Organometallic complex and organic electroluminescent device comprising same

Abstract

Provided is an organometallic complex, which contributes to substantial improvements in the luminous color and luminous efficiency of an organic electroluminescent device. An organic electroluminescent device according to the present invention comprises: a first electrode; a second electrode; one or more organic layers disposed between the first electrode and the second electrode; and an emission layer, wherein the emission layer contains an organometallic complex represented by chemical formula 1 of the present invention.

Description

Organometallic complexes and organic electroluminescent devices containing the same

[0001] The present invention relates to an organic metal complex and an organic electroluminescent device including the same, and more particularly, to an organic electroluminescent device having high luminous efficiency and a novel organic metal complex therefor.

[0002] In the display industry, OLED (Organic Light Emitting Diodes) is attracting attention as a display that utilizes the self-luminous phenomenon.

[0003] In OLEDs, the first attempt at carrier-injected electroluminescence (EL) using a single crystal of the aromatic hydrocarbon anthracene was made by Pope et al. in 1963. From this research, the basic mechanisms of charge injection, recombination, exciton generation, and luminescence in organic materials, as well as electroluminescence characteristics, have been understood and studied.

[0004] In particular, various approaches are being taken to increase luminous efficiency, including structural changes in the device and material development [Sun, S., Forrest, SR, Appl. Phys. Lett. 91, 263503 (2007) / Ken-Tsung Wong, Org. Lett., 7, 2005, 5361-5364].

[0005] The basic structure of an OLED display is generally composed of a multilayer structure of an anode, a hole injection layer (HIL), a hole transporting layer (HTL), an emission layer (EML), an electron transporting layer (ETL), and a cathode, and the electro-organic multilayer film is formed in a sandwich structure between two electrodes.

[0006] Generally, organic light emitting diodes (OLEDs) are devices that convert electrical energy into light energy using organic materials. Organic light emitting diodes (OLEDs) typically have a structure comprising an anode, a cathode, and an organic layer between them. These organic layers are often multilayered, composed of different materials, to enhance the efficiency and stability of the device. For example, they may include a hole injection layer, a hole transport layer, a light emitting layer, an electron transport layer, and an electron injection layer.

[0007] In the structure of these organic light-emitting devices, when a voltage is applied between the two electrodes, holes are injected from the anode and electrons are injected from the cathode into the organic layer, and when the injected holes and electrons meet, excitons are formed, and when these excitons fall to the ground state, light is emitted. These organic light-emitting devices are known to have characteristics such as self-luminescence, high brightness, high efficiency, low operating voltage, wide viewing angle, high contrast, and high-speed response.

[0008] Materials used as organic layers in organic light-emitting devices can be classified according to their function into light-emitting materials and charge transport materials, such as hole injection materials, hole transport materials, electron transport materials, and electron injection materials.

[0009] Luminescent materials are available in blue, green, and red depending on their luminescent color, as well as in yellow and orange luminescent materials for better natural color realization. In addition, a host / dopant system can be used as a luminescent material to increase color purity and luminescent efficiency through energy transfer. The principle is that when a small amount of a dopant with a smaller energy band gap and superior luminescent efficiency than the host, which mainly constitutes the luminescent layer, is mixed into the luminescent layer, excitons generated in the host are transported to the dopant, resulting in high efficiency light emission. At this time, the wavelength of the host shifts to the wavelength of the dopant, so light of a desired wavelength can be obtained depending on the type of dopant used.

[0010] To improve the characteristics of light-emitting devices, the use of phosphorescent materials in the light-emitting layer of organic EL devices has been proposed. Phosphorescence, a phenomenon in which light emission occurs from a singlet excited state to a triplet excited state through a nonradiative transition called interstitial crossing, is known to exhibit higher quantum efficiency than fluorescence, a phenomenon in which light emission occurs from a singlet excited state. Using organic compounds exhibiting these properties as light-emitting materials is expected to achieve high luminous efficiency.

[0011] Organic EL devices using these phosphorescent materials have been developed to date using various complexes with iridium as the central metal, but recently, development of complexes with platinum as the central metal is also in progress. Among them, an organic EL device using a red phosphorescent material has been reported that uses the platinum complex (2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphinato-N,N,N,N)platinum(II) (Pt(OEP)) in the light-emitting layer (Patent Document: Japanese Patent Laid-Open No. 2002-175884).

[0012] As described above, various approaches are actively being studied to improve the performance and lifespan of next-generation display devices. Among these, organic EL devices utilizing phosphorescent materials derived from platinum complexes are attracting particular attention for their potential to enhance device characteristics. However, this research is still in its infancy, and numerous challenges remain, including optimization of device luminescence characteristics, luminescence efficiency, color purity, and structure. To address these challenges, the development of novel phosphorescent materials and efficient methods for supplying these materials are urgently needed.

[0013] The present inventors have discovered a compound having a novel structure.

[0014] In addition, it was discovered that when the organic layer of an organic light-emitting device is formed using the novel compound, the device can exhibit effects such as increased efficiency, decreased operating voltage, and increased stability.

[0015] Accordingly, the present invention aims to provide a novel organic metal complex and an organic electroluminescent device using the same.

[0016] The present invention provides an organometallic complex represented by the following chemical formula 1.

[0017] [Chemical Formula 1]

[0018]

[0019] In the above chemical formula 1,

[0020] Z1 is N-(L1) p -Ar1,

[0021] L1 is a substituted or unsubstituted arylene group,

[0022] Ar1 is selected from a substituted or unsubstituted phenyl group, a naphthyl group, a benzofuran group, a benzothiophene group, a benzoxazole group, a benzothiazole group, a dibenzofuran group, a dibenzothiophene group, and a non-aromatic condensed phenyl group,

[0023] A, B, C, and D are each independently selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted non-aromatic aromatic condensed polycyclic group, and an aromatic condensed polycyclic group,

[0024] p is an integer of 1 or 2,

[0025] X1 is O or S,

[0026] X2, X3 and X4 are each independently C or N,

[0027] Among the bonds between X2 and Pt, the bond between X3 and Pt, and the bond between X4 and Pt, one bond is a covalent bond, and among the bonds between X2 and Pt, the bond between X3 and Pt, and the bond between X4 and Pt, the remaining two bonds are coordinate bonds.

[0028] According to another aspect of the present invention, an organic electroluminescent device comprising the above-described organometallic complex is provided.

[0029] According to another aspect of the present invention, an organic light-emitting device is provided, comprising a first electrode, a second electrode, and at least one organic layer disposed between the electrodes, wherein the organic layer includes the organic metal complex.

[0030] According to another aspect of the present invention, an organic electroluminescent device is provided, characterized in that the organic metal complex is included in any one layer selected from the group consisting of an electron blocking layer, an electron transport layer, an electron injection layer, a functional layer having both an electron transport function and an electron injection function, and a light-emitting layer constituting the organic material layer.

[0031] The novel organometallic complex according to the present invention can be used as an organic material layer material for organic electronic devices, including organic light-emitting devices, by introducing various aryl groups, heteroaryl groups, etc. Organic electronic devices, including organic light-emitting devices, using the compound represented by Chemical Formula 1 according to the present invention as an organic material layer material exhibit excellent characteristics in terms of efficiency, operating voltage, lifespan, etc.

[0032] FIG. 1 is a schematic cross-sectional view of an organic light-emitting device according to one embodiment of the present invention.

[0033] As used herein, the term "aryl" means a polyunsaturated, aromatic, hydrocarbon substituent which may be a single ring or multiple rings (one to three rings) fused or covalently bonded together, unless otherwise specified.

[0034] The term "heteroaryl" means an aryl group (or ring) containing from one to four heteroatoms selected from N, O and S (in each separate ring in the case of multiple rings), the nitrogen and sulfur atoms being optionally oxidized and the nitrogen atom(s) being optionally quaternized. The heteroaryl group may be bonded to the remainder of the molecule through carbon or a heteroatom.

[0035] The above aryl includes a single or fused ring system, suitably containing 4 to 7 ring atoms in each ring, preferably 5 or 6 ring atoms. It also includes a structure in which one or more aryls are bonded through a chemical bond. Specific examples of the above aryl include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, phenanthryl, triphenylenyl, pyrenyl, perylenyl, chrysenyl, naphthacenyl, pyrenyl, fluoranthenyl, and the like.

[0036] The above heteroaryl includes a 5-6 membered monocyclic heteroaryl, and a polycyclic heteroaryl fused with one or more benzene rings, and may be partially saturated. Also included is a structure in which one or more heteroaryls are bonded via a chemical bond. The above heteroaryl group includes a divalent aryl group in which a heteroatom within the ring is oxidized or quaternized to form, for example, an N-oxide or a quaternary salt.

[0037] Specific examples of the above heteroaryl include monocyclic heteroaryls such as furyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothiophenyl, isobenzofuranyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, isoindolyl, indolyl, indazolyl, benzothiadiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenanthridinyl, Polycyclic heteroaryls such as benzodioxolyl and their corresponding N-oxides (e.g., pyridyl N-oxide, quinolyl N-oxide), quaternary salts thereof, etc. are included, but are not limited thereto.

[0038] As used herein, the term "substituted or unsubstituted" means that one or more hydrogen atoms in a hydrocarbon are each, independently of one another, replaced by the same or different substituent. Useful substituents include, but are not limited to, the following:

[0039] These substituents are, -F; -Cl; -Br; -CN; -NO2; -OH; C1~C20 alkyl group unsubstituted or substituted with -F, -Cl, -Br, -CN, -NO2 or -OH; C1~C20 alkoxy group unsubstituted or substituted with -F, -Cl, -Br, -CN, -NO2 or -OH; C6~C30 aryl group unsubstituted or substituted with C1~C20 alkyl group, C1~C20 alkoxy group, -F, -Cl, -Br, -CN, -NO2 or -OH; C6~C30 heteroaryl group unsubstituted or substituted with C1~C20 alkyl group, C1~C20 alkoxy group, -F, -Cl, -Br, -CN, -NO2 or -OH; It may be at least one selected from the group consisting of a C1~C20 alkyl group, a C1~C20 alkoxy group, a C5~C20 cycloalkyl group unsubstituted or substituted with -F, -Cl, -Br, -CN, -NO2 or -OH; a C5~C30 heterocycloalkyl group unsubstituted or substituted with a C1~C20 alkyl group, a C1~C20 alkoxy group, -F, -Cl, -Br, -CN, -NO2 or -OH; and a group represented by -N(G1)(G2). At this time, G1 and G2 may each independently be hydrogen; a C1~C10 alkyl group; or a C6~C30 aryl group unsubstituted or substituted with a C1~C10 alkyl group.

[0040]

[0041] Hereinafter, the present invention will be described in detail.

[0042] An organic metal complex according to one embodiment of the present invention can be represented by the following chemical formula 1.

[0043] [Chemical Formula 1]

[0044]

[0045] In the above chemical formula 1,

[0046] Z1 is N-(L1) p -Ar1,

[0047] L1 is a substituted or unsubstituted arylene group,

[0048] Ar1 is selected from a substituted or unsubstituted phenyl group, a naphthyl group, a benzofuran group, a benzothiophene group, a benzoxazole group, a benzothiazole group, a dibenzofuran group, a dibenzothiophene group, and a non-aromatic condensed phenyl group,

[0049] A, B, C, and D are each independently selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted non-aromatic aromatic condensed polycyclic group, and an aromatic condensed polycyclic group,

[0050] p is an integer of 1 or 2,

[0051] X1 is O or S,

[0052] X2, X3 and X4 are each independently C or N,

[0053] Among the bonds between X2 and Pt, the bond between X3 and Pt, and the bond between X4 and Pt, one bond is a covalent bond, and among the bonds between X2 and Pt, the bond between X3 and Pt, and the bond between X4 and Pt, the remaining two bonds are coordinate bonds.

[0054] The above chemical formula 1 can provide an organometallic complex represented by the following chemical formula 2.

[0055] [Chemical Formula 2]

[0056]

[0057] In the above chemical formula 2,

[0058] R1 to R5 are independently selected from hydrogen, deuterium, CD3, -F, -CF3, an alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted cycloalkyl condensed polycyclic phenyl group,

[0059] a, b, c, d, and e are independently 1, 2, or 3,

[0060] When a, b, c, d and e are two or more, they can optionally combine with each other to form a substituted or unsubstituted carbocyclic group.

[0061] The above chemical formula 2 can provide an organometallic complex represented by any one of the following chemical formulas 2-1 to 2-4.

[0062] [Chemical Formula 2-1]

[0063]

[0064] [Chemical Formula 2-2]

[0065]

[0066] [Chemical Formula 2-3]

[0067]

[0068] [Chemical Formula 2-4]

[0069]

[0070] In the above chemical formulas 2-1 to 2-4,

[0071] R6 to R 21 is hydrogen or methyl group,

[0072] L2, L 3, L4 and L5 are each independently -CH2- or -CH2CH2-.

[0073] Specific examples of the compounds represented by the chemical formula 1 of the present invention include those represented by the following chemical formulas 3 to 6. However, the compounds represented by the chemical formula 1 of the present invention are not limited to the compounds represented by the following chemical formulas 3 to 6.

[0074] [Chemical Formula 3]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

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[0100]

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[0128]

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[0130]

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[0134]

[0135]

[0136]

[0137] [Chemical Formula 4]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

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[0200] [Chemical Formula 5]

[0201]

[0202]

[0203]

[0204]

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[0206]

[0207]

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[0238] [Chemical Formula 6]

[0239]

[0240]

[0241]

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[0270]

[0271]

[0272]

[0273]

[0274]

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[0279]

[0280]

[0281] The organometallic complex represented by the above chemical formula 1 can be synthesized using a known organic synthesis method. The synthesis method of the organometallic complex can be easily understood by those skilled in the art by referring to the manufacturing examples described below.

[0282] In addition, according to the present invention, an organic electroluminescent device including an organic metal complex represented by the above chemical formula 1 is provided.

[0283] The organic metal complex of the above chemical formula 1 is useful as a light-emitting layer material and can be used as a material for other multi-layer organic electroluminescent devices.

[0284] In addition, the organic electroluminescent device according to the present invention includes a first electrode, a second electrode, and at least one organic layer disposed between the electrodes. The organic layer may include at least one organic metal complex represented by the chemical formula 1.

[0285] The first electrode and the second electrode can function as a cathode and an anode, respectively, and have the roles of a cathode and an anode depending on the work function energy position of the electrode material. When voltage is applied, the anode injects holes into the organic layer, and the cathode injects electrons. The injected holes and electrons move through the organic layer in opposite voltage directions. When the moving electrons meet within the van der Waals radius in the organic layer, an electron-hole pair, an "exciton", is formed. Since a hole is a positive polaron, it is actually a particle with a mobility that is one electron short, so when it meets an electron, it receives the missing electron and relaxes to a stable state, and at this time, light is emitted in the amount of the difference in energy between the electron and the hole.

[0286] While OLEDs have traditionally been known to operate solely through the singlet-state emission phenomenon of "fluorescence," recent advances have yielded OLEDs that utilize the triplet-state emission phenomenon of "phosphorescence." This approach utilizes organometallic complexes centered on transition metals such as Ir, Pt, and Re, which possess high heavy-atom effects, to induce light emission from triplet-state electrons, enabling phosphorescent OLEDs to achieve 100% internal quantum efficiency.

[0287] The present invention relates to an organometallic complex to be used as an additive in a light-emitting layer of a phosphorescent OLED having an internal quantum efficiency of 100%.

[0288] Figure 1 illustrates a cross-sectional view of a schematic structure of an organic light-emitting device according to one embodiment of the present invention. The material of each layer is not limited, and any material with electrical and chemical properties suitable for the corresponding role may be used in duplicate.

[0289] The device (100) forms an electrode and an organic layer on a substrate (110), and at this time, a hard or soft material can be used as the substrate material. For example, as a hard material, soda lime glass, alkali-free glass, aluminosilicate glass, etc. can be used, and as a soft material, PC (polycarbonate), PES (polyethersulfone), COC (cyclic olefin copolymer), PET (polyethylene ether phthalate), PEN (polyethylene naphthalate), etc. can be used.

[0290] The anode (120) can be formed on the upper part of the substrate using a material deposition method, electron beam evaporation method, sputtering method, etc. The anode material can be selected from materials having a high work function to facilitate hole injection into the organic light emitting device. Depending on the light emitting direction of the organic light emitting device, a reflective electrode is used for front emission, a transmissive electrode is used for back emission, and a semi-transmissive electrode is used for double-sided emission. These materials are formed using ITO (indium tin oxide), IZO (indium zinc oxide), SnO2 (tin oxide), ZnO (zinc oxide), etc. to an appropriate thickness and are manufactured by controlling the transmittance. Alternatively, it can be manufactured using a metal such as Mg (magnesium), Al (aluminum), Al-Li (aluminum-lithium), Ca (calcium), Mg-In (magnesium-indium), Mg-Ag (magnesium-silver), which is not an oxide. Recently, carbon substrate flexible electrode materials such as CNT (carbon nanotube) and Graphene may also be used.

[0291] The hole injection layer (130), hole transport layer (140), and electron blocking layer (150) are also called hole transport regions and play a role in smoothly injecting and transporting holes into the organic light-emitting device. In general, since the hole mobility of the organic layer is faster than the electron mobility, they have a thickness greater than that of the electron transport region.

[0292] Among the above hole transport regions, the hole injection layer (130) can be formed on the anode by various methods such as vacuum deposition, spin coating, casting, and LB.

[0293] When forming a hole injection layer by vacuum deposition, the deposition conditions can be freely adjusted at a deposition rate of about 1Å / s at 100 to 500°C depending on the compound used as the hole injection layer material, the structure and thermal characteristics of the target hole injection layer, etc., and are not limited to specific conditions.

[0294] When forming a hole injection layer by spin coating, the coating conditions vary depending on the characteristics of the compound used as the hole injection layer material and the layers formed at the interface, but for uniform film formation, coating speed and heat treatment to remove the solvent after coating are required.

[0295] The above hole transport region is, for example, m-MTDATA, TDATA, 2-TNATA, NPB, β-NPB, TPD, Spiro-TPD, Spiro-NPB, methylated-NPB, TAPC, HMTPD, TCTA (4,4',4"-tris(Ncarbazolyl) triphenylamine), Pani / DBSA (Polyaniline / Dodecylbenzenesulfonic acid), PEDOT / PSS (Poly(3,4-ethylenedioxythiophene) / Poly(4-styrene sulfonate)), Pani / CSA (Polyaniline / Camphor sulfonicacid), PANI / PSS (Polyaniline) / Poly(4-styrenesulfonate): It may include polyaniline) / poly(4-styrenesulfonate) etc.

[0296]

[0297]

[0298] The thickness of the above hole transport region can be formed to be about 100 to about 10,000 Å, and the corresponding organic layers of each hole transport region are not limited to the same thickness. For example, if the thickness of the hole injection layer is 50 Å, the thickness of the hole transport layer can be formed to be 1000 Å, and the thickness of the electron blocking layer can be formed to be 500 Å. The thickness condition of the hole transport region can be determined to a degree that satisfies efficiency and lifespan within a range where the driving voltage increase of the organic light-emitting device does not increase significantly.

[0299] The hole transport region, like the emissive layer, can be doped to enhance its properties, and doping of charge-generating materials into this hole transport region can improve the electrical properties of the organic light-emitting device.

[0300] Charge-generating materials are generally composed of materials with very low HOMO and LUMO. For example, the LUMO of the charge-generating material has a value similar to the HOMO of the hole transport layer (215) material. Due to this low LUMO, the empty electron characteristic of the LUMO is utilized to easily transfer holes to the adjacent hole transport layer (215), thereby improving the electrical properties.

[0301] The charge-generating material may be, for example, a p-dopant. The p-dopant may be, but is not limited to, one of a quinone derivative, a metal oxide, and a cyano group-containing compound. For example, non-limiting examples of the p-dopant include, but are not limited to, quinone derivatives such as tetracyanoquinonedimethane (TCNQ) and 2,3,5,6-tetrafluoro-tetracyano-1,4-benzoquinonedimethane (F4-TCNQ); metal oxides such as tungsten oxide and molybdenum oxide; and cyano group-containing compounds.

[0302]

[0303] The electron blocking layer (150) is a layer that prevents electron injection from the electron transport region to the hole transport region. The electron blocking layer not only blocks electrons moving to the hole transport region, but also uses a material having a high T1 value to prevent excitons formed in the light-emitting layer (220) from diffusing into the hole transport region. For example, a host of the light-emitting layer, which generally has a high T1 value, can be used as the electron blocking layer material.

[0304] The light-emitting layer (160) is a region where holes and electrons meet to form excitons. The material forming the light-emitting layer must have an appropriate energy band gap to exhibit high light-emitting characteristics and a desired light-emitting color, and is generally composed of two materials that have two roles as a host and a dopant, but is not limited thereto.

[0305] The above host may include at least one of the following: TPBi, TBADN, ADN (also referred to as "DNA"), CBP, CDBP, TCP, mCP, and the material is not limited thereto, provided the properties are appropriate.

[0306]

[0307] The dopant of the light-emitting layer uses an organic metal compound represented by the chemical formula 1 mentioned in the present invention as a material, and the content of the general dopant can be selected from 0.01% to 20%, but is not limited thereto in some cases.

[0308] An electron transport region is deposited on the light-emitting layer, and the electron transport region is composed of a hole blocking layer (170), an electron transport layer (180), and an electron injection layer (190), and an organic electroluminescent device is manufactured by including at least one organic layer.

[0309] The formation of the above electron transport region is formed under the same conditions as the hole transport region, and the formation conditions and method refer to the hole transport region formation conditions.

[0310] The hole blocking layer (170) in the electron transport region may include one of BCP, Bphen, and Balq below, but the composition of the material may vary depending on the characteristics of the material and the purpose of the organic electroluminescent device.

[0311]

[0312] The electron transport layer (180) may include at least one of the above BCP, Bphen, and the following Alq3, Balq, TAZ, and NTAZ.

[0313]

[0314] The electron transport layer is selected from a material with fast or slow electron mobility depending on the structure of the organic light-emitting device, so a variety of materials must be selected, and in some cases, Liq or Li is doped.

[0315] The electron injection layer (190) is made of a metal material that facilitates the injection of electrons, and may include at least one selected from among LiF, NaCl, CsF, Li2O, and BaO.

[0316] Unlike the anode, the cathode (200) can be used by combining metals, electrically conductive compounds, alloys, etc. that have a relatively low work function. For example, Li (lithium), Mg (magnesium), Al (aluminum), Al-Li (aluminum-lithium), Ca (calcium), Mg-In (magnesium-indium), Mg-Ag (magnesium-silver), etc. can be used as the cathode.

[0317] The cathode's transmittance and material are determined by the light-emitting direction of the organic electroluminescent device. For top-emitting devices, a semi-transparent electrode material and thickness are selected to maximize the micro-resonance effect. For bottom-emitting devices, a material with high reflectivity is selected.

[0318] The above organic light-emitting device can have low voltage operation, high efficiency, and long life by including the organometallic compound applied to the present invention in the light-emitting layer as described above.

[0319] To further illustrate the present specification, examples will be provided in detail. However, the embodiments described herein may be modified in various ways, and the scope of this application is not limited to the embodiments described below. The embodiments of this application are provided to more fully explain the present specification to those of average skill in the art.

[0320]

[0321] [Manufacturing example]

[0322] Intermediate synthesis example 1: Synthesis of intermediate (1)

[0323]

[0324] After adding 6.7 g (223.5 mmol) of paraformaldehyde, 8.9 g (149.1 mmol) of magnesium chloride and 200 mL of THF, 20.8 mL (149.1 mmol) of TEA was slowly added dropwise. After stirring at room temperature for 10 minutes, 10.0 g (74.5 mmol) of 2,3-dihydro-1H-inden-5-ol was added little by little over 20 minutes, and then stirred under reflux overnight. After removing the solvent by concentration under reduced pressure, DCM and distilled water were added, and the organic layer was extracted. The mixture was washed with 1 N HCl aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:n-hexane) to obtain 11.2 g (yield: 92.6%) of a compound (intermediate (1)) as a pale yellow liquid.

[0325]

[0326] Intermediate synthesis example 2: Synthesis of intermediate (4)

[0327]

[0328] (Synthesis of intermediate (2))

[0329] 5-(tert-butyl)-[1,1'-biphenyl]-2-amine (50.0 g, 221.9 mmol) and tetrahydrofuran (1000.0 mL) were mixed and cooled to -78°C. 2.5 M n-BuLi (in Hexanes) (97.6 mL, 244.1 mmol) was slowly added dropwise at -78°C, and the mixture was stirred for 1 hour. 1-bromo-3-fluoro-2-nitrobenzene (58.6 g, 266.3 mmol) was dissolved in 118.0 mL of tetrahydrofuran, and the mixture was slowly added dropwise at -78°C, and the mixture was stirred for 30 minutes. After stirring for 30 minutes, the mixture was stirred at room temperature for one day. After the reaction was completed, the organic matter was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: n-Hexanes), and then recrystallized from hexane (n-Hexanes) to obtain 65.1 g (yield: 69.0%) of an orange solid compound (intermediate (2)).

[0330] (Synthesis of intermediate (3))

[0331] Intermediate (2) 65.1 g (153.1 mmol), Fe 42.7 g (765.3 mmol), and ethanol (EtOH) 976.5 mL were mixed, and 153.1 mL (306.2 mmol) of 2.0 M NH4Cl aqueous solution was added and refluxed and stirred for one day. After the reaction was completed, the reaction solution was filtered through a pad of celite using dichloromethane to remove inorganic substances, and then the organic substances were extracted with dichloromethane. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol and hexane to obtain 30.8 g (yield: 50.9%) of an off-white solid compound (intermediate (3)).

[0332] (Synthesis of intermediate (4))

[0333] Intermediate (3) 5.0 g (12.7 mmol), intermediate (1) 2.5 g (15.2 mmol), Na2S2O5 2.9 g (15.2 mmol), and dimethylformamide 80.0 mL were mixed and stirred at 130°C for one day. After the reaction was completed, the organic matter was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: n-Hexanes), and then solidified with dichloromethane and methanol to obtain 4.1 g (yield: 60.3%) of a pale yellow solid compound (intermediate (4)).

[0334]

[0335] Intermediate synthesis example 3: Synthesis of intermediate (7)

[0336]

[0337] (Synthesis of intermediate (5))

[0338] In a nitrogen atmosphere, 20.0 g (83.5 mmol) of 2-chloro-4-iodopyridine, 12.2 g (100.0 mmol) of phenylboronic acid, 2.8 g (2.5 mmol) of tetrakis(triphenylphosphine)palladium(0), and 23.0 g (167.0 mmol) of potassium carbonate were added to a mixture of 300 mL of toluene, 75 mL of ethanol, and 75 mL of distilled water, and the mixture was reacted for 12 hours while maintaining the temperature at 75-80 °C. After the reaction was completed, extraction was performed with distilled water and dichloromethane, and the mixture was treated with anhydrous magnesium sulfate (MgSO4) and filtered. The filtered solution was distilled under reduced pressure, and the resulting reaction mixture was purified by silica gel column chromatography (DCM: n-Hexanes) and dried to obtain 13.2 g (yield: 83.3%) of a yellow liquid compound (intermediate (5)).

[0339] (Synthesis of intermediate (6))

[0340] In a nitrogen atmosphere, 13.2 g (69.6 mmol) of intermediate (5), 15.6 g (73.0 mmol) of (3-(tert-butyl)-5-chlorophenyl)boronic acid, 2.4 g (2.0 mmol) of tetrakis(triphenylphosphine)palladium(0), and 19.2 g (139.2 mmol) of potassium carbonate were added to a mixture of 200 mL of toluene, 50 mL of ethanol, and 50 mL of distilled water, and the mixture was reacted for 12 hours while maintaining the temperature at 75-80°C. After completion of the reaction, extraction was performed with distilled water and dichloromethane, and the mixture was treated with anhydrous magnesium sulfate (MgSO4) and filtered. The filtered solution was distilled under reduced pressure, and the resulting reaction mixture was purified by silica gel column chromatography (DCM:n-Hexanes) and dried to obtain 21.9 g (yield: 97.7%) of a brown liquid compound (intermediate (6)).

[0341] (Synthesis of intermediate (7))

[0342] Intermediate (6) 21.9 g (68.3 mmol), PIN2B 226.0 g (102.4 mmol), Pd(dba) 22.0 g (3.4 mmol), XPhos 3.6 g (10.2 mmol), KOAc 16.8 g (170.6 mmol) and toluene 341 mL were mixed and refluxed and stirred for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic matter was extracted using toluene. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 18.3 g (yield: 65.0%) of a gray solid compound (intermediate (7)).

[0343]

[0344] Intermediate synthesis example 4: Synthesis of intermediate (8)

[0345]

[0346] Intermediate (4) 5.0 g (9.3 mmol), intermediate (7) 4.6 g (11.2 mmol), Pd(OAc)2104.4 mg (0.5 mmol), SPhos 572.8 mg (1.4 mmol), K2CO3 3.9 g (27.9 mmol), xylene 100 mL, and distilled water 10 mL were mixed, then refluxed and stirred for 4 hours. After the reaction was completed, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.3 g (yield: 47.7%) of a pale yellow solid compound (intermediate (8)).

[0347]

[0348] Intermediate synthesis example 5: Synthesis of intermediate (11)

[0349]

[0350] (Synthesis of intermediate (9))

[0351] 2-chloro-4-iodopyridine (50.0 g, 208.8 mmol), (4-fluorophenyl)boronic acid (35.1 g, 250.6 mmol), Pd(PPh3) (47.2 g, 6.3 mmol), K2CO3 (72.1 g, 522.0 mmol), toluene (500 mL), ethanol (EtOH) (125 mL), and H2O (125 mL) were mixed and stirred at 70°C for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite using toluene, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with dichloromethane and hexane to obtain 38.7 g (yield: 89.4%) of an orange solid compound (intermediate (9)).

[0352] (Synthesis of intermediate (10))

[0353] Intermediate (9) 38.7 g (186.4 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 51.5 g (242.3 mmol), Pd(PPh3) 46.5 g (5.6 mmol), K2CO 364.4 g (466.0 mmol), toluene 621 mL, ethanol (EtOH) 155 mL, and H2O 155 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 63.3 g (yield: 100.0%) of a yellow oily compound (intermediate (10)).

[0354] (Synthesis of intermediate (11))

[0355] Intermediate (10) 63.3 g (186.3 mmol), PIN2B 261.5 g (242.2 mmol), Pd(dba) 23.2 g (5.6 mmol), XPhos 8.9 g (18.6 mmol), KOAc 54.9 g (558.9 mmol) and toluene 931 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with dichloromethane and methanol to obtain 45.7 g (yield: 56.9%) of an off-white solid compound (intermediate (11)).

[0356]

[0357] Intermediate synthesis example 6: Synthesis of intermediate (13)

[0358]

[0359] Intermediate (4) 5.0 g (9.3 mmol), intermediate (12) 4.8 g (11.2 mmol), Pd(OAc) 2104.4 mg (0.5 mmol), SPhos 572.8 mg (1.4 mmol), K2CO 3 3.9 g (27.9 mmol), xylene 100 mL and distilled water 10 mL were mixed and refluxed and stirred for 4 hours. After the reaction was completed, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 2.9 g (yield: 40.9%) of a pale yellow solid compound (intermediate (13)).

[0360]

[0361] Intermediate synthesis example 7: Synthesis of intermediate (15)

[0362]

[0363] (Synthesis of intermediate (14))

[0364] 20.0 g (149.1 mmol) of 2,3-dihydro-1H-inden-5-ol and 100 mL of dichloromethane were mixed and cooled to 0°C. 18.0 mL (223.6 mmol) of pyridine was added, followed by the slow addition of 37.6 mL (223.6 mmol) of trifluoromethanesulfonic anhydride. The mixture was stirred at 0°C for 30 minutes and then at room temperature for one day. After the reaction was complete, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 39.6 g (yield: 100.0%) of a yellow liquid compound (intermediate (14)).

[0365] (Synthesis of intermediate (15))

[0366] Intermediate (14) 39.6 g (148.7 mmol), PIN2B 249.1 g (193.4 mmol), Pd(dppf)Cl2DCM 3.6 g (4.5 mmol), KOAc 36.5 g (371.9 mmol) and toluene 743 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 30.0 g (yield: 82.6%) of intermediate (15) as a yellow liquid.

[0367]

[0368] Intermediate synthesis example 8: Synthesis of intermediate (18)

[0369]

[0370] (Synthesis of intermediate (16))

[0371] 2-chloro-4-iodopyridine (25.0 g (104.4 mmol), intermediate (15) (30.6 g (125.3 mmol), Pd(PPh3) (43.6 g (3.1 mmol), K2CO3 (36.1 g (261.0 mmol), toluene (260 mL), ethanol (EtOH) (130 mL), and H2O (130 mL)) were mixed and stirred at 70°C for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water, and the extracted organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered through silica gel and celite using toluene, and the solvent was removed by concentration under reduced pressure to obtain 20.0 g (yield: 83.3%) of the compound (intermediate (16)) as a yellow liquid.

[0372] (Synthesis of intermediate (17))

[0373] Intermediate (16) 20.0 g (87.1 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 22.2 g (104.5 mmol), Pd(PPh3) 43.0 g (2.6 mmol), K2CO3 30.1 g (217.7 mmol), toluene 445.0 mL, ethanol (EtOH) 111.2 mL, and H2O 111.2 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 26.5 g (yield: 89.4%) of a yellow oily compound (intermediate (17)).

[0374] (Synthesis of intermediate (18))

[0375] Intermediate (17) 26.5 g (73.2 mmol), PIN2B 227.9 g (109.8 mmol), Pd(dba) 22.1 g (3.7 mmol), XPhos 3.8 g (11.0 mmol), KOAc 18.0 g (183.1 mmol) and toluene 366 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water and dried over anhydrous magnesium sulfate. The residue was filtered through silica gel and celite using toluene, and the solvent was removed by concentration under reduced pressure. The obtained reaction mixture was solidified with methanol to obtain 20.1 g (yield: 60.5%) of an off-white solid compound (intermediate (18)).

[0376]

[0377] Intermediate synthesis example 9: Synthesis of intermediate (19)

[0378]

[0379] Intermediate (4) 5.0 g (9.3 mmol), intermediate (18) 5.1 g (11.2 mmol), Pd(OAc) 2104.4 mg (0.5 mmol), SPhos 572.8 mg (1.4 mmol), K2CO 3 3.9 g (27.9 mmol), xylene 100 mL, and distilled water 10 mL were mixed, then refluxed and stirred for 4 hours. After the reaction was completed, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 2.5 g (yield: 34.2%) of a pale yellow solid compound (intermediate (19)).

[0380]

[0381] Intermediate synthesis example 10: Synthesis of intermediate (21)

[0382]

[0383] (Synthesis of intermediate (20))

[0384] 20.0 g (135.0 mmol) of 5,6,7,8-tetrahydronaphthalen-2-ol and 200.0 mL of dichloromethane were mixed and cooled to 0°C. 16.3 mL (202.4 mmol) of pyridine was added, followed by slow addition of 34.2 mL (202.4 mmol) of trifluoromethanesulfonic anhydride. The mixture was stirred at 0°C for 30 minutes and then at room temperature for one day. After the reaction was complete, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 37.8 g (yield: 100.0%) of a yellow liquid compound (intermediate (20)).

[0385] (Synthesis of intermediate (21))

[0386] Intermediate (20) 37.8 g (134.9 mmol), PIN2B 244.5 g (175.4 mmol), Pd(dppf)Cl2DCM 3.3 g (4.0 mmol), KOAc 33.1 g (337.3 mmol) and toluene 756 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 27.5 g (yield: 78.9%) of intermediate (21) as a yellow liquid.

[0387]

[0388] Intermediate synthesis example 11: Synthesis of intermediate (24)

[0389]

[0390] (Synthesis of intermediate (22))

[0391] 2-chloro-4-iodopyridine (21) 21.3 g (88.8 mmol), intermediate (21) 27.5 g (106.5 mmol), Pd(PPh3) 43.1 g (2.7 mmol), K2CO3 30.7 g (222.0 mmol), toluene 444 mL, ethanol (EtOH) 111 mL, and H2O 111 mL were mixed and stirred at 70°C for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water, and the extracted organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered through silica gel and celite using toluene, and the solvent was removed by concentration under reduced pressure to obtain 21.7 g (yield: 100.0%) of the compound (intermediate (22)) as a yellow liquid.

[0392] (Synthesis of intermediate (23))

[0393] Intermediate (22) 21.7 g (89.0 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 22.7 g (106.8 mmol), Pd(PPh3) 43.1 g (2.7 mmol), K2CO3 30.8 g (222.5 mmol), toluene 445 mL, ethanol (EtOH) 111 mL, and H2O 111 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 33.5 g (yield: 100.0%) of a yellow oily compound (intermediate (23)).

[0394] (Synthesis of intermediate (24))

[0395] Intermediate (23) 33.5 g (89.1 mmol), PIN2B 229.4 g (115.8 mmol), Pd(dba) 21.5 g (2.7 mmol), XPhos 4.2 g (8.9 mmol), KOAc 26.2 g (267.3 mmol) and toluene 445 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water and then dried over anhydrous magnesium sulfate. The residue was filtered through silica gel and celite using toluene, and the solvent was removed by concentration under reduced pressure. The obtained reaction mixture was solidified with methanol to obtain 28.6 g (yield: 68.7%) of an off-white solid compound (intermediate (24)).

[0396]

[0397] Intermediate synthesis example 12: Synthesis of intermediate (25)

[0398]

[0399] Intermediate (4) 5.0 g (9.3 mmol), intermediate (24) 5.2 g (11.2 mmol), Pd(OAc)2104.4 mg (0.5 mmol), SPhos 572.8 mg (1.4 mmol), K2CO3 3.9 g (27.9 mmol), xylene 100 mL, and distilled water 10 mL were mixed, then refluxed and stirred for 4 hours. After the reaction was completed, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 2.2 g (yield: 29.6%) of a pale yellow solid compound (intermediate (25)).

[0400]

[0401] Intermediate synthesis example 13: Synthesis of intermediate (29)

[0402]

[0403] (Synthesis of intermediate (26))

[0404] 74.5 g (509.0 mmol) of 2,5-dimethylhexan-2,5-diol and 1.1 L of 35% aqueous hydrochloric acid were added, and the mixture was stirred at room temperature for 1 hour. After stirring at room temperature for 3 hours, the resulting solid was filtered and washed with 500 mL of distilled water. The obtained solid was dissolved in dichloromethane (DCM) and washed twice with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 85.7 g (yield: 91.9%) of the compound (intermediate (26)) as a white solid.

[0405] (Synthesis of intermediate (27))

[0406] Intermediate (26) 48.9 g (223 mmol), phenol 20.0 g (213.0 mmol), and dichloromethane (DCM) 200 mL were added, and the mixture was cooled to -5 to 5 °C. At -5 to 5 °C, AlCl 3 28.3 g (213.0 mmol) was added little by little over 30 minutes, and the mixture was stirred at -5 to 5 °C for 2 hours. The reactant was slowly added dropwise to ice water, and the organic layer was extracted. The organic layer was washed with distilled water and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was recrystallized from hexane to obtain 39.1 g (yield: 90.1%) of the compound (intermediate (27)) as a white solid.

[0407] (Synthesis of intermediate (28))

[0408] After adding 39.1 g (191.0 mmol) of intermediate (27), 23.1 mL (287.0 mmol) of pyridine, and 400 mL of DCM, the mixture was cooled to 4–10°C. At 4–10°C, 40.2 mL (239.0 mmol) of Tf2O was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. After adding distilled water to terminate the reaction, the organic layer was extracted and washed with 1H HCl aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 65.1 g (yield: 100.0%) of the compound (intermediate (28)) as a yellow liquid.

[0409] (Synthesis of intermediate (29))

[0410] Intermediate (28) 65.1 g (194.0 mmol), PIN2B 273.7 g (290.0 mmol), PdCl2dppf·DCM 5.7 g (7.7 mmol), KOAc 57.0 g (581.0 mmol), and dioxane 600 mL were added, and the mixture was refluxed overnight. After cooling to room temperature, the solvent was removed under reduced pressure, and distilled water was added. The reactant was extracted with dichloromethane, and the separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to remove the solvent. After dissolving in DCM / n-hexane, the mixture was passed through a silica gel pad. The filtrate was concentrated, slurried with methanol for 1 hour, and filtered to obtain 50.0 g (yield: 82.2%) of the compound (intermediate (29)) as a white solid.

[0411]

[0412] Intermediate synthesis example 14: Synthesis of intermediate (32)

[0413]

[0414] (Synthesis of intermediate (30))

[0415] 15.8 g (50.1 mmol) of intermediate (29) and 10.0 g (41.8 mmol) of 2-chloro-4-iodopyridine, 41.5 g (1.3 mmol) of Pd(PPh3), 11.2 g (104.0 mmol) of Na2CO3, 100 mL of toluene, 20 mL of ethanol, and 20 mL of distilled water were added, and the mixture was stirred at 65°C for one day. Distilled water was added, and the mixture was cooled to room temperature. The organic layer was extracted and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hexanes), and then slurried with n-hexane to obtain 7.9 g (yield: 63.1%) of the compound (intermediate (30)) as a white solid.

[0416] (Synthesis of intermediate (31))

[0417] Intermediate (30) 8.0 g (26.7 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 7.4 g (34.7 mmol), Pd(PPh3) 41.5 g (1.3 mmol), K2CO 3 9.2 g (66.8 mmol), toluene 133 mL, ethanol (EtOH) 33 mL, and H2O 33 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 11.5 g (yield: 100.0%) of a compound (intermediate (31)) as a light-colored solid.

[0418] (Synthesis of intermediate (32))

[0419] Intermediate (31) 11.5 g (26.6 mmol), PIN2B2 10.1 g (39.9 mmol), Pd2(dba)2 730.7 mg (0.8 mmol), XPhos 1.3 g (2.7 mmol), KOAc 6.5 g (66.5 mmol) and toluene 177 Ml were mixed and refluxed and stirred for one day. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 10.5 g (yield: 75.5%) of a yellow solid compound (intermediate (32)).

[0420]

[0421] Intermediate synthesis example 15: Synthesis of intermediate (33)

[0422]

[0423] Intermediate (4) 5.0 g (9.3 mmol), intermediate (32) 5.8 g (11.2 mmol), Pd(OAc)2104.4 mg (0.5 mmol), SPhos 556.1 mg (1.4 mmol), K2CO3 3.9 g (27.9 mmol), xylene 100 mL, and distilled water 10 mL were mixed, then refluxed and stirred for 4 hours. After the reaction was completed, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 2.8 g (yield: 35.2%) of a pale yellow solid compound (intermediate (33)).

[0424]

[0425] Intermediate synthesis example 16: Synthesis of intermediate (38)

[0426]

[0427] (Synthesis of intermediate (34))

[0428] 20.0 g (134.0 mmol) of 4-(tert-butyl)aniline and 400 mL of acetonitrile were mixed and cooled to 0°C. 23.9 g (134.0 mmol) of N-bromosuccinimide was slowly added at 0°C and stirred at room temperature for one day. After completion of the reaction, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure to remove the solvent to obtain 32.1 g (yield: 100.0%) of a red liquid compound (intermediate (34)).

[0429] (Synthesis of intermediate (35))

[0430] Intermediate (34) 32.1 g (140.7 mmol), benzofuran-2-ylboronic acid 34.2 g (211.1 mmol), Pd(PPh3) 48.1 g (7.0 mmol), 2.0 M Cs2CO3 176.0 mL (351.8 mmol) of an aqueous solution and 703 mL of tetrahydrofuran were mixed and stirred at 70°C for one day. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 26.6 g (yield: 71.4%) of a red liquid compound (intermediate (35)).

[0431] (Synthesis of intermediate (36))

[0432] Intermediate (35) 26.6 g (100.2 mmol) and tetrahydrofuran 532 mL were mixed and cooled to -78°C. 2.0 M n-BuLi (in cyclohexane) 60.1 mL (120.3 mmol) was slowly added dropwise at -78°C, and stirred for 1 hour. 1-bromo-3-fluoro-2-nitrobenzene 26.5 g (120.3 mmol) was dissolved in 53 mL of tetrahydrofuran, and slowly added dropwise at -78°C, and stirred for 1 hour. After stirring for 1 hour, the mixture was stirred at room temperature for 1 day. After the reaction was completed, the organic layer was extracted using dichloromethane and distilled water, and the extracted organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) and then recrystallized with hexane and ethanol to obtain 21.6 g (yield: 46.3%) of an orange solid compound (intermediate (36)).

[0433] (Synthesis of intermediate (37))

[0434] Intermediate (36) 21.6 g (46.4 mmol), Fe 15.5 g (278.5 mmol), and ethanol (EtOH) 432 mL were mixed, and 2.0 M NH4Cl aqueous solution 46.4 mL (92.8 mmol) was added and refluxed and stirred for 3 hours. After the reaction was completed, the reaction solution was filtered through a pad of Celite to remove inorganic substances, and the organic layer was extracted with dichloromethane. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 18.0 g (yield: 89.6%) of a red liquid compound (intermediate (37)).

[0435] (Synthesis of intermediate (38))

[0436] Intermediate (37) 10.0 g (23.0 mmol), intermediate (1) 4.5 g (27.6 mmol), Na2S2O5 5.2 g (27.6 mmol) and dimethylformamide (N,N'-Dimethylformamide) 200.0 mL were mixed and stirred at 130°C for one day. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then recrystallized from dichloromethane and methanol to obtain 7.8 g (yield: 58.8%) of an off-white solid compound (intermediate (38)).

[0437]

[0438] Intermediate synthesis example 17: Synthesis of intermediate (41)

[0439]

[0440] (Synthesis of intermediate (39))

[0441] 2-chloro-4-iodopyridine (50.0 g, 208.8 mmol), 4-tolylboronic acid (34.1 g, 250.5 mmol), Pd(PPh3) (47.2 g, 6.3 mmol), Na2CO3 (55.3 g, 522.0 mmol), toluene (1044 mL), ethanol (EtOH) (261 mL), and H2O (261 mL) were mixed and stirred at 65°C for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes) and then solidified with hexane to obtain 26.5 g (yield: 62.3%) of a white solid compound (intermediate (39)).

[0442] (Synthesis of intermediate (40))

[0443] Intermediate (39) 30.0 g (147.3 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 40.7 g (191.5 mmol), Pd(PPh3) 48.5 g (7.4 mmol), K2CO3 61.1 g (441.9 mmol), toluene 589 mL, ethanol (EtOH) 147 mL, and H2O 147 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol to obtain 42.5 g (yield: 86.0%) of a gray solid compound (intermediate (40)).

[0444] (Synthesis of intermediate (41))

[0445] Intermediate (40) 42.5 g (126.5 mmol), PIN2B 248.2 g (189.8 mmol), Pd(dba) 23.6 g (6.3 mmol), XPhos 9.0 g (19.0 mmol), KOAc 31.0 g (316.3 mmol), and toluene 632 mL were mixed, then refluxed and stirred for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 36.0 g (yield: 66.6%) of the compound (intermediate (41)) as a gray solid.

[0446]

[0447] Intermediate synthesis example 18: Synthesis of intermediate (42)

[0448]

[0449] Intermediate (38) 3.0 g (5.2 mmol), intermediate (41) 2.7 g (6.2 mmol), Pd(OAc) 258.3 mg (0.3 mmol), SPhos 310.5 mg (0.8 mmol), K2CO3 2.2 g (15.6 mmol), xylene 57 mL, and H2O 6 mL were mixed and stirred at 130°C for 2 hours. After the reaction was completed, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then recrystallized with dichloromethane and methanol to obtain 3.6 g (yield: 86.8%) of the compound (intermediate (42)) as an off-white solid.

[0450]

[0451] Intermediate synthesis example 19: Synthesis of intermediate (46)

[0452]

[0453] (Synthesis of intermediate (43))

[0454] In a nitrogen atmosphere, 17.5 g (76.7 mmol) of intermediate (34), 17.1 g (80.0 mmol) of dibenzo[b,d]furan-4-ylboronic acid, 2.6 g (2.3 mmol) of tetrakis(triphenylphosphine)palladium(0), and 21.2 g (153.4 mmol) of potassium carbonate were added to a mixture of 300 mL of toluene, 75 mL of ethanol, and 75 mL of distilled water, and the mixture was reacted for 12 hours while maintaining the temperature at 75-80°C. After completion of the reaction, extraction was performed with distilled water and dichloromethane, and the mixture was treated with anhydrous magnesium sulfate and filtered. The filtered solution was concentrated under reduced pressure, and the resulting reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) and dried to obtain 18.1 g (yield: 74.8%) of a transparent liquid compound (intermediate (43)).

[0455] (Synthesis of intermediate (44))

[0456] In a nitrogen atmosphere, 18.1 g (57.3 mmol) of intermediate (43) was dissolved in 200 mL of tetrahydrofuran, cooled to -78°C, 31.5 mL (63.1 mmol) of n-butyllithium (2.0 M) was slowly added dropwise, and the mixture was stirred for 1 hour while maintaining -78°C. Then, 13.8 g (63.1 mmol) of 1-bromo-3-fluoro-2-nitrobenzene was dissolved in 100 mL of tetrahydrofuran, slowly added dropwise while maintaining -78°C, and reacted for 12 hours. After completion of the reaction, extraction was performed with distilled water and dichloromethane, and the mixture was filtered after treating with anhydrous magnesium sulfate. The filtered solution was concentrated under reduced pressure, and the resulting reaction mixture was purified by silica gel column chromatography (CHCl3:Hexanes) and dried to obtain 14.8 g (yield: 50.1%) of a red liquid compound (intermediate (44)).

[0457] (Synthesis of intermediate (45))

[0458] Intermediate (44) 14.9 g (28.9 mmol), iron (Fe) 8.0 g (144.5 mmol), and 28 mL of 1 M ammonium chloride aqueous solution were mixed in 300 mL of ethanol, and stirred at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through Celite, extracted with distilled water and dichloromethane, treated with anhydrous magnesium sulfate, and filtered. The filtered solution was concentrated under reduced pressure, and the obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) and dried to obtain 10.4 g (yield: 74.1%) of a yellow liquid compound (intermediate (45)).

[0459] (Synthesis of intermediate (46))

[0460] Intermediate (45) 10.4 g (21.4 mmol), intermediate (1) 4.2 g (25.7 mmol), and Na2S2O5 4.9 g (25.7 mmol) were mixed in 150 mL of dimethylformamide, and stirred at 110°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, extracted with water and dichloromethane, treated with anhydrous magnesium sulfate, and filtered. The filtered solution was concentrated under reduced pressure, and the obtained reaction mixture was purified by silica gel column chromatography (CHCl3:Hexanes) and solidified with hexane to obtain 12.5 g (yield: 92.9%) of a white solid compound (intermediate (46)).

[0461]

[0462] Intermediate synthesis example 20: Synthesis of intermediate (47)

[0463]

[0464] In a nitrogen atmosphere, 6.0 g (9.6 mmol) of intermediate (46), 4.9 g (11.5 mmol) of intermediate (41), 0.1 g (0.5 mmol) of tetrakis(triphenylphosphine)palladium(0), and 4.0 g (28.7 mmol) of potassium carbonate were added to a mixture of 200 mL of toluene, 50 mL of ethanol, and 50 mL of distilled water, and the mixture was reacted at 75 to 80°C for 24 hours. After the reaction was completed, extraction was performed with distilled water and dichloromethane, and the mixture was filtered after treating with anhydrous magnesium sulfate. The filtered solution was concentrated under reduced pressure, and the obtained reaction mixture was purified by silica gel column chromatography (EA: Hexanes) and solidified with methanol to obtain 1.8 g (yield: 22.2%) of the compound (intermediate (47)) as a yellow solid.

[0465]

[0466] Intermediate synthesis example 21: Synthesis of intermediate (48)

[0467]

[0468] 7 mL (48.9 mmol) of triethylamine, 4.8 g (50.2 mmol) of MgCl, 2.2 g (73.4 mmol) of paraformaldehyde, and 50 mL of tetrahydrofuran were added, and the mixture was stirred at room temperature for 30 minutes. 5.0 g (24.5 mmol) of intermediate (27) was dissolved in 5 mL of tetrahydrofuran, slowly added dropwise, and stirred under reflux for 12 hours. 1 M aqueous HCl solution and EtOAc were added, and the organic layer was separated. The separated organic layer was concentrated. The concentrate was purified by silica gel column chromatography (DCM: Hexanes), and recrystallization was performed under DCM and Hexanes solvent conditions to obtain 4.1 g (yield: 72.7%) of the compound (intermediate (48)) as a white solid.

[0469]

[0470] Intermediate synthesis example 22: Synthesis of intermediate (49)

[0471]

[0472] Intermediate (3) 5.0 g (12.7 mmol), intermediate (48) 3.2 g (13.9 mmol), sodium metabisulfite 3.1 g (16.4 mmol), and DMF 50 mL were mixed and stirred at 120°C for 12 hours. After completion of the reaction, distilled water and DCM were added, and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM:Hexanes), recrystallization was performed under DCM / Hexanes solvent conditions to obtain 2.4 g (yield: 31.6%) of the compound (Intermediate (49)) as an ivory solid.

[0473]

[0474] Intermediate synthesis example 23: Synthesis of intermediate (50)

[0475]

[0476] Intermediate (49) 2.4 g (4.0 mmol), intermediate (41) 1.9 g (4.3 mmol), Pd(PPh3) 40.1 g (0.1 mmol), K2CO3 1.6 g (11.9 mmol), 20 mL toluene, 8 mL distilled water, and 4 mL ethanol were added and stirred under reflux overnight. After cooling to room temperature, DCM and distilled water were added, and the organic layer was separated. The separated organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / Hexanes), recrystallization was performed under DCM / Hexanes solvent conditions to obtain 2.6 g (yield: 80.7%) of the compound (intermediate (50)) as a white solid.

[0477]

[0478] Intermediate synthesis example 24: Synthesis of intermediate (55)

[0479]

[0480] (Synthesis of intermediate (51))

[0481] 30.0 g (186.2 mmol) of 4-(trifluoromethyl)aniline and 600 mL of acetonitrile were mixed and cooled to 0°C. 33.2 g (186.2 mmol) of N-bromosuccinimide was slowly added at 0°C and stirred at room temperature for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure to remove the solvent to obtain 44.7 g (yield: 100.0%) of a yellow liquid compound (intermediate (51)).

[0482] (Synthesis of intermediate (52))

[0483] Intermediate (51) 44.7 g (186.2 mmol), phenylboronic acid 29.5 g (242.1 mmol), Pd(PPh3) 410.8 g (9.3 mmol), K2CO3 77.2 g (558.6 mmol), toluene 745 mL, ethanol (EtOH) 186 mL, and H2O 186 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) and then solidified with cooled hexane to obtain 37.4 g (yield: 84.7%) of a white solid compound (intermediate (52)).

[0484] (Synthesis of intermediate (53))

[0485] Intermediate (52) 20.0 g (84.3 mmol) and tetrahydrofuran 400 mL were mixed and cooled to -78°C. 2.5 M n-BuLi (in Hexanes) 37.1 mL (92.7 mmol) was slowly added dropwise at -78°C, and the mixture was stirred for 1 hour. 1-bromo-3-fluoro-2-nitrobenzene 22.3 g (101.2 mmol) was dissolved in 44.5 mL of tetrahydrofuran, and the mixture was slowly added dropwise at -78°C, and the mixture was stirred for 30 minutes. The mixture was stirred at room temperature for 1 day. After the reaction was completed, the organic matter was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) and then recrystallized with ethanol to obtain 12.4 g (yield: 33.6%) of an orange solid compound (intermediate (53)).

[0486] (Synthesis of intermediate (54))

[0487] Intermediate (53) 12.3 g (28.1 mmol), Fe 9.4 g (168.8 mmol), and ethanol (EtOH) 246 mL were mixed, and 1.0 M NH4Cl aqueous solution 56 mL (56.2 mmol) was added and refluxed for 3 hours. After the reaction was completed, the reaction solution was filtered through a celite pad using dichloromethane to remove inorganic substances, and then concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract the organic layer. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure to remove the solvent to obtain 11.4 g (yield: 100.0%) of a pale brown solid compound (intermediate (54)).

[0488] (Synthesis of intermediate (55))

[0489] Intermediate (54) 9.6 g (23.5 mmol), intermediate (48) 6.0 g (25.8 mmol), Na2S2O55.4 g (28.2 mmol) and dimethylformamide 191 mL were mixed and stirred at 120°C for one day. After the reaction was completed, it was cooled to room temperature and distilled water was added to precipitate a solid. The precipitated solid was washed with distilled water and filtered under reduced pressure. The obtained solid was dissolved in dichloromethane, dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 7.9 g (yield: 54.1%) of a compound (intermediate (55)) as an off-white solid.

[0490]

[0491] Intermediate synthesis example 25: Synthesis of intermediate (56)

[0492]

[0493] Intermediate (55) 3.5 g (5.6 mmol), intermediate (41) 3.1 g (7.3 mmol), Pd(OAc) 263.4 mg (0.3 mmol), SPhos 344.8 mg (0.8 mmol), K2CO3 2.3 g (16.8 mmol), xylene 70 mL, and distilled water 8 mL were mixed, and then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.5 g (yield: 74.7%) of the compound (intermediate (56)) as an off-white solid.

[0494]

[0495] Intermediate synthesis example 26: Synthesis of intermediate (60)

[0496]

[0497] (Synthesis of intermediate (57))

[0498] 50.0 g (0.281 mol) of 4-(4-methoxyphenyl)butan-2-one and 500 mL of THF were added, and the mixture was cooled to 0°C. At 0°C, 121 mL (3.0 M in diethyl ether, 365.0 mmol) of MeMgBr was slowly added dropwise, and the mixture was stirred for 3 hours. After quenching the reaction with an aqueous NH4Cl solution, the solvent was removed under reduced pressure. Distilled water and DCM were added, and the organic layer was separated and washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexanes) to obtain 42.3 g (yield: 77.6%) of the compound (intermediate (57)) as a pale yellow liquid.

[0499] (Synthesis of intermediate (58))

[0500] Intermediate (57) 42.3 g (218.0 mmol) and H3PO4 340 mL (6.5 mol) were mixed and stirred at 120°C overnight. The reaction mixture was cooled to room temperature and poured into ice water, and then DCM was added to extract the organic layer. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM: Hexanes) to obtain 10.6 g (yield: 27.6%) of the compound (intermediate (58)) as a transparent liquid.

[0501] (Synthesis of intermediate (59))

[0502] Intermediate (58) 10.6 g (60.1 mmol) was mixed with 100 mL of DCM, and then cooled to 0°C. At 0°C, BBr 38.6 mL (90.2 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. After quenching the reaction with distilled water, additional DCM was added, and the organic layer was separated. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was slurried with hexanes to obtain 8.6 g (yield: 88.3%) of the compound (intermediate (59)) as a white solid.

[0503] (Synthesis of intermediate (60))

[0504] 4.8 g (159.0 mmol) of paraformaldehyde, 10.1 g (106.0 mmol) of magnesium chloride, and 200 mL of THF were added, and then 14.8 mL (106 mmol) of triethylamine (TEA) was slowly added dropwise. After stirring at room temperature for 10 minutes, 8.6 g (53.0 mmol) of intermediate (59) was added little by little over 20 minutes, and then stirred under reflux overnight. After removing the solvent by concentration under reduced pressure, DCM and distilled water were added, and the organic layer was separated. It was washed with 1 N HCl aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexanes) to obtain 9.8 g (yield: 97.2%) of the compound (intermediate (60)) as a pale yellow liquid.

[0505]

[0506] Intermediate synthesis example 27: Synthesis of intermediate (61)

[0507]

[0508] Intermediate (3) 4.0 g (10.1 mmol), intermediate (60) 2.3 g (12.1 mmol), Na2S2O5 2.3 g (12.1 mmol) and dimethylformamide 80 mL were mixed and stirred at 130°C for one day. After the reaction was completed, the organic matter was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.8 g (yield: 65.8%) of the compound (intermediate (61)) as a pale yellow solid.

[0509]

[0510] Intermediate synthesis example 28: Synthesis of intermediate (62)

[0511]

[0512] Intermediate (61) 3.0 g (5.3 mmol), intermediate (41) 2.7 g (6.4 mmol), Pd(OAc) 259.5 mg (0.3 mmol), SPhos 326.4 mg (0.8 mmol), K2CO3 2.2 g (15.9 mmol), xylene 60 mL, and distilled water 7 mL were mixed, then refluxed and stirred for 4 hours. After the reaction was completed, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 2.6 g (yield: 63.4%) of a pale yellow solid compound (intermediate (62)).

[0513]

[0514] Intermediate synthesis example 29: Synthesis of intermediate (64)

[0515]

[0516] (Synthesis of intermediate (63))

[0517] Intermediate (39) 32.9 g (161.7 mmol), 2-(3-chloro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 53.1 g (210.3 mmol), Pd(PPh3) 49.3 g (8.1 mmol), K2CO3 55.9 g (404.3 mmol), toluene 539 mL, ethanol (EtOH) 134 mL, and H2O 134 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes) to obtain 42.7 g (yield: 90.2%) of a pale yellow oily compound (intermediate (63)).

[0518] (Synthesis of intermediate (64))

[0519] Intermediate (63) 42.7 g (145.3 mmol), PIN2B 255.3 g (218.0 mmol), Pd2(dba) 34.0 g (4.4 mmol), XPhos 6.9 g (14.5 mmol), KOAc 35.6 g (363.3 mmol) and toluene 854 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 33.7 g (yield: 60.2%) of the compound (intermediate (64)) as an off-white solid.

[0520]

[0521] Intermediate synthesis example 30: Synthesis of intermediate (65)

[0522]

[0523] Intermediate (55) 3.5 g (5.6 mmol), intermediate (64) 2.8 g (7.3 mmol), Pd(OAc) 263.4 mg (0.3 mmol), SPhos 344.8 mg (0.8 mmol), K2CO3 2.3 g (16.8 mmol), xylene 70 mL, and distilled water 8 mL were mixed, and then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.3 g (yield: 73.9%) of the compound (intermediate (65)) as an off-white solid.

[0524]

[0525] Intermediate synthesis example 31: Synthesis of intermediate (70)

[0526]

[0527] (Synthesis of intermediate (66))

[0528] 4-Aminotoluene (30.0 g, 200.0 mmol) was mixed with dichloromethane, and the mixture was cooled to 10°C while stirring. NBS (35.7 g, 200.0 mmol) was slowly added dropwise, and the mixture was stirred at room temperature overnight. After quenching the reaction with distilled water, the layers were separated to remove the aqueous layer. The organic layer was dried over anhydrous magnesium sulfate and filtered. The concentrate was purified by silica gel column chromatography (DCM: Hexanes) to obtain 39.4 g (yield: 86.4%) of the compound (intermediate (66)) as a red liquid.

[0529] (Synthesis of intermediate (67))

[0530] Intermediate (66) 11.2 g (60.0 mmol), phenylboronic acid 8.8 g (72.2 mmol), Pd(PPh3) 43.4 g (3.0 mmol), K2CO3 24.8 g (180.0 mmol), toluene 110 mL, ethanol 55 mL, and distilled water 55 mL were mixed. The reaction mixture was stirred under reflux overnight. After the reaction was quenched with distilled water, the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (DCM:Hexanes) to obtain 10.2 g (yield: 93.5%) of the compound (intermediate (67)) as a red liquid.

[0531] (Synthesis of intermediate (68))

[0532] Intermediate (67) 10.2 g (55.6 mmol) and THF 200 mL were mixed and cooled to -78°C while stirring. 2.0 M n-BuLi 24.4 ml (61.0 mmol) and 1-bromo-3-fluoro-2-nitrobenzene 12.2 g (55.6 mmol) were added dropwise, stirred at -78°C for 1 hour, and then stirred at room temperature overnight. After quenching the reaction with distilled water, ethyl acetate and distilled water were added to the reaction solution, and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (DCM: Hexanes) to obtain 15.1 g (yield: 70.9%) of a red liquid compound (intermediate (68)).

[0533] (Synthesis of intermediate (69))

[0534] Intermediate (68) 15.1 g (39.3 mmol), Fe 10.1 g (197.0 mmol), NH4Cl 2.1 g (39.3 mmol), ethanol 150 mL, and distilled water 29 mL were added. The reaction mixture was stirred under reflux overnight. After completion of the reaction, the reaction solution was filtered through Celite at 70°C. The filtrate was concentrated under reduced pressure, and dichloromethane and distilled water were added to the concentrate, and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (DCM: Hexanes) to obtain 12.5 g (yield: 90.5%) of the compound (intermediate (69)) as a red liquid.

[0535] (Synthesis of intermediate (70))

[0536] Intermediate (69) 3.5 g (9.9 mmol), intermediate (48) 2.3 g (9.9 mmol), Na2S2O5 2.2 g (11.8 mmol), and DMF 35 mL were mixed. The reaction mixture was stirred at 110°C overnight. After the reaction was quenched with distilled water, the reaction solution was extracted with dichloromethane. The extracted organic layer was washed with brine and distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (DCM: Hexanes) to obtain 3.1 g (yield: 55.3%) of the compound (intermediate (70)) as a beige solid.

[0537]

[0538] Intermediate synthesis example 32: Synthesis of intermediate (71)

[0539]

[0540] Intermediate (70) 3.1 g (5.5 mmol), intermediate (64) 2.5 g (6.6 mmol), Pd(PPh3) 40.3 g (0.2 mmol), K2CO3 2.3 g (16.4 mmol), toluene 30 mL, ethanol 15 mL, and distilled water 15 mL were mixed. The reaction mixture was stirred under reflux overnight. After the reaction was quenched with distilled water, the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (EtOAc:Hexanes) and crystallized from hexane to obtain 3.0 g (yield: 75.0%) of the compound (intermediate (71)) as a pale beige solid.

[0541]

[0542] Intermediate synthesis example 33: Synthesis of intermediate (74)

[0543]

[0544] (Synthesis of intermediate (72))

[0545] 2-chloro-4-iodopyridine (20.0 g, 83.5 mmol), 4-(tert-butyl)phenyl)boronic acid (16.4 g, 91.9 mmol), Pd(PPh3) (42.9 g, 2.5 mmol), K2CO3 (34.6 g, 250.6 mmol), 210 mL toluene, 70 mL ethanol, and 70 mL distilled water were mixed and stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (Hexanes: CHCl3) to obtain 20.1 g (yield: 97.9%) of a red liquid compound (intermediate (72)).

[0546] (Synthesis of intermediate (73))

[0547] Intermediate (72) 20.1 g (81.8 mmol), 3-(tert-butyl)-5-chlorophenyl)boronic acid 17.4 g (81.8 mmol), Pd(PPh3) 44.7 g (4.1 mmol), K2CO3 33.9 g (245.4 mmol), 240 mL toluene, 80 mL ethanol and 80 mL distilled water were mixed and then stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (CHCl3) to obtain 23.8 g (yield: 77.0%) of a yellow solid compound (intermediate (73)).

[0548] (Synthesis of intermediate (74))

[0549] Intermediate (73) 23.8 g (63.0 mmol), pinacol diboron (Bis(pinacolato)diboron) 24.0 g (94.5 mmol), Pd(dba) 21.8 g (3.2 mmol), X-Phos 3.0 g (6.3 mmol), KOAc 18.5 g (188.9 mmol) and xylene 250 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, passed through a silica gel pad (Hex:EA), concentrated under reduced pressure, and purified with hexane to obtain 23.1 g (yield: 78.1%) of the compound (intermediate (74)) as a white solid.

[0550]

[0551] Intermediate synthesis example 34: Synthesis of intermediate (75)

[0552]

[0553] Intermediate (49) 3.5 g (5.8 mmol), intermediate (74) 3.3 g (6.9 mmol), Pd(OAc) 264.7 mg (0.3 mmol), SPhos 344.3 mg (0.9 mmol), K2CO3 2.4 g (17.3 mmol), xylene 70 mL, and distilled water 8 mL were mixed, and then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.3 g (yield: 65.8%) of the compound (intermediate (75)) as an off-white solid.

[0554]

[0555] Intermediate synthesis example 35: Synthesis of intermediate (78)

[0556]

[0557] (Synthesis of intermediate (76))

[0558] 2-chloro-4-iodopyridine (10.0 g (41.8 mmol), (4-(methyl-d3)phenyl)boronic acid) (6.4 g (45.9 mmol), Pd(PPh3) (41.4 g (1.3 mmol), K2CO3 (14.4 g (104.4 mmol), toluene (200 mL), ethanol (50 mL), and distilled water (50 mL)) were mixed and reacted at 80°C for one day. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was purified by silica gel column chromatography (toluene), obtaining 7.6 g (yield: 88.0%) of a yellow solid compound (intermediate (76)).

[0559] (Synthesis of intermediate (77))

[0560] Intermediate (76) 7.6 g (36.8 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 10.2 g (47.8 mmol), Pd(PPh3) 41.3 g (1.1 mmol), K2CO3 12.7 g (91.9 mmol), toluene 180 mL, ethanol 45 mL, and distilled water 45 mL were mixed and stirred at 90°C for one day. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extracted with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was filtered through a silica gel pad (toluene) and solidified with nuclease to obtain 10.4 g (yield: 83.5%) of a white solid compound (intermediate (77)).

[0561] (Synthesis of intermediate (78))

[0562] Intermediate (77) 10.4 g (30.7 mmol), pinacol diboron (Bis(pinacolato)diboron) 9.4 g (36.8 mmol), Pd(dba) 2882.3 mg (1.5 mmol), KOAc 9.0 g (98.1 mmol), X-Phos 1.5 g (3.1 mmol) and toluene 150 mL were mixed and reacted at 110 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad (tol), and the obtained mixture was purified by silica gel column chromatography (CHCl3:EtOAc) and solidified with nuclease to obtain 10.1 g (yield: 76.5%) of a light yellow solid compound (intermediate (78)).

[0563]

[0564] Intermediate synthesis example 36: Synthesis of intermediate (79)

[0565]

[0566] Intermediate (49) 6.0 g (9.8 mmol), intermediate (78) 5.1 g (11.8 mmol), Pd(PPh3)4341.2 mg (295.3 μmol), K2CO3 3.4 g (24.6 mmol), toluene 50 mL, ethanol 12 mL, and distilled water 12 mL were mixed and reacted at 90°C for one day. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, filtered, and washed with methanol. The obtained mixture was dissolved in hot toluene, filtered through a silica gel pad, and recrystallized from toluene to obtain 5.3 g (yield: 64.5%) of a white solid compound (intermediate (79)).

[0567]

[0568] Intermediate synthesis example 37: Synthesis of intermediate (82)

[0569]

[0570] (Synthesis of intermediate (80))

[0571] 2-chloro-4-iodopyridine 7.0 g (29.2 mmol), (phenyl-d5)boronic acid 4.1 g (32.2 mmol), Pd(PPh3) 41.7 g (1.5 mmol), K2CO3 10.1 g (73.1 mmol), toluene 90 mL, ethanol 30 mL, and distilled water 30 mL were mixed and then stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (CHCl3) to obtain 5.6 g (yield: 99.1%) of a yellow solid compound (intermediate (80)).

[0572] (Synthesis of intermediate (81))

[0573] Intermediate (80) 3.6 g (18.5 mmol), 3.9 g (18.5 mmol) of 3-(tert-butyl)-5-chlorophenyl)boronic acid, 41.1 g (924.6 μmol) of Pd(PPh3), 7.7 g (55.5 mmol) of K2CO3, 60 mL of toluene, 15 mL of ethanol, and 15 mL of water were mixed and then stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (Hex:DCM=1:2) to obtain 4.6 g (yield: 75.3%) of a yellow liquid compound (intermediate (81)).

[0574] (Synthesis of intermediate (82))

[0575] Intermediate (81) 4.6 g (13.9 mmol), pinacol diboron (Bis(pinacolato)diboron) 5.3 g (20.9 mmol), Pd(dba) 2800.4 mg (1.4 mmol), X-Phos 1.3 g (2.8 mmol), KOAc 4.1 g (41.8 mmol) and xylene 50 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, it was cooled to room temperature, passed through a silica gel pad (CHCl3), and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (Hexanes: EtOAc) to obtain 5.2 g (yield: 88.8%) of the compound (intermediate (82)) as a yellow liquid.

[0576]

[0577] Intermediate synthesis example 38: Synthesis of intermediate (83)

[0578]

[0579] Intermediate (49) 3.5 g (5.7 mmol), intermediate (82) 2.4 g (5.7 mmol), Pd(PPh3)4331.7 mg (287.1 μmol), K2CO32.4 g (17.2 mmol), toluene 20 mL, ethanol 5 mL, and distilled water 5 mL were mixed and then stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (CHCl3) and solidified with a mixed solvent (Acetone / MeOH) to obtain 2.7 g (yield: 57.2%) of the compound (intermediate (83)) as a white solid.

[0580]

[0581] Intermediate synthesis example 39: Synthesis of intermediate (88)

[0582]

[0583] (Synthesis of intermediate (84))

[0584] 60.0 g (611.3 mmol) of 4-methylpent-3-en-2-one and 1380.0 mL of benzene were mixed and cooled to 0°C. 106.0 g (795.0 mmol) of aluminum chloride was slowly added at 0°C and stirred at room temperature for 1 day. After the reaction was complete, the reaction solution was slowly added to ice water and stirred for 1 hour. After stirring for 1 hour, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 92.3 g (yield: 85.7%) of an orange liquid compound (intermediate (84)).

[0585] (Synthesis of intermediate (85))

[0586] Intermediate (84) 104.0 g (590.0 mmol) and tetrahydrofuran 1040.0 mL were mixed and cooled to 0°C. 295.0 mL (885.1 mmol) of a 3.0 M methylmagnesium bromide solution was slowly added at 0°C. After stirring at 0°C for 30 minutes, the mixture was stirred at room temperature for one day. After the reaction was complete, the mixture was cooled to 0°C, distilled water was slowly added to the reaction solution, and the mixture was stirred for 2 hours. After stirring for 2 hours, the organic matter was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent to obtain 108.0 g (yield: 95.2%) of a yellow liquid compound (intermediate (85)).

[0587] (Synthesis of intermediate (86))

[0588] 108.0 g (561.6 mmol) of intermediate (85) was added and cooled to 0°C. 60.2 mL (1.1 mol) of H2SO4 (sulfuric acid) was slowly added at 0°C. The mixture was stirred at 0°C for 3 hours. After the reaction was completed, the organic matter was extracted using ethyl acetate and distilled water. The extracted organic layer was washed with saturated Na2CO3 After washing with an aqueous solution, the mixture was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The resulting reaction mixture was purified by silica gel column chromatography (Hexanes) to obtain 29.5 g (yield: 30.2%) of a transparent liquid compound (intermediate (86)).

[0589] (Synthesis of intermediate (87))

[0590] Intermediate (86) 21.0 g (120.5 mmol) and dichloromethane 420.0 mL were mixed and cooled to 0°C. Bromine 13.0 mL (253.0 mmol) was diluted in dichloromethane 202 mL and slowly added at 0°C. The mixture was stirred at room temperature for one day. After the reaction was completed, saturated Na2S2O5 After adding the aqueous solution, the mixture was stirred for 1 hour. After stirring for 1 hour, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and a celite pad using dichloromethane, and concentrated under reduced pressure to remove the solvent to obtain 30.5 g (yield: 100.0%) of a yellow liquid compound (intermediate (87)).

[0591] (Synthesis of intermediate (88))

[0592] Intermediate (87) 30.5 g (120.5 mmol), B2PIN239.8 g (156.6 mmol), Pd(dppf)Cl2 · DCM 4.9 g (6.0 mmol), KOAc 29.6 g (301.3 mmol), and toluene 610 mL were mixed and refluxed and stirred for 4 hours. After the reaction was completed, the organic layer was extracted using toluene. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) and solidified with methanol to obtain 19.7 g (yield: 54.5%) of the compound (intermediate (88)) as a white solid.

[0593]

[0594] Intermediate synthesis example 40: Synthesis of intermediate (92)

[0595]

[0596] (Synthesis of intermediate (89))

[0597] In a nitrogen atmosphere, 12.0 g (52.6 mmol) of intermediate (34), 19.0 g (63.1 mmol) of intermediate (88), 3.0 g (2.6 mmol) of tetrakis(triphenylphosphine)palladium(0), and 14.5 g (105.2 mmol) of potassium carbonate were added to a mixture of 300 mL of toluene, 75 mL of ethanol, and 75 mL of distilled water, and the mixture was reacted at 75 to 80 °C for 12 hours. After the reaction was completed, extraction was performed with distilled water and dichloromethane, and the mixture was filtered after treating with anhydrous magnesium sulfate. The filtered solution was concentrated under reduced pressure, and the obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) and dried to obtain 15.1 g (yield: 89.2%) of the compound (intermediate (89)) as a transparent liquid.

[0598] (Synthesis of intermediate (90))

[0599] Intermediate (89) 15.1 g (47.0 mmol) and tetrahydrofuran 300 mL were mixed and cooled to -78°C. 2.5 M n-BuLi (in Hexanes) 20.7 mL (51.7 mmol) was slowly added dropwise at -78°C, and the mixture was stirred for 1 hour. 1-bromo-3-fluoro-2-nitrobenzene 12.4 g (56.4 mmol) was dissolved in 30 mL of tetrahydrofuran, and the mixture was slowly added dropwise at -78°C, and the mixture was stirred for 30 minutes. After stirring for 30 minutes, the mixture was stirred at room temperature for 1 day. After the reaction was completed, the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) and then recrystallized with hexane to obtain 17.2 g (yield: 70.2%) of an orange solid compound (intermediate (90)).

[0600] (Synthesis of intermediate (91))

[0601] Intermediate (90) 17.2 g (33.0 mmol), Fe 9.2 g (164.9 mmol), and ethanol (EtOH) 260 mL were mixed, and 33 mL (66.0 mmol) of 2.0 M NH4Cl aqueous solution was added and refluxed and stirred for one day. After the reaction was completed, the reaction solution was filtered through a pad of celite using dichloromethane to remove inorganic substances, and the organic layer was extracted with dichloromethane. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol and hexane to obtain 8.1 g (yield: 49.9%) of a compound (intermediate (91)) as an off-white solid.

[0602] (Synthesis of intermediate (92))

[0603] Intermediate (91) 8.1 g (16.5 mmol), intermediate (48) 4.6 g (19.8 mmol), Na2S2O5 3.8 g (19.8 mmol), and dimethylformamide 80 mL were mixed and stirred at 120°C for one day. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, and a solid was precipitated. The precipitated solid was washed with methanol and filtered under reduced pressure. The obtained solid was dissolved in dichloromethane, and the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, and then purified by silica gel column chromatography (DCM: Hexanes). The obtained mixture was solidified with dichloromethane and methanol to obtain 9.5 g (yield: 81.9%) of a compound (intermediate (92)) as an off-white solid.

[0604]

[0605] Intermediate synthesis example 41: Synthesis of intermediate (93)

[0606]

[0607] Intermediate (92) 9.5 g (13.5 mmol), Intermediate (12) 7.0 g (16.2 mmol), Pd(OAc)2151.5 mg (0.7 mmol), SPhos 806.9 mg (2.0 mmol), 2.0 M K2CO3 20.3 mL (40.5 mmol) of aqueous solution and 16 mL of xylene were mixed, then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes), and then solidified with dichloromethane and methanol to obtain 4.2 g (yield: 33.5%) of a white solid compound (intermediate (93)).

[0608]

[0609] Intermediate Synthesis Example 42: Synthesis of Intermediate (101)

[0610]

[0611] (Synthesis of intermediate (94))

[0612] Intermediate (14) 37.0 g (139.0 mmol), benzophenone imine 32.7 g (180.7 mmol), Pd2(dba) 32.6 g (2.8 mmol), BINAP 3.5 g (5.6 mmol), t-BuONa 40.1 g (416.9 mmol) and toluene 400 mL were mixed. After stirring at 100 °C for 3 hours, the mixture was cooled to room temperature. Distilled water was added, the organic layer was extracted, passed through a silica gel pad, and concentrated under reduced pressure. After adding 200 mL of EtOAc, 15 mL of 35% aqueous hydrochloric acid solution was added, and the mixture was stirred for 1 hour. After neutralizing with aqueous sodium bicarbonate solution, the layers were separated to obtain the organic layer. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexanes) to obtain 12.5 g (yield: 67.5%) of a brown liquid compound (intermediate (94)).

[0613] (Synthesis of intermediate (95))

[0614] After mixing 12.5 g (93.9 mmol) of intermediate (94) and 38.0 mL (469.2 mmol) of pyridine, 20.4 mL (215.9 mmol) of acetic anhydride was slowly added dropwise, and the mixture was stirred at 70°C overnight. After quenching the reaction with distilled water, pyridine was removed under reduced pressure. After adding DCM and distilled water, the organic layer was extracted and washed with 1 N HCl. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was recrystallized from DCM and hexanes to obtain 9.5 g (yield: 58.0%) of the compound (intermediate (95)) as a white solid.

[0615] (Synthesis of intermediate (96))

[0616] After mixing 9.4 g (53.6 mmol) of intermediate (95) and 100 mL of DCM, 10.0 g (56.3 mmol) of NBS (N-Bromosuccimide) was added little by little at room temperature. After stirring at room temperature for 2 hours, distilled water was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was slurried with a mixed solvent (EtOAc:Hexanes) to obtain 12.0 g (yield: 88.0%) of intermediate (96) as a white solid.

[0617] (Synthesis of intermediate (97))

[0618] Intermediate (96) 12.0 g (47.2 mmol) was mixed with 60 mL of ethanol and 20 mL (23.6 mmol) of 35% aqueous hydrochloric acid solution, and the mixture was refluxed overnight. After cooling to room temperature, the mixture was neutralized with 2 N aqueous NaOH solution, and extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 9.3 g (yield: 92.9%) of the compound (intermediate (97)) as a brown liquid.

[0619] (Synthesis of intermediate (98))

[0620] Intermediate (97) 9.3 g (43.8 mmol), phenylboronic acid 8.0 g (65.8 mmol), Pd(PPh3) 41.0 g (0.9 mmol), K2CO3 18.3 g (131.5 mmol), toluene 150 mL, ethanol 30 mL, and distilled water 30 mL were added, and the mixture was stirred at 90°C for 3 hours. After cooling to room temperature, distilled water was added, the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (EtOAc:Hexanes), the mixture was recrystallized with a mixed solvent (DCM:Hexanes) to obtain 8.5 g (yield: 82.8%) of the compound (intermediate (98)) as a white solid.

[0621] (Synthesis of intermediate (99))

[0622] Intermediate (98) 8.5 g (40.5 mmol) and tetrahydrofuran 100 mL were mixed and cooled to -78°C. n-BuLi 19.2 mL (2.5 M in hexane, 47.9 mmol) was slowly added and stirred for 1 hour. Maintaining -78°C, 1-bromo-3-fluoro-2-nitrobenzene 8.1 g (36.8 mmol) was dissolved in THF 20 mL and slowly added dropwise to the reaction mixture. After stirring at -78°C for 2 hours, the temperature was slowly increased to room temperature and then stirred at room temperature for 3 hours. Distilled water was added to terminate the reaction, and the solvent was removed by concentration under reduced pressure. Extraction was performed with DCM. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (EtOAc:Hexanes) yielded 10.0 g (yield: 66.4%) of a red liquid compound (intermediate (99)).

[0623] (Synthesis of intermediate (100))

[0624] Intermediate (99) 10.0 g (24.4 mmol), Fe 6.8 g (122.0 mmol), ammonium chloride 1.3 g (24.4 mmol), ethanol 90 mL, and distilled water 10 mL were mixed and stirred under reflux overnight. The mixture was passed through a pad of Celite and washed with DCM. Distilled water was added, and the separated organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 9.1 g (yield: 98.2%) of the compound (intermediate (100)) as a light brown liquid.

[0625] (Synthesis of intermediate (101))

[0626] Intermediate (100) 9.1 g (24.0 mmol), 3-tert-butylsalicylic aldehyde 4.7 g (26.4 mmol), Na2S2O5 5.9 g (31.2 mmol), and DMF 60 mL were added, and stirred at 120°C overnight. After cooling to room temperature, DMF was removed under reduced pressure. DCM and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM:Hexanes), 8.2 g (yield: 64.1%) of the compound (intermediate (101)) as an ivory-colored solid was obtained.

[0627]

[0628] Intermediate Synthesis Example 43: Synthesis of Intermediate (102)

[0629]

[0630] Intermediate (101) 5.0 g (9.3 mmol), Intermediate (41) 4.8 g (11.2 mmol), Pd(OAc)2104.4 mg (0.5 mmol), SPhos 572.8 mg (1.4 mmol), 2.0 M K2CO3 14 mL (27.9 mmol) of aqueous solution and 100 mL of xylene were mixed and stirred at 120°C for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.3 g (yield: 46.8%) of the compound (intermediate (102)) as a pale yellow solid.

[0631]

[0632] Intermediate Synthesis Example 44: Synthesis of Intermediate (103)

[0633]

[0634] Intermediate (101) 3.9 g (7.3 mmol), Intermediate (12) 4.1 g (9.4 mmol), Pd(OAc)282.0 mg (0.4 mmol), SPhos 0.3 g (0.8 mmol), 2.0 M K2CO3 11 mL (21.9 mmol) of aqueous solution and 78 mL of xylene were mixed and stirred at 120°C for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 4.6 g (yield: 84.0%) of the compound (intermediate (103)) as a pale yellow solid.

[0635]

[0636] Intermediate Synthesis Example 45: Synthesis of Intermediate (104)

[0637]

[0638] Intermediate (101) 4.0 g (7.4 mmol), Intermediate (32) 4.7 g (8.9 mmol), Pd(OAc) 283.5 mg (0.4 mmol), SPhos 458.3 mg (1.1 mmol), 2.0 M K2CO3 11 mL (22.3 mmol) of aqueous solution and 83 mL of xylene were mixed and stirred at 120°C for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.1 g (yield: 48.7%) of the compound (intermediate (104)) as a pale yellow solid.

[0639]

[0640] Intermediate Synthesis Example 46: Synthesis of Intermediate (105)

[0641]

[0642] Intermediate (100) 5.7 g (15.2 mmol), 5-fluoro-2-hydroxybenzaldehyde 2.6 g (18.2 mmol), Na2S2O5 3.8 g (19.7 mmol), and DMF 76 mL were mixed and reacted at 130°C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and washed with distilled water and methanol. The obtained mixture was solidified with methanol to obtain 5.3 g (yield: 69.4%) of the compound (intermediate (105)) as a white solid.

[0643]

[0644] Intermediate Synthesis Example 47: Synthesis of Intermediate (107)

[0645]

[0646] (Synthesis of intermediate (106))

[0647] 50.0 g (219.0 mmol) of 4-adamantanephenol (4-((3r,5r,7r)-adamantan-1-yl)phenol) was dissolved in 700 mL of dichloromethane, 52.6 mL (656.9 mmol) of pyridine was added dropwise, and the temperature was lowered to 0 ℃. 44.1 mL (262.8 mmol) of Tf2O was slowly added dropwise, and the temperature was raised to room temperature and reacted for 12 hours. After washing the reactant with distilled water, the separated organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CHCl3) to obtain 78.0 g (yield: 99.0%) of a white solid compound (intermediate (106)).

[0648] (Synthesis of intermediate (107))

[0649] Intermediate (106) 15.0 g (41.6 mmol), Bis(pinacolato)diboron 15.9 g (62.4 mmol), Pd(dppf)Cl2 - CH2Cl2 1.7 g (2.1 mmol), KOAc 12.3 g (124.9 mmol) and xylene 200 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, passed through a silica gel pad (CHCl3), concentrated under reduced pressure, and solidified with a mixed solvent (DCM / EtOH) to obtain 10.1 g (yield: 71.7%) of the compound (intermediate (107)) as a white solid.

[0650]

[0651] Intermediate Synthesis Example 48: Synthesis of Intermediate (108)

[0652]

[0653] 1-bromo-3-(tert-butyl)-5-chlorobenzene 20.0 g (80.8 mmol), Bis(pinacolato)diboron 24.6 g (96.9 mmol), Pd(dppf)Cl 2-CH2Cl2 1.3 g (1.6 mmol), KOAc 23.8 g (242.4 mmol), and xylene 270 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, passed through a silica gel pad (Hexanes:EtOAc), and concentrated under reduced pressure to obtain 23.8 g (yield: 99.9%) of a white liquid compound (intermediate (108)).

[0654]

[0655] Intermediate Synthesis Example 49: Synthesis of Intermediate (111)

[0656]

[0657] (Synthesis of intermediate (109))

[0658] 2-chloro-4-iodopyridine (7.0 g, 29.2 mmol), intermediate (107) (9.9 g, 29.2 mmol), Pd(PPh3) (41.0 g, 877.0 μmol), K2CO3 (12.1 g, 87.7 mmol), toluene (90 mL), ethanol (30 mL), and distilled water (30 mL) were mixed and stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (DCM) and solidified with a mixed solvent (DCM / EtOH) to obtain 9.5 g (yield: 100%) of the compound (intermediate (109)) as a white solid.

[0659] (Synthesis of intermediate (110))

[0660] Intermediate (109) 9.5 g (29.2 mmol), intermediate (108) 9.5 g (32.2 mmol), Pd(PPh3) 41.7 g (1.5 mmol), K2CO3 12.1 g (87.7 mmol), toluene 90 mL, ethanol 30 mL, and distilled water 30 mL were mixed and then stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (CHCl3) to obtain 13.0 g (yield: 97.5%) of a yellow liquid compound (intermediate (110)).

[0661] (Synthesis of intermediate (111))

[0662] Intermediate (110) 13.0 g (28.5 mmol), pinacol diboron (Bis(pinacolato)diboron) 10.9 g (42.8 mmol), Pd(dba) 2819.5 mg (1.4 mmol), X-Phos 1.4 g (2.9 mmol), KOAc 8.4 g (85.5 mmol) and xylene 110 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, it was cooled to room temperature, passed through a silica gel pad (Hexanes:EtOAc), and concentrated under reduced pressure to obtain 11.6 g (yield: 74.3%) of the compound (intermediate (111)) as a yellow solid.

[0663]

[0664] Intermediate synthesis example 50: Synthesis of intermediate (112)

[0665]

[0666] Intermediate (105) 5.0 g (10.0 mmol), intermediate (111) 5.5 g (10.0 mmol), Pd(OAc) 2224.8 mg (1.0 mmol), X-Phos 822.1 mg (2.0 mmol), K2CO 34.2 g (30.0 mmol), xylene 40 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (DCM) and solidified with a mixed solvent (DCM / EtOH) to obtain 4.8 g (yield: 57.0%) of the compound (intermediate (112)) as a white solid.

[0667]

[0668] Intermediate Synthesis Example 51: Synthesis of Intermediate (116)

[0669]

[0670] (Synthesis of intermediate (113))

[0671] Intermediate (97) 20.0 g (94.3 mmol), 2-naphthylboronic acid 16.5 g (113.2 mmol), Pd(PPh3) 45.5 g (4.7 mmol), K2CO3 26.1 g (188.6 mmol), toluene 240 mL, ethanol 120 mL, and distilled water 120 mL were added, and the mixture was stirred at 90°C for 3 hours. After cooling to room temperature, distilled water was added, the layers were separated, and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:Hexanes) and recrystallized from a mixed solvent (DCM:Hexanes) to obtain 20.1 g (yield: 82.1%) of the compound (intermediate (113)) as a white solid.

[0672] (Synthesis of intermediate (114))

[0673] Intermediate (113) 20.1 g (77.5 mmol) was mixed with 200 mL of tetrahydrofuran, and then cooled to -78°C. n-BuLi 37.2 mL (2.5 M in hexane, 93.0 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour. 18.8 g (85.3 mmol) of 1-bromo-3-fluoro-2-nitrobenzene was dissolved in 40 mL of THF, and then slowly added dropwise to the reaction mixture. After stirring at -78°C for 2 hours, the mixture was stirred at room temperature for 3 hours. Distilled water was added, the reaction was terminated, and the mixture was concentrated under reduced pressure. The mixture was extracted with DCM, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The compound (intermediate (114) 18.2 g (yield: 51.1%) was obtained as a red liquid by purification using silica gel column chromatography (EtOAc:Hexanes).

[0674] (Synthesis of intermediate (115))

[0675] Intermediate (114) 18.2 g (39.6 mmol), Fe 11.1 g (198.1 mmol), 2M ammonium chloride aqueous solution 40 mL (39.6 mmol), and EtOH 200 mL were mixed and refluxed overnight. The mixture was passed through a pad of Celite and washed with DCM. Distilled water was added, and the organic layer was separated and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The compound (intermediate (115) 16.5 g (yield: 96.9%) was obtained as a light brown liquid by purification by silica gel column chromatography (DCM: Hexanes).

[0676] (Synthesis of intermediate (116))

[0677] Intermediate (115) 16.5 g (38.4 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 10.8 g (46.1 mmol), Na2S2O 59.5 g (50.0 mmol), and DMF 370 mL were mixed and reacted at 130 °C for 2 days. After the reaction was completed, the mixture was cooled to room temperature, filtered, and washed with distilled water. The obtained mixture was purified by silica gel column chromatography (Hexanes: DCM) and solidified with hexane to obtain 22.5 g (yield: 90.9%) of the compound (intermediate (116)) as a white solid.

[0678]

[0679] Intermediate Synthesis Example 52: Synthesis of Intermediate (119)

[0680]

[0681] (Synthesis of intermediate (117))

[0682] 2-chloro-4-iodopyridine (10.0 g, 41.8 mmol), (4-(trifluoromethyl)phenyl)boronic acid (9.5 g, 50.1 mmol), Pd(PPh3) (41.4 g, 1.3 mmol), Na2CO3 (11.1 g, 104.4 mmol), toluene (200 mL), ethanol (50 mL), and distilled water (50 mL) were mixed and reacted at 75°C for one day. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was filtered through a silica gel pad (toluene) and solidified with a nuclease to obtain 3.7 g (yield: 34.4%) of a white solid compound (intermediate (117)).

[0683] (Synthesis of intermediate (118))

[0684] Intermediate (117) 3.7 g (14.4 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 3.7 g (17.2 mmol), Pd(PPh3) 48 29.8 mg (0.7 mmol), K2CO 3 4.0 g (28.7 mmol), toluene 40 mL, ethanol (EtOH) 15 mL, and H2O 15 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 5.6 g (yield: 100.0%) of a yellow oily compound (intermediate (118)).

[0685] (Synthesis of intermediate (119))

[0686] Intermediate (118) 5.6 g (14.4 mmol), pinacol diboron (Bis(pinacolato)diboron) 4.4 g (17.2 mmol), Pd(dba) 2659.3 mg (0.7 mmol), X-Phos 748.7 g (2.2 mmol), KOAc 4.2 g (43.1 mmol) and xylene 57 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, passed through a silica gel pad (Hexanes:EtOAc), and concentrated under reduced pressure to obtain 5.1 g (yield: 73.7%) of the compound (intermediate (119)) as a yellow solid.

[0687]

[0688] Intermediate synthesis example 53: Synthesis of intermediate (120)

[0689]

[0690] Intermediate (116) 5.0 g (7.8 mmol), intermediate (119) 4.5 g (9.3 mmol), Pd(OAc) 287.2 mg (0.4 mmol), X-Phos 478.4 mg (1.2 mmol), K2CO3 3.2 g (23.3 mmol), xylene 80 mL, and distilled water 20 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (DCM) and solidified with a mixed solvent (DCM / EtOH) to obtain 3.5 g (yield: 49.0%) of the compound (intermediate (120)) as a white solid.

[0691]

[0692] Intermediate Synthesis Example 54: Synthesis of Intermediate (121)

[0693]

[0694] Intermediate (116) 5.0 g (7.8 mmol), Intermediate (24) 4.4 g (9.3 mmol), Pd(OAc) 287.2 mg (0.4 mmol), SPhos 478.4 mg (1.2 mmol), 2.0 M K2CO3 12 mL (23.3 mmol) of aqueous solution and 86 mL of xylene were mixed and stirred at 120°C for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 4.2 g (yield: 59.7%) of a pale yellow solid compound (intermediate (121)).

[0695]

[0696] Intermediate Synthesis Example 55: Synthesis of Intermediate (129)

[0697]

[0698] (Synthesis of intermediate (122))

[0699] Intermediate (87) 37.0 g (139.0 mmol), benzophenone imine 32.7 g (180.7 mmol), Pd2(dba) 32.6 g (2.8 mmol), BINAP 3.5 g (5.6 mmol), t-BuONa 40.1 g (416.9 mmol) and toluene 400 mL were mixed. After stirring at 100°C for 3 hours, the mixture was cooled to room temperature. Distilled water was added, the organic layer was extracted, passed through a silica gel pad, and concentrated under reduced pressure. After adding 200 mL of EtOAc, 15 mL of 35% aqueous hydrochloric acid solution was added, and the mixture was stirred for 1 hour. After neutralizing with aqueous sodium bicarbonate solution, the layers were separated to obtain the organic layer. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexanes) to obtain 12.5 g (yield: 67.5%) of a brown liquid compound (intermediate (122)).

[0700] (Synthesis of intermediate (123))

[0701] After mixing 12.5 g (93.9 mmol) of intermediate (122) and 38.0 mL (469.2 mmol) of pyridine, 20.4 mL (215.9 mmol) of acetic anhydride was slowly added dropwise, and the mixture was stirred at 70°C overnight. After quenching the reaction with distilled water, pyridine was removed under reduced pressure. After adding DCM and distilled water, the organic layer was extracted and washed with 1 N HCl. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was recrystallized from DCM and hexanes to obtain 9.5 g (yield: 58.0%) of the compound (intermediate (123)) as a white solid.

[0702] (Synthesis of intermediate (124))

[0703] After mixing 9.4 g (53.6 mmol) of intermediate (123) and 100 mL of DCM, 10.0 g (56.3 mmol) of NBS (N-Bromosuccimide) was added little by little at room temperature. After stirring at room temperature for 2 hours, distilled water was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was slurried with a mixed solvent (EtOAc:Hexanes) to obtain 12.0 g (yield: 88.0%) of the compound (intermediate (124)) as a white solid.

[0704] (Synthesis of intermediate (125))

[0705] 12.0 g (47.2 mmol) of intermediate (124) was mixed with 60 mL of ethanol and 20 mL (23.6 mmol) of a 35% aqueous hydrochloric acid solution, and the mixture was refluxed overnight. After cooling to room temperature, the mixture was neutralized with a 2 N aqueous NaOH solution, and extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 9.3 g (yield: 92.9%) of the compound (intermediate (125)) as a brown liquid.

[0706] (Synthesis of intermediate (126))

[0707] Intermediate (125) 9.3 g (43.8 mmol), phenylboronic acid 8.0 g (65.8 mmol), Pd(PPh3) 41.0 g (0.9 mmol), K2CO3 18.3 g (131.5 mmol), toluene 150 mL, ethanol 30 mL, and distilled water 30 mL were mixed and stirred at 90°C for 3 hours. After cooling to room temperature, distilled water was added, the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (EtOAc:Hexanes), 8.5 g (yield: 82.8%) of the compound (intermediate (126)) as a white solid was obtained.

[0708] (Synthesis of intermediate (127))

[0709] Intermediate (126) 8.5 g (40.5 mmol) and tetrahydrofuran 100 mL were mixed and cooled to -78°C. n-BuLi 19.2 mL (2.5 M in hexane, 47.9 mmol) was slowly added and stirred for 1 hour. Maintaining -78°C, 1-bromo-3-fluoro-2-nitrobenzene 8.1 g (36.8 mmol) was dissolved in THF 20 mL and slowly added dropwise to the reaction mixture. After stirring at -78°C for 2 hours, the temperature was slowly increased to room temperature and then stirred at room temperature for 3 hours. Distilled water was added to terminate the reaction, and the solvent was removed by concentration under reduced pressure. Extraction was performed with DCM. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (EtOAc:Hexanes) to obtain 10.0 g (yield: 66.4%) of a red liquid compound (intermediate (127)).

[0710] (Synthesis of intermediate (128))

[0711] Intermediate (127) 10.0 g (24.4 mmol), Fe 6.8 g (122.0 mmol), ammonium chloride 1.3 g (24.4 mmol), ethanol 90 mL, and distilled water 10 mL were mixed and stirred under reflux overnight. The mixture was passed through a pad of Celite and washed with DCM. Distilled water was added, and the separated organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 9.1 g (yield: 98.2%) of the compound (intermediate (128)) as a light brown liquid.

[0712] (Synthesis of intermediate (129))

[0713] Intermediate (128) 9.1 g (24.0 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 4.7 g (26.4 mmol), Na2S2O5 5.9 g (31.2 mmol), and DMF 60 mL were mixed and stirred at 120°C overnight. After cooling to room temperature, DMF was removed under reduced pressure. DCM and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM:Hexanes), 8.2 g (yield: 64.1%) of the compound (intermediate (129)) as an ivory solid was obtained.

[0714]

[0715] Intermediate Synthesis Example 56: Synthesis of Intermediate (130)

[0716]

[0717] Intermediate (129) 4.0 g (6.2 mmol), Intermediate (41) 3.2 g (7.4 mmol), Pd(OAc) 269.1 mg (0.3 mmol), SPhos 379.1 mg (0.9 mmol), 2.0 M K2CO3 9 mL (18.5 mmol) of aqueous solution and 70 mL of xylene were mixed and stirred at 120°C for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 2.9 g (yield: 54.1%) of the compound (intermediate (130)) as a pale yellow solid.

[0718]

[0719] Intermediate Synthesis Example 57: Synthesis of Intermediate (137)

[0720]

[0721] (Synthesis of intermediate (131))

[0722] Intermediate (26) 71.1 g (388.4 mmol), N-phenylacetamide 30.0 g (221.9 mmol) and DCM 300 mL were mixed and cooled to -5 to 5°C. At -5 to 5°C, AlCl 359.2 g (443.9 mmol) was added little by little over 1 hour, and the mixture was stirred at -5 to 5°C for 2 hours. The reactant was slowly poured into ice water, and the organic layer was extracted with DCM. The organic layer was washed with distilled water and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the mixture was recrystallized from the mixed solution (DCM:Hexanes) to obtain 24.5 g (yield: 45.0%) of the compound (Intermediate (131)) as a brown solid.

[0723] (Synthesis of intermediate (132))

[0724] Intermediate (131) 24.5 g (99.9 mmol), conc. HCl 42.3 mL (499.3 mmol), and ethanol 200 mL were mixed and stirred under reflux overnight. After cooling to room temperature, the solvent was removed under reduced pressure, distilled water and DCM were added, and the layers were separated to separate the organic layer. The separated organic layer was concentrated and purified by silica gel column chromatography (DCM: Hexanes) to obtain 16.1 g (yield: 79.3%) of the compound (intermediate (132)) as a brown liquid.

[0725] (Synthesis of intermediate (133))

[0726] After mixing 16.1 g (79.2 mmol) of intermediate (132) and 30 mL of DCM, 14.1 g (79.2 mmol) of NBS (N-Bromosuccimide) was slowly added dropwise at 0°C. After stirring overnight at room temperature, distilled water was added, and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM: Hexanes) to obtain 11.3 g (yield: 50.6%) of the compound (intermediate (133)) as a brown liquid.

[0727] (Synthesis of intermediate (134))

[0728] Intermediate (133) 11.3 g (40.0 mmol) and phenylboronic acid 7.3 g (60.1 mmol), Pd(PPh3) 4925.0 mg (0.8 mmol), K2CO3 13.9 g (100.1 mmol), toluene 100 mL, ethanol 25 mL, and distilled water 25 mL were mixed and stirred at 90°C for 2 hours. After cooling to room temperature, distilled water was added, and extraction was performed with DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM: Hexanes), and then recrystallized from hexane to obtain 8.8 g (yield: 79.1%) of the compound (intermediate (134)) as an ivory solid.

[0729] (Synthesis of intermediate (135))

[0730] Intermediate (134) 8.9 g (32.0 mmol) and 80 mL of tetrahydrofuran were mixed and cooled to -78°C. At -78°C, 15.8 mL (2.5 M in hexane, 39.6 mmol) of n-BuLi was slowly added dropwise, and the mixture was stirred for 2 hours. At -78°C, a solution of 6.7 g (30.5 mmol) of 1-bromo-3-fluoro-2-nitrobenzene in 20 mL of tetrahydrofuran was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. After the reaction was quenched with distilled water, tetrahydrofuran was removed under reduced pressure. DCM was added, the organic layer was extracted, and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hexanes) to obtain 6.5 g (yield: 44.5%) of an orange solid compound (intermediate (135).

[0731] (Synthesis of intermediate (136))

[0732] Intermediate (135) 6.5 g (13.6 mmol), Fe 3.8 g (67.8 mmol), and ethanol (EtOH) 124.0 mL were mixed, and 1.0 M NH4Cl aqueous solution 27.2 mL (27.2 mmol) was added, and the mixture was refluxed and stirred for 6 hours. After the reaction was completed, the reaction solution was filtered through a pad of celite using dichloromethane to remove inorganic substances, and the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite, and concentrated under reduced pressure to obtain 6.0 g (yield: 100.0%) of a brown liquid compound (intermediate (136)).

[0733] (Synthesis of intermediate (137))

[0734] Intermediate (136) 6.0 g (13.3 mmol), 3.7 g (16.0 mmol) of 3,5-di-tert-butyl-2-hydroxybenzaldehyde, 3.0 g (16.0 mmol) of Na2S2O5, and 60 mL of dimethylformamide were mixed and stirred at 130°C for one day. After the reaction was completed, the mixture was cooled to room temperature and distilled water was added to precipitate a solid. The precipitated solid was washed with distilled water and methanol and filtered under reduced pressure. The solid thus obtained was dissolved in dichloromethane, dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure to remove the solvent. The obtained mixture was solidified with dichloromethane and methanol to obtain 6.2 g (yield: 70.0%) of a pale pink solid compound (intermediate (137)).

[0735]

[0736] Intermediate Synthesis Example 58: Synthesis of Intermediate (138)

[0737]

[0738] Intermediate (137) 3.1 g (4.7 mmol), Intermediate (41) 3.0 g (7.0 mmol), Pd(OAc) 253.0 mg (0.2 mmol), SPhos 193.0 mg (0.5 mmol), 2.0 M K2CO3 aqueous solution 7.0 mL (14.1 mmol) and 62 mL of xylene were mixed and stirred at 130°C for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.2 g (yield: 78.0%) of the compound (intermediate (138)) as an off-white solid.

[0739]

[0740] Intermediate Synthesis Example 59: Synthesis of Intermediate (139)

[0741]

[0742] Intermediate (137) 3.0 g (4.5 mmol), Intermediate (74) 2.8 g (5.9 mmol), Pd(OAc) 251.0 mg (0.2 mmol), SPhos 164.0 mg (0.4 mmol), 2.0 M K2CO3 aqueous solution 7.0 mL (13.5 mmol) and 60 mL of xylene were mixed and stirred at 130°C for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with methanol to obtain 3.3 g (yield: 80.5%) of the compound (intermediate (139)) as an off-white solid.

[0743]

[0744] Intermediate synthesis example 60: Synthesis of intermediate (140)

[0745]

[0746] Intermediate (136) 3.0 g (6.67 mmol), 5-tert-butyl-2-hydroxybenzaldehyde 1.4 g (8.0 mmol), sodium metabisulfite 1.9 g (10.0 mmol), and DMF 30 mL were mixed and stirred at 120°C for 12 hours. After completion of the reaction, distilled water and dichlorobenzene were added, and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:Hexanes) and recrystallized with a mixed solvent (DCM:Hexanes) to obtain 3.5 g (yield: 86.6%) of the compound (intermediate (140)) as an ivory solid.

[0747]

[0748] Intermediate Synthesis Example 61: Synthesis of Intermediate (141)

[0749]

[0750] Intermediate (140) 3.5 g (5.8 mmol), intermediate (41) 2.7 g (6.3 mmol), Pd(PPh3) 40.2 g (0.2 mmol), K2CO3 2.4 g (17.3 mmol), toluene 28 mL, distilled water 14 mL, and ethanol 7 mL were mixed and stirred under reflux overnight. After cooling to room temperature, dichloromethane and distilled water were added, and the organic layer was separated. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM:Hexane) and recrystallized from a mixed solution (DCM:Hexanes) to obtain 3.0 g (yield: 63.5%) of the compound (Intermediate 141)) as a white solid.

[0751]

[0752] Intermediate synthesis example 62: Synthesis of intermediate (145)

[0753]

[0754] (Synthesis of intermediate (142))

[0755] In a nitrogen atmosphere, 20.0 g (70.9 mmol) of intermediate (133), 18.0 g (85.0 mmol) of dibenzo[b,d]furan-4-ylboronic acid, 4.1 g (3.5 mmol) of tetrakis(triphenylphosphine)palladium(0), and 19.6 g (141.7 mmol) of potassium carbonate were added to a mixture of 300 mL of toluene, 75 mL of ethanol, and 75 mL of distilled water, and the mixture was reacted for 12 hours while maintaining the temperature at 75-80°C. After completion of the reaction, extraction was performed with distilled water and dichloromethane, and the mixture was treated with anhydrous magnesium sulfate and filtered. The filtered solution was concentrated under reduced pressure, and the resulting reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) and dried to obtain 21.5 g (yield: 82.1%) of a transparent liquid compound (intermediate (142)).

[0756] (Synthesis of intermediate (143))

[0757] In a nitrogen atmosphere, 21.5 g (58.2 mmol) of intermediate (142) was dissolved in 200 mL of tetrahydrofuran, cooled to -78°C, 27.9 mL (69.8 mmol) of n-butyllithium (2.0 M) was slowly added dropwise, and the mixture was stirred for 1 hour while maintaining -78°C. Then, 14.1 g (64.0 mmol) of 1-bromo-3-fluoro-2-nitrobenzene was dissolved in 100 mL of tetrahydrofuran, slowly added dropwise while maintaining -78°C, and reacted for 12 hours. After the reaction was completed, extraction was performed with distilled water and dichloromethane, and the mixture was filtered after treating with anhydrous magnesium sulfate. The filtered solution was concentrated under reduced pressure, and the resulting reaction mixture was purified by silica gel column chromatography (CHCl3:Hexanes) and dried to obtain 15.0 g (yield: 45.2%) of a red liquid compound (intermediate (143)).

[0758] (Synthesis of intermediate (144))

[0759] Intermediate (143) 15.0 g (26.3 mmol), iron (Fe) 7.4 g (131.7 mmol), and 1 M ammonium chloride aqueous solution 53 mL were mixed in 300 mL of ethanol, and stirred at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through Celite, extracted with distilled water and dichloromethane, treated with anhydrous magnesium sulfate, and filtered. The filtered solution was concentrated under reduced pressure, and the obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) and dried to obtain 10.0 g (yield: 70.3%) of a yellow liquid compound (intermediate (144)).

[0760] (Synthesis of intermediate (145))

[0761] Intermediate (144) 10.0 g (18.5 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 5.2 g (22.2 mmol), and Na2S2O54.6 g (24.1 mmol) were mixed in 150 mL of dimethylformamide and stirred at 110°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, extracted with distilled water and dichloromethane, treated with anhydrous magnesium sulfate, and filtered. The filtered solution was concentrated under reduced pressure, and the obtained reaction mixture was purified by silica gel column chromatography (CHCl3:Hexanes) and solidified with hexane to obtain 12.1 g (yield: 86.6%) of the compound (intermediate (145)) as a white solid.

[0762]

[0763] Intermediate synthesis example 63: Synthesis of intermediate (146)

[0764]

[0765] Intermediate (145) 5.0 g (6.6 mmol), intermediate (41) 3.4 g (8.0 mmol), Pd(PPh3)4383.2 mg (0.3 mmol), K2CO3 1.8 g (13.3 mmol), toluene 40 mL, distilled water 20 mL, and ethanol 20 mL were mixed and stirred under reflux overnight. After cooling to room temperature, dichloromethane and distilled water were added, and the organic layer was separated. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM:Hexane) and recrystallized from a mixed solution (DCM:Hexanes) to obtain 2.9 g (yield: 44.8%) of the compound (Intermediate 146)) as a white solid.

[0766]

[0767] Intermediate synthesis example 64: Synthesis of intermediate (150)

[0768]

[0769] (Synthesis of intermediate (147))

[0770] Intermediate (34) 13.7 g (60.1 mmol), intermediate (15) 17.6 g (72.1 mmol), Pd(PPh3) 43.5 g (3.0 mmol), K2CO3 24.9 g (180.3 mmol), toluene 240 mL, ethanol (EtOH) 60 mL, and H2O 60 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 14.5 g (yield: 90.9%) of a red oily compound (intermediate (147)).

[0771] (Synthesis of intermediate (148))

[0772] Intermediate (147) 14.5 g (54.6 mmol) and 290 mL of tetrahydrofuran were mixed and cooled to -78°C. 24.0 mL (60.1 mmol) of 2.5 M n-BuLi (in Hexanes) was slowly added dropwise at -78°C, and the mixture was stirred for 1 hour. 14.4 g (65.5 mmol) of 1-bromo-3-fluoro-2-nitrobenzene was dissolved in 29 mL of tetrahydrofuran, and the mixture was slowly added dropwise at -78°C, and the mixture was stirred for 30 minutes. After stirring for 30 minutes, the mixture was stirred at room temperature for 1 day. After the reaction was completed, the organic matter was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 20.0 g (yield: 78.7%) of a red liquid compound (intermediate (148)).

[0773] (Synthesis of intermediate (149))

[0774] Intermediate (148) 20.0 g (43.0 mmol), Fe 14.4 g (258.0 mmol), and ethanol (EtOH) 400 mL were mixed, and 86 mL (86.0 mmol) of 1.0 M NH4Cl aqueous solution was added, and the mixture was refluxed and stirred for 6 hours. After the reaction was completed, the reaction solution was filtered through a pad of celite using dichloromethane to remove inorganic substances, and then concentrated under reduced pressure to remove the solvent. The organic layer of the obtained reaction mixture was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 12.8 g (yield: 68.4%) of a yellow oily compound (intermediate (149)).

[0775] (Synthesis of intermediate (150))

[0776] Intermediate (149) 18.5 g (42.5 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 11.0 g (46.7 mmol), Na2S2O 59.7 g (51.0 mmol), and dimethylformamide 185 mL were mixed and stirred at 120°C for one day. After the reaction was completed, the mixture was cooled to room temperature and the organic matter was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 16.3 g (yield: 59.0%) of a compound (intermediate (150)) as a beige solid.

[0777]

[0778] Intermediate synthesis example 65: Synthesis of intermediate (151)

[0779]

[0780] Intermediate (150) 4.0 g (6.2 mmol), Intermediate (41) 3.4 g (8.0 mmol), Pd(OAc) 270.0 mg (0.3 mmol), SPhos 254.5 mg (0.6 mmol), 2.0 M K2CO3 9.3 mL (18.6 mmol) of aqueous solution and 80 mL of xylene were mixed, then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with hexane and methanol to obtain 3.6 g (yield: 67.9%) of the compound (intermediate (151)) as an off-white solid.

[0781]

[0782] Intermediate synthesis example 66: Synthesis of intermediate (152)

[0783]

[0784] Intermediate (150) 4.0 g (6.2 mmol), Intermediate (78) 3.2 g (7.4 mmol), Pd(OAc) 270.0 mg (0.3 mmol), SPhos 254.5 mg (0.6 mmol), 2.0 M K2CO3 9.3 mL (18.6 mmol) of aqueous solution and 80 mL of xylene were mixed, then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with hexane and methanol to obtain 3.0 g (yield: 55.8%) of the compound (intermediate (152)) as an off-white solid.

[0785]

[0786] Intermediate synthesis example 67: Synthesis of intermediate (153)

[0787]

[0788] Intermediate (150) 4.0 g (6.2 mmol), Intermediate (74) 3.8 g (8.0 mmol), Pd(OAc) 270.0 mg (0.3 mmol), SPhos 254.5 mg (0.6 mmol), 2.0 M K2CO3 9.3 mL (18.6 mmol) of aqueous solution and 80 mL of xylene were mixed, then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with ethanol to obtain 2.2 g (yield: 39.3%) of a yellow solid compound (intermediate (153)).

[0789]

[0790] Intermediate Synthesis Example 68: Synthesis of Intermediate (154)

[0791]

[0792] Intermediate (91) 20.0 g (40.7 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 11.4 g (48.8 mmol), Na2S2O5 10.1 g (52.9 mmol), and dimethylformamide 200 mL were mixed and stirred at 120°C for one day. After the reaction was completed, the mixture was cooled to room temperature and the organic matter was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 15.2 g (yield: 52.9%) of a compound (intermediate (154)) as a beige solid.

[0793]

[0794] Intermediate synthesis example 69: Synthesis of intermediate (155)

[0795]

[0796] Intermediate (154) 5.0 g (7.1 mmol), Intermediate (41) 3.6 g (8.5 mmol), Pd(OAc) 279.5 mg (0.4 mmol), SPhos 436.2 mg (1.1 mmol), 2.0 M K2CO3 7.1 mL (14.2 mmol) of aqueous solution and 80 mL of xylene were mixed, then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with hexane and methanol to obtain 3.3 g (yield: 50.9%) of the compound (intermediate (155)) as an off-white solid.

[0797]

[0798] Intermediate synthesis example 70: Synthesis of intermediate (156)

[0799]

[0800] Intermediate (154) 5.0 g (7.1 mmol), Intermediate (74) 3.6 g (8.5 mmol), Pd(OAc) 279.5 mg (0.4 mmol), SPhos 436.2 mg (1.1 mmol), 2.0 M K2CO3 7.1 mL (14.2 mmol) of aqueous solution and 80 mL of xylene were mixed, then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with hexane and methanol to obtain 2.9 g (yield: 42.2%) of the compound (intermediate (156)) as an off-white solid.

[0801]

[0802] Intermediate synthesis example 71: Synthesis of intermediate (160)

[0803]

[0804] (Synthesis of intermediate (157))

[0805] Intermediate (34) 4.8 g (27.8 mmol), intermediate (29) 10.5 g (33.4 mmol), Pd(PPh3) 4963.7 mg (0.8 mmol), K2CO3 11.5 g (83.4 mmol), toluene 93 mL, ethanol (EtOH) 23 mL, and H2O 23 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 7.8 g (yield: 84.3%) of the compound (intermediate (157)) as a white solid.

[0806] (Synthesis of intermediate (158))

[0807] Intermediate (157) 7.8 g (27.9 mmol) and tetrahydrofuran 156 mL were mixed and cooled to -78°C. 2.0 M n-BuLi (in cyclohexane) 15.4 mL (30.7 mmol) was slowly added dropwise at -78°C, and the mixture was stirred for 1 hour. 1-bromo-3-fluoro-2-nitrobenzene 7.4 g (33.5 mmol) was dissolved in 15 mL of tetrahydrofuran, and the mixture was slowly added dropwise at -78°C, and the mixture was stirred for 1 hour. After stirring for 1 hour, the mixture was stirred at room temperature for 1 day. After the reaction was completed, the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 10.0 g (yield: 75.8%) of an orange solid compound (intermediate (158)).

[0808] (Synthesis of intermediate (159))

[0809] Intermediate (158) 10.0 g (20.9 mmol), Fe 7.0 g (125.2 mmol), and ethanol (EtOH) 200 mL were mixed, and 1.0 M NH4Cl aqueous solution 41.8 mL (41.8 mmol) was added, followed by reflux and stirring for 4 hours. After the reaction was completed, the reaction solution was filtered through a pad of celite to remove inorganic substances, and the organic layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent to obtain 7.9 g (yield: 84.4%) of compound (159) as a red liquid.

[0810] (Synthesis of intermediate (160))

[0811] Intermediate (159) 7.9 g (15.6 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 4.4 g (18.8 mmol), Na2S2O5 3.9 g (20.3 mmol), and dimethylformamide (N,N'-Dimethylformamide) 90 mL were mixed and stirred at 130°C for one day. After the reaction was completed, the mixture was cooled to room temperature, and the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 5.8 g (yield: 51.5%) of a compound (intermediate (160)) as a beige solid.

[0812]

[0813] Intermediate synthesis example 72: Synthesis of intermediate (161)

[0814]

[0815] Intermediate (160) 4.1 g (5.7 mmol), intermediate (41) 3.0 g (6.9 mmol), Pd(OAc) 265.0 mg (0.3 mmol), SPhos 246.3 mg (0.6 mmol), 2.0 M K3PO4 aqueous solution 8.7 mL (17.3 mmol), and toluene 70 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 4.7 g (yield: 87.6%) of the compound (intermediate (161)) as a pale yellow solid.

[0816]

[0817] Intermediate synthesis example 73: Synthesis of intermediate (162)

[0818]

[0819] Intermediate (160) 5.0 g (7.0 mmol), Intermediate (74) 3.9 g (8.3 mmol), Pd(OAc) 277.9 mg (0.3 mmol), SPhos 427.7 mg (1.0 mmol), 2.0 M K2CO3 10.4 mL (20.8 mmol) of aqueous solution and 80 mL of xylene were mixed, then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with hexane and methanol to obtain 3.0 g (yield: 43.9%) of the compound (intermediate (162)) as an off-white solid.

[0820]

[0821] Intermediate Synthesis Example 74: Synthesis of Intermediate (163)

[0822]

[0823] Intermediate (149) 12.8 g (29.4 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 5.8 g (32.3 mmol), Na2S2O 56.7 g (35.3 mmol), and dimethylformamide 128 mL were mixed and stirred at 120°C for one day. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, and a solid was precipitated. The precipitated solid was washed with distilled water and filtered under reduced pressure. The obtained solid was dissolved in dichloromethane, dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 11.1 g (yield: 63.6%) of a compound (intermediate (163)) as a beige solid.

[0824]

[0825] Intermediate synthesis example 75: Synthesis of intermediate (164)

[0826]

[0827] Intermediate (163) 3.5 g (5.9 mmol), intermediate (41) 3.3 g (7.7 mmol), Pd(OAc) 266.2 mg (0.3 mmol), SPhos 363.3 mg (0.9 mmol), K2CO3 2.5 g (17.7 mmol), xylene 70 mL, and distilled water 8 mL were mixed, and then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.5 g (yield: 73.1%) of compound (164) as an off-white solid.

[0828]

[0829] Intermediate synthesis example 76: Synthesis of intermediate (166)

[0830]

[0831] (Synthesis of intermediate (165))

[0832] 10.0 g (67.5 mmol) of 5,6,7,8-tetrahydronaphthalen-1-ol and 200 mL of DCM were mixed and cooled to 0 to 5°C. 12.5 mL (74.2 mmol) of Tf2O (trifluoromethanesulfonic anhydride) was slowly added dropwise and stirred at room temperature for 5 hours. After the reaction was completed, distilled water and DCM were added to extract the organic layer. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 15.2 g (yield: 80.4%) of the compound (intermediate (165)) as a light green liquid.

[0833] (Synthesis of intermediate (166))

[0834] Intermediate (165) 15.2 g (53.5 mmol), PIN2B2 17.7 g (69.6 mmol), Pd(dba) 20.9 g (1.6 mmol), XPhos 1.4 g (3.2 mmol), KOAc 15.8 g (161 mmol) and dioxane 150 mL were mixed and refluxed and stirred for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) and concentrated to obtain 12.3 g (yield: 66.6%) of the compound (intermediate (166)) as a pale gray liquid.

[0835]

[0836] Intermediate Synthesis Example 77: Synthesis of Intermediate (170)

[0837]

[0838] (Synthesis of intermediate (167))

[0839] Intermediate (34) 12.0 g (52.6 mmol), intermediate (166) 14.9 g (57.9 mmol), Pd(PPh3) 41.8 g (0.2 mmol), K2CO3 21.8 g (15.8 mmol), toluene 100 mL, distilled water 20 mL, and ethanol 20 mL were mixed and stirred under reflux overnight. After cooling to room temperature, DCM and distilled water were added, and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:Hexanes) to obtain 9.4 g (yield: 64.0%) of the compound (intermediate (167)) as a beige liquid.

[0840] (Synthesis of intermediate (168))

[0841] Intermediate (167) 9.2 g (32.9 mmol) was added to 160 mL of tetrahydrofuran and stirred at -78°C. n-BuLi (2.5 M) 13.5 mL (36.2 mmol) was slowly added dropwise, and the mixture was stirred for 4 hours. A solution of 7.2 g (32.9 mmol) of 1-bromo-3-fluoro-2-nitrobenzene in 20 mL of tetrahydrofuran was slowly added dropwise to the reaction mixture at -78°C, and the mixture was stirred at room temperature overnight. Ammonium chloride aqueous solution and DCM were added, and the organic layer was separated, washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Hexanes were added to the concentrate, stirred for 30 minutes, and filtered to obtain 12.4 g (yield: 78.6%) of an orange solid compound (intermediate (168)).

[0842] (Synthesis of intermediate (169))

[0843] Intermediate (168) 12.0 g (25.0 mmol), iron (Fe) 5.6 g (100.0 mmol), ammonium chloride 4.0 g (75.1 mmol), distilled water 12 mL, and ethanol 110 mL were mixed and stirred under reflux for 8 hours. After the reaction was completed, the mixture was filtered through a pad of Celite. DCM was added, the organic layer was separated, washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (DCM: Hexanes), and then hexanes were added. After stirring for 30 minutes and filtering, 10.1 g (yield: 89.8%) of the compound (intermediate (169)) as a yellow solid was obtained.

[0844] (Synthesis of intermediate (170))

[0845] Intermediate (169) 10.0 g (22.3 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 4.4 g (24.5 mmol), sodium metabisulfite 6.3 g (33.4 mmol), and DMF 100 mL were mixed and stirred at 120°C for 12 hours. After completion of the reaction, distilled water and DCM were added, and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:Hexanes) and recrystallized from a mixed solution (DCM:Hexanes) to obtain 7.2 g (yield: 53.4%) of the compound (intermediate (170)) as an ivory solid.

[0846]

[0847] Intermediate Synthesis Example 78: Synthesis of Intermediate (171)

[0848]

[0849] Intermediate (170) 5.0 g (8.2 mmol), intermediate (41) 3.9 g (9.1 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 3.4 g (24.7 mmol), toluene 40 mL, distilled water 20 mL, and ethanol 10 mL were mixed and stirred under reflux overnight. After cooling to room temperature, DCM and distilled water were added, and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM:Hexanes), the compound was recrystallized from a mixed solvent (DCM:Hexanes) to obtain 3.8 g (yield: 55.7%) of intermediate (171) as a white solid.

[0850]

[0851] Intermediate synthesis example 79: Synthesis of intermediate (175)

[0852]

[0853] (Synthesis of intermediate (172))

[0854] Intermediate (34) 12.0 g (52.6 mmol), intermediate (21) 14.9 g (57.9 mmol), Pd(PPh3) 41.8 g (0.2 mmol), K2CO3 21.8 g (15.8 mmol), toluene 100 mL, distilled water 20 mL, and ethanol 20 mL were mixed and stirred under reflux overnight. After cooling to room temperature, DCM and distilled water were added, and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:Hexanes) to obtain 9.4 g (yield: 64.0%) of the compound (intermediate (172)) as a beige liquid.

[0855] (Synthesis of intermediate (173))

[0856] Intermediate (172) 9.2 g (32.9 mmol) and 160 mL of tetrahydrofuran were added and stirred at -78°C. n-BuLi (2.5 M) 13.5 mL (36.2 mmol) was slowly added dropwise, and stirred for 4 hours. A solution of 7.2 g (32.9 mmol) of 1-bromo-3-fluoro-2-nitrobenzene in 20 mL of tetrahydrofuran was slowly added dropwise to the reaction mixture at -78°C, and stirred at room temperature overnight. Ammonium chloride aqueous solution and DCM were added, and the organic layer was separated, washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Hexanes were added to the concentrate, stirred for 30 minutes, and filtered to obtain 12.4 g (yield: 78.6%) of an orange solid compound (intermediate (173)).

[0857] (Synthesis of intermediate (174))

[0858] Intermediate (173) 12.0 g (25.0 mmol), iron (Fe) 5.6 g (100.0 mmol), ammonium chloride 4.0 g (75.1 mmol), distilled water 12 mL, and ethanol 110 mL were mixed and stirred under reflux for 8 hours. After the reaction was completed, the mixture was filtered through a pad of Celite. DCM was added, the organic layer was separated, washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (DCM: Hexanes), and then hexanes were added. After stirring for 30 minutes and filtering, 10.1 g (yield: 89.8%) of the compound (intermediate (174)) as a yellow solid was obtained.

[0859] (Synthesis of intermediate (175))

[0860] Intermediate (174) 10.0 g (22.3 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 4.4 g (24.5 mmol), sodium metabisulfite 6.3 g (33.4 mmol), and DMF 100 mL were mixed and stirred at 120°C for 12 hours. After completion of the reaction, distilled water and DCM were added, and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:Hexanes) and recrystallized from a mixed solution (DCM:Hexanes) to obtain 7.2 g (yield: 53.4%) of the compound (intermediate (175)) as an ivory solid.

[0861]

[0862] Intermediate synthesis example 80: Synthesis of intermediate (176)

[0863]

[0864] Intermediate (175) 5.0 g (8.2 mmol), intermediate (41) 3.9 g (9.1 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 3.4 g (24.7 mmol), toluene 40 mL, distilled water 20 mL, and ethanol 10 mL were mixed and stirred under reflux overnight. After cooling to room temperature, DCM and distilled water were added, and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM:Hexanes), the compound was recrystallized from a mixed solvent (DCM:Hexanes) to obtain 3.8 g (yield: 55.7%) of intermediate (176) as a white solid.

[0865]

[0866] Intermediate Synthesis Example 81: Synthesis of Intermediate (177)

[0867]

[0868] Intermediate (159) 7.0 g (13.8 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 2.7 g (15.2 mmol), Na2S2O5 3.1 g (16.5 mmol), and DMF 70 mL were mixed. The reaction mixture was stirred at 110°C overnight. After the reaction was quenched with distilled water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The compound (intermediate (177) 4.6 g (yield: 50.5%) was obtained as a white solid by purification by silica gel column chromatography (DCM:Hexanes).

[0869]

[0870] Intermediate Synthesis Example 82: Synthesis of Intermediate (178)

[0871]

[0872] Intermediate (177) 4.0 g (6.6 mmol), intermediate (41) 2.8 g (6.6 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.5 g (18.0 mmol), toluene 40 mL, ethanol 20 mL, and distilled water 20 mL were mixed. The reaction mixture was stirred under reflux overnight. After the reaction was quenched with distilled water, it was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA: Hexanes) to obtain 4.5 g (yield: 84.9%) of the compound (intermediate (178)) as a white solid.

[0873]

[0874] Intermediate Synthesis Example 83: Synthesis of Intermediate (182)

[0875]

[0876] (Synthesis of intermediate (179))

[0877] 4.8 g (27.8 mmol) of 2-bromoaniline, 10.5 g (33.4 mmol) of intermediate (29), 4963.7 mg (0.8 mmol) of Pd(PPh3), 11.5 g (83.4 mmol) of K2CO3, 93 mL of toluene, 23 mL of ethanol (EtOH), and 23 mL of H2O were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 7.8 g (yield: 84.3%) of the compound (intermediate (179)) as a white solid.

[0878] (Synthesis of intermediate (180))

[0879] Intermediate (179) 7.8 g (27.9 mmol) and tetrahydrofuran 156 mL were mixed and cooled to -78°C. 2.0 M n-BuLi (in cyclohexane) 15.4 mL (30.7 mmol) was slowly added dropwise at -78°C, and the mixture was stirred for 1 hour. 1-bromo-3-fluoro-2-nitrobenzene 7.4 g (33.5 mmol) was dissolved in 15 mL of tetrahydrofuran, and the mixture was slowly added dropwise at -78°C, and the mixture was stirred for 1 hour. After stirring for 1 hour, the mixture was stirred at room temperature for 1 day. After the reaction was completed, the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 10.0 g (yield: 75.8%) of an orange solid compound (intermediate (180)).

[0880] (Synthesis of intermediate (181))

[0881] Intermediate (180) 10.0 g (20.9 mmol), Fe 7.0 g (125.2 mmol), and ethanol (EtOH) 200 mL were mixed, and 1.0 M NH4Cl aqueous solution 41.8 mL (41.8 mmol) was added, followed by reflux and stirring for 4 hours. After the reaction was completed, the reaction solution was filtered through a pad of celite to remove inorganic substances, and the organic layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent to obtain 7.9 g (yield: 84.4%) of compound (181) as a red liquid.

[0882] (Synthesis of intermediate (182))

[0883] Intermediate (181) 7.9 g (15.6 mmol), 5-tert-butyl-2-hydroxybenzaldehyde 3.5 g (19.4 mmol), Na2S2O5 3.9 g (20.3 mmol), and dimethylformamide (N,N'-Dimethylformamide) 90 mL were mixed and stirred at 130°C for one day. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 5.8 g (yield: 54.3%) of the compound (intermediate (182)) as an off-white solid.

[0884]

[0885] Intermediate Synthesis Example 84: Synthesis of Intermediate (183)

[0886]

[0887] Intermediate (182) 3.5 g (5.7 mmol), intermediate (41) 3.0 g (6.9 mmol), Pd(OAc) 265.0 mg (0.3 mmol), SPhos 246.3 mg (0.6 mmol), 2.0 M K3PO4 aqueous solution 8.7 mL (17.3 mmol), and toluene 70 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 4.2 g (yield: 87.6%) of the compound (intermediate (183)) as a pale yellow solid.

[0888]

[0889] Intermediate Synthesis Example 85: Synthesis of Intermediate (185)

[0890]

[0891] (Synthesis of intermediate (184))

[0892] Intermediate (59) 4.5 g (27.7 mmol), pyridine 4.5 mL (4.4 mmol), and DCM 50 mL were mixed, and then cooled to 4-10°C. Tf2O 6.5 mL (11.0 mmol) was slowly added dropwise at 4-10°C, and the mixture was stirred at room temperature for 3 hours. Distilled water was added to stop the reaction, and the organic layer was separated. The organic layer was washed with a 1 N HCl aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 7.7 g (yield: 94.3%) of the compound (intermediate (184)) as a yellow liquid.

[0893] (Synthesis of intermediate (185))

[0894] Intermediate (184) 7.7 g (26.2 mmol), PIN2B2 10.0 g (39.3 mmol), PdCl2dppf·DCM 766.0 mg (1.1 mmol), KOAc 7.7 g (78.5 mmol), and dioxane 80 mL were mixed and stirred under reflux for 6 hours. After cooling to room temperature, the solvent was removed by concentration under reduced pressure, and distilled water was added. The reactant was extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After dissolving in a mixed solvent (DCM:Hexanes), it was passed through a silica gel pad. The filtrate was concentrated, slurried with methanol for 1 hour, and filtered to obtain 6.3 g (yield: 88.5%) of the compound (intermediate (185)) as a white solid.

[0895]

[0896] Intermediate Synthesis Example 86: Synthesis of Intermediate (189)

[0897]

[0898] (Synthesis of intermediate (186))

[0899] Intermediate (34) 4.6 g (20.2 mmol), intermediate (185) 6.5 g (24.2 mmol), Pd(PPh3) 41.2 g (1.0 mmol), Cs2CO3 19.7 g (60.6 mmol), toluene 80 mL, ethanol (EtOH) 20 mL, and H2O 20 mL were mixed and stirred at 80°C for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 5.1 g (yield: 86.4%) of the compound (intermediate (186)) as a yellow oil.

[0900] (Synthesis of intermediate (187))

[0901] Intermediate (186) 5.1 g (17.4 mmol) and tetrahydrofuran 102 mL were mixed and cooled to -78°C. 2.5 M n-BuLi (in Hexanes) 7.7 mL (19.1 mmol) was slowly added dropwise at -78°C, and the mixture was stirred for 1 hour. 1-bromo-3-fluoro-2-nitrobenzene 4.6 g (20.9 mmol) was dissolved in 9 mL of tetrahydrofuran, and then slowly added dropwise at -78°C. The mixture was stirred for 1 hour at -78°C, and then for 1 hour at room temperature. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was dissolved in hexane and then recrystallized with ethanol to obtain 3.5 g (yield: 41.6%) of an orange solid compound (intermediate (187)).

[0902] (Synthesis of intermediate (188))

[0903] Intermediate (187) 3.5 g (7.1 mmol), Fe 2.4 g (42.6 mmol), and ethanol (EtOH) 70 mL were mixed, and 14.2 mL (14.2 mmol) of 1.0 M NH4Cl aqueous solution was added and refluxed and stirred for 3 hours. After the reaction was completed, the reaction solution was filtered through a celite pad using dichloromethane to remove inorganic substances, and then concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was extracted with organic substances using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure to remove the solvent to obtain 3.2 g (yield: 100.0%) of a compound (intermediate (188)) as a pale-colored solid.

[0904] (Synthesis of intermediate (189))

[0905] Intermediate (188) 3.2 g (6.9 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 1.4 g (7.6 mmol), Na2S2O5 1.6 g (8.3 mmol), and dimethylformamide 64 mL were mixed and stirred at 120°C for one day. After the reaction was completed, the mixture was cooled to room temperature and distilled water was added to precipitate a solid. The precipitated solid was filtered under reduced pressure, dissolved in dichloromethane, dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.4 g (yield: 80.2%) of a white solid compound (intermediate (189)).

[0906]

[0907] Intermediate Synthesis Example 87: Synthesis of Intermediate (190)

[0908]

[0909] Intermediate (189) 3.4 g (5.5 mmol), intermediate (41) 2.8 g (6.6 mmol), Pd(OAc) 261.7 mg (0.3 mmol), SPhos 225.8 mg (0.6 mmol), K2CO3 2.3 g (16.5 mmol), xylene 85 mL, and distilled water 9 mL were mixed, then refluxed and stirred for 3 hours. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.6 g (yield: 77.2%) of the compound (intermediate (190)) as an off-white solid.

[0910]

[0911] Intermediate Synthesis Example 88: Synthesis of Intermediate (191)

[0912]

[0913] Intermediate (181) 7.9 g (15.6 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 4.4 g (18.8 mmol), Na2S2O5 3.9 g (20.3 mmol), and dimethylformamide (N,N'-Dimethylformamide) 90 mL were mixed and stirred at 130°C for one day. After the reaction was completed, the mixture was cooled to room temperature, and the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 5.8 g (yield: 51.5%) of a compound (intermediate (191)) as a beige solid.

[0914]

[0915] Intermediate Synthesis Example 89: Synthesis of Intermediate (192)

[0916]

[0917] Intermediate (191) 4.1 g (5.7 mmol), intermediate (41) 3.0 g (6.9 mmol), Pd(OAc) 265.0 mg (0.3 mmol), SPhos 246.3 mg (0.6 mmol), 2.0 M K3PO4 aqueous solution 8.7 mL (17.3 mmol), and toluene 70 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 4.7 g (yield: 87.6%) of the compound (intermediate (192)) as a pale yellow solid.

[0918]

[0919] Intermediate synthesis example 90: Synthesis of intermediate (195)

[0920]

[0921] (Synthesis of intermediate (193))

[0922] 5-(tert-butyl)-[1,1'-biphenyl]-2-amine (50.0 g, 221.9 mmol) and tetrahydrofuran (1000 mL) were mixed and cooled to -78°C. 2.5 M n-BuLi (in Hexanes) (97.6 mL, 244.1 mmol) was slowly added dropwise at -78°C, and the mixture was stirred for 1 hour. 1-bromo-3-fluoro-2-nitrobenzene (58.6 g, 266.3 mmol) was dissolved in 118 mL of tetrahydrofuran, and the mixture was slowly added dropwise at -78°C, and the mixture was stirred for 30 minutes. After stirring for 30 minutes, the mixture was stirred at room temperature for 1 day. After the reaction was completed, the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) and then recrystallized from hexane to obtain 65.1 g (yield: 69.0%) of an orange solid compound (intermediate (193)).

[0923] (Synthesis of intermediate (194))

[0924] Intermediate (193) 65.1 g (153.1 mmol), Fe 42.7 g (765.3 mmol), and ethanol (EtOH) 976.5 mL were mixed, and 153.1 mL (306.2 mmol) of 2.0 M NH4Cl aqueous solution was added and refluxed and stirred for one day. After the reaction was completed, the reaction solution was filtered through a pad of celite using dichloromethane to remove inorganic substances, and the organic layer was extracted with dichloromethane. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol and hexane to obtain 30.8 g (yield: 50.9%) of an off-white solid compound (intermediate (194)).

[0925] (Synthesis of intermediate (195))

[0926] Intermediate (194) 30.8 g (77.9 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 21.9 g (93.5 mmol), Na2S2O5 17.8 g (93.5 mmol), and dimethylformamide 308 mL were mixed and stirred at 120°C for one day. After the reaction was completed, it was cooled to room temperature, distilled water was added, and a solid was precipitated. The precipitated solid was washed with methanol and filtered under reduced pressure. The obtained solid was dissolved in dichloromethane, and the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, and then purified by silica gel column chromatography (DCM: Hexanes). The obtained mixture was solidified with dichloromethane and methanol to obtain 41.9 g (yield: 88.2%) of a beige solid compound (intermediate (195)).

[0927]

[0928] Intermediate synthesis example 91: Synthesis of intermediate (198)

[0929]

[0930] (Synthesis of intermediate (196))

[0931] Intermediate (185) 8.3 g (30.5 mmol), 2-chloro-4-iodopyridine 7.7 g (32.0 mmol), Pd(PPh3) 41.1 g (0.9 mmol), K2CO3 12.6 g (91.5 mmol), toluene 100 mL, distilled water 30 mL, and ethanol 30 mL were added, and the mixture was refluxed overnight. After cooling to room temperature, DCM and distilled water were added, and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The compound (intermediate (196)) 7.2 g (yield: 91.7%) was obtained as a light yellow solid by purification by silica gel column chromatography (DCM:Hexanes).

[0932] (Synthesis of intermediate (197))

[0933] Intermediate (196) 7.2 g (27.9 mmol), (3-(tert-butyl-5-chlorophenyl)boronic acid 6.2 g (29.3 mmol), Pd(PPh3) 41.0 g (0.8 mmol), K2CO3 11.6 g (83.8 mmol), toluene 100 mL, distilled water 30 mL, and ethanol 30 mL were mixed and stirred under reflux overnight. After cooling to room temperature, the organic layer was extracted with DCM and distilled water. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The compound (intermediate (197)) 9.5 g (yield: 87.3%) was obtained as a light yellow liquid by purification by silica gel column chromatography (DCM:Hexanes).

[0934] (Synthesis of intermediate (198))

[0935] Intermediate (197) 9.5 g (24.4 mmol), PIN2B 27.4 g (29.2 mmol), Pd(dba) 20.4 g (0.7 mmol), XPhos 0.7 g (14.6 mmol), KOAc 7.2 g (73.1 mmol) and dioxane 100 mL were mixed and stirred under reflux overnight. After the reaction was completed, the mixture was cooled to room temperature and concentrated. Dichloromethane and distilled water were added, and the organic layer was extracted. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) and recrystallized with a mixed solvent (DCM:Hexanes) to obtain 4.2 g (yield: 36.0%) of the compound (intermediate (198)) as an ivory solid.

[0936]

[0937] Intermediate synthesis example 92: Synthesis of intermediate (199)

[0938]

[0939] Intermediate (195) 2.7 g (4.4 mmol), intermediate (198) 2.0 g (4.2 mmol), Pd(PPh3) 40.2 g (0.1 mmol), K2CO3 1.7 g (12.5 mmol), toluene 20 mL, distilled water 6 mL, and ethanol 6 mL were mixed and stirred under reflux overnight. After cooling to room temperature, DCM and distilled water were added, and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The compound (intermediate (199)) as a light yellow solid 9.5 g (yield: 87.3%) was purified by silica gel column chromatography (DCM:Hexanes).

[0940]

[0941] Intermediate synthesis example 93: Synthesis of intermediate (202)

[0942]

[0943] (Synthesis of intermediate (200))

[0944] Intermediate (166) 51.6 g (200.0 mmol), 2-chloro-4-iodopyridine 47.8 g (200.0 mmol), Pd(PPh3) 44.6 g (4.0 mmol), Na2CO3 63.6 g (600 mmol), toluene 100 mL, ethanol (EtOH) 100 mL, and H2O 100 mL were mixed and stirred under reflux for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes), concentrated and dried to obtain 24.7 g (yield: 50.7%) of a wine-colored liquid compound (intermediate (200)).

[0945] (Synthesis of intermediate (201))

[0946] Intermediate (200) 18.3 g (75.0 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 16.0 g (75.0 mmol), Pd(PPh3) 44.3 g (3.7 mmol), K2CO3 31.0 g (225.0 mmol), toluene 180 mL, ethanol (EtOH) 40 mL, and H2O 40 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate and filtered. After concentration, it was dissolved in dichloromethane and passed through a silica gel pad. After concentrating the filtrate, it was solidified with methanol and filtered under reduced pressure to obtain 25.5 g (yield: 67.8%) of the compound (intermediate (201)) as a light yellow solid.

[0947] (Synthesis of intermediate (202))

[0948] Intermediate (201) 25.5 g (67.8 mmol), PIN2B 225.3 g (100.0 mmol), Pd(dba) 23.1 g (3.4 mmol), XPhos 3.2 g (6.7 mmol), KOAc 20.0 g (200.0 mmol), and toluene 250 mL were mixed and stirred under reflux overnight. After the reaction was completed, the mixture was cooled to room temperature, and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes). After concentration, the mixture was solidified with methanol and hexane to obtain 23.3 g (yield: 73.5%) of the compound (Intermediate (202)) as an off-white solid.

[0949]

[0950] Intermediate synthesis example 94: Synthesis of intermediate (203)

[0951]

[0952] Intermediate (195) 3.5 g (5.7 mmol), Intermediate (202) 3.5 g (7.5 mmol), Pd(OAc) 264.0 mg (0.3 mmol), SPhos 246.3 mg (0.6 mmol), 2.0 M K2CO3 aqueous solution 8.6 mL (17.1 mmol) and 70 mL of xylene were mixed and stirred at 130°C for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with methanol to obtain 3.5 g (yield: 70.1%) of the compound (intermediate (203)) as a pale yellow solid.

[0953]

[0954] Intermediate synthesis example 95: Synthesis of intermediate (206)

[0955]

[0956] (Synthesis of intermediate (204))

[0957] 2-chloro-4-iodopyridine (7.0 g (29.2 mmol), intermediate (88) (10.5 g (35.1 mmol), Pd(PPh3) (41.0 g (0.9 mmol), K2CO3 (10.1 g (73.0 mmol), toluene (117 mL), ethanol (EtOH) (29 mL), and H2O (29 mL) were mixed and stirred at 70°C for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water, and the extracted organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered through silica gel and celite (204) using toluene, and the solvent was removed by concentration under reduced pressure to obtain 8.3 g (yield: 100.0%) of the compound (intermediate (204)) as a red solid.

[0958] (Synthesis of intermediate (205))

[0959] Intermediate (204) 8.3 g (29.0 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 7.4 g (34.8 mmol), Pd(PPh3) 41.0 g (0.9 mmol), K2CO3 10.0 g (72.5 mmol), toluene 145 mL, ethanol (EtOH) 36 mL, and H2O 36 mL were mixed and refluxed and stirred for 4 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 12.1 g (yield: 100.0%) of a yellow oily compound (intermediate (205)).

[0960] (Synthesis of intermediate (206))

[0961] Intermediate (205) 12.1 g (28.9 mmol), B2PIN2 11.0 g (43.3 mmol), Pd(dba) 20.5 g (0.9 mmol), XPhos 1.4 g (2.9 mmol), KOAc 8.5 g (86.7 mmol), and toluene 242.0 mL were mixed and refluxed and stirred for 4 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes) to obtain 14.4 g (yield: 98.1%) of the compound (intermediate (206)) as a yellow solid.

[0962]

[0963] Intermediate synthesis example 96: Synthesis of intermediate (207)

[0964]

[0965] Intermediate (195) 4.5 g (7.4 mmol), Intermediate (206) 5.6 g (11.1 mmol), Pd(OAc)283.0 mg (0.4 mmol), SPhos 0.3 g (0.8 mmol), 2.0 M K2CO3 11.1 mL (22.2 mmol) of aqueous solution and 135 mL of xylene were mixed, then refluxed and stirred for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes), and then solidified with dichloromethane and methanol to obtain 3.7 g (yield: 55.8%) of the compound (intermediate (207)) as a white solid.

[0966]

[0967] Intermediate synthesis example 97: Synthesis of intermediate (208)

[0968]

[0969] Intermediate (195) 3.5 g (5.7 mmol), Intermediate (24) 3.5 g (7.5 mmol), Pd(OAc) 264.0 mg (0.3 mmol), SPhos 246.3 mg (0.6 mmol), 2.0 M K2CO3 aqueous solution 8.6 mL (17.1 mmol) and 70 mL of xylene were mixed and stirred at 120°C for 5 hours. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 4.3 g (yield: 86.0%) of the compound (intermediate (208)) as an off-white solid.

[0970]

[0971] Intermediate synthesis example 98: Synthesis of intermediate (209)

[0972]

[0973] Intermediate (195) 3.0 g (4.9 mmol), Intermediate (32) 3.1 g (5.9 mmol), Pd(OAc) 255.0 mg (0.2 mmol), SPhos 301.7 mg (0.7 mmol), K2CO3 2.0 g (14.7 mmol), 60 mL of xylene, and 6 mL of H2O were mixed, and the mixture was refluxed and stirred for 5 hours. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.4 g (yield: 74.6%) of the compound (intermediate (209)) as an off-white solid.

[0974]

[0975] Intermediate synthesis example 99: Synthesis of intermediate (213)

[0976]

[0977] (Synthesis of intermediate (210))

[0978] Intermediate (34) 20.0 g (87.7 mmol), 4-fluorophenylboronic acid 18.4 g (131.5 mmol), Pd(PPh3) 42.0 g (1.8 mmol), K2CO3 36.6 g (263.0 mmol), toluene 300 mL, ethanol 60 mL, and distilled water 60 mL were mixed and stirred at 90°C overnight. After cooling to room temperature, distilled water was added, and the organic layer was separated. The separated organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM: Hexanes) and recrystallized from dichloromethane and hexane to obtain 18.1 g (yield: 84.4%) of the compound (intermediate (210)) as a white solid.

[0979] (Synthesis of intermediate (211))

[0980] Intermediate (210) 18.3 g (75.0 mmol) and 200 mL of tetrahydrofuran were mixed and cooled to -78°C. n-BuLi 35.5 mL (2.5 M in hexane, 88.6 mmol) was slowly added and stirred at -78°C for 1 hour. 1-Bromo-3-fluoro-2-nitrobenzene 15.0 g (68.2 mmol) was dissolved in 30 mL of tetrahydrofuran and slowly added to the reaction mixture. After stirring at -78°C for 2 hours, the mixture was stirred at room temperature for 3 hours. Distilled water was added to terminate the reaction, and the mixture was concentrated under reduced pressure to remove tetrahydrofuran. DCM was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (EtOAc:Hexanes), 12.6 g (yield: 41.7%) of the compound (intermediate (211)) as a red solid was obtained by recrystallization with ethanol.

[0981] (Synthesis of intermediate (212))

[0982] Intermediate (211) 12.6 g (28.4 mmol), Fe 7.9 g (142.1 mmol), ammonium chloride 1.5 g (28.4 mmol), EtOH 135 mL and distilled water 15 mL were mixed and stirred under reflux overnight. The mixture was passed through a celite pad and washed with DCM. Distilled water was added, and the organic layer was separated. The separated organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The compound (intermediate (212) 11.0 g (yield: 93.6%) was obtained as a pale yellow liquid by purification by silica gel column chromatography (DCM: Hexanes).

[0983] (Synthesis of intermediate (213))

[0984] Intermediate (212) 11.0 g (26.6 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 6.6 g (27.9 mmol), Na2S2O5 6.3 g (33.3 mmol), and DMF 60 mL were mixed and stirred at 120°C overnight. After cooling to room temperature, DMF was removed under reduced pressure. DCM and distilled water were added, and the organic layer was separated. The separated organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM: Hexanes), 10.5 g (yield: 62.9%) of the compound (intermediate (213)) as a pale yellow solid was obtained.

[0985]

[0986] Intermediate synthesis example 100: Synthesis of intermediate (214)

[0987]

[0988] Intermediate (213) 4.0 g (6.4 mmol), Intermediate (24) 4.5 g (9.6 mmol), Pd(OAc) 272.0 mg (0.3 mmol), SPhos 262.7 mg (0.6 mmol), 2.0 M K2CO3 aqueous solution 9.6 mL (19.2 mmol) and 80 mL of xylene were mixed and stirred at 120°C for one day. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 5.0 g (yield: 89.8%) of the compound (intermediate (214)) as an off-white solid.

[0989]

[0990] Intermediate Synthesis Example 101: Synthesis of Intermediate (215)

[0991]

[0992] Intermediate (194) 4.0 g (10.1 mmol), 5-tert-butyl-2-hydroxybenzaldehyde 2.0 g (11.1 mmol), Na2S2O5 2.3 g (12.1 mmol), and dimethylformamide (N,N'-Dimethylformamide) 80 mL were mixed and stirred at 130°C for one day. After the reaction was completed, the mixture was cooled to room temperature and distilled water was added to precipitate a solid. The precipitated solid was washed with distilled water and filtered under reduced pressure. The obtained solid was dissolved in dichloromethane, and the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite and a silica gel pad, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was recrystallized from dichloromethane and methanol to obtain 3.5 g (yield: 62.5%) of a compound (intermediate (215)) as a light-colored solid.

[0993]

[0994] Intermediate Synthesis Example 102: Synthesis of Intermediate (216)

[0995]

[0996] Intermediate (215) 3.5 g (6.3 mmol), intermediate (32) 4.0 g (7.6 mmol), Pd2(dba) 30.3 g (0.3 mmol), SPhos 0.4 g (0.9 mmol), K3PO4 4.0 g (18.9 mmol), xylene 70 mL, and H2O 7 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then recrystallized from dichloromethane and methanol to obtain 3.5 g (yield: 64.0%) of the compound (intermediate (216)) as an off-white solid.

[0997]

[0998] Intermediate Synthesis Example 103: Synthesis of Intermediate (220)

[0999]

[1000] (Synthesis of intermediate (217))

[1001] Intermediate (34) 40.0 g (175.3 mmol), dibenzo[b,d]furan-4-ylboronic acid 44.6 g (210.4 mmol), Pd(PPh3) 46.1 g (5.3 mmol), K2CO3 72.7 g (525.9 mmol), toluene 701 mL, ethanol (EtOH) 175 mL, and H2O 175 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite using toluene, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with dichloromethane and ethanol to obtain 34.0 g (yield: 61.5%) of a pale yellow solid compound (intermediate (217)).

[1002] (Synthesis of intermediate (218))

[1003] Intermediate (217) 34.0 g (107.8 mmol) and tetrahydrofuran 680 mL were mixed and cooled to -78°C. 2.5 M n-BuLi (in Hexanes) 47.4 mL (118.6 mmol) was slowly added dropwise at -78°C, and the mixture was stirred for 2 hours. 1-bromo-3-fluoro-2-nitrobenzene 28.5 g (129.4 mmol) was dissolved in 57 mL of tetrahydrofuran, and the mixture was slowly added dropwise at -78°C, and the mixture was stirred for 30 minutes. After stirring for 30 minutes, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes), and then recrystallized from ethanol and hexane to obtain 23.0 g (yield: 41.4%) of an orange solid compound (intermediate (218)).

[1004] (Synthesis of intermediate (219))

[1005] Intermediate (218) 23.0 g (44.6 mmol), Fe 12.4 g (223.1 mmol), and ethanol (EtOH) 460 mL were mixed, and 2.0 M NH4Cl aqueous solution 44.6 mL (89.2 mmol) was added, and the mixture was refluxed and stirred for 4 hours. After the reaction was completed, the reaction solution was filtered through a pad of celite using dichloromethane to remove inorganic substances, and then concentrated under reduced pressure to remove the solvent. The organic layer of the obtained reaction mixture was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 19.2 g (yield: 88.6%) of an off-white solid compound (intermediate (219)).

[1006] (Synthesis of intermediate (220))

[1007] Intermediate (219) 19.2 g (39.6 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 7.8 g (43.5 mmol), Na2S2O 59.0 g (47.5 mmol), and dimethylformamide 192 mL were mixed and stirred at 110°C for one day. After the reaction was completed, the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained mixture was solidified with dichloromethane and methanol to obtain 14.0 g (yield: 54.9%) of the compound (intermediate (220)) as an off-white solid.

[1008]

[1009] Intermediate Synthesis Example 104: Synthesis of Intermediate (221)

[1010]

[1011] Intermediate (220) 4.0 g (6.2 mmol), Intermediate (24) 3.8 g (8.1 mmol), Pd(OAc) 270.0 mg (0.3 mmol), SPhos 254.5 mg (0.6 mmol), 2.0 M K2CO3 aqueous solution 9.3 mL (18.6 mmol) and 80 mL of xylene were mixed and stirred at 120°C for 7 hours. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 2.0 g (yield: 35.6%) of the compound (intermediate (221)) as an off-white solid.

[1012]

[1013] Intermediate Synthesis Example 105: Synthesis of Intermediate (222)

[1014]

[1015] Intermediate (215) 4.0 g (7.2 mmol), Intermediate (18) 3.9 g (8.8 mmol), Pd(OAc)281.1 mg (0.4 mmol), SPhos 445.0 mg (1.1 mmol), 2.0 M K2CO3 aqueous solution 10.8 mL (21.7 mmol) and 80 mL of xylene were mixed and stirred at 120°C for 7 hours. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 2.0 g (yield: 34.5%) of the compound (intermediate (222)) as an off-white solid.

[1016]

[1017] Using the intermediate compound synthesized above, various organometallic complexes were synthesized as follows.

[1018]

[1019] Manufacturing Example 1: Synthesis of Compound 3-1 (LT23-35-103)

[1020]

[1021] Intermediate (8) 2.5 g (3.4 mmol), K2PtCl4 1.7 g (4.0 mmol) and acetic acid 135 mL were mixed and stirred at 110°C for 2 days. Since the starting material remained, 27 mL of distilled water was added and stirred at 110°C for 1 day. After the reaction was completed, the mixture was concentrated under reduced pressure to remove acetic acid. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract the organic matter, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was adsorbed on silica gel, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 1.2 g (yield: 38.1%) of compound 3-1 (LT23-35-103) as a yellow solid.

[1022]

[1023] Manufacturing Example 2: Synthesis of compound 3-3 (LT23-35-105)

[1024]

[1025] Intermediate (13) 2.5 g (3.3 mmol), K2PtCl4 1.6 g (4.0 mmol) and acetic acid 130 mL were mixed and stirred at 110°C for 2 days. Since the starting material remained, 27 mL of distilled water was added and stirred at 110°C for 1 day. After the reaction was completed, the mixture was concentrated under reduced pressure to remove acetic acid. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract organic matter, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was adsorbed on silica gel, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 1.1 g (yield: 35.1%) of compound 3-3 (LT23-35-105) as a yellow solid.

[1026]

[1027] Manufacturing Example 3: Synthesis of Compound 3-21 (LT23-35-104)

[1028]

[1029] Intermediate (19) 2.5 g (3.2 mmol), K2PtCl4 1.6 g (3.8 mmol) and acetic acid 130 mL were mixed and stirred at 110°C for 2 days. Since the starting material remained, 27 mL of distilled water was added and stirred at 110°C for 1 day. After the reaction was completed, the mixture was concentrated under reduced pressure to remove acetic acid. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract organic matter, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was adsorbed on silica gel, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 1.3 g (yield: 41.7%) of compound 3-21 (LT23-35-104) as a yellow solid.

[1030]

[1031] Manufacturing Example 4: Synthesis of compound 3-25 (LT23-35-109)

[1032]

[1033] Intermediate (25) 2.2 g (2.8 mmol), K2PtCl4 1.4 g (3.3 mmol) and acetic acid 110 mL were mixed and stirred at 110°C for 2 days. Since the starting material remained, 27 mL of distilled water was added and stirred at 110°C for 1 day. After the reaction was completed, the mixture was concentrated under reduced pressure to remove acetic acid. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract the organic matter, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was adsorbed on silica gel, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 1.0 g (yield: 36.6%) of compound 3-25 (LT23-35-109) as a yellow solid.

[1034]

[1035] Manufacturing Example 5: Synthesis of Compound 3-26 (LT23-35-110)

[1036]

[1037] Intermediate (33) 2.8 g (3.3 mmol), K2PtCl4 1.6 g (3.9 mmol) and acetic acid 130 mL were mixed and stirred at 110°C for 2 days. Since the starting material remained, 27 mL of distilled water was added and stirred at 110°C for 1 day. After the reaction was completed, the mixture was concentrated under reduced pressure to remove acetic acid. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract organic matter, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was adsorbed on silica gel, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 1.3 g (yield: 37.8%) of compound 3-26 (LT23-35-110) as a yellow solid.

[1038]

[1039] Manufacturing Example 6: Synthesis of compound 3-41 (LT23-35-107)

[1040]

[1041] Intermediate (42) 3.6 g (4.5 mmol), K2PtCl4 2.3 g (5.4 mmol) and acetic acid 180 mL were mixed and stirred at 110℃ for one day. The reaction progress was confirmed through TLC and LC / MS to confirm whether there was any starting material remaining. Distilled water was added so that all the starting material remaining could participate in the reaction, and the mixture was refluxed and stirred for 5 hours. After the reaction was completed, it was cooled to room temperature, and the acetic acid was removed by concentration under reduced pressure, and the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then recrystallized from dichloromethane and hexane to obtain 2.6 g (yield: 58.1%) of compound 3-41 (LT23-35-107) as a yellow solid.

[1042]

[1043] Manufacturing Example 7: Synthesis of compound 3-65 (LT23-35-112)

[1044]

[1045] In a nitrogen atmosphere, 1.8 g (2.1 mmol) of intermediate (47) and 1.1 g (2.6 mmol) of potassium tetrachloroplatinate were added to a mixture of 83 mL of acetic acid and 27 mL of distilled water, and the mixture was reacted for 48 h while maintaining the temperature at 100°C. After completion of the reaction, the mixture was concentrated under reduced pressure, and the obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) and solidified with acetic acid to obtain 1.7 g (yield: 76.9%) of compound 3-65 (LT23-35-112) as a yellow solid.

[1046]

[1047] Manufacturing Example 8: Synthesis of compound 3-212 (LT22-30-161)

[1048]

[1049] 2.5 g (3.2 mmol) of intermediate (50), 1.6 g (3.8 mmol) of potassium tetrachloroplatinate (K2PtCl4), and 105 mL of acetic acid were added, and the mixture was stirred at 105°C for 36 hours. After cooling to room temperature, the acetic acid was concentrated, and methanol was added. The formed precipitate was filtered and washed with distilled water and methanol. The obtained solid was dried, purified by silica gel column chromatography (DCM:Hexanes), and recrystallized under DCM / Hexanes solvent conditions to obtain 2.4 g (yield: 75.4%) of compound 3-212 (LT22-30-161) as a yellow solid.

[1050]

[1051] Manufacturing Example 9: Synthesis of compound 3-214 (LT23-35-121)

[1052]

[1053] Intermediate (75) 3.0 g (3.5 mmol), potassium tetrachloroplatinate (K2PtCl4) 1.7 g (4.1 mmol), and acetic acid 138 mL were added and stirred at 105°C for 36 hours. After cooling to room temperature, the acetic acid was concentrated and methanol was added. The formed precipitate was filtered and washed with distilled water and methanol. The obtained solid was dried, purified by silica gel column chromatography (DCM:Hexanes), and recrystallized under DCM / Hexanes solvent conditions to obtain 1.5 g (yield: 40.9%) of compound 3-214 (LT23-35-121) as a yellow solid.

[1054]

[1055] Manufacturing Example 10: Synthesis of compound 3-228 (LT23-35-125)

[1056]

[1057] Intermediate (79) 5.3 g (6.4 mmol), K2PtCl4 3.4 g (8.3 mmol), 460 mL of acetic acid, and 155 ml of distilled water were mixed and reacted at 110°C for 2 days. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, filtered, and washed with methanol. The obtained mixture was purified by silica gel column chromatography (Hex:CHCl3 = 1:2) and recrystallized with acetone to obtain 3.4 g (yield: 52.0%) of compound 3-228 (LT23-35-125) as a yellow solid.

[1058]

[1059] Manufacturing Example 11: Synthesis of compound 3-229 (LT23-35-126)

[1060]

[1061] Intermediate (83) 2.7 g (3.3 mmol), K2PtCl4 1.6 g (4.0 mmol), AcOH 130 mL and distilled water 10 mL were mixed, then the temperature was increased to 130°C and the reaction was conducted for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, the solid was filtered, washed with distilled water and methanol, dried, purified by silica gel column chromatography (Hexanes: CHCl3), and solidified with a mixed solvent (DCM / Acetone) to obtain 2.3 g (yield: 68.9%) of compound 3-229 (LT23-35-126) as a yellow solid.

[1062]

[1063] Manufacturing Example 12: Synthesis of compound 3-302 (LT23-35-130)

[1064]

[1065] Intermediate (93) 4.2 g (4.5 mmol), K2PtCl4 2.4 g (5.9 mmol), acetic acid 180 mL, and H2O 20 mL were mixed and stirred at 100°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and distilled water was added. The precipitated solid was washed with distilled water and methanol and filtered under reduced pressure. The obtained solid was dissolved in dichloromethane and washed with distilled water, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 1.9 g (yield: 37.4%) of compound 3-302 (LT23-35-130) as a pale orange solid.

[1066]

[1067] Manufacturing Example 13: Synthesis of compound 3-323 (LT22-30-269)

[1068]

[1069] Intermediate (56) 3.5 g (4.2 mmol), K2PtCl4 2.1 g (5.0 mmol) and acetic acid 175 mL were mixed and refluxed and stirred for 5 days. After the reaction was completed, it was cooled to room temperature and the precipitated solid was filtered under reduced pressure. The obtained solid was dissolved in dichloromethane, and the organic matter was extracted using dichloromethane and distilled water, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and hexane to obtain 2.0 g (yield: 46.5%) of compound 3-323 (LT22-30-269) as a yellow solid.

[1070]

[1071] Manufacturing Example 14: Synthesis of compound 3-324 (LT22-30-267)

[1072]

[1073] Intermediate (65) 3.3 g (4.1 mmol), K2PtCl4 2.1 g (5.0 mmol) and acetic acid 165 mL were mixed and refluxed and stirred for 4 days. After the reaction was completed, it was cooled to room temperature and the precipitated solid was filtered under reduced pressure. The obtained solid was dissolved in dichloromethane, and the organic matter was extracted using dichloromethane and distilled water, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and hexane to obtain 3.2 g (yield: 78.0%) of compound 3-324 (LT22-30-267) as a yellow solid.

[1074]

[1075] Manufacturing Example 15: Synthesis of compound 3-329 (LT22-30-308)

[1076]

[1077] Intermediate (71) 3.0 g (4.0 mmol), K2PtCl4 2.0 g (4.8 mmol), and acetic acid 160 mL (4.0 mmol) were mixed. The reaction mixture was stirred at 110°C overnight. After the reaction was quenched with distilled water, dichloromethane was extracted from the reaction solution. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (DCM: Hexanes) and recrystallized from dichloromethane and hexane to obtain 2.4 g (yield: 64.8%) of compound 3-329 (LT22-30-308) as a yellow solid.

[1078]

[1079] Manufacturing Example 16: Synthesis of compound 3-370 (LT22-30-248)

[1080]

[1081] Intermediate (62) 2.5 g (3.2 mmol), K2PtCl4 1.6 g (3.8 mmol) and acetic acid 127 mL were mixed and stirred at 110°C for 2 days. Since the starting material remained, 25 mL of distilled water was added and stirred at 110°C for 1 day. After the reaction was completed, the mixture was concentrated under reduced pressure to remove acetic acid. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract organic matter, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was adsorbed on silica gel, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 1.0 g (yield: 32.3%) of compound 3-370 (LT22-30-248) as a yellow solid.

[1082]

[1083] Manufacturing Example 17: Synthesis of compound 4-11 (LT23-35-129)

[1084]

[1085] Intermediate (102) 3.3 g (4.4 mmol), K2PtCl4 2.2 g (5.2 mmol) and acetic acid 174 mL were mixed and refluxed and stirred for 3 days. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract the organic matter, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 1.3 g (yield: 31.4%) of compound 4-11 (LT23-35-129) as a yellow solid.

[1086]

[1087] Manufacturing Example 18: Synthesis of Compound 4-13 (LT23-30-001)

[1088]

[1089] Intermediate (103) 4.6 g (6.0 mmol), K2PtCl4 3.0 g (7.2 mmol), and acetic acid 184 mL were mixed, and then refluxed and stirred for 3 days. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract organic matter, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 3.2 g (yield: 55.5%) of compound 4-13 (LT23-30-001) as a yellow solid.

[1090]

[1091] Manufacturing Example 19: Synthesis of compound 4-18 (LT23-35-135)

[1092]

[1093] Intermediate (104) 3.1 g (3.6 mmol), K2PtCl4 1.8 g (4.4 mmol) and acetic acid 40 mL were mixed and refluxed and stirred for 3 days. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract the organic matter, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 1.1 g (yield: 28.9%) of compound 4-18 (LT23-35-135) as a yellow solid.

[1094]

[1095] Manufacturing Example 20: Synthesis of compound 4-26 (LT23-35-133)

[1096]

[1097] Intermediate (112) 4.8 g (5.7 mmol), K2PtCl4 2.9 g (6.9 mmol), AcOH 400 mL, and distilled water 100 mL were added, and the temperature was raised to 130℃ and reacted for 2 days. After the reaction was completed, it was cooled to room temperature, the solid was filtered, washed with distilled water and methanol, and dried. The solid thus obtained was dissolved in DCM, purified by silica gel column chromatography (Hexanes: CHCl3), and solidified with a mixed solvent (DCM / EtOAc) to obtain 2.2 g (yield: 37.2%) of compound 4-26 (LT23-35-133) as a yellow solid.

[1098]

[1099] Manufacturing Example 21: Synthesis of compound 4-32 (LT23-35-137)

[1100]

[1101] Intermediate (120) 3.5 g (3.8 mmol), K2PtCl4 1.9 g (4.6 mmol), AcOH 150 mL, and distilled water 15 mL were added, and the temperature was raised to 130℃ and reacted for 2 days. After the reaction was completed, it was cooled to room temperature, the solid was filtered, washed with distilled water and methanol, and dried. The solid thus obtained was dissolved in DCM, purified by silica gel column chromatography (Hexanes: CHCl3), and solidified with a mixed solvent (DCM / EtOAc) to obtain 1.2 g (yield: 28.3%) of compound 4-32 (LT23-35-137) as a yellow solid.

[1102]

[1103] Manufacturing Example 22: Synthesis of Compound 4-87 (LT23-35-172)

[1104]

[1105] Intermediate (121) 4.2 g (4.6 mmol), K2PtCl4 2.3 g (5.6 mmol), and acetic acid 185 mL (4.6 mmol) were mixed. The reaction mixture was stirred at 110°C overnight. After the reaction was quenched with distilled water, dichloromethane was extracted from the reaction solution. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (DCM: Hexanes) and recrystallized from dichloromethane and hexane to obtain 2.5 g (yield: 49.0%) of compound 4-87 (LT23-35-172) as a yellow solid.

[1106]

[1107] Manufacturing Example 23: Synthesis of Compound 4-92 (LT23-35-151)

[1108]

[1109] Intermediate (130) 2.9 g (3.3 mmol), K2PtCl4 1.7 g (4.0 mmol), and acetic acid 133 mL (3.3 mmol) were mixed. The reaction mixture was stirred at 110°C overnight. After the reaction was quenched with distilled water, dichloromethane was extracted from the reaction solution. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (DCM: Hexanes) and recrystallized from dichloromethane and hexane to obtain 1.5 g (yield: 42.3%) of compound 4-92 (LT23-35-151) as a yellow solid.

[1110]

[1111] Manufacturing Example 24: Synthesis of compound 4-182 (LT23-30-044)

[1112]

[1113] Intermediate (138) 3.2 g (3.6 mmol), K2PtCl4 2.0 g (4.7 mmol), acetic acid 160 mL, and H2O 53 mL were mixed and stirred at 105℃ (internal temperature) for 2 days. After the reaction was completed, it was cooled to room temperature, and the precipitated solid was washed with distilled water and methanol, filtered under reduced pressure, and dried. The obtained solid was dissolved in dichloromethane, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 2.7 g (yield: 69.4%, purity: 97.0%) of compound 4-182 as a yellow solid. 2.7 g of the solid was dissolved in dichloromethane, adsorbed onto silica gel, purified by silica gel column chromatography (EtOAc:Hexanes), and solidified with dichloromethane and hexane to obtain 0.9 g (yield: 24.4%) of compound 4-182 (LT23-30-044) as a yellow solid.

[1114]

[1115] Manufacturing Example 25: Synthesis of compound 4-183 (LT23-30-049)

[1116]

[1117] Intermediate (139) 3.3 g (3.6 mmol), K2PtCl4 1.9 g (4.6 mmol), acetic acid 165 mL, and H2O 55 mL were mixed and stirred at 110°C (internal temperature) for one day. After the reaction was completed, it was cooled to room temperature, and the precipitated solid was washed with distilled water and methanol and filtered under reduced pressure. The obtained solid was dissolved in dichloromethane, purified by silica gel column chromatography (DCM:Hexanes), and then solidified with acetone and hexane to obtain 1.4 g (yield: 35.0%) of compound 4-183 (LT23-30-049) as a yellow solid.

[1118]

[1119] Manufacturing Example 26: Synthesis of compound 4-191 (LT22-30-194)

[1120]

[1121] Intermediate (141) 3.0 g (3.6 mmol), potassium tetrachloroplatinate (K2PtCl4) 1.8 g (4.4 mmol), and acetic acid 120 mL were mixed and stirred at 105°C for 36 hours. After cooling to room temperature, the acetic acid was concentrated, methanol was added, and the formed solid was filtered and washed with distilled water and methanol. After drying, it was purified by silica gel column chromatography (DCM:Hexanes) and recrystallized from a mixed solution (DCM:Hexanes) to obtain 1.1 g (yield: 30.9%) of compound 4-191 (LT22-30-194) as a yellow solid.

[1122]

[1123] Manufacturing Example 27: Synthesis of compound 4-368 (LT23-35-139)

[1124]

[1125] Intermediate (146) 2.9 g (3.0 mmol), potassium tetrachloroplatinate (K2PtCl4) 1.5 g (3.6 mmol), and acetic acid 120 mL were mixed and stirred at 105°C for 36 hours. After cooling to room temperature, the acetic acid was concentrated, methanol was added, and the formed solid was filtered and washed with distilled water and methanol. After drying, it was purified by silica gel column chromatography (DCM:Hexanes) and recrystallized from a mixed solution (DCM:Hexanes) to obtain 1.3 g (yield: 37.4%) of compound 4-368 (LT23-35-139) as a yellow solid.

[1126]

[1127] Manufacturing Example 28: Synthesis of Compound 5-3 (LT23-30-075)

[1128]

[1129] Intermediate (151) 3.6 g (4.1 mmol), K2PtCl4 2.1 g (5.0 mmol), acetic acid 180 mL, and H2O 60 mL were mixed and stirred at 100°C (internal temperature) for 5 hours. After the reaction was completed, it was cooled to room temperature, and the precipitated solid was washed with methanol, filtered under reduced pressure, and dried in a vacuum oven to obtain 4.2 g of a solid. The obtained solid was dissolved in dichloromethane, adsorbed on silica gel, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and acetone to obtain 1.5 g (yield: 34.1%) of compound 5-3 (LT23-30-075) as a yellow solid.

[1130]

[1131] Manufacturing Example 29: Synthesis of Compound 5-4 (LT23-35-033)

[1132]

[1133] Intermediate (152) 3.0 g (3.4 mmol), K2PtCl4 1.7 g (4.1 mmol), acetic acid 140 mL, and H2O 50 mL were mixed and stirred at 100°C (internal temperature) for 5 hours. After the reaction was completed, it was cooled to room temperature, and the precipitated solid was washed with methanol, filtered under reduced pressure, and dried in a vacuum oven. The obtained solid was dissolved in dichloromethane, adsorbed on silica gel, purified by silica gel column chromatography (DCM:Hexanes), and then solidified with dichloromethane and acetone to obtain 1.2 g (yield: 32.7%) of compound 5-4 (LT23-35-033) as a yellow solid.

[1134]

[1135] Manufacturing Example 30: Synthesis of compound 5-5 (LT23-30-088)

[1136]

[1137] Intermediate (153) 2.2 g (2.4 mmol), K2PtCl4 1.3 g (3.1 mmol), acetic acid 110 mL, and H2O 37 mL were mixed and stirred at 100°C (internal temperature) for one day. After the reaction was completed, the mixture was cooled to room temperature, and the precipitated solid was washed with methanol, filtered under reduced pressure, and dried in a vacuum oven to obtain 2.8 g of a solid. The obtained solid was dissolved in dichloromethane, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with chloroform and acetone to obtain 0.8 g (yield: 30.0%) of compound 5-5 (LT23-30-088) as a yellow solid.

[1138]

[1139] Manufacturing Example 31: Synthesis of Compound 5-21 (LT23-30-119)

[1140]

[1141] Intermediate (155) 3.3 g (3.6 mmol), K2PtCl4 1.8 g (4.3 mmol), acetic acid 140 mL, and H2O 40 mL were mixed and stirred at 100°C (internal temperature) for one day. After the reaction was completed, it was cooled to room temperature, and the precipitated solid was washed with methanol, filtered under reduced pressure, and dried in a vacuum oven. The obtained solid was dissolved in dichloromethane, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with chloroform and acetone to obtain 1.8 g (yield: 45.1%) of compound 5-21 (LT23-30-119) as a yellow solid.

[1142]

[1143] Manufacturing Example 32: Synthesis of compound 5-23 (LT23-30-122)

[1144]

[1145] Intermediate (156) 2.9 g (3.0 mmol), K2PtCl4 1.5 g (3.6 mmol), acetic acid 120 mL, and H2O 20 mL were mixed and stirred at 100°C (internal temperature) for one day. After the reaction was completed, it was cooled to room temperature, and the precipitated solid was washed with methanol, filtered under reduced pressure, and dried in a vacuum oven. The obtained solid was dissolved in dichloromethane, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with chloroform and acetone to obtain 1.2 g (yield: 34.5%) of compound 5-23 (LT23-30-122) as a yellow solid.

[1146]

[1147] Manufacturing Example 33: Synthesis of compound 5-93 (LT23-30-103)

[1148]

[1149] Intermediate (161) 4.7 g (5.0 mmol), K2PtCl4 2.5 g (6.0 mmol) and acetic acid 250 mL were mixed and refluxed and stirred for one day. The reaction progress was confirmed through TLC and LC / MS to confirm whether there was any starting material remaining. Then, 50 mL of distilled water was added so that all the remaining starting material could participate in the reaction, and refluxed and stirred for 5 hours. After the reaction was completed, it was cooled to room temperature, and the acetic acid was removed by concentration under reduced pressure, and the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and hexane to obtain 3.2 g (yield: 56.4%) of compound 5-93 (LT23-30-103) as a yellow solid.

[1150]

[1151] Manufacturing Example 34: Synthesis of compound 5-95 (LT23-30-111)

[1152]

[1153] Intermediate (162) 3.0 g (3.1 mmol), K2PtCl4 1.5 g (3.7 mmol), acetic acid 120 mL, and H2O 20 mL were mixed and stirred at 100°C (internal temperature) for one day. After the reaction was completed, it was cooled to room temperature, and the precipitated solid was washed with methanol, filtered under reduced pressure, and dried in a vacuum oven. The obtained solid was dissolved in dichloromethane, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with chloroform and acetone to obtain 1.5 g (yield: 41.7%) of compound 5-95 (LT23-30-111) as a yellow solid.

[1154]

[1155] Manufacturing Example 35: Synthesis of Compound 5-111 (LT22-30-279)

[1156]

[1157] Intermediate (164) 3.5 g (4.3 mmol), K2PtCl4 2.1 g (5.2 mmol) and acetic acid 175 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the mixture was cooled to room temperature, and the precipitated solid was washed with methanol, filtered under reduced pressure, and dried in a vacuum oven to obtain 3.5 g of a solid. The obtained solid was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and ethyl acetate to obtain 2.0 g (yield: 46.5%) of compound 5-111 (LT22-30-279) as a yellow solid.

[1158]

[1159] Manufacturing Example 36: Synthesis of compound 5-165 (LT22-30-264)

[1160]

[1161] Intermediate (171) 3.8 g (4.2 mmol), potassium tetrachloroplatinate (K2PtCl4) 2.1 g (5.1 mmol), and acetic acid 140 mL were mixed and stirred at 120°C for 36 hours. After cooling to room temperature, the acetic acid was concentrated, methanol was added, filtered, and washed sequentially with distilled water and methanol. After drying, the residue was purified by silica gel column chromatography (DCM:Hexanes) and recrystallized with a mixed solvent (DCM:Hexanes) to obtain 2.5 g (yield: 55.0%) of compound 5-165 (LT22-30-264) as a yellow solid.

[1162]

[1163] Manufacturing Example 37: Synthesis of compound 5-184 (LT22-30-254)

[1164]

[1165] Intermediate (176) 3.8 g (4.2 mmol), potassium tetrachloroplatinate (K2PtCl4) 2.1 g (5.1 mmol), and acetic acid 140 mL were mixed and stirred at 120°C for 36 hours. After cooling to room temperature, the acetic acid was concentrated, methanol was added, filtered, and washed sequentially with distilled water and methanol. After drying, the residue was purified by silica gel column chromatography (DCM:Hexanes) and recrystallized with a mixed solvent (DCM:Hexanes) to obtain 2.5 g (yield: 55.0%) of compound 5-184 (LT22-30-254) as a yellow solid.

[1166]

[1167] Manufacturing Example 38: Synthesis of compound 5-202 (LT22-30-208)

[1168]

[1169] Intermediate (178) 4.0 g (4.5 mmol), K2PtCl4 2.2 g (5.4 mmol), and acetic acid (AcOH) 180 mL were mixed. The reaction mixture was stirred at 110°C overnight. After quenching the reaction with distilled water, the reaction solution was extracted with dichloromethane. The separated organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:Hexanes) and recrystallized from dichloromethane and hexane to obtain 3.4 g (yield: 70.8%) of compound 5-202 (LT22-30-208) as a yellow solid.

[1170]

[1171] Manufacturing Example 39: Synthesis of compound 5-218 (LT22-30-263)

[1172]

[1173] Intermediate (190) 3.6 g (4.3 mmol), K2PtCl4 2.1 g (5.1 mmol) and acetic acid 180 mL were mixed and refluxed and stirred for 2 days. After the reaction was completed, it was cooled to room temperature and the precipitated solid was filtered under reduced pressure. The obtained solid was dissolved in dichloromethane, and the organic matter was extracted using dichloromethane and distilled water, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and hexane to obtain 3.2 g (yield: 72.7%) of compound 5-218 (LT22-30-263) as a yellow solid.

[1174]

[1175] Manufacturing Example 40: Synthesis of compound 5-219 (LT22-30-165)

[1176]

[1177] Intermediate (183) 4.2 g (5.0 mmol), K2PtCl4 2.7 g (6.6 mmol) and acetic acid 250 mL were mixed and refluxed and stirred for 1 day. The reaction progress was confirmed through TLC and LC / MS to confirm whether there was any residue of the starting material, and then 50 mL of distilled water was added to completely complete the reaction, and refluxed and stirred for 5 hours. After the reaction was completed, it was cooled to room temperature, and the acetic acid was removed by concentration under reduced pressure, and the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and hexane to obtain 3.2 g (yield: 62.3%) of compound 5-219 (LT22-30-165) as a yellow solid.

[1178]

[1179] Manufacturing Example 41: Synthesis of compound 5-220 (LT22-30-246)

[1180]

[1181] Intermediate (192) 4.7 g (5.3 mmol), K2PtCl4 2.7 g (6.4 mmol) and acetic acid 210 mL were mixed and refluxed and stirred for one day. After the reaction was completed, the mixture was cooled to room temperature, and the acetic acid was removed by concentration under reduced pressure. The organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and hexane to obtain 1.9 g (yield: 33.1%) of compound 5-220 (LT22-30-246) as a yellow solid.

[1182]

[1183] Manufacturing Example 42: Synthesis of compound 6-6 (LT23-30-040)

[1184]

[1185] Intermediate (199) 2.4 g (3.3 mmol), potassium tetrachloroplatinate (K2PtCl4) 1.7 g (4.0 mmol), and acetic acid 100 mL were mixed and stirred at 110°C for 36 hours. After cooling to room temperature, acetic acid was concentrated and methanol was added. The formed solid was filtered and washed sequentially with distilled water and methanol. After drying, it was purified by silica gel column chromatography (DCM:Hexanes) and recrystallized from a mixed solution (DCM:Hexanes) to obtain 0.9 g (yield: 29.6%) of compound 6-6 (LT23-30-040) as a yellow solid.

[1186]

[1187] Manufacturing Example 43: Synthesis of compound 6-8 (LT23-30-090)

[1188]

[1189] Intermediate (207) 3.5 g (3.8 mmol), K2PtCl4 2.1 g (5.0 mmol), acetic acid 175 mL, and H2O 58 mL were mixed and stirred at 100°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and distilled water was added. The precipitated solid was washed with distilled water and methanol and filtered under reduced pressure. The obtained solid was dissolved in dichloromethane and washed with distilled water, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 2.4 g (yield: 57.1%) of compound 6-8 (LT23-30-090) as a pale orange solid.

[1190]

[1191] Manufacturing Example 44: Synthesis of Compound 6-9 (LT23-30-039)

[1192]

[1193] Intermediate (203) 3.5 g (4.0 mmol), K2PtCl4 2.5 g (6.0 mmol) and acetic acid 175 mL were mixed and stirred at 105℃ (internal temperature) for 2 days. After the reaction was completed, it was cooled to room temperature, and the precipitated solid was washed with distilled water and methanol, filtered under reduced pressure, and dried. The obtained solid was dissolved in dichloromethane, adsorbed onto silica gel, purified by silica gel column chromatography (DCM:Hexanes), and then solidified with dichloromethane and hexane to obtain 1.6 g (yield: 37.2%) of compound 6-9 (LT23-30-039) as a yellow solid.

[1194]

[1195] Manufacturing Example 45: Synthesis of compound 6-13 (LT23-30-014)

[1196]

[1197] Intermediate (208) 4.2 g (4.8 mmol), K2PtCl4 2.4 g (5.8 mmol) and acetic acid 210 mL were mixed and stirred at 110℃ (internal temperature) for 5 days. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract the organic matter, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was adsorbed onto silica gel, purified by silica gel column chromatography (DCM:Hexanes), and then solidified with dichloromethane and hexane to obtain 1.5 g (yield: 29.4%) of compound 6-13 (LT23-30-014) as a yellow solid.

[1198]

[1199] Manufacturing Example 46: Synthesis of compound 6-16 (LT22-30-274)

[1200]

[1201] Intermediate (209) 3.0 g (3.2 mmol), K2PtCl4 1.6 g (3.9 mmol) and acetic acid 150 mL were mixed and refluxed and stirred for 2 days. After the reaction was completed, it was cooled to room temperature, and the precipitated solid was washed with methanol and filtered under reduced pressure. The obtained solid was dissolved in dichloromethane, and the organic matter was extracted using dichloromethane and distilled water, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was dissolved in dichloromethane, and after silica gel adsorption, it was purified by silica gel column chromatography (DCM: Hexanes), and solidified with dichloromethane and methanol to obtain 2.2 g (yield: 61.1%) of compound 6-16 (LT22-30-274) as a yellow solid.

[1202]

[1203] Manufacturing Example 47: Synthesis of compound 6-27 (LT23-30-024)

[1204]

[1205] Intermediate (214) 4.8 g (5.4 mmol), K2PtCl4 2.7 g (6.5 mmol) and acetic acid 240 mL were mixed and stirred at 110℃ (internal temperature) for 6 days. After the reaction was completed, it was cooled to room temperature, and the precipitated solid was washed with distilled water and filtered under reduced pressure. After dissolving the obtained solid in dichloromethane, the organic matter was extracted using dichloromethane and distilled water, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (CHCl3:Hexanes), and then recrystallized three times with dichloromethane and hexane to obtain 1.5 g (yield: 25.9%) of compound 6-27 (LT23-30-024) as a yellow solid.

[1206]

[1207] Manufacturing Example 48: Synthesis of compound 6-39 (LT22-30-212)

[1208]

[1209] Intermediate (216) 3.4 g (3.9 mmol), K2PtCl4 1.9 g (4.7 mmol) and acetic acid 156 mL were mixed and stirred at 120°C for 3 days. After the reaction was completed, the mixture was cooled to room temperature, and the acetic acid was removed by concentration under reduced pressure. The organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 2.6 g (yield: 62.9%) of compound 6-39 (LT22-30-212) as a yellow solid.

[1210]

[1211] Manufacturing Example 49: Synthesis of compound 6-193 (LT23-30-016)

[1212]

[1213] Intermediate (221) 2.0 g (2.2 mmol), K2PtCl4 1.1 g (2.7 mmol) and acetic acid 100 mL were mixed and stirred at 110℃ (internal temperature) for 2 days. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The obtained reaction mixture was extracted with dichloromethane and distilled water to extract organic matter, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was adsorbed onto silica gel, purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 1.7 g (yield: 69.6%) of compound 6-193 (LT23-30-016) as a yellow solid.

[1214]

[1215] Manufacturing Example 50: Synthesis of compound 6-247 (LT22-30-337)

[1216]

[1217] Intermediate (222) 2.0 g (2.5 mmol), K2PtCl4 1.3 g (3.0 mmol), acetic acid 100 mL, and H2O 10 mL were mixed and stirred at 100°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and distilled water was added. The precipitated solid was washed with distilled water and methanol and filtered under reduced pressure. The obtained solid was dissolved in dichloromethane and washed with distilled water, and the extracted organic layer was concentrated under reduced pressure to remove the solvent. The obtained mixture was purified by silica gel column chromatography (DCM: Hexanes), and then solidified with dichloromethane and methanol to obtain 1.2 g (yield: 48.3%) of compound 6-247 (LT22-30-337) as a pale orange solid.

[1218] <Example 1>

[1219] For the compound of the present invention, the UV / VIS spectrum was measured using a Jasco V-630 instrument, and the PL (photoluminescence) spectrum was measured using a Jasco FP-8500 instrument, and the results are shown in Table 1 below.

[1220] Classification Compound UV (nm) PL (nm) Test Example 13-1 (LT23-35-103) 305, 348, 381, 411, 434, 520 Test Example 23-3 (LT23-35-105) 305, 348, 382, ​​411, 434, 522 Test Example 33-21 (LT23-35-104) 303, 347, 383, 431, 521 Test Example 43-25 (LT23-35-109) 302, 345, 382, ​​429, 519 Test Example 53-26 (LT23-35-110) 303, 347, 383, 431, 520 Test Example 63-41(LT23-35-107)303,347,383,431520 Exam Example 73-65(LT23-35-112)302,347,382,431520 Exam Example 83-212(LT22-30-161)348,384,408,434521 Exam Example 93-214(LT23-35-121)305,348,381,412,434520 Exam Example 103-228(LT23-35-125)293,305,348,382,435527 Exam Example 113-229(LT23-35-126)305,348,381,411,434520 Exam Example 123-302(LT23-35-130)305,348,382,411,434522Exam Example 133-323(LT22-30-269)303,349,415,439518Exam Example 143-324(LT22-30-267)303,349,386,415,439518Exam Example 153-329(LT22-30-308)304,348,385,408,435524Exam Example 163-370(LT22-30-248)304,348,384,409,434520Exam Example 174-11(LT23-35-129)347,383,431520 Test Example 184-13(LT23-30-001)303,346,382,404,430524 Test Example 194-18(LT23-35-135)304,347,381,412,434520 Test Example 204-26(LT23-35-133)304,347,381,412,434519 Test Example 214-32(LT23-35-137)301,344,378,434513 Test Example 224-87(LT23-35-172)304,347,381,411,434518 Test Example 234-92(LT23-35-151)304,347,381,412,434520 Exam Example 244-182 (LT23-30-044) 305,348,381,412,434521 Exam Example 254-183 (LT23-30-049) 305,348,382,412,434522 Exam Example 264-191 (LT22-30-194) 303,346,383,431520 Exam Example 274-368 (LT23-35-139) 304,348,381,411,434520 Exam Example 285-3 (LT23-30-075) 305,348,381,412,434521 Exam Example 295-4(LT23-35-033)304,347,381,412,434519 Test Example 305-5(LT23-30-088)305,348,381,412,434521 Test Example 315-21(LT23-30-119)305,348,381,412,434520 Test Example 325-23(LT23-30-122)293,305,348,382,435527 Test Example 335-93(LT23-30-103)305,348,381,411,434520 Test Example 345-95(LT23-30-111)305,348,382,411,434522Exam Example 355-111(LT22-30-279)303,347,383,431521Exam Example 355-165(LT22-30-264)302,345,382,429519Exam Example 375-184(LT22-30-254)303,347,383,431520Exam Example 385-202(LT22-30-208)303,347,383,431520Exam Example 395-218(LT22-30-263)302,347,382,431520Exam Example 405-219(LT22-30-165)347,383,431520 Test Example 415-220(LT22-30-246)304,348,381,411,434520 Test Example 426-6(LT23-30-040)304,347,381,412,434520 Test Example 436-8(LT23-30-090)304,347,381,412,434519 Test Example 446-9(LT23-30-039)301,344,378,434513 Test Example 456-13(LT23-30-014)304,347,381,411,434518 Test Example 466-16(LT22-30-274)304,347,381,412,434520 Exam Example 476-27(LT23-30-024)304,348,382,412,435516 Exam Example 486-39(LT22-30-212)302,346,383,431517 Exam Example 496-193(LT23-30-016)301,347,383,431519 Exam Example 506-247(LT22-30-337)302,346,383,431518,

[1221]

[1222] <Component Manufacturing>

[1223] For the fabrication of the device, ITO, a transparent electrode, was used as an anode layer, HATCN was used as a hole injection layer, HT2 was used as a hole transport layer, GH1 was used as a first host of the light-emitting layer, GH2 was used as a second host of the light-emitting layer, ET1 was used as an electron transport layer, Liq was used as an electron injection layer, Ag / Mg was used as a cathode, and HT1 was used as a capping layer. The structures of these compounds are as shown in the chemical formulas below.

[1224]

[1225] <Comparative Example of Device Manufacturing>

[1226] The phosphorescent organic light-emitting device was fabricated by depositing ITO / HT2 (91 nm) / HATCN (5 nm) / HT2 (40 nm) / H1:H2:dopant 10% (40 nm) / ET1:Liq (1:1, 30 nm) / Liq (2 nm) / AgMg (12 nm) / HT1 (60 nm) in that order.

[1227] Before depositing the organic material, the ITO electrode was 2 Х 10 - 2 Oxygen plasma treatment was performed at 125 W at Torr for 2 minutes.

[1228] Organic matter 9 Х 10 - 7Deposition was performed under a vacuum of 10 Torr, and Liq was deposited at 0.1 Å / sec, CBP at 0.18 Å / sec, dopants were simultaneously deposited at 0.02 Å / sec, and the remaining organic materials were all deposited at a rate of 1 Å / sec.

[1229] The dopant material used in the experiment was selected as REF 1 or REF 2.

[1230] After the device fabrication was complete, it was sealed in a glove box filled with nitrogen gas to prevent contact with air and moisture. A barrier was formed with 3M adhesive tape, and then barium oxide, a desiccant that removes moisture, was added, and a glass plate was attached.

[1231]

[1232] < Device Manufacturing Examples 1 to 50 >

[1233] In the above device fabrication comparative example, the device was fabricated in the same manner as the above device fabrication comparative example, except that each compound shown in Table 2 below was used instead of the comparative compound (REF).

[1234] The electrical luminescence characteristics of the organic light-emitting devices manufactured in the comparative examples of the above device fabrication and Examples 1 to 50 are shown in Table 2.

[1235]

[1236] Classification Compound Driving Voltage [V] Efficiency [cd / A] Lifespan (hr) Wavelength (nm) Example 13-1 (LT23-35-103) 2.7356.2538518 Example 23-3 (LT23-35-105) 2.7355.6836520 Example 33-21 (LT23-35-104) 2.7568.5945518 Example 43-25 (LT23-35-109) 2.7367.8844518 Example 53-26 (LT23-35-110) 2.7372.3566518 Example 63-41 (LT23-35-107) 2.7258.3439518 Example 73-65(LT23-35-112)2.7399.8272518Example 83-212(LT22-30-161)2.7357.6540519Example 93-214(LT23-35-121)2.7356.6545518Example 103-228(LT23-35-125)2.7357.6550519Example 113-229(LT23-35-126)2.7355.8547518Example 123-302(LT23-35-130)2.7260.2540520Example 133-323(LT22-30-269)2.7368.8468522Example 143-324(LT22-30-267)2.7755.2560521Example 153-329(LT22-30-308)2.7475.8463518Example 163-370(LT22-30-248)2.7256.2538518Example 174-11(LT23-35-129)2.7382.5360518Example 184-13(LT23-30-001)2.7180.4359518Example 194-18(LT23-35-135)2.7280.5265518Example 204-26(LT23-35-133)2.7360.2549522Example 214-32(LT23-35-137)2.7180.4359518Example 224-87(LT23-35-172)2.7382.5865518Example 234-92(LT23-35-151)2.7399.5885518Example 244-182(LT23-30-044)2.65130.51160518Example 254-183(LT23-30-049)2.7396.1973.2518Example 264-191(LT22-30-194)2.70108.32125518Example 274-368(LT23-35-139)2.71105.25110518Example 285-3(LT23-30-075)2.7380.3569518Example 295-4(LT23-35-033)2.7380.4480518Example 305-5(LT23-30-088)2.7385.6886518Example 315-21(LT23-30-119)2.7380.4480518Example 325-23(LT23-30-122)2.7385.6886518Example 335-93(LT23-30-103)2.7385.6985518Example 345-95(LT23-30-111)2.7395.59100518Example 355-111(LT22-30-279)2.7380.3569518Example 365-165(LT22-30-264)2.7382.6569518Example 375-184(LT22-30-254)2.7385.6975518Example 385-202(LT22-30-208)2.70107.01111518Example 395-218(LT22-30-263)2.7188.5269518Example 405-219(LT22-30-165)2.7195.6598518Example 415-220(LT22-30-246)2.70115.01120518Example 426-6(LT23-30-040)2.7090.1898519Example 436-8(LT23-30-090)2.7195.6690518Example 446-9(LT23-30-039)2.7093.20100518Example 456-13(LT23-30-014)2.70106.2198518Example 466-16(LT22-30-274)2.7398.87152518Example 476-27(LT23-30-024)2.65117.60122518Example 486-39(LT22-30-212)2.71110.66100518Example 496-193(LT23-30-016)2.7199.8592518Example 506-247(LT22-30-337)2.6994.7185519Comparative Example 1REF13.0140.228519Comparative Example 2REF22.8954.236518.

[1237]

[1238] From the results in Table 2 above, the novel compound according to the present invention can be used as a material for an organic layer of an organic electronic device, including an organic light-emitting device, and the organic electronic device, including an organic light-emitting device, using the novel compound exhibits desirable characteristics, such as high device efficiency, saturated emission color, and longer device lifespan. In particular, it was found that the novel compound according to the present invention exhibited a color shifted slightly toward darker green compared to the comparative compound (REF), while also exhibiting higher efficiency.

[1239] The organic compound according to the present invention can be used to improve the quality of an organic electroluminescent device by being used in an organic layer, particularly a light-emitting layer, disposed between a first electrode and a second electrode of the organic electroluminescent device.

[1240] When the above organic compound is used in the light-emitting layer of an organic electroluminescent device, the organic electroluminescent device can exhibit high efficiency characteristics and improved lifespan characteristics in the green light-emitting wavelength range while simultaneously exhibiting its original characteristics due to the characteristics of the organic compound.

Claims

1. An organic metal complex for organic electroluminescent devices represented by the following chemical formula 1. [Chemical Formula 1] In the above chemical formula 1, Z1 is N-(L1) p -Ar1, L1 is a substituted or unsubstituted arylene group, Ar1 is selected from a substituted or unsubstituted phenyl group, a naphthyl group, a benzofuran group, a benzothiophene group, a benzoxazole group, a benzothiazole group, a dibenzofuran group, a dibenzothiophene group, and a non-aromatic condensed phenyl group, A, B, C and D are each independently selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted non-aromatic aromatic condensed polycyclic group and an aromatic condensed polycyclic group, p is an integer of 1 or 2, X1 is O or S, X2, X3 and X4 are each independently C or N, Among the bonds between X2 and Pt, the bond between X3 and Pt, and the bond between X4 and Pt, one bond is a covalent bond, and among the bonds between X2 and Pt, the bond between X3 and Pt, and the bond between X4 and Pt, the remaining two bonds are coordinate bonds.

2. In paragraph 1, The above chemical formula 1 is an organic metal complex for an organic electroluminescent device represented by the following chemical formula 2. [Chemical Formula 2] In the above chemical formula 2, R1 to R5 are independently selected from hydrogen, deuterium, CD3, -F, -CF3, an alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted cycloalkyl condensed polycyclic phenyl group, a, b, c, d, and e are independently 1, 2, or 3, When a, b, c, d and e are 2 or more, they can optionally combine with each other to form a substituted or unsubstituted carbocyclic group, Ar1 is the same as defined in claim 1.

3. In paragraph 1, The above chemical formula 2 is an organic metal complex for an organic electroluminescent device represented by any one of the following chemical formulas 2-1 to 2-4. [Chemical Formula 2-1] [Chemical Formula 2-2] [Chemical Formula 2-3] [Chemical Formula 2-4] In the above chemical formulas 2-1 to 2-4, R6 to R 21 is hydrogen or methyl group, L2, L 3, L4 and L5 are each independently -CH2- or -CH2CH2-.

4. In paragraph 1, The organic metal complex of the above chemical formula 1 is an organic metal complex for an organic electroluminescent device selected from the group represented by the following chemical formulas 3 to 6. [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] 5. An organic electroluminescent device comprising an organometallic complex according to any one of claims 1 to 4.

6. In paragraph 5, An organic electroluminescent device characterized in that the above organic metal complex is used as a dopant material.

7. In an organic electroluminescent device comprising a first electrode, a second electrode, and one or more organic layers disposed between the electrodes, An organic electroluminescent device comprising an organic metal complex according to any one of claims 1 to 4, wherein the organic layer comprises:

8. In paragraph 7, An organic electroluminescent device characterized in that the organic layer includes a light-emitting region, and the light-emitting region includes one or more compounds represented by the chemical formula 1 and one or more hosts.

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