lyophilized, and tested for anti-HIV activity. When measuringthe efficiency of the process, the crude reaction mixtures wereadsorbed onto silica gel, loaded onto a pre-packed silica gel column(12 g), and chromatographed using either hexanes:EtOAc or CH2-Cl2:MeOH.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 6248 - 6265

55
3-acetyl-6-chloro-4-phenylquinolin-2-(1H)-one [ No CAS ]
[ 39891-04-8 ]
6-chloro-3-[3-(5-fluoropyridin-3-yl)acryloyl]-4-phenyl-1H-quinolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With sodium hydroxide; In ethanol; at 20℃;	Step 1 To a solution of 3-acetyl-6-chloro-4-phenyl-1H-quinolin-2-one (100 mg, 0.34 mmol) in EtOH (20 mL) was added <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (46 mg, 0.37 mmol) and NaOH (16 mg, 0.40 mmol). Then the mixture was stirred at room temperature overnight. LC/MS monitored the reaction. Resultant was concentrated to dryness and the residue was dissolved in DMF (2 mL), purified by Combi Flash (MeCN in water: 5% to 95%; 30 min) to afford 6-chloro-3[3-(5-fluoro-pyridin-3-yl)-acryloyl]-4-phenyl-1H-quinolin-2-one (61 mg, yield: 45%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6): delta=12.40 (s, 1H), 8.71 (s, 1H), 8.58 (d, J=2.4 Hz, 1H), 8.12 (d, J=9.6 Hz, 1H), 7.68 (dd, J=8.4, 2.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.94-7.42 (m, 4H), 7.34-7.32 (m, 2H), 7.00-6.96 (m, 2H). MS: m/z 405.2 (M+H+).

Reference： [1]Patent: US2018/44324,2018,A1 .Location in patent: Paragraph 0631; 0632

56
[ 39891-04-8 ]
3-acetyl-6-chloro-4-(4-fluorophenyl)quinolin-2(1H)-one [ No CAS ]
3-[(2E)-3-(5-fluoro-(3-pyridyl))prop-2-enoyl]-6-chloro-4-(4-fluorophenyl)hydroquinolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium hydroxide; In methanol; at 50℃; for 3h;	Step 3 The mixture of 3-acetyl-6-chloro-4-(4-fluorophenyl)quinolin-2(1H)-one (105 mg, 0.33 mmol), <strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (83 mg, 0.67 mmol) and NaOH (27 mg, 0.67 mmol) in mMeOH (25 mL) was stirred at 50 C. for 3 hrs. After cooled to room temperature, the mixture was diluted with water (2 mL), and the pH value was adjusted to 8 with 1 M HCl. The precipitate was filtered to afford yellow solid, which was dissolved in DMSO and purified by pre-HPLC to afford 3-[(2E)-3-(5-fluoro(3-pyridyl))prop-2-enoyl]-6-chloro-4-(4-fluorophenyphydroquinolin-2-one (29 mg, yield: 37%) as yellow solid. 1HNMR (400 MHz, DMSO-d6): delta=12.40 (s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 8.14-8.12 (m, 1H), 7.69-7.28 (m, 7H), 7.02-6.98 (m, 2H). MS: m/z 423.0 (M+H+).

Reference： [1]Patent: US2018/44324,2018,A1 .Location in patent: Paragraph 0658

57
[ 39891-04-8 ]
3-acetyl-6-chloro-4-(4-(trifluoromethoxy)phenyl)quinolin-2(1H)-one [ No CAS ]
3-[(2E)-3-(5-fluoro-(3-pyridyl))prop-2-enoyl]-6-chloro-4-[4-(trifluoromethoxy)phenyl]hydroquinolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With sodium hydroxide; In methanol; at 45℃;	Step 5 To a solution of 3-acetyl-6-chloro-4-(4-(trifluoromethoxy)phenyl)quinolin-2(1H)-one (100 mg, 0.26 mmol) in MeOH (20 mL) was added <strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (65 mg, 0.520 mmol) and NaOH (21 mg 0.52 mmol), and the mixture was stirred at 45 C. overnight. After cooled to room temperature, the mixture was concentrated and the residue was dissolved in EtOAc (30 mL). The mixture was washed with NH4Cl solution (20 mL) and brine (20 mL), and dried over Na2SO4. The solution was concentrated to dryness and the residue was purified by prep-TLC (DCM/MeOH=20/1) to afford 3-[(2E)-3-(5-fluoro(3-pyridyl))prop-2-enoyl]-6-chloro-4-[4-(trifluoromethoxy)phenyl]hydroquinolin-2-one (28 mg, yield: 22%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6): delta=12.44 (s, 1H), 8.71 (s, 1H), 8.60 (s, 1H), 8.13-8.11 (m, 1H), 7.70-7.45 (m, 7H), 7.04 (s, 1H), 7.00-6.98 (m, 1H). MS: m/z 489.0 (M+H+).

Reference： [1]Patent: US2018/44324,2018,A1 .Location in patent: Paragraph 0682; 0683

58
[ 39891-04-8 ]
[ 109-89-7 ]
[ 23586-99-4 ]

Reference： [1]Organic Letters,2018,vol. 20,p. 2011 - 2014

59
[ 39891-04-8 ]
3-((diethylamino)methyl)-5-fluoropyridine 1-oxide [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 2011 - 2014

60
[ 39891-04-8 ]
[ 2136-75-6 ]
3-(5-fluoropyridin-3-yl)acrylaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	In tetrahydrofuran; at 50℃;Inert atmosphere;	To a solution of <strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (43.8 g, 343 mmol) in THF (300 mL) stirred underargon at rt was added solid 2-(triphenylphosphoranylidene)acetaldehyde (112 g, 360 mmol)portion-wise. The reaction minxture was stirred at 50 C overnight. The reaction minxture was evaporated in vacuo to give a brown solid. The cmde solid was treated with toluene (100 mL) which led to precipitation of triphenylphosphine oxide, which was filtered off and discarded. The resulting filtrate was evaporated to dryness and retreated with toluene (50 mL) which ledto more precipitation of triphenylphosphine oxide, which was filtered off and discarded. The resulting filtrate was evaporated to dryness to give an orange oil which crystallized. The residue was recrystallized twice successively in the minimum amount of hot EtOH to afford 3-(5-fluoropyridin-3-yl)acrylaldehyde (26.6 g, 176 mmol, purity: 91 %, 9 % of triphenylphosphine oxide, recovery: 51 %) as light brown crystals. LCMS (mlz) 152 (M+H),retention time: 1.45 mm, Method 1. The filtrate was evaporated and solubilized in hot EtOH(25 mL) and crystallized at rt to afford, after filtration, 3-(5-fluoropyridin-3-yl)acrylaldehyde (8.7 g, 57.4 mmol, purity: 98 %, 2 % of triphenylphosphine oxide, recovery: 17 %) as light brown crystals. LCMS (mlz) 152 (M+H), retention time: 1.47 min LC/MS Method 1. ?H NMR (400 min-Tz, CDC13) delta ppm 9.77 (d, J=7.4 Hz, 1H), 8.61 (s, 1H), 8.55 (d, J=2.7 Hz, 1H),7.60 (dt, J 8.9, 2.2 Hz, 1H), 7.51 (d, J15.9 Hz, 1H), 6.79 (dd, J7.4 Hz, 1H).

Reference： [1]Patent: WO2018/92089,2018,A1 .Location in patent: Page/Page column 143

61
[ 39891-04-8 ]
(S)-6-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidin-1-yl)pyrimindine-4-carboxaminde [ No CAS ]

Reference： [1]Patent: WO2018/92089,2018,A1

62
[ 39891-04-8 ]
(S)-2-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidin-1-yl)pyrimindine-4-carboxaminde [ No CAS ]

Reference： [1]Patent: WO2018/92089,2018,A1

63
[ 39891-04-8 ]
3-(4,5-dihydro-1H-pyrazol-5-yl)-5-fluoropyridine [ No CAS ]

Reference： [1]Patent: WO2018/92089,2018,A1
[2]Patent: WO2019/224773,2019,A1

64
[ 39891-04-8 ]
tert-butyl 4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/92089,2018,A1

65
[ 39891-04-8 ]
(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(piperidin-4-yl)methanone [ No CAS ]

Reference： [1]Patent: WO2018/92089,2018,A1

66
[ 39891-04-8 ]
(S)-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(piperidin-4-yl)methanone (1R)-(-)-10-camphorsulphonic acid salt [ No CAS ]

Reference： [1]Patent: WO2018/92089,2018,A1

67
[ 39891-04-8 ]
(S)-5-chloro-2-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidin-1-yl)pyrimindine-4-carboxaminde [ No CAS ]

Reference： [1]Patent: WO2018/92089,2018,A1

68
[ 39891-04-8 ]
(S)-5-fluoro-6-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidin-1-yl)pyrimindine-4-carboxaminde [ No CAS ]

Reference： [1]Patent: WO2018/92089,2018,A1

69
[ 39891-04-8 ]
(S)-ethyl 5-fluoro-6-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidin-1-yl)pyrimindine-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/92089,2018,A1

70
[ 39891-04-8 ]
(S)-5-fluoro-6-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidin-1-yl)pyrimindine-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/92089,2018,A1

71
[ 39891-04-8 ]
[ 2136-75-6 ]
[ 1073495-85-8 ]

Yield	Reaction Conditions	Operation in experiment
77%	In dichloromethane; at 20℃; for 3h;	To a stirred solution of <strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (4.3g, 34 mmol) in DCM (50 mL) was added 2-(triphenyl-l5- phosphaneylidene)acetaldehyde (11.5 g, 37.8 mmol) in one portion. The resultant mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The resulting residue was triturated in 200 mL of Et2O and the solid precipitate was removed by filtration and the filtrate was concentrated. The residue was purified by normal phase column chromatography (EA in heptane from 5 to 60% EA) to afford (E)-3-(5-fluoropyridin-3-yl)acrylaldehyde (4.0 g, 77% yield) as a cream solid. LCMS (m/z) 159.1 (M+H)+, retention time: 0.45 min, LCMS Method 9. 1H NMR (400 MHz, DMSO-d6) d: 9.73 (d, J = 7.9 Hz, 1H), 8.56-8.88 (m, 2H), 8.12-8.41 (m, 1H), 7.82 (dd, J = 16.1, 1.4 Hz, 1H), 7.09 (dd, J = 16.1, 7.7 Hz, 1H).
	In dichloromethane; at 20℃;	A solution of <strong>[39891-04-8]5-fluoropyridine-3-carbaldehyde</strong> (10 g, 79.94 mmol) and (triphenylphosphoranylidene)acetaldehyde (24.33 g, 79.94 mmol) in DCM (200 mL) was stirred at rt overnight. The reaction mixture was treated with silica, evaporated under reduced pressure and purified by column chromatography eluting with a gradient of ethyl acetate (0 to 100%) in hexanes to provide a light yellow solid. 1H-NMR (400 MHz, CDC13): 9.78 (d, J 7.4 Hz, 1H), 8.64 (t, J 1.6 Hz, 1H),8.56 (d, J= 2.7 Hz, 1H), 7.62 (dddd, J= 8.9, 2.7, 1.8, 0.5 Hz, 1H), 7.54-7.49 (m, 1H), 6.79 (dd, J16.1, 7.4 Hz, 1H).
	In dichloromethane; at 20℃;	A solution of <strong>[39891-04-8]5-fluoropyridine-3-carbaldehyde</strong> (10 g, 79.94 mmol) and(triphenylphosphoranylidene)acetaldehyde (24.33 g, 79.94 mmol) in DCM (200 mL) was stirred at rtovernight. The reaction mixture was treated with silica, evaporated under reduced pressure and purified by column chromatography eluting with a gradient of ethyl acetate (0 to 100%) in hexanes to provide the title compound. 1H-NMR (400 MHz, CDC13): oe 9.78 (d,J= 7.4 Hz, 1H), 8.64 (t,J= 1.6 Hz, 1H), 8.56 (d, J = 2.7 Hz, 1H), 7.62 (dddd, J = 8.9, 2.7, 1.8, 0.5 Hz, 1H), 7.54-7.49 (m, 1H), 6.79 (dd, J = 16.1, 7.4 Hz, 1H).

Reference： [1]Patent: WO2019/224773,2019,A1 .Location in patent: Page/Page column 108-109
[2]Patent: WO2018/107060,2018,A1 .Location in patent: Paragraph 87
[3]Patent: WO2018/213634,2018,A1 .Location in patent: Page/Page column 58

72
[ 39891-04-8 ]
di-tert-butyl 3-(5-fluoro-3-pyridyl)-5-hydroxypyrazolidine-1,2-dicarboxylate [ No CAS ]

Reference： [1]Patent: WO2018/107060,2018,A1
[2]Patent: WO2018/213634,2018,A1

73
[ 39891-04-8 ]
[ 75-98-9 ]
6-(tert-butyl)-5-fluoronicotinaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With ammonium persulfate; sulfuric acid; silver nitrate; In water; at 20℃; for 3h;	[00270] To a stirred solution of <strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (1 , 0.6 g, 4.79 mmol), pivalic acid (2.44 g, 23.9 mmol) and silver nitrate (0.16 g, 0.959 mmol) in 10% aqueous sulfuric acid (5.5 ml_), was added a solution of ammonium persulfate (2.18 g, 9.59 mmol) in water (10 ml_). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was basified to pH 9 with aqueous ammonia and extracted with ethyl acetate (2 x 50 ml_). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified by silica gel column chromatography using 10% ethyl acetate in hexane to afford the title compound 6-(tert-butyl)-<strong>[39891-04-8]5-fluoronicotinaldehyde</strong> (2, 0.6 g, 70%) as pale brown liquid. Calculated (M+H): 182.09; Found (M+H): 182.3

Reference： [1]Patent: WO2018/119374,2018,A1 .Location in patent: Paragraph 00269-00270

74
[ 39891-04-8 ]
6-(6-(tert-butyl)-5-fluoropyridin-3-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2018/119374,2018,A1

75
[ 39891-04-8 ]
8-(6-(tert-butyl)-5-fluoropyridin-3-yl)-6-oxo-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazine-7-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2018/119374,2018,A1

76
[ 39891-04-8 ]
[ 1095380-87-2 ]