6-Bromo- N -(3-(diﬂuoromethyl)phenyl)quinolin -4-amine

: A routine synthesis was performed to furnish the title compound which incorporates a versatile diﬂuoromethyl group on the aniline substitution of a 4-anilinoquinoline kinase inhibitor motif. In addition, the small molecule crystal structure (of the HCL salt) was solved, which uncovered that the diﬂuoromethyl group was disordered within the packing arrangement and also a 126.08(7) ◦ out of plane character between the respective ring systems within the molecule. The compound was fully characterized with 1 H / 13 C-NMR and high-resolution mass spectra (HRMS), with the procedures described.


Crystal Structure of 8
A crystallographic analysis revealed 8 crystallized as the chloride salt with the difluoromethyl group disordered over two positions with approximate proportions of 70:30 throughout the crystal ( Figure 3). The molecule comprises two planar moieties. The quinoline moiety, i.e., N1 and C1-C9 exhibits a root mean square (r.m.s.) deviation of 0.006 Å with the maximum deviation from the plane being −0.011 Å for C2. The r.m.s. deviation of the difluoromethylphenyl moiety, i.e., C10-C15, is 0.009 Å with C12 and C15 displaying the maximum deviation of −0.012 Å and −0.013 Å, respectively. The dihedral angle between the two aforementioned planes is 126.08 (7). The C3-N2 bond distance of 1.342(3) Å is indicative of a double bond character in this bond consistent with conjugation in the quinoline moiety. All other bond distances and angles are within expected limits.
The chloride anion is integral to the solid-state structure. The structure comprises corrugated "tapes" of 8H + hydrogen bonded to Cl − via the quinoline N-H + and aniline N-H, respectively (N-

Crystal Structure of 8
A crystallographic analysis revealed 8 crystallized as the chloride salt with the difluoromethyl group disordered over two positions with approximate proportions of 70:30 throughout the crystal ( Figure 3). The molecule comprises two planar moieties. The quinoline moiety, i.e., N1 and C1-C9 exhibits a root mean square (r.m.s.) deviation of 0.006 Å with the maximum deviation from the plane being −0.011 Å for C2. The r.m.s. deviation of the difluoromethylphenyl moiety, i.e., C10-C15, is 0.009 Å with C12 and C15 displaying the maximum deviation of −0.012 Å and −0.013 Å, respectively. The dihedral angle between the two aforementioned planes is 126.08 (7). The C3-N2 bond distance of 1.342(3) Å is indicative of a double bond character in this bond consistent with conjugation in the quinoline moiety. All other bond distances and angles are within expected limits.
The chloride anion is integral to the solid-state structure. The structure comprises corrugated "tapes" of 8H + hydrogen bonded to Cl − via the quinoline N-H + and aniline N-H, respectively (N-Scheme 1. Synthesis route to furnish 4-anilinoquinoline (8).

Crystal Structure of 8
A crystallographic analysis revealed 8 crystallized as the chloride salt with the difluoromethyl group disordered over two positions with approximate proportions of 70:30 throughout the crystal ( Figure 3). The molecule comprises two planar moieties. The quinoline moiety, i.e., N1 and C1-C9 exhibits a root mean square (r.m.s.) deviation of 0.006 Å with the maximum deviation from the plane being −0.011 Å for C2. The r.m.s. deviation of the difluoromethylphenyl moiety, i.e., C10-C15, is 0.009 Å with C12 and C15 displaying the maximum deviation of −0.012 Å and −0.013 Å, respectively. The dihedral angle between the two aforementioned planes is 126.08 (7) • . The C3-N2 bond distance of 1.342(3) Å is indicative of a double bond character in this bond consistent with conjugation in the quinoline moiety. All other bond distances and angles are within expected limits.

Discussion
We demonstrated a robust route to access the title compound (8) in excellent yield. This methodology lends itself to rapid library development as previously described [6][7][8][9][10][22][23][24][25][26][27][28][29]. The diversity of commercial and easy to synthetically access heterocycles and substitution patterns provide an endless wealth of possibilities and expandable chemical space to tune the 4-anilino-quin(az)oline scaffold properties for the discovery of new chemical tools and probes.

Chemistry
All reactions were performed using flame-dried round-bottomed flasks or reaction vessels. Where appropriate, reactions were carried out under an inert atmosphere of nitrogen with dry solvents, unless otherwise stated. Yields refer to chromatographically and spectroscopically pure isolated yields. Reagents were purchased at the highest commercial quality and used without further purification. Reactions were monitored by thin-layer chromatography carried out on 0.25 mm E. Merck silica gel plates (60 F-254 ) using ultraviolet light as visualizing agent. NMR spectra were recorded on a Varian Inova 400 (Varian, Palo Alto, CA, USA) and were calibrated using residual undeuterated solvent as an internal reference (CDCl 3 : 1 H-NMR = 7.26, 13 C-NMR = 77.16). The following abbreviations or combinations thereof were used to explain the multiplicities observed: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Liquid chromatography (LC) and high-resolution mass spectra (HRMS) were recorded on a ThermoFisher hybrid LTQ FT (ICR 7T) (ThermoFisher, Waltham, MA, USA). The University of Southampton (Southampton, UK) small molecule x-ray facility collected and analyzed all X-ray diffraction data (Supplementary Materials). (8), 6-bromo-4-chloroquinoline (150 mg, 0.62 mmol, 1 eq) and 3-(difluoromethyl)aniline (97.3 mg, 0.68 mmol, 1.1 eq) were suspended in ethanol (10 mL) and refluxed for 18 h. This was followed by the addition of i Pr 2 NEt (0.225 mL, 1.36 mmol, 2.2 eq.). The reaction mixture was concentrated in vacuo and extracted with ethyl acetate/saturated ammonium chloride. The title compound was then purified by flash chromatography using EtOAc: hexane followed by 1-5% methanol in EtOAc. The solvent was concentrated in vacuo and the product was obtained as a light beige solid (179 mg, 0.5134 mmol, 83%).

Crystallography
Single colorless plate-shaped crystals of 8H + Cl − were crystallized from EtOH/water and several drops of dioxane/HCL (4 M). A suitable crystal 0.16 × 0.10 × 0.02 mm 3 was selected and mounted on a MITIGEN holder (MiTeGen, Ithaca, NY, USA) in perfluoroether oil on a Rigaku FRE+ equipped with VHF Varimax confocal mirrors and an AFC12 goniometer and HyPix 6000 detector. The crystal was kept at a steady T = 100(2) K during data collection. The structure was solved with the ShelXT [30] structure solution program using the using dual methods solution method and by using Olex2 [31] as the graphical interface. The model was refined with version 2018/3 of ShelXL [32] using full matrix least squares minimization on F 2 minimization. All non-hydrogen atoms were refined anisotropically. Hydrogen atom positions were calculated geometrically and refined using the riding model except for those bonded to N-atoms which were located in the difference map and refined with a riding model. The difluoromethyl group was disordered over two positions (ca. 70:30). Thermal restraints and 1,2 and 1,3 equal distance geometric restraints applied to all equivalent atom pairs of disorder components. Equal distance geometric restraints were additionally applied to all C-F bonds.
Crystal Data for C 16  Supplementary Materials: The following are available online, 1 H and 13 C NMR spectra and the crystallographic data for Compound 8H + Cl − in crystallographic information file (CIF) format. CCDC 2036373 also contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http: //www.ccdc.cam.ac.uk/conts/retrieving.html.