[ CAS No. 1103738-19-7 ] {[proInfo.proName]}

Name: 1103738-19-7|((3AS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone|98%
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Quality Control of [ 1103738-19-7 ]

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Product Details of [ 1103738-19-7 ]

CAS No. :	1103738-19-7	MDL No. :	MFCD25977365
Formula :	C₁₂H₁₉NO₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZHDDJWFZDNKWIC-REIXXSIJSA-N
M.W :	273.28	Pubchem ID :	25207258
Synonyms :

Safety of [ 1103738-19-7 ]

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

Application In Synthesis of [ 1103738-19-7 ]

* 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 [ 1103738-19-7 ]
Downstream synthetic route of [ 1103738-19-7 ]

[ 1103738-19-7 ] Synthesis Path-Upstream 1~13

1
[ 110-91-8 ]
[ 1103738-17-5 ]
[ 1103738-19-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In tetrahydrofuran at 20℃; for 6.5 h;	To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0 g, 24.5 mmol) in THF (100 ML, 20.x.) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20° C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20° C. for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2.x. .x.2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4: 1) to afford 4.3 g of the desired morpholine amide (64percent) as a white solid. ¹H NMR (CDCl₃), δ 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
64%	Stage #1: With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: at 20℃; for 6 h;	To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0 g, 24.5 mmol) in THF (100 mL, 20.x.) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20° C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20° C. for an additional 6 h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2.x. .x.2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64percent) as a white solid. ¹H NMR (CDCl₃), δ 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H)
64%	Stage #1: With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: at 20℃; for 6 h;	6. EXAMPLES Aspects of this invention can be understood from the following examples.6.1. Synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2.3-d][13]dioxol-5-yl)(morpholino)methanone To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose (504.40 g, 3.360 mol), acetone (5L, reagent grade) and anhydrous MgSO₄ powder (811.23g, 6.740 mol / 2.0 equiv). The suspension was set stirring at ambient and then concentrated H₂SO₄ (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24°C over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH₄OH solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50percent w/w aq. K₂HPO₄ until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wtpercent water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23g, 86percent yield, 96.7 areapercent pure by GC). ¹H NMR (400 MHz, DMSO-d₆)δ1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 - 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). ¹³C NMR (101MHz, DMSO-d₆) δ26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73. To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H₂O (125 mL, 5X) was added NaHC0₃ (33.0g, 3.0 equiv), NaBr (2.8g, 20 molpercent) and TEMPO (0.40g, 2 molpercent) at 20°C. The mixture was cooled to 0-5°C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20°C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20°C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0g, 79percent). ¹H NMR (methanol-d₄), δ 6.00 (d, J= 3.2 Hz, 1H), 4.72 d, J= 3.2 Hz, 1H), 4.53 (d, J= 3.2 Hz, 1H), 4.38 (d, J= 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H). To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20°C for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20°C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64percent) as a white solid. ¹H NMR (CDCl₃), 8 6.02 (d, J= 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J= 3.2 Hz, 1H), 4.58 (d, J= 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).

64%	Stage #1: With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: at 20℃; for 6 h;	To a solution of Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20°C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired 24 morpholine amide (64percent) as a white solid. ¹H NMR (CDCl₃), δ 6.02 (d, J = 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J = 3.2 Hz, 1H), 4.58 (d, J = 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
51.5%	Stage #1: With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In tetrahydrofuran at 20 - 30℃; for 0.5 h; Stage #2: for 8 h;	in room temperature,2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (137 g, 426.7 mmol)With N-methylmorpholine (48 mL, 440 mmol)(3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro [2,3-d] [1,3] dioxolane-5-carboxylic acid 1d (58.0 g, 284 mmol)In tetrahydrofuran (1000 mL)After stirring at room temperature for 30 minutes,Morpholine (38 mL, 436 mmol) was added,Stir for 8 hours.The solid was removed by filtration,Washed with tetrahydrofuran (200 mL x 3)The filtrate was collected and concentrated under reduced pressure. Purification by silica gel column chromatography [petroleum ether / ethyl acetate (v / v) = 2/1]The title compound 1e was obtained as a white solid (40.0 g, 51.5percent).

Reference： [1] Patent: US2009/30198, 2009, A1, . Location in patent: Page/Page column 8
[2] Patent: US2010/16422, 2010, A1, . Location in patent: Page/Page column 4
[3] Patent: EP2332947, 2011, A1, . Location in patent: Page/Page column 6-7
[4] Patent: EP2661256, 2018, B1, . Location in patent: Paragraph 0091
[5] Patent: CN106892948, 2017, A, . Location in patent: Paragraph 0195; 0196; 0197; 0198

2
[ 109-02-4 ]
[ 1103738-17-5 ]
[ 1103738-19-7 ]

Yield	Reaction Conditions	Operation in experiment
82.6%	With O‐(1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium tetrafluoroborate In tetrahydrofuran at 20 - 30℃;	The above obtained acid A (99.9 g, 0.49 mol) was added to a 3 L three-necked flask.Add 1 L of tetrahydrofuran, stir to dissolve,Add TBTU (235.76g, 0.74mol) in turnAnd N-methylmorpholine (NMM, 82 mL, 0.74 mol).The resulting reaction mixture was stirred at room temperature overnight. Filter the reaction solution,The filter cake was washed with 200 mL x 2 tetrahydrofuran.The filtrate was concentrated to dryness under reduced pressure at 35 to 45 °C.400 mL of hexane was added to the obtained slurry.Heat to 60 ~ 70 ° C for 1 hour, and cool to room temperature for 2 hours.Then cool down to 0 ~ 10 ° C for 2 hours.Filtered white solid111.02 g, yield 82.6percent.
48%	at 20℃; for 12 h;	To a solution of (3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyltetrahydrofuro [3,2- d][1,3] dioxole-5-carboxylic acid To a suspension of HBTU (25.1 g, 66.3 mmol, N, N, N', N'-tetramethyl-O- (1H- benzotriazol- 1-yl) uronium hexafluorophosphate) 4-Methylmorpholine (7.3 mL, 66.3 mmol) was added. 1 After the time, morpholine (5.8mL, 66.3 mmol) was added to the mixture at room temperature. 12 After this time, theresulting mixture was filtered and the filter cake was washed with tetrahydrofuran. Thefiltrate was concentrated in vacuo and the crude material was purified by silica gelcolumn chromatography to give the title compound (5.8 g, 48percent) as a yellow solid.

Reference： [1] Patent: CN108675976, 2018, A, . Location in patent: Paragraph 0069; 0070; 0071
[2] Patent: KR101770302, 2017, B1, . Location in patent: Paragraph 0337; 0338

3
[ 110-91-8 ]
[ 1103738-20-0 ]
[ 1103738-19-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With boric acid In toluene for 12 h; Heating / reflux; Industry scale	The morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (7.85 kg, 26.9 mol), morpholine (2.40 L, 27.5 mol) and boric acid (340 g, 5.49 mol, 0.2 eq) were added to toluene (31 L). The resulting slurry was degassed and heated at reflux with a Dean-Stark trap under nitrogen for 12 h and then cooled to room temperature. The mixture was filtered to remove insolubles and the filter cake washed with toluene (5 L). The filtrate was concentrated to about 14 L and flushed with toluene (80 L) to remove excess morpholine. When final volume reached 12 L, heptane (14 L) was added slowly at 60-70° C. The resulting slurry was cooled gradually to room temperature and aged for 3 h. It was then filtered and washed with heptane (12 L) and dry under nitrogen gave a slightly pink solid (6.26 kg, 97percent pure, 98percent yield). m.p.: 136° C. (DSC). ¹H NMR (CDCl₃), δ 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H). ¹³C NMR (methanol-d₄) δ 26.84, 27.61, 44.24, 47.45, 68.16, 77.14, 81.14, 86.80, 106.87, 113.68, 169.05.
98%	for 12 h; Inert atmosphere; Reflux; Dean-Stark trap	The morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (7.85 kg, 26.9 mol), morpholine (2.40 L, 27.5 mol) and boric acid (340 g, 5.49 mol, 0.2 eq) were added to toluene (31 L). The resulting slurry was degassed and heated at reflux with a Dean-Stark trap under nitrogen for 12 h and then cooled to room temperature. The mixture was filtered to remove insolubles and the filter cake washed with toluene (5 L). The filtrate was concentrated to about 14 L and flushed with toluene (80 L) to remove excess morpholine. When final volume reached 12 L, heptane (14 L) was added slowly at 60-70° C. The resulting slurry was cooled gradually to room temperature and aged for 3 h. It was then filtered and washed with heptane (12 L) and dry under nitrogen gave a slightly pink solid (6.26 kg, 97percent pure, 98percent yield). m.p.: 136° C. (DSC). ¹H NMR (CDCl₃), δ 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H). ¹³C NMR (methanol-d₄) δ 26.84, 27.61, 44.24, 47.45, 68.16, 77.14, 81.14, 86.80, 106.87, 113.68, 169.05
98%	With boric acid In toluene for 12 h; Industry scale; Inert atmosphere; Reflux	6.2. Alternative synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahvdrofuro[2.3-d][1,3]dioxol-5-yl)(morpholino)methanone A solution of the diol (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol in acetonitrile (5.38 kg, 65percent w/w, 3.50 kg active, 18.40 mol), acetonitrile (10.5 L) and TEMPO (28.4 g, 1 mol percent) were added to a solution of K₂HPO₄ (0.32 kg, 1.84 mol) and KH₂PO₄ (1.25 kg, 9.20 mol) in water (10.5 L). A solution of NaClO₂ (3.12 kg, 80percent w/w, 27.6 mole, 1.50 eq) in water (7.0 L) and a solution of K₂HPO₄ (2.89 kg, 0.90 eq) in water (3.0 L) were prepared with cooling. Bleach (3.0L, approximate 6percent household grade) was mixed with the K₂HPO₄ solution. Approximately 20percent of the NaClO₂ solution (1.6 L) and bleach/K₂HPO₄ solution (400 mL),.similar.1 mol percent) were added. The remainders of the two solutions were added simultaneously. The reaction mixture turned dark red brown and slow exotherm was observed. The addition rate of the NaClO₂ solution was about 40 mL/min (3-4 h addition) and the addition rate for the bleach/K₂HPO₄ solution was about 10-12 mL/min (10 hr addition) while maintaining the batch at 15-25°C. Additional charges of TEMPO (14.3g, 0.5 molpercent) were performed every 5-6 hr until the reaction went to completion (usually two charges are sufficient). Nitrogen sweep of the headspace to a scrubber with aqueous was performed to keep the green-yellowish gas from accumulating in the vessel. The reaction mixture was cooled to < 10°C and quenched with Na₂SO₃ (1.4 kg, 0.6 eq) in three portions over 1 hr. The reaction mixture was then acidified with H₃PO₄ until pH reached 2.0-2.1 (2.5-2.7 L) at 5-15°C. The layers were separated and the aqueous layer was extracted with acetonitrile (10.5 L x 3). The combined organic layer was concentrated under vacuo (.similar.100-120 torr) at < 35°C (28-32°C vapor, 45-50°C bath) to low volume (- 6-7 L) and then flushed with acetonitrile (40 L) until KF of the solution reached < 1percent when diluted to volume of about 12-15Lwith acetonitrile. Morpholine (1.61 L, 18.4 mol, 1.0 eq) was added over 4-6 h and the slurry was aged overnight under nitrogen. The mixture was cooled to 0-5°C and aged for 3 hours then filtered. The filter cake was washed with acetonitrile (10 L). Drying under flowing nitrogen gave 4.13 kg of the morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid as a white solid (92-94percent pure based on ¹H NMR with 1,4-dimethoxybenzene as the internal standard), 72-75percent yield corrected for purity. ¹H NMR (D₂O) δ5.96 (d, J = 3.6 Hz, 1H), 4.5 8 (d, J = 3.6 Hz, 1H), 4.53 (d, J =3.2Hz,1H), 4.30 (d, J= 3.2 Hz, 1H), 3.84 (m, 2H), 3.18 (m, 2H), 1.40 (s, 1H), 1.25 (s, 1H). ¹³H NMR (D₂O) 8 174.5, 112.5, 104.6, 84.2, 81.7, 75.0, 63.6, 43.1, 25.6, 25. 1. The morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (7.85 kg, 26.9 mol), morpholine (2.40 L, 27.5 mol) and boric acid (340 g, 5.49 mol, 0.2 eq) were added to toluene (31 L). The resulting slurry was degassed and heated at reflux with a Dean-Stark trap under nitrogen for 12 h and then cooled to room temperature. The mixture was filtered to remove insolubles and the filter cake washed with toluene (5 L). The filtrate was concentrated to about 14 L and flushed with toluene (-80 L) to remove excess morpholine. When final volume reached -12 L, heptane (14 L) was added slowly at 60-70°C. The resulting slurry was cooled gradually to room temperature and aged for 3 h. It was then filtered and washed with heptane (12 L) and dry under nitrogen gave a slightly pink solid (6.26 kg, 97percent pure, 98percent yield). m.p.: 136°C (DSC). ¹H NMR (CDCl₃), δ 6.02 (d, J = 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H). ¹³C NMR (methanol-d₄) δ 26.84, 27.61, 44.24, 47.45, 68.16, 77.14, 81.14, 86.80, 106.87, 113.68, 169.05.

Reference： [1] Patent: US2009/30198, 2009, A1, . Location in patent: Page/Page column 8
[2] Patent: US2010/16422, 2010, A1, . Location in patent: Page/Page column 5
[3] Patent: EP2332947, 2011, A1, . Location in patent: Page/Page column 7

4
[ 110-91-8 ]
[ 1103738-19-7 ]

Yield	Reaction Conditions	Operation in experiment
6.26 kg	With boric acid In toluene for 12 h; Reflux; Dean-Stark; Inert atmosphere; Large scale	The morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (7.85 kg, 26.9 mol), morpholine (2.40 L, 27.5 mol) and boric acid (340 g, 5.49 mol, 0.2 eq) were added to toluene (31 L). The resulting slurry was degassed and heated at reflux with a Dean-Stark trap under nitrogen for 12 h and then cooled to room temperature. The mixture was filtered to remove insolubles and the filter cake washed with toluene (5 L). The filtrate was concentrated to about 14 L and flushed with toluene (-80 L) to remove excess morpholine. When final volume reached -12 L, heptane (14 L) was added slowly at 60-70°C. The resulting slurry was cooled gradually to room temperature and aged for 3 h. It was then filtered and washed with heptane (12 L) and dry under nitrogen gave a slightly pink solid (6.26 kg, 97percent pure, 98percent yield). m.p.: 136°C (DSC). ¹H NMR (CDCl₃), δ 6.02 (d, J = 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J = 3.2 Hz, 1H), 4.58 (d, J = 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H). ¹³C NMR (methanol-d₄) δ 26.84, 27.61, 44.24, 47.45, 68.16, 77.14, 81.14, 86.80, 106.87, 113.68, 169.05.

Reference： [1] Patent: EP2661256, 2018, B1, . Location in patent: Paragraph 0093

5
[ 114861-22-2 ]
[ 1103738-19-7 ]

Reference： [1] Patent: EP2332947, 2011, A1,
[2] Patent: EP2332947, 2011, A1,
[3] Patent: CN106892948, 2017, A,
[4] Patent: KR101770302, 2017, B1,
[5] Patent: EP2661256, 2018, B1,
[6] Patent: EP2661256, 2018, B1,

6
[ 609-06-3 ]
[ 1103738-19-7 ]

Reference： [1] Patent: EP2332947, 2011, A1,
[2] Patent: EP2332947, 2011, A1,
[3] Patent: CN106892948, 2017, A,
[4] Patent: EP2661256, 2018, B1,
[5] Patent: EP2661256, 2018, B1,

7
[ 131156-47-3 ]
[ 1103738-19-7 ]

Reference： [1] Patent: CN106892948, 2017, A,

8
[ 87-72-9 ]
[ 1103738-19-7 ]

Reference： [1] Patent: KR101770302, 2017, B1,

9
[ 1352955-16-8 ]
[ 1103738-19-7 ]

Reference： [1] Patent: CN108675976, 2018, A,

10
[ 108-21-4 ]
[ 1103738-19-7 ]

Reference： [1] Patent: CN108675976, 2018, A,

11
[ 461432-23-5 ]
[ 1103738-19-7 ]
[ 1103738-30-2 ]

Yield	Reaction Conditions	Operation in experiment
86.3%	Stage #1: With n-butyllithium In tetrahydrofuran at -80 - -70℃; for 1 h; Stage #2: at -80 - 0℃;	Add Compound C-1 (10 g, 30.7 mmol) to a 250 mL three-necked flaskAnd 70mL of tetrahydrofuran, stir and dissolve.The resulting solution is cooled to -70 to -80 ° C,Slowly add n-butyllithium solution (2.5M THF solution) to the cooled solution.14.1 mL, 1.15 eq), and stirred at -70 to -80 ° C for 1 hour.Further, a solution of the compound B in tetrahydrofuran (9.6 g of B in 30 mL of tetrahydrofuran, 35.3 mmol, 1.15 eq) was added dropwise to the reaction mixture.The mixture was stirred at -70 to -80 ° C for 2 hours. The reaction solution is heated to -10 to 0 ° C.The reaction solution was diluted with a saturated aqueous solution of NH4Cl (20 mL).The reaction quenching solution was extracted twice by adding ethyl acetate (100 mL×2).The ethyl acetate layer was combined and washed with brine (100 mL).The organic layer was concentrated to dryness under reduced pressure at 40 to 50 °C. The obtained solid was recrystallized from ethyl acetate and n-hexane to give 11.5 g of compound.D-1, yield 86.3percent.

Reference： [1] Patent: CN108675976, 2018, A, . Location in patent: Paragraph 0083; 0084; 0085

12
[ 1103738-29-9 ]
[ 1103738-19-7 ]
[ 1103738-30-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at -5℃; for 3 h; Industry scale Stage #2: With tert-butylmagnesium chloride In tetrahydrofuran at -25 - -20℃; for 3.68333 h; Industry scale	To a 20 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet was charged with the iodide (3.00 kg, 8.05 mol) and THF (8 L, 4.x. to the morpholinoamide) at room temperature and cooled to -5° C. To the above solution was added dropwise a solution of i-PrMgCl in THF (Aldrich 2 M, 4.39 L, 8.82 mol) at -5° C. over 3 hours. This Grignard solution was used in the ketone formation below.To a 50 L reactor equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet was charged the morpholinoamide (HPLC purity=97 wt percent, 2.01 kg, 7.34 mol) and THF (11 L, 5.5.x.) at room temperature and stirred for 45 minutes at room temperature and for 15 minutes at 30° C. The homogeneous solution was then cooled to -25° C. To this solution was added a solution of t-BuMgCl in THF (Aldrich 1 M, 7.32 L, 7.91 mol) at -25° C. over 3 hours. Then the above Grignard solution was added to this solution at -20 over 41 minutes. The resulting solution was further stirred at -20° C. before quench. The reaction mixture was added to 10 wt percent aqueous NH₄Cl (10 L, 5.x.) at 0° C. with vigorous stirring, and stirred for 30 minutes at 0° C. To this mixture was added slowly 6 N HCl (4 L, 2.x.) at 0° C. to obtain a clear solution and stirred for 30 minutes at 10° C. After phase split, the organic layer was washed with 25 wt percent aq NaCl (5 L, 2.5.x.). Then the organic layer was concentrated to a 3.x. solution under the conditions (200 mbar, bath temp 50° C.). EtOAc (24 L, 12.x.) was added, and evaporated to a 3.x. solution under the conditions (150 mbar, bath temp 50° C.). After removed solids by a polish filtration, EtOAc (4 L, 2.x.) was added and concentrated to dryness (150 mbar, bath temp 50° C.). The wet cake was then transferred to a 50 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet. After EtOAc was added, the suspension was heated at 70° C. to obtain a 2.5.x. homogeneous solution. To the resulting homogeneous solution was added slowly heptane (5 L, 2.5.x.) at the same temperature. A homogeneous solution was seeded and heptane (15 L, 7.5.x.) was added slowly to a little cloudy solution at 70° C. After stirred for 0.5 h at 70° C., the suspension was slowly cooled to 60° C. and stirred for 1 h at 60° C. The suspension was then slowly cool to room temperature and stirred for 14 h at the same temperature. The crystals were collected and washed with heptane (8 L, 4.x.), dried under vacuum at 45° C. to give the desired ketone as fluffy solids (2.57 kg, 100 wt percent by HPLC, purity-adjusted yield: 81percent).
81%	Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at -5℃; for 3 h; Industry scale Stage #2: With tert-butylmagnesium chloride In tetrahydrofuran at -25 - -20℃; Industry scale	6.5. Alternative synthesis of (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone To a 20 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet was charged with the iodide (3.00 kg, 8.05 mol) and THF (8 L, 4X to the morpholinoamide) at room temperature and cooled to -5°C. To the above solution was added dropwise a solution of i-PrMgCl in THF (Aldrich 2 M, 4.39 L, 8.82 mol) at -5°C over 3 hours. This Grignard solution was used in the ketone formation below. To a 50 L reactor equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet was charged the morpholinoamide (HPLC purity = 97 wtpercent, 2.01 kg, 7.34 mol) and THF (11 L, 5.5X) at room temperature and stirred for 45 minutes at room temperature and for 15 minutes at 30°C. The homogeneous solution was then cooled to - 25°C. To this solution was added a solution of t-BuMgCl in THF (Aldrich 1 M, 7.32 L, 7.91 mol) at -25°C over 3 hours. Then the above Grignard solution was added to this solution at -20 over 41 minutes. The resulting solution was further stirred at -20°C before quench. The reaction mixture was added to 10 wtpercent aqueous NH₄Cl (10 L, 5X) at 0°C with vigorous stirring, and stirred for 30 minutes at 0°C. To this mixture was added slowly 6 N HCl (4 L, 2X) at 0°C to obtain a clear solution and stirred for 30 minutes at 10°C. After phase split, the organic layer was washed with 25 wtpercent aq NaCl (5 L, 2.5X). Then the organic layer was concentrated to a 3X solution under the conditions (200 mbar, bath temp 50°C). EtOAc (24 L, 12X) was added, and evaporated to a 3X solution under the conditions (150 mbar, bath temp 50°C). After removed solids by a polish filtration, EtOAc (4 L, 2X) was added and concentrated to dryness (150 mbar, bath temp 50°C). The wet cake was then transferred to a 50 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet. After EtOAc was added, the suspension was heated at 70°C to obtain a 2.5X homogeneous solution. To the resulting homogeneous solution was added slowly heptane (5 L, 2.5X) at the same temperature. A homogeneous solution was seeded and heptane (15 L, 7.5X) was added slowly to a little cloudy solution at 70°C. After stirred for 0.5 h at 70°C, the suspension was slowly cooled to 60°C and stirred for 1 h at 60°C. The suspension was then slowly cool to room temperature and stirred for 14 h at the same temperature. The crystals were collected and washed with heptane (8 L, 4X), dried under vacuum at 45°C to give the desired ketone as fluffy solids (2.57 kg, 100 wtpercent by HPLC, purity-adjusted yield: 81percent).
76%	With n-butyllithium In tetrahydrofuran at 0 - 20℃; for 4.5 h;	To a solution of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (500 mg, 1.34 mmol) in THF (5.0 mL) was added i-PrMgCl (2.0M in THF, 1.0 mL, 2.00 mmol) at 0-5° C., and the mixture was stirred for 1.5 h at 0-5° C. A solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (146.5 mg, 0.536 mmol) in THF (1.0 mL) was added dropwise at 0-5° C. and the mixture was kept stirring for 1 h, warmed to 20° C. and stirred at 20° C. for 2 hours. The reaction was quenched with saturated aq NH₄Cl, extracted with MTBE, washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (178 mg, 76percent) as a white solid. ¹H NMR (CDCl₃) δ 7.88 (dd, J=8.4, 2.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.07 (d, J=3.2 Hz, 1H), 5.21 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 4.56 (d, J=3.2 Hz, 1H), 4.16 (d, J=7.2 Hz, 2H), 4.03 (q, J=7.2 Hz, 2H), 1.54 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.37 (s, 3H).

76%	Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 5℃; for 1.5 h; Stage #2: at 0 - 20℃;	To a solution of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (500 mg, 1.34 mmol) in THF (5.0 mL) was added i-PrMgCl (2.0M in THF, 1.0 mL, 2.00 mmol) at 0-5° C., and the mixture was stirred for 1.5 h at 0-5° C. A solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (146.5 mg, 0.536 mmol) in THF (1.0 mL) was added dropwise at 0-5° C. and the mixture was kept stirring for 1 h, warmed to 20° C. and stirred at 20° C. for 2 hours. The reaction was quenched with saturated aq NH₄Cl, extracted with MTBE, washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (178 mg, 76percent) as a white solid. ¹H NMR (CDCl₃) δ 7.88 (dd, J=8.4, 2.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.07 (d, J=3.2 Hz, 1H), 5.21 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 4.56 (d, J=3.2 Hz, 1H), 4.16 (d, J=7.2 Hz, 2H), 4.03 (q, J=7.2 Hz, 2H), 1.54 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.37 (s, 3H)
178 mg	Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 5℃; for 1.5 h; Stage #2: at 0 - 20℃; for 3 h;	To a solution of 48 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (500mg, 1.34 mmol) in 20 THF (5.0 mL) was added 50 i-PrMgCl (2.0M in THF, 1.0 mL, 2.00 mmol) at 0-5°C, and the mixture was stirred for 1.5 h at 0-5°C. A solution of 13 (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (146.5 mg, 0.536 mmol) in THF (1.0 mL) was added dropwise at 0-5°C and the mixture was kept stirring for 1h, warmed to 20°C and stirred at 20°C for 2 hours. The reaction was quenched with saturated aq NH₄Cl, extracted with MTBE, washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired 51 ketone (178 mg, 76percent) as a white solid. ¹H NMR (CDCl₃) δ 7.88 (dd, J = 8.4, 2.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.07 (d, J = 3.2 Hz, 1H), 5.21 (d, J = 3.2 Hz, 1H), 4.58 (d, J = 3.2 Hz, 1H), 4.56 (d, J = 3.2 Hz, 1H), 4.16 (d, J = 7.2 Hz, 2H), 4.03 (q, J = 7.2 Hz, 2H), 1.54 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.37 (s, 3H).

Reference： [1] Patent: US2009/30198, 2009, A1, . Location in patent: Page/Page column 9-10
[2] Patent: EP2332947, 2011, A1, . Location in patent: Page/Page column 8
[3] Patent: US2009/30198, 2009, A1, . Location in patent: Page/Page column 9
[4] Patent: US2010/16422, 2010, A1, . Location in patent: Page/Page column 6
[5] Patent: EP2661256, 2018, B1, . Location in patent: Paragraph 0097

13
[ 1103738-29-9 ]
[ 1103738-19-7 ]
[ 1103738-30-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	With i-PrMgCl In tetrahydrofuran	6.4. Synthesis of (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]-dioxol-5-yl)methanone To a solution of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (500 mg, 1.34 mmol) in THF (5.0 mL) was added i-PrMgCl (2.0M in THF, 1.0 mL, 2.00 mmol) at 0-5° C., and the mixture was stirred for 1.5 h at 0-5° C. A solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (146.5 mg, 0.536 mmol) in THF (1.0 mL) was added dropwise at 0-5° C. and the mixture was kept stirring for 1 h, warmed to 20° C. and stirred at 20° C. for 2 hours. The reaction was quenched with saturated aq NH₄Cl, extracted with MTBE, washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (178 mg, 76percent) as a white solid. ¹H NMR (CDCl₃) δ 7.88 (dd, J=8.4, 2.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.07 (d, J=3.2 Hz, 1H), 5.21 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 4.56 (d, J=3.2 Hz, 1H), 4.16 (d, J=7.2 Hz, 2H), 4.03 (q, J=7.2 Hz, 2H), 1.54 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.37 (s, 3H).

Reference： [1] Patent: US2012/172320, 2012, A1,

[ 1103738-19-7 ] Synthesis Path-Downstream 1~88

1
aq NH₄Cl [ No CAS ]
[ 1103738-29-9 ]
[ 1103738-19-7 ]
[ 1103738-30-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	With i-PrMgCl; In tetrahydrofuran;	6.4. Synthesis of (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]-dioxol-5-yl)methanone To a solution of <strong>[1103738-29-9]1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene</strong> (500 mg, 1.34 mmol) in THF (5.0 mL) was added i-PrMgCl (2.0M in THF, 1.0 mL, 2.00 mmol) at 0-5 C., and the mixture was stirred for 1.5 h at 0-5 C. A solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (146.5 mg, 0.536 mmol) in THF (1.0 mL) was added dropwise at 0-5 C. and the mixture was kept stirring for 1 h, warmed to 20 C. and stirred at 20 C. for 2 hours. The reaction was quenched with saturated aq NH4Cl, extracted with MTBE, washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (178 mg, 76%) as a white solid. 1H NMR (CDCl3) delta 7.88 (dd, J=8.4, 2.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.07 (d, J=3.2 Hz, 1H), 5.21 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 4.56 (d, J=3.2 Hz, 1H), 4.16 (d, J=7.2 Hz, 2H), 4.03 (q, J=7.2 Hz, 2H), 1.54 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.37 (s, 3H).

Reference： [1]Patent: US2012/172320,2012,A1

2
[ 110-91-8 ]
[ 1103738-17-5 ]
[ 1103738-19-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In tetrahydrofuran; at 20℃; for 6.5h;	To a solution of <strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> (5.0 g, 24.5 mmol) in THF (100 ML, 20×) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20 C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20 C. for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2× ×2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4: 1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), delta 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
64%		To a solution of <strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> (5.0 g, 24.5 mmol) in THF (100 mL, 20×) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20 C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20 C. for an additional 6 h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2× ×2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), delta 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H)
64%		6. EXAMPLES Aspects of this invention can be understood from the following examples.6.1. Synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2.3-d][13]dioxol-5-yl)(morpholino)methanone To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose (504.40 g, 3.360 mol), acetone (5L, reagent grade) and anhydrous MgSO4 powder (811.23g, 6.740 mol / 2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24C over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt% water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23g, 86% yield, 96.7 area% pure by GC). 1H NMR (400 MHz, DMSO-d6)delta1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 - 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 13C NMR (101MHz, DMSO-d6) delta26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73. To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHC03 (33.0g, 3.0 equiv), NaBr (2.8g, 20 mol%) and TEMPO (0.40g, 2 mol%) at 20C. The mixture was cooled to 0-5C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid (<strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong>) as a yellow solid (21.0g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J= 3.2 Hz, 1H), 4.72 d, J= 3.2 Hz, 1H), 4.53 (d, J= 3.2 Hz, 1H), 4.38 (d, J= 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H). To a solution of <strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> (5.0g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20C for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), 8 6.02 (d, J= 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J= 3.2 Hz, 1H), 4.58 (d, J= 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).

64%		To a solution of Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired 24 morpholine amide (64%) as a white solid. 1H NMR (CDCl3), delta 6.02 (d, J = 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J = 3.2 Hz, 1H), 4.58 (d, J = 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
51.5%		in room temperature,2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (137 g, 426.7 mmol)With N-methylmorpholine (48 mL, 440 mmol)(3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro [2,3-d] [1,3] dioxolane-5-carboxylic acid 1d (58.0 g, 284 mmol)In tetrahydrofuran (1000 mL)After stirring at room temperature for 30 minutes,Morpholine (38 mL, 436 mmol) was added,Stir for 8 hours.The solid was removed by filtration,Washed with tetrahydrofuran (200 mL x 3)The filtrate was collected and concentrated under reduced pressure. Purification by silica gel column chromatography [petroleum ether / ethyl acetate (v / v) = 2/1]The title compound 1e was obtained as a white solid (40.0 g, 51.5%).
48%	With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In tetrahydrofuran; at 20℃; for 12h;	To a suspension of 183 (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxole-5-carboxylic acid (9.0 g, 44.2 mmol) and 185 HBTU (25.1 g, 66.3 mmol, N,N,N?,N?-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate) in 13 tetrahydrofuran was added 186 4-methylmorpholine (7.3 mL, 66.3 mmol) at room temperature. After 1 hour, to the mixture was added 187 morpholine (5.8 mL, 66.3 mmol) at room temperature. After 12 hours, the resulting mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo and the crude material was purified by silica gel column chromatography to obtain the 188 title compound (5.8 g, 48%) as a yellow solid. 1H NMR (400 MHz, CD3OD) delta 6.01 (d, J=3.6 Hz, 1H), 5.10 (s, 1H), 4.59 (d, J=2.4 Hz, 1H), 4.57 (d, J=3.6 Hz, 1H), 4.47 (d, J=2.4 Hz, 1H), 3.85-3.62 (m, 6H), 3.53-3.49 (m, 2H), 1.49 (s, 3H), 1.33 (s, 3H). [M+H]+ 274.

Reference： [1]Patent: US2009/30198,2009,A1 .Location in patent: Page/Page column 8
[2]Patent: US2010/16422,2010,A1 .Location in patent: Page/Page column 4
[3]Patent: EP2332947,2011,A1 .Location in patent: Page/Page column 6-7
[4]Patent: EP2661256,2018,B1 .Location in patent: Paragraph 0091
[5]Patent: CN106892948,2017,A .Location in patent: Paragraph 0195; 0196; 0197; 0198
[6]Patent: US2019/169174,2019,A1 .Location in patent: Paragraph 0359; 0360

3
[ 110-91-8 ]
[ 1103738-20-0 ]
[ 1103738-19-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With boric acid; In toluene; for 12h;Heating / reflux; Industry scale;Product distribution / selectivity;	The morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (7.85 kg, 26.9 mol), morpholine (2.40 L, 27.5 mol) and boric acid (340 g, 5.49 mol, 0.2 eq) were added to toluene (31 L). The resulting slurry was degassed and heated at reflux with a Dean-Stark trap under nitrogen for 12 h and then cooled to room temperature. The mixture was filtered to remove insolubles and the filter cake washed with toluene (5 L). The filtrate was concentrated to about 14 L and flushed with toluene (80 L) to remove excess morpholine. When final volume reached 12 L, heptane (14 L) was added slowly at 60-70 C. The resulting slurry was cooled gradually to room temperature and aged for 3 h. It was then filtered and washed with heptane (12 L) and dry under nitrogen gave a slightly pink solid (6.26 kg, 97% pure, 98% yield). m.p.: 136 C. (DSC). 1H NMR (CDCl3), delta 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H). 13C NMR (methanol-d4) delta 26.84, 27.61, 44.24, 47.45, 68.16, 77.14, 81.14, 86.80, 106.87, 113.68, 169.05.
98%	boric acid; In toluene; for 12h;Inert atmosphere; Reflux; Dean-Stark trap;	The morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (7.85 kg, 26.9 mol), morpholine (2.40 L, 27.5 mol) and boric acid (340 g, 5.49 mol, 0.2 eq) were added to toluene (31 L). The resulting slurry was degassed and heated at reflux with a Dean-Stark trap under nitrogen for 12 h and then cooled to room temperature. The mixture was filtered to remove insolubles and the filter cake washed with toluene (5 L). The filtrate was concentrated to about 14 L and flushed with toluene (80 L) to remove excess morpholine. When final volume reached 12 L, heptane (14 L) was added slowly at 60-70 C. The resulting slurry was cooled gradually to room temperature and aged for 3 h. It was then filtered and washed with heptane (12 L) and dry under nitrogen gave a slightly pink solid (6.26 kg, 97% pure, 98% yield). m.p.: 136 C. (DSC). 1H NMR (CDCl3), delta 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H). 13C NMR (methanol-d4) delta 26.84, 27.61, 44.24, 47.45, 68.16, 77.14, 81.14, 86.80, 106.87, 113.68, 169.05
98%	With boric acid; In toluene; for 12h;Industry scale; Inert atmosphere; Reflux;	6.2. Alternative synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahvdrofuro[2.3-d][1,3]dioxol-5-yl)(morpholino)methanone A solution of the diol (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol in acetonitrile (5.38 kg, 65% w/w, 3.50 kg active, 18.40 mol), acetonitrile (10.5 L) and TEMPO (28.4 g, 1 mol %) were added to a solution of K2HPO4 (0.32 kg, 1.84 mol) and KH2PO4 (1.25 kg, 9.20 mol) in water (10.5 L). A solution of NaClO2 (3.12 kg, 80% w/w, 27.6 mole, 1.50 eq) in water (7.0 L) and a solution of K2HPO4 (2.89 kg, 0.90 eq) in water (3.0 L) were prepared with cooling. Bleach (3.0L, approximate 6% household grade) was mixed with the K2HPO4 solution. Approximately 20% of the NaClO2 solution (1.6 L) and bleach/K2HPO4 solution (400 mL),?1 mol %) were added. The remainders of the two solutions were added simultaneously. The reaction mixture turned dark red brown and slow exotherm was observed. The addition rate of the NaClO2 solution was about 40 mL/min (3-4 h addition) and the addition rate for the bleach/K2HPO4 solution was about 10-12 mL/min (10 hr addition) while maintaining the batch at 15-25C. Additional charges of TEMPO (14.3g, 0.5 mol%) were performed every 5-6 hr until the reaction went to completion (usually two charges are sufficient). Nitrogen sweep of the headspace to a scrubber with aqueous was performed to keep the green-yellowish gas from accumulating in the vessel. The reaction mixture was cooled to < 10C and quenched with Na2SO3 (1.4 kg, 0.6 eq) in three portions over 1 hr. The reaction mixture was then acidified with H3PO4 until pH reached 2.0-2.1 (2.5-2.7 L) at 5-15C. The layers were separated and the aqueous layer was extracted with acetonitrile (10.5 L x 3). The combined organic layer was concentrated under vacuo (?100-120 torr) at < 35C (28-32C vapor, 45-50C bath) to low volume (- 6-7 L) and then flushed with acetonitrile (40 L) until KF of the solution reached < 1% when diluted to volume of about 12-15Lwith acetonitrile. Morpholine (1.61 L, 18.4 mol, 1.0 eq) was added over 4-6 h and the slurry was aged overnight under nitrogen. The mixture was cooled to 0-5C and aged for 3 hours then filtered. The filter cake was washed with acetonitrile (10 L). Drying under flowing nitrogen gave 4.13 kg of the morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid as a white solid (92-94% pure based on 1H NMR with 1,4-dimethoxybenzene as the internal standard), 72-75% yield corrected for purity. 1H NMR (D2O) delta5.96 (d, J = 3.6 Hz, 1H), 4.5 8 (d, J = 3.6 Hz, 1H), 4.53 (d, J =3.2Hz,1H), 4.30 (d, J= 3.2 Hz, 1H), 3.84 (m, 2H), 3.18 (m, 2H), 1.40 (s, 1H), 1.25 (s, 1H). 13H NMR (D2O) 8 174.5, 112.5, 104.6, 84.2, 81.7, 75.0, 63.6, 43.1, 25.6, 25. 1. The morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (7.85 kg, 26.9 mol), morpholine (2.40 L, 27.5 mol) and boric acid (340 g, 5.49 mol, 0.2 eq) were added to toluene (31 L). The resulting slurry was degassed and heated at reflux with a Dean-Stark trap under nitrogen for 12 h and then cooled to room temperature. The mixture was filtered to remove insolubles and the filter cake washed with toluene (5 L). The filtrate was concentrated to about 14 L and flushed with toluene (-80 L) to remove excess morpholine. When final volume reached -12 L, heptane (14 L) was added slowly at 60-70C. The resulting slurry was cooled gradually to room temperature and aged for 3 h. It was then filtered and washed with heptane (12 L) and dry under nitrogen gave a slightly pink solid (6.26 kg, 97% pure, 98% yield). m.p.: 136C (DSC). 1H NMR (CDCl3), delta 6.02 (d, J = 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H). 13C NMR (methanol-d4) delta 26.84, 27.61, 44.24, 47.45, 68.16, 77.14, 81.14, 86.80, 106.87, 113.68, 169.05.

Reference： [1]Patent: US2009/30198,2009,A1 .Location in patent: Page/Page column 8
[2]Patent: US2010/16422,2010,A1 .Location in patent: Page/Page column 5
[3]Patent: EP2332947,2011,A1 .Location in patent: Page/Page column 7

4
[ 1103738-29-9 ]
[ 1103738-19-7 ]
[ 1103738-30-2 ]

Yield	Reaction Conditions	Operation in experiment
81%		To a 20 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet was charged with the iodide (3.00 kg, 8.05 mol) and THF (8 L, 4× to the morpholinoamide) at room temperature and cooled to -5 C. To the above solution was added dropwise a solution of i-PrMgCl in THF (Aldrich 2 M, 4.39 L, 8.82 mol) at -5 C. over 3 hours. This Grignard solution was used in the ketone formation below.To a 50 L reactor equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet was charged the morpholinoamide (HPLC purity=97 wt %, 2.01 kg, 7.34 mol) and THF (11 L, 5.5×) at room temperature and stirred for 45 minutes at room temperature and for 15 minutes at 30 C. The homogeneous solution was then cooled to -25 C. To this solution was added a solution of t-BuMgCl in THF (Aldrich 1 M, 7.32 L, 7.91 mol) at -25 C. over 3 hours. Then the above Grignard solution was added to this solution at -20 over 41 minutes. The resulting solution was further stirred at -20 C. before quench. The reaction mixture was added to 10 wt % aqueous NH4Cl (10 L, 5×) at 0 C. with vigorous stirring, and stirred for 30 minutes at 0 C. To this mixture was added slowly 6 N HCl (4 L, 2×) at 0 C. to obtain a clear solution and stirred for 30 minutes at 10 C. After phase split, the organic layer was washed with 25 wt % aq NaCl (5 L, 2.5×). Then the organic layer was concentrated to a 3× solution under the conditions (200 mbar, bath temp 50 C.). EtOAc (24 L, 12×) was added, and evaporated to a 3× solution under the conditions (150 mbar, bath temp 50 C.). After removed solids by a polish filtration, EtOAc (4 L, 2×) was added and concentrated to dryness (150 mbar, bath temp 50 C.). The wet cake was then transferred to a 50 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet. After EtOAc was added, the suspension was heated at 70 C. to obtain a 2.5× homogeneous solution. To the resulting homogeneous solution was added slowly heptane (5 L, 2.5×) at the same temperature. A homogeneous solution was seeded and heptane (15 L, 7.5×) was added slowly to a little cloudy solution at 70 C. After stirred for 0.5 h at 70 C., the suspension was slowly cooled to 60 C. and stirred for 1 h at 60 C. The suspension was then slowly cool to room temperature and stirred for 14 h at the same temperature. The crystals were collected and washed with heptane (8 L, 4×), dried under vacuum at 45 C. to give the desired ketone as fluffy solids (2.57 kg, 100 wt % by HPLC, purity-adjusted yield: 81%).
81%		6.5. Alternative synthesis of (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone To a 20 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet was charged with the iodide (3.00 kg, 8.05 mol) and THF (8 L, 4X to the morpholinoamide) at room temperature and cooled to -5C. To the above solution was added dropwise a solution of i-PrMgCl in THF (Aldrich 2 M, 4.39 L, 8.82 mol) at -5C over 3 hours. This Grignard solution was used in the ketone formation below. To a 50 L reactor equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet was charged the morpholinoamide (HPLC purity = 97 wt%, 2.01 kg, 7.34 mol) and THF (11 L, 5.5X) at room temperature and stirred for 45 minutes at room temperature and for 15 minutes at 30C. The homogeneous solution was then cooled to - 25C. To this solution was added a solution of t-BuMgCl in THF (Aldrich 1 M, 7.32 L, 7.91 mol) at -25C over 3 hours. Then the above Grignard solution was added to this solution at -20 over 41 minutes. The resulting solution was further stirred at -20C before quench. The reaction mixture was added to 10 wt% aqueous NH4Cl (10 L, 5X) at 0C with vigorous stirring, and stirred for 30 minutes at 0C. To this mixture was added slowly 6 N HCl (4 L, 2X) at 0C to obtain a clear solution and stirred for 30 minutes at 10C. After phase split, the organic layer was washed with 25 wt% aq NaCl (5 L, 2.5X). Then the organic layer was concentrated to a 3X solution under the conditions (200 mbar, bath temp 50C). EtOAc (24 L, 12X) was added, and evaporated to a 3X solution under the conditions (150 mbar, bath temp 50C). After removed solids by a polish filtration, EtOAc (4 L, 2X) was added and concentrated to dryness (150 mbar, bath temp 50C). The wet cake was then transferred to a 50 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet. After EtOAc was added, the suspension was heated at 70C to obtain a 2.5X homogeneous solution. To the resulting homogeneous solution was added slowly heptane (5 L, 2.5X) at the same temperature. A homogeneous solution was seeded and heptane (15 L, 7.5X) was added slowly to a little cloudy solution at 70C. After stirred for 0.5 h at 70C, the suspension was slowly cooled to 60C and stirred for 1 h at 60C. The suspension was then slowly cool to room temperature and stirred for 14 h at the same temperature. The crystals were collected and washed with heptane (8 L, 4X), dried under vacuum at 45C to give the desired ketone as fluffy solids (2.57 kg, 100 wt% by HPLC, purity-adjusted yield: 81%).
76%	With n-butyllithium; In tetrahydrofuran; at 0 - 20℃; for 4.5h;	To a solution of <strong>[1103738-29-9]1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene</strong> (500 mg, 1.34 mmol) in THF (5.0 mL) was added i-PrMgCl (2.0M in THF, 1.0 mL, 2.00 mmol) at 0-5 C., and the mixture was stirred for 1.5 h at 0-5 C. A solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (146.5 mg, 0.536 mmol) in THF (1.0 mL) was added dropwise at 0-5 C. and the mixture was kept stirring for 1 h, warmed to 20 C. and stirred at 20 C. for 2 hours. The reaction was quenched with saturated aq NH4Cl, extracted with MTBE, washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (178 mg, 76%) as a white solid. 1H NMR (CDCl3) delta 7.88 (dd, J=8.4, 2.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.07 (d, J=3.2 Hz, 1H), 5.21 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 4.56 (d, J=3.2 Hz, 1H), 4.16 (d, J=7.2 Hz, 2H), 4.03 (q, J=7.2 Hz, 2H), 1.54 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.37 (s, 3H).

76%		To a solution of <strong>[1103738-29-9]1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene</strong> (500 mg, 1.34 mmol) in THF (5.0 mL) was added i-PrMgCl (2.0M in THF, 1.0 mL, 2.00 mmol) at 0-5 C., and the mixture was stirred for 1.5 h at 0-5 C. A solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (146.5 mg, 0.536 mmol) in THF (1.0 mL) was added dropwise at 0-5 C. and the mixture was kept stirring for 1 h, warmed to 20 C. and stirred at 20 C. for 2 hours. The reaction was quenched with saturated aq NH4Cl, extracted with MTBE, washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (178 mg, 76%) as a white solid. 1H NMR (CDCl3) delta 7.88 (dd, J=8.4, 2.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.07 (d, J=3.2 Hz, 1H), 5.21 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 4.56 (d, J=3.2 Hz, 1H), 4.16 (d, J=7.2 Hz, 2H), 4.03 (q, J=7.2 Hz, 2H), 1.54 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.37 (s, 3H)
178 mg		To a solution of 48 <strong>[1103738-29-9]1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene</strong> (500mg, 1.34 mmol) in 20 THF (5.0 mL) was added 50 i-PrMgCl (2.0M in THF, 1.0 mL, 2.00 mmol) at 0-5C, and the mixture was stirred for 1.5 h at 0-5C. A solution of 13 (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (146.5 mg, 0.536 mmol) in THF (1.0 mL) was added dropwise at 0-5C and the mixture was kept stirring for 1h, warmed to 20C and stirred at 20C for 2 hours. The reaction was quenched with saturated aq NH4Cl, extracted with MTBE, washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired 51 ketone (178 mg, 76%) as a white solid. 1H NMR (CDCl3) delta 7.88 (dd, J = 8.4, 2.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.07 (d, J = 3.2 Hz, 1H), 5.21 (d, J = 3.2 Hz, 1H), 4.58 (d, J = 3.2 Hz, 1H), 4.56 (d, J = 3.2 Hz, 1H), 4.16 (d, J = 7.2 Hz, 2H), 4.03 (q, J = 7.2 Hz, 2H), 1.54 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.37 (s, 3H).

Reference： [1]Patent: US2009/30198,2009,A1 .Location in patent: Page/Page column 9-10
[2]Patent: EP2332947,2011,A1 .Location in patent: Page/Page column 8
[3]Patent: US2009/30198,2009,A1 .Location in patent: Page/Page column 9
[4]Patent: US2010/16422,2010,A1 .Location in patent: Page/Page column 6
[5]Patent: EP2661256,2018,B1 .Location in patent: Paragraph 0097

5
[ 609-06-3 ]
[ 1103738-19-7 ]

Reference： [1]Patent: EP2332947,2011,A1
[2]Patent: EP2332947,2011,A1
[3]Patent: CN106892948,2017,A
[4]Patent: EP2661256,2018,B1
[5]Patent: EP2661256,2018,B1

6
[ 1103738-29-9 ]
[ 1103738-19-7 ]
(3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2,3,4,5-tetraol [ No CAS ]

Reference： [1]Patent: EP2332947,2011,A1

7
[ 114861-22-2 ]
[ 1103738-19-7 ]

Reference： [1]Patent: EP2332947,2011,A1
[2]Patent: EP2332947,2011,A1
[3]Patent: CN106892948,2017,A
[4]Patent: KR101770302,2017,B1
[5]Patent: EP2661256,2018,B1
[6]Patent: EP2661256,2018,B1
[7]Patent: US2019/169174,2019,A1

Yield	Reaction Conditions	Operation in experiment
		The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25 L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether.

9
[ 1103738-19-7 ]
(3aS,5S,6R,6aS)-5-{(R)-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)phenyl]-hydroxymethyl}-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol [ No CAS ]

Reference： [1]Patent: WO2012/140596,2012,A1

10
[ 1103738-19-7 ]
(3S,4R,5R,6S)-6-[4-bromo-3-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)phenyl]tetrahydropyran-2,3,4,5-tetraol [ No CAS ]

Reference： [1]Patent: WO2012/140596,2012,A1

11
[ 1103738-19-7 ]
[ 1402348-06-4 ]

Reference： [1]Patent: WO2012/140596,2012,A1

12
[ 1103738-19-7 ]
[ 1402348-08-6 ]

Reference： [1]Patent: WO2012/140596,2012,A1

13
[ 1103738-19-7 ]
[ 1402348-10-0 ]

Reference： [1]Patent: WO2012/140596,2012,A1

14
[ 1103738-19-7 ]
[ 1402348-12-2 ]

Reference： [1]Patent: WO2012/140596,2012,A1

15
[ 1103738-19-7 ]
[ 1402348-35-9 ]

Reference： [1]Patent: WO2012/140596,2012,A1

16
[ 1103738-19-7 ]
[ 1402348-36-0 ]

Reference： [1]Patent: WO2012/140596,2012,A1

17
[ 1103738-19-7 ]
acetic acid (3S,4R,5S,6S)-4,5-diacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethylphenyl]-2-methoxytetrahydropyran-3-yl ester [ No CAS ]

Reference： [1]Patent: WO2012/140596,2012,A1

18
[ 1103738-19-7 ]
[ 1402348-42-8 ]

Reference： [1]Patent: WO2012/140596,2012,A1

19
[ 1103738-19-7 ]
6-(2-bromo-5-iodobenzyl)-2,3-dihydro-benzo[1,4]dioxine [ No CAS ]
[ 1402348-00-8 ]

Yield	Reaction Conditions	Operation in experiment
		Step-V: To a cooled solution of ((3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyl-tetrahydro- furo[2,3-d][1 ,3]dioxol-5-yl)-morpholin-4-yl-methanone (1 1.05 g, 256 mmol) in THF (200 ml) was added 2.0 M solution of isopropylmagnesium chloride (12.78 ml, 256 mmol) under stirring at 0 C and stirred for additional 1.5 h. To this was added a solution of 6- (2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1 ,4]dioxine (4.0 g, 146 mmol) in THF (50 ml) at 0 C and then stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of aqueous saturated ammonium chloride solution and extracted with ethyl acetate (200 ml X 3). Combined organic layers were washed with brine (500 ml), dried over sodium sulfate, concentrated and purified by silica gel columnchromatography to give 4.7 g of [4-bromo-3-(2,3-dihydro-benzo[1 ,4]dioxin-6-ylmethyl)- phenyl]-((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1 ,3]dioxol-5-yl)- methanone. 1H NMR (400 MHz, CDCI3): delta 1.35 (s, 3H), 1.53 (s, 3H), 2.92 (d, J = 4.0 Hz, 1 H), 4.04 (d, J = 3.6 Hz, 2H), 4.23 (s, 4H), 4.54 (br s, 1 H), 4.56 (d, J = 3.6 Hz, 1 H), 5.21 (d, J = 2.8 Hz, 1 H), 6.05 (d, J = 3.2 Hz, 1 H), 6.67 (s, 2H), 6.79 (d, J = 9.2 Hz, 1 H), 7.68 (d, J = 9.2 Hz, 1 H), 7.75-7.77 (m, 2H). MS (ES) m/z 490.7 (M+1 ).

Reference： [1]Patent: WO2012/140596,2012,A1 .Location in patent: Page/Page column 56

20
[ 1103738-19-7 ]
[ 1373555-87-3 ]
[ 1373555-07-7 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system 1(a) (4.04g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) (which wassynthesized according to WO 2010/309197, starting from L-xylose, through bis-acetonide protection, selective acetonidedeprotection, oxidation, amidation, and the like) was added. The stirring was continued for 1 hr. Then the reaction wasquenched with a saturated NH4Cl solution. The aqueous phase was removed and extracted with ethyl acetate. Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4 and concentrated. The resulting residue was purified by a silica gel column chromatography (petroleumether/ethyl acetate = 2:1) to produce a pale yellow solid (2.1g). This compound (535mg, 1.1mmol) was dissolvedin methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was added at room temperature. The mixture was stirred for 20minsuntil it completely dissolved, and cooled to -78C. NaBH4 (50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) was added to quench the reaction. The reaction system was warmedto room temperature and subjected to the rotary-evaporation to remove the solvent. The resulting aqueous phase wasextracted with dichloromethane (3310mL). The organic phases were combined, washed with water and a saturatedaqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated to produce a crude pale yellowoily product 1(b). 1H NMR (400 Hz, CDCl3) delta1.24 (s, 6 H), 4.33 (s, 2 H), 4.59-4.61 (m, 2 H), 5.27 (d, J = 2 Hz, 1 H), 6.08(d, J = 3.2 Hz, 1 H), 6.82 (d, J = 3.6 Hz, 1 H),7.03-7.09 (m, 3 H), 7.50-7.54 (m, 3 H), 7.91-8.00 (m, 2 H).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0058-0059

21
[ 1103738-19-7 ]
C₂₅H₂₄ClFO₅S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

22
[ 1103738-19-7 ]
[ 1373554-85-8 ]

Reference： [1]Patent: EP2634184,2013,A1
[2]Patent: US2013/225514,2013,A1

23
[ 1103738-19-7 ]
[ 1373555-09-9 ]

Reference： [1]Patent: EP2634184,2013,A1
[2]Patent: US2013/225514,2013,A1

24
[ 1103738-19-7 ]
C₃₀H₂₈ClFO₉S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

25
[ 1103738-19-7 ]
C₂₈H₂₅BrClFO₇S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

26
[ 1103738-19-7 ]
C₂₈H₂₆ClFO₇S₂ [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

27
[ 1103738-19-7 ]
C₂₆H₂₇FO₅S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

28
[ 1103738-19-7 ]
C₂₅H₂₆FNO₅S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

29
[ 1103738-19-7 ]
C₁₉H₂₀Cl₂O₅S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

30
[ 1103738-19-7 ]
C₂₀H₂₃BrO₅S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

31
[ 1103738-19-7 ]
C₂₆H₂₅F₃O₅S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

32
[ 1103738-19-7 ]
C₂₆H₂₆F₂O₅S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

33
[ 1103738-19-7 ]
C₃₂H₃₄O₁₀S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

34
[ 1103738-19-7 ]
C₃₀H₃₁BrO₈S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

35
[ 1103738-19-7 ]
C₃₀H₃₂O₈S₂ [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

36
[ 1103738-19-7 ]
[ 1373555-37-3 ]

Reference： [1]Patent: EP2634184,2013,A1
[2]Patent: US2013/225514,2013,A1

37
[ 1103738-19-7 ]
C₂₇H₂₇NO₅S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

38
[ 1103738-19-7 ]
C₂₇H₂₈O₆S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

39
[ 1103738-19-7 ]
C₂₇H₂₈O₆S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

40
[ 1103738-19-7 ]
C₃₂H₄₀N₂O₅S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

41
[ 1103738-19-7 ]
C₃₁H₃₇NO₆S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

42
[ 1103738-19-7 ]
C₂₇H₂₈O₇S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

43
[ 1103738-19-7 ]
C₃₀H₃₃NO₆S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

44
[ 1103738-19-7 ]
C₃₂H₃₄O₉S₂ [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

45
[ 1103738-19-7 ]
C₃₀H₃₂O₇S₃ [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

46
[ 1103738-19-7 ]
[ 1373555-69-1 ]

Reference： [1]Patent: EP2634184,2013,A1
[2]Patent: US2013/225514,2013,A1

47
[ 1103738-19-7 ]
C₃₀H₃₁BrO₇S₂ [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

48
[ 1103738-19-7 ]
C₂₄H₂₆O₆S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

49
[ 1103738-19-7 ]
C₂₇H₃₀O₆S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

50
[ 1103738-19-7 ]
C₂₆H₂₉NO₅S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

51
[ 1103738-19-7 ]
C₂₇H₂₉FO₆S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

52
[ 1103738-19-7 ]
[ 898566-17-1 ]
[ 1373555-12-4 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 2(a) (3.9g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4, and concentrated. The resulting residuewas separated by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellowsolid (2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) wasadded at room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4 and concentrated to produce a crude pale yellow oily product 2(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0070-0071

53
[ 1103738-19-7 ]
[ 1373555-88-4 ]
[ 1373555-16-8 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 3(a) (3.87g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4, and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4 and concentrated to produce a crude pale yellow oily product 3(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0082; 0083

54
[ 1103738-19-7 ]
[ 1373555-89-5 ]
[ 1373555-20-4 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 4(a) (3.5g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4 and concentrated to produce a crude pale yellow oily product 4(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0094; 0095

55
[ 1103738-19-7 ]
[ 1373555-90-8 ]
[ 1373555-24-8 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added , and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 5(a) (3.7g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4 and concentrated to produce a crude pale yellow oily product 5(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0106-0107

56
[ 1103738-19-7 ]
[ 1373555-91-9 ]
[ 1373555-28-2 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 6(a) (4.2g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4, and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 6(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0118; 0119

57
[ 1103738-19-7 ]
[ 1373555-92-0 ]
[ 1373555-32-8 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 7(a) (4.4g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 7(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0131-0132

58
[ 1103738-19-7 ]
[ 1373555-93-1 ]
[ 1373769-08-4 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 8(a) (3.9g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4, and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 8(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0144; 0145

59
[ 1103738-19-7 ]
[ 1373555-93-1 ]
C₂₇H₃₀O₆S [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

60
[ 1103738-19-7 ]
[ 1373555-94-2 ]
[ 1373555-39-5 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 9(a) (3.9g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32 mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 9(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0158-0159

61
[ 1103738-19-7 ]
[ 1373555-95-3 ]
[ 1373555-43-1 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 10(a) (3.3g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4, and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 10(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0171-0172

62
[ 1103738-19-7 ]
[ 1373555-96-4 ]
[ 1373555-47-5 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 11(a) (4.0g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 11(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0184-0185

63
[ 1103738-19-7 ]
[ 1373555-97-5 ]
[ 1373555-51-1 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 12(a) (4.7g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 12(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0198-0199

64
[ 1103738-19-7 ]
[ 1373555-98-6 ]
[ 1373555-55-5 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 13(a) (4.6g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3x10mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 13(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0211; 0212

65
[ 1103738-19-7 ]
[ 1373555-99-7 ]
[ 1373555-59-9 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 14(a) (4.1g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.lmmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 14(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0225-0226

66
[ 1103738-19-7 ]
[ 1373556-00-3 ]
[ 1373555-63-5 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 15(a) (4.5g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl37H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3x10mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 15(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0237-0238

67
[ 1103738-19-7 ]
[ 1373556-01-4 ]
[ 1373555-67-9 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 16(a) (4.1g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 16(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0251-0252

68
[ 1103738-19-7 ]
[ 1373556-01-4 ]
C₂₇H₃₀O₅S₂ [ No CAS ]

Reference： [1]Patent: EP2634184,2013,A1

69
[ 1103738-19-7 ]
[ 1373556-02-5 ]
[ 1373555-71-5 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 17(a) (3.6g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 17(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0265-0266

70
[ 1103738-19-7 ]
[ 1373556-04-7 ]
[ 1373555-75-9 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 18(a) (3.8g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 18(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0279-0280

71
[ 1103738-19-7 ]
[ 1373556-05-8 ]
[ 1373555-79-3 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 19(a) (3.8g, 9.46mmol) was added in batch. Then the reaction system was kept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4, and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 19(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0292-0293

72
[ 1103738-19-7 ]
[ 1373556-07-0 ]
[ 1373555-83-9 ]

Yield	Reaction Conditions	Operation in experiment
2.1 g		To a single-neck bottle containing LiCl (1.0g, 23.66mmol), THF (10mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83mL) was added slowly. After the completion of the dropwise addition, themixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and dilutedwith THF (10mL). To the reaction system, 20(a) (4.1g, 9.46mmol) was added in batch. Then the reaction system waskept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3g, 8.5mmol) was added.The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueousphase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and asaturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residuewas purified by a silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to produce a pale yellow solid(2.1g). This compound (535mg, 1.1mmol) was dissolved in methanol (9mL). CeCl3·7H2O (490mg, 1.32mmol) was addedat room temperature. The mixture was stirred for 20mins until it completely dissolved, and cooled to -78C. NaBH4(50mg, 1.32mmol) was added in batch. One hour later, the starting material consumed completely. Water (5mL) wasadded to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotaryevaporationto remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3310mL). Theorganic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried withanhydrous Na2SO4, and concentrated to produce a crude pale yellow oily product 20(b).

Reference： [1]Patent: EP2634184,2013,A1 .Location in patent: Paragraph 0306-0307

73
[ 1103738-19-7 ]
[ 1373555-87-3 ]
C₂₅H₂₄ClFO₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a single-neck bottle containing LiCl (1.0 g, 23.66 mmol), THF (10 mL) was added, and then 2 mol/L i-PrMgCl/tetrahydrofuran solution (23.66 mmol, 11.83 mL) was added slowly. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hrs. Then this reaction system was placed in an ice-water bath, and diluted with THF (10 mL). To the reaction system 1(a) (4.04 g, 9.46 mmol) was added in batch. Then the reaction system was kept at this temperature and stirred for 1 hr. Then to the reaction system, the solid 1(a?) (2.3 g, 8.5 mmol) (which was synthesized according to WO 2010/009197, starting from L-xylose, through bis-acetonide protection, selective acetonide deprotection, oxidation, amidation, and the like) was added. The stirring was continued for 1 hr. Then the reaction was quenched with a saturated NH4Cl solution. The aqueous phase was removed and extracted with ethyl acetate. The organic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated. The resulting residue was purified by a silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to produce a pale yellow solid (2.1 g). This compound (535 mg, 1.1 mmol) was dissolved in methanol (9 mL). CeCl3.7H2O (490 mg, 1.32 mmol) was added at room temperature. The mixture was stirred for 20 mins until it completely dissolved, and cooled to -78 C. NaBH4 (50 mg, 1.32 mmol) was added in batch. One hour later, the starting material consumed completely. Water (5 mL) was added to quench the reaction. The reaction system was warmed to room temperature and subjected to the rotary-evaporation to remove the solvent. The resulting aqueous phase was extracted with dichloromethane (3×10 mL). The organic phases were combined, washed with water and a saturated aqueous NaCl solution successively, dried with anhydrous Na2SO4 and concentrated to produce a crude pale yellow oily product 1(b).

Reference： [1]Patent: US2013/225514,2013,A1 .Location in patent: Paragraph 0082; 0083

74
[ 1103738-19-7 ]
[ 1373554-97-2 ]

Reference： [1]Patent: US2013/225514,2013,A1

75
[ 1103738-19-7 ]
[ 1373554-98-3 ]

Reference： [1]Patent: US2013/225514,2013,A1

76
[ 1103738-19-7 ]
[ 1373554-99-4 ]

Reference： [1]Patent: US2013/225514,2013,A1

77
[ 1103738-19-7 ]
[ 1373555-01-1 ]

Reference： [1]Patent: US2013/225514,2013,A1

78
[ 1103738-19-7 ]
[ 1373555-02-2 ]

Reference： [1]Patent: US2013/225514,2013,A1

79
[ 1103738-19-7 ]
[ 1373555-03-3 ]

Reference： [1]Patent: US2013/225514,2013,A1

80
[ 1103738-19-7 ]
[ 1373555-04-4 ]

Reference： [1]Patent: US2013/225514,2013,A1

81
[ 1103738-19-7 ]
[ 1373555-00-0 ]

Reference： [1]Patent: US2013/225514,2013,A1

82
[ 1103738-19-7 ]
[ 1373555-05-5 ]

Reference： [1]Patent: US2013/225514,2013,A1

83
[ 1103738-19-7 ]
C₂₂H₂₀ClFO₅S [ No CAS ]

Reference： [1]Patent: US2013/225514,2013,A1

84
[ 1103738-19-7 ]
[ 1373555-08-8 ]

Reference： [1]Patent: US2013/225514,2013,A1

85
[ 131156-47-3 ]
[ 1103738-19-7 ]

Reference： [1]Patent: CN106892948,2017,A

86
[ 109-02-4 ]
[ 1103738-17-5 ]
[ 1103738-19-7 ]

Yield	Reaction Conditions	Operation in experiment
82.6%	With O?(1H?benzotriazol?1?yl)?N,N,N?,N??tetramethyluronium tetrafluoroborate; In tetrahydrofuran; at 20 - 30℃;	The above obtained acid A (99.9 g, 0.49 mol) was added to a 3 L three-necked flask.Add 1 L of tetrahydrofuran, stir to dissolve,Add TBTU (235.76g, 0.74mol) in turnAnd N-methylmorpholine (NMM, 82 mL, 0.74 mol).The resulting reaction mixture was stirred at room temperature overnight. Filter the reaction solution,The filter cake was washed with 200 mL x 2 tetrahydrofuran.The filtrate was concentrated to dryness under reduced pressure at 35 to 45 C.400 mL of hexane was added to the obtained slurry.Heat to 60 ~ 70 C for 1 hour, and cool to room temperature for 2 hours.Then cool down to 0 ~ 10 C for 2 hours.Filtered white solid111.02 g, yield 82.6%.
48%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; at 20℃; for 12h;	To a solution of (3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyltetrahydrofuro [3,2- d][1,3] dioxole-5-carboxylic acid To a suspension of HBTU (25.1 g, 66.3 mmol, N, N, N', N'-tetramethyl-O- (1H- benzotriazol- 1-yl) uronium hexafluorophosphate) 4-Methylmorpholine (7.3 mL, 66.3 mmol) was added. 1 After the time, morpholine (5.8mL, 66.3 mmol) was added to the mixture at room temperature. 12 After this time, theresulting mixture was filtered and the filter cake was washed with tetrahydrofuran. Thefiltrate was concentrated in vacuo and the crude material was purified by silica gelcolumn chromatography to give the title compound (5.8 g, 48%) as a yellow solid.

Reference： [1]Patent: CN108675976,2018,A .Location in patent: Paragraph 0069; 0070; 0071
[2]Patent: KR101770302,2017,B1 .Location in patent: Paragraph 0337; 0338

87
[ 461432-23-5 ]
[ 1103738-19-7 ]
[ 1103738-30-2 ]

Yield	Reaction Conditions	Operation in experiment
86.3%		Add Compound C-1 (10 g, 30.7 mmol) to a 250 mL three-necked flaskAnd 70mL of tetrahydrofuran, stir and dissolve.The resulting solution is cooled to -70 to -80 C,Slowly add n-butyllithium solution (2.5M THF solution) to the cooled solution.14.1 mL, 1.15 eq), and stirred at -70 to -80 C for 1 hour.Further, a solution of the compound B in tetrahydrofuran (9.6 g of B in 30 mL of tetrahydrofuran, 35.3 mmol, 1.15 eq) was added dropwise to the reaction mixture.The mixture was stirred at -70 to -80 C for 2 hours. The reaction solution is heated to -10 to 0 C.The reaction solution was diluted with a saturated aqueous solution of NH 4Cl (20 mL).The reaction quenching solution was extracted twice by adding ethyl acetate (100 mL×2).The ethyl acetate layer was combined and washed with brine (100 mL).The organic layer was concentrated to dryness under reduced pressure at 40 to 50 C. The obtained solid was recrystallized from ethyl acetate and n-hexane to give 11.5 g of compound.D-1, yield 86.3%.

Reference： [1]Patent: CN108675976,2018,A .Location in patent: Paragraph 0083; 0084; 0085

88
[ 915095-89-5 ]
[ 1103738-19-7 ]
(4-chloro-3-(4-(3(S)-tetrahydrofuranyloxy)benzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxolan-5-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.4%		Add Compound C-2 (10 g, 27.2 mmol) to a 250 mL three-necked flaskAnd 70mL of tetrahydrofuran, stir and dissolve.The resulting solution is cooled to -70 to -80 C,Slowly add n-butyllithium solution (2.5M THF solution) to the cooled solution.12.5 mL, 1.15 eq), and stirred at -70 to -80 C for 1 hour.Further, a solution of the compound B in tetrahydrofuran (8.5 g of B in 30 mL of tetrahydrofuran, 31.3 mmol, 1.15 eq) was added dropwise to the reaction mixture.The mixture was stirred at -70 to -80 C for 2 hours. The reaction solution is heated to -10 to 0 C.The reaction solution was diluted with a saturated aqueous solution of NH 4Cl (20 mL).Add ethyl acetate(100 mL × 2) The reaction quenching solution was extracted twice, and the ethyl acetate layer was combined.The organic layer was washed with saturated brine (100 mL).The organic layer was concentrated to dryness under reduced pressure at 40 to 50 C.The resulting solid was recrystallized from ethyl acetate and n-hexane.Having 11.4g of compoundD-2, yield 88.4%.

Reference： [1]Patent: CN108675976,2018,A .Location in patent: Paragraph 0086; 0087; 0088

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(4-Chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone

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(2-Chloro-5-iodophenyl)(4-ethoxyphenyl)methanone

[ 114861-22-2 ]

(3aS,5S,6R,6aS)-5-(Hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1103738-19-7 ] {[proInfo.proName]}

Quality Control of [ 1103738-19-7 ]

Related Doc. of [ 1103738-19-7 ]

Product Details of [ 1103738-19-7 ]

Safety of [ 1103738-19-7 ]

Application In Synthesis of [ 1103738-19-7 ]

[ 1103738-19-7 ] Synthesis Path-Upstream 1~13

[ 1103738-19-7 ] Synthesis Path-Downstream 1~88

Pharmaceutical Intermediates of [ 1103738-19-7 ]

Sotagliflozin Intermediates

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Pharmaceutical Intermediates of
[ 1103738-19-7 ]