[ CAS No. 22889-78-7 ] {[proInfo.proName]}

Name: 22889-78-7|3,5-Dichloropyridin-4-amine|98%
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SKU: A251906
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Quality Control of [ 22889-78-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 22889-78-7 ]

SDS Specification

Alternatived Products of [ 22889-78-7 ]

Product Details of [ 22889-78-7 ]

CAS No. :	22889-78-7	MDL No. :	MFCD00125023
Formula :	C₅H₄Cl₂N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ISIQAMHROGZHOV-UHFFFAOYSA-N
M.W :	163.00	Pubchem ID :	89888
Synonyms :

Calculated chemistry of [ 22889-78-7 ]

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 :	38.91 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.28 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.52
Log Po/w (XLOGP3) :	1.43
Log Po/w (WLOGP) :	1.98
Log Po/w (MLOGP) :	1.02
Log Po/w (SILICOS-IT) :	1.99
Consensus Log Po/w :	1.59

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.24
Solubility :	0.928 mg/ml ; 0.00569 mol/l
Class :	Soluble
Log S (Ali) :	-1.85
Solubility :	2.29 mg/ml ; 0.0141 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.89
Solubility :	0.211 mg/ml ; 0.00129 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.53

Safety of [ 22889-78-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 22889-78-7 ]

* 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.

Upstream synthesis route of [ 22889-78-7 ]
Downstream synthetic route of [ 22889-78-7 ]

[ 22889-78-7 ] Synthesis Path-Upstream 1~14

1
[ 7647-01-0 ]
[ 26482-55-3 ]
[ 626-61-9 ]
[ 33216-52-3 ]
[ 22889-78-7 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690

2
[ 22889-78-7 ]
[ 17228-71-6 ]

Reference： [1] Journal of the Chemical Society, 1911, vol. 99, p. 1682

3
[ 504-24-5 ]
[ 22889-78-7 ]

Reference： [1] Organic Process Research and Development, 1998, vol. 2, # 3, p. 157 - 168
[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
[3] Patent: EP741707, 1998, B1,
[4] Patent: EP741707, 1998, B1,
[5] Patent: US5935978, 1999, A,
[6] Patent: US5679696, 1997, A,
[7] Patent: US5935978, 1999, A,
[8] Patent: US5679696, 1997, A,
[9] Patent: CN102964297, 2018, B, . Location in patent: Paragraph 0023; 0281-0282

4
[ 144036-22-6 ]
[ 22889-78-7 ]
[ 159782-90-8 ]

Reference： [1] Patent: EP741707, 1998, B1,
[2] Patent: US5935978, 1999, A,
[3] Patent: US5679696, 1997, A,

5
[ 153463-65-1 ]
[ 22889-78-7 ]

Reference： [1] Heterocycles, 1998, vol. 48, # 6, p. 1203 - 1211

6
[ 33216-52-3 ]
[ 22889-78-7 ]

Reference： [1] Journal of the Chemical Society, 1911, vol. 99, p. 1682

7
[ 19798-77-7 ]
[ 22889-78-7 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690

8
[ 20511-15-3 ]
[ 22889-78-7 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690

9
[ 55934-00-4 ]
[ 22889-78-7 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690

10
[ 33216-52-3 ]
[ 7664-41-7 ]
[ 22889-78-7 ]

Reference： [1] Journal of the Chemical Society, 1911, vol. 99, p. 1682

11
[ 7647-01-0 ]
[ 26482-55-3 ]
[ 626-61-9 ]
[ 33216-52-3 ]
[ 22889-78-7 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690

12
[ 17122-17-7 ]
[ 22889-78-7 ]

Reference： [1] Journal of the Chemical Society, 1911, vol. 99, p. 1682

13
[ 504-24-5 ]
[ 7647-01-0 ]
[ 7732-18-5 ]
[ 7722-84-1 ]
[ 22889-78-7 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690

14
[ 22889-78-7 ]
[ 98-80-6 ]
[ 950224-92-7 ]
[ 149794-10-5 ]

Yield	Reaction Conditions	Operation in experiment
37%	With N₂; potassium carbonate In N,N-dimethyl-formamide	Example 10 7-phenyl-2-((S)-pyrrolidin-2-yl)thiazolo[5,4-c]pyridine 4-amino-3,5-dichloropyridine a (2.0 g, 12.3 mmol), tetrakis(triphenylphosphine)palladium (696 mg, 0.6 mmol), phenylboronic acid (1.9 g, 15.9 mmol) and potassium carbonate (2.2 g, 15.9 mmol) were mixed in a 10 mL microwave vial under N₂ atmosphere. DMF (6 mL) and deoxygenated H₂O (1.2 mL) were added. N₂ was bubbled through the mixture for 5 min and the mixture was heated for 20 min at 140° C. in the microwave. The mixture was diluted with water (30 mL) and extracted with EtOAc (3*20 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried with MgSO₄, filtered and concentrated. The resulting brown oil was adsorbed on silica gel and purified by flash chromatography (SiO₂, 0percent to 70percent ethyl acetate/hexanes) to afford 970 mg (37percent) of b as a colorless oil. MS: m/z=205 (M+H).

Reference： [1] Patent: US2011/46066, 2011, A1,

[ 22889-78-7 ] Synthesis Path-Downstream 1~76

1
[ 504-24-5 ]
[ 22889-78-7 ]

Yield	Reaction Conditions	Operation in experiment
	With aqueous hydrogen peroxide; In concentrated hydrochloric acid;	REFERENCE EXAMPLE 4 A stirred solution of 4-aminopyridine (40 g) in concentrated hydrochloric acid (500 ML) at 80C is treated dropwise with aqueous hydrogen peroxide solution (200 ML; 15% w/w), while keeping the temperature between 80C and 85C. The solution is then cooled and basified by dropwise treatment with aqueous sodium hydroxide solution (50% w/w), while keeping the temperature below 15C. The resulting white flocculent precipitate is recrystallized from toluene, to give 4-amino-3,5-dichloropyridine (61.5 g), m.p. 161.5-162.5C.
	With sodium hypochlorite; In concentrated hydrochloric acid;	REFERENCE EXAMPLE 5 A solution of 4-aminopyridine (47 g) in concentrated hydrochloric acid (355 ML) is treated portionwise at 80C with an aqueous solution of sodium hypochlorite (550 ML; 15% w/v). The mixture is cooled to 30C and basified by treatment with aqueous sodium hydroxide solution (300 ML; 35% w/v) during 20 minutes. The mixture is stirred and cooled for a further 30 minutes and then it is filtered. The solid is washed well with water and dried at 60C to give 4-amino-3,5-dichloropyridine (69.5 g).
	With sodium hydroxide; dihydrogen peroxide; In hydrogenchloride;	REFERENCE EXAMPLE 4 A stirred solution of 4-aminopyridine (40 g) in concentrated hydrochloric acid (500 mL) at 80 C. is treated dropwise with aqueous hydrogen peroxide solution (200 mL; 15% w/w), while keeping the temperature between 80 C. and 85 C. The solution is then cooled and basified by dropwise treatment with aqueous sodium hydroxide solution (50% w/w), while keeping the temperature below 15 C. The resulting white flocculent precipitate is recrystallized from toluene, to give 4-amino-3,5-dichloropyridine (61.5 g), m.p. 161.5-162.5 C.

	With sodium hydroxide; dihydrogen peroxide; In hydrogenchloride;	REFERENCE EXAMPLE 4 A stirred solution of 4-aminopyridine (40 g) in concentrated hydrochloric acid (500 mL) at 80 C. is treated dropwise with aqueous hydrogen peroxide solution (200 mL; 15% w/w), while keeping the temperature between 80 C. and 85 C. The solution is then cooled and basified by dropwise treatment with aqueous sodium hydroxide solution (50% w/w), while keeping the temperature below 15 C. The resulting white flocculent precipitate is recrystallized from toluene, to give 4-amino-3,5-dichloropyridine (61.5 g), m.p. 161.5-162.5 C.
	With sodium hydroxide; sodium hypochlorite; In hydrogenchloride;	REFERENCE EXAMPLE 5 A solution of 4-aminopyridine (47 g) in concentrated hydrochloric acid (355 mL) is treated portionwise at 80 C. with an aqueous solution of sodium hypochlorite (550 mL; 15% w/v). The mixture is cooled to 30 C. and basified by treatment with aqueous sodium hydroxide solution (300 mL; 35% w/v) during 20 minutes. The mixture is stirred and cooled for a further 30 minutes and then it is filtered. The solid is washed well with water and dried at 60 C. to give 4-amino-3,5-dichloropyridine (69.5 g).
	With hydrogenchloride; sodium hypochlorite; In water;Heating;	Dissolve 4-aminopyridine in dilute hydrochloric acid. An aqueous solution of sodium hypochlorite is added dropwise under heating conditions. After the reaction is over, adjust pH to alkaline with NaOH, precipitation of solids, filter, after washing the precipitate with water, dry to obtain compound SM-2.

Reference： [1]Organic Process Research and Development,1998,vol. 2,p. 157 - 168
[2]Recueil des Travaux Chimiques des Pays-Bas,1950,vol. 69,p. 673,690
[3]Patent: EP741707,1998,B1
[4]Patent: EP741707,1998,B1
[5]Patent: US5935978,1999,A
[6]Patent: US5679696,1997,A
[7]Patent: US5935978,1999,A
[8]Patent: CN102964297,2018,B .Location in patent: Paragraph 0023; 0281-0282

2
[ 19798-77-7 ]
[ 22889-78-7 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1950,vol. 69,p. 673,690

3
[ 33216-52-3 ]
[ 22889-78-7 ]

Reference： [1]Journal of the Chemical Society,1911,vol. 99,p. 1682

4
[ 22889-78-7 ]
[ 17228-71-6 ]

Reference： [1]Journal of the Chemical Society,1911,vol. 99,p. 1682

5
[ 22889-78-7 ]
[ 144036-19-1 ]
[ 144035-83-6 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 10 Compounds CH and A <strong>[22889-78-7]4-Amino-3,5-dichloropyridine</strong> (4.0 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.26 g) are intimately ground together in a mortar with a pestle, and transferred to a round-bottomed flask. The mixture is melted, using a hot air gun external to the flask, stirring with a magnetic stirrer. After 10 minutes, heating is ceased and the melt is allowed to cool. The resulting material is triturated with dichloromethane and the residual solid is filtered off. The filtrate is concentrated to give a fawn solid, which is subjected to flash chromatography on silica gel, eluding with diethyl ether, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (1.87 g), m.p. 155-157C. [Elemental analysis: C,56.3; H,4.7; N,7.2; Cl,18.4%; calculated: C,56.7; H,4.76; N,7.35; Cl,18.6%; IR spectrum: 1661 cm-1 3244 cm-1
		EXAMPLE 6 Compound AO <strong>[22889-78-7]4-Amino-3,5-dichloropyridine</strong> (4.0 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.26 g) are intimately ground together in a mortar with a pestle, and transferred to a round-bottomed flask. The mixture is melted, using a hot air gun external to the flask, stirring with a magnetic stirrer. After 10 minutes, heating is ceased and the melt is allowed to cool. The resulting material is triturated with dichloromethane and the residual solid is filtered off. The filtrate is concentrated to give a fawn solid, which is subjected to flash chromatography on silica gel, eluding with diethyl ether, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (1.87 g), m.p. 155-157 C. ?Elemental analysis: C,56.3; H,4.7; N,7.2; Cl, 18.4%; calculated: C,56.7; H,4.76; N,7.35; Cl,18.6%; IR spectrum: 1661 cm-1, 3244 cm-1!
		EXAMPLE 6 Compound AO <strong>[22889-78-7]4-Amino-3,5-dichloropyridine</strong> (4.0 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.26 g) are intimately ground together in a mortar with a pestle, and transferred to a round-bottomed flask. The mixture is melted, using a hot air gun external to the flask, stirring with a magnetic stirrer. After 10 minutes, heating is ceased and the melt is allowed to cool. The resulting material is triturated with dichloromethane and the residual solid is filtered off. The filtrate is concentrated to give a fawn solid, which is subjected to flash chromatography on silica gel, eluding with diethyl ether, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (1.87 g), m.p. 155-157 C. ?Elemental analysis: C,56.3; H,4.7; N,7.2; Cl,18.4%; calculated: C,56.7; H,4.76; N,7.35; Cl,18.6%; IR spectrum: 1661 cm-1, 3244 cm-1!.

Reference： [1]Organic Process Research and Development,1998,vol. 2,p. 157 - 168
[2]Journal of Medicinal Chemistry,1994,vol. 37,p. 1696 - 1703
[3]Patent: EP741707,1998,B1
[4]Patent: US5935978,1999,A
[5]Patent: US5679696,1997,A

6
[ 153463-65-1 ]
[ 22889-78-7 ]

Reference： [1]Heterocycles,1998,vol. 48,p. 1203 - 1211

7
[ 22889-78-7 ]
[ 184151-49-3 ]
[ 201285-55-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1867 - 1872

8
[ 33216-52-3 ]
[ 7664-41-7 ]
[ 22889-78-7 ]

Reference： [1]Journal of the Chemical Society,1911,vol. 99,p. 1682

9
[ 7647-01-0 ]
[ 26482-55-3 ]
[ 626-61-9 ]
[ 33216-52-3 ]
[ 22889-78-7 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1950,vol. 69,p. 673,690

10
[ 22889-78-7 ]
[ 98-80-6 ]
[ 950192-33-3 ]

Yield	Reaction Conditions	Operation in experiment
37%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 140℃; for 0.333333h;Microwave;	<strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> a (2.0 g, 12.3 mmol), tetrakis(triphenylphosphine)palladium (696 mg, 0.6 mmol), phenylboronic acid (1.9 g, 15.9 mmol) and potassium carbonate (2.2 g, 15.9 mmol) were mixed in a 10 mL microwave vial under N2 atmosphere. DMF (6 mL) and deoxygenated H2O (1.2 mL) were added. N2 was bubbled through the mixture for 5min and the mixture was heated for 20min at 14O0C in the microwave. The mixture was diluted with water (30 mL) and extracted with EtOAc (3x20 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried with MgSO4, filtered and concentrated. The resulting brown oil was adsorbed on silica gel and purified by flash chromatography (SiO2, 0% to 70% ethyl acetate/hexanes) to afford 970 mg (37%) of b as a colorless oil. MS: m/z = 205 (M+H).
37%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 140℃; for 0.333333h;Microwave irradiation;	Example 15 7-phenyl-2-((S)-pyrrolidin-2-yl)thiazolo[5,4-c]pyridine <n="82"/><strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> a (2.0 g, 12.3 mmol), tetrakis(triphenylphosphine)palladium (696 mg, 0.6 mmol), phenylboronic acid (1.9 g, 15.9 mmol) and potassium carbonate (2.2 g, 15.9 mmol) were mixed in a 10 mL microwave vial under N2 atmosphere. DMF (6 mL) and deoxygenated H2O (1.2 mL) were added. N2 was bubbled through the mixture for 5min and the mixture was heated for 20min at 1400C in the microwave. The mixture was diluted with water (30 mL) and extracted with EtOAc (3x20 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried with MgStheta4, filtered and concentrated. The resulting brown oil was adsorbed on silica gel and purified by flash chromatography (SiO2, 0% to 70% ethyl acetate/hexanes) to afford 970 mg (37%) of b as a colorless oil. MS: m/z = 205 (M+H).

Reference： [1]Patent: WO2007/106192,2007,A2 .Location in patent: Page/Page column 57
[2]Patent: WO2008/134679,2008,A1 .Location in patent: Page/Page column 80-81
[3]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2229 - 2233

11
[ 22889-78-7 ]
[ 463-71-8 ]
[ 1000709-58-9 ]

Yield	Reaction Conditions	Operation in experiment
31%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 73h;	Intermediate 14: 3,5-Dichloro-4-isothiocyanato-pyridine To a solution of <strong>[22889-78-7]3,5-dichloro-pyridin-4-ylamine</strong> (1.7 g, 10 mmol), iPr2NEt (2.7 g, 20 mmol) in CH2Cl2 was added thiophosgene (1.2 g, 10 mmol) at 0 C. After 1 h, the solution was allowed to warm to rt and stirred for 72 h. The resulting solution was concentrated and the crude residue was purified by FCC to afford a yellow solid (640 mg, 31%). MS (ESI): mass calcd. for C6H2Cl2N2S, 203.9; m/z found, 204.0 [M+H]+.
		3,5-Dichloro-4-isothiocyanatopyridine To a solution of <strong>[22889-78-7]3,5-dichloropyridin-4-amine</strong> (4.0 g, 24.53 mmol) in DCM (20 mL), was added N-ethyl di-isopropyl amine (6.3 g, 48.83 mmol). The reaction mixture was stirred at RT for 30 minutes. The reaction mixture was cooled at 0 C. and thiophosgene (2.76 g, 24.00 mmol) was added drop wise. The reaction mixture was stirred at 0 C. to RT for 3-4 h. The reaction mixture was diluted with DCM and the obtained crude was purified by column chromatography to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): delta 8.77 (s, 2H); MS [M+H]+: 205.20.
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	General procedure: N, N-Diisopropylethylamine (1.86 g, 18.41 mmol) was added slowly to a stirred solution of 2, 6-dichloroaniline (2 g, 12.34 mmol) in DCM (25 mL) at room temperature and then cooled to 0 oC. Then, thiophosgene (11.4 g, 13.55 mmol) was added dropwise at that temperature and further stirred at room temperature for 3-4 h. After the reaction completion, the reaction mixture was diluted with water and extracted with DCM. The organic portion was dried over Na2SO4, concentrated and purified by flash column using 5% EtOAc in hexane to afford 1, 3-dichloro-2-isothiocyanatobenzene (1.75 g) in 70% yield.

Reference： [1]Patent: US2008/4253,2008,A1 .Location in patent: Page/Page column 14
[2]Patent: US2012/108583,2012,A1 .Location in patent: Page/Page column 22-23
[3]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 5131 - 5138

12
[ 20511-15-3 ]
[ 22889-78-7 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1950,vol. 69,p. 673,690

13
[ 55934-00-4 ]
[ 22889-78-7 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1950,vol. 69,p. 673,690

14
C₁₅H₁₁ClO₃ [ No CAS ]
[ 22889-78-7 ]
3,5-dichloro-4-(4-ethoxy-dibenzo[b,d]furan-1-yl-carboxamido)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With sodium hydride; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at -10℃; for 0.5h;	To a stirred and cooled (-10 C) suspension of 60 % sodium hydride (58 mg, 1.4 mmol) in DMF (3 ml) was added <strong>[22889-78-7]3,5-dichloro-4-aminopyridine</strong> (120 mg, 0.70 mmol) and the mixture was stirred for 30 min. The acid chloride, prepared from intermediate 58 (150 mg 0.58 mmol) in THF (5 ml) was added to the reaction mixture in one portion and the mixture was further stirred at the same temperature for 30 min. The reaction mixture was quenched with ice-cold water (25 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with 1N HC1 (20 ml), water (20 ml), brine (20 ml) and dried (NA2SO4). The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 50 % ethyl acetate in petroleum ether to give 85 mg (36 %) of the product as white solid, mp 289-292 C ; IR (KBr) 3207, 2928,1665, 1488,1281 CM-I.'H NMR (300 MHz, CDC13) 8 1.61 (t, J= 6.9 Hz, 3 H), 4. 38 (q, J= 6.9 Hz, 2 H), 7.02 (d, J = 8.7 Hz, 1 H), 7.30 (t, J= 8.2 Hz, 1 H), 7.49 (t, J= 8.2 Hz, 1 H), 7.62 (s, 1 H), 7.66 (d, J = 8.2 Hz, 1 H), 7.76 (d, J= 8.7 Hz, 1 H), 8.50 (d, J = 8. 2 Hz, 1 H), 8.58 (s, 2 H).

Reference： [1]Patent: WO2004/37805,2004,A1 .Location in patent: Page 134-135

15
[ 22889-78-7 ]
[ 189306-94-3 ]
[ 720716-22-3 ]

Yield	Reaction Conditions	Operation in experiment
16.7%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 12.5h;	To a stirred suspension of 50 mg (1.25 mmol) of sodium hydride in 5 ML of THF, 100 mg (0. 62 MMOL) OF 4-AMINO-3, 5-DICHLOROPYRIDINE in 5 mi of THF was added. The mixture was allowed stirring 30 minutes at room temperature and then cooled to 0C. 150 mg (0. 52 MMOL) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3 (2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997,40, 1417) in 10 ml of THF was added. The reaction was allowed to warm to room temperature and to continue stirring for 12 hours. The mixture was acidified with 2N HCI to pH 2. Ethyl acetate was added and the organic layer was washed with water, brine, dried over NA2SO4 anhydride and evaporated. The residue obtained (210 mg) was purified by column chromatography (SILICA GEL, HEXANE/ETHYL acetate 1: 1) to yield the title compound (35 mg, 16.7 % yield).

Reference： [1]Patent: WO2004/58729,2004,A1 .Location in patent: Page 38; 127

16
[ 22889-78-7 ]
Potassium salt of 4-amino-3, 5-dichloropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In DMF (N,N-dimethyl-formamide); at 15 - 30℃;	A reaction vessel is charged with DMF and 4-amino-3, 5-dichloropyridine (1 equivalent). While stirring vigorously, potassium tert-butoxide (0.8-1. 1, preferably 0.9-1. 0 equivalent) is added in portions at a temperature between 15 and 30C. A suspension of the potassium salt of the anion of 4-amino-3,5- DICHLOROPYRIDINE is obtained and is employed without further purification for the subsequent coupling step.

Reference： [1]Patent: WO2004/80967,2004,A1 .Location in patent: Page 9
[2]Patent: WO2004/80967,2004,A1 .Location in patent: Page 10
[3]Patent: WO2004/80967,2004,A1 .Location in patent: Page 10
[4]Patent: WO2004/80967,2004,A1 .Location in patent: Page 9
[5]Patent: WO2004/80967,2004,A1 .Location in patent: Page 10

17
[ 22889-78-7 ]
[ 672883-68-0 ]
[ 162401-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; at 0℃; for 0.5h;	The product obtained from Example 2 (LOG) was heated with thionyl chloride (5.8g) and catalytic amount of dimethylformamide (0. 5ml) at 80 to 85C for 1 hour. The solution was evaporated in vacuo and the oily residue was dissolved in dry tetrahydrofuran (50 ml). This was added dropwise at 0C to a suspension prepared from sodium hydride (3.75 g, 60% suspension) and 4-amino-3, 5-dichloro pyridine (9. 5G) in dry tetrahydrofuran (50 ml) with stirring. The reaction mixture was stirred for 30 minutes and then acidified to pH 2 with hydrochloric acid (1 N). The reaction mixture was extracted with ethyl acetate. The extracted solvent was washed with sodium bicarbonate solution (5%) and water followed by evaporation in vacuum. The residue was dissolved in methanol (45 ml) at 60C and 5 ml of water was added to get precipitate. The mixture was then cooled to 10C and filtered to obtain roflumilast. Yield: 9.2 g Purity: 99% m. p.: 157-158C
		In a clean reaction vessel, tetrahydrofuran (5 vol. with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was taken and to this 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid (1 eq) was added under stirring to get a clear solution. To this thionyl chloride (1.5 eq with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was added drop wise at 20-25 C. and stirred for 30 min at 40-45 C. Thionyl chloride was distilled out at 40-45 C. to get an oil. This was swapped with tetrahydrofuran. In another flask sodium hydride (2.4 eq with respect to to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was taken in THF (5 vol. with respect to to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid). To this 4-amino 3,5 Dichloropyridine (1.2 eq with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was added and stirred for 30 minutes. The above obtained acid chloride was dissolved in tetrahydrofuran (5 vol. with respect to to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) and added dropwise to the above prepared mixture of 4-amino 3,5 Dichloropyridine and sodium hydride at a temperature below 30 C. The above reaction mixture was stirred for 1 hr at 20-25 C. To this EtOAc was added followed by the addition of water. EtOAc layer was separated and the aqueous layer was extracted with EtOAc. Combined EtOAc layer was washed with 10% HCl and then with 10% aq. NaOH solution. This was washed with water and ethyl acetate and distilled out at 45 50 C. to get a light yellow colored solid. To this isopropanol was added and heated to reflux until a clear solution was obtained. The solution was cooled to 20-25 C. slowly and maintained at 20-25 C. for 1 hour. The solid was filtered and washed with isopropanol to get crude Roflumilast.

Reference： [1]Patent: WO2005/26095,2005,A1 .Location in patent: Page/Page column 7
[2]Research on Chemical Intermediates,2013,vol. 39,p. 2107 - 2113
[3]Patent: US2014/275551,2014,A1 .Location in patent: Paragraph 0055

18
[ 22889-78-7 ]
[ 91872-02-5 ]

Yield	Reaction Conditions	Operation in experiment
	With peracetic acid; In chloroform; at 20℃; for 48h;	Example 25; 3,5-dichloro-4-(6-difluoromethoxybenzo[4,5]furo[2,3-d]pyridazine-9-ylcarboxamido)-1-pyridiniumolate; Step 1: 4-amino-3,5-dichloro pyridine-N-oxide; To a solution of 4-amino-3,5-dichloro pyridine (5.0 gm, 0.0306 moles) in chloroform (100 mL) was added 20% peracetic acid solution (200 ml, 0.597 moles) (20% peracetic acid was prepared as per Vogel's Practical Organic Chemistry, Vol. V, page no. 458). Reaction mixture was then stirred at room temperature for 48 hrs, cooled to 5-10 C. and quenched with sodium sulphite till iodide test disappeared. Chloroform as well as acetic acid was removed under reduced pressure. The residue obtained was purified on silica gel column using 5% methanol in chloroform as an eluent to give product as light yellow solid.Yield: 1.7 g.
	With peracetic acid; In chloroform; at 20℃; for 48h;	To a solution of 4-amino-3,5- dichloro pyridine (5.0gm, 0.0306 moles) in chloroform (100 mL) was added 20% peracetic acid solution (200 ml, 0.597 moles) (20% peracetic acid was prepared as per Vogel's Practical Organic Chemistry, Vol. V, page no. 458). Reaction mixture was then stirred at room temperature for 48 hrs, cooled to 5-lOoC and quenched with sodium sulphite till iodide test disappeared. Chloroform as well as acetic acid was removed under reduced pressure. The residue obtained was purified on silica gel column using 5% methanol in chloroform as an eluent to give product as light yellow solid.Yield: 1.7g

Reference： [1]Patent: US2009/306082,2009,A1 .Location in patent: Page/Page column 45
[2]Patent: WO2006/64355,2006,A2 .Location in patent: Page/Page column 98

19
[ 22889-78-7 ]
[ 1027054-25-6 ]
C₂₁H₁₉Cl₂N₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at -10 - 0℃;Inert atmosphere;	Step 9: 2-ethyl-5-(4-nitrophenyl)-8-methoxy-1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridine-2,5-dicarboxylate; A suspension of 2-ethyl-5-(4-nitrophenyl)-8-methoxy-1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridine-2,5-dicarboxylate (from step 8) (100 mg, 0.218 mmol) and 4-amino-3,5-dichloro pyridine (60 mg, 0.371 mmol) in dimethyl formamide (5 ml) was cooled to -10-0 C. under nitrogen Then sodium hydride (13 mg, 0.328 mmol) was added at once at the same temp. Under nitrogen. Progress of reaction was monitored by TLC. At the end, reaction mixture was cooled to 0-10 C. Water (25 ml) was added drop wise to the reaction mixture at 0-10 C. and acidified with dilute HCl. The precipitate obtained was filtered and dried in oven. The solid was purified by isopropanol leaching to pure product 80 mg. m.p.-decomposes above 270 C.IR (KBr): 3205, 2982, 1672, 1556, 1497, 1485, 1338, 1287, 1259, 1181, 1122, 1087, 1030, 946, 879 cm-1.1H nmr (300 MHz, DMSO-d6) delta 1.1 (t, 3H), 2.74 (t, 2H), 3.60 (t, 2H), 3.98 (s, 3H), 4.05 (q, 2H), 4.71 (s, 2H), 7.01 (d, 1H, J=9.0 Hz), 7.65 (d, 1H, J=9.0 Hz), 8.73 (s, 2H) 10.80 (s, 1H).
	With sodium hydride; In N,N-dimethyl-formamide; at -10 - 10℃;	A suspension of 2-ethyl-5-(4-nitrophenyl)-8-methoxy- 1,2,3,4- tetrahydrobenzo[4,5]thieno [2,3-c]pyridine-2,5-dicarboxylate (from step 8) (100 mg, 0.218 mmol) and 4-amino-3, 5-dichloro pyridine (60 mg, 0.371mmol) in dimethyl formamide (5 ml) was cooled to -10-00C under nitrogen .Then sodium hydride (13 mg, 0.328 mmol) was added at once at the same temp. Under nitrogen. Progress of reaction was monitored by TLC. At the end, reaction mixture was cooled to 0-100C. Water (25 ml) was added drop wise to the reaction mixture at 0-100C and acidified with dilute HCl. the precipitate obtained was filtered and dried in oven. The solid was purified by isopropanol leaching to pure product 80 mg. m.p. - decomposes above 27O0C.IR (KBr): 3205, 2982, 1672, 1556, 1497, 1485, 1338, 1287, 1259, 1181, 1 122, 1087, 1030, 946, 879 cm"1;1H nmr (300 MHz, DMSOd6) delta 1.1 (t, 3H), 2.74(t, 2H), 3.60 (t, 2H), 3.98(s, 3H), 4.05(q, 2H), 4.71(s, 2H), 7.01 (d, IH, J = 9.0 Hz),7.65 (d, IH, J = 9.0 Hz), 8.73(s, 2H) 10.80(s, I H).

Reference： [1]Patent: US2009/306082,2009,A1 .Location in patent: Page/Page column 32
[2]Patent: WO2006/64355,2006,A2 .Location in patent: Page/Page column 67

20
[ 22889-78-7 ]
[ 893555-33-4 ]
tert-butyl 5-(3,5-dichloro-4-pyridylcarbamoyl)-8-methoxy-1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at -10 - 0℃;Inert atmosphere;	Step 3: tert-butyl 5-(3,5-dichloro-4-pyridylcarbamoyl)-8-methoxy-1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridine-2-carboxylate A suspension of 2-(tert-butyl)-5-(4-nitrophenyl)-8-methoxy-1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridine-2,5-dicarboxylate (from step 2) (110 mg, 0.250 mmol) and 4-amino-3,5-dichloro pyridine (69 mg, 0.427 mmol) in dimethylformamide (5 ml) was cooled to -10-0 C. under nitrogen. Then sodium hydride (15 mg, 0.377 mmol) was added at once at the same temp. Under nitrogen. Progress of reaction was monitored by TLC. At the end, reaction mixture was cooled to 0-10 C. Water (25 ml) was added dropwise to the reaction mixture at 0-10 C. and acidified with dilute HCl. the precipitate obtained was filtered and dried in oven. And purified in chloroform: ethyl acetate (10%) to get pure product 90 mg buff colored solid was obtained IR (KBr): 3435, 3012, 2929, 2853, 1666, 1553, 1480, 1423, 1366, 1280, 1252, 1164, 1092, 1025, 868 cm-1. 1H nmr (300 MHz, DMSO-d6) delta 1.2 (s, 9H), 2.89 (t, 2H), 3.60 (t, 2H), 4.02 (t, 3H), 4.70 (s, 2H), 7.05 (d, 1H, J=9.0 Hz), 7.69 (d, 1H, J=9.0 Hz), 8.78 (s, 2H), 10.84 (s, 1H).
	With sodium hydride; In N,N-dimethyl-formamide; at -10 - 10℃;	A suspension of 2-(tert-butyl)-5-(4-nitrophenyl)-8-methoxy-l ,2,3,4-tetrahydrobenzo [4,5] thieno[2,3-c] pyridine-2,5-dicarboxylate (from step 2) (1 10 mg, 0.250mmol) and 4-amino-3,5-dichloro pyridine (69 mg, 0.427mmol) in dimethylformamide (5 ml) was cooled to -10-00C under nitrogen .Then sodium hydride (15 mg, 0.377mmol) was added at once at the same temp. Under nitrogen. Progress of reaction was monitored by TLC. At the end, reaction mixture was cooled to 0-100C. Water (25 ml) was added dropwise to the reaction mixture at 0-100C and acidified with dilute HCl. the precipitate obtained was filtered and dried in oven. . And purified in chloroform: ethyl acetate (10%) to get pure product 90 mg buff colored solid was obtained IR (KBr): 3435, 3012, 2929, 2853, 1666, 1553, 1480, 1423, 1366, 1280, 1252, 1 164, 1092, 1025, 868 cm"1;1H nmr (300 MHz, DMSO-d6) deltal .2(s, 9H), 2.89(t, 2H), 3.60(t, 2H), 4.02(t, 3H), 4.70 (s, 2H), 7.05(d, IH, J= 9.0 Hz), 7.69(d, IH, J= 9.0 Hz), 8.78(s, 2H), 10.84(s, IH).

Reference： [1]Patent: US2009/306082,2009,A1 .Location in patent: Page/Page column 33
[2]Patent: WO2006/64355,2006,A2 .Location in patent: Page/Page column 69

21
[ 22889-78-7 ]
[ 893555-48-1 ]
tert-butyl 9-(3,5-dichloro-4-pyridinylcarbamoyl)-6-methoxy-5-methyl-1,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 0℃;	Step 6: tert-butyl 9-(3,5-dichloro-4-pyridinylcarbamoyl)-6-methoxy-5-methyl-1,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carboxylate; A mixture of 2-tert-butyl 9-(4-nitrophenyl) 6-methoxy-5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-9-dicarboxylate (from step 5) (0.0006 mol) and <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> (0.0007 mol) in dry DMF (10 ml) was stirred at 0 C. for 20 min. to that solution was added sodium hydride (0.0018 mol) and stirred for 1 h. Reaction was quenched in water to get yellow suspension, 1N HCl was added slowly to get white solid which was filtered washed with water and dried.1H-nmr (DMSO-d6): delta 10.47 (1H, s, exchanged with D2O), 8.75 (2H, s), 7.48 (1H, d, J=8.1 Hz), 6.77 (1H, d, J=8.1 Hz), 4.47 (2H, bs), 3.96 (3H, s), 3.89 (3H, s), 3.68 (2H, t), 2.77 (2H, t), 1.38 (9H, s).IR (KBr): 2976, 2932, 1697, 1661, 1556, 1568, 1479, 1246, 1167, 1054, 769 cm-1.Melting Point: 226 C.
		A mixture of 2-t°lambdaV-butyl 9-(4-nitrophenyl) 6-methoxy-5-methyl-l,3,4,5-tetrahydro- 2H-pyrido [4, 3-b] indole-9-dicarboxylate (from step 5) (0.0006 mol) and 4-amino- 3,5-dichloropyridine (0.0007 mol) in dry DMF (10 ml) was stirred at 00C for 20 min. to that solution was added sodium hydride ( 0.0018 mol) and stirred for Ih. Reaction was quenched in water to get yellow suspension, IN HCl was added slowly to get white solid which was filtered washed with water and dried. EPO <DP n="78"/>Eta-nmr (DMSO-d6): delta 10.47 (IH, s, exchanged with D2O), 8.75 (2H, s), 7.48 (IH, d, J= 8.1Hz), 6.77 (IH, d, J= 8.1Hz), 4.47(2H, bs), 3.96 (3H, s), 3.89 (3H, s), 3.68 (2H, t), 2.77 (2H, t), 1.38 (9H, s).IR (KBr): 2976, 2932, 1697, 1661, 1556, 1568, 1479, 1246, 1167, 1054, 769 cm"1. Melting Point: 2260C.

Reference： [1]Patent: US2009/306082,2009,A1 .Location in patent: Page/Page column 35-36
[2]Patent: WO2006/64355,2006,A2 .Location in patent: Page/Page column 75-76

22
[ 22889-78-7 ]
[ 893555-60-7 ]
N-(3,5-dichloropyridin-4-yl)-2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 0℃;	Step 9: N-(3,5-dichloropyridin-4-yl)-2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetra hydro[1]benzofuro[2,3-c]pyridine-5-carboxamide To a solution of 4-amino-3,5-dichloro pyridine (0.125 g, 0.765 mmol) in dry DMF, sodium hydride (0.0162 g, 0.675 mmol) was added at 0 C. followed by 4-nitrophenyl 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylate (0.197 g, 0.45 mmol). Water was added to RM. Solid filtered out and purified on Silica Gel column with CHCl3: EtOAc to yield N-(3,5-dichloropyridin-4-yl)-2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxamide. 1H-nmr (DMSO-d6): 1.20 (t, 3H, J=6.9 Hz), 2.74 (br s, 2H), 3.64 (t, 2H), 4.01 (s, 3H), 4.095 (q, 2H, J=7.1 Hz), 4.63 (br s, 2H), 7.08 (d, 1H, J=8.1 Hz), 7.73 (d, 1H, J=8.4 Hz), 8.758 (s, 2H), 10.639 (s, 1H). IR (KBr)(cm-1):-3344, 3019, 2980, 1696, 1665, 1484, 1261, 1223.
	With sodium hydride; In N,N-dimethyl-formamide; at 0℃;	To a solution of 4-amino-3,5-dichloro pyridine (0.125 g, 0.765 mmol) in dry DMF, sodium hydride (0.0162 g, 0.675 mmol) was added at 0 0C followed by 4-nitrophenyl2-(ethoxycarbonyl)-8-methoxy- 1 ,2,3,4-tetrahydro[ 1 ]benzofuro[2,3-c]pyridine-5- carboxylate (0.197 g, 0.45 mmol). Water was added to RM. Solid filtered out and purified on Silica Gel column with CHCl3: EtOAc to yield N-(3,5-dichloropyridin-4- yl)-2-(ethoxycarbonyl)-8-methoxy-l,2,3,4-tetrahydro[l]benzofuro[2,3-c]pyridine-5- carbox amide.Eta-nmr (OMSO-d6): 1.20 (t, 3H, J = 6.9Hz), 2.74 (br s, 2H), 3.64 (t, 2H), 4.01 (s,3H), 4.095 (q, 2H, J= 7.1 Hz), 4.63 (br s, 2H), 7.08 (d, IH, J= 8.1 Hz), 7.73(d, IH, J= 8.4 Hz), 8.758 (s, 2H), 10.639(s, IH).IR (KBr) (cm"1):- 3344, 3019, 2980, 1696, 1665, 1484, 1261, 1223.

Reference： [1]Patent: US2009/306082,2009,A1 .Location in patent: Page/Page column 39
[2]Patent: WO2006/64355,2006,A2 .Location in patent: Page/Page column 84

23
[ 22889-78-7 ]
[ 893555-73-2 ]
N-(3,5-dichloropyridin-4-yl)-2,9-dimethyl-8-methoxy-1-oxo-1,2,3,4-tetrahydro-β-carboline-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydride; at 20℃; for 18h;	Step 7: N-(3,5-dichloropyridin-4-yl)-2,9-dimethyl-8-methoxy-1-oxo-1,2,3,4-tetrahydro-beta-carboline-5-arboxamide To a solution of p-nitrophenyl ester (from step 6) (1 mmol) and <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> (1.2 mmol), NaH (1.2 mmol) was added at once and the reaction mixture was stirred for 18 h at room temperature it was then acidified with few drops of 6N HCl. Desired amide precipitated out that was filtered and dried (80-90%). 1H-nmr (DMSO-d6): 2.96 (2H, t, J=6.9 Hz); 2.99 (3H, s); 3.98 (3H, s); 4.36 (3H, s); 6.92 (1H, d, J=8.4 Hz); 7.53 (1H, d, J=8.1 Hz); 8.75 (2H, s); 10.60 (1H, s). Melting above 250 C. IR (Neat) (cm-1): 3020, 1642, 1215, 771.
	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 18h;	To a solution of /7-nitrophenyl ester (from step 6) (1 mmol) and 4-amino-3,5- dichloropyridine (1.2 mmol), NaH (1.2 mmol) was added at once and the reaction mixture was stirred for 18h at room temperature it was then acidified with few drops of 6NHC1. Desired amide precipitated out that was filtered and dried (80-90%). Eta-nmr (DMSO-(Z6): 2.96 (2H, t, J = 6.9Hz); 2.99 (3H, s); 3.98 (3H, s); 4.36 (3H, s); 6.92 (IH, d, J= 8.4Hz); 7.53 (IH, d, J= 8.1Hz); 8.75 (2H, s); 10.60 (IH, s). Melting above 25O0C. IR (Neat) (cnV1): 3020, 1642, 1215, 771.

Reference： [1]Patent: US2009/306082,2009,A1 .Location in patent: Page/Page column 41-42
[2]Patent: WO2006/64355,2006,A2 .Location in patent: Page/Page column 90

24
[ 22889-78-7 ]
[ 893555-87-8 ]
N-(3,5-dichloro-4-pyridyl)-6-difluoromethoxy-benzo[4,5]furo[3,2-c]pyridine-9-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at -5℃;	Step 18: N9-(3,5-dichloro-4-pyridyl)-6-difluoromethoxybenzo[4,5]furo[3,2-c]pyridine-9-arboxamide; To a well stirred solution of 4-Nitrophenyl 6-difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (6.0 mg, 0.015 moles) and <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> (4.9 mg, 0.030 moles) in DMF (50.0 mL) was added sodium hydride (60% dispersion in mineral oil) (900 mg, 0.0225 moles) at -5 C. and stirred for 30-40 minutes. Excess of DMF was removed under reduce pressure, the residue obtained was diluted with water (500 mL) and acidified to pH 5-6 with acetic acid. The solid obtained was filtered, washed with water and dried to afford crude product (5.6 g). Purification thorough silica gel column using 25Methanol in chloroform as eluent gave 2.7 g product as off-white solid.m.p. >250 C.IR (Neat): 3199, 1662, 1556, 1496, 1387, 1281, 1198, 1159, 1049, 999, 813, 778 cm-1.1H nmr (300 MHz, d6-DMSO): delta 7.61 (t, 1H), 7.73 (d, 1H, J=8.4 Hz), 7.95 (d, 1H, J=5.4 Hz), 8.08 (d, 1H, J=8.4 Hz), 8.75 (d, 1H, J=5.4 Hz), 8.84 (s, 2H), 9.63 (s, 1H), 11.17 (s, 1H).
	With sodium hydride; In N,N-dimethyl-formamide; at -5℃; for 0.5 - 0.666667h;	To a well stirred solution of 4-Nitrophenyl 6-difluoromethyloxybenzo[4,5]furo[3,2- c]pyridine-9-carboxylate (6.0mg, 0.015 moles) and <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> (4.9 mg, 0.030 moles) in DMF (50.0 mL) was added sodium hydride (60% dispersion in mineral oil) (900mg, 0.0225 moles) at -50C and stirred for 30-40 minutes. Excess ofDMF was removed under reduce pressure, the residue obtained was diluted with water (500 mL) and acidified to pH 5-6 with acetic acid. The solid obtained was filtered, washed with water and dried to afford crude product (5.6g). Purification EPO <DP n="98"/>thorough silica gel column using 25Methanol in chloroform as eluent gave 2.7g product as off-white solid. m.p. > 25O0C.IR (Neat): 3199, 1662, 1556, 1496, 1387, 1281, 1 198, 1 159, 1049, 999, 813, 778 cm"1.1H nmr (300 MHz, d6-DMSO): delta 7.61 (t, IH), 7.73 (d, IH, J= 8.4 Hz), 7.95 (d, IH,J = 5.4 Hz), 8.08 (d, IH, J = 8.4 Hz), 8.75 (d, IH, J = 5.4 Hz), 8.84 (s, 2H), 9.63 (s,IH), 11.17 (s, IH).

Reference： [1]Patent: US2009/306082,2009,A1 .Location in patent: Page/Page column 44
[2]Patent: WO2006/64355,2006,A2 .Location in patent: Page/Page column 96-97

25
[ 22889-78-7 ]
[ 893555-95-8 ]
[ 893555-92-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at -30 - 40℃;Inert atmosphere;	Step IV: N9-(3,5-dichloro-4-pyridyl)-6-difluoromethoxy-3-ethyl-4-oxo-3,4-dihydro benzo[4,5]furo[2,3-d]pyridazine-9-carboxamide A suspension of 4-nitrophenyl 6-difluoromethoxy-3-ethyl-4-oxo-3,4-dihydrobenzo[4,5] furo[2,3-d]pyridazine-9-carboxylate (from step iii) (81 mg, 0.18 mmol) and 4-amino-3,5-dichloro pyridine (32 mg, 0.19 mmol) in dimethyl formamide (3 ml) was cooled to -30-40 C. under nitrogen. Then sodium hydride (15 mg, 0.36 mmol) was added lotwise at the same temp. under nitrogen. Progress of reaction was monitored by TLC. At the end, reaction mixture was cooled to 0-10 C. Water (100 ml) was added dropwise to the reaction mixture at 0-10 C. and acidified with dilute HCl. The precipitate obtained was filtered and dried in oven. The solid was purified by column chromatography using 20% acetone in chloroform. 178 mg pure product was obtained as off white solid. m.p.-above 270 C. IR (KBr):-3117, 2930, 1678, 1600, 1494, 1407, 1262, 1125, 1080, 823 cm-1. 1H nmr (300 MHz, DMSO-d6):-delta 1.37 (t, 3H), 4.28 (q, 2H), 7.63 (t, 1H, J=72.6 Hz), 7.78 (d, 1H, J=8.4 Hz), 8.17 (d, 1H, J=8.4 Hz), 8.83 (s, 3H), 11.20 (s, 1H).

Reference： [1]Patent: US2009/306082,2009,A1 .Location in patent: Page/Page column 47
[2]Patent: WO2006/64355,2006,A2 .Location in patent: Page/Page column 102

26
[ 22889-78-7 ]
[ 162401-59-4 ]
[ 162401-29-8 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride In tetrahydrofuran; toluene; mineral oil	1 1. 1. N-(3,5-Dichloropyrid-4-yl)-4-difluoromethoxy-3-methoxybenzamide 6.0 g of 4-difluoromethoxy-3-methoxybenzoic acid are heated at reflux in 40 ml of toluene with 19.6 g of thionyl chloride until the evolution of gas is complete. The solution is evaporated to dryness in vacuo and the residue is dissolved in about 60 ml of dry tetrahydrofuran. This solution is added dropwise at 15°-20° C. to a suspension--prepared from 4.9 g of 4-amino-3,5-dichloropyridine and 2.0 g of sodium hydride (80% strength in mineral oil) in 60 ml of dry tetrahydrofuran--with stirring and cooling. After stirring for one hour, the reaction mixture is acidified to pH 2 with 1N hydrochloric acid, the toluene/tetrahydrofuran phase is separated off and the aqueous phase is extracted a further 2 times with ethyl acetate. The combined organic phases are washed with saturated sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated in vacuo. The residue is crystallized from isopropanol. Yield 5.8 g (58.6% of theory) of the title compound of m.p. 170° C.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US5712298, 1998, A

27
[ 22889-78-7 ]
[ 883972-05-2 ]
N₁-(3,5-dichloro-4-pyridyl)-4-methoxy-1-phenazinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at -30 - 25℃; for 50h;	Example 4; Nl-(3, 5-dichloro-4-pyridyl)-4-methoxy-l-phenazinecarboxamide; />-nitrophenyl-4-methoxy-l-phenazine carboxylate (1 equivalent) (intermediate 3), was dissolved in dry DMF under nitrogen atmosphere. 3, 5-dichloro-4-aminopyridine (1 equivalent), dissolved in dry THF was added to the reaction mixture and resulting mixture was cooled at -3O0C. To this, pre-washed suspension of 60% NaH (2 equivalent) was added at O0C with vigorous stirring and the reaction mixture was stirred at O0C for 2h and then at 250C for 48h. After completion, the reaction mixture was poured onto brine and extracted with CHCl3. The organic layer was washed with IN NaOH solution, water and brine and dried over anhydrous Na2SO4. The solvent was removed by distillation under reduced pressure to give crude compound which was column chromatographed using 20 % acetone in chloroform to give yellow solid. Yield: 35% EPO <DP n="40"/>IR (KBr):3368, 3014, 2924, 2854, 1747, 1701, 1557, 1439, 1382, 1288, 1216, 1102, 7601H NMR (300 MHz, DMSO): 4.203 (s, 3H), 7.51 (d, IH, J = 8.7 Hz), 8.095 (m, 2H), 8.39 (d, IH, J= 8.1 Hz), 8.50 (d, IH, J = 8.3 Hz), 8.793 (s, 2H), 8.879 (d, IH, J= 8.4 Hz), 13.078 (s, IH, exchanges with D2O), M+1: 399

Reference： [1]Patent: WO2006/40650,2006,A1 .Location in patent: Page/Page column 38-39

28
[ 22889-78-7 ]
[ 883977-47-7 ]
[ 685875-02-9 ]

Yield	Reaction Conditions	Operation in experiment
86 - 90%	With sodium hydride; In N,N-dimethyl-formamide; at 25 - 35℃; for 1.83333 - 1.91667h;	In a 20 L 4 necked RB flask, fitted with a mechanical stirrer, reflux condenser, add p-ntrophenyl 4-difluoromethoxy-8-nitro dibenzofuran carboxylic acid ester (700 g, 1.56M) DMF(4 L), a suspension of <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> (307g, 1.88M) in DMF (IL) at temp. 25-350C under stirring. The reaction mixture was maintained at 25-350C for 20-25 min. Cool the reaction mixture to 0-50C under stirring for 30 min, 60% sodium hydride (125 g, 3.26 M) was added at 0-50C. After addition the reaction mixture was brought to 25-350C and maintained Ih. The progress of the reaction was monitored by HPLC. After ascertaining completion of the reaction by HPLC, the reaction mixture was cooled to 10-150C and 40% brine solution (500 ml), ice cold water (5 L) was added to the reaction mixture slowly and maintained for 10 min. 10% HCl (1.5 L) was added to the reaction mass till pH becomes 4.5-5.5 and maintained at pH 4.5-5.5 for 30 min. The precipitated product was filtered, washed with water (5 L x 4). The wet cake was subjected to leaching at temp. 85-9O0C with ethylene glycol mono ethyl ether (3.5 L) for 8-10 hr under stirring. The reaction mixture was brought to 25-350C, filter, wash the cake with diethylene glycol monoethyl ether EPO <DP n="35"/>(700ml) and dried in vacuum. Oven below 7O0C till MC < 1%. The dried product appears as cream color solid, weighs about 650-67Og, yield 86-90%, purity 98%, m.p.> 270 0C. The IR (KBr) spectrum shows 3146 cm-1 (CH, str) 1674 cm-1 (CONH str) 1340 (NO2 str) The IH NMR (DMSO d6) spectrum shows delta 8.0 (s, IH), 7.6 (s,lH), 8-9 (s,lH), 8.2 (s, 2H), 8.0 (s,lH), 7.6 (s,lH), 7.3 (s,lH). The CI mass spectrum shows m/z 468(M+).The elemental analysis shows calculated % C, 48.74%, % H 1.94; % N 8.97; observed % C, 48.64%, % H 1.86; % N 8.76.

Reference： [1]Patent: WO2006/40652,2006,A2 .Location in patent: Page/Page column 16; 23; 33-34

29
[ 22889-78-7 ]
[ 1006612-69-6 ]
[ 1006612-25-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With water; sodium hydride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at -5 - 25℃; for 4h;	153 mg (4.46 mmol) of NaH (60% in oil) were suspended in 1 ml of DMF and a solution of 873 mg (5.3 mmol) <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> in 2 ml DMF were added. The suspension was stirred at 250C for 3 hours. In parallel, a solution of 260 mg (0.26 mmol) of the product of example 11, step B, 153 mg (0.8 mmol) EDC and 78 mg (0.58 mmol) HOBt in 5 ml DMF was stirred for 1 hour at 250C. This solution was then added at -5 to O0C to the solution of <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> prepared above. The mixture was stirred at this temperature for 10 minutes and the reaction was quenched with 1 ml of water and the pH of the mixture was adjusted to pH 7-8 with aqueous HCl 2N. The mixture was concentrated and the residue was purified by preparative HPLC (Column: Purospher Star RP-18e, 5 mum, 125x25 mm flow: 25mL/min; detection: 254nm; mobile phase A: water + 0.01% formic acid; mobile phase B: acetonitrile; gradient: linear from 20% to 60% acetonitrile in lOmin; 5 min with 60% acetonitrile) to give 210 mg (70%) of the desired product as a white solid.1H-NMR (DMSO-d6): 10.68 (s, IH); 8.70 (t, 2H); 8.31 (s, IH); 8.24 (s, IH); 6.97 (t, 2H); 5.15 (m, IH); 4.85 (m, IH); 4.72 (m, IH); 4.62 (m, IH); 4.40 (m, 3H); 4.00 (m, IH); 3.66 (m, IH); 3.58 (t, 2H); 2.40 (s, 6H); 1.80 (m, 2H); 1.65 (m, 2H); 1.51 (m, 3H); 1.40 (s, 3H); 1.29 (s, 3H); 1.05-1.20 (m,16H); 1.00 (d, 3H); 0.93 (d, 3H); 0.73 (t, 3H). MS: accurate mass (ESI): 1152.4906 Da.

Reference： [1]Patent: WO2008/17696,2008,A1 .Location in patent: Page/Page column 60

30
[ 22889-78-7 ]
[ 1006612-51-6 ]
[ 1006612-52-7 ]

Yield	Reaction Conditions	Operation in experiment
96%		10.8 g (52.4 mmol) DCC and 5.0 g (37 mmol) HOBt were added to a solution of 8.7 g (26.3 mmol) of the product of example 7 step C in 150 ml DCM under an atmosphere of nitrogen and the mixture was stirred at 4O0C for 2 hours. The suspension was filtered and the filtrate was concentrated in vacuo. The resulting product was purified by column chromatography on silica gel (hexane/ethyl acetate 8/1) to give 8.5 g of a white solid. A solution of 4 g (8.9 mmol) of this white solid in 40 ml dry THF was added drop wise to a suspension of 1.6 g (9.8 mmol) 4-amino-3,5-dichloro-pyridine and 822 mg (35.8 mmol) NaH (60% in oil) in THF, which has been stirred at room temperature for 1.5 hours. The resulting mixture was stirred at 3O0C for 2 hours and then quenched with water. The mixture was extracted with 2 x 100 ml of ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by column chromatography on silica gel to give 4.1 g (96%) of the desired product as white solid. 1H-NMR (DMSO-d6): 8.47 (s, 2H); 8.39 (s, IH); 7.43 (d, IH); 7.26-7.17 (m, 5H); 6.88 (d, IH,); 4.38 (s, 2H); 3.92 (s, 3H); 3.84 (s, 3H); 3.54 (t, 2H); 3.08 (t, 2H); 2.09 (q, 2H).

Reference： [1]Patent: WO2008/17696,2008,A1 .Location in patent: Page/Page column 49

31
[ 162401-62-9 ]
[ 22889-78-7 ]
[ 162401-32-3 ]

Yield	Reaction Conditions	Operation in experiment
95%		2, 4, 6-trinitrochlorobenzene (294 g) was dissolved in 2 L of dioxane, <strong>[162401-62-9]3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid</strong> (258 g) was added to the above solution, stirred and cooled to 20~35C. Pyridine (160 g) was added dropwise to the above system, and stirred for 3 h. The starting material <strong>[162401-62-9]3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid</strong> was essentially disappeared by TLC analysis. 3,5-Dichloro-4-aminopyridine (164 g) was added dropwise to the reaction solution, and mixed for 2h. The completion of the reaction was analysed by TLC, filtered and the filtrate was washed with saturated NaHCO3 solution and saturated NaCl solution,dried, filtered and decompressed at 45 C to obtain the final product of roflumilast 270 g. The yield was 95% and the purity was 99.5%.
91%		22. 8g (130mmol) 2- chloro-4,6-dimethoxy-1,3,5-triazine was dissolved into 250mL of methylene chloride 15.2 g (150mml) N- methyl morpholine, the reaction mixture was stirred mixture of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid25. 8g (lOOmmol) was added to the methylene chloride solution, and incubated with stirring at 0~10 C, the addition was completed, stirring was continued at room temperature for 3h, TLC analysis of <strong>[162401-62-9]3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid</strong> disappeared 3,5-dichloro-4-aminopyridine 17.1g (105mmol) was dissolved in 100L of dichloromethane was added dropwise to the reaction mixture was added dropwise, stirring was continued for 2h, TLC analysis of the disappearance of the intermediate active ester, filtration, The filtrate was washed with saturated NaHCO3Solution, washed with saturated NaCl solution, dried over anhydrous Na2SO4Drying, filtration, pressure was lower than 45 final product roflumilast 38.8g, 96.3% yield, 98.9% purity The 10g (24.8mmol) Roflumilast crude added 50mL of acetonitrile was stirred and heated to 60-70 dissolved, 0.5g medical activated carbon, stirring, hot filtered and the filtrate was heated to slight reflux at the same temperature was added to the solution 20mL water, cooled to 50 and maintained at this temperature for 2 hours, at room temperature, and stirring was continued for 6-8 hours, the resulting crystals were collected by filtration, and the cake was washed with pure water, and dried under reduced pressure to give 9.1 roflumilast g, yield 91%, mp 157.7-158.6 , purity of 99.87% [HPLC normalization method: column HederaODS-2 (4.6mm * 150mm, 5um); mobile phase of acetonitrile - water (100: 50) detection wavelength: 215nm; column temperature was 25 ; flow rate of 1.0ml / min].
64%		At 25 C, 250ml three bottles, The compound (II) (0.1 mol, 25.8 g) was dissolved in THF (100 ml)in, Then, pivaloyl chloride (0.11 mol, 13.3 g) and Na2CO3 (0.12 mol, 12.7 g) were added, After stirring for 2 hours, A solution of 3,5-dichloro-4-aminopyridine (0.1 mol, 16.3 g) in THF (50 ml) was slowly added dropwise. After dripping, Heated to 50 C, Stirring was continued for 4 hours until the starting material 3,5-dichloro-4-aminopyridine disappeared (HPLC monitoring) Add ethyl acetate diluted after washing, The aqueous phase was extracted twice with ethyl acetate. Combine organic phase, After drying anhydrous sodium sulfate, Filtration, concentration and recrystallization gave the off-white solid flufflustast (25.6 g, 64% yield, HPLC purity: 99.5%)

58.6%

Following the disclosure provided in U. S. Patent No. 5,712, 298, 6.0 g of <strong>[162401-62-9]3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid</strong> are heated at reflux in 40 ml of toluene with 19.6 g of thionyl chloride until the evolution of gas is complete. The solution is evaporated to dryness under vacuum and the residue is dissolved in about 60 ml of dry tetrahydrofuran. This solution is added dropwise at 15-20 C. to a suspension prepared from 4.9 g of 4-amino-3, 5-dichloropyridine and 2. 0 g of sodium hydride (80% strength in mineral oil) in 60 mi of dry tetrahydrofuran, with stirring and cooling. After stirring for one hour, the reaction mixture is acidified to a pH of 2.0 with 1 N hydrochloric acid. The toluene/tetrahydrofuran phase is separated off and the aqueous phase is extracted two additional times with ethyl acetate. The combined organic phases are washed with saturated sodium hydrogen carbonate solution and water, dried over sodium sulphate, and evaporated under vacuum. The residue is crystallized from isopropanol. The yield is 5.8 g (58.6% of theory) of the 3- cyclo-propylmethoxy-4-difluoromethoxy-N- [3, 5-di-chloropyrid-4-yl]- benzamid compound having a melting point of 158C.

Reference： [1]Patent: CN104163793,2016,B .Location in patent: Paragraph 0050-0052
[2]Patent: CN105254559,2016,A .Location in patent: Paragraph 0045; 0046; 0047
[3]Patent: CN104513196,2017,B .Location in patent: Paragraph 0044; 0045; 0046; 0047; 0048; 0049; 0050-0059
[4]Patent: WO2005/41864,2005,A2 .Location in patent: Page/Page column 143-144

32
[ 389081-19-0 ]
[ 22889-78-7 ]
N-(3,5-dichloro-pyridin-4-yl)-2-(2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%		A solution of (2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetic acid (150 mg) in THF (10 ml) was combined with DMF (1 drop), and the mixture solution was combined with oxalyl chloride (0.06 ml), and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resultant residue was dissolved in THF (10 ml), and added dropwise to a suspension of <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> (100 mg) and sodium hydride (60%, in oil) (40 mg) in THF. After stirring at room temperature overnight, the reaction solution was combined with water, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and then concentrated. The resultant residue was purified by recrystallization from ethyl acetate-THF to obtain the title compound as a colorless crystal (60 mg, 28%). [0653] Melting point: 257-259 C. [0654] NMR (CDCl3) delta: 2.11 (2H, m), 2.27 (3H, m), 2.90 (2H, t, J=7 Hz), 2.99 (2H, t, J=7 Hz), 3.71 (6H, s), 6.54 (1H, s), 6,56 (2H, d, J=8 Hz), 6.86 (1H, bs), 7.06 (1H, s), 7.15 (1H, t, J=8 Hz), 7.33 (5H, m). [0655] IR(KBr): 1699, 1655, 1306, 1144 cm-1. [0656] Analysis for C25H18N2O3Cl2.0.3H2O [0657] Calcd (%): C:63.79H:3.98 N:5.95 [0658] Found (%): C:63.56H:4.10 N:5.71

Reference： [1]Patent: US2003/232809,2003,A1 .Location in patent: Page 44

33
C₁₈H₁₅ClO₃ [ No CAS ]
[ 22889-78-7 ]
3,5-dichloro-4-(4-cyclopentyloxy-dibenzo[b,d]furan-1-ylcarboxamido)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		To a stirred and cooled (-10 C) suspension of 60 % sodium hydride (50 mg, 1.4 mmol) in DMF (3 ml) was added <strong>[22889-78-7]3,5-dichloro-4-aminopyridine</strong> (100 mg, 0.70 mmol) and the mixture was stirred for 30 min. The acid chloride, prepared from intermediate 60 (150 mg, 0.50 mmol) in THF (5 ml) was added to the reaction mixture in one portion and the mixture was further stirred at the same temperature for 30 min. The reaction mixture was quenched with ice-cold water (25 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with 1N HCl (20 ml), water (20 ml), brine (20 ml) and dried (NA2SO4). The crude product was obtained after evaporation of the solvent as white solid 90 mg (40 %), mp 284-286 C ; IR (KBr) 3191,2953, 1659, 1487, 1277 CM"' ; 'H NMR (300 MHz, CDC13) 8 1.70-1. 77 (m, 2 H), 1.92-2. 00 (m, 2 H), 2.05-2. 11 (m, 4 H), 5.13 (QUINT. , J= 4.5 HZ, 1 H), 7.04 (D, J= 8.7 HZ, 1 H), 7.32 (T, J= 8.5 HZ, 1 H), 7.50 (t, J= 8.5 Hz, 1 H), 7.65 (d, J= 8.7 Hz, 1 H), 7.69 (s, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 8.53 (d, J= 8.7 Hz, 1 H), 8.60 (s, 2 H).

Reference： [1]Patent: WO2004/37805,2004,A1 .Location in patent: Page 137

34
C₁₄H₉ClO₂S [ No CAS ]
[ 22889-78-7 ]
3,5-dichloro-4-(4-methoxy-dibenzo[b,d]-thiophen-1-yl-carboxamido)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%		Sodium hydride (0.66mmols, 36 mg of 50% dispersed in oil) was added to a stirred dry DMF solution of <strong>[22889-78-7]3,5-dichloro-4-aminopyridine</strong> (0.083 g, 0.5 mmols) at-10 C. After 30 minutes dry THF (5 ml) solution of the acid chloride of intermediate 86 (0.46 mmols) was added to the reaction mixture at 0 C. The reaction mixture was stirred 3 hrs at room temperature and poured in ice-water mixture to get precipitate. The precipitated product was filtered, washed with water and dried which was further purified by silica gel column chromatography to get white solid. Yield: 0.078 g, (46 %), m. p.: 286-287 C. IR (KBr, CM-1) : 3434,3192, 2926,1665, 1567,1554, 1483,1287, 1265,1111, 1066, 1016 and 811. 84 CM-L. H-NMR : (CDC13,300 MHz, TMS, B) : 4.09 (s, 3H), 6.92 (d, 1H), 7. 38 (t, 1H), 7.47 (t, 1H), 7.63 (s, 1H), 7.78 (d, 1H), 7.88 (d, 1H), 8.52 (d, 1H) and 8.60 (s, 2H).

Reference： [1]Patent: WO2004/37805,2004,A1 .Location in patent: Page 190

35
C₁₈H₁₅ClO₂S [ No CAS ]
[ 22889-78-7 ]
3,5-dichloro-4-(4-cyclopentyloxy-dibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%		Sodium hydride (0.66 mmols, 36 mg of 50% dispersed in oil) was added to a stirred dry DMF solution of <strong>[22889-78-7]3,5-dichloro-4-aminopyridine</strong> (0.083 g, 0.5 mmols) AT-10 C. After 30 minutes dry THF (5 ml) solution of the acid chloride of intermediate 90 (0.25g, 0.8 mmols) was added to the reaction mixture at 0 C. The reaction mixture was stirred 3 hrs at room temperature and poured in ice-water mixture to get precipitate. The precipitated product was filtered a washed with water and dried which was further purified by silica gel column chromatography to yield a white solid. yield: 0.16 g ( (44%), white solid, m. p.: 285-286 C. IR (KBr, CM-1) : 3433,3198, 2955,1665, 1554,1481, 1441,1400, 1286,1262, 1167, 1104,1061, 985, and 820 'H-NMR : (CDC13+ DMSO-Do 300 MHz, TMS, 6) : 1.60-2. 04 (M, 8H), 5.05 (M, 1H), 6. 90 (d, 1H), 7.20-7. 47 (M, 2H), 7.63 (s, 1H), 7.74 (d, 1H), 7.85 (d, 1H), 8.50 (d, 1H) and 8.60 (s, 2H).

Reference： [1]Patent: WO2004/37805,2004,A1 .Location in patent: Page 190-191

36
4-methoxy-dibenzo[b,d]thiophene-1-carboxylic acid-5,5-dioxide [ No CAS ]
[ 22889-78-7 ]
3,5-dichloro-4-(4-methoxy-dibenzo[b,d]-thiophen-5,5-dioxide-1-yl-carboxamido)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%		To a solution of the 4-METHOXYDIBENZO [b, d] thiophene-l-carboxylic acid-5,5-dioxide (0.06g, 0.2 mmols) in dry DMF (2 ml) under N2 atmosphere N, N'-carbonyldiimidazole (0.039g, 0. 24 mmols) was added and this reaction mixture was stirred for 2 hrs at room temperature. This reaction mixture was then added to a stirring solution of 4-amino-3,5- dichloropyridine (0.048g, 0.29 mmols) in dry DMF (2 ml) and NaH (0.29 mmols, 0. 0IG of 50% dispersion in oil) at 0C. After the addition this reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. Ethyl acetate layer was washed with water, dried over sodium sulphate and contrated to get the crude product which was purified by silica gel. column chromatrography to to white solid product. Yield: 0.0. 27g (30 %), m. p.: 250 C (dec. ) IR (KBR, CM-1) : 3433,3267, 2927,1673, 1600,1553, 1495,1464, 1400,1305, 1281, 1161,1138, 1032,1011, 889,822, 766,749, 732 1H-NMR : (DMSO-D6, 300 MHz, TMS, B) : 4.06 (s, 3H), 7.45 (d, 1H), 7.76-7. 75 (m, 2H), 7.88 (d, 1H), 7.98 (d, 1H), 8.09 (d, 1H), 8.80 (s, 2H) and 11.28 (s, 1H)

Reference： [1]Patent: WO2004/37805,2004,A1 .Location in patent: Page 196

37
[ 22889-78-7 ]
C₁₇H₁₀F₂N₂O₂S [ No CAS ]
3,5-dichloro-4-(4-difluoromethoxy-dibenzo[b,d]-thiophen-1-yl-carboxamido)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		To a solution of intermediate 104 (0.1 g, 0.36 mmols) in dry DMF (5 ml) was added 1, 1'-carbonyldiimidazole (0.135 g, 0.882 mmols) under N2 atmosphere and reaction mixture was stirred for 2 hrs at room temperature. In another flask sodium hydride (1.10 mmols,. 052 g of 50% dispersion in oil) was added to <strong>[22889-78-7]3,5-dichloro-4-aminopyridine</strong> (0. 178 G, 1. 10 MMOLS) in dry DMF at room temperature and stirred for 30 minutes under nitrogen. To this reaction mixture the above imidazole INTERMEADIATE reaction mixture was added dropwise. After addition the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and ethyl acetate layer washed with water, brine and concentrated under vacuo to give the crude product which was purified by column chromatography. Yield: 0.1 g (85 %) white solid, M. P.: 249-251C IR (KBr, CM-1) : 3433,3183, 2927,1661, 1556,1499, 1483,1402, 1386,1286, 1254, 1124,1091, 1066,1049, 822,757 and 715. LH-NMR : (CDC13, 300 MHz, TMS, B) : 6.74 (t, J=72.6 Hz, 1H), 7.27 (d, 1H), 7.41 (t, 1H), 7.50 (t, 1H), 7.72 (fused s, 1H), 7.73 (fused d, 1H), 7.78 (fused d, 1H), 8.46 (d, 1H) and 8.60 (s, 2H).

Reference： [1]Patent: WO2004/37805,2004,A1 .Location in patent: Page 197

38
[ 22889-78-7 ]
[ 32315-10-9 ]
[ 1229442-28-7 ]
[ 1229442-29-8 ]

Yield	Reaction Conditions	Operation in experiment
70%		6.0 g (20.2 mmol) triphosgene was dissolved in 94 mL dichloromethane in a 500 mL flask. A filtered solution of 16.9 g of the title compound from Preparation 6 (57.5 mmol) and 8.5 mL triethylamine (60.9 mmol) in 165 mL dichloromethane was added and the mixture placed under argon atmosphere and stirred for 3 h. The mixture was evaporated to dryness and was re-evaporated twice more from tetrahydrofuran. The residue was taken up in 420 mL tetrahydrofuran and was filtered to remove triethylamine hydrochloride.Solution 2: 5.7 g sodium hydride (60% dispersion in oil, previously washed with pentane, 142 mmol) was suspended in 120 mL dry tetrahydrofuran in a 1 L flask. A solution of <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> dissolved in 140 mL tetrahydrofuran. The mixture was stirred for 2.5 h, forming a white suspension. The filtrate from solution 1 was added and the mixture stirred overnight at room temperature, precipitating a solid. The mixture was filtered, keeping both the solid and the filtrate (). The solid was dissolved in water and the solution acidified to pH 6-7 with 2M hydrochloric acid precipitating a solid. The solid was collected by filtration, washed with water, then with ether and was dried in a stream of air and then at 50 C under vacuum to give 12.2 g (44%) of the title compound. The filtrate () was evaporated to dryness. The residue was taken up in 700 mL water and acidified to pH 6-7 with 2M hydrochloric acid precipitating a solid. The solid was collected by filtration, washed with water, then with ether and was dried in a stream of air and then at 50 C under vacuum. The solid was dissolved in 500 mL hot methanol-dichloromethane (30:70) and was decolourised with activated carbon. Filtration and concentration to approx 120 mL precipitated a solid. The solid was collected by filtration, washed with methanol and was dried in a stream of air and then at 50 C under vacuum to give a further 7.2 g (26%) of the title compound. m.p. 176-178 C 1H NMR (300 MHz, DMSO-d6) ppm 9.94 (1 H, br. s.), 9.76 (1 H, s), 8.74 (2 H, s), 7.99 (1 H, s), 7.82 (1 H, d, J=8.0 Hz), 7.71 (1 H, d, J=8.0 Hz), 7.51 (1 H, t, J=7.8 Hz), 4.30 (2 H, q, J=7.1 Hz), 1.41 (3 H, t, J=7.1 Hz) HPLC/MS (15 min) retention time 10.30 min. LRMS: m/z 480/482/484 (M+1), 292/294

Reference： [1]Patent: EP2196465,2010,A1 .Location in patent: Page/Page column 26

39
[ 22889-78-7 ]
[ 890023-14-0 ]
[ 1242065-44-6 ]

Yield	Reaction Conditions	Operation in experiment
41%	With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere;	I .S-Dichloro-theta.theta-dimethyl-delta.thetay.delta-tetrahydroisoquinoline^-carbonitrile (2.Og, 7.84 mmol, see Preparation 5), 3,5-dichloropyridine-4-amine (1.5g, 9.4 mmol), potassium tert- butoxide (1.76g, 15.7 mmol), Pd2(dba)3 (72 mg, 0.08 mmol) and 1 ,3-bis(2,6- diisopropylphenyl)imidazolium chloride (67 mg, 0.16 mmol) are suspended in dioxane (30 ml) and the system is purged with argon. After heating at 1000C for 2h, the reaction mixture is poured on water and extracted with ethyl acetate. The remaining aqueous phase is acidified with 2N HCI and extracted with ethyl acetate. After usual work-up, the crude residue is purified by flash chromatography eluting with dichloromethane/methanol 98:2 and 1.23g of the final product are isolated. Yield= 41%.1H NMR (200 MHz, CHLOROFORM-cf) delta ppm 1.1 (s, 6 H) 1.7 (t, J=6.6 Hz, 2 H) 2.6 (t, J=6.6 Hz, 2 H) 2.7 (s, 2 H) 6.4 (s, 1 H) 8.5 (s, 2 H)

Reference： [1]Patent: WO2010/97172,2010,A1 .Location in patent: Page/Page column 17; 18

40
[ 22889-78-7 ]
[ 154083-41-7 ]
[ 913985-11-2 ]

Yield	Reaction Conditions	Operation in experiment
51%		Oxalyl chloride (3.0 g, 23.70 mmol) was added dropwise to a stirred solution of 3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-benzoic acid (4.1 g, 14.5 mmol) (Example 12) in dichloromethane (40 mL) and dimethylfo?namide (4 drops) at 0 0C under an inert atmosphere. The reaction mixture was then warmed to room temperature and the stirring was continued for about 2 hours. The solvent was removed by evaporation and the residue thus obtained was dissolved in dry dimethylformamide and then added dropwise to a pre- stirred suspension of <strong>[22889-78-7]3,5-dichloro-4-aminopyridine</strong> (2.96 g, 18.1 mmol) and sodium hydride (1.45 g, 36.3 mmol) in dry dimethylformamide at 0 0C under an inert atmosphere. The stirring was continued for about 30 minutes and then quenched with water. After extracting with ethyl acetate, the organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. The reaction mixture was purified using column chromatography to yield the title compound.Yield: 2.90 g (51%)

Reference： [1]Patent: WO2006/117653,2006,A1 .Location in patent: Page/Page column 50-51

41
[ 22889-78-7 ]
[ 913985-19-0 ]
N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(5-methyl-3-p-tolyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%		4-Methoxy-3-[(5-methyl-3-p-tolyl-4,5-dihydroisoxazol-5-yl)methoxy]benzoic acid (0.044 g, 0.124 mmol) (Example 28) was taken in 3-necked flask, fitted with septum, condenser under an inert atmosphere. Dry-dichloroethane (6 mL) and thionyl chloride (0.022 g, 0.19 mmol) were added. The reaction mixture was refluxed at 80 0C for about 1.5 hours. Excess of dichloroethane and thionyl chloride were removed under vacuum from the reaction mixture. In another round bottom flask, sodium hydride (0.08 g, 0.2106 moles) was taken in dry tetrahydrofuran (12 mL) at 0 0C and 3,5-dichloro-4-amino pyridine (0.03 g, 0.19 mmol) was added. After about half an hour, reaction mixture was cooled to 0 0C and the previously prepared acid chloride residue was dissolved in dry tetrahydrofuran (5 mL) and was slowly added to it at 0 0C. The reaction mixture was stirred at 0 0C to room temperature for 2 hours. Water (40 mL) was poured into reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude product was crystallized using 2% dichloromethane in hexane to yield the title compound.Yield: 15 mg (24%), m/z: 500(M++l).

Reference： [1]Patent: WO2006/117653,2006,A1 .Location in patent: Page/Page column 59

42
[ 22889-78-7 ]
[ 1044921-68-7 ]
N-(3,5-dichloro-pyridin-4-yl)-3-[3-(2-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-4-methoxy-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%		To a stirred solution of 3-[3-(2-fluorophenyl)-5-methyl-4,5-dihydroisoxazol-5- yl]methoxy}-4-methoxybenzoic acid (0.64g, 1.70 mmol) (Example 23) and triethyl amine (0.36 mL, 0.25 mmol) in dimethylformamide, isobutyl chloroformate (0.24 mL, 1.90 mmol) was added dropwise at 0 0C over a period of 5 minutes and the stirring was continued for about 1 hours at room temperature. The resulting solution was added to a suspension of 3,5 dichloro-4-amino pyridine (0.56 g, 3.40 mmol) and sodium hydride (0.17 g, 4.2 mmol, 60% w/w) in dimethylformamide at 0 0C over a period of 10 minutes under an inert atmosphere and the stirring was continued for about 1 hours at 0-50C. The reaction mixture was quenched with dilute hydrochloride solution (10%, 20 mL) and extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated to form the title compound.Yield: 0.32 g (38%), mp: 197 0C, m/z: 503.9(M+ +1)

Reference： [1]Patent: WO2006/117653,2006,A1 .Location in patent: Page/Page column 56

43
[ 22889-78-7 ]
[ 913985-23-6 ]
4-butoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%		To a stirred solution of 4-butoxy-3-[(5-methyl-3-pyridin-3-yl-4,5-dihydroisoxazol-5-yl)methoxy]benzoic acid (0.12 g, 0.31 mmol) (Example 40) and triethyl amine (0.06 mL, 0.40 mmol) in dimethylformamide (3.0 mL), isobutyl chloroformate (0.04 mL, 0.32 mmol) was added dropwise at 0 0C over a period of 5 minutes and the stirring was continued for about 1 hour at room temperature. The resulting solution was added to a suspension of 3,5 dichloro-4-amino pyridine (0.10 g, 0.62 mmol) and sodium hydride (0.026 g, 0.65 mmol, 60% w/w) in dimethylformamide (3.0 mL) at 0 0C over a period of 10 minutes under an inert atmosphere and the stirring was continued for about 1 hour at 0- 5 0C. The reaction mixture was quenched with dilute hydrochloride solution (10%, 20 mL) and extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated to form the title compound.Yield: 0.019 g (15%), m/z: 530 (M++.).

Reference： [1]Patent: WO2006/117653,2006,A1 .Location in patent: Page/Page column 63

44
[ 22889-78-7 ]
[ 913985-08-7 ]
[ 913985-09-8 ]

Yield	Reaction Conditions	Operation in experiment
27%		Oxalyl chloride (0.33 g, 2.20 mmol) was added dropwise to a stirred solution of 4- methoxy-3-(2-methyl-allyloxy)-benzoic acid (0.5 g, 2.2 mmol) (Example 5) in dichloromethane (3 rnL) and dimethylformamide (2 drops) at 0 0C. The reaction mixture was further stirred at room temperature for about 3 hours. The solvent was removed by evaporation and the residue thus obtained was dissolved in dry dimethylformamide under nitrogen atmosphere and added dropwise to the pre-stirred suspension of 3,5-dichloro-4- amino pyridine (0.36 g, 2.2 mmol) and sodium hydride (0.11 g, 4.40 mmol) in dry dimethylformamide at 00C under anhydrous condition. After completion of the reaction, the reaction mixture was acidified with dilute hydrochloric acid, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated. The residue thus obtained was purified by column chromatography to yield the title compound as white solid.Yield: 0.22 g (27%), m/z: 367.00 (M++l), 389 (M++23)

Reference： [1]Patent: WO2006/117653,2006,A1 .Location in patent: Page/Page column 47

45
[ 22889-78-7 ]
deoxygenated H₂O [ No CAS ]
[ 98-80-6 ]
[ 950224-92-7 ]
[ 149794-10-5 ]

Yield	Reaction Conditions	Operation in experiment
970 mg (37%)	With N2; potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide;	Example 10 7-phenyl-2-((S)-pyrrolidin-2-yl)thiazolo[5,4-c]pyridine 4-amino-3,5-dichloropyridine a (2.0 g, 12.3 mmol), tetrakis(triphenylphosphine)palladium (696 mg, 0.6 mmol), phenylboronic acid (1.9 g, 15.9 mmol) and potassium carbonate (2.2 g, 15.9 mmol) were mixed in a 10 mL microwave vial under N2 atmosphere. DMF (6 mL) and deoxygenated H2O (1.2 mL) were added. N2 was bubbled through the mixture for 5 min and the mixture was heated for 20 min at 140 C. in the microwave. The mixture was diluted with water (30 mL) and extracted with EtOAc (3*20 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried with MgSO4, filtered and concentrated. The resulting brown oil was adsorbed on silica gel and purified by flash chromatography (SiO2, 0% to 70% ethyl acetate/hexanes) to afford 970 mg (37%) of b as a colorless oil. MS: m/z=205 (M+H).

Reference： [1]Patent: US2011/46066,2011,A1

46
[ 22889-78-7 ]
[ 501-52-0 ]
[ 1370286-81-9 ]

Yield	Reaction Conditions	Operation in experiment
93.3%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 0.5h;	<strong>[22889-78-7]4-Amino-3,5-dichloropyridine</strong> (16.3 mg, 0.1 mmol)And hydrocinnamic acid (28.0 mg, 0.2 mmol) were dissolved in anhydrous dichloromethane(DCM, 2.0 ml).To the mixture was added EDC (43.1 mg, 0.2 mmol)And diisopropylethylamine (DIPEA, 29 mul, 0.2 mmol) were added and reacted at room temperature for 30 minutes. After the reaction,The DCM was dried using a rotary evaporator,The remaining residue is dissolved in EA (Ethyl Acetate)NaHCO2 & lt; / RTI & gt; saturated solution. The extracted EA solution was subjected to a dehydration process using sodium sulfate, filtered, and the obtained organic solvent was dried.A column using silica gel was performed to obtain a purified final product (2) with a yield of 93.3%.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 3687 - 3698
[2]Patent: KR101728898,2017,B1 .Location in patent: Paragraph 0104-0105; 0118-0119; 0142-0143

47
[ 22889-78-7 ]
[ 1009603-03-5 ]
[ 1009601-54-0 ]

Yield	Reaction Conditions	Operation in experiment
70%		General procedure: To a stirred solution of <strong>[22889-78-7]4-Amino-3,5-dichloropyridine</strong>-N-oxide (51.6 mg) in DMF (2.0 mL) was added 60% sodium hydride (23.1 mg) at 0 C. After stirring at room temperature for 30 min, the 4-nitrophenyl ester of 10 (80.0 mg) in DMF (3.00 mL) was added dropwise to the reaction mixture at 0 C. After stirring at room temperature for 3 h, the resulting mixture was added brine and extracted with EtOAc. The organic layer was washed with water followed by brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc : MeOH = 10 : 1 ) to give the title compound (51.5 mg, 64% over 2 steps) as a colorless powder.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5311 - 5316

48
[ 22889-78-7 ]
C₁₆H₁₀F₃N₃O₅ [ No CAS ]
[ 1454802-94-8 ]

Yield	Reaction Conditions	Operation in experiment
70%		General procedure: To a stirred solution of <strong>[22889-78-7]4-Amino-3,5-dichloropyridine</strong>-N-oxide (51.6 mg) in DMF (2.0 mL) was added 60% sodium hydride (23.1 mg) at 0 C. After stirring at room temperature for 30 min, the 4-nitrophenyl ester of 10 (80.0 mg) in DMF (3.00 mL) was added dropwise to the reaction mixture at 0 C. After stirring at room temperature for 3 h, the resulting mixture was added brine and extracted with EtOAc. The organic layer was washed with water followed by brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc : MeOH = 10 : 1 ) to give the title compound (51.5 mg, 64% over 2 steps) as a colorless powder. 1H-NMR (CDCl3): delta 4.30 (3H, s), 6.38 (1H, d, J = 8.0 Hz), 7.39 (1H, s), 7.66 (1H, brs), 7.96 (1H, d, J = 8.0 Hz), 8.28 (2H, s). HRMS (EI): calcd for C15H9Cl2F3N4O3 ([M]+) 420.0004, found 420.0025.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5311 - 5316

49
[ 22889-78-7 ]
[ 151103-09-2 ]
[ 1454574-39-0 ]

Yield	Reaction Conditions	Operation in experiment
73%		To a solution of IIb (30 g, 123.9 mmol, 1.0 eq) in toluene (150 mL) at 20-30 C. under N2 atmosphere were added trimethyl orthoformate (TMOF, 46.0 g, 433.7 mmol, 3.5 eq) and Amberlyst 15 wet (9.0 g, 30% w/w). The mixture was heated to reflux then kept refluxing until reaction completed. The solvent and excess TMOF were removed under reduced pressure at 50-60 C. to obtain IIIb. Toluene (150 mL) was added to the mixture and followed by the addition of IVa (21.2 g, 130.1 mmol, 1.05 eq) and TFA (2.8 g, 24.8 mmol, 0.2 eq) at a temperature of 40-50 C. The flask was connected with condenser and receiver, and the mixture was again heated to 110 C. and distillation was continued until the reaction was completed. The mixture was cooled to 50-60 C., then filtered and the solid was washed with toluene (30 mL). The filtrate was washed by saturated NaHCO3 (60 mL) and water (60 mL), respectively. The organic phase was removed under reduced pressure (30-50 mmHg). The flask was charged with 95% EtOH (150 mL) and then 75 mL of solvent was distilled under reduced pressure at 50 C. Repeatedly, 75 mL of 95% EtOH was charged to the residue then 75 mL of solvent was distilled to afford Vb in EtOH solution. The mixture was cooled to 25 C. then additional 95% EtOH was charged to the residue to 210 mL followed by H2O (90 mL) at the same temperature. The suspended solution was allowed to stirred for 30 min then cooled 0-5 C. then stirred for 1 hour. The slurry was filtered and the filter cake was washed with H2O (30 mL) and dried under reduced pressure at 40 C. for 2 hours to obtain Vb (35 g, 73% yield). MS m/z (M+1): 387.1; IR (KBr): 3000, 2940, 1635, 1550, 1270, 1550-1 cm. 1H NMR (300 MHz, CDCl3) delta 8.43 (s, 2H), 8.26 (s, 1H), 7.68 (s, 1H), 7.39-7.26 (m, 2H), 7.00-6.51 (t, 1H, J=75 Hz), 4.00 (d, 2H, J=6.9 Hz), 1.33 (m, 1H), 0.71-0.65 (m, 2H), 0.42-0.38 (m, 2H). 13C NMR (125 MHz, CDCl3) delta 165.38, 153.31, 150.98, 147.85, 144.15, 132.78, 124.23, 122.99, 122.29, 117.81 (CF2, JCF=260 Hz), 115.74 (CF2), 113.66 (CF2), 112.51, 74.01, 9.99, 3.22. 19F NMR (282 MHz, CDCl3) delta -82.24, -82.51.
23%		To a solution of lib (5.0 g, 20.6 mmol, 1.0 eq) in toluene (25 mL) were added PTSA (71 mg, 0.41 mmol, 0.02 eq) and TMOF (2.4 g, 22.6 mmol, 1.1 eq). The reaction mixture was heated to reflux for 2 hours. Then additional TMOF (2.4 g, 22.6 mmol, 1.1 eq) and PTSA (142 mg, 0.82 mmol, 0.04 eq) were added and heating was continued for 1 hour, after which the reaction was finished as assessed by TLC. The reaction temperature was lowered to 70-80C, and IVa (2.5 g, 15.3 mmol, 0.75 eq) and PTSA (142 mg, 0.82 mmol, 0.04 eq) were added. The mixture again was heated to reflux. After 15 hours, additional PTSA (355 mg, 2.05 mmol, 0.1 eq) and IVa (1.8 g, 11 mmol, 0.54 eq) were added and heating was continued for another 15 hours. Then, the mixture was cooled to room temperature and solvents were removed by evaporation. The residue was dissolved in dichloromethane and then washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgS04 and concentrated. The crude mixture was purified by column chromatography to afford 1.8 g (23% yield) of Vb as a colorless oil. 1H NMR (300 MHz, CDC13) delta 8.43 (s, 2H), 8.26 (s, 1H), 7.68 (s, 1H), 7.39-7.26 (m, 2H), 7.00-6.51 (t, 1H, J= 75 Hz), 4.00 (d, 2H, J= 6.9 Hz), 1.33 (m, 1H), 0.71-0.65 (m, 2H), 0.42-0.38 (m, 2H). 13C NMR (125 MHz, CDCl3) 6 165.38, 153.31, 150.98, 147.85, 144.15, 132.78, 124.23, 122.99, 122.29, 117.81 (CF2, JCF = 260 Hz), 115.74 (CF2), 113.66 (CF2), 112.51, 74.01, 9.99, 3.22. 19F NMR (282 MHz, CDCl3) delta - 82.24, - 82.51.
70%Chromat.	With N,O-Bis(trimethylsilyl)trifluoroacetamide; toluene-4-sulfonic acid; In acetonitrile; for 48h;Reflux;	As is evident from the embodiment, the synthesis of the compound of formula lib to the compound of formula Vb directly can be carried out with various Lewis acids in the presence of N,0-bis(trimethylsilyl)trifluoroacetamide (BSTFA). Table 2 shows the result using TMSOTf, TMSC1, PTSA, TfOH, MSA and TFA. The percentage of the convergence is observed via HPLC. The reaction is operated under conventional conditions in the presence of 0.2 equivalent of the Lewis acid. The reaction duration is from 3 to 48 hours. Table 2 Entry; Condition & materials; Vb HPLC purity 1) given respectively. IVa, BSTFA, TMSOTf, CH3CN, reflux for 3h 60%; 2). IVa, BSTFA, TMSCl, CH3CN, reflux for 24h 23%; 3). IVa, BSTFA, PTSA, CH3CN, reflux for 48h 70%; 4). IVa, BSTFA, TfDH, CH3CN, reflux for 5h 62%; 5). IVa, BSTFA, MSA, CH3CN, reflux for 20h 70%; 6). IVa, BSTFA, TFA, CH3CN, reflux for 18h 25%

Reference： [1]Patent: US2015/25246,2015,A1 .Location in patent: Paragraph 0080-0085
[2]Patent: WO2013/131255,2013,A1 .Location in patent: Paragraph 0045
[3]Patent: WO2013/131484,2013,A1 .Location in patent: Paragraph 0051

50
[ 22889-78-7 ]
[ 151103-09-2 ]
[ 162401-32-3 ]

Reference： [1]Patent: WO2013/131484,2013,A1
[2]Patent: US2015/25246,2015,A1

51
[ 22889-78-7 ]
[ 120-14-9 ]
[ 1454574-38-9 ]

Yield	Reaction Conditions	Operation in experiment
2.24 g	With toluene-4-sulfonic acid; In toluene; for 720h;Reflux;	To a solution of 3,4-dimethoxybenzaldehyde (5 g, 30 mmol, 1.2 eq.) in toluene (25 mL) were added PTSA (103 mg, 0.6 mmol, 0.02 eq.) and <strong>[22889-78-7]4-Amino-3,5-dichloropyridine</strong> (4.1 g, 25 mmol, 1.0 eq.). The reaction mixture was heated to reflux for 30 days. The mixture was cooled to room temperature and n-heptane (40 mL) was added. The precipitate was filtered, and the crude product was recrystallized from DCM/-heptane to give 2.24 g of the imine as a colorless solid. 1H NMR (300 MHz, CDCl3) delta 8.47 (s, 2H), 8.23 (s, 1H), 7.64 (s, 1H), 7.38 (d, 1H, J= 8.4 Hz), 6.98 (d, 1H, J= 8.4 Hz), 3.99 (s, 3H), 3.98 (s, 3H).
2.8 g		To a solution of 3,4-dimethoxybenzaldehyde (5 g, 30 mmol, 1.2 eq.) in toluene (25 mL) were added PTSA (103 mg, 0.6 mmol, 0.02 eq.) and TMOF (3.6 mL, 33 mmol, 1.32 eq.). The reaction mixture was heated to reflux for 2 hours and then cooled to 65 ± 5C. 4-Amino- 3,5-dichloropyridine (4.1 g, 25 mmol, 1.0 eq.) and additional PTSA (413 mg, 2 mmol, 0.08 eq.) were added and the reaction mixture was then heated to 120C and refluxed for 15 hours. The mixture was cooled to room temperature and w-heptane (40 mL) was added. The precipitate was filtered, and the crude product was recrystallized from DCM/w-heptane to give 2.8 g of the imine as a colorless solid. 1H NMR (300 MHz, CDCl3) delta 8.47 (s, 2H), 8.23 (s, 1H), 7.64 (s, 1H), 7.38 (d, 1H, J= 8.4 Hz), 6.98 (d, 1H, J= 8.4 Hz), 3.99 (s, 3H), 3.98 (s, 3H).
2.8 g		To a solution of 3,4-dimethoxybenzaldehyde (5 g, 30 mmol, 1.2 eq.) in toluene (25 mL) were added PTSA (103 mg, 0.6 mmol, 0.02 eq.) and TMOF (3.6 mL, 33 mmol, 1.32 eq.). The 15 reaction mixture was heated to reflux for 2 hours and then cooled to 65+-5 C. <strong>[22889-78-7]4-Amino-3,5-dichloropyridine</strong> (4.1 g, 25 mmol, 1.0 eq.) and additional PTSA (413 mg, 2 mmol, 0.08 eq.) were added and the reaction mixture was then heated to 120 C. and refluxed for 15 hours. The mixture was cooled to room temperature and n-heptane (40 mL) was added. The precipitate was filtered, and the crude product was recrystallized from DCM/n-heptane to give 2.8 g of the imine as a colorless solid. 1H NMR (300 MHz, CDCl3) delta 8.47 (s, 2H), 8.23 (s, 1H), 7.64 (s, 1H), 7.38 (d, 1H, J=8.4 Hz), 6.98 (d, 1H, J=8.4 Hz), 3.99 (s, 3H), 3.98 (s, 3H).

Reference： [1]Patent: WO2013/131484,2013,A1 .Location in patent: Paragraph 0050
[2]Patent: WO2013/131255,2013,A1 .Location in patent: Paragraph 0043
[3]Patent: US2015/25246,2015,A1 .Location in patent: Paragraph 0078

52
[ 22889-78-7 ]
[ 1590361-85-5 ]
[ 162401-32-3 ]

Yield	Reaction Conditions	Operation in experiment
88%		50 mL of DMSO were added to 7.58 g of 3,5-dicloropyridin-4-amine (III) (1 .2 eq) and 16.47 g of CsF (2.8 eq). The mixture was stirred at a temperature of 90C for 3 h. A suspension was obtained. A solution in DMSO of (3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)(1 H- imidazol-1 -yl)-methanone (IVa) was slowly loaded over the previous suspension for 30 min at a temperature of 90-95C. The reaction was allowed to react at this temperature for 6 h. Once the reaction was completed, 100 mL of water were added and the pH was adjusted to pH=5.0 with 1 N HCI. Product precipitation was seen and isolated by filtration. The filtered solid was washed with 100 mL of H20. The washed solid was dried in a vacuum oven for 14 h at 50C. 15.3 g of raw product were obtained and recrystallised with a mixture of isopropanol-water at 90%. The recrystallised solid was dried in a vacuum oven at 50C. 13.90 g of roflumilast were obtained (yield 88%). The X-ray diffraction diagram is consistent with that of Example 3.

Reference： [1]Patent: WO2014/60464,2014,A1 .Location in patent: Page/Page column 17

53
[ 22889-78-7 ]
[ 1601300-21-3 ]
[ 162401-32-3 ]

Yield	Reaction Conditions	Operation in experiment
79%		25 mL of DMSO were added to 3.79 g of 3,5-dicloropyridin-4-amine (III) (1 .2 eq) and 8.23 g of CsF (2.8 eq). The mixture was stirred at a temperature of 90C for 3 h. A suspension was obtained. A solution of (3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)(1 H-1 ,2,4-triazol-1 - yl)-methanone (IVb) in DMSO was slowly loaded over the previous suspension in DMSO at a temperature of 90-95C. The reaction was allowed to react at this temperature for 3 h. Once the reaction was completed, 50 mL of water were added and the pH was adjusted to pH=4.5 with 1 N HCI. Product precipitation was seen and isolated by filtration. The filtered solid was washed with 100 mL of H20. The washed solid was dried in a vacuum oven for 14 h at 50C. 6.55 g of raw product were obtained and recrystallised with a mixture of isopropanol-water at 90%. The recrystallised solid was dried in a vacuum oven at 50C. 6.15 g of Roflumilast were obtained (yield 79%). The X-ray diffraction diagram is consistent with that of Example 3.

Reference： [1]Patent: WO2014/60464,2014,A1 .Location in patent: Page/Page column 18-19

54
[ 22889-78-7 ]
[ 1422361-76-9 ]

Yield	Reaction Conditions	Operation in experiment
96.45%	With thionyl chloride; In tetrahydrofuran; toluene;	5-[5-[(3,5-dichloropyridin-4-yl)amino]carbonyl}-2-(difluoromethoxy) phenoxy]pentanoic acid 3,5-Dichloropyridin-4-amine (3.8 g, 23.3 mmol, 1.3 eq) was added in portions to a suspension of 60% NaH (1.58 g, 39.4 mmol, 2.2 eq) in anhydrous THF (50 ml) at 5 C. In a separate flask, a mixture of Intermediate 3 (6.2 g, 17.9 mmol, 1.0 eq) and SOCl2 (6.39 g, 53.7 mmol, 3.0 eq) in toluene (100 ml) was heated at 90 C. for 1.5 h. The solvent was evaporated and the yellow oily residue was dissolved in anhydrous THF (50 ml). This solution was added dropwise to the prepared suspension of <strong>[22889-78-7]3,5-dichloropyridin-4-amine</strong> and NaH in THF at 0-10 C. under N2. After stirring at 10 C. for 1 h, the yellow mixture was acidified to pH=2 with 1N HCl. The resulting mixture was extracted with EA (150 ml*2) and the solvent was evaporated under reduced pressure. The solid residue was purified by chromatography (silica gel, PE/EA from 2/1 to 1/1) to afford Compound 1 (4.5 g, 51.1% yield, 96.45% purity) as an off-white solid.

Reference： [1]Patent: US2014/187555,2014,A1 .Location in patent: Page/Page column

55
[ 22889-78-7 ]
[ 1953-99-7 ]
[ 1416419-34-5 ]

Yield	Reaction Conditions	Operation in experiment
2.6 g	With sodium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 5h;	0.60g (0.015 mol) of sodium hydroxide was added to a solution of 1.22g(0.0075 mol) of 3,5-dichloropyridin-4-amine in 40 mL of DMF, followed by addition of 2g (0.0075 mol) of 3,4,5,6-<strong>[1953-99-7]tetrachlorophthalonitrile</strong> under stirring, themixture was stirred for 5 h after addition at room temperature. After the reaction was over by Thin-Layer Chromatographymonitoring, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was washedwith water and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reducedpressure. The residue was purified through silica column (ethyl acetate/petroleum ether (boiling point range 60-90°C)= 1:4, as an eluent) to give 2.6 g of compound A-87 as yellow solid, m.p. 214-216°C.[0070] 1H-NMR (300MHz, internal standard TMS, solvent DMSO), 8.26(s, 2H, Py-2,6-2H), 11.0(br, 1H, NH).
2.6 g	With sodium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 5h;	0.60 g (0.015 mol) of sodium hydroxide was added to a solution of 1.22 g (0.0075 mol) of 3,5-dichloropyridin-4-amine in 40 mL of DMF, followed by addition of 2 g (0.0075 mol) of 3,4,5,6-<strong>[1953-99-7]tetrachlorophthalonitrile</strong> under stirring, the mixture was stirred for 5 h after addition at room temperature. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified through silica column (ethyl acetate/petroleum ether (boiling point range 60-90° C.)=1:4, as an eluent) to give 2.6 g of compound A-87 as yellow solid, m.p. 214-216° C. [0132] 1H-NMR (300 MHz, internal standard TMS, solvent DMSO), 8.26 (s, 2H, Py-2,6-2H), 11.0 (br, 1H, NH).

Reference： [1]Patent: EP2757092,2014,A1 .Location in patent: Paragraph 0068; 0069; 0070
[2]Patent: US2014/213598,2014,A1 .Location in patent: Paragraph 0130-0132

56
[ 22889-78-7 ]
[ 1897-41-2 ]
[ 1416422-20-2 ]

Yield	Reaction Conditions	Operation in experiment
2.16 g	With sodium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 5h;	0.60g (0.015 mol) of sodium hydroxide was added to a solution of 1.22g(0.0075 mol) of 3,5-dichloropyridin-4-amine in 40 mL of DMF, followed by addition of 2g (0.0075 mol) of <strong>[1897-41-2]2,3,5,6-<strong>[1897-41-2]tetrachloroterephthalonitrile</strong></strong> under stirring,the mixture was stirred for 5 h after addition at room temperature. After the reaction was over by Thin-Layer Chromatographymonitoring, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phasewas washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentratedunder reduced pressure. The residue was purified through silica column (ethyl acetate/petroleum ether (boiling pointrange 60-90°C) = 1:3, as an eluent) to give 2.16 g of compound C-124 as yellow solid, m.p. 202-204°C.[0132] 1H-NMR (300MHz, internal standard TMS, solvent CDCl3) delta(ppm): 7.28(br, 1H, NH), 8.30(s, 2H, Py-2,6-2H).
2.16 g	With sodium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 5h;	0.60 g (0.015 mol) of sodium hydroxide was added to a solution of 1.22 g (0.0075 mol) of 3,5-dichloropyridin-4-amine in 40 mL of DMF, followed by addition of 2 g (0.0075 mol) of <strong>[1897-41-2]2,3,5,6-<strong>[1897-41-2]tetrachloroterephthalonitrile</strong></strong> under stirring, the mixture was stirred for 5 h after addition at room temperature. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified through silica column (ethyl acetate/petroleum ether (boiling point range 60-90° C.)=1:3, as an eluent) to give 2.16 g of compound C-124 as yellow solid, m.p. 202-204° C. [0197] 1H-NMR (300 MHz, internal standard TMS, solvent CDCl3) delta (ppm): 7.28 (br, 1H, NH), 8.30 (s, 2H, Py-2,6-2H).

Reference： [1]Patent: EP2757092,2014,A1 .Location in patent: Paragraph 0130 - 0132
[2]Patent: US2014/213598,2014,A1 .Location in patent: Paragraph 0195-0197

57
[ 22889-78-7 ]
[ 669001-67-6 ]
3,4-bis(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl) benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.3%	With sodium hydride; In acetonitrile; at -5 - 0℃; for 1h;	A suspension of sodium hydride (0.50 g, 12.50 mmol) in anhydrous (17 mL) acetonitrile was stirred at -5-0 C for 20 minutes, then <strong>[22889-78-7]3,5-dichloropyridin-4-amine</strong> 7(2.33 g, 14.20 mmol) was added to the solution (CAUTION: hydrogen gas is liberated). After that, compound6dissolved in acetonitrile was added dropwise to the mixture, and the temperature remained unchanged for an hour (monitored by TLC). Then the mixture was filtered, concentrated and dissolved in dichloromethane. The organic phase was washed with 1 M aqueous solution of hydrochloric acid, saturated sodium hydrogen carbonate and brine, then dried with magnesium sulfate. The organic phase was concentrated to give a yellow solid. Then it was recrystallised in methanol to give 3,4-bis(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)benzamide 1(1.97 g, 85.3% yield) as a white solid. M.p. 206-207 C; IR (KBr, numax/cm-1): 3283 (nu NH), 3085, 3010 (nu CH on benzene or pyridine), 2913, 2871 (nu CH on cyclopropyl), 1656 (nu C=O), 1598, 1586 (nuC=C), 1558, 1548 (delta NH), 1500 (nuC=C), 1461 (nuC=C), 1399 (nuC=N), 1303 (nuCONHR), 1278, 1251 (nu C-O-Ar), 1239-1001, 868, 807 (delta CH on benzene), 750 (delta CH on pyridine). 1H NMR (400 MHz, DMSO-d6): delta 10.43 (s, 1 H, NH), 8.74 (s, 2 H, CH on pyridine), 7.64 (d, J = 8.4 Hz, 1 H, CH of benzene), 7.57 (s, 1 H, CH of benzene), 7.10 (d, J = 8.4 Hz, 1 H, CH of benzene), 3.93 (d, J = 6.8 Hz, 2 H, OCH2), 3.90 (d, J = 6.8 Hz, 2 H, OCH2), 1.28 (m, 2 H, CH), 0.59 (t, 4 H, CH2), 0.36 (t, 4 H, CH2). 13C NMR (100 MHz, DMSO-d6): delta164.8 (C=O), 152.6, 148.7, 148.5, 142.1, 131.3, 125.2, 122.3, 113.8, 113.3 (11 C on benzene or pyridine), 73.7, 73.5 (OCH2), 10.7, 10.6, 3.7 (4 C on CH2). HR-MS (ESI) m/z: [M + Na]+calcd for C20H20Cl2N2O3+ Na+429.0749; found 429.0753.

Reference： [1]Journal of Chemical Research,2014,vol. 38,p. 507 - 509

58
[ 22889-78-7 ]
C₁₂H₇ClF₂N₂O₄ [ No CAS ]
5-(6-chloro-2,2-difluoro-1,3-benzodioxol-5-yl)-N-(3,5-dichloro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%		Step 2: <strong>[22889-78-7]4-Amino-3,5-dichloropyridine</strong> (190 mg, 1.17 mmol) was added to a suspension of NaH (60% in mineral oil, 25 mg, 1.07 mmol) in dry DMF (2.8 mL) and the resulting mixture was stirred rt for 3 h. To this suspension was added at 0 C a solution of the intermediate of step 1 (100 mg, 316 pmol), HATU (144 mg 379 IJmol) and N,N-diisopropyl-N-ethylamine (64 pL, 379 pmol) in DMF (1 mL) and the mixturewas stirred at 5 C for 30 mm. The pH was adjusted to 6 through addition of aq. HCI (10%) and the volatiles were removed under reduced pressure. The residue was dissolved in EtOAc and was washed with water and brine. The organic layer was dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Interchim cartridge 5OSiHP / 12 g, Cy/EtOAc) to yield the title compound of example 14 (50 mg, 34%).LC-MS (Method 2): mlz [M+H] = 461.0 (MW calc. 461.63); R = 0.83 mm.1HNMR (DMSQ-d6), 6 = 10.28 (s, 1H), 8.73 (5, 2H), 7.94 (5, 1H), 7.76 (s, 1H), 6.89 (s, 1H), 3.78 (s, 3H) ppm.

Reference： [1]Patent: WO2015/90580,2015,A1 .Location in patent: Page/Page column 41

59
[ 22889-78-7 ]
(S)-tert-butyl (1-(2-(3,4-diethoxyphenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl)carbamate [ No CAS ]
(S)-tert-butyl (1-(4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(3,4-diethoxyphenyl)oxazol-5-yl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		Step 2: (S) -tert-Butyl (1- (4- ( (3, 5-dichloropyridin-4-yl) carbamoyl) -2- (3, 4-diethoxyphenyl) oxazol-5-yl) ethyl) carbamate[1705]To 5 mL of tetrahydrofuran were added 3, 5-dichloro-4-aminopyridine (469 mg, 2.84 mmol) and sodium hydride (114 mg, 2.84 mmol, 60) . The mixture was stirred at rt for 1 hour. To the mixture was added a solution of (S) -tert-butyl (1- (2- (3, 4-diethoxyphenyl) -4 - (fluorocarbonyl) oxazol-5-yl) ethyl) carbamate (1.00 g, 2.37 mmol) in tetrahydrofuran (10 mL) at 0 , and the reaction mixture was stirred at rt for 12 hours. The mixture was washed with saturated aqueous amonium chloride (20 mL × 3) . The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 5/1) to give the title compound as a white solid (264 mg, 20) .[1706]1H NMR (400 MHz, CDCl3) : delta ppm 8.63 (s, 2H) , 7.65 (dd, J1 8.4 Hz, J2 2.0 Hz, 1H) , 7.57 (d, J 2.0 Hz, 1H) , 6.97 (d, J 8.5 Hz, 1H) , 5.40 -5.27 (m, 1H) , 4.26 -4.18 (m, 4H) , 1.60 (d, J 7.0 Hz, 3H) , 1.55 -1.51 (m, 6H) , 1.44 (s, 9H) and MS-ESI: m/z 565.1 [M+H]+.

Reference： [1]Patent: WO2015/161830,2015,A1 .Location in patent: Paragraph 00621

60
[ 22889-78-7 ]
(S)-tert-butyl (1-(2-(3,4-dimethoxyphenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl)carbamate [ No CAS ]
(S)-tert-butyl (1-(4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(3,4-dimethoxyphenyl)oxazol-5-yl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%		Step 2: (S) -tert-Butyl (1- (4- ( (3, 5-dichloropyridin-4-yl) carbamoyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamate[0621]To 6 mL of tetrahydrofuran were added 3, 5-dichloro-4-aminopyridine (537.9 mg, 3.3 mmol) and sodium hydride (132 mg, 3.3 mmol, 60) . The mixture was stirred at rt for 1 hour. To the mixture was added a solution of (S) -tert-butyl (1- (2- (3, 4-dimethoxyphenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamate (0.86 g, 2.2 mmol) in tetrahydrofuran (9 mL) at 0 , and the reaction mixture was stirred at rt for 23 hours. To the mixture was added saturated aqueous amonium chloride (20 mL × 3) and the resulting mixture was extracted with ethyl acetate (20 mL × 3) . The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 3/1) to give the title compound as light yellow oil (325 mg, 27) .

Reference： [1]Patent: WO2015/161830,2015,A1 .Location in patent: Paragraph 00315

61
[ 22889-78-7 ]
(S)-tert-butyl (1-(2-(3-ethoxy-4-methoxyphenyl)-4-(fluorocarbonyl)oxazol-5-yl)ethyl)carbamate [ No CAS ]
(S)-tert-butyl (1-(4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(3-ethoxy-4-methoxyphenyl)oxazol-5-yl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%		Step 2: (S) -tert-Butyl (1- (4- ( (3, 5-dichloropyridin-4-yl) carbamoyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamate[0631]To 6 mL of tetrahydrofuran were added 3, 5-dichloro-4-aminopyridine (341.23 mg, 2.1 mmol) and sodium hydride (84 mg, 2.1 mmol, 60) , and the mixture was stirred at rt for 1 hour. To the mixture was added a solution of (S) -tert-butyl (1- (2- (3-ethoxy-4-methoxyphenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamate (0.57 g, 1.4 mmol) in tetrahydrofuran (9 mL) at 0 , and the reaction mixture was stirred at rt for 14 hours. To the mixture was added saturated aqueous ammonium chloride (20 mL) and the resulting mixture was extracted with ethyl acetate (20 mL × 3) . The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 3/1) to give the title compound as a light yellow solid (240 mg, 31) .[0632]1H NMR (400 MHz, CDCl3) : delta ppm 9.04 (s, 1H) , 8.62 (s, 2H) , 7.68 -7.65 (m, 1H) , 7.55 (d, J 1.9 Hz, 1H) , 6.98 (d, J 8.5 Hz, 1H) , 5.34 -5.30 (m, 1H) , 4.26 -4.21 (m, 2H) , 3.97 (s, 3H) , 1.60 (d, J 7.0 Hz, 3H) , 1.44 (s, 9H) , 1.28 (t, J 7.1 Hz, 3H) and MS-ESI: m/z 552.3 [M+H]+.

Reference： [1]Patent: WO2015/161830,2015,A1 .Location in patent: Paragraph 00318

62
[ 22889-78-7 ]
[ 1236067-44-9 ]
[ 1236067-41-6 ]

Yield	Reaction Conditions	Operation in experiment
46%		General procedure: Acid compound (6, 6a, 6b, 6c or 25 or 28 or 32; 1.0mmol), EDCI (1.0mmol), HOBt (1.0mmol), DMAP (0.5mmol) and DIPEA (5mmol) were taken in DMF (4mL for each 100mg of acid), stirred for 20 minutes and cooled to 0C. Corresponding amine (1.2mmol) was added and the temperature was brought to rt. The reaction mixture was stirred till completion of the reaction, cold water was added and the precipitate settled was filtered. If the precipitate could not be filtered, it was treated with MDC (3×25mL) and water (30mL). The organic layer was separated, washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography over silica gel using MDC/MeOH solvent combinations (up to 10% MeOH in MDC) to get the corresponding title compounds.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5702 - 5716

63
[ 22889-78-7 ]
C₁₉H₁₅NO₄S [ No CAS ]
[ 1236067-39-2 ]

Yield	Reaction Conditions	Operation in experiment
41%		General procedure: Acid compound (6, 6a, 6b, 6c or 25 or 28 or 32; 1.0mmol), EDCI (1.0mmol), HOBt (1.0mmol), DMAP (0.5mmol) and DIPEA (5mmol) were taken in DMF (4mL for each 100mg of acid), stirred for 20 minutes and cooled to 0C. Corresponding amine (1.2mmol) was added and the temperature was brought to rt. The reaction mixture was stirred till completion of the reaction, cold water was added and the precipitate settled was filtered. If the precipitate could not be filtered, it was treated with MDC (3×25mL) and water (30mL). The organic layer was separated, washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography over silica gel using MDC/MeOH solvent combinations (up to 10% MeOH in MDC) to get the corresponding title compounds.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5702 - 5716

64
[ 22889-78-7 ]
C₁₈H₁₃NO₄S [ No CAS ]
[ 1236067-40-5 ]

Yield	Reaction Conditions	Operation in experiment
25%		General procedure: Acid compound (6, 6a, 6b, 6c or 25 or 28 or 32; 1.0mmol), EDCI (1.0mmol), HOBt (1.0mmol), DMAP (0.5mmol) and DIPEA (5mmol) were taken in DMF (4mL for each 100mg of acid), stirred for 20 minutes and cooled to 0C. Corresponding amine (1.2mmol) was added and the temperature was brought to rt. The reaction mixture was stirred till completion of the reaction, cold water was added and the precipitate settled was filtered. If the precipitate could not be filtered, it was treated with MDC (3×25mL) and water (30mL). The organic layer was separated, washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography over silica gel using MDC/MeOH solvent combinations (up to 10% MeOH in MDC) to get the corresponding title compounds.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5702 - 5716

65
[ 22889-78-7 ]
C₁₈H₁₃NO₄S [ No CAS ]
[ 1236067-56-3 ]

Yield	Reaction Conditions	Operation in experiment
24%		General procedure: Acid compound (6, 6a, 6b, 6c or 25 or 28 or 32; 1.0mmol), EDCI (1.0mmol), HOBt (1.0mmol), DMAP (0.5mmol) and DIPEA (5mmol) were taken in DMF (4mL for each 100mg of acid), stirred for 20 minutes and cooled to 0C. Corresponding amine (1.2mmol) was added and the temperature was brought to rt. The reaction mixture was stirred till completion of the reaction, cold water was added and the precipitate settled was filtered. If the precipitate could not be filtered, it was treated with MDC (3×25mL) and water (30mL). The organic layer was separated, washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography over silica gel using MDC/MeOH solvent combinations (up to 10% MeOH in MDC) to get the corresponding title compounds.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5702 - 5716

66
[ 22889-78-7 ]
C₁₇H₉F₂NO₄S [ No CAS ]
[ 1236067-42-7 ]

Yield	Reaction Conditions	Operation in experiment
26%		General procedure: Acid compound (6, 6a, 6b, 6c or 25 or 28 or 32; 1.0mmol), EDCI (1.0mmol), HOBt (1.0mmol), DMAP (0.5mmol) and DIPEA (5mmol) were taken in DMF (4mL for each 100mg of acid), stirred for 20 minutes and cooled to 0C. Corresponding amine (1.2mmol) was added and the temperature was brought to rt. The reaction mixture was stirred till completion of the reaction, cold water was added and the precipitate settled was filtered. If the precipitate could not be filtered, it was treated with MDC (3×25mL) and water (30mL). The organic layer was separated, washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography over silica gel using MDC/MeOH solvent combinations (up to 10% MeOH in MDC) to get the corresponding title compounds.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5702 - 5716

67
[ 22889-78-7 ]
C₁₈H₁₂F₂N₂O₆S₂ [ No CAS ]
[ 1236067-62-1 ]

Yield	Reaction Conditions	Operation in experiment
32%		General procedure: Acid compound (6, 6a, 6b, 6c or 25 or 28 or 32; 1.0mmol), EDCI (1.0mmol), HOBt (1.0mmol), DMAP (0.5mmol) and DIPEA (5mmol) were taken in DMF (4mL for each 100mg of acid), stirred for 20 minutes and cooled to 0C. Corresponding amine (1.2mmol) was added and the temperature was brought to rt. The reaction mixture was stirred till completion of the reaction, cold water was added and the precipitate settled was filtered. If the precipitate could not be filtered, it was treated with MDC (3×25mL) and water (30mL). The organic layer was separated, washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography over silica gel using MDC/MeOH solvent combinations (up to 10% MeOH in MDC) to get the corresponding title compounds.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5702 - 5716

68
[ 22889-78-7 ]
8-(difluoromethoxy)-4-[(4-methoxyphenyl)methyl]-2,3-dihydro-1,4-benzoxazine-5-carbonyl chloride [ No CAS ]
N-(3,5-dichloro-4-pyridyl)-8-(difluoromethoxy)-4-[(4-methoxyphenyl)methyl]-2,3-dihydro-1,4-benzoxazine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%		At 0 CAnd N2,To a solution of <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> (1-12, 0.43 g, 2.64 mmol)In THF (50 mL)NaH (60% in mineral oil, 0.23 g, 5.81 mmol) was added in portions,The resulting mixture was stirred at 0 & lt; 0 & gt; C for 1.5 h,A solution of 8- (difluoromethoxy) -4 - [(4-methoxyphenyl) methyl] -2,3-dihydro-1,4-benzoxazine-5-carboxylic acid chloride (1- 11, 0.83 g, 2.2 mmol),The reaction temperature was raised to 10 C,Continue stirring 2h,TLC showed the reaction was complete and the reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetateTake (3 x 50 mL), combine the organic phase, evaporate to dryness under reduced pressure,The residue was purified by recrystallization from methanol to give N- (3,5-dichloro-4-pyridyl) -8- (difluoromethoxy) -4 - [(4-methoxyphenyl) Yl] -2,3-dihydro-1,4-benzoxazine-5-carboxamide (1-13, 0.51 g, yield: 46%).

Reference： [1]Patent: CN106588900,2017,A .Location in patent: Paragraph 0394; 0396; 0406

69
[ 22889-78-7 ]
8-(difluoromethoxy)-2-tert-butyl-4-[(4-methoxyphenyl)methyl]-2,3-dihydro-1,4-benzoxazine-5-carboxylic acid [ No CAS ]
N-(3,5-dichloro-4-pyridyl)-8-(difluoromethoxy)-2-tert-butyl-4-[(4-methoxyphenyl)methyl]2,3-dihydro-1,4-benzoxazine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		in room temperature,To NaH (60% in mineral oil, 62 mg, 1.55 mmol)Of anhydrous DMF (5 mL)Was added <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> (279 mg, 1.71 mmol)Stir for 1 h to give "Solution A".At room temperature,To a solution of 8- (difluoromethoxy) -2-tert-butyl-4-[(4-methoxyphenyl) methyl] -2,3-dihydro-1,4-benzoxazine-5-carboxylic acid(3-1,200 mg, 0.48 mmol.Prepared in the same manner as in Example 2-10, in the same manner as in Example 2-10) in anhydrous DMF (5 mL) was added HATU (260 mg, 0.68 mmol)And N, N-diisopropylethylamine (DIPEA, 220 mg, 1.70 mmol)Stir for 1h,Then "solution A" was added and the resulting mixture was stirred at room temperature for 1 h,Water (30 mL) was added and extracted with ethyl acetate (3 x 40)ML). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel columnChromatography (eluent: ethyl acetate / petroleum ether: 0-33%)To give the product as a yellow oilN- (3,5-dichloro-4-pyridyl) -8- (difluoromethoxy) -2-tert-butyl-4 - [(4-methoxyphenyl) methyl] 3-dihydro-1,4-benzoxazine-5-carboxamide (3-2, 0.106 g, yield: 39%)

Reference： [1]Patent: CN106588900,2017,A .Location in patent: Paragraph 0440-0443

70
[ 22889-78-7 ]
2-(1-benzyloxy-1-methylethyl)-8-(difluoromethoxy)-4-[(4-methoxyphenyl)methyl]-2,3-dihydro-1,4-benzoxazine-5-carboxylic acid [ No CAS ]
2-(1-benzyloxy-1-methylethyl)-N-(3,5-dichloro-4-pyridyl)-8-(difluoromethoxy)-4-[(4-methoxyphenyl)methyl]-2,3-dihydro-1,4-benzoxazine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%		in room temperature,To a solution of 2- (1-benzyloxy-1-methyl-ethyl) -8- (difluoromethoxy) -4 - [(4-methoxyphenyl) methyl] Hydrogen-1,4-benzoxazine-5-carboxylic acid (5-6,200 mg, 0.39 mmol)And HATU (220 g, 0.58 mmol)Of anhydrous DMF (5 mL)N, N-diisopropylethylamine (DIPEA, 151 mg, 1.17 mmol) was added to the solution,Stir for 1 h to give "Solution A".To a solution of <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> (1-12, 190 mg, 1.17 mmol)In anhydrous DMF (5 mL) was addedNaH (60% in mineral oil, 42 mg, 1.05 mmol)Stir for 1 h at room temperature to give "Solution B"."Solution B" was added to "Solution A"The resulting mixture was addedStirring at 45 C for 12 h,Add water (50 mL),Extracted with ethyl acetate (3 x 50 mL)The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure,The residue was purified by silica gel column chromatography(Eluent: ethyl acetate / petroleum ether: 0-30%)To give the product as a yellow oil2- (1-benzyloxy-1-methyl-ethyl) -N- (3,5-dichloro-4-pyridyl)(Difluoromethoxy) -4 - [(4-methoxyphenyl) methyl] -2,3-dihydro-1,4-benzoxazine-5-carboxamide(5-7, 115 mg, yield: 45%).

Reference： [1]Patent: CN106588900,2017,A .Location in patent: Paragraph 0469; 0471; 0477

71
[ 22889-78-7 ]
8-(difluoromethoxy)-2-(1-hydroxycyclohexyl)-4-[(4-methoxyphenyl)methyl]2,3-dihydro-1,4-benzoxazine-5-carboxylic acid [ No CAS ]
N-(3,5-dichloro-4-pyridyl)-8-(difluoromethoxy)-2-(1-hydroxycyclohexyl)-4-[(4-methoxyphenyl)methyl]-2,3-dihydro-1,4-benzoxazine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%		in room temperature,To NaH (60% in mineral oil, 70 mg, 1.75 mmol)Of anhydrous DMF (5 mL)Was added <strong>[22889-78-7]4-amino-3,5-dichloropyridine</strong> (1-12, 325 mg, 2.00 mmol)Stir for 1 h to give "Solution A".At room temperature,To a solution of 8- (difluoromethoxy) -2- (1-hydroxycyclohexyl) -4 - [(4-methoxyphenyl) methyl] -2,3-dihydro- Oxazine-5-carboxylic acid (7-2, 300 mg, 0.65 mmol)Of anhydrous DMF (10 mL)Was added HATU (370 mg, 0.97 mmol)And N, N-diisopropylethylamine (DIPEA, 335 mg, 2.60 mmol)Stir for 1h,Then add "solution A"The resulting mixture was added45 CStirring for 12h,Water (50 mL) was added and extracted with ethyl acetate (3 x 25 mL). The organic phases were combined,Dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: acetic acidEthyl ester / petroleum ether: 20-50%)To give the product as a brown oilN- (3,5-dichloro-4-pyridyl) -8- (difluoromethoxy) -2- (1-hydroxycyclohexyl) -4 - [(4-methoxyphenyl) ] -2,3-dihydro-1,4-benzoxazine-5-carboxamide(7-3, 150 mg, yield: 29%).

Reference： [1]Patent: CN106588900,2017,A .Location in patent: Paragraph 0493; 0495; 0498

72
[ 22889-78-7 ]
[ 84332-06-9 ]
N-(3,5-dichloropyridin-4-yl)-4-methoxy-2-(methylthio)pyrimidine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.06%		To a stirred solution of 426 4-methoxy-2-(methylthio)pyrimidine-5-carboxylic acid (1.7 g, 8.491 mmol, 1.0 eq), in 82 CH2Cl2 (50 mL) was added 429 (COCl)2 (1.45 mL, 16.982 mmol, 2.0 eq) and 47 DMF (0.01 mL) at 0 C. The resulting mixture was stirred at rt for 5 h. The reaction mixture was concentrated, dissolved in CH2Cl2 (5.0 mL) and added to a stirred solution of 430 <strong>[22889-78-7]3,5-dichloropyridin-4-amine</strong> (1.385 g, 8.491 mmol, 1.0 eq) and 431 NaH (680 mg, 16.982 mmol, 2.0 eq) in DMF (30 mL) at 0 C. The resulting mixture was stirred at rt for 2 h. The progress of reaction was monitored by LCMS. The reaction mixture was poured in ice cold 7 water (50 mL), extracted with EtOAc (2×100 mL), the combined organic layers were washed with water (50 mL), with brine (50 mL), dried over Na2SO4 concentrated and purified by flash chromatography [silica gel 100-200 mesh elution 0-30% 19 EtOAc in 20 hexane] to afford the desired compound 432 N-(3,5-dichloropyridin-4-yl)-4-methoxy-2-(methylthio)pyrimidine-5-carboxamide (2.2 g, 75.06%) as off white solid. (0500) LCMS: 344.9[M+1]+

Reference： [1]Patent: US2019/106436,2019,A1 .Location in patent: Paragraph 0496; 0499-0500

73
[ 22889-78-7 ]
[ 57320-63-5 ]
N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 3h;	Within 30 minutes,Potassium tert-butoxide was added to a solution of <strong>[22889-78-7]3,5-dichloro-4-aminopyridine</strong> in tetrahydrofuran at a concentration of 1.05 mol/l, and then a concentration of 0.51 mol/l was added dropwise.a solution of 4-(difluoromethoxy)benzoyl chloride in tetrahydrofuran,Adjust the temperature to room temperature,Incubate for 3 h, filter the filtrate, add ethyl acetate and water.The organic phase is extracted, and the mass fraction is 5 wt% hydrochloric acid aqueous solution,Washing the organic phase with a 5 wt% aqueous solution of sodium hydroxide,The organic phase was dried over anhydrous sodium sulfate and concentrated.Recrystallization from a mixed solvent of isopropyl alcohol and water in a volume ratio of 10:1 to give N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide.Among them, <strong>[22889-78-7]3,5-dichloro-4-aminopyridine</strong>,The molar ratio of potassium t-butoxide and 4-(difluoromethoxy)benzoyl chloride is 1:2:0.49.

Reference： [1]Patent: CN109516949,2019,A .Location in patent: Paragraph 0102-0104; 0108-0110; 0114-0116; 0120-0122

74
3,3,5,5-tetrachloropiperidin-4-one [ No CAS ]
[ 22889-78-7 ]

Yield	Reaction Conditions	Operation in experiment
89.7%	With ammonia; In methanol; at 40 - 45℃; for 4h;Autoclave;	In a 500 ml autoclave,Add 130 grams of methanol,13.7 g (0.05 mol) of 3,3,5,5-tetrachloropiperidin-4-one obtained in Example 5,35.0 g (0.2 mole) of a 10% ammonia methanol solution,Stir the reaction at 40-45 C for 4 hours.Cool to 20-25 ,Filtered, the filter cake was washed with 20 g of solvent, the filtrates were combined, and the solvent was recovered by distillation,7.31 g of 3,5-dichloro-4-aminopyridine was obtained as a white solid,Yield 89.7% (yield based on piperidin-4-one hydrochloride),The liquid purity was 99.3%.

Reference： [1]Patent: CN110483383,2019,A .Location in patent: Paragraph 0111-0114

75
[ 22889-78-7 ]
C₁₀H₁₂ClN₃O₂S [ No CAS ]
C₁₅H₁₅Cl₂N₅O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22.8%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tert-butyl alcohol; at 110℃; for 24h;Inert atmosphere;	A mixture of 1-11 (80 mg, 0.292 mmol), 4-amino-3,5-dichloropyiridine ([22889-78-7], 55.894 mg, 0.343 mmol), and CS2CO3 (209.482 mg, 0.643 mmol) in tBuOH (1.097 mL) was degassed with nitrogen. Pd(OAc)2 (6.561 mg, 0.0292 mmol) and Xantphos (16.91 mg, 0.0292 mmol) were added and the mixture was heated at 110 C for 24 h. The solvent was removed in vacuo and then the crude was diluted with water, and extracted with DCM. The combined organic extarcts were dried over MgS04, filtered and the solvent was removed. The crude was purified by reverse phase chromatography (eluent: MeOH and NH4C03) to obtain Co. No. 3 (26.7 mg, yield 22.8%) as a white powder.

Reference： [1]Patent: WO2019/243535,2019,A1 .Location in patent: Page/Page column 95

76
[ 22889-78-7 ]
[ 162401-69-6 ]
[ 162401-32-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 3-(difluoromethoxy)-4-(cyclopropylmethoxy)-benzoic acid With thionyl chloride In toluene for 2h; Reflux; Stage #2: 3,5-dichloro-4-aminopyridine With sodium hydride In tetrahydrofuran at 15 - 20℃;	Step 1) Acylation reaction: Add thionyl chloride (1075mL, 14.88mol) dropwise to 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (535g, 2.07mol) in toluene (4500mL) and the reaction mixture was heated to reflux for 2h, Then it was concentrated under reduced pressure to remove the solvent, and the residue after concentration was dissolved in about 5400 mL of tetrahydrofuran, and the solution was added dropwise to 15-20 under stirring. 4-amino-3,5-dichloropyridine (370g, 2.27mol) and sodium hydride (purity: 60%) (195g, 4.96mol) in 5400mL tetrahydrofuran solution; After stirring for 1 to 2 hours, the reaction solution was acidified with 1N hydrochloric acid to a pH of 2 to 3, the solution was separated into layers, and the aqueous layer was extracted twice with ethyl acetate, each with 4500 mL, and the organic phases were combined. The organic phase was washed with saturated sodium bicarbonate solution (about 5L) and water (about 5L), and then dried with 5Kg anhydrous sodium sulfate for 23h. Filter, concentrate the filtrate under reduced pressure to remove the solvent, add about 2500 mL of isopropanol to the resulting residue and heat under reflux for 30 min. Then the temperature is naturally lowered to room temperature, a large amount of crystals are precipitated, filtered with suction, and the filter cake is dried to obtain an off-white solid, which is the crude roflumilast product. The yield range is 65% to 75%.

Reference： [1]Current Patent Assignee: SHANDONG XIER KANGTAI PHARMACEUTICAL - CN111777550, 2020, A Location in patent: Paragraph 0013; 0016-0025

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Historical Records

Pharmaceutical Intermediates of
[ 22889-78-7 ]

Roflumilast Related Intermediates

[ 1895-39-2 ]

Sodium 2-chloro-2,2-difluoroacetate

[ 1243391-44-7 ]

3-(Cyclopropylmethoxy)-4-hydroxybenzoic acid

[ 151103-09-2 ]

3-(Cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde

[ 99-50-3 ]

3,4-Dihydroxybenzoic acid

[ 58123-77-6 ]

3-Hydroxy-4-iodobenzoic acid

Related Functional Groups of
[ 22889-78-7 ]

Chlorides

[ 19798-77-7 ]

4-Amino-3-chloropyridine

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[ 28443-69-8 ]

2,3,5-Trichloropyridin-4-amine

Similarity: 0.85

[ 195045-26-2 ]

3,5-Dichloro-2-methylpyridin-4-amine

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[ 2457-47-8 ]

3,5-Dichloropyridine

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1-(3,5-Dichloropyridin-4-yl)piperazine

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Amines

[ 19798-77-7 ]

4-Amino-3-chloropyridine

Similarity: 0.88

[ 28443-69-8 ]

2,3,5-Trichloropyridin-4-amine

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[ 195045-26-2 ]

3,5-Dichloro-2-methylpyridin-4-amine

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[ 184416-83-9 ]

2,3-Dichloropyridin-4-amine

Similarity: 0.78

[ 4214-74-8 ]

3,5-Dichloropyridin-2-amine

Similarity: 0.77

Related Parent Nucleus of
[ 22889-78-7 ]

Pyridines

[ 19798-77-7 ]

4-Amino-3-chloropyridine

Similarity: 0.88

[ 28443-69-8 ]

2,3,5-Trichloropyridin-4-amine

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[ 195045-26-2 ]

3,5-Dichloro-2-methylpyridin-4-amine

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[ 2457-47-8 ]

3,5-Dichloropyridine

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[ 175277-80-2 ]

1-(3,5-Dichloropyridin-4-yl)piperazine

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Code	Phrase
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Code	Phrase
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P322
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P378
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P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
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P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
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P411
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P413
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P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
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P501	Dispose of contents/container to ...
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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
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H222	Extremely flammable aerosol
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H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
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H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
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H315	Causes skin irritation
H316	Causes mild skin irritation
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H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
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H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 22889-78-7 ] {[proInfo.proName]}

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Calculated chemistry of [ 22889-78-7 ]

Physicochemical Properties

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Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 22889-78-7 ]

Application In Synthesis of [ 22889-78-7 ]

[ 22889-78-7 ] Synthesis Path-Upstream 1~14

[ 22889-78-7 ] Synthesis Path-Downstream 1~76

Pharmaceutical Intermediates of [ 22889-78-7 ]

Roflumilast Related Intermediates

Related Functional Groups of [ 22889-78-7 ]

Chlorides

Amines

Related Parent Nucleus of [ 22889-78-7 ]

Pyridines

Precautionary Statements-General

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Health hazards

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[ 22889-78-7 ]

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[ 22889-78-7 ]

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[ 22889-78-7 ]