Name: 660867-80-1|2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine|95%
Brand: Ambeed
SKU: A117906
Price: 6.0 USD
Availability: InStock
Rating: 90 (40 reviews)

1
[ 22282-99-1 ]
[ 73183-34-3 ]
[ 660867-80-1 ]

Yield	Reaction Conditions	Operation in experiment
39%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 4h;Inert atmosphere; Sealed tube;	To a previously degassed solution of 4-bromo-2-methylpidine (0.500 g, 2.906 mmol),4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi( 1 ,3,2-dioxaborolane) (0.812 g, 3.997 mmol),potassium acetate (0.854 g, 8.720 mmol) in 1,4-dioxane (5mL) in 50 mL sealed tube was added [1,1 ?-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.021 g, 0.029 mmol) and stirred at 80C 4 h. Evaporated off the solvent and purified column chromatography on silica gel (ethyl acetate pet ether = 3070) to give the titledcompound (0.250 g, 39%) as a off white solid .LCMS: mlz 220.1 [M+H] .
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); at 80℃; for 12h;	To a solution of 4-bromo-2-methylpyridine [(1] g, 5. 81 mmol) in DMF (25 mL) was added bis-boron pinacol ester (810 mg, 3.2 mmol), potassium acetate (1.71 g, 17.4 [MMOL),] Pd [(DPPF) 2 (140] mg, 0.174 mmol) and heated to [80] C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with DCM and filtered through celite, washed with DCM and concentrated under vacuum to afford [2-METHYL-4- (4,] 4,5, [5-TETRAMETHYL-1,] 3,2-dioxaborolan-2-yl) pyridine [(1.] 25 g). (Note: This material can be used w/o further purification in Example 12.)
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere;	a) 2-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine; To a solution of 4-bromo-2-methyl-pyridine (2.0 g, 12 mmol) in dioxane (20 mL) was added Pd(dppf)Cl2 (0.3 g, 1.0 mmol), potassium acetate (3.4 g, 35 mmol) and bis(pinacolato)diboron (3.8 g, 15 mmol) under an argon atmosphere and the reaction was heated at 80 C. for 12 hours. The resulting black suspension is diluted with dichloromethane, filtered and concentrated under vacuum to afford a black oil (1.53 g, 60%) which is used crude for the next step. 1H NMR (CDCl3, 300 MHz): delta (ppm)=8.53-8.51 (m, 1H), 7.51 (m, 1H), 7.43-7.41 (m, 1H), 2.56 (s, 3H), 1.35 (s, 12H).

	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere;	To a solution of 4-bromo-2-methyl-pyridine (2.0 g, 12 mmol) in dioxane ( 20 mL) was added Pd(dppf)Cl2 (0.3 g, 1.0 mmol), potassium acetate (3.4 g, 35 mmol) and bis(pinacolato)diboron (3.8 g, 15 mmol) under an argon atmosphere and the reaction was heated at 80C for 12 hours. The resulting black suspension is diluted with dichloromethane, filtered and concentrated under vacuum to afford a black oil (1.53 g, 60%) which is used crude for the next step.1H NMR (CDCls, 300 MHz): delta (ppm) = 8.53-8.51 (m, 1H), 7.51 (m, 1H), 7.43-7.41 (m, 1H), 2.56 (s, 3H), 1.35 (s, 12H).
	With potassium acetate;palladium(0)bis(tricyclohexylphosphine); In 1,4-dioxane; at 120℃;Sealed tube;	EXAMPLE 4; 5-(2-METHYLPYRIDIN-4-YL)-2-[7-(2,3,6-TRIFLUOROBEN2YL)IMIDAZO[l,5- &]P YRID AZIN-5 - YL] PYRIMIDIN-4- AMINE; Step A; A solution of 4-bromo-2-methyl pyridine (2g, 9.59 mmol) in 1,4-dioxane in a pressure tube was added potassium acetate (3.39g, 34.5 mmol), bis(pinacolato)diboron and the resulting mixture de-gassed. Bis(tricyclohexylphosphino)palladium (0) (0.64g, 0.959 mmol) was added and the reaction stirred at 120C for several hours. The reaction mixture was cooled to room temperature and quenched with IN HCI until the pH was 6. The resulting mixture was concentrated. The residue was purified by reverse phase HPLC (Gilson) using a gradient of 10-10%acetonitrile/water with 0.1%TFA to afford the desired product as a white solid. LC-MS:m/z=138.17 (M+1); rtO.56 min (Method C).
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In Isopropyl acetate; at 75℃; for 18h;	Example 34N-((2',3-dimethyl-r2,4'-bipyridinl-5-yl)methyl)-5-(pyrazin-2-yl)picolinamide fumarate MF: C16H24BN04 MW: 305.18Preparation of Intermediates[0239] 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl pyridine (34b). To a 5-L four-necked flask equipped with an overhead stirrer, a thermocouple and a condenser was charged 4-bromo-2-methylpyridine (34a, 192.7 g, 1120 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (312.9 g, 1232 mmol), Pd(dppf)Cl2'CH2Cl2 (4.57 g, 5.6 mmol), KOAc (219.7 g, 2240 mmol), and isopropyl acetate (1920 mL). The mixture was stirred at 75 C for 18h, cooled to 50 C and filtered through Celite. Concentration of the filtrate to almost dryness afforded the crude 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (34b) as a black oil.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran; at 80℃; for 15h;Inert atmosphere;	6.1.2 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4) To a solution of 4-bromo-2-methylpyridine (3) (1.5 g, 8.72 mmol), bis(pinacolato)diboron (2.4 g, 9.42 mmol) and Pd(dppf)Cl2 (142 mg, 0.17 mmol) in THF (20 mL) was added KOAc (1.7 g, 17.4 mmol). The reaction mixture was stirred at 80 C under N2 for 15 h. After cooling to room temperature, the mixture was diluted with dichloromethane (200 mL) and then filtered. The filtrate was concentrated to give 4 (3.3 g, crude) as a black oil, which was used directly in the next step without further purification.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran; at 80℃;Inert atmosphere;	To a suspension of 4-bromo-2-methylpyridine (500 mg, 2.90 mmol), bis(pinacolato)diboron (795 mg, 3.13 mmol) and Pd(dppf)Cl2 (42 mg, 0.058 mmol) in THF (10 mL) was added KOAc (568 mg, 5.80 mmol). The reaction mixture was stirred at 80 C under N2 overnight. After cooling to room temperature, the mixture was diluted with dichloromethane (200 mL) and then filtered. The filtration was concentrated to give the desired product (1.27 g, crude) as a black oil, which was used directly in the next step without further purification. To a suspension of the above crude oil (1.27 g), ethyl 2-(4-bromophenyl)acetate (640 mg, 2.63 mmol) and Pd(PPh3)4 (243 mg, 0.21 mmol) in THF (10 mL) was added Cs2CO3 (1.7 g, 5.26 mmol). The mixture was stirred at 75 C under N2 for 12 h. After cooling to room temperature, the mixture was evaporated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give the desired product (500 mg, 75%) as a colorless oil.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran;Inert atmosphere; Reflux;	To the 250 ml round-bottom flask compound A1-1 (6.9g, 40mmol), bis(pinacolato)diboron (11.2g, 44mmol), KOAc (7.8g, 80mmol), Pd (dppf)2Cl2 (1.63g, 2 . 0mmol) and tetrahydrofuran (100 ml) were added, purged with nitrogen, stirred aand reflux overnight, cooled to the room temperature, celite filtration, the filtrate was spin-dried to give crude black oil (15.6 g of, content: 27%), was used directly in the next step.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran; at 80℃;Inert atmosphere;	To a suspension of 4-bromo-2-methylpyridine (2.0 g,11.6 mmol), Pd(dppf)Cl2 (169 mg, 0.23 mmol) and KOAc (2.27 g,23.2 mmol) in THF (40 mL) was added bis(pinacolato)diboron (3.18 g, 12.5 mmol). The mixture was stirred at 80 C under N2 overnight. After cooling to room temperature, the mixture was diluted with DCM (250 mL) and then filtered. The filtrate was concentrated to give a black oil (5.1 g, crude), which was used directly in the next step without further purification.
	With tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; for 4h;Reflux; Inert atmosphere;	[0569] To a stirred solution of 4-bromo-2-methylpyridine (150 mg, 0.8 mmol) in 1,4- dioxane (5 mL) under argon atmosphere were added bis (pinacolato) diboron (243 mg, 0.9 mmol), potassium phosphate (171 mg, 2 mmol), Pd2(dba)3 (39 mg, 0.04 mmol), tricyclohexyl phosphine (366 mg, 1 mmol) and degassed under argon atmosphere for 30 mm at room temperature. The reaction mixture was stirred at reflux for 4 h.
31.4 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; for 5h;Inert atmosphere; Reflux;	Under a nitrogen atmosphere, 4-bromo-2-methylpyridine (24.8 g), bispinacolatodiboron (36.8 g),Potassium acetate (42.8 g), PdCl 2 (dppf) (2.5 g) and cyclopentyl methyl ether (400 ml)The flask containing was stirred at reflux temperature for 5 hours.After cooling the reaction solution to room temperature, the insoluble matter was filtered off with suction filtration,The solvent was removed under reduced pressure.The obtained solid was purified by activated carbon column chromatography (toluene), and the solvent of the eluate was distilled off under reduced pressure to give 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2). -Dioxaborolan-2-yl) pyridine(31.4 g) was obtained.

Reference： [1]Patent: WO2014/111871,2014,A1 .Location in patent: Page/Page column 199
[2]Patent: WO2004/14913,2004,A2 .Location in patent: Page 82
[3]Patent: US2011/190269,2011,A1 .Location in patent: Page/Page column 36
[4]Patent: WO2011/92272,2011,A1 .Location in patent: Page/Page column 73
[5]Patent: WO2011/119518,2011,A1 .Location in patent: Page/Page column 47-48
[6]Patent: WO2012/3189,2012,A1 .Location in patent: Page/Page column 109-111
[7]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868
[8]European Journal of Medicinal Chemistry,2016,vol. 108,p. 154 - 165
[9]Patent: CN105254613,2016,A .Location in patent: Paragraph 0046;0047; 0048; 0049; 0050; 0051
[10]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5861 - 5872
[11]Patent: WO2017/31325,2017,A1 .Location in patent: Paragraph 0569
[12]Organometallics,2017,vol. 36,p. 3429 - 3434
[13]Patent: JP5799772,2015,B2 .Location in patent: Paragraph 0103

2
[ 660867-80-1 ]
[ 579476-63-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium periodate; ammonium acetate; In water; acetone; at 20℃; for 12h;	To a solution of 2-methyl-4- (4, 4,5, [5-TETRAMETHYL-1,] 3,2-dioxaborolan-2-yl) pyridine (920 mg, 4.2 mmol) in acetone/water [70 [ML] [(1] : 1)] was added sodium periodate (2.69 g, 12.6 mmol) and ammonium acetate [(810] mg, 10.5 [MMOL),] and allowed to stir at room temperature for 12 hours. The reaction mixture was filtered and concentrated under vacuum to afford desired 2-methyl-4-pyridineboronic acid (575 mg). (Note: This material can be used w/o further purification in Example 13.)

Reference： [1]Patent: WO2004/14913,2004,A2 .Location in patent: Page 82-83

3
[ 660867-80-1 ]
[ 1138419-85-8 ]
[ 1138419-59-6 ]

Yield	Reaction Conditions	Operation in experiment
15.29%	With sodium carbonate;CyJohnPhos; In 1,2-dimethoxyethane; water; at 20 - 90℃;	6-bromo-2-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)- 1 ,2,4-triazine-3,5(2H,4H)-dione (P8,100 mg, 0.218 mmol) was suspended in a degassed mixture of 1 ,2-Dimethoxyethane (DME) (3.629 ml.)/ Water (0.726 ml_), then 2-methyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (143 mg, 0.653 mmol), SODIUM CARBONATE (69.2 mg, 0.653 mmol), 2-biphenylyl(dicyclohexyl)phosphane (15.26 mg, 0.044 mmol) and Tetrakis (50.3 mg, 0.044 mmol) were added. The mixture was then <n="49"/>heated at 9O0C and stirred at that temperature for 3 hours. The reaction mixture was then cooled down to room temperature, 2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine (143 mg, 0.653 mmol), 2-biphenylyl(dicyclohexyl)phosphane (15.26 mg, 0.044 mmol), SODIUM CARBONATE (69.2 mg, 0.653 mmol) and Tetrakis (50.3 mg, 0.044 mmol) were added again, the mixture was stirred at 9O0C for further 2 hours, then left stirring at room temperature overnight. The mixture was concentrated under reduced pressure and partitioned between AcOEt and water. Phases were separated, organic phase was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by Preparative HPLC affording 6-(2-methyl-4-pyridinyl)-2-(3- {(1 S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1 ,2,4-triazine- 3,5(2H,4H)-dione (E3, 15.7 mg, 0.033 mmol, 15.29 % yield).1H NMR (400 MHz, CHLOROFORM-d) delta: ppm 8.65-8.58 (d, 1 H), 7.86 (s, 1 H), 7.8-7.75 (d, 1 H), 7.57-7.51 (d, 2H), 7.25-7.19 (d, 2H), 4.24-4.14 (t, 2H), 3.48-3.40 (m, 1 H), 3.24- 3.15 (m, 1 H), 2.64-2.61 (m, 6H), 2.58-2.50 (m, 1 H), 2.12-2.00 (m, 2H), 1.85-1.77 (m, 1 H), 1.54-1.44 (m, 1 H), 0.93-0.84 (m, 1 H).

Reference： [1]Patent: WO2009/43884,2009,A1 .Location in patent: Page/Page column 46-47

4
[ 660867-80-1 ]
[ 1187366-97-7 ]
[ 1187367-27-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 24h;Inert atmosphere;	Intermediate D-05 (515 mg), 4-methylpyridine-4-boronic acid pinacol ester (480 mg) and potassium carbonate (990 mg) were added to DMF (15 mL). The reaction flask was purged with argon and tetrakis(triphenylphosphine)palladium(0) (120 mg) was added. The reaction was heated to 100 0C for 24 h. The mixture was cooled to RT and added to DCM (15 mL). The resulting mixture was filtered and washed with DCM (15mL). The DCM was removed under reduced pressure and the resulting DMF solution was purified using RP-LC/MS (ACN:eta2O-TFA peta 1). Yield: 120 mg.

Reference： [1]Patent: WO2009/112565,2009,A1 .Location in patent: Page/Page column 106

5
[ 660867-80-1 ]
[ 1187366-98-8 ]
[ 1187367-28-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 2h;Inert atmosphere; Microwave irradiation;	Intermediate D-06 (500 mg), 2-methylpyridine-4-boronic acid pinacol ester (480 mg) and potassium carbonate (990 mg) were added to DMF (15 mL). The reaction flask was purged with argon and tetrakis(triphenylphosphine)palladium(0) (120 mg) was added. The reaction was heated to 110 0C for 2 h in the microwave. The mixture was cooled to RT and added to DCM (15 mL). The resulting mixture was filtered and washed with DCM (15 mL). The DCM was removed under reduced pressure and the resulting DMF solution was purified using RP-LC/MS (ACN:eta2O-TFA pH 1). Yield: 226 mg.

Reference： [1]Patent: WO2009/112565,2009,A1 .Location in patent: Page/Page column 106

6
[ 3678-63-5 ]
[ 73183-34-3 ]
[ 660867-80-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate;bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine; In 1,4-dioxane; at 90℃;Inert atmosphere;	4-Chloro-2-picoline (3g, 0.0235mol) was dissolved in 1,4-dioxane (72 mL). Bis pinacolato diborane (7.76 g, 0.03 mol) was added to the reaction mixture. The reaction mixture was degassed with nitrogen for 45 mins. Potassium acetate (3.45 g, 0.035 mol), tricyclohexylphosphine (0.660 g, 2.3 mmol) and Pd(dba)2 (0.676 g, 1.1 mmol) were added. The mixture was heated at 900C for 3 h. The crude reaction mixture was cooled and filtered through Celite bed and washed with ethyl acetate. The filtrate was concentrated and used directly for next reaction without purification.

Reference： [1]Patent: WO2009/137404,2009,A1 .Location in patent: Page/Page column 33

7
[ 660867-80-1 ]
[ 103966-66-1 ]
[ 1195173-74-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere;	3-Methoxy-4-bromo nitrobenzene (4.9 g, 21 mmol) was dissolved in 1,2- dimethoxyethane (60 mLl). 2-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- pyridine (5.15 g, 23.5 mmol) was added. Sodium carbonate (5.15 g, 48.5 mmol) was dissolved in minimum amount of water and was added drop wise to the reaction mixture. The reaction mixture was degassed with nitrogen for 45 min. Pd(PPh3)4 (0.732 g, 0.6 mmol) was added under nitrogen. The reaction mixture was then heated overnight at 90 C. After completion of reaction, the reaction mixture was cooled and extracted with ethyl acetate. Purification was done by column chromatography using silica gel (100-200mesh) and 0-2% DCM, MeOH as eluent to give 4-(2-methoxy-4-nitrophenyl)-2-methylpyridine.

Reference： [1]Patent: WO2009/137404,2009,A1 .Location in patent: Page/Page column 33

8
[ 660867-80-1 ]
[ 1231881-07-4 ]
[ 1231880-97-9 ]

Yield	Reaction Conditions	Operation in experiment
24%	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 90℃; for 0.416667h;Inert atmosphere; Microwave irradiation;	Process Step [V9]: 4-[2-Ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]-2-methylpyridine (Ex. 96)In a microwave reactor, 100 mg (0.35 mmol) of 5-bromo-2-ethyl-4-(4-fluorophenyl)-1,3-thiazole, 100 mg (0.45 mmol) of <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong>, 1 ml of a 1M caesium carbonate solution and 28.7 mg (0.04 mmol) of [1,1'-bis(diphenylphosphino)-ferrocene/palladium(II) dichloride dichloromethane complex] in 2.5 ml of THF are, under argon, heated at 90 C. for 25 min. The reaction mixture is then filtered, the filter cake is washed with ethyl acetate (3×5 ml) and the combined filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 35 mg (24%) of the desired product; 1H-NMR(MeCN-d3) delta: 8.34 (d, 1H), 7.47 (m, 3H), 7.12 (s, 1H), 7.07 (m, 2H), 6.99 (d, 1H), 3.03 (q, 2H), 2.42 (s, 3H), 1.38 (t, 3H).

Reference： [1]Patent: US2010/168185,2010,A1 .Location in patent: Page/Page column 30; 31

9
[ 660867-80-1 ]
[ 77337-82-7 ]
[ 1195173-74-0 ]

Yield	Reaction Conditions	Operation in experiment
63%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; for 16h;Reflux;	2-Methylpyridine-4-boronic acid pinacol ester (3178 mg, 14.5 mmol) and Pd(PPtLs)4 (1.22 g, 1.06 mmol) were added to a solution of 2-bromo-5-nitroanisole (3.06 g, 13.2 mmol) in DME (40 ml), water (16 ml) and Cs2CO3 (1.33 g, 40.9 mmol). The resulting mixture was stirred and heated at reflux temperature for 16 h. The r.m. was cooled to r.t. and partitioned between H2O and DCM. The organic phase was separated, dried(MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo, yielding 2.04 g of intermediate 55 (63 %).
63%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 16h;Reflux;	2-Methylpyridine-4-boronic acid pinacol ester (3.18 g, 14.5 mmol) and Pd(PPli3)4 (1.22 g, 1.06 mmol) were added to a solution of 2-bromo-5-nitroanisole (3.06 g, 13.2 mmol) and Cs2C03 (1.33 g, 40.9 mmol) in DME (40 ml) and H20 (16 ml). The r.m. was stirred and heated at reflux for 16 h. The r.m. was cooled to r.t. and partitioned between H20 and DCM. The organic phase was separated, dried (MgS04), filtered and the solvent was evaporated. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo, yielding 2.04 g of intermediate 48 (63 %).
63%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 16h;Reflux;	2-Methylpyridine-4-boronic acid pinacol ester (3.18 g, 14.5 mmol) and Pd(PPl¾)4 (1.22 g, 1.06 mmol) were added to a solution of 2-bromo-5-nitroanisole (3.06 g, 13.2 mmol) and Cs2C03 (1.33 g, 40.9 mmol) in DME (40 ml) and H20 (16 ml). The r.m. was stirred and heated at reflux for 16 h. The r.m. was cooled to r.t. and partitioned between H20 and DCM. The organic phase was separated, dried (MgSC^), filtered and the solvent was evaporated. The combined organic layers were dried (MgSO i), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo, yielding 2.04 g of intermediate 48 (63 %).

63%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 16h;Reflux;	2-Methylpyridine-4-boronic acid pinacol ester (3.18 g, 14.5 mmol) and Pd(PPh3)4 (1.22 g, 1.06 mmol) were added to a solution of 2-bromo-5-nitroanisole (3.06 g, 13.2 mmol) and Cs2CO3 (1.33 g, 40.9 mmol) in DME (40 ml) and H2O (16 ml). The r.m. was stirred and heated at reflux for 16 h. The r.m. was cooled to r.t. and partitioned between H2O and DCM. The organic phase was separated, dried (MgSO4), filtered and the solvent was evaporated. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo, yielding 2.04 g of intermediate 48 (63%).
43%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 80℃; for 18h;Inert atmosphere;	b) 4-(2-Methoxy-4-nitro-phenyl)-2-methyl-pyridine; To a solution of 1-bromo-2-methoxy-4-nitro-benzene (6.35 g, 27 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (6.60 g, 30 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.58 g, 1.4 mmol) in dimethoxyethane (150 mL) under an argon atmosphere was added a solution of cesium carbonate (26.7 g, 82 mmol) dissolved in water (90 mL). The mixture was heated to 80 C. for 18 hours.The volatiles were removed under vacuum, water was added and the aqueous phase was extracted three times with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified by silica gel chromatography using n-heptane/TBME as eluent to give the title compound as a dark red solid (2.9 g, 43%).MS ISP (m/e): 245.2 (100) [(M+H)+].1H NMR (CDCl3, 300 MHz): delta (ppm)=8.58-8.56 (m, 1H), 7.95-7.92 (m, 1H), 7.85-7.84 (m, 1H), 7.47-7.45 (m, 1H), 7.29 (m, 1H), 7.25-7.24 (m, 1H), 3.94 (s, 3H), 2.63 (s, 3H).
43%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 18h;Inert atmosphere;	To a solution of l-bromo-2-methoxy-4-nitro-benzene (6.35 g, 27 mmol), 2-methyl-4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridine (6.60 g, 30 mmol) andtetrakis(triphenylphosphine)palladium(0) (1.58 g, 1.4 mmol) in dimethoxyethane (150 mL) under an argon atmosphere was added a solution of cesium carbonate (26.7 g, 82 mmol) dissolved in water (90 mL). The mixture was heated to 80C for 18 hours.The volatiles were removed under vacuum, water was added and the aqueous phase was extracted three times with dichloromethane. The combined organic layers were dried over Na2S04, filtered and the solvents were evaporated. The residue was purified by silica gel chromatography using n-heptane/ TBME as eluent to give the title compound as a dark red solid (2.9 g, 43%).MS ISP (m/e): 245.2 (100) [(M+H)+].1H NMR (CDCI3, 300 MHz): delta (ppm) = 8.58-8.56 (m, 1H), 7.95-7.92 (m, 1H), 7.85-7.84 (m, 1H), 7.47-7.45 (m, 1H), 7.29 (m, 1H), 7.25-7.24 (m, 1H), 3.94 (s, 3H), 2.63 (s, 3H).

Reference： [1]Patent: WO2010/89292,2010,A1 .Location in patent: Page/Page column 79
[2]Patent: WO2011/86098,2011,A1 .Location in patent: Page/Page column 75
[3]Patent: WO2011/86099,2011,A1 .Location in patent: Page/Page column 64
[4]Patent: US2012/295891,2012,A1 .Location in patent: Page/Page column 30
[5]Patent: US2011/190269,2011,A1 .Location in patent: Page/Page column 36-37
[6]Patent: WO2011/92272,2011,A1 .Location in patent: Page/Page column 73

10
[ 660867-80-1 ]
[ 183438-24-6 ]
[ 1243246-01-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 10h;Sealed tube;	To a sealed tube were added 5-bromo-2-iodopyrimidine 183-1 (114 mg, 0.4 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine 183-2 (88 mg, 0.4 mmol), Pd(PPh3 )4 (23 mg, 0.02 mmol), Na2CO3 ( 170 mg, 1.6 mmol), toluene (0.4 mL),H2O (0.4 mL) and ethanol (0.1 mL). The reaction mixture was stirred at 100 C for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (3 ml) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give 5-bromo-2-(2- methylpyridin-4-yl)pyrimidine 183-3. MS m/z 250.0 (M + 1).

Reference： [1]Patent: WO2010/101849,2010,A1 .Location in patent: Page/Page column 81-82

11
[ 660867-80-1 ]
[ 15250-46-1 ]
[ 1243245-68-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 90℃; for 10h;Inert atmosphere; Sealed tube;	To a sealed tube were added 2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridine (2.2g, 10 mmol), ethyl 2- (4-iodophenyl) acetate 26-1 (2.9 g, 10 mmol), Pd(PPh3)4 (0.231g, 0.2 mmol), toluene (30 mL), ethanol (10 mL) and 2M Na2CO3 (10 mL). The reaction mixture was flushed with nitrogen and stirred at 90C for 10 hours. After cooled down to room temperature, the reaction mixture was diluted into 200 mL ethyl acetate and washed with saturated sodium bicarbonate solution and then brine. The organic phase was dried over Na2SO4 and then taken to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 50% ethyl acetate in hexane to give ethyl 2-(4-(2- methylpyridin-4-yl)phenyl)acetate 26-2 as an oil. MS m/z 256.1 (M + 1).

Reference： [1]Patent: WO2010/101849,2010,A1 .Location in patent: Page/Page column 44-45

12
[ 660867-80-1 ]
[ 1243246-05-0 ]
[ 1243245-09-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 100℃;Sealed tube;	To a sealed tube were added N-(5-(4-acetylpiperazin-l-yl)pyridin-2-yl)-2- (5,6-dichloropyridin-3-yl)acetamide 184-5 (65 mg, 0.16 mmol), 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine 183-2 (42 mg, 0.19 mmol), Pd(PPh3)4 (9 mg, 0.08 mmol), Na2CO3 ( 84 mg, 0.79 mmol), DME (0.5 mL),H2O (0.5 mL) and ethanol (0.1 mL). The reaction mixture was stirred at 100 C overnight. After cooling to room temperature, the solvents were removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-l-yl)pyridin-2-yl)-2-(2-(2-methylpyridin-4-yl)pyrimidin- 5-yl)acetamide 184. MS m/z 465.2 (M + 1); 1H NMR 400 MHz (MeOD) delta 8.52(d, 2H), 8.46(d, IH), 7.98-7.95(m, 2H),7.87(d, IH), 7.53(s, IH), 7.49-7.46(m, IHz), 7.36(dd, IH), 3.81(s, 2H), 3.67 (t, 2H), 3.62(t, 2H), 3.13(t, 2H), 3.08(t, 2H), 2.56(s, 3H), 2.08(s, 3H).

Reference： [1]Patent: WO2010/101849,2010,A1 .Location in patent: Page/Page column 83; 84

13
[ 660867-80-1 ]
[ 1243246-06-1 ]
[ 1243246-07-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃;Inert atmosphere; Sealed tube;	To a sealed tube were added tert-butyl 2-(6-chloro-5-(trifluoromethyl) pyridin-3-yl)acetate 189-3 (318mg, 1.08 mmol), 2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridine (283 mg, 1.29 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Na2CO3 ( 342 mg, 3.22 mmol), Toluene (3 mL),H2O (3 mL) and ethanol (0.75 mL). The reaction mixture was stirred at 100 C overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (10 ml) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 30% ethyl acetate in hexane to tert-butyl 2-(2'- methyl-3-(trifluoromethyl)-2,4'-bipyridin-5-yl)acetate 189-4. MS m/z 35.2 (M + 1).

Reference： [1]Patent: WO2010/101849,2010,A1 .Location in patent: Page/Page column 85-86

14
[ 660867-80-1 ]
[ 1243246-10-7 ]
[ 1243245-15-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃;Sealed tube;	To a sealed tube were added N-(5-(4-acetylpiperazin-l-yl)pyridin-2-yl)-2-(6- chloro-5-fluoropyridin-3-yl)acetamide 190-5 (59 mg, 0.15 mmol), 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine 183-2 (49 mg, 0.23 mmol), Pd(PPh3)4 (9 mg, 0.08 mmol), Na2CO3 ( 79 mg, 0.75 mmol), Toluene (0.8 mL),H20 (0.8 mL) and ethanol (0.2 mL). The reaction mixture was stirred at 100 C overnight. After cooling to room temperature, the solvents were removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-l-yl)pyridin-2-yl)-2-(3-fluoro-2'-methyl-2,4'-bipyridin-5- yl)acetamide 190. MS m/z 449.2 (M + 1); 1H NMR 400 MHz (MeOD) delta 8.48-8.46(m, 2H), 7.96(s, IH), 7.87(d, IH), 7.81(s, IH), 7.75-7.69(m, 2Hz), 7.36(dd, IH), 3.84(s, 2H), 3.67(t, 2H), 3.62(t, 2H), 3.13(t, 2H), 3.08(t, 2H), 2.56(s, 3H), 2.08(s, 3H).

Reference： [1]Patent: WO2010/101849,2010,A1 .Location in patent: Page/Page column 86; 87

15
[ 660867-80-1 ]
[ 1243246-21-0 ]
[ 1243245-22-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃;Sealed tube;	To a sealed tube were added N-(5-(4-acetylpiperazin-l-yl)pyridin-2-yl)-2-(6- chloro-5-(methylsulfonyl)pyridin-3-yl)acetamide 197-7 (30 mg, 0.07 mmol), 2-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine 183-2 (22 mg, 0.10 mmol), Pd(PPh3)4 (4 mg, 0.003 mmol), Na2CO3 ( 22 mg, 0.20 mmol), Toluene (0.4 mL),H20 (0.4mL) and ethanol (0.1 mL). The reaction mixture was stirred at 100 C overnight. After cooling to room temperature, the solvents were removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-l-yl)pyridin-2-yl)-2-(2'-methyl-3- (methylsulfonyl)-2,4'-bipyridin-5-yl)acetamide 197. MS m/z 509.2 (M + 1); 1H NMR 400 MHz (MeOD) delta 8.8 l(d, IH), 8.52(d, IH), 8.49(d, IH), 7.97(s, IH), 7.87(d, IH), 7.47(s, IH) 7.41(dd, IH), 7.37(dd, IH), 3.95(s, 2H), 3.68(t, 2H), 3.63(t, 2H), 3.15(t, 2H), 3.09(t, 2H), 2.92(s, 3H), 2.57(s, 3H), 2.09(s, 3H).

Reference： [1]Patent: WO2010/101849,2010,A1 .Location in patent: Page/Page column 93; 94-95

16
[ 660867-80-1 ]
[ 589-87-7 ]
[ 65219-20-7 ]

Yield	Reaction Conditions	Operation in experiment
32.1%	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; for 17h;Reflux;	Step 1: 4-(4-bromophenyl)-2-methylpyridine (1) 1-Bromo-4-iodo-benzene (7.07 mmol), 2-methyl-4-boronic pinacole ester pyridine (14.14 nimol), potassium phosphate (28.3 mmol), and Pd(PPh3)4 (0.707 mmol) were added to 20.0 mL of degassed THF. The reaction was then refluxed for 17 hrs. The reaction was diluted with DCM and washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and concentrated down. The product was loaded in a minimal amount of DCM and purified by normal phase (DCMrMeOH). Pure fractions were pooled and dried down to afford the product as a solid (75% pure, 32.1% yield). LC-ESMS observed [M+H]+ 248.0 (calcd 248.0)

Reference： [1]Patent: WO2010/71741,2010,A1 .Location in patent: Page/Page column 75

17
[ 660867-80-1 ]
[ 1240911-26-5 ]
[ 1240911-27-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;Pd(t-Bu3P)2; In tetrahydrofuran; water; at 65℃; for 1.5h;Inert atmosphere;	5-(4-iodobe?zyl)-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4J3-c]cimiolin-3-one [(Example 45), 60 mg, 0.12 mmol] was dissolved in tetrahydrofuran (10 niL), treated with 2- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yI) and cesium carbonate (0.31 mL, 1 M aqueous, 0.31 mmol, 2.6 equiv). The mixture was sparged under nitrogen, treated with bis(t-tert- butylphosphine)palladium(O) (12 mg, 0.03 mmol, 0.2 equiv) and placed into an oil bath preheated at 65 C. After 1.5 hours, the mixture was cooled to ambient temperature, poured into water and extracted with ethyl acetate (3 x 60 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase EtaPLC (15:85 to 70:20; acetonitrile with 0.1% trifluoroacetic acid : water with 0.1% trifiuoroacetic acid) to afford the titled compound: 5H-NMR (400 MHz3 CDCl3) 6 8.53 (IH, d, J = 5.3 Hz), 8.30-8.27 (IH, m), 7.58 (2H, d, J = 8.5 Hz), 7.56-7.51 (3H, m), 7.38 (2H3 d3 J= 8.3 Hz)3 7.31 (IH5 s), 7.26-7.24 (IH7 m), 5.86 (2H, s), 4.76- 4.67 (IH, m), 4.04 (IH, ddd, J= 10.7, 4.53 1.7 Hz)3 4,01-3.96 (IH, m), 3.81 (IH3 ap t, J= 10.6 Hz)3 3.54- 3.47 (IH, m), 2.60 (3H, s), 2.29-2.18 (IH3 m), 2.16-2.09 (IH, m), 1.93-1.81 (2H3 m) ppm; high resolution mass spectrometry (ES+) m/z 452,2076 [(M+H)+; calculated for C27H25N5O2: 452.2081 ] .

Reference： [1]Patent: WO2010/96338,2010,A1 .Location in patent: Page/Page column 56; 57

18
[ 660867-80-1 ]
[ 98057-08-0 ]
[ 1299494-75-9 ]

Reference： [1]Chemistry Letters,2011,vol. 40,p. 264 - 265

19
[ 660867-80-1 ]
[ 1161361-88-1 ]

Reference： [1]Patent: WO2011/86098,2011,A1
[2]Patent: WO2011/86099,2011,A1
[3]Patent: US2011/190269,2011,A1
[4]Patent: WO2011/92272,2011,A1
[5]Patent: US2012/295891,2012,A1
[6]Patent: WO2009/137404,2009,A1

20
[ 660867-80-1 ]
[ 1319065-58-1 ]

Reference： [1]Patent: WO2011/92272,2011,A1

21
[ 636-98-6 ]
[ 660867-80-1 ]
[ 216059-91-5 ]

Reference： [1]Patent: WO2011/86098,2011,A1
[2]Patent: WO2011/86099,2011,A1
[3]Patent: US2012/295891,2012,A1

22
[ 636-98-6 ]
[ 660867-80-1 ]
[ 55218-69-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 16h;Reflux;	2-Methylpyridine-4-boronic acid pinacol ester (5 g, 22.8 mmol) and Pd(PPh3)4 (1.92 g, 1.66 mmol) were added to a solution of l-iodo-4-nitrobenzene (5.17 g, 20.7 mmol) and Cs2C03 (21 g, 64.3 mmol) in DME (40 ml) and water (25 ml). The resulting mixture was stirred and heated at reflux for 16 h. The r.m. was cooled to r.t. and partitioned between water and DCM. The organic phase was separated, dried (MgS04), filtered and the solvent was evaporated in vacuo. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash columnchromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo, yielding 3.1 g of intermediate 52(70 %).
70%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 16h;Reflux;	2-Methylpyridine-4-boronic acid pinacol ester (5 g, 22.8 mmol) and Pd(PPh3)4 (1.92 g, 1.66 mmol) were added to a solution of l-iodo-4-nitrobenzene (5.17 g, 20.7 mmol) and Cs2C03 (21 g, 64.3 mmol) in DME (40 ml) and water (25 ml). The resulting mixture was stirred and heated at reflux for 16 h. The r.m. was cooled to r.t. and partitioned between water and DCM. The organic phase was separated, dried (MgSC>4), filtered and the solvent was evaporated in vacuo. The combined organic layers were dried (MgSC^), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo, yielding 3.1 g of intermediate 52 (70 %).
70%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 16h;Reflux;	2-Methylpyridine-4-boronic acid pinacol ester (5 g, 22.8 mmol) and Pd(PPh3)4 (1.92 g, 1.66 mmol) were added to a solution of 1-iodo-4-nitrobenzene (5.17 g, 20.7 mmol) and Cs2CO3 (21 g, 64.3 mmol) in DME (40 ml) and water (25 ml). The resulting mixture was stirred and heated at reflux for 16 h. The r.m. was cooled to r.t. and partitioned between water and DCM. The organic phase was separated, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo, yielding 3.1 g of intermediate 52 (70%).

Reference： [1]Patent: WO2011/86098,2011,A1 .Location in patent: Page/Page column 76
[2]Patent: WO2011/86099,2011,A1 .Location in patent: Page/Page column 65
[3]Patent: US2012/295891,2012,A1 .Location in patent: Page/Page column 31

23
[ 660867-80-1 ]
[ 656-65-5 ]
[ 1314787-88-6 ]

Yield	Reaction Conditions	Operation in experiment
96%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 95℃; for 16h;	2-Methylpyridine-4-boronic acid pinacol ester (5.54 g, 25 mmol) and Pd(PPh3)4 (1.95 g, 1.68 mmol) were added to a solution of 4-bromo-3-fluoroaniline (4.0 g, 21 mmol) and Cs2C03 (21.3 g, 65.3 mmol) in DME (40 ml) and H20 (25 ml). The resulting mixture was stirred and heated at 95 C for 16 hours. The r.m. was cooled to r.t. and partitioned between water and DCM. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo, yielding 4.1 g of intermediate 50 (96 %).
96%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 95℃; for 16h;	2-Methylpyridine-4-boronic acid pinacol ester (5.54 g, 25 mmol) and Pd(PPh3)4 (1.95 g, 1.68 mmol) were added to a solution of 4-bromo-3-fluoroaniline (4.0 g, 21 mmol) and Cs2C03 (21.3 g, 65.3 mmol) in DME (40 ml) and H20 (25 ml). The resulting mixture was stirred and heated at 95 C for 16 hours. The r.m. was cooled to r.t. and partitioned between water and DCM. The combined organic layers were dried (MgSC^), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo, yielding 4.1 g of intermediate 50 (96 %).
96%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 95℃; for 16h;	2-Methylpyridine-4-boronic acid pinacol ester (5.54 g, 25 mmol) and Pd(PPh3)4 (1.95 g, 1.68 mmol) were added to a solution of 4-bromo-3-fluoroaniline (4.0 g, 21 mmol) and Cs2CO3 (21.3 g, 65.3 mmol) in DME (40 ml) and H2O (25 ml). The resulting mixture was stirred and heated at 95 C. for 16 hours. The r.m. was cooled to r.t. and partitioned between water and DCM. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo, yielding 4.1 g of intermediate 50 (96%).

Reference： [1]Patent: WO2011/86098,2011,A1 .Location in patent: Page/Page column 75; 76
[2]Patent: WO2011/86099,2011,A1 .Location in patent: Page/Page column 64-65
[3]Patent: US2012/295891,2012,A1 .Location in patent: Page/Page column 31

24
[ 660867-80-1 ]
[ 791642-68-7 ]
[ 1314787-91-1 ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 18h;	2-Methylpyridine-4-boronic acid pinacol ester (5.49 g, 25.1 mmol) and Pd(PPh3)4 (3.62 g, 3.1 mmol) was added to a solution of intermediate 54 (9.8 g, 31.3 mmol) in dioxane (200 ml), H20 (50 ml) and K2CO3 (13 g, 94 mmol). The resulting mixture was stirred and heated at 100 C for 18 h. The r.m. was cooled to r.t. and partitioned between H20 and DCM. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/4). The product fractions were collected and concentrated in vacuo, yielding 4.5 g of intermediate 55 (52 %).
52%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 18h;	2-Methylpyridine-4-boronic acid pinacol ester (5.49 g, 25.1 mmol) and Pd(PPh3)4 (3.62 g, 3.1 mmol) was added to a solution of intermediate 54 (9.8 g, 31.3 mmol) in dioxane (200 ml), H20 (50 ml) and K2CO3 (13 g, 94 mmol). The resulting mixture was stirred and heated at 100 C for 18 h. The r.m. was cooled to r.t. and partitioned between ¾0 and DCM. The combined organic layers were dried (MgSOzt), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/4). The product fractions were collected and concentrated in vacuo, yielding 4.5 g of intermediate 55 (52 %).
52%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 18h;	2-Methylpyridine-4-boronic acid pinacol ester (5.49 g, 25.1 mmol) and Pd(PPh3)4 (3.62 g, 3.1 mmol) was added to a solution of intermediate 54 (9.8 g, 31.3 mmol) in dioxane (200 ml), H2O (50 ml) and K2CO3 (13 g, 94 mmol). The resulting mixture was stirred and heated at 100 C. for 18 h. The r.m. was cooled to r.t. and partitioned between H2O and DCM. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 98/4). The product fractions were collected and concentrated in vacuo, yielding 4.5 g of intermediate 55 (52%).

Reference： [1]Patent: WO2011/86098,2011,A1 .Location in patent: Page/Page column 77; 78
[2]Patent: WO2011/86099,2011,A1 .Location in patent: Page/Page column 67
[3]Patent: US2012/295891,2012,A1 .Location in patent: Page/Page column 32

25
[ 660867-80-1 ]
[ 1314787-21-7 ]

Reference： [1]Patent: WO2011/86098,2011,A1

26
[ 660867-80-1 ]
[ 1314786-38-3 ]

Reference： [1]Patent: WO2011/86098,2011,A1

27
[ 660867-80-1 ]
[ 1314786-90-7 ]

Reference： [1]Patent: WO2011/86098,2011,A1

28
[ 660867-80-1 ]
[ 1314874-38-8 ]

Reference： [1]Patent: WO2011/86099,2011,A1
[2]Patent: US2012/295891,2012,A1

29
[ 660867-80-1 ]
[ 1350607-39-4 ]
[ 1350605-05-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium phosphate; water;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 110℃;Inert atmosphere;	To a solution of (racemic mixture) 2-(3-((3-chloropyrazin-2-yl)oxy)piperidin-l- yl)quinoline (see PREPARATION P2.3; 340 mg, 1.0 mmol), 2-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine ( 219 mg, 1.0 mmol ) and 3PO4 ( 424 mg, 2.0 mmol) inl,4- dioxane (10 mL) and water (2 mL) was added Pd(dppf)Ci2 (73 mg, 0.1 mmol) then the reaction mixture was stirred at 110C under 2 atmosphere overnight. The reaction mixture was filtered through CELITE and washed with CH2CI2 (30 mL). The filtrate was concentrated and the crude product was purified by silica gel column to give (racemic mixture) 2-(3-((3-(2-methylpyridin-4- yl)pyrazin-2-yl)oxy)piperidin-l-yl)quinoline (200 mg, 0.50 mmol, yield 60%). ESI-MS (M+l): 384 calc. for C23H2iN50 383.

Reference： [1]Patent: WO2011/143495,2011,A1 .Location in patent: Page/Page column 208

30
[ 660867-80-1 ]
[ 1350607-39-4 ]
[ 1350605-04-7 ]
[ 1350605-03-6 ]

Reference： [1]Patent: WO2011/143495,2011,A1

31
[ 660867-80-1 ]
[ 954125-17-8 ]
[ 1350918-25-0 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 85℃; for 16h;Inert atmosphere;	A mixture of bromoimidazole lrtt-1 b (1.00 g, 2.85 mmol), 2- methylpyridine 4-boronic acid pinacol ester (0.75 g, 3.42 mmol) and potassium carbonate (1.18 g, 8.55 mmoi) in DMF (15 mL) at r.t was purged with nitrogen gas for 5 min. PdCI2(dppf) was added. The mixture was heated at 85 C for 16 h. Water and ethyl acetate were added and the layers were separated. The separated aqueous layer was extracted with ethyl acetate. The separated organic layer was filtered through Celite, washed with brine and dried over sodium sulfate. The solvents were removed in vacuo and chromatographic purification (ethyl acetate - hexane) of the residue gave lnt-16a (0.61 g, 59%) as a yellow oil.

Reference： [1]Patent: WO2011/149874,2011,A2 .Location in patent: Page/Page column 86

32
[ 660867-80-1 ]
[ 1350917-89-3 ]
C₃₃H₄₇FN₆O₄Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With disodium hydrogenphosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere; Microwave irradiation;	Step D - Synthesis of tert-butyl (1-(2-(4-(2-methylpyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-caoyl)meA mixture of amide lnt-2c (74 mg, 0.12 mmoi), 2~methySpyridine-4- boronic acid ptnacol ester (31 mg, 0.14 mmoi) and sodium hydrogen phosphate (50 mg, 0.35 mmoi) in 1 ,4-dioxane (2 mL) and water (1 mL) at r.t. was purged with nitrogen gas for 5 min in a microwave vial. Tetrakistnphenylphosphorous palladium ( 4 mg, 0.012 mmoi) was added. The mixture was heated in a microwave reactor at 110 C for 1 h. Water and ethyl acetate were added and layers were separated. The separated aqueous layer was extracted with ethyl acetate. The separated organic layer was dried (MgS04) and filtered. The solvents were removed in vacuo and chromatographic purification (ethyl acetate - hexane) of the residue gave pyridine lnt-2d (62 mg, 82%) as a colorless oil. LCMS m/e (M + H*) = 639.3.

Reference： [1]Patent: WO2011/149874,2011,A2 .Location in patent: Page/Page column 60-61

33
[ 660867-80-1 ]
[ 1354354-50-9 ]

Reference： [1]Patent: WO2012/3189,2012,A1

34
[ 660867-80-1 ]
[ 1354356-16-3 ]

Reference： [1]Patent: WO2012/3189,2012,A1

35
[ 660867-80-1 ]
[ 1354356-19-6 ]

Reference： [1]Patent: WO2012/3189,2012,A1

36
[ 660867-80-1 ]
[ 1354356-09-4 ]

Reference： [1]Patent: WO2012/3189,2012,A1

37
[ 176433-43-5 ]
[ 660867-80-1 ]
[ 1354356-12-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In Isopropyl acetate; at 75℃; for 4h;	[0240] 2',3-dimethyl-r2,4'-bipyridinel-5-carbaldehvde (34d). To a 5-L four-necked flask equipped with an overhead stirrer, a thermocouple and a condenser was charged with 2-methyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (34b, 1120 mmol), 6-chloro-5- methylnicotinaldehyde (34c, 174.3 g, 1120 mmol), Pd(dppf)Cl2'CH2Cl2 (4.57 g, 5.6 mmol), K2CC"3 (309.6 g, 2240 mmol), and isopropyl acetate (1120 mL)/water (1120 mL). The mixture was stirred at 75 C for 4h, and cooled to 30 C. The organic layer was separated, washed with 10% NaCl (1120 g), and treated with activated charcoal (50 g) at 50 C for 2h before cooling to rt and filtered through Celite. Concentration of the filtrate to almost dryness afforded the crude 2',3-dimethyl-[2,4'-bipyridine]-5-carbaldehyde (34d) as a brown oil.

Reference： [1]Patent: WO2012/3189,2012,A1 .Location in patent: Page/Page column 111

38
[ 660867-80-1 ]
[ 1374310-40-3 ]
[ 1374309-62-2 ]

Yield	Reaction Conditions	Operation in experiment
14.71%		Example 10: c/s-2,6-Dimethyl-4-[6-(2-methyl-3-furanyl)-5-(2-methyl-4-pyridinvn-2- pyrazinyllmorpholine hydrochloride 2-Methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (131 mg, 0.596 mmol) was added to a solution of c/'s-4-[5-bromo-6-(2-methyl-3-furanyl)-2-pyrazinyl]-2,6- dimethylmorpholine (210 mg, 0.596 mmol) in a mixture of 1 ,4-dioxane (4 ml_), water (0.667 mL) and sodium carbonate (126 mg, 1 .192 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (68.9 mg, 0.060 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100 C for 1 hour. LC/MS showed starting material and desired product so the reaction mixture was stirred and heated at 100 C in the microwave for a further 1 hour. Crude LC/MS showed desired product and no starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The resulting solid was dissolved in 1 : 1 MeCN : DMSO (2.7 mL) and purified by MDAP. Fractions containing pure product were combined andconcentrated under reduced pressure. 1 .1 equivalents of HCI in diethyl ether were added to form the HCI salt and the resulting mixture was evaporated under reduced pressure to give the title compound as a yellow solid (37 mg, 0.088 mmol, 14.71 % yield).

Reference： [1]Patent: WO2012/55942,2012,A1 .Location in patent: Page/Page column 59-60

39
[ 660867-80-1 ]
[ 1374310-43-6 ]
[ 1374309-64-4 ]

Yield	Reaction Conditions	Operation in experiment
39.9%		Example 1 1 : 6-(c/'s-2,6-dimethyl-4-morpholinyl)-2'-methyl-4-(2-methyl-3-furanyl)-3,4'- bipyridine hydrochloride2-Methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (184 mg, 0.840 mmol) was added to a solution of cis-4-[5-bromo-4-(2-methyl-3-furanyl)-2-pyridinyl]-2,6- dimethylmorpholine (295 mg, 0.840 mmol) in a mixture of 1 ,4-dioxane (6 mL), water (1 .000 mL) and sodium carbonate (178 mg, 1 .680 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.084 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100 C for 1 hour. Crude LCMS showed starting material and desired product so the reaction mixture was stirred and heated at 100 C in the microwave for a further 1 hour. Crude LCMS showed desired product and no starting material can be seen. The reaction mixture was washed with ethyl acetate (200 ml_), water (100 ml_), filtered and then evaporated to dryness. This solid was dissolved in 1 : 1 MeCN : DMSO (5x0.9 mL) and purified by MDAP. Fractions containing pure product were combined and concentrated under reduced pressure. 1 .1 equivalents of HCI in diethyl ether were added to form the HCI salt and the resulting mixture was evaporated under reduced pressure to give the title compound as a yellow solid (141 mg, 0.335 mmol, 39.9 % yield).LC/MS [M+H]+ = 364; 1 H NMR (400MHz, d4-MeOD): delta 8.56-8.55 (1 H, d), 8.30 (1 H, s), 7.87 (1 H, s), 7.64-7.63 (1 H, m), 7.45-7.43 (1 H, d), 7.25 (1 H, s), 6.19-6.20 (1 H, d), 4.25- 4.22 (2H, d), 3.82-3.75 (2H, m), 2.92-2.86 (2H, m), 2.76 (3H, s), 2.19 (3H, s), 1 .29-1 .27 (6H, d).

Reference： [1]Patent: WO2012/55942,2012,A1 .Location in patent: Page/Page column 60-61

40
[ 660867-80-1 ]
[ 1374310-46-9 ]
[ 1374309-66-6 ]

Yield	Reaction Conditions	Operation in experiment
7.45%		Example 12: 6-(c/s-2.6-dimethyl-4-morpholinyl)-2'-methyl-2-(2-methyl-3-furanyl)-3.4'- bipyridine hydrochloride2-Methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (175 mg, 0.797 mmol) was added to a solution of c/'s-4-[5-bromo-6-(2-methyl-3-furanyl)-2-pyridinyl]-2,6- dimethylmorpholine (280 mg, 0.797 mmol) in a mixture of 1 ,4-dioxane (4 mL), water (0.667 mL) and sodium carbonate (169 mg, 1 .594 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.080 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100 C for 1 hour. Crude LC/MS showed starting material and desired product so the reaction mixture was stirred and heated at 100 C in the microwave for a further 1 hour. Crude LC/MS showed desired product and no starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. This solid was dissolved in 1 : 1 MeCN : DMSO (3.6 mL) and purified by MDAP. Fractions containing pure product were combined and concentrated under reduced pressure. This solid was dissolved in 1 : 1 MeCN : DMSO (1 .8 mL) and purified again by MDAP. Fractions containing pure product were combined and concentrated under reduced pressure. 1 .1 equivalents of HCI in diethyl ether was added to form the HCI salt and the resulting mixture was evaporated under reduced pressure to give the title compound as a yellow oil (25 mg, 0.059 mmol, 7.45 % yield). LC/MS [M+H]+ = 364; 1 H NMR (400 MHz, d4-MeOD): delta 8.61 -8.60 (1 H, d), 8.26-8.24 (1 H, d), 7.93 (1 H, s), 7.69-7.67 (1 H, d), 7.63-7.60 (1 H, d), 7.56 (1 H, s), 6.59 (1 H, s), 4.22-4.19 (2H, d), 3.86- 3.79 (2H, m), 3.06-3.00 (2H, m), 2.78 (3H, s), 2.10 (3H, s), 1 .29-1 .27 (6H, d).

Reference： [1]Patent: WO2012/55942,2012,A1 .Location in patent: Page/Page column 61-62

41
[ 660867-80-1 ]
[ 1374310-49-2 ]
[ 1374309-69-9 ]

Yield	Reaction Conditions	Operation in experiment
31%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; Microwave irradiation;	Example 13: c/s-2,6-Dimethyl-4-r3-(2-methyl-3-furanyl)-4-(2-methyl-4- pyridinyDphenyllmorpholine2-Methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (313 mg, 1 .428 mmol) was added to a solution of c/'s-4-[4-bromo-3-(2-methyl-3-furanyl)phenyl]-2,6- dimethylmorpholine (500 mg, 1 .428 mmol) in a mixture of 1 ,4-dioxane (6 mL), water (1 .000 mL) and sodium carbonate (303 mg, 2.86 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (165 mg, 0.143 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100 C overnight. Crude LCMS showed starting material and desired product so 2-methyl-4- (4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (0.5 equivalents),tetrakis(triphenylphosphine)palladium(0) (0.05 equivalents) and sodium carbonate (1 .0 equivalent) were added and the reaction mixture was stirred and heated at 100 C in the microwave for a further 1 hour. Crude LCMS showed desired product and no starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (~ 10 ml) and purified on silica by using a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure. This solid was dissolved in 1 : 1 MeCN : DMSO (3x0.9 mL) and purified by MDAP. Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a yellow oil (169 mg, 0.443 mmol, 31 .0 % yield). LC/MS [M+H]+ = 363; 1 H NMR (400MHz, d4-MeOD): delta 8.50-8.48 (1 H, d), 7.79 (1 H, s), 7.70-7.68 (1 H, d), 7.61 -7.59 (1 H, d), 7.48-7.45 (1 H, m), 7.39-7.40 (1 H, d), 7.34 (1 H, s), 6.25-6.24 (1 H, d), 4.03-3.96 (2H, m), 3.76-3.73 (2H, d), 2.88-2.82 (2H, m), 2.74 (3H, s), 2.02 (3H, s), 1 .28-1 .26 (6H, d).

Reference： [1]Patent: WO2012/55942,2012,A1 .Location in patent: Page/Page column 62-63

42
[ 660867-80-1 ]
[ 1374310-50-5 ]
[ 1374310-51-6 ]

Yield	Reaction Conditions	Operation in experiment
1.393%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 20 - 100℃;Inert atmosphere;	Intermediate 28: c/'s-2,6-Dimethyl-4-[4-(methyloxy)-5-(2-methyl-4-pyridinyl)-2- pyrimidinyllmorpholineTo a suspension of c/s-4-(5-bromo-4-methoxypyrimidin-2-yl)-2,6-dimethylmorpholine (671 mg, 2.22 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (632 mg, 2.89 mmol) and potassium carbonate (798 mg, 5.77 mmol) in 1 ,4-dioxane (3 mL) and water (0.5 mL) stirred in air at 20 C was added solid tetrakis(triphenylphosphine) palladium(O) (128 mg, 0.1 1 1 mmol). The reaction mixture was stirred under argon at 100 C overnight. The reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (x 3). The ethyl acetate layers were combined, dried over magnesium sulfate and evaporated under reduced pressure. The crude product was added to a silica gel column and was eluted with dichloromethane / methanol / triethylamine (20:1 :0.5). Collected fractions were evaporated to give the title compound (120 mg, 0.031 mmol, 1 .393 % yield). LC/MS [M+H]+ = 31 8.

Reference： [1]Patent: WO2012/55942,2012,A1 .Location in patent: Page/Page column 51

43
[ 660867-80-1 ]
[ 1353254-82-6 ]
[ 1353254-84-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere;	Synthesis of N-(5-(2,6-difluorobenzyl)-l-methyipiperidin-3-yl)-3-(2-methylpyridin- -yl)-l-trityl-lH-mdazole-5-carboxamide 3- bromo-N-(5-(2,6-difluorobenzyl)-l-methylpiperidin-3-yl)-l-trityl-lH-indazole-5- carboxamide (0.050 g, 0.0716 mmol), [l5l'-Bis(diphenylphosphino)ferrocene]- dichloropalladium(II) (0.0052 g, 0.00716 mmol), Potassium phosphate tribasic (0.046 g, 0.215 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-l}3,2-dioxaborolan-2-yl)pyridine (0.018 g, 0.0788 mmol) was added into a flask. After purging the reaction vessel with nitrogen gas, dioxane (0.215 mL) and water (0.043mL) was added. The reaction was allowed to stir at 80 C for 16hrs. The reaction was quenched with water (lmL) and extracted with dichloromethane (3 chi 1 mL). The extracts were combined, dried using sodium sulfate, filtered through celite, and concentrated under vacuo. The crude product was progressed to the next step without further purification. LC-MS found 718.2, calcd M+H 718.3.

Reference： [1]Patent: WO2011/163330,2011,A1 .Location in patent: Page/Page column 199

44
[ 660867-80-1 ]
[ 1129540-64-2 ]
[ 1394909-55-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; ethanol; water; at 120℃; for 2h;Inert atmosphere;	2-(2-methyl-4-pyridinyl)-5-(4-morpholinyl)-benzonitrile (Intermediate 11)(Intermediate 11)A mixture of Intermediate 10 (4.1 g, 15.35 mmol), 2-methylpyridine-4-boronic acid, pinacol ester ([660867-80-1], 3.70 g, 16.88 mmol), tetrakis(triphenylphosphine) palladium (0.88 g, 0.77 mmol), 1,4-dioxane (50 mL), and sodium carbonate (3.58 g, 33.67 mmol) dissolved in water (20 mL) and EtOH (30 mL) was degassed and the vessel was closed. The reaction mixture was stirred and heated under a nitrogen atmosphere at 120 C for 2 h. The solvent was evaporated. The residue was taken up in DCM and washed with water. The organic layer was dried with MgS04 and evaporated. The residue was purified by column chromatography on silica gel (eluent gradient from 100% DCM to 99/1 DCM/MeOH). The desired fractions were collected and evaporated, yielding 3.7 g (86 %) of Intermediate 11 after drying overnight under vacuum at 50 C.

Reference： [1]Patent: WO2012/113850,2012,A2 .Location in patent: Page/Page column 37-38

45
[ 660867-80-1 ]
[ 1392100-80-9 ]
[ 1392100-81-0 ]

Yield	Reaction Conditions	Operation in experiment
14%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130℃; for 0.5h;microwave irradiation;	A mixture of 0.74 g (3.0 mmol) E-9, 1.00 g (4.54 mmol) <strong>[660867-80-1](2-methylpyridine-4-yl)boronic acid pinacol ester</strong>, 0.24 g (0.16 mmol) tetrakis(triphenylphosphine)palladium(0), 0.93 g (6.7 mmol) potassium carbonate in 10 mL DME and 2 mL water is heated at 130C in a microwave oven for 30 min. DCM (10 mL) and water (5 mL) are added and the reaction mixture is acidified to pH 6 with 6N aqueous HC1. The phases are separated and the water phase is extracted with with 10 mL DCM. The combined organic phases are dried over MgS04 and concentrated under reduced pressure. The residual product is purified by P chromatography (silica gel, 0-10% MeOH containing 0.1% ¼ in DCM). Yield: 0.13 g (14%).
14%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 0.5h;Microwave irradiation;	A mixture of 0.74 g (3.0 mmol) E-9, 1.00 g (4.54 mmol) <strong>[660867-80-1](2-methylpyridine-4-yl)boronic acid pinacol ester</strong>, 0.24 g (0.16 mmol) tetrakis(triphenylphosphine)palladium(0), 0.93 g (6.7 mmol) potassium carbonate in 10 mL DME and 2 mL water is heated at 130 C. in a microwave oven for 30 min DCM (10 mL) and water (5 mL) are added and the reaction mixture is acidified to pH 6 with 6N aqueous HCl. The phases are separated and the water phase is extracted with 10 mL DCM.

Reference： [1]Patent: WO2012/101184,2012,A1 .Location in patent: Page/Page column 67; 68
[2]Patent: US2013/23533,2013,A1 .Location in patent: Paragraph 0288; 0289

46
[ 660867-80-1 ]
[ 1433904-28-9 ]
[ 1433904-29-0 ]

Yield	Reaction Conditions	Operation in experiment
15%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;	A suspension of 4-bromo-2-cyclopentyl-6-trifluoromethyl-quinoline-3-carbonitrile (130 mg, 352 ?????), 2-methylpyridine-4-boronic acid pinacol ester (92.6 mg, 423 ?????), cesium carbonate (103 mg, 317 ?????) and tetrakis(triphenylphosphine)palladium (0) (40.7 mg, 35.2 ?????) in DMF (5.2 ml) was heated to 90C for 16 h. The reaction mixture was poured on water and extracted with EtOAc. The combined extracts were washed with water and brine, dried with Na2S04 and evaporated. The remaining solid was purified by column chromatography (silica gel, n-heptane/EtOAc 4: 1) to afford the title compound (20 mg, 15%) as off-white solid. MS (ESI): 382.6 (M+H)+.
15%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;	Step D: 2-Cyclopentyl-4-(2-methyl-pyridin-4-yl)-6-trifluoromethyl-quinoline-3-carbonitrile A suspension of 4-bromo-2-cyclopentyl-6-trifluoromethyl-quinoline-3-carbonitrile (130 mg, 352 mumol), 2-methylpyridine-4-boronic acid pinacol ester (92.6 mg, 423 mumol), cesium carbonate (103 mg, 317 mumol) and tetrakis(triphenylphosphine)palladium (0) (40.7 mg, 35.2 mumol) in DMF (5.2 ml) was heated to 90 C. for 16 h. The reaction mixture was poured on water and extracted with EtOAc. The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining solid was purified by column chromatography (silica gel, n-heptane/EtOAc 4:1) to afford the title compound (20 mg, 15%) as off-white solid. MS (ESI): 382.6 (M+H)-.

Reference： [1]Patent: WO2013/64465,2013,A1 .Location in patent: Page/Page column 188
[2]Patent: US2013/116234,2013,A1 .Location in patent: Paragraph 1053; 1054

47
[ 660867-80-1 ]
[ 1434817-47-6 ]
[ 1434817-41-0 ]

Yield	Reaction Conditions	Operation in experiment
69%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 50℃; for 20h;	c1) 3-[4-(2-Methyl-pyridin-4-yl)-2-trifluoromethyl-phenylsulfanyl]-propionamide 3-(4-Bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (300 g, 914 mmol) was dissolved in N,N-dimethylformamide (3.0 L) and potassium carbonate (300 g, 2.17 mol). Then, 2-methylpyridine-4-boronic acid pinacol ester (285 g, 1.3 mol) and water (240 mL) were added. The solution was degassed and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 g, 41 mmol) was added. The mixture was stirred for 20 h at 50 C. After cooling to room temperature, it was poured onto ice cold water (5 C., 5 L) and extracted with ethyl acetate (13.5 L, 21.5 L). The combined organic extracts were washed with brine/water (1:1 v/v, 750 mL) and brine (750 mL), before methanol (600 mL) was added and the mixture was dried over sodium sulfate. Silica gel (400 g) was added, the slurry was filtered and washed with ethyl acetate/methanol (9:1 v/v, 1.5 L). The combined filtrates were concentrated in vacuo. The residue was suspended in toluene (600 mL) and n-heptane (300 mL) and stirred for 5 min at 60 C. and for 1 h at room temperature. The precipitate was filtered off, washed with toluene/n-heptane (4:1 v/v, 300 mL) and n-heptane (300 mL), and dried in vacuo to afford 230.3 g of brown crystalline material. The crystals were further purified by trituration in isopropanol/heptane (1:1 v/v, 600 mL) for 30 min at room temperature and 30 min at 0-4 C. (ice bath). The precipitate was filtered off, washed with n-heptane/isopropanol (4:1 v/v, 300 mL), and dried in vacuo at 65 C. to yield the title compound as a light brown crystalline solid (215.7 g, 69%). MS (EI): m/z=341.1 [M+H]. 1H NMR (d6-DMSO, 400 MHz): delta2.48 (t, J=7.2 Hz, 2H), 2.54 (s, 3H), 3.32 (t, J=7.2 Hz, 2H), 6.95 (bs, 1H), 7.41 (bs, 1H), 7.58 (dd, J=1.6 Hz, 5.4 Hz, 1H), 7.68 (s, 1H), 7.77 (d, J=9.1 Hz, 1H), 8.02-8.08 (m, 2H), 8.52 (d, J=5.1 Hz, 1H).
69%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 50℃; for 20h;	B5. Preparation of 3-[4-(2-methyl pyridin-4-yl)-2-trifluoromethyl phenylsulfanyl]propionamide. 3 -(4-Bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (300 g, 914 mmo 1) was dissolved in N,N-dimethylformamide (3.0 L) and potassium carbonate (300 g, 2.17 mol). Then, 2-methylpyridine-4-boronic acid pinacol ester (285 g, 1.3 mol) and water (240 mL) were added. The solution was degassed and [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 g, 41 mmol) was added. The mixture was stirred for 20 h at 50C. After cooling to room temperature, it was poured onto ice cold water (5C, 5 L) and extracted with ethyl acetate (1 x 3.5 L, 2 x 1.5 L). The combined organic extracts were washed with brine / water (1:1 v/v, 750 mL) and brine (750 mL), before methanol (600 mL) was added and the mixture was dried over sodium sulfate. Silica gel (400 g) was added, the slurry was filtered and washed with ethyl acetate / methanol (9:1 v/v, 1.5 L). The combined filtrates were concentrated in vacuo. The residue was suspended in toluene (600 mL) and n-heptane (300 mL) and stirred for 5 mm at 60C and for 1 h at room temperature. The precipitate was filtered off, washed with toluene / n-heptane (4:1 v/v, 300 mL) and n-heptane (300 mL), and dried in vacuo to afford 230.3 g of brown crystalline material. The crystals were further purified by trituration in isopropanol / heptane (1:1 v/v, 600 mL) for 30 mm at room temperature and 30 mm at 0 - 4C (ice bath). The precipitate was filtered off, washed with n-heptane / isopropanol (4:1 v/v, 300 mL), and dried in vacuo at 65C to yield the title compound as a light brown crystalline solid (215.7 g, 69%). MS (El): m/z = 341.1 [M + H]. 1H NMR (d6-DMSO, 400 MHz): delta 2.48 (t, J 7.2 Hz, 2H), 2.54 (s, 3H), 3.32 (t, J= 7.2 Hz, 2H), 6.95 (bs, 1H), 7.41 (bs, 1H), 7.58 (dd, J 1.6 Hz, 5.4 Hz, 1H), 7.68 (s, 1H), 7.77 (d,J= 9.1 Hz, 1H), 8.02-8.08 (m, 2H), 8.52 (d,J= 5.1 Hz, 1H).

Reference： [1]Patent: US2013/123512,2013,A1 .Location in patent: Paragraph 0187; 0188
[2]Patent: WO2013/68434,2013,A1 .Location in patent: Page/Page column 35; 36

48
[ 660867-80-1 ]
[ 1449330-41-9 ]
[ 1449330-10-2 ]

Yield	Reaction Conditions	Operation in experiment
37%	With potassium phosphate; 2?-(dimethylamino)-2-biphenylyl-palladium(II)chloride dinorbornylphosphine complex; In 1,4-dioxane; water; at 120℃; for 0.5h;Microwave irradiation;	To a 10 ml microwave vial was added example 41G) (0.05 g, 67.1 muiotaetaomicron, Eq: 1.00), 2- methylpyridine-4-boronic acid pinacol ester (16.2 mg, 73.8 muiotaetaomicron, Eq: 1.1) and tripotassium phosphate (42.7 mg, 201 muiotaetaomicron, Eq: 3) and 2'-(dimethylamino)-2-biphenyl-palladium (II) chloridedinorbornlphosphine complex (3.76 mg, 6.71 muiotaetaomicron, Eq: 0.1) in water (1.0 ml) and dioxane (2.5 ml). The vial was capped and heated in the microwave at 120C for 30 min.The crude material was purified by preparative HPLC to yield a colorless foam (0.019 g; 37%). m/z = 757.4 [M+H]+.
37%	With potassium phosphate; 2'-(dimethylamino)-2-biphenyl-palladium (II) chloridedinorbonylphosphine complex; In water; at 120℃; for 0.5h;Microwave irradiation;	To a 10 ml microwave vial was added example 41G) (0.05 g, 67.1 mumol, Eq: 1.00), 2-methylpyridine-4-boronic acid pinacol ester (16.2 mg, 73.8 mumol, Eq: 1.1) and tripotassium phosphate (42.7 mg, 201 mumol, Eq: 3) and 2?-(dimethylamino)-2-biphenyl-palladium (II) chloridedinorbomlphosphine complex (3.76 mg, 6.71 mumol, Eq: 0.1) in water (1.0 ml) and dioxane (2.5 ml). The vial was capped and heated in the microwave at 120 C. for 30 min. The crude material was purified by preparative HPLC to yield a colorless foam (0.019 g; 37%). m/z=757.4 [M+H]+

Reference： [1]Patent: WO2013/117512,2013,A1 .Location in patent: Page/Page column 52-53
[2]Patent: US2013/210799,2013,A1 .Location in patent: Paragraph 0318

49
[ 660867-80-1 ]
[ 1384070-72-7 ]
[ 1384070-97-6 ]

Yield	Reaction Conditions	Operation in experiment
46 mg	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 2h;Microwave irradiation;	Example 23b Synthesis of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methylpyridin-4-yl)-3H-pyrimidin-4-one 120 mg of 6-chloro-2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one, 96 mg of 2-methylpyridine-4-boronic acid pinacol ester, 45 mg of tetrakis(triphenylphosphine)palladium(0), 2.5 ml of 1,4-dioxane and 0.52 ml of an aqueous 1.5 M cesium carbonate solution are successively placed in a 5 ml microwave tube. The resulting suspension is stirred under microwave irradiation at a temperature of 100 C. for 2×1 hour. After cooling to ambient temperature, the reaction mixture is diluted with 6 ml of ethyl acetate and then filtered through Clarcel. The solid is washed with 3 ml of ethyl acetate, and then the filtrate is treated with 12 ml of water and stirred at ambient temperature for 1.5 hours. After settling out, the organic phase is separated and the aqueous phase is extracted with 3×10 ml of ethyl acetate. The organic extracts are combined, washed with 10 ml of saturated brine, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 25 g cartridge of 15-40 mum silica, by making a solid deposit and eluting with a 95/5 v/v dichloromethane/methanol mixture at a flow rate of 25 ml/min. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is taken up twice in diethyl ether, triturated, and then concentrated to dryness under reduced pressure. 46 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methylpyridin-4-yl)-3H-pyrimidin-4-one are thus obtained in the form of a white crystalline powder, the characteristics of which are the following:1H NMR spectrum (400 MHz): 2.54 (s, 3H); 3.23 (t, J=8.7 Hz, 2H); 3.99 (s, 2H); 4.27 (t, J=8.7 Hz, 2H); 6.88 (t, J=8.7 Hz, 1H); 6.99 (s, 1H); 7.24 (m, 1H); 7.75 (broad d, J=5.1 Hz, 1H); 7.82 to 7.88 (m, 2H); 8.54 (d, J=5.1 Hz, 1H); 12.65 (broad s, 1H)Mass spectrometry: method ARetention time Tr (min)=0.50;[M+H]+: m/z 365; [M-H]-: m/z 363Melting point (Kofler): 229 C.

Reference： [1]Patent: US2013/274253,2013,A1 .Location in patent: Paragraph 1807-1813

50
[ 660867-80-1 ]
[ 1449301-28-3 ]
[ 1449300-57-5 ]

Yield	Reaction Conditions	Operation in experiment
24 mg	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 6h;	Water (0.1 ml), potassium carbonate (48 mg) and tetrakis(triphenylphosphine)palladium (13 mg) were added to a solution of the compound obtained in Step 1 of Example 43 (61 mg) and <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (28 mg) in 1,4-dioxane (1.2 ml), and the mixture was stirred at 100 C. for six hours. After leaving to cool, the reaction solution was diluted with chloroform. The organic layer was washed with water and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->10:1 (v/v)] to give 24 mg of the title compound as a solid. 1H-NMR (CDCl3) delta: 2.61 (3H, s), 4.24-4.37 (2H, m), 4.74-4.92 (4H, m), 7.13-7.21 (2H, m), 7.27-7.36 (3H, m), 7.45-7.67 (5H, m), 7.84-7.91 (2H, m), 8.38 (1H, d, J=2.3 Hz), 8.51 (1H, d, J=5.0 Hz), 8.65 (1H, d, J=2.3 Hz). MS (ESI) m/z: 538 (M+H)+.

Reference： [1]Patent: US2013/281428,2013,A1 .Location in patent: Paragraph 0942; 0943; 0944; 0945

51
[ 660867-80-1 ]
(S)-4-benzyl-2-((4-bromophenoxy)methyl)morpholine [ No CAS ]
(S)-4-benzyl-2-((4-(2-methylpyridin-4-yl)phenoxy)methyl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step-2. Preparation of ((S)-4-benzyl-2-((4-(2-methylpyridin-4- yl)phenoxy)methyl)morpholine: A mixture of (S)-4-benzyl-2-((4-bromophenoxy)methyl)morpholine (1 eq), 2-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.2 eq) and potassium carbonate (1.4 eq) in DMF:H20 (5: 1) were sonicated for 2-3 minutes and stirred under argon atmosphere at an ambient temperature. The dichlorobis(triphenylphosphine)Palladium(II) (0.1 eq) was added to the reaction mixture and stirred at 50 C until complete consumption of the starting materials was indicated by TLC analysis (~3h). The reaction was diluted with EtOAc (50 mL) and filtered through a celite bed. The filtrate was washed with water (20 mL) and brine (5 mL). The organic layer was dried over anhydrous Na2S04, filtered, concentrated in vacuo and the residue obtained was purified by flash column chromatography (200-400 mesh size silica gel, 30% ethyl acetate/pet. ether, gradient elution) to yield (S)-4-benzyl-2-((4-(2- methylpyridin-4-yl)phenoxy)methyl)morpholine as a gummy oil. 1H NMR (DMSO-de, 300 MHz): delta 8.42 (d, J= 5.1 Hz, 1H), 7.72 (d, J= 8.7 Hz, 2H), 7.63- 7.51 (m, 5H), 7.43 (d, J = 5.1 Hz, 1H), 7.31-7.29 (m, 2H), 7.04 (d, J = 9.0 Hz, 2H), 4.00- 3.29 (m, 5H), 2.97-2.53 (m, 4H), 2.12-1.94 (m, 2H), 1.04 (s, 3H). MS (m/z): 375 (M+H)

Reference： [1]Patent: WO2013/148227,2013,A1 .Location in patent: Page/Page column 122

52
[ 660867-80-1 ]
[ 1569085-50-2 ]
[ 1569085-51-3 ]

Yield	Reaction Conditions	Operation in experiment
60%	With palladium diacetate; sodium carbonate; triphenylphosphine; In 1,2-dimethoxyethane; water; at 45℃; for 4h;	Example 30 (100 mg, 159 tmol, Eq: 1.00) was dissolved in 1,2-dimethoxyethane (2 ml).2-Methyl-4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridine (45.2 mg, 206 tmol, Eq:1.30), triphenylphosphine (8.32 mg, 31.7 tmol, Eq: 0.20), 2 M aqueous Na2CO3 solution(500 tl) and Pd(OAc)2 (3.56 mg, 15.9 tmol, Eq: 0.10) were added and stirred at 45 C for4 h. The reaction mixture was poured into 0.1 M aqueous HC1 solution (10 ml) andextracted with DCM (3 x 10 ml). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative HPLC to yield the title compound as an off-white foam (61 mg; 60 %). mlz = 642.1 [M+H].

Reference： [1]Patent: WO2014/29722,2014,A1 .Location in patent: Page/Page column 42

53
[ 109-06-8 ]
[ 73183-34-3 ]
2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine [ No CAS ]
[ 660867-80-1 ]
[ 1096689-44-9 ]

Yield	Reaction Conditions	Operation in experiment
	With (iPrPNP)CoCH2SiMe3; In tetrahydrofuran; at 80℃; for 24h;	EXAMPLE 10 - Borylation of Aromatic Six-Membered Heterocycle According to the reaction scheme illustrated in Figure 3, various pyridines underwent borylation with bis(pinacolato)diboron [B2Pin2] in the presence of bis(diisopropylphosphine) cobalt trimethylsilylmethane. Condition A employed 0.5 equiv. of B2Pin2 and Condition B employed 1.0 equiv. of B2Pin2. Reported numbers are percent conversions of the corresponding pyridine derivative determined by GC analysis using mesitylene as an internal standard. Values in parenthesis are isolated yield. Product ratios were determined by NMR analysis. Values under the percent conversions are selectivities, and the number in parenthesis denote the position of borylation. Selectivities were the same for Conditions A and B.

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4133 - 4136
[2]Patent: WO2015/89119,2015,A1 .Location in patent: Page/Page column 34

54
[ 660867-80-1 ]
5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-amine [ No CAS ]
6-methyl-5-((2’-methyl-[2,4’-bipyridin]-4-yl)oxy)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%		Example A11 A mixture of Example A8 (905 mg, 3.84 mmol), <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (1.010 g, 4.61 mmol), potassium carbonate (1.592 g, 11.52 mmol) and Pd(PPh3)4 (222 mg, 0.192 mmol) in dioxane (16 mL) and water (4 mL) was degassed with Ar, sealed and warmed to 85 C. overnight. The mixture was cooled to RT, diluted with EtOAc (40 mL) and water (50 mL), and filtered through diatomaceous earth. The organic phase was separated and washed with brine (50 mL). The organic phase was diluted with methanol (5 mL), treated with thiol-modified silica gel (4 g, 1.4 mmol thiol/g, 5.6 mmol)), and gently stirred for 3 h. The mixture was filtered, washing the slica gel plug with 3% MeOH/EtOAc (2*10 mL). The filtrates were evaporated at reduced pressure and the residue was purified by silica gel chromatography (0-10% MeOH/EtOAc) to give 6-methyl-5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-amine as a tan solid (806 mg, 71%). 1H NMR (400 MHz, DMSO-d6): delta 9.07 (d, J=2.3 Hz, 1H), 8.48 (d, J=5.7 Hz, 1H), 8.25 (dd, J=8.1, 2.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 6.35 (d, J=8.7 Hz, 1H), 5.96 (s, 2H), 2.50 (s, 3H), 2.08 (s, 3H). MS (ESI) m/z: 293.2 (M+H+).
71%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 85℃;Inert atmosphere; Sealed tube;	A mixture of Example A7 (905 mg, 3.84 mmol), <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (1.010 g, 4.61 mmol), potassium carbonate (1.592 g, 11.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (222 mg, 0.192 mmol) in dioxane (16 mL) and water (4 mL) was degassed with Ar, sealed and warmed to 85 C. overnight. The mixture was cooled to RT, diluted with EtOAc (40 mL) and water (50 mL), and filtered through diatomaceous earth. The organic phase was separated and washed with brine (50 mL). The organic phase was diluted with methanol (5 mL), treated with SiliaMetS Thiol, (1.42 mmol/g, 4 g, 5.68 mmol), and gently stirred for 3 h. The mixture was filtered, washing the slica gel plug with 3% MeOH/EtOAc (2*10 mL). The filtrates were evaporated at reduced pressure and the residue was purified by silica gel chromatography (0-10% MeOH/EtOAc) to give 6-methyl-5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-amine as a tan solid (806 mg, 71%). 1H NMR (400 MHz, DMSO-d6): delta 9.07 (d, J=2.3 Hz, 1H), 8.48 (d, J=5.7 Hz, 1H), 8.25 (dd, J=8.1, 2.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 6.35 (d, J=8.7 Hz, 1H), 5.96 (s, 2H), 2.50 (s, 3H), 2.08 (s, 3H). MS (ESI) m/z: 293.2 (M+H+).

Reference： [1]Patent: US2014/275080,2014,A1 .Location in patent: Paragraph 0299
[2]Patent: US2014/315917,2014,A1 .Location in patent: Paragraph 0325

55
[ 660867-80-1 ]
[ 1225278-67-0 ]
5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;	Example A16 A solution of Example A9 (0.440 g, 1.985 mmol) in dioxane (8 mL) was sparged with Ar, treated with a solution of K2CO3(0.549 g, 3.97 mmol) in water (2 mL) and <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (0.565 g, 2.58 mmol), sparged again with Ar, treated with Pd(PPh3)4 (0.229 g, 0.199 mmol) and heated at 80 C. overnight. The mixture was cooled to RT, diluted with EtOAc, the solids removed via filtration through diatomaceous earth and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-amine (490 mg, 89%) as a light brown solid. MS (ESI) m/z: 279.2 (M+H+).

Reference： [1]Patent: US2014/275080,2014,A1 .Location in patent: Paragraph 0305

56
[ 660867-80-1 ]
3-(tert-butyl)-1-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one [ No CAS ]
3-(tert-butyl)-1-(6-methyl-5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.8%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 85℃; for 16h;Inert atmosphere;	K2CO3 (0.1 g, 0.72 mmol) was dissolved in water (0.2 mL) and the solution was diluted with dioxane (1.2 mL). Example A3 (0.10 g, 0.28 mmol) and 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.08 g, 0.37 mmol) were added and the mixture was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.04 g, 0.04 mmol) was added and the reaction mixture was stirred at 85 C for 16 h. EtOAc (5 mL) was added and solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3 x 5 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM). The purified product was dissolved in MeCN and water, frozen to -78 C, and lyophilized to afford 3-(/er/-butyl)-l-(6-methyl-5-((2'- methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.038 g, 29.8 %) as a yellow solid. 1H NMR (400 MHz, DMSO-i: delta 11.99 (s, 1 H), 8.61 (s, 1 H), 8.53 (s, 1 H), 7.91 (s, 1 H), 7.89 (s, 1 H), 7.81 (d, J= 2.7 Hz, 1 H), 7.75 (s, 1 H), 7.69 (s, 1 H), 6.93 (d, J= 2.9 Hz, 1 H), 2.53 (s, 3 H), 2.35 (s, 3 H), 1.28 (s, 9 H); MS (ESI) m/z: All 2 (M+H+).

Reference： [1]Patent: WO2014/145023,2014,A1 .Location in patent: Paragraph 0401

57
[ 660867-80-1 ]
N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide [ No CAS ]
N-(5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 95℃; for 36h;Inert atmosphere;	A mixture of Example C1 (0.250 g, 0.598 mmol), K2CO3 (0.165 g, 1.197 mmol) and <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (0.157 g, 0.718 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.069 g, 0.060 mmol), sparged again with Ar and heated at 95 C. for 36 h. The mixture was cooled to RT, treated with satd. NaHCO3 and extracted with EtOAc (4*). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (56 mg, 20%). 1H NMR (400 MHz, DMSO-d6): delta 10.98 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.27 (d, J=3.0 Hz, 1H), 8.08 (d, J=9.1 Hz, 1H), 7.89 (s, 1H), 7.81-7.74 (m, 2H), 7.70 (d, J=2.4 Hz, 1H), 6.97 (dd, J=5.6, 2.4 Hz, 1H), 3.93-3.78 (m, 5H), 3.49-3.35 (m, 4H), 2.52 (s, 3H), 1.77-1.65 (m, 2H), 1.62-1.56 (m, 2H); MS (ESI) m/z: 475.2 (M+H+).

Reference： [1]Patent: US2014/315917,2014,A1 .Location in patent: Paragraph 0451

58
[ 660867-80-1 ]
N-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide [ No CAS ]
N-(6-methyl-5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;	Example 87 A mixture of Example C3 (0.377 g, 0.873 mmol) and K2CO3 (0.362 g, 2.62 mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar, treated with <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (0.201 g, 0.917 mmol) and Pd(Ph3P)4 (0.101 g, 0.087 mmol), sparged again with Ar and heated at 80 C. overnight. The mixture was cooled to RT, diluted with EtOAc, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc). The material was treated with Et2O, stirred at RT and the resulting solid collected via filtration and dried to afford N-(6-methyl-5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (151 mg, 35%). 1H NMR (400 MHz, DMSO-d6): delta 10.90 (s, 1H), 8.56 (d, J=5.6 Hz, 1H), 8.52 (d, J=5.2 Hz, 1H), 7.93-7.88 (m, 2H), 7.79 (dd, J=5.3, 1.6 Hz, 1H), 7.66-7.63 (m, 2H), 6.86 (dd, J=5.6, 2.4 Hz, 1H), 3.93-3.77 (m, 5H), 3.49-3.34 (m, 4H), 2.52 (s, 3H), 2.26 (s, 3H), 1.78-1.66 (m, 2H), 1.63-1.57 (m, 2H); MS (ESI) m/z: 489.2 (M+H+).

Reference： [1]Patent: US2014/315917,2014,A1 .Location in patent: Paragraph 0498

59
[ 660867-80-1 ]
5-((2-chloropyridin-4-yl)oxy)-6-ethylpyridin-2-amine [ No CAS ]
6-ethyl-5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
260 mg	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 85℃;Inert atmosphere;	A mixture of Example A13 (0.5 g, 2.002 mmol), <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (0.570 g, 2.60 mmol) and K2CO3 (0.720 g, 5.21 mmol) in dioxane (17 mL) and water (3 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.23 g, 0.199 mmol) and heated at 85 C. overnight. The mixture was cooled to RT, diluted with EtOAc and the solids removed via filtration through diatomaceous earth. The filtrate was concentrated to dryness, purified twice via silica gel chromatography (MeOH/DCM), then further purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). Combined fractions were neutralized, pooled and concentrated to dryness. The material was treated with MeCN, heated, then cooled to RT and the solid collected via filtration to afford 6-ethyl-5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-amine (260 mg, 42%). 1H NMR (400 MHz, DMSO-d6): delta 8.52 (m, 2H), 7.88 (s, 1H), 7.77 (d, J=5.4 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 6.76 (dd, J=5.7, 2.4 Hz, 1H), 6.36 (d, J=8.7 Hz, 1H), 5.98-5.96 (m, 2H), 2.53 (s, 3H), 2.40 (q, J=7.6 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 307.2 (M+H+).

Reference： [1]Patent: US2014/315917,2014,A1 .Location in patent: Paragraph 0468

60
[ 109-06-8 ]
[ 73183-34-3 ]
2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine [ No CAS ]
[ 660867-80-1 ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 7318 - 7327
[2]Journal of the American Chemical Society,2019,vol. 141,p. 7972 - 7979

61
[ 660867-80-1 ]
[ 591-50-4 ]
[ 15032-21-0 ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 7318 - 7327

62
[ 660867-80-1 ]
(7S)-3-bromo-7-methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [ No CAS ]
(7S)-7-methyl-3-(2-methylpyridin-4-yl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; palladium diacetate; triphenylphosphine; In 1,2-dimethoxyethane; water; at 75 - 80℃;Inert atmosphere;	Intermediate 1-18 was alternatively prepared in 70% yield according to the following general description of a synthesis performed at a large scale: A mixture of I-13a (1 eq.), 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- pyridine (1.1 eq.), anhydrous potassium phosphate (2 eq.), DME (7.5 mL/g I-13a) and purified water (2.5 mL/g I-13a) was evacuated and backfilled with nitrogen 3 times. Triphenyl phosphine (0.261 eq.) and palladium (II) acetate (0.131 eq.) were added in one portion under nitrogen. The mixture was evacuated and backfilled with nitrogen 3 times again, it was heated to 75-80 C and stirred at 75-80 C for 12-15 h under nitrogen. The aqueous layer was separated at 60-70 C and discarded, and then water (8 mL/g I- 13 a) was added to the organic layer. DME was removed by concentration below 40 C. Isopropyl acetate (15 mL/g I-13a) was added, the pH of the mixture was adjusted to 1-2 with cone. HCl. The mixture was filtered and the filter cake was washed with water (1 mL/g I-13a), the aqueous layer was separated and the organic layer was extracted with water (2 mL/g I- 13 a). The combined aqueous layers were washed with Isopropyl acetate (2 x 15 mL/g I- 13 a). The aqueous layer was concentrated to remove residual DME and isopropyl acetate. MTBE (2 mL/g I- 13 a) was added and the mixture was cooled to 0-5 C, stirred at 0-5 C for 2-3 h. 1-18 was filtered, washed with cooled water (1 mL/g I-13a), and dried in vacuum at 45-50 C to afford 1-18 as an off-white solid.
	With potassium phosphate; triphenylphosphine; In 1,2-dimethoxyethane; at 75 - 80℃;Inert atmosphere;	Intermediate 1-10 was alternatively prepared in 70% yield according to the following general description of a synthesis performed at a large scale: A mixture of I-8a (1 eq.), 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- pyridine (1.1 eq.), anhydrous potassium phosphate (2 eq.), DME (7.5 mL/g I-13a) and purified water (2.5 mL/g I- 13a) was evacuated and backfilled with nitrogen 3 times. Triphenyl phosphine (0.261 eq.) and palladium (II) acetate (0.131 eq.) were added in one portion under nitrogen. The mixture was evacuated and backfilled with nitrogen 3 times again, it was heated to 75-80 C and stirred at 75-80 C for 12-15 h under nitrogen. The aqueous layer was separated at 60-70 C and discarded, and then water (8 mL/g I- 13 a) was added to the organic layer. DME was removed by concentration below 40 C. Isopropyl acetate (15 mL/g I-13a) was added, the pH of the mixture was adjusted to 1-2 with cone. HCl. The mixture was filtered and the filter cake was washed with water (1 mL/g I-13a), the aqueous layer was separated and the organic layer was extracted with water (2 mL/g I- 13a). The combined aqueous layers were washed with Isopropyl acetate (2 x 15 mL/g I- 13 a). The aqueous layer was concentrated to remove residual DME and isopropyl acetate. MTBE (2 mL/g I- 13 a) was added and the mixture was cooled to 0-5 C, stirred at 0-5 C for 2-3 h. 1-10 was filtered, washed with cooled water (1 mL/g I- 13a), and dried in vacuum at 45-50 C to afford 1-10 as an off-white solid

Reference： [1]Patent: WO2014/195311,2014,A1 .Location in patent: Page/Page column 85
[2]Patent: WO2016/87489,2016,A1 .Location in patent: Page/Page column 34; 35

63
[ 660867-80-1 ]
(7S)-3-iodo-7-methyl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one [ No CAS ]
(7S)-7-methyl-3-(2-methylpyridin-4-yl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; Sealed tube;	Procedure C: Pd(PPh3)4 (384 mg, 0.332 mmol) was added to a stirred suspension of intermediate 1-23 (2 g, 4.74 mmol) and 2-methylpyridine-4-boronic acid pinacol ester (1.66 g, 7.60 mmol) in 1,4-dioxane (10 mL) and a sat. sol. of Na2C03 (5 mL) in a sealed tube under nitrogen. The mixture was stirred at 100 C for 16 h. Then the mixture was diluted with H20 and extracted with DCM and DCM with a small amount of EtOH. The organic layer was dried (Na2S04), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7M solution of ammonia in MeOH in DCM 0/100 to 3/97 then EtOAc in Heptane 0/100 to 100/0). The desired fractions were collected and evaporated in vacuo to yield compound 1 as a white solid (480 mg, 26%). (1.31 g of starting material was recovered).
26%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 100℃; for 16h;Sealed tube; Inert atmosphere;	Procedure C: Pd(PPh3)4 (384 mg, 0.332 mmol) was added to a stirred suspension of intermediate 1-15 (2 g, 4.74 mmol) and 2-methylpyridine-4-boronic acid pinacol ester (1.66 g, 7.60 mmol) in 1,4-dioxane (10 mL) and a sat. sol. of Na2C03 (5 mL) in a sealed tube under nitrogen. The mixture was stirred at 100 C for 16 h. Then the mixture was diluted with H20 and extracted with DCM and DCM with a small amount of EtOH. The organic layer was dried (Na2S04), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7M solution of ammonia in MeOH in DCM 0/100 to 3/97 then EtOAc in Heptane 0/100 to 100/0). The desired fractions were collected and evaporated in vacuo to yield (0323) compound 1 as a white solid (480 mg, 26%). (1.31 g of starting material was recovered)

Reference： [1]Patent: WO2014/195311,2014,A1 .Location in patent: Page/Page column 105
[2]Patent: WO2016/87489,2016,A1 .Location in patent: Page/Page column 42; 43

64
[ 660867-80-1 ]
6-bromo-3,3-dimethyl-1-(oxetan-3-yl)indolin-2-one [ No CAS ]
3,3-dimethyl-6-(2-methylpyridin-4-yl)-1-(oxetan-3-yl)indolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75 mg	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 2h;Inert atmosphere;	Example 51 3,3-Dimethyl-6-(2-methylpyridin-4-yl)-1-(oxetan-3-yl)indolin-2-one Through a suspension of 6-bromo-3,3-dimethyl-1-(oxetan-3-yl)indolin-2-one (example 49a, 130 mg, 439 imol) and 2-methyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridine (118 mg,527 imol) in dioxane (3.8 ml) and 2M aqueous solution of sodium carbonate (219 tl, 439 imol) was bubbled argon for 5 minutes. [1,1 ?-Bis(diphenylphosphino)ferroceneldichloropalladium(II), complex with dichloromethane (1:1) (17.9 mg, 21.9 imol) was added and argon was bubbled through again for 5 minutes. The reaction mixture was heated to 110 C for 2 hours. The solventwas evaporated and the residue was purified by silica gel chromatography using dichloromethane/ methanol with 1 % ammonia as eluent followed by preparative HPLC. The title compound was obtained as white solid (75 mg).MS ESI (m/z): 309.5 [(M+H)j.1H NMR (CDC13, 300 MHz): oe = 8.56 (d, J=5.0 Hz, 1H), 7.83 (d, J=0.8 Hz, 1H), 7.43 - 7.31 (m,4H), 5.65 (tt, J=5.9, 8.0 Hz, 1H), 5.24 - 5.05 (m, 4H), 2.64 (s, 3H), 1.42 (s, 6H).

Reference： [1]Patent: WO2014/202493,2014,A1 .Location in patent: Page/Page column 65; 66

65
[ 660867-80-1 ]
1-(4-bromobenzyl)-N-[(1,2-trans)-2-hydroxycyclopentyl]-4-oxo-1,4-dihydroquinoline-3-carboxamide [ No CAS ]
N-[(1,2-trans)-2-hydroxycyclopentyl]-1-[4-(2-methylpyridin-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.036 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 1h;Microwave irradiation;	To a solution (4 mL) of 1-(4-bromobenzyl)-N-[(1,2-trans)-2-hydroxycyclopentyl]-4-oxo-1,4-dihydroquinoline-3-carboxamide (0.1 g) obtained in Reference Example 16 and <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (0.075 g) in DME were added 2 M aqueous sodium carbonate solution (1 mL) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.01 g), and the mixture was stirred at 100C for 1 hr under microwave irradiation. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate-methanol) to give the title compound (0.036 g) as a pale-yellow solid. MS (ESI+): [M+H]+ 454.4 1H NMR (300MHz, DMSO-d6) delta 1.37-1.95 (5H, m), 2.02-2.18 (1H, m), 2.45 (3H, s), 3.89-4.11 (2H, m), 4.94 (1H, d, J = 3.4 Hz), 5.86 (2H, s), 7.36 (2H, d, J = 8.1 Hz), 7.41-7.57 (3H, m), 7.70-7.82 (4H, m), 8.36 (1H, d, J = 7.7 Hz), 8.47 (1H, d, J = 5.1 Hz), 9.13 (1H, s), 10.05 (1H, d, J = 7.2 Hz).

Reference： [1]Patent: EP2821401,2015,A1 .Location in patent: Paragraph 0312

66
[ 62224-19-5 ]
[ 660867-80-1 ]
5-(2-methylpyridin-4-yl)-thiophene-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/104688,2015,A1

67
[ 62224-19-5 ]
[ 660867-80-1 ]
methyl 5-(2-methylpyridin-4-yl)thiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrabutylammomium bromide; potassium carbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere;	General procedure: Step 1: Preparation of methyl 5-(2-methylpyridin-4-yl)thiophene-2-carboxylate Using the similar reaction conditions as described in step 7 of example 1, methyl 5- bromothiophene-2-carboxylate (460mg, 2.08 mmol) was coupled with 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (680mg, 3.10 mmol) using potassium carbonate (576mg, 4.17 mmol) TBAB (lOOmg, 0.310 mmol) and Pd(dppf)Cl2 (108mg, 0.1538 mmol) in dioxane/water (10/3mL) to get the crude product. The resultant crude was purified by 60-120 silica gel column chromatography using 50%ethyl acetate in hexane as eluent to obtain the title compound (552mg, 91%). LCMS: m/z = 234.0 (M+l)+.
91%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrabutylammomium bromide; potassium carbonate; In 1,4-dioxane; water; at 95℃;Sealed tube; Inert atmosphere;	To a sealed tube 6-bromo-N-(2-morpholinooxazolo [4,5-b]pyridin-6-yl)picolinamide (350 mg, 0.866 mmol), tert-butyl (5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridin-2-yl)carbamate (360 mg, 1.126 mmol) (intermediate 1), sodium carbonate (275 mg, 2.598 mmol) in 1,2-dime- thoxyethane (10 mL) and water (2 mL) were added. The reaction mixture was purged with argon for 10 mm, added Pd(PPh3)2C12 (31 mg, 0.043 mmol) and heated at 95 C. overnight. The solvent was distilled out. The resultant crude was purified by 60-120 silica gel column chromatography using 5% methanol in DCM as eluent to obtain the title compound (300 mg, 67.11%). Using the similar reaction conditions as describedin step 7 of example 1, methyl 5-bromothiophene-2-car-boxylate (460 mg, 2.08 mmol) was coupled with 2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine(680 mg, 3.10 mmol) using potassium carbonate (576 mg,4.17 mmol) TB AB (100 mg, 0.3 10 mmol) and Pd(dppf)C12(108 mg, 0.1538 mmol) in dioxane/water (10/3 mE) to getthe crude product. The resultant crude was purified by60-120 silica gel column chromatography using 50% ethylacetate in hexane as eluent to obtain the title compound (552mg, 91%). ECMS: mlz=234.0 (M+1).

Reference： [1]Patent: WO2015/104688,2015,A1 .Location in patent: Page/Page column 32
[2]Patent: US2016/340366,2016,A1 .Location in patent: Paragraph 0185; 0216

68
[ 2527-99-3 ]
[ 660867-80-1 ]
5-(2-methylpyridin-4-yl)furan-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/104662,2015,A1

69
[ 2527-99-3 ]
[ 660867-80-1 ]
methyl 5-(2-methylpyridin-4-yl)furan-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrabutylammomium bromide; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 12h;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H20 (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) andtricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc;7:3) to give the title compound (0.160 g, 61 %) as a light brown solid.?H NMR (400 MHz, DMSO-d6):oe8.69 (s, 1H), 8.43 (s, 1H), 7.50 (s, 1H), 5.12-5.05 (m, 1H), 2.33-2.20 (m, 3H), 2.19-2.01 (m, 2H), 1.93-1.83 (m, 2H), 1.75-1.65 (m, 2H), 0.94-0.79 (m, 2H),0.73-0.69 (m, 2H). LCMS: mlz: 272 (M+1).Using the similar reaction conditions as described in step 1 of example 6, methyl 5-bromofuran-2-carboxylate (214mg, 1 .O4O6mmol) was coupled with 2-methyl-4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridine (340mg, 1.561 mmol) using potassium carbonate (288mg, 2.O8mmol) TBAB (50mg, 0.lS6mmol) and Pd(dppf)C12 (54mg, 0.O78mmol) in dioxane/water (10/3mL) to get the crude product. The obtained crude was purified by 60-120 silica gel column chromatography using 50%ethyl acetate in hexane as eluent to obtain the titlecompound (301mg, 89%). LCMS: mlz = 217.8 (M+1).
89%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrabutylammomium bromide; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 12h;Inert atmosphere; Sealed tube;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H2O (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) and tricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C. for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc; 7:3) to give the title compound (0.160 g, 61%) as a light brown solid. ; Preparation of ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate ; Preparation of methyl 5-(2-methylpyridin-4-yl)furan-2-carboxylate Using the similar reaction conditions as described in step 1 of example 6, methyl 5-bromofuran-2-carboxylate (214 mg, 1.0406 mmol) was coupled with <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (340 mg, 1.561 mmol) using potassium carbonate (288 mg, 2.08 mmol) TBAB (50 mg, 0.156 mmol) and Pd(dppf)Cl2 (54 mg, 0.078 mmol) in dioxane/water (10/3 mL) to get the crude product. ;The obtained crude was purified by 60-120 silica gel column chromatography using 50% ethyl acetate in hexane as eluent to obtain the title compound (301 mg, 89%). LCMS: m/z=217.8 (M+1)+.

Reference： [1]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 32; 46
[2]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0180; 0251; 0252

70
[ 660867-80-1 ]
2-((2-(4-bromobenzyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl)oxy)-3-fluorobenzonitrile [ No CAS ]
3-fluoro-2-((2-(4-(2-methylpyridin-4-yl)benzyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl)oxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.071 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; at 80℃;Inert atmosphere;	To a solution of 2-((2-(4-bromobenzyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl)oxy)-3-fluorobenzonitrile (0.15 g) obtained in Example 71, <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (0.083 g) and 2M aqueous sodium carbonate solution (0.69 mL) in DME (3 mL) was added (1,1-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.025 g), and the mixture was stirred under an argon atmosphere at 80C overnight. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and solidified with ethyl acetate to give the title compound (0.071 g). MS: [M+H]+ 450.2 1H NMR (300 MHz, CDCl3) delta2.63 (3H, s), 4.32 (2H, s), 4.82 (2H, s), 6.77 (1H, d, J = 8.3 Hz), 7.16 (1H, d, J = 7.5 Hz), 7.24-7.33 (2H, m), 7.36 (1H, s), 7.39-7.48 (4H, m), 7.51 (1H, dt, J = 7.6, 1.5 Hz), 7.61 (2H, d, J = 8.3 Hz), 8.54 (1H, d, J = 5.3 Hz).

Reference： [1]Patent: EP2921480,2015,A1 .Location in patent: Paragraph 1116; 1117

71
[ 660867-80-1 ]
[ 886373-28-0 ]
7-(2,6-difluorophenoxy)-2-((5-fluoro-2'-methyl-3,4'-bipyridin-6-yl)methyl)isoindolin-1-one [ No CAS ]

Reference： [1]Patent: EP2921480,2015,A1

72
[ 660867-80-1 ]
[ 886373-28-0 ]
5-fluoro-2'-methyl-(3,4'-bipyridine)-6-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.33 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere;	A solution of 5-bromo-3-fluoropicolinonitrile (0.46 g), <strong>[660867-80-1]2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (0.60 g), sodium carbonate (0.49 g) and (1,1-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.17 g) in 1,2-dimethoxyethane (10 mL)-water (3 mL) was stirred under an argon atmosphere at 90C overnight. The reaction solution was diluted with water and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by NH silica gel chromatography (hexane-ethyl acetate) to give the title compound (0.33 g). 1H NMR (300 MHz, DMSO-d6) delta 2.57 (3H, s), 7.72 (1H, dd, J = 5.4, 1.4 Hz), 7.82 (1H, s), 8.58-8.66 (2H, m), 9.12 (1H, t, J = 1.6 Hz).

Reference： [1]Patent: EP2921480,2015,A1 .Location in patent: Paragraph 0539; 0540

73
[ 660867-80-1 ]
3-chloro-5-o-tolylpyrazin-2-amine [ No CAS ]
3-(2-methylpyridin-4-yl)-5-o-tolylpyrazin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 120℃; for 2h;Microwave irradiation;	Step 2: 3-(2-M ethylpyridin-4-yl)-5-o-tolylpyrazin-2-amineA mixture of Pd(PPh3)2C12 (0.125 g, 0.178 mmol), 3-chloro-5-o-tolylpyrazin-2-amine (step 1)(0.78 g, 3.55 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (0.8 g,3.65 mmol), sodium carbonate (1.1 g, 10.38 mmol) in DME (7.5 mL), EtOH (5.00 mL) andwater (2.5 mL) was heated to 120 00 in the microwave for 2 hours. The resulting mixture was diluted with ethyl acetate and water, using sonication to ensure all material was transferred from the microwave vial and evaporated under reduced pressure to remove organics. The remaining aqueous was extracted with ethyl acetate (2 x 5OmL), washed withsaturated sodium bicarbonate (5OmL) and brine (25mL), dried over anhydrous magnesium sulfate and filtered. The resulting dark brown solution was evaporated and bound to silica, then purified by flash column chromatography (80g silica, 70-100% ethyl acetate in isohexane, then 5-10% 2M methanolic ammonia in TBME). The product fractions were evaporated to give the title compound as a yellow solid;LC-MS: Rt 0.69 mm; mlz 277.6 [M+H]+; Method: 2minLowpH

Reference： [1]Patent: WO2015/162459,2015,A1 .Location in patent: Page/Page column 342

74
[ 660867-80-1 ]
2-(3-bromophenoxy)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide [ No CAS ]
2-(3-(2-methylpyridin-4-yl)phenoxy)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With 1,1'-bis-(diphenylphosphino)ferrocene; potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 105℃;Inert atmosphere;	General procedure: To a suspension of corresponding aryl bromide (1 equiv), 4 (1.2 equiv), Pd(dppf)Cl2 (0.04 equiv) and dppf (0.04 equiv) in 1,4-dioxane (10 mL) was added K3PO4 (2 equiv). The mixture was stirred at 105 C under N2 overnight. After cooling to room temperature,the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol) to afford the desired products 19-21. 6.1.9.1 2-(3-(2-Methylpyridin-4-yl)phenoxy)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide (19) White solid (yield: 23%). 1H NMR (400 MHz, CDCl3): delta 9.11 (s, 1H), 9.04 (d, J = 1.6 Hz, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.67-8.65 (m, 1H), 8.59-8.54 (m, 2H), 8.46 (d, J = 8.8 Hz, 1H), 8.42-8.39 (m, 1H), 7.49-7.44 (m, 1H), 7.37-7.28 (m, 4H), 7.07 (dd, J = 8.0, 2.4 Hz, 1H), 4.74 (s, 2H), 2.64 (s, 3H). ESI-MS (m/z): 398.2 [M+H]+.
23%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In tetrahydrofuran; at 85℃; for 20h;Inert atmosphere;	The B12 - 1 (100 mg, 0 . 26 mmol) and 2 - methyl pyridine -4 - boric acid pinacone ester (68 mg, 0 . 31 mmol) dissolved in tetrahydrofuran (3 ml) in, adding Pd (PPh3 )4 (24 mg, 0 . 021 mmol) and cesium carbonate (167 mg, 0 . 52 mmol). Under the protection of nitrogen, replace the nitrogen five times, heating to 85 C, reaction 20 hours. After cooling to room temperature the filtering, the filtrate is concentrated under reduced pressure. Column chromatography (dichloromethane: methanol=60:1) to obtain white solid (24 mg, 23%). After mass spectrometry and nuclear magnetic resonance spectrum analysis (Atlas data see table 1), the resulting solid is compound B12

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868
[2]Patent: CN104876912,2017,B .Location in patent: Paragraph 0047; 0123; 0124; 0127; 0128

75
[ 660867-80-1 ]
2-((3-bromophenyl)amino)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide [ No CAS ]
2-((3-(2-methylpyridin-4-yl)phenyl)amino)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With 1,1'-bis-(diphenylphosphino)ferrocene; potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 105℃;Inert atmosphere;	General procedure: To a suspension of corresponding aryl bromide (1 equiv), 4 (1.2 equiv), Pd(dppf)Cl2 (0.04 equiv) and dppf (0.04 equiv) in 1,4-dioxane (10 mL) was added K3PO4 (2 equiv). The mixture was stirred at 105 C under N2 overnight. After cooling to room temperature,the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol) to afford the desired products 19-21. 6.1.9.2 2-((3-(2-Methylpyridin-4-yl)phenyl)amino)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide (20) Light yellow solid (yield: 36%). 1H NMR (400 MHz, DMSO-d6): delta 10.73 (s, 1H), 9.30 (d, J = 1.6 Hz, 1H), 9.09 (d, J = 1.6 Hz, 1H), 8.72 (dd, J = 2.4, 1.6 Hz, 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.53 (dd, J = 8.8, 2.4 Hz, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.39 (d, J = 5.2 Hz, 1H), 7.26-7.21 (m, 1H), 7.00-6.95 (m, 2H), 6.71 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 6.31-6.26 (m, 1H), 4.09 (d, J = 6.4 Hz, 2H), 2.51 (s, 3H). ESI-MS (m/z): 397.2 [M+H]+.
18%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; at 90℃; for 20h;Inert atmosphere;	A mixture of B13-1 (70 mg, 0.18 mmol) and 2-methylpyridine-4-boronic acid pinacol ester (48 mg, 0.22 mmol) in dioxane (2 mL) was added Pd (PPh3) 4 (17 mg, 0.014 mmol) and cesium carbonate (117 mg, 0.36 mmol). Nitrogen protection , Replaced with nitrogen five times, heated to 90 C, the reaction for 20 hours. After cooling to room temperature and filtering, the filtrate was concentrated under reduced pressure. By the column (Dichloromethane: methanol = 80: 1) gave a pale yellow solid (13 mg, 18%). After mass spectrometry and NMR analysis (map The data shown in Table 1), the resulting solid for the compound Beta

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868
[2]Patent: CN104876912,2017,B .Location in patent: Paragraph 0047; 0129; 0130; 0133; 0134

76
[ 660867-80-1 ]
2-((3-bromophenyl)thio)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide [ No CAS ]
2-((3-(2-methylpyridin-4-yl)phenyl)thio)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%	With 1,1'-bis-(diphenylphosphino)ferrocene; potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 105℃;Inert atmosphere;	General procedure: To a suspension of corresponding aryl bromide (1 equiv), 4 (1.2 equiv), Pd(dppf)Cl2 (0.04 equiv) and dppf (0.04 equiv) in 1,4-dioxane (10 mL) was added K3PO4 (2 equiv). The mixture was stirred at 105 C under N2 overnight. After cooling to room temperature,the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol) to afford the desired products 19-21. 6.1.9.3 2-((3-(2-Methylpyridin-4-yl)phenyl)thio)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide (21) Yellow solid (yield: 11%). 1H NMR (400 MHz, CDCl3): delta 9.25 (s, 1H), 9.00 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 8.53 (d, J = 9.6 Hz, 2H), 8.34 (s, 2H), 7.65 (s, 1H), 7.51-7.39 (m, 3H), 7.31 (s, 1H), 7.25 (s, 1H), 3.87 (s, 2H), 2.60 (s, 3H). ESI-MS (m/z): 414.2 [M+H]+.
11%	With 1,1'-bis-(diphenylphosphino)ferrocene; potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 105℃;Inert atmosphere;	A mixture of B14-2 (140 mg, 0.35 mmol) and 2-methylpyridine-4-boronic acid pinacol ester (204 mg, 0.93 mmol) Pd (dppf) CI2CH2CI2 (12 mg, 0.014 mmol), dppf (8 mg, 0.014 mmol) and potassium phosphate (149 mg, 0.70 mmol) were added to the dioxane (10 mL), protected by nitrogen, heated to 105 C, overnight. Cooled to room temperature, concentrated under reduced pressure Column chromatography (petroleum ether: ethyl acetate = 1: 1) gave a yellow solid (16 mg, 11%). After mass spectrometry and NMR analysis (Fig The spectral data are shown in Table 1), and the resulting solid is compound B14

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868
[2]Patent: CN104876912,2017,B .Location in patent: Paragraph 0047; 0135; 0136; 0139; 0140

77
[ 660867-80-1 ]
[ 586-78-7 ]
[ 55218-69-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 12h;Inert atmosphere;	A mixture of B3-1 (1.95 g, 9.65 mmol) and 2-methylpyridine-4-boronic acid pinacol ester (1.9 g, 8.78 mmol) was dissolved in dioxane (45 mL) and water (15 mL) , Pd (dppf) CI2 (71 mg, 0.088 mmol) and potassium carbonate (3.6 g,26.3 mmol) under nitrogen, replaced with nitrogen five times, heated to 80 C and reacted for 12 hours. After cooling to room temperature, filter and filterThe solution is concentrated under reduced pressure. A yellow solid (1.8 g, 96%) was obtained by column chromatography (petroleum ether: ethyl acetate = 15: 1).
84%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere;	6.1.23 2-Methyl-4-(4-nitrophenyl)pyridine (51) To a solution of 1-bromo-4-nitrobenzene (2.0 g, 10 mmol), 4 (3.8 g, 58%, 10 mmol) and Pd(dppf)Cl2 (73 mg, 0.1 mmol) in 1,4-dioxane (45 mL) and H2O (15 mL) was added K2CO3 (4.1 g, 30 mmol), and the reaction mixture was stirred at 100 C under N2 for 12 h. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL * 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100:1) to give 51 (1.8 g, 84%) as a yellow solid. 1H NMR (400 MHz, CDCl3): delta 8.62 (d, J = 5.2 Hz, 1H), 8.34 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.39 (s, 1H), 7.33 (d, J = 5.2 Hz, 1H), 2.66 (s, 3H).

Reference： [1]Patent: CN104876912,2017,B .Location in patent: Paragraph 0047; 0062-0065
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868

78
[ 660867-80-1 ]
[ 25458-45-1 ]
4-(4-(methoxymethoxy)phenyl)-2-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In tetrahydrofuran; at 85℃; for 12h;Inert atmosphere;	The B6 - 1 (1.5 g, 6 . 91 mmol) and 2 - methyl pyridine -4 - boric acid pinacone ester (3.3 g, 55%, 8.29 mmol) dissolved in tetrahydrofuran (30 ml) in, adding Pd (PPh3 )4 (635 mg, 0 . 55 mmol) and cesium carbonate (2.7 g, 8 . 29 mmol). Under the protection of nitrogen, replace the nitrogen five times, heating to 85 C, reaction 12 hours. After cooling to room temperature the filtering, the filtrate is concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate=5:1) to obtain colorless oily matter (1.3 g, 82%).
1.3 g	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In tetrahydrofuran; at 75℃; for 12h;Inert atmosphere;	6.1.3 4-(4-(Methoxymethoxy)phenyl)-2-methylpyridine (5) To a solution of the above crude oil 4 (3.3 g), 2 (1.5 g, 6.91 mmol) and Pd(PPh3)4 (635 mg, 0.55 mmol) in THF (10 mL) was added Cs2CO3 (2.7 g, 8.29 mmol). The mixture was stirred at 75 C under N2 for 12 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1) to give 5 (1.3 g, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3): delta 8.48 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.32 (s, 1H), 7.27 (d, J = 5.2 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 5.22 (s, 2H), 3.49 (s, 3H), 2.60 (s, 3H).

Reference： [1]Patent: CN104876912,2017,B .Location in patent: Paragraph 0047; 0084; 0085; 0088; 0089
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868

79
[ 660867-80-1 ]
N-([1,1'-biphenyl]-4-yl)-2-(4-(2-methylpyridin-4-yl)phenoxy)acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868

80
[ 660867-80-1 ]
2-(4-(2-methylpyridin-4-yl)phenoxy)-N-(4-(pyridin-3-yl)phenyl)acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868

81
[ 660867-80-1 ]
2-(4-(2-methylpyridin-4-yl)phenoxy)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868

82
[ 660867-80-1 ]
N-methyl-4-(2-methylpyridin-4-yl)aniline [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868
[2]Patent: CN104876912,2017,B

83
[ 660867-80-1 ]
2-((4-(2-methylpyridin-4-yl)phenyl)amino)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868
[2]Patent: CN104876912,2017,B

84
[ 660867-80-1 ]
2-(methyl(4-(2-methylpyridin-4-yl)phenyl)amino)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868
[2]Patent: CN104876912,2017,B

85
[ 660867-80-1 ]
2-(4-(2-methylpyridin-4-yl)phenoxy)-N-(5-(pyrazin-2-yl)pyridin-2-yl)propanamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868

86
[ 660867-80-1 ]
[ 216059-91-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868
[2]Patent: CN104876912,2017,B

87
[ 660867-80-1 ]
4-(2-methylpyridin-4-yl)phenol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868

88
[ 660867-80-1 ]
3-(4-bromophenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)propanamide [ No CAS ]
3-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 108℃;Inert atmosphere;	6.1.31 3-(4-(2-Methylpyridin-4-yl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)propanamide (60) To a solution of 59 (140 mg, 0.37 mmol), 4 (207 mg, 58%, 0.55 mmol), Pd(dppf)Cl2 (24 mg, 0.03 mmol) and dppf (16 mg, 0.03 mmol) in 1,4-dioxane (8 mL) was added the solution of K3PO4 (155 mg, 0.73 mmol) in water (2 mL). The mixture was stirred at 108 C under N2 overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol = 50:1) to give 60 (68 mg, 47%) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 10.80 (s, 1H), 9.29 (d, J = 1.2 Hz, 1H), 9.07 (d, J = 2.0 Hz, 1H), 8.75-8.69 (m, 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.51 (dd, J = 8.8, 2.4 Hz, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.56 (s, 1H), 7.47 (d, J = 4.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 2.80 (t, J = 7.6 Hz, 2H), 2.51 (s, 3H). 13C NMR (100 MHz, DMSO-d6): delta 171.6, 158.5, 153.1, 149.5, 149.3, 147.1, 146.5, 144.4, 143.5, 142.3, 141.7, 136.4, 135.1, 129.1, 127.0, 126.8, 120.2, 118.2, 113.1, 37.5, 30.3, 24.2. HRMS (ESI) calcd for C24H21N5O [M+H]+: 396.1819, found: 396.1822.
21%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; at 90℃; for 20h;Inert atmosphere;	B2-2 (60 mg, 0.16 mmol) and 2-methylpyridine-4-boronic acid pinacol ester(42 mg, 0.19 mmol) was dissolved in dioxane(2 g) was added Pd (PPh3) 4 (15 mg, 0.013 mmol) and cesium carbonate (104 mg, 0.32 mmol).Under nitrogen protection, the mixture was purged with nitrogen five times and heated to 90 C for 20 hours. After cooling to room temperature and filtering, the filtrate was concentrated under reduced pressure.A white solid (13 mg, 21%) was obtained by column chromatography (dichloromethane: methanol = 80: 1). After analysis by mass spectrometry and NMR (graph data is shown in Table 1), the resulting solid is compound

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6855 - 6868
[2]Patent: CN104876912,2017,B .Location in patent: Paragraph 0047; 0057; 0060; 0061

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	660867-80-1	MDL No. :	MFCD08061590
Formula :	C₁₂H₁₈BNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MBTULFIFECUURA-UHFFFAOYSA-N
M.W :	219.09	Pubchem ID :	16414274
Synonyms :

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.58
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	65.68
TPSA :	31.35 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.05 cm/s

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.24
Log Po/w (WLOGP) :	1.69
Log Po/w (MLOGP) :	0.86
Log Po/w (SILICOS-IT) :	1.79
Consensus Log Po/w :	1.32

[ CAS No. 660867-80-1 ] {[proInfo.proName]}

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[ 660867-80-1 ] Synthesis Path-Upstream 1~6

[ 660867-80-1 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 660867-80-1 ]

Organoboron

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[ 660867-80-1 ]

Pyridines

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

Log S (ESOL) :	-2.82
Solubility :	0.331 mg/ml ; 0.00151 mol/l
Class :	Soluble
Log S (Ali) :	-2.53
Solubility :	0.641 mg/ml ; 0.00292 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.02
Solubility :	0.021 mg/ml ; 0.0000959 mol/l
Class :	Moderately soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.72

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

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P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
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

[ CAS No. 660867-80-1 ] {[proInfo.proName]}

Quality Control of [ 660867-80-1 ]

Related Doc. of [ 660867-80-1 ]

Product Details of [ 660867-80-1 ]

Calculated chemistry of [ 660867-80-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 660867-80-1 ]

Application In Synthesis of [ 660867-80-1 ]

[ 660867-80-1 ] Synthesis Path-Upstream 1~6

[ 660867-80-1 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 660867-80-1 ]

Organoboron

Related Parent Nucleus of [ 660867-80-1 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 660867-80-1 ]

Related Parent Nucleus of
[ 660867-80-1 ]