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61.
Eric E. Boros James B. Thompson Edgar R. Wood O. Bradley McDonald Timothy D. Spitzer Andrea M. Sefler Bryan R. Reep 《Journal of heterocyclic chemistry》2004,41(3):355-358
5‐Methoxy and 5‐anilinopyrido[2,3‐d]pyrimidin‐7(8H)‐ones 2a‐2f were obtained by a tandem Michael addition‐cyclization reaction of methanol and anilines with pyrimidinylpropynoate 5. Methoxy derivative 2a was obtained in 62% yield by treatment of 5 with methanol and potassium carbonate. Anilino derivatives 2b‐2f were prepared in 31–71% yields by reacting 5 with the corresponding anilines in refluxing methanol. This methodology accomplishes Michael‐addition and pyridopyrimidinone ring formation in one‐pot and affords the desired products in reasonable yield without chromatography. Propynoate 5 did not react with 4‐cyanoaniline under these conditions. Reaction of 5 with 2‐aminopyridine gave the unexpected arylpyrido[2,3‐d]pyrimidinone 8 in 58% yield and reaction of 5 with imidazole afforded Michael‐adduct 9 in 69% yield. Compounds 2a and 5 were submicromolar inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. 相似文献
62.
The asymmetric Michael addition of glycine imine esters to simple α,β-unsaturated ketones via PTC is investigated. It is found that by employing 1 mol % of a chiral quaternary ammonium salt, derived from α-methylnaphthylamine in conjunction with Cs2CO3, high enantioselectivities can be obtained in conjugate additions involving simple alkylvinylketones. 相似文献
63.
Jun Liu Kelton A. Schleyer Tyrel L. Bryan Changjian Xie Gustavo Seabra Yongmei Xu Arjun Kafle Chao Cui Ying Wang Kunlun Yin Benjamin Fetrow Paul K. P. Henderson Peter Z. Fatland Jian Liu Chenglong Li Hua Guo Lina Cui 《Chemical science》2021,12(1):239
Heparanase (HPA) is a critical enzyme involved in the remodeling of the extracellular matrix (ECM), and its elevated expression has been linked with diseases such as various types of cancer and inflammation. The detection of heparanase enzymatic activity holds tremendous value in the study of the cellular microenvironment, and search of molecular therapeutics targeting heparanase, however, no structurally defined probes are available for the detection of heparanase activity. Here we present the development of the first ultrasensitive fluorogenic small-molecule probe for heparanase enzymatic activity via tuning the electronic effect of the substrate. The probe exhibits a 756-fold fluorescence turn-on response in the presence of human heparanase, allowing one-step detection of heparanase activity in real-time with a picomolar detection limit. The high sensitivity and robustness of the probe are exemplified in a high-throughput screening assay for heparanase inhibitors.Heparanase, a critical enzyme involved in the remodeling of the extracellular matrix, activates a disaccharide probe HADP to give a strong fluorescence signal. 相似文献
64.
The collisional behaviour of electronically excited silicon atoms in the 3p2(1S0) state, 1.909 eV above the 3p2(3P0) ground state, is investigated by time-resolved attenuation of atomic resonance radiation at λ = 390.53 nm (4s(1Po1)←3p2 (1S0)). The optically metastable Si(31S0) atoms were generated by the repetitive pulsed irradiation of SiCl4 and their decay monitored in the presence of added gases. Absolute quenching rate constants (kQ, cm3 molecule?1 s?1, 300 K) are reported for the following collision partners: He (?1.3 × 10?15), SiCl4 ((9.1 ± 1.4) × 10?11), O2 ((1.5 ± 0.2) × 10?11) and N2O ((4.3 ± 0.4) × 10?11). The results for O2 and N2O are compared with analogous data reported hitherto for Si(3p2(3PJ)) and with those for the other np2(1S0) states of the group IV atoms C, Ge, Sn and Pb. The rate data for the silicon atoms are considered in terms of the nature of the potential surfaces arising from symmetry arguments based on the weak spin orbit coupling approximation. 相似文献
65.
Alpha-fluorosulfonamides were prepared by electrophilic fluorination of tertiary sulfonamides using N-fluorobenzenesulfonimide as fluorinating agent and utilizing the dimethoxybenzyl group (DMB) as a new sulfonamide protecting group. Removal of the DMB group with TFA/CH(2)Cl(2) gave primary and secondary alpha-fluorosulfonamides. 相似文献
66.
67.
Solid-phase extraction coupled with reversed-phase high-performance liquid chromatography and UV detection was employed for the analysis of the antibiotic vancomycin in patient plasma, bone, atrial appendage, and pericardial fluid. Vancomycin was quantitated in samples from patients undergoing cardiac surgery. Calibrations were linear in the range 3-100 micrograms/ml vancomycin; the lower limit of detection was approximately 3 micrograms/ml in fluids with an absolute limit of detection in bone samples of 0.75 microgram per injection. 相似文献
68.
Amber L. H. Gray Aleksandra Antevska Benjamin A. Link Bryan Bogin Susan J. Burke Samuel D. Dupuy J. Jason Collier Zachary A. Levine Michael D. Karlstad Thanh D. Do 《Chemical science》2021,12(16):5853
Despite being relatively benign and not an indicative signature of toxicity, fibril formation and fibrillar structures continue to be key factors in assessing the structure–function relationship in protein aggregation diseases. The inability to capture molecular cross-talk among key players at the tissue level before fibril formation greatly accounts for the missing link toward the development of an efficacious therapeutic intervention for Type II diabetes mellitus (T2DM). We show that human α-calcitonin gene-related peptide (α-CGRP) remodeled amylin fibrillization. Furthermore, while CGRP and/or amylin monomers reduce the secretion of both mouse Ins1 and Ins2 proteins, CGRP oligomers have a reverse effect on Ins1. Genetically reduced Ins2, the orthologous version of human insulin, has been shown to enhance insulin sensitivity and extend the life-span in old female mice. Beyond the mechanistic insights, our data suggest that CGRP regulates insulin secretion and lowers the risk of T2DM. Our result rationalizes how migraine might be protective against T2DM. We envision the new paradigm of CGRP : amylin interactions as a pivotal aspect for T2DM diagnostics and therapeutics. Maintaining a low level of amylin while increasing the level of CGRP could become a viable approach toward T2DM prevention and treatment.CGRP concentration is elevated in migraine conditions. The protective effect of migraine against type 2 diabetes is attributed to the ability of CGRP to remodel human amylin aggregation and to suppress the secretion of mouse insulin 2 (the orthologue of human insulin). 相似文献
69.
Saeh JC Lyne PD Takasaki BK Cosgrove DA 《Journal of chemical information and modeling》2005,45(4):1122-1133
The combination of 3D pharmacophore fingerprints and the support vector machine classification algorithm has been used to generate robust models that are able to classify compounds as active or inactive in a number of G-protein-coupled receptor assays. The models have been tested against progressively more challenging validation sets where steps are taken to ensure that compounds in the validation set are chemically and structurally distinct from the training set. In the most challenging example, we simulate a lead-hopping experiment by excluding an entire class of compounds (defined by a core substructure) from the training set. The left-out active compounds comprised approximately 40% of the actives. The model trained on the remaining compounds is able to recall 75% of the actives from the "new" lead series while correctly classifying >99% of the 5000 inactives included in the validation set. 相似文献
70.
Recent work performed at DERA (now QinetiQ) has shown how accelerating rate calorimetry (ARC) can be used to obtain time to maximum rate curves using larger samples of energetic materials. The use of larger samples reduces the influence of thermal inertia, permitting experimental data to be gathered at temperatures closer to those likely to be encountered during manufacture, transportation or storage of an explosive device. However, in many cases, extrapolation of the time to maximum rate curve will still be necessary. Because of its low detection limit compared to the ARC, heat conduction calorimetry can be used to obtain data points at, or below, the region where an explosive system might exceed its temperature of no return and undergo a thermal explosion.Paired ARC and heat conduction calorimetry experiments have been conducted on some energetic material samples to explore this possibility further. Examples of where both agreement and disagreement are found between the two techniques are reported and the significance of these discussed. Ways in which combining ARC and heat conduction calorimetry experiments can enhance, complement and validate the results obtained from each technique are examined. 相似文献