198995-91-4|Benzyl 3-oxocyclobutanecarboxylate| Ambeed

Structure of 198995-91-4

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Quality Control of [ 198995-91-4 ] Purity: 97% SDS Specification

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Product Details of [ 198995-91-4 ]

CAS No. :	198995-91-4
Formula :	C₁₂H₁₂O₃
M.W :	204.22
SMILES Code :	O=C(C1CC(C1)=O)OCC2=CC=CC=C2
MDL No. :	MFCD11848894
InChI Key :	OPGPYIKNRCXNQY-UHFFFAOYSA-N
Pubchem ID :	15830669

Safety of [ 198995-91-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 198995-91-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	54.81
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	43.37 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.6
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.03
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.56
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.5
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.56
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.65

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.79
Solubility	3.33 mg/ml ; 0.0163 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.53
Solubility	6.02 mg/ml ; 0.0295 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.26
Solubility	0.111 mg/ml ; 0.000545 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.81 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.83

Application In Synthesis of [ 198995-91-4 ]

* 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.

Downstream synthetic route of [ 198995-91-4 ]

[ 198995-91-4 ] Synthesis Path-Downstream 1~35

1
[ 198995-91-4 ]
benzyl 5-oxotetrahydrofuran-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With Candida antarctica Lipase type B; urea hydrogen peroxide adduct; In ethyl acetate; at 30℃; for 20h;Enzymatic reaction;	General procedure: Over a solution of the corresponding cyclobutanone 1a-l (0.25 mmol) in EtOAc (379 muL, 30.0 mmol), complex urea-hydrogen peroxide (UHP, 35 mg, 0.38 mmol) and CAL-B (12.5 mg) were added. The suspension was shaken for 20 h at 30 C and 250 rpm, then an aliquot was analyzed by GC. The reaction was left shaken until complete conversion was reached, then water was added (2 mL) and the enzyme filtered off. The solution was extracted with EtOAc (3× 5 mL) and the organic phases combined and washed with water (2× 5 mL) and brine (5 mL). The resulting organic phase was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to obtain the corresponding lactones 2a-l (51-99% isolated yield). For fluorinated lactone 2k a column chromatography on silica gel (30% EtOAc/hexane) was necessary, as the reaction did not lead to complete conversion.

References: [1]Journal of Molecular Catalysis B: Enzymatic,2015,vol. 114,p. 31 - 36.
[2]Synlett,1997,vol. 1997,p. 1151 - 1152.

2
[ 23761-23-1 ]
[ 100-39-0 ]
[ 198995-91-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In acetone; for 16h;Reflux;	A mixture of 3-oxocyclobutanecarboxylic acid (5 g, 44 mmol), potassium carbonate (12 g, 88 mmol) and benzyl bromide (11.2 g, 66 mmol) in acetone (50 mL) was refluxed for 16 hr. Solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were dried over anhydrous MgSO/t, filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane / EtOAc to give the desired compound (8.1 g, 90% yield). 1H NMR (400 MHz, CDC13): delta 7.45 - 7.27 (m, 5H), 5.19 (s, 2H), 3.55 - 3.36 (m, 2H), 3.33 - 3.11 (m, 3H).
90%	With potassium carbonate; In [(2)H6]acetone; hexane;	Step A: Benzyl 3-oxocyclobutanecarboxylate A mixture of 3-oxocyclobutanecarboxylic acid (5 g, 44 mmol), potassium carbonate (12 g, 88 mmol) and benzyl bromide (11.2 g, 66 mmol) in acetone (50 mL) was refluxed for 16 hr. Solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane/EtOAc to give the desired compound (8.1 g, 90% yield). 1H NMR (400 MHz, CDCl3): delta 7.45-7.27 (m, 5H), 5.19 (s, 2H), 3.55-3.36 (m, 2H), 3.33-3.11 (m, 3H).
53%	With triethylamine; In tetrahydrofuran; at 20℃; for 2h;	Example 261 : 2-N-Methyl-6-[5-(3-phenoxycyclobutyl)-1 ,2,4-oxadiazol-3-yl]-2-N-phenyl- 1 ,3,5-triazine-2,4-diamineTriethylamine (2 mL, 14.04 mmol) and benzyl bromide (1.2 mL, 10.0 mmol) were added to a solution of 3-oxocyclobutane-1-carboxylic acid (1.0 g, 8.77 mmol) in THF (10 mL) and the mixture was stirred at room temperature for 2 h. EtOAc (10 mL) was added and the mixture was washed with water followed by 1 M hydrochloric acid and then brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of 0-15% EtOAc in hexane to afford benzyl 3-oxocyclobutane-1-carboxylate (0.938 g, 53%). A portion of benzyl 3- oxocyclobutane-1-carboxylate (0.800 g, 3.92 mmol) was dissolved in a mixture of THF (2.5 mL) and water (2.5 mL) and cooled to 0 C. Sodium borohydride (0.051 g, 1.96 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum and EtOAc (10 mL) was added. This was washed with water and then brine and the organic layer was then dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with a gradient of 0-10% EtOAc in hexane to afford benzyl 3-hydroxycyclobutane-1-carboxylate (0.715 g, 88%). A portion of benzyl 3-hydroxycyclobutane-1-carboxylate (0.400 g, 1.94 mmol) was dissolved in THF (10 mL) and phenol (0.547 g, 5.83 mmol) and triphenylphosphine (0.662 g, 2.52 mmol) were added. Diethyl azodicarboxylate (0.4 mL, 2.52 mmol) was added gradually and the mixture was stirred at room temperature for 24 h. The mixture was evaporated and then extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of0- 15% EtOAc in hexane to afford benzyl 3-phenoxycyclobutane-1-carboxylate (0.450 g, 82%). A portion of benzyl 3-phenoxycyclobutane-1-carboxylate (0.400 g, 1.42 mmol) was dissolved in EtOH (10 mL) and 10% palladium on carbon (0.010 g) was added. The mixture was stirred under an atmosphere of hydrogen at room temperature for 2 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by FCC, eluting with a gradient of 0-10% EtOAc in hexane to afford 3-phenoxycyclobutane-1- carboxylic acid (0.245 g, 95%). 2-N-Methyl-6-[5-(3-phenoxycyclobutyl)-1 ,2,4-oxadiazol-3- yl]-2-N-phenyl-1 ,3,5-triazine-2,4-diamine was then prepared from 3-phenoxycyclobutane-1- carboxylic acid (0.190 g, 0.985 mmol) and 4-amino-N-hydroxy-6- [methyl(phenyl)amino]-1 ,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 1 , 0.150 g, 0.579 mmol) according to the method described for Example 209. The residue was purified by FCC, eluting with 10% MeOH in hexane to afford the title compound as a mixture of isomers (0.095 g, 42%).

41.9%	With potassium carbonate; In acetone; for 10h;Reflux;	3-Oxocyclobutanecarboxylic acid(3.0 g, 26.3 mmol), benzyl bromide(6.7 g, 39.4 mmol) and potassium carbonate(7.3 g, 52.6 mmol) was dissolved in acetone(30 mL), and then heated to reflux for 10 hours. After TLC showed that the reaction was completed, the reaction mixture was concentrated under reduce pressure to remove the solvent, added water (20 mL), and extracted with ethyl acetate (150 mL*2). The combined organic phase was washed with saturated salt water(50 mL), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified through silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give benzyl 3-oxocyclobutane-carboxylate (2.5 g, 41.9% yield) as a colorless liquid. MS (ESI) Calcd. for C12H12O3 [M+H]+ 205, Found 205.
36.7%	With caesium carbonate; In acetonitrile; at 20℃; for 20h;Inert atmosphere;	To a mixture of commercially available 3-oxocyclobutanecarboxylic acid (13.50 g,118.32 mmol) and Cs2003 (46.26 g, 141.98 mmol) in CH3CN (120 mL), was added bromomethylbenzene (21 .25 g, 124.24 mmol) in one portion at r.t. under N2. The mixture was stirred at r.t. for 20 hours. LCMS and TLC showed the reaction was completed. The residue was poured into water and stirred for 20 mm. The aqueous phase was extracted with EtOAc (120 mL). Thecombined organic phase was washed with saturated brine (140 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford reagent KR-Si (8.86 g, 36.7%).
	With triethylamine; In tetrahydrofuran; at 20℃; for 2h;	Triethylamine (2.0 mL) and benzyl bromide (1.2 mL) were added to a solution of 3-oxocyclobutanecarboxylic acid (J. Org. Chem., vol. 53, pp. 3841-3843 (1981)) (995 mg) in tetrahydrofuran (5.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and was sequentially washed with 1N aqueous HCl, saturated aqueous sodium hydrogencarbonate, and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate : hexane = 1:6), to thereby give the title compound (886 mg).1H-NMR(CDCl3) delta:3.22-3.33(3H, m), 3.37-3.48(2H, m), 5.19(2H, s), 7.31-7.42(5H, m).MS(FAB)m/z:205(M+H+).
	With sodium hydrogencarbonate; triethylamine; In tetrahydrofuran;	REFERENTIAL EXAMPLE 150 Benzyl 3-oxocyclobutanecarboxylate: Triethylamine (2.0 ml) and benzyl bromide (1.2 ml) were added to a solution of 3-oxocyclobutanecarboxylic acid (J. Org. Chem., Vol. 53, pp. 3841-3843, 1981) (995 mg) in tetrahydrofuran (5.0 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:6) to obtain the title compound (886 mg). 1H-NMR (CDCl3) delta: 3.22-3.33(3H,m), 3.37-3.48(2H,m), 5.19(2H,s), 7.31-7.42(5H,m).
		Step A:3-Oxocyclobutanecarboxylic acid (2-A) (1.0 g, 10.0 mmol) was dissolved in anhydrous ethanol (25 ml), and cesium carbonate (1.66 g, 5.1 mmol) was added. After stirring at room temperature under nitrogen for 4 hours, the reaction mixture was concentrated. The residue was redissolved in anhydrous acetonitrile (50 ml) and treated with benzyl bromide (1.2 ml, 10.0 ml). The mixture was allowed to stir at room temperature under nitrogen for 12 hours. Solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The crude product was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane/ethyl acetate to give 2-B.
	With triethylamine; In tetrahydrofuran; at 20℃; for 2h;	[Referential Example 150] benzyl 3-oxocyclobutanecarboxylate: triethylamine (2.0 ml) and benzyl bromide (1.2 ml) were added to a solution of 3-oxocyclobutanecarboxylic acid (J. Org. Chem., Vol. 53, pp. 3841-3843, 1981) (995 mg) in tetrahydrofuran (5.0 ml), and the mixture was stirred at room temperature for 2 hours.. The reaction mixture was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous sodium sulfate.. The solvent was then distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane = 1:6) to obtain the title compound (886 mg).1H-NMR (CDCl3) delta: 3.22-3.33(3H,m), 3.37-3.48(2H,m), 5.19(2H,s), 7.31-7.42(5H,m). MS (FAB) m/z: 205(M+H+).
	With potassium carbonate; In acetonitrile; at 20℃; for 24h;	BnBr was added to the mixture of compound 1 and K2CO3 in acetonitrile 150 mL. The mixture was stirred at room temperature over 24 h and the solid was filtered. The solvent was removed and the residue was purified by column chromatography to give compound 2.
	With potassium carbonate; In acetonitrile; at 20℃; for 24h;	Step 1: benzyl 3-oxocyclobutanecarboxylate (2) Referring to Scheme 6A, BnBr was added to the mixture of compound 1 and K2CO3 in acetonitrile 150 mL. The mixture was stirred at room temperature over 24 h and the solid was filtered. The solvent was removed and the residue was purified by column chromatography to give compound 2.
	With potassium carbonate; In [(2)H6]acetone; hexane;	Step A: Benzyl 3-oxocyclobutanecarboxylate A mixture of 3-oxocyclobutanecarboxylic acid (5 g, 44 mmol), potassium carbonate (12 g, 88 mmol) and benzyl bromide (11.2 g, 66 mmol) in acetone (50 mL) was refluxed for 16 h. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane/EtOAc to give the desired compound. 1H NMR (400 MHz, CDCl3): delta 7.45-7.27 (m, 5H), 5.19 (s, 2H), 3.55-3.36 (m, 2H), 3.33-3.11 (m, 3H).
	With potassium carbonate; In acetone; for 16h;Reflux;	Method Step A: Benzyl 3-oxocyclobutanecarboxylate. A mixture of 3-oxocyclobutanecarboxylic acid (5 g, 44 mmol), potassium carbonate (12 g, 88 mmol) and benzyl bromide (1 1.2 g, 66 mmol) in acetone (50 mL) was refluxed for 16 h. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were dried over anhydrous MgS04, filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane / EtOAc to give the desired compound. FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDC13): delta 7.45 - 7.27 (m, 5H), 5.19 (s, 2H), 3.55 - 3.36 (m, 2H), 3.33 - 3.11 (m, 3H).
		To a solution of commercially available 3-oxocyclobutanecarboxylic acid (14.9 g) in DMF (210 mL) were added potassium carbonate (27.07 g) and benzyl bromide (18.6 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added acetic acid (22.4 mL) over 12 min, and the mixture was stirred at room temperature for 10 min. Water (350 mL) was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed 4 times with saturated brine, dried over magnesium sulfate and concentrated. [1411] Toluene was added and the mixture was concentrated to give a crude product of compound 3-1. The obtained crude product of compound 3-1 was directly used in the next step.
	With potassium carbonate; In acetone; for 16h;Reflux;	A mixture of 3-oxocyclobutanecarboxylic acid (5g, 44 mmol), potassium carbonate (12 g, 88 mmol) and benzyl bromide (11.2 g, 66 mmol) in acetone (50 mL) was refluxed for 16 h. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were driedover anhydrous MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane EtOAc to givethedesired compound. ?H NMR (400 MHz, CDC13): 7.45 - 7.27 (m, 511), 5.19 (s, 211), 3.55-3.36 (m, 211), 3.33 -3.11 (m, 311).
	With potassium carbonate; In acetone; for 16h;Reflux;	Step A: Benzyl 3-oxocyclobutanecarboxylate. A mixture of 3-oxocycIobutanecarboxylic acid (5 g, 44 mmol), potassium carbonate ( 12 g, 88 mmol) and benzyl bromide (1 1.2 g, 66 mmol) in acetone (50 mL) was refluxed for 1 h. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were dried over anhydrous MgSC , filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane / EtOAc to give the desired compound. NMR (400 MHz, CDC13): delta 7.45 - 7.27 (m, 5H), 5.19 (s, 2H), 3.55 - 3.36 (m, 2H), 3.33 - 3.1 1 (m, 3H).

References: [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 1284 - 1289.
[2]Patent: WO2013/107405,2013,A1 .Location in patent: Page/Page column 42.
[3]Patent: US2015/87600,2015,A1 .Location in patent: Page/Page column.
[4]European Journal of Organic Chemistry,2015,vol. 2015,p. 6466 - 6471.
[5]Patent: WO2012/35023,2012,A1 .Location in patent: Page/Page column 91-92.
[6]Patent: EP3290418,2018,A1 .Location in patent: Paragraph 0178; 0179.
[7]Patent: WO2014/131855,2014,A1 .Location in patent: Page/Page column 67.
[8]Patent: EP1577301,2005,A1 .Location in patent: Page/Page column 144-145.
[9]Patent: US2005/20645,2005,A1 .
[10]Patent: US2008/262051,2008,A1 .Location in patent: Page/Page column 12.
[11]Patent: EP1405852,2004,A1 .Location in patent: Page 132.
[12]Patent: US2011/112052,2011,A1 .Location in patent: Page/Page column 148.
[13]Patent: US2012/122947,2012,A1 .Location in patent: Page/Page column 86.
[14]Patent: US2013/190249,2013,A1 .Location in patent: Page/Page column.
[15]Patent: WO2013/107291,2013,A1 .Location in patent: Page/Page column 61.
[16]Patent: US2014/221378,2014,A1 .Location in patent: Paragraph 1409; 1410; 1411.
[17]Patent: WO2015/10626,2015,A1 .Location in patent: Page/Page column 62.
[18]Patent: WO2015/10297,2015,A1 .Location in patent: Page/Page column 61.

3
[ 198995-91-4 ]
[ 480449-99-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium tetrahydroborate; water; In tetrahydrofuran; at 0 - 20℃; for 1h;	Example 261 : 2-N-Methyl-6-[5-(3-phenoxycyclobutyl)-1 ,2,4-oxadiazol-3-yl]-2-N-phenyl- 1 ,3,5-triazine-2,4-diamineTriethylamine (2 mL, 14.04 mmol) and benzyl bromide (1.2 mL, 10.0 mmol) were added to a solution of 3-oxocyclobutane-1-carboxylic acid (1.0 g, 8.77 mmol) in THF (10 mL) and the mixture was stirred at room temperature for 2 h. EtOAc (10 mL) was added and the mixture was washed with water followed by 1 M hydrochloric acid and then brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of 0-15% EtOAc in hexane to afford <strong>[198995-91-4]benzyl 3-oxocyclobutane-1-carboxylate</strong> (0.938 g, 53%). A portion of benzyl 3- oxocyclobutane-1-carboxylate (0.800 g, 3.92 mmol) was dissolved in a mixture of THF (2.5 mL) and water (2.5 mL) and cooled to 0 C. Sodium borohydride (0.051 g, 1.96 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum and EtOAc (10 mL) was added. This was washed with water and then brine and the organic layer was then dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with a gradient of 0-10% EtOAc in hexane to afford benzyl 3-hydroxycyclobutane-1-carboxylate (0.715 g, 88%). A portion of benzyl 3-hydroxycyclobutane-1-carboxylate (0.400 g, 1.94 mmol) was dissolved in THF (10 mL) and phenol (0.547 g, 5.83 mmol) and triphenylphosphine (0.662 g, 2.52 mmol) were added. Diethyl azodicarboxylate (0.4 mL, 2.52 mmol) was added gradually and the mixture was stirred at room temperature for 24 h. The mixture was evaporated and then extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of0- 15% EtOAc in hexane to afford benzyl 3-phenoxycyclobutane-1-carboxylate (0.450 g, 82%). A portion of benzyl 3-phenoxycyclobutane-1-carboxylate (0.400 g, 1.42 mmol) was dissolved in EtOH (10 mL) and 10% palladium on carbon (0.010 g) was added. The mixture was stirred under an atmosphere of hydrogen at room temperature for 2 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by FCC, eluting with a gradient of 0-10% EtOAc in hexane to afford 3-phenoxycyclobutane-1- carboxylic acid (0.245 g, 95%). 2-N-Methyl-6-[5-(3-phenoxycyclobutyl)-1 ,2,4-oxadiazol-3- yl]-2-N-phenyl-1 ,3,5-triazine-2,4-diamine was then prepared from 3-phenoxycyclobutane-1- carboxylic acid (0.190 g, 0.985 mmol) and 4-amino-N-hydroxy-6- [methyl(phenyl)amino]-1 ,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 1 , 0.150 g, 0.579 mmol) according to the method described for Example 209. The residue was purified by FCC, eluting with 10% MeOH in hexane to afford the title compound as a mixture of isomers (0.095 g, 42%).
53%	With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 0℃; for 0.5h;	Intermediate 32: benzyl 3-hydroxycyclobutanecarboxylate NaBH4 (215 mg; 5.68 mmol) was added to the solution of <strong>[198995-91-4]benzyl 3-oxocyclobutanecarboxylate</strong> (2.3 g; 11.3 mmol) in THF (30 mL) and MeOH (1.5 mL). The reaction mixture was stirred for 0.5 hour at 0 C., diluted with water (20 mL), and extracted with DCM (50 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reverse phase flash chromatography to afford 1.24 g (53%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) delta [ppm]: 7.49-7.22 (m, 5H), 5.12 (d, J=4.1 Hz, 2H), 4.28-4.08 (m, 1H), 2.72-2.50 (m, 3H), 2.41-2.09 (m, 3H).
47%	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;	To a solution of <strong>[198995-91-4]benzyl 3-oxocyclobutanecarboxylate</strong> (17.9 g, 88 mmol) in MeOH (150 ml) at 0C added sodium borohydride (3.32 g, 88 mmol) slowly. After addition, the reaction mixture was allowed slowly warm up to room temperature. After stirred for one hour, the reaction quenched with ice, extracted with 3x60 ml ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. Then applied onto a silica gel column and eluted with ethylacetate/hexane 0-100%. This resulted in 8.5 g (47%) of benzyl 3hydroxycyclobutanecarboxylate as colorless oil. Then separated by ChiralPak AY-20um (300x20mmI.D). Mobile phase: A for SFC C02 and B for isopropanol, gradient 10% B. This result in trans-benzyl 3-hydroxycyclobutanecarboxylate (4g, Rt = 3.51 min). LC-MS (ES, m/z) C, 2H 1403: 206; Found: 207[M+H]+, cis-benzyl 3- hydroxycyclobutanecarboxylate (361 mg, 2.83 min). LC-MS (ES, m/z) Ci2Hi403: 206; Found: 207[M+H]+

	With sodium tetrahydroborate; In tetrahydrofuran; methanol; at 0℃; for 0.5h;	To a mixture of the compound obtained in Referential Example 150 (781 mg), tetrahydrofuran (10 mL), and methanol (0.5 mL) was added sodium borohydride (76 mg) at 0C, and the thus-obtained mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the diluted mixture was sequentially washed with saturated aqueous sodium hydrogencarbonate and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate : hexane = 1:2), to thereby give the title compound (770 mg).1H-NMR(CDCl3) delta:2.13-2.27(3H, m), 2.55-2.71(3H, m), 4.14-4.23(1H, m), 5.12(2H, s), 7.28-7.39(5H, m). MS (FAB) m/z: 207(M+H+).
	With sodium tetrahydroborate; In tetrahydrofuran; methanol; at 0℃; for 0.5h;	[Referential Example 151] benzyl 3-hydroxycyclobutanecarboxylate: sodium borohydride (76 mg) was added to a solution of the compound (781 mg) obtained in Referential Example 150 in a mixed solvent of tetrahydrofuran (10 ml) and methanol (0.5 ml) at 0C, and the mixture was stirred at the same temperature for 30 minutes.. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride in that order and dried over anhydrous sodium sulfate.. The solvent was then distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane = 1:2) to obtain the title compound (770 mg).1H-NMR (CDCl3) delta: 2.13-2.27(3H,m), 2.55-2.71(3H,m), 4.14-4.23(1H,m), 5.12(2H,s), 7.28-7.39(5H,m). MS (FAB) m/z: 207(M+H+).

References: [1]Patent: WO2012/35023,2012,A1 .Location in patent: Page/Page column 91-92.
[2]Patent: US2015/133422,2015,A1 .Location in patent: Paragraph 0473; 0474.
[3]Patent: WO2013/74387,2013,A1 .Location in patent: Page/Page column 52.
[4]Patent: EP1577301,2005,A1 .Location in patent: Page/Page column 145.
[5]Patent: EP1405852,2004,A1 .Location in patent: Page 133.

4
[ 23761-23-1 ]
[ 100-51-6 ]
[ 198995-91-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With toluene-4-sulfonic acid; In toluene; for 3h;Heating;	To 3-oxocyclobutanecarboxylic acid (10 g, 87,6 mmol) in dry toluene (100 mL) was added benzyl alcohol (9,1 mL, 87,6 mmol) and p-toluenesulphonic acid (0,4 g, 2,1 mmol). The reaction was heated under Dean-Stark conditions for 3 h. The reaction was concentrated to dryness in vacuo to afford the crude product. Purification using silica chromatography (ethyl acetate/hexane, 0-100% gradient) gave benzyl 3-oxocyclobutanecarboxylate (6) (16 g; 89%) as a colourless oil.1H NMR CDCl3: delta ppm 7.30 (s, 5H), 5.10 (s, 2H), 3.43-3.29 (m, 2H), 3.28-3.13 (m, 3H).
84%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 20℃; for 18h;	Intermediate 1 (3. 5g, 30.7 mmol), benzyl alcohol (3.17 ml, 30.7 mmol), DMAP (375mg, 3.07 mmol), EDC (8.8g, 46.0 mmol) and DCM (100 ml) were mixed together and stirred at room temperature for 18 hours. The reaction mixture was washed with water (3x). The combined aqueous layer was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous MGS04, and concentrated IN VACUO. Crude product was purified by MPLC (30: 70, ethyl acetate: hexanes) to yield Intermediate 3 (5.25g, 84.0%). NMR (400 MHz, CDC13) 8 7.39 (m, 4H), 5.21 (s, 2H), 3.49-3. 41 (m, 2H), 3.36-3. 28 (m, 3H).
66%		Slowly add carbonyldiimidazole (42.6 g, 263 mmol) to a solution of 3-oxo- cyclopropane carboxylic acid (25.0 g, 219 mmol) in DCM (500 mL), stir at RT for 2 h, add benzyl alcohol (24.17 g, 223 mmol) and stir at RT for 16 h. Add water, extract with DCM (2x), wash the combined organics with brine, dry over Na2S04, concentrate to dryness and purify by silica gel chromatography (EtOAc/Hex) to afford the title compound (29.5 g, 66%) as a colorless syrup. 1H NMR (400 MHz, DMSO-d6): delta 7.38- 7.35 (m, 5 H); 5.14 (s, 2 H); 3.62 (m, 5 H); MS (ESI) m/z: 227.1 (M+Na+).

66%		Example 1 Carbonyldiimidazole (42.6 g, 263 mmol) was slowly added to a solution of 3-oxo-cyclopropane carboxylic acid (25.0 g, 219 mmol) in DCM (500 mL), stirred at RT for 2 h, treated with benzyl alcohol (24.17 g, 223 mmol) and stirred at RT for 16 h. The mixture was diluted with water, extracted with DCM (2*) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/Hex) to afford benzyl 3-oxocyclobutanecarboxylate (29.5 g, 66%) as a colorless syrup. 1H NMR (400 MHz, DMSO-d6): delta 7.38-7.35 (m, 5H); 5.14 (s, 2H); 3.62 (m, 5H); MS (ESI) m/z: 227.1 (M+Na+).
3.15 g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;	A mixture of 3-oxocyclobutanecarboxylic acid (2.15 g, 18.84 mmol), benzyl alcohol (2.145 mL, 20.73 mmol) and Nl-((ethylimino)methylene)-N3,N3- dimethylpropane- 1,3 -diamine, HC1 (5.42 g, 28.3 mmol) in DCM (100 mL) was stirred at room temperature for 18 hours. The reaction mixture was washed with water (3x) and the combined aqueous layers were extracted with DCM. The combined organic layesr were washed with brine, dried over anhydrous MgS04, and concentrated in vacuo. Crude product was purified by FCC (0% to 35% EtOAc- Hexanes) to yield the desired product Cap W-25/Cap W-26 Step A (3.15 g) as a colorless oil.1HNMR (400 MHz, CDC13) delta 7.39 (m, 5H), 5.21 (s, 2H), 3.49-3. 41 (m, 2H), 3.36-3. 28 (m, 3H).

References: [1]Patent: WO2011/6621,2011,A1 .Location in patent: Page/Page column 38.
[2]Patent: WO2004/82682,2004,A1 .Location in patent: Page 38.
[3]Patent: WO2013/134298,2013,A1 .Location in patent: Page/Page column 78.
[4]Patent: US2014/275080,2014,A1 .Location in patent: Paragraph 0407.
[5]Patent: WO2015/5901,2015,A1 .Location in patent: Page/Page column 613; 614.

5
(1R,3'R)-3'-methylspiro[indene-1,4'-piperidine] hydrochloride [ No CAS ]
[ 198995-91-4 ]
C₂₆H₂₉NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium tris(acetoxy)borohydride; diethylamine; In dichloromethane; at 20℃; for 60h;	Intermediate 3 (100 mg, 0.49 mmol), Intermediate 2 (116mg, 0.49 mmol), DIEA (171 BTL, 0.98 mmol), molecular sieves, NaBH (OAc) 3 (520mg, 2.45 mmol), and DCM (10 ml) were mixed together and stirred at room temperature for 60 hours. The reaction was purified by preparative TLC (2: 0.2 : 97.8, MeOH: NH40H : DCM) to yield the product (95mg, 50%). LC-MS for C26H29NO2 MW calculated 387.22, found 388.15.

References: [1]Patent: WO2004/82682,2004,A1 .Location in patent: Page 57-58.

6
[ 198995-91-4 ]
[ 149-73-5 ]
[ 766513-38-6 ]

Yield	Reaction Conditions	Operation in experiment
94.5%Chromat.	With toluene-4-sulfonic acid; In methanol; dichloromethane; for 2.5h;	A Intermediate 3 (4.93 g, 24.2 mmol) was dissolved in DCM (50 ML) and MeOH (50 ML) first before TMOF (26.5 mL, 242 mmol) was added. TSOH (460 mg, 2.42 mmol) was added last. The reaction mixture was stirred for 2.5 hours before being concentrated in vacuo. The concentrate was diluted with EtOAc, quenched with saturated NaHC03 solution, washed with brine, dried over anhydrous MGSO4, and concentrated IN VACUO. The crude product was purified by MPLC (20: 80, EtOAc: hexanes) to yield the desired product (5.71g, 94.5%). 1H NMR (500 MHz, CDC13) 8 7.37 (m, SH), 5.16 (s, 2H), 3.17 (d, J=11. 6 Hz, 6H), 2.95 (m, 1H), 2.44 (m, 4H).

References: [1]Patent: WO2004/82682,2004,A1 .Location in patent: Page 54.

7
[ 100-39-0 ]
[ 198995-91-4 ]

Yield	Reaction Conditions	Operation in experiment
		3-Oxocyclobutanecarboxylic acid (2-A) (1.0 g, 10.0 mmol) was dissolved in anhydrous ethanol (25 ml), and cesium carbonate (1.66 g, 5.1 mmol) was added. After stirring at room temperature under nitrogen for 4 hours, the reaction mixture was concentrated. The residue was redissolved in anhydrous acetonitrile (50 ml) and treated with benzyl bromide (1.2 ml, 10.0 ml). The mixture was allowed to stir at room temperature under nitrogen for 12 hours. Solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The crude product was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane/ethyl acetate to give 2-B. lH NMR (500 MHz, CDCI3): delta 3.30-3.48 (5H, m), 5.22 (2H, s), 7.37-7.41 (5H, m) ppm.

References: [1]Patent: WO2007/47625,2007,A2 .Location in patent: Page/Page column 23.

8
[ 198995-91-4 ]
[ 935273-86-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 16h;Inert atmosphere;	To a solution of benzyl 3- oxocyclobutanecarboxylate (1.23g, 6.03 mmol) in DCM (35 mL) was added DAST (0.8 mL, 6.03 mmol) dropwise under nitrogen. The mixture was stirred at r.t. for 16 h and then diluted with DCM. After washed successively in sequence with saturated sodium bicarbonate, IN aq. hydrochloric acid, and brine, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography with 93% hexane / EtOAc as eluent to give the desired compound as an oil (1 g, 71% yield). 1H NMR (400 MHz, CDC13): delta 7.47 - 7.27 (m, 5H), 5.16 (s, 2H), 3.09 - 2.95 (m, 1H), 2.90 - 2.60 (m, 4H).
71%	With diethylamino-sulfur trifluoride;	Step B: Benzyl 3,3-difluorocyclobutanecarboxylate To a solution of <strong>[198995-91-4]benzyl 3-oxocyclobutanecarboxylate</strong> (1.23 g, 6.03 mmol) in DCM (35 mL) was added DAST (0.8 mL, 6.03 mmol) dropwise under nitrogen. The mixture was stirred at r.t. for 16 h and then diluted with DCM. After washed successively in sequence with saturated sodium bicarbonate, 1N aq. hydrochloric acid, and brine, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography with 93% hexane/EtOAc as eluent to give the desired compound as an oil (1 g, 71% yield). 1H NMR (400 MHz, CDCl3): delta 7.47-7.27 (m, 5H), 5.16 (s, 2H), 3.09-2.95 (m, 1H), 2.90-2.60 (m, 4H).
36.54%	With dimethylaminosulphur trifluoride; In dichloromethane; at -60 - 15℃; for 10h;	To benzyl 3-oxocyclobutane-carboxylate(1.0 g, 4.9 mmol) in dichloromethane(35 mL), was added dropwise DAST(1.6 g, 9.8 mmol) at -60C. After adding, the reaction mixture was warmed slowly to 15C and stirred for 10 hours. After TLC showed that the reaction was completed, the reaction mixture was cooled to 0C. Saturated sodium bicarbonate solution(10 mL) for quenching reaction, the water phase was extracted with dichloromethane(30 mL*2). The organic phase was combined, washed with saturated salt water(10 mL), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified through silica gel column chromatography (petroleum ether/ethyl acetate=20:1?10:1) to give benzyl 3,3-difluorocyclobutane carboxylate(450 mg, 36.54% yield) as a colorless oil. MS (ESI) Calcd. for C12H12F2O2 [M+H]+ 227, Found 227.

	With ethanol; diethylamino-sulfur trifluoride; In dichloromethane; for 12h;	Benzyl 3-oxocyclobutanecarboxylate (2-B) (1.23 g, 6.03 mmol) was dissolved in methylene chloride (35 ml). DAST (8.0 ml, 6.03 mmol) was added under nitrogen, followed by anhydrous ethanol (0.4 ml, 7.23 mmol). The mixture was stirred for 12 hours before it was diluted with methylene chloride, washed successively with saturated sodium bicarbonate, IN aq. hydrochloric acid, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography with 93% hexane/ethyl acetate as eluent to give <n="25"/>2-C as an oil. lH NMR (500 MHz, CDCI3): delta 2.81-2.93 (4H, m), 3.01- 3.04 (IH, m), 5.20 (2H, s), 7.36- 7.42 (5H, m) ppm.
	With diethylamino-sulfur trifluoride; In ethanol; dichloromethane; for 12h;	Step B:Benzyl 3-oxocyclobutanecarboxylate (2-B) (1.23 g, 6.03 mmol) was dissolved in methylene chloride (35 ml). DAST (8.0 ml, 6.03 mmol) was added under nitrogen, followed by anhydrous ethanol (0.4 ml, 7.23 mmol). The mixture was stirred for 12 hours before it was diluted with methylene chloride, washed successively with saturated sodium bicarbonate, 1N aq. hydrochloric acid, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography with 93% hexane/ethyl acetate as eluent to give 2-C as an oil.
	With diethylamino-sulfur trifluoride;	Step B: Benzyl 3,3-difluorocyclobutanecarboxylate To a solution of <strong>[198995-91-4]benzyl 3-oxocyclobutanecarboxylate</strong> (1.23 g, 6.03 mmol) in DCM (35 mL) was added DAST (0.8 mL, 6.03 mmol) dropwise under nitrogen. The mixture was stirred at room temperature for 16 h and then diluted with DCM. After successive washes with saturated sodium bicarbonate, 1N aq. hydrochloride acid, and brine, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography with 93% hexane/EtOAc as eluent to give the desired compound as an oil. 1H NMR (400 MHz, CDCl3): delta 7.47-7.27 (m, 5H), 5.16 (s, 2H), 3.09-2.95 (m, 1H), 2.90-2.60 (m, 4H).
	With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 16h;Inert atmosphere;	Step B: Benzyl 3,3-difluorocyclobutanecarboxylate. To a solution of benzyl 3- oxocyclobutanecarboxylate (1.23g, 6.03 mmol) in DCM (35 mL) was added DAST (0.8 mL, 6.03 mmol) dropwise under nitrogen. The mixture was stirred at room temperature for 16 h and then diluted with DCM. After successive washes with saturated sodium bicarbonate, IN aq. hydrochloride acid, and brine, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography with 93% hexane / EtOAc as eluent to give the desired compound as an oil. H NMR (400 MHz, CDC13): delta 7.47 - 7.27 (m, 5H), 5.16 (s, 2H), 3.09 - 2.95 (m, 1H), 2.90 - 2.60 (m, 4H).
	With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 16h;Inert atmosphere;	To a solution of <strong>[198995-91-4]benzyl 3-oxocyclobutanecarboxylate</strong> (1 .23g, 6.03 mmol) in DCM (35 mL) was added DAST (0.8 mL, 6.03 mmol) dropwise under nitrogen. The mixture was stirred at room temperature for 16 hand then diluted with DCM. After successive washes with saturated sodium bicarbonate, iN aq. hydrochloride acid, and brine, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography with 93% hexane EtOAc as eluent to give the desired compound as an oil. ?H NMR (400 MHz, CDC13): 7.47 -7.27 (m, 511), 5.16 (s, 211), 3.09 -2.95 (m, 111), 2.90 -2.60 (m, 411).
	With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 16h;Inert atmosphere;	Step B: Benzyl 3, 3-difluorocyclobutanecarboxylate. To a solution of benzyl 3- oxocyclobutanecarboxylate (1 .23g, 6.03 mmol) in DCM (35 mL) was added DAST (0.8 mL, 6.03 mmol) dropwise under nitrogen. The mixture was stirred at room temperature for 16 h and then diluted with DCM . After successive washes with saturated sodium bicarbonate, IN aq. hydrochloride acid, and brine, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product waspurifiedby silica gel chromatography with 93% hexane / EtOAc as eluent to give the desired compound as an oiL H NMR (400MHz, CDC13): delta 7.47 - 7.27 (m, 5H), 5.16 (s, 2H), 3.09 - 2.95 (m, 1H), 2.90 - 2.60 (m, 4H).

References: [1]Patent: WO2013/107405,2013,A1 .Location in patent: Page/Page column 42.
[2]Patent: US2015/87600,2015,A1 .Location in patent: Page/Page column.
[3]Patent: EP3290418,2018,A1 .Location in patent: Paragraph 0178; 0180.
[4]Patent: WO2007/47625,2007,A2 .Location in patent: Page/Page column 23-24.
[5]Patent: US2008/262051,2008,A1 .Location in patent: Page/Page column 12-13.
[6]Patent: US2013/190249,2013,A1 .Location in patent: Page/Page column.
[7]Patent: WO2013/107291,2013,A1 .Location in patent: Page/Page column 61; 62.
[8]Patent: WO2015/10626,2015,A1 .Location in patent: Page/Page column 62.
[9]Patent: WO2015/10297,2015,A1 .Location in patent: Page/Page column 61-62.

9
[ 109-89-7 ]
[ 198995-91-4 ]
cis-3-diethylaminocyclobutane carboxylic benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%		To a solution of <strong>[198995-91-4]3-oxocyclobutane carboxylic benzyl ester</strong> (88.1 mg, 0.43 mmol) in dichloromethane (4.3 mL) were successively added diethylamine (0.18 mL, 1.73 mmol) and sodium triacetoxyborohydride (137.0 mg, 0.65 mmol). The mixture was stirred at room temperature for 5 hours, and then to the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then evaporated. The resulting residue was purified by silica gel column chromatography (chloroform/methanol = 20/1 to 5/1) to give the titled compound (66.3 mg, 59%). 1H NMR (CDCl3, 400 MHz) delta 7.42-7.30 (m, 5H), 5.10 (s, 2H), 3.10-3.00 (m, 1H), 2.80-2.72 (m, 1H), 2.51 (q, 4H, J = 7.1 Hz), 2.38-2.28 (m, 2H), 2.23-2.10 (m, 2H), 0.97 (t, 6H, J = 7.1 Hz).

References: [1]Patent: EP1935883,2008,A1 .Location in patent: Page/Page column 41.

10
[ 67-56-1 ]
[ 198995-91-4 ]
[ 98231-07-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With toluene-4-sulfonic acid; In toluene; for 10h;Heating / reflux;	To a solution of <strong>[198995-91-4]3-oxocyclobutane carboxylic benzyl ester</strong> (613 mg, 3 mmol) in toluene (6 mL) were added methanol (1.2 mL) and p-toluenesulfonic acid monohydrate (57 mg, 0.3 mmol), and the mixture was heated to reflux for 10 hours. The reaction solution was concentrated, and then thereto was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and then filtered. The filtrate was evaporated and purified by silica gel column chromatography (n-hexane/ethyl acetate = 20/1 to 3/ 1) to give the titled compound (378 mg, 72%). 1H NMR (CDCl3, 400 MHz) delta 3.70 (s, 3H), 3.17 (s, 3H), 3.15 (s, 3H), 2.94-2.84 (m, 1H), 2.48-2.34 (m, 4H).

References: [1]Patent: EP1935883,2008,A1 .Location in patent: Page/Page column 22.

11
[ 198995-91-4 ]
cis-benzyl 3-hydroxycyclobutanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		A solution of benzyl S-oxocyclobutanecarboxylate (6) (16 g, 78,3 mmol) in dry tetrahydrofurane under Argon was cooled to -78C. To the solution was added dropwise IM lithium tri-tert-butoxyaluminohydride in tetrahydrofurane (78,4 mL, 78,3mmol). After complete addition the reaction was stirred at -78C for 3h. The reaction was quenched by the addition of sat. ammonium chloride (aq) (100 mL). The organics were extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure. The crude compound was purified by column chromatography (ethyl acetate/hexane, 0-100% gradient) to give c/s-benzyl 3-hydroxycyclobutanecarboxylate (7) (14,5 g; 90 %), predominantly cis, as a colourless oil.1H NMR CDCl3: delta ppm 7.30 (s, 5H), 5.08 (s, 2H), 4,19-4,01 (m, IH), 2,65-2,47 (m, 3H), 2,22-2,06 (m, 2H)Compound 7 is the precursor for cold [19F]-labeling wherein hydroxy is replaced by [19F].

References: [1]Patent: WO2011/6621,2011,A1 .Location in patent: Page/Page column 38-39.

12
[ 198995-91-4 ]
(cis)-benzyI₃-(tosyloxy)-cyclobutanecarboxylate [ No CAS ]

References: [1]Patent: WO2011/6621,2011,A1 .

13
[ 198995-91-4 ]
trans-benzyl 3-fluorocyclobutanecarboxylate [ No CAS ]

References: [1]Patent: WO2011/6621,2011,A1 .

14
[ 198995-91-4 ]
trans-3-fluorocyclobutanecarboxylic acid [ No CAS ]

References: [1]Patent: WO2011/6621,2011,A1 .

15
[ 198995-91-4 ]
(18F)-trans-benzyl 3-fluorocyclobutanecarboxylate [ No CAS ]

References: [1]Patent: WO2011/6621,2011,A1 .

16
[ 198995-91-4 ]
(18F)-trans-3-fluorocyclobutanecarboxylic acid [ No CAS ]

References: [1]Patent: WO2011/6621,2011,A1 .

17
[ 676-58-4 ]
[ 198995-91-4 ]
benzyl 3-hydroxy-3-methylcyclobutanecarboxylate [ No CAS ]
[ 1303609-20-2 ]

Yield	Reaction Conditions	Operation in experiment
		MeMgCl in THF was added dropwise to the solution of compound 2 in diethyl ether at -78 C. and the mixture was stirred at the same temperature for half an hour. After TLC monitoring showed the disappearance of the starting material, the reaction was quenched by adding aqueous NH4Cl solution. The aqueous phase was extracted with ethyl acetate three times and the combined organic phase was washed with brine and dried (Na2SO4). The solid was filtered and the solvent was removed. The residue was purified by column chromatography to give compounds 3 and 4 (5:1 based on TLC analysis).

References: [1]Patent: US2011/112052,2011,A1 .Location in patent: Page/Page column 148.
[2]Journal of the American Chemical Society,2013,vol. 135,p. 7223 - 7234.

18
[ 198995-91-4 ]
[ 1263284-46-3 ]

References: [1]Patent: WO2012/35023,2012,A1 .

19
[ 198995-91-4 ]
[ 1366660-53-8 ]

References: [1]Patent: WO2012/35023,2012,A1 .

20
[ 198995-91-4 ]
[ 1366657-86-4 ]

References: [1]Patent: WO2012/35023,2012,A1 .

21
[ 676-58-4 ]
[ 198995-91-4 ]
C₁₃H₁₆O₃ [ No CAS ]
C₁₃H₁₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2 : benzyl 3-hydroxy-3-methylcyclobutanecarboxylates (3 and 4)MeMgCl in THF was added dropwise to the solution of compound 2 in diethyl ether at -78 C. and the mixture was stirred at the same temperature for half an hour. After TLC monitoring showed the disappearance of the starting material, the reaction was quenched by adding aqueous NH4Cl solution. The aqueous phase was extracted with ethyl acetate three times and the combined organic phase was washed with brine and dried (Na2SO4). The solid was filtered and the solvent was removed. The residue was purified by column chromatography to give compounds 3 and 4 (5:1 based on TLC analysis).

References: [1]Patent: US2012/122947,2012,A1 .Location in patent: Page/Page column 86.

22
[ 198995-91-4 ]
benzyl 3-(tert-butyldimethylsilyloxy)-3-methylcyclobutane carboxylate [ No CAS ]

References: [1]Journal of the American Chemical Society,2013,vol. 135,p. 7223 - 7234.

23
[ 198995-91-4 ]
3-(tert-butyldimethylsilyloxy)-3-methylcyclobutanecarboxylic acid [ No CAS ]

References: [1]Journal of the American Chemical Society,2013,vol. 135,p. 7223 - 7234.

24
[ 23761-23-1 ]
[ 501-53-1 ]
[ 198995-91-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap; triethylamine; In dichloromethane; at 0℃; for 1h;	To a mixture of 3-oxocyclobutanecarboxylic acid (175 mmol) and TEA (20.4 g, 202 mmol) in DCM (300 ml) at 0C added benzyl chloroformate (3 1.4 g, 184 mmol) slowly. After the addition, DMAP (2.14 g, 17.53 mmol) added. The reaction mixture stirred at 0C for one hour. Then concentrated under vacuum to get 35.8 g (100%) of benzyl 3-oxocyclobutanecarboxylate as colorless oil. LC-MS (ES, m/z) C12H12O3 : 204; Found: 205 [M+H]+.

References: [1]Patent: WO2013/74387,2013,A1 .Location in patent: Page/Page column 52.

25
[ 198995-91-4 ]
cis-benzyl 3-hydroxycyclobutanecarboxylate [ No CAS ]
trans-benzyl 3-hydroxycyclobutanecarboxylate [ No CAS ]