text:
Methyl 3-Bromo-5-carbamoylisothiazole-4-carboxylate
2,3-Bis((E)-4-hydroxybenzylidene)-N1,N4-bis(4-methylbenzyl)succinamide
(3-Methylene-2,3-dihydronaphtho[2,3-b][1,4]dioxin-2-yl)methanol
Molbank
10.3390/M1559
Stefano D'Errico
Annalisa Guaragna
Straniero, V.
Suigo, L.
Lodigiani, G.
Valoti, E.
Open AccessCommunication
Obtainment of Threo and Erythro Isomers of the 6-Fluoro-3-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide
Valentina Straniero
* ,
Lorenzo Suigo
Giulia Lodigiani
Ermanno Valoti
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Luigi Mangiagalli, 25, 20133 Milano, Italy
Molbank 2023, 2023(1), M1559; https://doi.org/10.3390/M1559
Received: 20 December 2022 / Revised: 13 January 2023 / Accepted: 15 January 2023 / Published: 18 January 2023
(This article belongs to the Special Issue Molecules from Side Reactions II)
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2,6-difluorobenzamides have been deeply investigated as antibacterial drugs in the last few decades. Several 3-substituted-2,6-difluorobenzamides have proved their ability to interfere with the bacterial cell division cycle by inhibiting the protein FtsZ, the key player of the whole process. Recently, we developed a novel family of 1,4-tetrahydronaphthodioxane benzamides, having an ethoxy linker, which reached sub-micromolar MICs towards Gram-positive Staphylococcus aureus and Bacillus subtilis. A further investigation of their mechanism of action should require the development of a fluorescent probe, and the consequent definition of a synthetic pathway for its obtainment. In the present work, we report the obtainment of an unexpected bicyclic side product, 6-fluoro-3-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide, coming from the substitution of one aromatic fluorine by the in situ formed alkoxy group, in the final opening of an epoxide intermediate. This side product was similarly achieved, in good yields, by opening the ring of both erythro and threo epoxides, and the two compounds were fully characterized using HRMS, 1H-NMR, 13C-NMR, HPLC and DSC.
2,6-difluorobenzamide; FtsZ inhibitors; nucleophilic aromatic substitution; side product
The development of novel antibiotics able to modulate innovative targets represents one of the main pursued strategies to fight the worrying problem of antimicrobial resistance [1]. This phenomenon is caused by several human-related factors, such as over-prescription of antibiotics and low investments in the antibiotic resistance field [2].
With the aim of combatting this threat, one of the most exploited and promising bacterial targets is FtsZ (Filamenting temperature sensitive Z) [3], the main protein actor of the bacterial division process, the inhibition of which leads to cell filamentation and lysis [4,5,6,7]. Physiologically, GTP-dependent FtsZ polymerization represents the first step of the whole division process, leading to the formation of the Z-ring, a polymeric circular structure, at the site partition. Other division proteins then intervene, forming the mature divisome that allows cytokinesis and cellular division [8].
In the last years, a huge number of FtsZ inhibitors have been developed, belonging to different chemical classes and interacting with the protein on two different binding sites: the GTP-binding site or the Interdomain Cleft (IDC) [4,9,10,11].
Considering the high variety of FtsZ inhibitors, in terms of chemical structure, origin and interaction site, they are able to inhibit the FtsZ functionality through several mechanisms of actions. For instance, PC190723 (Figure 1), one of the most studied S. aureus and B. subtilis FtsZ inhibitors, is able to stabilize a high-affinity FtsZ conformation responsible for the assembly, thus exerting antimicrobial activity [12], while other derivatives can interfere with the GTPase activity of FtsZ polymers, evoking again their antimicrobial activity [13].
Recently, our research group reported a novel class of 1,4-naphthodioxane- or 1,4-tetrahydronaphthodioxane-benzamides as strong antimicrobials [14], acting through the inhibition of FtsZ, which resulted to be more potent than other benzamides previously reported [5,15,16,17,18]. In particular, I and II (Figure 1) possess MIC values of 0.25 μg/mL and 0.1 μg/mL versus both Methicillin-sensitive and Methicillin-resistant S. Aureus, respectively. Moreover, I and II are both active vs. B. subtilis with MICs under 0.1 μg/mL [14].
After having proved their capability to interact and inhibit both S. aureus and B. subtilis FtsZ, the need of having a fluorescent analogue (Figure 2) of compound II, the strongest one, arose. An appropriate probe could indeed help to elucidate FtsZ inhibitors' mechanism of action, as well as to understand any possible off-target interaction, to screen for novel antibiotics, to track antibiotic uptake throughout cells and organisms, and also to detect bacterial infections. Nonetheless, despite the clear and broad utility, the number of fluorescent FZ-probes so far available [19,20] is, to the best of our knowledge, now limited to only a couple of examples.
When thinking how to properly introduce a fluorescent dye, a hydroxylated analogue of II, compound 1a, was designed (Scheme 1), taking inspiration from the work of Stokes and collaborators [21,22]. The introduction of the -OH was intended as a possible anchor point for the binding of a proper linker, and thus a fluorescent dye.
This substituent generates a second stereocenter, and the consequent formation of both erythro and threo isomers. The obtainment of 1a, for which we followed Scheme 1, involves the final ring opening of isolated erythro and threo epoxides. In the present work, we report how both these ring openings could surprisingly allow the achievement, in significant quantities, of the bicyclic side products 1b, the 6-fluoro-3-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamides.
We further confirmed how the obtainment of these byproducts 1b erythro and threo is favored during the epoxide opening at quite high temperatures and keeping long reaction times, which are the usual conditions adopted in the final condensation for the preparation of FtsZ inhibitors [14,17,18]. On the contrary, the formation of these side products is partially retarded, keeping milder reaction conditions.
The synthetic scheme developed for achieving 1a is shown in Scheme 1 and started from the 5,6,7,8-tetrahydronaphthalene-2,3-diol, obtained as previously described [14], which was treated with freshly prepared ethyl 2,3-dibromopropionate [23], giving racemic compound 2. The ester underwent basic hydrolysis, and the resulting carboxylic acid 3 was then converted into the Weinreb amide (4). Amide 4 was then quantitatively transformed into the corresponding methyl ketone 5, by treatment with methylmagnesium bromide, similarly to what was successfully done by our research group on structurally similar derivatives [24,25].
The bromination of methyl ketone 5 was conducted with a single equivalent of bromine at low temperature, to limit the formation of polybrominated side products, and to maximize the conversion into the bromoketone 6. Then, compound 6 underwent a tandem reaction: the first reduction of the carboxylic function with NaBH4, achieving the instable halohydrin that was soon treated with sodium hydride, affording the two epoxides 7, both erythro and threo isomers. The two spots of oxiranes 7 were easily distinguishable through TLC, and the two isomers were thus isolated by flash chromatography on silica gel. Their 1H-NMR spectra in CDCl3 revealed significant differences in terms of chemical shifts and multiplicity (Figure 3).
In particular, the first eluted epoxide showed six different signals, with a very clear and defined multiplicity: four doublets of doublets (two at 4.29 and 4.12 ppm, referring to the CH2 the 1,4-dioxane portion, and two at 2.90 and 2.80 ppm, which are the two hydrogens of the epoxidic CH2), a doublet of triplets (at 3.91 ppm, diagnostic of the hydrogen of the dioxane CH), and a double of doublets of doublets (3.13 ppm, characteristic for the epoxidic CH). The second eluted oxirane, on the contrary, showed only four multiplets: at 4.26 (1H), 4.07 (2H), 3.19 (1H) and 2.85 (2H) ppm. Moreover, the two appearances were completely different: the first eluted compound was a wax, whereas the second one was a colorless oil. The absence of any literature data on tetrahydronaphthodioxane epoxides moved us to consider the scarce and quite old data on 1,4-dioxane oxiranes [26,27].
Indeed, the peculiar NMR data of the first eluted oxirane were completely in line with what was observed by Clark and coworkers when preparing the enantiopure erythro-2-oxiranyl-1,4-benzodioxanes (2R, 1′S) and (2S, 1′R). Moreover, also 1,4-benzodioxane threo and erythro epoxide isomers were strongly different in terms of physic state: enantiopure erythro was a solid with a defined melting point (63–64 °C [27]), while the racemic one was defined as oil or with a lower melting point [26,27]. The perfect NMR overlapping, and comparable physical state difference let us define, without doubts, the diastereoisomeric identity of the two epoxides 7.
The two 7 isomers were parallelly treated at 70 °C for 18 h in basic conditions, in the presence of 2,6-difluoro-3-hydroxybenzamide, to achieve the two final products 1a. Unexpectedly, the TLC of the two reaction mixtures revealed the presence of two main products, different in terms of chromatographic run. In addition to the one that should refer to the desired compound 1a, a higher spot was clearly visible in both the reactions, suggesting the formation of a more lipophilic side product.
The two reaction mixtures were worked up and the crudes purified by flash chromatography, letting the isolation, similarly in the two cases, of an undesired compound. Their 1H-NMR spectra showed a surprising pattern for the aromatic signals of the benzamide. We indeed expected to observe the two doublets of triplets, which were diagnostic of the presence of two different fluorine atoms. On the contrary, both the NMR spectra revealed a triplet and a doublet of doublets, suggesting us the absence of one of the two fluorine atoms. Considering the basic reaction conditions and the prolonged reaction times, we hypothesize the formation of the two 1b side products, in which the epoxide ring opening was soon followed by the in situ generation of the alcoholate, and the subsequent benzodioxane ring closure, achieving the bicyclic derivatives 1b erythro and 1b threo.
We further confirmed the identity of the two side products by evaluating their 13C-NMR spectra and their HRMS spectra. The presence of six doublets, instead of six doublets of doublets, was indeed the clear sign of the presence of a single fluorine atom. Moreover, the mass analysis confirmed the hypothesis and the elemental compositions.
We also repeated the final steps, by decreasing the reaction temperature or the reaction times, and we noticed how the side products yields were a little lower, further confirming the importance of the reaction conditions.
Finally, we also treated both 1a erythro and 1a threo while keeping the same reaction conditions used in the ring openings, and we noticed the formation of both 1b erythro and 1b threo, even with low yields.
The partial obtainment of these side products, directly from 1a erythro and 1a threo, suggests how these byproducts are most favored during the epoxides opening. In our opinion, the side products formation could be promoted by a concerted mechanism, in which the ring opening by the phenate is simultaneous to the cyclization due to nucleophilic substitution of the fluorine atom in phenate ortho position.
Starting materials and solvents were purchased from commercial suppliers (Merck, Darmstadt, DE, Fluorochem, Hadfield, UK, and TCI Europe N.V., Zwijndrecht, BE) and were used without further purification.
1H- and 13C-NMR spectra were acquired on a Varian 300 Mercury NMR spectrometer operating at 300 MHz for 1H-NMR, and 75 MHz for 13C-NMR; the chemical shifts are reported in ppm. Signal multiplicity is used according to the following abbreviations: s = singlet, bs = broad singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublets of doublets, td = triplet of doublets, t = triplet and m = multiplet.
Melting points were measured with a TA Q20 DSC system. TLC were performed on standard analytical silica gel layers (thickness 200 µm; aluminum support silica gel 60 matrix with fluorescent indicator 254 nm, Sigma-Aldrich/Merck KGaA, Darmstadt, Germany). Chromatographic purifications were performed, in normal phase, using flash chromatography on Puriflash XS 420 (Sepachrom, Rho (Milan), Italy), and over different flash chromatography cartridges, filled with Merck high purity grade Silica Gel, 70–230 or 230–400 mesh particle size.
The final side products 1b erythro and 1b threo, as well as the benzamide derivatives 1a erythro and 1a threo, were analyzed by reverse-phase HPLC using a Waters XBridge C-18 column (5 μm, 4.6 mm × 150 mm) on an Elite LaChrom HPLC system with a diode array detector (Hitachi, San Jose, CA; USA). Mobile phase: A: H2O; B: acetonitrile; gradient, 90% A to 10% A in 25 min with 35 min run time and a flow rate of 1 mL/min. The purity was quantified at their λ max (289 nm) and was found to be >90% for all the compounds, and the relative retention time is reported in the experimental section. High-resolution mass spectrometry (HRMS) spectra were acquired on Q-Tof SYNAPT G2-Si HDMS 8K (Waters) coupled with an electrospray ionization (ESI) source in positive (ES+) ion mode. The characterization spectra of 1b erythro and 1b threo, in terms of NMR (both 1H and 13C) and HRMS, is reported in the Supplementary Material.
Ethyl 2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxine-2-carboxylate (2): A suspension of 5,6,7,8-tetrahydronaphthalene-2,3-diol (1.50 g, 9.14 mmol) and K2CO3 (2.78 g, 20.1 mmol) in DMF (15 mL) was stirred at room temperature for 30 min. Ethyl 2,3-dibromoproprionate (2.61 g, 10.05 mmol) was added dropwise and the reaction mixture was stirred at 70 °C for 1 h, the volatile solvent evaporated under vacuum, the residue diluted with ethyl acetate (20 mL), washed with 10% aqueous NaCl (5 × 15 mL), dried with Na2SO4, filtered, and concentrated under vacuum to give 1.86 g (78 %) of 2 as a yellowish oil. 1H-NMR (300 MHz, CDCl3): δ 6.70 (s, 1H), 6.56 (s, 1H), 4.77 (t, J = 3.8 Hz, 1H), 4.34 (m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.67 (m, 4H), 1.75 (m, 4H), and 1.29 (t, J = 7.1 Hz, 3H).
2,3,6,7,8,9-Hexahydronaphtho[2,3-b][1,4]dioxine-2-carboxylic acid (3): 10% aqueous NaOH (5.7 mL) was added to a solution of 2 (1.86 g, 7.09 mmol) in methanol (20 mL). The reaction mixture was stirred for 30 min at RT, volatile solvents were evaporated, and the residue was diluted with ethyl acetate. The organic layer was washed with 10% aqueous HCl then with brine, dried over Na2SO4, then filtered and concentrated under vacuum to yield 1.58 g (95%) of 3 as a yellow oil. 1H-NMR (300 MHz, CDCl3) δ 6.70 (s, 1H), 6.59 (s, 1H), 4.85 (dd, J = 5.1, 3.0 Hz, 1H), 4.41 (dd, J = 11.0, 5.1 Hz, 1H), 4.34 (dd, J = 11.0, 3.0 Hz, 1H), 2.66 (m, 4H), and 1.74 (m, 4H).
N-Methoxy-N-methyl-2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxine-2-carboxamide (4): 1,1′-Carbonyldiimidazole (1.64 g, 10.1 mmol) was added to a solution of 3 (1.58 g, 6.74 mmol) in DMF (16 mL). After stirring for 30 min, N,O-dimethyl hydroxylamine hydrochloride (0.99 g, 10 mmol) was added in portions, and the reaction mixture was stirred for 2 h. At completion, the DMF was evaporated, and the crude was diluted with ethyl acetate. The organic phase was washed with 10% aqueous NaHCO3, 10% aqueous HCl and finally with brine and then dried over Na2SO4, filtered and concentrated under vacuum to yield 1.76 g (95%) of 4 as a brownish oil. 1H-NMR (300 MHz, CDCl3, δ): δ 6.68 (s, 1H), 6.59 (s, 1H), 5.01 (dd, J = 6.7, 2.6 Hz, 1H), 4.37 (dd, J = 11.4, 2.6 Hz, 1H), 4.24 (dd, J = 11.4, 6.7 Hz, 1H), 3.78 (s, 3H), 3.26 (s, 3H), 2.66 (m, 4H), 1.74 (m, 4H).
1-(2,3,6,7,8,9-Hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)ethanone (5): 3.0 M Methyl magnesium bromide in diethyl ether (3.2 mL) was added dropwise to a solution of 4 (1.76 g, 6.35 mmol) in dry THF (65 mL) at 0 °C under N2. The reaction mixture was stirred at room temperature for 1.5 h and poured into a 1/1 mixture of ethyl acetate and 10% aqueous HCl (50 + 50 mL). The organic phase was then washed twice with 10% aqueous NaCl, dried over Na2SO4, filtered and concentrated under vacuum to yield 1.34 g (92%) of 5 as a yellowish oil. 1H-NMR (300 MHz, CDCl3): δ 6.69 (s, 1H), 6.58 (s, 1H), 4.56 (dd, J = 4.9, 3.5 Hz, 1H), 4.28 (dd, J = 11.4, 3.5 Hz, 1H), 4.25 (dd, J = 11.4, 4.9 Hz, 1H), 2.68 (m, 4H), 2.29 (s, 3H), and 1.75 (m, 4H).
2-Bromo-1-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)ethanone (6): Bromine (0.30 mL, 5.8 mmol) was added dropwise to a solution of 5 (1.34 g, 5.77 mmol) in diethyl ether (40 mL) at −5.0 °C. The mixture was stirred at that temperature for 3 h, washed Na2S2O5 (10 mL), dried over Na2SO4, filtered and concentrated under vacuum, to obtain 1.80 g of 6 as a yellowish oil (quantitative yield). 1H-NMR (300 MHz, CDCl3): δ 6.72 (s, 1H), 6.62 (s, 1H), 4.86 (dd, J = 4.7, 3.3 Hz, 1H), 4.40 (m, 2H), 4.33 (d, J = 14.0 Hz, 1H), 4.10 (d, J = 14.0 Hz, 1H), 2.70 (m, 4H), and 1.76 (m, 4H).
Erythro- and Threo- 2-(Oxiran-2-yl)-2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxine (7): NaBH4 (0.11 g, 2.9 mmol) was added in portions to a solution of 6 (1.80 g, 5.77 mmol) in MeOH (36 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then volatile solvents were removed under vacuum. The crude was diluted with THF (15 mL) and added dropwise to a suspension of 60% NaH (0.28 g, 6.92 mmol) in THF (5 mL) at 0°C under nitrogen atmosphere. After 30 min, the reaction mixture was warmed to RT and stirred for 18 h, then THF was evaporated, and the crude resumed with ethyl acetate (20 mL) and phosphate buffer pH = 7 (15 mL). The organic phase was washed with 10% aqueous NaCl, dried over Na2SO4, filtered and concentrated under vacuum to yield 1.40 g of a mixture of 7 isomers as a brown oil. Elution with 9/1 cyclohexane/ethyl acetate on silica gel gave 0.47 g of 7 erythro (first eluted) as white wax and 0.32 g of 7 threo (second eluted) as colorless oil (Cumulative yield of erythro and threo isomers = 59%).
7 Erythro:1H-NMR (300 MHz, CDCl3): δ 6.60 (s, 2H), 4.29 (dd, J = 11.4, 2.4 Hz, 1H), 4.12 (dd, J = 11.4, 6.6 Hz, 1H), 3.91 (td, J = 6.6, 2.4 Hz, 1H), 3.13 (ddd, J = 6.6, 4.1, 2.6 Hz, 1H), 2.90 (dd, J = 4.9, 4.1 Hz, 1H), 2.80 (dd, J = 4.9, 2.6 Hz, 1H), 2.67 (m, 4H), and 1.73 (m, 4H).
7 Threo:1H-NMR (300 MHz, CDCl3): δ 6.63 (s, 1H), 6.58 (s, 1H), 4.26 (m, 1H), 4.07 (m, 2H), 3.19 (m, 1H), 2.85 (m, 2H), 2.66 (m, 4H), and 1.74 (m, 4H).
Erythro 2,6-Difluoro-3-(2-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2-hydroxyethoxy)benzamide (1a erythro) and erythro 6-Fluoro-3-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide (1b erythro): A solution of 3-Hydroxy-2,6-difluorobenzamide (0.37 g, 2.1 mmol) in DMF (3 mL) was added to a solution of 7 erythro (0.47 g, 2.0 mmol) and K2CO3 (0.31 g, 2.2 mmol) in DMF (2 mL) at RT. Heating and stirring at 70 °C for 18 h led to the obtainment of the side product 1b erythro in 24% yield. DMF evaporation under vacuum, dilution with ethyl acetate (20 mL), washing with 10% aqueous NaCl (5 × 10 mL), drying over Na2SO4, filtering and concentration under vacuum gave a brown residue. Elution with 6/4 to 4/6 cyclohexane/ethyl acetate on silica gel allowed the isolation of 0.32 g (Yield = 39%) of 1a erythro and of 0.19 g (Yield = 24%) of 1b erythro as white solids.
1a erythro: HPLC: Tr = 14.9 min. Mp = 155 °C.
1H-NMR (300 MHz, d6-DMSO): δ 8.10 (s, 1H), 7.81 (s, 1H), 7.24 (dt, J = 9.3, 5.3 Hz, 1H), 7.04 (dt, J = 9.0, 1.8 Hz, 1H), 6.52 (s, 1H), 6.51 (s, 1H), 5.68 (d, J = 5.9 Hz, 1H), 4.32 (d, J = 9.5 Hz, 1H), 4.15 (m, 4H), 3.94 (m, 1H), 2.55 (m, 4H), and 1.64 (m, 4H)
13C-NMR (75 MHz, d6-DMSO): δ 161.8, 152.3 (dd, J = 239.3, 6.7 Hz), 148.3 (dd, J = 246.8, 8.2 Hz), 143.7 (dd, J = 10.5, 3.0 Hz), 143.3, 140.8, 129.9, 129.7, 117.0 (dd, J = 24.6, 20.3 Hz), 117.0, 116.9, 116.8, 116.7, 116.0 (dd, J = 8.5, 1.7 Hz), 111.3 (dd, J = 23.1, 3.0 Hz), 73.1, 71.4, 67.8, 64.9, 28.5, and 23.2.
1b erythro: HPLC: Tr = 15.3 min. Mp = 266 °C. HRMS (TOF ES+, Na+-adduct): m/z 408.1229, 409.1263, and 410.1289. Calculated mass 408.1218, evaluated mass 408.1229.
1H-NMR (300 MHz, d6-DMSO): δ 7.91 (s, 1H), 7.63 (s, 1H), 6.92 (d, J = 9.0, 5.4 Hz, 1H), 6.73 (t, J = 9.0 Hz, 1H), 6.58 (s, 1H), 6.55 (s, 1H), 4.44 (dd, J = 11.6, 3.5 Hz, 1H), 4.33–4.28 (m, 4H), 4.17 (dd, J = 12.1, 6.5 Hz, 1H), 2.57 (m, 4H), and 1.64 (m, 4H).
13C-NMR (75 MHz, d6-DMSO): δ 163.4, 153.1 (d, J = 237.0 Hz), 141.1, 140.1, 139.7 (d, J = 3.0 Hz), 139.5 (d, J = 9.0 Hz), 130.24, 130.17, 117.6 (d, J = 9.0 Hz), 117.03, 117.01, 116.9 (d, J = 27.0 Hz), 108.3 (d, J = 25.5 Hz), 70.1, 70.0, 64.3, 63.6, 28.5, and 23.2.
Threo 2,6-Difluoro-3-(2-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2-hydroxyethoxy)benzamide (1a threo) and threo 6-Fluoro-3-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide (1b threo): 1a and 1b threo were obtained from 7 threo (0.30 g, 1.3 mmol), following the same procedure of 1a erythro and 1b erythro, achieving 0.16 g (Yield = 31%) of 1a threo and 80 mg (Yield = 16%) of 1b threo as white solids.
1a threo: HPLC Tr = 14.5 min. Mp = 147 °C.
1H-NMR (300 MHz, d6-DMSO): δ 8.09 (s, 1H), 7.81 (s, 1H), 7.27 (dt, J = 9.4, 5.3 Hz, 1H), 7.05 (dt, J = 9.0, 1.9 Hz, 1H), 6.53 (s, 1H), 6.52 (s, 1H), 5.49 (d, J = 5.8 Hz, 1H), 4.33 (dd, J = 11.2, 2.0 Hz, 1H), 4.09 (m, 5H), 2.56 (m, 4H), and 1.64 (m, 4H).
1b threo: HPLC Tr = 13.3 min. Mp = 290 °C with decomposition. HRMS (TOF ES+, Na+-adduct): m/z 408.1222, 409.1253, and 410.1277. Calculated mass 408.1218, evaluated mass 408.1222.
1H-NMR (300 MHz, d6-DMSO): δ 7.75 (s, 1H), 7.56 (s, 1H), 6.91 (d, J = 8.9, 5.5 Hz, 1H), 6.71 (t, J = 8.9 Hz, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 4.48-4.37 (m, 4H), 4.21 (dd, J = 11.9, 8.1 Hz, 1H), 4.08 (dd, J = 11.9, 8.3 Hz, 1H), 2.56 (m, 4H), and 1.64 (m, 4H).
13C-NMR (75 MHz, d6-DMSO): δ 163.4, 153.2 (d, J = 236.8 Hz), 141.0, 140.8 (d, J = 3.0 Hz), 140.4 (d, J = 10.1 Hz), 139.7, 130.1, 130.0, 117.61 (d, J = 9.0 Hz), 117.59, 117.5, 117.0 (d, J = 21.1 Hz), 108.2 (d, J = 22.3 Hz), 72.1, 71.7, 64.5, 64.2, 28.5, and 23.2.
Conversion of 1a erythro to 1b erythro: A solution of 1a erythro (0.10 g, 0.25 mmol) in DMF (1 mL) was added to a suspension of K2CO3 (0.070 g, 0.50 mmol) in DMF (1 mL) at RT. The mixture was heated at 70 °C and stirred for 18 h, then DMF was evaporated under vacuum. The residue was diluted with ethyl acetate (10 mL), washed with 10% aqueous NaCl (5 × 5 mL), dried over Na2SO4, then filtered and concentrated under vacuum, yielding a brown residue. Elution with 1/1 cyclohexane/ethyl acetate on silica gel allowed the isolation of 34 mg (35%) of 1b erythro as a white solid.
Conversion of 1a threo to 1b threo: 1b threo was obtained from 1a threo (0.10 g, 0.25 mmol), following the same procedure seen for 1b erythro, achieving 29 mg (30%) of 1b threo as a white solid.
The two threo and erythro isomers of the 6-fluoro-3-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide were obtained as a significant and abundant side product, when opening the two isomers of the 2-(oxiran-2-yl)-2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxines with a 2,6-difluorophenate, stirring at 70 °C and keeping overnight reaction times.
The structure of these two side products was firstly hypothesized by carefully evaluating the 1H-NMR spectra, which revealed the absence of a fluorine atom, and then confirmed by both 13C-NMR and HRMS spectra. The diastereoisomeric identity was defined after having characterized the isomer nature of the starting epoxides, by NMR comparison with literature enantiopure 1,4-benzodixoane oxiranes. The side products were further characterized by HPLC and DSC, fully detailing these novel and unexpected byproducts.
The following are available online: Compound 1b erythro; Figure S1: Copy of 1H-NMR spectrum in DMSO-d6; Figure S2: Copy of 13C-NMR spectrum in DMSO-d6; Figure S3: Copy of HRMS spectrum; Figure S4: Copy of Elemental Composition Report; Compound 1b threo; Figure S5: Copy of 1H-NMR spectrum in DMSO-d6; Figure S6: Copy of 13C-NMR spectrum in DMSO-d6; Figure S7: Copy of HRMS spectrum; and Figure S8: Copy of Elemental Composition Report.
Conceptualization, L.S., V.S. and E.V.; investigation, L.S. and G.L.; data curation, L.S. and V.S.; writing—original draft preparation, V.S. and L.S.; writing—review and editing, V.S. and E.V.; supervision, V.S. and E.V. All authors have read and agreed to the published version of the manuscript.
This research received no external funding.
The data presented in this study are available in the Supplementary Materials.
Mass spectrometry analyses were performed at the Mass Spectrometry facility of Unitech COSPECT at the University of Milan (Italy). The authors acknowledge the support of the APC central fund of the University of Milan.
Sample Availability
Samples of the compounds are available from the authors.
World Health Organization. Global Action Plan on Antimicrobial Resistance. 2015. Available online: https://www.who.int/publications/i/item/9789241509763 (accessed on 15 October 2022).
World Health Organization. Antibiotic Resistance: Prevention and Control. Available online: https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance#:~:text=Antibiotic%20resistance%20is%20accelerated%20by,poor%20infection%20prevention%20and%20control (accessed on 15 October 2022).
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Figure 1. Structures of PC190723, derivatives I and II.
Figure 2. Structures of II and of the desired fluorescent analogue.
Scheme 1. Synthetic pathway for the obtainment of both 1a and 1b. Reagents and conditions: (a) Ethyl 2,3-dibromopropionate, K2CO3, DMF, 70 °C, 1 h; (b) 10% aqueous NaOH, MeOH, RT, 30 min; (c) CDI, N,O-Dimethyl hydroxylamine hydrochloride, DMF, RT, 2 h; (d) CH3MgBr, THF, RT, 1.5 h; (e) Br2, diethyl ether, −5 °C, 3 h; (f) (I) NaBH4, MeOH, 0–5 °C, 30 min; (II) NaH, THF, RT, 18 h; (g) 2,6-difluoro-3-hydroxybenzamide, K2CO3, DMF, 70 °C, 18 h.
Figure 3. 1H-NMR Spectra extracts of 7 erythro and 7 threo.
Straniero, V.; Suigo, L.; Lodigiani, G.; Valoti, E. Obtainment of Threo and Erythro Isomers of the 6-Fluoro-3-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide. Molbank 2023, 2023, M1559. https://doi.org/10.3390/M1559
Straniero V, Suigo L, Lodigiani G, Valoti E. Obtainment of Threo and Erythro Isomers of the 6-Fluoro-3-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide. Molbank. 2023; 2023(1):M1559. https://doi.org/10.3390/M1559
Straniero, Valentina, Lorenzo Suigo, Giulia Lodigiani, and Ermanno Valoti. 2023. "Obtainment of Threo and Erythro Isomers of the 6-Fluoro-3-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide" Molbank 2023, no. 1: M1559. https://doi.org/10.3390/M1559
Supplementary File 1:
PDF-Document (PDF, 812 KiB)
3D structure (MOL, 3 KiB) Display in JSmol Viewer
3D structure generated by CORINA Classic by MN-AM.
INCHI-Document (INCHI, 867 B)
MOL-Document (MOL, 3 KiB) Display in JSmol Viewer
Molbank, EISSN 1422-8599, Published by MDPI


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text:
Japanese doctor and aid worker Tetsu Nakamura shot dead in Afghanistan
WION Web Team New Delhi, India Dec 04, 2019, 05.01 PM(IST)
Men carry the coffin of an Afghan victim of an attack on a vehicle carrying Japanese doctor Tetsu Nakamura, in Jalalabad, Afghanistan December 4, 2019. Photograph:( Reuters )
The Japanese aid agency was shot on the right side of his chest when gunmen opened fire on his car in Jalalabad in Nangarhar province
By Mallika Singh
Japanse physician and aid worker, Tetsu Nakamura, was shot dead along with five Afghans including his bodyguards, driver and another passenger in an attack in Afghanistan on Wednesday.
The Japanese aid agency was shot on the right side of his chest when gunmen open fired on his car in Jalalabad in Nangarhar province, said Afghan officials.
The doctor underwent surgery at a local hospital and was in the process of being transferred to Bagram near Kabul when he passed away at the Jalalabad airport.
"Sadly, Dr Nakamura has passed away from the wounds he received in the armed attack this morning," said a spokesman for Nangarhar's governor.
The attack on the aid worker comes a week after a grenade attack on a United Nations vehicle in Kabul increasing fears of the humanitarian workers in the conflict-ridden region.
Nakamura, the head of Peace Japan Medical services - known as Peshawar-kai in Japanese - devoted 35 years of his life to healing the wounded in Afghanistan of which he became an honorary citizen last year in October.
The doctor had opened a clinic in a remote village in Afghanistan in 1991, before which he treated leprosy in Pakistanis and sick Afghan refugees. The native Fukuoka had been heading the Nangarhar aid group since 2008.
Nakamura, last year claimed last year that his posting was meant to be for "five or six years" in an interview with national broadcaster NHK. "The plan was to come home when I was done."
"We didn't have proper facilities (for surgery and rehabilitation) but I couldn't just run away and abandon these people," he said.
There was no immediate claim for the responsibility of the attack for which the Taliban has denied responsibility claiming to have "good relations" with organisations that "contribute to the reconstruction of Afghanistan."
Japan Prime Minister Shinzo Abe said he was "shocked" at the aid worker's death who risked his life to do "various work" for which the people of Afghanistan were thankful.
"I am shocked that he had to die in this way," Abe told reporters in a news conference in Tokyo.
"He risked his life in a dangerous environment to do various work, and the people of Afghanistan were very grateful to him," he added.
The police have launched a search operation to arrest the gunmen who fled the scene said officials who claimed to believe that the doctor was targeted for his work.
"Dr Nakamura has been doing great work in the reconstruction of Afghanistan, especially in irrigation and agriculture," the official said.
"The Afghan government strongly condemns the heinous and cowardly attack on Afghans' greatest friend, Dr Nakamura," said a spokesman for Afghan President Ashraf Ghani.
"He has dedicated all his life to change the lives of Afghans."

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text:
Six Reasons Why a Super Bowl In New York Is A Bad Idea—And Six Reasons Why Those Reasons Are Stupid
And yet! Some people are arguing that this is a lousy idea. After the jump, their six reasons why—and why their reasons are silly.
Anti-NYC Reason #1: Because it might snow! And that would be bad!
Wait, why would that be bad? Haven't some of the NFL's most memorable games been played in lousy weather? Specifically on the icy tundra of Lambeau Field? How about the Snowplow game? The Tuck Rule Game? If there is a blizzard on Super Bowl night, February 2014, the game will be talked about for years, no matter what happens on the field.
Anti-NYC Reason #2: Snow would be bad because it would reduce the quality of play.
If we're being reasonable, this can't simply be an argument against cold-weather stadiums. It has to be an argument for a domes-only policy, which no one seems to be making. After all, plenty of warm-weather, open-air stadiums are located in places that are prone to massive thunderstorms in February (like, say, Tampa Bay, which was the runner up in today's vote). And remember: it poured through Super Bowl XLI between the Colts and the Bears three years ago, and the quality of play was just fine, unless you count Rex Grossman, who would've sucked under any meteorological circumstances.
**Anti-NYC Reason #3: Snow (or bitter cold) would introduce a bias against the passing-oriented teams that the NFL clearly loves. **
So does rain. No one's complaining about that. Again: either we eliminate weather as a factor entirely and always play the game indoors, or we roll the dice that someday it will affect the game. And in any case, shouldn't a Super Bowl-caliber team be capable of adapting? When was the last time a football coach after any game, at any level said, "We would've won if stupid God hadn't made it rain"?
Anti-NYC Reason #4: The (wealthy, important, well-connected) ticket buyers will freeze!
Um, boo-hoo? Can't the more fortunate simply buy thicker winter coats? And yes, it will be cold. But we're not talking about icy-tundra cold. We've heard people peddle worst-case scenarios of a Super Bowl played in minus-20 degrees. Folks, this is north Jersey, not Alaska. And if a once-in-a-lifetime cold snap does happen to coincide with Super Bowl 48, awesome! We're pretty sure old people in Green Bay still boast about being at the Ice Bowl, and that was more than 40 years ago. Embrace "once-in-a-lifetime." It's almost always good for ratings.
**Anti-NYC Reason #5: It'll set a dangerous precedent. Now that New York-New Jersey got the game, Boston will expect to be next. Why do you think Patriots owner Bob Kraft voted for this? **
Tell Kraft he can have a Super Bowl as soon as he builds a glistening new stadium. And if he does, give him the darn game! Boston is a great sports town. And anyway, there's no such thing as precedents in this process. It's a one-vote-per-team competition. Putting the game in New York isn't going to make the owners suddenly feel as if they owe it to Cincinnati in 2019. If the owners don't want a Super Bowl there, they will vote against it. (And by the way, they will vote against it. Sorry, Cincy. You're never getting a Super Bowl. Unless you build a domed stadium. And change your name to "Miami.")
Anti-NYC Reason #6: The league is taking a big risk with its most valuable asset.
Oh yes, playing the Super Bowl in the MOST GLAMOROUS CITY IN THE WORLD is just insane. Who would wanna watch that?
Related Stories for GQNew York CitySuper BowlNFLNFL


text:
Q: UIMA RUTA wordlist matching issue I am trying to match some multi-word tokens using UIMA RUTA 2.6.0. And there are some phrases that are partially equal to each other, e. g. in the same file I has following entries: "includes the", "include the", "in this", "in the".
There is next piece of text in my input file: "1. "Agents or employees" includes the directors...". Obviously, there is a "includes the" match, but if other above 3 entries are present in wordlist then no match will be found. Moreover, the ordering of those entries in wordlist does not depend on matching success: it always fails.
And this issue occurs not only in single file. So, the question: how can I fix it? May be some settings of RUTA annotator?

A: Whitespaces in the wordlist can lead to missed matches. If the whitespaces are not important, set the configuration parameter 'dictRemoveWS' to true.
DISCLAIMER: I am a developer of UIMA Ruta

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In a previous article Introduction to Spring, we discussed What is Spring and why it so popular among Java developers and we also discussed how Spring has broken its complete framework into different-different modules based on the functionality.
Spring framework is organized into 20 modules which can again be grouped into Core Container, Web, Data Access/Integration, AOP, Aspect, Instrumentation, Messaging, and Test, as shown in the following diagram.
The Core and Beans modules provide the most fundamental parts of the framework and provide the IoC and Dependency Injection features. The basic concept here is the BeanFactorywhich provides a sophisticated implementation of the factory pattern. It removes the need for programmatic singletons and allows you to decouple the configuration and specification of dependencies from your actual program logic.
The Context module builds on the solid base provided by the Core and Beans modules: it provides a way to access objects in a framework-style manner in a fashion somewhat reminiscent of a JNDI-registry. The Context module inherits its features from the Beans module and adds support for internationalization (I18N) (using for example resource bundles), event-propagation, resource-loading, and the transparent creation of contexts by, for example, a servlet container. The Context module also contains support for some Java EE features like EJB, JMX, and basic remoting support. The ApplicationContext interface is the focal point of the Context module that provides these features.
The Expression Language module provides a powerful expression language for querying and manipulating an object graph at runtime. It can be seen as an extension of the unified expression language (unified EL) as specified in the JSP 2.1 specification. The language supports setting and getting of property values, property assignment, method invocation, accessing the context of arrays, collections, and indexers, logical and arithmetic operators, named variables, and retrieval of objects by name from Spring's IoC container. It also supports list projection and selection, as well as common list aggregators.
Spring's Web module provides basic web-oriented integration features, such as multipart file-upload functionality, the initialization of the IoC container using servlet listeners and a web-oriented application context. It also contains the web-related parts of Spring's remoting support.
The Web-Servlet module provides Spring's Model-View-Controller implementation for web-applications. Spring MVC framework is a full-featured MVC implementation for building Web applications. The MVC framework is highly configurable via strategy interfaces and accommodates numerous view technologies including JSP, Velocity, Tiles, iText, and POI. We can also create Rest APIs using the same annotation as we use in web MVC.
The Web-Portlet module provides the MVC implementation to be used in a portlet environment and mirrors what is provided in the Web-Servlet module.
The ORM module provides integration layers for popular object-relational mapping APIs, including JPA, JDO, Hibernate, and iBatis. Using the ORM package you can use all those O/R-mappers in combination with all the other features Spring offers, such as the simple declarative transaction management feature mentioned previously.
The OXM module provides an abstraction layer for using a number of Object/XML mapping implementations. Supported technologies include JAXB, Castor, XMLBeans, JiBX, and XStream.
The JMS module provides Spring's support for the Java Messaging Service. It contains features for both producing and consuming messages.
The Transaction module provides a way to do programmatic as well as declarative transaction management, not only for classes implementing special interfaces but for all your POJOs (plain old Java objects).
The Spring AOP module integrates Aspect Oriented Programming functionality directly into the Spring framework, which allows us to define segregate our cross-cutting functionalities from our business logic. As a result, we can easily AOP-enable any object managed by the Spring framework. The Spring AOP module provides transaction management services for objects in any Spring-based application.
There is also a separate Aspects module that provides integration with AspectJ.
The Instrumentation module provides class instrumentation support and classloader implementations to be used in certain application servers.
Spring framework's messaging module serves as a foundation for messaging-based applications. The module provides a set of classes e.g., Message, MessageChannelMessageHandler to send and receive messages from the application and it also provides a set of annotations for mapping messages to methods, similar to the Spring MVC annotation based programming model.
Spring framework's Test module provides abstraction over a lot of testing and mocking framework such as TestNG, JUnit, Mockito, PowerMock which makes writing unit and integration a lot easier.


text:
Transforming Mission, it's not just about young people
A voice said, "I remember you with plaits!" And Barbara Meades knew that the church she had walked into was where God wanted her to be. The voice was that of Stan, the vicar's father. The church, Penwerris in Falmouth where Barbara had just moved to. The plaits were the ones she wore as a child. And Stan was a man Barbara had helped pick up windfalls in an orchard in Caversham, way back in the 1940s. All of which helps to give Barbara reassurance as Penwerris Church becomes part of the Transforming Mission in Falmouth.
So when Barbara feels uncertain, she turns to her beloved Lord, knowing that He took great care and planning to make her feel at home when she was a stranger in Falmouth in 1994, and trusting that He is doing the same again amidst all the changes that are going on. There is, understandably, a huge buzz and a lot of excitement in Falmouth with the pioneering missionary and the anticipated explosion of faith within the student population as the town's Anglican churches amalgamate into a super resource hub at All Saints. But there are also a few quiet voices gently putting up their hands to ask, "What about us?"
The 'us' is the older, more traditional congregations of churches like Penwerris, where Barbara Meade has faithfully served since moving to Cornwall 23 years ago. The church, like so many across Cornwall, has suffered from dwindling numbers and an aging congregation that isn't being restored by younger members. But for Barbara, church and the faith she celebrates there, is everything. It's her rock, the framework that shapes her life and underpins everything she does.
Most people, particularly as they reach their twilight years, talk about imminent birthdays with pride. Barbara is a little different as it's not her 80th birthday she's looking forward to, but the celebration of 80 years as a Christian.
For Barbara, her baptism as an infant, on December 10th, 1937, at St Peter's in Caversham, marked the start of her journey with God. Although, she laughs as she tells the story, the baptism didn't go quite according to plan. "After processing to the font, the vicar leant in to find there was no water! My brother and sister howled with laughter!" says Barbara.
Twelve years later, to the day, Barbara was confirmed into the Church of England. "My mother was the main influence in my life, her faith was steadfast and she instilled that in me," says Barbara. "So much so, I cannot imagine life without the Lord." Barbara never married, choosing instead to look after her parents, but just before her mother died, aged 93, she told Barbara to go and do something for herself and, knowing how much she loved Cornwall, said she should move there.
Barbara did so, but before she left she spent six months living on Reading University's campus, where she had worked for the past 40 years as secretary to the bursar, and volunteered in the chaplaincy. "I got to know the students so much better than when working in the bursar's office, where I usually had to remind them they owed money!"
While living on campus, Barbara developed a great rapport with the students who were always asking for help sewing on buttons, ironing a dress-shirt, or stopping by to chat when they felt a bit homesick. "At the end of term, instead of leaving, they all waited until I got home from work, just so they could say goodbye," says Barbara.
Barbara's experience with students will be invaluable as the work for transforming mission gets underway. Just as the older congregation are anxious about a new, youthful influx, so too will the younger people be anxious about the older generation. Barbara's ability to build bridges will help to demonstrate that we are all part of God's family and that the wisdom, faith and experience of the older generation can support the fresh ideas, perspectives and energy of the younger generation.
Nevertheless, Barbara is still a little apprehensive, "I know that it's all in God's hands, it's just a bit hard at the moment to see where we will fit in," she says. But, as we've found out, Barbara knows better than most that God goes ahead, as He did when she arrived, seemingly randomly, at Penwerris Church. She further explains, "I tried the other churches in Falmouth, but for one reason or another, I didn't really connect with them. But when I walked into Penwerris the lady who handed me a prayer book was so kind and welcoming – in fact she's she still here today, aged 99 – and asked me where I was from. When I explained, she said their vicar Fr David Smith, was from the same area and had in fact worked at the Royal Berkshire Hospital, just across from where I was working." That was the first step, but affirmation came at an Epiphany party a few months later.
"I remember you with plaits!" said a voice. It was Fr David's father, who was visiting. "Your mother used to bring you along to the market garden, in Caversham – you used to help me pick up the windfalls!" Barbara looked closely at him and realised he was Stan, she never knew his surname, the man she had indeed helped to pick up apples from the orchard when she was a child.
"I was amazed. It felt like confirmation that this was where God wanted me to be. Once his son found out how involved I'd been at my previous church, well, that was it. I began as the electoral roll officer, then secretary to the PCC, then church warden…" And so, Barbara became just as much a part of church life at Penwerris as it became part of hers, so much so that the one probably wouldn't do so well without the other.
Barbara's trepidation at the changes that are afoot are understandable and have not been ignored. But just as God went before her to Penwerris, there is a very strong sense that He has done the same again, laying the groundwork for the changes ahead.
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`Braintree/Data` is our advanced fraud solution that is powered by `BTData`, PayPal and Kount. This system enables you to collect device data and correlate it with a session identifier on your server.

By default, we suggest you utilize the default merchant credentials embedded in `[[BTData alloc] initWithClient:client environment:BTDataEnvironmentProduction]`.

For direct Fraud Integration, please see [our documentation](https://developers.braintreepayments.com/ios/guides/fraud-tools#direct-fraud-tool-integration) or [contact our accounts team](accounts@braintreepayments.com).

**Note:** Use of `Braintree/Data` and `BTData` is optional.

**Note:** `Braintree/Data` no longer contains references to Apple's IDFA.

### Usage

First, add `pod "Braintree/Data"` to your `Podfile`.

#### Default

Please follow these steps to integrate Braintree Data in your app:

1. Initialize `BTData` using the convenience constructor `initWithClient:environment:` in your AppDelegate.
    * See [our documentation](https://developers.braintreepayments.com/ios/start/hello-client) for instructions on initializing BTClient
    * Be sure to pass the current Braintree environment, and remember to change this value before shipping to the app store.

2. Optionally, set a delegate to receive lifecycle notifications.

2. Retain your `BTData` instance for your entire application lifecycle.

3. Invoke `collect` (to generate a session id) or `collect:` (to provide a session id) as often as is needed. This will perform a device fingerprint and asynchronously send this data to Kount. This operation is relatively expensive. We recommend that you do this seldom and avoid interrupting your app startup with this call.

#### Direct Fraud Tool Integration

Direct fraud tool integration is similar to default.

After initializing `BTData` following the instructions above, invoke `setCollectorUrl:` and/or `setKountMerchantId:` with the appropriate data.

Please contact our account management team for more information.

### Server-Side Integration

When processing a user's purchase, pass the session id (returned by `collect` or passed into `collect:`) along with the other transaction details to your server.

On your *server* include the session id in your request to Braintree.

For example in Ruby:

```ruby
result = Braintree::Transaction.sale(
  :amount => "100.00",
  :credit_card => {
    :number => params["credit_card_number"],
    :expiration_date => params["credit_card_expiration_date"],
    :cvv => params["credit_card_cvv"]
  },
  :device_session_id => params["BRAINTREE_DATA_SESSION_ID"]
)
```

redpajama_set_name: RedPajamaGithub


text:
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Opinion: How Stephen Sondheim Keeps Broadway Fresh and Important
snopxNovember 27, 2021
If you're a fan of musical theater, it's fair to say that you're a fan of Stephen Sondheim, the Broadway legend who passed away Friday at the age of 91.
A gifted composer and lyricist, Sondheim created the most artistically significant performances of his generation. And what did they show: "The Company," "Follies," "Sweeney Todd," "Pacific Overtures," "A funny thing happened on the way to the forum," "A little night of music" "The main theme." Day in the Park with George" and "Into the Woods", among others. Oh, and let's not forget his early efforts – a couple of now landmark shows, "Gypsy" and "West Side Story," for which he just happened to provide the lyrics.
It's not just the Sondheim catalog itself that is so impressive. It's the fact he's a living link to the Golden Age of Broadway – the era of Rodgers and Hammerstein (and Sondheim mentored by Oscar Hammerstein), Lerner and Loewe, Frank Loesser and countless others. At the same time, he showed us a future Broadway, one that could be darker and more complex in theme and tone. And a tune can be embarrassing—you can hum a Sondheim tune almost any time—and strangely clever and sophisticated.
Sondheim did not need to write operas to prove his artistic merit. He understands that the great American musical is really just that – an art form that is great (and ours), but it can evolve to fit the times. And while Sondheim doesn't write in the vernacular contemporary music is rock (that's Andrew Lloyd Webber's territory – at least with "Jesus Christ Superstar" – and others) or hip-hop (it's the stage of Lin-Manuel Miranda), work never goes out of style.
I've followed Sondheim's career for as long as I've been in theaters – first as a daily spectator and, in recent years, as an art critic and reporter. In fact, my first Broadway show was the original production of "Company" in 1970 – I was six years old then (I suspect my parents were too cheap to hire a babysitter), so I can't say how much the show has earned. of an impression. But by the time I witnessed the off-Broadway resurgence as a teenager, Sondheim was everything to me.
"Company" is a good place to start when understanding Sondheim. It is a show that examines the loneliness and isolation of contemporary life in the form of a man who finds companionship among his married friends, but is unable to make a personal connection. deeper into his own relationship. In other words, this is silly, adult stuff – and that's only amplified by the fact that it features one scene set in a bedroom and another involving marijuana (this is Broadway in the year). 1970, remember).
But don't let "Company" sound a little too serious and personal, just consider a few tunes: bittersweet "Sorry-Grateful" (a poignant summary of love and marriage as any writer has written, be it for Broadway or in the form of a poem or novel); the number of close friends is "Next to each other"; and the last Broadway torch song, "The lunch ladies."
However, my favorite Sondheim musical – and I'm hardly alone here – would have to be "Sweeney Todd," the grim reaper of a show about murder, cannibalism and… love. An odd combination for sure, but one that has such a haunting effect. And oh, so many great songs! If I had to name one name that has stuck in my ears for the past few decades, I would say "Johanna," which manages to convey both a profound tenderness and a loathsome apprehension.
The hit against Sondheim has always shown he's not quite right commercially. Sondheim has earned his accolades in the Tony Award, the industry's highest honor, and many other accolades, but he's never had a big hit on the "Hamilton" circuit. I remember I was talking to a successful Broadway producer once about the shows he decided to invest in and he told me the key was to know where Not to give your money – and Sondheim is one of his biggest disinterested people.
Perhaps he is right, although I must believe that the investment in at least a few musicals in Sondheim has yielded some return. But the funny thing is that even if Sondheim isn't a definite moneymaker, his presence on Broadway has made it all richer – artistically for sure, but perhaps artistically finance to a certain extent. In a word, Sondheim made Broadway important — and he did so during some of the industry's toughest times (basically the 1970s).
And through Sondheim's mentoring and the encouragement of many young artists, he also saw that Broadway would continue. If you've seen "Tick, Tick… Boom!," Jonathan Larson's autobiographical musical has just been re-imagined as a movie (and is now on Netflix).
NFLX,
+ 1.12%
), you know that Larson got the boost he needed at a pivotal point in his career when Sondheim gave him a big vote. (And may I remind you that Larson went on to write "Rent," the last musical of the '90s.)
It's also important to note how relevant Sondheim continues to be. One of the most anticipated shows of the new Broadway season? A bold, gendered revival of "The company." One of the most anticipated movies of the holiday season? Steven Spielberg in charge "Western Tales." I'm sure I'll see both.
Meanwhile, I'll be listening to recordings of the "Company" and "Sweeney Todd" casts and lots of Sondheim shows that challenge and thrill me at the same time. Lending song title from "Company", thank you, Mr. Sondheim, that you are still alive.
https://www.marketwatch.com/story/sondheim-was-just-about-everything-how-the-musical-theater-great-kept-broadway-fresh-and-vital-11637973554?rss=1&siteid=rss Opinion: How Stephen Sondheim Keeps Broadway Fresh and Important
snopx
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Tracy Michelle Arnold & Melisa Pereyra, As You Like It, 2018.
Two of Shakespeare's favorite devices — cross-dressing and running away to the woods — are combined in this delightful pastoral comedy. Rosalind's uncle, the Duke, threatens to banish her, since she is overshadowing her cousin Celia in the court. Together, the two girls flee to the Forest of Arden, with Rosalind (Melisa Pereyra) in a boy's disguise. Coincidentally, Rosalind's love Orlando is also forced to run to the woods after being threatened by his brother. Dressed as the young man Ganymede, Rosalind teaches the young gentleman Orlando how to woo. This production will feature Tracy Michelle Arnold assuming the traditionally male role as Jaques, a melancholy nobleman who gives the famous "All the world's a stage" speech. Through Oct. 7.


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Posted on September 23, 2019 September 23, 2019 by Hussain Alokaily
Knives Out is a film best experienced with knowing as little as possible, so don't worry fellow reader! The following review is 100% spoiler free!
Knives Out is the newest film from acclaimed filmmaker Rian Johnson. The film stars an all-star cast that consists of Daniel Craig, Ana De Armas, Chris Evans, Toni Collette, Jamie Lee Curtis, Don Johnson, Michael Shannon, Lakeith Stanfeild, Christopher Plummer, Katherine Langford and Jaeden Martell. It revolves around a detective and a trooper, who travel to a lush estate, in order to interview the quirky relatives of a patriarch who passed away during his 85th birthday.
I have liked Johnson's prior work, such as Looper and The Last Jedi. However, until this point, I never really saw him as a great filmmaker. He's a very talented artist behind the camera, as he knows how to make visuals stimulating, as he really adds some dynamic techniques while directing. However my problem with him has always been that he isn't that great of a writer; which is easily his greatest kryptonite. I was still very excited for Knives Out, given the massive cast and the genre it represented. I went in expecting a very good film, and what I got at the end of the day, is what I can proudly say is my favorite film I saw at this year's Toronto International Film Festival!
The first thing that stood out about Knives Out for me was the unique structure of the narrative. The film begins in a way, that I have not seen done in many conventional high-budget films. Without saying much, Johnson really gets you into the lives of the whole entire cast of characters, and draws you in almost instantly as an external family member. What this all does in the end, is to create a surprising and truly thrilling experience that will have you on the edge of your seat. So much of what happens in the film truly subverted my expectations on what a film's genre can do in order to add onto a story. Every twist was not just only amazing, but made sense within the context of the story. The film will sure to have you engaged through it's twists and turns, where the film will come together to one hell of a third act, which had me truly locked in.
This all comes from the brilliant mind himself, Rian Johnson, who truly upped his writing and directing game to a whole new level. The screenplay he wrote here is stunning, to the point that it should honestly be in contention for best original screenplay at this year's Academy Awards. Like I mentioned before, the structure is so unique, and the film had me on the edge of my seat; which was fully because of the writing at play. There is also many complex themes that Johnson manages to write into the film, that adds so much more depth. To continue, the characters Johnson created are nothing short of excellent, as they are all super engaging and compelling throughout. Then their's his direction, which is equally just as marvelous as his intricate screenplay. Johnson manages to add such immense visual energy to the film; where the camera work really adds to the personality and vibrance of the plot.
The whole entire cast also kills it! There is just so many cast members involved, and while some get more screen time then other members, they all have a significant purpose towards the plot. There are three main stand outs in particular that I would like to mention. Daniel Craig was perfect as the lead detective, who really commands the screen whenever he is present. Ana De Armas is continuing to be such a wonderful actress, as she also gives a charming side-character performance. However, the biggest surprise of the cast was Chris Evans. Evans plays his character in such a way that I have never seen him accomplish before. From his behavior to mannerisms, I honestly really hope from now on, that he continues to choose more ambitious roles like this.
Knives Out is awesome! The reason why this was my favorite film at the Toronto International Film Festival, is that it reminded me why I love film in the first place. This is a project that is fun, engaging, thrilling, and has a plethora of engaging, well-written and directed characters. This film is gonna be huge come November,and I cannot wait to re-watch it then!I'm glad to say that I'm officially on the Rian Johnson hype train now!
Knives Out screened at this year's Toronto International Film Festival. The film will hit cinemas on November 27th
Published by Hussain Alokaily
View all posts by Hussain Alokaily
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Home » Microphones reviews » 10 Best Blue microphones
10 Best Blue microphones
Blue Microphones have dramatically changed all representations of different types of microphones – these were devices with outstanding sound, allowing to make each record unique and incredibly soulful. This production is focused on the problem of the future of the music industry and the latest standards. It is not surprising that many people want to buy Blue Microphones – best analog microphones for recording and performances.
The production of Blue Microphones is based on the use of the best transistors and components of the first-class. This technique is indispensable in the arsenal of professional directors of a sound console and actors of any orientation. All devices have in their structure capsules, which were thoroughly tested for performance verification.
Blue Spark Digital
Blue Yeti
Blue Yeti Pro
Blue Baby Bottle
Blue Blueberry
Blue Snowflake
Blue Snowball
Blue Nessie
Blue Mikey Digital
It should be noted at once – Spark Digital microphone is used in professional recording. That is, the singers record their tracks through the microphone, and then, after the treatment course, tracks are sent to the market. This shows the high quality of the device and clean recording. The microphone features a condenser capsule of a studio class that allows the product to record a clean and tight sound of speech, musical instruments, sound recording in noisy environments. The device comes with a fairly heavy and stable stand, which does not give the microphone to fall, even if you strongly sway a table.
To record a sound there are four modes of the microphone directivity, connected either via USB, or you can connect the product to the iPad and work with proprietary applications. The main body of the microphone has a headphone jack, the switch to work with different modes, volume, and mute key. When buying a gadget you also get the access to Blue's Cloud Production Bundle, which you can process the sound online.
Having conquered the professional studio and reached the tops in the analog recording, Blue Microphones could not help but pay attention to digital technology, and USB-microphone market could not withstand the pressure of creative engineers of Blue Microphones. Yeti model is one of the most popular in the world thanks to the ideal combination of price and quality.
This is the most advanced and versatile USB-multidirectional microphone from available ones at the moment. With the Yeti you can make recordings with remarkable clarity and precision, previously unheard for USB microphones.
Features, modes, and connection.
The is famous for its built-in three capsules. These capsules allow you to record the sound in four different modes: stereo, cardioid, omnidirectional, and bi-directional.
the stereo mode helps you to record vocals or play on any musical instrument;
the cardioid mode is good to record podcasts, voice, and singing (often I use this particular mode);
the omnidirectional mode is useful at any conferences. If your microphone is in the middle of the table, it will record the speech of everyone who is sitting at this table;
the bi-directional mode is needed mainly for interviews, but sometimes it is used for recording instruments, as well as podcasts.
The Yeti features high-quality analog-to-digital converter for processing and transmitting the high-quality digital signal directly to the computer without going through a lot of links – like in the case with conventional microphones. Built-in preamplifier for headphone allows monitoring the recorded signal without any delay. This feature is very useful for the recording of vocals and leadings of online broadcasts.
On the front side of the microphone, there is a mute button (an incredibly useful thing!), and the headphone volume control. Built-in microphone sound card is designed so that when connecting the Yeti to your computer, it displays not only your voice but also all sounds from your PC. Thus, you can connect headphones directly to the microphone, and not to the computer: it is useful for those people who have audio inputs on the back of the system unit.
Connecting and inputs
Blue Yeti is connected to your computer via the USB cable and works well with Windows, and with any other system, such as MacOS. All inputs are located on the bottom wall of the microphone: from the left, there is USB, from the right – an input for connecting headphones.
Voltage: 5V 150mA.
Sampling frequency: 48 kHz.
Bit rate: 16-bit.
Caps: three 14mm condenser capsules.
Frequency response: 20 Hz – 20 kHz.
The maximum sound pressure: 120 dB (THD: 0,5% to 1 kHz).
Impedance: 16 ohms.
Output power (RMS): 130 mW.
Signal to noise ratio: 100 dB.
Blue Yeti – is the device that has the most successful value for money. Buying the microphone, you should understand that this device is not for a professional recording, but rather, for the amateur, but quality. Yeti is an excellent option for bloggers, podcasters who want to delight their audience with pure sound.
Yeti Pro – is a more advanced development of Blue mics, this device has become the world's first USB-microphone that records audio at 24-bit / 192, and has an analog output XLR. Inside the microphone Yeti Pro microphone, there are advanced audio converters and discrete analog circuitry and elements that help to use the microphone with professional mixers and preamps.
It is one of the few times when the most expensive gadget in the compilation is really the best solution. Microphone Blue Yeti Pro is used by professional commentators of sporting events, commentators CS GO, Dota 2, LoL, podcasters, bloggers, etc. Due to the large weight of the stand, which is made of metal and has a rough bottom, to budge the microphone or to drop it without special effort will be a difficult task. The total weight is more than a kilo – this is a very hard platform.
The microphone itself has four modes of sound recording – cardioid, bi-directional, omnidirectional, stereo. The bit rate is 24 bit, the frequency range of 20-20,000 Hz, the maximum sound pressure – 120 dB. The main body has a connector to the XLR and USB, as well as a headphone jack. The main body has two levers – one is to switch the orientation of the type, and the second is to increase the incoming sound. There's also a mute button and a headphone volume. Due to its design and the quality of the recording the microphone deserves the title of the best in the market for tape drives, or simply to record your voice.
A model the Bottle is the flagship of the entire company and is the greatest achievement in the field of innovation and quality. Baby Bottle – this is the microphone with smooth high and neutral bottoms. It allows you to create a very classic, but at the same time, the modern-sounding audio. Equipped with a specially designed capsule under tension of 100 Volt, Baby Bottle gives the excellent rich sound, while also being the quietest microphone in its class.
Baby Bottle can be considered as the main universal microphone. It is designed to transmit clearly dedicated, warm middle with good detail, thanks to the successful design of the capsule. It is recommended for rock vocals of a certain type, if you have to write a lot of tops and bottoms, you can squeeze the middle range and keep the vocals in the center. It also works perfectly with a saxophone, trumpet, and cello. Because the cello does not fall too low, and you don't need a microphone to capture all this infrasound, which can lead to chaos in the mix.
Directivity: cardioids.
Frequency response: 20Hz – 20kHz.
Sensitivity: 33.5mV / Pa.
The maximum sound pressure: 132 dB SPL.
S / N ratio: 87 dB.
Phantom power: 48V.
Blueberry model consists of discrete microphone amplifier, carefully chosen specifically for this model, cardioid, a large diaphragm of manual collection. The company's specialists have calculated the input level of this model, focusing on the needs of both amateur musicians and professionals.
The timbre of the microphone capsule is configured in such a way that the end result resembles the sound of old microphones, and provides a signal, in which there are no low-frequency resonances, which, in turn, may adversely affect the further work with the record.
All microphones of the company have a hand volume control, and the user may be close to the microphone as far as it is convenient for him.
Blueberry was conceived as a large diaphragm microphone, specifically designed for acoustic guitar with steel strings. He has incredibly bright, sparkling sound. It also wonderfully conveys a breath of a singer that really like the performers of Pop and R&B. Some call Blueberry the "sexy" microphone.
Type: studio condenser.
Wireless interface.
Directionality: cardioids.
Bottom border of frequent range: 20 Hz.
Upper border of frequent range: 20 000 Hz.
Sensitivity: 20 mV / Pa.
Max. sound pressure level (SPL): 140 dB.
Impedance: 150 ohms.
Power: 48 V.
Diameter: 50 mm.
Weight: 520 g.
This is a compact condenser USB microphone -Raspberry, compatible with iPhone/iPad and computer on the Windows and Mac platforms. This model provides recording at resolutions up to 24 bit/48 kHz and can be used for creating podcasts, audio recordings for YouTube videos, voice narration, as well as the vocals and instruments.
The proprietary technology Internal Acoustic Diffuser (IAD) and removable Folding Stand – the main features of Blue Raspberry. The first allows you to minimize the background noise, and the second provides protection of the microphone against vibration thanks to the shock-absorbing surface of the legs. In addition, the stand provides additional protection during transit. Among other features, note the presence gain control with the button "Mute" and a headphone output with separate volume control for monitoring with no delay.
Frequency range: 20 … 20,000 Hz.
Type: electret condenser, 14 mm.
Polar pattern: cardioids.
Maximum SPL: 120 dB.
Gain adjustment range: 0 – 40 dB.
Dimensions with stand: 147.5 mm × 58,5 × 46,75 mm.
Weight with stand: 272.3 g.
The first professional portable USB-mic in the world. The microphone is extremely small, but apart from that has the original design – the microphone cable can be folded in a special department. Despite its small size Blue Snowflake has great opportunities – it covers the frequency included in
the range from 35 Hz to 20 KHz. And all because in the microphone there is the superior capsule, which, on a couple with precise digital converter, creates this sound.
It is an ideal choice for the recording of audio samples, interviews or dictation of the text. You can put it
on a table or mount on the lid of the notebook, with original built-in stand, any position will be sustained.
It works ideally with Garage Band systems, Logic 7 and Adobe Premier Elements, and is connected via the USB connector.
Features of USB-Microphone Blue Snowflake:
Compatible with computers running on Mac OS system and Windows.
Blue Snowflake – is the world's first professional USB-compact microphone. It provides excellent sound quality, despite its small size.
The microphone has a condenser capsule of Blue Microphones, which provides a professional sound quality. The microphone is ideal for voice recording, podcasting, interviews, creating sound track for home video, music, voice recognition, and presentations. It can be used in a variety of cases, and, of course, to communicate over the Internet with Skype and Go.
It connects directly to the USB port of a laptop or desktop computer. The cable, which is included, is conveniently removed in a special branch of the microphone stand.
With foldable stand, the microphone can be mounted directly on a laptop or on a table. In this and in another case, the microphone position will be sustained.
To use the microphone is not required the installation of additional drivers, it operates on a Plug and Play.
Compatible with a variety of software including Garage Band, Logic 7 and Adobe Premier Elements.
The microphone is very compact. Folded it fits easily in any bag.
Membrane: capacitor.
Diagram orientation: cardioids.
Frequency response: 35 Hz to 20 kHz.
Sampling frequency: 44.1 kHz.
Data transfer rate: 16 bits.
This is the professional USB-microphone with changeable patterns. Blue Microphones company was among the first in the world caught the trend and created a condenser microphone for recording podcasts, and real life has expanded the scope of the device to include a home, garage studio, as well as bloggers single.
Regardless of the scope of the Blue Snowball, one thing remains unchanged – professional quality. To immediately start writing of high-quality sound you need to connect the Snowball with the computer via USB port, regardless of whether it's Mac or PC, stationary machine, laptop or iPad.
In accordance with the type of problem to be solved one of the switch positions is selected from the rear of the "ball" with a diameter of 10.3 cm "1," "2" or "3". Thus, the Snowball is either omnidirectional microphone or catches the sound within the "heart" of the curve (cardioid), the third option – for extreme loudness levels: a filter is switched on, cut 10 dB.
Variation of a diagram type "circle" or "eight" is technically possible due to the presence of two sound pick-caps in the Snowball. The microphone copes with a signal from any source. At the exit, you will get an excellent record, retaining the maximum of the original features and minimum distortion.
Blue Snowball engineers conceived the mic as a desktop microphone (for the Snowball an anti-vibration suspension – Blue Ringer is designed). The Snowball is screwed and confidently stands on its own three-legged tripod. In the vertical plane, the "head" of the microphone can be lifted "up" or tilt the "down".
To start operation, no special software or drivers are needed. The first step – Plug – recite the text, sing or play, write or chat conference reports. The second step – Play of finished material, filled in on the online channel. With the Snowball everything is simple: recorded this evening in the kitchen will sound with studio clarity and purity.
Gamma colors of corps, offered by creators of the Snowball, is wide enough: black (GB, Gloss Black), orange (NO, Neon Orange), blue (EB, Electric Blue), green (Neon Green), white (TW, Textured White), silver ( BA, Brushed Aluminum).
The mic is designed for professional musicians and podcasters.
Microphone type: condenser.
Work both in omnidirectional or cardioid mode.
Frequency range: 44.1 kHz / 16 bit.
Sensitivity position 1-3: 40-18 kHz.
Extra advantages: it does not require driver installation when used with PC and Mac.
Weight/size: 460g/325mm in circumference.
Blue Microphones Nessie – is a stylish, elegant and really modern microphone which allows you to record the voiceover, live vocals and lots of musical instruments using a standard home computer. The main feature of this model is its portable design and high sound quality. Simply connect the microphone to your PC, and you can create tracks as if you are in a music studio.
Switching is done via the USB slot. Integrated POP-filter reduces the sharpness of explosive overtones. Adaptive damping system allows you to effectively cope with the vibrations. A flexible handler clears the tracks offline. Complete the picture the three working format, allowing to focus on the sound of the vocals or live instruments or keep the same classic recording.
This compact, efficient, but at the same time a simple device will open up new horizons for your home recording.
Destination: recording vocals and instruments.
Type: condenser table microphone.
Cardioid mode
Frequency range: 15 Hz – 22 kHz.
SPL: 100dB.
Blue Microphones Mikey Digital – is a super-compact stereo condenser type, designed specifically to turn your mobile phone or tablet into a portable device for recording audio. This model is perfect for on-site work: improvised interviews, rehearsals and recording music podcasts. If desire, you can easily record both vocal and instrumental music.
The wide frequency range (35 to 20 000 Hz) and a cardioid polar pattern create all the necessary conditions for the creation of clean, expressive and truly professional tracks. Therefore, choosing the Blue Microphones Mikey Digital, you take the right decision.
Destination: recording live music, podcasts, interview and vocal.
Type: stereo condenser microphone.
Cardioid mode.
Sampling: 44.1 kHz / 16-bit.
Quantization depth: 16 bits.
Weight: 0.4 kg.
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The Static is coming... it arrives tomorrow, April 5th. But today, a full day before the release of the Athens, Georgia four-piece Walden's new EP, we've got the exclusive premiere for all you musicheads. So, head below for a ton of info, tour dates, and the stream itself, but first check out the pre-order action on iTunes.
These alternative rockers have quickly risen to the top of the local Athens scene (and beyond) due largely to their well-crafted songwriting and elite musicianship. This isn't just four guys who were looking for a gig, but rather four determined young men who have been playing music together since they all picked up instruments around high school.
Sure, high school bands usually dissolve in a matter of weeks, but this quartet stuck together and were launched onto the national stage in 2016 when they won the "Road To Roo" competition that awarded them a spot on the Bonnaroo Music Festival lineup. Alas, the excitement was short-lived as they were disqualified due to both Eric Hangartner and Richard Becker being younger than the required age of 21. No big deal, though, as Walden kept on trucking and won the competition the following year when everyone was of "proper" age.
Sift through The Static to find some real sounds.
Fiending for more? Check out the song "Axioms" (The Static Sessions) here.
The cool cover artwork for The Static which, as a reminder, drops on April 5th.


text:
A day at the races for Autism Speaks
May 29th, 2015 · by Ashton Brown · Comments:
NASCAR Sprint Cup points leader Kevin Harvick's crew watches over his No. 4 Chevrplet with its Autism Speaks sticker, far right, on his driver's side door. (Delaware State News photo by Dave Chambers)
DOVER — For the fifth year, Dover International Speedway is partnering with FedEx and Autism Speaks for the "FedEx 400 benefiting Autism Speaks" NASCAR Sprint Cup Series race.
A decade and a half ago, Dover Motorsports President and CEO Denis McGlynn, Mark Rossi, speedway vice president of sales and marketing, and Artie Kempner, coordinating producer for NASCAR on Fox, began working together for the biannual NASCAR races at Dover.
It was Mr. Kempner's involvement in another organization — Autism Delaware — that piqued Dover's interest.
"Denis and Mark first approached me in 2005 about doing something with Autism Delaware to spread awareness so nine years ago we started working together just to spread awareness and raise a little money," Mr. Kempner said.
"But I never thought we'd get here, with Autism Speaks as the beneficiary of the race."
Mr. Kempner is the founder of Autism Delaware and a board member of Autism Speaks. The speedway officially added Autism Speaks as the beneficiary of the first of its two annual Sprint Cup races in 2011.
The FedEx 400 benefiting Autism Speaks begins at 1 p.m. Sunday. Pre-race activities start at 11:15 a.m. Visit www.doverspeedway.com for ticket information.
"When our partnership started, it was the first of its kind," Mr. Kempner said. "Before we teamed up, there wasn't a charity initiative from NASCAR like it."
The Furniture Row No. 78, driven by Martin Truex Jr., is also one of the cars with an Autism Speaks sticker.
Mr. Kempner credits Mr. Rossi with solidifying the partnership.
"He's a guy that likes to support the community and he brings that to the speedway," Mr. Kempner said. "He was the driving force behind this and it's remarkable how far he's been able to get us."
"About a decade ago, I just got into a conversation with Artie about autism," Mr. Rossi said. "I had heard about it before but didn't know what it was or how it worked but I wanted to learn more because I knew an employee had a son with it.
"After what I learned, I realized we needed to find an opportunity to get out not only awareness about autism but also the services and opportunities available to those with autism or a family member with it," he said.
The partnership with Autism Speaks doesn't only increase awareness and raise money, it also gives families and individuals on the autism spectrum the chance to enjoy a NASCAR race in ways never available to them before.
A special ticket package called Autism Speaks Day at the Races is available to these families. This is the package's fourth year.
It includes opportunities to meet drivers and NASCAR personalities, food and drinks, educational programs and access to a sensory-friendly environment to view the race.
The sensory-friendly area is air-conditioned with low lighting and sound, with a live stream of the race, toys and games.
"The Day at the Races is a great way for families and kids who usually wouldn't be able to enjoy an event like this to come and have the real fan experience," Mr. Kempner said. "And it's an environment where everyone will be understanding of the family's circumstances so it's also very welcoming."
This year, 500 tickets were available for purchase for the Day at the Races and all were sold out weeks before the race weekend. The program started with 127 participants the first year but has grown in size every year since.
"Kids and adults on the spectrum really like racing of any kind because of the structure of it and the patterns to watch and now they have a way to come to a NASCAR race and have their own quiet space where they can be at ease," Mr. Kempner said.
Throughout race weekend, donation booths for Autism Speaks will be scattered across the grounds and a track walk will take place after today's XFINITY race with Sprint Cup driver Denny Hamlin and his No. 11 team participating.
Also, many of the drivers in Sunday's Sprint Cup race will support autism awareness by sporting the autism puzzle piece logo on their cars.
NASCAR's support of Autism Speaks isn't confined to the track; more than 20 drivers participated in the 14th annual Drive for Autism, a golf tournament held Friday at DuPont Country Club in Wilmington. More than 275 golfers played in the tournament, all raising money for autism awareness.
"It's hard to meet someone like Artie who is so passionate about something and not be effected by it," Mr. Rossi said.
"It just made me realize it's important to get involved, spread awareness, educate people about autism and put an end to the fallacies."
Reach staff writer Ashton Brown at abrown@newszap.com. Follow @AshtonReports on Twitter.
Tags:Featured · NASCAR · NASCAR at Dover
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Salesforce is one of the most popular customer relationship management (CRM) programs on the market. Its popularity is partially due to its ability to integrate with a variety of tools that help your call center run more effectively and efficiently.
But with such a wide range of tools, it can be tough to figure out which one will work best for your call center and CRM setup. To help you make the right choice, we've compiled a list of some of the most popular programs for integrating call center applications with Salesforce.
Zapier is an integration tool that allows you to integrate over 500 apps and programs outside of Salesforce with your call center system. Programs like Eventbrite, MailChimp and Google Apps can be connected with your actions inside Salesforce to help your systems run in sync. This is helpful for call centers because it can allow you to more effectively communicate with the customers in your CRM by easily sending them an email, for example.
You can view all of Zapier's existing "zaps", or integrations, for Salesforce by clicking here.
Zapier offers several tiers of pricing, including a free plan that allows you to create or use 5 zaps (integrations) and run up to 100 tasks per month.
Zapier defines a task as every time a piece of data is pushed through the integration; so, if you created an integration that would transfer customer information from a form on your website to Salesforce, a task would be counted each time that your Zapier integration pushed that information into your Salesforce database.
The remaining plans range from $20 – $125 per month, and each tier comes with a free trial.
You can update contacts and files using the information you receive through these surveys or applications, allowing your call center to have a full picture of everyone in your CRM.
Please note that in order to use FormAssembly's Salesforce integration, you must choose one of the advanced plans. The integration is not available with the Basic plan.
If you're not quite ready to commit to using FormAssembly, you can always start with their 14 day free trial.
Informatica offers a variety of tools that can integrate with Salesforce. Their tools do everything from verifying contact information of your customers to consolidating files into one viewable page. Their tools are great for call centers because they can help you access and clean customer information more easily.
Informatica's services are not "one-size-fits-all," and they do not list pricing for their products or solutions on their website. In order to get a customized quote for your call center's needs, you can contact Informatics directly.
Scribe's pricing plans are also customized for each customer and implementation; however, you can learn more about how Scribe can enhance your call center by connecting to Salesforce here.
The integration tools above are a great addition to any call center currently utilizing Salesforce. They'll help you run your call center more successfully because they connect directly with your current CRM, allowing you to have a comprehensive view of your customer base.