A Vending Machine for Drug-like Molecules - Automated Synthesis of Virtual Screening Hits
McMillan, Angus E.; Wu, Wilson W. X.; Nichols, Paula L.; Wanner, Benedikt M.; Bode, Jeffrey W.; Chemical Science  (2022) –; doi:10.1039/D2SC05182F

data_1567876
_publ_section_title
;
 A Vending Machine for Drug-like Molecules - Automated Synthesis of
 Virtual Screening Hits
;
_journal_name_full               'Chemical Science'
_journal_paper_doi               10.1039/D2SC05182F
_journal_year                    2022
_chemical_absolute_configuration ad
_chemical_formula_moiety         'C18 H26 Cl N2 O, C2 F3 O2'
_chemical_formula_sum            'C20 H26 Cl F3 N2 O3'
_chemical_formula_weight         434.88
_space_group_crystal_system      monoclinic
_space_group_IT_number           4
_space_group_name_Hall           'P 2yb'
_space_group_name_H-M_alt        'P 1 21 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2020-09-28
_audit_creation_method
;
Olex2 1.3
(compiled 2020.07.31 svn.rc2a77460 for OlexSys, GUI svn.r6145)
;
_audit_update_record
;
2022-04-28 deposited with the CCDC.	2022-10-28 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 95.4560(10)
_cell_angle_gamma                90
_cell_formula_units_Z            2
_cell_length_a                   10.51880(10)
_cell_length_b                   8.84740(10)
_cell_length_c                   11.0858(2)
_cell_measurement_reflns_used    18046
_cell_measurement_temperature    100.0(1)
_cell_measurement_theta_max      79.6190
_cell_measurement_theta_min      4.0040
_cell_volume                     1027.02(2)
_computing_cell_refinement       'CrysAlisPro 1.171.40.68a (Rigaku OD, 2019)'
_computing_data_collection       'CrysAlisPro 1.171.40.68a (Rigaku OD, 2019)'
_computing_data_reduction        'CrysAlisPro 1.171.40.68a (Rigaku OD, 2019)'
_computing_molecular_graphics    'Olex2 1.3 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 1.3 (Dolomanov et al., 2009)'
_computing_structure_refinement  'SHELXL 2018/3 (Sheldrick, 2015)'
_computing_structure_solution    'SHELXT 2014/4 (Sheldrick, 2014)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      100.0(1)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 5.8140
_diffrn_detector_type            'Pilatus 300K'
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 0.983
_diffrn_measurement_details
;
List of Runs (angles in degrees, time in seconds):

  # Type    Start    End  Width  t~exp~   \w     \q     \k     \f   Frames
  1  \w    -64.00 -35.00   0.50    0.40    --  -48.62 -38.00   0.00   58
  2  \w     -2.00  26.00   0.50    0.40    --  -48.62  19.00  60.00   56
  3  \w    -67.00 -37.00   0.50    0.40    --  -48.62 -19.00  90.00   60
  4  \w    -73.00 -47.00   0.50    1.41    --  -70.00 -74.00  96.32   52
  5  \w    -72.00 -46.00   0.50    1.41    --  -70.00 -77.00  60.00   52
  6  \w    -76.00 -49.00   0.50    1.41    --  -70.00 -73.00 -21.83   54
  7  \w    -73.00 -45.00   0.50    1.41    --  -70.00 -80.00 -43.76   56
  8  \w    -73.00 -46.00   0.50    1.41    --  -70.00 -77.00-105.16   54
  9  \w    -79.00 -48.00   0.50    1.41    --  -70.00 -77.00   0.00   62
 10  \w    -78.00 -52.00   0.50    1.41    --  -70.00 -78.00  26.23   52
 11  \w    -84.00 -47.00   0.50    1.41    --  -70.00 -77.00  35.77   74
 12  \w    -92.00 -41.00   0.50    0.40    --  -48.62 -38.00 150.00  102
 13  \w    -73.00 -47.00   0.50    1.41    --  -70.00 -74.00 175.78   52
 14  \w   -123.00 -86.00   0.50    0.40    --  -48.62 -19.00  90.00   74
 15  \w   -124.00 -74.00   0.50    0.40    --  -48.62 -38.00   0.00  100
 16  \w   -119.00 -92.00   0.50    1.41    --  -70.00 -80.00 -43.76   54
 17  \w   -136.00-103.00   0.50    1.41    --  -70.00 -74.00  96.32   66
 18  \w    -25.00   8.00   0.50    0.40    --   48.62 -19.00  90.00   66
 19  \w     34.00  91.00   0.50    0.40    --   48.62  57.00   0.00  114
 20  \w     67.00  93.00   0.50    1.41    --   82.00  54.00 -39.34   52
 21  \w     71.00 119.00   0.50    1.41    --   90.00  65.00 -12.39   96
 22  \w    126.00 159.00   0.50    1.41    --   90.00  65.00 -12.39   66
 23  \w    134.00 166.00   0.50    1.41    --  110.00  77.00   0.00   64
 24  \w    127.00 162.00   0.50    1.41    --  110.00  77.00 -60.00   70
 25  \w    128.00 177.00   0.50    1.41    --  110.00 125.00 -90.00   98
 26  \w    152.00 177.00   0.50    1.41    --  110.00  57.00-180.00   50
 27  \w    126.00 157.00   0.50    1.41    --  110.00  77.00-120.00   62
 28  \w    114.00 146.00   0.50    1.41    --   82.00  74.00-143.66   64
 29  \w    105.00 141.00   0.50    1.41    --  110.00  38.00-120.00   72
 30  \w    101.00 144.00   0.50    1.41    --  110.00  57.00-180.00   86
 31  \w    106.00 135.00   0.50    1.41    --  110.00  19.00-120.00   58
 32  \w     99.00 177.00   0.50    1.41    --  110.00  38.00 -30.00  156
 33  \w    131.00 175.00   0.50    1.41    --  110.00  77.00  60.00   88
 34  \w    128.00 163.00   0.50    1.41    --  110.00  77.00  90.00   70
 35  \w    119.00 176.00   0.50    1.41    --  110.00  77.00  30.00  114
 36  \w    123.00 174.00   0.50    1.41    --  110.00  77.00 120.00  102
 37  \w    117.00 143.00   0.50    0.40    --   74.00  68.00 163.15   52
 38  \w    109.00 151.00   0.50    1.41    --   86.00  75.00 175.91   84
 39  \w     98.00 124.00   0.50    0.40    --   74.00  79.00 103.49   52
 40  \w     99.00 159.00   0.50    1.41    --  110.00  38.00 150.00  120
 41  \w     98.00 132.00   0.50    1.41    --  110.00  38.00  30.00   68
 42  \w     89.00 115.00   0.50    1.41    --  110.00  77.00   0.00   52
 43  \w     86.00 112.00   0.50    1.41    --  110.00  77.00 -60.00   52
 44  \w     87.00 123.00   0.50    1.41    --  110.00  77.00-120.00   72
 45  \w     96.00 160.00   0.50    1.41    --  110.00 125.00-150.00  128
 46  \w     87.00 161.00   0.50    1.41    --  110.00  77.00 -90.00  148
 47  \w     98.00 128.00   0.50    1.41    --  110.00  38.00  60.00   60
 48  \w     98.00 145.00   0.50    1.41    --  110.00  38.00  90.00   94
 49  \w     90.00 115.00   0.50    1.41    --  110.00  77.00 120.00   50
 50  \w     87.00 112.00   0.50    1.41    --  110.00  77.00  60.00   50
 51  \w     87.00 112.00   0.50    1.41    --  110.00  77.00  30.00   50
 52  \w     87.00 121.00   0.50    1.41    --  110.00  77.00  90.00   68
 53  \w     54.00  84.00   0.50    0.40    --   74.00  68.00 163.15   60
 54  \w     64.00 112.00   0.50    0.40    --   78.00  58.00 146.62   96
 55  \w     63.00 105.00   0.50    1.41    --   86.00  75.00 175.91   84
 56  \w     50.00  89.00   0.50    0.40    --   74.00  79.00 103.49   78
 57  \w     45.00  71.00   0.50    0.40    --   70.00  80.00 164.42   52
 58  \w     34.00  60.00   0.50    0.40    --   48.62  57.00  90.00   52
 59  \w     34.00  59.00   0.50    0.40    --   58.00  80.00 115.88   50
 60  \w     39.00  66.00   0.50    0.40    --   58.00  78.00 143.86   54
 61  \w     26.00  59.00   0.50    0.40    --   48.62  77.00 120.00   66
 62  \w     26.00  60.00   0.50    0.40    --   50.00  77.00  58.93   68
 63  \w     28.00  54.00   0.50    0.40    --   48.62  77.00   0.00   52
 64  \w     34.00  78.00   0.50    0.40    --   58.00  78.00 -80.11   88
 65  \w     62.00  97.00   0.50    1.41    --   82.00  74.00-143.66   70
 66  \w     66.00  97.00   0.50    0.40    --   48.62  19.00-120.00   62
 67  \w     60.00  96.00   0.50    1.41    --   82.00  74.00 -96.52   72
 68  \w     40.00  65.00   0.50    0.40    --   48.62  19.00-120.00   50
 69  \w     34.00  75.00   0.50    0.40    --   48.62  57.00-120.00   82
 70  \w     50.00  77.00   0.50    0.40    --   74.00  78.00-134.63   54
 71  \w     35.00  63.00   0.50    0.40    --   58.00  77.00-110.97   56
 72  \w     26.00  51.00   0.50    0.40    --   48.62  77.00-120.00   50
 73  \w     33.00  76.00   0.50    0.40    --   48.62  57.00-180.00   86
 74  \w     39.00  68.00   0.50    1.41    --  110.00 -57.00-180.00   58
 75  \w     56.00 105.00   0.50    1.41    --  110.00 -99.00-180.00   98
 76  \w     60.00 121.00   0.50    0.40    --   48.62-178.00-120.00  122
 77  \w     78.00 113.00   0.50    1.41    --  110.00-125.00 -60.00   70
 78  \w     45.00 107.00   0.50    1.41    --  110.00 -98.00 -20.31  124
 79  \w     85.00 112.00   0.50    1.41    --  110.00-125.00  60.00   54
 80  \w     69.00 105.00   0.50    1.41    --  110.00 -99.00  90.00   72
 81  \w     39.00  66.00   0.50    1.41    --  110.00 -57.00 150.00   54
 82  \w     39.00  66.00   0.50    1.41    --  110.00 -57.00  90.00   54
 83  \w     40.00  65.00   0.50    1.41    --  110.00 -57.00  30.00   50
 84  \w     38.00  64.00   0.50    1.41    --  110.00 -57.00   0.00   52
 85  \w     40.00  95.00   0.50    1.41    --  110.00 -99.00 -90.00  110
 86  \w     42.00  81.00   0.50    1.41    --  110.00-125.00  60.00   78
 87  \w    -82.00 -14.00   0.50    1.41    --  -70.00 125.00 -90.00  136
 88  \w     70.00 106.00   0.50    0.40    --   48.62 178.00 -30.00   72
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy, Dualflex, Pilatus 300K'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      0.1437360000
_diffrn_orient_matrix_UB_12      -0.0169495000
_diffrn_orient_matrix_UB_13      -0.0135849000
_diffrn_orient_matrix_UB_21      0.0218984000
_diffrn_orient_matrix_UB_22      0.1652335000
_diffrn_orient_matrix_UB_23      0.0406007000
_diffrn_orient_matrix_UB_31      0.0226102000
_diffrn_orient_matrix_UB_32      -0.0522286000
_diffrn_orient_matrix_UB_33      0.1328524000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           'Cu K\a'
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0391
_diffrn_reflns_av_unetI/netI     0.0245
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.983
_diffrn_reflns_limit_h_max       13
_diffrn_reflns_limit_h_min       -13
_diffrn_reflns_limit_k_max       11
_diffrn_reflns_limit_k_min       -11
_diffrn_reflns_limit_l_max       14
_diffrn_reflns_limit_l_min       -12
_diffrn_reflns_number            25423
_diffrn_reflns_point_group_measured_fraction_full 0.998
_diffrn_reflns_point_group_measured_fraction_max 0.961
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         80.158
_diffrn_reflns_theta_min         4.006
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    2.105
_exptl_absorpt_correction_T_max  1.000
_exptl_absorpt_correction_T_min  0.622
_exptl_absorpt_correction_type   gaussian
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.40.68a (Rigaku Oxford Diffraction, 2019)
Numerical absorption correction based on gaussian integration over
			a multifaceted crystal model
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            'clear light yellow'
_exptl_crystal_colour_lustre     clear
_exptl_crystal_colour_modifier   light
_exptl_crystal_colour_primary    yellow
_exptl_crystal_density_diffrn    1.406
_exptl_crystal_description       plank
_exptl_crystal_F_000             456
_exptl_crystal_size_max          0.278
_exptl_crystal_size_mid          0.111
_exptl_crystal_size_min          0.043
_refine_diff_density_max         0.230
_refine_diff_density_min         -0.187
_refine_diff_density_rms         0.038
_refine_ls_abs_structure_details
;
 Refined as an inversion twin.
;
_refine_ls_abs_structure_Flack   0.316(15)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.072
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     309
_refine_ls_number_reflns         4341
_refine_ls_number_restraints     117
_refine_ls_restrained_S_all      1.067
_refine_ls_R_factor_all          0.0299
_refine_ls_R_factor_gt           0.0286
_refine_ls_shift/su_max          0.000
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0390P)^2^+0.2427P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0755
_refine_ls_wR_factor_ref         0.0764
_reflns_Friedel_coverage         0.832
_reflns_Friedel_fraction_full    0.995
_reflns_Friedel_fraction_max     0.935
_reflns_number_gt                4178
_reflns_number_total             4341
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d2sc05182f2.cif
_cod_data_source_block           jb250920_1_1
_cod_database_code               1567876
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         C18H25ClN2O
_reflns_odcompleteness_completeness 100.00
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     66.97
_olex2_refinement_description
;
1. Twinned data refinement
 Scales: 0.684(15)
 0.316(15)
2. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H) groups, All N(H,H) groups
3. Restrained distances
 H2B-H2A
 1.44 with sigma of 0.02
 N2-H2A = N2-H2B
 0.93 with sigma of 0.02
 N1-H1
 0.93 with sigma of 0.02
 F1A-F2A \\sim F2A-F3A \\sim F3A-F1A \\sim F1B-F2B \\sim F2B-F3B \\sim F3B-F1B
 with sigma of 0.02
 F1A-C1A \\sim F3B-C1B \\sim F2B-C1B \\sim F2A-C1A \\sim F1B-C1B \\sim F3A-C1A
 with sigma of 0.02
 C2A-C1B \\sim C2A-C1A
 with sigma of 0.02
4. Rigid body (RIGU) restrains
 C2A, F1A, C1A, F2A, F3A, O1A, O2A, C1B, F2B, F3B, F1B
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
5. Others
 Sof(C1B)=Sof(F2B)=Sof(F3B)=Sof(F1B)=1-FVAR(1)
 Sof(F1A)=Sof(F2A)=Sof(F3A)=Sof(C1A)=FVAR(1)
6.a Ternary CH refined with riding coordinates:
 C7(H7), C12(H12), C16(H16)
6.b Secondary CH2 refined with riding coordinates:
 C8(H8A,H8B), C10(H10A,H10B), C11(H11A,H11B), C13(H13A,H13B), C14(H14A,H14B),
 C15(H15A,H15B), C17(H17A,H17B), C18(H18A,H18B)
6.c Aromatic/amide H refined with riding coordinates:
 C2(H2), C3(H3), C4(H4), C5(H5)
;
_shelx_res_checksum              75026
_olex2_date_sample_data_collection 2020-09-25
_olex2_date_sample_submission    2020-09-23
_olex2_submission_original_sample_id jb250920_1_1
_olex2_submission_special_instructions 'No special instructions were received'
_oxdiff_exptl_absorpt_empirical_details
;
Empirical correction (ABSPACK) includes:
- Absorption correction using spherical harmonics
- Frame scaling
;
_oxdiff_exptl_absorpt_empirical_full_max 1.369
_oxdiff_exptl_absorpt_empirical_full_min 0.791