1171919-75-7|2-Chloro-4-iodonicotinonitrile| Ambeed

Structure of 1171919-75-7

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 1171919-75-7 ] Purity: 98% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 1171919-75-7 ]

CAS No. :	1171919-75-7
Formula :	C₆H₂ClIN₂
M.W :	264.45
SMILES Code :	N#CC1=C(Cl)N=CC=C1I
MDL No. :	MFCD12401632
InChI Key :	BQFOSZGLMPGGLY-UHFFFAOYSA-N
Pubchem ID :	46737831

Safety of [ 1171919-75-7 ]

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

Application In Synthesis of [ 1171919-75-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1171919-75-7 ]

[ 1171919-75-7 ] Synthesis Path-Downstream 1~35

1
[ 153034-90-3 ]
[ 1171919-75-7 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; iodine; In tetrahydrofuran; at 20℃;	Step 1. 2-chloro-4-iodonicotinonitrileTo 2-chloro-4-iodonicotinaldehyde (1.0 g, 3.7 mmol) dissolved in THF (11 mL) was added ammonium hydroxide (11 mL, 280 mmol) followed by iodine (1040 mg, 4.11 mmol), the reaction was held at ambient temperature 3.5 h, color visibly lightens as reaction progresses until the end when it is nearly colorless. LCMS indicates reaction to be complete. Reaction was quenched by addition of saturated NaHSO3, extracted into EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide the crude product, 926 mg. Dissolved in CHCl3/MeOH and applied to 120 g silica gel column, the product fractions were concentrated in vacuo to give 728 mg product. The purified material was taken directly to next step.

References: [1]Patent: US2010/298334,2010,A1 .Location in patent: Page/Page column 97.

2
[ 1171919-75-7 ]
[ 97674-02-7 ]
[ 1257072-23-3 ]

Yield	Reaction Conditions	Operation in experiment
	tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 16h;	Step 1. 2-chloro-4-(1-ethoxyvinyl)nicotinonitrileA solution of <strong>[1171919-75-7]2-chloro-4-iodonicotinonitrile</strong> (from Example 122, Step 1; 240.0 mg, 0.9075 mmol) and tributyl(1-ethoxyvinyl)tin (398.58 μL, 1.1798 mmol) in toluene (3.2 mL) was degassed, and tetrakis(triphenylphosphine)palladium(0) (104.9 mg, 0.09075 mmol) was added. The reaction was degassed again and heated to 100 C. for 16 h. The reaction mixture was partitioned between water and EtOAc, the phases were separated and the aqueous phase was washed with additional EtOAc. The combined organic phase was washed with brine, dried over MgSO4 and filtered and concentrated in vacuo to provide the crude product, 195.6 mg. Crude product was chromatographed on 40 g column, recovered 143 mg product. 1H NMR (300 MHz CDCl3): δ 8.51 (d, 1H), 7.44 (d, 1H), 4.85 (d, 1H), 4.60 (d, 1H), 3.97 (q, 2H), 1.42 (t, 3H).

References: [1]Patent: US2010/298334,2010,A1 .Location in patent: Page/Page column 103.

3
[ 1171919-75-7 ]
[ 5188-07-8 ]
[ 1257072-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; at 20℃; for 40h;	Step 1. 2-chloro-4-(methylthio)nicotinonitrile2-Chloro-4-iodonicotinonitrile (from Example 122, Step 1; 209.5 mg, 0.7922 mmol) was dissolved in 1,4-dioxane (1.85 mL) and sodium methyl mercaptide (61.0 mg, 0.871 mmol) was added. The reaction was stirred at ambient temperature. After 40 h the reaction mixture was partitioned between water and EtOAc, the phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water, then brine, dried over MgSO4, filtered and concentrated in vacuo to provide 180 mg of the crude product. Dissolved in CHCl3/hexanes and applied to 40 g silica gel column; product recovered: 52 mg. LCMS calculated for C7H6ClN2S (M+H)+: m/z=184.994, observed 184.90.

References: [1]Patent: US2010/298334,2010,A1 .Location in patent: Page/Page column 100.

4
[ 18143-30-1 ]
[ 1171919-75-7 ]
2-chloro-4-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	To a solution of <strong>[1171919-75-7]2-chloro-4-iodonicotinonitrile</strong> (2.0 g, 7.6 mmol) and K2CO3 (1.57 g, 1 1.34 mmol) in DMF (7 mL) was added 2-(trimethylsilyl)ethanethiol (1.21 mL, 7.56 mmol) under dry 2 atmosphere at room temperature. The mixture was stirred at the room temperature for 16 hours. The crude UPLC did not show the desired peak but the TLC indicated complete consumption of starting material. The reaction mixture was concentrated under vacuo. The crude was adsorbed onto silica gel, and loaded onto silica gel column and eluted with hexane and ethyl acetate to give 2-chloro-4-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile. LC/MS [M+H]+: 271.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	Step A: 2-Chloro-4-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile (0649) To a solution of <strong>[1171919-75-7]2-chloro-4-iodonicotinonitrile</strong> (2.0 g, 7.6 mmol) and K2CO3 (1.57 g, 11.34 mmol) in DMF (7 mL) was added 2-(trimethylsilyl)ethanethiol (1.21 mL, 7.56 mmol) under dry N2 atmosphere at room temperature. The mixture was stirred at the room temperature for 16 hours. The crude UPLC did not show the desired peak but the TLC indicated complete consumption of starting material. The reaction mixture was concentrated under vacuo. The crude was adsorbed onto silica gel, and loaded onto silica gel column and eluted with hexane and ethyl acetate to give 2-chloro-4-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile. LC/MS [M+H]+: 271.

References: [1]Patent: WO2015/112441,2015,A1 .Location in patent: Page/Page column 169.
[2]Patent: US2016/333021,2016,A1 .Location in patent: Paragraph 0649.

5
[ 1171919-75-7 ]
2-chloro-4-((2-(trimethylsilyl)ethyl)sulfonyl)nicotinonitrile [ No CAS ]

References: [1]Patent: WO2015/112441,2015,A1 .
[2]Patent: US2016/333021,2016,A1 .

6
[ 1171919-75-7 ]
2-(4-(hydroxymethyl)phenyl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)nicotinonitrile [ No CAS ]

References: [1]Patent: WO2015/112441,2015,A1 .
[2]Patent: US2016/333021,2016,A1 .

7
[ 1171919-75-7 ]
(4-(3-(1H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)pyridin-2-yl)phenyl)methanol [ No CAS ]

References: [1]Patent: WO2015/112441,2015,A1 .
[2]Patent: US2016/333021,2016,A1 .

8
[ 1171919-75-7 ]
2-(4-(hydroxymethyl)phenyl)-3-(1H-tetrazol-5-yl)pyridine-4-sulfonamide [ No CAS ]

References: [1]Patent: WO2015/112441,2015,A1 .
[2]Patent: US2016/333021,2016,A1 .

9
[ 1171919-75-7 ]
sodium 5-chloropyrazino-2-thiolate [ No CAS ]
2-chloro-4-((5-chloropyrazin-2-yl)thio)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22 mg	With palladium diacetate; N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;	Intermediate C-4 2-chloro-4-((5-chloropyrazin-2-yl)thio)nicotinonitrile A mixture of sodium 5-chloropyrazino-2-thiolate (31.9 mg, 0.189 mmol), 2- chloro-4-iodonicotinonitrile (50 mg, 0.189 mmol), XantPhos (10.9 mg, 0.019 mmol), diacetoxypalladium (2.1 mg, 0.0095 mmol), and DIPEA (0.066 mL, 0.378 mmol) in dioxane (degassed, 1 mL) was stirred for 3 h at 100 C. After cooling to RT, the reaction mixture was diluted with aq. sat. NH4CI, extracted with EtOAc (2x). The combined organic layers were dried over MgSC , filtered, concentrated under reduced pressure, and the resulting residue was purified by silica chromatography (0 to 100% gradient of EtO Ac/heptane) to give 2-chloro-4-((5- chloropyrazin-2-yl)thio)nicotinonitrile (22 mg, 0.078 mmol). NMR (400 MHz, DMSO-i) δ ppm 8.88 (d, 7=1.3 Hz, 1H), 8.84 (d, 7=1.3 Hz, 1H), 8.54 (d, 7=5.5 Hz, 1H), 7.59 (d, 7=5.5 Hz, 1H). MS m/z. 283.1 (M+H)+.

References: [1]Patent: WO2016/203406,2016,A1 .Location in patent: Paragraph 00276.

10
[ 1171919-75-7 ]
[ 123-30-8 ]
2-chloro-3-cyano-4-(4-aminophenoxy)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		Step 2: Synthesis of 2-chloro-3-cyano-4-(4-aminophenoxy)pyridine A solution of 4-aminophenol (164 mg, 1.48 mmol) in anhydrous dimethyl sulfoxide (3 mL) was bubbled with nitrogen gas for 10 minutes, and potassium tert-butoxide (166 mg, 1.48 mmol) was then added to get a reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes, <strong>[1171919-75-7]2-chloro-4-iodonicotinonitrile</strong> (355 mg, 1.34 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours, and then diluted with water (30 mL) and extracted with ethyl acetate (30 mL3). The organic phases were combined. The combined organic phases were washed with water (30 mL2), washed with saline solution (30 mL*2), dried with anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=4:1, v/v) to get product as light yellow solid (210 mg, yield: 61%). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J=6.0 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.76 (d, J=6.0 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H), 5.29 (s, 2H) MS (ESI+): m/z 246.0 [M+H]+

References: [1]Patent: US2017/29404,2017,A1 .Location in patent: Paragraph 0159-0162.

11
[ 1171919-75-7 ]
1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-cyano-2-(1-methylpyrazol-4-yl)pyridin-4-yloxy)phenyl)urea [ No CAS ]

References: [1]Patent: US2017/29404,2017,A1 .

12
[ 1171919-75-7 ]
4-(3-cyano-2-(1-methyl-pyrazol-4-yl)-pyridin-4-yl-oxy)aniline [ No CAS ]

References: [1]Patent: US2017/29404,2017,A1 .

13
[ 6602-54-6 ]
[ 1171919-75-7 ]

Yield	Reaction Conditions	Operation in experiment
19%		Step 1: Synthesis of 2-chloro-4-iodonicotinonitrile In an atmosphere of argon gas, at -30 C., n-butyl lithium (2.4M hexane solution, 3.0 mL, 7.2 mmol) was added dropwise to a solution of diisopropylamine (0.728 g, 7.2 mmol) in anhydrous tetrahydrofuran (20 mL) to get a reaction mixture. The reaction mixture was stirred at -30 C. for 30 minutes, and then cooled to -78 C. A solution of 2-chloro-nicotinonitrile (1.0 g, 7.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the reaction mixture was then stirred at -78 C. for 60 minutes. A solution of iodine (1.8 g, 7.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the reaction mixture was then stirred at -78 C. for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), diluted with water (50 mL), and extracted with ethyl acetate (100 mL3). The organic phases were combined. The combined organic phases were washed with saline solution (100 mL3), dried with anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=80:1) to get product as yellow solid (0.357 g, yield: 19%). 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J=5.2 Hz, 1H), 8.15 (d, J=5.2 Hz, 1H) MS (ESI+): m/z 264.9 [M+H]+

References: [1]Patent: US2017/29404,2017,A1 .Location in patent: Paragraph 0155-0158.

14
[ 1171919-75-7 ]
[ 13024-16-3 ]
2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 100℃;Inert atmosphere;	To a round bottom flask under a N2 atmosphere were added 2-methyl-4-phenoxyaniline (30 g, 150 mmol), <strong>[1171919-75-7]2-chloro-4-iodopyridine-3-carbonitrile</strong> (51.6 g, 195 mmol), and dioxane (200 mL), followed by bis(2- diphenylphosphinophenyl)ether (DPEphos) (16 g, 30 mmol), Pd(OAc)2 (3.36 g, 15 mmol), and K3PO4 (89 g, 420 mmol). The reaction mixture was stirred at 100 C overnight. The reaction mixture was filtered and purified flash column chromatography to yield the title Compound (32 g, 63% yield) as a yellow solid.
63%	With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 100℃;Inert atmosphere;	To a round bottom flask under a N2 atmosphere were added 2-methyl-4-phenoxyaniline (30 g, 150 mmol), 2-chloro- 4-iodopyridine-3-carbonitrile (51.6 g, 195 mmol), and dioxane (200 mL), followed by bis(2- diphenylphosphinophenyl)ether (DPEphos) (16 g, 30 mmol), Pd(OAc)2 (3.36 g, 15 mmol), and K3PO4 (89 g, 420 mmol). The reaction mixture was stirred at 100 C overnight. The reaction mixture was filtered and purified flash column chromatography to yield the title compound (32 g, 63% yield) as a yellow solid.
63%	With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 100℃;Inert atmosphere;	To a round bottom flask under a N2 atmosphere were added 2-methyl-4-phenoxyaniline (30 g, 150 mmol), 2-chloro- 4-iodopyridine-3-carbonitrile (51.6 g, 195 mmol), and dioxane (200 mL), followed by bis(2-diphenylphosphinophenyl)ether (DPEphos) (16 g, 30 mmol), Pd(OAc)2 (3.36 g, 15 mmol), andK3P04 (89 g, 420 mmol). The reaction mixture was stirred at 100 C overnight. The reaction mixture was filtered and purified flash column chromatography to yield the title compound (32 g, 63% yield) as a yellow solid.

63%	With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 100℃;Inert atmosphere;	To a round bottom flask under a N 2 atmosphere were added 2-methyl-4-phenoxyaniline (30 g, 150 mmol), <strong>[1171919-75-7]2-chloro-4-iodopyridine-3-carbonitrile</strong> (51.6 g, 195 mmol), and dioxane (200 mL), followed by bis (2-diphenylphosphinophenyl) ether (DPEphos) (16 g, 30 mmol), Pd (OAc) 2 (3.36 g, 15 mmol), and K 3PO 4 (89 g, 420 mmol). The reaction mixture was stirred at 100 overnight. The reaction mixture was filtered and purified flash column chromatography to yield the title compound (32 g, 63% yield) as a yellow solid.
63%	With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 100℃;Inert atmosphere;	To a round bottom flask under a N 2 atmosphere were added 2-methyl-4-phenoxyaniline (30 g, 150 mmol), <strong>[1171919-75-7]2-chloro-4-iodopyridine-3-carbonitrile</strong> (51.6 g, 195 mmol), and dioxane (200 mL), followed by bis (2-diphenylphosphinophenyl) ether (DPEphos) (16 g, 30 mmol), Pd (OAc) 2 (3.36 g, 15 mmol), and K 3PO 4 (89 g, 420 mmol). The reaction mixture was stirred at 100 overnight. The reaction mixture was filtered and purified flash column chromatography to yield the title compound (32 g, 63%yield) as a yellow solid.

References: [1]Patent: WO2017/100662,2017,A1 .Location in patent: Page/Page column 105; 106.
[2]Patent: WO2017/100668,2017,A1 .Location in patent: Page/Page column 159.
[3]Patent: WO2018/103060,2018,A1 .Location in patent: Page/Page column 104; 105.
[4]Patent: WO2018/103058,2018,A1 .Location in patent: Page/Page column 159.
[5]Patent: WO2018/103058,2018,A1 .Location in patent: Page/Page column 192.
[6]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 782 - 790.

15
[ 1171919-75-7 ]
2-chloro-4-(4-hydroxy-2-methylanilino)pyridine-3-carbonitrile [ No CAS ]

References: [1]Patent: WO2017/100662,2017,A1 .
[2]Patent: WO2017/100668,2017,A1 .
[3]Patent: WO2018/103060,2018,A1 .
[4]Patent: WO2018/103058,2018,A1 .

16
[ 1171919-75-7 ]
2-chloro-4-[4-(cyclohexoxy)-2-methylanilino]pyridine-3-carbonitrile [ No CAS ]

References: [1]Patent: WO2017/100662,2017,A1 .
[2]Patent: WO2017/100668,2017,A1 .
[3]Patent: WO2018/103060,2018,A1 .
[4]Patent: WO2018/103058,2018,A1 .

17
[ 1171919-75-7 ]
6-isobutyl-4-methylpyridin-3-amine [ No CAS ]
[ 2365-48-2 ]
methyl 3-amino-4-((6-isobutyl-4-methylpyridin-3-yl)amino)thieno[2,3-b]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		To a round bottom flask under a N2 atmosphere were added 6-isobutyl-4- methylpyridin-3 -amine (53.5 g, 326 mmol), <strong>[1171919-75-7]2-chloro-4-iodopyridine-3-carbonitrile</strong> (94.8 g, 358 mmol) and dioxane (1000 mL), followed by bis(2-diphenylphosphinophenyl)ether (DPEphos) (10.5 g, 19.5 mmol), Pd(OAc)2 (2.92 g, 13.0 mmol), and Cs2C03 (265 g, 814 mmol). The reaction mixture was stirred at 105 C for 3 h. Methyl 2-mercaptoacetate (51.9 g, 489 mmol) was added, and the reaction was stirred at 105 C overnight. The reaction mixture was filtered and concentrated. The residue was suspended in MeOH (400 mL) and stirred for 2 h at room temperature. The resulting precipitate was isolated by filtration and dried under vacuum to give the title Compound (75.3 g, 62% yield) as a yellow solid.
62%		To a round bottom flask under a N2 atmosphere were added 6-isobutyl-4-methylpyridin-3-amine (53.5 g, 326 mmol), <strong>[1171919-75-7]2-chloro-4-iodopyridine-3-carbonitrile</strong> (94.8 g, 358mmol) and dioxane (1000 mL), followed by bis(2-diphenylphosphinophenyl)ether (DPEphos)(10.5 g, 19.5 mmol), Pd(OAc)2 (2.92 g, 13.0 mmol), and Cs2CO3 (265 g, 814 mmol). Thereaction mixture was stirred at 105 C for 3 h. Methyl 2-mercaptoacetate (51.9 g, 489 mmol)was added, and the reaction was stirred at 105 C overnight. The reaction mixture was filtered and concentrated. The residue was suspended in MeOH (400 mL) and stirred for 2 h at room temperature. The resulting precipitate was isolated by filtration and dried under vacuum to give the title compound (75.3 g, 62% yield) as a yellow solid.

References: [1]Patent: WO2017/100662,2017,A1 .Location in patent: Page/Page column 115; 116.
[2]Patent: WO2018/103060,2018,A1 .Location in patent: Page/Page column 114; 115.

18
[ 1171919-75-7 ]
[ 102-50-1 ]
2-chloro-4-(4-methoxy-2-methylanilino)pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 120℃;Inert atmosphere;	A mixture of 2-chloro- 4-iodopyridine-3-carbonitrile (1.7 g, 6.4 mmol), 4-methoxy-2-methylaniline (880 mg, 6.4 mmol), DPEPhos [bis(2-diphenylphosphinophenyl)ether] 690 mg, 1.3 mmol), palladium(II) acetate (145 mg, 0.646 mmol), and K3PO4 (3.7 mg, 0.017 mmol) in dioxane (20 mL) was degassed under vacuum and heated at 120 C overnight. The mixture was cooled to rt, concentrated to dryness, and purified by flash column chromatography to yield the title Compound (1.1 g, 63% yield) as a brown solid.
63%	With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 120℃;	To a round bottom flask were added <strong>[1171919-75-7]2-chloro-4-iodopyridine-3-carbonitrile</strong> (1.7 g, 6.4 mmol), 4-methoxy-2- methylaniline (880 mg, 6.4 mmol), DPEPhos [bis(2-diphenylphosphinophenyl)ether] (690 mg, 1.3 mmol), palladium(II) acetate (145 mg, 0.646 mmol), K3PO4 (3.7 g, 0.017 mmol), and dioxane (15 mL). The reaction mixture was degassed and heated at 120 C overnight. The mixture was cooled to rt, concentrated to dryness, and purified by flash column chromatography to yield the title compound (1.1 g, 63% yield) as a brown solid. MS (ESI): mass calcd. for ci4H12ciN3O, 273.1 ; m/z found, 274 [M+H]+.
63%	With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 120℃;	A mixture of 2-chloro- 4-iodopyridine-3-carbonitrile (1.7 g, 6.4 mmol), 4-methoxy-2-methylaniline (880 mg, 6.4 mmol),DPEPhos [bis(2-diphenylphosphinophenyl)ether] 690 mg, 1.3 mmol), palladium(II) acetate (145 mg, 0.646 mmol), and K3P04 (3.7 mg, 0.0 17 mmol) in dioxane (20 mL) was degassed under vacuum and heated at 120 C overnight. The mixture was cooled to rt, concentrated to dryness, and purified by flash column chromatography to yield the title compound (1.1 g, 63% yield) as a brown solid.

63%

With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 120℃;

To a round bottom flask were added <strong>[1171919-75-7]2-chloro-4-iodopyridine-3-carbonitrile</strong> (1.7 g, 6.4 mmol), 4-methoxy-2-methylaniline (880 mg, 6.4 mmol), DPEPhos [bis (2-diphenylphosphinophenyl) ether] (690 mg, 1.3 mmol), palladium (II) acetate (145 mg, 0.646 mmol), K 3PO 4 (3.7 g, 0.017 mmol), and dioxane (15 mL). The reaction mixture was degassed and heated at 120 overnight. The mixture was cooled to rt, concentrated to dryness, and purified by flash column chromatography to yield the title compound (1.1 g, 63% yield) as a brown solid. MS (ESI) : mass calcd. for C 14H 12ClN 3O, 273.1 m/z found, 274 [M+H] +.

References: [1]Patent: WO2017/100662,2017,A1 .Location in patent: Page/Page column 108.
[2]Patent: WO2017/100668,2017,A1 .Location in patent: Page/Page column 150.
[3]Patent: WO2018/103060,2018,A1 .Location in patent: Page/Page column 107.
[4]Patent: WO2018/103058,2018,A1 .Location in patent: Page/Page column 150.

19
[ 1171919-75-7 ]
6-cyclobutoxy-4-methylpyridin-3-amine [ No CAS ]
methyl 5-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 100℃;Inert atmosphere;	General procedure: To a round bottom flask under a N2 atmosphere were added 2-methyl-4-phenoxyaniline (30 g, 150 mmol), <strong>[1171919-75-7]2-chloro-4-iodopyridine-3-carbonitrile</strong> (51.6 g, 195 mmol), and dioxane (200 mL), followed by bis(2- diphenylphosphinophenyl)ether (DPEphos) (16 g, 30 mmol), Pd(OAc)2 (3.36 g, 15 mmol), and K3PO4 (89 g, 420 mmol). The reaction mixture was stirred at 100 C overnight. The reaction mixture was filtered and purified flash column chromatography to yield the title Compound (32 g, 63% yield) as a yellow solid.

References: [1]Patent: WO2017/100662,2017,A1 .Location in patent: Page/Page column 105; 106; 119.

20
2-methyl-6-phenoxypyridin-3-amine [ No CAS ]
[ 1171919-75-7 ]
2-chloro-4-((2-methyl-6-phenoxypyridin-3-yl)amino)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With palladium diacetate; caesium carbonate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 20℃; for 2h;Inert atmosphere;	To a round bottom flask containing <strong>[1171919-75-7]2-chloro-4-iodopyridine-3-carbonitrile</strong> (72.1 g, 273 mmol) and 2-methyl-6- phenoxypyridin-3-amine (Intermediate 49, 50.5 g, 252 mmol) were added Pd(OAc)2 (1.81 g, 8.06 mmol), followed by bis(2-diphenylphosphinophenyl)ether (DPEphos, 5.66 g, 10.5 mmol), and cesium carbonate (195 g, 598 mmol). The reaction mixture was evacuated, treated with 1,4- dioxane (550 ml) via cannula, vented to N2, then stirred at room temperature for 2 h. The reaction mixture was transferred to a 2 L flask and diluted with water to a total volume of 2000 mL. The mixture was stirred for 10 min, then the brown precipitate was collected by filtration. The solid was under vacuum at 60 C to give the title compound (94.8 g, 99% yield) as a light orange solid. MS (ESI): mass calcd. for ci8Hi3ClN40, 336.08; m/z found, 337.0 [M+H]+

References: [1]Patent: WO2017/100668,2017,A1 .Location in patent: Page/Page column 628; 629.

21
[ 1171919-75-7 ]
(R)-tert-butyl 3-(3-amino-4-((4-isopropoxyphenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2017/100668,2017,A1 .
[2]Patent: WO2018/103058,2018,A1 .
[3]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 782 - 790.

22
[ 1171919-75-7 ]
(R)-tert-butyl 3-(5-(4-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2017/100668,2017,A1 .
[2]Patent: WO2018/103058,2018,A1 .
[3]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 782 - 790.

23
[ 1171919-75-7 ]
(R)-tert-butyl 3-(5-(3-methyl-5-phenoxypyridin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate [ No CAS ]