Name: 109862-53-5|Dimethyl 5-(hydroxymethyl)isophthalate|97%
Brand: Ambeed
SKU: A825662
Rating: 93 (25 reviews)

1
[ 2672-58-4 ]
[ 109862-53-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium tetrahydroborate In tetrahydrofuran; methanol for 1.33333h; Inert atmosphere; Reflux;
63%	Stage #1: 1,3,5-tris-(methoxycarbonyl)benzene With lithium borohydride In tetrahydrofuran; acetic acid methyl ester at 50℃; for 3h; Stage #2: With water; acetic acid In tetrahydrofuran; acetic acid methyl ester	Synthesis of dimethyl-(5-hydroxymethyl)isophthalate QOAH-2 was accomplished according to the following synthesis scheme (0.1 mol) of trimethyl 1,3,5 benzenetricarboxylate was dissolved in 85 mL of methyl acetate at 50° C. 40.5 ml (0.08 mol) lithiumborohydride 2.0 M in THF was added drop wise and the mixture was stirred during 3 hour at 50° C. After this period 5.3 gram acetic acid (0.088 mol) and 3 mL water were added. The methyl acetate and THF were evaporated, 50 ml water and 50 ml n-hexane were added. The product QAOH-2 was filtered and washed with a small volume water and n-hexane. The yield was 63%.
61%	With methanol; sodium tetrahydroborate In tetrahydrofuran for 0.5h; Inert atmosphere; Reflux;	4 Preparation of dimethyl 5-hydroxymethylisophthalate (32) Preparation of dimethyl 5-hydroxymethylisophthalate (32) Trimethyl 1,3,5-benzenetricarboxylate (5.02 g, 19.9 mmol) was dissolved in THF (15 mL). The air was evacuated from the reaction system, and then Ar was charged therein. To the solution were added NaBH4 (901 mg, 23.8 mmol), and then a mixed solution of THF:MeOH (12.5 mL:3.7 mL) slowly dropwise. The reaction mixture was refluxed for 30 minutes. TLC was used to confirm the progress of the reaction. Then, the reaction was quenched with HCl (1N, 20 mL). The mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc =4:1 to 3:1) to isolate dimethyl 5-hydroxymethylisophthalate (32) (2.73 g, 61%) as white crystals. 1H-NMR (CDCl3, 400 MHz) δ = 8.60 (1H, s, Ar-H), 8.24 (2H, s, Ar-H), 4.82 (2H, d, J = 6.3 Hz, CH2O), 3.95 (6H, s, CH3CO2), 1.98 (1H, t, J= 6.3 Hz, OH) 13C-NMR (CDCl3, 100 MHz) δ = 166.2, 142.0, 131.9, 130.7, 129.7, 64.05, 52.37

57%	With sodium tetrahydroborate In tetrahydrofuran; methanol for 0.5h; Inert atmosphere; Reflux;
55%	With lithium borohydride In tetrahydrofuran at 0℃; Inert atmosphere; Reflux;	13 Preparation of compound AMA-5a A homogeneous solution of trimethyl-1, 3, 5 -benzenetri carboxyl ate (34.28 g, 135.91 mmol) in dry THF at 0 °C under N2 atmosphere was treated with 4M L1BH4 in THF (16.99 mL, 67.95 mmol) and heated to reflux overnight. After the reaction was cooled to room temperature, the mixture was acidified with 4N HC1 (pH 2) and quenched with H2O (800 mL). The mixture was extracted with EA (800 mL X 2). The organic layer was dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EA : HEX = 1 : 5 to 1 : 2) to give title compound AMA-5a (16.75 g, 55 %, 6.07 g Sm recovered) as a white solid. NMR (400 MHz, CDCh) S 8.59 (s, 1H), 8.23 (s, 2H), 4.81 (d, J= 6 Hz, 2H), 3.95 (s, 6H), 1.97 (t, J= 5.6 Hz, 1H).
53.2%	With methanol; sodium tetrahydroborate In tetrahydrofuran for 0.5h; Reflux;	1 Step 1. Preparation of dimethyl 5-(hydroxymethyl)isophthalate 59 Trimethyl benzene-1,3,5-tricarboxylate (58) (40 g, 159 mmol) and NaBH4 were stirred in THF at RT. MeOH (30 ml) in THF (120 ml) was added dropwise slowly. After complete addition the reaction was refluxed for 30 mins. After cooling the reaction was quenched with 1M HCl and extracted into EtOAc. The organics were washed sequentially with 1M HCl, NaHCO3, water and brine, dried (Na2SO4) and concentrated in-vacuo. The residue was purified by automated flash chromatography (50/50 EtOAc/hex) to give dimethyl 5-(hydroxymethyl)isophthalate (59) (20.5 g, 53.2%).1H NMR (400 MHz, CDCl3) d 8.59 (s, 1H), 8.23 (s, 2H), 4.81 (s, 2H), 3.95 (s, 6H). Product confirmed by MS (ESI +ve).
53.2%	With methanol; sodium tetrahydroborate In tetrahydrofuran at 20℃; for 0.5h; Reflux;	27.1 Step 1. Preparation of dimethyl 5-(hydroxymethyl)isophthalate 659 Trimethyl benzene-1,3,5-tricarboxylate (658) (40 g, 159 mmol) and NaBH4 were stirred in THF at RT. MeOH (30 ml) in THF (120 ml) was added dropwise slowly. After complete addition the reaction was refluxed for 30 mins. After cooling the reaction was quenched with 1M HCl and extracted into EtOAc. The organics were washed sequentially with 1M HCl, NaHCO3, water and brine, dried (Na2SO4) and concentrated in-vacuo. The residue was purified by automated flash chromatography (50/50 EtOAc/hex) to give dimethyl 5- (hydroxymethyl)isophthalate (659) (20.5 g, 53.2%).1H NMR (400 MHz, CDCl3) d 8.59 (s, 1H), 8.23 (s, 2H), 4.81 (s, 2H), 3.95 (s, 6H). Product confirmed by MS (ESI +ve).
	With lithium aluminium tetrahydride; diethyl ether
	Multi-step reaction with 2 steps 1: 76 percent / 0.1 M aq. NaOH / methanol / 18 h 2: 88 percent / borane-methyl sulfide / tetrahydrofuran / 24 h / 27 °C
	Multi-step reaction with 2 steps 1: sodium hydroxide / methanol 2: dimethyl sulfide borane / tetrahydrofuran / 20 °C
	Multi-step reaction with 2 steps 1: sodium hydroxide; water 2: dimethylsulfide borane complex
	Multi-step reaction with 2 steps 1: sodium hydroxide; water / methanol / 8 h 2: borane-THF / tetrahydrofuran / 24 h / 20 °C / Cooling with ice
	Multi-step reaction with 2 steps 1: sodium hydroxide / water; methanol / 18 h / 20 °C 2: dimethylsulfide borane complex / tetrahydrofuran / 24 h / 20 °C
	Multi-step reaction with 2 steps 1: sodium hydroxide; water / methanol / 22 h / 20 °C 2: dimethylsulfide borane complex / tetrahydrofuran / 25 h / 20 °C / Inert atmosphere
0.6%	With sodium tetrahydroborate In tetrahydrofuran for 0.5h; Inert atmosphere; Reflux;

Reference： [1]Liu, Yan; Ma, Jingjing; Xu, Cong; Yang, Yang; Xia, Minfang; Jiang, Huie; Liu, Weisheng [Dalton Transactions, 2018, vol. 47, # 38, p. 13543 - 13549]
[2]Current Patent Assignee: AGFA-GEVAERT - US8138238, 2012, B2 Location in patent: Page/Page column 29-30
[3]Current Patent Assignee: KITADE - EP2511260, 2012, A1 Location in patent: Page/Page column 25-26
[4]Wang, Jun; Dou, Wei; Kirillov, Alexander M.; Liu, Weisheng; Xu, Cailing; Fang, Ran; Yang, Lizi [Dalton Transactions, 2016, vol. 45, # 46, p. 18610 - 18621]
[5]Current Patent Assignee: INTOCELL - WO2021/111185, 2021, A1 Location in patent: Page/Page column 60; 61
[6]Current Patent Assignee: ARBUTUS BIOPHARMA CORP - WO2020/93053, 2020, A1 Location in patent: Page/Page column 59; 60
[7]Current Patent Assignee: ARBUTUS BIOPHARMA CORP; ROIVANT SCIENCES GMBH - WO2020/93061, 2020, A1 Location in patent: Page/Page column 204; 231-232
[8]Benning; Grosskinsky [Chemische Berichte, 1954, vol. 87, p. 54,56]
[9]Dimick, Sarah M.; Powell, Steven C.; McMahon, Stephen A.; Moothoo, Davina N.; Naismith, James H.; Toone, Eric J. [Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10286 - 10296]
[10]Pradhan, Tuhin; Maiti, Sukhendu; Kumar, Rajesh; Lee, Yun Hak; Kim, Jong Wan; Lee, Joung Hae; Kim, Jong Seung [Dyes and Pigments, 2015, vol. 121, p. 1 - 6]
[11]Verma, Ram P.; Shandilya, Ashutosh; Haridas [Tetrahedron, 2015, vol. 71, # 46, p. 8758 - 8765]
[12]Current Patent Assignee: AMGEN INC - US2016/24159, 2016, A1
[13]Pegoli, Andrea; She, Xueke; Wifling, David; Hübner, Harald; Bernhardt, Günther; Gmeiner, Peter; Keller, Max [Journal of Medicinal Chemistry, 2017, vol. 60, # 8, p. 3314 - 3334]
[14]Zenmyo, Naoki; Tokumaru, Hiroki; Uchinomiya, Shohei; Fuchida, Hirokazu; Tabata, Shigekazu; Hamachi, Itaru; Shigemoto, Ryuichi; Ojida, Akio [Bulletin of the Chemical Society of Japan, 2019, vol. 92, # 5, p. 995 - 1000]
[15]Chen, Yu-Sheng; Cheng, Qigan; Ma, Shengqian; Nafady, Ayman; Shan, Chuan; Wojtas, Lukasz; Zhang, Weijie; Zhang, X. Peter [Angewandte Chemie - International Edition, 2021, vol. 60, # 45, p. 24312 - 24317][Angew. Chem., 2021, vol. 133, # 45, p. 24514 - 24519]

2
[ 2672-58-4 ]
[ 193953-02-5 ]
[ 109862-53-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 20.1% 2: 23%	With lithium aluminium tetrahydride In tetrahydrofuran at 1 - 30℃; for 0.166667h;
	With lithium aluminium tetrahydride

Reference： [1]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Amrein, Walter [Helvetica Chimica Acta, 1997, vol. 80, # 4, p. 989 - 1026]
[2]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Bachmann, Beat M.; Amrein, Walter [Angewandte Chemie, 1996, vol. 108, # 23/24, p. 2969 - 2972]

3
[ 109862-53-5 ]
[ 58479-61-1 ]
[ 193953-04-7 ]

Yield	Reaction Conditions	Operation in experiment
92.8%	With dmap In N,N-dimethyl-formamide for 24h; Ambient temperature;

Reference： [1]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Amrein, Walter [Helvetica Chimica Acta, 1997, vol. 80, # 4, p. 989 - 1026]
[2]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Bachmann, Beat M.; Amrein, Walter [Angewandte Chemie, 1996, vol. 108, # 23/24, p. 2969 - 2972]

4
[ 38588-64-6 ]
[ 109862-53-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	With dimethylsulfide borane complex In tetrahydrofuran at 27℃; for 24h;
87%	With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 24h;
65%	With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 25h; Inert atmosphere;	Synthesis of 18 To an ice-cooled solution of 17 (500 mg, 2.10 mmol) in dry THF (3.5 mL) was added dropwise 2M BH3-Me2S in THF (2.1 mL, 4.20 mmol) under N2 atmosphere. The solution was stirred for 25 h atrt. After addition of MeOH (7.5 mL) on ice-cooling, the solution was stirred for 30 min at rt. Afterremoval of the solvent by evaporation, the residue was dissolved with AcOEt. The mixture waswashed with water, sat. NaHC3 aq. and brine followed by drying over Na2SO4. After removal of thesolvent by evaporation, the residue was purified by column chromatography on SiO2 (Hexane :AcOEt = 1 : 1) to give 18 (306 mg, 65%) as a white solid.

45%	With dimethyl sulfide borane In tetrahydrofuran at 20℃;
38.5%	With borane-THF In tetrahydrofuran at 20℃; for 24h; Cooling with ice;	3 3,5-bis(methoxycarbonyl)benzoic acid (10 g, 42.0 mmol) was dissolved in dry THF (80 mL). The flask was placed in ice-bath and bh3.thf (84 mL, 84 mmol) was added slowly (some bubbling occurred). The reaction mixture was left stirring at room temperature for 24 hours. After 14 hours reaction did not progress, another 3 eq. of bh3.thf (42.0 mL, 42.0 mmol) were slowly added and the reaction mixture was stirred at room temperature for hours. The reaction was completed (95% by LC-MS). (1046) The reaction mixture was quenched with MeOH (added slowly 80 mL) and left stirred for 1 hour at RT. The solvent was removed in vacuo. The product was re-dissolved in EtOAc (white solution 1000 mL) and the organic layer was washed with water (2×800 mL), sat. NaHCO3 (800 mL) and brine (800 mL). The EtOAc was dried with MgSO4, filtered and concentrated in vacuo (3.62 g; yield 38.5%).
	With dimethylsulfide borane complex
	With dimethylsulfide borane complex

Reference： [1]Dimick, Sarah M.; Powell, Steven C.; McMahon, Stephen A.; Moothoo, Davina N.; Naismith, James H.; Toone, Eric J. [Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10286 - 10296]
[2]Pegoli, Andrea; She, Xueke; Wifling, David; Hübner, Harald; Bernhardt, Günther; Gmeiner, Peter; Keller, Max [Journal of Medicinal Chemistry, 2017, vol. 60, # 8, p. 3314 - 3334]
[3]Zenmyo, Naoki; Tokumaru, Hiroki; Uchinomiya, Shohei; Fuchida, Hirokazu; Tabata, Shigekazu; Hamachi, Itaru; Shigemoto, Ryuichi; Ojida, Akio [Bulletin of the Chemical Society of Japan, 2019, vol. 92, # 5, p. 995 - 1000]
[4]Pradhan, Tuhin; Maiti, Sukhendu; Kumar, Rajesh; Lee, Yun Hak; Kim, Jong Wan; Lee, Joung Hae; Kim, Jong Seung [Dyes and Pigments, 2015, vol. 121, p. 1 - 6]
[5]Current Patent Assignee: AMGEN INC - US2016/24159, 2016, A1 Location in patent: Paragraph 1045-1046
[6]Location in patent: body text Haridas; Sharma, Yogesti K.; Naik, Sarala [European Journal of Organic Chemistry, 2009, # 10, p. 1570 - 1577]
[7]Verma, Ram P.; Shandilya, Ashutosh; Haridas [Tetrahedron, 2015, vol. 71, # 46, p. 8758 - 8765]

5
[ 109862-53-5 ]
[ 252210-01-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With thionyl chloride for 1.5h; Inert atmosphere; Reflux;
93%	With thionyl chloride for 1h; Heating;
93%	With thionyl chloride for 1h; Reflux; Inert atmosphere;

58%	With thionyl chloride In toluene at 40℃; for 4h;	Synthesis of dimethyl-(5-chloromethyl)isophthalate (QA-2) was accomplished according to the following synthesis scheme (0.1 mol) of dimethyl-(5-hydroxymethyl)isophthalate (QAOH-2) was dissolved in a mixture of 100 mL of Toluene and 0.2 g dimethylacetamide (catalyst). 15.4 g (0.13 mol) of thionylchloride was added drop wise and the mixture was stirred during 4 hour at 40° C. After this period, the mixture was cooled in an ice bath and 50 mL of methanol was added. This solid product QA-2 was filtered and washed with a small volume of methanol. The yield was 58%.
53%	With thionyl chloride for 1.5h; Reflux;	2 Step 2. Preparation of dimethyl 5-(chloromethyl)isophthalate 60 Dimethyl 5-(hydroxymethyl)isophthalate (59) (20.5 g, 80.5%) was refluxed in SOCl2 (11.1g, 94 mmol) for 1.5 h. The reaction was cooled, diluted with DCM and washed sequentially with 0.1 M NaOH (× 2), water and brine, dried (Na2SO4) and concentrated in-vacuo. The residue was purified by automated flash chromatography (20% EtOAc/Hex) to give dimethyl 5- (chloromethyl)isophthalate (60) (10.84 g, 53 %).1H NMR (400 MHz, CDCl3) d 8.65 (s, 1H), 8.27 (s, 2H), 4.66 (s, 2H), 3.97 (s, 6H). Product confirmed by MS (ESI +ve).
53%	With thionyl chloride for 1.5h; Reflux;	27.2 Step 2. Preparation of dimethyl 5-(chloromethyl)isophthalate 660 Dimethyl 5-(hydroxymethyl)isophthalate (659) (20.5 g, 80.5%) was refluxed in SOCl2 (11.1g, 94 mmol) for 1.5 h. The reaction was cooled, diluted with DCM and washed sequentially with 0.1 M NaOH (× 2), water and brine, dried (Na2SO4) and concentrated in-vacuo. The residue was purified by automated flash chromatography (20% EtOAc/Hex) to give dimethyl 5- (chloromethyl)isophthalate (660) (10.84 g, 53 %).1H NMR (400 MHz, CDCl3) d 8.65 (s, 1H), 8.27 (s, 2H), 4.66 (s, 2H), 3.97 (s, 6H). Product confirmed by MS (ESI +ve).
	With thionyl chloride Reflux;
	With thionyl chloride Reflux;

Reference： [1]Pegoli, Andrea; She, Xueke; Wifling, David; Hübner, Harald; Bernhardt, Günther; Gmeiner, Peter; Keller, Max [Journal of Medicinal Chemistry, 2017, vol. 60, # 8, p. 3314 - 3334]
[2]Dimick, Sarah M.; Powell, Steven C.; McMahon, Stephen A.; Moothoo, Davina N.; Naismith, James H.; Toone, Eric J. [Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10286 - 10296]
[3]Wang, Jun; Dou, Wei; Kirillov, Alexander M.; Liu, Weisheng; Xu, Cailing; Fang, Ran; Yang, Lizi [Dalton Transactions, 2016, vol. 45, # 46, p. 18610 - 18621]
[4]Current Patent Assignee: AGFA-GEVAERT - US8138238, 2012, B2 Location in patent: Page/Page column 29
[5]Current Patent Assignee: ARBUTUS BIOPHARMA CORP - WO2020/93053, 2020, A1 Location in patent: Page/Page column 59; 60
[6]Current Patent Assignee: ROIVANT SCIENCES GMBH; ARBUTUS BIOPHARMA CORP - WO2020/93061, 2020, A1 Location in patent: Page/Page column 204; 231-232
[7]Location in patent: body text Haridas; Sharma, Yogesti K.; Naik, Sarala [European Journal of Organic Chemistry, 2009, # 10, p. 1570 - 1577]
[8]Verma, Ram P.; Shandilya, Ashutosh; Haridas [Tetrahedron, 2015, vol. 71, # 46, p. 8758 - 8765]

6
[ 554-95-0 ]
[ 109862-53-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 95 percent / conc. H₂SO₄ / 24 h / Heating 2: 76 percent / 0.1 M aq. NaOH / methanol / 18 h 3: 88 percent / borane-methyl sulfide / tetrahydrofuran / 24 h / 27 °C
	Multi-step reaction with 2 steps 1: methanol / Reflux 2: sodium tetrahydroborate / tetrahydrofuran / 0.5 h / Inert atmosphere; Reflux

Reference： [1]Dimick, Sarah M.; Powell, Steven C.; McMahon, Stephen A.; Moothoo, Davina N.; Naismith, James H.; Toone, Eric J. [Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10286 - 10296]
[2]Chen, Yu-Sheng; Cheng, Qigan; Ma, Shengqian; Nafady, Ayman; Shan, Chuan; Wojtas, Lukasz; Zhang, Weijie; Zhang, X. Peter [Angewandte Chemie - International Edition, 2021, vol. 60, # 45, p. 24312 - 24317][Angew. Chem., 2021, vol. 133, # 45, p. 24514 - 24519]

7
[ 109862-53-5 ]
[ 252210-03-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 93 percent / SOCl₂ / 1 h / Heating 2: 97 percent / NaN₃ / acetone; H₂O / 16 h / Heating 3: 99 percent / 1 M aq. KOH / methanol / 1 h / Heating 4: 100 percent / SOCl₂ / 1 h / Heating
	Multi-step reaction with 4 steps 1: thionyl chloride / Reflux 2: sodium azide 3: sodium hydroxide; water 4: thionyl chloride / Reflux

Reference： [1]Dimick, Sarah M.; Powell, Steven C.; McMahon, Stephen A.; Moothoo, Davina N.; Naismith, James H.; Toone, Eric J. [Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10286 - 10296]
[2]Verma, Ram P.; Shandilya, Ashutosh; Haridas [Tetrahedron, 2015, vol. 71, # 46, p. 8758 - 8765]

8
[ 109862-53-5 ]
[ 178056-30-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 93 percent / SOCl₂ / 1 h / Heating 2: 97 percent / NaN₃ / acetone; H₂O / 16 h / Heating
	Multi-step reaction with 2 steps 1: thionyl chloride / Reflux 2: sodium azide
	Multi-step reaction with 2 steps 1: thionyl chloride / 1.5 h / Inert atmosphere; Reflux 2: sodium azide / water; acetone / Reflux

	Multi-step reaction with 2 steps 1: thionyl chloride / 1.5 h / Reflux 2: sodium azide / water; acetonitrile / 16 h / Reflux
	Multi-step reaction with 2 steps 1: thionyl chloride / 1.5 h / Reflux 2: sodium azide / water; acetone / 16 h / Reflux

Reference： [1]Dimick, Sarah M.; Powell, Steven C.; McMahon, Stephen A.; Moothoo, Davina N.; Naismith, James H.; Toone, Eric J. [Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10286 - 10296]
[2]Verma, Ram P.; Shandilya, Ashutosh; Haridas [Tetrahedron, 2015, vol. 71, # 46, p. 8758 - 8765]
[3]Pegoli, Andrea; She, Xueke; Wifling, David; Hübner, Harald; Bernhardt, Günther; Gmeiner, Peter; Keller, Max [Journal of Medicinal Chemistry, 2017, vol. 60, # 8, p. 3314 - 3334]
[4]Current Patent Assignee: ARBUTUS BIOPHARMA CORP - WO2020/93053, 2020, A1
[5]Current Patent Assignee: ROIVANT SCIENCES GMBH; ARBUTUS BIOPHARMA CORP - WO2020/93061, 2020, A1

9
[ 109862-53-5 ]
[ 252210-02-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 93 percent / SOCl₂ / 1 h / Heating 2: 97 percent / NaN₃ / acetone; H₂O / 16 h / Heating 3: 99 percent / 1 M aq. KOH / methanol / 1 h / Heating
	Multi-step reaction with 3 steps 1: thionyl chloride / Reflux 2: sodium azide 3: sodium hydroxide; water
	Multi-step reaction with 3 steps 1: thionyl chloride / 1.5 h / Reflux 2: sodium azide / water; acetonitrile / 16 h / Reflux 3: water; lithium hydroxide / methanol; tetrahydrofuran / 48 h / 20 °C

Multi-step reaction with 3 steps 1: thionyl chloride / 1.5 h / Reflux 2: sodium azide / water; acetone / 16 h / Reflux 3: lithium hydroxide; water / tetrahydrofuran; methanol / 48 h / 20 °C

Reference： [1]Dimick, Sarah M.; Powell, Steven C.; McMahon, Stephen A.; Moothoo, Davina N.; Naismith, James H.; Toone, Eric J. [Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10286 - 10296]
[2]Verma, Ram P.; Shandilya, Ashutosh; Haridas [Tetrahedron, 2015, vol. 71, # 46, p. 8758 - 8765]
[3]Current Patent Assignee: ARBUTUS BIOPHARMA CORP - WO2020/93053, 2020, A1
[4]Current Patent Assignee: ROIVANT SCIENCES GMBH; ARBUTUS BIOPHARMA CORP - WO2020/93061, 2020, A1

10
[ 109862-53-5 ]
5-azidomethyl-N,N'-bis[3-(O-α-D-mannopyranosyl)propyl]benzene-1,3-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 93 percent / SOCl₂ / 1 h / Heating 2: 97 percent / NaN₃ / acetone; H₂O / 16 h / Heating 3: 99 percent / 1 M aq. KOH / methanol / 1 h / Heating 4: 100 percent / SOCl₂ / 1 h / Heating 5: 53 percent / Et₃N / tetrahydrofuran / 16 h / 25 °C 6: 79 percent / 0.1 M NaOMe / 2 h / 25 °C

Reference： [1]Dimick, Sarah M.; Powell, Steven C.; McMahon, Stephen A.; Moothoo, Davina N.; Naismith, James H.; Toone, Eric J. [Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10286 - 10296]

11
[ 109862-53-5 ]
[ 252210-12-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 93 percent / SOCl₂ / 1 h / Heating 2: 97 percent / NaN₃ / acetone; H₂O / 16 h / Heating 3: 99 percent / 1 M aq. KOH / methanol / 1 h / Heating 4: 100 percent / SOCl₂ / 1 h / Heating 5: 53 percent / Et₃N / tetrahydrofuran / 16 h / 25 °C 6: H₂ / Pd/C

Reference： [1]Dimick, Sarah M.; Powell, Steven C.; McMahon, Stephen A.; Moothoo, Davina N.; Naismith, James H.; Toone, Eric J. [Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10286 - 10296]

12
[ 109862-53-5 ]
[ 252210-08-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 93 percent / SOCl₂ / 1 h / Heating 2: 97 percent / NaN₃ / acetone; H₂O / 16 h / Heating 3: 99 percent / 1 M aq. KOH / methanol / 1 h / Heating 4: 100 percent / SOCl₂ / 1 h / Heating 5: 53 percent / Et₃N / tetrahydrofuran / 16 h / 25 °C

Reference： [1]Dimick, Sarah M.; Powell, Steven C.; McMahon, Stephen A.; Moothoo, Davina N.; Naismith, James H.; Toone, Eric J. [Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10286 - 10296]

13
[ 109862-53-5 ]
[ 193953-06-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 92.8 percent / DMAP / dimethylformamide / 24 h / Ambient temperature 2: 78 percent / LiOH / methanol; dioxane; H₂O / 0.5 h
	Multi-step reaction with 2 steps 2: aq. alkali

Reference： [1]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Amrein, Walter [Helvetica Chimica Acta, 1997, vol. 80, # 4, p. 989 - 1026]
[2]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Bachmann, Beat M.; Amrein, Walter [Angewandte Chemie, 1996, vol. 108, # 23/24, p. 2969 - 2972]

14
[ 109862-53-5 ]
[ 186351-30-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 92.8 percent / DMAP / dimethylformamide / 24 h / Ambient temperature 2: 78 percent / LiOH / methanol; dioxane; H₂O / 0.5 h 3: (COCl)2 / dimethylformamide / 14 h
	Multi-step reaction with 3 steps 2: aq. alkali 3: (COCl)2

Reference： [1]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Amrein, Walter [Helvetica Chimica Acta, 1997, vol. 80, # 4, p. 989 - 1026]
[2]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Bachmann, Beat M.; Amrein, Walter [Angewandte Chemie, 1996, vol. 108, # 23/24, p. 2969 - 2972]

15
[ 109862-53-5 ]
[ 193953-23-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 92.8 percent / DMAP / dimethylformamide / 24 h / Ambient temperature 2: 78 percent / LiOH / methanol; dioxane; H₂O / 0.5 h 3: (COCl)2 / dimethylformamide / 14 h 4: pyridine, (t-Bu)Ph₂SiF / CH₂Cl₂ / 0 deg C, 3 h, RT, 8 h 5: 98 percent / H₂ / 10 percent Pd/C / various solvent(s)
	Multi-step reaction with 5 steps 2: aq. alkali 3: (COCl)2 5: 1,4-cyclohexadiene / Pd/C / dimethylformamide

Reference： [1]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Amrein, Walter [Helvetica Chimica Acta, 1997, vol. 80, # 4, p. 989 - 1026]
[2]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Bachmann, Beat M.; Amrein, Walter [Angewandte Chemie, 1996, vol. 108, # 23/24, p. 2969 - 2972]

16
[ 109862-53-5 ]
5-(tert-Butyl-diphenyl-silanyloxymethyl)-isophthalic acid bis-[(R)-2-((R)-2-chlorocarbonyl-1-methyl-ethoxycarbonyl)-1-methyl-ethyl] ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 92.8 percent / DMAP / dimethylformamide / 24 h / Ambient temperature 2: 78 percent / LiOH / methanol; dioxane; H₂O / 0.5 h 3: (COCl)2 / dimethylformamide / 14 h 4: pyridine, (t-Bu)Ph₂SiF / CH₂Cl₂ / 0 deg C, 3 h, RT, 8 h 5: 98 percent / H₂ / 10 percent Pd/C / various solvent(s) 6: oxalyl chloride / CH₂Cl₂ / Ambient temperature
	Multi-step reaction with 6 steps 2: aq. alkali 3: (COCl)2 5: 1,4-cyclohexadiene / Pd/C / dimethylformamide 6: (COCl)2

Reference： [1]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Amrein, Walter [Helvetica Chimica Acta, 1997, vol. 80, # 4, p. 989 - 1026]
[2]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Bachmann, Beat M.; Amrein, Walter [Angewandte Chemie, 1996, vol. 108, # 23/24, p. 2969 - 2972]

17
[ 109862-53-5 ]
[ 193953-24-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 92.8 percent / DMAP / dimethylformamide / 24 h / Ambient temperature 2: 78 percent / LiOH / methanol; dioxane; H₂O / 0.5 h 3: (COCl)2 / dimethylformamide / 14 h 4: pyridine / CH₂Cl₂ / 0 deg C, 3 h, RT, 21 h 5: 97 percent / H₂ / 10 percent Pd/C / various solvent(s)
	Multi-step reaction with 5 steps 2: aq. alkali 3: (COCl)2 5: 1,4-cyclohexadiene / Pd/C / dimethylformamide

Reference： [1]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Amrein, Walter [Helvetica Chimica Acta, 1997, vol. 80, # 4, p. 989 - 1026]
[2]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Bachmann, Beat M.; Amrein, Walter [Angewandte Chemie, 1996, vol. 108, # 23/24, p. 2969 - 2972]

18
[ 109862-53-5 ]
5-(tert-Butyl-diphenyl-silanyloxymethyl)-isophthalic acid bis-((R)-2-{(R)-2-[(R)-2-((R)-2-chlorocarbonyl-1-methyl-ethoxycarbonyl)-1-methyl-ethoxycarbonyl]-1-methyl-ethoxycarbonyl}-1-methyl-ethyl) ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 92.8 percent / DMAP / dimethylformamide / 24 h / Ambient temperature 2: 78 percent / LiOH / methanol; dioxane; H₂O / 0.5 h 3: (COCl)2 / dimethylformamide / 14 h 4: pyridine / CH₂Cl₂ / 0 deg C, 3 h, RT, 21 h 5: 97 percent / H₂ / 10 percent Pd/C / various solvent(s) 6: oxalyl chloride / CH₂Cl₂ / Ambient temperature
	Multi-step reaction with 6 steps 2: aq. alkali 3: (COCl)2 5: 1,4-cyclohexadiene / Pd/C / dimethylformamide 6: (COCl)2

Reference： [1]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Amrein, Walter [Helvetica Chimica Acta, 1997, vol. 80, # 4, p. 989 - 1026]
[2]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Bachmann, Beat M.; Amrein, Walter [Angewandte Chemie, 1996, vol. 108, # 23/24, p. 2969 - 2972]

19
[ 109862-53-5 ]
[ 193953-20-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 92.8 percent / DMAP / dimethylformamide / 24 h / Ambient temperature 2: 78 percent / LiOH / methanol; dioxane; H₂O / 0.5 h 3: (COCl)2 / dimethylformamide / 14 h 4: pyridine / CH₂Cl₂ / 0 deg C, 3 h, RT, 21 h
	Multi-step reaction with 4 steps 2: aq. alkali 3: (COCl)2

Reference： [1]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Amrein, Walter [Helvetica Chimica Acta, 1997, vol. 80, # 4, p. 989 - 1026]
[2]Seebach, Dieter; Herrmann, Guido F.; Lengweiler, Urs D.; Bachmann, Beat M.; Amrein, Walter [Angewandte Chemie, 1996, vol. 108, # 23/24, p. 2969 - 2972]

20
[ 109862-53-5 ]
[ 193953-22-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 92.8 percent / DMAP / dimethylformamide / 24 h / Ambient temperature 2: 78 percent / LiOH / methanol; dioxane; H₂O / 0.5 h 3: (COCl)2 / dimethylformamide / 14 h 4: pyridine / CH₂Cl₂ / 0 deg C, 3 h, RT, 8 h 5: 86 percent / H₂ / 10 percent Pd/C / various solvent(s)