[ CAS No. 1395417-57-8 ] {[proInfo.proName]}

Name: 1395417-57-8|Oxetan-3-ylmethyl 4-methylbenzenesulfonate|97%
Brand: Ambeed
SKU: A380769
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Quality Control of [ 1395417-57-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1395417-57-8 ]

SDS Specification

Alternatived Products of [ 1395417-57-8 ]

Product Details of [ 1395417-57-8 ]

CAS No. :	1395417-57-8	MDL No. :	MFCD27987281
Formula :	C₁₁H₁₄O₄S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DZDXQYOMYPRXBA-UHFFFAOYSA-N
M.W :	242.29	Pubchem ID :	86670828
Synonyms :

Calculated chemistry of [ 1395417-57-8 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.45
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	58.98
TPSA :	60.98 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.29
Log Po/w (XLOGP3) :	1.33
Log Po/w (WLOGP) :	2.43
Log Po/w (MLOGP) :	1.45
Log Po/w (SILICOS-IT) :	1.67
Consensus Log Po/w :	1.83

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.19
Solubility :	1.55 mg/ml ; 0.0064 mol/l
Class :	Soluble
Log S (Ali) :	-2.21
Solubility :	1.49 mg/ml ; 0.00614 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.2
Solubility :	0.153 mg/ml ; 0.00063 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.71

Safety of [ 1395417-57-8 ]

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 [ 1395417-57-8 ]

* 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 [ 1395417-57-8 ]
Downstream synthetic route of [ 1395417-57-8 ]

[ 1395417-57-8 ] Synthesis Path-Upstream 1~1

1
[ 98-59-9 ]
[ 1395417-57-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water; toluene at 5 - 20℃; for 6 h;	A 30percent aqueous solution of NaOH (1.99 mL; 19.9 mmol) was added gradually to a solution of p-toluenesulfonyl chloride (2.6 g; 13.6 mmol) and benzyltriethylammonium chloride (CAS 56-37-1 ) (0.194 g; 0.85 mmol) in toluene (5 mL) at 5°C. 3- Oxetanemethanol (CAS 6246-06-6) (0.915 mL; 11.35 mmol) was added drop wise below 10°C. The reaction mixture was stirred below 10°C for 1 hour and at room temperature for 5 hours. The reaction mixture was poured into ice and extracted with DCM (3 times). The organic layer was dried over MgS0₄, filtered and the solvent was evaporated to give 2.49 g (91 percent) of intermediate 49.
70%	With dmap; triethylamine In dichloromethane at 20℃; for 3 h;	To a solution of oxetan-3-ylmethanol (750 mg, 8.5 mmol) in DCM (15ml) was added N,N-dimethylpyridin-4-amine (122 mg, 1 mmol), TEA (2.0 g, 20 mmol) and4-methylbenzenesulfonyl chloride (1.6 g, 8.5 mmol). The mixture was stirred at rt for 3 h,concentrated, and the residue was purified by column chromatography using ethyl acatatein petroleum ether (1/4) to afford oxetan-3-ylmethyl4-methylbenzenesulfonate (1.4 g, 70percentyield). LCMS (ESI) m/z: 243.3 (M + 1t.
1 g	With dmap; triethylamine In dichloromethane at 15℃; for 16 h;	Step 1: Preparation of oxetan-3-ylmethyl 4-methylbenzenesulfonate To a stirred solution of 3-oxetanemethanol (500 mg, 5.67 mmol) in DCM (5 mL) was added Et₃N (1.0 g, 10.2 mmol) and DMAP (70 mg, 0.57 mmol). Then to the mixture was added a solution of 4-methylbenzenesulfonyl chloride (1.6 g, 8.51 mmol) in DCM (5 mL) dropwise. After being stirred at 15 ^oC for 16 hrs, the resulting mixture was diluted with DCM (50 mL), washed with H₂O (20 mL), 2 N HCl (20 mL) and brine (10 mL), then dried over anhydrous Na₂SO₄ and concentrated in vacuo to give oxetan-3-ylmethyl 4-methylbenzenesulfonate (1.0 g) as a colorless oil which was used in the next step directly without further purification.

100 mg

With pyridine In dichloromethane at 23 - 29℃; for 16 h;

To a solution of oxetan-3-ylmethanol (CAS registry number 6246-06-6; 100 mg, 1.14 mmol) in DCM (5 mL) were added TsC1 (260 mg, 1.36 mmol) and pyridine (180 mg, 2.27 mmol). Then the reaction was stirred at 23-29 °C for 16 h. TLC (PE: EA = 1: 1) confirmedthat starting material was consumed and a new product was formed. The mixture wasconcentrated and purified by chromatography column on silica gel, eluting with PE: EA = 5:1, to afford oxetan-3-ylmethyl 4-methylbenzenesulfonate (100mg). ‘HNMR (CDC13) 5 7.81(d, J 8.0 Hz, 2H), 7.37 (d, J 8.0 Hz, 2H), 4.73-4.77 (t, J= 6.8 Hz, 2H), 4.32-4.35 (t, J=5.6 Hz, 2H), 4.26 (d, J 7.2 Hz, 2H), 3.26-3.33 (m, 1H), 2.47 (s, 3H).

Reference： [1] Patent: WO2013/61080, 2013, A1, . Location in patent: Page/Page column 161; 162
[2] Patent: WO2018/154466, 2018, A1, . Location in patent: Paragraph 00451; 00453; 0054
[3] Patent: WO2014/49047, 2014, A1, . Location in patent: Page/Page column 85; 86
[4] Patent: US2015/210685, 2015, A1, . Location in patent: Paragraph 0570-0571
[5] Patent: WO2015/186056, 2015, A1, . Location in patent: Page/Page column 105
[6] Patent: WO2016/41892, 2016, A1, . Location in patent: Page/Page column 49
[7] Patent: US9382243, 2016, B2, . Location in patent: Page/Page column 81
[8] Patent: WO2016/177655, 2016, A1, . Location in patent: Page/Page column 129; 130
[9] Patent: WO2017/112768, 2017, A1, . Location in patent: Page/Page column 105; 106

[ 1395417-57-8 ] Synthesis Path-Downstream 1~37

1
3-hydroxymethyloxetane [ No CAS ]
[ 98-59-9 ]
[ 1395417-57-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide; In water; toluene; at 5 - 20℃; for 6h;	A 30% aqueous solution of NaOH (1.99 mL; 19.9 mmol) was added gradually to a solution of p-toluenesulfonyl chloride (2.6 g; 13.6 mmol) and benzyltriethylammonium chloride (CAS 56-37-1 ) (0.194 g; 0.85 mmol) in toluene (5 mL) at 5C. 3- Oxetanemethanol (CAS 6246-06-6) (0.915 mL; 11.35 mmol) was added drop wise below 10C. The reaction mixture was stirred below 10C for 1 hour and at room temperature for 5 hours. The reaction mixture was poured into ice and extracted with DCM (3 times). The organic layer was dried over MgS04, filtered and the solvent was evaporated to give 2.49 g (91 %) of intermediate 49.
70%	With dmap; triethylamine; In dichloromethane; at 20℃; for 3h;	To a solution of oxetan-3-ylmethanol (750 mg, 8.5 mmol) in DCM (15ml) was added N,N-dimethylpyridin-4-amine (122 mg, 1 mmol), TEA (2.0 g, 20 mmol) and4-methylbenzenesulfonyl chloride (1.6 g, 8.5 mmol). The mixture was stirred at rt for 3 h,concentrated, and the residue was purified by column chromatography using ethyl acatatein petroleum ether (1/4) to afford oxetan-3-ylmethyl4-methylbenzenesulfonate (1.4 g, 70%yield). LCMS (ESI) m/z: 243.3 (M + 1t.
66%	With dmap; triethylamine; In dichloromethane; at 20℃; for 16h;	In a round bottom flask, 3-oxetanemethanol (0.919 g, in dichloromethane (DCM) (25 mL).10.43 mmol),Triethylamine (2.181 mL, 15.65 mmol) and 4-toluenesulfonyl chloride (2.187 g, 11.47 mmol) were added andA colorless solution was obtained.4-dimethylaminopyridine (0.064 g, 0.522 mmol) is added,The mixture was stirred at room temperature for about 16 hours.The reaction was quenched with saturated aqueous NH 4 Cl (10 mL) and the layers were separated.Extract the aqueous layer with DCM (2 × 10 mL),The combined organic layers were washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL).The organic layer was dried over MgSO4 and concentrated under reduced pressure,A residue was obtained that was purified by silica gel chromatography eluting with 10-100% ethyl acetate: heptane to give the product (1.71 g, 66% yield).

45%		[00551] A mixture of 166-1 (200.00 mg, 2.27 mmol, 1.00 eq), TEA (459.38 mg, 4.54 mmol, 629.29 uL, 2.00 eq) and DMAP (27.73 mg, 227.00 umol, 0.10 eq) in DCM (10.00 mL) was stirred at 0C for 5 min under N2. Then 4-methylbenzenesulfonyl chloride (454.39 mg, 2.38 mmol, 1.05 eq) was added, and the mixture was stirred at 0C for 1 h. The crude LCMS showed no desired product MS value was detected, and the mixture was stirred at 0C for an additional 5 h. TLC(PE:EtOAc=2: l UV) indicated 166-1 was consumed completely and one new spot formed. The reaction mixture was diluted with DCM (20 mL), washed with brine (20 mL), and then extracted with DCM (25 mL*3). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 166-2 (0.25 g, 1.02 mmol, 45.00% yield).
	With pyridine; at 20℃; for 4h;	Example 54 2-[(4-Fluoro-benzenesulfonyl)-oxetan-3-ylmethyl-amino]-N-(4'-trifluoron-3-ylmethyl-amino]-N- (4' -trifluoro methyl-biphenyl-3-ylmethyl)-acetamide A solution of oxetan-3-yl-methanol (500 mg, 5.68 mmol) in pyridine (5 ml) was treated with p- toluene sulfonylchloride (1.2 g, 6.3 mmol and stirred for 4 h at ambient. The solution was diluted with a solution (50 ml) of 50% ethyl acetate/hexane and filtered. The solution was concentrated in vacuo and washed with 1 N HC1, brine, dried (MgS04) and concentrated in vacuo to afford toluene-4- sulfonic acid oxetan-3-yl methyl ester as an oil. lU NMR (400 MHz, CDC13) delta = 7.73 (d, 2H), 7.38 (d, 2H), 4.68 (t, 2H), 4.24 (t, 2H), 4.18 (d, 2H), 3.22 (m, 1H), 2.41 (s, 3H) ppm
	With dmap; triethylamine; In dichloromethane; at 20℃;	Oxetan-3-ylmethanol (0.5 g, 5.68 mmol) was dissolved in DCM (11.35 ml), then triethylamine (1.186 ml, 8.51 mmol), DMAP (0.069 g, 0.568 mmol), and Tosyl-C1 (1.298 g, 6.81 mmol) were added. The reaction was stirred overnight at rt, then diluted with EtOAc and saturated NH4Cl/water (1:1). The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chormatogaphy on a Biotage 50 g column by eluting with 5% to 70% EtOAc in Hexane to provide the desired product. 1H NMR delta (ppm) 7.82 (d, 2H), 7.39 (d, 2H), 4.76 (t, 2H), 4.34 (t, 2H), 4.28 (d, 2H), 3.31 (septet, 1H), 2.48 (s, 3H).
	With pyridine; at 20℃; for 3h;	p-Toluenesulfonyl chloride (370 mg, 1.94 mmol) is dissolved in pyridine (1.62 mL, 20 mmol). 3-Oxetanemethanol (150 mg, 1.62 mmol) is added. The sol. is stirred at rt for 3 h. The sol. is diluted with EtOAc, and washed with aq. 0.1 M HCI and with aq. sat. NaHC03. The org. layer is dried over Na2S04, filtered, and the solvents are removed under reduced pressure. Purification of the crude by automated FC (Combiflash, EtOAc/heptane 0:100? 50:50) yields the title product. LC-MS: tR = 0.75 min, MH+ = 243.12 (conditions 3).
	With pyridine; In N,N-dimethyl-formamide; at 20℃; for 3h;	Oxetan-3-ylmethyl 4-methylbenzenesulfonate. p-Toluenesulfonyl chloride (370 mg, 1.94 mmol) is dissolved in pyridine (1.62 mL, 20 mmol). 3-Oxetanemethanol (150 mg, 1.62 mmol) is added. The sol. is stirred at rt for 3 h. The sol. is diluted with EtOAc, and washed with aq. 0.1 M HCI and with aq. sat. NaHC03. The org. layer is dried over Na2S04, filtered, and the solvents are removed under reduced pressure. Purification of the crude by automated FC (Combiflash, EtOAc/heptane 0:100? 50:50) yields the title product. LC-MS: tR= 0.75 min, MH+= 243.12 (conditions 3).
	With dmap; triethylamine; In dichloromethane; at 20℃;	Oxetan-3-ylmethanol (0.5 g, 5.68 mmol) was dissolved in DCM (11.35 ml), then triethylamine (1.186 ml, 8.51 mmol), DMAP (0.069 g, 0.568 mmol), and Tosyl-Cl (1.298 g, 6.81 mmol) were added. The reaction was stirred overnight at rt, then diluted with EtOAc and saturated NH4Cl/water (1:1). The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage 50 g column by eluting with 5% to 70% EtOAc in Hexane to provide the desired product. 1H NMR delta (ppm) 7.82 (d, 2H), 7.39 (d, 2H), 4.76 (t, 2H), 4.34 (t, 2H), 4.28 (d, 2H), 3.31 (septet, 1H), 2.48 (s, 3H).
1 g	With dmap; triethylamine; In dichloromethane; at 15℃; for 16h;	Step 1: Preparation of oxetan-3-ylmethyl 4-methylbenzenesulfonate To a stirred solution of 3-oxetanemethanol (500 mg, 5.67 mmol) in DCM (5 mL) was added Et3N (1.0 g, 10.2 mmol) and DMAP (70 mg, 0.57 mmol). Then to the mixture was added a solution of 4-methylbenzenesulfonyl chloride (1.6 g, 8.51 mmol) in DCM (5 mL) dropwise. After being stirred at 15 oC for 16 hrs, the resulting mixture was diluted with DCM (50 mL), washed with H2O (20 mL), 2 N HCl (20 mL) and brine (10 mL), then dried over anhydrous Na2SO4 and concentrated in vacuo to give oxetan-3-ylmethyl 4-methylbenzenesulfonate (1.0 g) as a colorless oil which was used in the next step directly without further purification.
100 mg	With pyridine; In dichloromethane; at 23 - 29℃; for 16h;	To a solution of oxetan-3-ylmethanol (CAS registry number 6246-06-6; 100 mg, 1.14 mmol) in DCM (5 mL) were added TsC1 (260 mg, 1.36 mmol) and pyridine (180 mg, 2.27 mmol). Then the reaction was stirred at 23-29 C for 16 h. TLC (PE: EA = 1: 1) confirmedthat starting material was consumed and a new product was formed. The mixture wasconcentrated and purified by chromatography column on silica gel, eluting with PE: EA = 5:1, to afford oxetan-3-ylmethyl 4-methylbenzenesulfonate (100mg). ?HNMR (CDC13) 5 7.81(d, J 8.0 Hz, 2H), 7.37 (d, J 8.0 Hz, 2H), 4.73-4.77 (t, J= 6.8 Hz, 2H), 4.32-4.35 (t, J=5.6 Hz, 2H), 4.26 (d, J 7.2 Hz, 2H), 3.26-3.33 (m, 1H), 2.47 (s, 3H).
	With dmap; triethylamine; In dichloromethane; at 25℃; for 16h;	Compound WX058-1 (200 mg, 2.27 mmol, 1 eq) and dichloromethane (5 mL) were added into a 40 mL pre-dried reaction bottle, and triethylamine (344.56 mg, 3.41 mmol, 473.94 muL, 1.5 eq), dimethylaminopyridine (27.73 mg, 227.00 mumol, 0.1 eq) and p-toluenesulfonyl chloride (519.34 mg, 2.72 mmol, 1.2 eq) were added. The reaction solution was stirred at 25 C. for 16 hours. The reaction solution was added with saturated aqueous ammonium chloride solution (20 mL), and extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a thin layer chromatography silica gel plate (petroleum ether:ethyl acetate=3:1) to obtain WX058-2. 1H NMR (400 MHz, CHLOROFORM-d) delta=7.78 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 4.70 (dd, J=7.6, 6.4 Hz, 2H), 4.30 (t, J=6.4 Hz, 2H), 4.23 (d, J=76.8 Hz, 2H), 3.29-3.22 (m, 1H), 2.43 (s, 3H).
	With dmap; triethylamine; In dichloromethane; at 25℃; for 16h;	Compound WX011-1 (200 mg, 2.27 mmol, 1 eq) and dichloromethane (5 mL) were added into a pre-dried 40 mL reaction flask, followed by triethylamine (344.56 mg, 3.41 mmol, 473.94 muL, 1.5 eq), dimethylaminopyridine (27.73 mg, 227.00 mumol, 0.1 eq) and p-toluenesulfonyl chloride 1 (519.34 mg, 2.72 mmol, 1.2 eq). The reaction solution was stirred at 25C for 16 hours. A saturated aqueous solution of ammonium chloride (20 mL) was added to the reaction solution, and extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by thin layer chromatography silica gel plate (petroleum ether: ethyl acetate = 3:1) to give WX011-2. 1H NMR (400MHz, CHLOROFORM-d) delta = 7.78 (d, J=8.0Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 4.70(dd, J=7.6, 6.4 Hz, 2H), 4.30 (t, J=6.4 Hz, 2H), 4.23 (d, J=76.8 Hz, 2H), 3.29-3.22 (m, 1H), 2.43 (s, 3H).

Reference： [1]Patent: WO2013/61080,2013,A1 .Location in patent: Page/Page column 161; 162
[2]Patent: WO2018/154466,2018,A1 .Location in patent: Paragraph 00451; 00453; 0054
[3]Patent: JP6557436,2019,B1 .Location in patent: Paragraph 0483; 0484; 0485
[4]ChemMedChem,2019,vol. 14,p. 1560 - 1572
[5]Patent: WO2018/204532,2018,A1 .Location in patent: Paragraph 00551
[6]Patent: WO2014/49047,2014,A1 .Location in patent: Page/Page column 85; 86
[7]Patent: US2015/210685,2015,A1 .Location in patent: Paragraph 0570-0571
[8]Patent: WO2015/186056,2015,A1 .Location in patent: Page/Page column 105
[9]Patent: WO2016/41892,2016,A1 .Location in patent: Page/Page column 49
[10]Patent: US9382243,2016,B2 .Location in patent: Page/Page column 81
[11]Patent: WO2016/177655,2016,A1 .Location in patent: Page/Page column 129; 130
[12]Patent: WO2017/112768,2017,A1 .Location in patent: Page/Page column 105; 106
[13]Patent: US2019/375728,2019,A1 .Location in patent: Paragraph 0582
[14]Patent: EP3572412,2019,A1 .Location in patent: Paragraph 0164-0166

2
[ 269410-08-4 ]
[ 1395417-57-8 ]
[ 1578484-07-7 ]

Yield	Reaction Conditions	Operation in experiment
		The following Preparations were prepared according to Method H (Preparation 122) using 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole and the appropriate alkyl electrophile.

Reference： [1]Patent: WO2014/37751,2014,A1 .Location in patent: Paragraph 00419

3
[ 1395417-57-8 ]
[ 5680-79-5 ]
[ 1590397-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In acetonitrile; at 50 - 55℃; for 16h;	A solution of toluene -4-sulfonic acid oxetan-3-yl methyl ester (500 mg, 2.2 mmol) and amino-acetic acid methyl ester hydrochloride (950 mg, 7.6 mmol) in acetonitrile (10 ml) was combined with NaHC03 (1.32 g, 15.8 mmol) and stirred at 50-55 C for 16 h. The mixture was diluted with ether and filtered through Celite) and concentrated in vacuo. This crude material was purified by flash chromatography (ethyl acetate then 10% methanol/ CH2C12) to afford [(oxetan-3-ylmethyl)-amino]- acetic acid methyl ester an oil. lU NMR (400 MHz, CDC13) delta = 4.75 (t, 2H), 4.45 (t, 2H), 3.78 (s, 3H), 3.48 (d, 2H), 3.12 (M, 1H) ppm.

Reference： [1]Patent: WO2014/49047,2014,A1 .Location in patent: Page/Page column 86

Yield	Reaction Conditions	Operation in experiment
68.4%	With triethylamine; In dichloromethane; at 25℃; for 24h;	General procedure: P-toluenesulfonyl chloride (1.0g, 5.2mmol) at 25 CAnd triethylamine (2.2mL, 15.7mmol) were added to a 100mL single-necked flask,Add dichloromethane (10mL),Add oxetane-3-ol (0.5g, 6.7mmol) in portions, and continue the reaction for another 24 hours; add water (40mL), then add dichloromethane (20mL), separate the liquid, collect the organic phase, reduce Spin dry and separate by column chromatography (petroleum ether / ethyl acetate (v / v) = 10/1 to 5/1) to obtain the title compound as a light yellow solid (1.02g, 85.2%).
287 mg	With pyridine; In pyridine; at 0 - 35℃;Cooling with ice;	General procedure: A-1) To a solution of 1-methoxybutan-2-yl 4-methylbenzenesulfonate [0443] To a solution of 1-methoxybutan-2-ol (1.10 mL) in pyridine (5 mL) was added dropwise a solution of 4-methylbenzenesulfonyl chloride (2.75 g) in pyridine (15 mL) over 30 min or more at 0C. The reaction mixture was stirred overnight at room temperature, and poured into ice-water. The reaction mixture was stirred at 0C for 1 hr, and the precipitate was collected by filtration, and washed with cold water. The obtained solid was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.23 g). 1H NMR (300 MHz, DMSO-d6) delta 0.74 (3H, t, J = 7.4 Hz), 1.45-1.66 (2H, m), 2.42 (3H, s), 3.12 (3H, s), 3.33-3.40 (2H, m), 4.46-4.60 (1H, m), 7.46 (2H, d, J = 7.9 Hz), 7.74-7.84 (2H, m). A-2) 3-iodo-4-methoxy-1-(1-methoxybutan-2-yl)-1H-pyrrolo[3,2-c]pyridine

5
[ 1395417-57-8 ]
4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide [ No CAS ]
4-(1-(oxetan-3-ylmethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10 mg		B) 4-(1-(oxetan-3-ylmethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide [0651] To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (52.0 mg) obtained in Step B of Example 100 in DMF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 8.60 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (52.1 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (10.0 mg). 1H NMR (300 MHz, DMSO-d6) delta 3.44-3.59 (1H, m), 4.49 (2H, t, J = 6.2 Hz), 4.61-4.72 (4H, m), 6.75 (1H, d, J= 7.2 Hz), 7.30 (1H, d, J= 7.2 Hz), 7.39 (2H, brs), 7.87 (2H, d, J = 8.7 Hz), 8.48 (2H, d, J = 8.7 Hz), 11.19 (1H, brs). MS (ESI+) : [M+H]+361.1. MS (ESI+), found: 360.9

Reference： [1]Patent: EP2857400,2015,A1 .Location in patent: Paragraph 0651

6
[ 1395417-57-8 ]
[ 106-53-6 ]
C₁₀H₁₁BrO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		4-bromothiophenol (1 g, 5.29 mmol), <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (1.281 g, 5.29 mmol), and cesium carbonate (3.45 g, 10.58 mmol) were suspended in DMSO (5.29 ml). The reaction was stirred 2 days at rt, and then diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage 50 g column by eluting with 10% to 90% EtOAc:Hexane. The major peak was isolated, concentrated and dissolved in MeOH (8 mL), THF (8 mL) and water (4 mL). Oxone (5.9 g, 9.6 mmol) was added and the reaction was stirred overnight at rt. The reaction was then diluted with water and EtOAc. The organic phase was washed with water, Na2S2O3, and brine, and then dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage 50 g column by eluting with 10% to 90% EtOAc:Hexane to provide the desired product. 1H NMR delta 7.78-7.74 (m, 4H), 4.79 (t, 2H), 4.45 (t, 2H), 3.51-3.48 (m, 3H).

Reference： [1]Patent: US2015/210685,2015,A1 .Location in patent: Paragraph 0572-0573

7
[ 1256577-84-0 ]
[ 1395417-57-8 ]
C₂₈H₂₇N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; N-ethyl-N,N-diisopropylamine; potassium iodide; In N,N-dimethyl-formamide; at 55 - 80℃; for 48h;	A mixture of 7a (0.2 mmol), an appropriate bromide or methanesulfonate (0.4 mmol), K2CO3 (0.6 mmol), DIEA (0.4 mmol) and KI (0.04 mmol) in 4 mL DMF was heated at 55 o C-80 o C for 2 days until the completion of the reaction. The mixture was treated with EtOAc (100 mL), washed with brine and then dried over with Na2SO4, filtered, and evaporated. The crude product was purified by chromatograph (CHCl3/MeOH) to give the corresponding products.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 105,p. 39 - 56

8
[ 106-41-2 ]
[ 1395417-57-8 ]
[ 1393688-54-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 130℃; for 1.5h;	A mixture of oxetan-3-yl methyl 4-methylbenzenesulfonate (300 mg, 1.24 mmol), 4-bromphenol (236 mg, 1.36 mmol), Kl (88 mg, 0.43 mmol) and K2C03 (342 mg, 2.48 mmol) in DMF (1.8 mL) is stirred at 130 C for 1.5 h. The mixture is allowed to cool to rt, and is partitioned between EtOAc and water. The org. layer is washed with water (3x), dried over Na2S04, filtered, and the solvents are removed under reduced pressure. Purification of the crude by FC (Combiflash, 12 g silicagel, EtOAc / heptane 0: 100? 30:70) yields the title product. LC-MS: tR = 0.82 min (conditions 3).
	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 130℃; for 1.5h;	3-((4-Bromophenoxy)methyl)-3-oxetane. A mixture of <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (300 mg, 1.24 mmol), 4-bromphenol (236 mg, 1.36 mmol), Kl (88 mg, 0.43 mmol) and K2C03(342 mg, 2.48 mmol) in DMF (1.8 mL) is stirred at 130 C for 1.5 h. The mixture is allowed to cool to rt, and is partitioned between EtOAc and water. The org. layer is washed with water (3x), dried over Na2S04, filtered, and the solvents are removed under reduced pressure. Purification of the crude by FC (Combiflash, 12 g silicagel, EtOAc / heptane 0:100? 30:70) yields the title product. LC-MS: tR= 0.82 min (conditions 3).

Reference： [1]Patent: WO2015/186056,2015,A1 .Location in patent: Page/Page column 106
[2]Patent: WO2016/41892,2016,A1 .Location in patent: Page/Page column 49

9
[ 1395417-57-8 ]
[ 106-53-6 ]
C₁₀H₁₁BrOS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In dimethyl sulfoxide; at 20℃; for 48h;	4-bromothiophenol (1 g, 5.29 mmol), <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (1.281 g, 5.29 mmol), and cesium carbonate (3.45 g, 10.58 mmol) were suspended in DMSO (5.29 ml). The reaction was stirred 2 days at rt, and then diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage 50 g column by eluting with 10% to 90% EtOAc:Hexane. The major peak was isolated, concentrated and dissolved in MeOH (8 mL), THF (8 mL) and water (4 mL). Oxone (5.9 g, 9.6 mmol) was added and the reaction was stirred overnight at rt. The reaction was then diluted with water and EtOAc. The organic phase was washed with water, Na2S2O3, and brine, and then dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage 50 g column by eluting with 10% to 90% EtOAc:Hexane to provide the desired product. 1H NMR delta 7.78-7.74 (m, 4H), 4.79 (t, 2H), 4.45 (t, 2H), 3.51-3.48 (m, 3H).

Reference： [1]Patent: US9382243,2016,B2 .Location in patent: Page/Page column 81

10
[ 1395417-57-8 ]
(R)-tert-butyl 6-((4-((1-acryloylpiperidin-3-yl)amino)-5-fluoropyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]
(R)-1-(3-(5-fluoro-2-(2-(oxetan-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21.5%		A mixture of (R)-tert-butyl 6-((4-((1-acryloylpiperidin-3-yl)amino)-5- fluoropyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (27.2) (100 mg, 0.2 mmol) in TFA (3 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated to dryness and diluted with CH3CN (10 mL). K2CO3 (60 mg, 0.4 mmol) and oxetan-3-ylmethyl-4-methylbenzenesulfonate (50 mg, 0.2 mmol) were added. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (DCM/methanol: 10/1) to afford (R)-1-(3-(5-fluoro-2-(2-(oxetan-3-ylmethyl)- 1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one (I-32) as a yellow solid (20 mg, 21.5%). [00530] LCMS:467.2 [M+1]+. [00531] 1H NMR (400 MHz, DMSO-d6): delta 1.38-1.43 (m, 1H), 1.61-1.65 (m, 1H), 1.79-1.84 (m, 1H), 1.97-2.01 (m, 1H), 2.56 (br, 2H), 2.66-2.75 (m, 5H), 3.02-3.18 (m, 1H), 3.25 (t, 1H), 3.39 (s, 2H), 4.00 (dd, 2H), 4.19 (dd, 0.5H), 4.29 (t, 2H), 4.41-4.44 (m, 0.5H), 4.66 (dd, 2H), 5.47 (d, 0.5H), 5.71 (dd, 0.5H), 6.02 (dd, 0.5H), 6.10 (dd, 0.5H), 6.60 (dd, 0.5H), 6.82-6.88 (m, 1.5H), 7.28 (t, 1H), 7.35 (d, 1H), 7.55 (d, 1H), 7.90 (d, 1H), 8.95 (s, 1H).

Reference： [1]Patent: WO2016/90079,2016,A1 .Location in patent: Paragraph 00529-00531

11
[ 1395417-57-8 ]
(R)-1-(3-(5-fluoro-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]
(R)-1-(3-(5-fluoro-2-(2-(oxetan-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50.9%	With potassium carbonate; In acetonitrile; at 55℃;Inert atmosphere;	To a solution of (R)-1-(3-(5-fluoro-2-(1,2,3,4-tetrahydroisoquinolin-7- ylamino)pyrimidin-4-ylamino)-piperidin-1-yl)prop-2-en-1-one (I-33) (100 mg, 0.25 mmol) in CH3CN (150 mL) was added K2CO3 (277 mg, 0.50 mmol) and oxetan-3-ylmethyl 4- methylbenzenesulfonate (91.65 mg, 0.37 mmol). The reaction mixture was stirred at 55 C overnight under N2. TLC showed the reaction was complete. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (DCM:MeOH=10:1) to afford (R)-1-(3-(5-fluoro-2-(2- (oxetan-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)piperidin-1- yl)prop-2-en-1-one (I-36) as a yellow solid (60 mg, 50.9%). [00557] LCMS: 467.1 [M+1]+. [00558] 1H NMR (400 MHz, DMSO-d6): delta 1.40-1.43 (m, 1H), 1.60-1.64 (m, 1H), 1.65-1.86 (m, 1H), 1.98-2.00 (m, 1H), 2.58-2.75 (m, 6H), 2.99-3.14 (m, 1H), 3.23-3.26 (m, 1H), 3.38-3.39 (m, 3H), 4.00-4.03 (m, 2H), 4.22-4.28 (m, 2.5H), 4.43 (d, 0.5H), 4.63-4.68 (m, 2H), 5.48 (d, 0.5H), 5.70 (d, 0.5H), 6.11 (dd, 1H), 6.60 (dd, 0.5H), 6.83-6.89 (m, 1.5H), 7.24-7.39 (m, 2H), 7.49 (s, 1H),7.88 (d, 1H).

Reference： [1]Patent: WO2016/90079,2016,A1 .Location in patent: Paragraph 00556-00558

12
[ 1395417-57-8 ]
(R)-1-(3-((5-fluoro-2-((2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]
(R)-1-(3-((5-fluoro-2-((2-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With potassium carbonate; sodium iodide; In acetonitrile;Reflux;	A solution of (R)-1-(3-((5-fluoro-2-((2,3,4,5-tetrahydro-1H-benzo[c]azepin-7- yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (50.9) (0.39 mmol) and oxetan- 3-ylmethyl-4-methyl benzenesulfonate (142 mg, 0.58 mmol), K2CO3 (83 mg, 0.78 mmol), and NaI (58 mg, 0.39 mmol) in MeCN (5 mL) was heated at reflux overnight. TLC showed the reaction was complete. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was purified by column chromatography to afford (R)-1-(3-((5-fluoro-2-((2-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (I-50) as a yellow solid (50 mg, 27%). [00738] LCMS: 481.4 [M+1]+. [00739] 1HNMR (DMSO-d6): delta 1.39 (br, 1H), 1.55-1.67 (m, 3H), 1.80-1.84 (m, 1H), 1.97- 2.01 (m, 1H), 2.54 (s, 2H), 2.69-2.77 (m, 2H), 2.94-3.13 (m, 4H), 3.69 (s, 2H), 4.02 (d, 2H), 4.16-4.24 (m, 2.5H), 4.43 (d, 0.5H), 4.58 (t, 2H), 5.48 (d, 0.5H), 5.71 (d, 0.5H), 6.02 (d, 0.5H), 6.13 (d, 0.5H), 6.63 (dd, 0.5H), 6.86 (dd, 0.5H), 6.95 (d, 1H), 7.30 (t, 1H), 7.40 (t, 1H), 7.53 (s, 1H), 7.89 (s, 1H), 9.00 (s, 1H).

Reference： [1]Patent: WO2016/90079,2016,A1 .Location in patent: Paragraph 00737-00739

13
[ 1395417-57-8 ]
(R)-1-(3-(5-fluoro-2-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]
(R)-1-(3-(5-fluoro-2-(2-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With caesium carbonate; In acetonitrile; at 90℃; for 5h;	A mixture of (R)-1-(3-(5-fluoro-2-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-8- ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one (I-53) (200 mg, 0.49 mmol), <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (177 mg, 0.73 mmol), and Cs2CO3 (318 mg, 0.97 mmol) in acetonitrile (MeCN) (8 mL) was stirred at 90 C for 5 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM/MeOH: 10/1) to afford (R)-1-(3-(5-fluoro-2-(2-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8- ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one (I-56) as a white solid (30 mg, 13%). [00814] Mp: 103-105 C. [00815] LCMS: 481.2 [M+1]+. [00816] 1H NMR (400 MHz, DMSO-d6): delta 1.38-1.44 (m, 1H), 1.52-1.68 (m, 3H), 1.80-1.85 (m, 1H), 1.98-2.02 (m, 1H), 2.40-2.46 (m, 1H), 2.54-2.56 (m, 1H), 2.67-3.15 (m, 7H), 3.68-3.69 (m, 2H), 3.99-4.01 (m, 2H), 4.18-4.19 (m, 2.5H), 4.38-4.42 (m, 0.5H), 4.58 (t, 2H), 5.47-5.49 (m, 0.5H), 5.69-5.72 (m, 0.5H), 6.00-6.14 (m, 1H), 6.58-6.65 (m, 0.5H), 6.82-6.88 (m, 0.5H), 6.94 (d, 1H), 7.34-7.45 (m, 3H), 7.90 (s, 1H), 8.94 (s, 1H).

Reference： [1]Patent: WO2016/90079,2016,A1 .Location in patent: Paragraph 00813-00816

14
[ 1395417-57-8 ]
(R)-1-(3-(5-fluoro-2-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]
(R)-1-(3-(5-fluoro-2-(3-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With potassium carbonate; In acetonitrile; at 80℃;	To a solution of 1-[(3R)-3-[[5-fluoro-2-(2,3,4,5-tetrahydro-1H-3-benzazepin-7- ylamino)pyrimidin-4-yl]amino]-1-piperidyl]prop-2-en-1-one (I-57) (200 mg, 0.49mmol) in MeCN (20mL) was added oxetan-3-ylmethyl 4-methylbenzene sulfonate (118 mg, 0.49 mmol) and K2CO3 (103 mg, 0.97 mmol). The mixture was stirred at 80 C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated to afford the crude product. The crude product was purified by column chromatography (DCM/MeOH: 10/1) to afford (R)-1-(3-(5-fluoro-2-(3-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7- ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2- en-1-one (I-59) as an off-white solid (55 mg, 24%). [00850] Mp: 104-106 C [00851] LCMS: 481.3 [M+1]+. [00852] 1H NMR (400 MHz, DMSO-d6): delta 1.36-1.40 (m, 1H), 1.61-1.64 (m, 1H), 1.80-1.83 (m, 1H), 1.91-2.00 (m, 1H), 2.44-2.49 (m, 4H), 2.67-2.74 (m, 6H), 2.97-3.20 (m, 2H), 4.00-4.03 (m, 2H), 4.21-4.27 (m, 2.5H), 4.41-4.45 (m, 0.5H), 4.62-4.65 (m, 2H), 5.46-5.49 (m, 0.5H), 5.69- 5.72 (m, 0.5H), 5.99-6.15 (m, 1H), 6.56-6.62 (m, 0.5H), 6.83-6.92 (m, 1.5H), 7.27-7.30 (m, 1H), 7.36-7.40 (m, 1H), 7.46-7.50 (m, 1H), 7.88 (d, 1H), 8.94 (s, 1H).

Reference： [1]Patent: WO2016/90079,2016,A1 .Location in patent: Paragraph 00849-00852

15
[ 1395417-57-8 ]
(R)-1-(3-(5-fluoro-2-(isoindolin-5-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one trifluoroacetate [ No CAS ]
(R)-1-(3-((5-fluoro-2-((2-(oxetan-3-ylmethyl)isoindolin-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18.8%	With potassium carbonate; In acetonitrile; at 40℃;Inert atmosphere;	To a stirred solution of (R)-1-(3-((5-fluoro-2-(isoindolin-5-ylamino)pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one (I-1) (17mg, 0.31mmol) in acetonitrile (15 mL) was added K2CO3 (86.5 mg, 0.62 mmol) and <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong>. The reaction mixture was stirred at 40 C overnight under N2. TLC showed the reaction was complete. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (dichloromethane: methanol/20:1) to afford (R)-1-(3-((5-fluoro-2-((2-(oxetan-3- ylmethyl)isoindolin-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (I-15) as a yellow solid (26 mg, 18.8%). [00397] LCMS: 453.4 [M+1]+ [00398] 1H NMR (400 MHz, DMSO-d6): delta1.35-1.42 (m, 1H), 1.60-1.66 (m, 1H), 1.80-1.83 (m, 1H), 1.96-1.99 (m, 1H), 2.66-2.76 (m, 1H), 2.93-2.97 (m, 2H), 3.00-3.04 (m, 0.5H), 3.12- 3.19 (m, 1.5H), 3.69 (d, 4H), 3.99-4.03 (m, 2H), 4.23 (d, 0.5H), 4.30-4.31 (m, 2H), 4.45 (d, 0.5H), 4.67 (t, 2H), 5.48 (d, 0.5H), 5.73 (t, 0.5H), 6.01-6.15 (m, 1H), 6.59-6.66 (m, 0.5H), 6.84- 6.91 (m, 0.5H), 7.00 (d, 1H).

Reference： [1]Patent: WO2016/90079,2016,A1 .Location in patent: Paragraph 00396-00398

16
[ 1395417-57-8 ]
1-methyl-N-(1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ No CAS ]
1-methyl-N-(1-methylcyclopropyl)-3-(oxetan-3-ylmethyl)-2,4-dioxoquinazoline-6-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 16h;	1 -Methyl-N-(1 -methylcyclopropyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6- sulfonamide (Intermediate S3-C) (1 eq), sodium hydride (60% w/w) (1 .1 eq), alkyl halide or mesylate (1 .1 eq), (if mesylate was used, Nal (0.2 eq. added) in DMF was stirred at ambient temperature for 16 h (less if LCMS indicated reaction complete. Prepared using Method A3 (tosylate), from l-methyl-N-(l-methylcyclopropyl)2,4-dioxo-quinazoline-6-sulfonamide and <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong>. This gave the desired product (31 mg, 0.082 mmol, 42%) as a white powder.

Reference： [1]Patent: WO2016/92326,2016,A1 .Location in patent: Paragraph 00287; 00671

17
[ 1395417-57-8 ]
N-[1-(fluoromethyl)cyclopropyl]-3-[(3-methylisoxazol-5-yl)methyl]-2,4-dioxo-1H-quinazoline-6-sulfonamide [ No CAS ]
N-[1-(fluoromethyl)cyclopropyl]-3-[(3-methylisoxazol-5-yl)methyl]-1-(oxetan-3-ylmethyl)-2,4-dioxoquinazoline-6-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With sodium iodide; In N,N-dimethyl-formamide; at 80 - 100℃;Microwave irradiation;	General procedure: Quinazolinedione intermediate (Intermediates S4-01 and S4-C2) (1 eq), potassium carbonate (1 .2 eq), alkyl halide, mesylate or tosylate (1 .2 eq), in DMF was heated by microwave irradiation at 80 00 for 10-20 mm. The reaction mixture was monitored byLCMS and if <10% product conversion, further heated by microwave irradiation at 100 00 for1-2 h. In certain cases, as indicated, sodium iodide (1.2 eq) was added to the reaction mixture.Prepared using Method A10, from N-[1-(fluoromethyl)cyclopropyl]-3-[(3-methylisoxazol-5-yI)methyl]-2,4-dioxo-1 H-quinazoline-6-sulfonamide, <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> and 0.2 eq. Nal. This gave the desired product (22 mg, 0.0460 mmol, 31%) as a white powder.

Reference： [1]Patent: WO2016/92326,2016,A1 .Location in patent: Paragraph 00294; 00753

18
[ 111-77-3 ]
[ 1395417-57-8 ]
C₉H₁₈O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 48h;	Diethylene glycol monomethyl ether (20g, 170mmol) and sodium hydride (4g, 170mmol) in anhydrous tetrahydrofuran until no bubbles, and then at 0 3- methyl-3- (p-toluenesulfonic acid methyl ester) oxetane (43g, 170mmol) was added dropwise to the reaction system, the reaction was added dropwise at room temperature 48 hours after recovery.After the reaction, the reaction solution was diluted with water, and extracted by dichloromethane, distilled under reduced pressure to give a colorless liquid.Yield: 65%.1

Reference： [1]Patent: CN105523946,2016,A .Location in patent: Paragraph 0024; 0031; 0032

19
[ 109-86-4 ]
[ 1395417-57-8 ]
C₇H₁₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 48h;	Ethylene glycol monomethyl ether (12.9g, 170mmol) and sodium hydride (4g, 170mmol) until no bubbles produced in the reaction of anhydrous tetrahydrofuran, and then at 0 3- (methyl tosylate) oxy oxetane (41.2g, 170mmol) was added dropwise to the reaction system, the reaction was added dropwise at room temperature 48 hours after recovery.After the reaction, the reaction solution was diluted with water and extracted by dichloromethane, distilled under reduced pressure to give a colorless liquid.Yield: 60%.

Reference： [1]Patent: CN105523946,2016,A .Location in patent: Paragraph 0019; 0020

20
[ 1395417-57-8 ]
methyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-hydroxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate [ No CAS ]
methyl 2-([1-[(2-chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h;	To a solution of methyl 2-[[1-[(2- chlorophenyl)methylj -5 -(3 -hydroxyphenyl)pyrazol-3 -yljmethoxyl -2-methyl-propanoate (0.170 g, 0.410 mmol) in DMF was added <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (0.149 g, 0.615 mmol) and K2C03 (0.113 g, 0.820 mmol) at room temperature. The mixture was heated at 60 C for 16 h. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with EtOAc (20 mLx2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was chromatographed over Si02 using 0- 100% gradient of EtOAc in hexane to afford the title product. ?HNMR (CDC13): oe 1.54 (s, 6H), 3.33-3.36(m, 1H), 3.77(s, 3H), 3.97(d, 2H), 4.30 (t, 2H), 4.56(s, 2H), 4.84(t, 2H), 5.40(s, 2H), 6.53(s, 1H), 6.77-6.90(m, 4H), 7.19-7.37(m, 4H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h;	Methyl 2-([1-[(2-chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]1H-pyrazol-3-yl]methoxy)-2-methyl-propanoate.To a solution of methyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-hydroxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate (0.170 g, 0.410 mmol) in DMF was added <strong>[1395417-57-8][oxetan-3-yl]methyl 4-methylbenzenesulfonate</strong> (0.149 g, 0.615 mmol) and K2cO3 (0.113 g, 0.820 mmol) at room temperature. The mixture was heated at 60 C. for 16 h. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with EtOAc (20 mL*2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was chromatographed over SiO2 using 0-100% gradient of EtOAc in hexane to afford the title product. 1HNMR (CDCl3): delta 1.54 (s, 6H), 3.33-3.36(m, 1H), 3.77(s, 3H), 3.97(d, 2H), 4.30 (t, 2H), 4.56(s, 2H), 4.84(t, 2H), 5.40(s, 2H), 6.53(s, 1H), 6.77-6.90(m, 4H), 7.19-7.37(m, 4H).

Reference： [1]Patent: WO2016/201426,2016,A1 .Location in patent: Paragraph 0294
[2]Patent: US2018/162822,2018,A1 .Location in patent: Paragraph 0698

21
[ 1395417-57-8 ]
2,3-difluoro-5-(5-methyl-2-(pyrimidin-2-yl)-7,8-dihydropyrido [4,3-d]pyrimidin-6(5H)-yl)phenol [ No CAS ]
6-[3,4-difluoro-5-(oxetan-3-ylmethoxy)phenyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69 mg	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;	Step 2: Preparation of 6-[3,4-difluoro-5-(oxetan-3-ylmethoxy)phenyl]-5-methyl-2- pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine A mixture of 2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)phenol (100 mg, 0.28 mmol), <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (82 mg, 0.34 mmol) and Cs2CO3 (138 mg, 0.42 mmol) in DMF (3 mL) was heated to 80 oC with stirring for 12 hrs. The reaction mixture was cooled down to rt and diluted with EA (20 mL). The organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by the prep-HPLC to give 6-[3,4-difluoro-5-(oxetan-3- ylmethoxy)phenyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine (69 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) 9.04 (d, 2 H), 8.79 (s, 1 H), 7.45 (t, 1 H), 6.35 - 6.48 (m, 2 H), 4.98 (q, 1 H), 4.87 - 4.94 (m, 2 H), 4.52 - 4.63 (m, 2 H), 4.26 - 4.37 (m, 2 H), 3.66 - 3.78 (m, 1 H), 3.41 - 3.58 (m, 2 H), 3.21 - 3.38 (m, 2 H), 1.46 (d, 3 H). MS obsd. (ESI+) [(M+H)+] : 426.

Reference： [1]Patent: WO2016/177655,2016,A1 .Location in patent: Page/Page column 130

22
[ 1395417-57-8 ]
4-(2,6-diazaspiro[3.3]heptan-2-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine [ No CAS ]
4-(6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8 mg	With triethylamine; In N,N-dimethyl-formamide; at 100℃; for 16h;	To a solution of 4-(2,6-diazaspiro[3 .3 ]heptan-2-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3 - d]pyrimidine (40 mg, 0.14 mmol) in DMF (3 mL) were added <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (47 mg, 0.19 mmol) and TEA (40 mg, 0.39 mmol). Then the reaction was heated at 100 C for 16 h. The mixture was concentrated and purified by preparative RP-LCMS method D to give the title compound (8 mg); LCMS method C: R = 1.1 mm; (M+H) = 385.0; ?HNMR (methanol-d4) 5 8.27 (s, 1 H), 7.36 (s, 1 H), 4.76-4.80 (m, 2 H), 4.43-4.49 (m, 4 H), 4.41 (t, J= 7.6 Hz, 2 H), 3.84-3.92 (q, J 6.0 Hz, 2 H), 3.48 (s,4 H), 3.03-3.10 (m, 2H), 2.81 (d, J= 7.2 Hz, 1 H); ?9F NIVIR (methanol-d4) 5 -67.174.

Reference： [1]Patent: WO2017/112768,2017,A1 .Location in patent: Page/Page column 106

23
[ 1395417-57-8 ]
(1S,3’R,6’R,7’S,8’E)-6-chloro-7'-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-3,4-dihydro-2H,15’H-spiro[naphthalene-1,22’-[20]oxa[13]thia[1,12,14]triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16,18,24]tetraen]-15'-one-13',13'-dioxide [ No CAS ]
C₃₉H₅₄ClN₃O₆SSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of (1 S,3?R.6R,7S.8E)-6-chloro-7-[(tert-butyidimethyisiiy)oxy] -3 ,4-dihydro-2H. 15?H-spiro[naphthaiene- 1,22- [2ojoxa[ I 3thia[i ,12, 14Itriazatetracycio 14.7.2.03?6.0?9?24ipentacosa[8, 16,1 8,24itet raeni-15-one 13,13-dioxide (58mg, 0.085 mmol. Example 32, step 1) in THF (1 mL) in an oven-dried microwave tube was added lithium bis(trimethvisilvi)amide, 1.0 M solution in TI-IF (0.338 mL, 0.338 mrnoi) and the reaction was stirred at () C for 10 minutes followed by the addition of a solution of oxetan-3- ylmethyl 4-rnethylhenzenesuifonate (71.7 mg, 0.296 mmol) in THF (0.4 rnL). The resulting mixture was stirred at 100 C in a microwave oven for 3.5 hours. The reaction was quenched with saturated NH4CI and extracted with EtOAc. Theorganic extract was washed with brine, dried with MgSO4, filtered and concentrated to give a crude aikylation product. The crude was treated with tetrabutylammonium fluoride solution, (1.0 M in TI-IF, 0.994 rnL, 3.80 mmol) and a small arnout of molecular sieve at 55 C for 1 hour. After concentration the residue was purified by reversed phase preparatory HPLC (GeminiTM Prep Cu 5im column; Phenomenex, Torrance, CA; gradient elution of 45% to 85% MeCN in water, where both solvents contain 0.1% TFA, 30 mm method) to afford the title compound as a solid (42 mg, 0.065 l.tmoi, 77% yield).

Reference： [1]Patent: WO2017/147410,2017,A1 .Location in patent: Page/Page column 255; 256

24
[ 1395417-57-8 ]
[ 333-20-0 ]
[ 1622903-23-4 ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1130 - 1152

25
[ 1395417-57-8 ]
ethyl 9'-hydroxy-10'-methyl-2'-oxo-2',7'-dihydrospiro[cyclobutane-1,6'-pyrido[2,1-a]isoquinoline]-3'-carboxylate [ No CAS ]
ethyl 10'-methyl-9'-(oxetan-3-ylmethoxy)-2'-oxo-2',7'-dihydrospiro[cyclobutane-1,6'-pyrido[2,1-a]isoquinoline]-3'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium carbonate; In acetonitrile; at 85℃; for 6h;Schlenk technique;	A Schlenk was charged with ethyl 9'-hydroxy-1 0'-methyl-2'-oxo-2',7'-dihydrospiro[cyclobutane-1 ,6'-pyrido[2, 1-a]isoquinoline]-3'-carboxylate (1 00 mg, 0.29 mmol),<strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (43 mg, 0.35 mmol) and CH3CN (2 ml).Potassium carbonate (48 mg, 0.35 mmol) was added and the mixture stirred for 6 h at 85C. After cooling, the obtained inorganic salt was filtered off. Ethyl acetate was added to thefiltrate and washed with brine. After drying with anhydrous magnesium sulfate the solventwas evaporated and the residue purified by column chromatography to afford ethyl 1 0'methyl-9'-( oxetan-3-ylmethoxy)-2'-oxo-2', 7'-dihydrospiro[ cyclobutane-1 ,6'-pyrido[2, 1-a]isoquinoline]-3'-carboxylate (65 mg, 55% yield). LCMS (ESI) m/z: 410.2 (M + 1t.

Reference： [1]Patent: WO2018/154466,2018,A1 .Location in patent: Paragraph 00385; 00387; 00388

26
[ 1395417-57-8 ]
ethyl 10'-formyl-9'-hydroxy-2'-oxo-2',7'dihydrospiro[cyclobutane-1,6'-pyrido[2,1-a]isoquinoline]-3'-carboxylate [ No CAS ]
ethyl 10'-formyl-9'-(oxetan-3-ylmethoxy)-2'-oxo-2',7'-dihydrospiro[cyclobutane-1,6'-pyrido[2,1-a]isoquinoline]-3'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;	To a solution of ethyl 1 0'-formyl-9'-hydroxy-2'-oxo-2', 7'-dihydrospiro[cyclobutane-1 ,6'-pyrido[2, 1-a]isoquinoline]-3'-carboxylate (1 00 mg, 0.28 mmol)in DMF (4 ml) was added <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (136 mg, O.S6mmol) and K2C03 (116 mg, 0.84 mmol). The reaction mixture was heated at 90 C for 4 h,cooled to room temperature, poured into water (30 ml), and extracted with DCM (2S X 2ml). The combined organic layers were washed with brine (30 X 4 ml), concentrated, andthe residue purified by prep TLC eluting with MeOH in DCM (1/1S) to afford ethyl10'formyl-9'-( oxetan-3-ylmethoxy)-2'-oxo-2', 7'-d ihydrospiro[ cyclobutane-1 ,6'-pyrido[2, 1-a]isoquinoline]-3'-carboxylate (1 OS mg, 88% yield). LCMS (ESI) m/z: 424.4 (M + 1f.

Reference： [1]Patent: WO2018/154466,2018,A1 .Location in patent: Paragraph 00451; 00457; 00458

27
[ 1395417-57-8 ]
ethyl 10-formyl-9-hydroxy-6-isopropyl-6-methyl-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate [ No CAS ]
ethyl 10-formyl-6-isopropyl-6-methyl-9-(oxetan-3-ylmethoxy)-2-oxo-6,7 -dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2h;	To a mixture of ethyl 1 0-formyl-9-hydroxy-6-isopropyl-6-methyl-2-oxo-6, 7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate (640 mg,1.73 mmol) in DMF(20 ml) were added K2C03 (716 mg, 5.19 mmol) and oxetan-3-ylmethyl4-methylbenzenesulfonate (840 mg, 3.47 mmol). After stirring at 90 C for 2hr, the reactionmixture was quenched with H20 and extracted with EtOAc and the organic layer was driedover Na2S04. Solvent was removed under vacuum and the residue was purified to provideethyl 1 0-formyl-6-isopropyl-6-methyl-9-( oxetan-3-ylmethoxy)-2-oxo-6, 7 -dihyd ro-2Hpyrido[2, 1-a]isoquinoline-3-carboxylate (450 mg,59% yield) as a yellow solid. LCMS (ESI)m/z: 440.3 (M + 1t.

Reference： [1]Patent: WO2018/154466,2018,A1 .Location in patent: Paragraph 001306; 001308; 001309

28
[ 1395417-57-8 ]
ethyl 9'-hydroxy-2'-oxo-10'-(trifluoromethyl)-2',7'-dihydrospiro[cyclobutane-1,6'-pyrido[2,1-a]isoquinoline]-3'-carboxylate [ No CAS ]
ethyl 9'-(oxetan-3-ylmethoxy)-2'-oxo-10'-(trifluoromethyl)-2',7'-dihydrospiro[cyclobutane-1,6'-pyrido[2,1-a]isoquinoline]-3'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.6%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6h;Schlenk technique;	A Schlenk flask was charged with ethyl 9'-hydroxy-2'-oxo-1 0'-(trifluoromethyl)-2', 7'-dihydrospiro[ cyclobutane-1 ,6'-pyrido[2, 1-a]isoq uinoline ]-3'-carboxylate(70 mg, 0.2mmol), <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (73.5 mg, 0.54 mmol) andDMF (2 ml). To this reaction mixture, K2C03 (11 0 mg, 0.8 mmol) was added and then stirredfor 6 h by heating at 80 C. After cooling, the obtained inorganic salt was filtered off. Ethylacetate was added to the organic layer and washed with 1% brine. After drying withanhydrous magnesium sulfate, the solvent was evaporated, purified by columnchromatography to afford the title compound (65 mg, 70.6% yield). LCMS (ESI) m/z: 464.2(M + 1t.

Reference： [1]Patent: WO2018/154466,2018,A1 .Location in patent: Paragraph 001340; 001364; 001365

29
[ 1395417-57-8 ]
3-[[5-[2-[4-(trifluoromethyl)anilino]phenyl]tetrazol-2-yl]methyl]azetidin-3-ol [ No CAS ]
2-(2-(oxetan-3-ylmethyl)-2H-tetrazol-5-yl)-N-(4-(trifluoromethyl)phenyl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.44%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 1h;Microwave irradiation; Sealed tube;	[00552] 166-2 (100.00 mg, 412.73 umol, 1.20 eq), 166-2a (104.99 mg, 343.94 umol, 1.00 eq) and K2C03 (190.14 mg, 1.38 mmol, 4.00 eq) were taken up into a microwave tube in DMF (4.00 mL). The sealed tube was heated at 120C for 1 h under microwave conditions. The crude LCMS showed the desired product MS value was detected. The reaction mixture was combined with another batch, and the reaction mixture was quenched by addition of water (30 mL) and extracted with EtOAc (25 mL 3). The combined organic layers were washed with brine (20 mL 2), dried over Na2S04, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give the product, which was diluted with MeOH (5 mL) and water (5 mL). Most of MeOH was removed under reduced pressure, and the remaining aqueous layer was lyophilized to give provide Compound 166 (0.13253 g, 353.09 umol, 68.44% yield). LCMS (ESI): RT = 0.847 min, mass calc. for Ci8Hi6F3N50 375.35, m/z found 376.1 [M+l]+; 1HNMR (400 MHz, DMSO-i_) 3.49 - 3.62 (m, 1 H), 4.47 (t, J = 6.15 Hz, 2 H), 4.67 (dd, J= 7.65, 6.40 Hz, 2 H), 5.06 (d, J = 7.28 Hz, 2 H), 7.13- 7.24 (m, 3H), 7.46 - 7.58 (m, 4 H), 8.03 (d, J= 7.53Hz, 1 H), 8.72 (br, s, 1 H).

Reference： [1]Patent: WO2018/204532,2018,A1 .Location in patent: Paragraph 00552

30
[ 1395417-57-8 ]
(1S)-1-[1-[[5-[2-(4-piperazin-1-ylphenyl)ethynyl]isoxazol-3-yl]methyl]imidazol-2-yl]ethanol [ No CAS ]
(1S)-1-[1-({5-[(4-{4-[(oxetan-3-yl)methyl]piperazin-1-yl}phenyl)ethynyl]-1,2-oxazol-3-yl}methyl)-1H-imidazol-2-yl]ethan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%		To a solution of (1S)-l-[l-[[5-[2-(4-piperazin-l-ylphenyl)ethynyl]isoxazol-3-yl]methyl]imidazol-2-yl]ethanol (20 mg) in acetonitrile (0.5 mL) and DMF (0.5 mL) were added <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (15 mg) in acetonitrile (0.5 mL) and K2CO3 (11 mg) at room temperature. The reaction mixture was heated to 50 C for 1 hour, and heated to 80 C for 9 hours. Oxetan-3-ylmethyl 4-methylbenzenesulfonate (15 mg) in acetonitrile (0.5 mL) was added and the mixture was stirred for 1 hour. Sodium iodide (15 mg) was added the mixture was stirred for additional 1.5 hours. After cooling, the mixture was quenched by water and extracted with CHC -MeOH. The combined organic layer was concentrated in vacuo onto ISOLUTE HM-N. The residue was purified with NH-type silica gel column chromatography (5-10 % EtOAc in hexane) and preparative thin layer chromatography (5 % EtOAc in hexane) to give the title compound (8.3 mg, 35% yield) as colorless solid. -NMR, MS and LCMS retention time data of Compound-364 are shown in Table 3.

Reference： [1]Patent: WO2018/216822,2018,A1 .Location in patent: Page/Page column 234-235

31
[ 1395417-57-8 ]
methyl (R)-2-((tert-butoxycarbonyl)amino)-3-mercapto-3-methylbutanoate [ No CAS ]
methyl (2R)-2-[[(tert-butoxy)carbonyl]amino]-3-methyl-3-[(oxetan-3-ylmethyl)sulfanyl]butanoate [ No CAS ]

Reference： [1]ChemMedChem,2019,vol. 14,p. 1560 - 1572

32
[ 1395417-57-8 ]
(R)-2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol [ No CAS ]
(R)-2-chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetane-3-ylmethoxy)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%		Dimethylformamide of (R) -2-chloro-6- (3-methoxytetrahydrofuran-3-yl) pyridin-4-ol (0.909 g, 3.96 mmol) (Preparation Example 21) cooled to about 0 C. DMF)(33.0 mL) in solution with NaH (60% dispersion in mineral oil,0.190 g, 4.75 mmol) was added.The reaction is stirred for about 20 minutes,Then a solution of <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (1.15 g, 4.75 mmol) in 1 mL DMF was added slowly.Remove the reaction from the ice bath,Heated to about 100 C. for about 90 minutes.Continue heating to 100 C for another hour,Then it was left at room temperature for about 2 days.Brine (80 mL) and ethyl acetate (100 mL) are added to the reaction mixture,A small amount of water was added to clarify the solution.Separate the organic layer,The aqueous layer was then extracted again with ethyl acetate (30 mL).Combine the organic layers and wash with brine (50 mL).Dry over MgSO4, filter, concentrate under reduced pressure,To get a residue,Purify by silica gel chromatography eluting with 10-70% ethyl acetate / heptane,The product (0.822 g, 69% yield) was obtained.

Reference： [1]Patent: JP6557436,2019,B1 .Location in patent: Paragraph 0483; 0484; 0486

33
[ 1395417-57-8 ]
(S)-2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridine-4-ol [ No CAS ]
(S)-2-chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		Dimethylformamide of (S) -2-chloro-6- (3-methoxytetrahydrofuran-3-yl) pyridin-4-ol (0.178 g, 0.775 mmol) (Preparation Example 21a) cooled to about 0 C. To a solution in DMF) (6 mL) was added NaH (60% dispersion in mineral oil) (0.037 g, 0.93 mmol).The reaction was stirred for about 20 minutes, then a solution of <strong>[1395417-57-8]oxetan-3-ylmethyl 4-methylbenzenesulfonate</strong> (0.225 g, 0.930 mmol) (Preparation Example 23, Step 1) in 1 mL DMF was added slowly.Remove the reaction from the ice bath,Heated to about 100 C. for about 90 minutes.Increase the temperature and heat to 100 C. for an additional hour,Then it was left at room temperature for about 2 days.Brine (80 mL) and ethyl acetate (100 mL) were then added to the reaction mixture. Separate the organic layer,The aqueous layer was extracted with ethyl acetate (30 mL).Combine the organic layers and wash with brine (50 mL).Dry over MgSO4, filter, concentrate under reduced pressure,A residue was obtained, which was purified by silica gel chromatography eluting with 10-70% ethyl acetate / heptane,The product (0.156 g, 67% yield) was obtained.

Reference： [1]Patent: JP6557436,2019,B1 .Location in patent: Paragraph 0536; 0537; 0538

34
[ 1395417-57-8 ]
C₂₄H₂₂FN₇O₂ [ No CAS ]
C₂₈H₂₈FN₇O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	Compound WX008 (100 mg, 217.64 mumol, 1 eq) and N,N-dimethylformamide (4 mL) were added into a pre-dried 40 mL reaction vial, followed by sequential addition of potassium carbonate (45.12 mg, 326.46 mumol, 1.5 eq), potassium iodide (18.06 mg, 108.82 mumol, 0.5 eq) and Compound WX011-2 (63.28 mg, 261.17 mumol, 2.32 muL, 1.2 eq). The reaction solution was stirred at 80C for 16 hours. The reaction solution was filtered, separated and purified by rapid preparation. The reaction solution was separated and purified by rapid preparation to give WX011. 1H NMR (400MHz, DMSO-d6) delta = 10.83 (s, 1H), 8.17 (d, J=7.7 Hz, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.87 (dd, J=0.8, 7.6 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.40 (d, J=12.1 Hz, 1H), 7.24 (d, J=1.3 Hz, 1H), 4.68 (dd, J=6.2, 7.9 Hz, 2H), 4.47 (br t, J=5.7 Hz, 2H), 4.43 - 4.37 (m, 4H), 3.44 - 3.36 (m, 1H), 2.92 (t, J=6.3 Hz, 2H), 1.97 - 1.89 (m, 2H), 1.84 (br dd, J=5.2, 8.5 Hz, 3H), 0.81 - 0.75 (m, 2H), 0.68 - 0.63 (m, 2H).

Reference： [1]Patent: EP3572412,2019,A1 .Location in patent: Paragraph 0164-0165; 0167

35
[ 1395417-57-8 ]
C₂₄H₂₂N₈O₂ [ No CAS ]
C₂₈H₂₈N₈O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	Compound WX037 (100 mg, 220.03 mumol, 1 eq), potassium carbonate (60.82 mg, 440.06 mumol, 2 eq), N,N-dimethylformamide (4 mL) and compound WX058-2 (63.97 mg, 264.04 mumol, 3.12 muL, 1.2 eq) were added into a 40 mL pre-dried reaction bottle. The reaction solution was stirred at 80 C. for 16 hours. The reaction solution was filtered with a filter to give a clear N, N-dimethylformamide solution. The clear solution was separated and purified by flash chromatography {column: Agela Durashell C18 150*25 mm 5 mum; mobile phase: [water (10 mM NH4HCO3)-ACN]; B %: 20%-50%, 10.5 min} to give WX058. 1H NMR (400 MHz, CHLOROFORM-d) delta=8.59 (s, 1H), 8.47-8.43 (m, 1H), 8.42 (s, 1H), 8.28 (s, 1H), 8.11 (t, J=7.9 Hz, 1H), 7.99-7.94 (m, 1H), 7.74 (d, J=1.1 Hz, 1H), 7.36 (s, 1H), 7.03 (d, J=1.1 Hz, 1H), 5.50 (td, J=6.9, 13.6 Hz, 1H), 4.92 (dd, J=6.5, 7.6 Hz, 2H), 4.53 (t, J=6.1 Hz, 2H), 4.47 (d, J=7.1 Hz, 2H), 3.51 (td, J=6.8, 13.1 Hz, 2H), 1.97-1.88 (m, 1H), 1.58-1.58 (m, 3H), 1.57 (s, 3H), 0.94-0.88 (m, 2H), 0.86-0.80 (m, 2H).

Reference： [1]Patent: US2019/375728,2019,A1 .Location in patent: Paragraph 0583

36
[ 1395417-57-8 ]
[ 123-08-0 ]
4-(oxetan-3-ylmethoxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 14h;	General procedure: M-hydroxybenzaldehyde (1.5g, 12.3mmol),Oxetan-3-yl 4-methylbenzenesulfonate (2.0g, 8.7mmol) and N, N-dimethylformamide (10mL) were added to a 100mL single-necked round bottom flask, and potassium carbonate (2.6 g, 18.8 mmol), reaction at an oil bath at 100 C for 14 hours; stop the reaction, cool to room temperature, add water (50 mL) to quench, then add ethyl acetate (30 mL), separate the liquid, collect the organic phase, and spin dry under reduced pressure , Column chromatography separation and purification (petroleum ether / ethyl acetate (v / v) = 8/1) to give the title compound as a yellow oil (1.1g, 70%).

Reference： [1]Patent: CN110981876,2020,A .Location in patent: Paragraph 0268; 0274-0276; 0635; 0640-0643

37
[ 1395417-57-8 ]
[ 1849-36-1 ]
3-((4-nitrophenylthio)methyl)oxetane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.9%	With caesium carbonate In dimethyl sulfoxide at 20℃; for 16h;	1 To a stirred solution of 0494-2 (800 mg, 3.31 mmol) in DMSO (15 ml) was added 4- nitrobenzenethiol (465 mg, 3.00 mmol) and CS2CO3 (1.96 g, 6.00 mmol). The resulting reaction mixture was stirred for 16 h at rt. Then water (80 mL) was added. The aqueous phase was extracted with EA (40 mL X 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the desired product 0494-3 (600 mg, yield: 88.9%) as a yellow solid.

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA; SHANGPHARMA INNOVATION INC - WO2021/155004, 2021, A1 Location in patent: Paragraph 1034; 1037-1038

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P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
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H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
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H271	May cause fire or explosion; strong oxidizer
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Code	Phrase
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H302	Harmful if swallowed
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H304	May be fatal if swallowed and enters airways
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H361d	Suspected of damaging the unborn child
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H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1395417-57-8 ] {[proInfo.proName]}

Quality Control of [ 1395417-57-8 ]

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Product Details of [ 1395417-57-8 ]

Calculated chemistry of [ 1395417-57-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1395417-57-8 ]

Application In Synthesis of [ 1395417-57-8 ]

[ 1395417-57-8 ] Synthesis Path-Upstream 1~1

[ 1395417-57-8 ] Synthesis Path-Downstream 1~37

Related Functional Groups of [ 1395417-57-8 ]

Aryls

Sulfonates

Related Parent Nucleus of [ 1395417-57-8 ]

Aliphatic Heterocycles

Oxetanes

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1395417-57-8 ]

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[ 1395417-57-8 ]