Abstract:
A method of purifying 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacaciferol to obtain 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol in crystalline form. The method includes the steps of boiling a solvent such as acetone under inert atmosphere, dissolving a product containing 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol to be purified in the solvent, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol crystals, and recovering the 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol crystals.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS  
       [0001]    This application is based on and claims priority from U.S. Provisional Patent Application No. 60/341,138 filed Dec. 13, 2001. 
     
    
     
       BACKGROUND OF THE INVENTION  
         [0002]    The present invention relates to purification of organic compounds, and more particularly to the purification of 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol (referred to herein as 2MBP and/or 2-MbisP) by preparing it in crystalline form.  
           [0003]    Purification of organic compounds, especially those designated for pharmaceutical use, is of considerable importance for chemists synthesizing such compounds. Preparation of the compound usually requires many synthetic steps and, therefore, the final product can be contaminated not only with side-products derived from the last synthetic step of the procedure but also with compounds that were formed in previous steps. Even chromatographic purification, which is a very efficient but relatively time-consuming process, does not usually provide compounds which are sufficiently pure to be used as drugs.  
           [0004]    Depending on the method used to synthesize 1α-hydroxyvitamin D compounds, different minor undesirable compounds can accompany the final product. Thus, for example, if direct C-1 hydroxylation of 5,6-trans geometric isomer of vitamin D is performed, followed by SeO 2 /NMO oxidation and photochemical irradiation [see Andrews et al.,  J. Org. Chem.  51, 1635 (1986); Calverley et al.,  Tetrahedron  43, 4609 (1987); Choudry et al.,  J. Org. Chem.  58, 1496 (1993)], the final 1α-hydroxyvitamin D product can be contaminated with 1β-hydroxy- as well as 5,6-trans isomers. If the method consists of C-1 allylic oxidation of the 4-phenyl-1,2,4-triazoline-3,5-dione adduct of the previtamin D compound, followed by cycloreversion of the modified adduct under basic conditions [Nevinckx et al.,  Tetrahedron  47, 9419 (1991); Vanmaele et al.,  Tetrahedron  41, 141 (1985) and 40, 1179 (1991); Vanmaele et al.,  Tetrahedron Lett.  23, 995 (1982)], one can expect that the desired 1α-hydroxyvitamin can be contaminated with the previtamin 5(10),6,8-triene and 1β-hydroxy isomer. One of the most useful C-1 hydroxylation methods, of very broad scope and numerous applications, is the experimentally simple procedure elaborated by Paaren et al. [see  J. Org. Chem.  45, 3253 (1980) and  Proc. Natl. Acad. Sci. U.S.A.  75, 2080 (1978)]. This method consists of allylic oxidation of 3,5-cyclovitamin D derivatives, readily obtained from the buffered solvolysis of vitamin D tosylates, with SeO 2 /t-BuOOH and subsequent acid-catalyzed cycloreversion to the desired 1α-hydroxy compounds. Taking into account this synthetic path it is reasonable to assume that the final product can be contaminated with 1α-hydroxy epimer, 5,6-trans isomer and the previtamin D form. 1α-hydroxyvitamin D 4  is another undesirable contaminant found in 1α-hydroxyvitamin D compounds synthesized from vitamin D 2  or from ergosterol. 1α-hydroxyvitamin D 4  results from C-1 oxidation of vitamin D 4 , which in turn is derived from contamination of the commercial ergosterol material. Typically, the final product may contain up to about 1.5% by weight 1α-hydroxyvitamin D 4 . Thus, a purification technique that would eliminate or substantially reduce the amount of 1α-hydroxyvitamin D 4  in the final product to less than about 01.-0.2% would be highly desirable.  
           [0005]    The vitamin D conjugated triene system is not only heat- and light-sensitive but it is also prone to oxidation, leading to the complex mixture of very polar compounds. Oxidation usually happens when a vitamin D compound has been stored for a prolonged time. Other types of processes that can lead to a partial decomposition of vitamin D compounds consist of the some water-elimination reactions; their driving force is allylic (1α) and homoallylic (3β-) position of the hydroxy groups. The presence of such above-mentioned oxidation and elimination products can be easily detected by thin-layer chromatography. Thus, for example, using precoated aluminum silica sheets [with UV indicator; from EM Science (Cherry Hill, N.J.)] and solvent system hexane-ethyl acetate (4:6), the spot of 1α-OH-D 2  (R f  0.27) and its elimination products (R f &#39;s ca. 0.7-0.9) are visible in ultraviolet light. Also, after spraying with sulfuric acid and heating, an additional spot can be visualized (R f  0), derived from oxidation products.  
           [0006]    Usually, all 1α-hydroxylation procedures require at least one chromatographic purification. However, even chromatographically purified 1α-hydroxyvitamin D compounds, although showing consistent spectroscopic data, suggesting homogeneity, does not meet the purity criteria required for therapeutic agents that can be orally, parenterally or transdermally administered. Therefore, it was evident that a suitable method of purification of 2MBP is required.  
         SUMMARY OF THE INVENTION  
         [0007]    The present invention relates to a method of purifying 2MBP by means of crystallization to obtain 2MBP in crystalline form. The solvent plays a crucial role in the crystallization process, and is typically an individual liquid substance or a suitable mixture of different liquids. For crystallizing 2MBP, the most appropriate solvent and/or solvent system is characterized by the following factors:  
           [0008]    (1) low toxicity;  
           [0009]    (2) low boiling point;  
           [0010]    (3) significant dependence of solubility properties with regard to temperature (condition necessary for providing satisfactory crystallization yield); and  
           [0011]    (4) relatively low cost.  
           [0012]    It was found that highly apolar solvents (e.g. hydrocarbons) were not suitable due to the low solubility of 2MBP in them. Quite the reverse situation occurred in highly polar solvent media (e.g. alcohols), in which 2MBP showed too high solubility. Therefore, it was concluded that for the successful crystallization of 2MBP, a solvent of medium polarity is required. Interestingly, hexane, so frequently used for crystallization purposes, was found less suitable for crystallization of 2MBP. However, it was found that an individual solvent, namely acetone, was most useful for the crystallization of 2MBP. In addition, it is believed that solvent systems utilizing ethyl acetate, or isopropanol, or chloroform, or dichloromethane, or diethyl ether would also perform well. These solvents are all very easy to remove by evaporation or other well known methods. In all cases the crystallization process occurred easily and efficiently; and the precipitated crystals were sufficiently large to assure their recovery by filtration. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0013]    [0013]FIG. 1 is an illustration of the three dimensional structure of 2MBD as defined by the atomic positional parameters discovered and set forth herein. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0014]    The present invention provides 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol (2MBP) in crystalline form, a pharmacologically important compound, characterized by the formula shown below:  
                         
 
         [0015]    The present invention also provides a valuable method of purification of 2MBP. The purification technique involves obtaining the 2MBP product in crystalline form by utilizing a crystallization procedure wherein the 2MBP material to be purified is dissolved using as the solvent a single solvent system comprised of acetone, ethyl acetate, isopropanol, chloroform, dichloromethane, or diethyl ether. The preferred solvent is acetone. Thereafter, the solvent can be removed by evaporation, with or without vacuum, or other means as is well known. The technique can be used to purify a wide range of final products containing 2MBP obtained from any known synthesis thereof, and in varying concentrations, i.e. from microgram amounts to kilogram amounts. As is well known to those skilled in this art, the amount of solvent utilized should be minimized and/or adjusted according to the amount of 2MBP to be purified.  
         [0016]    The usefulness and advantages of the present crystallization procedures is shown in the following specific Examples 1 and 2. After crystallization, the precipitated material was observed under a microscope to confirm its crystalline form. Additionally, X-ray diffraction analysis was performed. Yields of crystallizations were high and the obtained crystals showed a relatively sharp melting point of 162-164° C.  
         [0017]    The described crystallization process of the synthetic 2MBP product represents a valuable purification method, which can remove not only some side products derived from the synthetic path, but, moreover, concomitant 1α-hydroxyvitamin D 4 . Such impurity is the result of the contamination of natural ergosterol with its 22,23-dihydro analog.  
       CRYSTALLIZATION OF 2MBP  
     EXAMPLE 1  
     Crystallization From Acetone  
       [0018]    (a) 2MBP product to be purified may be dissolved in boiling acetone (1.2 mL, Aldrich) under argon atmosphere, left at room temperature (68° F.) for a few hours (1-3 hrs) and then in a refrigerator (35-45° F.) overnight (8-12 hrs). The precipitated crystals should be filtered off, washed with a small volume of a cold (0° C.) acetone and dried.  
         [0019]    (b) These crystals of 2MBP may then be recrystallized with acetone (0.5 mL) as described in Example 1(a). The precipitated crystals have a relatively sharp melting point of 162-164° C., and were observed under a microscope to confirm their crystalline form.  
       EXAMPLE 2  
     Experimental  
       [0020]    A colorless plate-shaped crystal of dimensions 0.40×0.25×0.03 mm was utilized for the structural analysis. Intensity data were collected with a Siemens HISTAR area detector mounted on a platform goniometer using Cu Kα radiation (λ=1.54178 Å) focused with Goebel optics. The crystal was mounted on a thin nylon fiber with vacuum grease and data were collected at ambient temperature, 293° K. The intensity data were measured as a series of ω oscillation frames each of 0.25°; these were comprised of 5 scans (500 images each, 40 sec./image) at detector 2θ of −85° and 2 scans (500 images each, 20 sec./image) at detector 2Θ of −40°. The detector was operated in 512×512 mode and was positioned 6.0 cm from the sample. Coverage of unique data was 95.4% complete to 58.88 degrees in θ. The first 50 frames were repeated at the end of data collection and showed essentially no decay of the crystal diffraction during the data collection. A total of 6917 data was measured in the range 4.38&lt;θ58.88°. The data were merged and scaled to form a set of 2697 independent data with R(int)=0.0562 using SAINT (Bruker-AXS, Inc.).  
         [0021]    The orthorhombic space group P2(1)2(1)2(1) was determined by systematic absences and statistical tests and verified by subsequent refinement. The structure was solved by direct methods and refined by full-matrix least-squares methods on F 2  using SHELXL-97 (G. M. Sheldrick, 1994; SHELXTL Version 5 Reference Manual, Bruker-AXS, Inc.). Hydrogen atom positions were intially located in Fourier difference maps, but refined by a riding model with idealized geometries. Non-hydrogen atoms were refined with anisotropic displacement parameters. A total of 229 parameters were refined against 0 restraints and 2697 data to give wR(F 2 )=0.1369 and S=1.088 for weights of w=I/[s 2 (F 2 )+(0.0824 P) 2 ], where P=[F o   2 +2F c   2 ]/3. The final R(F) was 0.0544 for the 2697 observed, [F&gt;2s(F)], data. The final difference map had maxima and minima of 0.126 and −0.153 e/Å 3 , respectively.  
         [0022]    The three dimensional structure of 2MBP as defined by the following physical data and atomic positional parameters described and calculated herein is illustrated in FIG. 1.  
                         TABLE 1                       Crystal data and structure refinement for 2-MbisP.                                Empirical formula   C23 H36 O2       Formula weight   344.52       Temperature   293(2) K       Wavelength   1.54178 Å       Crystal system, space group   Orthorhombic, P2(1)2(1)2(1)       Unit cell dimensions   a = 6.6320(13) Å α = 90°           b = 15.514(3) Å β = 90°           c = 20.194(4) Å γ = 90°       Volume   2077.7(7) Å 3         Z, Calculated density   4, 1.101 Mg/m 3         Absorption coefficient   0.520 mm −1         F(000)   760       Crystal size   0.40 × 0.25 × 0.03 mm       Theta range for data collection   4.38 to 58.88°       Limiting indices   −7 &lt;= h &lt;= 5, −12 &lt;= k &lt;= 17,           −22 &lt;= 1 &lt;= 21       Reflections collected/unique   6917/2697 [R int  = 0.0562]       Completeness to theta = 25.00   95.4%       Refinement method   Full-matrix least-squares on F 2         Data/restraints/parameters   2697/0/229       Goodness-of-fit on F 2     1.088       Final R indices [I &gt; 2sigma(I)]   R1 = 0.0544, wR2 = 0.1369       R indices (all data)   R1 = 0.0622, wR2 = 0.1453       Largest diff. peak and hole   0.126 and −0.153 e/A −3                    
 
         [0023]    [0023]                                         TABLE 2                           Atomic coordinates (× 10 4 ) and equivalent isotropic       displacement parameters (Å 2  × 10 3 )       for 2-MbisP. U(eq) is defined as one third of the trace of       the orthogonalized Uij tensor.                    x   y   z   U(eq)                       O(1)    1842(3)   3525(1)   5011(1)    62(1)           O(3)    7954(4)   3113(1)   4476(2)    78(1)           C(1)    3883(5)   3729(2)   4852(2)    50(1)           C(2)    4569(5)   3359(2)   4201(2)    58(1)           C(3)    6698(5)   3569(2)   4030(2)    61(1)           C(4)    7074(6)   4537(2)   4057(2)    59(1)           C(5)    6301(5)   4937(2)   4686(2)    48(1)           C(6)    7497(5)   5433(2)   5059(2)    52(1)           C(7)    7012(5)   5872(2)   5673(2)    53(1)           C(8)    8248(5)   6371(2)   6020(2)    50(1)           C(9)   10390(5)   6589(2)   5828(2)    65(1)           C(10)    4161(5)   4704(2)   4851(2)    51(1)           C(11)   10739(6)   7562(2)   5809(2)    70(1)           C(12)   10108(6)   8006(2)   6452(2)    61(1)           C(13)    7933(5)   7806(2)   6640(1)    47(1)           C(14)    7696(5)   6814(2)   6661(2)    50(1)           C(15)    5663(6)   6668(2)   6982(2)    62(1)           C(16)    5453(5)   7416(2)   7474(2)    59(1)           C(17)    7251(5)   8038(2)   7353(2)    51(1)           C(18)    6466(6)   8205(2)   6135(2)    64(1)           C(19)    3405(7)   2898(3)   3811(2)    97(2)           C(20)    6703(6)   8967(2)   7542(2)    65(1)           C(21)    6012(8)   9017(3)   8269(2)    92(2)           C(22)    8368(7)   9636(2)   7418(2)    89(1)           C(23)   10284(9)   9512(3)   7809(3)   116(2)                        
         [0024]    [0024]                                 TABLE 3                       Bond lengths [Å] and angles [°] for 2-MbisP.                                O(1)-C(1)   1.426(4)   O(3)-C(3)   1.416(4)       C(1)-C(2)   1.505(5)   C(1)-C(10)   1.524(4)       C(2)-C(19)   1.314(5)   C(2)-C(3)   1.490(5)       C(3)-C(4)   1.522(4)   C(4)-C(5)   1.504(5)       C(5)-C(6)   1.335(4)   C(5)-C(10)   1.502(5)       C(6)-C(7)   1.452(4)   C(7)-C(8)   1.327(4)       C(8)-C(9)   1.511(5)   C(8)-C(14)   1.511(4)       C(9)-C(11)   1.527(5)   C(11)-C(12)   1.530(5)       C(12)-C(13)   1.523(5)   C(13)-C(18)   1.539(5)       C(13)-C(14)   1.548(4)   C(13)-C(17)   1.553(4)       C(14)-C(15)   1.513(5)   C(15)-C(16)   1.534(5)       C(16)-C(17)   1.553(5)   C(17)-C(20)   1.535(5)       C(20)-C(22)   1.536(6)   C(20)-C(21)   1.540(5)       C(22)-C(23)   1.508(7)       O(1)-C(1)-C(2)   113.5(2)   O(1)-C(1)-C(10)   109.6(2)       C(2)-C(1)-C(10)   109.9(3)   C(19)-C(2)-C(3)   122.5(3)       C(19)-C(2)-C(1)   123.6(3)   C(3)-C(2)-C(1)   113.9(3)       O(3)-C(3)-C(2)   107.5(3)   O(3)-C(3)-C(4)   111.9(3)       C(2)-C(3)-C(4)   111.3(3)   C(5)-C(4)-C(3)   112.5(3)       C(6)-C(5)-C(10)   125.1(3)   C(6)-C(5)-C(4)   120.7(3)       C(10)-C(5)-C(4)   114.2(3)   C(5)-C(6)-C(7)   128.3(3)       C(8)-C(7)-C(6)   126.0(3)   C(7)-C(8)-C(9)   125.1(3)       C(7)-C(8)-C(14)   124.6(3)   C(9)-C(8)-C(14)   110.3(3)       C(8)-C(9)-C(11)   111.7(3)   C(5)-C(10)-C(1)   110.8(2)       C(9)-C(11)-C(12)   112.5(3)   C(13)-C(12)-C(11)   112.2(3)       C(12)-C(13)-C(18)   110.6(3)   C(12)-C(13)-C(14)   107.8(3)       C(18)-C(13)-C(14)   110.8(3)   C(12)-C(13)-C(17)   117.3(3)       C(18)-C(13)-C(17)   109.7(3)   C(14)-C(13)-C(17)   100.1(2)       C(15)-C(14)-C(8)   121.0(3)   C(15)-C(14)-C(13)   104.6(3)       C(8)-C(14)-C(13)   113.8(2)   C(14)-C(15)-C(16)   104.2(3)       C(15)-C(16)-C(17)   107.4(3)   C(20)-C(17)-C(16)   111.3(3)       C(20)-C(17)-C(13)   121.2(3)   C(16)-C(17)-C(13)   103.0(2)       C(22)-C(20)-C(17)   115.0(3)   C(22)-C(20)-C(21)   1.09.6(3)       C(17)-C(20)-C(21)   110.8(3)   C(23)-C(22)-C(20)   115.7(4)                    
         [0025]    [0025]                                             TABLE 4                           Anisotropic displacement parameters (Å 2  × 10 3 ) for 2-MbisP.       The anisotropic displacement factor exponent takes the form:       −2π 2 [h 2  a* 2  U11 + . . . + 2 h k a* b* U12]                U11   U22   U33   U23   U13   U12               O(1)   36(1)   59(1)   92(2)    −7(1)    −3(1)    −5(1)       O(3)   42(1)   48(1)   145(2)       3(1)   −17(2)      2(1)       C(1)   34(2)   45(2)   70(2)    −5(2)   −11(2)    −1(1)       C(2)   39(2)   51(2)   83(2)   −21(2)   −14(2)      6(1)       C(3)   55(2)   52(2)   75(2)   −19(2)    −7(2)      8(2)       C(4)   60(2)   56(2)   61(2)    −2(2)      2(2)      0(2)       C(5)   52(2)   34(1)   58(2)      3(1)    −5(2)      1(1)       C(6)   51(2)   45(2)   61(2)      2(1)      5(2)    −9(2)       C(7)   56(2)   42(2)   62(2)      2(1)      6(2)    −8(2)       C(8)   47(2)   44(2)   58(2)      3(1)    −1(2)   −10(2)       C(9)   48(2)   75(2)   73(2)   −15(2)      3(2)   −12(2)       C(10)   44(2)   41(2)   66(2)   −11(1)    −6(2)      4(1)       C(11)   59(2)   78(2)   72(2)   −12(2)     11(2)   −32(2)       C(12)   59(2)   61(2)   63(2)    −5(2)      1(2)   −22(2)       C(13)   43(2)   51(2)   47(2)      5(1)    −6(2)    −7(2)       C(14)   45(2)   52(2)   53(2)      4(1)    −4(2)    −8(2)       C(15)   53(2)   64(2)   69(2)      1(2)      9(2)   −19(2)       C(16)   48(2)   71(2)   58(2)      3(2)      4(2)      0(2)       C(17)   49(2)   53(2)   50(2)      1(1)    −7(2)    −1(2)       C(18)   71(3)   66(2)   57(2)     10(2)   −11(2)    −5(2)       C(19)   53(3)   122(4)    117(3)    −68(3)    −9(3)    −8(2)       C(20)   73(3)   59(2)   64(2)    −5(2)    −2(2)      8(2)       C(21)   117(4)    82(3)   76(2)   −16(2)     20(3)      9(3)       C(22)   104(4)    63(2)   99(3)   −12(2)     18(3)    −6(2)       C(23)   107(4)    101(4)    140(5)    −39(3)    −4(4)   −25(3)                    
         [0026]    [0026]                                                                   TABLE 5                           Hydrogen coordinates (× 10 4 ) and isotropic displacement       parameters (Å 2  × 10 3 ) for 2-MbisP.                    x   y   z   U(eq)                            H(1O)   2030   2820   5188   75           H(3O)   9248   3381   4573   94           H(1)   4744   3489   5201   60           H(3)   6972   3366   3580   73           H(4A)   8510   4644   4021   71           H(4B)   6418   4808   3682   71           H(6)   8807   5506   4904   63           H(7)   5716   5796   5840   64           H(9A)   10678   6347   5395   78           H(9B)   11311   6330   6144   78           H(10A)   3261   4960   4528   61           H(10B)   3817   4933   5284   61           H(11A)   9979   7806   5444   84           H(11B)   12157   7673   5728   84           H(12A)   10992   7820   6807   74           H(12B)   10264   8624   6403   74           H(14)   8690   6614   6986   60           H(15A)   5627   6117   7210   74           H(15B)   4592   6682   6655   74           H(16A)   5482   7201   7925   71           H(16B)   4186   7714   7405   71           H(17)   8337   7857   7652   61           H(18A)   6780   8804   6077   97           H(18B)   5109   8148   6295   97           H(18C)   6593   7911   5719   97           H(19A)   3904   2689   3412   117           H(19B)   2083   2780   3935   117           H(20)   5547   9133   7268   78           H(21A)   7037   8779   8551   138           H(21B)   4785   8697   8323   138           H(21C)   5783   9609   8388   138           H(22A)   8703   9627   6950   106           H(22B)   7832   10203   7518   106           H(23A)   9974   9502   8273   174           H(23B)   11194   9978   7717   174           H(23C)   10902   8976   7684   174                        
         [0027]    [0027]                                 TABLE 6                       Torsion angles [°] for 2-MbisP.                                O(1)-C(1)-C(2)-C(19)   0.5(5)   C(10)-C(1)-C(2)-C(19)   −122.6(4)       O(1)-C(1)-C(2)-C(3)   179.9(3)   C(10)-C(1)-C(2)-C(3)   56.8(3)       C(19)-C(2)-C(3)-O(3)   −111.3(4)   C(1)-C(2)-C(3)-O(3)   69.2(3)       C(19)-C(2)-C(3)-C(4)   125.8(4)   C(1)-C(2)-C(3)-C(4)   −53.7(4)       O(3)-C(3)-C(4)-C(5)   −71.4(4)   C(2)-C(3)-C(4)-C(5)   48.9(4)       C(3)-C(4)-C(5)-C(6)   128.0(3)   C(3)-C(4)-C(5)-C(10)   −50.1(4)       C(10)-C(5)-C(6)-C(7)   −2.4(5)   C(4)-C(5)-C(6)-C(7)   179.7(3)       C(5)-C(6)-C(7)-C(8)   −178.8(3)   C(6)-C(7)-C(8)-C(9)   1.4(5)       C(6)-C(7)-C(8)-C(14)   −179.6(3)   C(7)-C(8)-C(9)-C(11)   125.7(3)       C(14)-C(8)-C(9)-C(11)   −53.4(4)   C(6)-C(5)-C(10)-C(1)   −125.0(3)       C(4)-C(5)-C(10)-C(1)   53.1(3)   O(1)-C(1)-C(10)-C(5)   179.9(2)       C(2)-C(1)-C(10)-C(5)   −54.7(3)   C(8)-C(9)-C(11)-C(12)   53.0(4)       C(9)-C(11)-C(12)-   −54.6(4)   C(11)-C(12)-C(13)-C(18)   −66.8(4)       C(13)       C(11)-C(12)-C(13)-   54.5(4)   C(11)-C(12)-C(13)-C(17)   166.4(3)       C(14)       C(7)-C(8)-C(14)-C(15)   3.9(5)   C(9)-C(8)-C(14)-C(15)   −177.0(3)       C(7)-C(8)-C(14)-C(13)   −122.0(3)   C(9)-C(8)-C(14)-C(13)   57.2(4)       C(12)-C(13)-C(14)-   168.8(3)   C(18)-C(13)-C(14)-C(15)   −70.1(3)       C(15)       C(17)-C(13)-C(14)-   45.6(3)   C(12)-C(13)-C(14)-C(8)   −57.1(3)       C(15)       C(18)-C(13)-C(14)-   64.1(4)   C(17)-C(13)-C(14)-C(8)   179.7(3)       C(8)       C(8)-C(14)-C(15)-   −163.1(3)   C(13)-C(14)-C(15)-C(16)   −33.1(3)       C(16)       C(14)-C(15)-C(16)-   7.4(4)   C(15)-C(16)-C(17)-C(20)   151.9(3)       C(17)       C(15)-C(16)-C(17)-   20.6(3)   C(12)-C(13)-C(17)-C(20)   79.2(4)       C(13)       C(18)-C(13)-C(17)-   −48.2(4)   C(14)-C(13)-C(17)-C(20)   −164.7(3)       C(20)       C(12)-C(13)-C(17)-   −155.7(3)   C(18)-C(13)-C(17)-C(16)   76.9(3)       C(16)       C(14)-C(13)-C(17)-   −39.5(3)   C(16)-C(17)-C(20)-C(22)   −178.0(3)       C(16)       C(13)-C(17)-C(20)-   −56.8(5)   C(16)-C(17)-C(20)-C(21)   56.9(4)       C(22)       C(13)-C(17)-C(20)-   178.1(3)   C(17)-C(20)-C(22)-C(23)   −62.9(5)       C(21)       C(21)-C(20)-C(22)-   62.8(5)       C(23)                    
         [0028]    [0028]                                                                                                                                                                                                                                                                   TABLE 7                           Observed and calculated structure factors for 2-MbisP.            h   k   l   10Fo   10Fc   10s   h   k   l   10Fo   10Fc   10s   h   k   l   10Fo   10Fc   10s   h   k   l   10Fo   10Fc   10s   h   k   l   10Fo   10Fc   10s                    4   0   0   51   50   3   1   15   0   43   53   3   0   6   1   298   328   8   −4   14   1   38   35   5   1   5   2   153   145   7       6   0   0   48   54   4   2   15   0   82   87   2   1   6   1   326   324   4   −3   14   1   54   53   3   2   5   2   175   176   2       1   1   0   108   125   1   3   15   0   53   49   3   2   6   1   62   70   2   −2   14   1   95   101   3   3   5   2   156   167   5       2   1   0   813   823   10   0   16   0   28   24   8   3   6   1   76   73   2   −1   14   1   78   78   2   4   5   2   194   188   2       4   1   0   448   435   4   1   16   0   25   18   5   4   6   1   68   62   1   0   14   1   73   68   1   5   5   2   99   96   2       5   1   0   62   62   1   2   16   0   17   12   8   5   6   1   125   129   2   1   14   1   78   79   1   6   5   2   84   79   3       6   1   0   65   72   2   1   17   0   54   37   10   6   6   1   89   91   2   2   14   1   97   101   2   7   5   2   70   47   4       0   2   0   650   820   8   1   0   1   304   297   5   −5   7   1   152   158   5   3   14   1   44   53   5   −6   6   2   65   66   3       1   2   0   510   519   6   2   0   1   86   79   1   −4   7   1   168   165   1   4   14   1   44   34   5   −5   6   2   60   66   2       2   2   0   88   88   2   4   0   1   115   107   1   −3   7   1   138   136   2   −3   15   1   33   5   5   −4   6   2   74   77   1       4   2   0   217   213   2   5   0   1   111   115   2   −2   7   1   101   94   2   −2   15   1   46   46   6   −3   6   2   130   128   3       5   2   0   120   117   1   6   0   1   36   28   4   −1   7   1   219   219   3   −1   15   1   25   30   6   −2   6   2   150   159   2       6   2   0   36   42   5   −6   1   1   56   55   3   0   7   1   223   236   2   0   15   1   38   30   2   −1   6   2   233   248   3       7   2   0   37   49   7   −5   1   1   107   120   2   1   7   1   213   220   3   1   15   1   38   30   5   0   6   2   529   545   4       1   3   0   352   375   3   −4   1   1   162   152   4   2   7   1   91   93   2   2   15   1   34   46   6   1   6   2   238   248   11       2   3   0   39   35   3   −2   1   1   338   350   3   3   7   1   136   137   1   3   15   1   27   4   5   2   6   2   152   158   2       3   3   0   58   55   2   −1   1   1   1141   1205   14   4   7   1   174   165   1   −2   16   1   24   27   7   3   6   2   131   128   1       4   3   0   84   80   1   1   1   1   1134   1206   11   5   7   1   160   158   2   −1   16   1   27   13   6   4   6   2   77   77   2       5   3   0   43   42   8   4   1   1   163   152   1   6   7   1   33   17   24   0   16   1   18   4   17   5   6   2   61   66   2       6   3   0   54   51   5   5   1   1   109   120   2   −6   8   1   61   46   10   1   16   1   33   13   8   6   6   2   69   66   3       7   3   0   34   7   7   6   1   1   56   55   11   −5   8   1   65   60   11   2   16   1   20   28   6   −6   7   2   39   49   13       0   4   0   114   118   2   7   1   1   19   16   18   −4   8   1   52   51   2   0   17   1   24   32   5   −5   7   2   96   98   3       1   4   0   17   3   3   −7   2   1   38   15   7   −3   8   1   150   145   1   1   17   1   17   3   17   −4   7   2   65   63   2       2   4   0   88   82   1   −6   2   1   41   44   4   −2   8   1   86   88   1   0   0   2   393   405   5   −3   7   2   99   90   2       4   4   0   87   87   1   −5   2   1   28   16   5   −1   8   1   68   69   5   1   0   2   332   336   8   −2   7   2   141   157   2       5   4   0   19   15   18   −4   2   1   256   252   5   0   8   1   378   391   3   2   0   2   412   409   8   −1   7   2   442   439   5       6   4   0   99   104   5   −3   2   1   108   98   2   1   8   1   69   68   2   4   0   2   137   137   3   0   7   2   252   268   2       7   4   0   66   56   4   −2   2   1   98   100   2   2   8   1   89   87   2   −6   1   2   34   44   5   1   7   2   447   439   14       1   5   0   17   4   7   −1   2   1   465   481   4   3   8   1   152   145   1   −5   1   2   114   119   4   2   7   2   146   157   2       2   5   0   72   64   1   0   2   1   15   2   3   4   8   1   54   51   6   −4   1   2   52   49   2   3   7   2   98   89   1       3   5   0   108   106   6   1   2   1   478   482   4   5   8   1   67   59   4   −2   1   2   174   178   1   4   7   2   69   63   2       4   5   0   86   82   1   2   2   1   93   99   2   6   8   1   46   46   4   −1   1   2   599   599   5   5   7   2   102   97   2       5   5   0   34   29   3   4   2   1   257   252   2   −6   9   1   37   28   12   0   1   2   166   164   2   6   7   2   51   48   4       6   5   0   29   22   6   5   2   1   17   16   8   −5   9   1   84   71   3   2   1   2   178   178   2   −6   8   2   20   16   13       7   5   0   57   41   6   6   2   1   41   44   6   −4   9   1   105   103   1   4   1   2   50   49   2   −5   8   2   53   52   4       0   6   0   645   708   8   7   2   1   17   14   16   −3   9   1   156   151   1   5   1   2   119   118   2   −4   8   2   118   118   1       1   6   0   360   437   50   −7   3   1   41   49   6   −2   9   1   54   46   1   6   1   2   47   44   3   −3   8   2   92   90   4       2   6   0   101   96   21   −6   3   1   52   50   4   −1   9   1   194   201   8   7   1   2   59   55   5   −2   8   2   40   37   2       3   6   0   36   39   3   −5   3   1   171   175   1   0   9   1   227   233   2   −7   2   2   39   34   6   −1   8   2   325   343   4       4   6   0   19   17   4   −4   3   1   239   231   3   1   9   1   190   201   7   −6   2   2   106   111   2   0   8   2   165   186   2       5   6   0   80   76   5   −3   3   1   457   454   6   2   9   1   50   46   3   −5   2   2   211   211   3   1   8   2   312   344   4       6   6   0   48   44   4   −2   3   1   306   308   4   3   9   1   157   151   1   −4   2   2   74   77   1   2   8   2   38   37   1       1   7   0   31   28   3   −1   3   1   375   403   4   4   9   1   114   103   1   −3   2   2   385   373   5   3   8   2   92   91   1       2   7   0   110   128   25   0   3   1   358   411   19   5   9   1   74   71   5   −2   2   2   96   91   1   4   8   2   118   118   3       3   7   0   72   70   1   1   3   1   394   402   3   6   9   1   36   28   6   −1   2   2   614   632   19   5   8   2   54   52   4       4   7   0   79   78   2   2   3   1   304   307   4   −5   10   1   54   57   4   0   2   2   371   373   7   6   8   2   32   16   15       5   7   0   171   167   2   3   3   1   472   455   6   −4   10   1   107   110   3   1   2   2   623   632   8   −6   9   2   76   71   5       6   7   0   49   48   4   4   3   1   240   231   2   −3   10   1   168   166   1   2   2   2   105   92   2   −5   9   2   42   36   6       0   8   0   134   137   2   5   3   1   169   176   3   −2   10   1   79   79   3   4   2   2   80   78   1   −4   9   2   170   164   2       1   8   0   226   226   8   6   3   1   44   50   5   −1   10   1   139   149   2   5   2   2   211   211   6   −3   9   2   83   82   1       2   8   0   211   196   3   7   3   1   54   49   5   0   10   1   127   138   1   6   2   2   116   111   3   −2   9   2   44   39   2       3   8   0   66   64   1   −7   4   1   46   41   5   1   10   1   145   148   1   7   2   2   34   35   7   −1   9   2   77   79   1       4   8   0   315   302   2   −6   4   1   81   84   2   2   10   1   74   79   1   −7   3   2   69   71   4   0   9   2   84   93   3       5   8   0   67   63   3   −5   4   1   34   26   20   3   10   1   168   165   1   −6   3   2   75   81   4   1   9   2   80   79   2       6   8   0   38   28   6   −4   4   1   171   165   1   4   10   1   107   110   2   −5   3   2   112   104   1   2   9   2   40   38   1       1   9   0   247   260   7   −3   4   1   189   193   3   5   10   1   62   57   4   −4   3   2   147   144   3   3   9   2   85   82   1       2   9   0   243   244   2   −2   4   1   199   199   3   −5   11   1   22   6   13   −3   3   2   190   177   3   4   9   2   172   164   4       3   9   0   193   186   2   −1   4   1   346   367   4   −4   11   1   77   79   2   −2   3   2   105   107   2   5   9   2   25   36   9       4   9   0   405   398   3   0   4   1   450   520   19   −3   11   1   51   50   1   −1   3   2   395   396   14   6   9   2   77   71   6       5   9   0   8   2   8   1   4   1   356   368   13   −2   11   1   70   71   1   0   3   2   252   272   12   −5   10   2   29   11   11       6   9   0   81   75   7   2   4   1   195   200   2   −1   11   1   92   93   2   1   3   2   391   396   5   −4   10   2   100   99   4       0   10   0   119   124   2   3   4   1   182   194   3   0   11   1   98   100   2   2   3   2   108   107   2   −3   10   2   176   168   3       1   10   0   54   49   1   4   4   1   176   166   3   1   11   1   94   93   2   4   3   2   146   144   1   −2   10   2   145   135   2       2   10   0   127   124   1   5   4   1   27   26   4   2   11   1   68   71   1   5   3   2   108   103   4   −1   10   2   167   159   3       3   10   0   116   115   1   6   4   1   83   84   3   3   11   1   52   50   2   6   3   2   89   81   3   0   10   2   187   189   3       4   10   0   26   0   5   7   4   1   37   41   6   4   11   1   79   79   2   7   3   2   75   70   3   1   10   2   168   158   2       5   10   0   63   63   4   −7   5   1   58   45   5   5   11   1   6   6   5   −6   4   2   95   101   2   2   10   2   142   135   1       1   11   0   77   75   2   −6   5   1   26   18   16   −5   12   1   49   46   8   −5   4   2   75   79   4   3   10   2   177   168   1       2   11   0   46   45   3   −5   5   1   79   76   2   −4   12   1   40   35   4   −4   4   2   172   175   3   4   10   2   99   100   3       3   11   0   15   15   5   −4   5   1   44   46   1   −3   12   1   52   55   2   −3   4   2   241   230   3   5   10   2   33   11   14       4   11   0   142   141   2   −3   5   1   136   137   2   −2   12   1   162   161   1   −2   4   2   431   439   5   −5   11   2   69   66   3       5   11   0   46   35   14   −2   5   1   337   336   4   −1   12   1   159   150   4   −1   4   2   58   62   2   −4   11   2   49   45   3       0   12   0   58   55   3   −1   5   1   171   174   2   0   12   1   113   117   2   0   4   2   242   268   20   −3   11   2   87   87   2       1   12   0   67   69   1   0   5   1   274   294   2   1   12   1   163   151   3   1   4   2   69   63   1   −2   11   2   106   103   4       2   12   0   145   145   1   1   5   1   174   174   2   2   12   1   158   161   1   2   4   2   438   438   7   −1   11   2   108   119   2       3   12   0   43   40   4   2   5   1   343   336   4   3   12   1   56   55   2   3   4   2   247   229   3   0   11   2   96   88   2       4   12   0   32   24   4   3   5   1   126   137   1   4   12   1   32   35   10   4   4   2   177   175   2   1   11   2   112   118   1       5   12   0   45   36   4   4   5   1   45   46   2   5   12   1   48   46   13   5   4   2   80   79   2   2   11   2   105   104   1       1   13   0   26   9   7   5   5   1   82   76   3   −4   13   1   41   23   9   6   4   2   106   101   3   3   11   2   87   87   2       2   13   0   161   164   1   6   5   1   24   18   14   −3   13   1   67   71   2   7   4   2   50   40   5   4   11   2   41   45   4       3   13   0   137   141   1   7   5   1   68   45   4   −2   13   1   45   47   2   −6   5   2   85   79   4   5   11   2   70   66   3       4   13   0   43   42   9   −6   6   1   87   91   4   −1   13   1   49   38   2   −5   5   2   94   96   7   −5   12   2   59   63   20       0   14   0   79   84   2   −5   6   1   125   128   2   0   13   1   23   25   3   −4   5   2   188   188   1   −4   12   2   65   59   3       1   14   0   40   32   2   −4   6   1   61   61   1   1   13   1   54   38   5   −3   5   2   162   167   3   −3   12   2   46   48   2       2   14   0   32   26   4   −3   6   1   77   73   1   2   23   1   50   47   4   −2   5   2   181   176   3   −2   12   2   39   46   6       3   14   0   87   89   2   −2   6   1   73   71   2   3   13   1   70   71   2   −1   5   2   151   146   2   −1   12   2   43   27   9       4   14   0   49   43   4   −1   6   1   327   325   4   4   13   1   41   23   7   0   5   2   901   990   15   0   12   2   21   13   3       1   12   2   38   27   9   1   4   3   305   297   3   0   11   3   72   67   1   1   3   4   316   326   2   −2   10   4   70   68   2       2   12   2   41   46   2   2   4   3   115   120   2   1   11   3   65   63   2   4   3   4   11   8   10   −1   10   4   81   80   1       3   12   2   43   48   2   4   4   3   86   85   2   2   11   3   141   137   2   5   3   4   38   44   3   0   10   4   49   49   1       4   12   2   66   59   3   5   4   3   139   136   3   3   11   3   159   153   1   6   3   4   81   78   3   1   10   4   81   79   3       5   12   2   53   63   9   6   4   3   72   68   4   4   11   3   130   130   2   7   3   4   42   41   5   2   10   4   70   67   2       4   13   2   34   34   8   7   4   3   48   42   5   5   11   3   96   92   2   −6   4   4   84   94   3   3   10   4   105   104   2       3   13   2   87   90   2   −6   5   3   52   51   11   −5   12   3   38   48   8   −5   4   4   28   32   4   4   10   4   77   68   2       2   13   2   36   20   5   −5   5   3   172   171   2   −4   12   3   29   25   5   −4   4   4   142   142   1   5   10   4   68   60   3       1   13   2   116   120   2   −4   5   3   76   72   2   −3   12   3   135   135   4   −3   4   4   235   222   3   −5   11   4   119   116   2       0   13   2   66   62   1   −3   5   3   21   12   7   −2   12   3   80   84   2   −2   4   4   186   180   2   −4   11   4   24   11   7       1   13   2   117   120   3   −2   5   3   223   216   3   −1   12   3   181   175   3   −1   4   4   400   390   8   −3   11   4   113   111   2       2   13   2   30   20   7   −1   5   3   186   196   2   0   12   3   45   49   2   0   4   4   327   325   3   −2   11   4   86   83   2       3   13   2   89   90   2   0   5   3   733   738   46   1   12   3   176   174   3   1   4   4   392   390   9   −1   11   4   164   160   2       4   13   2   38   34   5   1   5   3   197   196   2   2   12   3   81   84   3   2   4   4   186   180   6   0   11   4   109   111   1       4   14   2   60   57   8   2   5   3   225   217   3   3   12   3   133   136   1   3   4   4   208   222   3   1   11   4   162   161   2       3   14   2   41   43   3   3   5   3   15   12   10   4   12   3   15   24   14   4   4   4   153   142   2   2   11   4   83   83   1       2   14   2   56   61   2   4   5   3   79   73   2   5   12   3   50   48   3   5   4   4   31   32   4   3   11   4   117   111   1       1   14   2   34   25   3   5   5   3   176   171   4   −4   13   3   25   20   13   6   4   4   90   94   3   4   11   4   32   12   6       0   14   2   92   92   1   6   5   3   54   51   5   −3   13   3   64   62   2   7   4   4   25   6   10   5   11   4   112   115   2       1   14   2   22   25   6   −6   6   3   52   51   7   −2   13   3   38   36   2   −6   5   4   84   99   4   −5   12   4   59   47   8       2   14   2   61   61   4   −5   6   3   93   93   3   −1   13   3   49   48   2   −5   5   4   133   138   5   −4   12   4   19   4   10       3   14   2   41   42   4   −4   6   3   120   114   2   0   13   3   34   24   5   −4   5   4   57   59   2   −3   12   4   116   121   2       4   14   2   53   57   5   −3   6   3   62   60   2   1   13   3   44   48   3   −3   5   4   147   150   2   −2   12   4   44   32   5       3   15   2   36   36   4   −2   6   3   238   243   3   2   13   3   48   36   12   −2   5   4   177   182   3   −1   12   4   125   117   3       2   15   2   47   44   4   −1   6   3   88   86   2   3   13   3   63   62   3   −1   5   4   258   237   2   0   12   4   64   62   2       1   15   2   21   10   7   0   6   3   136   146   1   4   13   3   38   20   8   0   5   4   339   335   20   1   12   4   119   117   1       0   15   2   33   36   3   1   6   3   92   84   1   −4   14   3   37   38   8   1   5   4   247   237   2   2   12   4   41   32   3       1   15   2   25   10   5   2   6   3   233   242   3   −3   14   3   96   96   2   2   5   4   166   181   1   3   12   4   120   121   2       2   15   2   40   44   4   3   6   3   61   61   2   −2   14   3   94   106   2   3   5   4   152   151   2   4   12   4   31   4   31       3   15   2   34   37   4   4   6   3   125   114   2   −1   14   3   31   18   4   4   5   4   60   59   2   5   12   4   46   47   5       2   16   2   24   16   5   5   6   3   97   93   2   0   14   3   27   29   4   5   5   4   132   138   2   −4   13   4   59   56   3       1   16   2   27   29   6   6   6   3   58   51   4   1   14   3   24   19   5   6   5   4   94   99   3   −3   13   4   77   80   1       0   16   2   37   17   4   −6   7   3   32   23   9   2   14   3   101   106   3   −6   6   4   66   73   11   −2   13   4   98   98   1       1   16   2   29   29   3   −5   7   3   53   57   2   3   14   3   99   96   5   −5   6   4   59   58   3   −1   13   4   37   42   6       2   16   2   23   16   6   −4   7   3   232   230   2   4   14   3   37   38   4   −4   6   4   77   79   2   0   13   4   58   64   3       0   17   2   19   14   8   −3   7   3   59   56   2   −3   15   3   35   35   9   −3   6   4   67   64   1   1   13   4   40   42   3       1   17   2   37   28   6   −2   7   3   171   181   3   −2   15   3   36   33   3   −2   6   4   173   169   3   2   13   4   98   99   2       1   0   3   986   1006   11   −1   7   3   228   222   3   −1   15   3   32   21   6   −1   6   4   330   348   4   3   13   4   76   80   2       2   0   3   115   121   2   0   7   3   379   403   3   0   15   3   39   34   3   0   6   4   55   58   4   4   13   4   50   57   7       4   0   3   324   311   5   1   7   3   230   222   6   1   15   3   36   21   7   1   6   4   350   349   7   −4   14   4   62   58   6       6   0   3   57   51   14   2   7   3   167   180   3   2   15   3   31   33   6   2   6   4   157   169   2   −3   14   4   67   64   2       6   1   3   73   67   3   3   7   3   57   56   1   3   15   3   40   35   4   3   6   4   68   64   1   −2   14   4   22   14   5       5   1   3   253   250   9   4   7   3   231   230   7   −2   16   3   34   35   2   4   6   4   82   79   6   −1   14   4   38   39   6       4   1   3   176   170   3   5   7   3   59   57   3   −1   16   3   28   7   5   5   6   4   58   58   2   0   14   4   77   83   2       3   1   3   392   392   7   6   7   3   38   23   16   0   16   3   52   55   2   6   6   4   77   73   4   1   14   4   38   39   4       2   1   3   207   207   2   −6   8   3   32   28   10   1   16   3   29   7   6   −6   7   4   55   36   6   2   14   4   20   15   9       1   1   3   101   95   2   −5   8   3   31   15   4   2   16   3   42   36   4   −5   7   4   101   105   3   3   14   4   64   64   3       0   1   3   1115   1114   19   −4   8   3   73   78   2   0   17   3   68   76   3   −4   7   4   57   57   2   4   14   4   56   59   4       1   1   3   97   96   2   −3   8   3   193   191   2   0   0   4   372   431   7   −3   7   4   35   36   1   −3   15   4   42   42   2       2   1   3   205   206   2   −2   8   3   189   190   4   1   0   4   549   576   4   −2   7   4   147   139   3   −2   15   4   56   66   5       4   1   3   176   169   2   −1   8   3   310   324   4   2   0   4   64   65   1   −1   7   4   302   287   4   −1   15   4   49   55   8       5   1   3   252   249   9   0   8   3   234   243   11   4   0   4   38   42   23   0   7   4   175   175   14   0   15   4   44   36   3       6   1   3   69   66   2   1   8   3   308   325   7   5   0   4   99   100   3   1   7   4   299   287   4   1   15   4   61   55   3       7   1   3   42   18   6   2   8   3   185   191   3   6   0   4   116   121   7   2   7   4   142   139   2   2   15   4   54   66   4       6   2   3   77   80   2   3   8   3   188   191   2   −6   1   4   66   64   5   3   7   4   39   36   2   3   15   4   46   42   7       5   2   3   59   70   2   4   8   3   79   78   2   −5   1   4   100   102   2   4   7   4   58   57   2   −2   16   4   36   41   8       4   2   3   87   91   3   5   8   3   27   15   22   −4   1   4   90   77   2   5   7   4   108   106   2   −1   16   4   55   66   2       3   2   3   223   231   3   6   8   3   25   28   8   −3   1   4   141   148   1   6   7   4   49   36   5   0   16   4   24   6   6       2   2   3   377   364   3   −6   9   3   59   52   6   −2   1   4   112   111   2   −6   8   4   45   36   7   1   16   4   61   65   4       1   2   3   715   744   16   −5   9   3   82   80   4   −1   1   4   489   481   4   −5   8   4   176   177   2   2   16   4   32   41   7       0   2   3   1539   1543   19   −4   9   3   261   247   2   0   1   4   731   731   10   −4   8   4   88   93   1   1   0   5   97   112   2       1   2   3   723   744   8   −3   9   3   116   117   3   1   1   4   473   481   6   −3   8   4   207   208   6   2   0   5   313   371   45       2   2   3   359   364   4   −2   9   3   72   67   2   2   1   4   108   111   2   −2   8   4   119   121   3   3   0   5   180   174   2       4   2   3   83   91   1   −1   9   3   40   31   3   4   1   4   90   77   4   −1   8   4   231   230   6   4   0   5   115   109   2       5   2   3   63   70   1   0   9   3   52   55   2   5   1   4   102   103   5   0   8   4   180   186   10   5   0   5   316   289   4       6   2   3   86   80   3   1   9   3   32   31   1   6   1   4   74   64   4   1   8   4   236   230   7   −6   1   5   62   62   4       7   2   3   25   20   11   2   9   3   69   67   1   7   1   4   38   45   7   2   8   4   124   122   2   −5   1   5   209   197   3       6   3   3   79   84   4   3   9   3   116   117   1   −6   2   4   30   20   9   3   8   4   211   208   4   −4   1   5   136   128   2       5   3   3   127   121   2   4   9   3   256   247   4   −5   2   4   203   190   3   4   8   4   91   93   2   −3   1   5   101   112   2       4   3   3   217   214   8   5   9   3   83   80   5   −4   2   4   136   129   2   5   8   4   181   177   2   −2   1   5   261   256   2       3   3   3   87   77   2   6   9   3   66   52   9   −3   2   4   329   324   3   6   8   4   46   36   5   −1   1   5   290   294   6       2   3   3   217   219   2   −5   10   3   65   65   4   −2   2   4   236   241   2   −6   9   4   48   41   7   0   1   5   244   248   2       1   3   3   676   688   22   −4   10   3   146   144   1   −1   2   4   471   497   15   −5   9   4   51   48   3   1   1   5   287   295   3       0   3   3   461   472   10   −3   10   3   37   35   2   0   2   4   952   922   20   −4   9   4   107   104   3   2   1   5   249   257   3       1   3   3   675   687   5   −2   10   3   85   74   3   1   2   4   483   497   8   −3   9   4   74   74   1   4   1   5   135   128   2       2   3   3   228   219   3   −1   10   3   251   228   2   2   2   4   232   242   3   −2   9   4   101   98   2   5   1   5   201   197   3       4   3   3   220   213   2   0   10   3   43   41   1   4   2   4   125   129   1   −1   9   4   72   69   1   6   1   5   76   61   4       5   3   3   130   120   7   1   10   3   237   228   8   5   2   4   203   191   3   0   9   4   176   174   4   7   1   5   25   46   14       6   3   3   81   84   3   2   10   3   83   74   1   6   2   4   27   20   11   1   9   4   68   69   1   −5   2   5   118   119   2       7   3   3   54   45   5   3   10   3   34   35   2   7   2   4   38   9   7   2   9   4   102   97   4   −4   2   5   32   44   4       6   4   3   69   68   3   4   10   3   147   144   3   −6   3   4   82   78   3   3   9   4   76   73   2   −3   2   5   224   218   2       5   4   3   135   136   2   5   10   3   74   65   3   −5   3   4   44   44   7   4   9   4   104   104   2   −2   2   5   262   273   4       4   4   3   79   85   1   −5   11   3   96   92   4   −4   3   4   15   9   9   5   9   4   53   48   5   −1   2   5   713   749   40       3   4   3   109   103   2   −4   11   3   130   130   3   −3   3   4   275   287   4   6   9   4   36   41   6   0   2   5   403   403   3       2   4   3   119   121   2   −3   11   3   157   153   4   −2   3   4   262   259   7   −5   10   4   59   60   8   1   2   5   716   750   7       1   4   3   300   297   9   −2   11   3   148   137   2   −1   3   4   315   325   15   −4   10   4   74   68   3   2   2   5   262   272   3       0   4   3   261   268   3   −1   11   3   58   63   1   0   3   4   241   241   4   −3   10   4   104   104   2   4   2   5   41   44   3       5   2   5   124   119   2   −3   10   5   73   75   1   7   2   6   35   28   8   4   10   6   59   52   4   −3   4   7   172   165   1       6   2   5   66   56   4   −2   10   5   32   29   2   −4   3   6   147   143   2   5   10   6   92   97   2   −2   4   7   151   142   2       7   2   5   38   37   6   −1   10   5   109   112   2   −3   3   6   127   134   2   −5   11   6   34   22   7   −1   4   7   314   293   3       5   3   5   78   76   3   0   10   5   20   21   5   −2   3   6   361   357   3   −4   11   6   129   126   2   0   4   7   148   130   1       4   3   5   105   98   2   1   10   5   111   112   2   −1   3   6   287   275   2   −3   11   6   30   29   6   1   4   7   302   292   4       3   3   5   226   216   2   2   10   5   39   29   8   0   3   6   283   282   12   −2   11   6   113   115   1   3   4   7   174   165   2       2   3   5   206   194   4   3   10   5   70   75   1   1   3   6   273   276   2   −1   11   6   170   176   5   4   4   7   75   79   3       1   3   5   158   156   2   4   10   5   43   41   4   2   3   6   356   357   4   0   11   6   23   20   2   5   4   7   80   78   3       0   3   5   353   335   5   5   10   5   108   110   4   4   3   6   145   143   3   1   11   6   170   176   2   6   4   7   82   81   4       1   3   5   159   156   3   −5   11   5   33   27   6   5   3   6   201   198   3   2   11   6   111   116   2   −4   5   7   61   60   3       4   3   5   99   97   3   −4   11   5   90   84   2   6   3   6   61   50   5   3   11   6   31   29   16   −3   5   7   107   104   1       5   3   5   80   76   3   −3   11   5   29   27   3   −3   4   6   86   87   2   4   11   6   124   125   3   −2   5   7   162   153   4       6   3   5   60   51   5   −2   11   5   104   99   1   −2   4   6   113   101   1   5   11   6   23   22   7   −1   5   7   152   140   2       7   3   5   32   6   8   −1   11   5   97   106   2   −1   4   6   539   523   13   −4   12   6   38   33   6   0   5   7   181   186   28       4   4   5   20   21   19   0   11   5   18   2   8   0   4   6   65   59   1   −3   12   6   129   128   4   1   5   7   145   139   1       3   4   5   203   196   3   1   11   5   102   106   2   1   4   6   530   523   6   −2   12   6   100   93   3   2   5   7   152   153   2       2   4   5   248   242   5   2   11   5   100   100   1   2   4   6   102   101   2   −1   12   6   91   89   3   3   5   7   106   104   2       1   4   5   73   71   2   3   11   5   39   27   6   3   4   6   87   87   2   0   12   6   111   112   1   4   5   7   63   60   1       0   4   5   158   171   5   4   11   5   83   84   3   4   4   6   103   99   3   1   12   6   90   89   1   5   5   7   174   176   3       1   4   5   72   71   1   5   11   5   35   27   7   5   4   6   52   54   4   2   12   6   94   94   2   6   5   7   54   66   5       3   4   5   180   196   3   −4   12   5   52   55   4   6   4   6   72   60   4   3   12   6   131   128   3   −4   6   7   105   107   2       4   4   5   8   20   7   −3   12   5   53   44   4   −4   5   6   62   62   2   4   12   6   30   32   7   −3   6   7   135   133   1       5   4   5   58   63   2   −2   12   5   86   81   1   −3   5   6   27   8   3   −4   13   6   28   16   12   −2   6   7   171   160   1       6   4   5   126   122   3   −1   12   5   39   41   2   −2   5   6   166   164   2   −3   13   6   114   124   5   −1   6   7   201   200   2       5   5   5   46   42   5   0   12   5   31   5   7   −1   5   6   301   282   3   −2   13   6   104   105   2   0   6   7   198   195   3       4   5   5   26   23   3   1   12   5   43   41   2   0   5   6   109   98   1   −1   13   6   117   121   4   1   6   7   194   200   3       3   5   5   50   47   1   2   12   5   82   81   1   1   5   6   291   282   4   0   13   6   26   25   4   2   6   7   177   160   2       2   5   5   428   416   4   3   12   5   50   44   3   3   5   6   10   8   9   1   13   6   117   121   2   3   6   7   134   134   1       1   5   5   126   136   2   4   12   5   58   54   3   4   5   6   68   62   1   2   13   6   103   105   1   4   6   7   103   107   2       0   5   5   275   251   4   5   12   5   41   29   5   5   5   6   34   32   8   3   13   6   123   124   3   5   6   7   112   112   3       1   5   5   120   136   4   −4   13   5   31   22   10   6   5   6   83   73   4   4   13   6   27   16   8   6   6   7   46   35   6       3   5   5   50   47   1   −3   13   5   51   47   5   −5   6   6   68   64   5   −3   14   6   21   28   6   −5   7   7   108   106   6       4   5   5   26   23   4   −2   13   5   72   71   4   −4   6   6   52   48   2   −2   14   6   56   46   5   −4   7   7   88   81   1       5   5   5   46   42   4   −1   13   5   50   51   6   −3   6   6   112   107   1   −1   14   6   10   18   10   −3   7   7   63   66   4       6   5   5   100   92   3   0   13   5   33   33   5   −2   6   6   68   63   2   0   14   6   53   49   2   −2   7   7   82   81   1       5   6   5   65   62   5   1   13   5   53   51   2   −1   6   6   172   175   4   1   14   6   26   18   12   −1   7   7   75   76   1       4   6   5   56   57   2   2   13   5   71   72   3   0   6   6   240   239   25   2   14   6   47   47   7   0   7   7   258   286   23       3   6   5   95   97   1   3   13   5   50   47   3   1   6   6   168   175   2   3   14   6   31   28   5   1   7   7   74   76   2       2   6   5   173   162   4   4   13   5   33   22   5   2   6   6   60   63   2   −2   15   6   37   40   6   2   7   7   85   81   2       1   6   5   224   223   3   −3   14   5   38   39   4   3   6   6   113   107   1   −1   15   6   42   42   12   3   7   7   58   66   2       0   6   5   15   6   14   −2   14   5   88   91   2   4   6   6   49   48   2   0   15   6   61   68   6   4   7   7   84   81   2       1   6   5   223   222   3   −1   14   5   43   41   5   5   6   6   67   63   4   1   15   6   42   43   4   5   7   7   98   107   3       2   6   5   165   163   2   0   14   5   59   61   2   6   6   6   62   68   4   2   15   6   42   40   7   6   7   7   49   42   5       3   6   5   100   98   2   1   14   5   41   41   2   −5   7   6   124   120   5   3   15   6   56   57   5   −5   8   7   32   27   6       4   6   5   64   56   1   2   14   5   92   91   4   −4   7   6   57   58   1   −1   16   6   51   52   6   −4   8   7   90   93   3       5   6   5   61   62   4   3   14   5   35   39   9   −3   7   6   188   193   3   0   16   6   12   1   12   −3   8   7   104   103   1       6   6   5   76   68   4   −3   15   5   36   31   10   −2   7   6   53   55   1   1   16   6   52   52   3   −2   8   7   72   74   1       6   7   5   24   64   23   −2   15   5   74   80   2   −1   7   6   134   123   2   1   0   7   35   42   6   −1   8   7   268   261   1       5   7   5   83   89   4   −1   15   5   21   10   14   0   7   6   171   186   14   2   0   7   224   211   3   0   8   7   98   105   1       4   7   5   47   47   2   0   15   5   45   51   3   1   7   6   130   123   2   3   0   7   28   30   4   1   8   7   272   261   2       3   7   5   82   82   1   1   15   5   22   10   22   2   7   6   53   55   5   4   0   7   108   111   2   2   8   7   76   74   3       2   7   5   173   177   1   2   15   5   75   80   3   3   7   6   189   193   3   5   0   7   73   75   3   3   8   7   102   103   2       1   7   5   201   203   7   3   15   5   40   31   4   4   7   6   53   57   2   6   0   7   17   1   16   4   8   7   91   93   1       0   7   5   343   344   27   −2   16   5   26   10   9   5   7   6   118   120   2   −6   1   7   51   64   5   5   8   7   27   27   9       1   7   5   196   204   6   −1   16   5   64   63   3   6   7   6   43   35   6   −5   1   7   135   132   2   6   8   7   53   51   4       2   7   5   171   177   1   0   16   5   35   35   2   −5   8   6   67   61   9   −4   1   7   180   176   2   −5   9   7   22   6   21       3   7   5   81   83   1   1   16   5   59   63   2   −4   8   6   67   67   2   −3   1   7   162   168   2   −4   9   7   63   62   2       4   7   5   46   46   2   2   16   5   25   10   11   −3   8   6   39   35   1   −2   1   7   132   132   2   −3   9   7   95   90   1       5   7   5   82   89   2   0   0   6   402   451   15   −2   8   6   68   65   2   −1   1   7   191   189   4   −2   9   7   121   119   1       6   7   5   63   64   4   1   0   6   69   75   3   −1   8   6   112   115   1   0   1   7   250   250   2   −1   9   7   197   194   2       6   8   5   43   20   7   2   0   6   27   29   4   0   8   6   18   13   12   1   1   7   180   189   2   0   9   7   178   178   1       5   8   5   69   59   7   3   0   6   85   80   2   1   8   6   112   114   5   2   1   7   128   132   2   1   9   7   188   194   6       4   8   5   117   117   1   5   0   6   180   166   3   2   8   6   68   65   1   3   1   7   163   168   2   2   9   7   117   118   2       3   8   5   133   128   2   6   0   6   112   109   3   3   8   6   37   35   3   4   1   7   190   176   3   3   9   7   97   90   3       2   8   5   65   62   2   −6   1   6   205   205   3   4   8   6   69   67   1   5   1   7   138   132   3   4   9   7   68   62   3       1   8   5   371   376   3   −5   1   6   89   87   2   5   8   6   60   61   3   6   1   7   63   63   4   −5   10   7   43   43   7       0   8   5   24   31   6   −4   1   6   132   125   2   6   8   6   36   16   6   −5   2   7   93   90   3   −4   10   7   95   98   2       1   8   5   380   376   8   −3   1   6   215   217   3   −5   9   6   122   121   2   −4   2   7   31   31   4   −3   10   7   160   151   1       2   8   5   61   62   2   −2   1   6   329   336   6   −4   9   6   158   153   2   −3   2   7   61   70   2   −2   10   7   134   135   1       3   8   5   130   128   2   −1   1   6   174   173   1   −3   9   6   97   94   2   −2   2   7   140   132   4   −1   10   7   127   125   3       4   8   5   120   117   4   0   1   6   155   165   1   −2   9   6   133   129   3   −1   2   7   394   385   3   0   10   7   159   158   1       5   8   5   67   58   3   1   1   6   160   173   1   −1   9   6   105   101   1   0   2   7   111   114   1   1   10   7   125   125   1       6   8   5   33   20   7   2   1   6   333   336   4   0   9   6   143   153   2   1   2   7   378   385   6   2   10   7   135   135   1       5   9   5   28   33   8   3   1   6   207   218   3   1   9   6   101   101   1   4   2   7   37   30   3   3   10   7   154   151   3       4   9   5   96   98   1   4   1   6   127   124   2   2   9   6   134   129   4   5   2   7   87   91   3   4   10   7   93   98   5       3   9   5   94   92   1   5   1   6   91   87   3   3   9   6   96   94   2   6   2   7   67   76   4   5   10   7   31   43   6       2   9   5   138   136   2   6   1   6   207   205   3   4   9   6   153   153   3   −4   3   7   203   197   3   −5   11   7   54   42   4       1   9   5   165   157   2   −5   2   6   199   193   3   5   9   6   120   121   8   −3   3   7   104   105   2   −4   11   7   57   60   4       0   9   5   144   144   2   −4   2   6   77   79   2   −5   10   6   94   97   3   −2   3   7   355   347   9   −3   11   7   57   49   3       1   9   5   158   157   4   −3   2   6   121   120   1   −4   10   6   57   52   3   −1   3   7   387   366   3   −2   11   7   53   54   2       2   9   5   143   135   4   −2   2   6   295   299   7   −3   10   6   149   150   2   0   3   7   176   151   2   −1   11   7   53   46   4       3   9   5   91   91   2   −1   2   6   453   433   4   −2   10   6   197   196   2   1   3   7   375   367   5   0   11   7   42   39   2       4   9   5   99   98   4   0   2   6   271   248   2   −1   10   6   186   182   4   2   3   7   347   346   4   1   11   7   51   46   1       5   9   5   37   33   5   1   2   6   432   433   5   0   10   6   90   98   1   3   3   7   98   105   2   2   11   7   61   55   4       6   9   5   38   33   6   4   2   6   81   78   2   1   10   6   182   182   2   4   3   7   209   197   3   3   11   7   53   48   3       5   10   5   115   110   2   5   2   6   203   193   3   2   10   6   196   196   3   5   3   7   102   101   2   4   11   7   62   61   3       4   10   5   50   40   4   6   2   6   83   80   4   3   10   6   145   150   2   6   3   7   46   48   6   5   11   7   44   42   5       4   12   7   29   16   11   2   5   8   163   159   2   −1   14   8   38   38   5   4   7   9   89   87   2   2   2   10   177   185   3       3   12   7   79   84   3   3   5   8   25   21   3   0   14   8   23   15   9   5   7   9   39   27   25   3   2   10   85   87   3       2   12   7   126   117   2   4   5   8   33   38   2   1   14   8   43   37   3   −5   8   9   31   43   11   4   2   10   174   187   3       1   12   7   25   20   4   5   5   8   68   64   3   2   14   8   27   25   6   −4   8   9   58   57   4   −4   3   10   182   198   3       0   12   7   308   305   6   6   5   8   104   100   3   3   14   8   20   24   19   −3   8   9   52   47   2   −3   3   10   173   176   4       1   12   7   30   20   3   −4   6   8   57   59   2   −2   15   8   44   38   3   −2   8   9   150   146   2   −2   3   10   121   111   1       2   12   7   111   117   2   −3   6   8   64   61   2   −1   15   8   25   13   7   −1   8   9   74   76   2   −1   3   10   164   167   2       3   12   7   75   84   4   −2   6   8   152   140   2   0   15   8   68   63   2   0   8   9   94   99   1   0   3   10   121   121   1       4   12   7   18   16   17   −1   6   8   125   116   3   1   15   8   25   12   9   1   8   9   72   75   1   1   3   10   160   167   2       4   13   7   47   34   7   0   6   8   71   70   3   2   15   8   54   38   5   2   8   9   153   146   2   2   3   10   117   111   1       2   13   7   76   72   3   1   6   8   119   116   2   1   0   9   19   25   3   3   8   9   51   47   4   3   3   10   169   176   2       1   13   7   111   113   5   2   6   8   152   140   2   2   0   9   142   149   2   4   8   9   59   57   2   4   3   10   175   198   3       0   13   7   58   58   3   3   6   8   60   60   1   3   0   9   58   62   2   5   8   9   44   43   4   −4   4   10   71   64   3       1   13   7   109   113   1   4   6   8   58   59   1   4   0   9   160   183   2   −5   9   9   53   47   6   −3   4   10   56   55   1       2   13   7   75   72   2   5   6   8   49   41   5   5   0   9   103   105   2   −4   9   9   144   146   2   −2   4   10   43   40   2       3   13   7   26   22   7   6   6   8   49   44   5   −5   1   9   121   119   3   −3   9   9   57   60   2   −1   4   10   99   88   1       4   13   7   34   34   6   −4   7   8   80   83   1   −4   1   9   56   51   3   −2   9   9   29   21   7   0   4   10   328   328   8       3   14   7   29   28   20   −3   7   8   69   65   1   −3   1   9   26   30   5   −1   9   9   38   29   6   1   4   10   91   88   1       2   14   7   36   30   10   −2   7   8   60   58   2   −2   1   9   84   81   2   0   9   9   96   101   2   2   4   10   39   40   1       1   14   7   104   112   9   −1   7   8   94   91   1   −1   1   9   150   152   7   1   9   9   43   29   8   3   4   10   61   55   3       0   14   7   36   35   3   0   7   8   88   90   3   0   1   9   179   181   6   2   9   9   36   20   4   4   4   10   63   64   3       1   14   7   108   112   2   1   7   8   93   92   2   1   1   9   147   152   1   3   9   9   62   60   3   5   4   10   61   77   3       2   14   7   28   30   6   2   7   8   62   59   7   2   1   9   80   81   2   4   9   9   149   146   3   −4   5   10   166   170   3       3   14   7   37   28   9   3   7   8   71   66   2   3   1   9   34   30   3   5   9   9   48   47   6   −3   5   10   73   73   2       2   15   7   56   59   3   4   7   8   78   82   1   4   1   9   47   51   3   −5   10   9   35   26   8   −2   5   10   121   118   2       1   15   7   63   69   9   5   7   8   54   55   6   5   1   9   128   119   3   −4   10   9   49   37   11   −1   5   10   150   146   1       0   15   7   94   88   2   6   7   8   67   54   4   6   1   9   51   41   5   −3   10   9   39   29   3   0   5   10   75   75   1       1   15   7   69   68   2   −5   8   8   126   123   3   −4   2   9   115   122   3   −2   10   9   112   110   1   1   5   10   147   146   2       2   15   7   56   59   3   −4   8   8   40   33   5   −3   2   9   31   30   2   −1   10   9   246   241   2   2   5   10   115   118   4       1   16   7   48   45   3   −3   8   8   147   141   1   −2   2   9   200   201   2   0   10   9   151   138   2   3   5   10   71   74   3       0   16   7   34   31   4   −2   8   8   120   116   3   −1   2   9   284   274   3   1   10   9   248   241   2   4   5   10   147   170   3       0   0   8   458   523   44   −1   8   8   36   33   3   0   2   9   541   526   4   2   10   9   105   110   2   5   5   10   26   44   10       1   0   8   55   59   1   0   8   8   162   164   1   1   2   9   273   275   2   3   10   9   31   29   4   −4   6   10   69   66   4       2   0   8   226   227   3   1   8   8   30   32   4   2   2   9   192   201   3   4   10   9   39   37   4   −3   6   10   100   100   2       3   0   8   116   115   1   2   8   8   124   116   5   3   2   9   21   30   5   −4   11   9   35   44   6   −2   6   10   41   38   2       4   0   8   115   117   12   3   8   8   144   141   1   4   2   9   107   121   4   −3   11   9   106   104   2   −1   6   10   89   82   1       5   0   8   41   51   5   4   8   8   22   33   5   5   2   9   85   78   3   −2   11   9   176   175   2   0   6   10   198   187   2       6   0   8   85   79   4   5   8   8   116   123   11   6   2   9   100   95   3   −1   11   9   35   36   3   1   6   10   87   82   1       5   1   8   178   174   3   −5   9   8   42   6   21   −3   3   9   103   105   3   0   11   9   29   18   3   2   6   10   37   38   2       4   1   8   91   83   2   −4   9   8   97   96   3   −2   3   9   21   9   4   1   11   9   41   36   4   3   6   10   103   99   2       3   1   8   65   68   2   −3   9   8   53   58   2   −1   3   9   233   217   2   2   11   9   170   175   10   4   6   10   66   67   3       2   1   8   233   239   7   −2   9   8   132   126   3   0   3   9   44   36   2   3   11   9   103   103   2   5   6   10   62   67   4       1   1   8   407   410   9   −1   9   8   159   155   3   1   3   9   220   217   3   4   11   9   48   44   3   −4   7   10   73   71   4       0   1   8   116   124   1   0   9   8   174   173   1   3   3   9   101   104   2   −4   12   9   65   61   3   −3   7   10   69   68   1       1   1   8   394   410   3   1   9   8   157   155   4   4   3   9   123   123   9   −3   12   9   84   83   5   −2   7   10   99   98   1       2   1   8   221   238   3   2   9   8   131   126   5   5   3   9   78   75   3   −2   12   9   63   60   3   −1   7   10   46   40   2       3   1   8   70   69   1   3   9   8   53   58   3   6   3   9   105   107   3   −1   12   9   140   134   1   0   7   10   48   47   2       4   1   8   85   82   6   4   9   8   94   96   2   −4   4   9   62   70   3   0   12   9   43   26   4   1   7   10   41   40   2       5   1   8   181   173   3   5   9   8   24   6   7   −3   4   9   110   111   1   1   12   9   140   134   1   2   7   10   103   98   4       6   1   8   82   74   4   −5   10   8   35   37   6   −2   4   9   269   269   1   2   12   9   57   61   6   3   7   10   62   68   3       5   2   8   35   37   5   −4   10   8   71   66   3   −1   4   9   132   129   2   3   12   9   85   83   4   4   7   10   66   71   3       4   2   8   42   40   4   −3   10   8   33   20   7   0   4   9   253   231   9   4   12   9   45   61   5   5   7   10   36   46   7       3   2   8   214   231   7   −2   10   8   112   112   2   1   4   9   126   128   1   −3   13   9   78   85   2   −4   8   10   64   64   3       2   2   8   120   121   2   −1   10   8   136   136   4   2   4   9   252   269   2   −2   13   9   67   63   2   −3   8   10   50   45   4       1   2   8   130   126   1   0   10   8   126   122   2   3   4   9   114   111   2   −1   13   9   71   72   4   −2   8   10   103   105   1       0   2   8   172   160   2   1   10   8   133   136   2   4   4   9   57   70   2   0   13   9   78   76   2   −1   8   10   43   44   2       1   2   8   124   126   1   2   10   8   115   113   5   5   4   9   84   82   3   1   13   9   70   72   2   0   8   10   92   89   1       2   2   8   109   121   1   3   10   8   27   21   5   6   4   9   28   20   9   2   13   9   66   63   14   1   8   10   46   44   3       3   2   8   219   231   2   4   10   8   66   66   5   −4   5   9   82   82   2   3   13   9   84   85   3   2   8   10   101   105   3       4   2   8   38   40   2   5   10   8   35   38   5   −3   5   9   88   88   1   −2   14   9   29   16   10   3   8   10   46   45   4       5   2   8   46   37   4   −4   11   8   21   10   20   −2   5   9   85   82   2   −1   14   9   34   23   6   4   8   10   57   64   4       6   2   8   80   82   3   −3   11   8   123   123   3   −1   5   9   90   90   2   0   14   9   16   18   16   5   8   10   54   62   5       3   3   8   161   164   2   −2   11   8   105   105   1   0   5   9   66   72   2   1   14   9   15   23   15   −4   9   10   71   73   3       2   3   8   80   80   3   −1   11   8   130   129   3   1   5   9   95   90   2   2   14   9   39   16   6   −3   9   10   77   75   1       1   3   8   492   476   4   0   11   8   34   1   5   2   5   9   84   82   4   −2   15   9   54   51   4   −2   9   10   30   30   6       0   3   8   44   42   2   1   11   8   128   129   1   3   5   9   88   88   2   −1   15   9   31   28   6   −1   9   10   64   62   2       1   3   8   486   476   10   2   11   8   100   105   2   4   5   9   81   83   2   0   15   9   75   82   2   0   9   10   45   45   1       2   3   8   78   81   2   3   11   8   121   123   2   5   5   9   40   49   5   0   0   10   131   138   2   1   9   10   64   62   3       3   3   8   160   165   7   4   11   8   27   10   8   −4   6   9   109   107   2   1   0   10   112   115   2   2   9   10   27   30   7       4   3   8   84   85   1   −4   12   8   12   22   11   −3   6   9   31   36   2   2   0   10   4   19   4   3   9   10   78   75   3       5   3   8   64   59   3   −3   12   8   87   84   4   −2   6   9   121   121   1   3   0   10   176   186   3   4   9   10   71   73   4       6   3   8   66   60   5   −2   12   8   32   24   16   −1   6   9   105   110   1   4   0   10   105   123   2   5   9   10   49   57   7       3   4   8   133   122   1   −1   12   8   79   81   2   0   6   9   26   20   3   −4   1   10   167   184   2   −4   10   10   47   43   3       2   4   8   182   179   5   0   12   8   242   234   3   1   6   9   104   110   2   −3   1   10   153   164   3   −3   10   10   29   35   4       1   4   8   77   64   1   1   12   8   79   82   1   2   6   9   123   122   2   −2   1   10   80   79   1   −2   10   10   137   135   1       0   4   8   60   66   2   2   12   8   24   24   7   3   6   9   35   36   5   −1   1   10   272   278   2   −1   10   10   114   108   1       1   4   8   76   64   3   3   12   8   82   84   5   4   6   9   105   107   1   0   1   10   327   322   4   0   10   10   361   371   4       3   4   8   131   122   1   4   12   8   33   22   14   5   6   9   61   68   7   1   1   10   275   277   4   1   10   10   114   108   2       4   4   8   92   99   4   −3   13   8   39   30   5   6   6   9   19   49   6   2   1   10   78   79   1   2   10   10   138   134   3       5   4   8   77   68   3   −2   13   8   96   96   3   −4   7   9   86   87   3   3   1   10   149   164   4   3   10   10   24   35   11       6   4   8   73   71   4   −1   13   8   50   47   4   −3   7   9   94   94   1   4   1   10   173   183   3   4   10   10   32   43   9       4   5   8   42   38   6   0   13   8   57   45   3   −2   7   9   148   151   1   −4   2   10   167   187   3   −4   11   10   59   58   3       3   5   8   25   21   2   1   13   8   46   47   2   −1   7   9   52   55   1   −3   2   10   85   87   1   −3   11   10   116   120   2       2   5   8   161   158   1   2   13   8   99   96   2   0   7   9   90   87   2   −2   2   10   179   185   3   −2   11   10   74   82   2       1   5   8   136   135   2   3   13   8   33   30   7   1   7   9   52   55   1   −1   2   10   142   143   2   −1   11   10   144   144   1       0   5   8   71   70   4   −3   14   8   27   24   5   2   7   9   155   151   2   0   2   10   203   201   2   0   11   10   189   187   4       1   5   8   129   134   2   −2   14   8   24   25   8   3   7   9   95   95   2   1   2   10   138   143   3   1   11   10   143   144   3       2   11   10   68   81   3   5   6   11   60   74   4   2   2   12   114   111   1   2   11   12   51   48   16   0   7   13   23   18   5       3   11   10   115   120   3   −4   7   11   33   24   5   3   2   12   62   62   1   3   11   12   43   17   6   1   7   13   80   80   1       4   11   10   59   58   5   −3   7   11   130   131   2   4   2   12   57   60   3   4   11   12   27   44   10   2   7   13   110   107   1       4   12   10   28   42   11   −2   7   11   27   22   2   5   2   12   44   50   6   −3   12   12   48   44   9   3   7   13   100   96   3       3   12   10   31   37   5   −1   7   11   84   82   1   −4   3   12   93   92   2   −2   12   12   81   75   3   4   7   13   56   65   5       2   12   10   76   78   2   0   7   11   34   23   2   −3   3   12   33   27   2   −1   12   12   49   47   4   5   7   13   25   39   11       1   12   10   100   97   2   1   7   11   85   82   2   −2   3   12   67   65   2   0   12   12   36   32   5   −4   8   13   45   44   18       0   12   10   59   57   3   2   7   11   23   23   4   −1   3   12   100   103   1   1   12   12   53   47   4   −3   8   13   53   50   3       1   12   10   97   98   1   3   7   11   136   131   2   0   3   12   227   236   2   2   12   12   69   75   3   −2   8   13   88   88   1       2   12   10   72   78   4   4   7   11   34   24   8   1   3   12   103   103   3   3   12   12   49   44   5   −1   8   13   89   88   1       3   12   10   31   37   7   5   7   11   40   54   6   2   3   12   63   65   2   −2   13   12   74   72   5   0   8   13   222   221   1       4   12   10   56   42   5   −4   8   11   39   37   17   3   3   12   24   27   3   −1   13   12   45   37   9   1   8   13   87   88   1       3   13   10   24   26   6   −3   8   11   34   34   4   4   3   12   88   92   2   0   13   12   16   25   15   2   8   13   80   88   2       2   13   10   36   39   4   −2   8   11   45   41   2   5   3   12   89   104   3   1   13   12   23   37   8   3   8   13   48   51   6       1   13   10   59   51   2   −1   8   11   184   185   4   −4   4   12   59   64   5   2   13   12   62   72   8   4   8   13   45   44   6       0   13   10   43   51   4   0   8   11   34   31   2   −3   4   12   81   82   1   −1   14   12   24   24   9   −4   9   13   54   42   3       1   13   10   50   51   2   1   8   11   186   185   1   −2   4   12   66   63   1   0   14   12   48   54   3   −3   9   13   66   69   7       2   13   10   28   40   8   2   8   11   40   41   2   −1   4   12   66   67   1   1   14   12   19   24   18   −2   9   13   48   52   2       3   13   10   24   26   23   3   8   11   17   34   16   0   4   12   59   63   1   1   0   13   92   83   2   −1   9   13   30   21   8       2   14   10   36   30   4   4   8   11   45   37   6   1   4   12   70   67   1   2   0   13   37   37   2   0   9   13   58   95   1       1   14   10   48   52   3   5   8   11   20   27   20   2   4   12   64   63   3   3   0   13   205   205   2   1   9   13   34   21   5       0   14   10   56   55   3   −4   9   11   42   45   11   3   4   12   79   82   2   4   0   13   48   49   3   2   9   13   53   52   3       1   14   10   39   52   7   −3   9   11   122   123   1   4   4   12   51   64   4   −5   1   13   35   9   10   3   9   13   62   69   5       2   14   10   39   30   5   −2   9   11   88   86   1   5   4   12   28   41   10   −4   1   13   183   182   3   4   9   13   38   42   7       1   15   10   27   18   6   −1   9   11   145   144   1   −4   5   12   78   90   8   −3   1   13   88   88   2   −4   10   13   50   53   4       0   15   10   28   39   13   0   9   11   41   42   2   −3   5   12   30   33   3   −2   1   13   96   97   3   −3   10   13   70   76   3       1   0   11   76   85   2   1   9   11   141   144   1   −2   5   12   115   116   2   −1   1   13   164   167   2   −2   10   13   37   30   3       2   0   11   48   59   2   2   9   11   88   86   4   −1   5   12   32   29   2   0   1   13   109   106   1   −1   10   13   76   76   1       3   0   11   189   196   2   3   9   11   129   123   3   0   5   12   135   139   1   1   1   13   164   167   3   0   10   13   101   102   1       4   0   11   89   91   2   4   9   11   43   45   6   1   5   12   38   29   2   2   1   13   98   97   2   1   10   13   72   76   2       4   1   11   95   94   2   −4   10   11   31   34   13   2   5   12   112   116   2   3   1   13   87   88   1   2   10   13   27   30   8       3   1   11   158   159   4   −3   10   11   85   81   1   3   5   12   30   33   5   4   1   13   169   182   2   3   10   13   65   76   3       2   1   11   64   61   2   −2   10   11   118   109   2   4   5   12   81   90   3   −5   2   13   74   32   5   4   10   13   51   53   5       1   1   11   199   192   4   −1   10   11   32   33   4   5   5   12   16   35   16   −4   2   13   31   32   10   −3   11   13   21   19   20       0   1   11   50   42   5   0   10   11   303   302   2   −4   6   12   92   91   4   −3   2   13   44   41   2   −2   11   13   100   98   1       1   1   11   194   192   2   1   10   11   36   33   2   −3   6   12   42   45   4   −2   2   13   95   96   2   −1   11   13   32   30   3       2   1   11   68   60   1   2   10   11   112   110   5   −2   6   12   38   33   2   −1   2   13   141   145   1   0   11   13   90   85   3       3   1   11   155   159   4   3   10   11   77   80   3   −1   6   12   85   86   1   0   2   13   68   61   1   1   11   13   38   30   4       4   1   11   92   94   2   4   10   11   35   34   7   0   6   12   116   120   1   1   2   13   140   145   1   2   11   13   102   98   2       4   2   11   100   104   3   −4   11   11   43   48   6   1   6   12   86   85   1   2   2   13   101   96   1   3   11   13   25   19   11       3   2   11   23   14   10   −3   11   11   40   42   3   2   6   12   33   34   2   3   2   13   43   41   2   −2   12   13   25   24   6       2   2   11   98   95   2   −2   11   11   70   67   2   3   6   12   50   45   4   4   2   13   36   32   4   −1   12   13   35   35   3       1   2   11   279   296   4   −1   11   11   107   103   1   4   6   12   87   91   3   5   2   13   29   31   13   0   12   13   86   90   5       0   2   11   183   186   8   0   11   11   24   4   11   5   6   12   13   30   12   −4   3   13   61   61   4   1   12   13   29   35   20       1   2   11   287   296   3   1   11   11   104   103   1   −4   7   12   54   48   10   −3   3   13   35   22   11   2   12   13   15   24   14       2   2   11   97   95   1   2   11   11   66   67   3   −3   7   12   81   78   1   −2   3   13   96   96   2   3   12   13   40   33   6       3   2   11   17   15   5   3   11   11   33   42   21   −2   7   12   162   158   1   −1   3   13   88   89   1   −1   13   13   48   50   3       4   2   11   102   104   2   4   11   11   39   47   6   −1   7   12   110   108   1   0   3   13   163   158   1   0   13   13   24   4   10       4   3   11   74   74   2   −3   12   11   25   18   25   0   7   12   65   66   2   1   3   13   90   88   2   1   13   13   41   50   4       3   3   11   117   117   2   −2   12   11   76   77   5   1   7   12   111   108   1   2   3   13   96   96   1   0   0   14   92   95   2       2   3   11   46   48   3   −1   12   11   66   64   3   2   7   12   154   158   4   3   3   13   24   21   3   1   0   14   78   71   1       1   3   11   23   19   2   0   12   11   25   18   10   3   7   12   78   78   3   4   3   13   51   61   4   2   0   14   118   114   1       0   3   11   126   134   3   1   12   11   62   64   3   4   7   12   44   48   5   5   3   13   54   62   5   3   0   14   119   124   2       1   3   11   25   20   2   2   12   11   77   77   10   5   7   12   25   32   10   −4   4   13   76   80   6   4   0   14   102   97   2       2   3   11   47   47   1   3   12   11   22   18   18   −4   8   12   68   72   4   −3   4   13   56   49   2   5   0   14   43   71   8       3   3   11   112   117   3   −3   13   11   49   56   6   −3   8   12   71   67   2   −2   4   13   55   57   1   −5   1   14   31   29   10       4   3   11   73   74   3   −2   13   11   53   55   4   −2   8   12   87   84   1   −1   4   13   75   71   1   −4   1   14   36   44   3       5   3   11   45   52   5   −1   13   11   27   20   6   −1   8   12   90   89   1   0   4   13   18   19   3   −3   1   14   35   33   4       4   4   11   65   66   2   0   13   11   50   40   6   0   8   12   66   60   2   1   4   13   77   72   2   −2   1   14   23   8   4       3   4   11   189   186   3   1   13   11   36   20   8   1   8   12   90   89   1   2   4   13   59   58   2   −1   1   14   60   60   2       2   4   11   26   24   3   2   13   11   40   55   12   2   8   12   85   84   2   3   4   13   54   49   2   0   1   14   85   81   1       1   4   11   101   100   1   3   13   11   55   56   7   3   8   12   72   67   4   4   4   13   72   80   3   1   1   14   57   61   1       0   4   11   79   83   1   −2   14   11   25   13   7   4   8   12   66   72   5   5   4   13   24   32   11   2   1   14   22   7   3       1   4   11   101   100   1   −1   14   11   26   28   10   5   8   12   13   26   12   −4   5   13   37   38   4   3   1   14   38   33   5       2   4   11   26   24   5   0   14   11   36   41   4   −4   9   12   94   92   2   −3   5   13   80   79   2   4   1   14   38   44   4       3   4   11   185   186   3   1   14   11   18   28   17   −3   9   12   113   114   2   −2   5   13   81   79   1   5   1   14   4   28   4       4   4   11   63   66   3   2   14   11   27   14   7   −2   9   12   21   25   4   −1   5   13   26   26   2   −5   2   14   76   84   4       5   4   11   47   52   5   0   0   12   640   627   11   −1   9   12   112   107   2   0   5   13   266   274   2   −4   2   14   75   78   2       4   5   11   17   12   8   1   0   12   27   27   2   0   9   12   58   52   1   1   5   13   32   26   4   −3   2   14   215   215   7       3   5   11   106   101   4   2   0   12   153   155   1   1   9   12   109   107   2   2   5   13   84   79   2   −2   2   14   79   79   2       2   5   11   98   100   1   3   0   12   93   99   3   2   9   12   20   25   6   3   5   13   78   79   3   −1   2   14   152   146   1       1   5   11   136   133   2   4   0   12   110   113   2   3   9   12   107   114   3   4   5   13   39   38   6   0   2   14   19   1   4       0   5   11   78   75   1   −4   1   12   191   207   3   4   9   12   84   92   4   5   5   13   53   60   5   1   2   14   151   146   3       1   5   11   134   133   2   −3   1   12   150   158   3   −4   10   12   26   25   7   −4   6   13   81   88   8   2   2   14   84   79   1       2   5   11   94   101   2   −2   1   12   42   37   2   −3   10   12   33   13   13   −3   6   13   44   36   5   3   2   14   212   215   1       3   5   11   105   101   2   −1   1   12   132   137   2   −2   10   12   71   68   2   −2   6   13   111   110   1   4   2   14   73   78   2       4   5   11   30   12   6   0   1   12   130   121   1   −1   10   12   72   72   1   −1   6   13   143   140   1   5   2   14   54   84   5       5   5   11   46   42   6   1   1   12   131   137   1   0   10   12   161   162   2   0   6   13   23   11   3   −5   3   14   52   44   6       4   6   11   74   73   2   2   1   12   38   37   3   1   10   12   70   71   2   1   6   13   142   140   2   −4   3   14   33   39   5       3   6   11   63   60   3   3   1   12   145   157   4   2   10   12   71   69   2   2   6   13   112   110   1   −3   3   14   49   48   2       2   6   11   34   33   3   4   1   12   197   207   3   3   10   12   15   13   15   3   6   13   47   36   5   −2   3   14   57   50   5       1   6   11   141   145   1   −4   2   12   60   60   2   4   10   12   14   25   14   4   6   13   76   88   3   −1   3   14   83   81   1       0   6   11   47   30   3   −3   2   12   60   61   2   −3   11   12   32   17   9   5   6   13   24   44   11   0   3   14   63   65   1       1   6   11   142   145   2   −2   2   12   115   112   1   −2   11   12   46   48   5   −4   7   13   55   64   3   1   3   14   84   82   3       2   6   11   32   33   2   −1   2   12   192   198   2   −1   11   12   56   51   3   −3   7   13   100   95   2   2   3   14   54   50   1       3   6   11   60   60   3   0   2   12   104   106   1   0   11   12   35   26   4   −2   7   13   110   107   2   3   3   14   53   48   3       4   6   11   66   72   4   1   2   12   195   198   2   1   11   12   48   51   3   −1   7   13   80   80   2   4   3   14   31   39   8       5   3   14   26   44   11   2   1   15   160   151   2   1   11   15   25   20   8   −2   10   16   73   78   4   1   0   18   129   120   2       5   4   14   46   21   6   3   1   15   136   131   1   2   11   15   6   38   5   −1   10   16   25   23   6   2   0   18   197   195   2       4   4   14   23   12   8   4   1   15   49   57   5   −1   12   15   35   41   6   0   10   16   25   13   7   3   0   18   23   20   11       3   4   14   54   43   5   5   1   15   35   56   11   0   12   15   42   42   4   1   10   16   21   23   9   −4   1   18   48   50   4       2   4   14   34   19   3   −4   2   15   47   46   4   1   12   15   42   41   5   2   10   16   72   78   5   −3   1   18   44   41   4       1   4   14   49   46   1   −3   2   15   38   35   3   0   0   16   27   8   3   −1   11   16   28   13   12   −2   1   18   88   80   2       0   4   14   54   52   2   −2   2   15   42   37   3   1   0   16   70   62   1   0   11   16   30   13   5   −1   1   18   52   49   2       1   4   14   53   46   2   −1   2   15   170   165   1   2   0   16   31   18   3   1   11   16   17   14   17   0   1   18   26   23   4       2   4   14   28   19   6   0   2   15   166   157   2   3   0   16   91   95   1   0   12   16   29   18   7   1   1   18   56   49   2       3   4   14   45   43   3   1   2   15   172   165   3   4   0   16   13   12   12   1   0   17   19   2   5   2   1   18   83   80   3       5   4   14   31   21   7   2   2   15   41   37   4   −4   1   16   60   73   3   2   0   17   82   71   3   3   1   18   40   41   6       4   5   14   33   43   5   3   2   15   33   36   3   −3   1   16   64   62   2   3   0   17   78   73   2   4   1   18   33   50   6       3   5   14   59   49   3   4   2   15   38   46   5   −2   1   16   133   123   1   4   0   17   15   27   15   −4   2   18   34   39   14       2   5   14   29   23   3   5   2   15   45   37   9   −1   1   16   105   101   1   −4   1   17   30   32   5   −3   2   18   17   3   14       1   5   14   52   50   1   −5   3   15   60   57   5   0   1   16   32   20   3   −3   1   17   28   32   6   −2   2   18   135   126   1       0   5   14   27   30   3   −4   3   15   39   45   3   1   1   16   109   101   3   −2   1   17   150   139   1   −1   2   18   54   47   2       1   5   14   57   50   4   −3   3   15   47   36   3   2   1   16   131   123   1   −1   1   17   114   111   1   0   2   18   23   20   6       2   5   14   37   23   11   −2   3   15   134   131   2   3   1   16   60   62   4   0   1   17   26   1   7   1   2   18   52   47   2       3   5   14   56   50   2   −1   3   15   75   75   1   4   1   16   71   73   3   1   1   17   118   111   1   2   2   18   137   126   3       4   5   14   40   42   6   0   3   15   180   165   1   −4   2   16   55   59   4   2   1   17   147   139   2   3   2   18   19   3   19       4   6   14   58   57   3   1   3   15   78   74   1   −3   2   16   64   58   3   3   1   17   28   32   5   4   2   18   20   39   20       3   6   14   97   96   2   2   3   15   133   131   1   −2   2   16   69   61   1   4   1   17   37   32   7   −4   3   18   43   29   7       2   6   14   104   102   1   3   3   15   33   36   3   −1   2   16   152   147   1   −4   2   17   35   33   4   −3   3   18   25   5   6       1   6   14   42   41   2   4   3   15   40   46   6   0   2   16   36   22   2   −3   2   17   42   22   4   −2   3   18   63   57   2       0   6   14   21   8   4   5   3   15   43   57   6   1   2   16   153   147   3   −2   2   17   87   78   2   −1   3   18   29   23   4       1   6   14   42   41   2   −5   4   15   32   8   10   2   2   16   66   61   1   −1   2   17   63   60   1   0   3   18   54   53   4       2   6   14   106   102   1   −4   4   15   41   33   8   3   2   16   57   58   4   0   2   17   28   16   5   2   3   18   49   57   3       3   6   14   86   96   3   −3   4   15   80   81   4   4   2   16   45   59   4   1   2   17   60   60   3   3   3   18   16   4   15       4   6   14   54   56   5   −2   4   15   93   94   3   −4   3   16   40   46   9   2   2   17   87   79   3   4   3   18   27   29   18       4   7   14   73   82   9   −1   4   15   24   16   3   −3   3   16   64   59   2   3   2   17   23   22   7   −3   4   18   14   4   14       3   7   14   32   34   7   0   4   15   90   92   1   −2   3   16   25   16   3   4   2   17   20   33   19   −2   4   18   52   45   3       2   7   14   61   65   1   1   4   15   38   16   4   −1   3   16   137   133   1   −4   3   17   30   11   6   −1   4   18   35   33   3       1   7   14   176   179   1   2   4   15   96   94   5   0   3   16   36   20   2   −3   3   17   70   67   4   0   4   18   48   47   2       0   7   14   25   5   3   3   4   15   84   81   2   1   3   16   137   133   3   −2   3   17   57   46   2   1   4   18   42   32   4       1   7   14   181   179   2   4   4   15   25   33   12   2   3   16   24   17   12   −1   3   17   55   55   1   2   4   18   58   45   3       2   7   14   63   65   2   −4   5   15   45   33   4   3   3   16   59   59   3   0   3   17   40   28   3   4   4   18   31   44   10       3   7   14   29   34   10   −3   5   15   60   64   2   4   3   16   40   46   7   1   3   17   58   55   3   −3   5   18   43   35   3       4   7   14   73   81   4   −2   5   15   123   127   1   −4   4   16   41   38   10   2   3   17   54   46   4   −2   5   18   52   43   5       4   8   14   31   26   7   −1   5   15   46   48   1   −3   4   16   58   55   2   3   3   17   60   66   2   −1   5   18   53   49   3       3   8   14   50   65   3   0   5   15   116   109   2   −2   4   16   104   97   1   −4   4   17   39   38   5   0   5   18   52   48   2       2   8   14   72   69   2   1   5   15   50   48   2   −1   4   16   80   75   1   −3   4   17   46   43   3   1   5   18   53   49   5       1   8   14   71   68   1   2   5   15   124   127   2   0   4   16   47   42   2   −2   4   17   60   57   3   2   5   18   46   43   3       0   8   14   102   107   1   3   5   15   59   64   3   1   4   16   81   75   2   −1   4   17   88   90   1   3   5   18   36   35   8       1   8   14   70   68   3   4   5   15   4   33   4   2   4   16   105   97   3   0   4   17   12   5   11   −3   6   18   23   32   7       2   8   14   71   69   2   −4   6   15   43   36   7   3   4   16   54   54   4   1   4   17   89   90   2   −2   6   18   65   66   3       3   8   14   59   64   5   −3   6   15   38   39   7   4   4   16   27   38   9   2   4   17   55   57   2   −1   6   18   41   37   4       4   8   14   4   26   4   −2   6   15   76   73   1   −4   5   16   41   38   4   3   4   17   44   43   7   0   6   18   8   1   8       4   9   14   26   27   25   −1   6   15   112   121   1   −3   5   16   26   9   7   4   4   17   24   38   13   1   6   18   27   37   8       3   9   14   37   11   5   0   6   15   58   57   2   −2   5   16   78   79   1   −4   5   17   52   49   3   2   6   18   62   66   2       2   9   14   62   66   3   1   6   15   116   121   2   −1   5   16   41   41   2   −3   5   17   43   36   4   −3   7   18   25   17   10       1   9   14   60   59   2   2   6   15   70   73   2   0   5   16   84   88   1   −2   5   17   42   39   4   −2   7   18   45   38   3       0   9   14   34   28   3   3   6   15   33   39   8   1   5   16   44   40   2   −1   5   17   113   109   1   −1   7   18   30   17   5       1   9   14   57   59   2   4   6   15   17   36   16   2   5   16   78   79   2   0   5   17   70   68   2   0   7   18   42   45   15       2   9   14   69   66   2   −4   7   15   43   39   5   3   5   16   25   9   8   1   5   17   113   109   2   1   7   18   31   17   19       4   9   14   16   27   16   −3   7   15   33   31   12   4   5   16   26   38   10   2   5   17   36   39   4   2   7   18   36   38   3       3   10   14   39   37   4   −2   7   15   83   78   2   −4   6   16   45   23   10   3   5   17   31   36   4   −2   8   18   52   51   3       2   10   14   37   37   4   −1   7   15   38   29   5   −3   6   16   63   66   2   4   5   17   38   49   6   −1   8   18   61   61   3       1   10   14   46   43   2   0   7   15   54   45   3   −2   6   16   17   14   17   −3   6   17   45   7   5   0   8   18   55   65   3       0   10   14   72   75   2   1   7   15   44   29   8   −1   6   16   64   64   1   −2   6   17   26   17   6   1   8   18   55   61   9       1   10   14   45   43   5   2   7   15   79   78   2   0   6   16   77   80   1   −1   6   17   56   54   2   2   8   18   47   51   3       2   10   14   33   37   4   3   7   15   6   31   5   1   6   16   69   64   2   0   6   17   65   56   3   −1   9   18   39   41   5       3   10   14   43   37   6   4   7   15   36   39   7   2   6   16   21   14   7   1   6   17   60   53   3   0   9   18   16   12   13       3   11   14   27   19   9   −4   8   15   35   32   6   3   6   16   68   66   5   2   6   17   23   17   22   1   9   18   42   41   6       2   11   14   54   48   3   −3   8   15   48   53   6   4   6   16   9   23   9   3   6   17   18   7   18   1   0   19   15   6   15       1   11   14   51   53   3   −2   8   15   28   37   5   −4   7   16   28   3   7   −3   7   17   57   58   3   2   0   19   29   24   9       0   11   14   78   75   2   −1   8   15   47   42   4   −3   7   16   50   41   3   −2   7   17   96   98   2   3   0   19   37   25   20       1   11   14   53   53   4   0   8   15   120   122   2   −2   7   16   74   76   2   −1   7   17   58   62   4   −3   1   19   63   66   2       2   11   14   50   48   4   1   8   15   49   42   2   −1   7   16   96   97   2   0   7   17   97   96   5   −2   1   19   48   54   3       2   12   14   32   30   4   2   8   15   40   37   20   0   7   16   67   69   3   1   7   17   58   61   3   −1   1   19   53   52   4       1   12   14   69   71   2   3   8   15   58   53   5   1   7   16   98   97   2   2   7   17   92   98   3   0   1   19   17   8   12       0   12   14   22   4   8   −3   9   15   73   79   2   2   7   16   73   76   5   3   7   17   64   58   4   1   1   19   54   52   3       1   12   14   70   71   4   −2   9   15   37   39   5   3   7   16   25   41   13   −3   8   17   50   51   3   2   1   19   52   54   5       2   12   14   34   30   10   −1   9   15   55   53   6   4   7   16   4   3   4   −2   8   17   78   82   2   3   1   19   59   66   2       1   13   14   33   39   5   0   9   15   36   27   4   −3   8   16   62   61   2   −1   8   17   31   32   8   −3   2   19   36   50   4       0   13   14   28   28   8   1   9   15   59   53   3   −2   8   16   33   24   4   0   8   17   31   12   11   −2   2   19   48   34   3       1   13   14   15   39   14   2   9   15   41   39   7   −1   8   16   75   73   6   1   8   17   18   32   18   −1   2   19   34   29   4       1   0   15   309   302   3   3   9   15   63   79   9   0   8   16   48   51   4   2   8   17   83   82   6   0   2   19   29   12   7       2   0   15   63   62   1   −3   10   15   45   45   4   1   8   16   72   73   2   3   8   17   41   51   6   1   2   19   19   29   10       3   0   15   21   13   19   −2   10   15   21   22   7   2   8   16   28   24   5   −2   9   17   49   54   3   2   2   19   34   34   6       4   0   15   37   38   5   −1   10   15   59   48   3   3   8   16   62   62   4   −1   9   17   44   37   4   3   2   19   42   50   8       5   1   15   48   57   5   0   10   15   17   15   12   −3   9   16   23   28   8   0   9   17   35   1   9   −3   3   19   29   14   6       4   1   15   52   57   3   1   10   15   46   48   3   −2   9   16   43   47   3   1   9   17   36   37   4   −2   3   19   35   24   4       3   1   15   138   130   3   2   10   15   24   22   7   −1   9   16   48   39   3   2   9   17   55   54   2   −1   3   19   45   39   3       2   1   15   161   151   2   3   10   15   32   44   6   0   9   16   30   42   5   −1   10   17   27   21   4   0   3   19   35   33   7       1   1   15   102   95   1   −2   11   15   39   38   3   1   9   16   42   39   3   0   10   17   22   2   10   1   3   19   30   39   5       0   1   15   93   90   1   −1   11   15   33   20   4   2   9   16   40   47   3   1   10   17   18   21   12   2   3   19   41   24   4       1   1   15   101   95   2   0   11   15   22   21   8   3   9   16   26   28   12   0   0   18   27   7   6   −3   4   19   24   19   10       2   4   19   53   54   2   2   7   19   13   15   12   0   2   20   34   10   13   2   5   20   21   25   6   2   2   21   36   32   16       1   4   19   33   31   3   −1   8   19   57   58   3   1   2   20   27   41   7   −2   6   20   30   18   8   −2   3   21   39   37   6       0   4   19   50   51   4   0   8   19   43   41   4   2   2   20   71   71   3   −1   6   20   28   26   5   −1   3   21   37   17   6       1   4   19   20   31   10   1   8   19   54   58   13   3   2   20   46   47   6   0   6   20   20   5   11   1   3   21   25   17   7       2   4   19   46   54   5   0   0   20   41   45   5   −3   3   20   58   58   3   1   6   20   33   26   6   2   3   21   33   37   11       2   5   19   38   27   7   1   0   20   131   131   3   −2   3   20   39   37   4   0   7   20   21   2   15   −1   4   21   14   19   14       1   5   19   20   10   9   2   0   20   46   36   4   −1   3   20   31   33   4   1   7   20   13   7   12   0   4   21   41   29   5       0   5   19   19   18   11   3   0   20   30   9   7   0   3   20   29   20   9   1   0   21   45   43   4   0   5   21   29   15   14       2   5   19   33   28   10   −3   1   20   38   13   8   1   3   20   41   33   4   2   0   21   33   28   7   1   5   21   10   14   9       2   6   19   29   29   6   −2   1   20   63   65   4   2   3   20   36   37   3   −2   1   21   61   69   6   0   0   22   24   49   4       1   6   19   19   20   18   −1   1   20   34   37   5   −2   4   20   40   34   3   −1   1   21   50   51   6   1   0   22   44   35   5       0   6   19   29   12   6   0   1   20   38   43   3   −1   4   20   53   47   4   0   1   21   21   19   6   −1   1   22   39   31   6       1   6   19   31   20   5   1   1   20   32   37   6   0   4   20   31   30   4   1   1   21   61   51   3   0   1   22   27   13   6       2   6   19   22   29   8   2   1   20   65   65   6   1   4   20   57   47   9   2   1   21   55   69   4   1   1   22   21   31   20       2   7   19   34   15   10   3   1   20   34   13   9   2   4   20   26   34   5   −2   2   21   27   32   7   0   2   22   35   37   6       1   7   19   16   23   15   −3   2   20   46   47   10   −2   5   20   30   25   8   −1   2   21   44   47   3       0   7   19   27   20   15   −2   2   20   72   71   2   −1   5   20   27   20   6   0   2   21   28   24   5       1   7   19   32   23   5   −1   2   20   40   41   3   0   5   20   18   18   17   1   2   21   45   47   5                    
       SYNTHESIS OF 2MBP  
     EXAMPLE 3  
       [0029]    The preparation of 2MBP having the basic structure I can be accomplished by a common general method, i.e. the condensation of a bicyclic Windaus-Grundmann type ketone II with the allylic phosphine oxide III to the corresponding 2-methylene-19-nor-vitamin D analog IV followed by deprotection at C-1 and C-3 in the latter compound IV to obtain compound I, i.e. 2MBP.  
                         
 
         [0030]    In the structures II, III, and IV groups Y 1  and Y 2  are hydroxy-protecting groups, it being also understood that any functionalities that might be sensitive, or that interfere with the condensation reaction, be suitably protected as is well-known in the art. The process shown above represents an application of the convergent synthesis concept, which has been applied effectively for the preparation of vitamin D compounds [e.g. Lythgoe et al., J. Chem. Soc. Perkin Trans. 1, 590 (1978); Lythgoe, Chem. Soc. Rev. 9, 449 (1983); Toh et al., J. Org. Chem. 48, 1414 (1983); Baggiolini et al., J. Org. Chem. 51, 3098 (1986); Sardina et al., J. Org. Chem. 51, 1264 (1986); J. Org. Chem. 51, 1269 (1986); DeLuca et al., U.S. Pat. No. 5,086,191; DeLuca et al., U.S. Pat. No. 5,536,713].  
         [0031]    Hydrindanones of the general structure II are known, or can be prepared by known methods.  
         [0032]    For the preparation of the required phosphine oxides of general structure III, a synthetic route has been developed starting from a methyl quinicate derivative which is easily obtained from commercial (1R,3R,4S,5R)-(−)-quinic acid as described by Perlman et al., Tetrahedron Lett. 32, 7663 (1991) and DeLuca et al., U.S. Pat. No. 5,086,191.  
         [0033]    The overall process of the synthesis of compound I is illustrated and described more completely in U.S. Pat. No. 5,843,928 entitled “2-Alkylidene-19-Nor-Vitamin D Compounds” and in application Ser. No. 09/878,438 filed Jun. 11, 2001 entitled “1α-Hydroxy-2-Methylene-19-Nor-Homopregnacalciferol and its Uses” the specifications of which are specifically incorporated herein by reference.  
         [0034]    As used in the description and in the claims, the term “hydroxy-protecting group” signifies any group commonly used for the temporary protection of hydroxy functions, such as for example, alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafter referred to simply as “silyl” groups), and alkoxyalkyl groups. Alkoxycarbonyl protecting groups are alkyl-O-CO- groupings such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or allyloxycarbonyl. The term “acyl” signifies an alkanoyl group of 1 to 6 carbons, in all of its isomeric forms, or a carboxyalkanoyl group of 1 to 6 carbons, such as an oxalyl, malonyl, succinyl, glutaryl group, or an aromatic acyl group such as benzoyl, or a halo, nitro or alkyl substituted benzoyl group. The word “alkyl” as used in the description of the claims, denotes a straight-chain or branched alkyl radical of 1 to 10 carbons, in all its isomeric forms. Alkoxyalkyl protecting groups are groupings such as methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl. Preferred silyl-protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl and analogous alkylated silyl radicals. The term “aryl” specifies a phenyl-, or an alkyl-, nitro- or halo-substituted phenyl group.  
         [0035]    A “protected hydroxy” group is a hydroxy group derivatised or protected by any of the above groups commonly used for the temporary or permanent protection of hydroxy functions, e.g. the silyl, alkoxyalkyl, acyl or alkoxycarbonyl groups, as previously defined. The terms “hydroxyalkyl”, “deuteroalkyl”, “aminoalkyl”, “halogenalkyl”, “alkoxyalkyl”, “aryloxyalkyl”, and “fluoroalkyl” refer to an alkyl radical substituted by one or more hydroxy, deuterium, amino, halogen, alkoxy, aryloxy, or fluoro group respectively. A “halogen” group includes any of the five elements fluorine, chlorine, bromine, iodine and astatine that form a part of group VIIA of the periodic table.  
         [0036]    Referring now to Schemes I-III, there are illustrated three different methods of synthesizing 2MBP starting with vitamin D 2 . The first five steps are identical (shown in Scheme I) for each synthesis to obtain the protected 20(S)-aldehyde. Thereafter, in Schemes I and II the aldehyde is converted to a protected 20(S)-alcohol which in turn has its side chain converted to bis-homo in two different ways (Scheme I versus Scheme II). In contrast, Scheme III illustrates a direct conversion of the protected 20(S)-aldehyde to the bis-homo side chain.