Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[O:3].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>CN(C)C=O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[F:13][C:10]([F:11])([F:12])[C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccncc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccncc1)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Dissolve anhydrous cobalt(II) acetate (700 mg, 4 mmol) in dimethylformamide. Add 2,2'-dipyridyl (620 mg, 4 mmol) and stir for 30 minutes. Add 3-(trifluoromethyl)acetophenone (9.4 g, 50 mmol) and 4-pyridinecarboxaldehyde (5.3 g, 50 mmol). Heat at 80° C. for 18 hours. Evaporate the solvent and purify the residue by silica gel chromatography (1:1 toluene/ethyl acetate) to yield 9.4 g. Recrystallize (ethyl ether/hexane) to yield the title compound; mp 89°-90° C.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[F:13][C:14]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]2[C:15]=1[C:16]([N:34]1[C:42]3[C:37](=[N:38][CH:39]=[C:40]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH:41]=3)[C:36]([CH3:50])([CH3:49])[CH2:35]1)=[C:17]([CH3:33])[C:18]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH2:26])=[N:19]2>CS(C)=O.C1COCC1>[CH3:49][C:36]1([CH3:50])[C:37]2=[N:38][CH:39]=[C:40]([N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)[CH:41]=[C:42]2[N:34]([C:16]2[C:15]3[C:20](=[CH:21][C:22]([F:24])=[CH:23][C:14]=3[F:13])[N:19]=[C:18]([C:25]3([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:7][CH2:26]3)[C:17]=2[CH3:33])[CH2:35]1
Reactant: C=C(c1ccccc1)c1nc2cc(F)cc(F)c2c(N2CC(C)(C)c3ncc(N4CCOCC4)cc32)c1C
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1c(C2(c3ccccc3)CC2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Reaction time: 0.5 h

Procedure:
A suspension of trimethylsulfoxonium iodide (29.6 mg, 0.135 mmol) in dry DMSO (0.3 mL) was treated with potassium tert-butoxide (1.0M in THF, 0.135 mL, 0.135 mmol) at rt under a N2 atmosphere. The resulting solution was stirred for 30 min. A solution of 4-(1-(5,7-difluoro-3-methyl-2-(1-phenylvinyl)quinolin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (46 mg, 0.090 mmol) in dry THF (0.836 mL) was added dropwise to the stirring solution, and the reaction was stirred for 3 h. The reaction was then quenched with 1N HCl, and the product extracted twice with EtOAc. The organic phase was dried over MgSO4 and concentrated under reduced pressure to give a crude residue that was purified by reverse-phase HPLC (0-80% acetonitrile in water) to give 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-(1-phenylcyclopropyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 7.62-7.73 (1H, m), 7.49-7.53 (1H, m), 7.19-7.25 (2H, m), 7.12-7.19 (1H, m), 7.03-7.11 (2H, m), 6.98 (1H, ddd, J=11.8, 8.9, 2.5 Hz), 5.51-5.55 (1H, m), 3.80-3.89 (1H, m), 3.68-3.80 (4H, m), 3.51-3.61 (1H, m), 2.86-2.97 (4H, m), 2.10-2.15 (3H, m), 1.71-1.79 (1H, m), 1.55-1.64 (2H, m), 1.49-1.54 (3H, m), 1.45-1.49 (1H, m), 1.41-1.45 (3H, m). Mass Spectrum (ESI) m/e=527.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:9][NH:10][NH2:11].NN>C(O)C>[CH3:9][NH:10][N:11]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2]
Reactant: N#Cc1ccccn1
Reactant: CNN
Agent: NN
Solvent: CCO
Product: CNN=C(N)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
This compound was prepared by a modification of a reported procedure (J. Het Chem. 1975, 12, 855): A 2-L, 3-necked round bottom flask was charged with 2-cyanopyridine (40 g, 0.384 mol), methylhydrazine (93.7 g, 5.3 equiv, 2.035 mol), and ethanol (200 mL). The reaction was stirred under N2, overnight at room temperature. An additional equiv of hydrazine was added (6.3 equiv cumulative total in reaction mixture) and stirred for an additional 2–3 h at room temperature. The EtOH and excess hydrazine were distilled off in vacuo to afford a yellow crystalline solid. The yellow solid was triturated with benzene, affording a slurry of white crystals. The crystals were filtered, washed with a minimal amount of benzene and dried overnight in a vacuum oven at 50° C. The reaction yielded 41.33 g (71.6%) of the product as white crystals. 1H NMR (300 MHz, CDCl3): δ 2.97 (s, 3H), 4.02 (br s, 1H), 5.30 (br s, 1H), 7.20 (m, 1H), 7.66 (m, 1H), 8.08 (m, 1H), 8.45 (m, 1H). MS (APCI) calcd for C7H10N4: 150.09, found (M+H+): 151.3
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[F:8][C:4]1[C:3]([CH3:9])=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(N)cccc1F
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cccc(F)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-amino-3-fluoro-2-methylbenzene (1 equivalent) was dissolved in CH2Cl2 and acetic anhydride (2.0 equivalents) was added slowly. The solution was stirred at room temperature for 4 hours. The reaction mixture was then quenched with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with H2O, a 10% HCl solution, H2O, and brine. It was then dried over Na2SO4 and concentrated in vacuo, to yield N-(3-fluoro-2-methylphenyl)acetamide as a pink solid. LC/MS (m/z) 168.2 (MH+), Rt 1.91 minutes.
Reaction SMILES: C[O:2][CH2:3][CH2:4]OC.C([Zn]CC)C.ICI.[Br:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/CO)=[CH:18][CH:17]=1>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[CH2:23][C@@H:4]2[CH2:3][OH:2])=[CH:18][CH:17]=1
Reactant: OC/C=C/c1ccc(Br)cc1
Reactant: COCCOC
Agent: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Product: OC[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of DME (24.39 mL, 235 mmol) in DCM (700 mL) under nitrogen atmosphere was cooled to −10° C., and diethylzinc (235 mL, 1M in hexane, 235 mmol) was added over 5-10 minutes followed by diiodomethane (37.9 mL, 469 mmol). The product from Example 34C (33.0 g, 122 mmol) in 100 mL DCM was added in 5-10 minutes. The temperature was maintained from −5° to −10° C. throughout the additions. The product from Example 34A, (E)-3-(4-bromophenyl)prop-2-en-1-ol (20 g, 94 mmol) in DCM (150 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature for 16 hours. It was quenched with saturated aqueous NH4Cl (300 mL), HCl (1N, 480 mL) and diluted with ether (900 mL). The organic layer was separated. The aqueous layer was extracted with additional ether. The organic layers were combined and treated with NaOH (2N, 880 mL). To the solution, H2O2 (30%, 136 mL) was added dropwise while the reaction was cooled with an ice bath. The solution was stirred for 5-10 minutes. The organic layer was separated, washed with HCl (1N), saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and brine, dried and concentrated. The residue was chromatographed on silica gel eluting with 5-15% EtOAc/Hexane to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 228 (M+H)+. (ee 94%).
Reaction SMILES: [CH2:1]([N-:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O.[OH-].[Na+].C(N(CC)CC)C>C1COCC1>[CH2:16]([NH:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCC[N-]CCCCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCNCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
47 mmol of ditetradecylamide (20 g) were dissolved in 700 ml of anhydrous THF, under nitrogen, in a round-bottomed flask equipped with a condenser and a drying tube. The mixture was cooled to 0° C. and then 89 mmol of lithium aluminum hydride LiAlH4 (3.4 g) were added. After addition, the mixture was then heated under reflux for 5 hours, with vigorous stirring. Once the reaction was complete, the mixture was cooled to 0° C. in order to carry out the hydrolysis by successive addition of 3.4 ml of water, 6.8 ml of 1N sodium hydroxide and 3.4 ml of water. After stirring for 1 hour at room temperature, the crude reaction material was filtered on a Büchner funnel and the filtrate was concentrated. The product obtained was then purified on 1.5 equivalents of A-15 resin (15 g) in 300 ml of THF, with stirring for 30 minutes. The resin was filtered and redissolved in 300 ml of THF, with addition of 2 equivalents of triethylamine (19.2 ml). After stirring for 30 minutes, the solution was filtered and the filtrate was concentrated to give 17.72 g of a white solid (yield: 92%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].F[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>CN(C=O)C>[C:20]1([CH2:19][O:18][C:16]2[CH:15]=[C:10]([CH:9]=[C:8]([O:7][C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Temperature: 120 °C
Yield: 73.2 %

Procedure:
Potassium carbonate (3.21 g, 23.2 mmol) was added to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (3.00 g, 11.6 mmol) in DMF (30 mL) followed by addition of 1-fluoro-4-(methylsulfonyl)benzene (2.02 g, 11.6 mmol) and the reaction was heated at 120° C. for 3 h. The solvent was then removed in vacuo and the residue was taken up in saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (150 mL). The organic layer was separated, washed with 1M aqueous hydrochloric acid (50 mL) then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:4 to 1:1 ethyl acetate:hexanes, afforded the title compound as a colourless oil (3.50 g, 73%).
Reaction SMILES: [P:1]([O-:28])([O:24][CH2:25][CH2:26]Br)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[P:1]([O-:28])([O:24][CH2:25][CH2:26][N+:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: CCCCCCCCCCCCCCOCCOCCOP(=O)([O-])OCCBr
Reactant: c1ccncc1
Product: CCCCCCCCCCCCCCOCCOCCOP(=O)([O-])OCC[n+]1ccccc1

Procedure:
2-[2-(Tetradecyloxy)ethoxy]ethyl 2-bromoethyl phosphate obtained in Example 26 is reacted with pyridine and a conventional purification procedure of the reaction mixture gives the title compound as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Cl.Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O>CC#N.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Temperature: 70 °C
Yield: 85.5 %

Procedure:
A mixture of 2-chloro-4-nitro-phenol (202 mg, 1.16 mmol), 2-chloromethyl-quinoline hydrochloride (224 mg, 1.04 mmol), K2CO3 (354 mg, 2.55 mmol) in CH3CN (3.6 ml) was heated at 70° C. for 8 h. DMA (2 ml) was added, and the mixture was heated at 80° C. for 4 h. The mixture was cooled to rt, diluted with EtOAc (120 ml), washed with H2O (6×80 ml) and brine (1×80 ml), dried (MgSO4) and filtered. The filtrate was concentrated to give 12A (280 mg, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][NH:9][C:10](=[S:31])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NNC(=S)c1ccc([N+](=O)[O-])cc1F
Yield: 110.3 %

Procedure:
N′-(2-Fluoro-4-nitro-benzoyl)hydrazinecarboxylic acid tert-butyl ester (Step 1, 2.32 g, 7.75 mmol) and Lawesson's reagent (2.35 g, 5.81 mmol) in dioxane (50 ml) are heated at 85° C. overnight. The mixture is evaporated under vacuum and the residue purified by flash column chromatography (70% dichloromethane/hexane) to give the title compound as a bright orange solid (2.02 g, 82%), [M+H]+=316.
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:28]=[C:29]2[S:33][C:32](SC)=[N:31][C:30]2=[O:36])[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:16])[CH3:15]>C(O)C>[CH3:16][C:14]([C:17]1[CH:18]=[C:19]([CH:28]=[C:29]2[S:33][C:32]([N:5]([OH:6])[CH:2]([CH3:4])[CH3:3])=[N:31][C:30]2=[O:36])[CH:20]=[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:22]=1[OH:23])([CH3:13])[CH3:15]
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Reactant: CC(C)NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(C)N(O)C1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A mixture of N-isopropylhydroxylamine hydrochloride (5.5 g, 0.049 mole), potassium-t-butoxide (4.83 g, 0.043 mole), and ethanol (500 mL) is stirred at room temperature for 15 minutes. 5-[(3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene]-2-(methylthio)-4(5H)-thiazolone (7.27 g, 0.02 mole) is then added and the mixture is refluxed with stirring for six hours. After removal of the solvent under reduced pressure, the cooled reaction mixture is poured into a mixture of ice-water containing 1N hydrochloric acid and extracted with ether. The organic layer is washed with water, dried, and the solvent is evaporated to give 7.7 g of a residue. The residue is flash chromatographed on silica gel (202 g), eluting first with methylene chloride and then with methylene chloride-methanol (9:1) to give 7.0 g purified product. It is recrystallized from methylene chloride-ethyl acetate-ether to give 4.2 g (54%) of pure 5-[[3,5-Bis-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-[hydroxy(1-methylethyl)amino]-4(5H)-thiazolidinone, (Z)-, mp 208° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)n2)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Temperature: 40 °C
Yield: 78.3 %

Procedure:
Add 2,4,6-trifluorobenzoyl chloride (1.64 g, 8.42 mmol) to a solution of 4-(6-amino-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (preparation 71, 2.06 g, 7.02 mmol) in triethylamine (1.066 g, 1.5 mL, 10.53 mmol) and THF (70 mL). Heat at 40° C. overnight. Dilute the mixture with ethyl acetate, wash with 0.1 N HCl, saturated NaHCO3 solution and saturated NaCl solution sequentially. Dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 14% ethyl acetate in hexanes provides 2.482 g (78%) of the title compound: mass spectrum (ion spray): m/z=452.1 (M+1); 1H NMR (CDCl3, ppm): 8.01 (s, br, 1H), 7.87 (d, br, 1H), 7.67 (t, 1H), 6.81 (m, 2H), 6.55 (d, 1H), 5.11 (m, 1H), 3.73 (m, 2H), 3.33 (m, 2H), 1.93 (m, 2H), 1.74 (m 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH2:31][CH2:32][NH2:33]>>[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH2:31][CH2:32][NH:33][C:18]([C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:17])[N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:8](=[O:21])[NH:9]2)=[CH:14][CH:13]=1)=[O:20]
Reactant: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Reactant: CC1CCCCN1CCN
Product: CC1CCCCN1CCNC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1

Procedure:
15 mg (12%) of the target compound was obtained in the same manner of Example 1, using 3-(4-chloro-benzyl)-2,4-dioxoquinazoline-7-carboxylic acid (90 mg, 0.272 mol) obtained in Example 1 and 2-(2-methyl-piperidine-1-yl)-ethylamine (77 mL, 0.544 mmol).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1(=[O:13])[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7]1>N1C=CC=CC=1>[CH3:4][CH:3]1[CH:2]=[CH:1][C:7]2[C:6](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]=2[O:12]1
Reactant: C/C=C/C=O
Reactant: O=C1CCCC(=O)C1
Solvent: c1ccncc1
Product: CC1C=CC2=C(CCCC2=O)O1
Temperature: 25 °C
Yield: 33 %

Procedure:
A solution of crotonaldehyde (72.74 g, 1.04 mol) in 500 mL of pyridine was added to 1,3-cyclohexanedione (100 g, 0.892 mol) in 500 mL of pyridine and the mixture was heated to reflux under a nitrogen atmosphere for 1 hour. The mixture was cooled to room temperature and then filtered through magnesium sulfate (328 g). The filtrate was concentrated to dryness and the residue was partitioned between water and diethyl ether. The aqueous phase was extracted with diethyl ether and the combined diethyl ether layers were washed with 10% hydrochloric acid (3×150 mL). The diethyl ether layer was then washed with water to neutrality, dried (MgSO4), filtered and the filtrate concentrated to dryness. The residue was purified by Kugelrohr distillation (bp 109°-112° C. (1 to 2 mm)) to give 2-methyl-5,6,7,8-tetrahydro-2H-1-benzopyran-5-one (48.2 g, 0.294 mol) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=1.FC1C=C(F)C=CC=1OC1C([C:36]2[CH:37]=[C:38]([O:44][CH3:45])[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=2)=NC(CS(C)(=O)=O)=NC=1>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:36]2[CH:37]=[C:38]([O:44][CH3:45])[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=2)=[N:3][C:4]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:5][CH:6]=1
Reactant: COc1cc(-c2nc(CS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O
Reactant: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Product: COc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O

Procedure:
The title compound of Example 149, step 3 was reacted with 3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (see Example 146, step 3) in a manner similar to Example 149, step 4 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.35 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.12-7.08 (m, 1H), 7.08-7.04 (m, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 3.38 (s, 3H). LCMS: 423.9 (M+1)+
Reaction SMILES: [N:1]([C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+:2]=[N-:3].[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:30][CH3:31]>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:29]([C:30]1[N:3]=[N:2][N:1]([C@@H:4]2[NH:7][C:6](=[O:8])[C@H:5]2[NH:9][C:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:31]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)CC
Reactant: [N-]=[N+]=N[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn([C@@H]2NC(=O)[C@H]2NC(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Yield: 51.4 %

Procedure:
To a solution of 2.0 g of (3S,4S)-4-azido-3-tritylamino-2-azetidinone in 40 ml of toluene is added 1.33 g of ethyl propionate, and the mixture is refluxed for one hour and then cooled. The resulting crystalline is collected by filtration and dried to give 1.3 g of (3S,4S)-4-[4-(ethoxycarbonyl)-1,2,3-triazol-1-yl]-3-tritylamino-2-azetidinone.
Reaction SMILES: [O:1]=[C:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[BH4-].[Na+]>>[OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1
Reactant: O=C(CCC1CCC(=O)N1)Cc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCC(CCC(O)Cc2cccc(C(F)(F)F)c2)N1
Yield: 86 %

Procedure:
Analogous to the procedure described for Example 1A, Step B, 5-[3-oxo-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (1.37 g, 4.59 mmol) was reduced with NaBH4 (174 mg) at 0° C. over 2 h. Purification by medium pressure chromatography (2% MeOH in CH2Cl2) provided 5-[3-hydroxy-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (1.19 g). 1H NMR (CDCl3) δ7.42 (m, 4H), 6.26 (m, 1H), 3.82 (m, 1H), 3.65 (m, 1H), 2.84 (m, 1H), 2.72 (m, 1H), 2.27 (m, 3H), 1.86 (m, 1H), 1.75–1.42 (m, 5H); MS 302.2 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=[O:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: COC(=O)c1ccc(-c2ccc(C=O)cc2OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(CO)cc2OC)cc1

Procedure:
A solution of Example 122I (270 mg, 0.5 mmol), and sodium borohydride (80 mg) in methanol (5 mL) at room temperature was stirred for 30 minutes, diluted with ethyl acetate (70 mL), washed with water (20 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated to provide the desired product.