Name: 70987-78-9|(s)-(+)-oxirane-2-methanol p-toluenesulfonate|98%
Brand: Ambeed
SKU: A226221
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1
[ 36653-82-4 ]
[ 70987-78-9 ]
[ 120019-37-6 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 3408 - 3415
[2]Journal of Medicinal Chemistry,2005,vol. 48,p. 7305 - 7314
[3]Journal of Medicinal Chemistry,1994,vol. 37,p. 425 - 430
[4]Tetrahedron Letters,1988,vol. 29,p. 4393 - 4396
[5]Journal of Organic Chemistry,1989,vol. 54,p. 4637 - 4642

2
[ 4247-02-3 ]
[ 70987-78-9 ]
[ 104419-81-0 ]

Reference： [1]European Journal of Medicinal Chemistry,1994,vol. 29,p. 287 - 294
[2]European Journal of Medicinal Chemistry,1995,vol. 30,p. 39 - 46

3
[ 113826-06-5 ]
[ 638-08-4 ]
[ 116953-94-7 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 5547 - 5549

4
[ 70987-78-9 ]
[ 120-80-9 ]
[ 98572-00-0 ]

Yield	Reaction Conditions	Operation in experiment
56%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h;	To a suspension of pyrocathecol (0.58 g, 5.26 mmol) and K2C03 (0.73 g, 5.26 mmol) inanhydrous DMF (22 mL), was added (2R)-(-)-glycidyl tosylate (1.00 g, 4.38 mmol). Themixture was left stirring at 60 C for 16 hours, then poured into ice-water and extracted with Et20 until the organic phase was colorless. The organic layers were washed with brine, dried over Na2SO4 filtered and concentrated. Purification by flash chromatography (hexanes/EtOAc 80:20) afforded the pure product as white solid (0.41 g, 56 % yield). [a]5 =-33.1 (EtOH; c = 0.26). ?H-NMR (300 MHz, CDC13): 6.97-6.76 (m, 4H), 4.33-4.22 (m,2H), 4.17-4.05 (m, 1H), 3.87 (qd, J = 11.9, 4.4 Hz, 2H). ESI-MS calcd for C9H1003 mlz166.06, found 167.43 [M + Hjt
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60 C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol-50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	EXAMPLE 4 (2S)-(-)-N-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide (Compound #4) Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60 C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol-50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid.

	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 600C for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl <n="36"/>ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol - 50:1 ) to yield ((2S)-2,3-dihydro-benzo[1 ,4]dioxin-2-yl)- methanol as a solid.The solid (13.3 g, 68 mmol) was dissolved in pyridine (85 mL) cooled to 00C, p-toluenesulfonyl chloride (13.0 g, 68 mmol) was added and the reaction mixture stirred at room temperature for 2Oh. The reaction was diluted with diethyl ether (1 L) and 1 N HCI (1.2 L). The organic layer was separated and washed 2 times with 1 N HCI (500 mL), 4 times with water (150 mL), once with brine, dried (MgSO4) and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (Hept:EA - 2:1 ) to yield toluene-4- sulfonic acid (2S)-2,3-dihydro-benzo[1 ,4]dioxin-2-ylmethyl ester as a white solid. The white solid was combined with potassium phthalimide (14.4 g, 78 mmol) in DMF (250 mL) and heated to reflux for 1 h, cooled to room temperature and poured into vigorously stirring water (1.5 L) and stirred 30 min. White solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and let air dry to yield a (2S)-2-(2,3-Dihydro- benzo[1 ,4]dioxin-2-ylmethyl)-isoindole-1 ,3-dione as white powdery solid.The powdery white solid was combined with hydrazine (2.75 g, 86 mmol) in EtOH (225 mL) and heated at reflux for 2 h, cooled to room temperature and 1 N HCI added to pH 1 .0 and stirred for 15 min. White solid was filtered and washed with fresh EtOH (solid discarded) and the filtrate was evaporated in vacuo to a solid, which was partitioned between diethyl ether and dilute aqueous NaOH. The diethyl ether solution was dried (Na2SO4) and evaporated in vacuo to a yield a light yellow oil. The oil was purified by flash column chromatography (DCM:MeOH - 10:1 ) to yield an oil. A portion of the oil (4.82 g, 29 mmol) in 2-propanol (250 mL) was treated with 1 N HCI (30 mL) and heated on steambath until homogeneous and then let cool to room temperature. After 3 h, the mixture was ice cooled for 2 h. A white flaky solid (the corresponding HCI salt of (2S)-C-(2,3-Dihydro-benzo[1 ,4]dioxin-2-yl)- <n="37"/>methylamine) was filtered off and then recrystallized again from 2-propanol to yield a white solid.[alpha]D = -69.6 (c = 1 .06, EtOH)The white solid was partitioned between DCM and dilute NaOH, and the DCM was dried (NaSO4) and evaporated in vacuo to yield (2S)-C-(2,3-Dihydro- benzo[1 ,4]dioxin-2-yl)-methylamine as an oil. [alpha]D = -57.8 (c = 1.40, CHCI3)The oil (2.1 g, 12.7 mmol) and sulfamide (2.44 g, 25.4 mmol) were refluxed in dioxane (75 mL) for 2 h and the crude product was purified by flash column chromatography (DCM:MeOH 10:1 ) to yield a white solid, which was recrystallized from DCM to yield the title compound as a white crystalline solid. mp 102-103C [alpha]D = -45.1 (c = 1.05, M);1H NMR (DMSOd6) delta 6.86 (m, 4H), 6.81 (bd s, 3H, NH), 4.3 (m, 2H), 3.97 (dd, J = 6.9, 1 1 .4 Hz, 1 H), 3.20 (dd, J = 5.5, 13.7 Hz, 1 H), 3.10 (dd, J = 6.9, 13.7 Hz, 1 H)Elemental Analysis:Anal CaIc: C, 44.25; H, 4.95; N, 1 1.47; S, 13.13Anal Found: C, 44.20; H, 4.69; N, 1 1.40; S, 13.22.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	EXAMPLE 4 (2S)-(-)-N-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide (Compound #4) Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60 C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol-50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	EXAMPLE 4; (2S)-f-)-N-(2,3-Dihvdro-benzori.41dioxin-2-vlnniethvl)-sulfamide(Compound No.4); Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 ml_) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60C for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol - 50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60 C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol-50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60 C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol-50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60 C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol-50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid. The solid (13.3 g, 68 mmol) was dissolved in pyridine (85 mL) cooled to 0 C., p-toluenesulfonyl chloride (13.0 g, 68 mmol) was added and the reaction mixture stirred at room temperature for 20 h. The reaction was diluted with diethyl ether (1 L) and 1N HCl (1.2 L). The organic layer was separated and washed 2 times with 1 N HCl (500 mL), 4 times with water (150 mL), once with brine, dried (MgSO4) and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (Hept:EA-2:1) to yield toluene-4-sulfonic acid (2S)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester as a white solid. The white solid was combined with potassium phthalimide (14.4 g, 78 mmol) in DMF (250 mL) and heated to reflux for 1 h, cooled to room temperature and poured into vigorously stirring water (1.5 L) and stirred 30 min. White solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and let air dry to yield a (2S)-2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione as white powdery solid. The powdery white solid was combined with hydrazine (2.75 g, 86 mmol) in EtOH (225 mL) and heated at reflux for 2 h, cooled to room temperature and 1 N HCl added to pH 1.0 and stirred for 15 min. White solid was filtered and washed with fresh EtOH (solid discarded) and the filtrate was evaporated in vacuo to a solid, which was partitioned between diethyl ether and dilute aqueous NaOH. The diethyl ether solution was dried (Na2SO4) and evaporated in vacuo to a yield a light yellow oil. The oil was purified by flash column chromatography (DCM:MeOH-10:1) to yield an oil. A portion of the oil (4.82 g, 29 mmol) in 2-propanol (250 mL) was treated with 1 N HCl (30 mL) and heated on steambath until homogeneous and then let cool to room temperature. After 3 h, the mixture was ice cooled for 2 h. A white flaky solid (the corresponding HCl salt of (2S)-C-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-methylamine) was filtered off and then recrystallized again from 2-propanol to yield a white solid. [alpha]D=-69.6 (c=1.06, EtOH) The white solid was partitioned between DCM and dilute NaOH, and the DCM was dried (NaSO4) and evaporated in vacuo to yield (2S)-C-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-methylamine as an oil. [alpha]D=-57.8 (c=1.40, CHCl3) The oil (2.1 g, 12.7 mmol) and sulfamide (2.44 g, 25.4 mmol) were refluxed in dioxane (75 mL) for 2 h and the crude product was purified by flash column chromatography (DCM:MeOH 10:1) to yield a white solid, which was recrystallized from DCM to yield the title compound as a white crystalline solid. mp 102-103 C. [alpha]D=-45.1 (c=1.05, M); 1H NMR (DMSOd6) delta 6.86 (m, 4H), 6.81 (bd s, 3H, NH), 4.3 (m, 2H), 3.97 (dd, J=6.9, 11.4 Hz, 1H), 3.20 (dd, J=5.5, 13.7 Hz, 1H), 3.10 (dd, J=6.9, 13.7 Hz, 1H) Elemental Analysis: Anal Calc: C, 44.25; H, 4.95; N, 11.47; S, 13.13 Anal Found: C, 44.20; H, 4.69; N, 11.40; S, 13.22.
		Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60 C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol-50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid. The solid (13.3 g, 68 mmol) was dissolved in pyridine (85 mL) cooled to 0 C., p-toluenesulfonyl chloride (13.0 g, 68 mmol) was added and the reaction mixture stirred at room temperature for 20 h. The reaction was diluted with diethyl ether (1 L) and 1N HCl (1.2 L). The organic layer was separated and washed 2 times with 1N HCl (500 mL), 4 times with water (150 mL), once with brine, dried (MgSO4) and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (Hept:EA-2:1) to yield toluene-4-sulfonic acid (2S)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester as a white solid. The white solid was combined with potassium phthalimide (14.4 g, 78 mmol) in DMF (250 mL) and heated to reflux for 1 h, cooled to room temperature and poured into vigorously stirring water (1.5 L) and stirred 30 min. White solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and let air dry to yield a (2S)-2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione as white powdery solid. The powdery white solid was combined with hydrazine (2.75 g, 86 mmol) in EtOH (225 mL) and heated at reflux for 2 h, cooled to room temperature and 1N HCl added to pH 1.0 and stirred for 15 min. White solid was filtered and washed with fresh EtOH (solid discarded) and the filtrate was evaporated in vacuo to a solid, which was partitioned between diethyl ether and dilute aqueous NaOH. The diethyl ether solution was dried (Na2SO4) and evaporated in vacuo to a yield a light yellow oil. The oil was purified by flash column chromatography (DCM:MeOH-10:1) to yield an oil. A portion of the oil (4.82 g, 29 mmol) in 2-propanol (250 mL) was treated with 1N HCl (30 mL) and heated on steambath until homogeneous and then let cool to room temperature. After 3 h, the mixture was ice cooled for 2 h. A white flaky solid (the corresponding HCl salt of (2S)-C-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-methylamine) was filtered off and then recrystallized again from 2-propanol to yield a white solid. [alpha]D=-69.6 (c=1.06, EtOH) The white solid was partitioned between DCM and dilute NaOH, and the DCM was dried (NaSO4) and evaporated in vacuo to yield (2S)-C-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-methylamine as an oil. [alpha]D=-57.8 (c=1.40, CHCl3) The oil (2.1 g, 12.7 mmol) and sulfamide (2.44 g, 25.4 mmol) were refluxed in dioxane (75 mL) for 2 h and the crude product was purified by flash column chromatography (DCM:MeOH 10:1) to yield a white solid, which was recrystallized from DCM to yield the title compound as a white crystalline solid. mp 102-103 C. [alpha]D=-45.1 (c=1.05, M); 1H NMR (DMSOd6) delta 6.86 (m, 4H), 6.81 (bd s, 3H, NH), 4.3 (m, 2H), 3.97 (dd, J=6.9, 11.4 Hz, 1H), 3.20 (dd, J=5.5, 13.7 Hz, 1H), 3.10 (dd, J=6.9, 13.7 Hz, 1H) Elemental Analysis: Anal Calc: C, 44.25; H, 4.95; N, 11.47; S, 13.13 Anal Found: C, 44.20; H, 4.69; N, 11.40; S, 13.22.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60 C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol-50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60C for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol - 50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)- methanol as a solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60 C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol-50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	EXAMPLE 4 (2S)-(-)-N-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide (Compound #4) Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60 C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol-50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid.
36.4 g	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 48h;	To a solution of catechol (24.12 g, 219 mmol) and p-toluenesul-fonic acid (2R)-(-)-glycidyl ester (50 g, 219 mmol) in DMF (500 mL) was added potassium carbonate (45.4 g, 329 mmol) and the mixture was stirred at 60 oC for 48 h. The mixture was concen- trated in vacuo and quenched with water. After extraction with [EtOAc/hexane = 1:1] solution, the organic phase was washed with water and brine, then dried over Na2SO4, ltered and concentrated in vacuo to obtain (S)-(2,3-dihydrobenzo[b][1,4]dioxin-2- yl)methanol as a pale red solid (36.4 g). The solid was dissolved in pyridine (145 mL) and p-toluenesulfonyl chloride (50.1 g,263 mmol) was added to the solution. The mixture was stirred at room temperature for 2 h, then 3 N HCl (1000 mL) was slowly added at 0 oC. After extraction with ether, the organic phase was washed with water and brine, then dried over Na2SO4, ltered and concentrated in vacuo to obtain (R)-(2,3-dihydrobenzo[b][1,4]- dioxin-2-yl)methyl 4-methylbenzenesulfonate as a pale yellow oil (60.45 g). The oil was dissolved in DMF (300 mL) and phthalimide potassium salt (45.4 g, 245 mmol) was added to the mixture. The mixture was stirred at 90 oC for 20 h and cooled to room tempera- ture, then MeOH (1.5 L) was added with stirring. The resulting solid was ltered, washed with MeOH and dried in vacuo to give 4 as awhite solid (36.9 g, 57% from catechol).

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 3671 - 3674
[2]Patent: WO2016/100940,2016,A1 .Location in patent: Page/Page column 148
[3]Journal of Medicinal Chemistry,1989,vol. 32,p. 1402 - 1407
[4]Patent: US2007/155822,2007,A1 .Location in patent: Page/Page column 14
[5]Patent: US2007/155824,2007,A1 .Location in patent: Page/Page column 20
[6]Patent: WO2007/137167,2007,A2 .Location in patent: Page/Page column 34-36
[7]Patent: US2009/247616,2009,A1 .Location in patent: Page/Page column 15
[8]Patent: WO2006/7435,2006,A1 .Location in patent: Page/Page column 37-38
[9]Patent: US2007/155821,2007,A1 .Location in patent: Page/Page column 15
[10]Patent: US2007/155823,2007,A1 .Location in patent: Page/Page column 13
[11]Patent: US2007/155825,2007,A1 .Location in patent: Page/Page column 13
[12]Patent: US2007/155826,2007,A1 .Location in patent: Page/Page column 15-16
[13]Patent: US2007/155827,2007,A1 .Location in patent: Page/Page column 14
[14]Patent: WO2007/75833,2007,A2 .Location in patent: Page/Page column 33
[15]Patent: US2007/191474,2007,A1 .Location in patent: Page/Page column 15
[16]Patent: US2005/282887,2005,A1 .Location in patent: Page/Page column 17
[17]Journal of Medicinal Chemistry,2013,vol. 56,p. 9019 - 9030
[18]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 4792 - 4803

5
[ 107-18-6 ]
[ 98-59-9 ]
[ 70987-78-9 ]
[ 113826-06-5 ]

Reference： [1]Journal of Organic Chemistry,1986,vol. 51,p. 3710 - 3712
[2]Journal of the American Chemical Society,1987,vol. 109,p. 5765 - 5780

6
[ 113826-06-5 ]
[ 108-95-2 ]
[ 71031-03-3 ]

Yield	Reaction Conditions	Operation in experiment
73%		Preparation 2; Preparation of (25)-2-(phenoxymethYl . oxirane; A solution of phenol (17.57 g, 76.97 mmol) in dry DMF (200 mL) was added slowly to a suspension of sodium hydride (60% in mineral oil, 4.0 g, 100.06 mmol) in DMF at 0C and stirred at the same temperature for 30 minutes. Then, (2S)- (+)-glycidyl tosylate (17.57 g, 76.97 mmol) was added slowly. The resulting mixture was stirred at room temperature overnight and quenched with saturated ammonium chloride solution. The two-phase mixture was diluted with water and extracted with diethyl ether. The combined organic extracts were washed with saturated NaHCO3, brine, dried over anhydrous sodium sulfate, concentrated and purified by medium pressure column chromatography (eluant: hexanes/EtOAc 13: 1). The product was obtained as a colorless oil in 73% yield.

Reference： [1]Tetrahedron Asymmetry,2000,vol. 11,p. 2885 - 2898
[2]Patent: WO2005/56544,2005,A1 .Location in patent: Page/Page column 36
[3]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1377 - 1380

7
[ 740799-87-5 ]
[ 70987-78-9 ]
[ 740799-88-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 65℃; for 5h;	Into a 500 mL round bottom flask, were added 25.21 g (97.71 mmol) benzyl 3,4-dihydroxy-2-methylbenzoate, 22.28 g (97.71 mmol) of (2R)-(-)-glycidyl tosylate, 16.56 g (120 mmol) K2CO3, and 200 mL DMF. The reaction mixture was stirred at 65 C. in an oil bath for 5 hours. The reaction was allowed to cool, diluted with water (750 mL), and extracted with ether (3×300 mL). The ether phase was back-extracted with 100 mL water, and the combined organic phases were dried and evaporated to yield 31.1 g oil. TLC indicated completeness of the reaction: Rf=0.36 (1:1 ethyl acetate:hexane). Column chromatography using a gradient of 10-50% ethyl acetate in hexane provided 23.0 g pure 3-hydroxymethyl-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid benzyl ester (80% yield). 1H NMR (300 MHz, CD3OD) delta (ppm): 7.4 (m, 6H), 6.75 (d, 1H), 5.28 (s, 2H), 4.4 (d, 1H), 4.2 (m, 1H), 4.1 (dd, 1H), 3.8 (m, 2H), 2.46 (s, 3H).

Reference： [1]Patent: US2005/209283,2005,A1 .Location in patent: Page/Page column 37; 38

8
[ 38226-10-7 ]
[ 70987-78-9 ]
[ 187543-52-8 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3342 - 3355

9
[ 70987-78-9 ]
[ 635-93-8 ]
[ 187543-32-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;	General procedure: To a DMF (25mL) solution of 2-hydroxy-5-methoxybenzaldehyde (2.0g, 13.2mmol) were added potassium carbonate powder (2.2g, 15.8mmol) and epichlorohydrin (1.34mL, 17.2mmol). The resulting suspension was heated to 80C for 3h. The reaction mixture was cooled to ambient temperature and added AcOEt and water. The extracts are combined, and washed by brine, then dried over anhydrous Na2SO4. The mixture was concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether=1:10) to give compound 22a (1.6g, 58%) as a colorless oil.
50%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;	General procedure: 5-bromosalicylaldehyde (5.0 g, 25 mmol) was dissolved in N,N-dimethylformamide (80 mL). add potassium carbonate (6.91 g, 50 mmol) and epichlorohydrin (2.94 mL, 37.5 mmol) was heated to 80 C and stirred for 4 h. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 5/1). After the reaction mixture was completed, it was cooled to room temperature, diluted with water and extracted twice with ethyl acetate. The organic phase was combined, washed with water and brine, dried over anhydrous sodium sulfate. Filtered and the solvent was evaporated and the crude product purified by column chromatography (petroleum ether / ethyl acetate = 10/1), After purification, 3.2 g of a colorless liquid was obtained in a yield of 50%.

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5780 - 5791
[2]Journal of Medicinal Chemistry,1999,vol. 42,p. 3342 - 3355
[3]Patent: CN110092774,2019,A .Location in patent: Paragraph 0096-0099; 0165-0168

10
[ 4049-39-2 ]
[ 70987-78-9 ]
[ 291507-75-0 ]

Reference： [1]Archiv der Pharmazie,2000,vol. 333,p. 175 - 180
[2]ChemMedChem,2017,vol. 12,p. 728 - 737

11
[ 505-23-7 ]
[ 70987-78-9 ]
[ 68972-11-2 ]

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 17087 - 17089
[2]Chemistry - A European Journal,2012,vol. 18,p. 2948 - 2960
[3]Tetrahedron,2001,vol. 57,p. 6311 - 6327
[4]Journal of the American Chemical Society,2003,vol. 125,p. 2374 - 2375
[5]Synthesis,2010,p. 2787 - 2793

12
[ 31354-48-0 ]
[ 70987-78-9 ]
4-acetyl-3(S)-(hydroxymethyl)-3,4-dihydro-2H-pyrido[3,2-b]oxazine [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 1465 - 1468

13
[ 113826-06-5 ]
[ 1074-82-4 ]
(R)-1-chloro-3-phthalimidopropan-2-ol [ No CAS ]
[ 148857-42-5 ]

Reference： [1]Tetrahedron Asymmetry,2004,vol. 15,p. 763 - 770

14
[ 70987-78-9 ]
[ 671809-74-8 ]
[ 671810-06-3 ]

Yield	Reaction Conditions	Operation in experiment
76%		5,4'-O-dibenzyl-perazidonebramine 1a (2.78 g, 3.99 mmol) was dissolved in 30 mL dry DMF. The reaction mixture was purged with N2 and cooled to 0 C. To the solution was added 240 mg of 60% NaH (5.99 mmol) in paraffin over a 30 minute period. The resulting solution was allowed to stir for 30-45 minutes at 0 C. To the solution was added 1.37 g of (2R)-(-)-glycidyl tosylate (5.99 mmol) over a 30-minute period. The reaction was allowed to warm to room temperature and stirred 2 hours. The reaction was quenched with saturated ammonium chloride, extracted with diethyl ether, dried (Na2SO4) filtered and concentrated. The product was purified by flash column chromatography (35 g). Elution with 8:1 hexanes-ethyl acetate afforded the product 12a as a colorless oil: 2.28 g (76% yield); silica gel TLC Rf 0.55 (4:1 hexanes-ethyl actate); 1H NMR (400 MHz, CDCl3) delta 1.42 (t, 1H, J=13 Hz); 1.99-2.11 (m, 1H); 2.26 (dt, 1H, J=13, 4.5 Hz); 2.37 (dt, 1H, J=11.5, 4.5 Hz); 2.50 (dd, 1H, J=5, 3 Hz); 2.78 (t, 1H, J=4.5 Hz); 3.07 (dt, 1H, J=13, 4 Hz); 3.17-3.22 (m, 1H); 3.22 (m, 1H); 3.25 (t, 1H, J=9 Hz); 3.33-3.70 (m, 5H); 4.04 (dd, 1H, J=10.5, 3 Hz); 4.17-4.24 (m, 1H); 4.47 (d, 1H, J=11.5 Hz); 4.65 (d, 1H, J=11.5 Hz); 4.84 (d, 1H, J=10.5 Hz); 5.01 (d, 1H, J=10.5 Hz); 5.50 (d, 1H, J=3.5 Hz); 7.33 (m, 10H); 13C NMR (100 MHz, CDCl3) delta 28.16, 32.52, 40.87, 50.83, 51.58, 56.49, 59.95, 60.32, 71.27, 71.35, 72.36, 75.63, 75.66, 77.60, 84.67, 86.18, 97.17, 128.19, 128.25, 128.31, 128.47, 128.87, 128.96, 137.90, 138.2; mass spectrum (ESI), m/z 669.3 (M+Na)+ (C29H34N12NaO6 requires 669.3).

Reference： [1]Patent: US2004/58880,2004,A1 .Location in patent: Page 47
[2]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2123 - 2128

15
[ 2695-48-9 ]
[ 70987-78-9 ]
[ 862603-90-5 ]
[ 606490-50-0 ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 10396 - 10399

16
[ 854416-61-8 ]
[ 70987-78-9 ]
[ 1005411-54-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 1h;	Epoxide 5. R-(-)-Glycidyl tosylate (13.4 g, 58.8 mmol) and granular K2CO3 (14.3 g, 104 mmol) were added to a stirred solution of 4 (19.0 g, 47.0 mmol) in 70 mL of dry DMF. Under N2, the mixture was heated to 70 C. for 1 h then cooled to RT. EtOAc was added and the mixture was washed 3 times with water, dried (Na2SO4), filtered and concentrated. The residue was slurried with Et2O (75 mL) and the solid was collected and dried to give 19.0 g (88%) of 5.

Reference： [1]Patent: US2008/33183,2008,A1 .Location in patent: Page/Page column 4

17
[ 528-21-2 ]
[ 70987-78-9 ]
[ 474534-28-6 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 70℃; for 3.08333h;	To a solution of 2',3',4'-trihydroxyacetophenone (10.6 g, 63.0 mmole) in DMF (75 mL) was added potassium carbonate (17.4 g, 126 mmole). After 5 minutes <strong>[70987-78-9](R)-glycidyl tosylate</strong> (9.67 g, 42.3 mmole) was added then the heterogeneous mixture was heated to 70 C. for 3 hours. After removal of the solvent in vacuum, the residue was taken into water (800 mL) and was then extracted with ethyl acetate (4×300 mL). The combined organic layers were dried over MgSO4, filtered and evaporate to dryness in vacuum. The crude brown oil thus obtained was column chromatographed on silica gel with 40% hexane/ethyl acetate as eluant to give the (S)-enantiomer of the title compound as a yellow oil which solidifies upon standing (7.5 g, 78%). MS (ESI) m/z 223 (M-H)-. Elemental Analysis for: C11H12O5.0.10H2O Calc'd: C, 58.46; H, 5.44 Found: C, 58.02; H, 5.09
78%		To a solution of 2', 3', 4'-trihydroxyacetophenone (10.6 g, 63.0 mmole) in DMF (75 mL) was added potassium carbonate (17.4 [G,] 126 mmole). After 5 minutes <strong>[70987-78-9](R)-glycidyl tosylate</strong> (9.67 g, 42.3 mmole) was added, then the heterogeneous mixture was heated to 70 [C] for 3 hours. After removal of the solvent in vacuum, the residue was taken into water (800 mL) and was then extracted with ethyl acetate (4 x 300 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporate to dryness in vacuum. The crude brown oil thus obtained was column chromatographed on silica gel with 40% hexane/ethyl acetate as eluent to give the (S) -enantiomer of the title compound as a yellow oil which solidifies upon standing (7.5 g, 78%). MS [(ESI)] m/z 223 (M-H)-. Elemental Analysis for: [C11H12O5No.0.10 H2O] [CALC'D : C, 58.46 ; H, 5.44] Found: C, 58.02 ; H, 5.09
78%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 70℃; for 3h;	[0076] To a solution of 2', 3', 4'-trihydroxyacetophenone (10.6 g, 63.0 [MMOL)] in DMF (75 mL) was added potassium carbonate (17.4 g, 126 [MMOL).] After 5 minutes (R)- glycidyl tosylate (9.67 g, 42.3 [MMOL)] was added, then the heterogeneous mixture was heated to [70C] for 3 hours. After removal of the solvent in vacuum, the residue was taken into water (800 mL) and was then extracted with ethyl acetate (4 x 300 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporate to dryness in vacuum. The crude brown oil thus obtained was column chromatographed on silica gel with 40% hexane/ethyl acetate as eluant to give the (S) -enantiomer of the title compound as a yellow oil which solidifies upon standing (7.5 g, 78%). MS [(ESI)] m/z 223 (M-H)-

78%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 70℃; for 3h;	[0082] To a solution of 2', 3', 4'-trihydroxyacetophenone (10.6 [G,] 63.0 [MMOLE)] in DMF (75 mL) was added potassium carbonate (17.4 g, 126 mmole). After 5 minutes (R)-glycidyl tosylat (9.67 g, 42. [3 MMOLE)] was added, then the heterogeneous mixture was heated to [70C] for 3 hours. After removal of the solvent in vacuum, the residue was taken into water (800 mL) and was then extracted with ethyl acetate (4 x 300 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporate to dryness in vacuum. The crude brown oil thus obtained was column chromatographed on silica gel with 40% hexane/ethyl acetate as eluent to give the (S) -enantiomer of the title compound as a yellow oil which solidifies upon standing (7.5 g, 78%). MS (ESI) [M/Z] 223 (M-H)-.Elemental Analysis for: [C1 HT200 0. 10 H2O] Calc'd : C, 58.46 ; H, 5.44 Found: C, 58.02 ; H, 5.09
75%		To a solution of 2', 3', 4'-trihydroxyacetophenone (10.6 g, 63.0 mmole) in DMF (75 mL) was added potassium carbonate (17.4 g, 126 [MMOLE).] After 5 minutes <strong>[70987-78-9](R)-glycidyl tosylate</strong> (9.67 g, 42.3 mmole) was added, then the heterogeneous mixture was heated to [70C] for 3 hours. After removal of the solvent in vacuum, the residue was taken into water (800 mL) and was then extracted with ethyl acetate (4 x 300 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporate to dryness in vacuum. The crude brown oil thus obtained was column chromatographed on silica gel with 40% hexane/ethyl acetate as eluant to give the (S) -enantiomer of the title compound as a yellow oil which solidifies upon standing (7.5 g, 78%). MS [(ESI)] m/z 223 (M-H)-. Elemental Analysis for: [C"H, 2O5 0. 10 H2O] Calc'd : C, 58.46 ; H, 5.44 Found: C, 58.02 ; H, 5.09

Reference： [1]Patent: US2003/225157,2003,A1 .Location in patent: Page 6
[2]Patent: WO2004/24730,2004,A1 .Location in patent: Page 41
[3]Patent: WO2004/24734,2004,A1 .Location in patent: Page 40
[4]Patent: WO2004/24732,2004,A1 .Location in patent: Page 39
[5]Patent: WO2004/24733,2004,A1 .Location in patent: Page 41-42

18
[ 387-43-9 ]
[ 70987-78-9 ]
[ 247915-94-2 ]

Yield	Reaction Conditions	Operation in experiment
28%	With sodium hydride;18-crown-6 ether; In N,N-dimethyl-formamide; at 60℃; for 5h;	Example 6 1-N-(S)-Glycidyl-<strong>[387-43-9]4-fluoroindole</strong> (2S)-(+)-Glycidyl tosylate (1.7 g, 7.4 mmole) was added to a stirred solution of <strong>[387-43-9]4-fluoroindole</strong> (1.0 g, 7.4 mmole), sodium hydride (0.33 g, 8.1 mmole) and 18-crown-6 (10 mg) in anhydrous DMF (20 ml), and the mixture was heated at 60°C under nitrogen for five hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3 x 25 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a light yellow colored oil (1.15 g). This was purified by flash silica gel chromatography (30percent ethyl acetate in hexane) to afford the titled product as a light oil (0.4 g, 28percent yield). Elemental Analysis for : C11H10FNO Calculated: C, 69.10; H, 5.27; N, 7.33 Found: C, 69.27; H, 5.40; N, 7.43at;at;--3at;at;

Reference： [1]Patent: EP1075471,2004,B1 .Location in patent: Page 7

19
[ 4837-90-5 ]
[ 70987-78-9 ]
[ 247915-93-1 ]

Yield	Reaction Conditions	Operation in experiment
47%	With sodium hydride;18-crown-6 ether; In N,N-dimethyl-formamide; at 60℃; for 5h;	Example 5 1-N-(S)-Glycidyl-4-methoxyindole (2S)-(+)-Glycidyl tosylate (1.55 g, 6.8 mmole) was added to a stirred solution of 4-methoxyindole (1.0 g, 6.8 mmole), sodium hydride (0.3 g, 7.5 mmole) and 18-crown-6 (10 mg) in anhydrous DMF (20 ml), and the mixture was heated at 60C under nitrogen for five hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3 x 25 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a light yellow colored oil (1.15 g). This was purified by flash silica gel chromatography (30% ethyl acetate in hexane) to afford the titled product as a light oil (0.65 g, 47% yield). Elemental Analysis for: C12H13NO2 Calculated: C, 70.92; H, 6.45; N, 6.89 Found: C, 71.11; H, 6.59; N, 6.99 aa--3aa

Reference： [1]Patent: EP1075471,2004,B1 .Location in patent: Page 6-7

20
[ 740799-82-0 ]
[ 70987-78-9 ]
[ 740799-83-1 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5h;	To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added methyl 3,4-dihydroxy-2-methylbenzoate (24.0 g, 132 mmol), (2R)-(-)-glycidyl tosylate (30.1 g, 132 mmol), potassium carbonate (21.8 g, 158 mmol), and DMF (264 mL). This mixture was heated to 60 C. for 5 hours. The mixture was cooled to room temperature, diluted with ether, and washed once with water. The aqueous wash was back extracted once with ether and the ethereal solutions combined. These organic solutions were then washed 3 times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to give a brown oil. This oil was chromatographed on silica gel eluting with 25% ether in hexanes to give a yellow oil, 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester, (24.6 g, 103 mmol) in 78% yield. 1H-NMR (300 MHz, CD3COCD3) delta (ppm): 2.42 (s, 2H), 3.80 (s, 3H), 3.83 (m, 1H), 4.12 (dd, 1H), 4.23 (m, 2H), 4.42 (dd, 1H), 6.75 (d, 1H), 7.42 (d, 1H); TLC Rf=0.40 (1:1 ethyl acetate/hexane). Notes: (a) (2S)-(+)-Glycidyl tosylate can be used under identical conditions to give the opposite stereochemistry, (b) Formation of a Mosher's ester of this compound indicates the presence of a single regio and stereoisomer by 19F NMR, (c) X-ray crystal structure determination of the amide formed from (R)-(+)-1-(1-naphthyl)ethylamine confirmed the indicated regio and stereochemistry for the product 3-hydroxymethylbenzodioxan. Delgado, A.; Leclerc, G.; Lobato, C.; Mauleon, D. Tetrahedron Lett. 1988, 29(30), 3671.

Reference： [1]Patent: US2005/209283,2005,A1 .Location in patent: Page/Page column 34

21
[ 110894-91-2 ]
[ 70987-78-9 ]
[ 330651-27-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20℃;	Add a solution of 3-thieno[2,3-d]isoxazol-3-yl-phenol (Example 1, 0.42 g, 0.0019 mol) and dimethylformamide (4 mL) dropwise under nitrogen to a stirred mixture of sodium hydride (0.051 g, 0.0021 mol, 60% oil dispersion) and dry dimethylformamide (4 mL). Stir 20 min., and add a solution of (2R)-(-)glycidyl tosylate (recrystallize first from dichloromethane/heptane) and dimethylformamide (4 mL). Stir overnight at room temperature under nitrogen, pour into water (100 mL) and extract with ethyl acetate. Dry the extract (Na2SO4), filter and evaporate, and purify the residue by flash chromatography (silica gel, gradient elution with 0 to 1% methanol in dichloromethane), and recrystallize the recovered product from ethanol to afford the title compound, (0.47 g, 89% yield ), m.p. 86-87C, [alpha]D20 -3.45 (c=0.985, CHCl3). ANALYSIS: Calculated for: 61.53% C, 4.06%H, 5.12%N. Found: 61.66%C, 3.68%H, 5.02%N.

Reference： [1]Patent: EP1216250,2003,B1 .Location in patent: Page/Page column 27

22
[ 18362-30-6 ]
[ 70987-78-9 ]
(R)-2-chloro-6-(2,3-epoxypropoxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N-methyl-acetamide; dichloromethane; water; Petroleum ether;	EXAMPLE 2 A stirred mixture of <strong>[18362-30-6]2-chloro-6-hydroxybenzaldehyde</strong> (4.4 g), (R)-glycidyl 4-toluenesulphonate (5.0 g) and potassium carbonate (3.9 g) in dimethylformamide (120 ml) was heated at 60° C. for 5 hours then allowed to stand at ambient temperature for 18 hours. The solvent was removed in vacuo, water (60 ml) was added and the mixture extracted with ether (3*100 ml). The combined extracts were dried over magnesium sulphate and the solvent evaporated. The residue was purified by flash chromatography on silica eluding with a 1:1 mixture of petroleum ether (b.p. 60-80° C.) and dichloromethane followed by a 19:1 mixture of dichloromethane and industrial methylated spirit. Appropriate fractions were combined and the solvent was removed in vacuo to give (R)-2-chloro-6-(2,3-epoxypropoxy)benzaldehyde (2.8 g) m.p. 62-64° C.
	With potassium carbonate; In N-methyl-acetamide; dichloromethane; water; Petroleum ether;	EXAMPLE 9 A mixture of <strong>[18362-30-6]2-chloro-6-hydroxybenzaldehyde</strong> (4.4 g), (R)-glycidyl 4-toluenesulphonate (5.0 g) and potassium carbonate (3.9 g) in dimethylformamide (120 ml) was stirred and heated at 60° C. for 5 hours and allowed to cool over 18 hours. The solvent was removed in vacuo, water (60 ml) was added to the residue and the mixture extracted with ether (3*100 ml). The combined extracts were dried over magnesium sulphate and the solvent was evaporated. The residual oil was purified by flash chromatography on silica eluding with a 1:1 mixture of petroleum ether (b.p. 40-60° C.) and dichloromethane, followed by neat dichloromethane then a 19:1 mixture of dichloromethane and industrial methylated spirit. Appropriate fractions were combined and the solvent removed in vacuo to give (R)-2-chloro-6-(2,3-epoxypropoxy)benzaldehyde as a pale yellow solid (2.8 g). Other, incompletely purified, fractions gave material which was subjected to repeat chromatography, providing a second crop of product (0.5 g).

Reference： [1]Patent: US5935973,1999,A
[2]Patent: US5935973,1999,A

23
[ 913629-09-1 ]
[ 70987-78-9 ]
[ 913629-10-4 ]

Yield	Reaction Conditions	Operation in experiment
77%		Intermediate 80 (R)-2-(2',6'-Dichloro-5-fluoro-2-methoxy-biphenyl-3-yloxymethyl)-oxirane: To a suspension of sodium hydride (60%, 0.62 g, 15.4 mmol) in DMF was added 2',6'-dichloro-5-fluoro-2-methoxy-biphenyl-3-ol (2.95 g, 10.2 mmol) at 0 C. The mixture was stirred at room temperature for 30 min. Then a solution of the (R)-(-)-glydicyl tosylate (4.7 g, 20.4 mmol) in DMF was introduced at room temperature. The resulting mixture was heated at 100 C. overnight and poured into ice-water. The mixture was extracted with methylene chloride. The organic layer was washed with water and dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography with 20% ethyl acetate in hexanes afforded 2.73 g (77%) of title compound as a colorless oil. [alpha]=-13.2 (c 1% solution, MeOH); HRMS ESI m/e 360.0573 (M+NH4)+

Reference： [1]Patent: US2006/241172,2006,A1 .Location in patent: Page/Page column 56
[2]Patent: US2006/241172,2006,A1 .Location in patent: Page/Page column 38

24
[ 70987-78-9 ]
[ 42399-49-5 ]
[ 110-17-8 ]
(+)-cis-(2S,3S)-2-(4-methoxyphenyl)-3-hydroxy-5-[(3R)-3-dimethylamino-2-hydroxypropyl]-2,3-dihydro-5H-1,5-benzothiazepin-4-one fumarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dimethyl amine; In dimethyl sulfoxide;	EXAMPLE 7 0.393 g (0.0082 mole) of 50% strength sodium hydride and 40 ml of dimethyl sulphoxide are introduced under inert atmosphere into a 150-ml reactor. The mixture is stirred for 1 h at 70 C. and cooled to 20 C., and 2.37 g (0.0079 mole) of (+)-cis-(2S,3S)-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-5H-1,5-benzothiazepin-4-one, dissolved in 20 ml of dimethyl sulphoxide, are added. The stirring is maintained at 30 C. for 1 h, the mixture is allowed to cool to 25 C. and 2 g (0.0088 mole) of (-)-(R)-glycidyl tosylate are added in a single portion, and stirring is continued for 2 h 30 min at this temperature. 5 g (0.11 mole) of anhydrous dimethylamine are added, and the mixture is heated to 40 C. for 2 h and left with stirring overnight without heating. The mixture is poured into ice-cold saturated sodium bicarbonate solution and extracted three times with ether, and the organic phase is washed with water and dried over magnesium sulphate. The ether is evaporated off and the 3.2 g of crude residue are purified by chromatography on a column of silica, eluding with a 90:10:2 dichloromethane/methanol/ammonia solution mixture. 2 g of pure base are obtained, and this is treated with one equivalent of fumaric acid, and, after recrystallization in ethanol, 1.7 g of (+)-cis-(2S,3S)-2-(4-methoxyphenyl)-3-hydroxy-5-[(3R)-3-dimethylamino-2-hydroxypropyl]-2,3-dihydro-5H-1,5-benzothiazepin-4-one fumarate are isolated. M.p. 158 C. [alpha]D20 =+123 (c=1%, CH3 OH).

Reference： [1]Patent: US4743599,1988,A

25
[ 3428-24-8 ]
[ 70987-78-9 ]
[ 871824-63-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-Glycidyl tosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 C. for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 mL) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO4) and evaporated in vacuo to yield a viscous oil of (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	EXAMPLE 10 (2S)-(-)-N-(6,7Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide (Compound #29) 4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-Glycidyl tosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 C. for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 mL) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO4) and evaporated in vacuo to yield a viscous oil of (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 24h;	4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 ml_). (2R)-Glycidyl tosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 600C for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 mL) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO4) and evaporated in vacuo to yield a viscous oil of (2S)-2- (6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxine) methanol.The (2S)-2-(6,7 dichloro-2,3-dihydro-benzo[1 ,4]dioxine) methanol oil (6.4 g, 27 mmol) was dissolved in pyridine (50 mL) cooled to 00C. Then, p- toluenesulfonyl chloride (5.2 g, 27 mmol) was added and the reaction mixture was stirred at room temperature for 2Oh. The reaction mixture was diluted with diethyl ether and 1 N HCI (750 mL) and the organic layer was separated and washed 2 times with 1 N HCI (250 mL), once with water (150 mL), twice with brine, dried (MgSO4) and evaporated in vacuo to yield light yellow solid of toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxin-2- ylmethyl ester. <n="44"/>1H NMR (CDCI3): delta 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.94 (s, 1 H), 6.83 (s, 1 H), 4.37 (m, 1 H), 4.2 (m, 3H), 4.03 (dd, J = 6.3, 1 1.7 Hz, 1 H), 2.47 (s, 3H).Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxin- 2-ylmethyl ester (8.0 g, 20.5 mmol) was combined with potassium phthalimide (6.1 g, 33 mmol) in DMF (75 mL) and heated to reflux for 1 h, cooled to room temperature and poured into vigorously stirring water (0.5 L) and then stirred 30 min. White solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and then let air dry to yield (2S)-2-(6,7- dichloro-2,3-dihydro-benzo[1 ,4]dioxin-2-ylmethyl)-isoindole-1 ,3-dione (6.0 g, 80%) as a white powdery solid.The white powdery solid was combined with hydrazine (1.06 g, 33 mmol) in EtOH (80 mL) and heated at reflux for 2 h, then cooled to room temperature. 1 N HCI was added to adjust the reaction mixture's pH to pH 1.0 and the reaction mixture was then stirred for 15 min. White solid was filtered and washed with fresh EtOH (solid discarded) and the filtrate was evaporated in vacuo to a solid, which was partitioned between diethyl ether and dilute aqueous NaOH. The diethyl ether solution was dried (Na2SO4) and evaporated in vacuo to a yield a viscous oil of (2S)-2-aminomethyl-(6,7-dichloro-2,3- dihydro-benzo[1 ,4]dioxine).1H NMR (CDCI3): delta 6.98 (s, 1 H), 6.96 (s, 1 H), 4.25 (dd, J = 2.0, 1 1.2 Hz, 1 H), 4.15 (m, 1 H), 4.0 (m, 1 H), 2.97 (d, J = 5.5 Hz, 2H)A portion of the oil (3.8 g, 16 mmol) and sulfamide (3.1 g, 32.4 mmol) were refluxed in dioxane (100 mL) for 2 h and the crude product was purified by flash column chromatography (DCM:MeOH 20:1 ) to yield the title compound as a white solid, which was recrystallized from ethyl acetate / hexane to yield the title compound as a white crystalline solid.MS [M-H]" 31 1 .0 mp 1 19-121 C [alpha]D = -53.4 (c = 1.17, M)1H NMR (DMSOd6): delta 7.22 (s, 1 H), 7.20 (s, 1 H), 6.91 (bd s, 1 H), 6.68 (bd s, 2H), 4.35 (m, 2H), 4.05 (dd, J = 6.5, 1 1 .5 Hz, 1 H), 3.15 (m, 2H) Elemental Analysis: <n="45"/>Elemental Analysis:Measured: C, 34.52; H, 3.22; N, 8.95; Cl, 22.64; S, 10.24Calculated: C, 34.64; H, 2.68; N, 8.87; Cl, 22.94; S, 10.35.

	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	EXAMPLE 10 (2S)-(-)-N-(6,7 Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide (Compound #29) 4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-Glycidyl tosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 C. for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 mL) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO4) and evaporated in vacuo to yield a viscous oil of (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	Example 11; (2SW-)-N-(6,7Dichloro-2.3-dihvdro-benzon,41dioxin-2-vlmethvl)-sulfamide(Compound No.29); 4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 ml_). (2R)-Glycidyl tosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60C for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 ml_) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSCXj) and evaporated in vacuo to yield a viscous oil of (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-Glycidyl tosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 C. for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 mL) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO4) and evaporated in vacuo to yield a viscous oil of (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-Glycidyl tosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 C. for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 mL) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO4) and evaporated in vacuo to yield a viscous oil of (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-Glycidyl tosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 C. for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 mL) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO4) and evaporated in vacuo to yield a viscous oil of (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol. The (2S)-2-(6,7 dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol oil (6.4 g, 27 mmol) was dissolved in pyridine (50 mL) cooled to 0 C. Then, p-toluenesulfonyl chloride (5.2 g, 27 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with diethyl ether and 1N HCl (750 mL) and the organic layer was separated and washed 2 times with 1N HCl (250 mL), once with water (150 mL), twice with brine, dried (MgSO4) and evaporated in vacuo to yield light yellow solid of toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. 1H NMR (CDCl3): delta 7.79 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 6.94 (s, 1H), 6.83 (s, 1H), 4.37 (m, 1H), 4.2 (m, 3H), 4.03 (dd, J=6.3, 11.7 Hz, 1H), 2.47 (s, 3H). Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxin-2-ylmethyl ester (8.0 g, 20.5 mmol) was combined with potassium phthalimide (6.1 g, 33 mmol) in DMF (75 mL) and heated to reflux for 1 h, cooled to room temperature and poured into vigorously stirring water (0.5 L) and then stirred 30 min. White solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and then let air dry to yield (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%) as a white powdery solid. The white powdery solid was combined with hydrazine (1.06 g, 33 mmol) in EtOH (80 mL) and heated at reflux for 2 h, then cooled to room temperature. 1N HCl was added to adjust the reaction mixture's pH to pH 1.0 and the reaction mixture was then stirred for 15 min. White solid was filtered and washed with fresh EtOH (solid discarded) and the filtrate was evaporated in vacuo to a solid, which was partitioned between diethyl ether and dilute aqueous NaOH. The diethyl ether solution was dried (Na2SO4) and evaporated in vacuo to a yield a viscous oil of (2S)-2-aminomethyl-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine). 1H NMR (CDCl3): delta 6.98 (s, 1H), 6.96 (s, 1H), 4.25 (dd, J=2.0, 11.2 Hz, 1H), 4.15 (m, 1H), 4.0 (m, 1H), 2.97 (d, J=5.5Hz, 2H) A portion of the oil (3.8 g, 16 mmol) and sulfamide (3.1 g, 32.4 mmol) were refluxed in dioxane (100 mL) for 2 h and the crude product was purified by flash column chromatography (DCM:MeOH 20:1) to yield the title compound as a white solid, which was recrystallized from ethyl acetate/hexane to yield the title compound as a white crystalline solid. MS [M-H]- 311.0 mp 119-121 C. [alpha]D=-53.4 (c=1.17, M) 1H NMR (DMSOd6): delta 7.22 (s, 1H), 7.20 (s, 1H), 6.91 (bd s, 1H), 6.68 (bd s, 2H), 4.35 (m, 2H), 4.05 (dd, J=6.5, 11.5 Hz, 1H), 3.15 (m, 2H) Elemental Analysis: Elemental Analysis: Measured: C, 34.52; H, 3.22; N, 8.95; Cl, 22.64; S, 10.24 Calculated: C, 34.64; H, 2.68; N, 8.87; Cl, 22.94; S, 10.35.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-Glycidyl tosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 C. for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 mL) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO4) and evaporated in vacuo to yield a viscous oil of (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol. The (2S)-2-(6,7 dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol oil (6.4 g, 27 mmol) was dissolved in pyridine (50 mL) cooled to 0 C. Then, p-toluenesulfonyl chloride (5.2 g, 27 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with diethyl ether and 1N HCl (750 mL) and the organic layer was separated and washed 2 times with 1N HCl (250 mL), once with water (150 mL), twice with brine, dried (MgSO4) and evaporated in vacuo to yield light yellow solid of toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. 1H NMR (CDCl3): delta 7.79 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 6.94 (s, 1H), 6.83 (s, 1H), 4.37 (m, 1H), 4.2 (m, 3H), 4.03 (dd, J=6.3, 11.7 Hz, 1H), 2.47 (s, 3H). Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (8.0 g, 20.5 mmol) was combined with potassium phthalimide (6.1 g, 33 mmol) in DMF (75 mL) and heated to reflux for 1 h, cooled to room temperature and poured into vigorously stirring water (0.5 L) and then stirred 30 min. White solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and then let air dry to yield (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%) as a white powdery solid. The white powdery solid was combined with hydrazine (1.06 g, 33 mmol) in EtOH (80 mL) and heated at reflux for 2 h, then cooled to room temperature. 1N HCl was added to adjust the reaction mixture's pH to pH 1.0 and the reaction mixture was then stirred for 15 min. White solid was filtered and washed with fresh EtOH (solid discarded) and the filtrate was evaporated in vacuo to a solid, which was partitioned between diethyl ether and dilute aqueous NaOH. The diethyl ether solution was dried (Na2SO4) and evaporated in vacuo to a yield a viscous oil of (2S)-2-aminomethyl-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine). 1H NMR (CDCl3): delta 6.98 (s, 1H), 6.96 (s, 1H), 4.25 (dd, J=2.0, 11.2 Hz, 1H), 4.15 (m, 1H), 4.0 (m, 1H), 2.97 (d, J=5.5 Hz, 2H) A portion of the oil (3.8 g, 16 mmol) and sulfamide (3.1 g, 32.4 mmol) were refluxed in dioxane (100 mL) for 2 h and the crude product was purified by flash column chromatography (DCM:MeOH 20:1) to yield the title compound as a white solid, which was recrystallized from ethyl acetate/hexane to yield the title compound as a white crystalline solid. MS [M-H]- 311.0 mp 119-121 C. [alpha]D=-53.4 (c=1.17, M) 1H NMR (DMSOd6): delta 7.22 (s, 1H), 7.20 (s, 1H), 6.91 (bd s, 1H), 6.68 (bd s, 2H), 4.35 (m, 2H), 4.05 (dd, J=6.5, 11.5 Hz, 1H), 3.15 (m, 2H) Elemental Analysis: Elemental Analysis: Measured: C, 34.52; H, 3.22; N, 8.95; Cl, 22.64; S, 10.24 Calculated: C, 34.64; H, 2.68; N, 8.87; Cl, 22.94; S, 10.35.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-Glycidyl tosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 C. for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 mL) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO4) and evaporated in vacuo to yield a viscous oil of (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;	4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-Glycidyl tosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 600C for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 mL) and extracted with diethyl ether (4 times). The combined - organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO4) and evaporated in vacuo to yield a viscous oil of (2S)-2- (6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxine) methanol.

Reference： [1]Patent: US2007/155822,2007,A1 .Location in patent: Page/Page column 17
[2]Patent: US2007/155824,2007,A1 .Location in patent: Page/Page column 23
[3]Patent: WO2007/137167,2007,A2 .Location in patent: Page/Page column 42-44
[4]Patent: US2009/247616,2009,A1 .Location in patent: Page/Page column 18
[5]Patent: WO2006/7435,2006,A1 .Location in patent: Page/Page column 46
[6]Patent: US2007/155821,2007,A1 .Location in patent: Page/Page column 18
[7]Patent: US2007/155823,2007,A1 .Location in patent: Page/Page column 16
[8]Patent: US2007/155825,2007,A1 .Location in patent: Page/Page column 16
[9]Patent: US2007/155826,2007,A1 .Location in patent: Page/Page column 18-19
[10]Patent: US2007/155827,2007,A1 .Location in patent: Page/Page column 17
[11]Patent: WO2007/75833,2007,A2 .Location in patent: Page/Page column 41
[12]Patent: US2007/191474,2007,A1 .Location in patent: Page/Page column 18
[13]Patent: US2005/282887,2005,A1 .Location in patent: Page/Page column 20
[14]Journal of Medicinal Chemistry,2013,vol. 56,p. 9019 - 9030

26
[ 3316-09-4 ]
[ 70987-78-9 ]
[ 546072-97-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	EXAMPLE 1 Preparation of (S)-(7-Nitro-2,2-dihydro-benzo[1,4]dioxin-2-yl)methanol A mixture of 4-nitrobenzene-1,2-diol (1.0 g, 6.4 mmoles), (2R)-(-)-glycidyl tosylate (1.75 g, 7.7 mmoles) and K2CO3 (2.12 g, 15.4 mmoles) in DMF was stirred at room temperature overnight, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum. The resultant residue was recrystallized from ethanol to afford the title compound as an off white solid (1.08 g, 5.11 mmoles), identfied by H-NMR and mass spectral analyses.
180 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;	A suspension of <strong>[3316-09-4]4-nitrocatechol</strong> (310 mg, 2.00 mmol), (R)-glycidyl tosylate (545 mg, 2.40 mmol) and K2CO3 (663 mg, 4.80 mmol) in 5 mL DMF was heated at 60 C for 2 h. The mixture was poured onto 15 mL water and extracted with 4 × 20 mL diethyl ether. The combined organic phases were subsequently washed with 3 × 20 mL 10% aq. K2CO3, 20 mL water and 20 mL brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude product obtained was purified by column cromatography (petrolether:ethyl acetate = 1:1) to give 180 mg of yellow crystals (43%); mp 117-119 C; [alpha]D = -61.6 (c = 0.5 in CHCl3); 1H NMR (300 MHz, CDCl3): delta (ppm) 1.93 (t, J = 6.19 Hz, 1H, OH), 3.86-4.04 (m, 2H, CH2OH), 4.13-4.27 (m, 1H, CH), 4.30-4.47 (m, 2H, CH2O), 6.93-7.03 (m, 1H, Ar-H5), 7.75-7.86 (m, 2H, Ar-H6, Ar-H8).

Reference： [1]Patent: US2007/244179,2007,A1 .Location in patent: Page/Page column 8
[2]European Journal of Medicinal Chemistry,2013,vol. 62,p. 329 - 340

27
[ 3316-09-4 ]
[ 70987-78-9 ]
[ 124-63-0 ]
[ 1106940-84-4 ]

Yield	Reaction Conditions	Operation in experiment
		(S)-2-[(R)-3-(3-Hydroxy-phenyl)-piperidin-l-ylmethyl]-2,3-dihydrobenzo[1,4] dioxin-5-ol. 4-Nitrobenzene-l, 2-diol (12, 9 mmol, 2.0 g) was dissolved in dry DMF (15 ml). Anhydrous potassium carbonate (15,5 mmol, 2.1 g) was added and reaction mixture was warmed to 50C. (2R)-(-)-glycidyl tosylate (13, 5 mmol, 3.2 g) was dissolved to DMF (2 ml) and added drop wise at 50C. The reaction mixture was heated to 120C for 2h. After cooling the mixture was quenched with water and filtered. The water layer was extracted twice with ethyl acetate. The organic phases were combined and washed twice with water and saturated sodium chloride solution. The organic phase was dried (Na2SO4), filtered and evaporated to dryness. This gave 2.1 g of the title compound as a mixture of isomers (20/80). Purification was done by crystallizations (CHCl3 and chlorobenzen) to give 0.6 g of the title compound.1H NMR (DMSO): delta 3.62-3.71 (m, 2H), 4.14-4.19 (m, IH), 4.25-4.47 (m, IH), 4.47- 4.50 (m, IH), 5.13 (t, IH), 7.10 (d, IH), 7.12-7.78 (m, 2H). Methanesulfonic acid (R)-7-nitro-2,3-dihydro-benzo[l,4]dioxin-2-ylmethyl ester (S)>2-[(R)-3-(3-Hydroxy-phenyl)-piperidin- 1 -ylmethyl]-2,3-dihydro- benzo[l,4]dioxin-5-ol (2.84 mmol, 0.6Og) was dissolved in dry dichloromethane. Triethylamine (0.43 ml) was added and the mixture was cooled to 0C. Methanesulfonyl chloride (2.94 mmol, 0.34g) was added drop wise at 0C. The mixture was allowed to warm to RT and stirred over night. IM Hydrogen chloride solution (10 ml) was added. Water phase was extracted twice with DCM and the organic phases were combined. The organic phase was extracted with water and brine and evaporated to dryness. The crude product was purified by crystallization (EtOH) to give 0.48 g of the title compound.1H NMR (CDCl3): delta 3.11 (s, 3H), 4.19-4.24 (m, IH), 4.43-4.54 (m, 4H), 6.69 (d, IH), 7.81-7.84 (m, 2H).

Reference： [1]Patent: WO2009/13390,2009,A1 .Location in patent: Page/Page column 95-96

28
[ 394-32-1 ]
[ 70987-78-9 ]
[ 1106940-62-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 6h;	l-[5-Fluoro-2-((R)-l-(oxiranylmethoxy)-phenyl]-ethanone. A mixture of 5'-fluoro-2'-hydroxyacetophenone (2.04 g, 13.25 mmol), (2R)-(-)-glycidyl tosylate (2.75 g, 12.05 mmol), potassium carbonate (2.16 g, 15.66 mmol) and N,N- dimethyl formamide (20 ml) was heated to 60C. After 6 hours the reaction mixture was cooled down, water (20 ml) and ethyl acetate (20 ml) were added and the layers were separated. Organic phase was recovered and water layer was extracted twice with ethyl acetate. Organic phase and ethyl acetate extracts were combined and washed twice with water and evaporated to dryness. The crude product was crystallized from 2-propanol to yield 1.91 g (76%) of the pure title compound.1H NMR (CDCl3): delta 2.65 (s, 3H), 2.75-2.77 (m, IH), 2.93-2.95 (t, IH), 3.37-3.41 (m, IH), 3.95-4.00 (m, IH), 4.35-4.39 (m, IH), 6.91-6.94 (m, IH), 7.12-7.17 (m, IH), 7.44-7.47 (m, IH).

Reference： [1]Patent: WO2009/13390,2009,A1 .Location in patent: Page/Page column 80-81

29
[ 30992-63-3 ]
[ 70987-78-9 ]
[ 1106940-36-6 ]

Yield	Reaction Conditions	Operation in experiment
		l-[5-Benzyloxy-2-((R)-l-oxiranylmethoxy)phenyl]ethanone. To a stirred solution of l-(5-benzyloxy-2-hydroxyphenyl)ethanone (3.0 g, 12.4 mmol) in anhydrous DMF (15 ml) was added NaH (0.55 g, 13.6 mmol). The mixture was allowed to stir at RT for 30 min and then heated to 60 C. A solution of (i?)-oxiran-2- ylmethyl 4-methylbenzenesulfonate (2.83 g, 12.4 mmol) in DMF was added dropwise at 60 C during 1 h. Stirring was then continued at 60 C for 3 h. The cooled reaction was quenched by addition of water (80 ml) and extracted three times with EtOAc. The combined organic layers were extracted twice with aq 1 M NaOH and washed with water and brine. The organic layer was dried with Na2SO4 and concentrated. The crude product obtained was purified by column chromatography with EtO Ac/toluene as eluent to afford the title compound (2.35 g) as a white solid.1H NMR (CDCl3): delta 2.67 (s, 3H), 2.75 (m, IH), 2.93 (t, IH), 3.37-3.40 (m, IH), 3.96 (dd, IH), 4.32 (dd, IH), 5.04 (s, 2H), 6.89 (d, IH), 7.08 (dd, IH), 7.32-7.43 (m, 6H).

Reference： [1]Patent: WO2009/13390,2009,A1 .Location in patent: Page/Page column 53-54

30
[ 501-92-8 ]
[ 113826-06-5 ]
[ 1176891-21-6 ]

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 11701 - 11706

31
[ 853921-70-7 ]
[ 70987-78-9 ]
[ 890087-93-1 ]

Yield	Reaction Conditions	Operation in experiment
83%		To a stirred solution of the phenol from Preparation 1 (2.00 g, 5.67 mmol) in anhydrous N,N-dimethylformamide (DMF, 50 mL) was added NaH (60% dispersion in mineral oil, 0.227 g, 5.67 mmol) under nitrogen atmosphere. After 10 min (2R)-(-)-glycidyl tosylate (1.94 g, 8.51 mmol) was added and the mixture was heated at 70 C. for 1 h. Potassium carbonate (0.39 g, 2.84 mmol) was added and heating was continued for additional 1.5 h. DMF was evaporated and the residue was mixed with a saturated aqueous solution of sodium bicarbonate (50 mL) then extracted with ethyl acetate (50 mL*3). The combined extracts were dried over magnesium sulfate, filtered and evaporated to dryness. Chromatography on silica eluding with a gradient of 20% to 60% ethyl acetate/hexane gave the desired product as an oil (1.92 g, 83%) and starting material (0.27 g, 13%). LCMS (+APCI) m/z 410 (M+H), 1H NMR (600 MHz, CDCl3) delta 10.67 (s, 1H), 7.95 (s, 1H), 7.89 (d, J=12 Hz, 1H), 7.32-7.26 (m, 5H), 7.22 (d, J=6 Hz, 1H), 6.87 (d, J=6 Hz, 1H), 5.49 (d, J=6 Hz, 1H), 4.97-4.87 (m, 2H), 4.85-4.82 (m, 2H), 4.43 (dd, J=12, 6 Hz, 1H), 4.16 (bd, 2H), 3.41 (s, 1H), 2.96 (1H), 2.78 (m, 1H), 1.19 (d, J=12 Hz, 3H).

Reference： [1]Patent: US2006/122251,2006,A1 .Location in patent: Page/Page column 8

32
[ 913629-44-4 ]
[ 70987-78-9 ]
[ 913629-51-3 ]

Yield	Reaction Conditions	Operation in experiment
86%		Intermediate 127 (R)-2-(2-Benzyloxy-2',6'-dichloro-biphenyl-3-yl oxymethyl)-oxirane: To a suspension of sodium hydride (60%, 0.47 g, 11.7 mmol) in DMF was added 2-benzyloxy-2',6'-dichloro-biphenyl-3-ol (2.70 g, 7.8 mmol) at 0 C. The mixture was stirred at room temperature for 30 min. Then a solution of (R)-(-)-glydcidyl tosylate (3.57 g, 15.6 mmol) in DMF was introduced at room temperature. The resulting mixture was heated at 100 C. overnight and poured into the ice water. The mixture was extracted with methylene chloride. The organic layer washed with water and dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography with 20% ethyl acetate in hexanes afforded 2.2 g (86%) of title compound as a colorless oil. MS ESI m/e 418.0965 [M+NH4]+

Reference： [1]Patent: US2006/241172,2006,A1 .Location in patent: Page/Page column 61

33
[ 1402419-41-3 ]
[ 70987-78-9 ]
[ 1402419-43-5 ]

Yield	Reaction Conditions	Operation in experiment
90%		EXAMPLE 8SYNTHESIS OF (S)- 1 -(4-(2-(4-((R)-OXIRAN-2-YLMETHOXY)PHENYL)PROPAN-2- YL)PHENOXY)-3-(PROP-2-YNYLOXY)PROPAN-2-OL (11); Potassium carbonate anhydrous (162 mg, 1.17 mmol, 2.0 equiv) was added to a stirred solution of derivative 8 (200 mg, 0.58 mmol, 1 equiv) in anhydrous dimethyl formamide (1.5 mL) at room temperature, and the contents were stirred under an atmosphere of argon for 20 min. A solution of (2i?)-(-)-glycidyl tosylate 98% (267 mg, 1.17 mmol, 2.0 equiv) in anhydrous dimethyl formamide (1.5 mL) was added slowly via syringe, and the mixture was allowed to react at room temperature for 182 h. Then, the reaction was quenched by the addition of a saturated solution of ammonium chloride (1 mL), and the mixture was extracted with ethyl acetate (3 x 5 mL). The organic layer was washed with deionized water (5 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10% ethyl acetate in hexane to 40% ethyl acetate) to provide 11 (6S,24R) (210 mg, 90%>) as a clear foam.

Reference： [1]Patent: WO2012/139039,2012,A2 .Location in patent: Page/Page column 93-94

34
[ 3236-71-3 ]
[ 70987-78-9 ]
[ 1403963-69-8 ]

Yield	Reaction Conditions	Operation in experiment
78%		EXAMPLE 6SYNTHESIS OF (2R,2,R -2,2,-(4,4,-(9H-FLUORENE-9.9-DIYL BIS(4, 1- PHENYLENE))BIS(OXY)BIS(METHYLENE)DIOXIRANE (6)Sodium hydride (60% dispersion in mineral oil, 528 mg, 13.19 mmol, 2.5 equiv) was added slowly to a stirred solution of 4,4'-(9-Fluorenylidene)diphenol (1850 mg, 5.27 mmol, 1 equiv) in anhydrous dimethyl formamide (20 mL), at room temperature, and the contents were stirred under an atmosphere of argon for 20 min. A solution of (2i?)-(-)-glycidyl tosylate 98% (3010 mg, 13.19 mmol, 2.5 equiv) in anhydrous dimethyl formamide (5 mL) was added via syringe and the mixture was allowed to react at room temperature for 94 h. Then, the reaction was quenched by the addition of a saturated solution of ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with deionized water (20 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10% to 20% ethyl acetate in hexane) to provide 6 (1.91 g, 78%) as a white solid. H NMR (400 MHz, DMSO-d6): delta 7.90 (d, J = 7.6, 2H), 7.38 (t, J = 8.0, 4H), 7.30 (t, J = 7.2, 2H), 7.02 (d, J = 8.8, 4H), 6.84 (d, J = 8.8, 4H), 4.26-4.22 (dd, J = 1 1.6, 2.8, 2H), 3.79-3.74 (dd, J = 1 1.2, 6.4, 2H), 3.29-3.26 (m, 2H), 2.81 (t, J = 4.8, 2H), 2.67-2.65 (dd, J = 5.2, 2.8, 2H); 13C NMR (100 MHz, DMSO- ): delta 156.9, 151.1 , 139.3, 137.9, 128.7, 127.8, 127.5, 125.9, 120.5, 1 14.3, 68.9, 63.6, 49.6, 43.7; HRMS (ESI) (m/z): calc'd for Cs^eC^Na [M+Na]+: 485.1729, found: 485.1734.

Reference： [1]Patent: WO2012/145330,2012,A1 .Location in patent: Page/Page column 129

35
[ 50352-33-5 ]
[ 70987-78-9 ]
[ 1064662-55-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h;	C. Preparation of (2R)-2-J r2-fbenzylo.)-4-nitrophenoxy1mcthyl}oxirane[0104J A 500 mL round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar is charged with: 2-(ben/yloxy)-4-nitrophenol ( 10.00 g, 40.8 mmol), potassium carbonate (7.05 g, 51.0 mmol), (R)-(-)-glycidyl tosylate ( 10.00 g, 43.8 mmol) and DMF (65 mL). The mixture is immersed in an oil bath heated to 60 0C and stirred for 18 h. The solution is allowed to cool to rt, then water (200 mL) is slowly added. The resulting suspension is stirred for 2 h, the precipitate is collected by vacuum filtration and the filter cake is washed with water (25 mL). The cake is dried under suction to yield 10.70 g (87%) of the title compound as a light eliow powder. LCMS (Standard Method): 2.74 min. 302 (M+H) 1H NMR (300 MHz, CDCl1) delta 7.89 (dd, J = 2.6, 9.0 Hz, IH), 7.81 (d, J = 2.6 Hz, IH), 7.48-7.34 (m, 5H), 6.98 (d, J - 8.8 Hz. 1 H), 5.19 (s, 2H), 4.43 (dd, .7 = 2.7, 1 1.5 Hz, 1 H), 4.08 (dd, J - 5.8, 1 1 .5 Hz, I H), 3.43-3.39 (m, I H), 2.95-2.91 (m, I H), 2.81 -2.78 (m. J H).

Reference： [1]Patent: WO2008/118935,2008,A1 .Location in patent: Page/Page column 34

36
(S)-4-(2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol [ No CAS ]
[ 70987-78-9 ]
[ 1423569-15-6 ]

Yield	Reaction Conditions	Operation in experiment
94%		EXAMPLE 2SYNTHESIS OF (S)-2,2-DIMETHYL-4-((4-(2-(4-((R)-OXIRAN-2- YLMETHOXY)PHENYL)P OPAN-2-YL)PHENOXY)METHYL)- 1 ,3 -DIOXOLANESodium hydride (60%> dispersion in mineral oil, 391 mg, 9.78 mmol, 1.5 equiv) was added slowly to a stirred solution of derivative (a) (2230 mg, 6.52 mmol, 1 equiv) in anhydrous dimethyl formamide (15 mL), at room temperature, and the contents were stirred under an atmosphere of argon for 30 min. A solution of (2R)-(-)- glycidyl tosylate 98% (2230 mg, 9.78 mmol, 1.5 equiv) in anhydrous dimethyl formamide (5 mL) was added via syringe, and the mixture was allowed to react at room temperature for 16 h. The reaction was then quenched by addition of a saturated solution of ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with deionized water (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 20% to 40% ethyl acetate in hexane) to provide (b) (2S,20R) (2.53 g, 94%) as a clear foam. Other diastereomers or racemic mixtures are prepared by using and appropriate tosylate. H NMR (400 MHz, DMSO-d6): delta 7.1 1-7.08 (dd, J= 8.8, 1.2, 4H), 6.85-6.82 (dd, J = 6.4, 3.2, 4H), 4.41-4.35 (m, 1H), 4.28-4.25 (dd, J = 1 1.2, 2.4, 1H), 4.09-4.06 (dd, J = 8.4, 6.8, 1H), 3.95-3.94 (m, 2H), 3.81-3.72 (m, 2H), 3.32-3.29 (m, 1H), 2.82 (t, J = 4.8, 1H), 2.69-2.67 (dd, J= 4.8, 2.4, 1H), 1.57 (s, 6H), 1.35 (s, 3H), 1.29 (s, 3H); 13C NMR (100 MHz, DMSO-d6): delta 156.1 , 156.0, 142.9, 142.8, 127.4, 1 13.9, 1 13.8, 108.8, 73.7, 68.8, 68.6, 65.8, 49.7, 43.7, 41.2, 30.7, 26.6, 25.4; HRMS (ESI) (m/z): calc'd for C24H3o05Na [M+Na]+: 421.1991 , found: 421.1986.
94%		Example 2 Synthesis of (s)-2,2-dimethyl-4-((4-(2-(4-((R)-oxiran-2-ylmethoxy)phenyl)propan-2-yl)phenoxy)methyl)-1,3-dioxolane Sodium hydride (60% dispersion in mineral oil, 391 mg, 9.78 mmol, 1.5 equiv) was added slowly to a stirred solution of (S)-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol (2230 mg, 6.52 mmol, 1 equiv) in anhydrous dimethyl formamide (15 mL), at room temperature, and the contents were stirred under an atmosphere of argon for 30 min. A solution of (2R)-(-)-glycidyl tosylate 98% (2230 mg, 9.78 mmol, 1.5 equiv) in anhydrous dimethyl formamide (5 mL) was added via syringe and the mixture was allowed to react at room temperature for 16 h. Then, the reaction was quenched by the addition of a saturated solution of ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (3*20 mL). The organic layer was washed with deionized water (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 20% to 40% ethyl acetate in hexane) to provide the title compound (2.53 g, 94%) as a clear foam.

Reference： [1]Patent: WO2013/28572,2013,A1 .Location in patent: Page/Page column 53-54
[2]Patent: US2014/335080,2014,A1 .Location in patent: Paragraph 0218; 0219

37
[ 29799-07-3 ]
[ 70987-78-9 ]
(-)-(R)-[4-(1-adamantyl)phenoxymethyl]oxirane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		To a washed (THF) suspension of NaH (0.02 g, 0.83 mmol, 60% in mineral oil) in DMF (2 mL) at 25 ºC was added p-adamantylphenol SI-1 (0.1 g, 0.44 mmol) in DMF (2 mL). After stirring for 30 min, a solution of R-(-)-glycidyl tosylate (R)-SI-2 (0.1 g, 0.44 mmol) in DMF (2 mL) was added dropwise. After stirring for 3 h at the same temperature, EtOAc was added and the mixture was washed with water (3x). The organic layer was dried (Na2SO4) and the solvent was evaporated. The residue was purified by column chromatography (silica gel, 95:5 hexane/EtOAc) to afford 0.095 g (77%) of a solid identified as (R)-2-(4-adamantylphenoxymethyl)-oxirane (R)-SI-3. 1H-NMR (400.13 MHz, CDCl3): d 7.28-7.24 (m, 2H, ArH), 6.88-6.85 (m, 2H, ArH), 4.17 (dd, J = 11.1, 3.4 Hz, 1H, OCH2), 3.96 (dd, J = 11.1, 5.5 Hz, 1H, OCH2), 3.35-3.31 (m, 1H O-CH-), 2.88 (dd, J = 4.8, 4.3 Hz, 1H, OCH2), 2.73 (dd, J = 5.0, 2.7 Hz, 1H, OCH2), 2.07 (app. s, 3H, 3 x CH), 1.88-1.87 (m, 6H, 3 x CH2), 1.79-1.71 (m, 6H, 3 x CH2) ppm. 13C-NMR (100.62 MHz, CDCl3): d 156.4 (s), 144.5 (s), 126.0 (d, 2x), 114.3 (d, 2x), 68.9 (t), 50.4 (d), 44.9 (t), 43.5 (t, 3x), 36.9 (t, 3x), 35.7 (s), 29.1 (d, 3x) ppm. MS (EI): m/z (%) 285 ([M+1]+, 17), 284 ([M]+, 100), 228 (24), 227 (46), 171 (46), 84 (17). HMRS (EI): Calcd. for C19H24O2, 284.1776; found, 284.1775. IR (NaCl): n 2903 (s, C-H), 2847 (m, C-H), 1512 (m) cm-1. UV (MeOH): lmax 275, 223 nm. M.p.: 62-65 ºC (EtOAc/hexane). -7.4 (c 0.586, MeOH).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 2056 - 2067

38
[ 98-59-9 ]
[ 60456-23-7 ]
[ 70987-78-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 3h;	To a solution of (S)-glycidol (5.50 g, 74.24 mmol), triethylamine (8.26 g, 81.66 mmol) and 4-(dimethylamino)pyridine (2%, 181 mg, 1.48 mmol) in 60 mL dichloromethane at 0 C, tosyl chloride (14.15 g, 74.24 mmol) was added and the mixture was stirred at room temperature for 3 h with formation of a white precipitate. Dichloromethane (40 mL) was added and the mixture was subsequently washed with 100 mL 5% aq. K2CO3, 100 mL 1 M HCl, and 100 mL water. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude product (15.56 g colourless oil, 92% yield) was used in the next step without further purification; [alpha]D = -16.7 (c = 0.46, CHCl3), lit.: [50] [alpha]D = -17.0 (c = 2.83, CHCl3); 1H NMR (300 MHz, CDCl3): delta (ppm) 2.47 (s, 3H, CH3), 2.61 (dd, J = 4.8, 2.5 Hz, 1H, CH2O), 2.83 (t, J = .4 Hz, 1H, CH2O), 3.16-3.24 (m, 1H, CH), 4.0 (dd, J = 11.4, 6.0 Hz, 1H, CH2OS), 4.27 (dd, J = 11.4, 3.5 Hz, 1H, CH2OS), 7.37 (d, J = 8.1 Hz, 2H, Ar-H3, Ar-H5), 7.82 (d, J = 8.1 Hz, 2H, Ar-H2, Ar-H6).
	With dmap; triethylamine; In dichloromethane; at 25 - 35℃;	1000 ml MDC, 100.0 g (5)-Glycidol and 164 g triethylamine were added to RBF at 25C to 35C followed by addition of 255 g -toluene sulphonyl chloride portion wise and 1.6 g DMAP. The reaction mass was stirred for 3-4 hours and product was filtered and washed with 200 ml MDC and further stirred for 1-2 hours. MDC layer was washed with dilute HC1 solution and further with 2000 ml water, followed byseparation of layers and evaporation of solvent to afford (/?)-oxiran-2-ylmethyl 4- methylbenzenesulfonate of Formula (D).
	With dmap; triethylamine; In dichloromethane; at 25 - 35℃;	1000 ml MDC, 100.0 g (S)-Glycidol and 0.164 g triethylamine were added to RBF at 25 C. to 35 C. followed by addition of 255 g p-toluene sulphonyl chloride portion wise and 1.6 g DMAP. The reaction mass was stirred for 3-4 hours and product was filtered and washed with 200 ml MDC and further stirred for 1-2 hours. MDC layer was washed with dilute HCl solution and further with 2000 ml water, followed by separation of layers and evaporation of solvent to afford (R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate of Formula (D).

With triethylamine; In dichloromethane; at 0℃; for 3h;

General procedure: Paratoluenesulfonyl chloride (PTSC, 25.0 g) and (R)-oxiran-2-ylmethanol (6.0 mL) were dissolved in anhydrous dichloromethane (DCM, 250 mL), then, triethylamine (TEA, 36.0 mL) was dropwise added in the mixture at 0 C. After reacting for 3 h at 0 C, the reaction liquid was concentrated. At last, the residue was purified by flash column chromatography with ethyl acetate/petroleum ether to obtain the title compound 2 (17.6 g).

Reference： [1]Chemical Communications,2014,vol. 50,p. 6718 - 6721
[2]Angewandte Chemie - International Edition,2020,vol. 59,p. 5521 - 5525
Angew. Chem.,2020,vol. 132,p. 5564 - 5568,5
[3]European Journal of Medicinal Chemistry,2013,vol. 62,p. 329 - 340
[4]Patent: WO2013/98833,2013,A2 .Location in patent: Page/Page column 40-41
[5]Patent: US2014/378682,2014,A1 .Location in patent: Paragraph 0205; 0206
[6]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6632 - 6640

39
[ 3316-09-4 ]
[ 70987-78-9 ]
(S)-(6-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
212 mg		To a suspension of NaH (60% dispersion, 120 mg, 1.5 mmol) in 5 mL DMF at 0 C, <strong>[3316-09-4]4-nitrocatechol</strong> (310 mg, 2.00 mmol) in 1 mL DMF was added. The mixture was stirred at 0 C for 30 min (until gas formation ceased) and then a solution of (R)-glycidyl tosylate (502 mg, 2.20 mmol) in 1 mL DMF was added. The reaction mixture was stirred at room temperature for 30 min and then heated at 80 C for 2 h. Upon cooling, the mixture was poured onto 15 mL water. The mixture was extracted with 3 × 20 mL diethyl ether. The combined organic phases were dried over Na2SO4, filtered and evaporated to dryness. The crude product obtained was purified by column cromatography (petrolether:ethyl acetate = 1:1) to give 212 mg (50%) of pale yellow crystals; mp 112-114 C; [alpha]D = -86.6 (c = 0.51, CHCl3); 1H NMR (300 MHz, CDCl3): delta (ppm) 1.91 (t, J = 6.20 Hz, 1H, OH), 3.85-4.04 (m, 2H, CH2OH), 4.10-4.25 (m, 1H, CH), 4.33-4.46 (m, 2H, CH2O), 6.95-7.04 (m, 1H, Ar-H8), 7.76-7.88 (m, 2H, Ar-H5, Ar-H7).

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 62,p. 329 - 340

40
[ 136918-14-4 ]
[ 70987-78-9 ]
[ 161596-47-0 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutylammomium bromide; potassium carbonate; In acetone; at 35 - 60℃; for 12h;	2 L Acetone, 64 g Phthalamide and 190 g K2C03 were added to R&F at 25C to 35C and heated to 55C to 60C followed by addition of 100 g (^)-Glycidyl Tosylate of Formula (D) and 14 g TBAB and stirred for 12 hours at 55C to 60C. The product was washed with 100 ml acetone followed by addition of 1500 ml water into the above mass and stirring for 2 hours to afford the title compound as (5)-2-(oxiran-2- ylmethyl)isoindoline-l,3-dione of Formula (E).
	With tetrabutylammomium bromide; potassium carbonate; In acetone; at 25 - 60℃; for 12h;	2 L Acetone, 64 g Phthalamide and 190 g K2CO3 were added to RBF at 25 C. to 35 C. and heated to 55 C. to 60 C. followed by addition of 100 g (R)-Glycidyl Tosylate of Formula (D) and 14 g TBAB and stirred for 12 hours at 55 C. to 60 C. The product was washed with 100 ml acetone followed by addition of 1500 ml water into the above mass and stirring for 2 hours to afford the title compound as (S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione of Formula (E).

Reference： [1]Patent: WO2013/98833,2013,A2 .Location in patent: Page/Page column 41
[2]Patent: US2014/378682,2014,A1 .Location in patent: Paragraph 0207; 0208

41
[ 2138-22-9 ]
[ 70987-78-9 ]
[ 1074-82-4 ]
[ 98-59-9 ]
(S)-2-(7-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione [ No CAS ]
[ 1189115-71-6 ]