[ CAS No. 154748-63-7 ] {[proInfo.proName]}

Name: 154748-63-7|tert-Butyl (3-hydroxycyclobutyl)carbamate|97%
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SKU: A171653
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Quality Control of [ 154748-63-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 154748-63-7 ]

SDS Specification

Alternatived Products of [ 154748-63-7 ]

Product Details of [ 154748-63-7 ]

CAS No. :	154748-63-7	MDL No. :	MFCD11501030
Formula :	C₉H₁₇NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	187.24	Pubchem ID :	-
Synonyms :

Calculated chemistry of [ 154748-63-7 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.89
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	48.94
TPSA :	58.56 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) :	-6.82 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.19
Log Po/w (XLOGP3) :	0.87
Log Po/w (WLOGP) :	1.03
Log Po/w (MLOGP) :	0.56
Log Po/w (SILICOS-IT) :	0.3
Consensus Log Po/w :	0.99

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.28
Solubility :	9.71 mg/ml ; 0.0519 mol/l
Class :	Very soluble
Log S (Ali) :	-1.68
Solubility :	3.88 mg/ml ; 0.0207 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.91
Solubility :	23.2 mg/ml ; 0.124 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.88

Safety of [ 154748-63-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P273-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335-H413	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 154748-63-7 ]

* 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 [ 154748-63-7 ]
Downstream synthetic route of [ 154748-63-7 ]

[ 154748-63-7 ] Synthesis Path-Upstream 1~6

1
[ 154748-62-6 ]
[ 154748-63-7 ]

Reference： [1] Patent: WO2006/21544, 2006, A1, . Location in patent: Page/Page column 48
[2] Patent: WO2007/115999, 2007, A1, . Location in patent: Page/Page column 20

2
[ 871014-16-3 ]
[ 154748-63-7 ]

Reference： [1] Patent: WO2016/105485, 2016, A2, . Location in patent: Paragraph 0129

3
[ 23761-23-1 ]
[ 154748-63-7 ]

Reference： [1] Patent: WO2013/107291, 2013, A1,
[2] Patent: WO2013/107405, 2013, A1,
[3] Patent: WO2015/10626, 2015, A1,
[4] Patent: WO2015/10297, 2015, A1,

4
[ 130369-04-9 ]
[ 154748-63-7 ]

Reference： [1] Patent: US2013/79324, 2013, A1,

5
[ 389890-43-1 ]
[ 154748-63-7 ]

Reference： [1] Patent: WO2016/105485, 2016, A2,

6
[ 154748-63-7 ]
[ 4640-44-2 ]

Reference： [1] Patent: WO2013/96744, 2013, A1, . Location in patent: Page/Page column 221
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 5, p. 2161 - 2166
[3] Patent: WO2015/162456, 2015, A1, . Location in patent: Page/Page column 315

[ 154748-63-7 ] Synthesis Path-Downstream 1~86

1
[ 154748-63-7 ]
[ 98-59-9 ]
[ 878156-25-3 ]

Yield	Reaction Conditions	Operation in experiment
53%	With triethylamine; In dichloromethane; at 20℃;Inert atmosphere;	3-(tert-butoxycarbonylamino)cyclobutyl 4-methylbenzenesulfonate 3-(tert-butoxycarbonyl amino)cyclobutyl 4-methylbenzenesulfonate was prepared from tert-butyl 3-hydroxycyclobutylcarbamate and 4-methylbenzene-1-sulfonyl chloride using Method M. The product was purified by flash chromatography eluting with EtOAc in hexane (0% to 17% gradient) to yield tert-butyl N-(3-[[(4-methylbenzene)sulfonyl]oxy]cyclobutyl)carbamate as a yellow solid (915 mg, 53%).
	With triethylamine; In chloroform; at 0 - 20℃; for 2h;	c) tert-butyl (3-tosyl-cyclobutyl)-carbamate18.7 g (100 mmol) tert-butyl (3-hydroxy-cyclobutyl)-carbamate and 12.1 g (120 mmol) triethylamine are placed in 500 mL chloroform. 20.5 g (105 mmol) tosyl chloride, which is dissolved in 150 mL chloroform, is added dropwise to this solution at 00C with stirring. Then the reaction mixture is allowed to come up to 200C and stirred for a further 2 h. The organic phase is washed successively with water, with dilute hydrochloric acid, with sodium hydrogen carbonate solution and again with water. The organic phase is dried on magnesium sulphate and the solvent is eliminated in vacuo. Yield: 28.3 g MS (ESI): 342 (M +H)+

Reference： [1]Patent: WO2006/21544,2006,A1 .Location in patent: Page/Page column 48
[2]Patent: US2016/376283,2016,A1 .Location in patent: Paragraph 1158; 1159
[3]Patent: WO2007/115999,2007,A1 .Location in patent: Page/Page column 20

2
[ 154748-62-6 ]
[ 154748-63-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium dihydroxide; In methanol; at 45℃; under 33753.4 Torr; for 5h;	b) tert-butyl beta-hydroxy-cyclobuty^-carbamate2.77 g (10 mmol) tert-butyl beta-benzyloxy-cyclobuty^-carbamate are suspended in 100 mL methanol and combined with 200 mg palladium hydroxide. The reaction mixture is stirred for 5 h at 45C and 45 bar hydrogen pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is taken up in chloroform and washed 3 times with aqueous sodium hydrogen carbonate solution. The organic phase is dried on magnesium sulphate and the solvent is eliminated in vacuo. Yield: 1.53 g MS (ESI): 188 (M +H)+

Reference： [1]Patent: WO2006/21544,2006,A1 .Location in patent: Page/Page column 48
[2]Patent: WO2007/115999,2007,A1 .Location in patent: Page/Page column 20

3
3-(tert-butyloxycarbonylamino)cyclobutan-1-one [ No CAS ]
[ 154748-63-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium tetrahydroborate; In ethanol; at 0 - 25℃; for 1h;	NaBH4 (1.02 g, 26.96 mmol,0.50 eq.) was added slowly to a 0 C solution of tert-butyl N-(3-oxocyclobutyl)carbamate (10 g,53.99 mmol, 1.00 eq.) in ethanol (100 mL). The resulting solution was stirred for 1 hour at 25C and then concentrated under vacuum. This resulted in 9.9 g (98%) of tert-butyl N-(3-hydroxycyclobutyl)carbamate as a white solid.
98%	With sodium tetrahydroborate; ethanol; at 0 - 25℃; for 1h;	Step 1 : tert-butyl (3-hydroxycyclobuty])carbamate: NaBFL, (1.02 g, 26.96 mmol, 0.50 eq.) was added slowly to a 0 C solution of tert-butyl N-(3-oxocyclobutyl)carbamate (10 g, 53.99 mmol, 1.00 eq.) in ethanol (100 mL). The resulting solution was stirred for 1 hour at 25 C and then concentrated under vacuum. This resulted in 9.9 g (98%) of tert-butyl N-(3- hydroxycyclobutyl)carbamate as a white solid.
98%	With sodium tetrahydroborate; In ethanol; at 0 - 25℃; for 1h;	NaBH4 (1.02 g, 26.96 mmol, 0.50 eq.) was added slowly to a 0 C solution of tert-butyl N-(3-oxocyclobutyl)carbamate (10 g, 53.99 mmol, 1.00 eq.) in ethanol (100 mL). The resulting solution was stirred for 1 hour at 25 C and then concentrated under vacuum. This resulted in 9.9 g (98%) of tert-butyl N-(3- hydroxycyclobutyl)carbamate as a white solid.

98%	With sodium tetrahydroborate; ethanol; at 0 - 25℃; for 1h;	NaBH4 (1 02 g, 26 96 mmol, 0.50 eq.) was added slowly to a 0 C solution of tert-butyl N-(3-oxocyclobutyl)carbamate (10 g, 53.99 mmol, 1.00 eq.) in ethanol (100 mL). The resulting solution was stirred for 1 hour at 25 C and then concentrated under vacuum. This resulted in 9.9 g (98%) of tert-butyl N-(3- hydroxycyclobutyl)carbamate as a white solid.
94%	With sodium tetrahydroborate; ethanol; at 0 - 20℃;	To a solution of tert-bxtiyl 3- oxocyclobutylcarbamate (2 g, 10.8 mmol, 2 eq) in EtOH (20 mL) was added NaB (204 mg, 1 eq) at 0 C. The mixture was then allowed to warm to r.t. and stirred for 30 min. The mixture was concentrated in vacuo and the residue was purified by flash chromatography using petroleum ether / EtOAc (V: V, 2: 1 to pure EtOAc) as eluent to afford the desired product as a white solid (1.9 g, 94% yield). MS: 188.1 (M+l)+.
94%	With sodium tetrahydroborate; In ethanol; ethyl acetate; Petroleum ether;	Step A: Tert-butyl 3-hydroxycyclobutylcarbamate To a solution of tert-butyl 3-oxocyclobutylcarbamate (2 g, 10.8 mmol, 2 eq) in EtOH (20 mL) was added NaBH4 (204 mg, 1 eq) at 0 C. The mixture was then allowed to warm to r.t. and stirred for 30 min. The mixture was concentrated in vacuo and the residue was purified by flash chromatography using petroleum ether/EtOAc (V:V, 2:1 to pure EtOAc) as eluent to afford the desired product as a white solid (1.9 g, 94% yield). MS: 188.1 (M+1)+.
61%	With L-Selectride; In tetrahydrofuran; at -72 - 20℃; for 2.5h;	Step 4: Preparation of tert-butyl (cis-3-hydroxycyclobutyl)carbamate To a solution of tert-butyl (3-oxocyclobutyl)carbamate (100 g, 54 mmol) in THF (2000 mL) at -72 C. was added dropwise a solution of lithium trisec-butylhidridoborate (648 mL, 1 M) in THF over 1.5 hrs. The resulting solution was allowed to warm up to rt and stirred for another 1 hr. TLC (petroleum ether: EtOAc=2:1) showed that the starting material was consumed completely. The reaction was quenched with NH4Cl aqueous. Water (1000 mL) and EtOAc (2000 mL) were added to the mixture. The organic layer was separated, dried over MgSO4 and concentrated to give crude material, which was purified by column chromatography with petroleum ether: EtOAc from 10:1 to 1:2 to afford the title compound (62 g, 61% yield) as a white solid.
58%		To tert-butyl (3-oxocyclobutyl)carbamate (see PREPARATION 4A, STEP 1 ; 110 g, 0.594 mol, leq) in ethanol (600 mL) was slowly added sodium borohydride (1 1.23 g, 0.297 mol, 0.5 eq) at 0 C. Reaction mixture was warmed to RT and stirred at this temperature for 2h. It was quenched with water (1 L). Solvent was removed under reduced pressure. Water layer was extracted with EtOAc (3 X 2 L). Combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Residue was purified by column chromatography with aluminum oxide (Eluent: 20% EtOAc in hexane to 10% MeOH in DCM) to get 64 g of tert-butyl (3-hydroxycyclobutyl)carbamate as a white solid in 58 % yield.
	With sodium tetrahydroborate; In ethanol; at 0 - 20℃;	3-Amino-cyclobutanol (50) ; <n="72"/>To a 0 0C cold solution of 2.00 g (10.8 mmol) of (3-oxo-cyclobutyl)-carbamic acid tert- butyl ester in 20 ml_ of ethanol was added portionwise 204 mg (5.40 mmol) of sodium borohydride. The reaction mixture was stirred at room temperature until complete conversion was achieved. The solvent was evaporated, the crude product was taken up in dichloromethane and treated with sat. sodium bicarbonate solution. The phases were separated and the aqueous phase extracted twice with dichloromethane. The organic phases were combined, dried over magnesium sulfate and concentrated to give crude (3-hydroxy-cyclobutyl)-carbamic acid tert-butyl ester. Rt = 0.76 min (Method C). Detected mass: 132.2 (M-tBu+H+).
	With sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 5h;	To a solution of compound 1 (4.0 g, 21.6 mmol) in ethanol (40 mL) was added NaBIL (1.64 g, 43.2 mmol) slowly at 0 . The reaction mixture was stirred at RT for 5 h. The reaction mixture was quenched with NH4CI (50 mL) and extracted with ethyl acetate (50 mL3). The organic layer was dried and concentrated to give the product.
	With sodium tetrahydroborate; In ethanol; ethyl acetate; Petroleum ether;	Step A: Tert-butyl 3-hydroxycyclobutylcarbamate To a solution of tert-butyl 3-oxocyclobutylcarbamate (2 g, 10.8 mmol, 2 eq) in EtOH (20 mL) was added NaBH4 (204 mg, 1 eq) at 0 C. The mixture was then allowed to warm to room temperature and stirred for 30 min. The mixture was concentrated in vacuo and the residue was purified by column chromatography using petroleum ether/EtOAc (V:V, 2:1 to pure EtOAc) as eluent to afford the desired product as a white solid. MS: 188.1 (M+1)+.
	With sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 0.5h;	General procedures for the preparation of l-fluoro-3-isocyanocyclobutane C - I NaBH4 HCS- I PAST F_, MeOH/ HCI N- , HCOOE^ PPh3; CCI4; TEA^ - , DCM NHBoc ^ NHCHO NC Step A: Tert-butyl 3-hydroxycyclobutylcarbamate. To a solution of tert-butyl 3- oxocyclobutylcarbamate (2 g, 10.8 mmol, 2 eq) in EtOH (20 mL) was added NaBH4 (204 mg, 1 eq) at 0 C. The mixture was then allowed to warm to room temperature and stirred for 30 min. The mixture was concentrated in vacuo and the residue was purified by column chromatography using petroleum ether / EtOAc (V:V, 2: 1 to pure EtOAc) as eluent to afford the desired product as a white solid. MS: 188.1 (M+l)+.
	With sodium tetrahydroborate; ethanol; at 0 - 20℃; for 0.5h;	To a solution oftert-butyl 3-oxocyclobutylcarbamate (2 g, 10.8 mmol, 2 eq) in EtOH (20 mL) was added NaBH4 (204 mg, 1 eq) at 0 C. The mixture was then allowed to warm to room temperature and stirred for 30 mm.The mixture was concentrated in vacuo and the residue was purified by column chromatography using petroleum ether/EtOAc (V:V, 2:1 to pure EtOAc) as eluent to afford the desired product asawhite solid. MS: 188.1 (M+1).
	With sodium tetrahydroborate; ethanol; at 20℃; for 0.5h;	Step A: Tert-butyl 3-hydroxycyclobutylcarbamate. To a solution of /er/-butyl 3- oxocyclobutylcarbamate (2 g, 10.8 mmol, 2 eq) in EtOH (20 mL) was added NaBH4 (204 mg, 1 eq) at 0 C. The mixture was then allowed to warm to room temperature and stirred for 30 min. The mixture was concentrated in vacuo and the residue was purified by column chromatography using petroleum ether / EtOAc (V:V, 2: 1 to pure EtOAc) as eluent to afford the desired product as a white solid. MS: 1 88.1 (M+ l )+.
	With sodium tetrahydroborate; In ethanol; at 0 - 20℃;Inert atmosphere;	Intermediate B9 N-(3-Hydroxycyclobutyl)-4-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenesulfonamide Step 1 : 3-Aminocyclobutanol (2874) To a cooled ( 0C) stirring solution of tert-butyl 3-oxocyclobutylcarbamate (1 g, 5.40 mmol) in EtOH (27.0 ml_), under N2, was added NaBH4 (0.204 g, 5.40 mmol) portion wise. The reaction mixture was stirred 30 mins then allowed to warm to room temperature. After 3 hours, the reaction was quenched by dropwise addtion of water (100ml) and the product extracted into EtOAc (2 x 100ml). The organic extracts were combined, washed with brine, dried over MgS04, and concentrated under reduced pressure. To the resulting mixture was added 2.0M HCI in MeOH (27.0 ml_, 54.0 mmol). The solution was stirred for 3h at room temperature and the mixture was concentrated under reduced pressure to afford the title compound as a mixture or stereoisomers which was used as crude directly in the next step.
	With sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 1h;	To a solution of tert-butyl (3-oxocyclobutyl)carbamate (200 mg, 1.08 mmol) in ethanol (3 mL) was slowly added sodium borohydride (41 mg, 1.08 mmol) at 0C. The reaction mixture was warmed to room temperature and stirred at this temperature for 1 hr.It was quenched with water (5 mL). The solvent was removed under reduced pressure. The water layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine, dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting withdichloromethane/methanol(10: 1)to affordthe title compound: LCMS (ESI) calc?d for C9H,7N03 [M+hr- 56]:173, found 173; ?H NMR (300 MHz,CDC13):oe4.71-4.40(m, 1H), 4.13- 4.00 (m, 1H), 3.83-3.67 (m, 1H), 2.81-2.72 (m, 1H), 2.32-2.21 (m, 2H), 2.08-1.74 (m, 2H), 1.44 (s, 9H).
4.8 g	With sodium tetrahydroborate; ethanol; at 0 - 20℃; for 2h;	Tert-butyl 3-oxocyclobutylcarbamate (5 g, 26.99 mmol) was dissolved in ethonol (50 mL). At 0 C., sodium borohydride (525 mg, 13.87 mmol) was added, and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated, and then aqueous solution of sodium bicarbonate (10 mL) was added and the mixture was extracted with dichloromethane (30 mL) for 3 times. The organic phases were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium chloride, concentrated under reduced pressure to obtain 4.8 g of the title compound.

Reference： [1]Patent: WO2015/196071,2015,A1 .Location in patent: Paragraph 0341
[2]Patent: WO2016/105468,2016,A1 .Location in patent: Paragraph 0180
[3]Patent: WO2016/115090,2016,A1 .Location in patent: Paragraph 0334
[4]Patent: WO2017/40606,2017,A1 .Location in patent: Paragraph 0293
[5]Patent: WO2013/107405,2013,A1 .Location in patent: Page/Page column 43
[6]Patent: US2015/87600,2015,A1 .Location in patent: Page/Page column
[7]Patent: US2013/79324,2013,A1 .Location in patent: Paragraph 0940; 0941
[8]Patent: WO2011/143366,2011,A1 .Location in patent: Page/Page column 47-48
[9]Patent: WO2008/77551,2008,A1 .Location in patent: Page/Page column 70-71
[10]Patent: WO2013/96744,2013,A1 .Location in patent: Page/Page column 221
[11]Patent: US2013/190249,2013,A1 .Location in patent: Page/Page column
[12]Patent: WO2013/107291,2013,A1 .Location in patent: Page/Page column 63
[13]Patent: WO2015/10626,2015,A1 .Location in patent: Page/Page column 63; 64
[14]Patent: WO2015/10297,2015,A1 .Location in patent: Page/Page column 63
[15]Patent: WO2015/162456,2015,A1 .Location in patent: Page/Page column 315
[16]Patent: WO2016/105485,2016,A2
[17]Patent: WO2016/206101,2016,A1 .Location in patent: Page/Page column 266
[18]Patent: US2020/165265,2020,A1 .Location in patent: Paragraph 0343; 0344

4
[ 154748-63-7 ]
cis-3-aminocyclobutan-1-ol hydrochloride [ No CAS ]
(1r,3r)-3-aminocyclobutanol hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The crude alcohol was dissolved in 90 ml_ of dichloromethane and 11 mL of trifluoroacetic acid were added. After stirring overnight at room temperature, 100 mL of 2N hydrochloric acid were added, the phases were separated and the aqueous phase concentrated in vacuo. After twice dissolving the residue in water and subsequent lyophilization, 980 mg of the title compound 50 were isolated as its hydrochloride as a mixture of diastereoisomers. Rt = 0.19 min (Method C). Detected mass: 88.35 (M+H+).

Reference： [1]Patent: WO2008/77551,2008,A1 .Location in patent: Page/Page column 71

5
[ 4858-85-9 ]
[ 154748-63-7 ]
[ 1349184-51-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With caesium carbonate; In dimethyl sulfoxide; at 80℃;	To a mixture of 2,3-dichloro-pyrazine (3.0 g, 20 mmol ) and tert-butyl (3- hydroxycyclobutyl)carbamate (see PREPARATION 4B; 3.65 g, 20 mmol) in DMSO (50 mL) was added CS2CO3 (13.2 g, 40 mmol), and then the mixture was stirred at 80C overnight. The reaction mixture was diluted with water and filtered. The filtrate cake was washed with water, and dried to give tert-butyl (3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)carbamate (4.5 g, 15.2 mmol, 76%). ESI-MS (M+l): 300 calc. for Ci3Hi8ClN303 299.

Reference： [1]Patent: WO2011/143366,2011,A1 .Location in patent: Page/Page column 49

6
[ 154748-63-7 ]
[ 1349184-80-0 ]

Reference： [1]Patent: WO2011/143366,2011,A1

7
[ 154748-63-7 ]
[ 1349184-81-1 ]

Reference： [1]Patent: WO2011/143366,2011,A1

8
[ 154748-63-7 ]
[ 1349185-51-8 ]

Reference： [1]Patent: WO2011/143366,2011,A1

9
[ 154748-63-7 ]
[ 1349185-53-0 ]

Reference： [1]Patent: WO2011/143366,2011,A1

10
[ 154748-63-7 ]
[ 36178-05-9 ]
tert-butyl (3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%		To a solution of tert-butyl (3 -hydroxycyclobutyl)carbamate (see PREPARATION 4B; 1.08 g, 3.8 mmol) in DMF (20 mL) at RT was added sodium hydride (60percent wt in mineral oil) (0.18 g, 7.6 mmol). The mixture was stirred at RT for 10 min and then 3-Bromo-2-fluoro- pyridine (665 mg, 3.8 mmol) was added. The reaction mixture was stirred at RT for lh and then diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2S04, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash columnchromatography on silica gel (5percent to 30percent> EtOAc in hexanes) to give tert-butyl ((lS,3S)-3-((3- bromopyridin-2-yl)oxy)cyclobutyl)carbamate (391 mg, 1.14 mmol, 30percent> yield ) as white solid. ESI-MS (M+l): 343 calc. for Ci4Hi9BrN203 342.

Reference： [1]Patent: WO2011/143366,2011,A1 .Location in patent: Page/Page column 58

11
[ 36082-50-5 ]
[ 154748-63-7 ]
[ 1349185-49-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With caesium carbonate; In tetrahydrofuran;Reflux;	To a solution of <strong>[154748-63-7](3-hydroxy-cyclobutyl)-carbamic acid tert-butyl ester</strong> (2.5 g, 13.3 mmol) in THF (40 mL) were added CS2CO3 (8.6 g, 26.6 mmol) and 5-bromo-2,4- dichloro- pyrimidine (3 g, 13.3 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was filtered and concentrated, diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic extracts were washed with brine (60 mL), dried over MgSO*}, filtered, and concentrated. Purification by flash column chromatography on silica gel to give the product (4.75 g, 12.6 mmol, yield: 95%). ESI-MS (M+l): 378 calc. for CisHnBrClNsOs 377.

Reference： [1]Patent: WO2011/143366,2011,A1 .Location in patent: Page/Page column 154

12
[ 130369-04-9 ]
[ 154748-63-7 ]

Reference： [1]Patent: US2013/79324,2013,A1

13
[ 154748-63-7 ]
[ 950661-87-7 ]
[ 1428775-70-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium hexamethylsilazane; In tetrahydrofuran; at 20℃; for 1h;	Step 3: Preparation of tert-butyl {3-[(2-chloro-5-cyano-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamate To a solution of 2,4-dichloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (481 mg, 1.4 mmol) in THF (12 mL) was added a 1:1 cis:trans mixture of <strong>[154748-63-7]tert-butyl (3-hydroxycyclobutyl)carbamate</strong> (see Radchenko et al., Journal of Organic Chemistry, 75(17):5941-5952 (2010)) (288 mg, 1.54 mmol) and KHMDS (419 mg, 2.1 mmol). The reaction solution was stirred at rt for 1 hr. The reaction was quenched with brine (5 mL), then partitioned between EtOAc (120 mL) and water (30 mL). The organic layer was separated, washed with brine (20 mL), dried over Na2SO4 and evaporated to give a light yellow gum. The gum was purified using flash chromatography eluting with a gradient of 0%-40% EtOAc in heptanes. The product fractions were combined and evaporated to afford the title compound (508 mg, 73 yield) as a solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.64 (s, 1H) 7.27-7.52 (m, 1H) 5.63 (s, 2H) 5.04-5.60 (m, 1H) 3.73-4.32 (m, 1H) 3.53-3.69 (m, 2H) 2.88 (m, J=9.35, 6.91, 6.91, 3.02 Hz, 1H) 2.50-2.56 (m, 2H) 2.13-2.28 (m, 1H) 1.46 (d, J=4.78 Hz, 9H) 0.92 (t, J=8.06 Hz, 2H) 0.00 (d, J=1.51 Hz, 9H). m/z (APCI+) for C22H32ClN5O4Si 440.0 (M-tBu+H)+.

Reference： [1]Patent: US2013/79324,2013,A1 .Location in patent: Paragraph 0754; 0755

14
[ 154748-63-7 ]
[ 950661-87-7 ]
tert-butyl {3-[(5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamate [ No CAS ]

Reference： [1]Patent: US2013/79324,2013,A1

15
[ 154748-63-7 ]
tert-butyl ((1r,3r)-3-hydroxycyclobutyl)(methyl)carbamate [ No CAS ]

Reference： [1]Patent: US2018/125821,2018,A1

16
[ 154748-63-7 ]
[ 18162-48-6 ]
C₁₅H₃₁NO₃Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 20℃;	Step 5: Preparation of tert-butyl {cis-3-[1-methyl-1-(trimethylsilyl)ethoxy]cyclobutyl}carbamate To a solution of tert-butyl (cis-3-hydroxycyclobutyl)carbamate (62 g, 0.33 mol) in pyridine (1 L) was added TBSCI (159 g, 1.056 mol). After addition, the mixture was stirred at ambient temperature overnight. TLC (petroleum ether:EtOAc=2:1) showed the starting material was consumed completely. The reaction was then concentrated and diluted with EtOAc (1 L), and the organic layer was separated and washed with water (three*300 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated to dryness to give crude title compound (108 g), which was used for the next step directly without further purification.

Reference： [1]Patent: US2013/79324,2013,A1 .Location in patent: Paragraph 0942; 0943

17
[ 154748-63-7 ]
C₁₆H₃₃NO₃Si [ No CAS ]

Reference： [1]Patent: US2013/79324,2013,A1

18
[ 154748-63-7 ]
cis-3-[(tert-butoxycarbonyl)(methyl)amino]cyclobutyl methanesulfonate [ No CAS ]

Reference： [1]Patent: US2013/79324,2013,A1

19
[ 154748-63-7 ]
tert-butyl (trans-3-azidocyclobutyl)methylcarbamate [ No CAS ]

Reference： [1]Patent: US2013/79324,2013,A1

20
[ 154748-63-7 ]
tert-butyl (trans-3-aminocyclobutyl)methylcarbamate [ No CAS ]

Reference： [1]Patent: US2013/79324,2013,A1

21
[ 154748-63-7 ]
tert-butyl (cis-3-hydroxycyclobutyl)methylcarbamate [ No CAS ]

Reference： [1]Patent: US2013/79324,2013,A1

22
[ 154748-63-7 ]
[ 4640-44-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethyl acetate; at 20℃; for 2h;	Compound 2 (4g 21.6 mmol) was dissolved in HCI/EA (25 mL). The mixture was stirred at RT for 2 h. The solvent was removed to give the product.
	With hydrogenchloride; In methanol; water; at 20℃; for 3h;	Intermediate B9 N-(3-Hydroxycyclobutyl)-4-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenesulfonamide Step 1 : 3-Aminocyclobutanol (2874) To a cooled ( 0C) stirring solution of tert-butyl 3-oxocyclobutylcarbamate (1 g, 5.40 mmol) in EtOH (27.0 ml_), under N2, was added NaBH4 (0.204 g, 5.40 mmol) portion wise. The reaction mixture was stirred 30 mins then allowed to warm to room temperature. After 3 hours, the reaction was quenched by dropwise addtion of water (100ml) and the product extracted into EtOAc (2 x 100ml). The organic extracts were combined, washed with brine, dried over MgS04, and concentrated under reduced pressure. To the resulting mixture was added 2.0M HCI in MeOH (27.0 ml_, 54.0 mmol). The solution was stirred for 3h at room temperature and the mixture was concentrated under reduced pressure to afford the title compound as a mixture or stereoisomers which was used as crude directly in the next step.

Reference： [1]Patent: WO2013/96744,2013,A1 .Location in patent: Page/Page column 221
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2161 - 2166
[3]Patent: WO2015/162456,2015,A1 .Location in patent: Page/Page column 315

23
[ 154748-49-9 ]
[ 154748-63-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With L-Selectride In tetrahydrofuran at -78℃; for 1h;	63.1 Step 1 : A solution of N-Boc-aminocyclobutanone (2.5 g, 13.5 mmol) in 50 mL THF was cooled to -78 °C and treated with a 1 N solution of L-Selectride (16.2 mL, 16.2 mmol) in THF. After stirring for 1 h the reaction was quenched with 5 mL water and warmed to rt. Aqueous work-up with EtOAc and water and purification by ISCO chromatography (EtOAc/hexanes) provided the desired alcohol (2.5 g, 100%) as a white solid. This material proved a single isomer by 1H-NMR.
90%	With sodium tetrahydroborate; water In tetrahydrofuran at -70 - -50℃; for 1h;	51.2; 52.2 Step 2: tert-Butyl N-j(ls,3s)-3-Hydroxycyclobutyljcarbamate. To a 250-mL round-bottom flask was placed a solution of tert-butyl N-(3-oxocyclobutyl)carbamate (8.3 g, 44.81 mmol, 1.00 equiv) in THF/H20=9:1 (100 mL)thenNaBH4 (830 mg, 22.54 mmol, 0.50 equiv) was added in portions at -70°C. The resulting solution was stirred for 1 h at -50°C thenthe reaction was quenched by the addition of water. The mixture was extracted with EtOAc, the organic extracts were combined and the solvent was removed under reduced pressure. The residue was dissolved in 20 mL of toluene at 80°C, then the solution was cooled to RT and stirred for 1 h. The solids were collected by filtration affording 7.56 g (90%) of tert-butyl N[(ls,3s)-3-hydroxycyclobutyljcarbamate as a white solid. ‘H NMR (400 MHz, CDC13) ö 4.67(brs, 1H), 4.08-4.01 (m, 1H), 3.69-3.66 (m, 1H), 2.82-2.76 (m, 2H), 2.00 (brs, 1H), 1.88-1.75 (m, 2H), 1.46 (s, 9H).
90%	With sodium tetrahydroborate; water In tetrahydrofuran at -70 - -50℃; for 1h;	51.2; 52.2 Step 2: tert-Butyl N-j(ls,3s)-3-Hydroxycyclobutyljcarbamate. To a 250-mL round-bottom flask was placed a solution of tert-butyl N-(3-oxocyclobutyl)carbamate (8.3 g, 44.81 mmol, 1.00 equiv) in THF/H20=9:1 (100 mL)thenNaBH4 (830 mg, 22.54 mmol, 0.50 equiv) was added in portions at -70°C. The resulting solution was stirred for 1 h at -50°C thenthe reaction was quenched by the addition of water. The mixture was extracted with EtOAc, the organic extracts were combined and the solvent was removed under reduced pressure. The residue was dissolved in 20 mL of toluene at 80°C, then the solution was cooled to RT and stirred for 1 h. The solids were collected by filtration affording 7.56 g (90%) of tert-butyl N[(ls,3s)-3-hydroxycyclobutyljcarbamate as a white solid. ‘H NMR (400 MHz, CDC13) 3 4.67(brs, 1H), 4.08-4.01 (m, 1H), 3.69-3.66 (m, 1H), 2.82-2.76 (m, 2H), 2.00 (brs, 1H), 1.88-1.75 (m, 2H), 1.46 (s, 9H).

87.6%	With sodium tetrahydroborate In tetrahydrofuran; water at -80 - -50℃; for 5h;	12.2 Step 2: tert-butyl (cis-3-hydroxycyclobutyl)carbamate: a solution of tert-butyl(3-oxocyclobutyl)carbamate (200 mg, 1.0 eq.) in TI-IF (I mL) is added dropwise to a cold(below -70 °C) solution of NaBH4 (20.4 mg, 0.5 eq.) in a solution of THF (1.8 mL) and water(2 mL), maintaining the temperature at -80---’-70 °C (ca. for 2 h for completion of addition). Themixture is stirred at-60’--SO °C for 3 h, water (2 mL) is added to the reaction mixture andallowed to reach up to 15 °C. The reaction mixture is then extracted with ethyl acetate (2 mL,2*1 mL) and the combined organic layers are washed with brine (1 mE). The organic layer is concentrated under vacuum at 35-40 °C, the solid is dissolved in toluene (1 mL, 80-90 °C) and then is gradually cooled to 25-30 °C for 2.5 h. The mixture is stirred for 2 h at 25-30 °C,filtered, and the solid is dried in the air to give the product (177 mg with ratio of cis:trans (96.4:3.6), yield: 87.6%) as an off-white solid.
74%	Stage #1: 3-(tert-butyloxycarbonylamino)cyclobutan-1-one With L-Selectride In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: With dihydrogen peroxide; sodium hydroxide In tetrahydrofuran; water at 20℃; for 0.5h;	1.3 [0132] Step 3: tert-butyl cis-3-hydroxycyclobutyl)carbamate: a solution of L-Selectride(1M solution in THF) (8.053 mL, 8.05 mmol) was added dropwise over a period of 20 mm to asolution of tert-butyl (3-oxocyclobutyl)carbamate (1.0 g, 5.40 mmol) in THF (25 mL) under N2 atmosphere at -78 °C and the reaction mixture was stirred for lh at -78 °C. To the resulting reaction mixture was added a solution of NaOH (3.25 g) in water (4 mL) over a period of 10 mm followed by 30% aqueous H202 (3 mL) over a period of 20 mm. The reaction mixture wasallowed to warm to room temperature and diluted with ethyl acetate (100 mL). The organic layer was separated off and washed with 10% aq. Na2SO3 (40 mL) followed by brine (40 mL). The organic layer dried over Na2SO4 and concentrated under reduced pressure to get the crude compound which was further purified by neutral alumina column chromatography using 50 % ethyl acetate in n-hexane as eluent to afford the desired compound. The compound was washedwith n-hexane to get the product (0.750 g, 74%) as white solid. m. p. 119 °C (lit, value 117 °C). ‘H NMR (400 MHz, CDC13) ö 4.63 (br, 1H), 4.03 -3.96 (m, 1H), 3.66-3.64 (m, 1H), 2.76-2.72 (m, 2H), 1.91 (br, 1H), 1.79-1.76 (m, 2H), 1.42 (s, 9H).

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/90929, 2013, A1 Location in patent: Page/Page column 87
[2]Current Patent Assignee: YUMANITY THERAPEUTICS INC - WO2017/19589, 2017, A1 Location in patent: Paragraph 0251
[3]Current Patent Assignee: YUMANITY THERAPEUTICS INC - WO2017/112853, 2017, A1 Location in patent: Paragraph 0251; 0101; 0119
[4]Current Patent Assignee: YUMANITY THERAPEUTICS INC - WO2016/105477, 2016, A1 Location in patent: Paragraph 0161
[5]Current Patent Assignee: YUMANITY THERAPEUTICS INC - WO2015/196071, 2015, A1 Location in patent: Paragraph 0132

24
[ 154748-63-7 ]
[ 1284249-30-4 ]

Yield	Reaction Conditions	Operation in experiment
30.7%	With diethylamino-sulfur trifluoride; In dichloromethane; at -70 - 20℃;Inert atmosphere;	To a solution tert-butyl 3-hydroxycyclobutyl - carbamate (1 g, 5.35 mmol) in dry DCM (20 mL) at -70 C was added dropwise DAST (lg, 0.85 mL, 1.17 eq) under the atmosphere of N2. The mixture was then slowly warmed to r.t. and stirred overnight. The resulting mixture was washed with diluted aq. NaHC03. The organic layer was dried over anhydrous Mg2S04 and concentrated. The residue was purified by flash chromatography using petroleum ether / EtOAc (V:V, 20: 1 to 2: 1) as eluent to afford a white solid as the desired product (310 mg, 30.7% yield). MS : 190.1 (M+l)+.
30.7%	With diethylamino-sulfur trifluoride; In ethyl acetate; Petroleum ether;	Step B: Tert-butyl 3-fluorocyclobutylcarbamate To a solution tert-butyl 3-hydroxycyclobutylcarbamate (1 g, 5.35 mmol) in dry DCM (20 mL) at -70 C. was added dropwise DAST (1 g, 0.85 mL, 1.17 eq) under the atmosphere of N2. The mixture was then slowly warmed to r.t. and stirred overnight. The resulting mixture was washed with diluted aq. NaHCO3. The organic layer was dried over anhydrous Mg2SO4 and concentrated. The residue was purified by flash chromatography using petroleum ether/EtOAc (V:V, 20:1 to 2:1) as eluent to afford a white solid as the desired product (310 mg, 30.7% yield). MS: 190.1 (M+1)+.
	With diethylamino-sulfur trifluoride; In dichloromethane; at -70 - 20℃;Inert atmosphere;	Step B: Tert-butyl 3-fluorocyclobutylcarbamate. To a solution tert-butyl 3-hydroxycyclobutyl - carbamate (1 g, 5.35 mmol) in dry DCM (20 mL) at -70 C was added DAST dropwise (lg, 0.85 mL, 1.17 eq) under the atmosphere of N2. The mixture was then slowly warmed to room temperature and stirred overnight. The resulting mixture was washed with diluted aq. NaHC03. The organic layer was dried over anhydrous Mg2S04 and concentrated. The residue was purified by flash chromatography using petroleum ether / EtOAc (V:V, 20: 1 to 2: 1) as eluent to afford a white solid as the desired product. MS : 190.1 (M+l)+.

	With diethylamino-sulfur trifluoride; In dichloromethane; at -70 - 20℃;Inert atmosphere;	To a solutiontert-butyl 3-hydroxycyclobutyl-carbamate (lg, 5.35 mmol) in dry DCM (20 mL) at -70C was added DAST dropwise (lg, 0.85 mL, 1.l7eq) under the atmosphere of N2. The mixture was then slowly warmed to room temperature and stirred overnight. The resulting mixture was washed with diluted aq. NaHCO3. The organic layer was dried over anhydrous Mg2SO4and concentrated. The residue was purified by flash chromatography using petroleum ether EtOAc (V:V, 20:1 to 2:1) as eluent to afford a white solid as the desired product. MS: 190.1 (M+1).
	With diethylamino-sulfur trifluoride; In dichloromethane; at -70 - 20℃;Inert atmosphere;	Step B: Tert-butyl 3-fluorocyclobutylcarbamate. To a solution tert-butyl 3-hydroxycyclobutyl - carbamate ( 1 g, 5.35 mmol) in dry DCM (20 mL) at -70 C was added DAST dropwise (l g, 0.85 mL, 1 .17 eq) under the atmosphere of N2. The mixture was then slowly warmed to room temperature and stirred overnight. The resulting mixture was washed with diluted aq. NaHC03. The organic layer was dried over anhydrous Mg2S04 and concentrated. The residue was purified by flash chromatography using petroleum ether / EtOAc (V:V, 20: 1 to 2: 1 ) as eluent to afford a white solid as the desired product. MS : 190.1 (M+ l )+.

Reference： [1]Patent: WO2013/107405,2013,A1 .Location in patent: Page/Page column 44
[2]Patent: US2015/87600,2015,A1 .Location in patent: Page/Page column
[3]Patent: WO2013/107291,2013,A1 .Location in patent: Page/Page column 63
[4]Patent: WO2015/10626,2015,A1 .Location in patent: Paragraph 63; 64
[5]Patent: WO2015/10297,2015,A1 .Location in patent: Page/Page column 63

25
[ 23761-23-1 ]
[ 154748-63-7 ]

Reference： [1]Patent: WO2013/107291,2013,A1
[2]Patent: WO2013/107405,2013,A1
[3]Patent: WO2015/10626,2015,A1
[4]Patent: WO2015/10297,2015,A1

26
3-oxocyclobutane-1-carbonyl chloride [ No CAS ]
[ 154748-63-7 ]

Reference： [1]Patent: WO2013/107291,2013,A1
[2]Patent: WO2013/107405,2013,A1
[3]Patent: WO2015/10626,2015,A1
[4]Patent: WO2015/10297,2015,A1

27
C₅H₅N₃O₂ [ No CAS ]
[ 154748-63-7 ]

Reference： [1]Patent: WO2013/107291,2013,A1
[2]Patent: WO2013/107405,2013,A1
[3]Patent: WO2015/10626,2015,A1
[4]Patent: WO2015/10297,2015,A1

28
[ 154748-63-7 ]
[ 124-63-0 ]
[ 1221280-93-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine; In dichloromethane; at 0 - 25℃; for 3h;	methanesulfonyl chloride (6.7 g, 58.49 mmol, 1.10 eq.) was added dropwise (5 mm) to a 0C solution of <strong>[154748-63-7]tert-butyl N-(3-hydroxycyclobutyl)carbamate</strong> (9.9 g, 52.87 mmol, 1.00 eq.) and TEA (10.8 g, 106.73 mmol, 2.00 eq.) in dichloromethane (200 mL). The resulting solution wasstirred for 3 hours at 25 C, the mixture was diluted with 400 mL of water. The resulting solution was extracted with dichloromethane (3x200 mL) and the organic layers combined. The resulting mixture was washed with brine (3x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 11.4 g (8 1%) of tert-butylN-[3- (methanesulfonyloxy)cyclobutyl]carbamate as a yellow solid.
81%	With triethylamine; In dichloromethane; at 0 - 25℃; for 3h;	Step 2: 3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate: methanesulfonyl chloride (6.7 g, 58.49 mmol, 1.10 eq.) was added dropwise (5 min) to a 0C solution of <strong>[154748-63-7]tert-butyl N-(3-hydroxycyclobutyl)carbamate</strong> (9.9 g, 52.87 mmol, 1.00 eq.) and TEA (10.8 g, 106.73 mmol, 2.00 eq.) in dichloromethane (200 mL). The resulting solution was stirred for 3 hours at 25 C, the mixture was diluted with 400 mL of water. The resulting solution was extracted with dichloromethane (3x200 mL) and the organic layers combined. The resulting mixture was washed with brine (3x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1 1.4 g (81 %) of tert-butyl N-[3- (methanesulfonyloxy)cyclobutyl]carbamate as a yellow solid.
81%	With triethylamine; In dichloromethane; at 0 - 25℃; for 3.08333h;	methanesulfonyl chloride (6.7 g, 58.49 mmol, 1.10 eq.) was added dropwise (5 min) to a 0 C solution of <strong>[154748-63-7]tert-butyl N-(3-hydroxycyclobutyl)carbamate</strong> (9.9 g, 52.87 mmol, 1.00 eq.) and TEA (10.8 g, 106.73 mmol, 2.00 eq.) in dichloromethane (200 mL). The resulting solution was stirred for 3 hours at 25 C, the mixture was diluted with 400 mL of water. The resulting solution was extracted with dichloromethane (3x200 mL) and the organic layers combined. The resulting mixture was washed with brine (3x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 11.4 g (81 %) of tert-butyl N-[3- (methanesulfonyloxy)cyclobutyl]carbamate as a yellow solid.

81%	With triethylamine; In dichloromethane; at 0 - 25℃; for 3h;	methanesulfonyl chloride (6.7 g, 58.49 mmol, 1.10 eq.) was added dropwise (5 min) to a 0C solution of <strong>[154748-63-7]tert-butyl N-(3-hydroxycyclobutyl)carbamate</strong> (9.9 g, 52.87 mmol, 1.00 eq.) and TEA (10.8 g, 106.73 mmol, 2.00 eq.) in dichloromethane (200 mL). The resulting solution was stirred for 3 hours at 25 C, the mixture was diluted with 400 mL of water. The resulting solution was extracted with dichloromethane (3x200 mL) and the organic layers combined. The resulting mixture was washed with brine (3x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 11.4 g (81 %) of tert-butyl N-[3- (methanesulfonyloxy)cyclobutyl]carbamate as a yellow solid.
	With triethylamine; In dichloromethane; at -20 - 20℃; for 2.08333h;	In a round-bottomed flask charged with tert-butyl (3- hydroxycyclobutyl)carbamate (150 mg, 0.801 mmol) and triethylamine (243 mg, 2.403 mmol) was added dichloromethane (2 mL). Methanesulfonyl chloride (0.187 ml, 2.403 mmol) was added dropwise via syringe at -20Cover 5 mm. The reaction mixture was stirred at room temperature for 2hr, then diluted with water (15 mL) and extracted with dichloromethane (2 x 15 mL). The organic layer was washed with saturated NH4C1 and dried over Mg504. It was filtered and concentrated in vacuo to affordthe title compound: ?H NMR (300 MHz, CDC13):oe5.22-5.19 (m, 0.5H), 4.76-4.68 (m, 2H), 5.32-4.16 (m, 0.5H), 3.90-3.73 (m, 1H), 3.01 (s, 4H), 3.29-2.88 (m, 2H), 2.67-2.64 (m, 1H), 2.49-2.34 (m, 1H), 2.23-2.09 (m, 1H), 1.44 (s, 9H).
	In dichloromethane; at 0 - 30℃; for 0.5h;	A solution of tert-butyl (3-hydroxycyclobutane) carbamate 1a(1.2 g, 6.94 mmol,Prepared by the method disclosed in the patent application "WO2013107405") was dissolved in 5 mL of dichloromethane,Cooled to 0 C,Methylsulfonyl chloride was added dropwise(953 mg, 8.32 mmol),The reaction was stirred at room temperature for 30 minutes.The reaction solution was poured into 30 mL of ice water,Extracted with dichloromethane (30 mL) and the organic phase was washed successively with saturated sodium bicarbonate solution (30 mL), saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered,The filtrate was concentrated under reduced pressure to give the crude title product Ib (1.84 g)The product is subjected to the next step without further purification.

Reference： [1]Patent: WO2015/196071,2015,A1 .Location in patent: Paragraph 0342
[2]Patent: WO2016/105468,2016,A1 .Location in patent: Paragraph 0181
[3]Patent: WO2016/115090,2016,A1 .Location in patent: Paragraph 0335
[4]Patent: WO2017/40606,2017,A1 .Location in patent: Paragraph 0294
[5]Patent: WO2016/206101,2016,A1 .Location in patent: Page/Page column 266
[6]Patent: CN107033097,2017,A .Location in patent: Paragraph 0187; 0191; 0192-0194

29
[ 154748-63-7 ]
[ 1393180-29-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 16 h / 0 - 20 °C / Inert atmosphere 2: tetrabutylammomium bromide / N,N-dimethyl-formamide / 16 h / 120 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: STINGTHERA - WO2020/232378, 2020, A1

30
[ 154748-63-7 ]
[ 106-41-2 ]
tert-butyl N-[3-cis-(4-bromophenoxy)cyclobutyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With di-isopropyl azodicarboxylate; In tetrahydrofuran; at 50℃; for 8h;	tert-Butyl (3-(4-bromophenoxy)cyclobutyl)carbamate. Diisopropyl azodicarboxylate (0.76 mL, 3.88 mmol) was added into a mixture of tert-butyl (3- hydroxycyclobutyl)carbamate (485 mg, 2.59 mmol), 4-bromophenol (538 mg, 3.1 1 mmol) and THF (25 mL). The mixture was stirred at 50 C for 8 hours and then poured into water and extracted with EtOAc. The organics extracts were washed with brine and dried over anhydrous MgS04. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 4/1 ratio) to afford tert-butyl (3-(4- bromophenoxy)cyclobutyl)carbamate 1 as oil (487 mg, 55 % yield). XH NMR (500MHz, CDCk) delta ppm 7.33 (d, J= 8.0 Hz, 1H), 7.31 (d, J= 8.0 Hz, 1H), 6.74 (d, J= 8.0 Hz, 1H), 6.64 (d, J= 8.0 Hz, 1H), 4.79 (brs, 1H), 4.74-4.71 (m, 2H), 4.31-4.29 (m, 1H), 2.56-2.51 (m, 2H), 2.37-2.36 (m, 2), 1.45 (s, 9H).

Reference： [1]Patent: WO2015/179190,2015,A1 .Location in patent: Paragraph 0223

31
[ 154748-49-9 ]
[ 154748-63-7 ]
[ 154748-63-7 ]

Yield	Reaction Conditions	Operation in experiment
60 % de	With methanol; sodium tetrahydroborate at 0℃; for 0.833333h; Overall yield = 95 %; Overall yield = 590 mg;	28.4 Step 4. tert-Butyl (3 -hydroxy cyclobutyl)carbamate. Step 4. tert-Butyl (3 -hydroxy cyclobutyl)carbamate. To a cold ( 0 °C) mixture of tert-butyl (3-oxocyclobutyl)carbamate (620 mg, 3.35 mmol) in MeOH (10 mL) was added NaBH4 (126.7 mg, 3.35 mmol) portionwise over 20 minutes. The mixture was stirred for 30 additional minutes and then it was poured into cold water. The mixture was extracted with EtOAc (3x) and the organics were dried over anhydrous MgS04. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 1/1 ratio) to afford tert-butyl (3 -hydroxy cyclobutyl)carbamate (4/1 cis/trans isomeric ratio) as white solid (590 mg, 95% yield). The cis/trans isomers 4/1 ratio were inseparable and carried to the next step. XH NMR (500MHz, CDCh) δ ppm [4.64 (brs), 4.22 (brs) (1H)], [4.47 (m), 4.02(m), 1H)], [3.66(m), 2.77 (m), 2H], [2.3 l(m), 2.22 (m), 2H], [1.39 (m), 1.79 (m), 2H], 1.43 (s, 9H).
	With sodium tetrahydroborate; water In tetrahydrofuran at -80 - -50℃; Overall yield = 87.6 %; Overall yield = 177 mg;	5.2 Step 2: tert-butyl (cis-3-hydroxycyclobutyl)carbamate: a solution of tert-butyl (3-oxocyclobutyl)carbamate (200 mg, 1.0 eq.) in THF (1 mL) was added dropwise to a cold (below -70 °C) solution of NaBH4 (20.4 mg, 0.5 eq.) in THF (1.8 mL) and water (2 mL), maintaining the temperature at -80-70 °C (ca. for 2 h for completion of addition). The mixture was stirred at-60-50 °C for 3 h, water (2 mL) was added to the reaction mixture andallowed to reach up to 15 °C. The reaction mixture is then extracted with ethyl acetate (2 mL,2 x 1 mL) and the combined organic layers were washed with brine (1 mL). The organic layer was concentrated under vacuum at 3540 °C, the solid dissolved in toluene (1 mL, 8090 °C) and gradually cooled to 25-30 °C for 2.5 h. The mixture was stirred for 2 h at 25-30 °C, filtered, and the solid dried in air to give the product (177 mg with ratio of cis:trans (96.4:3.6),yield: 87.6%) as an off-white solid.

Reference： [1]Current Patent Assignee: NORTHEASTERN UNIVERSITY IN BOSTON, MASSACHUSETTS - WO2015/179190, 2015, A1 Location in patent: Paragraph 0180
[2]Current Patent Assignee: YUMANITY THERAPEUTICS INC - WO2017/19589, 2017, A1 Location in patent: Paragraph 0119

32
[ 154748-63-7 ]
tert-butyl (3-((4'-methyl-[1,1'-biphenyl]-4-yl)methoxy)cyclobutyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2015/179190,2015,A1

33
[ 154748-63-7 ]
[ 589-15-1 ]
tert-butyl (3-((4-bromobenzyl)oxy)cyclobutyl)carbamate [ No CAS ]