[ CAS No. 445264-61-9 ] {[proInfo.proName]}

Name: 445264-61-9|2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine|98%
Brand: Ambeed
SKU: A120696
Price: 9.0 USD
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2D 3D

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Quality Control of [ 445264-61-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 445264-61-9 ]

Product Details of [ 445264-61-9 ]

CAS No. :	445264-61-9	MDL No. :	MFCD05663858
Formula :	C₁₂H₁₈BNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QOGNDJLSYMJGPP-UHFFFAOYSA-N
M.W :	235.09	Pubchem ID :	16217714
Synonyms :

Calculated chemistry of [ 445264-61-9 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.58
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	67.2
TPSA :	40.58 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.21 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.14
Log Po/w (WLOGP) :	1.39
Log Po/w (MLOGP) :	0.69
Log Po/w (SILICOS-IT) :	1.32
Consensus Log Po/w :	1.11

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.77
Solubility :	0.395 mg/ml ; 0.00168 mol/l
Class :	Soluble
Log S (Ali) :	-2.62
Solubility :	0.559 mg/ml ; 0.00238 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.76
Solubility :	0.0409 mg/ml ; 0.000174 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.94

Safety of [ 445264-61-9 ]

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

Application In Synthesis of [ 445264-61-9 ]

* 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 [ 445264-61-9 ]
Downstream synthetic route of [ 445264-61-9 ]

[ 445264-61-9 ] Synthesis Path-Upstream 1~13

1
[ 445264-61-9 ]
[ 51834-97-0 ]

Yield	Reaction Conditions	Operation in experiment
2.4 g	With sodium perborate tetrahydrate In tetrahydrofuran; water at 20℃; for 2 h;	To a stirred suspension of sodium perborate tetrahydrate (6.87 g, 44.68 mmol) in water was added 2-methoxy-5 -(4,4,5,5 -tetramethyl-[ 1,3,2] dioxaborolan-2-yl)-pyridine (3.5 g, 14.68 mmol) in THF (70 mL) at room temperature. The resulting reaction mixture was stirred for 2 hr at room temperature. The reaction mass was extracted with ethyl acetate (200 mL), washed with brine dried over Na2SO4 and concentrated under reduced pressure to provide the crude which was purified by silica gel (100-200 mesh) column chromatography using 20percent EtOAc in hexane as eluent to afford 2.4 g of 6-methoxy-pyridin-3-ol. LCMS: 126 (M+H).

Reference： [1] Patent: WO2014/186035, 2014, A1, . Location in patent: Page/Page column 151

2
[ 445264-61-9 ]
[ 76053-45-7 ]

Reference： [1] Tetrahedron, 2014, vol. 70, # 45, p. 8624 - 8635

3
[ 1628-89-3 ]
[ 73183-34-3 ]
[ 445264-61-9 ]
[ 408502-23-8 ]

Reference： [1] Journal of the American Chemical Society, 2014, vol. 136, # 11, p. 4133 - 4136
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 37, p. 7318 - 7327
[3] Patent: US2015/65743, 2015, A1, . Location in patent: Paragraph 0372; 0373
[4] Patent: WO2015/89119, 2015, A1, . Location in patent: Page/Page column 34

4
[ 1628-89-3 ]
[ 73183-34-3 ]
[ 445264-61-9 ]
[ 408502-23-8 ]

Reference： [1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 37, p. 7318 - 7327

5
[ 13472-85-0 ]
[ 73183-34-3 ]
[ 445264-61-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In 1,4-dioxane at 108℃; Inert atmosphere	Step j: 2-methoxy-5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound R-3-2) A mixture of compound 303 (55 g, 0.29 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (90 g, 0.35 mol), potassium acetate (57 g, 0.58 mol) and bis(triphenylphosphine)palladium(II) chloride (2.2 g, 3 mmol) in anhydrous dioxane (500 mL) was heated at 108° C. under N₂ atmosphere overnight. The reaction mixture was concentrated and purified by column chromatography eluted with hexanes/ethyl acetate to afford title compound R-3-2 (58 g, 84percent).
84%	With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In 1,4-dioxane at 108℃; Inert atmosphere	A mixture of compound 303 (55 g, 0.29 mol), 4,4,4’,4’,5,5,5’,5’-octamethyl -2,2’- bi(1,3,2-dioxaborolane) (90 g, 0.35 mol), potassium acetate (57 g, 0.58 mol) and bis(triphenylphosphine)palladium(II) chloride (2.2 g, 3 mmol) in anhydrous dioxane (500 mL) was heated at 108°C under N2 atmosphere overnight. The reaction mixture wasconcentrated and purified by column chromatography eluted with hexanes/ethyl acetate to afford title compound R-3-2 (58 g, 84 percent). ‘H NMR (400 MHz, DMSO-d6): ö 1.30 (s, 12H), 3.88 (s, 3H), 6.81 (d, J= 8.0 Hz, 1H), 7.88 (dd, J 8.0 Hz, 2.0Hz, 1H), 8.41 (d, J2.0Hz, 1H).
3.6 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In toluene for 2 h; Inert atmosphere; Reflux	5-Bromo-2-methoxypyridine (5g, 26.59 mmol), bis(pinacolato)diborane (10.13 g, 39.89 mmol) and potassium acetate (10.44 g, 106 mmol) were taken in dry toluene (60 mL) and degassed with nitrogen for 20 mi Pd(dppf)C12.DCM (2.17 g, 2.66 mmol) was added to the reaction under nitrogen atmosphere and the resulting mixture was refluxed for 2 hr. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was cooled to 25°C and filtered through a Celite® reagent pad. Filtrate was diluted with ethyl acetate (200 mL), washed with water followed by brine, dried over Na2SO4 and concentrated under reduced pressure to provide the crude which was purified by silica gel (100-200 mesh) column chromatography using 10percent EtOAc in hexane as eluent to afford 3.6 g of 2-methoxy-5 -(4,4,5,5 -tetramethyl- [1,3 ,2]dioxaborolan-2-yl)- pyridine.

Reference： [1] Patent: US9249156, 2016, B2, . Location in patent: Page/Page column 36
[2] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 26; 28
[3] Patent: WO2014/186035, 2014, A1, . Location in patent: Page/Page column 151
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 12, p. 2496 - 2500
[5] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 19, p. 6477 - 6485
[6] Patent: CN105906557, 2016, A, . Location in patent: Paragraph 0005; 0014

6
[ 61676-62-8 ]
[ 445264-61-9 ]

Yield	Reaction Conditions	Operation in experiment
67.5%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at 20℃; for 1 h;	To a solution of 5-bromo-2-methoxy-pyridine (1.453 g, 7.73 mmol) in THF (50 mL) at -78° C. under N₂was added n-BuLi (3.4 mL, 2.5 M in hexanes, 8.5 mmol) dropwise. The mixture was stirred at -78° C. for 30 minutes, then 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.4 mL, 11.60 mmol) was added. The reaction mixture was warmed to room temperature for 1 hour, then poured into water and extracted with EtOAc. The combined extracts were washed with water and brine, dried (MgSO₄), filtered and concentrated to give 2A (1.221 g, 67.5percent) as a colorless oil.

Reference： [1] Patent: US2005/192310, 2005, A1, . Location in patent: Page/Page column 21

7
[ 1628-89-3 ]
[ 73183-34-3 ]
[ 445264-61-9 ]
[ 408502-23-8 ]

8
[ 13472-85-0 ]
[ 61676-62-8 ]
[ 445264-61-9 ]

Reference： [1] Synthesis, 2012, vol. 44, # 5, p. 735 - 746
[2] Synlett, 2009, # 15, p. 2508 - 2512

9
[ 6628-77-9 ]
[ 73183-34-3 ]
[ 445264-61-9 ]

Reference： [1] Journal of Organic Chemistry, 2013, vol. 78, # 5, p. 1923 - 1933

10
[ 1628-89-3 ]
[ 445264-61-9 ]

Reference： [1] Synthesis, 2012, vol. 44, # 5, p. 735 - 746
[2] Patent: WO2014/186035, 2014, A1,
[3] Patent: US9249156, 2016, B2,
[4] Patent: WO2018/85342, 2018, A1,

11
[ 1628-89-3 ]
[ 73183-34-3 ]
[ 445264-61-9 ]
[ 408502-23-8 ]

Reference： [1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 37, p. 7318 - 7327

12
[ 445264-61-9 ]
[ 74-88-4 ]
[ 1002309-52-5 ]

Reference： [1] Patent: WO2008/141119, 2008, A2, . Location in patent: Page/Page column 96-97

13
[ 445264-61-9 ]
[ 1339928-25-4 ]

Reference： [1] Patent: US9249156, 2016, B2,
[2] Patent: WO2018/85342, 2018, A1,

[ 445264-61-9 ] Synthesis Path-Downstream 1~88

1
[ 445264-61-9 ]
6-{1-[6-(3-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline [ No CAS ]
6-(1-{6-[3-(6-Methoxypyridin-3-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 120℃;	To a mixture of 6-{1-[6-(3-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline (16 mg, 0.036 mmol), <strong>[445264-61-9]2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (10 mg, 0.043 mmol), and potassium phosphate (30 mg, 0.14 mmol) in 1,4-dioxane (0.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (3 mg) and water (0.1 mL). The resulting mixture was heated at 120 C. overnight. The reaction mixture was cooled to RT and concentrated. The residue was dissolved in MeOH and purified by RP-HPLC (pH=10) to afford the desired compound 10 mg (60%). Analytical LCMS: (M+H)+=472.2.

Reference： [1]Patent: US2008/39457,2008,A1 .Location in patent: Page/Page column 36

3
[ 61676-62-8 ]
[ 445264-61-9 ]

Yield	Reaction Conditions	Operation in experiment
67.5%		To a solution of 5-bromo-2-methoxy-pyridine (1.453 g, 7.73 mmol) in THF (50 mL) at -78 C. under N2 was added n-BuLi (3.4 mL, 2.5 M in hexanes, 8.5 mmol) dropwise. The mixture was stirred at -78 C. for 30 minutes, then 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.4 mL, 11.60 mmol) was added. The reaction mixture was warmed to room temperature for 1 hour, then poured into water and extracted with EtOAc. The combined extracts were washed with water and brine, dried (MgSO4), filtered and concentrated to give 2A (1.221 g, 67.5%) as a colorless oil.

Reference： [1]Patent: US2005/192310,2005,A1 .Location in patent: Page/Page column 21

4
[ 445264-61-9 ]
6-Acetyl-2-chloro-3-fluoro-5,6-dihydro-pyrido[3,2-c][1]benzazocine [ No CAS ]
6-Acetyl-3-fluoro-5,6-dihydro-2-(6-methoxy-3-pyridinyl)-pyrido[3,2-c][1]benzazocine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 0.75h;	To a solution of 1D (20 mg, 0.066 mmol) in toluene (0.5 mL) and EtOH (0.3 mL) was added a 2M aqueous solution of Na2CO3 (0.3 mL, 0.6 mmol). The resulting solution was purged with argon for 30 minutes and 2A (23.3 mg, 0.099 mmol) was added, followed by a catalytic amount of Pd(PPh3)4. The reaction was heated to 100 C. for 15 minutes, then cooled to ambient temperature. EtOAc and H2O were added, the layers were separated and the organic phase was washed with saturated aqueous NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, 100% CH2Cl2 then 100% EtOAc) to afford 2B (23.7 mg, 96%). HPLC Rt=3.182 min; LCMS Found: (M+H)+=376.

Reference： [1]Patent: US2005/192310,2005,A1 .Location in patent: Page/Page column 21

5
[ 445264-61-9 ]
5-Acetyl-9-bromo-6,11-dihydro-5H-dibenzo[b,f]azocin-12-one [ No CAS ]
5-acetyl-6,11-dihydro-9-(6-methoxy-3-pyridinyl)-dibenzo[b,f]azocin-12(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 5h;	To a solution of Example 213B (10 mg, 0.03 mmol) in toluene (1 mL) was added a solution of 2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (10 mg, 0.04 mmol) in EtOH (1 mL). The reaction mixture was purged with argon. Pd(PPh3)4 (3 mg, 0.003 mmol) and Na2CO3 (45 l, 2 M solution in H2O, 0.09 mmol) were added. The mixture was heated to 80 C. for 5 hours, cooled to room temperature and concentrated. The residue was purified by flash chromatography (SiO2, 40% to 50% EtOAc/hexanes) to afford the desired product (6.8 mg, 61%). HPLC Rt=2.09(b) min. m/z=373 M+H+).

Reference： [1]Patent: US2005/250753,2005,A1 .Location in patent: Page/Page column 61-62

6
[ 445264-61-9 ]
[ 917969-63-2 ]
2-isobutyl-7-(6-methoxypyridin-3-yl)-8-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 150℃; for 0.166667h;Microwave irradiation;	Example 131 Preparation of 2-isobutyl-7-(6-methoxypyridin-3-yl)-8-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one To a stirring, degassed mixture of 7-bromo-2-isobutyl-8-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.015 g, 0.04 mmol), <strong>[445264-61-9]2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (0.04 g, 0.17 mmol), and tetrakis(triphenylphosphine)palladium (2.5 mg, 0.002 mmol) in dioxane (0.3 mL) at 20 C. was added K2CO3 (0.024 g, 0.17 mmol) in water (0.11 mL). The resulting reaction mixture was heated in a microwave reactor at 150 C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 5 mg of the title compound as a white solid. MS: [M+H]+=388.

Reference： [1]Patent: US2007/4772,2007,A1 .Location in patent: Page/Page column 68

7
[ 445264-61-9 ]
[ 74-88-4 ]
[ 1002309-52-5 ]

Yield	Reaction Conditions	Operation in experiment
	at 80℃; for 3h;	X. l-Methyl-5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridin-2(lH)-one; A mixture of 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine(235 mg, 1.00 mmol) and CH3I (426 mg, 3.00 mmol) was heated at 800C for 3 hours. The mixture was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, and evaporated to dryness to afford l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one that was directly used in next step without further purification.

Reference： [1]Patent: WO2008/141119,2008,A2 .Location in patent: Page/Page column 96-97

8
[ 445264-61-9 ]
[ 4857-06-1 ]
[ 1091605-91-2 ]

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 6667 - 6669

9
[ 445264-61-9 ]
[ 1007206-24-7 ]
[ 1007206-42-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In N,N-dimethyl-formamide; at 100℃; for 3h;	Example 1-B-10 4-(6-Methoxy-pyridin-3-yl)-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (B-10) [Show Image] To 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (20 mg, 0.0629 mmol), <strong>[445264-61-9]2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (29.6 mg, 0.126 mmol), palladium acetate (1.4 mg, 0.00630 mmol), S-Phos (5.2 mg, 0.0126 mmol) and potassium phosphate (26.7 mg, 0.126 mmol), dimethylformamide (1 ml) was added, followed by being degassed under ultrasonic irradiation. This was stirred at 100C for 3 hours, followed by extraction with ethyl acetate with the addition of water, and the organic layer was washed with brine. After drying over anhydrous sodium sulfate, concentration was carried out under reduced pressure, followed by elution with 2M ammonia methanol solution through SCX resin and then concentration. Purification by silica gel column chromatography (chloroform) afforded the desired compound as a yellow powder. 1H-NMR (CDCl3) delta: 9.11 (1H, d, J=2.5Hz), 8.72 (1H, d, J=2.3Hz), 8.30 (1H, dd, J=4.5, 1.3 Hz), 8.23 (1H, dd, J=8.9, 2.5Hz), 8.15 (1H, dq, J=8.4, 1.3 Hz), 7.32 (1H, dd, J=8.4, 4.5Hz), 6.85 (1H, d, J=8.9 Hz), 4.11 (2H, t, J=8.2Hz), 4.00 (3H, s), 3.87-3.78 (8H, m), 3.36 (2H, t, J=8.2Hz). ESI (LC-MS positive mode) m/z 391 ([M+H]+).

Reference： [1]Patent: EP2050749,2009,A1 .Location in patent: Page/Page column 152-153

10
[ 13472-85-0 ]
[ 61676-62-8 ]
[ 445264-61-9 ]

Reference： [1]Synthesis,2012,vol. 44,p. 735 - 746
[2]Synlett,2009,p. 2508 - 2512

11
[ 445264-61-9 ]
[ 947248-68-2 ]
[ 1244059-54-8 ]

Yield	Reaction Conditions	Operation in experiment
48%	With cesium fluoride;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 85℃; for 48h;	Step 3) Formation of6-(5-methoxypyridin-3-yl)[1,2,4]triazolo[1,5-a]pyridin-2-amine A mixture of 6-bromo[1 ,2,4]triazolo[1 ,5-a]pyridin-2-amine (200 mg; 0.94 mmol), 3- methoxypyridine-5-boronic acid pinacol ester (287 mg; 1.22 mmol), PdCI2(PPh3J2 (66 mg; 0.09 mmol), cesium fluoride (357 mg; 2.35 mmol) in dioxane (4 ml_) and water (2 mL) was stirred at 85C for 2 days. After concentration in vacuo, the residue was triturated in water, filtered and dried to afford the title compound (235 mg, quantitative yield) as a brown solid. LC/MS, M+(ESI): 242.1.

Reference： [1]Patent: WO2010/100144,2010,A1 .Location in patent: Page/Page column 165

12
[ 445264-61-9 ]
[ 1206907-38-1 ]
[ 1261352-07-1 ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 5628 - 5634

13
[ 445264-61-9 ]
[ 1272353-93-1 ]
[ 1272354-52-5 ]

Yield	Reaction Conditions	Operation in experiment
	tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere;	To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4- amine (200 mg, 0.58 mmol) in DMF (10 mL) and Iota¾0 (2 mL) under nitrogen was added 6-methoxypyridin-3-ylboronic acid pinacol ester (202 mg, 0.86 mmol) and potassium carbonate (160 mg, 1.16 mmol). Upon completion of addition, the mixture was degassed with nitrogen for 15 min and then tetrakis(triphenylphosphine)- palladium (66 mg, 0.0050 mmol) was added. The mixture was again degassed with nitrogen for 10 min. After this time, the reaction mixture was heated to 90 C where it stirred for 12h. The reaction mixture was then allowed to cool to room temperature and then quenched by the addition of water. The reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography using 16% ethyl acetate in petroleum ether to afford 2-(6- methoxypyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (140 mg) as a brown solid. XH NMR (400 MHz, DMSO-d6) delta (ppm): 9.26 (d, J= 2.4 Hz, 1H), 8.70-8.67 (dd, J= 8.8, 2.4 Hz, 1H), 8.23-8.22 (d, J= 5.2 Hz, 1H), 7.84-7.76 (m, 2H), 7.73-7.69 (dt, J= 8.0, 2.0 Hz, 1H), 7.58-7.48 (m, 5H), 7.32-7.30 (d, J= 7.6 Hz, 1H), 7.25-7.23 (m, 2H), 6.95-6.93 (d, J= 8.8 Hz, 1H), 6.81-6.79 (t, J= 4.0 Hz, 1H), 4.72- 4.71 (d, J= 4.0 Hz, 2H), 3.94 (s, 3H). LCMS Method S: retention time 3.96 min, [M+l] = 420.2. HPLC Method B: purity 98.9%, retention time 8.93 min.

Reference： [1]Patent: WO2011/28741,2011,A1 .Location in patent: Page/Page column 224-225

14
[ 445264-61-9 ]
[ 1021913-05-2 ]
C₂₇H₃₁BrClN₃O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2351 - 2358

15
[ 445264-61-9 ]
[ 1339925-42-6 ]
[ 1339925-49-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; dimethyl sulfoxide; at 120℃; for 4h;	Step 96a: (E)-Methyl 3-(3-(N-(2-(6-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d] pyrimidin-6-yl)sulfamoyl)phenyl)acrylate (Compound 1008-221)To a stirred mixture of 1007-218 (300 mg, 0.61 mmol) and 0602-221 (287 mg, 1.22 mmol) in DMSO (20 mL) was added Pd(PPh3)4 (36.7 mg, 0.032 mmol) and saturated aq. NaHC03 (2 mL). The resulting mixture was heated at 120 C for 4h. To the reaction mixture was added water and adjusted to pH = 6-7 with acetic acid. The precipitate was collected by filtration. The crude product was purified by column chromatography to afford the titled compound 1008-221 as a yellow solid (250 mg, yield 72%).1H NMR (400 MHz, DMSO-d6): delta 3.71(s, 3H), 3.76 (t, J= 4.4 Hz, 4H), 3.92-3.98 (m, 7H), 6.68 (d, J= 16.0 Hz, 1H), 6.97 (d, J= 8.8 Hz, 1H), 7.52-7.60 (m, 2H), 7.73 (d, J= 16.0 Hz,1H), 7.85 (d, J= 8.0 Hz, 1H), 7.94 (d, J= 5.4 Hz, 1H), 8.10 (s, 1H), 8.43-8.46 (m, 1H),9.02(s, 1H).
72%	With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In water; dimethyl sulfoxide; at 120℃; for 4h;	Step 96a: (E)-Methyl 3-(3-(N-(2-(6-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)sulfamoyl)phenyl)acrylate (Compound 1008-221)[0633]To a stirred mixture of 1007-218 (300 mg, 0.61 mmol) and 0602-221 (287 mg, 1.22 mmol) in DMSO (20 mL) was added Pd(PPh3)4 (36.7 mg, 0.032 mmol) and saturated aq. NaHCO3 (2 mL). The resulting mixture was heated at 120 C. for 4 h. To the reaction mixture was added water and adjusted to pH=6-7 with acetic acid. The precipitate was collected by filtration. The crude product was purified by column chromatography to afford the titled compound 1008-221 as a yellow solid (250 mg, yield 72%).[0634]1H NMR (400 MHz, DMSO-d6): delta 3.71 (s, 3H), 3.76 (t, J=4.4 Hz, 4H), 3.92-3.98 (m, 7H), 6.68 (d, J=16.0 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 7.52-7.60 (m, 2H), 7.73 (d, J=16.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.94 (d, J=5.4 Hz, 1H), 8.10 (s, 1H), 8.43-8.46 (m, 1H), 9.02 (s, 1H).

Reference： [1]Patent: WO2011/130628,2011,A1 .Location in patent: Page/Page column 240
[2]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0632; 0633; 0634

16
N-[(3S,3aS)-7-bromo-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl]methyl}acetamide [ No CAS ]
[ 445264-61-9 ]
[ 1341208-74-9 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7493 - 7502

17
[ 1628-89-3 ]
[ 445264-61-9 ]

Reference： [1]Synthesis,2012,vol. 44,p. 735 - 746
[2]Patent: WO2014/186035,2014,A1
[3]Patent: US9249156,2016,B2
[4]Patent: WO2018/85342,2018,A1
[5]Patent: US2020/78364,2020,A1

18
2-amino-6-bromo-4-methyl-8-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]
[ 445264-61-9 ]
2-amino-6-(6-methoxypyridin-3-yl)-4-methyl-8-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5098 - 5103

19
[ 445264-61-9 ]
[ 1322744-73-9 ]
[ 1322744-71-7 ]

Yield	Reaction Conditions	Operation in experiment
51%	With sodium carbonate;palladium diacetate; triphenylphosphine; In 1,4-dioxane; water; at 95℃; for 2.5h;Inert atmosphere;	The compound (13) was synthesized as in the following scheme. Specifically, 1.21 g (0.0021 mol, the compound (b)) of 1-bromo-4-[(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)sulfonyl]benzene, 0.5 g (0.0021 mol) of <strong>[445264-61-9]2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong>, 40 mL of a 2M sodium carbonate aqueous solution, and 40 mL of 1,4-dioxane were added to a 100-mL round-bottomed flask in a nitrogen atmosphere. Triphenylphosphine (0.34 g, 0.0013 mol) and palladium acetate (0.0754 g, 0.00034 mol) were further added thereto, and the mixture was vigorously stirred at 95C for 2.5 hours. After the flask atmosphere was returned to the air atmosphere, 50 mL of water was added thereto at room temperature, and stirred for 30 min to cool the interior. After the completion of the reaction, a solid was observed in the flask, and ethyl acetate was added to dissolve the solid. The content was transferred to a separating funnel; after a water phase was removed, an organic phase was washed three times with 1 M hydrochloric acid, and washed once with water and with brine each. Magnesium sulfate was added thereto to dry the organic phase, and magnesium sulfate was removed by filtration. A filtrate was concentrated by an evaporator, and purified by silica gel column chromatography; and the recrystallization was carried out with ethanol to obtain 0.64 g of a solid (yield: 51%). [Show Image] The structure of the obtained compound (13) was identified by IR (KBr) and 1H-NMR (CDCl3). The results were as follows. IR (KBr) v=1138.0, 1151.5, 1197.8, 1209.4, 1234.4, 1294.2, 1485.2, 1606.7 cm-1 1H-NMR (CDCl3) 2.24 (2H, m), 3.36 (2H, m), 4.01 (3H, s), 6.88 (1H, d, J=8.5 Hz), 7.76 (2H, d, J=8.5 Hz), 7.83 (1H, dd, J=8.5 Hz, 2.5 Hz), 8.00 (2H,d, J=8.5 Hz), 8.45 (1H, d, J=2.5 Hz) ppm

Reference： [1]Patent: EP2535328,2012,A1 .Location in patent: Page/Page column 15-16

20
[ 445264-61-9 ]
[ 1314141-62-2 ]
[ 1314141-63-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tri-1-napthylphosphine; palladium dichloride; In tetrahydrofuran; at 140℃; for 0.5h;Microwave;	In a microwave vial containing the above compound (04) (0.10 g, 0.23 mmol), 2,6-dimethoxy-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.11 g, 0.46 mmol), potassium carbonate (0.10 g, 0.69 mmol), palladium dichloride (2 mg, 0.01 mmol), and tri(l-naphthyl)phosphine (5 mg, 0.01 mmol) was added 1.2 mL THF. The reaction mixture was heated in the microwave at 140 C for 30 minutes, quenched with water, and extracted with ethyl acetate. The organic portion was dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford N- [(3R,4S)-3~ { [fert-butyl(dimethyl)silyl] oxy } tetrahydro-2H-pyran-4-yl] A~ [hydroxy(6- methoxypyridin-3-yl)methyl]quinoline-2-carboxamide (05) that gave a mass ion (ES+) of 524.5 for M+H+.

Reference： [1]Patent: WO2011/84368,2011,A1 .Location in patent: Page/Page column 62

21
[ 6628-77-9 ]
[ 73183-34-3 ]
[ 445264-61-9 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 1923 - 1933

22
[ 445264-61-9 ]
[ 1431542-53-8 ]
[ 1431541-99-9 ]

Yield	Reaction Conditions	Operation in experiment
48 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.166667h;Microwave irradiation; Inert atmosphere;	To a mixture of 1-{4-[3-(6-bromo-quinazolin-4-yl)-5-trifluoromethyl-benzoyl]-piperazin-1-yl}- ethanone (120 mg, 0.19 mmol, 80%purity(HPLC)), 2-methoxy-5-pyridine boronic acid (34.9mg, 0.228 mmol) and Pd(PPh3)4 (10.98 mg, 0.009 mmol) was added 2 mL of Acetonitrile. The reaction mixture was flushed with argon and a 1 M aqueous solution of Na2C03 (0.380 mL, 0.380 mmol) was added and the vial capped. The reaction mixture was heated to 120C for 10 min using a microwave oven then cooled down to rt, diluted with EtOAc, filtered through a Celite pad and washed with EtOAc. The filtrate was concentrated. Purification by preparative reverse phase Gilson HPLC and subsequent neutralization of the combined fractions over PL-S03H MP gave the title compound (48 mg, 47% yield) as a white powder. 1 H-NMR (400 MHz, DMSO-d6, 298 K): ? ppm 1 .91 - 2.03 (br.s., 3 H) 3.36 - 3.70 (m, 8 H) 3.91 (s, 3 H) 6.98 (d, 1 H) 8.06 (br.s., 1 H) 8.14 (d, 1 H) 8.25 (d, 3 H) 8.30 (br.s., 1 H) 8.44 (d, 1 H) 8.63 (br.s., 1 H) 9.42 (s, 1 H). MS: 536.6 [M+1]+, Rt(2) = 1 .18 min.

Reference： [1]Patent: WO2013/57711,2013,A1 .Location in patent: Page/Page column 125-126

23
[ 445264-61-9 ]
[ 1431542-29-8 ]
[ 1431542-43-6 ]

Yield	Reaction Conditions	Operation in experiment
800 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.25h;Microwave irradiation; Inert atmosphere;	To a mixture of 3-(6-bromo-quinazolin-4-yl)-benzoic acid ethyl ester (845 mg, 2.176 mmol), 2-methoxy-5-pyridineboronic acid (399 mg, 2.61 mmol) and Pd(PPh3)4 (126 mg, 0.109 mmol) was added 20 mL of DME. The reaction mixture was flushed with argon and a 1 M aqueous solution of Na2C03 (4.35 mL, 4.35 mmol) was added and the vial capped. The reaction mixture was heated to 120C for 15 min using a microwave oven then cooled down to rt, diluted with CH2CI2, filtered through a Celite pad and portioned between brine/ CH2CI2. The organic layer was washed with brine, dried over MgS04, filtered and evaporated. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5) gave the title compound (800 mg, 92% purity, 88% yield). MS: 386.5 [M+1]+, Rt(2) = 1 .45 min.

Reference： [1]Patent: WO2013/57711,2013,A1 .Location in patent: Page/Page column 114-115

24
[ 445264-61-9 ]
[ 1431542-39-0 ]
[ 1431542-41-4 ]

Yield	Reaction Conditions	Operation in experiment
910 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.333333h;Microwave irradiation; Inert atmosphere;	To a mixture of [5-(6-bromo-quinazolin-4-yl)-nicotinic acid ethyl ester (1 g, 2.79 mmol), 2- methoxy-5-pyridin boronic acid (0.448 g, 2.93 mmol) and Pd(PPh3)4 (0.161 mg, 0.140 mmol) was added 15 mL of DME. The reaction mixture was flushed with argon and a 1 M aqueous solution of Na2C03 (5.58 mL, 5.58 mmol) was added and the vial capped. The reaction mixture was heated to 120C for 20min using a microwave oven then cooled down to rt, diluted with EtOAc, filtered through a Celite pad and portioned between H20/EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and evaporated. The residue gave the title compound (910 mg, 93% purity, 78% yield). 1H-NMR (400 MHz, DMSO-d6, 298 K): ? ppm 1 .37 (t, 3 H) 3.91 (s, 3 H) 4.42 (q, 2 H) 6.96 (d, 1 H) 8.14 (dd, 1 H) 8.23-8.25 (m, 2 H) 8.43 (dd, 1 H) 8.62 (d, 1 H) 8.72 (t, 1 H) 9.31 (dd, 2 H) 9.43 (s, 1 H). MS: 387.1 [M+1]+, Rt(2) = 1 .24 min.

Reference： [1]Patent: WO2013/57711,2013,A1 .Location in patent: Page/Page column 105-106

25
[ 445264-61-9 ]
[ 1339925-83-5 ]
[ 1339925-90-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate; In ethanol; water; toluene; at 120℃;Inert atmosphere;	Step 104a: 6-{tert-Butoxycarbonyl-[2-(6-methoxy-pyridin-3-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-amino}-hexanoic acid ethyl ester (Compound 1103-233)[0668]A mixture of compound 1102-232 (200 mg, 0.39 mmol), 0602-221 (183 mg, 0.78 mmol), NaHCO3 (98 mg, 1.17 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.039 mmol) in toluene (14 mL), ethanol (8.8 mL) and water (3.5 mL) was flushed with nitrogen and heated at 120 C. overnight. The reaction mixture was concentrated and partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4. The crude product was purified by column chromatography eluted with dichloromethane/EtOAc to afford the titled compound 1103-233 as a white solid (200 mg, 88%). LCMS: 586.2 [M+1]+.

Reference： [1]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0667; 0668

26
[ 445264-61-9 ]
[ 1469858-46-5 ]
[ 1469858-56-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; toluene; at 100℃; for 8h;	A mixture of the corresponding 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.68 g, 1.4 mmol), 2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.33 g, 2.1 mmol), Na2CO3 (2 M, 3.3 mL), and Pd(PPh3)2Cl2 (13 mg, 1.1 mmol) in toluene/ ethanol (1:1, 8 mL) was heated at 100 C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-(6-methoxy-pyridin-3-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 75% yield.
75%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; toluene; at 100℃; for 8h;	The corresponding intermediate 2-bromo-6- (4-methoxy-phenyl) -4- (2-trimethylsilane-ethoxymethyl) -4,7-dihydro- 4,5-diazo-cyclopenta [a] cyclopentadiene (0.76 g, 1.5 mmol)2-methoxy-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridine(0.33 g, 2.1 mmol), Na2CO3 (2 M, 3.3 mL) and Pd (PPh3) 2Cl2 (13 mg, 1.1 mmol) in toluene / ethanol (1: 1, 8.0 mL) was heated to 100 C 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The title product was obtained as an orange solid by gravity column chromatography (20% EtOAc in hexanes)6- (4-Methoxy-phenyl) -2- (6-methoxy-pyridin-3-yl) -4- (2-trimethylsilane-ethoxymethyl) Dihydro-1-thio-4,5-diazo-cyclopenta [a] cyclopentadiene, 75% yield.

Reference： [1]Patent: US2013/274255,2013,A1 .Location in patent: Paragraph 0377
[2]Patent: TWI553010,2016,B .Location in patent: Page/Page column 103; 104

27
[ 445264-61-9 ]
[ 1548343-79-8 ]
[ 1548335-71-2 ]

Yield	Reaction Conditions	Operation in experiment
56%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 130℃; for 3h;Inert atmosphere;	Compound 108 (lS,)-2-(l-(6-amino-5-(6-methoxypyridin-3-yl)pyrimidin-4-yl)azetidin-2-yl)-5-chloro- 3-phenylpyrrolo [1,2-f] [1 ,2,4] triazin-4(3H)-one Scheme Compound 1 08 A mixture of 15a (50 mg, 0.106 mmol) (15a was prepared according to the procedure of Example 1), 2-methoxy-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (28 mg, 0.116 mmol), Pd(dppf)2Cl2 (9 mg, 0.0106 mmol) and Na2C03 (23 mg, 0.212 mmol) in dioxane (20 mL) and water (2 mL) was heated at 130 C under N2 atmosphere for 3 hours. Then the mixture was filtered, concentrated and purified by flash column chromatography eluting with MeOH/water to give Compound 108 as a white solid (30 mg, yield: 56%). MS (m/z): 500.6 (M+H)+. 1H NMR (400 MHz, DMSO-d6) delta: 8.18-7.39 (m, 8H), 7.29 (d, / = 6.4 Hz, 2H), 6.73-6.57 (m, 1H), 5.82 (s, 2H), 4.55-4.45 (m, 1H), 3.81 (s, 3H), 3.22-3.08 (m, 2H), 2.29-2.19 (m, 1H), 1.80-1.70 (m, 1H).
56%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 130℃; for 3h;Inert atmosphere;	A mixture of 14b (0.132 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5- carbonitrile (24 mg, 0.132 mmol) and TEA (0.09 mL, 0.66 mmol) in n-BuOH (10 mL) was heated at reflux for 2 hours. The reaction mixture was concentrated purified by flash column chromatography eluting with MeOH/water to afford compound 107 as a slight yellow solid (17 mg, yield: 31%). MS (m/z): 420.7 (M+H)+. 1H-NMR (400 MHz, DMSO-d6) delta: 8.29 (s, 1H), 8.03 (s, 1H), 6.77 (t, J= 5.1 Hz, 1H), 6.16 (t, J= 4.0 Hz, 1H), 5.50 (m, 1H), 4.26 (m, 1H), 4.15 - 4.08 (m, 2H), 3.69 (m, 1H), 2.37 - 2.01 (m, 5H), 1.00 (d, J= 6.6 Hz, 3H), 0.93 (d, J= 6.5 Hz, 3H).
56%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 130℃; for 3h;Inert atmosphere;	A mixture of 14b (0.132 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5- carbonitrile (24 mg, 0.132 mmol) and TEA (0.09 mL, 0.66 mmol) in n-BuOH (10 mL) was heated at reflux for 2 hours. The reaction mixture was concentrated purified by flash column chromatography eluting with MeOH/water to afford compound 107 as a slight yellow solid (17 mg, yield: 31%). MS (m/z): 420.7 (M+H)+. 1H NMR (400 MHz, DMSO-d6) delta: 8.18-7.39 (m, 8H), 7.29 (d, J = 6.4 Hz, 2H), 6.73-6.57 (m, 1H), 5.82 (s, 2H), 4.55-4.45 (m, 1H), 3.81 (s, 3H), 3.22-3.08 (m, 2H), 2.29-2.19 (m, 1H), 1.80-1.70 (m, 1H).

Reference： [1]Patent: WO2014/15675,2014,A1 .Location in patent: Page/Page column 122; 123
[2]Patent: WO2014/15523,2014,A1 .Location in patent: Page/Page column 95; 96
[3]Patent: WO2014/15830,2014,A1 .Location in patent: Page/Page column 121

28
[ 445264-61-9 ]
[ 1403396-20-2 ]
[ 1403396-70-2 ]

Yield	Reaction Conditions	Operation in experiment
37%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 1.5h;Microwave irradiation;	A solution of the compound (508 mg, 1.0 mmol) obtained in Example 16-4), 2-methoxypyridine-5-boronic acid pinacol ester (352 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130C for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate = 0:100 to 20:80, gradient) to obtain the title compound (200 mg, 37%) as a light yellow oily substance. 1H-NMR (500 MHz, CDCl3) delta: 0.05 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.19 (3H, s), 1.42-1.46 (1H, m), 1.47-1.51 (1H, m), 1.55-1.59 (1H, m), 1.64-1.68 (1H, m), 2.55 (1H, ddd, J = 15.6, 7.8, 2.4 Hz), 2.70 (1H, ddd, J = 15.6, 8.1, 1.7 Hz), 3.40 (2H, s), 3.51 (1H, d, J = 9.8 Hz), 3.55 (1H, d, J = 9.8 Hz), 3.97 (3H, s), 4.09 (1H, ddd, J = 14.4, 8.1, 1.7 Hz), 4.33 (1H, ddd, J = 14.4, 7.8, 2.4 Hz), 6.81 (1H, d, J = 8.3 Hz), 7.15 (2H, d, J = 8.3 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.75 (1H, dd, J = 8.3, 2.4 Hz), 8.35 (1H, d, J = 2.4 Hz)

Reference： [1]Patent: EP2700643,2014,A1 .Location in patent: Paragraph 0333

29
[ 1628-89-3 ]
[ 73183-34-3 ]
[ 445264-61-9 ]
[ 408502-23-8 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine; In tetrahydrofuran; at 80℃; for 19h;Inert atmosphere; Glovebox;	Example 4Borylation of PyridinesBorylation of 2-MethoxypyridineAn oven-dried 3 mL screw-cap Wheaton vial was charged inside a nitrogen-filled glovebox with [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol) and dtbpy (2.7 mg, 0.01 mmol). THF (1.5 mL) was added, followed B2pin2 (127 mg, 0.5 mmol) and 2-methoxypyridine (105 muL, 1.0 mmol). The vial was capped and heated outside of the glovebox at 80 C. for 19 h. The reaction solvent was removed on a rotary evaporator, and the residue was purified by flash column chromatography using hexanes-EtOAc mixtures as eluent providing a 1:1.4 mixture of 4- and 5-Bpin isomers, 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, as a colorless oil (153 mg, 67%): 1H NMR (300 MHz, CDCl3) delta 8.55 (s, 1H, Hd), 8.18 (d, J=5.1 Hz, 1H, Ha), 7.95 (dd, J=8.4, 1.8 Hz, 1H, He), 7.25-7.12 (m, 2H, Hb and He), 6.73 (d, 8.4 Hz, 1H, Hf), 3.99 (s, 3H, 5-Bpin isomer), 3.96 (s, 3H, 4-Bpin isomer), 1.32 (s, 12H, 4-Bpin isomer), 1.31 (s, 12H, 5-Bpin isomer)
	With (iPrPNP)CoCH2SiMe3; In tetrahydrofuran; at 80℃; for 24h;	EXAMPLE 10 - Borylation of Aromatic Six-Membered Heterocycle According to the reaction scheme illustrated in Figure 3, various pyridines underwent borylation with bis(pinacolato)diboron [B2Pin2] in the presence of bis(diisopropylphosphine) cobalt trimethylsilylmethane. Condition A employed 0.5 equiv. of B2Pin2 and Condition B employed 1.0 equiv. of B2Pin2. Reported numbers are percent conversions of the corresponding pyridine derivative determined by GC analysis using mesitylene as an internal standard. Values in parenthesis are isolated yield. Product ratios were determined by NMR analysis. Values under the percent conversions are selectivities, and the number in parenthesis denote the position of borylation. Selectivities were the same for Conditions A and B.

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4133 - 4136
[2]Organic and Biomolecular Chemistry,2014,vol. 12,p. 7318 - 7327
[3]Patent: US2015/65743,2015,A1 .Location in patent: Paragraph 0372; 0373
[4]Patent: WO2015/89119,2015,A1 .Location in patent: Page/Page column 34

30
[ 1628-89-3 ]
[ 73183-34-3 ]
[ 445264-61-9 ]
C₁₈H₂₉B₂NO₅ [ No CAS ]
C₁₈H₂₉B₂NO₅ [ No CAS ]
[ 408502-23-8 ]

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

31
[ 445264-61-9 ]
rac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl trifluoromethanesulfonate [ No CAS ]
rac-1-((2S_.3R_.4R)-2-cyclopropyl-6-(6-methoxypyridin-3-yl)-3-methyl-4-(phenylamino)-3.4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	A mixture of rac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahyd ro- 1,5-naphthyridin-2-yl trifluoromethanesulfonate (for a preparation see Intermediate 102, 75 mg, 0.160mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (45.1 mg, 0.192 mmol), PdCI2(dppf) (17.53 mg, 0.024 mmol) and potassium carbonate (66.2 mg, 0.479 mmol) in I ,4-dioxane (1 .4 mL) and water (0.35 mL) was stirred under nitrogen at 100 C for I h. The reaction mixture was allowed to cool then concentrated in vacuo. The sample was diluted with DCM (7 mL), washed withwater (3x1 0 mL) and dried through a hydrophobic frit. The solution was applied to a 5 g Flash SCX SPE column which had been pre-equilibriated with MeOH. The column was flushed with MeOH then with MeOH/NH3 (2 M). The MeOH/NH3 fraction was collected and the solvent was evaporated to give a brown gum. The sample was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (HpH). The solvent was evaporated in vacuo to give the product (25.1 mg, 0.059 mmol, 37%) as aclear gum. LCMS (2 mm Formic): Rt = 1 .27 mi [MH] = 429.

Reference： [1]Patent: WO2014/140076,2014,A1 .Location in patent: Page/Page column 291

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(+/-)-1-phenyl-6,7,10,10a-tetrahydro-3H-pyrido[1,2-a]azepin-4-one [ No CAS ]

Reference： [1]Tetrahedron,2014,vol. 70,p. 8624 - 8635
[2]Tetrahedron,2014,vol. 70,p. 8624 - 8635

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[ 76053-45-7 ]