Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]2[C:35]([O:37][C:38](=O)[C:28]=2[CH:27]=1)=[O:36]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:35](=[O:36])[C:29]2[C:28](=[CH:27][CH:26]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=2)[C:38]1=[O:37]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(-c2nc3cc(-c4ccc(Cl)cc4)ccc3o2)cc1N
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)cc4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-4-methoxyphenyl)-5-(4-chlorophenyl)benzoxazole (104 mg, 0.30 mmol) and 1,2,4-benzenetricarboxylic anhydride (58 mg, 0.33 mmol) the title compound was obtained (67 mg, 43%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.38–8.33(m, 3H), 8.12(d, 1H), 8.05(d, 1H), 7.86(d, 1H), 7.77(d, 1H), 7.70(dd, 1H), 7.55–7.48(m, 3H), 3.89(s, 3H). MS m/z 525.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]2[O:11]C(=O)[NH:9][CH:8]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:15]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C.[Cl-].[Na+].O>[NH2:9][CH:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:25])([F:26])[CH:22]([F:23])[F:24])[CH:15]=1)[CH:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:11]
Reactant: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2ccc(Cl)s2)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Cl)s1

Procedure:
(4RS,5RS)-5-(5-Chloro-2-thienyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one (8.480 g, 20.69 mmol) and sodium hydroxide (3.31 g, 82.8 mmol) were heated in ethanol (40 ml)-water (3 ml) under reflux for 4 hrs. The reaction solution was diluted with brine, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel (APS type) column chromatography (hexane/ethyl acetate=3/1-ethyl acetate) to give the objective substance.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:27])([C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1)[CH3:27]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1csc(C(C)(C)N)n1
Product: Cc1csc(C(C)(C)NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g; 100 mg, 0.42 mmol) and α,α,4-trimethyl-2-thiazolemethanamine (CAN 859466-62-9, 78.2 mg, 0.64 mmol) as starting materials, and isolated (12 mg, 9.22%) as colorless sticky solid, LC-MS (UV peak area, ESI) 99.24%, 373.4 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]([CH:22]=[O:23])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:24][C:25]1(C)[C:29](C)(C)OB(C(C)=C)O1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.O>O1CCOCC1.CC(O)=O.CC(O)=O.[Pd]>[CH:22]([C:3]1[C:2]([C:25]([CH3:29])=[CH2:24])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1)=[O:23]
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2C=O)cc1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: C=C(C)c1cc(C(F)(F)F)cc(-c2ccc(C(=O)OC)cc2)c1C=O
Temperature: 25 °C

Procedure:
Methyl 3′-chloro-2′-formyl-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (430 mg, 1.3 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.59 mL, 3.1 mmol), S-PHOS (103 mg, 0.3 mmol), Pd(Oac)2 (28 mg, 0.1 mmol) and K3PO4hydrate (1.3 g, 6.3 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.3 mL) and the resulting mixture was heated to 90° C. After 16 h the resulting mixture was cooled to room temperature and filtered through CELITE. The filtrate was diluted EtOAc, washed with water and saturated aqueous NaHCO3, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:13][CH2:14][CH2:15][N:16]1[C:24]2[CH:23]=[C:22]([CH3:25])[N:21]=[C:20](OC3C=CC=CC=3)[C:19]=2[N:18]=[C:17]1[CH2:33][O:34][CH2:35][CH3:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O>[CH2:6]([O:13][CH2:14][CH2:15][N:16]1[C:24]2[CH:23]=[C:22]([CH3:25])[N:21]=[C:20]([NH2:5])[C:19]=2[N:18]=[C:17]1[CH2:33][O:34][CH2:35][CH3:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)cc2n1CCOCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2c(N)nc(C)cc2n1CCOCc1ccccc1
Yield: 51.4 %

Procedure:
Ammonium acetate (25 g, 0.32 mol) and 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (2.5 g, 6.0 mmol) were heated at 150° C. in a sealed tube for 22 hours. The resulting solution was adjusted to pH 14 with the addition of 20% sodium hydroxide, and water (50 mL) was added. The mixture was stirred for several hours to provide a yellow precipitate, which was isolated by filtration. The precipitate (1.75 g) was recrystallized from a 50:50 mixture of hexane:ethyl acetate (29 mL/g), and the crystals were isolated by filtration and dried under vacuum for 23 hours at 60° C. to provide 1.05 g of 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine as small white crystals, mp. 127–128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]([CH3:16])([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH3:10])=[CH:4][CH:3]=1.[I-].[CH3:19][S+](C)(C)=O.[OH-].[Na+].CCCCCCCCCCCCCC[N+](C)(C)C.ClC(Cl)(Cl)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]([N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)([CH3:10])[CH3:16])[CH2:19][O:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)n1cncn1
Reactant: C[S+](C)(C)=O
Agent: CCCCCCCCCCCCCC[N+](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)(Cl)Cl
Product: CC(C)(n1cncn1)C1(c2ccc(Cl)cc2)CO1
Yield: 79 %

Procedure:
A mixture of 4'-chloro-2-methyl-2-(1H-1,2,4-triazol-1-yl)propiophenone (1.375 g), trimethyl sulphoxonium iodide (1.6 g), aqueous sodium hydroxide (5N; 13.5 ml.), cetrimide (80 mg.) and 1,1,1-trichloroethane (30 ml.) was heated at 80° for 24 hours. The solution was cooled and diluted with methylene chloride (30 ml.), and the organic layer was separated and dried (MgSO4). Removal of the solvent, followed by flash chromatography of the residue on silica (100 g.) using ethyl acetate/hexane/diethylamine (40:60:3 v/v/v) for elution, gave, after collection of appropriate fractions and evaporation, the title oxirane as an oil in 79% yield, 1.15 g.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1.CO.N.C(Cl)Cl>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][NH:19][CH2:18][CH2:17][CH2:16][NH:15][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1
Reactant: NCCCNCc1ccc(Cl)c(Cl)c1
Reactant: COc1cc(Cl)nc2ccc(C)cc12
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NCCCNCc2ccc(Cl)c(Cl)c2)nc2ccc(C)cc12
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of 2-chloro-4-methoxy-6-methylquinoline (94 mg, 0.45 mmol) and N-(3-aminoprop-1-yl)-3,4-dichlorobenzylamine (0.21 g) was heated at 70° C. for 15 h, at 100° C. for 2 h, and then at 120° C. for 15 h. The resulting mixture was submitted to column chromatography (silica gel, MeOH:NH3:CH2Cl2 20:2:100) to give the title compound as a red film, (65 mg, 36%). δH (CDCl3) 1.72-1.89 (m, 3H+H2O), 2.42 (s, 3H), 2.74 (t, J=6.4, 2H), 3.53-3.65 (m, 2H), 3.71 (s, 2H), 3.94 (s, 3H), 5.06 (br, s, 1H), 5.87 (s, 1H), 7.12 (dd, J=8.2. 2.0, 1H), 7.28-7.36 (m, 2H), 7.40-7.48 (m, 2H), 7.72 (br, s, 1H): MS (ES+) 404 (MH+, 43%), 229 (100).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][C:6]2=[O:25])#[N:2].[N-:26]=[N+:27]=[N-:28].[Na+].Cl.C(N(CC)CC)C.Cl>CCOC(C)=O.CN(C=O)C>[O:25]=[C:6]1[C:5]2[C:22](=[CH:23][CH:24]=[C:3]([C:1]3[NH:28][N:27]=[N:26][N:2]=3)[CH:4]=2)[O:21][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:7]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C#N)ccc1O2
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3nnn[nH]3)ccc1O2
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro-[chroman-2,4′-piperidine]-1′-carboxylate. Alternatively, 10 mL of pyrrolidine (121.31 mmol) may be used in this procedure. To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 23 g of tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (67.17 mmol), 13.10 g sodium azide (201.52 mmol), 27.74 g of triethylamine hydrochloride (201.52 mmol), and 460 mL of dry DMF was stirred under a nitrogen atmosphere at 100° C. for 12 hours. After cooling to room temperature, 506 mL of EtOAc were added, followed by 322 mL of 1M HCl (322 mmol). Alternatively, 0.5M HCl maybe added until pH=3. The resulting layers were separated, the organic layer was washed with water/methanol (115 ml/46 mL), and then concentrated to give tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 5.08 g of tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate (13.18 mmol), 8.8 mL of 12 M HCl (105.44 mmol) and 8 mL of methanol was heated to 50° C. until the reaction was complete. The resulting slurry was filtered, washed with 25 mL of methanol at room temperature, and dried to give 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-4-one hydrochloride salt.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.O[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:29]=[C:20]1[C:21]2[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:24])[N:19]1[O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CCC(OCCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCCON2C(=O)c3ccccc3C2=O)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
To a solution of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate 69 (0.9 g, 3.67 mmol, WO 2009/87649 A1) in THF (28 mL) were added N-hydroxyphthalimide (0.9 g, 5.51 mmol), triphenylphosphine (1.44 g. 5.51 mmol) and DIAD (1.07 mL, 5.51 mmol) sequentially at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min and at room temperature for 16 h. Solvent was evaporated off and the residue was subjected to chromatography to give 70 (0.69 g, 48%) as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(N=CC)(C)(C)C.P(Cl)(OCC)([O:18][CH2:19][CH3:20])=O.[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH:29]=O.C(O)(=O)C(O)=O>O1CCCC1.C1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH:29]=[CH:20][CH:19]=[O:18]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CCOP(=O)(Cl)OCC
Agent: CC(C)[N-]C(C)C
Agent: CC=NC(C)(C)C
Agent: O=C(O)C(=O)O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C=CC=O)c(OC)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
To a cooled solution (-78° C.) of lithium diisopropylamide in 8 mL of tetrahydrofuran was added acetaldehyde N-tert-butylimine (0.4 mL, 3.0 mmol) and the mixture was stirred for 30 minutes. Diethyl chlorophosphate (518 mg, 3.0 mmol) was added and the solution was stirred at -78° C. for 2 hours, allowed to warm to -10° C. over a period of 3 hours, and recooled to -78° C. 2,4-dimethoxybenzaldehyde (232 mg, 2.0 mmol) was added to the yellow solution and the mixture was stirred for 30 minutes and allowed to warm to ambient temperature overnight. The mixture was then treated with oxalic acid (6 mmol in 20 mL of water) and then 20 mL of benzene was added. The two phase system was stirred overnight at room temperature and the layers separated. The aqueous layer was extracted with ether and the organic layers were combined and washed successively with 5% oxalic acid, 15% sodium bicarbonate, and brine. Drying (potassium carbonate) and concentration of the organic phase followed by purification of the residue (distillation or preparative TLC, silica gel, 30 ethyl acetate-hexane) gave 261 mg of 2,4-dimethoxycinnamaldehyde (yield 68%). ##STR18##
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]([Sn:19]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])Cl)[CH2:16][CH2:17][CH3:18].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:25]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]1[S:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cc2sccc2cn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cnccc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a cold (−78° C.) solution of thieno[3,2-c]pyridine (2.000 g, 14.79 mmol) in anhydrous THF (50 mL) was added n-butyllithium (10.17 mL, 16.27 mmol) dropwise. The reaction mixture was stirred at −78° C. for 60 minutes. A solution of tributylchlorostannane (4.79 mL, 17.75 mmol) in anhydrous THF (10 mL) was added. The reaction mixture was stirred at −78° C. for 30 minutes and the solution was allowed to warm to room temperature over a period of 2 to 3 hours. Saturated aqueous NaHCO3 was added. The aqueous phase was extracted with ether (3×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography, eluting with a gradient of 10-50% EtOAc and hexane over a period of 60 minutes. The desired fractions were collected to give the title compound as a clear oil (4.2 g, 67%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.79-0.94 (m, 9H), 1.10-1.24 (m, 6H), 1.32 (sextet, J=7.32 Hz, 6H), 1.51-1.66 (m, 6H), 7.63-7.70 (m, 1H), 8.04 (d, J=5.37 Hz, 1H), 8.35 (d, J=5.86 Hz, 1H), 9.16 (d, J=0.98 Hz, 1H).
Reaction SMILES: [Na].C(O)C.[CH3:5][O:6][C:7]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]#[N:23].[C:24](=O)([O-:28])[O:25][CH2:26][CH3:27]>C1(C)C=CC=CC=1>[C:22]([CH:21]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:7]=1[O:6][CH3:5])[C:24]([O:25][CH2:26][CH3:27])=[O:28])#[N:23]
Reactant: COc1c(CC#N)cccc1Sc1ccccc1C
Reactant: CCOC(=O)[O-]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C#N)c1cccc(Sc2ccccc2C)c1OC
Yield: 96.3 %

Procedure:
Sodium metal (0.7 g), dried ethanol (20 ml), 2-[2-methoxy-3-(o-tolylthio)phenyl]acetonitrile (7.7 g), ethyl carbonate (13 g) and toluene (50 ml) were treated in a similar manner to that of Example 22-(1) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]acetate (9.4 g).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]3[N:27]=[C:28]([N:31]4[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]4)[S:29][CH:30]=3)[CH2:20][CH2:19]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH3:38].[OH-].[Na+].CO>C1COCC1>[OH:37][CH:34]1[CH2:33][CH2:32][N:31]([C:28]2[S:29][CH:30]=[C:26]([CH2:25][N:21]3[CH2:22][CH2:23][CH2:24][N:18]([C:17]4[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[C:9]([CH3:38])[CH:10]=[C:11]5[C:16]=4[N:15]=[CH:14][CH:13]=[CH:12]5)[CH2:19][CH2:20]3)[N:27]=2)[CH2:36][CH2:35]1
Reactant: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCN(Cc2csc(N3CCC(O)CC3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2cccnc2c(N2CCCN(Cc3csc(N4CCC(O)CC4)n3)CC2)c1OCCCC(=O)O
Reaction time: 3 h

Procedure:
The product from step 3 (3.27 mmol) was dissolved in THF (10.9 mL), and 1 N aq. NaOH (6.54 mL, 6.54 mmol) was added, followed by MeOH (5.5 mL). This solution was allowed to stir for 3 h, then concentrated. The crude product was then purified on a reverse phase column (MeCN:H2O+0.1% TFA), and the combined product fractions were basified to pH 9 using NH4OH, then extracted with CH2Cl2 (3×50 mL). The combined organic was then concentrated. The residue was lyophilized from MeCN/H2O to give the product as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.70 (dd, 1H, J=1.4, 4.2 Hz), 7.96 (dd, 1H, J=1.4, 8.2 Hz), 7.35 (s, 1H), 7.22 (dd, 1H, J=4.4, 8.0 Hz), 6.71 (s, 1H), 4.12-4.05 (m, 4H), 4.05-3.82 (m, 4H), 3.80-3.72 (m, 4H), 3.62-3.56 (m, 2H), 3.49-3.40 (m, 4H), 3.22-3.15 (m, 2H), 2.58 (t, 2H, J=7.0 Hz), 2.41 (s, 3H), 2.24-2.17 (m, 4H), 1.98-1.90 (m, 2H), 1.69-1.59 (m, 2H). MS (ES) m/z 540.5 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][CH2:38][OH:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: NCCCO
Product: O=C(NCCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-aminopropanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.05 Hz, 2 H), 1.52-1.65 (m, 4 H), 1.65-1.75 (m, 2 H), 2.04 (t, J=6.42 Hz, 2 H), 3.26 (t, J=5.48 Hz, 2 H), 3.39-3.53 (m, 4 H), 4.16 (s, 2 H), 4.39 (t, J=6.42 Hz, 2 H), 4.55-4.63 (m, 1 H), 7.11-7.17 (m, 2 H), 7.38-7.43 (m, 2 H), 8.20 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.32 (t, J=5.58 Hz, 1 H), 17.25 (s, 1 H); ES+ MS: 497 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:23])[C:11]([C:24]([O:26]CC)=[O:25])=[CH:10]1.Cl>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:23])[C:11]([C:24]([OH:26])=[O:25])=[CH:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 73.3 %

Procedure:
Employing ethyl 1-(2,4-difluorophenyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-caboxylate (4.3 g) and conc. hydrochloric acid: 90% acetic acid (1:4) (80 ml), the procedure of Reference Example 23 is repeated to give 1-(2,4-difluorophenyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (2.93 g), as white powder, m.p. 221°-222° C.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH:19]1[CH:23]=[N:22][C:21]([NH2:24])=[N:20]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]2[N:20]3[N:19]=[CH:23][N:22]=[C:21]3[NH:24][C:14]([CH3:15])=[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Reactant: Nc1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2ncnn2C1c1ccc(C#N)cc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (300 mg, 1.2 mmol) and 1H-1,2,4-triazole-3-amine (130 mg, 1.5 mmol, 1.2 eq.) were dissolved in DMF (3 ml) and solid sodium bicarbonate (518 mg, 6.2 mmol, 5 eq.) was added. The mixture was stirred at 65° C. for 12 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (233 mg, 50% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([N:26]3C(=O)C4=CC=CC=C4C3=O)[CH:6]=[C:7]([O:24][CH3:25])[C:8]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:3]=1.O.NN>C(O)C>[NH2:26][C:5]1[CH:6]=[C:7]([O:24][CH3:25])[C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[C:9]2[C:4]=1[N:3]=[C:2]([Cl:1])[CH:11]=[C:10]2[CH3:12]
Reactant: COc1cc(N2C(=O)c3ccccc3C2=O)c2nc(Cl)cc(C)c2c1Oc1cccc(C(F)(F)F)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(N)c2nc(Cl)cc(C)c2c1Oc1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
A suspension of 2-chloro-6-methoxy-4-methyl-8-phthalimido-5-(3-trifluoromethylphenoxy)quinoline (23.2 g, 45.2 mmol) in ethanol (900 mL) was treated with excess hydrazine hydrate (75%, 16.75 mL) and the mixture was refluxed with mechanical stirring for 3 hours. After cooling, the solids were collected and washed with CH2Cl2. The combined filtrate and washings were evaporated in vacuo to a small volume and dissolved in CH2Cl2 ( 500 mL). The solution was extracted with 20% KOH (3×200 mL), and with brine, dried (K2CO3) and evaporated in vacuo to an amber gum. Recrystallization from cyclohexane-ligroin (5:2, 500 mL) with charcoaling gave 15.4 g (89%) of 1st crop title compound, mp 133°-135° C. Further recrystallization did not change the melting point.