[ CAS No. 1073354-99-0 ] {[proInfo.proName]}

Name: 1073354-99-0|5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine|95%
Brand: Ambeed
SKU: A218050
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Quality Control of [ 1073354-99-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1073354-99-0 ]

Product Details of [ 1073354-99-0 ]

CAS No. :	1073354-99-0	MDL No. :	MFCD09260489
Formula :	C₁₁H₁₇BN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DAISWHFZWZZBBD-UHFFFAOYSA-N
M.W :	220.08	Pubchem ID :	43811068
Synonyms :

Calculated chemistry of [ 1073354-99-0 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.55
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	65.12
TPSA :	57.37 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.82 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.16
Log Po/w (WLOGP) :	0.97
Log Po/w (MLOGP) :	0.0
Log Po/w (SILICOS-IT) :	0.58
Consensus Log Po/w :	0.54

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.15
Solubility :	1.57 mg/ml ; 0.00713 mol/l
Class :	Soluble
Log S (Ali) :	-1.96
Solubility :	2.41 mg/ml ; 0.011 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.27
Solubility :	0.118 mg/ml ; 0.000535 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.9

Safety of [ 1073354-99-0 ]

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:

Application In Synthesis of [ 1073354-99-0 ]

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

Upstream synthesis route of [ 1073354-99-0 ]
Downstream synthetic route of [ 1073354-99-0 ]

[ 1073354-99-0 ] Synthesis Path-Upstream 1~2

1
[ 15862-30-3 ]
[ 73183-34-3 ]
[ 1073354-99-0 ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium acetate In 1,4-dioxane at 80 - 90℃; Inert atmosphere Stage #2: With hydrogen In 1,4-dioxane at 20℃;	Under nitrogen protection, 550 mL of dioxane and 3-nitro-5-bromopyridine (20.3 g, After 0.10 mol) of pinacol borate (25.4 g, 0.10 mol) and potassium acetate (14.7 g, 0.15 mol), after stirring uniformly, the catalyst PdCl2dppf (0.74 g, 0.001 mol) was finally added, and the temperature was slowly raised to 80- 90 ° C, Stir the reaction for 2-3 h. After the completion of the GC reaction, the reaction was stopped by cooling, and the reaction solution was filtered through celite to obtain a dark-black reaction solution. After charging at 1 atm of hydrogen, the mixture was reacted at room temperature overnight. After the reaction was completed, the activated carbon was decolorized, and the filtrate was distilled under reduced pressure until no liquid was poured. /Heptane mixed solvent is cooled and beaten for half an hour, filtered to obtain a light gray crude product, heated again with ethanol, and then cooled down, and the filter cake is rinsed with -20 ° C anhydrous ethanol, and dried to obtain a pale yellow solid 15.6 g, yield 71percent, HPLC purity 97.9percent

Reference： [1] Patent: CN108047258, 2018, A, . Location in patent: Paragraph 0005; 0014; 0015

2
[ 13535-01-8 ]
[ 73183-34-3 ]
[ 1073354-99-0 ]

Reference： [1] Patent: WO2013/126608, 2013, A1, . Location in patent: Paragraph 00394
[2] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1031 - 1050
[3] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 270 - 285

[ 1073354-99-0 ] Synthesis Path-Downstream 1~87

1
[ 1073354-99-0 ]
tert-butyl rac-exo-[6-(2-bromophenoxy)]-3-azabicyclo[3.2.1]octane-3-carboxylate [ No CAS ]
tert-butyl rac-exo-[6-(2-(5-aminopyridin-3-yl)phenoxy)]-3-azabicyclo[3.2.1]octane-3-carboxylate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 4749 - 4752

2
[ 1073354-99-0 ]
[ 1059065-41-6 ]
[ 1251948-67-0 ]

Yield	Reaction Conditions	Operation in experiment
33%	With cesium hydroxide;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere;	EXAMPLE 1; Representative Procedure for Synthesis of Benzo[e][l,4]diazepin-2(3H)-ones from Imidoyl Chlorides.Part I: Palladium- Coupling of a Heteroaryl Boronic Acid and an Imidoyl Chloride.5-(5-Aminopyridin-3-yl)-7-chloro-3-(2-chlorobenzyl)-l-(4-methoxybenzyl)-lH- benzo[e][l,4]diazepin-2(3H)-one. 5,7-Dichloro-3-(2-chlorobenzyl)-l-(4-methoxybenzyl)- lH-benzo[e][l,4]diazepin-2(3H)-one (240 mg) and 5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridin-3-amine (134 mg, 1.2 eq) were suspended in dioxane/water (6 niL/2 niL), and then cesium hydroxide (170 mg, 2 eq) was added and the mixture was degassed by pulling vacuum until bubbling occurred, and then introducing nitrogen gas. The degassing procedure was repeated twice, and then tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.05 eq) was added. The degassing procedure was repeated once, and then the reaction was heated to 90 0C for three hours. The crude mixture was then diluted with EtOAc (20 mL) and then washed with water, then brine, and then it was dried over sodium sulfate, and concentrated onto silica gel. The product was purified by chromatography (gradient: 75:25 hexanes:EtOAc to EtOAc) delivering the product as a solid (90 mg, 33% yield). MS (ES+) m/z 531.0 (M + 1).

Reference： [1]Patent: WO2010/121164,2010,A2 .Location in patent: Page/Page column 52-53

3
[ 866545-96-2 ]
[ 1073354-99-0 ]
C₁₄H₁₂N₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 7212 - 7215

4
[ 1073354-99-0 ]
[ 1261082-88-5 ]
[ 1261082-86-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 7212 - 7215
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 5337 - 5349
[3]Organic and Biomolecular Chemistry,2014,vol. 12,p. 4644 - 4655
[4]Journal of Medicinal Chemistry,2014,vol. 57,p. 6428 - 6443

5
[ 30493-41-5 ]
[ 1073354-99-0 ]
C₁₄H₁₂N₄O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

6
[ 1073354-99-0 ]
[ 1276110-10-1 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

7
[ 1073354-99-0 ]
[ 1276110-02-1 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

8
[ 474709-01-8 ]
[ 1073354-99-0 ]
C₁₅H₁₂N₆O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

9
[ 1073354-99-0 ]
[ 1276110-41-8 ]
[ 1276110-00-9 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

10
[ 1073354-99-0 ]
[ 1276110-41-8 ]
C₁₃H₁₁N₅O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

11
[ 1073354-99-0 ]
[ 1276109-83-1 ]
C₁₇H₁₃N₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

12
[ 1073354-99-0 ]
[ 1276109-86-4 ]
[ 1276110-13-4 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

13
[ 1073354-99-0 ]
[ 1276109-86-4 ]
C₁₆H₁₇N₅O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

14
[ 1073354-99-0 ]
[ 1313525-00-6 ]
[ 1276110-17-8 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

15
[ 1073354-99-0 ]
[ 1313525-00-6 ]
C₁₉H₁₃N₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

16
6-bromo-3-pyridin-4-ylimidazo[1,2-a]pyridine [ No CAS ]
[ 1073354-99-0 ]
C₁₇H₁₃N₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

17
6-bromo-3-pyridin-4-ylimidazo[1,2-a]pyridine [ No CAS ]
[ 1073354-99-0 ]
[ 1276110-21-4 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

18
[ 1073354-99-0 ]
[ 6188-23-4 ]
[ 1276109-89-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

19
[ 1073354-99-0 ]
[ 183208-35-7 ]
[ 1261082-75-0 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

20
[ 1073354-99-0 ]
[ 183208-35-7 ]
[ 1381859-24-0 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466

21
[ 1073354-99-0 ]
[ 1354290-08-6 ]
[ 1354286-36-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; tricyclohexylphosphine;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 90℃; for 19h;Inert atmosphere;	N-(5-bromo-2-morpholinopyridin-4-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)- quinolin-4-amine (50.1 mg, 0.1 mmol), <strong>[1073354-99-0]3-aminopyridine-5-boronic acid</strong>, pinacol ester (43.2 mg, 0.2 mmol), tricyclohexylphosphine (5.5 mg, 0.02 mmol), and tris(dibenzylideneacetone)dipalladium (0) (9.3 mg, 10.2 muiotaetaomicron) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (2.0 mL) and aq. 1.3M potassium phosphate tribasic (0.23 mL, 0.3 mmol) were added by syringe. The resulting reaction was heated to 90 C and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-75% of a premixed solution of 89:9: 1 DCM: MeOH: ammonium hydroxide in DCM) to afford a film that was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield an off- white solid as N4-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-6-morpholino- S^-bipyridine^'-diamine. 1H NMR (500 MHz, DMSO-d6) delta ppm 8.70 (1 H, d, J=4.2 Hz), 8.07 (1 H, m), 7.94 (3 H, m), 7.77 (2 H, s), 7.63 (1 H, dd, J=9.7, 1.6 Hz), 7.55 (2 H, m), 6.99 (1 H, m), 5.59 (1 H, s), 5.33 (2 H, s), 3.64 (4 H, m), 3.26 (4 H, m), 2.24 (3 H, s). Mass Spectrum (pos.) m/e: 526.2 (M+H)+.

Reference： [1]Patent: WO2012/3283,2012,A1 .Location in patent: Page/Page column 158

22
[ 1073354-99-0 ]
[ 1377503-74-6 ]
[ 1377503-52-0 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5337 - 5349

23
[ 225382-62-7 ]
[ 1073354-99-0 ]
[ 1257554-93-0 ]
C₂₁H₂₂N₆O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		VIII-01 VIII-18To a solution of 4-chloro-6-iodothieno[3,2-d]pyrimidine VIII-01 (30 mg, 0.101 mmol) in 1,2-dioxane (0.81 mL) was added <strong>[1073354-99-0]3-aminopyridine-5-boronic acid</strong>, pinacol ester (27 mg, 0.121 mmol), K2C03 1M (0.42 mL) and Pd(PPh3)4 (12 mg, 0.0 0 mmol). The reaction mixture was heated at 100 C for 1 h. Then 3-(N-Boc- aminomethyl)pyridine-5-boronic acid, pinacol ester (50 mg, 0.142 mmol), K2C03 1 (0.42 mL) and Pd(PPh3)4 (12 mg, 0.010 mmol) were added. The reaction mixture was heated at 100 C for 1 h. On cooling, the mixture was concentrated and the residue was purified by column chromatography (Biotage, cHex:EtOAc 100:0 to 0:100 and EtOAc:MeOH 100:0 to 80:20) to give intermediate VIII-18 (17 mg, 39%).

Reference： [1]Patent: WO2012/156756,2012,A2 .Location in patent: Page/Page column 87

24
[ 1073354-99-0 ]
[ 1420829-02-2 ]
[ 1420830-03-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In 1,4-dioxane; water; at 95℃; under 760.051 Torr; for 16h;	General procedure: Example 92[00657] Compound 109 was prepared from compound 2 according the the following procedure:Compound 2 (0.69 mmol, 1.0 equiv), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-amine (1.38 mmol, 2.0 equiv) and sodium carbonate (1.38 mmol, 2.0 equiv) were combined in dioxane (10 mL) and water (1 mL) and degassed under vacuum. AmPhos (25 mol %) was added and the solution was degassed and then heated to 95 C for 16h. The reaction was allowed to cool and transferred to a separtory funnel with excess dichloromethane. The organic layer was washed with water (2 x 25 mL) and brine (1 x 25 mL), dried over Na2S04 and concentrated to provide crude material which was purified by flash silica gel chromatography (gradient 3-8% MeOH/methylene chloride) to provide compound 109. ESI-MS m/z: 492.2 [M+H]+.

Reference： [1]Patent: WO2013/12918,2013,A1 .Location in patent: Paragraph 00657

25
[ 13535-01-8 ]
[ 73183-34-3 ]
[ 1073354-99-0 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; HK(1+)*C2H3O2(1-); In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;	5-Bromo-pyridin-3-ylamine (1.0 g, 5.8 mmol), bis(pinacolato)diboron (1.46 g, 5.7 mmol), Pd(dppf)Cl2 (200 mg), AcOK (1.1 g, 11.4 mmol) were stirred in 1,4-dioxane (15 mL) at 100C under N2 for 4 h. After cooled to room temperature, to the mixture was added 2- bromo-pyridine (0.91 g, 5.7 mmol), Cs2C03 (7.4 g, 22.8 mmol), Pd(PPh3)4 (200 mg), water (3 mL). The mixture was then heated to 100 C under N2 for 2 h. The solvent was concentrated under reduced pressure. The residue was dissolved in water and the aqueous phase was extracted with EtOAc (30 mL x3). The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated to dryness under reduced pressure. The crude was purified via silic gel column (DCM/MeOH, 20/1) to afford 300 mg (2-step yield: 30%) of [2,3]Bipyridinyl-5- ylamine. MS: m/z 172.0 (M+H+).
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 2h;Reflux; Inert atmosphere;	General procedure: A mixture of 5mmol of the appropriate amino-5-bromo pyridine and 1.96gm (20mmol) of potassium acetate and 0.18gm (0.25mmol) of Pd(dppf)Cl2 and 5.08gm (20mmol) of bis(pinacolato)diboron in dioxane was heated to reflux under argon for 2h to yield compounds A and B. The mixture was left to attain room temperature and then filtered under vacuum. Without further purification, a reaction flask containing the filtrate was charged with 6.5gm (20mmol) of Cs2CO3, 0.29gm (0.25mmol) of palladium-tetrakis(triphenylphosphine) and 6mmol of 2,4-dibromothiophene together with 30% water in a Suzuki coupling reaction. The reaction was left to reflux under argon for 3.5h. The mixture was concentrated in vacuo. The residue was partitioned between 150mL ethyl acetate and 50mL brine solution and then the aqueous layer was re-extracted using 3 portions of 100mL ethyl acetate. The organic layers were collected and the volume was reduced under reduced pressure. Afterwards the product was purified by CC to yield compounds C-D.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; for 2h;Reflux; Inert atmosphere;	A mixture of 5 mmol of the 3-amino-5-bromo pyridine and1.96 gm (20 mmol) of potassium acetate and 0.18 gm (0.25 mmol)of Pd (dppf)Cl2 and 5.08 gm(20 mmol) of bis(pinacolato)diboron indioxane was heated to reflux under argon for 2 h to yield compoundsA. The mixture was left to attain room temperature andthen filtered under vacuum. Without further purification, a reactionflask containing the filterate was charged with 6.5 gm(20 mmol) of Cs2CO3, 0.29 gm (0.25 mmol) of palladium-tetrakis(triphenylphosphine) and 6 mmol of the appropriate bromothiophenetogether with 30% water in a Suzuki coupling reaction. Thereaction was left to reflux under argon for 3.5 h. The mixture wasconcentrated in vacuo. The residue was partitioned between150 mLs ethyl acetate and 50 mLs brine solution and then theaqueous layer was re-extracted using 3 portions of 100 mLs ethylacetate. The organic layers were collected and the volume wasreduced under reduced pressure. Afterwards the product was purifiedby CC to yield compounds B, H.

With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;

To a stirred solution of 5-bromopyridin-3-amine (MANCHESTER ORGANICS, 1 g, 5.78 mmol) in 1 ,4-dioxane (15 mL) were added 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (ALFA-AESAR, 1.46 g, 5.78 mmol), potassium acetate (AVRA, 1.1 g, 1 1.56 mmol) and the reaction mixture was degassed with argon for 10 min. Followed by the addition of Pd(dppf)CI2.CH2Cl2 (ALFA-AESAR, 200 mg, 0.289 mmol). The reaction mixture was heated to 100 C and stirred for 4 h. The reaction mixture was cooled to 27 C and proceeded to next step without further purification. 1H NMR (400 MHz, CDCI3) delta ppm: 8.36 (s, 1 H), 8.22-8.13 (m, 1 H), 8.10-7.95 (m, 1 H), 7.36 (br s, 2H), 1.27 (s, 12H).

Reference： [1]Patent: WO2013/126608,2013,A1 .Location in patent: Paragraph 00394
[2]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1031 - 1050
[3]European Journal of Medicinal Chemistry,2018,vol. 158,p. 270 - 285
[4]Patent: WO2019/34701,2019,A1 .Location in patent: Page/Page column 53

26
[ 109-04-6 ]
[ 1073354-99-0 ]
[ 1245745-55-4 ]

Yield	Reaction Conditions	Operation in experiment
300 mg	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;	5-Bromo-pyridin-3-ylamine (1.0 g, 5.8 mmol), bis(pinacolato)diboron (1.46 g, 5.7 mmol), Pd(dppf)Cl2 (200 mg), AcOK (1.1 g, 11.4 mmol) were stirred in 1,4-dioxane (15 mL) at 100C under N2 for 4 h. After cooled to room temperature, to the mixture was added 2- bromo-pyridine (0.91 g, 5.7 mmol), Cs2C03 (7.4 g, 22.8 mmol), Pd(PPh3)4 (200 mg), water (3 mL). The mixture was then heated to 100 C under N2 for 2 h. The solvent was concentrated under reduced pressure. The residue was dissolved in water and the aqueous phase was extracted with EtOAc (30 mL x3). The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated to dryness under reduced pressure. The crude was purified via silic gel column (DCM/MeOH, 20/1) to afford 300 mg (2-step yield: 30%) of [2,3]Bipyridinyl-5- ylamine. MS: m/z 172.0 (M+H+).

Reference： [1]Patent: WO2013/126608,2013,A1 .Location in patent: Paragraph 00394

27
[ 3034-53-5 ]
[ 1073354-99-0 ]
[ 1374970-69-0 ]

Yield	Reaction Conditions	Operation in experiment
35%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere;	5-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (1.25 g, 5.7 mmol), 2-bromo-thiazole (923 mg, 5.7 mmol), Cs2C03 (7.4 g, 22.8 mmol), Pd(PPh3)4 (200 mg) were stirred in 1,4-dioxane (15 mL) and water (3 mL) at 100 C under N2 for 4 h. Then the solvent was concentrated under reduced-pressure. The residue was dissolved in water and the aqueous phase was extracted with EtOAc (30 mL x3). The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated to dryness under reduced pressure. The crude was purified via silica gel column (DCM/MeOH, 20/1) to afford 350 mg (yield: 35%) of 5- thiazol-2-yl-pyridin-3-ylamine. MS: m/z 177.9 (M+H+).

Reference： [1]Patent: WO2013/126608,2013,A1 .Location in patent: Paragraph 00437

28
[ 1073354-99-0 ]
[ 1469858-46-5 ]
[ 1469858-72-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; toluene; at 100℃; for 8h;	A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.1 g, 2.3 mmol), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (0.75 g, 3.4 mmol), Na2CO3 (2 M, 5.4 mL), and Pd(PPh3)2Cl2 (260 mg, 0.23 mmol) in toluene/ ethanol (1:1, 15 mL) was heated at 100 C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 5-[6-(4-Methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-3-ylamine as brown solid in 68% yield.
68%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; toluene; at 100℃; for 8h;	The corresponding intermediate 2-bromo-6- (4-methoxy-phenyl) -4- (2-trimethylsilane-ethoxymethyl) -4,7-dihydro- 4,5-diazo-cyclopenta [a] cyclopentadiene (1.1 g, 2.3 mmol)5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridin-3-ylamine(0.75 g, 3.4 mmol), Na2CO3 (2 M, 5.4 mL) and Pd (PPh3) 2Cl2 (226 mg, 0.1 mmol) in toluene / ethanol (1: 1, 15 mL) was heated to 100 C 8 hours. The solution was cooled to room temperature and extracted with ethyl acetate. The objective product was obtained as a brown solid by gravity column chromatography (30% EtOAc in hexanes)5- [6- (4-Methoxy-phenyl) -4- (2-trimethylsilane-ethoxymethyl) -4,7-dihydro-1-thia-4,5-diazepine Cyclopenta [a] cyclopentan-2-yl] -pyridin-3-ylamine in 68% yield.

Reference： [1]Patent: US2013/274255,2013,A1 .Location in patent: Paragraph 0435
[2]Patent: TWI553010,2016,B .Location in patent: Page/Page column 125

29
[ 1073354-99-0 ]
[ 1567837-18-6 ]
[ 1567837-19-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene; for 16h;Reflux; Inert atmosphere;	General procedure: 5(5-Iodothiophen-2-yl)-2-methylisoindolin- 1-one was reacted with 5-(4,4,5 ,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-amine (1.2 equivalents) according to general procedureC. The desired product was collected by filtration from the cooled reaction mixture and washed with H20, MeOH and CH2CI2. No further purification was required and the title compound was isolated as a green solid (84%), mp (MeOl-IICH2CI2) 244-248C. ?H NMR[400 MHz, (CD3)2S0] 8.12 (d,J= 2.0 Hz, 1 H), 7.92 (s, I H), 7.90 (d,J 2.5 Hz, I H),7.80 (dd, J= 8.0, 1.3 Hz, 1 H), 7.70 (d, J= 4.3 Hz, 1 H), 7.68 (s, I H), 7.54 (d, J 3.8 Hz,1 H), 7.16 (t, J = 2.2 Hz, 1 H), 5.51 (br s, 2 H), 4.51 (s, 2 H), 3.09 (s. 3 H). Anal.(C,6H10N203S2.0.25H20) C, H, N.
86%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene;Inert atmosphere; Reflux;	General procedure: 5-Bromo-2-methylisoindolin-1-one (520 mg, 2.30 mmol) and thiophene-2-boronic acid (442mg, 3.45 mmol) were dissolved in a mixure of toluene (12 mL) and EtOH (6 mL). A solutionof 2 M Na2CO3 (3 mL) and Pd(dppf)Cl2 (94 mg, 0.12 mmol) were added and the entiremixture heated at reflux under N2 for 2 h. Additional thiophene-2-boronic acid (294 mg, 2.30mmol) was added and reflux continued under N2 overnight. Upon cooling, the mixture wasdiluted with water (100 mL) and extracted with CH2Cl2 (6x50 mL). The combined organicfractions were dried (Na2SO4), filtered, and the solvent removed under reduced pressure togive a crude solid which was purified by flash column chromatography on silica gel (EtOAcas eluant). The title compound was isolated as a light-brown solid (510 mg, 97%).

Reference： [1]Patent: WO2014/28968,2014,A1 .Location in patent: Page/Page column 65; 66; 111
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1050 - 1054

30
[ 1073354-99-0 ]
[ 1567836-36-5 ]
[ 1567836-37-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene;Reflux; Inert atmosphere;	General procedure: 5(5-Iodothiophen-2-yl)-2-methylisoindolin- 1-one was reacted with 5-(4,4,5 ,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-amine (1.2 equivalents) according to general procedureC. The desired product was collected by filtration from the cooled reaction mixture and washed with H20, MeOH and CH2CI2. No further purification was required and the title compound was isolated as a green solid (84%), mp (MeOl-IICH2CI2) 244-248C. ?H NMR[400 MHz, (CD3)2S0] 8.12 (d,J= 2.0 Hz, 1 H), 7.92 (s, I H), 7.90 (d,J 2.5 Hz, I H),7.80 (dd, J= 8.0, 1.3 Hz, 1 H), 7.70 (d, J= 4.3 Hz, 1 H), 7.68 (s, I H), 7.54 (d, J 3.8 Hz,1 H), 7.16 (t, J = 2.2 Hz, 1 H), 5.51 (br s, 2 H), 4.51 (s, 2 H), 3.09 (s. 3 H). Anal.(C,6H10N203S2.0.25H20) C, H, N.
84%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene;Inert atmosphere; Reflux;	General procedure: 5-Bromo-2-methylisoindolin-1-one (520 mg, 2.30 mmol) and thiophene-2-boronic acid (442mg, 3.45 mmol) were dissolved in a mixure of toluene (12 mL) and EtOH (6 mL). A solutionof 2 M Na2CO3 (3 mL) and Pd(dppf)Cl2 (94 mg, 0.12 mmol) were added and the entiremixture heated at reflux under N2 for 2 h. Additional thiophene-2-boronic acid (294 mg, 2.30mmol) was added and reflux continued under N2 overnight. Upon cooling, the mixture wasdiluted with water (100 mL) and extracted with CH2Cl2 (6x50 mL). The combined organicfractions were dried (Na2SO4), filtered, and the solvent removed under reduced pressure togive a crude solid which was purified by flash column chromatography on silica gel (EtOAcas eluant). The title compound was isolated as a light-brown solid (510 mg, 97%).

Reference： [1]Patent: WO2014/28968,2014,A1 .Location in patent: Page/Page column 65; 66
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1050 - 1054

31
[ 1073354-99-0 ]
2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]
2-(5-aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1,4-dioxane; methanol; dichloromethane; water;	2-Chloro-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4.00 g, 11.9 mmol) and <strong>[1073354-99-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine</strong> (5.24 g, 23.8 mmol, commercial) were dissolved in dioxane (50 mL) and water (3 mL). To the reaction mixture was added K2CO3 (6.59 g, 47.6 mmol) and the reaction mixture was degassed with nitrogen for 15 minutes. Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.973 g, 1.19 mmol) was added and the resulting reaction mixture degassed with nitrogen for 20 minutes then heated to reflux at 110 C. for 14 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with CH2Cl2 and filtered through CELITE. The filtrate was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP, silica gel, 24 g, 0.5% methanol in CH2Cl2) to afford 5.0 g of impure 2-(5-aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine which was further purified by preparative HPLC (Condition B-61 as described in general methods) to afford 2-(5-aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (3.00 g, 64.0%). LCMS Condition B-12: retention time 1.92 min, [M+1]=394.4. HPLC Condition B-32: retention time 5.87 min, Purity 97.80%. 1H NMR (400 MHz, DMSO-d6) delta ppm 4.91 (d, J=4.8 Hz, 2H), 5.46 (s, 2H), 6.79 (d, J=2.4 Hz, 1H), 7.24 (t, J=2.8 Hz, 1H), 7.27-7.31 (m, 1H), 7.44-7.60 (m, 6H), 7.75 (dd, J=2.0 Hz, J=2.8 Hz, 1H), 7.79 (dt, J=2.0 Hz, J=7.6 Hz, 1H), 7.85 (d, J=2.8 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 8.39 (ddd, J=1.2 Hz, J=2.8 Hz, J=5.2 Hz, 1H), 8.60 (d, J=1.6 Hz, 1H).

Reference： [1]Patent: US2014/256719,2014,A1 .Location in patent: Page/Page column

32
[ 1073354-99-0 ]
N-benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]
2-(5-aminopyridin-3-yl)-N-benzyl-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.53%	With nitrogen; potassium carbonate; In 1,4-dioxane; water;	N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.200 g, 0.597 mmol) and <strong>[1073354-99-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine</strong> (0.263 g, 1.20 mmol, commercial) were dissolved in dioxane (10 mL) and water (2 mL). To the above solution was added K2CO3 (0.248 g, 1.79 mmol) and the reaction mixture was degassed with nitrogen for 15 minutes then PdCl2(dppf)-CH2Cl2 (0.0490 g, 0.0600 mmol) was added. The resulting reaction mixture was degassed for 20 minutes and heated to reflux at 110 C. for 14 h. The reaction mixture was allowed to cool, concentrated under reduced pressure and diluted with CH2Cl2 (10 mL). The resulting solid was filtered through a CELITE bed and the filtrate dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-62 as described in general methods) to afford 2-(5-aminopyridin-3-yl)-N-benzyl-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (20.0 mg, 8.53%). 1H NMR (400 MHz, DMSO-d6) delta ppm 4.81 (d, J=6.0 Hz, 2H), 5.46 (s, 2H), 6.54 (t, J=6.0 Hz, 1H), 6.78 (d, J=2.8 Hz, 1H), 7.26-7.54 (m, 10H), 7.75 (dd, J=2.0 Hz, J=2.8 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 8.58 (d, J=1.6 Hz, 1H). LCMS Condition B-47: retention time 2.20 min, [M+1]=393.2. HPLC Condition B-63: retention time 24.18 min, Purity 97.00%.

Reference： [1]Patent: US2014/256719,2014,A1 .Location in patent: Page/Page column

33
[ 1073354-99-0 ]
[ 1261082-88-5 ]
[ 1261082-79-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6428 - 6443

34
[ 1073354-99-0 ]
6-bromo-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine [ No CAS ]
6-(5-aminopyridin-3-yl)-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In ethanol; water; at 125℃; for 1h;Inert atmosphere; Microwave irradiation;	To a solution consisting of 6-bromo-4-chloroquinazoline (0.448 g, 1.84 mmol) in 2- propanol (10 mL) was added 4-(pyridine-4-yloxy)aniline (0.360 g, 1.93 mmol). The reaction mixture was heated (80 C) and stirred overnight under a flow of N2. The reaction mixture was cooled to room temperature and then the reaction mixture was filtered over a fritted funnel. The filtered solid was rinsed with excess 2-propanol and dried under high vacuum to afford 6-bromo-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (3F) as an off-white solid (313 mg, 43% yield,97% purity). MS (ESI + m/z 394.0, ESI - m/z 392.0). Next a solution consisting of 6-bromo-N- (4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (0.306 g, 0.77 mmol) in anhydrous ethanol (10 mL) was placed in a 20 mL microwave reaction vial containing a stir bar. Next, 3- aminopyridine-5- boronic acid pinacol ester (6, 0.176 g, 0.80 mmol) was added followed bySiliCatDPP-Pd (5 mol %, 0.26mmol/g loading, 0.150 g) and 10% aqueous potassium carbonate solution (2 equivalents, 1.15 mL, 1.6 mmol). The reaction mixture was placed under N2 atmosphere, capped, and then heated at 125 C for one horn in a Biotage Emrys Optimizer microwave. The reaction mixture was allowed to cool to room temperature and then filtered over a fritted funnel to collect SiliCat DPP-Pd. The filtered solid was rinsed with excess ethanoland the filtrate was concentrated under reduced pressure to afford the crude product.Purification of the crude product by Biotage Isolera flash chromatography using a gradient of 4-100% ethyl acetate in heptane, followed by 0-10% methanol in dichloromethane afforded 7F 6-(5-aminopyridin-3-yl)-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (50 mg, 15% yield,92% purity) as an off-white solid. MS (ESI + m/z 407.1, ESI m/z 405.1). To a roomtemperature solution of 6-(5 -aminopyridin-3 -yl)-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4- amine (50 mg, 0.12 mmol) in pyridine (3 mL) was added methanesulfonyl chloride (56 mg, 0.5 mmol). The reaction mixture turned dark red which persisted and was stirred for 15 minutes. The reaction mixture was poured into a saturated solution of sodium bicarbonate and the organic material was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The cmde solid was dissolved in methanol and ?dry loaded? on to a silica column eluted with a gradient of 1/9 to 3/7methanol/ethyl acetate to give N-(5-(4-((4-(pyridin-4-yloxy)phenyl)amino)quinazolin-6- yl)pyridin-3-yl)methanesulfonamide (5F, MOL-166, 20 mg, 33% yield, 96% purity) as a solid. ?H NMR (400MHz, DMSO-d6) oe 10.07 (s, 1H), 8.91 (s, 1H), 8.79 (d, J=1.9 Hz, 1H), 8.62 (s, 1H), 8.4-8.5 (m, 3H), 8.15 (dd,J=1.7, 8.6 Hz, 1H), 7.85-8.0(m, 4H), 7.24 (d,J8.9Hz, 2H),6.94 (d, J=4.7 Hz, 2H), 3.08 (s, 3H); MS: (ESI + m/z 485.1, ESI- m/z 483.0).

Reference： [1]Patent: WO2016/100347,2016,A2 .Location in patent: Page/Page column 71; 72

35
[ 1073354-99-0 ]
6-(5-(1H-tetrazol-1-yl)pyridin-3-yl)-N-(3-chlorophenyl)quinazolin-4-amine [ No CAS ]

Reference： [1]Patent: WO2016/100347,2016,A2

36
[ 307538-35-8 ]
[ 1073354-99-0 ]
6-(5-aminopyridin-3-yl)-N-benzylquinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In ethanol; water; at 100℃; for 0.0833333h;Inert atmosphere; Microwave irradiation;	A mixture of 6-bromo-4-chloroquinazoline (1.2 g, 4.9 mmol) and benzylamine (633 mg,5.9 mmol) in 30 mL of 1,4-dioxane was heated at 45 C for 2 hours then at 90 C for 1 hour. An additional amount of benzylamine (500 mg, 4.7 mmol) was added and the reaction mixture washeated at 90 C for an additional 2 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether and filtered through fritted glass. The filtrate was concentrated under vacuum and the crude solid was triturated under isopropyl alcohol, filtered and dried to give Nbenzyl-6-bromoquinazolin-4-amine (3G) as a solid (950 mg, 62% yield). ?H NMR (400MHz, DMSO-d6) oe 8.91 (t, J=5.9 Hz, 1H), 8.60 (d, J=2.2 Hz, 1H), 8.46 (s, 1H), 7.88 (dd, J2.2, 8.9Hz, 1H), 7.62 (d, J=8.9 Hz,1H), 7.25-7.40 (m, 4H), 7.23 (t, J9 Hz, 1H), 4.75 (d, J5.8 Hz, 2H). Next a solution consisting of N-benzyl-6-bromoquinazolin-4-amine (0.3 14 g, 1.0 mmol) in anhydrous ethanol (10 mL) was placed in a 20 mL microwave reaction vial containing a stir bar. Next, <strong>[1073354-99-0]<strong>[1073354-99-0]3-aminopyridine-5-boronic acid</strong> pinacol ester</strong> (6, 0.23 1 g, 1.05 mmol) was added followed by SiliCat DPP-Pd (5 mol %, 0.26mmol/g loading, 0.200 g) and 10% aqueous potassiumcarbonate solution (2 equivalents, 1.5 mL, 1.26 mmol). The reaction mixture was placed under N2 atmosphere, capped, and then heated at 100 C for 5 minutes in a Biotage Emrys Optimizer microwave. The reaction mixture was allowed to cool to room temperature and then filtered over a fritted funnel to collect SiliCat DPP-Pd. The filtered solid was rinsed with excess ethanol and the filtrate was concentrated under reduced pressure to afford the crude product. Purificationof the crude product by Biotage Isolera flash chromatography using a gradient of 4-100% ethyl acetate in heptane, followed by 0-10% methanol in dichloromethane afforded 6-(5- aminopyridin-3-yl)-N-benzylquinazolin-4-amine (7G) as a white solid (59 mg, 18% yield, 85% purity); MS: (ESI + m/z 328.1, ESI m/z 326.1). To a room temperature solution of 6-(5-aminopyridin-3-yl)-N-benzylquinazolin-4-amine (59 mg, 0.18 mmol) in pyridine (4 mL) was added methanesulfonyl chloride (83 mg, 0.72 mmol). The reaction mixture turned dark red which persisted and was stirred for 1 hour. The reaction mixture was poured into a saturated solution of sodium bicarbonate and the organic material was extracted with ethyl acetate. Theorganic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude solid was dissolved in methanol and ?dry loaded? on to a silica column eluted with a gradient of 1/9 to 3/7 methanol/ethyl acetate resulting in a partially purified pale yellow solid. This crude solid was triturated under a solution of 2- propanol/dichloromethane/ethyl acetate, filtered, and dried to give N-(5-(4-(benzylamino)quinazolin-6-yl)pyridin-3 -yl)methanesulfonamide (5G, MOL- 167, 6 mg, 8% yield, 96% purity) as a white powder; MS: (ESI + m/z 406.1, ESI - m/z 404.1).

Reference： [1]Patent: WO2016/100347,2016,A2 .Location in patent: Page/Page column 72; 73

37
[ 1073354-99-0 ]
6-bromo-N-(3-chloro-4-methoxyphenyl)quinazolin-4-amine [ No CAS ]
6-(5-aminopyridin-3-yl)-N-(3-chloro-4-methoxyphenyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90 - 95℃; for 4h;Inert atmosphere;	A mixture of 6-bromo-4-chloroquinazoline (1.65 g, 6.5 mmol) and 3-chloro-4-methoxyaniline (1.2 g, 7.8 mmol) in 40 mL of 1,4-dioxane was heated at 90 C for 3 hour. The reaction mixture was cooled to room temperature, diluted with diethyl ether and filtered through fritted glass. The solid was washed with diethyl ether and dried to give 6-bromo-N-(3-chloro-4- methoxyphenyl)quinazolin-4-amine (3H) as a yellow-gold solid (2.1 g, 89%); ?H NMR(400MHz, DMSO-d6) oe 11.5 (br s, 1H), 9.15 (s, 1H), 8.92 (s, 1H), 8.21 (d, J=9 Hz, 1H), 7.8-8.0 (m, 2H), 7.66 (dd, J=8.9, 2.3 Hz, 1H), 7.25 (d, J=8.9 Hz, 1H), 3.95 (s, 3H); MS: (ESI + m/z 364.0, 366.0 (Br isotope), ESI m/z 362.0, 364.0 (Br isotope)). A solution of 6-bromo-N-(3- chloro-4-methoxyphenyl)quinazolin-4-amine (1.85 g, 5.08 mmol) and 3-aminopyridine-5 - boronic acid pinacol ester (6, 932 mg, 4.23 mmol) in 1,4-dioxane (90 mL) and water (7.6 mL)was degassed. To the solution was added cesium carbonate (6.9 g, 21.1 mmol) and [1,1?- bis(diphenylphosphino)ferrocenejdichloropalladium(II) (366 mg). The reaction mixture was heated at 90 C - 95 C under N2 for 4 hours. The reaction mixture was diluted with ethyl acetate, dichloromethane and methanol, washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude materialwas purified by silica gel column chromatography eluting with a gradient of 2/98 to 25/75 methanol/ethyl acetate to afford 6-(5-aminopyridin-3 -yl)-N-(3 -chloro-4- methoxyphenyl)quinazolin-4-amine (7H) as an off white solid (524 mg, 33% yield). To a room temperature solution of 6-(5 -aminopyridin-3 -yl)-N-(3-chloro-4-methoxyphenyl)quinazolin-4-amine (250 mg, 0.66 mmol) in pyridine (15 mL) was added methanesulfonyl chloride (303 mg, 2.65 mmol). The reaction mixture turned dark red which persisted and was stirred for 1 hour. The reaction mixture was poured into a saturated solution of sodium bicarbonate and the organic material was extracted with ethyl acetate. The organic phase was washed with water and brine,dried over magnesium sulfate, filtered and concentrated under vacuum. The crude yellow solid was dissolved in methanol. Ethyl acetate and diethyl ether were added until cloudiness was observed. The mixture was stirred for 1 hour and the resulting solid was filtered, washed with ethyl acetate and dried to give N-(5-(4-((3-chloro-4-methoxyphenyl)amino)quinazolin-6- yl)pyridin-3-yl)methanesulfonamide (5H, MOL-153, 120 mg, 40% yield, 94% purity) as a brightyellow powder; ?H NMR (400MHz, DMSO-d6) oe 11.6 (br s, 1H), 10.3 (br s, 1H), 9.17 (s, 1H),8.95 (s, 1H), 8.88 (br s, 1H), 8.52 (br s, 1H), 8.40 (dd, J=1.3, 8.6 Hz,1H), 8.0-8.1 (m, 1H), 7.89(d, J2.6 Hz, 1H), 7.66 (dd, J2.6, 8.9 Hz, 1H), 7.28 (d, J=9.0 Hz, 1H), 3.90 (s, 3H), 3.16 (s,3H); MS: (ESI + m/z 456).

Reference： [1]Patent: WO2016/100347,2016,A2 .Location in patent: Page/Page column 73; 74

38
[ 1073354-99-0 ]
6-bromo-N-(3-chlorophenyl)quinazolin-4-amine hydrochloride [ No CAS ]
6-(5-aminopyridin-3-yl)-N-(3-chlorophenyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With potassium carbonate; In 1,4-dioxane; at 95℃;Inert atmosphere; Sealed tube;	A mixture consisting of 6-bromo-N-(3-chlorophenyl)quinazolin-4-amine - HC1 (500 mg 1.49mmol), 5 -(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridin-3-amine (274 mg, 1.24 mmol)and 2.OM K2C03 (3.1 mL) in 15 mL of 1,4-dioxane was degassed (vacuum/nitrogen, 3 times). To the reaction mixture was added SiliCat DPP-Pd (60 mg, 0.26 mmol/g loading). The reaction mixture was sealed and heated at 95 C for 1.25 hours. To the reaction was added 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3 -amine (90 mg, 0.41 mmol) and heated again at 95C overnight. The reaction mixture was cooled and filtered through a glass frit. The solids were washed with ethanol. The filtrate was concentrated under reduced pressure. The residue was chromatographed on a 40 g silica column using the dry loading method and eluted with a gradient of 1:99 to 15:85 methanol-ethyl acetate to give 126 mg (24%, purity 97.4%) of the title compound; MS (ES-API+) m/z 348.0 (M+1), 350.0 (Cl isotope), (ES-API-) m/z 346.0 (M-1),348.0 (Cl isotope); ?H NMR (400 MI-Tz, DMSO-d6) oe 9.99 (s, 1H), 8.81 (d, J=1.65 Hz, 1H), 8.66 (s, 1H), 8.24(d,J1.92Hz, 1H), 8.05-8.14(m, 2H), 7.99 (d,J2.47 Hz, 1H), 7.81-7.93 (m, 2H), 7.42 (t, J8.10 Hz, 1H), 7.29 (t, J2.29 Hz, 1H), 7.18 (d, J=8.18 Hz, 1H), 5.48 (s, 2H).

Reference： [1]Patent: WO2016/100347,2016,A2 .Location in patent: Page/Page column 92

39
[ 1073354-99-0 ]
3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
3-(5-aminopyridin-3-yl)-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110℃; for 2h;Microwave irradiation;	Example 108A 3-(5-Aminopyridin-3-yl)-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide (150 mg, 0.24 mmol) and <strong>[1073354-99-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-amine</strong> (63 mg, 0.29 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 mumol), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 120 min, cooled, filtered and purified by chromatography via HPLC (Method 10). This gave 29 mg (19% of theory) of the title compound. LC-MS (Method 4): Rt=0.88 min; MS (ESIpos): m/z=640.2 [M+H]+.

Reference： [1]Patent: US2016/244437,2016,A1 .Location in patent: Paragraph 1108; 1109; 1110

40
[ 64-18-6 ]
[ 1073354-99-0 ]
4-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
4-(5-aminopyridin-3-yl)-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)-carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide formate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7%		Example 73A 4-(5-Aminopyridin-3-yl)-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)-carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide formate 27.7 mg (23.9 mumol) of tetrakis(triphenylphosphine)palladium(0), 76.1 mg (0.72 mmol) of sodium carbonate and 0.36 ml (20.0 mmol) of water were added to a solution of 150 mg (0.24 mmol) of 4-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide and 79.0 mg (0.36 mmol) of <strong>[1073354-99-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-amine</strong> in 1.8 ml of DMSO. The mixture was treated in the microwave at 110 C. for 2.5 h. The mixture was filtered and purified by preparative HPLC (Method 10). 11 mg (7% of theory) of the title compound were obtained. LC-MS (Method 4): Rt=0.89 min; MS (ESIpos): m/z=640.4 [M+H-HCOOH]+.

Reference： [1]Patent: US2016/280699,2016,A1 .Location in patent: Paragraph 0651; 0652; 0653

41
[ 1073354-99-0 ]
4-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
N-alpha-[trans-4-(aminomethyl)cyclohexyl]carbonyl}-4-(5-aminopyridin-3-yl)-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2016/280699,2016,A1

42
[ 1073354-99-0 ]
[ 254454-54-1 ]
tert-butyl 3-(5-aminopyridin-3-yl)azetidine-1-carboxylate [ No CAS ]
C₁₃H₁₉N₃O₂ [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2017,vol. 359,p. 390 - 394

43
[ 1073354-99-0 ]
5-(5-iodofuran-2-yl)-2-methylisoindolin-1-one [ No CAS ]
5-(5-(5-aminopyridin-3-yl)furan-2-yl)-2-methylisoindolin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene;Inert atmosphere; Reflux;	General procedure: 5-Bromo-2-methylisoindolin-1-one (520 mg, 2.30 mmol) and thiophene-2-boronic acid (442mg, 3.45 mmol) were dissolved in a mixure of toluene (12 mL) and EtOH (6 mL). A solutionof 2 M Na2CO3 (3 mL) and Pd(dppf)Cl2 (94 mg, 0.12 mmol) were added and the entiremixture heated at reflux under N2 for 2 h. Additional thiophene-2-boronic acid (294 mg, 2.30mmol) was added and reflux continued under N2 overnight. Upon cooling, the mixture wasdiluted with water (100 mL) and extracted with CH2Cl2 (6x50 mL). The combined organicfractions were dried (Na2SO4), filtered, and the solvent removed under reduced pressure togive a crude solid which was purified by flash column chromatography on silica gel (EtOAcas eluant). The title compound was isolated as a light-brown solid (510 mg, 97%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1050 - 1054

44
[ 1073354-99-0 ]
[ 1567838-13-4 ]
[ 1567838-14-5 ]

Yield	Reaction Conditions	Operation in experiment
41%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene;Inert atmosphere; Reflux;	General procedure: 5-Bromo-2-methylisoindolin-1-one (520 mg, 2.30 mmol) and thiophene-2-boronic acid (442mg, 3.45 mmol) were dissolved in a mixure of toluene (12 mL) and EtOH (6 mL). A solutionof 2 M Na2CO3 (3 mL) and Pd(dppf)Cl2 (94 mg, 0.12 mmol) were added and the entiremixture heated at reflux under N2 for 2 h. Additional thiophene-2-boronic acid (294 mg, 2.30mmol) was added and reflux continued under N2 overnight. Upon cooling, the mixture wasdiluted with water (100 mL) and extracted with CH2Cl2 (6x50 mL). The combined organicfractions were dried (Na2SO4), filtered, and the solvent removed under reduced pressure togive a crude solid which was purified by flash column chromatography on silica gel (EtOAcas eluant). The title compound was isolated as a light-brown solid (510 mg, 97%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1050 - 1054

45
[ 1073354-99-0 ]
[ 1567837-23-3 ]
[ 1567837-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene;Inert atmosphere; Reflux;	General procedure: 5-Bromo-2-methylisoindolin-1-one (520 mg, 2.30 mmol) and thiophene-2-boronic acid (442mg, 3.45 mmol) were dissolved in a mixure of toluene (12 mL) and EtOH (6 mL). A solutionof 2 M Na2CO3 (3 mL) and Pd(dppf)Cl2 (94 mg, 0.12 mmol) were added and the entiremixture heated at reflux under N2 for 2 h. Additional thiophene-2-boronic acid (294 mg, 2.30mmol) was added and reflux continued under N2 overnight. Upon cooling, the mixture wasdiluted with water (100 mL) and extracted with CH2Cl2 (6x50 mL). The combined organicfractions were dried (Na2SO4), filtered, and the solvent removed under reduced pressure togive a crude solid which was purified by flash column chromatography on silica gel (EtOAcas eluant). The title compound was isolated as a light-brown solid (510 mg, 97%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1050 - 1054

46
[ 15862-30-3 ]
[ 73183-34-3 ]
[ 1073354-99-0 ]

Yield	Reaction Conditions	Operation in experiment
71%		Under nitrogen protection, 550 mL of dioxane and <strong>[15862-30-3]3-nitro-5-bromopyridine</strong> (20.3 g, After 0.10 mol) of pinacol borate (25.4 g, 0.10 mol) and potassium acetate (14.7 g, 0.15 mol), after stirring uniformly, the catalyst PdCl2dppf (0.74 g, 0.001 mol) was finally added, and the temperature was slowly raised to 80- 90 C, Stir the reaction for 2-3 h. After the completion of the GC reaction, the reaction was stopped by cooling, and the reaction solution was filtered through celite to obtain a dark-black reaction solution. After charging at 1 atm of hydrogen, the mixture was reacted at room temperature overnight. After the reaction was completed, the activated carbon was decolorized, and the filtrate was distilled under reduced pressure until no liquid was poured. /Heptane mixed solvent is cooled and beaten for half an hour, filtered to obtain a light gray crude product, heated again with ethanol, and then cooled down, and the filter cake is rinsed with -20 C anhydrous ethanol, and dried to obtain a pale yellow solid 15.6 g, yield 71%, HPLC purity 97.9%

Reference： [1]Patent: CN108047258,2018,A .Location in patent: Paragraph 0005; 0014; 0015

47
[ 1073354-99-0 ]
N-(5-(4-bromothiophen-2-yl)pyridin-3-yl)benzamide [ No CAS ]