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[ CAS No. 99395-88-7 ] {[proInfo.proName]}

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Chemical Structure| 99395-88-7

Chemical Structure| 99395-88-7

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Quality Control of [ 99395-88-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 99395-88-7 ]

CAS No. :	99395-88-7	MDL No. :	MFCD00043396
Formula :	C₉H₉NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QDMNNMIOWVJVLY-MRVPVSSYSA-N
M.W :	163.17	Pubchem ID :	730424
Synonyms :	(S)-(+)-4-Phenyl-2-oxazolidinone

Calculated chemistry of [ 99395-88-7 ] Expand+

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	47.3
TPSA :	38.33 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.41 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.48
Log Po/w (XLOGP3) :	1.25
Log Po/w (WLOGP) :	0.76
Log Po/w (MLOGP) :	1.12
Log Po/w (SILICOS-IT) :	1.6
Consensus Log Po/w :	1.24

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.94
Solubility :	1.86 mg/ml ; 0.0114 mol/l
Class :	Very soluble
Log S (Ali) :	-1.65
Solubility :	3.63 mg/ml ; 0.0222 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.67
Solubility :	0.35 mg/ml ; 0.00215 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.04

Safety of [ 99395-88-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 99395-88-7 ]

* 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 [ 99395-88-7 ]
Downstream synthetic route of [ 99395-88-7 ]

[ 99395-88-7 ] Synthesis Path-Upstream 1~8

1
[ 86217-38-1 ]
[ 123-62-6 ]
[ 90319-52-1 ]
[ 99395-88-7 ]
[ 160695-26-1 ]
[ 184363-66-4 ]

Reference： [1] Journal of the American Chemical Society, 2006, vol. 128, # 20, p. 6536 - 6537

2
[ 79-03-8 ]
[ 99395-88-7 ]
[ 184363-66-4 ]

Reference： [1] Organic Process Research and Development, 2005, vol. 9, # 6, p. 827 - 829
[2] Research on Chemical Intermediates, 2015, vol. 41, # 2, p. 749 - 760

3
[ 86217-38-1 ]
[ 123-62-6 ]
[ 90319-52-1 ]
[ 99395-88-7 ]
[ 160695-26-1 ]
[ 184363-66-4 ]

Reference： [1] Journal of the American Chemical Society, 2006, vol. 128, # 20, p. 6536 - 6537

4
[ 99395-88-7 ]
[ 220170-24-1 ]
[ 184363-66-4 ]

Reference： [1] Synthesis, 1996, # 11, p. 1283 - 1285

5
[ 99395-88-7 ]
[ 70627-52-0 ]

Reference： [1] Patent: CN105439929, 2016, A, . Location in patent: Paragraph 0029

6
[ 99395-88-7 ]
[ 149437-76-3 ]
[ 189028-93-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With dmap; dicyclohexyl-carbodiimide In dichloromethane	Example 1: Preparation of ezetimibe; (1-1) Preparation of 3-[5-(fluorophenyl)-l,5-dioxapentyl]-4(S)- phenyl-2-oxazolidinone (Formula 7); 200 g of 5-(4-fluorophenyl)-5-oxopentanoic acid of formula 8, 16O g of (S)-4-phenyloxazolidine-2-one of formula 9, and 11.6 g of 4-dimethylaminopyridine were dissolved in 600 m.pound. of dichloromethane to prepare a reaction mixture. A solution which was prepared by dissolving 157 g of N,N'-dicyclohexylcarboimide in 200 ml of dichloromethane was added to the reaction mixture and stirred for 2 hours. After completion of the reaction, the resulting reaction mixture was filtered to remove by-products. The filtrate thus obtained was washed successively with 1 I of 6N HCl, 1 .euro. of water, and 1 .euro. of saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and distilled under a reduced pressure to remove the solvent. The residue thus obtained was dissolved in 2 I of methanol by heating and cooled to induce crystallization. 2 .pound. of water was added thereto and stirred for 30 min. The solid thus obtained was isolated by filtering to obtain 289 g of the title compound as a white solid (yield: 86percent).¹H NMR(300MHz, CDCl₃) : δ 7.92 (2H, M), 7.35-7.13 (5H, m), 7.04 (2H, m), 5.43 (IH, q), 4.75(1H, t), 4.22 (IH, q), 3.05-2.93 (4H, m), 2.03 (2H, m)
85.7%	Stage #1: With dmap; pivaloyl chloride In N,N-dimethyl-formamide at 2 - 20℃; for 1.5 h; Stage #2: at 30 - 35℃; for 2 h;	5-(4-Fluorophenyl)-5-oxopentanoic acid (21.02 g, 100.0 mmol) and 4 dimethylamino- pyridine (16.25 g, 133.0 mmol) were dissolved in N,N-dimethylformamide (100 mL, 1.0 M) to afford a copious white precipitate suspended in solution. The reaction was cooled to 2 ⁰C (ice/water bath), and trimethylacetyl chloride (16.40 mL, 16.04 g, 133.0 mmol) was added drop-wise to afford a pale yellow mixture. The rate of addition was controlled in order to keep the temperature at or below 5 ⁰C. A heavy white precipitate was formed and the mixture was allowed to warm to room temperature and stirred for 1.5 h. The mixture was charged with (6)-(+)-4-phenyl-2- oxazolidinone (16.32 g, 100.0 mmol) and 4-dimethylaminopyridine (12.22 g, 100.0 mmol) both as solids to afford a yellow colored suspension. The reaction was stirred at 30 °C - 35 ⁰C for 2 h. An aliquot was removed for analysis by TLC and HPLC. The pale olive colored suspension was poured into water (400 mL) while stirring vigorously and cooling the mixture in an ice-brine bath, transferred with water (150 mL) and stirred with ice-cooling for 1.5 h to afford a solution with an off-white precipitate. The compound was filtered, transferred with water (2 x 25 mL), washed with water (50 mL) and air dried for 15 min to afford an off-white moist clumpy powder. The material was crystallized from isopropanol (58.0 mL; 1.6 mL/g theoretical yield) by heating to near reflux to afford a golden yellow colored solution. The solution was cooled slowly to room temperature over 12 h, a seed crystal was added and crystals began to precipitate. The mixture was cooled in an ice/water bath and stirred for 1 h. The crystals were filtered, transferred with cold isopropanol (2 x 10 mL), washed with cold isopropanol (25 mL), air dried and vacuum dried to constant weight to afford (45)-4-phenyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-l,3- oxazolidin-2-one (30.46 g, 85.7 percent yield) as a white crystalline solid; m.p. 91.0 ⁰C; EPO <DP n="43"/>R/ 0.40 (1:2 ethyl acetate-hexane); HPLC R_r7.02 min; HPLC purity 94 percent. ¹H NMR (300 MHz, CDCl₃) δ 7.93 (dd, J= 5.4, 9.0 Hz, 2H), 7.28-7.42 (m, 5H), 7.10 (dd, J= 8.5, 9.0 Hz, 2H), 5.43 (dd, J= 3.7, 8.7 Hz, IH), 4.70 (t, J= 8.9 Hz, IH), 4.28 (dd, J= 3.7, 8.7 Hz, IH), 3.05 (dt, J= 1.2, 7.3 Hz, 2H), 2.97 (t, J= 7.3, 2H), 2.05 (p, J= 7.3 Hz, 2H), ppm.
85%	Stage #1: With pivaloyl chloride; triethylamine In tetrahydrofuran at -10℃; for 4 h; Inert atmosphere Stage #2: With lithium chloride In tetrahydrofuran at 20℃; for 2 h; Inert atmosphere	To the soulution of compound 2 (700 g, 3.33 mol, 1.1 eq) dissolved in THF (5 L) was added triethylamine (1.2 L, 7.87 mol, 2.6 eq) at room temperature under N₂ atmosphere. Then the solution of pivalic acid chloride (400 g, 3.33 mol, 1.1 eq) in THF (700 mL) was added dropwise to the reaction mixture cooled to -10 °C for about 2 h. After addition, the mixture was stirred for 2 h at this temperature. TLC showed the compound 2 was consumed up, then the Evans auxiliary (493.5 g, 3 mol, 1 eq) and anhydrous LiCl (150.5 g, 3.5 mol,1.17 eq) were added sequencely. The mixture was warmed to room temperature and stirred for 2 h till the anhydride intermediate was consumed up. Then ethylacetate (2 L) and NH₄Cl aq (1 L) were added, stirred for 15 min, stayed and separated, the aqueous layer was extracted with ethyl acetate (500 mL×2), combined the organic phase, washed with water (250 mL ×2), concentrated.The residue was recrystallized from isopropanol (7 L) to afforded compound 4 as a white solid (913.6 g, 85.0percent yield). HPLC purity: 99.2percent, mp: 94-95 °C [lit.^9(b) 91°C]. ¹H-NMR (CDCl₃,400 MHz): δ 7.94-7.93 (m, 2H, J=2), 7.40-7.29 (m, 5H), 7.10-7.01 (m, 2H), 5.45-5.41 (m, 1H), 4.72-4.63 (m, 1H), 4.30-4.27 (m, 1H), 3.06 (t, 2H, J=8), 2.97 (t, 2H, J=12), 2.10-2.03 (m, 2H). ¹³C-NMR (CDCl₃, 100MHz): δ 197.7, 172.2, 167.0, 164.4, 153.8, 139.2, 133.3, 130.7, 130.6, 129.2, 128.7, 126.0, 115.7, 115.5, 70.1, 57.6, 37.3, 34.8, 18.5. MS (ESI) m/z calcd. for C₂₀H₁₈FNO₄: 355.12, calcd. for C₂₀H₁₈FNO₄Na (M+Na)=378.12, found 378.04 (M+Na).

70%	Stage #1: With pivaloyl chloride; triethylamine In dichloromethane Stage #2: With dmap In dichloromethane; N,N-dimethyl-formamide for 13 h; Reflux	Compound I (21 g, 0.1 mol) was added to a 500 ml three-necked flask, Triethylamine 20 ml and dichloromethane 250 ml, Stuttgart dropwise pivaloyl chloride (14.4g, 0.12mol), (4S) -4-phenyl-2-oxazolidinone (24.5 g, 0.15 mol), DMF 5 ml, 4,4-dimethylaminopyridine (1.22 g, 0.01 mol) was added after refluxing for 3 h, After refluxing for 10 h, Ice bath cooling, Then, 200 ml of 5 M hydrochloric acid was added dropwise at 0 ° C, Static stratification, The lower methylene chloride layer was washed successively with saturated sodium bicarbonate solution and water, Dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness, To give 24.9 g of a white solid compound II, Yield 70percent.
68%	Stage #1: With pivaloyl chloride; triethylamine In dichloromethane at 5 - 10℃; for 2.5 h; Stage #2: With dmap In dichloromethane; N,N-dimethyl-formamide at 15 - 45℃; for 3 h;	The compound (4) (30 g, 142.72 mmol) Triethylamine (26 g, 256.91 mmol) was dissolved in dichloromethane (150 ml)Cooling to 5 to 10 ° C, dropwise addition of pivaloyl chloride (17.3g, 142.62mmol), System has exothermic, 30min drop finished,5 to 10 deg C insulation reaction 2h, To the reaction system was added (S) -4-phenyl-2-oxazolidinone (23.3 g, 142.76 mmol) DMAP (2.4 g, 19.63 mmol), DMF (15 ml),Exothermic The temperature rose to 15 ° C, Heated to 45 reflux reaction 3h, Down to room temperature, Plus dichloromethane (150 ml), The organic phase was washed with water (60 ml) 1N hydrochloric acid (120 ml) Water (60ml) 2.5percent aqueous sodium hydroxide solution (180 ml) Add water (50ml) wash, Organic phase concentrated dry, Plus isopropyl alcohol (60 ml), Stirring for 24 h, Filter, Add isopropyl alcohol (10ml) leaching, To give a white solid, I.e. compound (5) (34.4 g, 68percent yield).

Reference： [1] Patent: WO2010/71358, 2010, A2, . Location in patent: Page/Page column 14-15
[2] Patent: WO2006/122216, 2006, A2, . Location in patent: Page/Page column 41-42
[3] Synthetic Communications, 2016, vol. 46, # 20, p. 1687 - 1693
[4] Patent: CN106397292, 2017, A, . Location in patent: Paragraph 0053; 0086; 0087
[5] Patent: CN104513187, 2017, B, . Location in patent: Paragraph 0063; 0064; 0065; 0066

7
[ 1056188-47-6 ]
[ 99395-88-7 ]
[ 189028-93-1 ]

Reference： [1] Patent: US2006/135755, 2006, A1, . Location in patent: Page/Page column 16
[2] Patent: EP1137634, 2005, B1, . Location in patent: Page/Page column 7

8
[ 99395-88-7 ]
[ 189028-93-1 ]

Reference： [1] Patent: CN105541742, 2016, A,

[ 99395-88-7 ] Synthesis Path-Downstream 1~77

1
[ 625-35-4 ]
[ 99395-88-7 ]
[ 111292-75-2 ]

Yield	Reaction Conditions	Operation in experiment
15.7 g		Step 1 To a stirred solution of (4S)-4-phenyl-1,3-oxazolidin-2-one (12 g, 73.5 mmol) in THF (200 mL) was added n-BuLi (2.5 M, 29.4 mL, 73.5 mmol) dropwise via a syringe at -78 C. The resulting reaction mixture was stirred at -78 C. for 5 minutes before (2E)-but-2-enoyl chloride (8.46 mL, 88.0 mmol) was added dropwise via a syringe. The reaction mixture was allowed to warm to ambient temperature and was quenched by addition of brine (100 mL) and water (100 mL). A mixture of ethyl acetate and hexanes (1:2, 100 mL) was added to partition the mixture and the organics were separated, dried over sodium sulfate, filtered and concentrated. The resultant oil was recrystallized in 5% ethyl acetate in hexanes (after seeding with crystals obtained from earlier batches) to yield (4S)-3-[(2E)-but-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one (15.7 g, 67.9 mmol). 1H NMR (500 MHz, CDCl3) delta7.4 (m, 6H), 5.5 (m, 1H) 4.73 (t, J=8.8 Hz, 1H), 4.30 (m, 1H), 1.97 (dd, J=6.8, 1.5 Hz, 3H).

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 12286 - 12293
[2]Journal of Organic Chemistry,1993,vol. 58,p. 7565 - 7571
[3]Chemical Communications,2019,vol. 55,p. 12936 - 12939
[4]Chemical Communications,2019,vol. 55,p. 11303 - 11306
[5]Tetrahedron Asymmetry,2010,vol. 21,p. 1635 - 1648
[6]Journal of Organic Chemistry,1993,vol. 58,p. 766 - 770
[7]Organic Letters,2012,vol. 14,p. 3514 - 3517
[8]Patent: US2013/109649,2013,A1 .Location in patent: Paragraph 0189; 0190

2
[ 368-39-8 ]
[ 99395-88-7 ]
[ 119109-55-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	In dichloromethane; at 0 - 20℃; for 18h;	General procedure: To (4S)-4-phenyl-l,3-oxazolidin-2-one (10) (0.405 g, 2.48 mmol, 1 equiv) in DCM (3.00 mL) cooled to 0 C was added a solution of triethyloxonium tetrafluoroborate (1.41 g, 7.44 mmol, 3 equiv) in DCM (3.00 mL). The mixture was allowed to warm slowly to rt and stirred for 18 h. The mixture was diluted with EtOAc (20 mL) and poured slowly over a cooled (0 C) solution of saturated aqueous NaHCC (25 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over Na2SC>4, filtered, and concentrated to afford (4S)-2-ethoxy-4-phenyl-4,5- dihydro-l,3-oxazole (17) (0.428 g, 90%): 1HNMR (CDC13) delta: 7.38-7.28 (m, 5H), 5.15 (dd, 1H), 4.47 (dd, 1H), 4.42-4.35 (m, 2H), 4.20 (t, 1H), 1.41 (t, 3H) ppm; MS: (m/e): 192 (M+l).

Reference： [1]Chemistry - A European Journal,2004,vol. 10,p. 2997 - 3005
[2]Patent: WO2017/192858,2017,A1 .Location in patent: Paragraph 0459
[3]Journal of the American Chemical Society,1989,vol. 111,p. 2211 - 2217

3
[ 60729-80-8 ]
[ 99395-88-7 ]

Reference： [1]Tetrahedron Letters,1985,vol. 26,p. 3783 - 3786

4
[ 99395-88-7 ]
[ 102-92-1 ]
[ 141209-95-2 ]

Yield	Reaction Conditions	Operation in experiment
97%		To (S)- (+)-4-PHENYL-2-OXAZOLIDINONE (9.88 g, 60 mmol) in THF (150 mL) AT-78C, was added n-butyl lithium (37.7 mL, 1. 6M in hexanes, 60 mmol) over a period of 30 minutes. THF (50 mL) was added to the resultant thick suspension and the reaction mixture allowed to warm up to facilitate stirring. Trans-cinnamoylchloride (11.5 g, 69 mmol) in THF (30 mL) was added dropwise. The'reaction was stirred at room temperature overnight. The reaction mixture was quenched with a saturated ammonium chloride solution (50. ML) and stirred for 0.5h. The solvent was removed in vacuo, the residue dissolved in ethyl acetate, washed with water (300 mL), 5% sodium bicarbonate (200 mL) and brine (100 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give a pale yellow solid. The compound was crystallized from ETHYLACETATE and washed with hexanes to give 17.12 g (97%) of (S)-4- PHENYL-3- [ (E)- (3-PHENYL-ACRYLOYL)]-OXAZOLIDIN-2-ONE. H NMR (400 MHz, CDC13) : 8 [ppm] 7.92 (d, 1H), 7. 77 (d, 1H), 7.59 (m, 2H), 7.40-7. 35 (m, 8H), 5.55 (dd, 1H), 4.74 (t, 1H) ; 4.31 (DD,. 1H).
97%		Step 1: To (S)-(+)-4-phenyl-2-oxazolidinone (9.88 g, 60 mmol) in THF (150 mL) at -78 C., was added n-butyl lithium (37.7 mL, 1.6M in hexanes, 60 mmol) over a period of 30 minutes. THF (50 mL) was added to the resultant thick suspension and the reaction mixture allowed to warm up to facilitate stirring. Trans-cinnamoylchloride (11.5 g, 69 mmol) in THF (30 mL) was added dropwise. The reaction was stirred at room temperature overnight. The reaction mixture was quenched with a saturated ammonium chloride solution (50 mL) and stirred for 0.5 h. The solvent was removed in vacuo, the residue dissolved in ethyl acetate, washed with water (300 mL), 5% sodium bicarbonate (200 mL) and brine (100 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give a pale yellow solid. The compound was crystallized from ethylacetate and washed with hexanes to give 17.12 g (97%) of (S)-4-phenyl-3-[(E)-(3-phenyl-acryloyl)]-oxazolidin-2-one. 1H NMR (400 MHz, CDCl3): delta [ppm] 7.92 (d, 1H), 7.77 (d, 1H), 7.59 (m, 2H), 7.40-7.35 (m, 8H), 5.55 (dd, 1H), 4.74 (t, 1H), 4.31 (dd, 1H).
94%		General procedure: n-Butyl lithium (11 mmol, 1.1 eq) was added to a solution of the chiral 4-substituted 1,3-oxazolidin-2-one (10 mmol, 1 eq) in THF (100 mL) at -78 C. After 15 min of stirring at -78 oC, cinnamoyl chloride (11 mmol, 1.1 eq ) was added in dropwise. The mixture was stirred at -78 C for a further 30 min then at 0 C for 15 min, the reaction was quenched with saturated NH4Cl aqueous solution and the resultant slurry was concentrated in vacuo. The residue was diluted with EA and washed with brine. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure to yield the crude product. The crude product was purified by silica flash column chromatography.

83%		To (S)-4-phenyloxazolidin-2-one 2(9.88 g, 60 mmol) in THF (150 mL) at - 78 oC, was added n-butyllithium (37.7 mL, 1.6 M inhexanes, 60 mmol) over a period of 30 min.THF (50mL) was added to the resultant thick suspension and the reactionmixture allowed warming up to facilitate stirring. trans-Cinnamoylchloride 3(11.5 g, 69 mmol) in THF (30 mL) was added drop wise. The reaction was stirred at room temperatureovernight. The reaction mixture wasquenched with a saturated NH4Cl (50 mL) and stirred for 0.5 hr. The solvent was removed in vacuo, the residuewas dissolved in ethyl acetate, washed with water (300 mL), 5% NaHCO3(200 mL) and brine (100 mL) and dried over Na2SO4. The solvent was removed with addition ofhexane to give a white microcrystalline (14.6 g, 83%) of the product 4 as a white solid: mp 170 C; Rf = 0.43 (20% EtOAc in hexanes);[alpha]D20 = +11.0o (c 0.81);1 HRMS(C18H15NO3): calcd294.1124, found 294.1095 [M+H]+; IR (neat) numax 3290.49,1757.13, 1678.11, 1204.13 cm-1; UV (nm) 220, 300; 1H NMR(CDCl3) delta 7.92 (d, J = 24 Hz, 1H), 7.81(d, J = 24 Hz, 1H), 7.62 (m, 2H), 7.42 (m,8H), 5.59 (dd, J = 9, 2.1 Hz, 1H),6.36 (dd, J = 8.7, 3.8 Hz, 1H), 4.77 (t,J = 8.5 Hz, 1H), 4.35 (dd, J = 8.7, 3.8 Hz, 1H); 13C NMR(CDCl3) delta 166.9, 164.8, 146.7, 139.1, 134.5, 130.7, 129.2, 128.7,128.6, 126.0, 116.9, 70.0, 57.9.
1.2 g		General procedure: n-Butyllithium (1.15mL, 1.0equiv, 2.3M in hexanes) was added to a cooled until -75C solution of the corresponding oxazolidinone (2.6mmol) in anhydrous THF (12mL), then the resulting solution was warmed to -30C and stirred for 20min. At the same temperature, a solution of cinnamoyl chloride (1.0equiv) in anhydrous THF (7mL) was added dropwise and then allowed to rise to at room temperature and left overnight with continuous stirring. After work-up with 10% NH4Cl (15mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×25ml). The combined organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude products were purified by chromatography or crystallized from appropriate solvents.

Reference： [1]Patent: WO2005/23809,2005,A1 .Location in patent: Page/Page column 104
[2]Patent: US2006/14769,2006,A1 .Location in patent: Page/Page column 13
[3]Tetrahedron Letters,2018,vol. 59,p. 537 - 540
[4]Journal of Organic Chemistry,2008,vol. 73,p. 3218 - 3227
[5]Tetrahedron Letters,2013,vol. 54,p. 5799 - 5801
[6]Tetrahedron Asymmetry,2010,vol. 21,p. 1635 - 1648
[7]Journal of Organic Chemistry,1993,vol. 58,p. 766 - 770
[8]Organic Letters,2009,vol. 11,p. 5366 - 5369
[9]Tetrahedron Asymmetry,2016,vol. 27,p. 843 - 851

5
[ 99395-88-7 ]
[ 220170-24-1 ]
[ 184363-66-4 ]

Reference： [1]Synthesis,1996,p. 1283 - 1285

6
[ 99395-88-7 ]
[ 79-04-9 ]
[ 191613-05-5 ]

Yield	Reaction Conditions	Operation in experiment
67%		Sodium hydride (60% by weight liquid paraffin dispersion, 270 mg, 6.75 mmol) was added to a tetrahydrofuran (15 mL) solution of (S) -4-phenyloxazolidin-2-one (1.00 g, 6.14 mmol) In addition,After stirring at 0 C. for 20 minutes, 2-chloroacetyl chloride (0.538 mL, 6.75 mmol) was added at 0 C.,And the mixture was stirred at 0 C. for 1 hour.Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the obtained aqueous solution was extracted three times with ethyl acetate,The organic layer was washed with a saturated aqueous sodium chloride solution,Dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, n-hexane / ethyl acetate)(S) -3- (2-chloroacetyl) -4-phenyloxazolidin-2-one(979 mg, 4.11 mmol, 67%)As a white powder.
		To a solution of sodium hydride (13.5 g) in tetrahydrofuran (920 mL) was added (4S)-4-phenyl-1,3-oxazolidin-2-one (50 g) portionwise at room temperature, and the resulted mixture was stirred for 1 hour. This reaction solution is referred to as Solution A. In a separate reaction vessel, a solution of chloroacetyl chloride (36.6 mL) in tetrahydrofuran (308 mL) was cooled to 0 C, and the above Solution A was added dropwise in about 5 mL for each portion. After stirred at 0 C for 1 hour, water (300 mL) was slowly added to the reaction solution. The resulted mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, the obtained residue was dissolved in dichloromethane (500 mL). To the resulted solution was added p-methoxybenzylthiol (47.2 g) at room temperature, followed by adding triethylamine (64 mL) dropwise using a dropping funnel over 1.5 hours. The resulted solution was then stirred at room temperature overnight. Water (300 mL) and dichloromethane (100 mL) were added to the reaction solution to separate the organic layer and the organic layer was then washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/5 ? 1/3 ? 1/2) to obtain the title compound (90 g, 82% yield for 2 steps). The NMR data of this compound is shown below. 1H-NMR (400 MHz, CDCl3): delta (ppm) = 3.49-3.61 (m, 3H), 3.77-3.81 (m, 1H), 3.78 (s, 3H), 4.28 (dd, 1H, J = 8.9, 3.9 Hz), 4.62 (dd, 1H, J = 8.9 Hz), 5.43 (dd, 1H, J = 8.9, 3.9 Hz), 6.78-6.81 (m, 2H), 7.14-7.18 (m, 2H), 7.34-7.43 (m, 5H).
		General procedure: Sodium hydride (2.2 g, 92.9 mmol) and tetrahydrofuran (100 ml) were added in a round bottom flask at room temperature under nitrogen atmosphere. Then this mixture was cooled to 10-20 C. To the cold mixture, 4-isopropyloxazolidin-2-one (77.4 mmol) added portion wise in 4-5 min interval. Reaction mixture was stirred at 10-20 C for 1h. Then chloroacetyl chloride (16.2 g, 143 mmol) was added slowly to the reaction mixture at 0-10 C. After complete addition, temperature raised to 20-30 C and stirred for 2h. Progress of the reaction monitored on thin layer chromatography. Then after completion of reaction water (30 ml) was added slowly to the reaction mixture and extracted reaction mixture twice with ethyl acetate (50ml). Organic layer was concentrated on the laboratory rotavapor under reduced pressure at 40-45 C to afford 6a. (12.4 g, Yield 85 %).

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 752 - 759
[2]Patent: JP2018/172309,2018,A .Location in patent: Paragraph 0072
[3]Patent: EP2133347,2009,A1 .Location in patent: Page/Page column 28
[4]Synthetic Communications,2019,vol. 49,p. 1173 - 1180

7
[ 6919-61-5 ]
[ 99395-88-7 ]
[ 590-86-3 ]
(S)-3-((S)-1-Benzoyl-3-methyl-butyl)-4-phenyl-oxazolidin-2-one [ No CAS ]

Reference： [1]Synlett,1998,p. 1147 - 1149

8
[ 99395-88-7 ]
[ 109-64-8 ]
N-(3'-bromopropyl)-(S)-4-phenyl-2-oxazolidinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium hydroxide; In dimethyl sulfoxide; at 15 - 20℃;	General procedure: In a round bottom flask dimethyl sulfoxide (50 ml) was added, followed by 1,3 dibromopropane (61.7 g, 306 mmol) and powdered potassium hydroxide (4.47 g, 80 mmol).[13] The reaction mixture was cooled to 15-20 C. To the cooled reaction mixture, was added (S)-4-phenyloxazolidin-2-one (10 g, 61.3 mmol) in 4 to 5 lots at an interval of 5 min each. The reaction mixture was stirred further at 15-20 C for 3-4h. Water (150 ml) was then added to the reaction mixture and it was extracted in dichloromethane (200 ml). The organic layer was concentrated on laboratory rotary evaporator. The resultant residue was purified on silica gel column using cyclohexane/ethyl acetate to get (1a) as colorless oil. Yield: 13.1 g (75%). 1b-1f were prepared in the same manneras 1a.

Reference： [1]Synthetic Communications,2018,vol. 48,p. 2435 - 2440
[2]Bioorganic and Medicinal Chemistry,2000,vol. 8,p. 1957 - 1968

9
[ 130406-31-4 ]
[ 99395-88-7 ]
[ 479687-21-3 ]
[(S)-2-((S)-2-Benzyloxycarbonylamino-2-phenyl-ethoxysulfinyloxy)-1-phenyl-ethyl]-carbamic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; triethylamine In dichloromethane

Reference： [1]Ghosh, Arun; Sieser, Janice E; Caron, Stephane; Watson, Timothy J N [Chemical Communications, 2002, # 15, p. 1644 - 1645]

10
[ 110143-62-9 ]
[ 259184-49-1 ]
[ 99395-88-7 ]
Benzoic acid (S)-1-((S)-2-tert-butoxycarbonylamino-2-phenyl-ethyl)-pyrrolidin-3-yl ester [ No CAS ]

Reference： [1]Chemical Communications,2002,p. 1644 - 1645

11
[ 779-89-5 ]
[ 99395-88-7 ]
[ 741280-87-5 ]

Reference： [1]Journal of Organic Chemistry,2004,vol. 69,p. 4984 - 4990

12
[ 18802-96-5 ]
[ 99395-88-7 ]
[ 184784-56-3 ]

Yield	Reaction Conditions	Operation in experiment
88%		4.1.23 (4S,2E)-3-(4'-Methylpent-2'-enoyl)-4-phenyloxazolidin-2-one 42<ce-sup primary_key="ce-sup-35850692-none">43,44 Butyllithium (1.60 M in hexanes, 8.24 mL, 20.6 mmol) was added slowly via syringe to a stirring solution of (4S)-4-phenyl-2-oxazolidinone 41 (3.37 g, 20.6 mmol) in THF (30 mL) under an atmosphere of nitrogen at -78 C. The resulting solution was stirred for 20 min at -78 C. A solution of (E)-4-methylpent-2-enoylchloride 40 (3.01 g, 22.8 mmol) in THF (17 mL) was added slowly by syringe. The temperature was maintained at -78 C for 30 min at which stage it was raised to 0 C and the reaction mixture stirred at this temperature for 1.5 h. The reaction mixture was then quenched by the addition of saturated aqueous ammonium chloride (30 mL) and the volatiles were removed under reduced pressure. Ethyl acetate (65 mL) was added, the organic phase separated and washed with saturated aqueous sodium bicarbonate (230 mL), brine (30 mL), dried and the solvent removed under reduced pressure to give the crude oxazolidinone 42. Purification by flash chromatography on silica gel eluting with ethyl acetate/hexane (20:80) gave the pure oxazolidinone 42 (4.71 g, 88%) as a white solid: mp 100-102 C (lit., 43 103-104 C); [alpha]D20 +105.8 (c 1.0, CHCl3) {lit., 43 [alpha]D20 +103.1 (c 1.0, CHCl3)}; numax/cm-1 (KBr) 2966, 1778, 1685, 1639; deltaH (300 MHz, CDCl3) 1.06, 1.07 [6H, 2 d, 2* J 6.9, CH(CH3)2], 2.42-2.63 [1H, sym m, CH(CH3)2], 4.27 [1H, dd, A of ABX, J 8.7, 3.9, one of C(5)H2], 4.69 [1H, dd appears as t, B of ABX, J 8.7, one of C(5)H2], 5.49 [1H, dd, X of ABX, J 8.7, 3.9, C(4)H], 7.05 [1H, dd, J 15.3, 6.6, C(3')H], 7.16-7.46 {6H, m, containing 7.22 [1H, dd, J 15.3, 1.2, C(2')H], ArH}; deltaC (75.5 MHz, CDCl3) 21.1, 21.2 [2* CH3, CH(CH3)2], 31.4 [CH, CH(CH3)2], 57.7 [CH, C(4)H], 69.9 [CH2, C(5)H2], 117.6 [CH, C(2')H], 125.9, 128.6, 129.1 (3* CH, aromatic CH), 139.1 (C, quaternary aromatic C), 153.7 (C, C=O), 158.1 [CH, C(3')H], 164.9 (C, C=O).

Reference： [1]Tetrahedron,2013,vol. 69,p. 1778 - 1794
[2]Journal of Organic Chemistry,2005,vol. 70,p. 580 - 589
[3]Journal of Organic Chemistry,2012,vol. 77,p. 2035 - 2040

13
[ 39887-30-4 ]
[ 99395-88-7 ]
[ 572923-17-2 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; potassium carbonate; rac-diaminocyclohexane In 1,4-dioxane Heating;

Reference： [1]Ghosh, Arun; Sieser, Janice E.; Caron, Stephane; Couturier, Michel; Dupont-Gaudet, Kristina; Girardin, Melina [Journal of Organic Chemistry, 2006, vol. 71, # 3, p. 1258 - 1261]

14
[ 86217-38-1 ]
[ 123-62-6 ]
[ 90319-52-1 ]
[ 99395-88-7 ]
[ 160695-26-1 ]
[ 184363-66-4 ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 6536 - 6537

15
[ 99395-88-7 ]
[ 223557-19-5 ]
4-(2-oxo-4-phenyl-oxazolidin-3-yl)-N-propyl-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
< 100%	With copper(l) iodide; potassium carbonate; rac-diaminocyclohexane; In 1,4-dioxane; at 110℃; for 15.5h;	S-(+)-4-PHENYL-OXAZOLIDIN-2-ONE (2.81 g, 17.2 MMOL), 4-bromo-N-propyl- benzamide (4.17 g, 17.2 MMOL), CUL (0.32 g, 1.72 MMOL) and potassium carbonate (4.76 g, 17.2 MMOL) were charged to a nitrogen-purged flask. The flask was evacuated and backfilled with nitrogen before addition of dioxane (17.2 ml). To the above reaction mixture, 1, 2-diaminocyclohexane (0.21 ML, 1.72 MMOL) was added via syringe. The resulting bright blue mixture was heated at 110C FOR 15.5 hours. Analysis (HPLC/MS) of the reaction mixture indicated that the reaction was complete. The oil bath was cooled to 45C, and any precipitated product was dissolved by the addition of DICHLOROMETHANE (50 ml). The mixture was filtered through celite and the solids were washed with an additional 50 ml of warm dichloromethane. The combined filtrates were concentrated and vacuum dried to give the desired OXAZOLIDINE as a light brown solid in near quantitative yield (5.6 g). Mass spec: 325 (m +1). 'H NMR (CDC13) 8 0.94 (t, J =7.5, 3H), 1.59 (m, 2H), 3.35 (m, 2H), 4.21 (m, 1 H), 4.80 (m, 1H), 5.43 (m, 1H), 6.16 (br, 1H), 7.27 (d, J=7.9, 2H), 7.34 (m, 3H), 7.46 (d, J =8.0, 2H), 7.64 (d, J =8.3, 2H). 3C NMR (CDC13) 8 11.66, 23. 08, 41.96, 60.54, 70.10, 120.10, 126,127. 95, 129.24, 129.75, 130.77, 137.96, 139.81, 155.84, 167. 02.

Reference： [1]Patent: WO2004/39785,2004,A1 .Location in patent: Page 15

16
[ 16957-70-3 ]
[ 99395-88-7 ]
[ 866108-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; lithium chloride; In ethyl acetate; at 75℃; for 20h;	A 20 L jacketed reactor was fitted with a reflux condenser and a nitrogen inlet. To the flask was charged 1006 g (8.81 mol) of (E) -2-methyl-2-pentenoic acid, 1250 g (7.661 mol) of (S)- (+)-4-phenyl-oxazolidin-2-one, 2179 g (8. 81 mol) of 2-ethoxy-1- ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), 81 g (1.915 mol) of lithium chloride, and 12.5 L of ethyl acetate (EtOAc). The reaction was heated to 75 0 C for 20 hours and then cooled to room temperature. The reaction solution was extracted 3x with 4 L aliquots of 1N HC1 and lx with 4 L of 0.2N NaOH. The 20 L reactor was fitted with a distillation head. The organic layer was distilled to remove, in succession: 6.5 L of EtOAc, after which 8 L of heptane was added back to the reactor; 4 L of EtOAc/heptane, after which 4 L of heptane was added to the reactor; and 4 L of EtOAc/heptane, after which 8 L of heptane was added to the reactor. After an additional 2 L of EtOAc/heptane was removed by distillation, the reaction mixture was cooled to an internal temperature of 40°C, and the reactor contents were charged to a filter and filtered under 5 psig of nitrogen washing with 8 L of heptane. The solids were dried under 5 psig of nitrogen overnight to give 1772 g of the titled compound : 1H-NMR (DMSO) 7.363-7. 243 (m, 5H), 6.137-6. 096 (m, 1H), 5.434-5. 394 (m, 1H), 4.721-4. 678 (t, 1H, J = 8.578), 4. 109-4. 069 (m, 1H), 2.119- 2.044 (m, 2H), 1.703-1. 700 (d, 3H, J = 1. 364), 0.945-0. 907 (t, 3H, J = 7.603) ; Anal Calc'd for Cl5Hl7Nl03 : C, 69.48 ; H, 6.61 ; N, 5.40. Found: C, 68.66 ; H, 6.60 ; N, 5.60 ; MS (Ion Mode: APCI) ? iZ= 260 [M+l l+.
	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; lithium chloride; In ethyl acetate; at 75℃; for 20h;	A 20 L jacketed reactor was fitted with a reflux condenser and a nitrogen inlet. To the flask was charged 1006 g (8.81 mol) of (E)-2-methyl-2-pentenoic acid, 1250 g (7.661 mol) of (S)-(+)-4-phenyl-oxazolidin-2-one, 2179 g (8.81 mol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 81 g (1.915 mol) of lithium chloride, and 12.5 L of ethyl acetate (EtOAc). The reaction was heated to 75°C for 20 hours and then cooled to room temperature. The reaction solution was extracted 3x with 4 L aliquots of 1 N HCI and 1 x with 4 L of 0.2N NaOH. The 20 L reactor was fitted with a distillation head. The organic layer was distilled to remove, in succession: 6.5 L of EtOAc, after which 8 L of heptane was added back to the reactor; 4 L of EtOAc/heptane, after which 4 L of heptane was added to the reactor; and 4 L of EtOAc/heptane, after which 8 L of heptane was added to the reactor. After an additional 2 L of EtOAc/heptane was removed by distillation, the reaction mixture was cooled to an internal temperature of 40°C, and the reactor contents were charged to a filter and filtered under 5 psig of nitrogen washing with 8 L of heptane. The solids were dried under 5 psig of nitrogen overnight to give 1772 g of the titled compound: 1H-NMR (DMSO) 7.363- 7.243 (m, 5H), 6.137-6.096 (m, 1 H), 5.434-5.394 (m, 1 H), 4.721-4.678 (t, 1 H, J = 8.578), 4.109-4.069 (m, 1H), 2.119-2.044 (m, 2H), 1.703-1.700 (d, 3H, J = 1.364), 0.945-0.907 (t, 3H, J = 7.603) ; Anal Calc'd for C15H17N1O3: C, 69.48; H, 6.61; N, 5.40. Found: C, 68.66; H, 6.60; N, 5.60; MS (Ion Mode: APCI) m/z= 260 [M+1]+.
	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; lithium chloride; In ethyl acetate; at 75℃; for 20h;	A 20 L jacketed reactor was fitted with a reflux condenser and a nitrogen inlet. To the flask was charged 1006 g (8.81 mol) of (E) -2-methyl-2-pentenoic acid, 1250 g (7.661 mol) of (S)-(+)-4-phenyl-oxazolidin-2-one, 2179 g (8.81 mol) of 2-ethoxy-1-ethoxycarbonyl-1,2- dihydroquinoline (EEDQ), 81 g (1.915 mol) of lithium chloride, and 12.5 L of ethyl acetate (EtOAc). The reaction was heated to 75°C for 20 hours and then cooled to room temperature. The reaction solution was extracted 3x with 4 L aliquots of IN HCI and 1x with 4 L of 0.2N NaOH. The 20 L reactor was fitted with a distillation head. The organic layer was distilled to remove, in succession: 6.5 L of EtOAc, after which 8 L of heptane was added back to the reactor; 4 L of EtOAc/heptane, after which 4 L of heptane was added to the reactor; and 4 L of EtOAc/heptane, after which 8 L of heptane was added to the reactor. After an additional 2 L of EtOAc/heptane was removed by distillation, the reaction mixture was cooled to an internal temperature of 40°C, and the reactor contents were charged to a filter and filtered under 5 psig of nitrogen washing with 8 L of heptane. The solids were dried under 5 psig of nitrogen overnight to give 1772 g of the title compound: 'H-NMR (DMSO) 8 7.363-7.243 (m, 5H), 6.137-6.096 (m, 1H), 5.434-5.394 (m, 1H), 4.721-4.678 (t, 1H, J = 8.578), 4.109-4.069 (m, 1H), 2.119-2.044 (m, 2H), 1.703-1.700 (d, 3H, J = 1.364), 0.945-0.907 (t, 3H, J = 7.603); Anal Calc'd for C15H17N1O3: C, 69.48; H, 6.61; N, 5.40. Found: C, 68.66; H, 6.60; N, 5.60; MS (Ion Mode: APCI) m/z= 260 [M+1]+.

Reference： [1]Patent: WO2005/92318,2005,A1 .Location in patent: Page/Page column 35
[2]Patent: WO2005/102389,2005,A2 .Location in patent: Page/Page column 65
[3]Patent: WO2005/102390,2005,A2 .Location in patent: Page/Page column 39-40

17
[ 1501-26-4 ]
[ 99395-88-7 ]
[ 133472-27-2 ]
[ 70627-52-0 ]
[ 191330-56-0 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1): To a solution of (S)-4-phenyl-2-oxazolidinone (41 g, 0.25 mol) in CH2Cl2 (200 mL), was added 4-dimethylaminopyridine (2.5 g, 0.02 mol) and triethylamine (84.7 mL, 0.61 mol) and the reaction mixture was cooled to 0 C. Methyl-4-(chloroformyl)butyrate (50 g, 0.3 mol) was added as a solution in CH2Cl2 (375 mL) dropwise over 1 h, and the reaction was allowed to warm to 22 C. After 17 h, water and H2SO4 (2N, 100 mL), was added the layers were separated, and the organic layer was washed sequentially with NaOH (10%), NaCl (sat'd) and water. The organic layer was dried over MgSO4 and concentrated to obtain a semicrystalline product. Step 2): To a solution of TiCl4 (18.2 mL, 0.165 mol) in CH2Cl2 (600 mL) at 0 C., was added titanium isopropoxide (16.5 mL, 0.055 mol). After 15 min, the product of Step 1 (49.0 g, 0.17 mol) was added as a solution in CH2Cl2 (100 mL). After 5 min., diisopropylethylamine (DIPEA) (65.2 mL, 0.37 mol) was added and the reaction mixture was stirred at 0 C. for 1 h, the reaction mixture was cooled to -20 C., and 4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) was added as a solid. The reaction mixture was stirred vigorously for 4 h at -20 C., then acetic acid was added as a solution in CH2Cl2 dropwise over 15 min, the reaction mixture was allowed to warm to 0 C., and H2SO4 (2N) was added. The reaction mixture was stirred an additional 1 h, the layers were separated, washed with water, separated and the organic layer was dried. The crude product was crystallized from ethanol/water to obtain the pure intermediate. Step 3): To a solution of the product of Step 2 (8.9 g, 14.9 mmol) in toluene (100 mL) at 50 C., was added N,O-bis(trimethylsilyl)acetamide (BSA) (7.50 mL, 30.3 mmol). After 0.5 h, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction mixture stirred at 50 C. for an additional 3 h. The reaction mixture was cooled to 22 C., CH3OH (10 mL), was added. The reaction mixture was washed with HCl (1 N), NaHCO3 (1 N) and NaCl (sat'd.), and the organic layer was dried over MgSO4. Step 4): To a solution of the product of Step 3 (0.94 g, 2.2 mmol) in CH3OH (3 mL), was added water (1 mL) and LiOH.H2O (102 mg, 2.4 mmole). The reaction mixture was stirred at 22 C. for 1 h and then additional LiOH.H2O (54 mg, 1.3 mmole) was added. After a total of 2 h, HCl (1 N) and EtOAc was added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the resultant product (0.91 g, 2.2 mmol) in CH2Cl2 at 22 C., was added ClCOCOCl (0.29 mL, 3.3 mmol) and the mixture stirred for 16 h. The solvent was removed in vacuo. Step 5): To an efficiently stirred suspension of 4-fluorophenylzinc chloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1 M in THF, 4.4 mL, 4.4 mmol) and ZnCl2 (0.6 g, 4.4 mmol) at 4 C., was added tetrakis(triphenyl-phosphine)palladium (0.25 g, 0.21 mmol) followed by the product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 mL). The reaction was stirred for 1 h at 0 C. and then for 0.5 h at 22 C. HCl (1 N, 5 mL) was added and the mixture was extracted with EtOAc. The organic layer was concentrated to an oil and purified by silica gel chromatography to obtain 1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(R)-(3-oxo-3-phenylpropyl)-2-azetidinone: HRMS calc'd for C24H19F2NO3=408.1429, found 408.1411.

Reference： [1]Patent: US2006/69080,2006,A1 .Location in patent: Page/Page column 26-27

18
[ 1501-26-4 ]
[ 99395-88-7 ]
[ 133472-27-2 ]
[ 70627-52-0 ]
[ 163222-31-9 ]

Yield	Reaction Conditions	Operation in experiment
		Compound of Formula (II); Step 1):; To a solution of (S)-4-phenyl-2-oxazolidinone (41 g, 0.25 mol) in CH2CI2 (200 mL), was added 4-dimethylaminopyridine (2.5 g, 0.02 mol) and triethylamine (84.7 mL, 0.61 mol) and the reaction mixture was cooled to 0C. Methyl-4-(chloroformyl)butyrate (50 g, 0.3 mol) was added as a solution in CH2CI2 (375 mL) dropwise over 1 h, and the reaction was allowed to warm to 22C. After 17 h, water and H2SO4 (2N, 100 mL), was added the layers were separated, and the organic layer was washed sequentially with NaOH (10%), NaCI (sat'd) and water. The organic layer was dried over MgSO4 and concentrated to obtain a semicrystalline product.; Step 2):; To a solution of TiCI4 (18.2 mL, 0.165 mol) in CH2CI2 (600 mL) at0C, was added titanium isopropoxide (16.5 mL, 0.055 mol). After 15 min, the product of Step 1 (49.0 g, 0.17 mol) was added as a solution in CH2CI2 (100 mL). After 5 min., diisopropylethylamine (DIPEA) (65.2 mL, 0.37 mol) was added and the reaction mixture was stirred at 0C for 1 h, the reaction mixture was cooled to -20C, and 4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) was added as a solid. The reaction mixture was stirred vigorously for 4 h at -20C, then acetic acid was added as a solution in CH2CI2 dropwise over 15 min, the reaction mixture was allowed to warm to 0C, and H2SO4 (2N) was added. The reaction mixture was stirred an additional 1 h, the layers were separated, washed with water, separated and the organic layer was dried. The crude product was crystallized from ethanol/water to obtain the pure intermediate.; Step 3):; To a solution of the product of Step 2 (8.9 g, 14.9 mmol) in toluene (100 mL) at 50C, was added N,O-bis(trimethylsilyl)acetamide (BSA) (7.50 mL, 30.3 mmol). After 0.5 h, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction mixture stirred at 50C for an additional 3 h. The reaction mixture was cooled to 22C, CH3OH (10 mL), was added. The reaction mixture was washed with HCI (1N), NaHCOe (1 N) and NaCI (sat'd.), and the organic layer was dried over MgSO4.; Step 4):; To a solution of the product of Step 3 (0.94 g, 2.2 mmol) in CH3OH (3 mL), was added water (1 mL) and LiOH-H2O (102 mg, 2.4 mmole). The reaction mixture was stirred at 22C for 1 h and then additional LiOH-H2O (54 mg, 1.3 mmole) was added. After a total of 2 h, HCI (1 N) and EtOAc was added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the resultant product (0.91 g, 2.2 mmol) in CH2CI2 at EPO <DP n="306"/>22C, was added CIC(O)C(O)CI (0.29 ml_, 3.3 mmol) and the mixture stirred for 16 h. The solvent was removed in vacuo.; Step 5):; To an efficiently stirred suspension of 4-fluorophenylzinc chloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1 M in THF, 4.4 mL, 4.4 mmol) and ZnCI2 (0.6 g, 4.4 mmol) at 4C, was added tetrakis(triphenyl- phosphine)palladium (0.25 g, 0.21 mmol) followed by the product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 mL). The reaction was stirred for 1 h at 0C and then for 0.5 h at 22C. HCI (1N, 5 mL) was added and the mixture was extracted with EtOAc. The organic layer was concentrated to an oil and purified by silica gel chromatography to obtain 1 -(4-f luorophenyl)-4(S)-(4-hydroxyphenyl)- 3(R)-(3-oxo-3-phenylpropyl)-2-azetidinone: HRMS calc'd for C24Hi9F2NO3 = 408.1429, found 408.1411.

Reference： [1]Patent: WO2006/60461,2006,A1 .Location in patent: Page/Page column 303-305

19
[ 1501-26-4 ]
[ 99395-88-7 ]
[ 477558-79-5 ]

Yield	Reaction Conditions	Operation in experiment
66.15%	With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; for 3h;Reflux;	(S) -4-phenyl-2-oxazolidinone was added to a 250 mL three-necked flask, 83 g (48 mmol), DIPEA (15 mL)Anhydrous dichloromethane 144 mL,DMF 3 drops and DMAP catalytic amount, heated to reflux, and slowly dropwise 11.5 g (72 mmol) of methyl chlorocaproate.Reflux reaction for 3 hours,TLC showed that the reaction was complete with 1M dilute hydrochloric acid to terminate the reaction, saturated sodium bicarbonate, saturated brine washing, anhydrous sodium sulfate drying, concentration, sand, the final column chromatography was pure 9.3g, income: 66.15%, mp : 54 C to 56 C
	With dmap; triethylamine; In dichloromethane; at 0 - 22℃; for 18h;	Step 1): To a solution of <strong>[99395-88-7](S)-4-phenyl-2-oxazolidinone</strong> (41 g, 0.25 mol) in CH2Cl2 (200 ml), was added 4-dimethylaminopyridine (2.5 g, 0.02 mol) and triethylamine (84.7 ml, 0.61 mol) and the reaction mixture was cooled to 0 C. Methyl-4-(chloroformyl)butyrate (50 g, 0.3 mol) was added as a solution in CH2Cl2 (375 ml) dropwise over 1 h, and the reaction was allowed to warm to 22 C. After 17 h, water and H2SO4 (2N, 100 ml), was added the layers were separated, and the organic layer was washed sequentially with NaOH (10%), NaCl (sat'd) and water. The organic layer was dried over MgSO4 and concentrated to obtain a semicrystalline product.
	With dimethyl aminopyrimidine; In dichloromethane; at 42 - 45℃; for 7h;	EXAMPLE 4 PREPARATION OF 1-[(5-METHOXY-1,5-DIOXOPENTA)-YL1-4-(S)-PHENYL OXAZOLIDIN-2-ONE (FORMULA III) 300 g of monomethyl glutarate was taken into a four neck round bottom flask containing 1500 ml of dichloromethane under stirring. 684 ml of triethyl amine was added at 20 C. followed by the addition of 306 ml of pivaloyl chloride. The reaction mixture was stirred at room temperature for 3 hours. 267 g of (S)-4-Phenyl-2-oxazolidinone and 17 g of dimethyl aminopyrimidine was added and heated to 45 C. The reaction mass was maintained at 42 to 45 C. for 7 hours. Reaction completion was confirmed by thin layer chromatography. The reaction mass was cooled to room temperature and 1500 ml of water was added to it. The aqueous layer was separated and extracted with 750 ml of dichloromethane in two equal lots. Total organic layer was washed with 750 ml of water in two equal lots. The organic layer was evaporated under vacuum at 63 C. to get an oily compound. 1200 ml of n-heptane was charged to this oily compound and stirred for 60 minutes. Filtered the separated solid and washed with 600 ml of n-heptane. The compound was dried at 30 C. for 8 hours to get 449 g of the title compound as a crystalline solid. (Yield 75%) Purity by HPLC: 93.48%.

Reference： [1]Patent: CN103864658,2016,B .Location in patent: Paragraph 0058; 0059
[2]Patent: US2005/96307,2005,A1 .Location in patent: Page/Page column 23
[3]European Journal of Medicinal Chemistry,2009,vol. 44,p. 1638 - 1643
[4]Patent: US2007/49748,2007,A1 .Location in patent: Page/Page column 9
[5]Letters in drug design and discovery,2011,vol. 8,p. 500 - 505

20
[ 99395-88-7 ]
[ 942485-56-5 ]

Yield	Reaction Conditions	Operation in experiment
93%		42 g (165 mmol) compound Formula IV, product of Example 1 was solved in 340 ml water- free terahydrofurane, and the vessel was rinsed by dry N2 gas. The solution was cooled to - 200C, and 55 ml (390 mmol) triethyl-amine was added. A mixture of 40 ml tetrahydrofurane and 20.2 ml pivaloyl chloride (19,8 g, 164 mmol) is added trough a drip-funnel for some 30 min at a temperature between -100C and -20 0C. The precipitate-containing mixture was stirred for 2 h at a temperature between -10 and -200C, and then 24,45 g (150 mmol) solid S (+)-4-phenyl-2-oxazolidinone (Va) and 7,5 g (177 mmol) water-free litium-chloride was sprinkled consecutively into it. Then the suspension was stirred for 4 h while it warmed up to 20-25 0C.The reaction was analytically controlled by thin-layer chromatography. When the spot of S (+)-4-phenyl-2-oxazolidinone decreased to 3%, the reaction was stopped with adding 300 ml toluene and 150 ml saturated ammonium-chloride solution. The phases were separated then the aqueous phase was extracted by 50 ml toluene. The united toluenic solution is washed by 2x150 ml 10% citric acid solution, 2x150 ml IM NaOH solution and at last with 3x 150 ml water. The organic phase was dried on anhydrous Na2SO4, the desiccant was filtered out, and the filtrate was evaporated in vacuum. The residue was crystallized at O0C with 150 ml isopropyl-alcohol. The product (Via) was dried in vacuum in the presence of P2O5. Yield: 55.7 g (93%) Melting point: 100-1020C[alpha]jf =+54.3, (c=l, dichloromethane)1H NMR data: (500 MHz, OMSO-d6, 25 0C) delta 1.42-1.56 (m, 2H), 1.76-1.85 (m, 2H), 2.80 (dt, J = 17.2, 7.5 Hz, IH), 2.90 (dt, / = 17.2, 7.5 Hz, IH), 3.61-3.71 (m, 2H), 3.89-3.99 (m, 2H), 4.13 (dd, J = 8.7, 3.6 Hz, IH), 4.71 (t, J = 8.7 Hz, IH), 5.43 (dd, J - 8.7, 3.6 Hz, IH), 7.12-7.19 (m, 2H), 7.23-7.28 (m, 2H), 7.29-7.34 (m, IH), 7.34-7.42 (m, 4H) ppm.

Reference： [1]Patent: WO2007/72088,2007,A1 .Location in patent: Page/Page column 16

21
[ 26209-00-7 ]
[ 99395-88-7 ]
[ 1028531-17-0 ]

Yield	Reaction Conditions	Operation in experiment
95%		A flame-dried 1 L round bottomed flask containing an MTBE solution of 6 (2.8 g, 33 mmol), and 800 mL of THF was chilled by a cold bath at -30 C. (dry ice/30% ethanol in ethylene glycol). The mixture was allowed to stir under nitrogen atmosphere. Distilled triethylamine (12.2 g, 17.0 mL, 120 mmol), and pivaloyl chloride (6.0 g, 6.2 mL, 50 mmol) were added sequentially, and stirring at -30 C. was continued for one hour. LiCl (7.0 g, 170 mmol) was added. After five minutes, (S)-4-phenyloxazolidinone (9.8 g, 60 mmol), and 4-dimethylamino pyridine (408 mg, 3.35 mmol) were added. The whole reaction mixture was allowed to stir overnight at room temperature. The solvents were removed under reduced pressure, and the residue was partitioned between 300 mL of CH2Cl2 and 300 mL water. The aqueous layer was extracted twice with 300 mL portions of CH2Cl2, and the combined organics were dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on silica gel. The initial eluent was 1:1:9 CH2Cl2:ethyl acetate:hexane, followed by elution with 1:3:7 CH2Cl2:ethyl acetate:hexane. The yield of 7 was 7.20 g (31.5 mmol, 95%). Compound 7 is a white solid. mp=118-119 C., [alpha]D+140.0 (c 1.00, THF).

Reference： [1]Patent: US2009/23916,2009,A1 .Location in patent: Page/Page column 9; 17
[2]Journal of Organic Chemistry,2008,vol. 73,p. 4283 - 4286

22
[ 54322-10-0 ]
[ 99395-88-7 ]
[ 1046809-83-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 2: Preparation of 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl esterDichloromethane (1.70 L) was added to the oil obtained above and the reaction mass was cooled to 15C. Triethylamine (428 ml) was added and the reaction mass was stirred for 5 minutes under nitrogen atmosphere. Pivaloyl chloride (220 ml) was added slowly while maintaining the <n="18"/>reaction temperature between 15-2O0C. After addition, the reaction mass was stirred for 60 minutes at 25-300C. (S)-(+)-4-Phenyl-2-oxazolidinone (172 g), 4-dimethylaminopyridine (30 g) and N,N-Dimethylformamide (184 ml) were added and the reaction mass was heated to 50-550C and then maintained at this temperature for 5 hours. After 5 hours the reaction mass was cooled to 2O0C, 2nu sulfuric acid solution (800 ml) was added and the reaction mass was stirred for 15 minutes. Organic layer was separated and washed with 5% aqueous sodium bisulfite solution (1.0 L) and then with brine (1.0 L). The organic layer was dried over sodium sulfate. Solvent was distilled off fully under vacuum. Ethanol (1.0 L) was added and the reaction mass was stirred at ambient temperature for 15 minutes and then a pinch of title compound was added. The reaction mass was stirred for 120 minutes at ambient temperature and then cooled to 0-50C and then maintained at 0-50C for 2 hours. The solid was filtered and washed with chilled ethanol (200 ml). Finally the solid was dried at 4O0C under vacuum to get 220 g of the title compound having purity of 98.16% by HPLC.

Reference： [1]Patent: WO2008/96372,2008,A2 .Location in patent: Page/Page column 16-17

23
[ 99395-88-7 ]
[ 563-76-8 ]
(S)-3-(2-Bromo-propionyl)-4-phenyl-oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.4%	With sodium methylate; In methanol; toluene; at 0 - 20℃; for 0.5h;Inert atmosphere;	The compound of formula II (250 g, 1.53 mol) was added to toluene (3750 mL)Heat to 70 degrees. Sodium methoxide methanol solution (29 wt%, 314 g, 1.68 mol) was added dropwise.Plus End, atmospheric distillation of methanol. Cooled to 0-5 C,The compound of formula III (364.4 g, 1.68 mol)Temperature is not higher than 20 . Add finished, the reaction 1-2 hours.After the reaction was completed, water (250 mL) was added, heated to 50-60 C, allowed to stand for delamination and the aqueous phase was separated.The organic phase is washed twice with water. The organic phase was concentrated to give the crude product.The crude product was beaten with n-hexane (1500 mL), filtered and dried to obtain the intermediate of formula IV.Yield: 436g, yield: 95.4%

Reference： [1]Patent: CN107573304,2018,A .Location in patent: Paragraph 0067-0071; 0072-0074; 0075-0077
[2]Tetrahedron Asymmetry,2008,vol. 19,p. 2789 - 2795

24
[ 99395-88-7 ]
[ 932-87-6 ]
(S)-4-phenyl-3-(2-phenylethynyl)oxazolidin-2-one [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 4630 - 4633
[2]Organic Letters,2012,vol. 14,p. 1732 - 1735
[3]European Journal of Organic Chemistry,2013,p. 6979 - 6989
[4]Organic and Biomolecular Chemistry,2014,vol. 12,p. 5945 - 5953
[5]Organic Letters,2017,vol. 19,p. 6200 - 6203
[6]Organic Letters,2018,vol. 20,p. 2778 - 2781

25
[ 53293-00-8 ]
[ 99395-88-7 ]
[ 1190391-59-3 ]

Yield	Reaction Conditions	Operation in experiment
85.4%		To a solution of 69.0 g (615 mmol) of 5-hexynoic acid and 214 mL (1540 mmol) of triethylamine in 1.0 L of anhydrous tetrahydrofuran at -25 C. under an atmosphere of nitrogen was added 83.0 mL (677 mmol) of trimethylacetyl chloride over 20 min. Upon addition a white precipitate formed and the resulting suspension was stirred for 2 h. Next, 28.7 g (677 mmol) of anhydrous lithium chloride and 100.0 g (615.0 mmol) of (4S)-4-phenyl-1,3-oxazolidin-2-one were added sequentially and the mixture was allowed to gradually warm to ambient temperature over 12 h. All volatiles were removed in vacuo and the residue was diluted with water (1 L) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 5-50% ethyl acetate in hexanes gradient to afford the title compound as a colorless solid (135 g, 85.4%). 1H NMR (500 MHz, CDCl3): delta 7.40-7.37 (m, 2H), 7.36-7.32 (m, 1H), 7.31-7.28 (m, 2H), 5.42 (dd, J=8.9, 3.7 Hz, 1H), 4.69 (t, J=8.9 Hz, 1H), 4.28 (dd, J=9.2, 3.7 Hz, 1H), 3.13-3.02 (m, 2H), 2.24-2.21 (m, 2H), 1.94 (t, J=2.6 Hz, 1H), 1.84 (quintet, J=7.1 Hz, 2H). LC-MS: m/z (ES) 258.2 (MH)+.
85.4%		To a solution of 69.0 g (615 mmol) of 5-hexynoic acid and 214 mL (1540 mmol) of triethylaraine in 1.0 L of ar ydrous tetrahydrofuran at -25C under an atmosphere of nitrogen was added 83.0 mL (677 mmol) of trimethylacetyl chloride over 20 min. Upon addition a white precipitate formed and the resulting suspension was stirred for 2 h. Next, 28.7 g (677 mmol) of anhydrous lithium chloride and 100.0 g (615.0 mmol) of (4S)-4-phenyl-l,3-oxazolidin-2-one were added sequentially and the mixture was allowed to gradually warm to ambient temperature over 12 h. All volatiles were removed in vacuo and the residue was diluted with water (1 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 5-50% ethyl acetate in hexanes gradient to afford the title compound as a colorless solid (135 g, 85.4%). 1H NMR (500 MHz, CDC13): delta 7.40-7.37 (m, 2H), 7.36-7.32 (m, 1H), 7.31-7.28 (m, 2H), 5.42 (dd, J= 8.9, 3.7 Hz, 1H), 4.69 (t, J= 8.9 Hz, IE), 4.28 (dd, J= 92, 3.7 Hz, 1H), 3.13-3.02 (m, 2H), 2.24-2.21 (m, 2H), 1.94 (t, J= 2.6 Hz, 1H), 1.84 (quintet, J- 7.1 Hz, 2H). LC-MS: m/z (ES) 258.2 (MH)+.
85.4%		INTERMEDIATE 45-({(2S, 5R)- 1 -(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrroiidin-2- yl ) methyl)pyridine-2 -carboxylic acidStep A: (4)USD^-3-Hex-5-ynoyl-4-pheny - 1.3-oxazolidin-2-one; To a solution of 69.0 g (615 mmol) of 5-hexynoic acid and 214 mL (1540 mmol) of triethylamine in 1.0 L of anhydrous tetrahydrofuran at -25 C under an atmosphere of nitrogen was added 83.0 mL (677 mmol) of trimethylacetyl chloride over 20 min. Upon addition a white precipitate formed and the resulting suspension was stirred for 2 h. Next, 28.7 g (677 mmol) of anhydrous lithium chloride and 100.0 g (615.0 mmol) of (4S)-4-phenyl-l,3-oxazolidin-2-one were added sequentially and the mixture was allowed to gradually warm to ambient temperature'~<4'3 " over 12 h. All volatiles were removed in vacuo and the residue was diluted with water (1 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 5-50% ethyl acetate in hexanes gradient to afford the title compound as a colorless solid (135 g, 85.4%). 1H NMR (500 MHz, CDC13): delta 7.40-7.37 (m, 2H), 7.36-7.32 (m, 1H), 7.31-7.28 (m, 2H), 5.42 (dd, J- 8.9, 3.7 Hz, 1H), 4.69 (t, J= 8.9 Hz, 1H), 4.28 (dd, J= 9.2, 3.7 Hz, 1H), 3.13-3.02 (m, 2H), 2.24-2.21 (m, 2H), 1.94 (t, J= 2.6 Hz, 1H), 1.84 (quintet, J= 7.1 Hz, 2H). LC-MS: m/z (ES) 258.2 (MH)+.

85.4%

To a solution of 69.0 g (615 mmol) of 5-hexynoic acid and 214 mL (1540 mmol) of triethylamine in 1.0 L of anhydrous tetrahydrofuran at -25C under an atmosphere of nitrogen was added 83.0 mL (677 mmol) of trimethylacetyl chloride over 20 min. Upon addition a white precipitate formed and the resulting suspension was stirred for 2 h. Next, 28.7 g (677 mmol) of anhydrous lithium chloride and 100.0 g (615.0 mmol) of (45)-4-phenyl-l,3-oxazolidin-2-one were added sequentially and the mixture was allowed to gradually warm to ambient temperature over 12 h. All volatiles were removed in vacuo and the residue was diluted with water (1 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 5-50% ethyl acetate in hexanes gradient to afford the title compound as a colorless solid (135 g, 85.4%). NMR (500 MHz, CDC13): delta 7.40-7.37 (m, 2H), 7.36-7.32 (m, 1H), 7.31-7.28 (m, 2H), 5.42 (dd, J= 8.9, 3.7 Hz, 1H), 4.69 (t, J- 8.9 Hz, 1H), 4.28 (dd, J- 9.2, 3.7 Hz, 1H), 3.13-3.02 (m, 2H), 2.24-2.21 (m, 2H), 1.94 (t, J= 2.6 Hz, 1 H), 1.84 (quintet, J- 7.1 Hz, 2H). LC-MS: m/z (ES) 258.2 (MH)+.

Reference： [1]Patent: US2009/253705,2009,A1 .Location in patent: Page/Page column 23
[2]Patent: WO2011/137054,2011,A1 .Location in patent: Page/Page column 37
[3]Patent: WO2012/12314,2012,A1 .Location in patent: Page/Page column 43-44
[4]Patent: WO2011/43942,2011,A1 .Location in patent: Page/Page column 17-18
[5]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1094 - 1098

26
[ 99395-88-7 ]
[ 162551-89-5 ]
[ 1176702-27-4 ]

Yield	Reaction Conditions	Operation in experiment
68%		To a solution of (E)-4- (benzyloxy)but-2-enoic acid 236 (2.5g, 13.01mmol) and triethylamine (1.45g, 14.31 mmol) in anhydrous THF (40 mL) under nitrogen at -78 C was added trimethylacetyl chloride (1.72g, 14.3 lmmol). The reaction mixture was stirred at -78 C for 10 minutes, 0 C for 1 hour, then re-cooled to -78C.At the same time, in a seperate flask charged with a solution of (S)-4-phenyloxazolidin-2- one 237 (0.42g, 2.6mmol) in anhydrous THF (40 mL) under nitrogen at -78 C was added dropwise a solution of LiHMDS (14.31 mL, 14.3 lmmol). The mixture was stirred at -78 C for 20 minutes and then transferred via a cannula into the reaction flask containing the mixed anhydride at -78 C. The reaction mixture was stirred at 0 C for 1 hour, then warmed to room temperature and stirred for 18 hours. The crude mixture was quenched with sat. NH4CI (200 mL), and concentrated in vacuo, to about half of its original volume under reduced pressure to remove THF. The remaining mixture was extracted with ethyl acetate (150 mL x 2). The organic layer was separated, combined, dried over anhydrous Na2SC>4 and concentrated to dryness. The residue was purified by silica gel column (PE : EA = 2 : 1) to give 238, (S,E)-3-(4-(benzyloxy)but-2-enoyl)-4-phenyloxazolidin-2-one (3 g, 68% yield). LC-MS (LC method 1): m/z 338 (M+l)+.

Reference： [1]Patent: WO2017/189866,2017,A1 .Location in patent: Paragraph 0263; 0264
[2]Organic Letters,2009,vol. 11,p. 3178 - 3181

27
[ 34722-37-7 ]
[ 99395-88-7 ]
[ 858104-45-7 ]

Yield	Reaction Conditions	Operation in experiment
77%		Method 59; (4S)-3-[(4-Methoxybenzyl) thio] acetyl}-4-phenyl-1, 3-oxazolidin-2-one; (4-Methoxy-benzylsulfanyl) -acetic acid (1.3 g, 6.1 mmol) was dissolved in dry DCM (40 ml) and cooled to 0C. N, N'-dicyclohexylcarbodiimide (6.1 g, 6.1 mmol) and DMAP (1.6 g, 12.9 mmol) were added and the mixture was stirred for 30 minutes. (S)- (+)-4-Phenyl-2- oxazolidinone (1,0 g, 6.1 mol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was filtrated, concentrated under reduced pressure and purified by flash-chromatography (Hex: EtOAc 8: 2 then 1 : 1). This afforded 1.7 g (77 %) of the title compound as a white solid. NMR (200 MHz) : 3.46-3. 59 (m, 3H), 3.74-3. 76 (m, 4H), 4.23- 4.28 (m, 1H), 4.68 (t, 1H), 5.38-5-42 (m, 1H), 6.78 (d, 2H), 7.14 (d, 2H), 7. 32-7. 40 (m, 5H).
77%		45)-3-[(4-Methoxybenzyl)thio]acetyl}-4-phenyl-l,3-oxazoIidin-2-one[(4-Methoxybenzyl)thio]acetic acid (1.3 g, 6.1 mmol) was dissolved in dry CH2Cl2 (40 ml) and given O0C. Nu,Nu'-Dicyclohexylcarbodiimide (DCC, 6.1 g, 6.1 mmol) and 4- 30 (dimethylamino)pyridine (DMAP, 1.6 g, 12.9 mmol) were added and the mixture was stirred for 30 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (1,0 g, 6.1 mol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was filtrated, concentrated under EPO <DP n="79"/>reduced pressure and purified by flash-chromatography (Hex : EtOAc 8:2 then 1:1). This afforded 1.7 g (77 %) of the title compound.1H-NMR (CDCl3, 200 MHz): delta 3.46-3.59 (m, 3H), 3.74-3.76 (m, 4H), 4.23-4.28 (m, IH), 4.68 (t, J= 8.8 Hz, IH), 5.38-5-42 (m, IH), 6.78 (d, J = 8.6 Hz, 2H), 7.14 (d, J= 8.6 Hz, 2H), 7.32-7.40 (m, 5H).
		(4S)-3-[(4-Methoxybenzyl)thio]acetyI}-4-phenyl-l,3-oxazolidin-2-one; [(4-Methoxybenzyl)thio] acetic acid (1.3 g, 6.1 mmol) was dissolved in dry CH2Cl2 (40 ml) and given O0C. N,N'-Dicyclohexylcarbodiimide (DCC, 6.1 g, 6.1 mmol) and 4- (dimethylamino)pyridine (DMAP, 1.6 g, 12.9 mmol) were added and the mixture was stirred for 30 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (1,0 g, 6.1 mol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was filtrated, concentrated under reduced pressure and purified by flash-chromatography (Hex : EtOAc 8:2 then 1:1). This afforded the title compound.1H-NMR (CDCl3, 200 MHz): delta 3.46-3.59 (m, 3H), 3.74-3.76 (m, 4H), 4.23-4.28 (m, IH), 4.68 (t, /= 8.8 Hz, IH), 5.38-5-42 (m, IH), 6.78 (d, 7= 8.6 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 7.32-7.40 (m, 5H)

		(4S)-3-[(4-Methoxybenzyl)thio]acetyl}-4-phenyl-l,3-oxazolidin-2-one[(4-Methoxybenzyl)thio]acetic acid (1.3 g, 6.1 mmol) was dissolved in dry CH2Cl2 (40 ml) and given O0C. N,N'-Dicyclohexylcarbodiimide (DCC, 6.1 g, 6.1 mmol) and 4- EPO <DP n="79"/>(dimethylamino)pyridine (DMAP, 1.6 g, 12.9 mmol) were added and the mixture was stirred for 30 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (1,0 g, 6.1 mol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was filtrated, concentrated under reduced pressure and purified by flash-chromatography (Hex : EtOAc 8:2 then 1:1). This 5 afforded the title compound as a white solid.1H-NMR (CDCl3, 200 MHz): delta 3.46-3.59 (m, 3H), 3.74-3.76 (m, 4H), 4.23-4.28 (m, IH), 4.68 (t, J = 8.8 Hz, IH), 5.38-5-42 (m, IH), 6.78 (d, /= 8.6 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 7.32-7.40 (m, 5H)
		4S)-3-[(4-Methoxybenzyl)thio]acetyl}-4-phenyI-l,3-oxazolidin-2-one; [(4-Methoxybenzyl)thio] acetic acid (1.3 g, 6.1 mmol) was dissolved in dry CH2Cl2 (40 ml) and given O0C. N,N'-Dicyclohexylcarbodiimide (DCC, 6.1 g, 6.1 mmol) and 4- (dimethylamino)pyridine (DMAP, 1.6 g, 12.9 mmol) were added and the mixture was stirred for 30 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (1,0 g, 6.1 mol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was filtrated, concentrated under reduced pressure and purified by flash-chromatography (Hex : EtOAc 8:2 then 1:1). This afforded the title compound.1H-NMR (CDCl3, 200 MHz): delta 3.46-3.59 (m, 3H), 3.74-3.76 (m, 4Hj, 4.23-4.28 (m, IH), 4.68 (t, J = 8.8 Hz, IH), 5.38-5-42 (m, IH), 6.78 (d, J = 8.6 Hz, 2H), 7.14 (d, / = 8.6 Hz, 2H), 7.32-7.40 (m, 5H).
		(45)-3-[(4-Methoxybenzyl)thio]acetyl}-4-phenyl-l,3-oxazolidin-2-one[(4-Methoxybenzyl)thio] acetic acid (1.3 g, 6.1 mmol) was dissolved in dry CH2Cl2 (40 ml) and given O0C. N,N'-Dicyclohexylcarbodiimide (DCC, 6.1 g, 6.1 mmol) and 4- (dimethylamino)pyridine (DMAP, 1.6 g, 12.9 mmol) were added and the mixture was stirred for 30 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (1,0 g, 6.1 mol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was filtrated, concentrated under reduced pressure and purified by flash-chromatography (Hex : EtOAc 8:2 then 1:1). This afforded the title compound.1H-NMR (CDCl3, 200 MHz): delta 3.46-3.59 (m, 3H), 3.74-3.76 (m, 4H), 4.23-4.28 (m, IH), 4.68 (t, J = 8.8 Hz, IH), 5.38-5-42 (m, IH), 6.78 (d, /= 8.6 Hz, 2H), 7.14 (d, /= 8.6 Hz, 2H), 7.32-7.40 (m, 5H).

Reference： [1]Patent: WO2005/61452,2005,A1 .Location in patent: Page/Page column 159-160
[2]Patent: WO2006/137795,2006,A1 .Location in patent: Page/Page column 77-78
[3]Patent: WO2006/137792,2006,A1 .Location in patent: Page/Page column 61
[4]Patent: WO2006/137796,2006,A1 .Location in patent: Page/Page column 76-77
[5]Patent: WO2006/137793,2006,A1 .Location in patent: Page/Page column 60
[6]Patent: WO2006/137797,2006,A1 .Location in patent: Page/Page column 75

28
[ 99395-88-7 ]
[ 149437-76-3 ]
[ 189028-93-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane;	Example 1: Preparation of ezetimibe; (1-1) Preparation of 3-[5-(fluorophenyl)-l,5-dioxapentyl]-4(S)- phenyl-2-oxazolidinone (Formula 7); 200 g of <strong>[149437-76-3]5-(4-fluorophenyl)-5-oxopentanoic acid</strong> of formula 8, 16O g of (S)-4-phenyloxazolidine-2-one of formula 9, and 11.6 g of 4-dimethylaminopyridine were dissolved in 600 m£ of dichloromethane to prepare a reaction mixture. A solution which was prepared by dissolving 157 g of N,N'-dicyclohexylcarboimide in 200 ml of dichloromethane was added to the reaction mixture and stirred for 2 hours. After completion of the reaction, the resulting reaction mixture was filtered to remove by-products. The filtrate thus obtained was washed successively with 1 I of 6N HCl, 1 ? of water, and 1 ? of saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and distilled under a reduced pressure to remove the solvent. The residue thus obtained was dissolved in 2 I of methanol by heating and cooled to induce crystallization. 2 £ of water was added thereto and stirred for 30 min. The solid thus obtained was isolated by filtering to obtain 289 g of the title compound as a white solid (yield: 86%).1H NMR(300MHz, CDCl3) : delta 7.92 (2H, M), 7.35-7.13 (5H, m), 7.04 (2H, m), 5.43 (IH, q), 4.75(1H, t), 4.22 (IH, q), 3.05-2.93 (4H, m), 2.03 (2H, m)
85.7%		5-(4-Fluorophenyl)-5-oxopentanoic acid (21.02 g, 100.0 mmol) and 4 dimethylamino- pyridine (16.25 g, 133.0 mmol) were dissolved in N,N-dimethylformamide (100 mL, 1.0 M) to afford a copious white precipitate suspended in solution. The reaction was cooled to 2 0C (ice/water bath), and trimethylacetyl chloride (16.40 mL, 16.04 g, 133.0 mmol) was added drop-wise to afford a pale yellow mixture. The rate of addition was controlled in order to keep the temperature at or below 5 0C. A heavy white precipitate was formed and the mixture was allowed to warm to room temperature and stirred for 1.5 h. The mixture was charged with (6)-(+)-4-phenyl-2- oxazolidinone (16.32 g, 100.0 mmol) and 4-dimethylaminopyridine (12.22 g, 100.0 mmol) both as solids to afford a yellow colored suspension. The reaction was stirred at 30 C - 35 0C for 2 h. An aliquot was removed for analysis by TLC and HPLC. The pale olive colored suspension was poured into water (400 mL) while stirring vigorously and cooling the mixture in an ice-brine bath, transferred with water (150 mL) and stirred with ice-cooling for 1.5 h to afford a solution with an off-white precipitate. The compound was filtered, transferred with water (2 x 25 mL), washed with water (50 mL) and air dried for 15 min to afford an off-white moist clumpy powder. The material was crystallized from isopropanol (58.0 mL; 1.6 mL/g theoretical yield) by heating to near reflux to afford a golden yellow colored solution. The solution was cooled slowly to room temperature over 12 h, a seed crystal was added and crystals began to precipitate. The mixture was cooled in an ice/water bath and stirred for 1 h. The crystals were filtered, transferred with cold isopropanol (2 x 10 mL), washed with cold isopropanol (25 mL), air dried and vacuum dried to constant weight to afford (45)-4-phenyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-l,3- oxazolidin-2-one (30.46 g, 85.7 % yield) as a white crystalline solid; m.p. 91.0 0C; EPO <DP n="43"/>R/ 0.40 (1:2 ethyl acetate-hexane); HPLC Rr7.02 min; HPLC purity 94 %. 1H NMR (300 MHz, CDCl3) delta 7.93 (dd, J= 5.4, 9.0 Hz, 2H), 7.28-7.42 (m, 5H), 7.10 (dd, J= 8.5, 9.0 Hz, 2H), 5.43 (dd, J= 3.7, 8.7 Hz, IH), 4.70 (t, J= 8.9 Hz, IH), 4.28 (dd, J= 3.7, 8.7 Hz, IH), 3.05 (dt, J= 1.2, 7.3 Hz, 2H), 2.97 (t, J= 7.3, 2H), 2.05 (p, J= 7.3 Hz, 2H), ppm.
85%		To the soulution of compound 2 (700 g, 3.33 mol, 1.1 eq) dissolved in THF (5 L) was added triethylamine (1.2 L, 7.87 mol, 2.6 eq) at room temperature under N2 atmosphere. Then the solution of pivalic acid chloride (400 g, 3.33 mol, 1.1 eq) in THF (700 mL) was added dropwise to the reaction mixture cooled to -10 C for about 2 h. After addition, the mixture was stirred for 2 h at this temperature. TLC showed the compound 2 was consumed up, then the Evans auxiliary (493.5 g, 3 mol, 1 eq) and anhydrous LiCl (150.5 g, 3.5 mol,1.17 eq) were added sequencely. The mixture was warmed to room temperature and stirred for 2 h till the anhydride intermediate was consumed up. Then ethylacetate (2 L) and NH4Cl aq (1 L) were added, stirred for 15 min, stayed and separated, the aqueous layer was extracted with ethyl acetate (500 mL×2), combined the organic phase, washed with water (250 mL ×2), concentrated.The residue was recrystallized from isopropanol (7 L) to afforded compound 4 as a white solid (913.6 g, 85.0% yield). HPLC purity: 99.2%, mp: 94-95 C [lit.9(b) 91C]. 1H-NMR (CDCl3,400 MHz): delta 7.94-7.93 (m, 2H, J=2), 7.40-7.29 (m, 5H), 7.10-7.01 (m, 2H), 5.45-5.41 (m, 1H), 4.72-4.63 (m, 1H), 4.30-4.27 (m, 1H), 3.06 (t, 2H, J=8), 2.97 (t, 2H, J=12), 2.10-2.03 (m, 2H). 13C-NMR (CDCl3, 100MHz): delta 197.7, 172.2, 167.0, 164.4, 153.8, 139.2, 133.3, 130.7, 130.6, 129.2, 128.7, 126.0, 115.7, 115.5, 70.1, 57.6, 37.3, 34.8, 18.5. MS (ESI) m/z calcd. for C20H18FNO4: 355.12, calcd. for C20H18FNO4Na (M+Na)=378.12, found 378.04 (M+Na).

70%		Compound I (21 g, 0.1 mol) was added to a 500 ml three-necked flask, Triethylamine 20 ml and dichloromethane 250 ml, Stuttgart dropwise pivaloyl chloride (14.4g, 0.12mol), (4S) -4-phenyl-2-oxazolidinone (24.5 g, 0.15 mol), DMF 5 ml, 4,4-dimethylaminopyridine (1.22 g, 0.01 mol) was added after refluxing for 3 h, After refluxing for 10 h, Ice bath cooling, Then, 200 ml of 5 M hydrochloric acid was added dropwise at 0 C, Static stratification, The lower methylene chloride layer was washed successively with saturated sodium bicarbonate solution and water, Dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness, To give 24.9 g of a white solid compound II, Yield 70%.
68%		The compound (4) (30 g, 142.72 mmol) Triethylamine (26 g, 256.91 mmol) was dissolved in dichloromethane (150 ml)Cooling to 5 to 10 C, dropwise addition of pivaloyl chloride (17.3g, 142.62mmol), System has exothermic, 30min drop finished,5 to 10 deg C insulation reaction 2h, To the reaction system was added (S) -4-phenyl-2-oxazolidinone (23.3 g, 142.76 mmol) DMAP (2.4 g, 19.63 mmol), DMF (15 ml),Exothermic The temperature rose to 15 C, Heated to 45 reflux reaction 3h, Down to room temperature, Plus dichloromethane (150 ml), The organic phase was washed with water (60 ml) 1N hydrochloric acid (120 ml) Water (60ml) 2.5% aqueous sodium hydroxide solution (180 ml) Add water (50ml) wash, Organic phase concentrated dry, Plus isopropyl alcohol (60 ml), Stirring for 24 h, Filter, Add isopropyl alcohol (10ml) leaching, To give a white solid, I.e. compound (5) (34.4 g, 68% yield).

Reference： [1]Patent: WO2010/71358,2010,A2 .Location in patent: Page/Page column 14-15
[2]Patent: WO2006/122216,2006,A2 .Location in patent: Page/Page column 41-42
[3]Synthetic Communications,2016,vol. 46,p. 1687 - 1693
[4]Patent: CN106397292,2017,A .Location in patent: Paragraph 0053; 0086; 0087
[5]Patent: CN104513187,2017,B .Location in patent: Paragraph 0063; 0064; 0065; 0066

29
[ 3038-48-0 ]
[ 99395-88-7 ]
[ 1240405-20-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	With pivaloyl chloride; triethylamine; In toluene; at 20℃;Reflux;	Example 1; [0058] Synthesis of (4S)-4-phenyl-3-[2-(trifluoromethyl)phenyllacetvU-l,3-oxazolin-2-one [Formula 35][0059]Triethylamine (51.5 mL, 368 mmol) was added to a suspension of 2- trifluoromethylphenylacetic acid (37.6 g, 184 mmol) and (s)-(+)-4-phenyl-2-oxazolidinone (15 g, 92 mmol) in toluene (450 mL) at room temperature. Pivaloyl chloride (22.7 mL, 184 mmol) was added dropwise to the suspension with stirring at room temperature. The resulting suspension was heated under reflux with stirring for 18 hours. After cooling to room temperature, 2 N hydrochloric acid (150 mL) was added, followed by extraction. The organic layer was sequentially washed with a saturated sodium bicarbonate solution (150 mL) twice, a 5% sodium chloride solution (150 mL) and water (150 mL) and concentrated under reduced pressure. Ethyl acetate (45 mL) was added to the resulting solid, and the solid was completely dissolved by heating to 5O0C. Heptane (180 mL) was added to the solution, followed by gradually cooling to room temperature. The resulting suspension was further cooled to ice-cold temperature, and then filtered, washed with heptane (150 mL) and dried under reduced pressure to obtain 27.7 g (content: 93%) of first crystals of the title compound. From the filtrate, 1.43 g (content: 87%) of second crystals were obtained. The crystals were combined to obtain the title compound as white crystals in a yield of 84%.1H-NMR (400 MHz, CDCl3): delta 4.34 (dd, J = 4.0, 8.8 Hz, IH), 4.47 (s, 2H), 4.76 (dd, J = 8.8, 9.2 Hz, IH), 5.44 (dd, J = 3.6, 8.8 Hz, IH), 7.21 (d, J = 7.6 Hz, IH), 7.26-7.40 (m, 6H), 7.46 (dd, J = 7.6, 7.6 Hz, IH), 7.62 (d, J = 8.0 Hz, IH).

Reference： [1]Patent: WO2010/98496,2010,A1 .Location in patent: Page/Page column 28

30
[ 99395-88-7 ]
[ 128677-85-0 ]
[ 146137-34-0 ]

Yield	Reaction Conditions	Operation in experiment
88%		In a separate flask, n-butyllithium (4.6 mL, 11.6 mmol, 2.5 M F in hexanes) was added to (S)-(+)-4-phenyl-2-oxazolidinone (2.0 g, 12.2 mmol) in anhydrous tetrahydrofuran at -78 C. and allowed to stir for 10 minutes. The lithiated oxazolidinone was transfered via cannula to the mixed anhydride at -78 C. and stirring continued for 2 hours. The reaction was quenched with water (25 mL) and extracted with ethyl acetate. The combined extracts were washed with water, brine and dried over sodium sulfate. The crude product was purified by chromatography over silica gel eluted with 2:3 ethyl acetate/hexanes and the resulting solid was recrystallized from ethyl acetate/hexanes to afford (S)-4-phenyl-3-((S)-3-phenyl-butyryl)-oxazolidin-2-one (1.63 g, 88% yield).

Reference： [1]Patent: US2006/41146,2006,A1 .Location in patent: Page/Page column 33

31
[ 1026984-25-7 ]
[ 99395-88-7 ]
[ 174485-45-1 ]

Yield	Reaction Conditions	Operation in experiment
75%		At the same time, in a seperate flask charged with a solution of (S)-(+)-4-phenyl-2-oxazolidinone (8.86 g, 54 mmol) in anhydrous tetrahydrofuran (130 mL) under nitrogen at -78 C. was added dropwise a solution of n-butyl lithium (22 mL, 54 mmol, 2.5 M in hexanes). The mixture was stirred at -78 C. for 20 minutes and then transferred via a cannula into the reaction flask containing the mixed anhydride at -78 C. The reaction mixture was stirred at 0 C. for 1 hour, then warmed to room temperature and stirred for 18 hours. The mixture was quenched with saturated aqueous ammonium chloride solution (200 mL), concentrated to about half of its original volume under reduced pressure to remove tetrahydrofuran. The remaining mixture was extracted with ethyl acetate (2*250 mL). The organic layer was separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluted with 2:1 ethyl acetate/hexanes to give (S)-3-((E)-pent-2-enoyl)-4-phenyl-oxazolidin-2-one as a white foam (9.9 g, 75%).

Reference： [1]Patent: US2006/41146,2006,A1 .Location in patent: Page/Page column 14

32
[ 99395-88-7 ]
[ 5437-45-6 ]
[ 910322-90-6 ]

Yield	Reaction Conditions	Operation in experiment
83%		To a solution of (4S)-phenyl-2-oxazolidinone (400 mg, 2.45 mmol) in DMF (5 mL) at 0 C. was added NaH (60% in mineral oil, 117 mg, 2.94 mmol), and the reaction mixture was stirred for 5 min. Benzyl-2-bromoacetate (737 muL, 4.65 mmol) was added and the reaction mixture was stirred at 23 C. for 17 h. The reaction mixture was partitioned between 1.0 N HCl (100 mL) and ethyl acetate (200 mL). The organic layer was washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL), dried over Na2SO4, and concentrated in vacuo to yield a brown oil that was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to yield (2-oxo-[4S]-phenyloxazolidin-3-yl) acetic acid benzyl ester (635 mg, 83%).

Reference： [1]Patent: US2006/211603,2006,A1 .Location in patent: Page/Page column 77

33
[ 960613-96-1 ]
[ 99395-88-7 ]
[ 1269646-39-0 ]

Yield	Reaction Conditions	Operation in experiment
79.8%		To a solution of (S)-4-phenyloxazolidin-2-one (0.737 g, 4.517 mmol) in DMF was added sodium hydride (0.189 g, 4.73 mmol) and the reaction stirred at ambient temperature for 45 minutes. 3-Bromo-5-chloropyrazolo[l,5-a]pyrimidine (1.00 g, 4.302 mmol) was added and the reaction stirred at ambient temperature for 3 hours. The reaction mixture was poured into water and the water layer extracted with ether. The combined organic layers were washed with brine, dried over MgSC^ and concentrated in vacuo. The crude material was purified by normal phase chromatography using 2% EtOAc/DCM as the eluent to yield (S)-3-(3-bromopyrazolo[l,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one (1.233 g, 3.433 mmol, 79.80 % yield).

Reference： [1]Patent: WO2011/29027,2011,A1 .Location in patent: Page/Page column 104

34
[ 153505-37-4 ]
[ 99395-88-7 ]
[ 1276025-35-4 ]

Yield	Reaction Conditions	Operation in experiment
13.6%	With rac-diaminocyclohexane; cesium fluoride;copper(l) iodide; In 1,4-dioxane; at 95℃; for 48h;Inert atmosphere;	The compound was synthesized starting from (S)-4-phenyloxazolidin-2-one (1 equiv., 0.328 g, 2 mmol), <strong>[153505-37-4]4-bromo-5-fluorobenzene-1,2-diamine</strong> (1 equiv., 0.412 g, 2 mmol), copper(I) iodide (0.1 equiv., 0.040 g, 0.2 mmol), cesium fluoride (2 equiv., 0.608 g, 4 mmol), cyclohexane-1,2-diamine (0.1 equiv., 0.024 mL, 0.2 mmol). The dried solids were given together in a reaction flask and the flask was purged with argon. A solution of cyclohexane-1,2-diamine in 4 mL dioxane was added to the flask. The reaction was stirred at 95 C. for 48 hours, before the reaction was cooled down to 45 C. and filtered through a pad of CELITE. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate product was purified via FPLC using a chloroform-methanol gradient (0?10%, product elutes at about 5%).Yield: 0.078 g (13.6%)

Reference： [1]Patent: US2011/92501,2011,A1 .Location in patent: Page/Page column 142

35
[ 153505-37-4 ]
[ 99395-88-7 ]
(S)-3-(6-fluoro-1H-benzo[d]imidazol-5-yl)-4-phenyloxazolidin-2-one trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2011/92501,2011,A1

36
[ 21304-38-1 ]
[ 99395-88-7 ]
[ 1276022-79-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With rac-diaminocyclohexane; cesium fluoride;copper(l) iodide; In 1,4-dioxane; at 95℃; for 20h;Inert atmosphere;	The compound was synthesized as trifluoroacetate salt starting from (S)-4-phenyloxazolidin-2-one (1 equiv., 0.163 g, 1 mmol), 4-iodobenzene-1,2-diamine (1 equiv., 0.234 g, 1 mmol), copper(I) iodide (0.1 equiv., 0.019 g, 0.1 mmol), cesium fluoride (2 equiv., 0.304 g, 2 mmol), cyclohexane-1,2-diamine (0.1 equiv., 0.012 mL, 0.1 mmol). The solids were given together in a reaction flask and the flask was purged with argon. A solution of cyclohexane-1,2-diamine in 4 mL dioxane was added to the flask. The reaction was stirred at 95 C. for 20 hours, before the reaction was cooled down to 45 C. and filtered through a pad of celite. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate product was purified via FPLC using a chloroform-methanol gradient (0?10%, product elutes at about 5%). Yield: 0.215 g (80%); MS m/z 270.3 (M+H)+ The (S)-3-(3,4-diaminophenyl)-4-phenyloxazolidin-2-one was dissolved in 12 mL of triethyl orthoacetate and the reaction was stirred at 150 C. for 0.5 h before the reaction was cooled down. The excess of triethyl orthoacetate was removed under reduced pressure. The final product was purified by means of FPLC using chloroform-methanol gradient (0?10%), followed by preparative HPLC using a water-acetonitrile gradient with 0.04% trifluoroacetic acid.Yield: 0.095 g (23.3%); MS m/z 294.2 (M+H)+; 1H NMR (400 MHz, DMSO-D6): delta 2.67 (s, 3H); 4.16-4.20 (m, H); 4.85-4.89 (m, H); 5.79-5.83 (m, H); 7.24-7.40 (m, 5H); 7.49 (dd, H, 3J=9.1 Hz, 4J=2.1 Hz); 7.63 (d, H, 3J=9.1 Hz); 7.76 (d, H, 4J=2.1 Hz), HPLC (lambda=214 nm), [B]: rt 8.69 min (100%).

Reference： [1]Patent: US2011/92501,2011,A1 .Location in patent: Page/Page column 118

37
[ 76153-06-5 ]
[ 99395-88-7 ]
[ 1276025-31-0 ]

Reference： [1]Patent: US2011/92501,2011,A1

38
[ 76153-06-5 ]
[ 99395-88-7 ]
[ 1276025-32-1 ]

Yield	Reaction Conditions	Operation in experiment
	With rac-diaminocyclohexane; cesium fluoride;copper(l) iodide; In 1,4-dioxane; at 95℃; for 48h;Inert atmosphere;	The compound was synthesized starting from (S)-4-phenyloxazolidin-2-one (1 equiv., 0.326 g, 2 mmol), <strong>[76153-06-5]5-bromo-3-methylbenzene-1,2-diamine</strong> (1 equiv., 0.402 g, 2 mmol), copper(I) iodide (0.1 equiv., 0.038 g, 0.2 mmol), cesium fluoride (2 equiv., 0.605 g, 4 mmol), cyclohexane-1,2-diamine (0.1 equiv., 0.024 mL, 0.2 mmol). The solids were given together in a reaction flask and the flask was purged with argon. A solution of cyclohexane-1,2-diamine in 10 mL dioxane was added to the flask. The reaction was stirred at 95 C. for 48 hours, before the reaction was cooled down to 45 C. and filtered through a pad of CELITE. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate product was purified via FPLC using a chloroform-methanol gradient (0?10%, product elutes at about 5%).

Reference： [1]Patent: US2011/92501,2011,A1 .Location in patent: Page/Page column 142

39
[ 517920-69-3 ]
[ 99395-88-7 ]
[ 1276025-38-7 ]

Yield	Reaction Conditions	Operation in experiment
	With rac-diaminocyclohexane; cesium fluoride;copper(l) iodide; In 1,4-dioxane; at 95℃; for 48h;Inert atmosphere;	The compound was synthesized starting from (S)-4-phenyloxazolidin-2-one (1 equiv., 0.082 g, 0.5 mmol), <strong>[517920-69-3]5-bromo-3-fluorobenzene-1,2-diamine</strong> (1 equiv., 0.103 g, 0.5 mmol), copper(I) iodide (0.1 equiv., 0.010 g, 0.05 mmol), cesium fluoride (2 equiv., 0.152 g, 1 mmol), cyclohexane-1,2-diamine (0.1 equiv., 0.006 mL, 0.05 mmol). The dried solids were given together in a reaction flask and the flask was purged with argon. A solution of cyclohexane-1,2-diamine in 4 mL dioxane was added to the flask. The reaction was stirred at 95° C. for 48 hours, before the reaction was cooled down to 45° C. and filtered through a pad of CELITE.(R).. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate product was purified via FPLC using a chloroform-methanol gradient (0-->10percent, product elutes at about 5percent).

Reference： [1]Patent: US2011/92501,2011,A1 .Location in patent: Page/Page column 142

40
[ 517920-69-3 ]
[ 99395-88-7 ]
(S)-3-(7-fluoro-1H-benzo[d]imidazol-5-yl)-4-phenyloxazolidin-2-one trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2011/92501,2011,A1

41
[ 1266549-09-0 ]
[ 99395-88-7 ]
[ 1266549-11-4 ]

Yield	Reaction Conditions	Operation in experiment
85%		Step 1 : To a 1 liter flask were added 39.21 grams (0.116 mol) compound L-1 (Z configuration), 300 ml of tetrahydrofuran and 19.0 ml (0.14ml) of isobutyl chloroformate. Then, 19.3 ml (0.14mmol) of triethylamine was added dropwise therein at a temperature of about -60C. After the addition, the mixture was warmed up to room temperature and the reaction lasted 30 minutes. The residue was filtered to obtain the mixed anhydride in tetrahydrofuran solution for further use. Step 2: To a 3 liter flask were added 22.69 grams (0.14ml) (S)-4-phenyl-2-oxazolidone and 0.6 liter of tetrahydrofuran . Then, 69.6 ml (2mol/L) of sodium bis(trimethylsilyl)amide was added dropwise therein at about -25C. The reaction lasted 30 minutes. Then, the tetrahydrofuran solution of mixed anhydride obtained from step 1 was added dropwise therein. After the addition, the mixture was warmed up to room temperature and the reaction lasted 1 hour. The residue was extracted 3 times with ethyl acetate (150 mlx3). The organic phases were combined, washed 3 times with brine, dried over anhydrous sodium sulfate and concentrated till dry to obtain 47.62 grams (0.10 mol) of compound III-1 (Z configuration), with the yield of 85%. 1H NMR (400 MHz, CDCl3) : delta 0.05 (s, 6 H, 2×-CH3), 0.86 (s, 9 H, 3×-CH3), 2.59-2.64 (m, 2 H, -CH2-), 3.13-3.18 (m, 2 H, -CH2-), 4.32-4.35 (m, 1 H, -CH2-), 4.52 (s, 2 H, -CH2-), 4.74 (t, 1 H, J = 8.8 Hz, -CH2-), 5.47-5.49 (m, 1 H, -CH-), 5.74 (t, 1 H, J = 7.5 Hz, -CH-), 6.99-7.03 (m, 2 H, Cpr-H), 7.31-7.41 (m, 7 H, Cpr-H); MS (m/z): 506 [M+Na].

Reference： [1]Patent: EP2465847,2012,A1 .Location in patent: Page/Page column 14; 21

42
[ 79-03-8 ]
[ 99395-88-7 ]
[ 184363-66-4 ]

Reference： [1]Organic Process Research and Development,2005,vol. 9,p. 827 - 829
[2]Research on Chemical Intermediates,2015,vol. 41,p. 749 - 760

43
(4S)-3-[(3R)-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4-phenyl-2-oxazolidinone [ No CAS ]
(βR)-ethyl-3-(phenylmethoxy)benzenepropanoic acid [ No CAS ]
[ 99395-88-7 ]

Yield	Reaction Conditions	Operation in experiment
92%; 3.9 g	With dihydrogen peroxide; lithium hydroxide; In tetrahydrofuran; water; at 20℃; for 4h;Cooling with ice;	Example 23 (betaR)-ethyl-3-(phenylmethoxy)benzenepropanoic acid [0108] 22 (11g, 25.6 mmol) was dissolved in tetrahydrofuran/ water (v/v = 4/1) in an ice-water bath, 30% hydrogen peroxide (3.2ml, 100mmol) and lithium hydroxide (1.0g, 43.5mmol) aqueous solution were added dropwise in sequence, then it was slowly warmed to room temperature and the reaction was continued for 4 hours. After that, sodium sulfite aqueous solution (2.5M, 40ml) was added dropwise to the reaction liquid, the reaction was carried out with stirring for 10 minutes, the reaction solution was concentrated to remove tetrahydrofuran, then extracted with dichloromethane for 3 times, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and recovered to give 4S-phenyl oxazolidin-2-one 3.9g. The pH of the aqueous phase was adjusted to appropreate 2 with 1N hydrochloric acid, then extracted with dichloromethane for three times, after that, the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and recrystallized with petroleum ether and ethyl acetate to give a white solid 6.7 g, yield: 92%. 1HNMR(300MHz, CDCl3): delta 7.3-7.5(5H, m), 7.2(1H, t, J=7.6,15.2), 6.8-6.9(3H, m), 5.0(2H, s), 3.0(1H, m), 2.6-2.7(2H, m), 1.7-1.8(1H, m), 1.6-1.7(1H, m), 0.8(3H, t, J=7.3,14.7). ESI-MS: 283.1(M-H).

Reference： [1]Patent: EP2671878,2013,A1 .Location in patent: Paragraph 0108; 0109

44
[ 33698-85-0 ]
[ 99395-88-7 ]
[ 174485-45-1 ]

Yield	Reaction Conditions	Operation in experiment
95%		Example 21 (S,E)-3-(pent-2-enoyl)-4-phenyl oxazolidin-2-one The 4S-phenyl-2-oxazolidinone (5.6g, 34.4mmol) was placed in a three-necked flask, after it was purged with nitrogen, tetrahydrofuran was added and it was cooled to -78C, then n-butyl lithium (1.6M, 22ml, 35.4mmol) was added dropwise, and the reaction was carried out for 30 minutes. After that, a solution of 2-pentenoyl chloride (4.2g, 35.5mmol) in tetrahydrofuran was added dropwise, and the reaction was continued for 30 minutes, then it was slowly raised to 0C, the reaction was continued for 2 hours and quenched with saturated ammonium chloride solution. The reaction solution was then concentrated to remove tetrahydrofuran and extracted with ethyl acetate 3 times, then the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and recrystallized with petroleum ether and ethyl acetate to give a white solid 8g, yield: 95%. 1HNMR(300MHz, CDCl3): delta 7.3-7.4(5H, m), 7.1-7.2(1H, m), 6.9-7.1(1H, m), 5.5(1H, dd, J=4.2,19.0), 4.8(1H, t, J=9.6, 18.7), 4.2(1H, dd, J=3.7,18.9), 2.2(2H, m), 1.0(3H, t, J=7.4,14.9). ESI-MS: 246.4(M+H).
95%		Example 21 (S,E)-3-(pent-2-enoyl)-4-phenyl oxazolidin-2-one The 4S-phenyl-2-oxazolidinone (5.6 g, 34.4 mmol) was placed in a three-necked flask, after it was purged with nitrogen, tetrahydrofuran was added and it was cooled to -78 C., then n-butyl lithium (1.6M, 22 ml, 35.4 mmol) was added dropwise, and the reaction was carried out for 30 minutes. After that, a solution of 2-pentenoyl chloride (4.2 g, 35.5 mmol) in tetrahydrofuran was added dropwise, and the reaction was continued for 30 minutes, then it was slowly raised to 0 C., the reaction was continued for 2 hours and quenched with saturated ammonium chloride solution. The reaction solution was then concentrated to remove tetrahydrofuran and extracted with ethyl acetate 3 times, then the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and recrystallized with petroleum ether and ethyl acetate to give a white solid 8 g, yield: 95%. 1HNMR (300 MHz, CDCl3): delta 7.3-7.4 (5H, m), 7.1-7.2 (1H, m), 6.9-7.1 (1H, m), 5.5 (1H, dd, J=4.2, 19.0), 4.8 (1H, t, J=9.6, 18.7), 4.2 (1H, dd, J=3.7, 18.9), 2.2 (2H, m), 1.0 (3H, t, J=7.4, 14.9). ESI-MS: 246.4 (M+H).

Reference： [1]Patent: EP2671878,2013,A1 .Location in patent: Paragraph 0104; 0105
[2]Patent: US2014/46074,2014,A1 .Location in patent: Paragraph 0191-0192

45
[ 1775-44-6 ]
[ 3282-30-2 ]
[ 99395-88-7 ]
[ 194031-58-8 ]

Yield	Reaction Conditions	Operation in experiment
93%		To the solution of (2E)-isohexenoic acid (2.67 g, 23.4 mmol)and Et3N (2.5 equiv) in THF (volume corresponded to 0.2 M of theoxazolidinone) was added trimethylacetyl chloride (2.62 g,21.7 mmol) at 20 C. A white solid was formed instantaneously.The mixture was stirred at 20 C for 2.0 h. Lithium chloride(0.92 g, 21.6 mmol) was added, followed by the oxazolidinone(2.92 g, 17.9 mmol). The mixture was allowed to warm to roomtemperature slowly and stirred for 4.0 h. The reaction wasquenched by addition of saturated NH4Cl and the solution wasextracted with EtOAc. The organic layer was washed subsequentlywith saturated NaHCO3, brine and water, dried over anhydrous Na2SO4 and filtered. EtOAc was removed in vacuo, and the residuewas purified by flash column chromatography (silica gel, 12% EtOAcin petroleum ether) provided the desired product 15 (4.33 g, 93%);1H NMR (300 MHz, CDCl3) d 7.40e7.30 (m, 5H), 7.22 (dd, J15.6,1.2 Hz, 1H), 7.05 (dd, J15.6, 6.6 Hz, 1H), 5.48 (dd, J8.7, 3.9 Hz, 1H),4.68 (t, J9.0 Hz, 1H), 4.26 (dd, J9.0, 3.9 Hz, 1H), 2.52 (m, 1H), 1.07(d, J6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 165.0, 158.2, 153.8,139.2, 129.1 (2C), 128.6, 126.0 (2C), 117.6, 69.8, 57.6, 31.3, 21.1, 21.0.

Reference： [1]Tetrahedron,2014,vol. 70,p. 7753 - 7762

46
(S)-3-(4-chlorophenyl)-3-(6-methoxypyridin-3-yl)propanoic acid [ No CAS ]
[ 99395-88-7 ]
(S)-3-((S)-3-(4-chlorophenyl)-3-(6-methoxypyridin-3-yl)propanoyl)-4-phenyloxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		To a precooled (0 C) solution of (S)-3-(4-chlorophenyl)-3-(6-methoxypyidin-3- yl)propanoic acid (3.30 g, 1 1.3 mmol) in THF (30.0 mL) was added pivolyl chloride (1.39 mL, 1 1.3 mmol), DMAP (cat) and triethylamine (3.15 mL, 22.6 mmol) drop-wise and stirred for 1 h. In another precooled (-78 C) suspension of (S)-4-phenyloxazolidin-2-one (2.03 g, 12.4 mmol) in THF (10.0 mL) was added ra-BuLi (2.50 M solution in hexanes, 9.30 mL, 14.9 mmol) drop- wise and stirred at -20 C for 1 h. The solution of the above mixed anhydride was added slowly and stirred for additional 3 h. The reaction mixture was quenched with saturated solution of NH4CI (250 mL) and extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were washed with brine (200 mL), dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified on 40 g S1O2 column using using a gradient elution of 0-40% EtOAc in hexanes. Fractions containing the product were combined and concentrated under reduced pressure to provide the product (3.20 g, 65%) as white solid. MS: m/z = 437 (M+H+).
65%		Step 4. (5)-3-((5)-3-(4-Chlorophenyl)-3-(6-methoxypyridin-3-yl)propanoyl)-4-phenyloxazolidin- 2-one To a precooled (0 C) solution of (5)-3-(4-chlorophenyl)-3-(6-methoxypyidin-3- yl)propanoic acid (3.30 g, 11.3 mmol) in THF (30.0 mL) was added pivolyl chloride (1.39 mL, 1 1.3 mmol), DMAP (cat) and triethylamine (3.15 mL, 22.6 mmol) drop-wise and stirred for 1 h. In another precooled (-78 C) suspension of (5)-4-phenyloxazolidin-2-one (2.03 g, 12.4 mmol) in THF (10.0 mL) was added w-BuLi (2.50 M solution in hexanes, 9.30 mL, 14.9 mmol) drop- wise and stirred at -20 C for 1 h. The solution of the above mixed anhydride was added slowly and stirred for additional 3 h. The reaction mixture was quenched with saturated solution of NH4C1 (250 mL) and extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were washed with brine (200 mL), dried ( a2S04), filtered and concentrated under reduced pressure. The residue was purified on 40 g S1O2 column using using a gradient elution of 0-40% EtOAc in hexanes. Fractions containing the product were combined and concentrated under reduced pressure to provide the product (3.20 g, 65%) as white solid. MS: m/z = 437 (M+H+).
		Step 4. (5)-3-((5)-3-(4-Chlorophenyl)-3-(6-methoxypyridin-3-yl)propanoyl)-4- phenyloxazolidin-2-one (0330) (0331) To a precooled (0 C) solution of (5)-3-(4-chlorophenyl)-3-(6-methoxypyidin-3- yl)propanoic acid (3.30 g, 1 1.3 mmol) in THF (30.0 mL) was added pivolyl chloride (1.39 mL, 1 1.3 mmol), DMAP (cat) and triethylamine (3.15 mL, 22.6 mmol) drop-wise and stirred for 1 h. In another precooled (-78 C) suspension of (5)-4-phenyloxazolidin-2-one (2.03 g, 12.4 mmol) in THF (10.0 mL) was added w-BuLi (2.50 M solution in hexanes, 9.30 mL, 14.9 mmol) drop- wise and stirred at -20 C for 1 h. The solution of the above mixed anhydride was added slowly and stirred for additional 3 h. The reaction mixture was quenched with saturated solution of NH4CI (250 mL) and extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were washed with brine (200 mL), dried ( a2S04), filtered and concentrated under reduced pressure. The residue was purified on 40 g S1O2 column using using a gradient elution of 0-40% EtOAc in hexanes. Fractions containing the product were combined and concentrated under reduced pressure to provide the the title product. MS: m/z = 437 (M+H)+.

Reference： [1]Patent: WO2015/13835,2015,A1 .Location in patent: Page/Page column 38; 39
[2]Patent: WO2015/17393,2015,A2 .Location in patent: Page/Page column 34; 35
[3]Patent: WO2015/138220,2015,A1 .Location in patent: Page/Page column 36

47
(S)-3-(4-chlorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)propanoic acid [ No CAS ]
[ 99395-88-7 ]
(S)-3-((S)-3-(4-chlorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)propanoyl)-4-phenyloxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		To a precooled (0 C) solution of (S)-3-(4-chlorophenyl)-3-(5- (trifluoromethyl)pyridin-3-yl)acrylicacid (1.30 g, 3.94 mmol) in THF (10.0 mL) was added pivolyl chloride (570 mg, 4.73 mmol), DMAP (cat), followed by triethylamine (796 mg, 7.88 mmol) and stirred for 1 h. In another precooled (0 C) suspension of 60% NaH (7.88 mmol) in THF, was added (S)-4-phenyloxazolidin-2-one (772 mg, 4.73 mmol) in THF (10.0 mL) drop- wise and stirred at 0 C for 1 h. The mixed anhydride was added to the reaction mixture and stirred for another 5 h. The reaction mixture was quenched with water (20.0 mL) and extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were washed with brine (100 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified on 12 g S1O2 using a gradient elution of 0-20% EtOAc in hexanes. Fractions containing the product were combined and concentrated under reduced pressure to provide the product (1.40 g, 76%) as a white solid. MS: m/z = 475 (M+H+).
76%		Step 4. (5)-3-((5)-3-(4-Chlorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)propanoyl)-4- phenyloxazolidin-2-one To a precooled (0 C) solution of (5)-3-(4-chlorophenyl)-3-(5- (trifluoromethyl)pyridin-3-yl)acrylicacid (1.30 g, 3.94 mmol) in THF (10.0 mL) was added pivolyl chloride (570 mg, 4.73 mmol), DMAP (cat), followed by triethylamine (796 mg, 7.88 mmol) and stirred for 1 h. In another precooled (0 C) suspension of 60% NaH (7.88 mmol) in THF, was added (5)-4-phenyloxazolidin-2-one (772 mg, 4.73 mmol) in THF (10.0 mL) drop- wise and stirred at 0 C for 1 h. The mixed anhydride was added to the reaction mixture and stirred for another 5 h. The reaction mixture was quenched with water (20.0 mL) and extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were washed with brine (100 mL), dried ( a2S04), filtered, and concentrated under reduced pressure. The residue was purified on 12 g S1O2 using a gradient elution of 0-20% EtOAc in hexanes. Fractions containing the product were combined and concentrated under reduced pressure to provide the product (1.40 g, 76%) as a white solid. MS: m/z = 475 (M+H+).

Reference： [1]Patent: WO2015/13835,2015,A1 .Location in patent: Page/Page column 49
[2]Patent: WO2015/17393,2015,A2 .Location in patent: Page/Page column 44

48
(E)-pent-2-enoic anhydride [ No CAS ]
[ 99395-88-7 ]
[ 174485-45-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine; lithium chloride; In tetrahydrofuran; at -20 - 20℃; for 60h;	99B. (S,E)-3-(Pent-2-enoyl)-4-phenyloxazolidin-2-one To a light suspension of (S)-4-phenyloxazolidin-2-one (3.8 g, 23 mmol), lithium chloride (1.017 g, 24 mmol) and triethylamine (4.32 mL, 31 mmol) in THF (50 mL) at -20 C. was added (E)-pent-2-enoic anhydride (5.09 g, 27.9 mmol) dropwise. After completion of addition, the cold bath was removed and the mixture was allowed to warm to rt. The mixture was stirred at rt for 2.5 days and the resulting thick suspension was diluted with EtOAc. The mixture was washed sequentially with 0.2M HCl, sat'd NaHCO3, water and sat'd NaCl. The organic layer was dried (Na2SO4) and concentrated to give an orange liquid which was purified via silica gel chromatography to afford (the desired product (4.37 g, 76% yield) as a white solid: LC-MS [M+H] 246.

Reference： [1]Patent: US9133163,2015,B2 .Location in patent: Page/Page column 113

49
[ 2935-35-5 ]
[ 105-58-8 ]
[ 99395-88-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sulfuric acid; potassium carbonate In toluene at 70 - 75℃; for 1.5h;	6-7 Preparation of compound 10: Add potassium carbonate (8.22g) and compound 9 (10g) to the solvent toluene (80g), raise the temperature to 70°C and stir; slowly add 8.6g diethyl carbonate dropwise under the control of the system at 75°C, and keep it warm after dripping. Stir and react for 1.5h. After the heat preservation is completed, atmospheric distillation is carried out. When the internal temperature is 95°C, an azeotrope of toluene and water will flow out. After the distillation, the temperature of the system will be lowered to below 40°C; after replacing the system with nitrogen, under nitrogen protection Add potassium carbonate (2g) in batches, stir and raise the temperature after the addition is complete; keep the temperature at 100°C and reflux for 30 minutes and then cool to below 40°C; add acetic acid (1.5g) and water (33g) dropwise; after the addition, cool the system to 10°C After stirring for 1 hour, (S)-4-phenyl-2-oxazolidinone compound 10 was obtained by filtration with a yield of 83%.
77%	With potassium carbonate at 130 - 140℃;	4.2.1 Synthesis of (R,S) 4-phenyloxazolidin-2-one 13 General procedure: A dry 250ml three-necked round bottom flask equipped with a thermometer and a 10cm vigreux column with a distillation head, was charged with 4.3g of the (R,S)-phenylglycinol (31.4mmol) obtained and added of 9.3g of diethyl carbonate (79.0mmol) and 0.43g of K2CO3 (3.10mmol). The mixture was heated carefully to 130-140°C and the ethanol was distils as it formed. The oily residue was cooled and added by 50ml of CH2Cl2 to facilitate the filtration of the remaining potassium carbonate. The organic phase was then washed with a satured solution of NaHCO3, separated and dried over anhydrous Na2SO4, filtrate and evaporated in vacuo. The residue was crystallized from AcOEt/Etp (1:3) to afford 4.3g (26.4mmol, 85%) of 13 as a white solid.

Reference： [1]Current Patent Assignee: GANSU BEISHENG KANGDE PHARMACEUTICAL - CN112724096, 2021, A Location in patent: Paragraph 0021-0022
[2]Zampieri, Daniele; Vio, Luciano; Fermeglia, Maurizio; Pricl, Sabrina; Wünsch, Bernhard; Schepmann, Dirk; Romano, Maurizio; Mamolo, Maria Grazia; Laurini, Erik [European Journal of Medicinal Chemistry, 2016, vol. 121, p. 712 - 726]

50
[ 99395-88-7 ]
[ 36239-09-5 ]
ethyl 3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		In a 500 ml three-necked flask, 20 g (0.122 mol, leq.) Of the (s) -4-phenyl-2-oxazolone raw material and tolueneWas cooled to between 0 and 10 C, and 22 g (0.146 piomicron1, 1.2 eq.) Of t-butyldimethylchlorosilane was added and maintained at 0 toL0 C for 30 minutes under stirring, diisopropylethylamine 19.6g (0.152mall, 1.25eq.), Dropping the process to control the material temperatureAfter 0-10 C, the mixture was stirred at 0-10 C for 2 hours until the (S) -4-phenyl-2-oxazolone was subjected to TLCThe reaction was completed (TLC conditions: petroleum ether / ethyl acetate = 2/1). Then 36.7 g monoethyl malonate chloride was added(0.244piomicron1,2 eq.), Dropping process control the material temperature between 0 ~ 10 C, after the completion of the drop by adding 0.32g anhydrous fourButyl ammonium fluoride (TBAF, 1.2 O1, O. Oleq.) Was added and the reaction was stirred at room temperature for 2-5 hours. After completion of the reaction, the reaction solution was addedPoured into 200 ml of ice water and stirred at room temperature for 30 minutes. The organic phase was separated and the organic phase was washed with 10% sodium carbonate solution,The organic phase was evaporated to dryness to give a crude product. To the crude product isopropyl alcohol l0ml, stirring at 10 ~ 15 C 2 small, And dried to obtain 31.4 g of a product compound in a yield of 93%.
90%		(S) -3-oxo-3- (2-oxo-4-phenyloxazolin-3-yl)Propionic acidEthyl ester,The structure is as follows:In a 500 ml three-necked flask,Join(S) -4-phenyl-2-oxazolone(0.122 mol, 1 eq.) AndDichloromethane 200 ml,Cooling to between 0 and 10 C,16 g (0.146 mol, 1.2 eq.) Of the TMSCl starting material was added,The mixture was stirred at 0 to 10 C for 30 minutes,15.4 g (0.152 mol, 1.25 eq.) Of triethylamine was added dropwise,Dropping process control material temperature between 0 ~ 10 ,After completion of the dropwise addition,Stirring was continued at 0 to 10 C for 2 hours((S) -4-phenyl-2-oxazolone TLC detection reaction was completed (TLC detection conditions:Petroleum ether / ethyl acetate = 2/1).Then 36.8 g was addedMalonic acidMonoethyl ester chloride (0.245 mol, 2 eq.) Was added dropwiseProcess control of material temperature at0 to 10 C,After completion of the dropwise addition,0.2 g of anhydrous tetrabutylammonium fluoride (TBAF,Gt; mmol, 0.005 eq.),The reaction solution was stirred at room temperature for 2 to 5 hours.After completion of the reaction,The reaction solution was poured into 200 mlIce-water, and the mixture was stirred at room temperature for 30 minutes,The organic phase was separated and the organic phase was washed with 10% sodium carbonate solution,The organic phase was separated and the organic phase was evaporated to dryness to give a crude product. To the crude product was added 100 ml of isopropanolStirred at 20 to 25C for 2 hours, and suction-filtered to obtain a white solid powder, which was dried to obtain 30.4 g of the product compound,Yield 90%,

Reference： [1]Patent: CN105524010,2016,A .Location in patent: Paragraph 0051; 0052; 0053
[2]Patent: CN105439929,2016,A .Location in patent: Paragraph 0033; 0034; 0035; 0036

51
[ 99395-88-7 ]
[ 814-68-6 ]
[ 259529-54-9 ]

Yield	Reaction Conditions	Operation in experiment
93%		In three 500ml flask, was added ( s) -4- phenyl-2-oxazolone 20g (0.122mol, 1eq.) And dichloromethane 200ml, cooled to between 0 ~ 10 , was added chlorotrimethylsilane 15.86g (0.146mol, 1.2eq.), kept under stirring at 0 ~ 10 30 minutes, a solution of diisopropylethylamine 39.30g (0.305mol, 2.50eq.), was added dropwise in the temperature control of the material during 0 ~ between 10 , after completion of the dropwiseaddition, stirring was continued for 2 hours at 0 ~ 10 until (s) -4- phenyl-2-oxazolone starting material by TLC the reaction was complete (monitored by TLC conditions: petroleum ether / ethyl acetate acetate = 2/1).acryloyl chloride WAS the then added 15.46 g (0.171 mol, 1.4 eq.), at The temperature at The Control of Material's at The Addition During the BETWEEN 0 ~ 10 deg.] C, the After Addition at The Complete WAS, WAS added of 1.6 g of anhydrous Tetrabutylammonium fluoride (of TBAF, 6.1 mmol, 0.05 eq.), at The Reaction WAS AT Stirred Room temperature for 2 hours.the After Completion of at The Reaction, Reaction Solution at The WAS Poured INTO ICE 200ml of Water, and Stirred AT Room temperature for 30 minutes, at The Organic Phase WAS Separated, at The Organic Phase WAS Washed the with 10% (wt) WAS Washed the with Sodium bicarbonate Solution, at The Organic Phase WAS Separated, Evaporated to Dryness to give at The crude Product the After at The Organic Phase.Isopropyl alcohol WAS added to at The crude Product 100ml, Stirred AT 25 Suction Filtration hours to 2 deg.] C to give A White Solid Powder, and dried to give Compound at The Product 24.6 g, a yield 93%.1

Reference： [1]Patent: CN105541742,2016,A .Location in patent: Paragraph 0052; 0053; 0054; 0055

52
[ 99395-88-7 ]
[ 149437-76-3 ]
[ 189028-95-3 ]

Yield	Reaction Conditions	Operation in experiment
		This invention adopts the "one-pot synthesis" according to bookletmai Bu intermediates for the synthesis of (4S)-3-[ (5S)-5-(4-fluoro phenyl)-5-hydroxy- fifth heavenly stem acyl group ]-4-phenyl -1, 3-oxygen nitrogen heterocyclic pentane-2-one (II), has the advantage of short synthetic route. One-pot synthesis (one-potreaction) is a high-efficiency organic synthetic method. "One-pot synthesis" in the reaction step from the reaction can be a plurality of relatively simple proceeding easily available raw materials, without intermediate separation, direct access to the molecules of the complex structure, thus having the advantage of the cost of synthesizing, and friendly to the environment.Firstly the 42g compound (I) dissolved in 420 ml in the reaction solution. The reaction solution includes: tetrahydrofuran, chloroform, dioxane or dichloromethane, and most preferably dichloromethane. In this embodiment, the reaction solution is dichloromethane, then added into the 1L three-necked bottle , will three-necked bottle is placed over the magnetic stirring device to mix uniformly to perform mechanical stirring. Compound (I) shown in the chemical structural formula as follows:In three-necked bottle is placed in the ice bath, ice-bath temperature is kept at 0 C three-necked bottle in until the oven is not higher than 10 C. Successive adds by drops Fu Suanji 30 ml and pivalyl chloride 75 ml. In this embodiment, the fu Suanji in particular to triethylamine. three-necked bottle is maintained during the dropping of the oven is not higher than 15 C. fu Suanji can absorb the acid generated in the reaction, a weakly alkaline substance with an acid salt, avoid acid influence the reaction or reaction balance. fu Suanji including triethylamine, pyridine, sodium methoxide or potassium hydroxide, and most preferably triethylamine. pivalyl chloride is an acylation reagent, pivaloyl chloride in organic synthesis in organic molecules can be oxygen, nitrogen, carbon, sulfur atom is introduced to the acyl.Triethylamine and pivalylchlorine instillment to room temperature reaction after 4 hours. Adding ice-bath to the oven is not higher than 10 C, dropwise S-4-phenyl-2-oxazolidinone 20g and N, N-dimethyl formamide 200 ml of the mixed solution, keep three-necked bottle the oven is not higher than 20 C, dropping temperature to reflux temperature of the reaction 2 hours. S-4-phenyl-2-oxazolidinone is an important pharmaceutical intermediates, is mainly used for asymmetric chiral organic synthesis.Salt bath to the oven is not higher than 0 C, successive instillment borane dimethyl sulfide 15 ml and (R)-2-methyl-CBS-oxazole borane 7.5 ml, maintain the oven is not higher than in three-necked bottle 5 C, after dropping temperature to stirring the mixture at room temperature for 30 minutes, add 150 ml dichloromethane, the reaction continued at room temperature for 3 hours. Borane dimethyl sulfide with synthesizing chiral the positioning function.Dropwise 300 ml quenching reaction of methanol, is added to the system again 100ml5% hydrogen peroxide and 20ml2N sulfuric acid, stirring 30 minutes, the organic layer is separated. Using 200ml2N sulfuric acid and 500ml5% wash once all sodium bisulfite solution, concentrating the organic layer to dry. Wherein F is fluoro, Ph is phenyl.Then using 200 ml isopropanol to dissolve residue, dripping 40 ml deionized water. Solid precipitated gradually during the dropping, the stirring at room temperature dropwise 2-3h, filtered, the filter cake drying to obtain 45g white solid.Detection method: high performance liquid chromatography (China Pharmacopoeia 2015 year version of the two-section appendix VD).Octadecyl silane bonds and silica gel as a filler, with cheap acetonitrile mobile phase, column temperature is 40 C, detection wavelength of 245 nm, flow rate is 0.5 ml/min. Isomer and weighed amount of product, respectively, using the mobile phase containing the dissolved and diluted into 0.01 mg/ml, diastereoisomer 0.01 mg/ml, isomer 0.01 mg/ml solution, as the system application solution. Applicability of system solution precision measuring 20ul, into the liquid chromatograph, and record chroatogram, diastereoisomer, vigiv, isomer peak in turn, non-enantiomer of the retention time of about 20 min, the main peak of the retention time of about 15 min, isomer produces the peak about 25 min, the main peak and the degree of separation of the isomer should be more than 2.0.The product weighed for proper amount of mobile phase containing the dissolved and diluted to 1.0 mg/ml solution is used for the solution of the sample. Sample solution taking precise quantity 20ul, into the liquid chromatograph, calculated normalization according to the area, such as in the chromatogram of the sample corresponding to isomer chromatographic peaks, the peak area of the isomer should not be more than the main peak and the sum of the peak area of 0.1%.Chromatographic conditions and system suitability test: with octadecyl silane bo...

Reference： [1]Patent: CN105237492,2016,A .Location in patent: Paragraph 0021-0034

53
(S)-5-(4-fluorophenyl)-5-hydroxypentanoic acid [ No CAS ]
[ 99395-88-7 ]
[ 1885-14-9 ]
C₂₇H₂₄FNO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.9%		The compounds of formula 21.2g taken with 110ml of DMF was dissolved and replaced with nitrogen, cooled to -10 ~ 0 C under nitrogen, temperature control, input portionwise 16g of lithium hydride, insulation 0.5h, slowly dropwise benzyl chloroformate ester 30.2g, control temperature -10 ~ 0 C, after the addition was complete insulation 1h, warmed to 20 ~ 25 C, into S-4- phenyl-2-oxazolidinone 15.5g, feeding ended, insulation, the reaction was complete, water and methyl tert-butyl ether extracts, standing layer, the organic layer was washed with saturated brine, evaporated under reduced pressure to give an oil. With a mixture of ethyl acetate and hexane to crystallize with stirring, suction filtered and washed with hexane, dried in vacuo to give a white solid product 38.8g, yield 92.9%, HPLC purity 94%. Without further purification, can be used directly in the next step.

Reference： [1]Patent: CN105461649,2016,A .Location in patent: Paragraph 0021

54
(S)-5-(4-fluorophenyl)-5-hydroxypentanoic acid [ No CAS ]
[ 3282-30-2 ]
[ 99395-88-7 ]
C₂₅H₂₈FNO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.1%		take 21.2g compound of formula with 110ml of DMF was dissolved and replaced with nitrogen, cooled to -10 ~ 0 C under a nitrogen atmosphere, temperature control, batch input 16g of sodium hydride, insulation 0.5h, pivaloyl chloride was slowly slow dropwise addition of pivaloyl chloride 30.2g, control temperature -10 ~ 0 C, after the addition was complete insulation 1h, warmed to 20 ~ 25 C, into S-4- phenyl-2-oxazolidinone 15.5g, feeding the end of incubation, the reaction completely, washed with water and methyl tert-butyl ether extracts, standing layer, the organic layer was washed with saturated brine, evaporated under reduced pressure to give an oil. With a mixture of ethyl acetate and hexane to crystallize with stirring, suction filtered and washed with hexane, dried in vacuo to give 38.9 g of the white solid, molar yield 93.1%, HPLC purity 95.8%. Without further purification, can be used directly in the next step. 1H NMR (400MHz, CDCl3) delta7.393-7.313 (m, 3H), 7.280-7.220 (m, 2H), 6.990 (t, J = 8.6,2H), 5.632 (dd, J = 6.0,7.6 , 1H), 5.394 (dd, J = 3.6,8.4,1H), 4.679 (t, J = 8.8,, 1H), 4.272 (dd, J = 3.6,9.2,1H), 3.016-2.886 (m, 2H) , 1.931-1.598 (m, 4H), 1.174 (s, 9H) . [alpha] D = + 18.703 (C = 1mol / L, methanol).

Reference： [1]Patent: CN105461649,2016,A .Location in patent: Paragraph 0019

55
(S)-5-(4-fluorophenyl)-5-hydroxypentanoic acid [ No CAS ]
[ 99395-88-7 ]
[ 79-22-1 ]
C₂₂H₂₂FNO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.9%		The compounds of formula I 21.2g taken with 110ml of DMF was dissolved and replaced with nitrogen, cooled to -10 ~ 0 C under nitrogen, temperature control, input portionwise 16g of lithium hydride, insulation 0.5h, slowly dropwise methyl chloroformate 30.2g, control temperature -10 ~ 0 C, after the addition was complete insulation 1h, warmed to 20 ~ 25 C, into S-4- phenyl-2-oxazolidinone 15.5g, feeding ended, insulation, the reaction was complete, water and methyl tert-butyl ether extracts, standing layer, the organic layer was washed with saturated brine, evaporated under reduced pressure to give an oil. With a mixture of ethyl acetate and hexane to crystallize with stirring, suction filtered and washed with hexane, dried in vacuo to give a white solid product 38.8g, molar yield 92.9%, HPLC purity 95%. Without further purification, can be used directly in the next step.

Reference： [1]Patent: CN105461649,2016,A .Location in patent: Paragraph 0020

56
[ 1878-85-9 ]
[ 99395-88-7 ]
(S)-3-(2-(2-methoxyphenoxy)acetyl)-4-phenyloxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With pivaloyl chloride; triethylamine In toluene at 80℃; Reflux;

Reference： [1]Huang, Gaochao; Shrestha, Ruben; Jia, Kaimin; Geisbrecht, Brian V.; Li, Ping [Organic Letters, 2017, vol. 19, # 7, p. 1820 - 1823]

57
[ 99395-88-7 ]
[ 109-52-4 ]
(4S)-3-pentanoyl-4-phenyl-1,3-oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		MTBE was added to the 1L reaction flask, 69.78 g pentanoic acid (Compound 1a, 1.2 eq.), Sodium bicarbonate (19.1 g, 2.7 eq), nitrogen was cooled to -40 .Specter pivaloyl chloride was slowly added dropwise 82.38 (compound 3a, 1.2 equiv).Kept stirring at -40 10 hours, 31.38 g of anhydrous lithium chloride (1.3 eq.).(S) -4- phenyl-oxazolidin-2-one (compound 2b, 92.91 g) was formulated into a solution of methyl t-butyl ether, was slowly added dropwise to the reaction solution.Warmed to 35 ~ 40 , stirring was continued for 4 hours.Filtered, the filtrate was added sodium hydroxide solution, and sufficiently stirred, the solvent was evaporated under reduced pressure and extracted with a solvent.The organic layer was washed with dilute hydrochloric acid, saturated brine, dried, filtered, and solvent removal, to obtain 125 g of colorless oil (S) -4- phenyl-3-pentanoyl-oxazolidin-2-one (Compound 4b, 90% purity, 89% yield).
243.6 g		To the mixture of n-valeric acid (156.5 g) and dichloromethane (1000 ml), (S)-4- phenyloxazoldin-2-one compound of formula-6a (200 g) and 4-dimethylaminopyridine (29.9 g) were added at 25-30C and stirred for 10 minutes at same temperature. The reaction mixture was cooled to 5-10C. A solution of N,N'-dicyclohexylcarbodiimide (316.1 g) in 200 ml of dichloromethane was slowly added to the reaction mixture at 5-10C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 0-5C and washed the reaction mixture with aqueous HC1 solution followed by water. The obtained organic layer was washed with aqueous sodium carbonate solution followed by water. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with n-heptane. To the obtained residue 1600 ml of n-heptane was added at 25-30C. Heated the reaction mixture to 50-55C and stirred for 15 minutes. The reaction mixture was slowly cooled to 0- 5C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.Yield: 243.6 g. M.R.: 42-45C.

Reference： [1]Patent: CN106008411,2016,A .Location in patent: Paragraph 0060; 0061; 0062; 0063
[2]Patent: WO2018/220646,2018,A1 .Location in patent: Page/Page column 24; 30

58
[ 99395-88-7 ]
[ 189028-95-3 ]

Reference： [1]Patent: CN104513187,2017,B

59
[ 32315-10-9 ]
[ 88026-82-8 ]
[ 99395-88-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With triethylamine In dichloromethane at 0 - 20℃; for 16h;	3 General procedure for the synthesis of oxazolidinone General procedure: To (2S)-2-amino-2-phenylethan-l-ol hydrochloride (9) (1.00 g, 7.30 mmol, 1 equiv) in DCM (35 mL) was added Et3N (2.55 mL, 18.3 mmol, 2.5 equiv). The mixture was cooled to 0 °C, and a solution of triphosgene (2.37 g, 8.00 mmol, 1.1 equiv) in DCM (35 mL) was added dropwise. The mixture was allowed to warm slowly to rt and stirred for 16 h. The mixture was cooled to 0 °C before it was diluted with EtOAc (100 mL) and H20 (100 mL). The mixture was allowed to stir at rt until layers became clear. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, brine, dried over MgSC , filtered, and concentrated. The resultant residue was purified by column chromatography (24 g ISCO EtOAc/hexanes 0 to 100%) to afford (4S)-4-phenyl-l,3- oxazolidin-2-one (10) (0.819 g, 69%): 1HNMR (CDC13) δ: 7.42-7.34 (m, 5H), 5.56 (broad s, 1H), 4.97 (t, 1H), 4.75 (t, 1H), 4.21 (dd, 1H) ppm; MS: (m/e): 164 (M+l).

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - WO2017/192858, 2017, A1 Location in patent: Paragraph 0455

60
[ 99395-88-7 ]
[ 108-12-3 ]
C₁₄H₁₇NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydride; In tetrahydrofuran; mineral oil; at 15 - 30℃;Inert atmosphere; Large scale;	(2) nitrogen protection, will (S)-4 - phenyl -2 oxazolidone (2.5 kg, 15.3 muM) is added to the in tetrahydrofuran (20L), stirring and dissolving, control the temperature of the reaction solution in the 15 - 25 C, batch repeatedly added 60% NaH (625g, 15.6 muM). Feeding after completely, adds by drops differently pivaloyl chloride (1.9 kg, 15.8 muM), to maintain the temperature of the reaction solution is lower than the 30 C. Dropping after completely, thermal insulation reaction 30min. TLC monitoring raw material the reaction is complete. The reaction liquid slowly poured into saturated NH4Cl (40L) in aqueous solution quenching, and the room temperature stirring reaction 2h, layered, separating the organic phase, the aqueous layer and then the extraction of ethyl acetate (15L × 2), the combined organic layer, steaming and to dry. In the concentrate is added to the petroleum ether (4L), full mixing, filtering, results in the type (I - S) compound of formula 3.41 kg. The yield is 90%.

Reference： [1]Patent: CN104058990,2017,B .Location in patent: Paragraph 0115; 0117

61
[ 99395-88-7 ]
[ 638-29-9 ]
(4S)-3-pentanoyl-4-phenyl-1,3-oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.6%		In a reaction flask, tetrahydrofuran (50 mL) was added, (S)-4-phenyloxazol-2-one (5.0 g, 30.6 mmol) was added, and the temperature was cooled to -70 C.; under nitrogen gas protection, the internal temperature was maintained at -65-75 C., 2.5 M n-butyllithium (12.9 mL, 32.2 mmol, 1.05 eq) solution was added dropwise, after the addition, the reaction was conducted for half an hour at a maintained temperature; then the internal temperature was maintained at -65-75 C., valeryl chloride (4.1 g, 34.0 mmol, 1.11 eq) was added dropwise and reacted for 1 hour, and TLC was used to detect the disappearance of (S)-4-phenyloxazol-2-one, and treatment was performed; then the temperature was raised to 0 C., 20 mL saturated aqueous ammonium chloride solution was added and quenched by butyl lithium to separate the phase. The organic phase was concentrated under a reduced pressure. The concentrate was dissolved in 50 mL methylene dichloride, washed with water twice (25 mL×2). The organic phase was dried over 10.0 g anhydrous sodium sulfate for 2 hours; filtered and concentrated under a reduced pressure to give the target product as a white solid (7.4 g, yield 97.6%). (0085) 1H NMR (600 MHz, CDCl3) delta 7.38 (dd, J=8.2, 6.6 Hz, 2H), 7.35-7.31 (m, 1H), 7.31-7.27 (m, 2H), 5.42 (dd, J=8.7, 3.7 Hz, 1H), 4.68 (t, J=8.8 Hz, 1H), 4.27 (dd, J=8.9, 3.7 Hz, 1H), 2.93 (td, J=7.4, 2.6 Hz, 2H), 1.63-1.53 (m, 3H), 1.33 (dtd, J=15.1, 7.6, 5.5 Hz, 2H), 0.89 (t, J=7.4 Hz, 3H). MS (ESI): m/z 248.1 [M+H]+. [alpha]D19 +60.0 (c=1.0 g/100 mL, CHCl3).
86%	With dmap; triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 0 - 5℃;	(S)-4-phenyloxazolidin-2-one (25g), dichloromethane (125 mL) and triethylamine (38 g) were charged into a round bottom flask at room temperature and stirred. To the reactionmixture, DMF (10 mL) and DMAP (5g) were added and stirred. The reaction mass wascooled to 0-5C and added valeryl chloride (23 g). The reaction mass was stirred followedby addition of water (125 mL). The organic layer was separated, washed with HC1 (150mL), sodium bicarbonate solution (150 mL) and distilled under reduced pressure to obtain a residue. To the residue n-Heptane (250 mL) was added under stirring, cooled the reaction mass to 10-15C and filtered. The obtained solid was washed with n-heptane (75 mL), suck dried and dried under vacuum to give the title compound as off-white to pale yellow solid. Yield: 33 g (86%)

Reference： [1]Patent: US2019/359583,2019,A1 .Location in patent: Paragraph 0083-0085
[2]Patent: WO2018/42393,2018,A1 .Location in patent: Page/Page column 22; 23

62
2-(1-(tert-butoxycarbonyl)-3-vinylazetidin-3-yl)acetic acid [ No CAS ]
[ 99395-88-7 ]
(S)-4-phenyl-3-(2-(1-(tert-butoxycarbonyl)-3-vinylazetidine-3-yl)acetyl)oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%		[0728] To a solution of 2-(1-(tert-butoxycarbonyl)-3-vinylazetidin-3-yl)acetic acid (40-3, 1.9 g, 8.12 mmol) in anhydrous THF (30 mL) and cooled to -15 oC was added triethylamine (1.2 mL, 8.93 mmol), followed by dropwise addition of pivaloyl chloride (1.04 mL, 8.52 mmol). The heterogeneous mixture was stirred for 20 min at 0 oC, then re-cooled to -78 oC and stirred for 15 min (solution 1). In a separate flask, (S)-(+)-4-phenyl-2-oxazolidinone (1.32 g, 8.12 mmol) was dissolved in anhydrous THF (30 mL) and cooled to -78 oC. A solution of n-butyl lithium (2.5 M in hexane, 3.2 mL, 8.12 mmol) was added dropwise followed by dropwise addition (15 min) of the mixed anhydride solution (solution 1). The resulting mixture was further stirred for 10 min at -78 oC at which time it was warmed to 0 oC and stirred for 40 min. The reaction mixture was quenched with 10% citric acid (13 mL) and extracted with ethyl acetate (120 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by CombiFlash column chromatography on silica gel (0- 40% EtOAc in hexane) to afford (S)-4-phenyl-3-(2-(1- (tert-butoxycarbonyl)-3-vinylazetidine-3-yl)acetyl)oxazolidin-2-one (40-4, 2.7 g, 87% yield) as white solid.1H NMR (250 MHz, CDCl3) delta ppm 1.41 (s, 9 H), 3.45 (s, 2 H), 3.77 (t, J = 10.71 Hz, 1 H), 3.82 - 3.93 (m, 2 H), 4.29 (dd, J = 8.90, 3.74 Hz, 1 H), 4.70 (t, J = 8.84 Hz, 1 H), 4.95 - 5.12 (m, 2 H), 5.40 (dd, J = 8.62, 3.57 Hz, 1 H), 6.03 (dd, J = 17.41, 10.71 Hz, 1 H), 7.24 - 7.44 (m, 5 H). MS: [M+H]+ = 386.6.

Reference： [1]Patent: WO2017/223349,2017,A1 .Location in patent: Paragraph 0728

63
4-[2-(4-fluoro-phenyl)-[1,3]dithiolan-2-yl]butyric acid [ No CAS ]
[ 99395-88-7 ]
4-[2-(4-Fluoro-phenyl)-[1,3]dithiane-2-yl]-butyryl-4-phenyl-oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.1%		In anhydrous and oxygen-free environment, 36g of 4-[2-(4-fluoro-phenyl)-[1,3]dithiacyclolan-2-yl]-butyric acid (IV) was added and 300ml of dichloromethane was added. Add 50ml triethylamine,A mixture of 20 ml of pivaloyl chloride and 50 ml of tetrahydrofuran was added dropwise at a temperature of -20C to -10C and reacted for 2 hours. Add 6.4g of anhydrous lithium chloride and stir for 2 hours.27g 4-phenyl-2-oxazolidone was added and the reaction mixture was stirred for 5-7 h, extracted,Crystalline Intermediate VI, yield 96.1%.
96.1%		In anhydrous and oxygen-free environment, 36g of 4-[2-(4-fluoro-phenyl)-[1,3]dithiacyclolan-2-yl]-butyric acid (IV) was added and 300ml of dichloromethane was added. Add 50ml triethylamine,A mixture of 20 ml of pivaloyl chloride and 50 ml of tetrahydrofuran was added dropwise at a temperature of -20C to -10C and reacted for 2 hours. Add 6.4g of anhydrous lithium chloride and stir for 2 hours.27g 4-phenyl-2-oxazolidone was added and the reaction mixture was stirred for 5-7 h.The intermediate VI was extracted and crystallized. The yield was 96.1%.
96.1%		In anhydrous and oxygen-free environment, 36g of 4-[2-(4-fluoro-phenyl)-[1,3]dithiacyclolan-2-yl]-butyric acid (IV) was added and 300ml of dichloromethane was added. ,Add 50ml triethylamine, temperature -20C-10C,A mixture of 20 ml of pivaloyl chloride + 50 ml of tetrahydrofuran is added dropwise.Reaction for 2 hours. Add 6.4g of anhydrous lithium chloride and stir for 2 hours.27g 4-phenyl-2-oxazolidone added,The reaction mixture was stirred for 5-7 h, and extracted and crystallized to obtain Intermediate VI.Yield 96.1%.

Reference： [1]Patent: CN107488138,2017,A .Location in patent: Paragraph 0064; 0074; 0075; 0086; 0097; 0108
[2]Patent: CN107488190,2017,A .Location in patent: Paragraph 0076; 0086; 0087; 0098; 0109; 0120
[3]Patent: CN107488165,2017,A .Location in patent: Paragraph 0070; 0080; 0081; 0092; 0103; 0114

64
(E)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylic acid [ No CAS ]
[ 99395-88-7 ]
(S,E)-3-(3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acryloyl)-4-phenyloxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		To a suspension of (E)-3-(1 ,4-dimethyl-1 H-benzo[d][1 ,2,3]triazol-5-yl)acrylic acid (82 g, 376 mmol) in tetrahydrofuran (1 .5 L) was added triethylamine (131 ml_, 939 mmol). The reaction mixture was cooled to -25C and pivaloyl chloride (46 ml, 376 mmol) was added dropwise and stirred for 30 min at -25C. Lithium chloride (17.52 g, 413 mmol) was added in one- portion, followed by (S)-4-phenyloxazolidin-2-one (58.8 g, 361 mmol) and the reaction mixture was allowed to warm to room temperature and was stirred for 1 hr. The mixture was cooled to -25C and pivaloyl chloride (12ml, 98 mmol) was added dropwise and allowed to stir for an additional 1 hr. THF (300 mL) was added followed by (S)-4-phenyloxazolidin-2-one (10 g, 61 mmol) and pivaloyl chloride (18 ml, 147 mmol) and the mixture was stirred at 10C for 1 hr and then room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate (1 L) and washed with 5% NaHS03(1 L). The resulting solid was collected by filtration and washed with water and diethyl ether to afford a light yellow solid (S,£)-3-(3-(1 ,4- dimethyl-1 H-benzo[c ][1 ,2,3]triazol-5-yl)acryloyl)-4-phenyloxazolidin-2-one (104.39 g, 288 mmol, 77 % yield). 1H NMR (DMSO-d6) delta: 8.05 (d, J=15.8 Hz, 1 H), 7.71 -7.88 (m, 3H), 7.30- 7.45 (m, 5H), 5.61 (m, 1 H), 4.83 (m, 1 H), 4.30 (s, 3H), 4.24 (m, 1 H), 2.78 (s, 3H). LC-MS: m/z 363.2 [M+H]+
77%		To a suspension of (E)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylic acid (82 g, 376 mmol) in tetrahydrofuran (1.5 L) was added triethylamine (131 mL, 939 mmol). The reaction mixture was cooled to -25 C and pivaloyl chloride (46 ml, 376 mmol) was added dropwise and stirred for 30 min at -25 C. Lithium chloride (17.52 g, 413 mmol) was added in one- portion, followed by (S)-4-phenyloxazolidin-2-one (58.8 g, 361 mmol) and the reaction mixture was allowed to warm to ambient temperature and was stirred for 1 hr. The mixture was cooled to -25 C and pivaloyl chloride (12ml, 98 mmol) was added dropwise and allowed to stir for an additional 1 hr. THF (300 mL) was added followed by (S)-4- phenyloxazolidin-2-one (10 g, 61 mmol) and pivaloyl chloride (18 ml, 147 mmol) and the mixture was stirred at 10 C for 1 hr and then ambient temperature for 18 hr. The reaction mixture was diluted with ethyl acetate (1 L) and washed with 5% NaHSO3 (1 L). The resulting solid was collected by filtration and washed with water and diethyl ether to afford a light yellow solid (S,E)-3-(3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)acryloyl)-4- phenyloxazolidin-2-one (104.39 g, 288 mmol, 77 % yield).1H NMR (DMSO-d6) delta: 8.05 (d, J=15.8 Hz, 1H), 7.71-7.88 (m, 3H), 7.30-7.45 (m, 5H), 5.61 (m, 1H), 4.83 (m, 1H), 4.30 (s, 3H), 4.24 (m, 1H), 2.78 (s, 3H). LC-MS: m/z = 363.2 [M+H]+.

Reference： [1]Patent: WO2018/109646,2018,A1 .Location in patent: Page/Page column 20; 47; 48
[2]Patent: WO2018/109647,2018,A1 .Location in patent: Page/Page column 161

65
[ 406-94-0 ]
[ 99395-88-7 ]
[ 243121-07-5 ]

Yield	Reaction Conditions	Operation in experiment
30%		To a solution of (£)- 4,4,4-trifluorobut-2-enoic acid (2.06 g, 14.7 mmol) in DCM (10 mL) at 0 C was added oxalyl chloride (1 .07 mL, 12.3 mmol). After 5 min, DM F (50 μ, 0.646 mmol) was added and the mixture was allowed to stir at RT for 2 h. In a separate vessel NaH (60% disp., 735 mg, 18.4 mmol) was added to a solution of (S)-4-phenyloxazolidin-2-one (2 g, 12.3 mmol) in THF (20 mL) at RT and the mixture was stirred for 2 h. The DMF solution of the acid chloride was then added to the sodiated (S)-4-phenyloxazolidin-2-one solution via syringe. After stirring for 18 h the mixture was diluted with water (50 mL) and the mixture extracted with DCM (3 x 20 mL) using a Biotage phase separator. The combined organic layers were concentrated and the residue purified by flash chromatography (50 g Biotage KP-Sil, 0-100% EtOAc in PE) to give the title compound (1.07 g, 30% yield) as a colourless solid. LCMS (Method A): RT = 1.33 min, m/z = 286 [M+H]+. 1 H NMR (300 MHz, CDCI3): 5 7.93 (dq, 1 H), 7.49-7.22 (m, 5H), 6.80 (dq, 1 H), 5.50 (dd, 1 H), 4.77 (t, 1 H), 4.36 (dd, 1 H).

Reference： [1]Patent: WO2018/73602,2018,A1 .Location in patent: Page/Page column 84; 85

66
[ 16957-70-3 ]
[ 99395-88-7 ]
[ 866108-42-1 ]

Reference： [1]Patent: WO2005/102389,2005,A2
[2]Patent: WO2005/102390,2005,A2

67
(S)-3-((S)-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)propanoyl)-4-phenyloxazolidin-2-one [ No CAS ]
[ 53617-36-0 ]
(S)-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)-1-(4-(4-methylpiperazine-1-yl)piperidin-1-yl)propan-1-one [ No CAS ]
[ 99395-88-7 ]

Yield	Reaction Conditions	Operation in experiment
38%; 78%	With Trimethyl borate; In toluene; at 100℃; for 0.5h;	(20.0 mg, 0.0634 mmol) of (S) -3 - ((S) -3-hydroxy-3- (1 -methyl- 1 H-imidazol-2-yl) propanoyl) Was dissolved in toluene (0.5 mL). 1-methyl-4- (piperidin-4-yl) piperazine (11.6 mg, 0.0633 mmol)Trimethoxyborane (3.5 muL, 0.032 mmol)And the mixture was stirred at 100 ° C. for 30 minutes.The reaction solution was concentrated to dryness, and ethyl acetate was added to the residue.The resulting ethyl acetate solution was washed with 1N hydrochloric acid.The organic layer was washed with a saturated aqueous sodium chloride solution,Dried over anhydrous sodium sulfate, filtered,The filtrate was concentrated under reduced pressure to give (S) -4-phenyloxazolidin-2-one (8.0 mg, 0.049 mmol, 78percent) as a white solid.On the other hand, the aqueous layer was adjusted to pH 11 by adding 1N sodium hydroxide aqueous solution.The resulting aqueous solution was extracted three times with a mixed solvent of chloroform / methanol (methanol 20percent v / v).The organic layer was dried over anhydrous sodium sulfate, filtered,The filtrate was concentrated under reduced pressure to obtain a residue,Purification by column chromatography (NH silica gel, chloroform / methanol)(S) -3-hydroxy-3-(1-methyl-1 H-imidazol-2-yl) -1- (4- (4-methylpiperazine-1-yl) piperidin-1-yl) propan-1-one(8.0 mg, 0.024 mmol, 38percent, 99percent ee)As a yellow oil.

Reference： [1]Patent: JP2018/172309,2018,A .Location in patent: Paragraph 0075

68
[ 99395-88-7 ]
[ 802294-64-0 ]
[ 184363-66-4 ]

Yield	Reaction Conditions	Operation in experiment
91.3%	With 2-chloro-1-methylpyridinium p-toluenesulfonate; triethylamine; In dichloromethane; at 25℃; for 5h;	Add 10 ml of dichloromethane, 500 ml of triethylamine (3.6 mol), and phenyloxazolidinone 163 g to a 5-liter four-necked bottle.(1 mol), propionic acid 80 g (1.1 mol), 300 g (1 mol)2-chloropyridine methyl p-toluenesulfonate salt 1000 ml of dichloromethaneThe solution was added and stirred at 25 C for 5 hours. TLC showed the reaction was complete, and the mixture was extracted with water and washed with water and saturated brine.The organic phase was dried over anhydrous sodium sulfate, concentrated, and then recrystallised to give product 200 g, yield: 91.3%, HPLC purity >99%.

Reference： [1]Patent: CN109020914,2018,A .Location in patent: Paragraph 0028; 0029; 0030; 0040; 0041; 0042

69
[ 591-80-0 ]
[ 99395-88-7 ]
(4S)-3-(pent-4-enoyl)-4-phenyl-1,3-oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%		Pent-4-enoic acid (1, 2.04 mL, 20 mmol) was dissolved in a DCM (dichloromethane) solvent (66 mL) and oxalyl chloride (2.03 mL, 24 mmol) was then added dropwise thereto. Subsequently, DMF (dimethylformamide) (200 muL) was added thereto, and the reaction was carried out at 40 C. for 1 hr. The reaction solution was cooled to room temperature and the solvent was removed therefrom using an evaporator. Subsequently, the resulting product was diluted with DCM (66 mL) and was then added dropwise to a solution of (S)-4-phenyloxazolidin-2-one (2, 3590 mg, 22 mmol), DIPEA (diisopropylethylamine) (6968 muL, 40 mmol), and DMAP (dimethylaminopyridine) (122.17 mg, 1 mmol) dissolved in DCM (36.6 mL). The resulting reaction solution was stirred at room temperature for 2 hr. After completion of the reaction, the reaction was terminated with 0.5 M HCl (50 mL), followed by extraction with DCM (60 mL, 20 mL×3). The DCM layer was dried with anhydrous MgSO4 and then filtered. Further, column chromatography (ethyl acetate:hexane=1:2) was performed, thus yielding a desired compound (S)-3-(pent-4-enoyl)-4-phenyloxazolidin-2-one (3, 4219 mg, 86%). (S)-3-(pent-4-enoyl)-4-phenyloxazolidin-2-one (3) 4219 mg, 86%, White solid; Rf=0.5 (ethyl acetate:hexane=1:2); 1H NMR (400 MHz, CDCl3) delta 7.41-7.29 (m, 5H), 5.85-5.75 (m, 1H), 5.43 (dd, J=8.7 Hz, 3.6 Hz, 1H), 5.06-4.95 (m, 2H), 4.69 (t, J=8.8 Hz, 1H), 4.29 (dd, J=8.9 Hz, 3.64 Hz, 1H), 3.07-3.03 (m, 2H), 2.39-2.34 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) delta 172.2, 153.9, 139.2, 136.7, 129.3, 128.9, 126.1, 115.8, 70.2, 57.7, 35.0, 28.2; IR (KBr) 3069, 2979, 1780, 1706, 1385, 1326, 1200, 1060 cm-1; HRMS (EI) m/z: [M]+ Calcd for C14H15NO3 245.1052; Found 245.1051.
	With dmap; pivaloyl chloride; triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 0 - 30℃;	4-Pentenoic acid (compound X), 4-dimethylammoniumpyridine (DMAP) was added to a mixture of methylene dichloride and DMF at about 20C to about 30C and the reaction mass was cooled to about 15C to about 20C. Triethylamine and (S)-(+)-4-Phenyl-2-oxazolidinone (compound GammaChi') was added to the reaction mass and the reaction mass was stirred for about 5-10 minutes. The reaction mass was then cooled to about 0C to about 5C. A solution of pivaloyl chloride in methylene dichloride was added to the reaction mass. The temperature of reaction mass was then raised to about 25C to about 30C and stirred for about 10-15 hours. After completion of reaction, the reaction mass was quenched in dilute sulfuric acid at about 0C to about 5C. The temperature of the reaction mass was raised to about 20C to about 30C and layers were separated. The aqueous layer was extracted with methylene dichloride. After washing with 5% potassium carbonate solution followed by brine, the organic layer was distilled off completely under reduced pressure to obtain oily residue. To this oily mass, cyclohexane was added at about 50C to about 55C and the reaction mass was cooled gradually to about 20C to about 30C and stirred for 2 hours, the reaction mass was filtered, the residue obtained was dried to get (4S)-3-(pent-4-enoyl)- 4-phenyl-l,3-oxazolidin-2-one (compound Vffl') as off-white to pale yellow solid. HPLC Purity more than 98.0%.

Reference： [1]Patent: US2019/256479,2019,A1 .Location in patent: Paragraph 0062-0064
[2]Patent: WO2019/87172,2019,A1 .Location in patent: Paragraph 0176

70
[ 99395-88-7 ]
[ 2802-61-1 ]
(S)-3-(2-fluoropyrimidin-4-yl)-4-phenyl-oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; Inert atmosphere;	General procedure: 1h (850 mg, 6.38 mmol) and 2,4-difluoropyrimidine (740 mg,6.37 mmol) were added to DMF (10 mL) under N2 and the mixturewas cooled to 0 C. After adding sodium hydride (310 mg,7.75 mmol) and stirring for 30 min, the reaction mixture waswarmed to rt and stirred for 2 h. After the reaction was completed,the reaction mixture was poured into ice-H2O (30 mL) thenextracted with EtOAc. The organic phase was combined andwashed once with H2O (60 mL) and once with brine (60 mL). Theorganic layer was washed with H2O and saturated aqueous NaCland dried over Na2SO4. it was then concentrated and purified viaflash chromatography on silica gel to get 1.1 g (Yield 75.2%) of whitecrystalline solid (1g).

Reference： [1]Cao, Hengyi; Zhu, Guangya; Sun, Lin; Chen, Ge; Ma, Xinxin; Luo, Xiao; Zhu, Jidong [European Journal of Medicinal Chemistry, 2019, vol. 183]

71
[ 99395-88-7 ]
[ 829-85-6 ]
[ 1103533-85-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: (S)-4-phenyl-2-oxazolidinone; diphenylphosphane In toluene at 20℃; for 0.5h; Schlenk technique; Inert atmosphere; Stage #2: With trifluorormethanesulfonic acid In toluene; mineral oil for 24h; Schlenk technique; Inert atmosphere; Reflux;

Reference： [1]Vigneswaran, Vipulan; MacMillan, Samantha N.; Lacy, David C. [Organometallics, 2019, vol. 38, # 22, p. 4387 - 4391]

72
(3R)-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidine-3-carbonyl]hexanenitrile [ No CAS ]
(R)-3-(hydroxymethyl)hexanenitrile [ No CAS ]
[ 99395-88-7 ]

Yield	Reaction Conditions	Operation in experiment
91.9%	With sodium tetrahydroborate; water; In tetrahydrofuran; at 20 - 40℃; for 2h;	In a reaction flask, tetrahydrofuran (8.0 mL) and water (2.0 mL) were added, then (R)-3-((S)-4-phenyl-2-oxooxazolidinyl-3-carbonyl) hexanenitrile (1.20 g, 4.85 mmol) was added, maintaining the internal temperature below 40 C., and then sodium borohydride (0.37 g, 9.78 mmol, 2.0 eq) was added portionwise. The reaction was conducted at room temperature for 2 hours, and TLC was used to detect the disappearance of (R)-3-((S)-4-phenyl-2-oxooxazolidinyl-3-carbonyl) hexanenitrile and treatment was performed; when the internal temperature was controlled below 40 C., saturated ammonium chloride (6.0 mL) was added dropwise for quenching, then the mixture was distilled under reduced pressure at 40 C. until no fraction, and extracted with ethyl acetate (10.0 mL) to separate phases, the organic phase was dried over anhydrous sodium sulfate (2.0 g), filtered and the filtrate was concentrated under a reduced pressure. After purification by column chromatography, the target compound was given as a colorless oily substance (0.57 g, yield 91.9%).

Reference： [1]Patent: US2019/359583,2019,A1 .Location in patent: Paragraph 0103-0104

73
[ 99395-88-7 ]
[ 1878-68-8 ]
[ 1598387-46-2 ]

Yield	Reaction Conditions	Operation in experiment
93.5%	With dicyclohexyl-carbodiimide In dichloromethane at 20℃;	4.1 step one: Dissolve 163 g (1.0 mol) of S-phenyloxazolidinone and 215 g (1.0 mol) of p-bromophenylacetic acid in 2000 mL of dichloromethane, add 207 g (1.1 mol) of DCC dehydrating agent, and stir at room temperature until TLC shows the reaction is complete , Add a mixture of 50mL of methanol and 50mL of acetic acid, stir for 2 hours and filter, and the filtrate is concentrated to obtain 335g of product. Yield: 93.0%.

Reference： [1]Current Patent Assignee: XIAMEN GINPOSOME PHARMACEUTICAL - CN110981826, 2020, A Location in patent: Paragraph 0120-0123

74
[ 99395-88-7 ]
[ 185137-29-5 ]

Yield	Reaction Conditions	Operation in experiment
61%	With tetraphosphorus decasulfide In toluene Reflux;

Reference： [1]Dong, Xiu-Qin; Liu, Yuanhua; Wang, Heng; Wang, Minyan; Yang, Xuanliang; Yi, Zhiyuan; Yin, Congcong; Zhang, Xumu [ACS Catalysis, 2020, vol. 10, # 19, p. 11153 - 11161]

75
[ 99395-88-7 ]
[ 153880-57-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 3-azapentane-1,5-diamine / 18 h / 140 °C 2: dichloromethane / 60 h / Reflux

Reference： [1]Dong, Xiu-Qin; Liu, Yuanhua; Wang, Heng; Wang, Minyan; Yang, Xuanliang; Yi, Zhiyuan; Yin, Congcong; Zhang, Xumu [ACS Catalysis, 2020, vol. 10, # 19, p. 11153 - 11161]

76
[ 99395-88-7 ]
[ 190970-57-1 ]

Yield	Reaction Conditions	Operation in experiment
91.6%	With sulfur In water at 40 - 50℃; for 8h; Inert atmosphere;	4-5 Example 4 Under the protection of nitrogen, 25g (0.153mol) of (S)-4-phenyl-2-oxazolidinone and 5.2g (0.161mol) of high-purity sulfur In the adsorption reaction flask, drop 87.8g (0.161mol) of 30% ammonia polysulfide aqueous solution at room temperature. After the addition, heat to 40-50°C reaction for 8 hours, sampling of raw materials is less than 0.5%. The aqueous phase was extracted once more with MTBE, combined with MTBE, concentrated, and recrystallized by adding n-heptane/acetic acid (6/1) under heating.Filter and dry to obtain 25.2 g of (S)-4-phenyl-2-oxazolidinthione, HPLC: 99.2%, yield 91.6%.

Reference： [1]Current Patent Assignee: GANSU HANJU PHARMACEUTICAL - CN112500361, 2021, A Location in patent: Paragraph 0034-0039

77
[ 99395-88-7 ]
[ 272778-12-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: pivaloyl chloride; triethylamine / dichloromethane / 1 h / 20 - 30 °C / Inert atmosphere 1.2: 2.5 h / Inert atmosphere; Reflux 2.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; dimethylsulfide borane complex / dichloromethane / 30 min / 5 - 10 °C / Inert atmosphere 3.1: dichloromethane / 30 min / Inert atmosphere 3.2: -10 - 5 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SHANGDONG NEW TIME PHARMACEUTICAL CO LTD - CN115583962, 2023, A

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Isomers

Technical Information

• Acyl Group Substitution • Amide Hydrolysis • Amide Hydrolysis • Amides Can Be Converted into Aldehydes • Amines Convert Acyl Chlorides into Amides • Benzylic Oxidation • Birch Reduction • Birch Reduction of Benzene • Blanc Chloromethylation • Chan-Lam Coupling Reaction • Complete Benzylic Oxidations of Alkyl Chains • Complete Benzylic Oxidations of Alkyl Chains • Complex Metal Hydride Reductions • Conversion of Amino with Nitro • Deprotonation of Methylbenzene • Directing Electron-Donating Effects of Alkyl • Electrophilic Chloromethylation of Polystyrene • Formation of an Amide from an Amine and a Carboxylic Acid • Formation of an Amide from an Amine and a Carboxylic Acid • Friedel-Crafts Alkylation of Benzene with Acyl Chlorides • Friedel-Crafts Alkylation of Benzene with Carboxylic Anhydrides • Friedel-Crafts Alkylation Using Alkenes • Friedel-Crafts Alkylations of Benzene Using Alkenes • Friedel-Crafts Alkylations Using Alcohols • Friedel-Crafts Reaction • Groups that Withdraw Electrons Inductively Are Deactivating and Meta Directing • Halogenation of Benzene • Hofmann Rearrangement • Hydride Reductions • Hydrogenation to Cyclohexane • Hydrogenolysis of Benzyl Ether • Lawesson's Reagent • Nitration of Benzene • Nucleophilic Aromatic Substitution • Nucleophilic Aromatic Substitution with Amine • Oxidation of Alkyl-substituted Benzenes Gives Aromatic Ketones • Preparation of Alkylbenzene • Preparation of Amines • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reduction of an Amide to an Amine • Reduction of an Amide to an Amine • Reductive Removal of a Diazonium Group • Reverse Sulfonation——Hydrolysis • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes • Sulfonation of Benzene • The Acylium Ion Attack Benzene to Form Phenyl Ketones • The Claisen Rearrangement • The Nitro Group Conver to the Amino Function • Vilsmeier-Haack Reaction

Historical Records

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[ 99395-88-7 ]

Arbaclofen Intermediates

[ 51-35-4 ]

(2S,4R)-4-Hydroxypyrrolidine-2-carboxylic acid

[ 104-88-1 ]

4-Chlorobenzaldehyde

[ 17342-08-4 ]

(S)-(+)-5-Hydroxymethyl-2-pyrrolidinone

[ 1615-02-7 ]

3-(4-Chlorophenyl)acrylic acid

[ 98-79-3 ]

(S)-5-Oxopyrrolidine-2-carboxylic acid

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[ 1501-27-5 ]

5-Methoxy-5-oxopentanoic acid

[ 163222-32-0 ]

(3R,4S)-4-(4-(Benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)azetidin-2-one

[ 4397-53-9 ]

4-(Benzyloxy)benzaldehyde

[ 190595-65-4 ]

(3R,4S)-4-(4-(Benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)azetidin-2-one

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Ghs Hazard Statements

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H200	Unstable explosive
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Code	Phrase
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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

; ;