15760-36-8|3-Methylenecyclobutanecarboxylic acid| Ambeed

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Quality Control of [ 15760-36-8 ] Purity: 98% SDS Specification

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Product Details of [ 15760-36-8 ]

CAS No. :	15760-36-8
Formula :	C₆H₈O₂
M.W :	112.13
SMILES Code :	O=C(C1CC(C1)=C)O
MDL No. :	MFCD00101901
InChI Key :	NNKLICLIBKMDOY-UHFFFAOYSA-N
Pubchem ID :	27475

Safety of [ 15760-36-8 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H315-H318-H335
Precautionary Statements:	P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P332+P313-P362-P403+P233-P405-P501
Class:	8
UN#:	3265
Packing Group:	Ⅲ

Application In Synthesis of [ 15760-36-8 ]

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

Downstream synthetic route of [ 15760-36-8 ]

[ 15760-36-8 ] Synthesis Path-Downstream 1~35

1
[ 15760-35-7 ]
[ 15760-36-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With water monomer; potassium hydroxide; In ethanol;Reflux;	Step 1: Preparation of 3-methylidenecyclobutanecarboxylic acid To a solution of 3-methylidenecyclobutanecarbonitrile (110 g, 1.18 mol) in ethanol (500 mL) and water (500 mL) was added potassium hydroxide (264 g, 4.7 mol) and the resulting mixture was refluxed overnight. The ethanol was removed under reduced pressure, and then the solution was cooled to below 10 C. and acidified with concentrated HCl to pH 1. The mixture was extracted with EtOAc (two*500 mL) and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to afford compound the title compound (132 g, 100% yield) as yellow oil.
100%	With potassium hydroxide; In ethanol; water monomer; for 2h;Reflux;	Compound I-10 was bought from a commercial source and the hydrolysis of I-10 was carried out following a literature procedure (J. Am. Chem. Soc. 1958, 80, 5507). To a solution of 3-methylenecyclobutanecarbonitrile I-10 (1 equivalent) in aqueous EtOH (50%) was added KOH (4 equivalents) and the homogeneous mixture was heated to reflux for 2 h. Upon cooling, all the volatile materials were evaporated and the solid was suspended in water. The pH of the solution was adjusted to 2 by the addition of 1N HCl and the desired compound was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and evaporated to obtain 3-methylenecyclobutanecarboxylic acid in quantitative yield. This material was carried forward directly for the next step.
100%	With ethanol; potassium hydroxide; for 2h;Reflux;	(3-methylenecyclobutyl)methanol (I-11): Compound I- 10 was bought from a commercial source and the hydrolysis of I- 10 was carried out following a literature procedure (J. Am. Chem. Soc. 1958, 80, 5507). To a solution of 3-methylenecyclobutanecarbonitrile I- 10 (1 equivalent) in aqueous EtOH (50%) was added KOH (4 equivalents) and the homogeneous mixture was heated to reflux for 2 h. Upon cooling, all the volatile materials were evaporated and the solid was suspended in water. The pH of the solution was adjusted to 2 by the addition of IN HC1 and the desired compound was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgS04 and evaporated to obtain 3-methylenecyclobutanecarboxylic acid in quantitative yield. This material was carried forward directly for the next step.

100%	With water monomer; potassium hydroxide; In ethanol;	To a solution of 3- methylenecyclobutanecarbonitrile (1 g, 10.74 mmol) in EtOH (5.5 mL) and H2O (5.5 mL) was added KOH (2.410 g, 43.0 mmol). The reaction was refluxed overnight. The ethanol was removed under reduced pressure, The solution was cooled to 0 C and acidified to pHl with concentrated HC1. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried and concentrated to yield E138A (1.204 g, 100%). NMR (500 MHz, CDCh) δ 4.90 - 4.75 (m, 2H), 3.22 - 3.08 (m, 1H), 3.08 - 2.86 (m, 4H).
100%	With water monomer; potassium hydroxide; In ethanol; at 80℃; for 3h;	Dissolve 3-methylenecyclobutane-1-carbonitrile (3.1g, 33.7mmol) in 20mL ethanol,Add potassium hydroxide (7.6g, 135mmol) in water (20mL),React at 80C for 3 hours.After LCMS monitors that the reaction is complete, spin off the organic solvent,The aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid, and extracted with ethyl acetate (50 mL×2).The combined organic phase was washed with saturated brine (50 mL), dried with anhydrous sodium sulfate,Filtered, spin-dried, and purified by column chromatography to obtain the product 23.1 (3.88 g, yield: 100%, colorless oil).
98%	With potassium hydroxide; In ethanol; at 20 - 90℃;	To a stirred solution of KOH (10 g, 178 mmol) in water (15 mL) and EtOH (15 mL) was added 3 -methyl enecyclobutanecarbonitrile (3.92 g, 42 mmol) at room temperature for 10 min. The mixture was allowed to warm to 90 C and stirred at the same temperature for 3.5 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (10 mL) at 0 C. The mixture was acidified with 6 M aqueous HCl to pH 1 and extracted with DCM. The organic layer was dried over MgS04 and concentrated under reduced pressure to provide compound A141-1 (4.65 g, 98%) as a colorless oil. The product was used for next step without futher purification.
97%	With water monomer; potassium hydroxide; In ethanol; at 105℃; for 2.5h;	To a solution of 3- methylidenecyclobutane-1-carbonitrile (6 g, 64.43 mmol, 1.00 eq.) in H20/EtOH (40/40 mL), was added potassium hydroxide (15 g, 267.33 mmol, 4.00 eq.) in several batches at 105C in 30 mm. The resulting solution was stirred for 2 hours at 105C. The resulting solution was dilutedwith water (200 mL) and the pH was adjusted to 2 with conc. hydrogen chloride aqueous (12M). The resulting solution was extracted with ethyl acetate (2x200 mL) and the organic layers combined. The resulting mixture was washed with brine (2x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give of 3-methylidenecyclobutane-1- carboxylic acid as yellow oil (7 g, 97%).
97%	With water monomer; potassium hydroxide; In ethanol; at 105℃; for 2.5h;	Step la: 3-methyIenecyclobutane-l-carboxylic acid: To a solution of 3- methylidenecyclobutane-l -carbonitrile (6 g, 64.43 mmol, 1.00 eq.) in H20/EtOH (40/40 mL), was added potassium hydroxide (15 g, 267.33 mmol, 4.00 eq.) in several batches at 105C in 30 min. The resulting solution was stirred for 2 hours at 105 C. The resulting solution was diluted with water (200 mL) and the pH was adjusted to 2 with cone, hydrogen chloride aqueous (12 M). The resulting solution was extracted with ethyl acetate (2x200 mL) and the organic layers combined. The resulting mixture was washed with brine (2x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give of 3-methylidenecyclobutane-l - carboxylic acid as yellow oil (7 g, 97%).
97%	With water monomer; potassium hydroxide; In ethanol; at 105℃; for 2.5h;	To a solution of 3- methylidenecyclobutane-l-carbonitrile (6 g, 64.43 mmol, 1.00 eq.) in H20/EtOH (40/40 mL), was added potassium hydroxide (15 g, 267.33 mmol, 4.00 eq.) in several batches at 105C in 30 min. The resulting solution was stirred for 2 hours at 105C. The resulting solution was diluted with water (200 mL) and the pH was adjusted to 2 with cone, hydrogen chloride aqueous (12 M). The resulting solution was extracted with ethyl acetate (2x200 mL) and the organic layers combined. The resulting mixture was washed with brine (2x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give of 3-methylidenecyclobutane-l- carboxylic acid as yellow oil (7 g, 97%).
97%	With water monomer; potassium hydroxide; In ethanol; at 105℃; for 2.5h;	To a solution of 3- methylidenecyclobutane-l-carbonitrile (6 g, 64.43 mmol, 1.00 eq.) in H20/EtOH (40/40 mL), was added potassium hydroxide (15 g, 267.33 mmol, 4.00 eq.) in several batches at 105 C in 30 min. The resulting solution was stirred for 2 hours at 105C. The resulting solution was diluted with water (200 mL) and the pH was adjusted to 2 with cone, hydrogen chloride aqueous (12 M). The resulting solution was extracted with ethyl acetate (2x200 mL) and the organic layers combined. The resulting mixture was washed with brine (2x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give of 3- methylidenecyclobutane-l-carboxylic acid as yellow oil (7 g, 97%).
96%	With potassium hydroxide; In ethanol; water monomer; at 105℃;	To a solution of 3-methylene-cyclobutanecarbonitrile (11.2 g, 120 mmol) in ethanol (30 mL) and water (30 mL) was added potassium hydroxide (33.7 g, 602 mmol). The mixture was stirred at 105 C overnight. After cooled down, it was concentrated. The aqueous residue was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate (50 mL) for three times. The combined organic layers were washed withbrine (20 mL) twice, dried over Na2 SO4() and filtered. The filtrate was concentrated under reduced pressure to give the title compound (13.0 g, 96 % yield) as colorless oil.‘H NIVIR (400 1VIHz, DMSO-d6) 12.21 (s, 1H), 4.79-4.76 (m, 2H), 3.10-3.01 (m, 1H), 2.85 - 2.82 (m, 4H).
95%	With water monomer; potassium hydroxide; In ethanol;Reflux;	To a solution of 3-methylenecyclobutanecarbonitrile (5.0 g, 53.7 mmol) in Ethanol (20 mL) was added aqueous KOH (35%) (34.4 g, 215 mmol) and the resulting mixture was refluxed overnight.The ethanol was removed under reduced pressure. The solution was then cooled below 10 C and acidified with concentrated HCI to pH = 5. The mixture was extracted with EtOAc (2x50 mL), the combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound 3- methylenecyclobutanecarboxylic acid (6 g, 50.8 mmol, 95 % yield) as yellow oil. m/z: [M - H]" Calcd for C6H702 1 1 1 .1 ; Found 1 1 1 .
94.5%	With potassium hydroxide; In ethanol; water monomer; at 100℃; for 4h;	3-methylenecyclobutane-1-carbonitrile (24 g, 258.0 mmol, 1.0 equiv) was dissolved in ethanol (180 mL) and water (180 mL). Potassium hydroxide (72.25 g, 1290.3 mmol, 5 equiv) was added and the reaction mixture was stirred at 100 C for 4 hours. The reaction mixture was concentrated. The residue was quenched with water, acidified by 1.0 N HCI aqueous solution to the pH 2 to 4 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 3.1.57a (27.3 g, 94.5 % yield). LCMS (mlz): 111 [M+H]. 1H NMR (400 MHz, DMSO)6 12.25(s, 1H), 4.89-4.64(m, 2H), 3.06 (dt, J= 16.3, 8.0 Hz, 1H), 2.83(d, J8.1 Hz, 4H).
94%	With water monomer; potassium hydroxide; In ethanol; at 80℃; for 16h;	Potassium hydroxide (61 g, 1087 mmol) was added to a solution of 3- methylenecyclobutanecarbonitrile (25 g, 268 mmol) in a mixture of ethanol (150 mL) and water (150 mL) at 27C. The reaction mixture was heated at 80 C for sixteen hours. On completion, the reaction mixture was concentrated under reduced pressure to remove the ethanol. Ice water (250 mL) was added to the residue and the mixture was acidified with concentrated hydrochloric acid (pH = ~1) (250 mL), extracted with ethyl acetate (500 mL, 2X), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-methylenecyclobutanecarboxylic acid (30 g, 252 mmol, 94% yield) as a colorless liquid. 1H NMR (400 MHz, CD3SOCD3) δ 2.82 (d, J = 8 Hz, 4 H), 3.04 (p, J = 8 Hz, 1 H), 4.76 (p, J = 2 Hz, 2 H), 12.20 (br s, 1 H); LC-MS (LC- ES) M+H = 1 13.
91%	With water monomer; potassium hydroxide; In ethanol; at 100℃; for 2h;	3- methylenecyclobutanecarbonitrile (10.0g, 107mmol) and potassium hydroxide (18.1g, 322mmol) was dissolved in ethanol (100 mL) and water (50mL), and reacted at 100C for 2 hours. 1N hydrochloric acid (120 mL) was added. Extracted with dichloromethane (30mLx3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3-methylene cyclobutane carboxylic acid (11.0 g of, yellow oil). Yield: 91%.
90%	With water monomer; potassium hydroxide; In ethanol; at 105℃; for 4h;	The solution of 3-methylenecyclobutanecarbonitrile 1 (27.9g, 0.3mol) in ethanol (200mL) and water (200mL) was treated with potassium hydroxide (84g, 1.5mol). The resulting mixture was stirred and heated to 105C for 4h. The ethanol was removed under reduced pressure. The residue was cooled to 0C, and the pH was adjusted to 1 ~2, then extracted with ethyl acetate, dried over sodium sulfate4, filtered and the solvent was removed. (30.2g, yield= 90%).
77%	With potassium hydroxide; In ethanol; water monomer; at 80℃; for 16h;	To a solution of commercially available 3-methylenecyclobutanecarbonitrile (R-06b-1 , 10 g, 107 mmol) in EtOH/H20 (1 :1 , 200 ml.) was added KOH (24.1 g, 430 mmol) and the mixture was stirred at 80 C for 16 hours. Then, EtOH was removed under reduced pressure and then the solution was cooled to below 10 C and acidified with 1 M HCI to pH 1 . The mixture was extracted with EtOAc and the combined organic layer was dried over anhydrous Na2S04,filtered and concentrated to obtain R-06b-2 (9.3 g, 77%) as yellow oilsolid. This compound was used in the next step without further characterization.
68%		Reference Example 1 3-methylenecyclobutanecarboxylic acid 3-Methylenecyclobutanecarbonitrile (CAS# 15760-35-7, 33.84 g, 0.368 mole), sodium hydroxide (38 g, 0.95 mole) and water (50 mL) were mixed and heated at 110 C. for 30 min to give a two-phase mixture. Tetrabutylammonium hydroxide (40 wt. % in water, 0.7 mL) was added and the organic phase became brown. Within 10 minutes, gas was evolved, and the two phases became well mixed to give a light brown homogeneous solution. Heating was continued at 110 C. for two days. The mixture was cooled to room temperature and then to 0 C. Concentrated hydrochloric acid (95 mL) was added very slowly to adjust the pH to 0.5-1.0. A white slurry was formed, which was extracted with ether (500 mL*2). The organic layer was dried (over Na2SO4), and concentrated to give an oil. This oil was distilled and collected at 108 C.-110 C. to give a colorless liquid (27.74 g, 68% yield). 1H NMR (300 MHz, CDCl3) δ ppm 4.77-4.88 (m, 2H), 3.10-3.24 (m, 1H), 2.86-3.09 (m, 4H).
9%	With water monomer; potassium hydroxide; In ethanol; for 16h;Reflux;	2-((frans)-4-(Dibenzylamino)cyclohexyl)-1 ,1 ,1 -trifluoropropan-2-ol (Intermediate 20B) (0.27 g, 0.69 mmol) and 20 wt % palladium hydroxide on carbon (0.097 g, 0.14 mmol) were stirred in ethanol (6 mL) and purged with hydrogen via balloon (3X) before stirring under a hydrogen atmosphere at room temperature overnight. The reaction was filtered through a pad of Celite and rinsed with ethanol. The filtrate was concentrated under reduced pressure to give the title compound as an oil (136 mg, 93%). 1H NMR (CD3OD) δ 1 .02-1 .28 (m, 7 H), 1 .51 - 1 .61 (m, 1 H), 1 .79-2.00 (m, 4 H), 2.51 -2.62 (m, 1 H); LC-MS (LC-ES) M+H = 212.
		To a solution of 3- methylenecyclobutanecarbonitrile (10.0 g, 107.4 mmol) in ethanol (100 mL) and water (100 mL) was added potassium hydroxide (28.0 g, 430 mmol, 85% pure); the resulting mixture was refluxed for 8 h. Ethanol was removed under reduced pressure, then the solution was cooled to 0 C and acidified with conc. HC1 to pH = 1. The mixture was extracted with diethyl ether (4 x 100 mL). The combined organic phases were dried over anhydrous sodium sulfate. Concentration in vacuo afforded the desired product as a colorless oil; 1H NMR (CDC13, 400 MHz) 8 2.91-3. 18 (m, 4H), 3.14-3. 22 (m, 1H), 4.83 (m, 2H); 13C NMR (CDC13, 100 MHz) 8 32.95, 35.30, 107.14, 143.77, 181. 02 ppm
		To a solution of 3-methylenecyclobutanecarbonitrile (10.0 g, 107.4 mmol) in ethanol (100 mL) and water (100 mL) was added potassium hydroxide (28.0 g, 430 mmol, 85% pure); the resulting mixture was refluxed for 8 h. Ethanol was removed under reduced pressure, then the solution was cooled to 0 C. and acidified with conc. HCl to pH=1. The mixture was extracted with diethyl ether (4*100 mL). The combined organic phases were dried over anhydrous sodium sulfate. Concentration in vacuo afforded the desired product as a colorless oil; 1H NMR (CDCl3, 400 MHz) δ 2.91-3.18 (m, 4H), 3.14-3.22 (m, 1H), 4.83 (m, 2H); 3C NMR (CDCl3, 100 MHz) δ 32.95, 35.30, 107.14, 143.77, 181.02 ppm.
		To a solution of 3-methylenecyclobutanecarbonitrile (100.0 g, 1.042 mol) in ethanol (1.00 L) and water (1.00 L) was added potassium hydroxide (230.0 g, 4.2 mol). The resulting mixture was heated at reflux for 7 hr then the EtOH was removed in vacuo and the solution was cooled to 0 C. and acidified with (300.0 mL) of conc. HCl to pH=1. The mixture was extracted with diethyl ether (4×1 L) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to yield desired product. 1H NMR (400 MHz, CDCl3) δ ppm 2.64-3.44 (m, 5H), 4.60-4.98 (m, 2H) and 10.64 (br. s., 1H).
		3-Methylene-cyclobutane carboxylic acid To a stirring solution of KOH (70.0 g, 1.25 mol) in EtOH/H2O (500 mL,1 :1 v/v) was added 3-methylenecyclobutane carbonitrile (25.0 g, 0.26 mol) and the reaction mixture was refluxed for 6 h. The reaction progress was monitored by TLC and, upon completion, the mixture was cooled and acidified to pH 3-4 with HCl. The ethanol was evaporated, and the remaining aqueous layer was extracted with Et2O (200 mL). The organic layer was washed with water (2 x 20 mL), brine (30 ml), dried overNa2SO4, filtered and concentrated to dryness to yield 3-methylene-cyclobutane carboxylic acid, which was carried through to the next step without further purification:1H NMR (250 MHz, CDCl3) δ 10.75 (bs, 1 H), 4.80 (s, 2 H), 2.85-3.26 (m, 5 H).
		To a solution of 3-methylenecyclobutanecarbonitrile (100.0 g, 1.042 mol) in ethanol (1.00 L) and water (1.00 L) was added potassium hydroxide (230.0 g, 4.2 mol). The resulting mixture was heated at reflux for 7 hr then the EtOH was removed in vacuo and the solution was cooled to 0 C. and acidified with (300.0 mL) of conc. HCl to pH=1. The mixture was extracted with diethyl ether (4×1 L) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to yield desired product. 1H NMR (400 MHz, CDCl3) δ ppm 2.64-3.44 (m, 5H), 4.60-4.98 (m, 2H) and 10.64 (br.s., 1H).
		To a stirring solution of KOH (70.0 g, 1.25 mol) in EtOH/H2O (500 niL, 1:1 v/v) was added 3-methylenecyclobutane carbonitrile (25.0 g, 0.26 mol) and the reaction mixture was refluxed for 6 h. The reaction progress was monitored by TLC and, upon completion, the mixture was cooled and acidified to pH 3-4 with HCl. The ethanol was evaporated, and the remaining aqueous layer was extracted with Et2O (200 mL). The organic layer was washed with water (2 x 20 mL), brine (30 ml), dried over Na2SO4, filtered and concentrated to dryness to yield 3-methylene-cyclobutane carboxylic acid, which was carried through to the next step without further purification: 1H NMR (250 MHz, CDCl3) δ 10.75 (bs, 1 H), 4.80 (s, 2 H), 2.85-3.26 (m, 5 H).
		To a stirring solution of KOH (70.0 g, 1.25 mol) in EtOH/H20 (500 mL, 1 : 1 v/v) was added 3-methylenecyclobutane carbonitrile (25.0 g, 0.26 mol) and the reaction mixture was refluxed for 6 h. The reaction progress was monitored by TLC and, upon completion, the mixture was cooled and acidified to pH 3-4 with HCl. The ethanol was evaporated, and the remaining aqueous layer was extracted with Et20 (200 mL). The organic layer was washed with water (2 x 20 mL), brine (30 ml), dried over Na2S04, filtered and concentrated to dryness to yield 3-methylene-cyclobutane carboxylic acid, which was carried through to the next step without further purification: 1H NMR (250 MHz, CDC13) δ 10.75 (bs, 1 H), 4.80 (s, 2 H), 2.85-3.26 (m, 5 H).
		To a stirring solution of KOH (70.0 g, 1.25 mol) in EtOH/H20 (500 mL, 1:1 v/v) was added 3-methylenecyclobutane carbonitrile (25.0 g, 0.26 mol) and the reaction mixture was refluxed for 6 h. The reaction progress was monitored by TLC and, upon completion, the mixture was cooled and acidified to pH 3-4 with HCl. The ethanol was evaporated, and the remaining aqueous layer was extracted with Et20 (200 mL). The organic layer was washed with water (2 x 20 mL), brine (30 ml), dried over Na2S04, filtered and concentrated to dryness to yield 3-methylene-cyclobutane carboxylic acid, which was carried through to the next step without further purification: 1H NMR (250 MHz, CDC13) δ 10.75 (bs, 1 H), 4.80 (s, 2 H), 2.85-3.26 (m, 5 H).
	With water monomer; potassium hydroxide; In ethanol; for 6h;Reflux;	To a stirring solution of KOH (70.0 g, 1.25 mol) in EtOH/H20 (500 mL,1:1 v/v) was added 3-methylenecyclobutane carbonitrile (25.0 g, 0.26 mol) and the reaction mixture was refluxed for 6 h. The reaction progress was monitored by TLC and, upon completion, the mixture was cooled and acidified to pH 3-4 with HCl. The ethanol was evaporated, and the remaining aqueous layer was extracted with Et20 (200 mL). The organic layer was washed with water (2 x 20 mL), brine (30 ml), dried over Na2S04, filtered and concentrated to dryness to yield 3-methylene-cyclobutane carboxylic acid, which was carried through to the next step without further purification: 1H NMR (250 MHz, CDCl3) δ 10.75 (bs, 1 H), 4.80 (s, 2 H), 2.85-3.26 (m, 5 H).
	With water monomer; potassium hydroxide; In ethanol; for 6h;Reflux;	To a stirring solution of KOH (70.0 g, 1.25 mol) in EtOH/H20 (500 mL, 1:1 v/v) was added 3-methylenecyclobutane carbonitrile (25.0 g, 0.26 mol) and the reaction mixture was refluxed for 6 h. The reaction progress was monitored by TLC and, upon completion, the mixture was cooled and acidified to pH 3-4 with HCl. The ethanol was evaporated, and the remaining aqueous layer was extracted with Et20 (200 mL). The organic layer was washed with water (2 x 20 mL), brine (30 ml), dried over Na2SC filtered and concentrated to dryness to yield 3-methylene-cyclobutane carboxylic acid, which was carried through to the next step without further purification: ¾ NMR (250 MHz, CDC13) δ 10.75 (bs, 1 H), 4.80 (s, 2 H), 2.85-3.26 (m, 5 H).
	With potassium hydroxide; In ethanol; water monomer; at 100℃; for 2h;	Step 1. 3-Methylenecyclobutanecarboxylic acid Into a round bottom flask equipped with a condenser was added 3-methylenecyclobutanecarbonitrile (BePharma, 10.0 g, 0.107 mol). To the flask was added a solution of potassium hydroxide (24.1 g, 0.365 mol) in ethanol (112 mL) and water (88 mL) and the mixture was heated at 100 C. After about 2 hours, ammonia evolution ceased and the solvent was evaporated to dryness under reduced pressure. The solids were dissolved in water (75 mL), cooled in an ice-bath, and acidified to pH of about 1 with concentrated hydrochloric acid. The resulting upper layer was extracted with dichloromethane twice. The organic layers were combined and dried over anhydrous magnesium sulfate. Removal of the organic solvents gave the desired crude product (11.8 g, 97.67%).
	With water monomer; potassium hydroxide; In ethanol; for 2h;Reflux;	3-Methylenecyclobutanecarbonitrile (244 g; 2.62 mol) was added to a solution of potassium hydroxide (85 wt-% pellets; 750 g; 11.4 mol) in a mixture of water (2.7 L) and EtOH (2,7 L). The mixture was heated to obtain a gentle reflux. The reaction was complete, after approximately 2 h, when a moist pH paper did not color blue at the top of the reflux condenser, i.e. ammonia evolution had ceased. The mixture was cooled and was subsequently extracted with toluene (2 x 0.5 L) and Et20 (4 x 0.5 L). The combined organic phases were dried overNa2SC>4. After removal of the drying agent, the resulting solution was concentrated under reduced pressure yielding an oily residue. 13C NMR (CDC13): δ 179.3; 146.2; 107.5; 36.7; 34.8.
	With potassium hydroxide; In ethanol; water monomer; for 2h;Reflux;	Compound I- 10 was bought from a commercial source and the hydrolysis of I- 10 was carried out following a literature procedure (J. Am. Chem. Soc. 1958, 80, 5507). To a solution of 3-methylenecyclobutanecarbonitrile I- 10 (1 equivalent) in aqueous EtOH (50%) was added KOH (4 equivalents) and the homogeneous mixture was heated to reflux for 2 h. Upon cooling, all the volatile materials were evaporated and the solid was suspended in water. The pH of the solution was adjusted to 2 by the addition of IN HCl and the desired compound was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgS04 and evaporated to obtain 3-methylenecyclobutanecarboxylic acid in quantitative yield. This material was carried forward directly for the next step. To a suspension of LiAlH4 (1.5 equivalents) in THF was added 3-methylene- cyclobutanecarboxylic acid (in THF) (1 equivalent) slowly at 0 C. The cooling bath was removed and the reaction mixture was warmed to room temperature and stirred for 3 h. Following a Fischer workup, the desired compound 1-11 was obtained as colorless oil in 89% yield. This material was used for the next step without any purification.
	With water monomer; potassium hydroxide; In ethanol; for 2h;Reflux;	Compound 1-10 was bought from a commercial source and the hydrolysis of I- 10 was carried out following a literature procedure (J. Am. Chem. Soc. 1958, 80, 5507). To a solution of 3-methylenecyclobutanecarbonitrile 1-10 (1 equivalent) in aqueous EtOH (50%) was added KOH (4 equivalents) and the homogeneous mixture was heated to reflux for 2 h. Upon cooling, all the volatile materials were evaporated and the solid was suspended in water. The pH of the solution was adjusted to 2 by the addition of IN HC1 and the desired compound was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgS04 and evaporated to obtain 3-methylenecyclobutanecarboxylic acid in quantitative yield. This material was carried forward directly for the next step.
6.01 g	With water monomer; potassium hydroxide; In ethanol;Reflux;	Description 653-Methylenecyclobutanecarboxylic acid (D65) To a solution of 3-methylenecyclobutanecarbonitrile (5.0 g) in ethanol (20 mL) was added KOH aqueous solution (35%, 34.4 g) and the resulting mixture was heated to reflux overnight. The ethanol was removed under reduced pressure. The residue was cooled to below 10C and acidifiedwith concentrated HC1 to pH = 5. The mixture was extracted with EtOAc (2x50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (6.01 g) as yellow oil. MS (ESI): C6H802 requires 112; found 111 [M-Hf.
	With ethanol; potassium hydroxide;Reflux;	Preparation of reagent R-1 1 a: ethyl 3-methylenecvclobutanecarboxylate To a solution of commercially available 3-methylenecyclobutanecarbonitrile (10.7 g, 1 15 mmol) in EtOH (70 mL) was added KOH (25.2 g, 450 mmol), then the mixture was stirred at reflux overnight. The resulting mixture was stirred at reflux overnight until TLC showed the starting material was consumed completely, the solvent was evaporated and water was added. 1 N HCI was added to bring pH to ~3 and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give the crude product (12.3 g,~95%). The crude product (12.3 g, 1 10 mmol) was dissolved in DMF (120 mL). Then Etl (21 .5 g, 138 mmol) and K2CO3 (31 .7 g, 230 mmol) were added to this solution. The mixture was stirred at r.t. for 8 h. Then water was added and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give a crude which was purified by column to give the reagent R-1 1 a (13.6 g, 88% yield) as a pale yellow oil. GC-MS (M): 140 calc. for C8H12O2: 140.08.
		Example 17; Preparation of tert-butyl-3 -oxocyclobutyl carbamate; A solution of 70 g of KOH in 500 ml of mixture EtOH/H2O (1/1, v/v) was added to a 2 L round bottom flask equipped with magnetic stir bar and condenser followed by 3 -methyl enecyclobutane carbonitrile (Maybrige) (25 g, 0.26 mol). The reaction mixture was refluxed with stirring in an oil bath for 5-6 hours. The reaction was monitored for completion by TLC. Upon completion of reaction, the mixture was cooled and acidified with HCl to a pH of 3-4. Ethanol was evaporated, and the remaining aqueous layer was extracted with 200 mL of Et2O. Combined organics were washed with water (2 x 20 mL) followed by brine (once by 30 ml). Organics were dried over Na2SO4, filtered and evaporated. The resulting product, 3- methylenecyclobutane carboxylic acid (shown above), was used without further purification in the next step.
		Example 46; 6'-(Methyl-(l-hydroxy-3-amino-cyclobutyl)-l-(4-amino-2(S)-hydroxy-butyryl)- sisomicin3-Methylene-cyclobutane carboxylic acidTo a stirring solution of KOH (70.0 g, 1.25 mol) in EtOH/H2O (500 mL, 1 :1 v/v) was added 3 -methyl enecyclobutane carbonitrile (25.0 g, 0.26 mol) and the reaction mixture was refluxed for 6 h. The reaction progress was monitored by TLC and, upon completion, the mixture was cooled and acidified to pH 3-4 with HCl. The ethanol was evaporated, and the remaining aqueous layer was extracted with Et2O (200 mL). The organic layer was washed with water (2 x 20 mL), brine (30 ml), dried over Na2SO4, filtered and concentrated to dryness to yield 3-methylene-cyclobutane carboxylic acid, which was carried through to the next step without further purification: 1H NMR (250 MHz, CDCl3) δ 10.75 (bs, 1 H), 4.80 (s, 2 H), 2.85-3.26 (m, 5 H).
		3-Methylene-cyclobutane carboxylic acid To a stirring solution of KOH (70.0 g, 1.25 mol) in EtOH/H2O (500 mL,1 :1 v/v) was added 3-methylenecyclobutane carbonitrile (25.0 g, 0.26 mol) and the reaction mixture was refluxed for 6 h. The reaction progress was monitored by TLC and, upon completion, the mixture was cooled and acidified to pH 3-4 with HCl. The ethanol was evaporated, and the remaining aqueous layer was extracted with Et2O (200 mL). The organic layer was washed with water (2 x 20 mL), brine (30 ml), dried overNa2SO4, filtered and concentrated to dryness to yield 3-methylene-cyclobutane carboxylic acid, which was carried through to the next step without further purification:1H NMR (250 MHz, CDCl3) δ 10.75 (bs, 1 H), 4.80 (s, 2 H), 2.85-3.26 (m, 5 H).
		3-Methylene-cyclobutane carboxylic acidTo a stirring solution of KOH (70.0 g, 1.25 mol) in EtOH/H2O (500 mL, 1:1 v/v) was added 3-methylenecyclobutane carbonitrile (25.0 g, 0.26 mol) and the reaction mixture was refluxed for 6 h. The reaction progress was monitored by TLC and, upon completion, the mixture was cooled and acidified to pH 3-4 with HCl. The ethanol was evaporated, and the remaining aqueous layer was extracted with Et2O (200 mL). The organic layer was washed with water (2 x 20 mL), brine (30 ml), dried over Na2SO4, filtered and concentrated to dryness to yield 3-methylene-cyclobutane carboxylic acid, which was carried through to the next step without further purification:1H NMR (250 MHz, CDCl3) δ 10.75 (bs, 1 H), 4.80 (s, 2 H), 2.85-3.26 (m, 5 H).N-Boc-S-Methylene-cyclobutanainine

References: [1]Patent: US2013/79324,2013,A1 .Location in patent: Paragraph 0934; 0935.
[2]Patent: US2014/142081,2014,A1 .Location in patent: Paragraph 0242; 0244.
[3]Patent: WO2014/79136,2014,A1 .Location in patent: Page/Page column 89-90.
[4]Patent: WO2018/89355,2018,A1 .Location in patent: Page/Page column 221; 222.
[5]Patent: CN111217834,2020,A .Location in patent: Paragraph 0456-0462.
[6]Patent: WO2015/129926,2015,A1 .Location in patent: Page/Page column 108.
[7]Patent: WO2015/196071,2015,A1 .Location in patent: Paragraph 0173.
[8]Patent: WO2016/105468,2016,A1 .Location in patent: Paragraph 0135.
[9]Patent: WO2016/115090,2016,A1 .Location in patent: Paragraph 0170.
[10]Patent: WO2017/40606,2017,A1 .Location in patent: Paragraph 0129.
[11]Patent: WO2019/1420,2019,A1 .Location in patent: Page/Page column 42.
[12]Patent: WO2019/63748,2019,A1 .Location in patent: Page/Page column 234.
[13]Patent: WO2015/66413,2015,A1 .Location in patent: Page/Page column 131.
[14]Patent: WO2018/229629,2018,A1 .Location in patent: Page/Page column 73; 96.
[15]Patent: CN105566324,2016,A .Location in patent: Paragraph 0197; 0198; 0199; 0200.
[16]Patent: WO2012/154204,2012,A1 .Location in patent: Page/Page column 67; 68.
[17]Patent: WO2018/229139,2018,A1 .Location in patent: Page/Page column 39; 40.
[18]Electrochimica Acta,2022,vol. 419.
[19]Patent: US2007/66588,2007,A1 .Location in patent: Page/Page column 28.
[20]Journal of Medicinal Chemistry,2016,vol. 59,p. 8967 - 9004.
[21]Patent: WO2018/69863,2018,A1 .Location in patent: Page/Page column 127.
[22]Journal of the American Chemical Society,1958,vol. 80,p. 5507,5512.
[23]Journal of the American Chemical Society,1959,vol. 81,p. 2723,2725.
[24]Chemische Berichte,1967,vol. 100,p. 2107 - 2116.
[25]Patent: WO2005/37836,2005,A2 .Location in patent: Page/Page column 144.
[26]Patent: US2006/84654,2006,A1 .Location in patent: Page/Page column 64-65.
[27]Patent: US2007/112005,2007,A1 .Location in patent: Page/Page column 60.
[28]Patent: WO2010/42850,2010,A1 .Location in patent: Page/Page column 62-63.
[29]Patent: US2007/280928,2007,A1 .Location in patent: Page/Page column 56.
[30]Patent: WO2010/132757,2010,A2 .Location in patent: Page/Page column 106-107.
[31]Patent: WO2011/44501,2011,A2 .Location in patent: Page/Page column 72.
[32]Patent: WO2011/44498,2011,A1 .Location in patent: Page/Page column 76-77.
[33]Patent: WO2011/44503,2011,A1 .Location in patent: Page/Page column 74-75.
[34]Patent: WO2011/44538,2011,A1 .Location in patent: Page/Page column 101-102.
[35]Patent: US2011/207754,2011,A1 .Location in patent: Page/Page column 11.
[36]Patent: WO2012/58187,2012,A1 .Location in patent: Page/Page column 52.
[37]Patent: WO2014/79011,2014,A1 .Location in patent: Page/Page column 79.
[38]Patent: WO2014/79150,2014,A1 .Location in patent: Page/Page column 105; 106.
[39]Patent: WO2015/180612,2015,A1 .Location in patent: Page/Page column 59; 60.
[40]Patent: WO2016/20307,2016,A1 .Location in patent: Page/Page column 46.
[41]Patent: WO2008/124821,2008,A1 .Location in patent: Page/Page column 62.
[42]Patent: WO2009/67692,2009,A1 .Location in patent: Page/Page column 170.
[43]Patent: WO2010/42851,2010,A1 .Location in patent: Page/Page column 62-63.
[44]Patent: WO2010/132777,2010,A2 .Location in patent: Page/Page column 178.
[45]Journal of the American Chemical Society,2021,vol. 143,p. 3723 - 3728.

2
[ 15760-36-8 ]
[ 23761-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium osmate(VI) dihydrate; sodium periodate; In tetrahydrofuran; water; at 28℃;Industry scale;	To a solution of crude 3-methylenecyclobutane-carboxylic acid (280 g, 2.25 mol), water (5.5 L), THF (2.5 L) and potassium osmate dihydrate (2.11 g; 5.7 mmol), was charged portion-wise sodium periodate (1.1 kg, 5.14 mol) over a 1.5 h period. The inner temperature was kept below 28 C. To complete conversion additional potassium osmate dihydrate (0.5 g; 1,35 mmol) and sodium periodate (0.45 kg; 2.1 mol) were added. After 2 h stirring, the solids were removed via filtration and were subsequently washed with THF (1 L). The resulting filtrate was extracted with CH2C12 (7 x 1.5 L and 5 x 2 L) and EtOAc (9 2 L). The first 1.5 L CH2CI2 extract was set aside because of the relative large amount of by-product present. The other organic phases were combined and concentrated under reduced pressure. The solid material (approximately 140 g) was redissolved in CH2CI2 and was treated with charcoal (7 g). The charcoal was removed by filtration over Celite and the resulting filtrate was concentrated under reduced pressure, yielding a crystalline mass. This material was redissolved in toluene (150 mL) and to the solution was dosed hexane (1 0 mL). This yielded 52 g light yellowish/brown crystals, which darkened upon standing. Concentration of the mother liquor and recrystallization of the solid mass (70 g) from toluene (150 mL) yielded 48 g yellowish/brown material. The first CH2C12 extract which was set aside, was concentrated yielding 70 g of residue. To the residue CH2CI2 (30 mL) was added and the remaining solution was stored at -15C, which initiated crystallization. From this slurry, 55 g of dark grey/black needle-like crystals were recovered. All crystalline material was combined and was dissolved in EtOAc (750 mL) upon heating, charcoal (7.5 g) was added and the mixture was stirred for 1 h at ambient temperature. The charcoal was removed by filtration over Celite. Approximately 500 mL of EtOAc were removed under reduced pressure. At that point the product started to crystallize and severe foaming was observed. Hexane (500 mL) was added and the mixture was rotated on the rotary evaporator for 1 h. Filtration of the crystalline mass yielded pure product. Anal. Calcd. for C5H6O3: C, 52.63; H, 5.30. Found: C, 52.67; H, 5.31. MS (FIA/ES; negative ionization mode): m/e 430 [M-H] NMR (CDC13): δ 11.47 (br s, 1 H); 3.2-3.5 (m, 5 H). 13C NMR (CDC13): δ 203.1; 180.1; 51.5; 27.2.

References: [1]Journal of the American Chemical Society,1958,vol. 80,p. 5837,5839.
[2]Patent: WO2012/58187,2012,A1 .Location in patent: Page/Page column 52; 53.

3
[ 15760-36-8 ]
[ 98198-78-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With thionyl chloride; at 90℃; for 3h;	Reference Example 2 <strong>[15760-36-8]3-methylenecyclobutanecarboxylic acid</strong> chloride In a 50 mL round-bottom flask equipped with a dropping funnel and water condenser with drying tube, the carboxylic acid prepared above (26.19 g, 0.234 mole) was charged. Thionyl chloride (20.5 mL, 0.281 mole, 1.2 equiv) was added dropwise. The mixture was heated at reflux (oil bath temperature 90 C.) for 3 h then cooled to room temperature. The condenser was replaced with a distillation head and the mixture was distilled under vacuum. A clear colorless liquid was collected at 43-45 C. (23 g, 75% yield). 1H NMR (300 MHz, CDCl3) δ ppm 4.85-4.93 (m, 2H), 3.50-3.63 (m, 1H), 2.95-3.19 (m, 4H).
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;	Step 2. N-methoxy-N-methyl-3-methylenecyclobutanecarboxamide To a mixture of <strong>[15760-36-8]3-methylenecyclobutanecarboxylic acid</strong> (Step 1, 5.88 g, 52.4 mmol) in methylene chloride (100 mL) was added oxalyl chloride (Aldrich, 5.33 mL, 62.9 mmol), followed by a catalytic amount of dimethyl formamide (DMF). The reaction was stirred at rt for 2 h, then evaporated to dryness. The crude acid chloride was dissolved in methylene chloride (200 mL). To the resulting solution was added N,O-dimethylhydroxylamine hydrochloride ((Aldrich, 0.14 g, 62.9 mmol), followed by triethylamine (TEA) (21.9 mL, 0.157 mol), dropwsie, at 0 C. The reaction was stirred at rt overnight, and TEA HCl salt was filtered out. The filtrate was washed with 1 N HCl, then aq. sodium bicarbonate, brine, and dried over magnesium sulfate and evaporated to dryness. The crude amide (7.30 g, 89.7%) was used directly in next step. LCMS calculated for C8H14NO2(M+H)+: m/z=156.1; Found: 156.3.
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 4h;	To a solution of 3 -methyl enecy cl obutane-1-carboxylic acid (1.22 g, 10.88 mmol) in DCM (9.1 mL) was added DMF (0.042 mL, 0.544 mmol) followed by oxalyl chloride (0.95 mL, 10.88 mmol). The reaction was stirred at RT for 4h.

References: [1]Journal of the Chemical Society. Perkin transactions II,1987,p. 231 - 236.
[2]Patent: US2007/66588,2007,A1 .Location in patent: Page/Page column 28.
[3]Journal of the American Chemical Society,1956,vol. 78,p. 4012,4022.
[4]Journal of Organic Chemistry,1991,vol. 56,p. 4659 - 4664.
[5]Patent: US2011/207754,2011,A1 .Location in patent: Page/Page column 11.
[6]Patent: WO2019/126094,2019,A1 .Location in patent: Page/Page column 112-113.

4
[ 15760-36-8 ]
[ 99769-39-8 ]

References: [1]Journal of the American Chemical Society,1958,vol. 80,p. 5507,5512.

5
[ 15760-36-8 ]
[ 124-40-3 ]
[ 98425-72-0 ]

References: [1]Journal of the American Chemical Society,1958,vol. 80,p. 5507,5512.

6
[ 463-49-0 ]
[ 79-10-7 ]
[ 92723-44-9 ]
[ 15760-36-8 ]

References: [1]Journal of the American Chemical Society,1959,vol. 81,p. 2723,2725.
[2]Journal of the American Chemical Society,1959,vol. 81,p. 2723,2725.

7
[ 186581-53-3 ]
[ 15760-36-8 ]
[ 15963-40-3 ]

References: [1]Chemische Berichte,1967,vol. 100,p. 2107 - 2116.

8
[ 15760-36-8 ]
[ 89464-20-0 ]

References: [1]Journal of the American Chemical Society,1961,vol. 83,p. 3671 - 3678.

9
[ 15760-36-8 ]
[ 100114-49-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium azide;tetrabutylammomium bromide; zinc trifluoromethanesulfonate; In tetrahydrofuran; at 40℃;	To a stirring solution of 3-methylene-cyclobutane carboxylic acid (1.0 g,8.9 mmol) in THF (90 mL) was added NaN3 (2.0 g, 31.1 mmol), followed by tetrabutyl ammonium bromide (0.48 g, 1.5 mmol) and Zn(OTf)2 (0.1 g, 0.3 mmol), and the reaction mixture was heated to 40C. Boc20 (2.1 g, 9.8 mmol) was then added at once, and the reaction was heated at 45 C overnight. The reaction was then cooled to 0C and was quenched with 10% aq. NaN02 (180 mL). The THF was evaporated and the aqueous layer was extracted with EtOAc (180 n L). The organic layer was washed with 5 % aq. NaHC03 (2 x 20 mL), brine (30 ml), dried over Na2S04, filtered and concentrated to dryness to yield a crude, which was purified by flash chromatography (silica gel/hexanes: ethyl acetate: 0-90%) to yield the desired N-Boc-3-methylene- cyclobutanamine (0.57 g, 3.1 mmol, 34.9% yield): NMR (250 MHz, CDC13) δ 4.83 (s, 2 H), 4.79 (bs, 1 H), 4.05-4.23 (m, 1 H), 2.92-3.1 1 (m, 2 H), 2.50-2.65 (m, 2 H), 1.44 (s, 9 H).

References: [1]Journal of the American Chemical Society,1962,vol. 84,p. 784 - 788.
[2]Patent: WO2011/44501,2011,A2 .Location in patent: Page/Page column 72-73.

10
[ 15760-36-8 ]
[ 10555-45-0 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium aluminium hydride; In tetrahydrofuran; at 0 - 20℃; for 3h;	To a suspension of LiAlH4 (1.5 equivalents) in THF was added <strong>[15760-36-8]3-methylenecyclobutanecarboxylic acid</strong> (in THF) (1 equivalent) slowly at 0 C. The cooling bath was removed and the reaction mixture was warmed to room temperature and stirred for 3 h. Following a Fischer workup, the desired compound I-11 was obtained. This material was used for the next step without any purification.
	With lithium aluminium hydride; In tetrahydrofuran; at 0 - 20℃; for 3h;	Compound I- 10 was bought from a commercial source and the hydrolysis of I- 10 was carried out following a literature procedure (J. Am. Chem. Soc. 1958, 80, 5507). To a solution of 3-methylenecyclobutanecarbonitrile I- 10 (1 equivalent) in aqueous EtOH (50%) was added KOH (4 equivalents) and the homogeneous mixture was heated to reflux for 2 h. Upon cooling, all the volatile materials were evaporated and the solid was suspended in water. The pH of the solution was adjusted to 2 by the addition of IN HCl and the desired compound was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgS04 and evaporated to obtain <strong>[15760-36-8]3-methylenecyclobutanecarboxylic acid</strong> in quantitative yield. This material was carried forward directly for the next step. To a suspension of LiAlH4 (1.5 equivalents) in THF was added 3-methylene- cyclobutanecarboxylic acid (in THF) (1 equivalent) slowly at 0 C. The cooling bath was removed and the reaction mixture was warmed to room temperature and stirred for 3 h. Following a Fischer workup, the desired compound 1-11 was obtained as colorless oil in 89% yield. This material was used for the next step without any purification.
	With lithium aluminium hydride; In tetrahydrofuran; at 0 - 20℃; for 3h;	To a suspension of LiAlH4 (1.5 equivalents) in THF was added 3-methylene- cyclobutanecarboxylic acid (in THF) (1 equivalent) slowly at 0 C. The cooling bath was removed and the reaction mixture was warmed to room temperature and stirred for 3 h. Following a Fischer workup, the desired compound 1-11 was obtained. This material was used for the next step without any purification.

With lithium aluminium hydride; In tetrahydrofuran; at 0 - 20℃; for 3h;

To a suspension of LiAlI-Li (1.5 equivalents) in THF was added 3-methylene- cyclobutanecarboxylic acid (in THF) (1 equivalent) slowly at 0 C. The cooling bath was removed and the reaction mixture was warmed to room temperature and stirred for 3 h. Following a Fischer workup, the desired compound 1-11 was obtained. This material was used for the next step without any purification.

References: [1]Electrochimica Acta,2022,vol. 419.
[2]Journal of the Chemical Society. Perkin transactions II,1987,p. 231 - 236.
[3]Bulletin of the Chemical Society of Japan,1967,vol. 40,p. 144 - 146.
[4]Patent: US2014/142081,2014,A1 .Location in patent: Paragraph 0242; 0243; 0245.
[5]Patent: WO2014/79011,2014,A1 .Location in patent: Page/Page column 79.
[6]Patent: WO2014/79136,2014,A1 .Location in patent: Page/Page column 89-90.
[7]Patent: WO2014/79150,2014,A1 .Location in patent: Page/Page column 106.
[8]Journal of the American Chemical Society,2021,vol. 143,p. 3723 - 3728.
[9]Patent: CN113493438,2021,A .

11
[ 15760-36-8 ]
[ 75-03-6 ]
[ 286442-84-0 ]

References: [1]Bioorganic and Medicinal Chemistry,2000,vol. 8,p. 897 - 907.

12
(3-chloropyrazin-2-yl)methylamine bis-hydrochloride [ No CAS ]
[ 15760-36-8 ]
[ 867165-51-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Product distribution / selectivity;	C-(3-Chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC) (1.31 g, 6.47 mmol, 1.4 eq.), 4-dimethylamino pyridine (DMAP) (0.141 g, 1.15 mmol, 0.25 eq.), and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) were dissolved in anhydrous CH2Cl2 (25 mL). To this solution, a solution of <strong>[15760-36-8]3-methylenecyclobutanecarboxylic acid</strong> (0.622 g, 5.54 mmol, 1.2 eq.) in anhydrous CH2Cl2 (25 mL) was added under N2 and the reaction was allowed to stir overnight at rt. Reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with water (2×), NaHCO3 (1×), water (1×), and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20% -40% -70%], affording the title compound as a pale yellow solid. Additionally, the title compound could be prepared by the following route: 1,1'-Carbonyldiimidazole (CDI) (0.824 g, 5.08 mmol, 1.1 eq.) and <strong>[15760-36-8]3-methylenecyclobutanecarboxylic acid</strong> (0.570 g, 5.08 mmol, 1.1 eq.) were dissolved in anhydrous THF (12 mL) and allowed to stir at 60 C. for 2 h. A solution of C-(3-chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol) and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) in anhydrous CH2Cl2 (13 mL) was added to the acid mixture and the reaction was allowed to stir at 60 C., under N2, overnight. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with NaHCO3 (2×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.86-2.96 (m, 2H), 3.03-3.19 (m, 3H), 4.72 (dd, J=4.4, 0.8 Hz, 2H), 4.79-4.84 (m, 2H), 6.78 (s, -NH), 8.32-8.34 (m, 1H), 8.46 (d, J=2.8 Hz, 1H); MS (ES+): m/z 238.19 (90) [MH+]; HPLC: tR=2.67 min (OpenLynx, polar-7 min).
		C-(3-Chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC) (1.31 g, 6.47 mmol, 1.4 eq.), 4-dimethylamino pyridine (DMAP) (0.141 g, 1.15 mmol, 0.25 eq.), and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) were dissolved in anhydrous CH2Cl2 (25 mL). To this solution, a solution of <strong>[15760-36-8]3-methylenecyclobutanecarboxylic acid</strong> (0.622 g, 5.54 mmol, 1.2 eq.) in anhydrous CH2Cl2 (25 mL) was added under N2 and the reaction was allowed to stir overnight at rt. Reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with water (2×), NaHCO3 (1×), water (1×), and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20% -40% -70%], affording the title compound as a pale yellow solid. Additionally, the title compound could be prepared by the following route: 1,1'-Carbonyldiimidazole (CDI) (0.824 g, 5.08 mmol, 1.1 eq.) and <strong>[15760-36-8]3-methylenecyclobutanecarboxylic acid</strong> (0.570 g, 5.08 mmol, 1.1 eq.) were dissolved in anhydrous THF (12 mL) and allowed to stir at 60 C. for 2 h. A solution of C-(3-chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol) and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) in anhydrous CH2Cl2 (13 mL) was added to the acid mixture and the reaction was allowed to stir at 60 C., under N2, overnight. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with NaHCO3 (2×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.86-2.96 (m, 2H), 3.03-3.19 (m, 3H), 4.72 (dd, J=4.4, 0.8 Hz, 2H), 4.79-4.84 (m, 2H), 6.78 (s, -NH), 8.32-8.34 (m, 1H), 8.46 (d, J=2.8 Hz, 1H); MS (ES+): m/z 238.19 (90) [MH+]; HPLC: tR=2.67 min (OpenLynx, polar-7 min).; 1,1'-Carbonyldiimidazole (CDI) (8.24 g, 50.81 mmol) and <strong>[15760-36-8]3-methylenecyclobutanecarboxylic acid</strong> (5.70 g, 50.81 mmol) were dissolved in anhydrous THF (100 mL) and allowed to stir at 60 C. for 4 h. A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride (10.0 g, 46.19 mmol) and diisopropylethylamine (DIPEA) (32.30 mL, 184.76 mmol) in anhydrous CH2Cl2 (150 mL) was added to the mixture and the reaction was allowed to stir at rt for 24 h. The mixture was concentrated in vacuo, the residue dissolved in EtOAc and the resulting solution washed with saturated NaHCO3 (aq.) water H2O and Brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude product, which was purified by chromatography over silica gel eluting with 50-70% EtOAc/hexane to yield desired product. 1H NMR (400 MHz, CDCl3) δ ppm 2.92-2.94 (2 H, m), 3.05-3.14 (2 H, m), 4.60 (2 H, d, J=4.24 Hz), 4.80-4.84 (2 H, m), 6.75 (1 H, brs), 8.33 (1 H, d, J=4.22 Hz) and 8.45 (1 H, d, J=2.54 Hz). MS (ES+): m/z 238 and 240 [MH+].

References: [1]Patent: US2007/280928,2007,A1 .Location in patent: Page/Page column 53.
[2]Patent: US2007/280928,2007,A1 .Location in patent: Page/Page column 53; 57.

13
[ 15760-36-8 ]
[ 40896-96-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	Iodoethane (7.5 mL, 93.0 mol) was added at rt to a mixture of <strong>[15760-36-8]3-methylenecyclobutanecarboxylic acid</strong> (10.0 g, 80.0 mmol) and cesium carbonate (56.0 g, 170.0 mmol) in anhydrous N,N-dimethylformamide (500.00 mL) under an atmosphere of nitrogen. The reaction was stirred for 16 hr then partitioned between diethyl ether (1 L) and brine (1 L). The aqueous layer was extracted with diethyl ether (3×500 mL) and the combined organic phases washed with water (2×1 L), dried over sodium sulfate, filtered and concentrated in vacuo to yield desired product 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, 3H), 2.71-3.27 (m, 5H), 4.15 (q, J=7.07 Hz, 2H) and 4.53-4.96 (m, 2H).

References: [1]Patent: US2007/280928,2007,A1 .Location in patent: Page/Page column 56.

14
[ 15760-36-8 ]
[ 100191-89-7 ]

References: [1]Journal of the American Chemical Society,1956,vol. 78,p. 4012,4022.

15
[ 15760-36-8 ]
[ 24070-81-3 ]

References: [1]Journal of the American Chemical Society,1958,vol. 80,p. 5507,5512.

16
[ 15760-36-8 ]
[ 100971-15-1 ]

References: [1]Journal of the American Chemical Society,1958,vol. 80,p. 5507,5512.

17
[ 15760-36-8 ]
[ 101871-23-2 ]