[ CAS No. 110100-00-0 ] {[proInfo.proName]}

Name: 110100-00-0|1-(2-Chloropyrimidin-5-yl)ethanone|95%
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SKU: A141686
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Quality Control of [ 110100-00-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 110100-00-0 ]

CAS No. :	110100-00-0	MDL No. :	MFCD10697144
Formula :	C₆H₅ClN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LISVHIVILJZRDH-UHFFFAOYSA-N
M.W :	156.57	Pubchem ID :	13715742
Synonyms :

Calculated chemistry of [ 110100-00-0 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	37.24
TPSA :	42.85 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.65 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.45
Log Po/w (XLOGP3) :	0.85
Log Po/w (WLOGP) :	1.33
Log Po/w (MLOGP) :	-0.08
Log Po/w (SILICOS-IT) :	1.82
Consensus Log Po/w :	1.08

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.72
Solubility :	2.95 mg/ml ; 0.0189 mol/l
Class :	Very soluble
Log S (Ali) :	-1.33
Solubility :	7.27 mg/ml ; 0.0464 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.59
Solubility :	0.402 mg/ml ; 0.00257 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.49

Safety of [ 110100-00-0 ]

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

Application In Synthesis of [ 110100-00-0 ]

* 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 [ 110100-00-0 ]
Downstream synthetic route of [ 110100-00-0 ]

[ 110100-00-0 ] Synthesis Path-Upstream 1~3

1
[ 122372-20-7 ]
[ 110100-00-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With hydrogenchloride In tetrahydrofuran; water at 20℃; for 2 h;	To a solution of Example 72-1 (15 g, 81.25 mmol, 1.0 eq) in tetrahydrofuran (200 mL) was added hydrochloric acid (1 M, 122 mL, 1.5 eq). The mixture was stirred at 20°C for 2 hours. The mixture was concentrated and the residue partitioned between saturated aqueous sodium bicarbonate (150 mL) and ethyl acetate (100 mL). The organic layer was washed with brine (50 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by colunm chromatography (silica gel, Petroleum ether/Ethyl acetate=10/1 to 5:1) to give the target compound (10 g, 79percent yield) as a light yellow solid. ‘H NMR (400 MHz, CDCl3’) ö 9.10 (s, 2H’), 2.64 (s, 3H’)
450 mg	With hydrogenchloride In tetrahydrofuran; water at 20℃; for 5 h;	To a solution of crude 31 (560 rng, 3.0 mrnole) in THF (20 mL) is added aqueous HCI solution (1 M. 5 mL) art room temperature. After stirring at room temperature for 5 hours, the mixture is concentrated and the residue is partitioned between saturated aqueous sodium bicarbonate (20 rnL) and EA (100 mL). The organic layer is washed with brine (20 mL 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM:PE 1 1) to give 32 as a white solid (450 111g. 95percent yield). (MS: [M+H] 157.0)

Reference： [1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 11, p. 3705 - 3720
[2] Acta Chemica Scandinavica, 1989, vol. 43, # 1, p. 62 - 68
[3] Patent: WO2018/218251, 2018, A1, . Location in patent: Paragraph 00497
[4] Patent: WO2010/127152, 2010, A2, . Location in patent: Page/Page column 78-80
[5] Patent: WO2017/176812, 2017, A1, . Location in patent: Paragraph 0261

2
[ 97674-02-7 ]
[ 32779-36-5 ]
[ 110100-00-0 ]

Reference： [1] Patent: WO2016/30443, 2016, A1, . Location in patent: Page/Page column 180
[2] Patent: WO2017/144637, 2017, A1, . Location in patent: Page/Page column 99; 100

3
[ 917-54-4 ]
[ 110099-99-5 ]
[ 110100-00-0 ]
[ 110100-09-9 ]

Reference： [1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1986, vol. 40, # 9, p. 764 - 767

[ 110100-00-0 ] Synthesis Path-Downstream 1~53

1
[ 917-54-4 ]
[ 110099-99-5 ]
[ 110100-00-0 ]
[ 110100-09-9 ]

Reference： [1]Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry,1986,vol. 40,p. 764 - 767

2
[ 110100-00-0 ]
[ 87573-88-4 ]

Reference： [1]Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry,1986,vol. 40,p. 764 - 767

3
[ 122372-20-7 ]
[ 110100-00-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With hydrogenchloride; In tetrahydrofuran; water; at 20℃; for 2h;	To a solution of Example 72-1 (15 g, 81.25 mmol, 1.0 eq) in tetrahydrofuran (200 mL) was added hydrochloric acid (1 M, 122 mL, 1.5 eq). The mixture was stirred at 20C for 2 hours. The mixture was concentrated and the residue partitioned between saturated aqueous sodium bicarbonate (150 mL) and ethyl acetate (100 mL). The organic layer was washed with brine (50 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by colunm chromatography (silica gel, Petroleum ether/Ethyl acetate=10/1 to 5:1) to give the target compound (10 g, 79% yield) as a light yellow solid. ?H NMR (400 MHz, CDCl3?) oe 9.10 (s, 2H?), 2.64 (s, 3H?)
		Synthesis of 2-chloro-5-(2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl)pyrimidine (I-4a) and 2-bromo-5-(2-(2-chloro-6-fluorophenyl)- lH-imidazol-4-yl)pyrimidine (I-4b) R-7 70 0C, 12h R-9 rt, 2h R-IO [000209] Pd Cl2(PPh3)2 (0.65 mmol) was added to a solution of 5-bromo-2- chloropyrimidine (R-7) (12.9 mmol) and tributyl(l-ethoxy vinyl) stannane (R-8) (14.2 mmol) in THF (25 niL). The flask was evacuated and backfilled with nitrogen twice and then heated at 70 0C for 12 hours. The reaction mixture was quenched with 2M KF (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with 2M KF (1 x 20 mL), brine, dried over Na2SO4, and concentrated under vacuum to afford 2-chloro-5- (1-ethoxy vinyl )pyrimidine (R-9) as a yellow residue which was used in the next step without purification.[000210] The above 2-chloro-5-(l-ethoxyvinyl)pyrimidine (R-9) crude (12.9 mmol) was diluted with MeOH (30 mL) and IM HCl (10 mL) added. The resulting yellow solution was stirred at room temperature for 2 hours, and then the organic solvent was removed under reduced pressure. The residue was diluted with water (50 mL), the pH neutralized with IN NaOH and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude was purified by silica chromatography (hexane : DCM = 8 : 2) to yield l-(2-chloropyrimidin-5-yl)ethanone (R-IO). 1H NMR (400 MHz, CDCl3) delta 9.13 (s, 2H), 2.67 (s, 3H). MS (m/z) (M+l)+: 157.1. [000211] Pyridine tribromide (1.4 mmol) was added over 1 hour to a solution of l-(2- chloropyrimidin-5-yl)ethanone (R-10) (1.4 mmol) in AcOH (10 mL). After the addition was complete the reaction mixture was stirred at room temperature until complete conversion (approx. 6 hours). The flask was cooled in an ice-bath and 5N NaOH was slowly added to adjust to pH 6. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with 2N NaOH (2 x 20 rnL) and brine, dried over Na2SO4 and concentrated under vacuum to afford a reddish residue containing a 2: 1 mixture of 2-chloro- l-(2-chloropyrimidin-5-yl)ethanone (R-IIa) and 2-bromo-l-(2-bromopyrimidin-5- yl)ethanone (R-IIb), which was used in the next step without further purification. MS (m/z) (M+l)+: 236.1 for (R-Ha); 278.0 and 280.1 for (R-Hb).[000212] Using the same conditions as described for the synthsis of (1-1) the above mixture of 2-chloro-l-(2-chloropyrimidin-5-yl)ethanone (R-Ha) and 2-bromo-l-(2-bromopyrimidin- 5-yl)ethanone (R-Hb) was converted to 2-halo-5-(2-(2-chloro-6-fluorophenyl)-lH- imidazol-4-yl)pyrimidine mixture (I-4a and I-4b). The mixture was purified by preparative EtaPLC (MeCN gradient 10-90%) to afford a 2:1 mixture of 2-chloro-5-(2-(2-chloro-6- fluorophenyl)-lH-imidazol-4-yl)pyrimidine (I-4a) and 2-bromo-5-(2-(2-chloro-6- fluorophenyl)-lH-imidazol-4-yl)pyrimidine (I-4b). MS (m/z) (M+l)+: 310.1 for (I-4a); 352.0 and 354.1 for (I-4b).
450 mg	With hydrogenchloride; In tetrahydrofuran; water; at 20℃; for 5h;	To a solution of crude 31 (560 rng, 3.0 mrnole) in THF (20 mL) is added aqueous HCI solution (1 M. 5 mL) art room temperature. After stirring at room temperature for 5 hours, the mixture is concentrated and the residue is partitioned between saturated aqueous sodium bicarbonate (20 rnL) and EA (100 mL). The organic layer is washed with brine (20 mL 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM:PE 1 1) to give 32 as a white solid (450 111g. 95% yield). (MS: [M+H] 157.0)

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 3705 - 3720
[2]Acta Chemica Scandinavica,1989,vol. 43,p. 62 - 68
[3]Patent: WO2018/218251,2018,A1 .Location in patent: Paragraph 00497
[4]Patent: WO2010/127152,2010,A2 .Location in patent: Page/Page column 78-80
[5]Patent: WO2017/176812,2017,A1 .Location in patent: Paragraph 0261

4
[ 110-91-8 ]
[ 110100-00-0 ]
[ 265107-51-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 3705 - 3720

5
[ 110100-00-0 ]
2-amino-4-(3-bromophenyl)-6-[2-(4-morpholinyl)-5-pyrimidinyl]nicotinonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 3705 - 3720

6
[ 110100-00-0 ]
5-(3-bromo-phenyl)-7-(2-morpholin-4-yl-pyrimidin-5-yl)-pyrido[2,3-<i>d</i>]pyrimidin-4-ylamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 3705 - 3720

7
[ 110100-00-0 ]
[ 110100-06-6 ]

Reference： [1]Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry,1986,vol. 40,p. 764 - 767

8
[ 110100-00-0 ]
[ 75-05-8 ]
[ 1239719-84-6 ]

Yield	Reaction Conditions	Operation in experiment
43%		Trifluoromethanesulfonic acid (7.63 ml, 86 mmol) was added to a sol. of iodobenzene diacetate (7.41 g, 23 mmol) in CH3CN (50 ml) and the r.m. was stirred at r.t. for 20 min under N2. A sol. of l-(2-chloro-5-pyrimidinyl)-ethanone (3 g, 19.2 mmol) in CH3CN (10 ml) was added at once at r.t. to the sol. and the r.m. was then refluxed for 2 h and subsequently cooled to r.t. CH3CN was evaporated and the residue was extracted with - -DCM. The organic phase was washed with a sat. aq. NaHCO3 sol., dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography over Silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated under reduced pressure. Yield: 1.6 g of intermediate 57 (43 %).

Reference： [1]Patent: WO2010/89292,2010,A1 .Location in patent: Page/Page column 79-80

9
[ 1170884-07-7 ]
[ 110100-00-0 ]
[ 98-80-6 ]
[ 1254171-25-9 ]

Yield	Reaction Conditions	Operation in experiment
		Synthesis of 2-chloro-5-(2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl)pyrimidine (I-4a) and 2-bromo-5-(2-(2-chloro-6-fluorophenyl)- lH-imidazol-4-yl)pyrimidine (I-4b) R-7 70 0C, 12h R-9 rt, 2h R-IO [000209] Pd Cl2(PPh3)2 (0.65 mmol) was added to a solution of 5-bromo-2- chloropyrimidine (R-7) (12.9 mmol) and tributyl(l-ethoxy vinyl) stannane (R-8) (14.2 mmol) in THF (25 niL). The flask was evacuated and backfilled with nitrogen twice and then heated at 70 0C for 12 hours. The reaction mixture was quenched with 2M KF (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with 2M KF (1 x 20 mL), brine, dried over Na2SO4, and concentrated under vacuum to afford 2-chloro-5- (1-ethoxy vinyl )pyrimidine (R-9) as a yellow residue which was used in the next step without purification.[000210] The above 2-chloro-5-(l-ethoxyvinyl)pyrimidine (R-9) crude (12.9 mmol) was diluted with MeOH (30 mL) and IM HCl (10 mL) added. The resulting yellow solution was stirred at room temperature for 2 hours, and then the organic solvent was removed under reduced pressure. The residue was diluted with water (50 mL), the pH neutralized with IN NaOH and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude was purified by silica chromatography (hexane : DCM = 8 : 2) to yield l-(2-chloropyrimidin-5-yl)ethanone (R-IO). 1H NMR (400 MHz, CDCl3) delta 9.13 (s, 2H), 2.67 (s, 3H). MS (m/z) (M+l)+: 157.1. [000211] Pyridine tribromide (1.4 mmol) was added over 1 hour to a solution of l-(2- chloropyrimidin-5-yl)ethanone (R-10) (1.4 mmol) in AcOH (10 mL). After the addition was complete the reaction mixture was stirred at room temperature until complete conversion (approx. 6 hours). The flask was cooled in an ice-bath and 5N NaOH was slowly added to adjust to pH 6. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with 2N NaOH (2 x 20 rnL) and brine, dried over Na2SO4 and concentrated under vacuum to afford a reddish residue containing a 2: 1 mixture of 2-chloro- l-(2-chloropyrimidin-5-yl)ethanone (R-IIa) and 2-bromo-l-(2-bromopyrimidin-5- yl)ethanone (R-IIb), which was used in the next step without further purification. MS (m/z) (M+l)+: 236.1 for (R-Ha); 278.0 and 280.1 for (R-Hb).[000212] Using the same conditions as described for the synthsis of (1-1) the above mixture of 2-chloro-l-(2-chloropyrimidin-5-yl)ethanone (R-Ha) and 2-bromo-l-(2-bromopyrimidin- 5-yl)ethanone (R-Hb) was converted to 2-halo-5-(2-(2-chloro-6-fluorophenyl)-lH- imidazol-4-yl)pyrimidine mixture (I-4a and I-4b). The mixture was purified by preparative EtaPLC (MeCN gradient 10-90%) to afford a 2:1 mixture of 2-chloro-5-(2-(2-chloro-6- fluorophenyl)-lH-imidazol-4-yl)pyrimidine (I-4a) and 2-bromo-5-(2-(2-chloro-6- fluorophenyl)-lH-imidazol-4-yl)pyrimidine (I-4b). MS (m/z) (M+l)+: 310.1 for (I-4a); 352.0 and 354.1 for (I-4b).; Synthesis of 5-(5-bromo-2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl)-2-phenylpyrimidine (EX-7)[000248] To a solution of the 2-chloro-5-(2-(2-chloro-6-fluorophenyl)-lH-imidazol-4- yl)pyrimidine (I-4a) and 2-bromo-5-(2-(2-chloro-6-fluorophenyl)-lH-imidazol-4- yl)pyrimidine (I-4b) mixture (0.054 mmol) in toluene (1.5 niL) was added phenyl boronic acid (R-34) (0.065 mmol), 2M aq K2CO3 (O.l lmmol), and Pd(PPh3)4 (0.0005 mmol). The vial was evacuated and backfilled with nitrogen twice and heated at 80 0C for 4 hours. The reaction was then diluted with a saturated solution of NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by prepapative TLC (hexane : EtOAc = 1 : 1) to afford 5-(2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl)-2-phenylpyrimidine (1-21). MS (m/z) (M+ 1)+: 351.1.[000249] A solution of 5-(2-(2-chloro-6-fluorophenyl)- lH-imidazol-4-yl)-2- phenylpyrimidine (1-21) was brominated with NBS using same procedure as described for the synthesis of 1-3. The crude reaction mixture was purified by preparative TLC (hexane : EtOAc = 1 : 1) to afford 5-(5-bromo-2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl)-2- phenylpyrimidine (EX-7) as pale yellow solid. MS (m/z) (M+l)+: 428.0 and 430.1.

Reference： [1]Patent: WO2010/127152,2010,A2 .Location in patent: Page/Page column 78-80; 94-95

10
[ 110100-00-0 ]
[ 1007883-29-5 ]
[ 1254170-90-5 ]

Yield	Reaction Conditions	Operation in experiment
		Synthesis of 2-chloro-5-(2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl)pyrimidine (I-4a) and 2-bromo-5-(2-(2-chloro-6-fluorophenyl)- lH-imidazol-4-yl)pyrimidine (I-4b) R-7 70 0C, 12h R-9 rt, 2h R-IO [000209] Pd Cl2(PPh3)2 (0.65 mmol) was added to a solution of 5-bromo-2- chloropyrimidine (R-7) (12.9 mmol) and tributyl(l-ethoxy vinyl) stannane (R-8) (14.2 mmol) in THF (25 niL). The flask was evacuated and backfilled with nitrogen twice and then heated at 70 0C for 12 hours. The reaction mixture was quenched with 2M KF (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with 2M KF (1 x 20 mL), brine, dried over Na2SO4, and concentrated under vacuum to afford 2-chloro-5- (1-ethoxy vinyl )pyrimidine (R-9) as a yellow residue which was used in the next step without purification.[000210] The above 2-chloro-5-(l-ethoxyvinyl)pyrimidine (R-9) crude (12.9 mmol) was diluted with MeOH (30 mL) and IM HCl (10 mL) added. The resulting yellow solution was stirred at room temperature for 2 hours, and then the organic solvent was removed under reduced pressure. The residue was diluted with water (50 mL), the pH neutralized with IN NaOH and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude was purified by silica chromatography (hexane : DCM = 8 : 2) to yield l-(2-chloropyrimidin-5-yl)ethanone (R-IO). 1H NMR (400 MHz, CDCl3) delta 9.13 (s, 2H), 2.67 (s, 3H). MS (m/z) (M+l)+: 157.1. [000211] Pyridine tribromide (1.4 mmol) was added over 1 hour to a solution of l-(2- chloropyrimidin-5-yl)ethanone (R-10) (1.4 mmol) in AcOH (10 mL). After the addition was complete the reaction mixture was stirred at room temperature until complete conversion (approx. 6 hours). The flask was cooled in an ice-bath and 5N NaOH was slowly added to adjust to pH 6. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with 2N NaOH (2 x 20 rnL) and brine, dried over Na2SO4 and concentrated under vacuum to afford a reddish residue containing a 2: 1 mixture of 2-chloro- l-(2-chloropyrimidin-5-yl)ethanone (R-IIa) and 2-bromo-l-(2-bromopyrimidin-5- yl)ethanone (R-IIb), which was used in the next step without further purification. MS (m/z) (M+l)+: 236.1 for (R-Ha); 278.0 and 280.1 for (R-Hb).[000212] Using the same conditions as described for the synthsis of (1-1) the above mixture of 2-chloro-l-(2-chloropyrimidin-5-yl)ethanone (R-Ha) and 2-bromo-l-(2-bromopyrimidin- 5-yl)ethanone (R-Hb) was converted to 2-halo-5-(2-(2-chloro-6-fluorophenyl)-lH- imidazol-4-yl)pyrimidine mixture (I-4a and I-4b). The mixture was purified by preparative EtaPLC (MeCN gradient 10-90%) to afford a 2:1 mixture of 2-chloro-5-(2-(2-chloro-6- fluorophenyl)-lH-imidazol-4-yl)pyrimidine (I-4a) and 2-bromo-5-(2-(2-chloro-6- fluorophenyl)-lH-imidazol-4-yl)pyrimidine (I-4b). MS (m/z) (M+l)+: 310.1 for (I-4a); 352.0 and 354.1 for (I-4b).

Reference： [1]Patent: WO2010/127152,2010,A2 .Location in patent: Page/Page column 78-80

11
[ 1422469-45-1 ]
[ 110100-00-0 ]
[ 1422469-49-5 ]

Yield	Reaction Conditions	Operation in experiment
0.36 g	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 2h;	To 3-((3,5-bis(trifluoromethyl)benzylamino)methyl)-N,N-bis(cyclopropylmethyl)-7,7- dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine, obtained in step-5 of example 1 , (0.5 g, 0.9 mmol) in DMF (10 mL) were added l-(2-chloropyrimidin-5-yl)ethanone (0.14 g, 0.0009 mmol), potassium carbonate (0.39 g, 2.7 mmol). The reaction mixture was heated with stirring at about 70C for about 2 h. The reaction mixture was cooled to a temperature of about 20- 35C, diluted with water (20 mL) and the aqueous mass was then extracted with ethyl acetate (3x40 mL). The combined organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the crude product. The title compound was then isolated by preparative TLC using dichloromethane (0.36 g) as an eluent. 1H NMR (400 MHz, DMSO-d6):5 8.93-8.91 (m, 3H), 7.75 (s, 3H), 5.10 (s, 2H), 4.9 (s, 2H), 2.97 (d, J = 6.6 Hz, 4H), 2.71-2.67 (m, 2H), 2.52 (s, 3H), 1.96-1.94 (m, 2H), 0.89-0.81 (m, 2H), 0.32-0.28 (m, 4H), 0.07 (s, 6H), 0.04-0.01 (m, 4H). MS (ESI): 646 (M+l)+.

Reference： [1]Patent: WO2013/24358,2013,A2 .Location in patent: Page/Page column 30; 31

12
[ 920494-75-3 ]
[ 110100-00-0 ]
[ 1429200-46-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 70℃;	Step (ii): Preparation of l-(2-(((6-(bis(cyclopropylmethyl)amino)-l ,3-dimethyl-lH- pyrazolo[3,4-b]pyridin-5-yl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidin-5- yl)ethanone5-(((3,5-bis(trifluoromethyl)benzyl)amino)methyl)-N,N-bis (cyclopropylmethyl)- 1 ,3- dimethyl-lH-pyrazolo[3,4-b]pyridin-6-amine (0.761 mmol, 0.400 g) in DMF was treated withl-(2-chloropyrimidin-5-yl)ethanone (0.761 mmol, 0.1 19 g) and K2C03 (2.283 mmol, 0.315 g). The reaction mixture was stirred at 60-70 C for 12-16 h. The reaction mixture was then extracted with EtOAc. The combined organic layer was washed with water and brine solution, dried over sodium sulphate, concentrated under reduced pressure and purified by column chromatography using silica gel and 50% EtOAc in petroleum ether as eluent to get the title compound.1H NMR (400 MHz, CDC13) ? 8.9 (s, 1H), 7.70 (s, 1H), 7.60 (s, 2H), 7.50 (s, 1H), 5.10 (s, 2H), 4.80 (s, 2H), 3.90 (s, 3H), 3.10 (d, J = 6.0 Hz, 4H), 2.50 (s, 3H), 2.30 (s, 3H), 0.90 (m, 2H), 0.40 (m, 4H), 0.10 (m, 4H). MS (m/z): 646 (M++l , 50%).

Reference： [1]Patent: WO2013/46045,2013,A1 .Location in patent: Page/Page column 28

13
[ 110100-00-0 ]
[ 1569902-03-9 ]

Reference： [1]Patent: US2015/225353,2015,A1

14
[ 110100-00-0 ]
[ 1569902-06-2 ]

Reference： [1]Patent: US2015/225353,2015,A1

15
[ 110100-00-0 ]
[ 98-80-6 ]
[ 1071323-12-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	With palladium diacetate; sodium carbonate; triphenylphosphine; In 1,4-dioxane; at 110℃; for 14h;	Ketone 39 (0.72 g, 4.6 mmol), phenylboronic acid (0.841 g, 6.9 mmol), Pd(OAc)2 (0.041 g, 0.184 mmol, 4% Pd), PPh3 (0.241 g, 0.92 mmol), sat. Na2CO3 (23 mL), anhydrous dioxane (30 mL) were added to 100 mL screw cap pressure vessel. The mixture was stirred, degassed by purging with argon for 15 min, sealed and placed in an 110 C. oil bath for 14 h. The dark colored mixture was cooled and extracted with ether. The organic layer was filtered through a pad of celite, rinsed with ether, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by flash column chromatography (SiO2, 20 g, 5% EtOAc/hexanes) to afford the coupled ketone 42 as a white solid (0.66 g, 74%): TLC Rf=0.4 (25% EtOAc/hexanes); mp 154-156 C.; 1H NMR (500 MHz, CDCl3) delta 9.23 (s, 2H), 8.49 (dd, J=8.1, 1.6 Hz, 2H), 7.72-7.36 (m, 3H), 2.61 (s, 3H); 13C NMR (125 MHz, CDCl3) delta 195.2, 167.2, 157.5, 136.7, 132.1, 130.0, 128.9, 127.4, 26.8; IR (neat cm-1) 3077, 3036, 2049, 1681, 1537, 1429, 1376, 1271, 954, 744, 688; HRMS (DART, M++H) m/z 199.0868 (calculated for C12H11N2O, 199.0871).

Reference： [1]Patent: US2015/225353,2015,A1 .Location in patent: Paragraph 0096

16
[ 97674-02-7 ]
[ 32779-36-5 ]
[ 110100-00-0 ]

Yield	Reaction Conditions	Operation in experiment
		5-Bromo 2-chloro pyrimidine (2 g, 1 0.33 mmol, Combi-Blocks) was degassed for 30 min. 1-Ethoxy vinyl tributyltin (4.1 mL, 11 .3 mmol, Frontier Scientific) and bis(triphenylphosphine)palladium dichloride (0.36 g, 0.51 mmol) were added at rt. The resulting mixture was stirred overnight at 90 C. It was cooled to rt and filtered through celite. An aqueous HCl solution (6 N, 10 mL) was added and the mixture was stirred for 1 hour at rt. It was neutralized with sat. NaHCOs solution (15 mL), extracted with DCM (50 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by flash column chromatography to afford the title compound (pale yellow solid). 1H NM R (400 MHz, DMSO-d6): delta 8.90 (s, 2H), 2.65 (s, 3H). LCMS: (Method B) 162.0 (M+H), Rt. 4.6 min, 98.01 % (Max).
		5-Bromo 2-chloro pyrimidine (2 g, 10.33 mmol, Combi-Blocks) was degassed for 30 mm. 1-Ethoxy vinyl tributyltin (4.1 mL, 11.3 mmol, Frontier Scientific) and bis(triphenylphosphine)palladium dichloride (0.36 g, 0.51 mmol) were added at rt. The resulting mixture was stirred overnight at 90 C. It was cooled to rt and filtered through celite. An aqueous HCI solution (6 N, 10 mL) was added and the mixture was stirred for1 hour at rt. It was neutralized with sat.NaHCO3 solution (15 mL), extracted with DCM (50 mL), dried over anhydrous Na2504 and concentrated. The crude product was purified by flash column chromatography to afford the title compound (pale yellow solid). 1H NMR (400 MHz, DMSO-d6): 6 8.90 (s, 2H), 2.65 (s, 3H). LCMS: (Method B) 162.0 (M+H), Rt. 4.6 mm, 98.01% (Max).

Reference： [1]Patent: WO2016/30443,2016,A1 .Location in patent: Page/Page column 180
[2]Patent: WO2017/144637,2017,A1 .Location in patent: Page/Page column 99; 100

17
[ 110100-00-0 ]
1-(2-(4-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol [ No CAS ]

Reference： [1]Patent: WO2016/30443,2016,A1
[2]Patent: WO2017/144637,2017,A1

18
[ 110100-00-0 ]
(S)-1-(2-(4-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol [ No CAS ]
(S)-1-(2-(4-((R)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol [ No CAS ]

Reference： [1]Patent: WO2016/30443,2016,A1
[2]Patent: WO2017/144637,2017,A1

19
(S)-1-(1-(benzo[d][1,3]dioxol-5-yl) ethyl)piperazine hydrochloride [ No CAS ]
[ 110100-00-0 ]
(S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 12h;	To a stirred solution of Intermediate 16 (1.14 g, 4.24 mmol) in dry DMF (10 mL), TEA (1.1 mL, 16.5 mmol) and <strong>[110100-00-0]1-(2-chloropyrimidin-5-yl)ethan-1-one</strong> obtained in the previous step (0.6 g, 3.85 mmol) were added at rt. The resulting mixture was heated to 90 C for 12 h. It was cooled to rt and concentrated. Dichloromethane (50 mL) was added and was washed with a saturated NaCI solution (10 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by flash chromatography, affording the title compound (off white solid). 1H NMR (400 MHz, DMSO-d6): delta 8.83 (s, 2H), 6.90 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.74 (dd, J = 8.0, 1.2 Hz, 1H), 5.99-5.98 (m, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.40-3.36 (m, 1H), 2.49-2.47 (m, 5H), 2.38-2.35 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H). LCMS: (Method A) 355.0 (M+H), Rt. 2.61 min, 99.78% (Max). HPLC: (Method A) Rt. 2.55 min, 99.51 % (Max).

Reference： [1]Patent: WO2016/30443,2016,A1 .Location in patent: Page/Page column 180-181

20
4-(5-(methylsulfonyl)indolin-1-yl)-7-(piperidin-4-yl)furo[3,2-d]pyrimidine hydrochloride salt [ No CAS ]
[ 110100-00-0 ]
C₂₆H₂₆N₆O₄S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3249 - 3253

21
[ 110100-00-0 ]
C₂₆H₂₈N₆O₄S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3249 - 3253

22
(S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine hydrochloride [ No CAS ]
[ 110100-00-0 ]
(S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 12h;	To a stirred solution of Intermediate 16 (1.14 g, 4.24 mmol) in dry DMF (10 mL), TEA (1.lmL, 16.5 mmol) and <strong>[110100-00-0]1-(2-chloropyrimidin-5-yl)ethan-1-one</strong> obtained in the previous step (0.6 g, 3.85 mmol) were added at rt. The resulting mixture was heated to 90 C for 12 h. It was cooled to rt and concentrated. Dichloromethane (50 mL) was added and was washed with a saturated NaCI solution (10 mL), dried over anhydrous Na2SO4 andconcentrated. The crude product was purified by flash chromatography, affording the title compound (off white solid). 1H NMR (400 MHz, DMSO-d6): 68.83 (s, 2H), 6.90 (s, IH), 6.84 (d, J= 7.6 Hz, IH), 6.74 (dd, J= 8.0, 1.2 Hz, IH), 5.99-5.98 (m, 2H), 3.84 (t, J= 4.8 Hz, 4H), 3.40-3.36 (m, IH), 2.49-2.47 (m, 5H), 2.38-2.35 (m, 2H),1.27 (d, J= 6.8 Hz, 3H). LCMS: (Method A) 355.0 (M+H), Rt. 2.61 mm, 99.78% (Max). HPLC:(Method A) Rt. 2.55 mm, 99.51% (Max).

Reference： [1]Patent: WO2017/144637,2017,A1 .Location in patent: Page/Page column 100

23
[ 110100-00-0 ]
C₁₂H₁₇N₃O₃ [ No CAS ]

Reference： [1]Patent: WO2017/176812,2017,A1

24
[ 110100-00-0 ]
C₁₄H₂₅N₃O₂Si [ No CAS ]

Reference： [1]Patent: WO2017/176812,2017,A1

25
[ 110100-00-0 ]
C₁₉H₃₃N₃O₄Si [ No CAS ]

Reference： [1]Patent: WO2017/176812,2017,A1

26
[ 110100-00-0 ]
C₁₉H₃₅N₃O₄Si [ No CAS ]

Reference： [1]Patent: WO2017/176812,2017,A1

27
[ 110100-00-0 ]
C₁₉H₃₄ClN₃O₃Si [ No CAS ]

Reference： [1]Patent: WO2017/176812,2017,A1

28
[ 141-43-5 ]
[ 110100-00-0 ]
C₈H₁₁N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In ethanol; at 80℃; for 0.5h;	To a solution of 32 (130 rng, 0.67 mrnoi) in EtOH (5 niL) is added ethanolamine (50 mg, 0.67 mmoi) at room temperature. After stirring at 80 C for 30 minutes. the mixture is cooled and concentrated to give 33 as a colorless oil (162 mg, 100% yield).(MS: [MH-H] 1821)

Reference： [1]Patent: WO2017/176812,2017,A1 .Location in patent: Paragraph 0262

29
[ 593-51-1 ]
[ 110100-00-0 ]
[ 265107-49-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine; In tetrahydrofuran; at 20℃;	To a solution of 32 (117 mg. 0.76 nunol) in THF (30 niL) is added TEA (383 111g. 378 mrnoi) and methylamine hydrochloride (153 mg. 2.27 mmol). After stirring at room temperature overnight, the mixture is concentrated and purified by silica gel column chromatography (EA:PE == 1:4 to 1:1) to give 71 as a pale yellow solid (100 rng, 89% yield). (MS: [MH-Hi 152.1)

Reference： [1]Patent: WO2017/176812,2017,A1 .Location in patent: Paragraph 0310

30
(1-(3-(difluoromethyl)-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methanol [ No CAS ]
[ 110100-00-0 ]
1-[2-[[1-[3-(difluoromethyl)-4-fluorophenyl]triazol-4-yl]methoxy]pyrimidin-5-yl]ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	With caesium carbonate; In acetonitrile; at 110℃;	A solution of (1-(3-(difluoromethyl)-4-fluorophenyl)-1 H-i ,2,3-triazol-4- yl)methanol (Intermediate 9, 110 mg, 0.41 mmol), Cs2CO3 (535.9 mg, 1.64 mmol), and i-(2-chloropyrimidin-5-yl)ethan-i-one (83.6 mg, 0.53 mmol) in ACN (0.02 mL) was heated at 110 C overnight. The reaction mixture wascooled, diluted with EtOAc, and washed with sat. aq. NH4CI. The organic layer was dried (Na2504), filtered, and concentrated under reduced pressure. Purification (FCC, 5i02, 0-50% EtOAc in hexanes) afforded the title compound (12 mg, 8%). MS (ESI): mass calcd. for C15H12F3N502, 363.1; m/z found, 364.1 [M+H]. 1H NMR (500 MHz, CDCI3) oe 9.14-9.05 (5, 2H), 8.19-8.ii(s, 1 H), 7.98 - 7.87 (m, 2H), 7.40 - 7.31 (m, 1 H), 7.09 -6.80 (t, J = 54.6Hz, 1 H), 5.80 - 5.71 (5, 2H), 2.66 - 2.57 (5, 3H).

Reference： [1]Patent: WO2017/139428,2017,A1 .Location in patent: Page/Page column 199

31
(1-(3-(difluoromethyl)-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methanol [ No CAS ]
[ 110100-00-0 ]
(R/S)-1-[2-[[1-[3-(difluoromethyl)-4-fluorophenyl]triazol-4-yl]methoxy]pyrimidin-5-yl]ethanol [ No CAS ]

Reference： [1]Patent: WO2017/139428,2017,A1

32
[ 110100-00-0 ]
(S)-1-(2-chloropyrimidin-5-yl)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With nicotinamide adenine dinucleotide phosphate; In aq. phosphate buffer; isopropyl alcohol; at 30℃;Enzymatic reaction;	Ketoreductase (KRED) P3C3 (160 mg) (KRED Plate available from CODEXIS) and NADP (65 mg) was added to a 100 mL vial containing phosphate buffer (pH 7.0, 100 mM, 15 mL). The mixture was stirred until solids were dissolved. The solution was heated to 30 C. To this enzyme/buffer solution, a solution of <strong>[110100-00-0]1-(2-chloropyrimidin-5-yl)ethanone</strong> (0.658 g, 4.2 mmol) in 2-propanol (7 mL) was added dropwise. The reaction was stirred at 30 C. overnight. The mixture was diluted with water, extracted with EtOAc. The organic phase was washed with brine and water, dried over MgSO4, and evaporated to afford the title compound. LC/MS (m/z): 159 (M+H)+

Reference： [1]Patent: US2018/9796,2018,A1 .Location in patent: Paragraph 0320; 0321

33
[ 110100-00-0 ]
(S)-1-(2-chloropyrimidin-5-yl)ethyl methanesulfonate [ No CAS ]