2. 2-Isopropoxypropane by Asch

Query Query 1. Query O

Results

Date

127 reactions in Reaxys

2016-09-13 02h:52m:18s (EST)

Search as: As drawn, No salts, No mixtures, No isotopes, No charges, No radicals

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Rx-ID: 170633 View in Reaxys 1/127 Yield

Conditions & References With phosphoric acid, water, T= 165 - 290 °C , p= 69873.3 - 369960Torr , in fluessiger oder dampffoermiger Phase Majewski; Marek; Industrial and Engineering Chemistry; vol. 30; (1938); p. 205 View in Reaxys With sulfuric acid Patent; Socony-Vacuum Oil Co.; US2055720; (1933) View in Reaxys Patent; Shell Devel.Co.; US2178186; (1937) View in Reaxys Patent; Standard Alkohol Co.; FR793482 View in Reaxys Patent; Standard Alkohol Co.; FR821485 View in Reaxys Patent; Standard Alkohol Co.; US2105508; (1934) View in Reaxys Patent; Standard Alkohol Co.; US2109004; (1936) View in Reaxys Patent; Standard Alkohol Co.; US2160854; (1936) View in Reaxys Patent; Standard Alkohol Co.; FR818142 View in Reaxys The raw materials, water and propylene, are introduced, with pressure between 15 and 145 bar and temperature between 75°C and 3800C, into the hydration reactorRl (see Fig. 3). Inside the reactor, water and propylene cross the high efficiency catalyst obtaining diisopropyl ether, isopropyl alcohol and not reacted water. With water, zeolite ZSM-5 (alumina), T= 75 - 380 °C , p= 11251.1 - 108761Torr , Industry scale Patent; TULINO, Rosario, Rocco; LETIZIA, Santino; WO2009/133423; (2009); (A1) English View in Reaxys The process described above was carried out in a unit comprising a reactor (10), a throttling valve (12), acondenser (14), a decanter (15) and a separation column (11). The propylene hydration reactor was fed with inlet stream (6), including propylene stream (1) and water stream(2) and the recycle streams (3), (4) and (5) with the values given in the next tables. For the experiments a laboratorygas phase hydration reactor was filled with a phosphoric acid catalyst volume of 650 mL of hydration catalyst as describedin patent US 20040029718. The reaction temperature was adjusted to 190°C at the reactor inlet, leading to a reactorexit temperature of 207°C, at a pressure of 40 bar. The reactor outlet stream (17) was fed to condenser (14) and decanter (15). The condensation in condenser(14) was supported by throttling valve (12), using the Joule-Thompson-effect. The pressure in the condenser was adjustedto 19 bar and the temperature to 50°C. In table II the streams in the condenser (14) and the decanter (15) as measured are given (IPA = Isopropylalcohol, DIPE = Diisopropyl ether). Thereafter the organic phase (stream (13) of decanter (15)) was fed to separation column (11). The waterphase from the decanter (15) was recycled by stream (5) to the reactor inlet. The separation column had an innerdiameter of 50 mm and was equipped with a structured packing to improve the separation (Sulzer DX packing). In thenext table the separation column (11) streams for the distillation are given. To improve the heat recovery heat exchangers (8) and (9) were applied. Side stream (19) provides homogeneouswater distribution in the reactor, enabling favourable temperature profiles and ensuring long catalyst lifetime. This featurewas not used for the present example, but is favourable for larger reactor diameters as used in commercial plants. With phosphoric acid, water, T= 190 - 207 °C , p= 30003Torr Patent; Sasol Solvents Germany GmbH; Technische Universität Clausthal; The designation of the inventor has not yet been filed; EP2939995; (2015); (A1) English View in Reaxys

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Rx-ID: 742368 View in Reaxys 2/127 Yield 29 %

Conditions & References 1 :Isopropyl alcohol was exposed to a Deloxan ASP 1/7 acid catalyst (available from Degussa-Huls AG) under the conditions given below in a continuous flow reactor. The volume of the reactor was 10 ml and the flow rate of the solvent was 0.65 L/min. With Deloxan ASP 1/7 acid catalyst in carbon dioxide, T= 200 °C , p= 150015Torr Patent; THOMAS SWAN AND CO., LTD.; EP1185492; (2005); (B1) English View in Reaxys With molecular sieve, rate constants for dehydratation at various temperatures, Rate constant Karaiskakis, George; Katsanos, Nicholas A.; Georgiadou, Irene; Lycourghiotis, Alexis; Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases; vol. 78; (1982); p. 2017 - 2022 View in Reaxys With monoaluminum phosphate, T= 299.9 °C , Rate constant, Thermodynamic data Campelo, J. M.; Garcia, A.; Herencia, J. F.; Luna, D.; Marinas, J. M.; Romero, A. A.; Journal of Catalysis; vol. 151; nb. 2; (1995); p. 307 - 314 View in Reaxys With diisopropyl sulfate Katuno; ; vol. 43; (1940); p. 106,109; ; (1940); p. 6929 View in Reaxys With Fuller's Earth, T= 160 - 170 °C Nekrassow; Krentzel; Zhurnal Obshchei Khimii; vol. 19; (1949); p. 948; ; (1950); p. 1006 View in Reaxys With hydrogenchloride, zinc(II) chloride, T= 95 - 100 °C , p= 882.6Torr Patent; Wacker,A.; DE680328; (1934); View in Reaxys With sulfuric acid Katuno; ; vol. 41; (1938); p. 78; ; (1940); p. 2785; Chem. Zentralbl.; vol. 110; nb. I; (1939); p. 630 View in Reaxys With phosphoric acid Katuno; ; vol. 41; (1938); p. 78; ; (1940); p. 2785; Chem. Zentralbl.; vol. 110; nb. I; (1939); p. 630 View in Reaxys With boron trifluoride, benzene, T= 215 °C , p= 41188.4Torr Romadan; Peltscher; Izvestiya Vysshikh Uchebnykh Zavedenii, Khimiya i Khimicheskaya Tekhnologiya; vol. 2; (1959); p. 381; ; (1960); p. 4357 View in Reaxys With sulfuric acid Senderens; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 179; (1924); p. 1018; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 181; (1925); p. 700 View in Reaxys With quinoline hydrochloride, T= 160 °C van Hove; Chem. Zentralbl.; vol. 79; nb. II; (1908); p. 292 View in Reaxys

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With SO4/60percentZrO2/SBA-15 Landau; Titelman; Vradman; Wilson; Chemical Communications; nb. 5; (2003); p. 594 - 595 View in Reaxys b Patent; Phenolchemie GmbH and Co. KG; US6930213; (2005); (B1) English View in Reaxys O

Rx-ID: 23057686 View in Reaxys 3/127 Yield

Conditions & References

94.7 %, 2.8 %, 2.3 %

3 : Example 3 The catalyst used was the same as used in Example 1. Using the reactor shown in Fig. 1, propylene, nitrogen, acetic acid and water were fed in a molar ratio of 80.0:10.3:6.7:3.0 from the respective inlets at a space velocity of 1,500 hr-1 under a pressure of 0.9 MPa. Nitrogen was fed together with propylene and water was fed together with acetic acid. In this case, the temperature at which the acetic acid-water mixture vaporized was 105.6°C. When the reaction system was heated so that the catalyst layer had a peak temperature of 165°C, the reaction results were such that the STY of isopropyl acetate was 243 g/l-cat.bul.h and the selectivities of isopropyl acetate, isopropanol and diisopropyl ether were 94.7percent, 2.8percent and 2.3percent, respectively. With water, cesium nitrate; tungstophosphoric acid; water; mixture of, dried, tabletted, T= 105.6 - 165 °C , p= 6750.68Torr , Gas phase, Product distribution / selectivity Patent; SHOWA, DENKO K.K.; EP1218331; (2004); (B1) English View in Reaxys O

Rx-ID: 742335 View in Reaxys 4/127 Yield 59 %

Conditions & References 10 :Isopropanol (30.0 g, 0.50 mol) was dropped onto the ionic liquid [MIPS]/[HOTfJ (1:1.5)(10 mmol / 15 mmol) at 240 to 260 deg. C. The product was collected in a round bottom flask attached to the outlet of the condenser and cooled with dry ice and acetone. After 4 hours, 12.39 g propene, corresponding to a yield of 59percent, was collected in the Schlenk flask (along with 2.44 g unreacted isopropanol and water). Very little diisopropyl ether (bp= 68 deg. C) was observed by NMR. With [PMIM(SO3H)[OTf]], CF3O3S(1-)*CHF3O3S*C7H13N2O3S(1+), Time= 4h, T= 240 - 260 °C , Product distribution / selectivity Patent; BP p.l.c.; WO2007/12825; (2007); (A1) English View in Reaxys With sulfated zirconia oxide, Time= 0.0333333h, T= 100 °C , further catalysts, Rate constant Babou, F.; Coudurier, G.; Vedrine, J. C.; Journal de Chimie Physique et de Physico-Chimie Biologique; vol. 92; nb. 7-8; (1995); p. 1457 - 1471 View in Reaxys With aluminum oxide, Titanium(IV) oxide, T= 199.9 °C , other temperatures; percent conversion, Product distribution Lahousse, Christophe; Mauge, Francoise; Bachelier, Jean; Lavalley, Jean-Claude; Journal of the Chemical Society, Faraday Transactions; vol. 91; nb. 17; (1995); p. 2907 - 2912 View in Reaxys With LaY zeolite, T= 96.9 °C , catalytic dehydration of propan-2-ol by LaY zeolites at 353-407 K; activation energies for product formation; effect of propan-2-ol pressure, activation temeprature, lantanum contnt; catalytic poisonong with pyridine, Rate constant, Thermodynamic data

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Rudham, Robert; Spiers, Andrew I.; Journal of the Chemical Society - Faraday Transactions; vol. 93; nb. 7; (1997); p. 1445 - 1448 View in Reaxys With phosphoric acid Ashdown; Harris; Armstrong; Journal of the American Chemical Society; vol. 58; (1936); p. 850 View in Reaxys Ormandy; Craven; Journal of the Society of Chemical Industry, London; vol. 49; (1930); p. 376T View in Reaxys With phosphoric acid, palladium, T= 80 °C Otsuka, Kiyoshi; Yamanaka, Ichiro; Chemistry Letters; (1987); p. 1945 - 1948 View in Reaxys With hydrogen, molybdenum(VI) oxide, Time= 1h, T= 124.9 °C Matsuda, Takeshi; Hirata, Yasuyoshi; Sakagami, Hirotoshi; Takahashi, Nobuo; Chemistry Letters; nb. 12; (1997); p. 1261 - 1262 View in Reaxys With sodium alum, T= 150 - 160 °C Mailhe; de Godon; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 170; (1920); p. 329; Bulletin de la Societe Chimique de France; vol. <4>27; (1920); p. 121 View in Reaxys With Al3+-montmorillonite, Time= 4h, T= 200 °C , Yield given. Yields of byproduct given Ballantine, James A.; Davies, Mary; Purnell, Howard; Rayanakorn, Mongkon; Thomas, John M.; Williams, Kevin J.; Journal of the Chemical Society, Chemical Communications; nb. 9; (1981); p. 427 - 428 View in Reaxys With sulfated zirconia-silica, T= 140 °C , p= 760Torr , Product distribution, Further Variations: Catalysts, Temperatures Zhuang; Miller; Canadian Journal of Chemistry; vol. 79; nb. 8; (2001); p. 1220 - 1223 View in Reaxys With phosphate-zirconia-silica catalyst, T= 210 °C , p= 760Torr , Product distribution, Further Variations: Catalysts, Temperatures Zhuang; Miller; Canadian Journal of Chemistry; vol. 79; nb. 8; (2001); p. 1224 - 1228 View in Reaxys With sulfated ZrO2, T= 150 °C , p= 760.051Torr , Kinetics, Temperature Hsu, Ya-Sun; Wang, Yin-Lan; Ko, An-Nan; Journal of the Chinese Chemical Society; vol. 56; nb. 2; (2009); p. 314 - 322 View in Reaxys With C1-450, Inert atmosphere, Mechanism, Thermodynamic data, Reagent/catalyst, Temperature Bedia; Ruiz-Rosas; Rodriguez-Mirasol; Cordero; Journal of Catalysis; vol. 271; nb. 1; (2010); p. 33 - 42 View in Reaxys With VOx, T= 179.84 °C , Flow reactor Xue, Mingwei; Chen, Hui; Zhang, Huiliang; Auroux, Aline; Shen, Jianyi; Applied Catalysis A: General; vol. 379; nb. 1-2; (2010); p. 7 - 14 View in Reaxys With sulfated titania, T= 120 °C , Flow reactor, Inert atmosphere, Kinetics Ropero-Vega; Aldana-Perez; Gomez; Nino-Gomez; Applied Catalysis A: General; vol. 379; nb. 1-2; (2010); p. 24 29

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View in Reaxys With Nb2Sb-VO10 mixture, T= 299.84 °C Ziolek, Maria; Golinska-Mazwa, Hanna; Filipek, Elzbieta; Piz, Mateusz; Catalysis Today; vol. 187; nb. 1; (2012); p. 159 - 167 View in Reaxys 2.2. Catalyst testing Isopropanol dehydration was carried out under atmospheric pressure in a Pyrex fixed-bed reactor (9 mm internal diameter) fitted with on-line GC analysis as described previously [7]. Typical reaction conditions: 0.1-0.2 g catalyst (45-180 μm particle size), 0.94-5.52 kPa i-PrOH partial pressure, 55-135 °C temperature range (+/-0.1 °C) and 20 ml min-1 gas flow rate (N2 as a carrier gas). Before reaction, the catalysts were pre-treated in situ at a specified temperature. Reaction rates (in mol h-1) were calculated using the equation r = XF/W, where X is the isopropanol conversion (typically X = 2-25percent), F is the molar flow rate of isopropanol and W is the catalyst weight. For each catalyst, the rate was measured at least at four different temperatures in the temperature interval of 20-30 °C at a specified partial pressure of isopropanol (0.94 or 5.52 kPa), and at one temperature the effect of isopropanol pressure on the reaction rate was examined. From these results the reaction order in isopropanol was found to be zero (+/-0.1), hence isopropanol conversion was equivalent to the reaction rate. Turnover rates (per accessible Broensted site) were calculated as explained in the text. From zero-order kinetics, the values of true activation energy E (+/-4 kJ mol-1) and pre-exponential factor ln A (+/-1) (A in h-1) were obtained using the Arrhenius equation. With 15H3PW12O40/SiO2, T= 90 °C , p= 760.051Torr , Gas phase, Kinetics, Concentration, Reagent/catalyst, Temperature Bond, Geoffrey C.; Frodsham, Sarah J.; Jubb, Paul; Kozhevnikova, Elena F.; Kozhevnikov, Ivan V.; Journal of Catalysis; vol. 293; (2012); p. 158 - 164 View in Reaxys , T= 115 °C , Inert atmosphere, Reagent/catalyst Hernandez-Cortez; Manriquez, Ma.; Lartundo-Rojas; Lopez-Salinas; Catalysis Today; vol. 220-222; (2014); p. 32 - 38 View in Reaxys , T= 175 °C , Inert atmosphere, Reagent/catalyst, Temperature Hernandez-Cortez; Manriquez, Ma.; Lartundo-Rojas; Lopez-Salinas; Catalysis Today; vol. 220-222; (2014); p. 32 - 38 View in Reaxys With hydrogen, Time= 6h, T= 174.84 °C , Catalytic behavior, Reagent/catalyst, Overall yield = 89.5 percent Witsuthammakul, Ayut; Sooknoi, Tawan; Catalysis Science and Technology; vol. 5; nb. 7; (2015); p. 3639 - 3648 View in Reaxys

Rx-ID: 4835851 View in Reaxys 5/127 Yield 5 %, 1 %, 40 %

Conditions & References With Deloxan catalyst in carbon dioxide, T= 31.1 °C , p= 55354.4Torr Hitzler, Martin G.; Smail, Fiona R.; Ross, Stephen K.; Poliakoff, Martyn; Chemical Communications (Cambridge, United Kingdom); nb. 3; (1998); p. 359 - 360 View in Reaxys

40 %, 1 %, With Deloxan catalyst in carbon dioxide, T= 31.1 °C , p= 55354.4Torr 5% Hitzler, Martin G.; Smail, Fiona R.; Ross, Stephen K.; Poliakoff, Martyn; Chemical Communications (Cambridge, United Kingdom); nb. 3; (1998); p. 359 - 360 View in Reaxys

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O N O

N N

Rx-ID: 9303215 View in Reaxys 6/127 Yield 92 %

Conditions & References Stage 2: With sulfuric acid, hydrogen, platinum on activated charcoal in water, Time= 48h, p= 3878.61Torr Jursic, Branko S.; Stevens, Edwin D.; Tetrahedron Letters; vol. 44; nb. 10; (2003); p. 2203 - 2210 View in Reaxys OH

Rx-ID: 741744 View in Reaxys 7/127 Yield

Conditions & References With sulfuric acid Patent; Standard Alcohol Co.; FR821485 View in Reaxys Patent; Standard Alcohol Co.; US2131030; (1936) View in Reaxys Patent; Standard Alcohol Co.; US2216931; (1938) View in Reaxys Patent; Socony-Vacuum Oil Co.; US2077042; (1934) View in Reaxys 1 :Etherification ReactionEach of various alcohols was put in a 200-cc autoclave with stirrer in a predetermined amount, 0.20 g of the carbon-based solid acid A was added thereto followed by sealing, and each of various olefins was injected and sealed therein in a predetermined amount. The reaction mixture was heated to a predetermined temperature while stirring at 700 rpm, pressure-adjusted with nitrogen as needed, and then retained at the predetermined temperature to thereby perform etherification reaction for 2 hours. After completion of the reaction, the reaction mixture was cooled and then subjected to quantitative analysis by TCD-GC. The measurement of acid content of the catalyst was performed by back titration, and the measured acid content was compared with the acid content before the reaction to measure the reduction rate of the acid content. The reaction conditions and reaction results are shown in Table 1-2. TABLE 1-2 Amount of Acid content Reduction produced after rate of acid Amount of Amount of Alcohol/Olefin Pressure Temperature ethar reaction content Olefin olefin Alcohol Alcohol (molar ratio) (MPa) (° C.) (mmol/cat-g/h) (mmol/g) (mol percent) Propylene 21 g Isopropyl 15.0 g 0.5 5.0 110 Diisopropyl 2.49 29percent (0.5 mol) alcohol (0.25 mol) ether 0.40 Isobutene 28.1 g Ethanol 11.5 g 0.5 1.7 110 Ethyl t-butyl 2.18 38percent (0.5 mol) (0.25 mol) ether 878 With carbonized cellulose (degree of graphitization 0.63); sulfonated (C/S ratio 74.7), Time= 2h, T= 110 °C , p= 37503.8Torr , Product distribution / selectivity Patent; NIPPON OIL CORPORATION; TOKYO INSTITUTE OF TECHNOLOGY; US2009/99345; (2009); (A1) English View in Reaxys 1 :Etherification ReactionThe carbon-based solid acid E was subjected to etherification reaction by the same method as in Example 1. The reaction conditions and reaction results are shown in Table 4-2. The reduction rate of acid content in each reaction is large, compared with those of Examples, which shows that the heat resistance is low. TABLE 4-2 Amount of Acid content Reduction produced after rate of acid Amount of Amount of Alcohol/Olefin Pressure Temperature ether reaction content Olefin olefin Alcohol Alcohol (molar ratio) (MPa) (° C.) (mmol/cat-g/h) (mmol/g) (mol percent) Propylene 21 g Isopropyl 15.0 g 0.5 5.0 110 Diisopropyl 1.27 58percent (0.5 mol) alcohol (0.25 mol) ether 1.6 Isobutene 28.1 g Ethanol 11.5 g 0.5 1.7 110 Ethyl t-butyl 0.94 69percent (0.5 mol) (0.25 mol) ether 517 With carbonized glucose; sulfonated, Time= 2h, T= 110 °C , p= 37503.8Torr , Product distribution / selectivity Patent; NIPPON OIL CORPORATION; TOKYO INSTITUTE OF TECHNOLOGY; US2009/99345; (2009); (A1) English View in Reaxys

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3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethylthio)phenyl]-17α-(prop-1-ynyl)-Δ9 -estrene-5α,17β-diol

O O

11β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)Δ4,9 -estradiene-17α-ol-3-one

Rx-ID: 24882234 View in Reaxys 8/127 Yield

Conditions & References 43.C : STEP C: A mixture of 20.6 ml of 2N hydrochloric acid, 10.3 g of the product of Step B and 72 ml of methanol was stirred at 20° C. under an inert atmosphere for 25 minutes and was neutralized by addition of aqueous saturated sodium bicarbonate solution. 200 ml of diethyl oxide were added to the mixture and the decanted aqueous phase was extracted with diethyl oxide. The combined organic phases were washed with aqueous saturated sodium chloride solution, dried and evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 9-1 methylene chloride-methanol mixture yielded 3 g of 11β-[4-(N,N-dimethylaminoethylthio)phenyl]-17α-(prop-1-ynyl)-Δ4,9 -estradiene-17α-ol-3-one which after crystallization by empasting with diisopropyl oxide melted at 145° C. and had a specific rotation of [α]D 20 =+125°+-2° (c=1percent in chloroform). With hydrogenchloride, sodium hydrogencarbonate in methanol Patent; Roussel Uclaf; US4978657; (1990); (A1) English View in Reaxys

methyl (+)-threo-2-hydroxy-3-(2'-aminophenylthio)-3-(4"-methoxyphenyl)-propionate hydrochloride

Rx-ID: 24974272 View in Reaxys 9/127 Yield

Conditions & References 4 : Cis-(+)-2-(4'-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)one hydrochloride EXAMPLE 4 Cis-(+)-2-(4'-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride A mixture of 13.5 g (250 mmol) of sodium methoxide in 120 ml of dimethylformamide is formed under a slow nitrogen stream, and said mixture is then cooled to the temperature of -10° C. With the temperature being always kept at values lower than -5° C., 37.0 g (100 mmol) of methyl (+)-threo-2-hydroxy-3-(2'-aminophenylthio)-3-(4"-methoxyphenyl)-propionate hydrochloride is incrementally added to this mixture. A mixture of 26.0 g (180 mmol) of 2-chlorodimethylaminoethane hydrochloride, 50 ml of an aqueous solution of 15percent of sodium hydroxide and 40 ml of isopropyl ether is separately prepared. With sodium methylate in N-methyl-acetamide Patent; FIS--Fabbrica Italiana Sintetici S.p.A.; US5128468; (1992); (A1) English View in Reaxys O

2,3-dimethoxy-5-methyl-1,4-benzohydroquinone Rx-ID: 25129963 View in Reaxys 10/127 Yield

Conditions & References R.52 : REFERENCE EXAMPLE 52 REFERENCE EXAMPLE 52 In toluene (150 ml) was suspended 2,3-dimethoxy-5-methyl-1,4-benzohydroquinone (18.2 g, 0.1 mole), and to the suspension were added dihydrofuran (15 g, 0.204 mole) and camphorsulfonic acid (0.15 g), followed by stirring at room temperature for 1 hour. Without isolating the product, camphorsulfonic acid (2.2 g) was further added to the reaction solution, followed by stirring at 60° C. for 3 hours. The reaction solution was cooled, washed with water, dried (over MgSO4) and freed of the solvent by distillation. The residue was chromatographed on a column of silica gel, and developing with isopropyl ether yielded 2,3-dimethoxy-5-methyl-6-(tetrahydrofur-2-yl)-1, 4-benzyhydroquinone (20.8 g, 82percent, mp. 77° to 78° C.).

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With camphor-10-sulfonic acid in toluene Patent; Takeda Chemical Industries, Ltd.; US4393075; (1983); (A1) English View in Reaxys

O H 2N

N H

Rx-ID: 24209392 View in Reaxys 11/127 Yield

Conditions & References N-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)formamide N-(10-Methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)formamide 250 mg of 8-aminomethyl-10-methoxymethyl-10H-pyrazino-[2,3-b][1,4]benzothiazine was heated under reflux in 10 ml of ethyl formate for 3 hours. Then the reaction mixture was brought back to room temperature and distributed into an aqueous solution of ammonium chloride and ethyl acetate. The organic layer was extracted, washed with water and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were filtered after adding diisopropyl ether. Thus 230 mg of the title compound was obtained as yellow crystals. 1H-NMR(DMSO-d ) δ ppm: 3.37(s, 3H), 4.22(d, J=6.0 Hz, 2H), 5.22(s, 2H), 6.91(dd, J=1.4, 8.0 Hz, 1H), 7.03(d, 6 J=1.4 Hz, 1H), 7.07(d, J=8.0 Hz, 1H), 7.92(d, J=2.8 Hz, 1H), 7.96(d, J=2.8 Hz, 1H), 8.12(s, 1H), 8.51(br.t, J=6.0 Hz, 1H) With ammonium chloride in ethyl acetate, formic acid ethyl ester Patent; Eisai Co., Ltd.; US6518423; (2003); (B1) English View in Reaxys O

H N

Rx-ID: 24512116 View in Reaxys 12/127 Yield

Conditions & References 1 : STAGE B: Ethyl cyano-[(1-oxo-pentyl)-amino]-acetate. STAGE B: Ethyl cyano-[(1-oxo-pentyl)-amino]-acetate. 4.24 cm3 of pyridine, then over 30 minutes, 6.31 cm3 of pentanoyl chloride are added to a solution agitated at 0° C. of 6.71 g of the product obtained in Stage A above in 100 cm3 of methylene chloride, keeping the temperature below 6° C. The mixture is then evaporated to dryness under reduced pressure, the excess pyridine is entrained with toluene and the residue is taken up in 200 cm3 of methylene chloride, washed twice with water then evaporated again under vacuum. After impasting the residue obtained in isopropyl ether, 8.4 g of the desired product is collected. M.p.=88° C. With pyridine in dichloromethane Patent; Roussel-Uclaf; US5412101; (1995); (A1) English View in Reaxys

O O

N N

O NH 2

O O

NH 2

Rx-ID: 24516456 View in Reaxys 13/127

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Yield

Conditions & References W.13 : 13f 13g) Methyl 2,8-diethoxypurine-6-carboxylate A solution of the diamino compound obtained in Working Example 13f) (0.285 g), tetraethoxymethane (0.52 g) and acetic acid (0.09 g) in dioxane (3 ml) was stirred at 110° C. for 2.5 hours. The reaction mixture was concentrated to dryness. To the resulting residue was added isopropyl ether to give pale yellow prisms (0.328 g, 92percent), m.p. 100°-101° C. 1 H-NMR(200 MHz,CDCl ) δ: 1.44(3H,t), 1.51(3H,t), 4.04(3H,s), 4.50(2H,q), 4.75(2H,q), 9.40(1H,brs) IR(Nujol) cm-1: 3 3270, 1695, 1590 With acetic acid in 1,4-dioxane Patent; Takeda Chemical Industries, Ltd.; US5389641; (1995); (A1) English View in Reaxys

OH O–

Na +

H 2N

OH N

Rx-ID: 23991865 View in Reaxys 14/127 Yield

Conditions & References R.1 : 2-Amino-4-(3,5-di-t-butyl-4-hydroxyphenyl)thiazole Reference Example 1 2-Amino-4-(3,5-di-t-butyl-4-hydroxyphenyl)thiazole Thiourea (4.56 g) was added to a solution of 3,5-di-t-butyl-4-hydroxyphenacyl bromide (9.81 g) in acetone (50 ml). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the residue. The mixture was stirred and partitioned. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and then concentrated. The resulting residue was solidified by addition of IPE and hexane. The solid was filtered and dried to afford the title compound (8.92 g). 1H-NMR (400 MHz, DMSO-d , TMS): δ(ppm) 1.44 (9H, s), 6.71 (1H, s), 7.26 (1H, s), 6.96 (2H, s), 6.97 (1H, s), 7.52 6 (1H, s). With thiourea in ethyl acetate, acetone Patent; SANKYO COMPANY, LIMITED; US2003/134859; (2003); (A1) English View in Reaxys

N Z

O NH

N Z

O H N

O O

NH 2

O O O

Rx-ID: 25121390 View in Reaxys 15/127 Yield

Conditions & References 1 : (R and S)-1-Acetoxyethyl (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate EXAMPLE 1 (R and S)-1-Acetoxyethyl (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4carboxylate

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Potassium carbonate (760 mg, 5.5 mmole) was added to a solution of (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (4.57 g, 11 mmole) in N,N-dimethylformamide (25 ml) and the mixture was stirred at ca 20° for 25 minutes. 1-Bromoethyl acetate (1.8 g, 11 mmole) in N,N-dimethylformamide (5 ml) was added to the above solution and the reaction mixture was stirred for 40 minutes at ca 20°. The reaction mixture was worked up by pouring it into excess 2 N hydrochloric acid, followed by extraction with ethyl acetate (3 times). The combined organic extracts were washed with 2 N hydrochloric acid and saturated sodium bicarbonate solution, dried (magnesium sulphate) and evaporated in vacuo to yield a foam which was dissolved in ethyl acetate and precipitated from ether. The resulting precipitate was filtered off and dried to give the title compound (780 mg). The mother liquors were evaporated to a foam which was dissolved in ethyl acetate and precipitated from di-isopropyl ether to give a further crop of the title compound (1.21 g). This sample was dried in vacuo for 2 days at 22° in order to remove di-isopropyl ether. The physical constants of the second crop of the title compound are: mp (M50 2) 72°; [α]D +84° (c 0.87, DMSO); λmax (EtOH)277 nm (E1cm 1percent 355, ε18,120); microanalysis before drying in vacuo [Found; C, 46.6; H, 4.4; N. 10.95; S, 6.2; C20 H22 N4 O10 S (510.5) requires C, 47.1; H, 4.3; N, 10.9; S, 6.3percent]. The infrared and nmr spectra are shown in Table 1 hereinafter. With hydrogenchloride, potassium carbonate in ethyl acetate, N,N-dimethyl-formamide Patent; Glaxo Laboratories Limited; US4267320; (1981); (A1) English View in Reaxys

HO O

Rx-ID: 25208306 View in Reaxys 16/127 Yield

Conditions & References R.3.b : (b) 6-Acetoxy-2,2-dimethylhexanoic acid (4.5 g) was dissolved in 47percent aqueous hydrobromic acid (25 ml), and the solution was heated at 130° C. for 4 hours. After the completion of the reaction, water (100 ml) was added to the solution, and the product was extracted with ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, and development with isopropyl ether yielded 6-bromo-2,2-dimethylhexanoic acid (4 g, 91percent). in water, hydrogen bromide Patent; Takeda Chemical Industries, Ltd.; US4518602; (1985); (A1) English View in Reaxys R.3.b : b) 6-Acetoxy-2,2-dimethylhexanoic acid (4.5 g) was dissolved in 47percent aqueous hydrobromic acid (25 m), and the solution was heated at 130°C for 4 hours. After the completion of the reaction, water (100 m) was added to the solution, and the product was extracted with ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, and development with isopropyl ether yielded 6-bromo-2,-2-dimethylhexanoic acid (4 g, 91percent). in water, hydrogen bromide Patent; Takeda Chemical Industries, Ltd.; EP111997; (1991); (B1) English View in Reaxys O

Rx-ID: 9894851 View in Reaxys 17/127

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Yield

Conditions & References

95 % Spectr., 5 % Spectr.

With hydrogen, bis(1,5-cyclooctadiene)diiridium(I) dichloride, T= 22 °C , p= 2068.59Torr , Kinetics, Further Variations: Solvents, Reagents, proton sponge studies Oezkart, Saim; Finke, Richard G.; Journal of the American Chemical Society; vol. 127; nb. 13; (2005); p. 4800 4808 View in Reaxys With B(C6Cl5)(C6F5)2, hydrogen in tetrahydrofuran, Time= 3h, T= 65 °C , p= 3000.3Torr , Glovebox, Inert atmosphere, Reagent/catalyst, Pressure, Temperature Scott, Daniel J.; Fuchter, Matthew J.; Ashley, Andrew E.; Journal of the American Chemical Society; vol. 136; nb. 45; (2014); p. 15813 - 15816 View in Reaxys O

Rx-ID: 170585 View in Reaxys 18/127 Yield

Conditions & References With sulfuric acid, water, T= 110 °C Patent; Esso Research and Eng.Co.; US2825746; (1956) View in Reaxys With water, T= 150 °C , p= 51485.6Torr , in Gegenwart von Ionen-Austauschern Patent; Sinclair Refining Co.; US2803677 View in Reaxys Patent; Sinclair Refining Co.; US2845463; (1955) View in Reaxys With water, T= 150 °C , p= 29420.3Torr , in Gegenwart von Ionen-Austauschern Patent; Sinclair Refining Co.; US2803677 View in Reaxys Patent; Sinclair Refining Co.; US2845463; (1955) View in Reaxys

O O

O N

N O

HO HN

Rx-ID: 24978180 View in Reaxys 19/127 Yield

Conditions & References 28 : EXAMPLE 28 EXAMPLE 28 To a solution of 6-(3,4-dimethoxyphenyl)-1-(2,3-epoxypropyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (0.6 g) in ehtanol (20 ml) was added tert-butylamine (2 ml). The mixture was refluxed for 2.5 hours and evaporated in vacuo. The resulting syrup was triturated in a mixture of diethyl ether and diisopropyl ether to give 1-(3-tert-butylamino-2hydroxy-1-propyl)-6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)pyrimidinedione (0.66 g). mp: 123°-125° C. IR (Nujol): 1700, 1655 cm-1 NMR (CDCl3, δ): 6.93 (3H, br. s), 5.68 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 3.77 (2H, br. s), 3.7-4.0 (1H, m), 3.37 (3H, s), 2.1-2.8 (2H, m), 2.0 (2H, br. s), 1.00 (9H, s).

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in tert-butylamine Patent; Fujisawa Pharmaceutical Co., Ltd.; US4612376; (1986); (A1) English View in Reaxys OH

Rx-ID: 41760470 View in Reaxys 20/127 Yield

Conditions & References

88 %Spectr.

With hydrochlorid acid in water, Time= 0.25h, T= 120 °C , p= 5171.62Torr , Flow reactor Borukhova, Svetlana; Nol, Timothy; Hessel, Volker; ChemSusChem; vol. 9; nb. 1; (2016); p. 67 - 74 View in Reaxys

N N NH H 2N

OH S

H 2N

S OO

N N

NH 2 N

Rx-ID: 24501058 View in Reaxys 21/127 Yield

Conditions & References 106 : 7-n-Propyl-5-methyl-2-amino-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidine EXAMPLE 106 7-n-Propyl-5-methyl-2-amino-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidine Formula (XII): R1 =n-propyl, R2 =methyl, X=N, Y=C--NH2, X Y=double bond, STR180 10 g of 6-n-propyl-2-methyl-4-hydrazino-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 12, and 5 g of 2-methyl-2-thiopseudourea sulphate are heated to reflux for 16 hours. After the addition of water, the crystals formed are drained and washed with ether and then with ethyl acetate before taken up in dilute sodium hydroxide solution and extracted with chloroform. The organic phase is dried over magnesium sulphate and evaporated under vacuum, to give a residue which crystallises in a mixture of isopropyl ether and ethyl acetate to give 1.8 g of 7-n-propyl-5-methyl-2-amino-8-[(2 '-cyano-4biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidine in the form of crystals of melting point 150° C. in water Patent; Laboratoires UPSA; US5358950; (1994); (A1) English View in Reaxys

Rx-ID: 22955244 View in Reaxys 22/127 Yield

Conditions & References 6 :Example 6Conversion of Oxygenate Impurities in the Presence of Highly Unsaturated Olefin [00271] A feed comprising dimethyl ether, methyl acetylene, and propadiene was exposed to a commercial gas-phase methyl acetylene/ propadiene (MAPD) hydrogenation catalyst obtained from SCI of Louisville, Ky., USA. The catalyst was reduced under hydrogen at 232 C. (450 F.) and 360 GHSV and then cooled to reaction temperature under helium flow. Hydrocarbon was fed to the reactor at a rate of 3.2 WHSV with respect to total catalyst weight (960 GHSV, with respect to total catalyst volume). The feed consisted of 84.13 mol percent propylene, 9.56 mol percent propane, 2.63 mol percent methyl acetylene, 3.68 mol percent propadiene and 183 ppm dimethyl ether. Hydrogen was co-fed to attain varying H2/MAPD (hydrogen to methyl acetylene and propadiene) molar ratios. [00272] TABLE 2 shows a typical hydrocarbon product distribution at 209 C. and approximately 310 psig. Under these conditions, MAPD conversion was about 87 mol percent. In addition, a DME conversion of about 50 mol percent was attained. [00273] Major oxy-

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genate products included acetone and methyl isopropyl ether, which could be easily separated from light olefins in a depropanizer distillation column. TABLE 3 shows a product distribution from the converted DME. [TABLE-US-00002] TABLE 2 Reaction Conditions and Product Distribution from MAPD Conversion WRSV (h-1) 3.2 Temperature ( C.) 209 Pressure kPaa (psig) 2240 (309.6) H2/MAPD (mol) 1.10 FEED (mol percent except as noted) C3 = 84.13 C3 9.56 Methyl Acetylene 2.63 Propadiene 3.68 DME (ppm) 183 PRODUCT C1 0.00 C2 = 0.05 C2 0.01 C3 11.26 Methyl Acetylene 0.26 Propadiene 0.56 iC4 and nC4 0.03 C4 = 0.03 C4 == 0.04 C5s 0.02 C6s 0.26 Benzene 0.00 C6s + 0.08 DME (ppm) 93 Estimated Oxygenates (ppm) 90 [TABLE-US-00003] TABLE 3 Distribution of Oxygenated Products Oxygenate Product Selectivity (mol percent) Methyl Isopropyl Ether 56.7 Acetone 27.7 Isopropanol 7.1 Methanol 5.4 Diisopropyl Ether 3.2 With hydrogen, hydrogenation catalyst from SCI of Louisville, Ky., USA, T= 209 °C , p= 16801.7Torr Patent; ExxonMobil Chemical Patents Inc; US6717025; (2004); (B1) English View in Reaxys O

Rx-ID: 3517252 View in Reaxys 23/127 Yield

Conditions & References With Titanium(IV) oxide, T= 209.9 - 245.9 °C , Mechanism Rochester, Colin H.; Graham, John; Rudham, Robert; Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases; vol. 80; (1984); p. 2459 - 2466 View in Reaxys With oxygen, vanadium pentoxide, T= 100 - 200 °C , p= 50Torr , variation of pressure, rate of O2; poisoned by pyridine, Kinetics, Mechanism Dupin, Thierry; Germain, Jean-Eugene; Bulletin de la Societe Chimique de France; vol. 1; nb. 7-8; (1980); p. 260 268 View in Reaxys With oxygen, mixed oxide V-Mo-O, T= 100 - 200 °C , p= 50Torr , variation of composition of the catalyst; by adsorption of pyridine or acetic acid; activation energy investigated, Kinetics, Mechanism, Thermodynamic data Dupin, Thierry; Germain, Jean-Eugene; Bulletin de la Societe Chimique de France; vol. 1; nb. 7-8; (1980); p. 269 274 View in Reaxys With Cs2HPW12O40, T= 50 °C , p= 760Torr , ΔH, other catalysts (activity); other temps., Mechanism, Product distribution, Thermodynamic data Anwar, A.; Abdel-Ghaffar, A. A.; Journal de Chimie Physique et de Physico-Chimie Biologique; vol. 89; nb. 3; (1992); p. 681 - 694 View in Reaxys With 12-molybdophosphoric acid HPMo in gas, Time= 0.0833333h, T= 300 °C , other Ni- and Co-12-molybdophosphates; selectivity, Product distribution Ebeid, F. M.; Ali, L. I.; Ali, A. G. A.; Bulletin de la Societe Chimique de France; nb. 5; (1991); p. 644 - 647 View in Reaxys With air, vanadium pentoxide, Titanium(IV) oxide, Time= 0.000277778h, T= 170 °C , also var. alkali metal cations promoted V2O5/TiO2 catalysts, Product distribution Grabowski, R.; Grzybowska, B.; Wcislo, K.; Polish Journal of Chemistry; vol. 68; nb. 9; (1994); p. 1803 - 1812 View in Reaxys With vanadium phosphate in gas, T= 140 °C , effect of the catalyst dopant (zirconium or chromium), Product distribution Batis, N.Harrouch; Ghorbel; Journal de Chimie Physique et de Physico-Chimie Biologique; vol. 94; nb. 1; (1997); p. 77 - 92 View in Reaxys

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With ammonium heptamolybdate, Titanium(IV) oxide, T= 169.9 °C , with different catalyst and temp., Product distribution Martin, Cristina; Martin, Ines; Rives, Vicente; Grzybowska, Barbara; Gressel, Irena; Spectrochimica Acta - Part A Molecular Spectroscopy; vol. 52; nb. 7 PART A; (1996); p. 733 - 740 View in Reaxys With Cs3PW12O40, Time= 2h, T= 120 °C , effect of other cations of the catalyst, Product distribution Chelighem; Launay; Essayem; Coudurier; Fournier; Journal de Chimie Physique et de Physico-Chimie Biologique; vol. 94; nb. 11-12; (1997); p. 1831 - 1837 View in Reaxys With Ni 12-molybdophosphate NiPMo in gas, Time= 0.0833333h, T= 300 °C , Title compound not separated from byproducts Ebeid, F. M.; Ali, L. I.; Ali, A. G. A.; Bulletin de la Societe Chimique de France; nb. 5; (1991); p. 644 - 647 View in Reaxys With 12-molybdophosphoric acid HPMo in gas, Time= 0.0833333h, T= 300 °C , Title compound not separated from byproducts Ebeid, F. M.; Ali, L. I.; Ali, A. G. A.; Bulletin de la Societe Chimique de France; nb. 5; (1991); p. 644 - 647 View in Reaxys With Co 12-molybdophosphate CoPMo in gas, Time= 0.0833333h, T= 300 °C , Title compound not separated from byproducts Ebeid, F. M.; Ali, L. I.; Ali, A. G. A.; Bulletin de la Societe Chimique de France; nb. 5; (1991); p. 644 - 647 View in Reaxys With monoaluminum phosphate, T= 299.9 °C , Title compound not separated from byproducts Campelo, J. M.; Garcia, A.; Herencia, J. F.; Luna, D.; Marinas, J. M.; Romero, A. A.; Journal of Catalysis; vol. 151; nb. 2; (1995); p. 307 - 314 View in Reaxys With oxygen, Cs2.8H1.2PMo11FeO39, Time= 2h, T= 179.85 °C Min, Joon-Seok; Misono, Makoto; Taguchi, Akira; Mizuno, Noritaka; Chemistry Letters; nb. 1; (2001); p. 28 - 29 View in Reaxys With air, K-doped V2O5, Titanium(IV) oxide, Product distribution, Further Variations: Catalysts, Temperatures Grzybowska; Gressel; Samson; Wcislo; Stoch; Mikolajczyk; Dautzenberg; Polish Journal of Chemistry; vol. 75; nb. 10; (2001); p. 1513 - 1519 View in Reaxys With WC750-H2, T= 150 °C , Product distribution, Further Variations: Catalysts, Temperatures Granger; Giraudon; Delannoy; Leclercq; Journal of Catalysis; vol. 206; nb. 2; (2002); p. 358 - 362 View in Reaxys With CrAPO-5, T= 279.85 °C , Product distribution, Further Variations: Catalysts Zadrozna, Gabriela; Souvage, Emmanuelle; Kornatowski, Jan; Journal of Catalysis; vol. 208; nb. 2; (2002); p. 270 - 275 View in Reaxys With hydrogen, molybdenum(VI) oxide, palladium dichloride, T= 124.85 °C , Kinetics, Product distribution, Further Variations: Catalysts Matsuda, Takeshi; Uozumi, Shuhei; Takahashi, Nobuo; Physical Chemistry Chemical Physics; vol. 6; nb. 3; (2004); p. 665 - 672 View in Reaxys

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With H2-reduced MoO3, Time= 6h, T= 124.84 °C , Dehydration, dehydrogenation, Product distribution, Further Variations: Reagents Uchijima, Fumiko; Takagi, Tomoaki; Itoh, Hidenobu; Matsuda, Takeshi; Takahashi, Nobuo; Physical Chemistry Chemical Physics; vol. 2; nb. 5; (2000); p. 1077 - 1083 View in Reaxys With V-Ag-O complex oxide, T= 179.84 °C , Flow reactor Xue, Mingwei; Chen, Hui; Zhang, Huiliang; Auroux, Aline; Shen, Jianyi; Applied Catalysis A: General; vol. 379; nb. 1-2; (2010); p. 7 - 14 View in Reaxys With 3-[2-(2-aminoethylamino)ethylamino]propyl-trimethoxysilane linked to aluminosilicate AlMCM-41 mesoporous molecular sieve, T= 149.84 °C , Inert atmosphere Blasco-Jimenez, Davinia; Sobczak, Izabela; Ziolek, Maria; Lopez-Peinado, Antonio J.; Martin-Aranda, Rosa M.; Catalysis Today; vol. 152; nb. 1-4; (2010); p. 119 - 125 View in Reaxys With aluminum oxide, T= 226.84 °C , Inert atmosphere, Kinetics, Reagent/catalyst, Temperature Turek, Wincenty; Krowiak, Agnieszka; Applied Catalysis A: General; vol. 417-418; (2012); p. 102 - 110 View in Reaxys With SbVO5-T-Nb2O5 Mixture, T= 249.84 °C Ziolek, Maria; Golinska-Mazwa, Hanna; Filipek, Elzbieta; Piz, Mateusz; Catalysis Today; vol. 187; nb. 1; (2012); p. 159 - 167 View in Reaxys , T= 115 °C , Inert atmosphere Hernandez-Cortez; Manriquez, Ma.; Lartundo-Rojas; Lopez-Salinas; Catalysis Today; vol. 220-222; (2014); p. 32 - 38 View in Reaxys With 3 wtpercent of chromium on MCM-41 mesoporous solid [3Cr(n)MCM-41], T= 299.84 °C , Inert atmosphere, Flow reactor, Reagent/catalyst Trejda, MacIej; Brys, Malgorzata; Ziolek, Maria; RSC Advances; vol. 4; nb. 108; (2014); p. 62940 - 62946 View in Reaxys Rx-ID: 29106951 View in Reaxys 24/127 Yield

Conditions & References With zeolite ZSM-5, Time= 425h, T= 400 °C , p= 15201Torr , Fixed bed reactor Mentzel, Uffe V.; Shunmugavel, Saravanamurugan; Hruby, Sarah L.; Christensen, Claus H.; Holm, Martin S.; Journal of the American Chemical Society; vol. 131; nb. 46; (2009); p. 17009 - 17013 View in Reaxys H O+

Rx-ID: 3031134 View in Reaxys 25/127 Yield

Conditions & References With acetophenone in gas, T= 64.9 °C , Gibbs energy ΔGB, Thermodynamic data Decouzon, Michele; Ertl, Peter; Exner, Otto; Gal, Jean-Francois; Maria, Pierre-Charles; Journal of the American Chemical Society; vol. 115; nb. 25; (1993); p. 12071 - 12078 View in Reaxys

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O O

OH C

Rx-ID: 25905649 View in Reaxys 26/127 Yield

Conditions & References 6; 7 :Example 6Reaction Kinetics MeasurementsThe apparatus used to conduct reaction kinetics measurements for Pt-Re/C is described elsewhere (37). Fresh catalyst was loaded into a 1/2-inch outer diameter tubular stainless steel reactor. The catalyst bed was contained between an end plug of quartz wool (Alltech) and fused SiO2 granules (-4+16 mesh; Sigma-Aldrich) which aid in vaporization of the liquid feed. The Pt-Re/C catalyst powder was mixed with equal volumes of crushed SiO2 granules to decrease the pressure drop across the catalyst bed. For combined glycerol conversion with Fischer-Tropsch synthesis experiments, a bed of 1.0 wt percent Ru/TiO2 was loaded downstream of the Pt-Re/C bed. Type-K thermocouples (Omega) were attached to the outside of the reactor to measure reactor temperature, which was controlled with a series 16A type temperature controller (Dwyer Instruments). Fresh catalyst was reduced in flowing H2, as described in the previous section. Mass-flow controllers (5850 Brooks Instruments) were used to control the flow rate of H2. An HPLC pump (Model 301, Alltech) was used to introduce the aqueous feed solution into a 6-inch needle with a point 5 style tip (Hamilton) soldered into a section of -inch stainless steel tubing. This needle introduces liquid feed solutions into the reactor. The liquid effluent from the reactor was water-cooled in a double-pipe heat exchanger and was drained periodically for gas chromatography (GC) analysis (Agilent 6890 with a flame ionization detector (FID) and HP-Innowax column or Shimadzu GC-2010 with an FID detector and Rtx-5 column) and total organic carbon analysis (Shimadzu TOC-V CSH). Each effluent was tested for the presence of glycerol and other liquid byproducts.The effluent gas stream passed through a back-pressure regulator (GO Regulator, Model BP-60) which controlled the system pressure. The effluent gas was analyzed with gas chromatography: H2 with a Carle GC (series 8700) using a thermal conductivity detector (TCD), CO and CH4 using an HP 5890 GC with TCD and washed molecular sieve 5A 80/100 column (Alltech), and CO2 and light alkanes (C2-C3) using an HP 5890 GC with TCD and a Porapak QS 100/120 column (Alltech). All feed solutions were prepared by mixing glycerol (99.5percent, ACS reagent, Sigma-Aldrich) with deionized water. The apparatus used to conduct FischerTropsch synthesis experiments is similar to that used for reaction kinetics measurements of Pt-Re/C, except the outlet lines from the reactor were heated at 373 K. The 2.9 wt percent Ru/TiO2 catalyst was mixed with an equal volume of crushed SiO2 granules to help dissipate the heat generated by the exothermic Fischer-Tropsch reaction and loaded into a 1/2-inch outer diameter, stainless steel tubular reactor. The liquid phase products were collected in a gasliquid separator and analyzed by GC (Shimadzu GC-2010 with an FID detector and Rtx-5 column). The effluent gas stream was analyzed for C1-C10 hydrocarbons with a Varian GC-MS (Saturn 3) using an FID detector and GS-Q capillary column. CO and CO2 were analyzed with an HP 5890 GC with TCD and a Porapak QS 100/120 column (Alltech). Ultra-high purity CO and H2 (Linde) were used, and aqueous solutions of acetone, acetol, and ethanol were introduced into the reactor in a similar way as the above glycerol solutions.Example 7Carbon Distributions(a) Conversion of Glycerol Over Pt-Re/C:FIG. 6 shows the conversion to gas-phase products and the CO/CO2 and H2/CO molar ratios, and Table 10 shows the outlet carbon distribution for conversion of a 30 wt percent glycerol solution over 520 mg of 10 wt percent Pt-Re/C (atomic ratio 1:1). The total inlet flow rate of carbon (as glycerol) for this experiment was 833 μmol min-1 (feed flow rate of 0.08 cm3 min-1), and the total conversion of glycerol was 91percent (58percent to gas phase products and 33percent to liquid phase products).Tables 11-13 show the outlet carbon distributions and carbon balances for conversion of 50 and 80 wt percent glycerol solutions over 1.0 g of 10 wt percent Pt-Re/C (atomic ratio 1:1) at 548 K and total pressures between 1-11 bar. The inlet liquid flow rate was 0.04 cm3 min-1 for the 50 wt percent solution and 0.03 cm3 min-1 for the 80 wt percent solution. The total conversion of glycerol was 100percent for each condition.(b) Fischer-Tropsch Synthesis Over Ru/TiO2 Tables 14 and 15 show the carbon distributions and carbon balances for Fischer-Tropsch synthesis of 150 cm3 min-1 of an H2/CO mixture with H2:CO=2 along with co-feeds of water and aqueous solutions of oxygenated molecules at 548 K over 4 g of 2.9 wt percent Ru/TiO2. Conversion of acetol co-feed to products was 100percent, whereas less than 20percent of ethanol formed products and less than 10percent of acetone formed products.(c) Combined Glycerol Conversion and FischerTropsch Synthesis:Tables 16-18 give the carbon product distribution for conversion of an 80 wt percent glycerol solution via conversion to synthesis gas with subsequent Fischer-Tropsch synthesis in a two-bed reactor at 548 K and 5 bar. FIG. 7 shows the molecular weight distribution for these experiments. This distribution deviates from AndersonSchulz-Flory kinetics. A glycerol feed flow rate of 0.04 cm3 min-1 was used with 1.0 g of 10 wt percent Pt-Re (1:1)/C and 1.7-3.0 g 1.0 wt percent Ru/TiO2.The sum of the species in the carbon distribution tables (Tables 10-12, 14, and 16-18) may differ slightly from the total COut values in the carbon balance tables (Tables 13 and 15). This difference results from the omission of minor product species from the carbon distribution tables.

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With water, 5.1Pt-4.9Re/C, 1Ru/TiO2, T= 274.84 °C , p= 3750.38Torr , Product distribution / selectivity Patent; Cortright, Randy D.; Dumesic, James A.; US2007/225383; (2007); (A1) English View in Reaxys H N

NH 2

Rx-ID: 32907722 View in Reaxys 27/127 Yield

Conditions & References

Ca. 79 With ammonia, hydrogen, Time= 0.0833333h, T= 190 °C , p= 760.051Torr , In nitrogen flow %Chromat. Cho, Jun Hee; Park, Jung Hyun; Chang, Tae-Sun; Seo, Gon; Shin, Chae-Ho; Applied Catalysis A: General; vol. 417-418; (2012); p. 313 - 319 View in Reaxys O

Rx-ID: 1846718 View in Reaxys 28/127 Yield

Conditions & References With water, ferrierite zeolite in gas, T= 150 °C , p= 3677.5Torr , other pressure, other temp., other catalyst, Product distribution Eguchi, Koichi; Tokiai, Takeo; Kimura, Yoshio; Arai, Hiromichi; Chemistry Letters; (1986); p. 567 - 570 View in Reaxys

Rx-ID: 9674327 View in Reaxys 29/127 Yield

Conditions & References

75.6 %, 5.4 %, 1.5 %, 8.2 %

With hydrogen, Pd on nickel-silica composite hollow nanospheres, T= 199.85 °C , Product distribution, Further Variations: Catalysts Jin, Pu; Chen, Qianwang; Hao, Liqing; Tian, Ruifen; Zhang, Lixin; Wang, Lin; Journal of Physical Chemistry B; vol. 108; nb. 20; (2004); p. 6311 - 6314 View in Reaxys

O Cl HN

Cl HN

Rx-ID: 24589181 View in Reaxys 30/127 Yield

Conditions & References 34.a : 3-[1-(3,4-Dichlorophenyl)-3-(4-(2-oxoperhydropyrimidine-1-yl)piperidino)propyl]-7-isopropoxy-2-methyl-2,3-dihydroisoindol-1-one hydrochloride a. 3-[1-(3,4-Dichlorophenyl)but-3-enyl]-7-isopropoxy-3-methyl-2,3-dihydroisoindol-1-one. 3-[1-(3,4-dichlorophenyl)but-3-enyl]-7-hydroxy-3-methyl-2,3-dihydroisoindol-1-one (0.3 g), prepared as described in Example 31, was treated as described in Example 42 sub-part a. to afford the crude product. Chromatography, with hexane:isopropanol (2:1) gave the isopropyl ether (0.225 g): MS: m/z=404; NMR: 1.34 (m,6), 2.7 (t, J=7.8, 2) 3.04 (s,3), 3.37 (m,1), 4.6 (m,2), 5.09 (m,2), 5.71 (m,1), 7.01 (m,6) Patent; Zeneca Limited; US5589489; (1996); (A1) English View in Reaxys

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Rx-ID: 2865736 View in Reaxys 31/127 Yield

Conditions & References With ammonia, Irradiation, in the gas phase Hall, David G.; Gupta, Chakra; Morton, Thomas Hellman; Journal of the American Chemical Society; vol. 103; nb. 9; (1981); p. 2416 - 2417 View in Reaxys I

Rx-ID: 3528317 View in Reaxys 32/127 Yield

Conditions & References With diiodo monosilane in chloroform-d1, Time= 0.166667h, Ambient temperature, other reaction time: 80 min, effect of iodine, Yield given. Further byproducts given. Yields of byproduct given. Title compound not separated from byproducts Keinan, E.; Perez, D.; Sahai, M.; Shvily, R.; Journal of Organic Chemistry; vol. 55; nb. 9; (1990); p. 2927 - 2938 View in Reaxys

OH C

Rx-ID: 3516328 View in Reaxys 33/127 Yield

Conditions & References

22 %, 12 %, 9 %

With hydrogen, CoRh, iodine, Time= 2h, T= 200 °C , p= 315025Torr , other promoter, other pressure, Product distribution Jenner, Gerard; Journal of Organometallic Chemistry; vol. 346; (1988); p. 237 - 252 View in Reaxys

Rx-ID: 26441775 View in Reaxys 34/127 Yield

Conditions & References above 50°C irreversible, below 50°C reversible reaction Brown, H. C.; Adams, R. M.; Journal of the American Chemical Society; vol. 64; (1942); p. 2557 - 2563 ; (from Gmelin) View in Reaxys above 50°C irreversible, below 50°C reversible reaction vol. B: SVol.1; 4.4.4, page 177 - 187 ; (from Gmelin) View in Reaxys

Rx-ID: 25596672 View in Reaxys 35/127 Yield

Conditions & References 11 :The method of Example 10 was repeated using pentan-1-ol instead of isopropanol After 4 hours, 19. Ig of isomeric pentenes, corresponding to a yield of 55percent, were collected. Very little diisopropyl ether (b p = 68 deg. C)

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was observed by NMR. The pentene isomers were present in the following amounts: pent-1-ene 9 cw-pent-2-ene 26 troeroe-pent-2-ene 51 2-methylbut-l-ene 33-methylbut-l-ene 02-methylbut-2-ene 9 With CF3O3S(1-)*CHF3O3S*C7H13N2O3S(1+), Time= 4h, T= 240 - 260 °C , Product distribution / selectivity Patent; BP p.l.c.; WO2007/12825; (2007); (A1) English View in Reaxys

P O

Rx-ID: 2974946 View in Reaxys 36/127 Yield

Conditions & References Ambient temperature Grochowski, Edward; Hilton, Bruce D.; Kupper, Robert J.; Michejda, Christopher J.; Journal of the American Chemical Society; vol. 104; nb. 24; (1982); p. 6876 - 6877 View in Reaxys O–

12 4

O–

6 Nd 3+

5 O2-

Nd 3+

Rx-ID: 26645664 View in Reaxys 37/127 Yield

Conditions & References

80 %

drying (vac., room temp., 48 h); elem. anal. Poncelet, Olivier; Hubert-Pfalzgraf, Liliane G.; Polyhedron; vol. 8; (1989); p. 2183 - 2188 ; (from Gmelin) View in Reaxys

O O

(v4)

O2Ti

Rx-ID: 26177440 View in Reaxys 38/127 Yield 11 %, 87 %, 2 %

Conditions & References in gas, byproducts: CH3CHCH2; decomposition at a pressure of ca. 0.01 mm of Hg at 550°C; further compound: H2 was obtained with a yield of <0.5percent; org. compounds collected in a liquid-N2 trap; NMR; GC; mass spectra Nandi, Manish; Rhubright, Doug; Sen, Ayusman; Inorganic Chemistry; vol. 29; (1990); p. 3065 - 3066 ; (from Gmelin) View in Reaxys OH

Rx-ID: 33545050 View in Reaxys 39/127 Yield

Conditions & References With MCM-41, T= 300 °C , Gas phase, Friedel Crafts alkylation Selvakumar; Stanly; Arabindoo, Banumathi; Asian Journal of Chemistry; vol. 22; nb. 7; (2010); p. 5313 - 5322 View in Reaxys

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O O

Rx-ID: 28781271 View in Reaxys 40/127 Yield

Conditions & References

80 %Spectr., 16 %Spectr.

With [Cp*IrCl2(C(NBuCHCHNBu))], silver trifluoromethanesulfonate, Time= 12h, T= 110 °C Prades, Amparo; Corberan, Rosa; Poyatos, Macarena; Peris, Eduardo; Chemistry - A European Journal; vol. 14; nb. 36; (2008); p. 11474 - 11479 View in Reaxys

Rx-ID: 58210 View in Reaxys 41/127 Yield

Conditions & References With silver(l) oxide Erlenmeyer; Justus Liebigs Annalen der Chemie; vol. 126; (1863); p. 305; Justus Liebigs Annalen der Chemie; vol. 139; (1866); p. 211 View in Reaxys Glass; Hinshelwood; Journal of the Chemical Society; (1929); p. 1817 View in Reaxys

Rx-ID: 8832057 View in Reaxys 42/127 Yield

Conditions & References T= 4 °C , Irradiation Likhotvorik, Igor R.; Tippmann, Eric; Platz, Matthew S.; Tetrahedron Letters; vol. 42; nb. 17; (2001); p. 3049 3051 View in Reaxys

OH HO

S OO

Rx-ID: 7062088 View in Reaxys 43/127 Yield

Conditions & References Waermetoenung der Reaktion Nasarow; Oblap; Juntsson; ; (1944); p. 4503; Chem. Zentralbl.; vol. 114; nb. II; (1943); p. 613 View in Reaxys T= 286 °C , p= 154457Torr , laesst sich bereits 1.4prozentige H2SO4 fuer die Hydratation anwenden Patent; N.V.de Bataafsche Petr.Mij.; DE681268; (1935); View in Reaxys bevorzugte Bildung von Diisopropylaether Patent; Shell Devel Co.; US2178186; (1937) View in Reaxys Patent; Standard Alcohol Co.; FR793482 View in Reaxys Patent; Standard Alcohol Co.; FR821485 View in Reaxys Patent; Standard Alcohol Co.; US2105508; (1934) View in Reaxys

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Patent; Standard Alcohol Co.; US2109004; (1936) View in Reaxys Patent; Standard Alcohol Co.; US2160854; (1936) View in Reaxys Patent; Standard Alcohol Co.; FR818142 View in Reaxys Reaktiongeschwindigkeiten und Gleichgewichte bei verschiedenen Konzentrationen, Temperaturen und Drucken und folgende Hydrolyse Gutyrja; Buinitzkaja; Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation); vol. 10; (1937); p. 882; Chem. Zentralbl.; vol. 109; nb. I; (1938); p. 3326 View in Reaxys Katuno; ; vol. 43; p. 9,68; ; (1940); p. 5821,6929 View in Reaxys Shiffler; Holm; Brooke; Industrial and Engineering Chemistry; vol. 31; (1939); p. 1101 View in Reaxys Remis; Frost; Zhurnal Obshchei Khimii; vol. 7; p. 67; Chem. Zentralbl.; vol. 108; nb. II; (1937); p. 4026 View in Reaxys Joffe; Morosowskaja; Zhurnal Fizicheskoi Khimii; vol. 21; p. 545; ; (1947); p. 6798 View in Reaxys Ratman; Zhurnal Obshchei Khimii; vol. 7; p. 14; Chem. Zentralbl.; vol. 108; nb. II; (1937); p. 2511 View in Reaxys Markowitsch; Moor; ; vol. 19; (1930); p. 604; Chem. Zentralbl.; 1931I 2454,1932I 322 View in Reaxys Davis; Crandall; Journal of the American Chemical Society; vol. 52; (1930); p. 3774,3782 View in Reaxys Davis; Schuler; Journal of the American Chemical Society; vol. 52; (1930); p. 727 View in Reaxys O

Rx-ID: 3517204 View in Reaxys 44/127 Yield

Conditions & References With P(H2), palladium, T= 80 °C , Pd/H3PO4/Pd, effects of current, pressure of H2, Product distribution, Mechanism Otsuka, Kiyoshi; Yamanaka, Ichiro; Chemistry Letters; (1987); p. 1945 - 1948 View in Reaxys H O+

O+ H

Rx-ID: 1912351 View in Reaxys 45/127 Yield

Conditions & References T= 335 °C , -ΔGo, Thermodynamic data Meot-Ner (Mautner), Michael; Journal of the American Chemical Society; vol. 104; nb. 1; (1982); p. 5 - 10 View in Reaxys O

Rx-ID: 2616074 View in Reaxys 46/127 Yield

Conditions & References in cyclohexane, T= 20 °C , Equilibrium constant Bellon, Louis; Taft, Robert W.; Abboud, Jose-Luis M.; Journal of Organic Chemistry; vol. 45; nb. 6; (1980); p. 1166 - 1168 View in Reaxys

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H O+

+HO

Rx-ID: 3390392 View in Reaxys 47/127 Yield

Conditions & References T= 24.9 °C , ΔG0, Thermodynamic data Bromilow, J.; Abboud, J. L. M.; Lebrilla, C. B.; Taft, R. W.; Scorrano, G.; Lucchini V.; Journal of the American Chemical Society; vol. 103; nb. 18; (1981); p. 5448 - 5453 View in Reaxys H O+

O C+ O

Rx-ID: 3390396 View in Reaxys 48/127 Yield

Rx-ID: 3517253 View in Reaxys 49/127 Yield

Conditions & References With hydrogen, NiOs3(η-C5H5)(μ-H)2(Cu(PPh3))(CO)9, T= 230 °C , other temp., Product distribution Castagno, Fabrizio; Castiglioni, Mario; Sappa, Enrico; Tiripicchio, Antonio; Camellini, Marisa Tiripicchio; et al.; Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999); (1989); p. 1477 - 1482 View in Reaxys

S OO

S O

Rx-ID: 7062092 View in Reaxys 50/127 Yield

Conditions & References T= 20 - 80 °C , p= 1471.02 - 5884.06Torr , Geschwindigkeit der Reaktion verschiedener Konzentration Schultze et al.; ; vol. 8; (1955); p. 402,404 View in Reaxys T= 42 - 90 °C , Geschwindigkeit der Reaktion verschiedener Konzentration Entelis et al.; Doklady Akademii Nauk SSSR; vol. 114; (1957); p. 848; Doklady Physical Chemistry; 112-117<1957>389 View in Reaxys T= 20 - 70 °C , Geschwindigkeit der Reaktion verschiedener Konzentration Lumbroso et al.; ; (1958); p. Bd.1,S.624,626 View in Reaxys T= 70 °C , Geschwindigkeit der Reaktion verschiedener Konzentration Korowina et al.; Doklady Akademii Nauk SSSR; vol. 121; (1958); p. 1038; Doklady Physical Chemistry; 118-123<1958>597 View in Reaxys

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O OH

Rx-ID: 4532684 View in Reaxys 51/127 Yield

Conditions & References With phosphorus pentoxide, 1.) 70 deg C, 10 h, 2.) from 120 deg C to 190 deg C, 4 h, Yield given. Multistep reaction. Yields of byproduct given Munik, S. N.; Eliseenkov, V. N.; Ivanov, B. E.; Russian Journal of General Chemistry; vol. 65; nb. 3.1; (1995); p. 378 - 382; Zhurnal Obshchei Khimii; vol. 65; nb. 3; (1995); p. 431 - 435 View in Reaxys O

OH HO

S OO

Rx-ID: 5804016 View in Reaxys 52/127 Yield

Conditions & References T= 100 °C , p= 15445.7Torr Patent; Standard Alcohol Co.; FR821485 View in Reaxys Patent; Standard Alcohol Co.; US2131030; (1936) View in Reaxys Patent; Standard Alcohol Co.; US2216931; (1938) View in Reaxys Patent; Socony-Vacuum Oil Co.; US2077042; (1934) View in Reaxys

Rx-ID: 5804022 View in Reaxys 53/127 Yield

Conditions & References T= 40 - 180 °C , Produkt5: Diisopropylsulfit Bissinger; Kung; Journal of the American Chemical Society; vol. 69; (1947); p. 2162 Anm.17 View in Reaxys F

O O

Cl F

Rx-ID: 26681367 View in Reaxys 54/127 Yield

Conditions & References 100°C for 15 min, excess of alcohol Connet, J. E.; Chemistry and Industry (London, United Kingdom); (1965); p. 1695 - 1696 ; (from Gmelin) View in Reaxys 100°C for 15 min, excess of alcohol vol. F: PerFHalOrg.2; 1.3.4, page 137 - 166 ; (from Gmelin) View in Reaxys Cl

Cl O

Rx-ID: 4966210 View in Reaxys 55/127

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Yield

Conditions & References in cyclohexane, T= 24.9 °C , Equilibrium constant Abraham, Michael H.; Prior, David V.; Schulz, Ronald A.; Morris, Jeffrey J.; Taylor, Peter J.; Journal of the Chemical Society - Faraday Transactions; vol. 94; nb. 7; (1998); p. 879 - 885 View in Reaxys Cl

Cl O

2 Cl

Rx-ID: 4966323 View in Reaxys 56/127 Yield

water Rx-ID: 6221069 View in Reaxys 57/127 Yield

Conditions & References With H3[PW12O40], Time= 0.000369444h, T= 109.9 - 149.9 °C , Product distribution Viswanathan, B.; Omana, M. J.; Varadarajan, T. K.; Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical and Analytical; vol. 27; nb. 8; (1988); p. 674 - 676 View in Reaxys O

Rx-ID: 10226056 View in Reaxys 58/127 Yield

Conditions & References With vanadium pentoxide, T= 200 °C , Product distribution, Further Variations: Catalysts Klisinska; Gressel; Grzybowska; Mikolajczyk; Stoch; Polish Journal of Chemistry; vol. 80; nb. 5; (2006); p. 825 833 View in Reaxys O

Rx-ID: 40788869 View in Reaxys 59/127 Yield

Conditions & References With hydrogen, Time= 6h, T= 174.84 °C , Catalytic behavior, Overall yield = 61.9 percent Witsuthammakul, Ayut; Sooknoi, Tawan; Catalysis Science and Technology; vol. 5; nb. 7; (2015); p. 3639 - 3648 View in Reaxys O

H2O Rx-ID: 8515758 View in Reaxys 60/127

Yield

Conditions & References With copper aluminum spinel, T= 319.85 °C , var. substituted copper aluminate catalysts; var. temp., Product distribution Gupta, M. Dutta; Rao, E. Nageswara; Ghose; Journal of the Indian Chemical Society; vol. 74; nb. 4; (1997); p. 302 - 305

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View in Reaxys O

Rx-ID: 8832032 View in Reaxys 61/127 Yield

Conditions & References With Na2O, aluminum oxide, T= 280 °C , Product distribution, Further Variations: different persentage compositions of reactans Jain; Journal of the Indian Chemical Society; vol. 77; nb. 7; (2000); p. 355 - 357 View in Reaxys O

Fuller's earth Rx-ID: 5804018 View in Reaxys 62/127 Yield

Conditions & References T= 160 - 170 °C Nekrassow; Krentzel; Zhurnal Obshchei Khimii; vol. 19; (1949); p. 948; ; (1950); p. 1006 View in Reaxys

O O

Rx-ID: 844782 View in Reaxys 63/127 Yield

Conditions & References T= 251 °C , Produkt5:Butyl-sek.-butyl-aether; Produkt6:Butyl-tert.-butyl-aether; Produk7:Isopropyl-sek.-butyl-aether; Produkt8:Isopropylalkohol Patent; I.G.Farbenind.; US2198046; (1937) View in Reaxys Patent; I.G.Farbenind.; DE728530; (1936); View in Reaxys Newitt; Semerano; Proceedings of the Royal Society of London, Series A: Mathematical, Physical and Engineering Sciences; vol. 157; (1936); p. 354 View in Reaxys

H O+

C+

Rx-ID: 2181621 View in Reaxys 64/127 Yield

Conditions & References T= 34.9 °C , ΔG0, Thermodynamic data Mishima, Masaaki; Ariga, Toshifumi; Tsuno, Yuho; Ikenaga, Kazutoshi; Kikukawa, Kiyoshi; Chemistry Letters; nb. 3; (1992); p. 489 - 492 View in Reaxys

H O+

C+

Rx-ID: 2533385 View in Reaxys 65/127

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Yield

H O+

C+

Rx-ID: 3031133 View in Reaxys 66/127 Yield

dehydrated alum Rx-ID: 5804021 View in Reaxys 67/127 Yield

Conditions & References T= 150 - 160 °C Mailhe; de Godon; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 170; (1920); p. 329; Bulletin de la Societe Chimique de France; vol. <4>27; (1920); p. 121 View in Reaxys O O

Rx-ID: 2004917 View in Reaxys 68/127 Yield

Conditions & References With toluene-4-sulfonic acid, quantity of toluene-4-sulphonic acid Taylor, Roger; Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999); (1988); p. 737 - 744 View in Reaxys O

OH HO

S OO

Rx-ID: 5804019 View in Reaxys 69/127 Yield

Conditions & References T= 100 - 140 °C , Dehydratation Katuno; ; vol. 41; (1938); p. 59,75; ; (1939); p. 6236,1940 2785; Chem. Zentralbl.; vol. 110; nb. I; (1939); p. 630 View in Reaxys

OH HO

S OO

complex/es iron cyanides Rx-ID: 7062090 View in Reaxys 70/127

Yield

Conditions & References Patent; Shell Devel.Co.; US1944622; (1929) View in Reaxys Patent; Shell Devel.Co.; GB323748 View in Reaxys Patent; N.V.de Bataafsche Petr.Mij.; DE541628; (1929); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 18; p. 178,20 99

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View in Reaxys Patent; N.V.de Bataafsche Petr.Mij.; DE580929; (1931) View in Reaxys O

58 percent sulfuric acid Rx-ID: 5804017 View in Reaxys 71/127 Yield

Conditions & References Senderens; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 179; (1924); p. 1018; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 181; (1925); p. 700 View in Reaxys O

boron fluoride dihydrate Rx-ID: 7062089 View in Reaxys 72/127 Yield

Conditions & References beim Destillieren der erhaltenen Additionsverbindung in verd. Alkalilauge Meerwein; Pannwitz; Journal fuer Praktische Chemie (Leipzig); vol. <2>141; (1934); p. 131,145 View in Reaxys Patent; du Pont de Nemours and Co.; US2135455; (1935) View in Reaxys O

OH HO

copper salts

S OO

Rx-ID: 7062091 View in Reaxys 73/127 Yield

Conditions & References Patent; Dow Chem.Co.; US2210316; (1937) View in Reaxys Patent; Shell Devel.Co.; US1995908; (1932) View in Reaxys Patent; Shell Devel.Co.; FR695707 View in Reaxys O

S O

Rx-ID: 741769 View in Reaxys 74/127 Yield

Conditions & References Katuno; ; vol. 43; (1940); p. 106; ; (1940); p. 6929 View in Reaxys O

Al2O3 Rx-ID: 5804020 View in Reaxys 75/127 Yield

Conditions & References bei hohen Temperatur und Druck Ipatjew; Chemische Berichte; vol. 37; (1904); p. 2997; Chem. Zentralbl.; vol. 75; nb. II; (1904); p. 1021 View in Reaxys

HO S O

Rx-ID: 741953 View in Reaxys 76/127

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Yield

Conditions & References Dehydratation Katuno; ; vol. 41; (1938); p. 59,75; ; (1939); p. 6236,1940 2785; Chem. Zentralbl.; vol. 110; nb. I; (1939); p. 630 View in Reaxys O

Rx-ID: 742239 View in Reaxys 77/127 Yield

Conditions & References Dehydratation Katuno; ; vol. 41; (1938); p. 59,75; ; (1939); p. 6236,1940 2785; Chem. Zentralbl.; vol. 110; nb. I; (1939); p. 630 View in Reaxys

OH HO

P OH O

Rx-ID: 7062087 View in Reaxys 78/127 Yield

Conditions & References Geschwindigkeit und Gleichgewicht der Reaktion CH3CH:CH2+H2=<=>CH3CH(OH)CH3 Majewski; Marek; Industrial and Engineering Chemistry; vol. 30; (1938); p. 205 View in Reaxys O

Rx-ID: 6947414 View in Reaxys 79/127 Yield 86%

Conditions & References 2.a : Preparation of 5-(2-parachlorobenzenesulphonamidoethyl)-2,3-dihydro-2-benzofurancarboxylic acid (compound 2) a) Sodium salt of N-ethoxycarbonylparachlorobenzenesulphonamide XX (R7 =EtOCO, R=p-ClC6 H4; Na salt) (2a) A mixture formed from 85 g (0.443 mole) of parachlorobenzenesulphonamide and 157.2 g (1.13 mole) of K2 CO3 /KI 98/02 in 500 ml of acetone is treated at 25° C. with 62.6 g (0.576 mole) of ethyl chloroformate, added dropwise in the course of 30 min, with mechanical stirring. The reaction is slightly exotermic and, after the temperature has stabilized at 40° C., the mixture is brought progressively to reflux for 2 hours. After cooling, the mixture is poured into 500 ml of crushed ice and the sulphonamide is extracted with ether. The residue obtained after washing, drying and evaporating to dryness is dissolved in 80 ml of hot isopropyl ether and is then precipitated by adding cyclohexane to obtain 100 g (yield =86percent) of white derivative of formula STR16 empirical formula: C9 H10 ClNO4 S molecular weight: 263.70 broken white crystals melting point: 80° C. Patent; Pierre Fabre Medicament; US5385931; (1995); (A1) English View in Reaxys

85%

1.c : (c) A solution of 340 g of the ester obtained according to (b) and 80 g sodium hydroxide in 1.3l. 75percent aqueous ethanol is maintained at reflux for 20 minutes. 1 l. water is added, the alcohol removed and the mixture acidified by the addition of 10percent hydrochloric acid. The acid is extracted in ethyl ether. After evaporation of the solvent, 270 g recrystallisable with an 85percent yield from acetone or isopropyl ether are obtained. Melting Point=164° C.

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This acid may also be prepared by reaction of thiophene-2-carboxylic acid chloride with 1-naphthyloxyacetic acid using the same preparational method as described in (b); the yields for this reaction are however lower. Patent; Albert Rolland S.A.; US4195093; (1980); (A1) English View in Reaxys 75%

21 : Recrystallization: isopropyl ether Recrystallization: isopropyl ether Yield: 75percent Melting point: 123°-125° C. Patent; Adir Et Compagnie; US5712294; (1998); (A1) English View in Reaxys

65%

9 : Recrystallization: isopropyl ether Recrystallization: isopropyl ether Yield: 65percent Melting point: 123°-124° C. Patent; Adir Et Compagnie; US5712294; (1998); (A1) English View in Reaxys

60%

20 : Recrystallization: isopropyl ether Recrystallization: isopropyl ether Yield: 60percent Melting point: 195° C. Patent; Adir Et Compagnie; US5712294; (1998); (A1) English View in Reaxys

55%

19 : Recrystallization: isopropyl ether Recrystallization: isopropyl ether Yield: 55percent Melting Point: 123°-124° C. Patent; Adir Et Compagnie; US5712294; (1998); (A1) English View in Reaxys

33%

6 : Recrystallization: isopropyl ether Recrystallization: isopropyl ether Yield: 33percent Melting point: 144°-145° C. Patent; Adir Et Compagnie; US5712294; (1998); (A1) English View in Reaxys

30%

12 : Recrystallization: isopropyl ether Recrystallization: isopropyl ether Yield: 30percent Melting point: 159°-160° C. Patent; Adir Et Compagnie; US5712294; (1998); (A1) English View in Reaxys

23%

3.b : [1(R)]-N-hydroxy-α,3-dimethyl-3-[4-(1-methylethoxy)phenyl]-2-oxo-1-pyrrolidineacetamide (3b) A mixture of the phenol from (3a) (460 mg, 1.66 mmol) and N,N'-dimethyl-O-isopropylisourea (5 mL) was heated to 70° C. for 4 h and then cooled to rt. Following addition of acetic acid (2 mL) and dichloromethane (2 mL), the mixture was stirred for 30 min. The mixture was then filtered through a silica gel pad and the filter cake washed with ethyl acetate-hexane (40:60). The filtrate was concentrated and purified by silica gel chromatography (ethyl acetate-hexane, 40:60) to give the isopropyl ether (123.2 mg, 23percent) as a 1:1 mixture of two isomers. MS found: (M+H)+ =320. Patent; E. I. du Pont de Nemours and Company; US6057336; (2000); (A1) English View in Reaxys

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Verzele,M. et al.; Journal of the Chemical Society; (1963); p. 5598 - 5600 View in Reaxys Salomon; Journal of the American Chemical Society; vol. 99; nb. 10; (1977); p. 3500 - 3501 View in Reaxys Howard; Brown; Journal of Organic Chemistry; vol. 26; (1961); p. 1026 View in Reaxys Doyle et al.; Journal of Organic Chemistry; vol. 39; (1974); p. 2740,2742,2746 View in Reaxys Patent; Dow Chem. Co.; US3170958; (1965); ; vol. 63; nb. 5530a; (1965) View in Reaxys Kolesnikov et al.; J. Appl. Chem. USSR (Engl. Transl.); vol. 48; (1975); p. 2019,2087 View in Reaxys Linde; Freeman; Journal of the American Chemical Society; vol. 92; (1970); p. 4417 View in Reaxys Calas; Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques; vol. 264; (1967); p. 1402 View in Reaxys d:d To a solution of 12.0 g (0.05 mol) of 4-hydroxy-p-(methoxycarbonyl)-benzenebutanoic acid in 200 ml of glacial acetic acid were added 150 ml of water and 8.0 g sodium acetate and then a solution of 15.58 g (0.0975 mol) of bromine in 60 ml of glacial acetic acid was added dropwise. The mixture was stirred for a further hour at room temperature, then evaporated down to two thirds in vacuo and the residue was divided between water and ethyl acetate. The ethyl acetate extracts were washed with water, dried over sodium sulphate and evaporated down in vacuo. After stirring with diisopropylether a colourless crystal was obtained. Yield: 12.0 g (62.2percent of theory). Rf=0.4 (eluant: ethyl acetate/petroleum ether/glacial acetic acid 49.8/49.8/0.4 v/v/v). IR(KBr): 1724 cm-1 (C=0) MS: M (Br2)

+=394/396/398

Patent; Rudolf, Klaus; Eberlein, Wolfgang; Engel, Wolfhard; Pieper, Helmut; Doods, Henri; Hallermayer, Gerhard; Entzeroth, Michael; Wienen, Wolfgang; US2001/36946; (2001); (A1) English View in Reaxys 1 : Preparation of 3-Hydroxythiophenol Example 1 Preparation of 3-Hydroxythiophenol 3-Aminothiophenol (5 g, 40 mmol) was oxidized to 3-aminophenyl disulfide with one equivalent dimethyl sulfoxide (DMSO) (20 g, 26 mmol) at 80-90° C. in near quantitative yield as shown by GC. Without isolation, the reaction mixture was poured into a dilute sulfuric acid solution (7.2 mL concentrated sulfuric acid in 50 mL water) to obtain a milklike white suspension which was doubly diazotized using a solution of NaNO2 (2.5 g) in water (8 mL) at room temperature. The diazonium salt solution (orange color) was then thermally decomposed by carefully dripping into a refluxing solution of sulfuric acid (20 mL) and water (10 mL). A dark brown mixture was obtained when the addition was completed. The reaction was monitored by GC by extracting an aliquot into isopropyl ether, which showed a near clean formation of the desired disulfide. The reaction mixture was then cooled in an ice-water bath followed by rapid addition of Zn dust. The reaction was gradually warmed to room temperature and heated at reflux. The dark brown color faded away and the reaction mixture became off-white. The reaction was monitored by GC by extracting an aliquot into isopropyl ether. Patent; AlliedSignal Inc; US6054622; (2000); (A1) English View in Reaxys 3.b : a. b. Preparation of the title compound To the above prepared sulfamoyl chloride solution was added 8 g (0.04 mole) of 3-(2-methoxyphenoxy)-1,2-propanediol (which is glyceryl guaiacolate) in a solution of 15.2 ml (0.176 mole) of pyridine in 20 ml of acetonitrile at -3° C. to +15° C. over a 13 min period. The cold bath was removed and the reaction mixture was stirred for 2 hr. Ethyl acetate, 30 ml, was added and the mixture was extracted thrice with saturated sodium chloride solution.

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The aqueous layers were back extracted twice with a 1:1 vol mixture of ethyl acetate:acetonitrile. The organic layers were combined and dried over sodium sulfate and evaporated to give a glassy residue. Crystallization using isopropyl alcohol and isopropyl ether produced 10.3 g (74.5percent) of slightly impure title product in 2 crops. The crystals were triturated with water and a small amount of isopropyl alcohol and then subjected to filtration, dried and dissolved in warm acetonitrile. A small amount of solid was removed by filtration. The filtrate was mixed with water and subjected to slow evaporation. The resulting suspension was filtered and the solid was rinsed with water, isopropyl alcohol and isopropyl ether. The white solid was dried in a vacuum oven at 40° C. overnight, mp 151°-153° C. Analysis: Calculated for C10 H16 N2 O8 S2: C, 33.70; H, 4.53; N, 7.86. Found: C, 34.16; H, 4.65; N, 8.20. Patent; A. H. Robins Company, Incorporated; US5192785; (1993); (A1) English View in Reaxys 3.b : 1-[(2-Methoxyphenoxy)methyl]-1,2-ethanediol bisulfamate (ester) b. Preparation of the title compound. To the above prepared sulfamoyl chloride solution was added 8 g (0.04 mole) of 3-(2-methoxyphenoxy)-1,2-propanediol (which is glyceryl guaiacolate) in a solution of 15.2 ml (0.176 mole) of pyridine in 20 ml of acetonitrile at -3° C. to +15° C. over a 13 min period. The cold bath was removed and the reaction mixture was stirred for 2 hr. Ethyl acetate, 30 ml, was added and the mixture was extracted thrice with saturated sodium chloride solution. The aqueous layers were back extracted twice with a 1:1 vol mixture of ethyl acetate:acetonitrile. The organic layers were combined and dried over sodium sulfate and evaporated to give a glassy residue. Crystallization using isopropyl alcohol and isopropyl ether produced 10.3 g (74.5percent) of slightly impure title product in 2 crops. The crystals were triturated with water and a small amount of isopropyl alcohol and then subjected to filtration, dried and dissolved in warm acetonitrile. A small amount of solid was removed by filtration. The filtrate was mixed with water and subjected to slow evaporation. The resulting suspension was filtered and the solid was rinsed with water, isopropyl alcohol and isopropyl ether. The white solid was dried in a vacuum oven at 40° C. overnight, mp 151°-153° C. Analysis: Calculated for C10 H16 N2 O8 S2: C,33.70; H,4.53; N,7.86; Found: C,34.16; H,4.65; N,8.20. Patent; A. H. Robins Company, Incorporated; US5194446; (1993); (A1) English View in Reaxys 3 : EXAMPLE 3 Then 280 grams (about 2.2 mol) of 60percent sodium sulfide were added to the solution and the reaction was carried out at 130° C. for 1 hour. When the resultant solution was acidified by adding 500 cm3 of water and 460 cm3 of 62.5percent sulfuric acid, an oily substance was separated. The residual solution was extracted 4 times with 200 grams of isopropyl ether. The total extractives were combined into one and the isopropyl ether was recovered by distillation at reduced pressure. Patent; Tomioka; Tetsuzo; US5256818; (1993); (A1) English View in Reaxys R.5 : Preparation of 7-O-(2,6-dideoxy-2-fluoro-α-L-talopyranosyl) adriamycinon REFERENCE EXAMPLE 5 Preparation of 7-O-(2,6-dideoxy-2-fluoro-α-L-talopyranosyl) adriamycinon In a mixed solvent of 4.6 ml of absolute methanol and 7 ml of anhydrous dioxane were suspended 190 mg of 7-O(2,6-dideoxy-2-fluoro-α-L-talopyranosyl) daunomycinon prepared in Reference Example 4. 0.26 ml of methyl orthoformate were added thereto and the mixture was allowed to react. The reaction suspension was cooled to 0° C., a solution of 75 mg of bromine water in 0.75 ml of anhydrous methylene chloride was added thereto, and the mixture was allowed to react for 1 hour and stirred at room temperature for 2 hours. The red precipitates formed by addition of 60 ml of isopropyl ether were recovered by centrifugation and washed twice with isopropyl ether.

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Patent; Dong-A Pharmaceutical Co., Ltd.; US5374746; (1994); (A1) English View in Reaxys 1 : Preparation of 5-(parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylic acid (compound 1) A suspension of 5.8 g (20.2 mmoles) of ethyl 5-aminoacetyl-2,3-dihydro-2-benzofurancarboxylate hydrochloride (1c) in 65 ml of pyridine cooled to -5° C. is treated with 5.5 g (26.1 mmoles) of parachlorobenzenesulphonyl chloride. The mixture is kept at this temperature for 1/4 hour and stirring is then continued for a further 2 hours after returning to 20°. The reaction mixture is hydrolysd with 100 ml of water and then extracted with ethyl acetate. The organic phase is washed twice with 100 ml of water, the pH of which has been adjusted to 5.5 by the addition of concentrated HCl, and is then washed with saline water, dried over sodium sulphate and evaporated. The residue yields two amounts of crystals of formula 1d by dissolving in ethyl acetate and precipitating from ether or isopropyl ether (weight=6.3 g-yield =73percent) STR14 Compound 1d Patent; Pierre Fabre Medicament; US5385931; (1995); (A1) English View in Reaxys Preparation of the intermediate nitriles of the invention via O-Triflates The amine was converted into the fumarate salt and recrystallized in ethanol: isopropyl ether: m.p. 105°-08° C. (fumarate); MS m/e calc'd for NO2 SC15 H23: 281.145, found 281.143; 281.25 (M+, 2.9), 253.15 (16.1), 252.15 (100), 129.15 (9.6), 70.15 (6.4). Patent; The Upjohn Company; US5462947; (1995); (A1) English View in Reaxys 1.ii : (ii) (ii) Synthesis of Compound 5. A 500 mg portion of the Compound 4a was dissolved in 4 ml of dichloromethane, the resulting solution was added with 0.5 ml of anisole and 2 ml of trifluoroacetic acid with stirring under ice cooling, the mixture was stirred at the same temperature for 15 minutes and then at room temperature for 50 minutes followed by evaporation of the solvent, the resulting residue was again added with 4 ml of trifluoroacetic acid and 1.3 ml of water in this order with stirring under ice cooling, the mixture was stirred at the same temperature for 15 minutes and then at room temperature for 3 hours followed by distilling off the solvent, the resulting residue was solidified by adding isopropyl ether, and then the thus solidified substance was collected by filtration and washed with isopropyl ether to obtain 255 mg of the trifluoroacetate of Compound 5. This was applied to a column packed with 100 ml of polystyrene resin "HP20" manufactured by Mitsubishi Kasei Corp. and developed with water containing 20 to 30percent methanol to obtain 29 mg (10percent) of Compound 5. Identification data of the Compound 5 are as follows. IR νmax Nujol cm-1: 3322, 3211, 3066, 1778, 1666, 1634, 1312, 1261, 1159, 1111, 1045, 995, 972, 858, 802, 771, 721. NMR δ (DMSO-d6 +CD3 OD) ppm: 3.67 (2H, br.s), 3.89 (3H, s), 5.06 (1H, d, J=4.5), 5.33 (2H, d, J=5), 5.66 (1H, d, J=4.5), 6.27 (1H, m), 6.81 (1H, s), 7.02 (1H, m), 7.48 (1H, s), 7.6-9.5 (4H, m). Patent; Katayama Seiyakusyo Co., Ltd.; Ajinomoto Co., Inc.; US5534508; (1996); (A1) English View in Reaxys 854 mg (74%)

3.i : Synthesis of Compound 12 (7β-[2-(2-aminothiazol-4-yl)-2-syn-hydroxyiminoacetamido]-3-[(E)-3-[3-(2aminothiazol-4-yl)pyridinio]-1-propenyl]-3-cephem-4-carboxylate). (i) Synthesis of Compound 10 (p-methoxybenzyl 7β-[2-(2-tritylaminothiazol-4-yl)-2-syn-trityloxyiminoacetamido]-3[(E)-3-[3-(2-aminothiazol-4-yl)pyridinio]-1-propenyl]-3-cephem-4-carboxylate iodide). 917 mg of Compound 7 (p-methoxybenzyl 7β-[2-(2-tritylaminothiazol-4-yl)-2-syn-trityloxyiminoacetamido]-3-[(Z)-3chloro-1-propenyl]-3-cephem-4-carboxylate) was dissolved in 25 ml of acetone, the resulting solution was added with 394 mg of NaI with stirring under ice cooling, the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 45 minutes followed by distillation removal of the solvent, the resulting residue was dissolved in ethyl acetate, and the solution was washed with an aqueous sodium chloride solution and dried on Na2 SO4 followed by removing the solvent by evaporation. The thus obtained residue was added with 140 mg of Compound 8 (3-(2-aminothiazol-4-yl)pyridine) and made into a solution by adding 10 ml of DMF under ice cooling, the thus obtained solution was stirred at room temperature for 4

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hours followed by distilling off the DMF under reduced pressure, the resulting residue was solidified by adding isopropyl ether, and then the thus solidified substance was collected by filtration and washed with isopropyl ether to obtain 854 mg (74percent) of Compound 10. Identification data of the Compound 10 are as follows. IR νmax Nujol cm-1: 3287, 1784, 1722, 1666, 1612, 1304, 1250, 1221, 1177, 1157, 1101, 1061, 1032, 1003, 966, 827, 754, 700, 660. NMR δ (CDCl3 +CD3 OD) ppm: 3.28, 3.56 (2H, ABq, J=18), 3.71 (3H, s), 5.03 (1H, d, J=4.5), 5.14 (2H, s), 5.2-5.5 (2H, m), 6.42 (1H, s), 6.77 (2H, d, J=9), 6.8-7.8 (33H, m), 7.9-9.4 (4H, m). Patent; Katayama Seiyakusyo Co., Ltd.; Ajinomoto Co., Inc.; US5534508; (1996); (A1) English View in Reaxys 34 : ISOPROPYL ESTER OF N-PIVALOYL-N'-ACETYL-DI-LYSO GM1 EXAMPLE 34 ISOPROPYL ESTER OF N-PIVALOYL-N'-ACETYL-DI-LYSO GM1 5 g (3.18 mM) of the inner ester of N-pivaloyl N'-acetyl-di Lyso GM1 are dissolved in 200 ml of an anhydrous mixture of methylene chloride/isopropanol 2:1. To this solution are added 261 mg (3.18 mM) of sodium isopropylate dissolved in 50 ml of anhydrous isopropanol and the mixture is left to reflux for 2 hrs. After the reaction the mixture is neutralized with anhydrous Dowex resin AG 50x8 H+ form, the resin is separated by filtration and washed with isopropanol/methylene chloride 1:1 and the solution is then dried. The residue is gathered with 50 ml of methylene chloride/isopropanol 1:1 and the product is precipitated with 250 ml of acetone. The raw product thus obtained (4.9 g) is purified by medium pressure preparative chromatography (12 atm) with Merck silica gel, using as solvent a mixture of chloroform/methanol/isopropanol/ammonium carbonate 2percent 1140:620:180:140. The pure fractions are pooled, evaporated to dryness, and redissolved in 15 ml of chloroform/methanol 1:1, and the product is precipitated with 75 ml of acetone. Yield of isopropyl ester of N-pivaloyl-N'-acetyl-di Lyso GM1 =4.2 g (81.0percent theoretical). Patent; FIDIA S.p.A.; US5484775; (1996); (A1) English View in Reaxys 24 : EXAMPLE 24 STR88 EXAMPLE 24 STR88 250 mg of STR89 are dissolved in 10 ml of methanol and adjusted to a pH of 10 with a few drops of 1N NaOCH3 solution in methanol. After reacting for 15 minutes, the solution is neutralised with an ion exchanger (e.g. AMBERLYST.(R). 15, H+), and the ion exchanger is filtered off. The filtrate is concentrated and the residue treated for 5 minutes with 3 ml of trifluoroacetic acid. The title compound is precipitated as the trifluoroacetate by adding 20 ml of diisopropylether, and is isolated in pure form as a white lyophilisate after filtration, drying and chromatography on silica gel (eluant: CHCl3 /MeOH/HOAc/H2 O 7/3/0.5/0.5). [α]D 20 =-39.2° (c=0.60 in HOAc 95percent) F: 0.91 The starting product may be produced as follows: Patent; Sandoz Ltd.; US5656721; (1997); (A1) English View in Reaxys 6.B : B. The title compound of Example 6A (231.2 mg, 0.46 mmol) was mixed with hydrochloric acid (3 ml of a 6M solution) and acetic acid (3 ml) and heated to 100° for 24 hours. The resulting solution was cooled and concentrated in vacuo to provide a residue which was mixed with isopropanol and isopropyl ether and filtered. The filtrate was concentrated, and the product triturated with a small quantity of cold isopropanol to provide a white solid, which was dissolved in a minimum quantity of sodium hydroxide solution and acidified with hydrochloric acid until a precipitate appeared. Filtration provided the title product as a yellow solid, mp 201°-203° (40 mg, 0.086 mmol, 19percent yield). 1 H NMR (D20/NaOD): 8.25 (s, 1H), 7.80 (d, J=13 Hz, 1H), 7.45 (m, 1H), 7.15 (m, 2H), 3.5 (vbm, 4H), 2.70 (bd, J=13 Hz, 1H), 2.60 (bd, J=13 Hz, 1H), 1.39 (bs, 1H), 0.68 (bs, 1H), 0.20 (bs, 1H).

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Patent; Pfizer Inc; US5164402; (1992); (A1) English View in Reaxys 3 : Methyl 2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]ethane-1-carboxylate Methyl 2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]ethane-1-carboxylate 6.1 g (0.016 mol) of the above sulphur compound are dissolved in 100 ml of tetrahydrofuran and after the addition of 1 g of hydrazine hydrate, stirred for 30 minutes at 45° to 50° C. The mixture is then evaporated down in vacuo. 5 to 5.2 g of oil are left behind, which crystallise with isopropylether (m.p. 175°-177° C.). Patent; Boehringer Ingelheim KG; US4900729; (1990); (A1) English View in Reaxys 1.B : B. B. Preparation of the Title Compound. To the above prepared sulfamoyl chloride solution was added 8 g (0.04 mole) of 3-(2-methoxyphenoxy)-1,2-methoxyphenoxy)-1,2-propanediol (glyceryl guaiacolate) in a solution of 15.2 ml (0.176 mole) of pyridine in 20 ml of acetonitrile at -3° C. to +15° C. over a 13 min period. The cold bath was removed and the reaction mixture was stirred for 2 hr. Ethyl acetate (30 ml) was added and the mixture was extracted thrice with saturated sodium chloride solution. The combined aqueous layers were extracted twice with a 1:1 mixture of ethyl acetate:acetonitrile. The organic layers were combined and dried over sodium sulfate and evaporated to give a glassy residue. Crystallization using isopropyl alcohol and isopropyl ether produced 10.3 g (74.5percent) of slightly impure title product in 2 crops. The crystals were triturated with water and a small amount of isopropyl alcohol, filtered, dried and dissolved in warm acetonitrile. A small amount of solid was removed by filtration. The filtrate was mixed with water and subjected to slow evaporation. The resulting suspension was filtered and the solid was rinsed with water, isopropyl alcohol and isopropyl ether. The white solid was dried in a vacuum oven at 40° C. overnight, mp 151°-153° C. Analysis: Calculated for C10 H16 N2 O8 S2: C, 33.70; H, 4.53; N, 7.86. Found: C, 34.16; H, 4.65; N, 8.20. Patent; A. H. Robins Co., Inc.; US5025031; (1991); (A1) English View in Reaxys 1.g : (g) (g) Methyl 2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]ethane-1-carboxylate The above sulfur compound (6.1 g, 0.016 mol) is dissolved in tetrahydrofuran (100 ml) and, after the addition of hydrazine hydrate (1 g), stirred for 30 minutes at 45°-50° C. Then the mixture is evaporated in vacuo. The oil which remains (5 to 5.2 g), crystallizes with isopropylether (m.p. 175°-177° C.). Patent; Boehringer Ingelheim KG; US4968794; (1990); (A1) English View in Reaxys ii : COMPARATIVE TEST A (ii) isopropyl ether 254 g, were charged into an apparatus similar to the one used in Example 1, but using a 500 cc reactor. The reaction mixture was heated to 70° C. under stirring, and, at this temperature, 3.36 liters of chlorine were introduced over 40 minutes. Patent; Rhone-Poulenc Chimie; US4954662; (1990); (A1) English View in Reaxys aromatic derivatives such as: xylenes, toluene, ketones such as:

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... acetophenone, diisopropyl ketone, methyl isopropyl ketone, dibutyl ketone, isopropyl ether, methyl isobutyl ether, Patent; Rhone-Poulenc; US5026900; (1991); (A1) English View in Reaxys 34 : EXAMPLE 34 EXAMPLE 34 This Example illustrates the preparation of chlorinated heterocyclic alkyl electrophile intermediate compounds from alcohols. Thionyl chloride (SOCl2, 6.2 ml) in chloroform (15 ml) was added dropwise to an ice chilled solution of 2-(2-hydroxyethyl)pyridine (Aldrich, 10 g, 81 mmol in chloroform (10 ml. After addition was complete, the reaction mixture was stirred for 15 hours. The solvent and excess thionyl chloride were removed on a vacuum rotary evaporator followed by exposure to high vacuum (90 minutes, 0.5 mm Hg, 80° C.) Recrystallization of the crude brown solid from isopropanol-isopropyl ether yielded 10.8 g of pure 2-(2-pyridinyl)ethyl chloride hydrochloride (mp. 124°-125° C., lit. mp., about 120° C., Gump et al., U.S. Pat. No. 2,533,243; Chem. Abstr., 1950, 45, p. 4271c) as light tan beads. Patent; Anaquest, Inc.; US5053411; (1991); (A1) English View in Reaxys III : N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-hydroxybenzamide, (E)-2-butenedioate (1:1) STR9 EXAMPLE III N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-hydroxybenzamide, (E)-2-butenedioate (1:1) STR9 Tetrahydrofuran (50 ml) is added to a mixture of 5-chlorosalicylic acid (1.72 g, 0.01 mole) and 1,1'-carbonyldiimidazole (1.62 g, 0.01 mole) and the mixture is stirred for 18 hours. The resultant solution is treated with 3-aminoquniuclidine (1.26 g, 0.01 mole) in one portion and the reaction mixture is stirred for another 20 hours. The reaction mixture is concentrated to an oil composed of product and imidazole. The oil is dissolved in methylene chloride (50 ml) and shaken with water (50 ml) to remove the imidazole. The product separates as a white solid, and it is collected by filtration, and washed with water (25 ml). After drying under ambient conditions for 4 hours, the solid weighs 1.92 g (69percent yield). The solid (1.50 g) and fumaric acid (0.62 g) are heated together in boiling absolute ethanol (20 ml) until a clear solution is obtained, and then isopropyl ether is added until a persistent cloudiness is obtained. Patent; A. H. Robins Company, Incorporated; US5084460; (1992); (A1) English View in Reaxys 50 : EXAMPLE 50 EXAMPLE 50 The following compounds were prepared in an analogous manner to that described in Example 40: 3-[{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}methyl]pyridine, m.p. 151°-152° (from methyl chloride/isopropyl ether), is obtained from 2-[(2,6 -dichlorophenyl)imino]-1-hydroxyimidazolidine and 3-chloromethylpyridine; the corresponding dihydrochloride melts at 222° with decomposition (from acetonitrile/dioxane); Patent; Hoffman-La Roche Inc.; US4244957; (1981); (A1) English View in Reaxys A.B : Stage B Stage B 37 g of the polymer obtained above are dissolved in 150 cc of dimethylformamide. To this solution are added 5.08 g of dodecylamine in solution in 20 cc of dimethylformamide. This mixture is heated for 12 hours at 90° C. There are then added 26 g of diethanolamine and the resulting mixture is again heated for 30 hours at 90° C. The dimethyl formamide is distilled off under reduced pressure. The dry dye polymer thus obtained is re-dissolved in 150 cc of isopropanol and precipitated by the addition of the same volume of isopropyl ether. After washing with a 1:1 mixture of isopropanol and isopropyl ether and drying under reduced pressure, 40 g of a very water soluble purple colored polymer are obtained.

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Patent; L'Oreal; US4314808; (1982); (A1) English View in Reaxys 2 : EXAMPLE 2 EXAMPLE 2 3-Chloromethyl-5-(4-fluorophenyl)-4,5-dihydroisoxazole (40 g), 52 g of 4-(5-chloro-2-oxo-1-benzimidazolinyl)piperidine, 30 g of potassium carbonate, 15 g of potassium iodide and 1 liter of ethanol are heated to a temperature of 70° to 75° C. with stirring for 48 hours. The reaction mixture is then filtered and the mother liquor is condensed under reduced pressure. To the residue are added 800 ml of chloroform and 500 ml of water and the mixture is stirred. The organic layer is separated off, washed with water and dried on magnesium sulfate, and the solvent is distilled off. To the resulting residue are added 130 ml of acetone and 100 ml of isopropyl ether. Patent; Yoshitomi Pharmaceutical Industries Ltd.; US4397853; (1983); (A1) English View in Reaxys 8 : EXAMPLE 8 STR12 EXAMPLE 8 STR12 The procedure of Example 7 is repeated using isopropanol as alcohol component, to give the corresponding isopropyl ether with a melting point of 50° C. Patent; Ciba-Geigy Corporation; US4507420; (1985); (A1) English View in Reaxys 44 : Preparation of 3-(2-phenyl-indolyl)-acetic acid Example 44 Preparation of 3-(2-phenyl-indolyl)-acetic acid 167.5 ml of 40percent strength dimethylamine followed by 45 ml of 40percent strength formaldehyde are added to 450 ml of acetic acid cooled to 10° C. The solution thus obtained is then poured onto 45 g of 2-phenyl-indole. The mixture is left for 8 hours at ambient temperature and then filtered and rendered alkaline with a potassium hydroxide solution. Thereafter it is extracted with ether. The organic phase is dried and concentrated in vacuo. The residue is dissolved in a mixture containing 300 ml of ethanol and 150 ml of ether, to which 30 ml of methyl iodide are added. The whole is left to stand overnight and after adding isopropyl ether an oil is obtained, which is recovered. Patent; Societe Anonyme dite: L'Oreal; US4522808; (1985); (A1) English View in Reaxys 58 : Example 58 Example 58 To a solution of 2.0 g (6.16 m mol) of 5-hydroxy-2,2,4,6,7 -pentamethyl-3-(4-isopropylphenyl)-2,3-dihydrobenzofuran obtained in Example 20 in 10 ml of dibutyl ether were added 740 mg (7.4 m mol) of anhydrous succinic acid and 0.1 ml of conc. sulfuric acid. This was stired at 80° C. for 1 hour. After cooling, the reaction mixture was washed with water, dried and concentrated. The resulting residue was purified by silica gel chromatography (eluted by isopropyl ether). Patent; Takeda Chemical Industries, Ltd.; US4857516; (1989); (A1) English View in Reaxys Sodium 7β-[D-2-amino-2-(p-hydroxyphenyl)acetamido]-3-[(Z)-1-buten-1-yl]-3-cephem-4-carboxylate (Compound 13, BB-S1058 Sodium Salt) Sodium 7β-[D-2-amino-2-(p-hydroxyphenyl)acetamido]-3-[(Z)-1-buten-1-yl]-3-cephem-4-carboxylate (Compound 13, BB-S1058 Sodium Salt) A solution of 1.08 g. (1.61 m. mol.) of 12 in 11 ml. of TFA containing 1percent of water was allowed to stand for one hour at room temperature. The mixture was concentrated to about 2 ml. in vacuo and the resulting syrup was triturated with about 20 ml. of diisopropyl ether to give 796 mg. of yellow powder. Patent; Bristol-Myers Company; US4520022; (1985); (A1) English

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View in Reaxys 29 : 6-(o-Cinnamidophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxyamide mucate (Racemate A). EXAMPLE 29 6-(o-Cinnamidophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxyamide mucate (Racemate A). Reaction of the Racemate A of 6-(o-aminophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide (5.1 g., 0.16 mole) obtained in Example 4f with cinnamoyl chloride (3.2 g., 0.19 mole) in 70 ml. of pyridine according to the method of Example 25 provides 7.3 g. of the free piperidine carboxamide base. The free base reacted with mucic acid in boiling methanol provides the mucate salt. This methanol soluble mucate salt is dissolved in methanol and precipitated therefrom the addition of isopropyl ether. Crystallization from ethanol-isopropyl ether provides 3.4 g. of 6-(o-cinnamidophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide mucate hydrated with water, m.p. 79°-110°C. Analysis. Calcd. for C28 H37 N3 O2.1/2C 6 H10 O8.1/2H 2 O: C, 64.45; H, 7.50; N, 7.27. Found: C, 64.38; H, 7.69; N, 6.89. Patent; Mead Johnson and Company; US3931195; (1976); (A1) English View in Reaxys 4 : EXAMPLE 4 EXAMPLE 4 A total of 22.3 g of potassium were dissolved in 450 ml of tert.-butanol with vigorous stirring and the solution heated to reflux. After the addition of 300 ml of dimethylformamide, the mixture was cooled to -15° and treated with a solution of 42.5 g of 1-methyl-2-isopropyl-5-nitroimidazole in 60 ml of triethylphosphite and 150 ml of dimethylformamide. Dry oxygen was conducted through the mixture for 5 hours at -15° with vigorous stirring. The mixture was then poured into a mixture of 1.5 liter of ice-water and 50 ml of 36percent hydrochloric acid and extracted 6 times with 400 ml portions of ether. The combined ether extracts were washed twice with 250 ml portions of water and evaporated. The crude 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole (33.8 g; 72.7percent) was purified by recrystallization from 150 ml of water. There were obtained 15.6 g of pure product, melting point 105°-108°. Crystallization of the mother liquor from isopropyl ether yielded a further 8.6 g, melting point 103°-106° (total yield 52percent). Patent; Hoffmann-La Roche Inc.; US4042597; (1977); (A1) English View in Reaxys 1.B : (B) (B) 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide--Compound (VII) A mixture prepared by adding 30 parts red phosphorus to 300 parts glacial acetic acid was cooled in an ice-water bath, and after gradual addition of 180 parts bromine the resultant was filtered to collect the filtrate. After adding 32.7 parts of Compound (VI) to 70 parts of the filtrate, the mixture was subjected to reaction for four hours. Following addition of 100 parts chloroform and sufficient stirring, the mixture was poured into 200 parts ice water and subsequently the chloroform layer was recovered with a separating funnel. The layer was water-washed until it became chemically neutral, then calcium chloride was added, it was dried thoroughly and concentrated. Two repetitions of crystallization of the concentrate from isopropyl ether yielded 28.5 parts crystalline 2,3,4,6-tetra-Oacetyl-alpha-D-glucoypranosyl bromide, hereinafter referred to as Compound (VII), with a melting point of 89° C. Patent; Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo; US4089606; (1978); (A1) English View in Reaxys 10 : EXAMPLE 10 EXAMPLE 10 A solution of 2 g of flumethasone (Δ1,4 -6α,9α-difluoro-16α-methyl-11β,17α,21-trihydroxy-3,20-dioxo-pregnadiene) in 100 ml of tetrahydrofuran is treated with a solution of 5 ml of concentrated hydrochloric acid in 20 ml of water, and the mixture is refluxed for 10 hours in an atmosphere of nitrogen. After cooling, the solution is treated with 100 ml of water, and the tetrahydrofuran is evaporated under reduced pressure. The resulting suspension is extracted with a 3:1 mixture of ether and methylene chloride, the extract is washed with water, dilute potassium bicarbonate solution, and again with water, dried and evaporated in vacuo. The resulting residue is chromatographed on 60 g of silica gel.

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The first eluates (methylene chloride with 1percent of acetone) yield oily products. There follow eluates whose residues crystallize well from ether. The colorless substance, which melts at 216° - 248° C, is Δ1,4 17(20) -6α,9α-difluoro-16α-methyl-11β,20-dihydroxy-3,21-dioxo-pregnatriene. On further elution with methylene chloride containing 2-6percent of acetone, there are obtained after evaporation of the eluates yellow products which crystallize when dissolved in methylene chloride and precipitated with isopropyl ether. Patent; Ciba-Geigy Corporation; US4076737; (1978); (A1) English View in Reaxys 17 : EXAMPLE 17 EXAMPLE 17 A solution of 5 g 3-bromo-rifamycin S in 50 ml methanol was reacted at 2° C with 2 g benzaldehyde thiosemicarbazone. The temperature was then risen to 22° C and the solution stirred for 12 hours. The reaction mixture was extracted with 200 ml chloroform, washed three times with 150 ml water and the organic layer was evaporated to dryness at reduced pressure. The residue was suspended with 100 ml boiling isopropanol and allowed to stand for 12 hours at 5° C. The suspension was filtered and after further 24 hours of standing at 5° C the filtrate separated a rubbery solid. The liquid was decanted and the solid suspended with 200 ml ethyl acetate. The ethyl acetate solution was washed five times with 50 ml buffer phosphate pH 7.4, dried on sodium sulphate and dry evaporated. A residue was obtained, which upon crumbling with isopropyl ether yielded 3 g product of formula II, wherein X is -N= CH--C6 H5. I.R. 3375, 3200(Sh), 1725, 1645(Sh), 1620, 1585, 1550, 1310, 1265, 1235, 1165, 1068, 1055, 1020, 1010, 980, 950, 895, 810, 765 and 700 cm-1. Patent; Archifar Industrie Chimiche del Trentino S.p.A.; US4116957; (1978); (A1) English View in Reaxys 6 : EXAMPLE 6 EXAMPLE 6 A total of 100 ml of triethylphosphite and 6.8 g of sodium ethylate were added to a solution, pre-cooled to -10°, of 85 g of 1-methyl-2-isopropyl-5-nitroimidazole in 500 ml of dimethylformamide. While the solution was further cooled with an ice/sodium chloride bath, dry oxygen was conducted through the solution with vigorous stirring. In so doing, the solution warmed to +5° to +8°. This temperature was maintained during the entire duration of the reaction by corresponding cooling. At intervals of 0.5 hour, 6.8 g aliquots of sodium ethylate were added to the mixture. After 4.5 hours and the addition of a total of 61.2 g of sodium ethylate, the dark-colored solution was poured into 3 liters of water and extracted four times with 1 liter portions of ethyl acetate. The ethyl acetate extracts were combined, washed twice with 0.5 liter portions of water and evaporated. The residue consisted of 76.1 g (81.8percent) crystalline 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole which upon recrystallization from 400 ml of isopropyl ether yielded 64.4 g of pure product, melting point 107°-108° (69.6percent). Patent; Hoffmann-La Roche Inc.; US4042597; (1977); (A1) English View in Reaxys The method of Example 2 was repeated with comparable results employing each of the following co-solvents: ethanol n-propanol n-butanol ethyl ether isopropyl ether dimethoxy ethane 2-methoxy ethanol 2-ethoxy ethanol Patent; Pfizer Inc.; US4082717; (1978); (A1) English View in Reaxys

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34 : ISOPROPYL ESTER OF N-PIVALOYL-N--ACETYL-DI-LYSO GM1 Example 34 ISOPROPYL ESTER OF N-PIVALOYL-N--ACETYL-DI-LYSO GM1 5 g (3.18 mM) of the inner ester of N-pivaloyl N--acetyl-di Lyso GM1 are dissolved in 200 ml of an anhydrous mixture of methylene chloride/isopropanol 2:1. To this solution are added 261 mg (3.18 mM) of sodium isopropylate dissolved in 50 ml of anhydrous isopropanol and the mixture is left to reflux for 2 hrs. After the reaction the mixture is neutralized with anhydrous Dowex resin AG 50x8 H+ form, the resin is separated by filtration and washed with isopropanol/methylene chloride 1:1 and the solution is then dried. The residue is gathered with 50 ml of methylene chloride/isopropanol 1:1 and the product is precipitated with 250 ml of acetone. The raw product thus obtained (4.9 g) is purified by medium pressure preparative chromatography (12 atm) with Merck silica gel, using as solvent a mixture of chloroform/methanol/isopropanol/ammonium carbonate 2percent 1140:620:180:140. The pure fractions are pooled, evaporated to dryness, and redissolved in 15 ml of chloroform/methanol 1:1, and the product is precipitated with 75 ml of acetone. Yield of isopropyl ester of N-pivaloyl-N--acetyl-di Lyso GM1 = 4.2 g (81.0percent theoretical). Patent; FIDIA S.p.A.; EP410881; (1991); (A2) English View in Reaxys 6.B : B. The title compound of Example 6A (231.2 mg, 0.46 mmol) was mixed with hydrochloric acid (3 ml of a 6M solution) and acetic acid (3 ml) and heated to 100° for 24 hours. The resulting solution was cooled and concentrated in vacuo to provide a residue which was mixed with isopropanol and isopropyl ether and filtered. The filtrate was concentrated, and the product triturated with a small quantity of cold isopropanol to provide a white solid, which was dissolved in a minimum quantity of sodium hydroxide solution and acidified with hydrochloric acid until a precipitate appeared. Filtration provided the title product as a yellow solid, mp 201-203° (40 mg, 0.086 mmol, 19percent yield). 1H NMR (D O/NaOD): 8.25 (s, 1H), 7.80 (d, J=13 Hz, 1H), 7.45 (m, 1H), 7.15 (m, 2H), 3.5 (vbm, 4H), 2.70 (bd, J=13 2 Hz, 1H), 2.60 (bd, J=13 Hz, 1H), 1.39 (bs, 1H), 0.68 (bs, 1H), 0.20 (bs, 1H). Patent; PFIZER INC.; EP413455; (1991); (A2) English View in Reaxys X : EXAMPLE X EXAMPLE X The procedure of Example IX was repeated except that 6.4 parts of 2-propyl tosylate was used in lieu of the n-butyl tosylate to obtain the 2-propyl ether of the alkyl polyglucoside. Patent; Master Chemical Corporation; US6958314; (2005); (B2) English View in Reaxys Trifluoroacetic acid (TFA) 1-Hydroxybenzotriazole (HOBt) Diisopropylether (DIPE) Piperidine Patent; Takeda Pharmaceutical Company Limited; US2010/112089; (2010); (A1) English View in Reaxys 3 : Example 3 Example 3 Deprotection of Mono and Bicyclic RLX1A, RLX2A, Met(O)24-RLX1B and Met(O)25-RLX2B. General Procedure: The protected RLX obtained as described above in Example 1 (0.005 mmol) was treated with a mixture of 5 mL of TFA/triisopropylsilane (TIPS)/anisole/water (91:4:1:4) for three hours at 5° C. and for one hour at 15° C. The resulting solution was then concentrated in vacuum and precipitated by the addition of diisopropylether and washed three times with 5 ml diisopropylether. The obtained solid was then dried in vacuum (25° C., 15 Torr) to constant weight. The procedure was repeated for each chain A and chain B. Patent; Chemical and Biopharmaceutical Laboratories of Patras S.A.; US2011/39778; (2011); (A1) English

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View in Reaxys O O O

O O

Rx-ID: 24982345 View in Reaxys 80/127 Yield

Conditions & References

80%

J.1 : J1. J1. diethyl 2-nitro-4-benzoylphenylmalonate To a solution of sodium ethoxide, formed by reacting 4.6 g. (0.2 mole) of sodium metal with 200 ml. of ethanol, at 0° C. was added 32 g. (0.2 mole) of diethyl malonate followed by 26.1 g. (0.1 mole) of 4-chloro-3-nitrobenzophenone. The mixture was allowed to stir at room temperature for 2 hours and was then poured into 400 ml. of ice cold 2N hydrochloric acid and 300 ml. of methylene chloride. The organic layer was separated, dried over magnesium sulfate and concentrated to an oil. The residual oil was induced to crystallize by trituration with hexane containing trace amounts of diisopropyl ether, 34.75 g., m.p. 68°-70° C. The sample was further purified by trituration with hot hexane-diisopropyl ether, 30.84 g. (80percent yield). Anal. Calcd. for C20 H19 NO7: C, 62.3; H, 5.0; N, 3.6. Found: C, 62.3; H, 4.9; N, 3.6. Patent; Pfizer Inc.; US4725616; (1988); (A1) English View in Reaxys

80%

J.1 : J1. J1. diethyl 2-nitro-4-benzoylphenylmalonate To a solution of sodium ethoxide, formed by reacting 4.6 g. (0.2 mole) of sodium metal with 200 ml. of ethanol, at 0°C. was added 32 g. (0.2 mole) of diethyl malonate followed by 26.1 g. (0.1 mole) of 4-chloro-3-nitrobenzophenone. the mixture was allowed to stir at room temperature for 2 hours and was then poured into 400 ml. of ice cold 2 N hydrochloric acid and 300 ml. of methylene chloride. The organic layer was separated, dried over magnesium sulfate and concentrated to an oil. The residual oil was induced to crystallize by trituration with hexane containing trace amounts of diisopropyl ether, 34.75 g., m.p. 68-70°C. The sample was further purified by trituration with hot hexane-diisopropyl ether, 30.84 g. (80percent yield). Patent; PFIZER INC.; EP208510; (1991); (B1) English View in Reaxys O

O S O O

N N

S O

(v3)

Rx-ID: 23935794 View in Reaxys 81/127 Yield 83%

Conditions & References 235 : N-[4-[4-(N,N-Dimethanesulfonylamino)phenyl]phenyl]-(2-chloro-5-nitrophenyl)carboxamide Example 235 N-[4-[4-(N,N-Dimethanesulfonylamino)phenyl]phenyl]-(2-chloro-5-nitrophenyl)carboxamide Triethylamine (0.55 ml, 4.0 mmol) and methanesulfonyl chloride (0.17 ml, 2.2 mmol) were added to a solution of N[4-(4-aminophenyl)phenyl]-(2-chloro-5-nitrophenyl)carboxamide (0.37 g, 1.0 mmol) prepared in Example 192 in THF (10 ml). The mixture was stirred for 3 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and ethyl acetate and the resulting mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate. The organic layer was separated, washed sequentially with saturated aqueous potassium bisulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated.

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The resulting residue was solidified by addition of diisopropyl ether and hexane and the resulting solid was filtered to afford the title compound (0.44 g, yield 83percent). 1H-NMR (DMSO-d , 400 MHz): δ(ppm) 3.56 (6H, s), 7.60 (2H, d, J=8.4 Hz), 7.78 (2H, d, J=8.8 Hz), 7.78 (2H, d, 6 J=8.4 Hz), 7.84 (2H, d, J=8.8 Hz), 7.92 (1H, d, J=8.8 Hz), 8.36 (1H, dd, J=8.8, 2.7 Hz), 8.50 (1H, d, J=2.7 Hz), 10.86 (1H, s); MS(FAB) m/z: 524 (M+H)+. Patent; SANKYO COMPANY, LIMITED; US2003/134859; (2003); (A1) English View in Reaxys

N-{2-cyclopentyloxy-6-[(3,5-dichloro-pyridin-4-yl-methyl)acetyl]-3-methoxy-phenyl}-malonaminic acid methyl ester

Rx-ID: 24216926 View in Reaxys 82/127 Yield 74%

Conditions & References 34 : Synthesis of N-{2-Cyclopentyloxy-6-[(3,5-dichloro-pyridin-4-yl-methyl)acetyl]-3-methoxy-phenyl}-malonaminic Acid Methyl Ester EXAMPLE 34 Synthesis of N-{2-Cyclopentyloxy-6-[(3,5-dichloro-pyridin-4-yl-methyl)acetyl]-3-methoxy-phenyl}-malonaminic Acid Methyl Ester A solution under nitrogen of 1-(2-amino-3-cyclopentyloxy-4-methoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl-methyl)-etanone (4 g, 10 moles), obtained as described in example 31, in acetic acid (50 ml) was added with methyl-malonyl cliloride (1.32 ml, 11 moles), and the mixture was left under stirring overnight, then dried under vacuum, taken up in methylene chloride, twice washed with an aqueous solution of NaHCO3 and concentrated under vacuum to give a residue which tritured with isopropyl ether gave 3.68 g of the title product (yield: 74percent). (200 MHz, CDCl3) δ (ppm): 9.39 (m, 1H); 8.47 (s, 2H); 7.58 (d, 1H, JHH=8.8 Hz); 6.83 (d, 1H); 4.87-4.79

1H-NMR

(m, 1H); 4.60 (s, 2H); 3.90 (s, 3H); 3.73 (s, 3H); 3.40 (s, 2H); 1.86-1.50 (m, 8H). Patent; Zambon Group S.p.A.; US6297257; (2001); (B1) English View in Reaxys O S

N NH

N O

Rx-ID: 24366405 View in Reaxys 83/127 Yield 80%

Conditions & References 18.2 : Step 2 Step 2 To 450 mg of 2-[N-(4-cyanobenzoyl)amino]-4-hydroxycarbonyl-1,3-thiazole, 10 ml of anhydrous methylene chloride were added. Under an argon gas atmosphere, 803 mg of 1,1'-carbonyldiimidazole were added and the resulting mixture was stirred for one hour. To the reaction mixture, 720 mg of 2-diisopropylaminoethanol were added and the resulting mixture was stirred for 1.5 hours. Chloroform was added to the reaction mixture. The resulting mixture was washed successively with water, a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (chloroform:methanol=9:1). To the resulting solid, diisopropyl ether was added, followed by trituration, whereby 528 mg of the title compound were obtained as a colorless solid. Yield: 80percent. Melting point: 152 to 153° C. MS (FAB) m/z: 401 (MH+); IR (KBr) cm-1: 2969, 2230, 1725, 1673, 1545; 1 H-NMR (CDCl3) δ: 1.01(6H,d), 2.71(2H,t), 2.94-3.07(2H,m), 4.14(2H,t), 7.79-7.83(2H,m), 7.91(1H,s), 7.99-8.03(2H,m). Patent; Zeria Pharmaceutical Co., Ltd.; US6121301; (2000); (A1) English View in Reaxys

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O Cl O

O O HN

Rx-ID: 24595423 View in Reaxys 84/127 Yield 63%

Conditions & References 48 : 4-(2-Chlorophenyl)-2,6-dimethyl-5-(2-methoxyethoxycarbonyl)-1,4-dihydropyridine-3-carboxylic acid-3[N-(1,2-benzisothiazolyl-3-(2H)one-1,1-dioxide)]-propylester EXAMPLE 48 4-(2-Chlorophenyl)-2,6-dimethyl-5-(2-methoxyethoxycarbonyl)-1,4-dihydropyridine-3-carboxylic acid-3-[N-(1,2-benzisothiazolyl-3-(2H)one-1,1-dioxide)]-propylester A mixture of 15 g (0.03M) of 2-(2-chlorobenzylidene)-acetyl acetic acid-3-[N-(1,2-benzisothiazolyl-3(2H)one-1,1-dioxide)]-propylester (obtained as described.in Example 32) and 5.33 g (0.03M) of 3-amino crotonic acid-2-methoxyethylester is heated at reflux and stirred in 35 ml of absolute ethanol for 24 hours. After that time the solvent is removed by distillation under reduced pressure and the resulting residue dissolved in 15 ml of boiling diisopropylether. Finally the resulting solution is cooled overnight to -10° C. to give a yellow solid having a melting point of 99° to 101° C. (recrystallized from ethanol). The yield is 63percent. Patent; Sunkel; Carlos; Fau De Casa-Juana; Miguel; Santos; Luis; Alonso; Salvador; Garcia; Antonio; Priego; Jaime; US5691361; (1997); (A1) English View in Reaxys

63 %

48 : Example 48 Example 48 4-(2-Chlorophenyl)-2,6-dimethyl-5-(2-methoxyethoxycarbonyl)-1,4-dihydropyridine-3-carboxylic acid-3-[N-(1,2-benzisothiazolyl-3(2H)one-1,1-dioxide)]-propylester A mixture of 15 g (0.03 M) of 2-(2-chlorobenzylidene)-acetyl acetic acid-3-[N-(1,2-benzisothiazolyl-3(2H)one-1,1-dioxide)]-propylester (obtained as described in Example 32) and 5.33 g (0.03 M) of 3-amino crotonic acid-2-methoxyethylester is heated at reflux and stirred in 35 ml of absolute ethanol for 24 hours. After that time the solvent is removed by distillation under reduced pressure and the resulting residue dissolved in 15 ml of boiling diisopropylether. Finally the resulting solution is cooled overnight to -10°C to give a yellow solid having a melting point of 99 to 101°C (recrystallized from ethanol). The yield is 63 percent. Patent; ALTER, S.A.; EP441736; (1991); (A2) English View in Reaxys O

1,1'-dibenzoimidazole Rx-ID: 24216927 View in Reaxys 85/127 Yield 61.7%

Conditions & References 10.a : a) a) Preparation of 1,1'-dibenzoimidazole 200 ml of a solution of potassium permanganate (1.6 g) are dripped in a suspension of 2,2'-diphormyl-1,1'dibenzoimidazole (3.00 g) in water (200 ml), benzene (70 ml) and 1.12 g of sodium carbonate. The mix is left under stirring for 48 hours. Sodium bisulfite is added until the manganese bioxide disappears, then the solution is brought to an acid pH with a 10percent solution of hydrochloric acid and the organic phase is extracted with methylene chloride, anhydrified with sodium sulfate and freed from the solvent under reduce pressure to produce a residue which is crust-freed with isopropyl ether, supplying 1.5 g of product with m.p. 188° C. (61.7percent yield). 1 H-NMR: 7.02 (2H, d, in position 4 and 4'); 7,3-7,5 (4H, m, in position 5 and 5', 6 and 6'); 7.92 (2H, d, in position 7 and 7'); 8.17 (2H, s, in position 2 and 2').

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Patent; Italfarmaco Sud S.p.A.; US5907045; (1999); (A1) English View in Reaxys

O Cl

N Cl O

Rx-ID: 24366402 View in Reaxys 86/127 Yield 21.9 g (35.6%)

Conditions & References 15 : 3-(4-Chlorophenoxy)-1-azetidinecarbonyl chloride Preparation 15 3-(4-Chlorophenoxy)-1-azetidinecarbonyl chloride A solution of 32.34 g (0.33 mole) of phosgene in 200 ml of methylene chloride cooled with a tap water bath was treated with 45.5 g (0.33 mole) of potassium carbonate and stirred for 30 min, then 105 g (0.3 mole) of 3-(4-chlorophenoxy)-1-diphenylmethylazetidine in 600 ml of methylene chloride was added dropwise. After stirring for an additional 18 hr, the reaction mixture was filtered to remove the inorganic salts then concentrated in vacuo to a dark oily residue, 127.7 g. A solid formed upon standing which was triturated with boiling 30/60 petroleum ether 3 times to remove diphenylmethyl chloride. The residue, 33 g of dark brown crystalline material, was mainly starting materia. Upon standing, a white crystalline material separated from the petroleum ether triturates (4.4 g, m.p. 78°-80° C.). The triturates were concentrated in vacuo, yielding 31 g of pale yellow tacky crystals. Trituration of these crystals with isopropyl ether yielded 21.9 g (35.6percent) of pale yellow crystalline product. Analysis: Calculated for C10 H9 Cl2 NO2: C,48.81; H,3.69; N,5.69 Found: C,49.10; H,3.61; N,5.63 Patent; A. H. Robins Company, Incorporated; US5183902; (1993); (A1) English View in Reaxys

21.9 g (35.6%)

15 : 3-(4-Chlorophenoxy)-1-azetidinecarbonyl chloride PREPARATION 15 3-(4-Chlorophenoxy)-1-azetidinecarbonyl chloride A solution of 32.34 g (0.33 mole) of phosgene in 200 ml of methylene chloride cooled with a tap water bath was treated with 45.5 g (0.33 mole) of potassium carbonate and stirred for 30 min, then 105 g (0.3 mole) of 3-(4-chlorophenoxy)-1-diphenylmethylazetidine in 600 ml of methylene chloride was added dropwise. After stirring for an additional 18 hr, the reaction mixture was filtered to remove the inorganic salts then concentrated in vacuo to a dark oily residue, 127.7 g. A solid formed upon standing which was triturated with boiling 30/60 petroleum ether 3 times to remove diphenylmethyl chloride. The residue, 33 g of dark brown crystalline material, was mainly starting material. Upon standing, a white crystalline material separated from the petroleum ether triturates (4.4 g, m.p. 78°-80° C.). The triturates were concentrated in vacuo, yielding 31 g of pale yellow tacky crystals. Trituration of these crystals with isopropyl ether yielded 21.9 g (35.6percent) of pale yellow crystalline product. Analysis: Calculated for C10 H9 Cl2 NO2: C,48.81; H,3.69; N,5.69. Found: C,49.10; H,3.61; N,5.63. Patent; A. H. Robins Company, Inc.; US4956359; (1990); (A1) English View in Reaxys

21.9 g (35.6%)

15 : 3(4-Chlorophenoxy)-1-azetidinecarbonyl chloride PREPARATION 15 3(4-Chlorophenoxy)-1-azetidinecarbonyl chloride A solution of 32.34 g (0.33 mole) of phosgene in 200 ml of methylene chloride cooled with a tap water bath was treated with 45.5 g (0.33 mole) of potassium carbonate and stirred for 30 min, then 105 g (0.3 mole) of 3-(4-chlorophenoxy)-1-diphenylmethylazetidine in 600 ml of methylene chloride was added dropwise. After stirring for an additional 18 hr, the reaction mixture was filtered to remove the inorganic salts then concentrated in vacuo to a dark oily residue, 127.7 g. A solid formed upon standing which was triturated with boiling 30/60 petroleum ether 3 times to remove diphenylmethyl chloride. The residue, 33 g of dark brown crystalline material, was mainly starting material. Upon standing, a white crystalline material separated from the petroleum ether triturates (4.4 g, m.p. 78°-80° C.).

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The triturates were concentrated in vacuo, yielding 31 g of pale yellow tacky crystals. Trituration of these crystals with isopropyl ether yielded 21.9 g (35.6percent) of pale yellow crystalline product. Analysis: Calculated for C10 H9 Cl2 NO2: C,48.81; H,3.69; N,5.69. Found: C,49.10; H,3.61; N.563. Patent; A. H. Robins Company Incorporated; US5068231; (1991); (A1) English View in Reaxys 21.9 g (36%)

6 : 3-(4-Chlorophenoxy)-1-azetidinecarbonyl chloride PREPARATION 6 3-(4-Chlorophenoxy)-1-azetidinecarbonyl chloride A solution of 32.34 g (0.33 mole) of phosgene in 200 ml of methylene chloride cooled with a tap water bath was treated with 45.5 g (0.33 mole) of potassium carbonate and stirred for 30 min. Then 105 g (0.3 mole) of 3-(4-chlorophenoxy)-1-(diphenylmethyl)azetidine in 600 ml of methylene chloride was added dropwise. After stirring for an additional 18 h, the reaction mixture was filtered to remove the inorganic salts then concentrated in vacuo to a oily residue, 127.7 g. A solid formed upon standing which was triturated with boiling petroleum ether 3 times to remove the diphenylmethyl chloride. The residue, 33 g of dark brown crystalline material, was mainly starting material. Upon standing a white crystalline material separated from the petroleum ether triturates (4.4 g, mp 78°-80° C., sent for elemental analysis). The triturates were concentrated in vacuo yielding 31 g of pale yellow tacky crystals. Trituration of these crystals with 2-propyl ether yielded 21.9 g (36percent) of pale yellow crystalline product. Analysis: Calculated for C10 H9 Cl2 NO2: C, 48.807; H, 3.687; N, 5.692. Found: C, 49.10; H, 3.61; N, 5.63. Patent; A. H. Robins Company, Incorporated; US5095014; (1992); (A1) English View in Reaxys

O Cl

N O

Rx-ID: 24366403 View in Reaxys 87/127 Yield

Conditions & References 16 : 3-(3-Bromophenoxy)-1-azetidinecarbonyl chloride Preparation 16 3-(3-Bromophenoxy)-1-azetidinecarbonyl chloride A solution of 22.7 g (0.23 mole) of phosgene in 200 ml of methylene chloride was treated with 29 g (0.23 mole) of potassium carbonate, stirred for 30 min, then 75.4 g (0.19 mole) of 3-(3-bromophenoxy)-1-diphenylmethylazetidine in 150 ml of methylene chloride was added dropwise. After stirring for 5 hr, the inorganic salts were removed by filtration and the filtrate was washed with water to destroy excess phosgene. Concentration (after drying) in vacuo yielded 96.85 g of oily residue. Trituration of the residue with isopropyl ether yielded 42 g of crude tan-gray product. A sample for analysis was recrystallized from isopropyl ether, m.p. 87°-88° C. Analysis: Calculated for C10 H9 BrClNO2: C,41.34; H,3.12; N,4.82 Found: C,41.12; H,3.14; N,4.78 Patent; A. H. Robins Company, Incorporated; US5183902; (1993); (A1) English View in Reaxys 16 : 3-(3-Bromophenoxy)-1-azetidinecarbonyl chloride PREPARATION 16 3-(3-Bromophenoxy)-1-azetidinecarbonyl chloride A solution of 22.7 g (0.23 mole) of phosgene in 200 ml of methylene chloride was treated with 29 g (0.23 mole) of potassium carbonate, stirred for 30 min, then 75.4 g (0.19 mole) of 3-(3-bromophenoxy)-1-diphenylmethylazetidine in 150 ml of methylene chloride was added dropwise. After stirring for 5 hr, the inorganic salts were removed by filtration and the filtrate was washed with water to destroy excess phosgene.

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Concentration (after drying) in vacuo yielded 96.85 g of oily residue. Trituration of the residue with isopropyl ether yielded 42 g of crude tan-gray product. A sample for analysis was recrystallized from isopropyl ether, m.p. 87°-88° C. Analysis: Calculated for C10 H9 BrClNO2: C,41.34; H,3.12; N,4.82. Found: C,41.12; H,3.14; N,4.78. Patent; A. H. Robins Company, Inc.; US4956359; (1990); (A1) English View in Reaxys 16 : 3-(3-Bromophenoxy)-1-azetidinecarbonyl chloride PREPARATION 16 3-(3-Bromophenoxy)-1-azetidinecarbonyl chloride A solution of 22.7 g (0.23 mole) of phosgene in 200 ml of methylene chloride was treated with 29 g (0.23 mole) of potassium carbonate, stirred for 30 min, then 75.4 g (0.19 mole) of 3-(3-bromophenoxy)-1-diphenylmethylazetidine in 150 ml of methylene chloride was added dropwise. After stirring for 5 hr, the inorganic salts were removed by filtration and the filtrate was washed with water to destroy excess phosgene. Concentration (after drying) in vacuo yielded 96.85 g of oily residue. Trituration of the residue was isopropyl ether yielded 42 g of crude tan-gray product. A sample for anaylsis was recrystallized from isopropyl ether, m.p. 87°-88° C. Analysis: Calculated for C10 H9 BrClNO2: C,41.34; H,3.12; N,4.82. Found: C,41.12; H,3.14; N,4.78. Patent; A. H. Robins Company Incorporated; US5068231; (1991); (A1) English View in Reaxys

O O F F

N HN E

Rx-ID: 24366404 View in Reaxys 88/127 Yield 3.75 g (59.7%)

Conditions & References 26 : (E)-N-(2-Butenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide EXAMPLE 26 (E)-N-(2-Butenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide A solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in 60 ml of methylene chloride was cooled in an ice bath while stirring under nitrogen while 1.6 g (0.022 mole) of trans-crotylamine was added dropwise. After warming to ambient temperature, 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate was added all at once followed in 0.25 hr by 5 ml of triethylamine with stirring continued for 72 hr. The reaction solution was washed with 2*50 ml of water, dried over magnesium sulfate and concentrated on a rotary evaporator to a solid residue, 7 g. Recrystallization from methanol-water gave 5.5 g of slightly yellow product. A second recrystallization with charcoal treatment from isopropyl ether yielded 3.75 g (59.7percent) of fine white crystals, m.p. 127°-128° C. Analysis: Calculated for C15 H17 F3 N2 O2: C,57.32; H,5.45; N,8.91 Found: C,57.35; H,5.47; N,8.94 Patent; A. H. Robins Company, Incorporated; US5183902; (1993); (A1) English View in Reaxys

3.75 g (59.7%)

26 : (E)-N-(2-Butenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide EXAMPLE 26 (E)-N-(2-Butenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide A solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in 60 ml of methylene chloride was cooled in an ice bath while stirring under nitrogen while 1.6 g (0.022 mole) of trans-crotylamine was added dropwise. After warming to ambient temperature, 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate was added all at once followed in 0.25 hr by 5 ml of triethylamine with stirring continued for 72 hr. The reaction solution was washed with 2*50 ml of water, dried over magnesium sulfate and concentrated on a rotary evaporator to a solid residue, 7 g. Recrystallization from methanol-water gave 5.5 g of slightly yellow product.

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A second recrystallization with charcoal treatment from isopropyl ether yielded 3.75 g (59.7percent) of fine white crystals, m.p. 127°-128° C. Analysis: Calculated for C15 H17 F3 N2 O2: C,57.32; H,5.45; N,8.91. Found: C,57.35; H,5.47; N,8.94. Patent; A. H. Robins Company, Inc.; US4956359; (1990); (A1) English View in Reaxys 3.75 g (59.7%)

26 : (E)-N-(2-Butenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide EXAMPLE 26 (E)-N-(2-Butenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide A solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in 60 ml of methylene chloride was cooled in an ice bath while stirring under nitrogen while 1.6 g (0.022 mole) of trans-crotylamine was added dropwise. After warming to ambient temperature, 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate was added all at once followed in 0.25 hr by 5 ml of triethylamine with stirring continued for 72 hr. The reaction solution was washed with 2*50 ml of water, dried over magnesium sulfate and concentrated o n a rotary evaporator to a solid residue. 7 g. Recrystallization from methanol-water gave 5.5 g of slightly yellow product. A second recrystallization with charcoal treatment from isopropyl ether yielded 3.75 g (59.7percent) of fine white crystals, m.p. 127°-128° C. Anaylsis: Calculated for C15 H17 F3 N2 O2: C,57.32; H,5.45; N,8.91. Found: C,57.35; H,5.47; N, 8.94. Patent; A. H. Robins Company Incorporated; US5068231; (1991); (A1) English View in Reaxys O

H N

O O O

OH O

S O

Rx-ID: 24005620 View in Reaxys 89/127 Yield 18%

Conditions & References 1.7 : Step 7 Step 7 4-[4-(2-Chloro-benzyloxy)-benzenesulfonyl]-3-hydroxy-TETRAHYDRO-pyran-3-carboxylic acid hydroxyamide To a mixture of the product from the previous step (160 mg, 0.4 mmoles), 1-hydroxybenzotriazole hydrate (76 mg, 0.6 mmoles), allyl hydroxylamine hydrochloride (62 mg, 0.6 mmoles), diisopropylethylamine (0.13 ml, 0.7 mmoles) in 2 ml of anhydrous methylene chloride at room temperature, was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI). After stirring for 48 hours, the mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 4 ml of 20percent water in acetonitrile and was treated with 1.6 g of 5:2 (v/v) formic acid-triethylamine and 44 mg of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4). After being shaken at 85° C. for 30 minutes, the mixture was diluted with ether and extracted 4 times into 1 M sodium hydroxide. The combined aqueous layers were washed 3 times with ether, acidified to pH 1 with 6M hydrochloric acid and were extracted 3 times into ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The compound was purified by preparative TLC plate eluding with 10percent methanol in methylene chloride. The silica was washed with 20percent methanol in methylene chloride with 1percent acetic acid, the filtrate concentrated in vacuo. After trituration and collection with isopropyl ether the product was isolated as a colorless solid (30mg, 18percent). Patent; Noe, Mark C.; US2002/19534; (2002); (A1) English View in Reaxys

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O E

N H

Rx-ID: 24294163 View in Reaxys 90/127 Yield

Conditions & References

18%

8.A : (E)-4- [(3-Phenyl-prop-2-enyl) carbamoyl]benzohydroxamic acid A. 1.75 g (13 mmoles) of trans-cinnamol were dissolved in 130 ml of acetonitrile under argon atmosphere, then 5 g (19 mmoles) of N,N'-disuccinimidyl-carbonate were added heating until complete dissolution, then the mixture was cooled at 20° C. and added with pyridine (0.65 ml, 1 g, 12 mmoles). The reaction mixture was covered with aluminium and stirred at room temperature for 30 hours. The solvent was evaporated off in the cold, the residue was taken up into ethyl acetate and washed repeatedly with 0.1N HCl, finally with water. The solution was dried, then evaporated to dryness in the cold, to give a crude which was dissolved in 26 ml of dioxane and added to a solution of p-aminobenzoic acid (1.79 g, 13 mmoles) in 26 ml of water with 1.38 (13 mmoles) of sodium carbonate. The solution was stirred at room temperature for 60 hours, then added with THF and brine. The organic phase was separated and washed with 0.1N HCl (twice) and again with brine, then dried and!portata a secco stripped. The resulting crude was taken up into isopropyl ether and filtered, thereby obtaining 0.7 g of (E)-4-[(3-phenyl-prop-2enyl)-carbamoyl]benzoic acid (18percent yield); m.p.=176-178° C. 1 H-NMR d 12.70 (s, 1H, exchange with D O), 10.20 (s, 1H), 7.93 (d, 2H), 7.61 (d, 2H), 7.557.25 (m, 5H), 6.78 (d, 2 1H), 6.46 (dt, 1H), 4.87 (d, 2H). Patent; Italfarmaco S.p.A.; US6034096; (2000); (A1) English View in Reaxys

N O

H N

O O

HN O

O P

O O

Rx-ID: 24982346 View in Reaxys 91/127 Yield

Conditions & References 3.d : (d) (d) (R and S)-1-Acetoxyethyl (6R,7R)-3-Dimethoxyphosphorylcarbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate Potassium iodide (2.50 g) and acetyl chloride (0.56 ml) were successively added, at 0°, to a solution of the product of (b) above (2.38 g) in dimethylformamide (15 ml). The reaction mixture was stirred for 70 minutes at 0° and was then partitioned between ethyl acetate (100 ml) and 2 N-hydrochloric acid (100 ml). The aqueous phase was extracted with ethyl acetate (2*50 ml) and the combined organic extracts were successively washed with 2 N-hydrochloric acid (100 ml), aqueous sodium metabisulphite solution (2*100 ml), 2 N-hydrochloric acid (100 ml), water (100 ml), saturated aqueous sodium bicarbonate solution (100 ml), water (100 ml) and saturated brine (100 ml). The organic extract was dried (magnesium sulphate) and evaporated in vacuo to a yellow foam which on precipitation from diisopropyl ether afforded the title ester (1.722 g) as a pale-yellow solid, m.p. (M70 2) 101°, [α]D 22.5 +22.4° (c 0.89, DMSO). Patent; Glaxo Group Limited; US4258183; (1981); (A1) English View in Reaxys 4.c : (c)

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(c) (R and S)-1-Acetoxyethyl (6R,7R)-3-Dimethoxyphosphorylcarbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate Potassium iodide (2.50 g) and acetyl chloride (0.56 ml) were successively added, at 0°, to a solution of the product of (b) above (2.38 g) in DMF (15 ml). The reaction mixture was stirred for 70 minutes at 0° and was then partitioned between ethyl acetate (100 ml) and 2 N-hydrochloric acid (100 ml). The aqueous phase was extracted with ethyl acetate (2*50 ml) and the combined organic extracts were successively washed with 2 N-hydrochloric acid (100 ml), aqueous sodium metabisulphite solution (2*100 ml), 2 N-hydrochloric acid (100 ml), water (100 ml), saturated aqueous sodium bicarbonate solution (100 ml), water (100 ml) and saturated brine (100 ml). The organic extract was dried (magnesium sulphate) and evaporated in vacuo to a yellow foam which on precipitation from diisopropyl ether afforded the title ester (1.722 g) as a pale-yellow solid, m.p. (M70 2) 101°, [α]D 22.5 +22.4° (c 0.89, DMSO). Patent; Glaxo Group Limited; US4284766; (1981); (A1) English View in Reaxys

N O

H N

O O

HN O

O P

O O

Rx-ID: 24982347 View in Reaxys 92/127 Yield

Conditions & References 3.c : (c) (c) (R and S)-1-Acetoxyethyl (1S,6R,7R)-3-Dimethoxyphosphorylcarbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate, 1-oxide m-Chloroperbenzoic acid (0.944 g) in dichloromethane (10 ml) was added at 0° to a stirred solution of two batches of (R and S)-1-acetoxyethyl (6R,7R)-3-dimethoxyphosphorylcarbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate and its Δ2 isomer (ratio ca 3:2) (3.34 g) in dry dichloromethane (20 ml). After 25 minutes reaction was not complete (by t.l.c) so another portion of m-chloroperbenzoic acid (93 mg) was added and the reaction mixture was stirred for a further 10 minutes and evaporated in vacuo to a foam. T.l.c. indicated incomplete oxidation so the foam was re-dissolved in dichloromethane and treated with further m-chloroperbenzoic acid (0.236 g) for 20 minutes by which time reaction was complete. The reaction mixture was then evaporated in vacuo to a foam which was dissolved in ethyl acetate (5 ml) and precipitated from excess di-isopropyl ether to give the title compound (3.033 g) as a pale-yellow solid, m.p. (M130 2) 150°, [α]D 22 +67.5° (c 0.98, DMSO). Patent; Glaxo Group Limited; US4258183; (1981); (A1) English View in Reaxys 4.b : (b) (b) (R and S)-1-Acetoxyethyl (1S,6R,7R)-3-Dimethoxyphosphorylcarbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate, 1-oxide m-Chloroperbenzoic acid (0.944 g) in dichloromethane (10 ml) was added at 0° to a stirred solution of two batches of (R and S)-1-acetoxyethyl (6R,7R)-3-dimethoxyphosphorylcarbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate and its Δ2 isomer (ratio ca 3:2) (3.34 g) in dry dichloromethane (20 ml). After 25 minutes reaction was not complete (by t.l.c) so another portion of m-chloroperbenzoic acid (93 mg) was added and the reaction mixture was stirred for a further 10 minutes and evaporated in vacuo to a foam. T.l.c. indicated incomplete oxidation so the foam was re-dissolved in dichloromethane and treated with further m-chloroperbenzoic acid (0.236 g) for 20 minutes by which time reaction was complete.

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The reaction mixture was then evaporated in vacuo to a foam which was dissolved in ethyl acetate (5 ml) and precipitated from excess di-isopropyl ether to give the title compound (3.033 g) as a pale-yellow solid, m.p. (M130 2) 150°, [α]D 22 +67.5° (c 0.98, DMSO). Patent; Glaxo Group Limited; US4284766; (1981); (A1) English View in Reaxys

O N

HO O

O OH

N O O

Rx-ID: 25059823 View in Reaxys 93/127 Yield

Conditions & References 2 : 1-Isopropyl-3,3-diphenyl-4-[2-(4-phenyl-4-propionoxypiperidinyl)ethyl]-2-pyrrolidinone Oxalate EXAMPLE 2 1-Isopropyl-3,3-diphenyl-4-[2-(4-phenyl-4-propionoxypiperidinyl)ethyl]-2-pyrrolidinone Oxalate A stirred mixture of 0.04 mole of 4-[2-(4-hydroxy-4-phenyl-1-piperidinyl)ethyl]-1-isopropyl-3,3-diphenyl-2-pyrrolidinone and 60 g. of potassium carbonate in 50 ml. of chloroform was treated with 4.5 g. (0.05 mole) of propionyl chloride in 25 ml. of chloroform. After stirring for one hour the mixture was cooled to 0° in ice and treated with 100 ml. of crushed ice. The mixture was stirred until the ice melted, the chloroform layer was separated, dried over magnesium sulfate and evaporated to an oil. The oxalate salt was prepared in isopropanol and precipitated with isopropyl ether. Recrystallization from the same solvent system gave 14.5 g. (58percent), m.p. 178°-180° C. Analysis: Calculated for C37 H44 N2 O7: C,70.68; H,7.05; N,4.45; Found: C,70.47; H,6.82; N,4.66. Patent; A. H. Robins Company, Inc.; US4324791; (1982); (A1) English View in Reaxys 2 : 1-Isopropyl-3,3-diphenyl-4-[2-(4-phenyl-4-propionoxypiperidinyl)ethyl]-2-pyrrolidinone Oxalate EXAMPLE 2 1-Isopropyl-3,3-diphenyl-4-[2-(4-phenyl-4-propionoxypiperidinyl)ethyl]-2-pyrrolidinone Oxalate A stirred mixture of 0.04 mole of 4-[2-(4-hydroxy-4-phenyl-1-piperidinyl)ethyl]-1-isopropyl-3,3-diphenyl-2-pyrrolidinone and 60 g. of potassium carbonate in 50 ml. of chloroform was treated with 4.5 g. (0.05 mole) of propionyl chloride in 25 ml. of chloroform. After stirring for one hour the mixture was cooled to 0° in ice and treated with 100 ml. of crushed ice. The mixture was stirred until the ice melted, the chloroform layer was separated, dried over magnesium sulfate and evaporated to an oil. The oxalate salt was prepared in isopropanol and precipitated with isopropyl ether. Recrystallization from the same solvent system gave 14.5 g. (58percent), m.p. 178°-180° C. Analysis: Calculated for C37 H44 N2 O7: C, 70.68; H, 7.05; N, 4.45. Found: C, 70.47; H, 6.82; N, 4.66. Patent; A. H. Robins Company, Incorporated; US4120969; (1978); (A1) English View in Reaxys O

2,2'-bis diphenylphosphin)-4,4',6,6'-tetramethyl-3,3'-dibenzo[b]thiophene

Rx-ID: 24216928 View in Reaxys 94/127 Yield

Conditions & References 1.b : Preparation of the chiral diphosphines (III R) and (III S). In a solution of 0.35 g of 4,4',6,6'-tetramethyl-3,3'-dibenzo[b]thiophene and 0.39 g of TMEDA in 20 ml of anhydrous THF, 1.1 ml of BuLi 1.6M were dripped in inert atmosphere and at a temperature of -50° C.

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After half an hour, the temperature was raised to 0° C. and 0.5 mI of diphenylchlorophosphine were dripped. The reaction mix was left to react for 12 hours and then was freed from the solvent under reduced pressure and treated with water. The organic phase was extracted with ether, made anhydrous on Na2 SO4, and the solvent was eliminated under reduced pressure. The residue obtained was treated with isopropylether and 0.4 g of 2,2'-bis diphenylphosphin)-4,4',6,6'-tetramethyl-3,3'-dibenzo[b]thiophene were obtained. 1 H-NMR (300 MHz) (CDCl ) (ppm): 1.6 (6H, s, 2CH ), 2.4 (6H, s, 2CH ), 6.7 (2H, s, aromatic in 5,5'), 6,9-7,5 (22H, 3 3 3 m, aromatic in 7,7'+4C6 H5). Mass spectrometry (e.i.): (M+) 690. P-NMR (200 MHz) (CDCL3) (ppm: -24.98 (2P, s).

Patent; Italfarmaco Sud S.p.A.; US5907045; (1999); (A1) English View in Reaxys O

methyl N-[2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]carbamate fumarate

Rx-ID: 24443472 View in Reaxys 95/127 Yield

Conditions & References 133 : Methyl N-[2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]carbamate fumarate EXAMPLE 133 Methyl N-[2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]carbamate fumarate A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.0 gm, 7.6 mmol) and triethylamine (1.0 gm, 10 mmol) in DCM (50 ml) was treated with methyl chloroformate (860 mg, 9.12 mmol) dropwise at room temperature. The mixture was stirred for 1 hr. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over MgSO4 and concentrated to a crude oil. The purification was done by flash chromatography over a silica gel column (28 gm of Sorbsil C-30, eluted with DCM and MeOH/DCM). The pure oil thus obtained weighed 2.34 gm. It was converted to a fumarate salt by treatment with fumaric acid (840 mg, 1.0 eq) in ethanol. Crystallization was induced by adding drops of isopropyl ether, yield: 2.31 gm, m.p.=163°-165° C. Patent; Hoechst-Roussel Pharmaceuticals, Inc.; US5364866; (1994); (A1) English View in Reaxys

methyl 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl carbamate fumarate

Rx-ID: 24595421 View in Reaxys 96/127 Yield

Conditions & References 133 : Methyl 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl carbamate fumarate EXAMPLE 133 Methyl 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl carbamate fumarate A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.0 g, 7.6 mmol) and triethylamine (1.0 g, 10 mmol) in DCM (50 ml) was treated with methyl chloroformate (860 mg, 9.12 mmol) dropwise at room temperature. The mixture was stirred for I hour. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over MgSO4 and concentrated to a crude oil. The purification was done by flash chromatography over a silica gel column (28 g of Sorbsil C-30, eluted with DCM and MeOH/DCM). The pure oil thus obtained weighed 2.34 g. It was converted to a fumarate salt by treatment with fumaric acid (840 mg, 1.0 eq) in ethanol. Crystallization was induced by adding drops of isopropyl ether, yield: 2.31 g, m.p.=163°-165° C. Analysis: Calculated for C16 H20 FN3 O3.C4 H4 O4: 54.92percent C 5.53percent H 9.61percent N Found: 54.49percent C 5.45percent H 9.24percent N

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Patent; Hoechst Roussel Pharmaceuticals, Inc.; US5605913; (1997); (A1) English View in Reaxys N-(1-t-butyl)-2-[3-((3-carbomethoxy)phenyl)ureido)-2-oxo-5-(phenyl)-8-methyl-2,3,4,5tetrahydro-1H-(1)benzazepin-1-yl]ethanoic acid amide

Rx-ID: 24595422 View in Reaxys 97/127 Yield 410 mg (93%)

Conditions & References 33 : N-(1-t-butyl)-2-[3-((3-carbomethoxy)phenyl)ureido)-2-oxo-5-(phenyl)-8-methyl-2,3,4,5tetrahydro-1H(1)benzazepin-1-yl]ethanoic acid amide EXAMPLE 33 N-(1-t-butyl)-2-[3-((3-carbomethoxy)phenyl)ureido)-2-oxo-5-(phenyl)-8-methyl-2,3,4,5tetrahydro-1H-(1)benzazepin-1yl]ethanoic acid amide To a 100 ml round bottomed flask equipped with condenser and a nitrogen inlet were added 143 mg (0.792 mmol) 3carbomethoxybenzoic acid, 0.188 mL (0.872 mmol) diphenylphosphorylazide, 0.121 mL (0.872 mmol) triethylamine, and 5 mL dry benzene. The reaction was heated to reflux for 1 hour, cooled, 300 mg (0.792 mmol) N-(1-t-butyl)-2-[3-amino-2-oxo-5-(phenyl)-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoic acid amide was added, and the reaction refluxed for an additional 18 hours. The reaction mixture was then chromatographed on silica gel using ethyl acetate in methylene chloride as eluant to afford the product as an oil, 410 mg (93percent), which was triturated to a solid with isopropyl ether, 290 mg (66percent), M.P. 150°-160° C. 1 H NMR (δ, CDCl ): 1.25 (s, 9H), 2.31 (s, 3H), 2.7-3.0 (m, 3H), 3.27 (AB , J 3 q AB =16, Δv=274), 3.77 (s, 3H), 4.15 (m, 1H), 4.61 (m, 1H), 6.08 (s, 1H), 6.59 (d, 1H), 6.9-7.5 (m, 11H), 7.96 (s, 1H), 8.08 (s, 1H). 13 C. NMR (δ, DMSO-d ): 21.1, 28.6, 37.2, 43.9, 50.2, 51.6, 52.0, 60.4, 119.9, 123.2, 123.3, 123.5, 126.2, 126.3, 6 128.3, 128.5, 128.7, 130.4, 130.6, 135.1, 139.0, 139.8, 141.0, 142.0, 155.1, 167.2, 167.4, 171.2, 173. IR (KBr, cm.-1): 1682, 1668, 1652 (C=O) MS (percent): 557 (70, parent+1), 484 (100), 307 (37), 234 (48), 208 (7), 119 (5). Anal. Calc'd for C32 H36 N4 O5: C, 69.05; H, 6.52;N, 10.06. Found: C, 68.84; H, 6.59;N, 9.99. Patent; Pfizer Inc.; US5618811; (1997); (A1) English View in Reaxys

methyl 2-rsaquo;4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl carbamate fumarate

Rx-ID: 24664119 View in Reaxys 98/127 Yield

Conditions & References 133 : Methyl 2-4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl carbamate fumarate EXAMPLE 133 Methyl 2-4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl carbamate fumarate A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.0 g, 7.6 mmol) and triethylamine (1.0 g, 10 mmol) in DCM (50 ml) was treated with methyl chloroformate (860 mg, 9.12 mmol) dropwise at room temperature. The mixture was stirred for 1 hour. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over MgSO4 and concentrated to a crude oil. The purification was done by flash chromatography over a silica gel column (28 g of Sorbsil C-30, eluted with DCM and MeOH/DCM). The pure oil thus obtained weighed 2.34 g. It was converted to a fumarate salt by treatment with fumaric acid (840 mg, 1.0 eq) in ethanol. Crystallization was induced by adding drops of isopropyl ether, yield: 2.31 g, m.p.=163-165° C. ANALYSIS: Calculated for C16 H2 FN3 O3 *C4 H4 O4: 54.92percent C 5.53percent H 9.61percent N; Found: 54.49percent C 5.45percent H 9.24percent N Patent; Hoechst Marion Roussel, Inc.; US5776963; (1998); (A1) English View in Reaxys

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monosodium salt.monohydrate Rx-ID: 24903721 View in Reaxys 99/127 Yield

Conditions & References 60 : Monosodium salt.monohydrate of Compound 35 (Compound 35') EXAMPLE 60 Monosodium salt.monohydrate of Compound 35 (Compound 35') In this example, 1.00 g of 11-(2-diethylaminoethyl)imino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid (Compound 35) is dissolved in 100 ml of methanol and 5.5 ml of 28percent sodium methoxide methanol solution is added thereto. After stirring the mixture for one hour, the solvent is distilled away under reduced pressure. The residue is triturated by adding isopropylether and is recovered by filtration to obtain 0.98 g of the desired product as a white solid. Melting point: vague owing to absorption of moisture Patent; Kyowa Hakko Kogyo Co., Ltd.; US5116863; (1992); (A1) English View in Reaxys O

N-(1,1-dimethylethyl)-3-[2-[1-1H-indol-4-yl)ethenyl]-phenoxy]-propanamide

Rx-ID: 24903722 View in Reaxys 100/127 Yield

Conditions & References 24.B : STEP B: STEP B: N-(1,1-dimethylethyl)-3-[2-[1-1H-indol-4-yl)-ethenyl]-phenoxy]-propanamide and its hydrochloride Using the procedure of Step F of Example 1, with heating for 6 hours at 120° C., 70 g of the product of Step A, 50 ml of tert-butylamine and 2.9 g of potassium carbonate in 50 ml of ethanol were reacted to obtain after chromatography and crystalization from isopropyl ether, 7.4 g of the expected product in the form of the base melting at 112° C. The hydrochloride was prepared as in Step C of Example 22 using 4.6 g of the base to obtain 3.35 g of the expected hydrochloride melting at 238° to 240° C. Analysis: C23 H28 N2 O. HCl: Calculated: percent C, 71.76; percent H, 7.59; percent Cl, 9.21; percent N 7.28. Found: percent C, 71.8; percent H, 7.6; percent Cl, 9.4; percent N, 7.0. Patent; Roussel Uclaf; US5086070; (1992); (A1) English View in Reaxys

1-Isopropyl-3,3-diphenyl-4-[2-phenyl-4-ethoxycarbonylpiperidinyl)ethyl]-2-pyrrolidinone Oxalate

Rx-ID: 25059824 View in Reaxys 101/127 Yield

Conditions & References 3 : 1-Isopropyl-3,3-diphenyl-4-[2-phenyl-4-ethoxycarbonylpiperidinyl)ethyl]-2-pyrrolidinone Oxalate EXAMPLE 3 1-Isopropyl-3,3-diphenyl-4-[2-phenyl-4-ethoxycarbonylpiperidinyl)ethyl]-2-pyrrolidinone Oxalate A stirred mixture of 15 g. (0.044 mole) of 4-(2-chloroethyl)-1-isopropyl-3,3-diphenyl-2-pyrrolidinone, 0.044 mole of 4ethoxycarbonyl-4-phenylpiperidine and 15 g. of potassium carbonate in 50 ml. of n-butanol was refluxed for 24 hours. The mixture was cooled, filtered and evaporated to an oil. An oxalate salt was prepared in isopropanol and precipitated with isopropyl ether. The white salt was amorphous and solvated but gave a good analysis after drying at 110° C. under vacuum. The compound melted over a wide range below 100° C. The dried salt weighed 22.5 g. (80percent). Analysis: Calculated for C37 H44 N2 O7: C,70.68; H,7.05; N,4.45; Found: C,70.45; H,6.94; N,4.34. Patent; A. H. Robins Company, Inc.; US4324791; (1982); (A1) English View in Reaxys

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1-{4-[4-chlorobenzylhomopiperazinyl-(1)]-n-butyl}theobromine Rx-ID: 25136418 View in Reaxys 102/127 Yield

Conditions & References

5.8 g (67.5%)

3 : Preparation of 1-{4-[4-chlorobenzylhomopiperazinyl-(1)]-n-butyl}theobromine EXAMPLE 3 Preparation of 1-{4-[4-chlorobenzylhomopiperazinyl-(1)]-n-butyl}theobromine A mixture of 7.5 g of 1-(4-bromo-n-butyl)theobromine, 4.5 g of p-chlorobenzylhomopiperazine and 4.0 g of triethylamine is stirred under reflux in benzene as solvent. Thereafter, the reaction product is treated in the same way as described in Example 1. The resulting oily matter is mixed with isopropyl ether, is left standing while being cooled with ice and is allowed to crystallize. The resulting crude crystals are recrystallized from ethanol to give 5.8 g (67.5percent) of the title compound 1-{4-[4p-chlorobenzylhomopiperazinyl-(1)]-n-butyl}theobromine. M.P.: 71°-73° C. Elementary analysis calculated for C23 H31 O2 N6 Cl Patent; Eisai Co., Ltd.; US4493837; (1985); (A1) English View in Reaxys

bis-[1-(1,2,4-triazolyl-(1))-2-(2,4-dichlorophenoxy)-4,4-dimethylpentan-3-one] tin(IV) chloride

Rx-ID: 25209977 View in Reaxys 103/127 Yield

Conditions & References 11.a : EXAMPLE 11 6.5 g (0.025 mole) of tin tetrachloride (SnCl4) were added dropwise, while stirring, to 17.1 g (0.05 mole) of 1-[1,2,4triazolyl-(1)]-2-(2,4-dichlorophenoxy)-4,4-dimethyl-pentan-3-one, dissolved in 100 ml of ethanol. The mixture was stirred for a further 2 hours at room temperature. The colorless crystals which had precipitated were filtered off and rinsed with 20 ml of diisopropyl ether. 23 g (97percent of theory) of bis-[1-(1,2,4-triazolyl-(1))-2-(2,4-dichlorophenoxy)-4,4-dimethyl-pentan-3-one] tin(IV) chloride of melting point 235°-236° C were obtained. The following compounds of the general formula STR157 were prepared by methods analogous to those described in Examples 4 to 11. Patent; Bayer Aktiengesellschaft; US4005083; (1977); (A1) English View in Reaxys

1-Isopropyl-3,3-diphenyl-4-[2-phenyl-4-ethoxycarbonyl piperidinyl)ethyl]-2-pyrrolidinone Oxalate

Rx-ID: 25283160 View in Reaxys 104/127 Yield

Conditions & References 3 : 1-Isopropyl-3,3-diphenyl-4-[2-phenyl-4-ethoxycarbonyl piperidinyl)ethyl]-2-pyrrolidinone Oxalate EXAMPLE 3 1-Isopropyl-3,3-diphenyl-4-[2-phenyl-4-ethoxycarbonyl piperidinyl)ethyl]-2-pyrrolidinone Oxalate A stirred mixture of 15 g. (0.044 mole) of 4-(2-chloroethyl)-1-isopropyl-3,3-diphenyl-2-pyrrolidinone, 0.044 mole of 4ethoxycarbonyl-4-phenylpiperidine and 15 g. of potassium carbonate in 50 ml. of n-butanol was refluxed for 24 hours. The mixture was cooled, filtered and evaporated to an oil. An oxalate salt was prepared in isopropanol and precipitated with isopropyl ether. The white salt was amorphous and solvated but gave a good analysis after drying at 110° C. under vacuum. The compound melted over a wide range below 100° C. The dried salt weighed 22.5 g. (80percent). Analysis: Calculated for C37 H44 N2 O7: C, 70.68; H, 7.05; N, 4.45. Found: C, 70.45; H, 6.94; N, 4.34. Patent; A. H. Robins Company, Incorporated; US4120969; (1978); (A1) English View in Reaxys

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N-triphenylmethyl-5-[2-(4'-bromomethyl-biphenylyl)]tetrazole Rx-ID: 25412858 View in Reaxys 105/127 Yield

Conditions & References 6 : N-triphenylmethyl-5-[2-(4'-bromomethyl-biphenylyl)]tetrazole EXAMPLE 6 N-triphenylmethyl-5-[2-(4'-bromomethyl-biphenylyl)]tetrazole To a solution of N-triphenylmethyl-5-[2-(4'-methylbiphenylyl)]tetrazole (31.0 g, 0.065 mole) in carbon tetrachloride (390.0 ml) was added N-bromosuccinimide (11.50 g, 0.065 mole) and dibenzoylperoxide (1.10 g, 0.0045 mole) at room temperature. The reaction mixture was refluxed for 3 hrs., cooled to 40° and filtered. Evaporation of the filtrate in vacuo followed by trituration of the residue with isopropyl ether (100.0 ml) yielded Ntriphenylmethyl-5-[2-(4'-bromomethyl-biphenylyl)]tetrazole (33.10 g, 92percent), m.p. 135°-138°. 1 H NMR (CDCl3) δ: 8.20-6.70 (complex, 23H); 4.33 (s, 2H). Patent; E. I. Du Pont de Nemours and Company; US4820843; (1989); (A1) English View in Reaxys

6-Cyano-1,1-(ethylenedioxy)-7-methyl-5oxo-Δ6 (8)-tetrahydroindolizine

Rx-ID: 25471141 View in Reaxys 106/127 Yield

Conditions & References 1 : 6-Cyano-1,1-(ethylenedioxy)-7-methyl-5-oxo-Δ6(8)-tetrahydroindolizine Example 1 6-Cyano-1,1-(ethylenedioxy)-7-methyl-5-oxo-Δ6(8)-tetrahydroindolizine To 7.5 g of the ketone (5) obtained in Preparation Example 8 were added 100 ml of acetonitrile and 30 ml of ethylene glycol to dissolve the former in the latter, followed by the addition of 10 ml of a boron trifluoride-ether complex salt. The resulting mixture was stirred at an external temperature of 50° C. for one hour. After the completion of the reaction, 1.0 g of activated charcoal was added to the reaction mixture and they were stirred for 30 minutes. From the reaction mixture, the activated charcoal was filtered off. The filtrate was evaporated under reduced pressure. To the crystals so precipitated, a mixture of methanol and isopropyl ether was added, followed by slurry stirring. The crystals were collected by filtration and then dried, whereby 6.4 g of the title compound were obtained. Patent; Daiichi Pharmaceutical Co., Ltd.; US6172230; (2001); (B2) English View in Reaxys

O NH N

Rx-ID: 24005619 View in Reaxys 107/127 Yield

Conditions & References 1.A : 6-(1-Hydroxycyclohexyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-6-carbonitrile Step A 6-(1-Hydroxycyclohexyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-6-carbonitrile 4.1 g of the product obtained in Preparation 3 are dissolved in 215 ml of tetrahydrofuran. The reaction mixture is cooled to -80° C. and 19.25 ml of a 2.5M solution of n-butyllithium in hexane are added. When the addition is complete, stirring is maintained for 20 minutes and then 6.2 ml of cyclohexanone are poured in over the course of 3 minutes. After 2 hours' contact at 80° C., the reaction mixture is left to return to room temperature, and 23 ml of an aqueous saturated ammonium chloride solution, and then 135 ml of water, are introduced. After decanting, the organic phase is washed with a saturated sodium chloride solution, dried and concentrated. The resulting residue is solidified with isopropyl ether and filtered to obtain the desired product, and the filtrate is purified by chromatography over silica gel (CH2Cl2/AcOEt: 90/10) to isolate an additional amount of the expected product. Melting point: 168-170° C.

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Patent; Peglion, Jean-Louis; Dessinges, Aimee; Goument, Bertrand; Millan, Mark; Lejeune, Francoise; Brocco, Mauricette; US2002/19380; (2002); (A1) English View in Reaxys 2HCl

OH O

Rx-ID: 24145410 View in Reaxys 108/127 Yield

Conditions & References 50 : 1-[3-[(4-Fluorophenyl)methyl]-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-3-[1-[(4-hydroxyphenyl)methyl]-4piperidinyl]-1-propanone Dihydrochloride EXAMPLE 50 1-[3-[(4-Fluorophenyl)methyl]-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-3-[1-[(4-hydroxyphenyl)methyl]-4-piperidinyl]-1-propanone Dihydrochloride A mixture of 1-[3-[(4-fluorophenyl)methyl]-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-3-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-1-propanone (65 mg, 0.11 mmol, free base), obtained in Example 40, and 48percent hydrobromic acid (4 ml) was heated for 2 hours with stirring. After cooling, the reaction mixture was made basic with 10percent sodium hydroxide/H2O and extracted with ethyl acetate. The extract was washed with saturated NaCl/H2O and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=10:1) to provide the free base (50 mg) of the title compound as colorless oil. 1H-NM-R (CDCl , free base) δ: 1.37-1.60 (3H, m), 1.63-1.88(4H, m), 2.14-2.34 (2H, m), 2.55-2.68 (4H, m), 2.88-3.05 3 (6H, m), 3.12-3.27 (2H, m), 3.59 (2H, s), 3.68 (2H, s), ca. 5.8 (1H, br), 6.70 (2H, d, J=8.4 Hz), 7.01 (2H, t-like, J=8.6 Hz), 7.08-7.20 (3H, m), 7.24-7.37 (2H, m), 7.63-7.73 (2H, m). The above free base (45 mg) was dissolved in methanol, treated with 2 molar equivalents of HCl (dissolved in ethyl acetate), and precipitated from isopropyl alcohol-ether to provide the title compound (35 mg) as colorless powders melting at 166-169° C. Elemental analysis, for C32H37FN2O2.2HCl.H2O. Calcd.: C, 64.97; H, 6.99; N, 4.74. Found: C, 64.72; H, 7.05; N, 4.66. Patent; Takeda Chemical Industries, Inc.; US6534496; (2003); (B1) English View in Reaxys

O O

Rx-ID: 24294164 View in Reaxys 109/127 Yield

Conditions & References 85 : Example 85 Example 85 Sodium hydride (60percent in mineral oil, 55 mg) was added into a solution of benzyl indole-3-carboxylate (0.311 g) in N,N-dimethylformamide (2 ml) under ice-cooling. After the mixture was stirred for 30 minutes at same temperature, 4-tert-butyl-2-[5-(bromoacetyl)benzofuran-2-yl]thiazole (0.47 g) was added to the mixture. After being stirred continuously 3 hours, the resulting mixture was poured into ice-water and the mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure.

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The residue was treated with 4N hydrochloride in ethyl acetate solution. The resulting precipitates were collected by filtration and washed diisopropyl ether to give the hydrochloride salt of the objective compound. The hydrochloride salt was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give benzyl 1-{2-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-2-oxoethyl}indole-3-carboxylate (0.14 g). IR (Nujol): 1675, 1580, 1530, 1500, 1360 cm-1 NMR (CDCl3, δ): 1.42 (9H, s), 5.39 (2H, s), 5.60 (2H, s), 7.05 (1H, s), 7.20-7.50 (8H, m), 7.65 (1H, d, J=8.7 Hz), 7.87 (1H, s), 8.02 (1H, dd, J=1.7, 8.7 Hz), 8.20-8.25 (1H, m), 8.31 (1H, d, J=1.7 Hz) Patent; Fujisawa Pharmaceutical Co., Ltd.; US5994378; (1999); (A1) English View in Reaxys

H N

Rx-ID: 24519766 View in Reaxys 110/127 Yield

Conditions & References 1 : Production of N-(2,6-diisopropylphenyl)-2-(tetradecylthio)acetamide (compound 1): EXAMPLE 1 Production of N-(2,6-diisopropylphenyl)-2-(tetradecylthio)acetamide (compound 1): A mixture consisting of N-(2,6-diisopropylphenyl)-2-chloroacetamide (2.54 g), tetradecylmercaptan (2.3 g), potassium carbonate (3.6 g), sodium iodide (60 mg) and ethanol (50 ml) was subjected to 6 hours of reflux under an argon atmosphere. After removing the reaction solvent by distillation under a reduced pressure, the resulting product was mixed with ethyl acetate, washed successively with water and saturated brine and then dried on anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under a reduced pressure, and the resulting residue was subjected to crystallization using isopropyl ether to obtain the title compound (3.14 g) in the form of colorless needle crystals. Melting point: 62.5°-64° C. Patent; Taisho Pharmaceutical Co., Ltd.; US5475130; (1995); (A1) English View in Reaxys

O– O

N+

N Cl

Rx-ID: 24519767 View in Reaxys 111/127 Yield

Conditions & References 5 : EXAMPLE 5 STR31 EXAMPLE 5 STR31 2.65 g of 4-phenylquinuclidine and 8.3 g of the benzenesulfonate prepared according to PREPARATION VII (c) are dissolved in 40 ml of acetonitrile and the reaction mixture is refluxed for 6 hours. The mixture is concentrated under vacuum and the residue is taken up in CH2 Cl2 and washed successively with a 1percent aqueous solution of benzenesulfonic acid and then with water. The organic phase is dried over Na2 SO4, filtered and concentrated under vacuum. The residue precipitates from isopropyl ether to give 8 g of optically pure (+)-1-[2-[3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]piperidin-3-yl]ethyl]-4-phenyl-1-azoniabicyclo[2.2.2]octane benzenesulfonate (compound 5). M.p.=195.5° C. Compounds 6 to 12 described in TABLES I and II below are prepared by following EXAMPLES 1 to 5. Patent; Sanofi; US5583134; (1996); (A1) English View in Reaxys

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N H O

Rx-ID: 24664120 View in Reaxys 112/127 Yield

Conditions & References 26 : Preparation of 2-methyl-3-tert.-butoxycarbonyl-4-benzoylaminopyrrole STR46 EXAMPLE 26 Preparation of 2-methyl-3-tert.-butoxycarbonyl-4-benzoylaminopyrrole STR46 In a 250 ml three-necked flask, 16.3 g (0.083 mol) of compound C are introduced into 100 ml of methanol. With stirring, 18.0 g (0.1 mol) of a 30percent sodium methanolate solution are added dropwise and the reaction mixture is heated under reflux for 30 minutes. It is then neutralised with 6.0 g (0.1 mol) of glacial acetic acid, and 10.1 g (0.1 mol) of triethylamine are added. After the dropwise addition of 11.7 g (0.083 mol) of benzoyl chloride, the reaction mixture is left to stand overnight. The precipitate formed is filtered off. The filtrate is concentrated and the resulting residue is estracted in portions with isopropyl ether. The extracts are concentrated and cooled to give a beige-coloured precipitate which is dried until the weight is constant. Yield: 11.3 g (=45.4 percent of the theoretical amount) Melting point: 170° C. Patent; Ciba-Geigy Corporation; US5155152; (1992); (A1) English View in Reaxys O

O NH 2

Rx-ID: 24903723 View in Reaxys 113/127 Yield

Conditions & References 55 : EXAMPLE 55 (3aRS,7aRS)-2-[(2-tert-butoxycarbonylaminophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (1.5 g) is treated with a 5.7N solution (15 cc) of hydrochloric acid in dry dioxane at 20° C. for 4 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is purified by dissolving in acetonitrile (20 cc) and precipitating from isopropyl ether (30 cc). The solid is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-2-[(2-aminophenyl)acetyl]-7,7-diphenyl-4perhydroisoindolone hydrochloride (1.1 g) is obtained in the form of a slightly pink solid. Patent; Rhone-Poulenc Sante; US5102667; (1992); (A1) English View in Reaxys O

O HN

O Cl

Rx-ID: 24903724 View in Reaxys 114/127 Yield

Conditions & References 1.2 : 1.2. 1.2. 2-Acetamido-5-methyl-2'-chlorobenzophenone The Grignard reagent prepared from 312.5 g (1.63 mol) of 2-bromochlorobenzene and 39.6 g (1.63 mol) of magnesium in 1.2 liters of anhydrous ether is added dropwise, in 2.5 hours, to a stirred solution of 270 g (1.54 mol) of 2,6dimethyl-4H-3,1-benzoxazin-4-one in 4 liters of absolute ether at room temperature. The mixture is then allowed to react for a further 2 hours at the same temperature.

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While cooling in ice, the mixture is cautiously hydrolyzed with 2N hydrochloric acid and then the aqueous phase is separated off. The organic phase is washed first with dilute sodium hydroxide solution and then with water. The organic phase is dried and concentrated. The resulting residue is induced to crystallise with isopropyl ether. Yield: 194 g (44percent of theory), melting point 156°-158° C. Patent; Boehringer Ingelheim KG; US5116971; (1992); (A1) English View in Reaxys

O N E Cl

Rx-ID: 24982348 View in Reaxys 115/127 Yield

Conditions & References 46 : EXAMPLE 46 EXAMPLE 46 The following compound was prepared in an analogous manner to that described in Example 40, but toluene was used as the solvent instead of methylene chloride and 28percent strength caustic soda solution was used instead of 2 N caustic soda solution: 2-[{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}methyl]pyridine, m.p. 116°-118° (from isopropyl ether) is obtained from 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine and 2-chloromethylpyridine; the corresponding dihydrochloride melts at 175°-176°, with decomposition (from methanol/acetonitile). Patent; Hoffman-La Roche Inc.; US4244957; (1981); (A1) English View in Reaxys Cl HO

N E

O N

NH Cl

Rx-ID: 24982349 View in Reaxys 116/127 Yield

Conditions & References 25 : EXAMPLE 25 EXAMPLE 25 The following compound was prepared in an analogous manner to that described in Example 22: 3-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}-1-propanol, m.p. 115°-117° (from methylene chloride/diisopropyl ether) is obtained from 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine and 4-[2-(tetrahydropyranyl)oxy]bromopropane. The corresponding hydrochloride melts at 150°-152° (from isopropanol/ethyl acetate). Patent; Hoffman-La Roche Inc.; US4244957; (1981); (A1) English View in Reaxys Cl N E

N NH Cl

Rx-ID: 24982350 View in Reaxys 117/127 Yield

Conditions & References 47 : EXAMPLE 47 EXAMPLE 47 The following compound was prepared in an analogous manner to that described in Example 20: 2-[(2,6-dichlorophenyl)imino]-1-(3-pentynyloxy)imidazolidine, m.p. 104°-105° (from isopropyl ether), is obtained from 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine and pentyn-3-yl p-toluenesulfonate.

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Patent; Hoffman-La Roche Inc.; US4244957; (1981); (A1) English View in Reaxys

O N O

OH Cl NH

Rx-ID: 25059825 View in Reaxys 118/127 Yield

Conditions & References 73 : 8-Methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylic Acid Hydrochloride EXAMPLE 73 8-Methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylic Acid Hydrochloride A portion of the 8-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylic acid, 4.35 g from Example 72 was triturated with 100 ml hot absolute ethanol. After cooling, the solid was collected by filtration and air dried to give 3.87 g. The solid was suspended in 25 ml of absolute ethanol and excess ethereal hydrogen chloride solution added. A clear solution was obtained. Addition of isopropyl ether produced a yellow precipitate which was collected and recrystallized from absolute ethanol-isopropyl ether to yield 3.14 g solid m.p. 257° C. (d). Analysis: Calculated for C18 H17 N2 O3 Cl: C,62.70; H,4.97; N,8.12. Found: C,62,53; H,4.93; N,8.18. Patent; A. H. Robins Company, Inc.; US4343804; (1982); (A1) English View in Reaxys

O N

Rx-ID: 25059826 View in Reaxys 119/127 Yield

Conditions & References 10 : cis-5,6-Dimethoxy-1,2-dimethyl-3-[2-(4-phenyl-1-piperazinyl)ethyl]indoline furmarate EXAMPLE 10 cis-5,6-Dimethoxy-1,2-dimethyl-3-[2-(4-phenyl-1-piperazinyl)ethyl]indoline furmarate The product of Example 9, 0.96 g., is dissolved in 5.0 ml. of hot ethanol and added to a hot solution of 0.57 g. of fumaric acid in 5.0 ml. of ethanol. The mixture is cooled to give a dark oil. The oil is triturated with isopropyl ether to give 1.03 g. of a brown glass. The product of the Example is obtained by twice dissolving the above material in ethanol, cooling and triturating with isopropyl ether, mp. 161° C. (dec.). Patent; American Cyanamid Company; US4302589; (1981); (A1) English View in Reaxys

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H 2N

Rx-ID: 25136416 View in Reaxys 120/127 Yield

Conditions & References

350 mg. (75%)

7β-[D-2-Amino-2-(p-hydroxyphenyl)acetamido]-3-[(Z)-3-methoxy-1-propen-1-yl]-3-cephem-4-carboxylic Acid (Compound 17, BB-S1092) 7β-[D-2-Amino-2-(p-hydroxyphenyl)acetamido]-3-[(Z)-3-methoxy-1-propen-1-yl]-3-cephem-4-carboxylic Acid (Compound 17, BB-S1092) Compound 16 was deblocked with TFA (3 ml.) at room temperature for one hour. Evaporation of the solvent followed by precipitation from isopropyl ether gave the trifluoroacetate of the product, which was purified by HP-20 column chromatography. The column was washed with H2 O (500 ml.) and eluted with 30percent MeOH (500 ml.) to afford 350 mg. (75percent) of desired product. Estimated purity, 90percent (by HPLC). M.p. 160° C. (dec.). IR: νmax KBr cm-1 3400, 3180, 1760, 1680. UV: λmax phosphate buffer pH 7 nm(ε) 228 (11500), 279 (9400). NMR:δD 2 O ppm 3.40 (3H, s, OCH3), 3.40 (2H, ABq, 2--CH2), 4.0 (2H, m, --CH2 OMe), 5.19 (1H, d, 4.5 Hz, 6-H), 5.25 (1H, s, --CH--ND2), 5.77 (1H, d, 7-H), ca. 5.8 (1H, m, =CH--CH2 --), 6.20 (1H, d, 11 Hz, --CH=CH--CH2), 7.05 and 7.45 (each 2H, each d, HO--Ph--). Patent; Bristol-Myers Company; US4520022; (1985); (A1) English View in Reaxys OH

H 2N

Rx-ID: 25136417 View in Reaxys 121/127 Yield

Conditions & References 76.A : STEP A STEP A 3-phenoxy-2-hydroxy-benzene-ethanethioamide Hydrogen sulfide was bubbled through a solution of 20 g of α-cyano-3-phenoxy-benzyl alcohol, 200 ml of toluene and 4.5 ml of triethylamine for 22 hours and the mixture was then poured into aqueous N hydrochloric acid. The decanted organic phase was washed with water, dried and evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 benzene-ethyl acetate mixture and cyrstallization from isopropyl ether yielded 18.5 g of 3-phenoxy-2-hydroxy-benzene-ethanethioamide melting at 70° C. Patent; Roussel Uclaf; US4833163; (1989); (A1) English View in Reaxys OH

H N

N N

Rx-ID: 25136419 View in Reaxys 122/127 Yield

Conditions & References I : 1-hydroxy-1-phenyl-3-(1,2,3-thiadiazole-5-yl)-urea EXAMPLE I 1-hydroxy-1-phenyl-3-(1,2,3-thiadiazole-5-yl)-urea

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The solution of 7.25 g (0.105 mole) sodium nitrite in 100 ml water and 200 ml toluene are introduced into a triple branch tubulated 1 liter round flask provided with a thermometer and stirrer. Into this mixture within 30 minutes at a temperature of from 0° to 5° C. a solution as follows is introduced in dropwise fashion, 14.4 g (0.1 mole) 1,2,3-thiadiazole-5-carboxylic acid hydrazide, 100 ml water and 8 ml (about 0.1 mole) concentrated hydrochloric acid. The mixture is stirred for about 15 minutes at about 0° to 5° C., thereafter the toluene phase is separated off and dried over magnesium sulfate. In a triple branched tubulated 1 liter round flask provided with a stirrer thermometer and reflux cooler there is at this time heated to 110° C. 50 ml of toluene. The dried 1,2,3-thiadiazole-5-carboxylic acid azide solution and a solution of 11.0 g (0.11 mole) phenylhydroxylamine in 200 ml toluene are simultaneously but separately within about 15 minutes introduced in dropwise fashion so that the temperature is maintained at from 100° to 110° C. Stirring is continued for a further 10 minutes under reflux whereby even before the end of this period light yellow colored crystals separate out. The reaction mixture is then cooled down to about 5° C., the crystals separated off, digested with about 50 ml diisopropylether and dried in vacuum at about 40° C. until a constant weight is obtained. Yield: 19.6 g=82.9percent of theory Fp.: 177° C. (decomposition) DC: flow agent=acetic acid ester Rf -value: 0.445 Analysis: calculated C 45.76percent; H 3.41percent; N 23.72percent; S 13.54percent; found C 45.67percent; H 3.29percent; N 23.54percent; S 13.19percent. Patent; Schering Aktiengesellschaft; US4515619; (1985); (A1) English View in Reaxys

NH N S HN HN

NH NH

S N HN

Rx-ID: 25209978 View in Reaxys 123/127 Yield

Conditions & References 1.c : 1,2-bis-[N'-(2-(5-methyl-4 -imidazolylmethylthio)ethyl) thioureido]ethane. c. A solution of the above hydriodide (5.5 g) in absolute ethanol (60 ml) was added to a solution of sodium (0.325 g) in ethanol (100 ml). Following filtration, a solution of 1,2-diaminoethane (0.424 g) in ethanol (30 ml) was added to the filtrate which was heated under reflux for 24 hours. Following concentration, the residual oil was purified by repeated reprecipitation from isopropanol with water and from isopropanol with ether. Finally chromatographic purification on a column of silica gel with ethyl acetate-ethanol (3:1) as eluant and final precipitation from isopropanol-ether gave the title compound as a colorless low melting solid, containing approximately 4.5percent diethyl ether. The NMR spectrum of a solution in 2 H6 dimethyl sulphoxide, recorded at 60 mHZ showed the following resonances: Patent; Smith Kline and French Laboratories Limited; US3968227; (1976); (A1) English View in Reaxys

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HN N S S

NH NH

S N HN

Rx-ID: 25209979 View in Reaxys 124/127 Yield

Conditions & References 2 : 1,3-bis-[N'-(2-(5-methyl-4-imidazolyl methylthio)ethyl) thioureido]propane EXAMPLE 2 1,3-bis-[N'-(2-(5-methyl-4-imidazolyl methylthio)ethyl) thioureido]propane S-Methyl-N'-[2-(5-methyl-4-imidazolyl)methylthio)ethyl] dithiocarbamate hydriodide (7.8 g) was converted into the free base with sodium (0.46 g) in ethanol. Reaction wtih 1,3-diaminopropane (0.74 g) and purification by the method described in Example 1 gave the product which was further purified by successive treatment of a solution in methanol-water with cationic and anionic exchange resins. Following precipitation from isopropanol-ether, the title compound was obtained as a colorless low melting solid containing approximately 4.5percent diethyl ether. The NMR spectrum of a solution in 2 H6 dimethyl sulphoxide recorded at 60 mHZ showed the following resonances. The spectrum also showed the presence of 4.5percent weight/weight diethyl ether. (Found: N, 21.7; S, 24.6; C19 H32 N8 S4 + 4.5percent C4 H10 O requires: N, 21.4; S, 24.5percent). Patent; Smith Kline and French Laboratories Limited; US3968227; (1976); (A1) English View in Reaxys O

Rx-ID: 25412859 View in Reaxys 125/127 Yield

Conditions & References 2 : Synthesis of Ethylene Glcyol Isopropyl Ether EXAMPLE 2 Synthesis of Ethylene Glcyol Isopropyl Ether To a 300 cc pressure reactor fitted with heating, mixing and temperature controls was charged a mixture of ethylene glycol (62.0g, 1.0 mole) and 12-tungstophosphoric acid (1.0g). The reactor was flushed with nitrogen and pressured with propylene (21.0g, 0.5 mole), then heated to 180°C with mixing. After 4 hours at temperature, the reactor was cooled and the product (70.0g) recovered. Patent; TEXACO CHEMICAL COMPANY; EP419077; (1991); (A2) English View in Reaxys OH

O HN O

N N S

Rx-ID: 25857807 View in Reaxys 126/127 Yield

Conditions & References 84.1 : Example 84 (1)

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To a suspension of lithium aluminium hydride 4.15 g in tetrahydrofuran 150 ml is added a solution of 2-methylthio-4(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 67-(1)) 38.32 g in tetrahydrofuran 100 ml at 5-10° C. under ice cooling over a period of 1 hour. After addition the mixture is stirred for a hour without an ice bath. Water 4.15 ml is added under ice cooling thereto, followed by addition of 3N aqueous sodium hydroxide solution 4.15 ml. To the mixture is added water 4.15 ml three times and the mixture is stirred at room temperature for 1 hour. After treating with magnesium sulfate and filtration, the resulting cake-like substances are washed with terahydrofuran. The filtrate is concentrated in vacuo and triturated with ethyl acetate-isopropyl ether. The resulting crystals are filtered and washed well with isopropyl-ether to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidine as a pale yellow crystalline powder. The first product; yield 25.10 g, mp 162-163° C. The second product; yield 2.32 g, mp 159-160° C. Further the above cake-like substances are again washed with isopropyl ether, and the filtrate is concentrated in vacuo to give colorless crystals. The crystals are suspended in isopropyl ether, and filtered. The precipitates are washed well isopropyl ether and hexane to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidine as colorless crystals, 4.26 g. mp 161-162° C. Patent; Yamada, Koichiro; Matsuki, Kenji; Omori, Kenji; Kikkawa, Kohei; US2004/142930; (2004); (A1) English View in Reaxys

HO O O N

Rx-ID: 25857808 View in Reaxys 127/127 Yield

Conditions & References (2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetic Acid (3R)-1-azabicyclo[2.2.2]oct-3-yl Ester. (2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetic Acid (3R)-1-azabicyclo[2.2.2]oct-3-yl Ester. Several treatments of the oil mixture of diastereomers with diferent mixtures of diethyl ether/hexane and diisopropyl ether/hexane (cooling at -60° C.) yield 4.3 g of a white solid identified by 1H-RMN as an enriched diastereomer I-5a. Patent; Prat Quinones, Maria; Fernandez Forner, Maria Dolors; Buil Albero, Maria Antonia; US2004/72863; (2004); (A1) English View in Reaxys

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