Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][SH:23])[CH3:16].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][S:23][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2)[CH3:16]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: Ic1ccc2c(ccc3nccn32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nccn32)c1
Temperature: 80 °C

Procedure:
1g (120 mg, 0.5 mmol) and 3-mercaptopropionic acid 2-ethylhexyl ester (110 mg, 0.5 mmol) were dissolved in 1,4-dioxane (5 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.15 mL, 0.84 mmol), Pd2dba3 (10 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.02 mmol) were added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 80° C. overnight, then cooled to room temperature, concentrated, and purified by silica gel chromatography to give the desired product, 1i.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH:3]=1.[BH4-].[Na+].Cl>CO>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[CH:3]=1
Reactant: CC(=O)CCc1cc(O)n2nccc2n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CCc1cc(O)n2nccc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The compound obtained in step (2), 5.7 g, was dissolved in 120 ml of methanol. Sodium borohydride, 0.53 g, was added to the solution under ice-cooling. The mixture was stirred at 0° C. for 2 hours. After completion of the reaction, the reaction mixture was acidified by adding diluted hydrochloric acid dropwise and then extracted with chloroform. The organic layer was collected, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol-n-hexane to provide 4.16 g of 7-hydroxy-5-(3-hydroxybutyl)pyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:31]([O:32]C(=O)C)[C@H:30]([O:36]C(=O)C)[C@@H:29]([CH2:40][O:41]C(=O)C)[O:28][C@H:9]1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)(=O)C>CO>[O:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)[C@@H:9]1[O:28][C@H:29]([CH2:40][OH:41])[C@@H:30]([OH:36])[C@H:31]([OH:32])[C@H:8]1[OH:7]
Reactant: COC(=O)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Sodium methoxide (0.006 g) was added to a solution of 2-(4-methoxycarbonylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.066 g) in methanol (5 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give 2-(4-methoxycarbonylbenzyl)phenyl β-D-glucopyranoside (0.040 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4](=[O:6])[CH3:5].[Br:9]Br.C(=O)(O)[O-].[Na+]>CO.C(#N)C.C(#N)C>[Br:9][CH2:5][C:4](=[O:6])[CH:3]([O:7][CH3:8])[O:2][CH3:1]
Reactant: BrBr
Reactant: COC(OC)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COC(OC)C(=O)CBr
Yield: 70.4 %

Procedure:
A solution of 1,1-bis(methyloxy)-2-propanone (40.1 mL, 339 mmol) in 5% (v/v) methanol/acetonitrile (200 mL) was cooled to <5° C. while stirring. A 1 mL portion of a solution of bromine (17.44 mL, 339 mmol) in acetonitrile (30 mL) was added and the mixture was stirred until the solution was decolorized. The remainder of the bromine solution was added to the reaction mixture over 6-8 hrs while maintaining an internal temperature of <10° C. The mixture was stirred at RT overnight. Sodium bicarbonate (30.2 g, 360 mmol) was added and the mixture was stirred for 1 hr, then filtered. The filtrate was concentrated and t-butyl methyl ether (30 mL) and heptane (15 mL) were added. The mixture was washed with aqueous sodium bicarbonate (6.0 g in 60 mL water) and the organic layer was dried over sodium sulfate. The solvent was evaporated to give the title compound (47.03 g, 70%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 4.64 (s, 1H), 4.13 (s, 2H), 3.35 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([S:22]C(=O)N(C)C)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+].S(=O)(=O)(O)O>C(O)C>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([SH:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(SC(=O)N(C)C)ccc(C(C)=O)c1OCCCC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(S)ccc(C(C)=O)c1OCCCC(=O)OCC
Temperature: 0 °C
Yield: 89.7 %

Procedure:
Ethyl 4-(6-acetyl-3-(N,N-dimethylcarbamoylthio)-2-propylphenoxy)butyrate (10.6 g) and potassium hydroxide (4.5 g) in ethanol (100 ml) were heated with stirring under refluxing for 1.5 hours. Ice water and conc. sulfuric acid were added thereto (pH 1), and then the mixture was subjected to extraction. The organic layer was washed with water and aqueous solution of sodium chloride, followed by being dried over sodium sulfate and then concentrated under a reduced pressure. To the resultant residue was added a mixture of ethanol (30 ml) and conc. sulfuric acid (0.5 ml), and the mixture was heated with stirring and refluxing for 1.5 hours. Ice water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water and thereafter was dried over sodium sulfate, followed by being concentrated under a reduced pressure. Ethyl 4-(6-acetyl-3-mercapto-2-propylphenoxy)butyrate (7.8 g, 89.7%) was obtained as brown oil.
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[CH3:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([OH:23])=[C:14]2[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:23][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[CH3:8])[C:14]=1[C:19]([F:20])([F:21])[F:22]
Reactant: Cc1cccc2c(C(F)(F)F)c(O)ccc12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C)cccc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
Dimethylsulfate (1.13 g, 8.75 mmol, 0.85 mL) was added to a stirred suspension of 5-methyl-1-(trifluoromethyl)-2-naphthalenol (1.8 g, 7.96 mmol) and potassium carbonate (2.2 g, 15.9 mmol) in dimethylformamide (20 mL). After stirring the reaction mixture for 2 hr at 25° C., the solid in the reaction mixture was removed by filtration. The filtrate was extracted with hexane (400 mL). The extract was washed with brine, dried (MgSO4) and concentrated to dryness giving 1.7 g (90% yield) of the title compound. This product was used for the reaction described in the next example. A sample of the product, recrystallized from hexane, had mp 70°-71° C.; nmr (CDCl3) δ 2.65 (s, 3H), 3.95 (s, 3H), 7.2 (m, 2H), 7.35 (q, J=8 Hz, 1H), 8.0 (m, 1H), 8.1 (d, J=9 Hz, 1H); ir (CHCl3) 1390, 1340, 1280, 1255, 1245, 1110, 1095, 1085,1045 cm-1 ; uvλmax (MeOH) 336 nm (ε2,910), 323 (2,645), 297 (4,440), 286 (4,880), 236 (30,050), 224 (46,730).
Reaction SMILES: [CH:1]1([Ru:6][CH:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.P(=O)(O)(O)O.[OH-].[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([C:7]1([Ru:6][CH:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[CH:11]=[CH:10][CH:9]=[CH:8]1)(=[O:21])[CH3:20]
Reactant: C1=CC([Ru]C2C=CC=C2)C=C1
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C1([Ru]C2C=CC=C2)C=CC=C1
Temperature: 85 °C

Procedure:
Bis(cyclopentadienyl)ruthenium (3 g), acetic anhydride (10 ml), and 85% phosphoric acid (2.0 ml) were placed in a round-bottom flask, and the mixture was heated at 85° C. for one hour. The formed reaction product was neutralized by use of sodium hydroxide, recrystallized, and subjected to extraction by use of hexane, thereby yielding 1.8 g of (acetylcyclopentadienyl)cyclopentadienylruthenium.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][C:11]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]#[N:31]>CC(C)=O>[CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:29][C:30]#[N:31])=[CH:19][CH:20]=3)=[CH:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2
Reactant: Cn1c2c(c3cc(-c4ccc(O)cc4)ccc31)CCCC2
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c2c(c3cc(-c4ccc(OCC#N)cc4)ccc31)CCCC2

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-phenol (0.194 g, 0.699 mmol) was reacted with K2CO3 (0.116 g, 0.839 mmol) and bromoacetonitrile (0.101 g, 0.839 mmol) in acetone (8 ml) to give the product (0.153 g, 0.484 mmol, 69%) as a white solid, mp 204-206° C. 1H NMR (DMSO-d6) δ 1.77-1.82 (m, 2H), 1.84-1.90 (m, 2H), 2.67 (t, J=5.8 Hz, 2H), 2.72 (t, J=5.8 Hz, 2H), 3.61 (s, 3H), 5.19 (s, 2H), 7.12 (d, J=8.7 Hz, 2H), 7.33 (dd, J=1.4, 8.4 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.59 (s, 1H), 7.65 (d, J=8.6 Hz, 2H); [ESI(+)], m/z 317 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[CH:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][C:18]([F:21])([F:20])[F:19])[C:7]=2[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][CH3:31])=[C:26]([CH3:32])[CH:25]=2)[CH2:5][CH2:4]1.[CH3:33][O:34][C:35](=[O:46])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][C:37]=1[O:44][CH3:45]>CN(C=O)C.O>[CH3:33][O:34][C:35](=[O:46])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][N:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:7]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][C:18]([F:20])([F:21])[F:19])[N:9]=[CH:10][C:6]=3[CH:3]3[CH2:4][CH2:5]3)=[CH:25][C:26]=2[CH3:32])[CH3:31])=[CH:38][C:37]=1[O:44][CH3:45]
Reactant: COC(=O)c1ccc(CBr)cc1OC
Reactant: CNc1ccc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C)c2ccc(OCc3c(C4CC4)cnn3-c3ccccc3OC(F)(F)F)cc2C)cc1OC
Temperature: 40 °C
Yield: 67.8 %

Procedure:
Sodium hydride (60% in mineral oil, 30 mg, 0.75 mmol) is added to a solution of {4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amine (0.31 g, 0.75 mmol) and 4-bromomethyl-2-methoxy-benzoic acid methyl ester (0.320 g, 1.23 mmol) in DMF (3 mL) at room temperature. The reaction is heated to 40° C. for 2 h. The mixture is diluted with water and is extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4. The crude residue is purified via radial chromatography (2 mm plate, 20 to 40 THF-heptane) to afford 4-[({4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-methoxy-benzoic acid methyl ester (303 mg, 68%). ES/MS m/e 596.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:29]([C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1)([CH3:31])[CH3:30].CC(C)([O-])C.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:29]([C:32]1[N:33]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)([CH3:31])[CH3:30]
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CC(C)c1nc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
2-(1-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.73 g) was reacted with 2-isopropyl-1H-benzo[d]imidazole and sodium tert-butoxide (instead of cesium carbonate) via General Procedure C to produce 0.192 g of 112 following reverse phase HPLC purification. MS (Q1) 530.3 (M)+
Reaction SMILES: [OH:1][C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O1CCOCC1.Cl>CO>[NH2:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:2]2([OH:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC2(O)CCOCC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC1CCN(CC2(O)CCOCC2)CC1
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of tert-butyl ({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)carbamate as prepared in 1(3) (50.28 g, 153 mmol) in methanol (100 mL) was added 4N hydrochloric acid dioxane solution (200 mL, 800 mmol) at room temperature. After 4 h, the volatile materials were removed by evaporation. The resulting amorphous was precipitated with diethyl ether/methanol (v/v=5/1). The precipitate was collected and added to the ice cooled 6N aqueous sodium hydroxide solution (200 mL) gradually. The mixture was extracted with dichloromethane/methanol (v/v=10/1, 500 mL×4). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 24.90 g (99%) of the title compound as a pale brown amorphous solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CN(C=O)C.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>O>[O:20]=[C:18]1[N:17]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:16](=[O:21])[CH:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:23][CH:22]=2)[S:19]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Sodium hydride (60% in mineral oil, 66 mg, 1.65 mmol) was added into a mixture of 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (500 mg, 1.65 mmol) (which was obtained in Example 38) and DMF. The mixture was stirred for one hour at room temperature, and then ethyl bromoacetate (0.27 mL, 2.47 mmol) was added. The new mixture was stirred for 30 minutes, poured into water, and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate 2/1) gave a viscous oil (295 mg, 46% yield); 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J=7.16 Hz, 3H), 2.40 (m, 4H), 2.95–3.00 (m, 1H), 3.4 (m, 1H), 3.60 (m, 2H), 4.10 (q, J=7.16 Hz, 2H), 4.30 (s, 2H), 6.97 (m, 2H), 7.16 (m, 2H); MS (ES) m/z: 391 (MH+);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O.COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15](=[O:17])[CH:16]=[CH:23][C:22]3[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccnc1Nc1ccc(F)cc1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1cc(C=CC(=O)c2cccnc2Nc2ccc(F)cc2)cc(OC)c1OC
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
To a solution of 1-(2-(4-fluorophenylamino)pyridin-3-yl)ethanone (100 mg, 0.434 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 3,4,5-trimethoxybenzaldehyde (85.30 mg, 0.434 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 8h and the reaction was monitored by TLC. After 6h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (7f) (160 mg, 90% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([CH3:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[N:11]1([C:14]2[C:23]([CH3:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:26][CH2:27]3)=[CH:16][C:15]=2[F:32])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1c(N2CCN(Cc3ccccc3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To 7-(4-benzyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4 -dihydro-4-oxoquinoline-3-carboxylic acid (84 mg) are added acetic acid (3 ml) and 10% Pd-C (10 mg), and the mixture is subjected to catalytic reduction at 70° C. for one hour. After the catalytic reduction, the reaction mixture is cooled and the catalyst is filtered off. The filtrate is concentrated, and to the residue is added aqueous sodium hydrogen carbonate, and the resulting precipitates are separated by filtration to give 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (45 mg), as white crystals, m.p. 291°-295° C. (decomp.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:27]=[C:26]4[C:21]([CH:22]=[N:23][C:24]5[N:25]4[N:28]=[C:29]([CH3:31])[CH:30]=5)=[CH:20][C:19]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:31][C:29]1[CH:30]=[C:24]2[N:23]=[CH:22][C:21]3[CH:20]=[C:19]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5([NH2:7])[CH2:11][CH2:10][CH2:9]5)=[CH:17][CH:16]=4)=[N:27][C:26]=3[N:25]2[N:28]=1
Reactant: Cc1cc2ncc3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3n2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2ncc3cc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)nc3n2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Compound (4-2) (7 mg, 0.14 mmol, 1 eq.) in CH2Cl2 (3 mL) was added trifluoroacetic acid (1 mL) and the mixture stirred at room temperature for 15 minutes. The volatiles were removed under reduced pressure and the residue was purified by reverse phase HPLC using TFA:CH3CN and water as the eluant to provide Compound (4-3). MS (M+H)+: observed=406.2027, calculated=406.2032
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1([OH:22])[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1)=[O:6].[CH3:23]I.O>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1([O:22][CH3:23])[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1)=[O:6]
Reactant: CI
Reactant: COC(=O)C1(O)CCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(OC)CCN(C(=O)OCc2ccccc2)C1
Temperature: 17 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a suspension of NaH (52 g, 1.3 mol) in 2.2 L of anhydrous DMF at 8° C., was added a solution of 3-Hydroxy-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester 3a (278 g, 1.0 mol) in 700 DMF, keeping the reaction temperature below 11° C. After complete addition (˜20 min), ice bath was removed, stirred at 16-18° C. for 1 h, and then at ambient temperature for 1 h. Cooled back to 15° C., added MeI (81 mL, 1.3 mol) slowly. Reaction mixture was stirred at ambient temperature for 1 overnight. The reaction mixture was then poured in a cold water (4 L) and then extracted with Et2O (6 L) and EtOAc (2 L), washed the organic later with water (5 L), brine (700 mL), dried over magnesium sulfate, filtered and evaporated to give crude 3-Methoxy-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester 4a 289 g (99% crude yield, contains mineral oil) (stirring/separation with pentane wash gave 4a, 268.2 g (92%).
Reaction SMILES: [Cl:1][C:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[N:9]=2)[NH:4][CH:3]=1.P(Br)(Br)[Br:16].O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:16][C:11]1[C:2]([Cl:1])=[CH:3][N:4]=[C:5]2[C:10]=1[N:9]=[C:8]([O:13][CH3:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]cc(Cl)c(=O)c2n1
Reactant: BrP(Br)Br
Agent: COc1ccc2ncc(Cl)c(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Cl)c(Br)c2n1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 3-chloro-6-(methyloxy)-1,5-naphthyridin-4(1H)-one (3-chloro-6-(methyloxy)-1,5-naphthyridin-4-ol, for a synthesis see WO2004058144, Example 1(a) (5.1 g, 24.28 mmol) in DMF (50 ml) at 0° C. was added phosphorous tribromide dropwise (2.77 ml, 29.1 mmol) keeping the internal temperature below 20° C. The reaction mixture was then stirred at 10° C. for 0.5 h and then at 25° C. for 1 h. The mixture was then poured on 200 ml of water and the water basified to neutral pH with potassium carbonate. The solid formed was filtered off, washed with water and dried in the oven and then in the desiccator to afford the desired compound (5.8 g, 88%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:29])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19]OC(=O)C3C=CC=CC=3)[CH:16]=2)[O:11][CH2:10][CH2:9]1.[H-].C([O:34][CH2:35][CH3:36])(=O)C.[Cl-].[NH4+]>C(OCC)C>[CH3:29][C:8]1([CH3:7])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:8]3[CH:17]=[CH:16][C:36]([CH2:35][OH:34])=[CH:10][CH:9]=3)[CH:16]=2)[O:11][CH2:10][CH2:9]1
Reactant: CCOC(C)=O
Reactant: CC1(C)CCOc2ccc(C#COC(=O)c3ccccc3)cc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CC1(C)CCOc2ccc(C#Cc3ccc(CO)cc3)cc21
Temperature: -65 °C
Reaction time: 1 h

Procedure:
A 250 ml 3-necked flask is fitted with a stirrer, a dripping funnel, a nitrogen inlet and a thermometer. In the flask is placed a solution of 379.5 mg (10 mmol) of lithium aluminum hydride in 30 ml of dry diethyl ether. The solution is cooled to -65° C. under nitrogen and a solution of 3.3441 g (10 mmol) of ethyl-4-((4,4-dimethylchroman-6-ylethynyl)benzoate in 15 ml of dry ether is added dropwise at a rate such that the temperature does not exceed -60° C. The mixture is stirred at -30° C. for 1 hour and the excess hydride is then destroyed by the addition of 300 mg (3.4 mmol) of ethyl acetate. The reaction mixture is then hydrolyzed by adding 3 ml of saturated ammonium chloride solution and allowing the temperature to rise to room temperature. The mixture is then filtered and the residue washed with ether. The ether layer is then washed with saturated sodium chloride solution, dried (MgSO4) and then concentrated in vacuo. The residue is purified by chromatography followed by recrystallization to give the title compound.