[ CAS No. 22353-40-8 ] {[proInfo.proName]}

Name: 22353-40-8|2,3-Dichloro-5-nitropyridine|98%
Brand: Ambeed
SKU: A217190
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Quality Control of [ 22353-40-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 22353-40-8 ]

Product Details of [ 22353-40-8 ]

CAS No. :	22353-40-8	MDL No. :	MFCD03840432
Formula :	C₅H₂Cl₂N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XLPDVAVQKGDHNO-UHFFFAOYSA-N
M.W :	192.99	Pubchem ID :	2763106
Synonyms :

Calculated chemistry of [ 22353-40-8 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	43.08
TPSA :	58.71 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) :	-5.84 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.34
Log Po/w (XLOGP3) :	2.31
Log Po/w (WLOGP) :	2.3
Log Po/w (MLOGP) :	0.49
Log Po/w (SILICOS-IT) :	0.59
Consensus Log Po/w :	1.4

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.83
Solubility :	0.286 mg/ml ; 0.00148 mol/l
Class :	Soluble
Log S (Ali) :	-3.18
Solubility :	0.127 mg/ml ; 0.000659 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.64
Solubility :	0.441 mg/ml ; 0.00229 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.09

Safety of [ 22353-40-8 ]

Signal Word:	Danger	Class:	8,6.1
Precautionary Statements:	P261-P280-P301+P310-P305+P351+P338	UN#:	2923
Hazard Statements:	H301-H315-H318-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 22353-40-8 ]

* 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 [ 22353-40-8 ]
Downstream synthetic route of [ 22353-40-8 ]

[ 22353-40-8 ] Synthesis Path-Upstream 1~16

1
[ 22353-40-8 ]
[ 97966-00-2 ]

Reference： [1] Patent: US2004/242641, 2004, A1,

2
[ 22353-38-4 ]
[ 22353-40-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	at 0 - 120℃; for 2 h; Inert atmosphere	Quinoline (48.5 ml, 0.41 mol) was added to POCl3 (164.0 ml, 1.75 mol) at 0 C under nitrogen. To this stirred mixture, 2-hydroxy- 3-chloro-5-nitropyridine (204 mg, 1.17 mol) was added. The reaction mixturewas heated at 120 C for 2 h, cooled to 0 C followed by addition of ice-cold water. The precipitate obtained was filtered, washed thoroughly with water and dried to give 2,3-dichloro-5- nitropyridine. Yield: 220 g, (97percent). M.P.: 53 C. 1H NMR (300 MHz, DMSO-d6): d 9.16 (d, 1H, J ¼ 2.4 Hz), 8.94 (d, 1H, J ¼ 2.4 Hz). 13C NMR (300 MHz, DMSO-d6): d 158.69, 137.36, 132.51, 130.13, 124.39. MS (ES): 193 (M þ 1).
70.3%	at 0 - 120℃; for 2 h; Inert atmosphere	Quinoline (0.3 mL, 2.34 mmol) was added to POCl₃(0.5 mL 4.68 mmol) at 0 °C under nitrogen. To this stirred mixture was added 2-hydroxy-3-chloro-5-nitro pyridine (816 mg, 4.68 mmol) (product obtained in step i) The reaction mixture was heated at 120 °C for 2 hours, cooled to 0 °C followed by addition of ice cold water. The precipitate obtained was filtered, washed with water and dried to obtain 2,3-dichloro-5-nitro pyridine. Yield: 630 mg (70.3 percent); m.p.: 53 °C; *H NMR (DMSO-d₆) δ: 8.94 (d, 1H, J = 2.5 Hz), 9.16 (d, 1H, J = 2.5 Hz).
70.3%	at 0 - 120℃; for 2 h; Inert atmosphere	Quinoline (0.3 mL, 2.34 mmol) was added to POCl₃ (0.5 mL 4.68 mmol) at 0 °C under nitrogen. To this stirred mixture was added 2-hydroxy-3-chloro-5-nitropyridine (816 mg, 4.68 mmol) obtained in step a. The reaction mixture was heated at 120 °C for 2 h, and was cooled to 0 °C followed by addition of ice-cold water. The precipitate obtained was filtered, washed with water and dried to obtain 2,3-dichloro-5-nitropyridine. Yield: 70.3 percent; *H NMR (DMSO-d₆): δ 9.16 (d, J=1.8HZ, 1H), 8.60 (d, J=1.8Hz, 1H); MS (ES): m/z 193 (M+l).

Reference： [1] Synthesis, 1990, # 6, p. 499 - 501
[2] European Journal of Medicinal Chemistry, 2012, vol. 58, p. 355 - 360
[3] Patent: WO2013/117963, 2013, A1, . Location in patent: Page/Page column 21
[4] Patent: WO2014/207508, 2014, A1, . Location in patent: Page/Page column 55
[5] Roczniki Chemii, 1968, vol. 42, p. 2079,2084[6] Chem.Abstr., 1969, vol. 70, p. 106327
[7] Yakugaku Zasshi, 1952, vol. 72, p. 378,380[8] Chem.Abstr., 1953, p. 6403
[9] Journal of Scientific and Industrial Research, 1962, vol. 21 B, p. 483,486
[10] Patent: WO2004/50637, 2004, A2, . Location in patent: Page 66-67
[11] Patent: US2004/242644, 2004, A1, . Location in patent: Page 4
[12] Patent: US2006/35937, 2006, A1, . Location in patent: Page/Page column 10
[13] Patent: US2003/114457, 2003, A1,
[14] Patent: US5922732, 1999, A,
[15] Patent: US2005/261348, 2005, A1,
[16] Patent: WO2008/35306, 2008, A1, . Location in patent: Page/Page column 24
[17] Patent: WO2007/53394, 2007, A1, . Location in patent: Page/Page column 12-13
[18] Patent: US2004/242641, 2004, A1, . Location in patent: Page 4
[19] Patent: WO2008/35306, 2008, A1, . Location in patent: Page/Page column 24

3
[ 22353-38-4 ]
[ 7732-18-5 ]
[ 22353-40-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With trichlorophosphate In quinoline	To phosphorus oxychloride (37.4 mL, 0.4 mol) at 0° C. was added quinoline (23.6 mL, 0.2 mol), followed by 3-chloro-2-hydroxy-5-nitropyridine (70 g, 0.4 mol) from above. The mixture was heated at 120° C. for 2.5 hours, during which time it became a dark liquid. After cooling to 100° C., H₂ O (150 mL) was added cautiously, and the mixture was cooled to 0° C. The precipitated solid was collected by filtration, washed with cold H₂ O, and dried under vacuum at 50° C. to afford 2,3-dichloro-5-nitropyridine (68.6 g, 89percent).

Reference： [1] Patent: US6133253, 2000, A,

4
[ 5418-51-9 ]
[ 22353-40-8 ]

Reference： [1] Synthesis, 1990, # 6, p. 499 - 501
[2] Yakugaku Zasshi, 1952, vol. 72, p. 378,380[3] Chem.Abstr., 1953, p. 6403
[4] Patent: WO2006/88920, 2006, A1, . Location in patent: Page/Page column 112
[5] European Journal of Medicinal Chemistry, 2012, vol. 58, p. 355 - 360
[6] Patent: WO2013/117963, 2013, A1,
[7] Patent: WO2014/207508, 2014, A1,
[8] Patent: US2004/242641, 2004, A1,

5
[ 22353-38-4 ]
[ 10025-87-3 ]
[ 22353-40-8 ]

Reference： [1] Patent: US6432880, 2002, B1,

6
[ 89-73-6 ]
[ 22353-40-8 ]
[ 59-49-4 ]
[ 22353-38-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h;	General procedure: To a solution of N-hydroxysalicylamide (0.5 g, 3.26 mmol) in anhydrous DMF (5 ml) was added 2a or 2b (3.26 mmol) and freshly calcinated K2CO3 (1.35 g, 9.78 mmol) and the mixture was kept, with stirring at the room temperature overnight. DMF was removed in vacuo and the residue was treated with water (10 ml) and then extracted with CH2Cl2 (5 ml). The organic layer was separated, washed with water, dried over anhydrous CaCl2, and purified by flesh chromatography on silica gel using CH2Cl2 as eluent. Dichloromethane was evaporated in vacuo. The resulting residue was benzo[d]oxazol-2(3H)-one 11. The water layer was acidify by hydrochloric acid, filtered and washed with water. The resulting residue was compound 12a(b).

Reference： [1] Tetrahedron Letters, 2016, vol. 57, # 52, p. 5877 - 5880

7
[ 22353-40-8 ]
[ 22353-38-4 ]

Reference： [1] Patent: US1778784, 1928, ,

8
[ 22353-40-8 ]
[ 124-41-4 ]
[ 22353-53-3 ]

Yield	Reaction Conditions	Operation in experiment
45.8 mg	at 20℃; for 1.5 h;	Sodium methoxide (5M methanol solution) (0.5 ml) was added to a methanol (1 ml) solution of 2,3-dichloro-5-nitropyridine (50 mg), followed by stirring at room temperature for 1.5 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and colorless oily matter of 3-chloro-2-methoxy-5-nitropyridine (45.8 mg) was thus obtained.

Reference： [1] Patent: EP2589592, 2018, B1, . Location in patent: Paragraph 1105; 1106

9
[ 22353-40-8 ]
[ 13061-96-6 ]
[ 51984-62-4 ]

Yield	Reaction Conditions	Operation in experiment
344 mg	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate In 1,4-dioxane at 100℃; for 6 h;	Cesium carbonate (338 mg), methylboronic acid (47 mg), and tetrakis(triphenylphosphine)palladium (60 mg) were added to a 1,4-dioxane (3 ml) solution containing 2,3-dichloro-5-nitropyridine (100 mg), followed by stirring at 100°C for 6 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and 3-chloro-2-methyl-5-nitropyridine (344 mg) was thus obtained.

Reference： [1] Patent: EP2589592, 2018, B1, . Location in patent: Paragraph 1190; 1191

10
[ 22353-40-8 ]
[ 98121-41-6 ]

Reference： [1] Synthesis, 1990, # 6, p. 499 - 501
[2] Patent: US2004/242644, 2004, A1, . Location in patent: Page 4
[3] Patent: US2005/261348, 2005, A1,
[4] Tetrahedron Letters, 2013, vol. 54, # 19, p. 2303 - 2307
[5] Patent: US2004/242641, 2004, A1, . Location in patent: Page 4

11
[ 22353-40-8 ]
[ 7439-89-6 ]
[ 98121-41-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With magnesium sulfate In water; acetic acid; ethyl acetate	EXAMPLE 10 3-amino-5,6-dichloropyridine 77.2 g (0.4 mol) of 2,3-dichloro-5-nitropyridine were dissolved in 135 ml of glacial acetic acid, and 800 ml of water were added with stirring. 111.7 g (2 mol) of iron powder were introduced in portions into the mixture (temperature<=50° C.). After completion of the reaction, the mixture is filtered under suction and the product extracted using ethyl acetate. The organic phase was washed with water until neutral, dried using MgSO₄ and concentrated by evaporation. The product was recrystallized from toluene. Yield 85percent Melting point 107° C.

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

12
[ 22353-40-8 ]
[ 7732-18-5 ]
[ 98121-41-6 ]

Reference： [1] Patent: US6133253, 2000, A,

13
[ 22353-40-8 ]
[ 110860-92-9 ]

Reference： [1] Synthesis, 1990, # 6, p. 499 - 501
[2] Tetrahedron Letters, 2013, vol. 54, # 19, p. 2303 - 2307

14
[ 22353-40-8 ]
[ 488713-31-1 ]

Reference： [1] Patent: EP2975031, 2016, A1,
[2] Patent: EP3192791, 2017, A1,

15
[ 22353-40-8 ]
[ 488713-30-0 ]

Yield	Reaction Conditions	Operation in experiment
32.8%	Stage #1: at 200℃; for 1 h; Microwave irradiation Stage #2: With hydrogenchloride; iron(III) chloride hexahydrate In 1-methyl-pyrrolidin-2-one at 20℃; for 0.666667 h;	A mixture of 2,3-dichloro-5-nitropyridine (15.24 g, 78.97 mmol) and copper cyanide (28.3 g, 315.88 mmol) in NMP (128 mL) was stirred under microwave irradiation at 200°C for 1 hr. The reaction mixture was added to 0.5 N HCl (1300 mL) and iron(III) chloride 6 hydrate (107 g, 394.84 mmol), and the mixture was stirred at room temperature for 40 min and extracted with ethyl acetate/hexane mixed solution (3:1). The organic layer was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 2→10percent ethyl acetate/hexane) to give 3-chloro-5-nitropicolinonitrile (4.76 g, 25.9 mmol, 32.8percent) as a pale-yellow solid. NMR (300 MHz, CDCl₃):δ 8.68(1H,d,J=2.3 Hz), 9.40(1H,d,J=2.3 Hz).

Reference： [1] Patent: EP3192791, 2017, A1, . Location in patent: Paragraph 0506

16
[ 22353-40-8 ]
[ 488713-30-0 ]

Reference： [1] Patent: EP2975031, 2016, A1,

[ 22353-40-8 ] Synthesis Path-Downstream 1~85

1
[ 22353-40-8 ]
[ 22353-38-4 ]

Reference： [1]Patent: US1778784,1928,

2
[ 22353-40-8 ]
[ 64007-60-9 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; water; potassium hydrosulfide

Reference： [1]Raeth [Justus Liebigs Annalen der Chemie, 1931, vol. 487, p. 105,115]

3
[ 22353-38-4 ]
[ 22353-40-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With quinoline; trichlorophosphate; at 0 - 120℃; for 2h;Inert atmosphere;	Quinoline (48.5 ml, 0.41 mol) was added to POCl3 (164.0 ml, 1.75 mol) at 0 C under nitrogen. To this stirred mixture, 2-hydroxy- 3-chloro-5-nitropyridine (204 mg, 1.17 mol) was added. The reaction mixturewas heated at 120 C for 2 h, cooled to 0 C followed by addition of ice-cold water. The precipitate obtained was filtered, washed thoroughly with water and dried to give 2,3-dichloro-5- nitropyridine. Yield: 220 g, (97%). M.P.: 53 C. 1H NMR (300 MHz, DMSO-d6): d 9.16 (d, 1H, J ¼ 2.4 Hz), 8.94 (d, 1H, J ¼ 2.4 Hz). 13C NMR (300 MHz, DMSO-d6): d 158.69, 137.36, 132.51, 130.13, 124.39. MS (ES): 193 (M th 1).
70.3%	With quinoline; trichlorophosphate; at 0 - 120℃; for 2h;Inert atmosphere;	Quinoline (0.3 mL, 2.34 mmol) was added to POCl3(0.5 mL 4.68 mmol) at 0 C under nitrogen. To this stirred mixture was added 2-hydroxy-3-chloro-5-nitro pyridine (816 mg, 4.68 mmol) (product obtained in step i) The reaction mixture was heated at 120 C for 2 hours, cooled to 0 C followed by addition of ice cold water. The precipitate obtained was filtered, washed with water and dried to obtain 2,3-dichloro-5-nitro pyridine. Yield: 630 mg (70.3 %); m.p.: 53 C; *H NMR (DMSO-d6) delta: 8.94 (d, 1H, J = 2.5 Hz), 9.16 (d, 1H, J = 2.5 Hz).
70.3%	With quinoline; trichlorophosphate; at 0 - 120℃; for 2h;Inert atmosphere;	Quinoline (0.3 mL, 2.34 mmol) was added to POCl3 (0.5 mL 4.68 mmol) at 0 C under nitrogen. To this stirred mixture was added <strong>[22353-38-4]2-hydroxy-3-chloro-5-nitropyridine</strong> (816 mg, 4.68 mmol) obtained in step a. The reaction mixture was heated at 120 C for 2 h, and was cooled to 0 C followed by addition of ice-cold water. The precipitate obtained was filtered, washed with water and dried to obtain 2,3-dichloro-5-nitropyridine. Yield: 70.3 %; *H NMR (DMSO-d6): delta 9.16 (d, J=1.8HZ, 1H), 8.60 (d, J=1.8Hz, 1H); MS (ES): m/z 193 (M+l).

	With thionyl chloride; at 20 - 100℃; for 2h;	2-HYDROXY-5-NITROPYRIDINE (50 g, 357 mmol) AND N-CHLOROSUCCINIMIDE (55 g, 410 mmol) were suspended in anhydrous DMF (150 mL). The suspension was stirred at room temperature for 18 hours. The resulting homogeneous reaction mixture was diluted by the slow addition of water (750 mL), which resulted in a pale yellow precipitate. The solids were isolated via filtration and dried under high vacuum to provide 3-CHLORO-5-NITRO- 2-hydroxypyridine (59 g, 95% yield). 3-CHLORO-5-NITRO-2-HYDROXY-PYRIDINE (20 g) was added in small portions to thionylchloride (200 mL) under vigorous stirring. The suspension was heated to 100 C within 1 hour, stirred at 100 C for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water (3 x 200 mL) and the organic layer was dried over MGS04. The solvent was removed under reduced pressure to give 2, 3-dichloro-5-nitropyridine (18 g) was obtained as a pale yellow solid. A solution of 2, 3-dichloro-5-nitropyridine (9.75 g) and potassium iodide (29 g) in acetic acid (120 mL, degassed with nitrogen) was heated to 100 C for 1.5 hours under nitrogen. The brown solution was cooled to room temperature and then ethyl acetate (300 ML) added. The organic phase was separated and washed with water (2 x 100 mL) and dilute aqueous sodium sulfite (100 mL). Evaporation of the solvent gave crystalline 3-chloro-2-iodo-5-nitro-pyridine (13.11 g). A suspension of copper cyanide (7 g) and 3-CHLORO-2-IODO-5-NITRO-PYRIDINE (7 g) in acetonitrile (200 mL) was heated to 80 C within 1 hour and stirred at 80 C for 5 hours. The solvent was evaporated and the residue was filtered in ethyl acetate over silicon dioxide gave 3-CHLORO-2-CYANO-5-NITRO-PYRIDINE (4.26 g). A solution of tin chloride (52 g) and 3-CHLORO-2-CYANO-5-NITRO-PYRIDINE (10.3 g) was stirred in ethyl acetate (200 ML) at room temperature for 10 minutes and at 70 C for 4 hours. The solution was cooled to room temperature and diluted with ethyl acetate (500 mL). Sodium bicarbonate (100 g) added in four portions to the mixture within 4 hours. The mixture was stirred vigorously for 20 hours. The suspension was filtered and the filtrate was washed with saturated aqueous sodium bicarbonate solution. The solvent was evaporated to give 5-amino-3-chloro-2-cyanopyridine (4.34 g) as an off-white powder. Step (f) Bromine (7.22 g) was added to a stirring mixture of 5-amino-3-chloro- 2-CYANOPYRIDINE (4.61 g) and sodium acetate (4.81 g) in anhydrous acetic acid (150 mL) at room temperature. The mixture was stirred at 60C for 2 hours. The solvents and excess bromine were evaporated and the residue was recrystalliezed from ethyl acetate to give 5-AMINO-6-BROMO-3-CHLORO-2-CYANO-PYRIDINE (6.23 g). 5-Amino-6-bromo-3-chloro-2-cyano-pyridine (1.6 g) was dissolved in tetrahydrofuran (5 mL) at room temperature. NN-DIMETHYLAMINOPYRIDINE (0.5 g) followed by di-tert-butyl dicarbonate (3.78 g) in small portions were added to the solution and the mixture was stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue was dissolved in dicloromethane (60 mL). Trifluoroacetic acid (1 g) was added to the solution and the mixture was stirred for 1 hour. The solvent was removed by evaporation and product was purified from the residue by column chromatography (EtOAc/hexanes 1/1) to give tert-butyl 2-bromo-5-chloro-6-cyano-pyridin-3-yl-carbamate (1 g). MS (obs. ) : 333 (M + 1)
	With quinoline; trichlorophosphate; at 0 - 120℃; for 1.5h;	A 2L flask with mechanical stirrer and thermocouple was charged with POCl3 (200 g, 1.30 mol). The flask was cooled in an ice bath to an internal temperature of 0-5 C. as quinoline (84 g, 0.65 mol) was added. The product of Example 2A (227 g, 1.30 mol) was added in portions, so as to maintain the reaction temperature below 10 C. The cold bath was removed, and the mixture was warmed to 120 C. for 90 minutes. The temperature was decreased to 100 C. and the reaction mixture was quenched by addition of water (500 mL) maintaining the internal temperature between 100-110 C. After complete addition, the mixture was cooled in ice to 0-5 C. for 1 hour and filtered. The filter cake was washed with cold water and dried under vacuum at 40 C. to provide the title compound. 1H NMR (CDCl3, 300 MHz) delta 8.39 (d, J=3 Hz, 1H), 9.16 (d, J=3 Hz, 1H).
	With trichlorophosphate; In water; acetonitrile; at 23 - 80℃; for 27h;	A mixture of <strong>[22353-38-4]3-chloro-2-hydroxy-5-nitropyridine</strong> (36.0 g), acetonitrile (72 mL), and phosphorus oxychloride (37.5 g) was heated to 80 C. The reaction was then stirred at this temperature for about 15 hours. After cooling the reaction to 40 C., water (27 g) was added, while maintaining the temperature below 70 C. The temperature was adjusted to 45 C., and then more water (189 g) was added slowly. The reaction was then cooled to 23 C., stirred for at least 12 hours, and then filtered. After washing the wet cake with water, the product was dried in a vacuum oven. 1H NMR (400 MHz/CDCl3) delta 9.10 (d, J=2.5 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H)
	In thionyl chloride; ethyl acetate;	Step (b) 3-Chloro-5-nitro-2-hydroxy-pyridine (20 g) was added in small portions to thionylchloride (200 mL) under vigorous stirring. The suspension was heated to 100 C. within 1 h and stirred at 100 C. for 1 h. After cooling the solution to RT, the solvent was removed under reduced pressure, the residue dissolved in AcOEt, and washed with water (3* 200 mL). The organic layer was dried over MgSO4, and the solvent was removed under reduced pressure. 2,3-Dichloro-5-nitropyridine (18 g) was obtained as a pale yellow solid.
	With phosphorus pentachloride; trichlorophosphate; In water;	EXAMPLE 12 This example illustrates the preparation of exo-3-(5,6-dichloropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane. <strong>[22353-38-4]3-Chloro-2-hydroxy-5-nitropyridine</strong> (4.8 g) was added to phosphorus oxychloride (11 ml) and phosphorus pentachloride (4.45 g) and the mixture refluxed overnight. The mixture was then cooled to room temperature and evaporated under reduced pressure. Iced water was added to the mixture and a solid product formed. The solid was removed by filtration, washed with water and air-dried to give 2,3-dichloro-5-nitropyridine (3.94 g).
	With trichlorophosphate; In quinoline; water;	Example 2B 2,3-dichloro-5-nitropyridine A 2 L flask with mechanical stirrer and thermocouple was charged with POCl3 (200 g, 1.30 mol). The flask was cooled in an ice bath to an internal temperature of 0-5 C. as quinoline (84 g, 0.65 mol) was added. The product of Example 2A (227 g, 1.30 mol) was added in portions, so as to maintain the reaction temperature below 10 C. The cold bath was removed, and the mixture was warmed to 120 C. for 90 minutes. The temperature was decreased to 100 C. and the reaction mixture was quenched by addition of water (500 mL) maintaining the internal temperature between 100-110 C. After complete addition, the mixture was cooled in ice to 0-5 C. for 1 hour and filtered. The filter cake was washed with cold water and dried under vacuum at 40 C. to provide the title compound. 1H NMR (CDCl3, 300 MHz) delta 8.39 (d, J=3 Hz, 1H), 9.16 (d, J=3 Hz, 1H).
	With quinoline; trichlorophosphate; at 120℃; for 2h;	Place phosphorus oxychloride (11.28 mL, 121 mmol) in a round-bottom flask and cool to 0 C. Add quinoline (7.15 mL, 60.5 mmol) followed by <strong>[22353-38-4]3-chloro-5-nitro-pyridin-2-ol</strong> (21.13 g, 121 mmol) in <n="14"/>portions. Heat reaction to 120 C for 2 hours. Pour reaction onto ice and triturate with water. Filter off the solid and wash with water. Dry thoroughly to yield 19.95 g (86%) of the title compound: 1H NMR deltaH (400 MHz, DMSO) 9.20 (s, IH), 8.97 (s, IH).
	With quinoline; trichlorophosphate; at 0 - 120℃; for 1.5h;	EXAMPLE 2B 2,3-dichloro-5-nitropyridine A 2 L flask with mechanical stirrer and thermocouple was charged with POCl3 (200 g, 1.30 mol). The flask was cooled in an ice bath to an internal temperature of 0-5 C. as quinoline (84 g, 0.65 mol) was added. The product of Example 2A (227 g, 1.30 mol) was added in portions, so as to maintain the reaction temperature below 10 C. The cold bath was removed, and the mixture was warmed to 120 C. for 90 minutes. The temperature was decreased to 100 C. and the reaction mixture was quenched by addition of water (500 mL) maintaining the internal temperature between 100-110 C. After complete addition, the mixture was cooled in ice to 0-5 C. for 1 hour and filtered. The filter cake was washed with cold water and dried under vacuum at 40 C. to provide the title compound. 1H NMR (CDCl3, 300 MHz) delta 8.39 (d, J=3 Hz, 1H), 9.16 (d, J=3 Hz, 1H).
	With quinoline; trichlorophosphate; at 0 - 120℃; for 2h;	Quinoline (0.3 mL, 2.34 mmol) was added to POCl3 (0.5 mL 4.68 mmol) at 0 0C under nitrogen. To this stirred mixture was added 2-hydroxy-3-chloro-5-nitro pyridine (816 mg,4.68 mmol) (product obtained in step i ) The reaction mixture was heated at 120 0C for 2 hours, cooled to 0 0C followed by addition of ice cold water. The precipitate obtained was filtered, washed with water and dried to obtain 2,3-dichloro-5-nitro pyridine.Yield: 630 mg (70.3%); m.p.: 53 0C; 1H NMR (DMSOd6) delta: 8.94 (d, IH, J = 2.5 Hz), 9.16(d, IH, J = 2.5 Hz) .

Reference： [1]Synthesis,1990,p. 499 - 501
[2]European Journal of Medicinal Chemistry,2012,vol. 58,p. 355 - 360
[3]Patent: WO2013/117963,2013,A1 .Location in patent: Page/Page column 21
[4]Patent: WO2014/207508,2014,A1 .Location in patent: Page/Page column 55
[5]Roczniki Chemii,1968,vol. 42,p. 2079,2084
Chem.Abstr.,1969,vol. 70,p. 106327
[6]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1952,vol. 72,p. 378,380
Chem.Abstr.,1953,p. 6403
[7]Patent: WO2004/50637,2004,A2 .Location in patent: Page 66-67
[8]Patent: US2004/242644,2004,A1 .Location in patent: Page 4
[9]Patent: US2006/35937,2006,A1 .Location in patent: Page/Page column 10
[10]Patent: US2003/114457,2003,A1
[11]Patent: US5922732,1999,A
[12]Patent: US2005/261348,2005,A1
[13]Patent: WO2007/53394,2007,A1 .Location in patent: Page/Page column 12-13
[14]Patent: US2004/242641,2004,A1 .Location in patent: Page 4
[15]Patent: WO2008/35306,2008,A1 .Location in patent: Page/Page column 24

4
[ 22353-40-8 ]
[ 98121-41-6 ]

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

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

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

5
[ 22353-40-8 ]
[ 75336-86-6 ]
[ 900184-05-6 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3719 - 3742

6
[ 22353-40-8 ]
[ 951771-92-9 ]

Yield	Reaction Conditions	Operation in experiment
32%		(3-Chloro-5-nitro-pyridin-2-yl)-(4-chloro-phenyl)-amineA suspension of NaH (2.07 g, 51.8 mmol) in anhydrous THF (60 ml) was treated with a solution of chloroaniline (6.68 g, 51.8 mmol) in THF (40 ml) and the mixture was stirred for 2 h at rt. A solution of <strong>[22353-40-8]2,3-dichloro-5-nitro-pyridine</strong> (5.0 g, 25.9 mmol) in THF (40 ml) was then added and the mixture was heated to reflux for 18 h. It was then poured onto a sat. aq. solution of Na2COs and the THF was evaporated. The aq. phase was extracted with EtOAc and the combined org. layers were then dried and concentrated in vacuo. Purification by flash chromatography (Hex/EtOAc 9:1 ) and crystallization from Hex/EtOAc afforded (3- chloro-5-nitro-pyridin-2-yl)-(4-chloro-phenyl)-amine (2.36 g, 32 %). LC/MS (ES+): 284, 286 [M+H].

Reference： [1]Patent: WO2007/113276,2007,A1 .Location in patent: Page/Page column 38

7
[ 22353-40-8 ]
[ 110860-92-9 ]

Reference： [1]Synthesis,1990,p. 499 - 501
[2]Tetrahedron Letters,2013,vol. 54,p. 2303 - 2307
[3]Patent: US6133253,2000,A

8
[ 22353-40-8 ]
[ 488713-29-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide; In acetic acid; at 100℃; for 1.5h;	2-HYDROXY-5-NITROPYRIDINE (50 g, 357 mmol) AND N-CHLOROSUCCINIMIDE (55 g, 410 mmol) were suspended in anhydrous DMF (150 mL). The suspension was stirred at room temperature for 18 hours. The resulting homogeneous reaction mixture was diluted by the slow addition of water (750 mL), which resulted in a pale yellow precipitate. The solids were isolated via filtration and dried under high vacuum to provide 3-CHLORO-5-NITRO- 2-hydroxypyridine (59 g, 95% yield). 3-CHLORO-5-NITRO-2-HYDROXY-PYRIDINE (20 g) was added in small portions to thionylchloride (200 mL) under vigorous stirring. The suspension was heated to 100 C within 1 hour, stirred at 100 C for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water (3 x 200 mL) and the organic layer was dried over MGS04. The solvent was removed under reduced pressure to give 2, 3-dichloro-5-nitropyridine (18 g) was obtained as a pale yellow solid. A solution of 2, 3-dichloro-5-nitropyridine (9.75 g) and potassium iodide (29 g) in acetic acid (120 mL, degassed with nitrogen) was heated to 100 C for 1.5 hours under nitrogen. The brown solution was cooled to room temperature and then ethyl acetate (300 ML) added. The organic phase was separated and washed with water (2 x 100 mL) and dilute aqueous sodium sulfite (100 mL). Evaporation of the solvent gave crystalline 3-chloro-2-iodo-5-nitro-pyridine (13.11 g). A suspension of copper cyanide (7 g) and 3-CHLORO-2-IODO-5-NITRO-PYRIDINE (7 g) in acetonitrile (200 mL) was heated to 80 C within 1 hour and stirred at 80 C for 5 hours. The solvent was evaporated and the residue was filtered in ethyl acetate over silicon dioxide gave 3-CHLORO-2-CYANO-5-NITRO-PYRIDINE (4.26 g). A solution of tin chloride (52 g) and 3-CHLORO-2-CYANO-5-NITRO-PYRIDINE (10.3 g) was stirred in ethyl acetate (200 ML) at room temperature for 10 minutes and at 70 C for 4 hours. The solution was cooled to room temperature and diluted with ethyl acetate (500 mL). Sodium bicarbonate (100 g) added in four portions to the mixture within 4 hours. The mixture was stirred vigorously for 20 hours. The suspension was filtered and the filtrate was washed with saturated aqueous sodium bicarbonate solution. The solvent was evaporated to give 5-amino-3-chloro-2-cyanopyridine (4.34 g) as an off-white powder. Step (f) Bromine (7.22 g) was added to a stirring mixture of 5-amino-3-chloro- 2-CYANOPYRIDINE (4.61 g) and sodium acetate (4.81 g) in anhydrous acetic acid (150 mL) at room temperature. The mixture was stirred at 60C for 2 hours. The solvents and excess bromine were evaporated and the residue was recrystalliezed from ethyl acetate to give 5-AMINO-6-BROMO-3-CHLORO-2-CYANO-PYRIDINE (6.23 g). 5-Amino-6-bromo-3-chloro-2-cyano-pyridine (1.6 g) was dissolved in tetrahydrofuran (5 mL) at room temperature. NN-DIMETHYLAMINOPYRIDINE (0.5 g) followed by di-tert-butyl dicarbonate (3.78 g) in small portions were added to the solution and the mixture was stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue was dissolved in dicloromethane (60 mL). Trifluoroacetic acid (1 g) was added to the solution and the mixture was stirred for 1 hour. The solvent was removed by evaporation and product was purified from the residue by column chromatography (EtOAc/hexanes 1/1) to give tert-butyl 2-bromo-5-chloro-6-cyano-pyridin-3-yl-carbamate (1 g). MS (obs. ) : 333 (M + 1)
	With Ki; sodium sulfate; In acetic acid; ethyl acetate;	Step (c) A solution of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (9.75 g) and KI (29 g) in HOAc (120 mL, degassed with N2) was heated to 100 C. for 1.5 h under N2. The brown solution was cooled to room temperature, AcOEt (300 mL) added and the organic phase washed with water (2 times 100 mL) and dilute aequ. Na2SO3 (100 mL). Evaporation of the solvent gave crystalline 3-chloro-2-iodo-5-nitro-pyridine (13.11 g).
	With acetic acid; sodium iodide; at 90℃; for 4h;	<strong>[22353-40-8]2,3-Dichloro-5-nitropyridine</strong> (2.892 g, 14.99 mmol) and sodium iodide (11.23 g, 74.9 mmol) were dissolved in acetic acid (15 mL). The reaction was heated to 90C for 4 hours, then diluted with water and filtered. The resulting solid was dried on the filter for a few minutes, and then transferred to a flask and dried invacuo over the weekend to give the title compound, which was used in the next step without further purification. NMR oe (ppm)(CDC13): 9.07 (d, 2H), 8.40 (d, 2H).

With acetic acid; potassium iodide; at 10 - 100℃; for 3h;

(Step 1) (1066) To a solution of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (1.0 g, 5.181 mmol) in acetic acid (12 mL) was added potassium iodide (3.01 mg, 18.13 mmol) at room temperature, and the mixture was stirred at 100C for 3 hr. The reaction mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; 20% ethyl acetate/hexane) to give crude 3-chloro-2-iodo-5-nitropyridine (1.6 g) as a brown solid.

Reference： [1]Patent: WO2004/50637,2004,A2 .Location in patent: Page 66-67
[2]Patent: US2003/114457,2003,A1
[3]Patent: WO2014/139388,2014,A1 .Location in patent: Page/Page column 147; 148
[4]Patent: EP2975031,2016,A1 .Location in patent: Paragraph 1066

9
[ 22353-40-8 ]
[ 207284-20-6 ]
[ 906819-18-9 ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine; In dichloromethane; at 20℃; for 24.25h;	Solid <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (1 , 20 g, 88 mmol) was finely ground and added portion wise over -15 min to a stirred solution of 2(S)-ethylpiperazine (2, 11 g, 90%; 10 g, 8.8 mmol) and triethylamine (14 ml_, 9.7 g, 96 mmol) in dichloromethane (400 mL). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed by rotary EPO <DP n="114"/>evaporation under reduced pressure and the resulting brown liquid was adsorbed onto ~75 g silica gel. Purification by silica gel chromatography [2.5% (7 M ammonia in methanol) in dichloromethane) gave piperazinylpiperidine 3 as a yellow-orange semi-solid (17 g, 72% yield). MS: [M + H]+ = 271.

Reference： [1]Patent: WO2006/88920,2006,A1 .Location in patent: Page/Page column 112-113

10
[ 22353-38-4 ]
[ 10025-87-3 ]
[ 22353-40-8 ]

Yield	Reaction Conditions	Operation in experiment
	In quinoline;	Intermediate 1.2: 2,3-Dichloro-5-nitropyridine At 0 C., 39.9 g of quinoline and, after 5 minutes and a little at a time, 108 g of <strong>[22353-38-4]3-chloro-2-hydroxy-5-nitropyridine</strong> were added to 95 g of phosphorus oxytrichloride. After addition of a further 30 ml of phosphorus oxytrichloride, the mixture was heated at reflux temperature for 2 hours. For work-up, the reaction mixture was cooled to 50-60 C. and stirred into approximately 3 1 of ice-water. The mixture was subsequently stirred for another 2 hours, and the resulting solid fraction was then filtered off, washed with 500 ml of water and dried under reduced pressure. Yield: 110.7 g.

Reference： [1]Patent: US6432880,2002,B1

11
[ 22353-40-8 ]
[ 7439-89-6 ]
[ 98121-41-6 ]

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

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

12
[ 22353-40-8 ]
[ 57260-71-6 ]
[ 936368-58-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 60h;	Place <strong>[22353-40-8]2,3-dichloro-5-nitro-pyridine</strong> (2.0 g, 10.36 mmol), piperazine-1-carboxylic acid tert-butyl ester (2.12 g, 11.40 mmol), and potassium carbonate (1.72 g, 12.43 mmol) in DMF (20 mL). Heat to 80 C for 2.5 days. Cool to room temperature and add ethyl acetate and water. Separate organic layer and wash with water and saturated aq. sodium chloride. Collect organic layer, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 20% EtOAc:hexane to yield 3.29 g (93%) of 4-(3-chloro-5-nitro-pyridin-2-yl)-piperazine-l-carboxylic acid tert- butyl ester. MS(ES): m/z = 341 [M+H]

Reference： [1]Patent: WO2007/53394,2007,A1 .Location in patent: Page/Page column 14-15

13
[ 580-18-7 ]
[ 22353-40-8 ]
[ 1013695-65-2 ]

Yield	Reaction Conditions	Operation in experiment
100%		In a 250 ml of round bottom flask, 14.5 g (0.1 mol) of quinolin-3- ol was placed and 100ml of dry dimethyl formamidewas added. To the stirred solution, 39.0 g (0.12 mol) of Cs2CO3 was added at 0 C. Stirring was continued and after 30 min 1.9 g (0.1 mol) of 2,3- dichloro-5-nitropyridine (3) was added. Stirring was continued further for 3e4 h and the reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-water and extracted with ethyl acetate. Organic layer was separated and dried over sodium sulfate (Na2SO4), solvent was removed under vacuum and to the resulting mass was added water (50 ml), extracted with ethyl acetate, dried over sodium sulfate and concentrated under vacuum to obtain crude 3-((3-chloro-5-nitropyridin-2-yl)oxy) quinoline that was purified using flash chromatography. 1H NMR (300 MHz, DMSO-d6): d 9.03 (d, J ¼ 2.4 Hz, 2H), 8.95 (d, J ¼ 2.4 Hz, 1H), 8.35 (d, J ¼ 2.7 Hz, 1H), 8.09 (d, J ¼ 8.1 Hz, 1H), 7.98 (d, J ¼ 8.1 Hz, 1H), 7.82 (t, J ¼ 6.9 Hz, 1H), 7.69 (t, J ¼ 8.1 Hz, 1H). HRMS (m/z): [M]th calcd for C14H8ClN3O3, 301.0323; found, 301.1109.
96%		Dry dimethylformamide (10 mL) was added to 3-hydroxy quinoline (459 mg, 3.16 mmol) under stirring. To the stirred solution was added CS2CO3 (1.03 g, 3.16 mmol) at room temperature. After 30 minutes 2,3-dichloro-5-nitro pyridine (610 mg, 3.16 mmol) obtained in, step ii, was added and the stirring was continued further for 18 hours. The solvent was removed under vacuum and to the resulting mass was added water (20 mL), extracted with ethyl acetate, dried over sodium sulfate and concentrated under vacuum to obtain crude 3-(3- chloro-5-nitro-pyridin-2-yloxy)-quinoline that was purified by column chromatography(silica gel, gradient 10-30 % ethyl acetate in pet ether to obtain the title compound.Yield: 911 mg (96%); m.p.: 123-127 0C; 1H NMR (DMSOd6) delta: 7.69 (t, IH, J= 6.99), 7.82(t, IH, J = 6.89), 7.98 (d, IH, J = 8.09 Hz), 8.09 (d, IH, J = 8.39 Hz), 8.35 (d, IH, J = 2.8Hz), 8.95 (d, IH, 2.51 Hz), 9.03 (d, 2H, J = 2.5 Hz); MS: 302 (M+l).
	With caesium carbonate; In N-methyl-acetamide; methanol; chloroform; water;	Step 1 Preparation of 3-(3-chloro-5-nitro-pyridin-2-yloxy)-quinoline Dry dimethylformamide (10 mL) was added to <strong>[580-18-7]3-hydroxy-quinoline</strong> (459 mg, 3.16 mmol) under stirring and cesium carbonate was added (1.03 g, 3.16 mmol) at room temperature (25 C.). After 30 minutes 2,3-dichloro-5-nitro pyridine (610 mg, 3.16 mmol) (as obtained in step 2, example 5), was added and the stirring was continued further for 18 hours. The solvent was removed under vacuum and to the resulting mass was added water (20 mL), extracted with ethyl acetate, dried over sodium sulfate and concentrated under vacuum to obtain crude product that was further purified by column chromatography (silica gel-~200 mesh, 1% methanol in chloroform) to obtain the title compound. Yield: 911 mg (96%); 1H NMR (DMSO-d6, 300 MHz): delta 7.69 (t, 1H), 7.82 (t, 1H), 7.98 (d, 1H), 8.09 (d, 1H), 8.35 (d, 1H), 8.95 (d, 1H), 9.03 (d, 2H).

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 58,p. 355 - 360
[2]Patent: WO2008/35306,2008,A1 .Location in patent: Page/Page column 24
[3]Patent: US2009/318465,2009,A1

14
[ 580-18-7 ]
[ 22353-40-8 ]
[ 1013695-97-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 8 N-[5-Chloro-6-(quinolin-3-yloxy)-pyridine-3-yl]-4-methoxy-benzene sulfonamide (Compound 8) The title compound was prepared in three steps starting from 2,3-dichloro-5-nitro pyridine and <strong>[580-18-7]3-hydroxy-quinoline</strong>

Reference： [1]Patent: US2009/318465,2009,A1

15
[ 22353-40-8 ]
[ 75-89-8 ]
[ 1206539-38-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h;	A solution of <strong>[22353-40-8]2,3-dichloro-5-nitro-pyridine</strong> (5 g, Synthesis, 1990 (6), 499- 501), 2,2,2-trifluoroethanol (2.6 g) and potassium carbonate (5.4 g) X N.N- dimethylformamide (50 ml) was stirred at 800C for 1 hour. The reaction mixture was poured into ice water. The precipitate was isolated by filtration and dried under high vacuum to afford 3-chloro-5-nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine (5.65 g).

Reference： [1]Patent: WO2010/9968,2010,A1 .Location in patent: Page/Page column 45

16
[ 22353-40-8 ]
[ 98-17-9 ]
[ 940303-07-1 ]

Yield	Reaction Conditions	Operation in experiment
		Production of 3-chloro-5-nitro-2- [ 3- ( trifluoromethyl )phenoxy] pyridineUnder an argon atmosphere, to a solution of 3- ( trifluoromethyl ) phenol (0.42 g) in tetrahydrofuran (8.0 mL) was added sodium hydride (60% dispersion in mineral oil, 0.11 g) under ice-cooling. After stirring under ice-cooling for 1 hr, 2 , 3-dichloro-5-nitropyridine (0.50 g) was added. After stirring at room temperature for 2.5 hr, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=9 : l->3 : 1 ) to give the title compound (746 mg) as a colorless oil.1H-NMR (CDCl3) delta: 7.35-7.43 (IH, m) , 7.45-7.51 (IH, m) , 7.55-7.65 (IH, m) , 8.61 (IH, d, J= 2.7 Hz), 8.88 (IH, d, J= 2.7 Hz)

Reference： [1]Patent: WO2007/64045,2007,A1 .Location in patent: Page/Page column 292
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 8030 - 8050

17
[ 22353-40-8 ]
[ 920-66-1 ]
[ 1355070-93-7 ]

Yield	Reaction Conditions	Operation in experiment
100%		Preparation 513-Chloro-2-(1 ,1 ,1 ,3,3, -hexafluoropropan-2-yloxy)-5-nitropyridine1 ,1 ,1 ,3,3,3-Hexafluoropropan-2-ol (1 .74 g, 10.35 mmol) was added to a suspension of sodium hydride in mineral oil (60%, 450 mg, 1 1 .25 mmol) in anhydrous THF (10 mL) at 0C and over 15 minutes. The resulting suspension was stirred for 30 minutes and 2,3- dichloro-5-nitropyridine (1 .50 g, 7.77 mmol) was added portionwise. The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The resulting crude was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). Combined organics were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as an orange oil (2.55 g, 100%).1H NMR (400 MHz, CDCI3): delta 6.48 (m, 1 H), 8.58 (m, 1 H), 9.00 (m, 1 H).19F NMR (400 MHz, CDCI3): delta -73.0LCMS Rt = 3.48 minutes MS Molecular ion not observed

Reference： [1]Patent: WO2012/7869,2012,A2 .Location in patent: Page/Page column 94

18
[ 110-85-0 ]
[ 22353-40-8 ]
[ 1368438-85-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	In N,N-dimethyl-formamide; at 20℃; for 3h;	Amine-A: l-(3-chloro-5-nitroA mixture of piperazine (569 mg, 6.61 mmol) and <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (255mg, 1.320 mml) in DMF (5ml) was stirred at r.t. for 3hrs. The mixture was poured into water, extracted w/EtOAc (4x). The combined organic layer was dried (Na2S04) andconcentrated to afford l-(3-chloro-5-nitropyridin-2-yl)piperazine (286mg, 1.120 mmol, 85 % yield). 1H-NMR(CDCl3, 400MHz) delta 8.96 (1H, s), 8.32 (1H, s), 3.70 (4H,m), 3.02 (1H, s), 3.70 (4H,m).

Reference： [1]Patent: WO2012/44531,2012,A1 .Location in patent: Page/Page column 51

19
[ 22353-40-8 ]
[ 761446-44-0 ]
[ 1445968-58-0 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In acetonitrile; at 80℃;	A mixture of chloropyridine 36a (150 g, 0.78 mol), 23d (177.9 g, 0.855 mol), Pd(dppf)CI2 (17 g, 0.023 mol) and Na2C03 (972 mL, 1.943 mol) in MeCN (1200 mL) is heated to 80C overnight. The mixture is poured into H20 (1500 mL) and extracted with EtOAc (500 ml_ x 2). The combined organic layers are washed with brine and dried (Na2S04). The solvent is evaporated in vacuo to afford pyrazole 36b.

Reference： [1]Patent: WO2013/91096,2013,A1 .Location in patent: Page/Page column 55-56

20
[ 7651-81-2 ]
[ 22353-40-8 ]
[ 1013695-67-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;	Isoquinolin-3-ol was reacted with 2,3-dichloro-5-nitro pyridine in dry DMF and CS2CO3as base at room temperature to obtain 3-(3-chloro-5-nitropyridin-2-yloxy)isoquinoline which was further converted to 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine by reaction with stannous chloride dehydrate as reducing agent at room temperature to obtain 5-chloro-6- (isoquinolin-3-yloxy)pyridin-3-amine.

Reference： [1]Patent: WO2013/117963,2013,A1 .Location in patent: Page/Page column 21

21
[ 22353-40-8 ]
[ 32864-38-3 ]
tert-butyl ethyl (3-chloro-5-nitropyridin-2-yl)malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 20 - 30℃;	Step 1. tert-Butyl ethyl (3-chloro-5-nitropyridin-2-yl)malonate <strong>[22353-40-8]2,3-Dichloro-5-nitropyridine</strong> (1.78 g, 9.22 mmol, Matrix Scientific) and tert-butyl ethyl propane-1,3-dioate (1.9 mL, 10 mmol, Sigma-Aldrich) were dissolved in dimethyl sulfoxide (20 mL). K2CO3 (2.5 g, 18 mmol) was added and the reaction mixture was stirred at room temperature overnight. Then water was added and the pH was adjusted to pH 7 with 1 M aq. HCl. The mixture was then extracted with EtOAc and the organic phase was washed with brine and dried over Na2SO4. After solvent evaporation under reduced pressure, a liquid product was obtained which was used in the next step without further purification. LCMS calc. for C10H10ClN2O6 (M-tBu-F2H)+ m/z=289.0. found: 289.0.

Reference： [1]Patent: US2015/57265,2015,A1 .Location in patent: Paragraph 1620; 1621

22
[ 22353-40-8 ]
[ 1572-99-2 ]
ethyl 2-(3-chloro-5-nitropyridin-2-yl)-2-cyanopropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;	Step 1: Synthesis of ethyl 2-(3-chloro-5-nitropyridin-2-yl)-2-cyanopropanoate To a solution of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (90g, 466 mmol) in 500 ml of dimefhylformamide, 60g of ethyl 2-cyanopropanoate (472 mmol) and 150g of potassium carbonate were added. The resulting reaction mixture was stirred overnight at 60C. After cooling down, 2.0 L of water were added and the reaction mixture was extracted with ethyl acetate (3 x 300 ml). The combined organic layers were washed with water (200 ml), brine (200 ml), dried over over anhydrous sodium sulphate and concentrated. This afforded 105g of the title compound (80%), which was used in the next steep without purification.

Reference： [1]Patent: WO2015/55535,2015,A1 .Location in patent: Page/Page column 147

23
[ 5382-16-1 ]
[ 22353-40-8 ]
1-(3-chloro-5-nitropyridin-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.78 g	With potassium hydrogencarbonate; In ethyl acetate; at 20℃;Inert atmosphere;	Step 1: 1-(2-fluoro-4-nitrophenyl)piperidin-4-ol[003391 To a solution of 1,2-difluoro-4-nitrobenzene (4.77 g, 30.00 mmol) in EtOAc (50 mL) was added TEA (9.llg, 90.00 mmol) and piperidin-4-ol (3.64 g, 36.00 mmol). The mixture was stirred at ft under N2 overnight. After the completion of the reaction, the mixture was filtered and the filtrate was concentrated in vacuo. The crude was purified by silica column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a yellow solid (4.00 g, 55.5 %). Step 1: 1-(3-chloro-5-nitropyridin-2-yl)piperidin-4-ol[004991 The title compound was prepared by the procedure described in step 1 of Example 28 using <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (1.93 g, 10.0 mmol), piperidin-4-ol (1.11 g, 11.0 mmol) and potassium bicarbonate (2.00 g, 20.0 mmol) to give the title compound as a yellow solid (2.78 g, 108 %). The compound was characterized by the following spectroscopic data:MS(ESI, pos.ion)m/z: 258.0(M+1); exact mass of C,0H,2C1N303: 257.06.
905 mg	In N,N-dimethyl-formamide; at 50℃; for 0.5h;	<strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (1.0g) in N, N- dimethylformamide (5.1) at room temperature was added 4-hydroxypiperidine(1.05g) and It was stirred for 0.5 h at 50 . After the reaction, it cooled to room temperature and, after addition of water, the precipitated solid was collected by filtration. Suspension by washing the resulting solid with ethanol, 1- (3-chloro-5-nitro-pyridin-2-yl) piperidin-4-ol to give the (905mg) as a yellow solid

Reference： [1]Patent: WO2015/90232,2015,A1 .Location in patent: Paragraph 00339; 00499
[2]Patent: KR2015/2661,2015,A .Location in patent: Paragraph 0419; 0420; 0421

24
[ 22353-40-8 ]
4-(3-fluorobenzyl)piperidine hydrochloride salt [ No CAS ]
3-chloro-2-(4-(3-fluorobenzyl)piperidin-1-yl)-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6.42 g	With potassium hydrogencarbonate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere;	Step 5: 3-((1-(2-chloro-4-nitrophenyl)piperidin-4-yl)methyl)benzonitrile[001881 To a solution of 2-chloro-1-fluoro-4-nitrobenzene (1.53 g, 6.46 mmol) in DMF (25 mL) was added potassium carbonate (4.47 g, 32.31 mmol) and 3-(piperidin-4-ylmethyl)benzonitrile hydrochloride (1.53 g, 6.46 mmol). The mixture was stirred at 90C under N2 overnight. After the reaction was finished, the mixture was cooled to ft overnight, and then poured in DCM (100 mL). The resulted mixture was washed with water (100 mL x 2) and brine (100 mL). The organic phase was dried over anhydrous Na2SO4 (10 g), filtered and concentrated in vacuo. The crude was purified by silica column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow solid (1.10 g, 47.8 %). Step 1: 3-chloro-2-(4-(3-fluorobenzyl)piperidin-1-yl)-5-nitropyridine[004891 The title compound was prepared by the procedure described in step 5 of Example 3 using 2,3-dichloro-5-nitropyndine (3.00 g, 15.54 mmol), 4-(3-fluorobenzyl)pipendine hydrochloride (4.29 g, 18.67 mmol) and potassium bicarbonate (4.67 g, 46.64 mmol) to give the title compound as a yellow solid (6.42 g, 118.2 %). The compound was characterized by the following spectroscopic data:MS(ESI, pos.ion)m/z: 350.2(M+1); exact mass of C,7H,7C1FN302: 349.10.

Reference： [1]Patent: WO2015/90232,2015,A1 .Location in patent: Paragraph 00188; 00489

25
[ 22353-40-8 ]
[ 78-83-1 ]
3-chloro-2-isobutoxy-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 16h;	To a mixture of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (Aldrich) (192 g, 1 mol) and 2-methylpropan-1-ol (112 g, 1.5 mol) in THF (1 l) was added t-BuOK (168 g, 1.5 mol) by portion with ice-bath. After addition, the reaction mixture was stirred at room temperature for 16 hrs. When TLC indicated the reaction was completed, the reaction mixture was quenched with saturated NH4Cl aqueous solution, extracted with EtOAc (3). The combined organic phases were washed with brine (2), dried over anhydrous magnesium sulfate and filtered. The filtration solution was concentrated under reduced pressure to give the title compound. LC-MS m/z Rt=1.01 mins; [M+H]+ 231, Method 5-95AB 1.5minLC_v003 1H NMR (400 MHz, CDCl3) delta 8.95 (1H, d), 8.44 (1H, d), 4.27 (2H, d), 2.17 (1H, m), 1.06 (6H, d).
	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 16h;Cooling with ice;	Step 1 : 3-chloro-2-isobutoxy-5-nitropyridine: To a mixture of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (Aldrich) (192 g, 1 mol) and 2-methylpropan-1-ol (1 12 g, 1.5 mol) in THF (1 I) was added f-BuOK (168 g, 1.5 mol) by portion with ice-bath. Aftrer addition, the reaction mixture was stirred at room temperature for 16 hrs. When TLC indicated the reaction was completed, the reaction mixture was quenched with saturated NH4CI aqueous solution, extracted with EtOAc (x3). The combined organic phases were washed with brine (x2), dried over anhydrous magnesium sulfateand filtered. The filtration solution was concentrated under reduced pressure to give the title compound. LC-MS m/z Rt = 1.01 mins; [M+H]+ 231 , Method 5-95AB 1.5minl_C_v003 1H NMR (400 MHz, CDCI3) delta 8.95 (1 H, d), 8.44 (1 H, d), 4.27 (2H, d), 2.17 (1 H, m), 1.06 (6H, d).

Reference： [1]Patent: US2015/183802,2015,A1 .Location in patent: Paragraph 1364-1367
[2]Patent: WO2015/102929,2015,A1 .Location in patent: Page/Page column 160

26
[ 22353-40-8 ]
[ 822-36-6 ]
3-chloro-2-(4-methyl-1H-imidazol-1-yl)-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate; In acetonitrile; at 20℃; for 10h;Inert atmosphere;	To a stirred solution of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (2 g, 10.36 mmol) in CH3CN (30 mL) under an argon atmosphere was added potassium carbonate (2.86 g, 20.72 mmol) and 4-methyl imidazole (1.7 g, 20.72 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with cold water (500 mL) and extracted with EtOAc (2 x 300 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 30% EtOAc:hexanes to afford 3-chloro-2-(4-methyl-1H-imidazol-1-yl)-5-nitropyridine (1.8 g, 73%) as an off-white solid. 1H-NMR (CDCl3, 400 MHz): delta 9.20 (s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 7.51 (s, 1H), 2.30 (s, 3H); LCMS: 238.8 (M+1); (column; X-Select CSH C-18 (50 × 3.0 mm, 3.5 mum); RT 1.03 min 0.05% Aq TFA: ACN; 0.80 mL/min).
73%	With potassium carbonate; In acetonitrile; at 20℃; for 10h;Inert atmosphere;	Synthesis of 3-chloro-2-(4-methyl-1H-imidazol-1-yl)-5-nitropyridine To a stirred solution of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (2 g, 10.36 mmol) in CH3CN (30 mL) under an argon atmosphere was added potassium carbonate (2.86 g, 20.72 mmol) and 4-methyl imidazole (1.7 g, 20.72 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with cold water (500 mL) and extracted with EtOAc (2300 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 30% EtOAc:hexanes to afford 3-chloro-2-(4-methyl-1H-imidazol-1-yl)-5-nitropyridine (1.8 g, 73%) as an off-white solid. 1H-NMR (CDCl3, 400 MHz): delta 9.20 (s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 7.51 (s, 1H), 2.30 (s, 3H); LCMS: 238.8 (M+1); (column; X-Select CSH C-18 (503.0 mm, 3.5 mum); RT 1.03 min 0.05% Aq TFA: ACN; 0.80 mL/min).

Reference： [1]Patent: WO2015/109109,2015,A1 .Location in patent: Paragraph 0734
[2]Patent: US2017/44182,2017,A1 .Location in patent: Paragraph 1014

27
[ 22353-40-8 ]
[ 178043-48-6 ]
3-chloro-2-(3-{2,6-dichloro-4-[(3,3-dichloroprop-2-en-1-yl)oxy]phenoxy}propoxy)-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.46 g	With sodium hydride; In tetrahydrofuran; at 20℃;Cooling with ice;	furnished with magnetic stirring, constant pressure dropping funnel, and the drying duct of the reaction bottle by adding sodium hydride (3.5mmol) and tetrahydrofuran (20 ml), ice-bath cooling and stirring 25-30min rear, dropping respectively 3-[ (2, 6-dichloro-4-(3, 3- two chlorine alkene propoxy)) phenoxy] propanol (2.85mmol) and 2, 3-dichloro-5-nitro pyridine (2.85mmol) tetrahydrofuran (10 ml) solution, slowly increasing the temperature to room temperature after the drop finishes reaction 10-12hr rear, water, ethyl acetate extraction, water washing, drying by anhydrous sodium sulfate, column chromatography (Vpetroleum ether/Vethyl acetate= 60/1) purification gets nocolor mucus title object 0.46 g.

Reference： [1]Journal of Agricultural and Food Chemistry,2015,vol. 63,p. 7469 - 7475
[2]Patent: CN105254558,2016,A .Location in patent: Paragraph 0168; 3142; 0169; 0170

28
[ 22353-40-8 ]
[ 6295-87-0 ]
(3-chloro-5-nitropyridin-2-yl)(pyridin-1-ium-1-yl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In acetonitrile; at 23℃; for 4h;	General procedure: Potassium carbonate (9.0 mmol) for 3a-t or triethylamine (9.0 mmol) for 3u was added to a solution of <strong>[6295-87-0]1-aminopyridinium iodide</strong> 1 (3.0 mmol) in acetonitrile (25 mL) for 3a-t or EtOH (25 mL) for 3u. The reaction mixtures were stirred vigorously for 10-20 min at room temperature to give a dark purple solution, to which electrophiles 2a-u (3.0 mmol) were added in one portion. The mixtures were stirred at rt for 3-24 h except for 3e, which was heated under reflux for 5h. Mixtures 3a-t were filtered to remove inorganic salts, which were washed with acetonitrile 3-5 times. The combined filtrates were concentrated in vacuo and the residues were purified either by gradient elution chromatography over silica gel and/or by recrystallization.

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 20 - 24

29
[ 22353-40-8 ]
[ 288-36-8 ]
3-chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate; In tetrahydrofuran; at 20℃;	Potassium carbonate (14.0 g, 101 .35 mmol) was added to solution of 2,3-dichloro-5- nitropyridine (10.0 g, 51 .82 mmol) in THF (60 mL) followed by addition of 2H-1 ,2,3-triazole (3.4 mL, 58.7 mmol). The resulting mixture was stirred at rt until reaction was deemed completed as judged by TLC (-16 h), then diluted with water (300 mL). The aqueous layer was extracted with EtOAc (2 x 300 mL), the organic layer was dried over sodium sulphate, filtered and (0326) concentrated under reduced pressure. The crude product was purified by column (0327) chromatography on silica (100-200 mesh), eluted at 20% EtOAc in p.ether which gave the title compound (7.0 g, 60%) as a solid with 99.42% LCMS purity. MS (ES+) 226.03 [M+H]+.
60%	With potassium carbonate; In tetrahydrofuran; at 20℃; for 4h;Inert atmosphere;	Potassium carbonate (14.0 g, 101.35 mmol) was added to solution of 2,3-dichloro-5- nitropyridine (10.0 g, 51.82 mmol) in THF (60 mL) followed by addition of 2H-1,2,3-triazole (3.4 mL, 58.7 mmol). The resulting mixture was stirred at rt until reaction was deemed completed as judged by TLC (-16 h), then diluted with water (300 mL). The aqueous layer was extracted with EtOAc (2 x 300 mL), the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (100-200 mesh), eluted at 20% EtOAc in p. ether which gave the title compound (7.0 g, 60%) as a solid with 99.42% LCMS purity. MS (ES+) 226.03 [M+H]+.
44%	With potassium carbonate; In tetrahydrofuran; at 20℃;	2H-1,2,3-Triazole (760 mg, 11 mmol) was added to a suspension of 2,3-dichloro-5-nitro-pyridine (965 mg, 5 mmol) and anhydrous potassium carbonate (1.03 g, 7.5 mmol) in THF (50 mL), and the mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (100 mL), washed with water and brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography (hexane: EtOAc = 5:1 to 1:1) to give the title compound (505 mg, 44%). ?H NMR (400 MHz, DMSO-d6): 9.39 (d, 1H), 9.15 (d, 1H), 8.34 (s, 2H).

	With potassium carbonate; In tetrahydrofuran; at 20℃;	To a soution of 23-dichoro-5-nitropyridine (lOg, 5.18 mmo) and K2003 (1.43 g, 10.4 mmo) in THF (5 m) was added 2H-1,2.3-triazoe (0.360 m, 6.22 mrnoD. The reaction mixture was stirred for overnight at RT. Since the reaction was uncompete, additiona 2H-1,2,3-triazoe (0.300 mL 5.18 mmo) was added and reaction mixture was stirred over2 days at RT. Water was added and the mixture was extracted with AcOEt. The organic ayer was washed with brine, dried over Na2SO4, fi[tered and concentrated under vacuum. The residue taken-up in DCM, the soHd was fHtered off and the fi[trate was evaporated. The residue was purified by flash cournn chromatography on si?ica g& (cycohexane/AcOEt: 1/0 to 7/3) to afford 3-choro-5-nitro-2-(2H-1 2,3-triazo-2- y)pyridine. Rt = 0.75 mm (UPLC Method BI), 1H NMR (400 MHz, DMSO-d6) O ppm:939 (d, IH), 9.15 (d, IH), 833 (s, 2H).
	With potassium carbonate; In tetrahydrofuran; at 20℃; for 48h;Inert atmosphere;	To a solution of 2,3-dichloro-5-nitropyridine (1.0g, 5.18 mmol) and K2CO3 (1.43 g, 10.4 mmol) inTHF (5 ml) was added 2H-1,2,3-triazole (0.360 ml, 6.22 mmol). The reaction mixture was stirredovernight at RT. Since the reaction was uncomplete, additional 2H-1,2,3-triazole (0.300 ml, 5.18mmol) was added and reaction mixture was stirred for 2 days at RT. Water was added and themixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4,filtered and concentrated under vacuum. The residue was taken-up in DCM, the solid wasfiltered off and the filtrate was evaporated. The crude product was purified by flashchromatography on silica gel (cyclohexane/AcOEt: 1/0 to 7/3) to afford 3-chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine.

Reference： [1]Patent: WO2018/141749,2018,A1 .Location in patent: Page/Page column 37
[2]Patent: WO2018/226150,2018,A1 .Location in patent: Page/Page column 52
[3]Patent: WO2018/165385,2018,A1 .Location in patent: Paragraph 00398
[4]Patent: WO2015/181747,2015,A1 .Location in patent: Page/Page column 88; 89
[5]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2153 - 2158

30
[ 22353-40-8 ]
[ 847818-74-0 ]
3-chloro-2-(1-methyl-1H-pyrazol)-5-yl-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 140℃; for 0.333333h;Inert atmosphere; Microwave irradiation;	To 23-dichoro-5-nitropyridine (0.30 g, 1.56 mrno) in 1,4-dioxane (10.5 m) were added 1-methy-1H-pyrazoe-5-boronic acid pinaco ester (0.32 g, 1.56 rnmo), water (2.4 m) and K2003 (1 29 g, 9.3 mmoD. Under argon, Pd(PPh3)4 (90 mg, 0.078 mmoD was added and the reaction mixture was stirred in microwave at 140C for 20 mm. Water and AcOEt were added, the organic phase was dried over Na2SO4, fitered and evaporated. The crude product was purified by flash chromatography on sHica ge (heptane/AcOEt 85/15 to 15/85) to afford 3-choro-2-(1 -methy- I H-pyrazo5-y-5-nitropyridmne. M/z = 239-241 [M+H]+, Rt = 0.85 mm (U PLC Method 82).

Reference： [1]Patent: WO2015/181747,2015,A1 .Location in patent: Page/Page column 88

31
[ 22353-40-8 ]
[ 488713-30-0 ]

Reference： [1]Patent: EP2975031,2016,A1

32
[ 22353-40-8 ]
[ 488713-31-1 ]

Reference： [1]Patent: EP2975031,2016,A1
[2]Patent: EP3192791,2017,A1

33
[ 22353-40-8 ]
[ 42726-73-8 ]
1-(tert-butyl) 3-methyl 2-(3-chloro-5-nitropyridin-2-yl)malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		Preparation 58 1-(tert-Butyl) 3-methyl 2-(3-chloro-5-nitropyridin-2-yl)malonate To a solution of NaH (6 g, 150 mmol) in DMF (30 mL) was added tert-butylmethylmalonate (5 g, 28.7 mmol) slowly. The mixture was stirred at room temperature for 30 minutes before the addition of 2,3-dichloro-5-nitropyridine (5 g, 26 mmol) dropwise. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and purified by silica gel column chromatography to get afford the title compound (6.6 g, 77percent) as red oil.

Reference： [1]Patent: US2016/52930,2016,A1 .Location in patent: Paragraph 0629

34
[ 22353-40-8 ]
[ 1171897-03-2 ]
(S)-tert-butyl (1-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
922 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 50 - 75℃;Inert atmosphere;	General procedure: Step 1: tert-butyl (trans- l-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3-hydroxy-3- methylcyclobutyl)carbamate: A mixture of 2,3-dichloro-5-nitropyridine (383 mg, 1.98 mmol), iert-butyl (iraws-S-hydroxy-S-methyl- 1 -(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan- 2-yl)phenyl)cyclobutyl)carbamate (800 mg, 1.98 mmol, prepared according to Org.Process Res. Dev., 2012, 16, 1069) and ieirafc 5,-(triphenylphosphine)palladium(0) (229 mg, 0.198 mmol) in dioxane (10 ml) was treated with 2 M Na2C03(aq) (2.2 ml, 4.46 mmol). The vessel was purged with N2 and then heated at 75 C for 2 days. The reaction mixture was cooled and filtered through a glass microfibre filter, washing with MeCN, and concentrated in vacuo to afford a brown oil. The oil was partitioned between DCM (50 ml) and water (50 ml), filtered through a phase separation cartridge and the organic phase concentrated in vacuo. The residue was purified by column chromatography (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (501 mg, 1.05 mmol, 94%purity) as a yellow solid. LCMS (Method 1): m/z 378 (M+H-C4)+ at 2.25 min. 1H NMR (400 MHz, Chloroform-^ delta 9.40 (d, / = 2.3 Hz, 1H), 8.62 (d, / = 2.3 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.61 - 7.54 (m, 2H), 5.11 (s, 1H), 2.82 - 2.52 (m, 4H), 1.63 (s, 3H), 1.43 (br s, 9H).

Reference： [1]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 108

35
[ 22353-40-8 ]
[ 1032528-06-5 ]
tert-butyl (1-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)cyclobutyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water;Reflux;	General procedure: Step 1: tert-butyl (trans- l-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3-hydroxy-3- methylcyclobutyl)carbamate: A mixture of 2,3-dichloro-5-nitropyridine (383 mg, 1.98 mmol), iert-butyl (iraws-S-hydroxy-S-methyl- 1 -(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan- 2-yl)phenyl)cyclobutyl)carbamate (800 mg, 1.98 mmol, prepared according to Org.Process Res. Dev., 2012, 16, 1069) and ieirafc 5,-(triphenylphosphine)palladium(0) (229 mg, 0.198 mmol) in dioxane (10 ml) was treated with 2 M Na2C03(aq) (2.2 ml, 4.46 mmol). The vessel was purged with N2 and then heated at 75 C for 2 days. The reaction mixture was cooled and filtered through a glass microfibre filter, washing with MeCN, and concentrated in vacuo to afford a brown oil. The oil was partitioned between DCM (50 ml) and water (50 ml), filtered through a phase separation cartridge and the organic phase concentrated in vacuo. The residue was purified by column chromatography (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (501 mg, 1.05 mmol, 94%purity) as a yellow solid. LCMS (Method 1): m/z 378 (M+H-C4)+ at 2.25 min. 1H NMR (400 MHz, Chloroform-^ δ 9.40 (d, / = 2.3 Hz, 1H), 8.62 (d, / = 2.3 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.61 - 7.54 (m, 2H), 5.11 (s, 1H), 2.82 - 2.52 (m, 4H), 1.63 (s, 3H), 1.43 (br s, 9H).

Reference： [1]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 102; 103; 112

36
[ 22353-40-8 ]
tert-butyl (1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate [ No CAS ]
tert-butyl (1-(4-(3-chloro-5-nitropyridin-2-yl)-2-fluorophenyl)cyclopropyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
820 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 18h;Inert atmosphere;	General procedure: Step 1: tert-butyl (trans- l-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3-hydroxy-3- methylcyclobutyl)carbamate: A mixture of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (383 mg, 1.98 mmol), iert-butyl (iraws-S-hydroxy-S-methyl- 1 -(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan- 2-yl)phenyl)cyclobutyl)carbamate (800 mg, 1.98 mmol, prepared according to Org.Process Res. Dev., 2012, 16, 1069) and ieirafc 5,-(triphenylphosphine)palladium(0) (229 mg, 0.198 mmol) in dioxane (10 ml) was treated with 2 M Na2C03(aq) (2.2 ml, 4.46 mmol). The vessel was purged with N2 and then heated at 75 C for 2 days. The reaction mixture was cooled and filtered through a glass microfibre filter, washing with MeCN, and concentrated in vacuo to afford a brown oil. The oil was partitioned between DCM (50 ml) and water (50 ml), filtered through a phase separation cartridge and the organic phase concentrated in vacuo. The residue was purified by column chromatography (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (501 mg, 1.05 mmol, 94%purity) as a yellow solid. LCMS (Method 1): m/z 378 (M+H-C4)+ at 2.25 min. 1H NMR (400 MHz, Chloroform-^ delta 9.40 (d, / = 2.3 Hz, 1H), 8.62 (d, / = 2.3 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.61 - 7.54 (m, 2H), 5.11 (s, 1H), 2.82 - 2.52 (m, 4H), 1.63 (s, 3H), 1.43 (br s, 9H).

Reference： [1]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 102; 103; 211

37
[ 22353-40-8 ]
[ 1313441-88-1 ]
tert-butyl (1-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)cyclopropyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
585 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 50 - 60℃;Inert atmosphere;	Step 3: tert-butyl (l-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)cyclopropyl)carbamate: 2,3- dichloro-5-nitropyridine (505 mg, 2.62 mmol), the product from Step 2 above (941 mg, 2.52 mmol, 96% purity), ieirafc 5,-(triphenylphosphine)palladium(0) (303 mg, 0.262 mmol) and Na2C03 (694 mg, 6.55 mmol) were combined in dioxane (20 ml) and water (5 ml). The vessel was purged with N2 and heated at 50 C overnight. The mixture was diluted with water (5 ml) and heated at 60 C for 4 h. The mixture was concentrated in vacuo to remove most of the dioxane and the residue was partitioned between EtOAc (100 ml) and brine (50 ml). The phases were separated and the organic phase dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g cartridge, 0-25% EtOAc/isohexane) to afford the title compound (585 mg, 1.43 mmol, 95% purity). 1H NMR (400 MHz, DMSO- ) delta 9.40 (d, / = 2.3 Hz, 1H), 8.86 (d, / = 2.3 Hz, 1H), 7.80 (br s, 1H, major), 7.72 (d, / = 8.4 Hz, 2H), 7.52 (br s, 1H, minor), 7.27 (d, J = 8.4 Hz, 2H), 1.41 (br s, 9H, major), 1.28 (br s, 9H, minor), 1.24 - 1.18 (m, 4H).

Reference： [1]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 115

38
[ 22353-40-8 ]
tert-butyl (trans-3-hydroxy-3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate [ No CAS ]
tert-butyl (trans-1-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3-hydroxy-3-methylcyclobutyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 75℃; for 48h;Inert atmosphere;	Step 1: tert-butyl (trans- l-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3-hydroxy-3- methylcyclobutyl)carbamate: A mixture of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (383 mg, 1.98 mmol), iert-butyl (iraws-S-hydroxy-S-methyl- 1 -(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan- 2-yl)phenyl)cyclobutyl)carbamate (800 mg, 1.98 mmol, prepared according to Org.Process Res. Dev., 2012, 16, 1069) and ieirafc 5,-(triphenylphosphine)palladium(0) (229 mg, 0.198 mmol) in dioxane (10 ml) was treated with 2 M Na2C03(aq) (2.2 ml, 4.46 mmol). The vessel was purged with N2 and then heated at 75 C for 2 days. The reaction mixture was cooled and filtered through a glass microfibre filter, washing with MeCN, and concentrated in vacuo to afford a brown oil. The oil was partitioned between DCM (50 ml) and water (50 ml), filtered through a phase separation cartridge and the organic phase concentrated in vacuo. The residue was purified by column chromatography (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (501 mg, 1.05 mmol, 94%purity) as a yellow solid. LCMS (Method 1): m/z 378 (M+H-C4)+ at 2.25 min. 1H NMR (400 MHz, Chloroform-^ delta 9.40 (d, / = 2.3 Hz, 1H), 8.62 (d, / = 2.3 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.61 - 7.54 (m, 2H), 5.11 (s, 1H), 2.82 - 2.52 (m, 4H), 1.63 (s, 3H), 1.43 (br s, 9H).

Reference： [1]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 102; 103

39
[ 22353-40-8 ]
tert-butyl (trans-1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-hydroxy-3-methylcyclobutyl)carbamate [ No CAS ]
tert-butyl (trans-1-(4-(3-chloro-5-nitropyridin-2-yl)-2-fluorophenyl)-3-hydroxy-3-methylcyclobutyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
538 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;	Step 1: tert-butyl (trans-l-(4-(3-chloro-5-nitropyridin-2-yl)-2-fluorophenyl)-3-hydroxy-3- methylcyclobutyl)carbamate: A suspension of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (300 mg, 1.56 mmol), the product from Example 111 Step 9 (688 mg, 1.31 mmol, 80% purity), tetrakis- (triphenylphosphine)palladium(O) (180 mg, 0.155 mmol) and 2 M Na2C03(aq) (1.94 ml, 3.89 mmol) in dioxane (10 ml) was degassed with N2 for 5 min and the resultant mixture was heated at 80 C overnight. The reaction mixture was cooled to room temperature and concentrated on to silica, then purified by column chromatography (40 g cartride, 0-50% EtOAc/isohexane) to afford the title compound (538 mg, 1.13 mmol, 95% purity) as a yellow oil. LCMS (Method 1): m/z 474 (M+Na)+ at 2.25 min.

Reference： [1]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 287

40
[ 22353-40-8 ]
tert-butyl (3,3-difluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate [ No CAS ]
tert-butyl (1-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3,3-difluorocyclobutyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;	Step 1: tert-butyl (l-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3,3- difluorocyclobutyl)carbamate: A mixture of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (244 mg, 1.27 mmol), tert-butyl (3,3-difluoro-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclobutyl)carbamate (170 mg, 0.415 mmol, prepared according toWO2009148916) and ieirafos-(triphenylphosphine)palladium(0) (133 mg, 0.115 mmol) in dioxane (30 ml) was treated with 2 M Na2C03(aq) (1.29 ml, 2.59 mmol). The vessel was purged with N2 and then heated at 80 C overnight. The reaction mixture was cooled and filtered through Celite, washing with DCM, and concentrated in vacuo to afford a brown oil. The residue was purified by column chromatography (40 g cartridge, 0-50%EtOAc/isohexane) to afford the title compound (146 mg, 0.299 mmol, 90% purity) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) (two rotamers in a 3: 1 ratio) delta 9.41 (d, /= 2.3 Hz, 1H), 8.88 (d, / = 2.3 Hz, 1H), 8.09 (br s, 1H), 7.79 (d, / = 8.4 Hz, 2H), 7.56 (d, / = 8.3 Hz, 2H), 3.15 (br t, / = 12.2 Hz, 4H), 1.37 (br s, 9H, major), 1.18 (br s, 9H, minor).

Reference： [1]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 105; 106

41
[ 22353-40-8 ]
benzyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate [ No CAS ]
benzyl (3-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)oxetan-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere;	General procedure: Step 1: tert-butyl (l-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3,3- difluorocyclobutyl)carbamate: A mixture of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (244 mg, 1.27 mmol), tert-butyl (3,3-difluoro-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclobutyl)carbamate (170 mg, 0.415 mmol, prepared according toWO2009148916) and ieirafos-(triphenylphosphine)palladium(0) (133 mg, 0.115 mmol) in dioxane (30 ml) was treated with 2 M Na2C03(aq) (1.29 ml, 2.59 mmol). The vessel was purged with N2 and then heated at 80 C overnight. The reaction mixture was cooled and filtered through Celite, washing with DCM, and concentrated in vacuo to afford a brown oil. The residue was purified by column chromatography (40 g cartridge, 0-50%EtOAc/isohexane) to afford the title compound (146 mg, 0.299 mmol, 90% purity) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) (two rotamers in a 3: 1 ratio) delta 9.41 (d, /= 2.3 Hz, 1H), 8.88 (d, / = 2.3 Hz, 1H), 8.09 (br s, 1H), 7.79 (d, / = 8.4 Hz, 2H), 7.56 (d, / = 8.3 Hz, 2H), 3.15 (br t, / = 12.2 Hz, 4H), 1.37 (br s, 9H, major), 1.18 (br s, 9H, minor).

Reference： [1]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 105; 106; 119

42
[ 22353-40-8 ]
tert-butyl (trans-3-fluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate [ No CAS ]
tert-butyl (trans-1-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3-fluorocyclobutyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
146 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere;	General procedure: Step 1: tert-butyl (l-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3,3- difluorocyclobutyl)carbamate: A mixture of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (244 mg, 1.27 mmol), tert-butyl (3,3-difluoro-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclobutyl)carbamate (170 mg, 0.415 mmol, prepared according toWO2009148916) and ieirafos-(triphenylphosphine)palladium(0) (133 mg, 0.115 mmol) in dioxane (30 ml) was treated with 2 M Na2C03(aq) (1.29 ml, 2.59 mmol). The vessel was purged with N2 and then heated at 80 C overnight. The reaction mixture was cooled and filtered through Celite, washing with DCM, and concentrated in vacuo to afford a brown oil. The residue was purified by column chromatography (40 g cartridge, 0-50%EtOAc/isohexane) to afford the title compound (146 mg, 0.299 mmol, 90% purity) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) (two rotamers in a 3: 1 ratio) delta 9.41 (d, /= 2.3 Hz, 1H), 8.88 (d, / = 2.3 Hz, 1H), 8.09 (br s, 1H), 7.79 (d, / = 8.4 Hz, 2H), 7.56 (d, / = 8.3 Hz, 2H), 3.15 (br t, / = 12.2 Hz, 4H), 1.37 (br s, 9H, major), 1.18 (br s, 9H, minor).

Reference： [1]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 105; 106; 122

43
[ 335592-60-4 ]
[ 22353-40-8 ]
tert-butyl (2-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)propan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.27 g	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 18h;Inert atmosphere; Reflux;	General procedure: Step 1: tert-butyl (trans- l-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3-hydroxy-3- methylcyclobutyl)carbamate: A mixture of 2,3-dichloro-5-nitropyridine (383 mg, 1.98 mmol), iert-butyl (iraws-S-hydroxy-S-methyl- 1 -(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan- 2-yl)phenyl)cyclobutyl)carbamate (800 mg, 1.98 mmol, prepared according to Org.Process Res. Dev., 2012, 16, 1069) and ieirafc 5,-(triphenylphosphine)palladium(0) (229 mg, 0.198 mmol) in dioxane (10 ml) was treated with 2 M Na2C03(aq) (2.2 ml, 4.46 mmol). The vessel was purged with N2 and then heated at 75 C for 2 days. The reaction mixture was cooled and filtered through a glass microfibre filter, washing with MeCN, and concentrated in vacuo to afford a brown oil. The oil was partitioned between DCM (50 ml) and water (50 ml), filtered through a phase separation cartridge and the organic phase concentrated in vacuo. The residue was purified by column chromatography (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (501 mg, 1.05 mmol, 94%purity) as a yellow solid. LCMS (Method 1): m/z 378 (M+H-C4)+ at 2.25 min. 1H NMR (400 MHz, Chloroform-^ delta 9.40 (d, / = 2.3 Hz, 1H), 8.62 (d, / = 2.3 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.61 - 7.54 (m, 2H), 5.11 (s, 1H), 2.82 - 2.52 (m, 4H), 1.63 (s, 3H), 1.43 (br s, 9H).

Reference： [1]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 102; 103; 104

44
[ 22353-40-8 ]
tert-butyl (2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)carbamate [ No CAS ]
tert-butyl (2-(4-(3-chloro-5-nitropyridin-2-yl)-2-fluorophenyl)propan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
477 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 18h;Inert atmosphere;	General procedure: Step 1: tert-butyl (trans- l-(4-(3-chloro-5-nitropyridin-2-yl)phenyl)-3-hydroxy-3- methylcyclobutyl)carbamate: A mixture of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (383 mg, 1.98 mmol), iert-butyl (iraws-S-hydroxy-S-methyl- 1 -(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan- 2-yl)phenyl)cyclobutyl)carbamate (800 mg, 1.98 mmol, prepared according to Org.Process Res. Dev., 2012, 16, 1069) and ieirafc 5,-(triphenylphosphine)palladium(0) (229 mg, 0.198 mmol) in dioxane (10 ml) was treated with 2 M Na2C03(aq) (2.2 ml, 4.46 mmol). The vessel was purged with N2 and then heated at 75 C for 2 days. The reaction mixture was cooled and filtered through a glass microfibre filter, washing with MeCN, and concentrated in vacuo to afford a brown oil. The oil was partitioned between DCM (50 ml) and water (50 ml), filtered through a phase separation cartridge and the organic phase concentrated in vacuo. The residue was purified by column chromatography (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (501 mg, 1.05 mmol, 94%purity) as a yellow solid. LCMS (Method 1): m/z 378 (M+H-C4)+ at 2.25 min. 1H NMR (400 MHz, Chloroform-^ delta 9.40 (d, / = 2.3 Hz, 1H), 8.62 (d, / = 2.3 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.61 - 7.54 (m, 2H), 5.11 (s, 1H), 2.82 - 2.52 (m, 4H), 1.63 (s, 3H), 1.43 (br s, 9H).

Reference： [1]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 102; 103; 128

45
[ 22353-40-8 ]
[ 111-45-5 ]
2-(2-(allyloxy)ethoxy)-3-chloro-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%		To a solution of 2-allyloxyethanol (5.8 g, 57 mmol, 1.1 eq.) in dry THF (10 mL), was added NaH (1.37 g, 57 mmol, 1.1 eq.). After stirring at room temperature for 30 min, the solution was dropped into a solution of 2, 3-dichloro-5-nitropyridine (10 g, 52 mmol, 1 eq.) in THF (10 mL) at -20 C. The reaction was stirred for 1 hr. at room temperature, quenched with water (50 mL), and extracted with EtOAc. The organic phase was washed with water, dried over Na2S04, and concentrated to give compound 73 (13 g, 97%) as a brown oil.

Reference： [1]Patent: WO2016/103037,2016,A1 .Location in patent: Paragraph 00680

46
[ 22353-40-8 ]
5-chloro-2-hydroxy-N-isopropylbenzenesulfonamide [ No CAS ]
8-chloro-11-isopropyl-3-nitro-11H-benzo[b]pyrido[2,3-f][1,4,5]oxathiazepine 10,10-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In N,N-dimethyl-formamide; at 45℃; for 7h;Inert atmosphere;	General procedure: The respective 2-hydroxybenzenesulfonamide 5 (2 mmol) and 1,2-dihaloarene (1-halo-2-nitroarene) partner 9 (2 mmol) were combined in anhydrous DMF (7 mL) with freshly calcinated K2CO3 (829 mg, 6 mmol) and the mixture was kept, with stirring, at the temperature and for the time period indicated in Table 2. DMF was removed in vacuo and the residue was treated with water (10 mL), which caused a viscous oil to separate. It was extracted with CH2Cl2 (5 mL), the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using an appropriate gradient of CH2Cl2 in hexanes as eluent.

Reference： [1]Tetrahedron,2016,vol. 72,p. 7570 - 7578

47
[ 22353-40-8 ]
N-ethyl-5-fluoro-2-hydroxybenzenesulfonamide [ No CAS ]
11-ethyl-8-fluoro-3-nitro-11H-benzo[b]pyrido[2,3-f][1,4,5]oxathiazepine 10,10-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In N,N-dimethyl-formamide; at 45℃; for 7h;Inert atmosphere;	General procedure: The respective 2-hydroxybenzenesulfonamide 5 (2 mmol) and 1,2-dihaloarene (1-halo-2-nitroarene) partner 9 (2 mmol) were combined in anhydrous DMF (7 mL) with freshly calcinated K2CO3 (829 mg, 6 mmol) and the mixture was kept, with stirring, at the temperature and for the time period indicated in Table 2. DMF was removed in vacuo and the residue was treated with water (10 mL), which caused a viscous oil to separate. It was extracted with CH2Cl2 (5 mL), the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using an appropriate gradient of CH2Cl2 in hexanes as eluent.

Reference： [1]Tetrahedron,2016,vol. 72,p. 7570 - 7578

48
[ 89-73-6 ]
[ 22353-40-8 ]
[ 59-49-4 ]
[ 22353-38-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;	General procedure: To a solution of N-hydroxysalicylamide (0.5 g, 3.26 mmol) in anhydrous DMF (5 ml) was added 2a or 2b (3.26 mmol) and freshly calcinated K2CO3 (1.35 g, 9.78 mmol) and the mixture was kept, with stirring at the room temperature overnight. DMF was removed in vacuo and the residue was treated with water (10 ml) and then extracted with CH2Cl2 (5 ml). The organic layer was separated, washed with water, dried over anhydrous CaCl2, and purified by flesh chromatography on silica gel using CH2Cl2 as eluent. Dichloromethane was evaporated in vacuo. The resulting residue was benzo[d]oxazol-2(3H)-one 11. The water layer was acidify by hydrochloric acid, filtered and washed with water. The resulting residue was compound 12a(b).

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 5877 - 5880

49
[ 22353-40-8 ]
[ 39602-93-2 ]
(3-chloro-5-nitropyridin-2-yl)(1-methyl-4H-1,2,4-triazol-1-ium-4-yl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%		General procedure: Potassium carbonate or trimethylamine (9.0 mmol) was added to a solution of <strong>[39602-93-2]4-amino-1-methyl-1H-1,2,4-triazol-4-ium iodide</strong>,1 (3.0 mmol) in acetonitrile or ethanol (25 mL) and each reaction mixture was vigorously stirred at room temperature for 20 min to give a purple solution, to which nitrophenyl halides 2a-c nitropyridinyl halides 2d-l or pyridinium iodide 2m (3.0 mmol)were added in one portion. Each mixture was stirred at rt for 72 h except for 2l (rt for 24 h) and 2m (82 C for 72 h). The mixtures were concentrated in vaccuo and the residues purified either by gradient elution chromatography over silica gel or by recrystallization.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1079 - 1085

50
[ 22353-40-8 ]
copper(l) cyanide [ No CAS ]
[ 488713-30-0 ]

Yield	Reaction Conditions	Operation in experiment
32.8%		A mixture of 2,3-dichloro-5-nitropyridine (15.24 g, 78.97 mmol) and copper cyanide (28.3 g, 315.88 mmol) in NMP (128 mL) was stirred under microwave irradiation at 200C for 1 hr. The reaction mixture was added to 0.5 N HCl (1300 mL) and iron(III) chloride 6 hydrate (107 g, 394.84 mmol), and the mixture was stirred at room temperature for 40 min and extracted with ethyl acetate/hexane mixed solution (3:1). The organic layer was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 2?10% ethyl acetate/hexane) to give 3-chloro-5-nitropicolinonitrile (4.76 g, 25.9 mmol, 32.8%) as a pale-yellow solid. NMR (300 MHz, CDCl3):delta 8.68(1H,d,J=2.3 Hz), 9.40(1H,d,J=2.3 Hz).

Reference： [1]Patent: EP3192791,2017,A1 .Location in patent: Paragraph 0506

51
[ 22353-40-8 ]
[ 64-17-5 ]
3-chloro-2-ethoxy-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		At 0C, iBuOK (208.7 mg, 1.86 mmol, 1.2 equiv) is added to ethanol (0.45 mL, 7.77 mmol, 5.0 equiv), the resulting mixture is stirred at room temperature for 15 min, then the solution of 2,3-dichloro-5- nitro-pyridine (300 mg, 1.55 mmol, 1.0 equiv) in dry THF (1.5 mL, 1 M) is added at 0C. The resulting mixture is stirred at room temperature for 10 min, then heated at 50C for 3 h. The mixture is diluted with DCM and saturated NaHC03 solution. The aqueous phase is extracted with DCM. The combined organic phase is filtered through a phase separator and concentrated under vacuum to afford the desired compound

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 6724 - 6735
[2]Patent: WO2017/148787,2017,A1 .Location in patent: Paragraph 0258

52
(isoxazol-4-yl)boronic acid [ No CAS ]
[ 22353-40-8 ]
4-(3-chloro-5-nitropyridin-2-yl)isoxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere;	To a solution of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (0.5 g, 2.59 mmol) and isoxazol-4-ylboronic acid (0.292 g, 2.59 mmol) in dioxane (10 mL) and water (2 mL) was added K2C03 (0.716 g, 5.18 mmol). The resulting mixture was thoroughly deoxygenated by purging nitrogen for 30 min and then PdCI2(dppf)-CH2CI2 adduct (0.212 g, 0.259 mmol) was addded. The resulting mixture was heated at 100eC for 16 h. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash colu mn chromatography (silica gel) to afford 0.11 g (19%) of the titled compound as a yellow solid. ESI-MS (m/z) 225.75 (MH)

Reference： [1]Patent: WO2018/20474,2018,A1 .Location in patent: Page/Page column 140

53
[ 21156-84-3 ]
[ 22353-40-8 ]
3-chloro-2-(2-(1-methylpiperidin-4-yl)ethoxy)-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		At a stirreed and cooled (OeC) solution of 2-(1-methylpiperidin-4-yl)ethanol (3.50 g, 24.4 mmol) in tetrahydrofuran (100 mL) was added NaH (1.46 g, 36.7 mmol) portionwise and the resulting mixture was heated at 50eC for 30 min. The reaction was then cooled to OeC before the addition of a solution of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (4.72 g, 24.4 mmol) in tetrahydrofuran (25 mL). The resulting mixture was then stirred at RT for 5 h. Reaction mass was cooled to OeC, diluted with ethyl acetate (100 mL) and 10% MeOH in DCM (30 mL) followed by the addition of crushed ice (2.0 g). The solvent was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, 7% MeOH in DCM as eluent) to afford 4.80 g (65%) of the titled product as white solid. 1HNMR (400 MHz, DMSO-de) U9.05 (d, J = 2.5 Hz, 1H), 8.73 (d, J = 2.5 Hz, 1H), 4.54 (t, J = 6.5 Hz, 2H), 2.95 (d, J = 11.5 Hz, 2H), 2.33 (s, 3H), 2.19 (t, J = 11.7 Hz, 2H), 1.80-1.67 (m, 4H), 1.36-1.16 (m, 3H); ESI-MS (m/z) 300.46 (MH)

Reference： [1]Patent: WO2018/20474,2018,A1 .Location in patent: Page/Page column 162-163

54
[ 21156-84-3 ]
[ 22353-40-8 ]
5-chloro-6-(2-(1-methylpiperidin-4-yl)ethoxy)pyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 50 °C 1.2: 5 h / 0 - 20 °C 2.1: ammonium chloride; iron / ethanol; water / 2 h / 100 °C

Reference： [1]Current Patent Assignee: LUPIN LIMITED - WO2018/20474, 2018, A1

55
[ 7170-01-6 ]
[ 22353-40-8 ]
3-chloro-2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitropyridine [ No CAS ]
3-chloro-2-(5-methyl-1H-1,2,4-triazol-1-yl)-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;	2,3-Dichloro-5-nitropyridine (2 g, 10.36 mmol), <strong>[7170-01-6]<strong>[7170-01-6]3-methyl-1H-1,2,4-triazol</strong>e</strong> (1.722 g, 20.73 mmol) and Cs2CO3 (6.798 g, 20.73 mmol) were added to DMF (30 mL) and the reaction was stirred at rt for 12 h. The reaction mixture was quenched with water (200 mL). The mixture was extracted with ethyl acetate (100 mL*3). The organic layer was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The crude residue was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100:0 to 50:50) to afford a mixture of compounds 20a and 20a-1 (780 mg, 31%) as a white solid.

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 0960; 0961

56
[ 288-36-8 ]
[ 22353-40-8 ]
3-chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate; In acetonitrile; at 40℃;	A mixture of 2,3-dichloro-5-nitropyridine (50 g, 259.08 mmol), 1H-<strong>[288-36-8]1,2,3-triazole</strong> (19.683 g, 284.99 mmol), potassium carbonate (46.549 g, 336.81 mmol) and CH3CN (200 mL) was heated to 40 C. and stirred overnight. Ethyl acetate (500 mL) was added. The mixture was washed with water (500 mL*2) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was triturated with DCM (100 mL), filtered, and the solid was collected to afford compound 1i (40 g, 68%) as an off-white solid. LC-MS: (ES, m/z): [M+1]+ 225.9. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.40 (d, J=2.0 Hz, 1H), 9.15 (d, J=2.0 Hz, 1H), 8.33 (s, 2H).
68%	With potassium carbonate; In acetonitrile; at 40℃;	A mixture of 2,3-dichloro-5-nitropyridine (50 g, 259.08 mmol), 1H-<strong>[288-36-8]1,2,3-triazole</strong> (19.683 g, 284.99 mmol), potassium carbonate (46.549 g, 336.81 mmol) and CH3CN (200 mL) was heated to 40 C. and stirred overnight. Ethyl acetate (500 mL) was added. The mixture was washed with water (500 mL*2) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was triturated with DCM (100 mL), filtered, and the solid was collected to afford compound INT2A (40 g, 68%) as an off-white solid. LC-MS: (ES, m/z): [M+1]+ 225.9. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.40 (d, J=2.0 Hz, 1H), 9.15 (d, J=2.0 Hz, 1H), 8.33 (s, 2H).
68%	With potassium carbonate; In acetonitrile; at 40℃;	A mixture of 2,3-dichloro-5-nitropyridine (50 g, 259.08 mmol), 1H-<strong>[288-36-8]1,2,3-triazole</strong> (19.683 g, 284.99 mmol), potassium carbonate (46.549 g, 336.81 mmol) and CH3CN (200 mL) was heated to 40 C. and stirred overnight. Ethyl acetate (500 mL) was added. The mixture was washed with water (500 mL*2) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was triturated with DCM (100 mL), filtered, and the solid was collected to afford compound 1g (40 g, 68%) as an off-white solid. LC-MS: (ES, m/z): [M+1]+ 225.9. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.40 (d, J=2.0 Hz, 1H), 9.15 (d, J=2.0 Hz, 1H), 8.33 (s, 2H).

44%

With potassium carbonate; In tetrahydrofuran; at 20℃;

lH-<strong>[288-36-8]Triazole</strong> (760 mg, 11 mmol) was added to a suspension of 2,3-dichloro-5-nitro-pyridine (965 mg, 5 mmol) and anhydrous potassium carbonate (1.03 g, 7.5 mmol) in THF (50 mL), and the mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (100 mL), washed with water and brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography (hexane: EtOAc= 5: 1 to 1: 1) to give the title compound (505 mg, 44%). 1H NMR (400 MHz, DMSO-iM): delta 9.39 (d, 1H), 9.15 (d, 1H), 8.34 (s, 2H).

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 0830; 0831
[2]Patent: US2019/381019,2019,A1 .Location in patent: Paragraph 0498-0499
[3]Patent: US2019/381012,2019,A1 .Location in patent: Paragraph 0331-0332
[4]Patent: WO2018/85247,2018,A1 .Location in patent: Paragraph 00304

57
[ 37622-90-5 ]
[ 22353-40-8 ]
ethyl 1-(3-chloro-5-nitropyridin-2-yl)-1H-pyrazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.6%	With caesium carbonate; In [(2)H6]acetone; at 80℃; for 16h;	<strong>[22353-40-8]2,3-Dichloro-5-nitropyridine</strong> (500 mg, 2.59 mmol), ethyl 1H-pyrazole-4-carboxylate (435.7 mg, 3.11 mmol) and cesium carbonate (1.01 g, 3.11 mmol) were added to MeCN (10 mL) and stirred at 80 C. for 16 h. The reaction mixture was filtered and the residue was washed with EtOAc (20 mL*3). The combined organic layers were concentrated under reduced pressure to afford crude product as a yellow solid, which was purified by FCC (petroleum ether/ethyl acetate from 100:0 to 70:30) to afford the title compound (650 mg, 84.6%) as a yellow solid.

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 1539; 1540

58
[ 22353-40-8 ]
[ 1107620-72-3 ]
tert-butyl ((1-(3-chloro-5-nitropyridin-2-yl)-1H-pyrazol-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 18h;	A suspension of <strong>[22353-40-8]2,3-dichloro-5-nitro-pyridine</strong> (579 mg, 3.0 mmol), ie/ -butyl N-(1H- pyrazol-4-ylmethyl)carbamate (592 mg, 3.0 mmol) and potassium carbonate (621 mg, 4.5 mmol) in DMF (10 mL) was heated to 50 C and stirred for 18 hours, then cooled and and filtered. The filtrate was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography (hexane: EtOAc= 20: 1) to give the title compound (705 mg, 66%). 1H NMR (400 MHz, CDC13): delta 9.20 (d, 1H), 8.70 (d, 1H), 8.35 (s, 1H), 7.84 (s, 1H), 4.85 (bs, 1H), 4.30 (m, 2H), 1.26 (s, 9H). MS m/z 353.85 [M+H]+.
66%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	To solution of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (400 mg, 2.07 mmol) in DMF (10 mL) was added potassium carbonate (350 mg, 2.53 mmol) followed by tert-butyl ((1 H-pyrazol-4- yl)methyl)carbamate (410 mg, 2.08 mmol), the resulting mixture was stirred at room (0347) temperature for 6 h, then diluted with Water (20 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column (0348) chromatography on silica gel eluted with 10-20% EtOAc in p. ether which gave the title compound (520 mg, 66% yield) a solid. MS (ES+) 354.10 [M+H]+.
66%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;Inert atmosphere;	To solution of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (400 mg, 2.07 mmol) in DMF (10 mL) was added potassium carbonate (350 mg, 2.53 mmol) followed by tert-butyl ((1H-pyrazol-4- yl)methyl)carbamate (410 mg, 2.08 mmol), the resulting mixture was stirred at room temperature for 6 h, then diluted with Water (20 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluted with 10-20% EtOAc in p. ether which gave the title compound (520 mg, 66% yield) a solid. MS (ES+) 354.10 [M+H]+.

Reference： [1]Patent: WO2018/85247,2018,A1 .Location in patent: Paragraph 00317
[2]Patent: WO2018/141749,2018,A1 .Location in patent: Page/Page column 39-40
[3]Patent: WO2018/226150,2018,A1 .Location in patent: Page/Page column 55

59
[ 22353-40-8 ]
[ 145214-05-7 ]
2-(3-chloro-5-nitropyridin-2-yl)oxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.4%	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 16h;Inert atmosphere;	<strong>[22353-40-8]2,3-Dichloro-5-nitropyridine</strong> (216 mg, 1.119 mmol) and 2-(tributylstannyl)oxazole (400.1 mg, 1.119 mmol) were dissolved in DMF (3 mL) and purged with N2. Pd(PPh3)4 (129 mg, 0.112 mmol) was added and the reaction was stirred at 110 C. for 16 h. The combined reaction mixture was concentrated under reduced pressure to afford a crude black oil. The oil was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30) to afford 2-(3-chloro-5-nitropyridin-2-yl)oxazole, 6a (150 mg, 59.4%) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta ppm 7.49-7.55 (m, 1H) 7.93-7.99 (m, 1H) 8.66-8.72 (m, 1H) 9.40-9.47 (m, 1H); LCMS (ESI) m/z M+1: 225.9.

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 0873; 0874

60
[ 273-05-2 ]
[ 22353-40-8 ]
1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [ No CAS ]
N-(6-(2H-[1,2,3]triazolo[4,5-c]pyridin-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ No CAS ]
N-(6-(1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.3%; 9.4%		3H-[1,2,3]triazolo[4,5-c]pyridine (0.62 g, 5.18 mmol) was added to a mixture of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (1 g, 5.18 mmol) and potassium carbonate (3.58 g, 25.9 mmol) in acetonitrile (20 mL). The mixture was stirred at rt for 3 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow solid. The crude product was purified by column chromatography over silica gel (petroleum ether/ethyl acetate=1:0 to petroleum ether/ethyl acetate=0:1). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (580 mg, 40%). Iron (0.535 g, 9.58 mmol) and ammonium chloride (0.512 g, 9.58 mmol) were added to the mixture of 2-(3- chloro-5-nitropyridin-2-yl)-2H-[1 ,2,3]triazolo[4,5-c]pyri- dine and 1 -(3-chloro-5-nitropyridin-2-yl)-1 H-[ 1 ,2,3]triazolo [4,5-c]pyridine (530 mg, 0.958 mmol) in THF (20 mE), water (10 mE) and methanol (10 mE). The reaction was stirred at 80 C. for 2 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with EtOAc (20 mEx2). The combined filtrates were concentrated to dryness to give a crude product as a brown solid. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 0/100). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford product as a brown oil (330 mg, 69.8%). 11745] P0C13 (0.49 mE, 5.36 mmol) was added to a mixture of 6-(2H-[1 ,2,3]triazolo[4,5-c]pyridin-2-yl)-5-chlo- ropyridin-3-amine and 6-(1H-[1 ,2,3]triazolo[4,5-c]pyridin- 1 -yl)-5-chloropyridin-3-amine (330 mg, 1.34 mmol), 1 -(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxylicacid, 3b (493.9 mg, 1.61 mmol), and pyridine (0.54 mE, 6.70 mmol) in dichioromethane (5 mE). The reaction mixture was stirred at 20 C. for 2 h. Sat. NaHCO3 solution (20 mE) was added to the mixture. The mixture was extracted with ethyl acetate (30 mEx2). The organic layers were concentrated under reduced pressure to afford a crude product, which was purified by reverse phase HPEC (27% to 57% (v/v) CH3CN and H20 with 0.05% HC1) to afford N-(6-(2H-[1,2,3]tri- azolo[4,5-c]pyridin-2-yl)-5-chloropyridin-3-yl)-1 -(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxamide, Cpd 162 (340 mg, 47.3%). ?H NMR (400 MHz, DMSO-d5) oe ppm 11.73 (1H, s), 9.87 (1H, s), 9.06-9.12 (2H, m), 8.87 (1H, d, J=2.20 Hz), 8.77 (1H, d, J=5.95 Hz), 8.75 (1H, s), 8.36 (1H, d, J=8.60 Hz), 8.07 (1H, d, J=5.51 Hz), 7.98-8.03 (1H, m), 7.94-7.98 (1H, m), 7.69-7.76 (2H, m). EC-MS:(ES, mlz): [M+1] 535.9; and11746] N-(6-(1H-[1 ,2,3]triazolo[4,5-c]pyridin-1 -yl)-5- chioropyridin-3-yl)-1 -(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide, Cpd 163 (70 mg, 9.4%). ?H NMR (400 MHz, DMSO-d5) oe ppm 11.77 (1H, s), 9.53 (1H, d, J=0.88 Hz), 9.08-9.18 (2H, m), 8.88 (1H, d, J=2.21 Hz), 8.78 (1H, s), 8.70 (1H, d, J=5.95 Hz), 8.37-8.44 (2H, m),7.98-8.09 (2H, m), 7.83-7.89 (1H, m), 7.75-7.82 (1H, m). EC-MS: (ES, mlz): [M+1] 535.9

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 1739; 1740; 1741; 1742

61
[ 288-13-1 ]
[ 22353-40-8 ]
3-chloro-5-nitro-2-(1H-pyrazol-1-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.907%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	<strong>[22353-40-8]2,3-Dichloro-5-nitropyridine</strong> (1 g, 5.18 mmol), pyrazole (529 mg, 7.77 mmol), and Cs2CO3 (5.06 g, 15.50 mmol) were added to DMF (15 mL) and stirred at 20 C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude yellow oil. The yellow oil was purified by column chromatography over silica gel (petroleum ether/ethyl acetate=1:0 to petroleum ether/ethyl acetate=10:1) to give compound 14a (511 mg, 43.907%) as a yellow solid. LCMS (ESI) m/z M+1: 224.8; 1H NMR (400 MHz, CDCl3) delta ppm 6.57 (d, J=1.76 Hz, 1H), 7.90 (s, 1H), 8.37-8.46 (m, 1H), 8.42 (d, J=2.65 Hz, 1H), 8.71 (d, J=2.21 Hz, 1H), 9.21 (d, J=2.21 Hz, 1H).

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 0921; 0922

62
[ 22353-40-8 ]
[ 16545-68-9 ]
3-chloro-2-cyclopropoxy-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%		Cyclopropanol (4.304 g, 74.10 mmol) was slowly added to a mixture of NaH (4.042 g, 101.0 mmol) in THF (30 mL) at room temperature. The mixture was stirred at 40 C. for 1 h. 2,3-Dichloro-5-nitropyridine in THF (20 mL) was added to the mixture at 0 C. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (50 mL). The mixture was extracted with ethyl acetate (200 mL*3). The organic layer was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 90/10) to afford 3-chloro-2-cyclopropoxy-5-nitropyridine, 18a (9 g, 53%) as a yellow solid.

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 0944; 0945

63
[ 7170-01-6 ]
[ 22353-40-8 ]
5-chloro-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-amine [ No CAS ]
5-chloro-6-(5-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		2,3-Dichloro-5-nitropyridine (2 g, 10.36 mmol), <strong>[7170-01-6]<strong>[7170-01-6]3-methyl-1H-1,2,4-triazol</strong>e</strong> (1.722 g, 20.73 mmol) and Cs2CO3 (6.798 g, 20.73 mmol) were added to DMF (30 mL) and the reaction was stirred at rt for 12 h. The reaction mixture was quenched with water (200 mL). The mixture was extracted with ethyl acetate (100 mL*3). The organic layer was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The crude residue was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100:0 to 50:50) to afford a mixture of compounds 20a and 20a-1 (780 mg, 31%) as a white solid. A mixture of 3-chloro-2-(3-methyl-i H-i ,2,4-tri-azol- i -yl)-5-nitropyridine, 20a and 3-chloro-2-(5-methyl-i H-i ,2,4-triazol-i -yl)-5-nitropyridine, 20a- i (780 mg, i .63mmol) was dissolved in MeOH (20 mE), and Zn (0) (i.058g, i 6.28 mmol) and aqueous NH4C1 (20 mE) were added.The reaction mixture was stirred at rt for i 6 h. The reactionmixture was filtered though a pad of diatomaceous earth andthe pad washed with ethyl acetate (20 mEx3). Water (50 mE)was added and the organic layer was separated, dried overNa2SO4, filtered and the filtrate was concentrated to drynessto give a crude mixture of compounds 20b and 20b- i (400mg, 59%) as a yellow solid. ?H NMR (400 MHz, METHANOE-d 4) oe ppm 2.43 (s, 3H), 2.85 (d, J=0.66 Hz, iH), 2.99(s, iH), 7.2i-7.23 (m, iH), 7.82 (d, J=2.65 Hz, iH), 7.86(dd, J=4.85, 2.43 Hz, iH), 8.02 (s, iH), 8.6i-8.65 (m, iH),8.63 (s, iH).

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 0960; 0961; 0962; 0963

64
[ 7170-01-6 ]
[ 22353-40-8 ]
1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [ No CAS ]
N-(5-chloro-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ No CAS ]
N-(5-chloro-6-(5-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-1-(isoquinolin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		2,3-Dichloro-5-nitropyridine (2 g, 10.36 mmol), <strong>[7170-01-6]<strong>[7170-01-6]3-methyl-1H-1,2,4-triazol</strong>e</strong> (1.722 g, 20.73 mmol) and Cs2CO3 (6.798 g, 20.73 mmol) were added to DMF (30 mL) and the reaction was stirred at rt for 12 h. The reaction mixture was quenched with water (200 mL). The mixture was extracted with ethyl acetate (100 mL*3). The organic layer was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The crude residue was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100:0 to 50:50) to afford a mixture of compounds 20a and 20a-1 (780 mg, 31%) as a white solid. A mixture of 3-chloro-2-(3-methyl-i H-i ,2,4-tri-azol- i -yl)-5-nitropyridine, 20a and 3-chloro-2-(5-methyl-i H-i ,2,4-triazol-i -yl)-5-nitropyridine, 20a- i (780 mg, i .63mmol) was dissolved in MeOH (20 mE), and Zn (0) (i.058g, i 6.28 mmol) and aqueous NH4C1 (20 mE) were added.The reaction mixture was stirred at rt for i 6 h. The reactionmixture was filtered though a pad of diatomaceous earth andthe pad washed with ethyl acetate (20 mEx3). Water (50 mE)was added and the organic layer was separated, dried overNa2SO4, filtered and the filtrate was concentrated to drynessto give a crude mixture of compounds 20b and 20b- i (400mg, 59%) as a yellow solid. ?H NMR (400 MHz, METHANOE-d 4) oe ppm 2.43 (s, 3H), 2.85 (d, J=0.66 Hz, iH), 2.99(s, iH), 7.2i-7.23 (m, iH), 7.82 (d, J=2.65 Hz, iH), 7.86(dd, J=4.85, 2.43 Hz, iH), 8.02 (s, iH), 8.6i-8.65 (m, iH),8.63 (s, iH).10965] A mixture of compounds 5-chloro-6-(3-methyl-1 H-i ,2,4-triazol- i -yl)pyridin-3-amine, 20b and 5-chioro-6- (5-methyl-i H-i ,2,4-triazol- i -yl)pyridin-3-amine, 20b- i (iOO mg, 0.3i mmol), i-(isoquinolin-4-yl)-5-(trifluorom- ethyl)-iH-pyrazole-4-carboxylic acid, 4c (263.0 mg, 0.63 mmol), and pyridine (62.0 mg, 0.78 mmol) were dissolved in dichioromethane (iO mE), and P0C13 (96.2 mg, 0.63 mmol) was added. The mixture was stirred at rt for 2.5 h. Sat. aqueous NH4C1 (20 mE) was added and the mixture was extracted with dichloromethane (20 mEx2). The combined organic layers were dried over Na2504, filtered, and the filtrates were concentrated under reduced pressure to afford a crude yellow oil. The crude oil was purified by reverse phase HPEC (A: water (0.05% HC1)-CAN, B: MeCN, AB:(48%/52%). The pure fractions were concentrated under reduced pressure and lyophilized to dryness to afford a mixture of compounds 53 and 54 (90 mg). The mixture was separated by Supercritical Fluid Chromatography (0.i% NH3H2O: MEOH. Mobile phase: A: CO2 B: 0.i% NH3H2O:MEOH; AB 75/25).10966] Cpd 53:10967] N-(5-chloro-6-(3-methyl- iH- i ,2,4-triazol-i -yl)pyridin-3-yl)- i -(isoquinolin-4-yl)-5-(trifluoromethyl)- iHpyrazole-4-carboxamide, (37.8 mg, 24.i%) as a white solid. ECMS (ESI) mlz M+i: 498.9. ?H NMR (400 MHz, DMSOd 5) oe ppm 2.34-2.40 (m, 3H), 7.27-7.30 (m, iH), 7.8i-7.90 (m, iH), 7.90-7.97 (m, iH), 8.33-8.4i (m, iH), 8.66-8.72 (m, iH), 8.74-8.82 (m, 2H), 8.86-8.98 (m, 2H), 9.60 (s, iH).10968] Cpd 54:10969] N-(5-chloro-6-(5-methyl-i H-i ,2,4-triazol-i -yl)pyridin-3-yl)- i -(isoquinolin-4-yl)-5-(trifluoromethyl)- iHpyrazole-4-carboxamide (i8.4 mg, 11.7%) as a white solid.ECMS (ESI) mlz M+i: 499.0. ?H NMR (400 MHz, DMSOd 5) oe ppm 2.34-2.37 (m, 3H), 7.23-7.32 (m, iH), 7.82-7.90(m, iH), 7.9i-7.98 (m, iH), 8.06-8.i2 (m, iH), 8.33-8.4i(m, iH), 8.59-8.64 (m, iH), 8.65-8.70 (m, iH), 8.75-8.8i(m, iH), 8.85-8.90 (m, iH), 9.58-9.64 (m, iH).

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 0960; 0961; 0962; 0963; 0964; 0965; 0966; 0969

65
[ 27808-16-8 ]
[ 22353-40-8 ]
3-chloro-2-(4-methyl-2H-1,2,3-triazol-2-yl)-5-nitropyridine [ No CAS ]
3-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 20℃; for 12h;	A solution of 4-methyl-iH-i,2,3-triazole (500 mg,6.02 mmol), 2,3-dichloro-5-nitropyridine (1277.42 mg, 6.62 mmol), K2C03 (2491.22 mg, 18.05 mmol) in CH3CN (5 mE) was stirred at it for 12 h. The mixture was concentrated under reduced pressure, the crude product was purified by colunm chromatography over silica gel (petroleum ether ethyl acetate from 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford i25a (1.1 g, 76.3%) as a yellow solid. ECMS (ESI) mlz M+i: 239.7.

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 1452; 1453

66
[ 27808-16-8 ]
[ 22353-40-8 ]
5-chloro-6-(4-methyl 2H-1,2,3-triazol-2-yl)pyridin-3-amine [ No CAS ]
5-chloro-6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 4-methyl-iH-i,2,3-triazole (500 mg,6.02 mmol), 2,3-dichloro-5-nitropyridine (1277.42 mg, 6.62 mmol), K2C03 (2491.22 mg, 18.05 mmol) in CH3CN (5 mE) was stirred at it for 12 h. The mixture was concentrated under reduced pressure, the crude product was purified by colunm chromatography over silica gel (petroleum ether ethyl acetate from 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford i25a (1.1 g, 76.3%) as a yellow solid. ECMS (ESI) mlz M+i: 239.7. Zn (1491.96 mg, 22.95 mmol) was added to a solution of mixture of 3-chloro-2-(4-methyl-2H-i,2,3-tri- azol-2-yl)-5-nitropyridine and 3-chloro-2-(4-methyl-i H-i, 2,3-triazol-i-yl)-5-nitropyridine, i25a (1.1 g, 2.30 mmol) in aqNH4C1 (30 mE) and H20 (30 mE). The mixture was stirred at it for 16 h. To the suspension was added aq NaHCO3 to adjust to pH 9-10, and the mixture was filtered through a pad of diatomaceous earth. The filter cake was washed with CH2C12 (100 mEx3). The combined filtrates were washed with brine (200 mE), dried over MgSO4 and concentrated under reduced pressure to afford mixture of 5-chloro-6-(4-methyl-2H- 1 ,2,3-triazol-2-yl)pyridin-3-amine and 5-chloro-6-(4-methyl-i H-i ,2,3-triazol- 1 -yl)pyriF din-3-amine, 125b (1 g) as a brown solid, used directly for the next step. LCMS (ESI) mlz M+H: 209.7

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 1452; 1453; 1454; 1455

67
[ 27808-16-8 ]
[ 22353-40-8 ]
1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [ No CAS ]
N-(5-chloro-6-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4- carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
208 mg		A solution of 4-methyl-iH-i,2,3-triazole (500 mg,6.02 mmol), 2,3-dichloro-5-nitropyridine (1277.42 mg, 6.62 mmol), K2C03 (2491.22 mg, 18.05 mmol) in CH3CN (5 mE) was stirred at it for 12 h. The mixture was concentrated under reduced pressure, the crude product was purified by colunm chromatography over silica gel (petroleum ether ethyl acetate from 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford i25a (1.1 g, 76.3%) as a yellow solid. ECMS (ESI) mlz M+i: 239.7. Zn (1491.96 mg, 22.95 mmol) was added to a solution of mixture of 3-chloro-2-(4-methyl-2H-i,2,3-tri- azol-2-yl)-5-nitropyridine and 3-chloro-2-(4-methyl-i H-i, 2,3-triazol-i-yl)-5-nitropyridine, i25a (1.1 g, 2.30 mmol) in aqNH4C1 (30 mE) and H20 (30 mE). The mixture was stirred at it for 16 h. To the suspension was added aq NaHCO3 to adjust to pH 9-10, and the mixture was filtered through a pad of diatomaceous earth. The filter cake was washed with CH2C12 (100 mEx3). The combined filtrates were washed with brine (200 mE), dried over MgSO4 and concentrated under reduced pressure to afford mixture of 5-chloro-6-(4-methyl-2H- 1 ,2,3-triazol-2-yl)pyridin-3-amine and 5-chloro-6-(4-methyl-i H-i ,2,3-triazol- 1 -yl)pyriF din-3-amine, 125b (1 g) as a brown solid, used directly for the next step. LCMS (ESI) mlz M+H: 209.7 P0C13 (182.86 mg, 1.19 mmol) was added to a solution of 125b (300 mg, 0.72 mmol), 1-(quinolin-5-yl)-5- (trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (183.19 mg, 0.60 mmol), pyridine (117.91 mg 1.49 mmol) in CH2C12 (10 mE). The mixture was stirred at it for 2h, 50 mE H20 and 50 mE CH2C12 were added to the mixture. The organic layer was washed with brine (50 mE), dried over MgSO4 and concentrated under reduced pressure to afford the crude product, which was purified by preparative HPEC (35% to 65% (v/v) CH3CN and H20 with 0.05% HC1) and lyophilized to dryness to afford the title compound (208 mg 69.8% yield) as a white solid. ECMS (ESI) mlz M+1: 499.0. ?H NMR (400 MHz, DMSO-d5) oe ppm 11.45 (s, 1H), 9.06 (t, J=2.54 Hz, 1H), 8.89 (s, 1H), 8.60-8.75 (m, 2H), 8.33 (d, J=8.38 Hz, 1H), 7.88-8.03 (m, 3H), 7.68 (d, J=2.65 Hz, 2H), 2.34 (s, 3H).

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 1452; 1453; 1454; 1455; 1456; 1457

68
[ 273-05-2 ]
[ 22353-40-8 ]
6-(2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-5-chloropyridin-3-amine [ No CAS ]
6-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-5-chloropyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		<strong>[273-05-2]1H-<strong>[273-05-2][1,2,3]triazolo[4,5-c]pyridine</strong></strong> (3.5 g, 18.14 mmol) was added to a mixture of 2,3-dichloro-5-nitropyri- dine (2.18 g, 18.14 mmol) and potassium carbonate (7.5 g, 54.41 mmol) in acetonitrile (50 mE). The mixture was stirred at rt for 12 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow solid. The crude product was purified by column chromatography over silica gel (petroleum ether/ethyl acetate=1 00:0 to petroleum ether/ethyl acetate=70:30). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (4.2 g, 83.7%). Iron (2.02 g, 36.1 mmol) and ammonium chloride (1.93 g, 36.1 mmol) were added to a mixture of 2-(3-chloro- 5-nitropyridin-2-yl)-2H-[1 ,2,3]triazolo[4,5-b]pyridine and3-(3-chloro-5-nitropyridin-2-yl)-3H-[1 ,2,3]triazolo[4,5-b] pyridine (4.0 g, 7.23 mmol) in THF (40 mE), water (10 mE) and methanol (20 mE). The reaction was stirred at 80 C. for 2 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with EtOAc (20 mEx3). The combined filtrates were concentrated to dryness to give crude product as a brown solid. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 10:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford the product as a brown oil (3.2 g, 86.1%).

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 1749; 1750; 1751; 1752

69
[ 273-05-2 ]
[ 22353-40-8 ]
2-(3-chloro-5-nitropyridin-2-yl)-2H-[1,2,3]triazolo[4,5-b]pyridine [ No CAS ]
3-(3-chloro-5-nitropyridin-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 20℃; for 12h;	<strong>[273-05-2]1H-<strong>[273-05-2][1,2,3]triazolo[4,5-c]pyridine</strong></strong> (3.5 g, 18.14 mmol) was added to a mixture of 2,3-dichloro-5-nitropyri- dine (2.18 g, 18.14 mmol) and potassium carbonate (7.5 g, 54.41 mmol) in acetonitrile (50 mE). The mixture was stirred at rt for 12 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow solid. The crude product was purified by column chromatography over silica gel (petroleum ether/ethyl acetate=1 00:0 to petroleum ether/ethyl acetate=70:30). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (4.2 g, 83.7%).

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 1749; 1750

70
[ 273-05-2 ]
[ 22353-40-8 ]
1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [ No CAS ]
N-(6-(2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ No CAS ]
N-(6-(2H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-5-chloropyridin-3-yl)-1-(quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16.9%; 9.6%		<strong>[273-05-2]1H-<strong>[273-05-2][1,2,3]triazolo[4,5-c]pyridine</strong></strong> (3.5 g, 18.14 mmol) was added to a mixture of 2,3-dichloro-5-nitropyri- dine (2.18 g, 18.14 mmol) and potassium carbonate (7.5 g, 54.41 mmol) in acetonitrile (50 mE). The mixture was stirred at rt for 12 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow solid. The crude product was purified by column chromatography over silica gel (petroleum ether/ethyl acetate=1 00:0 to petroleum ether/ethyl acetate=70:30). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (4.2 g, 83.7%). Iron (2.02 g, 36.1 mmol) and ammonium chloride (1.93 g, 36.1 mmol) were added to a mixture of 2-(3-chloro- 5-nitropyridin-2-yl)-2H-[1 ,2,3]triazolo[4,5-b]pyridine and3-(3-chloro-5-nitropyridin-2-yl)-3H-[1 ,2,3]triazolo[4,5-b] pyridine (4.0 g, 7.23 mmol) in THF (40 mE), water (10 mE) and methanol (20 mE). The reaction was stirred at 80 C. for 2 h. The reaction mixture was filtered though a pad of diatomaceous earth and the pad was washed with EtOAc (20 mEx3). The combined filtrates were concentrated to dryness to give crude product as a brown solid. The crude product was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 10:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford the product as a brown oil (3.2 g, 86.1%). P0C13 (239 mg, 1.56 mmol) was added to a mixture of 6-(2H-[ 1 ,2,3]triazolo[4,5-b]pyridin-2-yl)-5-chloro- pyridin-3-amine and 6-(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3- yl)-5-chioropyridin-3-amine (200 mg, 0.39 mmol), 1 -(quinolin-5-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-car- boxylic acid, 3b (143.5 mg, 0.47 mmol), and pyridine (185 mg, 2.34 mmol) in dichloromethane (8 mE). The reaction mixture was stirred at 20 C. for 4 h. Sat. NaHCO3 solution (10 mE) was added to the mixture. The mixture was extracted with dichioromethane (20 mEx3). The organic layers were concentrated under reduced pressure to afford a crude product, which was purified by reverse phase HPEC (35% to 65% (v/v) CH3CN and H20 with 0.05% HC1) to afford N-(6-(2H-[1 ,2,3]triazolo[4,5-b]pyridin-2-yl)-5-chlo- ropyridin-3-yl)-1 -(quinolin-5-yl)-5-(trifluoromethyl)-1 Hpyrazole-4-carboxamide, Cpd 164 (35.7, 16.9%). ?H NMR (400 MHz, DMSO-d5) oe ppm 11.44 (s, 1H), 9.06 (br s, 1H), 8.98 (s, 1H), 8.84 (br d, J=3.7 Hz, 1H), 8.78 (s, 1H), 8.63 (s, 1H), 8.35 (br dd, J=8.2, 16.5 Hz, 2H), 8.01-7.88 (m, 2H),7.76-7.59 (m, 3H). EC-MS: (ES, m/z): [M+1] 535.9; and11756] N-(6-(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-5- chioropyridin-3-yl)-1 -(quinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide, Cpd 165 (21 mg, 9.6%). ?H NMR (400 MHz, DMSO-d5) oe ppm 11.51 (s, 1H), 9.08 (dd, J=2.2, 3.5 Hz, 1H), 9.02 (d, J=2.2 Hz, 1H), 8.84-8.75 (m, 3H), 8.68 (s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.02-7.94 (m, 2H),7.73-7.68 (m, 2H), 7.64 (dd, J=4.6, 8.4 Hz, 1H). EC-MS:(ES, mlz): [M+1] 535.9.

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 1749; 1750; 1751; 1752; 1753; 1754; 1755

71
[ 5908-62-3 ]
[ 22353-40-8 ]
2-(3-chloro-5-nitropyridin-2-yl)isothiazolidine 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;	(1S,2S)-N1,N2-Dimethylcyclohexane-1,2-diamine (46.1 mg, 0.30 mmol) and copper iodide (56.3 mg, 0.30 mmol) were added to a mixture of 2,3-dichloro-5-nitropyridine (571 mg, 2.96 mmol), <strong>[5908-62-3]isothiazolidine 1,1-dioxide</strong> (430 mg, 3.55 mmol) and potassium carbonate (817.5 mg, 5.92 mmol) in dioxane (6 mL) under N2. The reaction mixture was stirred at 100 C. for 16 h. The mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The resultant crude product was purified by flash chromatography (petroleum ether/ethyl acetate=100:0 to petroleum ether/ethyl acetate=50:50) to afford compound 58a as a white solid (600 mg, 73%).

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 1243; 1244

72
[ 22353-40-8 ]
[ 4967-77-5 ]
methyl 2-(5-amino-3-chloropyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate [ No CAS ]
methyl 1-(5-amino-3-chloropyridin-2-yl)-1H-1,2,3-triazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45.7%; 28%		A. mixture of methyl 2-(3-chloro-5-nitropyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate and methyl 1-(3-chloro-5-nitropyridin-2-yl)-1H-1,2,3-triazole-5-carboxylate, 168a Potassium carbonate (10.0 g, 72.5 mmol) was added to a solution of 2,3-dichloro-5-nitropyridine (7.0 g, 36.3 mmol) and <strong>[4967-77-5]methyl 1H-1,2,3-triazole-4-carboxylate</strong> (4.61 g, 36.3 mmol) in MeCN (30 mL). The mixture was reacted at 60 C. for 16 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was purified by column chromatography over silica gel (petroleum ether/ethyl acetate=100:0 to petroleum ether/ethyl acetate=40:60). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (8.8 g, 42.8 yield). 11780] A mixture of methyl 2-(3-chloro-5-nitropyridin-2- yl)-2H-1 ,2,3-triazole-4-carboxylate and methyl 1 -(3-chloro- 5-nitropyridin-2-yl)- 1H- 1 ,2,3-triazole-5-carboxylate (8.8 g,15.5 mmol) was added to a mixture of iron (8.66 g, 155.1 mmol), NH4C1 (8.30 g, 155.1 mmol) in THF (30 mE) and water (15 mE). The reaction was stirred at 60 C. for 2 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give the crude product as a brown oil, the crude product was purified by colunm chromatography over silica gel (petroleum ether/ethyl acetate=2: 1 to ethyl acetate). The desired fractions were collected and the solvent was concentrated under reduced pressure to give methyl 2-(5-amino-3-chioropyridin-2-yl)-2H-i ,2,3-triazole- 4-carboxylate as a yellow solid, 168c (1.80 g, 45.7%). ?H NMR (400 MHz, CHEOROFORM-d) oe ppm 3.98 (s, 3H), 4.21 (s, 2H), 7.16 (d, J=2.51 Hz, 1H), 7.90 (d, J=2.51 Hz, 1H), 8.26-8.33 (m, 1H). EC-MS: (ES, m/z): [M+i] 254.0;and11781] methyl 1 -(5-amino-3-chloropyridin-2-yl)-i H-i ,2,3-triazole-5-carboxylate as a yellow oil, i68d (1.10 g,28.0%), ?H NMR (400 MHz, CHEOROFORM-d) oe ppm3.99 (s, 3H), 4.33 (br s, 2H), 7.20 (d, J=2.5i Hz, iH), 7.91(d, J=2.76 Hz, iH), 8.48 (s, iH), 8.46-8.53 (m, iH). EC-MS:(ES, mlz): [M+i] 254.0

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 1777; 1778; 1779; 1780

73
[ 22353-40-8 ]
[ 4967-77-5 ]
methyl 2-(3-chloro-5-nitropyridin-2-yl)-2H-1,2,3-triazole-4-carboxylate [ No CAS ]
methyl 1-(3-chloro-5-nitropyridin-2-yl)-1H-1,2,3-triazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 60℃; for 16h;	Potassium carbonate (10.0 g, 72.5 mmol) was added to a solution of 2,3-dichloro-5-nitropyridine (7.0 g, 36.3 mmol) and methyl 1H-i,2,3-triazole-4-carboxylate (4.6i g, 36.3 mmol) in MeCN (30 mE). The mixture was reacted at 60 C. for 16 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was purified by column chromatography over silica gel (petroleum ether/ethyl acetate=i00:0 to petroleum ether/ethyl acetate=40:60). The pure fractions were collected and the solvent was concentrated under reduced pressure to give the product as a yellow solid (8.8 g, 42.8 yield).

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 1328; 1329; 1775; 1776

74
[ 22353-40-8 ]
[ 13061-96-6 ]
[ 51984-62-4 ]

Yield	Reaction Conditions	Operation in experiment
344 mg	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; at 100.0℃; for 6.0h;	Cesium carbonate (338 mg), methylboronic acid (47 mg), and tetrakis(triphenylphosphine)palladium (60 mg) were added to a 1,4-dioxane (3 ml) solution containing 2,3-dichloro-5-nitropyridine (100 mg), followed by stirring at 100C for 6 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and 3-chloro-2-methyl-5-nitropyridine (344 mg) was thus obtained.

Reference： [1]Patent: EP2589592,2018,B1 .Location in patent: Paragraph 1190; 1191

75
[ 22353-40-8 ]
[ 124-41-4 ]
[ 22353-53-3 ]

Yield	Reaction Conditions	Operation in experiment
45.8 mg	In methanol; at 20.0℃; for 1.5h;	Sodium methoxide (5M methanol solution) (0.5 ml) was added to a methanol (1 ml) solution of 2,3-dichloro-5-nitropyridine (50 mg), followed by stirring at room temperature for 1.5 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and colorless oily matter of 3-chloro-2-methoxy-5-nitropyridine (45.8 mg) was thus obtained.

Reference： [1]Patent: EP2589592,2018,B1 .Location in patent: Paragraph 1105; 1106

76
[ 22353-40-8 ]
[ 97966-00-2 ]

Reference： [1]Patent: US2004/242641,2004,A1

77
[ 22353-40-8 ]
[ 934-05-4 ]
methyl 1-(3-chloro-5-nitropyridin-2-yl)-4-bromo-1H-pyrrole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate; In N,N-dimethyl-formamide; at 55℃; for 24h;Sealed tube;	Methyl 4-bromo-1H-pyrrole-2-carboxylate (12 mmol), 2,3-dichloro-5-nitropyridine (48 mmol), potassium carbonate(48 mmol) and DMF (50 mL) were sequentially added to a thick-walled pressure-resistant bottle, sealed, and magnetically stirred at 55 C for 24 h.Cool and dilute the reaction with water (100 mL).Extract with ethyl acetate (2 x 100 mL).The organic layers were combined, washed successively with water, saturated NaCI solution, dried over anhydrous Na2SO4, filtered, and evaporated,Ethyl acetate column chromatography gave a pale yellow liquid, yield62%.

Reference： [1]Patent: CN108689988,2018,A .Location in patent: Paragraph 0065; 0067; 0068; 0069

78
[ 288-36-8 ]
[ 22353-40-8 ]
3-chloro-5-nitro-2-(1H-1,2,3-triazol-1-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With potassium carbonate; In tetrahydrofuran; at 20℃; for 16h;Inert atmosphere;	Potassium carbonate (7.0 g, 50.6 mmol) and 1H-1,2,3-triazole (2.0 g, 29.0 mmol) were added to a stirred solution of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (5 g, 25.9 mmol) in THF (30 mL). The resulting mixture was stirred at rt for 16 h, then diluted with water (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL) and the combined organic layers were dried (Na2S04), filtered and concentrated under reduced pressure. The afforded crude compound was stirred with 10% MeOH in DCM (50 mL) for 20 min, then filleted, which gave the title compound (2.0 g, 32%) as a solid. LCMS (ES+) m/z 226.20 [M+H].

Reference： [1]Patent: WO2018/226150,2018,A1 .Location in patent: Page/Page column 61

79
[ 22353-40-8 ]
[ 98121-41-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	With acetic acid;	To 2,3-dichloro-5-nitropyridine (68.5 g, 0.39 mol) in a mixture of H2 O (800 mL) and acetic acid (160 mL) were added bits of metallic iron with stirring until the starting material was consumed (TLC analysis). The mixture was filtered, and the filter cake was washed repeatedly with EtOAc. The aqueous filtrate was extracted with EtOAc and the organic fractions were combined and concentrated. The residue was chromatographed (silica gel; MeOH: CHCl3, 0.5:99.5 to 1:99) to afford the title compound (44.5 g, 70%) as a light orange powder: MS (CI/NH3) m/z 163 and 165 (M+H+), 180 and 182 (M+NH4)+.

Reference： [1]Patent: US6133253,2000,A

80
[ 22353-38-4 ]
[ 22353-40-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With trichlorophosphate; In quinoline;	To phosphorus oxychloride (37.4 mL, 0.4 mol) at 0 C. was added quinoline (23.6 mL, 0.2 mol), followed by <strong>[22353-38-4]3-chloro-2-hydroxy-5-nitropyridine</strong> (70 g, 0.4 mol) from above. The mixture was heated at 120 C. for 2.5 hours, during which time it became a dark liquid. After cooling to 100 C., H2 O (150 mL) was added cautiously, and the mixture was cooled to 0 C. The precipitated solid was collected by filtration, washed with cold H2 O, and dried under vacuum at 50 C. to afford 2,3-dichloro-5-nitropyridine (68.6 g, 89%).

Reference： [1]Patent: US6133253,2000,A

81
[ 22353-40-8 ]
[ 205448-65-3 ]
methyl 4-((3-chloro-5-nitropyridin-2-yl)oxy)-7-methoxyquinoline-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of Compound 4 (2 g, 8.58 mmol, 1 eq) in CH3CN (30 mL) was added CS2CO3 (5.59 g, 17.15 mmol, 2 eq) in one portion at 20 C. After stirring at 20 C for 30 min, 2,3- dichloro-5-nitro-pyridine (1.82 g, 9.43 mmol, 1.1 eq) was added. The mixture was stirred at 20 C for 36 h. The reaction mixture was filtered and the filter cake was washed with 100 mL of EtOAc. The filter cake diluted with water (100 mL) and extracted with DCM (3 x 150 mL). The combined DCM extracts were washed with aq saturated NaCl (10 mL), filtered, and concentrated under reduced pressure to give crude Compound 6 as a yellow solid (1.8 g, 53.85% yield). 1H NMR (400 MHz, DMSO-d6) d 9.03 (d, 1H), 8.99 - 8.95 (m, 2H), 8.26 (s, 1H), 7.64 (s, 1H), 7.42 (d, 1H), 3.99 (s, 3H), 3.82 (s, 3H); MS (El) for C17H12CIN3O6, found 389.9 (MH+).

Reference： [1]Patent: WO2019/148043,2019,A1 .Location in patent: Paragraph 000415-000416

82
[ 3731-51-9 ]
[ 22353-40-8 ]
3-chloro-5-nitro-N-(pyridin-2-ylmethyl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	In acetonitrile; at 25℃; for 4h;Inert atmosphere;	A mixture of <strong>[22353-40-8]2,3-dichloro-5-nitropyridine</strong> (1.50 g, 7.77 mmol, 1.00 eq), pyridin-2- ylmethanamine (1.01 g, 9 33 mmol, 951 uL, 1.20 eq) in acetonitrile (30.0 mL) was stirred at 25 C'C for 4 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFfash Silica Flash Column, Eluent of 0~1% Ethyl aeetate/Petroleum ether gradient 60 mL/min) to give 3-chloro~5~mtro~N- (pyridin-2-ylmethyl)pyridin-2-amine (1.50 g, 5.67 mmol, 73% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) d = 8.87 (d, J = 2.2 Hz, 1 H), 8.52 (br d, J = 4.8 Hz, 2 H), 8.43 (d, J = 2.4 Hz, 1 H), 7.74 (td, J = 7.6, 1.6 Hz, 1 H), 7.40 - 7.14 (m, 2 H), 4.82 (d, J = 6.0 Hz, 2 H).

Reference： [1]Patent: WO2020/68867,2020,A1 .Location in patent: Page/Page column 487

83
[ 22353-40-8 ]
[ 3236-71-3 ]
[ 2572398-62-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate In N,N-dimethyl acetamide at 80℃; for 12h; Inert atmosphere;	3.1 38.598g (0.2mol) 2,3-dichloro-5-nitropyridine, 35.041g (0.1mol) 9,9-bis(4-hydroxyphenyl) fluorene, 20.73g (0.15mol) carbonic acid Mix potassium with 350mL N,N-dimethylacetamide, heat to 80, react at constant temperature for 12h, then use thin layer chromatography (TLC) method to determine the end of the reaction; then cool the reaction solution to room temperature and pour it into 700mL In the water, the solid product precipitated, and then filtered. The filter cake was washed with deionized water and dried to obtain 60 g of white solid (i.e., crude dinitro compound containing fluorenyl and pyridine heterocyclic structure). The white solid was combined with 540 mL of N , N-Dimethylacetamide was mixed, heated to 120, and then naturally cooled to 90, when 108mL of water was added dropwise, solids began to precipitate, stop adding water, naturally cooled to room temperature and let stand for 12h, the reaction solution of solids precipitated After filtering, the solid obtained was washed with a mixture of N,N-dimethylacetamide and water mixed in a volume ratio of 5:1 and then dried to obtain 53 g of dinitro groups containing fluorenyl and pyridine heterocyclic structures Compound, the calculated yield is 81%

Reference： [1]Current Patent Assignee: DONGHUA UNIVERSITY - CN112142654, 2020, A Location in patent: Paragraph 0111-0117

84
[ 22353-40-8 ]
[ 265309-82-8 ]
(R)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)-3-chloro-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: (2R)-2-[tert-butyl(dimethyl)silyl]oxypropan-1-ol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1h; Stage #2: 2,3-dichloro-5-nitropyridine In N,N-dimethyl-formamide; mineral oil at 25℃; for 18h;	74.3 Step 3: (R)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)-3-chloro-5-nitropyridine To a stirred solution of (R)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol (1.0 g, 5.2 mmol) in N,N-Dimethylformamide (10 mL) was added NaH (231 mg, 5.9 mmol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Then 2,3-dichloro-5-nitropyridine (1.2 g, 6.3 mmol) was added and the reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was quenched with water (20 mL). The resulting solution was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 96% petroleum ether and 4% ethyl acetate as eluent to afford (R)-2-(2-((tert- butyldimethylsilyl)oxy)propoxy)-3-chloro-5-nitropyridine (0.8 g, 35% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ: 9.03 (d, J = 2.8 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H), 4.36-4.39 (m, 2H), 4.20-4.25 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H), 0.81 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H). LC-MS: m/z 347 [M+H]+.

Reference： [1]Current Patent Assignee: SCHROEDINGER LLC - WO2021/134004, 2021, A1 Location in patent: Page/Page column 326-327

85
[ 22353-40-8 ]
[ 1520-31-6 ]
((3-chloro-5-nitropyridin-2-yl)imino)dimethyl-λ⁶-sulfanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 2h; Inert atmosphere;	85.1 Step 1: ((3-chloro-5-nitropyridin-2-yl)imino)dimethyl-λ⁶-sulfanone To a stirred solution of methyl 2,3-dichloro-5-nitropyridine (1.0 g, 5.2 mmol) and iminodimethyl-λ6-sulfanone (579.2 mg, 6.2 mmol) in dioxane (10 mL) were added Pd2(dba)3 (474.6 mg, 518.1 μmol), XantPhos (599.0 mg, 1.1 mmol) and Cs2CO3 (2.5 g, 7.7 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 100 oC for 2 h. The mixture was cooled to 25 oC. The reaction mixture was quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 60% petroleum ether and 40 % ethyl acetate as eluent to afford ((3-chloro-5-nitropyridin-2-yl)imino)dimethyl-λ6-sulfanone (700 mg, 48% yield) as a yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 8.96 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 3.47 (s, 6H). LC-MS: m/z 250 [M+H]+.

Reference： [1]Current Patent Assignee: SCHROEDINGER LLC - WO2021/134004, 2021, A1 Location in patent: Page/Page column 364

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P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
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
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
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
H280	Contains gas under pressure; may explode if heated
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
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
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. 22353-40-8 ] {[proInfo.proName]}

Quality Control of [ 22353-40-8 ]

Related Doc. of [ 22353-40-8 ]

Product Details of [ 22353-40-8 ]

Calculated chemistry of [ 22353-40-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 22353-40-8 ]

Application In Synthesis of [ 22353-40-8 ]

[ 22353-40-8 ] Synthesis Path-Upstream 1~16

[ 22353-40-8 ] Synthesis Path-Downstream 1~85

Related Functional Groups of [ 22353-40-8 ]

Chlorides

Nitroes

Related Parent Nucleus of [ 22353-40-8 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 22353-40-8 ]

Related Parent Nucleus of
[ 22353-40-8 ]