[ CAS No. 13958-93-5 ] {[proInfo.proName]}

Name: 13958-93-5|3,5-Dichloroisonicotinic acid|97%
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Quality Control of [ 13958-93-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 13958-93-5 ]

Product Details of [ 13958-93-5 ]

CAS No. :	13958-93-5	MDL No. :	MFCD01861975
Formula :	C₆H₃Cl₂NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BUQPTOSHKHYHHB-UHFFFAOYSA-N
M.W :	192.00	Pubchem ID :	605763
Synonyms :

Calculated chemistry of [ 13958-93-5 ]

Physicochemical Properties

Num. heavy atoms :	11
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 :	41.22
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) :	1.09
Log Po/w (XLOGP3) :	1.63
Log Po/w (WLOGP) :	2.09
Log Po/w (MLOGP) :	0.09
Log Po/w (SILICOS-IT) :	2.04
Consensus Log Po/w :	1.39

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.39
Solubility :	0.773 mg/ml ; 0.00403 mol/l
Class :	Soluble
Log S (Ali) :	-2.3
Solubility :	0.97 mg/ml ; 0.00505 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.63
Solubility :	0.446 mg/ml ; 0.00232 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.41

Safety of [ 13958-93-5 ]

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 [ 13958-93-5 ]

* 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 [ 13958-93-5 ]
Downstream synthetic route of [ 13958-93-5 ]

[ 13958-93-5 ] Synthesis Path-Upstream 1~8

1
[ 124-38-9 ]
[ 2457-47-8 ]
[ 13958-93-5 ]

Yield	Reaction Conditions	Operation in experiment
41%	With lithium diisopropyl amide In tetrahydrofuran at -78 - 20℃; for 2 h;	Intermediate 1 3.5-Dichloropyridine-4-carboxylic acid A solution of 3,5-dichloropyridine (5.00 g, 33.8 mmol) in THF (25 ml) was added to a solution of LDA [generated from NBuLi (2.5M solution hexanes, 14.9 ml, 37.2 mmol) and diisopropylamine (4.10 g, 5.7 ml, 40.6 mmol)] in THF (25 ml) at -78° then CO2 gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to room temperature over 2 h, then quenched with water (20 ml) and partitioned between diethylether (100 ml) and 1M NaOH (100 ml).. The aqueous layer was separated and acidified to PH1 with concentrated hydrochloric acid and then extracted with 10percent MeOH in DCM (100 ml*3).. The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to give a brown solid that was recrystallized from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63 g, 41percent): δH (DMSO d6) 8.72 (2H, s).
41%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 2 h;	A solution of 3, [5-DICHLOROPYRIDINE] (5. [00G,] 33. [8MMOL)] in THF [(25ML)] was added to a solution of LDA [generated from nBuLi (2.5M solution in hexanes, 14. [9MI,] 37. [2MMOL)] and diisopropylamine (4. 10g, 5. [7MOI,] 40. 6mmol)] in THF [(25MOI)] [AT-78 . ? UNDER] nitrogen, to give a yellow/brown slurry. The reaction was stirred for 30min [AT-78XB0;] then C02 gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to room temperature over 2h, then quenched with water [(20MI)] and partitioned between [ET2O] [(100MOI)] and [1 M NAOH] [(100ML).] The aqueous layer was separated and acidified to pH 1 with concentrated hydrochloric acid and then extracted with 10percent [MEOH] in DCM [(100MIX3).] The combined organic layers were dried [(MGS04)] and the solvent removed under vacuum to give a brown solid that was [RECRYSTALLISED] from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63g, [41percent). 8H] (DMSO-d6) 8.74 (2H, s).
41%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 2 h;	A solution of 3, [5-DICHLOROPYRIDINE (5. 00G,] 33. [8MMOL)] in THF [(25ML)] was added to a solution of LDA [generated from nBuLi (2.5M solution in hexanes, 14. [9MOI,] 37. [2MMOL)] and diisopropylamine (4. [1 OU,] 5. [7MI,] 40. 6mmol)] in THF [(25ML)] at- [78-UNDER] nitrogen, to give a [YELLOW/BROWN SLURRY.] The reaction was stirred for 30min [AT-78G] then COs gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to RT over 2h, then quenched with water [(20MI)] and partitioned between [ET20] [(100ML)] and [1 M NAOH] [(100MI).] The aqueous layer was separated and acidified to pH 1 with concentrated hydrochloric acid and then extracted with 10percent [MEOH] in DCM [(1 00MIX3).] The combined organic layers were dried [(MGS04)] and the solvent removed under vacuum to give a brown solid that was recrystallised from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63g, [41percent). 5H] (DMSO-d6) 8.74 (2H, s). 8C (DMSO-d6) 163.5, 147.7, 141.0, 126.7.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 3, p. 567 - 571
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 4, p. 709 - 712
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 1, p. 386 - 390
[4] Patent: US6348463, 2002, B1, . Location in patent: Page column 18
[5] Patent: WO2004/6918, 2004, A1, . Location in patent: Page/Page column 15
[6] Patent: WO2004/7428, 2004, A1, . Location in patent: Page 42
[7] Journal of Medicinal Chemistry, 1989, vol. 32, # 9, p. 2178 - 2199
[8] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 12, p. 1591 - 1594
[9] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 7, p. 1051 - 1054
[10] Patent: WO2014/131855, 2014, A1, . Location in patent: Page/Page column 53

2
[ 2457-47-8 ]
[ 13958-93-5 ]

Reference： [1] Patent: US2003/8861, 2003, A1,
[2] Patent: US2002/193399, 2002, A1,
[3] Patent: EP1325903, 2003, A1,

3
[ 75-09-2 ]
[ 2457-47-8 ]
[ 13958-93-5 ]

Reference： [1] Patent: US4592866, 1986, A,
[2] Patent: US4705853, 1987, A,

4
[ 55-22-1 ]
[ 13958-93-5 ]
[ 88912-27-0 ]

Reference： [1] Chemische Berichte, 1928, vol. 61, p. 2214

5
[ 42935-09-1 ]
[ 13958-93-5 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1937, vol. <2> 148, p. 13,16

6
[ 55-22-1 ]
[ 7719-09-7 ]
[ 13958-93-5 ]
[ 88912-27-0 ]

Reference： [1] Chemische Berichte, 1928, vol. 61, p. 2214

7
[ 55-22-1 ]
[ 13958-93-5 ]
[ 88912-27-0 ]

Reference： [1] Chemische Berichte, 1928, vol. 61, p. 2214

8
[ 55-22-1 ]
[ 7719-09-7 ]
[ 13958-93-5 ]
[ 88912-27-0 ]

Reference： [1] Chemische Berichte, 1928, vol. 61, p. 2214

[ 13958-93-5 ] Synthesis Path-Downstream 1~87

1
[ 13958-93-5 ]
[ 2457-47-8 ]

Reference： [1]Chemische Berichte,1928,vol. 61,p. 2214

2
[ 42935-09-1 ]
[ 13958-93-5 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1937,vol. <2> 148,p. 13,16

3
[ 13220-33-2 ]
[ 13958-93-5 ]
Sodium; 3-chloro-5-(1-methyl-pyrrolidin-3-yloxy)-isonicotinate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2178 - 2199

4
[ 124-38-9 ]
[ 2457-47-8 ]
[ 13958-93-5 ]

Yield	Reaction Conditions	Operation in experiment
41%	With lithium diisopropyl amide; In tetrahydrofuran; at -78 - 20℃; for 2h;	Intermediate 1 3.5-Dichloropyridine-4-carboxylic acid A solution of 3,5-dichloropyridine (5.00 g, 33.8 mmol) in THF (25 ml) was added to a solution of LDA [generated from NBuLi (2.5M solution hexanes, 14.9 ml, 37.2 mmol) and diisopropylamine (4.10 g, 5.7 ml, 40.6 mmol)] in THF (25 ml) at -78 then CO2 gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to room temperature over 2 h, then quenched with water (20 ml) and partitioned between diethylether (100 ml) and 1M NaOH (100 ml).. The aqueous layer was separated and acidified to PH1 with concentrated hydrochloric acid and then extracted with 10% MeOH in DCM (100 ml*3).. The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to give a brown solid that was recrystallized from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63 g, 41%): deltaH (DMSO d6) 8.72 (2H, s).
41%		A solution of 3, [5-DICHLOROPYRIDINE] (5. [00G,] 33. [8MMOL)] in THF [(25ML)] was added to a solution of LDA [generated from nBuLi (2.5M solution in hexanes, 14. [9MI,] 37. [2MMOL)] and diisopropylamine (4. 10g, 5. [7MOI,] 40. 6mmol)] in THF [(25MOI)] [AT-78 . ? UNDER] nitrogen, to give a yellow/brown slurry. The reaction was stirred for 30min [AT-78XB0;] then C02 gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to room temperature over 2h, then quenched with water [(20MI)] and partitioned between [ET2O] [(100MOI)] and [1 M NAOH] [(100ML).] The aqueous layer was separated and acidified to pH 1 with concentrated hydrochloric acid and then extracted with 10% [MEOH] in DCM [(100MIX3).] The combined organic layers were dried [(MGS04)] and the solvent removed under vacuum to give a brown solid that was [RECRYSTALLISED] from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63g, [41%). 8H] (DMSO-d6) 8.74 (2H, s).
41%		A solution of 3, [5-DICHLOROPYRIDINE (5. 00G,] 33. [8MMOL)] in THF [(25ML)] was added to a solution of LDA [generated from nBuLi (2.5M solution in hexanes, 14. [9MOI,] 37. [2MMOL)] and diisopropylamine (4. [1 OU,] 5. [7MI,] 40. 6mmol)] in THF [(25ML)] at- [78-UNDER] nitrogen, to give a [YELLOW/BROWN SLURRY.] The reaction was stirred for 30min [AT-78G] then COs gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to RT over 2h, then quenched with water [(20MI)] and partitioned between [ET20] [(100ML)] and [1 M NAOH] [(100MI).] The aqueous layer was separated and acidified to pH 1 with concentrated hydrochloric acid and then extracted with 10% [MEOH] in DCM [(1 00MIX3).] The combined organic layers were dried [(MGS04)] and the solvent removed under vacuum to give a brown solid that was recrystallised from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63g, [41%). 5H] (DMSO-d6) 8.74 (2H, s). 8C (DMSO-d6) 163.5, 147.7, 141.0, 126.7.

To a solution of the commercially available 3,5-dichloropyridine (10 g, 0.067mol) in THE (20 mL) was added LDA (60 mL, 0.074 mol), the reaction was stirred at 780C for 1 hour. Then dry ice (5.9 g, 0.134 mol) was added to the solution. After 0.5 h, the mixture was quenched by adding water and adjusted the pH to 3-4. The solution was partitioned with EA and water. The combined organic layers were washed with brine, dried over anhydrous Na2504 andconcentrated to give the crude product KR-i (7 g, 55% yield) as a pale white solid. ESI-MS (Mi-i): 192 calc. for C6H3C12N02: 190.95.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 567 - 571
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 709 - 712
[3]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 386 - 390
[4]Patent: US6348463,2002,B1 .Location in patent: Page column 18
[5]Patent: WO2004/6918,2004,A1 .Location in patent: Page/Page column 15
[6]Patent: WO2004/7428,2004,A1 .Location in patent: Page 42
[7]Journal of Medicinal Chemistry,1989,vol. 32,p. 2178 - 2199
[8]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 1591 - 1594
[9]Patent: WO2014/131855,2014,A1 .Location in patent: Page/Page column 53

5
[ 287202-42-0 ]
[ 13958-93-5 ]
4-(4-but-2-ynyloxy-benzenesulfonylmethyl)-1-(3,5-dichloro-pyridine-4-carbonyl)-piperidine-4-carboxylic acid <i>tert</i>-butoxy-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 34 - 39

6
[ 13958-93-5 ]
4-(4-but-2-ynyloxy-benzenesulfonylmethyl)-1-(3,5-dichloro-pyridine-4-carbonyl)-piperidine-4-carboxylic acid hydroxyamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 34 - 39

7
[ 13958-93-5 ]
(S)-3-[2-(2,6-Dichloro-phenyl)-benzooxazol-5-yl]-2-[(3,5-dichloro-pyridine-4-carbonyl)-amino]-propionic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2331 - 2334

8
[ 13958-93-5 ]
(4-{(4-Bromo-phenyl)-[(Z)-ethoxyimino]-methyl}-4'-methyl-[1,4']bipiperidinyl-1'-yl)-(3,5-dichloro-1-oxy-pyridin-4-yl)-methanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 709 - 712

9
[ 13958-93-5 ]
(3,5-Dichloro-1-oxy-pyridin-4-yl)-(4-methyl-4-{(S)-3-methyl-4-[(S)-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-piperidin-1-yl)-methanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 567 - 571

10
[ 13958-93-5 ]
[ 263276-28-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1051 - 1054
[2]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 1591 - 1594

11
[ 13958-93-5 ]
[ 263276-03-5 ]

Reference： [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 1591 - 1594
[2]Patent: WO2006/115918,2006,A2

12
[ 13958-93-5 ]
(S)-3-{4-[(3,5-Dichloro-pyridine-4-carbonyl)-amino]-phenyl}-2-(2-isopropoxy-3,4-dioxo-cyclobut-1-enylamino)-propionic acid ethyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1051 - 1054

13
[ 13958-93-5 ]
S-3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)propanoic acid [ No CAS ]

Reference： [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 1591 - 1594

14
[ 13958-93-5 ]
[ 479667-30-6 ]

Reference： [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 1591 - 1594

15
[ 13958-93-5 ]
[ 117449-96-4 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2178 - 2199

16
[ 13958-93-5 ]
[ 117449-50-0 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2178 - 2199

17
[ 13958-93-5 ]
[ 544704-09-8 ]
C₂₅H₃₁Cl₂IN₄O [ No CAS ]

Reference： [1]Patent: US6391865,2002,B1 .Location in patent: Page column 73

18
[ 13958-93-5 ]
[ 544704-10-1 ]
C₂₆H₃₁Cl₂N₅O [ No CAS ]

Reference： [1]Patent: US6391865,2002,B1 .Location in patent: Page column 84

19
[ 13958-93-5 ]
[ 264123-70-8 ]

Yield	Reaction Conditions	Operation in experiment
		3,5-Dichloroisonicotinic acid (5 g) was suspended in 12 mL of thionyl chloride and stirred under reflux for 18 hours. The reaction mixture was concentrated. The resulting acid chloride (1.30 g, 6.2 mmol) was dissolved in 5 mL of 1,4-dioxane at 0C. The reaction mixture was stirred at 0C for 15 minutes and allowed to warm to room temperature and stirred for an additional 30 minutes. It was then cooled to 0C and carefully quenched with 15 mL of water. The reaction mixture was extracted with CH2Cl2 and the combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by chromatography (3: 1 hexanes/EtOAc) to afford 650 mg of the alcohol intermediate. This alcohol intermediate was dissolved in 1 mL of thionyl chloride and stirred under reflux for an hour. The resulting reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the chloromethyl pyridine derivative as a yellow solid.

Reference： [1]Patent: WO2004/92170,2004,A2 .Location in patent: Page 23; 24

20
[ 13958-93-5 ]
[ 70593-51-0 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 1A 3,5-Dichloroisonicotinamide A solution of <strong>[13958-93-5]3,5-dichloro-isonicotinic acid</strong> (9.54 g, 49.6 mmol, commercially available form TCI) in benzene (100 mL) was treated with oxalyl chloride (8.7 mL), a catalytic amount of DMF (5 drops), stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in diglyme (10 mL) and added dropwise to 35% NH2OH in water (150 mL). The mixture was filtered to provide 8.2 g of the title compound as a white powder. MS ((DCI (+)) m/e 190.9 (M+H)+.

Reference： [1]Patent: US2006/178378,2006,A1 .Location in patent: Page/Page column 16

21
[ 13958-93-5 ]
N-benzyl-3,3-difluoro-N-(4'-methyl-1,4'-bidiperidin-4-yl)cyclobutanecarboxamide dihydrochloride [ No CAS ]
N-benzyl-N-{1'-(3,5-dichloroisonicotinoyl)-4'-methyl-1,4'-bipiperidinyl-4-yl}-3,3-difluorocyclobutanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one; In dichloromethane; at 20℃; for 24h;	Example 8 difluorocyclobutanecarboxamide.2HCI; 3,5-Dichloroiso?icotinic acid (84mg, 0.4mmol), the compound of Preparation 42 (150mg, 0.3mmol), 3- (diethoxyphosphoryloxy)-1 ,2,3-benzotriazin-4(3H)-one (132mg, 0.4mmol) and triethylamine (0.16mL, 1.2mmol) were dissolved in dichloromethane and stirred at room temperature for 24hours. The reaction was quenched by the addition of saturated sodium hydrogen carbonate solution and extracted using dichloromethane. The combined organic extracts were concentrated in vacuo to give the crude product. The crude mixture was purified by column chromatography on silica gel using dichloromethane-.methanol EPO <DP n="35"/>(100:0 to 90:10) as eluent. The resulting product was then dissolved in dichloromethane (5mL) and treated with 2M hydrochloric acid in diethyl ether (5mL), the solvents were removed in vacuo to give 43mg of title compound as a white solid.1H NMR (400MHz CDCI3) delta 0.95 (3H, s), 1.20-1.85 (9H, m), 1.85-2.00 (1 H, m), 2.05-2.30 (2H, m), 2.45(1 H, bs), 2.70-3.10 (6H, m), 3.25-3.50 (2H, m), 4.05-4.20 (1H, m), 4.40-4.65 (2H, m), 7.10-7.40 (5H1 m),8.50 (2H, bs).LRMS: m/z APCI+579[MH+]

Reference： [1]Patent: WO2006/77499,2006,A1 .Location in patent: Page/Page column 33-34

22
[ 13958-93-5 ]
[ 55533-24-9 ]
N-(BOC)-4-((3',5'-dichloroisonicotinoyl)amino)-(L)-phenylalanine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; thionyl chloride; In dichloromethane; N,N-dimethyl-formamide;	Step A N-(BOC)-4-((3',5'-dichloroisonicotinoyl)amino)-(L)-phenylalanine, methyl ester A slurry of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (3.1 g, 16.11 mmol) in 10 mL of CH2Cl2 was treated with DMF (50 muL) and thionyl chloride (1.23 mL, 16.91 mmol) and heated to reflux for 5 h. The reaction was concentrated to give a yellow oil. This oil was dissolved in 5 mL of CH2Cl2 and added to N-(BOC)-4-amino-(L)-phenylalanine, methyl ester (4.00 g, 14.39 mmol) and 4-methylmorpholine (2.7 mL, 24.21 mmol) in 25 mL of CH2Cl2 at 0° C. After stirring for 2 h at this temperature, the reaction was quenched with water (50 mL) and extracted into CH2Cl2 (3*100 mL). The combined organics were combined, dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow solid. Trituration with CH2Cl2 gave 5.5 g of a while solid 1H NMR (500 MHz, CDCl3): delta 8.63 (s, 2H); 7.58 (d, J=8.2 Hz, 2H); 7.23 (d, J=8.2 Hz, 2H); 6.91 (d, J=8.4 Hz, 1H); 4.39 (m, 1H); 3.70 (s, 3H); 3.11 (m, 1H); 2.91 (m, 1H); 2.00 (s, 9H); MS m/e 468.20 (M+).

Reference： [1]Patent: US2003/8861,2003,A1

23
[ 2457-47-8 ]
[ 13958-93-5 ]

Yield	Reaction Conditions	Operation in experiment
	With CO2; diisopropylamine; In tetrahydrofuran;	REFERENCE EXAMPLE 1 3,5-Dichloroisonicotinic acid To a solution of 3,5-dichloropyridine (10.00 g, 67.57 mmol) in 70 mL of THF was added 35.4 mL of a 2.0 M solution of LDA in THF at -78 C. The reaction was stirred for 1 h, then CO2 gas was bubbled through the solution for 20 mins. The reaction was allowed to warm to rt over 1 h then quenched with 1N NaOH (100 mL) and washed with Et2O (50 mL). The aqueous layer was acidified with conc HCl which caused a precipitate to form. The precipitate was collected by filtration and recrystallized from EtOH to give the title compound as a pale yellow solid (7.1 g, 36.97 mmol, 55%). 1H NMR (500 MHz, DMSO-d6): delta 8.73 (s, 2H).
	With CO2; diisopropylamine; In tetrahydrofuran; TiF;	REFERENCE EXAMPLE 1 3,5-Dichloroisonicotinic acid To a solution of 3,5-dichloropyridine (10.00 g, 67.57 mmol) in 70 mL of THF was added 35.4 mL of a 2.0 M solution of LDA in TiF at -78 C. The reaction was stirred for 1 h, then CO2 gas was bubbled through the solution for 20 mins. The reaction was allowed to warm to rt over 1 h then quenched with 1N NaOH (100 mL) and washed with Et2O (50 mL). The aqueous layer was acidified with conc HCl which caused a precipitate to form. The precipitate was collected by filtration and recrystallized from EtOH to give the title compound as a pale yellow solid (7.1 g, 36.97 mmol, 55%). 1H NMR (500 MHz, DMSO-d6): delta8.73 (s, 2H).
	With hydrogenchloride; n-butyllithium; diisopropylamine; In tetrahydrofuran; water;	[Example 39] Preparation of 3-[4-(3,5-dichloropyridine-4-carbonylamino)phenyl]-2-{3-[(2,2-dimethylpropionyl)iso butylamino]-4-methoxyphenyl}propionic acid Diisopropylamine (31 mL, 221 mmol) was dissolved in tetrahydrofuran (200 mL), and the solution was added drop-wisely with a 1.6 mol/L hexane solution of n-butyllithium (128 mL, 205 mmol) at -78ØC. The mixture was stirred for 15 minutes, and was added drop-wisely with a tetrahydrofuran solution (200 mL) of 3,5-dichloropyridine (25.1 g, 170 mmol) while keeping the temperature at -78ØC, and then stirred for additional 1 hour. The reaction solution was added with dry ice to thereby gradually heat to room temperature, and further stirred for 15 hours. The mixture was treated with water (1 L), added with a 1 mol/L aqueous sodium hydroxide solution (100 mL), and washed with ether. The separated aqueous phase was adjusted to be acidic using a 6 mol/L hydrochloric acid, and the resultant precipitate was collected by filtration. The filtrate was extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate, evaporated under reduced pressure so as to remove the solvent, and the mixture of the resultant residue and the precipitate previously colleted were re-crystallized from ethanol, which yielded 3,5-dichloropyridine-4-carboxylic acid (yield: 23 g, yield ratio: 70%) as a yellow crystal.

Reference： [1]Patent: US2003/8861,2003,A1
[2]Patent: US2002/193399,2002,A1
[3]Patent: EP1325903,2003,A1

24
[ 109-02-4 ]
[ 136081-18-0 ]
[ 13958-93-5 ]
3,5-Dichloro-N-[4-(2-hydroxy-ethyl)-benzyl]-isonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With benzotriazol-1-ol; In N,N-dimethyl-formamide;	Preparation of 3,5-Dichloro-N-[4-(2-hydroxy-ethyl)-benzyl]-isonicotinamide: Using the EDCI coupling general procedure F: Reaction of 2-(4-Aminomethyl-phenyl)-ethanol (306 mg, 2.03 mmol), <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (385 mg, 2.03 mmol), 1-hydroxybenzotriazole (301 mg, 2.22 mmol), 4-methyl morpholine (0.50 mL, 4.45 mmol), and EDCI (426 mg, 2.22 mmol) in anhydrous DMF (5 mL) overnight at room temperature and overnight at 40 C. followed by column chromatography on silica gel (2:2:96 MeOH-NH4OH-CH2Cl2) gave the title compound (291 mg, 44%) as a white foam.

Reference： [1]Patent: US2002/147192,2002,A1

25
[ 13958-93-5 ]
[ 623-04-1 ]
3,5-dichloro-N-(4-hydroxymethyl-phenyl)-isonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	In tetrahydrofuran; thionyl chloride;	Preparation of 3,5-dichloro-N-(4-hydroxymethyl-phenyl)-isonicotinamide: A suspension of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (128 mg, 0.667 mmol) in thionyl chloride (2 mL) was heated at reflux for 2 h, then concentrated. To the residue was added 4-aminobenzyl alcohol (123 mg, 0.999 mmol) and THF (2.2 mL), and the mixture was stirred at room temperature for 19 h. The mixture was filtered, and the filtrate was concentrated to give a yellow foam (125 mg, 63%). 1H NMR (CD3OD) delta 4.60 (s, 2H), 7.38 (d, 2H, J=8.7 Hz), 7.63 (d, 2H, J=8.4 Hz), 8.66 (s, 2H).

Reference： [1]Patent: US2002/147192,2002,A1

26
[ 13958-93-5 ]
[ 229328-97-6 ]
[ 18107-18-1 ]
[ 223784-52-9 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; hydrogen bromide; In N,N-dimethyl-formamide; benzene;	Example C(63) [4-Amino-2-(1H-benzoimidazol-5-yl-amino)-thiazol-5-yl]-(3,5-dichloro-pyridin-4-yl)-methanone 4-Bromoacetyl-3,5-dichloropyridine, which has the structural formula was first prepared as follows. A mixture of <strong>[13958-93-5]3,5-dichloropyridine-4-carboxylic acid</strong> (4.00 g, 20.9 mmol; Cale et al., J. Med. Chem., vol. 32 (1989), pp. 2178-2199), benzene (20 mL), DMF (0.4 mL), and thionyl chloride (3.80 mL, 52.0 mmol) was heated at reflux for 60 min, allowed to cool to ambient temperature, concentrated in vacuo, suspended in ether (20 mL), and cautiously treated with a solution of trimethylsilyldiazomethane (25 mL of 2.0 M in hexanes). After 72 hours, 48% HBr (18 mL) was carefully added dropwise over 20 min, initially with vigorous gas evolution. After 30 min, the mixture was made alkaline carefully with NaHCO3 and extracted with ether. The ethereal layers were dried over Na2SO4 and evaporated to give an orange oil, which was purified via column chromatography with 50% CH2Cl2/hex eluant to separate 2.50 g (51%) of 3,5-dichloropyridine-4-carbonyl chloride as a yellow oil, providing desired product, 2.00 g (36%) of pale yellow crystals that darkened at ambient temperature, which was used without further purification. NMR (CDCl3): delta 8.58 (2H, s), 4.37 (2H, s). Anal. Calcd for C7H4BrCl2NO.0.02C6H14: C, 31.60; H, 1.59; N, 5.18. Found: C, 31.92; H, 1.59; N, 5.24.

Reference： [1]Patent: US6569878,2003,B1

Yield	Reaction Conditions	Operation in experiment
		The following compounds, for example, are illustrative: ... 4-methylnicotinic acid, 3-methylisonicotinic acid, 3-methylthioisonicotinic acid, 2-trifluoromethylnicotinic acid, 3,5-dichloroisonicotinic acid, 2-chloro-4-methylnicoticic acid, 2,4-dimethylnicotinic acid, 4-ethylnicotinic acid, ...

28
[ 75-09-2 ]
[ 2457-47-8 ]
[ 13958-93-5 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; diisopropylamine; In tetrahydrofuran; sodium hydroxide; hexane;	Preparation 27 3,5-Dichloro-4-pyridinecarboxylic acid To a solution of 4.96 ml (0.036 mole) of diisopropylamine in 200 ml of tetrahydrofuran at -65 C. under a nitrogen blanket was added dropwise 14.9 ml of 2.5M n-butyllithium in hexane while maintaining the above temperature. Twenty minutes subsequent to that addition, a solution 5.0 g (0.034 mole) of 3,5-dichloropyridine in 30 ml tetrahydrofuran at -60 to -70 C. was added. The reaction mixture was stirred at -70 C. for 1/2 hr, poured onto a large excess of dry ice and allowed to evaporate overnight at room temperature. The residue was taken up in 100 ml of dilute aqueous sodium hydroxide, washed with 3*30 ml of methylenechloride and filtered. The filtrate was acidified to ~pH 2 with dilute hydrochloric acid to precipitate out the product. After cooling, the precipitate was collected and recrystallized from ethyl acetate/hexane giving 1.9 g (29%) of white analytically pure crystals, m.p. 231-35 C. (decomp.). Analysis: Calculated for C6 H3 NO2 Cl2: C, 37.53; H, 1.57; N, 7.30 Found: C, 37.33; H, 1.56; N, 7.21
	With n-butyllithium; diisopropylamine; In tetrahydrofuran; sodium hydroxide; hexane;	PREPARATION 27 3,5-Dichloro-4-pyridinecarboxylic acid To a solution of 4.96 ml (0.036 mole) of diisopropylamine in 200 ml of tetrahydrofuran at -65 C. under a nitrogen blanket was added dropwise 14.9 ml of 2.5M n-butyllithium in hexane while maintaining the above temperature. Twenty minutes subsequent to that addition, a solution 5.0 g (0.034 mole) of 3,5-dichloropyridine in 30 ml tetrahydrofuran at -60 to -70 C. was added. The reaction mixture was stirred at -70 C. for 1/2 hr, poured onto a large excess of dry ice and allowed to evaporate overnight at room temperature. The residue was taken up in 100 ml of dilute aqueous sodium hydroxide, washed with 3*30 ml of methylenechloride and filtered. The filtrate was acidified to ~pH 2 with dilute hydrochloric acid to precipitate out the product. After cooling, the precipitate was collected and recrystallized from ethyl acetate/hexane giving 1.9 g (29%) of white analytically pure crystals, m.p. 231-35 C. (decomp.). Analysis: Calculated for C6 H3 NO2 Cl2: C, 37.53; H, 1.57; N, 7.30. Found: C, 37.33; H, 1.56; N, 7.21.

Reference： [1]Patent: US4592866,1986,A
[2]Patent: US4705853,1987,A

29
[ 4606-65-9 ]
[ 79-37-8 ]
[ 13958-93-5 ]
[ 558448-43-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide;	Preparation of (3,5-dichloro-pyridin-4-yl)-(3-hydroxymethyl-piperidin-1-yl)-methanone: To a suspension of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (250 mg, 1.30 mmol) in CH2Cl2 (6.5 mL) was added DMF (cat.) and oxalyl chloride (0.45 mL, 5.2 mmol), and the mixture was stirred at room temperature for 2 h then concentrated in vacuo. To the residue was added THF (2 mL), Et3N (0.27 mL, 1.9 mmol), and a solution of 3-piperidinemethanol (150 mg, 1.30 mmol) in THF (4.5 mL), and the mixture was stirred at room temperature for 21 h. The mixture was diluted with CH2Cl2 (50 mL) and brine (30 mL) and the phases were separated. The organic layer was washed with brine (250 mL) and saturated NaHCO3 (250 mL). The organic layer was dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a crude oil. Purification of the crude material by column chromatography on silica gel (100:5:1 CH2Cl2/MeOH/NH4OH) gave a yellow oil (mixture of isomers) (147 mg, 39%). 1H NMR (CDCl3) delta 1.28-1.96 (m, 4H), 2.89-3.26 (m, 3H), 3.35-3.45 (m, 1H), 3.50-3.72 (m, 2H), 4.29-4.56 (m, 1H), 8.54 (m, 2H).

Reference： [1]Patent: US2004/19058,2004,A1

30
[ 558447-30-6 ]
[ 79-37-8 ]
[ 13958-93-5 ]
aqueous NaCl [ No CAS ]
[ 144-55-8 ]
[ 558447-75-9 ]

Yield	Reaction Conditions	Operation in experiment
40%	With triethylamine; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide;	To a mixture of <strong>[13958-93-5]3,5-dichloro-isonicotinic acid</strong> (52 mg, 0.27 mmol) in CH2Cl2 (1.1 mL) cooled to 0 C. was added oxalyl chloride (70 mL, 0.81 mmol.) and DMF (1 drop) and the resulting mixture was stirred at 0 C. for 5 minutes and at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure and dried in vacuo for 5 minutes. To the resulting beige solid in THF (3 mL) was added N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine from above (100 mg, 0.30 mmol) and Et3N (76 muL, 0.54 mmol) and the resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, diluted with EtOAc (40 mL) and washed consecutively with saturated aqueous NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL). The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2C212MeOH/NH4OH, 100:1:1) afforded COMPOUND 153 (55 mg, 40%) as a white foam. 1H NMR (CDCl3) delta 1.70-1.94 (m, 4H), 2.04-2.15 (m, 1H), 2.26-2.33 (m, 1H), 2.64-2.96 (m, 4H), 3.10-3.15 (m, 1H), 3.68 (d, 1H, J=15.6 Hz), 3.80 (d, 1H, J=15.6 Hz), 3.98-4.07 (m, 1H), 4.19-4.25 (m, 1H), 6.83 (dd, 1H, J=7.8, 4.8 Hz), 7.20-7.23 (m, 2H), 7.35-7.40 (m, 2H), 7.66-7.68 (m, 2H), 8.34 (s, 2H), 8.78 (br s, 1H); 13C NMR (CDCl3) delta 21.69, 21.92, 26.70, 29.38, 39.04, 49.41, 49.87, 59.45, 111.10, 119.37, 122.63, 122.95, 129.27, 135.68, 138.29, 143.68, 146.10, 147.70, 154.94, 157.51, 162.27. ES-MS m/z 510 (M+H). Anal. Calcd. for C26H26N6Cl2O.0.3CH2Cl2.0.1H2O: C, 58.86; H, 5.03; N, 15.66; Cl, 17.17. Found: C, 59.22; H, 5.21; N, 15.74; Cl, 16.80.

Reference： [1]Patent: US2004/19058,2004,A1

31
[ 558441-90-0 ]
[ 79-37-8 ]
[ 13958-93-5 ]
N-{4-[(1H-benzimidazol-2-ylmethyl)-(R)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-3,5-dichloro-isonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide;	Example 155 Compound 155: Preparation of N-{4-[(1H-benzimidazol-2-ylmethyl)-(R)-5,6,7,8-tetrahydroquinolin-8-yl-amino]-butyl}-3,5-dichloro-isonicotinamide. To a suspension of <strong>[13958-93-5]3,5-dichloropyridine-4-carboxylic acid</strong> (135 mg, 0.70 mmol) and DMF (2 drops) in CH2Cl2 (7 mL) was added oxalyl chloride (0.18 mL, 2.1 mmol). The resulting suspension was stirred at room temperature under nitrogen for 35 minutes and then the solvent was evaporated under reduced pressure. The crude acid chloride was dried under reduced pressure, and then a solution of N1-(1H-Benzimidazol-2-ylmethyl)-N1-(R)-5,6,7,8-tetrahydroquinolin-8-yl-butane-1,4-diamine (120 mg, 0.344 mmol) in THF (4 mL) and NEt3 (0.06 mL, 0.4 mmol) were added. The resulting suspension was stirred at room temperature under nitrogen for 1 hour. The reaction was diluted with saturated aqueous NaHCO3 (25 mL) and was extracted with CH2Cl2 (25 mL*3). The combined organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH2Cl2/MeOH/NH4OH, 32:1:0.2) gave the amide as a white foam (134 mg, 0.256 mmol, 74%). 1H NMR (CDCl3) delta 1.47-1.61 (m, 4H), 1.63-1.78 (m, 1H), 1.81-195 (m, 1H), 2.02-2.13 (m, 1H), 2.15-2.25 (m, 1H), 2.60-2.85 (m, 4H), 3.10-3.23 (m, 1H), 3.31-3.43 (m, 1H), 3.87 (d, 1H, J=16.2 Hz), 3.98 (d, 1H, J=16.2 Hz), 4.05 (dd, 1H, J=9.6, 5.7 Hz), 6.94 (br. t, 1H), 7.12 (dd, 1H, J=7.8, 4.8 Hz), 7.15-7.20 (m, 2H), 7.42 (d, 1H, J=7.8 Hz), 7.44-7.62 (m, 2H), 8.39 (s, 2H), 8.47 (d, 1H, J=4.8 Hz). 13C NMR (CDCl3) delta 21.6, 23.9, 25.8, 26.9, 29.4, 39.6, 49.6, 50.5, 62.1, 122.1, 122.7, 129.2, 135.1, 138.0, 143.2, 146.8, 147.7, 156.4, 157.7, 162.6. ES-MS m/z 523 (M+H), 525 (M+2+H). Anal. Calcd. for C27H28Cl2N6O.0.3H2O.0.2CH2Cl2: C, 59.85; H, 5.35; N, 15.40; Cl, 15.59. Found: C, 59.62; H, 5.38; N, 15.22; Cl, 15.98.

Reference： [1]Patent: US2004/19058,2004,A1

32
[ 862854-54-4 ]
[ 13958-93-5 ]
C₂₂H₂₀Cl₂N₄O₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1331 - 1335

33
[ 13958-93-5 ]
[ 1068436-46-3 ]
[ 1068436-33-8 ]

Yield	Reaction Conditions	Operation in experiment
31.4%	With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In dichloromethane; at 0 - 25℃; for 48.1667h;	Solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.042 g, 0.13 mmol) was added portionwise to a stirred solution of methyl 3-{5-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]-2-thienyl}-L-alaninate (0.043 g, 0.12 mmol), <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (0.022 g, 0.11 mmol) and 4-methylmorpholine (0.016 ml, 0.14 mmol) dissolved in DCM (100 ml) over a period of 10 minutes at 0 C. The resulting solution was stirred at 25 C. for 2 days. The reaction mixture was basified with a saturated aqueous solution of sodium hydrogencarbonate and extracted with DCM (1×100 ml). The combined organic phases were washed with water (2×20 ml), dried over magnesium sulfate and concentrated to afford the crude product as a clear orange oil. The crude product was purified by flash chromatography on silica gel eluting with 0 to 40% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford methyl N-(3,5-dichloroisonicotinoyl)-3-{5-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]-2-thienyl}-L-alaninate (31.4%) as a white crystalline solid.Mass Spectrum [M+H]+: 535.

Reference： [1]Patent: US2008/255183,2008,A1 .Location in patent: Page/Page column 52-54

34
[ 13958-93-5 ]
[ 18107-18-1 ]
[ 223785-65-7 ]
[ 229328-97-6 ]

Reference： [1]Patent: EP1215208,2002,A2 .Location in patent: Example C(63)

35
[ 13958-93-5 ]
[ 1108615-74-2 ]
[ 1239321-20-0 ]

Yield	Reaction Conditions	Operation in experiment
68.4%	With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	Step G. Preparation of 3,5-dichloro-N-((2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methyl)isonicotinamide from (2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methanamine.; A mixture of ^-methyl^-azabicycloP^^Joctan- 1 -yl)(phenyl)methanamine (0.025g, 0.11 mmol), <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (0.026g, 0.14 mmol), and HOBT (0.021g, 0.14 mmol) in DMF (1.0 mL) was treated with TBTU (0.044g, 0.14 mmol) and DIPEA (0.050 mL, 0.29 mmol). The mixture was stirred at room temperature for 18 hours and was then concentrated. The resulting residue was treated with ethyl acetate and washed with saturated aqueous potassium carbonate, water, and then saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. This new residue was purified by flash column chromatography (SiO2, 0-5% (2 M ammonia in methanol) in dichloromethane) to afford an oil that solidified on standing. This solid was triturated with hexanes and dried under vacuum at 5O0C for 4 hours to afford 3,5-dichloro-N-((2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methyl)isonicotinamide (30 mg, 68.4%) as a solid. IH NMR (300 MHz, chloroform-d) delta ppm 1.25 - 1.75 (m, 8 H), 1.89 - 2.05 (m, 1 H), 2.42 (s, 3 H), 2.44 - 2.57 (m, 1 H), 3.16 - 3.30 (m, 1 H), 4.81 (s, 1 H), 7.02 - 7.40 (m, 6 H), 8.52 (s, 2 H). m/z (ES+), (M+H)+ 404.1290, 406.1265; MS2, HPLC tR = 0.83 min.

Reference： [1]Patent: WO2010/87761,2010,A1 .Location in patent: Page/Page column 50

36
[ 13958-93-5 ]
[ 100-51-6 ]
[ 1253799-61-9 ]

Yield	Reaction Conditions	Operation in experiment
67%		Synthesis ofSl-2,S1-2Sodium hydride (60% dispersion in mineral oil, 4.37 g, 109 mmol) was added portion wise to a solution of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (10.24 g, 53.3 mmol) in NMP (100 mL). After gas evolution ceased, benzyl alcohol (5.52 mL, 53.3 mmol) was added drop wise. After gas evolution ceased, the reaction mixture was heated to 80 C. After 1 hr, the reaction was complete and was allowed to cool to rt and stand overnight. The reaction mixture was diluted with water (300 mL) and was washed with Et2O (2 x 100 mL, discarded). The aqueous layer was brought to pH ~2 with cone. HCl, causing a precipitate to form. The mixture was diluted with brine (100 mL) and was allowed to stand for 30 minutes. The solid was collected by filtration, washed with water (3x), and was dried in a 45 C vacuum oven overnight. This gave 9.36 g (67%) of the product as a white solid. 1H NMR (400 MHz, DMSO- d6) delta 14.30-14.10 (bs, 1 H), 8.52 (s, IH), 8.34 (s, 1 H), 7.50-7.30 (m, 5 H), 5.33 (s, 2 H); MS (ESI) m/z 264.20 (M+H).
67%		Sodium hydride (60% dispersion in mineral oil, 4.37 g, 109 mmol) was added portionwise to a solution of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (10.24 g, 53.3 mmol) in NMP (100 mL). After gas evolution ceased, benzyl alcohol (5.52 mL, 53.3 mmol) was added dropwise. After gas evolution ceased, the reaction mixture was heated to 80 0C. After 1 hour, the reaction was complete and was allowed to cool to RT and stand overnight. The reaction mixture was diluted with water (300 mL) and was washed with Et2O (2 x 100 mL, discarded). The aqueous layer was brought to pH ~2 with cone. HCl, causing a precipitate to form. The mixture was diluted with brine (100 mL) and was allowed to stand for 30 minutes. The solid was collected by filtration, washed with water (3x), and was dried in a 45 0C vacuum oven overnight. This gave 9.36 g (67%) of the product 87 as a white solid. 1H NMR (400 MHz, OMSO-d6) delta 14.30-14.10 (bs, 1 H), 8.52 (s, IH), 8.34 (s, 1 H), 7.50-7.30 (m, 5 H), 5.33 (s, 2 H); MS (ESI) m/z 264.20 (M+H).
2.57 g		To a solution of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (3.16 g) in 1-methyl-2-pyrrolidone (80 mL) was added 60% sodium hydride (1.38 g) at 0C, and the mixture was stirred at the same temperature for 10 min. To the reaction solution was added phenylmethanol (1.78 g), and the mixture was stirred under an argon atmosphere at 80C for 2 hr. The reaction solution was diluted with water, and the aqueous layer was washed with diethyl ether. The aqueous layer was separated, concentrated hydrochloric acid was added, and the solution was adjusted to about pH 2. To the solution was added saturated brine, and the resulting precipitate was collected by filtration to give the title compound (2.57 g). 1H NMR (300 MHz, DMSO-d6) delta 5.34 (2H, s), 7.30-7.49 (5H, m), 8.36 (1H, s), 8.54 (1H, s), 14.12 (1H, brs).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 34-35
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1511 - 1528
[3]Patent: WO2010/126607,2010,A2 .Location in patent: Page/Page column 184/251-185/251
[4]Patent: EP2921480,2015,A1 .Location in patent: Paragraph 0397; 0398

37
[ 13958-93-5 ]
[ 454-81-9 ]
[ 1192021-00-3 ]

Yield	Reaction Conditions	Operation in experiment
		Reference Production Example 11A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5- trifluoromethylphenyl)isonicotinamide.1H-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, 1H), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.5, 2.2 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H)
		A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5- trifluoromethylphenyl)isonicotinamide.1H-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, IH), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, IH), 7.30 (dd, J=8.5, 2.2 Hz, IH), 7.04 (d, J=8.5 Hz, IH)
		A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5- trifluoromethylphenyl)isonicotinamide.1 H-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, IH), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, IH), 7.30 (dd, J=8.5, 2.2 Hz, IH), 7.04 (d, J=8.5 Hz, IH)

		Reference Production Example 11A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5- trifluoromethylphenyl)isonicotinamide.1H-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, 1H), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.5, 2.2 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H)
		Reference Production Example 11A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5- trifluoromethylphenyl)isonicotinamide.-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, 1H), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.5, 2.2 Hz, IH), 7.04 (d, J=8.5 Hz, IH)

Reference： [1]Patent: WO2011/40629,2011,A1 .Location in patent: Page/Page column 206
[2]Patent: WO2011/49220,2011,A1 .Location in patent: Page/Page column 205
[3]Patent: WO2011/49221,2011,A1 .Location in patent: Page/Page column 205-206
[4]Patent: WO2011/49223,2011,A1 .Location in patent: Page/Page column 205
[5]Patent: WO2011/49222,2011,A1 .Location in patent: Page/Page column 209-210

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[ 1259931-91-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 7401 - 7404

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[ 1192021-00-3 ]

Reference： [1]Patent: US2011/39843,2011,A1

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[ 1192019-04-7 ]

Reference： [1]Patent: US2011/39843,2011,A1

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[ 1254367-45-7 ]