[ CAS No. 796851-03-1 ] {[proInfo.proName]}

Name: 796851-03-1|2,5-Dichloro-4-iodopyridine|98%
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SKU: A133886
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Quality Control of [ 796851-03-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 796851-03-1 ]

SDS Specification

Alternatived Products of [ 796851-03-1 ]

Product Details of [ 796851-03-1 ]

CAS No. :	796851-03-1	MDL No. :	MFCD13185538
Formula :	C₅H₂Cl₂IN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IWCZLVRNVBSAPH-UHFFFAOYSA-N
M.W :	273.89	Pubchem ID :	53400965
Synonyms :

Calculated chemistry of [ 796851-03-1 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	46.97
TPSA :	12.89 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.78 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.07
Log Po/w (XLOGP3) :	3.09
Log Po/w (WLOGP) :	2.99
Log Po/w (MLOGP) :	2.6
Log Po/w (SILICOS-IT) :	3.67
Consensus Log Po/w :	2.89

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.98
Solubility :	0.0288 mg/ml ; 0.000105 mol/l
Class :	Soluble
Log S (Ali) :	-3.03
Solubility :	0.257 mg/ml ; 0.000937 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.21
Solubility :	0.017 mg/ml ; 0.0000622 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.06

Safety of [ 796851-03-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 796851-03-1 ]

* 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 [ 796851-03-1 ]
Downstream synthetic route of [ 796851-03-1 ]

[ 796851-03-1 ] Synthesis Path-Upstream 1~6

1
[ 16110-09-1 ]
[ 796851-03-1 ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; 2-Methylpentane at -78℃; for 1.5 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuran; 2-Methylpentane at -78℃; Inert atmosphere	a) A solution of 2,5-dichloropyridine (10 g, 67.57 mmol) in THF (17 mL) was added dropwise to a stirred solution of n-BuLi in isohexane (33.8 mL, 67.57 mmol) and diisopropylamine (9.63 mL, 67.57 mmol) in THF (68.0 mL) cooled to -78⁰C, over a period of 1 hour under a nitrogen atmosphere. The resulting mixture was stirred at -78⁰C for 30 minutes and then a solution of I₂ (17.49 g, 68.92 mmol) in THF (17.0 mL) was added dropwise. The resulting solution was stirred at -78 ⁰C for 1 hour and then quenched with water (75 mL) and allowed to warm to room temperature. The mixture was extracted with Et₂O (3x 100 mL) and the combined organic layers were dried over MgSO₄, and then evaporated. The residue was triturated with CH₂Cl₂ to give a solid which was dried under vacuum to afford 2,5-dichloro-4-iodopyridine (9.72 g, 53percent yield). The filtrate was evaporated and the residue purified by chromatography on silica, eluting with a gradient of 50-100percent CH₂Cl₂ in isohexane. Fractions containing product were combined and evaporated and the residue triturated with MeOH to leave a second crop of 2,5-dichloro-4- iodopyridine (5.74 g, 31percent yield); ¹H NMR spectrum: (300 MHz, DMSO) δ 7.85 (IH, s), 8.34 (IH, s).

Reference： [1] Tetrahedron Letters, 2004, vol. 45, # 42, p. 7873 - 7877
[2] Patent: WO2009/153589, 2009, A1, . Location in patent: Page/Page column 117
[3] Patent: WO2009/66786, 2009, A1, . Location in patent: Page/Page column 120
[4] Patent: US2017/29404, 2017, A1, . Location in patent: Paragraph 0267-0269
[5] ACS Chemical Neuroscience, 2017, vol. 8, # 9, p. 1980 - 1994

2
[ 16110-09-1 ]
[ 942206-23-7 ]
[ 1353056-41-3 ]
[ 1353056-42-4 ]
[ 796851-03-1 ]

Reference： [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297

3
[ 81290-20-2 ]
[ 796851-03-1 ]
[ 1156542-30-1 ]

Reference： [1] Patent: WO2009/66786, 2009, A1, . Location in patent: Page/Page column 123

4
[ 81290-20-2 ]
[ 796851-03-1 ]
[ 89719-92-6 ]

Reference： [1] Patent: WO2009/66786, 2009, A1, . Location in patent: Page/Page column 120-121

5
[ 796851-03-1 ]
[ 1224887-10-8 ]

Reference： [1] Patent: WO2013/3575, 2013, A1,

6
[ 16110-09-1 ]
[ 942206-23-7 ]
[ 1353056-41-3 ]
[ 1353056-42-4 ]
[ 796851-03-1 ]

Reference： [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297

[ 796851-03-1 ] Synthesis Path-Downstream 1~88

2
[ 81290-20-2 ]
[ 796851-03-1 ]
[ 89719-92-6 ]

Yield	Reaction Conditions	Operation in experiment
		<Reference Production Example 9>Copper iodide (1.67 g) and potassium fluoride (0.51 g) were subjected to a reduced pressure (1 Torr) using a vacuum pump, and were heated with a heat gun for 20 minutes while stirring slowly. Under the argon atmosphere, 14 ml of N- <n="122"/>methylpyrrolidine and 1.25 g of trifluoromethyltrimethylsilane were added, and a temperature was elevated to 5O0C over 20 minutes. After further stirring for 30 minutes, 2 g of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> was added, and the mixture was stirred for 20 hours. After allowing to cool, the reaction solution was poured into a 12% aqueous ammonia solution, the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1 g of 2,5-dichloro-4-trifluoromethylpyridine. 2, 5 -Dichloro-4-trifluoromethylpyridine1H-NMR: 7.62 (s, IH), 8.55 (s, IH)19F-NMR: -64.53 (s, 3H)

Reference： [1]Patent: WO2009/66786,2009,A1 .Location in patent: Page/Page column 120-121

3
[ 81290-20-2 ]
[ 796851-03-1 ]
[ 1156542-30-1 ]

Yield	Reaction Conditions	Operation in experiment
		<Reference Production Example 13>Copper iodide (1.51 g) and potassium fluoride (0.46 g) were subjected to a reduced pressure (1 Torr) using a vacuum pump, and were heated with a heat gun for 20 minutes while stirring slowly. Under the argon atmosphere, 13 ml of N- methylpyrrolidine and 1.13 g of trifluoromethyltrimethylsilane were added at room temperature, and a temperature was elevated to 50C over 20 minutes. After further stirring for 1 hour, 2 g of 2-bromo-5-fluoro-4-iodopyridine was added, and the mixture was stirred for 23 hours. After allowing to cool; the reaction solution was poured into a 12 % aqueous ammonia solution, and the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.8 g of 2-bromo-5-fluoro-4- trifluoromethylpyridine. 2-Bromo-5-fluoro-4-trifluoromethylpyridine1H-NMR: 7.71 (d, IH), 8.45 (s, IH) 19F-NMR: -63.58 (d, 3H), -131.87-131.82 (m, IH)

Reference： [1]Patent: WO2009/66786,2009,A1 .Location in patent: Page/Page column 123

4
[ 133776-41-7 ]
[ 796851-03-1 ]
[ 1201935-46-7 ]

Yield	Reaction Conditions	Operation in experiment
33%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere;	a) Palladium(II) acetate (0.066 g, 0.29 mmol) was added to 2,5-dichloro-4- iodopyridine (2 g, 7.30 mmol), 2-amino-N-methoxy-N-methylbenzamide (1.316 g, 7.30 mmol), cesium carbonate (4.76 g, 14.60 mmol) and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (0.254 g, 0.44 mmol) in dioxane (100 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 800C for 18 hours and then allowed to cool to room temperature. The mixture was filtered and the filtrate evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-5% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to afford 2- [(2,5-dichloropyridin-4-yl)amino]-N-methoxy-N-methylbenzamide (0.775 g, 33% yield);10 1H NMR spectrum: (300 MHz, DMSO) delta 3.18 (3H, s), 3.48 (3H, s), 6.61 (IH, d), 7.34 - 7.40 (IH, m), 7.45 - 7.47 (IH, m), 7.54 - 7.57 (2H, m), 8.19 (IH, s), 8.47 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 326.0 and 328.0 and 330.0.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 131

5
[ 878160-07-7 ]
[ 127-19-5 ]
[ 796851-03-1 ]
2-((2,5-dichloropyridin-4-yl)amino)-N-methyl-5-(4-methylpiperazin-1-yl)benzamide DMA adduct [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; at 100℃; for 1h;Inert atmosphere; Microwave irradiation;	a) A mixture of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (0.56 g, 2.04 mmol), 2-amino-N-methyl- 5-(4-methylpiperazin-l-yl)benzamide (0.508 g, 2.04 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (0.071 g, 0.12 mmol), cesium carbonate (1.332 g, 4.09 mmol) and palladium(II) acetate (0.018 g, 0.08 mmol) was suspended in DMA (15 mL). The mixture was heated at 1000C for 1 hour in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first using MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford 2-[(2,5-dichloropyridin-4- yl)amino]-N-methyl-5-(4-methylpiperazin-l-yl)benzamide as a DMA adduct (0.990 g); 1H NMR spectrum: (300 MHz, DMSO) delta 2.23 (3H, s), 2.44 - 2.50 (4H, m), 2.73 (3H, d), 3.16 - 3.21 (4H, m), 6.90 (IH, s), 7.10 - 7.14 (IH, m), 7.20 (IH, d), 7.40 (IH, d), 8.19 (IH, s), 8.58 (IH, d), 9.67 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 394.09.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 145

6
7-amino-2-methylisoindolin-1-one [ No CAS ]
[ 796851-03-1 ]
[ 1201935-55-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 0.5h;Inert atmosphere; Microwave irradiation;	a) A mixture of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (0.2 g, 0.73 mmol), 7-amino-2-methyl- 3H-isoindol-l-one (0.118 g, 0.73 mmol), palladium(II) acetate (6.56 mg, 0.03 mmol), 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (0.025 g, 0.04 mmol) and cesium carbonate (0.476 g, 1.46 mmol) were suspended in dioxane (5 mL). The mixture was heated at 1000C for 30 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first with MeOH and then with a 7M solution OfNH3 in MeOH. Fractions containing product were combined and evaporated. A solid recovered from the top of the column was washed with water, dried in vacuo, and combined with the evaporated residue to afford 7-[(2,5-dichloropyridin-4- yl)amino]-2-methyl-3H-isoindol-l-one (0.160 g, 71% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 3.07 (3H, s), 4.50 (2H, s), 7.25 - 7.28 (IH, m), 7.48 (IH, s), 7.56 - 7.63 (2H, m), 8.36 (IH, s), 9.80 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 308.01 and 309.97 and 311.99.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 143

7
[ 869936-86-7 ]
[ 796851-03-1 ]
[ 1201935-60-5 ]

Yield	Reaction Conditions	Operation in experiment
26%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere;	a) A mixture of palladium(II) acetate (53.4 mg, 0.24 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (206 mg, 0.36 mmol), cesium carbonate (3875 mg, 11.89 mmol), 2-amino-6-fluoro-N-methylbenzamide (1000 mg, 5.95 mmol) and 2,5-dichloro-4- iodopyridine (1710 mg, 6.24 mmol) in dioxane (50 mL) under an atmosphere of nitrogen washeated at 800C for 18 hours. The mixture was allowed to cool to room temperature, <n="152"/>filtered and then evaporated.The residue was dissolved in EtOAc (150 rnL) and the mixture washed sequentially with a saturated solution of NaHCO3 (2x 100 mL), water (100 mL) and then with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford 2-[(2,5-dichloropyridin-4-yl)amino]-6-fluoro-N- methylbenzamide (486 mg, 26% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 2.74 (3H, d), 6.96 (IH, d), 7.15 (IH, ddd), 7.37 (IH, d), 7.54 (IH, td), 8.26 (IH, s), 8.54 (IH, m), 9.09 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 314.26 and 316.21 and 318.23.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 150-151

8
[ 1201935-49-0 ]
[ 796851-03-1 ]
[ 1201935-48-9 ]

Yield	Reaction Conditions	Operation in experiment
48%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 0.5h;Inert atmosphere; Microwave irradiation;	a) 2,5-Dichloro-4-iodopyridine (0.2 g, 0.73 mmol), 6-amino-4-methyl-2,3-dihydro- l,4-benzoxazepin-5-one (0.140 g, 0.73 mmol), palladium(II) acetate (6.56 mg, 0.03 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.025 g, 0.04 mmol) and cesium carbonate (0.476 g, 1.46 mmol) were suspended in dioxane (5 mL). The mixture was <n="134"/>heated at 1000C for 30 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first with MeOH and then with a 7M solution OfNH3 in MeOH. Fractions containing product were combined and evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-5% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to afford 6-[(2,5-dichloropyridin-4-yl)amino]-4-methyl-2,3- dihydro-l,4-benzoxazepin-5-one (0.118 g, 48% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 3.10 (3H, s), 3.55 (2H, t), 4.34 (2H, t), 6.88 - 6.91 (IH, m), 7.13 (IH, s), 7.36 - 7.39 (IH, m), 7.50 (IH, t), 8.26 (IH, s), 9.31 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 337.96 and 339.99 and 341.96.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 132-133

9
[ 878155-22-7 ]
[ 796851-03-1 ]
[ 1201935-52-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere;	a) Palladium(II) acetate (0.093 g, 0.41 mmol) was added to 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (0.360 g, 0.62 mmol), cesium carbonate (6.76 g, 20.74 mmol), <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (2.84 g, 10.37 mmol) and 8-amino-2-methyl-3,4- dihydroisoquinolin-1-one (1.827 g, 10.37 mmol) in dioxane (100 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 800C for 18 hours then allowed to cool to room temperature. The mixture was filtered and then evaporated. The residue was dissolved in EtOAc (100 mL), and washed sequentially with a saturated solution of NaHCtheta3 (50 mL), water (50 mL), and finally with a saturated solution of NaCl (50 mL). The organic layer was separated, dried over MgSO4, and then evaporated. The residue was triturated with Et2O to leave a solid. The solid was purified by chromatography on silica, eluting with a gradient of 0-5% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to afford 8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4- dihydroisoquinolin-1-one (2.398 g, 72% yield); 1U NMR spectrum: (300 MHz, DMSO) delta 2.97 (2H, t), 3.05 (3H, s), 3.57 (2H, t), 7.00 (IH, m), 7.34 (IH, s), 7.44 - 7.51 (2H, m), 8.31 (IH, s), 11.63 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 322.29 and 324.28 and 326.29.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 136

10
[ 4141-08-6 ]
[ 796851-03-1 ]
[ 1061358-83-5 ]

Yield	Reaction Conditions	Operation in experiment
57.8%	With palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; for 11h;Reflux; Inert atmosphere;	2-Amino-N-methylbenzamide (2.00 g, 13.3 mmol), <strong>[796851-03-1]2,5-dichloro-4-iodo-pyridine</strong> (3.65 g, 13.3 mmol), potassium phosphate (5.92 g, 33.3 mmol), Pd(OAc) 2 (0.06 g, 0.3 mmol), DPEphos (0.59 g,1.1 mmol) was sequentially added to a 250 mL double-necked round bottom flask, and the temperature was refluxed for 11 h under N2 protection, and the material disappeared by TLC. Adjust pH to about 6 with a small amount of concentrated hydrochloric acid, filter with celite, spin dry the filtrate to give a yellow solid, and then use 10mL (THF / MeOH = 1)Slurry, filter, wash with a little MeOH, leave the filter cake,Obtained 2.28 g of a yellow-white solid with a yield of 57.8%.
56%	With potassium phosphate; bis[2-(diphenylphosphino)phenyl] ether;palladium diacetate; In 1,4-dioxane;Heating;	1a) 2-[(2,5-Dichloro-4-pyridinyl)amino]-N-methylbenzamide A 150-mL sealed tube was charged with <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (3.5 g, 12.78 mmol), 2-amino-N-methylbenzamide (1.919 g, 12.78 mmol) and tripotassium phosphate (8.14 g, 38.3 mmol) in 1,4-dioxane (100 mL). The reaction mixture was degassed with nitrogen for 10 min. Bis(2-diphenylphosphinophenyl)ether (DPEPhos, 0.688 g, 1.278 mmol) and Pd(OAc)2 (0.115 g, 0.511 mmol) were added and the reaction mixture was heated in a 120 C. oil bath over night. The reaction mixture was filtered through celite, which was washed with dioxane. The solvent was evaporated to dryness and the solid was washed with EtOH (10 mL*3) to give 2.14 g (56%) of product as an off white solid.
	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere;	a) Palladium(II) acetate (0.393 g, 1.75 mmol) was added to 2,5-dichloro-4- iodopyridine (12 g, 43.81 mmol), 2-amino-N-methylbenzamide (6.58 g, 43.81 mmol), cesium carbonate (28.6 g, 87.63 mmol) and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (1.521 g, 2.63 mmol) in dioxane (600 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 8O0C for 18 hours, allowed to cool to room temperature and then filtered. The filtrate was evaporated and the residue triturated with CH2Cl2 to leave 2-[(2,5-dichloropyridin-4-yl)amino]-N-methylbenzamide (6.306 g, 48% yield). The CH2Cl2 solution was evaporated and the residue triturated with CH2Cl2 to leave a second crop of 2-[(2,5-dichloropyridin-4-yl)amino]-N-methylbenzamide (1.87 g, 14% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 2.78 (2H, d), 7.19 - 7.21 (2H, m), 7.54 - 7.60 (2H, m), 7.73 (IH, d), 8.28 (IH, s), 8.70 (IH, d), 10.41 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 296.0 and 298.0 and 300.0.

Reference： [1]Patent: CN108948019,2018,A .Location in patent: Paragraph 0435; 0439; 0440
[2]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 13
[3]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 120

11
[ 1017789-26-2 ]
[ 796851-03-1 ]
[ 1201935-59-2 ]

Yield	Reaction Conditions	Operation in experiment
50%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;	a) Palladium(II) acetate (35.9 mg, 0.16 mmol) was added to 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (139 mg, 0.24 mmol), cesium carbonate (2604 mg, 7.99 mmol), <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (1094 mg, 4.00 mmol) and 2-amino-3-fluoro-N- methylbenzamide (672 mg, 4.00 mmol) in dioxane (20 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 800C for 24 hours and then allowed to <n="150"/>cool to room temperature. The mixture was evaporated and the residue dissolved in EtOAc (150 mL) and then washed sequentially with a saturated solution of NaHCO3 (100 mL), water (100 mL), and then with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were evaporated to afford 2-[(2,5-dichloropyridin-4-yl)amino]-3-fluoro-N- methylbenzamide (624mg, 50% yield); 1U NMR spectrum: (300 MHz, DMSO) delta IH NMR (300.132 MHz, DMSO) delta 2.74 (3H, d), 6.39 (IH, d), 7.42 (IH, td), 7.49 - 7.59 (2H, m), 8.25 (IH, s), 8.64 (IH, m), 9.31 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 314.20 and 316.20 and 318.17.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 148-149

12
[ 881415-15-2 ]
[ 796851-03-1 ]
[ 1201935-57-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl acetamide; at 100℃; for 1h;Inert atmosphere; Microwave irradiation;	a) A mixture of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (0.4Og, 1.46 mmol), 7-amino-2-methyl-4- (4-propan-2-ylpiperazin-l-yl)-3H-isoindol-l-one (0.421 g, 1.46 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (0.051 g, 0.09 mmol), cesium carbonate (0.952 g, 2.92 mmol) and palladium(II) acetate (0.013 g, 0.06 mmol) was suspended in DMA (15 mL). The mixture was heated at 1000C for 1 hour in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first with MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford 7-[(2,5-dichloropyridin-4- yl)amino]-2-methyl-4-(4-propan-2-ylpiperazin-l-yl)-3H-isoindol-l-one (0.630 g, 99% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 1.01 - 1.18 (3H, d), 2.60 - 2.64 (4H, m), 3.04 - 3.09 (5H, m), 4.51 (2H, s), 7.16 (IH, d), 7.29 (IH, s), 7.50 (IH, d), 8.28 (IH, s), 9.59 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 434.0 and 436.0 and 438.0.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 147

13
[ 40928-15-2 ]
[ 796851-03-1 ]
[ 1201935-41-2 ]

Yield	Reaction Conditions	Operation in experiment
53%	With potassium phosphate; bis[2-(diphenylphosphino)phenyl] ether;palladium diacetate; In 1,4-dioxane; at 110℃;	2-(2,5-Dichloropyridin-4-ylamino)-N-methoxy-benzamide (CR637-KS210635-027A1) A mixture of <strong>[796851-03-1]2,5-dichloro-4-iodo-pyridine</strong> (40 g, 146.5 mmole, 1 eq), 2-amino-N-methoxy-benzamide (24.32 g, 146.5 mmole, 1 eq) and K3PO4(77.72 g 366.2 mmole, 2.5 eq) in 1,4-dioxane (600 mL) was degassed with N2 for 1 h. To this were added Pd(OAc)2 (0.657 g, 2.93 mmole, 0.02 eq), DPEPhos (6.31 g, 11.7 mmole, 0.08 eq) and again degassed for 15 min with N2. The resulting mixture was stirred at 110 C. for overnight. After completion of reaction, solid material was collected by filtration, dissolved in water (500 mL) and extracted with ethyl acetate (5*200 mL). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Solid compound so obtained was purified by washing with hexane to give the title compound as yellowish solid (40 g, 53%). 1H-NMR (400 MHz, DMSO-d6): delta 3.63 (s, 3H), 7.06 (s, 1H), 7.15-7.22 (m, 1H), 7.48-7.57 (m, 2H), 7.66-7.67 (d, 1H, J=7.48 Hz), 8.25 (s, 1H), 10.66-11.45 (brs, 1H). LC-MS [M+H]+=312.3.
48.8%		2-Amino-N-methoxybenzamide (4.00 g, 24.1 mmol), <strong>[796851-03-1]2,5-dichloro-4-iodo-pyridine</strong> (6.60 g, 24.1 mmol) and potassium phosphate (12.80 g, 60.30 mmol) Add a 250 mL two-neck round bottom flask in turn.Add 180mL of 1,4-dioxane,Stir at room temperature for 10 min under N2 protection, then add Pd(OAc) 2 (0.11 g, 0.49 mmol), DPEphos (1.05 g,1.95mmol), under the protection of N2, the temperature was refluxed for 8 hours, and the raw materials disappeared by TLC. Filter and spin dry, sample by silica gel column chromatography, eluent(PE: EA = 2:1), 3.67 g of pale yellow powder was obtained, and the yield was 48.8%.
33%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80 - 85℃; for 42h;Inert atmosphere;	a) Palladium acetate (0.071 g, 0.32 mmol) was added under a nitrogen atmosphere to2-amino-N-methoxybenzamide (1.32 g, 7.94 mmol) in dioxane (80 mL) containing 2,5- dichloro-4-iodopyridine (2.176 g, 7.94 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (0.276 g, 0.48 mmol) and cesium carbonate (5.18 g, 15.89 <n="118"/>mmol). The resulting suspension was heated at 8O0C for 18 hours and then at 850C for a further 24 hours. The mixture was filtered through Celite and then concentrated in vacuo. The residue was diluted with MeOH and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a 7N solution OfNH3 in MeOH. Fractions containing product were combined and then evaporated. The residue was triturated with Et2O to leave 2-[(2,5-dichloropyridin-4-yl)amino]-N-methoxybenzamide (0.823 g, 33% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 3.66 (3H, s), 7.02 (IH, s), 7.26 (IH, m), 7.38 (IH, m), 7.56 - 7.64 (2H, m), 8.27 (IH, s), 9.66 (IH, s), 11.88 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 311.93 and 313.96 and 315.92.

Reference： [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 28-29
[2]Patent: CN108948019,2018,A .Location in patent: Paragraph 0372; 0376; 0377
[3]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 116-117

14
[ 1224888-02-1 ]
[ 796851-03-1 ]
[ 1224887-33-5 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In 1,4-dioxane; at 120℃;Sealed tube;	Example 66 2-[(2,5-Di chloro-4-pyridinyl)amino]-5-[4-(2-hydroxyethyl)-1-piperazinyl]-N-methylbenzamide 6 A sealed tube was charged with <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong>, 2-amino-5-[4-(2-hydroxyethyl)-1-piperazinyl]-N-methylbenzamide 4, and cesium carbonate in 1,4-dioxane. The reaction mixture was degassed by nitrogen for 10 min. At same time BINAP and palladium(II) acetate were added into it and the reaction mixture was heated in 120 C. in an oil bath over night. TLC in 10% EtOAc/hexane showed no <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong>. TLC in 10% MeOH/CH2Cl2 showed no 2-amino-5-[4-(2-hydroxyethyl)-1-piperazinyl]-N-methylbenzamide. LCMS showed the reaction had a peak that could be the desired product. While the reaction mixture temperature was maintained at around 80 C., it was filtered, and the solid was washed with THF and CH3CN. The solid was filtered, dried by vacuum, and purified by flash column 1-8% MeOH/CH2Cl2, to give the captioned product as a brown oil. MS (ES) m/e 426 [M+2H].

Reference： [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 38

15
[ 118-92-3 ]
[ 796851-03-1 ]
[ 1184931-56-3 ]

Yield	Reaction Conditions	Operation in experiment
60.2%	With potassium phosphate; bis[2-(diphenylphosphino)phenyl] ether;palladium diacetate; for 44h;Heating;	2-[(2,5-Dichloro-4-pyridinyl)amino]benzoic acid A mixture of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (10 g, 36.5 mmol), 2-aminobenzoic acid (4.85 g, 35.4 mmol), DPEPhos [bis(2-diphenylphosphinophenyl)ether] (1.6 g, 2.97 mmol), palladium(II) acetate (160 mg, 0.713 mmol) and K3PO4 (20 g, 94 mmol) was degassed and heated at 120 C. (oil bath temp) for 20 h. After 20 h, LCMS showed there was 33% (relative to the desired product) starting material left. Added another 160 mg of Pd(OAc)2 to the mixture, and heated to 120 C. for another 24 h. LCMS showed conversion complete. The mixture was cooled to room temperature, followed by filtration, and washing with EtOAc. The solids were acidified to pH=7-8, followed by filtration. However, the mixture was a paste, and collected solids could not be dried completely. The solids (11 g) was acidified with 6N HCl to pH=1. The resulting paste was filtered, and washed with water and TBME. The solid was dried under vacuum over P2O5 for 2 days to give the title compound (7.32 g, 60.2% yield). MS: M (C12H8Cl2N2O2)=283.11, (M+H)+=283.8; 1H NMR (400 MHz, DMSO) delta ppm 13.6 (s, 1H) 10.2 (s, 1H) 8.3 (s, 1H) 8.0 (d, 1H) 7.6 (q, 2H) 7.3 (s, 1H) 7.2 (m, 1H).

Reference： [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 21

16
[ 1885-29-6 ]
[ 796851-03-1 ]
[ 1224887-80-2 ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium triphosphate; bis[2-(diphenylphosphino)phenyl] ether;palladium diacetate; In 1,4-dioxane; for 18h;Reflux;	2-[(2,5-Dichloro-4-pyridinyl)amino]benzonitrile The solution of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (100 g, 365 mmol), 2-aminobenzonitrile (43.1 g, 365 mmol) and potassium triphosphate (233 g, 1095 mmol) in 1,4-dioxane (2.5 L) was degassed by N2 stream. To this solution was added DPEPhos (15.73 g, 29.2 mmol) and palladium acetate (3.28 g, 14.60 mmol). The reaction mixture was stirred at reflux for 18 hour. The solution was filtered through 0.5 in. celite and 0.2 inch of silica. The solution was evaporated. Solid was suspended in the diethyl ether and filtered. Diethyl ether was concentrated, and the resulting solid was filtered. 2-[(2,5-Dichloro-4-pyridinyl)amino]benzonitrile (80 g, 288 mmol, 79% yield) was isolated as an orange solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 6.49 (s, 1H) 7.50 (td, J=7.58, 1.01 Hz, 1H) 7.56 (d, J=7.58 Hz, 1H) 7.80 (td, J=7.83, 1.77 Hz, 1H) 7.95 (dd, J=7.83, 1.52 Hz, 1H) 8.26 (s, 1H) 9.05 (brs, 1H); HPLC Rt=2.88 min, MS (ESI): 263.9, 265.9 [M+H]+.
79%	With potassium triphosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; for 18h;Inert atmosphere; Reflux;	Intermediate 12-[(2,5-Dichloro-4-yridinyl)amino1benzonitrileThe solution of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (100 g, 365 mmol), 2-aminobenzonitrile (43.1 g, 365 mmol) and potassium triphosphate (233 g, 1095 mmol) in 1,4-dioxane (2.5 L)was degassed by N2 stream. To this solution was added DPEPhos (15.73 g, 29.2 mmol)and palladium acetate (3.28 g, 14.60 mmol). The reaction mixture was stirred at reflux for18 hour. The solution was filtered through 0.5 in. celite and 0.2 inch of silica. The solutionwas evaporated. Solid was suspended in the diethyl ether and filtered. Diethyl ether was concentrated, and the resulting solid was filtered. 2-[(2,5-Dichloro-4- pyridinyl)amino]benzonitrile (80 g, 288 mmol, 79 % yield) was isolated as an orange solid. 1 H NMR (400 MHz, DMSO-d6) 6 ppm 6.49 (s, 1 H) 7.50 (td, J=7.58, 1.01 Hz, 1 H) 7.56 (d, J=7.58 Hz, 1 H) 7.80 (td, J=7.83, 1 .77 Hz, 1 H) 7.95 (dd, J=7.83, 1 .52 Hz, 1 H) 8.26 (s, 1H) 9.05 (brs, 1 H); HPLC Rt= 2.88 mm, MS (ESI): 263.9, 265.9 [M+H].

Reference： [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 24
[2]Patent: WO2013/3575,2013,A1 .Location in patent: Page/Page column 53; 54

17
[ 80517-22-2 ]
[ 1124-16-9 ]
[ 796851-03-1 ]
[ 1224888-13-4 ]

Yield	Reaction Conditions	Operation in experiment
33.9%		Step 1 To a degassed solution of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (5 g, 18.26 mmol), 2-amino-4-fluorobenzonitrile (2.485 g, 18.26 mmol) and potassium triphosphate (11.63 g, 54.8 mmol) in 1,4-dioxane (60 ml) stirred under nitrogen at the room temperature was added DPEPhos (0.787 g, 1.460 mmol) and palladium acetate (0.164 g, 0.730 mmol). The reaction mixture was stirred at the reflux for 18 hr. The reaction mixture was filtered. 3-Methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (2.54 g, 18.26 mmol) and cesium carbonate (17.84 g, 54.8 mmol) were added. The reaction mixture was degassed and palladium acetate (0.164 g, 0.730 mmol) and DPEPhos (0.787 g, 1.460 mmol) were added. The reaction mixture was refluxed overnight. The reaction mixture was filtered. NaOH (60 mL, 60.0 mmol) was added and the reaction mixture refluxed overnight. Ethyl acetate was added and the layers were separated. The combined organics were washed with 1 M NaOH (40 ml). The combined aqueous layers were washed with ethyl acetate, and neutralized with acetic acid. 2-[(5-Chloro-2-[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-4-fluorobenzoic acid (2.5 g, 6.19 mmol, 33.9% yield) was isolated by filtration as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.29 (d, J=6.57 Hz, 6H) 2.12 (s, 3H) 4.43 (quin, J=6.57 Hz, 1H) 5.99 (s, 1H) 6.86 (s, 1H) 6.87-6.93 (m, 1H) 7.34 (dd, J=11.62, 2.53 Hz, 1H) 8.03-8.10 (m, 2H) 8.62 (s, 1H) 10.65 (br. s., 1H); HPLC Rt=2.57 min, MS (ESI): 404.2 [M+H]+.

Reference： [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 42

18
[ 38487-86-4 ]
[ 796851-03-1 ]
[ 1224888-03-2 ]

Yield	Reaction Conditions	Operation in experiment
57.1%	With potassium triphosphate; bis[2-(diphenylphosphino)phenyl] ether;palladium diacetate; In 1,4-dioxane; at 20℃; for 18h;Inert atmosphere; Reflux;	Step 1 To a degassed solution of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (4.5 g, 16.43 mmol), 2-amino-4-chlorobenzonitrile (2.507 g, 16.43 mmol) and potassium triphosphate (10.46 g, 49.3 mmol) in 1,4-dioxane (60 ml) stirred under nitrogen at the room temperature was added DPEPhos (0.708 g, 1.314 mmol) and palladium acetate (0.148 g, 0.657 mmol). The reaction mixture was stirred at the reflux for 18 hr. The reaction mixture was filtered. The solution was evaporated. Ether (50 ml) was added and the formed solid was filtered. 4-chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (2.8 g, 9.38 mmol, 57.1% yield) was isolated as an orange solid. 1H NMR (400 MHz, DMSO-d6) ppm 6.70 (s, 1H) 7.53 (dd, J=8.34, 2.02 Hz, 1H) 7.65 (d, J=2.02 Hz, 1H) 7.95 (d, J=8.34 Hz, 1H) 8.28 (s, 1H) 9.12 (br. s., 1H); HPLC Rt=3.50 min, MS (ESI): 298.0, 300.0 [M+H]+.

Reference： [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 39

19
[ 5922-60-1 ]
[ 796851-03-1 ]
[ 1224888-05-4 ]

Yield	Reaction Conditions	Operation in experiment
33%	With potassium triphosphate; bis[2-(diphenylphosphino)phenyl] ether;palladium diacetate; In 1,4-dioxane; at 20℃;Inert atmosphere; Reflux;	Step 1 To a degassed solution of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (4.5 g, 16.43 mmol), 2-amino-5-chlorobenzonitrile (2.507 g, 16.43 mmol) and potassium triphosphate (10.46 g, 49.3 mmol) in 1,4-dioxane (60 ml) stirred under nitrogen at the room temperature was added DPEPhos (0.708 g, 1.314 mmol) and palladium acetate (0.148 g, 0.657 mmol). The reaction mixture was stirred at reflux for 18 hr. The reaction mixture was filtered. The reaction mixture was evaporated. Ether (50 ml) was added and the solid was filtered. 5-chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (1.8 g, 5.43 mmol, 33.0% yield) was isolated as orange solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 6.63 (s, 1H) 7.52 (d, J=8.59 Hz, 1H) 7.81 (dd, J=8.59, 2.53 Hz, 1H) 8.09 (d, J=2.53 Hz, 1H) 8.24 (s, 1H) 9.06 (br. s., 1H); HPLC Rt=3.53 min, MS (ESI): 298.0, 299.9 [M+H]+.

Reference： [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 39-40

20
[ 61272-77-3 ]
[ 796851-03-1 ]
[ 1224888-08-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium triphosphate; bis[2-(diphenylphosphino)phenyl] ether;palladium diacetate; In 1,4-dioxane; at 20℃;Inert atmosphere; Reflux;	Step 1 To a degassed solution of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (8 g, 29.2 mmol), 2-amino-5-fluorobenzonitrile (3.98 g, 29.2 mmol) and potassium triphosphate (18.60 g, 88 mmol) in 1,4-dioxane (100 ml) stirred under nitrogen at the room temperature was added DPEPhos (1.258 g, 2.337 mmol) and palladium acetate (0.262 g, 1.168 mmol). The reaction mixture was stirred at the reflux for 18 hr. The reaction mixture was filtered. The solvent was evaporated. Ether (50 ml) was added and the solid was filtered. 2-[(2,5-Dichloro-4-pyridinyl)amino]-5-fluorobenzonitrile (7.09 g, 25.1 mmol, 86% yield) was isolated as an orange solid. 1H NMR (400 MHz, METHANOL-d4) delta ppm 6.44 (s, 1H) 7.46-7.58 (m, 2H) 7.66 (dd, J=8.08, 2.78 Hz, 1H) 8.08 (s, 1H); HPLC Rt=3.23 min, MS (ESI): 382.0, 384.19 [M+H]+.

Reference： [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 40

21
[ 16110-09-1 ]
[ 942206-23-7 ]
[ 1353056-41-3 ]
[ 1353056-42-4 ]
[ 796851-03-1 ]

Reference： [1]Chemistry - A European Journal,2011,vol. 17,p. 13284 - 13297

22
[ 287192-97-6 ]
[ 796851-03-1 ]
[ 1382136-80-2 ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 55℃; for 2h;Inert atmosphere;	Copper(l) iodide (0.50 g), bis-(triphenylphosphine)-palladium(ll) chloride (0.50 g), and triethylamine (3.4 ml_) are added successively to a solution of 2,5-dichloro-4-iodo- pyridine (6.54 g) in N,N-dimethylformannide (45 ml_) under Ar atmosphere at room temperature. The resulting mixture is stirred at room temperature for 1 h prior to the addition of 4-ethynyl-piperidine-1 -carboxylic acid tert-butyl ester (5.15 g). The mixture is stirred at 55 C for 2 h. The solvent is evaporated and the residue is diluted with ethyl acetate. The resulting mixture is washed with water and brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 85:15?50:50) to give the title compound. LC (method 3): tR = 1 .66 min; Mass spectrum (ESI+): m/z = 355/357/359 (2 CI) [M+H]+.
		4-(2,5-Dichloro-pyridin-4-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester Copper(I) iodide (0.50 g), bis-(triphenylphosphine)-palladium(II) chloride (0.50 g), and triethylamine (3.4 mL) are added successively to a solution of <strong>[796851-03-1]2,5-dichloro-4-iodo-pyridine</strong> (6.54 g) in N,N-dimethylformamide (45 mL) under Ar atmosphere at room temperature. The resulting mixture is stirred at room temperature for 1 h prior to the addition of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (5.15 g). The mixture is stirred at 55 C. for 2 h. The solvent is evaporated and the residue is diluted with ethyl acetate. The resulting mixture is washed with water and brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 85:15?50:50) to give the title compound. LC (method 3): tR=1.66 min; Mass spectrum (ESI+): m/z=355/357/359 (2 Cl) [M+H]+.

Reference： [1]Patent: WO2013/127828,2013,A1 .Location in patent: Page/Page column 59
[2]Patent: US2013/225601,2013,A1 .Location in patent: Paragraph 0245; 0246

23
[ 1188163-01-0 ]
[ 796851-03-1 ]
[ 1445890-91-4 ]

Yield	Reaction Conditions	Operation in experiment
39%	With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In 1,4-dioxane; at 105℃; for 20h;Sealed tube;	Step 1: ethyl 4-(2-chlorophenyl)-1-(2,5-dichloropyridin-4-yl)-1H-pyrrole-3-carboxylate To a mixture of copper(I) iodide (0.011 g, 0.060 mmol) in 1,4-dioxane (10 mL) were added <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (0.49 g, 1.80 mmol), ethyl 4-(2-chlorophenyl)-1H-pyrrole-3-carboxylate (0.078 g, 0.31 mmol), trans-1,2-bis(methylamino)cyclohexane (0.019 mL, 0.12 mmol) and potassium carbonate (0.25 g, 1.80 mmol). The reaction mixture was allowed to stir at 105 C. in a sealed vessel overnight and then allowed to cool to rt. The contents were filtered through celite and washed with EtOAc. The filtrate was washed with ammonium hydroxide and brine and then concentrated. The reside was purified by column chromatography to give ethyl 4-(2-chlorophenyl)-1-(2,5-dichloropyridin-4-yl)-1H-pyrrole-3-carboxylate (0.048 g, 39%). LCMS (FA): m/z=397.3 (M+H).

Reference： [1]Patent: US2013/165464,2013,A1 .Location in patent: Paragraph 0957

24
[ 796851-03-1 ]
[ 1451163-56-6 ]

Reference： [1]Patent: WO2013/127828,2013,A1
[2]Patent: US2013/225601,2013,A1

25
[ 796851-03-1 ]
[ 1451163-34-0 ]

Reference： [1]Patent: WO2013/127828,2013,A1
[2]Patent: US2013/225601,2013,A1

26
[ 796851-03-1 ]
[ 1451163-35-1 ]

Reference： [1]Patent: WO2013/127828,2013,A1
[2]Patent: US2013/225601,2013,A1

27
[ 796851-03-1 ]
[ 1224887-82-4 ]

Reference： [1]Patent: WO2013/3575,2013,A1

28
[ 796851-03-1 ]
[ 1224887-83-5 ]

Reference： [1]Patent: WO2013/3575,2013,A1

29
[ 796851-03-1 ]
[ 1224887-10-8 ]

Reference： [1]Patent: WO2013/3575,2013,A1

30
[ 796851-03-1 ]
2-[(5-chloro-2-[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-N-(methyloxy)benzamide monohydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/3575,2013,A1

31
[ 173382-28-0 ]
[ 796851-03-1 ]
2-(2,5-dichloropyridin-4-yl)thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60 mg	With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; for 12h;Inert atmosphere; Reflux;	[0234] Method R-Step a: 2-(2,5-Dichloropyridin-4-yl)thiazole [0235] 1 ,2-Diromobutane (40 mg, 0.21 mmol) was added to a suspension of zinc powder (300 mg, 4.61 mmol) in THF (2 mL). The mixture was heated to 50 C for 5 minutes and then TMSCl (20 mg, 0.18 mmol) was added. Meanwhile, a solution of 2-bromothiazole (200 mg, 1.22 mmol) in THF (1 mL) was added dropwise, and the mixture was stirred at 50 C for 1 hour. After that, the solution of 2-thiazolyzinc bromide was injected into a solution of 2,5- dichloro-4-iodopyridine (300 mg, 1.09 mmol) and Pd(PPh3)4 (40 mg, 0.034 mmol) in THF (10 mL). The reaction was carried out at reflux for 12 hours under the nitrogen atmosphere. After that, the mixture was filtered and the filtrate was concentrated and the residue was purified by silica gel column chromatography (Petroleum ether:CH2Cl2= 3:2), to give a white solid (60 mg, 24%). *H NMR (300 MHz, CDC13) delta 8.53 (s, 1H), 8.51 (s, 1H), 8.08-8.07 (m, 1H), 7.68-7.67 (m, 1H).

Reference： [1]Patent: WO2014/113191,2014,A1 .Location in patent: Paragraph 0234; 0235
[2]ACS Chemical Neuroscience,2017,vol. 8,p. 1980 - 1994

32
[ 796851-03-1 ]
6-(5-chloro-4-(thiazol-2-yl)pyridin-2-yl)-N-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: WO2014/113191,2014,A1
[2]ACS Chemical Neuroscience,2017,vol. 8,p. 1980 - 1994

33
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine [ No CAS ]
[ 796851-03-1 ]
5-(2,5-dichloropyridin-4-yl)-2-(trifluoromethyl)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 60℃; for 3h;Inert atmosphere;	Into a 3000-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (120 g, 438.14 mmol, 1.00 equiv), 1,4-Dioxane (1800 mL), water (180 mL), potassium carbonate (182 g, 1.32 mol, 3.00 equiv), 5- (te1ramethyl-l ,3,2-dioxaborolan-2-yl)-2-(1rifiuoromethyl)pyrimidine (132.6 g, 483.86 mmol, 1.10 equiv), and Pd(dppf)Cl2 (6 g, 8.20 mmol, 0.02 equiv). The resulting solution was stirred at 60 C for 3 h, cooled to room temperature, quenched by the addition of 4 L of water/ice, and extracted with 2x2 L of ethyl acetate. The combined organic layers were washed with lxl L of H20 and lxl L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 100) to afford 78 g (61%) of 5-(2,5- dichloropyridin-4-yl)-2-(trifluoromethyl)pyrimidine as a white solid.
53%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 60℃; for 12h;Inert atmosphere;	A mixture of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (3.86 g, 14.09 mmol, 1.00 equiv), 5-(tetramethyl- 1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (4.26 g, 15.54 mmol, 1.10 equiv), potassium carbonate (5.83 g, 42.19 mmol, 2.99 equiv), and Pd(dppf)C12 (516 mg, 0.70 mmol, 0.05 equiv) in dioxane (50 mL)/water (5 mL) was stirred for 12 h at 60C under nitrogen. The solids were filtered out. The filtrate was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with acetate/petroleum ether (1/100) to afford the title compound (2.2 g, 53%) as a yellow solid.

Reference： [1]Patent: WO2018/15410,2018,A1 .Location in patent: Paragraph 0403-0406
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 3641 - 3659
[3]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 02066; 02067

34
6-(trifluoromethyl)-3-pyridinylboronic acid [ No CAS ]
[ 796851-03-1 ]
2,5-dichloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 12h;Inert atmosphere;	A mixture of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (10 g, 36.5 11 mmol, 1.00 equiv), [6- (trifluoromethyl)pyridin-3-yl]boronic acid (6.7 g, 35.094 mmol, 1.00 equiv), Pd(dppf)C12(2.67 g, 3.649 mmol, 0.10 equiv), 1,4-dioxane (250 mL), potassium carbonate (15 g, 108.534 mmol, 3.00 equiv), and water (25 mL) was stirred for 12 h at 80C under nitrogen. The solids were filtered out and the solution was concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:20). This resulted in the title compound (9.9 g, 93%) as a white solid.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01229; 01230

35
[ 796851-03-1 ]
methyl 5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/52264,2015,A1

36
[ 796851-03-1 ]
[5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanol [ No CAS ]

Reference： [1]Patent: WO2015/52264,2015,A1

37
[ 796851-03-1 ]
2-([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione [ No CAS ]

Reference： [1]Patent: WO2015/52264,2015,A1

38
[ 796851-03-1 ]
[5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine [ No CAS ]

Reference： [1]Patent: WO2015/52264,2015,A1

39
[ 796851-03-1 ]
tert-butyl(2S,4R)-2-[([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/52264,2015,A1

40
[ 796851-03-1 ]
(2S,4R)-N-([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/52264,2015,A1

41
[ 796851-03-1 ]
(2S,4R)-N-([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/52264,2015,A1

42
[ 796851-03-1 ]
4-(5-chloro-2-(1-methylpyrazol-4-yl)pyridin-4-yloxy)aniline [ No CAS ]

Reference： [1]Patent: US2017/29404,2017,A1

43
[ 796851-03-1 ]
1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(1-methylpyrazol-4-yl)-5-chloropyridin-4-yloxy)phenyl)urea [ No CAS ]

Reference： [1]Patent: US2017/29404,2017,A1

44
[ 123-30-8 ]
[ 796851-03-1 ]
2,5-dichloro-4-(4-aminophenoxy)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.34 g		Step 2: Synthesis of 2,5-dichloro-4-(4-aminophenoxy)pyridine 4-Aminophenol (1.59 g, 14.6 mmol) was dissolved in anhydrous dimethyl sulfoxide (30 mL), and purged with nitrogen gas for 10 minutes, potassium tert-butoxide (1.68 g, 15 mmol) was added, and then stirred at room temperature for 30 minutes, <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (4 g, 14.6 mmol) was added, then reacted at room temperature for 5 hours, TLC showed that the reaction was finished. Ethyl acetate (80 mL) was added, sufficiently stirred, then water (100 mL) was added. After phase separation, water phase was extracted with ethyl acetate (100 mL3). The ethyl acetate phases were combined, washed with water (150 mL2), washed with saline solution (100 mL*2), dried with anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=4:1, v/v) to get product as light yellow solid (0.34 g, yield: 9.1%). MS (ESI+): 255.0 [M+H]+

Reference： [1]Patent: US2017/29404,2017,A1 .Location in patent: Paragraph 0270-0272

45
[ 796851-03-1 ]
1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(5-chloro-2-(1-methylpyrazol-4-yl)pyridin-4-yloxy)phenyl)urea p-toluene sulfonate [ No CAS ]

Reference： [1]Patent: US2017/29404,2017,A1

46
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine [ No CAS ]
[ 796851-03-1 ]
tert-butyl N-([5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2018/15410,2018,A1

47
[ 14446-75-4 ]
[ 796851-03-1 ]
5-chloro-2-[(3S,5R)-3,5-dimethyl-1-piperidyl]-4-iodopyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 18h;	To <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (SM-8a) (1 .00 g; 3.65 mmol) and SM-4d (413 mg; 3.65 mmol) in DMF (4.0 mL) is added DIPEA (943 mg; 7.30 mmol) and the reaction mixture is stirred at 100 C for 18 h. After cooling to rt the mixture is filtered, evaporated and the residue is purified by preparative RP-HPLC under basic conditions using a MeCN/H20 gradient from 40:60 to 80:20 as eluent over 6 min. The product containing fractions are freeze dried to give 5-chloro-2-[c/s-3,5-dimethylpiperidin-1 -yl]-4-iodopyridine (IM-3"a).

Reference： [1]Patent: WO2018/108704,2018,A1 .Location in patent: Page/Page column 94

48
[ 14446-75-4 ]
[ 796851-03-1 ]
2-[6-({5-chloro-2-[cis-3,5-dimethylpiperidin-1-yl]pyridin-4-yl}amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl]oxy}-N-methylacetamide [ No CAS ]

Reference： [1]Patent: WO2018/108704,2018,A1

49
5-(cyclopropylmethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ No CAS ]
[ 796851-03-1 ]
2,5-dichloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.5%	With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In 1,2-dimethoxyethane; at 80℃; for 2h;Inert atmosphere;	To a mixture of <strong>[796851-03-1]2,5-dichloro-4-iodopyridine</strong> (104-1, 523.13 mg, 1.91 mmol, 1.00 eq) and compound 1 (500.8 mg, 1.91 mmol, 1.0 eq) in DME (10 mL) were added Na2CO3 (2M, 2.87 mL, 3.00 eq) and Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloro palladium (II) (67.62 mg, 95.50 imol, 67.62 iL, 0.05 eq). The resulting mixture was stirred at 80 C for 2 h under nitrogen, cooled to room temperature, concentrated and purified by column chromatography to give 104-2 (200 mg, 659.3 imol, 34.5% yield, 93.0% purity) as a yellow oil. LCMS: RT = 0.825 mi m/z 282.0 [M+Hjt

Reference： [1]Patent: WO2018/142393,2018,A1 .Location in patent: Page/Page column 31

50
[ 1201935-49-0 ]
[ 796851-03-1 ]
[ 1201934-01-1 ]