Name: 18742-02-4|2-(2-Bromoethyl)-1,3-dioxolane|96%
Brand: Ambeed
SKU: A152028
Rating: 92 (22 reviews)

1
[ 18742-02-4 ]
[ 874-33-9 ]
3-(N-Methyl-N-(o-methyl)benzylamino)propionaldehyd-ethylenacetal [ No CAS ]

Reference： [1]Archiv der Pharmazie,1993,vol. 326,p. 209 - 215

2
[ 18742-02-4 ]
[ 95091-91-1 ]
[ 109065-57-8 ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium; copper(I) bromide 1.) THF, 30 deg C, 30 min, 2.) THF, 20 deg C, 1 h; Yield given. Multistep reaction;
	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With magnesium In tetrahydrofuran at 20℃; for 1h; Stage #2: N-methoxy-N-methylpyridine-3-carboxamide With Amberlite IRC-50 In tetrahydrofuran

Reference： [1]Kruse, Chris G.; Bouw, Jan P.; Hes, Roelof van; Kuilen, Aalt van de; Hartog, Jack A. J. den [Heterocycles, 1987, vol. 26, # 12, p. 3141 - 3151]
[2]Vega, Ismael El Drubi; Gale, Philip A.; Light, Mark E.; Loeb, Stephen J. [Chemical Communications, 2005, # 39, p. 4913 - 4915]

3
[ 18742-02-4 ]
[ 116332-61-7 ]
[ 116332-53-7 ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium; copper(I) bromide 1.) THF, 30 deg C, 30 min, 2.) THF, 20 deg C, 1 h; Yield given. Multistep reaction;

Reference： [1]Kruse, Chris G.; Bouw, Jan P.; Hes, Roelof van; Kuilen, Aalt van de; Hartog, Jack A. J. den [Heterocycles, 1987, vol. 26, # 12, p. 3141 - 3151]

4
[ 18742-02-4 ]
[ 116332-54-8 ]
[ 116332-55-9 ]

Reference： [1]Heterocycles,1987,vol. 26,p. 3141 - 3151

5
[ 18742-02-4 ]
[ 116332-64-0 ]
4-(3-[1,3]Dioxolan-2-yl-propionyl)-benzonitrile [ No CAS ]

Reference： [1]Heterocycles,1987,vol. 26,p. 3141 - 3151

6
[ 18742-02-4 ]
[ 33513-42-7 ]
[ 82962-18-3 ]

Yield	Reaction Conditions	Operation in experiment
57.1%	With magnesium In tetrahydrofuran for 1.5h; Ambient temperature;
28%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With iodine; magnesium In tetrahydrofuran at 20℃; for 2h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -78℃; for 2h;	22.22A Example 22; N-r(5Z)-2-tert-butyl-4-(1.3-dioxolan-2-ylmethyl)isothiazol-5(2H)-ylidene]-5-chloro-2- methoxybenzamide; Example 22A; 3 -(I ,3-dioxolan-2-yl)propanal; To the solution of 2-(2-bromoethyl)-l,3-dioxolane (10 g, 55.2 mmol) in THF (50 mL) was added magnesium (1.6 g, 66.3 mmol) and trace amount of I2 as initiator. The reaction mixture was stirred at rt for 2 hrs. After cooling to -78 0C, the mixture was quenched with dry DMF (1.39 g, 66.3 mmol) and kept at -78 0C for 2 hrs. After dilution with H2O the reaction mixture was extracted with CH2Cl2 (2X), followed by distillation (45-55 0C @ 8mmHg) to afford 2 g (28 %) of the title compound. MS (DCI/NH4+) m/z 131 (M + H)+.
28%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With magnesium In tetrahydrofuran at 20℃; for 2h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -78℃; for 2h;	22.22A Example 22 A; 3-(l ,3-dioxolan-2-yl)propanal; To the solution of 2-(2-bromoethyl)-l,3-dioxolane (10 g, 55.2 mmol) in THF (50 mL) was added magnesium (1.6 g, 66.3 mmol) and trace amount of I2 as initiator. The reaction mixture was stirred at rt for 2 hrs. After cooling to -78 0C, the mixture was quenched with dry DMF (1.39 g, 66.3 mmol) and kept at -78 0C for 2 hrs. After dilution with H2O the reaction mixture was extracted with CH2Cl2 (2X), followed by distillation (45-55 0C (at) 8mmHg) to afford 2 g (28 %) of the title compound. MS (DCI/NH4+) m/z 131 (M + H)+.

Reference： [1]Lucchesini, Francesco [Tetrahedron, 1992, vol. 48, # 45, p. 9951 - 9966]
[2]Current Patent Assignee: ABBOTT LABORATORIES INC - WO2010/54024, 2010, A2 Location in patent: Page/Page column 71
[3]Current Patent Assignee: ABBVIE INC - WO2008/130953, 2008, A2 Location in patent: Page/Page column 54-55

7
[ 18742-02-4 ]
[ 100-46-9 ]
[ 134261-49-7 ]

Yield	Reaction Conditions	Operation in experiment
66.5%	With triethylamine In N,N-dimethyl-formamide for 23.5h; Ambient temperature;
56%	With N-ethyl-N,N-diisopropylamine In acetonitrile for 3h; Reflux;	11.1 Step 2; 5-((2-(1,3-dioxolan-2-yl)ethyl)(methyl)carbamoyl)thiophene-2-carboxylic acid To a solution of benzylamine (7.36 g, 68.7 mmol) in acetonitrile (100 mL) was added 2-(2-bromoethyl)-1,3-dioxolane (6.22 g, 34.3 mmol) and DIPEA (9.0 mL, 51.7 mmol) and the resultant mixture heated under reflux for 3 hours. The solvent was concentrated at reduced pressure and the residue dissolved in DCM. The organic phase was washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, the suspension filtered and the filtrate was concentrated at reduced pressure. The residue was purified by column chromatography (eluent 100% DCM to 5% methanol / DCM) to afford the title compound (4.0 g, 56 NMR (400 MHz, DMSO-de); δ 7.32 - 7.29 (m, 3H), 7.23- 7.20 (m, 2H), 4.84 (dd, J=4.9, 4.9 Hz, 1H), 3.87 - 3.71 (m, 4H), 3.67 (s, 2H), 2.59 - 2.55 (m, 2H), 1.76 - 1.71 (m, 2H).
40%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 72h;	10.1 Step 1: N-Benzyl-2-(1,3-dioxolan-2-yl)ethanamine Step 1: N-Benzyl-2-(1,3-dioxolan-2-yl)ethanamine To a mixture of benzylamine (2.18 mL, 20.0 mmol) and di-iso-propylethylamine (2.61 mL, 15.0 mmol) in acetonitrile (30 mL) was added 2-(2-bromoethyl)-1,3-dioxolane (1.17 mL, 10.0 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0 to 4% methanol/dichloromethane to afford the title compound (0.836 g, 40%). 1H NMR (400 MHz, CDCl3): δ 7.52-7.22 (m, 5H); 4.95-4.88 (m, 1H); 3.96-3.79 (m, 7H); 2.80-2.76 (m, 2H); 1.93-1.88 (m, 2H).

Reference： [1]Wilson; Di Grandi [Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4766 - 4772]
[2]Current Patent Assignee: Valline SRL - WO2016/193241, 2016, A1 Location in patent: Page/Page column 70
[3]Current Patent Assignee: Valline SRL - US2014/163066, 2014, A1 Location in patent: Paragraph 0393-0395

8
[ 18742-02-4 ]
[ 105-53-3 ]
[ 23985-06-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: diethyl propanedioate With potassium etoxide In ethanol at 55℃; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In ethanol at 55℃; for 0.416667h;
71%	With potassium etoxide In methanol at 80℃; for 3h;
71%	With potassium etoxide In ethanol at 80℃; for 3h;

70%	With potassium carbonate In acetonitrile at 50℃;	Synthesis of compounds 3a-3c, 9 General procedure: A mixture of 0.01 mol of CH acid 2, 0.015 mol of haloalkyl-1,3- dioxolane 1 or 8, 0.01 mol of K2CO3 (or 0.01 mol of triethylamine in the case of compound 2b), 50 mL of acetonitrile, and 10% Catamine AB was stirred at 50°C for 6-8 h. In the case of dioxolane 8, the reaction mixture was microwave-irradiated for 1 h. After the reaction was complete (GLC control), the mixture was cooled, washed with water (in the case of compound 2b, the mixture was washed successively with a 30% sodium bicarbonate solution and with water), extracted with chloroform, dried with potassium carbonate, and evaporated. The residue was distilled in vacuum (3a) or purified by chromatography (3b, 3c, 9) using benzene-ethyl acetate (9 : 1) as the eluent. Diethyl [2-(1,3-dioxolan-2-yl)ethyl]malonate (3a). Yield 1.8 g (70%), bp 161-162°C (3 mmHg). 1H NMR spectrum, δ, ppm (J, Hz): 1.24 t (6H, CH3, 3J = 7.1), 1.70 t.d (2H, C6H2, 3J = 7.1, 4.5), 2.01 q (2H, C7H2, 3J = 7.6), 3.38 t (1H, C8H, 3J = 7.6), 3.85 d.d (2H, C4HA, C5HA, 2J = 10.5, 3J = 3.5), 3.95 d.d (2H, C4HB, C5HB, 2J = 10.5, 3J = 3.5), 4.16 q (4H, C11H2, C12H2, 3J = 7.1), 4.86 t (1H, C2H, 3J = 4.5). 13C NMR spectrum, δC, ppm: 14.01 (CH3), 22.97 (C7), 31.16 (C6), 51.56 (8), 61.28 (C11, C12), 64.95 (C4, C5), 103.73 (C2), 169.22 (C=). Mass spectrum, m/e, (Irel, %): 215 (2), 171 (5), 99 (15), 73 (100), 45 (15).
68%	With potassium etoxide In ethanol 1.) 50 deg C, 5 min; 2.) reflux, 4 h;
59%	Stage #1: diethyl propanedioate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide; mineral oil at 80℃; for 4h;	Diethyl 2-(2-(1,3-dioxolan-2-yl)ethyl)malonate (56): The following protocol is inspired fromthe reported procedure [17]. Under a calcium chloride-protected atmosphere,diethylmalonate (13.77 g, 0.0859 mol) was dissolved in dry DMF (110 mL, dried over 4 Åmolecular sieves), This was cooled to 0 °C and 60% sodium hydride suspended in oil (3.33g, 0.0832 mol) was added by portion. At the end of the hydrogen evolution, 2-(2-bromoethyl)-1,3-dioxolane (9.8 mL, 0.0834 mol) was added. The reaction wessel was brought back toroom temperature and then heated at 80 °C for 4 hours. The resulting suspension wasconcentrated, the residue dissolved in a mixture of water and diethyether, the organic layerwas washed with water four times, brine, dried over magnesium sulfate and concentrated todryness. A distillation under a 5 mbar vaccum led to a fraction boiling at 148-150 °C whichcontained pure compound 56 (13.28 g, 59 %).
52%	Stage #1: diethyl propanedioate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In tetrahydrofuran; mineral oil at 20℃; for 12h;
50%	Stage #1: diethyl propanedioate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25h; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In tetrahydrofuran; mineral oil at 20℃; for 12h;
	With sodium hydride; dimethyl sulfoxide
	With potassium etoxide In ethanol
	Stage #1: diethyl propanedioate With natrium In ethanol at 20℃; for 0.5h; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In ethanol for 24h; Reflux;	General procedure for the synthesis of acrylic acids of type 3 General procedure: Sodium (1.0 equiv) is slowly added and dissolved in abs. ethanol (1.4mL/mmol). Then, diethyl malonate (1.0 equiv) is added dropwise and the resulting mixture is stirred during 30 min at room temperature. Then, the respective bromide is added dropwise at room temperature and the resulting mixture is refluxed during 24 h. After removal of volatiles, H2O is added and extractions with Et2O (×3) are performed. The combined organic layers are dried with Na2SO4 and evaporated to afford the crude product which is assumed to contain only the target monoalkylated diethyl ester of type 6. The residue is dissolved in EtOH (0.5 mL/mmol of 6) and cooled at 0°C. At the same temperature, a solution of KOH (2.0 equiv) in EtOH (1.5 mL/mmol of 6) is slowly added. The mixture is stirred at rt and the progress of the reaction is followed by TLC, until diethylester 6 is fully consumed (if needed, up to 1.0 equiv of KOH is gradually added). Typically, reaction time is 24h. The mixture is concentrated and the residue is diluted H2O and Et2O. The aqueous phase is separated, washed with Et2O (×2), acidified with HCl 2M to pH ~1 and extracted with AcOEt (×3). The combined organic layers are dried over Na2SO4 and evaporated to afford diacid of type 7. The latter is dissolved/suspended to ΑcOEt (1.8 mL/mmol of 7) and Et2NH (1.2 equiv) is added slowly at 0 °C. The temperature is raised at rt, ΗCHO (1.4 equiv) is added and the mixture is refluxed for 4 h. Then, the mixture is concentrated, treated with aq. NaHCO3 5% and washed with Et2O (×3). The aqueous phase is acidified with HCl 2M to pH ~1 and extracted with AcOEt (×3). The combined organic layers are dried over Na2SO4 and evaporated to afford acrylic acid of type 3 inadequately pure form to be used in the P-Michael reaction without further purification.

Reference： [1]Kanoh; Ishihara; Yamamoto; Murai [Synthesis, 2000, # 13, p. 1878 - 1893]
[2]Jousse-Karinthi, Céline; Zouhiri, Fatima; Mahuteau, Jacqueline; Desmaële, Didier [Tetrahedron, 2003, vol. 59, # 12, p. 2093 - 2099]
[3]Jousse-Karinthi, Celine; Riche, Claude; Chiaroni, Angele; Desmaele, Didier [European Journal of Organic Chemistry, 2001, # 19, p. 3631 - 3640]
[4]Raskil’dina; Borisova, Yu. G.; Spirikhin; Zlotsky [Russian Journal of General Chemistry, 2017, vol. 87, # 5, p. 1097 - 1100][Zh. Obshch. Khim., 2017, vol. 87, # 5, p. 872 - 875,4]
[5]Yamanaka; Narushima; Inukai; Sakai [Chemical and Pharmaceutical Bulletin, 1986, vol. 34, # 1, p. 77 - 81]
[6]Coutant, Eloi P.; Hervin, Vincent; Gagnot, Glwadys; Ford, Candice; Baatallah, Racha; Janin, Yves L. [Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 2853 - 2860]
[7]Tian, Ming-Qing; Shen, Zhen-Yao; Zhao, Xuefei; Walsh, Patrick J.; Hu, Xu-Hong [Angewandte Chemie - International Edition, 2021, vol. 60, # 17, p. 9706 - 9711][Angew. Chem., 2021, vol. 133, # 17, p. 9792 - 9797,6]
[8]Gao, Ya; Hu, Xu-Hong; Qin, Wei; Tian, Ming-Qing; Zhao, Xuefei [Advanced Synthesis and Catalysis, 2022]
[9]Leal; Hasegawa; Sawada; Ono [Journal of Chemical Ecology, 1994, vol. 20, # 7, p. 1705 - 1718]
[10]Location in patent: scheme or table Vulovic, Bojan; Bihelovic, Filip; Matovic, Radomir; Saicic, Radomir N. [Tetrahedron, 2009, vol. 65, # 50, p. 10485 - 10494]
[11]Kokkala, Paraskevi; Voreakos, Kostas; Lelis, Angelos; Patiniotis, Konstantinos; Skoulikas, Nikolaos; Devel, Laurent; Ziotopoulou, Angeliki; Kaloumenou, Eleni; Georgiadis, Dimitris [Molecules, 2022, vol. 27, # 4]

9
[ 18742-02-4 ]
[ 82891-99-4 ]

Yield	Reaction Conditions	Operation in experiment
38%	With sodium nitrite; In dimethyl sulfoxide; at 0 - 18℃; for 6h;Inert atmosphere;	To a solution of commercially available 2-(2-bromoethyl)-1,3-dioxolane (40.73 g, 225 mmol) in anhydrous DMSO (350 mL) was added a solution of NaNO2 (27.95 g, 405 mmol) in anhydrous DMSO (350 mL) slowly at 0C and the resulting mixture was stirred at 18C for 6 hours under N2. Then, the reaction mixture was poured into water and extracted with MTBE. The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography to give intermediate 2-(2-nitroethyl)-1,3-dioxolane (12.50 g, 38%) as a yellow liquid . A mixture of this intermediate (3.97 g, 27 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (6.61 g, 31) in TEA (3.00 g, 30 mmol) was stirred at 18C for 8 hours. Then a solution of DMAP (330 mg, 2.70 mmol) in Ac2O (4.13 g, 40 mmol) was added and the reaction mixture was stirred at 18C for 7 hours. The reaction was quenched with water and then extracted with EtOAc. The combined organic phase was washed with saturated brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography to afford intermediate tert-butyl 4-[(Z)-3-(1,3-dioxolan-2-yl)-2-nitro-prop-1-enyl]piperidine-1-carboxylate (5.64 g, 61%) as a yellow liquid. Finally, a stirred suspension of this intermediate (2.50 g, 7.30 mmol) in absolute EtOH (100 mL) and CHCl3 (8 mL) containing PtO2 (414 mg, 1.83 mmol) was placed under H2 (50 Psi) at 18C after 15 hours, the mixture was filtered through Celite and washed with EtOH. The filtrate was concentrated to dryness to give desired reagent R-04b (2.02 g, 88% crude) as a yellow syrup which was used for next step without further purification. ESI-MS (M+1): 315.3 calc. for C16H30N2O4: 314.2.
35%	With sodium nitrite; In N,N-dimethyl-formamide; at 20℃; for 6h;	2d: To a solution of bromo compound (5.4 g, 30 mmol) in DMF (60 mL) was added NaNO2 (3.5 g, 50 mmol). After stirring at r.t. for 6 h, the reaction mixture was poured into ice-water (60 mL) and layered over with petroleum ether (100 mL). The aqueous phase was extracted with diethyl ether (60 mL × 3). The organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by flash column chromatography on silica gel with 5% Et2O in hexane as eluent to afford 2d (1.5 g, 35%) as pale yellow oil. 1H NMR (CDCl3): delta 2.40-2.47 (m, 1H), 3.85-4.02 (m, 4H), 4.51 (t, J = 7.2 Hz, 2H), 5.03 (t, J = 3.6 Hz, 1H).

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 4040 - 4045
[2]Journal of the American Chemical Society,1986,vol. 108,p. 2662
[3]Tetrahedron,1984,vol. 40,p. 3809 - 3814
[4]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3427 - 3430
[5]Patent: WO2017/85053,2017,A1 .Location in patent: Page/Page column 55
[6]Journal of Fluorine Chemistry,2012,vol. 133,p. 108 - 114
[7]Journal of Organic Chemistry,1990,vol. 55,p. 4585 - 4595
[8]Letters in Organic Chemistry,2017,vol. 14,p. 39 - 42

10
[ 18742-02-4 ]
[ 111752-08-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium azide In dimethyl sulfoxide at 20℃; for 14h;
99%	With sodium azide In dimethyl sulfoxide at 20℃; for 14h;
99%	With sodium azide In dimethyl sulfoxide at 20℃; for 14h;

90%	With sodium azide; tetrahexylammonium bromide In water for 2h;
	With sodium azide In dimethyl sulfoxide at 20℃;
	With sodium azide In dimethyl sulfoxide at 25℃; Inert atmosphere;	Synthesis of azides This azide was synthesized according to an adapted Alvarez1 method. Sodium azide (1.305 g, 20.074 mmol) was suspended in DMSO (50 mL) and stirred for 25 min at 35 °C to obtain a clear solution then 2-(2-bromoethyl)-1,3-dioxolane (1.95 mL, 16.61 mmol) was added dropwise. The solution was stirred overnight at 25 °C under argon atmosphere. After cooling, the reaction mixture was poured in 200 mL of an ice/water mixture. The aqueous phase was extracted with dichloromethane (3 120 mL). The organic phase was then washed with deionised water (3 50 mL), dried on a WA filter and concentrated to give azide 1b. Yellowish oil; 2.541 g that contained 14% DMSO, yield: 92%. 1H NMR (300 MHz, CDCl3): δ = 4.96 (t, 1H, J = 4.2 Hz; CH), 4.05-3.80 (m, 4H; CH2CH2), 3.43 (t, 2H, J = 6.9 Hz; CH2N3), 1.96 ppm (m, 2H; CH2CH2N3).
	With sodium azide In dimethyl sulfoxide at 20℃;
	With sodium azide In N,N-dimethyl-formamide at 6℃;
	With sodium azide

Reference： [1]Diez-Gonzalez, Silvia; Correa, Andrea; Cavallo, Luigi; Nolan, Steven P. [Chemistry - A European Journal, 2006, vol. 12, # 29, p. 7558 - 7564]
[2]Diez-Gonzlez, Silvia; Nolan, Steven P. [Angewandte Chemie - International Edition, 2008, vol. 47, # 46, p. 8881 - 8884]
[3]Diez-Gonzalez, Silvia; Escudero-Adan, Eduardo C.; Benet-Buchholz, Jordi; Stevens, Edwin D.; Slawin, Alexandra M. Z.; Nolan, Steven P. [Dalton Transactions, 2010, vol. 39, # 32, p. 7595 - 7606]
[4]Gribble, Gordon W.; Switzer, Frank L. [Synthetic Communications, 1987, vol. 17, # 4, p. 377 - 384]
[5]Diez-Gonzalez, Silvia; Stevens, Edwin D.; Nolan, Steven P. [Chemical Communications, 2008, # 39, p. 4747 - 4749]
[6]Ionescu, Alexandra; Cornut, Damien; Soriano, Sébastien; Guissart, Céline; Van Antwerpen, Pierre; Jabin, Ivan [Tetrahedron Letters, 2013, vol. 54, # 45, p. 6087 - 6089]
[7]Collinson, John-Michael; Wilton-Ely, James D. E. T.; Diez-Gonzalez, Silvia [Chemical Communications, 2013, vol. 49, # 97, p. 11358 - 11360]
[8]Zhu, Biwei; Zhang, Hailong; Pan, Sijun; Wang, Chenyu; Ge, Jingyan; Lee, Jun-Seok; Yao, Shao Q. [Chemistry - A European Journal, 2016, vol. 22, # 23, p. 7824 - 7836]
[9]Johnson, David A.; Gribble, Gordon W. [Arkivoc, 2019, vol. 2019, # 5, p. 178 - 195]

11
[ 107-21-1 ]
[ 107-02-8 ]
[ 18742-02-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	With hydrogen bromide In 1,4-dioxane at 5 - 20℃; for 0.5h;	Typical procedure for the preparation of 2-(2-bromoalkyl)-1,3-dioxolanes with HBr/1,4-dioxane (1c) To a mixture of acrolein (90%, 374 mg, 6.0 mmol), ethylene glycol(460 mg, 7.4 mmol) in 1,4-dioxane (5 mL), 1c (17%, 4.0 g,8.4 mmol) was added at 5 C. The mixture was then warmed to room temperature for 30 min with stirring. The resulting mixture was quenched with saturated aq. NaHCO3 (20 mL) and extracted with diethyl ether (15 mL 3). The combined organic layer was washed with brine (25 mL 3), dried over Na2SO4 (10 g) and concentrated in vacuo. The crude residue was purified by column chromatography on florisil (eluent: pentane) to afford 10a (890 mg, 82%) as a colourless liquid. 1H NMR (500 MHz, CDCl3) δ 2.22 (dt, J = 4.6 Hz, J = 7.4 Hz, 2H), 3.47 (t, J = 7.1 Hz, 2H), 3.88 (m,2H), 3.96 (m, 2H), 5.01 (t, J = 4.6 Hz, 1H); 13C NMR (126 MHz,CDCl3) δ 27.14, 36.97, 64.78 (2C), 102.34.
76%	Stage #1: ethylene glycol With hydrogen bromide In 1,4-dioxane at 20℃; for 0.9h; Stage #2: acrolein In 1,4-dioxane at 5 - 20℃; for 1.5h;	1 Preparation of 2-(2-bromoethyl)-1,3-dioxolane A stirrer, a thermometer, a Dimroth condenser, a hydrogen bromide gas inlet tube were attached to a 50 mL three-necked flask, and 1,4-dioxane (10 mL) and ethylene glycol (2.461 g, 39.6 mmol) were added. Hydrogen bromide gas was introduced at room temperature for 54 minutes at a rate of 16.6 mL / min (material amount of introduced hydrogen bromide gas: 40.0 mmol). The reaction mixture was cooled to 5 ° C and acrolein (1.894 g, 33.8 mmol) was slowly added via syringe pump over 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour. (Over time, the reaction solution changed from a colorless single phase to colorless and light yellow two phases). To the solution after completion of the reaction, 5 mL of acetone and weighed amount of dimethylformamide (internal standard) were added and after stirring for 5 minutes, GC analysis was carried out,The GC yield was calculated (93%). The solution was diluted with diethyl ether, washed three times with water, and once with saturated brine, dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated to give 5.51 g of a brown liquid. When the content of the target compound in the concentrate was calculated by GC analysis, The yield of the target compound was 4.65 g, and the yield was 76%.
60%	With hydrogen bromide

45%	With hydrogen bromide at 0 - 20℃;
	With hydrogen bromide

Reference： [1]Nishio, Yuya; Mifune, Ryota; Sato, Taisuke; Ishikawa, Shin-ich; Matsubara, Hiroshi [Tetrahedron Letters, 2017, vol. 58, # 12, p. 1190 - 1193]
[2]Current Patent Assignee: OSAKA PREFECTURE UNIVERSITY; TOSOH CORPORATION - JP2016/84325, 2016, A Location in patent: Paragraph 0039
[3]Hao, Nguen Kong; Mavrov, M. V.; Serebryakov, E. P. [Bulletin of the Academy of Sciences of the USSR Division of Chemical Science, 1987, vol. 36, # 4, p. 833 - 837][Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1987, # 4, p. 906 - 910]
[4]Cordova, Armando; Lin, Shuangzheng; Tseggai, Abrehet [Advanced Synthesis and Catalysis, 2012, vol. 354, # 7, p. 1363 - 1372]
[5]Segi, Masahito; Takahashi, Mamoru; Nakajima, Tadashi; Suga, Sohei; Sonoda, Noboru [Synthetic Communications, 1989, vol. 19, # 13-14, p. 2431 - 2440]

12
[ 18742-02-4 ]
[ 143017-63-4 ]
1-<3,3-(ethylenedioxy)propyl>-4-(4-methoxyphenyl)-1,2,5,6-tetrahydropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In N,N-dimethyl-formamide at 80℃;

Reference： [1]Solyom, Sandor; Abraham, Gizella; Szoellosy, Marta; Pallagi, Istvan; Csuzdi, Emese; et al. [Heterocycles, 1995, vol. 41, # 6, p. 1139 - 1168]

13
[ 18742-02-4 ]
[ 51304-61-1 ]
4-(4-chlorophenyl)-1-<3,3-(ethylenedioxy)propyl>-1,2,5,6-tetrahydropyridine [ No CAS ]

Reference： [1]Heterocycles,1995,vol. 41,p. 1139 - 1168

14
[ 18742-02-4 ]
[ 18927-05-4 ]
(R,S)-methyl α-<2-(1,3-dioxolanyl-2-ethyl)>-3-methoxyphenylacetate [ No CAS ]

Reference： [1]Tetrahedron,1995,vol. 51,p. 12211 - 12216
[2]Tetrahedron Asymmetry,1997,vol. 8,p. 283 - 291

15
[ 18742-02-4 ]
[ 2716-23-6 ]
[ 197150-02-0 ]

Reference： [1]Monatshefte fur Chemie,1997,vol. 128,p. 619 - 624

16
[ 18742-02-4 ]
[ 20117-44-6 ]

Yield	Reaction Conditions	Operation in experiment
83%	With iodine; magnesium; ethylene dibromide In diethyl ether for 25h; Heating;
	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With magnesium; ethylene dibromide In tetrahydrofuran at 40 - 55℃; for 16h; Stage #2: With water; ammonium chloride In tetrahydrofuran	1.1A To a suspension of Mg powder (86.7 g, 3.6 mol) and iodine (cat) in anhydrous THF (0.7 L) was added slowly 1,2-dibromoethane (460 g, 2.4 mol) in anhydrous THF (2 L) slowly at a rate as to keep the internal temperature between 40-55 °C. After the addition, a solution of 2-(2-bromoethyl)-l,3-dioxolane (lOOg, 0.56 mol) in anhydrous THF (750 mL) was added dropwise. The reaction mixture was kept at 40-55 °C for 16h and was quenched by addition of aqueous solution of ammonium chloride. The mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate, and concentrated to give the title product (27 g) as yellow oil, which was directly used without further purification.
	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With magnesium; ethylene dibromide In tetrahydrofuran at 40 - 55℃; for 16h; Stage #2: With water; ammonium chloride In tetrahydrofuran	1A Preparation of 2-cyclopropoxyethanol (1) [0099] To a suspension of Mg powder (86.7 g, 3.6 mol) and iodine (cat) in anhydrous THF (0.7 L) was added slowly 1,2-dibromoethane (460 g, 2.4 mol) in anhydrous THF (2 L) slowly at a rate as to keep the internal temperature between 40-55 °C. After the addition, a solution of 2-(2-bromoethyl)-l,3-dioxolane (lOOg, 0.56 mol) in anhydrous THF (750 mL) was added dropwise. The reaction mixture was kept at 40-55 °C for 16h and was quenched by addition of aqueous solution of ammonium chloride. The mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate, and concentrated to give the title product (27 g) as yellow oil, which was directly used without further purification

	With iodine; magnesium; ethylene dibromide In tetrahydrofuran at 40 - 50℃; for 30h; Inert atmosphere; Large scale;	3 Example 3. Preparation of 2-cyclopropoxyethyl 4-methylbenzenesulfonate (2) Example 3. Preparation of 2-cyclopropoxyethyl 4-methylbenzenesulfonate (2) [0139] The title compound was prepared in two steps from 2-(2-bromoethyl)-l,3-dioxolane using a Barbier-like magnesium mediated intramolecular ring opening/cyclization. [0140] A 1500 L glass-lined reactor equipped with bottom fed nitrogen sparging was charged with THF (200 kg, 1.67 eq) with stirring (80 RPM) followed by the addition of magnesium turnings (27.4 kg, 1.7 eq) and iodine (1.0 kg, 0.06 eq). The mixture was warmed to between 30 to 40 °C and a nitrogen-sparged solution of 152-dibromoethane (5.0 kg) in THF (20.0 kg) was added dropwise. Once the Grignard reaction commenced, a solution of 1 ,2-dibromoethane (53.6 kg) in THF (250.0 kg) was added over 10 h while keeping the internal temperature about 50 °C. [0141] After the addition was complete, the solution of 2-(2-bromoethyl)-l,3-dioxolane (120.0 kg, 1.0 eq) in THF (270.0 kg, 2.25 w/w) was added slowly over 10 h, while keeping the internal temperature about 50 °C. The reaction mixture was stirred at 40~50 °C for 20 h while copious amounts of white solids (probably magnesium (II) bromide) formed. [0142] Under nitrogen sparging, the mixture was cooled to 0 °C and de-oxygenated water (160 kg) was added very slowly while keeping the internal temperature below 10 °C. Concentrated hydrogen chloride (67.2 kg, 0.56 eq) was added to a saturated solution of brine (420 kg) with efficient stirring. This resulting HCl-brine solution was added very slowly to the Grignard reaction mixture while keeping the temperature below 10 °C. The mixture was stirred at 10 to 20 °C for 2 h before the organic layer was separated and the aqueous layer was extracted with 2-methyltetrahydrofuran (3 x 160 kg). [0143] The above organic solution of 2-cyclopropoxyethanol was cooled to 0 °C and an aqueous solution of sodium hydroxide (80.0 kg) in water (300.0 kg) was added. p-Toluenesulfonyl chloride (151.0 kg, 1,2 eq) was added over 8 h while keeping the internal temperature below 5 °C. The reaction mixture was cooled to 0 °C and stirred for another 16 h. Cooling was stopped and the phases were separated while the mixture slowly warmed to 20 to 25 °C. The aqueous layer was diluted with water (240.0 kg) and extracted with MTBE (180.0 kg). The combined organic phases were washed with saturated brine (240.0 kg). The organic layer was concentrated under reduced pressure (while keeping the bath temperature below 45 °C) to give an oil (130 kg). [0144] Absolute ethanol (156.0 kg) was added to the above oil. De-ionized water (65.0 kg) was added and the mixture was gently warmed to about 30 °C until the solution became clear. The solution was cooled to 0 °C and stirred for 5 h at -5 to 0 °C. The solids were filtered. The solids (120.0 kg) were added to absolute ethanol (135.0 kg). De-ionized water (57.5 kg) was added and the mixture gently warmed until the solution became clear (about 30 °C). The mixture was cooled to 0 °C, and then cooled for 5 h at -5 to 0 °C. The mixture was filtered and the solids collected and dried under vacuum to give 107 kg of the title compound (66.3% yield). NMR (400 MHz, CDC13) δ 7.82 (d, J= 8.4 Hz, 2H), 7.36 (d, J= 8.4 Hz, 2H), 4.17 (t, J= 4.8 Hz, 2H), 3.70 (t, J= 4.8 Hz, 2H), 3.30-3.24 (m, 1H), 2.47 (s, 3H), 0.55-0.42 (m, 4H). DSC onset 18 °C, [0145] Alternatively, a 40 mL of glass bottle was charged with the above oil (1.0 g) and methanol/n-hexane (10:1, 5 mL) with stirring at 30 to 35 °C. After the mixture became a clear solution, the mixture was cooled to -10 to -5 °C and stirred for another 4 hours. The mixture was filtered and the filter cake was dried under freeze drying for over 24 hours to give a white solid. Yield: 0.82 g (82.0%). [0146] Crystallization conditions for compound 2 are found in the following tables: a V/W= 2.25 [0147] Side Products A and B have the following structures: Side Product A Side Product B Other solvents used: 3: 1 EtOH:water, 2:1 EtOH:water, 3:4 EtOH:n-hexane, 6:2:3 EtOH:water:n- hexane, 3:2: 1 EtOH:water:n-hexane, 1 : 1 EtOH:n-hexane and 1 :1 MeOH:n-heptane.
	With magnesium In tetrahydrofuran at 25 - 60℃; Inert atmosphere;	7 Preparation of 2-cyclopropoxyethanol Preparation of 2-cyclopropoxyethanol [0179] THF (500 mL) and magnesium (30 g, 1.2 mole). After stirring and sparging with nitrogen for 45 minutes at ambient temperature (23 to 28° C.), 2-(2-bromoethyl)-1,3-dioxolane (20 g, 13.1 mL, 0.1 mole) was added in one portion. After stirring for 5 minutes, the reaction was initiated and the internal temperature rose from 25° C. to 45° C. (a water bath was used to maintain the outer temperature below 30° C.). [0181] The remaining 2-(2-bromoethyl)-1,3-dioxolane (180 g, 118.1 mL, 1.0 mole) was added to the mixture via a suitable addition funnel over 2.5 hours under nitrogen sparging at a rate that kept the internal temperature at 40° C. to 60° C. (the outer temperature of water bath was kept 20° C. to 30° C.). After the addition was completed, the reaction was cooled slowly to 20° C. to 30° C. over 4 hours. The reaction was then warmed to 60° C. and stirred under nitrogen sparging overnight. [0182] Nitrogen-sparged water (200 g, 11.1 mole) was added dropwise to the reaction mixture over 1 hour while keeping the temperature between -15° C. and -10° C. (deionized water was degassed by sparging with nitrogen for 40 minutes before addition). A nitrogen-sparged aqueous solution of glycolic acid (75.6 g, 0.99 mole) and sodium chloride (100 g, 1.7 mol) in water (400 g, 22.2 mole) was added dropwise to the reaction mixture over 3 hours while keeping the internal temperature between -15° C. and -10° C. (the aqueous solution was degassed by sparging with nitrogen for 1 hour before addition). After the addition was completed, the reaction was stirred at -15 to -10° C. for 10 minutes. The reaction mixture was warmed to 10° C. to 15° C. The reaction was extracted with three 200 g portions of 2-methyltetrahydrofuran. The combined organic solution was directly used for the next step.
	With iodine; magnesium; ethylene dibromide In tetrahydrofuran at 20 - 45℃; for 16h;	1.1 Step 1 2-ethanol(cyclopropyloxy) 1b Under room temperature, will mg (24.0g, 994 . 2mmol), I2(4.2g, 16 . 6mmol) added to the stirring tetrahydrofuran (200 ml) in. Heating to 45 °C, the 1,2-Dibromoethane (124.0g, 662 . 8mmol) tetrahydrofuran (500 ml) solution, 2 - (2-bromo ethyl) - 1,3-dioxolane 1a (30.0g, 165 . 7mmol) is dripped into the reaction solution, continue to maintain 45 °C stirring 16 hours. After the reaction is ended, with 100 ml saturated ammonium chloride aqueous solution quenching reaction, the resulting mixture, pressure-reducing filter. The filtrate is washed with a saturated salt water (300 ml × 3), dried anhydrous sodium sulfate, filtered, concentrated filtrate under reduced pressure, to obtain title compound 1b crude product of (9.2g, yellow oily matter), yield: 54.0%. The crude product is directly used for the next step.

Reference： [1]Huang, Jui-Wen; Chen, Chiar-Dy; Leung, Man-kit [Tetrahedron Letters, 1999, vol. 40, # 49, p. 8647 - 8650]
[2]Current Patent Assignee: THERACOS INC - WO2011/153712, 2011, A1 Location in patent: Page/Page column 29-30
[3]Current Patent Assignee: THERACOS INC - WO2011/153953, 2011, A1 Location in patent: Page/Page column 30; 31
[4]Current Patent Assignee: THERACOS INC - WO2015/51484, 2015, A1 Location in patent: Paragraph 0139-0147
[5]Current Patent Assignee: THERACOS INC - US2015/210634, 2015, A1 Location in patent: Paragraph 0178-0179
[6]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN105461762, 2016, A Location in patent: Paragraph 0178; 0180; 0181; 0182

17
[ 18742-02-4 ]
[ 192945-49-6 ]
1-(2-[1,3]dioxolan-2-yl-ethyl)-1<i>H</i>-indazole-4-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 41 - 58

18
[ 18742-02-4 ]
Tributyl-[(E)-5-(tetrahydro-pyran-2-yloxy)-pent-1-enyl]-stannane [ No CAS ]
2-((E)-7-[1,3]Dioxolan-2-yl-hept-4-enyloxy)-tetrahydro-pyran [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With 3 A molecular sieve; methyldi-t-butylphosphine; tetramethylammonium fluoride In tetrahydrofuran at 20℃; for 24h;
60%	With PCy(1-pyrrolidinyl)2; 3 A molecular sieve; tetramethylammonium fluoride In tetrahydrofuran at 20℃;

Reference： [1]Menzel, Karsten; Fu, Gregory C. [Journal of the American Chemical Society, 2003, vol. 125, # 13, p. 3718 - 3719]
[2]Tang, Haifeng; Menzel, Karsten; Fu, Gregory C. [Angewandte Chemie - International Edition, 2003, vol. 42, # 41, p. 5079 - 5082]

19
[ 18742-02-4 ]
Tributyl-[(E)-2-methyl-5-(tetrahydro-pyran-2-yloxy)-pent-1-enyl]-stannane [ No CAS ]
2-((E)-7-[1,3]Dioxolan-2-yl-4-methyl-hept-4-enyloxy)-tetrahydro-pyran [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With 3 A molecular sieve; methyldi-t-butylphosphine; tetramethylammonium fluoride In tetrahydrofuran at 20℃; for 24h;
54%	With PCy(1-pyrrolidinyl)2; 3 A molecular sieve; tetramethylammonium fluoride In tetrahydrofuran at 20℃;

Reference： [1]Menzel, Karsten; Fu, Gregory C. [Journal of the American Chemical Society, 2003, vol. 125, # 13, p. 3718 - 3719]
[2]Tang, Haifeng; Menzel, Karsten; Fu, Gregory C. [Angewandte Chemie - International Edition, 2003, vol. 42, # 41, p. 5079 - 5082]

20
[ 18742-02-4 ]
[ 15448-47-2 ]
[ 918328-65-1 ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With magnesium In tetrahydrofuran at 20℃; for 0.5h; Stage #2: (R)-propylene oxide With copper(l) iodide In tetrahydrofuran cooling;
58%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With magnesium In tetrahydrofuran for 0.5h; Stage #2: (R)-propylene oxide With copper(l) iodide In tetrahydrofuran at 0 - 25℃;	(R)-5-(1,3-Dioxolan-2-yl)pentan-2-ol (5) The solution of 2-(2-bromoethyl)-1,3-dioxolane (9.1 g,6.0 mL, 50 mmol,) in anhydrous THF (25 mL) was addeddropwise (25-30 min) to a stirred mixture of magnesiumturnings (1.5 g, 60 mmol) and anhydrous THF (5 mL) at rt(water bath, inner temperature should not exceed 30°C). Theresulting solution was allowed for further 30 min, then it wascooled to 0°C in an ice bath. After that catalytic amounts of CuI (ca. 20 mg, 0.1 mmol) were added to this ice cooledmixture. At this temperature, a solution of freshly distilled(R)- propylene oxide 4 (5 mL, 4.1 g, 70 mmol) in anhydrousTHF (25 mL) was slowly added dropwise within 30-40 min.After complete addition, the reaction mixture was slowlyallowed to warm to 25°C (6 h). Then, it was saturated withammonium chloride solution (100 mL) and extracted withEt2O (5 50 mL). The organic layers were then combinedand washed with sat. NaCl solution (100 mL). It was thendried on Na2SO4 and filtered. Removal of solvent in vacuumafforded a slightly yellow liquid, which was distilled at lowpressure to give the desired (5R)-5- hydroxyhexanal ethandiolacetal 5, yield 4.6 g as a colorless liquid (58%, bp 72-76°C at 1 mbar). This acetal was immediately used in thenext step

Reference： [1]Khartulyari, Anton S.; Kapur, Manmohan; Maier, Martin E. [Organic Letters, 2006, vol. 8, # 25, p. 5833 - 5836]
[2]Umanadh, Yapuri; Omprakash, Gudaparthi; Srinivasareddy, Narahari [Letters in Organic Chemistry, 2015, vol. 12, # 6, p. 424 - 428]

21
[ 18742-02-4 ]
2-[1,3]dioxolan-2-yl-ethanethiol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium hydrogen sulfide In N,N-dimethyl-formamide at 0℃;
80.4%	With sodium hydrogen sulfide In N,N-dimethyl-formamide at 0 - 20℃; for 20h;	Referring now to FIG. 2D, synthesi s of monomer 14 begi ns w ith compound 10, sodium hydrosulfide (2.477 g, 44.2 mmol ), which was dissolved in DMF and chilled to 0 °C. Compound 9 (2.59 mL, 22. 1 mmol ) was dripped in and the reaction was allowed to warm to room temperature and stirred 20 h. The reaction was quenched by adding water. The reaction mixture was extracted 4X with hexanes, after which the combined organic was dried over MgSCu and concentrated to yield compound 10 (2.384 g, 80.4%) as a colorless oil . NMR analysis results for compound 10: NMR (600 MHz, CDC h) δ 4.96 (t, J = 4.5 Hz, IH), 4.00 - 3.92 (m, 2H), 3.90 - 3.81 (m, 2H), 2.64 (q, J = 15.1, 7.8 Hz, 2H), 1.99 (dt, J = 10.2, 4.2 Hz, 2H), 1.48 (t, J = 7.8 Hz, 1H). 13C NMR (151 MHz, CDCh) δ 103.1, 65. 1 , 38.2, 19.2.
	Multi-step reaction with 2 steps 1: 86 percent / dimethylformamide / 46 h / Ambient temperature 2: 3M aq. NaOH / acetone / Ambient temperature

Reference： [1]Olejniczak, Jason; Chan, Minnie; Almutairi, Adah [Macromolecules, 2015, vol. 48, # 10, p. 3166 - 3172]
[2]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2016/164828, 2016, A1 Location in patent: Page/Page column 15; 16
[3]Zheng, Tu-Cai; Burkart, Maureen; Richardson, David E. [Tetrahedron Letters, 1999, vol. 40, # 4, p. 603 - 606]

22
[ 18742-02-4 ]
[ 5754-35-8 ]

Reference： [1]Synthetic Communications,1987,vol. 17,p. 377 - 384
[2]Journal of Organic Chemistry,1982,vol. 47,p. 4040 - 4045
[3]Chemistry - A European Journal,2016,vol. 22,p. 7824 - 7836
[4]Arkivoc,2019,vol. 2019,p. 178 - 195

23
[ 18742-02-4 ]
[ 82144-38-5 ]
[ 716327-38-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium <i>tert</i>-butylate In DMF (N,N-dimethyl-formamide); <i>tert</i>-butyl alcohol at 80℃;	V Synthesis of Intermediate 3 ethyl 2-CYANO-2- (3, 4-DICHLOROPHENYL)-4- (1, 3-DIOXOLAN-2-YL) butanoate To a solution of 1 (7.02 g, 27.32 MMOL) and 2- (2-bromoethyl)-1, 3-dioxolane compound 2 (3.85 mL, 32.78 MMOL) in anhydrous DMF (100 mL), potassium t- butoxide (32.78 mL, 1 M in T-BUOH) was added. The content was heated to 80 °C and stirred overnight. H20 (400 mL) and brine (200 mL) were added to the content and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. Flash column chromatography with hexane/ethyl acetate (6/1) afforded 9.5 g brown oil (-85% PRODUCT+-15% SM).
	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at -78 - 20℃; Inert atmosphere;

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/55016, 2004, A1 Location in patent: Page 75-76
[2]Location in patent: body text Kazmierski, Wieslaw M.; Aquino, Christopher; Chauder, Brian A.; Deanda, Felix; Ferris, Robert; Jones-Hertzog, Deborah K.; Kenakin, Terrence; Koble, Cecilia S.; Watson, Christian; Wheelan, Pat; Yang, Hanbiao; Youngman, Michael [Journal of Medicinal Chemistry, 2008, vol. 51, # 20, p. 6538 - 6546]

24
[ 18742-02-4 ]
[ 73942-87-7 ]
3-(2-[1,3]-dioxolan-2-yl-ethyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium hydroxide; In 1-methyl-pyrrolidin-2-one; water; at 2 - 60℃; for 3h;Product distribution / selectivity;	EXAMPLE 1; 3-[2-(1,3-Dioxolan-2-yl)-ethyl]-<strong>[73942-87-7]7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one</strong>-Procedure in the Presence of Sodium Hydroxide; Introduce 100 g of <strong>[73942-87-7]7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one</strong>, 200 ml of N-methylpyrrolidone and 115 g of 2-(2-bromoethyl)-1,3-dioxolane into a reactor and then bring the temperature of the reaction mixture to 40 C. and add 71 g of 30% sodium hydroxide solution, while maintaining the temperature of the mixture at 40 C. Then heat the mixture at 60 C. and stir for 2 hours; then pour in 400 ml of water at 60 C. and cool the reaction mixture to 20 C. and then, after 1 hour, to 2 C. Filter off the precipitate obtained, wash it and dry it. The title compound is obtained in a yield of 87%.
80%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 130℃; for 9h;Product distribution / selectivity;	EXAMPLE 2; 3-[2-(1,3-Dioxolan-2-yl)-ethyl]-<strong>[73942-87-7]7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one</strong>-Procedure in the Presence of Potassium Carbonate; Introduce 100 g of <strong>[73942-87-7]7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one</strong>, 250 ml of N-methylpyrrolidone and 180.4 g of potassium carbonate into a reactor and then stir the mixture for 3 hours at 130 C. Then add 2-(2-bromoethyl)-1,3-dioxolane on three occasions (90.8 g, 40.7 g and then 16.3 g) at intervals of 2 hours and at 130 C., whilst stirring vigorously. After returning to ambient temperature, the compound is isolated by precipitation from water, chilling, filtration and drying. The title compound is obtained in a yield of 80%.

Reference： [1]Patent: US2005/227962,2005,A1 .Location in patent: Page/Page column 3
[2]Patent: US2005/227962,2005,A1 .Location in patent: Page/Page column 3

25
[ 18742-02-4 ]
[ 26441-40-7 ]
[ 889652-22-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With lithium In tetrahydrofuran at 0 - 20℃; for 5h;	8 Example 817-Hydroxy-15?,16?-methylene-3-methoxy-17?-pregpa-3,5-diene-21-carboxaldehvde cyclic 1,2-ethanediyl acetal10.5 kg of 15?,16?-methylene-3-methoxyandrosta-3,5-diene-17-one is dissolved in 147 1 of dry tetrahydrofuran under vigorous stirring in argon atmosphere at room temperature. The solution is cooled to 0 0C and 1.89 kg of lithium metal is added. To the solution 12.6 1 of 2-(2-bromoethyi)-l,3-dioxolane is added under intensive stirring and cooling at a temperature of 10-20 C. Stirring at 15-20 C is continued for 5 hours, then the excess of lithium is decomposed with 10 1 of methanol and 100 of water to form lithium hydroxide. After the complete decomposition the methanol and tetrahydrofuran are distilled off, to the residue 80 1 of water is added. When the precipitate is dense enough it is filtered, washed with portions of water to neutral and dried in vacuo to constant weight at a temperature below 40 0C to give 13.8 kg of crude title compound which is crystallized from methanol. Yield: 12.87 kg (92 %) Mp: 164-166 0C.[a? = -141.3 (c=l, dioxane).1H NMR (500 MHz. CDOU(TMS). ??pm)): 0.24 & 1.00 (2H,m & m,CP(15?,16?)(CH2));0.95 (3H,s,18-Me); 1.00 (3H,s,19-Me); 1.06 (lH,m,H-9); 1.19 (lH,m,H-15); 1.32 (lH,m,H- 16); 1.66 & 1.75 (2H,m & m,H-20); 1.69 (lH,m,H-14); 1.88 (H-l,m,H-8); 1.94 & 2.06 (2H,m & m,H-21); 3.58 (3H,m, -O-CH3); 3.87 & 4.00 (4H,m & m,2 x -0-CH2-); 4.94 (lH,t,H-22); 5.15 (lH,m,H-4); 5.27 (lH,m,H-6).13C NMR ( 125 MHz. CDCk(TMSV ?fppm)): 7 . 4 ( C P ( 1 5 ?,16?)(CH2)); 16.0 (C-15): 18.9 (C-19); 19.4 (C-18); 23.0 (C-16); 28.4 (C-21); 30.9 (C-20); 31.3 (C-8); 49.0 (C-9); 53.2 (C- 14); 54.3 (-0-CH3); 64.96 & 64.99(2 x -0-CH2-); 82.2 (C- 17); 98.6 (C-4); 105.1 (C-22); 118.1 (C-6); 141.2 (C-5); 155.4 (C-3).

Reference： [1]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - WO2006/59167, 2006, A1 Location in patent: Page/Page column 22-23

26
[ 18742-02-4 ]
[ 1074-82-4 ]
[ 185563-61-5 ]

Yield	Reaction Conditions	Operation in experiment
75.7%	In N,N-dimethyl-formamide at 100℃; for 1.5h;	20 Synthesis of 2-[2-(1,3-dioxolan-2-yl)ethyl]-1H-isoindole-1,3(2H)-dione A solution of 2-(2-bromomethyl)-1,3-dioxolane (90%, 2.00 g, 11.1 mmol) and potassium phthalimide (2.05 g, 11.1 mmol) in N,N-dimethylformamide (20 ml) was stirred at 100°C for 1.5 hours. After completion of the reaction, a saturated aqueous sodium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the thus obtained solid was washed with a hexane-diethyl ether mixed solvent to obtain the title compound (2.06 g, 75.7%).; 1H-NMR(CDCl3) 7.80-7.85 (m,2H), 7.67-7.75 (m,2H), 4.96 (t,2H,J=4.4Hz), 3.78-4.00 (m,6H), 2.08 (dt,2H,J=4.4,6.9Hz).
75%	With potassium iodide In N,N-dimethyl-formamide at 65℃; for 18h;	1.10 < 1 - 10> 2-(2-[l ,3]-dioxolan-2-yl-ethyl)-isoindol- 1 ,3-dione; Potassium phthalimide (20 g, 108 mmol) and 100 mi of N,N- dimethylformamide were mixed and stirred at room temperature, bromoethyl dioxorein (22 g, 119 mmol) and potassium iodide (1.8 g, 11 mmol) were added thereto, and the resulting solution was heated to 65 °C and then stirred for 18 hours. The solution was extracted with 500 mi of ethylacetate and washed with salt solution (500 mi><3) and 500 ml of water. The resulting organic layer was dried over magnesium sulfate and distilled under a reduced pressure to obtain the title compound 20 g (yield: 75 %).1H NMR (CDCl3) δ: 7.86-7.80 (m, 2H), 7.73-7.66 (m, 2H)5 4.95 (t, IH)5 3.96-3.92 (m, 2H), 3.86-3.78 (m, 4H), 2.10-2.04 (m, 2H).

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); Sumitomo Pharma (in: Sumitomo Chemical); SUMITOMO CHEMICAL COMPANY LIMITED - EP1640369, 2006, A1 Location in patent: Page/Page column 29
[2]Current Patent Assignee: HANMI PHARM CO LTD - WO2007/55513, 2007, A1 Location in patent: Page/Page column 23

27
[ 18742-02-4 ]
NH₂NH_2.H₂O [ No CAS ]
Bu₄N+HSO₄- [ No CAS ]
[ 1074-82-4 ]
[ 5754-35-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	In ethanol; toluene;	A) 2-(2-Aminoethyl)-1,3-dioxolane A suspension of 50 g of 2-(2-bromoethyl)-1,3-dioxolane (product known in literature, CAS RN = 5754-35-8) (0.27 mL, 32.5 mol), 62.5 g of potassium phthalimide (0.34 mol), 9.16 g of Bu4N+HSO4- (0.027 mol) in 150 ml of toluene was heated to 100C and under N2 stream for 3 h. After cooling to room temperature, the mixture was filtered and evaporated to dryness. By crystallization of the residue from abs. EtOH the phthalimido derivative was obtained. A solution of 58.5 g of NH2NH2.H2O (1.17 ml; 56.8 mol), 64.36 g of phthalimido derivative (0.26 mol) in 2 l of abs. EtOH was heated to reflux under N2 stream for 2.5 h. After cooling to 0C, the precipitated phthalhydrazide was filtered through a sintered funnel. By evaporation of the filtrate to dryness, 23.26 g of the desired product (0.198 mol) were obtained. Yield: 73% The 1H-NMR, 13C-NMR, IR and MS spectra are consistent with the indicated structure.

Reference： [1]Patent: EP760683,2000,B1

28
[ 18742-02-4 ]
[ 620-95-1 ]
[ 108-18-9 ]
2-[3-phenyl-3-(pyridin-3-yl)propyl]-1,3-dioxolane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride In tetrahydrofuran	7.2 (2) Under Ar, n-butyl lithium (1.61 M, n-hexane solution, 1.86 ml, 3 mmol) was dropwise added to a tetrahydrofuran (8 ml) solution of N,N-diisopropylamine (0.42 ml, 3 mmol) at -78°C, then the mixture was stirred at 0°C for 30 minutes. This was again cooled to -78°C, then a tetrahydrofuran solution (0.5 ml) of 3-benzylpyridine (0.49 ml, 3 mmol) was added dropwise and the mixture was stirred at 0°C for 30 minutes. The resultant mixture was again cooled to -78°C, then 2-(2-bromoethyl)-1,3-dioxolane (0.35 ml, 3 mmol) was added dropwise and the mixture was stirred at the same temperature for 1 hour and then at 0°C for 10 minutes. After the reaction, a saturated aqueous solution of ammonium chloride was added dropwise and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate, then the solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain 2-[3-phenyl-3-(3-pyridyl)propyl]-1,3-dioxolane (601 mg).

Reference： [1]Current Patent Assignee: KOWA COMPANY, LTD. - EP807626, 1997, A1

29
[ 18742-02-4 ]
[ 49805-30-3 ]
[ 1023307-00-7 ]

Reference： [1]Advanced Synthesis and Catalysis,2007,vol. 349,p. 1231 - 1246

30
[ 872455-00-0 ]
[ 18742-02-4 ]
[ 1012041-93-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl acetamide; N,N-dimethyl-formamide at 70℃; for 12h; Stage #2: (E)-ethyl 4-chloropent-2-enoate With sodium chloride In N,N-dimethyl acetamide; N,N-dimethyl-formamide at -10℃; for 24h; Further stages.;

Reference： [1]Son, Sunghee; Fu, Gregory C. [Journal of the American Chemical Society, 2008, vol. 130, # 9, p. 2756 - 2757]

31
[ 18742-02-4 ]
[ 17176-77-1 ]
[ 954104-93-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydride; N,N-dimethyl-formamide at 20℃;
83%	With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 20℃; for 80h;	68.1 Step 1: dibenzyl [2-( l,3-dioxolan-2-yl)ethyl]phosphonate To a solution of dibenzylphosphonate (2.50 g, 9.53 mmol, 1.0 eq.) in DMF (19 mL) at room temperature, were added (-BufiNI (704 mg, 1.91 mmol, 0.2 eq.), CS2CO3 (4.66 g, 14.30 mmol, 1.5 eq.) and 2-(2-bromoethyl)- 1 ,3-dioxolane (1.34 mL, 11.4 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 80 h. Water and MTBE were added and the layers were separated. The aqueous phase was extracted with MTBE. The combined organic extracts were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure to afford a colorless oil. The residue was purified by column chromatography to afford the title compound (2.86 g, 83%) as a colorless oil. (1588) MS (ESI4): [M+H]4 = 363.1 (1589) NMR (500 MHz, CDCls) d (ppm): 7.43-7.30 (m, 10H), 5.07 (dd, J = 11.9, 8.8 Hz, 2H), 4.99 (dd, J = 11.9, 7.9 Hz, 2H), 4.95-4.87 (m, 1H), 3.98-3.90 (m, 2H), 3.90-3.81 (m, 2H), 2.07-1.84 (m, 4H) (1590) 31P NMR (CDCI3, 202 MHz) d (ppm): 33.1
74%	With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere;

Reference： [1]Ortmann, Regina; Wiesner, Jochen; Silber, Katrin; Klebe, Gerhard; Jomaa, Hassan; Schlitzer, Martin [Archiv der Pharmazie, 2007, vol. 340, # 9, p. 483 - 490]
[2]Current Patent Assignee: NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; QUANTUM GENOMICS; COLLEGE DE FRANCE - WO2020/84131, 2020, A1 Location in patent: Page/Page column 129
[3]Midrier, Camille; Montel, Sonia; Braun, Ralf; Haaf, Klaus; Willms, Lothar; Van Der Lee, Arie; Volle, Jean-Noel; Pirat, Jean-Luc; Virieux, David [RSC Advances, 2014, vol. 4, # 45, p. 23770 - 23778]

32
[ 18742-02-4 ]
[ 82543-16-6 ]
[ 1104734-54-4 ]

Yield	Reaction Conditions	Operation in experiment
82%		EXAMPLE 12 17alpha-(2-[1,3]Dioxolan-2-ylethyl)-6beta,7beta,15beta,16beta-dimethylen-5beta-androstane-3beta,5,17beta-triol 3beta,5-dihydroxy-6beta,7beta,15beta,16beta-dimethylen-5beta-androst-17-one (60.00 g, 0.182 mol) is dissolved in tetrahydrofuran (900 mL) and cooled to -20C. Lithium (granular, 13.86 g, 2.003 mol) is then added and stirred for 20 to 30 minutes. 2-(2-Bromoethyl)-1,3-dioxolane (180.81 g, 0.999 mol) is added dropwise maintaining the temperature below 0C and stirring is continued between -20 and -15C. The reaction is monitored by TLC analysis and when no more starting material is present (2 hours), the mixture is poured into water/ice/sodium bicarbonate (830 mL/1070 g/120 g) and vigorously stirred until the remaining lithium is completely dissolved. The mixture is extracted twice with ethyl acetate (1100 mL, 850 mL) and the organic layers are washed with water (800 mL, 700 mL). After separation of the phases, removal of ethyl acetate at 50C under reduced pressure affords the crude product as an oily mixture (110.44 g). Purification performed by column chromatography on silica gel eluding with n-hexane/ethyl acetate affords the title compound (64.25 g, 0.149 mol, 82%). 1H-NMR {200 MHz, CDCl3, delta (ppm)}: 0.34-2.28 (26H); 0.86 (s, 3H, CH3-18); 0.90 (s, 3H, CH3-19); 2.54 (s, 1H, OH-17); 3.34 (d, J=6Hz, 1H, OH-3); 4.05-3.85 (m, 5 H, H-3, 2 x CH2-O); 4.95 (t, J=4.6 HZ, 1H, O-CH-O). 13C-NMR {200 MHz, CDCl3, delta (ppm)}: 7.8 (CH2); 11.6 (CH2); 15.0 (CH); 16.0 (CH); 19.0 (CH3); 19.2 (CH3); 21.7 (CH2); 22.5 (CH); 25.0 (CH); 26.7 (CH2); 27.6 (CH2); 28.2 (CH2); 30.8 (CH2); 34.2 (CH); 36.5 (CH2); 40.3 (C); 42.7 (C); 43.0 (CH2); 44.8 (CH); 52.7 (CH); 64.8 (2 x CH2); 67.0 (CH); 74.7 (C); 81.8 (C); 105.0 (CH). HPLC-MS (ESI): [M+Na]+ =455; [M+K]+ =471; [2M+Na]+ = 887

Reference： [1]Patent: EP2019114,2009,A1 .Location in patent: Page/Page column 14-15

33
[ 18742-02-4 ]
[ 1048674-88-9 ]
[ 1048674-89-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 14h;	1.C A slurry of the above pyrazole (10 g, 22.8 mmol) and Cs2CO3 (11.9 g, 45.6 mmol) in DMF (75 mL) was stirred at rt for 2 h. 2-(2-Bromoethyl)1,3-dioxolane (3.5 mL, 34.2 mmol) was added dropwise and stirring maintained for 12 h. Ice H2O was added slowly to form a precipitate. The white solid was collected by suction filtration and washed with H2O and Et2O to afford the desired product (10.4 g, 85%). HPLC: Rt=6.98. MS (ESI): mass calcd. for C18H21ClIN3O4S, 537.8; m/z found, 538.2 [M+H]+. 1H NMR (CDCl3): 8.15 (s, 1H), 7.46-7.45 (m, 2H), 4.83 (t, J=4.6, 1H), 4.49 (s, 2H), 4.17 (t, J=7.1, 2H), 4.01-3.97 (m, 2H), 3.89-3.86 (m, 2H), 3.65 (t, J=5.8, 2H), 2.89 (s, 3H), 2.87 (t, J=5.8, 2H), 2.28-2.26 (m, 2H).
85%	With caesium carbonate In N,N-dimethyl-formamide regioselective reaction;
85%	Stage #1: 3-(4-chloro-3-iodo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide for 48h;	C 3-(4-Chloro-3-trimethylsilanylethynyl-phenyl)-5-methanesulfonyl-1-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine C. 3-(4-Chloro-3-iodo-phenyl)-1-(2-[1,3]dioxolan-2-yl-ethyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. A slurry of the above pyrazole (10 g, 22.8 mmol) and Cs2CO3 (11.9 g, 45.6 mmol) in DMF (75 mL) was stirred at rt for 2 h. 2-(2-Bromoethyl)1,3-dioxolane (3.5 mL, 34.2 mmol) was added dropwise and stirring maintained for 2 days. Ice water was added slowly to form a precipitate. The white solid was collected by suction filtration and washed with H2O and Et2O to afford the desired product (10.4 g, 85%). HPLC: Rt=6.98. MS (ESI): mass calcd. for C18H21CIIN3O4S, 537.8; m/z found, 538.2 [M+H]+. 1H NMR (CDCl3): 8.15 (s, 1H), 7.46-7.45 (m, 2H), 4.83 (t, J=4.6, 1H), 4.49 (s, 2H), 4.17 (t, J=7.1, 2H), 4.01-3.97 (m, 2H), 3.89-3.86 (m, 2H), 3.65 (t, J=5.8, 2H), 2.89 (s, 3H), 2.87 (t, J=5.8, 2H), 2.28-2.26 (m, 2H).

Reference： [1]Current Patent Assignee: SUNESIS PHARMACEUTICALS INC - US2008/207683, 2008, A1 Location in patent: Page/Page column 11-12
[2]Location in patent: scheme or table Ameriks, Michael K.; Axe, Frank U.; Bembenek, Scott D.; Edwards, James P.; Gu, Yin; Karlsson, Lars; Randal, Mike; Sun, Siquan; Thurmond, Robin L.; Zhu, Jian [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 21, p. 6131 - 6134]
[3]Current Patent Assignee: SUNESIS PHARMACEUTICALS INC - US2008/200454, 2008, A1 Location in patent: Page/Page column 17

34
[ 18742-02-4 ]
[ 1049103-01-6 ]
[ 1049103-02-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With caesium carbonate In N,N-dimethyl-formamide
93%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 18h;	1.D D. 2-[5-[1-(2-[1,3]Dioxolan-2-yl-ethyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-p]pyridin-3-yl]-2-trifluoromethyl-phenylsulfanyl]-ethanol. To a solution of 2-[5-(5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethanol (3.0 g, 7.1 mmol) and Cs2CO3 (4.6 g, 14.2 mmol) in DMF (30 mL) was added 2-(2-bromoethyl)-1,3-dioxolane (1.3 mL, 10.7 mmol). The reaction mixture was stirred at rt for 18 h and poured into cold satd. aq. NH4Cl (100 mL). The resulting precipitate was filtered and rinsed with H2O to afford an off-white solid (3.3 g, 93%) that was used without further purification. MS (ESI): mass calcd. for C21H26F3N3O5S2, 521.13; m/z found, 522.1 [M+H]+. 1H NMR (DMSO-d6): 7.76 (s, 1H), 7.55 (d, J=8.5, 1H), 7.08 (br s, 1H), 5.05 (t, J=5.4, 1H), 4.84 (t, J=4.6, 1H), 4.47 (s, 2H), 4.19-4.12 (m, 2H), 3.93-3.90 (m, 2H), 3.80-3.77 (m, 2H), 3.67-3.62 (m, 2H), 3.55-3.50 (m, 2H), 3.18 (t, J=6.6, 2H), 2.99 (s, 3H), 2.89-2.86 (m, 2H).

Reference： [1]Location in patent: scheme or table Lee-Dutra, Alice; Wiener, Danielle K.; Arienti, Kristen L.; Liu, Jing; Mani, Neelakandha; Ameriks, Michael K.; Axe, Frank U.; Gebauer, Damara; Desai, Pragnya J.; Nguyen, Steven; Randal, Mike; Thurmond, Robin L.; Sun, Siquan; Karlsson, Lars; Edwards, James P.; Jones, Todd K.; Grice, Cheryl A. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 7, p. 2370 - 2374]
[2]Current Patent Assignee: SUNESIS PHARMACEUTICALS INC - US2009/99157, 2009, A1 Location in patent: Page/Page column 14-15

35
[ 18742-02-4 ]
[ 106-93-4 ]
[ 20117-44-6 ]

Yield	Reaction Conditions	Operation in experiment
49.6%	With iodine; magnesium In tetrahydrofuran at 40 - 55℃; for 16h;	8 General procedure for synthesis Dl-8 To a suspension of Mg (67.1 g, 2.76 mol, 10 eq) and I2 (701 mg, 2.76 mmol, 0.01 eq) in THF (350 mL) was added slowly 1 ,2-dibromoethane (259 g, 1.38 mol, 5.0 eq) in THF (1 L) slowly at a rate as to keep the internal temperature between 40-55 °C. After the addition, a solution of Dl-7 (50 g, 276 mmol, 1 eq) in THF (375 mL) was added drop-wise. The reaction mixture was kept at 40-55 °C for 16 h. TLC (petroleum ether / ethyl acetate = 2/1, Dl-8: Rf = 0.27) indicated Dl-7 was consumed completely and many new spots formed. The reaction was quenched with saturated NH4Cl (3 L) slowly at 0°C. The mixture was extracted and the aqueous phase was extracted with DCM / i-PrOH (v/v = 10/1, 2.5 L and 1 L). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (Si02, petroleum ether/ethyl acetate=l0/l to 3/1). Dl-8 (14 g, 137 mmol, 49.6% yield) was obtained as yellow oil, which was used into next step without further purification.
19%	With iodine; magnesium In tetrahydrofuran; methanol at 40 - 55℃; for 16h;
13%	Stage #1: ethylene dibromide With iodine; magnesium In tetrahydrofuran at 40 - 55℃; for 0.333333h; Inert atmosphere; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In tetrahydrofuran at 40 - 55℃; for 16h;

	Stage #1: 2-bromo-2-(2-ethyl)dioxolane; ethylene dibromide With magnesium In tetrahydrofuran at 40 - 55℃; Stage #2: With water; ammonium chloride In tetrahydrofuran	5.5A To a suspension of Mg powder (86.7 g, 3.6 mol) and iodine (cat) in anhydrous THF(0.7 L) was added slowly 1 ,2-dibromoethane (460 g, 2.4 mol) in anhydrous THF (2 L) slowly at a rate as to keep the internal temperature between 40-55 0C. After the addition, a solution of 2-(2-bromoethyl)-l,3-dioxolane (10Og, 0.56 mol) in anhydrous THF (750 mL) was added dropwise. The reaction mixture was kept at 40-55 0C for 16h and was quenched by addition of aqueous solution of ammonium chloride. The mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate, and concentrated to give the title product (27 g) as yellow oil, which was directly used without further purification
	Stage #1: ethylene dibromide With iodine; magnesium In tetrahydrofuran at 30 - 50℃; for 10h; Inert atmosphere; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In tetrahydrofuran at 40 - 50℃; for 30h; Stage #3: With hydrogenchloride In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere;	5.A Example 5a. Preparation of 2-cvclopropoxvethyl4-methylbenzenesulfonate (2); Preparation of 2-cyclopropoxyethanol The title compound was prepared in two steps from 2-(2-bromoethyl)-l,3-dioxolane using a Barbier-like magnesium mediated intramolecular ring opening/cyclization.; A 1500 L glass-lined reactor equipped with bottom fed nitrogen spargingwas charged with THF (200 kg, 1.67 eq) with stirring (80 RPM) followed by the addition of magnesium turnings (27.4 kg, 1.7 eq) and iodine (1.0 kg, 0.06 eq).The mixture was warmed to between 30 to 40 °C and a nitrogen-sparged solutionof 1,2-dibromoethane (5.0 kg) in THF (20.0 kg) was added dropwise. Once the Grignard reaction commenced, a solution of 1,2-dibromoethane (53.6 kg) in THF (250.0 kg) was added over 10 h while keeping the internal temperature about 50°C. After the addition was complete, the solution of 2-(2-bromoethyl)-l,3-dioxolane (120.0 kg, 1.0 eq) in THF (270.0 kg, 2.25 w/w) was added slowly over 10 h, while keeping the internal temperature about 50 °C.The reaction mixture was stirred at 40-50 °C for 20 h while copious amounts o fwhite solids (probably magnesium (II) bromide) formed. Under nitrogen sparging, the mixture was cooled to 0 °C and de-oxygenated water (160 kg) was added very slowly while keeping the internal temperature below 10 °C. Concentrated hydrogen chloride (67.2 kg, 0.56 eq) was added to a saturated solution of brine (420 kg) with efficient stirring. This resulting HCl-brine solution was added very slowly to the Grignard reaction mixture while keeping the temperature below 10 °C. The mixture was stirred at 10 to 20 °C for 2 h before the organic layer was separated and the aqueous layer was extracted with 2-methyltetrahydrofuran (3 x 160 kg).
	With magnesium In tetrahydrofuran Cooling with ice; Reflux;	19 To a suspension of Mg powder (0.87 g, 36.1 mmol) and iodine (catalytic) in THF (4 mL) was added slowly BrCH2CH2Br (4.6 g, 24.5 mmol) in THF (8 mL). The exothermic reaction was cooled in an ice-bath. After complete addition OfBrCH2CH2Br, a solution of 2- (2-bromoethyl)-l,3-dioxolane (1 g, 5.6 mmol) was added dropwise. The reaction mixture was then kept at reflux for 24 h, quenched by addition of aqueous NH4Cl, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude intermediate BO (400 mg) as yellow oil.

Reference： [1]Current Patent Assignee: QURIENT CO LTD - WO2019/229251, 2019, A1 Location in patent: Page/Page column 74-75
[2]Li, Yao; Shi, Zongjun; Chen, Lei; Zheng, Suxin; Li, Sheng; Xu, Bo; Liu, Zhenhong; Liu, Jianyu; Deng, Chongyang; Ye, Fei [Journal of Medicinal Chemistry, 2017, vol. 60, # 10, p. 4173 - 4184]
[3]Current Patent Assignee: GASHERBRUM BIO - WO2022/28572, 2022, A1 Location in patent: Paragraph 256-257
[4]Current Patent Assignee: THERACOS INC - WO2010/22313, 2010, A2 Location in patent: Page/Page column 47
[5]Current Patent Assignee: THERACOS INC - WO2015/51597, 2015, A1 Location in patent: Paragraph 0152-0155
[6]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 71

36
[ 505-23-7 ]
[ 18742-02-4 ]
[ 6138-90-5 ]
C₁₉H₃₂O₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 1,3 dithiane With n-butyllithium In tetrahydrofuran; hexane at -78 - -20℃; Stage #2: geranyl bromide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; hexane at -78℃; for 0.5h; Stage #3: 2-bromo-2-(2-ethyl)dioxolane	Preparation of Compound 4; Compound 4 was prepared according to Step a of Scheme 1 which is described as follows. 1,3-Dithiane was dissolved in THF, and treated dropwise with 1.1 equivalents of n-BuLi (2.5 M in hexane) while stirring at -78° C. Stirring was continued at -20° C. for 2 hours and the anion so obtained was cooled to -78° C. HMPA was added and stirring was kept for 15 minutes. 1.1 Equivalents of neryl bromide 2 was added to the above solution. After stirring for 30 minutes at -78° C., another portion of 1.1 equivalents of n-BuLi (2.5 M in hexane) was added to the solution. Stirring was continued for 2 h, and 1.1 equivalents of 3 were added dropwise at -78° C. Acetal 4 was purified by flash column chromatography (90% yield).Compound 4 was characterized by the following experimental data: Rf=0.48 (silica gel, hexane/EtOAc, 4:1); 1H NMR (300 MHz, CDCl3) δ 5.26 (t, J=7.0 Hz, 1H), 5.12 (br s, 1H), 4.90 (t, J=4.5 Hz, 1H), 3.99-3.95 (m, 2H), 3.87-3.84 (m, 2H), 2.88-2.84 (m, 2H), 2.78-2.64 (m, 2H), 2.55 (d,J=7.0 Hz, 2H), 2.07-2.03 (m, 6H), 1.96-1.89 (m, 2H), 1.84-1.77 (m, 2H), 1.74 (d,J=1.2 Hz, 3H), 1.68 (s, 3H), 1.61 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 138.3, 131.5, 124.0, 118.4, 104.1, 64.8, 52.9, 36.7, 32.2, 31.6, 28.9, 26.3, 25.9, 25.6, 25.1, 23.5, 17.5; IR (CH2Cl2) 2933, 1734 cm-1; LRMS (EI, 20 eV) m/z 356 (M+, 4), 219 (100) 113 (55); HRMS (EI) calcd for C19H32O2S2 [M]+ 356.1844, found 356.1830.

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF HONG KONG; MORNINGSIDE VENTURES LTD - US2009/247503, 2009, A1 Location in patent: Page/Page column 19

37
[ 18742-02-4 ]
[ 628-16-0 ]
[ 1144853-96-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: hexa-1,5-diyne With n-butyllithium In tetrahydrofuran; pentane at -78 - 20℃; for 0.916667h; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; pentane at -70℃; for 24h;
61%	With n-butyllithium In tetrahydrofuran; hexane at -78℃;	3.2.1. 2-(3,7-Octadiynyl)-1,3-dioxolane (3) It was as obtained as a colorless oil in a 61% yield from the reaction of 3.7 mL (19.23 mmol) of 1,5-hexadiyne in 40 ml of dry THF with 5.1 mL (55.47 mmol) of n-BuLi (2.5 M in hexane) at -78 °C and 1.5 mL (12.85 mmol) of 2-(2-bromoethyl)-1,3-dioxolane following the procedure already described and with identical spectral data as previously reported [7].

Reference： [1]Location in patent: experimental part Carballeira, Nestor M.; O'Neill, Rosann; Silva, Diana [Chemistry and Physics of Lipids, 2008, vol. 156, # 1-2, p. 41 - 44]
[2]Carballeira, Nestor M.; Montano, Nashbly; Alvarez-Velilla, Raquel; Prada, Christopher F.; Reguera, Rosa M.; Balana-Fouce, Rafael [Marine Drugs, 2013, vol. 11, # 10, p. 3661 - 3675]

38
[ 18742-02-4 ]
[ 19808-30-1 ]
[ 1241947-04-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 4060 - 4064

39
[ 43157-50-2 ]
[ 18742-02-4 ]
[ 1176335-34-4 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7669 - 7677

40
[ 18742-02-4 ]
[ 55758-32-2 ]
[ 1154579-68-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With caesium carbonate; In N,N-dimethyl acetamide; at 100℃; for 12h;Inert atmosphere;	Preparation of 5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine 2-(2-Bromoethyl)-1,3-dioxolane (2.49 ml, 19.9 mmol) and cesium carbonate (15.1 g, 46.4 mmol) were added to an N,N-dimethylacetamide solution (25 ml) of <strong>[55758-32-2]6-fluoropyridin-3-ol</strong> (1.5 g, 13.3 mmol), and stirred under a nitrogen atmosphere at 100C for 12 hours. The reaction solution was cooled with ice, water and ethyl acetate were added, and the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate = 5:1 1 to 1:1) to obtain 5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine (2.43 g, yield: 86 %) as a colorless oil.

Reference： [1]Patent: EP2221301,2010,A1 .Location in patent: Page/Page column 37

41
[ 18742-02-4 ]
5-chloro-6-fluoropyridin-3-ol [ No CAS ]
[ 1154579-96-0 ]

Yield	Reaction Conditions	Operation in experiment
83%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 4h;	20.4 Preparation of 3-chloro-5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine Cesium carbonate (14 g, 44 mmol) and 2-(2-bromoethyl)-1,3-dioxolane (4.5 g, 25 mmol) were added to an N,N-dimethylformamide suspension (16 ml) of the alcohol product (2.8 g, 19 mmol) obtained in the above reaction, and stirred at 100°C for 4 hours. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 75:25) to obtain 3-chloro-5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine (3.9 g, yield: 83 %) as a colorless oil.

Reference： [1]Current Patent Assignee: MERCK & CO INC - EP2221301, 2010, A1 Location in patent: Page/Page column 46

42
[ 18742-02-4 ]
[ 318-49-0 ]
[ 935686-74-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With magnesium In tetrahydrofuran at 70℃; Stage #2: 2-(4-fluorobenzyl)isoindoline-1,3-dione In tetrahydrofuran for 2.66667h; Stage #3: With water; ammonium chloride In tetrahydrofuran	7.B B. 3-(3-[1,3]Dioxolan-2-ylethyl)-2-(4-fluorobenzyl)-3-hydroxy-2,3-dihydroisoindol-1-one; Mg metal (800 mg, 0.033 g·atoms) and 1-(2-Bromoethyl)-[1,3]dioxolane (426 mg, 2.4 mmol) in 50 mL THF were heated to 70° C. in a dry flask until approximately half of the magnesium was consumed. The product from Part A (3.0 g, 11.8 mmol), as a solution in THF, was added dropwise over 40 min. Stirring continued for 2 h, then the reaction was stopped by addition of aqueous ammonium chloride. The product was purified by silica gel chromatography (3.1 g, 83%).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2007/99930, 2007, A1 Location in patent: Page/Page column 32

43
[ 18742-02-4 ]
[ 36801-01-1 ]
[ 950857-78-0 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 4-cyanobenzenethiol With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide at 20℃; for 2.5h;	29 Sodium hydride (60% dispersion in mineral oil) (0.84 g, 21 mmol) was added to a solution of 4-cyanobenzenethiol (1.37 g, 10.11 mmol) in dry DMF (20 ml) under nitrogen. The reaction mixture was stirred at RT for 0.5 h before 2-(2-bromoethyl)- 1 ,3-dioxolane (2.0 ml, 17.04 mmol) was added. After 2.5 h at RT, the reaction was quenched by careful addition of water (2 ml) under nitrogen with external cooling (ice/water bath). The mixture was partitioned between water (150 ml) and Et2O (200 ml). The organic layer was separated, washed with water (100 ml), dried (Na2SO4) and evaporated to give pale yellow oil. The oil was purified on an Isolute Si Il cartridge (50 g) eluting with 40%, DCM in pentane, 70% DCM in pentane, 100% DCM and then 20% Et2O in DCM. The required product was isolated as colourless oil.Yield: 1.98 g (83%)1H-NMR (400 MHz, CDCI3): δ = 7.53 (2H, d), 7.32 (2H, d), 5.00 (1H, t), 4.00 (2H, m), 3.90 (2H, m), 3.09 (2H, t), 2.06 (2H, m).

Reference： [1]Current Patent Assignee: CHARLES RIVER LABORATORIES INTERNATIONAL INC - WO2007/107706, 2007, A2 Location in patent: Page/Page column 32

44
[ 18742-02-4 ]
[ 135427-08-6 ]
[ 1100154-96-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of Mg turnings (1.1 g, 0.05 g-at.) and catalytic amount of iodine in 200 mL THF was added dropwise 2-(2-bromoethyl)-[1,3]dioxolane (4.3 g, 0.02 mol) with heating over a period of 30 min. The resulting mixture was stirred for 30 min at 63 C. and then cooled to -30 C. and <strong>[135427-08-6]4-fluoro-3-methyl-benzaldehyde</strong> (3.0 g, 0.02 mol) added slowly as a solution in 50 mL of THF. The temperature was maintained at -30 C. for 1 h and then slowly raised to room temperature over a period of 3 h. The excess Grignard was destroyed by the careful addition of 200 mL saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic layers washed with brine (2×50 mL) and dried over Na2SO4. After evaporation of the solvent, the product was isolated by flash column chromatography eluting with 0% to 50% ethyl acetate/hexanes to give 1.6 g of the title compounds as a light yellow oil.LC/MS: tR=7.8 min. MS (API-ES) m/z 241 (M+H+).
2.7 g		To a suspension of Mg turnings (709 mg, 29.2 mmol) and catalytic amount of iodine in 80 ml_ THF was added dropwise 2-(2-bromoethyl)-1 ,3-dioxolane (264.3 mg, 14.6 mmol) with heating over a period of 30 min. After stirring for an additional 30 min at 25 C, the mixture was cooled to -78 C and 4-fluoro-3- methylbenzaldehyde (2.0 g, 14.5 mmol) was added slowly as a solution in 5 mL THF. The temperature was maintained at -78 to -30 C for 1 h and slowly raised to room temperature. The excess Grignard reagent was destroyed by careful addition of saturated aqueous NH4CI (40 ml_). The mixture was extracted with ethyl acetate (3 x 40 ml_) and the combined organic layers were washed with brine (2 x 30 ml_) and dried over Na2S04. After removal of the solvent under reduced pressure the product was isolated by flash column chromatography (silica gel) to afford 2.7 g of the title compound as a light yellow oil. LC/MS (Method A): tR = 5.2 min. MS (API- ES) m/z 463 (M+Na+)

Reference： [1]Patent: US2010/286125,2010,A1 .Location in patent: Page/Page column 19
[2]Patent: WO2019/178063,2019,A1 .Location in patent: Paragraph 0066

45
[ 18742-02-4 ]
[ 2627-86-3 ]
(S)-N-(2-(1,3-dioxolan-2-yl)ethyl)-1-phenylethanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate In acetonitrile at 20℃; for 5h; Reflux;	(S)-N-(2-(1,3-Dioxolan-2-yl)ethyl)-1-phenylethanamine To a stirred suspension of K2CO3 (1.3 g, 7.42 mmol) in 50 mL of CH3CN at room temperature, was added a solution of (S)-(-)-phenylethylamine (0.82 g, 6.75 mmol) in 1 mL CH3CN and a solution of 2-(2-bromo-ethyl)-[1.3]dioxolane (1.2 g, 6.75 mmol) in 1 mL of CH3CN. The resulting mixture was refluxed until the total consume of starting materials (5 h). Then, the mixture was cooled to room temperature, filtered off and the solvent was removed under reduced pressure. The crude reaction was purified by column chromatography (SiO2, AcOEt / petroleum ether, 50:50) yielding (S)-N-(2-(1,3-Dioxolan-2-yl)ethyl)-1-phenylethanamine as a colourless oil in 84% yield; [α]D = -37.5 (CH2Cl2, c = 1.00). 1H NMR (400 MHz, CDCl3) d: 1.35 (d, J = 6.6 Hz, 3H), 1.83 (m, 3H), 2.59 (m, 2H), 3.73 (q, J = 6.6 Hz, 1H), 3.82 (m, 2H), 3.92 (m, 2H), 4.87 (t, J = 4.7, 1H), 7.20-7.31 (m, 5H); 13C NMR (100 MHz, CDCl3) d: 24.3, 33.9, 42.9, 58.4, 64.8, 103.86, 126.5, 126.6, 126.8, 128.4, 145.6 FABS m/z 221.1421 (M+H)+ (Calcd for C13H19NO2: 221.1416).

Reference： [1]Fuentes, Lilia; Quintero, Leticia; Cordero-Vargas, Alejandro; Eustaquio, Cesar; Terán, Joel L.; Sartillo-Piscil, Fernando [Tetrahedron Letters, 2011, vol. 52, # 28, p. 3630 - 3632]

46
[ 18742-02-4 ]
[ 120-72-9 ]
[ 1318759-40-8 ]

Yield	Reaction Conditions	Operation in experiment
72%	With dichloro bis(acetonitrile) palladium(II); norbornene; water; potassium carbonate In N,N-dimethyl acetamide at 70℃; for 14h; Inert atmosphere; regioselective reaction;
72%	With dichloro bis(acetonitrile) palladium(II); potassium carbonate; norbornene In N,N-dimethyl acetamide; water at 70℃; for 14h; Schlenk technique; Inert atmosphere; regioselective reaction;	Procedure 1a (Tables 1 and 2) General procedure: A 50-mL Schlenk flask equipped with a magnetic stirring bar and a rubber septum was charged with 1H-indole substrate 1 (1.00 mmol), norbornene (188 mg, 2.00 mmol), the base [K2CO3 (276 mg, 2.00mmol), KHCO3 (300 mg, 3.00 mmol), or K2HPO4 (522 mg, 3.00mmol) as indicated], and PdCl2(MeCN)2 (25.9 mg, 0.100 mmol). A 0.5 M solution of H2O in DMA (5 mL) was added. The alkyl bromide 2 (2.00 mmol) was then added from a syringe, and the resulting mixture was degassed by three freeze-pump-thaw cycles with liquid nitrogen under high vacuum. The flask was then placed in an oil bath preheated to 70 °C or 90 °C, as indicated, and the mixture was stirred vigorously under balloon pressure of argon. Upon completion of the reaction (TLC), the mixture was cooled to r.t., diluted with Et2O (30 mL), and filtered. The filtrate was concentrated in arotary evaporator (60 °C water bath, 8-10 mbar) to remove the Et2O and most of the DMA. The residue was purified directly by flash column chromatography [silica gel (dry loading)] to give the alkylation product 3.
	With norborn-2-ene; dichloro bis(acetonitrile) palladium(II); potassium carbonate In N,N-dimethyl acetamide; water Inert atmosphere; Heating;

Reference： [1]Jiao, Lei; Bach, Thorsten [Journal of the American Chemical Society, 2011, vol. 133, # 33, p. 12990 - 12993]
[2]Jiao, Lei; Bach, Thorsten [Synthesis, 2014, vol. 46, # 1, p. 35 - 41]
[3]Touge, Taichiro; Arai, Takayoshi [Journal of the American Chemical Society, 2016, vol. 138, # 35, p. 11299 - 11305]

47
[ 18742-02-4 ]
[ 1006-94-6 ]
[ 1318759-44-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	With dichloro bis(acetonitrile) palladium(II); norbornene; water; potassium carbonate In N,N-dimethyl acetamide at 70℃; for 14h; Inert atmosphere; regioselective reaction;
62%	With dichloro bis(acetonitrile) palladium(II); potassium carbonate; norbornene In N,N-dimethyl acetamide; water at 70℃; for 14h; Schlenk technique; Inert atmosphere; regioselective reaction;	Procedure 1a (Tables 1 and 2) General procedure: A 50-mL Schlenk flask equipped with a magnetic stirring bar and a rubber septum was charged with 1H-indole substrate 1 (1.00 mmol), norbornene (188 mg, 2.00 mmol), the base [K2CO3 (276 mg, 2.00mmol), KHCO3 (300 mg, 3.00 mmol), or K2HPO4 (522 mg, 3.00mmol) as indicated], and PdCl2(MeCN)2 (25.9 mg, 0.100 mmol). A 0.5 M solution of H2O in DMA (5 mL) was added. The alkyl bromide 2 (2.00 mmol) was then added from a syringe, and the resulting mixture was degassed by three freeze-pump-thaw cycles with liquid nitrogen under high vacuum. The flask was then placed in an oil bath preheated to 70 °C or 90 °C, as indicated, and the mixture was stirred vigorously under balloon pressure of argon. Upon completion of the reaction (TLC), the mixture was cooled to r.t., diluted with Et2O (30 mL), and filtered. The filtrate was concentrated in arotary evaporator (60 °C water bath, 8-10 mbar) to remove the Et2O and most of the DMA. The residue was purified directly by flash column chromatography [silica gel (dry loading)] to give the alkylation product 3.

Reference： [1]Jiao, Lei; Bach, Thorsten [Journal of the American Chemical Society, 2011, vol. 133, # 33, p. 12990 - 12993]
[2]Jiao, Lei; Bach, Thorsten [Synthesis, 2014, vol. 46, # 1, p. 35 - 41]

48
[ 18742-02-4 ]
[ 50820-65-0 ]
[ 1318759-48-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With dichloro bis(acetonitrile) palladium(II); potassium hydrogencarbonate; norbornene; In N,N-dimethyl acetamide; water; at 70℃; for 14h;Schlenk technique; Inert atmosphere;	General procedure: A 50-mL Schlenk flask equipped with a magnetic stirring bar and a rubber septum was charged with 1H-indole substrate 1 (1.00 mmol), norbornene (188 mg, 2.00 mmol), the base [K2CO3 (276 mg, 2.00mmol), KHCO3 (300 mg, 3.00 mmol), or K2HPO4 (522 mg, 3.00mmol) as indicated], and PdCl2(MeCN)2 (25.9 mg, 0.100 mmol). A 0.5 M solution of H2O in DMA (5 mL) was added. The alkyl bromide 2 (2.00 mmol) was then added from a syringe, and the resulting mixture was degassed by three freeze-pump-thaw cycles with liquid nitrogen under high vacuum. The flask was then placed in an oil bath preheated to 70 C or 90 C, as indicated, and the mixture was stirred vigorously under balloon pressure of argon. Upon completion of the reaction (TLC), the mixture was cooled to r.t., diluted with Et2O (30 mL), and filtered. The filtrate was concentrated in arotary evaporator (60 C water bath, 8-10 mbar) to remove the Et2O and most of the DMA. The residue was purified directly by flash column chromatography [silica gel (dry loading)] to give the alkylation product 3.

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 12990 - 12993
[2]Synthesis,2014,vol. 46,p. 35 - 41

49
[ 18742-02-4 ]
[ 108-95-2 ]
[ 92971-91-0 ]

Yield	Reaction Conditions	Operation in experiment
73.7%	Stage #1: phenol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide at 65℃; Inert atmosphere;	4.1.15 Synthesis of compounds 12a-12f General procedure: General procedure: The solution of the substituted phenols (11a-11f, 10.0mmol) and anhydrous K2CO3 (2.76g, 20.0mmol) in DMF (40mL) was stirred 30min at room temperature, and then 2-(2-bromoethyl)-1,3-dioxolane (1.99g, 11.0mmol) was added slowly and the mixture was allowed to warm up 65°C overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After that, the resulting residue was diluted with water (30mL) and extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography column to provide compound 12a-12f. 4.1.15.1 2-(2-phenoxyethyl)-1,3-dioxolane (12a). The tittle compound was synthesized as described in the general procedure using phenol (940mg, 10.0mmol). The crude product was purified by flash column chromatography (Petroleum ether/EtOAc, 25:1) to afford the desired product as a colorless oil (1.43g, 73.7% yield). 1H NMR (600MHz, Chloroform-d) δ 7.27 (t, J=7.8Hz, 2H), 6.94 (t, J=7.8Hz, 1H), 6.91 (d, J=7.8Hz, 2H), 5.10 (t, J=4.8Hz, 1H), 4.12 (t, J=6.5Hz, 2H), 4.03 - 3.95 (m, 2H), 3.91 - 3.85 (m, 2H), 2.16 (dt, J=6.5, 4.8Hz, 2H); 13C NMR (150MHz, Chloroform-d) δ 158.75, 129.41 (2×C), 120.68, 114.47 (2×C), 102.05, 64.91 (2×C), 63.44, 33.81.
73.7%	With potassium carbonate In N,N-dimethyl-formamide at 65℃;	1.1 (1) Synthesis of compound S3a: Phenol S2a (940mg, 10.0mmol) and anhydrous K2CO3 (2.76g, 20.0mmol) were placed in a 100mL round bottom flask, Using DMF (40mL) as solvent, Add 3-bromopropionaldehyde ethylene acetal (1.99g, 11.0mmol) dropwise at room temperature, and the addition is complete. Transfer to 65°C and stir overnight to stop the reaction. Suction filtration, concentrate the filtrate under reduced pressure, Add water (30mL), extract with ethyl acetate (3×30ml), combine the organic phases, Saturated NaCl solution (30mL) washed the organic phase once, dried with anhydrous Na2SO4, filtered, concentrate. The residue was subjected to silica gel column chromatography and eluted with petroleum ether/ethyl acetate (volume ratio 25:1), S3a (1.43 g, 73.7% yield) was obtained as a colorless oil.
	Stage #1: phenol With potassium carbonate; potassium iodide Stage #2: 2-bromo-2-(2-ethyl)dioxolane

Reference： [1]Wu, Wenxi; Mu, Yu; Liu, Bo; Wang, Zixuan; Guan, Peipei; Han, Li; Jiang, Mingguo; Huang, Xueshi [Bioorganic Chemistry, 2021, vol. 111]
[2]Current Patent Assignee: NORTHEASTERN UNIVERSITY IN SHENYANG, CHINA - CN113105425, 2021, A Location in patent: Paragraph 0046-0049
[3]Location in patent: scheme or table Tyrrell, Elizabeth; Mazloumi, Khatebeh; Banti, Donatella; Sajdak, Paulina; Sinclair, Alex; Le Gresley, Adam [Tetrahedron Letters, 2012, vol. 53, # 33, p. 4280 - 4282]

50
[ 18742-02-4 ]
[ 959616-42-3 ]
5-[2-(1,3-dioxolan-2-yl)ethyl]-3-methoxypyrido[2,3-b]pyrazin-6(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 3-methoxypyrido[2,3-b]pyrazin-6(5H)-one With sodium hydride; lithium bromide In N,N-dimethyl-formamide at 20℃; for 1.5h; Cooling with ice; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide at 20℃; Cooling with ice;	23 5-[2-(1,3-Dioxolan-2-yl)ethyl]-3-methoxypyrido[2,3-b]pyrazin-6(5H)-one 3-Methoxypyrido[2,3-b]pyrazin-6(5H)-one (400 mg, 2.26 mmol) was dissolved in N,N-dimethylformamide (12 ml). Lithium bromide (206 mg, 2.37 mmol) and sodium hydride (55%, 104 mg, 2.37 mmol) were added to the solution under cooling on ice and stirred for one and a half hours while the temperature of the reaction solution was raised to room temperature. The reaction solution was cooled on ice again, 2-(2-bromoethyl)-1,3-dioxolane (0.345 mmol, 2.94 mmol) was added thereto and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate and washed with saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 731 mg (quantitative) of the title compound in the form of a yellow oily product. 1H-NMR(400MHz,CDCl3)δ:2.15(2H,td,J=7.3,4.6Hz),3.82-3.89(2H,m),3.92-3.98(2H,m),4.09(3H,s),4.60(2H,t,J=7.3Hz),5.03(1H,t,J=4.6Hz),6.76(1H,d,J=9.5Hz),7.83(1 H,d,J=9.8Hz),8.11(1 H,s).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2674430, 2013, A1 Location in patent: Paragraph 0114

51
[ 18742-02-4 ]
[ 55687-23-5 ]
1-[2-(1,3-dioxolan-2-yl)ethyl]-6-fluoroquinoxalin-2(1H)one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%		Lithium hydride (57 mg, 7.3 mmol) was added to a solution of 6-fluoroquinoxalin-2(1 H)one (1 g, 6.0 mmol) in N,N-dimethylformamide (6 ml) under cooling on ice and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled on ice again and a solution of 2-(2-bromoethyl)-1,3-dioxolane (0.88 ml, 7.3 mmol) in N,N-dimethylformamide (2 ml) was gradually added thereto and the mixture was stirred for 4 hours. Water was added thereto, the mixture was then extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 0.5 g (32%) of the title compound. 1H-NMR(400MHz,DMSO-d6)delta:1.93-1.99(2H,m),3.76-3.80(2H,m),3.89-3.92(2H,m),4.23-4.27(2H,m),4.96-4.99(1H,m),7.17-7.28(1H,m),7.45-7.48(1H,m),7.88-7.90(1 H,m),8.18(1 H,s). MS(ESI)m/z:265(M+H)+.

Reference： [1]Patent: EP2674430,2013,A1 .Location in patent: Paragraph 0204

52
[ 18742-02-4 ]
C₇H₁₁NO₂ [ No CAS ]
ethyl 5-(2-(1,3-dioxolan-2-yl)ethyl)-1H-pyrrole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With dichloro bis(acetonitrile) palladium(II); potassium hydrogencarbonate; norbornene In N,N-dimethyl acetamide at 90℃; for 22h; regioselective reaction;	Procedure 2 (Tables 3 and 4) A reaction tube (30 × 190 mm) equipped with a magnetic stirring bar and a rubber septum was charged with 1H-pyrrole substrate 4 (1.00 mmol), norbornene (188 mg, 2.00 mmol), KHCO3 (300 mg,3.00 mmol), PdCl2(MeCN)2 (25.9 mg, 0.100 mmol), and alkyl bromide 2 (2.00 mmol). Anhydrous DMA (1 mL) was added, and the tube was heated in an aluminum block at 90 °C under a balloon pressure of air. When the reaction was complete (TLC), the mixture was cooled to r.t., diluted with Et2O (30 mL), and filtered. The filtrate was washed with H2O (20 mL), and the organic phase was separated.The aqueous layer was extracted with Et2O (2 × 20 mL). The organic layers were combined, washed with brine (40 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel) to afford the alkylation product 5.

Reference： [1]Jiao, Lei; Bach, Thorsten [Synthesis, 2014, vol. 46, # 1, p. 35 - 41]

53
[ 18742-02-4 ]
(E)-diethyl 2-fluoro-3-phenyl-2-propen-1-ylphosphate [ No CAS ]
2-fluoro-6,6-(ethylenedioxy)-3-phenyl-1-hexene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With magnesium In tetrahydrofuran at 20℃; for 0.833333h; Inert atmosphere; Stage #2: With copper(l) cyanide In tetrahydrofuran at -78 - -10℃; for 0.25h; Inert atmosphere; Stage #3: (E)-diethyl 2-fluoro-3-phenyl-2-propen-1-ylphosphate In tetrahydrofuran at -40℃; for 0.25h; regioselective reaction;	4.5 Allylic substitution reactions of β-fluoroallylic phosphate with organocuprates Typical procedure for the preparation of Grignard reagent: To a suspension of magnesium (0.13g, 5.32mmol) in anhydrous THF (1mL) was added dropwise 1-bromobutane (0.1g, 0.71mmol) at room temperature under an argon. After the reaction started, a THF solution of the remaining 1-bromobutane (0.57g, 4.19mmol/anhydrous THF 4mL) was dropwise into the reaction mixture at that temperature. After stirring for 50min, 0.8M of n-BuMgBr in THF was obtained. (The concentration was determined by the titration experiment.) (0038) Method A: To a suspension of CuCN (0.059g, 0.66mmol) in anhydrous THF (1mL) was added dropwise a THF solution of n-BuMgBr (0.8M, 0.83mL, 0.66mmol, prepared from n-BuBr and magnesium) at -78°C under argon. After stirring for 5min, the mixture was warmed to -10°C, and then stirred for 10min. The reaction mixture was again cooled to -40°C, and to this mixture was added dropwise a solution of (E)-diethyl 2-fluoro-3-phenyl-2-propenylphosphate (0.086g, 0.3mmol) in anhydrous THF (2mL). After 15min, the reaction was quenched with an aqueous saturated NH4Cl solution and the whole was extracted with diethyl ether. The combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography to give 2-fluoro-3-phenyl-1-heptene (13a) (quant., 19F NMR yield).

Reference： [1]Nihei, Takashi; Kubo, Yusuke; Ishihara, Takashi; Konno, Tsutomu [Journal of Fluorine Chemistry, 2014, vol. 167, p. 110 - 121]

54
[ 18742-02-4 ]
[ 330469-22-2 ]
N-(2-(1,3-dioxolan-2-yl)ethyl)-N-(3-chloro-4-methylphenyl)-4-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: N-(3-chloro-4-methylphenyl)-4-fluorobenzamide With sodium hydride In N,N-dimethyl-formamide; mineral oil for 1h; Cooling with ice; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide; mineral oil at 80℃; for 12h;	4.1.12.2. N-(2-(1,3-Dioxolan-2-yl)ethyl)- N-(3-chloro-4-methylphenyl)acetamide (24a). General procedure: To an ice-cooled stirred solution of N-(3-chloro-4-methylphenyl)acetamide 23a (0.65 g, 4.00 mmol) inDMF (8.00 mL) was added NaH (60% in oil, 160 mg, 4.00 mmol).After 1 h the mixture was treated with 2-(2-bromoethyl)-1,3-dioxolane (0.47 mL, 4 mmol) and stirred at 80 C for 12 h. The mixture was concentrated in vacuo, diluted with water (20 mL), andextracted with DCM (3 20 mL). The organic layer was dried(MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/PE 1:1) to givethe product (0.81 g, yield 71%) as oil.

Reference： [1]Hu, Suwen; Wang, Zhilong; Hou, Tingjun; Ma, Xiaodong; Li, Jing; Liu, Tao; Xie, Xin; Hu, Yongzhou [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 1157 - 1168]

55
[ 18742-02-4 ]
1-acetyl-N-(3-chloro-4-methylphenyl)piperidine-3-carboxamide [ No CAS ]
N-(2-(1,3-dioxolan-2-yl)ethyl)-1-acetyl-N-(3-chloro-4-methylphenyl)piperidine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 1-acetyl-N-(3-chloro-4-methylphenyl)piperidine-3-carboxamide With sodium hydride In N,N-dimethyl-formamide; mineral oil for 1h; Cooling with ice; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide; mineral oil at 80℃; for 12h;	4.1.12.2. N-(2-(1,3-Dioxolan-2-yl)ethyl)- N-(3-chloro-4-methylphenyl)acetamide (24a). General procedure: To an ice-cooled stirred solution of N-(3-chloro-4-methylphenyl)acetamide 23a (0.65 g, 4.00 mmol) inDMF (8.00 mL) was added NaH (60% in oil, 160 mg, 4.00 mmol).After 1 h the mixture was treated with 2-(2-bromoethyl)-1,3-dioxolane (0.47 mL, 4 mmol) and stirred at 80 C for 12 h. The mixture was concentrated in vacuo, diluted with water (20 mL), andextracted with DCM (3 20 mL). The organic layer was dried(MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/PE 1:1) to givethe product (0.81 g, yield 71%) as oil.

Reference： [1]Hu, Suwen; Wang, Zhilong; Hou, Tingjun; Ma, Xiaodong; Li, Jing; Liu, Tao; Xie, Xin; Hu, Yongzhou [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 1157 - 1168]

56
[ 18742-02-4 ]
[ 68301-59-7 ]
C₁₃H₁₅ClO₄ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2015,vol. 13,p. 6353 - 6370

57
[ 18742-02-4 ]
[ 2892-29-7 ]
C₁₃H₁₅ClO₄ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2015,vol. 13,p. 6353 - 6370

58
[ 18742-02-4 ]
[ 610791-05-4 ]
C₁₅H₂₅NO₆ [ No CAS ]

Reference： [1]Synlett,2015,vol. 26,p. 1815 - 1818

59
[ 18742-02-4 ]
[ 10420-33-4 ]
dimethyl 2-(2-(1,3-dioxolan-2-yl)ethyl)-2-acetylsuccinate [ No CAS ]

Reference： [1]Israel Journal of Chemistry,2016,vol. 56,p. 156 - 168

60
[ 18742-02-4 ]
[ 92-88-6 ]
C₂₂H₂₆O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate In acetone at 60℃; for 48h;	(Polymerizable compound (RM3) synthesize) Was added 4,4'-biphenol with a cooling tube in the eggplant-shaped flask 5 00ml1 1,2g (60mmol), 2- (2 ■ bromoethyl) -1,3-dioxolane 25.0g (1 3 8mmol), potassium carbonate 35.9g (260mmol), and 200ml of acetone as a mixture, in 60 ° C - side stirring it for 48 hours to react. After completion of the reaction, the solvent was distilled off under reduced pressure to give a yellow wet solid. Thereafter the solid was mixed with water, 200ml, 100ml chloroform was added and extracted. It was extracted 3 times. The combined organic layer was separated, dried over anhydrous magnesium sulfate was added, filtered and the solvent was distilled off under reduced pressure to give a yellow solid. The solid was dissolved in chloroform, using hexane with (hexane / chloroform = 2/1) after precipitation, to give a white solid 17.6g. The solid results were measured by NMR of as follows. The results of the white solid was confirmed by the following reaction formula as the compound (RM3-A) in Fig. The yield was 76%.

Reference： [1]Current Patent Assignee: NISSAN CHEMICAL CORPORATION - TWI520948, 2016, B Location in patent: Page/Page column 62; 63

61
[ 18742-02-4 ]
[ 14321-27-8 ]
N-benzyl-2-(1,3-dioxolan-2-yl)-N-ethylethanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In acetonitrile at 50℃; for 18h;	8.1 Step 2; 4-((4-formylbenzyl)oxy)benzoic acid stirred solution of N-benzylethanamine (3 g, 22.22 mmol) and DIPEA (5.8 mL, 33.33 mmol) in acetonitrile (50 mL) was added 2-(2-bromoethyl)-1,3-dioxolane (2.87 mL, 24.44 mmol) and the reaction mixture heated at 50 °C for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, the suspension filtered and the filtrate was concentrated at reduced pressure. The residue was purified by column chromatography (eluant 0% to 60% ethyl acetate in i-hexanes) to afford the title compound (4.53 g, 87%). NMR (400 MHz, DMSO-de); δ 7.31 - 7.29 (m, 4H), 7.25 - 7.20 (m, 1H), 4.80 (dd, J=4.9, 4.9 Hz, 1H), 3.87 - 3.70 (m, 6H), 3.52 (s, 2H), 2.47 - 2.40 (m, 2H), 1.74 - 1.68 (m, 2H), 0.96 (dd, J=7.1, 7.1 Hz, 3H).

Reference： [1]Current Patent Assignee: Valline SRL - WO2016/193241, 2016, A1 Location in patent: Page/Page column 62-63

62
[ 18742-02-4 ]
[ 134461-75-9 ]
9-[2-(1,3-dioxolan-2-yl)ethyl]-9H-purine-6-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In N,N-dimethyl-formamide at 153℃; for 6h;	9-[2-(1,3-Dioxolan-2-yl)ethyl]-9H-purin-6-amine(1). Potassium carbonate, 5.1 g (37 mmol), was added to a mixture of 1.3 g (7.41 mmol) of 2-(2-bromoethyl)-1,3-dioxolane and 1 g (7.41 mmol) of adenine in DMF. The mixture was stirred for 6 h at 153°C, the precipitate was filtered off, and the solvent was removed under reduced pressure. Yield 1.6 g (90%), mp 152-152°C (from toluene). IR spectrum, ν, cm-1: 3289,3103 (N-H), 1619 (C=Carom). 1H NMR spectrum(CD3OD), δ, ppm: 2.22-2.28 m (2H, CH2), 3.78-3.88 m (2H, CH2), 3.89-3.98 m (2H, CH2), 4.92 t (1H,CH, J = 4.3 Hz), 8.12 s (1H, Harom), 8.22 (1H, Harom).13C NMR spectrum (CD3OD), δC, ppm: 33.02, 33.78,64.64, 101.88, 118.68, 141.62, 149.35, 152.23, 155.88. Found, %: C 50.79; H 5.48; N 29.60. C10H13N5O2. Calculated, %: C 51.06; H 5.57; N 29.77.

Reference： [1]Smolobochkin; Gazizov; Vagapova; Burilov; Bogdanov; Pudovik [Russian Journal of Organic Chemistry, 2017, vol. 53, # 1, p. 96 - 98][Zh. Org. Khim., 2017, vol. 53, # 1, p. 100 - 102,3]

63
[ 18742-02-4 ]
[ 5470-65-5 ]
C₁₁H₁₂BrNO₅ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2017,vol. 15,p. 5790 - 5796

64
[ 18742-02-4 ]
[ 1202366-72-0 ]
(4R,6R)-6-(tert-butyldimethylsilyloxy)-1-(1,3-dioxolan-2-yl)heptan-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With magnesium In tetrahydrofuran at 20℃; for 0.5h; Stage #2: tert-butyldimethyl(((R)-1-((S)-oxiran-2-yl)propan-2-yl)oxy)silane With copper(l) iodide In tetrahydrofuran Cooling with ice; regioselective reaction;	(4R,6R)-6-(tert-Butyldimethylsilyloxy)-1-(1,3-dioxolan-2-yl)heptan-4-ol (6, C16H34O4Si) The solution of 2.41 g 2-(2-bromoethyl)-1,3-dioxolane(13.33 mmol) in 20 cm3 anhydrous THF was added dropwise (25-30 min) to a stirred mixture of 0.51 g magnesium turnings (22.22 mmol) and 5 cm3 anhydrous THF at rt. The resulting solution was stirred for further 30 min, then cooled in an ice bath, followed by the addition of catalytic amounts of CuI (20 mg, 0.1 mmol).At this temperature, a solution of 2.4 g epoxide 3(11.11 mmol) in 10 cm3 anhydrous THF was slowly added dropwise within 30-40 min. After complete addition, the reaction mixture was slowly allowed to warm to rt. Then, the mixture was treated with 100 cm3 saturated NH4Cl solution and extracted with Et2O (5 9 50 cm3).The combined organic extracts were washed with 100 cm3 sat. NaCl solution, dried with Na2SO4, and filtered. Solvent was evaporated under reduced pressure and the residue was purified by column chromatography (60-120 silica gel, 8% EtOAc in pet. ether) to furnish acetal 6 (2.57 g, 73%) as a colorless liquid. 1H NMR(CDCl3, 300 MHz): d = 4.86-4.80 (m, 1H), 3.97-3.88(m, 2H), 3.86-3.73 (m, 3H), 3.57 (m, 1H), 3.01 (brs, 1H),1.71-1.32 (m, 8H), 1.08 (d, 3H, J = 6.1 Hz), 0.83 (s,9H), 0.14 (s, 3H), 0.08 (s, 3H) ppm; 13C NMR (CDCl3,75 MHz): d = 102.3, 69.3, 65.6, 47.1, 38.3, 33.6, 25.9,24.1, 20.2, 18.3, -4.2, -4.9 ppm; ESI-MS: m/z = 341([M+Na]+).

Reference： [1]Ramanujan; Sreenivasulu, Reddymasu; Chavali, Murthy; Kumar, Chebolu Naga Sesha Sai Pavan [Monatshefte fur Chemie, 2017, vol. 148, # 10, p. 1865 - 1869]

65
[ 18742-02-4 ]
[ 13673-62-6 ]
C₁₂H₁₃NO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		Preparation Example 6. Synthesis of Compound 36 (1) Synthesis of Intermediate 1 and Intermediate 2 To a 1 L single-neck reactor were added Oxolane, i.e., 2-bromoethyl-1,3-dioxolane (52.6 g, 0.290 mol), potassium iodide (64.3 g, 0.387 mol) and acetonitrile (320 mL) were placed, and the mixture was stirred at 50 C. for 1 hour. Then, <strong>[13673-62-6]2-(methylthio)benzoxazole</strong> (32.0 g, 0.193 mol) was added to the reactor, and the mixture was stirred under reflux for 20 hours, cooled, concentrated and purified by column to obtain Intermediate 1 (30.2 g, 0.120 mol, 62%). 1H-NMR (400 MHz, CDCl3) delta 7.40-7.28 (m, 4H), 4.93 (t, J=4.4 Hz, 1H), 4.33 (t, J=6.8 Hz, 2H), 4.10-3.90 (m, 2H), 3.84-3.78 (m, 2H), 2.22-2.00 (m, 2H).

Reference： [1]Patent: US2017/306155,2017,A1 .Location in patent: Paragraph 0193-0194

66
[ 18742-02-4 ]
(R)-N-(2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide [ No CAS ]
C₁₆H₂₃F₂NO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With magnesium In tetrahydrofuran at -40 - 35℃; for 5h;	2.2 Embodiment 2: compound 2 synthesis of Step two: step a synthesis of the imine compound I 16 g is dissolved into dichloromethane 200 ml, cooling to the -40 °C, slowly adding embodiment 1 preparation of compound 1 of the mixed solution, in the adding process maintain the temperature not more than -35 °C, canada finishes, at this temperature to continue the reaction 5 h. Add saturated ammonium chloride aqueous solution quenching reaction, liquid, dichloromethane is used for extracting the aqueous phase, the organic phase drying, to remove the organic solvent, to obtain compound 2 crude product, compound 2 of the crude product by column chromatography purification (eluting agent is petroleum ether ethyl acetate (3:1)), to obtain 18.4 g, yield 81%, isomers are greater than 95%

Reference： [1]Current Patent Assignee: ZHEJIANG NORMAL UNIVERSITY - CN107286070, 2017, A Location in patent: Paragraph 0068; 0069; 0070; 0072

67
[ 18742-02-4 ]
[ 884497-46-5 ]
6-fluoro-3-formaldehyde-1H-indole-4-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.1%		Under argon protection,To the reactor was added 1.31 g of zinc powder (20 mmol) and 0.47 g of anhydrous lithium chloride,Join anhydrous tetrahydrofuran 10mL stirring,2.5 mol% 1,2-dibromoethane was added dropwise for 10 minutes,Then a solution of 1.81 g (10 mmol)2- (2-bromoethyl) -1,3-dioxolane in 10 mL of tetrahydrofuran,After stirring at room temperature for 3 hours,4.50g of zinc bromide (20mmol) was added with stirring,Cooled to -15 ,Then a solution of 3.22 g (12 mmol)A solution of 3-fluoro-5-methoxycarbonylbenzenediazonium tetrafluoroborate in 20 mL of tetrahydrofuran,After the addition is completed,Warmed to room temperature,1.09 g (10 mmol) of Me3SiCl,0.12 g of rhodium acetate,Heated to 87 C for 4 hours,Cool to room temperature,A small amount of dilute hydrochloric acid was added dropwise to heat to 35 C,After stirring for 2 hours,The reaction solution was extracted with ethyl acetate,The organic phase was dried and concentrated under reduced pressure.Flash column chromatography (Al2O3, ethyl acetate: petroleum ether = 1: 10),2.06 g of a white solid was obtained,Yield 93.1%

Reference： [1]Patent: CN106748958,2017,A .Location in patent: Paragraph 0035; 0036; 0037; 0038-0056; 0059-0062

68
[ 18742-02-4 ]
[ 57229-67-1 ]
C₂₈H₃₄N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With norborn-2-ene; potassium carbonate; palladium dichloride In water; N,N-dimethyl-formamide at 60℃; for 24h;

Reference： [1]Xiao, Tao; Chen, Zhi-Tao; Deng, Lin-Feng; Zhang, Dan; Liu, Xiao-Yu; Song, Hao; Qin, Yong [Chemical Communications, 2017, vol. 53, # 94, p. 12665 - 12667]

69
[ 18742-02-4 ]
methyl 3-(3-cyanophenyl)-1H-indole-6-carboxylate [ No CAS ]
methyl 1-(2-(1,3-dioxolan-2-yl)ethyl)-3-(3-cyanophenyl)-1H-indole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: methyl 3-(3-cyanophenyl)-1H-indole-6-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide; mineral oil at 0 - 20℃;	7 Methyl 1-(2-(1,3-dioxolan-2-yl)ethyl)-3-(3-cyanophenyl)-1H-indole-6-carboxylate (131- 3). To an anhydrous DMF solution (2.0 mL) of methyl 3-(3-cyanophenyl)-1H-indole-6- carboxylate (100 mg, 0.36 mmol) at 0 oC under N2 atmosphere was added NaH (40 mg, 1.67 mmol) and stirred for 30 min.2-(2-Bromoethyl)-1,3-dioxolane (126 uL, 1.08 mmol) was added into the above mixture via syringe, and resulting mixture was stirred and gradually warmed to rt over 2 h. The mixture was worked up by ethyl acetate (40 mL) and water (10 mL, X3). The ethyl acetate layer was concentrated in vacuo and residue was purified by flash chromatography on silica gel with hexanes and ethyl acetate (0-50%) to give product (120 mg, 89% ).1H NMR (600 MHz, CD3OD) δ 8.24 (s, 1H), 8.06 (s, 1H), 8.01 (m, 2H), 7.86 (d, J = 6.0 Hz, 1H), 7.83 (s, 1H), 7.64 (m, 2H), 4.92 (t, J = 6.0 Hz, 1H), 4.45 (t, J = 6.0 Hz, 2H), 3.98 (m, 2H), 3.95 (s, 3H), 3.86 (m, 2H), 2.24 (m, 2H).

Reference： [1]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2017/197240, 2017, A1 Location in patent: Page/Page column 204

70
[ 18742-02-4 ]
[ 1663-39-4 ]
[ 68716-52-9 ]
tert-butyl (E)-3-(2-(2-(1,3-dioxolan-2-yl)ethyl)naphthalen-1-yl)acrylate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 7161 - 7165
Angew. Chem.,2018,vol. 130,p. 7279 - 7283,5

71
[ 18742-02-4 ]
[ 1118567-05-7 ]

Reference： [1]Patent: WO2009/26537,2009,A1

72
[ 18742-02-4 ]
[ 124-38-9 ]
[ 64097-92-3 ]
4-(3-(1,3-dioxolan-2-yl)propyl)-4-phenyl-1H-benzo[d][1,3]oxazin-2(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In dimethyl sulfoxide for 24h; Schlenk technique; Irradiation;	7 4- (3- (1,3-dioxolan-2-yl) propyl) -4-phenyl-1H-benzo [d] [1,3] oxazin-2 (4H) -one In a dried Schlenk tube, add: 2- (α-styryl) aniline (0.2 mmol, 39.2 mg), 1,5,7-triazidebicyclo (4.4.0) dec-5 -Ene (0.6 mmol, 83.5 mg), 2- (2-bromoethyl) -1,3-epoxypentane (0.30 mmol, 54 mg), tetratriphenylphosphine palladium Pd (PPh3)4(0.01 mmol , 11.6 mg), 2 mL of dimethyl sulfoxide,replace the gas in the reaction tubewith CO2three times, and finallypour0.1 MPa of CO2into the reaction tube, and place the above-mentioned Schlenk tube under 6W blue LED light irradiation conditions And stir for 24h.The reaction was terminated, the reaction solution was quenched with 2 mL of saturated saline, and then extracted with ethyl acetate (4 mL × 5) multiple times. The organic phases were combined, and the solvent was removed on a rotary evaporator.Finally, it was separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1: 3) to obtain 4- [3- (2- (1,3-epoxypentyl)) propyl]- 4-phenyl-1,3-benzoxazine-2 (4H) -one (50.3 mg, isolated yield: 75%), the compound is a colorless oily liquid.
72%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In dimethyl sulfoxide at 20℃; for 24h; Inert atmosphere; Schlenk technique; Sealed tube; Irradiation;

Reference： [1]Current Patent Assignee: CHANGZHOU UNIVERSITY - CN110372625, 2019, A Location in patent: Paragraph 0054-0058
[2]Sun, Song; Zhou, Cong; Yu, Jin-Tao; Cheng, Jiang [Organic Letters, 2019, vol. 21, # 16, p. 6579 - 6583]

73
[ 18742-02-4 ]
[ 5326-38-5 ]
2-deutero-3-(2-ethyl-1,3-dioxolan)-5-nitrotoluene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium dihydrogenphosphate; norbornene; potassium acetate; palladium diacetate; sodium formate; triphenylphosphine; In N,N-dimethyl-formamide; at 50℃; for 16h;Inert atmosphere;	Palladium acetate palladium (44.9 mg, 0.2 mmol) was added to a 25 mL eggplant bottle.Triphenylphosphine (52.4 mg, 0.2 mmol),Sodium formate (276 mg, 4 mmol),Norbornene (188 mg, 2 mmol),Potassium phosphate (2.544 g, 12 mmol),Potassium acetate (392 mg, 4 mmol),<strong>[5326-38-5]2-iodo-5-nitrotoluene</strong> (526 mg, 2 mmol),2-(2-Bromoethyl)-1,3-dioxane (1.448 g, 8 mmol) and dimethylformamide (10 ml).High purity nitrogen replacement three times,After 16 hours of reaction at 50oC,The mixture is extracted with dichloromethane and water, and the organic phases are combined.The organic solvent is concentrated, and the product is further purified by column chromatography.2-Chloro-3-(2-ethyl-1,3-dioxolan)-5-nitrotoluene is obtainedThe yield was 69%.

Reference： [1]Patent: CN110054541,2019,A .Location in patent: Paragraph 0022

74
[ 18742-02-4 ]
[ 66256-28-8 ]
2-deutero-3-(2-ethyl-1,3-dioxolan)-5-fluorotoluene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium dihydrogenphosphate; norbornene; potassium acetate; palladium diacetate; sodium formate; triphenylphosphine In N,N-dimethyl-formamide at 50℃; for 16h; Inert atmosphere;	10 Example 10: Preparation method of 2-deuterated-3-(2-ethyl-1,3-dioxolan)-5-fluorotoluene Palladium acetate palladium (44.9 mg, 0.2 mmol) was added to a 25 mL eggplant bottle, triphenylphosphine (52.4 mg, 0.2 mmol),Sodium formate (276 mg, 4 mmol),Norbornene (188 mg, 2 mmol),Potassium phosphate (2.544 g, 12 mmol), Potassium acetate (392 mg, 4 mmol),2-iodo-5-fluorotoluene (472 mg, 2 mmol), 2-(2-Bromoethyl)-1,3-dioxane (1.448 g, 8 mmol) and dimethylformamide (10 ml). High purity nitrogen replacement three times,After 16 hours of reaction at 50oC,Extracting the mixture with dichloromethane and water,Combine the organic phase, concentrate the organic solvent,Further purification of the product by column chromatography,get2-deuterated-3-(2-ethyl-1,3-dioxolan)-5-fluorotolueneThe yield was 71%.

Reference： [1]Current Patent Assignee: ANHUI SHOLON NEW MATERIAL TECHNOLOGY CO LTD - CN110054541, 2019, A Location in patent: Paragraph 0022

75
[ 18742-02-4 ]
[ 524-38-9 ]
2-(2-(1,3-dioxolan-2-yl)ethoxy)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.6%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 80℃;
82%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 50℃; for 4h;
82%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 50℃; for 4h;	1.1 Step 1. Synthesis of 2-(2-(1,3-dioxolan-2-yl)ethoxy)isoindoline-1,3-dione (Z2). To a solution of compound Z1 (1 g, 5.5 mmol) in DMF (5 mL) were added 2-hydroxyisoindoline-1,3-dione (0.9 g, 5.5 mmol) and DBU (1.6 mL, 11.0 mmol). The reaction mixture was heated to 50° C. for 4 h. The reaction was monitored by UPLC. Upon completion, the reaction mixture was purified by reverse column chromatography to give compound Z2 (1.2 g, 4.5 mmol, 82% yield) as yellow solid. 1H NMR (600 MHz, Methanol-d4) δ8.36-7.40 (m, 4H), 5.10 (t, J=4.7 Hz, 1H), 4.31 (t, J=6.6 Hz, 2H), 3.98-3.93 (m, 2H), 3.87-3.82 (m, 2H), 2.09 (td, J=6.6, 4.6 Hz, 2H). UPLC >95%, tR=1.12 min. MS (ESI) [M+H]+=264.1638.

82%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 50℃; for 4h;	1.1 Step 1. Synthesis of 2-(2-(1,3-dioxolan-2-yl)ethoxy)isoindoline-1,3-dione (Z2). To a solution of compound Z1 (1 g, 5.5 mmol) in DMF (5 mL) were added 2-hydroxyisoindoline-1,3-dione (0.9 g, 5.5 mmol) and DBU (1.6 mL, 11.0 mmol). The reaction mixture was heated to 50° C. for 4 h. The reaction was monitored by UPLC. Upon completion, the reaction mixture was purified by reverse column chromatography to give compound Z2 (1.2 g, 4.5 mmol, 82% yield) as yellow solid. 1H NMR (600 MHz, Methanol-d4) δ8.36-7.40 (m, 4H), 5.10 (t, J=4.7 Hz, 1H), 4.31 (t, J=6.6 Hz, 2H), 3.98-3.93 (m, 2H), 3.87-3.82 (m, 2H), 2.09 (td, J=6.6, 4.6 Hz, 2H). UPLC >95%, tR=1.12 min. MS (ESI) [M+H]+=264.1638.
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 50℃; for 4h;

Reference： [1]Current Patent Assignee: CULLGEN SHANGHAI - WO2021/239117, 2021, A1 Location in patent: Paragraph 001363; 001366; 001367
[2]Wei, Jieli; Hu, Jianping; Wang, Li; Xie, Ling; Jin, Margaret S.; Chen, Xian; Liu, Jing; Jin, Jian [Journal of Medicinal Chemistry, 2019, vol. 62, # 23, p. 10897 - 10911]
[3]Current Patent Assignee: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI - US2021/395244, 2021, A1 Location in patent: Paragraph 0596-0598
[4]Current Patent Assignee: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI - US2021/395244, 2021, A1 Location in patent: Paragraph 0596-0598
[5]Hu, Jianping; Wei, Jieli; Yim, Hyerin; Wang, Li; Xie, Ling; Jin, Margaret S.; Kabir, Md; Qin, Lihuai; Chen, Xian; Liu, Jing; Jin, Jian [Journal of Medicinal Chemistry, 2020, vol. 63, # 24, p. 15883 - 15905]

76
[ 18742-02-4 ]
[ 1620-77-5 ]
3-(1,3-dioxolan-2-yl)-1-(5-methylpyridin-2-yl)propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With magnesium In tetrahydrofuran at 30 - 50℃; Inert atmosphere; Stage #2: 5-methylpicolinonitrile In tetrahydrofuran at 0℃; for 2h; Inert atmosphere;	5.1.19 General procedure for the synthesis of 41a-d General procedure: To a solution of Mg (44mmol, 2.2 eq) and I2 (20mg) in dry THF (10mL) at room temperature was added the THF solution (2mL) of 2-(2-bromoethyl)-1,3-dioxolane (4.0mmol, 0.20 eq) under nitrogen protection. The mixture was stirred at 40-50°C until the iodine color disappeared. The THF solution (18mL) of 2-(2-bromoethyl)-1,3-dioxolane (36mmol, 1.8 eq) was then added dropwise to the turnings at room temperature to keep the inner temperature below 30°C. The reaction was stirred at room temperature for an additional 1.5h. This mixture was added dropwise to the solution of 40a-d (20mmol, 1.0 eq) in dry THF (50mL) at 0°C and stirred at the same temperature for 2h. The saturated ammonium chloride solution (20mL) was added, extracted with ethyl acetate (30mL 3). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the desired product.

Reference： [1]Li, Zhanhui; Wang, Xu; Lin, Yu; Wang, Yujie; Wu, Shuwei; Xia, Kaijiang; Xu, Chen; Ma, Haikuo; Zheng, Jiyue; Luo, Lusong; Zhu, Fang; He, Sudan; Zhang, Xiaohu [European Journal of Medicinal Chemistry, 2020, vol. 205]

77
[ 18742-02-4 ]
2-(4-bromo-2-ethoxy-5-hydroxyphenyl)-8-chlorochromen-4-one [ No CAS ]
2-[4-bromo-5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-ethoxyphenyl]-8-chlorochromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 16h; Inert atmosphere;	39.3 Step 4: Synthesis of tert- butyl 3-[2-[2-bromo-5-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy- phenoxy]ethoxy]cyclobutanecarboxylate General procedure: To a solution of 2-(4-bromo-5-hydroxy-2-methoxy-phenyl)-8-chloro-chromen-4-one(100.0 mg, 0.260 mmol, compound 1c) and cis-tert- butyl 3- [2 -(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (0.45 mL, Intermediate AP) in dry DMF (10 mL) was added potassium carbonate (72.44 mg). The reaction mixture was degassed with N2 for 3 times. After being stirred at 100 °C for 16 hrs, the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc (50 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (eluting with EtOAc/PE = 1/4) to give tert- butyl 3-[2-[2-bromo-5- (8-ch loro-4-oAo-chromen-2-yl)-4- methoxy-phenoxy]ethoxy]cyclobutanecarboxylate (180 mg, 85% yield, compound 1d) as a yellow solid. MS obsd. (ESI+): 579.1 [(M+H)+], 581.1 [(M+2+H)+] .

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/148354, 2020, A1 Location in patent: Page/Page column 48; 112; 114

78
[ 18742-02-4 ]
2-(4-bromo-2-chloro-5-hydroxyphenyl)-8-chlorochromen-4-one [ No CAS ]
C₂₀H₁₅BrCl₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 16h; Inert atmosphere;	43.4 Step 4: Synthesis of tert- butyl 3-[2-[2-bromo-5-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy- phenoxy]ethoxy]cyclobutanecarboxylate General procedure: To a solution of 2-(4-bromo-5-hydroxy-2-methoxy-phenyl)-8-chloro-chromen-4-one(100.0 mg, 0.260 mmol, compound 1c) and cis-tert- butyl 3- [2 -(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (0.45 mL, Intermediate AP) in dry DMF (10 mL) was added potassium carbonate (72.44 mg). The reaction mixture was degassed with N2 for 3 times. After being stirred at 100 °C for 16 hrs, the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc (50 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (eluting with EtOAc/PE = 1/4) to give tert- butyl 3-[2-[2-bromo-5- (8-ch loro-4-oAo-chromen-2-yl)-4- methoxy-phenoxy]ethoxy]cyclobutanecarboxylate (180 mg, 85% yield, compound 1d) as a yellow solid. MS obsd. (ESI+): 579.1 [(M+H)+], 581.1 [(M+2+H)+] .

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/148354, 2020, A1 Location in patent: Page/Page column 48; 123; 125-126

79
[ 18742-02-4 ]
[ 71962-74-8 ]
ethyl 1-[2-(1,3-dioxolan-2-yl)ethyl]piperidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; sodium iodide In neat (no solvent) at 0 - 20℃; for 51h; Darkness;	Synthesis of ethyl nipecotate precursors rac-15a-15f(general procedure/GP1) General procedure: Potassium carbonate and sodium iodide were added to asolution of racemic ethyl nipecotate rac-16 (1.0 equiv) inthe solvent stated. The organic halide was added to thismixture that was stirred for the time period and at thetemperature indicated in the respective experiment. Themixture was concentrated under vacuum, dissolved in ethylacetate, and washed with water. Drying of the organic phase(Na2SO4) and removal of the solvent under vacuum affordedthe crude product which was purified by FC.

Reference： [1]Rudy, Heinrich-Karl A.; Höfner, Georg; Wanner, Klaus T. [Medicinal Chemistry Research, 2021, vol. 30, # 3, p. 586 - 609]

80
[ 18742-02-4 ]
[ 4010-81-5 ]
4-(9-(2-(1,3-dioxolan-2-yl)ethyl)-2-chloro-9H-purin-6-yl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium hydroxide; In ethanol; water; at 20℃; for 12.5h;	Dissolve 2-(2-bromoethyl)-1,3-dioxolane (3.77g, 0.0208mol) in 20ml of absolute ethanol for later use. Into a 250ml reactor, put KOH (2.34g, 0.042mol) and purified water (100ml), and stir until completely dissolved. Add <strong>[4010-81-5]4-(2-chloro-9H-purin-6-yl)morpholine</strong> (5g, 0.0208mol) and stir for 30min, add 2-(2-bromoethyl)-1,3-dioxolane and ethanol mixture, React at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure at 40C for 20 min. The concentrated solution was added with ethanol (3×30ml) for extraction and liquid separation. The organic phase is washed with saturated sodium chloride solution and dried with Na2SO4. Vacuum distillation4-(9-(2-(1,3-dioxopent-2-yl)ethyl)-2-chloro-9H-purin-6-yl)morpholine(5.3g, 75%).

Reference： [1]Patent: CN111875606,2020,A .Location in patent: Paragraph 0035-0040; 0045-0046

81
[ 18742-02-4 ]
[ 98-17-9 ]
2-[2-[3-(trifluoromethyl)phenoxy]ethyl]-1,3-dioxolane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.1%	Stage #1: 3-Trifluoromethylphenol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide at 65℃; Inert atmosphere;	4.1.15 Synthesis of compounds 12a-12f General procedure: General procedure: The solution of the substituted phenols (11a-11f, 10.0mmol) and anhydrous K2CO3 (2.76g, 20.0mmol) in DMF (40mL) was stirred 30min at room temperature, and then 2-(2-bromoethyl)-1,3-dioxolane (1.99g, 11.0mmol) was added slowly and the mixture was allowed to warm up 65°C overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After that, the resulting residue was diluted with water (30mL) and extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography column to provide compound 12a-12f.
72.1%	With potassium carbonate In N,N-dimethyl-formamide at 65℃;	4.1 (1) Synthesis of compound S3d: 3-Trifluoromethylphenol S2d (1.62g, 10.0mmol) and anhydrous K2CO3 (2.76g, 20.0mmol) were placed in a 100mL round bottom flask, Using DMF (40mL) as solvent, Add 3-bromopropionaldehyde ethylene acetal (1.99g, 11.0mmol) dropwise at room temperature, and the addition is complete. Transfer to 65°C and stir overnight to stop the reaction. Suction filtration, concentrate the filtrate under reduced pressure, Add water (30mL), extract with ethyl acetate (3×30ml), combine the organic phases, Wash the organic phase with saturated NaCl solution (30mL) once, dry with anhydrous Na2SO4, Filter and concentrate. The residue was subjected to silica gel column chromatography, Elute with petroleum ether/ethyl acetate (volume ratio 25:1), S3d was obtained as a colorless oil (1.89 g, 72.1% yield).

Reference： [1]Wu, Wenxi; Mu, Yu; Liu, Bo; Wang, Zixuan; Guan, Peipei; Han, Li; Jiang, Mingguo; Huang, Xueshi [Bioorganic Chemistry, 2021, vol. 111]
[2]Current Patent Assignee: NORTHEASTERN UNIVERSITY IN SHENYANG, CHINA - CN113105425, 2021, A Location in patent: Paragraph 0079-0082

82
[ 18742-02-4 ]
[ 402-45-9 ]
2-[2-[4-(trifluoromethyl)phenoxy]ethyl]-1,3-dioxolane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.7%	Stage #1: 4-hydroxybenzotrifluoride With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide at 65℃; Inert atmosphere;	4.1.15 Synthesis of compounds 12a-12f General procedure: General procedure: The solution of the substituted phenols (11a-11f, 10.0mmol) and anhydrous K2CO3 (2.76g, 20.0mmol) in DMF (40mL) was stirred 30min at room temperature, and then 2-(2-bromoethyl)-1,3-dioxolane (1.99g, 11.0mmol) was added slowly and the mixture was allowed to warm up 65°C overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After that, the resulting residue was diluted with water (30mL) and extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography column to provide compound 12a-12f.

Reference： [1]Wu, Wenxi; Mu, Yu; Liu, Bo; Wang, Zixuan; Guan, Peipei; Han, Li; Jiang, Mingguo; Huang, Xueshi [Bioorganic Chemistry, 2021, vol. 111]

83
[ 18742-02-4 ]
[ 372-20-3 ]
2-[2-(3-fluorophenoxy)ethyl]-1,3-dioxolane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.9%	Stage #1: 3-fluorophenol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide at 65℃; Inert atmosphere;	4.1.15 Synthesis of compounds 12a-12f General procedure: General procedure: The solution of the substituted phenols (11a-11f, 10.0mmol) and anhydrous K2CO3 (2.76g, 20.0mmol) in DMF (40mL) was stirred 30min at room temperature, and then 2-(2-bromoethyl)-1,3-dioxolane (1.99g, 11.0mmol) was added slowly and the mixture was allowed to warm up 65°C overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After that, the resulting residue was diluted with water (30mL) and extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography column to provide compound 12a-12f.
67.9%	With potassium carbonate In N,N-dimethyl-formamide at 65℃;	5.1 (1) Synthesis of compound S3e: 3-Fluorophenol S2e (1.12g, 10.0mmol) and anhydrous K2CO3 (2.76g, 20.0mmol) were placed in a 100mL round bottom flask, Using DMF (40mL) as solvent, Add 3-bromopropionaldehyde ethylene acetal (1.99g, 11.0mmol) dropwise at room temperature, and the addition is complete. Transfer to 65°C and stir overnight to stop the reaction. Suction filtration, concentrate the filtrate under reduced pressure, Add water (30mL), extract with ethyl acetate (3×30ml), combine the organic phases, Wash the organic phase with saturated NaCl solution (30mL) once, dry with anhydrous Na2SO4, Filter and concentrate. The residue was subjected to silica gel column chromatography, Elute with petroleum ether/ethyl acetate (volume ratio 25:1), S3e (1.44 g, 67.9% yield) was obtained as a yellow oil.

Reference： [1]Wu, Wenxi; Mu, Yu; Liu, Bo; Wang, Zixuan; Guan, Peipei; Han, Li; Jiang, Mingguo; Huang, Xueshi [Bioorganic Chemistry, 2021, vol. 111]
[2]Current Patent Assignee: NORTHEASTERN UNIVERSITY IN SHENYANG, CHINA - CN113105425, 2021, A Location in patent: Paragraph 0090-0093

84
[ 18742-02-4 ]
[ 108-39-4 ]
2-[2-(3-methylphenoxy)ethyl]-1,3-dioxolane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.2%	Stage #1: 3-methyl-phenol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide at 65℃; Inert atmosphere;	4.1.15 Synthesis of compounds 12a-12f General procedure: General procedure: The solution of the substituted phenols (11a-11f, 10.0mmol) and anhydrous K2CO3 (2.76g, 20.0mmol) in DMF (40mL) was stirred 30min at room temperature, and then 2-(2-bromoethyl)-1,3-dioxolane (1.99g, 11.0mmol) was added slowly and the mixture was allowed to warm up 65°C overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After that, the resulting residue was diluted with water (30mL) and extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography column to provide compound 12a-12f.
70.2%	With potassium carbonate In N,N-dimethyl-formamide at 65℃;	2.1 (1) Synthesis of compound S3b: 3-methylphenol S2b (1.08mg, 10.0mmol) and anhydrous K2CO3 (2.76g, 20.0mmol) were placed in a 100mL round bottom flask, Using DMF (40mL) as solvent, Add 3-bromopropionaldehyde ethylene acetal (1.99g, 11.0mmol) dropwise at room temperature, and the addition is complete. Transfer to 65°C and stir overnight to stop the reaction. Suction filtration, concentrate the filtrate under reduced pressure, Add water (30mL), extract with ethyl acetate (3×30ml), combine the organic phases, Wash the organic phase with saturated NaCl solution (30mL) once, dry with anhydrous Na2SO4, Filter and concentrate. The residue was subjected to silica gel column chromatography, Elute with petroleum ether/ethyl acetate (volume ratio 25:1), S3b was obtained as a colorless oil (1.46 g, 70.2% yield).

Reference： [1]Wu, Wenxi; Mu, Yu; Liu, Bo; Wang, Zixuan; Guan, Peipei; Han, Li; Jiang, Mingguo; Huang, Xueshi [Bioorganic Chemistry, 2021, vol. 111]
[2]Current Patent Assignee: NORTHEASTERN UNIVERSITY IN SHENYANG, CHINA - CN113105425, 2021, A Location in patent: Paragraph 0057-0060

85
[ 18742-02-4 ]
[ 150-76-5 ]
[ 92971-94-3 ]

Yield	Reaction Conditions	Operation in experiment
65.6%	Stage #1: 4-methoxy-phenol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-bromo-2-(2-ethyl)dioxolane In N,N-dimethyl-formamide at 65℃; Inert atmosphere;	4.1.15 Synthesis of compounds 12a-12f General procedure: General procedure: The solution of the substituted phenols (11a-11f, 10.0mmol) and anhydrous K2CO3 (2.76g, 20.0mmol) in DMF (40mL) was stirred 30min at room temperature, and then 2-(2-bromoethyl)-1,3-dioxolane (1.99g, 11.0mmol) was added slowly and the mixture was allowed to warm up 65°C overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After that, the resulting residue was diluted with water (30mL) and extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography column to provide compound 12a-12f.
65.6%	With potassium carbonate In N,N-dimethyl-formamide at 65℃;	3.1 (1) Synthesis of compound S3c: 4-Methoxyphenol S2c (1.24g, 10.0mmol) and anhydrous K2CO3 (2.76g, 20.0mmol) were placed in a 100mL round bottom flask, Using DMF (40mL) as solvent, Add 3-bromopropionaldehyde ethylene acetal (1.99g, 11.0mmol) dropwise at room temperature, and the addition is complete. Transfer to 65°C and stir overnight to stop the reaction. Suction filtration, concentrate the filtrate under reduced pressure, Add water (30mL), extract with ethyl acetate (3×30ml), combine the organic phases, Wash the organic phase with saturated NaCl solution (30mL) once, dry with anhydrous Na2SO4, Filter and concentrate. The residue was subjected to silica gel column chromatography, Elute with petroleum ether/ethyl acetate (volume ratio 15:1), S3c (1.47 g, 65.6% yield) was obtained as a colorless oil.

Reference： [1]Wu, Wenxi; Mu, Yu; Liu, Bo; Wang, Zixuan; Guan, Peipei; Han, Li; Jiang, Mingguo; Huang, Xueshi [Bioorganic Chemistry, 2021, vol. 111]
[2]Current Patent Assignee: NORTHEASTERN UNIVERSITY IN SHENYANG, CHINA - CN113105425, 2021, A Location in patent: Paragraph 0068-0071

86
[ 18742-02-4 ]
[ 35233-17-1 ]
3-(2-(1,3-dioxolan-2-yl)ethoxy)-8-methoxy-6H-benzo[c]chromen-6-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With potassium carbonate In N,N-dimethyl-formamide at 80 - 120℃; for 24h;

Reference： [1]Tang, Long; Jiang, Jianchun; Song, Guoqiang; Wang, Yajing; Zhuang, Ziheng; Tan, Ying; Xia, Yan; Huang, Xianfeng; Feng, Xiaoqing [International Journal of Molecular Sciences, 2021, vol. 22, # 11]

87
[ 18742-02-4 ]
[ 124-38-9 ]
[ 4388-56-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With diisobutylaluminium hydride; magnesium In tetrahydrofuran; toluene at 23℃; for 4h; Inert atmosphere; Stage #2: carbon dioxide In tetrahydrofuran; toluene at 23℃; for 2h; Inert atmosphere;
72%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With diisobutylaluminium hydride; magnesium In tetrahydrofuran; toluene at 23℃; for 0.5h; Stage #2: carbon dioxide In tetrahydrofuran; toluene at 23℃; for 2h;	Acid 8: Freshly dried magnesium turnings (29.40 g, 1.21 mol, 3.55 equiv) were suspended in tetrahydrofuran (585 mL) at 23 °C and a pressure-equalizing addition funnel was charged with a solution of 2-(2-bromoethyl)-1,3-dioxolane (7) (40.0 mL, 61.68 g, 341 mmol) in tetrahydrofuran (175 mL). To the suspension were added sequentially approximately 10% of the alkyl bromide solution and a solution of diisobutylaluminum hydride (25% wt. in toluene, 2.3 mL, 485 mg of diisobutylaluminum hydride, 3.41 mmol, 1 mol%). A gentle exotherm indicated initiation of the reaction after ca.5 min, and the remainder of the alkyl bromide solution was added to the magnesium turnings suspension dropwise at such a rate as to maintain a gentle exotherm (3.5 h). When the addition was complete, the mixture was stirred for an additional 30 min at 23 °C and was then sparged with carbon dioxide gas for 2 h, controlling the resulting exotherm with a room temperature water bath. The reaction mixture was then quenched with solid dry ice (ca.20 g) and was stirred at 23 °C for 16 h. The suspension was filtered through a Celite pad, washing with ethyl ether (250 mL) and water (250 mL). The filtrate was concentrated in vacuo to remove the organic solvents. The aqueous solution was washed with ethyl ether (2 × 400 mL) and was then acidified to pH 3 using a 6 M aqueous solution of HCl. The solution was extracted with ethyl ether (12 × 500 mL) and the combined organic layers were dried over magnesium sulfate. The dried solution was filtered through a sintered glass funnel and was concentrated in vacuo to provide acid 8 (35.71 g, 72%) as a colorless oil that solidified to an amorphous white solid on standing.1H NMR (500 MHz, CDCl3) δ: 10.84 (br s, 1H), 4.82 (t, J = 4.2 Hz, 1H), 3.88-3.79 (m, 2H), 3.75-3.70 (m, 2H), 2.33 (t, J = 7.6 Hz, 2H), 1.87 (td, J = 4.2, 7.6 Hz, 2H);13C NMR (125 MHz, CDCl3) δ: 178.4, 102.8, 64.8, 28.3, 27.7; FTIR (neat), cm-1: 3462, 2931, 1720, 1680, 1410, 1196, 905.
72%	Stage #1: 2-bromo-2-(2-ethyl)dioxolane With diisobutylaluminium hydride; magnesium In tetrahydrofuran; toluene at 23℃; for 0.5h; Stage #2: carbon dioxide In tetrahydrofuran; toluene at 23℃; for 2h;	Acid 8: Freshly dried magnesium turnings (29.40 g, 1.21 mol, 3.55 equiv) were suspended in tetrahydrofuran (585 mL) at 23 °C and a pressure-equalizing addition funnel was charged with a solution of 2-(2-bromoethyl)-1,3-dioxolane (7) (40.0 mL, 61.68 g, 341 mmol) in tetrahydrofuran (175 mL). To the suspension were added sequentially approximately 10% of the alkyl bromide solution and a solution of diisobutylaluminum hydride (25% wt. in toluene, 2.3 mL, 485 mg of diisobutylaluminum hydride, 3.41 mmol, 1 mol%). A gentle exotherm indicated initiation of the reaction after ca.5 min, and the remainder of the alkyl bromide solution was added to the magnesium turnings suspension dropwise at such a rate as to maintain a gentle exotherm (3.5 h). When the addition was complete, the mixture was stirred for an additional 30 min at 23 °C and was then sparged with carbon dioxide gas for 2 h, controlling the resulting exotherm with a room temperature water bath. The reaction mixture was then quenched with solid dry ice (ca.20 g) and was stirred at 23 °C for 16 h. The suspension was filtered through a Celite pad, washing with ethyl ether (250 mL) and water (250 mL). The filtrate was concentrated in vacuo to remove the organic solvents. The aqueous solution was washed with ethyl ether (2 × 400 mL) and was then acidified to pH 3 using a 6 M aqueous solution of HCl. The solution was extracted with ethyl ether (12 × 500 mL) and the combined organic layers were dried over magnesium sulfate. The dried solution was filtered through a sintered glass funnel and was concentrated in vacuo to provide acid 8 (35.71 g, 72%) as a colorless oil that solidified to an amorphous white solid on standing.1H NMR (500 MHz, CDCl3) δ: 10.84 (br s, 1H), 4.82 (t, J = 4.2 Hz, 1H), 3.88-3.79 (m, 2H), 3.75-3.70 (m, 2H), 2.33 (t, J = 7.6 Hz, 2H), 1.87 (td, J = 4.2, 7.6 Hz, 2H);13C NMR (125 MHz, CDCl3) δ: 178.4, 102.8, 64.8, 28.3, 27.7; FTIR (neat), cm-1: 3462, 2931, 1720, 1680, 1410, 1196, 905.

Reference： [1]Mason, Jeremy D.; Myers, Andrew G.; Pote, Aditya R.; Terwilliger, Daniel W. [Journal of the American Chemical Society, 2021, vol. 143, # 29, p. 11019 - 11025]
[2]Current Patent Assignee: SILVESTRE KATHERINE J; HARVARD UNIVERSITY; MYERS ANDREW G; MASON JEREMY D; MITCHELTREE MATTHEW JAMES - WO2021/236911, 2021, A1 Location in patent: Paragraph 00378
[3]Current Patent Assignee: SILVESTRE KATHERINE J; HARVARD UNIVERSITY; MYERS ANDREW G; MASON JEREMY D; MITCHELTREE MATTHEW JAMES - WO2021/236911, 2021, A1 Location in patent: Paragraph 00378

88
[ 18742-02-4 ]
[ 120-72-9 ]
3-((2-(1,3-dioxolan-2-yl)ethyl)selanyl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With selenium; sodium t-butanolate In acetonitrile at 40℃; for 6h; Sealed tube;	3.1. 0.3 mmol scale General procedure: To a 8.0-mL scintillation vial equipped with a magnetic stirrer, indole 1a (0.36 mmol, 1.2 equiv.), selenium powder 2 (0.36 mmol, 1.2 equiv.), t-BuONa (0.45 mmol, 1.5 equiv.), solvent CH3CN (1.0 mL) and (3-bromopropyl)benzene 3a (0.30 mmol, 1.0 equiv.) sequentially added at room temperature. The vial was sealed with a screw-top septum cap and placed in a heating block that was preheated to 40 °C for 6h. After the indicated reaction time, an aqueous saturated NH4Cl solution and EtOAc were added and the layers were separated. The aqueous phase was extracted with EtOAc (x 3) and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (eluent: Petroleum ether/EtOAc) to give the target product 4aa as a Colorless oil.

Reference： [1]Liu, Huan; Cai, Zhong-Jian; Ji, Shun-Jun [Chinese Chemical Letters, 2022, vol. 33, # 9, p. 4303 - 4305]

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CAS No. :	18742-02-4	MDL No. :	MFCD00003216
Formula :	C₅H₉BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GGZQLTVZPOGLCC-UHFFFAOYSA-N
M.W :	181.03	Pubchem ID :	87776
Synonyms :

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	34.08
TPSA :	18.46 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.7 cm/s

[ CAS No. 18742-02-4 ] {[proInfo.proName]}

Quality Control of [ 18742-02-4 ]

Related Doc. of [ 18742-02-4 ]

Product Details of [ 18742-02-4 ]

Calculated chemistry of [ 18742-02-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 18742-02-4 ]

Application In Synthesis of [ 18742-02-4 ]

[ 18742-02-4 ] Synthesis Path-Upstream 1~2

[ 18742-02-4 ] Synthesis Path-Downstream 1~88

Pharmaceutical Intermediates of
[ 18742-02-4 ]

Bexagliflozin Related Intermediates

Related Functional Groups of
[ 18742-02-4 ]

Bromides

Related Parent Nucleus of
[ 18742-02-4 ]

Aliphatic Heterocycles

Dioxolanes

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Log Po/w (iLOGP) :	2.1
Log Po/w (XLOGP3) :	0.99
Log Po/w (WLOGP) :	1.14
Log Po/w (MLOGP) :	0.8
Log Po/w (SILICOS-IT) :	1.9
Consensus Log Po/w :	1.39

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

Log S (ESOL) :	-1.45
Solubility :	6.36 mg/ml ; 0.0352 mol/l
Class :	Very soluble
Log S (Ali) :	-0.97
Solubility :	19.6 mg/ml ; 0.108 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.62
Solubility :	4.33 mg/ml ; 0.0239 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.65

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P210-P261-P264-P270-P271-P280-P301+P310+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P233-P403+P235-P405-P501	UN#:	2810
Hazard Statements:	H227-H301-H315-H319-H335	Packing Group:	Ⅲ
GHS Pictogram:

Yield	Reaction Conditions	Operation in experiment
38%	With sodium nitrite In dimethyl sulfoxide at 0 - 18℃; for 6 h; Inert atmosphere	To a solution of commercially available 2-(2-bromoethyl)-1,3-dioxolane (40.73 g, 225 mmol) in anhydrous DMSO (350 mL) was added a solution of NaNO₂ (27.95 g, 405 mmol) in anhydrous DMSO (350 mL) slowly at 0°C and the resulting mixture was stirred at 18°C for 6 hours under N₂. Then, the reaction mixture was poured into water and extracted with MTBE. The combined organic phase was washed with brine, dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography to give intermediate 2-(2-nitroethyl)-1,3-dioxolane (12.50 g, 38percent) as a yellow liquid . A mixture of this intermediate (3.97 g, 27 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (6.61 g, 31) in TEA (3.00 g, 30 mmol) was stirred at 18°C for 8 hours. Then a solution of DMAP (330 mg, 2.70 mmol) in Ac₂O (4.13 g, 40 mmol) was added and the reaction mixture was stirred at 18°C for 7 hours. The reaction was quenched with water and then extracted with EtOAc. The combined organic phase was washed with saturated brine, dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography to afford intermediate tert-butyl 4-[(Z)-3-(1,3-dioxolan-2-yl)-2-nitro-prop-1-enyl]piperidine-1-carboxylate (5.64 g, 61percent) as a yellow liquid. Finally, a stirred suspension of this intermediate (2.50 g, 7.30 mmol) in absolute EtOH (100 mL) and CHCl₃ (8 mL) containing PtO₂ (414 mg, 1.83 mmol) was placed under H₂ (50 Psi) at 18°C after 15 hours, the mixture was filtered through Celite and washed with EtOH. The filtrate was concentrated to dryness to give desired reagent R-04b (2.02 g, 88percent crude) as a yellow syrup which was used for next step without further purification. ESI-MS (M+1): 315.3 calc. for C16H₃0N₂O₄: 314.2.
35%	With sodium nitrite In N,N-dimethyl-formamide at 20℃; for 6 h;	2d: To a solution of bromo compound (5.4 g, 30 mmol) in DMF (60 mL) was added NaNO₂ (3.5 g, 50 mmol). After stirring at r.t. for 6 h, the reaction mixture was poured into ice-water (60 mL) and layered over with petroleum ether (100 mL). The aqueous phase was extracted with diethyl ether (60 mL .x. 3). The organic phase was dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by flash column chromatography on silica gel with 5percent Et₂O in hexane as eluent to afford 2d (1.5 g, 35percent) as pale yellow oil. ¹H NMR (CDCl₃): δ 2.40-2.47 (m, 1H), 3.85-4.02 (m, 4H), 4.51 (t, J = 7.2 Hz, 2H), 5.03 (t, J = 3.6 Hz, 1H).

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