Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:36](Br)[CH:37]=[CH2:38]>>[CH2:36]([N:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)[CH2:9][CH2:10]1)[N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=3)[CH:25]=2)(=[O:23])=[O:22])[CH2:17][C:16]1=[O:35])[CH:37]=[CH2:38]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(NN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Product: C=CCN(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O

Procedure:
Similarly to Method A in Example 38 and using 1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (390 mg) and allyl bromide (2 ml) instead of methyl iodide, the title compound (69 mg) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH:13]([CH3:18])[CH2:12]1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)[C:15](=[O:17])[CH2:14][CH:13]([CH3:18])[CH2:12]1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COc1cccc(OC)c1C1CC(C)CC(=O)N1
Product: COc1cccc(OC)c1C1CC(C)CC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)-4-methylpiperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.13 min.; [M+H]+: 423.91 g/mol.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([OH:12])=[O:11])[CH3:6].[CH2:17](O)[CH3:18]>>[CH2:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([O:12][CH2:17][CH3:18])=[O:11])[CH3:6]
Reactant: CCO
Reactant: CCc1cc(C(=O)O)ccc1O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(O)c(CC)c1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
Thionyl chloride (3 ml) was added dropwise over a period of 2 minutes to ethanol (50 ml) at -10° C. whilst under an atmosphere of argon. The reaction mixture was stirred at -10° C. for 20 minutes and then allowed to warm to ambient temperature. A solution of 3-ethyl-4-hydroxybenzoic acid (3.5 g) in ethanol was added to the reaction mixture dropwise, with cooling (ice-bath). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The ethanol was removed by evaporation and the residue was partitioned between ethyl acetate (100 ml) and 1M aqueous sodium hydroxide solution (50 ml). The phases were separated and the aqueous phase washed with ethyl acetate (50 ml). The ethyl acetate extracts were combined, washed with water (50 ml) brine (50 ml), dried (MgSO4) and evaporated. The residue, an oil, crystallised on standing to give a solid which was triturated with 10% diethyl ether/pentane to give ethyl 3-ethyl-4-hydroxybenzoate as a solid (1.4 g), m.p. 73°-74° C.; microanalysis, found: C, 68.4; H, 7.7%; C11H14O3 requires: C, 68.0; H, 7.3%; NMR: 1.15(3H,t), 1.3(3H,t), 2.55(2H,q), 4.25(2H,q), 6.85(2H,d), 7.65(2H,m), 10.15(1H,s).
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([NH:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]([OH:27])[CH3:26])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1.C(=O)([O-])[O-].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CO>[CH2:36]([O:35][C:33]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]([OH:27])[CH3:26])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:10]1)=[O:34])[CH3:37]
Reactant: CC(O)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)O)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(1-hydroxy-ethyl)-naphthalene-1-sulfonic acid piperidin-4-ylamide acetic acid salt 37 (290 mg, 0.74 mmol) in MeOH (10 mL) was added MP-Carbonate (1.45 g, 3.69 mmol, 2.54 mmol/g). After shaking at 25° C. for 1 h, the solution was filtered. To the resultant solution was added ethyl chloroformate (120 mg, 1.11 mmol). After stirred for another 2 h at 25° C., the solution was concentrated in vacuo to give a solid. The crude material was purified by Flash column chromatography (CH2Cl2:MeOH) to provide 4-[4-(1-hydroxy-ethyl)-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester 38. LCMS showed m/z: 407 (M+H)+.
Reaction SMILES: [OH-].[Na+:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:15])[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[CH3:16]I.Cl>CO>[O:15]=[C:11]([CH:10]([C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)[CH3:16])[C:12]([O-:14])=[O:13].[Na+:2]
Reactant: O=C(O)C(=O)Cc1ccc(F)cc1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)C(=O)[O-])c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 3N aqueous solution of sodium hydroxide (5.0 ml, 15 mmoles) and 20 ml of methanol were added to p-fluorophenylpyruvic acid (0.92 g, 5.0 mmoles) to form a solution. Then, 2.0 ml of methyl iodide was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with three 30 ml portions of ether. The ether layers were dried over magnesium sulfate, and concentrated under reduced pressure to give a pale yellowish white solid. To the product was added 2 ml of a 3N aqueous solution of sodium hydroxide, and the mixture was concentrated under reduced pressure. Ether was added to the resulting semi-solid mixture, and the precipitated sodium 2-oxo-3-(p-fluorophenyl)butanoate was isolated by filtration as a white solid (yield 26 %).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]([F:29])([F:28])[C:23]1[N:24]=[CH:25][NH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:21][C:22]([F:29])([F:28])[C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:27]=1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3cnc(C(F)(F)F)c3)nc2c1
Temperature: 50 °C
Yield: 101.2 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of 4-(trifluoromethyl)-1H-imidazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.40 g of 2-{3-[4-(trifluoromethyl)imidazole-1-yl]pyridin-4-yl}-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 57”).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](F)[CH:7]=1.[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[Na+]>C(O)(C)(C)C.C(OCC)(=O)C>[C:12]([O:14][C:6]1[CH:7]=[C:2]([F:1])[C:3]([C:9]#[N:10])=[N:4][CH:5]=1)([CH3:15])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ncc(F)cc1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1cnc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A solution (30 mL) of 3,5-difluoropyridine-2-carbonitrile (1.51 g, 10.8 mmol) in tert-butanol was added dropwise to a solution (40 mL) of sodium tert-butoxide (1.04 g, 10.8 mmol) in tert-butanol (40 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give a mixture (1.63 g) of 5-tert-butoxy-3-fluoropyridine-2-carbonitrile and 3-tert-butoxy-5-fluoropyridine-2-carbonitrile. To the obtained mixture (1.62 g, 8.34 mmol) was added 4N hydrogen chloride-dioxane (40 mL), and the mixture was stirred at 60° C. for 2 hr, and concentrated. To a solution of the obtained residue (1.46 g, 8.34 mmol) and potassium carbonate (2.31 g, 16.7 mmol) in DMF (20 mL) was added cyclopropylmethyl bromide (1.21 mL, 12.5 mmol), and the mixture was stirred at 60° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0 to 7:3) to give the title compound (365 mg, yield 23%).
Reaction SMILES: [O:1]([C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:24]([O:26][C:27](=[O:31])[C:28]([OH:30])=O)[CH3:25]>C(Cl)CCl>[CH2:24]([O:26][C:27](=[O:31])[C:28]([N:17]([CH2:18][CH3:19])[C:16]([O:15][CH2:14][CH2:13][O:12][C:11]1[CH:21]=[CH:22][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)=[O:20])=[O:30])[CH3:25]
Reactant: CCOC(=O)C(=O)O
Reactant: CCNC(=O)OCCOc1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)C(=O)N(CC)C(=O)OCCOc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C

Procedure:
9.0 g of N-ethyl-carbamic acid-2-(4-phenoxyphenoxy)ethyl ester are dissolved in 90 ml of ethylene chloride. To this solution are added 9.6 g of oxalic acid monoethyl ester chloride, and stirring is maintained for 10 hours under mild refluxing conditions. The cooled reaction mixture is then poured into 200 ml of ice-water, and the organic phase is separated. This is washed with cold water, dried over sodium sulfate, concentrated by evaporation and taken up in dichloromethane. Chromatography on silica gel with dichloromethane as the eluant thus yields the compound of the formula ##STR6## in the form of white crystals having a m.p. of 56°-58° C.
Reaction SMILES: [F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:4]=2[O:3]1.F[C:14]1[C:19]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1>>[F:12][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:14]3[C:19]([C:20]4[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]([CH2:28][C:29]5[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=5)[CH2:37][C:38]5[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=5)[N:21]=4)=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc4c(c3)OC(F)(F)O4)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 2,2-difluorobenzo[d][1,3]dioxol-5-amine (0.055 g, 0.320 mmol) (Apollo Scientific Limited) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.095 g, 0.213 mmol), and isolated as a brown oil (100%). 1H NMR (400 MHz, d6-DMSO) δ 11.98 (br. s., 1H); 8.79 (d, J=7.6 Hz, 1H); 8.35 (br. s., 1H); 7.92 (br. s., 1H); 7.20-7.29 (m, 5H); 7.16 (d, J=8.4 Hz, 1H); 6.83-6.97 (m, 5H); 4.81 (d, J=7.4 Hz, 4H); 3.72 (d, J=12.7 Hz, 6H); 2.57 (br. s., 3H). m/z (ESI, +ve ion) 599.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH3:13])=[N:7]2.[NH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[S:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:14][C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=3[S:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH3:13]
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: CCc1ccc2c(Cl)ccnc2n1
Product: CCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1

Procedure:
The product from Example 3f (92 mg, 0.47 mmol) was reacted with the product from Example 18b (130 mg, 0.47 mmol) for 22 h following the procedure from Example 1g giving the title compound as a solid after purification of the crude product by HPLC with TFA as a trifluoroacetic acid salt (68 mg, 26%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (t, J=7.72 Hz, 1H) 2.04 (s, 3H) 2.35 (s, 3H) 3.05 (q, J=7.72 Hz, 2H) 6.31 (d, J=6.98 Hz, 1H) 7.15 (d, J=8.83 Hz, 1H) 7.20-7.35 (m, 3H) 7.49 (d, J=8.83 Hz, 2H) 7.82 (d, J=8.82 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.82 Hz, 1H) 10.04 (s, 1H) 11.01 (br s, 1H) 14.39 (br s, 1H). MS (ESI+) m/z 429 (M+H−Cl)+; (ESI−) m/z 427 (M−H−Cl)−.
Reaction SMILES: [CH3:1][C:2]12[CH2:17][CH:5]([C:6]3([CH3:16])[C:10]1([CH3:11])[C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[Br:18]N1C(=O)CCC1=O>O1CCCC1.CN(C)C=O>[Br:18][C:13]1[CH:14]=[CH:15][C:8]2[O:7][C:6]3([CH3:16])[CH:5]4[CH2:17][C:2]([CH3:1])([C:10]3([CH3:11])[C:9]=2[CH:12]=1)[CH2:3][CH2:4]4
Reactant: CC12CCC(C1)C1(C)Oc3ccccc3C21C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC12CCC(C1)C1(C)Oc3ccc(Br)cc3C21C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11.42 g (50 mmol) of (-)-1,2,3,4-tetra-hydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran obtained in Example 1 were dissolved in 110 ml of tetrahydrofuran and were treated dropwise with a solution containing 8.9 g of N-bromosuccinimide (NBS) in 50 ml of dimethylformamide (DMF). The reaction mixture was maintained under stirring at room temperature for 2 h, 30 min, and was then poured into ice-cold water and extracted with 500 ml of ethyl ether. After rinsing with water, drying over magnesium sulfate, filtering and evaporating, 13.8 g (90%) of the expected derivative, melting at 119.8° C., were isolated after chromatography on silica in hexane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(-c2ccccc2C#N)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(-c2ccccc2C#N)ccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
2-(3-Methylphenyl)benzonitrile (18.1 mmoles, 3.5 g) was added slowly at -5° C. to a mixture of 10 ml nitric acid and 10 ml sulfuric acid. After 5 minutes, the reaction was diluted with cold water. The solid was collected, dissolved in THF. The solution was dried and concentrated. The solid was recrystallized from ether and hexane to yield 2.45 g of 2-(3-methyl-4-nitrophenyl)benzonitrile. (MS)
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[Cl:6][C:1]([CH2:2][O:3][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:3][CH2:2][C:1]([Cl:6])=[O:5])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccccc1
Product: O=C(Cl)COc1ccccc1OCC(=O)Cl
Reaction time: 96 h

Procedure:
30 g. Of the above acid are added to a mixture of 200 ml. anhydrous benzene. Then 35 g. oxalylchloride are added, the flask being protected by a calcium chloride tube. The mixture is stirred for four days and the diacid progressively dissolves as it is being transformed into the corresponding dichloride. The solution is then evaporated to dryness (without heating) leaving a brownish solid residue which is recrystallized from a mixture of chloroform-benzene giving white crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH3:26])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OCC)(=O)C>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:26][N:17]1[CH:18]=[C:19]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Yield: 91.3 %

Procedure:
To a solution of 4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyridine (1.28 g) in ethanol (50 ml)/ethyl acetate (50 ml) in a parr bottle was added Palladium hydroxide (500 mg). The parr bottle was charged to 40 psi on a shaker for 6 h. The reaction mixture was filtered and concentrated. MPLC biotage chromatography eluting with methanol (1-7%)/chloroform provided the title compound (860 mg, 91%). 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 8.39 (d, J=5.8 Hz, 2 H), 7.15 (m, 4H), 6.72 (d, J=8.7 Hz, 1H), 3.84 (s, 3H); MS: (M+H m/z=252.2).
Reaction SMILES: [Na+].[Br:2][C:3]1[C:4]([Cl:17])=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([NH:9][CH2:10][C:11]([O-])=[O:12])[CH:8]=1.O.O.[Sn](Cl)Cl>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[Cl:17])[NH:14][C:11](=[O:12])[CH2:10][NH:9]2
Reactant: O=C([O-])CNc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CNc2cc(Br)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of N-(5'-bromo-4'-chloro-2'-nitrophenyl)glycine sodium salt (0.255 g, 0.824 mmol, as prepared above) and tin (II) chloride dihydrate (0.560 g, 2.48 mmol, Aldrich, used as received) in ethanol (6 mL) was refluxed for 3 h. It was then cooled to room temperature and allowed to stand overnight at room temperature. The white solid was filtered and dried to yield 0.038 g (18%) of the pure (1H NMR) title compound as white flakes; m.p. 230°-232° C.; 1H NMR (DMSO-d6): δ3.732 (s, 2H), 6.371 (s, 1H), 6.830 (s, 1H), 6.912 (s, 1H), 10.437 (s, 1H). Extraction of the filtrate with ethyl acetate (30 mL) gave 0.136 g (68%) more product for a combined yield of 86%. The product was used as such for the next reaction.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([NH2:17])[N:4]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([NH:17][C:26](=[O:27])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1ccc(Nc2cc(N(C)C)nc(N)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Nc2cc(N(C)C)nc(NC(=O)Cc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
A mixture of N4,N4-dimethyl-N6-(4-methylphenyl)-2,4,6-pyrimidinetriamine (122 mg, 0.50 mmol), phenylacetyl chloride (84 mg, 0.55 mmol), and triethylamine (100 mg, 1.00 mmol) in CH2Cl2 was stirred at room temperature for 16 h. The crude product was concentrated in vacuo and treated with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic layer was washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC using hexane/EtOAc (1:3), giving the desired product (60 mg, 33%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([F:27])[CH:21]=1>C(O)C>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])=[C:22]([F:27])[CH:21]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Solvent: CCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2cc1[N+](=O)[O-]
Reaction time: 3.5 h

Procedure:
A mixture of 5.017 g (19.0 mmol) 4-chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, and 2.55 ml 22.8 mmol) 4-chloro-2-fluoroaniline was heated to reflux under N2. At 3.5 hours, removed heat and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids, and washed with water. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent, and dried in vacuo, giving 6.54 g of yellow solid: mass spectrum (electrospray m/e): M+H=372.8, 374.8.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]([CH3:34])[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>>[CH3:34][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:32][CH:33]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Product: CN(C)CCCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(3-dimethylaminopropoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-dimethyl-3-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenoxy]propan-1-amine.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([CH2:33][N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:41][CH:40]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Reactant: Cc1cc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)no1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(Cn6cccn6)cc5)nc34)CC2)no1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.040 g, 0.10 mmol) and EtOH (3.5 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.024 g, 0.13 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 3%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.020 g, 38%). 1H-NMR (500 MHz, DMSO-d6) 2.40 (s, 3H, isoxazole 5-CH3), 2.63 (br s, 4H, piperazine N(CH2)2), 3.60 (s, 2H, NCH2 isoxazole), 3.66 (br s, 4H, piperazine N(CH2)2), 5.42 (s, 2H, C6H4CH2N), 6.24 (s, 1H, isoxazole 4-H), 6.30 (t, J=2.0 Hz, 1H, pyrazole 4-H), 7.35 (d, J=8.3 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4 and 2,6-C6H4), 7.49 (d, J=1.4 Hz, pyrazole-H), 7.86 (d, J=2.0 Hz, 1H, pyrazole-H), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.50 (br s, 1H, imidazo[4,5-b]pyridine N—H);