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Quality Control of [ 5409-39-2 ] Purity: 95% SDS Specification

COA

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NMR

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Product Details of [ 5409-39-2 ]

CAS No. :	5409-39-2
Formula :	C₅H₄ClN₃O₂
M.W :	173.56
SMILES Code :	NC1=NC=C(Cl)C=C1[N+]([O-])=O
MDL No. :	MFCD00092011
InChI Key :	GILTXHIJUUIMPI-UHFFFAOYSA-N
Pubchem ID :	224168

Safety of [ 5409-39-2 ]

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

Computational Chemistry of [ 5409-39-2 ] 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	1.0
Molar Refractivity	42.47
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	84.73 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.82
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	1.51
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.23
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.	-0.29
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	-0.77
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.5

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.2
Solubility	1.08 mg/ml ; 0.00624 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.	-2.9
Solubility	0.22 mg/ml ; 0.00127 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	-1.66
Solubility	3.81 mg/ml ; 0.0219 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.	-6.29 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)	2.09

Application In Synthesis of [ 5409-39-2 ]

* 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 [ 5409-39-2 ]

[ 5409-39-2 ] Synthesis Path-Downstream 1~31

1
[ 5409-39-2 ]
[ 452-58-4 ]

References: [1]Journal of the American Chemical Society,1949,vol. 71,p. 1891.

2
[ 5409-39-2 ]
[ 25710-20-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With hydrogen;2 % platinum on carbon; In methanol; at 25℃; for 2h;	The compound of formula BD was prepared as follows. A mixture of the compound of formula BC (<strong>[5409-39-2]5-chloro-3-nitropyridin-2-amine</strong>, 1736mg, lOmmol, Sigma- Aldrich) and 2% platinum on carbon (200mg, Sigma-Aldrich) in methanol (2OmL) was stirred under a hydrogen atmosphere at a temperature of about 250C for 2h. After filtering off the Pt/C and washing with EtOAc, the filtrate was concentrated under reduced pressure. The resulting solid was washed with 1 : 1 n-hexane: diethyl ether, filtered, washed with n-hexane, and dried under reduced pressure at a temperature of about 250C to provide the compound of formula BD as a pale brown solid (yield 88%). <n="189"/>The identity of the compound of formula BD was confirmed using 1H NMR.Compound BD: 1H NMR: δH (300 MHz, DMSO): 7.21 (IH, d, J=I.2Hz), 6.69 (IH, d, J= 1.2Hz), 5.57 (2H, m), 5.01 (2H, m).
77%	With ethanol; tin(ll) chloride; for 4h;Reflux;	5-Chloro-3-nitropyridin-2-amine 40a (346 mg, 2 mmol) was dissolved in ethanol (20 ml), then stannous chloride (756 mg, 4 mmol) was added and heated and refluxed for 4 hr. After cooling to room temperature, quenched with water, then with 1N sodium hydroxide solution was adjusted to pH = 8-9 and extracted with ethyl acetate (30ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate is then removed under reduced pressure to give the desired product 5-chloropyridine-2,3-diamine.40b (220 mg, brown solid), yield: 77%.This product was used directly in the next step without further purification.
70%		To a suspension of <strong>[5409-39-2]5-chloro-3-nitropyridin-2-amine</strong> (1.04 g, 6.00 mmol) in ethanol (6 ml), SnC-2-2H2θ (6.77 g, 30.0 mmol) was added portionwise at room temperature and stirred at 90 C for 1 hour. After cooling, the reaction mixture was basified with aqueous NaOH solution (pH = 14), extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to give 5-chloropyridine-2,3-diamine (604 mg, 70 %, tan solid).

References: [1]New Journal of Chemistry,2015,vol. 39,p. 3936 - 3947.
[2]Journal of Medicinal Chemistry,1997,vol. 40,p. 3679 - 3686.
[3]Patent: WO2008/89201,2008,A2 .Location in patent: Page/Page column 187-188.
[4]European Journal of Organic Chemistry,2020.
[5]Patent: CN109956927,2019,A .Location in patent: Paragraph 0142-0143; 0403-0404.
[6]Patent: WO2008/8398,2008,A2 .Location in patent: Page/Page column 370.
[7]Chemical and pharmaceutical bulletin,1958,vol. 6,p. 443).
[8]Journal of the American Chemical Society,1949,vol. 71,p. 1885.
[9]Journal of the American Chemical Society,1949,vol. 71,p. 1885.
[10]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2749 - 2754.
[11]Journal of Medicinal Chemistry,2000,vol. 43,p. 3052 - 3066.
[12]Chemistry of Heterocyclic Compounds,2020,vol. 56,p. 92 - 100.
Khim. Geterotsikl. Soedin.,2020,vol. 56,p. 92 - 100,9.

3
[ 5409-39-2 ]
[ 97941-89-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	With hydrogenchloride; tin(ll) chloride; In water; at 80 - 100℃; for 0.5h;	5-Chloro-3-nitropyridin-2-amine (2000.0 mg, 11.52 mmol) and SnCl2 (8740.0 mg, 46.09 mmol) were added in conc. HCl (20.0 mL) and then stirred at 80-100 C. for 0.5 hour. The reaction mixture was neutralized with saturated 1N NaOH aqueous solution (pH=7), and it was then extracted with EtOAc (200.0 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and then distilled under reduced pressure. The residue was purified by column chromatography (n-Hex:EtOAc=90:10) on silica. The fractions containing the product were collected and evaporated to obtain ivory solid compound of 5,6-dichloropyridin-2,3-diamine (1000.0 mg, 49%). [0523] 1H-NMR (300 MHz, DMSO-d6); δ: 6.80 (s, 1H), 6.04 (s, 2H), 5.11 (s, 2H)

References: [1]Patent: US2014/315888,2014,A1 .Location in patent: Paragraph 0522-0523.
[2]Journal of Organic Chemistry,1959,vol. 24,p. 1455,1459.

4
[ 5409-39-2 ]
[ 21427-62-3 ]

Yield	Reaction Conditions	Operation in experiment
60%		5-Chloro-3-nitro-2-pyridinamine (5.0 g, 28.8 mmol) was dissolved in cone. HCI (50 mL) and cooled to -10 0C in an ice-salt bath. Sodium nitrite (4.97 g, 72 mmol) in water (10 mL) was added dropwise to the cooled solution over 1 h and stirred at 0 C for 1 h longer. The reaction mixture was cooled to -10 0C in an ice-salt bath and neutralized with 2N sodium hydroxide to pH 9.0 keeping the temperature below 0 0C. EtOAc (150 mL) was added and the mixture was filtered. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford the title compound as 3.36 g (60% yield) of a light brown solid; 1H NMR (cfe-DMSO) δ 8.62 (d, 1 H, 2.5 Hz), 8.26 (d, 1 H, 2.2 Hz).
58.5%	With hydrogenchloride; sodium nitrite; In water; at -10 - 0℃; for 1.5h;	<strong>[5409-39-2]5-chloro-3-nitropyridine-2-amine</strong> 10.0g of (57.6 mmol) was dissolved in concentrated hydrochloric acid 100 mL, and stirred at -10 C.. Here, sodium nitrite 9.94g of (144 mmol) Yuki dropwise over 30 minutes a liquid obtained by dissolving water 20 mL, after the addition, the mixture was stirred 1 hour at 0 C.. By adding 1N aqueous sodium hydroxide solution to the reaction solution and pH 9, and extracted with ethyl acetate. Insolubles were removed by filtration, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Filtered and the filtrate was evaporated under reduced pressure to give the title compound 6.50g of (58.5% yield) as a solid.
58.5%		<strong>[5409-39-2]5-chloro-3-nitropyridine-2-amine</strong> 10.0g of (57.6 mmol) was dissolved in concentrated hydrochloric acid 100 mL, and stirred at -10 C.. Here, sodium nitrite 9.94g of (144 mmol) add dropwise over 30 minutes a liquid obtained by dissolving water 20 mL, after the addition, the mixture was stirred 1 hour at 0 C.. By adding 1N aqueous sodium hydroxide solution to the reaction solution and pH 9, and extracted with ethyl acetate. Insolubles were removed by filtration, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Filtered and the filtrate was evaporated under reduced pressure to give the title compound 6.50g of (58.5% yield) as a solid.

58.5%	With hydrogenchloride; sodium nitrite; In water; at -10 - 0℃; for 1.5h;	(Step 1) 2,5-Dichloro-3-nitropyridine 5-Chloro-3-nitropyridin-2-amine (10.0 g, 57.6 mmol) was dissolved in concentrated hydrochloric acid (100 mL), and the solution was stirred at -10C. A solution of sodium nitrite (9.94 g, 144 mmol) dissolved in water (20 mL) was added dropwise thereto over 30 minutes. After the completion of the addition, the mixture was stirred at 0C for 1 hour. The pH of the reaction solution was adjusted to 9 by the addition of a 1 N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. Insoluble matter was removed by filtration, and the organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After filtration, the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (6.50 g, yield: 58.5%) as a solid. 1H-NMR (CDCl3) δ: 8.60 (1H, d, J = 2.9 Hz), 8.24 (1H, d, J = 2.6 Hz).
	With tert.-butylnitrite; copper dichloride; In acetonitrile; at 70℃; for 17.5h;	Example 14; Preparation of Compound 14A ; To a stirred solution of tert-butyl nitrite (55.2 ml, 466 mmol) and anhydrous Cu(II)Cl2 (50.0 g, 372 mmol) in CH3CN (500 mL), maintained at 70 C., was added 2-amino-5-chloro-3-nitrobenzene 38 (53.6 g, 310 mmol) portionwise over 30 min. The mixture turned from greenish to brown, and gas evolution was observed. Stirring at 70 C. was continued for 16 h. The reaction mixture was cooled and partitioned between 20% aqueous HCl (400 mL) and diethyl ether (1 l). Layers were separated, and the aqueous phase was extracted with EtOAc (500 mL). Combined extracts were washed successively with 20% aqueous HCl (200 mL) and brine (300 mL), dried over anhydrous MgSO4, filtered and concentrated under vacuum. The residue was flash chromatographed on silica gel, eluting with EtOAc-hexanes (1:4), to provide 17.3 g of compound 39 as a yellow oil, which spontaneously crystallized upon standing at room temperature.

References: [1]Patent: WO2007/67875,2007,A2 .Location in patent: Page/Page column 15.
[2]Patent: JP2016/56134,2016,A .Location in patent: Paragraph 0165; 0166; 0167.
[3]Patent: JP2016/56133,2016,A .Location in patent: Paragraph 0158; 0159.
[4]Patent: EP3109239,2016,A1 .Location in patent: Paragraph 0189.
[5]Journal of the Chemical Society,1952,p. 2042,2044.
[6]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2625 - 2637.
[7]Patent: US2007/167435,2007,A1 .Location in patent: Page/Page column 29.

5
[ 5409-39-2 ]
[ 58596-57-9 ]

References: [1]Liebigs Annalen der Chemie,1991,p. 875 - 878.

6
[ 1072-98-6 ]
[ 5409-39-2 ]

Yield	Reaction Conditions	Operation in experiment
67%		To a mixture of 2-amino-5-chloropyridine (2.57 g, 20.0 mmol) and sulfuric acid (6.30 ml), huming HNO3 (0.860 ml, 21.1 mmol) was added dropwise over 15 minutes at 55 C and stirred at 55 "C for 1 hour. After cooling, the reaction mixture was poured into ice-water (60 g) and neutralized with aqueous NaOH solution (pH = 11). The precipitated material was collected, washed with H2O and dried under reduced pressure at 50 0C to give 5-chloro-3-nitropyridin-2-amine (2.31 g, 67 %, yellow solid).
51.0%		To a 250 mL 3 necked RK flask charged with conc.H2S04 (30 mL) at 0CC, 5 chloropyridin-2-amine (12.5 g) was added portion wise and allowed to stir for 1 h and heated at 50 00 to dissolve starting material completely. Then, conc. HNO3 (8 mL) was added drop wise through addition funnel. The reaction was monitored by every 10 minutes. After completion, 40% sodium hydroxide solution (pH=6-7) was added,the product was extracted with ethyl acetate, washed with water, and dried over anhydrous Na2SO4. The solvent was removed under vacuo to yield the product (11 .0 g, 51.0%) as a pale green solid. LCMS: (M-H) = 172.9
51%		To a 250 mL 3 necked RK flask charged with conc.H2S04 (30 mL) at 000, 5 chloropyridin-2-amine (12.5 g) was added portion wise and solution was allowed to stir for 1 h and heated at 50 00 to dissolve starting material completely. Then, conc. HNO3 (8 mL) was added drop wise to the resulting solution through addition funnel. The reaction was monitored at every 10 minutes. After completion, 40% sodiumhydroxide solution (PH=6-7) was added, the product was extracted with ethyl acetate, washed with water, and dried over anhydrous Na2SO4. The solvent was removed under vacuo to yield the product (11.0 g, 51.0%) as a pale green solid. LOMS: (M-H) = 172.9

References: [1]Synthetic Communications,2012,vol. 42,p. 2791 - 2796.
[2]Patent: WO2008/8398,2008,A2 .Location in patent: Page/Page column 369.
[3]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2061 - 2071.
[4]New Journal of Chemistry,2015,vol. 39,p. 3936 - 3947.
[5]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 669 - 674.
[6]Journal of Medicinal Chemistry,1997,vol. 40,p. 3679 - 3686.
[7]Patent: WO2014/202580,2014,A1 .Location in patent: Page/Page column 100.
[8]Patent: WO2014/202528,2014,A1 .Location in patent: Page/Page column 96.

7
[ 5409-39-2 ]
[ 407-25-0 ]
[ 35195-91-6 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 669 - 674.

8
[ 5409-39-2 ]
[ 74-89-5 ]
[ 58596-57-9 ]
2-amino-5-chloro-6-(methylamino)-3-nitropyridine [ No CAS ]

References: [1]Advanced Synthesis and Catalysis,1999,vol. 341,p. 75 - 78.

9
[ 5409-39-2 ]
[ 58596-57-9 ]
2-amino-5-chloro-6-(methylamino)-3-nitropyridine [ No CAS ]

References: [1]Advanced Synthesis and Catalysis,1999,vol. 341,p. 75 - 78.

10
5-chloro-2-nitramino-pyridine [ No CAS ]
[ 5409-39-2 ]

References: [1]Journal of the American Chemical Society,1949,vol. 71,p. 1886.

11
[ 5409-39-2 ]
6-chloro-[1,2,5]oxadiazolo[3,4-b]pyridine 1-oxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With [bis(acetoxy)iodo]benzene; In benzene; for 2h;Reflux;	General procedure: PhI(OAc)2 (1.93 g, 6 mmol) was added to a suspension ofcompound 9b-d (4.6 mmol) in PhH (40 ml). The mixturewas refluxed for 2 h. The solvent was removed underreduced pressure, and the residue was washed thoroughlywith hexane and dried on air.Methyl [1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate1-oxide (12b). Yield 0.79 g (88%), yellow solid, mp 104-106C (mp 106.5-107.5C25). 1H NMR spectrum (DMSO-d6),δ, ppm: 9.21 (1H, br. s, H Ar); 8.69 (1H, br. s, H Ar); 3.94(3H, s, OCH3). Found, m/z: 196.0348 [M+H]+. C7H6N3O4.Calculated, m/z: 196.0353

References: [1]Chemistry of Heterocyclic Compounds,2020,vol. 56,p. 92 - 100.
Khim. Geterotsikl. Soedin.,2020,vol. 56,p. 92 - 100,9.
[2]Journal of Physical Organic Chemistry,2000,vol. 13,p. 480 - 488.

12
[ 5409-39-2 ]
[ 75806-86-9 ]

Yield	Reaction Conditions	Operation in experiment
73.0%	With hydrogen bromide; bromine; sodium nitrite; In water; at 0 - 20℃; for 1h;	To a solution of intermediate 32a (10.0 g, 57.6 mmol) in HBr [(31 .0 mL (100%), 286.4 mmol)] at 0 00 sodium nitrite (13.8 g, 199.9 mmol) was added drop wise. To the stirred solution Br2 (10.0 mL, 197.1 mmol) was added in water and stirred at room temperature for 1 h. The reaction mixture was basified with NaHCO3 solution (pH=7) and extracted with ethyl acetate, washed with water, and dried over anhydrousNa2SO4 The solvent was removed under vacuo to yield the title product (10.0 g,73.0%) as a yellow solid.
73%	With hydrogen bromide; bromine; sodium nitrite; In water; at 0 - 20℃; for 1h;	To a solution of intermediate 32a (10.0 g, 57.6 mmol) in HBr [(31.0 mL (100%), 286.4 mmol)] at 0 00, sodium nitrite (13.8 g, 199.9 mmol) was added drop wise. To the stirred solution Br2 (10.0 mL, 197.1 mmol)in water was added and stirred at roomtemperature for 1 h. The reaction mixture was basified with NaHCO3 solution (PH=7) and extracted with ethyl acetate, washed with water, and dried over anhydrous Na2SO4 The solvent was removed under vacuo to yield the title product (10.0 g, 73.0%) as a yellow solid.
51.5%	With sodium hydroxide; hydrogen bromide; bromine; sodium nitrite; In ethanol; water;	2-Bromo-5-chloro-3-nitropyridine (103) To a stirred, ice bath cooled solution of HBr (48%, 214 mL, d=1.49, 1.89 mol) was added <strong>[5409-39-2]2-amino-5-chloro-3-nitropyridine</strong> (2) (66.0 g, 376 mmol). The mixture was stirred until the internal temperature was less than 0 C., and then bromine (65 mL, d=3.102, 1.3 mol) was added dropwise. The resulting orange mixture was stirred at a temperature below 0 C. A solution of NaNO2 (91.3 g, 1.32 mol, used as received) in water (125 mL) was added slowly to the mixture so as to maintain the internal temperature below 0 C. The mixture was stirred for an additional 45 min at below 0 C., and then NaOH (139.3 g, 3.482 mol) in water (200 mL) was slowly added to the mixture to maintain the internal temperature below 20 C. The mixture was stirred at below 20 C. for an additional hour, and then gravity filtered. The recovered brown solid was dried at 25 C. under vacuum for 6 h. It was purified by recrystalization from 95% ethanol to obtain 103 as a yellow solid (46.0 g, 51.5%), mp 68-73 C. (Lit., 75 C., Berrie et al., J. Chem. Soc. 2042 (1952)); 1 H NMR (CDCl3): δ8.15 (d, J=2.1 Hz, 1H), 8,57 (d, J=2.1 Hz, 1H).

References: [1]Patent: WO2014/202580,2014,A1 .Location in patent: Page/Page column 100.
[2]Patent: WO2014/202528,2014,A1 .Location in patent: Page/Page column 97.
[3]Synthetic Communications,2012,vol. 42,p. 2791 - 2796.
[4]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 2061 - 2071.
[5]Patent: US5801183,1998,A .

13
[ 5409-39-2 ]
2,8-dichloro-4,5-dihydro-3H-pyrido[3,4-b][1,4]diazepine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2625 - 2637.
[2]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2625 - 2637.

14
[ 5409-39-2 ]
[ 710349-85-2 ]

References: [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2625 - 2637.
[2]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2625 - 2637.

15
[ 5409-39-2 ]
3-(3-amino-5-chloro-pyridin-2-ylamino)-propionic acid ethyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2625 - 2637.
[2]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2625 - 2637.

16
[ 5409-39-2 ]
8-chloro-2-(4-phenyl-piperazin-1-yl)-4,5-dihydro-3H-pyrido[3,4-b][1,4]diazepine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2625 - 2637.
[2]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2625 - 2637.

17
[ 5409-39-2 ]
[ 27330-34-3 ]