Name: 1012084-56-8|2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine|97%
Brand: Ambeed
SKU: A144246
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1
[ 1012084-56-8 ]
[ 144918-96-7 ]
[ 1065481-93-7 ]

Yield	Reaction Conditions	Operation in experiment
86.43%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 100℃; for 3h;	Example 96: Preparation of N-((S)-l-(8-Chloro-2-(2-methylpyridin-3-yl)- quinolin-3-yl)ethyI)-9H-purin-6-amine and N-((R)-l-(8-chloro-2-(2- methylpyridin-3-yl)quinolin-3-yl)ethyI)-9H-purin-6-amine; 8-Chloro-2-(2-methylpyridin-3-yl)quinoline-3-carbaldehyde; <n="172"/>A mixture of 2,8-dichloroquinoline-3-carbaldehyde (Prepared in Example 2, 1.0000 g, 4.424 mmol), tetrakis(triphenylphosphine)palladium (0.2556 g, 0.2212 mmol), and sodium carbonate anhydrous (2.344 g, 22.12 mmol) in 90 mL of CH3CN-H2O (3:1) was stirred at 1000C. After 3 h, the mixture was cooled to room temperature and partitioned between EtOAc (150 mL) and water (150 mL). The organic layer was washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow solid. The yellow solid was purified by silica gel column chromatography on a 80 g of Redi- Sep column using 0 to 100% gradient of EtOAc in hexane over 25 min and then 100% isocratic of EtOAc for 10 min as eluent to give 8-chloro-2-(2- methylpyridin-3-yl)quinoline-3-carbaldehyde as an off-white solid: 1H NMR (400 MHz, DMSO-dbeta) delta ppm 9.96 (1 H, s), 9.16 (1 H, s), 8.62 (1 H, dd, J=4.9, 1.8 Hz), 8.31 (1 H, dd, J=8.2, 1.2 Hz), 8.18 (1 H, dd, J=7.4, 1.2 Hz), 7.80 (1 H, dd, J=7.6, 1.8 Hz), 7.76 (1 H, dd, J=8.2, 7.4 Hz), 7.40 (1 H, dd, J=7.4, 4.7 Hz), 2.35 (3 H, s); LC-MS (ESI) m/z 283.0 [M+H]+.

Reference： [1]Patent: WO2008/118468,2008,A1 .Location in patent: Page/Page column 170-171

2
[ 1012084-56-8 ]
[ 1138419-85-8 ]
[ 1138419-62-1 ]

Yield	Reaction Conditions	Operation in experiment
40.4%	With sodium carbonate;CyJohnPhos; In 1,2-dimethoxyethane; water; at 20 - 90℃; for 4.5h;	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) (3629 mul)/Water (726 mul), then 2-methyl-3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (167 mg, 0.653 mmol), SODIUM CARBONATE (92 mg, 0.871 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 heated to 9O0C and stirred for 3 hours then it was cooled down to room temperature and 2-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (167 mg, 0.653 mmol), 2- biphenylyl(dicyclohexyl)phosphane (15.26 mg, 0.044 mmol), SODIUM CARBONATE (92 mg, 0.871 mmol) and Tetrakis (50.3 mg, 0.044 mmol) were added again. The mixture was stirred at 9O0C for further 1.5 hours until it was gone to completion. Solvents were evaporated under reduced pressure and the residue was partitioned between AcOEt and water. Phases were separated and organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude was purified by Preparative HPLC, then further purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1 ) affording 6-(2-methyl-3-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 (E5, 41.5 mg, 0.088 mmol, 40.4 % yield). 1H NMR (400 MHz, CHLOROFORM-d) delta: ppm 8.65-8.60 (m, 1 H), 7.78-7.72 (m, 1 H), 7.56-7.52 (m, 2H), 7.27-7.19 (m, 3H), 4.17-4.07 (m, 2H), 3.50-3.44 (m, 1 H), 3.27-3.19 (m, 1 H), 2.72-2.59 (m, 6H), 2.58-2.51 (m, 1 H), 2.09-1.96 (m, 2H), 1.85-1.77 (m, 1 H), 1.49- 1.42 (m, 1 H), 0.91-0.83 (m, 1 H).

Reference： [1]Patent: WO2009/43884,2009,A1 .Location in patent: Page/Page column 48

3
[ 73183-34-3 ]
[ 38749-79-0 ]
[ 1012084-56-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate;[1,1-bis(diphenylphosphino)ferrocene]palladium(II) bis methylene chloride; In N,N-dimethyl-formamide; at 80℃; for 16h;	Intermediate 1: 2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine 3-Bromo-2-pinnacol (1 g, 5.8 mmol) was dissolved in DMF (20 mL). To this was added potassium acetate (2 g, 20.3 mmol) followed by 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (1.9 g, 7.5 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) bis methylene chloride (0.47 g, 10% mol). The reaction was heated to 80 C. for 16 hrs then poured into water and extracted with ethyl acetate. The organic layer was separated and brined then dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude purified by flash chromatography on silica gel in ethyl acetate. A greenish/black oil 0.2 g was recovered.
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 80℃; for 16h;	2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine 3-Bromo-2-pinnacol (1 g, 5.8 mmol) was dissolved in DMF (20 mL). To this was added potassium acetate (2 g, 20.3 mmol) followed by 4,4,5,5,4',4',5',5'-Octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (1.9 g, 7.5 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II)bis methylene chloride (0.47 g, 10% mol). The reaction was heated to 80 C. for 16 hrs then poured into water and extracted with ethyl acetate. The organic layer was separated and brined then dried over magnesium Examples 121-125 were made according to the procedure given in scheme 1 (Example 19) using 2-fluoro-4-trifluoromethyl nitrobenzene and the appropriate boronic acid or pinnacle boronate (method B, intermediate 14A).
	With potassium acetate;{1,1-bis(diphenylphosphino)ferrocene} palladium (II)-bis-dichloromethane; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere of argon;	3-Bromo-2-picoline (1 g, 5.8 mmol) was dissolved in dry DMF (20 mL). To this was added potassium acetate (2 g, 3.5 eq), followed by bis(pinacolato)diboron (1.9 g, 1.3 eq). Argon was bubbled through the reaction vessel for 1 min and {1,1-bis(diphenylphosphino)ferrocene} palladium (II)-2CH2Cl2 (0.47 g, 10 mole %) was added. The reaction was sealed and heated to 80 C. for 16 h, then cooled to room temperature and poured into water. The aqueous solution was extracted with ethyl acetate and the organic layer separated, washed with brine, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel in ethyl acetate. 0.2 g of greenish oil was recovered; MS (ESI) 220.1 [M+1]+; 1H NMR (400 MHz, d6-DMSO) delta ppm 8.45 (m, 1H), 7.88 (m, 1H), 7.14 (m, 1H), 2.57 (s, 3H), 1.26 (s, 12H).

Reference： [1]Patent: US2009/143361,2009,A1 .Location in patent: Page/Page column 52
[2]Patent: US2009/143367,2009,A1 .Location in patent: Page/Page column 37
[3]Patent: US2010/120763,2010,A1 .Location in patent: Page/Page column 47
[4]European Journal of Organic Chemistry,2012,p. 595 - 603

4
[ 1012084-56-8 ]
[ 1259438-59-9 ]
[ 1259512-25-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water;Reflux;	To a stirred solution of 2,4-dichloro-7-fluoro-3-methylquinoline (400 mg, 1.74 mmol) in 1,4-dioxane: water (5 mL:l mL) was added PdCl2(PPhS)2 (122 mg, 0.17 mmol), sodium carbonate (553 mg, 5.22 mmol) and 2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The reaction was heated at reflux overnight. After this time the reaction was diluted with EtOAc (100 mL) and water (50 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (hexane:EtOAc, 1 :0 to 1 :1) gave 4- chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline.

Reference： [1]Patent: WO2010/151737,2010,A2 .Location in patent: Page/Page column 70-71

5
[ 108-86-1 ]
[ 1012084-56-8 ]
[ 3256-89-1 ]

Reference： [1]European Journal of Organic Chemistry,2012,p. 595 - 603

6
[ 1012084-56-8 ]
[ 1362850-84-7 ]
[ 343338-28-3 ]
[ 1362850-88-1 ]

Yield	Reaction Conditions	Operation in experiment
73%		INTERMEDIATE 13 2-Methylpropane-2(6 -sulfinic acid N-[8-chloro-2-(2-methylpyridin-3-yl)quinolin-3-yll- meth-(E)-ylideneamideA mixture of Intermediate 9 (5.0 g, 15.2 mmol), <strong>[1012084-56-8]2-methylpyridin-3-ylboronic acid pinacol ester</strong> (5 g, 22.43 mmol), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.17 mmol) and 2M aqueous sodium bicarbonate solution (20 mL) in 1,4-dioxane (80 mL) was degassed and heated under refluxed in a nitrogen atmosphere for 3 h. The reaction mixture was cooled to room temperature, partitioned between EtOAc and brine, and the aqueous layer was extracted once more using EtOAc. The combined organic extracts were dried (MgS04) and the solvent was removed under reduced pressure. To a solution of the resulting material in 2-propanol (10 mL) was added a solution prepared by stirring potassium phosphate (2.8 g, 13.21 mmol) and (5)-2-methyl-2-propanesulfinamide (1.85 g, 15.3 mmol) in water (10 mL) for 15 minutes. The reaction mixture was stirred for 1 h. Ice-water was added and the resulting material was extracted using DCM. The organic extract was dried (MgS04) and the solvent was removed in in vacuo. Columnchromatography (Si02, 50-60% EtOAc in hexane) gave the title compound (4.3 g, 73%) as pale yellow foam. deltaEta (CDC13) 8.91 (s, IH), 8.66 (dd, J5.0, 1.7 Hz, IH), 8.55 (s, IH), 7.97 (m, 2H), 7.67 (dd, J 7.7, 1.6 Hz, IH), 7.60 (m, IH), 7.33 (dd, J 7.6, 5.0 Hz, IH), 2.30 (s, 3H), 1.24 (s, 9H). LCMS (ES+) 386 (M+H)+, RT 1.49 minutes.

Reference： [1]Patent: WO2012/32334,2012,A1 .Location in patent: Page/Page column 29-30

7
[ 1012084-56-8 ]
[ 1167542-21-3 ]
[ 1362851-16-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 24h;Inert atmosphere;	INTERMEDIATE 417-Fluoro-8-methyl-2-(2-methylpyridin-3-yl)quinoline-3-carbaldehydeA mixture of 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (8.0 g, 35.77 mmol), <strong>[1012084-56-8]2-methylpyridin-3-ylboronic acid pinacol ester</strong> (9.58 g, 39.35 mmol), tetrakis- (triphenylphosphine)palladium(O) (207 mg, 18mmol) and Na2C03 (5.69 g, 53.66 mmol) in water (50 mL) and DME (100 mL) was degassed and flushed three times with nitrogen gas, then heated at 90C for 24 h. The mixture was allowed to cool to room temperature. The reaction mixture was diluted with DCM (150 mL) and washed with water (150 mL). The aqueous phase was extracted with DCM (2 x 100 mL) and the combined organic fractions were washed with brine (150 mL), then dried (phase separator) and evaporated in vacuo. The crude material was triturated in hexane (50 mL), then the solid was filtered off and dried under vacuum to give the title compound (9.07 g, 90%) as a pale yellow solid. deltaEta (DMSO-de) 9.94 (s, IH), 9.09 (IH, s), 8.61 (dd, J4.9, 1.7 Hz, IH), 8.26 (dd, J 8.9, 6.4 Hz, IH), 7.78 (dd, J 7.7, 1.7 Hz, IH), 7.69 (t, J 9.2 Hz, IH), 7.40 (dd, J 7.7, 4.9 Hz, IH), 2.61 (d, J2.4 Hz, 3H), 2.34 (s, 3H). LCMS (ES+) 281 (M+H)+, RT 2.26 minutes.

Reference： [1]Patent: WO2012/32334,2012,A1 .Location in patent: Page/Page column 42-43

8
[ 3435-24-3 ]
[ 1012084-56-8 ]
[ 1425657-15-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With tetrakis(triphenylphosphine) palladium(0); potassium acetate; sodium carbonate; In acetonitrile; at 100℃; for 1h;Inert atmosphere; Microwave irradiation;	Step 3: Synthesis of 4-(2-Methylpyridin-3-yl)-6-tert-butylpyrimidine (abbreviation: HtBumpypm)[0712]Next, in a 100 mL round-bottom flask were put 2.0 g of 4-chloro-6-tert-butylpyrimidine obtained in Step 2, 3.0 g of <strong>[1012084-56-8]2-methylpyridine-3-boronic acid pinacol ester</strong>, 17 mL of 1M potassium acetate solution, 17 mL of 1M sodium carbonate solution, and 40 mL of acetonitrile, and the air in the flask was replaced with argon. To this mixture was added 0.78 g of tetrakis(triphenylphosphine)palladium(0), and the mixture was irradiated with microwaves under conditions of 100 C. and 100 W for 1 hour to cause a reaction. This reaction mixture was extracted with ethyl acetate, and washing with saturated saline was performed. Anhydrous magnesium sulfate was added to the obtained solution of the extract for drying, and the resulting mixture was gravity-filtered to give a filtrate. The resulting filtrate was dissolved in a mixed solvent of ethyl acetate and hexane, and the mixture was filtered through Celite, alumina, and Celite. The resulting filtrate was purified by silica gel column chromatography. As a developing solvent, a mixed solvent of hexane and ethyl acetate in a ratio of 3:2 (v/v) was used. The resulting fraction was concentrated to give an oily substance. This oily substance was dissolved in a mixed solvent of hexane and ethyl acetate, and the solution was filtered through a filter aid in which Celite, alumina, and Celite were stacked in this order. The resulting filtrate was concentrated to give 4-(2-methylpyridin-3-yl)-6-tert-butylpyrimidine (abbreviation: HtBumpypm) (light-yellow oily substance, yield of 92%). A synthesis scheme of Step 3 is shown in (P-3).
92%	With tetrakis(triphenylphosphine) palladium(0); potassium acetate; sodium carbonate; In water; acetonitrile; at 100℃; for 1h;Inert atmosphere; Microwave irradiation;	Next, 2.0 g of 4-chloro-6-tert-butylpyrimidine obtained in Step 2, 3.0 g of <strong>[1012084-56-8]2-methylpyridine-3-boronic acid pinacol ester</strong>, 17 mL of 1M aqueous solution of potassium acetate, 17 mL of 1M aqueous solution of sodium carbonate, and 40 mL of acetonitrile were put in a 100 mL round-bottom flask, and the air in the flask was replaced with argon. To this mixture, 0.78 g of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was irradiated with microwaves under conditions of 100 C. and 100 W for 1 hour to cause a reaction. This reaction mixture was extracted with ethyl acetate, and washing with saturated brine was performed. Anhydrous magnesium sulfate was added to the obtained solution of the extract for drying, and the resulting mixture was gravity-filtered to give a filtrate. The resulting filtrate was dissolved in a mixed solvent of ethyl acetate and hexane, and the mixture was filtered through Celite, alumina, and Celite. The resulting filtrate was purified by silica gel column chromatography. As a developing solvent, a mixed solvent of hexane and ethyl acetate in a ratio of 3:2 (v/v) was used. The obtained fractions were condensed to give an oily substance. This oily substance was dissolved in a mixed solvent of hexane and ethyl acetate, and the solution was filtered through a filter aid in which Celite, alumina, and Celite were stacked in this order. The resulting filtrate was condensed to give 4-(2-methylpyridin-3-yl)-6-tert-butylpyrimidine (abbreviation: HtBumpypm) (light-yellow oily substance, yield of 92%). A synthetic scheme of Step 3 is shown in (a-3) below.

Reference： [1]Patent: US2013/48964,2013,A1 .Location in patent: Paragraph 0712; 0719
[2]Patent: US8889858,2014,B2 .Location in patent: Page/Page column 41

9
[ 1012084-56-8 ]
(6-bromopyridin-3-yl)acetic acid methyl ester [ No CAS ]
[ 1428761-13-0 ]

Yield	Reaction Conditions	Operation in experiment
76%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In tetrahydrofuran; water; toluene; at 80℃; for 3h;Inert atmosphere;	To a mixture of (6-bromo-pyridin-3-yl)-acetic acid methyl ester 142 (500 mg 2.17 mmol), 2-Methyl-3-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-pyridine (570 mg, 2.60 mmol) and Cs2C03 (2.12 g, 6.51 mmol) in Toluene/THF/water(v:v:v=2:2: l , 10 mL) was added Pd(dppf)Cl2 (100 mg) under N2. The mixture was stirred at 80 C for 3 hr, then cooled to r.t. and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc (3x20 mL). The organic layer was dried over Na2SC>4, filtered and concentrated to afford the crude product, which was purified by column chromatography with silica gel (PE/EtOAc =10: 1?5: 1?2: 1) to afford the desired compound 143 (306 mg, 76%). LCMS: m/z 243 (M+l)+.

Reference： [1]Patent: WO2013/43232,2013,A2 .Location in patent: Paragraph 00629

10
[ 1012084-56-8 ]
[ 313405-50-4 ]
[ 1448015-76-6 ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 847 - 857

11
[ 1012084-56-8 ]
[ 1310049-89-8 ]
[ 76-05-1 ]
[ 1448015-73-3 ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 847 - 857

12
[ 1012084-56-8 ]
8-bromo-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one [ No CAS ]
4-methyl-8-(2-methyl-pyridin-3-yl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Under inert atmosphere, a mixture of halide F, D, K or P (1.0 equiv.), boronic acid derivative R1-M G or J (1.5 equiv.), PdCI2(dppf)2 (0.1 equiv.) and aqueous Na2CO3 (1.2 M - 3.0 equiv.) in DMF (C=0.15 molL-1) was submitted to microwave irradiation (150C, 15 min, P< 70W). After cooling, the reaction mixture was centrifuged, the surnatant was removed and the remaining deposit was washed three times with DMSO (3 ml of DMSO each time). Upon addition of 15 ml of water, an unfilterable precipitate was obtained. The precipitate was extracted in AcOEt three times. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified by flash chromatography to afford the product.. To a solution or suspension of the free base in MeOH, HCl in MeOH (1.25N, 5 equiv.) was added. The mixture was vigorously stirred, then concentrated. The residue was taken in Et2O. The resulting solid was collected, washed with Et2O and dried at 50C under reduced pressure with P2O5.

Reference： [1]Patent: WO2013/174822,2013,A1 .Location in patent: Page/Page column 73; 74; 149; 150

13
[ 1012084-56-8 ]
(2S,4R)-4-(4-bromo-2-chlorobenzenesulfonyl)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]
(2S,4R)-4-[2-chloro-4-(2-methylpyridin-3-yl)benzenesulfonyl]-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With palladium diacetate; sodium carbonate; triphenylphosphine; In 1,2-dimethoxyethane; water; at 22 - 60℃; for 54h;	Example 35a) (700 mg, 1.31 mmol, Eq: 1.00) was dissolved in 1,2-dimethoxyethane (8ml). 2-Methyl-3- (4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridine (345 mg, 1.58mmol, Eq: 1.20), triphenylphosphine (68.9 mg, 263 tmol, Eq: 0.20), 2 M aqueous Na2CO3 solution (2 ml) and palladium (II) acetate (29.5 mg, 131 tmol, Eq: 0.10) were added and stilTed at 22 C for 24 h. After that, the reaction mixture was stilTed at 50 C for 24 h. Then, 2-methyl-3-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridine (57.6 mg, 263tmol, Eq: 0.2) was added to the reaction mixture which was then stiffred at 60 C for 6 h. The reaction mixture was poured into 0.1 M aqueous HC1 solution (50 ml) and extracted with DCM (3 x 20 ml).The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% EtOAc in heptane) to yield the title compound as a light yellow oil (200 mg; 28%).mlz = 545.3 [M+H].

Reference： [1]Patent: WO2014/29722,2014,A1 .Location in patent: Page/Page column 45

14
[ 1012084-56-8 ]
[ 1620294-98-5 ]
[ 1620294-40-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Sealed tube; Inert atmosphere;	In a sealed tube, a degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-i of example-23) (0.200 g, 0.519 mmol) in i,4-dioxane: water (9:1) (i0 mL) was added 2-methyl-3-(4,4,5,5- tetramethyl-i,3,2-dioxaborolan-2-yl)pidine (0.i25 g, 0.571 mmol), followed bypotassium carbonate (0.i08 g, 0.780 mmol) and i,i?-Bis(diphenylphosphino)ferrocenepalladium(II)dichloride dichloromethane complex (0.042 g, 0.0520 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 16 h at 90 C. The reaction mixture was diluted with water (i0 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried oversodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 96/4) to give titled compound (0.195g, 94%) as a solid. LCMS: m/z 398.2 [M+ H] .

Reference： [1]Patent: WO2014/111871,2014,A1 .Location in patent: Page/Page column 197; 198

15
[ 1012084-56-8 ]
[ 1620294-98-5 ]
[ 1620294-42-9 ]

Reference： [1]Patent: WO2014/111871,2014,A1

16
[ 1012084-56-8 ]
4,6-bis(2-methylpyridin-3-yl)pyrimidine [ No CAS ]

Reference： [1]Patent: US8889858,2014,B2

17
[ 1193-21-1 ]
[ 1012084-56-8 ]
4-chloro-6-(2-methylpyridin-3-yl)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With tetrakis(triphenylphosphine) palladium(0); potassium acetate; sodium carbonate; In water; acetonitrile; at 70℃; for 2h;Inert atmosphere; Microwave irradiation;	First, 3.01 g of 4,6-dichloropyrimidine, 10.9 g of <strong>[1012084-56-8]2-methylpyridine-3-boronic acid pinacol ester</strong>, 60 mL of 1M aqueous solution of potassium acetate, 60 mL of 1M aqueous solution of sodium carbonate, and 60 mL of acetonitrile were put in a 300 mL three-neck flask, and the air in the flask was replaced with argon. To this mixture, 1.40 g of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was irradiated with microwaves under conditions of 70 C. and 400 W and for 2 hours to cause a reaction. This reaction mixture was extracted with ethyl acetate, and washing with saturated brine was performed. Anhydrous magnesium sulfate was added to the obtained solution of the extract for drying, and the resulting mixture was gravity-filtered to give a filtrate. A residue obtained by condensing the filtrate was purified by flash column chromatography using ethyl acetate as a developing solvent. A solid obtained by condensing the fraction was purified by flash column chromatography using hexane and ethyl acetate in a ratio of 1:1 as a developing solvent, so that 4-chloro-6-(2-methylpyridin-3-yl)pyrimidine was obtained (a yellow white solid, yield of 24%). A synthetic scheme of Step 1 is shown in (c-1) below.

Reference： [1]Patent: US8889858,2014,B2 .Location in patent: Page/Page column 49

18
[ 1012084-56-8 ]
4-chloro-6-(2-methylpyridin-3-yl)pyrimidine [ No CAS ]
4,6-bis(2-methylpyridin-3-yl)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With tetrakis(triphenylphosphine) palladium(0); potassium acetate; sodium carbonate; In water; acetonitrile; for 1h;Inert atmosphere; Microwave irradiation;	Next, 0.99 g of 4-chloro-6-(2-methylpyridin-3-yl)pyrimidine obtained in the above Step 1, 1.34 g of <strong>[1012084-56-8]2-methylpyridine-3-boronic acid pinacol ester</strong>, 7.2 mL of 1M aqueous solution of potassium acetate, 7.2 mL of 1M aqueous solution of sodium carbonate, and 15 mL of acetonitrile were put in a 100 mL round-bottom flask, and the air in the flask was replaced with argon. To this mixture, 0.33 g of tetrakis(triphenylphosphine)palladium(0) was added, and the reaction container was heated by being irradiated with microwaves (2.45 GHz, 100 W) for 60 minutes. This reaction mixture was extracted with ethyl acetate, and washing with saturated brine was performed. Anhydrous magnesium sulfate was added to the obtained solution of the extract for drying, and the resulting mixture was gravity-filtered to give a filtrate. A residue obtained by condensing the filtrate was purified by flash column chromatography using ethyl acetate and methanol in a ratio of 4:1 as a developing solvent, so that 4,6-bis(2-methylpyridin-3-yl)pyrimidine (abbreviation: Hdmpypm) was obtained (a yellow solid, yield of 93%). A synthetic scheme of Step 2 is shown in (c-2) below.

Reference： [1]Patent: US8889858,2014,B2 .Location in patent: Page/Page column 50

19
[ 1012084-56-8 ]
4-chloro-6-(2,5-dimethylphenyl)pyrimidine [ No CAS ]
4-(2,5-dimethylphenyl)-6-(2-methylpyridin-3-yl)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With tetrakis(triphenylphosphine) palladium(0); potassium acetate; sodium carbonate; In water; acetonitrile; for 1h;Inert atmosphere; Microwave irradiation;	Next, 1.98 g of 4-chloro-6-(2,5-dimethylphenyl)pyrimidine obtained in the above Step 1, 2.41 g of <strong>[1012084-56-8]2-methylpyridine-3-boronic acid pinacol ester</strong>, 14 mL of 1M aqueous solution of potassium acetate, 14 mL of 1M aqueous solution of sodium carbonate, and 30 mL of acetonitrile were put in a 100 mL round-bottom flask, and the air in the flask was replaced with argon. Then, 0.63 g of tetrakis(triphenylphosphine)palladium(0) was added to this mixture, and the reaction container was heated by being irradiated with microwaves (2.45 GHz, 100 W) for 60 minutes. This reaction mixture was extracted with ethyl acetate, and washing with saturated brine was performed. Anhydrous magnesium sulfate was added to the obtained solution of the extract for drying, and the resulting mixture was gravity-filtered to give a filtrate. The residue obtained by condensing the filtrate was purified by flash column chromatography using hexane and ethyl acetate in a ratio of 1:1 as a developing solvent. The fraction was condensed and the obtained oily substance was dissolved in dichloromethane. Then, filtration was performed through a filter aid in which Celite, alumina, and Celite were stacked in this order, so that the target pyrimidine derivative Hdmpmpypm (abbreviation) was obtained (orange oily substance, a yield of 87%). A synthetic scheme of Step 2 is shown in (d-2) below.

Reference： [1]Patent: US8889858,2014,B2 .Location in patent: Page/Page column 66

20
[ 1012084-56-8 ]
[ 1350607-38-3 ]
[ 1350604-60-2 ]

Yield	Reaction Conditions	Operation in experiment
60%		General procedure: A glass microwave vesselwas chargedwith compound 60 (40 mg,0.128mmol), 4-(hydroxymethyl)phenylboronic acid (29 mg,0.192mmol), sodium carbonate (41 mg, 0.384 mmol), and dioxane/water (1.0mL:0.18 mL). The solution was purged with nitrogen for5 min, then Pd(PPh3)4 (15mg, 0.013 mmol) was added. The reactionmixture was stirred and heated at 120 C for 64 h. The reactionmixturewas filtered and washed with EtOAc/MeOH. The was concentratedand purified by reverse phase HPLC to give 21 mg (43%) ofthe title compound as an amorphous solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 6570 - 6585

21
[ 1012084-56-8 ]
4-chloro-2-(pyridin-2-ylmethoxy)-5,6,7,8-tetrahydroquinoline [ No CAS ]
4-(2-methylpyridin-3-yl)-2-(pyridin-2-ylmethoxy)-5,6,7,8-tetrahydroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4,5-bis-(di-tert-butyl-phosphanyl)-9,9-dimethyl-9H-xanthene; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 5h;Inert atmosphere;	Example 100 4-(2-Methylpyridin-3-yl)-2-(pyridin-2-ylmethoxy)-5, 6,7,8-tetrahydroquinoline hydrochloride To 4-chloro-2-(pyridin-2-ylmethoxy)-5,6,7,8-tetrahydro quinoline, <strong>[1012084-56-8]2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> Pd2(dba)3·CHCl3 (19 mg), t-Bu-X-Phos (19 mg) and potassium carbonate (76 mg) was added 1,4-dioxane/water (3/1, 1.8 mL), and the mixture was degassed, then stirred under Ar atmosphere at 80C for 5 hours. After the reaction mixture was allowed to return to room temperature, diluted with ethyl acetate, dried over anhydrous sodium sulfate, filtered through Celite, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-(2-methylpyridin-3-yl)-2-(pyridin-2-ylmethoxy)-5, 6,7,8-tetrahydroquinoline.The resulting compound was dissolved in ethyl acetate, followed by the addition of 1N HCl/Et2Osolution (0.03 mL), and the mixture was stirred at room temperature overnight. The resulting precipitate was collectedby filtration to give the title compound as a white powder.[MS (ESI) m/z 332.3 (M+H)+]

Reference： [1]Patent: EP2891656,2015,A1 .Location in patent: Paragraph 0244

22
[ 1012084-56-8 ]
[ 460081-18-9 ]
ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.8%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 95℃;Inert atmosphere;	General procedure: Step 1: Preparation of ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate Using the same reaction conditions as described in step 7 of example 1, 2-methyl-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (lg, 7.09 mmol) was coupled with ethyl 2- chlorooxazole-4-carboxylate (1.86g, 0.851 mmol) using sodium carbonate (2.25g, 21.2 mmol) and Pd(dppf)Cl2 (289mg, 0.332 mmol) in 1 ,2-dimethoxyethane/water (30/6mL) to get the crude product. The resultant crude was purified by 60-120 silica gel column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (lg, 59.8%).
59.8%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; tricyclohexylphosphine; In 1,2-dimethoxyethane; water; at 90℃; for 12h;Sealed tube; Inert atmosphere;	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 same reaction conditions as described in step 1 of example 6, 2-methyl-3- (4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridine (1 g, 7.O9mmol) was coupled with ethyl 2- chlorooxazole-4-carboxylate (1.86g, 0.85 immol) using sodium carbonate (2.25g, 21.2mmol) and Pd(dppf)C12 (289mg, 0.332mmo1) in 1,2-dimethoxyethane/water (30I6mL) to get the crudeproduct. The obtained crude was purified by 60-120 silica gel column chromatography using20% ethyl acetate in hexane as eluent to obtain the title compound (ig, 59.8%).
59.8%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; 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 ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate Using the same reaction conditions as described in step 1 of example 6, <strong>[1012084-56-8]2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (1 g, 7.09 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (1.86 g, 0.851 mmol) using sodium carbonate (2.25 g, 21.2 mmol) and Pd(dppf)Cl2 (289 mg, 0.332 mmol) in 1,2-dimethoxyethane/water (30/6 mL) to get the crude product. The obtained crude was purified by 60-120 silica gel column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (1 g, 59.8%).

59.8%

With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 95℃;Sealed tube; Inert atmosphere;

Using the same reaction conditions as described in step 7 of example 1, 2-methyl-3-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridine (1 g, 7.09 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (1.86 g, 0.851 mmol) using sodium carbonate (2.25 g, 21.2 mmol) and Pd(dppf)C12 (289 mg, 0.332 mmol) in 1,2-dimethoxyethane/ water (3 0/6 mE) to get the crude product. The resultant crude was purified by 60-120 silica gel column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (1 g, 59.8%). 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%).

Reference： [1]Patent: WO2015/104688,2015,A1 .Location in patent: Page/Page column 28
[2]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 26; 27; 46
[3]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0147; 0251; 0252
[4]Patent: US2016/340366,2016,A1 .Location in patent: Paragraph 0158; 0216

23
[ 1012084-56-8 ]
2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid [ No CAS ]

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

24
[ 1012084-56-8 ]
tert-butyl 4-((5-Bromo-3-methyl-2-oxo-1,2-dihydro-1,7-naphthyridin-8-yl)amino)piperidine-1-carboxylate [ No CAS ]
tert-butyl 4-((3-methyl-5-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,7-naphthyridin-8-yl)amino)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5649 - 5673

25
[ 1012084-56-8 ]
8-bromo-N-((5-fluorobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine [ No CAS ]
N-((5-fluorobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 90℃; for 1h;Inert atmosphere;	Example 207 N-((5-Fluorobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (0542) (0543) To a solution of 8-bromo-N-((5-fluorobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (C1) (50 mg, 0.14 mmol) in dioxane (2 ml) was added <strong>[1012084-56-8]2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (45 mg, 0.21 mmol), Pd(dppf)Cl2 (23 mg, 0.028 mmol), NaHCO3 (35 mg, 0.42 mmol) and water (1 mL). The reaction mixture was purged with N2 for 3 times, then stirred at 90 C. for 1 h. The mixture was filtered, the solid was washed with DMSO (2 mL). The filtrate was concentrated and purified by prep-HPLC (NH4HCO3) to give the title compound (13 mg, 48%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) delta ppm 2.40 (s, 3H), 5.01 (s, 2H), 7.21-7.25 (m, 2H), 7.31 (dd, 1H), 7.62 (dd, 1H), 7.66 (s, 1H), 7.75 (d, 1H), 8.08 (d, 1H), 8.50 (t, 1H), 8.86 (s, 1H), 9.46 (s, 1H). LC-MS: [M+H]+=375.1.

Reference： [1]Patent: US2016/176882,2016,A1 .Location in patent: Paragraph 0542; 0543

26
[ 1012084-56-8 ]
C₁₃H₁₂BrN₃O₂ [ No CAS ]
5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 95℃; for 16h;Inert atmosphere;	To a solution of 14 (100 mg, 0.31 mmol) in 1 ,4-dioxane (3 mE) and water (0.5 mE) was added 2-methyl-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridine (88 mg, 0.40 mmol), sodium carbonate (66 mg, 0.62 mmol) and tetrakis(triphenylphosphine)palladium (0) (18 mg, 0.016 mmol). The reaction mixture was purged with nitrogen and then heated at 95 C. for 16 h. The mixture was diluted with methylene chloride (50 mE) and washed with brine (2x 10 mE). The organic layerwas dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-5% methanol/methylene chloride) afforded Example Compound 4 (55 mg, 53%) as a white solid: ?H NMR (300 MHz, DMSOd5) oe 11.17 (s, 1H), 8.54 (dd, J=5.0, 1.7 Hz, 1H), 7.74 (dd, J=7.6, 1.8 Hz, 1H), 7.36-7.29 (m, 1H), 7.00 (d, J=1.8 Hz, 1H), 6.78 (d, J=1 .5Hz, 1H), 2.70 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H); ESI mlz 335 [M+H].
53%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 95℃; for 16h;Inert atmosphere;	General procedure: To a solution 14 (100mg, 0.31mmol) in 1,4-dioxane (3mL) and water(0.5mL) was added <strong>[1012084-56-8]2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (88mg, 0.40mmol), sodium carbonate(66mg, 0.62mmol) and tetrakis(triphenylphosphine)palladium)(18mg, 0.016mmol). The reaction mixture was purged with nitrogen, and thenIt was heated at 95 16h. The mixture was diluted andwashed with brine (2 × 10mL) with dichloromethane(50mL). The organic layer was sulfuric acidSodium sulfate, filtered and concentrated. By chromatography (silica gel,0-5% methanol / dichloromethane) to give a white solid of ExampleCompound 4 (55mg, 53%)

Reference： [1]Patent: US2016/145248,2016,A1 .Location in patent: Paragraph 0287; 0293
[2]Patent: CN105473581,2016,A .Location in patent: Paragraph 0319; 0320; 0326; 0375; 0377

27
[ 1012084-56-8 ]
8-bromo-N-[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine [ No CAS ]
N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere;	(0523) Alternatively, Example 2 was prepared as follows. To a suspension of A1 (25.5 g, 70 mmol), <strong>[1012084-56-8]2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (30.6 g, 140 mmol) and NaHCO3 (35.3 g, 420 mmol) in a mixture solution of 1,4-dioxane (300 mL) and H2O (100 mL) was added PdCl2(dppf) (5.94 g, 612 mmol). The mixture was degassed with N2, heated at 110 C. for 1 h. The resulting mixture was cooled to rt and concentrated under reduced pressure. The residue was purified over column chromatography (EtOAc: MeOH=20:1) to give 14 g of the desired product. 200 mL of acetone was added to the product, and the resulting suspension was heated at 50 C. for 2 h. The white solid was collected by filtration and dried under vacuum to give Example 2 (13.6 g, 52%)1H-NMR (500 MHz, DMSO-d6) delta ppm 2.40 (s, 3H), 3.33 (t, 2H), 4.56 (t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H), 6.96 (dd, 1H), 7.31 (dd, 1H), 7.66 (s, 1H), 7.74 (d, 1H), 8.51 (d, 1H), 8.72 (t, 1H), 9.49 (s, 1H). LC-MS: [M+H]+=376.9.
52%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 110℃; for 1h;	N- ( (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methyl) -8- (2-methylpyridin-3-yl) - [1, 2, 4] triazolo [4, 3-c] pyrimidin-5-amine was prepared as follows. To a suspension of A1 (25.5 g, 70 mmol) , 2-methyl-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (30.6 g, 140 mmol) and NaHCO3(35.3 g, 420 mmol) in a mixture solution of 1, 4-dioxane (300 mL) and H2O (100 mL) was added PdCl2(dppf) (5.94 g, 612 mmol) . The mixture was degassed with N2,heated at 110 for 1 h. The resulting mixture was cooled to rt and conentrated under reduced pressure. The residue was purified over column chromatography (EtOAc: MeOH 20: 1) to give 14 g of the desired product. 200 mL of acetone was added to the product, and the resulting suspension was heated at 50 for 2 h. The white solid was collected by filtration and dried under vacuum to give N- ( (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methyl) -8- (2-methylpyridin-3-yl) - [1, 2, 4] triazolo [4, 3-c]pyrimidin-5-amine (13.6 g, 52)1H-NMR (500 MHz, DMSO-d6) delta ppm 2.40 (s, 3H) , 3.33 (t, 2H) , 4.56 (t, 2H) , 4.72 (s, 2H) , 6.72 (dd, 1H) , 6.96 (dd, 1H) , 7.31 (dd, 1H) , 7.66 (s, 1H) , 7.74 (d, 1H) , 8.51 (d, 1H) , 8.72 (t, 1H) , 9.49 (s, 1H) . LC-MS: [M+H]+ 376.9.

Reference： [1]Patent: US2016/176882,2016,A1 .Location in patent: Paragraph 0521; 0523
[2]Patent: WO2017/219948,2017,A1 .Location in patent: Paragraph 00163

28
[ 1012084-56-8 ]
5-[3-[(3S)-4-(3-bromophenyl)-3-methylpiperazin-1-yl]-3-oxopropyl]-5-cyclopropylimidazolidine-2,4-dione [ No CAS ]
5-cyclopropyl-5-[3-[(3S)-3-methyl-4-[3-(2-methyl-3-pyridyl)phenyl]piperazin-1-yl]-3-oxopropyl]imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; Sealed tube;	A vial is loaded with bromo derivative (1 eq.), boronic acid or boronic ester (1.3 to 2 eq.), Na2C03 (3 eq.) and a mixture dioxane/water (9/1) degassed with N2. PdCl2(dppf) (0.05 to 0.2 eq.) is added, the vial is sealed and stirred at 90C for 3h to 20h. The reaction mixture is quenched with water and extracted with EtOAc. The combined organic layers are washed with brine, dried (filtration over hydrophobic column or anhydrous MgS04), concentrated in vacuo and purified by flash chromatography on silica gel or preparative HPLC to afford the expected compound.

Reference： [1]Patent: WO2016/102347,2016,A1 .Location in patent: Paragraph 0388

29
[ 66533-31-1 ]
[ 1012084-56-8 ]
2′,4,5-trimethyl-2,3′-bipyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.8%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; for 72h;Inert atmosphere; Reflux;	2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.178 g, 5.37 mmol), 2-bromo-4,5-dimethylpyridine (1 g, 5.37 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.249 g, 0.215 mmol) were charged into a reaction vessel with 75 mL of toluene. Potassium carbonate (2.225 g, 16.12 mmol) was dissolved in 15 mL of water and was charged into the reaction vessel. The reaction mixture was degassed with nitrogen then was heated at reflux. The reaction mixture was heated at reflux for 3 days. The reaction mixture was then diluted with 100 mL ethyl acetate and 50 mL of water. The organic layer was separated and dried over magnesium sulfate. The organics were then filtered and concentrated under vacuum. The crude product was purified using silica gel chromatography using 1-5% methanol/DCM as the eluant. 2?,4,5-trimethyl-2,3?-bipyridine (0.35 g, 1.765 mmol, 32.8% yield) was isolated as a tan solid.

Reference： [1]Patent: KR2015/83017,2015,A .Location in patent: Paragraph 0207; 0208

30
[ 1012084-56-8 ]
1-(3-iodophenyl)-4-(4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl)pyrrolidin-2-one [ No CAS ]
1-(3-(2-methylpyridin-3-yl)phenyl)-4-(4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl)pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.7 mg	With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); caesium carbonate; In water; toluene; at 100℃; for 0.25h;Microwave irradiation;	Example 139 1-(3-(2-Methylpyridin-3-yl)phenyl)-4-(4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl)pyrrolidin-2-one A mixture of 1-(3-iodophenyl)-4-(4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl)pyrrolidin-2-one (50 mg), <strong>[1012084-56-8]2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (34.1 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.34 mg), cesium carbonate (67.6 mg) and toluene (3 mL)/water (1 mL) was heated at 100 C. for 15 min under microwave irradiation. The organic layer was separated, purified by column chromatography (NH silica gel, methanol/ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound (32.7 mg). 1H NMR (300 MHz, CDCl3) delta 2.52 (3H, s), 2.57-2.72 (5H, m), 2.74-2.85 (1H, m), 3.29 (1H, t, J=7.2 Hz), 3.77-4.04 (4H, m), 4.36-4.61 (2H, m), 7.08-7.15 (1H, m), 7.19 (1H, dd, J=7.7, 4.9 Hz), 7.45 (1H, t, J=7.9 Hz), 7.50-7.55 (2H, m), 7.57-7.65 (2H, m), 7.88 (1H, d, J=3.2 Hz), 8.51 (1H, dd, J=4.8, 1.8 Hz).

Reference： [1]Patent: US2016/318864,2016,A1 .Location in patent: Paragraph 1617; 1618

31
[ 1012084-56-8 ]
3-fluoro-5-(2-methylpyridin-3-yl)aniline [ No CAS ]

Reference： [1]Patent: US2016/318864,2016,A1

32
[ 1012084-56-8 ]
(3R)-N-(3-fluoro-5-(2-methylpyridin-3-yl)phenyl)-4-hydroxy-3-(4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl)butanamide [ No CAS ]

Reference： [1]Patent: US2016/318864,2016,A1

33
[ 1012084-56-8 ]
(4R)-1-(3-fluoro-5-(2-methylpyridin-3-yl)phenyl)-4-(4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl)pyrrolidin-2-one [ No CAS ]

Reference： [1]Patent: US2016/318864,2016,A1

34
[ 1012084-56-8 ]
1-(3-iodophenyl)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-one [ No CAS ]
1-(3-(2-methylpyridin-3-yl)phenyl)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.3 mg	With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); caesium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 1h;Inert atmosphere;	To a solution of 1-(3-iodophenyl)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-one (50 mg), <strong>[1012084-56-8]2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (48.8 mg) and cesium carbonate (72.5 mg) in DMF (1 mL) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.49 mg) and water (0.1 mL) at ambient temperature. The mixture was stirred at 80 C. under nitrogen atmosphere for 1 hr. The reaction mixture was diluted with ethyl acetate, quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine successively, dried over sodium sulfate and concentrated in vacuo. The residue was triturated with 2-propyl acetate/diisopropyl ether to give the title compound (34.3 mg). 1H NMR (300 MHz, CDCl3) delta 2.52 (3H, s), 2.54-2.62 (4H, m), 2.64-2.75 (1H, m), 2.76-2.86 (1H, m), 3.20-3.33 (1H, m), 3.84-3.92 (5H, m), 3.94-4.03 (1H, m), 6.51 (1H, t, J=4.7 Hz), 7.09-7.15 (1H, m), 7.19 (1H, dd, J=7.5, 4.9 Hz), 7.45 (1H, t, J=7.9 Hz), 7.53 (1H, dd, J=7.6, 1.8 Hz), 7.57-7.65 (2H, m), 8.31 (2H, d, J=4.7 Hz), 8.51 (1H, dd, J=4.9, 1.7 Hz).

Reference： [1]Patent: US2016/318864,2016,A1 .Location in patent: Paragraph 1673; 1674

35
[ 1012084-56-8 ]
1-(3-bromo-5-fluorophenyl)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-one [ No CAS ]
1-(3-fluoro-5-(2-methylpyridin-3-yl)phenyl)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28 mg	With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); caesium carbonate; In water; toluene; at 100℃; for 0.25h;Microwave irradiation;	Example 406 1-(3-Fluoro-5-(2-methylpyridin-3-yl)phenyl)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-one A mixture of 1-(3-bromo-5-fluorophenyl)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-one (35 mg), <strong>[1012084-56-8]2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (27.4 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.90 mg), cesium carbonate (54.3 mg) and toluene (1 mL)/water (0.333 mL) was heated at 100 C. for 15 min under microwave irradiation. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine successively, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, ethyl acetate/hexane and then methanol/ethyl acetate) to give the title compound (28.0 mg) after triturating with ethyl acetate. 1H NMR (300 MHz, CDCl3) delta 2.52 (3H, s), 2.54-2.62 (4H, m), 2.65-2.76 (1H, m), 2.76-2.89 (1H, m), 3.20-3.34 (1H, m), 3.75-4.02 (6H, m), 6.47-6.55 (1H, m), 6.78-6.88 (1H, m), 7.15-7.24 (1H, m), 7.31 (1H, s), 7.48-7.56 (2H, m), 8.32 (2H, d, J=4.7 Hz), 8.53 (1H, dd, J=4.8, 1.8 Hz).

Reference： [1]Patent: US2016/318864,2016,A1 .Location in patent: Paragraph 1735; 1736

36
[ 1012084-56-8 ]
[ 7087-65-2 ]
3-(3-fluoro-5-nitrophenyl)-2-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
235 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; toluene; at 150℃; for 0.5h;Microwave irradiation;	A) 3-(3-Fluoro-5-nitrophenyl)-2-methylpyridine A mixture of 1-nitro-3-fluoro-5-bromobenzene (274 mg), <strong>[1012084-56-8]2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (300 mg) and toluene (3 mL) was added 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (45.5 mg) and 2 M aqueous sodium carbonate solution (1.245 mL). The mixture was heated at 150 C. for 30 min under microwave irradiation. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine successively, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, ethyl acetate/hexane) to give the title compound (235 mg). MS: [M+H]+ 233.2.

Reference： [1]Patent: US2016/318864,2016,A1 .Location in patent: Paragraph 1771; 1772

37
[ 1012084-56-8 ]
3-bromo-2-chlorobenzo[b]thiophen-5-amine [ No CAS ]
2-chloro-3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-amine [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 338 - 343

38
[ 1012084-56-8 ]
9-chloro-5,6,6-trimethyl-5,6-dihydrobenzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one [ No CAS ]
5,6,6-trimethyl-9-(2-methylpyridin-3-yl)-5,6-dihydrobenzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;	Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of example 222 (1.0 equiv.), <strong>[1012084-56-8]2-methylpyridine-3-boronic acid pinacol ester</strong> (2.0 equiv.) and tripotassium phosphate (2.0 equiv.) in dioxane (0.17 mol.L-1) and water (1.0 mol.L-1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and the resulting precipitate was collected by filtration, washed with water and dried by succion. Purification by preparative HPLC afforded the product as a white solid in 45% yield. Salt formation was performed according to method VII(i).1H-NMR (400 MHz, DMSO-D6): 8.82 (d, J 5.6 Hz, 1H, Ar); 8.43 (d, J 7.5 Hz, 1H, Ar); 7.90 (dd, J 7.5, 5.6 Hz, 1H, Ar); 7.80 (d, J 8.2 Hz, 1H, Ar); 7.71 (d, J 1.6 Hz, 1H, Ar); 7.58 (m, 2H, Ar); 6.90 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.49 (dd, J 3.8, 2.8 Hz, 1H, Ar); 3.12 (s, 3H, CH3); 2.74 (s, 3H, CH3); 2.04 (s, 3H, CH3); 1.20 (s, 3H, CH3). M/Z (M+H)+ = 332.1. MP = 230-250 C

Reference： [1]Patent: WO2017/81483,2017,A1 .Location in patent: Page/Page column 238

39
[ 1012084-56-8 ]
9-bromo-5-methylspiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1'-cyclopropan]-4(5H)-one [ No CAS ]
5-methyl-9-(2-methylpyridin-3-yl)spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1'-cyclopropan]-4(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate; In water; at 110℃; for 16h;Inert atmosphere;	General procedure: Method (ii): under oil bath heating: (0667) Under inert atmosphere, a mixture of halide F, F?, F??, Fi, I, or T, T?, T??, T1, T2, T3, T4 (1.0 equiv.), boronic acid derivative G or J, Ji (1.5 equiv.) and PdCl2(dppf)2 (0.10 equiv.) in a mixture of DMF or DMA (0.10 mol.L-1) and aqueous Na2CO3 (1.2 mol.L-1) was heated at 110C for 16 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, Example 20: 5-Methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1?- cyclopropan]-4(5H)-one. (0672) (0673) Example 20 was obtained according to general procedure VI(ii) starting from example 1 in presence of <strong>[1012084-56-8]2-methylpyridine-3-boronic pinacol ester</strong>. Purification by flash column chromatography on silica gel (MeOH in CH2Cl2, 1% to 5%) afforded the product as a grey solid in 62% yield.1H-NMR (400 MHz, DMSO-D6): 8.50 (dd, J 4.8, 1.6 Hz, 1H, Ar); 7.73 (dd, J 7.6, 1.6 Hz, 1H, Ar); 7.60 (d, J 7.6 Hz, 1H, Ar); 7.58 (d, J 1.6 Hz, 1H, Ar); 7.56 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.38 (dd, J 7.7, 1.6 Hz, 1H, Ar); 7.33 (dd, J 7.7, 4.8 Hz, 1H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.40 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.95 (s, 3H, CH3); 2.69 (s, 3H, CH3); 1.50 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). M/Z (M+H)+ = 330.0. MP: 200- 210C.

Reference： [1]Patent: WO2017/81483,2017,A1 .Location in patent: Page/Page column 126-127

40
[ 1012084-56-8 ]
4-bromo-1-(5-bromo-2-cyanophenyl)-1H-pyrrole-2-carboxylic acid methyl ester [ No CAS ]
1-[2-cyano-5-(2-methylpyridin-3-yl)phenyl]-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In tetrahydrofuran; at 70℃; for 24h;Inert atmosphere;	General procedure: General procedure V: Formation of R1-substituted intermediate Ci from dibromo- substituted intermediate C (Scheme 4) Under inert atmosphere, a mixture of dibromo-intermediate C (1.0 equiv.), boronic acid or ester G (1.1 equiv.), cesium fluoride (3.0 equiv.) and tetrakis(triphenylphosphine)palladium (0.10 equiv.) in THF (0.15 mol.L-1) was heated at 70C for 24 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, concentrated and purified by flash column chromatography (using a gradient of EtOAc in cyclohexane as eluent) to afford the product. Compound 33: 1-[2-Cyano-5-(2-methyl-pyridin-3-yl)-phenyl]-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester. (0654) Compound 33 was obtained according to general procedure V, starting from compound 2 and <strong>[1012084-56-8]2-methylpyridine-3-boronic acid pinacol ester</strong>. It was isolated as a beige solid in 78% yield.1H- NMR (400 MHz, DMSO-D6): 8.53 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.09 (d, J 7.9 Hz, 1H, Ar); 7.75 (m, 2H, Ar); 7.72 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.69 (d, J 1.9 Hz, 1H, Ar); 7.36 (dd, J 7.9, 4.8 Hz, 1H, Ar); 7.17 (d, J 1.9 Hz, 1H, Ar); 3.67 (s, 3H, CH3); 2.47 (s, 3H, CH3). M/Z (M[79Br]+H)+ = 396.

Reference： [1]Patent: WO2017/81483,2017,A1 .Location in patent: Page/Page column 122-123

41
[ 1012084-56-8 ]
8-bromo-N-(2-fluoro-6-methoxybenzyl)-[1,2,4]triazolo[4,3-a]pyridin-5-amine [ No CAS ]
N-(2-fluoro-6-methoxybenzyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 120℃; for 5h;Inert atmosphere; Sealed tube;	Example 2 N-(2-Fluoro-6-methoxybenzyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-5- amine [00215] A mixture of 4a (8 g, 22.78 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (6.99 g, 31.9 mmol), PdCl2(dppf) (1.667 g, 2.278 mmol) and Na2CO3 (7.24 g, 68.3 mmol) in dioxane (100 mL) and H2O ( 50 mL) was placed under N2, sealed and heated at 120 C for 5 h with oil-bath. The reaction mixture was cooled to rt, extracted with EA (100mL×3). The organic extracts were combined, dried over Na2SO4. The residue was purified by column chromatography (eluted with DCM:MeOH, 100:3 to 100:10, column: 120g silica gel) to give the title compound (5.8 g, 70%).1H- NMR (400 MHz, DMSO-d6) delta ppm 2.37 (s, 3H), 3.89 (s, 3H), 4.50 (s, 2H), 6.14 (d, 1H), 6.90 (t, 1H), 6.97 (d, 1H), 7.27 - 7.33 (m, 2H), 7.38 - 7.44 (m, 1H), 7.52 (s, 1H), 7.73 (dd, 1H), 8.48 (dd, 1H), 9.50 (s, 1H). LC-MS: [MH]+ = 364.1.

Reference： [1]Patent: WO2017/221092,2017,A1 .Location in patent: Paragraph 00215

42
[ 1012084-56-8 ]
1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one [ No CAS ]
1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(2-methyl-3-pyridinyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 40℃; for 18h;	General procedure: A mixture of 1 -(4-(4,7-dichloro-6-(2-fluoro-6- hydroxyphenyl)phthalazin- 1 -yl)piperazin- 1 -yl)prop-2-en- 1-one (Intermediate I, 25 mg, 0.056 mmol), 2-tolylboronic acid (30.4 mg, 0.224 mmol, Frontier Scientific Inc., Logan UT, USA), Pd(PPh3)4 (6.46 mg, 5.59 imol, Strem Chemicals Inc., NewburyPort, MA, USA), and 2M aqueous Na2CO3 (0.084 mL, 0.168 mmol) in 1,4-dioxane (0.3 mL) was stirred at 40 C for 18 h. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (15 mL). The organic layer was separated and sequentially washed with brine (15 mL), dried over Mg504, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc in heptane) furnished 1-(4-(7-chloro-6-(2-fluoro-6- hydroxyphenyl)-4-(o-tolyl)phthalazin- 1 -yl)piperazin- 1 -yl)prop-2-en- 1-one: ?H NMR (400 MHz, DMSO-d6) oe 10.15 (br s, 1H) 8.33 (s, 1H) 7.36 - 7.45 (m, 2H) 7.24 - 7.36 (m, 4H) 6.90 (dd, J 16.63, 10.37 Hz, 1H) 6.70 - 6.80 (m, 2H) 6.18 (dd, J 16.73, 2.25 Hz, 1H) 5.75 (dd, J 10.56, 2.15 Hz, 1H) 3.83 - 3.97 (m, 4H) 3.47 - 3.62 (m, 4H) 1.98 - 2.06 (m, 3H). m/z (ESI, +ve) 503.1 (M+H)t
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 40℃; for 18h;	A mixture of 1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one (Intermediate I, 25 mg, 0.056 mmol), 2-tolylboronic acid (30.4 mg, 0.224 mmol, Frontier Scientific Inc., Logan Utah, USA), Pd(PPh3)4 (6.46 mg, 5.59 mol, Strem Chemicals Inc., NewburyPort, Mass., USA), and 2M aqueous Na2CO3 (0.084 mL, 0.168 mmol) in 1,4-dioxane (0.3 mL) was stirred at 40 C. for 18 h. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (15 mL). The organic layer was separated and sequentially washed with brine (15 mL), dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc in heptane) furnished 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(o-tolyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one: 1H NMR (400 MHz, DMSO-d6) delta 10.15 (br s, 1H) 8.33 (s, 1H) 7.36-7.45 (m, 2H) 7.24-7.36 (m, 4H) 6.90 (dd, J=16.63, 10.37 Hz, 1H) 6.70-6.80 (m, 2H) 6.18 (dd, J=16.73, 2.25 Hz, 1H) 5.75 (dd, J=10.56, 2.15 Hz, 1H) 3.83-3.97 (m, 4H) 3.47-3.62 (m, 4H) 1.98-2.06 (m, 3H). m/z (ESI, +ve) 503.1 (M+H)+.

Reference： [1]Patent: WO2018/119183,2018,A2 .Location in patent: Paragraph 0243
[2]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0444

43
[ 1012084-56-8 ]
C₁₇H₁₇IN₆O₂ [ No CAS ]
N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1,2'-dimethyl-6-oxo-1,6-dihydro-[3,3'-bipyridine]-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 95℃; for 20h;Inert atmosphere;	[0644] To a solution of Example 159a (462 mg, 1 mmol), Example 159b (219 mg, 1 mmol) and Pd(dppf)Cl2 (73 mg, 0.1 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Na2C03 (272 mg, 2 mmol). The mixture was degassed with N2 three times, then heated to 95C and stirred for 20 h. The mixture was concentrated under reduced pressure. The residue was purified with Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 mum, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product Example 159 (10 mg, yield 2%) as a pale brown solid. LCMS [M+l]+ =430.0 [0645] 1H NMR (400 MHz, DMSO-d6) delta 12.69 (s, 1H), 8.89 (s, 1H), 8.48 (d, J= 3.0 Hz, 2H), 8.39-8.30 (m, 2H), 8.02 (t, J = 8.0 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.69 (dd, J = 7.7, 1.8 Hz, 1H), 7.32 (dd, J = 7.7, 4.8 Hz, 1H), 5.29 (p, J= 6.7 Hz, 1H), 3.68 (s, 3H), 2.48 (s, 3H), 1.52 (d, J = 6.7 Hz, 6H).

Reference： [1]Patent: WO2018/151830,2018,A1 .Location in patent: Paragraph 0644-0645

44
[ 1012084-56-8 ]
9-chloro-5-methyl-5,6-dihydro-3-thia-5-azabenzo[e]azulen-4-one [ No CAS ]
5-methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-3-thia-5-azabenzo[e]azulen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	General procedure: Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 240

45
[ 1012084-56-8 ]
9-chloro-5-methyl-2-(2-trimethylsilanylethoxymethyl)-5,6-dihydro-2H-2,3,5-triazabenzo[e]azulen-4-one [ No CAS ]
C₂₄H₃₀N₄O₂Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;	General procedure: Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 242

46
[ 1012084-56-8 ]
2',9'-dichloro-6'-methylspiro[cyclopropane-1,5'-pyrido[3,4-f]pyrrolo[1,2-a][1,4]diazepin]-7'(6'H)-one [ No CAS ]
9'-chloro-2'-(2-methylpyridin-3-yl)-6'-methylspiro[cyclopropane-1,5'-pyrido[3,4-f]pyrrolo[1,2-a][1,4]diazepin]-7'(6'H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	General procedure: Under inert atmosphere, a mixture of halide F, Fl or F2 (1 0 equivj, boronic acid derivative G(1.5 equiv.) and PdCI2(dppf).CH2CI2 (010 equiv.) in a mixture of DMF or DMA (0.10 moLL1)and aqueous K2C03 (1.2 moW1) was heated at 110C for 16 hours. After cooling, the reactionmixture was hydrolysed and extracted twice with EtOAc, The organic layers were combined, washed with brine, dried over MgSO4, concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 201

47
[ 1012084-56-8 ]
9-chloro-5-methyl-5,6-dihydro-3H-3,5-diazabenzo[e]azulen-4-one [ No CAS ]
5-methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-3H-3,5-diazabenzo[e]azulen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	General procedure: Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 243

48
[ 1012084-56-8 ]
9-chloro-2-methoxymethyl-5-methyl-5,6-dihydro-2H-2,3,5-triazabenzo[e]azulen-4-one [ No CAS ]
2-methoxymethyl-5-methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-2H-2,3,5-triazabenzo[e]azulen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	General procedure: Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 246; 247

49
[ 1012084-56-8 ]
10-chloro-6-methyl-6,7-dihydrobenzo[e]pyrrolo[1,2-c][1,3]diazepin-5-one [ No CAS ]
6-methyl-10-(2-methylpyridin-3-yl)-6,7-dihydrobenzo[e]pyrrolo[1,2-c][1,3]diazepin-5-one hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%		General procedure: Example 79 was prepared according to genera procedure lV(i), starting from example 77 and2methylpyridine3boronic acid pinacol ester. Purification by column chromatography on siUcagel (using 0% to 4% MeCH in dichloromethane as eluent) afforded example 79 as a beige powder in 71% yield. Salt formation was performed according to method V(i). 1HNMR (400 MHz, DMSOD6): 8.77 (dd, J 5.6, 1.3 Hz, 1H, Ar); 8.37 (d, J 7,7 Hz, 1H, Ar); 7.87 (dd, J 7.7, 5.6 Hz, 1H, Ar); 7.76 (d, J 1.7 Hz, IH, Ar); 7.65 (d, J 7.7 Hz, 1H, Ar); 7.48 (dci, J 3.1, 1,8 Hz,1 H, Ar); 7.44 (dd, J 7,7, 1.7 Hz, I H, Ar), 6.77 (dd, J 3,5, 1.8 Hz, 1 H, Ar); 6.40 (t, J 3.3 Hz, I H, Ar); 4.39 (s, 2H, CH2); 3.15 (s, 3H, CH3); 2.68 (s, 3H, CH3); M/Z (M+H)4 304.0.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 255

50
[ 1012084-56-8 ]
8-chloro-4-methyl-3-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepine-1-carboxylic acid tert-butyl ester [ No CAS ]
4-methyl-8-(2-methylpyridin-3-yl)-3-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;	General procedure: Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 255; 256

51
[ 1012084-56-8 ]
[ 313339-92-3 ]
3-chloro-5-(2-methylpyridin-3-yl)pyrazine-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere;	Under inert atmosphere, a mxture of 3,5dichoropyrazine2carbonitrNe (1 equiv.), 2 methylpyridine3boronic acid pinacol ester (I equiv.), cesium carbonate (3 equiv.) and PdCl2(dppf).CH2C2 (0.1 equiv.) in doxane (0.10 moLL1) and water (0.80 moLL1) was heatedat 80 C for 1 hour. The reaction mixture was hydroysed and extracted twice with ethy acetate. The organic layers were combined, washed with brine, dried over MgSO4, concentrated under vacuum and purfied by flash column chromatography on sWca gel (usng 20% to 100% ethy acetate (EtOAc) in cyclohexane as eluent) to afford the product as a brown solid in 57% yield. 1HNMR (400 MHz, DMSOD6): 9.17 (s, 1H, Ar); 8.65 (dd, J4.8, 1.7 Hz, 1H,Ar); 8.02 (dd, J 7.8, 11 Hz, 1H, Ar); 7.46 (dd, J 7.8, 4.8 Hz, 1H, Ar); 2.62 (s, 3H, CH3). M/Z (M[35Cl]+H) = 230.9.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 197

52
[ 1012084-56-8 ]
9-(2-methylpyridin-3-yl)-5,6-dihydro-5,7,10,10b-tetraazabenzo[e]azulen-4-one [ No CAS ]

Reference： [1]Patent: WO2018/206820,2018,A1

53
[ 1012084-56-8 ]
5-methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-5,7,10,10b-tetraazabenzo[e]azulen-4-one dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2018/206820,2018,A1

54
[ 1012084-56-8 ]
1-[3-cyano-6-(2-methylpyridin-3-yl)pyrazin-2-yl]-1H-pyrrole-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Patent: WO2018/206820,2018,A1

55
[ 1012084-56-8 ]
1-(3,6-dichloro-pyridazin-4-yl)-1H-pyrrole-2-carboxylic acid methyl ester [ No CAS ]
1-[3-chloro-6-(2-methylpyridin-3-yl)pyridazin-4-yl]-1H-pyrrole-2-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;	Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 204; 205

56
[ 1012084-56-8 ]
9-chloro-5-methyl-5,6-dihydro-5,10,10b-triazabenzo[e]azulen-4-one [ No CAS ]
5-methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-5,10,10b-triazabenzo[e]azulen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; at 110℃; for 16h;	General procedure: Under inert atmosphere, a mixture of halide F, Fl or F2 (1 0 equivj, boronic acid derivative G(1.5 equiv.) and PdCI2(dppf).CH2CI2 (010 equiv.) in a mixture of DMF or DMA (0.10 moLL1)and aqueous K2C03 (1.2 moW1) was heated at 110C for 16 hours. After cooling, the reactionmixture was hydrolysed and extracted twice with EtOAc, The organic layers were combined, washed with brine, dried over MgSO4, concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 206; 207

57
[ 1012084-56-8 ]
1-(5-bromo-2-cyanopyridin-3-yl)-1H-pyrrole-2-carboxylic acid methyl ester [ No CAS ]
1-(6-cyano-2'-methyl-[3,3']bipyridinyl-5-yl)-1H-pyrrole-2-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere;	Under inert atmosphere, a mixture of compound 1 (1.0 equiv.), <strong>[1012084-56-8]2-methylpyridine-3-boronic acid pinacol ester</strong> (1.3 equiv.), cesium fluoride (3.0 equiv.) and Pd(PPh3)4 (0.1 equiv.) in anhydrous THF (0.15 mol.L"1) was heated at 70 C for 16 hours. After cooling to room temprerature, the reaction mixture was neutralized with aqueous NaHC03 and extracted twice with EtOAc. The combined organic layers were dried with brine, over MgS04, concentrated and purified by flash column chromatography on silica gel (using 0% to 80% EtOAc in cyclohexane as eluent) to afford the product as a white solid in 77% yield. 1 H-NMR (400 MHz, DMSO-D6): 8.90 (d, J 2.0 Hz, 1 H, Ar); 8.57 (dd, J 4.8, 1.8 Hz, 1 H, Ar); 8.33 (d, J 2.0 Hz, 1 H, Ar); 7.81 (dd, J 7.7, 1.8 Hz, 1 H, Ar); 7.51 (dd, J 2.8, 1.8 Hz, 1 H, Ar); 7.40 (dd, J 7.7, 4.8 Hz, 1 H, Ar); 7.18 (d, J 3.8, 1.8 Hz, 1 H, Ar); 6.50 (d, J 3.8, 2.8 Hz, 1 H, Ar); 3.68 (s, 3H, CH3); 2.49 (s, 3H, CH3). M/Z (M+H)+ = 319.3.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 201; 202

58
[ 1012084-56-8 ]
9-chloro-5-methyl-5,6-dihydro-5,8,10,10b-tetraazabenzo[e]azulen-4-one [ No CAS ]
5-methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-5,8,10,10b-tetraazabenzo[e]azulen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; at 80℃; for 1h;Inert atmosphere;	Under inert atmosphere, a mixture of halide F, Fl or F2 (1 0 equivj, boronic acid derivative G(1.5 equiv.) and PdCI2(dppf).CH2CI2 (010 equiv.) in a mixture of DMF or DMA (0.10 moLL1)and aqueous K2C03 (1.2 moW1) was heated at 110C for 16 hours. After cooling, the reactionmixture was hydrolysed and extracted twice with EtOAc, The organic layers were combined, washed with brine, dried over MgSO4, concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 209

59
[ 1012084-56-8 ]
10-chloro-6-methyl-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]
6-methyl-10-(2-methylpyridin-3-yl)-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	General procedure: Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 221

60
[ 1012084-56-8 ]
10-chloro-3-fluoro-6-methyl-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]
3-fluoro-6-methyl-10-(2-methylpyridin-3-yl)-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;	General procedure: Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 223

61
[ 1012084-56-8 ]
10-chloro-3-fluoro-6-methyl-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]
3-hydroxy-6-methyl-10-(2-methylpyridin-3-yl)-6,7-dihydro-4,6-diaza-dibenzo[a,c]cyclohepten-5-one [ No CAS ]

Reference： [1]Patent: WO2018/206820,2018,A1

62
[ 1012084-56-8 ]
10-chloro-3-methoxy-6-methyl-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]
3-methoxy-6-methyl-10-(2-methyl-pyridin-3-yl)-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;	General procedure: Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 226

63
[ 1012084-56-8 ]
10-chloro-3,6-dimethyl-6,7-dihydro-4,6-diaza-dibenzene[a,c]cyclohepten-5-one [ No CAS ]
3,6-dimethyl-10-(2-methylpyridin-3-yl)-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;	General procedure: Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 229

64
[ 1012084-56-8 ]
10-chloro-2,6-dimethyl-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]
2,6-dimethyl-10-(2-methylpyridin-3-yl)-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	General procedure: Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 230

65
[ 1012084-56-8 ]
10-chloro-2-fluoro-6-methyl-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]
2-fluoro-6-methyl-10-(2-methylpyridin-3-yl)-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	General procedure: Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of haNde F, Fl or F2 (1,0 equiv,), boronic acid derivative 0 (1.5 equiv,) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 moLLj and water (1.0 moLL?1). The reaction mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 232

66
[ 1012084-56-8 ]
10-chloro-2-fluoro-6-methyl-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]
2-methoxy-6-methyl-10-(2-methylpyridin-3-yl)-6,7-dihydro-4,6-diazadibenzo[a,c]cyclohepten-5-one [ No CAS ]

Reference： [1]Patent: WO2018/206820,2018,A1

67
[ 1012084-56-8 ]
2'-chloro-6'-methylspiro[cyclopropane-1,5'-pyrido[3,4-f]pyrrolo[1,2-a][1,4]diazepin]-7'(6'H)-one [ No CAS ]
2'-(2-methylpyridin-3-yl)-6'-methylspiro[cyclopropane-1,5'-pyrido[3,4-f]pyrrolo[1,2-a][1,4]diazepin]-7'(6'H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;	General procedure: Under inert atmosphere, a mixture of halide F, Fl or F2 (1 0 equivj, boronic acid derivative G(1.5 equiv.) and PdCI2(dppf).CH2CI2 (010 equiv.) in a mixture of DMF or DMA (0.10 moLL1)and aqueous K2C03 (1.2 moW1) was heated at 110C for 16 hours. After cooling, the reactionmixture was hydrolysed and extracted twice with EtOAc, The organic layers were combined, washed with brine, dried over MgSO4, concentrated and purified to afford the product.

Reference： [1]Patent: WO2018/206820,2018,A1 .Location in patent: Page/Page column 200; 201

68
[ 1012084-56-8 ]
tert-butyl (4R)-2-(5-(4-bromophenyl)-5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate [ No CAS ]
tert-butyl (4R)-4-hydroxy-2-(5-methyl-5-(4-(2-methylpyridin-3-yl)phenyl)-4-oxo-4,5-dihydro-1H-imidazol-2-yl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 1h;Microwave irradiation;	A solution of tot-butyl (4i?)-2-(5-(4-bromophenyl)-5-methyl-4-oxo-4,5- dihydro-lH-imidazol-2-yl)-4-hydroxypyrrolidine-l-carboxylate (Intermediate 4, 200 mg, 0.460 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (120 mg, 0.548 mmol), PdCl2(dppf) (66.8 mg, 0.0913 mmol) and Na2C03 (145 mg, 1.37 mmol) in dioxane (10 mL) and water (1.5 mL) was stirred at 80C for 1 hour in microwave. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0%-10% MeOH/DCM) to yield 150 mg (73%) of the title compound as a light yellow solid. LCMS (ESI): RT (min) = 0.860, [M+H]+ = 451, method = J.

Reference： [1]Patent: WO2019/84026,2019,A1 .Location in patent: Paragraph 0766

69
[ 1012084-56-8 ]
ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate [ No CAS ]
ethyl 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[1,2-c]pyrimidine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 105℃; for 1h;Inert atmosphere;	To a solution of ethyl 8-bromo-5-(((5-fluoro-2, 3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l, 2-c]pyrimidine-2-carboxylate (50.0 mg, 115 miho, 1.00 equiv), 2- methyl-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridine (37.8 mg, 172 pmol, 1.50 equiv) in dioxane (3.00 mL) was added water (1.00 mL) followed by Pd(dppf)Cl2 (8.41 mg, 11.5 pmol, 0.100 equiv) and sodium bicarbonate (29.0 mg, 345 pmol, 3.00 equiv). The reaction mixture was stirred at 105 C for 1 h under nitrogen. The mixture was cooled to 25 C and filtered. The filtrate was concentrated in vacuo to provide a residue. The crude material was purified by prep-TLC (dichloromethane/methanol = 10/1) to afford ethyl 5-(((5-fluoro-2, 3- dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l, 2-c]pyrimidine-2- carboxylate (40.0 mg, 75.0% yield, 96.4% purity) as a brown solid.

Reference： [1]Patent: WO2019/152419,2019,A1 .Location in patent: Paragraph 0405

70
[ 1012084-56-8 ]
ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate [ No CAS ]
ethyl 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[1,2-c]pyrimidine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.9%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 105℃; for 1h;Inert atmosphere;	A mixture of ethyl 8-bromo-5-(((5-fluorobenzofuran-4-yl)methyl)amino)imidazo[l, 2- c]pyrimidine-2-carboxylate (120 mg, 274 miho, 1.00 equiv), 2-m ethyl-3 -(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridine (120 mg, 548 pmol, 2.00 equiv), sodium bicarbonate (69.0 mg, 822 pmol, 32.0 pL, 3.00 equiv) and Pd(dppf)Cl2 (22.4 mg, 27.4 pmol, 0.100 equiv) in dioxane (3.00 mL) and water (0.600 mL) was purged with nitrogen and stirred at 105 C for 1 h under a nitrogen atmosphere. The mixture was concentrated at reduced pressure to give a residue. The crude material was purified by prep-TLC (DCM / Methyl alcohol = 20 / 1) to afford ethyl 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l, 2- c]pyrimidine-2-carboxylate (100 mg, 78.9% yield, 96.3% purity) as a brown solid. LCMS [M+l]: 446.2.

Reference： [1]Patent: WO2019/152419,2019,A1 .Location in patent: Paragraph 0408

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CAS No. :	1012084-56-8	MDL No. :	MFCD08669594
Formula :	C₁₂H₁₈BNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WXPRMDIXTKNFIG-UHFFFAOYSA-N
M.W :	219.09	Pubchem ID :	16414271
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. 1012084-56-8 ] {[proInfo.proName]}

Quality Control of [ 1012084-56-8 ]

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Physicochemical Properties

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[ 1012084-56-8 ] Synthesis Path-Upstream 1~1

[ 1012084-56-8 ] Synthesis Path-Downstream 1~70

Related Functional Groups of
[ 1012084-56-8 ]

Organoboron

Related Parent Nucleus of
[ 1012084-56-8 ]

Pyridines

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Inquiry

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 :	2.87

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

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Code	Phrase
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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.
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P411
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P413
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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. 1012084-56-8 ] {[proInfo.proName]}

Quality Control of [ 1012084-56-8 ]

Related Doc. of [ 1012084-56-8 ]

Product Details of [ 1012084-56-8 ]

Calculated chemistry of [ 1012084-56-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1012084-56-8 ]

Application In Synthesis of [ 1012084-56-8 ]

[ 1012084-56-8 ] Synthesis Path-Upstream 1~1

[ 1012084-56-8 ] Synthesis Path-Downstream 1~70

Related Functional Groups of [ 1012084-56-8 ]

Organoboron

Related Parent Nucleus of [ 1012084-56-8 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1012084-56-8 ]

Related Parent Nucleus of
[ 1012084-56-8 ]