21080-80-8|Ethyl 4-cyclopropyl-2,4-dioxobutanoate| Ambeed

Structure of 21080-80-8

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Quality Control of [ 21080-80-8 ] Purity: 97% SDS Specification

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Product Details of [ 21080-80-8 ]

CAS No. :	21080-80-8
Formula :	C₉H₁₂O₄
M.W :	184.19
SMILES Code :	O=C(OCC)C(CC(C1CC1)=O)=O
MDL No. :	MFCD09052462
InChI Key :	MHKXVJFDESXWFH-UHFFFAOYSA-N
Pubchem ID :	16779961

Safety of [ 21080-80-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 21080-80-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	0
Fraction Csp3	0.67
Num. rotatable bonds	6
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	44.95
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	60.44 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.54
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.67
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.43
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-0.05
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.47
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.81

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.01
Solubility	18.1 mg/ml ; 0.0982 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.52
Solubility	5.62 mg/ml ; 0.0305 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.26
Solubility	10.1 mg/ml ; 0.0546 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.95 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.97

Application In Synthesis of [ 21080-80-8 ]

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

Downstream synthetic route of [ 21080-80-8 ]

[ 21080-80-8 ] Synthesis Path-Downstream 1~35

1
[ 21080-80-8 ]
[ 100-63-0 ]
5-cyclopropyl-1-phenyl-1<i>H</i>-pyrazole-3-carboxylic acid ethyl ester [ No CAS ]

References: [1]Journal of Organic Chemistry,1952,vol. 17,p. 685,688.

2
[ 95-92-1 ]
1-cyclopropyl-ethanone-⁽¹⁾ [ No CAS ]
[ 21080-80-8 ]

References: [1]Journal of the American Chemical Society,1948,vol. 70,p. 497,499.
[2]Zhurnal Obshchei Khimii,1944,vol. 14,p. 1070.
Chem.Abstr.,1947,p. 101.

3
[ 765-43-5 ]
[ 95-92-1 ]
[ 21080-80-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium; In ethanol; at 0 - 80℃;Inert atmosphere;	Sodium metal was dissolved into a solution of EtOH (150ml) at RT under nitrogen atmosphere to form NaOEt (16.19 gm). This mixture was cooled to 0 0C. Diethyl oxalate (34.76gm) and isopropyl methyl ketone (20gm) was added drop wise for about 15 min and warmed to RT. Now EtOH (100 ml) was added and stirred at RT for about 1 hour. Heat this reaction mixture to 80 0C for about 45 minuets and cooled to RT and concentrated under reduced pressure. To this resulting solid, add EtOAC. Wash with EtOH and filtered on cloth to get fine smooth powder.. This solid is dissolved in water and acidified with dilute Sulphuric acid (pH-2). This compound is extracted with diethyl ether and dried over sodium sulphate and was concentrated under reduced pressure to obtain the brown colored liquid compound (4Og, 93% yield ).
93%	With sodium ethanolate; In ethanol; at 0 - 80℃; for 2h;Inert atmosphere;	Synthesis of (1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methanamine (Employed for the Synthesis of Example Compound no. 12)Step a: Sodium metal was dissolved into a solution of EtOH (150 ml) at RT under nitrogen atmosphere to form NaOEt (16.19 gm). This mixture was cooled to 0 C. Diethyl oxalate (34.76 gm) and isopropyl methyl ketone (20 gm) was added drop wise for about 15 min and warmed to RT. Now EtOH (100 ml) was added and stirred at RT for about 1 hour. Heat this reaction mixture to 80 C. for about 45 minutes and cooled to RT and concentrated under reduced pressure. To this resulting solid, add EtOAC. Wash with EtOH and filtered on cloth to get fine smooth powder. This solid is dissolved in water and acidified with dilute Sulphuric acid (pH-2). This compound is extracted with diethyl ether and dried over sodium sulphate and was concentrated under reduced pressure to obtain the brown colored liquid compound (40 g, 93% yield).
93%		Synthesis of (1-(3-chloroDhenyl)-3-cyclODroDyl-1H-pyrazol-5-yl)methanamine (employed for the synthesis of example compound no. 12); Step a; Sodium metal was dissolved into a solution of EtOH (150ml) at RT under nitrogen atmosphere to form NaOEt (16.19 gm). This mixture was cooled to 0 C. Diethyl oxalate (34.76gm) and isopropyl methyl ketone (20gm) was added drop wise for about 15 min and warmed to RT. Now EtOH (100 ml) was added and stirred at RT for about 1 hour. Heat this reaction mixture to 80 C for about 45 minuets and cooled to RT and concentrated under reduced pressure. To this resulting solid, add EtOAC. Wash with EtOH and filtered on cloth to get fine smooth powder.. This solid is dissolved in water and acidified with dilute Sulphuric acid (pH-2). This compound is extracted with diethyl ether and dried over sodium sulphate and was concentrated under reduced pressure to obtain the brown colored liquid compound (40g, 93% yield ).

74%	With sodium; In ethanol; for 2.5h;Reflux;	Intermediate 29ethyl 4-cyclopropyl-2,4-dioxobutanoateSodium metal (2.411 g, 105 mmol) was dissolved in ethanol (50 mL). The solution was heated to reflux followed by addition of a mixture of 1-cyclopropylethanone (8.4 g, 100 mmol) and diethyl oxalate (14.59 g, 100 mmol) dropwise over 30 minutes. The reaction mixture was heated at reflux for an additional 2h, and then allowed to cool to room temperature over a 2 d period. The contents were diluted with water (200 mL) and acidified by dropwise addition of 6N HC1. The contents were extracted with EtOAc (3 x 75 mL), washed with water, brine, dried over MgS04, filtered, and concentrated in vacuo. The final product was collected as 14.3g (74%). LCMS E-S (M+H) =184.8 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.03 (d, J=7.83 Hz, 2 H) 1.13 - 1.19 (m, 2 H) 1.31 (t, J=7.07 Hz, 3 H) 1.81 - 1.90 (m, 1 H) 4.29 (q, J=7.16 Hz, 2 H) 6.43 (s, 1 H).
66%	With sodium ethanolate; In ethanol; at 0 - 80℃;	Sodium ethoxide (10 g, 147 mmol) is combined with absolute EtOH (60 mL) in an oven-dried flask, under nitrogen and heated to 70 C. to aid dissolution. The mixture is cooled to 0 C., treated drop-wise with a mixture of cyclopropyl methyl ketone (14.56 mL, 147 mmol) and diethyl oxylate (19.96 mL, 147 mmol) and warmed to RT. Stirring was difficult, so additional EtOH (60 mL) is added and the mixture is stirred for 1 h, then heated to 80 C. for 45 min. The mixture is cooled to RT and concentrated to dryness. The resulting solid is triturated with EtOAc, filtered, and rinsed with EtOAc and Et2O to remove the reddish color. The solid is dissolved in water (300 mL), acidified to pH 2 with dilute H2SO4, extracted with Et2O (400 mL total), dried (Na2SO4) and concentrated to afford 18.0 g (66% yield) of ethyl 4-cyclopropyl-2,4-dioxobutanoate as an amber oil. HRMS (ESI) calcd for C9H12O4 +H: 185.0814, found 185.0821 (M+H)+. Ethyl 4-cyclopropyl-2,4-dioxobutanoate (12.92 g, 70.1 mmol) is combined with hydroxylamine hydrochloride (14.62 g, 210.4 mmol) in EtOH (250 mL), heated to reflux for 1 h, cooled, and concentrated to dryness. The residue is partitioned between H2O (250 mL) and EtOAc (2×250 mL) and the combined organics are dried (MgSO4) and concentrated to an amber oil (13.89 g). The crude material is chromatographed over 500 g silica gel, eluting with 25% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 10.71 g (84% yield) of ethyl 5-cyclopropylisoxazole-3-carboxylate as a yellow oil. MS (CI) m/z: 182 (M+H)+. Sodium hydroxide (1.76 g, 44.0 mmol) in H2O (5 mL) is added to a solution of ethyl 5-cyclopropylisoxazole-3-carboxylate (1.97 g, 10.9 mmol) in MeOH (10 mL). The mixture is stirred at RT for 3 h, concentrated to remove the MeOH, and acidified to pH 2 with 5% HCl. The acid is extracted with CH2Cl2 (6×20 mL), dried (MgSO4) and concentrated to afford 1.56 g (93% yield) of 5-cyclopropylisoxazole-3-carboxylic acid as a white solid. MS (Cl) m/z: 154 (M+H)+. 5-Cyclopropylisoxazole-3-carboxylic acid (1.53 g, 10 mmol) is dissolved in benzene (30 mL), treated with oxalyl chloride (3.46 mL, 40 mmol) and heated to reflux for 2 h. The mixture is cooled, concentrated to dryness and the residual benzene is azeotroped off with CH2Cl2. The resulting acid chloride is dissolved in Me2CO (15 mL) and treated with a solution of NaN3 (1.95 g, 30 mmol) in H2O (7 mL). The mixture is vigorously stirred for 1 h, concentrated to remove the Me2CO, triturated with H2O, filtered, rinsed with water and dried under vacuum to afford 1.76 g (99% yield) of 5-cyclopropylisoxazole-3-carbonyl azide as an off-white solid. 1H NMR (CDCl3, 400 MHz): delta 1.02, 1.14, 2.10, 6.35 ppm. 5-Cyclopropylisoxazole-3-carbonyl azide (447 mg, 2.5 mmol) is combined with 5-chloro-2,4-dimethoxyaniline (471 mg, 2.5 mmol) in anhydrous MeCN (30 mL) and heated to reflux for 18 h. The mixture is cooled and the resulting solid is filtered, rinsed with Et2O and dried in a vacuum oven to afford 619 mg (73% yield) of Example 621 as a very light purple solid. HRMS (ESI) calcd for C15H16N3O4Cl +H: 338.0907, found 338.0896 (M+H)+.
48%		Metal Na (6 g, 0.26 mol) was added to ethanol (1 .5 L) in portions and stirred until it dissolved. The above solution was cooled in an ice-water bath, and compound 5 (20 g, 0.24 mol) was added dropwise under N2 atmosphere. 0.5 h later, oxalic acid diethyl ester (31 .6 g, 0.22 mol) was added dropwise at 0C with strong stirring. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and concentrated to remove ethanol on a rotary evaporator (water bath be- low 40 C), and the residue was acidified to pH 2 by 6N aq. HCI and extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated on a rotary evaporator (water bath below 30 C) to give compound 6 (21 g, yield: 48%). H-NMR (CDCI3): delta= 6.47 (s, 1 H), 4.37-4.32 (m, 2H), 1.92-1.86 (m, 1 H), 1 .37 (t, 3H, J= 7.2 Hz), 1 .24-1 .04 (m, 4H).
31%	With sodium ethanolate; In ethanol; at 0 - 20℃;	To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1.2 eq) in EtOH (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 eq) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1.1 eq) dropwise at 00C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and EtOH was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 * 25 mL). The organic layer was washed with brine solution and dried (Na2SO4), filtered and concentrated to give a pale brown liquid (400 mg, 31%).
31%	With sodium methylate; In ethanol; at 0 - 20℃; for 3h;	Diethyl oxalate (0.92 mL, 6.85 mmol, 1 equiv.) was added at RT to a freshly prepared sodium methanolate solution (prepared by dissolving sodium (1 g, 8.2 mmol, 1.2 equiv.) in EtOH (30 mL)), and cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1.1 equiv.) was then added dropwise at 0 C. The reaction mixture was slowly heated to RT and stirred for a further 3 h. Ice-cold water (10 mL) was added and the EtOH was distilled off under reduced pressure. The remaining aqueous phase was diluted with 2N hydrochloric acid (15 mL) and extracted with diethyl ether (2×25 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over Na2SO and concentrated under reduced pressure. A pale brown liquid was obtained as product (400 mg, 31% yield).
31%	With ethanol; sodium; at 0 - 23℃; for 3h;	To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1.2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1.1 equivalents) dropwise at 0 C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 * 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 %).
31%	With sodium ethanolate; at 0 - 20℃; for 3h;	Step a: To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1.2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1.1 equivalents) dropwise at 0? C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCl (15 mL) and extracted with diethyl ether (2?-25 mL). The organic layer was washed with brine solution and dried over sodium sulfate, filtered and concentrated to give a pale brown liquid (400 mg, 31%).
31%	With sodium ethanolate; In ethanol; at 0 - 20℃; for 3h;	To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1 .2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1 .1 equivalents) dropwise at 0 C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 ? 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 %).
31%	With sodium ethanolate; at 0 - 23℃; for 3h;	Step a: To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1 .2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1 .1 equivalents) dropwise at 0 C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 chi 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 %).
31%	With sodium ethanolate; In ethanol; at 0 - 23℃; for 3h;	To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1 .2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1 .1 equivalents) dropwise at 0 '?. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 chi 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 %).
31%	With sodium ethanolate; at 0 - 23℃; for 3h;	Step a: To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1 .2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1 .1 equivalents) dropwise at 0 C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCL (15mL) and extracted with diethyl ether (2 chi 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 %)
	With potassium tert-butylate; In tetrahydrofuran; at 20℃;	General procedure: To a mixture of t-BuOK (92.0 g, 697 mmol) and THF (500 mL) was added a mixture of 3-methyl-2-butanone (50.0 g, 581 mmol) and diethyl oxalate (85.8 g, 587 mmol) dropwise over 1 h. The mixture was stirred at room temperature for 15 h to form ethyl 5-methyl-2,4-dioxohexanoate. Thereafter, AcOH (80 mL, 1.39 mol) and hydrazine hydrate (32.0 g, 639 mmol) were successively added. The mixture was heated under reflux with stirring for 2 h. After being cooled, the mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic solution was washed with sat. NaHCO3 and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/EtOAc, 9:1 to 1:1) to give 20a (57.7 g, 55%) as a brown oil.
	With sodium ethanolate; In ethanol; at 0 - 80℃;	Sodium metal was dissolved into a solution of EtOH (150ml) at RT under nitrogen atmosphere to form NaOEt (16.19 gm). This mixture was cooled to 0 C. Diethyl oxalate (34.76gm) and isopropyl methyl ketone (20gm) was added drop wise for about 15 min and warmed to RT. Now EtOH (100 ml) was added and stirred at RT for about 1 hour. Heat this reaction mixture to 80 C for about 45 minuets and cooled to RT and concentrated under reduced pressure. To this resulting solid, add EtOAC. Wash with EtOH and filtered on cloth to get fine smooth powder.. This solid is dissolved in water and acidified with dilute Sulphuric acid (pH-2). This compound is extracted with diethyl ether and dried over sodium sulphate and was concentrated under reduced pressure to obtain the brown colored liquid compound (40g, 93% yield ).
	With ethanol; sodium; at 0 - 80℃; for 2h;Inert atmosphere;	Into a 10-L 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen Na (164 g, 1.20 equiv) was added in portions to ethanol (5 L). A solution of (C02Et)2 (869 g, 1.00 equiv) and 1-cyclopropylethan-l-one (500 g, 5.94 mol, 1.00 equiv) was added dropwise with stirring at 0-20C. The resulting solution was stirred for 1 h at 20-30C and then for an additional 1 h at 80C. The resulting solution was diluted with 15 L of H20. The pH was adjusted to 2 with hydrochloric acid (12N). The resulting solution was extracted with ethyl acetate and the organic layers combined and washed with NaHCC (sat. aq.). The extract was concentrated under vacuum yielding 820 g (crude) of ethyl 4-cyclopropyl-2,4-dioxobutanoate as yellow oil. TLC (ethyl acetate/petroleum ether =1/5): Rf = 0.5.
	With sodium; In ethanol; at 0 - 80℃; for 2h;Inert atmosphere;	Into a 10-L 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen Na (164 g, 1.20 equiv) was added in portions to ethanol (5 L). A solution of (C02Et)2 (869 g, 1.00 equiv) and 1-cyclopropylethan-l-one (500 g, 5.94 mol, 1.00 equiv) was added dropwise with stirring at 0-20 C. The resulting solution was stirred for 1 h at 20-30 C and then for an additional 1 h at 80 C. The resulting solution was diluted with 15 L of H20. The pH was adjusted to 2 with hydrochloric acid (12N). The resulting mixture was extracted with ethyl acetate and the organic layers combined and washed with NaHC03 (sat. aq.). The extract was concentrated under vacuum yielding 820 g (crude) of ethyl 4-cyclopropyl-2,4-dioxobutanoate as yellow oil. TLC (ethyl acetate/petroleum ether =1/5): Rf = 0.5.
	In ethanol; at 0 - 80℃; for 2h;Inert atmosphere;	Into a 10-L 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen Na (164 g, 1.20 equiv) was added in portions to ethanol (5 L). A solution of (C02Et)2 (869 g, 1.00 equiv) and 1-cyclopropylethan-l-one (500 g, 5.94 mol, 1.00 equiv) was added dropwise with stirring at 0-20 C. The resulting solution was stirred for 1 h at 20-30 C and then for an additional 1 h at 80 C. The resulting solution was diluted with 15 L of H20. The pH was adjusted to 2 with hydrochloric acid (12N). The resulting mixture was extracted with ethyl acetate and the organic layers combined and washed with NaHC03 (sat. aq.). The extract was concentrated under vacuum yielding 820 g (crude) of ethyl 4-cyclopropyl-2,4-dioxobutanoate as yellow oil. TLC (ethyl acetate/petroleum ether =1/5): Rf = 0.5.
820 g	With sodium; In ethanol; at 20 - 80℃; for 2h;Inert atmosphere;	Into a 10-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen Na (164 g, 1.20 equiv) was added in portions to ethanol (5 L). A solution of (C02Et)2 (869 g, 1.00 equiv) and 1-cyclopropylethan-l-one (500 g, 5.94 mol, 1.00 equiv) was added dropwise with stirring at 0-20C. The resulting solution was stirred for 1 h at 20-30C and then for an additional 1 h at 80C. The resulting solution was diluted with 15 L of H20. The pH was adjusted to 2 with hydrochloric acid (12N). The resulting solution was extracted with ethyl acetate and the organic layers combined and washed with NaHC03 (sat. aq.). The extract was concentrated under vacuum yielding 820 g (crude) of ethyl 4-cyclopropyl-2,4-dioxobutanoate as yellow oil. TLC (ethyl acetate/petroleum ether =1/5): Rf = 0.5.
	With sodium; In ethanol; at 0 - 80℃; for 2h;Inert atmosphere;	Into a 10-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen Na (164 g, 1.20 equiv) was added in portions to ethanol (5 L). A solution of (CO2Et)2 (869 g, 1.00 equiv) and 1-cyclopropylethan-1-one (500 g, 5.94 mol, 1.00 equiv) was added dropwise with stirring at 0-20oC. The resulting solution was stirred for 1 h at 20-30o C and then for an additional 1 h at 80oC. The resulting solution was diluted with 15 L of H2O. The pH was adjusted to 2 with hydrochloric acid (12N). The resulting solution was extracted with ethyl acetate and the organic layers combined and washed with NaHCO3 (sat. aq.). The extract was concentrated under vacuum yielding 820 g (crude) of ethyl 4-cyclopropyl-2,4-dioxobutanoate as yellow oil. TLC (ethyl acetate/petroleum ether =1/5): Rf = 0.5.
	With sodium ethanolate; In ethanol; at -5℃; for 3h;	General procedure: Sodium ethylate (30.0 g, 0.45 mol) was added into 300 mL of anhydrous ethanol and stirred evenly in ice-salt baths. Then the mixture solution of acetone (14.7 g, 0.3 mol) and diethyl oxalate (46.7 g, 0.32 mol) was added dropwise into sodium ethoxide-ethanol solution to keep the reaction temperature below -5 C for 3 h. The mixture was poured into ice water. After using hydrochloric acid (1 mol/L) to keep the pH around 4, the aqueous phase was extracted with ethyl acetate (EA). The organic layer was washed twice with 150 mL water and dried over Na2SO4, filtered,and concentrated under reduced pressure; 46.5 g (94 %yield, 96 % purity) yellow liquid (1a) was obtained. Without further purification, compound 1a was used in the next reaction. 1b-h were obtained in analogous procedures.

References: [1]Patent: WO2010/127855,2010,A1 .Location in patent: Page/Page column 159.
[2]Patent: US2012/115903,2012,A1 .Location in patent: Page/Page column 40.
[3]Patent: WO2012/62463,2012,A1 .Location in patent: Page/Page column 87-88.
[4]Patent: WO2013/39988,2013,A1 .Location in patent: Page/Page column 138.
[5]Patent: US2003/236287,2003,A1 .Location in patent: Page 46, 47.
[6]Journal of Medicinal Chemistry,2014,vol. 57,p. 4720 - 4744.
[7]Patent: WO2013/104561,2013,A1 .Location in patent: Page/Page column 48.
[8]Patent: WO2010/127856,2010,A1 .Location in patent: Page/Page column 123.
[9]Patent: US2012/46301,2012,A1 .Location in patent: Page/Page column 33.
[10]Patent: WO2013/13815,2013,A1 .Location in patent: Page/Page column 111.
[11]Patent: US2013/29962,2013,A1 .Location in patent: Paragraph 0693.
[12]Patent: WO2013/68463,2013,A1 .Location in patent: Page/Page column 51.
[13]Patent: WO2013/68461,2013,A1 .Location in patent: Page/Page column 72.
[14]Patent: WO2013/68464,2013,A1 .Location in patent: Page/Page column 53.
[15]Patent: WO2013/68462,2013,A1 .Location in patent: Page/Page column 61.
[16]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4914 - 4919.
[17]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5620 - 5623.
[18]Journal of Combinatorial Chemistry,2010,vol. 12,p. 510 - 517.
[19]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 714 - 733.
[20]Patent: WO2012/62462,2012,A1 .Location in patent: Page/Page column 87.
[21]Patent: WO2016/40502,2016,A1 .Location in patent: Page/Page column 64.
[22]Patent: WO2016/40504,2016,A1 .Location in patent: Paragraph 0192.
[23]Patent: WO2016/40498,2016,A1 .Location in patent: Paragraph 0264.
[24]Patent: WO2016/40511,2016,A1 .Location in patent: Paragraph 0114.
[25]Patent: WO2016/40515,2016,A1 .Location in patent: Paragraph 0265.
[26]Chemical Papers,2017,vol. 71,p. 2053 - 2061.
[27]Journal of Medicinal Chemistry,2018,vol. 61,p. 9146 - 9161.

4
[ 21080-80-8 ]
[ 133261-06-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate; acetic acid; In tetrahydrofuran;Reflux;	General procedure: To a mixture of t-BuOK (92.0 g, 697 mmol) and THF (500 mL) was added a mixture of 3-methyl-2-butanone (50.0 g, 581 mmol) and diethyl oxalate (85.8 g, 587 mmol) dropwise over 1 h. The mixture was stirred at room temperature for 15 h to form ethyl 5-methyl-2,4-dioxohexanoate. Thereafter, AcOH (80 mL, 1.39 mol) and hydrazine hydrate (32.0 g, 639 mmol) were successively added. The mixture was heated under reflux with stirring for 2 h. After being cooled, the mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic solution was washed with sat. NaHCO3 and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/EtOAc, 9:1 to 1:1) to give 20a (57.7 g, 55percent) as a brown oil.

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4914 - 4919.
[2]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 714 - 733.

5
[ 21080-80-8 ]
[ 133261-06-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5620 - 5623.

6
[ 21080-80-8 ]
3-cyclopropyl-1H-pyrazole-5-carboxylic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4914 - 4919.

7
[ 21080-80-8 ]
[ 21080-81-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydroxylamine hydrochloride; In ethanol; for 1h;Heating / reflux;	Sodium ethoxide (10 g, 147 mmol) is combined with absolute EtOH (60 mL) in an oven-dried flask, under nitrogen and heated to 70° C. to aid dissolution. The mixture is cooled to 0° C., treated drop-wise with a mixture of cyclopropyl methyl ketone (14.56 mL, 147 mmol) and diethyl oxylate (19.96 mL, 147 mmol) and warmed to RT. Stirring was difficult, so additional EtOH (60 mL) is added and the mixture is stirred for 1 h, then heated to 80° C. for 45 min. The mixture is cooled to RT and concentrated to dryness. The resulting solid is triturated with EtOAc, filtered, and rinsed with EtOAc and Et2O to remove the reddish color. The solid is dissolved in water (300 mL), acidified to pH 2 with dilute H2SO4, extracted with Et2O (400 mL total), dried (Na2SO4) and concentrated to afford 18.0 g (66percent yield) of <strong>[21080-80-8]ethyl 4-cyclopropyl-2,4-dioxobutanoate</strong> as an amber oil. HRMS (ESI) calcd for C9H12O4 +H: 185.0814, found 185.0821 (M+H)+. Ethyl 4-cyclopropyl-2,4-dioxobutanoate (12.92 g, 70.1 mmol) is combined with hydroxylamine hydrochloride (14.62 g, 210.4 mmol) in EtOH (250 mL), heated to reflux for 1 h, cooled, and concentrated to dryness. The residue is partitioned between H2O (250 mL) and EtOAc (2.x.250 mL) and the combined organics are dried (MgSO4) and concentrated to an amber oil (13.89 g). The crude material is chromatographed over 500 g silica gel, eluting with 25percent EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 10.71 g (84percent yield) of ethyl 5-cyclopropylisoxazole-3-carboxylate as a yellow oil. MS (CI) m/z: 182 (M+H)+. Sodium hydroxide (1.76 g, 44.0 mmol) in H2O (5 mL) is added to a solution of ethyl 5-cyclopropylisoxazole-3-carboxylate (1.97 g, 10.9 mmol) in MeOH (10 mL). The mixture is stirred at RT for 3 h, concentrated to remove the MeOH, and acidified to pH 2 with 5percent HCl. The acid is extracted with CH2Cl2 (6.x.20 mL), dried (MgSO4) and concentrated to afford 1.56 g (93percent yield) of 5-cyclopropylisoxazole-3-carboxylic acid as a white solid. MS (Cl) m/z: 154 (M+H)+. 5-Cyclopropylisoxazole-3-carboxylic acid (1.53 g, 10 mmol) is dissolved in benzene (30 mL), treated with oxalyl chloride (3.46 mL, 40 mmol) and heated to reflux for 2 h. The mixture is cooled, concentrated to dryness and the residual benzene is azeotroped off with CH2Cl2. The resulting acid chloride is dissolved in Me2CO (15 mL) and treated with a solution of NaN3 (1.95 g, 30 mmol) in H2O (7 mL). The mixture is vigorously stirred for 1 h, concentrated to remove the Me2CO, triturated with H2O, filtered, rinsed with water and dried under vacuum to afford 1.76 g (99percent yield) of 5-cyclopropylisoxazole-3-carbonyl azide as an off-white solid. 1H NMR (CDCl3, 400 MHz): delta 1.02, 1.14, 2.10, 6.35 ppm. 5-Cyclopropylisoxazole-3-carbonyl azide (447 mg, 2.5 mmol) is combined with 5-chloro-2,4-dimethoxyaniline (471 mg, 2.5 mmol) in anhydrous MeCN (30 mL) and heated to reflux for 18 h. The mixture is cooled and the resulting solid is filtered, rinsed with Et2O and dried in a vacuum oven to afford 619 mg (73percent yield) of Example 621 as a very light purple solid. HRMS (ESI) calcd for C15H16N3O4Cl +H: 338.0907, found 338.0896 (M+H)+.
66.3%	With hydroxylamine hydrochloride; In ethanol; at 20 - 80℃; for 2h;	Into a 10 L round-bottom flask, was placed a solution of ethyl 4-cyclopropyl-2,4- dioxobutanoate (177 g) in ethanol (1.1 L) and NH2OH-HCl (200 g). The resulting solution was stirred for 1 h at 20-30°C. The resulting solution was allowed to react, with stirring, for an additional 1 h at 80°C. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 143 g (the two step yield was 66.3percent) of ethyl 5- cyclopropylisoxazole-3-carboxylate as a yellow oil. TLC (ethyl acetate/petroleum ether = l/5): Rf = 0.2.
143 mg	With hydroxylamine hydrochloride; In ethanol; water; at 20 - 80℃; for 2h;	Into a 10 L round-bottom flask, was placed a solution of ethyl 4-cyclopropyl-2,4- dioxobutanoate (177 g) in ethanol (1.1 L) and NH2OH-HCl (200 g). The resulting solution was stirred for 1 h at 20-30°C. The resulting solution was allowed to react, with stirring, for an additional 1 h at 80°C. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 143 g (the two step yield was 66.3percent) of ethyl 5- cyclopropylisoxazole-3-carboxylate as a yellow oil. TLC (ethyl acetate/petroleum ether =1/5): Rf = 0.2.

143 g	With hydroxylamine hydrochloride; In ethanol; at 20 - 80℃; for 2h;	Into a 10 L round-bottom flask, was placed a solution of ethyl 4-cyclopropyl-2,4- dioxobutanoate (177 g) in ethanol (1.1 L) and NH2OH-HCl (200 g). The resulting solution was stirred for 1 h at 20-30 °C. The resulting solution was allowed to react, with stirring, for an additional 1 h at 80°C. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 143 g (the two step yield was 66.3percent) of ethyl 5- cyclopropylisoxazole-3-carboxylate as a yellow oil. TLC (ethyl acetate/petroleum ether =1/5): Rf = 0.2.
143 g	With hydroxylamine hydrochloride; In ethanol; at 20 - 30℃; for 2h;	[0265] Into a 10 L round-bottom flask, was placed a solution of ethyl 4-cyclopropyl-2,4- dioxobutanoate (177 g) in ethanol (1.1 L) and NH2OH-HCl (200 g). The resulting solution was stirred for 1 h at 20-30 °C. The resulting solution was allowed to react, with stirring, for an additional 1 h at 80°C. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 143 g (the two step yield was 66.3percent) of ethyl 5- cyclopropylisoxazole-3-carboxylate as a yellow oil. TLC (ethyl acetate/petroleum ether = l/5): Rf = 0.2.
143 g	With hydroxylamine hydrochloride; In ethanol; at 20 - 80℃; for 2h;	Into a 10 L round-bottom flask, was placed a solution of ethyl 4-cyclopropyl-2,4- dioxobutanoate (177 g) in ethanol (1.1 L) and NH2OH-HCl (200 g). The resulting solution was stirred for 1 h at 20-30oC. The resulting solution was allowed to react, with stirring, for an additional 1 h at 80oC. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 143 g (the two step yield was 66.3percent) of ethyl 5- cyclopropylisoxazole-3-carboxylate as a yellow oil. TLC (ethyl acetate/petroleum ether =1/5): Rf = 0.2.

References: [1]Patent: US2003/236287,2003,A1 .Location in patent: Page 46, 47.
[2]Patent: WO2016/40511,2016,A1 .Location in patent: Paragraph 0115.
[3]Patent: WO2016/40502,2016,A1 .Location in patent: Page/Page column 65.
[4]Patent: WO2016/40504,2016,A1 .Location in patent: Paragraph 0193.
[5]Patent: WO2016/40498,2016,A1 .Location in patent: Paragraph 0265.
[6]Patent: WO2016/40515,2016,A1 .Location in patent: Paragraph 0266.

8
[ 21080-80-8 ]
[ 107-91-5 ]
[ 101184-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	With piperazine; In ethanol; at 20 - 65℃; for 15.5h;	Reference Example 15 3-Cyano-6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid ethyl ester While stirring at room temperature, 19.2 g of 2-cyanoacetamide was added to 300 ml of ethanol solution containing 41.9 g of <strong>[21080-80-8]2,4-dioxocyclopropanebutyric acid ethyl ester</strong>.. After completely dissolving the reagent by warming up to 65° C., 7.4 ml of piperazine was added dropwise to the solution.. One hour thereafter, this was cooled to room temperature and stirred for additional 15 hours and 30 minutes.. The thus precipitated crystals were collected by filtration and then washed with diethyl ether to obtain 24.1 g of the title compound.. This compound was used in the subsequent reaction without further purification.

References: [1]Patent: US6673799,2004,B1 .Location in patent: Page column 16.

9
[ 110-85-0 ]
[ 21080-80-8 ]
[ 107-91-5 ]
[ 101184-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;	3-Cyano-6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid ethyl ester While stirring at room temperature, 19.2 g of 2-cyanoacetamide was added to 300 ml of ethanol solution containing 41.9 g of <strong>[21080-80-8]2,4-dioxocyclopropanebutyric acid ethyl ester</strong>. After completely dissolving the reagent by warming up to 65°C, 7.4 ml of piperazine was added dropwise to the solution. One hour thereafter, this was cooled to room temperature and stirred for additional 15 hours and 30 minutes. The thus precipitated crystals were collected by filtration and then washed with diethyl ether to obtain 24.1 g of the title compound. This compound was used in the subsequent reaction without further purification.

References: [1]Patent: EP1122242,2001,A1 .

10
[ 21080-80-8 ]
[ 934-22-5 ]
[ 32863-33-5 ]
[ 1024610-91-0 ]

Yield	Reaction Conditions	Operation in experiment
8%		Compound 440: 1 -(1 H-Benzoimidazol-5-yl)-5-benzo[c][1 ,2,5]oxadiazol-5-yl-4- cyclopropanecarbonyl-S-hydroxy-I .S-dihydro-pyrrol^-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and Benzo[1 ,2,5]oxadiazole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 4-Cyclopropyl-2,4-dioxo-butyric acid ethyl ester (1 mmol) was added. The reaction was heated to 500C and stirred for 24h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 401.38 IC50 hQC (nM): 1 1.4Yield: 0.032g (8 percent); mp: 1700C, 1H NMR delta 0.73-0.75 (m, 1 H, CH2), 0.83-0.85 (m, 2 H, CH2), 0.94-0.96 (m, 1 H, CH2), 2.92-2.94 (CH-CH2), 6.37 (s, 1 H, CH-N), 7.40 (dd, 3J=9.5 Hz, 4J=1.2 Hz, 1 H, Ar), 7.64-7.66 (m, 2 H, Ar, Benzimid), 7.83 (d, 3J=9.5 Hz, 1 H, Ar), 8.05 (s, 1 H, Benzimid), 8.18 (s, 1 H, Benzimid), 9.10 (s, 1 H, Benzimid); MS m/z 402.2 (M+H)+, HPLC (254 nm): rt 2.75 min (100 percent)

References: [1]Patent: WO2008/55945,2008,A1 .Location in patent: Page/Page column 185.

11
[ 14510-06-6 ]
[ 21080-80-8 ]
[ 934-22-5 ]
[ 1024610-97-6 ]

Yield	Reaction Conditions	Operation in experiment
41%		Compound 446: 1 -(1 H-Benzoimidazol-S-ylJ^-cyclopropanecarbonyl-S-hydroxy-S-tdelta- hydroxy-quinolin-2-yl)-1 ,5-dihydro-pyrrol-2-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and 8-Hydroxy-quinoline-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3 4-Cyclopropyl-2,4-dioxo-butyric acid ethyl ester (1 EPO <DP n="188"/>mmol) was added. The reaction was heated to 500C and stirred for 24h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 426.44 IC50 hQC (nM): 1.35Yield: 0.174g (41 percent); mp: 155°C, 1H NMR delta 0.67-0.71 (m, 1 H, CH2), 0.77-0.85 (m, 2 H, CH2), 0.88-0.93 (m, 1 H, CH2), 2.85-2.96 (CH-CH2), 6.39 (s, 1 H, CH-N), 6.99 (dd, 3J=6.4 Hz, 4J=1.2 Hz, 1 H, Ar), 7.22 (dd, 3J=7.0 Hz, 4J=1.2 Hz, 1 H, Ar), 7.31 (t, 3J=7.8 Hz, 1 H, Ar), 7.51 (d, 3J=8.6 Hz, 1 H, Ar), 7.60 (d, 3J=9.0 Hz, 1 H, Benzimid), 7.75 (dd, 3J=9.0 Hz, 4J=1.9 Hz, 1 H, Ar), 8.09-8.1 1 (m, 2 H, Benzimid), 9.03 (s, 1 H, Benzimid), 9.53 (s, br., 1 H, NH); MS m/z 427.0 (M+H)+, HPLC (254 nm): rt 2.81 min (100 percent)

References: [1]Patent: WO2008/55945,2008,A1 .Location in patent: Page/Page column 186-187.

12
[ 21080-80-8 ]
[ 934-22-5 ]
[ 71605-72-6 ]
[ 1024609-37-7 ]

Yield	Reaction Conditions	Operation in experiment
16%		Compound 287: 1 -(1 H-Benzoimidazol-5-yl)-5-benzo[c][1 ,2,5]thiadiazol-5-yl-4- cyclopropanecarbonyl-S-hydroxy-I .S-dihydro-pyrrol^-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and Benzo[1 ,2,5]thiadiazole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 4-Cyclopropyl-2,4-dioxo-butyric acid ethyl ester (1 mmol) was added. The reaction was heated to 500C and stirred for 24h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 417.45 IC50 hQC (nM): 0.7Yield: 0.05 g (16 percent); mp: 270.000C, decomposed, 1H NMR delta 1 H-NMR (500 MHz, DMSO-D6): 0.66-0.71 (m, 1 H, CH2), 0.77-0.84 (m, 2 H, CH2), 0.89-0.95 (m, 1 H, CH2), 2.91-2.95 (CH-CH2), 6.36 (s, 1 H, CH-N), 7.45-7.50 (m, 3 H, Ar), 7.85-7.87 (m, 2 H, Benzimid), 8.12 (d, 4J=0.9 Hz, 1 H, Benzimid), 9.03 (s, 1 H, Benzimid). MS m/z 418.4 (M+H)+, HPLC (254 nm): rt 2.74 min (100 percent).

References: [1]Patent: WO2008/55945,2008,A1 .Location in patent: Page/Page column 177.

13
[ 21080-80-8 ]
[ 593-56-6 ]
[ 1254716-82-9 ]

Yield	Reaction Conditions	Operation in experiment
79%	In ethanol; at 20℃; for 1h;	Methoxyl amine hydrochloride (30percent solution in water, 0.4 mL, 0.651 mmol, 1.2 equiv.) was added at room temperature to the product obtained from step a (200 mg, 0.543 mmol, 1 equiv.) in EtOH (8 mL), and the reaction mixture was stirred for 1 h at RT. EtOH was evaporated under reduced pressure and the remaining aqueous phase was extracted with EA (15 mL). The organic phase was washed with water (10 mL), saturated sodium chloride solution (10 mL), dried over Na2SO4 and concentrated under reduced pressure. A pale yellow liquid was obtained as product (180 mg, 79percent yield).
78%	In ethanol; water; at 20℃; for 1h;	To a solution of step-a product (200 mg, 0.543 mmol, 1 eq) in EtOH (8 mL), methoxylamine hydrochloride (30percent solution in water, 0.4 mL, 0.651 mmol, 1.2 eq) was added at room temperature and the reaction mixture stirred for 1 h. EtOH was evaporated under reduced pressure and the residual aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), brine solution (10 ml), dried (Na2SO4), filtered and concentrated under reduced pressure to give a pale yellow liquid (180 mg, 78percent).
78%	In ethanol; water; at 23℃; for 1h;	To a solution of step-a product (200 mg, 0.543 mmol, 1 equivalent) in ethanol (8 mL), methoxylamine hydrochloride (30 percent solution in water, 0.4 mL, 0.651 mmol, 1.2 equivalents) was added at room temperature and the reaction mixture stirred for 1 h. ethanol was evaporated under reduced pressure and the residual aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a pale yellow liquid (180 mg, 78 percent).

78%	In ethanol; water; at 20℃; for 1h;	Step b: To a solution of step-a product (200 mg, 0.543 mmol, 1 equivalent) in ethanol (8 mL), methoxylamine hydrochloride (30percent solution in water, 0.4 mL, 0.651 mmol, 1.2 equivalents) was added at room temperature and the reaction mixture stirred for 1 h. ethanol was evaporated under reduced pressure and the residual aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a pale yellow liquid (180 mg, 78percent).
78%	In ethanol; water; at 20℃; for 1h;	To a solution of step-a product (200 mg, 0.543 mmol, 1 equivalent) in ethanol (8 mL), methoxylamine hydrochloride (30 percent solution in water, 0.4 mL, 0.651 mmol, 1 .2 equivalents) was added at room temperature and the reaction mixture stirred for 1 h. ethanol was evaporated under reduced pressure and the residual aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a pale yellow liquid (180 mg, 78 percent).
78%	In ethanol; water; at 23℃; for 1h;	Step b: To a solution of step-a product (200 mg, 0.543 mmol, 1 equivalent) in ethanol (8 mL), methoxylamine hydrochloride (30 percent solution in water, 0.4 mL, 0.651 mmol, 1 .2 equivalents) was added at room temperature and the reaction mixture stirred for 1 h. ethanol was evaporated under reduced pressure and the residual aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a pale yellow liquid (180 mg, 78 percent).
78%	In ethanol; water; at 23℃; for 1h;	To a solution of step-a product (200 mg, 0.543 mmol, 1 equivalent) in ethanol (8 mL), methoxylamine hydrochloride (30 percent solution in water, 0.4 mL, 0.651 mmol, 1 .2 equivalents) was added at room temperature and the reaction mixture stirred for 1 h. ethanol was evaporated under reduced pressure and the residual aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a pale yellow liquid (180 mg, 78 percent).
78%	In ethanol; water; at 23℃; for 1h;	Step b: To a solution of step-a product (200 mg, 0.543 mmol, 1 equivalent) in ethanol (8 mL), methoxylamine hydrochloride (30 percent solution in water, 0.4 mL, 0.651 mmol, 1 .2 equivalents) was added at room temperature and the reaction mixture stirred for 1 h. ethanol was evaporated under reduced pressure and the residual aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a pale yellow liquid (180 mg, 78 percent).

References: [1]Patent: US2012/46301,2012,A1 .Location in patent: Page/Page column 33.
[2]Patent: WO2010/127856,2010,A1 .Location in patent: Page/Page column 123.
[3]Patent: WO2013/13815,2013,A1 .Location in patent: Page/Page column 111.
[4]Patent: US2013/29962,2013,A1 .Location in patent: Paragraph 0694.
[5]Patent: WO2013/68463,2013,A1 .Location in patent: Page/Page column 51.
[6]Patent: WO2013/68461,2013,A1 .Location in patent: Page/Page column 72.
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14
[ 21080-80-8 ]
[ 1357002-33-5 ]
ethyl 3-(1-[2-chloro-4-(trifluoromethyl)benzyl]-3-propyl-1H-pyrazol-5-yl)propanoate [ No CAS ]