[ CAS No. 20511-15-3 ] {[proInfo.proName]}

Name: 20511-15-3|3-Amino-4-chloropyridine|98%
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Quality Control of [ 20511-15-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 20511-15-3 ]

Product Details of [ 20511-15-3 ]

CAS No. :	20511-15-3	MDL No. :	MFCD00235124
Formula :	C₅H₅ClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GTLFLMZOABSJSV-UHFFFAOYSA-N
M.W :	128.56	Pubchem ID :	581932
Synonyms :

Calculated chemistry of [ 20511-15-3 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.65
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) :	-6.52 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.16
Log Po/w (XLOGP3) :	0.8
Log Po/w (WLOGP) :	1.33
Log Po/w (MLOGP) :	0.4
Log Po/w (SILICOS-IT) :	1.37
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) :	-1.7
Solubility :	2.59 mg/ml ; 0.0201 mol/l
Class :	Very soluble
Log S (Ali) :	-1.2
Solubility :	8.14 mg/ml ; 0.0633 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.24
Solubility :	0.735 mg/ml ; 0.00571 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.25

Safety of [ 20511-15-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P264-P280-P302+P352-P337+P313-P362+P364-P332+P313	UN#:	N/A
Hazard Statements:	H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 20511-15-3 ]

* 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 [ 20511-15-3 ]
Downstream synthetic route of [ 20511-15-3 ]

[ 20511-15-3 ] Synthesis Path-Upstream 1~12

1
[ 20511-15-3 ]
[ 19798-77-7 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690

2
[ 13091-23-1 ]
[ 20511-15-3 ]

Reference： [1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 1, p. 51 - 54
[2] Journal of the American Chemical Society, 2015, vol. 137, # 24, p. 7552 - 7555
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 4, p. 519 - 525

3
[ 39910-67-3 ]
[ 504-24-5 ]
[ 20511-15-3 ]

Reference： [1] Heterocycles, 1982, vol. 19, # 6, p. 1043 - 1046

4
[ 20511-15-3 ]
[ 22889-78-7 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690

5
[ 20511-15-3 ]
[ 89284-61-7 ]

Yield	Reaction Conditions	Operation in experiment
44%	Stage #1: With tetrafluoroboric acid; sodium nitrite In ethanol; water at 0℃; for 0.5 h; Stage #2: With sodium cyanide In water; acetonitrile at 0 - 20℃; for 10 h;	[Example 719] Compound q1 4-Chloropyridine-3-carbonitrile [1519] aqueous tetrafluoroboric acid solution (10 ml) was added to a solution of 4-chloropyridin-3-amine (1.29 g, 10.0 mmol) in ethanol (10 ml) at 0°C. An aqueous solution (10 ml) of sodium nitrite (725 mg, 10.5 mmol) was added to the resultant mixed solution at the same temperature, and it was stirred at the same temperature for 30 minutes. The precipitate was collected by filtration and washed with ethanol, and the resultant brown solid (1.94 g) was then dissolved in acetonitrile (10 ml). A mixed solution of sodium cyanide (980 mg, 20.0 mmol) and copper(I) cyanide (896 mg, 10.0 mmol) in water (10 ml) and acetonitrile (1 ml) was added to the resultant solution at 0°C, and it was stirred while gradually warming to room temperature for 10 hours. The reaction mixture was cooled to 0°C, after which a saturated aqueous solution of sodium bicarbonate was added, and it was stirred for five minutes. The resultant solution was extracted with ethyl acetate, and the organic layer was then washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to yield the title compound (605 mg, 44percent) as a pale yellow solid. 1H-NMR (300 MHz, CDCl₃) δ: 8.87 (1H, s), 8.72 (1H, d, J = 3.9 Hz), 7.51 (1H, d, J = 3.9 Hz).

Reference： [1] Patent: EP2842939, 2015, A1, . Location in patent: Paragraph 1519; 1520

6
[ 20511-15-3 ]
[ 773837-37-9 ]
[ 89284-61-7 ]

Yield	Reaction Conditions	Operation in experiment
44%	Stage #1: With tetrafluoroboric acid; sodium nitrite In ethanol; water at 0℃; for 0.5 h; Stage #2: at 0 - 25℃; for 10 h;	A 48percent aqueous tetrafluoroboric acid solution (10 ml) was added to a solution of 4-chloropyridin-3-amine (1.29 g, 10.0 mmol) in ethanol (10 ml) at 0°C. A solution of sodium nitrite (725 mg, 10.5 mmol) in water (10 ml) was added to the resultant mixed solution at the same temperature, and it was stirred at the same temperature for 30 minutes. The precipitate was collected by filtration and washed with ethanol, and the resultant brown solid (1.94 g) was then dissolved in acetonitrile (10 ml). A mixed solution of sodium cyanide (980 mg, 20.0 mmol) and copper(I) cyanide (896 mg, 10.0 mmol) in water (10 ml) and acetonitrile (1 ml) was added to the resultant solution at 0°C, and it was stirred while gradually warming to room temperature for 10 hours. The reaction mixture was cooled to 0°C, after which a saturated aqueous solution of sodium bicarbonate was added, and it was stirred for five minutes. The resultant solution was extracted with ethyl acetate, and the organic layer was then washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to yield the title compound (605 mg, 44percent) as a pale yellow solid. 1H-NMR (300 MHz, CDCl₃) δ: 8.87 (1H, s), 8.72 (1H, d, J = 3.9 Hz), 7.51 (1H, d, J = 3.9 Hz).

Reference： [1] Patent: EP2842946, 2015, A1, . Location in patent: Paragraph 1536; 1537

7
[ 617-35-6 ]
[ 20511-15-3 ]
[ 24334-19-8 ]

Reference： [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 39, p. 11859 - 11862[2] Angew. Chem., 2016, vol. 128, p. 12038 - 12041,4

8
[ 20511-15-3 ]
[ 24334-19-8 ]

Reference： [1] Synthesis, 2005, # 15, p. 2571 - 2577

9
[ 20511-15-3 ]
[ 140-89-6 ]
[ 65128-66-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: at 95 - 100℃; for 15 h; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide for 0.5 h;	Thiazolo[4,5-c]pyridine-2-thiol (68): Compound 67 (1.0 g, 8.3 mmol) was dissolved in 15 mL of dry DMF under N₂. KSCSOEt (2.0 g, 12.5 mmol) was added EPO <DP n="147"/>to the solution as a solid. The reaction mixture was stirred at 95-100⁰C for 15h. TLC (70percent EtO Ac/Hex) showed consumption of starting material. The reaction was quenched with -35 mL OfH₂O followed by addition of 40 mL of IM HCl. The mixture was stirred for 30 min, during which time precipitate was obtained. The precipitate was filtered, washed with 250 mL of H₂O and dried under vacuum over P₄Oi₀ to yield compound 68 (0.98Og, 70percent).

Reference： [1] Patent: WO2006/122156, 2006, A2, . Location in patent: Page/Page column 145-146
[2] Advanced Synthesis and Catalysis, 2017, vol. 359, # 11, p. 1837 - 1843

10
[ 20511-15-3 ]
[ 98-80-6 ]
[ 146140-99-0 ]

Yield	Reaction Conditions	Operation in experiment
< 100 %Chromat.	With potassium carbonate In water at 100℃; for 3 h;	The following were charged into a 1000 ml reactor provided with a coolant, a magnetic stirrer, a thermocouple and a nitrogen atmosphere: [00164] 38.56 g (300 mmole) of 4-chloro-3-aminopyridine; [00165] 42.2 g (306 mmole) of 100percent potassium carbonate; [00166] 38.4 g (308 mmole) of 97percent phenylboronic acid; [00167] 20 mg (0.112 mmole) of palladium chloride; [00168] 400 g (22.2 mole) of degassed water. [00169] The reactants were charged into the reactor and heated under reflux (100° C.) with stirring and under nitrogen. [00170] The reaction was complete after 3 h. [00171] Extraction was carried out with isopropyl ether (200 ml). [00172] It was quickly decanted. [00173] The organic phase was washed with 2.x.60 ml of water. [00174] It was dried over magnesium sulphate then concentrated by evaporation. [00175] High performance liquid chromatography analysis measured 51 g of 4-phenyl-3-methylaniline, corresponding to a yield of close to 100percent.

Reference： [1] Patent: US6800784, 2004, B1, . Location in patent: Page column 9-10

11
[ 20511-15-3 ]
[ 1093211-85-8 ]
[ 1885-14-9 ]
[ 1346528-50-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: With pyridine In toluene at 2 - 5℃; for 7.5 h; Inert atmosphere Stage #2: at 6 - 20℃; for 15 h;	A 2 L, three-neck Morton flask equipped with a mechanical stirrer, thermocouple, and addition funnel under a nitrogen atmosphere was charged with 3-amino-4-chloropyridine (35.0 g, 272 mmol) and toluene (740 mL). The brown solution was cooled to 2 °C. Pyridine (25.3 mL, 310 mmol) was added in one portion, followed by the dropwise addition of phenyl chloroformate (32.6 mL, 259 mmol) over 30 min. The maximum internal temperature was 5 °C. After stirring at 2-5 °C for 7 h the reaction mixture became a thick yellow suspension. A cooled solution of K₂CO₃ (53.6 g, 388 mmol) in water (216 mL) was added over 3 min, during which the maximum internal temperature was 6 °C. 1 -(2,2-Difluoro-benzo[1 ,3]dioxol-5-ylmethyl)-piperazine (66.3 g, 259 mmol) was then added as a solid over 1 min. The mixture was allowed to warm slowly to room temperature and stirred for 15 h. Water (200 ml_) was added and the toluene layer was separated and extracted with aqueous HCI (1 .8 M, 600 ml_). The aqueous extract was washed with toluene (2 x 300 ml_). MeOH (500 ml_) was added to the aqueous layer and the solution was cooled to 5 °C. The pH was adjusted to pH 8-9 with the addition of NaOH solution (50 wtpercent, ca. 50 ml_). The addition was at such a rate that the internal temperature did not exceed 17 °C. The resulting suspension was stirred at 5 °C for 2 h. The product was collected by filtration and rinsed with MeOH/H₂O (1 :1 , 70 ml_). The solid was dried in vacuum oven at 50 °C for 24 h to afford the title compound as a yellow/green solid (73 g, 69percent).A 1 L, three-neck Morton flask equipped with a stir bar, thermocouple, and reflux condenser was charged with crude 4-(2,2-difluoro-benzo[1 ,3]dioxol- 5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide (98 g, 239 mmol) and isopropyl acetate (318 ml_). The suspension was heated to 65 °C, treated with activated charcoal (10.0 g) and stirred at 65 °C for 1 h. The mixture was then heated to 80 °C and quickly filtered through a thin celite pad. The filtrate was slowly cooled to room temperature and then placed in an ice bath for 30 min. The solid was collected by filtration, rinsed with cold iPrOAc (10 ml_), and dried to give product 4-(2,2-difluoro-benzo[1 ,3]dioxol-5-ylmethyl)- piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide as a yellow solid (72 g, 73percent).A 2 L, three-neck Morton flask equipped with a mechanical stirrer, thermocouple, and reflux condenser was charged with crude product 4-(2,2- difluoro-benzo[1 ,3]dioxol-5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro- pyridin-3-yl)-amide (191 g, 465 mmol) and isopropyl acetate (705 ml_). The suspension was heated to 65 °C, treated with activated charcoal (1 1 .2 g) and stirred at 65 °C for 1 h. The mixture was then heated to 75 °C and quickly filtered. The filtrate was slowly cooled to room temperature overnight and then placed in an ice bath for 30 min. The solid was collected by filtration, rinsed with cold iPrOAc (40 ml_), and dried in vacuum oven at 50 °C for 72 h. The product 4-(2,2-difluoro-benzo[1 ,3]dioxol-5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide was obtained as a slightly yellow solid (161 g, 84percent). MS (ESI⁺): calcd for Ci8Hi₇CIF₂N₄O3 m/z 410.1 , found 41 1 .1 (M+H)⁺. Anal. Calcd for Ci₈H₁₇CIF₂N₄O₃: C, 52.63; H, 4.17; N, 13.64. Found: C, 52.73; H, 4.15; N, 13.62; ¹ H NMR (600 MHz, CDCI₃) δ: 9.36 (s, 1 H), 8.19 (d, J = 5.2 Hz, 1 H), 7.29 (dd, J = 5.3, 0.3 Hz, 1 H), 7.13 (d, J = 0.9 Hz, 1 H), 7.02-6.98 (m, 5 2H), 6.84 (s, 1 H), 3.58-3.54 (m, 4H), 3.53 (s, 2H), 2.54-2.48 (m, 4H); ¹³C NMR (151 MHz, CDCIs) δ: 153.49, 144.02, 143.88, 143.28, 142.98, 134.05, 133.09, 131 .66 (t, JC-F = 254.6 Hz), 131 .55, 123.89, 123.53, 1 10.03, 109.02, 62.28, 52.47, 44.23.

Reference： [1] Patent: WO2011/139951, 2011, A1, . Location in patent: Page/Page column 24-26

12
[ 20511-15-3 ]
[ 1352792-74-5 ]

Reference： [1] Patent: CN106883169, 2017, A,

[ 20511-15-3 ] Synthesis Path-Downstream 1~88

1
[ 19788-49-9 ]
[ 20511-15-3 ]
[ 132872-45-8 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1990,vol. 332,p. 444 - 452

2
[ 936-61-8 ]
[ 20511-15-3 ]
[ 91813-44-4 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1765 - 1770

3
[ 20511-15-3 ]
[ 758-08-7 ]
[ 18504-86-4 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1990,vol. 332,p. 444 - 452

4
[ 20511-15-3 ]
[ 13749-75-2 ]
[ 109202-22-4 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1765 - 1770

5
[ 20511-15-3 ]
[ 13749-76-3 ]
[ 109202-23-5 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1765 - 1770

6
[ 20511-15-3 ]
[ 926-67-0 ]
[ 89786-57-2 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1765 - 1770

7
[ 20511-15-3 ]
[ 26028-04-6 ]
[ 116608-16-3 ]

Reference： [1]Synthetic Communications,1989,vol. 19,p. 713 - 719
[2]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1765 - 1770

8
[ 20511-15-3 ]
[ 62448-79-7 ]
[ 111931-88-5 ]

Reference： [1]Synthesis,1987,p. 363 - 364

9
[ 20511-15-3 ]
[ 73818-80-1 ]
[ 108923-77-9 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1765 - 1770

10
[ 20511-15-3 ]
[ 111931-94-3 ]
[ 111931-89-6 ]

Reference： [1]Synthesis,1987,p. 363 - 364

11
[ 20511-15-3 ]
[ 111931-95-4 ]
[ 111931-90-9 ]

Reference： [1]Synthesis,1987,p. 363 - 364

12
[ 20511-15-3 ]
[ 2365-48-2 ]
[ 18504-86-4 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1990,vol. 332,p. 444 - 452

13
[ 20511-15-3 ]
[ 147-93-3 ]
[ 106515-32-6 ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 519 - 525

14
[ 20511-15-3 ]
[ 144036-19-1 ]
N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-4-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine;	EXAMPLE 9 Compounds BP-CG A stirred solution of 4-chloropyrid-3-ylamine (1.94 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (3.85 g) in pyridine (50 ML) is heated at 80°C for 7 hours and then it is allowed to stand ovemight. The reaction mixture is evaporated, to give a brown oil, which is subjected to mplc on silica gel, using diethyl ether as eluent, to give N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.1 g), m.p. 130-132°C.

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 1696 - 1703
[2]Patent: EP741707,1998,B1

15
[ 39910-67-3 ]
[ 504-24-5 ]
[ 20511-15-3 ]

Reference： [1]Heterocycles,1982,vol. 19,p. 1043 - 1046

16
[ 13091-23-1 ]
[ 20511-15-3 ]

Reference： [1]Bulletin des Societes Chimiques Belges,1988,vol. 97,p. 51 - 54
[2]Journal of the American Chemical Society,2015,vol. 137,p. 7552 - 7555
[3]Journal of Medicinal Chemistry,1994,vol. 37,p. 519 - 525

17
[ 617-35-6 ]
[ 20511-15-3 ]
2-[(E)-4-Chloro-pyridin-3-ylimino]-propionic acid ethyl ester [ No CAS ]

Reference： [1]Synthesis,2005,p. 2571 - 2577

18
[ 20511-15-3 ]
[ 504-02-9 ]
3-[(4-chloropyridin-3-yl)amino]cyclohex-2-en-1-one [ No CAS ]

Reference： [1]Synthesis,2005,p. 2571 - 2577

19
[ 20511-15-3 ]
[ 140-89-6 ]
[ 66242-96-4 ]

Reference： [1]Heterocycles,2005,vol. 65,p. 2619 - 2634

20
[ 20511-15-3 ]
[ 1001353-85-0 ]
(S)-N-(4-chloropyridin-3-yl)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)-2-methylpyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%		109B MeMgBr (3M in ether, 0.3 ml, 0.9 mmol) was added to a solution of <strong>[20511-15-3]4-chloropyridin-3-amine</strong> (142 mg, 1.1 mmol) in THF (1 ml) at RT. The mixture was stirred at RT for 5 mins. A solution of pivaloate 109A (47 mg, 0.11 mmol) in 0.5 ml THF was added to above mixture. After 1 hr stirring at RT, 1.5 ml of 7M NH3 in MeOH was added and stirred for 20 mins. The crude mixture was diluted with methanol and the product was isolated by preparative HPLC. The fractions that contained the product were applied onto a MCX cartridge and then flushed with methanol. The free base product was eluted with a 2 N solution of ammonia in methanol and removal of the solvents left product (23 mg, 44percent yield): MS: 478 (M+H)+.

Reference： [1]Patent: US2008/9497,2008,A1 .Location in patent: Page/Page column 53

21
[ 20511-15-3 ]
[ 1001354-04-6 ]
(2S,4R)-N-(4-chloropyridin-3-yl)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)-4-fluoropyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With isopropylmagnesium chloride; In tetrahydrofuran; at 0 - 20℃; for 2h;	3-Amino-4-chloro-pyridine (142 mg, 1.1 mmol) was dissolved in 5 ml THF and cooled to 0° C. A solution of isopropyl magnesium chloride (2M in THF, 0.5 ml, 1.0 mmol) was added and the mixture stirred for 5 minutes. Then a solution of compound 203A (37 mg, 0.095 mmol, in 5 ml THF) was added. The mixture was stirred for 1 hour at 0° C., then 1 hour at ambient temperature. The reaction vessel is briefly immersed into an acetone/dry ice bath and the reaction quenched by addition of a mixture of 1 ml trifluoroacetic acid and 5 ml methanol. After evaporation of volatiles the product is purified by prep HPLC. The fractions containing the product are processed to the title compound, obtained as its free base, using a one gram (20 cc) Waters Oasis MCX Extraction Cartridge, following the general method described above, to give 18.0 mg of the pure title compound as a pale brown solid. LCMS m/e=482 ([M+H]+), Ret. Time 1.20 min on Phenomenex 10 u, 4.650 mm column, gradient over 2 minutes from 5percent CH3CN in water to 95percent CH3CN+5percent water, buffered with 10 mM NH4OAc. Analytical HPLC Ret. Time 4.95 min, on Waters Sunfire C18 4.6150 mm column, 3.5 um, 5 min gradient, 10-90percent B, 1 mL/min flow rate.

Reference： [1]Patent: US2008/9497,2008,A1 .Location in patent: Page/Page column 88

22
[ 20511-15-3 ]
[ 65136-48-3 ]
[ 1004764-35-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; at 20℃; for 32.5h;Heating / reflux;	A cold solution (0 0C) of 4-(3-chloropropoxy)benzoic acid x57 (9.18 g, 42.78 mmol, 1 eq) in dichloromethane (200 ml) is treated with oxalyl chloride (5.0 ml, 47.06 mmol, 1.1 eq) and N,N-dimethylformamide (0.5 ml). The mixture is left to warm up to 20 0C and stirred until gas evolution has ceased. The mixture is then concentrated under reduced pressure and the residue is dissolved in tetrahydrofuran (150 ml). A suspension of sodium hydride (60 percent dispersion in mineral oil, 2.26 g, 94.12 mmol, 2.2 eq) in tetrahydrofuran (200 ml) is treated with a solution of <strong>[20511-15-3]3-amino-4-chloropyridine</strong> (5.5 g, 42.78 mmol, 1 eq) in tetrahydrofuran <n="95"/>(100 ml). After 30 minutes stirring at 20 0C1 the resulting solution is treated dropwise with the previously obtained acyl chloride solution. The mixture is stirred for 24 h at 20 0C and 8 h at reflux. After cooling to room temperature, water (1 ml) is added to the mixture, which is left under stirring for 1 h. The mixture is finally concentrated under reduced pressure. The residue is dissolved in dichloromethane and the organic layer is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography over silicagel (dichloromethane/methanol/ammonia 99:1 :0.1 ) to afford 5.3 g of 4-(3-chloropropoxy)-N-(4-chloropyridin-3-yl)benzamide x58. Yield: 38percent LC-MS (MH+): 325/327

Reference： [1]ChemMedChem,2011,vol. 6,p. 1559 - 1565
[2]Patent: WO2008/12010,2008,A1 .Location in patent: Page/Page column 93-94

23
[ 20511-15-3 ]
[ 98382-93-5 ]
[ 503321-47-9 ]
[ 18504-84-2 ]

Reference： [1]Heterocycles,2007,vol. 71,p. 1347 - 1361

24
[ 20511-15-3 ]
[ 24334-19-8 ]

Reference： [1]Synthesis,2005,p. 2571 - 2577

25
[ 20511-15-3 ]
6,7,8,9-tetrahydro-5H-pyrido[3,4-b]indol-9-one [ No CAS ]

Reference： [1]Synthesis,2005,p. 2571 - 2577

26
[ 20511-15-3 ]
[ 478361-36-3 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of sodium nitrite (0.5 g, 7.5 mmol) in 3 ml of water was added to a solution of 4-chloropyridine-3 -amine (1 g, 7.8 mmol) in 6N HCl (7 ml) at OoC. The reaction was stirred for 45 min at OoC and a solution of SnC12 (4.5 g, 19.4 mmol) in 6N HCl (7 ml) was added and reaction stirred for a further 3 hrs while gradually warming to ambient temperature. The pH of the reaction was adjusted to 14 with 40percent NaOH solution and product extracted with iPAc. The organics were washed with brine, died and concentrated. The crude product was purified by flash column using a gradient of 100percent Hexanes to 100percent EtOAc to isolate the title compound as an off white solid. LC-MS m/z: 144 [M+l]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 5397 - 5405
[2]Patent: WO2013/62887,2013,A1 .Location in patent: Page/Page column 61-62

27
[ 20511-15-3 ]
[ 478361-35-2 ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 5397 - 5405

28
[ 20511-15-3 ]
[ 478361-33-0 ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 5397 - 5405

29
[ 20511-15-3 ]
N-(4-chloro-3-pyridyl)glycine hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 5397 - 5405

30
[ 20511-15-3 ]
(4-chloro-pyridin-3-ylamino)-acetic acid ethyl ester; hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 5397 - 5405

31
[ 20511-15-3 ]
2'-(4-chloro-3-pyridyl)-11β,17,21-trihydroxy-16α-methyl-20-oxopregn-4-eno[3,2-c]pyrazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 5397 - 5405

32
[ 20511-15-3 ]
[ 478361-39-6 ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 5397 - 5405

33
[ 20511-15-3 ]
4-[1-(4-Chloro-pyridin-3-yl)-7,7,10,10-tetramethyl-4,5,7,8,9,10-hexahydro-1H-naphtho[2,3-g]indol-3-yl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 3163 - 3173

34
[ 20511-15-3 ]
[ 132872-46-9 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1990,vol. 332,p. 444 - 452

35
[ 20511-15-3 ]
[ 132872-53-8 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1990,vol. 332,p. 444 - 452

36
[ 20511-15-3 ]
[ 132872-54-9 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1990,vol. 332,p. 444 - 452

37
[ 20511-15-3 ]
[ 52311-32-7 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1950,vol. 69,p. 673,690

38
[ 20511-15-3 ]
[ 22889-78-7 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1950,vol. 69,p. 673,690

39
[ 20511-15-3 ]
[ 98-80-6 ]
[ 146140-99-0 ]

Yield	Reaction Conditions	Operation in experiment
< 100%Chromat.	With potassium carbonate;palladium dichloride; In water; at 100℃; for 3h;	The following were charged into a 1000 ml reactor provided with a coolant, a magnetic stirrer, a thermocouple and a nitrogen atmosphere: [00164] 38.56 g (300 mmole) of <strong>[20511-15-3]4-chloro-3-aminopyridine</strong>; [00165] 42.2 g (306 mmole) of 100percent potassium carbonate; [00166] 38.4 g (308 mmole) of 97percent phenylboronic acid; [00167] 20 mg (0.112 mmole) of palladium chloride; [00168] 400 g (22.2 mole) of degassed water. [00169] The reactants were charged into the reactor and heated under reflux (100° C.) with stirring and under nitrogen. [00170] The reaction was complete after 3 h. [00171] Extraction was carried out with isopropyl ether (200 ml). [00172] It was quickly decanted. [00173] The organic phase was washed with 2.x.60 ml of water. [00174] It was dried over magnesium sulphate then concentrated by evaporation. [00175] High performance liquid chromatography analysis measured 51 g of 4-phenyl-3-methylaniline, corresponding to a yield of close to 100percent.

Reference： [1]Patent: US6800784,2004,B1 .Location in patent: Page column 9-10

40
[ 20511-15-3 ]
[ 144036-19-1 ]
AK [ No CAS ]
N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-4-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine;	EXAMPLE 5 Compounds AF, AG, AH, Al, AJ, AK, AL, AM and AN A stirred solution of 4-chloropyrid-3-ylamine (1.94 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (3.85 g) in pyridine (50 mL) is heated at 80° C. for 7 hours and then it is allowed to stand overnight. The reaction mixture is evaporated, to give a brown oil, which is subjected to mpic on silica gel, using diethyl ether as eluent, to give N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.1 g), m.p. 130-132° C.
	In pyridine;	EXAMPLE 5 Compounds AF, AG, AH, AI, AJ, AK, AL, AM and AN A stirred solution of 4-chloropyrid-3-ylamine (1.94 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (3.85 g) in pyridine (50 mL) is heated at 80° C. for 7 hours and then it is allowed to stand overnight. The reaction mixture is evaporated, to give a brown oil, which is subjected to mplc on silica gel, using diethyl ether as eluent, to give N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.1 g), m.p. 130°-132° C.

Reference： [1]Patent: US5935978,1999,A
[2]Patent: US5679696,1997,A

41
[ 20511-15-3 ]
[ 541-41-3 ]
[ 55463-33-7 ]

Yield	Reaction Conditions	Operation in experiment
49%		(XX) Synthesis of N 1 -alkylated pyridoimidazolone common intermediate.; Synthesis 131; Ethyl 4-chloro-2-nitropyridin-3-yl-carbamate; <strong>[20511-15-3]3-Amino-4-chloropyridine</strong> (6.7 g, 52 mmol) was dissolved in pyridine (90 mL) and ethyl chloroformate (9.7 mL, 101 mmol), was added dropwise. When the addition was finished, EPO <DP n="176"/>the reaction mixture was stirred for further 5 minutes, then the pyridine was evaporated. The residue was taken in water, and the precipitate recovered by filtration. The filtrate was extracted with chloroform, the organic layer was dried and evaporated. The residue was washed with water, the precipitate recovered by filtration and pooled with the solid from the first washing. After drying in dessicator over P2O5, the title product was obtained (5.15 g, 49percent). 1H-NMR (delta, ppm, DMSOd6): 1.25 (t, 3H1 CH3,Et, J=7.09 Hz), 4.15 (q, 2H, CH21Et), 7.59 (d, 1 H, HPy,5, J=5.28 Hz), 8.34 (d, 1H, HPy,6, J=5.32 Hz), 8.69 (s, 1H, HPy,2), 9.36 (s, 1 H, NHPy3).

Reference： [1]Patent: WO2006/43090,2006,A1 .Location in patent: Page/Page column 173-174

42
[ 20511-15-3 ]
[ 140-89-6 ]
[ 65128-66-7 ]

Yield	Reaction Conditions	Operation in experiment
70%		Thiazolo[4,5-c]pyridine-2-thiol (68): Compound 67 (1.0 g, 8.3 mmol) was dissolved in 15 mL of dry DMF under N2. KSCSOEt (2.0 g, 12.5 mmol) was added EPO <DP n="147"/>to the solution as a solid. The reaction mixture was stirred at 95-1000C for 15h. TLC (70percent EtO Ac/Hex) showed consumption of starting material. The reaction was quenched with -35 mL OfH2O followed by addition of 40 mL of IM HCl. The mixture was stirred for 30 min, during which time precipitate was obtained. The precipitate was filtered, washed with 250 mL of H2O and dried under vacuum over P4Oi0 to yield compound 68 (0.98Og, 70percent).

Reference： [1]Patent: WO2006/122156,2006,A2 .Location in patent: Page/Page column 145-146
[2]Advanced Synthesis and Catalysis,2017,vol. 359,p. 1837 - 1843

43
[ 20511-15-3 ]
2-(2-FURYL)OXAZOLO[4,5-c]PYRIDINE [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 23: 2-(2-FURYL)OXAZOLO[4,5-c]PYRIDINE Using the procedure described in Example 7, but replacing 3-amino-2-chloropyridine by <strong>[20511-15-3]3-amino-4-chloropyridine</strong>.

Reference： [1]Patent: US5077408,1991,A

44
[ 20511-15-3 ]
3-amino-4-chloro-1-methylpyridinium iodide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		47. The starting material was prepared by allowing a mixture of <strong>[20511-15-3]3-amino-4-chloropyridine</strong> and excess methyl iodide (no solvent) to stand at ambient temperature for 1 hour to give 3-amino-4-chloro-1-methylpyridinium iodide as a solid, n.m.r. in solvent F: 4.2(s, 3H); 7.9-8.3(m, 3H).

Reference： [1]Patent: US4678781,1987,A

45
[ 20511-15-3 ]
[ 75-36-5 ]
[ 138769-30-9 ]

Reference： [1]Angewandte Chemie - International Edition,2007,vol. 46,p. 7509 - 7512

46
[ 20511-15-3 ]
[ 1124199-53-6 ]
[ 1124197-94-9 ]

Yield	Reaction Conditions	Operation in experiment
16%	In tetrahydrofuran; for 1h;	A solution of <strong>[20511-15-3]3-amino-4-chloropyridine</strong> (129 mg, 1.0 mmol) in THF (2 mL) was treated with solid 5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (148 mg, 0.5 mmol, as prepared in Example 2 Method B) and allowed to stir for 1 hr. The reaction was then evaporated and the residue chromatographed on silica gel with EtOAc/hexanes (70percent) as eluant to afford product as a colorless solid (31 mg, 16percent). 1H NMR (CDCl3) 2.39 (d, J=1.5, 3H), 7.39 (d, J=5.3, 1H), 7.56 (d, J=7.56, 4.1, 1H), 7.72 (d, J=4.1, 1H), 8.22 (s, 1H), 8.33 (d, J=4.7, 1H), 9.61 (s, 1H). 13C NMR 8.0, 114.8, 118.7 (q, J=271), 129.0, 129, 7, 132.9, 134.6, 140.5, 143.8, 146.1, 157.7, 159.0, 19F NMR -63.1. LC/MS 6.34 min, [M+1]+ 388.

Reference： [1]Patent: US2009/62252,2009,A1 .Location in patent: Page/Page column 52

47
[ 20511-15-3 ]
[ 13250-46-9 ]
[ 97249-84-8 ]

Yield	Reaction Conditions	Operation in experiment
	In acetone; at 20 - 50℃; for 24h;	To a solution of 4-chloropyridin-3 -amine (2.54 g, 19.8 mmol) in acetone (40 mL) at room temperature was added ethanoyl isothiocyanate (1.90 mL, 2.19 g, 21.7 mmol). The reaction mixture was stirred at room temperature for 20 h, heated to 50°C for 4 h, and concentrated. The product, VV-(thiazolo[4,5-c]pyridin-2-yl)acetamide, was used without further purification.

Reference： [1]Patent: WO2009/9122,2009,A2 .Location in patent: Page/Page column 42

48
[ 20511-15-3 ]
[ 111-71-7 ]
[ 1130799-09-5 ]

Reference： [1]Synthesis,2008,p. 3981 - 3987

49
[ 20511-15-3 ]
[ 122-78-1 ]
[ 25797-05-1 ]

Reference： [1]Synthesis,2008,p. 3981 - 3987

50
[ 20511-15-3 ]
[ 1486-50-6 ]
[ 1174737-96-2 ]

Yield	Reaction Conditions	Operation in experiment
		17.2 Synthesis of 4-(benzyloxy)-N-(4-chloropyridin-3-yl)benzamide a58.A solution of <strong>[20511-15-3]3-amino-4-chloropyridine</strong> (10 g, 77.8 mmol, 1 eq) in N, N- dimethylformamide (300 ml) is treated with sodium hydride (60 percent dispersion in mineral oil, 6.85 g, 171 mmol, 2.2 eq). After 1 h stirring at 200C, the resulting solution is treated dropwise with a solution of 4-(benzyloxy)benzoyl chloride a57 (19.193 g, 77.8 mmol, 1 eq) in dichloromethane (300 ml). The mixture is stirred for 24 h at 20°C. The mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and the organic layer is washed with water then with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is taken up with methanol (700 ml) and treated with a suspension of sodium hydride (60 percent dispersion in mineral oil, 3.1 g, 124 mmol, 1.6 eq). After 2 h stirring at 200C, the mixture is concentrated under reduced pressure. The residue is taken up and sonicated in ethyl acetate (400 ml). The solid that settles (4-(benzyloxy)benzoic acid) is filtered off and the resulting solution is concentrated under reduced pressure. The residue is taken up with ethyl acetate (400 <n="87"/>ml) and left to stand overnight. The suspension is again filtered and the solid is washed with ethyl acetate and dried. The filtrate is concentrated and the residue is purified by chromatography over silicagel (dichloromethane/methanol 99:1 ). The two batches of solid are pooled together to yield a combined 10.8 g of 4-(benzyloxy)-N-(4- chloropyridin-3-yl)benzamide a58. Yield : 41 percent. LC-MS (MH+) : 339/341.

Reference： [1]Patent: WO2009/92764,2009,A1 .Location in patent: Page/Page column 85-86

51
[ 20511-15-3 ]
[ 5662-95-3 ]
[ 1347903-62-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2674 - 2678

52
[ 20511-15-3 ]
[ 425-75-2 ]
[ 1174988-23-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 3476 - 3480

53
[ 20511-15-3 ]
[ 333-27-7 ]
[ 1174988-14-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 3476 - 3480

54
[ 20511-15-3 ]
[ 1187081-22-6 ]
C₁₈H₁₈FN₃O₂S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4647 - 4651

55
[ 20511-15-3 ]
[ 2039-88-5 ]
[ 1246225-24-0 ]

Yield	Reaction Conditions	Operation in experiment
26%	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 115℃; for 6h;Inert atmosphere;	General procedure: A mixture of 2-bromostyrene (549mg, 3.00mmol), the appropriate 2-chloroaniline derivative (3.00mmol), Pd(dba)3 (68mg, 0.075mmol), DavePhos (79mg, 0.20mmol), and NaOtBu (864mg, 9.00mmol) in dry 1,4-dioxane (10mL) was stirred under a N2 atmosphere at 115C for 6h. After it had been cooled down to rt, EtOAc (150mL) was added. The mixture was washed with water (5×150mL) and subsequently with brine (150mL). The organic phase was separated and dried over MgSO4. After evaporation of the solvent, the residue was submitted to column chromatography (SiO2, eluent: petroleum ether/EtOAc 20:1). The yellow fraction was collected, and evaporation of the eluent in vacuo gave the desired product.

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 14048 - 14051
[2]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1077 - 1088

56
[ 20511-15-3 ]
[ 139469-06-0 ]
[ 1246225-34-2 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 14048 - 14051

57
[ 20511-15-3 ]
[ 4755-77-5 ]
[ 911463-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0 - 20℃;	To a solution of <strong>[20511-15-3]4-chloropyridin-3-amine</strong> (R-1 ) (5 g, 38.9 mmol) in THF (100 mL) was added Et3N (4.72 g, 6.5 mL, 46.7 mmol), followed by ethyl 2-chloro-2-oxoacetate (5.84 g, 4.78 mL, 42.8 mmol) in THF (5 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h, and then concentrated in vacuo. The resulting residue was dissolved in EtOAc, and washed with aqueous saturated NaHC03. The organic layer was separated, dried over Na2S04, and concentrated to give the title compound, which was used for the next step without further purification. MS (m/z): 229 (M+1 )+.
	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1h;	Ethyl 2-(4-chloropyridin-3-ylamino)-2-oxoacetate (R-2)To a solution of <strong>[20511-15-3]4-chloropyridin-3-amine</strong> (R-1) (5 g, 38.9 mmol) in THF (100 mL) was added Et3N (4.72 g, 6.5 mL, 46.7 mmol), followed by ethyl 2-chloro-2-oxoacetate (5.84 g, 4.78 mL, 42.8 mmol) in THF (5 mL) dropwise at 0° C.The resulting mixture was stirred at room temperature for 1 h, and then concentrated in vacuo.The resulting residue was dissolved in EtOAc, and washed with aqueous saturated NaHCO3.The organic layer was separated, dried over Na2SO4, and concentrated to give the title compound, which was used for the next step without further purification. MS (m/z): 229 (M+1)+.

Reference： [1]Patent: WO2011/79804,2011,A1 .Location in patent: Page/Page column 38
[2]Patent: US2012/245178,2012,A1 .Location in patent: Page/Page column 22-23

58
[ 20511-15-3 ]
[ 911463-38-2 ]

Reference： [1]Patent: WO2011/79804,2011,A1
[2]Patent: US2012/245178,2012,A1

59
[ 20511-15-3 ]
[ 1269531-56-7 ]

Reference： [1]Patent: WO2011/79804,2011,A1
[2]Patent: US2012/245178,2012,A1

60
[ 65626-23-5 ]
[ 20511-15-3 ]
[ 1334713-79-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In N,N-dimethyl acetamide; at 120℃;Inert atmosphere;	4-Chloro-3-aminopyridine (200 mg, 1.56 mmol) was dissolved in DMA (4 mL) and Pd2(dba)3 (71.2 mg, 0.08 mmol), X-Phos (74.2 mg, 0.16 mmol), potassium acetate (458 mg, 4.67 mmol) and (tetrahydro-pyran-4-yl)-acetaldehyde (598 mg, 4.67 mmol) were added under nitrogen. The reaction mixture was heated at 120 °C overnight, cooled to r.t. and partitioned between water (100 mL) and DCM (100 mL). The aqueous fraction was concentrated in vacuo and the residue was dissolved in DCM (100 mL), dried (MgS04) and concentrated in vacuo to give the crude title compound as an orange/brown solid (314 mg, 99.8percent). LCMS (ES+): 203.1 (M+H)+.
	With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; XPhos; In N,N-dimethyl acetamide; at 120℃;Inert atmosphere;	4-Chloro-3-aminopyridine (200 mg, 1.56 mmol) was dissolved in DMA (4 mL) and Pd2(dba)3 (71.2 mg, 0.08 mmol), X-Phos (74.2 mg, 0.16 mmol), potassium acetate (458 mg, 4.67 mmol) and (tetrahydro-pyran-4-yl)-acetaldehyde (598 mg, 4.67 mmol) were added under nitrogen. The reaction mixture was heated at 120° C. overnight, cooled to r.t. and partitioned between water (100 mL) and DCM (100 mL). The aqueous fraction was concentrated in vacuo and the residue was dissolved in DCM (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as an orange/brown solid (314 mg, 99.8percent). LCMS (ES+): 203.1 (M+H)+.

Reference： [1]Patent: WO2011/113798,2011,A2 .Location in patent: Page/Page column 61
[2]Patent: US2013/102587,2013,A1 .Location in patent: Paragraph 0281; 0282

61
[ 65626-23-5 ]
[ 20511-15-3 ]
[ 1334712-80-9 ]

Reference： [1]Patent: WO2011/113798,2011,A2
[2]Patent: US2013/102587,2013,A1

62
[ 20511-15-3 ]
[ 610-14-0 ]
[ 1338243-81-4 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In tetrahydrofuran; for 20h;	Example 13Synthesis of 1-(4-(9H-benzo[f]pyrido[4,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)cyclobutanamine hydrochlorideStep 1. Synthesis of N-(4-chloropyridin-3-yl)-2-nitrobenzamideA solution of <strong>[20511-15-3]3-amino-4-chloropyridine</strong> (5 g, 39 mmol), 2-nitrobenzoyl chloride (5.1 mL, 39 mmol) and pyridine (11 mL) in tetrahydrofuran (50 mL) was stirred for 20 hours. The reaction mixture was partitioned between water (200 mL) and dichloromethane (600 mL). The phases were separated and the organic phase was washed with water (150 mL) then brine (150 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10percent ethyl acetate in dichloromethane). The N-(4-chloropyridin-3-yl)-2-nitrobenzamide was obtained as a brown solid (2.0 g). LCMS [M+H]: 279.

Reference： [1]Patent: US2011/245236,2011,A1 .Location in patent: Page/Page column 104

63
[ 20511-15-3 ]
[ 1093211-85-8 ]
[ 1885-14-9 ]
[ 1346528-50-4 ]

Yield	Reaction Conditions	Operation in experiment
84%		A 2 L, three-neck Morton flask equipped with a mechanical stirrer, thermocouple, and addition funnel under a nitrogen atmosphere was charged with <strong>[20511-15-3]3-amino-4-chloropyridine</strong> (35.0 g, 272 mmol) and toluene (740 mL). The brown solution was cooled to 2 °C. Pyridine (25.3 mL, 310 mmol) was added in one portion, followed by the dropwise addition of phenyl chloroformate (32.6 mL, 259 mmol) over 30 min. The maximum internal temperature was 5 °C. After stirring at 2-5 °C for 7 h the reaction mixture became a thick yellow suspension. A cooled solution of K2CO3 (53.6 g, 388 mmol) in water (216 mL) was added over 3 min, during which the maximum internal temperature was 6 °C. 1 -(2,2-Difluoro-benzo[1 ,3]dioxol-5-ylmethyl)-piperazine (66.3 g, 259 mmol) was then added as a solid over 1 min. The mixture was allowed to warm slowly to room temperature and stirred for 15 h. Water (200 ml_) was added and the toluene layer was separated and extracted with aqueous HCI (1 .8 M, 600 ml_). The aqueous extract was washed with toluene (2 x 300 ml_). MeOH (500 ml_) was added to the aqueous layer and the solution was cooled to 5 °C. The pH was adjusted to pH 8-9 with the addition of NaOH solution (50 wtpercent, ca. 50 ml_). The addition was at such a rate that the internal temperature did not exceed 17 °C. The resulting suspension was stirred at 5 °C for 2 h. The product was collected by filtration and rinsed with MeOH/H2O (1 :1 , 70 ml_). The solid was dried in vacuum oven at 50 °C for 24 h to afford the title compound as a yellow/green solid (73 g, 69percent).A 1 L, three-neck Morton flask equipped with a stir bar, thermocouple, and reflux condenser was charged with crude 4-(2,2-difluoro-benzo[1 ,3]dioxol- 5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide (98 g, 239 mmol) and isopropyl acetate (318 ml_). The suspension was heated to 65 °C, treated with activated charcoal (10.0 g) and stirred at 65 °C for 1 h. The mixture was then heated to 80 °C and quickly filtered through a thin celite pad. The filtrate was slowly cooled to room temperature and then placed in an ice bath for 30 min. The solid was collected by filtration, rinsed with cold iPrOAc (10 ml_), and dried to give product 4-(2,2-difluoro-benzo[1 ,3]dioxol-5-ylmethyl)- piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide as a yellow solid (72 g, 73percent).A 2 L, three-neck Morton flask equipped with a mechanical stirrer, thermocouple, and reflux condenser was charged with crude product 4-(2,2- difluoro-benzo[1 ,3]dioxol-5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro- pyridin-3-yl)-amide (191 g, 465 mmol) and isopropyl acetate (705 ml_). The suspension was heated to 65 °C, treated with activated charcoal (1 1 .2 g) and stirred at 65 °C for 1 h. The mixture was then heated to 75 °C and quickly filtered. The filtrate was slowly cooled to room temperature overnight and then placed in an ice bath for 30 min. The solid was collected by filtration, rinsed with cold iPrOAc (40 ml_), and dried in vacuum oven at 50 °C for 72 h. The product 4-(2,2-difluoro-benzo[1 ,3]dioxol-5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide was obtained as a slightly yellow solid (161 g, 84percent). MS (ESI+): calcd for Ci8Hi7CIF2N4O3 m/z 410.1 , found 41 1 .1 (M+H)+. Anal. Calcd for Ci8H17CIF2N4O3: C, 52.63; H, 4.17; N, 13.64. Found: C, 52.73; H, 4.15; N, 13.62; 1 H NMR (600 MHz, CDCI3) delta: 9.36 (s, 1 H), 8.19 (d, J = 5.2 Hz, 1 H), 7.29 (dd, J = 5.3, 0.3 Hz, 1 H), 7.13 (d, J = 0.9 Hz, 1 H), 7.02-6.98 (m, 5 2H), 6.84 (s, 1 H), 3.58-3.54 (m, 4H), 3.53 (s, 2H), 2.54-2.48 (m, 4H); 13C NMR (151 MHz, CDCIs) delta: 153.49, 144.02, 143.88, 143.28, 142.98, 134.05, 133.09, 131 .66 (t, JC-F = 254.6 Hz), 131 .55, 123.89, 123.53, 1 10.03, 109.02, 62.28, 52.47, 44.23.

Reference： [1]Patent: WO2011/139951,2011,A1 .Location in patent: Page/Page column 24-26

64
[ 20511-15-3 ]
[ 1004764-36-6 ]

Reference： [1]ChemMedChem,2011,vol. 6,p. 1559 - 1565

65
[ 20511-15-3 ]
[ 1334179-64-4 ]

Reference： [1]ChemMedChem,2011,vol. 6,p. 1559 - 1565

66
[ 20511-15-3 ]
2-[4-(3-chloropropoxy)phenyl]-5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine [ No CAS ]

Reference： [1]ChemMedChem,2011,vol. 6,p. 1559 - 1565

67
[ 20511-15-3 ]
5-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine [ No CAS ]

Reference： [1]ChemMedChem,2011,vol. 6,p. 1559 - 1565

68
[ 20511-15-3 ]
2-[4-(3-chloropropoxy)phenyl]-4,5,6,7-tetrahydro-thiazolo[4,5-c]pyridine [ No CAS ]

Reference： [1]ChemMedChem,2011,vol. 6,p. 1559 - 1565

69
[ 20511-15-3 ]
5-acetyl-2-[4-(3-chloropropoxy)phenyl]-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine [ No CAS ]

Reference： [1]ChemMedChem,2011,vol. 6,p. 1559 - 1565

70
[ 20511-15-3 ]
5-acetyl-2-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine [ No CAS ]

Reference： [1]ChemMedChem,2011,vol. 6,p. 1559 - 1565

71
[ 20511-15-3 ]
[ 586-75-4 ]
[ 1354910-23-8 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate; In acetonitrile; for 24h;Reflux;	4-Bromo-N-(4-chloro-pyridin-3-yl)-benzamide (510). A mixture of 4-amino- 3-chloropyridine (509, 5.9g, 46,2 mmol), 4-bromobenzoyl chloride (15, 11.15g, 50.8mmol) and potassium carbonate (22.4g, 161.7 mmol) in acetonitril (150ml) was refluxed for 24hrs. The reaction mixture was concentrated in vacuo, redissolved in DCM and the solution was washed with water. The organic layer was dried (MgSCU), concentrated and the resulting oil was purified by silica gel column chromatography (DCM/MeOH, 99/1, v/v, Rf 0.2) to give pure 510 (10.4g, 72percent) as an oil. When a substituted compound 15 is used, the Rb in compound 510 is introduced.

Reference： [1]Patent: WO2012/4373,2012,A1 .Location in patent: Page/Page column 55-56

72
[ 20511-15-3 ]
[ 586-75-4 ]
[ 1354910-24-9 ]

Reference： [1]Patent: WO2012/4373,2012,A1

73
[ 20511-15-3 ]
[ 1692-15-5 ]
[ 52311-43-0 ]

Reference： [1]Inorganic Chemistry,2013,vol. 52,p. 4205 - 4216
[2]Angewandte Chemie - International Edition,2018,vol. 57,p. 8560 - 8566
Angew. Chem.,2018,vol. 130,p. 8696 - 8702,7

74
[ 20511-15-3 ]
[ 140-89-6 ]
[ 65128-66-7 ]

Yield	Reaction Conditions	Operation in experiment
80.9%	In 1-methyl-pyrrolidin-2-one; at 150℃; for 1h;Microwave irradiation;	Preparation of intermediate 2A:thiazolo[4,5-c]pyridine-2(3H)-thione4-Chloro-pyridin-3-ylamine (500 mg, 3.9 mmol) and ethylxanthic acid potassium salt (950 mg, 5.9 mmol) were dissolve in 6 mL of dry N-methylpyrrolidone, and heated in microwave to 150 °C and reacted under stirring for 1 h. The mixture was cooled to room temperature, to which were added 1 mL of acetic acid and 100 mL of water. The mixture was filtered, and the solid was washed with ethanol-water (1 :2) and dried to give 530 mg of black solid 2A. Yield: 80.9percent.MS (ESI, m/z): [M+H]+: 169.1; 1H-NMR (300 MHz, DMSC ¾): 8.52 (s, 1H ), 8.39 (d, 1H, J = 5.4 Hz), 7.81 (d, 1H, J= 5.1Hz).

Reference： [1]Patent: WO2013/56679,2013,A1 .Location in patent: Page/Page column 32

75
[ 20511-15-3 ]
[ 89786-54-9 ]

Reference： [1]Patent: US2013/178460,2013,A1

76
[ 20511-15-3 ]
[ 1147550-11-5 ]
[ 98-88-4 ]
N-thiazolo[4,5-c]pyridine-2-yl-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.6%		Step 1 N-Thiazolo[4,5-c]pyridine-2-yl-benzamide To a solution of ammonium thiocyanate (1.18 g, 15.6 mmol) in acetone (10 mL) was added benzoyl chloride (1.81 mL, 15.6 mmol) over 10 min. The reaction mixture was heated at 60° C. for 30 minutes, then <strong>[20511-15-3]4-chloropyridin-3-amine</strong> (2.0 g, 15.6 mmol) in acetone (10 mL) was added over 10 min. The reaction mixture was heated at 60° C. for 2 h. Cold water (100 mL) was poured to the reaction mixture. The solid precipitate was filtered, washed with water, and dried under high vacuum to give N-thiazolo[4,5-c]pyridine-2-yl-benzamide (2.21 g, 8.66 mmol, 55.6percent) as a light brown solid. This was used directly in the next step without further purification. LCMS m/z [M+H]=256.

Reference： [1]Patent: US2013/178460,2013,A1 .Location in patent: Paragraph 0251; 0252

77
[ 20511-15-3 ]
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid thiazolo[4,5-c]pyridine-2-ylamide [ No CAS ]

Reference： [1]Patent: US2013/178460,2013,A1

78
[ 110-91-8 ]
[ 20511-15-3 ]
[ 90648-26-3 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl acetamide; at 200℃; for 30h;	A solution of <strong>[20511-15-3]4-chloropyridin-3-amine</strong> (0.5 g, 3.89 mmol) and morpholine (0.68 g, 7.78 mmol) in DMAC (10 mL) was heated at 200 C for 30 h. After cooling to room temp, water was added and the solid was purified by column chromatography to give 4- morpholinopyridin-3-amine. MS (ESI) calcd for C9H13N3O: 179.11
	In N,N-dimethyl acetamide; at 200℃; for 30h;	A solution of <strong>[20511-15-3]4-chloropyridin-3-amine</strong> (0.5 g, 3.89 mmol) and morpholine (0.68 g, 7.78 mmol) in DMAC (10 mL) was heated at 200 C for 30 h. After cooling to room temp, water was added and the solid was purified by column chromatography to give 4-morpholinopyridin-3-amine. MS (ESI) calcd for C9H13N3O: 179.11

Reference： [1]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 169
[2]Patent: EP2768509,2017,B1 .Location in patent: Paragraph 0636; 0637

79
[ 20511-15-3 ]
[ 5720-06-9 ]
3-amino-4-(2-methoxyphenyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17 g	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In 1,4-dioxane; for 36h;Reflux;	To apre-mixed solution of tris(dibenzylideneacetone)dipalladium (5.83mmol, 5.34g) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (11.67mmol, 4.79g) in dioxane (120mL) was added 4-chloropyridin-3 -amine (117mmol, 15g), 2M Na2C03 (351mmol) and 2- methoxyboronic acid (152mmol, 23.05g). The mixture was diluted with an additional lOOmL of dioxane and refluxed for 36 h. The reaction was complete as judged by LCMS and TLC. The solution was allowed to cool to RT and diluted with EtOAc (lOOmL). The organic layer was washed with water and brine and dried with MgS04. The solution was filtered and concentrated under vacuum. The crude product was purified by chromatography on silica gel, eluting with EtOAc / Hexane to afford the title compound (17g). LC/MS: m/e 201.2 (M+H). 1H NMR (500 MHz, CDC13): delta 8.17 (IH, s), 8.08 (IH, d), 7.43 (1, t), 7.27 (IH, dd), 7.09 (IH, t), 7.05 (IH, d), 7.04 (IH, s), 3.85 (3H, s), 3.78 (2H, s).

Reference： [1]Patent: WO2013/62887,2013,A1 .Location in patent: Page/Page column 45-46

80
[ 20511-15-3 ]
[ 401-95-6 ]
N-((3,5-bis(trifluoromethyl)phenyl)methylene)-4-chloropyridine-3-amine [ No CAS ]