[ CAS No. 21717-95-3 ] {[proInfo.proName]}

Name: 21717-95-3|2-Amino-3-fluoropyridine|98%
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Quality Control of [ 21717-95-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 21717-95-3 ]

Product Details of [ 21717-95-3 ]

CAS No. :	21717-95-3	MDL No. :	MFCD04114135
Formula :	C₅H₅FN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WWEINXQNCAWBPD-UHFFFAOYSA-N
M.W :	112.11	Pubchem ID :	2762809
Synonyms :

Calculated chemistry of [ 21717-95-3 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	28.6
TPSA :	38.91 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) :	-6.56 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.19
Log Po/w (XLOGP3) :	0.6
Log Po/w (WLOGP) :	1.23
Log Po/w (MLOGP) :	0.62
Log Po/w (SILICOS-IT) :	1.15
Consensus Log Po/w :	0.96

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.47
Solubility :	3.82 mg/ml ; 0.034 mol/l
Class :	Very soluble
Log S (Ali) :	-0.99
Solubility :	11.4 mg/ml ; 0.102 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.89
Solubility :	1.46 mg/ml ; 0.013 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.49

Safety of [ 21717-95-3 ]

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

Application In Synthesis of [ 21717-95-3 ]

* 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 [ 21717-95-3 ]
Downstream synthetic route of [ 21717-95-3 ]

[ 21717-95-3 ] Synthesis Path-Upstream 1~9

1
[ 246847-98-3 ]
[ 21717-95-3 ]

Yield	Reaction Conditions	Operation in experiment
90.2%	With ammonium hydroxide; palladium on activated charcoal; hydrogen In methanol	In 1000ml single neck flask of 2-amino-3-fluoro-5-chloropyridine (50g, 0.341mol) was dissolved in methanol (600ml) was added aqueous ammonia (50ml), with hydrogen in the Pd (2.5g, 23.5mmol) under catalytic reduction, the reaction was completed, filtration to remove Pd / C, and the filter cake washed with methanol, the filtrate concentrated under reduced pressure to give a white solid crude, the crude dissolved in water, (200ml * 4) and extracted with ethyl acetate, the organic layer was collected with anhydrous NaSO₄Sulfate, and concentrated under reduced pressure, a small amount of petroleum ether beating, suction filtration to give white crystals 34.50g, 90.20percent yield.

Reference： [1] Patent: CN105669539, 2016, A, . Location in patent: Paragraph 0061; 0062; 0063

2
[ 1513-66-2 ]
[ 21717-95-3 ]

Reference： [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7564 - 7567

3
[ 67-63-0 ]
[ 939-48-0 ]
[ 21717-95-3 ]

Yield	Reaction Conditions	Operation in experiment
34 %Chromat.	at 75℃; for 6 h;	Different 03- and 05-substituted directing group were found to be suitable for the Zn(OAc)2.17H20- catalysed directed cleavage of I with iPrOH (lOa). Both electron-withdrawing (F, Cl, 000R, NO2, ON,OF3) and electron-donating (Alkyl, Ph, OR) groups in 03- and 05-position of the py-DG were evaluated (Example Table E2).

Reference： [1] Patent: WO2017/46133, 2017, A1, . Location in patent: Page/Page column 51; 53

4
[ 628322-77-0 ]
[ 21717-95-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 6, p. 1518 - 1522

5
[ 17282-04-1 ]
[ 21717-95-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 6, p. 1518 - 1522

6
[ 21717-95-3 ]
[ 17157-48-1 ]
[ 139022-26-7 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 6, p. 1518 - 1522

7
[ 21717-95-3 ]
[ 1321612-85-4 ]

Reference： [1] Patent: WO2013/123444, 2013, A1, . Location in patent: Page/Page column 209; 210

8
[ 21717-95-3 ]
[ 1211590-31-6 ]

Reference： [1] Patent: WO2013/101974, 2013, A1,
[2] Patent: US9617268, 2017, B2,

9
[ 21717-95-3 ]
[ 1532517-95-5 ]

Reference： [1] Patent: WO2017/133701, 2017, A1,

[ 21717-95-3 ] Synthesis Path-Downstream 1~88

1
[ 21717-95-3 ]
[ 92895-33-5 ]
[ 136117-53-8 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567

2
[ 628322-77-0 ]
[ 21717-95-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1518 - 1522

3
[ 21717-95-3 ]
[ 17157-48-1 ]
[ 139022-26-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1518 - 1522

4
[ 17282-04-1 ]
[ 21717-95-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1518 - 1522

5
[ 463-71-8 ]
[ 21717-95-3 ]
[ 899806-26-9 ]

Yield	Reaction Conditions	Operation in experiment
37%	In dichloromethane; at 0 - 20℃; for 1h;	[00314] Synthesis of 3-fluoropyridin-2-isothiocyanate; [00315] A solution of <strong>[21717-95-3]3-fluoro-pyridin-2-ylamine</strong> (928 mg, 8.28 mmol) in dichloromethane (3 mL) was added dropwise with stirring to a solution of thiophosgene (1.9 mL, 24.83 mmol) in dichloromethane (6 mL) at 0 0C. The reaction mixture was stirred for 1 hour at room temperature. The reaction was diluted with dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous solution extracted 3 times with dichloromethane. The organic layers were combined and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 10% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (479 mg, 37%): 1H NMR (400 MHz5 CDCl3) delta 8.22-8.23 (m, IH), 7.48-7.52 (m, IH)5 7.21-7.26 (m, IH).

Reference： [1]Patent: WO2006/76595,2006,A1 .Location in patent: Page/Page column 153

6
[ 21717-95-3 ]
5-bromo-3-fluoro-pyridin-2-ylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-Bromosuccinimide; In acetonitrile;	5-Bromo-<strong>[21717-95-3]3-fluoro-pyridin-2-ylamine</strong> To a solution of <strong>[21717-95-3]3-fluoro-pyridin-2-ylamine</strong> (0.30 g, 2.68 mmol) in acetonitrile (15 mL), in inert atmosphere, N-bromosuccinimide (0.48 g, 2.68 mmol) was added. The mixture was stirred for 4 hours. Solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (cHex/AcOEt 66/34) to give the title compound (0.46 g, 89%). C5H4BrFN2 Mass (calculated) [191]; (found) [M+H]+ = 193
89%	With N-Bromosuccinimide; In acetonitrile; for 4h;Inert atmosphere;	5-Bromo-<strong>[21717-95-3]3-fluoro-pyridin-2-ylamine</strong> To a solution of <strong>[21717-95-3]3-fluoro-pyridin-2-ylamine</strong> (0.30 g, 2.68 mmol) in acetonitrile (15 mL), in inert atmosphere, N-bromosuccinimide (0.48 g, 2.68 mmol) was added. The mixture was stirred for 4 hours. Solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (cHex/AcOEt 66/34) to give the title compound (0.46 g, 89%). C5H4BrFN2 Mass (calculated) [191]; (found) [M+H]+=193.
87.3%	With N-Bromosuccinimide; In acetonitrile; at 20℃; for 2h;Inert atmosphere;	Under nitrogen protection, 176 N-bromosuccinimide (NBS, 5.47 g, 30.57 mmol) was added portionwise into 177 <strong>[21717-95-3]3-fluoropyridine-2-amine</strong> (3.36 g, 29.97 mmol) in 95 acetonitrile (150 mL), and the reaction was reacted under nitrogen protection at room temperature for 2 hours. Acetonitrile was removed by concentrating under reduced pressure, quenched by adding saturated solution of 178 sodium thiosulfate, extracted with ethyl acetate (100 mL×3). The organic phase was combined and washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the filtrate was separated on column chromatography (eluant:petroleum ether/ethyl acetate (v/v)=5:1), to afford 5.0 g of a white solid, yield was 87.3%. LC-MS(APCI): m/z=191.1 (M+1).

85.1%	With N-Bromosuccinimide; In acetonitrile; at 20℃; for 3h;	The compound 288a (0.3 g, 2.68 mmol) was dissolved in acetonitrile (15 mL), and N-bromosuccinimide (0.48 g, 2.68 mmol) was added. Stir at room temperature for 3 hours. After removing the solvent, chromatography on silica gel (ethyl acetate:Petroleum ether = 40:60) was purified to give compound 288b as a white solid, 5-bromo-<strong>[21717-95-3]3-fluoropyridine-2-amine</strong> (0.436 g, 85.1% yield).
69%	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 1.33333h;	Step A: A solution of <strong>[21717-95-3]3-fluoropyridin-2-amine</strong> (1.0 g, 8.92 mmol) was dissolved in CH3CN (300 mL) at 0 C. N-Bromosuccinimide (800 mg, 4.5 mmol) was added to the solution. The reaction mixture was stirred at 0 C for 20 min, then at room temperature for 20 min. The mixture was cooled to 0 C. Additional N-bromosuccinimide (800 mg, 4.5 mmol) was added. The mixture warmed to room temperature over 40 minutes. An aqueous NaHS03 solution was added to the mixture to quench excess reagent, then the solvent was removed under vacuum. The residue was dissolved in EtOAc, then washed with aqueous K2C03. The organic layer was dried over MgSC^, then filtered and concentrated under vacuum. Trituration of the residue with 2: 1 hexanes: ether yielded 5-bromo-<strong>[21717-95-3]3-fluoropyridin-2-amine</strong> (1.18 g, 69%) as a white solid. 1H NMR (500 MHz, CDC13): delta 7.93 (1H, d, J= 2 Hz), 7.37 (1H, dd, J= 9.5 Hz, 2 Hz), 4.66 (2H, br s), 2.77 (3H, s).
69%	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 1.33333h;	Step A: A solution of <strong>[21717-95-3]3-fluoropyridin-2-amine</strong> (1.0 g, 8.92 mmol) was dissolved in CH3CN (300 mL) at 0 C. N-Bromosuccinimide (800 mg, 4.5 mmol) was added to the solution. The reaction mixture was stirred at 0 C. for 20 min, then at room temperature for 20 min. The mixture was cooled to 0 C. Additional N-bromosuccinimide (800 mg, 4.5 mmol) was added. The mixture warmed to room temperature over 40 minutes. An aqueous NaHSO3 solution was added to the mixture to quench excess reagent, then the solvent was removed under vacuum. The residue was dissolved in EtOAc, then washed with aqueous K2CO3. The organic layer was dried over MgSO4, then filtered and concentrated under vacuum. Trituration of the residue with 2:1 hexanes:ether yielded 5-bromo-<strong>[21717-95-3]3-fluoropyridin-2-amine</strong> (1.18 g, 69%) as a white solid. 1H NMR (500 MHz, CDCl3): delta 7.93 (1H, d, J=2 Hz), 7.37 (1H, dd, J=9.5 Hz, 2 Hz), 4.66 (2H, br s), 2.77 (3H, s).
68%	With N-Bromosuccinimide; In acetonitrile; at 20℃; for 1h;	To a mixture of <strong>[21717-95-3]3-fluoropyridin-2-amine</strong> (300 mg, 2.68 mmol) in acetonitrile (15 mL) was added N-bromosuccinimide (238 mg, 1.34 mmol). Shielded from light using an aluminum foil, the reaction mixture was stirred at rt for 30 min. Additional N-bromosuccinimide (238 mg, 1.34 mmol) and acetonitrile (5 mL) were added, and the reaction mixture was stirred at rt for another 30 min. The mixture was then partitioned between EtOAc (50 mL) and water (50 mL), and the aqueous layer was separated and extracted with EtOAc (2 ^ 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over MgS04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 0 - 40% EtOAc in hexanes to give 5-bromo-3- fluoropyridin-2-amine as a white solid (350 mg, 68%). 1H NMR (300 MHz, CHLOROFORM-t ) 7.95 (s, 1H), 7.39 (dd, J= 1.7, 9.8 Hz, 1H), 4.66 (br s, 2H). LC-MS (ESI) m/z 191 and 193 (M +H)+.
52%	With dihydrogen peroxide; 1-butylpyridinium bromide; toluene-4-sulfonic acid; In 1,2-dimethoxyethane; at 80℃; for 24h;Schlenk technique; Inert atmosphere; Green chemistry;	General procedure: To a mixture of 2-aminopyridine (0.5 mmol, 1 equiv), p-TSA (0.4 mmol,0.8 equiv), 1-butylpyridinium bromide (1.5 mmol, 3 equiv) in a 50 mL Schlenk tube were added 1,2-dimethoxyethane (2 mL) under air. Then H2O2 (1.2 mmol, 2.4 equiv) was added. The mixture was stirred at 80C for 24 h. And then the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the products.
	With N-Bromosuccinimide; In acetonitrile; at 0 - 25℃; for 3.25h;	To a solution of <strong>[21717-95-3]3-fluoro-pyridin-2-ylamine</strong> (1.0 g, 8.92 mmol) in 300 mL of acetonitrile, NBS (794 mg, 4.46 mmol) was added at 0 C. The reaction mixture was stirred vigorously for 15 minutes (protected from light) at 0 C. and then at room temperature for 1 hour. The additional portion of NBS (794 mg, 4.46 mmol) was added at 0 C. and the solution was stirred at room temperature for 2 hours. The reaction mixture was quenched by addition Na2S2O3 (saturated aqueous solution, 40 mL) and the product was extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (2×50 mL), dried over MgSO4 and concentrated in vacuo. The obtained crude yellowish solid was purified by Biotage using 3-20% EtOAc in hexane to afford 5-bromo-<strong>[21717-95-3]3-fluoro-pyridin-2-ylamine</strong> (1.2 g). 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.93 (d, J=1.56 Hz, 1H) 7.37 (dd, J=9.76, 1.95 Hz, 1H) 4.63 (br. s., 2H)
	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 3.25h;	To a round bottom flask is added R-11 (500 mg, 4.46 mmol) in CH3CN (120 ml) at 0 C, followed by the addition of N-bromosuccinimide (397 mg, 2.23 mmol). The reaction mixture is stirred (protected from light) vigorously for 15 minutes, then at room temperature for 1 hour. The additional portion of N-bromosuccinimide (397 mg, 2.23 mmol) is added at 0 C, then the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with sat Na2S203 (20 ml), brine, dried over anhy. Na2S04, filtered and concentrated. The residue is purified by flash chromatography (Si02, 0-20% EtO Ac/heptane) to afford the title intermediate (772 mg); m/z 190.89/192.86 [M/M+2H].
772 mg	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 3.25h;	Synthesis of 5-bromo-<strong>[21717-95-3]3-fluoro-pyridin-2-ylamine</strong> To a round bottom flask is added R-11 (500 mg, 4.46 mmol) in CH3CN (120 ml) at 0 C., followed by the addition of N-bromosuccinimide (397 mg, 2.23 mmol). The reaction mixture is stirred (protected from light) vigorously for 15 minutes, then at room temperature for 1 hour. The additional portion of N-bromosuccinimide (397 mg, 2.23 mmol) is added at 0 C., then the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with sat Na2S2O3 (20 ml), brine, dried over anhy. Na2SO4, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0-20% EtOAc/heptane) to afford the title intermediate (772 mg); m/z 190.89/192.86 [M/M+2H].
	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 2h;Inert atmosphere;	1.2.2. Illustrative synthesis of Intermediate Gen-1 -a : 2-amino-5-bromo-3-fluoropyridine [00270] To a solution of <strong>[21717-95-3]2-amino-3-fluoro-pyridine</strong> (9.4 g, 83.1 mmol, 1 eq.) in MeCN (470 mL) under argon at 0C was added NBS (7.4 g, 41.5 mmol, 0.5 eq.). The reaction mixture was stirred at r.t. for 1 h then cooled to 0C before introducing additional NBS (7.39 g, 41.5 mmol, 0.5 eq.). The reaction mixture was stirred at r.t. for 1 h then diluted in EtOAc. The organic layer was washed with a saturated NaHCOs solution, dried over Na2S04, filtered and concentrated in vacuo. The residue was diluted in DCM, washed with a 1 N NaOH solution. The organic phase was dried over Na2S04, filtered and concentrated in vacuo to afford Intermediate Gen-1 -a (2-amino-5-bromo-3-fluoropyridine). [00271] LC-MS: MW (calcd): 190 (79Br), 192 (81Br); m/z MW (obsd): 191 (79Br M+l), 193 (81Br M+l)
	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 1h;	To a mixture of <strong>[21717-95-3]3-fluoropyridin-2-amine</strong> (11.0 g, 98.0 mmol) in ACN (300 mL) was added NBS (8.72 g, 49.0 mmol) at 0C, and stirred for 1 h at r.t. and then another NBS (8.72 g, 49.0 mmol) was added dropwise. The reaction mixture was concentrated and diluted with water (100 mL). The mixture was filtered through Celite. The cake was washed with water and the filtrate was concentrated to give the title compound 5-bromo-<strong>[21717-95-3]3-fluoropyridin-2-amine</strong> (D-1) as crude. MS-ESI (m/z): 191 [M + 1].

Reference： [1]Patent: EP2878339,2015,A1 .Location in patent: Page/Page column
[2]Patent: US2016/297762,2016,A1 .Location in patent: Paragraph 0281-0282
[3]Patent: US2019/152954,2019,A1 .Location in patent: Paragraph 0361; 0362; 0681; 0682
[4]Patent: CN110627775,2019,A .Location in patent: Paragraph 0533-0534; 0535-0536
[5]Patent: WO2013/101974,2013,A1 .Location in patent: Paragraph 00792; 00793
[6]Patent: US9617268,2017,B2 .Location in patent: Page/Page column 365; 366
[7]Patent: WO2011/22473,2011,A1 .Location in patent: Page/Page column 193
[8]Tetrahedron Letters,2014,vol. 55,p. 5058 - 5061
[9]Patent: US2008/221149,2008,A1 .Location in patent: Page/Page column 24
[10]Patent: WO2012/24150,2012,A1 .Location in patent: Page/Page column 135
[11]Patent: US2013/195879,2013,A1 .Location in patent: Paragraph 0280; 0281
[12]Patent: WO2014/139882,2014,A1 .Location in patent: Paragraph 00270-00271
[13]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 507 - 512
[14]Patent: WO2017/133701,2017,A1 .Location in patent: Paragraph 179; 180

7
[ 1097180-24-9 ]
[ 21717-95-3 ]
[ 1097264-64-6 ]

Yield	Reaction Conditions	Operation in experiment
53%	In N,N-dimethyl-formamide; at 80℃; for 4h;	1,1-D1methylethyl (2S)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate D2 (42.80 g, 134 mmol) and 3-fluoro-2-pyridinamine (14.98 g, 134 mmol) were dissolved in dry DMF (240 ml) and the resulting solution was stirred at 80 C. for 4 h. The reaction mixture was cooled to 25 C. and was diluted with NaHCO3 sat aqueous solution/water 1/1 (470 ml) and extracted with Et2O (3×941 ml). The organic layers were combined, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica gel (Biotage 75 L, Cy/EtOAc/MeOH from 80/20/2.5 to 80/20/10) to afford 25.70 g of the title compound D19 contaminated with 3-fluoro-2-pyridinamine (25% from NMR analysis). The material was dissolved in DCM (650 ml). Ps-TsCl [38 g, 74.90 mmol (resin capacity 1.97 mmol/g)] and then DMAP (3 g, 24.56 mmol) were added. The resulting mixture was stirred at room temperature under Argon atmosphere overnight and filtered. The filtrate was dried (Na2SO4), the solvent removed under vacuum and the crude purified by flash chromatography on silica gel (Biotage 75 L, Cy/EtOAc/MeOH from 80/20/2 to 80/20/5) to afford the title compound D19 (23.56 g, 70.70 mmol, 53% yield from D2) contaminated with some residual 3-fluoro-2-pyridinamine (14% from NMR analysis).1H NMR (400 MHz, CDCl3) delta (ppm): 7.86 (d, 1H), 7.40-7.57 (bs, 1H), 6.79-6.90 (m, 1H), 6.60-6.71 (m, 1H), 4.63-4.77 (m, 1H), 3.97-4.16 (m, 1H), 3.18-3.34 (m, 1H), 2.86-3.03 (m, 2H), 1.33-1.81 (m, 6H), 1.13-1.37 (bs, 9H).
	In N,N-dimethyl-formamide; at 80℃; for 4h;	1,1-Dimethylethyl (25)-2-(3-bromo-2-oxopropyl)-l-piperidinecarboxylate D2 (42.80 g) and 3-fluoro-2-pyridinamine (14.98 g, 134 mmol) were dissolved in dry DMF (240 ml) and the resulting solution was stirred at 80 0C for 4 hours. The reaction mixture was cooled to 25 0C and was diluted with saturated NaHCO3 aqueous solution/water 1/1 (470 ml) and extracted with Et2O (3 x 941 ml). The organic layers were combined, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica gel (Biotage 75L column, Cy/EtOAc/MeOH from 80/20/2.5 to 80/20/10) to afford 25.70 g of the title compound D8 contaminated with 3-fluoro-2-pyridinamine (25% from NMR analysis). The material was dissolved in DCM (650 ml). Ps-TsCl [38 g, 74.90 mmol (resin capacity 1.97mmol/g)] and then DMAP (3 g, 24.56 mmol) were added. The resulting mixture was stirred at room temperature under Argon atmosphere overnight and filtered. The filtrate was dried (Na2SO4), the solvent removed under vacuum and the crude purified by flash chromatography on silica gel (Biotage 75L column, Cy/EtOAc/MeOH from 80/20/2 to 80/20/5) to afford the title compound D8 (23.56 g). Ci8H24FN3O2 requires 333. 1U NMR (400 MHz, CDCl3) delta ppm: 7.86 (d, 1 H), 7.40 - 7.57 (bs, 1 H), 6.79 - 6.90 (m, 1 H), 6.60 - 6.71 (m, 1 H), 4.63 - 4.77 (m, 1 H), 3.97 - 4.16 (m, 1 H), 3.18 - 3.34 (m, 1 H), 2.86 - 3.03 (m, 2 H), 1.33 - 1.81 (m, 6 H), 1.13-1.37 (bs, 9 H).

Reference： [1]Patent: US2009/22670,2009,A1 .Location in patent: Page/Page column 15
[2]Patent: WO2010/72722,2010,A1 .Location in patent: Page/Page column 25

8
[ 21717-95-3 ]
[ 79-04-9 ]
[ 1196093-59-0 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,2-dichloro-ethane; at 80℃; for 0.0833333h;Microwave irradiation;	a) 2-Chloro-N-(3-fluoro-pyridin-2-yl)-acetamide 2-Amino-3-fluoropyridine (1.5 g) was dissolved in DCE (15 mL) and chloroacetylchloride (1.1 mL) was added dropwise. The reaction was heated in a microwave at 80 C. for 5 mins. The reaction mixture was cooled and the resulting solid was filtered off, washed with DCE, MeCN and pentane then suspended in dichloromethane and aqueous NaHCO3 (sat) was added. The organic phase was separated and the aqueous layer was extracted with dichloromethane (*2). The combined organic layers were dried over sodium sulphate and concentrated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane to give the title compound as a white solid (800 mg). 1H NMR (400 MHz, DMSO-D6): delta 10.61 (s, 1H), 8.27 (dt, 1H), 7.83-7.77 (m, 1H), 7.41-7.35 (m, 1H), 4.37 (s, 2H).
	With triethylamine; In dichloromethane; at 20℃; for 5h;	General procedure: choloro acetylcholoride (24mmol) and Et3N (24mmol) was added to a solution of 2-chloro-3-aminopyridine 7e (20mmol) in CH2Cl2 (20mL) at room temperature. The mixture was stirred for 5 hrs, and the solvent was evaporated under vacuum. The residue was purified by column chromatography (CH2Cl2:CH3OH: 30:1) on silica gel to obtain pure compound 8e as a white powder in 72% yield. To a solution of amide derivative 8e (5mmol) and potassium carbonate (7.5mmol) in acetonitrile (20ml) was added isothiocyanate (6mmol) during about 5min. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum. The residue was extracted with ethyl acetate (20mL×3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The obtained residue was purified by silica gel flash chromatography column (CH2Cl2:CH3OH: 30:1) to afford 5l as a white solid in 82% yield. To a solution of 5l (1mmol) in glacial acetic acid (5mL) were added aldehyde 6b (1mmol) and beta-alanine (1mmol). The resulting mixture was stirred under reflux for 2h. Upon completion of the reaction, the mixture was cooled, the reaction was quenched with water, and the precipitate was filtered off, then the residue was purified by column chromatography (CH2Cl2:CH3OH: 15:1) on silica gel to obtain pure compound 2r as a faint yellow powder in 80% yield.

Reference： [1]Patent: US2011/172237,2011,A1 .Location in patent: Page/Page column 40
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2517 - 2520
[3]Patent: WO2009/138707,2009,A1 .Location in patent: Page/Page column 104-105

9
[ 21717-95-3 ]
[ 1694-29-7 ]
[ 1204526-85-1 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 20℃;Reflux;	To a stirred solution of <strong>[21717-95-3]3-fluoro-pyridin-2-ylamine</strong> (1.0 g, 8.92 mmol) in ethanol (20 mL) was added 3-chloro-pentane-2,4-dione (2.5 mL, 22.3 mmol) at room temperature. The reaction mixture was heated to reflux and then stirred for 48 hours. After the reaction completion, the volatiles were concentrated under reduced pressure and the residue was purified over silica gel column chromatography eluting with 2% MeOH/DCM to afford Int-1 (0.75 g, 44%) as off-white solid. Mass (m/z): 193 [M++1]. 1HNMR 200 MHz (CDCl3): delta 9.54 (d, J=7 Hz, 1H), 7.18 (t, J=7 Hz, 1H), 6.99-6.89 (m, 1H), 2.83 (s, 3H). 2.65 (s, 3H). A solution of Int-1 (0.75 g, 3.9 mmol) in DMF-DMA (10 mL) was stirred at reflux temperature for 48 hours. The reaction mixture was allowed room temperature and diluted with hexane (25 mL) and stirred for 10 minutes. The precipitated solid was filtered off, dried under vacuum to afford Int-2 (0.75 g, 78%) as brown color solid. Mass (m/z): 248 [M++1]. 1HNMR 200 MHz (CDCl3): delta 9.43 (d, J=6.2 Hz, 1H), 7.81 (d, J=12.4 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 6.84-6.77 (m, 1H), 5.56 (d, J=12.2 Hz, 1H), 2.96 (s, 3H), 2.88 (s, 3H), 2.78 (s, 3H). Synthesis of Int-4: To a solution of Int-2 (1.5 g, 6.07 mmol) in DMF (25 mL) was added Int-3 (3.5 g, 18.2 mmol), followed by K2CO3 (2.5 g, 18.2 mmol) at room temperature and the reaction mixture was stirred at 110 C. for 16 hours. The reaction mixture was allowed to room temperature, poured in to ice-cold water (70 mL) and stirred further for 20 minutes. The precipitated solid was filtered off, washed with water (2×10 mL) and dried under vacuum to afford Int-4 (1.5 g, 68%) as brown solid. Mass (m/z): 364 [M++1]. 1HNMR 200 MHz (dmso-d6): delta 10.29 (s, 1H), 9.63 (d, J=6.8 Hz, 1H), 8.69 (d, J=5.6 Hz, 1H), 7.88 (s, 3H), 7.70 (t, J=10.6 Hz, 1H), 7.29-7.23 (m, 2H), 4.83 (brs, 1H), 3.9 (s, 3H), 2.73 (s, 3H). A mixture of Int-4 (1.5 g, 3.97 mmol) and 4 N HCl (20 mL) was stirred at reflux temperature for 3 hours. The reaction mixture was cooled to 0 C. and stirred for 20 minutes. The precipitated solid was filtered off, washed with water (2×10 mL) and dried under vacuum to afford Int-5 (1.0 g, 71%) as pale yellow solid. Mass (m/z): 364 [M++1]. 1HNMR 200 MHz (dmso-d6): delta 10.29 (s, 1H), 9.63 (d, J=6.8 Hz, 1H), 8.69 (d, J=5.6 Hz, 1H), 7.88 (s, 3H), 7.70 (t, J=10.6 Hz, 1H), 7.29-7.23 (m, 2H), 4.83 (brs, 1H), 2.73 (s, 3H). To a stirred suspension of Int-5 (0.8 g, 2.20 mmol) in DMF (10 mL) were added HOBt (0.29 g, 2.20 mmol), EDCI (1.05 g, 5.5 mmol), N-ethyldiisopropylamine (1.0 mL, 5.5 mmol) and NH2OTHP (0.51 g, 4.40 mmol) at 0 C. The reaction mixture was warmed to room temperature and the stirring was continued for 16 hours. The reaction mixture was poured in to ice-cold water (50 mL) and stirred for 20 minutes. The precipitated solid was filtered off, washed with water (2×10 mL) and dried under vacuum. The crude material was purified over silica gel column chromatography eluting with 3% MeOH/DCM to afford Int-6 (0.45 g, 44%) as white solid. Mass (m/z): 463 [M++1].

Reference： [1]Patent: US2010/29638,2010,A1 .Location in patent: Page/Page column 98

10
[ 15568-85-1 ]
[ 21717-95-3 ]
[ 1198412-77-9 ]

Reference： [1]Heterocycles,2009,vol. 78,p. 2477 - 2488

11
[ 104-92-7 ]
[ 21717-95-3 ]
[ 1231925-96-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); tert-butyl XPhos; In toluene; at 100℃; for 3h;Inert atmosphere;	STEP 1. 3-FLUORO-N-(4-METHOXYPHENYL)PYRIDIN-2-AMINE A solution of the 4-bromo aninsole (1.0 g, 0.0053mol), <strong>[21717-95-3]2-amino-3-fluoropyridine</strong>(0.9 g,0.0080 mol.) and sodiuma tert-butoxide(1.017 g, 0.01 mol.) in 20 mL of toluene was purged by nitrogen for 15 mins. Then Pd2(dba)3 (75 mg, 0.10 mmol) and di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine) (0.112 g, 0.260 mmol) were added and the mixture was further degassed for 15 min. The reaction mixture was heated to 100 C. for 3.0 h. After cooling to RT, the reaction mixture was diluted with water and extracted by ethyl acetate(20*3 ml).Combined ethylacetate layers were filtered through celite and washed with ethyl acetate. The filtrate was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (Silica: 100-200 mess, Solvent: 15% Ethyl acetate:Hexane) to give the desired product. MS (ESI, pos. ion) m/z: 219.19 (M+1).

Reference： [1]Patent: US2010/160280,2010,A1 .Location in patent: Page/Page column 146-147

12
[ 1207852-61-6 ]
[ 21717-95-3 ]
[ 1233088-07-7 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 3528 - 3530

13
[ 1224708-12-6 ]
[ 21717-95-3 ]
[ 1224709-07-2 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 4755 - 4758

14
[ 21717-95-3 ]
[ 100-52-7 ]
[ 536-74-3 ]
[ 1245815-62-6 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 4605 - 4608

15
[ 1258298-00-8 ]
[ 21717-95-3 ]
[ 1258294-07-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 130℃; for 0.5h;Microwave irradiation; Inert atmosphere;	A 25 mL microwave tube containing N-(2-bromopyridin-4-yl)-2,6-dichlorobenzamide (100 mg, 0.29 mmol), <strong>[21717-95-3]3-fluoropyridin-2-amine</strong> (42 mg, 0.38 mmol), Pd2(dba)3 (8 mg, 0.008 mmol), Cs2CO3 (190 mg, 0.58 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 4 mg, 0.003 mmol), and dioxane (15 mL) was degassed and then charged by N2 (3×). The resulting mixture was then irradiated in a microwave reactor at 130 C. for 30 min. The mixture was diluted with dioxane (20 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (Gemini, 200 mm×25 mm, gradient: CH3CN/0.05% NH3.H2O, 50-80%, 10 min) to afford the desired product (377 mg, yield: 45%). 1H NMR (400 MHz, DMSO) delta 11.07 (s, 1H), 8.98 (s, 1H), 8.28-8.01 (m, 3H), 7.70-7.48 (m, 4H), 7.37 (s, 1H), 7.01 (s, 1H). LCMS (ESI) m/z: 378.5 [M+H+].

Reference： [1]Patent: US2010/317643,2010,A1 .Location in patent: Page/Page column 99; 100

16
[ 21717-95-3 ]
[ 1267851-05-7 ]

Reference： [1]Patent: WO2011/22473,2011,A1

17
[ 21717-95-3 ]
[ 1267851-06-8 ]

Reference： [1]Patent: WO2011/22473,2011,A1

18
[ 21717-95-3 ]
[ 1269440-67-6 ]

Yield	Reaction Conditions	Operation in experiment
		[00176] Intermediate. 3-Fluoro-4-iodopyridin-2-amine[00177] A solution of <strong>[21717-95-3]2-amino-3-fluoropyridine</strong> (1.0 g, 8.9 mmol) in anhydrousTHF (40 ml) was treated dropwise at -78C with n-butyllithium (1.6 M in hexanes, 13.9 ml, 22.3 mmol). Following the addition, the mixture was stirred at -78 0C for 1 h, then a solution of iodine (10.2 g, 40.1 mmol) in THF (20 ml) was added. The mixture was extracted with ethyl acetate, and the organic extracts were washed with sodium thiosulfate, sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (8:1 to 2:1 hexanes/ethyl acetate eluant) to provide the title compound. MS m/z 238.9 (M + 1).
61 g		50 g of <strong>[21717-95-3]2-amino-3-fluoropyridine</strong> was weighed, placed in a 2 L three-neck reaction flask, and 300 mL of tetrahydrofuran was added. Protected with nitrogen, cooled to -78C, and slowly added dropwise 2.5M n-butyl lithium-tetrahydrofuran solution (450 mL). The reaction was stirred under nitrogen at -78 C for 30 min. A solution of 510 g of iodine in tetrahydrofuran (300 mL) was then slowly added dropwise. After the addition was complete, the reaction was stirred at -78C for 30 min and the reaction was stirred at room temperature for 1 h. The reaction solution was slowly poured into ice water (lkg) and extracted three times with ethyl acetate.The resulting ethyl acetate phase was separated three times, washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, concentrate the filtrate3-Fluoro-4-iodoguanidine-amine 61 g was obtained.

Reference： [1]Patent: WO2011/25927,2011,A1 .Location in patent: Page/Page column 47
[2]Patent: CN107540699,2018,A .Location in patent: Paragraph 0005; 0009

19
[ 21717-95-3 ]
[ 1196091-77-6 ]

Reference： [1]Patent: US2011/172237,2011,A1
[2]Patent: WO2009/138707,2009,A1

20
C₆H₃BrCl₂N₂ [ No CAS ]
[ 21717-95-3 ]
[ 1224709-07-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4698 - 4701

21
[ 1817-49-8 ]
[ 21717-95-3 ]
[ 1245815-62-6 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 7308 - 7316

22
[ 67-56-1 ]
[ 131543-46-9 ]
[ 21717-95-3 ]
[ 1339673-93-6 ]

Yield	Reaction Conditions	Operation in experiment
31%	With perchloric acid; In water; at 70℃; for 48h;	Step A: (3-Fluoro-pyridin-2-ylamino)-acetic acid methyl ester. To a mixture of 40% glyoxal aqueous solution (1.5 ml) in MeOH (10 ml) was added a slurry of 3-Fluoro-pyridin-2-ylamine (1.17 g, 10.5 mmol) in HC104 (3 ml). The reaction mixture was heated to 70C for 48 hours. The resulting mixture was adjusted to pH>8 with saturated NaHC03 solution after being cooled to room temperature. The basic solution was extracted with ethyl acetate (3x10 ml). The combined organic layer was washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The residue was purified by flash column to give the (3-Fluoro-pyridin-2- ylamino)-acetic acid methyl ester as a white solid (600 mg, 31% yield). 1H NMR (400 MHz, CDC13): delta 7.88 (d, 2H, J = 4.8), 7.17 (m, 1H), 6.59 (m, 1H), 5.12 (br, 1H), 4.26 (d, 2H, J = 6.4), 3.78 (s, 3H).

Reference： [1]Patent: WO2012/9678,2012,A1 .Location in patent: Page/Page column 213-214

23
[ 21717-95-3 ]
(5-fluoro-pyridin-2-ylamino)-acetic acid hydrochloride [ No CAS ]

Reference： [1]Patent: WO2012/9678,2012,A1

24
[ 97980-71-7 ]
[ 21717-95-3 ]
[ 1447463-72-0 ]

Yield	Reaction Conditions	Operation in experiment
63%		General procedure: To a solution of the carboxylic acid 7 (31.4 mg, 0.1 mmol) in anhydrous CH2Cl2 was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (5.0 equiv) and 4-dimethylaminopyridine (1.0 equiv) at 0 C. The reaction mixture was stirred for 10 min at the same temperature. To the reaction mixture was added amine (3.0 equiv) and then the reaction mixture was slowly warmed to room temperature. After 12 hours at the same temperature, the reaction mixture was diluted with CH2Cl2 and washed with aqueous NH4Cl. The organic layer was dried over MgSO4. The mixture was concentrated at reduced pressure. The residue was purified by flash chromatography on silica gel (CH2Cl2/methanol, 15:1) to give desired amide 12 (32.7 mg, 70%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4324 - 4327

25
[ 21717-95-3 ]
[ 1450622-32-8 ]

Reference： [1]Patent: WO2013/123444,2013,A1

26
[ 21717-95-3 ]
[ 1450622-33-9 ]

Reference： [1]Patent: WO2013/123444,2013,A1

27
[ 21717-95-3 ]
[ 1450622-34-0 ]

Reference： [1]Patent: WO2013/123444,2013,A1

28
[ 21717-95-3 ]
2-(2-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)phenyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol [ No CAS ]

Reference： [1]Patent: WO2013/123444,2013,A1

29
[ 21717-95-3 ]
[ 1446333-80-7 ]

Reference： [1]Patent: WO2013/101974,2013,A1
[2]Patent: US9617268,2017,B2

30
[ 21717-95-3 ]
[ 1446331-60-7 ]

Reference： [1]Patent: WO2013/101974,2013,A1
[2]Patent: US9617268,2017,B2

31
[ 38761-67-0 ]
[ 21717-95-3 ]
2-bromo-8-fluoro-3-hexylimidazo[1,2-a]pyridine [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2013,vol. 355,p. 2263 - 2273

32
[ 932-88-7 ]
[ 21717-95-3 ]
8-fluoro-2-iodo-3-phenylimidazo[1,2-a]pyridine [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2013,vol. 355,p. 2263 - 2273

33
C₁₂H₉FN₂O₃ [ No CAS ]
[ 21717-95-3 ]
[ 1276618-69-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5779 - 5785

34
[ 1276619-87-4 ]
[ 21717-95-3 ]
[ 1276618-19-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5779 - 5785

35
[ 21717-95-3 ]
[ 933-88-0 ]
N-(3-fluoropyridin-2-yl)-2-methylbenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6393 - 6402

36
[ 21717-95-3 ]
C₁₇H₂₅BrFN₃ [ No CAS ]

Reference： [1]Patent: WO2014/139882,2014,A1

37
[ 21717-95-3 ]
N-(6-bromo-2-ethyl-8-fluoro-imidazo[1,2-a]pyridin-3-yl)-formamide [ No CAS ]

Reference： [1]Patent: WO2014/139882,2014,A1

38
[ 21717-95-3 ]
2-(5-Bromo-pyridin-3-yl)-hexanoic acid (5-bromo-3-fluoro-pyridin-2-yl)-amide [ No CAS ]

Reference： [1]Patent: EP2878339,2015,A1
[2]Patent: US2016/297762,2016,A1

39
[ 21717-95-3 ]
tert-butyl 2-((2-fluoro-4-(8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2-a]pyridin-6-yl)benzamido)methyl)piperidine-1-carboxylate [ No CAS ]