[ CAS No. 98273-19-9 ] {[proInfo.proName]}

Name: 98273-19-9|Methyl 4,6-dichloropicolinate|98%
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Quality Control of [ 98273-19-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 98273-19-9 ]

Product Details of [ 98273-19-9 ]

CAS No. :	98273-19-9	MDL No. :	MFCD12965121
Formula :	C₇H₅Cl₂NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MXHPWLMQTZILLL-UHFFFAOYSA-N
M.W :	206.03	Pubchem ID :	18922464
Synonyms :

Calculated chemistry of [ 98273-19-9 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	45.54
TPSA :	39.19 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) :	-5.69 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.01
Log Po/w (XLOGP3) :	2.63
Log Po/w (WLOGP) :	2.17
Log Po/w (MLOGP) :	1.51
Log Po/w (SILICOS-IT) :	2.49
Consensus Log Po/w :	2.16

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.01
Solubility :	0.2 mg/ml ; 0.000972 mol/l
Class :	Soluble
Log S (Ali) :	-3.1
Solubility :	0.162 mg/ml ; 0.000788 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.34
Solubility :	0.0944 mg/ml ; 0.000458 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.86

Safety of [ 98273-19-9 ]

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

Application In Synthesis of [ 98273-19-9 ]

* 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 [ 98273-19-9 ]
Downstream synthetic route of [ 98273-19-9 ]

[ 98273-19-9 ] Synthesis Path-Upstream 1~9

1
[ 98273-19-9 ]
[ 132683-62-6 ]

Reference： [1] Patent: US5750549, 1998, A,

2
[ 98273-19-9 ]
[ 88912-25-8 ]

Yield	Reaction Conditions	Operation in experiment
98.7%	With sodium hydroxide In ethanol; water	(3) Synthesis of 4,6-Dichloropicolinic Acid [Compound (II-17)] 4,6-Dichloropicolinic acid methyl ester (0.5 g, 2.43 mmol) was stirred in a mixture of sodium hydroxide (0.11 g, 2.43*1.1 mmol), 1.1 ml of water and 11 ml of ethanol at 60° C. for 1 hour. Ethanol in the reaction solution was distilled off and the residue was washed with dichloromethane. The aqueous layer was acidified with diluted hydrochloric acid. After being extracted with ethyl acetate, the product was washed with saturated saline solution and dried with sodium sulfate. White solid, yield: 0.46 g, percent yield: 98.7percent, m.p.: 114-116° C. IR KBr cm^-1: 3562, 1692, 1557, 1395, 1287, 819.
67%	With lithium hydroxide monohydrate; water In methanol at 0 - 20℃; for 16 h;	Lithium hydroxide monohydrate (1.46 g, 34.9 mmol) was added to a solution of methyl 4,6-dichloropicolinate (4.8 g, 23.3 mmol) in methanol: water (100 mL, 1 :0.1 v/v) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16h. The reaction mixture was concentrated under reduced pressure to get crude product which was diluted with water. The crude was acidified by 2N hydrochloric acid at 0°C to get white precipitate. The precipitate was filtered and dried under vacuum to get 3.0 g of 4,6-dichloropicolinic acid. Yield: 67percent. (0661) ES-MS [M+H]⁺: 190.02; Rt = 1.55 min (Method B).

Reference： [1] Patent: US6610853, 2003, B1,
[2] Patent: WO2018/122775, 2018, A1, . Location in patent: Page/Page column 98-99

3
[ 98-98-6 ]
[ 67-56-1 ]
[ 24484-93-3 ]
[ 98273-19-9 ]

Reference： [1] Organic Preparations and Procedures International, 1997, vol. 29, # 1, p. 117 - 122

4
[ 67-56-1 ]
[ 88912-25-8 ]
[ 98273-19-9 ]

Reference： [1] Patent: WO2017/7700, 2017, A1, . Location in patent: Page/Page column 134
[2] Patent: WO2017/189386, 2017, A1, . Location in patent: Page/Page column 32

5
[ 98-98-6 ]
[ 67-56-1 ]
[ 24484-93-3 ]
[ 98273-19-9 ]

Reference： [1] Organic Preparations and Procedures International, 1997, vol. 29, # 1, p. 117 - 122

6
[ 99-32-1 ]
[ 98273-19-9 ]

Reference： [1] Journal of Organic Chemistry, 1958, vol. 23, p. 1030

7
[ 41600-42-4 ]
[ 98273-19-9 ]

Reference： [1] Journal of Organic Chemistry, 1958, vol. 23, p. 1030

8
[ 67-56-1 ]
[ 98138-06-8 ]
[ 98273-19-9 ]

Reference： [1] Journal of Organic Chemistry, 1958, vol. 23, p. 1030

9
[ 98-98-6 ]
[ 67-56-1 ]
[ 2459-07-6 ]
[ 98273-19-9 ]

Reference： [1] Synthetic Communications, 1996, vol. 26, # 10, p. 2017 - 2025

[ 98273-19-9 ] Synthesis Path-Downstream 1~55

1
[ 67-56-1 ]
[ 98138-06-8 ]
[ 98273-19-9 ]

Reference： [1]Journal of Organic Chemistry,1958,vol. 23,p. 1030

2
[ 98273-19-9 ]
[ 858443-28-4 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1932,vol. <2> 133,p. 36,49

3
[ 98-98-6 ]
[ 67-56-1 ]
[ 2459-07-6 ]
[ 98273-19-9 ]
methyl 4-chloropyridine-2-carboxylate hydrochloride [ No CAS ]

Reference： [1]Synthetic Communications,1996,vol. 26,p. 2017 - 2025

4
[ 98-98-6 ]
[ 67-56-1 ]
[ 24484-93-3 ]
[ 98273-19-9 ]

Reference： [1]Organic Preparations and Procedures International,1997,vol. 29,p. 117 - 122

5
[ 98273-19-9 ]
4,6-dichloro-pyridine-2-carbonyl azide [ No CAS ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1932,vol. <2> 133,p. 36,49

6
[ 98273-19-9 ]
4,6-dichloro-pyridine-2-carboxylic acid benzylidenehydrazide [ No CAS ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1932,vol. <2> 133,p. 36,49

7
[ 99-32-1 ]
[ 98273-19-9 ]

Reference： [1]Journal of Organic Chemistry,1958,vol. 23,p. 1030

8
[ 41600-42-4 ]
[ 98273-19-9 ]

Reference： [1]Journal of Organic Chemistry,1958,vol. 23,p. 1030

9
[ 6317-46-0 ]
[ 98273-19-9 ]

Reference： [1]Journal of Organic Chemistry,1958,vol. 23,p. 1030

Yield	Reaction Conditions	Operation in experiment
26.6%		(2) Synthesis of 4,6-Dichloropicolinic Acid Methyl Ester [Compound (V-17)] N-Methylpyridonic acid (13 g, 0.066 mol) was stirred in thionyl chloride (50 ml) containing a catalytic amount of N,N-dimethylformamide (35 mg) at 90 C. for 1.5 hours. Thereafter, thionyl chloride was completely removed by distillation. The reaction mixture was added into 100 ml of methanol under cooling with water. After being stirred for 2 hours, methanol was distilled off and the residue was distributed with ethyl acetate and water. The organic layer was washed with saturated saline solution and dried with sodium sulfate. After the solvent was distilled off, the product was purified by silica gel column chromatography to obtain 4,6-dichloropicolinic acid methyl ester. White solid, yield: 3.63 g, percent yield: 26.6%, m.p.: 75-77 C. IR KBr cm-1: 3100, 1728, 1395, 1296, 810. 1H-NMR (60 MHz, CDCl3, delta): 3.9 (3H, s, COOCH3), 7.4 (1H, d, J=2 Hz, pyridine ring H), 7.9 (1H, d, J=2 Hz, pyridine ring H).

11
[ 98273-19-9 ]
[ 88912-25-8 ]

Yield	Reaction Conditions	Operation in experiment
98.7%	With sodium hydroxide; In ethanol; water;	(3) Synthesis of 4,6-Dichloropicolinic Acid [Compound (II-17)] 4,6-Dichloropicolinic acid methyl ester (0.5 g, 2.43 mmol) was stirred in a mixture of sodium hydroxide (0.11 g, 2.43*1.1 mmol), 1.1 ml of water and 11 ml of ethanol at 60 C. for 1 hour. Ethanol in the reaction solution was distilled off and the residue was washed with dichloromethane. The aqueous layer was acidified with diluted hydrochloric acid. After being extracted with ethyl acetate, the product was washed with saturated saline solution and dried with sodium sulfate. White solid, yield: 0.46 g, percent yield: 98.7%, m.p.: 114-116 C. IR KBr cm-1: 3562, 1692, 1557, 1395, 1287, 819.
67%	With lithium hydroxide monohydrate; water; In methanol; at 0 - 20℃; for 16h;	Lithium hydroxide monohydrate (1.46 g, 34.9 mmol) was added to a solution of <strong>[98273-19-9]methyl 4,6-dichloropicolinate</strong> (4.8 g, 23.3 mmol) in methanol: water (100 mL, 1 :0.1 v/v) at 0C. The reaction mixture was warmed to room temperature and stirred for 16h. The reaction mixture was concentrated under reduced pressure to get crude product which was diluted with water. The crude was acidified by 2N hydrochloric acid at 0C to get white precipitate. The precipitate was filtered and dried under vacuum to get 3.0 g of 4,6-dichloropicolinic acid. Yield: 67%. (0661) ES-MS [M+H]+: 190.02; Rt = 1.55 min (Method B).

Reference： [1]Patent: US6610853,2003,B1
[2]Patent: WO2018/122775,2018,A1 .Location in patent: Page/Page column 98-99

12
[ 98273-19-9 ]
[ 132683-62-6 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; diisobutylaluminium hydride; In water; toluene;	2-Formyl-4,6-dichloropyridine To a solution of 2-carbomethoxy-4,6-dichloropyridine (206 mg, 1 mmol) in 4 mL of dry toluene at -78 in a 25 mL round bottomed flask fitted with a stirrer bar and rubber septum, prepared by the procedure of D. G. Markees (vide supra) was slowly added 1.33 mL of 1.5M DIBAL (2 equivalents) in toluene. The mixture was stirred at -78 for 45 minutes, then at -50 for 30 minutes. The mixture was quenched with saturated ammonium chloride. After the effervescence ceased, the mixture was poured into 10 mL of water and extracted with 2*20 mL of methylene chloride. The organic layer was dried over anhydrous MgSO4, filtered and the solvent volume reduced. The residue was purifed by flash chromatography (85/15 hexane/ethyl acetate). Recovered 75 mg of product. NMR (CDCl3 200 Mhz): delta 7.59 (d, 1H, J=2 Hz), 7.87 (d, 1H, J=2 Hz), 9.97 (s, 1H).

Reference： [1]Patent: US5750549,1998,A

13
[ 110-91-8 ]
[ 98273-19-9 ]
[ 1186112-06-0 ]
[ 1353875-78-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; XPhos;palladium diacetate; In toluene; at 100℃; for 18h;	A screw-cap vial was charged with <strong>[98273-19-9]methyl 4,6-dichloropicolinate</strong> (0.300 g, 1.46 mmol), potassium carbonate (0.302 g, 2.18 mmol), palladium (II) acetate (0.016 g, 0.073 mmol), XPhos (0.104 g, 0.22 mmol), morpholine (0.127 mL, 1.46 mmol), and toluene (5 mL). The yellow solution was stirred at 100 C for 18 h, filtered through Celite and coned. The crude material was purified by columnchromatography (silica, 0-50% EtOAc in hexanes) to afford (in order of elution) methyl 4-chloro-6-morpholinopicolinate and methyl 6-chloro-4-morpholino- picolinate as white amorphous solids. Isomers assigned by NOESY. Mass Spectrum (ESI) m/e = 257.0 (M + 1); 257.0 (M + 1).
	With potassium carbonate;palladium diacetate; XPhos; In toluene; at 100℃; for 18h;	Methyl 4-chloro-6- and methyl 6-chloro-4-morpholinopicolinateA screw-cap vial was charged with <strong>[98273-19-9]methyl 4,6-dichloropicolinate</strong> (0.300 g, 1.456 mmol), potassium carbonate (0.302 g, 2.184 mmol), palladium (II) acetate (0.016 g, 0.073 mmol), XPhos (0.104 g, 0.22 mmol), morpholine (0.127 mL, 1.46 mmol), and toluene (5 mL). The yellow solution was stirred at 100 C for 18 h, then filtered through Celite and concentrated. The crude material was purified by column chromatography (silica, 0-50% ethyl acetate in hexanes) to afford (in order of elution) methyl 4-chloro-6-morpholinopicolinate and methyl 6-chloro-4- morpholinopicolinate as white amorphous solids. Isomers assigned by NOESY. Mass Spectrum (ESI) m/e = 257.0 (M + 1); 257.0 (M + 1).

Reference： [1]Patent: WO2012/3283,2012,A1 .Location in patent: Page/Page column 209-210
[2]Patent: WO2012/3264,2012,A1 .Location in patent: Page/Page column 56

14
[ 98273-19-9 ]
[ 1353875-68-9 ]

Reference： [1]Patent: WO2012/3283,2012,A1
[2]Patent: WO2012/3264,2012,A1

15
[ 98273-19-9 ]
[ 1353875-69-0 ]

Reference： [1]Patent: WO2012/3283,2012,A1
[2]Patent: WO2012/3264,2012,A1

16
[ 98273-19-9 ]
[ 1353875-54-3 ]

Reference： [1]Patent: WO2012/3283,2012,A1
[2]Patent: WO2012/3264,2012,A1

17
[ 98273-19-9 ]
[ 1353875-70-3 ]

Reference： [1]Patent: WO2012/3283,2012,A1
[2]Patent: WO2012/3264,2012,A1

18
[ 98273-19-9 ]
[ 1353875-71-4 ]

Reference： [1]Patent: WO2012/3283,2012,A1
[2]Patent: WO2012/3264,2012,A1

19
[ 98273-19-9 ]
[ 1353875-55-4 ]

Reference： [1]Patent: WO2012/3283,2012,A1
[2]Patent: WO2012/3264,2012,A1

20
[ 98273-19-9 ]
[ 1355052-34-4 ]
[ 1355052-62-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With tetrabutyl ammonium fluoride;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In tetrahydrofuran; at 60℃; for 14h;Inert atmosphere;	Step 1 : Synthesis of Pyridine amide 10[0444] According to Scheme 34, a 100 mL round bottom flask was charged with diphenyl ether borate 4 (3.14 g, 10 mmol), 2,4-dichloropyridine ester (Astatech, 2.05 g, 10 mmol), Pd(dppf)Cl2 (408 mg, 0.50 mmol) and a THF solution of TBAF (IN in THF). The mixture was purged with argon and stirred at 60C under argon for 14 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The EtOAc was isolated and dried over MgS04. The EtOAc was evaporated and the residue was subjected to flash column chromatography (hexanes/EtOAc) to give compound 9 as white solid (yield 75%) (/n/z + H) 358.
33%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water;Inert atmosphere; Reflux;	Step 1:Scheme 45Sythesis of methyl 4-chloro-6-(4-(4-fluorophenoxy)phenyl)picolinate4,6-Dichloropicolinate was synthesized according to the procedures described in WO 2006/053227. To a solution of the <strong>[98273-19-9]methyl 4,6-dichloropicolinate</strong> (2.52 g, 12.2 mmol) in dioxane (100 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (3.83 g, 12.2 mmol), 2M aqueous Na2C03 solution (12.5 mL, 25 mmol) and PdCl2(dppf) (0.502 g, 0.62 mmol). The vessel was heated at reflux under nitrogen overnight. After cooling, the reaction was partitioned between 100 mL EtOAc and 50 mL brine and washed with additional brine. The organics were dried over MgS04, filtered and concentrated in vacuo. The residue was dissolved in MeOH (150 mL) and concentrated H2S04 (1.5 mL) was added. The vessel was heated at reflux under nitrogen overnight. After cooling the reaction was quenched by addition of 10 g NaHC03. The mixture was evaporated in vacuo and the residue partitioned between 100 mL EtOAc and 50 mL brine. The organics were washed once with 50 mL brine. The combined aqueous washes were extracted once with 50 mL EtOAc. The combined organics were dried over MgS04, filtered and concentrated in vacuo. The residue was chromatographed over silica gel eluting with 5-25% EtOAc in hexanes. The product fractions were isolated and evaporated in vacuo to yield the product methyl 4-chloro-6-(4-(4-fluorophenoxy)phenyl)picolinate as a pale tan oil (1.426 g, 3.99 mmol, 33% yield, LC/MS: m/z = 358.1 [M+H]+).

Reference： [1]Patent: WO2012/35421,2012,A2 .Location in patent: Page/Page column 199
[2]Patent: WO2012/7836,2012,A1 .Location in patent: Page/Page column 119

21
[ 98273-19-9 ]
[ 1359844-10-2 ]
[ 1367127-90-9 ]
[ 1367127-88-5 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutyl ammonium fluoride;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In tetrahydrofuran; at 50 - 55℃;Inert atmosphere;	Step 3: Synthesis of methyl 6-chloro-4-(4'-fluoro-[l,r-biphenyl]-4- yl)picolinate (compound I) and methyl 4-chloro-6-(4'-fluoro-[l ,l'-biphenyl]- 4-yl)picolinate (compound II)To THF (62 mL) degassed by purging argon was added 2-(4'-fluoro- [l,l'-biphenyl]-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.1 g, 10.3 mmol), <strong>[98273-19-9]methyl 4,6-dichloropicolinate</strong> (2.132 g, 10.3 mmol) and tetrabutylammonium fluoride (1M in THF, 20.7 mL, 20.7 mmol), and the mixture was degassed again. Pd(dppf)Cl2 (372 mg, 0.51 mmol) was added and the reaction mixture was degassed again for 15 minutes. The reaction mixture was heated at 50C in an oil bath overnight. TLC (silica gel, 4/1 heptane / ethyl acetate) showed the reaction had not gone to completion. After heating at 55C for an additional four hours, TLC showed almost complete reaction. The reaction was diluted with ethyl acetate and extracted with brine. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (230-400 mesh silica gel) to give compound I (1.0 g) which eluted with 0- 6% ethyl acetate in heptane and compound II (0.80 g) which eleuted with 8-12% ethyl acetate in heptane.

Reference： [1]Patent: WO2012/35421,2012,A2 .Location in patent: Page/Page column 294-295

22
[ 98273-19-9 ]
potassium trifluoro(3-{2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl}phenyl)boranuide [ No CAS ]
ethyl 4-chloro-6-(3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; at 70℃;	Similar to as described in General Procedure U, <strong>[98273-19-9]methyl 4,6-dichloropyridine-2-carboxylate</strong> was reacted with potassium(R)-trifluoro(3-((3 -hydroxy- 1 -methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the titlecompound (400 mg, 21%) as a light brown solid. LC-MS (ES, mlz): 399 [M+H]. A tube containing a solution of arylchloride/bromide (1 eq) and aryltrifluoroborate (1 eq) in Ethanol was purged with nitrogen before addition of Pd(OAc)2 (0.06 eq), RuPhos (0.12 eq), and Sodium Carbonate (2 eq). The tube was sealed with a cap lined with a disposable Teflon septum was heated at 85 C for 12-20 hours. The reaction mixture was allowedto cool to room temperature and was either filtered through Celite and submitted directly to reverse phase HPLC purification or extracted with dichloromethane and a solution of saturated ammonium chloride before drying, evaporating and submitting to reverse phase purification or using in the subsequent step without purification.

Reference： [1]Patent: WO2015/25026,2015,A1 .Location in patent: Page/Page column 97; 263

23
[ 98273-19-9 ]
(4,6-dichloropyridin-2-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With diisobutylaluminium hydride; In hexane; dichloromethane; at -78 - 20℃;Inert atmosphere;	[01161] DIBAL-H (73 mL, 1M in hexane, 3.00 equiv) was added dropwise into a solution of <strong>[98273-19-9]methyl 4,6-dichloropyridine-2-carboxylate</strong> (5 g, 24.26 mmol, 1.00 equiv) in dichloromethane (100 mL) at -78C under N2. The resulting solution was stirred for overnight at room temperature. The reaction was quenched by methanol and concentrated under vacuum. The residue was purified by a silica gel colunm eluting with ethyl acetate/petroleum ether (1/20) to afford the title compound (9.5 g, 84%) aslight yellow solid. LCMS [M+H] 178.
84%	With diisobutylaluminium hydride; In hexane; dichloromethane; at -78 - 20℃;Inert atmosphere;	DIBAL-H (73 mL, 1 M in hexane, 3.00 equiv) was added dropwise into a solution of <strong>[98273-19-9]methyl 4,6-dichloropyridine-2-carboxylate</strong> (5 g, 24.26 mmol, 1.00 equiv) in dichloromethane (100 mL) at -78 C under N2. The resulting solution was stirred for overnight at room temperature. The reaction was quenched by methanol and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1/20) to afford the title compound (9.5 g, 84%) as a light yellow solid. LCMS [M+H+] 178
	With methanol; sodium tetrahydroborate; at 0 - 70℃; for 24.25h;	To a stirred solution of 72 (20.0 g, 97 mmol) in CH3OH (80 mL) was charged with NaBH4 (14.35 g, 388 mmol) portionwise for 15 mm at 0C. The reaction mixture was stirred at 70C for 24 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and portioned between water (200 mL) and EtOAc (3x300 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL). Theorganic layer was dried over anhydrous Na2504 and concentrated in vacuo to afford 73 [18.5 g (crude)j as a solid. MS (MM) m/z 179.1 [M + Hj.

With methanol; sodium tetrahydroborate; at 0 - 70℃; for 24h;

Preparation of 1-73: A stirred solution of 1-72 (20.0 g, 97 mmol) in CH3OH (80 mL) was charged with NaBH4 (14.35 g, 388 mmol) portion wise for 15 min at 0C. The reaction mixture was stirred at 70C for 24 h. The reaction mixture was cooled to RT, concentrated under reduced pressure and partitioned between water (200 mL) and EtOAc (3 chi 300 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo to afford 1-73 as a solid. (0266) MS (MM) m/z 179.1 [M + H]+.

Reference： [1]Patent: WO2016/128529,2016,A1 .Location in patent: Paragraph 01159; 01160; 01161
[2]Patent: WO2018/15410,2018,A1 .Location in patent: Paragraph 0454-0457
[3]Patent: WO2017/7700,2017,A1 .Location in patent: Page/Page column 134
[4]Patent: WO2017/189386,2017,A1 .Location in patent: Page/Page column 32

24
[ 98273-19-9 ]
2-((4,6-dichloropyridin-2-yl)methyl)isoindoline-1,3-dione [ No CAS ]

Reference： [1]Patent: WO2016/128529,2016,A1
[2]Patent: WO2018/15410,2018,A1

25
[ 98273-19-9 ]
2-((4-chloro-6-cyclopropylpyridin-2-yl)methyl)isoindoline-1,3-dione [ No CAS ]

Reference： [1]Patent: WO2016/128529,2016,A1
[2]Patent: WO2018/15410,2018,A1

26
[ 98273-19-9 ]
2-((6-cyclopropyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione [ No CAS ]

Reference： [1]Patent: WO2016/128529,2016,A1
[2]Patent: WO2018/15410,2018,A1

27
[ 98273-19-9 ]
C₁₄H₁₃F₃N₄ [ No CAS ]

Reference： [1]Patent: WO2016/128529,2016,A1
[2]Patent: WO2018/15410,2018,A1

28
[ 98273-19-9 ]
C₇H₇Cl₂NO₃S [ No CAS ]

Reference： [1]Patent: WO2017/7700,2017,A1
[2]Patent: WO2017/189386,2017,A1

29
[ 98273-19-9 ]
C₆H₄Cl₂N₄ [ No CAS ]

Reference： [1]Patent: WO2017/7700,2017,A1
[2]Patent: WO2017/189386,2017,A1

30
[ 98273-19-9 ]
C₆H₆Cl₂N₂*ClH [ No CAS ]

Reference： [1]Patent: WO2017/7700,2017,A1

31
[ 98273-19-9 ]
C₇H₆Cl₂N₂O [ No CAS ]

Reference： [1]Patent: WO2017/7700,2017,A1
[2]Patent: WO2017/189386,2017,A1

32
[ 98273-19-9 ]
C₇H₄Cl₂N₂ [ No CAS ]

Reference： [1]Patent: WO2017/7700,2017,A1
[2]Patent: WO2017/189386,2017,A1

33
[ 98273-19-9 ]
C₁₃H₁₇ClN₄O₂S [ No CAS ]

Reference： [1]Patent: WO2017/7700,2017,A1

34
[ 98273-19-9 ]
C₁₈H₂₅ClN₄O₂ [ No CAS ]

Reference： [1]Patent: WO2017/7700,2017,A1

35
[ 98273-19-9 ]
C₁₃H₁₇ClN₄*ClH [ No CAS ]

Reference： [1]Patent: WO2017/7700,2017,A1

36
[ 98273-19-9 ]
C₁₅H₁₉ClN₄O [ No CAS ]

Reference： [1]Patent: WO2017/7700,2017,A1

37
[ 98273-19-9 ]
4-{7-chloroimidazo[1,5-a]pyridin-5-yl}-1-methanesulfonyl-2,2-dimethylpiperazine [ No CAS ]

Reference： [1]Patent: WO2017/7700,2017,A1

38
[ 67-56-1 ]
[ 88912-25-8 ]
[ 98273-19-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 20 - 70℃; for 2h;	To a stirred solution of 71 (20.0 g, 104.1 mmol) in CH3OH (200 mL) was charged with conc H2S04 (1.0 mL) at room temperature. The reaction mixture was heated at 70C for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (100 mL) and poured into saturated NaHCO3 solution (80 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (2450 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 72 [20.0 g (crude)j as a liquid. MS (MM) m/z 207.1 [M + Hj.
	With sulfuric acid; at 70℃; for 2h;	Preparation of 1-72: A stirred solution of 1-71 (20.0 g, 104.1 mmol) in CH3OH (200 mL) was charged with cone H2SO4 (1.0 mL) at RT. The reaction mixture was heated at 70C for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (100 mL) and poured into saturated NaHCC solution (80 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 chi 150 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford 1-72 as a liquid. (0264) MS (MM) m/z 207.1 [M + H]+.

Reference： [1]Patent: WO2017/7700,2017,A1 .Location in patent: Page/Page column 134
[2]Patent: WO2017/189386,2017,A1 .Location in patent: Page/Page column 32

39
[ 98273-19-9 ]
C₆H₆Cl₂N₂*(x)ClH [ No CAS ]

Reference： [1]Patent: WO2017/189386,2017,A1

40
[ 98273-19-9 ]
8-{7-chloroimidazo[1,5-a]pyridin-5-yl}-6,6-dimethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione [ No CAS ]

Reference： [1]Patent: WO2017/189386,2017,A1

41
[ 98273-19-9 ]
8-{7-chloroimidazo[1,5-a]pyridin-5-yl}-1,3,8-triazaspiro[4.5]decane-2,4-dione [ No CAS ]

Reference： [1]Patent: WO2017/189386,2017,A1

42
[ 98273-19-9 ]
2-((benzyl(methyl)amino)methyl)-6-chloropyridin-4-amine [ No CAS ]

Reference： [1]Patent: WO2018/122775,2018,A1

43
[ 98273-19-9 ]
6-((benzyl(methyl)amino)methyl)-N-(p-tolyl)pyridine-2,4-diamine [ No CAS ]

Reference： [1]Patent: WO2018/122775,2018,A1

44
[ 98273-19-9 ]
N-benzyl-4,6-dichloro-N-methylpicolinamide [ No CAS ]

Reference： [1]Patent: WO2018/122775,2018,A1

45
[ 98273-19-9 ]
N-benzyl-1-(4,6-dichloropyridin-2-yl)-N-methylmethanamine [ No CAS ]

Reference： [1]Patent: WO2018/122775,2018,A1

46
[ 75-30-9 ]
[ 98273-19-9 ]
methyl 4,6-dichloro-5-isopropylpyridine-2-carboxylate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 10933 - 10940

47
[ 75-30-9 ]
[ 98273-19-9 ]
methyl 6-chloro-5-isopropylpyridine-2-carboxylate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 10933 - 10940

48
bromo(cyclopropyl)zinc [ No CAS ]
[ 98273-19-9 ]
methyl 4-chloro-6-cyclopropylpyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
600 mg	With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60 - 65℃; for 24h;	To a solution of methyl 4,6- dichloropyridine-2-carboxylate (1.0 g, 4.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.29 mmol) in THF (11 mL) was added bromo(cyclopropyl)zinc (11 mL of 0.5 M solution in THF, 5.6 mmol). The solution was heated at 60-65 C for 24 h. The solution was allowed to cool to rt, then poured into saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic phases were dried, filtered and concentrated onto Celite. Purification was by silica gel chromatography using 0-15% EtO Ac/hex to afford the title compound (600 mg) as a colorless solid.

Reference： [1]Patent: WO2019/148005,2019,A1 .Location in patent: Paragraph 1812

49
[ 98273-19-9 ]
methyl 6-cyclopropyl-4-[(4-methoxyphenyl)methoxy]pyridine-2-carboxylate [ No CAS ]