846023-24-3|2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide| Ambeed

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Quality Control of [ 846023-24-3 ] Purity: 97% SDS Specification

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Product Details of [ 846023-24-3 ]

CAS No. :	846023-24-3
Formula :	C₁₀H₈Cl₂N₂O₂
M.W :	259.09
SMILES Code :	O=C(NC1=CC(OC)=C(Cl)C=C1Cl)CC#N
MDL No. :	MFCD08143656
InChI Key :	RPWHAQJEZWBZGX-UHFFFAOYSA-N
Pubchem ID :	16099178

Safety of [ 846023-24-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302+H312+H332
Precautionary Statements:	P280

Computational Chemistry of [ 846023-24-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	6
Fraction Csp3	0.2
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	61.82
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	62.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.85
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.94
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.66
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.71
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.6
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.35

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.31
Solubility	0.126 mg/ml ; 0.000487 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.91
Solubility	0.0321 mg/ml ; 0.000124 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.25
Solubility	0.0145 mg/ml ; 0.000056 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.79 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.94

Application In Synthesis of [ 846023-24-3 ]

* 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.

Downstream synthetic route of [ 846023-24-3 ]

[ 846023-24-3 ] Synthesis Path-Downstream 1~35

1
[ 98446-49-2 ]
[ 372-09-8 ]
[ 846023-24-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	With diisopropyl-carbodiimide; In tetrahydrofuran; for 0.5h;Heating / reflux;Product distribution / selectivity;	EXAMPLE 4 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide 2,4-Dichloro-5-methoxyaniline (5.00 g, 26 mmol) and cyanoacetic acid (2.28 g, 26.8 mmol) were mixed in 50 mL of tetrahydrofuran until a solution formed. This solution was heated to reflux and 1,3-diisopropylcarbodiimide (4.2 mL, 26.8 mmol) was added dropwise. After 30 minutes the mixture was cooled to ~15 C. in an ice-bath. The solid was collected by filtration and washed with tetrahydrofuran. The filtrate was slowly poured into water and stirred for 30 minutes. The white solid was collected by filtration, washed with water, and was then dissolved in 500 mL of ethyl acetate. The solution was dried over sodium sulfate and concentrated in vacuo to give 5.9 g (88%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide as a white solid, mp 180-181 C.; 1H NMR (400 MHz, DMSO-d6) delta 3.84 (s, 3H), 4.02 (s, 2H), 7.58 (s, 1 H), 7.66 (s, 1 H), 10.00 (s, 1 H); MS (ES) m/z257.0, 259.0 (M-H)- Analysis for C10H8Cl2N2O2; Calcd: C, 46.36; H, 3.11; N, 10.81. Found: C, 46.25; H, 3.10; N, 10.85.
88%	With diisopropyl-carbodiimide; In tetrahydrofuran; for 0.5h;	Reference Example 1; 2-Cvano-N-(2,4-dichloro-5-methoxyphenv0acetamide; 2,4-Dichloro-5-methoxyaniline (5.00 g, 26 mmol) and cyanoacetic acid (2.28 g, 26.8 mmol) were mixed in 50 ml_ of tetrahydrofuran, under N2, until a solution formed. This solution was heated to reflux and 1 ,3-diisopropylcarbodiimide (4.2 ml_, 26.8 mmol) was added dropwise. After 30 minutes a TLC check (5% MeOH in CH2CI2) indicated that the reaction was complete. The mixture was cooled to ~15C in an ice- bath. The solid was collected by filtration and washed with tetrahydrofuran. The filtrate was slowly poured into water and stirred for 30 minutes. The white solid was collected by filtration, washed with water and then dissolved in 500 ml_ of ethyl acetate. The solution was dried over Na2SO4 and concentrated in vacuo to give 5.9 g (88%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide as a white solid, mp 180-1810C; MS 257.0, 259.0 (M-H)-. EPO <DP n="15"/>Analysis for C10H8CI2N2O2:Calcd: C, 46.36; H, 3.11 ; N, 10.81.Found: C, 46.25; H, 3.10; N, 10.85.
97 g		Cyanoacetic acid (50 g) was added to ethyl acetate (400 mL) at 25 C followed by addition of dimethylformamide (2 mL). The obtained reaction mixture was cooled to 0C and oxalyl chloride (82.6 g) was slowly added at 0C to 5C over a period of about 60 minutes. The temperature of the reaction mixture was raised up to 25C to 28C and stirred for 2 hours. 2,4-dichloro-5-methoxyaniline (100 g, obtained from Step-3) was added to the reaction mixture and heated up to 55C to 60C under stirring for about 2 hours. Deionized water (200 mL) was added to the reaction mixture at 20C to 30C followed by stirring for 1 hour. The product obtained was filtered and washed with ethyl acetate (50 mL) followed by deionized water (500 mL) and ethyl acetate (200 mL) respectively. The wet product was dried in air oven to provide the title product. Yield: 97 g Chromatographic Purity: 99.67%

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7868 - 7876.
[2]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 3; 6.
[3]Patent: WO2006/47262,2006,A1 .Location in patent: Page/Page column 13-14.
[4]Letters in drug design and discovery,2011,vol. 8,p. 9 - 13.
[5]Patent: WO2019/186429,2019,A1 .Location in patent: Page/Page column 4; 5; 6.

2
[ 846023-24-3 ]
[ 846023-60-7 ]
[ 122-51-0 ]
[ 846023-62-9 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7868 - 7876.

3
[ 846023-24-3 ]
[ 19056-41-8 ]
[ 122-51-0 ]
[ 846023-35-6 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; for 6h;Heating / reflux;	EXAMPLE 17 3-Bromo-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (900 mg, 3.46 mmol) in 100 mL of iso-propanol was added 3-bromo-4-methoxyaniline (700 mg, 3.46 mmol). This mixture was heated to reflux and triethylorthoformate (3.3 mL, 19.8 mmol) was added dropwise. The reaction mixture was heated at reflux for 6 hours. The mixture was filtered while still warm and the collected white solid was washed with iso-propanol to give 376 mg of 3-bromo-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide, mp >250 C.; MS (ES) m/z 467.7, 469.9, 471.7 (M-H)- Analysis for C18H14BrCl2N3O3; Calcd: C, 45.89; H, 3.00; N, 8.92. Found: C, 45.75; H, 2.77; N, 8.78.

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7868 - 7876.
[2]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 8-9.

4
[ 846023-24-3 ]
[ 74587-12-5 ]
[ 122-51-0 ]
[ 846023-38-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	In isopropyl alcohol;Heating / reflux;	EXAMPLE 20 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-iodo-4-methoxyphenyl)amino]prop-2-enamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (5.00 g, 19.30 mol) in 400 mL of iso-propanol, under N2, was added 3-iodo-p-anisidine (5.80 g, 23.16 mmol). This mixture was heated to reflux to give a clear yellow solution. To this solution, triethylorthoformate (8.60 mL, 52.11 mmol) was added dropwise and the reaction mixture was heated at reflux overnight. An additional 10 mL of triethylorthoformate was added and the mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature and the white solid was collected by filtration, washed with isopropanol, and dried overnight at ~40 C. under reduced pressure. Purification by suspension in hot ethyl acetate followed by addition of cold hexanes gave 8.50 g (85%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-iodo-4-methoxyphenyl)amino]prop-2-enamide as a yellow solid, mp 289-290 C.; MS (ES) m/z 516.7 (M-H)- Analysis for C18H14Cl2IN3O3; Calcd: C, 41.73; H, 2.72; N, 8.11. Found: C, 40.66; H, 2.94; N, 7.90.
85%	In isopropyl alcohol;Heating / reflux;	Reference Example 2; 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl )-3-r(3-iodo-4-methoxyphenv?amino1- prop-2-enamide; To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (5.00 g, 19.30 mol) in 400 ml_ of /so-propanol, under N2, is added 3-iodo-p-anisidine (5.80 g, 23.16 mmol). This mixture is heated to reflux to give a clear yellow solution. To this solution, triethylorthoformate (8.60 ml_, 52.11 mmol) is added dropwise and the reaction mixture is heated at reflux overnight. An additional 10 ml_ of triethylorthoformate is added and the mixture is heated at reflux overnight. The mixture is allowed to cool to room temperature and the white solid is collected by filtration, washing with /so-propanol, and dried overnight at -4O0C under reduced pressure. Purification by suspension in hot ethyl acetate followed by addition of cold hexanes gives 8.50 g (85%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-iodo- 4-methoxyphenyl)amino]prop-2-enamide as a yellow solid, mp 289-290 0C; MS (ES) m/z 516.7 (M-H)-. Analysis for C18H14CI2IN3O3:Calcd: C, 41.73; H, 2.72; N, 8.11. Found: C, 40.88; H, 2.64; N, 7.90.

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7868 - 7876.
[2]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 9.
[3]Patent: WO2006/47262,2006,A1 .Location in patent: Page/Page column 14.
[4]Letters in drug design and discovery,2011,vol. 8,p. 9 - 13.

5
[ 846023-24-3 ]
[ 846023-27-6 ]
[ 122-51-0 ]
[ 846023-41-4 ]

Yield	Reaction Conditions	Operation in experiment
54%	In isopropyl alcohol;Heating / reflux;	EXAMPLE 23 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-ethoxy-3-iodophenyl)amino]acrylamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (5.44 g, 21.0 mmol) in 350 mL of iso-propanol, under N2, was added (4-ethoxy-3-iodophenyl)amine (5.0 g, 19.30 mmol). This mixture was heated to reflux and triethylorthoformate (8.53 mL, 51.30 mmol) was added dropwise and the reaction mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature and the yellow solid was collected by filtration, washed with iso-propanol, and dried overnight at ~40 C. under reduced pressure to give 5.46 g (54%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-ethoxy-3-iodophenyl)amino]prop-2-enamide as a yellow solid, mp >245 C.; MS (EI) m/z 531.01 (M)+ Analysis for C19H16Cl2IN3O3; Calcd: C, 42.88; H, 3.03; N, 7.90. Found: C, 42.99; H, 2.97; N, 7.74.
54%	In isopropyl alcohol;Heating / reflux;	Reference Example 6; 2-Cvano-N-(2,4-dichloro-5-methoxyphenyl )-3-F(4-ethoxy-3- iodophenvDaminoiacrylamideTo a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (5.44 g, 21.0 mmol) in 350 mL of /so-propanol, under N2 Js added (4-ethoxy-3-iodophenyl)- amine (5.0 g, 19.30 mmol). This mixture is heated to reflux and triethylorthoformate(8.53 mL, 51.30 mmol) is added dropwise and the reaction mixture is heated at reflux overnight. The mixture is allowed to cool to room temperature and the yellow solid is collected by filtration, washing with /so-propanol, and dried overnight at -4O0C under reduced pressure to give 5.46 g (54%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-ethoxy-3-iodophenyl)amino]prop-2-enamide as a yellow solid, mp >245 0C; MS(El) m/z 531.01 (M)+.Analysis for C19H16CI2IN3O3:Calcd: C, 42.88; H, 3.03; N, 7.90. Found: C, 42.99; H, 2.97; N, 7.74.

References: [1]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 9 - 10.
[2]Patent: WO2006/47262,2006,A1 .Location in patent: Page/Page column 16.
[3]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1358 - 1361.

6
[ 846023-24-3 ]
7-bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7868 - 7876.

7
[ 846023-24-3 ]
[ 846023-51-6 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7868 - 7876.
[2]Letters in drug design and discovery,2011,vol. 8,p. 9 - 13.

8
[ 846023-24-3 ]
[ 918660-41-0 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7868 - 7876.

9
[ 846023-24-3 ]
[ 918660-40-9 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7868 - 7876.

10
[ 846023-24-3 ]
4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[5-(4-methyl-piperazin-1-ylmethyl)-furan-2-yl]-quinoline-3-carbonitrile [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7868 - 7876.

11
[ 846023-24-3 ]
[ 122-51-0 ]
[ 591-19-5 ]
2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-bromophenyl)amino]acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol;Heating / reflux;	EXAMPLE 25 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-bromo)phenyl)amino]acrylamide A suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (3.0 g, 11.5 mmol) and 3-bromoaniline (1.3 mL, 11.9 mmol) in 250 mL of iso-propanol was heated to reflux and triethylorthoformate (12 mL, 72.2 mmol) was added dropwise. The reaction mixture was heated at reflux overnight. The mixture was allowed to cool slightly and the solid was collected by filtration while still warm, washed with iso-propanol and diethyl ether to give 2.05 g of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-bromo)phenyl)amino]acrylamide as a yellow solid, mp >250 C.; MS (ES) 437.8, 439.7, 441.8 (M-H)- Analysis for C17H12BrCl2N3O2; Calcd: C, 46.29; H, 2.74; N, 9.53. Found: C, 46.33; H, 2.73; N, 9.40.

References: [1]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 10.

12
[ 98446-49-2 ]
[ 372-09-8 ]
[ 538-75-0 ]
[ 846023-24-3 ]
[ 2387-23-7 ]

Yield	Reaction Conditions	Operation in experiment
	In DMF (N,N-dimethyl-formamide); at 10 - 20℃; for 2h;Product distribution / selectivity;	[0059] A reaction flask was charged with dimethylformamide (DMF) (500 mL), 2,4-dichloro-5-methoxyaniline (100 g, 0.52 mol) and cyanoacetic acid (46.6 g, 0.55 mol). The mixture was cooled to 10 C. in an ice bath. To the cooled mixture was added, dropwise, a solution of N,N' dicyclohexylcarbodiimide (119.1 g, 0.58 mol) in DMF (240 mL) so as to keep the temperature below 15 C. After the addition was completed, cooling was discontinued and the reaction was stirred for 2 hours. The urea by-product was then removed via filtration and the cake was washed twice with DMF. To the filtrate was added 700 mL of water. The solid product emerged from solution. The slurry was cooled to 5 C. and held for at least 30 minutes. The product was collected by filtration and washed with water and then dried in vacuo at 60 C. to give 127.08 g of light tan solid.

References: [1]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 6.

13
[ 846023-24-3 ]
[ 399-39-3 ]
[ 122-51-0 ]
[ 846023-39-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	In isopropyl alcohol; for 60h;Heating / reflux;	EXAMPLE 21 4-Ethoxy-3-fluoroanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (5.9 g, 22.7 mmol) in 400 mL of isopropanol was added 4-ethoxy-3-fluoroaniline (3.7 g, 23.8 mmol). This mixture was heated to reflux to give a clear solution. To this solution, triethylorthoformate (11.6 mL, 69.6 mmol) was added dropwise and the reaction mixture was heated at reflux for 18 hours. Additional triethylorthoformate (11.6 mL, 69.6 mmol) was added dropwise and the reaction mixture was heated at reflux for 42 hours. The mixture was allowed to cool to room temperature and the solid was collected by filtration, washed with ethyl acetate, and dried in vacuo at 40 C. to give 6.4 g (67%) of 4-ethoxy-3-fluoroanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide as a grey solid, mp 245-247 C.; MS 424.1, 426.1 (M+H)+ Analysis for C19H16Cl2FN3O3; Calcd: C, 53.79; H, 3.80; N, 9.90. Found: C, 53.39; H, 3.97; N, 9.69.

References: [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 405 - 412.
[2]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 9.

14
[ 846023-24-3 ]
[ 366-99-4 ]
[ 122-51-0 ]
[ 846023-47-0 ]

Yield	Reaction Conditions	Operation in experiment
68%	In isopropyl alcohol;Heating / reflux;	EXAMPLE 15 3-Fluoro-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (1.00 g, 3.86 mmol) in 200 mL of isopropanol was added 3-fluoro-p-anisidine (0.60 g, 4.25 mmol). This mixture was heated to reflux to give a clear yellow solution. To this solution, triethylorthoformate (1.72 mL, 10.34 mmol) was added dropwise and the reaction mixture was heated at reflux overnight. An additional 2 mL of triethylorthoformate was added and the mixture was heated at reflux overnight. An additional 2 mL of triethylorthoformate was added and the mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature and the white solid was collected by filtration, washed with isopropanol, and dried overnight at ~40 C. under reduced pressure. Purification by suspension in hot ethyl acetate followed by addition of cold hexanes gave 1.08 g (68%) of 3-fluoro-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide as a white solid, mp 275-276 C.; MS 408.1, 410.1 (M-H)- Analysis for C18H14Cl2FN3O3; Calcd: C, 52.70; H, 3.44; N, 10.24. Found: C, 52.44; H, 3.26; N, 10.14.

References: [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 405 - 412.
[2]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 8.

15
[ 846023-24-3 ]
[ 17721-06-1 ]
[ 122-51-0 ]
[ 846023-40-3 ]

Yield	Reaction Conditions	Operation in experiment
26%	In isopropyl alcohol;Heating / reflux;	EXAMPLE 22 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-(thien-3-ylamino)prop-2-enamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (1.57 g, 6.06 mmol) in 200 mL of iso-propanol was added 3-aminothiophene (600 mg, 6.06 mmol). This mixture was heated to reflux and triethylorthoformate (6.5 mL, 39.1 mmol) was added dropwise. The reaction mixture was heated at reflux overnight. Additional 3-aminothiophene (214 mg, 2.16 mmol) was added and the reaction mixture was heated at reflux for 5 hours. Additional 3-aminothiophene (100 mg, 1.01 mmol) was added and the reaction mixture was heated at reflux for 2.5 hours. The mixture was allowed to cool to room temperature and the solid was collected by filtration, washed with iso-propanol to give 572 mg (26%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-(thien-3-ylamino)prop-2-enamide as a tan solid, mp >250 C.; MS 366.0, 368.2 (M-H)- Analysis for C15H11Cl2N3O2S-1.0 H2O; Calcd: C, 46.64; H, 3.39; N, 10.88. Found: C, 46.37; H, 2.94; N, 10.60.

References: [1]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 9.

16
[ 846023-24-3 ]
[ 19056-40-7 ]
[ 122-51-0 ]
[ 846023-37-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	In isopropyl alcohol;Heating / reflux;	EXAMPLE 19 4-Bromo-3-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (6.1 g, 23.5 mmol) in 500 mL of isopropanol was added 5-amino-2-bromoanisole (5.0 g, 24.8 mmol). This mixture was heated to reflux to give a clear yellow solution. To this solution, triethylorthoformate (10.6 mL, 63.5 mmol) was added dropwise and the reaction mixture was heated at reflux for 5 hours. An additional 10.6 mL of triethylorthoformate was added and the mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature. The solid was collected by filtration, washed with isopropanol and ethyl acetate, and then dried overnight at ~40 C. under reduced pressure to give 8.1 g (73%) of 4-bromo-3-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide as a yellow solid, mp >250 C.; MS (ES) m/z470.0, 472.0 (M+H)+ Analysis for C18H14BrCl2N3O3; Calcd: C, 45.89; H, 3.00; N, 8.92.

References: [1]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 9.

17
[ 846023-24-3 ]
[ 101251-12-1 ]
[ 122-51-0 ]
[ 846023-36-7 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol;Heating / reflux;	EXAMPLE 18 3-Bromo-4-ethoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (715 mg, 2.74 mmol) in 50 mL of iso-propanol was added 3-bromo-4-ethoxyaniline (586 mg, 2.71 mmol). This mixture was heated to reflux and triethylorthoformate (2.7 mL, 16.2 mmol) was added dropwise. The reaction mixture was heated at reflux overnight. The mixture was filtered while still warm and the collected white solid was washed with iso-propanol to give 666 mg of 3-bromo-4-ethoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide, mp >250 C.; MS (ES) m/z 482.0, 484.0, 486.0 (M-H)- Analysis for C19H16BrCl2N3O3; Calcd: C, 47.04; H, 3.32; N, 8.66. Found: C, 46.64; H, 3.40; N, 8.59.

References: [1]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 9.

18
[ 846023-24-3 ]
[ 846023-25-4 ]
[ 122-51-0 ]
[ 846023-34-5 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol;Heating / reflux;	EXAMPLE 16 3-(3-Chloropropoxy)-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (738 mg, 2.84 mmol) in 100 mL of isopropanol was added 3-(3-chloropropoxy)-4-methoxyaniline (611 mg, 2.84 mmol). This mixture was heated to reflux and triethylorthoformate (3.0 mL, 18.0 mmol) was added dropwise. The reaction mixture was heated at reflux overnight. The mixture was filtered while still warm and the collected white solid was washed with isopropanol to give 610 mg of 3-(3-chloropropoxy)-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide, mp 185-192 C.; MS (ES) m/z 482.1, 484.2, 486.0 (M-H)- Analysis for C21H20Cl3N3O4; Calcd: C, 52.03; H, 4.16; N, 8.67. Found: C, 51.89; H, 4.11; N, 8.53.

References: [1]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 8.

19
[ 846023-24-3 ]
[ 846023-29-8 ]
[ 122-51-0 ]
[ 846023-42-5 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol;Heating / reflux;	EXAMPLE 24 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[3-iodo-4-(2-methoxyethoxy)phenyl]amino}acrylamide A suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (3.2 g, 12.4 mmol) and [3-iodo-4-(2-methoxyethoxy)phenyl]amine (4.0 g, 13.7 mmol) in 350 mL of iso-propanol was heated to reflux and triethylorthoformate (5.6 mL, 33.7 mmol) was added dropwise. The reaction mixture was heated at reflux for 3 hours. Additional triethylorthoformate (2.0 mL, 12.0 mmol) was added dropwise and the reaction mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature and the solid was collected by filtration, washed with iso-propanol, diethyl ether, and ethyl acetate and then dried in vacuo to give 5.5 g of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[3-iodo-4-(2-methoxyethoxy)phenyl]amino}acrylamide as a yellow solid, mp 209-210 C.; MS (ES) 560.0, 562.1 (M-H)- Analysis for C20H18Cl2IN3O4; Calcd: C, 42.73; H, 3.23; N, 7.47. Found: C, 43.04; H, 3.07; N, 7.28.

References: [1]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 10.

20
[ 846023-24-3 ]
[ 846023-60-7 ]
[ 122-51-0 ]
(2E)-2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amino]acrylamide [ No CAS ]
(2Z)-2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amino]acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; for 25h;Heating / reflux;	EXAMPLE 49 2E/Z)-2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amino]acrylamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (261 mg, 1.01 mmol) in 5 mL of iso-propanol was added triethylorthoformate (0.504 mL, 3.03 mmol). The mixture was heated to reflux and (4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amine (320 mg, 1.06 mmol) in 9 mL of iso-propanol was added dropwise. This mixture was heated at reflux for 25 hours. The mixture was allowed to cool to room temperature and the solid was collected by filtration, washed with iso-propanol, to provide 465 mg (81%) of (2E/Z)-2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amino]acrylamide as a gray solid, mp 198-199 C.; MS 570.1 (M+H)+. Analysis for C28H29Cl2N5O4-0.2 H2O: Calcd: C, 58.58; H, 5.16; N, 12.20. Found: C, 58.50; H, 5.07; N, 12.07.

References: [1]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 4; 15.

21
[ 846023-24-3 ]
[ 846023-55-0 ]
[ 846023-56-1 ]

References: [1]Organic Process Research and Development,2013,vol. 17,p. 500 - 504.

22
[ 846023-24-3 ]
[ 846023-55-0 ]
[ 122-51-0 ]
[ 846023-56-1 ]

Yield	Reaction Conditions	Operation in experiment
93%		EXAMPLE 44 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{4-methoxy-3-[3-(4-methylpiperazin-1-yl)-propoxy]-phenylamino}-acrylamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (1.75 g, 6.75 mmol) in 8.2 mL of iso-propanol was added triethylorthoformate (1.5 g, 10.1 mmol). The mixture was heated to reflux. After 20 minutes, 4-methoxy-3-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenylamine in 20 mLs of iso-propanol was added dropwise so as to maintain reflux. After 26 hours, the reaction was cooled to room temperature and the suspended solids were filtered. The solids were rinsed with iso-propanol until effluent was colorless. The yellow solid was dried in vacuo to give 3.45 g (93%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{4-methoxy-3-[3-(4-methylpiperazin-1-yl)-propoxy]-phenylamino}-acrylamide as a mixture of isomers. 1H NMR (300 MHz, CDCl3) delta 11.35 (br d, 1H), 8.17 (m, 2H), 7.76 (d, 1H), 7.41 (s, 1H), 6.88 (m, 1H) 6.69 (m, 2H), 4.10 (t, J=7 Hz, 2H), 3.96 (s, 3H), 3.87 (s, 3), 2.55 (t, J=7 Hz, 2H), 2.48 (m, 8H), 2.29 (s, 3H), 2.06 (m, 2H); MS (ES) m/z548.1 (M+) Analysis for C10H14ClNO2; Calcd: C, 55.69; H, 6.54; N, 6.49. Found: C, 55.49; H, 6.59; N, 6.32.

References: [1]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 3-4; 14.

23
[ 846023-24-3 ]
4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-trimethylsilanylethynyl-quinoline-3-carbonitrile [ No CAS ]