[ CAS No. 496786-98-2 ]

Name: 496786-98-2|tert-Butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate|97%
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Quality Control of [ 496786-98-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 496786-98-2 ]

Product Details of [ 496786-98-2 ]

CAS No. :	496786-98-2	MDL No. :	MFCD04039875
Formula :	C₂₀H₃₂BN₃O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JWUBVPJWWYYRLJ-UHFFFAOYSA-N
M.W :	389.30	Pubchem ID :	16217947
Synonyms :

Calculated chemistry of [ 496786-98-2 ]

Physicochemical Properties

Num. heavy atoms :	28
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.7
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	117.91
TPSA :	64.13 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.58 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.95
Log Po/w (WLOGP) :	1.68
Log Po/w (MLOGP) :	1.35
Log Po/w (SILICOS-IT) :	1.16
Consensus Log Po/w :	1.43

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.94
Solubility :	0.0446 mg/ml ; 0.000115 mol/l
Class :	Soluble
Log S (Ali) :	-3.96
Solubility :	0.0428 mg/ml ; 0.00011 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.24
Solubility :	0.0226 mg/ml ; 0.0000581 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.85

Safety of [ 496786-98-2 ]

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

Application In Synthesis of [ 496786-98-2 ]

* 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 [ 496786-98-2 ]
Downstream synthetic route of [ 496786-98-2 ]

[ 496786-98-2 ] Synthesis Path-Upstream 1~5

1
[ 73183-34-3 ]
[ 153747-97-8 ]
[ 496786-98-2 ]

Yield	Reaction Conditions	Operation in experiment
56%	With potassium acetate; palladium diacetate; triphenylphosphine In N,N-dimethyl-formamide at 80℃; Inert atmosphere	[0951] A solution ofcompound 90b (125 g, 366 mmol) inDMF (1.30 L)was treatedwith, 4,4,4',4',5,5,5',5'-octamethyl2,2'-bi(1,3,2-dioxaborolane) (186 g, 732 mmol), Pd(OAc) 2(4.09 g, 18.3 mmol), PPh3 (19.2 g, 73.2 mmol) and KOAc(108 g, 1.10 mol) under a nitrogen atmosphere. The resultingmixture was stirred overnight at 80° C. Upon cooling to roomtemperature, the solids were collected by filtration. The filtrate was concentratedunderreduced pressure, and the resultant residue was purified by flash colunm chromatography onsilica gel (EtOAc/petroleum ether (1 :50 v/v)) to obtain compound 90c as a white solid (80.0 g, 56percent yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C20H32BN3 0 4 : 390.2(M+H). found 390.2.
2.55 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In dimethyl sulfoxide at 80℃; for 2 h; Inert atmosphere	Under nitrogen protection,Tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (2.0 g, 5.84 mmol),Bis(boronic acid) pinacol ester (2.2 g, 8.77 mmol) andPotassium acetate (1.72 g, 17.53 mmol)To a solution of dimethyl sulfoxide (10 mL) was added Pd(dppf)Cl2.CH2Cl2 (473.0 mg, 0.58 mmol).The reaction was heated to 80°C and stirred for 2 hours.Cool toDiluted with ethyl acetate (100 mL) at room temperature and filtered through celite. The filtrate was washed with saturated brine (100 mL x 4), anhydrousSodium sulfate was dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc (v/v) = 3/1) to give the title compoundThe product was an off-white solid (2.55 g, 112percent).

Reference： [1] Patent: US2014/364414, 2014, A1, . Location in patent: Paragraph 0945; 0950-0951
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5361 - 5379
[3] Patent: US2013/225548, 2013, A1, . Location in patent: Paragraph 0531; 0632
[4] Patent: CN104650049, 2018, B, . Location in patent: Paragraph 0426; 0427

2
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[ 153747-97-8 ]
[ 919347-67-4 ]
[ 496786-98-2 ]

Reference： [1] Patent: WO2015/88045, 2015, A1, . Location in patent: Paragraph 0239
[2] Patent: US2017/8885, 2017, A1, . Location in patent: Paragraph 0656; 0658
[3] Patent: WO2017/38909, 2017, A1, . Location in patent: Paragraph 0308; 0309; 0311

3
[ 73406-97-0 ]
[ 496786-98-2 ]

Reference： [1] Patent: US2014/364414, 2014, A1,
[2] Patent: CN104650049, 2018, B,

4
[ 53939-30-3 ]
[ 496786-98-2 ]

Reference： [1] Patent: US2014/364414, 2014, A1,

5
[ 766-11-0 ]
[ 496786-98-2 ]

Reference： [1] Patent: CN104650049, 2018, B,

[ 496786-98-2 ] Synthesis Path-Downstream 1~68

1
6-bromo-4-(3,4-dimethoxy-phenyl)-quinazoline [ No CAS ]
[ 496786-98-2 ]
4-{5-[4-(3,4-dimethoxy-phenyl)-quinazolin-6-yl]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 105℃; for 1.5h;	To 105 mg (0.41 mmol) of 6-bromo-4-chloro-quinazoline (Example 1 c), 18 mg (0.025 mmol) of bis(triphenylphosphine)palladium (II) dichloride (Fluka, Buchs, Switzerland) and 75 mg (0.41 mmol) of 3,4-dimethoxyphenylboronic acid (Frontier Scientific, Logan, USA; B1) in 4 ml DMF under argon, 1 ml of a 1 M aqueous solution of K2CO3 is added. The mixture is <n="60"/>stirred for 20 min at 1050C (oil bath). LC-MS confirms the formation of desired intermediate 6-bromo-4-(3,4-dimethoxy-phenyl)-quinazoline (Example 1 b). Then 192 mg (0.492) of 4-[5- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert- butyl ester (CB Research Development, New Castle, USA; B2), 18 mg (0.025 mmol) of bis(triphenylphosphine)palladium (II) dichloride and 1 ml of a 1 M aqueous solution of K2CO3 are added. The reaction mixture is stirred for 1.5 h at 105" C under argon. After this time, the mixture is quenched with sat. aqueous NaHCOs and extracted with EtOAc (2x). The organic layer is washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue is purified by flash chromatography (CH2CI2-MeOH 1 :0 to 24:1 ) to give the title compound as a yellow solid. ES-MS: 528 (M + H)+ ; analytical HPLC: tret.= 3.25 min (Grad 1 ).

Reference： [1]Patent: WO2008/12326,2008,A1 .Location in patent: Page/Page column 58-59

2
[ 929040-09-5 ]
[ 496786-98-2 ]
1,1-dimethylethyl 4-(5-{1-[5-[(methyloxy)carbonyl]-4-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thienyl]-1H-benzimidazol-5-yl}-2-pyridinyl)-1-piperazinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl acetamide; water; at 80℃; for 1.5h;	1 ,1-Dimethylethyl 4-[5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- pyridinyl]-1-piperazinecarboxylate (1.0 g, 2.5 mmol) was suspended in N1N- dimethylacetamide (14 mL) and treated with aqueous 1 N sodium carbonate (6 mL, 6 mmol), methyl 5-(5-bromo-1 /.pound.benzimidazol-1-yl)-3-({(1 /t)-1-[2- (trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (800 mg, 1.5 mmol) and 1 ,1 '-bis diphenylphosphinoferracene dichloropalladium(ll) dichloromethane adduct (210 mg, 0.26 mmol) and heated to 80 0C for 1.5 h. The reaction was allowed to cool to room temperature overnight. The reaction mixture was partitioned between 5:1 chloroform:methanol and saturated aqueous sodium bicarbonate. Toluene was added and the mixture concentrated (2x) to remove remaining Lambda/,Lambda.pound.dimethylacetamide. The crude compound was purified by column chromatography (hexanes:ethyl acetate, with 0.5percent triethylamine) to yield 1.0 g of the title compound as an oil. MS (APCI): 708.15 [M+H]+.

Reference： [1]Patent: WO2007/30366,2007,A1 .Location in patent: Page/Page column 182

3
[ 929040-09-5 ]
[ 496786-98-2 ]
[ 929040-11-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl acetamide; water; at 80℃; for 1.5h;	Step D - 1, 1-DimethyIethyl4-(5-{1-[5-[(methyloxy)carbonyI]-4-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thienyl]-1tt-benzimidazol-5-yl}-2- pyridinyl)-1-piperazinecarboxylate; i.i-DimethylethyU-IS^^.delta.delta-tetramethyl-I.S.a-dioxaborolan^-yl)^- pyridinyl]-1-piperazinecarboxylate (1.0 g, 2.5 mmol) was suspended in N,N- dimethylacetamide (14 ml_) and treated with aqueous 1 N sodium carbonate (6 mL, 6 mmol), methyl 5-(5-bromo-1Mbenzimidazol-1-yl)-3-({(1 /t)-1-[2- (trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (800 mg, 1.5 mmol) and 1,1 '-bis diphenylphosphinoferrocene dichloropalladium(ll) DCM adduct (210 mg, 0.26 mmol) and heated to 800C for 1.5 h. The reaction was allowed to cool to room temperature overnight. The reaction mixture was partitioned between 5:1 chloroform:MeOH and saturated aqueous NaHCO3. Toluene was added and the mixture concentrated (2x) to remove remaining N1N dimethylacetamide. The crude compound was purified by column chromatography (hexanes: EtOAc, with 0.5percent triethylamine) to yield 1.0 g of the title compound as an oil. MS (APCI): 708.15 [M+H]+.

Reference： [1]Patent: WO2007/30359,2007,A1 .Location in patent: Page/Page column 44

4
[ 7752-82-1 ]
[ 496786-98-2 ]
[ 1029715-29-4 ]

Yield	Reaction Conditions	Operation in experiment
63.9%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 1h;	Sodium carbonate (1.59 g) in water (6.0 mL) was added to a mixture of tert-butyl 4-[5- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine- 1 -carboxylate (0.205 g, 0.526 mmol), 5-bromopyrimidin-2-amine (0.0940 g, 0.54 mmol) and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) in ethanol (6.0 mL) and toluene (6.0 mL). The resulting mixture was heated at 120 0C for 1 h. The mixture was diluted with EtOAc and water. The precipitate was collected by filtration to give the desired product (120 mg, 63.9percent). LCMS: (M+H) = 357.1.

Reference： [1]Patent: WO2008/64157,2008,A1 .Location in patent: Page/Page column 71

5
[ 496786-98-2 ]
[ 1046159-07-2 ]

Yield	Reaction Conditions	Operation in experiment
26%		EXAMPLE 1.31 Synthesis of tert-butyl 4-(5-(4-oxo-2-butyl-4H-pyrido[1,2-a]pyrimidin-3-yl)pyridin-2-yl)piperazine-1-carboxylate Following the procedure as described in EXAMPLE 1 and making non-critical variations using <strong>[496786-98-2]2-(4-tert-butyloxycarbonyl-piperizin-1-yl)pyridine-5-boronic acid pinacol ester</strong> to replace 4-methoxyphenylboronic acid, tert-butyl 4-(5-(4-oxo-2-butyl-4H-pyrido[1,2-a]pyrimidin-3-yl)pyridin-2-yl)piperazine-1-carboxylate was obtained (26percent) as a yellow solid: mp 126-128° C.; 1H NMR (300 MHz, DMSO-d6) delta 8.87 (d, J=6.9 Hz, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.86 (ddd, J=8.6, 8.6, 1.4 Hz, 1H), 7.61 (d, J=8.9 Hz, 1H), 7.49 (dd, J=8.7, 2.4 Hz, 1H), 7.26 (ddd, J=6.9, 6.9, 1.3 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 3.51-3.41 (m, 8H), 2.54-2.46 (m, 3H), 1.62-1.52 (m, 2H), 1.39 (s, 9H), 1.28-1.11 (m, 2H), 0.74 (t, J=9.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) delta 165.1, 158.1, 157.5, 154.4, 149.4, 149.1, 140.2, 137.2, 127.4, 126.0, 120.4, 116.3, 113.1, 106.9, 79.4, 44.8, 35.3, 30.7, 28.5, 22.4, 14.2; MS (ES+) m/z 349.2 (M-100).

Reference： [1]Patent: US2008/194616,2008,A1 .Location in patent: Page/Page column 42

6
[ 496786-98-2 ]
[ 1300031-98-4 ]
1,1-dimethylethyl 4-{5-[(cis)-1-acetyl-2-methyl-4-([(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-2-pyridinyl}-1-piperazinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; toluene; at 100℃; for 1.5h;Inert atmosphere;	Example 21 -methylethyl {(2S,4/?)-1 -acetyl-2-methyl-6-[6-(1 -piperazinyl)-3-pyridinyl]-1 ,2,3,4- tetrahydro-4-quinolinyl}carbamate1 -Methylethyl [(2S,4R)-1 -acetyl-6-bromo-2-methyl-1 ,2,3,4-tetrahydro-4- quinolinyl]carbamate (for a preparation see Example 4)(1.09 g, 2.95 mmol) , potassium carbonate (0.816 g, 5.90 mmol), tetrakis(triphenylphosphine)palladium(0) (0.171 g, 0.148 mmol) and 1 ,1 -dimethylethyl 4-[5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- pyridinyl]-1 -piperazinecarboxylate (1 .379 g, 3.54 mmol, available from Aldrich) were dissolved in ethanol (10 mL) and toluene (10 mL). The reaction mixture was degassed for 30min then stirred and heated under nitrogen for 1 hr at 100 °C. The reaction mixture was filtered and the solvent evaporated under vacuum. The residue was partitioned between dichloromethane (30ml) and water (30ml). The organic layer was dried through a hydrophobic frit and concentrated in vacuo. The residue (2.08g) was dissolved with dichloromethane and purified by SP4 on a 40+M silica cartridge using a gradient of 30- 80percent EtOAc in cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give a Boc protected intermediate. This was dissolved with methanol (10ml) and treated with 2ml of acetyl chloride, the resulting mixture was stirred at room temp for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was loaded on a 50g SCX column which was previously conditioned with methanol. Columns was washed with methanol (3CV) and eluted with 2N ammonia in methanol (3CV). The appropriate fractions were combined and evaporated in vacuo to give the required product, yield 0.96 g as a white solid.LCMS (Method B): Rt 0.59 , MH+ = 4521 H NMR (DMSO-d6 ,400MHz): delta (ppm) 8.41 (d, J=2.0 Hz, 1 H), 7.80 (dd, J=8.8, 2.3 Hz, 1 H), 7.61 (d, J=8.5 Hz, 1 H), 7.46 - 7.54 (m, 1 H), 7.26 - 7.41 (m, 2H), 6.90 (d, J=8.9 Hz, 1 H), 4.78 - 4.91 (m, 1 H), 4.58 - 4.74 (m, 1 H), 4.33 - 4.48 (m, 1 H), 3.42 - 3.55 (m, 4H), 2.76 - 2.87 (m, 4H), 2.41 - 2.50 (m, 1 H), 2.07 (s, 3H), 1.13 - 1.32 (m, 7H), 1.04 (d, J=6.1 Hz, 3H)
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 100℃; for 1.5h;Inert atmosphere;	1-Methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (1.09 g, 2.95 mmol), potassium carbonate (0.816 g, 5.90 mmol), tetrakis(triphenylphosphine)palladium(0) (0.171 g, 0.148 mmol) and 1,1-dimethylethyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]-1-piperazinecarboxylate (1.379 g, 3.54 mmol, available from Aldrich) were dissolved in ethanol (10 mL) and toluene (10 mL). The reaction mixture was degassed for 30 min then stirred and heated under nitrogen for 1 hr at 100° C. The reaction mixture was filtered and the solvent evaporated under vacuum. The residue was partitioned between dichloromethane (30 ml) and water (30 ml). The organic layer was dried through a hydrophobic frit and concentrated in vacuo. The residue (2.08 g) was dissolved with dichloromethane and purified by SP4 on a 40+M silica cartridge using a gradient of 30-80percent EtOAc in cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give a Boc protected intermediate. This was dissolved with methanol (10 ml) and treated with 2 ml of acetyl chloride, the resulting mixture was stirred at room temp for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was loaded on a 50 g SCX column which was previously conditioned with methanol. Columns was washed with methanol (3 CV) and eluted with 2N ammonia in methanol (3 CV). The appropriate fractions were combined and evaporated in vacuo to give the required product, yield 0.96 g as a white solid.LCMS (Method B): Rt 0.59, MH+=4521H NMR (DMSO-d6, 400 MHz): delta (ppm) 8.41 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.8, 2.3 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.46-7.54 (m, 1H), 7.26-7.41 (m, 2H), 6.90 (d, J=8.9 Hz, 1H), 4.78-4.91 (m, 1H), 4.58-4.74 (m, 1H), 4.33-4.48 (m, 1H), 3.42-3.55 (m, 4H), 2.76-2.87 (m, 4H), 2.41-2.50 (m, 1H), 2.07 (s, 3H), 1.13-1.32 (m, 7H), 1.04 (d, J=6.1 Hz, 3H)

Reference： [1]Patent: WO2011/54841,2011,A1 .Location in patent: Page/Page column 109-110
[2]Patent: US2012/208798,2012,A1 .Location in patent: Page/Page column 50

7
[ 496786-98-2 ]
1-methylethyl [(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate [ No CAS ]
1,1-dimethylethyl 4-{5-[(cis)-1-acetyl-2-methyl-4-([(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-2-pyridinyl}-1-piperazinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 90℃; for 18h;	Example 91 -methylethyl {(cis)-1 -acetyl-2-methyl-6-[6-(1 -piperazinyl)-3-pyridinyl]-1 ,2,3,4- tetrah dro-4-quinolinyl}carbamate hydrochlorideRacemate of Example 2In a carousel tube, 1 -methylethyl [(cis)-1 -acetyl-6-bromo-2-methyl-1 ,2,3,4-tetrahydro-4- quinolinyl]carbamate (Example 61 , 80 mg, 0.217 mmol), potassium carbonate (59.9 mg, 0.433 mmol), tetrakis(triphenylphosphine)palladium(0) (12.52 mg, 10.83 muetaiotaomicronIota) and 1 ,1 - dimethylethyl 4-[5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-pyridinyl]-1 - piperazinecarboxylate (101 mg, 0.26 mmol, available from Aldrich) were dissolved in Ethanol (0.5 mL) and Toluene (0.5 ml_). The tubes were placed in a carousel and heated under nitrogen for 18 hr at 90 °C. The reaction mixtures were filtered and the solvent evaporated before being taken up in DCM and purified by SP4 on a 12+M silica cartridge using a gradient of 12-62percent EtOAc in cyclohexane. Appropriate fractions were collected and concentrated. 16mg was removed for analysis, characterisation and testing of the protected product, Example 8, 1 ,1 -dimethylethyl 4-{5-[(cis)-1 -acetyl-2-methyl-4-([(1 - methylethyl)oxy]carbonyl}amino)-1 ,2,3,4-tetrahydro-6-quinolinyl]-2-pyridinyl}-1 - piperazinecarboxylate. LCMS (Method C): Rt = 0.88, MH+ = 552 The remaining 1 ,1 -dimethylethyl 4-{5-[(cis)-1 -acetyl-2-methyl-4-([(1 - methylethyl)oxy]carbonyl}amino)-1 ,2,3,4-tetrahydro-6-quinolinyl]-2-pyridinyl}-1 - piperazinecarboxylate was dissolved in methanol and 0.5ml_ acetyl chloride was added. Solvents were evaporated to yield Example 9, 1 -methylethyl {(cis)-1 -acetyl-2-methyl-6-[6- (1 -piperazinyl)-3-pyridinyl]-1 ,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride as a pale yellow solid (40 mg). LCMS (Method C): Rt = 0.59, MH+ = 452
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 90℃; for 18h;Inert atmosphere;	In a carousel tube, 1-methylethyl [(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (Example 61, 80 mg, 0.217 mmol), potassium carbonate (59.9 mg, 0.433 mmol), tetrakis(triphenylphosphine)palladium(0) (12.52 mg, 10.83 mumol) and 1,1-dimethylethyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]-1-piperazinecarboxylate (101 mg, 0.26 mmol, available from Aldrich) were dissolved in Ethanol (0.5 mL) and Toluene (0.5 mL). The tubes were placed in a carousel and heated under nitrogen for 18 hr at 90° C. The reaction mixtures were filtered and the solvent evaporated before being taken up in DCM and purified by SP4 on a 12+M silica cartridge using a gradient of 12-62percent EtOAc in cyclohexane. Appropriate fractions were collected and concentrated. 16 mg was removed for analysis, characterisation and testing of the protected product, Example 8, 1,1-dimethylethyl 4-{5-[(cis)-1-acetyl-2-methyl-4-([(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-2-pyridinyl}-1-piperazinecarboxylate. LCMS (Method C): Rt=0.88, MH+=552

Reference： [1]Patent: WO2011/54841,2011,A1 .Location in patent: Page/Page column 114-115
[2]Patent: US2012/208798,2012,A1 .Location in patent: Page/Page column 52

8
[ 496786-98-2 ]
[ 1323919-53-4 ]
[ 1323919-74-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate tribasic trihydrate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 5h;Inert atmosphere;	EXAMPLE 20: Synthesis of 2-(5-Chloro-2-fluoro-phenyl)-4-(6'-piperazin-1-yl- [3,3']bipyridinyl-5-yl)-[1 ,8]naphthyridine (no. 32) and 2-(5-chloro-2-fluoro-phenyl)-4-[6'-(4- methyl-piperazin-1 -yl)-[3,3']bipyridinyl-5-yl]-[1 ,8}naphthyridine (no. 36)A slurry of 500 mg (1.21 mmol) 4-(5-bromo-pyridin-3-yl)-2-(5-chloro-2-fluoro-phenyl)- [1 ,8]naphthyridine, 516 mg (1.33 mmol) 4-[5-(4,4,5,5-tetramethyl-[1>3,2]dioxaborolan-2-yl)- pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester and 512 g (14.1 mmol) tri- potassium-phosphate-trihydrate in 30 ml 1 ,2-dimethoxyethane was heated to 80°C under nitrogen. Then 85 mg (0.12 mmol) bis-(triphenylphosphine)-palladium(ll)-chloride and 16 muIota triethylamine were added. The reaction mixture was stirred for 5 hours at 80°C. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with ethylacetate/methanol as eluent yielding 4-{5'-[2-(5-Chloro-2-fluoro- phenyl)-[1 ,8]naphthyridin-4-yl]-[3,3']bipyridinyl-6-yl}-piperazine-1 -carboxylic acid tert-butyl ester as yellow oil; HPLC-MS: 2.69 min, [M+H] 597.
	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate tribasic trihydrate; triethylamine; at 80℃; for 5h;Inert atmosphere;	A slurry of 500 mg (1.21 mmol) 4-(5-bromo-pyridin-3-yl)-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine, 516 mg (1.33 mmol) <strong>[496786-98-2]4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester</strong> and 512 g (14.1 mmol) tri-potassium-phosphate-trihydrate in 30 ml 1,2-dimethoxyethane was heated to 80° C. under nitrogen. Then 85 mg (0.12 mmol) bis-(triphenylphosphine)-palladium(II)-chloride and 16 mul triethylamine were added. The reaction mixture was stirred for 5 hours at 80° C. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with ethylacetate/methanol as eluent yielding 4-{5?-[2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[3,3?]bipyridinyl-6-yl}-piperazine-1-carboxylic acid tert-butyl ester as yellow oil; HPLC-MS: 2.69 min, [M+H] 597.

Reference： [1]Patent: WO2011/95196,2011,A1 .Location in patent: Page/Page column 106
[2]Patent: US2012/295902,2012,A1 .Location in patent: Paragraph 0378; 0379

9
[ 496786-98-2 ]
[ 1346703-55-6 ]
[ 1346703-66-9 ]

Yield	Reaction Conditions	Operation in experiment
47%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere;	a) tert-butyl 4-(5-(4-((l,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methylcarbamoyl)-l- isopropyl-3-methyl-lH-indazol-6-yl)pyridin-2-yl)piperazine-l-carboxylateTo a stirred solution of 6-brorno-N-((l,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)- l - isopropy 1-3 -methyl- lH-indazole-4-carboxamide (400 mg, 0.928 mmol) in DMF (20 mL) was added tert-butyl 4-(5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine- 1 -carboxylate (397 mg, 1.02 mmol) followed by sodium carbonate (246 mg, 2.32 mmol) dissolved in water (4 mL) and degassed with argon for 30 min. PdCl2(PPh3)2 (65 mg, 0.092 mmol) was added and the mixture again degassed with argon for 10 min. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3x150 mL). The combined organic layers were dried over anhydrous Na2S04 , filtered, and concentrated to afford the crude product (650 mg). The crude compound was purified by silica gel chromatography (eluent: 0- 10percent MeOH: DCM). The product was triturated with diethyl ether (150 mL) to afford the title compound as an off white solid (270 mg, 47percent). *H NMR (DMSO-d6, 400 MHz): delta 1.498 (s, 9H), 1.560 (d, J = 6.4 Hz, 6H), 2.128 (s, 3H), 2.413 (s, 3H), 2.526 (s, 3H), 3.579 (s, 8H), 4.610 (d, J = 5.6 Hz, 2H), 4.760-4.824 (m, 1H), 5.907 (s, 1H), 6.70 (d, J = 8.8 Hz, 1H ), 7.31 1-7.346 (m, 2H),7.454 (s, 1H), 7.735 (d, J = 8.8 Hz, 1H ), 8.463 (s, 1H), 10.991 (brs, 1H). LCMS (ES+): 614.25.

Reference： [1]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 103

10
[ 496786-98-2 ]
[ 1261221-96-8 ]
[ 1261222-13-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 0.5h;Microwave irradiation; Inert atmosphere;	128.87 mg (0.273 mmol) of 5-iodo-3-(5-methoxy-1H-benzimidazol-2-yl)pyridin-2-ylamine and 191.38 mg (0.492 mmol) of <strong>[496786-98-2]tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate</strong> are suspended in 2.5 ml of N,N-dimethylformamide in a nitrogen-filled microwave vessel, and 0.6 ml (1.2 mmol) of 2M sodium carbonate solution and 31.5 mg (0.027 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The reaction solution is irradiated with microwaves for 30 min at 120° C. in the Biotage SmithSynthesizer. The reaction mixture is cooled to room temperature and diluted with water/ethyl acetate and filtered. The aqueous phase is extracted a further 2.x. with ethyl acetate, and the combined organic phases are dried using sodium sulfate, filtered and evaporated to dryness. The residue is purified by means of RP-HPLC, giving tert-butyl 4-[6'-amino-5'-(6-methoxy-1H-benzimidazol-2-yl)-[3,3']bipyridinyl-6-yl]-piperazine-1-carboxylate.

Reference： [1]Patent: US2012/115861,2012,A1 .Location in patent: Page/Page column 39

11
[ 496786-98-2 ]
[ 1383481-14-8 ]
[ 1383481-17-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 110℃; for 3h;Inert atmosphere;	A mixture of <strong>[496786-98-2]tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate</strong> (46.3 mg, 0.119 mmol, Aldrich, Cat. No. 654337), N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N'-(2,2,2-trifluoroethyl)urea (40.0 mg, 0.108 mmol, Example 30, Step 3), tetrakis(triphenylphosphine)palladium(0) (6.25 mg, 0.00541 mmol) and sodium carbonate (34.4 mg, 0.324 mmol) in dioxane (1 mL) and water (0.3 mL) was degassed and recharged with nitrogen three times, and heated and stirred at 110° C. for 3 h. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was the desired product which was directly used in next step without further purification. LCMS (M+H)+: m/z=597.2.

Reference： [1]Patent: US2012/165305,2012,A1 .Location in patent: Page/Page column 42

12
[ 496786-98-2 ]
[ 1379522-33-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

13
[ 496786-98-2 ]
[ 1211542-18-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

14
[ 73183-34-3 ]
[ 153747-97-8 ]
[ 496786-98-2 ]

Yield	Reaction Conditions	Operation in experiment
56%	With potassium acetate; palladium diacetate; triphenylphosphine; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;	[0951] A solution ofcompound 90b (125 g, 366 mmol) inDMF (1.30 L)was treatedwith, 4,4,4',4',5,5,5',5'-octamethyl2,2'-bi(1,3,2-dioxaborolane) (186 g, 732 mmol), Pd(OAc) 2(4.09 g, 18.3 mmol), PPh3 (19.2 g, 73.2 mmol) and KOAc(108 g, 1.10 mol) under a nitrogen atmosphere. The resultingmixture was stirred overnight at 80° C. Upon cooling to roomtemperature, the solids were collected by filtration. The filtrate was concentratedunderreduced pressure, and the resultant residue was purified by flash colunm chromatography onsilica gel (EtOAc/petroleum ether (1 :50 v/v)) to obtain compound 90c as a white solid (80.0 g, 56percent yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C20H32BN3 0 4 : 390.2(M+H). found 390.2.
	With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium acetate; XPhos; In 1,4-dioxane; at 100℃; for 1h;Inert atmosphere;	To a mixture of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate obtained in Reference Example 10 (800 mg), Pin2B2 (653 mg), X-Phos (224 mg), potassium acetate (688 mg) and Pd2 (dba)3.CHCl3 (124 mg) was added 1,4-dioxane (48 mL), and the interior of the vessel was purged with argon. The reaction mixture was stirred at 100° C. for an hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To the resulting residue were successively added 2-[(6-chloro-4-cyclopropylpyridin-2-yl)amino]pyridine-4-carbonitrile obtained in Reference Example 3 (422 mg), S-Phos (256 mg), potassium phosphate (995 mg), 1,4-dioxane (24 mL), water (1.2 mL) and palladium(II) acetate (70 mg), and the interior of the vessel was purged with argon. The reaction mixture was stirred at 100° C. for an hour. The reaction mixture was diluted with water, and extracted 3 times with ethyl acetate, the combined organic layers were washed with saturated brine, and dried over magnesium, sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography. To a suspension of the obtained solid in methanol (24 mL) was added 4 N hydrogen chloride-dioxane (12 mL), and the mixture was stirred at room, temperature for 1.5 hours. The solvent was evaporated under reduced pressure, and the obtained compound was washed with ethyl acetate to give 502 mg of the title compound as a yellow solid.
2.55 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;	Under nitrogen protection,Tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (2.0 g, 5.84 mmol),Bis(boronic acid) pinacol ester (2.2 g, 8.77 mmol) andPotassium acetate (1.72 g, 17.53 mmol)To a solution of dimethyl sulfoxide (10 mL) was added Pd(dppf)Cl2.CH2Cl2 (473.0 mg, 0.58 mmol).The reaction was heated to 80°C and stirred for 2 hours.Cool toDiluted with ethyl acetate (100 mL) at room temperature and filtered through celite. The filtrate was washed with saturated brine (100 mL x 4), anhydrousSodium sulfate was dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc (v/v) = 3/1) to give the title compoundThe product was an off-white solid (2.55 g, 112percent).

Reference： [1]Patent: US2014/364414,2014,A1 .Location in patent: Paragraph 0945; 0950-0951
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379
[3]Patent: US2013/225548,2013,A1 .Location in patent: Paragraph 0531; 0632
[4]Patent: CN104650049,2018,B .Location in patent: Paragraph 0426; 0427

15
[ 496786-98-2 ]
[ 1396776-82-1 ]
[ 1396770-34-5 ]

Yield	Reaction Conditions	Operation in experiment
		Compound A-6[0755] A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)- 1 -isopropyl- 1 H-pyrazolo [3, 4-b]pyridine-4-carboxamide (1 equiv.) tert-butyl 4-(5-(4,4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-l -carboxylate (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1 ,4-dioxane was purged with argon for 10 min. Then, 2 M Na2C03 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na^SC^, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired product (70percent yield). LCMS: 601.30 (M + 1)+; HPLC: 99.80percent (@ 254 nm), (3/4; 6.124); NMR (DMSO-i3/4, 400 MHz) delta 1 1.54 (s, 1 H), 9.03 (d, 1H, J=2 Hz), 8.85 (t, 1H), 8.39 (dd, 1H, J=8.8, 2 Hz), 8.31 (s, 1 H), 8.08 (s, 1H). 6.99 (d, 1H, J=9.2 Hz), 5.89 (s, 1H), 5.32-5.25 (m, 1H), 4.40 (d, 2H, J=4.4 Hz), 3.63 (t, 4H), 3.45 (bs, 4H), 2.22 (s, 3H), 2.12 (s, 3H), 1.53 (d, 6H, J=6.4 Hz), 1.43 (s, 9H).

Reference： [1]Patent: WO2012/118812,2012,A2 .Location in patent: Page/Page column 230-231; 233-234

16
[ 496786-98-2 ]
21H,23H-10-bromo-5,15-diphenylporphine [ No CAS ]
5-[6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridine]-10,20-diphenylporphyrin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With tetrakis(triphenylphosphine) palladium(0); potassium phosphate monohydrate; In tetrahydrofuran; at 85℃; for 6h;Inert atmosphere; Darkness;	General procedure: To a solution of 5-bromo-10,20-diphenylporphyrin 1 (27 mg, 0.05 mmol) in anhydrous THF (10 mL), 231 mg of K3PO4·H2O (1 mmol), boronic acid pinacol ester (0.25 mmol), and 5.6 mg of Pd(PPh3)4 (0.005 mmol, 0.1 equiv) were added. The reaction mixture was heated to 85 °C and protected from light under a stream of argon with stirring until the starting bromoporphyrin had been completely consumed. The mixture was filtered through Celite, the solvent was evaporated, and the crude was dissolved in dichloromethane. The organic layer was washed with a saturated solution of sodium hydrogen carbonate (2×), brine (1×), and distilled water (1×) and then dried over anhydrous sodium sulfate. The solvent was evaporated and the crude was purified by silica gel column chromatography.

Reference： [1]Tetrahedron,2012,vol. 68,p. 8783 - 8788

17
[ 496786-98-2 ]
[ 1057140-05-2 ]
5,15-bis[6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridine]-10,20-diphenylporphyrin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With tetrakis(triphenylphosphine) palladium(0); potassium phosphate monohydrate; In tetrahydrofuran; at 85℃; for 14h;Inert atmosphere; Darkness;	General procedure: To a solution of 5-bromo-10,20-diphenylporphyrin 1 (27 mg, 0.05 mmol) in anhydrous THF (10 mL), 231 mg of K3PO4·H2O (1 mmol), boronic acid pinacol ester (0.25 mmol), and 5.6 mg of Pd(PPh3)4 (0.005 mmol, 0.1 equiv) were added. The reaction mixture was heated to 85 °C and protected from light under a stream of argon with stirring until the starting bromoporphyrin had been completely consumed. The mixture was filtered through Celite, the solvent was evaporated, and the crude was dissolved in dichloromethane. The organic layer was washed with a saturated solution of sodium hydrogen carbonate (2×), brine (1×), and distilled water (1×) and then dried over anhydrous sodium sulfate. The solvent was evaporated and the crude was purified by silica gel column chromatography.

Reference： [1]Tetrahedron,2012,vol. 68,p. 8783 - 8788

18
[ 496786-98-2 ]
[ 1403587-93-8 ]
[ 1419063-03-8 ]

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 1143 - 1148

19
[ 496786-98-2 ]
[ 1403588-00-0 ]
[ 1419063-02-7 ]

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 1143 - 1148

20
[ 496786-98-2 ]
[ 1346245-14-4 ]
[ 1431703-21-7 ]

Yield	Reaction Conditions	Operation in experiment
37%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;	Intermediate 5a (3.75 g; 7.68 mmol), 2-(4-boc-piperazine)pyridine-5-boronic acid pinacol (2.99 g; 7.68 mmol) and potassium phosphate (4.08 g; 19.2 mmol) in a mixture of 1 ,4- dioxane (100 ml_) and water (20 mL) was stirred and degassed at r.t. under a N2 flow (bubbling). After 10 min, Pd2(dba)3 (705 mg; 0.77 mmol) and S-Phos (315 mg; 0.768 mmol) were added. The r.m. was heated at 80°C for 2 h, cooled down to r.t. and evaporated to dryness. The oil was diluted with EtOAc and washed with water. The organic layer was dried over Na2S04, filtered and evaporated under reduced pressure. The residue was purified by chromatography over silica gel (mobile phase: gradient from 60percent heptane, 40percent EtOAc to 40percent heptane, 60percent EtOAc). The pure fractions were collected and concentrated to afford 2.14 g (37percent) of intermediate 42.

Reference： [1]Patent: WO2013/61081,2013,A1 .Location in patent: Page/Page column 175

21
[ 496786-98-2 ]
[ 1374144-00-9 ]
[ 1374146-04-9 ]

Yield	Reaction Conditions	Operation in experiment
600 mg	With potassium phosphate; palladium diacetate; In 1,4-dioxane; water; at 100℃; for 0.5h;Inert atmosphere;	To the resulting residue were successively added 2-[(6-chloro-4-cyclopropylpyridin-2-yl)amino]pyridine-4-carbonitrile obtained, in Reference Example 3 (300 mg), S-Phos (182 mg), potassium phosphate (706 mg), 1,4-dioxane (8 mL), water (2 mL) and palladium(II) acetate (50 mg), and the interior of the vessel was purged with argon. The reaction mixture was stirred at 100° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography to give 600 mg of the title compound as a pale yellow solid.

Reference： [1]Patent: US2013/225548,2013,A1 .Location in patent: Paragraph 0633

22
[ 496786-98-2 ]
[ 1374144-00-9 ]
[ 1374145-79-5 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	To a mixture of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate obtained in Reference Example 10 (800 mg), Pin2B2 (653 mg), X-Phos (224 mg), potassium acetate (688 mg) and Pd2 (dba)3.CHCl3 (124 mg) was added 1,4-dioxane (48 mL), and the interior of the vessel was purged with argon. The reaction mixture was stirred at 100° C. for an hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To the resulting residue were successively added 2-[(6-chloro-4-cyclopropylpyridin-2-yl)amino]pyridine-4-carbonitrile obtained in Reference Example 3 (422 mg), S-Phos (256 mg), potassium phosphate (995 mg), 1,4-dioxane (24 mL), water (1.2 mL) and palladium(II) acetate (70 mg), and the interior of the vessel was purged with argon. The reaction mixture was stirred at 100° C. for an hour. The reaction mixture was diluted with water, and extracted 3 times with ethyl acetate, the combined organic layers were washed with saturated brine, and dried over magnesium, sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography. To a suspension of the obtained solid in methanol (24 mL) was added 4 N hydrogen chloride-dioxane (12 mL), and the mixture was stirred at room, temperature for 1.5 hours. The solvent was evaporated under reduced pressure, and the obtained compound was washed with ethyl acetate to give 502 mg of the title compound as a yellow solid.

Reference： [1]Patent: US2013/225548,2013,A1 .Location in patent: Paragraph 0531

23
[ 496786-98-2 ]
[ 1374142-73-0 ]

Reference： [1]Patent: US2013/225548,2013,A1
[2]Patent: US2013/225548,2013,A1

24
[ 496786-98-2 ]
[ 1374145-79-5 ]

Reference： [1]Patent: US2013/225548,2013,A1

Yield	Reaction Conditions	Operation in experiment
		General procedure: Step-ii: 1-(2-fluorobenzyl)-4-( 4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole1-(2-fluorobenzyl)-4-iodo-1H-pyrazole (2.25 g, 7.4 mmol) and bispinocalatodiboron (2.07 g,8.2 mmol) were added to a solution of DMSO (20 ml) previously purged with argon (10min). The reaction mixture was purged with argon for a further 15mins, followed by the10 addition of potassium acetate (2.19 g, 22.3 mmol) andbis(triphenylphosphine)palladium(II)dichloride (261 mg, 0.3725 mmol). The resultingmixture was heated to reflux at 80 oc overnight. The reaction was monitored by TLC (40percentethyl acetate in hexane). The reaction mixture was cooled and diluted with ethyl acetate (100ml) and filtered over celite bed and the filtrate was washed with cold water (2x100 ml). The15 organic layer was dried over NazS04, and concentrated under reduced pressure to afford 2.3 gof the crude product which was taken as such for next reaction.

26
[ 496786-98-2 ]
[ 1536390-34-7 ]
[ 1536390-37-0 ]

Yield	Reaction Conditions	Operation in experiment
22%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 20h;Inert atmosphere;	Intermediate 7 (200 mg, 0.54 mmol) and tert-bvXy\ 4-[5-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-l -carboxylate (316 mg, 0.81 mmol) were dissolved in 1,4-dioxane (20 mL) and a 2M aqueous solution of potassium carbonate (1 mL) was added. The mixture was flushed with nitrogen and bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron-dichloropalladium-dichloromethane complex (12 mg, 0.01 mmol) was added. The mixture was heated at 90°C under nitrogen for 16 h. LCMS indicated incomplete conversion so additional tert-butyl 4-[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]piperazine-l-carboxylate (150 mg, 0.39 mmol) and bis[3- (diphenylphosphanyl)cyclopenta-2,4-dien-l-yl]iron-dichloropalladium-dichloromethane complex (12 mg, 0.01 mmol) were added and the mixture was heated at 90°C under nitrogen for 4 h. The mixture was diluted with ethyl acetate (30 mL) and washed with water (2 x 10 mL), then brine (10 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under vacuum to yield a dark grey solid. This was purified by flash chromatography, eluting with a gradient of 0-100percent ethyl acetate in heptane, followed by 0-20percent methanol in ethyl acetate. The resultant material was further purified by flash chromatography, eluting with a gradient of 0-5percent methanol in DCM. The resultant material was then further purified by preparative HPLC (Preparative Method B) to afford the title compound (66 mg, 22percent) as an off- white solid. 5H (250 MHz, CD3OD) 8.35-8.17 (m, 2H), 7.81-7.58 (m, 3H), 7.42-6.59 (m, 6H), 4.42 (s, 2H), 3.55 (br s, 8H), 2.48 (br s, 3H), 1.49 (s, 9H).

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 114; 115

27
[ 496786-98-2 ]
[ 1536390-56-3 ]
[ 1536391-35-1 ]

Yield	Reaction Conditions	Operation in experiment
16%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 11h;Inert atmosphere;	A mixture of Intermediate 16 (150 mg, 0.34 mmol), tert-butyl 4-[5-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine- 1 -carboxylate (148 mg, 0.38 mmol) and 2M aqueous potassium carbonate solution (0.69 mL) in 1 ,4-dioxane (4 mL) was degassed with nitrogen for 5 minutes. Bis[3-(diphenylphosphanyl)cyclopenta-2,4- dien- 1 -yl]iron-dichloropalladium-dichloromethane complex (14 mg, 0.02 mmol) wasadded and the reaction mixture was heated at 120°C for 8 h. The mixture was treated again with bis[3 -(diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yl]iron-dichloropalladiumdichloromethane complex (14 mg, 0.02 mmol) and heated for a further 3 h. The mixture was cooled to room temperature, filtered through Celite and purified by preparative HPLC (Method C) to afford the title compound (33 mg, 16percent) as a clear oil. oH (500MHz, CDC13) 8.09-7.90 (m, 2H), 7.65 (s, 1H), 7.46 (d,J9.0 Hz, 1H), 7.26 (s, 1H), 7.14-7.03 (m, 2H), 6.82 (d, J7.5 Hz, 1H), 6.74-6.32 (m, 2H), 4.27 (s, 2H), 3.58 (m, 8H), 2.53 (s, 3H), 1.49 (s, 9H). MH+ 618.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 133

28
[ 496786-98-2 ]
[ 1536390-70-1 ]
[ 1536391-28-2 ]

Yield	Reaction Conditions	Operation in experiment
56%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; at 90℃; for 1.5h;Inert atmosphere;	Intermediate 20 (60 mg, 0.16 mmol) and tert-butyl 4-[5-(4,4,5,5-tetramethyl-,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine- 1 -carboxylate (61 mg, 0.16 mmol) were dissolved in 1,4-dioxane (1 mL). A 2M aqueous potassium carbonate solution (0.28 mL) was added and the reaction mixture was degassed with nitrogen for 5 minutes. Bis[3- (diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yl]iron-dichloropalladium-dichloromethane complex (6 mg, 0.01 mmol) was added and the reaction mixture was heated at 90°C in apressure tube for 90 minutes. The reaction mixture was diluted with EtOAc and washed with water and brine, then dried (Na2SO4), filtered and concentrated to dryness. The residue obtained was purified by column chromatography (eluting with 40-100percent EtOAc in heptane) to yield the title compound (50 mg, 56percent). oH (250 MHz, CDC13) 8.03 (d, J 2.3 Hz, 1H), 7.49 (s, 1H), 7.45-7.35 (m, 2H), 7.21 (d, J7.0 Hz, 1H), 7.15-6.98 (m, 2H),6.90-6.23 (m, 3H), 4.23 (s, 2H), 3.59-3.54 (m, 7H), 2.46 (s, 3H), 2.33-2.16 (m, 4H), 1.49 (s, 9H). MH+ 564.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 131; 132

29
[ 496786-98-2 ]
[ 1537169-20-2 ]
[ 1537169-28-0 ]

Yield	Reaction Conditions	Operation in experiment
77%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 8h;Sealed tube; Inert atmosphere;	tert- butyl 4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]- piperazine-1 -carboxylate (101 mg, 0.26 mmol) and Intermediate 5 (100 mg, 0.26 mmol) were added to degassed 1,4-dioxane (1.5 mL) in a sealed tube. Degassed 1M aqueous sodium carbonate solution (0.781 mL, 0.781 mmol) was added, followed by bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.013 mmol), and the reaction mixture was heated under nitrogen at 100°C for 8 h. The reaction mixture was diluted with EtOAc (15 mL) and the organic layer was washed with saturated aqueous sodium bicarbonate solution (6 mL) followed by brine (6 mL), then dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with a gradient of 0-2.5percent (7M NH3 in MeOH) in DCM, to afford the title compound (117 mg, 77percent) as a light brown glass. deltaEta (500 MHz, CDCl3) 8.80 (m, 1H), 8.39 (d, J2.3 Hz, 1H), 8.35 (m, 1H), 7.91 (m, 2H), 7.33 (m, 2H), 7.04 (m, 1H), 6.63 (d, J 8.9 Hz, 1H), 6.38 (m, 2H), 5.50 (s, 1H), 3.53 (m, 8H), 2.28 (s, 3H), 1.47 (s, 9H)
77%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 8h;Sealed tube;	tert-Butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]-piperazine-1-carboxylate (101 mg, 0.26 mmol) and Intermediate 5 (100 mg, 0.26 mmol) were added to degassed 1,4-dioxane (1.5 mL) in a sealed tube. Degassed 1M aqueous sodium carbonate solution (0.781 mL, 0.781 mmol) was added, followed by bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.013 mmol), and the reaction mixture was heated under nitrogen at 100° C. for 8 h. The reaction mixture was diluted with EtOAc (15 mL) and the organic layer was washed with saturated aqueous sodium bicarbonate solution (6 mL) followed by brine (6 mL), then dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with a gradient of 0-2.5percent (7M NH3 in MeOH) in DCM, to afford the title compound (117 mg, 77percent) as a light brown glass. deltaH (500 MHz, CDCl3) 8.80 (m, 1H), 8.39 (d, J2.3 Hz, 1H), 8.35 (m, 1H), 7.91 (m, 2H), 7.33 (m, 2H), 7.04 (m, 1H), 6.63 (d, J8.9 Hz, 1H), 6.38 (m, 2H), 5.50 (s, 1H), 3.53 (m, 8H), 2.28 (s, 3H), 1.47 (s, 9H).

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 94
[2]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0478

30
[ 496786-98-2 ]
[ 1537169-11-1 ]
[ 1537169-36-0 ]

Yield	Reaction Conditions	Operation in experiment
22%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90 - 100℃; for 8h;Sealed tube;	Intermediate 6 (100 mg, 0.27 mmol) and tert-butyl 4-[5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-l-carboxylate (159 mg, 0.41 mmol) were combined in 1 ,4-dioxane (7 mL) and the mixture was degassed before the addition of 2M aqueous potassium carbonate solution (0.473 mL) and bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (11 mg, 0.014 mmol). The mixture was heated at 90°C for 4 h in a sealed tube, then left to stand at r.t. for 4 days. The mixture was heated at 90°C for 2 h, then at 100°C for a total of 8 h. The mixture was partitioned between EtOAc (20 mL) and water (15 mL). The aqueous layer was diluted with water (~15 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 0-100percent EtOAc in heptanes. The residue was then twice purified by FCC, eluting with mixtures of MeOH in DCM, to afford the title compound (35 mg, 22percent) as a white solid. Method B HPLC-MS: MH+ mlz 551, RT 2.10 minutes
22%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; at 20 - 100℃; for 110h;Inert atmosphere; Sealed tube;	Intermediate 6 (100 mg, 0.27 mmol) and <strong>[496786-98-2]tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate</strong> (159 mg, 0.41 mmol) were combined in 1,4-dioxane (7 mL) and the mixture was degassed before the addition of 2M aqueous potassium carbonate solution (0.473 mL) and bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (11 mg, 0.014 mmol). The mixture was heated at 90° C. for 4 h in a sealed tube, then left to stand at r.t. for 4 days. The mixture was heated at 90° C. for 2 h, then at 100° C. for a total of 8 h. The mixture was partitioned between EtOAc (20 mL) and water (15 mL). The aqueous layer was diluted with water (15 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 0-100percent EtOAc in heptanes. The residue was then twice purified by FCC, eluting with mixtures of MeOH in DCM, to afford the title compound (35 mg, 22percent) as a white solid. Method B HPLC-MS: MH+ m/z 551, RT 2.10 minutes.

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 100
[2]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0491

31
[ 496786-98-2 ]
[ 1571828-36-8 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4125 - 4128

32
[ 496786-98-2 ]
[ 1571828-54-0 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4125 - 4128

33
[ 496786-98-2 ]
[ 1571828-57-3 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4125 - 4128

34
[ 496786-98-2 ]
[ 34598-49-7 ]
[ 1571828-24-4 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4125 - 4128

35
[ 496786-98-2 ]
[ 1611001-28-5 ]
[ 1610999-91-1 ]

Yield	Reaction Conditions	Operation in experiment
41.4%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 140℃; for 0.666667h;Sealed tube; Microwave irradiation;	Bis(triphenylphosphin)-palladium(ll)-dichloride (6.29 mg, 8.96 muiotaetaomicronIota was added to a solution of the compound of example 75 (0.2 g, 0.560 mmol) and t-butyl 4-(5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (262 mg, 0.672 mmol), in DMF (5 mL) in a microwave tube followed by addition of potassium carbonate (1 16 mg, 0.840 mmol) solution in 1 mL of water. The tube was sealed and heated on microwave at 140°C for 40 min. The reaction mixture was quenched in cold water (20 mL) and extracted with ethyl acetate (2x25 mL). The organic layer was washed with water (2x50 mL) and brine (50 mL) and dried over anhydrous sodium sulphate The solvent was evaporated to obtain the crude material, which was purified by column chromatography (silica gel, 3 percent methanol in chloroform). Yield: 0.125 g (41 .40 percent); 1 H NMR (300 MHz, DMSO-d6): delta 1 .41 (s, 9H, 3CH3), 3.44 (d, 4H, J = 8.7 Hz, 5.1 Hz, 2CH2), 3.56 (d, 4H, J = 5.7 Hz, 2CH2), 6.61 (s, 2H, NH2, Exchangeable with D20), 6.99 (d, 1 H, J = 9.0 Hz, Ar), 7.55 (d, 1 H, J = 9.3 Hz, Ar), 7.66-7.69 (m, 2H, Ar), 7.91 (dd, 1 H, J = 8.7 Hz, J = 2.1 Hz, Ar), 8.04 (s, 1 H, Ar), 8.44(d, 1 H, Ar), 8.51 (d, 2H, d, J= 5.7 Hz, Ar); MS (ES+): m/e 540.0 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 60

36
[ 496786-98-2 ]
[ 1654738-73-4 ]

Reference： [1]Patent: WO2014/93225,2014,A2

37
[ 496786-98-2 ]
[ 1613643-22-3 ]

Reference： [1]Patent: WO2014/93225,2014,A2

38
[ 496786-98-2 ]
[ 367-24-8 ]
[ 1613643-71-2 ]

Yield	Reaction Conditions	Operation in experiment
0.24 g	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 95 - 104℃; for 1.4h;Microwave irradiation; Inert atmosphere;	2-(4-Boc-piperazine)pyridine-5-boronic acid pinacol ester (0.42 g, 1.07 mmol) and 2- Fluoro-4-bromoaniline (1 mmol, 0.19 g) were added into a microwave tube under Argon. Dioxane (4 mL) and aqueous K2C03 (4 mmol, 4 mL, 2 M) were added. Then Pd(PPh3)4 (0.1mmol, 0.1 g) was added. The mixture was under microwave irradiation (95°C, 1 hour then 104°C24 minutes) with stirring. The reaction was cooled down to room temperature and extracted with EtOAc and brine. The organic layer was dried over Na2SO4 and evaporated under vacuum. The residue was purified with silica gel column (eluent: EtOAc/hexanes = 0/100 to 40/100, v/v). A yellow solid (0.24 g) was obtained as product. LC-MS OK.

Reference： [1]Patent: WO2014/93225,2014,A2 .Location in patent: Page/Page column 184

39
[ 496786-98-2 ]
[ 1346576-39-3 ]
[ 1615203-18-3 ]

Yield	Reaction Conditions	Operation in experiment
51%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 80℃; for 5h;Inert atmosphere;	To a stirred solution of methyl 6-bromo-l-(sec-butyl)-3-methyl-lH-indole-4- carboxylate (1 g, 3.09 mmol) and tert-butyl 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)piperazine-l-carboxylate (1.32 g, 3.39 mmol) in dioxane/water mixture (8 mL + 2 mL), K3P04 (1.96 g, 9.25 mmol) was added and the solution was purged with argon for 20 min. Then Pd(dppf)Cl2 (0.252 g, 0.309 mmol) was added and argon was purged again for 15 min. The reaction mass was heated at 80 °C for 5 h. The progress of the reaction was monitored by TLC. Upon completion the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (0.8 g, 51percent).

Reference： [1]Patent: WO2014/100665,2014,A1 .Location in patent: Paragraph 0562; 0563
[2]Patent: WO2015/200650,2015,A1 .Location in patent: Paragraph 0655; 0668-0669

40
[ 496786-98-2 ]
[ 1611000-07-7 ]

Reference： [1]Patent: WO2014/80241,2014,A1

41
[ 496786-98-2 ]
[ 1611000-08-8 ]

Reference： [1]Patent: WO2014/80241,2014,A1

42
[ 496786-98-2 ]
[ 1611001-30-9 ]
[ 1611001-31-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 80 (250 mg, 0.733 mmol) was treated with t-butyl 4-(5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (342 mg, 0.879 mmol), in DMF (5 mL) in presence of bis(triphenylphosphin)-palladium(ll)- dichloride (15.43 mg, 0.022 mmol) and potassium carbonate (152 mg, 1 .099 mmol) solution in 1 mL of water according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 0.35 g (91 .00 percent); 1 H NMR (300 MHz, DMSO-de): delta 1 .41 (s, 9H, 3CH3 ), 3.44 (t, 4H, 2CH2 ), 3.58 (t, 4H, 2CH2 ), 7.01 (d, 1 H, J = 8.7 Hz, Ar), 7.70 - 7.79 (m, 3H, Ar), 7.94 (dd, 1 H, J = 9.0 Hz, J = 2.4, Ar ), 8.47 (d, 1 H, J = 2.1 Hz, Ar), 8.58 (s, 1 H, Ar), 8.78 (s, 1 H, Ar), 8.97 (s, 1 H, Ar), 9.24 (d, 1 H, J = 1 .5 Hz, Ar); MS (ES+): m/e 525.2 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 62

43
[ 496786-98-2 ]
[ 1611001-30-9 ]
[ 1611000-13-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 80 (400 mg, 1 .169 mmol) was treated with tert-butyl 4-(3- methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl) piperazine-1 - carboxylate (613 mg, 1 .520 mmol), in DMF (10 mL) in presence of [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane (28.6 mg, 0.035 mmol) and sodium carbonate (248 mg, 2.338 mmol) solution in 2 mL of water according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 0.487 g (76.00 percent) ; 1 H NMR (300 MHz, DMSO-d6): delta 1 .43(s, 9H, 3CH3), 2.35(s, 3H, CH3), 3.1 2 (s, 4H, 2CH2), 3.50 (s, 4H, 2CH2), 7.74 - 7.81 (m, 3H, Ar), 7.94 (s, 1 H, Ar), 8.52 (d, 1 H, J = 2.1 , Ar ), 8.61 (s, 1 H, Ar), 8.89 (s, 1 H, Ar ), 8.99 (s 1 H, Ar), 9.27 (s, 1 H, Ar) ; MS (ES+): m/e 539.2 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 75; 76

44
[ 496786-98-2 ]
[ 1611001-30-9 ]
[ 1611000-14-6 ]

Reference： [1]Patent: WO2014/80241,2014,A1

45
[ 496786-98-2 ]
[ 1611001-33-2 ]
[ 1610999-97-7 ]

Yield	Reaction Conditions	Operation in experiment
61.4%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 86 (0.25 g, 0.836 mmol) was treated with t-butyl 4-(5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (0.407 g, 1.045 mmol) in DMF (20 mL) in presence of [1,1'- bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane (0.02048 mg, 0.025 mmol) and sodium carbonate (0.177 g, 1.672 mmol) solution in 4 mL of water according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 0.25 g (61.40 percent); 1H NMR (300 MHz, DMSO-d6): delta 1.41 (s, 9H, 3CH3), 3.45 (s, 4H, 2CH2), 3.58 (s, 4H, 2CH2), 6.98 (d, 1 H, J= 9.0 Hz, Ar), 7.71 (d, 1 H, J = 1.5 Hz, Ar), 7.74 (d, 1 H, J = 9 Hz, Ar), 7.80 (s, 1 H, Ar), 7.92 (dd, 1 H, J = 9.0 Hz, J= 2.4 Hz, Ar), 8.11 (d, 1H, J= 8.1 Hz, Ar), 8.40 (dd, 1H, J= 8.1 Hz, J = 2.4 Hz, Ar), 8.45 (d, 1H, J = 2.1 Hz, Ar), 8.76 (s, 1H, Ar), 9.15 (d, 1H, J= 2.1 Hz, Ar) ; MS (ES+): m/e 482.2 (M+1).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 64

46
[ 496786-98-2 ]
[ 1611001-44-5 ]
[ 1611001-46-7 ]

Yield	Reaction Conditions	Operation in experiment
60.7%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 107 (1 .0 g, 3.03 mmol) was treated with t-butyl 4-(5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (1 .415 g, 3.63 mmol) in DMF (20 ml) in presence of [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloro palladium(ll) complex with dichloromethane (0.074 g, 0.091 mmol) and sodium carbonate (0.642 g, 6.06 mmol) solution in 4 mL according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 0.945 g (60.7 percent); 1 H NMR (300 MHz, DMSO-d6): delta 1 .43 (s, 9H, 3CH3), 3.45 (s, 4H, 2CH2 ), 3.61 (s, 4H, 2CH2), 3.97(s, 3H, OCH3), 7.02 (d, 1 H, J = 5.4 Hz, Ar), 7.89 (s, 1 H, Ar), 7.95 (dd, 1 H, J = 5.4 Hz, J = 1 .2 Hz, Ar), 8.43(s, 1 H, Ar), 8.48 (d, 1 H, J = 1 .2 Hz, Ar), 8.97 (s, 1 H, Ar), 9.01 (s, 2H, Ar); MS (ES+): m/e 513.3 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 72

47
[ 496786-98-2 ]
[ 1611000-85-1 ]
[ 1611000-76-0 ]

Yield	Reaction Conditions	Operation in experiment
18.61%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 3 (1 .0 g, 3.65 mmol) was treated with t-butyl 4-(5-(4, 4,5,5- tetramethyl-1 ,3, 2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (1 .56 g, 4.01 mmol) in the presence of [1 , 1 '-bis(diphenylphosphino)-ferrocene]dichloropalladium(l l) complex with dichloromethane (0.089 g, 0.109 mmol) and sodiumcarbonate (0.773 g, 7.30 mmol) in dry dimethylformamide according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 0.31 0 g (1 8.61 percent); 1 H NMR (DMSO-de, 300 MHz) : delta 1 .43 (s, 9H, 3CH3), 3.44 (s, 4H, 2CH2), 3.59 (s, 4H, 2CH2), 7.01 (d, 1 H, J=8.7 Hz, Ar), 7.47-7.51 (m, 1 H, Ar), 7.62-7.78 (m, 3H, Ar), 7.96 (d, 1 H, J=7.2 Hz, Ar), 8.14 (d, 1 H, J=7.8 Hz, Ar), 8.45 (s, 1 H, Ar), 8.58-8.60 (m, 2H, Ar), 8.94 (s, 1 H, Ar); MS (ES+) : m/e 457 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 129

48
[ 496786-98-2 ]
[ 1611001-66-1 ]
[ 1611000-40-8 ]

Yield	Reaction Conditions	Operation in experiment
51%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; 6-(6-methylpyridin-3-yl)-3-(4-morpholinophenyl)imidazo[1,2-a]pyridine-8-carbonitrile; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 164 (0.5 g, 1.55 mmol) was treated with t-butyl 4-(5-(4, 4,5,5- tetramethyl-1 ,3, 2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (0.725 g, 1.86 mmol) in the presence of [1 ,1 '-bis(diphenyl phosphino)-ferrocene]dichloropalladium(ll) complex with dichloromethane) (0.038 g, 0.047 mmol) and sodium carbonate (0.329 g, 3.10 mmol) in dry dimethylformamide according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 0.430 g (51 percent); 1 H NMR (DMSO-de, 300 MHz): delta 1 .43 (s, 9H, 3CH3), 3.45-3.51 (m, 4H, 2CH2), 3.59-3.60 (m, 4H, 2CH2), 3.89 (s, 3H, OCH3), 6.90.6.93 (m, 1 H, Ar), 7.02 (d, 1 H, J=9.0 Hz, Ar), 7.60- 7.64 (m, 1 H, Ar), 7.75 (s, 1 H, Ar), 7.94 (dd, 1 H, J=8.7, 2.4 Hz, Ar), 8.09 (dd, 1 H, J=8.7, 2.4 Hz, Ar), 8.39 (s, 1 H, Ar), 8.45 (d, 1 H, J=2.1 Hz, Ar), 8.52 (d, 1 H, J=2.1 Hz, Ar); MS (ES+): m/e 505 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 92; 93

49
[ 496786-98-2 ]
[ 1611001-74-1 ]
[ 1611000-47-5 ]

Yield	Reaction Conditions	Operation in experiment
52.3%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; 6-(6-methylpyridin-3-yl)-3-(4-morpholinophenyl)imidazo[1,2-a]pyridine-8-carbonitrile; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 181 (2 g, 5.62 mmol) was treated with t-butyl 4-(5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (2.186 g, 5.62 mmol) in the presence of [1 ,1 '-bis(diphenylphosphino)-ferrocene]dichloropalladium(ll) complex with dichloromethane (0.229 g, 0.281 mmol) and sodium carbonate (1 .164 g, 8.42 mmol) in dry dimethylformamide (10 mL) according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 1 .6 g (52.3 percent); 1 H NMR (DMSO-d6, 300 MHz): delta 1 .39 (s, 9H, 3CH3), 2.52 (d, 3H, J =1 .8 Hz, CH3), 3.46 (d, 4H, J =5.4 Hz, 2CH2), 3.60 (d, 4H, J =5.4 Hz, 2CH2), 7.03 (d, 1 H, J =9.0 Hz, Ar), 7.36 (d, 1 H, J =8.1 Hz, Ar), 7.84 (s, 1 H, Ar), 7.97 (dd, 1 H, J =2.4 Hz, J =8.7 Hz, Ar), 8.04 (s, 1 H, Ar), 8.09 (dd, 1 H, J =2.4 Hz, J =8.1 Hz, Ar), 8.47 (d, 1 H, J =2.4 Hz, Ar), 8.77 (s, 1 H, Ar), 8.85 (d, J =2.1 Hz, 1 H, Ar); MS (ES+): m/e 539.2 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 98

50
[ 496786-98-2 ]
[ 1611002-27-7 ]
[ 1611002-04-0 ]

Yield	Reaction Conditions	Operation in experiment
30%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 225 (0.300 g, 0.817 mmol) was treated with t-butyl 4-(5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (0.382 g, 0.981 mmol) in the presence of [1 ,1 '-bis(diphenylphosphino)- ferrocene]dichloropalladium(ll) complex with dichloromethane (0.033 g, 0.041 mmol) and sodium carbonate (0.169 g, 1.226 mmol) in dry dimethylformamide (10 mL) according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 0.140 g (30.0 percent); 1H NMR (DMSO-d6, 300 MHz): delta 1.43 (d, 9H, 3CH3), 3.45 (s, 4H, 2CH2), 3.62 (d, 4H, J =6.0 Hz, 2CH2), 7.03 (d, 1H, J =9.0 Hz, Ar), 7.88 (s, 1H, Ar), 7.97 (dd, 1H, J =3.0 Hz, J =9.0 Hz, Ar), 8.18 (d, 2H, J =9.0 Hz, Ar), 8.49-8.54 (m, 2H, Ar), 9.00 (s, 1H, Ar), 9.24 (d, 1H, J =3.0 Hz, Ar); MS (ES+): m/e 550.1 (M+1).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 114; 115

51
[ 496786-98-2 ]
[ 1611002-20-0 ]
[ 1611000-71-5 ]

Yield	Reaction Conditions	Operation in experiment
34.2%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 253 (0.300 g, 0.883 mmol) was treated with t-butyl 4-(5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (0.41 3 g, 1 .060 mmol) in the presence of [1 , 1 '-bis(diphenyl phosphino)- ferrocene]dichloropalladium(l l) complex with dichloromethane (0.036 g, 0.044 mmol) and sodium carbonate (0.1 83 g, 1 .325 mmol) in dry dimethylformamide (1 0 mL) according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 0.160 g (34.2 percent); 1H NMR (DMSO-d6, 300 MHz): delta 1 .43 (d, 9H, 3xCH3), 3.46 (d, 4H, J =6.0 Hz, 2xCH2), 3.61 (d, 4H, J =6.0 Hz, 2xCH2), 3.96 (s, 3H, OCHs), 7.00 (d, 1 H, J =9.0 Hz, Ar), 7.79 (s, 1 H, Ar), 7.90 (d, 1 H, J =1 .2 Hz, Ar), 7.93 (dd, 1 H, J =3.0 Hz, J =9.0 Hz, Ar), 8.46 (d, 1 H, J =3.0Hz, Ar), 8.66 (d, 1 H, J =1 .2 Hz, Ar), 8.99 (s, 2H, Ar); MS (ES+): m/e 523.2 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 125; 126

52
[ 496786-98-2 ]
[ 1611002-22-2 ]
[ 1611000-83-9 ]

Yield	Reaction Conditions	Operation in experiment
42.7%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 260 (0.5 g, 1 .545 mmol) was treated with t-butyl 4-(5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (0.722 g, 1 .854 mmol) in the presence of [1 , 1 '-Bis(diphenylphosphino)- ferrocene]dichloropalladium(l l) complex with dichloromethane (0.025 g, 0.031 mmol) and sodium carbonate (0.246 g, 2.318 mmol) in dry dimethylformamide (1 0ml) according to the preparation of compound of example 1 to give t-butyl 4-(5-(8-chloro-6- (2-methylpyrimidin-5-yl)imidazo[1 ,2-a]pyridin-3-yl)pyridin-2-yl)piperazine-1 -carboxylate. Yield: 0.351 g(42.7percent) ; 1 H NMR (DMSO-d6, 300 MHz): delta 1 .43 (s, 9H, 3xCH3), 2.67(s, 3H, CH3), 3.45 (t, 4H, J =3.0 Hz, 2CH2), 3.61 (t, 4H, J =3.0 Hz, 2CH2), 7.02 (d, 2H, J =6.0 Hz, Ar), 7.81 (s, 2H, Ar), 8.47(s, 1 H, Ar), 8.72 (s, 1 H, Ar), 9.08 (s, 2H, Ar) ; MS (ES+): m/e 507.3 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 132

53
[ 496786-98-2 ]
[ 1611000-90-8 ]
[ 1611000-78-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 1 2 (0.250 g, 0.862 mmol) was treated with t-butyl 4-(5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (0.369 g, 0.948 mmol) in the presence of [1 , 1 '-bis(diphenylphosphino)- ferrocene]dichloropalladium(l l) complex (0.021 g, 0.026 mmol) and sodium carbonate (0.1 83 g, 1 .73 mmol) according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 0.31 0 g (76 percent) ; 1 H NMR (DMSO-d6, 300 MHz): delta 1 .43 (s, 9H, 3CH3), 3.45 (s, 4H, 2CH2), 3.60 (s, 4H, 2CH2), 7.02 (d, 1 H, J=9.0 Hz, Ar), 7.47-7.52 (m, 1 H, Ar), 7.61 -7.77 (m, 4H, Ar), 7.95 (d, 1 H, J=6.9 Hz, Ar), 8.22 (d, 1 H, J=6.3 Hz, Ar), 8.47 (s, 1 H, Ar), 8.68-8.73 (m, 2H, Ar) ; MS (ES+) : m/e 457 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 130

54
[ 496786-98-2 ]
[ 1611000-96-4 ]
[ 1611000-80-6 ]

Yield	Reaction Conditions	Operation in experiment
19%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 19 (2.0g, 6.94 mmol) was treated with t-butyl 4-(5-(4, 4,5,5- tetramethyl-1 ,3, 2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (2.97 g, 7.64 mmol) in the presence of [1 , 1 '-Bis(diphenylphosphino)- ferrocene]dichloropalladium(l l)complex with dichloromethane (0.1 70 g, 0.208 mmol) and sodium carbonate (0.736 g, 6.94 mmol) in dry dimethylformamide according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 0.620 g (1 9 percent); 1 H NMR (DMSO-d6, 300 MHz): delta 1 .43 (s, 9H, 3CH3), 2.51 (s, 3H, CH3), 3.44 (s, 4H, 2CH2), 3.59 (s, 4H, 2CH2), 7.01 (d, 1 H, J=9.0 Hz, Ar), 7.35 (d, 1 H, J=8.1 Hz, Ar) 7.60-7.76 (m, 3H, Ar), 7.95 (d, 1 H, J=7.2 Hz, Ar), 8.02 (d, 1 H, J=6.0 Hz, Ar), 8.45 (s, 1 H, Ar), 8.56 (s, 1 H, Ar), 8.79 (s, 1 H, Ar); MS (ES+): m/e 471 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 130; 131

55
[ 496786-98-2 ]
[ 1611001-21-8 ]
[ 1610999-86-4 ]

Yield	Reaction Conditions	Operation in experiment
44%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 64 (2.0 g, 6.39 mmol) was treated with t-butyl 4-(5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (2.73 g, 7.03 mmol) in the presence of [1 , 1 '-bis(diphenylphosphino)-ferrocene]dichloropalladium(l l) complex with dichloromethane (0.083 g, 0.102 mmol) and sodium carbonate (1 .01 5 g, 9.58 mmol) in dry dimethylformamide according to the procedure for the preparation of the compound of example 2 to afford the title compound Yield: 1 .4 g (44 percent); 1 H NMR (DMSO-de, 300 MHz): delta 1 .43 (s, 9H, 3CH3), 2.60 (s, 3H, CH3), 3.47 (s, 4H, 2CH2), 3.58 (s, 4H, 2CH2), 7.01 (d, 1 H, J=9.0 Hz, Ar), 7.58 (s, 1 H, Ar), 7.71 (s, 1 H, Ar), 7.92 (dd, 1 H, J=8.7, 2.4 Hz, Ar), 8.1 3 (d, 1 H, J=8.4 Hz, Ar), 8.40-8.46 (m, 2H, Ar), 8.64 ( s, 1 H Ar), 9.1 6 ( d, 1 H, J=1 .5 Hz, Ar); MS (ES+): m/e 496 (M+1 )

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 56

56
[ 496786-98-2 ]
[ 6188-23-4 ]
[ 1611000-86-2 ]

Yield	Reaction Conditions	Operation in experiment
54.68%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide;Inert atmosphere;	A mixture of the compound of example 1 (1.0 g, 5.08 mmol) and t-butyl 4-(5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (1.97 g, 5.08 mmol) were treated with [1 ,1 '-bis(diphenylphosphino)-ferrocene]dichloropalladium(ll) complex with dichloromethane (0.124 g, 0.152 mmol) and sodium carbonate (2.15 g, 20.30 mmol) in dry dimethylformamide (100 mL) according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 1.05 g (54.68 percent); 1H NMR (DMSO-d6, 300 MHz): delta 1.39 (s, 9H, 3CH3), 3.44 (s, 4H, 2CH2), 3.55 (s, 4H, 2CH2), 6.95 (d, 1H, J=8.7 Hz, Ar), 7.50-7.62 (m, 3H, Ar), 7.87 (d, 1H, J=2.4 Hz, Ar), 7.90 (s, 1H, Ar), 8.46 (d, 1H, J=2.4 Hz, Ar), 8.83 (s, 1H, Ar); MS (ES+): m/e 380 (M+1).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 35

57
[ 496786-98-2 ]
[ 1616289-64-5 ]
[ 1616289-66-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; at 120℃; for 0.5h;Microwave irradiation;	A mixture of 2-[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77e, 60 mg, 0.110 mmol), <strong>[496786-98-2]tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate</strong> (64 mg, 0.164 mmol), Na2CO3 (200 muL, 0.400 mmol, 2 M solution), PdCl2(dPPf)-DCM (9 mg, 0.011 mmol), and 1,4-dioxane (2 mL) was stirred at 120° C. in microwave for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was separated, washed with brine (1*20 mL), dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-100percent EtOAc/heptanes) to give tert-butyl 4-{5-[2-[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyridin-2-yl}piperazine-1-carboxylate (77f, 46 mg, 58percent yield) as a solid.

Reference： [1]Patent: US2014/179667,2014,A1 .Location in patent: Paragraph 0882; 0888

58
[ 496786-98-2 ]
[ 1187313-22-9 ]
tert-butyl 4-(5-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.4%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 1.7h;Inert atmosphere; Reflux;	To a suspension of 4-(6-bromopyrazolo[l,5-a]pyrimidin-3-yl)quinoline (0.325 g, 0.999 mmol) (WO2009/114180 Al, 2009) and tert-butyl 4-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)piperazine-l-carboxylate (0.584 g, 1.499 mmol) in dioxane degassed with N2 was added Pd(PPh3)4 (0.058 g, 0.050 mmol) then aqueous sodium carbonate (2 M, 1.5 mL). The mixture was heated to reflux for 1.7 h. The mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was washed with brine, dried (Na2S04), filtered and concentrated. Triturated crude material with EtOH, filtered and washed solid with EtOH. Obtained tert-butyl 4-(5-(3-(quinolin-4- yl)pyrazolo[l,5-a]pyrimidin-6-yl)pyridin-2-yl)piperazine-l-carboxylate (0.22 g, 0.433 mmol, 43.4 percent yield) as a yellow solid.

Reference： [1]Patent: WO2014/160203,2014,A2 .Location in patent: Page/Page column 59-60

59
[ 496786-98-2 ]
[ 1187313-22-9 ]
4-(6-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline trifluroacetate [ No CAS ]

Reference： [1]Patent: WO2014/160203,2014,A2

60
[ 496786-98-2 ]
methyl 6-bromo-1-isopropyl-3,3-dimethyl-2-oxoindoline-4-carboxylate [ No CAS ]
methyl 6-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1-isopropyl-3,3-dimethyl-2-oxoindoline-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		Example 128: Methyl 6-(6-(4-(tert-butoxycarbonyl)piperazin-1 -yl)pyridin-3-yl)-1 -isopropyl-3,3- dimethyl-2-oxoindoline-4-carboxylate To a solution of the compound of example 127 (525 mg, 1 .543 mmol, 1 .0 equiv) in dioxane (26 ml_) was added te/t-butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (781 mg, 2.006 mmol, 1 .3 equiv) and PdCI2(dppf)-CH2CI2 adduct (37.8 mg, 0.046 mmol, 0.03 equiv) and stirred at room temperature for 10 min. To this reaction mixture was added 2 M aqueous sodium carbonate solution (2.3 ml_, 4.63 mmol, 3.0 equiv) and the reaction mixture was stirred and heated to 85 °C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated to obtain a residue. To this residue water was added and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with brine, dried over sodium sulfate, and concentrated to yield a crude product which was purified by column chromatography (silica gel, 4:6, EtOAc:CHCI3) to obtain the title compound. Yield: 625 mg (77 percent); 1 H NMR (DMSO-d6, 300 MHz): delta 8.52 (d, J = 2.4 Hz, 1 H), 7.96 - 7.92 (dd, J = 2.4 Hz, 1 H), 7.67 (s, 1 H), 7.58 (s, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 4.63 - 4.58 (m, 1 H), 3.89 (s, 3H), 3.56 (s, 4H), 3.44 (s, 4H), 1 .46 (s, 6H), 1 .43 (s, 9H), 1 .40 (s, 6H); MS (ESI+): m/z 523.4 (M+H)+.

Reference： [1]Patent: WO2014/155301,2014,A1 .Location in patent: Page/Page column 100; 101

61
[ 496786-98-2 ]
ethyl 2-chloro-5,6,7,8-tetrahydroquinazoline-4-carboxylate [ No CAS ]
ethyl 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-5,6,7,8-tetrahydroquinazoline-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18.53%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In water; at 90℃;Inert atmosphere;	Example 164: Ethyl 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-5,6,7,8- tetrahyd roqu i nazol i ne-4-car boxylate To a solution of the compound of example 163 B (250mg, 0.53 mmol) in 10 ml_ of 1 -4 dioxane, were added tert-butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 -carboxylate (566 mg, 1 .454 mmol) and sodium bicarbonate (262 mg, 3.12 mmol) in 2 ml_ of water. Argon gas was purged for 10 minutes. To this reaction mixture PdCI2(dppf) (22 mg, 0.031 mmol) was added. Argon was purged for 10 minutes and the reaction mass was heated for 12- 16 h at 90 °C. The reaction mass was concentrated and quenched by addition of water and the product obtained was extracted with ethyl acetate. The crude product obtained was purified by column chromatography (silica gel, DCM and methanol) to obtain the title compound. Yield: 90 mg (18.53 percent); 1H NMR (DMSO-d6, 500 MHz): delta 9.03 (s, 1 H), 8.36 (t, J = 8.5Hz, 1 H), 6.94 (d, J = 9Hz, 1 H), 4.40 (q, J = 7.0 Hz, 14.0 Hz, 2H), 3.63 (s 4H), 3.45 (s, 4H), 2.9(s, 2H), 2.78 (s, 2H), 1 .82 (d, J = 5Hz, 2H), 1 .74 (d, J = 4Hz, 2H), 1 .43 (s, 9H), 1 .33 (t, J = 7.0Hz, 3H); MS (ESI+): m/z 468.3 (M+H)+.

Reference： [1]Patent: WO2014/155301,2014,A1 .Location in patent: Page/Page column 115

62
[ 496786-98-2 ]
[ 1346575-52-7 ]
3-(aminomethyl)-1,4,6-trimethylpyridin-2(1H)-one hydrochloride [ No CAS ]
tert-butyl 4-(5-(1-isopropyl-4-(((1,4,6-trimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1H-indol-6-yl)pyridin-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 74: tert-Butyl 4-(5-(1 -isopropyl-4-(((1 ,4,6-trimethyl-2-oxo-1 ,2-dihydropyridin-3-yl) methyl)carbamoyl)-1 H-indol-6-yl)pyridin-2-yl)piperazine-1-carboxylate Step a: A solution of the compound of example 10 in dioxane and water was treated with te/t-butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2- yl)piperazine-1 -carboxylate and 1 ,1 '-bis(diphenylphosphino) ferrocene palladium dichloromethane complex according to the procedure described for the preparation of the compound of example 12 to obtain an intermediate compound. Step b: The compound obtained in the above step a was treated with compound of example 7 (1 .3 equiv) according to the procedure described for the preparation of the compound of example 14 to obtain the title compound. 1 H NMR (DMSO-de, 300 MHz): delta 8.59 (d, J = 2.1 Hz, 1 H), 8.24 (s, 1 H), 8.00 (dd, J = 2.4 & 6.6 Hz, 1 H), 7.87 (s, 1 H), 7.65 (s, 1 H), 7.60 (d, J = 3.3 Hz, 1 H), 6.95 (d, J = 9 Hz 1 H), 6.86 (d, J = 2.7 Hz, 1 H), 6.04 (s, 1 H), 4.90-4.94 (m, 1 H), 4.40 (d, J = 5.1 Hz, 2H), 3.52 (d, J = 5.4 Hz, 4H), 3.42 (s, 7H), 2.30 (s, 3H), 2.24 (s, 3H), 1 .45 (d, J = 6.3 Hz, 6H), 1 .43 (s, 9H); MS (ESI+): m/z 613.4 [M+H]+.

Reference： [1]Patent: WO2014/155301,2014,A1 .Location in patent: Page/Page column 81

63
[ 496786-98-2 ]
ethyl 2-bromo-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate [ No CAS ]
ethyl 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		Example 175: Ethyl 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine-4-carboxylate A mixture of the compound of example 174 B (0.230 g, 0.844 mmol) and tert- butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylate (0.553 g, 1 .421 mmol) along with sodium carbonate (2 M, 1 .55 mL) in 1 ,4-dioxane (10 mL) were sonicated for two minutes and stirred under argon atmosphere at an ambient temperature. The PdCI2(dppf).CH2Cl2 adduct (0.166 g, 0.2 mmol) was added to the reaction mixture and stirred at 1 10 °C until the reaction was complete. The reaction mass was diluted with EtOAc (50 mL) and filtered through a celite bed. The filtrate was washed with water (20 mL), brine (5 mL). The organic layer was dried over anhydrous Na2S04, filtered, concentrated and the residue obtained was purified by column chromatography (silica gel, 5 percent methanol in dichloromethane) to obtain the title compound Yield: 0.220 g (49 percent); MS (ESI+): m/z 454 (M+H)+.

Reference： [1]Patent: WO2014/155301,2014,A1 .Location in patent: Page/Page column 120

64
[ 496786-98-2 ]
methyl 6-bromo-1-isopropylindoline-4-carboxylate [ No CAS ]
methyl 6-(6-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)pyridin-3-yl)-1-isopropylindoline-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 65℃; for 1.5h;Inert atmosphere;	Example 12: Methyl 6-(6-(4-(3,3-dimethylbutanoyl)piperazin-1 -yl)pyridin-3-yl)-1 -isopropyl indoline-4-carboxylate To a solution of the compound of example 1 1 (2.0 g, 6.71 mmol) in dioxane (20 ml_) and water (20 ml_) were added te/t-butyl 4-(5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl) pyridin-2-yl)piperazine-1 -carboxylate (2.376 g, 6.10 mmol) and 1 ,1 'Bis(diphenylphosphino) ferrocene palladium dichloromethane complex (3.39 g, 8.72 mmol) under nitrogen atmosphere and stirred at room temperature for 10 min. To this mixture, 2 M sodium carbonate (0.164 g, 0.201 mmol) solution was added and the resulting reaction mixture was stirred at 65 SC for 1 .5 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was washed with water and brine, dried over anhydrous sodium sulphate, and concentrated to yield crude product. Further purification of the crude product was carried out by column chromatography (silica gel, 5 percent ethyl acetate in petroleum ether) to obtain the title compound. Yield: 2 g (62 percent); 1H NMR (CDCI3, 300 MHz): delta 8.45 (s, 1 H), 7.75 (d, J=7.5 Hz, 1 H), 7.37 (s, 1 H), 6.72 (d, J= 8.7 Hz, 1 H), 6.65 (s, 1 H), 3.90 (s, 3H), 3.88 (m, 1 H), 3.58 (m, 8H), 3.46 (t, J= 7.8 Hz & 7.2 Hz, 2H), 3.33 (t, J= 7.2 Hz & 7.8 Hz, 2H), 1 .50 (s, 9H), 1 .20 (d, J=6.6 Hz, 6H); MS (ESI+): m/z 481 .4 (M+H)+.

Reference： [1]Patent: WO2014/155301,2014,A1 .Location in patent: Page/Page column 57

65
[ 496786-98-2 ]
6-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1-isopropyl-3,3-dimethyl-2-oxoindoline-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2014/155301,2014,A1

66
[ 496786-98-2 ]
tert-butyl 4-(5-(1-isopropyl-3,3-dimethyl-4-(((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-oxoindolin-6-yl)pyridin-2-yl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/155301,2014,A1

67
[ 496786-98-2 ]
1-isopropyl-3,3-dimethyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-2-oxo-6-(6-(piperazin-1-yl)pyridin-3-yl)indoline-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2014/155301,2014,A1

68
[ 496786-98-2 ]
(E)-tert-butyl 4-(5-(8-morpholino-2-(2-(quinolin-2-yl)vinyl)imidazo[1,2-a]pyrazin-5-yl)pyridin-2-yl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2014/364414,2014,A1

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[ 496786-98-2 ]

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 496786-98-2 ]

Quality Control of [ 496786-98-2 ]

Related Doc. of [ 496786-98-2 ]

Product Details of [ 496786-98-2 ]

Calculated chemistry of [ 496786-98-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 496786-98-2 ]

Application In Synthesis of [ 496786-98-2 ]

[ 496786-98-2 ] Synthesis Path-Upstream 1~5

[ 496786-98-2 ] Synthesis Path-Downstream 1~68

Related Functional Groups of [ 496786-98-2 ]

Organoboron

Amides

Related Parent Nucleus of [ 496786-98-2 ]

Pyridines

Piperazines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 496786-98-2 ]

Related Parent Nucleus of
[ 496786-98-2 ]