[ CAS No. 96-35-5 ] {[proInfo.proName]}

Name: 96-35-5|Methyl 2-hydroxyacetate|95%
Brand: Ambeed
SKU: A152116
Price: 5.0 USD
Availability: InStock
Rating: 95 (25 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 96-35-5

Structure of 96-35-5 * Storage: {[proInfo.prStorage]}

Please Login or Create an Account to: See VIP prices and availability

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

* Shipping: {[proInfo.prShipping]}

For Research Only 120K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 96-35-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 96-35-5 ]

SDS Specification

Alternatived Products of [ 96-35-5 ]

Product Details of [ 96-35-5 ]

CAS No. :	96-35-5	MDL No. :	MFCD00004667
Formula :	C₃H₆O₃	Boiling Point :	-
Linear Structure Formula :	CH₂(OH)COOCH₃	InChI Key :	GSJFXBNYJCXDGI-UHFFFAOYSA-N
M.W :	90.08	Pubchem ID :	66774
Synonyms :

Calculated chemistry of [ 96-35-5 ] Expand+

Physicochemical Properties

Num. heavy atoms :	6
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.67
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	18.98
TPSA :	46.53 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) :	-7.23 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.09
Log Po/w (XLOGP3) :	-0.54
Log Po/w (WLOGP) :	-0.85
Log Po/w (MLOGP) :	-0.85
Log Po/w (SILICOS-IT) :	-0.48
Consensus Log Po/w :	-0.33

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	0.07
Solubility :	107.0 mg/ml ; 1.18 mol/l
Class :	Highly soluble
Log S (Ali) :	0.03
Solubility :	97.0 mg/ml ; 1.08 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	0.31
Solubility :	184.0 mg/ml ; 2.05 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.02

Safety of [ 96-35-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P210-P264-P270-P280-P301+P312-P330-P370+P378-P403+P235-P501	UN#:	N/A
Hazard Statements:	H302-H227	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 96-35-5 ]

* 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 [ 96-35-5 ]
Downstream synthetic route of [ 96-35-5 ]

[ 96-35-5 ] Synthesis Path-Upstream 1~13

1
[ 96-35-5 ]
[ 3530-14-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrazine In methanol at 20℃; for 74 h; Heating / reflux	Preparation 69: 2-Hydroxyacetohydrazide Hydrazine monohydrate (1.08 g, 22.2 mmol) was added to a solution of methyl glycolate (0.84 mL, 11.1 mmol) in methanol (10 mL) and the mixture was heated under reflux for 2 hours and stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo to afford the title compound as a white solid in quantitative yield. ¹H NMR(400 MHz, CDCl₃) δ: 4.04(s, 2H)

Reference： [1] Patent: US2006/160786, 2006, A1, . Location in patent: Page/Page column 35-36
[2] Patent: EP2725024, 2014, A1, . Location in patent: Paragraph 0340
[3] Patent: US2014/171431, 2014, A1, . Location in patent: Paragraph 0691

2
[ 67-56-1 ]
[ 9004-34-6 ]
[ 96-35-5 ]
[ 547-64-8 ]
[ 24332-20-5 ]

Reference： [1] ChemSusChem, 2017, vol. 10, # 7, p. 1390 - 1394

3
[ 110-91-8 ]
[ 96-35-5 ]
[ 51068-78-1 ]

Reference： [1] Patent: US2006/281772, 2006, A1, . Location in patent: Page/Page column 120

4
[ 96-35-5 ]
[ 292638-85-8 ]
[ 57595-23-0 ]

Yield	Reaction Conditions	Operation in experiment
24%	Stage #1: With sodium hydride In diethyl ether at 20℃; for 0.5 h; Stage #2: at 0℃; for 1 h;	To a stirred slurry of sodium hydride (2.2 g, 55 mmol) in dry ether (40 mL) at room temperature (rt) was added methyl glycolate (4.5 g, 50 mmol) dropwise. The reaction mixture was stirred for 14 h, then it was concentrated under vacuo. To the solid was added methyl acrylate (5.2 g, 55 mmol) in DMSO (20 mL) at O⁰C and the mixture was stirred for 15 min, and the cool bath was removed and it was stirred for 45 min. The mixture was poured into 5percent H₂SO₄ (60 mL), and it was extracted with ether (150 mL). The organic layer was dried, concentrated and purified by column chromatography to give 1.7 g (24percent) of the title compound. ¹H NMR (CDCl₃): 4.51-4.40 (m, 2H), 4.03 (q, J = 8.1 Hz, 2H), 3.80 (s, 3H), 3.54 (t, J = 8.1 Hz, IH).
31%	With sodium In dimethyl sulfoxide	Synthesis of 2,5-dihydro furan 3,4-dicarboxylic acid 2.3 g (0.1 mol) sodium was pulverized under toluene and the solvent was replaced with 75 ml ether. 11 ml (0.1 mol) methylglycolate was added to the mixture under stirring until the evolution of hydrogen gas had ceased. To the dry sodium derivative remaining after destination of the ether, a solution of 10 ml (0.12 mol) distilled methylacrylate in 50 ml DMSO was added while the reaction was kept at 4° C. After 15 minutes the solution was stirred for an additional 30-40 min at room temperature and poured into aqueous H₂SO₄ at 4° C. and extracted with ether. Washing of the organic layer with a saturated NaCl solution, drying over NaSO₄ and removal of the ether was followed by destination under reduced pressure to give 4.5 g (31percent) of 4-oxo-tetrahydro furane 3-carboxylic acidmethyl ester.

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 5, p. 2124 - 2130
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 1124 - 1130
[3] Patent: WO2008/21456, 2008, A2, . Location in patent: Page/Page column 32
[4] Patent: WO2018/137573, 2018, A1, . Location in patent: Page/Page column 104
[5] Tetrahedron Letters, 1989, vol. 30, # 45, p. 6129 - 6132
[6] Tetrahedron, 1991, vol. 47, # 27, p. 4847 - 4860
[7] Patent: US2003/203951, 2003, A1,
[8] Patent: WO2016/49100, 2016, A1, . Location in patent: Page/Page column 22; 23
[9] Patent: WO2016/45126, 2016, A1, . Location in patent: Page/Page column 20
[10] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 12, p. 1193 - 1198

5
[ 798541-68-1 ]
[ 96-35-5 ]
[ 57595-23-0 ]

Yield	Reaction Conditions	Operation in experiment
26%	Stage #1: With sodium hydride In diethyl ether at 20℃; for 2 h; Stage #2: at 0 - 20℃; for 1.25 h;	Sodium hydride (4 g, 60percent w/w in oil dispersion, 100 mmol) was added to a flame-dried flask along with ether (100 mL). To the reaction flask under nitrogen atmosphere, methyl glycolate (7.7 mL, 100 mmol) was added slowly with constant stirring. The reaction mixture was allowed to stir at room temperature for 2 hours under nitrogen atmosphere then solvent was removed in vacuo. To the residue, methyl acrylate (10.8 mL, 120 mmol) in DMSO (50 mL) was added in one portion while the reaction flask was kept immersed in an ice bath. The reaction mixture was allowed to stir at 0 °C for 15 minutes then at room temperature for 1 hour. The reaction mixture was then filtered through Celte'3', poured into ice-cold aqueous sulfuric acid solution (150 mL, 2N), and extracted with ether (2 x 200 mL). The organic layer was washed with saturated NaCl solution (500 mL), dried over anhydrous Na2S04, filtered, and solvent was removed in vacuo. The intermediate ketoester was recovered in 26percent yield (3.7 g, 25.7 mmol) afterpurificationby column chromatography on silica using 25percent ethyl acetate/hexanes as the eluent (Rf= 0.3). The ketoester intermediate (3.7g, 25.7 mmol) was added slowly to a solution of sodium hydride (1.4 g, 60percent w/w in oil dispersion, 34 mmol) in ether (80 mL) at 0 °C with constant stirring under nitrogen atmosphere. After 30 minutes, trifluoromethanesulfonic anhydride (5.3 mL, 31.4 mmol) was added dropwise over 5 minutes. The reaction mixture was allowed to stir at 0 °C for an additional 1.5 hours then the reaction was poured into water (80 mL) and the layers were separated. The aqueous phase was washed with dichloromethane (2 x 60 mL) and the organic phases were combined. The organic layer was dried over anhydrous Na2SO4, filtered, and solvent was removed in vacuo. The 2,5- dihydrofuran ester 13a was recovered in 23percent yield (1.6 g, 5.8 mmol) after purification by column chromatography on silica using 25percent ethyl acetate/hexanes as the eluent (Rf= 0.45). MS: calc. for C7H7F306S : 257.9 ; Found: GC-MS 7nl5 275 (MH).

Reference： [1] Patent: WO2005/40109, 2005, A1, . Location in patent: Page/Page column 78-79

6
[ 96-35-5 ]
[ 6361-21-3 ]
[ 20699-86-9 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium carbonate In N,N-dimethyl-formamide	Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5° C. was treated with K₂CO₃(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25° C. and stirred for 20 h. The solution was then poured into 250 ml of ice H₂O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69percent). LRMS: 237.0 (Calc.); 238.1 (found). ¹H NMR: (DMSO) δ (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).
69%	With potassium carbonate In N,N-dimethyl-formamide	Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5° C. was treated with K₂CO₃(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25° C. and stirred for 20h. The solution was then poured into 250 ml of ice H₂O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69percent). LRMS: 237.0 (Calc.); 238.1 (found). ¹H NMR: (DMSO) δ (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).
69%	With potassium carbonate In N,N-dimethyl-formamide	Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chlorobenzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5° C. was treated with K₂CO₃(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25° C. and stirred for 20 h. The solution was then poured into 250 ml of ice H₂O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69percent). LRMS: 237.0 (Calc.). 238.1 (found). ¹H NMR: (DMSO) δ (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).

Reference： [1] Patent: US2004/142953, 2004, A1,
[2] Patent: US2005/288282, 2005, A1,
[3] Patent: US6897220, 2005, B2,

7
[ 96-35-5 ]
[ 394-47-8 ]
[ 57805-85-3 ]

Yield	Reaction Conditions	Operation in experiment
48%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12 h; Heating / reflux	Preparation Example 1: Preparation of 3-amino-benzofuran-2-carboxylic acid methyl ester0.22 g (1.18 mmol) of σ-fluorobenzonitrile was dissolved in 5 ml of N₅N- dimethylformamide, 0.16 ml (2.18 mmol) of methyl glyconate and 0.62 g (4.54 mmol) of potassium carbonate were added thereto at room temperature, and the mixture was refluxed with heating for 12 hrs. After the reaction was completed, the reaction mixture was diluted with 10 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography <n="19"/>(hexane:ethyl acetate = 4:1) to obtain the title compound (0.10 g, 48percent yield).¹H NMR (300MHz, DMSO-d₆): δ 3.97(s, 3H), 4.98(s, 2H), 7.23-7.28(m, IH), 7.44-7.47(m, 2H), 7.56(d, IH)Mass(m/e, M⁺): 192

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 22, p. 6362 - 6365
[2] Patent: WO2009/48274, 2009, A2, . Location in patent: Page/Page column 16-17

8
[ 67-56-1 ]
[ 683-70-5 ]
[ 553-90-2 ]
[ 96-35-5 ]
[ 79-20-9 ]
[ 10076-48-9 ]
[ 96-34-4 ]

Reference： [1] Chemische Berichte, 1987, vol. 120, p. 1573 - 1580

9
[ 67-56-1 ]
[ 131543-46-9 ]
[ 79-14-1 ]
[ 2517-44-4 ]
[ 96-35-5 ]
[ 51673-84-8 ]

Yield	Reaction Conditions	Operation in experiment
11%	for 4 h;	[0041] A 40percent aqueous glyoxal solution was metered at a rate of 0.17 mol/h into the top of a heatable 1 m column (diameter 29 mm) filled with spheres of diameter 5 mm of the catalyst KA-3 (Sud-Chemie). At the same time, gaseous methanol was metered in at the bottom of the column. During the entire reaction, the apparatus was operated under nitrogen as a protective gas. The column was heated. A mixture of water and methanol was collected at the top of the column. The bottom effluent of the column consisted of a mixture of 1,1,2,2-tetramethoxyethane, 2,2-dimethoxyacetaldehyde, methyl 2-hydroxyacetate, 2-hydroxyacetic acid and methanol. The apparatus was operated for 4 hours, and the bottom effluent was analyzed by gas chromatography. According to the analysis, there were 11 g (0.07 mol, 11percent) of 1,1,2,2-tetramethoxyethane.

Reference： [1] Patent: US2004/186304, 2004, A1, . Location in patent: Page 3

10
[ 96-35-5 ]
[ 100-39-0 ]
[ 31600-43-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With silver(l) oxide In ethyl acetateHeating / reflux	Add BnBr (72.7 mL, 0.61 mol, 1.1 eq) and Ag2O (141.6 g, 0.61 mol, 1.1 eq) to a solution of methyl glycolate (50 g, 0.56 mol) in EtOAc (300 mL) and stir the mixture to reflux overnight. Follow the reaction by TLC (Hexane/EtOAC 1 : 1). Filter the reaction through celite and remove the solvent under vacuum. The oil is passed adsorbed onto flash silica. Place on top of a pad of flash silica (500g) and elute with 20percent ethyl acetate/hexane to give 75.8 g (75percent yield) of a colorless oil.; General Procedure for Scheme 6 Add BnBr (72.7 mL, 0.61 mol, 1.1 eq) and Ag2O (141.6 g, 0.61 mol, 1.1 eq) to a solution of methyl glycolate (50 g, 0.56 mol) in EtOAc (300 mL) and stir the mixture to reflux overnight. Follow the reaction by TLC (Hexane/EtOAC 1 : 1). Filter the reaction through celite and remove the solvent under vacuum. Pass adsorb the oil onto flash silica and place on top of a pad of flash silica (500g) and elute with 20percent ethyl acetate/hexane to give 75.8 g (75percent yield) of compound A of scheme 6. ; Add BnBr (72.7 mL, 0. 61 mol, 1.1 eq) and Ag2O (141.6 g, 0.61 mol, 1.1 eq) to a solution of methyl glycolate (50 g, 0.56 mol) in EtOAc (300 mL) and stir the mixture to reflux overnight. Follow the reaction by TLC (Hexane/EtOAC 1 : 1). Filter the reaction through celite and remove the solvent under vacuum. The oil is passed adsorbed onto flash silica. Place on top of a pad of flash silica (500g) and elute with 20percent ethyl acetate/hexane to give 75.8 g (75percent yield) of preparation 19 as a colorless oil.
70%	Stage #1: With silver(l) oxide In diethyl ether at 20℃; for 0.25 h; Stage #2: at 20℃; for 24 h;	To a stirred solution of methyl glycolate (2 g, 22.2 mmol) in anhydrous diethyl ether (100 niL), at RT, under a nitrogen atmosphere, was added silver(I)oxide (10.3 g, 44.4 mmol). The suspension was stirred for 15 min and benzyl bromide (4.5 g, 26.3 mmol) was added. The mixture was stirred at the same temperature for 24 hours, and the insoluble materials were removed by filtration through a short pad of celite. The filtrate was concentrated under reduced pressure, and the crude product chromatographed over a column of silica gel, eluting with 20percent diethyl ether-petroleum ether to give 70, as a colorless liquid in 70percent yield (2.8 g).[0395] 70 was confirmed as follows: ¹H NMR (500 MHz, CDCl₃) δ 7.39-7.29 (m, 5H), 4.62 (s, 2H), 4.16 (s, 2H), 3.78 (s, 3H).

Reference： [1] Organic Letters, 2003, vol. 5, # 23, p. 4521 - 4523
[2] Patent: WO2005/65683, 2005, A1, . Location in patent: Page/Page column 45; 73-75; 77
[3] Patent: WO2009/52319, 2009, A1, . Location in patent: Page/Page column 120

11
[ 96-35-5 ]
[ 20194-18-7 ]
[ 30379-58-9 ]

Reference： [1] Carbohydrate Research, 1993, vol. 245, # 2, p. 175 - 192

12
[ 96-35-5 ]
[ 123-08-0 ]
[ 73620-18-5 ]

Yield	Reaction Conditions	Operation in experiment
67%	With triphenylphosphine In tetrahydrofuran; diethylazodicarboxylate	EXAMPLE 44 Methyl 2-(4-formylphenoxy)ethanoate A solution of 4-hydroxy benzaldehyde, (1.22 g, 0.01 m), methyl glycolate (0.97 g, 0.01 m), and triphenylphosphine, (3.93 g, 0.015 m), in dry tetrahydrofuran, (50 ml) was stirred with cooling in ice and diethylazodicarboxylate, (2.61 g, 0.015 m), added dropwise. The solution was stirred at room temperature for 0.5 hours, then evaporated in vacuo to dryness. Column chromatography of the residue on silica gel eluding with chloroform yielded 1.30 g (67percent) of the title compound as an oil which crystallized on standing, mp 39°-41° C., ν_max (mull) 1750, 1680, 1595, 1575, 1505 cm^-1.

Reference： [1] Patent: US4713486, 1987, A,

13
[ 96-35-5 ]
[ 72287-26-4 ]

Reference： [1] Patent: US2014/163038, 2014, A1, . Location in patent: Page/Page column

[ 96-35-5 ] Synthesis Path-Downstream 1~108

1
[ 67-56-1 ]
[ 502-97-6 ]
[ 96-35-5 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1949,vol. 68,p. 618
[2]Green Chemistry,2013,vol. 15,p. 2817 - 2824

2
[ 96-35-5 ]
[ 64-19-7 ]
[ 13831-30-6 ]

Reference： [1]Industrial and Engineering Chemistry,1948,vol. 40,p. 536

3
[ 96-35-5 ]
[ 64-19-7 ]
[ 13831-30-6 ]
[ 5837-80-9 ]

Reference： [1]Industrial and Engineering Chemistry,1948,vol. 40,p. 536

4
[ 96-35-5 ]
[ 124-40-3 ]
[ 14658-93-6 ]

Yield	Reaction Conditions	Operation in experiment
21%	In water at 20℃;	Synthesis of compound 6a 1.2g (0.013mola) methyl glycolate in 2 mL THF was dissolved in a flaskwith stirring, 3 mL 40% aqueoussolution N, N-dimethyl aminewas then added. Reaction was continued for 48h at roomtemperature, then the excess ofreagents was removed under reduced pressure and the residue was purified bysilica gel column chromatography withethyl acetate as a mobile phase to give 0.286 gof 6a as a white solid. Yield 21% M. p. 42-43°C.

Reference： [1]Pawlak, Dorota; Schielmann, Marta; Wojciechowski, Marek; Andruszkiewicz, Ryszard [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 15, p. 3586 - 3589]
[2]Ratchford; Fisher [Journal of Organic Chemistry, 1950, vol. 15, p. 317,323]

5
[ 96-35-5 ]
[ 62-53-3 ]
[ 4746-61-6 ]

Reference： [1]Current Patent Assignee: PROCTER & GAMBLE CO - US2604481, 1949, A

6
[ 67-56-1 ]
[ 683-51-2 ]
[ 553-90-2 ]
[ 96-35-5 ]
[ 89-91-8 ]
[ 96-34-4 ]
[ 298-12-4 ]

Reference： [1]Chemische Berichte,1987,vol. 120,p. 1573 - 1580

7
[ 67-56-1 ]
[ 683-70-5 ]
[ 553-90-2 ]
[ 96-35-5 ]
[ 79-20-9 ]
[ 10076-48-9 ]
[ 96-34-4 ]

Reference： [1]Chemische Berichte,1987,vol. 120,p. 1573 - 1580

8
[ 96-35-5 ]
[ 84162-82-3 ]
[ 140213-13-4 ]

Reference： [1]Journal of Heterocyclic Chemistry,1993,vol. 30,p. 445 - 451

9
[ 96-35-5 ]
[ 98-88-4 ]
[ 29747-05-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 20℃; for 3h;	To dichloromethane (100 ml) solution of 4.5 g (50.0 mmol) of methyl glycolate was added 7.7 ml (55.0 mmol) of triethylamine, the mixture was cooled with ice, 6.00 ml (52.0 mmol) of benzoyl chloride was added thereto, and the resuling mixture was stirred at room temperature for 3 hours. Aqueous saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with 1 N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. This was filtered and concentrated under reduced pressure to obtain 11.3 g (quantitative) of the entitled compound as a pale yellow oil.1H-NMR(CDCl3)delta: 3.80(3H, s), 4.87(2H, s), 7.46(1H, m), 7.59(1H, m), 8.10(2H, m).

Reference： [1]Patent: EP1479681,2004,A1 .Location in patent: Page 128
[2]Liebigs Annalen der Chemie,1987,p. 687 - 692

10
[ 96-35-5 ]
[ 292638-85-8 ]
[ 57595-23-0 ]

Yield	Reaction Conditions	Operation in experiment
24%		To a stirred slurry of sodium hydride (2.2 g, 55 mmol) in dry ether (40 mL) at room temperature (rt) was added methyl glycolate (4.5 g, 50 mmol) dropwise. The reaction mixture was stirred for 14 h, then it was concentrated under vacuo. To the solid was added methyl acrylate (5.2 g, 55 mmol) in DMSO (20 mL) at O0C and the mixture was stirred for 15 min, and the cool bath was removed and it was stirred for 45 min. The mixture was poured into 5% H2SO4 (60 mL), and it was extracted with ether (150 mL). The organic layer was dried, concentrated and purified by column chromatography to give 1.7 g (24%) of the title compound. 1H NMR (CDCl3): 4.51-4.40 (m, 2H), 4.03 (q, J = 8.1 Hz, 2H), 3.80 (s, 3H), 3.54 (t, J = 8.1 Hz, IH).
4.5 g (31%)	With sodium; In dimethyl sulfoxide;	Synthesis of 2,5-dihydro furan 3,4-dicarboxylic acid 2.3 g (0.1 mol) sodium was pulverized under toluene and the solvent was replaced with 75 ml ether. 11 ml (0.1 mol) methylglycolate was added to the mixture under stirring until the evolution of hydrogen gas had ceased. To the dry sodium derivative remaining after destination of the ether, a solution of 10 ml (0.12 mol) distilled methylacrylate in 50 ml DMSO was added while the reaction was kept at 4 C. After 15 minutes the solution was stirred for an additional 30-40 min at room temperature and poured into aqueous H2SO4 at 4 C. and extracted with ether. Washing of the organic layer with a saturated NaCl solution, drying over NaSO4 and removal of the ether was followed by destination under reduced pressure to give 4.5 g (31%) of 4-oxo-tetrahydro furane 3-carboxylic acidmethyl ester.
		To a suspension of NaH (185 g, 4.6 mol, 60% weight) in THF (4 L) was charged methyl 2-hydroxyacetate (380 g, 4.2 mol) dropwise at 0 C. After the addition, the reaction mixture was stirred for 30 mm at ambient temperature and then re-cooled to 0 C. A solution of methylacrylate (400 g, 4.64 mol) in DMSO (2 L) was added dropwise over 2 hours at 0 C. The resulting reaction mixture was stirred for 30 mm at 0 C and for 2 h at 20 C. After TLC showed that the start material was consumed completely, the mixture was quenched with 1.5 L of 5% H2S04 (slowly) and extracted with EtOAc (3 L). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated to afford Methyl 4-oxotetrahydrofuran-3-carboxylate (11) as a liquid. The crude oil was used in the next step without further purification. ?H NMR (CDC13, 400 MHz) : 4.3 5-4.45 (m, 2H), 3.86-3.97 (m, 2H), 3.72 (s, 3H), 3.47 (t, 1H).

To a suspension of NaH (185 g, 4.6 mol, 60 weight) in T HF (4 L) was charged methyl 2-hydroxyacetate (380 g, 4.2 mol) dropwise at 0 . After the addition, the reaction mixture was stirred for 30 min at ambient temperature and then re-cooled to 0 . A solution of methyl acrylate (400 g, 4.64 mol) in DMSO (2 L) was added dropwise over 2 hours at 0 . The resulting reaction mixture was stirred for 30 min at 0 and for 2 h at 20 . After TLC showed that the start material was consumed completely, the mixture was quenched with 1.5 L of 5 H2SO4(slowly) and extracted with EtOAc (3 L) . The combined organic layers were washed with brine (1 L) , dried over Na2SO4, filtered and concentrated to afford Methyl 4-oxotetrahydrofuran-3-carboxylate (11) as a liquid. The crude oil was used in the next step without further purification.1H NMR (CDCl3, 400 MHz) delta: 4.35-4.45 (m, 2H) , 3.86-3.97 (m, 2H) , 3.72 (s, 3H) , 3.47 (t, 1H) .

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 2124 - 2130
[2]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 754 - 760
[3]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1124 - 1130
[4]Patent: WO2008/21456,2008,A2 .Location in patent: Page/Page column 32
[5]Patent: WO2018/137573,2018,A1 .Location in patent: Page/Page column 104
[6]Tetrahedron Letters,1989,vol. 30,p. 6129 - 6132
[7]Tetrahedron,1991,vol. 47,p. 4847 - 4860
[8]Patent: US2003/203951,2003,A1
[9]Patent: WO2016/49100,2016,A1 .Location in patent: Page/Page column 22; 23
[10]Patent: WO2016/45126,2016,A1 .Location in patent: Page/Page column 20
[11]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 1193 - 1198

11
[ 96-35-5 ]
[ 58479-61-1 ]
[ 154698-92-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With dmap; triethylamine; In dichloromethane; at 25℃; for 16h;Inert atmosphere;	Preparative Example A (0025) (0026) TBDPSC1 (7.7 g, 28.27 mmol) was added under N2 to a stirred solution of methyl 2-hydroxyacetate (2.3 g, 25.7 mmol), DMAP (1.7 g, 12.5 mmol) and Et3N (5.1 g, 51.4 mmol) in CH2Cl2 (30 mL). The reaction mixture was stirred at 25 C for 16 hours. The precipitate was removed by filtration and the filtrate was washed by 10% aqueous HCl (2 x 75 mL), then by water (2 x 50 mL), and dried over MgSO4. The solvent was evaporated and the product was obtained as a colorless oil (8.2 g, 98%). (0027) 1H NMR (500 MHz, CDCl3): delta 1.11 (s, 9H), 3.70 (s, 3H), 4.26 (s, 2H), 7.43 - 7.38 (m, 4H), 7.47 - 7.42 (m, 2H), 7.72 - 7.69 (m, 4H) ppm. (0028) 13C NMR (125 MHz, CDCl3): delta 19.49, 26.90, 51.48, 62.37, 128.00, 130.11, 135.81, 171.87 ppm. (0029) HRMS calculated for C10H7NO2 [M+H]+ 174.0561, found 174.0565.
97%	With pyridine; dmap; at 0 - 20℃;	To a solution of methyl glycolate (2.5 g, 27.7 mmol) in pyridine (10 mL) was added tert-butyldiphenylsilyl chloride (8.4 g, 30.5 mmol). A catalytic amount of DMAP was added at 0 C, and the reaction was stirred overnight at room temperature. H2O was then added and the resulting mixture was extracted with CH2Cl2 (3 × 10 mL), the organic phase was dried with MgSO4, concentrated under vacuum and purified by flash chromatography (5:95 EtOAc/hexane) to give 8 as a colourless oil (8.86 g, 97% yield). 1H NMR (400 MHz, CDCl3): delta 7.69-7.68 (m, 4H), 7.43-7.37 (m, 6H), 4.25 (s, 2H), 3.68 (s, 3H), 1.09 (s, 9H). 13C NMR (100 MHz, CDCl3): delta 171.7, 135.6, 132.8, 129.9, 127.8, 62.1, 26.7, 19.3. FT-IR (film): 1760 (CO). M/z 271.0 (M+-tBu), 251.1 (M+-Ph). Elemental Anal. Calcd: C, 69.47; H, 7.36. Obtained: C, 69.50; H, 7.08.

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 74 - 79
[2]Organic and Biomolecular Chemistry,2013,vol. 11,p. 7825 - 7829
[3]Patent: EP2957562,2015,A1 .Location in patent: Paragraph 0025; 0026; 0027; 0028; 0029
[4]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1236 - 1241
[5]Synthetic Communications,1998,vol. 28,p. 3727 - 3741
[6]Journal of the American Chemical Society,2010,vol. 132,p. 10920 - 10934
[7]European Journal of Organic Chemistry,2019,vol. 2019,p. 6296 - 6305

12
[ 553-90-2 ]
[ 96-35-5 ]
[ 107-21-1 ]

Yield	Reaction Conditions	Operation in experiment
86%; 13%	With C32H32Cl2N2P2Ru; hydrogen; sodium methylate; In para-xylene; toluene; at 5 - 100℃; under 37503.8 Torr; for 4h;Glovebox;	In an argon atmosphere glove box,Weigh 25.7 mg of catalyst III-A-1,20.5 mg sodium methoxide,0.89 g of dimethyl oxalate (substrate ester: sodium methoxide: catalyst = 200 : 10 : 1 (molar ratio)),After 6 mL of toluene and 50 muL of p-xylene (internal standard) in a 100 mL reactor,Assemble the kettle and remove the glove box.Then, the kettle was cooled to 5 C with ice water.The argon gas in the autoclave was replaced with hydrogen (10 bar) three times and then hydrogenated to 50 bar.The kettle was placed in a heating apparatus and heated to 100 C and maintained at this temperature for 4 h.After the reaction is completed, the temperature of the kettle body is quickly lowered to 5 C and the remaining hydrogen in the kettle is drained.The reaction solution was filtered through a short column of 1 cm silica gel and analyzed by gas chromatography (GC) (KB-Wax column 60 m × 0.32 mm × 0.33 mum).The yields of methyl glycolate (MG) and ethylene glycol (EG) were 86% and 13%, respectively.
	With hydrogen; In methanol; at 200 - 350℃; under 750.075 - 15001.5 Torr; for 4h;	Cu(NO3)2 was formulated with 0.3 mol/L aqueous solution with deionized water, a solution of 157 ml of this solution was placed in a beaker, while stirring slowly add ammonia, the pH of the solution in the beaker was 9.5 to 10.5. weighed 12 g of silica was added to the above-mentioned beaker containing Cu(NO3)2 solution, in the 30 C water bath stirring aging 4h, heated to 90 C steamed ammonia, until the beaker solution has a pH of 7 to 8. the resulting precipitate was filtered and washed to a filtrate at a pH of about 7. the washed precipitate was dried at 120 C for 12 h, 450 C calcination 4h, tablet crushing to 20 ~ 40 mesh, pre-reaction reduction to obtain catalyst A: 20 wt% Cu/silica. The above catalyst performance was evaluated in a continuous flowing gas solid phase reactor, The catalyst loading was 1.0g. using a pure hydrogen normal pressure 350 C reduction catalyst, flow rate of 100mL/min, the temperature is raised from room temperature to 350 C at a rate of 1 to 2 C/min, and keep 4h, down to the reaction temperature after the introduction of H2, a 15 wt.% DMO solution of methanol was poured into an advection pump. control the hydrogen ester ratio 150,The system pressure is 2.0 MPa, the reaction temperature was 200 C. chromatographic analysis raw materials dimethyl oxalate (DMO) and the product of methyl glycolate (MG), ethylene glycol (EG), ethanol (EO), 2-methoxyethylether (2-MEO), 1,2-propanediol (1,2POD), 1,2-butanediol (1,2BOD).The evaluation results of the catalyst performance are shown in Table 1.
	With hydrogen; In methanol; at 70℃; for 24h;Catalytic behavior;	The hydrogenation of DMO was investigated to testify the catalytic performance of Ru/SiO2and Ru-NH2-SiO2 catalyst (as seen inTable 2). The conversion of DMO was 54.7% over Ru-NH2-SiO2 cata-lyst, which was as twice as that on Ru/SiO2catalyst at 50C (entries1-2). As temperature increased to 70C (entries 3-4), a high conversion of 94.7% for DMO was achieved on Ru-NH2-SiO2 catalyst, whereas the conversion of DMO was only 30.1% on Ru/SiO2 catalyst. A nearly complete conversion of DMO was obtained at 80C on the Ru-NH2-SiO2 catalyst, however, the Ru/SiO2 catalyst still maintained lower catalytic performance even when the temperatures rose to 100C (entries 8). Moreover, it can be found that the attained TOF values (50C-100C) over Ru-NH2-SiO2 catalyst were about ten times of the values over Ru/SiO2. This result clearly revealed the higher intrinsic activity of Ru-NH2-SiO2 catalyst compared withRu/SiO2catalyst

	With hydrogen; at 170℃; under 15514.9 Torr;Flow reactor;Catalytic behavior;	FIG. 2 illustrates the selectivity of DMO to form EG and Methyl Glycolate Intermediate (MG) using various catalysts, according to some embodiments of the present disclosure. Hydrogenation conditions: catalyst mass corresponding to 0.3 g Cu (about 1.5 g of catalyst), 300 PSI pressure, temperature at least 170 C., weight hourly space velocity (WHSV) 0.8 (g DMO h/g cat), initial gaseous phase 92.6% v. % H2, 7.4 v % N2, H2/DMO mol ratio 80:1, initial liquid phase 10 wt % DMO/methanol. As shown in FIG. 2, catalysts 204-220 result in selectivity, i.e. products containing C-C bonds: only EG and MG, until 200 C. (as shown by the overlapping data points of 204-220). Catalysts produced using ammonia-based processes (described above) (catalysts 204, 206, 210 and 212) decrease in selectivity above 190 C. (Note: the 204 data point overlaps with the 218 data point at 200 C.). Catalysts prepared from ammonium carbonate (208, 216, 218 and 220) showed selectivity similar to the catalysts prepared using ammonia fast gelation (described above) (Note: 210 and 212) (the 216 data point overlaps with the 220 data point at 230 C.). (0041) FIG. 3 illustrates the conversion of DMO to EG and MG under the same hydrogenation conditions as FIG. 2, according to an embodiment of the present disclosure. As shown in FIG. 3, hydrogenation using a catalyst formed by gelation of Cu(NO3)2 in TEOS (202) displays the highest conversion, but, as shown in FIG. 2, the lowest selectivity of all catalysts tested. As shown in FIG. 3, hydrogenation reactions performed using catalysts prepared from ammonium carbonate (208, 216, 218 and 220) result in higher conversion % over a broad range of temperatures as compared to the catalysts synthesized by ammonia evaporation or other processes (202-206, 210-214). (Note: 204 data point overlaps with 216 data point at 170 C.; 218 data point overlaps 202 data point at 200 C.; 202 data point overlaps 220 data point at 210 C.; 208, 212, and 218 data points overlap 206 data point at 210 C.; 202, 208, and 216 data points overlap 220 data point at 220 C.; 204 data point overlaps with 210 data point at 240 C.). FIG. 2 and FIG. 3 cumulatively illustrate that preparation of catalysts using an ammonium salt, such as ammonium carbonate, results in hydrogenation catalysts with a superior combination of both selectivity and efficient conversion as compared to combination selectivity and conversion of catalysts not prepared using an ammonium salt. Catalysts synthesized with ammonium salts also show prolonged catalytic activity as compared to catalysts synthesized without an ammonium salt.
	With ethanol; [bis({2?[bis(propan?2?yl)phosphanyl]ethyl})amide](carbonyl)(hydride)iron(II); In toluene; at 100℃; for 16h;Inert atmosphere; Glovebox; Schlenk technique;	Under an inert atmosphere, an oven-dried 200-mL thick-wall Schlenk tube equipped with a stir-bar was charged with compound 1 c (0.1 mmol), dimethyl oxalate (0.01 mol, 1 .2 g, 99% pure), anhydrous EtOH (0.2 mol, 1 1 .7 mL), and 20 mL of anhydrous toluene. The resulting mixture was heated to 100QC for -16 h using an oil-bath. After -16 h, the brown colored solution was cooled to room temperature, volatiles were carefully vented inside the hood, and the resulting liquid was analyzed by gas chromatography Under these conditions, 47.8% of dimethyl oxalate was converted to yield 18.4% of ethylene glycol (EG) and 23.5% of methyl glycolate. EtOAc, MeOH, and trace amounts of methyl formate were also observed as other volatile byproducts.

Reference： [1]Patent: CN109776618,2019,A .Location in patent: Paragraph 0034; 0036
[2]ChemCatChem,2016,vol. 8,p. 527 - 531
[3]ChemCatChem,2016,vol. 8,p. 527 - 531
[4]Journal of Organometallic Chemistry,1986,vol. 299,p. 233 - 238
[5]Journal of Catalysis,2011,vol. 280,p. 77 - 88
[6]Journal of Molecular Catalysis A: Chemical,2011,vol. 346,p. 70 - 78
[7]Journal of Molecular Catalysis A: Chemical,2011,vol. 346,p. 70 - 78
[8]Chemical Communications,2012,vol. 48,p. 1177 - 1179
[9]Journal of the American Chemical Society,2012,vol. 134,p. 13922 - 13925
[10]ACS Catalysis,2013,vol. 3,p. 2738 - 2749
[11]ChemCatChem,2016,vol. 8,p. 1065 - 1073
[12]RSC Advances,2016,vol. 6,p. 45512 - 45518
[13]RSC Advances,2016,vol. 6,p. 45512 - 45518
[14]RSC Advances,2016,vol. 6,p. 111415 - 111420
[15]Patent: CN105622418,2016,A .Location in patent: Paragraph 0020; 0021; 0024; 0025
[16]Journal of Molecular Catalysis A: Chemical,2016,vol. 425,p. 68 - 75
[17]Patent: US10086364,2018,B2 .Location in patent: Page/Page column 8-9
[18]Patent: WO2019/27948,2019,A1 .Location in patent: Paragraph 0095; 0096
[19]Dalton Transactions,2019,vol. 48,p. 2290 - 2294
[20]Dalton Transactions,2019,vol. 48,p. 2290 - 2294
[21]Patent: US2020/140359,2020,A1 .Location in patent: Paragraph 0041; 0057
[22]Patent: US2020/140359,2020,A1 .Location in patent: Paragraph 0041; 0057

13
[ 96-35-5 ]
[ 7664-93-9 ]
[ 64-19-7 ]
[ 108-88-3 ]
[ 13831-30-6 ]

Reference： [1]Industrial and Engineering Chemistry,1948,vol. 40,p. 536

14
[ 96-35-5 ]
[ 7664-93-9 ]
[ 64-19-7 ]
[ 71-43-2 ]
[ 13831-30-6 ]
[ 5837-80-9 ]

Reference： [1]Industrial and Engineering Chemistry,1948,vol. 40,p. 536

15
[ 50918-08-6 ]
[ 7637-07-2 ]
[ 96-35-5 ]
[ 6290-49-9 ]
[ 7040-23-5 ]

Yield	Reaction Conditions	Operation in experiment
	at 75 - 100℃;

Reference： [1]Current Patent Assignee: DUPONT DE NEMOURS INC - US2405967, 1944, A

16
[ 34387-89-8 ]
[ 96-35-5 ]
N-tert-butyloxycarbonyl-N-phthalimidoglycine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 0.5h;
70%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 0.5h;

Reference： [1]Brosse, Nicolas; Pinto, Maria-Fatima; Jamart-Gregoire, Brigitte [European Journal of Organic Chemistry, 2003, # 24, p. 4757 - 4764]
[2]Brosse; Pinto; Bodiguel; Jamart-Gregoire [Journal of Organic Chemistry, 2001, vol. 66, # 8, p. 2869 - 2873]

17
[ 96-35-5 ]
[ 14227-66-8 ]
[ 602281-11-8 ]

Reference： [1]European Journal of Organic Chemistry,2003,p. 2462 - 2470

18
[ 96-35-5 ]
[ 100-39-0 ]
[ 31600-43-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With silver(l) oxide; In ethyl acetate;Heating / reflux;Product distribution / selectivity;	Add BnBr (72.7 mL, 0.61 mol, 1.1 eq) and Ag2O (141.6 g, 0.61 mol, 1.1 eq) to a solution of methyl glycolate (50 g, 0.56 mol) in EtOAc (300 mL) and stir the mixture to reflux overnight. Follow the reaction by TLC (Hexane/EtOAC 1 : 1). Filter the reaction through celite and remove the solvent under vacuum. The oil is passed adsorbed onto flash silica. Place on top of a pad of flash silica (500g) and elute with 20% ethyl acetate/hexane to give 75.8 g (75% yield) of a colorless oil.; General Procedure for Scheme 6 Add BnBr (72.7 mL, 0.61 mol, 1.1 eq) and Ag2O (141.6 g, 0.61 mol, 1.1 eq) to a solution of methyl glycolate (50 g, 0.56 mol) in EtOAc (300 mL) and stir the mixture to reflux overnight. Follow the reaction by TLC (Hexane/EtOAC 1 : 1). Filter the reaction through celite and remove the solvent under vacuum. Pass adsorb the oil onto flash silica and place on top of a pad of flash silica (500g) and elute with 20% ethyl acetate/hexane to give 75.8 g (75% yield) of compound A of scheme 6. ; Add BnBr (72.7 mL, 0. 61 mol, 1.1 eq) and Ag2O (141.6 g, 0.61 mol, 1.1 eq) to a solution of methyl glycolate (50 g, 0.56 mol) in EtOAc (300 mL) and stir the mixture to reflux overnight. Follow the reaction by TLC (Hexane/EtOAC 1 : 1). Filter the reaction through celite and remove the solvent under vacuum. The oil is passed adsorbed onto flash silica. Place on top of a pad of flash silica (500g) and elute with 20% ethyl acetate/hexane to give 75.8 g (75% yield) of preparation 19 as a colorless oil.
71%		To a solution of methyl 2-hydroxyacetate (20 g, 0.22 mol, 1.0 eq.) in dry THF (250 mL)was added NaH (60 % in mineral oil) (6.4 g, 0.26 mol, 1.2 eq.) at 0C over a period of 15 minutes. The reaction mixture was allowed to stir at that temperature for 30 minutes. To thatstirred solution were added TBAI (8.20 g, 0.022 mol, 0.1 eq.) followed by(bromomethyl)benzene (38 g, 0.22 mol, 1.0 eq.) at that temperature and allowed to stir at RT for16 h. Progress of reaction was monitored by TLC (10 % ethyl acetate-hexane). After completion,reaction mixture was diluted with ice-cold water (100 mL) and extracted with ethyl acetate (3 x250 mL). Combined organic layer was washed with brine and dried over anhydrous sodiumsulfate. Removal of solvent under reduced pressure afforded crude which was purified by Combi-Flash to afford methyl 2-(benzyloxy)acetate (28.4 g, 71 %).
70%		To a stirred solution of methyl glycolate (2 g, 22.2 mmol) in anhydrous diethyl ether (100 niL), at RT, under a nitrogen atmosphere, was added silver(I)oxide (10.3 g, 44.4 mmol). The suspension was stirred for 15 min and benzyl bromide (4.5 g, 26.3 mmol) was added. The mixture was stirred at the same temperature for 24 hours, and the insoluble materials were removed by filtration through a short pad of celite. The filtrate was concentrated under reduced pressure, and the crude product chromatographed over a column of silica gel, eluting with 20% diethyl ether-petroleum ether to give 70, as a colorless liquid in 70% yield (2.8 g).[0395] 70 was confirmed as follows: 1H NMR (500 MHz, CDCl3) delta 7.39-7.29 (m, 5H), 4.62 (s, 2H), 4.16 (s, 2H), 3.78 (s, 3H).

Reference： [1]Organic Letters,2003,vol. 5,p. 4521 - 4523
[2]Patent: WO2005/65683,2005,A1 .Location in patent: Page/Page column 45; 73-75; 77
[3]Patent: WO2019/103897,2019,A1 .Location in patent: Page/Page column 198
[4]Patent: WO2009/52319,2009,A1 .Location in patent: Page/Page column 120

19
[ 96-35-5 ]
[ 128143-88-4 ]
([2,2';6',2'']terpyridin-4'-yloxy)-acetic acid methyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 5707 - 5709

20
[ 96-35-5 ]
[ 147992-80-1 ]
[ 869802-18-6 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 7374 - 7388

21
[ 553-90-2 ]
[ 96-35-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With (o-PPh2C6H4NH2)[EtNH(CH2)2NHEt]RuCl2; hydrogen; sodium methylate; In tetrahydrofuran; para-xylene; at 5 - 100℃; under 7500.75 Torr; for 1.5h;Glovebox;	In an argon atmosphere glove box,Weighed catalyst I-A-2 (4.28 mg),Sodium methoxide (3.0 mg),Dimethyl oxalate (1.34g,Substrate with sodium methoxide,The molar ratio of the catalyst is 2000:10:1),Tetrahydrofuran (10 mL) and p-xylene (30 muL, internal standard) were placed in a 100 mL autoclave with a mechanical stirring apparatus, and the kettle was assembled and transferred out of the glove box.Subsequently, the autoclave was cooled to about 5 C with ice water, and the atmosphere in the autoclave was replaced with hydrogen (10 bar) for 3 times and then hydrogenated to 50 bar. The kettle body was placed in a heating apparatus and heated to 100 C and maintained at this temperature for 1 h. After the reaction is completed, the kettle body is rapidly cooled to about 5 C and the remaining hydrogen in the kettle is drained. The reaction solution is filtered through a short silica gel column and analyzed by gas chromatography with a hydrogen ion flame detector (column model KB- Wax, the specification is 60 m × 0.32 mm × 0.33 mum), and the yield of the hydrogenation reaction product methyl glycolate is 76%.; In the same experimental procedure as in the ninth embodiment, the catalyst was changed to IB-3 (3.21 mg), the amount of the catalyst was changed to 12.84 mg, the amount of sodium methoxide was changed to 12.0 mg, the pressure of hydrogen was decreased to 10 bar, and the reaction time was changed to 1.5 h to obtain the corresponding hydrogenation. The yield of the product methyl glycolate was 99%
	With hydrogen; In methanol; at 210℃; under 18751.9 Torr;Autoclave;	The DMO hydrogenation reaction was conducted in continu-ous flow mode in a stainless steel tubular reactor. Typically, 3.0 gof passivated Raney copper catalyst (40-60 meshes) was loadedinto the center of the reactor, and both sides of the catalyst bedwere packed with quartz powders (40-60 meshes). Before the test,the inert samples were firstly activated in 5% H2/95% N2(volumeratio) atmosphere at 200C for 4 h with a ramping rate of 2C /min.After that, 12.5 wt% DMO (purity 99.9%) in methanol and H2werefed into the reactor at a H2/DMO molar ratio of 100. The prod-ucts were analyzed with a GC-920 gas chromatograph fitted witha DB-FFAP capillary column (30.00 m × 0.45 mm × 0.85 m) and aflame ionization detector with relative standard deviation less than2%. Reaction conditions: T = 210C, P = 2.5 MPa, and Liquid HourlySpace Velocity (LHSV) = 2.0 h-1.
	With hydrogen; In methanol; at 220 - 350℃; under 750.075 - 15001.5 Torr; for 4h;	General procedure: Cu(NO3)2 was formulated with 0.3 mol/L aqueous solution with deionized water, a solution of 157 ml of this solution was placed in a beaker, while stirring slowly add ammonia, the pH of the solution in the beaker was 9.5 to 10.5. weighed 12 g of silica was added to the above-mentioned beaker containing Cu(NO3)2 solution, in the 30 C water bath stirring aging 4h, heated to 90 C steamed ammonia, until the beaker solution has a pH of 7 to 8. the resulting precipitate was filtered and washed to a filtrate at a pH of about 7. the washed precipitate was dried at 120 C for 12 h, 450 C calcination 4h, tablet crushing to 20 ~ 40 mesh, pre-reaction reduction to obtain catalyst A: 20 wt% Cu/silica. The above catalyst performance was evaluated in a continuous flowing gas solid phase reactor, The catalyst loading was 1.0g. using a pure hydrogen normal pressure 350 C reduction catalyst, flow rate of 100mL/min, the temperature is raised from room temperature to 350 C at a rate of 1 to 2 C/min, and keep 4h, down to the reaction temperature after the introduction of H2, a 15 wt.% DMO solution of methanol was poured into an advection pump. control the hydrogen ester ratio 150, The system pressure is 2.0 MPa, the reaction temperature was 200 C. chromatographic analysis raw materials dimethyl oxalate (DMO) and the product of methyl glycolate (MG), ethylene glycol (EG), ethanol (EO), 2-methoxyethylether (2-MEO), 1,2-propanediol (1,2POD), 1,2-butanediol (1,2BOD).The evaluation results of the catalyst performance are shown in Table 1. catalyst performance of catalyst D: 20 wt% Cu / ZSM-5 prepared in Example 3 was evaluated for catalyst performance, only the hydrogen ester ratio was changed to 10, the other was the same as in Example 11. The evaluation results of the catalyst performance are shown in Table 3.

	With hydrogen; In methanol; at 50℃; for 24h;Catalytic behavior;	The hydrogenation of DMO was investigated to testify the catalytic performance of Ru/SiO2and Ru-NH2-SiO2 catalyst (as seen inTable 2). The conversion of DMO was 54.7% over Ru-NH2-SiO2 cata-lyst, which was as twice as that on Ru/SiO2catalyst at 50C (entries1-2). As temperature increased to 70C (entries 3-4), a high conversion of 94.7% for DMO was achieved on Ru-NH2-SiO2 catalyst, whereas the conversion of DMO was only 30.1% on Ru/SiO2 catalyst. A nearly complete conversion of DMO was obtained at 80C on the Ru-NH2-SiO2 catalyst, however, the Ru/SiO2 catalyst still maintained lower catalytic performance even when the temperatures rose to 100C (entries 8). Moreover, it can be found that the attained TOF values (50C-100C) over Ru-NH2-SiO2 catalyst were about ten times of the values over Ru/SiO2. This result clearly revealed the higher intrinsic activity of Ru-NH2-SiO2 catalyst compared withRu/SiO2catalyst
	With hydrogen; In methanol; at 199.84℃; under 18751.9 Torr;Flow reactor;	The catalytic performance was carried out in a continuous flow unit equipped with a stainless-steel tube reactor placed vertically inside afurnace with a temperature controller. The catalyst (40-60 meshes) was packed in the center of the tube reactor. The reaction was carried out after the catalyst was reduced in pure hydrogen atmosphere at 623 K for 4 h. The reactant (20 wt. % DMO (99.9% purity) in methanol (AR purity) solution) was injected from the top of the reactor through a high-pressure pump (Lab Alliance Series II pump) with a system pressure of 2.5 MPa. The reaction was performed at 473 K, with the weight liquid hourly space velocity (WLHSV) of 1.5 gDMO gcat-1 h-1 (for short h-1). The products collected in a condenser were analyzed on an Agilent Micro GC 6820 with an HP-INNOWAX capillary column (Hewlett-Packard Company, 30m ×0.32mm ×0.50 mum) equipped with a flame ionization detector (FID). To ensure repeatability, 4-6 separate GC samples were taken and the results were averaged for each experimental data point, and uncertainties were typically within 3%.

Reference： [1]Patent: CN110003283,2019,A .Location in patent: Paragraph 0038-0046; 0066-0073
[2]ChemCatChem,2016,vol. 8,p. 527 - 531
[3]Chemical Communications,2006,p. 2289 - 2291
[4]Chemical Communications,2010,vol. 46,p. 4348 - 4350
[5]Journal of Molecular Catalysis A: Chemical,2011,vol. 346,p. 70 - 78
[6]Journal of Molecular Catalysis A: Chemical,2011,vol. 346,p. 70 - 78
[7]ACS Catalysis,2013,vol. 3,p. 2738 - 2749
[8]Catalysis Communications,2013,vol. 40,p. 129 - 133
[9]Applied Catalysis A: General,2016,vol. 509,p. 153 - 160
[10]RSC Advances,2016,vol. 6,p. 12788 - 12791
[11]ChemCatChem,2016,vol. 8,p. 1065 - 1073
[12]RSC Advances,2016,vol. 6,p. 45512 - 45518
[13]Patent: CN105622418,2016,A .Location in patent: Paragraph 0020; 0021; 0051; 0052
[14]Journal of Molecular Catalysis A: Chemical,2016,vol. 425,p. 68 - 75
[15]New Journal of Chemistry,2018,vol. 42,p. 10290 - 10299
[16]Journal of Materials Chemistry A,2018,vol. 6,p. 19133 - 19142
[17]Dalton Transactions,2019,vol. 48,p. 2290 - 2294
[18]Catalysis Today,2019

22
[ 96-35-5 ]
[ 107-21-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	With C24H38Cl2N3PRu; hydrogen; sodium methylate; In isopropyl alcohol; at 100℃; under 37503.8 Torr; for 2h;	General procedure: Hydrogenation of Other Ester Compounds Catalyzed by Synthetic Preparation of Bipyridine Tetradshed Ruthenium Complex 5 The results are shown in Table 2:Table 2 Hydrogenation of other ester compounds a; A Reaction conditions: S / C = 1000,3.0 mmol Substrate, 3.0 mumol 5, 3.0 mL lPrOH, 0.3 mmol NaOMe, 5 MPa H2, 25 C; D 100 C.
	With hydrogen;tris(2,4-pentanedionato)ruthenium(III); [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine]; In methanol; at 200℃; under 12751.3 - 103510 Torr; for 3h;Product distribution / selectivity;	Example 1Reduction of Methyl Glycolate in Methanol to Ethylene Glycol The following example shows the positive effect of adding a promoter to the catalyst mixture. Run 1 in the table below is a comparative example. Runs 2-9 represent variants of the current invention.A 300-milliliter autoclave was charged with Ru(Acac)3 (0.10 mmole), TRIPHOS (0.50 mmole), and the promoter in the amount specified in the table. Methanol (32 milliliters) and methyl glycolate (0.156 mole) were added, and the reactor was sealed under N2. The reactor was pressurized to 250 psig (1.7 MPa) with H2 and heated to 200 C. Upon reaching 200 C., the H2 pressure was raised to 2000 psig (13.8 MPa). The autoclave was stirred and held at 200 C., 2000 psig (13.8 MPa) for a total of 3 hours. The autoclave was then cooled, excess gas vented, and the contents recovered. The contents were analyzed by the use of an internal standard gas chromatography method for the presence of methyl glycolate (?MG?) and ethylene glycol (?EG?). The results are shown in the table below. Catalyst Activity Rate Amount of Conversion of Selectivity to (moles EG per Promoter MG EG mole of Ru Run Promoter (mmole) (%) (%) per hr) 1 none none 39.5 88.4 205 2 Zn 0.25 49.3 88.9 228 Acetonylacetonate 3Me4NBF4 0.025 99.7 98.2 509 4Me4NBF4 0.001 96.8 98.2 394 5NH4PF6 0.025 100 96.9 504 6NH4OAc 0.150 67.8 94.8 334 7Ph4PBr 0.025 84.1 97.8 428 8NaPh4B 0.500 81.1 93.5 394 9BuN4PF6 0.025 97.8 95.8 487 Analysis of the run without a promoter showed a 39.5% conversion of the methyl glycolate with 88.4% selectivity to ethylene glycol. The catalyst activity rate for this experiment was 205 moles of EG per mole of ruthenium per hour. On the other hand, runs with a promoter showed MG conversions of 49-100%, EG selectivities of 89-98%, and catalyst activity rates of 230-510 moles of EG per mole of ruthenium per hour. This data show the positive effects of adding a promoter to the reaction mixture.
	With hydrogen; toluene-4-sulfonic acid;tris(2,4-pentanedionato)ruthenium(III); [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine]; In methanol; at 200℃; under 12751.3 - 103510 Torr; for 3h;Product distribution / selectivity;	Example 5 Reduction of Glycolate Oligomers in Methanol to Ethylene Glycol A 300-milliliter autoclave was charged with Ru(Acac)3 (0.10 mmole), TRIPHOS (0.50 mmole), and toluenesulfonic acid (0.03 gram). Methanol (32 milliliters) and 14.0 grams of a mixture of methyl glycolate and oligomers were added to the autoclave. The glycolate mixture contained 40% methyl glycolate and higher molecular oligomers to give an average molecular weight for the mixture of 150. The reactor was sealed under N2 and then pressurized to 250 psig (1.7 MPa) with H2 and heated to 200 C. Upon reaching 200 C., the H2 pressure was raised to 2000 psig (13.8 MPa). The autoclave was stirred and held at 200 C., 2000 psig (13.8 MPa) for a total of 3 hours. The autoclave was then cooled, excess gas vented, and the contents recovered. The contents were analyzed by the use of an internal standard gas chromatography method to show the presence of a trace of methyl glycolate and 0.183 mole of ethylene glycol. The catalyst turnover rate for this example is 610 moles of EG per mole of ruthenium per hour.

	With hydrogen; tetraphenylphosphonium bromide;tris(2,4-pentanedionato)ruthenium(III); [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine]; In methanol; at 200℃; under 12751.3 - 103510 Torr; for 3h;Product distribution / selectivity;	Example 1Reduction of Methyl Glycolate in Methanol to Ethylene Glycol The following example shows the positive effect of adding a promoter to the catalyst mixture. Run 1 in the table below is a comparative example. Runs 2-9 represent variants of the current invention.A 300-milliliter autoclave was charged with Ru(Acac)3 (0.10 mmole), TRIPHOS (0.50 mmole), and the promoter in the amount specified in the table. Methanol (32 milliliters) and methyl glycolate (0.156 mole) were added, and the reactor was sealed under N2. The reactor was pressurized to 250 psig (1.7 MPa) with H2 and heated to 200 C. Upon reaching 200 C., the H2 pressure was raised to 2000 psig (13.8 MPa). The autoclave was stirred and held at 200 C., 2000 psig (13.8 MPa) for a total of 3 hours. The autoclave was then cooled, excess gas vented, and the contents recovered. The contents were analyzed by the use of an internal standard gas chromatography method for the presence of methyl glycolate (?MG?) and ethylene glycol (?EG?). The results are shown in the table below. Catalyst Activity Rate Amount of Conversion of Selectivity to (moles EG per Promoter MG EG mole of Ru Run Promoter (mmole) (%) (%) per hr) 1 none none 39.5 88.4 205 2 Zn 0.25 49.3 88.9 228 Acetonylacetonate 3Me4NBF4 0.025 99.7 98.2 509 4Me4NBF4 0.001 96.8 98.2 394 5NH4PF6 0.025 100 96.9 504 6NH4OAc 0.150 67.8 94.8 334 7Ph4PBr 0.025 84.1 97.8 428 8NaPh4B 0.500 81.1 93.5 394 9BuN4PF6 0.025 97.8 95.8 487 Analysis of the run without a promoter showed a 39.5% conversion of the methyl glycolate with 88.4% selectivity to ethylene glycol. The catalyst activity rate for this experiment was 205 moles of EG per mole of ruthenium per hour. On the other hand, runs with a promoter showed MG conversions of 49-100%, EG selectivities of 89-98%, and catalyst activity rates of 230-510 moles of EG per mole of ruthenium per hour. This data show the positive effects of adding a promoter to the reaction mixture.
	With hydrogen; sodium tetraphenyl borate;tris(2,4-pentanedionato)ruthenium(III); [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine]; In methanol; at 200℃; under 12751.3 - 103510 Torr; for 3h;Product distribution / selectivity;	Example 1Reduction of Methyl Glycolate in Methanol to Ethylene Glycol The following example shows the positive effect of adding a promoter to the catalyst mixture. Run 1 in the table below is a comparative example. Runs 2-9 represent variants of the current invention.A 300-milliliter autoclave was charged with Ru(Acac)3 (0.10 mmole), TRIPHOS (0.50 mmole), and the promoter in the amount specified in the table. Methanol (32 milliliters) and methyl glycolate (0.156 mole) were added, and the reactor was sealed under N2. The reactor was pressurized to 250 psig (1.7 MPa) with H2 and heated to 200 C. Upon reaching 200 C., the H2 pressure was raised to 2000 psig (13.8 MPa). The autoclave was stirred and held at 200 C., 2000 psig (13.8 MPa) for a total of 3 hours. The autoclave was then cooled, excess gas vented, and the contents recovered. The contents were analyzed by the use of an internal standard gas chromatography method for the presence of methyl glycolate (?MG?) and ethylene glycol (?EG?). The results are shown in the table below. Catalyst Activity Rate Amount of Conversion of Selectivity to (moles EG per Promoter MG EG mole of Ru Run Promoter (mmole) (%) (%) per hr) 1 none none 39.5 88.4 205 2 Zn 0.25 49.3 88.9 228 Acetonylacetonate 3Me4NBF4 0.025 99.7 98.2 509 4Me4NBF4 0.001 96.8 98.2 394 5NH4PF6 0.025 100 96.9 504 6NH4OAc 0.150 67.8 94.8 334 7Ph4PBr 0.025 84.1 97.8 428 8NaPh4B 0.500 81.1 93.5 394 9BuN4PF6 0.025 97.8 95.8 487 Analysis of the run without a promoter showed a 39.5% conversion of the methyl glycolate with 88.4% selectivity to ethylene glycol. The catalyst activity rate for this experiment was 205 moles of EG per mole of ruthenium per hour. On the other hand, runs with a promoter showed MG conversions of 49-100%, EG selectivities of 89-98%, and catalyst activity rates of 230-510 moles of EG per mole of ruthenium per hour. This data show the positive effects of adding a promoter to the reaction mixture.
	With ammonium acetate; hydrogen;tris(2,4-pentanedionato)ruthenium(III); [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine]; In methanol; at 200℃; under 12751.3 - 103510 Torr; for 3h;Product distribution / selectivity;	Example 1Reduction of Methyl Glycolate in Methanol to Ethylene Glycol The following example shows the positive effect of adding a promoter to the catalyst mixture. Run 1 in the table below is a comparative example. Runs 2-9 represent variants of the current invention.A 300-milliliter autoclave was charged with Ru(Acac)3 (0.10 mmole), TRIPHOS (0.50 mmole), and the promoter in the amount specified in the table. Methanol (32 milliliters) and methyl glycolate (0.156 mole) were added, and the reactor was sealed under N2. The reactor was pressurized to 250 psig (1.7 MPa) with H2 and heated to 200 C. Upon reaching 200 C., the H2 pressure was raised to 2000 psig (13.8 MPa). The autoclave was stirred and held at 200 C., 2000 psig (13.8 MPa) for a total of 3 hours. The autoclave was then cooled, excess gas vented, and the contents recovered. The contents were analyzed by the use of an internal standard gas chromatography method for the presence of methyl glycolate (?MG?) and ethylene glycol (?EG?). The results are shown in the table below. Catalyst Activity Rate Amount of Conversion of Selectivity to (moles EG per Promoter MG EG mole of Ru Run Promoter (mmole) (%) (%) per hr) 1 none none 39.5 88.4 205 2 Zn 0.25 49.3 88.9 228 Acetonylacetonate 3Me4NBF4 0.025 99.7 98.2 509 4Me4NBF4 0.001 96.8 98.2 394 5NH4PF6 0.025 100 96.9 504 6NH4OAc 0.150 67.8 94.8 334 7Ph4PBr 0.025 84.1 97.8 428 8NaPh4B 0.500 81.1 93.5 394 9BuN4PF6 0.025 97.8 95.8 487 Analysis of the run without a promoter showed a 39.5% conversion of the methyl glycolate with 88.4% selectivity to ethylene glycol. The catalyst activity rate for this experiment was 205 moles of EG per mole of ruthenium per hour. On the other hand, runs with a promoter showed MG conversions of 49-100%, EG selectivities of 89-98%, and catalyst activity rates of 230-510 moles of EG per mole of ruthenium per hour. This data show the positive effects of adding a promoter to the reaction mixture.
	With zinc(II) acetylacetonate; hydrogen;tris(2,4-pentanedionato)ruthenium(III); [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine]; In methanol; at 200℃; under 12751.3 - 103510 Torr; for 3h;Product distribution / selectivity;	Example 1Reduction of Methyl Glycolate in Methanol to Ethylene Glycol The following example shows the positive effect of adding a promoter to the catalyst mixture. Run 1 in the table below is a comparative example. Runs 2-9 represent variants of the current invention.A 300-milliliter autoclave was charged with Ru(Acac)3 (0.10 mmole), TRIPHOS (0.50 mmole), and the promoter in the amount specified in the table. Methanol (32 milliliters) and methyl glycolate (0.156 mole) were added, and the reactor was sealed under N2. The reactor was pressurized to 250 psig (1.7 MPa) with H2 and heated to 200 C. Upon reaching 200 C., the H2 pressure was raised to 2000 psig (13.8 MPa). The autoclave was stirred and held at 200 C., 2000 psig (13.8 MPa) for a total of 3 hours. The autoclave was then cooled, excess gas vented, and the contents recovered. The contents were analyzed by the use of an internal standard gas chromatography method for the presence of methyl glycolate (?MG?) and ethylene glycol (?EG?). The results are shown in the table below. Catalyst Activity Rate Amount of Conversion of Selectivity to (moles EG per Promoter MG EG mole of Ru Run Promoter (mmole) (%) (%) per hr) 1 none none 39.5 88.4 205 2 Zn 0.25 49.3 88.9 228 Acetonylacetonate 3Me4NBF4 0.025 99.7 98.2 509 4Me4NBF4 0.001 96.8 98.2 394 5NH4PF6 0.025 100 96.9 504 6NH4OAc 0.150 67.8 94.8 334 7Ph4PBr 0.025 84.1 97.8 428 8NaPh4B 0.500 81.1 93.5 394 9BuN4PF6 0.025 97.8 95.8 487 Analysis of the run without a promoter showed a 39.5% conversion of the methyl glycolate with 88.4% selectivity to ethylene glycol. The catalyst activity rate for this experiment was 205 moles of EG per mole of ruthenium per hour. On the other hand, runs with a promoter showed MG conversions of 49-100%, EG selectivities of 89-98%, and catalyst activity rates of 230-510 moles of EG per mole of ruthenium per hour. This data show the positive effects of adding a promoter to the reaction mixture.
	With hydrogen; tert-butylammonium hexafluorophosphate(V);tris(2,4-pentanedionato)ruthenium(III); [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine]; In methanol; at 200℃; under 12751.3 - 103510 Torr; for 3h;Product distribution / selectivity;	Example 1Reduction of Methyl Glycolate in Methanol to Ethylene Glycol The following example shows the positive effect of adding a promoter to the catalyst mixture. Run 1 in the table below is a comparative example. Runs 2-9 represent variants of the current invention.A 300-milliliter autoclave was charged with Ru(Acac)3 (0.10 mmole), TRIPHOS (0.50 mmole), and the promoter in the amount specified in the table. Methanol (32 milliliters) and methyl glycolate (0.156 mole) were added, and the reactor was sealed under N2. The reactor was pressurized to 250 psig (1.7 MPa) with H2 and heated to 200 C. Upon reaching 200 C., the H2 pressure was raised to 2000 psig (13.8 MPa). The autoclave was stirred and held at 200 C., 2000 psig (13.8 MPa) for a total of 3 hours. The autoclave was then cooled, excess gas vented, and the contents recovered. The contents were analyzed by the use of an internal standard gas chromatography method for the presence of methyl glycolate (?MG?) and ethylene glycol (?EG?). The results are shown in the table below. Catalyst Activity Rate Amount of Conversion of Selectivity to (moles EG per Promoter MG EG mole of Ru Run Promoter (mmole) (%) (%) per hr) 1 none none 39.5 88.4 205 2 Zn 0.25 49.3 88.9 228 Acetonylacetonate 3Me4NBF4 0.025 99.7 98.2 509 4Me4NBF4 0.001 96.8 98.2 394 5NH4PF6 0.025 100 96.9 504 6NH4OAc 0.150 67.8 94.8 334 7Ph4PBr 0.025 84.1 97.8 428 8NaPh4B 0.500 81.1 93.5 394 9BuN4PF6 0.025 97.8 95.8 487 Analysis of the run without a promoter showed a 39.5% conversion of the methyl glycolate with 88.4% selectivity to ethylene glycol. The catalyst activity rate for this experiment was 205 moles of EG per mole of ruthenium per hour. On the other hand, runs with a promoter showed MG conversions of 49-100%, EG selectivities of 89-98%, and catalyst activity rates of 230-510 moles of EG per mole of ruthenium per hour. This data show the positive effects of adding a promoter to the reaction mixture. Example 2 Reduction of Methyl Glycolate in Methanol to Ethylene Glycol A 300-milliliter autoclave was charged with Ru(Acac)3 (0.10 mmole), TRIPHOS (0.50 mmole), and tetrabutylammonium hexafluorophosphate (0.025 mmol). Methanol (32 milliliters) and methyl glycolate (0.156 mole) were added, and the reactor was sealed under N2. The reactor was pressurized to 250 psig (1.7 MPa) with H2 and heated to 200 C. Upon reaching 200 C., the H2 pressure was raised to 2000 psig (13.8 MPa). The autoclave was stirred and held at 200 C., 2000 psig (13.8 MPa) for a total of 3 hours. The autoclave was then cooled, excess gas vented, and the contents recovered. The contents were analyzed by the use of an internal standard gas chromatography method to show the presence of 0.0034 mole of methyl glycolate and 0.146 mole of ethylene glycol. The catalyst turnover rate for this example is 508 moles of EG per mole of ruthenium per hour.
	With ammonium hexafluorophosphate; hydrogen;tris(2,4-pentanedionato)ruthenium(III); [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine]; In methanol; at 200℃; under 12751.3 - 103510 Torr; for 3h;Product distribution / selectivity;	Example 1Reduction of Methyl Glycolate in Methanol to Ethylene Glycol The following example shows the positive effect of adding a promoter to the catalyst mixture. Run 1 in the table below is a comparative example. Runs 2-9 represent variants of the current invention.A 300-milliliter autoclave was charged with Ru(Acac)3 (0.10 mmole), TRIPHOS (0.50 mmole), and the promoter in the amount specified in the table. Methanol (32 milliliters) and methyl glycolate (0.156 mole) were added, and the reactor was sealed under N2. The reactor was pressurized to 250 psig (1.7 MPa) with H2 and heated to 200 C. Upon reaching 200 C., the H2 pressure was raised to 2000 psig (13.8 MPa). The autoclave was stirred and held at 200 C., 2000 psig (13.8 MPa) for a total of 3 hours. The autoclave was then cooled, excess gas vented, and the contents recovered. The contents were analyzed by the use of an internal standard gas chromatography method for the presence of methyl glycolate (?MG?) and ethylene glycol (?EG?). The results are shown in the table below. Catalyst Activity Rate Amount of Conversion of Selectivity to (moles EG per Promoter MG EG mole of Ru Run Promoter (mmole) (%) (%) per hr) 1 none none 39.5 88.4 205 2 Zn 0.25 49.3 88.9 228 Acetonylacetonate 3Me4NBF4 0.025 99.7 98.2 509 4Me4NBF4 0.001 96.8 98.2 394 5NH4PF6 0.025 100 96.9 504 6NH4OAc 0.150 67.8 94.8 334 7Ph4PBr 0.025 84.1 97.8 428 8NaPh4B 0.500 81.1 93.5 394 9BuN4PF6 0.025 97.8 95.8 487 Analysis of the run without a promoter showed a 39.5% conversion of the methyl glycolate with 88.4% selectivity to ethylene glycol. The catalyst activity rate for this experiment was 205 moles of EG per mole of ruthenium per hour. On the other hand, runs with a promoter showed MG conversions of 49-100%, EG selectivities of 89-98%, and catalyst activity rates of 230-510 moles of EG per mole of ruthenium per hour. This data show the positive effects of adding a promoter to the reaction mixture.
	With hydrogen; tetramethylammonium borohydride;tris(2,4-pentanedionato)ruthenium(III); [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine]; In methanol; at 200℃; under 12751.3 - 103510 Torr; for 3h;Product distribution / selectivity;	Example 1Reduction of Methyl Glycolate in Methanol to Ethylene Glycol The following example shows the positive effect of adding a promoter to the catalyst mixture. Run 1 in the table below is a comparative example. Runs 2-9 represent variants of the current invention.A 300-milliliter autoclave was charged with Ru(Acac)3 (0.10 mmole), TRIPHOS (0.50 mmole), and the promoter in the amount specified in the table. Methanol (32 milliliters) and methyl glycolate (0.156 mole) were added, and the reactor was sealed under N2. The reactor was pressurized to 250 psig (1.7 MPa) with H2 and heated to 200 C. Upon reaching 200 C., the H2 pressure was raised to 2000 psig (13.8 MPa). The autoclave was stirred and held at 200 C., 2000 psig (13.8 MPa) for a total of 3 hours. The autoclave was then cooled, excess gas vented, and the contents recovered. The contents were analyzed by the use of an internal standard gas chromatography method for the presence of methyl glycolate (?MG?) and ethylene glycol (?EG?). The results are shown in the table below. Catalyst Activity Rate Amount of Conversion of Selectivity to (moles EG per Promoter MG EG mole of Ru Run Promoter (mmole) (%) (%) per hr) 1 none none 39.5 88.4 205 2 Zn 0.25 49.3 88.9 228 Acetonylacetonate 3Me4NBF4 0.025 99.7 98.2 509 4Me4NBF4 0.001 96.8 98.2 394 5NH4PF6 0.025 100 96.9 504 6NH4OAc 0.150 67.8 94.8 334 7Ph4PBr 0.025 84.1 97.8 428 8NaPh4B 0.500 81.1 93.5 394 9BuN4PF6 0.025 97.8 95.8 487 Analysis of the run without a promoter showed a 39.5% conversion of the methyl glycolate with 88.4% selectivity to ethylene glycol. The catalyst activity rate for this experiment was 205 moles of EG per mole of ruthenium per hour. On the other hand, runs with a promoter showed MG conversions of 49-100%, EG selectivities of 89-98%, and catalyst activity rates of 230-510 moles of EG per mole of ruthenium per hour. This data show the positive effects of adding a promoter to the reaction mixture.
	With ethanol; [bis({2?[bis(propan?2?yl)phosphanyl]ethyl})amide](carbonyl)(hydride)iron(II); In toluene; at 100℃;Inert atmosphere; Glovebox; Schlenk technique;	Under an inert atmosphere, an oven-dried 200-mL thick-wall Schlenk tube equipped with a stir-bar was charged with compound 1 c (0.1 mmol), methyl glycolate (0.01 mol, 0.91 g, 98% pure), anhydrous EtOH (0.2 mol, 1 1 .7 imL), and 20 imL of anhydrous toluene. The resulting mixture was heated to 100eC for -16 h using an oil-bath. After -16 h, the brown colored solution was cooled to room temperature, volatiles were carefully vented inside the hood, and the resulting liquid was analyzed by gas (0167) chromatography. (0168) [0094] Under these conditions, 63.1 % of methyl glycolate was converted to yield 51 .7% of ethylene glycol (EG). EtOAc, MeOH, and trace amounts of methyl formate were also observed as other volatile byproducts.

Reference： [1]Green Chemistry,2014,vol. 16,p. 4081 - 4085
[2]Patent: CN103980317,2017,B .Location in patent: Paragraph 0098; 0099; 0100; 0101; 0104
[3]European Journal of Organic Chemistry,2006,p. 1981 - 1990
[4]Patent: US2009/143612,2009,A1 .Location in patent: Page/Page column 4
[5]Patent: US2009/143612,2009,A1 .Location in patent: Page/Page column 5
[6]Patent: US2009/143612,2009,A1 .Location in patent: Page/Page column 4
[7]Patent: US2009/143612,2009,A1 .Location in patent: Page/Page column 4
[8]Patent: US2009/143612,2009,A1 .Location in patent: Page/Page column 4
[9]Patent: US2009/143612,2009,A1 .Location in patent: Page/Page column 4
[10]Patent: US2009/143612,2009,A1 .Location in patent: Page/Page column 4-5
[11]Patent: US2009/143612,2009,A1 .Location in patent: Page/Page column 4
[12]Patent: US2009/143612,2009,A1 .Location in patent: Page/Page column 4
[13]Journal of Molecular Catalysis A: Chemical,2011,vol. 346,p. 70 - 78
[14]RSC Advances,2016,vol. 6,p. 45512 - 45518
[15]ChemSusChem,2017,vol. 10,p. 1390 - 1394
[16]Patent: WO2019/27948,2019,A1 .Location in patent: Paragraph 0093; 0094
[17]Dalton Transactions,2019,vol. 48,p. 2290 - 2294

23
[ 96-35-5 ]
[ 35276-83-6 ]
C₁₃H₁₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃;

Reference： [1]Lee, Sunkyung; Kim, Taemi; Lee, Byung Ho; Yoo, Sung-eun; Lee, Kyunghee; Yi, Kyu Yang [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1291 - 1295]

24
[ 96-35-5 ]
[ 21667-62-9 ]
C₁₂H₁₀ClNO₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1291 - 1295

25
[ 96-35-5 ]
[ 53882-81-8 ]
C₁₃H₁₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃;

Reference： [1]Lee, Sunkyung; Kim, Taemi; Lee, Byung Ho; Yoo, Sung-eun; Lee, Kyunghee; Yi, Kyu Yang [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1291 - 1295]

26
[ 75-44-5 ]
[ 38748-32-2 ]
[ 96-35-5 ]
triptolide 14-methoxycarbonylmethyl carbonate [ No CAS ]

Reference： [1]Patent: WO2003/101951,2003,A2 .Location in patent: Page 29

27
[ 96-35-5 ]
[ 79-14-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With water; at 95 - 97℃; under 760.051 Torr; for 2h;Reactive distillation;	As a reactive distillation apparatus, an apparatus obtained by connecting a 3-stage packed column to a flask and further providing a refluxing device at the top of the packed column was used. A mixed liquid obtained by mixing 150 g of water with 50 g of the distillate containing more than 98 wt % of methyl glycolate obtained in (3) above was put into the flask. Next, reactive distillation was carried out for 2 hours at normal pressure, maintaining the temperature at the base of the column of the reactive distillation apparatus (i.e. the liquid temperature) at 95 to 97 C. At this time, distillate containing methanol was distilled off. The temperature at the top of the column was 65 C. at the start of the reactive distillation, but had reached 100 C. by the end. [0322] After the reactive distillation had been completed, 114 g of an aqueous solution containing 36.1 wt % of glycolic acid was recovered from the flask. The yield of glycolic acid relative to the methyl glycolate was 100%. Regarding impurities, formaldehyde and chlorine compounds were not detected, and 20 ppm of oxalic acid and 76 ppm of ethylene glycol were detected.
	With water; In methanol; at 100℃;	The distilled mixture was pooled. 150 ml of deionized water was added to the ester hydrolysis kettle. The ester hydrolysis was carried out at 100C with stirring. Methanol was distilled off and then steamed part of the water (for recycling). An aqueous solution of glycolic acid having a commercial mass concentration of 70% was obtained. Yield 88%.

Reference： [1]Patent: US2004/138409,2004,A1 .Location in patent: Page 23
[2]Green Chemistry,2013,vol. 15,p. 2817 - 2824
[3]Patent: CN104744239,2016,B .Location in patent: Paragraph 0032

28
[ 96-35-5 ]
[ 3530-14-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrazine; In methanol; at 20℃; for 74h;Heating / reflux;	Preparation 69: 2-Hydroxyacetohydrazide Hydrazine monohydrate (1.08 g, 22.2 mmol) was added to a solution of methyl glycolate (0.84 mL, 11.1 mmol) in methanol (10 mL) and the mixture was heated under reflux for 2 hours and stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo to afford the title compound as a white solid in quantitative yield. 1H NMR(400 MHz, CDCl3) delta: 4.04(s, 2H)
	With hydrazine hydrate; In methanol; for 8h;Reflux;	General procedure: Intermediate D15-2-hydroxyacetohydrazide A mixture of methyl 2-hydroxyacetate (9g, 0.1mol, 1equiv) and hydrazine hydrate (9.6ml, 1.5equiv, 85%) in methanol (100ml) was refluxed for 8h before methanol and exceesive hydrazine hydrate were evaporated. Toluene was added and evaporated again to remove the residual water to give the title compound as a white solid which could be used in next step without further purification.
	With hydrazine hydrate; In methanol; for 8h;Reflux;	A mixture ofmethyl 2-hydroxyacetate (9 g, 0.1 mol,equiv) and hydrazine hydrate (9.6 ml, 1.5 equiv, 85%) in methanol (100 ml) was refluxed for 8 h before methanol and exceesive hydrazine hydrate were evaporated. Toluene was added and evaporated again to remove the residual water to give the title compound as a white solid which could be used in next step without further purification.

Reference： [1]Patent: US2006/160786,2006,A1 .Location in patent: Page/Page column 35-36
[2]Journal of Medicinal Chemistry,2020,vol. 63,p. 4117 - 4132
[3]Patent: EP2725024,2014,A1 .Location in patent: Paragraph 0340
[4]Patent: US2014/171431,2014,A1 .Location in patent: Paragraph 0691

29
[ 96-35-5 ]
[ 6358-08-3 ]
[ 870064-73-6 ]

Reference： [1]Patent: WO2006/72430,2006,A1 .Location in patent: Page/Page column 43-44

30
[ 96-35-5 ]
[ 89466-42-2 ]
[ 353293-46-6 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide;	First Step 0.4 g of sodium hydride was added to a mixture of 1.59 g of <strong>[89466-42-2]4-chloro-6-methoxy-2-methylthiopyrimidine</strong>, 0.98 g of methyl glycolate and 10 ml of N,N-dimethylformamide at 0 C. The mixture was stirred at room temperature for 5 hours, then, the reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.22 g of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylthiopyrimidine. 1H-NMR(CDCl3/250 MHz) delta(ppm): 2.48 (s, 3H), 3.77 (s, 3H), 3.93 (s, 3H), 4.88 (s, 2H), 5.87 (s, 1H)

Reference： [1]Patent: US6537948,2003,B1

31
[ 96-35-5 ]
[ 88016-31-3 ]

Yield	Reaction Conditions	Operation in experiment
68%	With pyridine; trifluoromethylsulfonic anhydride; In dichloromethane;	k Methyl trifluoromethylsulfonyloxyacetate To a solution of triflic anhydride (3.7 ml, 20.0 nmmol) in methylene chloride (10 ml) at -5 C. under argon, was added dropwise over 30 minutes a solution of methyl glycolate (1.8 g, 20.0 mmol), pyridine (1.55 ml, 20.0 mmol), and anhydrous methylene chloride (5 ml). The reaction was allowed to stir at between 0-5 C. for 1.5 h. The mixture was then washed with water several times. The organic extract was then washed with water, brine, and dried (MgSO4). After removing the solvent under reduced pressure, flash chromatography of the residue (silica gel, methylene chloride) afforded the title compound as a colorless oil (3.0 g, 68%).
68%	With pyridine; trifluoromethylsulfonic anhydride; In dichloromethane;	k) Methyl trifluoromethylsulfonyloxyacetate To a solution of triflic anhydride (3.7 ml, 20.0 mmol) in methylene chloride (10 ml) at -5 C. under argon, was added dropwise over 30 minutes a solution of methyl glycolate (1.8 g, 20.0 mmol), pyridine (1.55 ml, 20.0 mmol), and anhydrous methylene chloride (5 ml). The reaction was allowed to stir at between 0-5 C. for 1.5 h. The mixture was then washed with water several times. The organic extract was then washed with water, brine, and dried (MgSO4). After removing the solvent under reduced pressure, flash chromatography of the residue (silica gel, methylene chloride) afforded the title compound as a colorless oil (3.0 g, 68%).

Reference： [1]Patent: US5929106,1999,A
[2]Patent: US5736564,1998,A

32
[ 96-35-5 ]
[ 107-30-2 ]
[ 89-91-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane;	STEP 1. Methyl methoxymethyloxyacetate A solution of methyl glycolate (18.02 g) and triethylamine (20.24 g) in anhydrous methylene chloride (100 ml.) is added dropwise over 40 minutes to an ice-cold, stirring solution of chloromethyl methyl ether (17.7 g) in methylene chloride (200 ml.). The resulting mixture is allowed to stand overnight in a flask protected from moisture by a drying tube. The mixture is washed with water, 5% aqueous sodium bicarbonate, water, and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Distillation of the residue yields methyl methoxymethyloxyacetate.

Reference： [1]Patent: US3962224,1976,A

33
[ 698-51-1 ]
[ 96-35-5 ]
[ 62270-89-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In methanol; 1,1,2,2-tetrachloroethylene;	EXAMPLE 4 A reaction vessel was charged with 45.0 g (0.5 mole) of methyl glycolate and 13.3 g (0.125 mole) of anhydrous sodium carbonate. The resulting mixture was heated to 110 C. for 10 minutes, with methanol being allowed to strip off as it condensed. Thereafter 18.4 g (0.1 mole) of <strong>[698-51-1]3,5-dichloro-<strong>[698-51-1]2,6-difluoropyridine</strong></strong> was added to the reaction vessel, and the mixture was stirred at 110 C. for 1 hour. The stripped methanol (approximately 4 ml) and 64 g of fresh methanol were added to the slurry, which was refluxed for 1 hour at 70 C. and filtered. The filtrate was cooled to approximately 10 C. to give fine white crystals which were filtered, washed with cold methanol, and air dried. The resulting solid was further purified by being dissolved in warm perchloroethylene, filtered and cooled to give a solid precipitate. Filtration and air-drying gave 12.0 of a solid product which was identified by gas-liquid chromatography and nuclear magnetic resonance to be the desired product, 3,5-dichloro-6-fluoro-2-pyridinyloxyacetate, m.p. 72.2-73.0 C., of approximately 99% purity. The filtrates from the previous isolations were combined and concentrated by vacuum stripping. The residue was extracted twice with hot methylene chloride, and the filtered extracts were concentrated to remove the solvent, leaving 11.0 g of product which solidified on cooling.

Reference： [1]Patent: US4127582,1978,A

34
[ 96-35-5 ]
[ 14658-93-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dimethyl amine In water; ethyl acetate	84 A Preparation of N,N-dimethyl-2-hydroxyacetamide EXAMPLE 84 A Preparation of N,N-dimethyl-2-hydroxyacetamide Methyl-2-hydroxyethanoate (10 g) and dimethylamine (100 ml, 40 weight percent in water) were mixed and stirred at room temperature for three hours. The mixture was evaporated to dryness to provide approximately 10 g of material. This material was subjected to column chromatography eluding with a gradient of hexane/ethyl acetate (V:V, 4:1) to ethyl acetate. Removal of the solvent provided 8.12 g of crystalline product. ms (fd)=103 M+ m.p.=40°-42° C. I.R.=1655.4 cm-1 (carbonyl) Analysis for C4 H9 NO2: Theory: C, 46.59; H, 8.80; N, 13.59; Found: C, 46.44; H, 8.69; N, 13.60.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - US5250542, 1993, A

35
[ 110-91-8 ]
[ 96-35-5 ]
[ 51068-78-1 ]

Yield	Reaction Conditions	Operation in experiment
	at 150℃; for 3h;	EXAMPLE 172; 4-[7-(2-Morpholin-4-yl-2-oxo-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-pyrrolidin-1-yl-phenyl)-amide; a. 4-[7-(2-Morpholin-4-yl-2-oxo-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester; A mixture of morpholine (107.4 mg, 1.23 mmol) and methyl glycolate (77.5 mg, 860 mumol) was stirred at 150° C. for 3 hr. The resulting homogeneous clear amber oil was taken up in toluene (2.x.2 mL) with repeated rotary evaporation to remove methanol. The residue was taken up in dry THF (860 muL) and KOtBu was added (113 mg, 1.01 mmol). The mixture was stirred at 100° C. for 5-10 min until a brown slurry formed with no visible chunks. The mixture was then allowed to cool to rt, 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (302 mg, 912 mumol), as prepared in Example 65b, was added, and the resulting nearly homogeneous reddish-brown solution was stirred at rt for 1 hr, at which point the reaction solidified into a paste. The reaction was taken up in DCM (4 mL) and washed with 1M NaHCO3 (1.x.2 mL) and 1M NaH2PO4 (1.x.2 mL), and the organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica flash chromatography (9:1 DCM/acetone-->8:2-->8:2 DCM/acetone/3percent DMEA eluent) to provide the title compound as a pale yellow oil (94.8 mg, 24percent over two steps). LC/MS (ESI): calcd mass 456.2, found 457.3 (MH)+.

Reference： [1]Patent: US2006/281772,2006,A1 .Location in patent: Page/Page column 120

36
[ 96-35-5 ]
[ 59237-53-5 ]
[ 924279-03-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	With sodium hydride; In 1,4-dioxane; at 25℃; for 24h;	To a solution of methyl beta-chloro-delta-nitro-S-pyridinecarboxylate (2 g, 9.3 mmol) in dioxane (40 mL) were added NaH (0.4 g, 10.2 mmol, 60percent in mineral oil) and methyl EPO <DP n="43"/>hydroxyacetate (0.78 g, 9.3 mmol). After stirring at 25°C for 24 hr, the solution was partitioned between ethyl acetate and water. The aqueous solution was extracted several times with ethyl acetate. The organic fractions were combined, concentrated and purified with column chromatography (silica, 5 -30percent ehtyl acetate in hexane) to provide the title compound as a white solid (1.3 g, 56percent): LC/MS (ES) m/e 271 (M+H)+

Reference： [1]Patent: WO2007/16610,2007,A2 .Location in patent: Page/Page column 41; 42

37
(2S)-N-methyl-1-phenylpropan-2-amine hydrate [ No CAS ]
[ 96-35-5 ]
[ 6361-21-3 ]
[ 20699-86-9 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium carbonate; In N,N-dimethyl-formamide;	Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5 C. was treated with K2CO3(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25 C. and stirred for 20 h. The solution was then poured into 250 ml of ice H2O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69%). LRMS: 237.0 (Calc.); 238.1 (found). 1H NMR: (DMSO) delta (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).
69%	With potassium carbonate; In N,N-dimethyl-formamide;	Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5 C. was treated with K2CO3(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25 C. and stirred for 20h. The solution was then poured into 250 ml of ice H2O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69%). LRMS: 237.0 (Calc.); 238.1 (found). 1H NMR: (DMSO) delta (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).
69%	With potassium carbonate; In N,N-dimethyl-formamide;	Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chlorobenzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5 C. was treated with K2CO3(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25 C. and stirred for 20 h. The solution was then poured into 250 ml of ice H2O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69%). LRMS: 237.0 (Calc.). 238.1 (found). 1H NMR: (DMSO) delta (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).

Reference： [1]Patent: US2004/142953,2004,A1
[2]Patent: US2005/288282,2005,A1
[3]Patent: US6897220,2005,B2

38
[ 19432-68-9 ]
[ 96-35-5 ]
[ 1019196-86-1 ]

Reference： [1]Synlett,2008,p. 386 - 388
[2]Journal of Organic Chemistry,2009,vol. 74,p. 1124 - 1129

39
[ 96-35-5 ]
[ 402-46-0 ]
[ 98996-94-2 ]

Yield	Reaction Conditions	Operation in experiment
32%		Intermediate 93 : Methyl \|4-(aminosislfony1)pfoenoxvj acetate; <n="93"/>To a stirred suspension of NaH (2.8 g, 0.07 mol, 50% in mineral oil) in DMF (50 mL) is added dropwisc methyl glycolate (5.5 g, 0.06 mol) over a period of 10 min. The mixture is heated up to 5O0C for 3 h and cooled down to room temperature. 4-Fluorobenzenepsilonsulfonamide (2 g, 0.0114 mol) is added portionwise. After stirring at 503C for 10 h, the reaction mixture is cooled down and poured into ice-water containing IK 1. The product is extracted with DCM (2x100 mL). The combined organic phase is washed with water and dried over Xa;SOa. The solvent is evaporated under reduced pressure and the residue is purified by chromatography (silica gel 60-120 mesh) with chloroform/methanol (9/1) as eluent to afford 900 mg (32%) of the title compound as a solid. 1H NMR (CDCl,. 400MHz) delta 7.68-7.21 (in, 211), 7.10-7.12 (m, 2H), 6.45 (br s, 2H), 4.51 fs, 2H), 3.86 (s, 3H).

Reference： [1]Patent: WO2008/101979,2008,A1 .Location in patent: Page/Page column 91-92

40
[ 96-35-5 ]
[ 394-47-8 ]
[ 57805-85-3 ]

Yield	Reaction Conditions	Operation in experiment
48%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;Heating / reflux;	Preparation Example 1: Preparation of 3-amino-benzofuran-2-carboxylic acid methyl ester0.22 g (1.18 mmol) of ?-fluorobenzonitrile was dissolved in 5 ml of N5N- dimethylformamide, 0.16 ml (2.18 mmol) of methyl glyconate and 0.62 g (4.54 mmol) of potassium carbonate were added thereto at room temperature, and the mixture was refluxed with heating for 12 hrs. After the reaction was completed, the reaction mixture was diluted with 10 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography <n="19"/>(hexane:ethyl acetate = 4:1) to obtain the title compound (0.10 g, 48% yield).1H NMR (300MHz, DMSO-d6): delta 3.97(s, 3H), 4.98(s, 2H), 7.23-7.28(m, IH), 7.44-7.47(m, 2H), 7.56(d, IH)Mass(m/e, M+): 192

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6362 - 6365
[2]Patent: WO2009/48274,2009,A2 .Location in patent: Page/Page column 16-17

41
[ 67-56-1 ]
[ 141-46-8 ]
[ 30934-97-5 ]
[ 96-35-5 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane at 70℃; for 2 - 5h;	1.1.a 1.a. Transfer Hydrogenation Experiments; [075] In a typical experiment, 120 mg (2.0 mmol based on monomer) of glycolaldehyde were weighed into a glass bomb fitted with a Teflon valve. The bomb was evacuated and refilled with argon and metal catalyst (0.02 mmol) was added under a counterflow of argon. The bomb was then fitted with a rubber septa and 5 ml_ of dry methanol were injected followed by 30 μl_ of dioxane (internal standard). The septa was replaced by a Teflon valve and the system was heated in an oil bath at 700C for 2-5 hrs. The system was cooled and a sample of this mixture was then syringed out and passed through a Stratopheres plug to remove the transition metal. The sample was analyzed by GC and ethylene glycol quantified. Glycolaldehyde acetal and methylglycolate were obtained as the major by-products along with ethylene glycol. Yields of ethylene glycol ranging from 0-40% using RuCI2(PPh3)3, RuH2(PPh3)3, RuH2(PPh3)4, RuH(OAc)(PPh3)3, Ru(OAc)2(PPh3)3, Cplr(dpen)CI, CpRu(OMe)2 and [CplrCI2]2 were typically obtained. Substantial amounts of acetal were obtained primarily when RuCI2(PPh3)3, and particularly [CplrCI2]2, were used. A typical chromatogram is shown in Figure 3 showing the production of ethylene glycol.[076] The transfer hydrogenation step was studied first in a separate set of experiments. Ethylene glycol was produced in varied yields. Under some experimental conditions, significant amounts of glycolaldehyde dimethylacetal and methyl glycolate were also formed as by-products. While acetal formation can be completely suppressed depending on the transition-metal complex used, formation of methyl glycolate is unavoidable and appears intrinsic to the overall process. Figure 4 provides a scheme showing the formation of methyl glycolate. The hydrogen produced in this transformation may be transferred by the metal catalyst (e.g., Shvo's catalyst) and used for reduction of glycolaldehyde in the present processes. Figure 5 shows the reaction scheme and observed yields of ethylene glycol for a transfer hydrogenation process step of the present invention. As shown in Figure 5, yields of ethylene glycol from the transfer hydrogenation reaction of glycolaldehyde as large as 50% are achievable. Table 1 summarizes the observed yields of ethylene glycol for a number transition metal transfer hydrogen catalysts.
	With potassium carbonate In 1,4-dioxane at 70℃; for 2 - 5h;	1.1.b 1.b. Effect of Base; [079] The use of a base to generate metal hydrides in situ from metal chlorides and methanol was explored. Figure 6 provides the reaction scheme for transfer hydrogenation in the presence of a base to generate ethylene glycol. In a standard procedure, 120 mg (2.0 mmol based on monomer) of glycolaldehyde were weighed into a glass bomb fitted with a Teflon valve. The bomb was evacuated and refilled with argon and metal catalyst (0.02 mmol) followed by base (et3N, NaOH, KOH, Cs2CO3, Na2CO3 or K2CO3, 0.1 mmol) was added under a counterflow of argon. The bomb was then fitted with a rubber septa and 5 ml_ of dry methanol were injected followed by 30 μl_ of dioxane (internal standard). The septa was replaced by a Teflon valve and the system was heated in an oil bath at 700C for 2-5 hrs. The system was cooled and a sample of this mixture was then syringed and passed through a Stratopheres plug to remove the transition metal. The sample was analyzed by GC and ethylene glycol quantified. High yields were observed for certain bases, especially at lower temperatures, as shown in Table 2. At room temperature for some reaction conditions the amount of side products diminishes substantially, but ethylene glycol production is decreases after 3 hours and observed yields are lower.
	With caesium carbonate In 1,4-dioxane at 70℃; for 2 - 5h;	1.1.b 1.b. Effect of Base; [079] The use of a base to generate metal hydrides in situ from metal chlorides and methanol was explored. Figure 6 provides the reaction scheme for transfer hydrogenation in the presence of a base to generate ethylene glycol. In a standard procedure, 120 mg (2.0 mmol based on monomer) of glycolaldehyde were weighed into a glass bomb fitted with a Teflon valve. The bomb was evacuated and refilled with argon and metal catalyst (0.02 mmol) followed by base (et3N, NaOH, KOH, Cs2CO3, Na2CO3 or K2CO3, 0.1 mmol) was added under a counterflow of argon. The bomb was then fitted with a rubber septa and 5 ml_ of dry methanol were injected followed by 30 μl_ of dioxane (internal standard). The septa was replaced by a Teflon valve and the system was heated in an oil bath at 700C for 2-5 hrs. The system was cooled and a sample of this mixture was then syringed and passed through a Stratopheres plug to remove the transition metal. The sample was analyzed by GC and ethylene glycol quantified. High yields were observed for certain bases, especially at lower temperatures, as shown in Table 2. At room temperature for some reaction conditions the amount of side products diminishes substantially, but ethylene glycol production is decreases after 3 hours and observed yields are lower.

	With potassium hydroxide In 1,4-dioxane at 70℃; for 2 - 5h;	1.1.b 1.b. Effect of Base; [079] The use of a base to generate metal hydrides in situ from metal chlorides and methanol was explored. Figure 6 provides the reaction scheme for transfer hydrogenation in the presence of a base to generate ethylene glycol. In a standard procedure, 120 mg (2.0 mmol based on monomer) of glycolaldehyde were weighed into a glass bomb fitted with a Teflon valve. The bomb was evacuated and refilled with argon and metal catalyst (0.02 mmol) followed by base (et3N, NaOH, KOH, Cs2CO3, Na2CO3 or K2CO3, 0.1 mmol) was added under a counterflow of argon. The bomb was then fitted with a rubber septa and 5 ml_ of dry methanol were injected followed by 30 μl_ of dioxane (internal standard). The septa was replaced by a Teflon valve and the system was heated in an oil bath at 700C for 2-5 hrs. The system was cooled and a sample of this mixture was then syringed and passed through a Stratopheres plug to remove the transition metal. The sample was analyzed by GC and ethylene glycol quantified. High yields were observed for certain bases, especially at lower temperatures, as shown in Table 2. At room temperature for some reaction conditions the amount of side products diminishes substantially, but ethylene glycol production is decreases after 3 hours and observed yields are lower.
	With sodium hydroxide In 1,4-dioxane at 70℃; for 2 - 5h;	1.1.b 1.b. Effect of Base; [079] The use of a base to generate metal hydrides in situ from metal chlorides and methanol was explored. Figure 6 provides the reaction scheme for transfer hydrogenation in the presence of a base to generate ethylene glycol. In a standard procedure, 120 mg (2.0 mmol based on monomer) of glycolaldehyde were weighed into a glass bomb fitted with a Teflon valve. The bomb was evacuated and refilled with argon and metal catalyst (0.02 mmol) followed by base (et3N, NaOH, KOH, Cs2CO3, Na2CO3 or K2CO3, 0.1 mmol) was added under a counterflow of argon. The bomb was then fitted with a rubber septa and 5 ml_ of dry methanol were injected followed by 30 μl_ of dioxane (internal standard). The septa was replaced by a Teflon valve and the system was heated in an oil bath at 700C for 2-5 hrs. The system was cooled and a sample of this mixture was then syringed and passed through a Stratopheres plug to remove the transition metal. The sample was analyzed by GC and ethylene glycol quantified. High yields were observed for certain bases, especially at lower temperatures, as shown in Table 2. At room temperature for some reaction conditions the amount of side products diminishes substantially, but ethylene glycol production is decreases after 3 hours and observed yields are lower.

Reference： [1]Current Patent Assignee: CALIFORNIA INSTITUTE OF TECHNOLOGY - WO2009/49114, 2009, A1 Location in patent: Page/Page column 19-20
[2]Current Patent Assignee: CALIFORNIA INSTITUTE OF TECHNOLOGY - WO2009/49114, 2009, A1 Location in patent: Page/Page column 21-22
[3]Current Patent Assignee: CALIFORNIA INSTITUTE OF TECHNOLOGY - WO2009/49114, 2009, A1 Location in patent: Page/Page column 21-22
[4]Current Patent Assignee: CALIFORNIA INSTITUTE OF TECHNOLOGY - WO2009/49114, 2009, A1 Location in patent: Page/Page column 21-22
[5]Current Patent Assignee: CALIFORNIA INSTITUTE OF TECHNOLOGY - WO2009/49114, 2009, A1 Location in patent: Page/Page column 21-22

42
[ 67-56-1 ]
[ 141-46-8 ]
[ 30934-97-5 ]
[ 96-35-5 ]
[ 107-21-1 ]

Yield	Reaction Conditions	Operation in experiment
35%	In 1,4-dioxane at 70℃; for 2 - 5h;	1.1.a 1.a. Transfer Hydrogenation Experiments; [075] In a typical experiment, 120 mg (2.0 mmol based on monomer) of glycolaldehyde were weighed into a glass bomb fitted with a Teflon valve. The bomb was evacuated and refilled with argon and metal catalyst (0.02 mmol) was added under a counterflow of argon. The bomb was then fitted with a rubber septa and 5 ml_ of dry methanol were injected followed by 30 μl_ of dioxane (internal standard). The septa was replaced by a Teflon valve and the system was heated in an oil bath at 700C for 2-5 hrs. The system was cooled and a sample of this mixture was then syringed out and passed through a Stratopheres plug to remove the transition metal. The sample was analyzed by GC and ethylene glycol quantified. Glycolaldehyde acetal and methylglycolate were obtained as the major by-products along with ethylene glycol. Yields of ethylene glycol ranging from 0-40% using RuCI2(PPh3)3, RuH2(PPh3)3, RuH2(PPh3)4, RuH(OAc)(PPh3)3, Ru(OAc)2(PPh3)3, Cplr(dpen)CI, CpRu(OMe)2 and [CplrCI2]2 were typically obtained. Substantial amounts of acetal were obtained primarily when RuCI2(PPh3)3, and particularly [CplrCI2]2, were used. A typical chromatogram is shown in Figure 3 showing the production of ethylene glycol.[076] The transfer hydrogenation step was studied first in a separate set of experiments. Ethylene glycol was produced in varied yields. Under some experimental conditions, significant amounts of glycolaldehyde dimethylacetal and methyl glycolate were also formed as by-products. While acetal formation can be completely suppressed depending on the transition-metal complex used, formation of methyl glycolate is unavoidable and appears intrinsic to the overall process. Figure 4 provides a scheme showing the formation of methyl glycolate. The hydrogen produced in this transformation may be transferred by the metal catalyst (e.g., Shvo's catalyst) and used for reduction of glycolaldehyde in the present processes. Figure 5 shows the reaction scheme and observed yields of ethylene glycol for a transfer hydrogenation process step of the present invention. As shown in Figure 5, yields of ethylene glycol from the transfer hydrogenation reaction of glycolaldehyde as large as 50% are achievable. Table 1 summarizes the observed yields of ethylene glycol for a number transition metal transfer hydrogen catalysts.
35%	With triethylamine In 1,4-dioxane at 70℃; for 2 - 5h;	1.1.b 1.b. Effect of Base; [079] The use of a base to generate metal hydrides in situ from metal chlorides and methanol was explored. Figure 6 provides the reaction scheme for transfer hydrogenation in the presence of a base to generate ethylene glycol. In a standard procedure, 120 mg (2.0 mmol based on monomer) of glycolaldehyde were weighed into a glass bomb fitted with a Teflon valve. The bomb was evacuated and refilled with argon and metal catalyst (0.02 mmol) followed by base (et3N, NaOH, KOH, Cs2CO3, Na2CO3 or K2CO3, 0.1 mmol) was added under a counterflow of argon. The bomb was then fitted with a rubber septa and 5 ml_ of dry methanol were injected followed by 30 μl_ of dioxane (internal standard). The septa was replaced by a Teflon valve and the system was heated in an oil bath at 700C for 2-5 hrs. The system was cooled and a sample of this mixture was then syringed and passed through a Stratopheres plug to remove the transition metal. The sample was analyzed by GC and ethylene glycol quantified. High yields were observed for certain bases, especially at lower temperatures, as shown in Table 2. At room temperature for some reaction conditions the amount of side products diminishes substantially, but ethylene glycol production is decreases after 3 hours and observed yields are lower.
27%	With potassium carbonate In 1,4-dioxane at 20℃; for 2 - 5h;	1.1.b 1.b. Effect of Base; [079] The use of a base to generate metal hydrides in situ from metal chlorides and methanol was explored. Figure 6 provides the reaction scheme for transfer hydrogenation in the presence of a base to generate ethylene glycol. In a standard procedure, 120 mg (2.0 mmol based on monomer) of glycolaldehyde were weighed into a glass bomb fitted with a Teflon valve. The bomb was evacuated and refilled with argon and metal catalyst (0.02 mmol) followed by base (et3N, NaOH, KOH, Cs2CO3, Na2CO3 or K2CO3, 0.1 mmol) was added under a counterflow of argon. The bomb was then fitted with a rubber septa and 5 ml_ of dry methanol were injected followed by 30 μl_ of dioxane (internal standard). The septa was replaced by a Teflon valve and the system was heated in an oil bath at 700C for 2-5 hrs. The system was cooled and a sample of this mixture was then syringed and passed through a Stratopheres plug to remove the transition metal. The sample was analyzed by GC and ethylene glycol quantified. High yields were observed for certain bases, especially at lower temperatures, as shown in Table 2. At room temperature for some reaction conditions the amount of side products diminishes substantially, but ethylene glycol production is decreases after 3 hours and observed yields are lower.

27%	With caesium carbonate In 1,4-dioxane at 20℃; for 2 - 5h;	1.1.b 1.b. Effect of Base; [079] The use of a base to generate metal hydrides in situ from metal chlorides and methanol was explored. Figure 6 provides the reaction scheme for transfer hydrogenation in the presence of a base to generate ethylene glycol. In a standard procedure, 120 mg (2.0 mmol based on monomer) of glycolaldehyde were weighed into a glass bomb fitted with a Teflon valve. The bomb was evacuated and refilled with argon and metal catalyst (0.02 mmol) followed by base (et3N, NaOH, KOH, Cs2CO3, Na2CO3 or K2CO3, 0.1 mmol) was added under a counterflow of argon. The bomb was then fitted with a rubber septa and 5 ml_ of dry methanol were injected followed by 30 μl_ of dioxane (internal standard). The septa was replaced by a Teflon valve and the system was heated in an oil bath at 700C for 2-5 hrs. The system was cooled and a sample of this mixture was then syringed and passed through a Stratopheres plug to remove the transition metal. The sample was analyzed by GC and ethylene glycol quantified. High yields were observed for certain bases, especially at lower temperatures, as shown in Table 2. At room temperature for some reaction conditions the amount of side products diminishes substantially, but ethylene glycol production is decreases after 3 hours and observed yields are lower.
20%	With potassium hydroxide In 1,4-dioxane at 70℃; for 2 - 5h;	1.1.a 1.a. Transfer Hydrogenation Experiments; [075] In a typical experiment, 120 mg (2.0 mmol based on monomer) of glycolaldehyde were weighed into a glass bomb fitted with a Teflon valve. The bomb was evacuated and refilled with argon and metal catalyst (0.02 mmol) was added under a counterflow of argon. The bomb was then fitted with a rubber septa and 5 ml_ of dry methanol were injected followed by 30 μl_ of dioxane (internal standard). The septa was replaced by a Teflon valve and the system was heated in an oil bath at 700C for 2-5 hrs. The system was cooled and a sample of this mixture was then syringed out and passed through a Stratopheres plug to remove the transition metal. The sample was analyzed by GC and ethylene glycol quantified. Glycolaldehyde acetal and methylglycolate were obtained as the major by-products along with ethylene glycol. Yields of ethylene glycol ranging from 0-40% using RuCI2(PPh3)3, RuH2(PPh3)3, RuH2(PPh3)4, RuH(OAc)(PPh3)3, Ru(OAc)2(PPh3)3, Cplr(dpen)CI, CpRu(OMe)2 and [CplrCI2]2 were typically obtained. Substantial amounts of acetal were obtained primarily when RuCI2(PPh3)3, and particularly [CplrCI2]2, were used. A typical chromatogram is shown in Figure 3 showing the production of ethylene glycol.[076] The transfer hydrogenation step was studied first in a separate set of experiments. Ethylene glycol was produced in varied yields. Under some experimental conditions, significant amounts of glycolaldehyde dimethylacetal and methyl glycolate were also formed as by-products. While acetal formation can be completely suppressed depending on the transition-metal complex used, formation of methyl glycolate is unavoidable and appears intrinsic to the overall process. Figure 4 provides a scheme showing the formation of methyl glycolate. The hydrogen produced in this transformation may be transferred by the metal catalyst (e.g., Shvo's catalyst) and used for reduction of glycolaldehyde in the present processes. Figure 5 shows the reaction scheme and observed yields of ethylene glycol for a transfer hydrogenation process step of the present invention. As shown in Figure 5, yields of ethylene glycol from the transfer hydrogenation reaction of glycolaldehyde as large as 50% are achievable. Table 1 summarizes the observed yields of ethylene glycol for a number transition metal transfer hydrogen catalysts.

43
[ 96-35-5 ]
[ 52449-43-1 ]
[ 100074-43-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; for 8h;Reflux;	General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a)

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 1124 - 1129
[2]Molecules,2019,vol. 24

44
[ 96-35-5 ]
[ 27798-60-3 ]
[ 100074-47-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; for 8h;Reflux;	General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a)

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 1124 - 1129
[2]Molecules,2019,vol. 24

45
[ 96-35-5 ]
[ 18927-05-4 ]
[ 100074-48-4 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 1124 - 1129

46
[ 96-35-5 ]
[ 135325-18-7 ]
[ 1192748-52-9 ]

Yield	Reaction Conditions	Operation in experiment
53%	With potassium <i>tert</i>-butylate In tetrahydrofuran for 16h; Inert atmosphere; Reflux;

Reference： [1]Bellina, Fabio; Marchetti, Chiara; Rossi, Renzo [European Journal of Organic Chemistry, 2009, # 27, p. 4685 - 4690]

47
[ 67-56-1 ]
glycolic acid ; magnesium glycolate [ No CAS ]
[ 107-21-1 ]
[ 553-90-2 ]
[ 502-97-6 ]
[ 96-35-5 ]
[ 628-35-3 ]
[ 107-31-3 ]
[ 14396-72-6 ]
[ 144-62-7 ]

Yield	Reaction Conditions	Operation in experiment
		Synthesis of an alpha-hydroxycarboxylic acid ester was carried out using the Pb-Au alloy/TiO2-SiO2 catalyst obtained in (1) above. [0314] 62 g (1.0 mol) of ethylene glycol, 320 g (10 mol) of methanol, and 20 g of the above-mentioned catalyst were put into a rotating stirring type 1 L autoclave having a condenser tube, and the autoclave was hermetically sealed. Next, a mixed gas of oxygen and nitrogen (volume ratio 10/90) was blown into the liquid at a flow rate of 1 L/min while adjusting using a back pressure valve such that the pressure inside the system was maintained at 0.5 Mpa, and reaction was carried out for 5 hours at 90 C. while carrying out this bubbling. [0315] After that, cooling was carried out, and the autoclave was opened; upon analyzing the contents using gas chromatography, it was found that 0.180 mol of the ethylene glycol starting material was contained, and the contents of the products methyl glycolate, 2-hydroxyethyl glycolate, glycolide, dimethyl oxalate, and other oxalic acid compounds were 0.656 mol, 0.068 mol, 0.012 mol, 0.008 mol and 0.001 mol respectively. Moreover, the molar production ratios for methyl formate and 2-hydroxyethyl formate relative to methyl glycolate were 0.12 and 0.03 respectively. [0316] (3) Removal of Oxalic Acid Esters, Followed by Purification of Glycolic Acid Ester [0317] The reaction filtrate (404.9 g) obtained by separating away the catalyst from the reaction liquid obtained through the oxidative esterification reaction of (2) above contained ethylene glycol and methanol as residual starting materials, the reaction products, and water produced in the reaction. Out of the contents there was a total of 0.011 mol of oxalic acid esters, that is 0.008 mol (0.92 g) of dimethyl oxalate and 0.001 mol of other oxalic acid compounds (oxalic acid etc.). [0318] 3 mL of a methanol solution containing 0.013 mol of the magnesium salt of glycolic acid was added to the reaction solution, and then all of the solution was put into a 1 L autoclave, and after purging with nitrogen, the temperature was raised to 80 C. and stirring was carried out for 2 hours. After that, cooling was carried out, and the autoclave was opened, whereupon it was found that a white precipitate of magnesium oxalate had been produced. Then, after filtering, the reaction liquid was analyzed using gas chromatography, whereupon it was found that the signals corresponding to dimethyl oxalate and other oxalic acid compounds had virtually disappeared. [0319] After filtering off the magnesium oxalate, methanol and water were distilled off from the obtained filtrate under reduced pressure using a thin-layer distillation apparatus. After that, the methyl glycolate was distilled off using a 3-stage glass distillation column with a bottom temperature of 70 to 80 C. at a pressure of 5 to 10 torr. The purity of the methyl glycolate in the distillate was greater than 98 wt %; a total of approximately 1.5 wt % of methanol and water was contained, but the content of other impurities was less than 0.1 wt %. The total content of dimethyl oxalate and other oxalic acid compounds (oxalic acid etc.) was less than 100 ppm by weight. [0320]

Reference： [1]Patent: US2004/138409,2004,A1 .Location in patent: Page 21-23

48
[ 96-35-5 ]
[ 216574-58-2 ]
[ 216574-57-1 ]

Yield	Reaction Conditions	Operation in experiment
17%	Stage #1: glycolic acid methyl ester With sodium hydride In 1,2-dimethoxyethane at 0 - 20℃; for 1.33333h; Stage #2: 3-chloro-4,4-dimethylpent-2-enenitrile In 1,2-dimethoxyethane at 85℃; for 42h;	L-1.32.2 To a slurry of NaH (5.98 g, 0.24 mol, 2.6 equiv) in anh. DME (800 mL) at 0 °C was added methyl glycolate (23.0 g, 0.26 mol, 2.8 equiv) over 20 min. The mixture was stirred for 1 h at room temp. and a solution of 3-chloro-4,4-dimethyl-2-pentenenitrile (13.1 g, 0.091 mol) in DME (100 mL) was added. The resulting solution was heated to 85 °C for 42 h, cooled to room temp., and treated with H2O (100 mL). The resulting mixture was separated between H2O (200 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4), and concentrated under reduced pressure. The residual oil was purified by flash chromatography (300 g SiO2, gradient from 50% CH2Cl2/hexane to 20% EtOAc/CH2Cl2) to give methyl 3-amino-5-tert-butylfuran-2-carboxylate as a yellow solid (2.98 g, 17%): mp 91-2 °C; TLC (20% EtOAc/hexane) Rf 0.36; 1H NMR (CDCl3) δ 1.26 (s, 9H), 3.84 (s, 3H), 4.54 (br s, 2H), 5.75 (s, 1H); 13C NMR (CDCl3) δ 28.5 (3C), 33.0, 50.7, 98.5, 128.8, 131.0,160.7, 168.3.

Reference： [1]Current Patent Assignee: BAYER AG - EP1019040, 2004, B1 Location in patent: Page/Page column 29

49
[ 798541-68-1 ]
[ 96-35-5 ]
[ 57595-23-0 ]

Yield	Reaction Conditions	Operation in experiment
26%		Sodium hydride (4 g, 60% w/w in oil dispersion, 100 mmol) was added to a flame-dried flask along with ether (100 mL). To the reaction flask under nitrogen atmosphere, methyl glycolate (7.7 mL, 100 mmol) was added slowly with constant stirring. The reaction mixture was allowed to stir at room temperature for 2 hours under nitrogen atmosphere then solvent was removed in vacuo. To the residue, methyl acrylate (10.8 mL, 120 mmol) in DMSO (50 mL) was added in one portion while the reaction flask was kept immersed in an ice bath. The reaction mixture was allowed to stir at 0 C for 15 minutes then at room temperature for 1 hour. The reaction mixture was then filtered through Celte'3', poured into ice-cold aqueous sulfuric acid solution (150 mL, 2N), and extracted with ether (2 x 200 mL). The organic layer was washed with saturated NaCl solution (500 mL), dried over anhydrous Na2S04, filtered, and solvent was removed in vacuo. The intermediate ketoester was recovered in 26% yield (3.7 g, 25.7 mmol) afterpurificationby column chromatography on silica using 25% ethyl acetate/hexanes as the eluent (Rf= 0.3). The ketoester intermediate (3.7g, 25.7 mmol) was added slowly to a solution of sodium hydride (1.4 g, 60% w/w in oil dispersion, 34 mmol) in ether (80 mL) at 0 C with constant stirring under nitrogen atmosphere. After 30 minutes, trifluoromethanesulfonic anhydride (5.3 mL, 31.4 mmol) was added dropwise over 5 minutes. The reaction mixture was allowed to stir at 0 C for an additional 1.5 hours then the reaction was poured into water (80 mL) and the layers were separated. The aqueous phase was washed with dichloromethane (2 x 60 mL) and the organic phases were combined. The organic layer was dried over anhydrous Na2SO4, filtered, and solvent was removed in vacuo. The 2,5- dihydrofuran ester 13a was recovered in 23% yield (1.6 g, 5.8 mmol) after purification by column chromatography on silica using 25% ethyl acetate/hexanes as the eluent (Rf= 0.45). MS: calc. for C7H7F306S : 257.9 ; Found: GC-MS 7nl5 275 (MH).

Reference： [1]Patent: WO2005/40109,2005,A1 .Location in patent: Page/Page column 78-79

50
[ 83004-10-8 ]
[ 96-35-5 ]
[ 1093879-41-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 5h;	To a suspension of sodium hydride (0.50 g, 12.4 mmol) in N,N- dimethylformamide (20 mL) at O0C was added methyl hydroxyacetate (1.0 g, 11.3 mmol) and 2- bromo-6-(bromomethyl)pyridine (Example 8, Step 1) (3.4 g, 13.5 mmol). After stirring for 5 hours, the reaction was quenched with an isopropanol/methanol solution. The reaction mixture was poured into ice water and extracted with ether. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting material was purified by flash chromatography (silica, 10% ethyl acetate/hexanes) to afford the title compound. 1H NMR (400 MHz CDCl3): delta 7.55 (t, IH), 7.48 (d, 1H)S 7.39 (d, IH), 4.71 (s, 2H), 4.22 (s, 2H)5 3.77 (s, 3H).
	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 2h;	To a suspension of sodium hydride (60% in mineral oil, 72 mg, 1.8 mmol) in DMF (3.30 mL) at 0C was added dropwise a mixture of 2-bromo-6- (bromomethyl)pyridine (493 mg, 1.97 mmol) and methyl glycolate (148 mg, 1.64 mmol) in DMF (1.5 mL), and the reaction mixture was stirred for 2 hours at 0C. The reaction mixture was quenched with 1 :1 isopropanol methanol (5 mL) and then poured over ice. The reaction mixture was diluted with water and diethyl ether. The organics were separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford methyl [(6-bromopyridin-2-yl)methoxy]acetate. MS ESI calc'd. for C9HnBrN03 [M + H]+ 260 and 262, found 260 and 262. 1H NMR (500 MHz, CDC13) delta 7.58 (t, J= 7.7 Hz, 1H), 7.49 (d, J= 7.5 Hz, 1H), 7.40 (d, J= 7.8 Hz, 1H), 4.72 (s, 2H), 4.23 (s, 2H), 3.78 (s, 3H).

Reference： [1]Patent: WO2010/11375,2010,A2 .Location in patent: Page/Page column 62
[2]Patent: WO2013/52394,2013,A1 .Location in patent: Paragraph 00238

51
[ 96-35-5 ]
[ 920-46-7 ]
[ 13318-09-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In tetrahydrofuran; at 0 - 20℃;	To 17.09 g of Compound (5) shown below (methyl glycolate, manufactured by TCI), 30,00 g of tetrahydrofuran (THF) was added, and 21.15 g of triethylamine was further added. The mixture was cooled to 0C, and 20.85 g of methacrylic acid chloride was then added dropwise. After returning the temperature to room temperature, the mixture was stirred for 2 hours. A sodium hydrogencarbonate aqueous solution was added, followed by extraction with ethyl acetate. Organic layers were gathered, to which was then added MgSO4, and the resulting mixture was filtered and concentrated to obtain 28.51 g of Compound (6) (yield: 95 %). 1H-NMR, (400 MHz in (CD3)2CO): ? (ppm) = 1.94 to 2.04 (3H), 3.71 to 3.72 (3H), 4.73 (2H), 5.72 (1H), 6.15 (1H)
	With triethylamine; In dichloromethane; at 0℃;Inert atmosphere;	Under the conditions of temperature ?0 and argon (Ar)A certain amount of dissolved in anhydrous DCM (30 mL)Of methacryloyl chloride (0.072 mol)Was added dropwise to methyl glycolate (0.072 mol)TEA (0.144 mol),Anhydrous DC (50 mL), stirred overnight, washed and purified, and chromatographed to give the pure product.
	With triethylamine; In dichloromethane; at 0℃;Inert atmosphere;	A certain amount of methacryloyl chloride (0.144 mol) dissolved in anhydrous DCM (60 mL) was added dropwise to methyl glycolate (at a temperature of ?0 C and an argon (Ar) atmosphere) 0.144 mol), TEA (0.288 mol), anhydrous DCM (100 mL), stir overnight, wash and purify, and obtain pure product by column chromatography.

Reference： [1]Patent: EP2196462,2010,A1 .Location in patent: Page/Page column 19
[2]Biomacromolecules,2016,vol. 17,p. 2223 - 2232
[3]Molecular Pharmaceutics,2017,vol. 14,p. 4032 - 4041
[4]Patent: CN106963733,2017,A .Location in patent: Paragraph 0025
[5]Patent: CN107596383,2019,B .Location in patent: Paragraph 0034; 0040; 0042

52
[ 96-35-5 ]
[ 150683-30-0 ]
C₂₉H₃₀ClN₂O₇P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		Example 25; A quantity of 3.8 ml (20 mmol) of diphenyl phosphite was added to a pyridine solution (10 ml) of 3.0 g (6.7 mmol) of <strong>[150683-30-0]tolvaptan</strong> (compound (2)), and the obtained mixture was stirred at room temperature for 1 hour. To this mixture was added 5.2 ml (66.6 mmol) of methyl glycolate, and stirring was performed at room temperature for 12 hours. To the reaction mixture was added 50 ml of water, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with 1 N hydrochloric acid twice, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane : ethyl acetate = 50 : 50 ? 0 : 100) . The purified product was concentrated under reduced pressure to give 0.79 g of white amorphous solid target compound. Yield: 20%1H-NMR (Toluene-d8, 100 0C) delta ppm : 1.6-2.2 (4H, m) , 2.51 (3H, s) , 2.60 (3H, s), 3.2-4.4 (2H, m) , 3.53 (3H, s) , 4.43 (IH, s) , 4.47(IH, s), 5.87 (0.5H, s) , 5.9-6.1 (IH, m) , 6.6-6.8 (IH, m) , 6.8-7.0 (2H, m), 7.0-7.4 (5H, m) , 7.48 (IH, s) , 7.63 (IH, s) , 8.27 (0.5H, s) .

Reference： [1]Patent: WO2007/74915,2007,A1 .Location in patent: Page/Page column 46

53
[ 96-35-5 ]
[ 668-45-1 ]
[ 1139838-91-7 ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium carbonate In N,N-dimethyl-formamide at 20 - 100℃;

Reference： [1]Suh, Jeehee; Yi, Kyu Yang; Lee, Yun-Suk; Kim, Eunhee; Yum, Eul Kgun; Yoo, Sung-Eun [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 22, p. 6362 - 6365]

54
[ 96-35-5 ]
[ 136888-21-6 ]
[ 1198154-59-4 ]

Yield	Reaction Conditions	Operation in experiment
66%		b) Synthesis of (5-fluoro-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester Hydroxy-acetic acid methyl ester (0.96 g, 10.7 mmol) was dissolved in 2 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (0.42 g, 10.7 mmol) was added thereto at room temperature. After stirring for 30 minutes, <strong>[136888-21-6]2-chloro-5-fluoro-3-nitro-pyridine</strong> (1.57 g, 8.89 mmol) dissolved in 15 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain (5-fluoro-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow liquid (1.35 g, 66%). 1H-NMR (CDCl3, 300 MHz); delta=8.25 (d, J=2.7 Hz, 1H), 8.40 (dd, J=6.9 Hz, 2.7H, 1 Hz), 5.06 (s, 2H), 3.78 (s, 3H). MS (ESI); 231.1 (M++1).

Reference： [1]Patent: US2011/28467,2011,A1 .Location in patent: Page/Page column 52-53

55
[ 96-35-5 ]
[ 72587-15-6 ]
[ 1198154-06-1 ]

Yield	Reaction Conditions	Operation in experiment
68%		b) Synthesis of (3-nitro-5-trifluoromethyl-pyridin-2-yloxy)-acetic acid methyl ester In a 10 ml flask, hydroxy-acetic acid methyl ester (0.4 ml, 0.53 mmol) was dissolved in tetrahydrofuran (1.5 ml), and then sodium hydride (23 mg, 0.57 mmol) was added thereto. After 40 minutes, <strong>[72587-15-6]2-chloro-3-nitro-5-trifluoromethyl-pyridine</strong> (100 mg, 0.44 mmol) was added and then stirred for 2 hours at room temperature. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain white solid (84 mg, 68%). 1H-NMR (DMSO-d6, 300 MHz); delta=8.95 (s, 1H), 8.92 (s, 1H), 5.23 (s, 2H), 3.69 (s, 3H).

Reference： [1]Patent: US2011/28467,2011,A1 .Location in patent: Page/Page column 22-23

56
[ 67443-38-3 ]
[ 96-35-5 ]
[ 227963-72-6 ]

Yield	Reaction Conditions	Operation in experiment
99%		a) Synthesis of (5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester Hydroxy-acetic acid methyl ester (46 mg, 0.50 mmol) was dissolved in 2 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (40 mg, 1.0 mmol) was added thereto at room temperature. After stirring for 30 minutes, <strong>[67443-38-3]5-bromo-2-chloro-3-nitro-pyridine</strong> (100 mg, 0.42 mmol) dissolved in 1 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain (5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow solid (144 mg, 99%). 1H-NMR (CDCl3, 300 MHz); delta=8.47 (d, J=2.3 Hz, 1H), 8.40 (d, J=2.3 Hz, 1H), 5.07 (s, 2H), 3.78 (s, 3H). MS (ESI); 290.9 (M++1).

Reference： [1]Patent: US2011/28467,2011,A1 .Location in patent: Page/Page column 52

57
[ 96-35-5 ]
[ 358-23-6 ]
[ 88016-31-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	In dichloromethane; at 0 - 5℃; for 1.5h;Inert atmosphere;	To a solution of triflic anhydride (1 eq, 20 mmol) in DCM (10 mL) at 5C under Argon was added over 30 min a solution of methyl glycolate (1 eq, 20 mmol) in DCM (5 mL). The clear solution was stirred at 0C for 1h 30 min. The mixture was washed 5 times with water (15 mL x 5) and with saturated NaCl (10 mL) then dried filtered and evaporated to yield the desired product as a light brown oil (3.11g, 70%). 1H NMR (CDCl3) delta: 4.17 (s, 2H), 3.80 (s, 3H).
	With pyridine; In dichloromethane; at -10℃;	A mixture of methyl glycolate (0.182 g) and pyridine (0.196 mL) in dichloromethane (9.54 mL) was cooled to -10C and trifluoromethanesulfonic anhydride (0.41 mL) was added drop wise. The reaction was stirred at -10C for a further hour. The reaction was diluted with dichloromethane and water and the aqueous was extracted with further dichloromethane. The combined organic layers were dried with magnesium sulfate and concentrated to afford methyl 2-(trifluoromethylsulfonyloxy)acetate, which was used without further purification. To a solution of A/-ethylthiadiazole-5-carboxamide (0.15 g) in 1 ,2-dichloroethane (2.86 mL) was added the methyl 2-(trifluoromethylsulfonyloxy)acetate and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give methyl 2-[5- (ethylcarbamoyl)thiadiazol-3-ium-3-yl]acetate 2,2,2-trifluoroacetate.1 H NMR (400MHz, CDsOD) 9.94 (d, 1 H), 9.51-9.22 (m, 1 H), 6.05 (s, 2H), 3.89 (s, 3H), 3.56- 3.40 (m, 2H), 1.28 (t, 3H)

Reference： [1]Polyhedron,2010,vol. 29,p. 1925 - 1932
[2]Advanced Synthesis and Catalysis,2017,vol. 359,p. 3865 - 3879
[3]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 787 - 792
[4]Synlett,2020,vol. 31,p. 883 - 888
[5]Patent: WO2020/99406,2020,A1 .Location in patent: Page/Page column 43-44

58
[ 96-35-5 ]
[ 7124-41-6 ]
[ 886209-59-2 ]

Yield	Reaction Conditions	Operation in experiment
66%	With silver perchlorate; In toluene; at 20℃; for 1h;Inert atmosphere;	3.85 g of silver perchlorate (18.6 mmol) are added to a solution of 8,8-dibromobicyclo[5.1.0]octane 16 (2.5 g, 9.3 mmol) and methyl glycolate (6.35 ml, 83.9 mmol) dissolved in 5 ml of anhydrous toluene in a dry round-bottomed flask under Ar protected from light by an aluminum film. The reaction mixture is stirred at ambient temperature for 1 h 30 and then the silver salts are filtered off through a sintered glass funnel and washed with AcOEt. The solution is concentrated under vacuum to give a viscous brown oil which is purified by chromatography on silica gel (cyclohexane/2-15% AcOEt) to produce 17 in the form of a yellow oil (w=1.7 g, i.e. 66% yield).1H NMR (CDCl3, 200 MHz): delta (ppm) 0.7-2.2 (m, 8H, H4-4'-5-5'-6-6'-7-7'); 2.28 (m, 1H, H8); 2.70 (ddd, J=5.0-11.5-23.5 Hz, 1H, H8'); 3.72 (s, 3H, OMe); 3.94 (d, J=16.5 Hz, 1H, H9); 4.10 (dd, J=5.0-10.0 Hz, 1H, H3); 4.23 (d, J=16.5 Hz, 1H, H9'); 6.20 (dd, J=4.0-11.5 Hz, 1H, H1).
65%	With silver perchlorate; In toluene; at 20℃; for 1.5h;Inert atmosphere;	2-Synthesis of methyl 2-bromocyclooctene-3-glycolate 3.85 g of silver perchlorate (i.e., 18.6 mmol) are added to a solution of 8,8-diboromobicyclo[5.1.0]octane (2.5 g, i.e. 9.3 mmol) and methyl glycolate (6.35 ml, i.e. 83.9 mmol) dissolved in 5 ml of anhydrous toluene in a dry round-bottomed flask, under Ar and protected from the light by an aluminum film. The reaction mixture is stirred at ambient temperature for 1 h 30 and then the silver salts are filtered off on a sintered glass funnel and washed with AcOEt. The solution is concentrated under vacuum to give a brown viscous oil, which is purified by chromatography on silica gel (2-15% AcOEt in cyclohexane) in order to obtain the product in the form of a yellow oil with a w=1.6 g, i.e. 65% yield (litt. 22%5). Rf (petroleum ether/AcOEt 5%)=0.25; 1H NMR (CDCl3, 200 MHz): delta (ppm) 0.7-2.2 (m, 8H); 2.28 (m, 1H); 2.70 (ddd, J=5, 11.5 and 23.5 Hz, 1H); 3.72 (s, 3H, OMe); 3.94 (d, J9-9'=16.5 Hz, 1H, H9); 4.10 (dd, J3-4=5 Hz, J3-4'=10 Hz, 1H, H3); 4.23 (d, J9-9'=16.5 Hz, 1H, H9); 6.20 (dd, J1-8'=4 Hz, J1-8'=11.5 Hz, 1H, H1); 13C NMR (CDCl3, 50 MHz): 26.2; 28.0; 33.4; 36.5; 39.3 (C4-8); 51.8 (C3); 65.4 (C11); 84.8 (C9); 131.4 (C2 quat.); 133 (C1); 170.7 (C10 quat.); Mass: ESI+ m/z [M+H]+=277.6 and 279.6; [M+Na]+=299.6 and 301.6; [2M+H]+=553.0, 555.0 and 557.0; [2M+Na]=575.0, 576.9 and 578.8; IR: upsilon (cm-1) 2931 upsilonCH; 2856 upsilonCH2; 1754 upsilonC=O; 1445 upsilontrans C=C; 1132 upsilonether COC.
65%	With silver perchlorate; In toluene; at 20℃; for 1.5h;Inert atmosphere; Darkness;	To a solution of 8,8-dibromobicyclo[5.1.0]octane (2.5 g, i.e. 9.3 mmol) and of methyl glycolate (6.32 mL, i.e. 83.9 mmol) dissolved in 5 mL of anhydrous toluene in a dry round-bottomed flask, under Ar and protected from light by a film of aluminum, are added 3.85 g of silver perchlorate (i.e. 18.6 mmol). The reaction is stirred for 1 hour 30 minutes at room temperature, and the silver salts are then filtered off on a sinter and washed with EtOAc. The solution is concentrated under vacuum to give a viscous brown oil, which is purified by chromatography on silica gel (2-150 EtOAc in cyclohexane) to give the product in the form of a yellow oil of mass m=1.6 g, i.e. 65% yield. Rf (petroleum ether/5% EtOAc)=0.25; 1H NMR (CDCl3, 200 MHz): delta (ppm) 0.7-2.2 (m, 8H); 2.28 (m, 1H); 2.70 (ddd, J=5-11.5-23.5 Hz, 1H); 3.72 (s, 3H, OMe); 3.94 (d, J9-9'=16.5 Hz, 1H, H9); 4.10 (dd, J3-4=5 Hz, J3-4'=10 Hz, 1H, H3); 4.23 (d, J9-9'=16.5 Hz, 1H, H9'); 6.20 (dd, J1-8=4 Hz, J1-8'=11.5 Hz, 1H, H1); 13C NMR (CDCl3, 50 MHz): 26.2; 28.0; 33.4; 36.5; 39.3 (C4-8); 51.8 (C3); 65.4 (C11); 84.8 (C9); 131.4 (C2 quat.); 133 (C1); 170.7 (C10 quat.); Mass: ESI+ m/z [M+H]+=277.6-279.6; [M+Na]+=299.6-306.1; [2M+H]+=553.0-555.0-557.0; [2M+Na]+=575.0-576.9-578.8; IR: nu (cm-1) 2931 nuCH; 2856 nuCH2; 1754 nuC=O; 1445 nuC=C trans; 1132 nuCOC ether.

56%	With silver perchlorate; In toluene; at 20℃;Darkness;	The cyclooctyne moiety was synthesized starting from the cycloheptene through a carbene reaction to obtain the dibromobicicyclo intermediate 9?, followed by the ring expansion and formation of vinyl bromo intermediate 10? in the presence of silver perchlorate, and elimination to generate cycloocytne-acid 11? by using sodium methoxide (Scheme 2?).
22%	With silver perchlorate; In toluene; for 2h;	AgC1O4 (2.40 g, 11.6 mmol) was added to a solution of dibromobicycle 1 (1.00 g, 3.72 mmol) and methyl glycolate (6.0 ml, 78.2 mmol) dissolved in toluene (4 mL) in a flame-dried, aluminum-foil-wrapped flask. The reaction was stirredfor 2 h, diluted with pentane (20 mL), and filtered to removeinsoluble silver salts. The solution was concentrated and purified by silica gel chromatography (5-10% EtOAc: pet ether; R1(10% EtOAc: pet ether)=0.32) to yield 2 as a colorless oil(330mg 1.19 mmol, 22%). ?H NMR (300 MHz, CD3C1) oe6.20 (dd, 1H, J=3.9, 11.7)4.23 (d, 1H, J=16.5), 4.11 (m, 1H)3.96 (d, 1H, J=16.5), 3.73 (s, 1H), 2.70 (m, 1H), 2.25 (m, 1H),0.8-2.1 (m, 8H). El LRMS calculated C,,H,8O3Br [M+H]278.2 found 278.1.

Reference： [1]Patent: US2011/118484,2011,A1 .Location in patent: Page/Page column 6
[2]Patent: US2012/95247,2012,A1 .Location in patent: Page/Page column 7
[3]Patent: US8592619,2013,B2 .Location in patent: Page/Page column 6; 7
[4]Patent: WO2015/143092,2015,A1 .Location in patent: Page/Page column 74; 75; 76
[5]Patent: US9260371,2016,B2 .Location in patent: Page/Page column 50

59
[ 126954-66-3 ]
[ 96-35-5 ]
C₉H₇ClN₂O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6577 - 6581

60
[ 67-56-1 ]
[ 50-00-0 ]
[ 201230-82-2 ]
[ 96-35-5 ]
[ 7040-23-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 65.1 %Chromat. 2: 33.7 %Chromat.	Stage #1: formaldehyd; carbon monoxide With phosphotungstic acid In sulfolane at 140℃; Autoclave; Stage #2: methanol With nitric acid for 4h; Reflux;

Reference： [1]Location in patent: experimental part Barri, Sami A. I.; Chadwick, David [Catalysis Letters, 2011, vol. 141, # 6, p. 749 - 753]

61
[ 96-35-5 ]
[ 1411884-59-7 ]
[ 1411884-62-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 50h;Inert atmosphere;	To a solution of ester 14 (4.00 g, 17.1 mmol, 1.0 equiv) and methyl glycolate (1.60 mL, 1.87 g, 20.7 mmol, 1.2 equiv) in 80 mL of anhydrous DMF was slowly added 40 mL of a THF solution of potassium tert-butoxide (1 M, 40.0 mmol, 2.3 equiv). The resulting light yellow suspension was stirred under argon at rt for 50 h. The reaction mixture was then poured in one portion into 200 mL of ice cold aq 1 M HCl. The resulting suspension was subsequently kept in an ice bath for 20 min, filtered, and the filter cake washed with ice cold aq 1 M HCl. The filter cake was then dissolved in ethyl acetate and washed with water then brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting beige crystals of tetronic acid 15 (4.44 g, 99% yield) were pure enough for utilization in the next step. Mp 121-122.5 C; Rf=0.38 (10% MeOH/CH2Cl2+0.2% AcOH); IR (NaCl, film): nu 2925, 2871, 2696, 1695, 1652, 1608, 1425, 1394, 1293, 1253, 1172, 1052, 1003, 834, 738 cm-1; 1H NMR (400 MHz, acetone-d6): delta 7.90 (d, J=9.2 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 5.44 (t, J=7.2 Hz, 1H) 4.73 (s, 2H), 4.54 (d, J=6.8 Hz, 2H), 1.74 (s, 3H), 1.72 (s, 3H); 13C NMR (100 MHz, acetone-d6): delta 172.8, 171.4, 158.0, 137.0, 128.4, 123.0, 120.5, 114.3, 99.5, 65.9, 64.6, 25.1, 17.5; HRMS (ESI): m/z calcd for C15H16O4: 260.1049; found: 260.1059.

Reference： [1]Tetrahedron,2012,vol. 68,p. 9592 - 9597,6

62
[ 96-35-5 ]
[ 107-13-1 ]
[ 856945-68-1 ]

Yield	Reaction Conditions	Operation in experiment
45.2%		Preparation of 4-oxotetrahydrofuran-3-carbonitrile: To a suspension ofKOtBu (996.6 mg, 8.881 mmol) in THF (640.4 mg, 8.881 mmol) cooled to 0 C was added dropwise methyl 2-hydroxyacetate (675.7 mu,, 8.881 mmol) and stirred for 10 minutes. The acrylonitrile (589.1 mu, 8.881 mmol) was then added and the reaction stirred at ambient temperature. After 3 hours, the reaction was diluted with H20 (50 mL), then extracted with Et20 (25 mL) to remove any starting ester. The basic aqueous phase was acidified with 2M HCl (5 mL), then extracted with Et20 (2 x 50 mL). The combined organic phases were dried with MgS04, filtered, and concentrated to afford a light brown oil (446 mg, 45.2% yield). 1H NMR (CDC13) delta 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (d, 1H), 4.02 (d, 1H), 3.57 (t, 1H).
45.2%		[00382] Step A: Preparation of 4-oxotetrahvdrofuran-3-carbonitrile: To a suspension of KOtBu (996.6 mg, 8.881 mmol) in THF (640.4 mg, 8.881 mmol) cooled to 0 C was added dropwise methyl 2-hydroxyacetate (675.7 iL, 8.881 mmol) and stirred for 10 minutes. The acrylonitrile (589.1 mu, 8.881 mmol) was then added and the reaction stirred at ambient temperature. After 3 hours, the reaction was diluted with H20 (50 mL), then extracted with Et20 (25 mL) to remove any starting ester. The basic aqueous phase was acidified with 2M HC1 (5 mL), then extracted with Et20 (2 x 50 mL). The combined organic phases were dried with MgS04, filtered, and concentrated to afford a light brown oil (446 mg, 45.2% yield). 1H NMR (CDC13) delta 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (d, 1H), 4.02 (d, 1H), 3.57 (t, 1H).
45.2%		1005661 Step A: Preparation of 4-oxotetrahydrofuran-3-carbonitrile: To a suspension of KOtBu (996.6 mg, 8.881 mmol) in THF (640.4 mg, 8.881 mmol) cooled to 0 C was added dropwise methyl 2-hydroxyacetate (675.7 jtL, 8.88 1 mmol) and stirred for 10 minutes. The acrylonitrile (589.1 jiL, 8.881 mmol) was then added and the reaction stirred at ambient temperature. After 3 hours, the reaction was diluted with H20 (50 mL), then extracted with Et20 (25 mL) to remove any starting ester. The basic aqueous phase was acidified with 2M HC1 (5 mL), then extracted with Et20 (2 x 50 mL). The combined organic phases were dried with MgSO4, filtered, and concentrated to afford a light brown oil (446 mg, 45.2% yield). 1 NMR (CDC13) oe 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (d, 1H), 4.02 (d, 1H), 3.57 (t, 1H).

45.22%		Intermediate 19 2-phenyl-4,6-dihvdro-2H-raro[3,4-c]pyrazol-3-amine [00454] Step A: Preparation of 4-oxotetrahvdrofuran-3-carbonitrile: To a suspension of KOtBu (996.6 mg, 8.881 mmol) in THF (640.4 mg, 8.881 mmol) cooled to 0 C was added dropwise methyl 2-hydroxyacetate (675.7 , 8.881 mmol) and stirred for 10 minutes. Acrylonitrile (589.1 muIota>, 8.881 mmol) was then added and the reaction stirred at ambient temperature. After 3 hours, the reaction was diluted with H20 (50 mL), then extracted with Et20 (25 mL). The basic aqueous phase was acidified with 2M HC1 (5 mL), then extracted with Et20 (2 x 50 mL). The combined organic phases were dried with MgS04, filtered and concentrated to afford 4-oxotetrahydrofuran-3-carbonitrile (446 mg, 45.2% yield) as a light brown oil. 1H NMR (CDC13) delta 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (d, 1H), 4.02 (d, 1H), 3.57 (t, 1H).
45.2%		To a suspension of KOtBu (996.6 mg, 8.881 mmol) in THF (640.4 mg, 8.881 mmol) cooled to 0 C was added dropwise methyl 2-hydroxyacetate (675.7 mu, 8.881 mmol) and stirred for 10 minutes. The acrylonitrile (589.1 mu, 8.881 mmol) was then added and the reaction stirred at ambient temperature. After 3 hours, the reaction was diluted with H20 (50 mL), then extracted with Et20 (25 mL) to remove any starting ester. The basic aqueous phase was acidified with 2M HC1 (5 mL), then extracted with Et20 (2 x 50 mL). The combined organic phases were dried with MgS04, filtered, and concentrated to afford a light brown oil (446 mg, 45.2% yield). 1H NMR (CDC13) delta 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (d, 1H), 4.02 (d, 1H), 3.57 (t, 1H).
45.2%		Intermediate P1082-phenyl-4,6-dihydro-2H-furo [3 ,4-c]pyrazol-31006951 Step A: Preparation of 4-oxotetrahydrofuran-3-carbonitrile: To a suspension of KOtBu (996.6 mg, 8.88 1 mmol) in THF (640.4 mg, 8.88 1 mmol) cooled to 0 C was added dropwise methyl 2-hydroxyacetate (675.7 jiL, 8.881 mmol) and stirred for 10 minutes. The acrylonitrile (589.1 jiL, 8.881 mmol) was then added and the reaction stirred at ambient temperature. After 3 hours, the reaction was diluted with 1120 (50 mL), then extracted with Et20 (25 mL) to remove any starting ester. The basic aqueous phase was acidified with 2M HC1 (5 mL), then extracted with Et20 (2 x 50 mL). The combined organic phases were dried with MgSO4, filtered, and concentrated to afford a light brown oil (446 mg, 45.2% yield). ?H NMR (CDC13) 4.63 (t, 111), 4.24 (t, 111), 4.14 (d, 1H), 4.02 (d, 1H), 3.57 (t, 111).
45.2%		To a suspension of KOtBu (996.6 mg, 8.881 mmol) in THF (640.4 mg, 8.881 mmol) cooled to 0 C was added dropwise methyl 2-hydroxyacetate (675.7 mu, 8.881 mmol) and stirred for 10 minutes. The acrylonitrile (589.1 mu, 8.881 mmol) was then added and the reaction stirred at ambient temperature. After 3 hours, the reaction was diluted with H20 (50 mL), then extracted with Et20 (25 mL) to remove any starting ester. The basic aqueous phase was acidified with 2M HCl (5 mL), then extracted with Et20 (2 x 50 mL). The combined organic phases were dried with MgS04, filtered, and concentrated to afford a light brown oil (446 mg, 45.2% yield). FontWeight="Bold" FontSize="10" H NMR (CDC13) delta 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (d, 1H), 4.02 (d, 1H), 3.57 (t, 1H).
42%		Intermediate 4: 4-oxotetrahydrofuran-3-carbonitrile [00211] To a solution of potassium tert-butoxide (24.91g, 222.O3mmol) in THF (200mL) at 0Cwas added methyl glycolate (20.OOmL, 259mmo1) dropwise. The mixture was left to stir for 10 minutes before adding acrylonitrile (14.62mL, 222mmo1) dropwise. The reaction then allowed to warm to room temperature and left to stir for 3 hours. Water and EtOAc were added to the reaction mixture and the layers separated. The aqueous layer as then acidified to pHi with 1 M HCI and extracted twice with EtOAc. The combined organic layers were then washed with brine, dried over Na2SO4 and then passed through a hydrophobic frit before being concentrated under reducedpressure to afford 4-oxotetrahydrofuran-3-carbonitrile (10.29g, 93mmol, 42% yield) as a yellow solid.1H NMR (CDCI3, 400MHz) O/ppm: 4.65 (1H, t, J= 9.3Hz), 4.26 (1H, t, J= 9.3Hz), 4.18 (1H, d, J=17.5Hz), 4.02 (1H, d, J= 17.5Hz), 3.61 (1H, t, J= 9.3Hz).

Reference： [1]Patent: WO2012/158413,2012,A2 .Location in patent: Page/Page column 101
[2]Patent: WO2014/78322,2014,A1 .Location in patent: Paragraph 00382
[3]Patent: WO2014/78325,2014,A1 .Location in patent: Paragraph 00566
[4]Patent: WO2014/78408,2014,A1 .Location in patent: Paragraph 00454
[5]Patent: WO2014/78328,2014,A1 .Location in patent: Paragraph 00494
[6]Patent: WO2014/78331,2014,A1 .Location in patent: Paragraph 00695
[7]Patent: WO2014/78454,2014,A1 .Location in patent: Paragraph 00635
[8]Patent: WO2016/51193,2016,A1 .Location in patent: Paragraph 00210; 00211

63
[ 96-35-5 ]
[ 85482-13-9 ]
[ 1445985-82-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃;	To 2- (bromomethyl)-l ,4-dichlorobenzen.e (5 g, 20.84 mmol, LOO equiv) in DMF (30 ml.) was added methyl 2-hydroxyacetate (1.89 g, 20.98 mmol, 1.01 equiv) and the solution cooled to 0 C. To this was added in portions sodium hydride (1.0 g, 41.67 mmol, 2.00 equiv). and the resulting solution was allowed to warm to T and then stirred, overnight. The reaction was quenched by the addition of 50 mL of water, the resulting solution was extracted with 3 x 50 mL of ethyl acetate and the organic layers were combined and then wshed with 1 x 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5.2 g (80%) of intermediate 179a as yellow oil.

Reference： [1]Patent: WO2013/96771,2013,A1 .Location in patent: Page/Page column 242; 243

64
[ 96-35-5 ]
[ 55676-22-7 ]
ethyl 2-((5-acetylpyridin-2-yl)oxy)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With caesium carbonate; In N,N-dimethyl-formamide; at 25 - 90℃; for 18h;Inert atmosphere;	Step 1: Ethyl 2-((5-acetylpyridin-2-yl)oxy)acetate To a solution of 1-(6-chloropyridin-3-yl)ethanone (4.0 gm, 0.0257 mole) in DMF (15 mL), cesium carbonate (16.8 gm, 0.051 mole) was added followed by addition of methyl 2-hydroxyacetate (8.0 ml, 0.103 mmoles) at 25 C. under nitrogen atmosphere and the reaction mixture was stirred at 80-90 C. for 18 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was purified by column chromatography (Eluent: 16% ethyl acetate in hexane) to yield 1.25 gm (23%) of product as off white solid. 1H NMR: DMSO-d6, delta 2.55 (s, 3H), 3.67 (s, 3H), 5.02 (s, 2H), 7.04 (dd, J=8.8 & 0.4 Hz, 1H), 8.20 (dd, J=8.8 & 2.4 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H).

Reference： [1]Patent: US2013/281366,2013,A1 .Location in patent: Paragraph 0194; 0195

65
[ 96-35-5 ]
[ 1002355-96-5 ]
[ 1453315-80-4 ]

Yield	Reaction Conditions	Operation in experiment
83%		(2234) [00625] Into a 2-L round-bottom flask purged and maintained with an inert atmosphere of N2 (g), was placed a solution of NaH (8 g, 200 mmol, 60% dispersion in oil) in ether (1 L). This was followed by the addition of methyl 2-hydroxyacetate (18 g, 200 mmol) dropwise with stirring at 0 C over 30 min. After stirred for 30 min, the ether was removed in vacuo and to this was added a solution of ferf-butyl 3-(2-etiioxy-2-oxoethylidene)azetidine- 1 -carboxylate (40 g, 166 mmol) in DMSO (1 L) dropwise with stirring at RT over 30 min. The resulting solution was stirred overnight at RT. The pH value of the solution was adjusted to 4-5 with IN HCl and extracted with 3 x l L of ether. The organic phase washed with 3 x 500 raL of H2O and dried over anhydrous Na2S04, filtered, and concentrated under vacuum to afford 2-(fert-butyl) 8-ethyl 7- oxo-5-oxa-2-azaspiro[3.4]octane-2,8-dicarboxylate as yellow oil (46 g, 83%). LCMS (ESI, m/z): 300 [M+H]+.
5.5 g		To a solution of methyl 2-hydroxyacetate (3.05 g, 33.82 mmol) in THF (20 mL) was added sodium hydride (0.81 g, 33.82 mmol). The reaction was stirred at ambient temperature for 30 min. The reaction mixture was concentrated in vacuo. tert-Butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1- carboxylate (6.8 g, 28.18 mmol) in DMSO (40 mL) was added at 0 C. The reaction was stirred at ambient temperature for 24 h. water (20 mL) and EtOAc (400 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaCl (5 x 50 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 2-tert-butyl 8-ethyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2,8-dicarboxylate (5.5 g, 18.38 mmol) as a yellow oil without further purification.
		To a solution of NaH (1.2 g, 30.00 mmol, 60% dispersion in oil) in Et20 (20 mL) was added methyl 2-hydroxyacetate (2.69 g, 29.86 mmol) at 0 C. The resulting solution was stirred for 30 mm at room temperature and then concentrated under vacuum. The residue was diluted with 20 mL of DMSO and tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (6 g, 24.87 mmol) was added. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 4-5 with hydrochloric acid (iN). The resulting mixture was extracted with Et20 (4 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:10 to 1:5 EtOAc/pet. ether) afforded 2-(tert-butyl) 8-ethyl 7-oxo-5-oxa-2- azaspiro[3.4]octane-2,8-dicarboxylate as a light yellow solid. MS: (ESI, m/z): 300 [M+H]t

Reference： [1]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00625
[2]Organic Letters,2013,vol. 15,p. 4766 - 4769
[3]Patent: WO2018/26371,2018,A1 .Location in patent: Paragraph 0271
[4]Patent: WO2019/32863,2019,A1 .Location in patent: Paragraph 00286

66
[ 67-56-1 ]
[ 79-14-1 ]
[ 502-97-6 ]
[ 96-35-5 ]

Reference： [1]Asian Journal of Chemistry,2013,vol. 25,p. 8447 - 8450

67
[ 96-35-5 ]
[ 72287-26-4 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; Petroleum ether;	b) Preparation of NaH (60percent) (0.022 mol) was stirred in petroleum ether and then decanted (2*). THF (40 ml) was added. A solution of methyl glycolate 98percent (0.022 mol) in THF (40 ml) was added dropwise (exothermic temperature rise to 26° C.). The reaction mixture was stirred at room temperature for 2 hours. A solution of intermediate (41) (0.02 mol) in THF (40 ml) was added dropwise at 20° C./25° C. The reaction mixture was stirred and refluxed for 20 hours, giving reaction mixture (I). NaH (60percent) was stirred twice in petroleum ether and decanted twice. THF (40 ml) was added. Methyl glycolate 98percent in THF (40 ml) was added and the reaction mixture was stirred and refluxed for one hour, giving reaction mixture (II). Reaction mixture (I) was added and the whole was stirred and refluxed for another 24 hours. The mixture was cooled and the solvent was evaporated. The residue was partitioned between water and CH2Cl2. The layers were separated. The aqueous layer was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 6.2 g of intermediate (42).

Reference： [1]Patent: US2014/163038,2014,A1 .Location in patent: Page/Page column

68
[ 553-90-2 ]
[ 96-35-5 ]
[ 107-21-1 ]
[ 584-03-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen In methanol at 219.84℃; Inert atmosphere; Gas phase;	Catalytic activity measurement The catalytic activity test was conducted using a fixed-bed reac-tor. Typically, 0.9 g of catalyst (40-60 meshes) sample are packedinto a stainless steel tubular reactor (i.d. = 5 mm) with a thermocou-ple inserted into the catalyst bed. Catalyst activation was performedat 573 K for 4 h with a ramping rate of 2 K min-1from room tem-perature under the 5% H2/Ar (V/V) atmosphere. After cooling tothe reaction temperature, 10 wt.% DMO (purity > 99%) in methanoland pure H2are fed into the reactor at a H2/DMO molar ratioof 100 and a system pressure of 3.0 MPa. The reaction tempera-tures are set at 493 K and LHSV of DMO is set at the value rangingfrom 0.1 to 1.0 h-1. The products are condensed, and analyzedon a gas chromatograph (Finnigan Trace GC ultra) fitted with anHP-5 capillary column and a flame ionization detector (FID). Theidentification of the products is performed by using a GC-MS spec-trometer. Chromatography is performed on a Thermo Focus DSQgas chromatograph with a mass-selective detector with electronimpact ionization. Analysts are separated using a VF-5MS capillarycolumn of 30 m × 0.25 mm with a phase thickness of 0.25 m from HP, which was inserted directly into the ion source of the MS sys-tem.
	With hydrogen In methanol at 220 - 350℃; for 4h;	4 General procedure: Cu(NO3)2 was formulated with 0.3 mol/L aqueous solution with deionized water, a solution of 157 ml of this solution was placed in a beaker, while stirring slowly add ammonia, the pH of the solution in the beaker was 9.5 to 10.5. weighed 12 g of silica was added to the above-mentioned beaker containing Cu(NO3)2 solution, in the 30 °C water bath stirring aging 4h, heated to 90 °C steamed ammonia, until the beaker solution has a pH of 7 to 8. the resulting precipitate was filtered and washed to a filtrate at a pH of about 7. the washed precipitate was dried at 120 °C for 12 h, 450 ° C calcination 4h, tablet crushing to 20 ~ 40 mesh, pre-reaction reduction to obtain catalyst A: 20 wt% Cu/silica. The above catalyst performance was evaluated in a continuous flowing gas solid phase reactor, The catalyst loading was 1.0g. using a pure hydrogen normal pressure 350 ° C reduction catalyst, flow rate of 100mL/min, the temperature is raised from room temperature to 350 ° C at a rate of 1 to 2 ° C/min, and keep 4h, down to the reaction temperature after the introduction of H2, a 15 wt.% DMO solution of methanol was poured into an advection pump. control the hydrogen ester ratio 150,The system pressure is 2.0 MPa, the reaction temperature was 200 ° C. chromatographic analysis raw materials dimethyl oxalate (DMO) and the product of methyl glycolate (MG), ethylene glycol (EG), ethanol (EO), 2-methoxyethylether (2-MEO), 1,2-propanediol (1,2POD), 1,2-butanediol (1,2BOD).The evaluation results of the catalyst performance are shown in Table 1. The catalyst preparation and evaluation procedure was the same as in Example 1, change the quality of the alleged white silica to 14. 25g, the volume of Cu(NO3)2 solution with a change of the concentration of 3 mol / L was 39. 2 ml, preparation of catalyst Ε: 5 wt% Cu / silica,The evaluation temperature of the reaction was changed to 220 ° C, and the results are shown in Table 1.

Reference： [1]Wen, Chao; Li, Fanqi; Cui, Yuanyuan; Dai, Wei-Lin; Fan, Kangnian [Catalysis Today, 2014, vol. 233, p. 117 - 126]
[2]Current Patent Assignee: Dalian Institute of Chemical Physics (in: CAS); CHINESE ACADEMY OF SCIENCES - CN105622418, 2016, A Location in patent: Paragraph 0020; 0021; 0028; 0029

69
[ 5955-72-6 ]
[ 96-35-5 ]
[ 76513-69-4 ]
[ 873-74-5 ]
C₂₂H₂₅N₅O₅Si [ No CAS ]
C₂₂H₂₅N₅O₅Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 3. NaH (60%) in mineral oil was added portion-wise to a stirred suspension of 2-chloro-5- nitro-lH-benzo[d] imidazole (A/1482/81/1) in dry DMF at 0 C under a nitrogen atmosphere The ice-bath was removed, and the reaction mixture was stirred at RT. After 0.5 h the mixture was cooled to 0 C, and 2-trimethylsilylethyoxymethyl chloride (0.38 mL) was added drop-wise. The ice-bath was removed, and the resulting reaction mixture was stirred at RT. After lh, UPLC showed complete conversion. A saturated ammonium chloride solution and EA were added, the organic phase was separated, washed with water, dried over sodium sulfate and the solvent removed under vacuum. The crude material was purified by FC on silica (Snap 100, eluting with Cy EA from 100/0 to 80/20) to give the desired product A/1482/82/1 as yellow oil. Step 4. To a solution of methyl glycolate in dry THF (8 ml) cooled at 0 C was added NaH (60%) in mineral oil. The reaction was stirred at room temperature for 2h. The suspension was cooled at 0 C and a solution of A/1482/82/1 was added dropwise. The reaction mixture was stirred at room temperature for 16h. UPLC showed ~70% reaction completion, and another 1.1 eq of NaH was added. After stirring for 16h, UPLC showed formation of side products. The reaction was stopped, and S. NH4C1 and EtOAC were added. The organic phase was separated, dried and evaporated to give a crude product, which was then purified by silica column (CyHex to CyHex: EtOAc= 85:15). The product named A/1482/83/1 was recovered with a 50% of purity grade (by NMR), with the UPLC retention time of the impurity that same as that of the desired product. Step 5. To a stirred solution oh the A/1482/83/1 cooled to 0 C in THF, a solution of LiOH in water was added dropwise. The mixture was then stirred at room temperature for 2h. UPLC showed complete conversion. The solvent was evaporated under vacuum. The residue was portioned between water and EtOAc, the organic phase was separated and discarded. The water phase was evaporated to give the desired product as the corresponding lithium salt A/1482/84/1. Step 6. To a stirred solution of A/1482/84/1, 4-aminobenzonitrile and TEA in THF 3: 1, HATU was added at room temperature. After stirring for 5h, UPLC showed complete conversion. The solvent was evaporated and the residue partitioned between saturated aqueous NaHC03 and DCM. The organic phase was separated, dried and the solvent evaporated to give an impure product, which was further purified by Si02 column (DCM to DCM:MeOH). The desired product named A/1540/23/1 was recovered as a white solid.

Reference： [1]Patent: WO2014/176258,2014,A1 .Location in patent: Page/Page column 55; 56

70
[ 5955-72-6 ]
[ 96-35-5 ]
[ 76513-69-4 ]
C₁₆H₂₃N₃O₆Si [ No CAS ]
C₁₆H₂₃N₃O₆Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 3. NaH (60%) in mineral oil was added portion-wise to a stirred suspension of 2-chloro-5- nitro-lH-benzo[d] imidazole (A/1482/81/1) in dry DMF at 0 C under a nitrogen atmosphere The ice-bath was removed, and the reaction mixture was stirred at RT. After 0.5 h the mixture was cooled to 0 C, and 2-trimethylsilylethyoxymethyl chloride (0.38 mL) was added drop-wise. The ice-bath was removed, and the resulting reaction mixture was stirred at RT. After lh, UPLC showed complete conversion. A saturated ammonium chloride solution and EA were added, the organic phase was separated, washed with water, dried over sodium sulfate and the solvent removed under vacuum. The crude material was purified by FC on silica (Snap 100, eluting with Cy EA from 100/0 to 80/20) to give the desired product A/1482/82/1 as yellow oil. Step 4. To a solution of methyl glycolate in dry THF (8 ml) cooled at 0 C was added NaH (60%) in mineral oil. The reaction was stirred at room temperature for 2h. The suspension was cooled at 0 C and a solution of A/1482/82/1 was added dropwise. The reaction mixture was stirred at room temperature for 16h. UPLC showed ~70% reaction completion, and another 1.1 eq of NaH was added. After stirring for 16h, UPLC showed formation of side products. The reaction was stopped, and S. NH4C1 and EtOAC were added. The organic phase was separated, dried and evaporated to give a crude product, which was then purified by silica column (CyHex to CyHex: EtOAc= 85:15). The product named A/1482/83/1 was recovered with a 50% of purity grade (by NMR), with the UPLC retention time of the impurity that same as that of the desired product.

Reference： [1]Patent: WO2014/176258,2014,A1 .Location in patent: Page/Page column 55

71
[ 5955-72-6 ]
[ 96-35-5 ]
[ 76513-69-4 ]
C₁₅H₂₀N₃O₆Si^(1-)*Li⁽¹⁺⁾ [ No CAS ]
C₁₅H₂₀N₃O₆Si^(1-)*Li⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 3. NaH (60%) in mineral oil was added portion-wise to a stirred suspension of 2-chloro-5- nitro-lH-benzo[d] imidazole (A/1482/81/1) in dry DMF at 0 C under a nitrogen atmosphere The ice-bath was removed, and the reaction mixture was stirred at RT. After 0.5 h the mixture was cooled to 0 C, and 2-trimethylsilylethyoxymethyl chloride (0.38 mL) was added drop-wise. The ice-bath was removed, and the resulting reaction mixture was stirred at RT. After lh, UPLC showed complete conversion. A saturated ammonium chloride solution and EA were added, the organic phase was separated, washed with water, dried over sodium sulfate and the solvent removed under vacuum. The crude material was purified by FC on silica (Snap 100, eluting with Cy EA from 100/0 to 80/20) to give the desired product A/1482/82/1 as yellow oil. Step 4. To a solution of methyl glycolate in dry THF (8 ml) cooled at 0 C was added NaH (60%) in mineral oil. The reaction was stirred at room temperature for 2h. The suspension was cooled at 0 C and a solution of A/1482/82/1 was added dropwise. The reaction mixture was stirred at room temperature for 16h. UPLC showed ~70% reaction completion, and another 1.1 eq of NaH was added. After stirring for 16h, UPLC showed formation of side products. The reaction was stopped, and S. NH4C1 and EtOAC were added. The organic phase was separated, dried and evaporated to give a crude product, which was then purified by silica column (CyHex to CyHex: EtOAc= 85:15). The product named A/1482/83/1 was recovered with a 50% of purity grade (by NMR), with the UPLC retention time of the impurity that same as that of the desired product. Step 5. To a stirred solution oh the A/1482/83/1 cooled to 0 C in THF, a solution of LiOH in water was added dropwise. The mixture was then stirred at room temperature for 2h. UPLC showed complete conversion. The solvent was evaporated under vacuum. The residue was portioned between water and EtOAc, the organic phase was separated and discarded. The water phase was evaporated to give the desired product as the corresponding lithium salt A/1482/84/1.

Reference： [1]Patent: WO2014/176258,2014,A1 .Location in patent: Page/Page column 55

72
[ 5955-72-6 ]
[ 96-35-5 ]
[ 873-74-5 ]
N-(4-cyanophenyl)-2-((6-nitro-1H-benzo[d]imidazol-2-yl)oxy)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%		Step 3. NaH (60%) in mineral oil was added portion-wise to a stirred suspension of 2-chloro-5- nitro-lH-benzo[d] imidazole (A/1482/81/1) in dry DMF at 0 C under a nitrogen atmosphere The ice-bath was removed, and the reaction mixture was stirred at RT. After 0.5 h the mixture was cooled to 0 C, and 2-trimethylsilylethyoxymethyl chloride (0.38 mL) was added drop-wise. The ice-bath was removed, and the resulting reaction mixture was stirred at RT. After lh, UPLC showed complete conversion. A saturated ammonium chloride solution and EA were added, the organic phase was separated, washed with water, dried over sodium sulfate and the solvent removed under vacuum. The crude material was purified by FC on silica (Snap 100, eluting with Cy EA from 100/0 to 80/20) to give the desired product A/1482/82/1 as yellow oil. Step 4. To a solution of methyl glycolate in dry THF (8 ml) cooled at 0 C was added NaH (60%) in mineral oil. The reaction was stirred at room temperature for 2h. The suspension was cooled at 0 C and a solution of A/1482/82/1 was added dropwise. The reaction mixture was stirred at room temperature for 16h. UPLC showed ~70% reaction completion, and another 1.1 eq of NaH was added. After stirring for 16h, UPLC showed formation of side products. The reaction was stopped, and S. NH4C1 and EtOAC were added. The organic phase was separated, dried and evaporated to give a crude product, which was then purified by silica column (CyHex to CyHex: EtOAc= 85:15). The product named A/1482/83/1 was recovered with a 50% of purity grade (by NMR), with the UPLC retention time of the impurity that same as that of the desired product. Step 5. To a stirred solution oh the A/1482/83/1 cooled to 0 C in THF, a solution of LiOH in water was added dropwise. The mixture was then stirred at room temperature for 2h. UPLC showed complete conversion. The solvent was evaporated under vacuum. The residue was portioned between water and EtOAc, the organic phase was separated and discarded. The water phase was evaporated to give the desired product as the corresponding lithium salt A/1482/84/1. Step 6. To a stirred solution of A/1482/84/1, 4-aminobenzonitrile and TEA in THF 3: 1, HATU was added at room temperature. After stirring for 5h, UPLC showed complete conversion. The solvent was evaporated and the residue partitioned between saturated aqueous NaHC03 and DCM. The organic phase was separated, dried and the solvent evaporated to give an impure product, which was further purified by Si02 column (DCM to DCM:MeOH). The desired product named A/1540/23/1 was recovered as a white solid. Step 7. The SEM protected starting material A/1540/23/1 was dissolved in a mixture 9:1 TF A/water at 0 C. The solution was stirred at room temperature for 5h. UPLC showed formation of the desired product. Excess of TFA was evaporated in vacuo and the residue was partitioned between saturated aqueous NaHCC>3 and DCM (3 times). The organic phases were combined, dried and the solvent evaporated to provide crude material, which was then further purified by silica column (DCM to DCM MeOH 95:5). 15 mg of product were recovered. NMR showed a 80% of purity grade. A second purification by reverse phase chromatography was performed (water to water /MeOH 40:60) and 7 mg of the desired product, N-(4-cyanophenyl)-2-((6-nitro-lH-benzo[d]imidazol-2-yl)oxy)acetamide, was recovered (Y= 10%).

Reference： [1]Patent: WO2014/176258,2014,A1 .Location in patent: Page/Page column 55; 56

73
[ 96-35-5 ]
[ 55676-22-7 ]
[ 1384276-60-1 ]

Yield	Reaction Conditions	Operation in experiment
23%	With caesium carbonate; In N,N-dimethyl-formamide; at 25 - 90℃; for 18h;Inert atmosphere;	To a solution of l-(6-chloropyridin-3-yl)ethanone (4.0 gm, 0.0257 mole) in DMF (15 mL), cesium carbonate (16.8 gm, 0.051 mole) was added followed by addition of methyl 2-hydroxyacetate (8.0 ml, 0.103 mmoles) at 25 C under nitrogen atmosphere and the reaction mixture was stirred at 80-90 C for 18 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was purified by colunm chromatography (Eluent: 16% ethyl acetate in hexane) to yield 1.25 gm (23%) of product as off white solid. NMR: DMSO-< 6,? 2.55 (s, 3H), 3.67 (s, 3H), 5.02 (s, 2H), 7.04 (dd, J = 8.8 & 0.4 Hz, 1H), 8.20 (dd, J= 8.8 & 2.4 Hz, 1H), 8.78 (d, J= 2.0 Hz, 1H).
23%	With caesium carbonate; In N,N-dimethyl-formamide; at 25 - 90℃; for 18h;Inert atmosphere;	To a solution of 1-(6-chloropyridin-3-yl)ethanone (4.0 gm, 0.0257 mole) in DMF (15 mL), cesium carbonate (16.8 gm, 0.051 mole) was added followed by addition of methyl 2-hydroxyacetate (8.0 ml, 0.103 mmoles) at 25 C under nitrogen atmosphere and the reaction mixture was stirred at 80-90 C for 18 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was purified by colunm chromatography (Eluent: 16% ethyl acetate in hexane) to yield 1.25 gm (23%) of product as off white solid. 1H NMR: DMSO-d6, delta2.55 (s, 3H), 3.67 (s, 3H), 5.02 (s, 2H), 7.04 (dd, J = 8.8 & 0.4 Hz, 1H), 8.20 (dd, J = 8.8 & 2.4 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H).
23%	With caesium carbonate; In N,N-dimethyl-formamide; at 80 - 90℃; for 18h;	Step 1: Preparation of Ethyl 2-((5-acetylpyridin-2-yl)oxy)acetate To a solution of 1-(6-chloropyridin-3-yl)ethanone (4.0 gm, 0.0257 mole) in DMF (15 mL), cesium carbonate (16.8 gm, 0.051 mole) was added followed by addition of methyl 2-hydroxyacetate (8.0 ml, 0.103 mmoles) at 25 C. under nitrogen atmosphere and the reaction mixture was stirred at 80-90 C. for 18 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was purified by column chromatography (Eluent: 16% ethyl acetate in hexane) to yield 1.25 gm (23%) of product as off white solid. 1H NMR: DMSO-d6, delta 2.55 (s, 3H), 3.67 (s, 3H), 5.02 (s, 2H), 7.04 (dd, J=8.8 & 0.4 Hz, 1H), 8.20 (dd, J=8.8 & 2.4 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H).

Reference： [1]Patent: WO2014/192023,2014,A1 .Location in patent: Page/Page column 29-30
[2]Patent: EP2658851,2013,A1 .Location in patent: Paragraph 0060
[3]Patent: US2016/83380,2016,A1 .Location in patent: Paragraph 0227; 0228; 0229

74
[ 96-35-5 ]
4-(3-(3-fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]
methyl 2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorophenoxy)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.7%	With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; for 1h;Inert atmosphere;	4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2 -(trifluoromethyl)benzonitrile 1e (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of methyl glycolate (42 mg, 0.47 mmol), triphenylphosphine (93 mg, 0.35 mmol), 5 mL of dichloromethane and diisopropyl azodicarboxylate (72 mg, 0.35 mmol) successively. The reaction solution was stirred for 1 hour. The reaction solution was concentrated under the reduced pressure and the residue was purified by thin layer chromatography with elution system A to obtain the title compound methyl 2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorophenoxy)acetate 31a (104 mg, yield 89.7%) as a white solid. MS m/z (ESI): 496.2 [M+1]
89.7%	With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 20 - 30℃; for 1h;	4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 1e (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of methyl glycolate (42 mg, 0.47 mmol), triphenylphosphine (93 mg, 0.35 mmol), 5 mL of dichloromethane, and diisopropyl azodicarboxylate (72 mg, 0.35 mmol), successively. The reaction solution was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with elution system A to obtain the title compound methyl 2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorophenoxy)acetate 31a (104 mg, yield 89.7%) as a white solid. MS m/z (ESI): 496.2 [M+1]

Reference： [1]Patent: EP2894151,2015,A1 .Location in patent: Paragraph 0187; 0188
[2]Patent: US2015/225381,2015,A1 .Location in patent: Paragraph 0251-0253

75
[ 4487-56-3 ]
[ 96-35-5 ]
methyl 2-((2-chloro-5-nitropyridin-4-yl)oxy) acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil;Cooling with ice;	Sodium hydride (60percent in mineral oil, 31.2 mmol, 1.25 g) was added to a solution of 2, 4-dichloro-5- nitropyridine (26 mmol, 5.00 g) and methyl glycolate (31.2 mmol, 2.41 mL) in DMF (50 mL) cooled in an ice- water bath. The mixture was stirred overnight then poured into saturated aqueous ammonium chloride solution (30 mL) . The mixture was extracted with ethyl acetate (3 x 50 mL) . The combined organic extracts were dried (0804) (MgSO,}) then concentrated under reduced pressure to give dark oil which solidified on standing. The solid was triturated with isohexane containing a few drops of dichloromethane then filtered and dried under suction to give the title compound as a dark brown solid (4.32 g, 67percent).
	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;	To a stirred solution of <strong>[4487-56-3]2,4-dichloro-5-nitropyridine</strong> (26 mmol, 5 g) and methyl glycolate (31.2 mmol, 2.41 mL) in DMF at 0°C, sodium hydride was added (60percent in mineral oil, 31.2 mmol, 1.25 g) and the mixture was stirred at rt overnight. The reaction mixture wasquenched with ammonium chloride solution (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum. The resulting crude product was purified by column chromatography affording the title product (yellow solid). 1H NMR (400 MHz, DMSO-d6): 6 8.93 (5, IH), 7.71 (5, IH), 5.23 (5, 2H), 3.74 (5, 3H). LCMS: (Method A) 247.0 (M+H), Rt. 2.436 mm, 83.5percent (Max).

Reference： [1]Patent: WO2015/115673,2015,A1 .Location in patent: Page/Page column 80
[2]Patent: WO2017/144633,2017,A1 .Location in patent: Page/Page column 124; 125

76
[ 32601-86-8 ]
[ 96-35-5 ]
2-((3-methylquinoxalin-2-yl)oxy)acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		A mixture of <strong>[32601-86-8]<strong>[32601-86-8]2-chloro-3-methylquinoxalin</strong>e</strong> (500 mg, 2.8 mmol, Oakwood), methyl glycolate (1.06 mL, 14 mmol) and K2CO3 (1.93 g, 14 mmol) in DMF (14 mL) was stirred overnight at 60 C. By morning, the title compound had formed along with the methyl ester in approximately a 3:4, respectively. 1N NaOH (5.6 mL, 5.6 mmol), water (10 mL), and DCM (10 mL) were added and the reaction stirred overnight at room temperature while stirring vigorously. By morning, the product ratio had improved to approximately 1:1. Concentrated hydrochloric acid was added until a pH=3. The layers were separated and the aqueous layer was extracted with DCM twice more. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrate in vacuo. The crude material was purified by prep HPLC. Obtained 305 mg (50% yield) of the title compound as a white powder. 1H NMR (300MHz, CD3OD) delta = 7.93 - 7.86 (m, 1H), 7.82 - 7.75 (m, 1H), 7.69 - 7.53 (m, 2H), 5.10 (s, 2H), 2.67 (s, 3H)Retention time = 3.49 min. LCMS (ESI) m/z 219.02 (M+1)+

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3429 - 3435

77
[ 96-35-5 ]
[ 598-42-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	With urea at 160℃; for 3h;	1-4; 1-3; 5 Preparation of ethanolamide: Add 450g of methyl glycolate, 100g of urea and 15g of the obtained solid-liquid composite catalyst (5g of platinum-based solid catalyst-10g of tetraethyl titanate liquid) into a three-necked flask, raise the temperature to 160°C, react for 3 hours, and proceed with stirring ,As shown in Figure 3.After the reaction was completed and cooled, filtered and analyzed, the yield was calculated, and the yield of ethanolamide was 94%.
57%	With ammonia In methanol	Synthesis of compound4a 4.686g (0.052 mol) methyl glycolate was dissolved in 5 mL MeOH, thesolution was cooled to a temperature 00C,,then to the mixture 4.74mL 23% NH3 solution in MeOH was addeddropwise. The mixture was stirred atroom temperature for 6 h, then the whitecrystals were precipitated from the mixture by adding diethyl ether. The whitesolid was filtered off under reducedpressure to give 2.245 g pure crystals ofglycolamide. M. p. 114-116°C. Yield 57%
	With ammonia In methanol at 20℃; for 16h;	25.1 Step 1: A solution of methyl 2-hydroxyacetate (1.00 g, 11.1 mmol, 1.0 equiv) in a saturated solution of NH3(g) in MeOH (10 mL) was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in glycolamide (1 g, crude) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 7.17 (broad s, 2H), 5.43 (broad s, 2H), 3.73 (s, 2H).

Reference： [1]Current Patent Assignee: SHANDONG HUALU-HENGHSHENG CHEMICAL CO., LTD.; CHANGZHOU INSTITUTE OF TECHNOLOGY - CN112608244, 2021, A Location in patent: Paragraph 0047; 0050-0052; 0055-0057; 0059-0060; 0062-0063
[2]Pawlak, Dorota; Schielmann, Marta; Wojciechowski, Marek; Andruszkiewicz, Ryszard [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 15, p. 3586 - 3589]
[3]Current Patent Assignee: PROMETHEUS BIOSCIENCES INC - WO2022/20617, 2022, A1 Location in patent: Paragraph 00180

78
[ 96-35-5 ]
baloxavir acid [ No CAS ]
[ 1498-51-7 ]
C₂₉H₂₈F₂N₃O₉PS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%		ethylphosphonic dichloride (202mg, 1.24mmol) in dichloromethane (3mL) solution, at -78C, triethylamine (126mg, 1.24mmol) and dichloromethane (2mL) of methyl glycol acid (112mg, 1.24mmol) mixed the solution was dropped. After 2 hours stirring the reaction mixture at room temperature, Compound III-2 (200mg, 0.414mmol) and triethylamine (126 mg, 1.25 mmol) and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was concentrated and purified by silica gel column chromatography (ethyl acetate - methanol) to give the compound II-57 (143mg, 52% yield).
52%		Ethyl phosphorodichloridate (202 mg, 1.24 mmol)In dichloromethane (3 mL) at -78 C. was added triethylamine(126 mg, 1.24 mmol) and methyl glycolate(112 mg, 1.24 mmol) in dichloromethane (2 mL)The mixed solution was added dropwise. The reaction solution was stirred at room temperature for 2 hours,Compound III-2 (200 mg, 0.414 mmol)And triethylamine (126 mg, 1.25 mmol) were added,And the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate-methanol) to obtain Compound II-57(143 mg, yield 52%).

Reference： [1]Patent: JP5971830,2016,B1 .Location in patent: Paragraph 0083
[2]Patent: JP6267397,2018,B1 .Location in patent: Paragraph 0098

79
[ 96-35-5 ]
[ 19227-13-5 ]
[ 851181-04-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydroxide In dimethyl sulfoxide at 20℃; for 16h;	4.2. General procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C.

Reference： [1]Baykov, Sergey; Sharonova, Tatyana; Shetnev, Anton; Rozhkov, Sergey; Kalinin, Stanislav; Smirnov, Alexey V. [Tetrahedron, 2017, vol. 73, # 7, p. 945 - 951]

80
[ 96-35-5 ]
[ 570391-18-3 ]
(3-chloro-5-trifluoromethylphenoxy)acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20.0℃;Inert atmosphere;	3-Chloro-5-trifluoromethyl-phenoxy)-acetic acid methyl ester (9): [00226] To a solution of 3-Chloro-5-trifluoromethyl-phenol (6, 1 .0 g, 5.087 mmol) in THF (15 mL) was added 1 .2 equivalent of hydroxy-acetic acid methyl ester. To this solution was added under nitrogen-atmosphere dropwise during 1 hour a solution of DEAD (5.59 mmol) in THF (30 mL), followed by 1 .2 eq. of tnphenylphosphine, The reaction mixture was subsequently stirred at ambient temperature overnight. The THF was evaporated and diethyl ether, or a mixture of diethyl ether and hexane, was added in order to precipitate the formed tnphenylphosphine oxide, which was filtered off. The crude product was loaded on silica gel and purified by a short chromatography column, to yield the desired compound 3-Chloro-5-trifluoromethyl-phenoxy)-acetic acid methyl ester (9, 1 .2 g, 95%) as colorless viscous oil. 1 H-NMR (300 MHz, CDCI3): 6 7.38 (s, 1 H), 7.09 (s, 2H), 4.35 (s, 2H), 2.2 (s, 3H).

Reference： [1]Patent: WO2017/70795,2017,A1 .Location in patent: Paragraph 00226

81
[ 67-56-1 ]
[ 9004-34-6 ]
[ 96-35-5 ]
[ 547-64-8 ]
[ 24332-20-5 ]

Reference： [1]ChemSusChem,2017,vol. 10,p. 1390 - 1394

82
[ 75-15-0 ]
[ 96-35-5 ]
[ 74-88-4 ]
methyl ([(methylsulfanyl)carbonothioyl]oxy)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%		General procedure: Carbon disulfide (18.1 mL, 0.3 mol) was added dropwise at -30 C to the suspension of sodiumhydride (60% in mineral oil) (4.4 g, 0.11 mol) in anhydrous dimethylformamide (DMF) (200 mL).To this mixture the solution of corresponding hydroxyderivatives (0.1 mol) in anhydrous DMF (15mL) was added dropwise for 3 h with mechanistic stirring at -30 C. After addition was completed,the mixture was warmed to room temperature and stirred for 3 h. The color of the mixture graduallychanged to dark red. The reaction mixture was cooled to -10 C and methyl iodide (7.8 mL, 0.12 mol)was added dropwise. The mixture was warmed to room temperature, stirred for 3 h until the colorchanged from dark red to yellow and poured into ice (600 g), and extracted with tert-buthylmethylether (MTBE) (5 50 mL). The extract was washed with brine (5 50 mL) and dried with MgSO4.The solvent was removed at atmospheric pressure and the residue distilled in vacuum.3.1.1. Methyl ([(methylsulfanyl)carbonothioyl]oxy)acetate 1aYield 15.5 g (86%). Yellow oil: bp 129-130 C (20 Torr). 1H-NMR (400 MHz, CDCl3): delta 2.60 (s, 3H,SCH3), 3.77 (s, 3H, OCH3), 5.15 (s, 2H, CH2). 13C-NMR (100 MHz, CDCl3): delta 19.5 (s, SCH3), 52.4Molecules 2017, 22, 804 5 of 10(s, OCH3), 67.6 (s, CH2), 167.1 (s, C=O), 215.8 (s, C=S). GC-MS, 70 eV, m/z (rel. int.): 180 (69) [M]+.Anal. calcd for C5H8O3S2: C, 33.32; H, 4.47; S, 35.58; found: C, 33.14; H, 4.51; S, 35.51.

Reference： [1]Molecules,2017,vol. 22

83
[ 96-35-5 ]
[ 1679-51-2 ]
cyclohex-3-en-1-ylmethyl 2-hydroxyacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.1%	With toluene-4-sulfonic acid In n-heptane for 2h; Reflux; Dean-Stark;	6 EXAMPLE 6: Preparation of cyclohex-3-en-l-ylmethyl 2-hydroxyacetate 31.8 g (283.1 mmol) of 3 -cyclohexene-1 -methanol, 50.6 g (561.7 mmol) of methyl glycolate, 609 mg of p-toluenesulfonic acid, and 32 mL of heptane were added to a 200 mL three-neck flask equipped with a thermometer, Dean-Stark apparatus, and Dimroth condenser, and heat under reflux was performed. The methanol formed during this period was removed by the Dean-Stark apparatus, and 3 -cyclohexene-1 -methanol as a raw material disappeared 2 hours later. The thus obtained reaction solution was washed with 30 mL of saturated sodium hydrogen carbonate aqueous solution and 30 mL of saturated brine in this order and then heptane was evaporated to carry out distillation under a reduced pressure (95.5 °C/250 Pa), thereby obtaining 28.3 g of the intended cyclohex-3-en-l-ylmethyl 2-hydroxyacetate as a colorless oil (theoretical yield based on 3 -cy clohexene- 1 -methanol, 67.1%). (0170) 1H MR (500 MHz, CDC13) δ: 5.63-5.71(m, 2H), 4.17(bs, 2H), 4.1 l(d, J = 6.7 Hz, 2H), 2.56(bs, 1H), 2.05-2.14(m, 3H), 1.95-2.03(m, 1H), 1.74-1.81(m, 2H), 1.28- 1.36(m, 1H). 13C NMR (125 MHz, CDC13) δ: 173.5, 127.0, 125.2, 69.7, 60.5, 32.9, 27.9, 25.1, 24.2. (0171) GC/MS(EI): m/z(%) 171(1), 133(1), 1 1 1(2), 94(72), 79(100), 77(10), 67(10), (0172) 55(5).

Reference： [1]Current Patent Assignee: TAKASAGO INTERNATIONAL CORPORATION - WO2017/214455, 2017, A1 Location in patent: Page/Page column 27-28

84
[ 96-35-5 ]
[ 18162-48-6 ]
[ 105459-05-0 ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 593 - 597

85
[ 96-35-5 ]
[ 668262-52-0 ]
methyl 5-chloro-2-((2-methoxy-2-oxoethoxy)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		Methyl 2-hydroxyacetate (1.72 g, 19.2 mmol) was dissolved in DMF (50 mL) and treated with sodium hydride (460 mg, 19.2 mmol, 95%). The reaction mixture was stirred at room temperature for 30 mm, and then cooled in an ice bath. A solution of 2.53 g (9.60 mmol) of <strong>[668262-52-0]methyl 2-(bromomethyl)-5-chlorobenzoate</strong> (Thorarensen, A., et al W02004018414) in DMF (5 mL) was added, and the reaction mixture was stirred at 0C for 10 mm. Excess hydride was carefully quenched by the dropwise addition of saturated aqueous NH4C1 (20 mL). The mixture was diluted with water (50 mL) and extracted with EtOAc (4x60 mL). The combined organics were washed with brine (2x25 mL), anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (Si02, 5% EtOAc/hexanes) gave methyl 5-chloro-2-((2-methoxy-2- oxoethoxy)methyl)benzoate 1.1 (1.82 g, 70%) as a white solid. MS (ESI): m/z 273 [M+H]

Reference： [1]Patent: WO2018/23070,2018,A1 .Location in patent: Paragraph 0127

86
[ 96-35-5 ]
(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione [ No CAS ]
[ 1498-51-7 ]
methyl 2-(((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)(ethoxy)phosphoryl)oxy)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%		To a solution of ethyl phosphorodichloridate (45 mg, 0.279 mmol) in dichloromethane (1 at -78 C was added triethylamine (0.078 ml, 0.558 mmol) and a solution of methyl 2- hydroxyacetate (35 mg, 0.279 mmol) in dichloromethane (2 mL) dropwise. After the reaction mixture was stirred at room temperature for 2 hours, a solution of (9aR,10S)-10-(bis(4- fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1 ',2':4,5]pyrazino[1 ,2- b]pyridazine-3,5(7H)-dione (50 mg, 0.093 mmol) and triethylamine (3 equiv) in DCM (1 mL) was added. The mixture was stirred at RT for 3h, filtered and concentrated. SFC purification (1006) (CCVMeOH) provided methyl 2-(((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo- 3,5,8,9,9a, 10-hexahydro-7H-pyrrolo[1 ',2':4,5]pyrazino[1 ,2-b]pyridazin-4- yl)oxy)(ethoxy)phosphoryl)oxy)acetate (27 mg) in 46% yield. 1 H NMR (400 MHz, Chloroform-d) delta 7.45 (d, J = 5.2 Hz, 1 H), 7.39 - 7.31 (m, 2H), 7.12 (t, J = 8.5 Hz, 2H), 6.87 (q, J = 7.2 Hz, 2H), 6.80 (t, J = 8.4 Hz, 2H), 5.33 (dt, J = 10.0, 3.1 Hz, 1 H), 5.01 - 4.90 (m, 2H), 4.60 - 4.40 (m, 3H), 4.27 (dd, J = 10.1 , 2.3 Hz, 1 H), 3.80 (d, J = 7.1 Hz, 4H), 3.62 (dq, J = 12.0, 6.9 Hz, 1 H), 1 .99 (d, J = 13.6 Hz, 1 H), 1 .92 - 1 .78 (m, 2H), 1 .56 - 1 .34 (m, 4H). MS m/z 604.2 (MH+).

Reference： [1]Patent: WO2018/42303,2018,A1 .Location in patent: Page/Page column 136; 137

87
[ 96-35-5 ]
[ 150374-99-5 ]
4-((2-methoxy-2-oxoethoxy)sulfonyl)phenyl pivalate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 4323 - 4335

88
[ 96-35-5 ]
[ 2740-88-7 ]
3-(4-fluorobenzyl)-2-thioxooxazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	at 0 - 20℃;	8 Synthesis of 3-(4-fluorobenzyl)-2-thioxooxazolidin-4-one (8.1). To a solution of 1-fluoro-4-isothiocyanatomethyl benzene (8.2, 1.2 g, 7.18 mmol) in acetonitrile (30 mL) was added potassium carbonate (2.47 g, 17.90 mmol) in one portion followed by addition of methyl glycolate (0.646 g, 7.18 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion, water (50 mL) was added to the reaction and the mixture was extracted with diethyl ether (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography eluting with 5-10% ethyl acetate in hexanes to afford 3-(4-fluorobenzyl)-2-thioxooxazolidin-4-one (8.1). Yield; 0.160 g, 10%.

Reference： [1]Current Patent Assignee: GOSSAMER BIO INC - WO2018/126072, 2018, A1 Location in patent: Paragraph 0231; 0232

89
[ 96-35-5 ]
[ 2580-79-2 ]
[3,3'-bis(1,2,4-oxadiazole)]-5,5'-diyldimethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%	With potassium carbonate In N,N-dimethyl-formamide; toluene at 140℃; for 4h; Dean-Stark;

Reference： [1]Johnson, Eric C.; Sabatini, Jesse J.; Chavez, David E.; Sausa, Rosario C.; Byrd, Edward F. C.; Wingard, Leah A.; Guzmàn, Pablo E. [Organic Process Research and Development, 2018, vol. 22, # 6, p. 736 - 740]

90
[ 188290-36-0 ]
[ 96-35-5 ]
[ 19432-68-9 ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid; In 1,2-dichloro-ethane; for 4h;Reflux;	20 grams of thiophene was mixed with 10 volumes of dichloroethane. 1.1 equivalents of methyl glycolate and 1.1 equivalents of p-toluenesulfonic acid were added and refluxed for 4 hours. The resulting mixture was cooled to room temperature, the reaction solution was washed successively with cold water and saturated brine, dried, concentrated and the crude product obtained was used directly in the next hydrolysis reaction.

Reference： [1]Patent: CN108947960,2018,A .Location in patent: Paragraph 0049-0051

91
[ 502-97-6 ]
[ 96-35-5 ]

Reference： [1]ChemCatChem,2018,vol. 10,p. 5649 - 5655

92
[ 96-35-5 ]
[ 502-97-6 ]

Reference： [1]ChemCatChem,2018,vol. 10,p. 5649 - 5655

93
[ 96-35-5 ]
[ 95-50-1 ]
[ 6956-85-0 ]

Yield	Reaction Conditions	Operation in experiment
99%		To the obtained methyl hydroxyacetate, 54.83 g of 99.5% sodium methoxide was added.At 20 C, the alcohol formed by the reaction was simultaneously removed, and 148.48 g of 99% o-dichlorobenzene was added thereto, and the condensation reaction was carried out at 60 C.After the reaction, the unreacted o-dichlorobenzene is removed under reduced pressure.The condensation liquid is cooled to 20 C for filtration, and the filter cake is dried under reduced pressure.The dried fractions were collected and combined with the filtrate to obtain methyl o-chlorophenoxyacetate 201.45 g.The content is 98.6%, and the yield is 99.0%.

Reference： [1]Patent: CN108947816,2018,A .Location in patent: Paragraph 0058; 0060

94
[ 96-35-5 ]
[ 40851-62-5 ]
3-(2-methylphenyl)-4-hydroxyfuran-2(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium <i>tert</i>-butylate In tetrahydrofuran for 8h; Reflux;	4.2.2. General Procedure for Synthesis of the Key Lactone Intermediate II (6a-6k) General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a)

Reference： [1]Bao, Longzhu; Wang, Shuangshuang; Song, Di; Wang, Jingjing; Cao, Xiufang; Ke, Shaoyong [Molecules, 2019, vol. 24, # 7]

95
[ 96-35-5 ]
[ 55954-23-9 ]
3-(2,4-dichlorophenyl)-4-hydroxyfuran-2(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; for 8h;Reflux;	General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a)

Reference： [1]Molecules,2019,vol. 24

96
[ 96-35-5 ]
[ 57486-68-7 ]
[ 100074-41-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; for 8h;Reflux;	General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a)

Reference： [1]Molecules,2019,vol. 24

97
[ 96-35-5 ]
[ 54551-83-6 ]
C₁₀H₆Cl₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium <i>tert</i>-butylate In tetrahydrofuran for 8h; Reflux;	4.2.2. General Procedure for Synthesis of the Key Lactone Intermediate II (6a-6k) General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a)

Reference： [1]Bao, Longzhu; Wang, Shuangshuang; Song, Di; Wang, Jingjing; Cao, Xiufang; Ke, Shaoyong [Molecules, 2019, vol. 24, # 7]

98
[ 96-35-5 ]
[ 23786-13-2 ]
[ 100074-53-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium <i>tert</i>-butylate In tetrahydrofuran for 8h; Reflux;	4.2.2. General Procedure for Synthesis of the Key Lactone Intermediate II (6a-6k) General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a)

Reference： [1]Bao, Longzhu; Wang, Shuangshuang; Song, Di; Wang, Jingjing; Cao, Xiufang; Ke, Shaoyong [Molecules, 2019, vol. 24, # 7]

99
[ 96-35-5 ]
[ 57486-67-6 ]
[ 100074-44-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; for 8h;Reflux;	General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a)

Reference： [1]Molecules,2019,vol. 24

100
[ 2075-46-9 ]
[ 96-35-5 ]
[ 6715-84-0 ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 4312 - 4324

101
[ 93-58-3 ]
[ 96-35-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With C33H32Cl2N2P2Ru; hydrogen; sodium methylate; In para-xylene; toluene; at 5 - 100℃; under 37503.8 Torr; for 4h;Glovebox;	In the same experimental procedure as in the fourth embodiment, the catalyst was changed to III-C-1 (26.2 mg).The corresponding product MG yield was obtained as 100%. In the same manner as in the fourth experimental procedure, the substrate was converted to methyl benzoate (1.03 g) to obtain a yield of the corresponding product benzyl alcohol (BA) of 100%. In an argon atmosphere glove box,Weigh 25.7 mg of catalyst III-A-1,20.5 mg sodium methoxide,0.89 g of dimethyl oxalate (substrate ester: sodium methoxide: catalyst = 200 : 10 : 1 (molar ratio)),After 6 mL of toluene and 50 muL of p-xylene (internal standard) in a 100 mL reactor,Assemble the kettle and remove the glove box.Then, the kettle was cooled to 5 C with ice water.The argon gas in the autoclave was replaced with hydrogen (10 bar) three times and then hydrogenated to 50 bar.The kettle was placed in a heating apparatus and heated to 100 C and maintained at this temperature for 4 h.After the reaction is completed, the temperature of the kettle body is quickly lowered to 5 C and the remaining hydrogen in the kettle is drained.The reaction solution was filtered through a short column of 1 cm silica gel and analyzed by gas chromatography (GC) (KB-Wax column 60 m × 0.32 mm × 0.33 mum).The yields of methyl glycolate (MG) and ethylene glycol (EG) were 86% and 13%, respectively.

Reference： [1]Patent: CN109776618,2019,A .Location in patent: Paragraph 0038; 0040; 0042; 0044; 0046

102
[ 96-35-5 ]
[ 1082843-72-8 ]
6-bromo-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 50℃; for 19.0h;Inert atmosphere;	<strong>[1082843-72-8]6-bromo-3-chloropyrazin-2-amine</strong> (2g, 9.59 mmol) and methyl 2-hydroxyacetate (2.222 ml, 28.8 mmol) were suspended in Tetrahydrofuran (THF) (88 ml) under N2 at ambient temperature in a multi necked flask. Potassium tert-butoxide 1 M in THF (23.99 ml, 23.99 mmol) was added and the mixture was stirred under N2 and heated to 50C for 18hrs. The reaction was monitored by 2mins liquid chromatography-mass spectrometry (LCMS) (high pH). After 18hrs, starting material still present by LCMS. Potassium tert- butoxide 1 M in THF (9.59 ml, 9.59 mmol) was added and left to stir for an additional 1 hr. (0080) After a total of 19hrs, starting material consumed by LCMS. The mixture was allowed to cool to ambient temperature then partitioned between water (60ml) and ethyl acetate (60ml) (organic layer discarded). The aqueous layer was acidified to pH=4 with aq 2M HCI then extracted twice with ethyl acetate (60ml). The combined organic layers were washed with water (75ml) then dried by passing through a hydrophobic frit and evaporated under vacuum to give the crude material 6-bromo-2H-pyrazino[2,3- b][1 ,4]oxazin-3(4H)-one (1 .9618g, 7.93 mmol, 83 % yield, with a purity of 93 % by NMR) as a red/brown solid. Sample carried through to next step without further purification LCMS (2mins, high pH): V4100473-3 rt = 0.44 mins, MH- = 230 (0081) IH NMR (400 MHz, DMSO-de) d ppm 4.90 (s, 2 H) 7.92 (s, 1 H) 11.81 (s, 1 H)

Reference： [1]Patent: WO2019/180634,2019,A1 .Location in patent: Page/Page column 11-12

103
[ 372118-01-9 ]
[ 96-35-5 ]
methyl 6-chloro-4-(2-methoxy-2-oxoethoxy)pyridazine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%		Step 1: To a solution of methyl 2-hydroxyacetate (218 mg, 2.37 mmol) in THF (3 mL) was added NaH (93 mg, 2.33 mmol, 60 mass%) at 0 C. The reaction was stirred for 30 min at 0 C, and the resultant slurry was added slowly to a solution of <strong>[372118-01-9]methyl 4,6-dichloropyridazine-3-carboxylate</strong> (500 mg, 2.37 mmol) in THF (3 mL) at 0 C. The mixture was stirred for 30 min at room temperature. The reaction was quenched with sat. aq. NH4Cl and diluted with EtOAc and H20. The organic phase was dried over Na2S04 and concentrated. The residue was purified using silica gel chromatography eluting with a EtO Ac/hexanes gradient (20-50% EtOAc) to yield methyl 6- chloro-4-(2-methoxy-2-oxoethoxy)pyridazine-3-carboxylate (284 mg, 46%) as a white solid. MS m/z 261.4 [M+H]+.

Reference： [1]Patent: WO2020/5873,2020,A1 .Location in patent: Page/Page column 191

104
[ 67-56-1 ]
[ 502-97-6 ]
[ 96-35-5 ]
methyl bis(glycolyl)glycolate [ No CAS ]
[ 110271-85-7 ]

Reference： [1]Dalton Transactions,2020,vol. 49,p. 866 - 876

105
[ 96-35-5 ]
[ 1082041-90-4 ]
methyl 2-(5-bromo-4-chloro-2H-indazol-2-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
190 mg	With azodicarboxylic acid bis(2-methoxyethyl) ester; triphenylphosphine; In tetrahydrofuran; at 20℃; for 2.0h;	To a solution of <strong>[1082041-90-4]5-bromo-4-chloro-1H-indazole</strong> (500 mg, 2.16 mmol) and methyl glycolate (0.25 mL, 3.24 mmol) in THF (10 mL) was added DMEAD (759 mg, 3.24 mmol) and triphenylphosphine (850 mg, 3.24 mmol) at RT. The mixture was stirred at RT for 2 h. The reaction solution was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (gradient elution, 20 - 40% EtOAc/hexane) to give methyl 2-(5-bromo-4-chloro-2H-indazol-2-yl)acetate (190 mg). MS: [M+H] + = 303, 305.

Reference： [1]Patent: WO2020/22323,2020,A1 .Location in patent: Paragraph 0518; 0519

106
[ 456-24-6 ]
[ 96-35-5 ]
[ 353293-39-7 ]

Yield	Reaction Conditions	Operation in experiment
26.79%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;

Reference： [1]Current Patent Assignee: DIZAL (JIANGSU) PHARMACEUTICAL CO., LTD. - WO2020/211839, 2020, A1 Location in patent: Page/Page column 70

107
[ 96-35-5 ]
[ 41927-17-7 ]
[ 882873-10-1 ]

Yield	Reaction Conditions	Operation in experiment
44.89%	With lithium bromide at 80℃; for 12h; Inert atmosphere;	3 Step 3. Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 4-(benzyloxy)benzene-1,2-diamine (800.00 mg, 3.734 mmol, 1.00 equiv), methyl 2-hydroxyacetate (8.00 mL), LiBr (64.85 mg, 0.747 mmol, 0.2 equiv). The resulting solution was stirred for 12 hr at 80 °C in an oil bath. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 500 mg (44.89%) of [5- (benzyloxy)-1H-1,3-benzodiazol-2-yl]methanol as a brown solid. LCMS: [M+H]+=255.

Reference： [1]Current Patent Assignee: THE ROCKEFELLER UNIVERSITY; KHAN TANWEER; STAMFORD ANDREW; BRIDGE MEDICINES; MILLER MICHAEL - WO2021/127166, 2021, A1 Location in patent: Paragraph 00212; 00215

108
[ 24623-40-3 ]
[ 96-35-5 ]
methyl 2-[(3-chloro-7-methoxy-1-isoquinolyl)oxy]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃;	1.A.1 Method H: Nucleophilic Substitution Using Alcohols. To a mixture of C22 (5.09 g, 22.32 mmol) and methyl 2-hydroxy acetate (1.8 mL, 23.32 mmol), in THF (100 mL) was added dropwise KOtBu (25 mL of 1 M, 25.00 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 hours. More methyl 2-hydroxyacetate (1.8 mL, 23.32 mmol) and KOtBu (25 mL of IM, 25.00 mmol) were added to push the reaction to completion sat. NH4CI was added to the reaction mixture and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), water (2 x 50 mL), dried over anhydrous Na2S04, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (Column: 120g gold Combiflash ISCO. Gradient: 0-100% EtOAc in heptane) to give C137 (3560 mg, 55%). NMR (400 MHz, Chloroform-d) d 7.61 - 7.50 (m, 2H), 7.33 (dt, J = 9.0, 1.9 Hz, 1H), 7.24 (s, 1H), 5.12 (d, J = 1.4 Hz, 2H), 3.95 (d, J = 1.4 Hz, 3H), 3.82 (d, J = 1.4 Hz, 3H). LCMS m/z 282.18 [M+H]+.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2021/203028, 2021, A1 Location in patent: Paragraph 00141-00142; 00356

Recommend Products

Same Skeleton Products

Related Products

Isomers

Technical Information

• Acids Combine with Acyl Halides to Produce Anhydrides • Acyl Chloride Hydrolysis • Acyl Group Substitution • Add Hydrogen Cyanide to Aldehydes and Ketones to Produce Alcohols • Alcohol Syntheses from Aldehydes, Ketones and Organometallics • Alcohols are Weakly Basic • Alcohols as Acids • Alcohols Convert Acyl Chlorides into Esters • Alcohols from Haloalkanes by Acetate Substitution-Hydrolysis • Alcohols React with PX3 • Alcoholysis of Anhydrides • Aldehydes and Ketones Form Hemiacetals Reversibly • Aldol Addition • Alkene Hydration • Alkene Hydration • Amide Hydrolysis • Amide Hydrolysis • Amines Convert Esters into Amides • Anhydride Hydrolysis • Appel Reaction • Arndt-Eistert Homologation • Base-Catalyzed Hydration of α,β -Unsaturated Aldehydes and Ketones • Bouveault-Blanc Reduction • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Carbonation of Organometallics • Carboxylate Salt Formation • Carboxylic Acids React with Alcohols to Form Esters • Catalytic Hydrogenation • Chloroalkane Synthesis with SOCI2 • Chromium Reagents for Alcohol Oxidation • Chugaev Reaction • Claisen Condensations Produce β-Dicarbonyl Compounds • Claisen Condensations Produce β-Dicarbonyl Compounds • Complex Metal Hydride Reductions • Convert Esters into Aldehydes Using a Milder Reducing Agent • Convert Haloalkanes into Alcohols by SN2 • Corey-Kim Oxidation • Decarboxylation of 3-Ketoacids Yields Ketones • Decarboxylation of Substituted Propanedioic • Decomposition of Lithium Aluminum Hydride by Protic Solvents • Deprotection of Cbz-Amino Acids • Dess-Martin Oxidation • Ester Cleavage • Ester Hydrolysis • Esters Are Reduced by LiAlH4 to Give Alcohols • Esters Hydrolyze to Carboxylic Acids and Alcohols • Ether Synthesis by Oxymercuration-Demercuration • Ethers Synthesis from Alcohols with Strong Acids • Formation of an Amide from an Amine and a Carboxylic Acid • Formation of an Amide from an Amine and a Carboxylic Acid • Friedel-Crafts Alkylations Using Alcohols • Geminal Diols and Acetals Can Be Hydrolyzed to Carbonyl Compounds • Grignard Reagents Transform Esters into Alcohols • Grignard Reagents Transform Esters into Alcohols • Haloalcohol Formation from an Alkene Through Electrophilic Addition • Halogen and Alcohols Add to Alkenes by Electrophilic Attack • Halogen and Alcohols Add to Alkenes by Electrophilic Attack • Hantzsch Pyridine Synthesis • Heat of Combustion • Hemiaminal Formation from Amines and Aldehydes or Ketones • Hemiaminal Formation from Amines and Aldehydes or Ketones • HIO4 Oxidatively Degrades Vicinal Diols to Give Carbonyl Derivatives • Hunsdiecker-Borodin Reaction • Hydration of the Carbonyl Group • Hydride Reductions • Hydride Reductions of Aldehydes and Ketones to Alcohols • Hydride Reductions of Aldehydes and Ketones to Alcohols • Hydroboration-Oxidation • Hydroboration-Oxidation • Hydrolysis of Haloalkanes • Jones Oxidation • Ketones Undergo Mixed Claisen Reactions to Form β-Dicarbonyl Compounds • Martin's Sulfurane Dehydrating Reagent • Mitsunobu Reaction • Moffatt Oxidation • Nitriles Hydrolyze to Carboxylic Acids • Osmium Tetroxide Reacts with Alkenes to Give Vicinal Diols • Osmium TetroxideReacts with Alkenes to Give Vicinal Diols • Oxidation of Alcohols by DMSO • Oxidation of Aldehydes Furnishes Carboxylic Acids • Oxidation of Primary Alcohols Furnishes Carboxylic Acids • Oxymercuration-Demercuration • Passerini Reaction • Peptide Bond Formation with DCC • Periodic Acid Degradation of Sugars • Preparation of Alcohols • Preparation of Alkenes by Dehydration of Alcohols • Preparation of Alkenes by Dehydration of Alcohols • Preparation of Alkoxides with Alkyllithium • Preparation of Amines • Preparation of Carboxylic Acids • Primary Ether Cleavage with Strong Nucleophilic Acids • Reactions of Alcohols • Reactions of Amines • Reactions of Carboxylic Acids • Reactions with Organometallic Reagents • Reduction of an Ester to an Alcohol • Reduction of an Ester to an Aldehyde • Reduction of Carboxylic Acids by LiAlH4 • Reduction of Carboxylic Acids by Lithium Aluminum Hydride • Reduction of Carboxylic Acids by Lithium Aluminum Hydride • Ring Opening of an Oxacyclopropane by Lithium Aluminum Hydride • Ritter Reaction • Schmidt Reaction • Sharpless Olefin Synthesis • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes • Swern Oxidation • Synthesis of Alcohols from Tertiary Ethers • Synthesis of an Alkyl Sulfonate • The Conversion of Carboxylic Acids into Acyl Halides • The Cycloaddition of Dienes to Alkenes Gives Cyclohexenes • The Nucleophilic Opening of Oxacyclopropanes • Thiazolium Salt Catalysis in Aldehyde Coupling • Thiazolium Salts Catalyze Aldehyde Coupling • Thiazolium Salts Catalyze Aldehyde Coupling • Transesterification • Ugi Reaction • Use 1,3-dithiane to Prepare of α-Hydroxyketones • Vicinal Anti Dihydroxylation of Alkenes • Williamson Ether Syntheses

Historical Records

Related Functional Groups of
[ 96-35-5 ]

Aliphatic Chain Hydrocarbons

[ 623-50-7 ]

Ethyl 2-hydroxyacetate

Similarity: 0.89

[ 817-95-8 ]

Ethyl 2-ethoxyacetate

Similarity: 0.84

[ 625-45-6 ]

2-Methoxyacetic acid

Similarity: 0.82

[ 110-99-6 ]

2,2'-Oxydiacetic acid

Similarity: 0.78

[ 627-03-2 ]

2-Ethoxyacetic acid

Similarity: 0.78

Alcohols

[ 623-50-7 ]

Ethyl 2-hydroxyacetate

Similarity: 0.89

[ 623-61-0 ]

Isopropyl glycolate

Similarity: 0.76

[ 7397-62-8 ]

Butyl 2-hydroxyacetate

Similarity: 0.73

[ 50595-15-8 ]

tert-Butyl 2-hydroxyacetate

Similarity: 0.70

[ 79-14-1 ]

2-Hydroxyacetic acid

Similarity: 0.69

Esters

[ 623-50-7 ]

Ethyl 2-hydroxyacetate

Similarity: 0.89

[ 817-95-8 ]

Ethyl 2-ethoxyacetate

Similarity: 0.84

[ 623-61-0 ]

Isopropyl glycolate

Similarity: 0.76

[ 617-37-8 ]

2-Ethoxy-2-oxoacetic acid

Similarity: 0.76

[ 7397-62-8 ]

Butyl 2-hydroxyacetate

Similarity: 0.73

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	Inquiry	{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price) ]}	{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price) ]}	{[ item.pr_usastock ]}		{[ item.pr_chinastock ]}	{[ item.pr_remark ]}

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
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. 96-35-5 ] {[proInfo.proName]}

Quality Control of [ 96-35-5 ]

Related Doc. of [ 96-35-5 ]

Product Details of [ 96-35-5 ]

Calculated chemistry of [ 96-35-5 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 96-35-5 ]

Application In Synthesis of [ 96-35-5 ]

[ 96-35-5 ] Synthesis Path-Upstream 1~13

[ 96-35-5 ] Synthesis Path-Downstream 1~108

Technical Information

Related Functional Groups of [ 96-35-5 ]

Aliphatic Chain Hydrocarbons

Alcohols

Esters

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 96-35-5 ]