Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[ClH:11].Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:16]=1[NH:25][C:26]([NH:28][C:29]([NH2:31])=[NH:30])=[NH:27]>C(O)C>[ClH:11].[CH2:2]([CH:1]1[N:25]([C:16]2[CH:17]=[C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])[CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[C:26]([NH2:27])=[N:28][C:29]([NH2:31])=[N:30]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COc1ccc(C(C)(C)C)cc1NC(=N)NC(=N)N
Reactant: CCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCC1N=C(N)N=C(N)N1c1cc(C(C)(C)C)ccc1OC

Procedure:
100 ml of ethanol, 3.7 g (26.2 mmol) of 1-nonanal and 0.8 ml of concentrated hydrochloric acid were added to 6.0 g (20.0 mmol) of N1-(2-methoxy-5-tert-butylphenyl)-biguanide hydrochloride, and the mixture was refluxed for 20 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)). The eluate was dissolved in 80% aqueous ethanol, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol and ether to obtain 2.3 g of pale yellow crystals having a melting point of 217 to 219° C.
Reaction SMILES: [CH2:1]([N:3]([C:17]1[C:18]([CH3:28])=[N:19][N:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:21]=1)[C:4](=[O:16])[CH2:5][C:6]([OH:15])([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])[CH3:2].[H-].[Na+].IC.[CH3:33]COC(C)=O.CCCCCC>CN(C=O)C.O>[CH2:1]([N:3]([C:17]1[C:18]([CH3:28])=[N:19][N:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:21]=1)[C:4](=[O:16])[CH2:5][C:6]([O:15][CH3:33])([C:7]([F:9])([F:8])[F:10])[C:11]([F:14])([F:12])[F:13])[CH3:2]
Reactant: CCN(C(=O)CC(O)(C(F)(F)F)C(F)(F)F)c1cn(-c2cccnc2)nc1C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCCCCC
Product: CCN(C(=O)CC(OC)(C(F)(F)F)C(F)(F)F)c1cn(-c2cccnc2)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a solution of N-ethyl-4,4,4-trifluoro-3-hydroxy-N-(3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)butanamide (184 mg, 0.448 mmol) in DMF (3 mL) stirring at 0° C. was added sodium hydride (26.9 mg, 0.673 mmol). The solution was stirred at 0° C. for 0.5 hour. Then iodomethane (0.034 mL, 0.538 mmol) was added and ice bath was removed and the mixture was stirred at 25° C. overnight. Reaction was worked up by slow addition of water and further diluted with 20 mL of water, then extracted with 4×20 mL of EtOAc. The combined organic layers were washed with water, dried over Na2SO4 and concentrated. Silica Gel chromatography (0-100% EtOAc/hexane) gave N-ethyl-4,4,4-trifluoro-3-methoxy-N-(3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)butanamide (52 mg, 0.123 mmol, 27.3% yield) as a white solid: mp=83-86° C.; 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J=2.5 Hz, 1H), 8.59 (dd, J=4.7, 1.3 Hz, 1H), 8.01 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.85 (s, 1H), 7.44 (ddd, J=8.3, 4.8, 0.6 Hz, 1H), 4.00 (brs, 1H), 3.73 (s, 3H), 3.39 (brs, 1H), 2.86 (s, 2H), 2.26 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); ESIMS m/z 425 ([M+H]+); IR (Thin film) 1664 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].B(Cl)(Cl)Cl.C(Cl)Cl.Cl[CH2:18][C:19]#N.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[F:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[NH:4][CH:19]=[CH:18]2
Reactant: N#CCCl
Reactant: Nc1ccc(F)cc1Br
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: Fc1cc(Br)c2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
2-Bromo-4-fluoro-aniline (13.8 g, 72.6 mmol) was added dropwise to a solution of boron trichloride in methylene chloride (1.0 M, 81.1 mL, 81.1 mmol) cooled with ice water. The reaction mixture was warmed to room temperature, stirred for 30 min, and chloroacetonitrile (13.5 mL, 87.1 mmol) and aluminum chloride (13.5 g, 98.4 mmol) added, followed by 1,2-dichloroethane (95 mL). The reaction mixture was heated to 70° C. to distill off methylene chloride, and then refluxed for 24 h. After cooling to 0–5° C., the mixture was treated with 2.5 M HCl (130 mL) carefully, and then heated to 80° C. for 1 h until all solids dissolved. The aqueous layer was separated and extracted with methylene chloride. The combined organic solutions were washed with water and brine, dried (sodium sulfate) and concentrated to a yellow solid (11, 56.9%), which was used without further purification. The crude product was taken into dioxane (68 mL) and water (7.6 mL), and treated with sodium borohydride (1.64 g) in portions. After 30 min at room temperature, all the starting material was consumed, and the reaction mixture was heated to reflux for 18 h. The mixture was cooled to room temperature, treated with 0.1 N HCl (70 mL), 2N HCl (20 mL) and concentrated HCl (15 mL), and extracted with ethyl acetate. The organic layer was separated and washed with water and brine, dried (sodium sulfate), and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) gave 5-fluoro-7-bromoindole (4.4 g, 52.2%). 1H NMR (400 MHz, CDCl3) 6.49, (dd, J1=2.35 Hz, J2=3.13 Hz, 1H), 7.06 (d, J1=2.35 Hz, J2=8.60 Hz, 1H), 7.14˜7.17 (m, 2H), 8.18 (br, 1H); MS (ES, m/z): C8H5BrFN: 211.9 (M+(79Br)−1), 214.0 (M+(81Br)−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][C:14](=N)[C:13]=2[C:27]#[N:28])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C([O-])(O)=[O:30].[Na+]>C1COCC1.O.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][C:14](=[O:30])[C:13]=2[C:27]#[N:28])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(-c2c(C#N)c(=N)oc3c2ccc2c3ccn2C)cc(Br)c1OC
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2c(C#N)c(=O)oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 18 %

Procedure:
To a solution of 4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-7-methyl-2H-pyrrolo[2,3-h]chromene (100 mg, 0.216 mmol) in THF:water (10:2) was added a ZnCl2 solution (1 mL, 1.0 M in CH2Cl2). The solution was stirred at room temperature for approximately 7 h. The reaction mixture was made basic with saturated NaHCO3 (10 mL), and extracted with EtOAc (2×25 mL). The EtOAc extracts were washed with brine (10 mL), dried over MgSO4, and evaporated to yield a yellow solid. The solid was purified by flash column chromatography (silica gel, EtOAc:hexanes 30-70% EtOAc) to yield 17 mg (18%) of the product as a yellow solid. 1H NMR (acetone-d6): 7.51-7.48 (m, 2H), 7.42 (d, J=1.8 Hz, 1H), 7.34 (d, J=2.1 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 6.91 (dd, J=0.6, 3.3 Hz, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=3[Cl:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Product: CCCNC(=O)c1nnc2c(-c3cc(C(F)(F)F)ccc3Cl)cccc2c1N
Yield: 42.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-chloro-5-(trifluoromethyl)phenylboronic acid (224 mg, 1.000 mmol) were reacted to afford the title compound (85 mg, 44% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.51 (br, 1H), 7.98 (m, 1H), 7.81-7.63 (m, 5H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=409 (M+H). HPLC 2.46 min.
Reaction SMILES: CC(C)=[O:3].[CH3:5][C:6]([C@H:8]1[C@@H:12]2[C@@H:13]3[C@@:26]([CH3:29])([CH2:27][CH2:28][C@@:11]2([CH2:35][OH:36])[CH2:10][CH2:9]1)[C@@:25]1([CH3:30])[C@@H:16]([C@:17]2([CH3:34])[C@@H:22]([CH2:23][CH2:24]1)[C:21]([CH3:32])([CH3:31])[C@@H:20]([OH:33])[CH2:19][CH2:18]2)[CH2:15][CH2:14]3)=[CH2:7]>C(OCC)(=O)C>[CH3:7][C:6]([C@H:8]1[C@@H:12]2[C@@H:13]3[C@@:26]([CH3:29])([CH2:27][CH2:28][C@@:11]2([C:35]([OH:3])=[O:36])[CH2:10][CH2:9]1)[C@@:25]1([CH3:30])[C@@H:16]([C@:17]2([CH3:34])[C@@H:22]([CH2:23][CH2:24]1)[C:21]([CH3:32])([CH3:31])[C:20](=[O:33])[CH2:19][CH2:18]2)[CH2:15][CH2:14]3)=[CH2:5]
Reactant: CC(C)=O
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
In order to accomplish the above objects, an aspect of the present invention provides a method of purifying betulonic acid, including the steps of: a) injecting a Jones oxidation reagent (CrO3/c-H2SO4/H2O) into a mixed solution of acetone and betulin to obtain an organic synthesis reaction product and filtering and concentrating the obtained reaction product; b) introducing ethyl acetate into the concentrated reaction product to liquid-liquid extract betulonic acid; c) introducing a saturated aqueous sodium chloride solution (brine) into the ethyl acetate solution, in which the extracted betulonic acid is dissolved, to wash the ethyl acetate solution and remove impurities therefrom; d) introducing hexane or petroleum ether, as a nonpolar solvent, into the ethyl acetate solution to remove nonpolar substances, passing the washed ethyl acetate solution through an adsorption tower filled with aluminum oxide or silica gel, as a polar adsorbent, to remove polar substances, and then drying the ethyl acetate solution to produce betulonic acid (purity: more than 92%, yield to birch bark: 2.75 wt %); and e) dissolving the produced betulonic acid in a mixed solvent of ethanol and acetonitrile, separating and treating the mixed solution using a semi-preparative chromatography column filled with C18 stationary phase, and then drying the separated and treated mixed solution to produce high-purity betulonic acid (purity: more than 99.5%, yield to birch bark: 1.8 wt %).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1B(O)O.ClC1C=CSC=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:18]1[CH:17]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1sccc1Cl
Agent: Clc1ccsc1
Product: Clc1ccsc1-c1ccccn1
Yield: 14.2 %

Procedure:
3-Chlorothiophene-2-boronic acid (1.5 g, 9.24 mmol), prepared as described in EXAMPLE 48, Part A from 3-chlorothiophene was reacted with 3-bromopyridine (0.81 mL, 8.4 mmol) as described in EXAMPLE 48, Part B to give the title compound (0.232 g, 1.19 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[N:13]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:12]=2)[CH:3]=1.N1C=CC=CC=1.[S:54](Cl)(=[O:57])(=[O:56])[NH2:55]>O1CCCC1>[CH3:39][C:36]1[CH:37]=[CH:38][N:25]2[C:26]=1[C:27](=[O:35])[N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]([C@@H:21]([NH:20][C:18]1[C:19]3[C:11]([C:4]4[CH:3]=[C:2]([NH:1][S:54]([NH2:55])(=[O:57])=[O:56])[CH:10]=[C:9]5[C:5]=4[CH:6]=[CH:7][NH:8]5)=[CH:12][N:13]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[C:14]=3[N:15]=[CH:16][N:17]=1)[CH3:22])=[N:24]2
Reactant: NS(=O)(=O)Cl
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(N)(=O)=O)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.9 %

Procedure:
(S)-2-(1-((5-(6-Amino-1H-indol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (84 mg, 0.13 mmol) was treated with pyridine (15 μL, 0.18 mmol) and sulfamoyl chloride (18 mg, 0.16 mmol) in tetrahydrofuran (1.0 ml) according to the method described in Preparation 175 but stirring at room temperature during 48 h. The residue was purified using SP1® Purification System (0% to 50% hexane-ethyl acetate) to obtain 47 mg (49% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:11][C@H:10]2[C@H:5]([O:6][C:7]([CH3:13])([CH3:12])[O:8][CH2:9]2)[C@H:4]1[OH:14].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:22][C:21]1[CH:23]=[CH:24][C:18]([S:15]([O:14][C@@H:4]2[C@H:5]3[O:6][C:7]([CH3:12])([CH3:13])[O:8][CH2:9][C@H:10]3[O:11][C@@H:3]2[O:2][CH3:1])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: COC1O[C@@H]2COC(C)(C)O[C@@H]2[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CO[C@H]1O[C@@H]2COC(C)(C)O[C@@H]2[C@H]1OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
Compound 35.3 (35.42 g, 174 mmol) was dissolved in anhydrous pyridine, cooled to 0° C. and then treated with tosyl chloride (52.96 g, 278 mmol). The mixture was stirred at r.t. for 16 h and the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2, and washed with 3×100 mL water. The organic layer was collected, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a reverse phase column chromatography eluting with 50% EtOAc in hexane to give compound 35.4 (57.88 g, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+].O>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a solution of 2,4-dichloropyrimidine (32.4 g) in methanol (200 ml) was added dropwise a solution of sodium methoxide (11.7 g) in methanol (120 ml) over 40 min and the mixture was stirred for 30 min. The reaction mixture was poured into water (500 ml) and extracted with chloroform (300 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from hexane to give the title compound (21.5 g) as white crystals, m.p.=50-52° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[C:7](=[O:16])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:11]([C:8]2[C:7](=[O:16])[C:6]3[CH:17]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=3[O:10][N:9]=2)=[O:13])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1noc2ccc(I)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1noc2ccc(I)cc2c1=O
Temperature: 100 °C
Yield: 979 %

Procedure:
A mixture of ethyl 6-iodo-4-oxo4H-1,2-benzoxazine-3-carboxylate (Preparation 17, 48 mg) and 4-chlorobenzylamine (41 mg) and toluene (1 mL) is heated to 100° C. for 2 minutes. The mixture is cooled and concentrated in vacuo, and the residue is crystallized from ethanol-ether mixture to give 0.60 g (48%) of the title compound. Physical characteristics: mp 188-190° C.; 1H NMR (400 MHz, DMSO-d6) δ 4.49, 7.41, 7.59, 8.25, 8.32, 9.2; IR (drift) 3284, 1680, 1656, 1599, 1571, 1490, 1453, 1433, 1199, 1158, 928, 921, 819, 782, 619 cm−1; MS (FAB) m/z 441 (MH+, 65); HRMS (FAB) m/z 440.9507 (C16H10ClIN2O3+H). Anal. Found: C, 43.56; H, 2.43; N, 6.32; Cl, 8.04.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[C:25]([O:32][CH3:33])[N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:24]=[C:25]([O:32][CH3:33])[C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:27][N:28]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCCC5)C4)sc3c2)c(OC)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 62A for the product of Example 1E and substituting 2,6-dimethoxy-5-pyrimidineboronic acid for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.32 (s, 1H) 8.02 (d, J=8.48 Hz, 1H) 7.97 (d, J=1.70 Hz, 1H) 7.57 (dd, J=8.65, 1.86 Hz, 1H) 4.03-4.10 (s, 3H) 3.95-4.03 (m, 1H) 3.26-3.42 (m, 1H) 2.43-2.78 (m, 6H) 1.79-1.98 (m, 4H) 1.45-1.66 (m, 2H). MS: (M+H)+=397.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.O.O.C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[C:8]([Br:28])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc2c1CC(N1CCCC1)CC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c2c1CC(N1CCCC1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-acetamido-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalene (0.36 g, 1.4 mmol) and sodium acetate trihydrate (0.38 g, 2.8 mmol) in acetic acid (15 mL) was treated with bromine (0.27 g, 1.7 mmol) and stirred at room temperature for 2 h. A precipitate was collected by filtration and the filtrate evaporated. The two solids were combined and dissolved in methylene chloride; water. The mixture was basified with 12.5% NaOH, and the organic phase separated. The aqueous layer was back extracted and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was heated in diethyl ether to form a solid, which was collected and dried (0.31 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1NC(=O)/C=C/c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(/C=C/c1ccc(Cl)cc1)Nc1ccccc1C(=O)O

Procedure:
Prepared analogously to Example 2 from trans-4-chlorocinnamic acid-N-(2-methoxycarbonyl-phenyl)-amide and sodium hydroxide solution in methanol.
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.FC1C=CC(C(OC)=O)=C(C)C=1[N+]([O-])=O.[CH:31]1([C:36]2[NH:37][CH:38]=[CH:39][N:40]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1.C(#N)C>C(OCC)(=O)C.O.C(N(CC)CC)C>[CH:31]1([C:36]2[N:37]([C:2]3[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=3)[CH:38]=[CH:39][N:40]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: c1c[nH]c(C2CCCC2)n1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1C
Agent: COC(=O)c1ccc(F)c([N+](=O)[O-])c1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(-n2ccnc2C2CCCC2)cc1C
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To 2.74 g of a mixture of methyl 4-fluoro-2-methyl-5-nitrobenzoate and methyl 4-fluoro-2-methyl-3-nitrobenzoate, 1.75 g of 2-cyclopentyl-1H-imidazole, and 17.5 mL of acetonitrile, was added 4.9 mL of triethylamine, followed by stirring at 70° C. for 7 hours. To the reaction mixture were added water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and then solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane/ethyl acetate) to obtain 2.12 g of methyl 4-(2-cyclopentyl-1H-imidazol-1-yl)-2-methyl-5-nitrobenzoate.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]5[CH2:26][O:25][CH2:24]5)[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:33][CH:32]([OH:34])[CH2:31][NH:30][CH2:29][CH2:28]1>>[O:25]1[CH2:26][CH:23]([C:21]2[CH:22]=[C:17]([C:14]3[N:13]=[CH:12][C:11]4[CH:10]=[N:9][N:8]([C:6]5[N:7]=[C:2]([N:27]6[CH2:33][CH:32]([OH:34])[CH2:31][NH:30][CH2:29][CH2:28]6)[CH:3]=[CH:4][CH:5]=5)[C:16]=4[CH:15]=3)[CH:18]=[N:19][CH:20]=2)[CH2:24]1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5COC5)c4)cc32)n1
Reactant: OC1CNCCNC1
Product: OC1CNCCN(c2cccc(-n3ncc4cnc(-c5cncc(C6COC6)c5)cc43)n2)C1
Yield: 6 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-(6-fluoropyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepan-6-ol, 116 was obtained as an off-white solid (7.2 mg, 6%). 1H NMR (400 MHz, DMSO) δ 9.35-9.29 (s, 1H), 9.23-9.16 (dd, J=8.9, 2.0 Hz, 1H), 9.11-9.04 (d, J=8.6 Hz, 1H), 8.77-8.62 (m, 2H), 8.55-8.46 (dd, J=15.4, 8.6 Hz, 1H), 7.74-7.67 (t, J=8.1 Hz, 1H), 7.21-7.16 (d, J=7.7 Hz, 1H), 6.77-6.68 (dd, J=8.5, 2.9 Hz, 1H), 5.69-5.45 (d, J=72.4 Hz, 1H), 5.06-5.00 (dd, J=8.1, 6.2 Hz, 1H), 4.81-4.70 (dd, J=13.5, 6.7 Hz, 2H), 4.48-4.40 (m, 1H), 4.06-3.85 (dd, J=32.4, 13.9 Hz, 3H), 3.74-3.53 (m, 2H), 3.00-2.93 (d, J=2.3 Hz, 2H), 2.83-2.77 (dd, J=13.8, 3.8 Hz, 1H), 2.70-2.62 (dd, J=13.2, 6.0 Hz, 1H); MS (ESI) m/z: 444.2 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13].Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:15][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Nc1cc(Br)ccc1C(=O)O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (1 g) in pyridine (5 ml) was added isopropylamine (1.94 ml) at room temperature and the mixture was stirred at 100° C. overnight. The mixture was poured into aqueous hydrochloric acid (1N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 4-bromo-2-(isopropylamino)benzoic acid (218 mg).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[O-]CC.[Ta+5:12].[O-]CC.[O-]CC.[O-]CC.[O-]CC>C1(C)C=CC=CC=1>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Ta+5:12].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Ta+5:12]
Reactant: Oc1ccccc1O
Agent: [Ta+5]
Agent: CC[O-]
Solvent: Cc1ccccc1
Product: [O-]c1ccccc1[O-]
Temperature: 100 °C

Procedure:
A solution of catechol (5.51 g, 50.0 mmol) and toluene (50 ml) was dehydrated by distilling 10 mL of the solution. Thereafter, 8.13 g (20.0 mmol) of tantalum(V) ethoxide was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 110° C. or higher, distilled until the amount of the solution became half. After the distillation, volatile components of the residual mixed solution were vaporized under reduced pressure by a rotary evaporator. The residual solid content was further heated to 100° C. under vacuum using a vacuum dryer so that the remaining volatile components were completely removed. The solid content (catechol-tantalum complex) was yellow in color. The yield amount was 9.02 g (20.0 mmol), and the yield percentage was 100%. 4.51 g of catechol-tantalum complex was dissolved into 100 mL of 1:4 acetylacetone/toluene to produce a coating liquid.