[ CAS No. 70593-57-6 ] {[proInfo.proName]}

Name: 70593-57-6|4,6-Dichloronicotinamide|98%
Brand: Ambeed
SKU: A138142
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Quality Control of [ 70593-57-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 70593-57-6 ]

CAS No. :	70593-57-6	MDL No. :	MFCD01646073
Formula :	C₆H₄Cl₂N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IQVYHPUXNYVYFW-UHFFFAOYSA-N
M.W :	191.02	Pubchem ID :	600044
Synonyms :

Calculated chemistry of [ 70593-57-6 ]

Physicochemical Properties

Num. heavy atoms :	11
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 :	42.35
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) :	-6.53 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.97
Log Po/w (XLOGP3) :	1.32
Log Po/w (WLOGP) :	1.49
Log Po/w (MLOGP) :	0.79
Log Po/w (SILICOS-IT) :	1.8
Consensus Log Po/w :	1.27

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.19
Solubility :	1.22 mg/ml ; 0.0064 mol/l
Class :	Soluble
Log S (Ali) :	-2.1
Solubility :	1.53 mg/ml ; 0.00801 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.85
Solubility :	0.27 mg/ml ; 0.00142 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.6

Safety of [ 70593-57-6 ]

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 [ 70593-57-6 ]

* 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 [ 70593-57-6 ]
Downstream synthetic route of [ 70593-57-6 ]

[ 70593-57-6 ] Synthesis Path-Upstream 1~9

1
[ 70593-57-6 ]
[ 7321-93-9 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium hydroxide; water; bromine In 1,4-dioxane at 0 - 25℃; for 18 h;	NaOH (6.60 g, 165 mmol) was dissolved in H₂O (31 mL) and cooled in an ice bath. Bromine (2.08 mL, 40.6 mmol) was added dropwise and the yellow solution was stirred for 15 min. 4,6-Dichloro-nicotinamide (7.27 g, 38.1 mmol) in 1,4-dioxane (21 mL) was added dropwise to the bromine solution over 30 min. The reaction was allowed to warm slowly to 25° C. over 18 h. The volatiles were removed in vacuo and the resultant solution was diluted with brine and poured into EtOAc. The aqueous phase was separated and extracted twice with EtOAc. The organic layers were combined, dried (Na₂SO₄), decanted and concentrated to afford an orange oil. The resultant oil was purified on a 100 g SiO₂ flash chromatography cartridge with 25 percent EtOAc-hexanes to afford 4,6-dichloro-pyridin-3-ylamine as a tan solid (4.54 g, 73percent). 30percent Aqueous H₂O₂ solution (29 mL) was cooled in an ice bath.

Reference： [1] Patent: US2006/217417, 2006, A1, . Location in patent: Page/Page column 13

2
[ 70593-57-6 ]
[ 166526-03-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With pyridine; trichlorophosphate In acetonitrile at 20 - 60℃; for 1.5 h;	4,6-Dichloro-nicotinonitrile (3) (1175) Pyridine (20.3 mL, 250 mmol) was added to a suspension of 4,6-dichloro-nicotinamide (8.00 g, 41.9 mmol) in acetonitrile (180 mL) at room temperature POCl₃(11.7 mL, 126 mmol) was added over 3 minutes at room temperature. The reaction mixture was heated at 60° C. with for 1.5 hours. The reaction solution was cooled to room temperature and poured into aqueous NaOH (0.8M, 600 mL) followed by extraction with EtOAc (6×400 mL). The organic extracts were combined, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash column chromatography (30percent ethyl acetate/hexanes) to give the title compound as a light orange solid (6.41 g, 88percent) ¹H NMR 400 MHz (CDCl₃) 88.67 (s, 1H), 7.58 (s, 1H).

Reference： [1] Patent: US2015/291629, 2015, A1, . Location in patent: Paragraph 1175

3
[ 73027-79-9 ]
[ 70593-57-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: at 20℃; for 3 h; Stage #2: With ammonium hydroxide In dichloromethane at 25℃; for 1.5 h;	4,6-Dichloro-nicotinamide (2) (1173) Oxalyl chloride (7.70 mL, 88.3 mmol) was added over 1 hour to a suspension of 4,6-dichloronicotinic acid (8.47 g, 44.1 mmol) in dimethylformamide (200 mL) at room temperature. The reaction mixture was stirred for an additional 3 hours at room temperature then concentrated in vacuo. The residue was dissolved in CH₂Cl₂(200 mL) followed by the dropwise addition of NH₄OH (8.3 mL, 130 mmol) over 30 minutes [Note: reaction is exothermic upon addition of NH₄OH and care was taken to control the rate of addition so that the reaction temperature did not exceed 25° C.]. The reaction mixture was stirred for an additional 1 hour at room temperature then diluted with water (600 mL) and extracted with EtOAc (4×600 mL). The organic extracts were combined, dried over Na₂SO₄, filtered and concentrated to give the title compound as a light brown solid (8.05 g, 95percent yield). This material was carried forward without further purification. (1174) ¹H NMR 400 MHz (d₆-DMSO) δ 8.48 (s, 1H), 8.10 (br s, 1H), 7.87 (br s, 2H).
71%	Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; for 3 h; Stage #2: With ammonia In tetrahydrofuran; water at 0℃; for 1 h;	4,6-Dichloro-nicotinic acid (10.3 g, 53.4 mmol) was suspended in CH₂Cl₂ (200 mL). Oxalyl chloride (14 mL, 158 mmol) was added and the reaction was placed in an ice bath. DMF (1.0 mL) was added and the reaction was fitted with an air cooled condenser. The reaction was stirred for 3 h and allowed to warm to 25° C. The volatiles were removed in vacuo and the crude residue was resuspended in THF (200 mL) and cooled to 0° C. To this stirred suspension was added concentrated aqueous ammonia (75 mL) dropwise and the reaction was allowed to stir for 1 h. The volatiles were removed and the crude was redissolved in EtOAc and poured into brine. The aqueous phase was separated and extracted twice with EtOAc. The organic layers were combined, dried (Na₂SO₄), decanted and concentrated to afford 4,6-dichloro-nicotinamide as a beige solid (7.27 g, 71percent).

Reference： [1] Patent: US2015/291629, 2015, A1, . Location in patent: Paragraph 1173-1174
[2] Patent: US2006/217417, 2006, A1, . Location in patent: Page/Page column 12; 13

4
[ 5466-62-6 ]
[ 70593-57-6 ]

Reference： [1] Patent: WO2010/129802, 2010, A1, . Location in patent: Page/Page column 207
[2] Patent: US2012/108566, 2012, A1, . Location in patent: Page/Page column 55

5
[ 73027-79-9 ]
[ 2592-95-2 ]
[ 70593-57-6 ]

Reference： [1] Patent: US2012/108566, 2012, A1, . Location in patent: Page/Page column 55

6
[ 65973-52-6 ]
[ 70593-57-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 21, p. 4908 - 4913

7
[ 40296-46-6 ]
[ 70593-57-6 ]

Reference： [1] Patent: US2012/108566, 2012, A1,

8
[ 73027-79-9 ]
[ 7664-41-7 ]
[ 70593-57-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 21, p. 4908 - 4913

9
[ 70593-57-6 ]
[ 1187190-69-7 ]

Reference： [1] Patent: US2015/291629, 2015, A1,

[ 70593-57-6 ] Synthesis Path-Downstream 1~75

2
[ 73027-79-9 ]
[ 70593-57-6 ]

Yield	Reaction Conditions	Operation in experiment
95%		4,6-Dichloro-nicotinamide (2) (1173) Oxalyl chloride (7.70 mL, 88.3 mmol) was added over 1 hour to a suspension of 4,6-dichloronicotinic acid (8.47 g, 44.1 mmol) in dimethylformamide (200 mL) at room temperature. The reaction mixture was stirred for an additional 3 hours at room temperature then concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL) followed by the dropwise addition of NH4OH (8.3 mL, 130 mmol) over 30 minutes [Note: reaction is exothermic upon addition of NH4OH and care was taken to control the rate of addition so that the reaction temperature did not exceed 25 C.]. The reaction mixture was stirred for an additional 1 hour at room temperature then diluted with water (600 mL) and extracted with EtOAc (4×600 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated to give the title compound as a light brown solid (8.05 g, 95% yield). This material was carried forward without further purification. (1174) 1H NMR 400 MHz (d6-DMSO) delta 8.48 (s, 1H), 8.10 (br s, 1H), 7.87 (br s, 2H).
71%		4,6-Dichloro-nicotinic acid (10.3 g, 53.4 mmol) was suspended in CH2Cl2 (200 mL). Oxalyl chloride (14 mL, 158 mmol) was added and the reaction was placed in an ice bath. DMF (1.0 mL) was added and the reaction was fitted with an air cooled condenser. The reaction was stirred for 3 h and allowed to warm to 25 C. The volatiles were removed in vacuo and the crude residue was resuspended in THF (200 mL) and cooled to 0 C. To this stirred suspension was added concentrated aqueous ammonia (75 mL) dropwise and the reaction was allowed to stir for 1 h. The volatiles were removed and the crude was redissolved in EtOAc and poured into brine. The aqueous phase was separated and extracted twice with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated to afford 4,6-dichloro-nicotinamide as a beige solid (7.27 g, 71%).

Reference： [1]Patent: US2015/291629,2015,A1 .Location in patent: Paragraph 1173-1174
[2]Patent: US2006/217417,2006,A1 .Location in patent: Page/Page column 12; 13

3
[ 70593-57-6 ]
[ 7321-93-9 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium hydroxide; water; bromine; In 1,4-dioxane; at 0 - 25℃; for 18h;	NaOH (6.60 g, 165 mmol) was dissolved in H2O (31 mL) and cooled in an ice bath. Bromine (2.08 mL, 40.6 mmol) was added dropwise and the yellow solution was stirred for 15 min. 4,6-Dichloro-nicotinamide (7.27 g, 38.1 mmol) in 1,4-dioxane (21 mL) was added dropwise to the bromine solution over 30 min. The reaction was allowed to warm slowly to 25° C. over 18 h. The volatiles were removed in vacuo and the resultant solution was diluted with brine and poured into EtOAc. The aqueous phase was separated and extracted twice with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated to afford an orange oil. The resultant oil was purified on a 100 g SiO2 flash chromatography cartridge with 25 percent EtOAc-hexanes to afford 4,6-dichloro-pyridin-3-ylamine as a tan solid (4.54 g, 73percent). 30percent Aqueous H2O2 solution (29 mL) was cooled in an ice bath.

Reference： [1]Patent: US2006/217417,2006,A1 .Location in patent: Page/Page column 13

4
[ 70593-57-6 ]
[ 910815-16-6 ]

Yield	Reaction Conditions	Operation in experiment
62%	With urea hydrogen peroxide adduct; trifluoroacetic anhydride; In acetonitrile; at 0 - 20℃; for 3h;	Example 3 Synthesis of 4-[(4-aminomethyl-cyclohexylmethyl)-amino]-6-(2-chloro-benzylamino)-nicotinamide To a suspension of <strong>[70593-57-6]4,6-dichloro-nicotinamide</strong> (1.94 g, 10.26 mmol) in acetonitrile (20 mL) at ambient temperature, was added urea hydrogen peroxide (UHP) (2.90 g, 30.80 mmol). The mixture was cooled to 0 C. before trifluoroacetic anhydride (2.85 mL, 20.52 mmol) was added. The resulting mixture was allowed to warm up to ambient temperature and stirred for 3 h. 4,6-Dichloro-1-oxy-nicotinamide was obtained by filtration of the reaction mixture and was combined with another portion isolated by purifying the residual filtrate by silica gel column chromatography (EtOAc then CH2Cl2/MeOH, 20:1 v/v). The two batches were combined to afford the product (1.30 g, 62%).

Reference： [1]Patent: US2006/217417,2006,A1 .Location in patent: Page/Page column 16

5
[ 3731-52-0 ]
[ 70593-57-6 ]
[ 1227486-66-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 60℃; for 20h;	A mixture of 4,6-Dichloronicotinamide (1, 950 mg, 5 mmoles), 3-picolylamine (756 mg, 7 mmoles) and DIEA (12 mmoles) in NMP (5 mL) was stirred at 60 0C for 20 hrs. The reaction mixture was concentrated under an oil pump. The residue was washed with water and dried under an oil pump. The desired 6-chloro-4-(pyridin-3-ylmethylamino)nicotinamide (2, 1.085 g) was obtained. MS+: 263.1, UV: lambda = 220.9; 260.9 nm. 1H NMR: (CDCl3) delta8.96(s,lH), delta8.60(s,lH), delta8.57(d,J=3.2 Hz,lH), delta8.30(s,lH), delta7.64(d,J=7.6Hz,lH), 67.31 (dd,Jl=7.6Hz,J2=3.2Hz,lH), delta6.51(s,lH), delta5.80(b,2H), delta4.47(s, IH), delta4.45(s, IH).
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 60℃; for 20h;	A mixture of 4,6-Dichloronicotinamide (28.1, 950 mg, 5 mmol), 3-picolylamine (756 mg, 7 mmol) and DIPEA (12 mmol) in NMP (5 mL) was stirred at 60 C. for 20 hrs. The reaction mixture was concentrated under an oil pump. The residue was washed with water and dried under an oil pump. The desired 6-chloro-4-(pyridin-3-ylmethylamino)nicotinamide (28.2, 1.085 g) was obtained. MS+: 263.1, UV: lambda=220.9; 260.9 nm. 1H NMR: (CDCl3) delta8.96 (s, 1H), delta8.60 (s, 1H), delta8.57 (d, J=3.2 Hz, 1H), delta8.30 (s, 1H), delta7.64 (d, J=7.6 Hz, 1H), delta7.31 (dd,J1=7.6 Hz,J2=3.2 Hz, 1H), delta6.51 (s, 1H), delta5.80 (b, 2H), delta4.47 (s, 1H), 84.45 (s, 1H).

Reference： [1]Patent: WO2010/129802,2010,A1 .Location in patent: Page/Page column 207
[2]Patent: US2012/108566,2012,A1 .Location in patent: Page/Page column 55

6
[ 5466-62-6 ]
[ 70593-57-6 ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of 4,6-dihydroxynicotinic acid (3.10 g, 20 mmoles) in phosphoryl trichloride (50 mL) was stirred at 100 0C for 4 hrs. After cooled to room temperature, the reaction solution was poured into a cold ammonium hydroxide solution (27-30 %) in several portions and kept the mixture basic. The first portion of desired product as precipitate was collected by filtration. The second portion of desired product was obtained by extraction of mother aqueous liquid with DCM. The total amount of 4,6-Dichloronicotinamide (1) was 2.78 g. MS+: 191.0, UV: lambda = 201.0; 269.2 nm, 1H NMR: (CDCl3) delta8.77(s,lH), delta7.45(s,lH), delta6.34(b,lH), 56.21(b,lH).
		A suspension of 4,6-dihydroxynicotinic acid (3.10 g, 20 mmol) in phosphoryl trichloride (50 mL) was stirred at 100 C. for 4 hrs. After cooled to room temperature, the reaction solution was poured into a cold ammonium hydroxide solution (27-30%) in several portions and kept the mixture basic. The first portion of desired product as precipitate was collected by filtration. The second portion of desired product was obtained by extraction of mother aqueous liquid with DCM. The total amount of 4,6-Dichloronicotinamide (28.1) was 2.78 g. MS+: 191.0, UV: lambda=201.0; 269.2 nm, 1H NMR: (CDCl3) delta8.77 (s, 1H), delta7.45 (s, 1H), delta6.34 (b, 1H), delta6.21 (b, 1H).

Reference： [1]Patent: WO2010/129802,2010,A1 .Location in patent: Page/Page column 207
[2]Patent: US2012/108566,2012,A1 .Location in patent: Page/Page column 55

7
[ 27489-62-9 ]
[ 70593-57-6 ]
[ 1190424-87-3 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; N,N-dimethyl acetamide; at 60℃;	Example 142; Synthesis of 2-[4-(quinolin-3-yl)-9H-carbazol-9-yl]-4-(4-trans-hydroxycyclohexylamino)pyridine-5-carboxamide; Stage 1:; In a 50 ml single-necked round-bottomed flask, 500 mg of <strong>[70593-57-6]4,6-dichloronicotinamide</strong> are dissolved in 7.5 ml of ethanol and 7.5 ml of dimethylacetamide, and then 663 mg of trans-4-aminocyclohexanol are added. The mixture is then heated overnight at 60 C. After concentration under reduced pressure, 360 mg of 6-chloro-4-(4-trans-hydroxycyclohexyl)aminonicotinamide are obtained, the characteristic of which is the following: 1 H NMR spectrum (400 MHz, DMSO-d6) delta ppm 1.09-1.42 (m, 4 H) 1.79 (dd, J=13.1, 2.8 Hz, 2 H) 1.91 (dd, J=12.8, 2.6 Hz, 2 H) 3.38-3.52 (m, 2 H) 4.56 (d, J=3.9 Hz, 1 H) 6.73 (s, 1 H) 7.41 (broad s, 1 H) 8.03 (broad s, 1 H) 8.38 (s, 1 H) 8.76 (d, J=7.8 Hz, 1 H).

Reference： [1]Patent: US2011/166169,2011,A1 .Location in patent: Page/Page column 109

8
[ 27489-62-9 ]
[ 70593-57-6 ]
[ 1190424-86-2 ]

Reference： [1]Patent: US2011/166169,2011,A1

9
[ 33024-60-1 ]
[ 70593-57-6 ]
[ 1190424-78-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethanol; N,N-dimethyl acetamide; at 60℃;	Example 137; Synthesis of 2-[4-(quinolin-3-yl)-9H-carbazol-9-yl]-4-(tetrahydropyran-4-yl)amino)pyridine-5-carboxamide; Stage 1:; In a 25 ml single-necked round-bottomed flask, 300 mg of <strong>[70593-57-6]4,6-dichloronicotinamide</strong> are dissolved in 4.5 ml of ethanol and 4.5 ml of dimethylacetamide, and then 238 mg of 4-aminotetrahydropyran hydrochloride and 711 mg of diisopropylethylamine are added. The mixture is then heated overnight at 60° C. After concentration under reduced pressure, the residue is extracted with dichloromethane, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on 25 g of silica, elution being carried out with a mixture of ethyl acetate and heptane (85/15 by volume), 132.5 mg of 6-chloro-4-(tetrahydropyran-4-yl)aminonicotinamide are obtained, the characteristic of which is the following: 1H NMR spectrum (400 MHz, DMSO-d6, delta ppm): 1.32-1.46 (m, 2 H) 1.88 (d, J=11.2 Hz, 2 H) 3.47 (td, J=11.2, 2.2 Hz, 2 H) 3.66-3.77 (m, 1 H) 3.82 (dt, J=11.7, 3.6 Hz, 2 H) 6.82 (s, 1 H) 7.45 (broad s, 1 H) 8.07 (broad s, 1 H) 8.41 (s, 1 H) 8.86 (d, J=8.1 Hz, 1 H).

Reference： [1]Patent: US2011/166169,2011,A1 .Location in patent: Page/Page column 106-107

10
[ 33024-60-1 ]
[ 70593-57-6 ]
[ 1190424-76-0 ]

Reference： [1]Patent: US2011/166169,2011,A1

11
[ 771573-20-7 ]
[ 70593-57-6 ]
[ 1227486-30-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1h;Microwave irradiation;	To a mixture of <strong>[70593-57-6]4,6-dichloronicotinamide</strong> (300 mg) and N-methyl-2-pyrrolidinone (1.5 mL) were added N,N-diisopropylethylamine (1.09 mL) and 2,6-difluoro-4-methoxybenzylamine (326 mg), followed by microwave irradiation and stirring at 140C for 1 hour. After cooling the reaction liquid, the reaction liquid was added to water, followed by stirring at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with diisopropyl ether, and then dried under reduced pressure to obtain 6-chloro-4-[(2,6-difluoro-4-methoxybenzyl)amino]nicotinamide (514 mg).

Reference： [1]Patent: EP2361902,2011,A1 .Location in patent: Page/Page column 39

12
[ 771573-20-7 ]
[ 70593-57-6 ]
[ 1227481-53-9 ]

Reference： [1]Patent: EP2361902,2011,A1

13
[ 70593-57-6 ]
[ 100-46-9 ]
[ 1227861-73-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-ethyl-N,N-diisopropylamine; In ethanol; for 12h;Reflux;	5.00 g of <strong>[70593-57-6]4,6-dichloropyridine-3-carboxyamide</strong> synthesized according to the method described in US 2006/0217417 was dissolved in 50 mL of ethanol, to which 3.37 g of benzylamine and 4.40 g of N,N-diisopropylethylamine were added, and heated at reflux for 12 hours. After cooling, the solvent was evaporated, and 100 mL of water was added to the residue. After cooling with ice, the deposited crystals were filtered, washed with water and hexane, and air-dried. It was further dried under reduced pressure (100 C., 2 hours) to obtain the title compound (5.96 g, 87%) as light yellow needle crystals.1H-NMR (400 MHz, CDCl3) delta: 4.42 (2H, d, J=5.6 Hz), 5.82 (2H, br), 6.53 (1H, s), 7.26-7.39 (5H, m), 8.28 (1H, s), 8.90 (1H, br).

Reference： [1]Patent: US2011/237590,2011,A1 .Location in patent: Page/Page column 22

14
[ 108-91-8 ]
[ 70593-57-6 ]
[ 1227866-03-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; In ethanol; for 8h;Reflux;	200 mg of <strong>[70593-57-6]4,6-dichloropyridine-3-carboxyamide</strong> synthesized according to the method described in US2006/0217417 was dissolved in 2 mL of ethanol, to which 156 mg of cyclohexylamine and 203 mg of N,N-diisopropylethylamine were added, and heated at reflux for 8 hours. After cooling, the solvent was evaporated, and 10 mL of water was added to the residue, neutralized by adding 2 mol/L hydrochloric acid in water under ice cooling, extracted with chloroform, and the extract was dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was recrystallized from chloroform-hexane to obtain 243 mg (92%) of the title compound as colorless needle crystals.1H-NMR (400 MHz, CDCl3) delta: 1.23-1.46 (5H, m), 1.60-1.68 (1H, m), 1.74-1.82 (2H, m), 1.93-2.01 (2H, m), 3.27-3.37 (1H, m), 5.82 (2H, br), 6.53 (1H, s), 8.25 (1H, s), 8.49 (1H, brd, J=6.8 Hz).

Reference： [1]Patent: US2011/237590,2011,A1 .Location in patent: Page/Page column 112

15
[ 108-91-8 ]
[ 70593-57-6 ]
[ 1227866-08-1 ]

Reference： [1]Patent: US2011/237590,2011,A1

16
[ 70593-57-6 ]
[ 1227862-57-8 ]

Reference： [1]Patent: US2011/237590,2011,A1

17
[ 70593-57-6 ]
[ 1227865-71-5 ]

Reference： [1]Patent: US2011/237590,2011,A1

18
[ 70593-57-6 ]
[ 1227866-36-5 ]

Reference： [1]Patent: US2011/237590,2011,A1

19
[ 73027-79-9 ]
[ 2592-95-2 ]
4-(1H-benzo[d][1,2,3]triazol-1-yloxy)-6-chloronicotinamide [ No CAS ]
[ 70593-57-6 ]

Yield	Reaction Conditions	Operation in experiment
		Carboxylic acid 28.8 (4.37 g, 23 mmol) was dissolved in 25 mL of DMF. To this was added HOBt (4.1 g, 27 mmol) and EDC (5.2 g, 27 mmol). After stirring ca. 30 min the reaction was checked by UPLC which showed consumption of the starting carboxylic acid. Aqueous ammonia (3.3 mL, 46 mmol) was then added and the reaction stirred at rt for 1 hr. The reaction was then diluted with water and extracted twice with ethyl acetate, the combined organic layers were then washed once with saturated sodium carbonate. The organic phase was then concentrated and dried in vacuo affording the desired dichloro amide (MS found for C6H4Cl2N2O as (M+H)+ 191.0, 193.0. UV: lambda=202, 271 nm) as a light brown oil contaminated with a small amount of 4-(1H-benzo[d][1,2,3]triazol-1-yloxy)-6-chloronicotinamide (MS found for C12H8ClN5O2 as (M+H)+ 290.0, 292.1. UV: lambda=202 nm).

Reference： [1]Patent: US2012/108566,2012,A1 .Location in patent: Page/Page column 55

20
[ 27757-85-3 ]
[ 70593-57-6 ]
[ 1227486-75-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; for 18h;	A solution of <strong>[70593-57-6]4,6-dichloronicotinamide</strong> (123 mg, 0.643 mmol), thiophen-2-ylmethanamine (0.065 mL, 0.634 mmol) and DIPEA (0.230 mL, 1.32 mmol) in NMP (4 mL) was stirred at 90 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, and concentrated in vacuo to give 6-chloro-4-(thiophen-2-ylmethylamino)nicotinamide as a solid (168 mg).

Reference： [1]Patent: US2012/108566,2012,A1 .Location in patent: Page/Page column 78

21
[ 40296-46-6 ]
4-(1H-benzo[d][1,2,3]triazol-1-yloxy)-6-chloronicotinamide [ No CAS ]
[ 70593-57-6 ]

Reference： [1]Patent: US2012/108566,2012,A1

22
[ 70593-57-6 ]
[ 1254216-71-1 ]

Reference： [1]Patent: US2012/108566,2012,A1

23
[ 70593-57-6 ]
[ 1374211-57-0 ]

Reference： [1]Patent: US2012/108566,2012,A1

24
[ 70593-57-6 ]
[ 1374212-53-9 ]

Reference： [1]Patent: US2012/108566,2012,A1

25
[ 70593-57-6 ]
[ 1374213-82-7 ]

Reference： [1]Patent: US2012/108566,2012,A1

26
[ 70593-57-6 ]
[ 1374213-83-8 ]

Reference： [1]Patent: US2012/108566,2012,A1

27
[ 70593-57-6 ]
[ 1374215-25-4 ]

Reference： [1]Patent: US2012/108566,2012,A1

28
[ 70593-57-6 ]
[ 1374211-55-8 ]

Reference： [1]Patent: US2012/108566,2012,A1

29
[ 70593-57-6 ]
[ 1374212-52-8 ]

Reference： [1]Patent: US2012/108566,2012,A1

30
[ 70593-57-6 ]
[ 1374215-26-5 ]

Reference： [1]Patent: US2012/108566,2012,A1

31
[ 41049-53-0 ]
[ 70593-57-6 ]
[ 1374215-15-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 48h;	To a suspension of <strong>[70593-57-6]4,6-dichloronicotinamide</strong> (191 mg, 1 mmol) in AcCN (2 mL) was added 1-phenylcyclopropanamine (160 mg, 1.2 mmol) and DIPEA (0.213 mL, 1.2 mmol). The mixture was heated at 60 C. for 2 days. The mixture was concentrated and purified by column chromatography to give 6-chloro-4-(1-phenylcyclopropylamino)nicotinamide (105 mg).

Reference： [1]Patent: US2012/108566,2012,A1 .Location in patent: Page/Page column 80

32
[ 696-40-2 ]
[ 70593-57-6 ]
[ 1374215-24-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; for 48h;	A solution of <strong>[70593-57-6]4,6-dichloronicotinamide</strong> (400 mg, 2.09 mmol), 3-iodobenzylamine (0.285 mL, 2.13 mmol) and DIEA (0.500 mL, 2.87 mmol) in NMP (5 mL) was stirred at 90 C for 48 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with 0-100% EtOAc in hexane to give 6-chloro-4-(3-iodobenzylamino)nicotinamide as a solid (266 mg).

Reference： [1]Patent: US2012/108566,2012,A1 .Location in patent: Page/Page column 105

33
[ 70593-57-6 ]
tert-butyl3-(4-(4-benzamidophenoxy)-5-carbamoylpyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/61247,2015,A2

34
[ 70593-57-6 ]
tert-butyl 3-(4-(4-benzamidophenoxy)-5-carbamoylpyridin-2-yl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/61247,2015,A2

35
[ 70593-57-6 ]
4-(4-benzamidophenoxy)-6-(pyrrolidin-3-yl)nicotinamide [ No CAS ]

Reference： [1]Patent: WO2015/61247,2015,A2

36
[ 70593-57-6 ]
6-(1-acryloylpyrrolidin-3-yl)-4-(4-benzamidophenoxy)nicotinamide [ No CAS ]

Reference： [1]Patent: WO2015/61247,2015,A2

37
[ 15457-50-8 ]
[ 70593-57-6 ]
4-(4-benzamidophenoxy)-6-chloronicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.4%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;	To a stuffed solution of <strong>[70593-57-6]4,6-dichloro-nicotinamide</strong> (500.00 mg; 2.59 mmol; 1.00 eq.) in DMF (5.00 ml; 10.00 V) was added N-(4-hydroxy-phenyl)-benzamide (669.79 mg; 3.11 mmol; 1.20 eq.) and cesium carbonate (2611.36 mg; 7.77 mmol; 3.00 eq.) at RT. The resulting reaction mixture was stirred for 5h. The reaction completion was confirmed by TLC. After completion, the reaction mixture was quenched by the addition of water (20 mL). The solid was filtered and dried under vacuum. The solid was further triturated with acetonitrile (25 mL), filtered and dried under vacuum to afford 4- (4-benzoylamino-phenoxy)-6-chloro-nicotinamide (900.00 mg; 94.4 %; off white solid). HPLC: 95.20% purity. MS: m/z = 368.0 [M+Hf?.

Reference： [1]Patent: WO2015/61247,2015,A2 .Location in patent: Paragraph 00521

38
[ 70593-57-6 ]
4-ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenoxy]nicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

39
[ 70593-57-6 ]
6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-4-methoxynicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

40
[ 70593-57-6 ]
[ 166526-03-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With pyridine; trichlorophosphate; In acetonitrile; at 20 - 60℃; for 1.5h;	4,6-Dichloro-nicotinonitrile (3) (1175) Pyridine (20.3 mL, 250 mmol) was added to a suspension of 4,6-dichloro-nicotinamide (8.00 g, 41.9 mmol) in acetonitrile (180 mL) at room temperature POCl3 (11.7 mL, 126 mmol) was added over 3 minutes at room temperature. The reaction mixture was heated at 60 C. with for 1.5 hours. The reaction solution was cooled to room temperature and poured into aqueous NaOH (0.8M, 600 mL) followed by extraction with EtOAc (6×400 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (30% ethyl acetate/hexanes) to give the title compound as a light orange solid (6.41 g, 88%) 1H NMR 400 MHz (CDCl3) 88.67 (s, 1H), 7.58 (s, 1H).

Reference： [1]Patent: US2015/291629,2015,A1 .Location in patent: Paragraph 1175

41
[ 70593-57-6 ]
[ 1187190-69-7 ]

Reference： [1]Patent: US2015/291629,2015,A1

42
[ 70593-57-6 ]
6-chloro-4-[2-(tetrahydropyran-2-yloxy)ethoxy]nicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

43
[ 70593-57-6 ]
6-(4-bromo-3-formylphenoxy)-4-[2-(tetrahydropyran-2-yloxy)ethoxy]nicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

44
[ 70593-57-6 ]
6-[3-formyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenoxy]-4-[2-(tetrahydropyran-2-yloxy)ethoxy]nicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

45
[ 70593-57-6 ]
6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-4-[2-(tetrahydropyran-2-yloxy)ethoxy]nicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

46
[ 70593-57-6 ]
6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-4-(2-hydroxyethoxy)nicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

47
[ 70593-57-6 ]
4-ethoxy-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

48
[ 70593-57-6 ]
6-(4-bromo-3-formylphenoxy)-4-ethoxynicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

49
[ 70593-57-6 ]
6-chloro-4-ethoxynicotinonitrile [ No CAS ]
4-chloro-6-ethoxynicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291629,2015,A1

50
[ 70593-57-6 ]
C₁₆H₂₁ClN₄O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 5221 - 5237

51
[ 70593-57-6 ]
tert-butyl (rac)-2-(((5-cyano-2-((5-cyanopyrazin-2-yl)amino)pyridin-4-yl)amino)methyl)morpholine-4-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 5221 - 5237

52
[ 70593-57-6 ]
(rac)-5-((5-cyano-4-((morpholin-2-ylmethyl)amino)pyridin-2-yl)amino)pyrazine-2-carbonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 5221 - 5237

53
[ 140645-53-0 ]
[ 70593-57-6 ]
tert-butyl (rac)-2-(((5-carbamoyl-2-chloropyridin-4-yl)amino)methyl)morpholine-4-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 5221 - 5237

54
[ 70593-57-6 ]
4-((2-chlorophenyl)amino)-6-(pyridin-2-ylamino)nicotinamide [ No CAS ]

Reference： [1]Patent: WO2017/89985,2017,A1
[2]Patent: TW2019/631,2019,A

55
[ 70593-57-6 ]
4-((2-chlorophenyl)amino)-6-((6-methylpyridin-2-yl)amino)nicotinamide [ No CAS ]

Reference： [1]Patent: WO2017/89985,2017,A1
[2]Patent: TW2019/631,2019,A

56
[ 70593-57-6 ]
[ 95-51-2 ]
6-chloro-4-((2-chlorophenyl)amino)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.8 g	With sodium hexamethyldisilazane; In tetrahydrofuran; at 0 - 25℃;Inert atmosphere;	At 0C a 1 M solution of sodium bis(trimethylsilyl)amide (NaHMDS) in THF (340.8 mL)was added dropwise to a solution of 1 (9.3 g, 48.7 mmol) and 2 (7.68 mL, 73 mmol) in THF (100 mL) and the mixture stirred for 3 hat 25C under an atmosphere of nitrogen. The mixture was quenched with water, extracted with ethyl acetate, dried with sodium sulfate and concentrated under reduced pressure. The crude product was stirred with diethyl ether (200 mL) for 0.5 h and filtered to give 3 (12.8 g, 95% purity) as a pale yellow solid. MS: 282.0 (M+1)+; 1H NMR (DMSOd6) delta=8.52(1 H, s), 11.00(1 H, s), 9.74 (1 H, m), 8.59 (1 H, s), 8.09 (2 H, m), 7.70 (1 H, d), 7.59 (1 H, d), 7.52 (1 H, t), 7.43 (1 H, t), 7.40 (1 H, m), 7.17 (2 H, m), 6.72 (1 H, d), 2.26 (3 H, s).
12.8 g	With sodium hexamethyldisilazane; In tetrahydrofuran; at 0 - 25℃; for 3h;Inert atmosphere;	At 0 C, To a solution of 1 (9.3 g, 48.7 mmol) and 2 (7.68 mL, 73 mmol) in THF (100 mL), sodium bis(trimethyldecyl)decylamine (NaHMDS) in THF (340.8 mL) 1 M solution,The mixture was stirred at 25 C for 3 hours under a nitrogen atmosphere.The mixture is quenched with water,Extracted with ethyl acetate,Dry with sodium sulfate,It was concentrated under reduced pressure.The crude product was stirred with diethyl ether (200 mL) for 0.5 h and filtered. 3 (12.8 g, 95% purity) was obtained as a pale yellow solid.

Reference： [1]Patent: WO2017/89985,2017,A1 .Location in patent: Page/Page column 14; 15
[2]Patent: TW2019/631,2019,A .Location in patent: Page/Page column 15

57
[ 70593-57-6 ]
4-(3-nitrobenzylamino)-6-(phenylamino)nicotinamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4622 - 4625

58
[ 70593-57-6 ]
4-(3-aminobenzylamino)-6-(phenylamino)nicotinamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4622 - 4625

59
[ 70593-57-6 ]
4-(3-acrylamidobenzylamino)-6-(phenylamino)nicotinamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4622 - 4625

60
[ 70593-57-6 ]
C₂₂H₂₃N₅O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4622 - 4625

61
[ 7409-18-9 ]
[ 70593-57-6 ]
[ 1227862-29-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 120℃; for 2h;	N-Ethyl-N-isopropylpropan-2-amine(3.66 mL, 20.94 mmol) was added in one portion to a solution of <strong>[70593-57-6]4,6-dichloronicotinamide</strong> (2 g, 10.47 mmol) and (3-nitrophenyl)methanamine(1.752 g, 11.52 mmol) in anhydrous DMA (20.94 mL). The reaction mixture was then allowed to heatto 120 C for 2hrs before cooling to 0 C in an ice bath. This cooled solution was then poured ontoice-water (ca. 30mL) and the resulting precipitate was filtered and allowed todry in the funnel (vacuum applied) overnight.This gave 6-chloro-4-(3-nitrobenzylamino)nicotinamide (2.8 g, 9.13 mmol,87 % yield) as a tan solid that was used immediately in the next step. 1H NMR (500 MHz, DMSO-d6)delta 9.38 - 9.13 (m, 1H), 8.49 - 8.35 (m, 1H), 8.23 - 8.03 (m, 3H), 7.83 - 7.75(m, 1H), 4.73 - 4.60 (m, 2H). HPLC(a):100%, rt=1.305 min. HPLC(b): 98.6%, rt= 3.856 min. LC-MS: M+1 307.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4622 - 4625

62
[ 3182-95-4 ]
[ 70593-57-6 ]
C₁₅H₁₆ClN₃O₂ [ No CAS ]