Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[C:36]([F:47])=[C:37]2[C:42](=[C:43]([O:45][CH3:46])[CH:44]=1)[O:41][CH2:40][CH2:39][CH2:38]2)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:47][C:36]1[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:44][C:43]([O:45][CH3:46])=[C:42]2[C:37]=1[CH2:38][CH2:39][CH2:40][O:41]2
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
After adding 23 mg of 2-hydrazinopyrimidine and 35 μl of triethylamine to a solution of 113 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 5 ml of methanol and 0.5 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (82 mg) as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N+:10]([O-:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:13].[Br:14]Br>CO>[Br:14][CH2:1][C:2]1[CH:11]=[N+:10]([O-:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:13]
Reactant: Cc1c[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: BrBr
Solvent: CO
Product: [O-][n+]1cc(CBr)[n+]([O-])c2ccccc21
Reaction time: 1 h
Yield: 32 %

Procedure:
To a thick slurry of 106 g. (0.6 mole) of 2-methyl quinoxaline 1,4-dioxide in 400 ml of methanol was added with stirring over a period of 1 hour, 96 g. (0.6 mole) of bromine. The reaction was then stirred for 5 days at room temperature. The reaction mixture was filtered and the collected yellow solid was washed with 200 ml. of ether. This solid was air dried to obtain 50 g. (32percent yield of the title compound, mp-158°-159°.
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.FC(F)(F)C([O-])=O>C(NC(C)C)(C)C>[CH2:16]([N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:5]2[CH2:4][N:3]([CH2:1][CH3:2])[CH2:15][CH2:14][C:6]1=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Reactant: ClCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: CC(C)NC(C)C
Product: CCN1CCc2c(c3ccccc3n2Cc2ccccc2)C1
Yield: 34.4 %

Procedure:
Preparation of the title compound was carried out according to General Method 5. 2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example 5) (100 mg, 0.5 mmol), benzyl chloride (158 mg, 1.25 mmol) in diisopropylamine (2 mL) were heated at 80° C. for 12 h to obtain 50 mg of 5-benzyl-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as trifluoroacetate salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:12][O:13][CH2:14][CH2:15][O:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: COCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 89.8 %

Procedure:
To a mixture of 4-hydroxy-2-nitroaniline (25.0 g), 2-methoxyethanol (21.0 g), tributylphosphine (49.2 g) and tetrahydrofuran (700 mL) was added 1,1′-(azodicarbonyl)dipiperidine (61.3 g) at room temperature, and the mixture was stirred at room temperature for 2.5 days. The precipitate was filtered off, and the filtrate was concentrated. Diisopropyl ether was added to the residue, and the insoluble substance was filtered off. The filtrate was concentrated, and the residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (2:1, volume ratio). The obtained crude product was further subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-2:1, volume ratio) to give the title compound (30.9 g, yield 90%) as orange crystals. The crystals were recrystallized from hexane-ethyl acetate to give orange prism crystals. melting point 89-90° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][CH:18](Br)[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[CH:21]([Br:24])[CH2:22]Br)=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][C:18]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:19]2[C:20]([CH3:26])([CH3:25])[CH:21]([Br:24])[CH2:22][O:27]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C(=O)C(Br)Oc1ccc(Cl)cc1)C(Br)CBr
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C(=C(Oc2ccc(Cl)cc2)n2ccnc2)OCC1Br
Temperature: 90 °C
Reaction time: 10 h
Yield: 10.3 %

Procedure:
35 g (0.5 mole) of imidazole and 103.5 g (0.75 mole) of potassium carbonate are dissolved in 700 ml of toluene at 60° C. 132 g (0.269 mole) of 1-(4-chlorophenoxy)-3,3-dimethyl-1,4,5-tribromo-2-pentanone in 100 ml of toluene are added dropwise to this solution in the course of 20 minutes. The reaction mixture is subsequently stirred at 90° C. for 10 hours and cooled and water is added. The organic phase is separated off, washed with water dried over sodium sulphate and concentrated. The residue is purified by column chromatography (silica gel; ethyl acetate/cyclohexane=3:1). 10.6 g (10% of theory) of (4-chlorophenoxy)-(imidazol-1-yl)-(4-bromo-3,3-dimethyltetrahydrofuran-2-ylidene)-methane of refractive index nD20 1.5837 are obtained.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[C:18](=[O:19])[CH:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=O)[NH:15][C:14]1=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[Cl:3][C:16]1[NH:15][C:14](=[O:28])[N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:18](=[O:19])[C:17]=1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1NC(=O)N(Cc2ccccc2)C(=O)C1Cc1ccccc1
Solvent: CCO
Product: O=c1[nH]c(Cl)c(Cc2ccccc2)c(=O)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 16.8 ml of 50% ethanol, 78.7 ml (844 mmol) of phosphorus oxychloride was added drop by drop, with stirring under ice cooling conditions. To this solution, 30.83 g (100 mmol) of 3,5-dibenzylpyrimidine-2,4,6(1H,3H)-trione was added little by little. This mixture was stirred at 50° C. for 30 minutes and then at 100° C. for 90 minutes. After cooling, the reaction mixture was poured into ice water and stirred for 1 hour. The resulting precipitate was collected by filtration, washed with water and n-hexane and dried to yield 32.62 g (99.8%, light white crystal) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:48]=[CH:47][C:20]([C:21]([N:23]([CH3:46])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39]C4C=CC=CC=4)=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:46])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([N:53]4[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]4)=[O:39])=[O:22])=[CH:47][CH:48]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCNC(=O)Oc3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCNC(=O)N3CCN(C)CC3)cc2)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 64.9 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-phenoxycarbonylaminopentyloxy)phenyl]benzamide (290 mg) in N,N-dimethylformamide (15 ml) was added 1-methylpiperazine (271 mg) at ambient temperature. The reaction mixture was stirred at 80° C. for 10 hours. The reaction mixture was cooled and extracted with ethyl acetate and washed with saturated sodium hydrogen carbonate and brine. The organic solution was dried over sodium sulfate. The solvent was removed by evaporation and subjected to silica gel column chromatography (SiO2; 30 g, 5% methanol in chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-carbonylamino)pentyloxy]phenyl]benzamide (190 mg).
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH2:10]([C:12]1[NH:13][C:14]([CH2:33][CH3:34])=[C:15]([C:29]([O:31][CH3:32])=[O:30])[CH:16]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:17]=1[C:18]([O:20]C)=[O:19])[CH3:11].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:33]([C:14]1[NH:13][C:12]2[CH:10]([CH3:11])[O:20][C:18](=[O:19])[C:17]=2[CH:16]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[C:15]=1[C:29]([O:31][CH3:32])=[O:30])[CH3:34]
Reactant: CCC1=C(C(=O)OC)C(c2ccc(Cl)cc2)C(C(=O)OC)=C(CC)N1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC1=C(C(=O)OC)C(c2ccc(Cl)cc2)C2=C(N1)C(C)OC2=O
Reaction time: 0.5 h

Procedure:
In a similar manner 2.02 grams (2.52 grams of 80 percent; 6.31 millimoles) of pyridinium bromide perbromide is added in a single portion to a cooled to 0° C. solution of 1.91 grams (5.26 millimoles) of dimethyl 2,6-diethyl-4-(4-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.79 gram (10.1 millimoles) of pyridine in 40 milliliters of chloroform. The resulting mixture is stirred at this temperature for 30 minutes, then at reflux temperature for 90 minutes. The mixture is then allowed to cool, diluted with chloroform, the diluted solution washed with 2N hydrochloric acid and brine, and dried; the solvent then is evaporated to obtain the methyl 2-ethyl-4-(4-chlorphenyl)-5-oxo-7-methyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine 3-carboxylate product as residue. The residue is purified by chromatographing on silica gel using ethyl acetate-hexane as eluant.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4ccccc4C(F)(F)F)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 2-trifluoromethylbenzeneboronic acid by the method described for Example 36 Step 3. MS (ES+) 588 ([MH]+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.Br[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31].Cl.[OH-].[Na+:37]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([Cl:26])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:28][CH2:29][C:30]([O-:32])=[O:31])[CH:3]=1.[Na+:37]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]cc(Cl)c4c3)no2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)c(Cl)cn4CCC(=O)[O-])no2)cc1Cl
Temperature: 120 °C

Procedure:
D7 (200 mg) and Cs2O3 (336 mg) were placed in a microwave vial, treated with DMF (2.8 ml) and ethyl 3-bromopropionate (99 ul) and sonicated for 10 minutes. The mixture was then heated to 120° C. in a microwave reactor for 25 mins. The reaction mixture was then evaporated, re-dissolved in MeOH (10 ml) and treated with 2 M aq. NaOH (10 ml). This mixture was sonicated briefly and then heated to 50° C. overnight. The reaction mixture was then evaporated, diluted with H2O (70 ml) and extracted with EtOAc, adding NaCl and acetone to improve the extraction. The organic extracts were evaporated to give the crude product which was acidified with HCl to give the free-acid. This was insufficiently soluble for purification by chromatography and so was triturated with MeOH, treated with 2M aq. NaOH (1.5 eq.), evaporated, dissolved in EtOAc, filtered and evaporated to give the title compound (56 mg) as a brown solid. δH (methanol-d4, 400 MHz): 1.42 (6H, d), 2.66 (2H, t), 4.47 (2H, t), 4.82 (1H, m), 7.29 (1H, d), 7.44 (1H, s), 7.65 (1H, d), 7.98 (1H, d), 8.12 (1H, d), 8.20 (1H, s), 8.30 (1H, s). MS (ES): C22H1935Cl2N3O4 requires 459; found 460 (MH+).
Reaction SMILES: [CH:1]1([C:4](=[O:25])[C:5](=[CH:21]OCC)[C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1.Cl.[NH2:27]O.C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]1([C:4]2[O:25][N:27]=[CH:21][C:5]=2[C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)c1ccc2scc(OC)c2c1OC)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1csc2ccc(C(=O)c3cnoc3C3CC3)c(OC)c12
Yield: 44.5 %

Procedure:
A solution containing 5-(3-cyclopropyl-2-ethoxymethylene-1,3-dioxoprop-1-yl)-3,4-dimethoxybenzo[b]thiophene (0.59 g) and hydroxylamine hydrochloride (0.137 g) was stirred for 15 minutes in ethanol. Sodium acetate (anhydrous, 0.161 g) was added and the mixture stirred for 4 hours, before evaporation of the ethanol and addition of water. The mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulphate) and evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with ether/cyclohexane to yield 5-cyclopropyl-4-(3,4dimethoxybenzo[b]thien-5-oyl)isoxazole (compound 3, 0.24 g) as an oil, NMR δ1.20 (2H,m), 1.35 (2H,m), 2.80 (1H,m), 3.84 (3H,s), 4.00 (3H,s), 6.39 (1H,s), 7.40 (1H, d), 7.59 (1H, d), 8.29 (1H,s).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1>>[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:21][CH2:20]1
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCOc2ccccc21

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 270 mg of 3,4-dihydro-2H-1,4-benzoxazine in place of the 2,4-difluoroaniline. After purification by silica column chromatography, elution being carried out with CH2Cl2/MeOH 95/05, 150 mg of 2-[2-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:26]=3)[C:23](O)=[O:24])[CH:16]=2)[NH:11][N:10]=1.C1[CH:32]=[CH:31][C:30]([CH2:33][NH:34]S(C2C=CC3N=NN(O)C=3C=2)(=O)=O)=CC=1.Cl.CCN=C=NCCCN(C)C.N1CCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:26]=[C:22]([C:23]([N:34]4[CH2:33][CH2:30][CH2:31][CH2:32]4)=[O:24])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: O=S(=O)(NCc1ccccc1)c1ccc2nnn(O)c2c1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cncc(C(=O)O)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cncc(C(=O)N4CCCC4)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1 %

Procedure:
(5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-nicotinic acid (350 mg, 62% pure, 0.63 mmol) was dissolved in anhydrous DMF (20 mL) at 50-60° C. and the solution was cooled to room temperature when PS-HOBt resin (Argonaut Technologies) (0.9 mmol·g−1 loading, 2.20 g, 1.98 mmol), DMAP (32 mg, 0.26 mmol) and EDCI (375 mg, 1.95 mmol) were added. The mixture was shaken at room temperature for 16 h. The resin was filtered off, washing six times with DMF and subsequently three times with ether and dried. The resin and (5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-nicotinate) (460 mg, theoretical loading 105 μmol) were suspended in anhydrous DMF (3 mL) containing pyrrolidine (110 μl, 1.3 mmol) and shaken for 22 h. The resin is filtered off, washing with dichloromethane, ether and DMF. The filtrate and washings were combined and concentrated. The resulting residue is purified by mass-triggered reverse phase HPLC using a gradient of acetonitrile in water containing 0.1% of formic acid to afford {5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-3-yl}-pyrrolidin-1-yl-methanone (2.4 mg, 6 μmol, 6% yield) as a light brown solid. 1H-NMR (500 MHz, d6-MeOH) δ 68.98 (d, 1H), 8.87 (d, 1H), 8.74 (d, 1H), 8.50 (d, 1H), 8.31 (t, 1H), 7.67 (dd, 1H), 7.48 (ddd, 1H), 7.21 (d, 1H), 7.11 (dt, 1H), 3.89 (s, 3H), 3.65 (t, 2H), 3.58 (t, 2H), 2.02 (m, 2H), 1.96 (m, 2H). MS: m/z 400 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cccc(Cl)c1Cl
Product: O=C(O)Cc1ccccc1Nc1cccc(Cl)c1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,3-dichloroaniline to yield 2-[(2,3-dichlorophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[O:6]=[C:7]1[CH2:10][CH:9]([C:11]([OH:13])=O)[CH2:8]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:11]([CH:9]1[CH2:8][C:7](=[O:6])[CH2:10]1)=[O:13]
Reactant: O=C1CC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC(=O)C1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (5.2 g, 0.054 mol), and 3-oxocyclobutanecarboxylic acid (4.0 g, 0.035 mol) in dichloromethane (30 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.0 g, 0.052 mol), 1-hydroxybenzotriazole (7.1 g, 0.052 mol) followed by triethylamine (34 mL, 0.24 mol) at 0° C. The mixture was stirred at rt over night, then quenched with water. The mixture was extracted with EtOAc. The organic layers were dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-5% for 30 min followed by 5-20% EtOAc/Hex) to give the desired product (4.3 g, 78%) as light yellow oil. LCMS calculated for C7H12NO3(M+H)+: 158.1. Found: 158.3.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][C:2]1=[O:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][C:2]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCC2=C(CCCC2=O)N1
Reactant: BrCc1ccccc1
Product: O=C1CCCC2=C1CCC(=O)N2Cc1ccccc1

Procedure:
Prepared analogously to Example H from 3,4,7,8- tetrahydro-2,5(1H,6H)-quinolinedione and benzyl bromide.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([N:19]3[CH2:26][CH2:25][C:24]4([CH3:30])[C:27]([CH3:29])([CH3:28])[CH:20]3[CH2:21][C:22]3[CH:34]=[C:33]([C:35]([NH:37]O)=[NH:36])[CH:32]=[CH:31][C:23]=34)=[O:18])=[CH:16][C:11]=2[N:10]=[CH:9]1>CC1C=C(C)C=C(C)N=1>[NH:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([N:19]3[CH2:26][CH2:25][C:24]4([CH3:30])[C:27]([CH3:28])([CH3:29])[CH:20]3[CH2:21][C:22]3[CH:34]=[C:33]([C:35]5[N:36]=[C:5]([CH3:6])[O:7][N:37]=5)[CH:32]=[CH:31][C:23]=34)=[O:18])=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: CC12CCN(C(=O)c3ccc4[nH]cnc4c3)C(Cc3cc(C(=N)NO)ccc31)C2(C)C
Reactant: CC(=O)OC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1nc(-c2ccc3c(c2)CC2N(C(=O)c4ccc5[nH]cnc5c4)CCC3(C)C2(C)C)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (0.1 mL) is added to a solution of 3-(1H-benzoimidazole-5-carbonyl)-N-hydroxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carboxamidine (0.15 g) in 2,4,6-trimethylpyridine (2 mL). The resulting solution is stirred at ambient temperature for 1 h and then at 120° C. for 3 h. After cooling to room temperature, the mixture is concentrated under reduced pressure and the residue is taken up in methanol (10 mL). Concentrated aqueous ammonia solution (1 mL) is added and the solution is stirred at ambient temperature for 1 h. The solution is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (water/MeCN) to give the title compound as a white foam-like solid.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:19])[CH2:11][C:12]([CH2:15][N:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:18][N:16]([CH2:15][C:12]1[CH2:11][C:10](=[O:19])[C:9]([OH:8])=[CH:14][N:13]=1)[CH3:17]
Reactant: CN(C)CC1=NC=C(OCc2ccccc2)C(=O)C1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1=NC=C(O)C(=O)C1
Yield: 147.4 %

Procedure:
5-Benzyloxy-2-(N,N-dimethylamino)methyl-4-pyridone 1.0 g) in methanol (15 ml) was subjected to catalytic reduction with 10% palladium on activated carbon (200 mg) at atmospheric pressure. After removal of catalyst, the solution was concentrated under reduced pressure to give 2-(N,N-dimethylamino)methyl-5-hydroxy-4-pyridone (0.96 g).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([O:23]C)=[O:22].O.[OH-].[K+].Cl>CO>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([OH:23])=[O:22]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Methyl androst-4-ene-3-one-17β-carboxylate (20 g, 60 mmol) was dissolved in 700 ml of a 20:1 solution of methanol:water and potassium hydroxide (7 g) was added and the solution was refluxed under argon for 24 hours. The reaction mixture was then acidified with 5% hydrochloric acid and 250 ml water was added. After aging for 1 hour, the mixture was filtered and dried to yield 18 g (94%) of androst-4-ene-3-one-17β-carboxylic acid as a white crystalline solid.