3537-14-2|5-Nitro-2,3-pyridinediamine| Ambeed

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Quality Control of [ 3537-14-2 ] Purity: 95% SDS Specification

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Product Details of [ 3537-14-2 ]

CAS No. :	3537-14-2
Formula :	C₅H₆N₄O₂
M.W :	154.13
SMILES Code :	NC1=NC=C([N+]([O-])=O)C=C1N
MDL No. :	MFCD10697697
InChI Key :	JOQJNCSAEMIZOU-UHFFFAOYSA-N
Pubchem ID :	3480151

Safety of [ 3537-14-2 ]

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

Computational Chemistry of [ 3537-14-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	41.87
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	110.75 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.24
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	-0.35
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.17
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.	-1.48
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	-2.13
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	-0.71

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.91
Solubility	18.8 mg/ml ; 0.122 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.	-1.51
Solubility	4.72 mg/ml ; 0.0306 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	-0.67
Solubility	32.7 mg/ml ; 0.212 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.	-7.49 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.	0.55

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	2.0 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)	2.25

Application In Synthesis of [ 3537-14-2 ]

* 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 [ 3537-14-2 ]

[ 3537-14-2 ] Synthesis Path-Downstream 1~35

1
[ 91-52-1 ]
[ 3537-14-2 ]
[ 127356-21-2 ]

References: [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 2231 - 2239.

2
[ 72856-73-6 ]
[ 3537-14-2 ]
[ 127356-22-3 ]

References: [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 2231 - 2239.

3
[ 144-62-7 ]
[ 3537-14-2 ]
[ 144435-09-6 ]

References: [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 1331 - 1338.
[2]Journal of Medicinal Chemistry,1997,vol. 40,p. 3679 - 3686.

4
[ 3073-30-1 ]
[ 3537-14-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonium sulfide; In methanol; water; at 75℃;	3,5-Dinitropyridin-2-amine (4.0 g, 21.7 mmol) was suspended in methanol (150 mL), and a 20% aqueous solution of ammonium sulfide (31.7 mL, 109 mmol, 5 eq.) was then added. A mixture resulted as the temperature was raised to 75C for 30 minutes. The mixture was allowed to cool and then placed in an ice bath, where a precipitate formed. The solids were collected by filtration, yielding 5-nitropyridine-2,3-diamine (3.4 g, 100%) as a solid. 1H NMR (400 MHz, DMSOd6) delta 8.28-8.29 (m, IH), 7.35-7.37 (m, IH), 6.99 (br s, 2H), 5.32 (br s, 2H).
99%	With diammonium sulfide; In methanol; water; at 75℃; for 0.5h;	3,5-Dinitropyridin-2-amine (300.0 mg, 1.63 mmol) and ammonium sulfide solution (2.4 mL, 8.15 mmol) was dissolved in MeOH (11.3 mL), and it was stirred at 75 C. for 30 minutes and then cooled to room temperature. The formed solid was filtered and then dried under reduced pressure to obtain red solid compound of 5-nitropyridine-2,3-diamine (250.0 mg, 99%). [1183] LCMS ESI (+): 155 (M+1) [1184] 1H-NMR (400 MHz, DMSO-d6); delta:8.29 (d, 1H, J=1.8 Hz), 7.36 (d, 1H, J=1.8 Hz), 6.99 (s, 2H), 5.32 (s, 2H)
3.2 g	With diammonium sulfide; In methanol; water; for 1h;Reflux;	A solution of 3,5-Dinitropyridine-2-amine (3.9 g, 21.2 mmol, 1 eq) in Methanol (80 ml) was treated with 20% aqueous (NH^S (36.1 ml, 106 mmol, 5 eq) and heated to reflux for 1 hour. After cooling, the solid was collected by filtration and dried. The product was used without further purification. Yield: 3.2 g (98%); ESI-MS m/z: 155.0 [M+H]+; HPLC (Gradient A): rt 4.08 min, 100 %; 1H-NMR (DMSO-d6) d: 5.31 (br s, 2H), 6.98 (br s, 2H), 7.36 (d, 1 H, 4J=2.2 Hz), 8.28 (d, 1 H, 4J=2.6 Hz)

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5896 - 5899.
[2]Patent: WO2009/111277,2009,A1 .Location in patent: Page/Page column 53.
[3]Patent: US2014/315888,2014,A1 .Location in patent: Paragraph 1182-1184.
[4]Journal of Medicinal Chemistry,1997,vol. 40,p. 3679 - 3686.
[5]Patent: WO2019/162458,2019,A1 .Location in patent: Page/Page column 34.
[6]Chemistry of Heterocyclic Compounds,2020,vol. 56,p. 92 - 100.
Khim. Geterotsikl. Soedin.,2020,vol. 56,p. 92 - 100,9.

6
[ 13205-48-6 ]
[ 3537-14-2 ]
[ 896114-88-8 ]

Yield	Reaction Conditions	Operation in experiment
		1.0 g <strong>[3537-14-2]2,3-diamino-5-nitropyridine</strong> and 1.125 g 4-methylsulfanylbenzoic acid in 20 ml polyphosphoric acid were heated to 160 C. with stirring for 15 hrs. The mixture was cooled and poured into water. The pH was adjusted to 4-5 by addition of sodium hydroxide and the precipitate collected by filtration. The filtration residue was stirred in 50 ml pyridine at 60 C., cooled and insoluble components removed by filtration. The filtrate was evaporated and the residue used without further purification in the next steps. Yield 0.656 g of 30% purity
		Example 4-1 [2-(4-Methylsulfanyl-phenyl)-3H-imidazo[4,5-b]pyridin-6-yl]-carbamic acid isopropyl ester a) 2-(4-Methylsulfanyl-phenyl)-6-nitro-3H-imidazo[4,5-b]pyridine; 1.0 g <strong>[3537-14-2]2,3-diamino-5-nitropyridine</strong> and 1.125 g 4-methylsulfanylbenzoic acid in 20 ml polyphosphoric acid were heated to 160 C. with stirring for 15 hrs. The mixture was cooled and poured into water. The pH was adjusted to 4-5 by addition of sodium hydroxide and the precipitate collected by filtration. The filtration residue was stirred in 50 ml pyridine at 60 C., cooled and insoluble components removed by filtration. The filtrate was evaporated and the residue used without further purification in the next steps. Yield 0.656 g of 30% purity

References: [1]Patent: US2008/39460,2008,A1 .Location in patent: Page/Page column 20.
[2]Patent: US2008/9492,2008,A1 .Location in patent: Page/Page column 23-24.

7
[ 34036-07-2 ]
[ 3537-14-2 ]
[ 896114-98-0 ]

Yield	Reaction Conditions	Operation in experiment
	In nitrobenzene; at 160℃; for 26h;	1.00 g 2,3-diamino-5-nitro-pyridine and 0.95 g 3,4-difluorobenzaldehyde were stirred in 60 ml nitrobenzene at 160 C for 26 hrs. The solvent was removed under vacuum and the residue dissolved in 40 ml pyridine at 60 C. The solution was cooled in an ice bath. Precipitated product was isolated by filtration and dried to yield 0.5 g of the title product.
	In nitrobenzene; at 160℃; for 26h;	Example 10-1 [2-(3,4-Difluoro-phenyl)-3H-imidazo[4,5-b]pyridin-6-yl]-carbamic acid isopropyl ester a) 2-(3,4-Difluoro-phenyl)-6-nitro-3H-imidazo[4,5-b]pyridine; 1.00 g 2,3-diamino-5-nitro-pyridine and 0.95 g 3,4-difluorobenzaldehyde were stirred in 60 ml nitrobenzene at 160 C. for 26 hrs. The solvent was removed under vacuum and the residue dissolved in 40 ml pyridine at 60 C. The solution was cooled in an ice bath. Precipitated product was isolated by filtration and dried to yield 0.5 g of the title product.

References: [1]Patent: US2008/39460,2008,A1 .Location in patent: Page/Page column 24.
[2]Patent: US2008/9492,2008,A1 .Location in patent: Page/Page column 29.

8
[ 619-21-6 ]
[ 3537-14-2 ]
[ 896116-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	In nitrobenzene; at 160℃; for 30h;	0.87 g 3-carboxybenzaldehyde and 0.866 g <strong>[3537-14-2]2,3-diamino-5-nitropyridine</strong> in 50 ml nitrobenzene were heated to 160 C. for 30 hrs. The mixture was cooled to room temperature and 200 ml ethyl acetate and 100 ml ethyl ether were added. The precipitated product was collected by filtration and dried. Yield 1.135 g

References: [1]Patent: US2008/39460,2008,A1 .Location in patent: Page/Page column 18.

9
[ 2578-45-2 ]
[ 3537-14-2 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 3679 - 3686.
[2]Patent: US5620978,1997,A .
[3]Patent: WO2009/111277,2009,A1 .
[4]Patent: WO2019/162458,2019,A1 .

10
[ 3537-14-2 ]
6,7-Dinitro-1,4-dihydro-pyrido[2,3-b]pyrazine-2,3-dione [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 1331 - 1338.

11
[ 3537-14-2 ]
[ 127356-05-2 ]

References: [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 2231 - 2239.

12
[ 3537-14-2 ]
[ 127356-23-4 ]

References: [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 2231 - 2239.

13
[ 3537-14-2 ]
[ 127356-43-8 ]

References: [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 2231 - 2239.

14
[ 79-14-1 ]
[ 3537-14-2 ]
[ 908248-20-4 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 49; Preparation of (6-Amino-3H-imidazo[4,5-b]pyridin-2-yl)-methanol; (6-Nitro-3H-imidazo[4,5-b]pyridin-2-yl)-methanol Solid <strong>[3537-14-2]2,3-Diamino-5-nitropyridine</strong> (prepared according to J. Med. Chem. 1997, 40, 3679-3686; 610 mg, 0.0040 mol) and solid glycolic acid (750 mg, 0.0099 mol) were combined in a sealed tube (left open) and heated to 145 C. and stirred for approx. 30-45 min (solid fuses together, liquifies then re-solidifies). After allowing to cool to rt the solid was extracted with 1N HCl. The aqueous mixture was concentrated under vacuum to leave a crude solid that was basified using conc. NH4OH solution. The ammonia solution was concentrated under vacuum to leave a crude solid that was dry-loaded on to silica and purified by column chromatography (using the ISCO system) to give a solid (450 mg) that was used directly in the next step.
	at 145℃; for 0.5 - 0.75h;	Intermediate 12 Preparation of (6-Amino-3H-imidazo[4,5-b]pyridin-2-yl)-methanol (6-Nitro-3H-imidazo[4,5-b]pyridin-2-yl)-methanol; Solid <strong>[3537-14-2]2,3-Diamino-5-nitropyridine</strong> (prepared according to J. Med. Chem. 1997, 40, 3679-3686; 610 mg, 0.0040 mol) and solid glycolic acid (750 mg, 0.0099 mol) were combined in a sealed tube (left open) and heated to 145 C. and stirred for approx. 30-45 min (solid fuses together, liquifies then re-solidifies). After allowing to cool to rt the solid was extracted with 1N HCl. The aqueous mixture was concentrated under vacuum to leave a crude solid that was basified using conc. NH3 solution. The ammonia solution was concentrated under vacuum to leave a crude solid that was dry-loaded on to silica and purified by column chromatography (using the ISCO system) to give a solid (450 mg) that was used directly in the next step.

References: [1]Patent: US2006/194801,2006,A1 .Location in patent: Page/Page column 51.
[2]Patent: US2006/205773,2006,A1 .Location in patent: Page/Page column 27-28.

15
[ 7647-01-0 ]
[ 3537-14-2 ]
[ 144435-09-6 ]

Yield	Reaction Conditions	Operation in experiment
308 mg (74%)	With oxalic acid;	5-Aza-7-nitro-1,4-dihydroquinoxaline-2,3-dione (63) A mixture of 62 (308 mg, 2.0 mmol), oxalic acid (270 mg, 3.0 mmol) and 2N aq HCl (3 mL) was refluxed for 4 h, then cooled to 0 C. The precipitate was filtered, washed with cooled water (3*1 mL), then dried to give 308 mg (74%) of 63 as a black powder, mp >370 C. IR (KBr) 1702, 1596, 1519, 1343 cm-1. 1 H NMR (DMSO-d6): 8.086 (d, 1H, J=2.4), 8.913 (d, 1H, J=2.4), 12.224 (bs, 2H). Purity was 99.5% by HPLC. HRMS, Calcd. for C7 H4 N4 O4: 208.231; Found: 208.233.

References: [1]Patent: US5620978,1997,A .

16
aq. (NH₄)2 S [ No CAS ]
[ 3073-30-1 ]
[ 3537-14-2 ]

Yield	Reaction Conditions	Operation in experiment
1.092 g (80%)	In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;	2,3-Diamino-5-nitropyridine (62) To a suspension of 61 (1.617 g, 8.79 mmol) in MeOH (75 mL) was added 20% aq. (NH4)2 S (15 mL, 44 mmol) dropwise at room temperature with stirring. The resulting dark-red solution was stirred at room temperature for 0.5 h, then refluxed for 0.5 h, then cooled to room temperature. The resulting mixture was filtered. The filtrate was concentrated to about 30 mL and cooled in ice-water. The precipitate was filtered, washed with cooled EtOH (2*5 mL), and dried to give 1.092 g (80%) of 62 as a deep red powder, mp 260-2 C.(dec) (Lit., 260 C., Chemical Abstracts 65:3826 (1966)). 1 H NMR (DMSO-d6): 5.311 (s, 2H), 6.984 (s, 2H), 7.342(d, 1H, J=2.2), 8.171 (d, 1H, J=2.2).

References: [1]Patent: US5620978,1997,A .

17
[ 117550-54-6 ]
[ 3537-14-2 ]
[ 122771-62-4 ]
2-Amino-3-(2-methyl-6-methoxycarbonylaminobenzylamino)-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		PREPARATION 21 2-Amino-3-(2-methyl-6-methoxycarbonylaminobenzylamino)-5-nitropyridine was obtained by reacting <strong>[3537-14-2]2,3-diamino-5-nitropyridine</strong> with 2-methyl-6-methoxycarbonylaminobenzyl chloride according to a similar manner to that of Preparation 16. mp: 181 to 183 C. IR (Nujol): 3410, 3320, 1720, 1655, 1590, 1520 cm-1. NMR (DMSO-d6, delta): 2.33 (3H, s), 3.57 (3H, s), 4.18 (2H, d, J=5Hz), 5.12 (1H, t, J=3Hz), 6.90-7.37 (6H, m), 8.28 (1H, d, J=2Hz), 8.80 (1H, s).

References: [1]Patent: US4920129,1990,A .

18
[ 100-52-7 ]
[ 3537-14-2 ]
[ 896114-82-2 ]

Yield	Reaction Conditions	Operation in experiment
	In nitrobenzene; at 140 - 150℃; for 15h;	Experimental Procedures; Starting materials; 2-phenyl-3H-imidazo[4,5-blpyridin-6-ylamine; a); 6-Nitro-2-phenyl-3H-imidazo[4,5-b] pyridine; 14.05 g <strong>[3537-14-2]2,3-diamino-5-nitropyridine</strong> and 9.68 g benzaldehyde in 250 mL nitrobenzene were heated to 140-150 0C for 15 hours (hrs). The solvent is removed by vacuum distillation and the residue is dispersed in ethyl acetate, filtered, and the filter residue washed thoroughly with ethyl acetate.Yield 16.0 g
	In nitrobenzene; at 140 - 150℃; for 15h;	Example a) 6-Nitro-2-phenyl-3H-imidazo[4,5-b]pyridine; 14.05 g <strong>[3537-14-2]2,3-diamino-5-nitropyridine</strong> and 9.68 g benzaldehyde in 250 ml nitrobenzene were heated to 140-150 0C for 15 hrs. The solvent is removed by vacuum distillation and the residue is dispersed in ethyl acetate, filtered, and the filter residue washed thoroughly with ethyl acetate. Yield 16.O g
	In nitrobenzene; at 140 - 150℃; for 15h;	14.05 g <strong>[3537-14-2]2,3-diamino-5-nitropyridine</strong> and 9.68 g benzaldehyde in 250 ml nitrobenzene were heated to 140-150 C. for 15 hrs. The solvent is removed by vacuum distillation and the residue is dispersed in ethyl acetate, filtered, and the filter residue washed thoroughly with ethyl acetate. Yield 16.0 g

In nitrobenzene; at 140 - 150℃; for 15h;

Example 1-1 (2-Phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-carbamic acid 1-methyl-allyl ester a) 6-Nitro-2-phenyl-3H-imidazo[4,5-b]pyridine; 14.05 g <strong>[3537-14-2]2,3-diamino-5-nitropyridine</strong> and 9.68 g benzaldehyde in 250 ml nitrobenzene were heated to 140-150 C. for 15 hrs. The solvent is removed by vacuum distillation and the residue is dispersed in ethyl acetate, filtered, and the filter residue washed thoroughly with ethyl acetate. Yield 16.0 g

References: [1]Patent: WO2007/14707,2007,A1 .Location in patent: Page/Page column 19.
[2]Patent: WO2007/17143,2007,A1 .Location in patent: Page/Page column 24.
[3]Patent: US2008/39460,2008,A1 .Location in patent: Page/Page column 15.
[4]Patent: US2008/9492,2008,A1 .Location in patent: Page/Page column 18.

19
[ 122-04-3 ]
[ 3537-14-2 ]
[ 675200-23-4 ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine;	N-(2-Amino-5-nitropyridin-3-yl)-4-nitrobenzamide (6). To a solution of <strong>[3537-14-2]2,3-Diamino-5-nitropyridine</strong> (3) in dry pyridine (85 mL) was added 4-nitrobenzoylchloride (0.875 g, 4.7 mmol) and the mixture was stirred at room temperature for 20 h. The mixture was then poured into H2O (250 mL) and stirred for 30 minutes. The resulting yellow solid was collected by filtration and rinsed with H2O until no pyridine remained. The solid was dried in vacuuo at 80 C to give 6 as a yellow solid (1.15 g, 3.8 mmol, 81%). 1H NMR (500 MHz, DMSO-d6) delta10.12 (br s, 1H), 8.83 (d, J=2.55 Hz, 1H), 8.84 (d, J=8.5 Hz, 2H), 8.35 (d, J=2.45 Hz, 2H), 8.24 (d, J=8.7 Hz, 2H), 7.62 (br s, 2H). EIMS M-1 302.3.

References: [1]Patent: US2004/116466,2004,A1 .

20
(NH₄)2S [ No CAS ]
[ 3073-30-1 ]
[ 3537-14-2 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol;	2,3-Diamino-5-nitropyridine (3). To a stirred suspension of 2-Amino-3,5-dinitropyridine (2) (1.62g, 8.8 mmol) in MeOH (75 mL) was added an aqueous solution of (NH4)2S (20%, 15 mL, 44 mmol) dropwise at room temperature over 20 minutes. The mixture was stirred for an additional 30 minutes at room temperature and then heated at reflux for 30 minutes. The solution was cooled to room temperature and the solid collected by filtration, rinsed with cold MeOH (2*20 mL), and dried in vacuo at room temperature to give 3 as a red solid (0.812 g, 5.27 mmol, 60%). 1H NMR (500 MHz, DMSO-d6) delta5.31 (s, 2H), 6.98 (s, 2H), 7.35 (d, J=2.55 Hz, 1H), 8.28 (d, J=2.91 Hz, 1H). EIMS M+1 155.1.
	In methanol;	2,3-Diamino-5-nitropyridine (3). To a stirred suspension of 2-Amino-3,5-dinitropyridine (2) (2 g, 10.8 mmol) in MeOH (75 mL) was added an aqueous solution of (NH4)2S (20%, 19 mL) dropwise at room temperature over 20 minutes. The mixture was stirred for an additional 30 minutes at room temperature and then heated at reflux for 30 minutes. The solution was cooled to room temperature and the solid collected by filtration, rinsed with cold MeOH (2*20 mL), and dried in vacuo at room temperature to give 3 as a red solid (1.31 g, 8.5 mmol, 79%). 1H NMR (500 MHz, DMSO-d6) 65.31 (s, 2H), 6.98 (s, 2H), 7.35 (d, J=2.55 Hz, 1H), 8.28 (d, J=2.91 Hz, 1H). EIMS M+1 155.1.

References: [1]Patent: US2004/116466,2004,A1 .
[2]Patent: US2004/116466,2004,A1 .

21
[ 3537-14-2 ]
[ 65-85-0 ]
[ 896114-82-2 ]

Yield	Reaction Conditions	Operation in experiment
43%	With trichlorophosphate; for 16h;Reflux;	5-Nitropyridine-2,3-diamine (100 mg, 0.65 mmol, see Example 1) and benzoic acid (87 mg, 0.71 mmol, 1.1 eq.) were combined in POCl3 (5 mL) and heated to reflux for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the resulting residue was taken up in saturated sodium bicarbonate solution, and extracted with 25% IPA/DCM (2 X). The extracts were dried over sodium sulfate and concentrated to 6-nitro-2-phenyl-3H-imidazo[4,5-b]pyridine (67 mg, 43%) as a solid. 1H NMR (400 MHz, DMSO-d6) delta 9.24-9.27 (m, IH), 8.81 (br s, IH), 8.27-8.32 (m, 2H), 7.61-7.67 (m, 3H); m/z (APCI-neg) M-I = 239.3.

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5896 - 5899.
[2]Patent: WO2009/111277,2009,A1 .Location in patent: Page/Page column 54.

22
[ 64-18-6 ]
[ 3537-14-2 ]
[ 3537-09-5 ]

Yield	Reaction Conditions	Operation in experiment
98%		5-Nitropyridine-2,3-diamine (0.050 g, 0.32 mmol) was dissolved in formic acid (10 mL) and heated to 100C for 6 hours. The reaction was diluted with water (10 mL) and brought to a pH of 7 with 3N NaOH. The aqueous portion was extracted with 25% isopropyl alcohol ("IPA")/DCM (6 X), dried over Na2SO4 and concentrated to give 6- nitro-3H-imidazo[4,5-b]pyridine (52 mg, 98%) as a solid.

References: [1]Patent: WO2009/111277,2009,A1 .Location in patent: Page/Page column 53.
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5896 - 5899.

23
[ 103-72-0 ]
[ 3537-14-2 ]
[ 1186224-99-6 ]

Yield	Reaction Conditions	Operation in experiment
		A scintillation vial was charged with <strong>[3537-14-2]5-nitropyridine-2,3-diamine</strong> (44 mg, 0.285 mmol), phenyl isothiocyanate (250 muL, 2.09 mmol) and THF (5 mL). The reaction vessel was sealed and heated to 70C for 30 minutes. The vessel was then cooled to room temperature, and PS-carbodiimide (1.25 mmol/g; 1.20 g, 1.50 mmol) was added. The vessel was re-sealed and heated to 70C for 24 hours. The reaction mixture was filtered through GF/F paper, and the solids were rinsed with excess CH2Cl2 and MeOH alternately. The <n="58"/>filtrate was concentrated in vacuo, and the residue was triturated with 5% MeOH/CH2Cl2 to afford 6-nitro-N-phenyl-3H-imidazo[4,5-b]pyridin-2-amine.

References: [1]Patent: WO2009/111277,2009,A1 .Location in patent: Page/Page column 56-57.

24
[ 55-22-1 ]
[ 3537-14-2 ]
[ 1186223-82-4 ]

Yield	Reaction Conditions	Operation in experiment
25%	With triphenyl phosphite; In pyridine; at 200℃; for 0.25h;Irradiation with microwave;	A 2-5 mL Biotage Microwave reaction vial was charged with 5- nitropyridine-2,3 -diamine (100 mg, 0.65 mmol), isonicotinic acid (80 mg, 0.65 mmol, 1 eq.), and triphenyl phosphite (204 muL, 0.78 mmol, 1.2 eq.) in pyridine (3 mL). This mixture was heated in the microwave at 200C for 15 minutes and then concentrated under reduced pressure. Preparative TLC of the resulting material (4 X 1.0 mm plates, 100% EtOAc as the eluant) afforded 6-nitro-2-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridine (40 mg, 25%) as a solid. 1H NMR (400 MHz, DMSOd6) delta 9.30-9.31 (m, IH), 8.91-8.94 (br m, IH), 8.83-8.88 (br m, 2H), 8.18-8.21 (m, 3H); m/z (APCI-neg) M-I = 240.4, (APCI-pos) M+l = 242.2.

References: [1]Patent: WO2009/111277,2009,A1 .Location in patent: Page/Page column 58.

25
[ 3537-14-2 ]
[ 64-19-7 ]
[ 79781-75-2 ]

Yield	Reaction Conditions	Operation in experiment
87%	at 175℃; for 1.25h;Irradiation with microwave;	A 10-20 mL Biotage Microwave reaction vial was charged with 5- nitropyridine-2,3 -diamine (85 mg, 0.55 mmol, Example 1, Step B) and acetic acid (5 mL). This mixture was subjected to microwave irradiation at 175C for 75 minutes and then poured into a saturated sodium bicarbonate solution (200 mL). The solution was extracted with 25% IPA/DCM (2 X), and the extracts were dried over sodium sulfate. The extracts were concentrated to a solid, 2-methyl-6-nitro-3H-imidazo[4,5-b]pyridine (85 mg, 87%). 1H NMR (400 MHz, DMSOd6) delta 13.43 (br s, IH), 9.15-9.17 (m, IH), 8.67-8.69 (m, IH), 2.61 (s, 3H); m/z (APCI-neg) M-I = 177.1.

References: [1]Patent: WO2009/111277,2009,A1 .Location in patent: Page/Page column 57.
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5896 - 5899.

26
[ 108-24-7 ]
[ 3537-14-2 ]
[ 79781-75-2 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; at 15 - 140℃; for 9.25h;	EXAMPLE 12; Compound 11; N-(2-Methyl-3H-imidazo[4,5-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide; 12.1 2-Methyl-6-nitro-3H-imidazo[4,5-b]pyridine; 2.3 mL (24.33 mol) of acetic anhydride are added to a solution, stirred at 15 C., of 1.5 g (9.73 mmol) of <strong>[3537-14-2]2,3-diamino-5-nitropyridine</strong> in 15 mL of acetic acid. After stirring for 15 minutes at room temperature, the mixture is heated at 110 C. for 2 hours and then at 140 C. for 7 hours. The resulting mixture is concentrated under reduced pressure and taken up in 100 mL of water. A precipitate is collected by filtration. After purification by chromatography on a column of silica, 0.4 g of the expected product is obtained.LCMS: [MH]+=1791H NMR (DMSO D6), delta (ppm): 9.2 (d, 1H); 8.7 (d, 1H); 2.62 (s, 3H).

References: [1]Patent: US2011/9400,2011,A1 .Location in patent: Page/Page column 14-15.

27
[ 3537-14-2 ]
[ 76-05-1 ]
[ 13578-34-2 ]

Yield	Reaction Conditions	Operation in experiment
48%	at 70℃; for 16h;	General procedure: In a screw-cap vial, the diamine or aminothiophenol (1 mmol) was dissolved in fluorinated carboxylic acid (2 mL, 0.5 M) and the reaction was stirred at 70 C for 16 hours. The fluorinated carboxylic acid was then evaporated under reduced pressure and the crude product was purified by silica gel column chromatography to yield the corresponding product.

References: [1]Tetrahedron Letters,2013,vol. 54,p. 201 - 204.

28
[ 3537-14-2 ]
[ 79-31-2 ]
[ 1186224-83-8 ]