98121-41-6|3-Amino-5,6-dichloropyridine| Ambeed

Structure of 98121-41-6

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Quality Control of [ 98121-41-6 ] Purity: 98% SDS Specification

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Product Details of [ 98121-41-6 ]

CAS No. :	98121-41-6
Formula :	C₅H₄Cl₂N₂
M.W :	163.01
SMILES Code :	NC1=CN=C(C(=C1)Cl)Cl
MDL No. :	MFCD03840434
InChI Key :	XTCHZNJJTQACES-UHFFFAOYSA-N
Pubchem ID :	14595219

Safety of [ 98121-41-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H317-H319
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 98121-41-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	38.66
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.37
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	1.8
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.98
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.	1.02
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	1.99
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.63

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.48
Solubility	0.542 mg/ml ; 0.00333 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.	-2.24
Solubility	0.946 mg/ml ; 0.00581 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	-2.89
Solubility	0.211 mg/ml ; 0.00129 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	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.	-6.02 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	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)	1.8

Application In Synthesis of [ 98121-41-6 ]

* 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 [ 98121-41-6 ]

[ 98121-41-6 ] Synthesis Path-Downstream 1~54

1
[ 22353-40-8 ]
[ 98121-41-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; tin(ll) chloride; In water; at 0 - 65℃; for 2h;	Anhydrous SnCl2 (300 g, 1.58 mol) and concentrated HCl (350 mL) were charged to a 5L flask with mechanical stirrer and thermocouple. The flask was cooled in ice and the product of Example 2B (100 g, 0.518 mol) was added in portions maintaining the temperature below 65 C. After the addition was complete, the cold bath was removed, and the mixture was stirred for 2 hours at ambient temperature. The mixture was cooled in ice as 25% aqueous NaOH (1000 mL) was added to bring the mixture to pH>10. The mixture was extracted with CH2Cl2 (1600 mL, 2400 mL) and the combined extracts were washed with brine (200 mL), dried (MgSO4), and concentrated under vacuum. The residual solid was crystallized from a mixture of water (500 mL) and ethanol (100 mL) to provide the title compound as a solid. 1H NMR (CDCl3, 300 MHz) delta 3.80 (br s, 2H), 7.10 (d, J=3 Hz, 1H), 7.77 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 180/182/184 (M+NH4)+163/165/167 (M+H)+.
	With hydrogenchloride; stannous chloride; In sodium hydroxide; ethanol;	Example 2C 5-amino-2,3-dichloropyridine Anhydrous SnCl2 (300 g, 1.58 mol) and concentrated HCl (350 mL) were charged to a 5 L flask with mechanical stirrer and thermocouple. The flask was cooled in ice and the product of Example 2B (100 g, 0.518 mol) was added in portions maintaining the temperature below 65 C. After the addition was complete, the cold bath was removed, and the mixture was stirred for 2 hours at ambient temperature. The mixture was cooled in ice as 25% aqueous NaOH (1000 mL) was added to bring the mixture to pH>10. The mixture was extracted with CH2Cl2 (1600 mL, 2400 mL) and the combined extracts were washed with brine (200 mL), dried (MgSO4), and concentrated under vacuum. The residual solid was crystallized from a mixture of water (500 mL) and ethanol (100 mL) to provide the title compound as a solid. 1H NMR (CDCl3, 300 MHz) delta 3.80 (br s, 2H), 7.10 (d, J=3 Hz, 1H), 7.77 (d, J=3 Hz, 1H); MS (DCI/NH3) m/Z 180/182/184 (M+NH4)+163/165/167 (M+H)+.
	With iron; acetic acid; at 25℃;	2,3-Dichloro-5-nitropyridine (100 g, 0.518 mol, 1.0 equiv.) was dissolved in acetic acid (1000 mL) and iron (metallic, chips) (115.7 g, 2.07 mol, 4.0 equiv.) added in portions, keeping the temperature below 50 C. and the mixture was stirred at 25 C overnight. The solid was filtered and washed with MeOH. The organic phase was evaporated in vacuo, and the residue was dissolved in EtOAc and washed with water, dried (Na2SO4), evaporated in vacuo to afford a gray yellow solid.

EXAMPLE 2C 5-amino-2,3-dichloropyridine Anhydrous SnCl2 (300 g, 1.58 mol) and concentrated HCl (350 mL) were charged to a 5 L flask with mechanical stirrer and thermocouple. The flask was cooled in ice and the product of Example 2B (100 g, 0.518 mol) was added in portions maintaining the temperature below 65 C. After the addition was complete, the cold bath was removed, and the mixture was stirred for 2 hours at ambient temperature. The mixture was cooled in ice as 25% aqueous NaOH (1000 mL) was added to bring the mixture to pH >10. The mixture was extracted with CH2Cl2 (1*600 mL, 2*400 mL) and the combined extracts were washed with brine (200 mL), dried (MgSO4), and concentrated under vacuum. The residual solid was crystallized from a mixture of water (500 mL) and ethanol (100 mL) to provide the title compound as a solid. 1H NMR (CDCl3, 300 MHz) delta 3.80 (br s, 2H), 7.10 (d, J=3 Hz, 1H), 7.77 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 180/182/184 (M+NH4)+163/165/167 (M+H)+.

References: [1]Synthesis,1990,p. 499 - 501.
[2]Patent: US2004/242644,2004,A1 .Location in patent: Page 4.
[3]Patent: US2005/261348,2005,A1 .
[4]Tetrahedron Letters,2013,vol. 54,p. 2303 - 2307.
[5]Patent: US2004/242641,2004,A1 .Location in patent: Page 4.

2
[ 98121-41-6 ]
[ 130284-57-0 ]
[ 130284-58-1 ]

References: [1]Synthesis,1990,p. 499 - 501.

3
[ 98121-41-6 ]
[ 108-24-7 ]
[ 110861-18-2 ]

Yield	Reaction Conditions	Operation in experiment
84 g		To a solution of 5,6-dichloro-pyridin-3-ylamine (40.0 g, 0.245 mol, 1.0 equiv.) in dichloromethane (300 mL) at 0 C was added boron trifluoride diethyl etherate (42.0 g, 0.296 mol, 1.2 equiv.) followed by 2-methyl-2-nitrosooxy-propane (38.0 g, 0.369 mol, 1.5 equiv.). The resulting reaction was allowed to warm to 25 C. The slurry of the product was stirred at this temperature for 30-60 min and filtered to afford 5,6-dichloro-pyridine-3-diazonium tetrafluoroborate (51.0 g, 0.195 mol).5,6-Dichloro-pyridine-3-diazonium tetrafluoroborate (180 g, 0.688 mol, 1.0 equiv.) was dissolved in Ac2O (540 mL) and stirred at RT for a few minutes. Then, the mixture was heated to 60 C. Acetic acid 5,6-dichloro-pyridin-3-yl ester was detected by LCMS. The acetic acid was evaporated, the precipitate was diluted with DCM and evaporated in vacuo. The mixture was purified on silica gel (1% EtOAc in petroleum ether as eluent) to afford acetic acid 5,6-dichloro-pyridin-3-yl ester (84.0 g, 0.408 mol).

References: [1]Synthesis,1990,p. 499 - 501.
[2]Tetrahedron Letters,2013,vol. 54,p. 2303 - 2307.

4
[ 5418-51-9 ]
[ 98121-41-6 ]

References: [1]Synthesis,1990,p. 499 - 501.
[2]Patent: US2004/242641,2004,A1 .
[3]Patent: US6133253,2000,A .

5
[ 22353-38-4 ]
[ 98121-41-6 ]

References: [1]Synthesis,1990,p. 499 - 501.
[2]Patent: US2004/242641,2004,A1 .
[3]Patent: US6133253,2000,A .

6
[ 98121-41-6 ]
[ 110860-92-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrite; In sulfuric acid; water; toluene;	EXAMPLE 11 5,6-dichloro-3-pyridinol Process (a) 8.15 g (50 mmol) of <strong>[98121-41-6]3-amino-5,6-dichloropyridine</strong> were dissolved in 100 ml of 8N H2 SO4 and diazotized at 0 C. using 3.55 g (53 mmol) of sodium nitrite in 9 ml of water. The cold diazonium salt solution was added dropwise to 100 C. warm 60% strength sulfuric acid. After completion of the nitrogen elimination, the mixture was neutralized and extractively distilled using toluene. The dried toluene phase was concentrated by evaporation and the residue was recrystallized repeatedly from toluene. Melting point 184-185 C.

References: [1]Synthesis,1990,p. 499 - 501.
[2]Patent: US4756739,1988,A .
[3]Tetrahedron Letters,2013,vol. 54,p. 2303 - 2307.
[4]Patent: WO2016/91731,2016,A1 .
[5]Patent: US6133253,2000,A .

7
[ 98121-41-6 ]
[ 97966-00-2 ]

Yield	Reaction Conditions	Operation in experiment
		A 5L flask with mechanical stirrer, thermocouple, and addition funnel was charged with the product of Example 2C (70 g, 429 mmol) and 48% HBraq (240 mL). The suspension was maintained at 0-5 C. as a solution of NaNO2 (32.0g, 464 mmol) in water (100 mL) was added dropwise over 1 hour. Additional water (200 mL) was added and the mixture was stirred for 10 minutes at 0-5 C. The mixture was treated with CuBr (32.6 g, 227 mmol) in portions over 20 minutes followed by additional water to maintain a fluid reaction mixture. The mixture was allowed to warm to room temperature and diluted with water. The mixture was distilled at ambient pressure, until the distillate ran clear (1.5 L collected). The distillate was extracted with EtOAc (3*500 mL) and the combined extracts were washed with brine (100 mL), dried (MgSO4), and concentrated to provide 5-bromo-2,3-dichloropyridine as a solid. 1H NMR (CDCl3, 300 MHz) delta 7.94 (d, J=3 Hz, 1H), 8.38 (d, J=3 Hz, 1H).
	With sodium nitrite;copper(I) bromide; In water;	Example 2D 5-bromo-2,3-dichloropyridine A 5 L flask with mechanical stirrer, thermocouple, and addition funnel was charged with the product of Example 2C (70 g, 429 mmol) and 48% HBraq (240 mL). The suspension was maintained at 0-5 C. as a solution of NaNO2 (32.0 g, 464 mmol) in water (100 mL) was added dropwise over 1 hour. Additional water (200 mL) was added and the mixture was stirred for 10 minutes at 0-5 C. The mixture was treated with CuBr (32.6 g, 227 mmol) in portions over 20 minutes followed by additional water to maintain a fluid reaction mixture. The mixture was allowed to warm to room temperature and diluted with water. The mixture was distilled at ambient pressure, until the distillate ran clear (1.5 L collected). The distillate was extracted with EtOAc (3*500 mL) and the combined extracts were washed with brine (100 mL), dried (MgSO4), and concentrated to provide 5-bromo-2,3-dichloropyridine as a solid. 1H NMR (CDCl3, 300 MHz) delta 7.94 (d, J=3 Hz, 1H), 8.38 (d, J=3 Hz, 1H).
		EXAMPLE 2D 5-bromo-2,3-dichloropyridine A 5 L flask with mechanical stirrer, thermocouple, and addition funnel was charged with the product of Example 2C (70 g, 429 mmol) and 48% HBraq (240 mL). The suspension was maintained at 0-5 C. as a solution of NaNO2 (32.0g, 464 mmol) in water (100 mL) was added dropwise over 1 hour. Additional water (200 mL) was added and the mixture was stirred for 10 minutes at 0-5 C. The mixture was treated with CuBr (32.6 g, 227 mmol) in portions over 20 minutes followed by additional water to maintain a fluid reaction mixture. The mixture was allowed to warm to room temperature and diluted with water. The mixture was distilled at ambient pressure, until the distillate ran clear (1.5 L collected). The distillate was extracted with EtOAc (3*500 mL) and the combined extracts were washed with brine (100 mL), dried (MgSO4), and concentrated to provide 5-bromo-2,3-dichloropyridine as a solid. 1H NMR (CDCl3, 300 MHz) delta 7.94 (d, J=3 Hz, 1 H), 8.38 (d, J=3 Hz, 1H).

References: [1]Patent: US2004/242644,2004,A1 .Location in patent: Page 4.
[2]Patent: US2005/261348,2005,A1 .
[3]Patent: US2004/242641,2004,A1 .Location in patent: Page 4.

8
[ 624-92-0 ]
[ 98121-41-6 ]
[ 203731-39-9 ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylnitrite; In ice-water; hexane; dichloromethane;	Precursor alpha: 2,3-Dichloro-5-methylthiopyridine A solution of 50.6 g (0.3 mol) of <strong>[98121-41-6]3-amino-5,6-dichloropyridine</strong> in 700 ml of methylene chloride was slowly added dropwise at 40 C. to a solution of 56.6 g (0.6 mol) of dimethyl disulfide and 46.7 g (0.45 mol) of tert-butyl nitrite in 320 ml of dry methylene chloride. The mixture was then stirred for 1 hour at 40 C. and subsequently for another approximately 15 hours at approximately 20 C., whereupon 500 ml of ice-water were added to the reaction mixture. The organic phase which was separated off was washed once with 1 N hydrochloric acid and once with water, dried over sodium sulfate and finally concentrated. After the crude product had been stirred with n-hexane, 21 g of a dark solid were obtained (purity 94% according to GC). After the hexane solution was concentrated, a further 21.3 g of product of value remained which had a purity of 77% (according to GC). Total yield: 62%; m.p.: 66-67 C.; 1H-NMR (in d6 dimethyl sulfoxide): delta [ppm]=2.6 (s, CH3); 8.1 and 8.3 (2*d, pyr H).

References: [1]Patent: US6448205,2002,B1 .

9
[ 110-81-6 ]
[ 98121-41-6 ]
[ 203736-68-9 ]

Yield	Reaction Conditions	Operation in experiment
42%	With tert.-butylnitrite; In dichloromethane;	Precursor alpha: 2,3-Dichloro-5-ethylthiopyridine 24.45 g (0.15 mol) of <strong>[98121-41-6]3-amino-5,6-dichloropyridine</strong> in 280 ml of methylene chloride were reacted with 36.6 g (0.3 mol) of diethyl disulfide and 23.2 g (0.225 mol) of tert-butyl nitrite in 130 ml of methylene chloride by a method similar to Example 1, Precursor alpha. After working up and subsequently washing the crude product with ethanol, 13.3 g of product of value were obtained. Yield: 42%; 1H-NMR (in d6 dimethyl sulfoxide): delta [ppm]=1.25 (t, CH3); 3.10 (d, CH2); 8.15 and 8.3 (2*d, pyr H).

References: [1]Patent: US6448205,2002,B1 .

10
[ 4253-89-8 ]
[ 98121-41-6 ]
[ 203736-71-4 ]

Yield	Reaction Conditions	Operation in experiment
40%	With tert.-butylnitrite; In dichloromethane;	Precursor alpha: 2,3-Dichloro-5-isopropylthiopyridine 13.1 g (0.08 mol) of <strong>[98121-41-6]3-amino-5,6-dichloropyridine</strong> in 120 ml of methylene chloride were reacted with 25 g (0.16 mol) of diisopropyl disulfide and 12.4 g (0.12 mol) of tert-butyl nitrite in 70 ml of methylene chloride by a method similar to Example 1, Precursor alpha. This gave 30 g of the dark oil (approximately 40% of product of value) which was further reacted without further purification. 1H-NMR (in d6 dimethyl sulfoxide): delta [ppm]=1.25 (d, 2CH3); 3.7 (m, CH); 8.2 and 8.3 (2d, pyr H).

References: [1]Patent: US6448205,2002,B1 .

11
[ 540-80-7 ]
[ 98121-41-6 ]
2,3-dichloro -5-fluoropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroborane diethyl ether; In hexane; dichloromethane;	<strong>[98121-41-6]5-Amino-2,3-dichloropyridine</strong> (0.80 g) in dichloromethane (10 ml) was added to boron trifluoride etherate (0.92 ml) at -15 C. under nitrogen. Dichloromethane (15 ml) was added followed by t-butylnitrite (0.71 ml) in dichloromethane (5 ml). After 15 minutes the mixture was allowed to warm to -5 C. over 20 minutes. Hexane was added and the resulting solid was filtered, air-dried and washed with ether and stored at approximately -20 C. overnight. The solid was then heated until gas evolution had ceased and the product kugelrohr distilled to give 2,3-dichloro-5-fluoropyridine (0.104 g).

References: [1]Patent: US5922732,1999,A .

12
[ 22353-40-8 ]
[ 7439-89-6 ]
[ 98121-41-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With magnesium sulfate; In water; acetic acid; ethyl acetate;	EXAMPLE 10 3-amino-5,6-dichloropyridine 77.2 g (0.4 mol) of 2,3-dichloro-5-nitropyridine were dissolved in 135 ml of glacial acetic acid, and 800 ml of water were added with stirring. 111.7 g (2 mol) of iron powder were introduced in portions into the mixture (temperature?50 C.). After completion of the reaction, the mixture is filtered under suction and the product extracted using ethyl acetate. The organic phase was washed with water until neutral, dried using MgSO4 and concentrated by evaporation. The product was recrystallized from toluene. Yield 85% Melting point 107 C.
	In water; ethyl acetate;	2,3-Dichloro-5-nitropyridine (3.9 g) and iron powder (3.0 g) were added to isopropyl alcohol (40 ml) and water (8 ml) and the mixture refluxed for 4 hours. The mixture was then cooled to room temperature and filtered (celite). The filtrate was evaporated under reduced pressure and chromatographed ?SiO2; hexane:ethyl acetate (80:20) to[(50:50)] to give 5-amino-2,3-dichloropyridine (1.71 g).

References: [1]Patent: US4756739,1988,A .
[2]Patent: US5922732,1999,A .

13
[ 540-80-7 ]
diazonium tetrafluoroborate salt [ No CAS ]
Na₂ S₂ O₃ [ No CAS ]
[ 98121-41-6 ]
[ 97966-01-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	With pyridine; Ki; In 1,2-dimethoxyethane; acetonitrile; pentane;	8a. 2,3-Dichloro-5-iodopyridine <strong>[98121-41-6]5-Amino-2,3-dichloropyridine</strong> (15.0 g, 92.0 mmol, prepared according to V. Koch and S. Schnatterer, Synthesis, 1990, 499-501) was dissolved in DME (30 mL) and subjected to diazotization conditions according to the procedure of M. P. Doyle and W. J. Bryker (Journal Of Organic Chemistry, 1979, 44, 1572). The dissolved pyridine analog was added to a solution of BF3 etherate complex (17 mL, 138 mmol) at -15 C. t-Butyl nitrite in DME (92 mL) was then added at a rate such that the temperature never rose above -5 C. Alter complete addition, the reaction mixture was allowed to warm to 5 C. and stir an additional 45 minutes. Pentane was added and the resultant slurry filtered. The filter cake was washed with cold Et2 O, and the solid was air dried to afford a light orange solid (22.3 g). A sample of the crude diazonium tetrafluoroborate salt (5.1 g, 19.5 mmol) and KI (3.5 g, 21.4 mmol) were combined in CH3 CN (130 mL) and allowed to stir at ambient temperature for 18 hours. A 10% solution of Na2 S2 O3 was carefully added, the biphasic mixture was poured over Et2 O, and the phases were separated. The organic phase was dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; hexanes/CH2 Cl2, 10:1) to afford a white solid (4.0 g, 75%). mp 55-57 C. Rf =0.43 (hexanes/CH2 Cl2, 2:1). 1 H NMR (CDCl3, 300 MHz) delta8.09 (d, J=1.8 Hz, 1H), 8.5 (d, J=1.8 Hz, 1H).

References: [1]Patent: US5733912,1998,A .

14
[ 98121-41-6 ]
[ 110861-18-2 ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium sulfate; sodium nitrite; In HBF4; water; acetic anhydride;	Process (b) 7.8 g (0.6 mol) of <strong>[98121-41-6]3-amino-5,6-dichloropyridine</strong> were dissolved in 900 ml of 50% strength HBF4 and diazotized at 0 C. using 43.5 g (0.63 mol) of sodium nitrite in 600 ml of water. The mixture was stirred for 0.5 hours, and the diazonium salt was filtered off under suction and washed with ice-water and ether. The dried salt was then warmed slowly to 70 C. in 600 ml of acetic anhydride. When the N2 evolution was complete, the mixture was concentrated on a rotary evaporator, and the residue was taken up in ether, washed with water until neutral, dried using MgSO4, concentrated by evaporation and distilled in vacuo. 3-acetoxy-5,6-dichloropyridine of boiling point 102-103 C. 0.01 mbar was obtained.

References: [1]Patent: US4756739,1988,A .
[2]Patent: WO2017/51294,2017,A1 .
[3]Patent: WO2017/51303,2017,A1 .
[4]Patent: WO2017/51276,2017,A1 .

15
[ 98121-41-6 ]
[ 75-36-5 ]
[ 1186637-85-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃;	To a stirred solution of <strong>[98121-41-6]5,6-dichloropyridin-3-amine</strong> (commercially available) and triethyl amine (3 eq) in CH2Cl2 (0.2 M) at 0 C. was added acetyl chloride (2 eq). After stirring at room temperature overnight the reaction mixture was concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford N-(5,6-dichloropyridin-3-yl)acetamide.
	With triethylamine; In dichloromethane; at 0 - 20℃;	To a stirred solution of <strong>[98121-41-6]5,6-dichloropyridin-3-amine</strong> (commercially available) and triethyl amine (3 eq) in CH2CI2 (0.2 M) at 0 0C was added acetyl chloride (2 eq). After stirring at room temperature overnight the reaction mixture was concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 20 - 50% EtOAc in hexanes) to affordN-(5,6-dichloropyridin-3-yl)acetamide.

References: [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 98.
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 206.

16
[ 24424-99-5 ]
[ 98121-41-6 ]
[ 275383-96-5 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 0 - 40℃;	To a solution of <strong>[98121-41-6]5,6-dichloropyridin-3-amine</strong> (commercially available) in THF (0.2 M) stirred at 0 C. was added (BOC)2O (1.2 eq). The reaction mixture was heated at 40 C. until full conversion as monitored by TLC. The reaction mixture was then concentrated. Flash chromatography (silica gel, 20-50% EtOAc in hexanes) of the crude afforded tert-butyl 5,6-dichloropyridin-3-ylcarbamate.
	In tetrahydrofuran; at 0 - 40℃;	To a solution of <strong>[98121-41-6]5,6-dichloropyridin-3-amine</strong> (commercially available) in THF (0.2 M) stirred at 0 0C was added (BOC)2O (1.2 eq). The reaction mixture was heated at 40 0C until full conversion as monitored by TLC. The reaction mixture was then concentrated. Flash chromatography (silica gel, 20 - 50% EtOAc in hexanes) of the crude afforded tert-butyl 5,6- dichloropyridin-3-ylcarbamate.

References: [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 95.
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 203.

17
[ 287-27-4 ]
[ 98121-41-6 ]
[ 1202497-68-4 ]

Yield	Reaction Conditions	Operation in experiment
	With tert-butylhypochlorite; ammonia; In dichloromethane; at -78 - 20℃;	A solution of 1BuOCI (0.65 g, 6.01 mmol) in CH2CI2 (20 ml.) was added dropwise to a solution of <strong>[98121-41-6]3-amino-5,6-dichloropyridine</strong> (1 g, 6.01 mmol) and thietane (0.46 g, 6.01 mmol) in CH2CI2 (35 ml.) at -78 0C. The resulting green suspension was stirred at -78 0C for 1 h, then an excess of NH3 was condensed into the mixture. The suspension was then allowed to slowly warm to ambient temperature and concentrated to a volume of ca. 20 ml_. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure to give 1.9 g of crude sulfilimine (3.1). The crude product was dissolved in CHCb and the solution was refluxed for 3 h. Following evaporation of the solvent, the crude sulfenamide (3.2) was redissolved in CH2CI2 (60 ml.) and cooled to 0 0C. At this temperature, cyanamide (0.32 g, 7.5 mmol) and diacetoxyio- dosobenzene (2.4 g, 7.5 mmol) were added and the solution was stirred at 0 0C for 1 h, then allowed to warm to ambient temperature within 1 h. H2O was added and the aqueous phase was extracted twice with CH2CI2. The combined organic phases were washed with saturated aqueous NaCI-solution, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (NH2- <n="118"/>modified Sitheta2, gradient of cyclohexane/EtOAc) to yield 0.5 g (30% overall) of sulfilimi- namide (45).LC-MS: mass calcd. for C9Hi0CI2N4S [M+H]+ 276, found 276; tR = 2.17 min.

References: [1]Patent: WO2009/156336,2009,A1 .Location in patent: Page/Page column 116-117.

18
[ 98121-41-6 ]
[ 5188-07-8 ]
[ 203731-39-9 ]

Yield	Reaction Conditions	Operation in experiment
		2.85 Example 85 (Prepared according to Scheme 15); (/?)-4-(3-Chloro-5-(methylsulfonyl)pyridine-2-yl)-2-methyl-N-(4-(trimethylsilyl)phenyl)piperazine-l- carboxamide; To a solution of <strong>[98121-41-6]3-amino-5,6-dichloropyridine</strong> (6.13mmol) in HCl (37%, 5ml) at 00C was added sodium nitrite (9.20mmol) in water (2ml) in a dropwise fashion. The reaction was stirred at 00C for 1 hr. The reaction was filtered to remove sodium chloride. A suspension of sodium methanethiolate (7.36mmol) and copper (II) tetrafluoroborate hydrate (0.061mmol) in acetonitrile (5 ml) was cooled to 00C. The solution of the diazonium salt was added dropwise with much nitrogen evolution. The resulting orange suspension was stirred at room temperature for 4 hours. The reaction was quenched with NaOH (50ml) and extracted with ethyl acetate (2x50ml). The organics were combined, washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (0-30% ethyl acetate in petroleum ether) yielding the product 2,3-dichloro-5-(methylthio)pyridine (3.77mmol) 1H NuMR (400 MHz, CDCl3) delta 8.16 - 8.34 (m, IH), 7.59 - 7.76 (m, IH), 2.59 (s, 3H)A solution of 2,3-dichloro-5-(methylthio)pyridine (3.77mmol) in DCM was cooled to 00C. To this was added mCPBA (7.53mmol) the reaction was warmed to room temperature and stirred for 48hr. The reaction was quenched with sat. sodium bicarbonate (50 ml) and extracted with DCM (50 ml x 2) the organic phases were combined, washed with brine, dried (phase separation cartridge) and concentrated under reduced pressure. The resultant white solid was purified by flash chromatography (0-30 % ethyl acetate in petroleum ether) yielding 2,3-dichloro-5-(methylsulfonyl)pyridine (3.72mmol). 1H NuMR (400 MHz, CDCl3) delta 8.61 - 8.99 (m, IH), 8.09 - 8.47 (m, IH), 3.08 (s, 3H).The title compound was synthesized in accordance with Example 23 from the intermediate described above. MS: ES+ 481.1. 1H NuMR (400 MHz, CDCl3) delta 8.62 - 8.69 (m, IH), 8.03 - 8.10 (m, IH), 7.43 - 7.55 (m, 2H), 7.32 - 7.43 (m, 2H), 6.37 (s, IH), 4.35 - 4.48 (m, IH), 4.17 - 4.29 (m, IH), 4.05 - 4.17 (m, IH), 3.93 - 4.03 (m, IH), 3.43 - 3.57 (m, IH), 3.33 - 3.43 (m, IH), 3.13 - 3.26 (m, IH), 3.1 1 (s, 3H), 1.35 - 1.46 (m, 3H), 0.27 (s, 9H)

References: [1]Patent: WO2010/92342,2010,A1 .Location in patent: Page/Page column 65-66.

19
[ 98121-41-6 ]
5,6-dichloropyridine-3-sulfonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		With cooling with ice, an aqueous solution (2.5 ml) of sodium nitrite (1.1 g, 16.0 mmol) was added to a hydrochloric acid solution (15 ml) of <strong>[98121-41-6]5,6-dichloropyridine-3-amine</strong> (2.0 g, 12.3 mmol), stirred for 30 minutes, and the reaction solution was filtered. The filtrate was added to a mixed hydrochloric acid (35 ml)/water (8 ml) solution of sodium sulfite (3.87 g, 30.7 mmol) and copper sulfate (0.29 g, 1.84 mmol) along with an aqueous solution (8 ml) of sodium sulfite (3.87 g, 30.7 mmol) thereto, with cooling with ice, and stirred for 30 minutes. The reaction solution was extracted with chloroform, the organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5,6-dichloropyridine-3-sulfonyl chloride (2.41 g, yield: 80 %) as a brown oil.

References: [1]Patent: EP2221301,2010,A1 .Location in patent: Page/Page column 70.

20
[ 98121-41-6 ]
C₂₄H₃₀ClN₅O₆ [ No CAS ]