Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[N-:22]=[N+]=[N-].[Na+].O>CN(C)C=O.[C].[Pd]>[CH3:15][C:14]1[C:3]2[C:4](=[N:5][C:6]3[C:11]([C:2]=2[NH2:22])=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(N)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.44 g, 4.89 mmol) and sodium azide (0.35 g, 5.37 mmol) in N,N-dimethylformamide (10 mL) was heated under reflux at 100° C. for 30 minutes. The solution was cooled to room temperature, poured into water, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. To a solution of the residue thus obtained in ethanol (70 mL), 10% palladium-carbon (2 g, 50% hydrate) was added and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The solution was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (ethyl acetate:methanol=95:5) to give the title compound (760 mg, 57% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:31]5[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc(S(C)(=O)=O)cc3)cc1-2
Yield: 40 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 4-(methylsulfonyl)phenylboronic acid were reacted to give 230 (0.072 g, 40%). 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J=2.3, 1H), 8.03 (d, J=8.4, 2H), 7.94 (s, 1H), 7.82 (d, J=8.4, 2H), 7.59-7.48 (m, 1H), 7.20 (d, J=8.4, 1H), 5.94-5.79 (m, 1H), 4.48 (t, J=4.9, 2H), 3.46 (dd, J=10.7, 5.8, 2H), 3.12 (s, 3H), 1.65 (d, J=6.6, 6H). MS (ESI(+)): m/z 467.1 (M+H)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.F[C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CCCNC1
Reactant: COC(=O)c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccccc1N1CCCC(C(=O)NCc2sc(-c3ccc(Cl)cc3)nc2C)C1
Temperature: 160 °C
Reaction time: 6 h
Yield: 3.9 %

Procedure:
N-[[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]methyl]piperidine-3-carboxamide hydrochloride (198 mg, 0.513 mmol) and methyl 2-fluorobenzoate (0.0653 mL, 0.513 mmol) were dissolved in dimethylsulfoxide (5 mL). To this solution, potassium carbonate (142 mg, 1.03 mmol) was added and the mixture was stirred for 6 hours at 160° C. Subsequently, the mixture was allowed to cool and water was added. The mixture was then extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=5:1->1:1) gave 9.80 mg (4%) of the desired compound as a colorless oil.
Reaction SMILES: [C:1]1([P:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[OH:32]O>C(Cl)(Cl)Cl>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([P:17](=[O:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:1]2[C:14]3[C:15]4=[C:16]5[C:11](=[CH:12][CH:13]=3)[CH:10]=[CH:9][CH:8]=[C:7]5[CH:6]=[CH:5][C:4]4=[CH:3][CH:2]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(P(c2ccccc2)c2ccc3ccc4cccc5ccc2c3c45)cc1
Reactant: OO
Solvent: ClC(Cl)Cl
Product: COc1ccc(P(=O)(c2ccccc2)c2ccc3ccc4cccc5ccc2c3c45)cc1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
Pyrenylphenyl-4-methoxyphenylphosphine [Va] (1.68 g, 4.03 mmol) was dissolved in 25 mL of chloroform, and 5 mL of hydrogen peroxide was slowly added dropwise to the solution. The mixture was stirred for 5 minutes and then the reaction was quenched with 25 mL of 10% sodium thiosulfate. The mixture was extracted with chloroform (20 mL×3). The organic layer was dried over sodium sulfate and concentrated on an evaporator to give white crystals in 97% yield. The white crystals obtained were identified by 1H-NMR, 31P-NMR and 13C-NMR.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:12])[CH:5]=1.[CH2:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl[O-].[Na+]>C(Cl)Cl.O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:11]([C:6]2[CH:5]=[C:4]([C:3]3[CH2:23][CH:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:1][N:2]=3)[N:9]=[C:8]([CH3:10])[N:7]=2)=[O:12])=[CH:20][CH:19]=1
Reactant: COc1ccc(CNC(=O)c2cc(C=NO)nc(C)n2)cc1
Reactant: C=Cc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNC(=O)c2cc(C3=NOC(c4ccccc4)C3)nc(C)n2)cc1
Reaction time: 2 h
Yield: 34.8 %

Procedure:
To a stirred suspension of 6-((hydroxyimino)methyl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.15 g, 0.50 mmol, Preparation #B.1.1) and styrene (0.057 g, 0.50 mmol) in DCM (10 mL) was added 4% sodium hypochlorite solution (1.5 mL, Sd Fine Chem.) drop wise for about 10 min at RT and stirred for about another 2 h. The reaction mixture was diluted with water (50 mL) and the product extracted with DCM (3×25 mL). The organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure. The resulting mixture was purified by silica gel (60-120 mesh) chromatography eluting with 20 to 30% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford N-(4-methoxybenzyl)-2-methyl-6-(5-phenyl-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide as a white solid 0.07 g (34%). LC/MS (Table 1, method-b) Rt=1.93 min; MS m/z: 403 (M+H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1>C(=S)=S>[CH3:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:5]([CH3:6])=[O:7])=[CH:14][CH:13]=1
Reactant: CCCc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCc1ccc(C(C)=O)cc1
Reaction time: 8 h

Procedure:
Crushed anhydrous aluminium trichloride (1.28 mole) was suspended in dry carbon disulphide (348 ml). Acetylchloride (1.1 mole) and n-propylbenzene (1.0 mole) was dissolved in dry carbon disulphide (348 ml) and added to the suspension of aluminium trichloride under anhydrous conditions. The mixture was then left to stir overnight. The solvent was distilled from the reaction mixture and the viscous residue poured onto crushed ice and stirred for 0.5 hours. The product was extracted into ether and the extract washed with water and dried (Na2SO4). The ether was removed by distillation and the oily residue distilled. The product had mpt 132° C. at 0.1 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[N:17][N:16]=[CH:15]2>C1COCC1.CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH:22]([CH3:27])[C:23]([F:26])([F:24])[F:25])=[N:17][N:16]=[CH:15]2
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(C(C)C(F)(F)F)nncc3c2)c1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(C(C)C(F)(F)F)nncc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of methyl 4-methyl-3-(1-(1,1,1-trifluoropropan-2-yl)phthalazin-6-yl)benzoate (91 mg, 243 μmol) in THF (1200 μl) and methanol (600 μl) was added NAOH (1N aqueous solution; 1215 μl, 1215 μmol) and stirred at 50° C. for 2 h, during which LC-MS indicated completion of reaction. After concentrating in vacuo, the slurry was diluted with water and the pH was adjusted with 10% aqueous HCl solution to ˜7, resulting in the precipitation of 4-methyl-3-(1-(1,1,1-trifluoropropan-2-yl)phthalazin-6-yl)benzoic acid (86 mg, 98% yield) as a yellow solid. MS (ES+): 361.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34]C1C=CC=CC=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20](C(OC)=O)[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:34][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([NH:12][CH:13]([C:14]([N:42]([CH3:41])[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:6]([OH:7])=[O:5])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: CCCCCNC
Product: CCCCCN(C)C(=O)C(Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 59.7 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and N-methylamylamine (29 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (33 mg). 1H-NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 7.5-7.15 (m, 6H), 7.04 (d, 1H), 5.02 (m, 1H), 4.81 (s, 2H), 4.28 (m, 1H), 3.25-2.7 (m, 9H), 1.10-1.5 (m, 15H), 0.89 (t, 3H); HRMS m/z 613.2982 (calc. of monoisotopic mass for C32H43N3O9 gives 613.2999).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25]I)[CH:12]=3)=[CH:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[NH:43]1[CH2:48][CH2:47][CH:46]([CH2:49][CH2:50][OH:51])[CH2:45][CH2:44]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][N:43]4[CH2:48][CH2:47][CH:46]([CH2:49][CH2:50][OH:51])[CH2:45][CH2:44]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCC(CCO)CC3)c2cc1OC
Reaction time: 2 h
Yield: 57 %

Procedure:
A suspension of 0.280 g of 4-chloro-2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 0.061 g of potassium carbonate and 0.114 g of 2-piperidin-4-ylethanol in 30 ml of acetonitrile is brought to a temperature in the region of 60° C. After heating at this temperature for approximately 5 hours, 0.061 g of potassium carbonate and 0.114 g of 2-piperidin-4-ylethanol are again added and the mixture is agitated at this temperature for approximately 2 hours. After returning to a temperature in the region of 20° C., the mixture is concentrated to dryness under reduced pressure (13 kPa), and then taken up with 50 ml of water and extracted with three times 40 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: dichloromethane/methanol (95/5 by volume)]. 0.16 g of 2-[1-(2-{3-[4-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxyindol-1-yl}ethyl)piperidin-4-yl]ethanol is obtained in the form of an oil, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18](Cl)=[O:19]>>[C:1]([C:5]1[C:6]([NH:14][C:18](=[O:19])[CH2:17][C:16]([CH3:22])([CH3:21])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)Nc1nn2cccnc2c1C(C)(C)C

Procedure:
The product from Example 105B and 3,3-dimethylbutanoyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.05 (s, 9H), 1.45 (s, 9H), 2.20 (s, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 8.47 (dd, J=4.1, 1.7 Hz, 1H), 8.94 (dd, J=7.0, 1.9 Hz, 1H), 9.59 (br s, 1H); MS (DCI) m/z 289 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1B(O)O>>[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: OB(O)c1ccc(F)cc1Cl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1Cl

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-chloro-4-fluorophenyl-boronic acid (CAS RN 313545-72-1) and using preparative HPLC for the chromatographic purification. Brown sticky solid (33%). MS (ESI): m/z=476.8 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[CH:15]=[C:14]([C:23](=[O:31])[NH:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)[CH:13]=2)=[CH:7][N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[CH3:21][C:19]1([CH3:22])[CH2:18][C:17]2[C:12]([O:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[CH:13][C:14]([C:23](=[O:31])[NH:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)=[CH:15][C:16]=2[O:20]1
Reactant: COC(=O)c1ccc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)O)nc3)c3c(c2)OC(C)(C)C3)n1
Temperature: 60 °C
Yield: 79 %

Procedure:
To a solution of 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid methyl ester (179) (524 mg, 1.24 mmol) in 10 mL THF was added 2 mL 1 N aqueous NaOH. The mixture was heated at 60° C. for 1 hr, and concentrated in vacuo. The residue was acidified to pH ˜1 with 1N aqueous HCl, filtered, washed with water, and dried under vacuum at 60° C. overnight to give an off-white solid (400 mg, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.74 (br. s., 1 H) 8.51 (br. s., 2 H) 7.97-8.17 (m, 1 H) 7.46-7.64 (m, 2 H) 7.23 (br. s., 2 H) 6.54 (br, s, 1 H) 3.76 (s, 3 H) 2.91 (s, 2 H) 1.44 (s, 6 H); LCMS for C21H20N4O5 m/z 409.20 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[CH3:11][C:12]1([CH3:39])[C:23]2[C:15](=[CH:16][C:17]3[NH:18][C:19]([S:24][CH2:25][C:26]4[C:31]([CH3:32])=[C:30]([N+]([O-])=O)[CH:29]=[CH:28][N:27]=4)=[N:20][C:21]=3[CH:22]=2)[C:14]([CH3:37])([CH3:36])[C:13]1=[O:38]>C(O)C>[CH2:2]([O:3][C:30]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:25][S:24][C:19]2[NH:18][C:17]3[CH:16]=[C:15]4[C:23](=[CH:22][C:21]=3[N:20]=2)[C:12]([CH3:11])([CH3:39])[C:13](=[O:38])[C:14]4([CH3:37])[CH3:36])[C:31]=1[CH3:32])[CH3:1]
Reactant: CC[O-]
Reactant: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)C3(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C
Reaction time: 0.5 h

Procedure:
A mixture of 10.5 g of sodium ethylate, 20 g of sodium carbonate and 400 ml of ethanol was stirred at 50° under argon for 30 minutes and then treated with 7 g of 5,7-dihydro-5,5,7,7-tetramethyl-2-[[(3-methyl-4-nitro-2-pyridyl)methyl]thio]indeno[5,6-d]imidazol-6(1H)-one. After stirring at 50° for 5 hours under argon the reaction mixture was concentrated in vacuo. The residue was treated with methylene chloride and buffered by means of glacial acetic acid; the methylene chloride solution was extracted with sodium bicarbonate solution, dried and concentrated. The residue was chromatographed on silica gel while eluting with methylene chloride/ethyl acetate (3:1), the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. There was obtained 2-[[(4-ethoxy-3-methyl-2-pyridyl)methyl]thio]5,7-dihydro-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one which melts at 175°-176° after recrystallization from ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[Br:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)=[N:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[O:16])[CH2:26]2)=[N:22][CH:23]=1
Reactant: O=C(O)c1ccccc1-c1cccc(F)c1
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Product: O=C(c1ccccc1-c1cccc(F)c1)N1CCC[C@@H](Nc2ncc(Br)cn2)C1

Procedure:
prepared by reaction of 3′-fluoro-biphenyl-2-carboxylic acid with (R)-(5-bromo-pyrimidin-2-yl)-piperidine-3-yl-amine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12]C)=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: COc1cc2ccsc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cc2ccsc2c(Cl)c1Cl
Reaction time: 1 h
Yield: 1 %

Procedure:
A mixture of 45 g of 6,7-dichloro-5-methoxybenzo[b]thiophene and 5 g of pyridine hydrochloride is stirred at 180° for 1 hour. The mixture is cooled, triturated with water and extracted thrice with ether. The ether solution is washed with water, dried and concentrated to give 0.42 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene as a tan-colored solid. Recrystallization from acetone-hexane gives prisms, mp 97°-98°.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[CH:13][C:12]=1[CH3:24]>>[CH3:7][O:6][C:3]([CH:19]1[C:20](=[O:23])[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[N:16][C:11]([O:10][CH3:9])=[C:12]([CH3:24])[CH:13]=2)[CH2:18]1)=[O:8]
Reactant: COc1ncc(N2CCC(=O)CC2)cc1C
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CN(c2cnc(OC)c(C)c2)CCC1=O
Temperature: 90 °C
Yield: 77.2 %

Procedure:
To a stirred suspension of sodium hydride (60%, 153 mg, 6.36 mmol) in dimethyl carbonate (3.82 mL, 45.4 mmol) at room temperature was slowly added 6′-methoxy-5′-methyl-2,3,5,6-tetrahydro-[1,3′]bipyridinyl-4-one (1 g, 4.54 mmol). The reaction mixture was heated to reflux (90° C.) for 1 h and then cooled to room temperature. The mixture was partitioned between CH2Cl2 and water and a solution of 1N HCl was added cautiously. The aqueous layer was separated and washed with an addition portion of CH2Cl2. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the crude product, which was purified by flash-chromatography on silica gel (heptane/ethylacetate 3/1) to afford 6′-methoxy-5′-methyl-4-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-3-carboxylic acid methyl ester (975 mg, yield 77%) as a white solid. 1H-NMR (400 MHz, DMSO, 298K) (mixture of keto and enol tautomers observed) δ ppm 2.12 (s, 6H) 2.36-2.69 (m, 4H) 3.26-3.96 (m, 20H) 7.34-7.77 (m, 4H) 11.84 (s, 1H). LCMS: [M+H]+=279.1, Rt(3)=1.51 min (tautomer 1) and 1.70 min (tautomer 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[CH2:24][CH3:25])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Cl.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[CH2:24][CH3:25])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: CCc1nc2ccccc2c(=O)n1-c1ccc(OCCCCl)c(Br)c1
Solvent: CCOCC
Product: CCc1nc2ccccc2c(=O)n1-c1ccc(OCCCN2CCCCC2)c(Br)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
3-[3-bromo-4-(3-chloropropoxy)phenyl]-2-ethyl -4(3H)-quinazolinone (70 mg) was dissolved in piperidine (1 mL), and stirred at 80° C. for 5 hours. The reaction solution was diluted with diethyl ether, and insoluble matter was filtered off. The filtrate was concentrated, dried under vacuum, and the title compound (80 mg, 99%) was thus obtained as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8](=[O:12])[C:7]1=[O:13]
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O

Procedure:
1-(2,4-Dimethoxybenzyl)-2,3-dioxopiperazine was reacted with ethyl 4-bromobutyrate by the same method as in Reference Example 12 to obtain ethyl 4-[4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]butyrate as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][O:29][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[O:11][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[N:19]=[CH:18][N:17]=[C:16]2[O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCCN1CCOCC1
Temperature: 110 °C
Yield: 68.3 %

Procedure:
4-(3-Chloropropyl)morpholine (0.9 g, 4.5 mmol), (J. Am- Chem. Soc. 1945, 67, 736, 174 mg, 1.06 mmol), was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.0 g, 3.7 mmol), potassium carbonate (2.6 g, 18.8 mmol) in DMF (30 ml). The mixture was heated at 110° C. for 4 hours and then allowed to cool. The solids were removed by filtration, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol, (96/4) to give 6-methoxy-7-(3-morpholinopropoxy)-4-phenoxyquinazoline (1.0 g, 68%).