Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[N:4]1[S:8][N:7]=[C:6]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=[CH:12][C:5]=12.[OH-].[Na+].Cl>O>[N:4]1[S:8][N:7]=[C:6]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:5]=12
Reactant: COC(=O)c1ccc2nsnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2nsnc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To 30 ml of ethanol was dissolved 2.0 g (10 mmol) of methyl benzo[1,2,5]thiadiazole-5-carboxylate, followed by the addition of 3.3 g of a 25% aqueous solution of sodium hydroxide and stirring at room temperature for 3 hours. To the reaction liquid was added 50 ml of water and a dilute hydrochloric acid to make pH of 2. Crystal precipitated was filtered off and dried under reduced pressure to obtain 1.7 g (yield: 92%) of benzo[1,2, 5]thiadiazole-5-carboxylic acid. In a separate reactor, 0.50 g (2.2 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.43 g (2.4 mmol) of benzo[1,2,5]thiadiazole-5-carboxylic acid were dissolved in 7 ml of N,N-dimethylformamide, followed by the addition of 0.37 g (4.4 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 0.44 g (yield: 64%) of 6,6-difluoro-5-methyl-5-hexenyl benzo[1,2,5]thiadiazole-5-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH:11]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)=[O:12].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH:8]1([C:5]2[N:4]=[CH:3][C:2]([C:16]3[CH:17]=[CH:18][C:13]([CH:11]=[O:12])=[CH:14][CH:15]=3)=[CH:7][CH:6]=2)[CH2:10][CH2:9]1
Reactant: Brc1ccc(C2CC2)nc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: OCCO
Product: O=Cc1ccc(-c2ccc(C3CC3)nc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
A mixture of 3-bromo-6-(cyclopropyl)pyridine (2.00 g), 4-formylphenylboronic acid (1.82 g), palladium(II) acetate (113 mg), tripotassium phosphate (4.50 g) and ethylene glycol (16.8 mL) was stirred at 80° C. for 3 hours. After cooling the reaction mixture to room temperature, water was added to it and two extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine and thereafter the crude product was adsorbed on diatomaceous earth, with the solvent being distilled off under reduced pressure. The crude product adsorbed on the diatomaceous earth was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-50:50) to give the titled compound as a colorless solid (1.81 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([S:16][CH2:17][CH2:18][CH3:19])=[C:14]([C:20]([OH:22])=O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].[C:23]12([NH2:33])[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[C:23]12([NH:33][C:20]([C:14]3[CH:13]=[N:12][N:11]([C:8]4[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=4)[C:15]=3[S:16][CH2:17][CH2:18][CH3:19])=[O:22])[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:26][CH:25]([CH2:31]3)[CH2:24]1)[CH2:32]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(C(=O)OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCSc1c(C(=O)NC23CC4CC(CC(C4)C2)C3)cnn1-c1ccc(C(=O)OC)cc1
Reaction time: 18 h
Yield: 63.1 %

Procedure:
1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate #7) (160 mg, 0.5 mmol), 1-adamantylamine (76 mg, 0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (174 μL, 1.0 mmol) were dissolved in DMF (5 mL) and treated at ambient temperature with EDCI (115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and then diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and brine, dried (MgSO4) and volatiles removed by evaporation. The residue was purified by chromatography on silica gel (12 g silica 0-50% EtOAc/isohexane) to give the title compound as a colourless gum (143 mg, 63%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:23][CH:22]=2)/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCCCN1C(=O)/C(=N\NC(=O)c2ccc(OC)cc2)c2ccccc21
Yield: 79 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and 4-methoxybenzhydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 79%. 1H NMR (DMSO-d6): δ 0.85 (t, J=6.9 Hz, 3H), 1.26-1.36 (m, 6H), 1.65 (m, 2H), 3.79 (t, J=7.2 Hz, 2H), 3.87 (s, 3H), 7.14-7.24 (m, 4H), 7.48 (t, J=7.8 Hz, 1H), 7.65 (d, J=7.5 Hz, 1H), 7.89 (d, J=9 Hz, 2H), 13.86 (br s, 1H). 13C NMR (DSMO-d6): δ 14.33 (CH3), 22.43 (CH2), 26.39 (CH2), 27.41 (CH2), 31.32 (CH2), 39.77 (CH2), 56.07 (O—CH3), 110.63 (CH), 114.97 (CH), 119.76 (C), 121.13 (CH), 123.64 (CH), 124.46 (C), 129.98 (CH), 132.02 (CH), 143.30 (C═N), 161.63 (C═O), 163.68 (C═O). HRMS (ES+) calcd for C22H26N3O3 (M+H+), m/e, 380.1974; found, 380.1969.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH:38][CH3:39])(=[O:37])=[O:36])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:10](=[CH:11][CH:12]=2)[CH:9]2[CH2:13][CH2:14][CH:5]3[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:8]2)=[N:23][CH:24]=1
Reactant: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl

Procedure:
2-{5-Chloro-2-[10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzenesulfonamide was prepared from 1-(4-amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide in an analogous manner to Example 276. Product isolated as an off-white solid (557 mg, 88%). m.p.=160-163° C.; LCMS (m/e) 581 (M+1); 1H-NMR (CDCl3, 400 MHz) major rotomer δ 9.10 (s, 1H), 8.45 (d, 1H, J=8.3 Hz), 8.08 (s, 1H), 7.97 (t, 1H, J=2.0 Hz), 7.61-7.54 (m, 1H), 7.42-7.20 (m, 3H), 7.10-6.97 (m, 2H), 4.87-4.77 (m, 1H), 3.88-3.77 (m, 1H), 3.60-3.40 (m, 2H), 3.27-3.01 (m, 2H), 2.65 (s, 3H), 2.10-1.98 (m, 2H), 1.85-1.73 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2C)=[O:9])[CH:3]=1.C(N(CC)CC)C.[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([N:27]([CH3:26])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[O:9])[CH:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CNC1CCCCC1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cc(C(=O)Nc2ccc(O)cc2)ncn1)C1CCCCC1
Reaction time: 24 h

Procedure:
A solution of 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide, Intermediate 7 (75.0 mg; 0.30 mmol) in THF (4 mL) was treated with triethylamine (42 μl; 0.30 mmol) and N-methylcyclohexylamine (Aldrich, 43 μl; 0.33 mmol). The reaction mixture was stirred for 24 h. The solvents were removed in vacuo, then the crude product was purified by column chromatography (silica), eluting with cyclohexane containing an increasing amount of EtOAc. The title compound was obtained as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C1([B:15]2[O:23][C:20]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[O:16]2)C=CC=CC=1.IC1C=C(O)C=CC=1.BrC1C=CC(O)=CC=1.[B]1OC(C)(C)C(C)(C)O1.CSC.B.IC1C=CC(O)=CC=1>>[CH3:18][C:17]1([CH3:19])[C:20]([CH3:22])([CH3:21])[O:23][B:15]([C:6]2[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:7]=2)[O:16]1
Reactant: Oc1ccccc1I
Reactant: CC1(C)OB(c2ccccc2)OC1(C)C
Agent: B
Agent: CC1(C)O[B]OC1(C)C
Agent: Oc1ccc(Br)cc1
Solvent: CSC
Product: CC1(C)OB(c2ccc(O)cc2)OC1(C)C

Procedure:
The above reaction procedure used for 2-iodophenol was followed. The reaction was also faster, being again complete before the first sample for gc analysis was withdrawn after 1 h 50 min reaction time. The amount of phenylboronic acid pinacol ester was about that found in the 3-iodophenol reaction. The reaction in which 4-bromophenol is used as substrate is slower but does go to completion. Pinacolborane prepared in situ from the dimethylsulfide adduct of borane can also be used with both the 4-bromophenol and 4-iodophenol.
Reaction SMILES: [ClH:1].[CH:2]([CH:4]1[CH2:6][C:5]1([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8])=[CH2:3].[Cl-].[Al+3].[Cl-].[Cl-]>COCCOC>[Cl:1][CH:4]([CH2:6][CH:5]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CC1CC1(C(=O)OC)C(=O)OC
Reactant: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COCCOC
Product: C=CC(Cl)CC(C(=O)OC)C(=O)OC
Reaction time: 8 h

Procedure:
400 g of 1,2-dimethoxy ethane were introduced into a 1 liter glass flask equipped with a stirrer and a thermometer and admixed with 69 g of gaseous hydrogen chloride. 184.1 g of 1-vinyl-2,2-dicarbomethoxy cyclopropane (93.7% pure, 0.937 mol) and 0.65 g of aluminum chloride were then added to the contents, and the mixture was stirred. The temperature of the mixture rose to 40° C. The reaction was allowed to go to completion by letting the mixture stand overnight. After filtering off a slight turbidity, the reaction mixture was distilled in a 70 cm column. After collecting the 1,2-dimethoxy ethane which distilled over first and became available for reuse as a solvent in subsequent batches, the target product distilled over in pure form at 87° C./0.8 mbar.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:15]2[C:16]([O:18][C:19](=O)[C:14]=12)=[O:17]>>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]2[C:16](=[O:17])[C:15]3=[C:21]([Cl:24])[CH:22]=[CH:23][C:13]([Cl:12])=[C:14]3[C:19]2=[O:18])[CH2:3][CH2:4]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCN1CCC(N)CC1
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Product: CCCCN1CCC(N2C(=O)c3c(Cl)ccc(Cl)c3C2=O)CC1

Procedure:
4-Amino-1-n-butylpiperidine and 3,6-dichlorophthalic anhydride are reacted in a similar manner to that described in Example 3 to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: CC1Cc2cccc(Cl)c2C1=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Product: CC1Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2C1=O
Temperature: 125 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Using a method similar to Example 16 d), 6.28 g (0.035 mol) of (1), 7.6 g (0.040 mol) of 4-trifluoromethylphenylboronic acid and 8.16 g (77.3 mmol) of sodium carbonate were placed in 160 ml of ethylene glycol/17 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 57 mg (0.283 mmol) of palladium acetate and 0.47 g (0.848 mmol) of TMSPP, the reaction mixture was stirred for 2 hours at 125° C. After addition of 170 ml of water, the aqueous phase was extracted 4 times with 100 ml each time of ether, the combined ether phases were washed with 60 ml of water and 60 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 9.54 g of 2-methyl-7-(4-trifluoromethylphenyl)-1-indanone.
Reaction SMILES: [CH2:1]([N:5]([C:17](=O)[CH2:18][NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:23]([O:22][C:20]([NH:19][CH2:18][CH:17]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH2:7][CH2:6][N:5]1[CH2:1][CH2:2][CH2:3][CH3:4])=[O:21])[CH3:24]
Reactant: CCCCN(CCc1c[nH]c2ccccc12)C(=O)CNC(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCN1CCc2c([nH]c3ccccc23)C1CNC(=O)OCC
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
To a solution of 3.40 g of N-n-butyl-N-(N-ethoxycarbonylglycyl)-tryptamine in 40 ml of anhydrous toluene are added 10 ml of phosphorus oxychloride, and the mixture is stirred at 120° C. for 45 minutes. The mixture is condensed under reduced pressure, and 100 ml of ethanol are added to the residue. Then, sodium borohydride is added to the mixture until said mixture becomes alkaline, and the mixture is stirred at room temperature for 30 minutes. After the reaction, the reaction mixture is condensed, and water is added to the residue. The aqueous mixture is extracted with chloroform, and the extract is washed, dried and then evaporated to remove solvent. The residue (oil, 4.0 g) thus obtained is purified by silica gel chromatography (Solvent: chloroform-ethyl acetate (1:1)). 2.50 g of 1,2,3,4-tetrahydro-1-((N-ethoxycarbonylamino)methyl)-2-n-butyl-β-carboline are thereby obtained as a pale yellow oil. Yield: 77.6% The physico-chemical properties of this product are identical with those of the product obtained in Example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=1)[NH:6][C:5]2=[O:22].Cl.Br[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].N1C=CC=CC=1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:7]2[NH:6][C:5](=[O:22])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:3]=3)[N:8]=2)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: COc1cc(OC)cc(-c2nc3ccc(N)cc3c(=O)[nH]2)c1
Reactant: Brc1ccncc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: c1ccncc1
Product: COc1cc(OC)cc(-c2nc3ccc(Nc4ccncc4)cc3c(=O)[nH]2)c1

Procedure:
6-Amino-2-(3,5-dimethoxy-phenyl)-3H-quinazolin-4-one (297 mg, 1.00 mmol), 4-bromopyridine hydrochloride (194 mg, 1.00 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol), 1,1′-bis(diphenylphosphino)ferrocene (17 mg, 0.03 mmol), sodium tert-butoxide (230 mg, 2.40 mmol) and pyridine (3 mL) were heated at 140° C. in microwave oven (150 W) for 1 hour. The mixture was concentrated under vacuum to dryness. The residue was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane and then 10% 2 N NH3 in methanol and dichloromethane as eluent) to give the title compound as a brown/beige solid. Yield: 176 mg (47%). MP 289-290° C. 1H NMR (400 MHz, DMSO-d6): δ 9.24 (s, 1H), 8.29 (d, J=5.6 Hz, 2H), 7.90 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.38 (s, 2H), 7.03 (d, J=5.2 Hz, 2H), 6.69 (s, 1H), 3.85 (s, 6H). MS (ES+) m/z: 375.13 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12](I)[C:11]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][N:10]3[C:9]2=[O:26])=[CH:4][CH:3]=1.[CH3:27]B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CN(C=O)C.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([CH3:27])[C:11]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][N:10]3[C:9]2=[O:26])=[CH:4][CH:3]=1
Reactant: CB(O)O
Reactant: O=c1n(-c2ccc(F)cc2)cc(I)c2nc(COc3ccccc3)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(F)cc2)c(=O)n2cc(COc3ccccc3)nc12
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 71.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2.63 mg, 0.0023 mmol) was added to a stirred suspension of 6-(4-fluoro-phenyl)-8-iodo-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (35 mg, 0.076 mmol), methylboronic acid (22.7 mg, 0.38 mmol) and K2CO3 (31.5 mg, 0.23 mmol) in a mixture of 1,4-dioxane (4 mL) and DMF (1 mL) under nitrogen and in a sealed tube. The mixture was stirred at 150° C. for 45 minutes under microwave irradiation. The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 6-(4-fluoro-phenyl)-8-methyl-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (19 mg, 72% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 2.36 (d, J=1.2 Hz, 3H), 5.22 (s, 2H), 6.92 (d, J=1.2 Hz, 1H), 6.97 (br. t, J=7.4, 7.4 Hz, 1H), 7.02 (br. d, J=8.1 Hz, 2H), 7.16-7.24 (m, 2H), 7.27-7.34 (m, 2H), 7.36-7.44 (m, 2H), 7.84 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[CH3:17][O:18][C:19](=[O:26])[CH:20]([O:24][CH3:25])[C:21](O)=[O:22]>>[CH3:17][O:18][C:19](=[O:26])[CH:20]([O:24][CH3:25])[C:21]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:22]
Reactant: COC(=O)C(OC)C(=O)O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Product: COC(=O)C(OC)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Yield: 41 %

Procedure:
The title compound is prepared in analogy to example 2 from 4-(3-Fluoro-benzyloxy)-phenylamine and 2-methoxy-malonic acid monomethyl ester (Swan et al.; J. Chem. Soc. Perkin Trans. 1; 1985; 1757-1766). Yield=41%. Colorless solid. MS: m/e=348.2 (M++H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][N:23]([CH3:32])[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39].Cl>O1CCOCC1>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][N:23]([CH2:24][C:25]([OH:27])=[O:26])[CH3:32])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39]
Reactant: COCc1cc(-c2nc(-c3cccc(CCN(C)CC(=O)OC(C)(C)C)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3cccc(CCN(C)CC(=O)O)c3)no2)ccc1-c1ccccc1C
Temperature: 70 °C

Procedure:
To tert-butyl N-[2-(3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)ethyl]-N-methylglycinate (86 mg, 0.15 mmol) was added a 4N solution of HCl in dioxane and the mixture was heated in a tube at 70° C. for 3 hours. The solvent was then removed in vacuo and the residue was purified by preparative HPLC to give the title compound as a pale yellow oil. LC/MS (Method A): 472 (M+H)+, 470 (M−H)−. HPLC (Method K) Rt=18.0 min (Purity: 92.2%).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[CH:14]=[C:13]([N:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH3:23])[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:8][C:2]([O:30][C:27]1[CH:26]=[CH:25][C:24]([N:22]([C:13]2[N:12]=[C:11]([Cl:10])[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=3)[CH3:23])=[CH:29][CH:28]=1)([CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Temperature: 100 °C
Yield: 54.7 %

Procedure:
A mixture of ethyl 2-bromo-2-methylpropionate (0.54 g), 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (0.74 g), potassium carbonate (0.38 g) dimethylformamide was heated at 100° C. for 28 hrs. The mixture was cooled, diluted with dichloromethane, washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give an oil, which was purified by column chromatography over silica gel (eluent dichloromethane) to give ethyl 2-methyl-2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]-phenoxy}propionate (0.55 g) as a yellow oil.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[NH2:17][C:18]1[C:19]([Cl:33])=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([F:26])[CH3:25]>O.O1CCOCC1>[Cl:33][C:19]1[C:18]([N:17]=[C:1]=[S:2])=[C:31]([Cl:32])[CH:30]=[CH:29][C:20]=1[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:25])([F:26])[CH3:27]
Reactant: CC(C)(F)C(=O)NCc1ccc(Cl)c(N)c1Cl
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(F)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (1.21 g, 5.2 mmol) is added to a mixture of N-(3-amino-2,4-dichloro-benzyl)-2-methyl-2-fluoro-propionamide (1.32 g, 4.7 mmol) and dioxane (25 mL) and it is stirred at reflux for 2 d. The mixture is diluted with water, most of the dioxane is removed under reduced pressure and the resulting precipitate is collected by filtration, washed with water and dried.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].[CH:30]1[C:43]2[C:34](=[N:35][C:36]3[C:41]([C:42]=2[NH:44][C:45]2[CH:46]=[C:47]([NH:53][C:54](=[O:58])[CH:55]([NH2:57])[CH3:56])[CH:48]=[C:49]([CH2:51][OH:52])[CH:50]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=1>>[CH:40]1[C:41]2[C:36](=[N:35][C:34]3[C:43]([C:42]=2[NH:44][C:45]2[CH:46]=[C:47]([NH:53][C:54]([CH:55]([NH:57][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:7])[CH3:56])=[O:58])[CH:48]=[C:49]([CH2:51][OH:52])[CH:50]=2)=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:37]=[CH:38][CH:39]=1
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(O)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(O)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 41.9 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3-hydroxyphenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.