[ CAS No. 6802-75-1 ] {[proInfo.proName]}

Name: 6802-75-1|Diethyl isopropylidenemalonate|95%
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SKU: A448780
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Quality Control of [ 6802-75-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 6802-75-1 ]

Product Details of [ 6802-75-1 ]

CAS No. :	6802-75-1	MDL No. :	MFCD00009147
Formula :	C₁₀H₁₆O₄	Boiling Point :	-
Linear Structure Formula :	(CH₃CCOOC₂H₅)₂	InChI Key :	WEISAZNMMVPNTH-UHFFFAOYSA-N
M.W :	200.23	Pubchem ID :	81255
Synonyms :

Calculated chemistry of [ 6802-75-1 ] Expand+

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.6
Num. rotatable bonds :	6
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	52.28
TPSA :	52.6 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.85 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.64
Log Po/w (XLOGP3) :	2.36
Log Po/w (WLOGP) :	1.45
Log Po/w (MLOGP) :	1.46
Log Po/w (SILICOS-IT) :	1.52
Consensus Log Po/w :	1.88

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.17
Solubility :	1.35 mg/ml ; 0.00673 mol/l
Class :	Soluble
Log S (Ali) :	-3.1
Solubility :	0.157 mg/ml ; 0.000786 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.71
Solubility :	3.89 mg/ml ; 0.0194 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	4.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.37

Safety of [ 6802-75-1 ]

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

Application In Synthesis of [ 6802-75-1 ]

* 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 [ 6802-75-1 ]

[ 6802-75-1 ] Synthesis Path-Downstream 1~108

1
[ 5765-44-6 ]
[ 6802-75-1 ]
[ 141-52-6 ]
[ 861537-98-6 ]

Reference： [1]Chemische Berichte,1915,vol. 48,p. 261
[2]Chemische Berichte,1915,vol. 48,p. 261

2
[ 5765-44-6 ]
[ 6802-75-1 ]
[ 861537-98-6 ]

Reference： [1]Chemische Berichte,1915,vol. 48,p. 261

3
[ 917-64-6 ]
[ 6802-75-1 ]
[ 759-24-0 ]

Reference： [1]Synthetic Communications,2010,vol. 40,p. 342 - 350
[2]Arkiv foer Kemi,1947,vol. 23 B,p. 3
[3]Journal of the American Chemical Society,1953,vol. 75,p. 2949
[4]Journal of the American Chemical Society,1969,vol. 91,p. 2703 - 2715
[5]Journal of Organic Chemistry,1967,vol. 32,p. 3950 - 3955
[6]Australian Journal of Chemistry,1974,vol. 27,p. 1693 - 1710
[7]Journal of the Chemical Society. Perkin transactions I,1984,p. 1241 - 1246
[8]Chemische Berichte,1986,vol. 119,p. 1196 - 1207
[9]Journal of Molecular Structure,1987,vol. 162,p. 321 - 332
[10]European Journal of Organic Chemistry,2013,p. 7044 - 7049

4
[ 6802-75-1 ]
[ 925-90-6 ]
[ 78775-61-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: isopropylidenemalonic acid diethyl ester With copper (I) iodide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: ethynylmagnesium bromide In tetrahydrofuran at 0℃; for 3h;	167.1 Step 1: Diethyl 2-(1,1-dimethylpropyl)propanedioate To a solution of diethyl isopropylidenemalonate (2 g, 9.9884 mmol) in THF (60 mL) was added CuI (2.85 g, 14.965 mmol). After stirring for 30 minutes at 0°C, ethylmagnesium bromide solution in THF (30 mL of 1 M, 30.000 mmol) was added dropwise and the mixture was stirred at 0°C for 3 hours. The mixture was quenched with 1N HCl (50 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic phases was washed with brine (2x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford diethyl 2-(1,1-dimethylpropyl)propanedioate (2.4 g, 99%) as a brownish oil.1H NMR (400 MHz, CDCl3) δ 4.18 (q, J = 7.2 Hz, 4H), 3.33 (s, 1H), 1.48 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.2 Hz, 6H), 1.09 (s, 6H), 0.87 (t, J = 7.6 Hz, 3H). ESI-MS m/z calc.230.15181, found 231.2 (M+1)+; Retention time: 1.98 minutes; LC method X.
	With diethyl ether

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2022/76622, 2022, A2 Location in patent: Paragraph 00872
[2]Gol'mow; Malewannaja [Zhurnal Obshchei Khimii, 1958, vol. 28, p. 3075;engl.Ausg.S.3106]

5
[ 6802-75-1 ]
[ 920-39-8 ]
[ 100538-59-8 ]

Yield	Reaction Conditions	Operation in experiment
98%		Step 1: diethyl 2-(2, 3-dimethylbutan-2-yl)malonate A solution of <strong>[6802-75-1]diethyl 2-(propan-2-ylidene)malonate</strong> (2 g, 10.0 mmol) in THF (60 mL) was cooled to 0 C., followed by copper(I) iodide (2.9 g, 15.0 mmol). The mixture was stirred at 0 C. for 0.5 h. Then isopropylmagnesium bromide (1 mol/L, 30.0 mL, 30.0 mmol) was added dropwise into the above mixture at 0 C. The mixture was stirred at 0 C. for 2 h. The mixture was quenched with HCl (1 mol/L), extracted with with EtOAc (60 mL2). The organic phase was separated, washed with water (100 mL2), and brine (130 mL), dried (Na2SO4), filtered and concentrated in vacuum to afford diethyl 2-(2,3-dimethylbutan-2-yl)malonate (2.4 g, 10.0 mmol, 98%) as a yellow solid. ESI-MS (EI+, m/z): 245.3 [M+H]+.
98%		A solution of <strong>[6802-75-1]diethyl 2-(propan-2-ylidene)malonate</strong> (2 g, 10.0 mmol) in THF (60 mL) was cooled to 0 C, followed by copper(I) iodide (2.9 g, 15.0 mmol). The mixture was stirred at 0 C for 0.5 h. Then isopropylmagnesium bromide (1 mol/L, 30.0 mL, 30.0 mmol) was added dropwise into the above mixture at 0 C. The mixture was stirred at 0 C for 2 h. The mixture was quenched with HC1 (1 mol / L), extracted with with EtOAc (60 mL*2). The organic phase was separated, washed with water (100 mL x 2), and brine (130 mL), dried (Na2SO4), filtered and concentrated in vacuum to afford diethyl 2-(2,3-dimethylbutan-2-yl)malonate (2.4 g, 10.0 mmol, 98%) as a yellow solid. ESI-MS (EI, m/z): 245.3 [M+H] .

Reference： [1]Patent: US2017/114080,2017,A1 .Location in patent: Paragraph 0485
[2]Patent: WO2018/200625,2018,A1 .Location in patent: Paragraph 00372; 00337; 00374
[3]Zhurnal Obshchei Khimii,1958,vol. 28,p. 3075;engl.Ausg.S.3106

6
[ 6802-75-1 ]
phenylmagnesium bromide [ No CAS ]
[ 78775-63-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With copper(l) chloride In diethyl ether for 0.5h; Heating;

Reference： [1]Holmberg, Carl [Liebigs Annalen der Chemie, 1981, # 4, p. 748 - 760]
[2]Prout et al. [Journal of the American Chemical Society, 1954, vol. 76, p. 1911]

7
[ 6802-75-1 ]
[ 4441-90-1 ]

Yield	Reaction Conditions	Operation in experiment
42%	With potassium hydroxide In ethanol; water Heating;
	With potassium hydroxide
	With lithium hydroxide In methanol; water at 25℃; for 2h;

Reference： [1]Reed; Capitosti; Zhu; Modarelli [Journal of Organic Chemistry, 2001, vol. 66, # 1, p. 287 - 299]
[2]Meyenberg [Chemische Berichte, 1895, vol. 28, p. 786]
[3]Grote, Marius; Schulz, Frank [ChemBioChem, 2019, vol. 20, # 9, p. 1183 - 1189]

8
[ 6802-75-1 ]
[ 13830-91-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 1.5h;Heating / reflux; Illumination, Kodak Ectagraphic slide projector lamp ELH (300 Watt);	EXAMPLE 1 Synthesis of Diethyl Bromoisopropylidenemalonate (5) Diethyl isopropylidenemalonate (4, 50 g, 0.25 mol) was refluxed with stirring with N-bromosuccinimide (44.3 g, 0.25 mol) and dibenzoyl peroxide (1.0 g, 4.1 mmol) in carbon tetrachloride (100 mL) with illumination using Kodak Ectagraphic slide projector lamp ELH (300 Watt) for 1.5 h. The reaction was completed as indicated by a negative starch-iodine test for N-bromosuccinimide. The resulting mixture was diluted with carbon tetrachloride (100 mL) and it was cooled in an ice-bath. The precipitated succinimide was filtered off and the filtrate was evaporated in vacuo at room temperature. The residual pale yellow oil of diethyl bromo-isopropylidene-malonate (5, 71.1 g) was used without purification in the Example 2.

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 5386,5387, 5392
[2]Helvetica Chimica Acta,1966,vol. 49,p. 1937 - 1950
[3]Journal of Medicinal Chemistry,2004,vol. 47,p. 566 - 575
[4]Patent: US2005/113393,2005,A1 .Location in patent: Page/Page column 6
[5]Organic Letters,2015,vol. 17,p. 4010 - 4013
[6]Organic Letters,2017,vol. 19,p. 2690 - 2693
[7]European Journal of Organic Chemistry,2019,vol. 2019,p. 3658 - 3661

9
[ 6802-75-1 ]
isopropenyl-isopropyl-malonic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With toluene + diethyl ether; ammonia; sodium amide at 110℃; und anschliessendem Kochen mit Isopropyljodid in Toluol;

Reference： [1]Cope; Hancock [Journal of the American Chemical Society, 1938, vol. 60, p. 2646]

10
[ 6802-75-1 ]
[ 500791-06-0 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; sodium amide zuletzt in Aether und Toluol bei 110grad und beim anschliessenden Kochen mit Butyljodid;
	With sodium; benzene und beim anschliessenden Kochen mit Butyljodid;

Reference： [1]Cope; Hancock [Journal of the American Chemical Society, 1938, vol. 60, p. 2646]
[2]Current Patent Assignee: MERCK & CO INC - US2188874, 1936, A

11
[ 6802-75-1 ]
[ 500555-10-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium amide at 110℃; anfangs in fluessigem NH₃, zuletzt in Toluol+Aether,und anschliessendes Kochen mit Pentylbromid in Toluol;

Reference： [1]Cope; Hancock [Journal of the American Chemical Society, 1938, vol. 60, p. 2646]

12
[ 67-64-1 ]
[ 105-53-3 ]
[ 6802-75-1 ]

Yield	Reaction Conditions	Operation in experiment
50%	With acetic anhydride; zinc(II) chloride; for 24h;Reflux;	According to a published procedure4 a mixture of diethyl malonate (350 g, 2.19 mol), acetone (191 g, 4.98 mol), Ac2O (289 g, 2.83 mol), and ZnCl2 (44.7 g, 329 mmol) in a 1 l round bottom flask was heated to reflux for 24 h, cooled, and toluene (200 mL) was added. The solution was extracted with H2O (3×350 mL) and the aqueous layers were washed with toluene (100 mL). The organic layers were combined, concentrated at reduced pressure and the residue was distilled (110 C, 13 mbar) to yield diethyl 2-propan-2-ylidenemalonate (220 g, 1.10 mol, 50%) as a yellowish oil. 1H NMR (300 MHz, CDCl3) delta 1.27 (t, 6 H, 3J = 7.1 Hz, CH2CH3), 2.05 [s, 6 H, C(CH3)2], 4.22 (q, 4 H, 3J = 7.1 Hz, CH2) ppm.
48%	With acetic anhydride; zinc(II) chloride; for 24h;Reflux;	To a stirred solution of diethyl malonate (20 mL, 131.87 mmol), acetone (14.5 mL 197.81 mmol) and acetic anhydride (15.57 mL, 164.84 mmol) anhydrous zinc dichloride (2.68 g, 19.78 mmol) was added. The reaction mixturewas heated at reflux for 24 h and checked by TLC using EtOAc/lightpetroleum 0.5/9.5 as eluent. After cooling at room temperature, toluene (50 mL) was added and the organic phase was washed twice with water (20 mL each), the organic phase was concentrated in vacuo and the crude product purified by flash chromatography (EtOAc/Light petroleum 0.5/9.5) to yield compound 1, Yield 12.63 g (48%). 1H NMR (400 MHz, CDCl3): 4.27-4.17 (4H, q, J = 7 Hz, OCH2CH3), 2.05 (6H, s, 2CH3), 1.31-1.24 (6H,t, J = 7 Hz, 2(OCH2CH3)). MS (ESI): [MH]+ = 201.

Reference： [1]Synthetic Communications,2010,vol. 40,p. 342 - 350
[2]Tetrahedron Letters,2016,vol. 57,p. 5608 - 5610
[3]Pharmazie,2014,vol. 69,p. 496 - 499
[4]Angewandte Chemie - International Edition,2015,vol. 54,p. 5900 - 5904
Angew. Chem.,2015,vol. 127,p. 5998 - 6002,5
[5]Chemische Berichte,1895,vol. 28,p. 786
[6]Journal of the Chemical Society,1928,p. 2025
[7]Journal of the American Chemical Society,1938,vol. 60,p. 2646
[8]Tetrahedron,1973,vol. 29,p. 635 - 638
[9]Journal of the Chemical Society. Perkin transactions II,1983,p. 555 - 562
[10]Bulletin de la Societe Chimique de France,1982,vol. 2,p. 385 - 390
[11]Zeitschrift fur Chemie,1981,vol. 21,p. 356 - 357
[12]Journal of Molecular Structure,1987,vol. 162,p. 321 - 332
[13]Organic Letters,2009,vol. 11,p. 2707 - 2710
[14]Chemical Communications,2014,vol. 50,p. 8900 - 8903

13
[ 6802-75-1 ]
[ 6921-34-2 ]
[ 5415-86-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With copper(l) chloride In tetrahydrofuran at -78℃; for 12h;

Reference： [1]Dong, Yuyang; Lund, Colton J.; Porter, Gerard J.; Clarke, Ryan M.; Zheng, Shao-Liang; Cundari, Thomas R.; Betley, Theodore A. [Journal of the American Chemical Society, 2021, vol. 143, # 2, p. 817 - 829]
[2]Prout et al. [Journal of the American Chemical Society, 1954, vol. 76, p. 1911] Goerner [Journal of Organic Chemistry, 1959, vol. 24, p. 888]

14
[ 6802-75-1 ]
[ 75-52-5 ]
[ 34687-05-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1,3,3-tetramethylguanidine
	With N,N,N',N'-tetramethylguanidine at 20℃; for 16h;	28.1 A mixture of 2-isopropylidene-malonic acid diethyl ester (20.0 mL, 0.102 mol), nitromethane (55.4 mL, 1.02 mol) and N,N,N',N'-tetramethylguanidine (6.4 mL, 0.051 mol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 2N HCI (200 mL). The organic layer was separated, washed with a saturated sodium chloride solution, dried over sodium sulfate, and evaporated to yield the title compound as yellow oil (26.7g, purity 94.0%, yield 70.6%). 1HNMR (DMSO- d6): 4.75 (s, 2H), 4.16 (q, 2H), 4.12 (q, 2H)1 3.67 (s, 1H), 1.19 (t, 6H), 1.15 (s, 6H).

Reference： [1]Pollini,G.P. et al. [Synthesis, 1972, p. 44 - 45]
[2]Current Patent Assignee: BIOGEN IDEC INC. - WO2010/117425, 2010, A1 Location in patent: Page/Page column 101-102

15
[ 6802-75-1 ]
[ 1730-25-2 ]
[ 32119-46-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With copper(l) iodide; In diethyl ether; at -30 - 20℃; for 2h;	Allyl magnesium bromide (1.0M in ether) (137 mL, 137 mmol) was added to copper (I) chloride (6.24 mmol) in ether (250 mL) and cooled to -30C. Diethyl isopropylidenemalonate (24.5 mL, 125 mmol) was added and the reaction allowed to warm to room temperature for 2 hrs. The reaction was quenched with sat. NH4CI solution and this was stirred for 30 min. The organic layer was separated, dried, filtered and concentrated to afford diethyl 2-(2-methylpent-4-en-2-yl)malonate (30.3 g, 128 mmol, 100% yield) as light yellow oil. 1H NMR (400 MHz, chloroform-d) delta ppm 1.12 (s, 6 H) 1.27 (t, J=7.l5 Hz, 6 H) 2.23 (d, J=7.53 Hz, 2 H) 3.31 (s, 1 H) 4.18 (q, J=7.11 Hz, 4 H) 4.98 - 5.12 (m, 2 H) 5.70 - 5.92 (m, 1 H).
91%		General procedure: To a solution of CuCl (9.00 g, 91.0 mmol) in Et2O (910 mL) was added 1.0 M Et2O solution ofallyl magnesium bromide (200 mL, 200 mmol) at -40 C and stirred for 1 hour. To the mixturewas added 6 (37.4 mL, 191 mmol) at -40 C, and the mixture was stirred at room temperaturefor 30 min. The reaction was quenched with saturated aqueous solution of NH4Cl, and themixture was extracted with Et2O (x3). The combined organic layers were washed with brine,dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residuewas purified by silica-gel column chromatography (Hexane/AcOEt = 50/1) to give S1 (42.0 g,173 mmol, 91%) as a yellow oil. 1H NMR (500 MHz, CDCl3): delta 5.81 (ddt, J = 17.1, 10.0, 7.5Hz, 1H), 5.09 (dd, J = 10.1, 2.0 Hz, 1H), 5.05 (dd, J = 17.1, 1.3 Hz, 1H), 4.18 (q, J = 7.1 Hz,4H), 3.30 (s, 1H), 2.23 (d, J = 7.5 Hz, 2H), 1.26 (t, J = 7.2 Hz, 6H), 1.11 (s, 6H); 13C NMR (125MHz, CDCl3): delta 168.4, 134.1, 118.4, 60.9, 59.2, 45.1, 36.3, 25.0, 14.1; IR (KBr): 3077, 2980,1750, 1730, 1367, 1227, 1037, 913 cm-1; HRMS-ESI (m/z): [M + H]+ calcd for C13H23O4,243.1596; found, 243.1595.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 43 - 48
[2]Tetrahedron Letters,2020,vol. 61
[3]Synlett,2009,p. 2445 - 2448
[4]Journal of Organic Chemistry,1988,vol. 53,p. 1632 - 1641
[5]Acta Chemica Scandinavica (1947),1970,vol. 24,p. 3490 - 3494
[6]Australian Journal of Chemistry,1983,vol. 36,p. 545 - 556
[7]Chemistry - A European Journal,2004,vol. 10,p. 6343 - 6352

16
[ 6802-75-1 ]
[ 151-50-8 ]
[ 51939-85-6 ]

Yield	Reaction Conditions	Operation in experiment
	With water

Reference： [1]Banerjee,D.K. et al. [Journal of the Indian Chemical Society, 1974, vol. 51, p. 67 - 72]

17
[ 6802-75-1 ]
[ 759-36-4 ]

Yield	Reaction Conditions	Operation in experiment
>= 99%	With C40H56N2RuSi4; hydrogen; In toluene; at 25℃; under 7600.51 Torr; for 9h;Schlenk technique; Autoclave;	A magnetic stirrer was placed in a 20 mE Schlenk tube and the tube was dried by heating under a reduced pressureof 5 Pa, after which the tube interior was purged with argon.Ruthenium Complex C (7.7 mg, 0.010 mmol) was added asthe catalyst to this Schlenk tube and dissolved in toluene (2 mE). To this solution was added diethyl isopropylidenemalonate (200 mg, 1.0 mmol). The resulting solution wastransferred to an autoclave and the interior of the autoclavewas purged with hydrogen. Next, the solution was stirred forhours at room temperature under a hydrogen atmospherea pressure of 10 atmospheres. Anisole was added as an internal reference, the ?H-NMR spectrum was measured,and the structure and yield of the product were determined.The structure of the resulting compound was confirmed fromthe ?H and ?3C-NMR spectra. These results are shown as Entry 8 in Table 6.?H-NMR (400 MHz, CDC13) oe=0.99 (d, JHH=6.3 Hz, 3H,CH3), 1.26 (t, Hz, 3H, CH3), 2.38 (doublet ofseptet, JHH=6.3, 8.7 Hz, 1H, CHMe2), 3.10 (d, JHH=8.7 Hz,1H, Me2CH-CH----), 4.82 (q, Hz, 2H, CH2).?3C-NMR (100 MHz, CDC13) oe=14.3, 20.5, 28.9, 59.3, 61.3, 169.0

Reference： [1]Patent: US9884316,2018,B2 .Location in patent: Page/Page column 44; 46
[2]Journal of the American Chemical Society,2018,vol. 140,p. 4119 - 4134
[3]Synthetic Communications,1987,vol. 17,p. 1007 - 1014
[4]Russian Journal of General Chemistry,1997,vol. 67,p. 396 - 399
[5]Journal of the American Chemical Society,1969,vol. 91,p. 2703 - 2715
[6]Journal of Organic Chemistry,1965,vol. 30,p. 2748 - 2754
[7]Journal of Organic Chemistry,1976,vol. 41,p. 3328 - 3329

18
[ 6802-75-1 ]
[ 13830-94-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide In tetrachloromethane Heating; Irradiation;
	With N-Bromosuccinimide

Reference： [1]Haefliger,W.; Petrzilka,T. [Helvetica Chimica Acta, 1966, vol. 49, p. 1937 - 1950]
[2]Ehrlich,K.; Emerson,G.F. [Journal of the American Chemical Society, 1972, vol. 94, # 7, p. 2464 - 2470]

19
[ 6802-75-1 ]
[ 2035-85-0 ]

Yield	Reaction Conditions	Operation in experiment
35%	With diisobutylaluminium hydride; In dichloromethane; at -78 - 0℃; for 1h;	Example XV; Scheme 17; 2-ISOPROPYLIDENE-PROPANE-1, 3-DIOL; To a solution of diisobutylaluminum hydride (1.0 M in CH2CI2, 6.75 mL, 6.75 MMOL) in CH2Cl2 (5 mL) at-78C was added a solution of 2-isopropylidene malonic acid diethyl ester (300 mg, 1.50 MMOL) in CH2Cl2 (2 mL). The reaction mixture was allowed to warmed up to 0C, stirred at this temperature for 1 h, and quenched with MEOH (8 mL). The precipitated solid was filtered through Celite and washed with CH2CI2/MEOH. The filtrate was concentrated to give 61 mg (35%) of 17-A ; H NMR (300 MHz, CDCl3) 8 4.27 (s, 4 H), 3.25 (brs, 2 H), 1.78 (s, 6 H).

Reference： [1]Liebigs Annales,1996,p. 1705 - 1715
[2]Journal of the American Chemical Society,1992,vol. 114,p. 8921 - 8927
[3]Patent: WO2005/30694,2005,A1 .Location in patent: Page/Page column 68
[4]Journal of Organic Chemistry,1971,vol. 36,p. 178 - 183
[5]Chemical Communications (London),1967,p. 753 - 754

20
[ 6802-75-1 ]
[ 31469-15-5 ]
[ 114724-32-2 ]

Yield	Reaction Conditions	Operation in experiment
83%	With trifluorormethanesulfonic acid; trimethylaluminum In dichloromethane for 6h; Ambient temperature;

Reference： [1]Minowa, Nobuto; Mukaiyama, Teruaki [Chemistry Letters, 1987, p. 1719 - 1722]

21
[ 6802-75-1 ]
[ 57956-49-7 ]
[ 114701-94-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With trifluorormethanesulfonic acid; trimethylaluminum In dichloromethane for 6h; Ambient temperature;

Reference： [1]Minowa, Nobuto; Mukaiyama, Teruaki [Chemistry Letters, 1987, p. 1719 - 1722]

22
[ 6802-75-1 ]
[ 13651-55-3 ]
2-[2-(2,3-Dimethyl-phenyl)-1,1-dimethyl-ethyl]-malonic acid diethyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society. Chemical communications,1989,p. 274 - 276

23
[ 6802-75-1 ]
[ 4808-00-8 ]
2-[(2E,4E,6E)-1-Methyl-7-(2,6,6-trimethyl-cyclohex-1-enyl)-hepta-2,4,6-trien-(E)-ylidene]-malonic acid monoethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With N-benzyl-trimethylammonium hydroxide In methanol; water for 1.5h; Ambient temperature;

Reference： [1]Giraud, Michel; Andriamialisoa, Zo; Valla, Alain; Zennache, Sakina; Potier, Pierre [Tetrahedron Letters, 1994, vol. 35, # 19, p. 3077 - 3080]

24
[ 6802-75-1 ]
[ 80121-73-9 ]
[ 87603-82-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium hydride; lithium diisopropyl amide In tetrahydrofuran at 0℃;

Reference： [1]Majetich, George; Desmond, Richard; Casares, Ada M. [Tetrahedron Letters, 1983, vol. 24, # 18, p. 1913 - 1916]

25
[ 6802-75-1 ]
[ 71478-44-9 ]
[ 61962-43-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	In tetrahydrofuran for 1h; 1.) 0 deg C, 2.) 20 deg C,;

Reference： [1]Cahiez, Gerard; Alami, Mouad [Tetrahedron, 1989, vol. 45, # 13, p. 4163 - 4176]

26
[ 6802-75-1 ]
[ 125001-55-0 ]
[ 125001-56-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	In tetrahydrofuran for 1h; 1.) 0 deg C, 2.) 20 deg C,;

Reference： [1]Cahiez, Gerard; Alami, Mouad [Tetrahedron, 1989, vol. 45, # 13, p. 4163 - 4176]

27
[ 6802-75-1 ]
[ 18257-46-0 ]
[ 142385-37-3 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4751 - 4763

28
[ 6802-75-1 ]
1,9-Nonandiylbis(magnesiumbromid) [ No CAS ]
2,14-Bis-ethoxycarbonyl-3,3,13,13-tetramethyl-pentadecanedioic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.68 g	With copper dichloride In tetrahydrofuran at 25℃; for 36h;

Reference： [1]Bar-Tana, Jacob; Ben-Shoshan, Shoshana; Blum, Jochanan; Migron, Yoelit; Hertz, Rachel; et al. [Journal of Medicinal Chemistry, 1989, vol. 32, # 9, p. 2072 - 2084]

29
[ 6802-75-1 ]
C₁₄H₂₈Br₂Mg₂ [ No CAS ]
[ 103199-02-6 ]

Yield	Reaction Conditions	Operation in experiment
2 g	With copper dichloride In tetrahydrofuran at 25℃;

Reference： [1]Bar-Tana, Jacob; Ben-Shoshan, Shoshana; Blum, Jochanan; Migron, Yoelit; Hertz, Rachel; et al. [Journal of Medicinal Chemistry, 1989, vol. 32, # 9, p. 2072 - 2084]

30
[ 6802-75-1 ]
C₁₆H₃₂Br₂Mg₂ [ No CAS ]
[ 122332-90-5 ]

Yield	Reaction Conditions	Operation in experiment
	With copper dichloride In tetrahydrofuran at 25℃;

Reference： [1]Bar-Tana, Jacob; Ben-Shoshan, Shoshana; Blum, Jochanan; Migron, Yoelit; Hertz, Rachel; et al. [Journal of Medicinal Chemistry, 1989, vol. 32, # 9, p. 2072 - 2084]

31
[ 6802-75-1 ]
C₁₂H₁₆Br₂Mg₂ [ No CAS ]
[ 103198-79-4 ]

Yield	Reaction Conditions	Operation in experiment
67%	With copper dichloride In tetrahydrofuran for 3h; Heating;

Reference： [1]Bar-Tana, Jacob; Ben-Shoshan, Shoshana; Blum, Jochanan; Migron, Yoelit; Hertz, Rachel; et al. [Journal of Medicinal Chemistry, 1989, vol. 32, # 9, p. 2072 - 2084]

32
[ 6802-75-1 ]
[ 90-02-8 ]
[ 41436-06-0 ]
[ 41436-05-9 ]
[ 143724-15-6 ]
[ 143661-09-0 ]

Yield	Reaction Conditions	Operation in experiment
1: 35% 2: 3% 3: 9%	With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 8h; Further byproducts given;
1: 35% 2: 9% 3: 3%	With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 8h; Yield given. Further byproducts given. Title compound not separated from byproducts;
1: 9% 2: 3% 3: 35%	With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 8h; Further byproducts given. Yields of byproduct given;

Reference： [1]Yamaguchi, Seiji; Saitoh, Takenao; Kamiumezawa, Megumi; Enomoto, Hiroko; Kawase, Yoshiyuki [Journal of Heterocyclic Chemistry, 1992, vol. 29, # 4, p. 755 - 758]
[2]Yamaguchi, Seiji; Saitoh, Takenao; Kamiumezawa, Megumi; Enomoto, Hiroko; Kawase, Yoshiyuki [Journal of Heterocyclic Chemistry, 1992, vol. 29, # 4, p. 755 - 758]
[3]Yamaguchi, Seiji; Saitoh, Takenao; Kamiumezawa, Megumi; Enomoto, Hiroko; Kawase, Yoshiyuki [Journal of Heterocyclic Chemistry, 1992, vol. 29, # 4, p. 755 - 758]

33
[ 6802-75-1 ]
[ 100-63-0 ]
[ 133043-39-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With sodium ethanolate In toluene for 4h; Heating;

Reference： [1]Hlasta; Casey; Ferguson; Gangell; Heimann; Jaeger; Kullnig; Gordon [Journal of Medicinal Chemistry, 1991, vol. 34, # 5, p. 1560 - 1570]

34
[ 6802-75-1 ]
[ 589-15-1 ]
[ 102568-18-3 ]

Yield	Reaction Conditions	Operation in experiment
54.26%		l-Bromo-4-(bromomethyl)benzene (10.0 g, 40.0 mmol) in diethyl ether (60 mL) was added dropwise to a suspension of magnesium (0.972 g, 40.0 mmol) in diethyl ether (20 ml) as to maintain a gentle reflux. Following the addition, it was refluxed by heating for 1 hour. It was then cooled to 0C, and copper (I) chloride (0.0914 g, 0.923 mmol) was added with vigorous stirring. Diethyl 2-(propan-2-ylidene)malonate (6.01 mL, 30.8 mmol) was added dropwise, and the reaction was allowed to warm to ambient temperature and stir overnight. It was quenched by pouring onto 1M sulfuric acid, and it was extracted twice with diethyl ether. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated. It was purified by silica gel chromatography (2-30% EtOAc/hexanes linear gradient) to yield diethyl 2-(l -(4-bromophenyl)-2- methylpropan-2-yl)malonate (6.2 g, 16.70 mmol, 54.26% yield).

Reference： [1]Patent: WO2011/123674,2011,A1 .Location in patent: Page/Page column 60-61
[2]Journal of Medicinal Chemistry,1991,vol. 34,p. 3261 - 3267

35
[ 6802-75-1 ]
[ 762-72-1 ]
[ 32119-46-3 ]

Yield	Reaction Conditions	Operation in experiment
57.9%	With N,N,N,N,N,N-hexamethylphosphoric triamide; tetrabutyl ammonium fluoride; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 20℃; for 2h;Molecular sieve;	To a solution of compound 26-1 (1 g, 5 mmol) in DMF (10 mL) was added 4A molecular sieves (1 g) and TBAF (0.6 mL, 1 M in THF) at 0 C followed by HMPA (2.69 g, 15 mmol) and ally ltrimethyl silane (1.7 g, 15 mmol). After addition, the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc and washed with saturated aqueous NH4C1 solution and brine, dried with anhydrous Na2S04, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel (eluted with PE: EtOAc= 60: 1) to afford compound 26-2 (700 mg, yield 57.9%) as a yellow oil.

Reference： [1]Patent: WO2020/51532,2020,A2 .Location in patent: Page/Page column 453; 510; 511
[2]Tetrahedron Letters,1983,vol. 24,p. 1909 - 1912

36
[ 6802-75-1 ]
[ 74-88-4 ]
[ 759-24-0 ]

Yield	Reaction Conditions	Operation in experiment
93%		MeI (49.3 mL, 1.58 mol) in Et2O (100 mL) were added slowly (with slight boiling of the solvent) according to a published procedure4 to Mg turnings (18.2 g, 749 mmol) in Et2O (100 mL) at 0 C under Ar. CuCl (980 mg, 9.90 mmol) was added and <strong>[6802-75-1]diethyl 2-(propan-2-ylidene)malonate</strong> (99.0 g, 494 mmol) in Et2O (100 mL) was added within 1.5 h. The ice bath was removed and the mixture was poured after 30 min carefully to a mixture of ice (1 L) and conc. H2SO4 (100 mL). The aqueous layer was extracted with Et2O (3×200 mL) and the combined organic layers were dried (Na2SO4), and concentrated and the residue was distilled in vacuo (80 C) to yield diethyl 2-tert-butylmalonate (100 g, 462 mmol, 93%) as a dark liquid. Extraction with Na2SO3 solution led to decolorization. 1H NMR (300 MHz, CDCl3) delta 1.10 (s, 9 H, tBu), 1.24 (t, 6 H, 3J = 7.1 Hz, CH2CH3), 3.19 (s, 1 H, 2-H), 4.15 (q, 4 H, 3J = 7.1 Hz, CH2CH3) ppm.

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 5608 - 5610
[2]Liebigs Annalen der Chemie,1981,p. 748 - 760

37
[ 6802-75-1 ]
[ 591-51-5 ]
1,1-dimethyl-2,2-bis(diphenylhydroxymethyl)ethene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	In diethyl ether; cyclohexane at -40 - 20℃;

Reference： [1]Head, Nicholas J.; Olah, George A.; Prakash, G. K. Surya [Journal of the American Chemical Society, 1995, vol. 117, # 45, p. 11205 - 11210]

38
[ 6802-75-1 ]
[ 108-98-5 ]
[ 220573-66-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-benzyl-trimethylammonium hydroxide In tetrahydrofuran; methanol 1.) -78 deg C, 15 min, 2.) -78 deg C to r.t., 1 h; r.t., 48 h;
	With N-benzyl-trimethylammonium hydroxide

Reference： [1]Adams, Harry; Anderson, James C.; Bell, Richard; Jones, D. Neville; Peel, Michael R.; Tomkinson, Nicholas C. O. [Journal of the Chemical Society. Perkin transactions I, 1998, # 23, p. 3967 - 3973]
[2]Location in patent: scheme or table Aversa, Maria Chiara; Barattucci, Anna; Bonaccorsi, Paola [European Journal of Organic Chemistry, 2009, # 36, p. 6355 - 6359]

39
[ 594-71-8 ]
[ 996-82-7 ]
[ 6802-75-1 ]

Yield	Reaction Conditions	Operation in experiment
	With ethanol at 40 - 45℃;

Reference： [1]van Tamelen; van Zyl [Journal of the American Chemical Society, 1949, vol. 71, p. 837]

40
[ 6802-75-1 ]
[ 42374-07-2 ]
[ 210244-25-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate In N,N-dimethyl-formamide at 130℃;
	With potassium carbonate In <i>N</i>-methyl-acetamide	5 Preparation 5 Preparation 5 A suspension of 2-hydroxy-3,4,6-trimethylbenzaldehyde (16.45 g), diethyl isopropylidenemalonate (20.05 g), and anhydrous potassium carbonate (40.10 g) in dimethylformamide (DMF) (11) was heated at 130-135° C. for 8 hours. After removing the solvent under reduced pressure, the mixture was diluted with water, and extracted with ethyl acetate (AcOEt). The organic phase was washed with water and brine, dried over magnesium sulfate (MgSO4), and evaporated to give a residue. The residue was purified by chromatography over silica gel (AcOEt-hexane 3:97 as eluent) to give ethyl (2,5,7,8-tetramethyl-2H-chromen-2-yl)acetate as an oil (22.45 g). bp: 152-153° C. (2 mm) IR (Neat): 1735, 1608 cm-1 1H-NMR (200 MHz, CDCl3, δ): 1.23 (3H, t, J=7.1 Hz), 1.57 (3H, s), 2.07 (3H, s), 2.19 (3H, s), 2.23 (3H, s), 2.67 and 2.71 (2H, ABq, J=14.0 Hz), 4.11 (2H, q, J=7.1 Hz), 5.72 (1H, d, J=9.9 Hz), 6.54 (1H, s), 6.55 (1H, d, J=9.9 Hz)

Reference： [1]García, Oscar; Nicolás, Ernesto; Albericio, Fernando [Tetrahedron Letters, 2003, vol. 44, # 28, p. 5319 - 5321]
[2]Current Patent Assignee: ASTELLAS PHARMA INC. - US6225480, 2001, B1

41
[ 13830-91-6 ]
[ 6802-75-1 ]
[ 106352-19-6 ]

Yield	Reaction Conditions	Operation in experiment
23%	With potassium tert-butylate; In tert-butyl alcohol; for 0.25h;Heating / reflux;	EXAMPLE 2 Diethyl Methylenecyclopropane-2,2-dicarboxylate (6) Compound 5 (43.4 g, 0.156 mol) from Example 1 was added to a vigorously stirred refluxing solution of potassium tert-butoxide (17.5 g, 0.156 mol) in tert-butyl alcohol (500 mL) under nitrogen. The stirring was continued for 15 min. and the mixture was immediately cooled in an ice bath. Acetic acid was then added, the solid portion was filtered off and thoroughly washed with ether. The filtrate was concentrated in vacuo, diluted with ether and the organic layer was washed several times with water. After drying with magnesium sulfate, the solution was evaporated in vacuo and the residue was distilled, bp. 99-93 C./0.3 torr, yield 14.8 g (47%) of a 1:1 mixture of 4+6. This mixture was chromatographed on a silica gel column using first hexanes-ether (40:1) and then (20:1) to give product 6 (7.3 g, 23%) as a colorless liquid. 1H NMR (CDCl3,300 MHz) delta 1.24 (t, 6H, J=7.2 Hz, CH3), 2.15 (t, 2H, J=2.4 Hz, H3), 4.17 (q, 4H, J=7.2 Hz, OCH2), 5.53 (t, 1H, J=2.1 Hz) and 5.62 (s, 1H, J=2.6 Hz, C=CH2). 13C NMR (CDCl3, 75 MHz) ppm 14.21 (CH3), 18.24 (C3), 23.26 (C2), 61.02 (CH2O), 105.20 (=CH2), 130.46 (C1), 167.91 (CO).

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 566 - 575
[2]Patent: US2005/113393,2005,A1 .Location in patent: Page/Page column 6

42
[ 6802-75-1 ]
[ 7652-46-2 ]
[ 839708-99-5 ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 1986 - 1992
[2]Phosphorus, Sulfur and Silicon and the Related Elements,2005,vol. 180,p. 1203 - 1208

43
[ 6802-75-1 ]
[ 172749-96-1 ]
[ 839708-83-7 ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 1986 - 1992
[2]Phosphorus, Sulfur and Silicon and the Related Elements,2005,vol. 180,p. 1203 - 1208

44
[ 6802-75-1 ]
2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranoside [ No CAS ]
2-{1-[(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl)thio]-(1-methyl)ethyl}-malonic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranoside With N-benzyl-trimethylammonium hydroxide In tetrahydrofuran; methanol at -78℃; for 0.166667h; Stage #2: diethyl isopropylidenemalonate In tetrahydrofuran; methanol at -78 - 20℃;

Reference： [1]Aversa, Maria C.; Barattucci, Anna; Bilardo, Maria Cristina; Bonaccorsi, Paola; Giannetto, Placido; Rollin, Patrick; Tatibouet, Arnaud [Journal of Organic Chemistry, 2005, vol. 70, # 18, p. 7389 - 7396]

45
[ 6802-75-1 ]
[ 19879-84-6 ]
2-{1-[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thio]-(1-methyl)ethyl}-malonic acid diethyl ester [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 7389 - 7396
[2]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1456 - 1463
[3]European Journal of Organic Chemistry,2009,p. 6355 - 6359
[4]Phosphorus, Sulfur and Silicon and the Related Elements,2011,vol. 186,p. 1220 - 1224

46
[ 6802-75-1 ]
2,3,4,6-tetra-O-acetyl-1-thio-D-galactopyranose [ No CAS ]
2-{1-[(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)thio]-(1-methyl)ethyl}-malonic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 2,3,4,6-tetra-O-acetyl-1-thio-D-galactopyranose With N-benzyl-trimethylammonium hydroxide In tetrahydrofuran; methanol at -78℃; for 0.166667h; Stage #2: diethyl isopropylidenemalonate In tetrahydrofuran; methanol at -78 - 20℃;

47
[ 6802-75-1 ]
[ 86549-23-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: CuCl / tetrahydrofuran / 0.17 h / -15 °C 1.2: tetrahydrofuran / 2 h / -15 - 25 °C 2.1: 1.93 g / aq. LiCl / dimethylsulfoxide / Heating
	Multi-step reaction with 2 steps 1: 1.) cuprous chloride / 1.) ether, -45 deg C, 10 min, 2.) ether, from -35 deg C to RT, 2 h 2: 86 percent / lithium chloride, water / dimethylsulfoxide / 14 h / Heating
	Multi-step reaction with 2 steps 1: copper(l) iodide / diethyl ether / 2 h / -30 - 20 °C 2: lithium chloride / dimethyl sulfoxide / 48 h / 160 °C

Reference： [1]Liu, Cong; Wang, Xiang; Pei, Tao; Widenhoefer, Ross A. [Chemistry - A European Journal, 2004, vol. 10, # 24, p. 6343 - 6352]
[2]Beckwith, Athelstan L. J.; Easton, Christopher J.; Lawrence, Tony; Serelis, Algirdas K. [Australian Journal of Chemistry, 1983, vol. 36, # 3, p. 545 - 556]
[3]Bowsher, Michael; Hiebert, Sheldon; Li, Rongti; Wang, Alan X.; Friborg, Jacques; Yu, Fei; Hernandez, Dennis; Wang, Ying-Kai; Klei, Herbert; Rajamani, Ramkumar; Mosure, Kathy; Knipe, Jay O.; Meanwell, Nicholas A.; McPhee, Fiona; Scola, Paul M. [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 1, p. 43 - 48]

48
[ 6802-75-1 ]
[ 80348-45-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: CuCl / tetrahydrofuran / 0.17 h / -15 °C 1.2: tetrahydrofuran / 2 h / -15 - 25 °C 2.1: 1.93 g / aq. LiCl / dimethylsulfoxide / Heating 3.1: LDA / tetrahydrofuran / 0.5 h / -78 °C 3.2: 15 percent / tetrahydrofuran / 25 °C 4.1: 42 percent / CuCl₂ / [PdCl₂(CH₃CN)2] / 1,2-dichloro-ethane / 70 °C

Reference： [1]Liu, Cong; Wang, Xiang; Pei, Tao; Widenhoefer, Ross A. [Chemistry - A European Journal, 2004, vol. 10, # 24, p. 6343 - 6352]

49
[ 6802-75-1 ]
[ 106352-19-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NBS; dibenzoyl peroxide / CCl₄ / 1.5 h / Heating; irradiation 2: 23 percent / t-BuOK / 2-methyl-propan-2-ol / 0.25 h / Heating
	Multi-step reaction with 2 steps 1: dibenzoyl peroxide; tetrachloromethane; <i>N</i>-bromo-succinimide / unter Belichtung 2: potassium <i>tert</i>-butylate; <i>tert</i>-butyl alcohol
	Multi-step reaction with 2 steps 1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1.5 h / Inert atmosphere; Irradiation; Reflux 2: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 0.25 h / Inert atmosphere; Reflux

	Multi-step reaction with 2 steps 1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 1.5 h / Reflux; Inert atmosphere 2: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 0.25 h / Reflux; Inert atmosphere
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide; dibenzoyl peroxide / water; tetrachloromethane / 1.5 h / Inert atmosphere; Irradiation; Reflux 2: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 0.5 h / 100 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 1.5 h / Irradiation; Reflux 2: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 0.5 h / 100 °C

Reference： [1]Zhou, Shaoman; Breitenbach, Julie M.; Borysko, Katherine Z.; Drach, John C.; Kern, Earl R.; Gullen, Elizabeth; Cheng, Yung-Chi; Zemlicka, Jiri [Journal of Medicinal Chemistry, 2004, vol. 47, # 3, p. 566 - 575]
[2]Ullmann [Journal of the American Chemical Society, 1959, vol. 81, p. 5386,5387, 5392]
[3]Tsunoi, Shinji; Maruoka, Yoshiaki; Suzuki, Itaru; Shibata, Ikuya [Organic Letters, 2015, vol. 17, # 16, p. 4010 - 4013]
[4]Suzuki, Itaru; Tsunoi, Shinji; Shibata, Ikuya [Organic Letters, 2017, vol. 19, # 10, p. 2690 - 2693]
[5]Suzuki, Itaru; Shimazu, Jun-ya; Tsunoi, Shinji; Shibata, Ikuya [European Journal of Organic Chemistry, 2019, vol. 2019, # 22, p. 3658 - 3661]
[6]Ogura, Kazuki; Shibata, Ikuya; Shimazu, Jun-ya; Suzuki, Itaru [European Journal of Organic Chemistry, 2021, vol. 2021, # 19, p. 2785 - 2787]

50
[ 6802-75-1 ]
C₃₀H₂₅⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 37 percent / diethyl ether; cyclohexane / -40 - 20 °C 2: FSO₃H / various solvent(s) / -80 °C

Reference： [1]Head, Nicholas J.; Olah, George A.; Prakash, G. K. Surya [Journal of the American Chemical Society, 1995, vol. 117, # 45, p. 11205 - 11210]

51
[ 6802-75-1 ]
[ 85268-65-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: 1.) Mg, CuCl 2: 87.4 percent / Heating 3: 42.5 percent 4: 89.4 percent 5: 65.5 percent / PPA 6: LiAlH₄ 8: 84.1 percent / H₂ / Pd/C / methanol

Reference： [1]Morin,F.G.; Horton,W.J.; Grant,D.M. [Journal of the American Chemical Society, 1983, vol. 105, p. 3992]

52
[ 6802-75-1 ]
[ 26430-96-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 35 percent / LiAlH₄ / diethyl ether 2: 76 percent / PBr₃, conc. aq. HBr / 19 h / 0 - 20 °C
	Multi-step reaction with 2 steps 1: (i) LiAlH₄, Et₂O, (ii) AcOEt, (iii) aq. KOH, MeOH 2: aq. HBr, PBr₃
	Multi-step reaction with 2 steps 1: LiAlH₄ 2: PBr₃ / diethyl ether; hexane; pyridine

Reference： [1]Gleiter, Rolf; Merger, Roland; Nuber, Bernhard [Journal of the American Chemical Society, 1992, vol. 114, # 23, p. 8921 - 8927]
[2]Marshall,J.A.; Warne,T.M. [Journal of Organic Chemistry, 1971, vol. 36, p. 178 - 183]
[3]Marshall,J.A. et al. [Chemical Communications (London), 1967, p. 753 - 754]

53
[ 6802-75-1 ]
[ 143857-52-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 35 percent / LiAlH₄ / diethyl ether 2: 76 percent / PBr₃, conc. aq. HBr / 19 h / 0 - 20 °C 3: 81 percent / CuCl / tetrahydrofuran / 4 h / 60 °C 4: 1.) n-BuLi / 1.) THF, hexane, -78 deg C, 10 min, 2.) THF, hexane, 60 deg C, 72 h 5: 24 percent / t-BuOK / 2-methyl-propan-2-ol; tetrahydrofuran / 4 h / -78 - 20 °C
	Multi-step reaction with 4 steps 1: 35 percent / LiAlH₄ / diethyl ether 2: 76 percent / PBr₃, conc. aq. HBr / 19 h / 0 - 20 °C 3: 1.) n-BuLi / 1.) THF, hexane, -78 deg C, 10 min, 2.) THF, hexane, 60 deg C, 72 h 4: 24 percent / t-BuOK / 2-methyl-propan-2-ol; tetrahydrofuran / 4 h / -78 - 20 °C

Reference： [1]Gleiter, Rolf; Merger, Roland; Nuber, Bernhard [Journal of the American Chemical Society, 1992, vol. 114, # 23, p. 8921 - 8927]
[2]Gleiter, Rolf; Merger, Roland; Nuber, Bernhard [Journal of the American Chemical Society, 1992, vol. 114, # 23, p. 8921 - 8927]

54
[ 6802-75-1 ]
[ 143857-48-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 35 percent / LiAlH₄ / diethyl ether 2: 76 percent / PBr₃, conc. aq. HBr / 19 h / 0 - 20 °C 3: 1.) n-BuLi / 1.) THF, hexane, -78 deg C, 10 min, 2.) THF, hexane, 60 deg C, 18 h

Reference： [1]Gleiter, Rolf; Merger, Roland; Nuber, Bernhard [Journal of the American Chemical Society, 1992, vol. 114, # 23, p. 8921 - 8927]

55
[ 6802-75-1 ]
[ 143857-49-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 35 percent / LiAlH₄ / diethyl ether 2: 76 percent / PBr₃, conc. aq. HBr / 19 h / 0 - 20 °C 3: 81 percent / CuCl / tetrahydrofuran / 4 h / 60 °C 4: 1.) n-BuLi / 1.) THF, hexane, -78 deg C, 10 min, 2.) THF, hexane, 60 deg C, 72 h
	Multi-step reaction with 3 steps 1: 35 percent / LiAlH₄ / diethyl ether 2: 76 percent / PBr₃, conc. aq. HBr / 19 h / 0 - 20 °C 3: 1.) n-BuLi / 1.) THF, hexane, -78 deg C, 10 min, 2.) THF, hexane, 60 deg C, 72 h

56
[ 6802-75-1 ]
[ 143843-12-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 35 percent / LiAlH₄ / diethyl ether 2: 76 percent / PBr₃, conc. aq. HBr / 19 h / 0 - 20 °C 3: 81 percent / CuCl / tetrahydrofuran / 4 h / 60 °C

Reference： [1]Gleiter, Rolf; Merger, Roland; Nuber, Bernhard [Journal of the American Chemical Society, 1992, vol. 114, # 23, p. 8921 - 8927]

57
[ 6802-75-1 ]
[ 143843-10-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 35 percent / LiAlH₄ / diethyl ether 2: 76 percent / PBr₃, conc. aq. HBr / 19 h / 0 - 20 °C 3: 1.) n-BuLi / 1.) THF, hexane, -78 deg C, 10 min, 2.) THF, hexane, 60 deg C, 20 h

Reference： [1]Gleiter, Rolf; Merger, Roland; Nuber, Bernhard [Journal of the American Chemical Society, 1992, vol. 114, # 23, p. 8921 - 8927]

58
[ 6802-75-1 ]
[ 143843-11-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 35 percent / LiAlH₄ / diethyl ether 2: 76 percent / PBr₃, conc. aq. HBr / 19 h / 0 - 20 °C 3: 1.) n-BuLi / 1.) THF, hexane, -78 deg C, 10 min, 2.) THF, hexane, 60 deg C, 18 h

Reference： [1]Gleiter, Rolf; Merger, Roland; Nuber, Bernhard [Journal of the American Chemical Society, 1992, vol. 114, # 23, p. 8921 - 8927]

59
[ 6802-75-1 ]
[ 143843-09-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 35 percent / LiAlH₄ / diethyl ether 2: 76 percent / PBr₃, conc. aq. HBr / 19 h / 0 - 20 °C 3: 81 percent / CuCl / tetrahydrofuran / 4 h / 60 °C 4: 1.) n-BuLi / 1.) THF, hexane, -78 deg C, 10 min, 2.) THF, hexane, 60 deg C, 72 h
	Multi-step reaction with 3 steps 1: 35 percent / LiAlH₄ / diethyl ether 2: 76 percent / PBr₃, conc. aq. HBr / 19 h / 0 - 20 °C 3: 1.) n-BuLi / 1.) THF, hexane, -78 deg C, 10 min, 2.) THF, hexane, 60 deg C, 72 h

60
[ 6802-75-1 ]
[ 102568-21-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 1.) Mg, 2.) Cu(I)Cl / 1.) Et₂O, reflux, 1.5 h, 2.) Et₂O, from 0 deg C to RT, 1 h 2: 55 percent / aq. KOH / ethanol / 48 h / Ambient temperature 3: 99 percent / 0.5 h / 200 °C 4: 95 percent / polyphosphoric acid / 1 h / 100 °C
	Multi-step reaction with 4 steps 1.1: magnesium / diethyl ether / 1 h / Reflux 1.2: 0 - 20 °C 2.1: potassium hydroxide; water / ethanol / 24 h / 70 °C 3.1: 1 h / 200 °C 4.1: polyphosphoric acid / 1 h / 100 °C

Reference： [1]Ashwood, Valerie A.; Cassidy, Frederick; Evans, John M.; Gagliardi, Stefania; Stemp, Geoffrey [Journal of Medicinal Chemistry, 1991, vol. 34, # 11, p. 3261 - 3267]
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2011/123674, 2011, A1

61
[ 6802-75-1 ]
[ 102568-20-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1.) Mg, 2.) Cu(I)Cl / 1.) Et₂O, reflux, 1.5 h, 2.) Et₂O, from 0 deg C to RT, 1 h 2: 55 percent / aq. KOH / ethanol / 48 h / Ambient temperature 3: 99 percent / 0.5 h / 200 °C
	Multi-step reaction with 3 steps 1.1: magnesium / diethyl ether / 1 h / Reflux 1.2: 0 - 20 °C 2.1: potassium hydroxide; water / ethanol / 24 h / 70 °C 3.1: 1 h / 200 °C

62
[ 6802-75-1 ]
[ 102568-19-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1.) Mg, 2.) Cu(I)Cl / 1.) Et₂O, reflux, 1.5 h, 2.) Et₂O, from 0 deg C to RT, 1 h 2: 55 percent / aq. KOH / ethanol / 48 h / Ambient temperature
	Multi-step reaction with 2 steps 1.1: magnesium / diethyl ether / 1 h / Reflux 1.2: 0 - 20 °C 2.1: potassium hydroxide; water / ethanol / 24 h / 70 °C

63
[ 6802-75-1 ]
[ 3437-29-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: ethanol / 7 h / 80 °C 2: 2M potassium hydroxid / H₂O / 0.75 h / 18 °C 3: thionyl chloride / benzene / 0.5 h / 60 °C 4: 101 mg / liquid ammonia / tetrahydrofuran / -78 - 17 °C

Reference： [1]Arnott, David M.; Harrison, Peter J.; Henderson, Graeme B.; Sheng, Zhi-Chu; Leeper, Finian J.; Battersby, Alan R. [Journal of the Chemical Society. Perkin transactions I, 1989, p. 265 - 278]

64
[ 6802-75-1 ]
[ 99839-17-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: ethanol / 7 h / 80 °C 2: 2M potassium hydroxid / H₂O / 0.75 h / 18 °C
	Multi-step reaction with 2 steps 1: aqueous ethanol 2: aqueous methanol. NaOH-solution

65
[ 6802-75-1 ]
[ 1010-48-6 ]

Reference： [1]Journal of the American Chemical Society,1954,vol. 76,p. 1911

66
[ 824-42-0 ]
[ 6802-75-1 ]
[ 143661-09-0 ]

Yield	Reaction Conditions	Operation in experiment
63%	In water; N,N-dimethyl-formamide	8 Preparation of (2-Methyl-2H-chromen-2-yl)-acetic acid ethyl ester (Compound 8A) Preparation of (2-Methyl-2H-chromen-2-yl)-acetic acid ethyl ester (Compound 8A) A suspension of 2-hydroxy-3-methylbenzylaldehyde (5.0 g, 40.9 mmol) and diethyl isopropylidenemalonate (8.2 g, 40.9 mmol) in DMF (200 mL) was heated to 135° C. for over night. DMF was removed by rotovap and the residue was treated with water and EtOAc. Layers were separated and the aqueous layer was extracted with EtOAc (100 mL*3). The combined organics were dried over MgSO4 and filtered. Solvent was removed and the crude product was purified through silica gel column to give the desired product as a white solid (5.98 g, 63%). MS 233 (M+1)+

Reference： [1]Current Patent Assignee: PFIZER INC - US2003/207915, 2003, A1

67
[ 6802-75-1 ]
[ 142385-37-3 ]

Yield	Reaction Conditions	Operation in experiment
98.4%	With potassium tert-butylate; In N-methyl-acetamide;	2. 2-Butyl-6,6-dimethyl-4-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid, ethyl ester To the solution of the title 1 compound (3.53 g, 25.87 mmol) in dimethylformamide (7.0 mL) at 0 C. under argon was added potassium tert-butoxide (2.57 g, 22.85 mmol). The cooling bath was removed and the resulting suspension was stirred at room temperature for 30 minutes. To the reaction mixture was added <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> (4.0 g, 19.9 mmol) in dimethylformamide (5 mL). It was stirred at room temperature overnight and then heated at 70 C. for two hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a light yellow oil (4.97 g, 98.4%).

Reference： [1]Patent: US5234923,1993,A

68
[ 6802-75-1 ]
ethyl 2-chlorocarbonyl-3-methyl-2-butenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; thionyl chloride In ethanol; dichloromethane	XXV Preparation of ethyl 2-chlorocarbonyl-3-methyl-2-butenoate EXAMPLE XXV Preparation of ethyl 2-chlorocarbonyl-3-methyl-2-butenoate Diethyl isopropylidenemalonate (30 grams, 0.15 mole) was saponified with 10.0 grams (0.15 mole) of potassium hydroxide in 200 milliliters of ethanol solution and worked up to give the monocarboxylic acid which was then reacted with thionyl chloride (10 milliliters, 0.1 mole) in methylene chloride solution in a manner similar to the procedure described in Example XVIII. Removal of solvent gave 9.6 grams (0.05 mole) of ethyl 2-chlorocarbonyl-3- methyl-2-butenoate. NMR analysis of the residue product in CDCl3 solution indicated complete conversion of the carboxylic acid to the acid chloride as evidenced by absence of a downfield carboxylic acid proton.
	With potassium hydroxide; thionyl chloride In ethanol; dichloromethane	XXV Preparation of ethyl 2-chlorocarbonyl-3-methyl-2-butenoate EXAMPLE XXV Preparation of ethyl 2-chlorocarbonyl-3-methyl-2-butenoate Diethyl isopropylidenemalonate (30.0 grams, 0.15 mole) was saponified with 10.0 grams (0.15 mole) of potassium hydroxide in 200 milliliters of ethanol solution and worked up to give the monocarboxylic acid which was then reacted with thionyl chloride (10 milliliters, 0.1 mole) in methylene chloride solution in a manner similar to the procedure described in Example XVIII. Removal of solvent gave 9.6 grams (0.05 mole) of ethyl 2-chlorocarbonyl-3-methyl-2-butenoate. NMR analysis of the residue product in CDCl3 solution indicated complete conversion of the carboxylic acid to the acid chloride as evidenced by absence of a downfield carboxylic acid proton.

Reference： [1]Current Patent Assignee: SANOFI - US5292937, 1994, A
[2]Current Patent Assignee: SANOFI - US5123951, 1992, A

69
[ 6802-75-1 ]
potassium ter-butoxide [ No CAS ]
2-Butyl-1-[[2'-carboxy[1,1'-biphenyl]-4-yl]-methyl]-4-chloro-1,6-dihydro-6-methyl-1-pyrimidine-5-carboxylic acid, ethyl ester [ No CAS ]
2-Butyl-6,6-dimethyl-4-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylic Acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In <i>N</i>-methyl-acetamide	6.A A. A. 2-Butyl-6,6-dimethyl-4-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylic Acid, Ethyl Ester To the solution of the title A compound of Example 1 (3.53 g, 25.87 mmol) in dimethylformamide (7.0 mL) at 0° C. under argon was added potassium ter-butoxide (2.57 g, 22.85 mmol). The cooling bath was removed and the resulting suspension was stirred at room temperature for 30 minutes. To the reaction mixture was added diethyl isopropylidenemalonate (4.0 g, 19.9 mmol) in dimethylformamide (5 mL). It was stirred at room temperature overnight and then heated at 70° C. for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title A compound as a light yellow oil (4.97 g). 1 H NMR (CDCl3) δ 9.6 (br s, 1H), 4.2 (m, 2H), 3.25 (s, 1H), 2.3 (t, J=7.7 Hz, 2H), 1.6 (qn, J=7.7 Hz, 2H), 1.38 (m, 2H), 1.32 (t, J=7.1 Hz, 3H), 1.26 (s, 6H), 0.91 (t, J=7.1 Hz, 3H); 13 C NMR (CDCl3) 168.2, 167.3, 152.3, 61.13, 56.18, 55.95, 34.95, 28.27, 27.8, 25.05, 21.9, 13.85, 13.5 ppm.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US5470975, 1995, A

70
[ 6802-75-1 ]
[ 78775-63-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; phenylmagnesium bromide; In ethanol;	EXAMPLE 175 Ethyl Hydrogen (alpha,alpha-dimethylbenzyl)malonate. Diethyl (alpha,alpha-dimethylbenzyl)malonate was prepared by the congugate addition of phenyl magnesium bromide to <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> as described by C. Holmberg [Liebigs Ann. Chem., 748 (1981)]. A solution of this diester (42.1 g, 0.15 mole) in ethanol (100 mL) was treated by dropwise addition with a solution of potassium hydroxide (8.48 g, 0.13 mole) in 100 mL of ethanol. After heating at 90 C. for 1 h and at 50 C. for 20 h, the reaction mixture was evaporated on the rotary evaporator to a residue. The residue was diluted with water and extracted with ether to remove unreacted starting material. The aqueous phase was cooled to 5 C., acidified to pH 3, with 6N HCl and extracted with methylene chloride. The organic layer was washed with brine solution and dried over magnesium sulfate.
	With potassium hydroxide; phenylmagnesium bromide; In ethanol;	EXAMPLE 84 Ethyl hydrogen (alpha,alpha-dimethylbenzyl)malonate. Diethyl(alpha,alpha-dimethylbenzyl)malonate was prepared by the conjugate addition of phenyl magnesium bromide to <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> as described by C. Holmberg [Liebigs Ann. Chem. 748 (1981)]. A solution of this diester (42.1 g, 0.15 mmol) in ethanol (100 ml) was treated by dropwise addition with a solution of potassium hydroxide (8.48 g, 0.13 mmol) in 100 ml of ethanol. After heating at 90 C. for 1 h and at 50 C. for 20 h, the reaction mixture was evaporated on the rotary evaporator to a residue. The residue was diluted with water and extracted with ether to remove unreacted starting material. The aqueous phase was cooled to 5 C., acidified to pH 3 with 6N HCl, and extracted with methylene chloride. The organic layer was washed with brine solution and dried over magnesium sulfate.
	With potassium hydroxide; phenylmagnesium bromide; In ethanol;	EXAMPLE 114 Ethyl hydrogen (alpha,alpha-dimethylbenzyl)malonate Diethyl (alpha, alpha -dimethylbenzyl)malonate was prepared by the conjugate addition of phenyl magnesium bromide to <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> as described by C. Holmberg [Liebigs Ann. Chem., 748 (1981)]. A solution of this diester (42.1 g, 0.15 mol) in ethanol (100 ml) was treated by dropwise addition with a solution of potassium hydroxide (8.48 g, 0.13 mol) in 100 ml of ethanol. After heating at 90 C. for 1 h and at 50 C. for 20 h, the reaction mixture was evaporated on the rotary evaporator to a residue. The residue was diluted with water and extracted with ether to remove unreacted starting material. The aqueous phase was cooled to 5 C., acidified to pH 3 with 6N HCl, and extracted with methylene chloride. The organic layer was washed with brine solution and dried over magnesium sulfate.

	With potassium hydroxide; phenylmagnesium bromide; In ethanol;	Example 103 Ethyl hydrogen (alpha,alpha-dimethylbenzyl)malonate. Diethyl (alpha,alpha-dimethylbenzyl)malonate was prepared by the conjugate addition of phenyl magnesium bromide to <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> as described by C. Holmberg [ Liebigs Ann. Chem. , 748 (1981)]. A solution of this diester (42.1 g, 0.15 mmol) in ethanol (100 ml) was treated by dropwise addition with a solution of potassium hydroxide (8.48 g, 0.13 mmol) in 100 ml of ethanol. After heating at 90C for 1 h and at 50C for 20 h, the reaction mixture was evaporated on the rotary evaporator to a residue. The residue was diluted with water and extracted with ether to remove unreacted starting material. The aqueous phase was cooled to 5C, acidified to pH 3 with 6 N HCl, and extracted with methylene chloride. The organic layer was washed with brine solution and dried over magnesium sulfate.
	With potassium hydroxide; phenylmagnesium bromide; In ethanol;	Example 101 Ethyl hydrogen (alpha,alpha-dimethylbenzyl)malonate. Diethyl (alpha,alpha-dimethylbenzyl)malonate was prepared by the conjugate addition of phenyl magnesium bromide to <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> as described by C. Holmberg [ Liebigs Ann. Chem. , 748 (1981)]. A solution of this diester (42.1 g, 0.15 mmol) in ethanol (100 ml) was treated by dropwise addition with a solution of potassium hydroxide (8.48 g, 0.13 mmol) in 100 ml of ethanol. After heating at 90C for 1 h and at 50C for 20 h, the reaction mixture was evaporated on the rotary evaporator to a residue. The residue was diluted with water and extracted with ether to remove unreacted starting material. The aqueous phase was cooled to 5C, acidified to pH 3 with 6 N HCl, and extracted with methylene chloride. The organic layer was washed with brine solution and dried over magnesium sulfate.

Reference： [1]Patent: US5032577,1991,A
[2]Patent: US5063208,1991,A
[3]Patent: US4857507,1989,A
[4]Patent: EP341602,1989,A2
[5]Patent: EP307837,1989,A2

71
[ 6802-75-1 ]
[ 37688-96-3 ]
[ 7699-41-4 ]
[ 103199-02-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	copper(l) chloride; In tetrahydrofuran; petrol ether; benzene;	EXAMPLE 20 1,1,18,18-tetra(carboethoxy)-2,2,17,17-tetramethyloctadecane The procedure of Example 1 was followed except that the bis-Grignard reagent was prepared from 3.0 g of 1,14-dibromotetradecane and 0.75 g of Mg turnings in 40 ml of dry THF. The bis-Grignard reagent was then added dropwise to a stirred suspension of 0.031 g CuCl and 3.72 g of <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> in 15 ml of dry THF. The addition product was protonated and extracted into ether as in Example 1 followed by silicic acid (400 mesh) chromatography in benzene:petrol ether 1:2.5 to yield the title compound. 86% yield. NMR (CDCl3): 4.3 (q, 8H); 3.5 (s, 2H); 1.5 (m, 40H); 1.1 (m, 12H).

Reference： [1]Patent: US4689344,1987,A

72
[ 105-53-3 ]
[ 6802-75-1 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic anhydride;Zinc chloride; In acetone; benzene;	REFERENCE EXAMPLE 36 Diethyl isopropylidenemalonate (36) STR55 There were placed diethyl malonate (133 g, 0.83 mol), acetone (72 g, 1.24 mol), acetic anhydride (106 g, 1.05 mol) and zinc chloride (17.0 g, 0.125 mmol in a 500 ml three neck flask. After 24 hour reflux, benzene (200 ml) was added and the reaction mixture was washed with water (100 ml4). The aqueous layer was further extracted with benzene (50 ml2). The organic layers were combined and concentrated. The residue was distilled under reduced pressure to give oily product, diethyl isopropylidenemalonate (68.0 g, 0.34 mol, 41.0%, b.p.: 112 C./9 mmHg). The structure was confirmed by the following data. IR (liquid film): 2980, 1730, 1650, 1450, 1380, 1300, 1260, 1220, 1120, 1070, 1030, 930, 870, 800, 740 cm-1 NMR (90 MHz, CDCl3, delta): 1.29 (6H, t, J=7.1 Hz); 2.01 (6H, s); 4.23 (4H, q, J=7.1 Hz).

Reference： [1]Patent: US4775692,1988,A

73
[ 6802-75-1 ]
aqueous hydrogen chloride [ No CAS ]
hydrated copper acetate [ No CAS ]
[ 927-77-5 ]
[ 867-76-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In tetrahydrofuran	R.37 Ethyl 2-ethyoxycarbonyl-3,3-dimethylhexanoate (37) STR56 REFERENCE EXAMPLE 37 Ethyl 2-ethyoxycarbonyl-3,3-dimethylhexanoate (37) STR56 To a solution of n-propylmagnesium bromide in THF (1.62N, 149 ml, 242 mmol), anhydrous THF (200 ml) was added and the mixture was cooled to -50° C. After adding hydrated copper acetate (2.42 g, 12.1 mmol), a solution of diethyl isopropylidenemalonate (22 g, 110 mmol) in anhydrous THF (100 ml) was slowly added to the solution at -50° C., and the mixture was stirred at -50° C. for 2 hours. Aqueous hydrogen chloride (1N, 260 ml) was added at room temperature and the mixture was extracted with ethyl acetate (500 ml, 100 ml*3). Aqueous saturated solution of sodium hydrogencarbonate (100 ml) was added to the combined organic layers and filtered. The aqueous layer was separated from the organic layer of the filtrate. The organic layer was washed with brine (300 ml), dried over magnesium sulfate, and concentrated. The residue was distilled under reduced pressure to give ethyl 2-ethoxycarbonyl-3,3-dimethylhexanoate (24.92 g, 102 mmol, 92.7%, b.p.: 85°-87° C./1 mmHg). The structure was identified by the following data. IR (liquid film): 2960, 1750, 1730, 1460, 1390, 1370, 1310, 1230, 1200, 1120, 1090, 1040 cm-1. NMR (90 MHz, CDCl3, δ): 0.7-1.0 (3H, m); 1.0-1.6 (10H, m); 1.14 (6H, s); 3.31 (1H, s); 4.17 (4H, q, J=7.1 Hz).

Reference： [1]Current Patent Assignee: TORAY INDUSTRIES INC - US4775692, 1988, A

74
[ 6802-75-1 ]
Cu₂ Cl₂ [ No CAS ]
[ 4101-68-2 ]
1,1,14,14-tetra(ethoxycarbonyl)-2,2,13,13-tetramethyltetradecane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium carbonate In tetrahydrofuran	1 1,1,14,14-Tetra(ethoxycarbonyl)-2,2,13,13-tetramethyltetradecane EXAMPLE 1 1,1,14,14-Tetra(ethoxycarbonyl)-2,2,13,13-tetramethyltetradecane The bis-Grignard reagent prepared from 3.5 g of Mg turnings and 21.0 g of 1,10-dibromodecane in 90 ml of tetrahydrofuran (THF), was added dropwise by means of a syringe to a stirred suspension of 0.25 g of Cu2 Cl2 and 25.0 g of diethyl isopropylidenemalonate in 50 ml of dry THF cooled to -70° C. The reaction mixture was allowed to gradually reach room temperature under stirring and the stirring was continued at that temperature for 16 hours. The reaction mixture was then poured into a mixture of 100 ml of concentrated hydrochloric acid and 150 g of ice, under vigorous stirring, then diluted with water and extracted thrice with diethyl ether. The ether extracts were combined, washed with water and with a 10% solution of sodium carbonate and dried over anhydrous magnesium sulfate. The ether solution was filtered and evaporated to dryness. 34.0 g of the title compound were obtained and proved to be pure on this layer chromatography. NMR (CDCl3): 4.17 (q, J=7 Hz, 8H); 3.30 (s, 2H); 1.27 (br.s, 32H); 1.10 (br.s, 12H).
	With hydrogenchloride; sodium carbonate In tetrahydrofuran	1 1,1,14,14-Tetra(ethoxycarbonyl)-2,2,13,13-tetramethyltetradecane EXAMPLE 1 1,1,14,14-Tetra(ethoxycarbonyl)-2,2,13,13-tetramethyltetradecane The bis-Grignard reagent prepared from 3.5 g of Mg turnings and 21.0 g of 1,10 -dibromodecane in 90 ml of tetrahydrofuran (THF), was added dropwise by means of a syringe to a stirred suspension of 0.25 g of Cu2 Cl2 and 25.0 g of diethyl isopropylidenemalonate in 50 ml of dry THF cooled to -70° C. The reaction mixture was allowed to gradually reach room temperature under stirring and the stirring was continued at that temperature for 16 hours. The reaction mixture was then poured into a mixture of 100 ml of concentrated hydrochloric acid and 150 g of ice, under vigorous stirring, then diluted with water and extracted thrice with diethyl ether. The ether extracts were combined, washed with water and with a 10% solution of sodium carbonate and dried over anhydrous magnesium sulfate. The ether solution was filtered and evaporated to dryness. 34.0 g of the title compound were obtained and proved to be pure on this layer chromatography. NMR (CDCl3): 4.17 (q, J=7 Hz, 8H); 3.30 (s, 2H); 1.27 (br.s, 32H); 1.10 (br.s, 12H).

Reference： [1]Current Patent Assignee: SYNDROME X - US4634795, 1987, A
[2]Current Patent Assignee: SYNDROME X - US4689344, 1987, A

75
[ 6802-75-1 ]
[ 626-88-0 ]
[ 7429-94-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; sulfuric acid; magnesium; In diethyl ether; ethanol; water;	ii) For those compounds wherein R2 and R3 are methyl and X is methylene: 4-Methylpentylmagnesium bromide was prepared from <strong>[626-88-0]4-methylpentyl bromide</strong> (59.7g, 0.33 mole) and magnesium (8.02g 0.33 g atoms) in diethyl ether (150ml). The Grignard solution so obtained was then diluted with diethyl ether (400ml), and to this solution was added a solution of diethyl isopropylidenemalonate (60g, 0.30 mole) in diethyl ether (50ml) at such a rate as to maintain a steady reflux. After the addition was complete, the reaction mixture was heated under reflux for a further 1.5h. The reaction complex was then decomposed by the controlled addition of dilute sulphuric acid (10% w/v. 500 ml). The organic layer was separated, and the aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with water and then brine, dried, and evaporated to dryness to yield a mobile oil. Distillation gave a fraction bp 108-140C/0.2mm Hg. The distilled oil was dissolved in ethanol (200ml), and the solution was heated under reflux with a solution of potassium hydroxide (20.6g) in water (50ml) for 20h. The reaction mixture was cooled, diluted with water (250ml) and extracted twice with diethyl ether. The basic, aqueous solution was acidified with concentrated hydrochloric acid (30ml), and extracted 3 times with diethyl ether.

Reference： [1]Patent: EP307115,1989,A1

76
[ 6802-75-1 ]
[ 38769-92-5 ]
[ 939463-38-4 ]

Yield	Reaction Conditions	Operation in experiment
		Diethylisopropylidenemalonate (6.686 ml, 34.09 mmol) was dissolved in 300 ml Et2O and cooled to -78C. 4-Methoxybenzylmagnesium chloride (150.000 ml, 37.50 mmol) was added and stirring was continued for 5h. The temperature was warmed up to 00C. <n="160"/>The reaction was hydrolyzed with 0.5 M HCl and extracted 3 x EtOAc. Glass col. Chromatography (10-50 %EtOAc in Hex.) provided diethyl 2-(l-(4-methoxyphenyl)-2- methylpropan-2-yl)malonate. MS m/z: 323.1 (M+l).

Reference： [1]Patent: WO2007/61670,2007,A1 .Location in patent: Page/Page column 157-158

77
[ 6802-75-1 ]
[ 23719-80-4 ]
[ 1021939-03-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of copper iodide (7.61 g, 40.0 mmol) in THF (50 mL) at -50 0C was added cyclopropylmagnesium bromide (160 mL, 80.0 mmol, 0.5 M in THF) under nitrogen. After stirring for 15 minutes, the suspension was allowed to warm up and stirred at rt for 20 min before cooling back to -5O0C. A solution of <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> (4.0 g, 20.0 mmol) in THF (50 mL) was added, and the reaction was allowed to warm to rt over 3 h. The reaction mixture was then quenched with saturated sodium bicarbonate (200 mL), and filtered through Celite. The filtrate was extracted with ethyl acetate (3 x 250 mL). The combined extracts were dried over sodium sulfate and concentrated, and the resulting residue was purified by silica gel chromatography eluting with diethyl ether/hexanes (1 : 10) to afford 2-(l-cyclopropyl-l- methylethyl)malonic acid diethyl ester.

Reference： [1]Patent: WO2008/51405,2008,A1 .Location in patent: Page/Page column 77

78
[ 6802-75-1 ]
[ 53868-73-8 ]
[ 4111-54-0 ]
[ 139138-96-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: α-[3-(dimethylamino)propyl]-3-methoxybenzeneacetonitrile; lithium diisopropyl amide In tetrahydrofuran at -20℃; for 0.5h; Stage #2: diethyl isopropylidenemalonate In tetrahydrofuran at -50℃; for 0.5h; Stage #3: With hydrogenchloride In tetrahydrofuran; water at 10℃; Acidic aqueous solution;	1.A Preparation of diethyl 2-[2-cyano-5-(dimethylamino)-2-(3-methoxy-phenyl)-1,1-dimethylpentyl] propanedioate, monohydrochloride Example 1 Preparation of 3 (3-methoxyphenyl)-3- (3-dimethylaminopropyl)-4. 4-dimethyl- [piperidine-2.] 6-dione pamoate (AGN 2979 pamoate) (A) Preparation of diethyl [2- [2-cyano-5- (dimethylamino)-2- (3-methoxy-] phenyl)-1, [1-dimethylpentyl] propanedioate, monohydrochloride] a nitrogen atmosphere was applied to a reaction vessel and 50 ml of dry tetrahydrofuran is added. the solvent was cooled to less [than-40c] and 32 [mmoles] of lithium diisopropylamide in [tetrahydrofuranne-heptane] was added (16 ml of a 2 m solution). a solution of 6.97 g (30 mmoles) of [a- [3- (dimethylamino) propyl]-3-] methoxybenzeneacetonitrile in 30 ml of tetrahydrofuran was added at less [than-20c] and left at this temperature for 30 min. the mixture was then cooled [to-50c] and a solution of 6.62 g (33 mmoles) of diethyl isopropylidenemalonate in 30 ml of tetrahydrofuran was added to the reaction mixture at a rate such that the temperature did not [exceed-50c.] the mixture was stirred [at-50c] for 30 min and the cold reaction mixture added to a stirred solution of 30 ml of aqueous hydrochloric acid (36% w/w) in 100 ml of water cooled to [10C.] The mixture was extracted twice with toluene and the toluene phase is back extracted with a solution of 2 ml of hydrochloric acid (36% w/w) in 8 ml of water. The aqueous acidic extract was combined with the aqueous acidic phase from above and extracted twice with 50 ml portions of methylene chloride. The combined methylene chloride extracts were washed with water and the methylene chloride phase filtered and concentrated to low volume by distillation at atmospheric pressure. A 100 ml portion of ethyl acetate was added and the resulting slurry cooled to [5-10C.] The resulting solid was collected by filtration, washed with ethyl acetate and dried at [50C] to give 10.1 g of white powder.

Reference： [1]Current Patent Assignee: BAUSCH HEALTH COMPANIES INC - WO2004/17970, 2004, A1 Location in patent: Page 7

79
[ 6802-75-1 ]
[ 15015-57-3 ]
[ 1069086-89-0 ]

Reference： [1]Synthesis,2008,p. 2023 - 2032

80
[ 6802-75-1 ]
[ 6954-27-4 ]
[ 1139695-41-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	With N-benzyl-trimethylammonium hydroxide In tetrahydrofuran; methanol at -78 - 20℃; Inert atmosphere;

Reference： [1]Location in patent: experimental part Aversa, Maria C.; Barattucci, Anna; Bonaccorsi, Paola; Marino-Merlo, Francesca; Mastino, Antonio; Sciortino, Maria T. [Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 4, p. 1456 - 1463]

81
[ 6802-75-1 ]
[ 873-77-8 ]
[ 1168107-54-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	With copper(l) chloride In tetrahydrofuran at 0 - 10℃; for 0.5h;

Reference： [1]Location in patent: experimental part Reeves, Jonathan T.; Fandrick, Daniel R.; Tan, Zhulin; Song, Jinhua J.; Yee, Nathan K.; Senanayake, Chris H. [Tetrahedron Letters, 2009, vol. 50, # 25, p. 3077 - 3080]

82
[ 6802-75-1 ]
[ 33324-92-4 ]
[ 1160846-77-4 ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: (2-methylallyl)magnesium bromide With copper(l) chloride In tetrahydrofuran at -15℃; for 0.25h; Stage #2: diethyl isopropylidenemalonate In tetrahydrofuran at -15℃; for 2h; Stage #3: With water; ammonium chloride In tetrahydrofuran

Reference： [1]Wu, Liang; Qiu, Shuifa; Liu, Guosheng [Organic Letters, 2009, vol. 11, # 12, p. 2707 - 2710]

83
[ 6802-75-1 ]
(5-fluoro-2-methylphenyl)magnesium bromide [ No CAS ]
[ 1192941-07-3 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) chloride In tetrahydrofuran at 0 - 15℃; Inert atmosphere;	1 0.10 g of copper (I) chloride was added to a 500 mL flask and the system was purged with nitrogen. 107.0 mL of 5-fluoro-2-methylphenylmagnesium bromide (1.0 M in THF) was added via cannulation. The batch temperature was set to 00C +/- 2°C. 20.0 mL of diethyl isopropylidene malonate was added at a rate to maintain the batch temperature between 00C to 150C (approximately 20 minutes). The reaction mixture was aged for 30 minutes at 00C to 150C. The batch was cooled to 00C +/- 50C. A solution of 25 mL of concentrated HCl in 25 mL of water was added at a rate to maintain the batch temperature below 35°C. The mixture was agitated vigorously until the batch temperature reached 200C +/- 5°C. Layers were separated and the organic phase was concentrated to remove THF. 36.1 g of crude 2- [l-(5-fluoro-2-methylphenyl)-l-methylethyl]malonic acid diethyl ester was obtained as a light green oil which was used directly without additional purification in Stage 2.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2009/134737, 2009, A1 Location in patent: Page/Page column 19

84
[ 6802-75-1 ]
[ 31608-22-7 ]
[ 41302-06-1 ]

Yield	Reaction Conditions	Operation in experiment
		A one molar solution of Grignard reagent THP-O(CH2)4-O-(CH2)4MgBr in diethyl ether is prepared from THP-O(CH2)4-O-(CH2)4Br and magnesium turnings in the usual manner under an inert atmosphere. To this solution is slowly added a solution of 1 mole of diethyl isopropylidinemalonate dissolved in 2 liter of dry diethylether. The reaction mixture is refluxed 12 hours and the mixture treated with aqueous ammonium chloride. The ether solution is separated from the salts, and concentrated to dryness. The residue is purified by distillation using a wiped-film evaporator to give the diethylester, THP-O(CH2)4C(CH3)2CH(COOEt)2. The tetrahydropyranyl group is then removed by treating the above THP ether with IN HCl in THF followed by usual workup to give the corresponding alcohol HO(CH2)4C(CH3)2CH(COOEt)2.

Reference： [1]Patent: US2005/101572,2005,A1 .Location in patent: Page/Page column 8

85
[ 6802-75-1 ]
[ 7239-41-0 ]
C₂₉H₅₂O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4,4'-dibromo-di-n-butyl ether With magnesium In diethyl ether Stage #2: diethyl isopropylidenemalonate In diethyl ether for 12h; Heating / reflux; Stage #3: With ammonium chloride In diethyl ether; water	5.1 A one molar solution of Grignard reagent BrMg(CH2)4-O-(CH2)4MgBr in diethyl ether is prepared from Bis(4-bromobutyl)ether, and magnesium turnings in the usual manner under an inert atmosphere. To this solution is slowly added a solution of 400.46 g (2 moles) of diethyl isopropylidinemalonate dissolved in 2 liter of dry diethylether. The reaction mixture is refluxed 12 hours and the mixture treated with aqueous ammonium chloride. The ether solution is separated from the salts, and concentrated to dryness. The residue is purified by distillation using a wiped-film evaporator to give the intermediate tetraethylester, (EtOOC)2CHC(CH3)2(CH2)4-O-(CH2)4C(CH3)2CH(COOEt)2

Reference： [1]Current Patent Assignee: SSV THERAPEUTICS - US2005/101572, 2005, A1 Location in patent: Page/Page column 7

86
[ 6802-75-1 ]
[ 371-40-4 ]
[ 1206801-26-4 ]

Yield	Reaction Conditions	Operation in experiment
39%	With 1H-imidazole; at 200℃; for 3h;Inert atmosphere;	Preparation 125 Ethyl 2-(4-fluorophenylcarbamoyl)-3-methylbut-2-enoate To a solution of 4-fluoroaniline (2 g, 18 mmol) in <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> (10 g, 50 mmol) is added 1H-imidazole (0.25 g, 3.67 mmol). The reaction mixture is stirred at 200 C. under N2 for 3 hours. After the reaction is cooled, silica gel is added. The mixture is loaded onto a silica gel column, and eluted first with PE and then PE:EtOAc (3:1) to give the product (1.85 g, 39% yield). MS (m/z): 266.1 (M+H).
31%	With 1H-imidazole; at 200℃; for 3h;Sealed tube; Inert atmosphere;	A solution of 4-fluoroaniline (1.73 mL, 18.0 mmol) and lH-imidazole (0.249 g, 3.67 mmol) in <strong>[6802-75-1]diethyl 2-(propan-2-ylidene)malonate</strong> (9.80 mL, 50 mmol) were combined in a sealed tube and heated to 200 C under argon for 3 h. The reaction mixture was cooled to room temperature and purified over silica gel (25% EtOAc in hexanes) to afford ethyl 2-((4- fluorophenyl)carbamoyl)-3-methylbut-2-enoate (2.13 g, 31%).
28%	With 1H-imidazole; at 200℃; for 5h;	A mixture of 4-fluoroaniline (0.20 mL, 2.05 mmol), <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> (1.60 mL, 8.20 mmol) and imidazole (139 mg, 2.05 mmol) was stirred at 200 C. for 5 hours. The residue obtained by cooling to room temperature and concentrated under reduced pressure was purified by column chromatography to obtain the title compound (151 mg, yield: 28%, yellow oil).

28%

With 1H-imidazole; at 200℃; for 5h;

A mixture of 4-fluoroaniline (0.20 mL, 2.05 mmol), <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> (1.60 mL, 8.20 mmol), and imidazole (139 mg, 2.05 mmol) was stirred at 200 C for 5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound (151 mg, yield: 28%, yellow oil). 1H NMR (500MHz, DMSO-d6) d 10.25 (s, 1H), 7.65-7.62 (m, 2H), 7.17-7.13 (m, 2H), 4.12 (qt, J = 5.0 Hz, 2H), 2.16 (s, 3H), 1.88 (s, 3H), 1.16 (t, J = 5.0 Hz, 3H)

Reference： [1]Patent: US2010/22529,2010,A1 .Location in patent: Page/Page column 16-17
[2]Patent: WO2020/47184,2020,A1 .Location in patent: Paragraph 001128; 001131
[3]Patent: KR2019/106802,2019,A .Location in patent: Paragraph 0258; 0259-0262
[4]Patent: WO2019/182274,2019,A1 .Location in patent: Page/Page column 33

87
[ 7758-89-6 ]
[ 6802-75-1 ]
[ 1730-25-2 ]
[ 32119-46-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1 Allyl magnesium bromide (1.0M in ether) (137 mL, 137 mmol) was added to copper (I) chloride (6.24 mmol) in ether (250 mL) and cooled to -30 C. Diethyl isopropylidenemalonate (24.5 mL, 125 mmol) was added and the reaction allowed to warm to r.t. for 2 hrs. The reaction was quenched with sat. NH4Cl solution and this was stirred for 30 min. The organic layer was separated, dried, filtered and concentrated to give diethyl 2-(2-methylpent-4-en-2-yl)malonate (30.3 g, 128 mmol, 100% yield) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.12 (s, 6H) 1.27 (t, J=7.15 Hz, 6H) 2.23 (d, J=7.53 Hz, 2H) 3.31 (s, 1H) 4.18 (q, J=7.11 Hz, 4H) 4.98-5.12 (m, 2H) 5.70-5.92 (m, 1H).

Reference： [1]Patent: US2010/80770,2010,A1

88
[ 6802-75-1 ]
[ 542-92-7 ]
C₁₅H₂₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	With aluminum (III) chloride; In chloroform; at 62℃; for 10h;	To 33.0 g of the Compound (12) shown below, 100.0 g of the Compound (13) shown below and 13.3 g of aluminum chloride, 50 g of CHCl3 was added, and the mixture was heated at 62 C and stirred for 10 hours. The reaction solution was added to ice water and extracted with ethyl acetate. An organic layer was concentrated, and the concentrate was then purified by means of column chromatography to obtain 13.3 g of the Compound (14) shown below (yield: 10 %).

Reference： [1]Patent: EP2196462,2010,A1 .Location in patent: Page/Page column 21

89
[ 6802-75-1 ]
[ 352-13-6 ]
[ 295329-88-3 ]

Yield	Reaction Conditions	Operation in experiment
98%		A mixture of the Grignard reagent (90 ml, 90 mmol) and CuI (18 mg, 0.02 mmol) was stirred for 15 minutes after which it was cooled in an ice bath. A solution of the di-ester (18.9 ml, 96.7 mmol) in 25 ml THF was added in 90 min and the reaction mixture was, stirred at 0 C. for 2 h. 100 ml saturated NH4Cl was added dropwise and the aqueous layer was extracted with Et2O. The Et2O fraction was washed with brine (1×) and dried (MgSO4). The drying agent was removed by filtration and the solvent by evaporation under reduced pressure. The residue was chromatographed with CH2Cl2/petroleum ether 1/1 as eluent to give 26.17 g (98%) of the adduct.
88%		At 0C, a mixture of (4-fluorophenyl)magnesium bromide (2N, 50 ml_, 100 mmol) and Cul (38 mg, 0.2 mmol) was stirred for 15 min before the addition of a solution of diethyl 2- (propan-2-ylidene)malonate (22 g, 110 mmol) in THF (50 ml_). After stirred at 0C for 2 hr, the resulting mixture was quenched with sat. NH4CI aq. solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give the crude product which was purified by flash chromatography (silica gel, PE) to afford the title compound (26 g, 88% yield) as a yellow oil. LCMS (ESI) m/z calcd for Ci6H2iF04: 296.14. Found: 297.55 (M+1)+.

Reference： [1]Patent: US2006/122189,2006,A1 .Location in patent: Page/Page column 28
[2]Patent: WO2018/116107,2018,A1 .Location in patent: Page/Page column 21-22

90
[ 5162-44-7 ]
[ 6802-75-1 ]
[ 113086-99-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: 1-bromo-4-butene With iodine; magnesium In tetrahydrofuran at 50℃; for 1.5h; Inert atmosphere; Stage #2: With copper(l) iodide In tetrahydrofuran at -30℃; Inert atmosphere; Stage #3: diethyl isopropylidenemalonate In tetrahydrofuran at -30 - 23℃; for 1.5h; Inert atmosphere;

Reference： [1]Ravu, Vengala Rao; Leung, Gulice Y. C.; Lim, Chek Shik; Ng, Sin Yee; Sum, Rong Ji; Chen, David Y.-K. [European Journal of Organic Chemistry, 2011, # 3, p. 463 - 468]

91
[ 106-39-8 ]
[ 6802-75-1 ]
[ 1168107-54-7 ]

Yield	Reaction Conditions	Operation in experiment
52%		To a suspension of Mg powder (254 mg, 10.5 mmol) in Et2<D (5 mL) was slowly added a solution of 1 -bromo-4-chlorobenzene (2 g, 10.5 mmol) in ether (5 mL). After stirred at r.t. for 30 min, Cul (103 mg, 1 .1 mmol) was introduced and the resulting mixture was cooled down to -10C before the addition of <strong>[6802-75-1]diethyl 2-(propan-2-ylidene)malonate</strong> (2.1 g, 10.5 mmol). After stirred under refluxing temperature for 3 hr, the reaction was quenched with 1 N HCI aq. solution (20 ml_) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give the crude product which was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to afford the title compound (1 .7 g, 52% yield). LCMS (ESI) m/z calcd for Ci6H2iCI04: 312.1 1 . Found: 313.25/315.25 (M/M+2)+.
25%		Example 249ADiethyl[2-(4-chlorophenyl)propan-2-yl]malonate; Under argon, 1 g (5.23 mmol) of 1-bromo-4-chlorobenzene in 2.5 ml of diethyl ether was added slowly to 254 mg (10.45 mmol) of magnesium turnings in 5 ml of diethyl ether. After the reaction had started, a further 1 g (5.23 mmol) of 1-bromo-4-chlorobenzene in 2.5 ml of diethyl ether was metered into the reaction mixture. The reaction mixture was stirred at room temperature for 30 min, 103 mg (1.05 mmol) of copper(I) chloride were added and the mixture was then cooled to -10 C. 2.09 g (10.45 mmol) of diethyl propan-2-ylidenemalonate were then slowly added dropwise. The reaction mixture was subsequently heated to reflux and stirred at this temperature for 3 h. 20 ml of ice-cold 1 M hydrochloric acid were then added very slowly. After separation of the phases, the aqueous phase was extracted three more times with diethyl ether. The combined organic phases were dried over magnesium sulphate and then concentrated to dryness. The crude product was purified by preparative HPLC (mobile phase methanol/water 70:30). This gave 800 mg of the title compound (25% of theory).MS (DCI): m/z=330 (M+NH4)+.GC-MS (Method 1): Rt=6.19 min; m/z=312 (M)+.

Reference： [1]Patent: WO2018/116107,2018,A1 .Location in patent: Page/Page column 31-32
[2]Patent: US2011/130445,2011,A1 .Location in patent: Page/Page column 99

92
[ 6802-75-1 ]
[ 32400-25-2 ]
[ 1393132-07-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: t-butyl pent-4-enoate With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: diethyl isopropylidenemalonate In tetrahydrofuran; hexane at -78 - -40℃; Inert atmosphere; diastereoselective reaction;

Reference： [1]Holan, Martin; Pohl, Radek; Cisarova, Ivana; Jahn, Ullrich [European Journal of Organic Chemistry, 2012, # 18, p. 3459 - 3475]

93
[ 6802-75-1 ]
[ 4101-68-2 ]
1,1,14,14-tetra(ethoxycarbonyl)-2,2,13,13-tetramethyltetradecane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.1%		Example 4: Process for the preparation of l,l,14,14-Tetra(ethoxycarbonyl)- 2,2,13,13-tetramethyltetradecane A 500 mL 3 neck round bottom flask was charged with magnesium turnings (2.19 g). The flask was flushed with nitrogen and anhydrous tetrahydrofuran (100 mL) was added. A solution of 1,12-dibromododecane (14.0 g) in tetrahydrofuran (10 mL) was added dropwise to the magnesium suspension over 20 min. The reaction mixture got warm during the addition. The reaction was stirred at room temperature for 4 h after the addition was complete. The mixture was cooled in an ice bath and copper(I) chloride (0.150 g) was added. Diethyl isopropylidenemalonate (18.0 g) was added dropwise from a syringe over 15 min. The cooling bath was removed and the reaction was allowed to warm to room temperature and stir overnight. The reaction was quenched with 3 N hydrochloric acid (80 mL). Heptane (100 mL) was added and the layers were separated. The aqueous layer was extracted with methyl ieributyl ether (100 mL). The combined organic extracts were filtered through a plug of silica gel (60 mL fritted funnel filled 2/3 full with silica gel). The silica gel was further washed with 1: 1 heptane - methyl ieri-butyl ether (100 mL). The filtrate was concentrated under reduced pressure to give a light amber oil. The crude product was distilled using a Kugelrohr apparatus under vacuum (5 mm Hg) with an oven temperature of 180 C. A small amount of colorless liquid distilled which was predominately unreacted <strong>[6802-75-1]diethyl isopropylidenemalonate</strong>. The residue was allowed to cool to room temperature and was weighed to give l,l,14,14-tetra(ethoxycarbonyl)-2,2,13,13-tetramethyltetradecane (15.9 g, 72.1%).

Reference： [1]Patent: WO2013/84237,2013,A1 .Location in patent: Page/Page column 18; 19

94
[ 6802-75-1 ]
[ 3344-70-5 ]
1,1,16,16-tetra(ethoxycarbonyl)-2,2,15,15-tetramethyl-hexadecane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.3%		Example 1: Process for the preparation of l,l,16,16-Tetra(ethoxycarbonyl)- 2,2,15,15-tetramethylhexadecane A 500 mL 3 neck round bottom flask was charged with magnesium turnings (2.19 g). The flask was flushed with nitrogen and anhydrous tetrahydrofuran (100 mL) was added. A solution of 1,12-dibromododecane (14.0 g) in tetrahydrofuran (10 mL) was added dropwise to the magnesium suspension over 20 min. The reaction mixture became warm during the addition. The reaction was stirred at room temperature for 4 h after the addition was complete. The mixture was cooled in an ice bath and copper(I) chloride (0.150 g) was added. Diethyl isopropylidenemalonate (18.0 g) was added dropwise from a syringe over 15 min. The cooling bath was removed and the reaction was allowed to warm to room temperature and stir overnight. The reaction was quenched with 3 N hydrochloric acid (80 mL). Heptane (100 mL) was added and the layers were separated. The aqueous layer was extracted with methyl ieributyl ether (100 mL). The combined organic extracts were filtered through a plug of silica gel (60 mL fritted funnel filled 2/3 full with silica gel). The silica gel was further washed with 1:1 heptane - methyl ieri-butyl ether (100 mL). The filtrate was concentrated under reduced pressure to give a light amber oil. The crude product was distilled using a Kugelrohr apparatus under vacuum (5 mm Hg) with an oven temperature of 180 C. A small amount of colorless liquid distilled which was predominately unreacted <strong>[6802-75-1]diethyl isopropylidenemalonate</strong>. The residue was allowed to cool to room temperature and was weighed to give l,l,16,16-tetra(ethoxycarbonyl)-2,2,15,15-tetramethylhexadecane (19.6 g, 80.3%).

Reference： [1]Patent: WO2013/84237,2013,A1 .Location in patent: Page/Page column 15; 16

95
[ 6802-75-1 ]
[ 62-53-3 ]
ethyl 2-(anilinocarbonyl)-3-methylbut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With 1H-imidazole; at 200℃; for 3h;	A mixture of 12 (15.0g, 74.9mmol), aniline (1.71mL, 18.7mmol) and imidazole (1.27g, 18.7mmol) were heated at 200C for 3h. The mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography (EtOAc/hexane) to get 13 (2.86g, 62%) as yellow solid. 1H NMR (DMSO-d6) delta 1.16 (3H, t, J=7.0Hz), 1.89 (3H, s), 2.16 (3H, s), 4.13 (2H, q, J=7.0Hz), 7.00-7.13 (1H, m), 7.27-7.45 (2H, m), 7.50-7.88 (2H, m), 10.20 (1H, s).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7686 - 7698

96
[ 6802-75-1 ]
[ 17890-12-9 ]
4,4-Dimethyl-2-oxo-1-phenylpyrrolidine-3-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: diethyl isopropylidenemalonate; N-Phenyl-N-<(trimethylsilyl)methyl>amine With 2BF₄^(1-)*C₄₀H₄₀IrN₄⁽²⁺⁾ In 1-methyl-pyrrolidin-2-one for 18h; Schlenk technique; Inert atmosphere; Irradiation; Stage #2: With potassium <i>tert</i>-butylate In 1-methyl-pyrrolidin-2-one at 20℃; for 4h; Schlenk technique; Inert atmosphere;

Reference： [1]Nakajima, Kazunari; Kitagawa, Mai; Ashida, Yuya; Miyake, Yoshihiro; Nishibayashi, Yoshiaki [Chemical Communications, 2014, vol. 50, # 64, p. 8900 - 8903]

97
[ 6802-75-1 ]
[ 75-26-3 ]
[ 100538-59-8 ]

Yield	Reaction Conditions	Operation in experiment
11%		In a two neck round bottom flask, under argon atmosphere, diethyl ether (20 mL), magnesium (82.4 mg, 3.4 mmol) and isopropylbromide (0.38 mL, 4.06 mmol) were added. When all the metallic magnesium was consumed, the solution was cooled at -5C and a catalytically amount of copper (I) chloride (4.5 mg, 0.045 mmol) was added. After 15 min compound 1 (451.5 mg, 2.26 mmol) dissolved in diethyl ether were added. After 4 h, 10mL of 10% sulphuric acid were added and the organic phase was separated, dried over sodium sulphate and purified by flash chromatography (EtOAc/ light petroleum 0.5/9.5) to give compound 2, Yield 60.66 mg (11%). 1H NMR (400 MHz, CDCl3): 4.19-4.11 (4H, q, J = 7.2 Hz, OCH2CH3,), 3.50 (1H,s, CH(COOEt)2), 1.85-1.79 (1H, m, CH), 1.28-1.21 (6H, t, J = 7.2 Hz,2(OCH2CH3)), 1.04 (6H, s, -C(CH3)2), 0.87-0.84 (6H, d, J = 6.8 Hz, - CH(CH3)2). 13C NMR (100 MHz, CDCl3): 168.7, 60.8, 58.6, 39.1, 34.5,20.9, 17.3, 14.2. MS (ESI): [MH]+ = 245.

Reference： [1]Pharmazie,2014,vol. 69,p. 496 - 499

98
[ 6802-75-1 ]
[ 2043-61-0 ]
diethyl 2-(1-cyclohexyl-2-methyl-1-oxo-2-propyl)malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With (di-p-tert-butylbenzoxyiodo)benzene In acetonitrile at 20℃; for 18h; Inert atmosphere; Irradiation;

Reference： [1]Moteki, Shin A.; Usui, Asuka; Selvakumar, Sermadurai; Zhang, Tiexin; Maruoka, Keiji [Angewandte Chemie - International Edition, 2014, vol. 53, # 41, p. 11060 - 11064][Angew. Chem., 2014, vol. 126, # 41, p. 11240 - 11244,4]

99
[ 6802-75-1 ]
silver isopropylidenemalonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.2%	With nitric acid; silver nitrate; In water;	Example 8 Preparation of Silver Isopropylidenemalonate 24.03 g (0.12 mol) of <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> was added to 250 ml of a 10% ethanolic KOH solution. The mixture was allowed to react under reflux for 12 h. After completion of the reaction, the reaction mixture in the form of a slurry was dissolved in 250 ml of distilled water to obtain a transparent solution. A dilute aqueous solution of nitric acid was added to the transparent solution until the pH reached 7.0 and then an aqueous solution of 42.47 g (0.25 mol) of silver nitrate (AgNO3) in 150 ml of water was slowly added dropwise to precipitate a white solid. The precipitate was filtered, sufficiently washed sequentially with water and methanol, and dried in a vacuum oven, affording 44.31 g (yield 89.2%) of the title product as a white solid.

Reference： [1]Patent: US2016/168408,2016,A1

100
[ 6802-75-1 ]
[ 460-00-4 ]
[ 295329-88-3 ]

Yield	Reaction Conditions	Operation in experiment
65%		To a stirred solution of magnesium (0.139 g, 5.71 mmol) and pinch of iodine in dry diethyl ether (5.0 mL), 1-bromo-4-fluorobenzene (0.500 g, 2.86 mmol) in 2 mL THF was added at room temperature. Reaction was stirred for 30 minutes at room temperature. Reaction mixture was cooled to -10 C. and <strong>[6802-75-1]diethyl isopropylidenemalonate</strong> (1.144 g, 5.71 mmol) dissolved in 1 mL THF was added dropwise over 2 minutes. Reaction mixture was stirred for 20 minutes at room temperature, followed by reflux for 3 h. Reaction mixture was cooled to rt and quenched with ice cold 1 N HCl. The aqueous layer was extracted with diethyl ether (50 mL), dried over sodium sulfate, concentrated under reduced pressure to give 15A (light yellow liquid, 550 mg, 1.856 mmol, 65% yield). LC-MS Anal. Calc'd. for C16H21FO4, 296.14. found [M+H] 297.2, Tr=1.47 min (Method BA).

Reference： [1]Patent: US2016/289171,2016,A1 .Location in patent: Paragraph 0532

101
[ 6802-75-1 ]
[ 4270-70-6 ]
C₁₀H₁₇O₇S^(1-)*C₁₈H₁₅S⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: diethyl isopropylidenemalonate With sodium hydrogensulfite; triethylamine In methanol; water at 55℃; for 18h; Stage #2: triphenylsulfonium chloride In methanol; dichloromethane; water at 20℃; for 6h;	26 Synthesis of Compound (S-1) (0311) After 1.25 g (7.0 mmol) of N-cyclohexylmaleimide (compound (S-1′)) as the compound represented by the above formula (4) was added to a 100 mL eggplant-shaped flask charged with 15 mL of methanol and 15 mL of water as a solvent, 0.95 g (9.1 mmol) of sodium bisulfite was further added thereto. Subsequently, the reaction was allowed while stirring the mixture with heating at 55° C. for 18 hours, followed by distillation of the solvent. Then, to the resultant solid matter, 1.46 g (4.9 mmol) of triphenylsulfonium chloride, and 20 mL of dichloromethane and 15 mL of water as a solvent were added, and the reaction was allowed by stirring the mixture at a room temperature for 6 hours. Thereafter, the reaction product thus obtained was extracted using dichloromethane as an extraction solvent, followed by washing with water five times. Then, drying over anhydrous sodium sulfate, followed by distillation of the extraction solvent gave 2.18 g of a compound (S-1) represented by the following formula (yield: 85%).

Reference： [1]Current Patent Assignee: JSR CORPORATION - US9477149, 2016, B2 Location in patent: Page/Page column 47; 48; 51; 59

102
[ 6802-75-1 ]
C₈H₇ClMn [ No CAS ]
C₁₅H₂₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With copper(l) chloride In tetrahydrofuran at 0 - 20℃;

Reference： [1]Marquais; Alami; Cahiez [Organic Syntheses, 1995, vol. 72, p. 135 - 135]

103
[ 6802-75-1 ]
[ 71478-47-2 ]
[ 78775-63-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	In tetrahydrofuran at 20℃;

Reference： [1]Marquais; Alami; Cahiez [Organic Syntheses, 1995, vol. 72, p. 135 - 135]

104
[ 6802-75-1 ]
[ 402-51-7 ]
C₁₇H₂₁F₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With copper(l) chloride; In tetrahydrofuran; at 0 - 20℃; for 3h;	j0323J To a solution of compound S1-2 (320 mmol, 1.0 eq) in THF (500 mL) was added CuC1 (3.17 g, 32 mmol, 0.1 eq). When the solution was cooled to 0C the compound S1-3 (64 g, 320 mmol, 1.0 eq) was added dropwise. The reaction mixture was stirred at rt for 3 h, quenched with saturated NH4C1 solution, extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under vacuum. The residue was purified by column chromatography (PE/EA, 50:110:1) to afford the title compound S1-4 (51 g, 46%). 1H NMR (400 IVIFIz, CDC13) 7.57-7.49 (m, 4H), 4.08-4.03 (m, 4H), 3.80 (d, J = 2.4 Hz, 1H), 1.62-1.58 (m, 6H), 1.13-1.09 (m, 6H)TLC: PE/EA= 10:1, UV254 nm Rf(Compound S1-4) = 0.5

Reference： [1]Patent: WO2018/213281,2018,A1 .Location in patent: Paragraph 0323

105
[ 6802-75-1 ]
[ 64168-34-9 ]
diethyl [1-(3-fluorophenyl)-2-methylpropan-2-yl]propanedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.5%	In 2-methyltetrahydrofuran; diethyl ether; at 20℃; for 22h;Inert atmosphere;	Under argon 33 ml (16.5 mmol) of 0.5M 3-fluorobenzylmagnesium chloride (Alfa Aesar) solution in 2-Me-THF was slowly added via a dropping funnel to a solution of 3.0 g (15.0 mmol) of <strong>[6802-75-1]diethyl (propan-2-ylidene)propanedioate</strong> (Aldrich) and 150 mL of diethyl ether in 4 hours. Then the stirring was continued at room temperature for 18 hours. After that, the reaction was quenched with 1 M hydrochloric acid solution, extracted with ethyl acetate, the combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na2S04, filtered and concentrated. Thus, 4.30 g (92.5%) of the title product was obtained as a yellow oil. MS (ESI) m/z 31 1.1 (M+H)+.

Reference： [1]Patent: WO2019/116325,2019,A1 .Location in patent: Page/Page column 112

106
[ 2403-88-5 ]
[ 6802-75-1 ]
C₂₄H₄₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With di(n-butyl)tin oxide; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Dean-Stark; Reflux; Inert atmosphere;	In a reaction vessel with a stirring device, thermometer, cooling tube, Dean Stark (Dean Stark) tube,So 15.0g (0.075mol) of diethyl 2- (propan-2-ylidene) malonate 1,25.9g (0.166mol) of <strong>[2403-88-5]4-hydroxy-2,2,6,6-tetramethylpiperidine</strong> 2And 0.19g (0.763mmol) of dibutyltin oxide dissolved in xylene (60mL),And heated to reflux under nitrogen atmosphere for 48 hours.The methanol produced on the way is separated by Dean Stark.After cooling at room temperature, the reaction solution was diluted with water and dichloromethane, and multiple phases were separated.Thereafter, after extracting the organic layer, it was washed with distilled water and dried in magnesium sulfate.Using a solution in which n-heptane: ethyl acetate = 1: 1 and 5% by weight of triethylamine is dissolved,Elution was performed in a silica gel column to obtain compound X (21.3 g, 65% yield).

Reference： [1]Patent: CN110835317,2020,A .Location in patent: Paragraph 0283-0287

107
[ 6802-75-1 ]
[ 100-61-8 ]
4,4-Dimethyl-2-oxo-1-phenylpyrrolidine-3-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With Quinuclidine; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate In acetonitrile for 16h; Sealed tube; Inert atmosphere; Irradiation;

Reference： [1]Zhao, Huaibo; Leonori, Daniele [Angewandte Chemie - International Edition, 2021, vol. 60, # 14, p. 7669 - 7674][Angew. Chem., 2021, vol. 133, # 14, p. 7747 - 7752,6]

108
[ 6802-75-1 ]
[ 931-50-0 ]
diethyl 2-(2-cyclohexylpropan-2-yl)malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: diethyl isopropylidenemalonate With copper(l) iodide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: cyclohexylmagnesium bromide In tetrahydrofuran at 0℃; for 2h;	109.1 A solution of diethyl 2-(propan-2-ylidene)malonate (1) (5 g, 25.00 mmol), in THF (100 mL) was cooled to 0°C, followed by copper (I) iodide (7.1 g, 37.00 mmol). The mixture was stirred at 0 °C for 0.5 h. Then cyclohexylmagnesium bromide 1.0 M in THF (75 mL, 75.00 mmol) was added drop-wise into the above mixture at 0 °C. The mixture was stirred at 0 °C for 2 h. Progress of the reaction was monitored by TLC and LCMS. The mixture was quenched with 1N HCI and extracted with ethyl acetate (2 x 100 mL) and washed with water (2 x 100 mL), dried over sodium sulfate, concentrated under reduced pressure to afford diethyl 2-(2-cyclohexylpropan-2-yl)malonate (3). TLC system: 5% Ethyl acetate in Pet ether l: 0.6 LCMS (ESI): m/z 471.27 [M+Na] +

Reference： [1]Current Patent Assignee: COCRYSTAL PHARMA, INC. - WO2021/206876, 2021, A1 Location in patent: Paragraph 001438-001439

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Isomers

Technical Information

• 1,4-Addition of an Amine to a Conjugated Enone • 1,4-Addition of an Amine to a Conjugated Enone • 1,4-Additions of Organometallic Reagents • Acid-Catalyzed Equilibration of Alkenes • Acid-Catalyzed Rearrangement of Alkenes • Acyl Group Substitution • Addition of a Hydrogen Halide to an Internal Alkyne • Addition of Hydrogen Halides Forms Geminal Dihaloalkanes • Addition of Radicals to Alkenes • Alcohols Convert Acyl Chlorides into Esters • Alcoholysis of Anhydrides • Aldol Condensation • Alkene Hydration • Alkenes React with Ozone to Produce Carbonyl Compounds • Alkylation of Enolate Ions • Allylic Deprotonation • Allylic Halides Undergo SN1 Reactions • Allylic Substitution • Amines Convert Esters into Amides • Base-Catalyzed Hydration of α,β -Unsaturated Aldehydes and Ketones • Baylis-Hillman Reaction • Bouveault-Blanc Reduction • Brown Hydroboration • Carbene Addition to Double Bonds • Catalytic Hydrogenation • Catalytic Hydrogenation of Alkenes • Claisen Condensations Produce β-Dicarbonyl Compounds • Claisen Condensations Produce β-Dicarbonyl Compounds • Complex Metal Hydride Reductions • Conjugated Enone Takes Part in 1,4-Additions • Convert Esters into Aldehydes Using a Milder Reducing Agent • Decarboxylation of 3-Ketoacids Yields Ketones • Deprotection of Cbz-Amino Acids • Deprotonation of a Carbonyl Compound at the α -Carbon • Dimerization, Oligomerization of Alkenes • Dissolving-Metal Reduction of an Alkyne • Electrocyclic Reactions • Electrophilic Addition of Halogen to Alkynes • Electrophilic Addition of HX to Alkenes • Elimination from Dihaloalkanes to Give Haloalkenes • Enamine Formation • Enamines Can Be Used to Prepare Alkylated Aldehydes • Enol-Keto Equilibration • Epoxidation • Epoxidation by Peroxycarboxylic Acids • Ester Cleavage • Ester Hydrolysis • Ether Synthesis by Oxymercuration-Demercuration • Exclusive 1,4-Addition of a Lithium Organocuprate • Friedel-Crafts Alkylation Using Alkenes • Friedel-Crafts Alkylations of Benzene Using Alkenes • Grignard Reagents Transform Esters into Alcohols • Halogen and Alcohols Add to Alkenes by Electrophilic Attack • Halogen and Alcohols Add to Alkenes by Electrophilic Attack • Halogenation • Halogenation of Alkenes • Halogenation-double Dehydrohalogenation • Hantzsch Pyridine Synthesis • Heat of Combustion • Heck Reaction • Hydroboration-Oxidation • Hydrogen Bromide Add to Alkenes in Anti-Markovnikov Fashion • Hydrogenation • Hydrogenation by Palladium on Carbon Gives the Saturated Carbonyl Compound • Hydrogenation with Lindlar Catalyst • Hydrogenation with Lindlar Catalyst • Hydroxylation • Isomerization of β, γ -Unsaturated Carbonyl Compounds • Ketones Undergo Mixed Claisen Reactions to Form β-Dicarbonyl Compounds • Lithium Organocuprate may Add to the α ,β -Unsaturated Carbonyl Function in 1,4-Fashion • Michael Addition • Osmium Tetroxide Reacts with Alkenes to Give Vicinal Diols • Oxidation of Alcohols to Carbonyl Compounds • Oxidative Cleavage of Double Bonds • Oxymercuration-Demercuration • Paternò-Büchi Reaction • Pauson-Khand Cyclopentenone Synthesis • Polymerization of Alkenes • Preparation of Alkenes • Preparation of Alkenes by Dehydration of Alcohols • Preparation of Alkenes by Dehydration of Alcohols • Prins Reaction • Radical Addition of a Thiol to an Alkene • Radical Addition of HBr to Terminal Alkynes • Radical Addition of HBr to Terminal Alkynes • Radical Allylic Substitution • Reactions of Alkenes • Reactions of Amines • Reactions with Organometallic Reagents • Reduction of an Ester to an Alcohol • Reduction of an Ester to an Aldehyde • Reductive Amination • Sharpless Asymmetric Amino Hydroxylation • Sharpless Asymmetric Dihydroxylation • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Vilsmeier Reagent • The Cycloaddition of Dienes to Alkenes Gives Cyclohexenes • The Heck Reaction • The Wittig Reaction • Transesterification • Vicinal Anti Dihydroxylation of Alkenes • Wacker Oxidation • Woodward Cis-Dihydroxylation

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[ 6802-75-1 ]

Alkenes

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H200	Unstable explosive
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H203	Explosive; fire, blast or projection hazard
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H205	May mass explode in fire
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H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
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H250	Catches fire spontaneously if exposed to air
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H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
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Health hazards
Code	Phrase
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H301	Toxic if swallowed
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H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 6802-75-1 ] {[proInfo.proName]}

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Water Solubility

Medicinal Chemistry

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Application In Synthesis of [ 6802-75-1 ]

[ 6802-75-1 ] Synthesis Path-Downstream 1~108

Technical Information

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Alkenes

Aliphatic Chain Hydrocarbons

Esters

Precautionary Statements-General

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[ 6802-75-1 ]