Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH2:21])=[O:20])=[CH:13][C:12]=3[CH2:22][N:23]([CH3:25])[CH3:24])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.O>C1COCC1>[S:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:13][C:12]=3[CH2:22][N:23]([CH3:25])[CH3:24])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN(C)Cc1cc(/C=C/C(N)=O)ccc1Oc1ccc2c(c1)SCC2
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cc(CCC(N)=O)ccc1Oc1ccc2c(c1)SCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
A solution of Sml2 in THF (0.1 M, 21.9 mL, 2.19 mmol) was added to a solution of the alkene of Example 50 (194 mg, 0.55 mmol) in THF (5 mL) under nitrogen followed by water (1 mL). After stirring at room temperature for 10 min the reaction was quenched with 6M NaOH (10 mL) and stirred for 30 min. The organic phase was separated and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4) and evaporated to an oil, which was purified by column chromatography [SiO2; 93:7:1 (DCM/MeOH/880 NH3) increasing polarity to 90:10:1] to give the title compound (90 mg, 46%); δH (CDCl3, 400 MHz) 2.25 (6H, s), 2.54 (2H, t), 2.97 (2H, t), 3.22 (2H, t), 3.36 (2H, t), 3.42 (2H, s), 5.20-5.46 (2H, br), 6.54 (1H, d), 6.73 (1H, s), 6.81 (1H, d), 7.05 (2H, m), 7.31 (1H, s); MS m/z (TS+) 357 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]1[C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[C:29]([C:33]([O:35]CC)=[O:34])=[CH:28][CH:27]=[CH:26]4)=[CH:19][CH:18]=2)=[C:13]([CH:38]([CH3:40])[CH3:39])[O:12][N:11]=1.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][C:10]1[C:14]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=[CH:26]4)=[CH:21][CH:22]=2)=[C:13]([CH:38]([CH3:40])[CH3:39])[O:12][N:11]=1
Reactant: CCOC(=O)c1cccc2cc(-c3ccc(OCc4c(Cc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1onc(Cc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)cc1
Temperature: 100 °C
Yield: 102.5 %

Procedure:
A solution of ethyl 6-[4-({[3-[(2,6-dichlorophenyl)methyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.116 g, 0.20 mmol) in tetrahydrofuran (2 mL) was placed in a microwave reaction tube. Ethanol (1 mL) was added followed by 1 N sodium hydroxide (0.312 mL, 0.31 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 500 seconds. Additional sodium hydroxide solution (0.2 mL, 0.2 mmol) was added and the solution was heated in a microwave reactor to 100° C. for another 500 seconds. The solution was neutralized with 1 N hydrochloric acid and concentrated. The residue was slurried in hexanes. The solid was slurried in water and the mixture was decanted and the solid dried to yield the title compound as a white solid (0.112 g, 100% as 0.15EtOAc). 1H NMR (DMSO-d6) 13.14 (s, 1H), 8.91 (d, J=9 Hz, 1H), 8.26 (s, 1H), 8.20 (d, J=8 Hz, 1H), 8.10 (d, J=7 Hz, 1H), 7.96 (dd, J=2, 9 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.58 (m, 1H), 7.46 (d, J=8 Hz, 2H), 7.31 (t, J=8 Hz, 1H), 7.16 (d, J=9 Hz, 2H), 5.08 (s, 2H), 4.29 (s, 2H), 3.36 (septet, J=7 Hz, overlapping H2O 1H), 1.22 (d, J=7 Hz, 6H). HRMS C31H25NO4Cl2 m/z 546.1239 (M+H)+Cal; 546.1226 (M+H)+Obs.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[CH2:13]([O:20][C:21](=[O:25])[CH2:22][C:23]#[N:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:13]([O:20][C:21](=[O:25])[CH:22]([C:23]#[N:24])[C:5]1[CH:4]=[C:3]([CH3:12])[C:2]([F:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CCC(=O)OCc1ccccc1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(C#N)C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1F
Temperature: 60 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
A suspension of 1,4-difluoro-2-methyl-5-nitrobenzene (1.00 g), cyanoacetic acid benzyl ester (1.01 g) and potassium carbonate (1.76 g) in N,N-dimethylformamide (20.0 mL) was stirred at 60° C. for 1 day. To this reaction mixture was added 1 mol/L hydrochloric acid (25.4 mL), and this mixture was extracted with diethyl ether. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure. This residue was washed with ethanol to give the title compound (1.54 g).
Reaction SMILES: O.[OH-].[Li+].BrC1C=CC(C([O:11][C@H:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]4)[C:15]=3[C@H:14]([CH3:34])[CH2:13]2)=O)=CC=1.O>C1COCC1>[OH:11][C@H:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[C:15]=2[C@H:14]([CH3:34])[CH2:13]1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc(Br)cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
Lithium hydroxide hydrate (0.779 mL, 28.0 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-(4-bromobenzoyloxy)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (5.8 g, 11.2 mmol) in THF:H2O (150 mL, 2:1) at 0° C. The mixture was allowed to warm to room temperature and stirred at for 1 hour. The mixture was concentrated in vacuo, taken up into saturated sodium bicarbonate (100 mL) and extracted into EtOAc (2×200 mL). The reaction was dried over Na2SO4 and concentrated in vacuo to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (3.8 g, 11.4 mmol, 100% yield) as a foam. Similarly, tert-butyl 4-05R,7S)-7-(4-bromobenzoyloxy)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.29 g, 2.49 mmol) was dissolved in THF:H2O (10 mL, 2:1), cooled to 0° C. and then treated with solid lithium hydroxide hydrate. The solution was stirred at ambient temperature for 16 hours. The reaction was quenched with saturated NH4Cl and concentrated in vacuo. The resulting residue was diluted with ethyl acetate and a small amount of water. The layers were separated, and the aqueous layer was washed with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 (2×), saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The resulting residue was dried under high vacuum to give tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate as a foam (0.843 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]([CH3:15])[CH3:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(O)c(CC(C)C)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccccc1

Procedure:
Ethyl 4-hydroxy-3-isobutylbenzoate (25.6 g), potassium carbonate (31.8 g), and benzyl bromide were refluxed with stirring in acetone (150 ml) for 4 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was concentrated under a vacuum and the residue, after water (50 ml), potassium hydroxide (12.9 g), and ethanol (100 ml) were added thereto, was refluxed with heating for 2 hours. The reaction mixture, after water added thereto, was neutralized with hydrochloric acid and then extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid aqueous solution and water, dried over magnesium sulfate anhydride and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 29.0 g of the aimed compound.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][CH2:35][CH2:36][NH:37][CH3:38])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][CH2:35][CH2:36][N:37]([CH3:38])[C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(O)C(=O)O
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)C(C)(C)O
Yield: 39 %

Procedure:
The procedure described in Example 1 was repeated using 2-hydroxy-2-methylpropanoic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 39% yield; NMR spectrum (DMSO-d6) 1.20 (s, 6H), 3.34 (s, 3H), 3.89 (s, 2H), 4.43 (s, 2H), 5.27 (s, 1H), 5.31 (s, 2H), 7.18 (d, 1H), 7.24 (d, 1H), 7.32-7.40 (m, 2H), 7.53-7.57 (m, 1H), 7.58 (d, 1H), 7.70-7.76 (m, 1H), 7.86-7.91 (m, 2H), 8.43 (s, 1H), 8.59-8.61 (m, 1H), 9.75 (s, 1H); Mass spectrum MH+ 522.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.S([Cl:27])(C)(=O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:27])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(4-hydroxymethylphenyl)propionic acid ethyl ester (P5, 2.9 g, 13.9 mmol) in triethylamine (4.0 mL, 27.8 mmol) and dichloromethane (30 mL) was slowly added at 0° C. mesyl chloride (1.6 mL, 20.9 mmol). The solution was stirred at room temperature for 18 hours, then the solution was washed with 1N aqueous hydrochloric acid. The organic phase was dried (anhydrous magnesium sulfate) and concentrated to afford the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([O:26]C)=[O:25])(=[O:17])=[O:16])=[O:13])[N:4]=1.[OH-].[K+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:26])=[O:25])(=[O:17])=[O:16])=[O:13])[N:4]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
N-[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide (15 g) was added to a warm solution of 7.5 g of potassium hydroxide in 7.5 ml of water and 60 ml of ethanol. The mixture was stirred at room temperature overnight and then poured into dilute hydrochloric acid. The solid was filtered, washed with water and dried to afford 12.5 g of the desired product: m.p. 155°-157° C. IR (cm-1) 3000, 1720.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:9]([O:17][CH3:18])=[N:10][N:11]2[C:15](Br)=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2].[Si]([O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31](B(O)O)=[C:30]([O:39][CH3:40])[CH:29]=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:9]([O:17][CH3:18])=[N:10][N:11]2[C:15]([C:31]3[C:30]([O:39][CH3:40])=[CH:29][C:28]([OH:27])=[CH:33][C:32]=3[O:34][CH3:35])=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)cc(OC)c1B(O)O
Reactant: COc1nn2c(Br)csc2c1NC(=O)OC(C)(C)C
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: O
Product: COc1cc(O)cc(OC)c1-c1csc2c(NC(=O)OC(C)(C)C)c(OC)nn12
Temperature: 110 °C
Yield: 53.1 %

Procedure:
To a solution of tert-butyl(3-bromo-6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl)carbamate (375 mg, 1.08 mmol) in 1,4-dioxane (25 ml) and water (12.5 ml) were added (4-{[tert-butyl(dimethyl)silyl]oxy}-2,6-dimethoxyphenyl)boronic acid (505 mg, 1.61 mmol), tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.108 mmol) and potassium carbonate (298 mg, 2.15 mmol), and the mixture was heated to reflux at 110° C. for two hours and 35 minutes. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (n-heptane/ethyl acetate=10% then 70%) to obtain the title compound (242 mg, 0.574 mmol).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][C:9](=[O:18])[C:10]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:20]#[N:21].CN1CCCC1=O.N>S([O-])([O-])(=O)=O.[Cu+2].O>[C:20]([C:2]1[C:7]2[CH2:8][C:9](=[O:18])[C:10]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:21]
Reactant: N#C[Cu]C#N
Reactant: O=C1Cc2c(Cl)cccc2Sc2ccc(F)cc21
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cccc2c1CC(=O)c1cc(F)ccc1S2

Procedure:
The mixture of 3.4 g of 9-chloro-2-fluoro-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin, 2.1 g of copper cyanide, 0.2 g of anhydrous copper sulfate and 50 ml of N-methyl pyrrolidone was heated at 200°-210° C. overnight. After cooling, to the reaction mixture were added 10 ml of conc. aqueous ammonia and 100 ml of water and the resulting mixture was extracted with benzene. The benzene layer thus obtained was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was chromatographed over silica gel, and eluted with chloroform and benzene. There was obtained from benzene eluate 0.3 g of 9-cyano-2-fluoro-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin as yellow needles having a melting point of 174°-175° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][N:7]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[NH2:30].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:30][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(C=O)c2)cnc1N
Reactant: Nc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(=O)c1nc(-c2cccc(CNc3ccc4ccccc4c3)c2)cnc1N
Yield: 26.2 %

Procedure:
A solution of 3-amino-6-(3-formylphenyl)-N-methylpyrazine-2-carboxamide (0.075 g, 0.29 mmol), naphthalen-2-amine (0.21 g, 1.5 mmol), glacial AcOH (0.033 mL, 0.56 mmol) and NaBH(OAc)3 (0.093 g, 0.44 mmol) in THF (1.1 mL) was heated to 80° C. for 12 h. Upon cooling, saturated NaHCO3 (aq) was added (25 mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified via HPLC (reverse-phase, CH3CN/H2O with 0.1% TFA). Upon removal of CH3CN/H2O, the product was taken up in MeOH and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo, to provide 29.1 mg (26% yield) of 3-amino-N-methyl-6-{3-[(naphthalen-2-ylamino)methyl]phenyl}pyrazine-2-carboxamide: 1H NMR (400 MHz, 4-DMSO): 8.84 (s, 1H), 8.77 (d, 1H), 8.22 (s, 1H), 8.05 (dt, 1H), 7.62 (t, 2H), 7.51 (d, 1H), 7.41 (d, 2H), 7.27 (dt, 1H), 7.10 (dt, 2H), 6.77 (d, 1H), 6.57 (t, 1H), 4.46 (d, 2H), 2.85 (d, 3H); MS (EI) for C23H21N5O: 384 (MH+)
Reaction SMILES: Cl[CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[C:7]([Cl:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:14][N:15]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:16]1=[O:26]>C(O)(C)C>[OH:13][CH:3]([CH2:4][O:5][C:6]1[C:7]([Cl:12])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][N:23]1[CH2:22][CH2:21][CH:20]([N:17]2[CH2:18][CH2:19][N:15]([CH3:14])[C:16]2=[O:26])[CH2:25][CH2:24]1
Reactant: CN1CCN(C2CCNCC2)C1=O
Reactant: OC(CCl)COc1cccnc1Cl
Solvent: CC(C)O
Product: CN1CCN(C2CCN(CC(O)COc3cccnc3Cl)CC2)C1=O

Procedure:
A mixture of 7.3 g of 1-chloro-3-(2-chloro-3-pyridyloxy)-2-propanol and 5.0 g of 3-methyl-1-(4-piperidyl)-imidazolidin-2-one is refluxed in 100 ml of isopropanol for 2 hours. Working up analogously to Example 1 yields oily 1-{1-[2-hydroxy-3-(2-chloro-3-pyridyloxy)-propyl]-4-piperidyl}-3-methyl-imidazolidin-2-one.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](C#N)=[CH:7][C:6]=1[F:13].[C:14](=[O:17])(O)[O-:15].[Na+].C(O)(=O)C>O.S(=O)(=O)(O)O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:14]([OH:15])=[O:17])=[CH:7][C:6]=1[F:13]
Reactant: N#Cc1ccc(OCCBr)c(F)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(OCCBr)c(F)c1
Yield: 65 %

Procedure:
4-(2-Bromoethoxy)-3-fluorobenzonitrile (3.78 g, 15.5 mmol) in water (18 mL) and concentrated sulfuric acid (18 mL) was heated at 110° C. for 12 hours. The solution was then cooled to room temperature and neutralized with solid sodium bicarbonate. Acidification with glacial acetic acid gave a white solid precipitate, which was collected by filtration and dissolved in dichloromethane. The resultant solution was dried over sodium sulfate. The dichloromethane solution was then filtered and evaporated to give the product as a beige-colored solid (2.65 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ 13.00 (brs, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.69 (d, J=12.0 Hz, 1H), 7.29 (dd, J=8.8 Hz, 8.4 Hz, 1H), 4.48 (t, J=5.2 Hz, 2H), 3.85 (t, J=5.2 Hz, 2H).
Reaction SMILES: O[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].S(Cl)(Cl)=O.[CH3:16][C:17]1[CH:18]=[N:19][C:20]2[N:21]([N:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:25]=2)[CH:22]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH3:16][C:17]1[CH:18]=[N:19][C:20]2[N:21]([N:23]=[C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:25]=2[CH2:2][N:3]2[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]2=[O:11])[CH:22]=1
Reactant: CCCC1CC(=O)N(CO)C1
Reactant: Cc1cnc2cc(-c3ccccc3)nn2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(C)cnc23)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (3.18 mmol, 1 eq, 0.5 g) in toluene (20 ml) is added thionyl chloride (3.5 mmol, 1.1 eq, 0.416 g). The mixture is stirred vigorously overnight at 80° C. After this time, 6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x122 (3.18 mmol, 1 eq, 0.665 g) and AlCl3 (3.18 mmol, 1 eq, 0.424 g) are successively added. The mixture is stirred at 80° C. for 2 hours. After evaporation of the solvent under reduced pressure, the crude mixture is poured to water and extracted with dichloromethane. The cumulated organic layers are dried over MgSO4, filtered over celite and evaporated under reduced pressure. The crude reaction mixture is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH 98/2/0.2 (v/v/v)) and crystallized with AcOEt to afford 0.5 g of 1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 202.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([O:19][CH3:22])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(O)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 38.1 %

Procedure:
To the stirred solution of 8-chloro-9-hydroxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.3 g, 1.092 mmol) in DMF (10 mL) cooled to 0° C., was added NaH (0.052 g, 2.184 mmol) followed by methyl iodide (0.205 mL, 3.28 mmol). The resultant mixture was allowed to stir at ambient temperature for 10 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layers were separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 70% ethyl acetate in petroleum ether to afford 8-chloro-9-methoxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.12 g, 0.416 mmol, 38% yield) as a semi-solid. LC/MS (ESI) m/e 288.4 [(M)+, calcd for C15H13ClN2O2 288.1]; LC/MS retention time (Method A): tR=1.9 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:16]([Mg]Br)=[CH2:17].Cl>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C:9]([OH:10])([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:16]=[CH2:17])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(c1cc(F)cc(F)c1)c1nccs1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(O)(c1cc(F)cc(F)c1)c1nccs1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of (3,5-difluorophenyl)(thiazol-2-yl)methanone (1 g, 4.4 mmol, Step 2) in dry THF (40 mL) was added at 0° C. (4.4 mL, 4.4 mmol) of a 1.0M THF solution of vinyl magnesium bromide (Aldrich). The reaction mixture was stirred for 30 min. and then transferred to a 1N aqueous HCl solution. The resulting mixture was extracted with EtOAc and the combined organic phase were washed with brine, dried over MgSO4 and evaporated to give a residue which was chromatographed on silica gel eluting with 85:15 mixture of hexane: EtOAc to afford 635 mg (56%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:2]=1>C(O)C.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([S:7]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)(=[O:8])=[O:9])[CH2:2]1
Reactant: O=S(=O)(c1cccnc1)N1CCOCC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: O
Product: O=S(=O)(C1CCCNC1)N1CCOCC1
Reaction time: 70 h
Yield: 22.2 %

Procedure:
4-(Pyridine-3-sulfonyl)-morpholine (25 mmol, 5.7 g) was shaken with platinum (IV) oxide (500 mg) in ethanol (50 mL) at 60° C. under hydrogen at 50 psi for 16 h. Reduction was incomplete so the catalyst was removed by filtration, the solvent evaporated under vacuum and the residue dissolved in a mixture of water (50 mL) and acetic acid (10 mL) with warming. Platinum (IV) oxide (1 g) was added and hydrogenation at 50 psi was continued for a further 70 h at 60° C. The catalyst was removed by filtration and the solvent was evaporated under vacuum to give an orange gum which was redissolved in water and the solution (pH 4-5) was extracted with dichloromethane (×3). The aqueous layer was evaporated to a small volume under vacuum, made strongly basic by the addition of 4 M sodium hydroxide solution, xylenes were added and the solvents were removed under vacuum. The residue was agitated with dichloromethane and anhydrous sodium sulfate, the solids removed by flitration through Celite® and the filtrate evaporated under vacuum to give 4-(piperidine-3-sulfonyl)-morpholine as a waxy orange solid (1.3 g, 22%).