[ CAS No. 142266-62-4 ] {[proInfo.proName]}

Name: 142266-62-4|2,5,6-Trichloronicotinamide|97%
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Quality Control of [ 142266-62-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 142266-62-4 ]

Product Details of [ 142266-62-4 ]

CAS No. :	142266-62-4	MDL No. :	MFCD22493418
Formula :	C₆H₃Cl₃N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DBAVDGXPOXFHRC-UHFFFAOYSA-N
M.W :	225.46	Pubchem ID :	53750930
Synonyms :

Calculated chemistry of [ 142266-62-4 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	47.36
TPSA :	55.98 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) :	-6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.47
Log Po/w (XLOGP3) :	2.28
Log Po/w (WLOGP) :	2.14
Log Po/w (MLOGP) :	1.38
Log Po/w (SILICOS-IT) :	2.47
Consensus Log Po/w :	1.95

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.98
Solubility :	0.237 mg/ml ; 0.00105 mol/l
Class :	Soluble
Log S (Ali) :	-3.09
Solubility :	0.182 mg/ml ; 0.000808 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.47
Solubility :	0.0764 mg/ml ; 0.000339 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.84

Safety of [ 142266-62-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 142266-62-4 ]

* 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 [ 142266-62-4 ]
Downstream synthetic route of [ 142266-62-4 ]

[ 142266-62-4 ] Synthesis Path-Upstream 1~10

1
[ 58584-88-6 ]
[ 142266-62-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonia In 1,4-dioxane; water at 0℃; for 0.166667 h;	A solution of 2,5,6-trichloronicotinoyl chloride (Method 46, 2.5 g, 10.2 mmol) in dioxane (20 ml) was added dropwise to 10 ml ammonium hydroxide (28percent NH₃ in water) at0 ⁰C. Upon completion of the addition, the reaction was allowed to stir for an additional 10 minutes, and then extracted with DCM (3 x 50 ml). The combined organic fractions were dried over Na₂SO₄, filtered, and concentrated to give the title compound (2.3 g, 100percent), which was used without further purification.

Reference： [1] Patent: WO2006/82392, 2006, A1, . Location in patent: Page/Page column 109
[2] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 6, p. 1793 - 1804
[3] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2958 - 2961

2
[ 40381-92-8 ]
[ 142266-62-4 ]

Reference： [1] Patent: WO2011/94450, 2011, A1, . Location in patent: Page/Page column 157

3
[ 530-62-1 ]
[ 142266-62-4 ]

Reference： [1] Patent: US2018/334454, 2018, A1,

4
[ 54718-39-7 ]
[ 142266-62-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 6, p. 1793 - 1804
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2958 - 2961

5
[ 52465-59-5 ]
[ 142266-62-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 6, p. 1793 - 1804

6
[ 29553-51-3 ]
[ 142266-62-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2958 - 2961

7
[ 58584-95-5 ]
[ 142266-62-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2958 - 2961

8
[ 4553-62-2 ]
[ 142266-62-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2958 - 2961

9
[ 75993-42-9 ]
[ 142266-62-4 ]

Reference： [1] Patent: WO2011/94450, 2011, A1,

10
[ 142266-62-4 ]
[ 40381-92-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: at 90℃; for 1 h; Stage #2: With water; sodium carbonate In dichloromethane	A suspension of 2,5,6-trichloronicotinamide (Method 45, 2.3 g, 10.2 mmol) in POCl₃ (20 ml) was heated to 90 ⁰C for 1 hour. The reaction was then cooled to room temperature, and the POCl₃ was removed under vacuum. The resulting residue was taken up in DCM (50 ml) and ice water (50 ml) was then added, followed by the careful addition of an aqueous solution OfNa₂CO₃ until pH 8 was achieved. The organic fraction was then dried over Na₂SO₄, filtered, and concentrated to give the title compound (2.1 g, 80percent) which was used without further purification. ¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, IH).

Reference： [1] Patent: WO2006/82392, 2006, A1, . Location in patent: Page/Page column 108
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2958 - 2961

[ 142266-62-4 ] Synthesis Path-Downstream 1~53

1
[ 58584-88-6 ]
[ 142266-62-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonia; In 1,4-dioxane; water; at 0℃; for 0.166667h;	A solution of 2,5,6-trichloronicotinoyl chloride (Method 46, 2.5 g, 10.2 mmol) in dioxane (20 ml) was added dropwise to 10 ml ammonium hydroxide (28% NH3 in water) at0 0C. Upon completion of the addition, the reaction was allowed to stir for an additional 10 minutes, and then extracted with DCM (3 x 50 ml). The combined organic fractions were dried over Na2SO4, filtered, and concentrated to give the title compound (2.3 g, 100%), which was used without further purification.

Reference： [1]Patent: WO2006/82392,2006,A1 .Location in patent: Page/Page column 109
[2]Bioorganic and Medicinal Chemistry,2002,vol. 10,p. 1793 - 1804
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2958 - 2961

2
[ 142266-62-4 ]
[ 465513-31-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2002,vol. 10,p. 1793 - 1804

3
[ 52465-59-5 ]
[ 142266-62-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: HgNO₃; CuSO₄*5H₂O; HNO₃ / H₂SO₄ 2: 81 percent / SOCl₂ / benzene; dimethylformamide / 2.5 h / Heating 3: 90 percent / 10 percent NH₄OH / dioxane / 1 h / 4 °C

Reference： [1]Laeckmann, Didier; Rogister, Françoise; Dejardin, Jean-Victor; Prosperi-Meys, Christelle; Géczy, Joseph; Delarge, Jacques; Masereel, Bernard [Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 6, p. 1793 - 1804]

4
[ 54718-39-7 ]
[ 142266-62-4 ]

Yield	Reaction Conditions	Operation in experiment
92%		1,1'-Carbonyldiimidazole (40 g, 247 mmol) was added in portions to 2,5,6-trichloronicotinic acid (50.7 g, 224 mmol, Combi-Blocks, San Diego, Calif., USA) in THF (400 mL), allowing gas evolution to cease between additions. The resulting mixture was stirred for 5 min and then was degassed with house vacuum and flushed with nitrogen (2). The resulting mixture was heated to 50 C. for 60 min, then diluted with toluene (100 mL) and concentrated to half volume. The resulting mixture was cooled to 0 C. and ammonium hydroxide (60 mL, 437 mmol) was added slowly via syringe. The reaction was stirred for 10 min at room temperature, diluted with EtOAc (200 mL) and washed with water (3100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in 9:1 heptane/EtOAc (300 mL) and filtered. The filtered solids were collected and the remaining mother liquor was partially evaporated to half volume, cooled to 0 C., and filtered. The two crops of filtered solids were combined to provide 2,5,6-trichloronicotinamide (Intermediate P, 46.2 g, 92% yield).
	With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 50℃; for 65h;Inert atmosphere;	Step 1: 2,5,6-trichloronicotinamide (Intermediate P) 1,1'-Carbonyldiimidazole (40 g, 247 mmol) was added in portions to 2,5,6-trichloronicotinic acid (50.7 g, 224 mmol, Combi-Blocks, San Diego, Calif., USA) in THF (400 mL), allowing gas evolution to cease between additions. The resulting mixture was stirred for 5 min and then was degassed with house vacuum and flushed with nitrogen (2). The resulting mixture was heated to 50 C. for 60 min, then diluted with toluene (100 mL) and concentrated to half volume. The resulting mixture was cooled to 0 C. and ammonium hydroxide (60 mL, 437 mmol) was added slowly via syringe. The reaction was stirred for 10 min at room temperature, diluted with EtOAc (200 mL) and washed with water (3100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in 9:1 heptane/EtOAc (300 mL) and filtered. The filtered solids were collected and the remaining mother liquor was partially evaporated to half volume, cooled to 0 C., and filtered. The two crops of filtered solids were combined to provide 2,5,6-trichloronicotinamide.
		1,1 ?-Carbonyldiimidazole (40 g, 247 mmol) was added in portions to 2,5,6- trichloronicotinic acid (50.7 g, 224 mmol, Combi-Blocks, San Diego, Calif.) in THF (400 mE), allowing gas evolution to cease between addition. The resulting mixture was stirred for 5 mm and then was degassed with house vacuum and flushed with nitrogen. The resulting mixture was heated to 50 C. for 60 mm, then diluted with toluene (100 mE) and concentrated to half the initial volume. The resulting mixture was cooled to 0 C. and ammonium hydroxide (60 mE, 437 mmol) was added slowly via syringe. The reaction was stirred for 10 mm at it, diluted with EtOAc (200 mE) and washed with water (3x100 mE). The organic layer was dried over anhydrous Na2504 and concentrated in vacuo. The residue was suspended in 9:1 heptane/EtOAc (300 mE) and filtered. The filtered solids were collected and the remaining mother liquor was partially evaporated to half the initial volume, cooled to 0 C., and filtered. The two crops of filtered solids were combined to provide 2,5,6-trichloroni- cotinamide.

Reference： [1]Patent: US2019/374542,2019,A1 .Location in patent: Paragraph 0784-0785
[2]Bioorganic and Medicinal Chemistry,2002,vol. 10,p. 1793 - 1804
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2958 - 2961
[4]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0569
[5]Patent: US2019/77801,2019,A1 .Location in patent: Paragraph 0215; 0216
[6]Journal of Medicinal Chemistry,2020

5
[ 142266-62-4 ]
[ 40381-92-8 ]

Yield	Reaction Conditions	Operation in experiment
80%		A suspension of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Method 45, 2.3 g, 10.2 mmol) in POCl3 (20 ml) was heated to 90 0C for 1 hour. The reaction was then cooled to room temperature, and the POCl3 was removed under vacuum. The resulting residue was taken up in DCM (50 ml) and ice water (50 ml) was then added, followed by the careful addition of an aqueous solution OfNa2CO3 until pH 8 was achieved. The organic fraction was then dried over Na2SO4, filtered, and concentrated to give the title compound (2.1 g, 80%) which was used without further purification. 1H NMR (400 MHz, CD3OD) delta 8.54 (s, IH).

Reference： [1]Patent: WO2006/82392,2006,A1 .Location in patent: Page/Page column 108
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2958 - 2961

6
[ 29553-51-3 ]
[ 142266-62-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2958 - 2961

7
[ 40453-77-8 ]
[ 142266-62-4 ]
[ 1319804-38-0 ]

Yield	Reaction Conditions	Operation in experiment
41%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;Inert atmosphere;	[0553] Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (8.01 g, 31.8 mmol, 0.90 equiv) in DMF (200 mL) and 2,3-dimethoxypropan-l-ol (4.75 g, 37.2 mmol, 1.00 equiv, 94%). This was followed by the addition of sodium hydride (950 mg, 39.6 mmol, 1.00 equiv) in portions at 0 C. The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of water/ice. The reaction mixture was cooled with a water/ice bath. The solid was collected by filtration. This resulted in 4.95 g (41%) of 5,6-dichloro-2-(2,3- dimethoxypropoxy Nicotinamide as a light yellow solid.

Reference： [1]Patent: WO2011/94450,2011,A1 .Location in patent: Page/Page column 162-163

8
[ 109-59-1 ]
[ 142266-62-4 ]
[ 1319804-31-3 ]

Yield	Reaction Conditions	Operation in experiment
59%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;Inert atmosphere;	EXAMPLE 1la. 5-chloro-6-(l-hydroxy-l,3-dihydrobenzo[c] [l,2]oxaborol-5-yloxy)-2-(2- isopropoxyethoxy)nicotinonitrile D230[0543] Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (4.00 g, 17.9 mmol, 1.00 equiv) in DMF (5 mL) and 2-isopropoxyethanol (1.857 g, 17.86 mmol, 1.00 equiv). This was followed by the addition of sodium hydride (714 mg, 29.8 mmol, 1.00 equiv) in portions at 0 C. The resulting solution was stirred for 3 h at room temperature, then quenched by the addition of 40 mL of H20. The solid was collected by filtration and dried in an oven under reduced pressure. This resulted in 3.4 g (59%) of 5,6-dichloro-2-(2-isopropoxyethoxy Nicotinamide as a yellow solid.

Reference： [1]Patent: WO2011/94450,2011,A1 .Location in patent: Page/Page column 159

9
[ 1071-73-4 ]
[ 142266-62-4 ]
[ 1319804-33-5 ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;Inert atmosphere;	[0546] Into a 100-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (4.00 g, 17.9 mmol, 1.00 equiv) in DMF (30 mL) and 5-hydroxypentan-2-one (2.00 g, 19.6 mmol, 1.10 equiv). This was followed by the addition of sodium hydride (470 mg, 19.58 mmol, 1.10 equiv) in portions at 0 C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 40 mL of water. The solid was collected by filtration and dried in an oven under reduced pressure. This resulted in 2.31 g (40%>) of 5,6-dichloro-2-(4- oxopentyloxy Nicotinamide as a yellow solid.

Reference： [1]Patent: WO2011/94450,2011,A1 .Location in patent: Page/Page column 160

10
[ 40381-92-8 ]
[ 142266-62-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 60℃; for 1h;	[0535] A solution of 2,5,6-trichloronicotinonitrile (30 g, 144.92 mmol, 1.00 equiv) in sulfuric acid (98%, 162 mL, 1.00 equiv) was stirred for 1 h at 60 C in an oil bath. The reaction mixture was cooled and then quenched by the addition of water/ice. The solid was collected by filtration and dried in an oven under reduced pressure. This resulted in 26 g of 2, 5, 6-trichloronicotinamide as a white solid. LC-MS (ES, m/z): 225 [M+H]+. 1H-NMR (300MHz, DMSO-<¾) delta (ppm) 9.38 (1H, s), 8.12 (1H, s), 7.95 (1H, s).

Reference： [1]Patent: WO2011/94450,2011,A1 .Location in patent: Page/Page column 157

11
[ 321916-68-1 ]
[ 142266-62-4 ]
[ 1319804-40-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃;	[0557] A mixture of compound <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (0.6 g, 2.7 mmol), 1- (3-hydroxypropyl)cyclopropanol (370 mg, 3.2 mmol) and tert- uOK (363 mg, 3.2 mmol) in DMF was stirred at room temperature overnight and the reaction mixture was then poured into cold water, the mixture was extracted twice with ethyl acetate, the combined organic layers were washed with brine twice, dried over Na2S04 and concentrated, the residue was purified by column chromatography (silica gel, Petroleum ether: EtOAc = 1 :0 to 5: 1) to give the 5,6-dichloro-2-(3-(l- hydroxycyclopropyl)propoxy Nicotinamide (0.72 g, 73%). 1H-NMR (400MHz, OMSO-d6) delta (ppm) 8.65 (s, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 5.48 (s, 1H), 4.82 (t, 2H, J = 6.4 Hz), 2.36 (m, 2H), 1.97(m, 2H), 0.94 (t, 2H), 0.73 (t, 2H).

Reference： [1]Patent: WO2011/94450,2011,A1 .Location in patent: Page/Page column 164

12
2-(trifluoromethoxy)ethan-1-ol [ No CAS ]
[ 142266-62-4 ]
[ 1319804-43-7 ]

Yield	Reaction Conditions	Operation in experiment
8%	With potassium tert-butylate; In 1,2-dimethoxyethane; N,N-dimethyl-formamide; at 20℃;	5-Chloro-6-(l-hydroxy-l, 3-dihydrobenzo[ c] [ l,2]oxaborol-5-yloxy)-2-(3-( 1- hydroxycyclopropyl)propoxy)nicotinonitrile D235[0563] To a mixture of compound 2-(trifluoromethoxy)ethanol (9.5 mmol) in DMF/DME (20/50 mL) was added <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (2.1g, 9.5 mmol) and tert-BuOK (1.30 g, 11.4 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was poured into 100 mL of cold water, diluted with 100 mL of EtOAc, the organic layer was separated and the aqueous phase was further extracted twice with EtOAc, the combined organic layers were washed with brine twice, dried over Na2S04 and concentrated, the residue was purified by silica gel chromatography (Petroleum ether: EtOAc = 1 :0 to 5: 1) to give 5,6-dichloro-2-(2- (trifluoromethoxy)ethoxy)nicotinamide (0.24g, 8%). 1H-NMR (400MHz, DMSO-<¾) 5 (ppm) 8.31 (s, 1H), 7.97 (s, 1H), 7.59 (s, 1H), 4.62 (t, 2H, J = 4.0 Hz), 4.51 (t, 2H, J = 4.0 Hz).

Reference： [1]Patent: WO2011/94450,2011,A1 .Location in patent: Page/Page column 166

13
[ 79-37-8 ]
[ 5266-85-3 ]
[ 142266-62-4 ]
2,5,6-trichloro-N-((2-isopropyl-6-methylphenyl)carbamoyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: 2,5,6-trichloro-N-((2-isopropyl-6-methylphenyl)carbamoyl)nicotinamide To a mixture of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 1.13 g, 5.0 mmol) in THF (30 mL) was added oxalyl chloride (2M solution in DCM, 2.7 mL, 5.4 mmol). The resulting slurry was heated at 65 C. for 40 min, then heating was stopped and the reaction was allowed to cool to room temperature. 2-Isopropyl-6-methylaniline (0.80 mL, 5.36 mmol, Enamine, Monmouth Junction, N.J., USA) was added and the reaction was stirred at room temperature for 14 h. The reaction was concentrated and the residue was partitioned between EtOAc (50 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was suspended in 5:1 heptane/EtOAc (10 mL) and filtered. The filtered solids were collected to provide 2,5,6-trichloro-N-((2-isopropyl-6-methylphenyl)carbamoyl)nicotinamide. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 9.63 (s, 1H), 9.35 (br s, 1H), 8.25 (s, 1H), 7.19-7.26 (m, 2H), 7.13 (d, J=7.3 Hz, 1H), 3.14 (quin, J=6.9 Hz, 1H), 2.29 (s, 3H), 1.23 (d, J=6.8 Hz, 6H). m/z (ESI, +ve ion): 400.0 (M+H)+.

Reference： [1]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0570
[2]Journal of Medicinal Chemistry,2020

14
[ 79-37-8 ]
4-methyl-2-(1-methylethyl)-3-pyridinamine [ No CAS ]
[ 142266-62-4 ]
2,5,6-trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		To a -78 C. slurry of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 3.10 g, 13.8 mmol) in THF (46 mL) was added oxalyl chloride (2 M solution in DCM, 7.4 mL, 14.7 mmol) slowly via syringe. The resulting slurry was heated at 60 C. for 3.5 h, then heating was stopped and the reaction was cooled to -78 C. Triethylamine (6.0 mL, 42.6 mmol) was added followed by a solution of 2-isopropyl-4-methylpyridin-3-amine (Intermediate R, 2.12 g, 14.1 mmol) via cannula. The resulting slurry was warmed to room temperature and stirred for 1 h, then was partitioned between water (120 mL) and EtOAc (175 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in 9:1 heptane/EtOAc and filtered. The filtered solids were collected to provide 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (4.71 g, 85% yield). 1H NMR (400 MHz, DMSO-d6) delta 11.31 (s, 1H), 9.54 (s, 1H), 8.66 (s, 1H), 8.34 (d, J=4.8 Hz, 1H), 7.16 (d, J=5.0 Hz, 1H), 3.24-3.33 (m, 1H), 2.22 (s, 3H), 1.17 (d, J=6.6 Hz, 6H). m/z (ESI, +ve ion): 400.9 (M+H)+.
		Step 2: 2,5,6-Trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide To a -78 C. slurry of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 3.10 g, 13.8 mmol) in THF (46 mL) was added oxalyl chloride (2 M solution in DCM, 7.4 mL, 14.7 mmol) slowly via syringe. The resulting slurry was heated at 60 C. for 3.5 h, then heating was stopped and the reaction was cooled to -78 C. Triethylamine (6.0 mL, 42.6 mmol) was added followed by a solution of 2-isopropyl-4-methylpyridin-3-amine (Intermediate R, 2.12 g, 14.1 mmol) via cannula. The resulting slurry was warmed to room temperature and stirred for 1 h, then was partitioned between water (120 mL) and EtOAc (175 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in 9:1 heptane/EtOAc and filtered. The filtered solids were collected to provide 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.31 (s, 1H), 9.54 (s, 1H), 8.66 (s, 1H), 8.34 (d, J=4.8 Hz, 1H), 7.16 (d, J=5.0 Hz, 1H), 3.24-3.33 (m, 1H), 2.22 (s, 3H), 1.17 (d, J=6.6 Hz, 6H). m/z (ESI, +ve ion): 400.9 (M+H)+.
		To a -78 C. slurry of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate A, 3.10 g, 13.8 mmol) in THF (46 mL) was added oxalyl chloride (2 M solution in DCM, 7.4 mL, 14.7 mmol) slowly via syringe. The resulting slurry was heated at 60 C. for 3.5 h, then heating was stopped and the reaction was cooled to -78 C. Triethylamine (6.0 mL, 42.6 mmol) was added followed by a solution of 2-isopropyl-4-methylpyridin-3-amine (Intermediate B, 2.12 g, 14.1 mmol) via cannula. The resulting slurry was warmed to rt and stirred for 1 h, then was partitioned between water (120 mL) and EtOAc (175 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was suspended in 9:1 heptane/EtOAc and filtered. The filtered solids were collected to provide 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.31 (s, 1H), 9.54 (s, 1H), 8.66 (s, 1H), 8.34 (d, J=4.8 Hz, 1H), 7.16 (d, J=5.0 Hz, 1H), 3.24-3.33 (m, 1H), 2.22 (s, 3H), 1.17 (d, J=6.6 Hz, 6H). m/z (ESI, +ve ion): 400.9 (M+H)+.

Reference： [1]Patent: US2019/374542,2019,A1 .Location in patent: Paragraph 0802; 0804
[2]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0578
[3]Patent: US2019/77801,2019,A1 .Location in patent: Paragraph 0215; 0218
[4]Journal of Medicinal Chemistry,2020

15
[ 79-37-8 ]
[ 1211399-76-6 ]
[ 142266-62-4 ]
2,5,6-trichloro-N-((2-cyclopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: 2,5,6-Trichloro-N-((2-cyclopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide To a solution of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 3.5 g, 15.5 mmol) in THF (30 mL) was added oxalyl chloride (2 M solution in DCM, 11.6 mL, 23.3 mmol) slowly via syringe. The resulting mixture was heated at 65 C. for 2 h, then heating was stopped and the reaction was concentrated. The residue was dissolved in THF (30 mL) and treated with a solution of 2-cyclopropyl-4-methylpyridin-3-amine (Intermediate T, 2.5 g, 17.1 mmol) in THF (15 mL) via cannula. The resulting mixture was stirred at room temperature for 2 h, then was quenched with water and extracted with EtOAc (3*). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to provide 2,5,6-trichloro-N-((2-cyclopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide. This material was used without further purification in the following step. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.30 (br s, 1H), 9.44-9.73 (m, 1H), 8.64 (s, 1H), 8.21 (d, J=5.0 Hz, 1H), 7.07 (d, J=5.0 Hz, 1H), 2.22 (s, 3H), 0.92 (s, 2H), 0.91 (d, J=3.5 Hz, 2H). m/z (ESI, +ve ion): 400.9 (M+H)+.

Reference： [1]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0608

16
[ 79-37-8 ]
4,6-diisopropylpyrimidin-5-amine [ No CAS ]
[ 142266-62-4 ]
2,5,6-trichloro-N-((4,6-diisopropylpyrimidin-5-yl)carbamoyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: 2,5,6-Trichloro-N-((4,6-diisopropylpyrimidin-5-yl)carbamoyl)nicotinamide A solution of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 3.30 g, 14.6 mmol) in 1,2-dichloroethane (49 mL) was treated with oxalyl chloride (2 M solution in DCM, 11.0 mL, 22.0 mmol). The mixture was heated at 80 C. for 45 min, then the heating was stopped and the reaction was concentrated. The residue was dissolved in acetonitrile (49 mL), cooled to -10 C., and a solution of 4,6-diisopropylpyrimidin-5-amine (Intermediate U, 3.15 g, 17.6 mmol) in acetonitrile (5 mL) was added via cannula. The resulting mixture was stirred at room temperature overnight and then was concentrated. The residue was suspended in warm 10:1 heptane/EtOAc (110 mL) and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (eluent: 0-40% EtOAc/heptane) to provide 2,5,6-trichloro-N-((4,6-diisopropylpyrimidin-5-yl)carbamoyl)nicotinamide. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.30-11.46 (m, 1H), 9.66 (br s, 1H), 8.95-9.01 (m, 1H), 8.65-8.72 (m, 1H), 3.26 (s, 2H), 1.17 (d, J=6.6 Hz, 12H). m/z (ESI, +ve ion): 432.0 (M+H)+.
		A solution of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate A, 3.30 g, 14.6 mmol) in 1,2-dichloroethane (49 mL) was treated with oxalyl chloride (2 M solution in DCM, 11.0 mL, 22.0 mmol). The mixture was heated at 80 C. for 45 min, then the heating was stopped and the reaction was concentrated in vacuo. The residue was dissolved in acetonitrile (49 mL), cooled to -10 C., and a solution of 4,6-diisopropylpyrimidin-5-amine (3.15 g, 17.6 mmol) in acetonitrile (5 mL) was added via cannula. The resulting mixture was stirred at rt overnight and was then concentrated in vacuo. The residue was suspended in warm 10:1 heptane/EtOAc (110 mL) and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (eluent: 0-40% EtOAc/heptane) to provide 2,5,6-trichloro-N-((4,6-diisopropylpyrimidin-5-yl)carbamoyl)nicotinamide. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.30-11.46 (m, 1H), 9.66 (br s, 1H), 8.95-9.01 (m, 1H), 8.65-8.72 (m, 1H), 3.26 (s, 2H), 1.17 (d, J=6.6 Hz, 12H). m/z (ESI, +ve ion): 430.0 (M+H)+.

Reference： [1]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0602
[2]Patent: US2019/77801,2019,A1 .Location in patent: Paragraph 0250; 0252
[3]Journal of Medicinal Chemistry,2020

17
[ 79-37-8 ]
2-ethyl-4-methylpyridin-3-amine [ No CAS ]
[ 142266-62-4 ]
2,5,6-trichloro-N-((2-ethyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: 2,5,6-Trichloro-N-((2-ethyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide To a solution of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 2.5 g, 11.1 mmol) in THF (20 mL) was added oxalyl chloride (2 M solution in DCM, 5.4 mL, 10.8 mmol) slowly via syringe. The resulting mixture was heated at 65 C. for 1.5 h, then heating was stopped and the reaction was allowed to cool to room temperature. A solution of 2-ethyl-4-methylpyridin-3-amine (Intermediate W, 1.5 g, 10.7 mmol) in THF (15 mL) was added via cannula. The resulting mixture was stirred at room temperature for 1 h, and then was partially concentrated to remove most of the THF. The residue was partitioned between saturated aqueous sodium bicarbonate (30 mL) and EtOAc (50 mL). The organic layer was washed with brine (1*), dried over anhydrous sodium sulfate and concentrated. The residue was suspended in 10:1 heptane/EtOAc (60 mL) and filtered to provide 2,5,6-trichloro-N-((2-ethyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide. The product was carried on directly into the next step.

Reference： [1]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0619

18
[ 79-37-8 ]
4,6-diethylpyrimidin-5-amine [ No CAS ]
[ 142266-62-4 ]
2,5,6-trichloro-N-((4,6-diethylpyrimidin-5-yl)carbamoyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 3: 2,5,6-Trichloro-N-((4,6-diethylpyrimidin-5-yl)carbamoyl)nicotinamide To a suspension of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 4.67 g, 20.7 mmol) in THF (100 mL) was added oxalyl chloride (2 M solution in DCM, 15.5 mL, 31.0 mmol). The resulting mixture was heated at 65 C. for 1 h, then heating was stopped and the reaction was concentrated to one-third volume. Toluene (100 mL) was added and the mixture was cooled to 0 C. A solution of 4,6-diethylpyrimidin-5-amine (Intermediate X, 3.13 g, 20.7 mmol) in 1,2-dichloroethane (20 mL) was added dropwise via cannula. The resulting mixture was warmed to room temperature and stirred for 15 min, and then was concentrated. The residue was suspended in MTBE (50 mL) and filtered. The filtered solids were dried briefly in a vacuum oven at 50 C. to provide 2,5,6-trichloro-N-((4,6-diethylpyrimidin-5-yl)carbamoyl)nicotinamide. m/z (ESI, +ve ion): 402.1 (M+H)+.

Reference： [1]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0627

19
[ 72632-66-7 ]
[ 79-37-8 ]
[ 142266-62-4 ]
2,5,6-trichloro-N-((4-isopropylthiazol-5-yl)carbamoyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: 2,5,6-Trichloro-N-((4-isopropylthiazol-5-yl)carbamoyl)nicotinamide To a mixture of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 1.00 g, 4.5 mmol) in THF (20 mL) was added oxalyl chloride (2 M solution in DCM, 2.4 mL, 4.9 mmol). The resulting mixture was heated at 70 C. for 30 min, then heating was stopped and the reaction was allowed to cool to room temperature. 4-(Propan-2-yl)-1,3-thiazol-5-amine (715 mg, 5.0 mmol, Enamine, Monmouth Junction, N.J., USA) was added. The reaction mixture was stirred at room temperature for 10 min and then was concentrated. The residue was suspended in MeOH and filtered. The filtered solids were discarded and the filtrate was concentrated to provide 2,5,6-trichloro-N-((4-isopropylthiazol-5-yl)carbamoyl)nicotinamide. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.69 (br s, 1H), 10.64 (br s, 1H), 8.71 (s, 1H), 8.58 (s, 1H), 3.13 (br d, J=6.4 Hz, 1H), 1.25 (d, J=6.8 Hz, 6H). m/z (ESI, +ve ion): 393.0 (M+H)+.

Reference： [1]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0633
[2]Journal of Medicinal Chemistry,2020

20
[ 79-37-8 ]
[ 6310-21-0 ]
[ 142266-62-4 ]
N-((2-(tert-butyl)phenyl)carbamoyl)-2,5,6-trichloronicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: N-((2-(tert-Butyl)phenyl)carbamoyl)-<strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> To a mixture of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 1.02 g, 4.5 mmol) in THF (20 mL) was added oxalyl chloride (2 M solution in DCM, 2.5 mL, 5.0 mmol). The resulting mixture was heated at 70 C. for 40 min, then heating was stopped and the reaction was allowed to cool to room temperature. 2-tert-butylaniline (0.708 mL, 4.5 mmol, Ark Pharm, Arlington Heights, Ill., USA) was added. The reaction mixture was stirred at room temperature for 10 min and then was concentrated. The residue was suspended in MeOH and filtered. The filtered solids were collected to provide N-((2-(tert-butyl)phenyl)carbamoyl)-<strong>[142266-62-4]2,5,6-trichloronicotinamide</strong>. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.43 (br s, 1H), 9.79-10.16 (m, 1H), 8.65 (s, 1H), 7.49 (br dd, J=7.5, 1.7 Hz, 1H), 7.43 (br d, J=7.7 Hz, 1H), 7.18-7.28 (m, 2H), 1.40 (s, 9H). m/z (ESI, +ve ion): 422.0 (M+Na)+.

Reference： [1]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0639
[2]Journal of Medicinal Chemistry,2020

21
[ 79-37-8 ]
[ 3524-50-3 ]
[ 142266-62-4 ]
2,5,6-trichloro-N-((1-isopropyl-4-methyl-1H-pyrazol-5-yl)carbamoyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: 2,5,6-Trichloro-N-((1-isopropyl-4-methyl-1H-pyrazol-5-yl)carbamoyl)nicotinamide To a mixture of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 2.43 g, 10.8 mmol) in THF (21.5 mL) was added oxalyl chloride solution (2 M in DCM, 5.70 mL, 11.4 mmol) at room temperature. The resulting mixture was heated at 65 C. for 3 h, then heating was stopped and the reaction was allowed cooled to 0 C. A solution of 1-isopropyl-4-methyl-1H-pyrazol-5-amine (1.50 g, 10.8 mmol, ChemBridge, San Diego, Calif., USA) in THF (15 mL) was added via cannula. The resulting mixture was stirred at 0 C. for 30 min and then was warmed to room temperature and stirred for an additional 16 h. The reaction mixture was filtered, and the filtered solids were collected and washed with acetonitrile (20 mL) to provide 2,5,6-trichloro-N-((1-isopropyl-4-methyl-1H-pyrazol-5-yl)carbamoyl)nicotinamide. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.39 (br s, 1H), 9.51 (br s, 1H), 8.62 (s, 1H), 7.29 (s, 1H), 4.33-4.44 (m, 1H), 1.87 (s, 3H), 1.33 (d, J=6.6 Hz, 6H). m/z (ESI, +ve ion): 389.9 (M+H)+.

Reference： [1]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0663
[2]Journal of Medicinal Chemistry,2020

22
[ 142266-62-4 ]
6,7-dichloro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione [ No CAS ]

Reference： [1]Patent: US2018/334454,2018,A1
[2]Patent: WO2019/213516,2019,A1
[3]Journal of Medicinal Chemistry,2020

23
[ 142266-62-4 ]
6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-methyl-6-(2-propanyl)phenyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one [ No CAS ]