Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:8](=[O:13])C(Cl)(Cl)Cl)[N:5]([CH3:7])[CH:6]=1.[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:8]([C:4]1[N:5]([CH3:7])[CH:6]=[C:2]([Br:1])[N:3]=1)=[O:13]
Reactant: C[O-]
Reactant: Cn1cc(Br)nc1C(=O)C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(Br)cn1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 337.7 %

Procedure:
To the solution of 1.18 g of 1-(-4-bromo-1-methyl-1H-imidazol-2-yl)-2,2,2-trichloroethanone in 10 mL of methanol was added 42 mg of sodium methoxide and the resulting mixture was stirred at 25° C. for 20 min. TLC showed completion of the reaction. The solution was evaporated, redissolved in 30 mL of DCM, washed with water (15 mL×2) and brine (15 mL). The solution was dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel column (DCM/MeOH=60/1) to give 4-bromo-1-methyl-1H-imidazole-2-carboxylic acid methyl ester (0.575 g, yield 68%). 1H NMR (300 MHz, CDCl3) δ 7.02 (s, 1H), 4.00 (s, 3H). 3.93 (s, 3H). LC-MS calcd for C6H7BrN2O2 (m/e) 217.97, obsd 219 and 221 [M+1]+
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][C:23]=1[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH2:10][C:11]3[C:2]([O:38][C:35]4[CH:36]=[CH:37][C:32]([C:23]5[CH:24]=[N:25][C:26]6[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=6)[N:22]=5)=[CH:33][CH:34]=4)=[CH:3][CH:4]=[N:5][C:6]=3[NH:7][C:8]2=[O:21])=[CH:14][CH:15]=1
Reactant: COc1ccc(CN2Cc3c(Cl)ccnc3NC2=O)cc1
Reactant: Oc1ccc(-c2cnc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(Oc4ccc(-c5cnc6ccccc6n5)cc4)ccnc3NC2=O)cc1
Temperature: 130 °C
Yield: 42.7 %

Procedure:
A suspension of 5-chloro-3-(4-methoxy-benzyl)-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-2-one (100.00 mg; 0.33 mmol; 1.00 eq.), 4-quinoxalin-2-ylphenol (91.46 mg; 0.41 mmol; 1.25 eq.), and cesium carbonate (214.54 mg; 0.66 mmol; 2.00 eq.) in DMF (2.00 ml) was heated in a microwave at 130° C. for 4 hours. The reaction was concentrated, redissolved in DMSO, syringe filtered, and purified via prep HPLC to afford 69 mg of 280 as an off-white solid. LC-MS (M+H=490, obsd.=490).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=O)=O.C1(O)C=CC=CC=1.O[C@@H](C1C=CC=C(O)C=1)CCNC(=O)OC(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Oc1cccc(Br)c1
Reactant: CS(=O)(=O)OCC1CCOCC1
Agent: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: Oc1ccccc1
Product: Brc1cccc(OCC2CCOCC2)c1

Procedure:
Alkylation of 3-bromophenol with (tetrahydro-2H-pyran-4-yl)methyl methanesulfonate following the method used in preparation of phenol (7, Intermediate I) gave 4-((3-bromophenoxy)methyl)tetrahydro-2H-pyran as a white solid which was used in the next step without additional purification. Yield (quant.).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][C:6](N)=[CH:5][N:4]=1.N([O-])=O.[Na+].[OH-].[Na+].[BrH:22]>O>[Br:22][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][CH:5]=1
Reactant: Br
Reactant: CN(c1ccc(N)cn1)C1CCOCC1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(c1ccc(Br)cn1)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of N2-methyl-N2-(tetrahydro-2H-pyran-4-yl)pyridine-2,5-diamine (150 mg, 0.73 mmol) in 2 mL of aq HBr was added a solution of NaNO2 (55 mg, 0.80 mmol) in 1 mL of H2O at 0° C. Then the mixture was stirred at 0° C. for 40 minutes. After that, the mixture was poured into a solution of CuBr (220 mg, 1.53 mmol) in 2 mL aq HBr at 0° C., the reaction was heated to 60° C. and stirred for 2 hours. After cooling, the mixture was based with 2M NaOH to pH=8-9 and extracted with EA, washed with H2O and brine, dried and concentrated, purified on TLC (EA:PE=1:1) to give white solid. MS (m/z): 273 (M+H)+
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:17])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>CCO.[OH-].[Pd+2].[OH-]>[OH:17][C:11]1([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C(O)C1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the solution of 1-benzyl-4-hydroxypiperidine-4-carboxylic acid (1.0 g, 4.25 mmol) in EtOH (15.0 mL) was added palladium hydroxide (0.40 g, 40% w/w) at rt and the mixture stirred at rt for 20 h under H2 atmosphere. After completion of reaction (by TLC) the mixture was passed through celite and the solvent evaporated. The crude (0.70 g) residue was carried forward for next step without further purification. MS: 145.99 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[CH2:7][CH2:6][N:5]([CH:8]([F:27])[CH2:9][CH:10]([NH:19]CC2C=CC=CC=2)[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[ClH:38]>[Pd].C(O)C.[H][H]>[ClH:38].[OH:1][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=2)[CH2:7][CH2:6][N:5]([CH:8]([F:27])[CH2:9][CH:10]([NH2:19])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: O=C(c1ccccc1)C(CC(F)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC(CC(F)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)C(=O)c1ccccc1

Procedure:
A mixture of γ-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidin-1-yl]-2-benzylamino-4-fluorobutyrophenone (3.8 g), 10 % palladium on charcoal (1.0 g) and 35 % hydrochloric acid (2.0 g) in ethanol (45 ml) was vigorously stirred in hydrogen atmosphere at 25°C until an equimolar amount of hydrogen was consumed. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to afford γ-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidin-1-yl]-2-amino-4-fluorobutyrophenon hydrochloride. M.P. 230° - 235°C (decomposition). The hydrochloride was shaken with a mixture of aqueous ammonia and ether. The ethereal layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the free base, which was recyrstallized from aqueous ethanol. M.P. 105° - 107°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11](C(OCC)=O)[C:12]([O:14]CC)=[O:13].[OH-].[K+]>CO.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1Br
Temperature: 70 °C

Procedure:
A solution of diethyl (2-bromo-4-nitrophenyl)propanedioate (5.6 g, 17 mmol) in 120 mL of methanol and 100 mL of water was added KOH (2.8 g, 50 mmol), and the mixture was heated to 70° C. for 3.5 hours. The reaction was cooled to ambient temperature, distilled off methanol under reduce pressure and adjusted pH to 2 with conc. HCl. Extracted with EtOAc and the organic layers were washed with water, brine and dried over anhydrous sodium sulfate, concentrated to get (2-bromo-4-nitrophenyl)acetic acid. 1H-NMR (300 MHz, CDCl3) δ ppm 8.39 (s, 1H), 8.07˜8.11 (m, 1H), 7.43 (d, J=8.3 Hz, 1H), 3.88 (s, 2H).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>CN(C)C=O>[N+:16]([C:6]1[CH:5]=[C:4]([CH2:3][N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(CCBr)ccc1-c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
4-(Bromoethyl)-2-nitro-1-phenylbenzene (584.3 mg, 2.0 mmol) and potassium phthalimide (555.0 mg, 3.0 mmol) were dissolved in N,N-dimethylformamide (8 mL) and the mixture was stirred at 110° C. for 3 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 2-[(3-nitro-4-phenylphenyl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione (600.8 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.I[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cccc(I)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C(O)c1cccc(-c2cc(F)cc(F)c2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The mixture of 3,5-difluorophenyl-dihydroxyborane (3 g), 3-iodobenzoic acid (3.37 g), sodium carbonate (4.31 g) and palladium(II) acetate (0.030 g) in water (60 ml) was stirred at room temperature for six hours. The reaction mixture was filtered and was washed with ether (30 ml) twice. The aqueous layer was adjusted to pH 2 with 6N hydrochloric acid. The crystalline was collected, washed with water and dried to afford 3-(3,5-difluorophenyl)benzoic acid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1.C1COCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH:3]=2)[CH:8]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a mixture of 2-bromo-6-methoxynaphthalene (23.79 g, 100.3 mmol) and tetrakis(triphenylphosphine)palladium (5.8 g, 5 mmol) was added a solution of 4-methoxyphenylmagnesium bromide in THF (400 mL of 0.5 N solution, 200 mmol). The stirred solution was heated to reflux for 3 hr, cooled to RT, and stirred into 200 mL of 1 N HCl. The mixture was extracted with dichloromethane and filtered through a short silica plug with dichloromethane. The solvent was removed to yield a crude yellow solid which was further purified by silica chromatography (20-50% ethyl acetate-hexanes) to yield 25.68 g (97%) of the title compound as a white solid: mp 190° C.; 1H NMR (CDCl3): δ 3.86 (3H, s), 3.93 (3H, s), 7.01 (2H, d, J=8.57 Hz), 7.14-7.18 (2H, m), 7.63 (2H, d, J=8.50 Hz), 7.67 (1H, dd, J=1.68 Hz, J=8.73 Hz), 7.76-7.80 (2H, m), 7.91 (1H, d, J=0.94 Hz); MS (ESI) m/z265 (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:5])=[O:4].[C:29]([O:32][CH2:33][C:34](Cl)=[O:35])(=[O:31])[CH3:30].C(N(CC)CC)C.O>ClCCl>[C:29]([O:32][CH2:33][C:34]([N:26]1[CH2:27][CH2:28][CH:23]([C:20]2[S:21][CH:22]=[C:18]([C:15]3[CH2:14][CH:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][S:3]([CH3:2])(=[O:4])=[O:5])[O:17][N:16]=3)[N:19]=2)[CH2:24][CH2:25]1)=[O:35])(=[O:31])[CH3:30]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OS(C)(=O)=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.7 %

Procedure:
To 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (500 mg) in dichloromethane (6 ml) under argon were added 2-chloro-2-oxoethyl acetate (154 mg) and triethylamine (342 mg). The reaction mixture was stirred at room temperature for 18 hours. Then water was added thereto, and it was filtered, dried and concentrated. Purification by column chromatography gave 2-{4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}-2-oxoethyl acetate (170 mg, 30%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=3)[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1ccc2ccn(Cc3ccccc3)c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1ccc(-c2ccc3ccn(Cc4ccccc4)c3c2)cc1
Yield: 70.9 %

Procedure:
Following the procedure described in Step 2 of Example 5, 1-benzyl-6-bromo-1H-indole (0.490 g, 1.71 mmol), was coupled to 4-trifluoromethylbenzeneboronic acid (0.376 g, 1.98 mmol), using tetrakis(triphenylphosphine) palladium (0.0663 g, 0.057 mmol) and sodium carbonate (0.733 g, 6.92 mmol) in water (3.5 mL), ethanol (2 mL) and toluene (10 mL). Purification by flash chromatography using 0-1% ethyl acetate in hexane as an eluant yielded the title compound as a yellow solid (0.426 g, 71%), mp: 83-85° C. 1HNMR (300 MHz, DMSO-d6): δ 7.9 (d, 3H, J=7.7 Hz), 7.8 (d, 2H, J=7.7 Hz), 7.7 (d, 1H, J=7.7 Hz), 7.6 (d, 1H, J=3.9 Hz), 7.4 (d, 1H, J=7.7 Hz), 7.2-7.4 (m, 5H), 6.55 (d, 1H, J=2.3 Hz), and 5.55 ppm (s, 2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][C:4]1[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=1.O.[N+:13]([CH:16]([CH:19]=O)[CH:17]=O)([O-:15])=[O:14].[Na]>O>[N+:13]([C:16]1[CH:17]=[C:8]2[C:4]([CH2:3][C:2]([F:1])([F:10])[F:11])=[N:5][NH:6][C:7]2=[N:9][CH:19]=1)([O-:15])=[O:14]
Reactant: Nc1cc(CC(F)(F)F)n[nH]1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na]
Solvent: O
Product: O=[N+]([O-])c1cnc2[nH]nc(CC(F)(F)F)c2c1
Temperature: 85 °C
Yield: 36.1 %

Procedure:
A round-bottom flask was charged with 3-(2,2,2-trifluoroethyl)-1H-pyrazol-5-amine (0.145 g, 0.878 mmol, WO 2008/005956), sodium nitromalonaldehyde monohydrate (0.150 g, 0.966 mmol) and water (3.5 mL). The reaction mixture was heated at 85° C. for 16 hours. The reaction mixture was poured into water and subsequently extracted with ethyl acetate (2×). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford 5-nitro-3-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine (0.078 g, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Cl:14][C:15]1[CH:28]=[CH:27][C:18]2[S:19][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:21]([CH3:22])[C:17]=2[CH:16]=1>N1C=CC=CC=1>[Cl:14][C:15]1[CH:28]=[CH:27][C:18]2[S:19][C:20]([S:23]([NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:12][CH3:13])(=[O:24])=[O:25])=[C:21]([CH3:22])[C:17]=2[CH:16]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(OC)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.4 %

Procedure:
Into 4 mL of pyridine were dissolved 120 mg of methyl 4-amino-3-methoxybenzoate and 150 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene, followed by 14 hours of stirring at room temperature. After confirmation of disappearance of the starting material, the reaction was terminated by adding water at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and then the residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain 110 mg of the title compound as colorless amorphous.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][C:10]([CH3:15])=[CH:11][C:12](O)=[O:13]>S(=O)(=O)(O)O>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:9])[O:5][C:4]=2[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: CC(C)=CC(=O)O
Agent: O=S(=O)(O)O
Product: CC1(C)CC(=O)c2ccc(O)cc2O1
Reaction time: 8 h
Yield: 62.5 %

Procedure:
Resorcinol (165 g) and 3,3-dimethylacrylic acid (100 g) were mixed, cooled in an ice bath, and treated carefully with concentrated sulfuric acid (180 mL). The internal temperature rose to 68° C. The mixture turned gradually to a viscous orange mass and the internal temperature dropped to 25° C. The ice bath was removed and stirring was continued overnight at room temperature (“RT”) during which the mixture solidified. Small amounts of water and ethyl acetate were carefully added alternatively until the mixture dissolved, and it was transferred to a 5 L conical flask with water (2 L) and ethyl acetate (1.5 L). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed once with water and carefully treated with solid sodium bicarbonate until effervescence stopped. The organic layer was washed with water, concentrated in vacuo, and the resulting white solid was dissolved in 10% sodium hydroxide. The resulting solution was adjusted to pH 2 with concentrated hydrochloric acid and the resulting solid was filtered, dissolved in boiling glacial acetic acid (220 mL), stirred, diluted with boiling water (220 mL), and immediately cooled. The resulting solid was filtered, washed, and dried in vacuo at 50° C. to give the title compound (120 g).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH3:13])=[CH:6][CH:5]=1)([O-])=O>C(O)C.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH3:13])=[CH:25][CH:26]=1
Reactant: CN(CCCOc1ccc([N+](=O)[O-])cc1)Cc1cnc2ccccc2n1
Agent: O=[Pt]=O
Solvent: CCO
Product: CN(CCCOc1ccc(N)cc1)Cc1cnc2ccccc2n1
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
A mixture of 2-[N-[3-(4-nitrophenoxy)propyl]methylamino methyl]quinoxaline (1.75 g, 4.97 mmol) and PtO2 (0.14 g, 0.62 mmol) in ethanol (170 mL) was charged with 1 atmosphere H2 (g). After 30 minutes, the mixture was filtered through solka floc and concentrated to afford crude product which was purified by HPLC to yield 1.18 g (74%) of a yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[N:7](CC2C=CC=CC=2)[C@@H:6]([CH3:15])[CH2:5][N:4]([C:16]2[CH:17]=[C:18]([NH2:24])[C:19](OC)=[N:20][CH:21]=2)[CH2:3]1.C[C@H]1N[C@@H](C)CN(C2C=C(NC(=O)C(F)(F)F)C=NC=2)C1>>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:15])[CH2:5][N:4]([C:16]2[CH:17]=[C:18]([NH2:24])[CH:19]=[N:20][CH:21]=2)[CH2:3]1
Reactant: COc1ncc(N2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)cc1N
Agent: C[C@@H]1CN(c2cncc(NC(=O)C(F)(F)F)c2)C[C@H](C)N1
Product: C[C@@H]1CN(c2cncc(N)c2)C[C@H](C)N1

Procedure:
The title compound was prepared in a manner similar to 5-[cis-3,5-dimethyl-4-(phenylmethyl)-1-piperazinyl]-2-(methyloxy)-3-pyridinamine (D29) using N-{5-[cis-3,5-dimethyl-1-piperazinyl]-3-pyridinyl}-2,2,2-trifluoroacetamide (D35) as the starting material.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:13]Br>ClCCCl>[Br:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH:5]=[O:12]
Reactant: BrBr
Reactant: O=Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a mixture of 1,2-dichloroethane (250 g) with 98% aluminum chloride (0.65 mol, 88.6 g) was added 97% benzaldehyde (0.50 mol, 54.6 g) over 1 hour at 40° C. After bromine (0.55 mol, 88.0 g) was added over 2 hours at 40° C., this mixture was stirred for 2 hours at the same temperature. After the reaction mixture being added to ice water (375.0 g) and stirred thoroughly, this was allowed to stand and separated. The organic phase was washed with 100 ml of water, further with 100 ml of 0.5% aqueous solution of sodium carbonate, and finally with 100 ml of water. Then, 241.0 g of solvent were recovered and the residue was distilled, obtaining 83.5 g of 3-bromobenzaldehyde.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:52]=[CH:51][C:33]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:52]=[CH:51][C:33]([O:34][CH2:35][CH2:36][CH2:37][N:38]5[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:42][CH2:43]5)=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3CCNCC3)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
DIPEA (2.417 mL, 13.88 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (2.059 g, 9.25 mmol) and tert-butyl 4-[3-[4-(piperidin-4-yl)phenoxy]propyl]piperazine-1-carboxylate (3.92 g, 9.71 mmol) in DMF (30 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The resulting solid was triturated with water, then collected by filtration, washed with ether and dried to afford tert-butyl 4-[3-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]propyl]piperazine-1-carboxylate (4.67 g, 86%) as a solid.