[ CAS No. 57266-69-0 ] {[proInfo.proName]}

Name: 57266-69-0|3-Chloropicolinic acid|98%
Brand: Ambeed
SKU: A538028
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Quality Control of [ 57266-69-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 57266-69-0 ]

Product Details of [ 57266-69-0 ]

CAS No. :	57266-69-0	MDL No. :	MFCD01646325
Formula :	C₆H₄ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XTMUXJBJCMRWPG-UHFFFAOYSA-N
M.W :	157.55	Pubchem ID :	824632
Synonyms :

Calculated chemistry of [ 57266-69-0 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	36.21
TPSA :	50.19 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) :	-6.31 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.01
Log Po/w (XLOGP3) :	1.34
Log Po/w (WLOGP) :	1.43
Log Po/w (MLOGP) :	-0.51
Log Po/w (SILICOS-IT) :	1.39
Consensus Log Po/w :	0.93

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.04
Solubility :	1.44 mg/ml ; 0.00914 mol/l
Class :	Soluble
Log S (Ali) :	-2.0
Solubility :	1.59 mg/ml ; 0.0101 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.0
Solubility :	1.57 mg/ml ; 0.00998 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.32

Safety of [ 57266-69-0 ]

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

Application In Synthesis of [ 57266-69-0 ]

* 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 [ 57266-69-0 ]
Downstream synthetic route of [ 57266-69-0 ]

[ 57266-69-0 ] Synthesis Path-Upstream 1~12

1
[ 38180-46-0 ]
[ 57266-69-0 ]

Reference： [1] Patent: US4853027, 1989, A,
[2] Patent: CN105218437, 2016, A, . Location in patent: Paragraph 0007

2
[ 1702-17-6 ]
[ 98-98-6 ]
[ 57266-69-0 ]

Reference： [1] Electrochimica Acta, 2016, vol. 210, p. 762 - 772
[2] Electrochimica Acta, 2016, vol. 210, p. 762 - 772

3
[ 72093-03-9 ]
[ 57266-69-0 ]

Reference： [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 11, p. 1827 - 1837

4
[ 98-98-6 ]
[ 57266-69-0 ]

Reference： [1] Tetrahedron, 2002, vol. 58, # 33, p. 6723 - 6728

5
[ 462-08-8 ]
[ 57266-69-0 ]

Reference： [1] Patent: CN105218437, 2016, A,

6
[ 2402-77-9 ]
[ 57266-69-0 ]

Reference： [1] Patent: CN105218437, 2016, A,

7
[ 57841-92-6 ]
[ 57266-69-0 ]

Reference： [1] Synthetic Communications, 1997, vol. 27, # 6, p. 1075 - 1086

8
[ 10354-53-7 ]
[ 57266-69-0 ]

Reference： [1] Synthetic Communications, 1997, vol. 27, # 6, p. 1075 - 1086

9
[ 1462-86-8 ]
[ 57266-69-0 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1932, vol. <2> 133, p. 36,49

10
[ 57266-69-0 ]
[ 114080-95-4 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1932, vol. <2> 133, p. 36,49

11
[ 57266-69-0 ]
[ 60588-81-0 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: With isopropyl chloroformate; triethylamine In tetrahydrofuran at 0 - 20℃; for 1 h; Stage #2: at 20℃; for 2 h;	To a solution of 3-chloropyridine-2-carboxylic acid (2.1 g, 13.33 mmol, 1.00 equiv) in THF (40 mL) was added Et₃N (2.7 g, 26.68 mmol, 2.00 equiv), followed by the addition of chloro(propan-2-yloxy)methanone (2.45 g, 19.99 mmol, 1.50 equiv) dropwise with stirring at 0° C. The solution was strried for 1 h at room temperture. The solid was removed by filtration. To the filtrate was added NaBH₄ (1.53 g, 40.44 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at rt, then diluted with 50 mL of H₂O and extracted with 2*100 mL of EtOAc. The combined organic layers were washed with 50 mL of saturated Nacl, dried over Na₂SO₄, concentrated under vacuum, and purified with silica gel chromatography using with EtOAc/petroleum ether (1:6) to afford 0.9 g (47percent) of the title compound as a colorless oil.

Reference： [1] Patent: US2018/162822, 2018, A1, . Location in patent: Paragraph 0606
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 11, p. 1827 - 1837

12
[ 57266-69-0 ]
[ 206181-90-0 ]

Reference： [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 11, p. 1827 - 1837

[ 57266-69-0 ] Synthesis Path-Downstream 1~87

1
[ 57266-69-0 ]
[ 128073-02-9 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;	EXAMPLE 27; Synthesis of (3-chloropyridin-2-yI)(2-isopropylpyrazolo[l,5-a]pyridin-3-yl)methanone; Picolinic acid was reacted with thionyl chloride to yield the corresponding acid chloride, which was used without purification to acylate 2-isopropylpyrazolo[l,5- a]rhoyridine in the presence of 300mg of AICI3 at RT for 4 days. 5g of crude product were obtained after workup, followed by purification on an AI2O3 column to produce 373mg of (3-chloropyridin-2-yl)(2-isopropylpyrazolo[l ,5-a]pyridin-3-yl)methanone. The structure was assigned by NMR and LC-MS. Compound 1038.
	With thionyl chloride; N,N-dimethyl-formamide; In toluene; for 1h;Reflux;	Step 1 : Synthesis of 3-chloropyridine-2-carbonyl chlorideTo a solution of <strong>[57266-69-0]3-chloropicolinic acid</strong> (20.006 g, 126.98 mmol) in toluene (200 mL) was added thionyl chloride (23.2 mL, 37.8 g, 317 mmol, 2.5 equiv.) and a catalytic amount of DMF (10 drops) and the mixture was heated at reflux for 1 h. After cessation of the gas evolution, the mixture was cooled and all volatiles were removed in vacuum to obtain to obtain the title com- pound (24.38 g, quant.) as a crude product, which was used in the next step without further purification.
	With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 110℃; for 1h;	Step 1 .1 : Synthesis of 3-chloro-pyridine-2-carbonyl chloride To a solution of <strong>[57266-69-0]3-chloropicolinic acid</strong> (20.0 g, 127 mmol) in toluene (200 ml.) was added thionyl chloride (37.7 g, 317 mmol) and dimethylformaide (10 drops). The mixture was heated under reflux (1 10C) for 1 h and evaporated. The residue was taken up into more toluene and evaporated again to give the title product (24.3 g) used in its crude form in the next step.

	With thionyl chloride; N,N-dimethyl-formamide; In toluene; for 1h;Reflux;	To a solution of <strong>[57266-69-0]3-chloropicolinic acid</strong> (20.006 g, 126.98 mmol) in toluene (200 mL) was added thionyl chloride (23.2 mL, 37.8 g, 317 mmol, 2.5 equiv.) and a catalytic amount of DMF (10 drops) and the mixture was heated at reflux for 1 h. After cessation of the gas evolution, the mixture was cooled and all volatiles were removed in vacuum to obtain to obtain the title compound (24.38 g, quant.) as a crude product, which was used in the next step without further purification.
	With thionyl chloride; In toluene; at 120℃; for 20h;Inert atmosphere;	Preparation of (38) 1-Oxo-1-((4?-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (38) Step 1 3-Chloropicolinoyl chloride (34) To a suspension of <strong>[57266-69-0]3-chloropicolinic acid</strong> (1.58 g, 10 mmol) in toluene (6 mL) was added an excess of thionyl chloride (9.52 g, 5.84 mL, 80.0 mmol) at room temperature under a nitrogen atmosphere. The resulting suspension was heated to 120 C. (oil bath temperature) and stirred for 20 h. Then, the solvent and excess of thionyl chloride were removed under vacuum and the residue was dissolved one more time in toluene and the solvent was removed again. The resulting residue was dried under high vacuum and used in the next step.
	With thionyl chloride; N,N-dimethyl-formamide; at 80℃; for 3h;	General procedure: To a solution of 3m-o (5mmol) and catalyzed DMF (3-4 drops) in anhydrous thionyl chloride (20mL) was stirred at 80C for about 3 hours. After cooling to room temperature, the solution was removed under vacuum, the residue was directly used in the next step, without further purified.
	With thionyl chloride;Reflux;	In a 100 ml single-necked reaction flask, 1.6 g (11.2 mmol) of 2- (3-chloropyridine) carboxylic acid was added.20 ml of dichlorosulfoxide, then heated under reflux until the solid completely disappeared,Continue refluxing for 2 to 3 hours, and dry the solvent on a rotary evaporator.Add a small amount of dichloromethane to dissolve it, and then spin dry to remove excess dichlorosulfoxide as much as possible.Then add a certain amount of dichloromethane to dissolve it and use it in the next step.

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 125 - 128
[2]Patent: WO2007/146087,2007,A2 .Location in patent: Page/Page column 60
[3]Patent: WO2013/24004,2013,A1 .Location in patent: Page/Page column 81-82
[4]Patent: WO2013/24171,2013,A1 .Location in patent: Page/Page column 109
[5]Patent: WO2013/24006,2013,A1 .Location in patent: Page/Page column 82;
[6]Patent: US2014/194432,2014,A1 .Location in patent: Paragraph 0228-0231
[7]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3201 - 3204
[8]Patent: CN107602507,2020,B .Location in patent: Paragraph 0075-0078

2
[ 57266-69-0 ]
[ 74-88-4 ]
3-chloro-2-(methoxycarbonyl)pyridine [ No CAS ]

Reference： [1]Synthetic Communications,1997,vol. 27,p. 1075 - 1086

3
[ 57841-92-6 ]
[ 57266-69-0 ]

Reference： [1]Synthetic Communications,1997,vol. 27,p. 1075 - 1086

4
[ 98-98-6 ]
[ 57266-69-0 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 6723 - 6728

5
[ 57266-69-0 ]
[ 60588-81-0 ]

Yield	Reaction Conditions	Operation in experiment
47%		To a solution of <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> (2.1 g, 13.33 mmol, 1.00 equiv) in THF (40 mL) was added Et3N (2.7 g, 26.68 mmol, 2.00 equiv), followed by the addition of chloro(propan-2-yloxy)methanone (2.45 g, 19.99 mmol, 1.50 equiv) dropwise with stirring at 0° C. The solution was strried for 1 h at room temperture. The solid was removed by filtration. To the filtrate was added NaBH4 (1.53 g, 40.44 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at rt, then diluted with 50 mL of H2O and extracted with 2*100 mL of EtOAc. The combined organic layers were washed with 50 mL of saturated Nacl, dried over Na2SO4, concentrated under vacuum, and purified with silica gel chromatography using with EtOAc/petroleum ether (1:6) to afford 0.9 g (47percent) of the title compound as a colorless oil.

Reference： [1]Patent: US2018/162822,2018,A1 .Location in patent: Paragraph 0606
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 1827 - 1837

6
[ 57266-69-0 ]
[ 206181-90-0 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 1827 - 1837

7
[ 57266-69-0 ]
3-chloro-2',6'-dimethyl-5'-nitro-1',4'-dihydro-[2,4']bipyridinyl-3'-carboxylic acid phenethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 1827 - 1837

8
[ 10354-53-7 ]
[ 57266-69-0 ]

Reference： [1]Synthetic Communications,1997,vol. 27,p. 1075 - 1086

9
[ 57266-69-0 ]
[ 83282-18-2 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 125 - 128

10
[ 4418-61-5 ]
[ 57266-69-0 ]
[ 83282-18-2 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;	EXAMPLE 9 0.53 g of <strong>[57266-69-0]3-chloro-2-pyridinecarboxylic acid</strong>, 10 ml of thionyl chloride and 0.27 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.28 g of N-(5-tetrazolyl)-3-chloro-2-pyridinecarboxamide is obtained. M.p. 252-254 C. (decomp.) Sodium salt: M.p. 210-218 C. (decomp.) (The product begins to darken at about 70 C.).

Reference： [1]Patent: US4404214,1983,A

11
[ 38180-46-0 ]
[ 57266-69-0 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; sodium hydroxide; dichloromethane;	64.1 g of 10B was refluxed in 460 ml of 2N aqueous sodium hydroxide solution for 1 hour. The mixture was cooled, acidified to pH=2.5 with concentrated hydrochloric acid, stripped of water under reduced pressure, then azeotroped with methanol. The residue was stirred with 250 ml of a 1:1 v:v mixture of methylene chloride and methanol, and the resulting mixture was filtered. The filtrate was stripped of volatiles (water bath temperature 60 C). This purification procedure was repeated, to give 3-chloropicolinic acid (10C), as a yellow solid, m.p.: 125.5-127.5 C.
	With sodium hydroxide; at 95℃; for 2h;pH 2-3;	After the first three-necked 1L flask, 35g of 3-aminopyridine, to the flask was added 300mL of hydrochloric acid concentration of 60%, with mechanical stirring and completely dissolved, then as to a water bath to control the temperature of 5 wherein Add 100mL mass fraction of 10% hydrogen peroxide, and maintaining the reaction mixture was stirred at this temperature for 2h, after stirring the reaction temperature was lowered to -5 deg.] C, after the addition of 100g NaNO2And stirring continued for 25min, a solution of diazonium salt; take another 1L three-necked flask, to which were added 20gCuCl, 250mL of dichloromethane and 5mL of 70% mass fraction of concentrated hydrochloric acid, followed by stirring under the conditions of the above prepared diazonium salt solution was slowly added to the flask, and the temperature controlled at 15 , after the addition was complete stirring maintained at this temperature for 20min, the temperature was raised to 30 , reaction was continued for 1h, the reaction was cooled to room temperature, treated with NaOH solution pH was adjusted to neutral, adjusting the solution was transferred to a separatory funnel, was added 50mL of methylene chloride. the combined organic phases were rotary evaporated to give crystals of 2,3-dichloropyridine; 50g of 2,3 to take the above - dichloropyridine into 500mL flask, 380mL of absolute ethanol was added and dissolved, 100mL added dropwise a solution of mass fraction of 50% hydrazine hydrate, refluxed for 6h under nitrogen, at reflux. after cooling to room temperature the solution ends, filtered, washed twice with sodium bicarbonate solution and filtered, to give 3-chloro-2-cyanopyridine; equipped with a thermometer, reflux condenser 250mL three-necked round-bottomed flask, the above-mentioned 3 were added 15g - chloro-2-cyanopyridine, to which was added 100mL of distilled water, with magnetic stirring 30min, 10mL was added thereto at a concentration of 30% NaOH solution placed in an oil bath heated to 95 deg.] C, and maintained at this temperature 2h, after completion of the reaction cooled to 75 , with a mass fraction of 50% HCl pH 7, 0.7g of active carbon was added thereto, decolorization 50min, the conditioned filter the mass fraction of the filtrate was added 50% hydrochloric acid to pH 2 , cooled to 20 , washed with water by filtration to give 3-chloro-2-carboxylic acid; take 60g of the above prepared 3-chloro-2-carboxylic acid was added to a 500mL flask, to which was added 90mL of carbon tetrachloride the solvent oil bath under nitrogen was heated to reflux, after addition 1gN--bromosuccinimide, the reaction with stirring 30min, the reaction was allowed to cool to room temperature after the end, filtered, and then the cleaning 15mL of carbon tetrachloride residue 2 times, then dried at 60 1h, to give 3-bromo-2-chloro-5-pyridine-carboxylic acid.

Reference： [1]Patent: US4853027,1989,A
[2]Patent: CN105218437,2016,A .Location in patent: Paragraph 0007

12
[ 57266-69-0 ]
[ 960249-80-3 ]
N-(2-(5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-ylcarbonylaminomethyl)-3,3,3-trifluoro-2-hydroxypropyl)-3-chloro-N-ethyl-2-pyridinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2.5h;	Example 3: N-({2-[([5-Amino-1-(4-fluorophenyl)-1 H-pyrazol-4- yl1carbonyl)amino)methyl1-3,3,3-trifluoro-2-hvdroxypropyl)-3-chloro-lambda/-ethyl-2- pyridinecarboxamide. To a solution of O-J(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (316mg, 0.832mmol) in dimethylformamide was added <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> (131.1 mg, 0.832mmol). After ca. IOmins diisopropylethylamine (292.6mg,2.27mmol) and 5-amino-N-{2-[(ethylamino)methyl]- 3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1 H-pyrazole-4-carboxamide (294mg, 0.756mmol) in dimethylformamide were added. The solution was stirred under nitrogen at room temperature. After 2.5hr the reaction mixture was concentrated in vacuo. The reaction mixture was partitioned between dichloromethane and water, the organic phase was separated via the use of a hydrophobic frit. The organic layer was then concentrated in vacuo. Purification on silica (5Og) using the Flashmaster using a 0-25% methanokdichloromethane gradient over 40mins gave, upon combination and concentration of the appropriate fractions, impure product (700mg). This was partitioned between ether and water and the organic layer was concentrated in vacuo. Further purification was on silica (5Og) using the Flashmaster 2 eluting with 0-100% ethyl acetate:cyclohexane gradient over 30mins. Combination and concentration in vacuo of the appropriate fractions gave the title compound (152mg).1H NMR (600 MHz, DMSOd6) deltappm 8.61 (d, 1 H) 8.12 (d, 1 H) 8.04 (t, 1 H) 7.85 (s, 1 H) 7.55 - 7.61 (m, 3 H) 7.33 - 7.39 (m, 2 H) 6.35 (br. s., 2 H) 4.16 - 4.23 (m, 1 H) 3.92 - 3.98 (m, 1 H) 3.47 - 3.55 (m, 3 H) 3.18 - 3.26 (m, 1 H) 1.02 - 1.08 (m, 3 H). LC-MS Retention Time 3.07mins, MH+ 529. A sample of Example 3 was further separated into its enantiomers (Enantiomer 1 and 2) using a Chiralpak AD column eluting with 60% isopropanol in heptane at a flow rate of 15ml/min.Enantiomer 1Analytical Chiral HPLC (25cm Chiralpak AD column, 60% ethanol in heptane eluting at 1 ml/min) - Retention time delta.Omins. Circular Dichroism (MeCN, RT, 0.000140M, v =350-200nm, cell length = 0.2cm) 215.2nm (de = -3.79). 271.0nm (de = -5.09).Enantiomer 2 Analytical Chiral HPLC (25cm Chiralpak AD column, 60% ethanol in heptane eluting at 1 ml/min) - Retention time 8.3mins.Circular Dichroism (MeCN, RT, 0.000149M, v =350-200nm, cell length = 0.2cm)214.0nm (de = 3.82).271.0nm (de = 4.97).

Reference： [1]Patent: WO2008/74814,2008,A1 .Location in patent: Page/Page column 64-65

13
[ 57266-69-0 ]
[ 1198409-41-4 ]
3-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[57266-69-0]3-chloropicolinic acid</strong> (380mg, 2.42mmol, available from Fluorochem Ltd.) in DMF (5ml) was added HATU (920mg, 2.42mmol) and DIPEA (1.266ml, 7.25mmol). The mixture was stirred at room temperature for 20mins then 6-(1 H-indol-4-yl)-1 H-indazol-4- amine (300mg, 1.21 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give a volume of approx. 1 ml which was added to the top of a 2Og aminopropyl cartridge that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 2h before being eluted with MeOH. The solvent was removed in vacuo to give a brown oil that was purified by chromatography using silica gel (70 g cartridge, FlashMaster II) eluting with 0- 25% MeOH in DCM over 30mins to afford the title compound (130mg) as a brown solid. LCMS (Method B) Rt = 0.94 mins, MH+ = 388

Reference： [1]Patent: WO2009/147190,2009,A1 .Location in patent: Page/Page column 115

14
[ 57266-69-0 ]
[ 1158975-01-9 ]
[ 1254364-42-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5839 - 5842

15
[ 57266-69-0 ]
[ 1111942-06-3 ]
[ 1408251-48-8 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 9793 - 9809

16
[ 57266-69-0 ]
[ 1383840-76-3 ]
[ 1421951-51-0 ]

Yield	Reaction Conditions	Operation in experiment
3.6 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 9h;	[ 0322] Production Example 9(1) To a mixture of 5-iodo-N2-methyl-pyridin-2 , 3-diamine (1.9 g) and pyridine (6 ml) were added WSC (1.28 g) , HOBt (86 mg) and <strong>[57266-69-0]3-chloro-pyridin-2-carboxylic acid</strong> (1.3 g) , and the mixture was stirred at room temperature for 9 hours. To this reaction mixture was added water, and the mixture was filtered to collect the precipitated powder. The collected powder was washed with chloroform to give 3- chloro-pyridin-2-carboxylic acid ( 5-iodo-2-methylamino- pyridin-3-yl ) -amide (3.6 g) , which , is hereinafter referred to as "intermediate compound (M20-7)". Intermediate compound (M20-7) XH-NMR ( DMSO-d6) delta: 9.95 (lH,s), 8.65 (lH,d), 8.15-8.10 (2H,m), 8.00 (lH,d), 7.65 (lH,dd), 6.30 (lH,d), 2.81 (3H,d)
3.6 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 9h;	Production example 9 (1) To a mixture of 5-iodo-N2-methyl-pyridine-2,3-diamine 1.9 g and pyridine 6 mL was added EDC hydrochloride 1.28 g, HOBt 86 mg, and <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> 1.3 g, and the mixture was stirred at RT for 9 hr. To the reaction mixture was added water, and the precipitated powder was collected by filtration, and washed with chloroform to give <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> (5-iodo-2-methylamino-pyridin-3-yl)-amide (hereinafter referred to as Intermediate compound (M20-7)) 3.6 g. Intermediate compound (M20-7) (0633) 1H-NMR(DMSO-D6)delta: 9.95(1H, s), 8.65(1H, d), 8.15-8.10(2H, m), 8.00(1H, d), 7.65(1H, dd), 6.30(1H, d), 2.81(3H, d).
3.6 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 9h;	Production example 9 (1) To a mixture of 5-iodo-N2-methyl-pyridine-2,3-diamine 1.9 g and pyridine 6 mL was added EDC hydrochloride 1.28 g, HOBt 86 mg, and <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> 1.3 g, and the mixture was stirred at RT for 9 hr. To the reaction mixture was added water, and the precipitated powder was collected by filtration, and washed with chloroform to give <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> (5-iodo-2-methylamino-pyridin-3-yl)-amide (hereinafter referred to as Intermediate compound (M20-7)) 3.6 g.

3.6 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 9h;	To a mixture of 5-iodo-N2-methyl-pyridine-2,3-diamine 1.9 g and pyridine 6 mL was added EDC hydrochloride 1.28 g, HOBt 86 mg, and <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> 1.3 g, and the mixture was stirred at RT for 9 hr. To the reaction mixture was added water, and the precipitated powder was collected by filtration, and washed with chloroform to give <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> (5-iodo-2-methylamino-pyridin-3-yl)-amide (hereinafter referred to as Intermediate compound (M20-7)) 3.6 g. Intermediate Compound (M20-7) (1060) (1061) 1H-NMR (DMSO-D6) delta: 9.95 (1H, s), 8.65 (1H, d), 8.15-8.10 (2H, m), 8.00 (1H, d), 7.65 (1H, dd), 6.30 (1H, d), 2.81 (3H, d).
3.6 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 9h;	To a mixture of 5-iodo-N2-methyl-pyridine-2,3-diamine 1.9 g and pyridine 6 mL was added EDC hydrochloride 1.28 g, HOBt 86 mg, and <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> 1.3 g, and the mixture was stirred at RT for 9 hr. To the reaction mixture was added water, and the precipitated powder was collected by filtration, and washed with chloroform to give <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> (5-iodo-2-methylamino-pyridin-3-yl)-amide (hereinafter referred to as Intermediate compound (M20-7)) 3.6 g. Intermediate compound (M20-7) 1H-NMR(DMSO-D6)delta: 9.95(1H, s), 8.65(1H, d), 8.15-8.10(2H, m), 8.00(1H, d), 7.65(1H, dd), 6.30(1H, d), 2.81(3H, d).
3.6 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 9h;	Production example 9 (1) To a mixture of 5-iodo-N2-methyl-pyridine-2,3-diamine 1.9 g and pyridine 6 mL was added EDC hydrochloride 1.28 g, HOBt 86 mg, and <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> 1.3 g, and the mixture was stirred at RT for 9 hr. To the reaction mixture was added water, and the precipitated powder was collected by filtration, and washed with chloroform to give <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> (5-iodo-2-methylamino-pyridin-3-yl)-amide (hereinafter referred to as Intermediate compound (M20-7)) 3.6 g. Intermediate compound (M20-7) 1H-NMR(DMSO-D6)delta: 9.95(1H, s), 8.65(1H, d), 8.15-8.10(2H, m), 8.00(1H, d), 7.65(1H, dd), 6.30(1H, d), 2.81(3H, d).

Reference： [1]Patent: WO2013/18928,2013,A1 .Location in patent: Paragraph 0322
[2]Patent: EP2952099,2015,A1 .Location in patent: Paragraph 0632; 0633
[3]Patent: EP2952097,2015,A1 .Location in patent: Paragraph 0674; 0675
[4]Patent: US2015/359219,2015,A1 .Location in patent: Paragraph 1059-1061
[5]Patent: EP2952098,2015,A1 .Location in patent: Paragraph 0628; 0629
[6]Patent: EP2952100,2015,A1 .Location in patent: Paragraph 0661; 0662

17
[ 57266-69-0 ]
[ 1421949-99-6 ]

Reference： [1]Patent: WO2013/18928,2013,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952098,2015,A1
[6]Patent: EP2952100,2015,A1

18
[ 57266-69-0 ]
[ 1421950-00-6 ]
[ 1421950-01-7 ]

Reference： [1]Patent: WO2013/18928,2013,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952098,2015,A1
[6]Patent: EP2952100,2015,A1

19
[ 57266-69-0 ]
[ 1421951-52-1 ]

Reference： [1]Patent: WO2013/18928,2013,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952100,2015,A1

20
[ 57266-69-0 ]
[ 1421950-02-8 ]

Reference： [1]Patent: WO2013/18928,2013,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952100,2015,A1

21
[ 57266-69-0 ]
[ 1421951-57-6 ]

Reference： [1]Patent: WO2013/18928,2013,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952098,2015,A1
[6]Patent: EP2952100,2015,A1

22
[ 57266-69-0 ]
[ 89571-66-4 ]
[ 1421951-55-4 ]

Yield	Reaction Conditions	Operation in experiment
0.45 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 12h;	Production Example 12(1) A mixture of 3-amino-5-trifluoromethylpyridin-2-thiol (0.45 g) , 3-chloropyridin-2-carboxylic acid (0.39 g) , WSC (0.67 g) , HOBt (31 mg) and pyridine (4 ml) was stirred at room temperature for 12 hours. To the reaction mixture was added water, and the mixture was filtered to collect a solid. The resulting solid was washed with water, followed by n-hexane, and dried to give 3-chloropyridin-2-carboxylic acid ( 2-mercapto-5-trifluoromethylpyridin-3-yl ) -amide (0.45 g) , which is hereinafter referred to as "intermediate compound (M20-11)". Intermediate compound (M20
0.45 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 12h;	Production example 12 (1) A mixture of 3-amino-5-trifluoromethylpyridine-2-thiol 0.45 g, <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> 0.39 g, EDC hydrochloride 0.67 g, HOBt 31 mg, and pyridine 4 mL was stirred at RT for 12 hr. To the reaction mixture was added water, and the precipitated solid was collected by filtration. The resulting solid was washed with water, and n-hexane, and dried to give <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> (2-mercapto-5-trifluoromethylpyridin-3-yl)-amide (hereinafter referred to as Intermediate compound (M20-11)) 0.45 g. Intermediate compound (M20-11) (0647)
0.45 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 12h;	Production example 12 (1) A mixture of 3-amino-5-trifluoromethylpyridine-2-thiol 0.45 g, <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> 0.39 g, EDC hydrochloride 0.67 g, HOBt 31 mg, and pyridine 4 mL was stirred at RT for 12 hr. To the reaction mixture was added water, and the precipitated solid was collected by filtration. The resulting solid was washed with water, and n-hexane, and dried to give <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> (2-mercapto-5-trifluoromethylpyridin-3-yl)-amide (hereinafter referred to as Intermediate compound (M20-11)) 0.45 g.

0.45 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 12h;	A mixture of 3-amino-5-trifluoromethylpyridine-2-thiol 0.45 g, <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> 0.39 g, EDC hydrochloride 0.67 g, HOBt 31 mg, and pyridine 4 mL was stirred at RT for 12 hr. To the reaction mixture was added water, and the precipitated solid was collected by filtration. The resulting solid was washed with water, and n-hexane, and dried to give <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> (2-mercapto-5-trifluoromethylpyridin-3-yl)-amide (hereinafter referred to as Intermediate compound (M20-11)) 0.45 g.
0.45 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 12h;	A mixture of 3-amino-5-trifluoromethylpyridine-2-thiol 0.45 g, <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> 0.39 g, EDC hydrochloride 0.67 g, HOBt 31 mg, and pyridine 4 mL was stirred at RT for 12 hr. To the reaction mixture was added water, and the precipitated solid was collected by filtration. The resulting solid was washed with water, and n-hexane, and dried to give <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> (2-mercapto-5-trifluoromethylpyridin-3-yl)-amide (hereinafter referred to as Intermediate compound (M20-11)) 0.45 g.
0.45 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In water; at 20℃; for 12h;	Production example 12 (1) A mixture of 3-amino-5-trifluoromethylpyridine-2-thiol 0.45 g, <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> 0.39 g, EDC hydrochloride 0.67 g, HOBt 31 mg, and pyridine 4 mL was stirred at RT for 12 hr. To the reaction mixture was added water, and the precipitated solid was collected by filtration. The resulting solid was washed with water, and n-hexane, and dried to give <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> (2-mercapto-5-trifluoromethylpyridin-3-yl)-amide (hereinafter referred to as Intermediate compound (M20-11)) 0.45 g.

Reference： [1]Patent: WO2013/18928,2013,A1 .Location in patent: Paragraph 328
[2]Patent: EP2952099,2015,A1 .Location in patent: Paragraph 0646; 0647
[3]Patent: EP2952097,2015,A1 .Location in patent: Paragraph 0687; 0688
[4]Patent: US2015/359219,2015,A1 .Location in patent: Paragraph 1079
[5]Patent: EP2952098,2015,A1 .Location in patent: Paragraph 0642; 0643
[6]Patent: EP2952100,2015,A1 .Location in patent: Paragraph 0674; 0675

23
[ 57266-69-0 ]
[ 89571-66-4 ]
[ 1421951-56-5 ]

Reference： [1]Patent: WO2013/18928,2013,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: US2015/359219,2015,A1

24
[ 57266-69-0 ]
[ 1369893-78-6 ]
[ 1440954-99-3 ]

Yield	Reaction Conditions	Operation in experiment
930 mg	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 100℃; for 12h;	Production Example 21(3) A mixture of 4-iodo-N1-methyl-benzene-l , 2-diamine (850 mg) , <strong>[57266-69-0]3-chloro-pyridin-2-carboxylic acid</strong> (590 mg) , SC (790 mg) , HOBt (46 mg) , and pyridine (10 ml) was stirred at 100C for 12 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2- (3- chloro-pyridin-2-yl ) -5-ipdo-l-methyl-lH-benzimidazole (930 mg) , which is hereinafter referred to as "intermediate compound (M6-21)". Intermediate compound (M6-21) [ 0343]
930 mg	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 100℃; for 12h;	Production example 21 (3) A mixture of 4-iodo-N1-methyl-benzene-1,2-diamine 850 mg, <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> 590 mg, EDC hydrochloride 790 mg, HOBt 46 mg, and pyridine 10 mL at 100C for 12 hr was stirred. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resultant residue was treated with silica gel column chromatography to give 2-(3-chloro-pyridin-2-yl)-5-iodo-1-methyl-1H-benzimidazole (hereinafter referred to as Intermediate compound (M6-21)) 930 mg.
930 mg	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 100℃; for 12h;	Production example 21 (3) A mixture of 4-iodo-N1-methyl-benzene-1,2-diamine 850 mg, <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> 590 mg, EDC hydrochloride 790 mg, HOBt 46 mg, and pyridine 10 mL at 100C for 12 hr was stirred. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resultant residue was treated with silica gel column chromatography to give 2-(3-chloro-pyridin-2-yl)-5-iodo-1-methyl-1H-benzimidazole (hereinafter referred to as Intermediate compound (M6-21)) 930 mg.

930 mg	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 100℃; for 12h;	A mixture of 4-iodo-N1-methyl-benzene-1,2-diamine 850 mg, <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> 590 mg, EDC hydrochloride 790 mg, HOBt 46 mg, and pyridine 10 mL at 100 C. for 12 hr was stirred. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resultant residue was treated with silica gel column chromatography to give 2-(3-chloro-pyridin-2-yl)-5-iodo-1-methyl-1H-benzimidazole (hereinafter referred to as Intermediate compound (M6-21)) 930 mg.
930 mg	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 100℃; for 12h;	A mixture of 4-iodo-N1-methyl-benzene-1,2-diamine 850 mg, <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> 590 mg, EDC hydrochloride 790 mg, HOBt 46 mg, and pyridine 10 mL at 100C for 12 hr was stirred. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resultant residue was treated with silica gel column chromatography to give 2-(3-chloro-pyridin-2-yl)-5-iodo-1-methyl-1H-benzimidazole (hereinafter referred to as Intermediate compound (M6-21)) 930 mg.
930 mg	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In water; at 100℃; for 12h;	Production example 21 (3) A mixture of 4-iodo-N1-methyl-benzene-1,2-diamine 850 mg, <strong>[57266-69-0]3-chloro-pyridine-2-carboxylic acid</strong> 590 mg, EDC hydrochloride 790 mg, HOBt 46 mg, and pyridine 10 mL at 100C for 12 hr was stirred. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resultant residue was treated with silica gel column chromatography to give 2-(3-chloro-pyridin-2-yl)-5-iodo-1-methyl-1H-benzimidazole (hereinafter referred to as Intermediate compound (M6-21)) 930 mg.

Reference： [1]Patent: WO2013/18928,2013,A1 .Location in patent: Paragraph 0342
[2]Patent: EP2952099,2015,A1 .Location in patent: Paragraph 0677
[3]Patent: EP2952097,2015,A1 .Location in patent: Paragraph 0717
[4]Patent: US2015/359219,2015,A1 .Location in patent: Paragraph 1122
[5]Patent: EP2952098,2015,A1 .Location in patent: Paragraph 0672
[6]Patent: EP2952100,2015,A1 .Location in patent: Paragraph 0704; 0705

25
[ 57266-69-0 ]
[ 1423122-29-5 ]

Reference： [1]Patent: WO2013/24004,2013,A1

26
[ 57266-69-0 ]
[ 1423030-56-1 ]

Reference： [1]Patent: WO2013/24004,2013,A1
[2]Patent: WO2013/24171,2013,A1
[3]Patent: WO2013/24006,2013,A1

27
[ 57266-69-0 ]
[ 1072314-47-6 ]

Reference： [1]Patent: WO2013/24004,2013,A1
[2]Patent: WO2013/24171,2013,A1

28
[ 57266-69-0 ]
[ 1423030-57-2 ]

Reference： [1]Patent: WO2013/24004,2013,A1
[2]Patent: WO2013/24171,2013,A1

29
[ 57266-69-0 ]
[ 1423030-58-3 ]

Reference： [1]Patent: WO2013/24004,2013,A1
[2]Patent: WO2013/24171,2013,A1

30
[ 57266-69-0 ]
[ 1423036-79-6 ]

Reference： [1]Patent: WO2013/24004,2013,A1
[2]Patent: WO2013/24171,2013,A1

31
[ 57266-69-0 ]
[ 1423036-78-5 ]

Reference： [1]Patent: WO2013/24171,2013,A1

32
[ 57266-69-0 ]
[ 1433966-82-5 ]
[ 1433966-01-8 ]

Yield	Reaction Conditions	Operation in experiment
143 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	Step 3: 3-chloiO-N-IT1 -r2-fluoro-4-(trifluoromethyl)phenyllcvclopropyllmethyllpyridine-2- carboxamide (compound A37)To a solution of [1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl]methanamine (0.500 ml_, 0.510 mmol) in dry dichloromethane (2.0 ml_, 0.510 mmol) was added, under argon, Et3N (0.144 ml_, 1 .02 mmol) , then the mixture was cooled at 0C. There were added EDCI.HCI (0.196 g, 1 .02 mmol), HOBT.H20 (0.139 g, 1.02 mmol), <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> (0.0803 g, 0.510 mmol) and the reaction mixture was stirred overnight at RT. Water was added, the aqueous solution was extracted with dichloromethane (3 times), the combined organic layers were washed by NaCI, dried over Na2S04, filtrated and evaporated under reduced pressure to give an oil (0.316 mg).which was purified by flash chromatography (Cyclohexane to Cyclohexane/AcOEt :4/1 ).The desired compound was isolated as a colorless oil (143.0 mg).1H-NMR (CDCI3): 8.43 (d, 1 H), 7.88 (bs, 1 H), 7.80 (d, 1 H), 7.46 (t, 1 H), 7.40-7.30 (m, 3H), 3.63 (d, 2H), 1 .10 (m, 2H), 0.91 (m, 2H).

Reference： [1]Patent: WO2013/64520,2013,A1 .Location in patent: Page/Page column 94

33
[ 57266-69-0 ]
ethyl 2-(3-chloropyridine-2-carbonyl)-3-dimethylaminoprop-2-enoate [ No CAS ]

Reference： [1]Patent: WO2013/24006,2013,A1

34
[ 57266-69-0 ]
[ 1617524-08-9 ]
1-(3-chloroisonicotinoyl)-N-(2-(7-methoxynaphthalen-1-yl)ethyl)azetidine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 24h;	General procedure: N-(2-(7-methoxynaphthalen-1-yl)ethyl)azetidine-3-carboxamide hydrochloride (800 mg, 2.50 mmol) and DIPEA (1.5 mL, 9.08 mmol) was dissolved in CH2Cl2 (20 mL) and DMF (3 mL), then different substituted carboxylic acid (2.74 mmol), EDC (574 mg, 2.99 mmol), HOBt (404 mg, 2.99 mmol) and DMAP (91 mg, 0.748 mmol) was added. After stirring at room temperature for 24 h, the reaction mixture was diluted with CH2Cl2 (20 mL), then washed with H2O (20 mL), 10% HCl (20 mL), NaHCO3 saturated solution (20 mL) and brine (20 mL). The organic layer was driedover Na2SO4, filtered and concentrated under reduced pressure and the residue was purified by chromatography on silica gel to affordrespective compounds 6m-t.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 82,p. 263 - 273

35
[ 57266-69-0 ]
[ 1617540-23-4 ]

Reference： [1]Patent: US2014/194432,2014,A1

36
[ 57266-69-0 ]
[ 1617540-24-5 ]

Reference： [1]Patent: US2014/194432,2014,A1

37
[ 57266-69-0 ]
[ 1617540-25-6 ]

Reference： [1]Patent: US2014/194432,2014,A1

38
[ 57266-69-0 ]
[ 1617540-26-7 ]

Reference： [1]Patent: US2014/194432,2014,A1

39
[ 57266-69-0 ]
5-(2-aminoethyl)-3-methoxy-2-(2,4,6-trimethylphenyl)cyclopent-2-en-1-one [ No CAS ]
C₂₃H₂₅ClN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	Step Four: Synthesis of 3-chloro-/V-[2-[2,4-dioxo-3-(2,4,6- trimethylphenyl)cyclopentyl]ethyl]pyridine-2-carboxamide To a stirred solution of the 5-(2-aminoethyl)-3-methoxy-2-(2,4,6-trimethylphenyl)cyclopent-2- en-1 -one (0.250g, 0.91 mmol) in /V,/V-dimethylformamide (9ml_) was added Hunig's base (Lambda/,/V-diisopropylethylamine) (0.40ml_, 2.29mmol) and <strong>[57266-69-0]3-chloropicolinic acid</strong> (0.16g, 1 .01 mmol). The reaction was then cooled to 0C and benzotriazol-1 -yloxy(tripyrrolidin-1 - yl)phosphonium hexafluorophosphate (0.97g, 1 .83mmol) was added. Once the addition was complete the reaction was allowed to warm to room temperature and stirred two hours. The reaction was then evaporated to dryness under reduced pressure and the crude product carried forward to the next step without further purification. To a solution of the crude enol ether in EtOH (4ml_) was added 2M hydrochloric acid (4ml_) and the mixture was then heated to 60C for 4 hours. The reaction was then allowed to cool to room temperature and then evaporated to dryness under reduced pressure. The crude product was then purified on a FractionLynx mass-directed purification system to give the desired product (0.072g, 18%) as an off-white solid. 1 H NMR (400 MHz, d4-methanol) delta, 8.50-8.54 (m, 1 H), 7.94-7.98 (m, 1 H), 7.47-7.52 (m, 1 H), 6.84-6.88 (s, 2H) 3.49-3.64 (m, 2H), 2.91 -2.99 (m, 1 H), 2.81 -2.90 (m, 1 H), 2.47-2.55 (m, 1 H), 2.16-2.27 (m, 4H), 2.03-2.07 (s, 6H), 1 .67-1 .78 (1 H, m).

Reference： [1]Patent: WO2014/170413,2014,A1 .Location in patent: Page/Page column 119-120

40
[ 57266-69-0 ]
2-(2-chlorophenyl)cyclobutanamine [ No CAS ]
3-chloro-N-[(1,2-cis)-2-(2-chlorophenyl)cyclobutyl]pyridine-2-carboxamide [ No CAS ]
trans-3-chloro-N-[2-(2-chlorophenyl)cyclobutyl]pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20.8%; 18.9%	With triethylamine; HATU; In dichloromethane; at 20℃; for 3h;	Step 4: cis-3-chloro-N-12-(2-chlorophenyl)cyclobutyljpyridine-2-carboxamide (compound 247) and trans-3-chloro-N- 12-(2-chlorophenyl)cyclobutyljpyridine-2-carboxamide (compound 238)To a solution of 2-(2-chlorophenyl)cyclobutanamine (150 mg, 1.0 eq) in dichloromethane (DCM) (3 mL) was added triethylamine (0.34 mL, 3.0 eq), <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> (143 mg, 1.1 eq) followed by HATU (O-(7-azabenzotriazol- 1 -yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate) (470 mg, 1.5 eq) at RT and stirred at RT for 3h. After work-up and column purification, the title compound was isolated as a cis/trans mixture. Both isomers were separated by preparative HPLC,yielding 55 mg (20.8%) of cis-3-chloro-N-[2-(2-chlorophenyl)cyclobutyl]pyridine-2-carboxamide and50 mg (18.9%) of trans-3 -chloro-N- [2-(2-chlorophenyl)cyclobutyl]pyridine-2-carboxamide.cis-Isomer: HPLC-MS: logP = 2.79; Mass (m/z): 321.0 (M+H) ?H-NMR [CDC13] 2.09 -2.16 (m, 1H),2.32 - 2.39 (m, 1H), 2.42 - 2.48 (m, 1H), 2.57 -2.63 (m, 1H), 4.30 - 4.36 (m, 1H), 5.03 - 5.09 (m, 1H),7.21 - 7.23 (m, 1H), 7.34- 7.41 (m, 3H), 7.48 - 7.49 (m, 1H), 7.98 (s, 1H), 8.47 (s, 1H).trans-Isomer: HPLC-MS: logP = 3.06; Mass (mlz): 321.0 (M+H) ?H-NMR [CDC13] 1.66 - 1.76 (m,1H), 1.98 -2.08 (m, 1H), 2.39-2.47 (m, 2H), 3.77- 3.85 (m, 1H), 4.86-4.95 (m, 1H), 7.13 - 7.17 (m,1H), 7.28 - 7.38 (m, 3H), 7.59 - 7.61 (m, 1H), 7.80 - 7.82 (m, 1H), 8.20 - 8.22 (m, 1H), 8.45 - 8.46 (m,1H).

Reference： [1]Patent: WO2014/177487,2014,A1 .Location in patent: Page/Page column 238

41
[ 57266-69-0 ]
[ 825-41-2 ]
N-(3-chloro-4-nitrophenyl)-3-chloropicolinamide [ No CAS ]

Reference： [1]ACS Chemical Biology,2014,vol. 9,p. 2334 - 2346

42
[ 57266-69-0 ]
N-(4-amino-3-chlorophenyl)-3-chloropicolinamide [ No CAS ]

Reference： [1]ACS Chemical Biology,2014,vol. 9,p. 2334 - 2346

43
[ 57266-69-0 ]
C₂₁H₁₃Cl₂N₃O₃ [ No CAS ]

Reference： [1]ACS Chemical Biology,2014,vol. 9,p. 2334 - 2346

44
[ 57266-69-0 ]
C₂₁H₁₃Cl₂N₃O₃ [ No CAS ]

Reference： [1]ACS Chemical Biology,2014,vol. 9,p. 2334 - 2346

45
[ 57266-69-0 ]
3-chloro-N-[3-chloro-4-(4-chloro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)phenyl]-2-pyridinecarboxamide [ No CAS ]

Reference： [1]ACS Chemical Biology,2014,vol. 9,p. 2334 - 2346

46
[ 57266-69-0 ]
C₂₀H₁₀Cl₃N₃O₃ [ No CAS ]

Reference： [1]ACS Chemical Biology,2014,vol. 9,p. 2334 - 2346

47
[ 57266-69-0 ]
C₂₀H₁₀Cl₂FN₃O₃ [ No CAS ]

Reference： [1]ACS Chemical Biology,2014,vol. 9,p. 2334 - 2346

48
[ 57266-69-0 ]
C₂₀H₁₀Cl₂FN₃O₃ [ No CAS ]

Reference： [1]ACS Chemical Biology,2014,vol. 9,p. 2334 - 2346

49
[ 57266-69-0 ]
[ 19348-53-9 ]
C₂₀H₁₁Cl₂N₃O₃ [ No CAS ]

Reference： [1]ACS Chemical Biology,2014,vol. 9,p. 2334 - 2346

50
[ 57266-69-0 ]
3-ethylsulfanyl-N-(3,5-bistrifluoromethylphenyl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

51
[ 57266-69-0 ]
3-ethylsulfonyl-N-(3,5-bistrifluoromethylphenyl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

52
[ 57266-69-0 ]
[ 34486-24-3 ]
3-chloro-N-(6-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.33 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 70℃; for 2h;	Production Example 6 (1) A mixture of 0.81 g of 2-amino-6-trifluoromethylpyridine, 0.78 g of <strong>[57266-69-0]3-chloropicolinic acid</strong>, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 70C for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 1.33 g of 3-chloro-N-(6-trifluoromethylpyridin-2-yl)picolinamide. 3-Chloro-N-(6-trifluoromethylpyridin-2-yl)picolinamide 1H-NMR (CDCl3) delta: 10.60 (1H, brs), 8.66 (1H, d), 8.58 (1H, d), 7.97-7.87(2H, m), 7.53-7.43(2H, m).

Reference： [1]Patent: EP2881386,2015,A1 .Location in patent: Paragraph 0708

53
[ 57266-69-0 ]
[ 106447-97-6 ]
3-chloro-N-(4-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.33 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 70℃; for 2h;	Production Example 7 (1) [0712] A mixture of 0.81 g of 2-amino-4-trifluoromethylpyridine, 0.78 g of <strong>[57266-69-0]3-chloropicolinic acid</strong>, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 70C for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 1.33 g of 3-chloro-N-(4-trifluoromethylpyridin-2-yl)picolinamide. RRN 383-Chloro-N-(4-trifluoromethylpyridin-2-yl)picolinamide [0713] 1H-NMR (CDCl3) delta: 10.69 (1H, brs), 8.75 (1H, s), 8.57 (1H, d), 8.52 (1H, d), 7.92 (1H, d), 7.49 (1H, dd), 7.30 (1H, d).

Reference： [1]Patent: EP2881386,2015,A1 .Location in patent: Paragraph 0712; 0713

54
[ 57266-69-0 ]
[ 455-14-1 ]
3-chloro-N-(4-trifluoromethylphenyl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.34 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 2h;	Production Example 8 (1) [0716] A mixture of 0.80 g of 4-trifluoromethylaniline, 0.78 g of <strong>[57266-69-0]3-chloropicolinic acid</strong>, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 1.34 g of 3-chloro-N-(4-trifluoromethylphenyl)picolinamide. 3-Chloro-N-(4-trifluoromethylphenyl)picolinamide 1H-NMR (CDCl3) delta: 10.16 (1H, s), 8.55 (1H, d), 7.95-7.87(3H, m), 7.64(2H, d), 7.47 (1H, dd).

Reference： [1]Patent: EP2881386,2015,A1 .Location in patent: Paragraph 0716

55
[ 57266-69-0 ]
[ 455-14-1 ]
3-ethylsulfanyl-N-(4-trifluoromethylphenyl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

56
[ 57266-69-0 ]
[ 328-74-5 ]
3-chloro-N-(3,5-bistrifluoromethylphenyl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.67 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 2h;	Production Example 9 (1) [0718] A mixture of 1.15 g of 3,5-bistrifluoromethylaniline, 0.78 g of <strong>[57266-69-0]3-chloropicolinic acid</strong>, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 1.67 g of 3-chloro-N-(3,5-bistrifluoromethylphenyl)picolinamide. 3-Chloro-N-(3,5-bistrifluoromethylphenyl)picolinamide 1H-NMR (CDCl3) delta: 10.38 (1H, brs), 8.57 (1H, d), 8.30(2H, s), 7.94 (1H, d), 7.65 (1H, s), 7.51 (1H, dd).

Reference： [1]Patent: EP2881386,2015,A1 .Location in patent: Paragraph 0718

57
[ 57266-69-0 ]
[ 74784-70-6 ]
3-chloro-N-(5-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.51 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 2h;	Production Example 2 (1) [0697] A mixture of 0.81 g of 2-amino-5-trifluoromethylpyridine, 0.78 g of <strong>[57266-69-0]3-chloropicolinic acid</strong>, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 60C for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.51 g of 3-chloro-N-(5-trifluoromethylpyridin-2-yl)picolinamide. 3-Chloro-N-(5-trifluoromethylpyridin-2-yl)picolinamide 1H-NMR (CDCl3) delta: 10.69 (1H, brs), 8.62 (1H, s), 8.60-8.55(2H, m), 7.99 (1H, dd), 7.92 (1H, dd), 7.49 (1H, dd)

Reference： [1]Patent: EP2881386,2015,A1 .Location in patent: Paragraph 0697

58
[ 57266-69-0 ]
3-ethylsulfanyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

59
[ 57266-69-0 ]
3-ethylsulfonyl-N-(5-trifluoromethylpyridin2-yl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

60
[ 57266-69-0 ]
3-ethylsulfonyl-N-(1-oxy-5-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

61
[ 57266-69-0 ]
N-ethyl-3-ethylsulfanyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

62
[ 57266-69-0 ]
N-ethyl-3-ethylsulfonyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

63
[ 57266-69-0 ]
3-ethylsulfonyl-N-methyl-N-(3,5-bistrifluoromethylphenyl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

64
[ 57266-69-0 ]
3-ethylsulfanyl-N-methyl-N-(5-trifluoromethyl-pyridin-2-yl) picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

65
[ 57266-69-0 ]
3-ethylsulfonyl-N-methyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

66
[ 57266-69-0 ]
[ 34486-24-3 ]
3-ethylsulfanyl-N-(6-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

67
[ 57266-69-0 ]
[ 106447-97-6 ]
3-ethylsulfanyl-N-(4-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

68
[ 57266-69-0 ]
(1S,2S)-1-N-(6-fluoro-1,3-benzothiazol-2-yl)cyclopentane-1,2-diamine hydrochloride [ No CAS ]
3-chloro-N-[(1S,2S)-2-[(6-fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; HATU; In dichloromethane; at 20 - 25℃; for 3h;	To a solution of (7S,2S)-l-N-(6-fluoro-l,3-benzothiazol-2-yl)cyclopentane-l,2-diamine hydrochloride (Intermediate 1; 50 mg, 0.17 mmol), <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> (CAS number 57266-69-0; 41 mg, 0.26 mmol) and triethylamine (0.073 mi, 0.52 mmol) in DCM (2 ml) was added HATU (99 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 3 hours then partitioned between DCM and a saturated solution of sodium bicarbonate. The organics were filtered through a hydrophobic frit and (0517) concentrated in vacuo. The cmde material was purified by reverse phase preparative HPLC (eluted with acetonitriie / water containing 0.1 % ammonia) to afford the title compound. 1H NMR (MeOH-i /; ) delta ppm 1.65-1.80 (m, 2 H), 1.85-1.95 (m, 2 H), 2.14-2.26 (m, 2 H), 4.14-4.24 (m, 2 1 1 }.. 6.93-7.01 (m, I 1 1 }.. 7.25-7.40 (m, 2 1 1 }.. 7.43-7.48 (m, 1 1 1 }.. 7.88-7.94 (m, 1 H), 8.46-8.49 (m, 1 H). (0518) MS ES+: 391

Reference： [1]Patent: WO2015/124934,2015,A1 .Location in patent: Page/Page column 49

69
[ 57266-69-0 ]
[ 1421950-05-1 ]
[ 1421950-19-7 ]

Reference： [1]Patent: EP2952099,2015,A1
[2]Patent: EP2952100,2015,A1

70
[ 57266-69-0 ]
[ 1421950-55-1 ]

Reference： [1]Patent: EP2952099,2015,A1

71
[ 57266-69-0 ]
[ 1421951-56-5 ]

Reference： [1]Patent: EP2952100,2015,A1

72
[ 57266-69-0 ]
[ 1421950-44-8 ]

Reference： [1]Patent: EP2952100,2015,A1

73
[ 57266-69-0 ]
C₁₄H₁₁ClN₂O [ No CAS ]
C₂₀H₁₃Cl₂N₃O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 1869 - 1872

74
[ 57266-69-0 ]
C₁₄H₁₀Cl₂N₂O [ No CAS ]
C₂₀H₁₂Cl₃N₃O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 1869 - 1872

75
[ 57266-69-0 ]
C₁₄H₁₀Cl₂N₂O [ No CAS ]
C₂₀H₁₂Cl₃N₃O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 1869 - 1872

76
[ 57266-69-0 ]
1-[amino(3-bromophenyl)methyl]cyclopentanol [ No CAS ]
N-[(3-bromophenyl)(1-hydroxycyclopentyl)methyl]-3-chloropyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
250 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;Microwave irradiation;	(1) A solution of <strong>[57266-69-0]3-chloropyridine-2-carboxylic acid</strong> (180 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg) and 1-hydroxybenzotriazole (240 mg) in N,N-dimethylformamide (4.0 mL) was stirred at 0 C. for 10 minutes. A solution of 1-[amino(3-bromophenyl)methyl]cyclopentanol (300 mg) in N,N-dimethylformamide (3.0 mL) was added to the reaction mixture and stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with an aqueous saturated sodium hydrogen carbonate solution, water and saline, the organic layers were combined and dried over anhydrous magnesium sulfate. After filtering off the desiccating agent, the organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=67:33 to 0:100) to obtain N-[(3-bromophenyl)(1-hydroxycyclopentyl)methyl]-3-chloropyridine-2-carboxamide (250 mg).

Reference： [1]Patent: US2016/130278,2016,A1 .Location in patent: Paragraph 0995; 0996

77
[ 57266-69-0 ]
6-[4-(azetidin-3-yloxymethyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one [ No CAS ]
6-[4-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]oxymethyl]-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h;	To a solution of 6-[4-(azetidin-3-yloxymethyl)-l-(2-trimethylsilylethoxymethyl)-pyrazol- 3-yl]-5-fluoro-l-methyl-3,4-dihydroquinolin-2-one (200 mg, 0.43 mmol), EDCI (100 mg, 0.52 mmol) and HOBT (70 mg, 0.52 mmol) in DCM (15 mL) was added 3-chloropyridine- 2-carboxylic acid (67 mg, 0.43 mmol) and DIPEA (110 mg, 0.86 mmol). The resulting reaction mixture was stirred at room temperature for 3 h before it was quenched with satd. aq. NH4CI (20 mL), diluted with H20 (50 mL), and extracted with DCM (3 x 10 mL). The combined organics were washed with brine (2 x 20 mL), dried over anhy. Na2S04, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography (DCM: MeOH=40: 1) to afford the desired title compound (100 mg, 42%) as yellow oil. MS: 600.2 (M+H+).

Reference： [1]Patent: WO2016/66597,2016,A1 .Location in patent: Page/Page column 65; 66

78
[ 110-91-8 ]
[ 57266-69-0 ]
(3-chloropyridin-2-yl)(morpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	<strong>[57266-69-0]3-chloropicolinic acid</strong> (1eq), the dimethylformamide (DMF) to the dissolved, morpholine (1.01 eq) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC, 1.1 eq), 1 - hydroxybenzotriazole (HOBT, 1.1 eq) was added dropwise, and triethylamine (TEA, 3 eq) sequentially. After stirring overnight at room temperature, then terminate the reaction with a small amount of water, extracted with EtOAc and water and a small amount of water in the organic layer was removed by using anhydrous MgSO4, and evaporated under reduced pressure to remove the solvent and dried in vacuo. Then, separated by column to give the title compound in 43% yield.

Reference： [1]Patent: KR101555033,2015,B1 .Location in patent: Paragraph 0126-0128

79
[ 462-08-8 ]
[ 57266-69-0 ]

Reference： [1]Patent: CN105218437,2016,A

80
[ 2402-77-9 ]
[ 57266-69-0 ]

Reference： [1]Patent: CN105218437,2016,A

81
[ 57266-69-0 ]
[ 1060815-76-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; In tetrachloromethane; for 0.5h;Inert atmosphere; Reflux;	After the first three-necked 1L flask, 35g of 3-aminopyridine, to the flask was added 300mL of hydrochloric acid concentration of 60%, with mechanical stirring and completely dissolved, then as to a water bath to control the temperature of 5 wherein Add 100mL mass fraction of 10% hydrogen peroxide, and maintaining the reaction mixture was stirred at this temperature for 2h, after stirring the reaction temperature was lowered to -5 deg.] C, after the addition of 100g NaNO2And stirring continued for 25min, a solution of diazonium salt; take another 1L three-necked flask, to which were added 20gCuCl, 250mL of dichloromethane and 5mL of 70% mass fraction of concentrated hydrochloric acid, followed by stirring under the conditions of the above prepared diazonium salt solution was slowly added to the flask, and the temperature controlled at 15 , after the addition was complete stirring maintained at this temperature for 20min, the temperature was raised to 30 , reaction was continued for 1h, the reaction was cooled to room temperature, treated with NaOH solution pH was adjusted to neutral, adjusting the solution was transferred to a separatory funnel, was added 50mL of methylene chloride. the combined organic phases were rotary evaporated to give crystals of 2,3-dichloropyridine; 50g of 2,3 to take the above - dichloropyridine into 500mL flask, 380mL of absolute ethanol was added and dissolved, 100mL added dropwise a solution of mass fraction of 50% hydrazine hydrate, refluxed for 6h under nitrogen, at reflux. after cooling to room temperature the solution ends, filtered, washed twice with sodium bicarbonate solution and filtered, to give 3-chloro-2-cyanopyridine; equipped with a thermometer, reflux condenser 250mL three-necked round-bottomed flask, the above-mentioned 3 were added 15g - chloro-2-cyanopyridine, to which was added 100mL of distilled water, with magnetic stirring 30min, 10mL was added thereto at a concentration of 30% NaOH solution placed in an oil bath heated to 95 deg.] C, and maintained at this temperature 2h, after completion of the reaction cooled to 75 , with a mass fraction of 50% HCl pH 7, 0.7g of active carbon was added thereto, decolorization 50min, the conditioned filter the mass fraction of the filtrate was added 50% hydrochloric acid to pH 2 , cooled to 20 , washed with water by filtration to give 3-chloro-2-carboxylic acid; take 60g of the above prepared 3-chloro-2-carboxylic acid was added to a 500mL flask, to which was added 90mL of carbon tetrachloride the solvent oil bath under nitrogen was heated to reflux, after addition 1gN--bromosuccinimide, the reaction with stirring 30min, the reaction was allowed to cool to room temperature after the end, filtered, and then the cleaning 15mL of carbon tetrachloride residue 2 times, then dried at 60 1h, to give 3-bromo-2-chloro-5-pyridine-carboxylic acid.

Reference： [1]Patent: CN105218437,2016,A .Location in patent: Paragraph 0007

82
[ 57266-69-0 ]
ethyl 3-morpholinopicolinate [ No CAS ]

Reference： [1]Patent: WO2017/15449,2017,A1

83
[ 57266-69-0 ]
3-morpholinopicolinohydrazide [ No CAS ]

Reference： [1]Patent: WO2017/15449,2017,A1

84
[ 57266-69-0 ]
[ 64-17-5 ]
ethyl 3-Chloro-2-pyridinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With sulfuric acid; for 3h;Reflux;	A solution of <strong>[57266-69-0]3-chloropicolinic acid</strong> (1 g, 6.37 mmol) and H2SO4 (1 mL) in EtOH (20 mL) was refluxed for 3 hours. It was concentrated and purified by reverse phase C18 column chromatography (MeCN/H2O) to give ethyl 3-chloropicolinate as a yellow oil (0.85 g, 72%). ESI-MS m/z: 186.0 [M+H]+.
	With sulfuric acid; for 3h;Reflux;	A solution of <strong>[57266-69-0]3-chloropicolinic acid</strong> (1 g, 6.37 mmol) and H2S04 (1 mL) in EtOH (20 mL)was refluxed for 3 hours. It was concentrated and purified by reverse phase C18 columnchromatography (MeCN/H20) to give ethyl 3-chloropicolinate as a yellow oil (0.85 g, 72%). ESI-MS m/z: 186.0 [M+Hf

Reference： [1]Patent: WO2019/67864,2019,A1 .Location in patent: Page/Page column 120
[2]Patent: WO2017/15449,2017,A1 .Location in patent: Page/Page column 118

85
[ 57266-69-0 ]
[ 460-00-4 ]
3-chloro-2-(4-fluorophenyl)pyridine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 3917 - 3925

86
[ 57266-69-0 ]
5-hydroxypyrazolo[1,5-a]pyrido[2,3-e]pyrimidine-3-carbonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3201 - 3204

87
[ 57266-69-0 ]
tert-butyl N-[(1S,2R,4S,5R)-4-aminobicyclo[3.1.0]hexan-2-yl]carbamate [ No CAS ]
tert-butyl N-[(1S,2R,4S,5R)-4-[(3-chloropyridine-2-carbonyl)amino]-2-bicyclo[3.1.0]hexanyl]carbamate [ No CAS ]

Reference： [1]Patent: WO2017/133667,2017,A1 .Location in patent: Page/Page column 259

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[ 57266-69-0 ]

Chlorides

[ 894074-82-9 ]

3-Chloro-6-methylpicolinic acid

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3-Chloro-6-hydroxypicolinic acid

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5-Bromo-3-chloropicolinic acid

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3-Chloro-5-fluoropicolinic acid

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(3-Chloropyridin-2-yl)methanol

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Carboxylic Acids

[ 894074-82-9 ]

3-Chloro-6-methylpicolinic acid

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3-Chloro-6-hydroxypicolinic acid

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5-Bromo-3-chloropicolinic acid

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Related Parent Nucleus of
[ 57266-69-0 ]

Pyridines

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3-Chloro-6-hydroxypicolinic acid

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5-Bromo-3-chloropicolinic acid

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3-Chloro-5-fluoropicolinic acid

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(3-Chloropyridin-2-yl)methanol

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 57266-69-0 ] {[proInfo.proName]}

Quality Control of [ 57266-69-0 ]

Related Doc. of [ 57266-69-0 ]

Product Details of [ 57266-69-0 ]

Calculated chemistry of [ 57266-69-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 57266-69-0 ]

Application In Synthesis of [ 57266-69-0 ]

[ 57266-69-0 ] Synthesis Path-Upstream 1~12

[ 57266-69-0 ] Synthesis Path-Downstream 1~87

Related Functional Groups of [ 57266-69-0 ]

Chlorides

Carboxylic Acids

Related Parent Nucleus of [ 57266-69-0 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 57266-69-0 ]

Related Parent Nucleus of
[ 57266-69-0 ]