[ CAS No. 321724-19-0 ] {[proInfo.proName]}

Name: 321724-19-0|5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine|97%
Brand: Ambeed
SKU: A153887
Price: 7.0 USD
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Quality Control of [ 321724-19-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 321724-19-0 ]

SDS Specification

Alternatived Products of [ 321724-19-0 ]

Product Details of [ 321724-19-0 ]

CAS No. :	321724-19-0	MDL No. :	MFCD05155223
Formula :	C₁₀H₁₅BN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WSRGGSAGSUEJKQ-UHFFFAOYSA-N
M.W :	206.05	Pubchem ID :	4192667
Synonyms :		Chemical Name :	5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

Calculated chemistry of [ 321724-19-0 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.6
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	58.51
TPSA :	44.24 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.71 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.19
Log Po/w (WLOGP) :	0.78
Log Po/w (MLOGP) :	-0.15
Log Po/w (SILICOS-IT) :	0.79
Consensus Log Po/w :	0.52

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.1
Solubility :	1.65 mg/ml ; 0.00799 mol/l
Class :	Soluble
Log S (Ali) :	-1.72
Solubility :	3.97 mg/ml ; 0.0193 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.26
Solubility :	0.114 mg/ml ; 0.000553 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.75

Safety of [ 321724-19-0 ]

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 [ 321724-19-0 ]

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

Upstream synthesis route of [ 321724-19-0 ]
Downstream synthetic route of [ 321724-19-0 ]

[ 321724-19-0 ] Synthesis Path-Upstream 1~2

1
[ 4595-59-9 ]
[ 73183-34-3 ]
[ 321724-19-0 ]

Reference： [1] Patent: WO2008/88881, 2008, A1, . Location in patent: Page/Page column 38
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 12, p. 5053 - 5074

2
[ 289-95-2 ]
[ 73183-34-3 ]
[ 321724-19-0 ]

Reference： [1] Journal of the American Chemical Society, 2014, vol. 136, # 11, p. 4287 - 4299

[ 321724-19-0 ] Synthesis Path-Downstream 1~78

1
[ 321724-19-0 ]
3,5-dibromo-1-(3-pyridyl)benzene [ No CAS ]
[ 363134-71-8 ]

Reference： [1]Angewandte Chemie - International Edition,2001,vol. 40,p. 2620 - 2622

2
[ 106-37-6 ]
[ 321724-19-0 ]
[ 174303-53-8 ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 9260 - 9261

3
[ 550999-07-0 ]
[ 321724-19-0 ]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(5-pyrimidinyl)-1-benzofuran-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); water; at 90℃;	Zu einer Mischung aus [250] mg (0.72 mmol) N [ (3R)-1-Azabicyclo [2.2. 2] [OCT-3-YL]-5-] brom-l-benzofuran-2-carboxamid (Beispiel [3Ae)] und 52 mg (0.07 mmol) [PDCL2] (dppf) in 3 mL DMF werden 177 mg (0.86 mmol) [5- (4,] 4,5, [5-TETRAMETHYL-1,] 3,2-dioxa- borolan-2-yl) -pyrimidin und 2.15 mL 1 N Natronlauge gegeben. Das Reaktion- gemisch wird ueber Nacht auf [90C] erhitzt. Das Solvens wird unter reduziertem Druck entfernt und das Rohprodukt in Methanol aufgenommen und ueber Kieselgur filtriert. Die Reinigung erfolgt durch praeparative HPLC. Das Produkt wird in Methanol geloest und mit einem Ueberschuss an 1 N Salzsaeure versetzt. Das Loesungs- mittel wird unter reduziertem Druck entfernt. Nach Umkristallisieren des Rueckstands - aus Isopropanol und Trocknen im Hochvakuum werden 28 mg (10 % d. Th. ) der Titelverbindung erhalten. [LH-NMR] (300 MHz, DMSO-d6) : 8 [= 10.] 30 (s, [1H),] 9.22-9. 13 (m, 4H), 8.24 (m, 1H), 7.93-7. 81 (m, 3H), 4.39 (m, [1H),] 3.68-3. 48 (m, [1H),] 3.45-3. 13 (m, 5H), 2.28-2. 20 (m, 1H), 2.18-2. 07 [(M,] [1H),] 1.97-1. 88 (m, 2H), 1.80-1. 57 (m, 1H). HPLC (Methode [1)] : Rt = 3.26 min. MS (ESIpos) : [M/Z] = 349 (M+H) [+] (freie Base).

Reference： [1]Patent: WO2003/104227,2003,A1 .Location in patent: Page 154

4
[ 569658-00-0 ]
[ 321724-19-0 ]
[ 637039-39-5 ]

Yield	Reaction Conditions	Operation in experiment
8%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); dichloromethane; at 120℃; for 12.0h;	100 mg (0.253 mmol) der Verbindung Beispiel XI werden in 10 ml Dimethyl- formamid vorgelegt und mit 350 mg (2.53 mmol) Kaliumcarbonat versetzt. Es werden 52.13 mg (2.53 mmol) [5- (4,] 4,5, 5-Tetramethyl-1, 3,2-dioxaborolan-2-yl) pyri- midin und 20.7 mg (0.025 mmol) [L,] [LAPOS;-BIS] (diphenylphosphin) ferrocen-dichlor- palladium (II)-komplex mit Dichlormethan im Argongegenstrom zugegeben. Die Reaktionsloesung faerbt sich nach kurzer Zeit schwarz. Es wird ueber Nacht bei [120°C] geruehrt. Nach dem Abkuehlen wird das Reaktionsgemisch mit ca. 30 ml Ethylacetat verduennt und mit Wasser extrahiert. Die waessrige Phase wird noch zweimal mit 20ml Ethylacetat extrahiert. Die organische Phase wird einmal mit gesaettigter Natriumchloridloesung gewaschen, ueber Natriumsulfat getrocknet und im Vakuum eingeengt. Der Rueckstand wird ueber Kieselgel 60 (Laufmittel : Dichlormethan- Methanol 20 : 1) und anschliessend ueber eine praeparative HPLC gereinigt. Man erhaelt 9 mg (8percent d. Th. ) des Produktes. 'H-NMR (400 MHz, DMSO-d6) : [8] [=] 6.66 (s, 1H), 7.33 (d, 2H), 7.55-7. 65 (m, 2H), 8.40 (dd, 1H), 8.50 (br. s, 2H), 9.25 (s, 2H), 9.32 (s, 1H), 10.26 (br. s, 1H) MS (ESIpos) : m/z = 392 [(M+H) +] HPLC (Methode [1)] : [RT=] 3.53 min

Reference： [1]Patent: WO2003/106450,2003,A1 .Location in patent: Page column 78,79

5
[ 691906-29-3 ]
[ 321724-19-0 ]
[ 691906-30-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 95℃; for 24.0h;	To the above tert-butyl ester (2.0 g) in degassed dimethoxyethane (30 mL) was added 5- (4,4, 5, 5,-TETRAMETHYL- [1, 3,2] dioxaborolan-2-yl) -pyrimidine (1.2 g), K2CO3 (1. 61 g), and PDCL2 (DPPF) CH2CL2 (0.24 g). The reaction was heated to 95 °C for 24 h then cooled to room temperature and the volatiles were removed. The residue was diluted in CH2C12 and washed with H20. The organic layers were combined, dried (NA2S04), filtered and concentrated. The resultant residue was purified by silica gel chromatography to afford (S)-1- [ (R)-7- (3, 5-DICHLORO-PHENYL)-5-METHYL-6-OXO-5- (4-PYRIMIDIN-5-YL-BENZYL)-6, 7- DIHYDRO-5H-IMIDAZO [1, 2-A] IMIDAZOLE-3-SULFONYL]-PYRROLIDINE-2-CARBOXYLIC acid tert-butyl ester (1.5 g).

Reference： [1]Patent: WO2004/41273,2004,A1 .Location in patent: Page/Page column 37-39

6
[ 321724-19-0 ]
[ 402960-40-1 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 14 N-(((5S)-3-(3-fluoro-4-(pyrimidin-5-ylethynyl)phenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide The desired product was prepared as in Example 13 with substitution of <strong>[321724-19-0]5-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-pyrimidine</strong> (38.7 mg, prepared according to the procedure described in Tetrahedron Letters, 1997, 38, 3447-3450), for 5-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-pyrimidin-2-ylamine. MS (ESI(+)) m/e 355 (M+H)+; 1H NMR (300 MHz, MeOH) delta 9.11 (s, 1H), 8.93 (s, 2H), 7.65 (dd, J=2.1, 12 Hz, 1H), 7.62 (t, J=8.4 Hz, 1H), 7.38 (dd, J=2.1, 8.4 Hz, 1H), 4.8 (m, 1H), 4.18 (t, J=9 Hz, 1H), 3.85 (dd, J=6.3, 9.6 Hz, 1H), 3.57(d, J=5.4 Hz, 2H), 1.96 (s, 3H).

Reference： [1]Patent: US2002/45625,2002,A1

7
[ 321724-19-0 ]
2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-6-pyrimidin-5-yl-benzothiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.5%		Example 19 2-[2-(2-(R)-Methyl-pyrrolidin-1-yl)-ethyl]-6-pyrimidin-5-yl-benzothiazole The title compound was prepared according to the procedure described in Example 12F, but substituting <strong>[321724-19-0]5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine</strong> for 3-pyridinyl boronic acid. The crude product was purified by column chromatography on silica gel, eluding with 10:90 MeOH:CHCl3, to afford the title compound (63.5percent yield). 1H NMR (CDCl3, 400 MHz) delta 1.15 (delta, 3H, J=8 Hz), 1.41-1.52 (m, 1H), 1.71-1.89 (m, 2H), 1.93-2.01 (m, 1H), 2.24-2.31 (q, 1H, J=8 Hz,) 2.44-2.49 (m, 1H), 2.61-2.68 (m, 1H), 3.23-3.40 (m, 4H), 7.64 (dd, 1H, J=8, 3 Hz), 8.05 (m, 1H), 8.08 (d, 1H, J=8 Hz), 8.99 (s, 1H), 9.21 (s, 1H); 13C NMR (CDCl3, 400 MHz) 19.3, 22.1, 33.1, 34.0, 52.6, 53.7, 60.0, 119.7, 123.1, 124.6, 130.5, 133.8, 136.6, 152.8, 154.6, 157.1; (DCl/NH3) m/z 325 (M+H)+.

Reference： [1]Patent: US2004/224953,2004,A1

8
[ 321724-19-0 ]
2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-5-pyrimidin-5-yl-1H-benzoimidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 111 2-[2-(2-(R)-Methyl-pyrrolidin-1-yl)-ethyl]-5-pyrimidin-5-yl-1H-benzoimidazole The title compound was prepared according to the procedures described for Example 93D, except substituting <strong>[321724-19-0]5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine</strong> for 4-cyanophenylboronic acid. 1H NMR (400 MHz, CDCl3) delta 1.21 (d, 3H), 1.55-1.64 (m, 1H), 1.80-1.98 (m, 2H), 2.05-2.14 (m, 1H), 2.34 (q, 1H), 2.52-2.61 (m, 1H), 2.62-2.67 (m, 1H), 3.15-3.24 (m, 2H), 3.27-3.37 (m, 2H), 7.41 (dd, J=1.7 and 8.3, 1H), 7.66 (d, 1H), 7.76 (d, 1H), 8.99 (s, 2H), 9.16 (s, 1H); 13C NMR (400 MHz, CDCl3) delta 19.3, 22.2, 27.3, 33.1, 51.6, 53.3, 60.8, 120.8, 127.8, 134.8, 154.5, 156.1, 156.4 (1 peak overlapping and some 13C peaks were not readily identified due to exchange broadening). DCI-MS: (M+1)30 at 308 m/z.

Reference： [1]Patent: US2004/224953,2004,A1

9
[ 4595-59-9 ]
[ 73183-34-3 ]
[ 321724-19-0 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of 7a (0.50g, 3.14mmol), 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl (l ,3,2-dioxaborolan-2-yl))-l ,3,2-dioxaborolane (0.96g, 3.77mmol) and KOAc (0.926g, 9.43mmol) in DMSO (12mL) was purged with nitrogen for lOmin, was then added Pd(dppf)2Cl2. CH2Cl2 (77mg, 0.09mmol). The resulting mixture was stirred at 1000C overnight and evaporated. The residue was dissolved in ethyl acetate and filtered. The filtrate was washed with brine (15mL><2), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (EA: methanol =10:1) to afford 7b (673mg, 25% purity, 26% yield).
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; N,N-dimethyl-formamide; at 100℃; for 2.0h;Inert atmosphere;	A mixture of 5-bromopyrimidine (1 g, 6.29 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.76 g, 6.93 mmol, 1.10 eq), Pd(dppf)Cl2 CH2CI2 (513.66 mg, 628.99 muiotaetaomicron, 0.1 eq), KOAc (1.85 g, 18.87 mmol, 3 eq) in 1,4- dioxane (40 mL) and DMF (10 mL) was stirred at 100 C for 2 h under N2 atmosphere. The mixture was concentrated. The residue was purified on silica gel column chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.23) to yield 5-(4,4,5,5-tetramethyl-1l,3,2-dioxaborolan- 2-yl)pyrimidine (1.5 g, 5.82 mmol, 92.6% yield, 80% purity) as red oil. MR (400 MHz, CDCb) S ppm 9.25 (s, 1H), 9.00 (br s, 2H), 1.33 (s, 12H).

Reference： [1]Patent: WO2008/88881,2008,A1 .Location in patent: Page/Page column 38
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 5053 - 5074
[3]Patent: WO2018/195397,2018,A2 .Location in patent: Paragraph 001138-001139
[4]Organic Letters,2019,vol. 21,p. 8158 - 8163

10
[ 1040376-43-9 ]
[ 321724-19-0 ]
[ 1040376-56-4 ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 80℃;	To a solution of 7b (368mg, 0.45mmol) and C (lOOmg, 0.30mmol) in DMF (1OmL) was added Pd(Ph3)2Cl2 (16.7mg, 0.024mmol) under the protection of nitrogen, followed by aqueous IN Na2CO3 (1.3mL) drop-wise. The reaction mixture <n="40"/>was degassed with nitrogen for 3 times and heated at 8O0C overnight. After being evaporated, the mixture was purified by column chromatography (EA: PE=I :3) and re- crystallized from methanol to give the final compound (45mg, 40percent). IH-NMR (300MHz, CD3OD): delta=9.18(s, IH), 9.13(s, 2H), 7.56-7.58(m, IH), 7.46-7.49(m, IH), 7.07(s, IH), 6.53(s, 2H), 6.27-6.34(m, IH), 1.81-1.83 (d, 3H). LC-MS [M+H]+ : 379.9.

Reference： [1]Patent: WO2008/88881,2008,A1 .Location in patent: Page/Page column 38-39

11
[ 1104951-03-2 ]
[ 321724-19-0 ]
[ 1104951-07-6 ]

Reference： [1]Chemistry - A European Journal,2008,vol. 14,p. 10012 - 10028

12
[ 1188405-53-9 ]
[ 321724-19-0 ]
[ 1188405-58-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4622 - 4625

13
[ 1272356-79-2 ]
[ 321724-19-0 ]
[ 1272356-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 110℃; for 12.0h;Inert atmosphere;	To a solution of methyl 4-((2-chloro-5-phenylquinazolin-4- ylamino)methyl)benzoate (550 mg, 1.36 mmol) in DMF (16 mL) and 3/40 (0.5 mL) under nitrogen were added pyrimidine-5-ylboronic acid pinacol ester (422 mg, 2.04 mmol) and potassium carbonate (377 mg, 2.72 mmol). The resulting mixture was degassed with nitrogen for 15 min and then (l, l '-bis(diphenylphosphino)ferrocene)- palladium (II) chloride dichloromethane complex (50 mg, 0.068 mmol) was added. Upon completion of addition, the reaction mixture was again degassed for 10 min. with nitrogen. The reaction mixture was then heated to 1 10 °C where it stirred for 12h. After this time, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was quenched by the addition of water and then extracted with ethyl acetate. 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 0.5percent MeOH in CH2CI2 to afford methyl 4-((5-phenyl-2-(pyrimidin-5-yl)quinazolin-4- ylamino)methyl)benzoate (400 mg) as an off-white solid. XH NMR (400 MHz, DMSO-d6) delta (ppm): 9.62 (s, 2H), 9.31 (s, 1H), 7.93-7.86 (m, 4H), 7.54-7.49 (m, 5H), 7.37 (d, J= 6.8 Hz, 1H), 7.28 (d, J= 8.0 Hz, 2H), 5.94 (t, J= 4.8 Hz, 1H), 4.71 (d, J= 5.2 Hz, 1H), 3.85 (s, 3H). LCMS Method C: retention time 2.15 min, [M+l] = 448.2. HPLC Method B: purity 98.5percent, retention time 9.81 min.

Reference： [1]Patent: WO2011/28741,2011,A1 .Location in patent: Page/Page column 229-230

14
[ 944401-95-0 ]
[ 321724-19-0 ]
[ 1254697-42-1 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 34 - 38

15
[ 1286275-56-6 ]
[ 321724-19-0 ]
[ 1286275-13-5 ]

Yield	Reaction Conditions	Operation in experiment
77.8%	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; dichloromethane; at 120℃; for 0.25h;Microwave irradiation;	Example 11Synthesis of (S)-4-(2-chloro-9-ethyl-8-(pyrimidin-5-yl)-9H-purin-6-yl)-3-methylmorpholine (k-1) In a 5-mL microwave vessel equipped with a stirbar was placed (S)-4-(2-chloro-9-ethyl-8-iodo-9H-purin-6-yl)-3-methyl-morpholine (30 mg, 0.074 mmol), <strong>[321724-19-0]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (22.7 mg, 0.110 mmol, 1.5 eq.), potassium phosphate (46.9 mg, 0.22 mmol, 3.0 eq.), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (3.0 mg, 0.0037 mmol, 0.05 eq.), and degassed 1,4-dioxane (3.0 mL). The microwave tube was capped, and the reaction mixture was heated under microwave irradiation (300 watts, 120° C.) for 15 minutes. The reaction mixture was diluted with ethyl acetate (10 mL) and filtered through a pad of Celite. The organic layer was washed with water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100percent ethyl acetate in heptane) to give the desired compound (k-1) as a foam (20.6 mg, 77.8percent). 1H NMR (CDCl3, 400 MHz) delta ppm 9.34 (s, 1H), 9.13 (s, 2H), 6.00 to 4.60 (broad s, 2H), 4.42 to 4.28 (m, 2H), 4.11 to 3.97 (m, 1H), 3.87 to 3.72 (m, 2H), 3.71 to 3.59 (m, 1H), 3.59 to 3.40 (broad s, 1H), 1.51 to 39 (m, 6H); LC-MS m/z (method A): RT=2.21 min, [M+H]+=360.

Reference： [1]Patent: US2011/86841,2011,A1 .Location in patent: Page/Page column 30

16
[ 1201198-99-3 ]
[ 321724-19-0 ]
[ 1201196-88-4 ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 80℃; for 4.0h;Inert atmosphere;	326 mg (1.26 mmol) of the chlorothiazolecarboxamide from Stage 1, 200 mg (0.97 mmol) of the pyrimidylboric ester and 21 mg (0.029 mmol) of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride were initially charged in 10 ml of dimethoxyethane. 1.45 ml of 2M potassium carbonate solution were added and the mixture was stirred under argon at 80° C. for 4 h. For workup, the mixture was partitioned between water and dichloromethane, and the organic phase was dried over magnesium sulphate and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/ethyl acetate).Yield: 64 mg (21percent of theory), log P (HCOOH) 1.611H NMR (d6-DMSO): 2.60 (s, 3H), 4.05 (m, 2H), 8.85 (m, 1H), 9.25 (m, 2H).

Reference： [1]Patent: US2011/98287,2011,A1 .Location in patent: Page/Page column 23

17
[ 446880-83-7 ]
[ 321724-19-0 ]
[ 1333492-64-0 ]

Yield	Reaction Conditions	Operation in experiment
5%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene;Reflux; Inert atmosphere; Microwave irradiation;	General procedure: To a solution of 13 (30-90 mM) in toluene under an argon atmosphere was added Pd(Ph3P)4 (10 molpercent) and the mixture stirred for 0.5-1 h. An aqueous solution of 2M Na2CO3 (5.3 eq.) was then added followed by boronic acid (2.7 eq.) or boronic acid pinacol ester (2.7 eq.) and the mixture stirred for 30 min and then for 2-18 h at reflux. The resultant mixture was cooled, poured onto ice and extracted with toluene. The organic extract was then dried (Na2SO4), filtered and solvent removed in vacuo to give the crude product. This was purified or used crude in the following trityl deprotection step as indicated.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5642 - 5645

18
[ 1345827-87-3 ]
[ 321724-19-0 ]
C₃₂H₃₇N₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 0.166667h;Microwave irradiation;	General Procedure: To a solution of tert-butyl 5-bromo-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-1H-indole-1-carboxylate (1.0 equiv.) in DME/2M Na2CO3 (4:1) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3 equiv.) followed by Pd(dppf)Cl2-DCM (0.1 equiv.). The reaction was heated in the microwave for 10 min at 120 °C. The organic phase was separated, dried with sodium sulfate, filtered and concentrated. The crude was purified via prep-HPLC and the pure fractions were lyophilized for several days to give the Boc protected product. This product was stirred in DCM/TFA (30percent TFA) until full deprotection, then concentrated under vacuo and purified via prep-HPLC. The pure fractions were lyophilized for several days to give the desired product as a yellow solid in 23percent yield for the two steps. LC/MS: 355.2, Rt = 1.74 min

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6366 - 6369

19
[ 1354344-46-9 ]
[ 321724-19-0 ]
[ 1354344-69-6 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2011,vol. 54,p. 763 - 768

20
[ 1394930-32-5 ]
[ 321724-19-0 ]
[ 1394930-27-8 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium fluoride dihydrate; In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 0.833333h;Microwave irradiation;	General procedure: A vial was charged with 2-amino-5-bromo-N-[1-(2,6-dichloro-3-fluorophenyl)ethyl]pyridine-3-carboxamide 22 (350 mg, 0.86 mmol), 1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (179 mg, 0.86 mmol), KF.2H2O (243 mg, 2.58 mmol), Pd(PPh3)4 (50 mg, 0.43 mmol) and 5 ml of DME/H2O/EtOH (v/v/v, 7/3/2). Then the vial was capped and heated at 110 °C for 50 min under microwave irradiation. The reaction mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (MeOH/CH2Cl2, 1/50) to afford compound 24m as a white solid. Yield: 39percent;

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5169 - 5180

21
[ 689260-53-5 ]
[ 321724-19-0 ]
[ 1458652-87-3 ]

Yield	Reaction Conditions	Operation in experiment
446 mg	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 60℃; for 3.0h;Inert atmosphere; Sealed tube;	Step 1: 5-(4-Bromo-3,5-dimethylphenyl)pyrimidine In a microwave vial <strong>[689260-53-5]2-bromo-5-iodo-1,3-dimethylbenzene</strong> (1 g) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (665 mg) are suspended in N,N-dimethylformamide (15 mL) and Na2CO3 (4 mL of a 2 M aqueous solution). The mixture is purged for 5 minutes with argon. [1,1'-Bis(diphenylphosphino)-ferrocene]-dichloropalladium dichloromethane complex (85 mg) is added, the vial is sealed and the mixture is stirred at 60° C. for 3 hours. After cooling to room temperature the mixture is Partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with brine. Then the organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20?50:50) to give the title compound. Yield: 446 mg; LC (method 9): tR=1.05 min; Mass spectrum (ESI+): m/z=263 [M+H]+.
446 mg	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 60℃; for 3.0h;Microwave irradiation; Sealed tube; Inert atmosphere;	In a microwave vial 2-bromo-5-iodo-1 ,3-dimethylbenzene (1 g) and 5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (665 mg) are suspended in N,N- dimethylformamide (15 mL) and Na2CO3 (4 mL of a 2 M aqueous solution). The mixture is purged for 5 minutes with argon. [1 ,1 '-Bis(diphenylphosphino)-ferrocene]- dichloropalladium dichloromethane complex (85 mg) is added, the vial is sealed and the mixture is stirred at 60°C for 3 hours. After cooling to room temperature the mixture is Partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with brine. Then the organ ic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20?50:50) to give the title compound. Yield: 446 mg; LC (method 9): tR = 1 .05 min; Mass spectrum (EST): m/z = 263 [M+H]+.
446 mg	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 60℃; for 3.0h;Inert atmosphere; Microwave irradiation; Sealed tube;	In a microwave vial 2-bromo-5-iodo-1 ,3-dimethylbenzene (1 g) and 5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (665 mg) are suspended in N,N- dimethylformamide (15 mL) and Na2CO3 (4 mL of a 2 M aqueous solution). The mixture is purged for 5 minutes with argon. [1 ,1 '-Bis(diphenylphosphino)-ferrocene]- dichloropalladium dichloromethane complex (85 mg) is added, the vial is sealed and the mixture is stirred at 60°C for 3 hours. After cooling to room temperature the mixture is Partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with brine. Then the organ ic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20?50:50) to give the title compound. Yield: 446 mg; LC (method 9): tR = 1 .05 min; Mass spectrum (ESI+): m/z = 263 [M+H]+.

Reference： [1]Patent: US2013/252937,2013,A1 .Location in patent: Paragraph 0483
[2]Patent: WO2013/144097,2013,A1 .Location in patent: Page/Page column 88
[3]Patent: WO2013/144098,2013,A1 .Location in patent: Page/Page column 142

22
5-bromo-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]sulfanyl}pyridin-2-amine [ No CAS ]
[ 321724-19-0 ]
3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]sulfanyl}-5-(pyrimidin-5-yl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28.7%	With tetrakis(triphenylphosphine) palladium(0); potassium fluoride dihydrate; In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 0.833333h;Microwave irradiation;	General procedure: A vial was charged with 10a (200 mg, 0.50 mmol), 25c (140 mg, 0.50 mmol), KF·2H2O (143 mg, 1.51 mmol), Pd(PPh3)4 (29 mg, 0.25 mmol) and 5 mL of DME/H2O/EtOH (v/v/v, 7:3;2). Then the vial was capped and heated at 110 °C for 50 min under microwave irradiation. The reaction mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash column chromatography (0-3percent MeOH/CH2Cl2 gradient) and further separated by reverse HPLC (75-80percent MeOH/H2O gradient) to afford compound 10c in 30percent yield.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 6804 - 6820

23
5-bromo-6-(2-methoxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide [ No CAS ]
[ 321724-19-0 ]
6-(2-methoxyethoxy)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In toluene; at 110℃; for 6.0h;	A mixture of 5-bromo-6-(2-methoxyethoxy)-N-(4- (trifluoromethoxy)phenyl)nicotinamide (Stage 51.1, 50 mg, 0.115 mmol) Pd(Ph3P)4 (13 mg, 0.011 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (36 mg, 0.172 mmol) and toluene (0.5 mL) was stirred for 15 min. at RT. K3P04 (73 mg, 0.345 mmol) was added and the RM was stirred at 110°C for 6 h. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative SFC (Column DEAP, from 7percent to 12percent in 6 min)to afford the title compound was lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR = 1.04 min, m/z = 435.1 [M+H]+.

Reference： [1]Patent: WO2013/171641,2013,A1 .Location in patent: Paragraph 00317

24
5-bromo-6-(2-hydroxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide [ No CAS ]
[ 321724-19-0 ]
6-(2-hydroxyethoxy)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In toluene; at 110℃; for 6.0h;	A mixture of 5-bromo-6-(2-hydroxyethoxy)-N-(4- (trifluoromethoxy)phenyl)nicotinamide (Stage 52.1, 50 mg, 0.119 mmol), Pd(Ph3P)4 (14 mg, 0.012 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (37 mg, 0.178 mmol) in toluene (0.5 mL) was stirred for 15 min. at RT. K3P04 (76 mg, 0.356 mmol) was added and the RM was stirred at 110°C for 6 h. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative SFC (Column DEAP, from 12percent to 17percent in 6 min.) to afford the title compound as an off-white powder. UPLC-MS (Condition 2) tau = 0.93 min, m/z = 419.1 [M+H ; XH-NMR (600 MHz, DMSO-d6) delta ppm 3.74 (q, J=4.83 Hz, 2 H) 4.48 (t, J=4.71 Hz, 2 H) 4.90 (t, J=5.27 Hz, 1 H) 7.39 (d, J=8.66 Hz, 2 H) 7.87 (d, J=8.85 Hz, 2 H) 8.50 (d, J=1.51 Hz, 1 H) 8.81 (s, 1 H) 9.19 (s, 2 H) 9.21 (s, 1 H) 10.46 (s, 1 H).

Reference： [1]Patent: WO2013/171641,2013,A1 .Location in patent: Paragraph 00320

25
[ 289-95-2 ]
[ 73183-34-3 ]
[ 321724-19-0 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4287 - 4299

26
[ 1575608-93-3 ]
[ 321724-19-0 ]
[ 1575609-55-0 ]