Name: 579476-63-4|(2-Methylpyridin-4-yl)boronic acid|97%
Brand: Ambeed
SKU: A405189
Price: 8.0 USD
Availability: InStock
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1
[ 952402-39-0 ]
[ 579476-63-4 ]
5-(2-methyl-4-pyridinyl)-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); CyJohnPhos; In 1,2-dimethoxyethane; water; at 90℃; for 3.0h;	Example 23: 5-(2-methyl-4-pyridinyl)-1-(3-{(1S,5/?)-1-[4-(trifluoromethyl)phenyl]-3- azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1 H,3AV)-pyrimidinedione hydrochloride (E23)5-lodo-1 -{3-[(1 S,5R)-1 -(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-propyl}-1 H- pyrimidine-2,4-dione (Prep40,123 mg, 0.24 mmol) was dissolved in degassed DME-water solution (5-1 , 5 mL). 2-Methylpyridine 4-boronic acid (66 mg, 0.49 mmol), Na2CO3 (51 mg, 0.49 mmol), 2-(dicyclohexylphosphino)biphenyl (20 mg, 0.05 mmol) and Pd(PPh3)4 (57 mg, 0.05 mmol) were added and the mixture stirred for 3 hours at 900C. AcOEt was added and the mixture washed with water. The organic phase was dried (Na2SO4) and evaporated; the crude was purified by flash chromatography with DCM-MeOH-NH4OH (98-2-0.2) to give the title compound (30 mg, 27percent yield) as free base

Reference： [1]Patent: WO2007/113232,2007,A1 .Location in patent: Page/Page column 145

2
[ 939437-25-9 ]
[ 579476-63-4 ]
[ 939437-26-0 ]

Yield	Reaction Conditions	Operation in experiment
27%		Example 1 - Compound A1 (prepared by Step 1.4) [2-[Bis-(4-fluoro-phenyl)methyl]-4-(2-methylpyridin-4-yl)thiazol-5-yl]acetic acid. Suzuki coupling: lntermediate-3 (0.38 g, 0.77 mmol), 2-picoline-4-boronic acid (0.21 g, 1.5 mmol) and sat. Na2CO3 solution (1.2 ml.) was suspended in dry dioxane (3 ml). The reaction mixture was flushed with N2 for 15 min. PdCI2(dppf) (10 mg, 0.038 mmol) was added under under N2. The reaction mixture was stirred at 80 0C over night. 1 N HCI was added and then the mixture was extracted with DCM. The organic phase was passed through a phase separation filter and concentrated. The residue was purified on a PEAX SPE column (equilibrated with 100percent MeOH and then eluted with 10percent AcOH in MeOH) and then on a SiO2 column (0-5percent MeOH in DCM) to give the product as a solid (89.7 mg, 27percent). LC/MS (tfa20p5): Rt = 2.1 min, m/z 437 [M+H]+. 1H NMR (DMSO-Cf6): delta 2.52 (m, 3H), 4.00 (s, 2H), 6.06 (s, 1 H), 7.20 (t, 4H), 7.40 (m, 6H), 8.51 (d, 1 H).

Reference： [1]Patent: WO2007/62677,2007,A1 .Location in patent: Page/Page column 9

3
[ 914606-86-3 ]
[ 579476-63-4 ]
6-(4-cyclopropylpiperazin-1-yl)-2'-methyl-[3,4']bipyridine trihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%		Example 16-(4-Cyclopropylpiperazin-1-yl)-2'-methyl-[3,4']bipyridinyl, 3 HCI1-(5-Bromopyridin-2-yl)-4-cyclopropylpiperazine (0.3 g, 1 .06 mmol), <strong>[579476-63-4]2-methylpyridine-4-boronic acid</strong> (0.16 g; 1.17 mmol) and triphenylphosphinpalladium(ll)dichloride (37 mg) were mixed under N2 in a 5 ml microwave vial in acetonitrile (2.5 ml) and 1 N sodium carbonate (Na2CO3; 2.5 ml). The reaction mixture was heated for 500 seconds at 130°C. The reaction mixture was seperated in two phases. The acetonitile phase was removed and the water phase was extracted with another 2.5 ml of acetonitrile. The combined acetonitrile phases were evaporated in vacuo, redissolved in methanol (MeOH) and purified on a Gilson preparative HPLC (HPLC Method B). (HPLC_E9.S.02_LSk1 ) The <n="15"/>RP-purification was performed on a Gilson system (3 Gilson 306 pumps, Gilson 170 DAD detector and a Gilson 215 liquid handler) using a Waters XTerra.(R). Prep RPi8 (10 mum, 30 mm x 150 mm) with gradient elution, 5percent to 95percent solvent B (acetonitrile) in solvent A (0.05percent trifluoroacetic acid (hereinafter designated TFA) in water) within 15 minutes, 40 mL/min, detection at 210 nm, room temperature. The title compound was isolated as the TFA salt. The TFA salt was dissolved in MeOH and hydrochlorid acid (HCI) in diethylether was added. Evaporation in vacuo gave the title compound as the trihydrochloride (145 mg, Yield: 34percent).1H-NMR (400MHz): (DMSO-c/6) delta= 8.95(d, 1 H), 8.7(d, 1 H), 8.45(m, 3H), 8.2(d,d, 1 H), 4.6(d, 2H), 3.5(m, 4H), 3.25(m, 2H), 2.85(m, 1 H), 2.7(s, 3H), 1.2(m, 2H), 0.8(m, 2H).HPLC-MS (electrospray): m/z: 295 M+1 =296 Rt= 0.58 min.Elementary analyses gave the following result: 52.8percent C, 6.7percent H, 12.7percent N, 25.3percent Cl.

Reference： [1]Patent: WO2007/135111,2007,A1 .Location in patent: Page/Page column 13-14

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

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

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

5
[ 134604-07-2 ]
[ 579476-63-4 ]
[ 1161362-06-6 ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium phosphate;bis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium (II) Dichloride; In 1,4-dioxane; water; at 100℃;	Reference: 11; Synthesis of 5-Amino-2-(2-methylpyridin-4-yl)benzonitrile Step 1To a mixture of potassium phosphate hydrate (2.3 g, 9.9 mmol), 2-methylpyridin-4-ylboronic acid (1.2 g, 8.8 mmol), 2-bromo-5-nitrobenzonitrile (1.0 g, 4.4 mmol) in dioxane (45 mL) and water (9 mL) purged with nitrogen was added bis (di-t-butylphenylphosphine)- dichloropalladium catalyst (0.096 g, 0.15 mmol). The reaction mixture was heated to 100 0C overnight. The reaction mixture was diluted saturated Na2CO3 and EtOAc. The organic phase was separated. The aqueous phase was extracted with a mixture OfCHCl3: i-PrOH (3:1) three times. The organic phase was dried over Na2SO4, and concentrated in vacuo. Purification by silica gel chromatography (25-100%, then 100% EtOAc-hexane) afforded 2-(2-methylpyridin- 4-yl)-5-nitrobenzonitrile as a tan solid (0.67 g, 64%).

Reference： [1]Patent: WO2009/75874,2009,A1 .Location in patent: Page/Page column 105

6
[ 1231922-04-5 ]
[ 579476-63-4 ]
[ 1231923-35-5 ]

Yield	Reaction Conditions	Operation in experiment
18.99%	With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In 1,2-dimethoxyethane; water; at 80℃;	To a round-bottomed flask was added (4-(3-(2-methylpyridin-4-yl)pyrazin-2-yloxy)phenyl)(pyridin-2-yl)methanone (0.0617 g, 0.167 mmol, 18.99percent yield), 2-methylpyridin-4-ylboronic acid (0.362 g, 2.65 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.050 g, 0.071 mmol), and sodium carbonate (0.547 g, 4.41 mmol) in DME and water at 80° C. Upon completion, the reaction mixture was diluted with water and brine and extracted with dichloromethane. The organic extract was washed with water, sat NaCl, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide (4-(3-(2-methylpyridin-4-yl)pyrazin-2-yloxy)phenyl)(pyridin-2-yl)methanone (0.0617 g, 0.167 mmol, 18.99percent yield). MS (ESI, pos. ion) m/z: 369 (M+1). IC50 (uM) 0.4939.

Reference： [1]Patent: US2010/160280,2010,A1 .Location in patent: Page/Page column 121

7
[ 121404-83-9 ]
[ 579476-63-4 ]
[ 1234016-11-5 ]

Yield	Reaction Conditions	Operation in experiment
58.8%	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.166667h;Microwave irradiation; Sealed tube;	3-Methoxy-4-(2-methyl-pyridin-4-yl)-benzaldehyde: 4-Iodo-3-methoxy-benzaldehyde (LOO g, 3.82 mmol), (2-methyl -4-pyridinyl)- boronic acid (1.045 g, 7.63 mmol), PdC12(dppf) (0.558 g, 0.763 mmol) and sodium carbonate (0.809 g, 7,63 mmol) were dissolved in Dioxane (32 ml) and Water (8.00 ml), placed in a sealed tube and heated in a microwave reactor at 100 0C for 10 min. The reaction mixture was then filtered through a celite plug, which was rinsed with 50 mL methanol. The solution was concentrated and re-suspended in dichloromethane, washed with Brine and dried with magnesium sulfate. The residue was concentrated and purified by preparative HPLC Normal phase on silica gel, eluting with ethyl acetate/hexane (20percent- 100percent), to give 3~Methoxy-4-(2-methyl-pyridin-4-yl)-benzaldehyde (510 mg, 2.244 mmol, 58.8 percent yield) as a dark solid. 1H NMR (SOO MHz, cdcl3) delta 10.03 (s, IH), 8.55 (d, J= 5.1, IH), 7.55 (dd, J= 7.6, 1.1, IH), 7.51 (s, IH), 7.48 (d, J= 7.6, IH), 7.31 (s, IH), 7.28 (d, J= 5.1, IH), 3.91 (s, 3H), 2.62 (s, 3H). MS (EI) [M+H]+ calc'd 228.3 found 228.1.

Reference： [1]Patent: WO2010/77582,2010,A1 .Location in patent: Page/Page column 21

8
[ 1235494-84-4 ]
[ 579476-63-4 ]
[ 1235494-83-3 ]

Yield	Reaction Conditions	Operation in experiment
35%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; for 18.0h;	A mixture of N-(4-bromo-3-methoxyphenyl)-4-phenyl-4,5,6,7- tetrahydrobenzo[d]thiazol-2-amine, TFA (70 mg, 0.13 mmol), 2-methylpyridin-4- ylboronic acid (36 mg, 0.26 mmol), tetrakis(triphenylphosphlne)palladium(0) (7.6 mg, 6.6 mumol) and Cs2CO3 (172 mg, 0.529 mmol) in DME (994 muL) / water (328 muL) was heated at 100 0C for 18 h. The crude reaction products were purified using preparatory HPLC (Solvent A = 10percent MeOH - 90percent water - 0.1percent TFA, Solvent B = 90percent MeOH - 10percent water - 0.1percent TFA. Column: Phenomenex Luna 30 x 100mm, SlO, flow rate: 40 ml / min, 40 - 100percent B5 40 min) to afford 30 mg (35percent yield) of the titled compound as a yellow oil. LC-MS (M+H)* 428.2.

Reference： [1]Patent: WO2010/83141,2010,A1 .Location in patent: Page/Page column 140

9
[ 383868-64-2 ]
[ 579476-63-4 ]
[ 1240524-44-0 ]

Yield	Reaction Conditions	Operation in experiment
50%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In butan-1-ol; at 100℃;	4-(4-(Benzyloxy)-3-nitrophenyl)-2-methylpyridine (64.A). Bromide 13.B(9.00 g, 29.2 mmol), 2-methylpyridine-4-yl-boronic acid (4.40 g, 32.1 mmol), K3PO4 (15.5 g, 73.0 mmol), Pd2(dba)3 (669 mg, 0.73 mmol), and S-Phos (600 mg, 1.46 mmol), were heated in n-butanol (0.2 L) at 100 0C overnight. The reaction mixture was partitioned withH2OZEtOAc. The organic layer was washed with H2O (2X), dried with sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel (33O g, 0-100% EtOAc:DCM). The desired fractions were concentrated to yield 64.A as a yellow solid (4.70 g, 50%). LC-MS (+esi, M+H+=321.1).

Reference： [1]Patent: WO2010/93849,2010,A2 .Location in patent: Page/Page column 164

10
[ 16618-67-0 ]
[ 579476-63-4 ]
[ 1240525-68-1 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In butan-1-ol; at 110℃; for 12.0h;Inert atmosphere;	3-(2-Methylpyridin-4-yl)-5-nitrobenzenamine (65.B). To a rt solution of65.A (available fromGLSynthesis Inc.) (5.00 g, 22.0 mmol) and 2-methylpyridin-4-ylboronic acid (available from CombiPhos Catalysts, Inc.) (2.71 g, 21.4mmol) in n-BuOH (38 rnL) was added potassium phosphate (available from Strem Chemicals, Inc.) (7.00 g, 33.0 mmol) and tris(dibenzylideneacetone)dipalladium (o) (available from Strem Chemicals, Inc.) (1.01 g, 1.2 mmol). After being purged with N2 for 15 mins, the mixture was stirred at 110 0C under N2 atmosphere for 12 hrs and resulting solution was concentrated. The residue was re-dissolved in EtOAc (60 mL), washed with water and brine, and dried over MgSO4. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-9percent MeOH/ CH2Cl2 for elution gave the title product 65.B as yellow solid (4.8O g, 91percent).

Reference： [1]Patent: WO2010/93849,2010,A2 .Location in patent: Page/Page column 166

11
[ 1240523-38-9 ]
[ 579476-63-4 ]
[ 1240523-39-0 ]

Yield	Reaction Conditions	Operation in experiment
53%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 2.0h;	(2S)-N-(3-(2-methylpyridin-4-yl)phenyl)-3-phenyl-2-(thiazol-4- ylmethylamino)propanamide (39). To a 5 mL flask was added (S)-N-(3-bromophenyl)-3- phenyl-2-(thiazol-4-ylmethylamino)propanamide 39.B (50mg, 0.12 mmol), 2-methylpyridin- 4-yl boronic acid (21 mg, 0.16 mmol, available from Combi-Phos), tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol), DMF (0.5 mL) and saturated aqueous K2CO3 (0.5 mL). The reaction mixture was stirred at 1000C for 2 hours. The mixture was diluted with methanol (3 mL), filtered and purified directly on reverse phase preparative HPLC to afford (2S)-N-(3-(2-methylpyridin-4-yl)phenyl)-3-phenyl-2-(thiazol-4- ylmethylamino)propanamide 39 (27.2 mg, 53percent yield) as a white solid. LCMS ESI (pos.) m/e: 429.1. (M+l). IH NMR (500 MHz, MeOH-D4) delta ppm 9.12 (d, J=I.96 Hz, 1 H), 8.74 (d, J=6.36 Hz, I H), 8.19 (s, 1 H), 8.12 (dd, J=6.36, 1.96 Hz, 1 H), 8.11 (t, J=1.71 Hz, 1 H), 7.82 (d, J=I.96 Hz, 1 H), 7.68 - 7.75 (m, 1 H), 7.58 (t, J=7.83 Hz, 1 H), 7.52 - 7.56 (m, 1 H), 7.23 - 7.37 (m, 5 H), 4.53 (d, J=4.65 Hz, 2 H), 4.35 (dd, J=9.29, 5.87 Hz, 1 H), 3.46 (dd, J=13.45, 5.87 Hz, 1 H), 3.28 (dd, J=13.45, 9.29 Hz, 1 H), 2.88 (s, 3 H).

Reference： [1]Patent: WO2010/93849,2010,A2 .Location in patent: Page/Page column 123-124

12
[ 1008304-85-5 ]
[ 579476-63-4 ]
[ 1240523-48-1 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In butan-1-ol; at 100℃; for 8.0h;Inert atmosphere;	2-Chloro-6-methoxypyridin-4-amine (41.6.B). A solution of2,6-dichloropyridin-4-amine 41.6.A (available from Aldrich) (3.10 g, 19.0 mmol) in 20percent NaOMe/MeOH (15 mL) was refluxed for 72 hr. The reaction mixture was diluted with H2O (40 mL) and extracted with 30percent 1PrOHZCHCl3 (3 x 30 mL). The combined organic layers were washed with water (2 x 20 mL), brine (15 mL) and dried over MgSO4. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-10percent MeOH/ CH2Cl2 for elution gave title product 41.6.B as white solid (2.45 g, 81.2percent). [0430] 2-Methoxy-6-(2-methylpyridin-4-yl)pyridin-4-amine (41.6.C). To a mixture of 41.6. B (719 mg, 4.53 mmol), 2-methylpyridin-4-ylboronic acid (available from CombiPhos Catalysts, Inc.) (931 mf, 6.80 mmol) and potassium phosphate (2.89 g, 13.6 mmol) in n-BuOU (10 mL) was added Pd(PPh3)4 (available from Aldrich) (318 mg, 0.45 mmol). After being purged with N2 for 15 min, the mixture was stirred at 100 0C under N2 atmosphere for 8.0 hrs. The resulting reaction solution was concentrated, re-dissolved in 30percent 1PrOHZCHCl3 (25 mL), washed with water and brine, and dried over MgSO4. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-4percentMeOH/CH2Cl2 for elution gave the title product 41.6.C as colorless solid (721 mg, 74percent).

Reference： [1]Patent: WO2010/93849,2010,A2 .Location in patent: Page/Page column 126; 127

13
[ 1240523-63-0 ]
[ 579476-63-4 ]
[ 1240523-65-2 ]

Yield	Reaction Conditions	Operation in experiment
66%	With cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 85℃; for 8.0h;	(2S)-2-Amino-N-(3-chloro-5-(2-methylpyridin-4-yl)phenyl)-3- phenylpropanamide (46.F). 2-methylpyridin-4-ylboronic acid (327 mg, 2.39 mmol), (S)-tert-butyl 1 -(3 -bromo-5 -chlorophenylamino)- 1 -oxo-3 -phenylpropan-2-ylcarbamate (542 mg, 1.19 mmol), tetrakis(triphenylphosphine)palladium (345 mg, 0.30 mmol), cesium fluoride (544 mg, 3.58 mmol) were added to a vial then DME (4778 mul, 1194 mumol) was added and the mixture was heated to 85°C for 8 h. The reaction was loaded and purified on Phenomenex Geminni C18 HPLC 50 mm x 250 mm runnning ACN/Water/0.1percentTFA in a linear gradient. The fractions containing the desired product were combined and concentrated to afford tert-butyl (S)-l-(3-chloro-5-(2-methylpyridin-4-yl)phenylamino)-l- oxo-3-phenylpropan-2-ylcarbamate (367 mg, 66percent yield), tert-butyl (S)-l-(3-chloro-5-(2- methylpyridin-4-yl)phenylamino)-l -oxo-3 -phenylpropan-2-ylcarbamate (367 mg, 0.78 mmol) was dissolved in DCM (3 mL) and TFA (1 mL) add stirred for 3 h. The solution was concentrated to afford (2S)-2-amino-N-(3-chloro-5-(2-methylpyridin-4-yl)phenyl)-3- phenylpropanamide (280 mg, 99percent).

Reference： [1]Patent: WO2010/93849,2010,A2 .Location in patent: Page/Page column 134-135

14
[ 1973-04-2 ]
[ 683240-76-8 ]
[ 1820-80-0 ]
[ 74-89-5 ]
[ 579476-63-4 ]
[ 1239980-02-9 ]
[ 1239980-03-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,4-dichloro-6-methyl-1,3,5-triazine; 5-bromo-2-chloro-1H-benzo[d]imidazole With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; Stage #2: methylamine In tetrahydrofuran; 1,4-dioxane at 20℃; Stage #3: 3-aminopyrazole; 2-methylpyridine-4-boronic acid	9.1; 9.2; 9.3; 9.4 Example 9; Synthesis of 1 -(4-methyl-6-(methylamino)- 1 ,3 ,5 -triazin-2-yl)-6-(2-methylpyridin-4-yl)-N-( 1 H- pyrazol-3-yl)-l H-benzo [d]imidazol-2-amine 2,2,2-trifluoroacetate and l-(4-methyl-6-(methylamino)- 1 ,3 ,5 -triazin-2-yl)-5 -(2-methylpyridin-4-y l)-N-( 1 H-pyrazol-3 -yl)- 1 H- benzo[d]imidazol-2-amine 2,2,2-trifluoroacetate; Step l; Followed procedure in Example 1, step 2 using dioxane as the solvent and 5-bromo-2- chloro-1 H-benzo [d]imidazole to make 6-bromo-2-chloro-l-(4-chloro-6-methyl-l,3,5-triazin-2- yl)-lH-benzo[d]imidazole and 5-bromo-2-chloro-l-(4-chloro-6-methyl-l,3,5-triazin-2-yl)-lH- benzo[d]imidazole (2.86 g, 41% yield) as a 1 :1 mixture of regioisomers.; Step 2; To a solution of 6-bromo-2-chloro-l-(4-chloro-6-methyl-l,3,5-triazin-2-yl)-lH- benzo [d]imidazole and 5 -bromo-2-chloro- 1 -(4-chloro-6-methyl- 1 ,3 ,5-triazin-2-yl)- 1 H- benzo[d]imidazole as a 1 :1 mixture of regioisomers (2.86 g, 8 mmol) in 1,4-dioxane (40 mL) was added methylamine, 2.0 M solution in THF (8 mL, 1.59 mmol) at room temperature and the resulting mixture was stirred overnight. The reaction mixture was concentrated to yield 4- (6-bromo-2-chloro-lH-benzo[d]imidazol-l-yl)-N,6-dimethyl-l,3,5-triazin-2-amine and 4-(5- bromo-2-chloro-lH-benzo[d]imidazol-l-yl)-N,6-dimethyl-l,3,5-triazin-2-amine (2.542 g, 90% yield).; Step 3; To a microwave vessel charged with 4-(6-bromo-2-chloro-lH-benzo[d]imidazol-l-yl)-N,6-dimethyl-l,3,5-triazin-2-amine and 4-(5-bromo-2-chloro-lH-benzo[d]imidazol-l-yl)-N,6- dimethyl-l,3,5-triazin-2-amine as a 1 :1 mixture of regioisomers (2.542 g, 7.2 mmol) and 3- aminopyrazole (0.597 mL, 7.2 mmol) was added 2-butanol (36 mL). The reaction vessel was sealed and heated in the microwave (Biotage Initiator) at 100 0C for 15 min. The solid was collected by vacuum filtration to yield pure 6-bromo-l-(4-methyl-6-(methylamino)-l,3,5- triazin-2-yl)-N-(lH-pyrazol-3-yl)-lH-benzo[d]imidazol-2-amine hydrochloride and 5-bromo- l-(4-methyl-6-(methylamino)-l,3,5-triazin-2-yl)-N-(lH-pyrazol-3-yl)-lH-benzo[d]imidazol-2- amine hydrochloride (3.00 g, 96% yield) as a yellow solid.; Step 4; To a sealable vessel charged with 6-bromo-l-(4-methyl-6-(methylamino)-l,3,5-triazin-2-yl)-N-(lH-pyrazol-3-yl)-lH-benzo[d]imidazol-2-amine hydrochloride and 5-bromo-l-(4- methyl-6-(methylamino)-l,3,5-triazin-2-yl)-N-(lH-pyrazol-3-yl)-lH-benzo[d]imidazol-2- amine hydrochloride as a 1 :1 mixture of regioisomers (200 mg, 4.58 mmol), 1,1- bis(diphenylphosphino)ferrocene]dichloropalladium (37.4 mg, 46 μmol), and 2-methylpyridin- 4-ylboronic acid (157 mg, 1.15 mmol) was added 1,4-dioxane (2.3 mL) followed by sodium carbonate (194 mg, 1.83 mmol) as a 2 M solution in water. The reaction vessel was sealed and heated on a hot plate at 80 0C for 16 h. Crude material was filtered through Celite washing with methanol (20 mL). The filtrate was concentrated and was diluted with minimal MeOH/DMSO and purified by preparative HPLC (Gilson: 5-90% (0.1% TFA in CH3CN) in H2O over 15 min). Clean fractions were combined and concentrated to afford l-(4-methyl-6- (methylamino)- 1 ,3 ,5 -triazin-2-yl)-6-(2-methylpyridin-4-yl)-N-( 1 H-pyrazol-3 -yl)- 1 H- benzo[d]imidazol-2-amine 2,2,2-trifluoroacetate and l-(4-methyl-6-(methylamino)-l,3,5- triazin-2-yl)-5-(2-methylpyridin-4-yl)-N-(lH-pyrazol-3-yl)-lH-benzo[d]imidazol-2-amine 2,2,2-trifluoroacetate (4.5 mg, 5% yield) as a brown solid. LCMS (formic acid modifier, ESI) m/z: 413.4 (M+l). 1U NMR (400 MHz, DMSO-J6) δ ppm 2.64 - 2.82 (m, 3 H); 2.86 - 3.12 (m, 3 H); 3.57 (s, 1 H); 6.76 - 6.95 (m, 1 H); 7.57 (d, J=7.92 Hz, 1 H); 7.67 - 8.49 (m, 5 H); 8.52 - 8.92 (m, 3 H); 9.09 (br s, 1 H); 11.58 - 12.21 (m, 1 H).

Reference： [1]Current Patent Assignee: AMGEN INC - WO2010/96314, 2010, A1 Location in patent: Page/Page column 56-57

15
[ 418762-26-2 ]
[ 579476-63-4 ]
[ 1243246-11-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 10h;Inert atmosphere; Reflux;	To a round bottom flask charged with <strong>[418762-26-2]4-bromo-2-fluoro-5-methylaniline</strong> 191- 1 (2.04 g, 10 mmol), 2-methylpyridin-4-ylboronic acid 191-2 (1.37 g, 10 mmol) and Pd(PPh3)4 (0.4 g, 0.35 mmol) was added toluene (30 niL), ethanol (10 niL) and saturated sodium carbonate (10 niL). The flask was flushed with nitrogen and the reaction was heated to reflux for 10 hours. After the reaction was cooled down to room temperature, it was partitioned between ethyl acetate and saturated NaHCO3 and the organic phase was washed with brine and dried over Na2SO4. The solvent was removed by rotary evaporation and the residue was purified by silica gel flash chromatography, eluted with 50% ethyl acetate in hexane to give 2-fluoro-5-methyl-4- (2-methylpyridin-4-yl)aniline 191-3. MS m/z 217.1 (M+l).

Reference： [1]Patent: WO2010/101849,2010,A1 .Location in patent: Page/Page column 87-88

16
[ 1310475-15-0 ]
[ 579476-63-4 ]
[ 1310475-97-8 ]

Yield	Reaction Conditions	Operation in experiment
30%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dichloromethane; N,N-dimethyl-formamide; at 160℃; for 0.333333h;Inert atmosphere; Microwave irradiation;	Example 238Trans-4-(4-(3-methyl-pyridin-4-yl)-3-methyl-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amideTrans-4-(4-Bromo-3-methyl-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 154, 100 mg, 0.201 mmol), Pd(dppf)Cl2. DCM (33 mg, 0.04 mmol), 2M Na2CO3 (1 ml, 2.01 mmol) and 2-methyl-4-pyridine boronic acid (41 mg, 0.302 mmol) were dissolved in DMF (1 ml) under N2.The reaction mixture was microwaved at 160° C. for 20 min., after which LCMS indicated that the reaction was complete.The mixture was diluted with EtOAc and washed with H2O (*2).The organic layer was concentrated in vacuo, and the crude material was purified via column chromatography using a biotage SP1 25+S column with a gradient 100percent EtOAc.Product fractions combined and concentrated to give the title compound as a white solid (31 mg, 30percent). MS MH+ 510.1

Reference： [1]Patent: US2011/136735,2011,A1 .Location in patent: Page/Page column 111-112

17
[ 884495-38-9 ]
[ 579476-63-4 ]
C₁₃H₁₂N₂O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4891 - 4899

18
[ 28948-60-9 ]
[ 579476-63-4 ]
C₁₃H₁₀N₂OS [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4823 - 4827

19
[ 97004-04-1 ]
[ 579476-63-4 ]
[ 1354355-39-7 ]

Yield	Reaction Conditions	Operation in experiment
45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	(6-chloropyridin-3-yl)methanamine (300mg, 2.1 mmol) and 2-methylpyridin-4-ylboronic acid (345mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL), K3P04 (893mg, 4.2mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21mmol) were added under the nitrogen protection. The reaction was heated to 125C for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2S04, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6-(2-methylpyridin-4-yl)pyridin-3-yl)methanarnine (0.19g , yield -45%). MS m/z 200.1 (M + 1).
Ca. 45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	Step 3: (6-chloropyridin-3-yl)methanamine (300mg, 2.1 mmol) and 2-methylpyridin-4-ylboronic acid (345mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL). K3P04 (893mg, 4.2mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21mmol) were added under the nitrogen protection. The reaction was heated to 125C for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2S04, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6-(2-rnethylpyridin-4-yl)pyridin-3-yl)methanainine (0.19g , yield -45%). MS m z 200.1 (M + 1).
Ca. 45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	[0191] (6-chloropyridin-3-yl)methanamine (300mg, 2.1 mmol) and 2-methylpyridin-4-ylboronic acid (345mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL). K3PO4 (893mg, 4.2mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21mmol) were added under the nitrogen protection. The reaction was heated to 125C for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2S04, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6-(2-methylpyridin-4-yl)pyridin-3-yl)methanamine (0.19g , yield -45%). MS m/z 200.1 (M + 1).

Ca. 45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	(6-chloropyridin-3-yl)methanamine (300mg, 2.1 mmol) and 2-methylpyridin-4-ylboronic acid (345mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL). K3PO4 (893mg, 4.2mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21mmol) were added under the nitrogen protection. The reaction was heated to 125C for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2SO4, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6-(2-methylpyridin-4-yl)pyridin-3-yl)methanamine (0.19g , yield -45%). MS m/z 200.1 (M + 1).
Ca. 45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	6-chloropyridin-3-yl)methanamine (300 mg, 2.1 mmol) and 2-methylpyridin-4-ylboronic acid (345 mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL). K3PO4 (893 mg, 4.2 mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21 mmol) were added under the nitrogen protection. The reaction was heated to 125 C. for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2SO4, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6-(2-methylpyridin-4-yl)pyridin-3-yl)methanamine (0.19 g, yield ~45%). MS m/z 200.1 (M+1).
Ca. 45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Sealed tube; Inert atmosphere;	(6-chloropyridin-3-yl) methanamine (300 mg, 2.1 mmol) and 2-methylpyridine 4-ylboronic acid (345 mg, 2.52 mmol) was dissolved in n-butanol (10 mL) and water (2 mL) In a pressure tube. K 3 PO 4 (893 mg, 4.2 mmol), Pd 2 (dba) 3 (96.3 mg, 0.105 mmol) and S-phos (86.4 mg, 0.21 mmol) were added under nitrogen protection. The reaction was heated to 125 C. for 30 minutes and then cooled to room temperature. The solution was poured into water, And 3 times with EA. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude was further purified by flash chromatography with 10% MeOH in DCM (containing ~ 2 N NH3) to give pure (6- (2-methylpyridin-4-yl) pyridin-3-yl) methanamine (0.19 G, yield ~ 45%).
45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	6-chloropyridin-3-yl)methanamine (300mg, 2.1 mmol) and 2-methylpyridin-4- ylboronic acid (345mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL). K3P04 (893mg, 4.2mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21 mmol) were added under the nitrogen protection. The reaction was heated to 125C for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2S04, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6- (2-methylpyridin-4-yl)pyridin-3-yl)methanamine (0.19g , yield -45%). MS m/z 200.1 (M + 1).
	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 96℃;Inert atmosphere;	Example 7N-((2'-methyl-r2,4'-bipyridinl-5-yl)methyl)-4-(pyrazin-2-yl)benzamide (18) Compound 18[0169] Step 1: A mixture of <strong>[579476-63-4](2-methylpyridin-4-yl)boronic acid</strong> 15-1 (476 mg, 3.48 mmol), (6-chloropyridin-3-yl)methanamine 18-1 (496 mg, 3.48 mmol), Pd(PPh3)4 (202 mg, 0.175 mmol) and K3P04 (1113 mg, 5.25 mmol) in dioxane (5 mL) was stirred at 96 C under argon overnight. After cooling to room temperature, the mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated by rotavap and the residue subjected to silica gel column chromatography with 7% ammonia-saturated methanol in dichloromethane as eluent to give (2'-methyl-[2,4'-bipyridin]-5-yl)methanamine 18-2 as an oil.

Reference： [1]Patent: WO2012/88712,2012,A1 .Location in patent: Page/Page column 16-17
[2]Patent: WO2013/185353,2013,A1 .Location in patent: Page/Page column 28
[3]Patent: WO2014/159733,2014,A1 .Location in patent: Paragraph 0190-0191
[4]Patent: WO2014/165232,2014,A1 .Location in patent: Paragraph 0204; 0205
[5]Patent: US2015/119387,2015,A1 .Location in patent: Paragraph 0205; 0206
[6]Patent: JP2017/95498,2017,A .Location in patent: Paragraph 0125; 0126
[7]Patent: WO2016/191525,2016,A1 .Location in patent: Paragraph 0259-0260
[8]Patent: WO2012/3189,2012,A1 .Location in patent: Page/Page column 78-79

20
[ 72235-58-6 ]
[ 579476-63-4 ]
[ 1354355-37-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 96℃;Inert atmosphere;	Example 6N-(3-fluoro-4-(2-methylpyridin-4-yl)benzyl)-4-(pyrimidin-5-yl)benzamide (15) Compound 15[0167] Step 1 : A mixture of (2-methylpyridin-4-yl)boronic acid 15-1 (822 mg, 6.2 mmol), <strong>[72235-58-6](4-chloro-3-fluorophenyl)methanamine</strong> 15-2 (798 mg, 5.00 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol) and K3P04 (1.59 g, 7.50 mmol) in dioxane (10 mL) and water (1 mL) was stirred at 96 C under argon overnight. After cooling to room temperature, the mixture was filtered through celite, washed with ethyl acetate, and dried with Na2S04. The filtrate was concentrated by rotavap and the residue subjected to silica gel column chromatography with 6% ammonia- saturated methanol in dichloromethane as eluent to give (3-fluoro-4-(2-methylpyridin-4- yl)phenyl)methanamine 15-3 as an oil.

Reference： [1]Patent: WO2012/3189,2012,A1 .Location in patent: Page/Page column 77-78

21
[ 72235-58-6 ]
[ 579476-63-4 ]
[ 1354353-53-9 ]

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

22
[ 97483-77-7 ]
[ 579476-63-4 ]
[ 1384182-08-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 95℃;Inert atmosphere;	5-bromopicolinonitrile (500mg, 2.7 mmol) and 2-methylpyridin-4-ylboronic acid (561.2 mg, 4.1 mmol) were added in a flask, followed by Pd2(dba)3 (250mg, 0.27mmol), s-Phos (224.3mg, 0.54mmol) and K3PO4 (1.16g, 5.4mmol) under the N2 protection. 25mL n-butanol and 5mL water were added into the reaction and the reaction was stirred well at 95°C for overnight. After cooling down the reaction to the RT, lOOmL water was added into the flask and then extracted by EA for three times. The combined organic layer was washed with brine, dried over Na2S04 and concentrated under the vacuum. The crude product was further purified by flash chromatography using EA/Hexane (1:1) to get 5-(2-memylpyiidm-4-yl)pyridine-2-carbomtrile (368mg, yield -70percent). Re- dissolved the solid into 50mL ethanol, after de-gas, 40mg raney nickel and 3 drops of ammonia water were added and the reaction was stirred at RT under a 3/4 balloon for overnight. After filtering through the c elite, the solution was concentrated under the vacuum. The crude product was jEiirther purified by flash chromatography using 10percentMeOH in DCM to get the final compound (5-(2- methylpyridin-4-yl)pyridin-2-yl)methanamine (246mg, yield -65percent ). MS m/z 200.1 (M + 1).

Reference： [1]Patent: WO2012/88712,2012,A1 .Location in patent: Page/Page column 19-20

23
[ 1353254-09-7 ]
[ 579476-63-4 ]
[ 1353255-14-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 80℃;Inert atmosphere;	Synthesis of ethyl 3-(2-methylpyridin-4-yl)-l-trifyl-lH-indazole-5-carboxylateethyl 3-bromo-l-trityl-lH-indazole-5-carboxylate (510 mg, 1.0 mol) was added to a vial containing 2-methylpyridin~4-ylboronic acid (128 mg, 1.04 mol) andtetrakis(triphenylphosphine)palladium (140 mg, 0.104 mol). After purging the vial with nitrogen gas, dioxane (5 mL) and 2M sodium carbonate (5 mL) was added to the vial respectively. The reaction mixture was stirred and was heated to 80 °C for overnight. Upon completion, the mixture was concentrated under vacuo. The mixture was extracted using ethyl acetate (3 chi 100 mL). The extracts were combined and dried using anhydrous sodium sulfate. The resulting mixture was purified using flash chromatography to give the desired compound in 85percent yield

Reference： [1]Patent: WO2012/87772,2012,A1 .Location in patent: Page/Page column 68

24
[ 5600-21-5 ]
[ 579476-63-4 ]
[ 1392100-75-2 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water;Reflux;	A mixture of 2.00 g (13.9 mmol) 2-amino-4-chloro-6-methylpyrimidine, 2.48 g (18.1 mmol) 2-picoline-4-b o r o n i c a c i d , 0 . 4 3 g ( 2 . 8 m m o l ) tetrakis(triphenylphosphine)palladium(0) and 3.85 g (27.9 mmol) potassium carbonate in 40 mL 1,2-dimethoxy ethane and 4 mL water is heated to reflux temperature and stirred overnight. The reaction mixture is concentrated under reduced pressure, water is added and the precipitated product is filtered off and dried in vacuo at 40 C. Yield: 1.94 g (69%).
69%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water;Reflux;	A mixture of 2.00 g (13.9 mmol) 2-amino-4-chloro-6-methylpyrimidine, 2.48 g (18.1 mmol) 2-picoline-4-boronic acid, 0.43 g (2.8 mmol) tetrakis(triphenylphosphine)palladium(0) and 3.85 g (27.9 mmol) potassium carbonate in 40 mL 1,2-dimethoxyethane and 4 mL water is heated to reflux temperature and stirred overnight. The reaction mixture is concentrated under reduced pressure, water is added and the precipitated product is filtered off and dried in vacuo at 40 C. Yield: 1.94 g (69%).

Reference： [1]Patent: WO2012/101184,2012,A1 .Location in patent: Page/Page column 53
[2]Patent: US2013/23533,2013,A1 .Location in patent: Paragraph 0219; 0220

25
[ 1391979-23-9 ]
[ 579476-63-4 ]
[ 1392099-58-9 ]

Yield	Reaction Conditions	Operation in experiment
42%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 120℃; for 1.0h;microwave irradiation;	To a mixture of 75 mg (0.21 mmol) E-l, 42 mg (0.31 mmol) 2-picoline-4-boronic acid, 54 mg (0.39 mmol) potassium carbonate and 0.11 mL water in 1 mL dioxane is added 24 mg (21 mupiiotaomicron) tetrakis(triphenylphospine)palladium(0) and the reaction mixture is stirred at 120°C for 1 h under microwave irradiation. The product is purified with RP HPLC. Yield: 36.4 mg (42percent). HPLC-MS: M+H = 408; tR = 1.00 min.
42%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 120℃; for 1.0h;Microwave irradiation;	To a mixture of 75 mg (0.21 mmol) E-1, 42 mg (0.31 mmol) 2-picoline-4-boronic acid, 54 mg (0.39 mmol) potassium carbonate and 0.11 mL water in 1 mL dioxane is added 24 mg (21 mumol) tetrakis(triphenylphospine)palladium(0) and the reaction mixture is stirred at 120° C. for 1 h under microwave irradiation. The product is purified with RP HPLC. Yield: 36.4 mg (42percent). HPLC-MS: M+H=408; tR=1.00 min

Reference： [1]Patent: WO2012/101184,2012,A1 .Location in patent: Page/Page column 70
[2]Patent: US2013/23533,2013,A1 .Location in patent: Paragraph 0298; 0299

26
[ 1391979-24-0 ]
[ 579476-63-4 ]
[ 1392099-64-7 ]

Yield	Reaction Conditions	Operation in experiment
36%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 130℃; for 0.5h;microwave irradiation;	To a mixture of 40 mg (89 mupiiotaomicron) E-2, 18 mg (0.13 mmol) 2-picoline-4-boronic acid, 27 mg (0.20 mmol) potassium carbonate and 0.2 mLwater in 1 mL DMF is added 7 mg (4 mupiiotaomicron) tetrakis(triphenylphospine)palladium(0) and the reaction mixture is stirred at 130°C for 30 min under microwave irradiation. The product is purified with RP HPLC. Yield: 16.2 mg (36percent). HPLC-MS: M+H = 506; tR = 1.23 min.
36%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 130℃; for 0.5h;Microwave irradiation;	To a mixture of 40 mg (89 mmol) E-2, 18 mg (0.13 mmol) 2-picoline-4-boronic acid, 27 mg (0.20 mmol) potassium carbonate and 0.2 mLwater in 1 mL DMF is added 7 mg (4 mumol) tetrakis(triphenylphospine)palladium(0) and the reaction mixture is stirred at 130° C. for 30 min. under microwave irradiation. The product is purified with RP HPLC. Yield: 16.2 mg (36percent). HPLC-MS: M+H=506; tR=1.23 min

Reference： [1]Patent: WO2012/101184,2012,A1 .Location in patent: Page/Page column 73
[2]Patent: US2013/23533,2013,A1 .Location in patent: Paragraph 0310; 0311

27
[ 1391979-25-1 ]
[ 579476-63-4 ]
[ 1392100-79-6 ]

Yield	Reaction Conditions	Operation in experiment
41%	With sodium carbonate;[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); In 1-methyl-pyrrolidin-2-one; water; at 120℃; for 0.25h;microwave irradiation;	To a solution of 1.0 g (3.6 mmol) E-3 and 603 mg (4.4 mmol) 2-picoline-4-boronic acid in 9.2 mL 2 M aqueous sodiumcarbonate and 6 mL MP is added 161 mg (0.22 mmol) [Iota, Gamma- bis(diphenylphosphino)ferrocene]dichloropalladium (II) and the mixture is stirred at 120°C for 15 min. under microwave irradiation. Water is added until a precipitate is formed. The product is filtered off an dried in vacuo. Yield: 53.4 mg (41percent).

Reference： [1]Patent: WO2012/101184,2012,A1 .Location in patent: Page/Page column 66

28
[ 1401310-80-2 ]
[ 579476-63-4 ]
[ 1401310-87-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 90℃;Inert atmosphere;	Preparation E: l-[8-(aminomethyl)-5-(2-methyl-pyridin-4-yl)-isoquinolin-3-yl]-3- ethyl-urea:Starting from the compound of Preparation B (500 mg) and <strong>[579476-63-4]2-methylpyridine-4-boronic acid</strong>, and proceeding in analogy to Procedure AJ, the title compound was obtained, after purification by CC (DCM/MeOH +1percent NH4OH 100:0 to 90: 10), as a yellow solid (478 mg; 80percent yield).1H NMR (d6-DMSO) delta: 9.33 (d, J = 0.5 Hz, 1H); 9.02 (s, 1H); 8.55 (d, J = 5.1 Hz, 1H); 8.00 (s, 1H); 7.55-7.45 (m, 2H); 7.33 (s, 1H); 7.26 (dd, J = 5.1, 1.4 Hz, 1H); 7.18 (t, J = 5.4 Hz, 1H); 4.26 (s, 2H); 3.17-3.06 (m, 2H); 2.55 (s, 3H); 1.95 (br s, 2H); 1.04 (t, J = 7.2 Hz, 3H).MS (ESI, m/z): 336.1 [M+H+]. Procedure AJ (Suzuki coupling with tricyclohexylphosphine): To the aromatic halide (1.0 mmol; 1.0 eq.), the required boronic acid (1.5 eq.), Pd2(dba)3 (0.05 eq.) and PCy3 (0.12 eq.) in a glass vial, under inert atmosphere (N2), are added degassed dioxane (3.3 mL) and a degassed aq. 1N K3P04 solution (1.7 mL; 1.7 eq.) at rt. The reaction mixture is stirred at 90°C and monitored by LC-MS. Upon reaction completion, the reaction mixture is either directly concentrated to give the crude product, or diluted with 9: 1 DCM/MeOH and a sat. aq. NaHC03 solution. The layers are separated and the aq. layer is extracted with 9: 1 DCM/MeOH (3x). The combined org. layers are washed with a sat. aq. NaHC03 solution, water and brine, dried over MgS04, filtered and concentrated under reduced pressure. In both cases, the purification of the residue gives the desired product.

Reference： [1]Patent: WO2012/131588,2012,A1 .Location in patent: Page/Page column 113
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 3755 - 3775

29
[ 622387-27-3 ]
[ 579476-63-4 ]
[ 1093217-88-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 85℃; for 0.416667h;microwave;	Step 1 :2"-Methyl-3,4,5,6-tetrahydro-2H-[4,2';5',4"]terpyridine-1-carboxylic acid tert-butyl ester:5-Bromo-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1 '-carboxylic acid tert-butyl ester (0.6 g, 1.76 mmol), <strong>[579476-63-4]2-methylpyridine-4-boronic acid</strong> (264 mg, 1.9 mmol), bis(triphenylphosphine)- palladium(ll)chloride (0.06 g, 0.09 mmol), 1 M Na2CO3 (4 ml) and acetonitrile (4 ml) were mixed in a 5 ml microwave vial. Another (2 ml) and acetonitrile (2 ml) were added. The reaction mixture was heated for 1500sec. at 85°C. Water layer was removed. The acetonitrile phase was added DCM (2OmL). The organic phase was filtered and evaporated in vacuo. The crude mixture was purified on a silicagel column with EtOAc/heptane (4:1 ) and then EtOAc/heptane (9:1 ). The product was collected as a clear oil (540mg, 87percent).LC-MS (electrospray): m/z: 354 (M+1 ); Rt= 1.12min.1H NMR (300 MHz, CDCI3) delta: 8.85(d, 1 H), 8.6(d, 1 H), 7.48(s, 1 H), 7.35(d, 1 H), 7.28(d, 2H), 4.2(m, 2H), 2.8(m, 3H), 2.65(s, 3H), 1.95(m, 2H), 1.65-1.8(m, 2H), 1.5(d, 9H).

Reference： [1]Patent: WO2008/154126,2008,A1 .Location in patent: Page/Page column 40

30
[ 190273-89-3 ]
[ 579476-63-4 ]
6-(2-methylpyridin-4-yl)quinazolin-2-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 1996 - 2015

31
[ 1260809-13-9 ]
[ 579476-63-4 ]
[ 1446819-42-6 ]

Yield	Reaction Conditions	Operation in experiment
58%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 75℃;Inert atmosphere;	A 25 niL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4-[(4-bromo-2- fluorophenyl)methyl]piperazine-l-carboxylate (1.00 g, 2.68 mmol, 1.00 equiv), (2- methylpyridin-4-yl)boronic acid (0.737 g, 5.38 mmol, 2.01 equiv), Tetrakis(triphenylphosphine)palladium (0.31 1 g, 0.270 mmol, 0.10 equiv), potassium carbonate (1.10 g, 7.96 mmol, 2.97 equiv), dioxane (10 mL) and water (2 mL). The resulting solution was stirred overnight at 75 °C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/2) to yield 0.600 g (58percent yield) of tert-butyl 4-[[2-fluoro-4-(2-methylpyridin-4- yl)phenyl]methyl]piperazine-l-carboxylate as yellow oil. LCMS (ESI, m/z): 386 [M+H]+.

Reference： [1]Patent: WO2013/103973,2013,A1 .Location in patent: Paragraph 00354

32
[ 1446819-44-8 ]
[ 579476-63-4 ]
[ 1460035-33-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 75℃;Inert atmosphere;	Step 2: Preparation of tert-butyl 4-[[2-methyl-4-(2-methylpyridin-4- yl)phenyl]methyl]piperazine-l-carboxylate [00410] A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen then charged with tert-butyl 4-[(4-bromo-2- methylphenyl)methyl]piperazine-l-carboxylate (2.00 g, 5.42 mmol, 1.00 equiv), (2- methylpyridin-4-yl)boronic acid (1.50 g, 10.9 mmol, 2.02 equiv), Pd(PPh3)4 (0.624 g, 0.540 mmol, 0.10 equiv), potassium carbonate (2.25 g, 16.3 mmol, 3.01 equiv), dioxane (20 mL), and water (4 mL). The resulting solution was stirred overnight at 75 °C. Reaction progress was monitored by LCMS. The reaction was then quenched by water (30 mL). The resulting solution was extracted with ethyl acetate (3 x 30 mL), and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to provide 1.70 g (82percent yield) of ter/-butyl 4-[[2-methyl-4-(2- methylpyridin-4-yl)phenyl]methyl]piperazine-l-carboxylate as a yellow oil. LCMS (ESI, m/z): 382 [M+H]+.

Reference： [1]Patent: WO2013/142307,2013,A1 .Location in patent: Paragraph 00410

33
[ 267901-75-7 ]
[ 579476-63-4 ]
5,7-dimethyl-6-(2-methylpyridin-4-yl)-4-phenyl-2H-chromen-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium phosphate; 2-(dicyclohexylphosphino)-2'-methylbiphenyl; In 1,4-dioxane; water; at 150℃; for 0.5h;	A mixture of 6-bromo-5,7-dimethyl-4-phenyl-2H-chromen-2-one (8) (66 mg, 0.20 mmol), 2-memthylpyridine-4-boronic acid (41 mg, 0.30 mmol), potassium phosphate (127 mg, 0.60 mmol), 2-dicyclohexylphosphino-2?-methylbiphenyl (29 mg, 0.08 mmol) and palladium acetate (9 mg, 0.04 mmol) in a mixture of 1,4-dioxane and water (9:1, 3 mL) was stirred at 150°C for 30 min. After cooled to room temperature, the mixture was evaporated and the residue was dissolved with chloroform-methanol (9:1) and water. Organic phase was separated and dried over magnesium sulfate. Evaporation of the solvents give a residue, which was chromatographed on silica gel (AcOEt:hexanes=1:9~1:1) to give the title compound 1r (47 mg, 69percent yield). 1H NMR (300 MHz, CDCl3) delta 8.54 (d, J = 5.0, 1H), 7.47 ? 7.39 (m, 3H), 7.33 ? 7.27 (m, 2H), 7.22 (s, 1H), 6.89 (s, 1H), 6.86 ? 6.80 (m, 1H), 6.26 (s, 1H), 2.58 (s, 3H), 2.07 (s, 3H), 1.48 (s, 3H). MS(ESI) m/z +342.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6052 - 6059

34
6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine [ No CAS ]
[ 579476-63-4 ]
6-chloro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;	Step 3: 6-chloro-3-(2-methylpyridin-4-yl)-l-trityl-l^ -pyrazolo[4,3-c]pyridine (4a) (R1=2-methyl pyridine) 6-chloro-3-iodo-l-trityl-lH-pyrazolo[4,3-c]pyridine (2.465 g, 4.72 mmol), 2- methylpyridine-4-boronic acid (0.966 g, 7.05 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.579 g, 0.709 mmol) and K C03 (1.959 g, 14.17 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL)/U2 (2.5 mL). The reaction mixture was degassed for 5 min, heated to 80 °C overnight, cooled to RT and diluted with EtOAc. Reaction was filtered through Celite and then partitioned between EtOAc and saturated NaHC03. The organic layer was extracted with EtOAc (3x) and the combined organic layers were dried (Na2S04) and concentrated in vacuo. The residue was purified by chromatography on silica gel over a gradient of 0-75percent EtOAc in hexanes to yield 6-cUoro-3-(2-methylpyridin-4-yl)-l-tri1yl-lH-pyrazolo[4,3-c]pyridine (1.02 g, 2.09 mmol, 44percent) as a solid. MS ESI calc'd. for C31H24C1N4 [M+l]+487, found 487.
44%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃;	(2.465 g, 4.72 mmol), <strong>[579476-63-4]2-methylpyridine-4-boronic acid</strong> (0.966 g, 7.05 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.579 g, 0.709 mmol) and K2CO3 (1.959 g, 14.17 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL)/H2O (2.5 mL). The reaction mixture was degassed for 5 min, heated to 80 °C overnight, cooled to RT and diluted with EtOAc. Reaction was filtered through Celite and then partitioned between EtOAc and saturated NaHCO3. The organic layer was extracted with EtOAc (3x) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel over a gradient of 0-75percent EtOAc in hexanes to yield 6-chloro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.02 g, 2.09 mmol, 44percent) as a solid. MS ESI calc'd. for C31H24ClN4 [M+1]+487, found 487

Reference： [1]Patent: WO2013/63214,2013,A1 .Location in patent: Page/Page column 74-76
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 6501 - 6511
[3]Patent: EP2770987,2018,B1 .Location in patent: Paragraph 0297; 0298

35
6-chloro-2,7-naphthyridin-1-(2H)-one [ No CAS ]
[ 579476-63-4 ]
6-(2-methylpyridin-4-yl)-2,7-naphthyridin-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
Ca. 61%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 130℃; for 1.0h;Inert atmosphere;	Example 2 : N-(3-methyl-4-(2-methyIpyridin-4-yl)benzyl)-6-(2-methylpyridin-4-yI)-2,7- naphthyridin-l-amine (Compound No. 2) 6-c loro-2,7-naphthyridin-l(2H)-one (200 mg, 1.10 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (227.60 mg, 1.66 mmol) were dissolved in BuOH (5.0 mL) and water (1.0 mL). K3P04 (705.20 g, 3.32 mmol), Pd2(dba)3 (49.60 mg, 0.22 mmol) and S-phos (91.00 mg, 0.11 mmol) were added under N2. The reaction mixture in the pressure tube was heated up to 130C for lh. After cooling down the reaction to RT, poured the mixture into the water, extracted by EA for three times. The combined organic layer was washed with brine, dried over Na2SC> , concentrated under the vacuum to get the crude. The crude product was purified by column with 5% MeOH in DCM to get the final compound 6-(2-methylpyridin-4-yl)- 2,7-naphthyridin-l(2H)-one (yield ~ 61%). MS m/z 238.1 (M + 1).
Ca. 61%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 130℃; for 1.0h;Inert atmosphere;	[0180] 6-chloro-2,7-naphthyridin- 1 (2H)-one (200 mg, 1.10 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (227.60 mg, 1.66 mmol) were dissolved in BuOH (5.0 mL) and water (1.0 mL). K3P04 (705.20 g, 3.32 mmol), Pd2(dba)3 (49.60 mg, 0.22 mmol) and S-phos (91.00 mg, 0.1 1 mmol) were added under N2. The reaction mixture in the pressure tube was heated up to 130C for lh. After cooling down the reaction to RT, poured the mixture into the water, extracted by EA for three times. The combined organic layer was washed with brine, dried over Na2S04, concentrated under the vacuum to get the crude. The crude product was purified by column with 5% MeOH in DCM to get the final compound 6-(2-methylpyridin- 4-yl)-2,7-naphthyridin-l(2H)-one (yield - 61%). MS m/z 238.1 (M + 1).
Ca. 61%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 130℃; for 1.0h;Inert atmosphere; Sealed tube;	6-chloro-2,7-naphthyridin-1 (2H)-one (200 mg, 1.10 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (227.60 mg, 1.66 mmol) were dissolved in BuOH (5.0 mL) and water (1.0 mL). K3PO4 (705.20 g, 3.32 mmol), Pd2(dba)3 (49.60 mg, 0.22 mmol) and S-phos (91.00 mg, 0.11 mmol) were added under N2. The reaction mixture in the pressure tube was heated up to 130C for 1h. After cooling down the reaction to RT, poured the mixture into the water, extracted by EA for three times. The combined organic layer was washed with brine, dried over Na2SO4, concentrated under the vacuum to get the crude. The crude product was purified by column with 5% MeOH in DCM to get the final compound 6-(2-methylpyridin- 4-yl)-2,7-naphthyridin-1(2H)-one (yield - 61%). MS m/z 238.1 (M + 1).

Ca. 61%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 130℃; for 1.0h;Inert atmosphere;	6-chloro-2,7-naphthyridin-1(2H)-one (200 mg, 1.10 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (227.60 mg, 1.66 mmol) were dissolved in BuOH (5.0 mL) and water (1.0 mL). K3PO4 (705.20 g, 3.32 mmol), Pd2(dba)3 (49.60 mg, 0.22 mmol) and S-phos (91.00 mg, 0.11 mmol) were added under N2. The reaction mixture in the pressure tube was heated up to 130 C. for 1 h. After cooling down the reaction to RT, poured the mixture into the water, extracted by EA for three times. The combined organic layer was washed with brine, dried over Na2SO4, concentrated under the vacuum to get the crude. The crude product was purified by column with 5% MeOH in DCM to get the final compound 6-(2-methylpyridin-4-yl)-2,7-naphthyridin-1(2H)-one (yield ~61%). MS m/z 238.1 (M+1).
Ca. 61%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 130℃; for 1.0h;Inert atmosphere;	6-Chloro-2,7-naphthyridin-1 (2H) -one (200 mg, 1.10 mmol) and 2-methylpyridine 4-yl-4-boronic acid (227.60 mg, 1.66 mmol) was dissolved in BuOH (5.0 mL) and water (1.0 mL). K 3 PO 4 (705.20 g, 3.32 mmol), Pd 2 (dba) 3 (49.60 mg, 0.22 mmol) and S-phos (91.00 mg, 0.11 mmol) were added under N 2. The reaction mixture was heated to 130 C. for 1 hour in a pressure tube. After cooling the reaction to RT, The mixture was poured into water and extracted three times with EA. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give crude. The crude product was purified by column with 5% MeOH in DCM to give the final compound 6- (2-methylpyridin-4-yl) -2,7-naphthyridin- 1 (2H) -one (yield ~ 61% Was obtained.
61%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; In water; butan-1-ol; at 130℃; for 1.0h;Inert atmosphere;	(200 mg, 1.10 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (227.60 mg, 1.66 mmol) were dissolved in butanol 5.0 mL) and water (1.0 mL).K3PO4 (705.20 g, 3.32 mmol), Pd2 (dba) 3 (49.60 mg, 0.22 mmol) and S-phos (91.00 mg, 0.11 mmol) were added under N2. Reverse the pressure tubeThe mixture was heated to 130 C for 1 h.After the reaction was cooled to RT, the mixture was poured into water and extracted three times with EA. The combined organic layers were washed with saturated brine, dried over Na 2 SO 4 and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography with 5% methanol in DCM to obtain the final compound6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1 (2H) -one(Yield ~ 61%).
61%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 130℃; for 1.0h;Inert atmosphere;	6-chloro-2,7-naphthyridin-1 (2H)-one (200 mg, 1 .10 mmol) and 2-methylpyridin-4- yl-4-boronic acid (227.60 mg, 1 .66 mmol) were dissolved in BuOH (5.0 mL) and water (1 .0 mL). K3PO4 (705.20 g, 3.32 mmol), Pd2(dba)3 (49.60 mg, 0.22 mmol) and S-phos (91 .00 mg, 0.1 1 mmol) were added under N2. The reaction mixture in the pressure tube was heated up to 130C for 1 h. After cooling down the reaction to RT, poured the mixture into the water, extracted by EA for three times. The combined organic layer was washed with brine, dried over Na2S04, concentrated under the vacuum to get the crude. The crude product was purified by column with 5% MeOH in DCM to get the final compound 6-(2-methylpyridin-4- yl)-2,7-naphthyridin-1 (2H)-one (yield ~ 61 %). MS m/z 238.1 (M + 1).

Reference： [1]Patent: WO2013/185353,2013,A1 .Location in patent: Page/Page column 25
[2]Patent: WO2014/159733,2014,A1 .Location in patent: Paragraph 0179-0180
[3]Patent: WO2014/165232,2014,A1 .Location in patent: Paragraph 0193; 0194
[4]Patent: US2015/119387,2015,A1 .Location in patent: Paragraph 0194; 0195
[5]Patent: JP2017/95498,2017,A .Location in patent: Paragraph 0108; 0109
[6]Patent: CN104530042,2017,B .Location in patent: Paragraph 0204; 0207; 0208; 0209
[7]Patent: WO2016/191525,2016,A1 .Location in patent: Paragraph 0248-0249

36
[ 3959-07-7 ]
[ 579476-63-4 ]
[ 1354355-33-1 ]

Yield	Reaction Conditions	Operation in experiment
Ca. 89%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); palladium(II) hydroxide; In water; butan-1-ol; at 125℃; for 1.0h;Inert atmosphere; Sealed tube;	Step 8: (4-bromophenyl)methanamine (1.00 g, 5.37 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (883.30 mg, 6.45 mmol) were dissolved in BuOH (10.0 mL) and water (2.0 mL). K3P04 (2.28 g, 10.75 mmol), Pd2(dba)3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added in under N2. The reaction mixture was sealed in a pressure tube and heated up to 125C for lh. After cooling down the reaction to RT, the mixture was poured into the water and extracted by lOOmL x 3 EA. The combined organic layer was washed with brine, dried over Na2SCand concentrated under the vacuum to give the crude product. The solid was purified by silicone gel column with 10% MeOH (containing ~2N N) in DCM to get the pure (4-(2-memylpyridin-4-yl)phenyl)methanamine (yield ~ 89%). MS m/z 199.1 (M + 1).
Ca. 89%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 1.0h;Inert atmosphere; Sealed tube;	(4-bromophenyl)methanamine (1.00 g, 5.37 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (883.30 mg, 6.45 mmol) were dissolved in BuOH (10.0 mL) and water (2.0 mL). K3P04 (2.28 g, 10.75 mmol), Pd2(dba)3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added in under N2. The reaction mixture was sealed in a pressure tube and heated up to 125C for lh. After cooling down the reaction to RT, the mixture was poured into the water and extracted by 1 OOmL x 3 EA. The combined organic layer was washed with brine, dried over Na2S04, and concentrated under the vacuum to give thecrude product. The solid was purified by silicone gel column with 10% MeOH (containing ~2N NH3) in DCM to get the pure (4-(2-methylpyridin-4-yl)phenyl)methanamine (yield ~ 89%). MS m/z 199.1 (M +
Ca. 89%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 1.0h;Inert atmosphere; Sealed tube;	4-bromophenyl)methanamine (1.00 g, 5.37 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (883.30 mg, 6.45 mmol) were dissolved in BuOH (10.0 mL) and water (2.0 mL). K3PO4 (2.28 g, 10.75 mmol), Pd2(dba)3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added in under N2. The reaction mixture was sealed in a pressure tube and heated up to 125 C. for 1 h. After cooling down the reaction to RT, the mixture was poured into the water and extracted by 100 mL*3 EA. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under the vacuum to give the crude product. The solid was purified by silicone gel column with 10% MeOH (containing ~2N NH3) in DCM to get the pure (4-(2-methylpyridin-4-yl)phenyl)methanamine (yield ~89%). MS m/z 199.1 (M+1).

Ca. 89%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 1.0h;Inert atmosphere; Sealed tube;	(4-bromophenyl) methanamine (1.00 g, 5.37 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (883.30 mg, 6.45 mmol) was dissolved in BuOH (10.0 mL) and water (2.0 mL) . K 3 PO 4 (2.28 g, 10.75 mmol), Pd 2 (dba) 3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added under N 2. The reaction mixture was sealed in a pressure tube and heated to 125 C. for 1 hour. After cooling the reaction to RT, the mixture was poured into water and extracted with 100 ml × 3 EA. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo A crude product was obtained. The solid was washed with 10% MeOH in DCM (containing ~ 2 N NH3) With a silicone gel column to give pure (4- (2-methylpyridin-4-yl) Phenyl) methanamine (yield ~ 89%).
89%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; In butan-1-ol; at 125℃; for 1.0h;Inert atmosphere;	(4-bromophenyl) methanamine (1.00 g, 5.37 mmol) and 2-methylpyridin-4-ylboronic acid (883.30 mg, 6.45 mmol) were dissolved in butanol mL).K3PO4 (2.28 g, 10.75 mmol), Pd2 (dba) 3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added under N2.The reaction mixture was sealed in a pressure tube and heated to 125 C for 1 h.After the reaction cooled to RT, the mixture was poured into water and extracted with 100 mL x 3EA. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the crude product. The solid was purified by silica gel column with DCM in 10% methanol containing ~ 2N ammonia to obtain pure(4- (2-methylpyridin-4-yl) phenyl) methanamine(Yield ~ 89%)
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 1.0h;Inert atmosphere; Sealed tube;	[0173] (4-bromophenyl)methanamine (1.00 g, 5.37 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (883.30 mg, 6.45 mmol) were dissolved in BuOH (10.0 mL) and water (2.0 mL). K3P04 (2.28 g, 10.75 mmol), Pd2(dba)3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added in under N2. The reaction mixture was sealed in a pressure tube and heated up to 125C for lh. After cooling down the reaction to RT, the mixture was poured into the water and extracted by 1 OOmL x 3 EA. The combined organic layer was washed with brine, dried over Na2S04, and concentrated under the vacuum to give the crude product. The solid was purified by silicone gel column with 10% MeOH (containing ~2N NH3) in DCM to get the pure (4-(2-methylpyridin-4-yl)phenyl)methanamine (yield ~ 89%). MS m/z 199.1 (M + 1).
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 1.0h;Sealed tube; Inert atmosphere;	(4-bromophenyl)methanamine (1 .00 g, 5.37 mmol) and 2-methylpyridin-4-yl-4- boronic acid (883.30 mg, 6.45 mmol) were dissolved in BuOH (10.0 mL) and water (2.0 mL). K3P04 (2.28 g, 10.75 mmol), Pd2(dba)3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added in under N2. The reaction mixture was sealed in a pressure tube and heated up to 125C for 1 h. After cooling down the reaction to RT, the mixture was poured into the water and extracted by 10OmL x 3 EA. The combined organic layer was washed with brine, dried over Na2S04, and concentrated under the vacuum to give the crude product. The solid was purified by silicone gel column with10% MeOH (containing ~2N NH3) in DCM to get the pure (4-(2-methylpyridin-4-yl)phenyl)methanamine (yield ~ 89%). MS m/z 199.1 (M + 1).

Reference： [1]Patent: WO2013/185353,2013,A1 .Location in patent: Page/Page column 23
[2]Patent: WO2014/165232,2014,A1 .Location in patent: Paragraph 0186; 0187
[3]Patent: US2015/119387,2015,A1 .Location in patent: Paragraph 0187; 0188
[4]Patent: JP2017/95498,2017,A .Location in patent: Paragraph 0097; 0098
[5]Patent: CN104530042,2017,B .Location in patent: Paragraph 0171; 0195; 0196; 0197
[6]Patent: WO2014/159733,2014,A1 .Location in patent: Paragraph 0172-0173
[7]Patent: WO2016/191525,2016,A1 .Location in patent: Paragraph 0241-0242

37
N-(4-(2-methylpyridin-4-yl)benzyl)-6-chloro-2,7-naphthyridine-1-amine [ No CAS ]
[ 579476-63-4 ]
N-(4-(2-methylpyridin-4-yl)benzyl)-6-(2-methylpyridin-4-yl)-2,7-naphthyridin-1-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
Ca. 70%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 105℃;Inert atmosphere; Sealed tube;	Step 10: N-(4-(2-methyIpyridin-4-yl)benzyl)--6-chloro-2,7--naphthyridin-l-amine (50.00 mg, 0.14 mmol) and 2- methylpyridin-4-yl-4-boronic acid (56.90 mg, 0.42 mmol) were dissolved in BuOH (3.0 mL) and water (0.6 mL). K3PO4 (88.20 mg, 0.028 mmol), Pd2(dba)3 (6.20 mg, 0.014 mmol) and S-phos (11.40 mg, 0.011 mmol) were added into the mixture under N2. The reaction was sealed in a pressure tube and heated up to 105C for overnight. After cooling down the reaction to RT, the mixture was poured in water and extracted by EA for three times. The combined organic layer was washed with brine, dried by Na2S0 , and concentrated under the vacuum. The crude product was further purified by prep-TLC with 5% MeOH in DCM to get the final product N-(4-(2-memylpyridin-4-yl)benzyl)-6-(2-methylpyridin-4-yl)-2,7- naphthyridin-1 -amine (yield -70%). MS m/z 418.2 (M + 1). 'HNMR (300 MHz, CDC13): 52.46 (s, 3H), 2.63 (s, 3H), 4.94 (d, J= 5.10 Hz, 2H), 5.94 (br, 1H), 6.97 (d, J= 5.70 Hz, 1H), 7.31 (d, J= 4.20 Hz, 1H), 7.36 (s, 1H), 7.54 (d, J= 8.10 Hz, 2H), 7.63 (d, /= 8.40 Hz, 2H), 7.90 (s, 1H), 8.19 (d, /= 6.00 Hz, 1H), 8.22 (s, 1H), 8.51 (m, 2H), 9.08 (s, 1H), 9.30 (s, 1H).
Ca. 70%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 105℃;Inert atmosphere; Sealed tube;	[0177] N-(4-(2-methylpyridin-4-yl)benzyl)-6-chloro-2,7-naphthyridin-l-amine (50.00 mg, 0.14 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (56.90 mg, 0.42 mmol) were dissolved in BuOH (3.0 mL) and water (0.6 mL). K3P04 (88.20 mg, 0.028 mmol), Pd2(dba)3 (6.20 mg, 0.014 mmol) and S-phos (1 1.40 mg, 0.01 1 mmol) were added into the mixture under N2. The reaction was sealed in a pressure tube and heated up to 105C for overnight. After cooling down the reaction to RT, the mixture was poured in water and extracted by EA for three times. The combined organic layer was washed with brine, dried by Na2S04, and concentrated under the vacuum. The crude product was further purified by prep-TLC with 5% MeOH in DCM to get the final product N-(4-(2-methylpyridin-4-yl)benzyl)-6-(2-methylpyridin-4-yl)-2,7- naphthyridin-1 -amine (yield -70%). MS m/z 418.2 (M + 1). 1HNMR (300 MHz, CDC13): 82.46 (s, 3H), 2.63 (s, 3H), 4.94 (d, J= 5.10 Hz, 2H), 5.94 (br, 1H), 6.97 (d, J= 5.70 Hz, 1H), 7.31 (d, J= 4.20 Hz, 1H), 7.36 (s, 1H), 7.54 (d, J= 8.10 Hz, 2H), 7.63 (d, J= 8.40 Hz, 2H), 7.90 (s, 1H), 8.19 (d, J= 6.00 Hz, 1H), 8.22 (s, 1H), 8.51 (m, 2H), 9.08 (s, 1H), 9.30 (s, 1H).
Ca. 70%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 105℃;Inert atmosphere; Sealed tube;	N-(4-(2-methylpyridin-4-yl)benzyl)-6-chloro-2,7-naphthyridin-l -amine (50.00 mg, 0.14 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (56.90 mg, 0.42 mmol) were dissolved in BuOH (3.0 mL) and water (0.6 mL). K3P04 (88.20 mg, 0.028 mmol), Pd2(dba)3 (6.20 mg, 0.014 mmol) and S-phos (1 1.40 mg, 0.01 1 mmol) were added into the mixture under N2. The reaction was sealed in a pressure tube and heated up to 105C for overnight. After cooling down the reaction to RT, the mixture was poured in water and extracted by EA for three times. The combined organic layer was washed with brine, dried by Na2S04, and concentrated under the vacuum. The crude product was further purified by prep-TLC with 5% MeOH in DCM to get the final product N-(4-(2-methylpyridin-4-yl)benzyl)-6-(2-methylpyridin-4-yl)-2,7- naphthyridin-1 -amine (yield -70%). MS m/z 418.2 (M + 1). 1HNMR (300 MHz, CDC13): 82.46 (s, 3H), 2.63 (s, 3H), 4.94 (d, J= 5.10 Hz, 2H), 5.94 (br, 1H), 6.97 (d, J= 5.70 Hz, 1H), 7.31 (d, J= 4.20 Hz, 1H),7.36 (s, 1H), 7.54 (d, J= 8.10 Hz, 2H), 7.63 (d, J= 8.40 Hz, 2H), 7.90 (s, 1H), 8.19 (d, J= 6.00 Hz, 1H), 8.22 (s, 1H), 8.51 (m, 2H), 9.08 (s, 1H), 9.30 (s, 1H).

Ca. 70%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 105℃;Inert atmosphere; Sealed tube;	N-(4-(2-methylpyridin-4-yl)benzyl)-6-chloro-2,7-naphthyridin-1-amine (50.00 mg, 0.14 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (56.90 mg, 0.42 mmol) were dissolved in BuOH (3.0 mL) and water (0.6 mL). K3PO4 (88.20 mg, 0.028 mmol), Pd2(dba)3 (6.20 mg, 0.014 mmol) and S-phos (11.40 mg, 0.011 mmol) were added into the mixture under N2. The reaction was sealed in a pressure tube and heated up to 105 C. for overnight. After cooling down the reaction to RT, the mixture was poured in water and extracted by EA for three times. The combined organic layer was washed with brine, dried by Na2SO4, and concentrated under the vacuum. The crude product was further purified by prep-TLC with 5% MeOH in DCM to get the final product N-(4-(2-methylpyridin-4-yl)benzyl)-6-(2-methylpyridin-4-yl)-2,7-naphthyridin-1-amine (yield ~70%). MS m/z 418.2 (M+1). 1HNMR (300 MHz, CDCl3): delta2.46 (s, 3H), 2.63 (s, 3H), 4.94 (d, J=5.10 Hz, 2H), 5.94 (br, 1H), 6.97 (d, J=5.70 Hz, 1H), 7.31 (d, J=4.20 Hz, 1H), 7.36 (s, 1H), 7.54 (d, J=8.10 Hz, 2H), 7.63 (d, J=8.40 Hz, 2H), 7.90 (s, 1H), 8.19 (d, J=6.00 Hz, 1H), 8.22 (s, 1H), 8.51 (m, 2H), 9.08 (s, 1H), 9.30 (s, 1H).
Ca. 70%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 105℃;Sealed tube; Inert atmosphere;	N- (4- (2-methylpyridin-4-yl) benzyl) -6-chloro-2,7- naphthyridin-1-amine (50.00 mg, 0.14 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (56.90 mg, 0.42 mmol) were dissolved in BuOH (3.0 mL) and water (0.6 mL). K 3 PO 4 (88.20 mg, 0.028 mmol), Pd 2 (dba) 3 (6.20 mg, 0.014 mmol) and S-phos (11.40 mg, 0.011 mmol) were added to the mixture under N 2. The reaction was sealed in a pressure tube, Heat to 105 C. overnight. After cooling the reaction to RT, the mixture was poured into water, It was extracted 3 times with EA. The combined organic layers were washed with brine, dried with Na 2 SO 4 and concentrated in vacuo. The crude product was further purified by prep-TLC with 5% MeOH in DCM to give the final product N- (4- (2-methylpyridin-4-yl) benzyl) -6- (2-methylpyridin- Yl) -2,7-naphthyridin-1-amine (yield ~ 70%).
70%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; In water; butan-1-ol; at 105℃;Inert atmosphere; Sealed tube;	A solution of N- (4- (2-methylpyridin-4-yl) benzyl) -6-chloro-2,7-naphthyridin- 1 -amine (50.00 mg, 0.14 mmol) and 2- 4-yl-4-boronic acid (56.90 mg, 0.42 mmol) was dissolved in butanol (3.0 mL) and water (0.6 mL).K3PO4 (88.20 mg, 0.028 mmol), Pd2 (dba) 3 (6.20 mg, 0.014 mmol) and S-phos (11.40 mg, 0.011 mmol) were added to the mixture under N2. The mixture was sealed in a pressure tube and then heated to 105 C overnight.After the reaction was cooled to RT, the mixture was poured into water and extracted three times with EA. The combined organic layers were washed with brine, dried over Na 2SO 4 and concentrated in vacuo. The crude product was further purified by preparative thin-layer chromatography with 5% methanol in DCM to obtain the final productN- (4- (2-methylpyridin-4-yl) benzyl) -6- (2- methylpyridin- 4-yl) -2,7-naphthyridin- 1 -amine(Yield ~ 70%).
70%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 105℃;Inert atmosphere; Sealed tube;	N-(4-(2-methylpyridin-4-yl)benzyl)-6-chloro-2,7-naphthyridin-1 -amine (50.00 mg, 0.14 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (56.90 mg, 0.42 mmol) were dissolved in BuOH (3.0 mL) and water (0.6 mL). K3P04 (88.20 mg, 0.028 mmol), Pd2(dba)3 (6.20 mg, 0.014 mmol) and S-phos (1 1 .40 mg, 0.01 1 mmol) were added into the mixture under N2. The reaction was sealed in a pressure tube and heated up to 105C for overnight. After cooling down the reaction to RT, the mixture was poured in water and extracted by EA for three times. The combined organic layer was washed with brine, dried by Na2S04, and concentrated under the vacuum. The crude product was further purified by prep-TLC with 5% MeOH in DCM to get the final product N-(4-(2-methylpyridin-4-yl)benzyl)-6-(2- methylpyridin-4-yl)-2,7-naphthyridin-1 -amine (yield -70%). MS m/z 418.2 (M + 1). 1HNMR (300 MHz, CDCIs): 52.46 (s, 3H), 2.63 (s, 3H), 4.94 (d, J = 5.10 Hz, 2H), 5.94 (br, 1 H), 6.97 (d, J = 5.70 Hz, 1 H), 7.31 (d, J = 4.20 Hz, 1 H), 7.36 (s, 1 H), 7.54 (d, J = 8.10 Hz, 2H), 7.63 (d, J = 8.40 Hz, 2H), 7.90 (s, 1 H), 8.19 (d, J = 6.00 Hz, 1 H), 8.22 (s, 1 H), 8.51 (m, 2H), 9.08 (s, 1 H), 9.30 (s, 1 H).

Reference： [1]Patent: WO2013/185353,2013,A1 .Location in patent: Page/Page column 24
[2]Patent: WO2014/159733,2014,A1 .Location in patent: Paragraph 0176-0177
[3]Patent: WO2014/165232,2014,A1 .Location in patent: Paragraph 0190; 0191
[4]Patent: US2015/119387,2015,A1 .Location in patent: Paragraph 0191; 0192
[5]Patent: JP2017/95498,2017,A .Location in patent: Paragraph 0073; 0074; 0103; 0104
[6]Patent: CN104530042,2017,B .Location in patent: Paragraph 0171; 0201; 0202; 0203
[7]Patent: WO2016/191525,2016,A1 .Location in patent: Paragraph 0245-0246

38
[ 23616-35-5 ]
[ 579476-63-4 ]
5-chloro-2-(2-methylpyridin-4-yl)-1,6-naphthyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
Ca. 56%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4.0h;	Step 4: 2,5-dichloro-l,6-naphthyridine (200mg, l.Ommol), 2-methyIp ridin-4-yl-4-boronic acid (137mg, l.Ommol), Na2C03 (424mg, 4.0mmol) and Terrakis(triphenylphosphine)palladium (116mg, O.lmmol) were added in a flask, dioxane 16mL and water 4mL were further added. The reaction was stirred very well and heated to 90C for 4 hours. After cooling down the reaction to RT, the solution was diluted by lOOmL water and extracted by EA for 3 times. The combined organic layer was dried over Na2S04, and concentrated under the vacuum. The crude was further purified by flash chromatography with EA/Hexane (1 : 1) to get the solid 5-chloro-2-(2-methylpyridin-4-yl)-l,6-naphthyridine (143mg, yield ~56%). MS m/z 256.1 (M + l)
Ca. 56%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4.0h;	[0204] 2,5-dichloro-l,6-naphthyridine (200mg, l .Ommol), <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (137mg, l .Ommol), Na2C03 (424mg, 4.0mmol) and Tetrakis(triphenylphosphine)palladium (1 16mg, O. lmmol) were added in a flask, dioxane 16mL and water 4mL were further added. The reaction was stirred very well and heated to 90C for 4 hours. After cooling down the reaction to RT, the solution was diluted by lOOmL water and extracted by EA for 3 times. The combined organic layer was dried over Na2S04, and concentrated under the vacuum. The crude was further purified by flash chromatography with EA/Hexane (1 : 1) to get the solid 5-chloro-2-(2-methylpyridin-4-yl)-l,6-naphthyridine (143mg, yield -56%). MS m/z 256.1 (M + 1)
Ca. 56%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4.0h;	2,5-dichloro-l,6-naphthyridine (200mg, 1.0mmol), <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (137mg, l .Ommol), Na2CO3 (424mg, 4.0mmol) and Tetrakis(triphenylphosphine)palladium (116mg, 0.1mmol) were added in a flask, dioxane 16mL and water 4mL were further added. The reaction was stirred very well and heated to 90C for 4 hours. After cooling down the reaction to RT, the solution was diluted by 100mL water and extracted by EA for 3 times. The combined organic layer was dried over Na2SO4, and concentrated under the vacuum. The crude was further purified by flash chromatography with EA/Hexane (1 : 1) to get the solid 5-chloro-2-(2-methylpyridin-4-yl)-1,6-naphthyridine (143mg, yield -56%). MS m/z 256.1 (M + 1)

Ca. 56%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4.0h;	2,5-dichloro-1,6-naphthyridine (200 mg, 1.0 mmol), <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (137 mg, 1.0 mmol), Na2CO3 (424 mg, 4.0 mmol) and Tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) were added in a flask, dioxane 16 mL and water 4 mL were further added. The reaction was stirred very well and heated to 90 C. for 4 hours. After cooling down the reaction to RT, the solution was diluted by 100 mL water and extracted by EA for 3 times. The combined organic layer was dried over Na2SO4, and concentrated under the vacuum. The crude was further purified by flash chromatography with EA/Hexane (1:1) to get the solid 5-chloro-2-(2-methylpyridin-4-yl)-1,6-naphthyridine (143 mg, yield ~56%). MS m/z 256.1 (M+1)
Ca. 56%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4.0h;	2,5-Dichloro-1,6-naphthyridine (200 mg, 1.0 mmol), 2-methylpyridin-4-yl- boronic acid (137 mg, 1.0 mmol), Na 2 CO 3 (424 mg, 4.0 mmol) and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) were added to the flask and 16 ml of dioxane and 4 ml of water were further added. The reaction was stirred very well and heated to 90 C. for 4 hours. After cooling the reaction to RT, the solution was diluted with 100 ml of water and extracted three times with EA. The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. The crude was further purified by flash chromatography with EA / hexane (1: 1) to give solid 5-chloro-2- (2-methylpyridin-4-yl) -1,6- naphthyridine (143 mg, yield ~ 56 %) Was obtained.
56%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4.0h;	2,5-Dichloro-1,6-naphthyridine(200 mg, 1.0 mmol), <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (137 mg,1.0 mmol), Na2CO3 (424 mg, 4.0 mmol) and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) were added to the flask followed by 16 mL of dioxane and 4 mL of water.The reaction was stirred well and heated to 90 C for 4h.After the reaction was cooled to RT, the solution was diluted with 100 mL of water and extracted three times with EA. The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. The crude product was further purified by flash chromatography with EA / hexanes (1: 1) to give a solid5-Chloro-2- (2-methylpyridin-4-yl) -1,6-naphthyridine(143 mg, yield ~ 56%).
56%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4.0h;	2,5-dichloro-1 ,6-naphthyridine (200mg, I .Ommol) , <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (137mg, I .Ommol), Na2C03 (424mg, 4.0mmol) and Tetrakis(triphenylphosphine) palladium (1 16mg, 0.1 mmol) were added in a flask, dioxane 16ml_ and water 4ml_ were further added. The reaction was stirred very well and heated to 90C for 4 h. After cooling down the reaction to RT, the solution was diluted by 100ml_ water and extracted by EA for 3 times. The combined organic layer was dried over Na2S04, and concentrated under the vacuum. The crude was further purified by flash chromatography with EA/hexane (1 : 1 ) to get the solid 5-chloro-2-(2-methylpyridin-4-yl)-1 ,6-naphthyridine (143mg, yield -56%) . MS m/z 256.1 (M + 1 )

Reference： [1]Patent: WO2013/185353,2013,A1 .Location in patent: Page/Page column 31
[2]Patent: WO2014/159733,2014,A1 .Location in patent: Paragraph 0203-0204
[3]Patent: WO2014/165232,2014,A1 .Location in patent: Paragraph 0215; 0216
[4]Patent: US2015/119387,2015,A1 .Location in patent: Paragraph 0218; 0219
[5]Patent: JP2017/95498,2017,A .Location in patent: Paragraph 0145; 0146
[6]Patent: CN104530042,2017,B .Location in patent: Paragraph 0234; 0246; 0247; 0248
[7]Patent: WO2016/191525,2016,A1 .Location in patent: Paragraph 0272-0273

39
[ 875514-62-8 ]
[ 579476-63-4 ]
[ 1611472-70-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 80℃; for 2.0h;	Example 90 8-(2-Methylpyridin-4-yl)- 1 ,6-naphthyridine-2-carboxamide To a suspension of 8-bromo-l,6-naphthyridine-2-carboxamide (0.04 g, 0.16 mmol) and 2- methylpyridin-4-ylboronic acid (0.02 g, 0.16 mmol) and cesium carbonate (0.06 g, 0.18 mmol) in dioxane (5 ml) and water (0.5 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (0.01 g, 0.01 mmol). The mixture was stirred at 80°C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, methanol / dichloromethane = 0: 100 to 20:80) and trituration with diethyl ether yielded the title compound as brown solid (0.04 g, 93percent). MS: m/e = 265.4 [M+H]+.

Reference： [1]Patent: WO2014/79787,2014,A1 .Location in patent: Page/Page column 81

40
[ 67303-38-2 ]
[ 579476-63-4 ]
[ 1616830-51-3 ]

Yield	Reaction Conditions	Operation in experiment
71%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 95℃; for 18.0h;	a) 7-Methoxy-4- (2-methylpyridin-4-yl)indoline-2,3-dione4-Bromo-7-methoxyindoline-2,3-dione (CAS67303-3 8-2, 1.28 g, 5.00 mmol), 2-methylpyridin-4-ylboronic acid (0.69 g, 5.00 mmol) and potassium carbonate (0.69 g, 5.00 mmol) were combined with dioxane (70 ml) and water (7.0 ml) to give a brown suspension. Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.37 g, 0.50 mmol) were added and the reaction mixture was stirred at 95 °C for 18 hours. Chromatography (silica gel, methanol /dichloromethane = 0:100 to 10:90) yielded the title compound as red solid (0.95 g, 71 percent). MS:mle = 266.8 [M-H].

Reference： [1]Patent: WO2014/102233,2014,A1 .Location in patent: Page/Page column 126

41
6-chloro-4-iodo-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile [ No CAS ]
[ 579476-63-4 ]
6-chloro-4-(2-methylpyridin-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 18.0h;Inert atmosphere; Sealed tube;	6-Chloro-4-(2-methylpyridin-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile A mixture of 6-chloro-4-iodo-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (900 mg, 2.07 mmol) and <strong>[579476-63-4](2-methylpyridin-4-yl)boronic acid</strong> (450 mg, 2.07 mmol) in 1,4-dioxane (20.0 mL) and water (4.0 mL) was degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol) and caesium carbonate (1.01 g, 3.11 mmol) were then added, and the reaction mixture was allowed to stir at 100° C. in a sealed tube for 18 h. On completion of the reaction (monitored by TLC), water was added and the mixture extracted with ethyl acetate (3*30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was subjected to silica-gel (100-200 mesh) column chromatography, eluted with 30percent ethyl acetate in petroleum ether, to afford compound 6-chloro-4-(2-methylpyridin-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (500 mg, 60percent) as an off white solid; LC-MS (Method E) (m/z) 399 [M+H]+; tR=3.81.
60%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 18.0h;Inert atmosphere; Sealed tube;	A mixture of 6-chloro-4-iodo-l-[2-(trimethylsilyl)ethoxy]methyl}-lH- pyrrolo[2,3-b]pyridine-3-carbonitrile (900 mg, 2.07 mmol) and (2-methylpyridin- 4-yl)boronic acid (450 mg, 2.07 mmol) in 1,4-dioxane (20.0 mL) and water (4.0 mL) was degassed with nitrogen for 15 min.Tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol) and caesium carbonate (1.01 g, 3.11 mmol) were then added, and the reaction mixture was allowed to stir at 100 °C in a sealed tube for 18 h. On completion of the reaction (monitored by TLC), water was added and the mixture extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was subjected to silica-gel (100-200 mesh) column chromatography, eluted with 30percent ethyl acetate in petroleum ether, to afford compound 6-chloro-4-(2-methylpyridin-4-yl)-l-[2- (trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[2,3-b]pyridine-3-carbonitrile (500 mg, 60percent) as an off white solid; LC-MS (Method E) (m/z) 399 [M+H]+; tR = 3.81.

Reference： [1]Patent: US2014/315901,2014,A1 .Location in patent: Paragraph 0200; 0201; 0202
[2]Patent: WO2014/170248,2014,A1 .Location in patent: Page/Page column 58; 59
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 8945 - 8962

42
(4S)-7-chloro-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b] [1,4]diazepine [ No CAS ]
[ 579476-63-4 ]
(4S)-7-(2-methylpyridin-4-yl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With tris-(dibenzylideneacetone)dipalladium(0); O4P(3-)3HK3H2O; tricyclohexylphosphine; In 1,4-dioxane; water; at 110℃;	General procedure: To a solution of (4S)-7-chloro-2,3,4,5-tetrahydro-l,4-methanopyrido[2,3-b][l,4]- diazepine (500 mg, 2.55 mmol) in degassed dioxane/H20 (14 mL, v/v=10/l) was added 2- methylpyridin-4-boronic acid (1.048 g, 7.65 mmol), PCy3 (286 mg, 1.02 mmol), Kappa3Rho04·3Eta20 (1.698 g, 6.375 mmol) and Pd2(dba)3 (234 mg, 0.255 mmol). The resulting mixture was stirred at 110 C overnight. The mixture was cooled to room temperature then concentrated. The residue was partitioned between EtOAc and water (50 mL each). The organic layer was washed with water and brine, dried over Na2S04, and concentrated to dryness. The residue was purified by silica gel chromatography (CH2C12/THF = 3/2) to give (4S)-7-(2-methylpyridin-4-yl)-2,3,4,5-tetrahydro-l,4-methanopyrido[2,3- b][l,4]diazepine (418 mg, 82%) as a light yellow solid. MS (ESI) calcd for Ci5Hi6N4: 252.1; found: 253.2 [M+H]
82%	With tris-(dibenzylideneacetone)dipalladium(0); potassium phosphate tribasic trihydrate; tricyclohexylphosphine; In 1,4-dioxane; water; at 110℃;Inert atmosphere;	To a solution of (4S)-7-chloro-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]-diazepine (500 mg, 2.55 mmol) in degassed dioxane/ H2O (14 mL, v/v=10/1) was added 2-methylpyridin-4-boronic acid (1.048 g, 7.65 mmol), PCy3 (286 mg, 1.02 mmol), K3PO4.3H2O (1.698 g, 6.375 mmol) and Pd2(dba)3 (234 mg, 0.255 mmol). The resulting mixture was stirred at 110 C. overnight. The mixture was cooled to room temperature then concentrated. The residue was partitioned between EtOAc and water (50 mL each). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by silica gel chromatography (CH2Cl2/THF=3/2) to give (4S)-7-(2-methylpyridin-4-yl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine (418 mg, 82%) as a light yellow solid. MS (ESI) calcd for C15H16N4: 252.1. found: 253.2 [M+H].
62%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In water; butan-1-ol; at 100℃; for 3.0h;	To a degassed solution of (4S)-7-chloro-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine (30 g, 153 mmol), <strong>[579476-63-4](2-methylpyridin-4-yl)boronic acid</strong> (25.2 g, 184 mmol) and Potassium Phosphate Tri basic (65.1 g, 307 mmol) in 1-butanol (300 mL) and water (50.0 mL) were added tris(dibenzylideneacetone)dipalladium(0) (7.02 g, 7.67 mmol) and dicyclohexyl(2?,4?,6?-triisopropyl-[1,1?-biphenyl]-2-yl)phosphine (7.31 g, 15.33 mmol). The reaction mixture was heated at 100 C. for 3 h. The n-butanol solvent was evaporated under reduced pressure. The resulting residue was diluted with water (200 ml) and extracted with DCM (2×400 ml). The combined organic layer was washed with water, brine, dried over sodium sulfate and solvent was evaporated under reduced pressure to obtain the crude product. The crude product was triturated with diethyl ether and n-pentane (1:1) for 3 times (3×250 mL) afford (4S)-7-(2-methylpyridin-4-yl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine (25 g, 99.2 mmol, 62%) as an off white solid (TLC: 10% MeOH in EtOAc Rf: 0.2), LCMS (m/z) 252.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta 8.45 (dd, J=5.2, 0.8 Hz, 1H), 7.73 (dt, J=1.4, 0.7 Hz, 1H), 7.67-7.60 (m, 1H), 7.24-7.16 (m, 2H), 7.10 (d, J=7.7 Hz, 1H), 3.93 (td, J=5.0, 2.5 Hz, 1H), 3.19-2.98 (m, 2H), 2.92-2.71 (m, 2H), 2.50 (s, 3H), 2.11-1.96 (m, 1H), 1.94-1.81 (m, 1H).

62%

With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In water; butan-1-ol; at 100℃; for 3.0h;

To a degassed solution of (4S)-7-chloro-2,3,4,5-tetrahydro-l,4-methanopyrido[2,3- £][l,4]diazepine (30 g, 153 mmol), <strong>[579476-63-4](2-methylpyridin-4-yl)boronic acid</strong> (25.2 g, 184 mmol) and Potassium Phosphate Tri basic (65.1 g, 307 mmol) in 1-butanol (300 mL) and water (50.0 mL) were added tris(dibenzylideneacetone)dipalladium(0) (7.02 g, 7.67 mmol) and dicyclohexyl(2',4',6'-triisopropyl-[l, -biphenyl]-2-yl)phosphine (7.31 g, 15.33 mmol). The reaction mixture was heated at 100 C for 3h. The n-butanol solvent was evaporated under reduced pressure. The resulting residue was diluted with water (200 ml) and extracted with DCM (2x 400 ml). The combined organic layer was washed with water, brine, dried over sodium sulfate and solvent was evaporated under reduced pressure to obtain the crude product. The crude product was triturated with diethyl ether and n- pentane (1 : 1) for 3 times (3X250 mL) afford (45)-7-(2-methylpyridin-4-yl)-2,3,4,5- tetrahydro-l,4-methanopyrido[2,3-£][l,4]diazepine (25 g, 99.2 mmol, 62%) as an off white solid (TLC: 10% MeOH in EtOAc Rf: 0.2), LCMS (m/z) 252.9 [M+H]+.1H NMR (400 MHz, DMSO-i): delta 8.45 (dd, J= 5.2, 0.8 Hz, 1H), 7.73 (dt, J= 1.4, 0.7 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.24 - 7.16 (m, 2H), 7.10 (d, J = 7.7 Hz, 1H), 3.93 (td, J = 5.0, 2.5 Hz, 1H), 3.19 - 2.98 (m, 2H), 2.92 - 2.71 (m, 2H), 2.50 (s, 3H), 2.11 - 1.96 (m, 1H), 1.94 - 1.81 (m, 1H).

Reference： [1]Patent: WO2014/186313,2014,A1 .Location in patent: Page/Page column 88
[2]Patent: US2015/152108,2015,A1 .Location in patent: Paragraph 0559; 0560
[3]Patent: US2015/152108,2015,A1 .Location in patent: Paragraph 0335; 0336; 0337
[4]Patent: WO2016/79709,2016,A1 .Location in patent: Page/Page column 145

43
[ 1252464-84-8 ]
[ 579476-63-4 ]
N-methyl-5-(2-methylpyridin-4-yl)-N-(m-tolyl)thiophene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 150℃; for 0.333333h;Sealed tube; Inert atmosphere; Microwave irradiation;	General procedure: In a sealed tube the previously prepared bromo-N-heteroarylcarboxamide derivative (1 eq.) was introduced followed by the corresponding boronic acid (1.5 eq.), cesium carbonate (3 eq.), tetrakis(triphenylphosphine)palladium (0.02 eq.) and a mixture of DME/EtOH/H2O (1:1:1, v:v:v, 3 mL) as solvent. The reactor was flushed with N2 and submitted to microwave irradiation (150°C, 150 W) for 20 minutes. After cooling to room temperature, a mixture of EtOAc/H2O (1:1, v:v, 2 mL) was added to stop the reaction. The aqueous layer was extracted with EtOAc (3 × 10 mL). The organic layer was washed once with brine and once with water, dried over MgSO4, filtered and the solution was concentrated under reduced pressure. The residue was purified by column chromatography using n-hexane and EtOAc as eluent to afford the desired compound.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 87,p. 203 - 219

44
(7S)-3-iodo-7-methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [ No CAS ]
[ 579476-63-4 ]
(7S)-7-methyl-3-(2-methylpyridin-4-yl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; water; at 100℃; for 16.0h;Inert atmosphere; Sealed tube;	Intermediate 18 (1-18) 75'-Methyl-3-(2-methyl-pyridin-4-yl)-6,7-dihydro-5H-pyrazolo[l,5-a]pyrazin-' Pd(PPh3)4 (0.33 g, 0.29 mmol) was added to a stirred suspension of intermediate 1-13 (1.6 g, 5.77 mmol) and 2-picoline-4-boronic acid (0.95 g, 6.93 mmol) in 1,4-dioxane (8 mL) and a sat. sol. of NaHC03 (4 mL) in a sealed tube under nitrogen. The mixture was stirred at 100 °C for 16 h. Then the mixture was diluted with H20 and extracted with DCM. The organic layer was separated, dried (Na2S04), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 6/94). The desired fractions were collected and the solvents evaporated in vacuo to yield intermediate compound 1-18 as a white solid (1 g, 71percent), mp 173.20 °C. 1H NMR (500 MHz, CDC13) delta ppm 1.67 (d, J=6.65 Hz, 3 H) 2.60 (s, 3 H) 3.52 (ddd, J=12.79, 7.15, 2.89 Hz, 1 H) 3.84 (dt, J=12.72, 4.00 Hz, 1 H) 4.57 - 4.66 (m, 1 H) 6.10 (br. s., 1 H) 7.51 (dd, J=5.20, 1.44 Hz, 1 H) 7.55 (s, 1 H) 7.78 (s, 1 H) 8.50 (d, J=5.20 Hz, 1 H). LC-HRMS (ESI+) Calculated for C13H14IN4O (M+H)+: 243.1246, Found: m/z 243.1250 (+0.4mDa), Rt = 0.82 min (Method 13, see table 2). [a] = +32.8 0 (589 nm, c 0.52 w/v percent, DMF, 20 °C).
71%	With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; at 100℃; for 16.0h;Inert atmosphere; Sealed tube;	Pd(PPh3)4 (0.33 g, 0.29 mmol) was added to a stirred suspension of intermediate 1-8 (1.6 g, 5.77 mmol) and 2-picoline-4-boronic acid (0.95 g, 6.93 mmol) in 1,4-dioxane (8 mL) and a sat. sol. of NaHC03 (4 mL) in a sealed tube under nitrogen. The mixture was stirred at 100 °C for 16 h. Then the mixture was diluted with H20 and extracted with DCM. The organic layer was separated, dried (Na2S04), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 6/94). The desired fractions were collected and the solvents evaporated in vacuo to yield intermediate compound I- 10 as a white solid (1 g, 71percent), mp 173.20 °C. 1H NMR (500 MHz, CDC13) delta ppm 1.67 (d, J=6.65 Hz, 3 H) 2.60 (s, 3 H) 3.52 (ddd, J=12.79, 7.15, 2.89 Hz, 1 H) 3.84 (dt, J=12.72, 4.00 Hz, 1 H) 4.57 - 4.66 (m, 1 H) 6.10 (br. s., 1 H) 7.51 (dd, J=5.20, 1.44 Hz, 1 H) 7.55 (s, 1 H) 7.78 (s, 1 H) 8.50 (d, J=5.20 Hz, 1 H). LC-HRMS (ESI+) Calculated for Ci3Hi4IN40 (M+H)+: 243.1246, Found: m/z 243.1250 (+0.4mDa), Rt = 0.82 min (Method 13, see table 2). [a] = +32.8 0 (589 nm, c 0.52 w/v percent, DMF, 20 °C)

Reference： [1]Patent: WO2014/195311,2014,A1 .Location in patent: Page/Page column 84-85
[2]Patent: WO2016/87489,2016,A1 .Location in patent: Page/Page column 34

45
[ 158326-84-2 ]
[ 579476-63-4 ]
3,3-dimethyl-6-(2-methylpyridin-4-yl)indolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water for 12h; Inert atmosphere; Reflux;	24.b b) 3,3-Dimethyl-6-(2-methylpyridin-4-yl)indolin-2-one b) 3,3-Dimethyl-6-(2-methylpyridin-4-yl)indolin-2-one To a suspension of 6-bromo-3,3-dimethylindolin-2-one (120 mg, 500 imol) and 2-methylpyridin-4-ylboronic acid (105 mg, 750 imol) in dioxane (2 ml) and an aqueous solutionof sodium carbonate (2M, 667 tl) [1,1’-bis(diphenylphosphino)ferrocenel dichloropalladium(II)(18.3 mg, 25.0 imo1) was added under an argon atmosphere. The reaction mixture was heated to reflux and stirred at this temperature under an argon atmosphere for 12 hours.The mixture was diluted with ethyl acetate and 2M aqueous solution of sodium carbonate. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed withbrine, dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate heptane as eluent. The title compound was obtained as off-white foam (60 mg).MS ESI (mz): 253.1 [(M+H)j.1H NMR (CDC13, 400 MHz): ö (ppm) = 8.55 (d, J=5.2 Hz, 1H), 8.33 (br s, 1H), 7.40 - 7.27 (m,4H), 7.20 - 7.13 (m, 1H), 2.63 (s, 3H), 1.45 (s, 6H).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/202493, 2014, A1 Location in patent: Page/Page column 45; 46

46
(4R)-7-chloro-N-(pyrazin-2-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide [ No CAS ]
[ 579476-63-4 ]
(9R)-5-(2-methylpyridin-4-yl)-N-(pyrazin-2-yl)-1,6,8-triazatricyclo[7.2.1.0^2,7]dodeca-2⁽⁷⁾,3,5-triene-8-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49.2%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 110℃; for 2.0h;Inert atmosphere;	To a de-gassed solution of (4R)-7-chloro-N-(pyrazin-2-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide (700 mg, 2.210 mmol), <strong>[579476-63-4](2-methylpyridin-4-yl)boronic acid</strong> (454 mg, 3.31 mmol) and K3PO4 (1825 mg, 6.63 mmol) in 1,4-dioxane (20 mL) and water (5.00 mL) were added X-Phos (211 mg, 0.442 mmol) and Pd2(dba)3 (202 mg, 0.221 mmol). The reaction mixture was heated at 110 C. for 2 h and allowed to cool to room temperature. Diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford (4R)-7-(2-methylpyridin-4-yl)-N-(pyrazin-2-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide (392 mg, 49.2% yield) as an off-white solid (TLC: eluent; 10% methanol in dichloromethane, Rf=0.3), LCMS (m/z): 374.18 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta ppm 13.76 (s, 1H), 9.43 (d, J=1.53 Hz, 1H), 8.59 (d, J=5.26 Hz, 1H), 8.46 (dd, J=2.63, 1.53 Hz, 1H), 8.39 (d, J=2.41 Hz, 1H), 8.31 (s, 1H), 8.16-8.06 (m, 1H), 7.92-7.78 (m, 1H), 7.78-7.69 (m, 1H), 5.52 (dd, J=5.81, 3.18 Hz, 1H), 3.37 (m, 1H), 3.28-3.06 (m, 2H), 2.98 (dd, J=11.95, 3.18 Hz, 1H), 2.61 (s, 3H), 2.41-2.15 (m, 1H), 2.05-1.84 (m, 1H).
49.2%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 110℃; for 2.0h;	To a de-gassed solution of (4R)-7-chloro-N-(pyrazin-2-yl)-3,4-dihydi methanopyrido[2,3-£][l,4]diazepine-5(2H)-carboxamide (700 mg, 2.210 mmol), (2- methylpyridin-4-yl)boronic acid (454 mg, 3.31 mmol) and K3PO4 (1825 mg, 6.63 mmol) in 1,4-dioxane (20 mL) and water (5.00 mL) were added X-Phos (21 1 mg, 0.442 mmol) and Pd2(dba)3 (202 mg, 0.221 mmol). The reaction mixture was heated at 1 10 C for 2 h and allowed to cool to room temperature. Diluted with water (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford (4R)-7-(2-methylpyridin-4-yl)-N- (pyrazin-2-yl)-3,4-dihydro-l,4-methanopyrido[2,3-^][l,4]diazepine-5(2H)-carboxamide (392 mg, 49.2% yield) as an off-white solid (TLC: eluent; 10 % methanol in dichloromethane, Rf= 0.3), LCMS (m/z): 374.18 [M+H]+.1H NMR (400 MHz, DMSO-i): delta ppm 13.76 (s, 1H), 9.43 (d, J=1.53 Hz, 1 H), 8.59 (d, J=5.26 Hz, 1 H), 8.46 (dd, J=2.63, 1.53 Hz, 1 H), 8.39 (d, J=2.41 Hz, 1 H), 8.31 ( s, 1 H), 8.16-8.06 (m, 1 H), 7.92-7.78 (m, 1H), 7.78-7.69 (m, 1 H), 5.52 (dd, J=5.81, 3.18 Hz, 1 H), 3.37 (m, 1 H), 3.28-3.06 (m, 2H), 2.98 (dd, J=1 1.95, 3.18 Hz, 1 H), 2.61 (s, 3 H), 2.41- 2.15 (m, 1 H), 2.05-1.84 (m, 1 H).

Reference： [1]Patent: US2015/152108,2015,A1 .Location in patent: Paragraph 1148; 1149; 1150
[2]Patent: WO2016/79709,2016,A1 .Location in patent: Page/Page column 442

47
(5R,9S)-2-chloro-7,8,9,10-tetrahydro-6H-5,9-methanopyrido[2,3-b][1,4]diazocine [ No CAS ]
[ 579476-63-4 ]
(9S)-2-(2-methylpyridin-4-yl)-7,8,9,10-tetrahydro-6H-5,9-methanopyrido[2,3-b][1,4]diazocine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.9%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In water; butan-1-ol; at 25 - 120℃; for 16.0h;Inert atmosphere;	To a solution of (9S)-2-chloro-7,8,9,10-tetrahydro-6H-5,9-methanopyrido[2,3-b][1,4]diazocine (10 g, 47.7 mmol), <strong>[579476-63-4](2-methylpyridin-4-yl)boronic acid</strong> (8.49 g, 62.0 mmol) and Potassium phosphate (30.4 g, 143 mmol) in 1-Butanol (300 ml), water (100 ml) stirred under nitrogen at 25° C., purged with Argon gas for 20 minutes was added X-Phos (2.274 g, 4.77 mmol), Pd2(dba)3 (2.184 g, 2.385 mmol). The reaction mixture was stirred at 120° C. for 16 hr. Before being concentrated and the residue was taken up in DCM (700 mL). The solution was washed with water and brine, dried over Na2SO4, filtered and concentrated to get brown semisolid crude product. The crude product was purified by washing with hexane to get off white solid product (9 g, 32.4 mmol, 67.9percent yield), LCMS (m/z): 267.3 (M+H)+.

Reference： [1]Patent: US2015/152108,2015,A1 .Location in patent: Paragraph 0347; 0348

48
[ 68819-84-1 ]
[ 579476-63-4 ]
tert-butyl 4-(2-methylpyridin-4-yl)benzylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.80 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; at 90℃;Inert atmosphere;	A solution of tert-butyl 4-bromobenzylcarbamate (1.0 g), (2-methylpyridin-4-yl)boronic acid (0.72 g), 2 mol/L aqueous sodium carbonate solution (3.49 mL) and (1,1-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.26 g) in 1,2-dimethoxyethane (7 mL) was stirred under an argon atmosphere at 90C overnight. The reaction solution was diluted with water and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by chromatography (NH silica gel, hexane-ethyl acetate) to give the title compound (0.80 g). 1H NMR (300 MHz, DMSO-d6) delta 1.40 (9H, s), 2.52 (3H, s), 4.18 (2H, d, J = 6.2 Hz), 7.36 (2H, d, J = 8.3 Hz), 7.41-7.51 (2H, m), 7.57 (1H, s), 7.74 (2H, d, J = 8.1 Hz), 8.48 (1H, d, J = 5.3 Hz).

Reference： [1]Patent: EP2921480,2015,A1 .Location in patent: Paragraph 0435; 0436

49
6-(2-chloropyrimidin-4-yl)-1,3,3-trimethylindolin-2-one [ No CAS ]
[ 579476-63-4 ]
1,3,3-trimethyl-6-(2-(2-methylpyridin-4-yl)pyrimidin-4-yl)indolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In tetrahydrofuran; water; at 80℃; for 16.0h;Inert atmosphere;	A mixture of 6-(2-chloropyrimidin-4-yl)-l,3,3-trimethylindolin-2-one (110 mg), 2- methylpyridin-4-ylboronic acid (106 mg) and cesium carbonate (500 mg) in THF (3 ml) and water (1.5 ml) was flushed with argon, [Iota,Gamma- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (32 mg) was added and stirring was continued at 80 °C for 16 h. The mixture was evaporated and the residue purified by flash chromatography (Si-NH2, gradient, 0percent to 40percent EtOAc in n-heptane) to give the title compound (90 mg, 68percent) as a light yellow foam. MS (ESI, m/z): 345.6 [(M+H)+].

Reference： [1]Patent: WO2015/177110,2015,A1 .Location in patent: Page/Page column 91-92

50
[ 93131-78-3 ]
[ 579476-63-4 ]
4-methyl-7-(2-methylpyridin-4-yl)-2H-chromen-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; tetra-n-butylammoniumfluoride trihydrate; In methanol; 1,2-dimethoxyethane; at 20 - 80℃; for 0.5h;Inert atmosphere; Microwave irradiation;	General procedure: To a solution of 4-methyl-7-nonauorobutylsulfonyloxy coumarin (3b, 1 equiv.) in DME?MeOH (3:1), were added Pd(OAc) 2(0.05 equiv.) and dppp (0.1 equiv.). The solution was purged with nitrogen and stirred at room temperature for 10 min, at which time boronic acid (1.5 equiv.) and TBAF 3H2O (3 equiv.) was added. The reaction solution was purged again with nitrogen and then placed in the microwave and heated for 20?30 min at 80°C at 110 W. When TLC and LC?MS showed full consumption of starting materials, the reaction mixture was diluted with ethyl acetate, separated the organic layer, given water wash, brine wash and was dried over anhydrous sodium sulfate and distilled under reduced pressure to get the crude material. The crude product was further puried by column chromatography and eluted in varying polarities to obtain the diaryls 4a?x.

Reference： [1]Journal of Fluorine Chemistry,2016,vol. 182,p. 109 - 120

51
2-bromoimidazopyrazine [ No CAS ]
[ 579476-63-4 ]
2-(2-methylpyridin-4-yl)-1H-imidazo[4,5-b]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); cesium fluoride; In 1,2-dimethoxyethane; water; at 100℃; for 0.5h;Inert atmosphere; Microwave irradiation;	General procedure: To a solution of 2-bromoimidazopyrazine intermediate 3 (1 equiv.) in DME-H2O (4:1), were added boronic acid (1.5 equiv.), CsF (3 equiv.), and (A-taphos)2PdCl2 (10 mol percent), and the solution was purged with argon and stirred at room temperature for 10 min. The reaction solution was then placed in the microwave and heated for 20?30 min at 100 °C. When TLC and LC-MS showed full consumption of starting materials, the reaction mixture was filtered and diluted with ethyl acetate. The ethyl acetate layer was extracted, washed in water, washed in brine, dried over anhydrous sodium sulfate, and distilled in vacuum to get the crude material. The crude product was purified by column chromatography and eluted in varying polarities to obtain the substituted diaryls 4a-n.

Reference： [1]Chinese Chemical Letters,2016,vol. 27,p. 31 - 36

52
6-chloro-3,3-dimethyl-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one [ No CAS ]
[ 579476-63-4 ]
3,3-dimethyl-6-(2-methyl-4-pyridyl)-1H-pyrrolo[3,2-c]pyridin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 6.0h;Sealed tube;	A degazed suspension of 6-chloro-3,3-dimethyl-1H-pyffolo[3,2-c]pyridin-2(3H)-one (400 mg,2.03 mmol, Eq: 1, prepared according to Woolford et al., WO 2012143726), <strong>[579476-63-4](2-methylpyridin-4-yl)boronic acid</strong> (418 mg, 3.05 mmol, Eq: 1.5) in dioxane (8.14 ml), an aqueous solution ofsodium carbonate (2M, 2.03 ml) and [1,1?-bis(diphenylphosphino)feffocene]dichloropalladium(II) (74.4 mg, 102 imol, Eq: 0.05) washeated at 110°C for 6h in a sealed vial. Volatiles were removed in vacuo and the residue was purified by chromatography on silica gel to give the desired compound as a light brown solid (415 mg, 77percent). MS (mlz) = 254.2 (M+H)

Reference： [1]Patent: WO2015/197567,2015,A1 .Location in patent: Page/Page column 77

53
methyl 4-(5-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-tosyl-1H-pyrrole-2-carboxylate [ No CAS ]
[ 579476-63-4 ]
methyl 4-(2-methyl-5-(2-methylpyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-tosyl-1H-pyrrole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 65℃;Inert atmosphere;	A solution of methyl 4-(5-bromo-2-methyl- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- pyrrolo[2,3-b]pyridin-3-yl)-l-tosyl-lH-pyrrole-2-carboxylate (XXV) (200 mg, 0.324 mmol), 2- methylpyridin-4-ylboronic acid (53 mg, 0.388 mmol), Pd(dppf)Cl2 (23 mg, 0.032 mmol), and Na2C03 (69 mg, 0.648 mmol) in DMF/H20 (4 mL/0.4 mL) was stirred at 65 °C overnight under nitrogen atmosphere. The mixture was diluted with EtOAc (50 mL), washed with H20 (15 mL x 2) and brine (30 mL), dried over Na2S04, and concentrated. The residue was purified by column Chromatography (Petrolem Ether : EtOAc = 4: 1 to 2: 1) to give the title compound methyl 4-(2- methyl-5-(2-methylpyridin-4-yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrrolo[2,3 -bjpyridin- 3-yl)-l-tosyl-lH-pyrrole-2-carboxylate (XXVI) as a yellow solid ( 132 mg, yield: 65percent).

Reference： [1]Patent: WO2016/26078,2016,A1 .Location in patent: Paragraph 089

54
[ 91446-15-0 ]
[ 579476-63-4 ]
4-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 120℃; for 1.0h;Inert atmosphere; Microwave irradiation;	In a 10-20 mL microwave vial 4-chloro-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine (153mg, 0.64 mmol) and sodium carbonate (135mg, 1 .28 mmol) were suspended in 1 ,4-dioxane (4 mL) and water(1 mL). Nitrogen was bubbled through the solution for 5 mins, after which (2-methyl-4- pyridinyl)boronic acid (105mg, 0.77 mmol) and [1,1?- bis(diphenylphosphino)ferrocene]dichloropalladium (II). CH2CI2 (52mg, 0.06 mmol) were added the vial was capped and the reaction was heated under microwave irradiation at 120 °C for 1 hour. LCMS showed that the reaction had completed. The reaction was quenched by the addition of sat. NaHCO3and extracted three times with EtOAc. Combined organic extracts were reduced in vacuo and deposited onto silica. The crude product was purified by flash column chromatography (12g column, 0 to 100percent EtOAc in Heptane then 0 to 5percent MeOH in EtOAc) to furnish 4-(2-methyl-4-pyridyl)-1- tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine (1 30mg, 0.44 mmol, 69percent yield) as an orange oil.MS Method 2: RT 1.16 mi ES m/z 296 [M+H]1H NMR (400MHz, CDCI3) O/ppm: 9.16 (5, 1H), 8.78 (dd, 1H, J = 5.2, 0.6 Hz), 8.43 (5, 1H), 7.92 (bs,1H), 7.81 (ddd, 1H, J = 5.2, 1.7, 0.6 Hz), 6.17 (dd, 1H, J = 10.4, 2.6 Hz), 4.20-4.14 (m, 1H), 3.90-3.82 (m, 1H), 2.74 (5, 3H), 2.72-2.63 (m, 1H), 2.24-2.15 (m, 1H), 2.07-2.00 (m, 1H), 1.87-1.65 (m,3H).

Reference： [1]Patent: WO2016/55790,2016,A1 .Location in patent: Paragraph 00172

55
(4S)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-1][1,4]diazepine [ No CAS ]
[ 579476-63-4 ]
(4S)-9-methyl-7-(2-methylpyridin-4-yl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.3%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 110℃; for 3.0h;	To a degassed solution of (4S)-7-chloro-9-methyl-2,3,4,5-tetrahydro-l,4- methanopyrido[2,3-b][l,4]diazepine (500 mg, 2.385 mmol),<strong>[579476-63-4](2-methylpyridin-4-yl)boronic acid</strong> (490 mg, 3.58 mmol) and K3P04 (1519 mg, 7.15 mmol) in 1,4-Dioxane (40 mL);Water (10 mL) and was added x-phos (227 mg, 0.477 mmol), Pd2(dba)3 (218 mg, 0.238 mmol). The reaction mixture was stirred at 1 10 C for 3 hr. The reaction was monitored by TLC. The reaction mixture was poured in to ice (50mL) and extracted with ethyl acetate (3x100 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude product, that was added to a Neutral alumina column and was eluted with 40%Ethylacetate in Petether Collected fractions are evaporated to afford (4S)-9-methyl-7-(2-methylpyridin-4-yl)-2,3,4,5- tetrahydro-l,4-methanopyrido[2,3-b][l,4]diazepine (450 mg, 1.653 mmol, 69.3 % yield) as a pale Yellow solid LCMS (m/z) 267.21 [M+H]+.

Reference： [1]Patent: WO2016/79709,2016,A1 .Location in patent: Page/Page column 247

56
tert-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylate [ No CAS ]
[ 579476-63-4 ]
tert-butyl (3R)-3-[5-fluoro-6-(2-methylpyridin-4-yl)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere;	a)fer Butyl(3 ?)-3-[5-fluoro-6-(2-methylpyridin-4-yl)-2-pyrazolo[1,5-a]pyridin-3- ylpyrimidin-4-yl] amino}piperidine-1 -carboxylate To a solution of ferf-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidine-1-carboxylate (1.0 g, 2.24 mmol), (2-methylpyridin-4- yl)boronic acid (0.46g , 3.36 mmol) and 0.18 g (0.22 mmol) of [1 ,1 - Bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane in dioxane (50 ml.) was added a 2M aqueous solution of cesium carbonate (3.36 ml_). The resulting mixture was stirred at 90 °C under nitrogen atmosphere overnight, then cooled to room temperature, filtered through Celite®, the solvent was removed and the residue was purified first by flash chromatography (dichloromethane to dichloromethane/methanol 90:10) and then by reverse phase chromatography (C-18 silica from Waters®, water/1 :1 acetonitrile-methanol as eluents [0.1percent v/v ammonium formate buffered] 0percent to 100percent) to yield the title compound (0.827 g, 73percent) as a light yellow solid. LRMS (m/z): 504 (M+1 )+.

Reference： [1]Patent: WO2016/198663,2016,A1 .Location in patent: Page/Page column 55-56

57
methyl 3-bromo-1-(1-ethoxyethyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate [ No CAS ]
[ 579476-63-4 ]
methyl 1-(1-ethoxyethyl)-3-(2-methylpyridin-4-yl)-1H-thieno[2,3-c]pyrazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 4.0h;Inert atmosphere;	A solution of methyl 3 -bromo- 1 -(1 -ethoxyethyl)- 1 H-thieno[2,3 -c]pyrazole- 5- carboxylate (500 mg, 1.50 mmol), 2-methylpyridin-4-ylboronic acid (250 mg, 1.80 mmol), Pd(PPh3)4 (122 mg, 0.15 mmol) and Na2CO3 (318 mg, 3.0 mmol) in dioxane/H20 (lOmL / 2 mL) was stirred at 80 °C under nitrogen atmosphere for 4h. The mixture was cooled to rt, diluted with EtOAc (100 mL), washed by H20 (30 mL x 2) and brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 3/1) to give the title compound methyl 1 -(1 -ethoxyethyl)-3 -(2-methylpyridin-4-yl)- 1 H-thieno[2,3 - c]pyrazole-5-carboxylate (370 mg, yield: 72percent).

Reference： [1]Patent: WO2017/28314,2017,A1 .Location in patent: Paragraph 0148

58
[ 33443-53-7 ]
[ 579476-63-4 ]
6-(2-methylpyridin-4-yl)-4-phenylquinazolin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 140℃;Microwave irradiation;	General procedure: A mixture of 6-bromo-4-phenylquinazolin-2(1H)-one (200 mg, 0.66 mmol, 1 eq.), DMF (1.5 mL), H2O (0.6 mL), 4-pyridylboronic acid (106 mg, 0.864 mmol, 1.3 eq.), Pd(PPh3)4 (53 mg, 0.046 mmol, 0.07 eq.), and sodium carbonate (162 mg, 1.52 mmol, 2.3 eq.) in a microwave vessel (2 ? 5 mL) was heated in the microwave at 140 °C for 4 - 24 min. After completion of the reaction (monitored by LC/MS), the mixture was allowed to cool to room temperature, and H2O (8 mL) was added. The resulting precipitate was collected by vacuum filtration and washed with H2O and diethyl ether to afford the crude product as a solid. The crude product was dissolved in a minimal amount of 1,4-dioxane (1 - 10 mL) and any insoluble material was removed by vacuum filtration. A solution of HCl in dioxane (4.0 M) was then added dropwise until a precipitate was formed. The resulting precipitate was collected by vacuum filtration. All Suzuki reactions followed this general procedure, using the appropriate boronic acid, unless otherwise noted.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3629 - 3635

59
(S)-tert-butyl (1-((7-bromobenzo[d]thiazol-4-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]
[ 579476-63-4 ]
(S)-tert-butyl (2,4-dimethyl-1-((7-(2-methylpyridin-4-yl)benzo[d]thiazol-4-yl)oxy)pentan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 85℃; for 12.0h;Inert atmosphere;	A stirred solution of (5)-tert-butyl (1 -((7-bromobenzo[djthiazol-4-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (40 mg, 0.060 mmol), <strong>[579476-63-4](2-methylpyridin-4-yl)boronic acid</strong> (8.15 mg, 0.060 mmol) and cesium carbonate (38.8 mg, 0.119 mmol) in a mixture of 1,4-dioxane (10 mL) and water (2 mL) was purged argon for 2 mm. PdC12(dppf)-CH2C12 adduct (2.431 mg, 2.98 imol) was added in one portion and the reaction mixture was heated at 85 °C for 12 h.The reaction mixture was allowed to cool to room temperature. Water (50 mL) was added and the solution was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography(EtOAc in hexanes) to afford (5)-tert-butyl (2,4-dimethyl-1-((7-(2-methylpyridin-4- yl)benzo[djthiazol-4-yl)oxy)pentan-2-yl)carbamate (26 mg, 0.055 mmol, 93percent yield) in 97percent purity based on UV from LCMS. LCMS (ESI) m/e 456.2 [(M+H), calcd for C25H34N303S, 456.21; LC/MS retention time (method Al) tR = 2.58 mm.

Reference： [1]Patent: WO2017/59080,2017,A1 .Location in patent: Page/Page column 72

60
[ 65550-77-8 ]
[ 579476-63-4 ]
5-chloro-2',3-dimethyl-2,4'-bipyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
Ca. 100%	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); triethylamine; In water; acetone; at 20℃; for 4.0h;	2.8 g (20.4 mmol) of (2-methylpyridin-4-yl)boronic acid and 6.3 g (30.6 mol / 1 .5 eq.) of <strong>[65550-77-8]2-bromo-5-chloro-3-methylpyridine</strong> was provided in a reaction mixture comprising 5.0 mol% PdCI2(dtbpf) and 2.0 eq. TEA in 28 ml (10 V) 2% TPGS-750-M in water and 5.6 ml (2V) THF. The reaction mixture formed a stable emulsion and the reaction was allowed to proceed for 18 h at 40C under stirring. The product 5-chloro-2',3-dimethyl- 2,4'-bipyridine was obtained with a yield of about 100%. (0097) (0098) The same reaction using 1 V acetone as co-solvents, wherein 1 .5 eq. or 1 .1 eq. 2- bromo-5-chloro-3-methylpyridine was added, also resulted in about 100% yield after 4 h at room temperature.

Reference： [1]Patent: WO2017/168303,2017,A1 .Location in patent: Page/Page column 16

61
[ 97004-04-1 ]
[ 579476-63-4 ]
(6-(2-methylpyridin-4-yl)pyridin-3-yl)methanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	(6-Chloropyridin-3-yl) methanamine (300 mg, 2.1 mmol) was treated with n-butanol (10 mL) and waterAnd 2-methylpyridin-4-ylboronic acid (345 mg, 2.52 mmol) were dissolved in a pressure tube.Under a nitrogen atmosphere, K3PO4 (893 mg,4.2 mmol), Pd2 (dba) 3 (96.3 mg, 0.105 mmol) and S-phos (86.4 mg, 0.21 mmol).The reaction was heated to 125 ° C for 30 minutes and then cooled to room temperature.The solution was poured into water and extracted three times with EA. The combined organic layers were washed with saturated brine and dried over Na2SO4 and then concentrated under vacuum. The crude product was further purified by flash chromatography with DCM containing 10percent methanol containing ~ 2N ammonia to obtain pure (6- (2-methylpyridin-4-yl) pyridin-3-yl) methanamine(0.19 g, yield ~45percent).

Reference： [1]Patent: CN104530042,2017,B .Location in patent: Paragraph 0216; 0225; 0226; 0227

62
[ 460081-20-3 ]
[ 579476-63-4 ]
ethyl 2-(2-methylpyridin-4-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In acetonitrile; at 85℃; for 12h;	To a mixture of <strong>[460081-20-3]ethyl 2-bromooxazole-4-carboxylate</strong> (500 mg, 2.27 mmol) and (2- methylpyridin-4-yl)boronic acid (622 mg, 4.55 mmol) in acetonitrile (5 mL) was added cesium carbonate (1.48 g, 4.55 mmol) and l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (185 mg). The mixture was heated and stirred at 85 C for 12 h. The mixture was filtered, and the filtrate was concentrated and purified by preparatory thin layer chromatography (petroleum ether : ethyl acetate = 1 : 1) to give ethyl 2-(2-methylpyridin-4-yl)oxazole-4-carboxylate (200 mg, 38%) as a light brown solid. 1H NMR (400 MHz, CDC13): delta 8.66 (d, J = 5.6 Hz, 1H), 8.34 (s, 1H), 7.87 (s, 1H), 7.75 (d, J = 4.8 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). LCMS (ESI): m/z = 233.1 [M+H]+.

Reference： [1]Patent: WO2018/234343,2018,A1 .Location in patent: Page/Page column 88

63
[ 1380917-35-0 ]
[ 579476-63-4 ]
5-bromo-3-(2-methylpyridin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 65℃;Inert atmosphere;	A solution of 5-bromo-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (55 g, 135 mmol) , (2-methylpyridin-4-yl) boronic acid (20.3 g, 148 mmol) , Pd (dppf) Cl2·DCM (5.5 g, 6.75 mmol) and Na2CO3(28.6 g, 270 mmol) in dioxane (500 mL) /H2O (100 mL) was stirred at 65 under N2protection overnight. The mixture was then cooled to room temperature and diluted with H2O (300 mL) , extracted with EA (300 mL x3) . The combined organic layers were washed with H2O (200 mL) and brine (200 mL) , dried over anhydrous Na2SO4, filtered off, and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography to give the title compound (35.5 g, 71percentyield) .

Reference： [1]Patent: WO2019/37640,2019,A1 .Location in patent: Page/Page column 53; 54; 55

64
5-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine [ No CAS ]
[ 579476-63-4 ]
5-chloro-3-(2-methylpyridin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 65℃;Inert atmosphere;	A mixture of 5-chloro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-c] pyridine (1.08 g, 3 mmol) , (2-methylpyridin-4-yl) boronic acid (493 mg, 3.6 mmol) , Pd (dppf) Cl2·DCM (123 mg,0.15 mmol) and Na2CO3(636 mg, 6 mmol) in dioxane (20 mL) and H2O (4 mL) was stirred at 65 under N2overnight. After cooling to room temperature, it was diluted with EtOAc (50 mL) , which was washed with H2O (50 mL x 2) , brine (15 mL) , dried over anhydrous Na2SO4, filtered off, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE: EtOAc = 10: 12: 1) to give the title compound (661 mg, yield: 67percent) .

Reference： [1]Patent: WO2019/37640,2019,A1 .Location in patent: Page/Page column 128; 129

65
5-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine [ No CAS ]
[ 579476-63-4 ]
5-chloro-3-(2-methylpyridin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 65℃;Inert atmosphere;	The mixture of 5-chloro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4, 3-b] -pyridine (2.85 g, 7.86 mmol) , (2-methylpyridin-4-yl) boronic acid (1.13 g, 8.26 mmol) , Na2CO3(1.67 g, 15.73 mmol) and Pd (dppf) Cl2·DCM (644 mg, 0.79 mmol) in dioxane (30 mL) /H2O (6 mL) was stirred at 65 overnight under N2protection. The reaction mixture was cooled to room temperature and diluted with EA (90 mL) , washed with brine (20 mLx2) , dried over anhydrous Na2SO4, filtered off, and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography eluting with hexanes/ethyl acetate (4: 11: 2) to give the title compound (1.72 g, 66percentyield) .

Reference： [1]Patent: WO2019/37640,2019,A1 .Location in patent: Page/Page column 70; 71

66
[ 116272-41-4 ]
[ 579476-63-4 ]
4-(5-bromo-2-fluorophenyl)-2-methylpyridine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 5773 - 5796

67
(3aR,6aS)-3,3a,4,6a-tetrahydro-1H-spiro[pentalene-2,2'-[1,3]dioxolane]-5-yl trifluoromethanesulfonate [ No CAS ]
[ 579476-63-4 ]
2-methyl-4-((3aR,6aS)-3,3a,4,6a-tetrahydro-1H-spiro[pentalene-2,2'-[1,3]dioxolane]-5-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 110℃;Inert atmosphere;	The reaction mixture (3aR,6aS)-3,3a,4,6a-tetrahydro-1H-spiro[pentalene-2,2'-[1,3]dioxolane]-5-yl trifluoromethanesulfonate 1c (9.55g, 30.4mmol), (2-methylpyridin-4-yl) boronic acid (5g, 36.5mmol), [1,1'-bis (diphenylphosphine)ferrocene]palladium dichloromethane complex (1.24g, 1.52mmol), Sodium carbonate (6.44 g, 60.8 mmol), N,N-dimethylformamide (100 mL) and water (10 mL) were heated to 110 C. under nitrogen protection and stirred overnight. Cool to room temperature and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10/1), The target product 2-methyl-4-((3aR,6aS)-3,3a,4,6a-tetrahydro-1H-spiro[pentalene-2,2'-[1,3]dioxolane]-5-yl)pyridine 1d (6 g, yellow oil), yield: 77%.

Reference： [1]Patent: CN110540521,2019,A .Location in patent: Paragraph 0107-0109; 0118-0121

68
[ 86-76-0 ]
[ 579476-63-4 ]
C₁₈H₁₃NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With tetrakis(triphenylphosphine) palladium(0); tetrabutyl-ammonium chloride; potassium carbonate; In ethanol; water; toluene; at 78℃; for 10.0h;Inert atmosphere;	Intermediate IA (3.0g, 12.14mmol), intermediate IK-1 (2.21g, 16.18mmol), tetrakis (triphenylphosphine) palladium (0.70g, 0.61mmol), potassium carbonate (3.36g, 24.28mmol) , Tetrabutylammonium chloride (0.17g, 0.61mmol), toluene (30mL), ethanol (16mL) and deionized water (8mL) were added to the round bottom flask, heated to 78 C under nitrogen protection, and stirred for 10 hours; The reaction solution was cooled to room temperature, toluene (200 mL) was added for extraction, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure; the resulting crude product was purified by silica gel column chromatography using n-heptane as the mobile phase, and then used The dichloromethane / ethyl acetate system was purified by recrystallization to obtain the intermediate IK-2 (3.48 g, yield 83%)

Reference： [1]Patent: CN111018847,2020,A .Location in patent: Paragraph 0164; 0165

69
4-chloro-6-(4-fluorophenyl)-5-iodo-2-aminopyrimidine [ No CAS ]
[ 579476-63-4 ]
4-chloro-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.71%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 20 - 45℃;Inert atmosphere;	To a stirred mixture of 4-chloro-6- (4-fluorophenyl) -5-iodopyrimidin-2-amine (900 mg, 2.57 mmol, 1 equiv), (2-methylpyridin-4-yl) boronic acid (705.3 mg, 5.2 mmol, 2.0 equiv) and Cs 2CO 3 (2516.8 mg, 7.7 mmol, 3 equiv) in 1, 4-dioxane (30 mL) and H2O (5 mL) was added Pd (dppf) Cl 2 (188.4 mg, 0.26 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 45C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2Cl 2 /MeOH (97: 3) to afford 4-chloro-6- (4-fluorophenyl)-5-(2-methylpyridin-4-yl) pyrimidin-2-amine (800 mg, 98.71%) as a Brown yellow State. LCMS: m/z (ESI), [M+H] + = 315.2.

Reference： [1]Patent: WO2020/52631,2020,A1 .Location in patent: Page/Page column 76-77

70
[ 105512-81-0 ]
[ 579476-63-4 ]
4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.43%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 80℃; for 2h; Inert atmosphere;	58.1 Step 1: Preparation of 4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-amine (Intermediate C) mixture of 4-(3-bromophenyl)thiazol-2-amine (1 g, 3.92 mmol), (2-methyl-4-pyridyl)boronic acid (590.43 mg, 4.31 mmol), K2CO3 (1.63 g, 11.76 mmol) and Pd(dppf)Cl2 (286.79 mg, 391.95 mmol) in dioxane (10 mL) and H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 3/1) and concentrated to afford Intermediate C (1 g, 3.74 mmol, 95.43% yield) as yellow solid. LCMS (ESI) m/z [M+H]+=268.2; 1H NMR (400 MHz, CDCl3) d 8.57 (d, J=5.2 Hz, 1H), 8.10-8.08 (m, 1H), 7.85-7.83 (m, 1H), 7.59-7.54 (m, 1H), 7.53-7.47 (m, 1H), 7.45 (s, 1H), 7.40-7.38 (m, 1H), 6.84 (s, 1H), 5.04 (br s, 2H), 2.66 (s, 3H
95.43%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 80℃; for 2h; Inert atmosphere;	37.1 A mixture of 4-(3-bromophenyl)thiazol-2-amine (1 g, 3.92 mmol), (2-methyl-4-pyridyl)boronic acid (805.13 mg, 5.88 mmol), K2CO3 (1.63 g, 11.76 mmol), Pd(dppf)Cl2 (286.79 mg, 391.95 μmol) in dioxane (10 mL) , H20 (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hr under N2 atmosphere. The reaction mixture was poured into water (30 mL) , and extracted with EA (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=10/1 to 1 :1) and concentrated in vacuum to give Intermediate C (1 g, 3.74 mmol, 95.43% yield) as a yellow solid. LCMS (ESI) m/z [M+H]+ =268.3. 1 H NMR (400 MHz, DMSO) δ = 8.56-8.49 (m, 1 H), 8.18-8.16 (m, 1 H), 7.89 (d, J=8.0 Hz, 1 H), 7.71-7.63 (m, 1 H), 7.60 (s, 1 H), 7.54-7.48 (m, 2H), 7.20 (s, 1 H), 7.11 (s, 2H), (0332) 2.55 (s, 3H) ppm.

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2020/160180, 2020, A1 Location in patent: Page/Page column 170
[2]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1 Location in patent: Page/Page column 118

71
[ 1214361-39-3 ]
[ 579476-63-4 ]
2'-methyl-6-(trifluoromethyl)-[3,4'-bipyridin]-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 80℃; for 2h; Inert atmosphere;	432.1; 433.1 J A mixture of 3-bromo-6-(trifluoromethyl)pyridin-2-amine (500 mg, 2.07 mmol), (2- methylpyridin-4-yl)boronic acid (512 mg, 2.48 mmol), K2CO3(0.860 g, 6.22 mmol) and Pd(dppf)Ch (152 mg, 0.207 mmol) in 1,4-dioxane (25 mL) and water (5 niL) was stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, 30% EtOAc in petroleum ether) to give 2'-methyl-6-(tnfiuoromeihyl)~[3,4'~bipyridin]-2-amine (524 mg, yield: 99%) as a yellow solid. H NMR (400 MHz, CDCI3): d = 8.63 (d, .7= 5.2 Hz, IH), 7.52-7.48 (m, IH), 7.50 (d, ./ =7.6 Hz, IH), 7.27-7.25 (m, IH), 7.24-7.20 (m, IH), 7.22 id../ 4.8 Hz, 111). 7.14 (d../ 7.6 Hz, IH),4.87 (s, 2H), 2.64 (s, 3H).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2021/150574, 2021, A1 Location in patent: Paragraph 1111

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CAS No. :	579476-63-4	MDL No. :	MFCD03095364
Formula :	C₆H₈BNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UFYBTLOLWSABAU-UHFFFAOYSA-N
M.W :	136.94	Pubchem ID :	4192664
Synonyms :

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	39.03
TPSA :	53.35 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.02 cm/s

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.16
Log Po/w (WLOGP) :	-0.93
Log Po/w (MLOGP) :	-1.02
Log Po/w (SILICOS-IT) :	-0.77
Consensus Log Po/w :	-0.51

[ CAS No. 579476-63-4 ] {[proInfo.proName]}

Quality Control of [ 579476-63-4 ]

Related Doc. of [ 579476-63-4 ]

Product Details of [ 579476-63-4 ]

Calculated chemistry of [ 579476-63-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 579476-63-4 ]

Application In Synthesis of [ 579476-63-4 ]

[ 579476-63-4 ] Synthesis Path-Upstream 1~4

[ 579476-63-4 ] Synthesis Path-Downstream 1~71

Related Functional Groups of
[ 579476-63-4 ]

Organoboron

Related Parent Nucleus of
[ 579476-63-4 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-1.17
Solubility :	9.3 mg/ml ; 0.0679 mol/l
Class :	Very soluble
Log S (Ali) :	-0.84
Solubility :	19.9 mg/ml ; 0.145 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.27
Solubility :	7.3 mg/ml ; 0.0533 mol/l
Class :	Soluble

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

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

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Code	Phrase
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P342	If experiencing respiratory symptoms:
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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:
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P372	Explosion risk in case of fire.
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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
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P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling