[ CAS No. 41051-15-4 ] {[proInfo.proName]}

Name: 41051-15-4|Methyl 4-methoxy-3-oxobutanoate|98%
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Quality Control of [ 41051-15-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 41051-15-4 ]

SDS Specification

Alternatived Products of [ 41051-15-4 ]

Product Details of [ 41051-15-4 ]

CAS No. :	41051-15-4	MDL No. :	MFCD00010183
Formula :	C₆H₁₀O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QGBPKJFJAVDUNC-UHFFFAOYSA-N
M.W :	146.14	Pubchem ID :	123500
Synonyms :

Calculated chemistry of [ 41051-15-4 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.67
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	33.53
TPSA :	52.6 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.3 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.66
Log Po/w (XLOGP3) :	-0.15
Log Po/w (WLOGP) :	-0.24
Log Po/w (MLOGP) :	-0.57
Log Po/w (SILICOS-IT) :	0.38
Consensus Log Po/w :	0.22

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.32
Solubility :	69.7 mg/ml ; 0.477 mol/l
Class :	Very soluble
Log S (Ali) :	-0.5
Solubility :	46.2 mg/ml ; 0.316 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.82
Solubility :	22.1 mg/ml ; 0.151 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.86

Safety of [ 41051-15-4 ]

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 [ 41051-15-4 ]

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

Upstream synthesis route of [ 41051-15-4 ]
Downstream synthetic route of [ 41051-15-4 ]

[ 41051-15-4 ] Synthesis Path-Upstream 1~15

1
[ 41051-15-4 ]
[ 856972-65-1 ]

Reference： [1] Journal of the American Chemical Society, 1947, vol. 69, p. 3072,3075

2
[ 32807-28-6 ]
[ 41051-15-4 ]

Yield	Reaction Conditions	Operation in experiment
91.7%	With hydrogenchloride; sodium methylate In water; acetonitrile	EXAMPLE 1 77.4 g of sodium methylate, 97 percent, was suspended in 100 g of acetonitrile at ambient temperature. To this well-stirred suspension, 101.9 g of 97.5 percent 4-chloroacetoacetic acid methyl ester was added by drops through a drip funnel with a drop counter over a 5 to 6 minute period under N₂ atmosphere. The temperature rose and was kept by means of cooling at 68° to 70° C. As soon as the heat development slackened, the cooling water was turned off and the reaction mass was heated with 70° C. hot water. This pastelike, mustard-yellow reaction mixture continued to be stirred at 70° C. for 24 to 25 minutes and, with stirring, was then slowly introduced into a solution of 6 g of glacial acetic acid and 215 g of water cooled in an ice bath. At the same time, 37.4 percent hydrochloric acid was introduced drop by drop from a burette. At the same time, the pH was measured by means of a glass electrode and kept between 4.5 and 8 by adjusting the addition rate of the reaction mixture and/or HCl. At the end of the neutralization, the pH was 6.1+-0.1. For the neutralization, 56.4 ml of hydrochloric acid were used (37.4 percent) and the temperature was kept at 30° to 35° C. The neutralized mixture was put into a separating funnel. After standing a short time, the resultant layers were separated. The aqueous layer was extracted once with 200 ml and then twice each time with 100 ml of acetonitrile. The united organic phases were concentrated in a rotary evaporator at 30° to 35° C. and 20 torr up to a constant weight. The solvent evaporated off was regenerated and used with the next batch. The raw product was distilled at 0.5 to 1.5 torr/90° C. 4-methoxyacetoacetic acid methyl ester was obtained in a yield of 91.7 percent, based on the amount of chloroester used. The purity of the product was 98.8 percent.
74%	With hydrogenchloride In tetrahydrofuran; methanol; nitrogen; toluene	REFERENCE EXAMPLE 1 Synthesis of Methyl (R)-4-Methoxy-3-Hydroxybutyrate: In a 2 liter four-necked flask were charged 88.0 g (2.2 mol) of 60percent sodium hydride and 753 ml of tetrahydrofuran in a nitrogen stream, and a mixture of 150.6 g (1.0 mmol) of methyl 4-chloro-3-oxo-butyrate and 35.2 g (1.1 mol) of methanol was added thereto dropwise at room temperature (22 to 24° C.). After the addition, the mixture was stirred at room temperature (22 to 24° C.) for 1 hour. The reaction mixture was cooled with ice, and 600 ml (1.2 mol) of 2N hydrochloric acid was added dropwise. The tetrahydrofuran was recovered from the reaction mixture, and 400 ml of toluene was added to the residue. The aqueous phase was extracted with three 200 ml portions of toluene. The organic phase was washed with a 5percent sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The residue was distilled under reduce pressure (boiling point: 90° C./1000 Pa) to give 107.7 g (74percent) of methyl 4-methoxy-3-oxobutyrate as liquid. ¹H-NMR (200 MHz, CDCl₃, δ ppm): 4.08 (s, 2H), 3.74 (s, 3H), 3.52 (s, 2H), 3.42 (s, 3H)

Reference： [1] Patent: US4564696, 1986, A,
[2] Patent: US6403804, 2002, B1,
[3] Patent: US4892966, 1990, A,

3
[ 382141-76-6 ]
[ 68665-45-2 ]
[ 41051-15-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogen In 1,2-dichloro-benzene	EXAMPLE 6 HYDROGENATION OF METHYL 4-METHOXYACETOACETATE TO 3-HYDROXY-4-METHOXYBUTYRIC ACID METHYL ESTER. A 2 mL reactor was charged with 0.150 mL of a 1.00 M solution of 4-methoxyacetoacetate and 0.050 mL of a 0.030 M solution of [Cp*Ru(CO)₂]₂(μ-H)}⁺OTf^- in dichlorobenzene. The reaction was heated at 90°C for 12 hours at 820 psi (5.7 MPa) of hydrogen gas. The reaction was cooled, and analyzed using gas chromatography/mass spectroscopy. Analysis indicated 100percent conversion of the 4-methoxyacetoacetate with a greater than 90percent yield of 3-hydroxy-4-methoxybutyric acid methyl ester.

Reference： [1] Patent: EP1292555, 2004, B1,

4
[ 67-56-1 ]
[ 32807-28-6 ]
[ 41051-15-4 ]

Yield	Reaction Conditions	Operation in experiment
74 g	With potassium methanolate; sodium hydride In tetrahydrofuran; mineral oil at 15 - 25℃; for 9 h; Inert atmosphere	In 2L pre-reaction bottle by adding 250 ml tetrahydrofuran, under the protection of argon, are started to stir, the oven 25 °C, the inner temperature 15-25 °C added in batches under the condition of 30g (0.74mol) sodium hydride (containing 40 wt percent mineral oil) and 50g (0.74mol) potassium methoxide, continue adding tetrahydrofuran after adding 450 ml; the inner temperature 20 °C slowly dropping under the condition of 30g methanol and 100g (0.67mol) 4-chloro acetyl mixed solution of methyl acetate, regulate the stirring in the rate of 310 R/min the left and the right, about 4h finish; to temperature rise within 20-25 °C stirring 5h, TLC detection complete raw material reaction: cooling system, can be seen and the color is yellowish solution a large number of solid suspended, the inner temperature 11 °C add under the condition of 200 ml tetrahydrofuran, to be oven to -2 ° C time, slowly adding 100 ml molar concentration is 2mol/L hydrochloric acid solution (pre-cooling to 0-5 °C), keep the oven in the 0 °C the following, about 20 min after adding, pH= 10 of the reaction system at this time, in the process of dropping the solid significant increase in the reaction bottle, immediately after adding filtering, the filter cake is a white solid, cake obtained drying filters 92g solid; the resulting solid is added to the 770g in ethyl acetate, the temperature of the reaction system to 0 °C, slow instillment mole concentration is 6mol/L hydrochloric acid solution, maintaining the temperature of the reaction system is not variable, the dropping white solid gradually disappear in the process, the reaction system is adjusted pH= 4, reaction liquid contains a small amount of inorganic salt white solid, filtering the reaction solution, the filtrate layer, the organic phase is separated, the organic phase by adding 5g activated carbon, in the 30 °C under the condition of stirring 1h, filtered, filtrate in the 35 °C ethyl acetate under the condition of the vacuum distillation to the colorless liquid 74g, HPLC checking the purity of 99.6percent.
89 g	With potassium methanolate; sodium hydride In tetrahydrofuran; mineral oil at 20 - 25℃; for 9 h; Inert atmosphere	In a 2 L reaction flask, 250 ml of a solvent tetrahydrofuran (AR) was added. Under argon protection, stirring was started and at this time the kettle temperature is 25°C. Was added portionwise 30 g (0.75 mol) of industrial sodium hydride (containing 40 wtpercent mineral oil) and 53 g (0.75 mol) of potassium methoxide. After the addition, continue to add solvent tetrahydrofuran 450ml; The temperature in the kettle was 20°C. Was slowly added dropwise 30 g of methanol mixed with 100 g (0.68 mol) methyl 4-chloro-3-oxo-butanoate and stirred reaction for 4h. The reactor temperature increased to 25°C and stirred for 5h. TLC detection reaction is completed. The system began to cool down. Solution color is khaki and a large number of solid suspension. When the temperature inside the kettle drops to 6°C, 2M hydrochloric acid solution (pre-cooled to 0-5 ° C) was slowly added to the system pH = 7; Standing stratification. After separation, the upper layer was concentrated to dryness to remove the solvent tetrahydrofuran. The resulting residue was added with 60 ml of ethyl acetate. After concentrating by rotary evaporation, ehyl acetate (60 ml) was added thereto. Concentrated by rotary evaporation, ethyl acetate (200 ml) was added thereto. After stirring for a while, the lower aqueous phase was extracted three times with ethyl acetate (80 ml, 60 ml, 60 ml). All organic phases were combined. Saturated sodium chloride wash (60mlx2) to pH = 7 or so. Concentrated to give a pale yellow oil, which was subjected to wiping film molecular distillation. When the degree of vacuum was 30 Pa, at a temperature of 50°C, scraper speed of 400r / min, to obtain 89 g of methyl 4-methoxyacetoacetate as a colorless oily liquid, purity was 95.4percent by HPLC.

Reference： [1] Patent: CN105418420, 2016, A, . Location in patent: Paragraph 0015; 0016; 0017; 0018; 0019; 0020
[2] Patent: CN104478719, 2016, B, . Location in patent: Paragraph 0034; 0035

5
[ 382141-76-6 ]
[ 68665-45-2 ]
[ 41051-15-4 ]

Reference： [1] Patent: US6462206, 2002, B1,

6
[ 107-03-9 ]
[ 141-97-9 ]
[ 41051-15-4 ]

Reference： [1] Patent: US4120956, 1978, A,

7
[ 32807-28-6 ]
[ 124-41-4 ]
[ 41051-15-4 ]

Reference： [1] Patent: US2015/133475, 2015, A1, . Location in patent: Paragraph 0107; 0108

8
[ 38330-80-2 ]
[ 31059-08-2 ]
[ 41051-15-4 ]

Reference： [1] Organic and Biomolecular Chemistry, 2009, vol. 7, # 23, p. 4960 - 4964

9
[ 6290-49-9 ]
[ 96-32-2 ]
[ 41051-15-4 ]

Reference： [1] Journal of the American Chemical Society, 1954, vol. 76, p. 5389

10
[ 17790-81-7 ]
[ 124-41-4 ]
[ 41051-15-4 ]

Reference： [1] Tetrahedron, 1986, vol. 42, # 14, p. 3767 - 3774

11
[ 105-45-3 ]
[ 41051-15-4 ]

Reference： [1] Patent: US2015/133475, 2015, A1,

12
[ 67-56-1 ]
[ 41051-15-4 ]

Reference： [1] Synthesis, 1999, # 11, p. 1951 - 1960

13
[ 64-17-5 ]
[ 41051-15-4 ]
[ 66762-68-3 ]

Reference： [1] New Journal of Chemistry, 2016, vol. 40, # 10, p. 8786 - 8808

14
[ 41051-15-4 ]
[ 1335210-23-5 ]

Reference： [1] Patent: WO2011/119566, 2011, A1,
[2] Patent: WO2016/125192, 2016, A2,

15
[ 41051-15-4 ]
[ 1335210-24-6 ]

Reference： [1] Patent: WO2011/119566, 2011, A1,

[ 41051-15-4 ] Synthesis Path-Downstream 1~72

1
[ 41051-15-4 ]
[ 105940-00-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With 4-toluenesulfonyl azide; diethylamine; In diethyl ether; at 0 - 20℃; for 0.75h;	Step A: Methyl 2-diazo-4-methoxy-3-oxobutanoate Methyl 4-methoxy-3-oxobutanoate (4.28 g, 0.029 mol) was dissolved in ether (20 mL). The solution was cooled in an ice bath. To the solution was added p-toluenesulfonyl azide (5.78 g, 0.029 mol) followed by N-ethylethanamine (2.0 mL, 0.019 mol). The solution was stirred at 0° C. for 15 minutes, then at rt for 30 minutes. Upon evaporation, the tosyl amide bi-product solidified. This was filtered off and the filtrate was purified by flash chromatography to give the desired product (4.5 g, 89percent) as a light oil. 1H NMR (400 MHz, CDCl3): delta 4.55 (s, 2H), 3.83 (s, 3H), 3.45 (s, 3H). MF=C6H8N2O4. LCMS calculated for C6H9N2O4 (M+H)+: m/z=173.0.
		PREPARATION EXAMPLE 4 STR56 Methyl 2-diazo-4-methoxy-3-oxobutanoate As described for preparation Example 1, 3.05 g (89percent) of the title compound were obtained as a pale yellow oil, Rf: 0.35 (toluene:ethyl acetate 3:1), from 2.92 g (20 mmol) of methyl 4-methoxyacetoacetate and chromatography of the crude product on 900 g of silica gel (toluene:ethyl acetate 3:1). IR (CHCl3) 2138 (N2), 1711 (C=O), 1665 cm-1 (C=O). 1 H-NMR (250 MHz, CDCl3) delta 3.48 (s, 3H, COOCH3), 3.86 (s, 3H, OCH3), 4.53 (s, 2H, CH2).
607 mg	With 4-toluenesulfonyl azide; triethylamine; In toluene; at 0 - 20℃; for 24h;Inert atmosphere;	<strong>[41051-15-4]Methyl 4-methoxyacetoacetate</strong> (0.709 ml, 5.31 mmol) is dissolved in dry toluene (10 ml) before triethylamine (0.795 ml, 5.71 mmol) is added. Under argon atmosphere, a solution of p-toluenesulfonyl azide 1 1 -15percent in toluene (7.5 ml) is added to the mixture dropwise at 0°C. The mixture is stirred at RT for 24 h. Heptane/Ch C 9:1 is added to the mixture to precipitate the salts. It is then filtered and washed with heptane. The filtrate is concentrated under reduced pressure. The crude is purified by FC (siliga gel, Hept / EtOAc) to get 607 mg of methyl 2-diazo-4-methoxy-3-oxobutanoate as a colorless oil. LC-MS (acidic): tR = 0.51 , [M+H]+ = 172.95. 1 H NMR (400 MHz, CDC ) <5: 4.55 (s, 2 H), 3.86 (s, 3 H), 3.49 (s, 3 H).

Reference： [1]Molecules,2020,vol. 25
[2]Patent: US2007/185165,2007,A1 .Location in patent: Page/Page column 57
[3]Chemical Communications,2015,vol. 51,p. 15328 - 15331
[4]Chemical Communications,2016,vol. 52,p. 5856 - 5859
[5]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 477 - 480
[6]Patent: US4841042,1989,A
[7]Organic Letters,2017,vol. 19,p. 2777 - 2780
[8]Organic and Biomolecular Chemistry,2017,vol. 15,p. 8054 - 8058
[9]Patent: WO2019/34725,2019,A1 .Location in patent: Page/Page column 100

2
[ 41051-15-4 ]
[ 4637-24-5 ]
[ 127958-23-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 20℃; for 24h;	Step 3. The synthesis of methyl 2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate B.3 (R4 = methoxymethyl) was accomplished by first mixing methyl 4- methoxy-3-oxobutanoate B.I (R4 = methoxymethyl, 1 mL, 8.69 mmol) and dimethoxy- N,N-dimethylmethanamine B.2 (2.32 mL, 17.4 mmol) at room temperature for 24 hours followed by removing excess unreacted dimethoxy-N,N-dimethylmethanamine under vacuum to give B.3 (R4 = methoxymethyl, 1.55 g, 100%).
97%	In N,N-dimethyl-formamide; at 120℃; for 0.5h;Inert atmosphere; microwave irradiation;	A solution of methyl 4-methoxy-3-oxobutanoate (8.21 mmol, 1.20 g) and of 1 , 1 -dimemoxy-NN-dimethylmethanamine (8.21 mmole, 1.09 mL) in DMF (12 mL) was heated in the microwave for 30 min at 120C. After evaporation of the solvent, 1.61 g (7.98 mmol, 97%) of methyl 2- ((dimethylamino)methylene)-4-methoxy-3-oxobutanoate as a brown oil was obtained and used without further purification.UPLC-MS: RT = 0.44 min; MS m/z ES+= 202.
50%	at 20 - 90℃; for 20h;	Methyl-4-methoxyacetoacetate 3 (9 ml, 70 mmol) was added to dimethylformamide dimethylacetal (18.8 ml, 139 mmol) and the reaction stirred at 90 C. for 2 hours before cooling to room temperature and stirring for 18 hours. The reaction was concentrated in vacuo and purified by silica gel column chromatography, eluting with 70:30 to 100:0 ethyl acetate:heptane to afford the title compound 5 as an oil (7.68 g, 50% yield).

50%	at 20 - 90℃; for 20h;	Preparation 13Methyl 2-f(dimethylamino)methylene1-4-methoxy-3-oxobutanoateMethyl-4-methoxyacetoacetate (9 ml, 70 mmol) was added to dimethylformamide dimethylacetal (18.8 ml, 139 mmol) and the reaction stirred at 9O0C for 2 hours before cooling to room temperature and stirring for 18 hours. The reaction was concentrated <n="62"/>in vacuo and purified by silica gel column chromatography, eluting with 70:30 to 100:0 ethyl acetate: heptane to afford the title compound as an oil (7.68 g, 50% yield).1HNMR (CDCI3): 2.87 (br s, 3H), 3.25 (br s, 3H), 3.39 (s, 3H), 3.72 (s, 3H), 4.37 (s, 2H), 7.74 (s, 1H)
	In toluene; for 2.16667h;Reflux;	To a solution of Compound II-24(4-methoxy-3-oxobutanoic acid methyl ester, 9.87g) in toluene(99ml) was added dropwise 1,1-dimethoxy-N,N-dimethylmethanamine(26.9ml) over 10min, then the reaction mixture was refluxed for 2hrs. After termination of the reaction, the mixture was concentrated. The obtained product was used for the next reaction. According to the above procedure, the obtained residue was dissolved in acetonitrile soln.(136ml), and 80% hydrazine ethanol(6.58g) was added to the resulting solution. The reaction mixture was stirred at 50 C for one hour. After termination of the reaction, the mixture was concentrated. 1N aqueous HCl was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 and brine successively, and dried over magnesium sulfate and concentrated. The residue was purified by silicagel columnchromatography to give Compound II-26(9.74g).
	at 20℃; for 1.5h;	A. l-[2,2-Bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyIoxy)carbonyl]-4-oxo-l,4-dihydro- 3-pyridinecarboxylic acidA mixture of methyl 4-methoxyacetoacetate (20 mL) and DMFDMA (24 mL) was stirred at room temperature for 1.5 h. The reaction mixture was diluted with MeOH (50 mL) and aminoacetaldehyde dimethyl acetal (16.7 mL) was added. The mixture was stirred for 1 h at room temperature, concentrated, and then diluted with MeOH (113 mL). Dimethyl oxalate (45.66 g) was charged followed by portion-wise addition of LiH (2.15 g) while maintaining the reaction temperature below 25 C. The reaction content was heated to 40 C for 14 h. The reaction mixture was cooled to -5 C and LiOH (14.82 g) was added while maintaining the reaction temperature below 5 C. When addition was complete, the mixture was stirred for a further 2 h at 3-5 C for 1 h. The reaction mixture was quenched with aqueous HC1 (2 N, 367 mL), maintaining the reaction temperature below 5 C. When addition was complete, EtOAc (450 mL) was added and the mixture was warmed to 20 C. The reaction mixture was filtered and the aqueous layer discarded. Water (225 mL) was added and the organic layer was removed under reduced pressure. The product was collected by filtration and dried in a vacuum oven overnight at 50 C. The product was obtained as a solid.
	In toluene; at 20℃; for 11h;	Example 5 First StepCompound 5A (598 mg, 4.09 mmol) and N,N-dimethylformamide dimethyl acetal (488 mg, 4.09 mmol) were dissolved in toluene (1 ml), and the mixture was stirred at room temperature for 11 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue (containing Compound 5B) was used in Second step without purification.
	In toluene; at 20℃; for 11h;	Compound 5A (598 mg, 4.09 mmol) and N,N-dimethylformamide dimethyl acetal (488 mg, 4.09 mmol) were dissolved in toluene (1 ml), and the solution was stirred at room temperature for 11 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the obtained residue (containing compound 5B) was used in Step 2 without being purified.
	at 20 - 27℃; for 8h;	Methyl-4-methoxyacetoacetate (100 gm) was charged followed by slow addition of 1,1-dimethoxy dimethylethanamine (DMF-DMA) (98 gm) at a temperature of 20C. The reaction content was warmed to 27C and maintained the reaction mass for 8 hours at the same temperature. The reaction mixture was diluted with methanol (200 mL) and aminoacetaldehyde dimethyl acetal (78.8 gm) was added. The mixture was stirred for 2 hours at a temperature of 20C, distilled of the solvent and extracted with methylene dichloride. Lithium hexamethyldisilazane (LiHDMS) in THF (tetrahydrofuran) solution (1685 mL) was added slowly followed by gradual addition of dimethyloxalate (202 gm) while maintained the reaction temperature below 4C. The reaction content was heated to a temperature of 45C, stirred for 26 hours and then cooled to a temperature of 27C. The pH of the reaction mixture was adjusted to 3-4 with 2N HC1 solution (615 mL) and the product was extracted with ethyl acetate (1500 mL). The obtained crude product was purified by flash chromatography to get a purified compound of Formula 18 (65 gm).
	at 25 - 35℃;	N,N-Dimethyl-l, l-bis(methyloxy)methanamine (196 g) was added to methyl-4-methoxy acetoacetate (formula 8a, 200 g) at 0-5 C. The temperature of the reaction mass was raised to 25-35 C and stirred at the same temperature until complete consumption of starting material. The reaction mass was then diluted with methanol and cooled to 15-20 C. Allylamine (86 g) was added and stirring was continued at 25-35 C until completion of reaction, as monitored by TLC. (NMR data of compound 6a: 1H NMR (CDC13): delta 3.61 (s, 3H), 4.40 (s, 2H), 3.29 (s, 3H), 8.02 (d, 1H, J=14.1Hz), 4.05 (t, 2H, J=5.7Hz), 5.87-6.00 (m, 1H), 5.16-5.22 (m, 2H), 10.80- 10.84 (broad, 1H)) Thereafter, the solution was concentrated under reduced pressure and then diluted with methanol (700 mL). Dimethyl oxalate (404 g) was then added and the solution was warmed to 40-45 C. Next, a sodium methoxide solution (530 g of sodium methoxide dissolved in 1.4 L of methanol) was added and the solution was stirred until complete consumption of the starting material, as monitored by TLC. The reaction mass was poured into a mixture of water (3.5 L) and methylene dichloride (2.4 L). The pH adjusted to 4-5 using acetic acid and the solution was filtered. The organic layer was separated and concentrated to yield a crude residue of dimethyl l-allyl-3-methoxy-4-oxo-l,4-dihydropyridine-2,5-dicarboxylate (NMR data of compound 5b: 1H NMR (CDC13): delta 8.39 (s, 1H), 4.63 (d, 2H, J=5.7Hz), 5.86-5.99 (m, 1H), 5.15-5.21 (dd, 1H, J=17.1Hz, 1.2Hz), 5.26-5.30 (dd, 1H, J=10.2Hz, 0.9Hz), 3.77 (s, 3H), 3.74 (s, 3H), 3.88 (s, 3H)) Boric acid (85 g) was added in portions to acetic anhydride (560 g) and heated to 70 C. The boroacetate solution was heated further to 90 C and maintained at that temperature for an hour. The crude residue of dimethyl l-allyl-3-methoxy-4-oxo-l,4- dihydropyridine-2,5-dicarboxylate (formula 5b) diluted in acetic acid (440 mL) was then added to the boroacetate solution at 70-75 C and stirring was maintained until complete conversion of starting material. The reaction mass was cooled to 2-5 C, water was added, and the solution was filtered to yield formula 5c (NMR data of compound of formula 5c: 1H NMR (CDCI3): delta 9.22 (s, 1H), 5.10 (d, 2H, J=6.3Hz), 6.00-6.13 (m, 1H), 5.33-5.43 (m, 2H), 3.84 (s, 3H), 4.00 (s, 3H), 1.92 (s, 6H)). Formula 5c was then hydrolyzed with methanolic HC1 (150 mL) at 25-35 C to give l-allyl-5-methoxy-6-(methoxycarbonyl)-4-oxo-l,4-dihydropyridine-3-carboxylic acid as white solid (formula 4a, 239 g, 1H NMR (DMSO-d6): delta 8.75 (s, 1H), 4.83 (d, 2H, J=5.7Hz), 5.89-6.02 (m, 1H), 5.22-5.28 (dd, 1H, J=17.1, 0.9Hz), 5.30-5.34 (dd, 1H, J=10.2, 0.9Hz), 3.89 (s, 3H), 3.93 (s, 3H), 15.28 (s, 1H)).
	at 20℃; for 1.5h;	<strong>[41051-15-4]Methyl 4-methoxyacetoacetate</strong> (8 ml, 61.8 mmol),9.6 ml of N,N-dimethylformamide dimethyl acetal (DMF-DMA, 72.26 mmol) was stirred in a 150 ml round bottom flask for 1.5 h at room temperature.The solution gradually turns from yellow to brownish yellow, and the reaction gives compound 1(Rf = 0.14, TLC developing solvent: AcOEt/petroleum ether = 5/1).The reaction solution was diluted with 20 ml of methanol, and 6.68 ml (61.31 mmol) of aminoacetaldehyde dimethylacetal was added, and the mixture was stirred at room temperature for 1 h.The solution turns into wine red and the reaction gives compound 2(Rf = 0.56, TLC developing agent: AcOEt).The reaction solution was concentrated under reduced pressure to give a red brown oil,45.2 ml of methanol and dimethyl oxalate (18.34 g, 155.34 mmol) were added.After the dimethyl oxalate was completely dissolved, LiH (0.86 g, 108.67 mmol) was added in portions under the control of ice water bath at 25 C.The solution is a brown-red suspension. After the addition is completed, the reaction solution is placed at a bath temperature of 40 C for 14 hours.The solution changes from a suspension to a brick red solution, and the reaction gives compound 3(Rf = 0.23, TLC developing solvent: AcOEt).The reaction solution was cooled to 3-5 C and anhydrous LiOH (5.94 g, 123.8 mmol) was added to continue the reaction for 2 h.The reaction mixture was changed from brick red to orange yellow suspension, and the reaction gave Compound 3 (Rf=0.12, TLC developing solvent: AcOEt).The reaction was quenched by the addition of 2N HCl (146.8 mL).180 ml of ethyl acetate was added to the obtained reaction solution, and the solid was discarded by filtration.The liquid phase was collected and liquid-separated, 90 ml of water was added to the organic phase, and the organic solvent was evaporated under reduced pressure to give a large white solid.Filter by suction and wash the filter cake with a small amount of water.Obtained after vacuum drying at 50 C6.93g of compound 4(Rf = 0.44, TLC developing solvent: CH2Cl2 / MeOH = 40/1 + 0.5% HOAc),It was a colorless solid with a total yield of 36%.

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 790 - 794
[2]Patent: WO2008/45484,2008,A1 .Location in patent: Page/Page column 34
[3]Patent: WO2012/9009,2012,A2 .Location in patent: Page/Page column 40; 41
[4]Il Farmaco,1990,vol. 45,p. 167 - 186
[5]Patent: US2015/133475,2015,A1 .Location in patent: Paragraph 0109; 0110
[6]Patent: WO2008/135830,2008,A1 .Location in patent: Page/Page column 60-61
[7]Patent: EP2163543,2010,A1 .Location in patent: Page/Page column 90
[8]Patent: WO2011/119566,2011,A1 .Location in patent: Page/Page column 8
[9]Patent: US2012/22251,2012,A1 .Location in patent: Page/Page column 29
[10]Patent: EP2602260,2013,A1 .Location in patent: Paragraph 0150
[11]Patent: WO2015/19310,2015,A1 .Location in patent: Page/Page column 13
[12]Patent: WO2016/125192,2016,A2 .Location in patent: Page/Page column 25-26
[13]Angewandte Chemie - International Edition,2018,vol. 57,p. 7181 - 7185
Angew. Chem.,2018,vol. 130,p. 7299 - 7303,5
[14]Patent: CN109293675,2019,A .Location in patent: Paragraph 0004; 0031-0032
[15]Journal of Heterocyclic Chemistry,2019

3
[ 41051-15-4 ]
[ 166539-00-0 ]

Yield	Reaction Conditions	Operation in experiment
> 99.5%Chromat.	With hydrogen; In isopropyl alcohol; at 50℃; under 30003.0 Torr; for 10h;Autoclave; Glovebox;	General procedure: As a typical run for asymmetric hydrogenation of beta-keto esters, 0.026 g Ru/5-BINAPPOPs-1 catalyst, 0.20 g methyl acetoacetate, and 2 mL of isopropanol (ipro) were added to a 30-mL autoclave in a glove box. After the reactor was purged with H2 four times, its pressure was finally adjusted to the desired value, heated from room temperature to the reaction temperature of 50 °C, and stirred for 10 h. The catalyst was separated by centrifugation, and the product was analysed using gas chromatography (GC; Agilent 7890B gas chromatograph equipped with a flame ionization detector and a Cyclosil-B capillary column).

Reference： [1]Chemistry - A European Journal,2006,vol. 12,p. 7364 - 7377
[2]Tetrahedron Letters,2000,vol. 41,p. 621 - 624
[3]Journal of the American Chemical Society,1995,vol. 117,p. 4423 - 4424
[4]Cuihua Xuebao/Chinese Journal of Catalysis,2017,vol. 38,p. 890 - 897

4
[ 41051-15-4 ]
[ 34036-07-2 ]
[ 57-13-6 ]
[ 192574-28-0 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4778 - 4793
[2]Journal of Medicinal Chemistry,2000,vol. 43,p. 2703 - 2718
[3]Canadian Journal of Chemistry,2002,vol. 80,p. 646 - 652
[4]Molecules,2013,vol. 18,p. 12119 - 12143

5
[ 75-77-4 ]
[ 41051-15-4 ]
[ 290305-57-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With triethylamine; In benzene; at 20℃; for 24h;	Example 54 (Synthesis of 2-(4-hydroxy-3-methoxy-5-oxofuran-2(5H)-ylidene) acetate (Compound 3-55)) <strong>[41051-15-4]Methyl 4-methoxyacetoacetate</strong> (25 g, 171.1 mmol) was dissolved in benzene (350 mL), and triethylamine (22.61 g, 223.4 mmol) and trimethylsilyl chloride (25 g, 230.1 mmol) were then added sequantially to the solution. Following stirring for a full day at room temperature, the reaction mixture was filtered with celite and washed with hexane. The filtrate was concentrated using an evaporator, and by subsequently distilling the residue under reduced pressure, methyl 4-methoxy-3-(trimethylsilyloxy)but-2-enoate (77 to 78°C at 5 mmHg) was obtained in an amount of 28.14 g, a yield of 71percent.

Reference： [1]Journal of Organic Chemistry,2001,vol. 66,p. 2222 - 2226
[2]Patent: EP2902387,2015,A1 .Location in patent: Paragraph 0218-0219

6
[ 5272-86-6 ]
[ 41051-15-4 ]
2-[(3,5-dimethyl-1<i>H</i>-pyrazol-4-yl)-hydrazono]-4-methoxy-3-oxo-butyric acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	Stage #1: 4-amino-3,5-dimethyl-1H-pyrazole With hydrogenchloride; sodium nitrite at 0 - 5℃; Stage #2: 4-methoxyacetoacetic acid methylester With sodium acetate

Reference： [1]Kocyigit, Kaymakcioglu B; Rollas [Il Farmaco, 2002, vol. 57, # 7, p. 595 - 599]

7
[ 28466-21-9 ]
[ 41051-15-4 ]
methyl 2-[(1,3,5-trimethylpyrazole-4-yl)hydrazono]-4-methoxy-3-oxobutyrate [ No CAS ]

Reference： [1]Il Farmaco,2002,vol. 57,p. 595 - 599

8
[ 41051-15-4 ]
[ 1903-91-9 ]
[ 3122-77-8 ]

Reference： [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 1967 - 1971

9
[ 41051-15-4 ]
[ 103899-66-7 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium acetate; In cyclohexane; at 90℃; for 4h;Molecular sieve;	A mixture containing 30 g of presublimed ammonium acetate, 165 ml of cyclohexane and 15 ml of methyl 4-methoxy-3-oxobutanoate and 4 molecular sieves is placed under nitrogen. The mixture is stirred for 4 hours at 90 C. and then evaporated to dryness. The residue is washed and extracted with DCM and the organic phase is then filtered and evaporated. The product obtained is used without further purification in the following step.

Reference： [1]Patent: US2008/21070,2008,A1 .Location in patent: Page/Page column 10

10
[ 41051-15-4 ]
[ 89-98-5 ]
[ 897627-76-8 ]

Yield	Reaction Conditions	Operation in experiment
3%	With ammonia; In ethanol; water; at 20 - 95℃; for 4h;	<strong>[41051-15-4]Methyl 4-methoxyacetoacetate</strong> (1.33 mL, 97percent, 10.0 mmol) and 2- chlorobenzaldehyde (562 muL, 99percent, 5.00 mmol) were taken up in EtOH (1 mL) at rt. NH4OH (500 muL) was added, the mixture was stirred at rt Ih, 80 0C Ih, then the mixture was heated to 95 0C. After 2h, the reaction mixture was cooled to ambient temperature, dried over Na2SO4, filtered and crystallized from EtOAc/hexane (1 :9) to afford 54 mg (3percent) of dimethyl 4-(2- chlorophenyl)-l,4-dihydro-2,6-bis(methoxymethyl)pyridine-3,5-dicarboxylate as a white solid: MP 137-138 0C; 1H NMR (500 MHz, CDCl3) delta 3.48 (s, 6H), 3.61 (s, 6H), 4.64 (d, J = 16.0 Hz, 2H), 4.73 (d, J = 16.2 Hz, 2H), 5.10-5.13 (m, 2H) 5.45 (s, IH), 7.03-7.07 (m, IH), 7.12-7.17 (m, IH), 7.23-7.26 (m, IH), 7.37-7.40 (m, IH), 8.36 (brs, IH); 13C NMR (125 MHz, CDCl3) delta 36.8, 50.7, 69.0, 69.7, 101.5, 127.0, 127.4, 129.2, 131.3, 132.2, 145.3, 145.7, 167.4; MS (ES) m/z 813 (2M+Na)+, 418 (M+Na)+, 396 (M+H)+, 364, 332, 284; m/z 396.098 (calcd for Ci9H23ClNO6 (M+H)+: 396.121).

Reference： [1]Patent: WO2008/6070,2008,A2 .Location in patent: Page/Page column 126

11
[ 41051-15-4 ]
[ 1122-91-4 ]
[ 897627-90-6 ]

Yield	Reaction Conditions	Operation in experiment
53%	With ammonia; In ethanol; water; at 20 - 95℃; for 26h;	<strong>[41051-15-4]Methyl 4-methoxyacetoacetate</strong> (4.14 mL, 97percent, 30.0 mmol) and A- bromobenzaldehyde (1.87 g, 99percent, 10.0 mmol) were taken up in EtOH (5 mL) at rt. NH4OH (1.5 mL) was added, the mixture was stirred at rt 30 min, 50 0C 1.5h, then the mixture was heated to 95 0C. After 24h, the reaction mixture was cooled to ambient temperature, diluted with CH2Cl2 (20 mL) and dried over Na2SO4. Crystallization from EtOAc/hexane (1 :9) to afford 2.32 g (53percent) of dimethyl 4-(4-bromophenyl)-l,4-dihydro-2,6- bis(methoxymethyl)pyridine-3,5-dicarboxylate as a white solid: MP 162-163 0C; 1H NMR (500 MHz, CDCl3) delta 3.49 (s, 6H), 3.65 (s, 6H), 4.64 (d, J = 16.1 Hz, 2H), 4.73 (d, J = 16.1 Hz, 2H), 4.97 (s, IH), 7.13-7.17 (m, 2H), 7.33-7.37 (m, 2H), 8.40 (brs, IH); 13C NMR (125 MHz, CDCl3) delta 38.9, 51.0, 59.1, 69.8, 101.1, 120.1, 129.5, 131.1, 145.4, 146.3, 167.3.

Reference： [1]Patent: WO2008/6070,2008,A2 .Location in patent: Page/Page column 148-149

12
[ 41051-15-4 ]
[ 325685-59-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NaOMe / methanol; ethanol / 21 h / Heating 2: 29.0 g / POCl₃ / 3 h / Heating

Reference： [1]Gardinier, Kevin M.; Khoury, Richard G.; Lehn, Jean-Marie [Chemistry - A European Journal, 2000, vol. 6, # 22, p. 4124 - 4131]

13
[ 41051-15-4 ]
[ 130187-94-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 81 percent / 1 h / Heating 2: 82 percent / acetic acid / ethanol / 2 h / Heating 3: 1) KOH, 2) HCl / 1) 95percent EtOH, reflux, 5 h

Reference： [1]Menozzi; Mosti; Schenone; Donnoli; Schiariti; M armo [Il Farmaco, 1990, vol. 45, # 2, p. 167 - 186]

14
[ 41051-15-4 ]
[ 856972-65-1 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 3072,3075

15
[ 41051-15-4 ]
[ 6313-33-3 ]
[ 3122-78-9 ]

Yield	Reaction Conditions	Operation in experiment
		[0530] To the mixture of methyl 4-methoxyacetoacetate (14.6 g, 0.1 mol.) and formami-dine hydrogen chloride salt (16.1 g, 0.2 mol.) in 70 mL of dry MeOH was added a 25percent solution of sodium methoxide (70 mL, 0.3 mol.) in MeOH portionwise. A white precipitate was formed immediately. The reaction mixture was stirred at room temperature for 1.0 hr. Acetic acid (28.6 mL, 0.5 mol.) was added and the reaction mixture was concentrated in vacuo. Water was added to the residue and the mixture was supersaturated with NaCl and extracted with EtOAc (.x.5). Combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give 8.13 g of compound 501A as a yellow solid.

Reference： [1]Patent: US2004/54186,2004,A1 .Location in patent: Page 127-128

16
[ 848047-49-4 ]
[ 41051-15-4 ]
[ 832692-60-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 20℃;	3. 4-Hydroxy-2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]napthyridine-3-carboxylic acid methyl ester Add a solution of 6-amino-3'-trifluoromethyl-[2,2']bipyridinyl-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (10.4 g, 27.3 mmol) in 50 mL dry THF to a mixture of potassium tert-butoxide (7.36 g, 65.6 mmol) and methyl 4-methoxy-aceoacetate (8.77 g, 60.7 mmol) in dry THF (100 mL). Stir the reaction overnight at room temperature. Add water (30 mL) and concentrate. Extract the mixture with ether (250 mL). Acidify the aqueous layer with concentrated hydrochloric acid and extract with CH2Cl2 (4100 mL). Dry the combined organic extracts over Na2SO4 and remove the solvent under reduced pressure to yield the title compound as a light brown oil that solidifies upon standing.
	With potassium tert-butylate; In tetrahydrofuran; at 20℃;	3. 4-HYDROXY-2-METHOXYMETHYL-7-(3-TRIXUOROMETHYL-PYRIDIN-2-YL)- [1, 8] NAPHTHYRIDINE-3-CARBOXYLIC ACID METHYL ESTER; Add a solution of 6-AMINO-3 -TRIFLUOROMETHYL- [2, 2 ] bipyridinyl-5-carboxylic acid 2,5- DIOXO-PYRROLIDIN-1-YL ester (10.4 g, 27. 3 mmol) in 50 mL dry THF in one portion to a mixture of potassium t-butoxide (7.36g, 65.6 mmol) and methyl 4-methoxy-aceoacetate (8.77 g, 60.7 mmol) in dry THF (100 mL). Stir the reaction overnight at room temperature. Add water (30 mL) and concentrate the solution (-30 mL). Extract the resulting mixture with ether (2 x 50 mL). Acidify the aqueous portion with concentrated hydrochloric acid and extract with CH2C12 (4 x 100 mL). Dry the combined organic extracts over NA2S04 and remove the solvent under reduced pressure to yield the title compound as a light brown oil that solidifies upon standing.
	With potassium tert-butylate; In tetrahydrofuran; at 20℃;	A SOLUTION OF 6-AMINO-3 -TRIFLUOROMETHYL- [2, 2 ] BIPYRIDINYL-5-CARBOXYLIC ACID 2, 5- DIOXO-PYRROLIDIN-1-YL ester (10.4 g, 27.3 mmol) in 50 mL dry THF is added in one portion to a mixture of potassium t-butoxid (7. 36G, 65.6 mmol) and methyl 4-methoxy-acetoacetate (8.77 g, 60.7 mmol) in dry THF (100 mL). The reaction is stirred overnight at room temperature. Water (30 mL) is added and the solution concentrated (-30 mL). The resulting mixture is extracted with ether (2 x 50 mL). The aqueous portion is acidified with concentrated hydrochloric acid and extracted with CHOC12 (4 x 100 mL). The combined organic extracts are dried over NA2S04 and the solvent removed under reduced pressure to yield the title compound as a light brown oil that solidifies upon standing.

Reference： [1]Patent: US2007/203133,2007,A1 .Location in patent: Page/Page column 22
[2]Patent: WO2005/23807,2005,A2 .Location in patent: Page/Page column 68
[3]Patent: WO2005/7652,2005,A2 .Location in patent: Page/Page column 36; 60

17
[ 41051-15-4 ]
[ 372-09-8 ]
C₈H₁₁NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium acetate; acetic acid; In toluene; at 20℃; for 5h;	The appropriate ss-keto ester (200 mmol), cyanoacetic acid (18g, 212 mmol), ammonium acetate (3.87g) and acetic acid (6g) were stirred at room temperature for 5 hours in toluene (100ml). The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. After drying over magnesium sulphate and concentration under reduced pressure, the remaining oil was dissolved in ethanol (100ml). Sulphur (4g) was added, followed by the dropwise addition of diethylamine (13ml) to give a red solution, which was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. After drying over magnesium sulphate and concentration under reduced pressure, the remaining oil was purified by flash chromatography, using ethyl acetate: hexane (2: 1, by volume) as eluant, to yield the desired aminothiophene. The aminothiophene DO was obtained using the general procedure as yellowish crystals (11. 9g, 40 percent). m. p. 131-132°C ; 1H NMR 8H (300MHz, CDC13) : 6.8 (1H, s), 4.7 (2H, s), 4.3 (2H, s), 3.8 (3H, s) and 3.45 (3H, s) ppm ; m/z (-ve ion): 200 (M-H) 100percent.

Reference： [1]Patent: WO2005/44008,2005,A2 .Location in patent: Page/Page column 90-91

18
[ 79779-64-9 ]
[ 41051-15-4 ]
5-(2-chloro-5-trifluoromethyl-phenyl)-2-methoxymethyl-1-[(R)-1-(tetrahydro-furan-2-yl)methyl]-1H-pyrrole-3-carboxylic acid cyclohexylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		61 5-(2-Chloro-5-trifluoromethyl-phenyl)-2-methoxymethyl-1-[(R)-1-(tetrahydro-furan-2-yl)methyl]-1H-pyrrole-3-carboxylic acid cyclohexylamide The title compound was synthesised in analogy to example 7, using 4-methoxy-3-oxo-butanoic acid methyl ester as compound of formula R, 2-bromo-1-[2-chloro-5-(trifluoromethyl)phenyl]-ethanone as compound of formula S, (R)-tetrahydro-furfurylamine as R3-(CH2)m-NH2 and cyclohexylamine as R1R2NH, MS (ISP) 499.4 (M+H)+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2005/250769, 2005, A1 Location in patent: Page/Page column 21

19
[ 41051-15-4 ]
[ 3473-63-0 ]
[ 3122-78-9 ]

Yield	Reaction Conditions	Operation in experiment
37.1%		Step A: 6-(Methoxymethyl)pyrimidin-4-ol To a solution of methyl 4-methoxy-3-oxobutanoate (3.54 mL, 26.5 mmol) in methanol (30 ml) was added formamidine acetate (3.07 g, 29.2 mmol) and sodium methoxide (13 mL, 58.4 mmol). The mixture was then heated to reflux for 18 hours and cooled to ambient temperature, then concentrated. The residue was taken up in water and the pH adjusted to 7 with 1N HCl. The aqueous mixture was extracted with chloroform. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford 6-(methoxymethyl)pyrimidin-4-ol (1.38 g, 9.85 mmol, 37.1percent yield). MS (LC/MS) R.T.=0.19; [M+H]+=141.20.
37.1%		Step A: 6-(methoxymethyl)pyrimidin-4-olTo a solution of methyl 4-methoxy-3-oxobutanoate (3.54 mL, 26.5 mmol) in methanol (30 ml) was added formamidine acetate (3.07 g, 29.2 mmol) and sodium methoxide (13 mL, 58.4 mmol). The mixture was then heated to reflux for 18 hours and cooled to ambient temperature, then concentrated. The residue was taken up in water and the pH adjusted to 7 with IN HC1. The aqueous mixture was extracted with chloroform. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford 6-(methoxymethyl)pyrimidin-4-ol (1.38 g, 9.85 mmol, 37.1 percent yield). MS (LC/MS) R.T. = 0.19; [M+H]+ = 141.20.
	With sodium methylate; In methanol; water;	6-(Methoxymethyl)pyrimidin-4-ol (24-2) To a solution of methyl 4-methoxyacetoacetate (2.0 g, 13.69 mmole) in MeOH (15 mL) was added formamidine acetate (1.57 g, 15.05 mmole) and NaOMe (6.5 mL of a 25percent by weight solution in MeOH, 30.11 mmole) then the mixture was heated to reflux. After 18 hours, the mixture was cooled to room temperature and concentrated to dryness. The residue was taken up in H2O and the pH adjusted to 7. The aqueous mixture was extracted with CHCl3 (3*). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound which was sufficiently pure for use in the next step without purification. 1H-NMR (500 MHz, CDCl3) delta8.17 (s, 1 H), 6.60 (s, 1 H), 4.38 (s, 2 H), 3.50 (s, 3 H).

With sodium; In methanol;

(a) A solution of 86 g of sodium in 1.5 1 of methanol was added to a solution of 250 g of methyl 4-methoxyacetoacetate and 200 g of formamidine acetate in 1.5 1 of methanol. The reaction solution was heated at 60° C. for 48 hours, then concentrated in vacuo and poured into ice-water. Neutralization with hydrochloric acid was followed by extraction with dichloromethane, drying over sodium sulfate and concentration in vacuo. Purification on a silica gel column resulted in 100 g of 6-hydroxy-4-methoxymethylpyrimidine (melting point 160° C.).

Reference： [1]Patent: US2009/270405,2009,A1 .Location in patent: Page/Page column 126
[2]Patent: WO2011/53292,2011,A1 .Location in patent: Page/Page column 220
[3]Patent: US2002/137755,2002,A1
[4]Patent: US4956366,1990,A

20
[ 32807-28-6 ]
[ 41051-15-4 ]

Yield	Reaction Conditions	Operation in experiment
91.7%	With hydrogenchloride; sodium methylate; In water; acetonitrile;	EXAMPLE 1 77.4 g of sodium methylate, 97 percent, was suspended in 100 g of acetonitrile at ambient temperature. To this well-stirred suspension, 101.9 g of 97.5 percent 4-chloroacetoacetic acid methyl ester was added by drops through a drip funnel with a drop counter over a 5 to 6 minute period under N2 atmosphere. The temperature rose and was kept by means of cooling at 68° to 70° C. As soon as the heat development slackened, the cooling water was turned off and the reaction mass was heated with 70° C. hot water. This pastelike, mustard-yellow reaction mixture continued to be stirred at 70° C. for 24 to 25 minutes and, with stirring, was then slowly introduced into a solution of 6 g of glacial acetic acid and 215 g of water cooled in an ice bath. At the same time, 37.4 percent hydrochloric acid was introduced drop by drop from a burette. At the same time, the pH was measured by means of a glass electrode and kept between 4.5 and 8 by adjusting the addition rate of the reaction mixture and/or HCl. At the end of the neutralization, the pH was 6.1+-0.1. For the neutralization, 56.4 ml of hydrochloric acid were used (37.4 percent) and the temperature was kept at 30° to 35° C. The neutralized mixture was put into a separating funnel. After standing a short time, the resultant layers were separated. The aqueous layer was extracted once with 200 ml and then twice each time with 100 ml of acetonitrile. The united organic phases were concentrated in a rotary evaporator at 30° to 35° C. and 20 torr up to a constant weight. The solvent evaporated off was regenerated and used with the next batch. The raw product was distilled at 0.5 to 1.5 torr/90° C. 4-methoxyacetoacetic acid methyl ester was obtained in a yield of 91.7 percent, based on the amount of chloroester used. The purity of the product was 98.8 percent.
107.7 g (74%)	With hydrogenchloride; In tetrahydrofuran; methanol; nitrogen; toluene;	REFERENCE EXAMPLE 1 Synthesis of Methyl (R)-4-Methoxy-3-Hydroxybutyrate: In a 2 liter four-necked flask were charged 88.0 g (2.2 mol) of 60percent sodium hydride and 753 ml of tetrahydrofuran in a nitrogen stream, and a mixture of 150.6 g (1.0 mmol) of methyl 4-chloro-3-oxo-butyrate and 35.2 g (1.1 mol) of methanol was added thereto dropwise at room temperature (22 to 24° C.). After the addition, the mixture was stirred at room temperature (22 to 24° C.) for 1 hour. The reaction mixture was cooled with ice, and 600 ml (1.2 mol) of 2N hydrochloric acid was added dropwise. The tetrahydrofuran was recovered from the reaction mixture, and 400 ml of toluene was added to the residue. The aqueous phase was extracted with three 200 ml portions of toluene. The organic phase was washed with a 5percent sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The residue was distilled under reduce pressure (boiling point: 90° C./1000 Pa) to give 107.7 g (74percent) of methyl 4-methoxy-3-oxobutyrate as liquid. 1H-NMR (200 MHz, CDCl3, delta ppm): 4.08 (s, 2H), 3.74 (s, 3H), 3.52 (s, 2H), 3.42 (s, 3H)
	With hydrogenchloride; sodium methylate; acetic acid; In acetonitrile;	(a) 113.4 g (2.1 mmol) of sodium methylate are suspended in 150 ml of acetonitrile. 150.5 g (1 mol) of methyl 4-chloroacetoacetate are thereupon allowed to flow in within 5 minutes. The temperature rises, but it is held at 68°-70° C. by cooling. The mixture is subsequently stirred at 70° C. for a further 25 minutes. The reaction mixture is poured into a solution of 350 ml of distilled water and 9 g of acetic acid and held at a pH value of 6-7 by the addition of a total of 83 ml of 32percent hydrochloric acid. The organic layer is separated in a separating funnel and the aqueous layer is extracted 3 times with 200 ml of acetonitrile each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product distils at 55°-57° C./0.6 mbar. There are obtained 132.34 g (90.6 percent) of methyl 4-methoxy-acetoacetate. IR (liq. film): 3450m, 1750s, 1700s, 1660m cm-1 NMR (CDCl3)60MHz: 3.44 (s/3H), 3.52 (s/2H), 3.76 (s/3H), 4.10 (s/2H) ppm MS (m/e): 146 (M+), 115, 101, 59, 45 (100percent).

Reference： [1]Patent: US4564696,1986,A
[2]Patent: US6403804,2002,B1
[3]Patent: US4892966,1990,A

21
[ 41051-15-4 ]
[ 288309-39-7 ]

Yield	Reaction Conditions	Operation in experiment
54%	With trifluoromethanesulfonic acid anhydride; triethylamine; In hexane; dichloromethane; ethyl acetate;	Part A. Methyl (Z)-4-methoxy-3-[(trifluoromethyl)sulfonyl]-oxy}-2-butenoate To a solution of methyl 4-methoxy-3-oxobutanoate (5 g, 34.2 mmol) in 20 ml anhydrous dichloromethane was added triethylamine (5.24 ml, 37.6 mmol). Reaction was cooled under argon to -78° C. to which trifluoromethanesulfonic anhydride (10.6 gml, 37.6 mmol) was added dropwise via syringe over 5 minutes. Reaction was allowed to warm to room temperature and stirred over night. Next morning the reaction was diluted with 25 ml dichloromethane, organic was washed with 250 ml water, 250 ml 1N HCl, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude oil was chromatographed on silica gel using a gradient of 5percent EtOAc in hexane to 10percent EtOAc in hexane as the eluent to give methyl (Z)-4-methoxy-3-[(trifluoromethyl)sulfonyl]-oxy}-2-butenoate (5.1 g, 54percent) as a clear colorless oil after drying. H1NMR (CDCl3) 3.342 (s, 3H); 3.711 (s, 3H); 3.99 (s, H); 6.02 (s, H).

Reference： [1]Patent: US6399627,2002,B1

22
[Cp*Ru(CO)2]2(μ-H)}+OTf-in dichlorobenzene [ No CAS ]
[ 382141-76-6 ]
[ 68665-45-2 ]
[ 41051-15-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogen;	Example 6 HYDROGENATION OF METHYL 4-METHOXYACETOACETATE TO 3-HYDROXY-4-METHOXYBUTYRIC ACID METHYL ESTER. A 2 mL reactor was charged with 0.150 mL of a 1.00 M solution of 4-methoxyacetoacetate and 0.050 mL of a 0.030 M solution of [Cp*Ru(CO)2]2(mu-H)}+OTf-in dichlorobenzene. The reaction was heated at 90 C. for 12 hours at 820 psi (5.7 MPa) of hydrogen gas. The reaction was cooled, and analyzed using gas chromatography/mass spectroscopy. Analysis indicated 100% conversion of the 4-methoxyacetoacetate with a greater than 90% yield of 3-hydroxy-4-methoxybutyric acid methyl ester.

Reference： [1]Patent: US6462206,2002,B1

23
[ 41051-15-4 ]
[ 6334-18-5 ]
[ 142-62-1 ]
[ 115972-99-1 ]

Yield	Reaction Conditions	Operation in experiment
96.5%	With pyridine; In benzene;	Stage A: 2-(2,3-Dichlorobenzylidene)-3-oxo-4-methoxybutanoic acid methyl ester A solution containing 160 ml of anhydrous benzene, 5 g of 2,3-dichlorobenzaldehyde, 4.2 g of 4-methoxy-3-oxobutanoic acid methyl ester, 16 drops of pyridine and 22 drops of hexanoic acid is heated under reflux for one hour, removing the water formed. The mixture is then washed with a saturated sodium bicarbonate solution and then with a 0.1N hydrochloric acid solution. The organic phase is taken and evaporated to dryness so as to obtain 8.3 g of an oil. Yield: 96.5percent Proton nuclear magnetic resonance spectrum (CDCl3): 3.3-3.4 ppm, d, 3H; 3.7-3.9 ppm, d, 3H; 4.0-4.3 ppm, d, 2H; 7.0-7.7 ppm, m, 3H; 8 ppm, d, 1H.

Reference： [1]Patent: US4983740,1991,A

24
[ 41051-15-4 ]
[ 6334-18-5 ]
[ 142-62-1 ]
2-(2,3-Dichlorobenzylidene)-3-oxo-4-methoxybutanoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.5%	With pyridine; In benzene;	STAGE A 2-(2,3-Dichlorobenzylidene)-3-oxo-4-methoxybutanoic acid methyl ester. A solution containing 160 ml of anhydrous benzene, 5 g of 2,3-dichlorobenzaldehyde, 4.2 g of 4-methoxy-3-oxo-butanoic acid methyl ester, 16 drops of pyridine and 22 drops of hexanoic acid is heated under reflux for one hour, removing the water formed. The mixture is then washed with a saturated sodium bicarbonate solution and then with a 0.1N hydrochloric acid solution. The organic phase is taken and evaporated to dryness so as to obtain 8.3 g of an oil. Yield: 96.5percent. Proton nuclear magnetic resonance spectrum (CDCl3): 3.3-3.4 ppm, d, 3H; 3.7-3.9 ppm, d, 3H; 4.0-4.3 ppm, d, 2H; 7.0-7.7 ppm, m, 3H; 8 ppm, d, 1H.

Reference： [1]Patent: US4870091,1989,A

25
[ 41051-15-4 ]
[ 90-04-0 ]
[ 122-51-0 ]
methyl 2-methoxyacetyl-3-(2-methoxyphenylamino)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.5%	With acetic anhydride; In ethanol; ethyl acetate;	A. Preparation of methyl 2-methoxyacetyl-3-(2-methoxyphenylamino)acrylate <strong>[41051-15-4]Methyl 4-methoxyacetoacetate</strong> (43 ml, 0.33 mol), acetic anhydride (31 ml, 0.33 mol) and triethyl orthoformate (110 ml, 0.66 mol) were heated under reflux for 2 hours, then the excess triethyl orthoformate and the produced ethyl acetate were evaporated from the mixture under reduced pressure. o-Anisidine (43 ml, 0.35 mol) was added and ethanol (15 ml) was distilled over under atmospheric pressure. When cool, the mixture was poured slowly into hexane to produce methyl 2-methoxyacetyl-3-(2-methoxyphenylamino)acrylate (55 g, 59.5percent).

Reference： [1]Patent: US4806549,1989,A

26
[ 41051-15-4 ]
[ 34036-07-2 ]
methyl 2-[(3,4-difluorophenyl)-methylene]-3-oxo-4-methoxybutyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With piperdinium acetate;silica gel; In chloroform; ethyl acetate; benzene;	a Methyl 2-[(3,4-difluorophenyl)methylene]-3-oxo-4-methoxybutyrate (Scheme 2; C) To a solution of methyl 4-methoxyacetoacetate (84.32 g, 0.577 mol), 3,4-difluorobenzaldehyde (82 g, 0.577 mmol), and piperidinium acetate (5.86 g, 0.068 mol) in benzene (1.5 L) were added molecular sieves (400 g) and the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (100:3) to get the product as an oil (67 g, 47percent). This product was a mixture of cis and trans isomers.
	With piperdinium acetate;silica gel; In chloroform; ethyl acetate; benzene;	a) Methyl 2-[(3,4-difluorophenyl)methylene]-3-oxo-4-methoxybutyrate. A solution of methyl 4-methoxyacetoacetate (84.32 g, 0.577 mol), 3,4-difluorobenzaldehyde (82 g, 0.577 mmol), and piperidinium acetate (5.86 g, 0.068 mol) in benzene (1.5 L) were added molecular sieves (400 g) and the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (100:3) to get the product as an oil (67 g, 47percent).

Reference： [1]Patent: US6172066,2001,B2
[2]Patent: US6245773,2001,B1

27
[ 41051-15-4 ]
[ 84746-34-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuryl dichloride; In dichloromethane; at 20℃;	46.0 g <strong>[41051-15-4]Methyl 4-methoxyacetoacetate</strong> were dissolved in 500 ml dichloromethane. 28.1 ml Sulfuryl chloride were added in one portion. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the resulting residue was dissolved in 300 ml ethyl acetate and washed with 100 ml water and 100 ml brine. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The resulting residue was purified by chromatography on silica gel with the eluent n-heptane:ethyl acetate = 5:1 => 2:1 to obtain 45.Og 2-chloro- 4-methoxy-3-oxo-butyric acid methyl ester as a yellow oil. C6H9CIO4 (180.59), MS(ESI): 181.2 (M+H+), Rf(n-heptane : ethyl acetate = 2:1) = 0.31.
	With sulfuryl dichloride; In dichloromethane; at 20℃;	46.0 g <strong>[41051-15-4]Methyl 4-methoxyacetoacetate</strong> were dissolved in 500 ml dichloromethane. 28.1 ml Sulfuryl chloride were added in one portion. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the resulting residue was dissolved in 300 ml ethyl acetate and washed with 100 ml water and 100 ml brine. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The resulting residue was purified by chromatography on silica gel with the eluent n-heptane:ethyl acetate=5:1=>2:1 to obtain 45.0 g 2-Chloro-4-methoxy-3-oxo-butyric acid methyl ester as a yellow oil.C6H9ClO4 (180.59), MS (ESI): 181.2 (M+H+), Rf (n-heptane:ethyl acetate=2:1)=0.31

Reference： [1]Patent: WO2020/1448,2020,A1 .Location in patent: Page/Page column 39; 267
[2]Patent: WO2007/39172,2007,A1 .Location in patent: Page/Page column 145
[3]Patent: US2008/261979,2008,A1 .Location in patent: Page/Page column 55-56

28
[ 857414-00-7 ]
[ 41051-15-4 ]
[ 935758-19-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	piperdinium acetate; In isopropyl alcohol; at 20℃; for 6h;	Synthesis of 2-(lH-indol-4-ylmethylene)-4-methoxy-3-oxobutyric acid methyl ester (27): To a solution of 4-methoxy-3-oxo-butyric acid methylester (1 g, 6.88 mmol) in anhydrous isopropanol (10 mL) were added lH-indole-4-carbaldehyde (0.3 g, 4.39 mmol) followed by catalytic amount of piperidine acetate (0.1 g, 0.68 mmol) and the reaction mixture was stirred at ambient temperature for 6 hours. The separated yellow solid was filtered to get 2-(lH-indol-4-ylmethylene)-4-methoxy-3-oxo-butyric acid methyl ester in 75 percent yield (1.41 g). LC-MS (method: 20-100-5 min) retention time (Rt) = 1.61 min. MS calc'd for C15H15NO4 (MH+): 273.1 Found 273.1

Reference： [1]Patent: WO2007/51062,2007,A2 .Location in patent: Page/Page column 155-156

29
[Cp*Ru(CO)2]2(μ-H)}+OTf- [ No CAS ]
[ 382141-76-6 ]
[ 68665-45-2 ]
[ 41051-15-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogen; In 1,2-dichloro-benzene;	EXAMPLE 6 HYDROGENATION OF METHYL 4-METHOXYACETOACETATE TO 3-HYDROXY-4-METHOXYBUTYRIC ACID METHYL ESTER. A 2 mL reactor was charged with 0.150 mL of a 1.00 M solution of 4-methoxyacetoacetate and 0.050 mL of a 0.030 M solution of [Cp*Ru(CO)2]2(mu-H)}+OTf- in dichlorobenzene. The reaction was heated at 90C for 12 hours at 820 psi (5.7 MPa) of hydrogen gas. The reaction was cooled, and analyzed using gas chromatography/mass spectroscopy. Analysis indicated 100% conversion of the 4-methoxyacetoacetate with a greater than 90% yield of 3-hydroxy-4-methoxybutyric acid methyl ester.

Reference： [1]Patent: EP1292555,2004,B1

30
[ 41051-15-4 ]
4-cyanophenyl guanidine hydrochloride [ No CAS ]
[ 373690-07-4 ]

Yield	Reaction Conditions	Operation in experiment
57%		To a solution of intermediate A (0.0102 mol), prepared as in example 1, in ethanol (25 ml) was added sodium ethoxide (21percent) (0.0153 mol, 1.5 eq.) followed by methyl 4-methoxyacetoacetate (0.0102 mol, 1 eq.). The resulting mixture was stirred at reflux for 6 hours and then allowed to cool down to room temperature. Water was added and the mixture acidified with acetic acid (until pH = 6). The resulting precipitate was filtered to give 1.5 g of intermediate E (57percent yield).
57%		To a solution of intermediate A (0.0102 mol), prepared as in example 1, in ethanol (25 ml) was added sodium ethoxide (21percent) (0.0153 mol, 1.5 eq.) followed by methyl 4-methoxyacetoacetate (0.0102 mol, 1 eq.). The resulting mixture was stirred at reflux for 6 hours and then allowed to cool down to room temperature. Water was added and the mixture acidified with acetic acid (until pH = 6). The resulting precipitate was filtered to give 1.5 g of intermediate B (57percent yield).

Reference： [1]Patent: WO2008/80964,2008,A1 .Location in patent: Page/Page column 28
[2]Patent: WO2008/80965,2008,A2 .Location in patent: Page/Page column 28

31
[ 41051-15-4 ]
[ 618-39-3 ]
[ 339278-89-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate In methanol; ethanol Heating / reflux;	1.1.3 1.3. 6-methoxymethyl-2-phenyl-pyrimidin-4-ol; Benzamidine (15 g), methyl-4-methoxyacetate (18.2 g) and sodium methoxide (30% in MeOH, 23.1 ml) were dissolved in EtOH (130 ml) and the resulting mixture was refluxed overnight. It was cooled down and filtered off. The solid was washed with EtOH. The resulting ethanolic solutions were evaporated off and the residue high-vacuum dried. 27 g of a brown-yellow solid were obtained.LC-MS (A): tR=0.79 min; [M+H]+: 217.02; [M-H]-: 215.08.
	With sodium methylate In methanol; ethanol Reflux;	1.1.3 1.3. 6-methoxymethyl-2-phenyl-pyrimidin-4-ol Benzamidine (15 g), methyl-4-methoxyacetate (18.2 g) and MeONa (30% in MeOH, 23.1 ml) were dissolved in EtOH (130 ml) and the resulting mixture was refluxed overnight. It was cooled down and filtered off. The solid was washed with EtOH. The resulting ethanolic solutions were evaporated off and the residue high-vacuum dried, 27 g of a brown-yellow solid were obtained. LC-MS: tR=0.69 min; [M+H]+: 217.20.
	With sodium methylate In methanol; ethanol Reflux;	1.1.3 1.3. 6-methoxymethyl-2-phenyl-pyrimidin-4-ol; Benzamidine (15 g), methyl-4-methoxyacetate (18.2 g) and MeONa (30% in MeOH, 23.1 ml) were dissolved in EtOH (130 ml) and the resulting mixture was refluxed overnight. It was cooled down and filtered off. The solid was washed with EtOH. The resulting ethanolic solutions were evaporated off and the residue high-vacuum dried. 27 g of a brown-yellow solid were obtained. LC-MS: tR = 0.69 min; [M+H]+: 217.20.

Reference： [1]Current Patent Assignee: IDORSIA PHARMACEUTICALS LTD - US2008/194576, 2008, A1 Location in patent: Page/Page column 48
[2]Current Patent Assignee: IDORSIA PHARMACEUTICALS LTD - US2009/291962, 2009, A1 Location in patent: Page/Page column 12
[3]Current Patent Assignee: IDORSIA PHARMACEUTICALS LTD - EP2079711, 2010, B1 Location in patent: Page/Page column 20

32
[ 41051-15-4 ]
[ 60-34-4 ]
[ 866472-71-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	In toluene; at 0 - 100℃; for 1.83333h;	Reference Example 845-(methoxymethyl)-2-methyl-2,4-dihydro-3H-pyrazol-3-oneTo a solution of methyl 4-methoxyacetacetate (3.48 g) in toluene (110 mL) was added dropwise a solution of methylhydrazine (1.10 g) in toluene (35 mL) over 20 min at 0° C., and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether-hexane to give the title compound (3.20 g, yield 95percent) as brown crystals.1H-NMR (300 MHz, CDCl3) delta:3.29 (s, 2H), 3.31 (s, 3H), 3.39 (s, 3H), 4.17 (s, 2H).

Reference： [1]Patent: US2008/194617,2008,A1 .Location in patent: Page/Page column 68

33
[ 5153-67-3 ]
[ 41051-15-4 ]
2-(2-methoxyacetyl)-4-nitro-3-phenylbutyric acid methyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 14416 - 14417

34
[ 41051-15-4 ]
[ 74-88-4 ]
[ 1090903-27-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 16h;	To a solution of methyl 4-methoxyacetoacetate (2.0 mL, 15.5 mmol) and iodomethane (3.0 mL, 48.1 mmol) in DMSO (20 mL) was added potassium carbonate (4.7 g, 34.0 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (150 mL) and washed with H2O (150 mL x3). The organic layer was dried over sodium sulfate and concentrated to afford the desired 4-methoxy-2,2-dimethyl-3-oxo-butyric acid methyl ester (2.7 g, 100percent).

Reference： [1]Patent: WO2008/147697,2008,A1 .Location in patent: Page/Page column 211

35
[ 41051-15-4 ]
[ 14205-43-7 ]
[ 104-87-0 ]
[ 851579-97-0 ]

Yield	Reaction Conditions	Operation in experiment
50%		1) A solution (40 mL) of methyl 4-methoxyacetoacetate (5.85 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol), piperidine (340 mg, 4 mmol) and acetic acid (240 mg, 4 mmol) in isopropanol was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure to give a residue. 3-Methyl 5-tert-butyl 2- (methoxymethyl)-6-methyl-4- (4-methylphenyl)-1, 4- dihydropyridine-3, 5-dicarboxylate (5.85 g, yield 50%) was obtained as a yellow oil from the obtained residue and tert- butyl 3-aminocrotonate (4.71 g, 30.0 mol) according to a method similar to the method of Example 1-2). That is, the aforementioned residue and tert-butyl 3-aminocrotonate were dissolved in methanol (30 mL) and the mixture was heated under reflux for 1.5 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-methyl 5-tert-butyl 2- (methoxymethyl)-6-methyl-4- (4-methylphenyl)-1, 4- dihydropyridine-3,5-dicarboxylate. 1H-NMR (CDC13) USD : 1.40 (9H, s), 2.28 (3H, s), 2.32 (3H, s), 3.45-3. 46 (3H, m), 3.62-3. 63 (3H, m), 4.55-4. 76 (2H, m), 4.89- 4.95 (1H, m), 6.94 (1H, brs), 7.01 (2H, d, J = 7.7 Hz), 7.15 (2H, d, J = 8.1 Hz).

Reference： [1]Patent: WO2005/42488,2005,A1 .Location in patent: Page/Page column 181-182

36
[ 41051-15-4 ]
[ 1073-70-7 ]
[ 4637-24-5 ]
[ 158120-46-8 ]

Yield	Reaction Conditions	Operation in experiment
66%		4-Methoxy-3-oxobutyric acid methyl ester (1.50 g, 10.3 mmol) was mixed with dimethylformamide dimethylacetal (1.83 g, 15.4 mmol) and a catalytic amount of para- toluene sulfonic acid and heated in the microwave for 15 min at 13O0C. The mixture was cooled to room temp, and then concentrated in vacuo to afford a red oil. In a second flask para-chlorophenylhydrazine hydrochloride (1.84 g, 10.3 mmol) was placed in acetonitrile (10 mL) and then treated with the above red oil in triethylamine (6 mL). The mixture was stirred for 14 h, concentrated in vacuo and purified by silica chromatography (5percent ethylacetate in hexanes) to afford l-(4-Chloro-phenyl)-5-methoxymethyl-lH-pyrazole-4- carboxylic acid methyl ester (1.90 g, 66percent).

Reference： [1]Patent: WO2009/137338,2009,A1 .Location in patent: Page/Page column 76-77

37
[ 578-66-5 ]
[ 41051-15-4 ]
[ 4637-24-5 ]
[ 1238702-46-9 ]

Yield	Reaction Conditions	Operation in experiment
77%		Reference Example 127Methyl 5-methoxy-4-oxo-1-quinolin-8-yl-1,4-dihydropyridazine-3-carboxylate To a suspension of quinolin-8-amine (10.0 g, 69.4 mmol) in 6 M HCl aqueous solution (69.4 mL) was added a solution of NaNO2 (5.74 g, 83.2 mmol) in water (13.9 mL) at 0° C. To a suspension of methyl 4-methoxy-3-oxobutanoate (8.98 mL, 69.4 mmol) and NaOAc (104 g) in EtOH (118 mL) was added the above solution at 0° C. The mixture was stirred at 0° C. for 10 min. The precipitates were collected by filtration, washed with water andEtOAc, and dried. To the solid was added N,N-dimethylformamide dimethyl acetal (255 mL) at room temperature. The mixture was heated to reflux for 2.5 h and cooled to room temperature. The precipitates were collected by filtration, washed with hexane and dried to yield the title compound (16.6 g, 77percent yield) as a gray solid: 1H NMR (DMSO-d6, 300 MHz): delta ppm 3.77 (3H, s), 3.80 (3H, s), 7.72 (1H, dd, J=8.5, 4.0 Hz), 7.81 (1H, t, J=7.9 Hz), 8.09 (1H, d, J=7.2 Hz), 8.25 (1H, d, J=8.3 Hz), 8.58 (1H, s), 8.65 (1H, s), 8.97-9.04 (1H, m).

Reference： [1]Patent: US2010/197651,2010,A1 .Location in patent: Page/Page column 72

38
[ 41051-15-4 ]
5-methoxymethyl-2,4-dihydro-pyrazol-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; hydrazine; In methanol; at 20℃; for 1h;	To a solution of ketoester 1 A (2.92 g, 20 mmol) and anhydrous hydrazine (640 mg, 20 mmoi) in MeOH (100 ml_) was added NaOMe (25percent solution in MeOH, 1 drop) and the resulting reaction was allowed to stir at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica gel (0-5percent MeOH/CH2Cb) to provide compound 1B.

Reference： [1]Patent: WO2010/75069,2010,A1 .Location in patent: Page/Page column 30-31

39
[ 41051-15-4 ]
[ 4637-24-5 ]
[ 106876-54-4 ]
[ 1238702-60-7 ]

Yield	Reaction Conditions	Operation in experiment
71%		Reference Example 133Methyl 1-(2,2-difluoro-1,3-benzodioxol-4-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate A solution of sodium nitrite (1.4 g, 21 mmol) in H2O (10 mL) was added dropwise to a solution of 2,2-difluoro-1,3-benzodioxol-4-amine (3.0 g, 17 mmol) in 6 M HCl aqueous solution (18 mL, 108 mmol) at 0° C. After stirring for 15 min at 0° C., the mixture was added to a suspension of methyl 4-methoxyacetoacetate (2.2 mL, 17 mmol) and sodium acetate (9.0 g, 110 mmol) in MeOH (40 mL) pre-cooled at 0° C. The mixture was partitioned between AcOEt and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure.A solution of the residue in N,N-dimethylformamide dimethyl acetal (20 mL, 150 mmol) was refluxed for 3 h. The mixture was concentrated under reduced pressure. The residual solid was washed with AcOEt/hexane (1/3) to give the title compound (4.1 g, 71percent yield) as an orange solid: 1H NMR (300 MHz, CDCl3): delta ppm 3.96 (3H, s), 3.99 (3H, s), 7.15 (1H, dd, J=8.0, 1.1 Hz), 7.23-7.30 (1H, m), 7.56 (1H, dd, J=8.5, 1.1 Hz), 8.01 (1H, s).

Reference： [1]Patent: US2010/197651,2010,A1 .Location in patent: Page/Page column 74

40
[ 504-24-5 ]
[ 41051-15-4 ]
[ 1238702-34-5 ]

Yield	Reaction Conditions	Operation in experiment
19%		Reference Example 122Methyl 4-methoxy-3-oxo-2-(pyridin-4-ylhydrazono)butanoate 4-Aminopyridine (3.6 g, 38 mmol) was added to a mixture of phosphoric acid (10 mL, 150 mmol) and nitric acid (5 mL, 78 mmol) at -6° C. Sodium nitrite (3.2 g, 46 mmol) was added portionwise to the mixture at -6° C., and then crushed ice (ca. 25 g) was added into the solution. After stirring at -6° C. for 10 min, the mixture was poured into a suspension of methyl 4-methoxyacetoacetate (5.0 mL, 38 mmol) and sodium acetate (44 g, 540 mmol) in MeOH (100 mL) at 0° C. The mixture was partitioned between AcOEt and water. The aqueous layer was extracted with AcOEt. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residual solid was washed with AcOEt/hexane (1/3) to give the title compound (1.8 g, 19percent yield) as a yellow solid: 1H NMR (300 MHz, CDCl3): delta ppm 3.48-3.53 (3H, m), 3.89-3.95 (3H, m), 4.64-4.69 (2H, m), 7.17-7.34 (2H, m), 8.54-8.60 (2H, m), 12.65 (1H, brs).

Reference： [1]Patent: US2010/197651,2010,A1 .Location in patent: Page/Page column 71

41
[ 348-54-9 ]
[ 41051-15-4 ]
[ 1238701-34-2 ]

Yield	Reaction Conditions	Operation in experiment
94%		Reference Example 80Methyl 2-[(2-fluorophenyl)hydrazono]-4-methoxy-3-oxobutanoate A solution of NaNO2 (1.66 g, 24 mmol) in H2O (5 mL) was added dropwise at 0° C. to a mixture of 2-fluoroaniline (1.93 mL, 20 mmol) and 6 M HCl aqueous solution (20 mL, 120 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (2.59 mL, 20 mmol) and NaOAc (9.84 g, 120 mmol) in MeOH (40 mL) pre-cooled at 0° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (5.03 g, 94percent yield) as pale yellow crystals: mp 121-126° C.; 1H NMR (300 MHz, CDCl3): delta ppm 3.51 (3H, s), 3.94 (3H, s), 4.68 (2H, s), 7.08-7.25 (3H, m), 7.63 (1H, dt, J=1.5, 7.9 Hz), 13.06 (1H, br s). Anal. Calcd for C12H13FN2O4: C, 53.73; H, 4.88; N, 10.44. Found: C, 53.69; H, 4.96; N, 10.47.

Reference： [1]Patent: US2010/197651,2010,A1 .Location in patent: Page/Page column 60
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9627 - 9643

42
[ 41051-15-4 ]
[ 29632-74-4 ]
[ 1238701-71-7 ]

Yield	Reaction Conditions	Operation in experiment
80%		Reference Example 94Methyl 2-[(2-fluoro-4-iodophenyl)hydrazono]-4-methoxy-3-oxobutanoate A solution of NaNO2 (1.66 g, 24 mmol) in H2O (5 mL) was added dropwise at 0° C. to a mixture of 2-fluoro-4-iodoaniline (4.74 g, 20 mmol) and 6 M HCl aqueous solution (20 mL, 120 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (2.59 mL, 20 mmol) and NaOAc (9.84 g, 120 mmol) in MeOH (40 mL) pre-cooled at 0° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (6.29 g, 80percent yield) as yellow crystals: mp 141-146° C.; 1H NMR (300 MHz, CDCl3): delta ppm 3.50 (3H, s), 3.93 (3H, s), 4.64 (2H, s), 7.35 (1H, t, J=8.5 Hz), 7.49-7.55 (2H, m), 12.97 (1H, br s).Anal. Calcd for C12H12FIN2O4: C, 36.57; H, 3.07; N, 7.11. Found: C, 36.74; H, 3.10; N, 7.32.

Reference： [1]Patent: US2010/197651,2010,A1 .Location in patent: Page/Page column 63
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9627 - 9643

43
[ 41051-15-4 ]
[ 123572-58-7 ]
methyl 2-[2-fluoro-4-(trifluoromethoxy)phenyl]hydrazono}-4-methoxy-3-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%		Reference Example 144Methyl 2-[2-fluoro-4-(trifluoromethoxy)phenyl]hydrazono}-4-methoxy-3-oxobutanoate A solution of sodium nitrite (1.9 g, 28 mmol) in H2O (10 mL) was added dropwise to a solution of 2-fluoro-4-(trifluoromethoxy)aniline (4.6 g, 24 mmol) in 6 M HCl (24 mL, 144 mmol) at 0° C. After stirring for 15 min at 0° C., the mixture was added to a suspension of methyl 4-methoxyacetoacetate (3.1 mL, 24 mmol) and sodium acetate (12 g, 144 mmol) in MeOH (50 mL) pre-cooled at 0° C. The formed precipitate was collected by filtration, washed with water and dried under reduced pressure to give the title compound (4.8 g, 58percent yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): delta ppm 3.51 (3H, s), 3.94 (3H, s), 4.65 (2H, s), 7.06-7.14 (2H, m), 7.59-7.68 (1H, m), 12.98 (1H, brs).

Reference： [1]Patent: US2010/197651,2010,A1 .Location in patent: Page/Page column 77

44
[ 41051-15-4 ]
[ 98-16-8 ]
[ 1238701-59-1 ]

Yield	Reaction Conditions	Operation in experiment
88%		Reference Example 89Methyl 4-methoxy-3-oxo-2-[3-(trifluoromethyl)phenyl]hydrazono}butanoate A solution of NaNO2 (4.14 g, 60 mmol) in H2O (15 mL) was added dropwise at 0° C. to a mixture of 3-(trifluoromethyl)aniline (6.24 mL, 50 mmol) and 6 M HCl aqueous solution (50 mL, 300 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (7.31 mL, 50 mmol) and NaOAc (24.6 g, 300 mmol) in EtOH (80 mL) pre-cooled at 0° C. The precipitate was collected by filtration, washed with water, and dissolved in AcOEt. The organic solution was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was crystallized from hexane/AcOEt to give the title compound (14.0 g, 88percent yield) as pale yellow crystals: 1H NMR (300 MHz, CDCl3): delta ppm 3.51 (3H.x.0.36, s), 3.52 (3H.x.0.64, s), 3.90 (3H.x.0.36, s), 3.94 (3H.x.0.64, s), 4.68 (2H.x.0.64, s), 4.70 (2H.x.0.36, s), 7.41-7.59 (3H+1H.x.0.64, m), 7.71 (1H.x.0.36, s), 13.00 (1H.x.0.64, s), 14.87 (1H.x.0.36, s).

Reference： [1]Patent: US2010/197651,2010,A1 .Location in patent: Page/Page column 62
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9627 - 9643

45
4-benzyloxy-2-fluoroaniline [ No CAS ]
[ 41051-15-4 ]
methyl 2-[4-(benzyloxy)-2-fluorophenyl]hydrazono}-4-methoxy-3-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%		Reference Example 139Methyl 2-[4-(benzyloxy)-2-fluorophenyl]hydrazono}-4-methoxy-3-oxobutanoate A solution of NaNO2 (2.07 g, 30 mmol) in H2O (5 mL) was added dropwise at 0° C. to a mixture of 4-(benzyloxy)-2-fluoroaniline (5.43 g, 25 mmol) and 6 M HCl aqueous solution (25 mL, 150 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (3.24 mL, 24 mmol) and NaOAc (12.3 g, 150 mmol) in MeOH (50 mL) pre-cooled at 0° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (8.48 g, 91percent yield) as a yellow solid: 1H NMR (300 MHz, CDCl3): delta ppm 3.500 (3H.x.0.46, s), 3.502 (3H.x.0.54, s), 3.88 (3H.x.0.54, s), 3.92 (3H.x.0.46, s), 4.65 (2H.x.0.46, s), 4.68 (2H.x.0.54, s), 5.06 (2H.x.0.54, s), 5.07 (2H.x.0.46, s), 6.75-6.86 (2H, m), 7.32-7.44 (5H, m), 7.53 (1H.x.0.46, t, J=9.0 Hz), 7.76 (1H.x.0.54, t, J=9.0 Hz), 13.12 (1H.x.0.46, brs), 15.13 (1H.x.0.54, brs).

Reference： [1]Patent: US2010/197651,2010,A1 .Location in patent: Page/Page column 75

46
[ 41051-15-4 ]
[ 22236-04-0 ]
[ 1238701-43-3 ]

Yield	Reaction Conditions	Operation in experiment
96%		Reference Example 84Methyl 2-[2-(difluoromethoxy)phenyl]hydrazono}-4-methoxy-3-oxobutanoate A solution of NaNO2 (2.378 g, 34.5 mmol) in H2O (10 mL) was added dropwise at 0° C. to a solution of 2-(difluoromethoxy)aniline. (3.59 mL, 28.7 mmol) in 6 M HCl aqueous solution (28.7 mL, 172 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (3.72 mL, 28.7 mmol) and NaOAc (14.14 g, 172 mmol) in MeOH (50 mL) pre-cooled at 0° C. The precipitate was collected by filtration, washed with water, and dissolved in AcOEt. The organic solution was washed with water, saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (3/1) to give the title compound (8.70 g, 96percent yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): delta ppm 3.51 (3H, s), 3.89 (3H.x.0.5, s), 3.94 (3H.x.0.5, s), 4.68 (1H.x.0.5, s), 4.70 (1H.x.0.5, s), 6.63 (1H.x.0.5, t, J=72.7 Hz), 6.66 (1H.x.0.5, t, J=72.3 Hz), 7.10-7.34 (4H, m), 7.67 (1H.x.0.5, dd, J=8.3, 1.5 Hz), 7.90 (1H.x.0.5, dd, J=8.3, 1.5 Hz), 13.14 (1H.x.0.5, s), 14.96 (1H.x.0.5, br s).

Reference： [1]Patent: US2010/197651,2010,A1 .Location in patent: Page/Page column 61

47
[ 41051-15-4 ]
[ 120934-05-6 ]
[ 1238703-19-9 ]

Yield	Reaction Conditions	Operation in experiment
85%		Reference Example 158Methyl 4-methoxy-3-oxo-2-[(2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)hydrazono]butanoate To a suspension of 2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-amine (4.87 g, 20.2 mmol) in 6 M HCl aqueous solution (20.2 mL) was added a solution of NaNO2 (1.67 g, 24.2 mmol) in water (4 mL) at 0° C. The mixture was stirred at 0° C. for 15 min. To a suspension of methyl 4-methoxy-3-oxobutanoate (2.61 mL, 20.2 mmol) and NaOAc (30.3 g) in EtOH (34 mL) was added the above solution at 0° C. The mixture was stirred at 0° C. for 15 min. The precipitates were collected by filtration, washed with water, dissolved in EtOAc, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield the title compound (6.84 g, 85percent yield) as a red solid: 1H NMR (DMSO-d6, 300 MHz): delta ppm 3.33 (3H, s), 3.82 (3H, s), 4.68 (2H, s), 7.66-7.93 (2H, m), 12.16 (1H, brs).

Reference： [1]Patent: US2010/197651,2010,A1 .Location in patent: Page/Page column 80-81

48
[ 50329-91-4 ]
[ 41051-15-4 ]
[ 1343474-12-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium carbonate; In tetrahydrofuran; at 50℃; for 6h;	General procedure: To a solution of 1 (0.100 g, 0.5 mmol) in THF (10 mL) was added K2CO3 (0.140 g, 2.0 equiv). To the stirred solution was dropwise added the 1,3-dicarbonyl compound (2.0 equiv). The reaction mixture was allowed to stir at 50 °C and was monitored by TLC. After the complete consummation of the starting material 1, the reaction mixture was acidified using hydrochloric acid (1 M) and the mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, heptanes/EtOAc).

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 5910 - 5912

49
[ 41051-15-4 ]
[ 1335210-23-5 ]

Reference： [1]Patent: WO2011/119566,2011,A1
[2]Patent: WO2016/125192,2016,A2
[3]Patent: CN109293675,2019,A
[4]Journal of Heterocyclic Chemistry,2019
[5]Patent: WO2019/159199,2019,A1

50
[ 41051-15-4 ]
[ 1335210-24-6 ]

Reference： [1]Patent: WO2011/119566,2011,A1
[2]Patent: WO2019/159199,2019,A1

51
[ 41051-15-4 ]
[ 37885-07-7 ]
[ 1361297-06-4 ]

Yield	Reaction Conditions	Operation in experiment
16%	With hydrogenchloride; In water; at 75℃; for 0.1h;Microwave;	A mixture of 4.0 g (19.7 mmol) 1-(2-amino-4-(trifluoromethyl)phenyl)ethanone, 11.5 ml (98.5 mmol) 4-chloro-diacetic acid ethyl ester and 1.7 ml (19.7 mmol) cone, hydrochloric acid was heated to 75 C for 6 min in a sealed vessel by microwaves (50 W). The mixture was subsequently diluted with EtOAc and water. The organic phase was separated, washed with a 1 M aq. NaHC03 sol., dried over MgS04 and concentrated in a vacuum. The raw product (7.47 g) obtained after CC (EtOAc/hexane 3:17) of the residue was dissolved in eOH (76 ml) and 35.3 ml (70.6 mmol) of a 2M aq. LiOH sol. was added. The mixture was subsequently stirred for 16 h at RT and heated to 60 C for a further 24 h. After cooling to RT, the mixture was diluted with water and EtOAc. The organic phase was separated, dried over MgS04 and concentrated in a vacuum. After CC (EtOAc/hexane 1 :3) of the residue, 985 mg (3.1 mmol, 16%) 2-(methoxymethyl)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid methyl ester was obtained.

Reference： [1]Patent: WO2012/25238,2012,A1 .Location in patent: Page/Page column 60

52
[ 41051-15-4 ]
[ 1357191-95-7 ]
[ 1357191-96-8 ]

Yield	Reaction Conditions	Operation in experiment
4.87 g		To a mixture of 2- (benzyloxy) -4- (3, 4-difluoro-lH-pyrrol- 1-yl) aniline (7.51 g) and 6M hydrochloric acid (50 mL) was added dropwise a solution of sodium nitrite (3.45 g) in water (10 mL) at 0°C and the mixture was stirred for 15 min. The reaction mixture was added to a suspension of methyl 4- methoxyacetoacetate (3.24 mL) and sodium acetate (24.6 g) in methanol (50 mL) at 0°C. The reaction mixture was stirred for 15 min, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate, and recrystallized from hexane/tetrahydrofuran to give the title compound (4.87 g) . XH NMR (300 MHz, CDC13) delta 3.51 (3H, s) , 3.90 (3H, s) , 4.68 (2H, s), 5.27 (2H, s), 6.59-6.69 (2H, m) , 6.87 (1H, d, J = 2.3 Hz), 6.94 (1H, dd, J = 8.7, 2.3 Hz), 7.34-7.52 (5H, m) , 7.61 (1H, d, J = 8.7 Hz) , 13.27 (1H, s) .
4.87 g		F) methyl 2-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]hydrazono}-4-methoxy-3-oxobutanoate To a mixture of 2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)aniline (7.51 g) and 6M hydrochloric acid (50 mL) was added dropwise a solution of sodium nitrite (3.45 g) in water (10 mL) at 0° C., and the mixture was stirred for 15 min. The reaction mixture was added to a suspension (cooled to 0° C.) of 4-methyl methoxyacetoacetate (3.24 mL) and sodium acetate (24.6 g) in methanol (50 mL). The reaction mixture was stirred for 15 min, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate, and recrystallized from hexane/THF to give the title compound (4.87 g). 1H NMR (300 MHz, CDCl3) delta 3.51 (3H, s), 3.90 (3H, s), 4.68 (2H, s), 5.27 (2H, s), 6.59-6.69 (2H, m), 6.87 (1H, d, J=2.3 Hz), 6.94 (1H, dd, J=8.7, 2.3 Hz), 7.34-7.52 (5H, m), 7.61 (1H, d, J=8.7 Hz), 13.27 (1H, s).

Reference： [1]Patent: WO2013/27845,2013,A1 .Location in patent: Paragraph 0398
[2]Patent: US2013/150344,2013,A1 .Location in patent: Paragraph 0506; 0507

53
[ 41051-15-4 ]
[ 62-53-3 ]
methyl 4-methoxy-3-oxo-2-(phenylhydrazono)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With hydrogenchloride; sodium acetate; sodium nitrite; In methanol; water; at 0 - 20℃; for 2h;	A solution of sodium nitrite (55.6 g, 803 mmol) in water(142 mL) was added dropwise to a solution of 3 (50 g, 539 mmol)in 6 MHCl aq (536 mL) at 0 C. The mixture was added to a suspensionof methyl 4-methoxyacetoacetate (78.5 g, 537 mmol) andsodium acetate (264 g, 3220 mmol) in MeOH (1400 mL) and water(350 mL) at 0 C. After the mixture was stirred at room temperaturefor 2 h, the mixture was diluted with water and stirred for30 min. The formed precipitate was collected by filtration, washedwith water, EtOH/IPE, and IPE, successively, and dried to give 4(111.2 g, 83percent) as a yellow solid. 1H NMR (CDCl3) d 3.51 (3H, s),3.88 (3H, s), 4.69 (2H, s), 7.18?7.25 (1H, m), 7.37?7.48 (4H, m),14.99 (1H, br s).
111.2 g	With hydrogenchloride; sodium acetate; sodium nitrite; In methanol; water; for 2h;Cooling with ice;	A) methyl 4-methoxy-3-oxo-2-(phenylhydrazono)butanoate To a solution of aniline (50 g) in 6N hydrochloric acid (536 mL) was added dropwise with stirring under ice-cooling an aqueous solution (142 mL) of sodium nitrite (55.6 g). The solution was added dropwise to a mixed solution of methyl 4-methoxy-3-oxobutanoate (78.5 g) and sodium acetate (264 g) in methanol/water (1.4 L/0.35 L) with stirring under ice-cooling. The total amount was added dropwise, and the mixture was stirred at the same temperature for 2 hr. Water was added to the reaction mixture, and the mixture was stirred for 30 min. The precipitated yellow crystals were collected by filtration, washed successively with water, ethanol/diisopropyl ether (1/9) and diisopropyl ether, and dry to give the title compound (111.2 g) as yellow crystals. 1H NMR (300 MHz, CDCl3): delta 3.51 (3H, s), 3.88 (3H, s), 4.69 (2H, s), 7.18-7.25 (1H, m), 7.37-7.48 (4H, m), 14.99 (1H, br. s.).

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 3447 - 3455
[2]Patent: US2013/137700,2013,A1 .Location in patent: Paragraph 0476; 0477

54
[ 41051-15-4 ]
[ 93-91-4 ]
methyl 4-benzoyl-3-(methoxymethyl)-5-methyl-1H-pyrrole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20.5%		Production Example 45-1 Synthesis of methyl 4-benzoyl-3-(methoxymethyl)-5-methyl-1H-pyrrole-2-carboxylate [compound No. 45] To a solution of methyl 4-methoxyacetoacetate (725 mg, 5 mmol) in acetic acid (4 ml), an aqueous solution (4 ml) of sodium nitrite (345 mg, 5 mmol) was added at 5° C. After 12 hours, a solution of benzoylacetone (811 mg, 5 mmol) in acetic acid (2 ml) and subsequently zinc powder (649 mg, 9.9 mmol) and sodium acetate (562 mg, 6.9 mmol) were added to the mixture. Then, the reaction mixture was heated to reflux. After 1 hour, the reaction solution was quenched by the addition of ice water. The reaction solution was rendered weakly basic by the addition of a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate. After filtering off of magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain the compound of interest (295 mg, yield: 20.5percent, yellow oil). 1H-NMR (400 MHz, CDCl3) delta: 2.28 (3H, s), 3.06 (3H, s), 3.89 (3H, s), 4.49 (2H, s), 7.44-7.47 (2H, m), 7.52-7.56 (1H, m), 7.74-7.79 (2H, m), 9.10 (1H, s).

Reference： [1]Patent: US2014/343017,2014,A1 .Location in patent: Paragraph 0678; 0679; 0680

55
[ 41051-15-4 ]
[ 1335210-35-9 ]

Reference： [1]Patent: WO2015/19310,2015,A1
[2]Patent: WO2016/125192,2016,A2
[3]Patent: WO2016/125192,2016,A2
[4]Patent: WO2016/125192,2016,A2
[5]Patent: CN109293675,2019,A
[6]Patent: WO2019/159199,2019,A1

56
[ 41051-15-4 ]
[ 134541-08-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 20 h / 20 - 90 °C 2: hydroxylamine hydrochloride / methanol / 7 h / Reflux 3: hydrogenchloride; acetic acid; water / 6 h / Reflux
	Multi-step reaction with 3 steps 1: 20 h / 20 - 90 °C 2: hydroxylamine hydrochloride / methanol / 7 h / Heating / reflux 3: hydrogenchloride; water; acetic acid / 6 h / Heating / reflux
	Multi-step reaction with 3 steps 1: 20 h / 20 - 90 °C 2: hydroxylamine hydrochloride / methanol / 7 h / Heating / reflux 3: hydrogenchloride; water / acetic acid / 6 h / Heating / reflux

Reference： [1]Current Patent Assignee: CELLIXBIO PRIVATE LTD - US2015/133475, 2015, A1
[2]Current Patent Assignee: PFIZER INC - WO2008/135830, 2008, A1
[3]Current Patent Assignee: PFIZER INC - WO2008/135826, 2008, A2

57
[ 41051-15-4 ]
[ 1357192-11-0 ]
methyl 2-[(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)hydrazono]-4-methoxy-3-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		A solution of sodium nitrite (0.081 g, 1.17 mmol) in water (1 mL) was added dropwise to a solution of 12a (0.19 g, 0.978 mmol) in 6 M HCl aq (2 mL) at 0°C. After stirring at 0°C for 15 min, the mixture was added to a suspension of methyl 4-methoxyacetoacetate (0.127 mL, 0.978 mmol) and sodium acetate (1.0 g, 12.19 mmol) in MeOH (5 mL) at 0°C. The formed precipitate was dissolved in EtOAc, and the solution was washed with water and saturated NaHCO3 aqueous solution. The organic layer was dried over MgSO4, and concentrated under reduced pressure to give13 (0.25 g, 73percent) as a yellow solid.1H NMR (CDCl3) d1.54(6H, s), 3.51 (3H, s), 3.88 (3H1/2, s), 3.93 (3H1/2, s), 4.66(2H1/2, s), 4.69 (2H1/2, s), 6.78 (1H, d, J= 8.3 Hz), 7.48(1H1/2, t, J= 7.9 Hz), 7.72 (1H1/2, t, J= 8.1 Hz), 7.88(1H1/2, br s), 7.92 (1H1/2, br s), 13.18 (1H1/2, s), 15.12(1H1/2, s).

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 7138 - 7149

58
[ 41051-15-4 ]
[ 100-46-9 ]
C₁₃H₁₇NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With acetic acid; In toluene; at 60℃; for 5h;	A solution of 4-methoxy-3-oxo-butyric acid methyl ester (25 g, 170 mmol), benzyl amine (18.3 mL, 171 mmol), and acetic acid (0.50 mL, 8.5 mmol) in toluene (120 mL) is heated at 60° C. for 5 h then cooled to room temperature. The mixture is concentrated under reduced pressure and the residue is azeotroped with toluene 2 times to provide A-5-1 (40 g, 100percent yield).

Reference： [1]Patent: US2016/24059,2016,A1 .Location in patent: Paragraph 0251-0252

59
[ 41051-15-4 ]
2,5-dioxopyrrolidin-1-yl 2-((4-chlorobenzyl)amino)-4,5-difluorobenzoate [ No CAS ]
methyl 1-(4-chlorobenzyl)-6,7-difluoro-2-(methoxymethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		Methyl 4-methoxy-3-oxobutanoate (285muL, 2.2mmol, 2.2 equiv.) was addeddropwise to a suspension of NaH (60percent dispersion in mineral oil, 88mg, 2.2mmol,2.2 equiv.) in dry toluene (10mL), the reaction mixture was vigorously stirred atroom temperature for 1 hour, then compound 8 (395 mg, 1.0 mmol, 1.0 equiv.) wasadded in one portion and the whole mixture was stirred vigorously at ambienttemperature for 3 hours and refluxed at 130°C for another 2 hours. After the reactioncompleted, the mixture was diluted with ethyl acetate (150mL) and washed withwater (150mL×3). The organic layer was dried over anhydrous Na2SO4, filtered andconcentrated to give an oily residue, which was purified by silica gelchromatography to give compound 9c as a crystalline solid (300mg, 74percent). 1H NMR(400 MHz, Methanol-d4) delta 8.06 ? 7.98 (m, 1H), 7.50 (dd, J = 12.5, 6.4 Hz, 1H), 7.31(d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 5.63 (s, 2H), 4.51 (s, 2H), 3.89 (s, 3H),3.30 (s, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2900 - 2906

60
[ 67-56-1 ]
[ 32807-28-6 ]
[ 41051-15-4 ]

Yield	Reaction Conditions	Operation in experiment
93%		General procedure: To a suspension of sodium hydride (2.2 eq) in THF (0.5 M) at RT, an alcohol (1.1 eq) was added dropwise. The mixture was stirred for 5 min before methyl 4-chloro-3-oxobutanoate (1 eq) was dropwise added. This mixture was stirred for 30 min and then concentrated in vacuum. Water was added, and the pH was adjusted to 6-7 by the addition of 2N aq. HCl. The resulting mixture was extracted with dichloromethane (×2) and ethyl acetate (×2), and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane as eluent to afford the corresponding dicarbonyl compound.
74 g	With potassium methanolate; sodium hydride; In tetrahydrofuran; mineral oil; at 15 - 25℃; for 9h;Inert atmosphere;	In 2L pre-reaction bottle by adding 250 ml tetrahydrofuran, under the protection of argon, are started to stir, the oven 25 C, the inner temperature 15-25 C added in batches under the condition of 30g (0.74mol) sodium hydride (containing 40 wt % mineral oil) and 50g (0.74mol) potassium methoxide, continue adding tetrahydrofuran after adding 450 ml; the inner temperature 20 C slowly dropping under the condition of 30g methanol and 100g (0.67mol) 4-chloro acetyl mixed solution of methyl acetate, regulate the stirring in the rate of 310 R/min the left and the right, about 4h finish; to temperature rise within 20-25 C stirring 5h, TLC detection complete raw material reaction: cooling system, can be seen and the color is yellowish solution a large number of solid suspended, the inner temperature 11 C add under the condition of 200 ml tetrahydrofuran, to be oven to -2 C time, slowly adding 100 ml molar concentration is 2mol/L hydrochloric acid solution (pre-cooling to 0-5 C), keep the oven in the 0 C the following, about 20 min after adding, pH= 10 of the reaction system at this time, in the process of dropping the solid significant increase in the reaction bottle, immediately after adding filtering, the filter cake is a white solid, cake obtained drying filters 92g solid; the resulting solid is added to the 770g in ethyl acetate, the temperature of the reaction system to 0 C, slow instillment mole concentration is 6mol/L hydrochloric acid solution, maintaining the temperature of the reaction system is not variable, the dropping white solid gradually disappear in the process, the reaction system is adjusted pH= 4, reaction liquid contains a small amount of inorganic salt white solid, filtering the reaction solution, the filtrate layer, the organic phase is separated, the organic phase by adding 5g activated carbon, in the 30 C under the condition of stirring 1h, filtered, filtrate in the 35 C ethyl acetate under the condition of the vacuum distillation to the colorless liquid 74g, HPLC checking the purity of 99.6%.
89 g	With potassium methanolate; sodium hydride; In tetrahydrofuran; mineral oil; at 20 - 25℃; for 9h;Inert atmosphere;	In a 2 L reaction flask, 250 ml of a solvent tetrahydrofuran (AR) was added. Under argon protection, stirring was started and at this time the kettle temperature is 25C. Was added portionwise 30 g (0.75 mol) of industrial sodium hydride (containing 40 wt% mineral oil) and 53 g (0.75 mol) of potassium methoxide. After the addition, continue to add solvent tetrahydrofuran 450ml; The temperature in the kettle was 20C. Was slowly added dropwise 30 g of methanol mixed with 100 g (0.68 mol) methyl 4-chloro-3-oxo-butanoate and stirred reaction for 4h. The reactor temperature increased to 25C and stirred for 5h. TLC detection reaction is completed. The system began to cool down. Solution color is khaki and a large number of solid suspension. When the temperature inside the kettle drops to 6C, 2M hydrochloric acid solution (pre-cooled to 0-5 C) was slowly added to the system pH = 7; Standing stratification. After separation, the upper layer was concentrated to dryness to remove the solvent tetrahydrofuran. The resulting residue was added with 60 ml of ethyl acetate. After concentrating by rotary evaporation, ehyl acetate (60 ml) was added thereto. Concentrated by rotary evaporation, ethyl acetate (200 ml) was added thereto. After stirring for a while, the lower aqueous phase was extracted three times with ethyl acetate (80 ml, 60 ml, 60 ml). All organic phases were combined. Saturated sodium chloride wash (60mlx2) to pH = 7 or so. Concentrated to give a pale yellow oil, which was subjected to wiping film molecular distillation. When the degree of vacuum was 30 Pa, at a temperature of 50C, scraper speed of 400r / min, to obtain 89 g of methyl 4-methoxyacetoacetate as a colorless oily liquid, purity was 95.4% by HPLC.

Reference： [1]Patent: EP3480201,2019,A1 .Location in patent: Paragraph 0288; 0289; 0291; 0292
[2]Patent: CN105418420,2016,A .Location in patent: Paragraph 0015; 0016; 0017; 0018; 0019; 0020
[3]Patent: CN104478719,2016,B .Location in patent: Paragraph 0034; 0035

61
[ 106-60-5 ]
[ 41051-15-4 ]
C₄₄H₅₂N₄O₁₆ [ No CAS ]

Reference： [1]New Journal of Chemistry,2016,vol. 40,p. 7445 - 7455

62
[ 41051-15-4 ]
[ 79-04-9 ]
methyl 2-(methoxymethyl)-4-oxo-4,5-dihydrofuran-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		Step 1: methyl 2-(methoxymethyl)-4-oxo-4,5-dihydrofuran-3-carboxylate The reaction was run in duplicate and combined for purification. To a solution of methyl 4-methoxy-3-oxobutanoate (10 g, 68.4 mmol) in toluene (150 mL) was added magnesium ethoxide (12.67 g, 89 mmol) at room temperature. The mixture was stirred at 110° C. for 4 hours. The reaction was cooled to 0° C. and solid was removed from the solution. 2-Chloroacetyl chloride (14.00 ml, 137 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The duplicate reaction mixtures were combined. The mixture was diluted by the addition of water and extracted with ethyl acetate (200 mL*3). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and eluted with EtOAc/PE to give the titled compound (10 g, yield 39percent). 1H NMR (400 MHz, CDCl3) delta ppm 4.59 (s, 2H), 4.52 (s, 2H), 3.84-3.81 (m, 3H), 3.45 (s, 3H).

Reference： [1]Patent: US2017/73353,2017,A1 .Location in patent: Paragraph 0477

63
[ 41051-15-4 ]
[ 100-83-4 ]
[ 17356-08-0 ]
methyl 4-(3-hydroxyphenyl)-6-(methoxymethyl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With ytterbium(III) triflate; In acetonitrile; at 120℃; for 4h;Microwave irradiation;	General procedure: The appropriate beta-keto ester (0.75?3.0mmol, 1.5 equiv.), the appropriate aldehyde (0.5?2.0mmol, 1 equiv.), the appropriate urea or thiourea (0.5?2.0mmol, 1 equiv.) and Yb(OTf)3 (0.05?0.20mmol, 0.10 equiv.) were placed in a microwave oven vial (0.5?2.0mL) with a magnetic stirring bar and dissolved in THF or MeCN (0.5?1.0mL). The resulting mixture is heated to 120°C for 30?60min using microwave irradiation. The resulting mixture is poured onto an ice-water mixture and left for precipitation. The resulting crude solids were purified by recrystallization, DCVC or flash chromatography.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 138,p. 300 - 312

64
[ 41051-15-4 ]
[ 106-93-4 ]
methyl 1-(2-methoxyacetyl)cyclopropanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With tetrabutylammomium bromide; potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere;	General procedure: K2CO3 (6.910 g, 50.0 mmol) followed by 1,2-dibromoethane (2.25 ml, 26.0 mmol) and TBAB (0.032 g,0.1 mmol) were added to a solution of beta-oxoester 5b (3.844 g,20.0 mmol) in DMF (12 ml). The mixture was stirred atroom temperature for 20 h till the full consumption ofstarting material (TLC control: eluent petroleum ether ?EtOAc, 10:1). To the reaction mixture, EtOAc (25 ml) andH2O (35 ml) were added and the organic phase was separated.The aqeuous phase was washed with EtOAc (3 × 25 ml)and the combined organic phases were washed withsaturated aqeuous NaCl (2×30 ml). Combined organicphase was dried over Na2SO4, filtered, and concentratedunder reduced pressure.

Reference： [1]Chemistry of Heterocyclic Compounds,2017,vol. 53,p. 989 - 996
Khim. Geterotsikl. Soedin.,2017,vol. 53,p. 989 - 996,8

65
[ 41051-15-4 ]
[ 1335210-35-9 ]
N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide [ No CAS ]
(R)-N-(2,4-difluorobenzyl)-2-(4-hydroxybutan-2-yl)-9-methoxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 7181 - 7185
Angew. Chem.,2018,vol. 130,p. 7299 - 7303,5
[2]Angewandte Chemie - International Edition,2018,vol. 57,p. 7181 - 7185
Angew. Chem.,2018,vol. 130,p. 7299 - 7303,5

66
[ 553-90-2 ]
[ 107-31-3 ]
[ 41051-15-4 ]
[ 1246616-82-9 ]

Yield	Reaction Conditions	Operation in experiment
68%		Synthesis step: 105 ml of 1 M hexamethyldisilazide lithium tetrahydrofuran solution was added to the three-necked flask.Cool to -15 ° C under nitrogen protection,14.6 g of methyl 4-methoxyacetoacetate was added dropwise, and then 6.0 g of methyl formate was continuously added dropwise thereto, and the reaction was kept for 2 hours.120 ml of a 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran was added, and 13.4 g of dimethyl oxalate was added thereto, and the mixture was heated to 20-25 ° C for 3 h.The reaction solution was transferred to pre-cooled 300 ml of 2N hydrochloric acid, stirred at room temperature for 2 h, concentrated to remove tetrahydrofuran, extracted with ethyl acetate, and washed with organic phase.Concentration and finally crystallization from isopropanol gave 16.5 g of dimethyl 4-oxo-3-methoxy-4H-pyran-2,5-dicarboxylate in a yield of 68percent.

Reference： [1]Patent: CN107778273,2018,A .Location in patent: Paragraph 0015

67
[ 41051-15-4 ]
[ 3122-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium methylate / 18 h / Reflux 2: trichlorophosphate / dichloromethane / 18 h / 20 °C

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - JP5714745, 2015, B2

68
[ 41051-15-4 ]
[ 463-52-5 ]
[ 3122-78-9 ]

Yield	Reaction Conditions	Operation in experiment
37.1%	Stage #1: 4-methoxyacetoacetic acid methylester; formamidine With sodium methylate for 18h; Reflux; Stage #2: With hydrogenchloride In water	218.A Step A: 6-(Methoxymethyl)pyrimidin-4-01 To a solution of methyl 4-methoxy-3-oxobutanoate(3.54 ml., 26.5 mmol) in methanol (30 ml) was added formamidine acetate (3.07 g, 29.2 mmol) and sodium methoxide (13 ml., 58.4 mmol). The mixture was then heated to refluxf or 18 hours and cooled to ambient temperature, then concentrated.The residue was taken up in water and the pH adjusted to 7 with IN HCI. The aqueous mixture was extracted with chloroform. The combined organic layers were dried overmagnesium sulfate, filtered and concentrated to afford 6-(methoxymethyl)pyrimidin-4-ol (1.38 g, 9.85 mmol,37.1% yield).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - JP5714745, 2015, B2 Location in patent: Paragraph 0383; 0384

69
[ 120-72-9 ]
[ 41051-15-4 ]
[ 621-63-6 ]
methyl 4-(1H-indol-3-yl)-2-(methoxymethyl)-4,5-dihydrofuran-3-carboxylate [ No CAS ]

Reference： [1]Green Chemistry,2019,vol. 21,p. 2061 - 2069

70
[ 41051-15-4 ]
[ 142266-62-4 ]
methyl 2,3-dichloro-7-(methoxymethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.9%	With copper(l) iodide; caesium carbonate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere;	[0318] Step 1: Methyl 2,3-dichloro-7-(methoxymethyl)-5-oxo-5,6-dihydro-1,6- naphthyridine-8-carboxylate . A mixture of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 5.0 g, 22 mmol), 4-methoxy-3-oxo-butanoic acid methyl ester (4.86 mL, 33.3 mmol), copper(I) iodide (0.42 g, 2.22 mmol) and cesium carbonate (14.45 g, 44.4 mmol) was purged with N2 followed by the addition of 1,4-dioxane (110 mL) and the reaction mixture was heated at 80 C under nitrogen for 16 h. The mixture was quenched with 9:1 sat. NH4Cl/NH4OH and extracted with EtOAc. The combined organics were concentrated to give methyl 2,3-dichloro- 7-(methoxymethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (4.0 g, 12.6 mmol, 56.9 % yield). m/z (ESI, +ve ion): 317.0 (M+H)+. The crude material was used as is in the subsequent step.
	With copper(l) iodide; caesium carbonate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere;	A mixture of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 5.0 g, 22 mmol), 4-methoxy-3-oxo-butanoic acid methyl ester (4.86 mL, 33.3 mmol), copper(I) iodide (0.42 g, 2.22 mmol) and cesium carbonate (14.45 g, 44.4 mmol) was purged with N2 followed by the addition of 1,4-dioxane (110 mL) and the reaction mixture was heated at 80 C. under nitrogen for 16 h. The mixture was quenched with 9:1 sat. NH4Cl/NH4OH and extracted with EtOAc. The combined organics were concentrated to give methyl 2,3-dichloro-7-(methoxymethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (4.0 g, 12.6 mmol, 56.9% yield). m/z (ESI, +ve ion): 317.0 (M+H)+. The crude material was used as is in the subsequent step. 13

Reference： [1]Patent: WO2019/213516,2019,A1 .Location in patent: Paragraph 0318
[2]Patent: US2019/374542,2019,A1 .Location in patent: Paragraph 0808-0809

71
[ 41051-15-4 ]
[ 76593-36-7 ]
7-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidine-1-yl)-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one [ No CAS ]

Reference： [1]Patent: WO2022/15988,2022,A1
[2]Patent: WO2022/15988,2022,A1

72
[ 41051-15-4 ]
[ 76593-36-7 ]
7-chloro-2-(methoxymethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With polyphosphoric acid; at 120℃; for 1.5h;	To a solution of 6-choro-3-amino-4,5-dimethylpyridazine (1 g) in polyphosphoric acid (9 mL) was added methyl 4-methoxy-3-oxo-butanoate (1.23 mL). The mixture was heated to 85 C for 1 hour, then 120 C for 30 minutes. The mixture was then quenched by slow addition to a solution of saturated sodium bicarbonate (~150 L) and 4:1 chloroform/' PA (~50 L). The organic layer was isolated and the aqueous layer further extracted (x3). The organic layers were pooled, dried over magnesium sulfate, filtered, and concentrated. The crude product was dissolved in DMSO (9 mL) and solid was filtered off. The filtrate was purified using the Gilson (Basic, 50 x 250 mm column, 5 - 55% ACM/ 0.05% aqueous NH4OH, 16 min run). Fractions containing product were concentrated to give the title compound (219 g) as a solid. The solid was washed with hexanes then dissolved in DCM and purified using a Teledyne ISCG Combi-Flash system (liquid loading with DCM, 80G column, 0-2% MeQH/DCM/NhUOH, 10 min run). Fractions containing product were concentrated to give the title compound (682 mg; 43% yield) as a solid. *H NMR (400 MHz, CDCI3) 6 6.77 (t, J = 1.0 Hz, 1H), 4.45 (d, J = 1.0 Hz, 2H), 3.51 (s, 3H), 2.59 (d, J = 0 9 Hz, 3H), 2.49 (d, J = 1.0 Hz, 3H). ES-MS [M+l]+: 254.
43%	With polyphosphoric acid; at 120℃; for 1.5h;	To a solution of 6-choro-3-amino-4,5-dimethylpyridazine (1 g) in polyphosphoric acid (9 mL) was added methyl 4-methoxy-3-oxo-butanoate (1.23 mL). The mixture was heated to 85 C for 1 hour, then 120 C for 30 minutes. The mixture was then quenched by slow addition to a solution of saturated sodium bicarbonate (~150 L) and 4:1 chloroform/' PA (~50 L). The organic layer was isolated and the aqueous layer further extracted (x3). The organic layers were pooled, dried over magnesium sulfate, filtered, and concentrated. The crude product was dissolved in DMSO (9 mL) and solid was filtered off. The filtrate was purified using the Gilson (Basic, 50 x 250 mm column, 5 - 55% ACM/ 0.05% aqueous NH4OH, 16 min run). Fractions containing product were concentrated to give the title compound (219 g) as a solid. The solid was washed with hexanes then dissolved in DCM and purified using a Teledyne ISCG Combi-Flash system (liquid loading with DCM, 80G column, 0-2% MeQH/DCM/NhUOH, 10 min run). Fractions containing product were concentrated to give the title compound (682 mg; 43% yield) as a solid. *H NMR (400 MHz, CDCI3) 6 6.77 (t, J = 1.0 Hz, 1H), 4.45 (d, J = 1.0 Hz, 2H), 3.51 (s, 3H), 2.59 (d, J = 0 9 Hz, 3H), 2.49 (d, J = 1.0 Hz, 3H). ES-MS [M+l]+: 254.
43%	With polyphosphoric acid; at 120℃; for 1.5h;	To a solution of 6-choro-3-amino-4,5-dimethylpyridazine (1 g) in polyphosphoric acid (9 mL) was added methyl 4-methoxy-3-oxo-butanoate (1.23 mL). The mixture was heated to 85 C for 1 hour, then 120 C for 30 minutes. The mixture was then quenched by slow addition to a solution of saturated sodium bicarbonate (~150 L) and 4:1 chloroform/' PA (~50 L). The organic layer was isolated and the aqueous layer further extracted (x3). The organic layers were pooled, dried over magnesium sulfate, filtered, and concentrated. The crude product was dissolved in DMSO (9 mL) and solid was filtered off. The filtrate was purified using the Gilson (Basic, 50 x 250 mm column, 5 - 55% ACM/ 0.05% aqueous NH4OH, 16 min run). Fractions containing product were concentrated to give the title compound (219 g) as a solid. The solid was washed with hexanes then dissolved in DCM and purified using a Teledyne ISCG Combi-Flash system (liquid loading with DCM, 80G column, 0-2% MeQH/DCM/NhUOH, 10 min run). Fractions containing product were concentrated to give the title compound (682 mg; 43% yield) as a solid. *H NMR (400 MHz, CDCI3) 6 6.77 (t, J = 1.0 Hz, 1H), 4.45 (d, J = 1.0 Hz, 2H), 3.51 (s, 3H), 2.59 (d, J = 0 9 Hz, 3H), 2.49 (d, J = 1.0 Hz, 3H). ES-MS [M+l]+: 254.

Reference： [1]Patent: WO2022/15988,2022,A1 .Location in patent: Paragraph 00397
[2]Patent: WO2022/15988,2022,A1 .Location in patent: Paragraph 00397
[3]Patent: WO2022/15988,2022,A1 .Location in patent: Paragraph 00397

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P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
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. 41051-15-4 ] {[proInfo.proName]}

Quality Control of [ 41051-15-4 ]

Related Doc. of [ 41051-15-4 ]

Product Details of [ 41051-15-4 ]

Calculated chemistry of [ 41051-15-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 41051-15-4 ]

Application In Synthesis of [ 41051-15-4 ]

[ 41051-15-4 ] Synthesis Path-Upstream 1~15

[ 41051-15-4 ] Synthesis Path-Downstream 1~72

Related Functional Groups of [ 41051-15-4 ]

Aliphatic Chain Hydrocarbons

Ethers

Esters

Ketones

Precautionary Statements-General

Prevention

Response

Storage

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Physical hazards

Health hazards

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Inquiry

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[ 41051-15-4 ]