Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[N:14]1[CH:18]=[C:17]([Cl:19])[N:16]=[CH:15]1)[CH:2]=[CH2:3].CO.[Cl-].[NH4+]>[Fe].O>[Cl:19][C:17]1[N:16]=[CH:15][N:14]([C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])[CH:18]=1
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: C=CCOc1cc(N)ccc1-n1cnc(Cl)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
Iron powder-325 mesh (737 mg, 12.5 mmol) was added to a round bottom flask charged with a mixture of 1-(2-(allyloxy)-4-nitrophenyl)-4-chloro-1H-imidazole (500 mg, 1.8 mmol), absolute methanol (10 mL), and ammonium chloride (768 mg, 14 mmol). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated to 65° C. with vigorous stirring for 30 min. The reaction mixture was filtered, and washed with methanol. The solvent was removed in vacuo. EtOAc was added to the residue, and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 4-(4-chloro-1H-imidazol-1-yl)-3-allyloxyaniline (380 mg, 83% yield). LC-MS (M+H)+250.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.48 (d, J=1.22 Hz, 1H), 6.97-7.02 (m, 2H), 6.26-6.32 (m, 2H), 5.87-5.98 (m, 1H), 5.20-5.34 (m, 2H), 4.48 (d, J=5.19 Hz, 2H), 3.86 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc(N)c2ncccc12
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)c2ccccc2)c2ncccc12
Yield: 28.2 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-methylquinolin-8-amine (Intermediate 44) (150 mg, 0.95 mmol) and benzenesulfonyl chloride (200 mg, 1.14 mmol) gave the title compound (80 mg, 28%) after column chromatography with DCM as the eluent.
Reaction SMILES: Cl.[C]=O.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:16](C)[C:17](O)=O)[CH:10]=[CH:9]2>Cl[Pd]Cl.C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:16]=[CH2:17])[CH:10]=[CH:9]2
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: [C]=O
Solvent: C1CCOC1
Product: C=Cc1ccc2cc(OC)ccc2c1

Procedure:
Charged to a 1000-gallon reactor are the filtered THF-DEK-MVN solution produced in the above procedure containing 550 kg of MVN, 825 kg of DEK, and 825 kg of THF, followed by 0.3 kg of PdCl2, 0.64 kg of CuCl2, 3.1 kg of NMDP, and 200 kg of 10 wt % HCl. The reactor is then pressured to 100 psig with carbon monoxide and the reactor temperature is adjusted to 70° C. The reactor is then pressured to 360 psig with carbon monoxide and held at this pressure until the uptake of carbon monoxide is completed. The reactor is then cooled and the pressure is vented. The reaction typically takes 4-8 hours to go to completion with >95% MVN conversion and a yield of (±)-2-(6-methoxy-2-naphthyl)propionic acid of approximately 90%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(=O)C.[Na+].[C:49]([NH2:53])(=[O:52])[CH:50]=[CH2:51]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OC(=O)C)C.CN(C)C=O>[NH2:53][C:49](=[O:52])/[CH:50]=[CH:51]/[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Br)cc(Cl)c2OC1C(F)(F)F
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(/C=C/C(N)=O)cc(Cl)c2OC1C(F)(F)F
Temperature: 110 °C
Reaction time: 85 h
Yield: 61.2 %

Procedure:
To the mixture of 0.4 g (1.0 mmol) of ethyl 6-Bromo-8-Chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate, 45 mg (0.2 mmol) of palladium acetate, 122 mg (0.4 mmol) of tri-o-tolylphosphine, 451 mg (5.5 mmol) of sodium acetate under nitrogen atmosphere was added 6 mL of anhydrous dimethylformamide, followed by addition of 107 mg (1.5 mmol) of acrylamide. The resulting mixture was shaken at 110° C. for 85 hrs. LC-MS indicated that the reaction was done. To the reaction was added 50 mL of ethylacetate. The resulting organic solution was washed with brine and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified by reverse phase chromatography to afford 0.23 g off-white solid, which was carried on to the next step.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:10][C:4]=2[NH:3]1.FC(F)(F)C(O)=O>C(Cl)Cl.CO>[NH:14]1[CH2:13][CH2:12][CH:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[NH:3][C:4]=3[CH:10]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3[nH]c(=O)[nH]c3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=c1[nH]c2ccc(C3CCNCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of compound 17 (0.95 g, 3 mmol) in a mixture of CH2Cl2 (15 mL) and CH3OH (20 mL) was added trifluoroacetic acid (3 mL) at 0° C., and the mixture was stirred for 6 h at room temperature. Solvents were evaporated under reduced pressure, and triturating with diethyl ether gave the title compound 5. Yield: 90%, light yellow solid, mp 214-215° C. IR (KBr, cm−1) 3238 (CONH), 3043 (Ar—H), 2956 (Alph-H), 1692 (CO), 1612, 1446 (C—C), 1180 (C—N), 1126 (C-0); 1HNMR (500 MHz, DMSO d6) δ 1.73-188 (m, 3H, CH, CH2), 2.77 (m, 2H, CH2), 2.97 (m, 2H, CH2), 3.44 (obscured by H2O, 2H, CH2), 4.46 (m, 1H, CH), 6.74-6.84 (m, 3H, H-4, H-6, H-7), 10.50 (br. s, 1H, NH), 10.54 (br. s, 1H, NH). 13C NMR (125.7 MHz, DMSO d6) δ 30.04 (CH2), 33.37 (CH), 43.86 (CH2), 106.66 (C-4), 118.43 (C-7), 118.94 (C-6), 128.37 (C-8), 129.87 (C-9), 137.24 (C-5), 155.56 (CO). Anal. Calcd for C14H16F3N3O3: C, 50.76; H, 4.87; N, 12.68%. Found: C, 50.70; H, 4.92; N, 12.60%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(OCC)(=O)C>[NH2:5][C:4]1[C:19]2[CH2:18][N:17]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21][C:20]=2[N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=12
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1c2c(nc3ccccc13)CCN(Cc1ccccc1)C2
Yield: 96.8 %

Procedure:
11.55 g (97.80 mmol) of 2-aminobenzonitrile and 24.07 g (127.14 mmol) of N-benzylpiperidine-4-one were dissolved in 200 ml of ethyl acetate, to which 50.00 g (225.00 mmol) of trimethylsilyltrifluoromethane sulfonate was added dropwise at room temperature. After the end of the dropwise addition, the mixture was refluxed under heating for 6 hours. After air cooling, the produced crystals were filtered out and washed with 320 ml of ethyl acetate. The obtained crystals were dried, added to a mixed solution of 400 ml of water and 200 ml of ethanol and dissolved by heating. After air cooling, 250 ml of a 1N sodium hydroxide solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and then the drying agent was filtered out. The filtrate was concentrated under reduced pressure and the residue was suspended in a mixed solution of 200 ml of ethyl acetate and 200 ml of hexane. The produced crystals were filtered out and further washed with the above mixed solution to obtain the title compound (27.39 g, 95% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:8][O:9][C:5]=2[CH:4]=1.[H-].[Na+].[CH3:19]I.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[C:7]([CH:10]([CH3:19])[C:11]([O:13][CH3:14])=[O:12])=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: CI
Reactant: COC(=O)Cc1noc2cc(OC)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)c1noc2cc(OC)ccc12
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of methyl (6-methoxy-1,2-benzisoxazol-3-yl)acetate (3.00 g, 13.6 mmol) in anhydrous THF (70 mL) was added 60% sodium hydride (544 mg, 13.6 mmol) under ice-cooling. After stirring for 30 min, methyl iodide (0.929 mL, 14.9 mmol) in THF (4 mL) was added dropwise thereto, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. This solution was applied to basic silica gel column chromatography (ethyl acetate) to give the title compound (3.19 g, quantitative) as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([SH:6])=[N:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[CH:20][CH:19]=1)=[O:17]>ClCCl>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[CH2:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:16](=[O:17])[CH2:15][S:6][C:3]2[N:4]=[CH:5][NH:1][N:2]=2)=[CH:23][CH:22]=1
Reactant: Sc1nc[nH]n1
Reactant: O=C(CBr)c1ccc(OCc2c(F)cccc2F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CSc1nc[nH]n1)c1ccc(OCc2c(F)cccc2F)cc1
Reaction time: 0.83 h

Procedure:
To a solution of 1H-1,2,4-Triazole-3-thiol (0.250 g, 2.4 mmol) and triethylamine (2.50 g, 2.4 mmol) in dry dichloromethane (20 ml) was added 2-Bromo-1-(4-(2,6-difluorobenzyloxy)phenyl)-1-Ethanone (Step B, 0.851 g, 2.4 mmol) in dry dichloromethane (5 ml) at room temperature. The reaction mixture was stirred for 50 minutes and then concentrated in vacuo. The crude residue was taken in EtOAc and washed with 0.1M HCl, and brine. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography on silica gel column (chloroform:methanol, 9:1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C1C(=O)N([Br:18])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1csc2ccccc12
Yield: 42.2 %

Procedure:
3-Methylbenzo[b]thiophene (9.9 g, 67 mmol) is heated in carbon tetrachloride (133 ml) to near reflux in the presence of n-bromosuccinimide (11.9 g, 67 mmol, 1.0 eq.). 2,2′Azobisisobutyronitrile (2.2 g, 13.3 mmol, 0.2 eq.) is added and the resulting mixture is refluxed for two hours. After cooling, the reaction mixture is filtered through a glass-fritted funnel, and the filtrate is concentrated. The residue is triturated with petroleum ether and toluene to afford 6.42 g of 3-Bromomethylbenzo[b]thiophene (42%). The title amine is prepared from 3-(bromomethyl)-benzo[B]thiophene in a similar fashion as described in U.S. Pat. No. 4,321,398.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: BrCCCCC1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 220 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 4-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[C:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH:18]=1.[BH4-].[Na+].FC(F)(F)C(O)=O.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: COc1cc(C)c2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c2[nH]cc(C3CCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
To a suspension of 5-methoxy-7-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.1 mole, 24.71 g) in tetrahydrofuran (295 mL) at room temperature was added sodium borohydride (0.2 mole, 7.29 g). Trifluoroacetic acid (0.3 mole, 32.97 g) was added over a 15 minute period. The reaction was stirred at room temperature for 1.5 hours. To the heavy suspension was added 5N hydrochloric acid (200 mL). The resulting solution was stirred at room temperature for 1.5 hours. To the reaction was added ethyl acetate (500 mL) then the pH was adjusted to >12 with 50% wt/wt sodium hydroxide. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×500 mL). The organic phases were combined, dried over sodium sulfate then filtered. The filtrate was filtered through a pad of silica (height of silica=7.0 cm) in a scinter glass funnel (inner diameter of funnel=14.5 cm). After the first fraction was collected the next two fractions were eluted with chloroform (1.2 L each). The remaining fractions were eluted with 90:10:1 chloroform:methanol:ammonium hydroxide (1.2 L fractions collected). The desired fractions were combined and concentrated in vacuo to afford 18.94 g (76%) of the title compound as a white solid: mass spectrum (ion spray): m/z=259 (M+1); 1H NMR (DMSOd6): 7.02 (d, 1H), 6.81 (d, 1H), 6.53 (d, 1H), 3.74 (s, 3H), 2.84 (m, 2H), 2.62 (m, 1H), 2.39 (s, 3H), 2.23 (s, 3H), 2.06 (m, 2H), 1.90 (m, 2H), 1.67 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[I-:14].[Na+].Cl[O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([I:14])[N:7]=1
Reactant: COC(=O)CCc1ncccc1O
Reactant: [I-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: COC(=O)CCc1nc(I)ccc1O
Temperature: 15 °C
Yield: 32.7 %

Procedure:
A solution of 15 g of 3-(3-hydroxy-2-pyridyl)-propionic acid methyl ester in 250 ml of methanol is mixed with 12.4 g of sodium iodide, cooled to 15° C., and 74 ml of aqueous sodium hypochlorite solution (6.5% active chlorine) is instilled. The yellow suspension is concentrated by evaporation, the residue is taken up in water, acidified to pH 4 with 2n sulfuric acid and shaken out with ethyl acetate. The organic phase is washed with 10% sodium thiosulfate solution, dried with sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-50% ethyl acetate. 8.3 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester of melting point 145°-148° C. is obtained.
Reaction SMILES: [OH-].[Na+].O.[F:4][C:5]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:6]=1[CH:7]=O.[CH3:14][C:15]([CH3:17])=[O:16]>>[F:4][C:5]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:6]=1[CH:7]=[CH:14][C:15](=[O:16])[CH3:17]
Reactant: CC(C)=O
Reactant: O=Cc1cc(F)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(F)ccc1F
Reaction time: 0.5 h

Procedure:
A mixture of acetone (45 ml), sodium hydroxide (3.1 g) and water (230 ml) was combined at room temperature with a solution of 2,5-difluorobenzaldehyde (10.0 g) in acetone (10 ml) and stirred at the same temperature for 30 minutes. Acetone was distilled off under reduced pressure and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and concentrated under reduced pressure to obtain 4-(2,5-difluorophenyl)-3-buten-2-one (13.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[N:12]=2)[N:3]=1.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:17]2[CH:18]=[C:13]3[N:12]=[C:11]([CH2:10][CH2:9][C:4]4[N:3]=[C:2]([NH2:1])[CH:7]=[C:6]([CH3:8])[CH:5]=4)[NH:20][C:14]3=[N:15][CH:16]=2)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1cc(N)nc(CCc2nc3cc(Br)cnc3[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4ccc(OCc5ccccc5)cc4)cnc3[nH]2)c1
Yield: 43.5 %

Procedure:
The title compound is synthesized according to General Procedure A. 100 mg of 2-[2-(2-amino-4-methylpyridin-6-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine in 5.0 ml dioxane, 903 μl Na2CO3 solution, 78 mg of 4-benzoxyphenylboronic acid, 13 mg of PdCl2(PCy3)2, 110° C. for 70 h, 20 ml of CH2Cl2/H2O, 120 mg of crude title compound is purified by recrystallization from 5.0 ml isopropyl alcohol to yield 57 mg of the pure title compound as colorless solid. M.p. 225° C. ESI-MS: 436.3 (MH+). TLC: Rf=0.35 (dichloromethane/methanol 10:1).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][CH:13]=[CH:14][N:4]2[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][CH:13]=[CH:14][N:4]3[N:3]=2)[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: Clc1nn2ccnc2c2c1CCCC2
Product: CN1CCN(c2nn3ccnc3c3c2CCCC3)CC1
Temperature: 0 °C

Procedure:
A mixture of 15 g of 6-chloro-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine and 36.2 g of 1-methylpiperazine was heated at reflux for 48 hours during which time the reaction mixture turned brown. The reaction was poured into about 150 ml of ice water. The solid which formed was separated by filtration and air-dried to give 6-(4-methyl-1-piperazinyl)-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine melting at about 79.5° C.
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH3:16])[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].F[C:18]1[CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>CS(C)=O>[CH3:16][N:5]([CH3:4])[CH2:6][CH2:7][CH:8]([O:9][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1cccc([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
57 ml of dimethylsulfoxide were added at 60°-65° C. to 5.7 g of a 50% oil-sodium hydride suspension and after cooling the mixture to 25° C., 10.55 g of N,N-dimethyl-3-phenyl-3-hydroxy-propanamine hydrochloride were added thereto under an inert atmosphere. The mixture stood at room temperature and 10.6 ml of 3-fluoro-nitrobenzene were added thereto. After standing at 25° C. for 18 hours, the mixture was extracted with methylene chloride and the organic phase was washed with water and evaporated to dryness under reduced pressure to obtain 25 g of raw product. The latter was extracted twice with 50 ml of N hydrochloric acid and the neutral fraction was extracted twice with 100 ml of ether. The aqueous phase was made alkaline with an excess of sodium hydroxide solution and was extracted with methylene chloride. The organic phase was washed with water and evaporated to dryness under reduced pressure to obtain 11 g of N,N-dimethyl-γ-(3-nitrophenoxy)-benzene-propanamine.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=2[F:30])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>B#[Ni].CO>[C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=2[F:30])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:31])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1cc(C)c(C(=O)c2ccccc2)n1C
Agent: B#[Ni]
Agent: Cl
Solvent: CO
Product: CCOC(=O)C(c1ccc(N)cc1F)c1cc(C)c(C(=O)c2ccccc2)n1C
Yield: 95.3 %

Procedure:
A mixture of ethyl 2-(5-benzoyl-1,4-dimethylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)-acetate (6.0 g, 14.1 mmol) [prepared as in Example 1, Step (b)], nickel boride (8.0 g, 62.4 mmol), hydrochloric acid (50 ml, 1M) and methanol (150 ml) was heated at reflux for 1 h. The reaction mixture was cooled and filtered through Celite®. After removing the methanol in vacuo, the resulting aqueous mixture was made basic with ammonium hydroxide, and the product was extracted into ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Evaporation of the organic layer gave ethyl 2-(5-benzoyl-1,4-dimethyl-pyrrol-2-yl)-2-(2-fluoro-4-aminophenyl)acetate (5.3 g, 95%). ##STR20##
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:7]=2[C:8]=1[CH3:9])(=O)[CH3:2].[OH-].[K+].NN.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)CO>[CH2:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:7]=2[C:8]=1[CH3:9])[CH3:2]
Reactant: CC(=O)c1oc2cccc(O)c2c1C
Agent: NN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: OCCO
Product: CCc1oc2cccc(O)c2c1C
Temperature: 180 °C
Yield: 64.9 %

Procedure:
A mixture of 2-acetyl-4-hydroxy-3-methylbenzofuran (2 g; 10.5mmoles), potassium hydroxide pellets (4 g; 73mmoles), ethylene glycol (50 ml) and 99% hydrazine (3 ml) was heated at 100° C. for 2 hours and at 180° C. for 2 hours. The mixture was acidified with excess 20% citric acid solution and extracted with ether. The ether layer was dried (Na2SO4), filtered, concentrated, and chromatographed to obtain 1.2 g of the title compound as an oil which crystallized from hexane.
Reaction SMILES: C(N=[C:10]=[S:11])(=O)C1C=CC=CC=1.[CH3:12][C:13]1[C:17]([CH2:18][NH:19][C:20]2[N:21]=[CH:22][NH:23][C:24]=2[C:25]([NH2:27])=[O:26])=[C:16]([CH3:28])[O:15][N:14]=1>CC(C)=O>[CH3:12][C:13]1[C:17]([CH2:18][N:19]2[C:20]3[N:21]=[CH:22][NH:23][C:24]=3[C:25](=[O:26])[NH:27][C:10]2=[S:11])=[C:16]([CH3:28])[O:15][N:14]=1
Reactant: Cc1noc(C)c1CNc1nc[nH]c1C(N)=O
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: Cc1noc(C)c1Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Yield: 9.3 %

Procedure:
Benzoyl isothiocyanate (0.62 mL, 4.64 mmol) was added, dropwise, to a solution of 4-{[(3,5-dimethylisoxazol-4-yl)methyl]amino}-1H-imidazole-5-carboxamide (0.91 g, 3.86 mmol, obtained from Example 21(a)) in acetone (20 mL). After stirring o.n., the solvent was evaporated in vacuo and the residue triturated with dichloromethane. The solid was removed by filtration and the filtrate was concentrated in vacuo. A solution of ammonia in methanol (7 N, 20 mL) was added to the resulting residue and this solution was transferred to a sealable tube. The vessel was sealed and placed in an 80° C. oil bath for 3 h. After cooling to r.t., the solution was concentrated in vacuo. The product was purified by recrystallization from DMSO/water, filtered and triturated sequentially with water, methanol and dichloromethane, providing the title compound (0.10 g, 10% yield) as a solid.