167837-43-6|(E)-3-(6-Aminopyridin-3-yl)acrylic acid| Ambeed

Structure of 167837-43-6

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Quality Control of [ 167837-43-6 ] Purity: 97% SDS Specification

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Product Details of [ 167837-43-6 ]

CAS No. :	167837-43-6
Formula :	C₈H₈N₂O₂
M.W :	164.16
SMILES Code :	O=C(O)/C=C/C1=CC=C(N)N=C1
MDL No. :	MFCD14585070
InChI Key :	RKTFOZFRTWRSLT-DUXPYHPUSA-N
Pubchem ID :	10487224

Safety of [ 167837-43-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 167837-43-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	45.31
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	76.21 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.93
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	0.46
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.66
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.	0.13
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	0.47
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.53

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.39
Solubility	6.76 mg/ml ; 0.0412 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.63
Solubility	3.86 mg/ml ; 0.0235 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-1.12
Solubility	12.5 mg/ml ; 0.0759 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	No
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	No
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.	-6.97 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	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

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	1.0 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<1.0
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)	2.01

Application In Synthesis of [ 167837-43-6 ]

* 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.

Downstream synthetic route of [ 167837-43-6 ]

[ 167837-43-6 ] Synthesis Path-Downstream 1~35

1
[ 67-56-1 ]
[ 167837-43-6 ]
[ 179625-70-8 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4053 - 4061.

2
[ 167834-66-4 ]
[ 167837-43-6 ]
[ 167838-46-2 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4062 - 4079.

3
[ 160648-18-0 ]
[ 167837-43-6 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4053 - 4061.

4
[ 1072-97-5 ]
[ 79-10-7 ]
[ 167837-43-6 ]

Yield	Reaction Conditions	Operation in experiment
62%	With sodium carbonate;palladium dichloride; In water;	a) (E)-3-(6-Aminopyridin-3-yl)acrylic acid Acrylic acid (23 mL, 0.33 mole) was added carefully to a solution of 2-amino-5-bromopyridine (25.92 g, 0.15 mole) and Na2CO3 (55.64 g, 0.53 mole) in H2O (600 mL). PdCl2 (0.53 g, 0.003 mole) was then added, and the mixture was heated at reflux. After 24 hr, the reaction was cooled to RT and filtered, and the filtrate was adjusted to pH 6 with aqueous HCl. Additional H2O (0.5 L) was added to improve mixing, and the mixture was stirred for 1 hr. The pH was readjusted to 6, then the solid was collected by suction filtration. The filter pad was washed sequentially with H2O (2 x 0.5 L), cold absolute EtOH (100 mL), and Et2O (2 x 250 mL). Drying in high vacuum at elevated temperature gave the title compound (15.38 g, 62%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) delta 8.11 (d, J = 2.0 Hz, 1 H), 7.75 (dd, J = 8.7, 2.0 Hz, 1 H), 7.43 (d, J = 15.8 Hz, 1 H), 6.53 (s, 2 H), 6.45 (d, J = 8.7 Hz, 1 H), 6.22 (d, J = 15.8 Hz, 1 H); MS (ES) m/e 165 (M + H)+.

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3246 - 3256.
[2]Patent: EP1226138,2004,B1 .
[3]RSC Advances,2018,vol. 8,p. 23698 - 23710.

5
[ 3514-15-6 ]
[ 167837-43-6 ]
[ 335027-53-7 ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3246 - 3256.

6
[ 335030-18-7 ]
[ 167837-43-6 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium hydroxide; In methanol; water;	b) (E)-3-(6-Aminopyridin-3-yl)acrylic acid A solution of benzyl (E)-3-(6-aminopyridin-3-yl)acrylate (1.3 g, 5.1 mmole) and 1.0 N NaOH (10 mL, 10 mmole) in MeOH was heated at reflux overnight. The solution was concentrated in vacuo, and the residue was dissolved in H2O. The pH was adjusted to 6 with dilute HCl, and the solid precipitate was collected by suction filtration and dried to give the title compound (0.6 g, 72%) as a white solid: MS (ES) m/e 165 (M + H)+.
72%	With sodium hydroxide; In methanol; water;	b (E)-3-(6-Aminopyridin-3-yl)acrylic Acid A solution of benzyl (E)-3-(6-aminopyridin-3-yl)acrylate (1.3 g, 5.1 mmole) and 1.0 N NaOH (10 mL, 10 mmole) in MeOH was heated at reflux overnight. The solution was concentrated in vacuo, and the residue was dissolved in H2O. The pH was adjusted to 6 with dilute HCl, and the solid precipitate was collected by suction filtration and dried to give the title compound (0.6 g, 72%) as a white solid: MS (ES) m/e 165 (M+H)+.

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3246 - 3256.
[2]Patent: EP1226138,2004,B1 .
[3]Patent: US2004/53814,2004,A1 .

7
[ 167837-43-6 ]
[ 194928-62-6 ]
[ 194928-65-9 ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 2853 - 2863.

8
[ 1072-97-5 ]
[ 167837-43-6 ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3246 - 3256.

9
[ 7169-97-3 ]
[ 167837-43-6 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4053 - 4061.

10
[ 167837-43-6 ]
[ 179625-72-0 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4053 - 4061.

11
[ 167837-43-6 ]
[ 179625-71-9 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4053 - 4061.

12
[ 167837-43-6 ]
[ 179625-73-1 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4053 - 4061.

13
[ 189268-39-1 ]
[ 167837-43-6 ]
[ 189266-56-6 ]

Yield	Reaction Conditions	Operation in experiment
		The following compounds were obtained according to a similar manner to that of Example 2-(4). 2-[(E)-3-(6-Aminopyridin-3-yl)acryloylaminomethyl]-1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]pyrrole. NMR (DMSO6, delta): 2.59 (3H, s), 4.00-4.10 (1H, m), 4.19-4.21 (1H, m), 5.32-5.45 (2H, m), 6.16-6.22 (2H, m), 6.29 (1H, d, J=16 Hz), 6.38-6.45 (2H, m), 6.48 (1H, d, J=8 Hz), 6.83-6.87 (1H, m), 7.11-7.23 (2H, m), 7.37-7.48 (2H, m), 7.48-7.58 (2H, m), 7.61 (1H, d, J=8 Hz), 7.70 (1H, d, J=8 Hz), 7.99-8.09 (2H, m), 8.20 (1H, d, J=8 Hz).

References: [1]Patent: US6344462,2002,B1 .Location in patent: Page column 30.

14
[ 709649-53-6 ]
[ 167837-43-6 ]
[ 709652-68-6 ]

Yield	Reaction Conditions	Operation in experiment
47%		EDC (231 mg, 1.2 mmol) was added to a solution of (E)-3- (6-amino-pyridin-3- yl) acrylic acid (164 mg, 1.0 mmol), (2-propoxy-3-methoxy-benzyl) methylamine (230 mg, 1.1 mmol), HOBT'H20 (149 mg, 1.1 mmol) and DIPEA (525 L) L, 3.0 mmol) in dry DMF (10 mL). After 18 hr of stirring, the mixture was diluted with water (60 mL) and extracted with EtOAc (2X20 mL). The organic layer was washed with brine (2X30 mL), dried and evaporated. Flash chromatography (silica 1-3% MEOH in CH2CL2) furnished pure free base which was dissolved in CHZCLZ (10 mL). After addition of HCl (1.5 mL, 1M in ether), the solvents were evaporated; the residue was washed with ether and dried to afford the title compound (185 mg, 47%). 1H NMR (300 MHz, DMSO-d6) 8 8.16 (m, 3H), 7.48 and 7.45 (rotamers, 2d, J= 15.4 Hz, 1H), 7.23 (d, J= 15. 4 Hz, 1H), 7.00 (m, 3H), 6.61 (m, 1H), 4.78 and 4.63 (rotamers, 2s, 2H), 3.87 (m, 2H), 3.79 (s, 3H), 3.09 and 2.85 (rotamers, 2s, 3H), 1.71 (m, 2H), 0.97 (m, 3H). MS (ESI) M/E 356 (M+H) +.

References: [1]Patent: WO2004/52890,2004,A1 .Location in patent: Page 182.

15
[ 36218-58-3 ]
[ 167837-43-6 ]
[ 768378-58-1 ]

Yield	Reaction Conditions	Operation in experiment
32%		To a solution of acenaphthen-5-ylmethyl-methylamine (216 mg, l. lmmol), (E)-3- (6-amino-pyridin-3-yl) acrylic acid (164 mg, 1 mmol), HOBt (148 mg, L. lmmol) and diisopropylethylamine (0.8 mL, 4.4 mmol) in DMF (20 mL) was added EDC hydrochloride (210 mg, 1.1 mmol). The mixture was stirred overnight at room temperature. Water (100 mL) was added and the solution stirred for 1 hour. The precipitate was collected by filtration. The yellow solid was preabsorded onto silica gel and purified by column chromatography (95: 5 CH2CIZ/MEOH). THE residue was dissolved into methylene chloride followed by addition of 1M HCL/ETHER. The precipitate was collected by filtration to afford (E)-N-ACENAPHTHEN-5-YLMETHYL-3-(6-AMINO-PYRIDIN-3-YL)-N-METHYL-ACRYLAMIDE hydrochloride (120 mg, 32%) as a white solid and as a mixture of amide ROTOMERS.'H NMR (300 MHz, DMSO-d6) 8 8.44-8. 28 (m, 3H), 7.84-7. 72 (m, 1H), 7.59-7. 12 (m, 6H), 7.07- 6.92 (m, 1H), 5.15-5. 02 (2 x s, 2H), 3.35-3. 15 (bs, 2H), 3.18 (s, 4H), 3.07-2. 90 (2 x s, 3H); ESI MS m/z 344 [C22H21N30 + H] +.

References: [1]Patent: WO2004/52890,2004,A1 .Location in patent: Page 183-184.

16
[ 709651-54-7 ]
[ 167837-43-6 ]
[ 709652-76-6 ]

Yield	Reaction Conditions	Operation in experiment
76.9%		To a solution OF METHYL- (2-METHYLBENZOFURAN-3-YLMETHYL)-AMINE (176 mg, 1.0 mmol), 3- (6-AMINO-PYRIDIN-3-YL)-ACRYLIC acid (150 mg, 0.91 mmol), HOBt (135 mg, 1.0 mmol) and diisopropylethylamine (0.46 mL, 2.7 mmol) in DMF (10 mL) was added EDC (209 mg, 1. 1 mmol). The yellow solution was stirred overnight at room temperature. The reaction mixture was cooled to 0 C then treated with H20 (40 mL) to form a precipitate. The precipitate was filtered, washed with H20 (20 mL) then with a 10% EtOAc: hexanes solution (10 mL). The solid was dissolved in a 10% MeOH: CH2Cl2 solution (20 mL), cooled to 0 C then treated with 2 mL of a 1.0 M HCl in ET20. After stirring for 10 minutes, the yellow solution was concentrated to dryness then triturated with Et2O (20 mL). The title compound was collected and dried under vacuo to yield the title compound (76.9%) as a mixture of amide rotamers. 1H NMR (300 MHz, DMSO-D6) 8 8. 41-8. 33 (m, 3H), 7.58- 7.02 (m, 6H), 4.93 and 4.74 (2 x s, 2H), 3.05 and 2.82 (2 x s, 3H), 2.53 and 2.48 (2 x s, 3H); MS (ESI) NALE 322 (M+ H) +.

References: [1]Patent: WO2004/52890,2004,A1 .Location in patent: Page 186-187.

17
[ 709649-54-7 ]
[ 167837-43-6 ]
[ 709652-69-7 ]

Yield	Reaction Conditions	Operation in experiment
46%		EDC (231 mg, 1.2 mmol) was added to a solution of (4-3-(6-AMINO-PYRIDIN-3- yl) acrylic acid (164 mg, 1.0 mmol), (2-isopropoxy-3-methoxy-benzyl) methylamine (230 mg, 1.1 mmol), HOBT'H20 (149 mg, 1.1 mmol) and DIPEA (525 UL, 3.0 mmol) in dry DMF (10 mL). After 18 hr of stirring, the mixture was diluted with water (60 mL) and extracted with EtOAc (2X20 mL). The organic layer was washed with brine (2x30 mL), dried and evaporated. Flash chromatography (silica 1-3% MEOH in CH2CL2) of the residue furnished pure free base which was dissolved in CHUCK (10 mL). After addition OF HCL (1.5 mL, 1M in ether) the solvents were evaporated; the residue was washed with ether and dried to afford the title compound (180 mg, 46%). 1H NMR (300 MHz, DMSO-D6) 8 8.31 (m, 3H), 7.46 and 7.45 (rotamers, 2d, J= 15.4 Hz, 1H), 7.23 and 7.17 (rotamers, 2d, J= 15.4 Hz, 1H), 6.99 (m, 3H), 6.62 (m, 1H), 4.76 and 4.63 (rotamers, 2s, 2H), 4. 51 (M, 1H), 3.79 (s, 3H), 3.06 and 2.85 (rotamers, 2s, 3H), 1.22 (d, J= 6. 1Hz, 3H) 1.21 (d, J= 6. 1Hz, 3H). MS (ESI) INLE 356 (M+H) +.

References: [1]Patent: WO2004/52890,2004,A1 .Location in patent: Page 182-183.

18
[ 709649-59-2 ]
[ 167837-43-6 ]
[ 709652-67-5 ]

Yield	Reaction Conditions	Operation in experiment
46%		EDC (231 mg, 1.2 mmol) was added to a solution of (E)-3-(6-AMINO-PYRIDIN-3- yl) acrylic acid (164 mg, 1.0 mmol), (2-ethoxy-3-methoxy-benzyl) methylamine (215 mg, 1.1 mmol), HOT HO (149 mg, 1.1 mmol) and DIPEA (525 1L, 3.0 mmol) in dry DMF (10 mL). After 18 hr of stirring, the mixture was diluted with water (60 mL) and extracted with EtOAc (2X20 mL). The organic layer was washed with brine (2x30 mL), dried and evaporated. Flash chromatography (silica 1-3% MEOH in CH2CL2) furnished pure free base which was dissolved in CH2CL2 (10 mL). After addition of HCl (1.5 mL, 1M in ether), the solvents were evaporated and the residue was washed with ether and dried to afford the title compound (172 mg, 46%). 1H NMR (300 MHz, DMSO-d6) 8 8.28 (m, 3H), 7.48 and 7.45 (rotamers, 2d, J= 15.4 Hz, 1H), 7.25 and 7.23 (rotamers, 2d, J= 15.4 Hz, 1H), 7.00 (m, 3H), 6.62 (m, 1H), 4.78 and 4.63 (rotamers, 2s, 2H), 3.98 (m, 2H), 3.79 (s, 3H), 3.08 and 2.84 (rotamers, 2s, 3H), 1.28 (m, 3H). MS (ESI) mle 342 (M+H) +.

References: [1]Patent: WO2004/52890,2004,A1 .Location in patent: Page 181-182.

19
[ 92367-50-5 ]
[ 167837-43-6 ]
[ 709652-70-0 ]

Yield	Reaction Conditions	Operation in experiment
54%		EDC (231 mg, 1.2 mmol) was added to a solution of (E)-3- (6-AMINO-PYRIDIN-3- yl) acrylic acid (164 mg, 1.0 mmol), methyl- (3-methyl-benzofuran-2-ylmethyl) amine (193 mg, 1.1 mmol), HOBTNo.H2O (149 mg, 1.1 mmol) and DIPEA (525 PL, 3.0 mmol) in dry DMF (10 mL). After 18 hr of stirring, the mixture was diluted with water (60 mL) and extracted with EtOAc (2X20 mL). The oraganic layer was washed with brine (2 x 30 mL), dried and evaporated. Flash chromatography (silica 1-3% MEOH in CH2Cl2) of the residue furnished pure free base which was dissolved in CH2C12 (10 mL). After addition OF HCL (1.5 mL, 1M in ether), the solvents were evaporated, washed with ether and dried to afford the title compound (195 mg, 54%). 1H NMR (300 MHz, DMSO-d6) 8 8.36 (m, 3H), 7.50 (m, 3H), 7.25 (m, 3H), 7.02 (m, 1H), 4.98 and 4.79 (rotamers, 2s, 2H), 3.17 and 2.92 (rotamers, 2s, 3H), 2.26 (s, 3H). MS (ESI) nile 322 (M+H) +.

References: [1]Patent: WO2004/52890,2004,A1 .Location in patent: Page 183.

20
[ 709649-71-8 ]
[ 167837-43-6 ]
[ 709652-64-2 ]

Yield	Reaction Conditions	Operation in experiment
61%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); water; at 20℃;	EDC hydrochloride (118 mg, 0.62 mmol) was added to a solution of methyl- thieno [3,2-c] PYRIDINE-2-YLMETHYL-AMINE (100 mg, 0.56 mmol), (E)-3-(6-AMINO-PYRIDIN-3- yl) acrylic acid (101 mg, 0.62 mmol), HOBT H2O (83 mg, 0.62 mmol) and triethylamine (235 FL, 1.68 mmol) in anhydrous DMF (5 mL). The mixture was stirred at room temperature overnight then diluted with H20 (10 mL) and extracted with CH2C12 (3 x 50 mL). The combined organic fractions were dried over MGS04, filtered and evaporated to give a yellow residue which was subjected to flash chromatography on silica gel (10% MeOH : CH2C12) to yield the title compound (61. 0%).'H-NMR (300 MHz, CDC13) 6 9.04 (s, 1H), 8.45 (d, J= 5.3Hz, 1H), 8.26 (s, 1H), 7.76-7. 67 (m, 3H), 7.32 (d, J= 15. 0Hz, 1H), 6.76 (d, J= 15.2 Hz, 1H), 6.53 (d, J= 8.3 Hz, 1H), 4.95 (s, 2H), 4.76 (br s, 2H), 3.22 (s, 3H); MS (ES) m/e 325.1 (M+H) +.

References: [1]Patent: WO2004/52890,2004,A1 .Location in patent: Page 180.

21
[ 167837-43-6 ]
[ 179625-70-8 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In methanol;	(1) To methanol (5 ml) in dry ice-acetone bath was added thionyl chloride (0.41 ml) dropwise over 5 minutes. After <strong>[167837-43-6](E)-3-(6-Aminopyridin-3-yl)acrylic acid</strong> (700 mg) was added to the mixture, the reaction mixture was heated at reflux for 1 hour, and the solvent was removed under reduced pressure. The reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The precipitate was collected by vacuum filtration and washed with isopropyl ether to give methyl (E)-3-(6-aminopyridin-3-yl)acrylate (725 mg) as a solid. mp: 173-175 C. NMR (DMSO-d6, delta): 3.67 (3H, s), 6.32 (1H, d, J=16 Hz), 6.45 (1H, d, J=8 Hz), 6.57 (2H, s), 7.51 (1H, d, J=16 Hz), 7.79 (1H, dd, J=2, 8 Hz), 8.15 (1H, d, J=2 Hz).

References: [1]Patent: US5994368,1999,A .

22
[ 709649-51-4 ]
[ 167837-43-6 ]
(E)-3-(6-aminopyridin-3-yl)-N-((5-fluoro-3-methylbenzo[b]thiophen-2-yl)methyl)-N-methylacrylamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%		Example 62; Preparation of (El-S-f-aminopyridin-S-v?-N-fCS-fluoro-S-methylbenzofblthiorjhen-?- ylimethvD-N-methylacrylamide hydrochloride;To a solution of (5-fluoro-l-methyl-lH-indol-2-yl)-N-methyhnethanamine (168 mg, 0.8 mmol) in DMF (5 mL) were added in sequential order (E)-3-(6-aminopyridin-3- yi)acrylic acid (120 mg, 0.73 mmol), 1-hydroxybenzotriazole (111 mg, 0.8 mmol), diisopropylethylamine (391 uL, 2.19 mmol), and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide (160 mg, 0.8 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product was extracted with ethyl acetate (3 x 1OmL), dried, filtered and concentrated. The crude free base was re-solvated in methylene chloride (1OmL) to which was added HCl (1 mL, 4M in dioxane), with the product precipitating out with the addition of ether. The title compound is triturated with ether (2 x 10 mL) to yield the product as a pale brown solid (76 mg, 25%): 1HNMR (300 MHz, DMSO-J6) delta 8.2-8.49 (m, 3H), 7.86-7.99 (m, IH), 7.46-7.64 (m, 2H), 7.16-7.29 (m, 2H), 6.99 (d, J= 12.0 Hz, IH), 4.83-5.13 (rotamers, 2s, 2H), 2.95-3.16 (rotamers, 2s, 3H), 2.41 (s, 3H); MS (ESI) m/e 356 (C19H18FN3OS + H)+.

References: [1]Patent: WO2007/53131,2007,A2 .Location in patent: Page/Page column 168.

23
[ 894852-22-3 ]
[ 167837-43-6 ]
3-(6-amino-pyridin-3-yl)-N-(3-cyano-1H-indol-2-ylmethyl)-N-methyl-acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 72.0h;	e) 3-(6-amino-pyridin-3-yl)-N-(3-cyano-lH-indol-2-yhnethyl)-N-methyl-acrylamide; EDC (250 mg, 1.3 mmol) was added to a solution of (£)-3-(6-Amino-pyridin-3-yl)- acrylic acid (172 mg, 1.05 mmol), 2-methylaminomethyl-lH-indole-3-carbonitrile (186 mg, 1.0 mmol), HOBf H2O (135 mg, 1.0 mmol) and DPEA (510 muL, 3.0 mmol) in dry DMF (4 mL). After 3 days of stirring, the mixture was diluted with water (50 mL) at 100C. The resulting precipitate was filtered, washed with water and dried to afford the title compound (277 mg, 84%). 1H NMR (300 MHz, DMSO-d6, delta): 12.1 (m, IH), 8.16 (s, IH), 7.84 (s, IH), 7.5 (m, 3H), 7.2 (m, 2H), 6.97 (m, IH), 6.44 (s, 2H), 5.08 and 4.88 (rotamers, 2s, 2H), 3.22 and 2.96 (rotamers, 2s, 3H). MS (ESI): m/e 332 (M+H)+.

References: [1]Patent: WO2007/53131,2007,A2 .Location in patent: Page/Page column 143.

24
[ 941604-68-8 ]
[ 167837-43-6 ]
(R,E)-3-(6-aminopyridin-3-yl)-N-(1-(3-ethylbenzofuran-2-yl)ethyl)-N-methylacrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 40℃; for 60.0h;	To a solution of <strong>[167837-43-6](E)-<strong>[167837-43-6]3-(6-aminopyridin-3-yl)acrylic acid</strong></strong> (123 mg, 0.75 mmol) in DMF (4 mL) was added (lambda)-methyl-[l-(3-ethyl-benzofuran-2-yl)-ethyl]amine (183 mg, 0.90 mmol), EDCI (187 mg, 0.98 mmol), HOBt (112 mg, 0.83 mmol) and DIPEA (0.45 mL, 2.33 mmol). The mixture was stirred at 40 0C for 60 hours. The mixture was diluted with H2O (30 mL) and the solid collected by filtration. The solid was washed with 100 mL H2O and then dried under reduced pressure overnight. It was purified by chromatography (silica, 1.5% MeOH in CH2Cl2) to give 79 mg (25%) of title compound as a mixture of amide rotamers. 1H NMR (300 MHz, CDCl3, delta) 8.22 (s, IH), 7.7-7.1 (m, 6H), 6.8-6.2 (m, 3H), 4.72 (s, 2H) 3.06 (s, 3H), 2.74 (s, 2H), 1.9-1.1 (m, 6H); MS (ESI) m/e 350 (M + H)+.

References: [1]Patent: WO2007/67416,2007,A2 .Location in patent: Page/Page column 133.

25
HOBt · H2O [ No CAS ]
[ 76532-33-7 ]
[ 167837-43-6 ]
[ 335029-08-8 ]