Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][NH:3]1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C.C(OCC)(=O)C>[CH:15]1([NH:18][C:12]([CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[NH:3][CH2:4]2)=[O:14])[CH2:17][CH2:16]1
Reactant: O=C(O)c1c[nH]c(=O)c2ccccc12
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1NCC(C(=O)NC2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.50 g (12.30 mmol) of methyl 1-oxo-1,2-dihydroisoquinoline-4-carboxylate and 1.30 g of 10% strength palladium on carbon were suspended in an autoclave, and the mixture was hydrogenated at 70° C. and 20 bar of hydrogen for 4 h. The autoclave was vented, after which the catalyst was filtered off and the solvent was removed under reduced pressure, and the crude product was purified by chromatography (ethyl acetate: n-heptane 2:1). This gave 2.28 g (88%) of the desired methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate. 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.10 (d, 1H), 7.52 (t, 1H), 7.44 (t, 1H), 7.31 (d, 1H), 6.17 (br. s, 1H), 3.98 (dt, 1H), 3.88 (m, 1H), 3.29 (dd, 1H), 3.71 (s, 3H). 2.28 g (11.11 mmol) of methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate were dissolved in 20 ml of tetrahydrofuran, and 20 ml of 1 N aqueous sodium hydroxide solution were added. The solution was stirred at room temperature for 8 h, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and 1 N hydrochloric acid. The phases were separated, the organic phase was dried over magnesium sulphate and the solvent was removed under reduced pressure. In this manner, 2.12 g (94% of theory) of the desired 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid were obtained. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 12.65 (br. s, 1H), 7.94 (d, 1H), 7.83 (d, 1H), 7.51 (t, 1H), 7.41-7.35 (m, 2H), 3.89 (t, 1H), 3.68-3.54 (m, 2H). 0.200 g (1.046 mmol) of 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid were dissolved in 10 ml of acetonitrile, and 0.109 ml (1.569 mmol) of cyclopropylamine, 0.170 g (1.255 mmol) of 1-hydroxy-1H-benzotriazole and 0.221 g (1.151 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The solution was stirred at room temperature for 8 h, diluted with ethyl acetate and the organic phase was extracted initially with saturated sodium bicarbonate solution and then with 1 N hydrochloric acid.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([CH2:26][N+:27]#[C-])(C1C=CC(C)=CC=1)(=O)=O.C(O)C.CC(C)([O-])C.[K+]>COCCOC>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:26]#[N:27])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-benzoyl-4-piperidone (2.0 g, 9.8 mmol), tosylmethyl isocyanide (2.5 g, 12.8 mmol) and ethanol (1.0 mL, 17.1 mmol) in 30 mL DME was cooled in an ethanol/ice bath, and potassium tert-butoxide was added at such a rate to maintain the reaction temperature at <10° C. The cold bath was removed, and the reaction was allowed to stir overnight at room temperature. The solids were removed by filtration, rinsed with DME, and the filtrate was evaporated. The residue was dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered through silica gel, and concentrated to give 2.14 g (66%) of a slightly yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]2[S:21](=[O:23])(=[O:22])[N:20]([C:24](=[CH2:26])C)[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C[O:30]CC1.O>C(OCC)(=O)C.O=[Os](=O)(=O)=O>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]2[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH:26]=[O:30])[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C1CCOC1
Reactant: C=C(C)N1CCCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)S1(=O)=O
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCC2CCCN(CC=O)S2(=O)=O)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 89 (0.50 g, 1.29 mmol), THF (16 mL), H2O (12 mL), and NaIO4 (0.69 g, 3.2 mmol) was added OsO4 (1 mL, 0.1 mmol; 2.5%/tert-butanol) to effect a white precipitate. After 3.0 h, the reaction mixture was diluted with ethyl acetate and washed with H2O, 5% KHSO4, sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give aldehyde 90 as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CCN(C(C)C)C(C)C>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2cccc(OC3CCOCC3)c2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc2cccc(OC3CCOCC3)c2n1
Reaction time: 4 h
Yield: 56.4 %

Procedure:
To a mixture of 2,4-dichloro-8-(tetrahydro-2H-pyran-4-yloxy)quinazoline (4 g, 13.4 mmol), DIPEA (2.07 g, 16.8 mmol) and Pd/C (0.4 g, 10%) in ethyl acetate (10 mL) was stirred under 1 atm of H2 for 4 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The mixture was filtered through a Celite pad, and the filtrate was concentrate in vacuo. The residue was purified by chromatography (petroleum ether:ethyl acetate=20:1, 10:1) to give the title compound (2 g, 57%) as a light yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.789 (d, 1H), 7.551 (t, 1H), 7.317 (d, 1H), 4.723 (m, 1H), 4.038 (m, 2H), 3.556 (m, 2H), 2.068 (m, 2H), 1.950 (m, 2H)
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3S(C)(=O)=O)cc2=O)n1
Yield: 54 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2-methanesulfonyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 48) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methanesulfonyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid (0.74 g, 54%); ES+-HRMS m/e calcd for C26H33N5O6S [M+Na+] 566.2044 found 566.2045. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.10 (m, 1H), 1.28-1.76 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.36 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.48 (dd, J=4.4, J=10.9 Hz, 1H), 5.96 (d, J=2.8 Hz, 1H), 6.41 (d, J=2.2 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.56-7.66 (m, 2H), 7.87 (m, 1H), 8.00 (dd, Jo=8.0 Hz, Jm=1.6 Hz, 1H), 8.21 (d, J=2.8 Hz, 1H), 10.83 (s, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]C)=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:26][CH:25]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 61.1 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.262 g, 1.19 mmol) the acid chloride was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol) and triethylamine (0.242 g, 2.39 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-octylbenzamide (0.220 g, 69% yield). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, 2H), δ 7.37 (t, 1H), δ 7.17 (d, 2H), 63.56 (q, 2H), δ 3.44 (t, 2H), δ 2.59 (t, 2H), δ 1.58 (m, 2H), δ 1.27 (m, 10H), 60.86 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.4, 147.3, 131.7, 128.8, 127.4, 50.9, 39.7, 36.1, 32.1, 31.5, 29.7, 29.5, 29.5, 22.9, 14.3 ppm; HRMS (ESI) calcd for C17H28N4O (M+) 302.2107. found 302.2104.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:25][CH:26]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)=[N:11][N:12]=1.[CH3:31][NH2:32]>C1COCC1.CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:25][CH:26]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:32][CH3:31])=[CH:15][CH:14]=2)=[N:11][N:12]=1
Reactant: CCC(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Reactant: CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccc(CNC)cc4)o3)n2)CC1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A solution of 1-[4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]propan-1-one (20 mg, 0.04 mmol) and a solution of methanamine (107 μL of 2 M, 0.21 mmol) in THF was heated at 65° C. for 6 h. The reaction mixture was allowed to cool to room temperature and the solvents were evaporated under reduced pressure. The crude material obtained was dissolved in DMF (1 mL), filtered and purified by mass directed reverse phase LC/MS (1-99% ACN/H2O (5 mM HCl)) to yield 1-[4-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]propan-1-one (9 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 2H), 8.58 (s, 1H), 8.18 (d, J=7.7 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.63 (s, 2H), 6.66 (s, 1H), 4.30-4.13 (m, 4H), 3.70 (dt, J=16.2, 5.4 Hz, 2H), 2.71 (s, 1H), 2.59 (t, J=5.2 Hz, 4H), 2.41 (dt, J=21.8, 7.3 Hz, 2H), 1.03 (q, J=7.0 Hz, 3H). LC/MS m/z 420.5 [M+H]+.
Reaction SMILES: C1(C[NH:8][CH:9]([C@:18]2([CH2:33][OH:34])[O:22][C@@H:21]([N:23]3[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]3=[O:25])[CH2:20][C@@H:19]2[OH:32])NCC2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[NH2:8][CH2:9][C@:18]1([CH2:33][OH:34])[O:22][C@@H:21]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:20][C@@H:19]1[OH:32]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@](CO)(C(NCc3ccccc3)NCc3ccccc3)O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
4′-C-(1,1′-diphenylmethylaminomethyl)thymidine (3) (0.65 g, 1.5 mmol) was dissolved in absolute ethanol (50 mL). Cyctohexene (12 mL), glacial acetic acid (5 mL) and 5%-palladium on charcoal (0.6 g) were added and the mixture heated under reflux with stirring. The solution was heated for 5 hours and then allowed to cool to ambient temperature. Palladium catalyst was removed by filtration through celite and the filtrate was concentrated under vacuum to give the crude title compound (4), which was used in the following step without further purification. ES +ve m/z 272(M+H)+, 242(M—CH2NH2)+. For an alternative synthesis of this compound see: Wang et al; Tetrahedron Letters 1996, 37, 6515–6518.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(#N)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH:2]2[CH2:3][O:4][C:5]3([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]3)[O:1]2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCC2COC3(CCNCC3)O2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,4-Dioxa-8-azaspiro[4.5]-decane (18.62 g, 130 mmoles) in 50 mL of acetonitrile was stirred under argon and treated with anhydrous potassium carbonate (27.60 g, 200 mmoles). The mixture was cooled to 0° C. and 2-(4-nitrophenyl)ethylbromide (23.01 g, 100 mmoles) was added in one portion. After 10 minutes, the ice bath was removed and the reaction was stirred for 14 hrs at room temperature. The mixture was diluted with 220 mL of ethyl acetate and 200 mL of water. The aqueous phase was separated, the organic phase washed with water (3×100 mL), and brine (2×50 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give 28.60 g (98%) of N(2-(4-nitrophenyl)ethyl-1,4-dioxa-8-azaspiro[4.5]-decane as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11](OCC)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(CCO)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (6-nitro-3-pyridinyl)acetate (468 mg, 2.60 mmol) in tetrahydrofuran was added LiAlH4 and stirred for 2 h at room temperature. The reaction was quenched with saturated 25% NH3 aqueous solution and the precipitate was removed. The filtrate was concentrated to give a title compound as yellow oil.
Reaction SMILES: CN(C)C=O.N(OC(C)(C)C)=O.Cl.N[C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][C:42]=1[N:43]1[CH:47]=[N:46][CH:45]=[N:44]1)[C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]([C:28]([F:37])([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])=[CH:23][C:22]=1[CH2:38][CH3:39])=[O:19]>O>[CH2:38]([C:22]1[CH:23]=[C:24]([C:28]([F:37])([C:33]([F:34])([F:35])[F:36])[C:29]([F:31])([F:32])[F:30])[CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:18](=[O:19])[C:17]1[CH:40]=[CH:41][C:42]([N:43]2[CH:47]=[N:46][CH:45]=[N:44]2)=[CH:15][CH:16]=1)[CH3:39]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(-n2cncn2)c(N)c1
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(-n2cncn2)cc1
Temperature: 65 °C
Yield: 64 %

Procedure:
N,N-dimethylformamide (3 ml) was heated to 65° C. and added with tert-butyl nitrite (0.15 g). To the solution, an N,N-dimethylformamide solution (2 ml) in which 3-amino-N-[2-ethyl-4-(1,1,1,2,3, 3,3-heptafluoropropan-2-yl)-6-methylphenyl]-4-(1H-1,2,4-triazol-1-yl) benzamide (0.5 g) has been dissolved was slowly added dropwise, while maintaining the temperature of 65° C. After confirming that no more gas is generated, the mixture was adjusted to room temperature and added with a mixture including 2N hydrochloric acid and a small amount of ice. The mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with 2N hydrochloric acid, and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-4-(1H-1,2,4-triazol-1-yl)benzamide (0.31 g, yield 61%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:12][C:13]([Cl:30])([Cl:29])[C:14]([N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=2)[CH2:17]1)=[O:15]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:30][C:13]([Cl:12])([Cl:29])[C:14]([N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([S:25]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)(=[O:27])=[O:26])[CH:22]=2)[CH2:17]1)=[O:15]
Reactant: O=C(N1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(Cl)(Cl)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(N1Cc2ccc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)cc2C1)C(Cl)(Cl)Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 70.7 %

Procedure:
To a solution of 4-trifluoromethyl aniline (213 μL, 1.70 mmol) in pyridine (270 μL) was added 2-(trichloroacetyl)-2,3-dihydro-1 H-isoindole-5-sulfonyl chloride (617 mg, 1.70 mmol) at room temperature, and the mixture was stirred at 60° C. for 1.5 hr. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with 1 mol/L hydrochloric acid, brine and water. The organic layer was dried over anhydrous sodium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to afford the title compound as a colorless powder (586 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[O:14]([C:21]([N:23]1[CH2:28][CH:27]=[C:26](OS(C(F)(F)F)(=O)=O)[CH2:25][CH:24]1[CH2:37][CH3:38])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:14]([C:21]([N:23]1[CH2:28][CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:25][CH:24]1[CH2:37][CH3:38])=[O:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCC1CC(OS(=O)(=O)C(F)(F)F)=CCN1C(=O)Oc1ccccc1
Product: CCC1CC(c2ccc3ccccc3c2)=CCN1C(=O)Oc1ccccc1
Yield: 75.3 %

Procedure:
Beginning with 3.62 gm (21.1 mMol) naphthalene-2-boronic acid and 5.70 gm (15.0 mMol) 1-phenoxycarbonyl-2-ethyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine, 4.04 gm (75%) of the desired compound were prepared substantially as described in EXAMPLE 11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:20][C:21]([N:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[N:28][C:27]([NH:33][CH:34]([CH3:36])[CH3:35])=[N:26][C:25]=3[CH2:24]2)=[O:22])[CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][CH2:11][CH2:10][CH:9]([NH:20][C:21]([N:23]1[CH2:32][CH2:31][C:30]2[CH:29]=[N:28][C:27]([NH:33][CH:34]([CH3:36])[CH3:35])=[N:26][C:25]=2[CH2:24]1)=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)NC(CCNC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)NC(CCN)c1ccc(Cl)c(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 300 (29 mg, 0.0540 mmol) in DCM (2 mL) was added TFA (1 mL, 13.0 mmol). The reaction was stirred at RT 30 min, concentrated, and partitioned between DCM (15 mL) and satd. aq. NaHCO3 (15 mL). The phases were separated and the aqueous phase extracted with DCM (15 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified on a preparative SiO2 TLC plate (0.5 mm) developed with MeOH/DCM/NH4OH (9/90/1) to afford 11 mg (47%) of I-110 as a colorless glass: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.63 (br s, 1H), 7.39 (d, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.15 (dd, 1H), 4.97 (m, 1H), 4.83 (d, 1H), 4.38 (m, 2H), 4.10 (m, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 2.89 (br s, 2H), 2.64 (t, 2H) 1.97 (m, 1H), 1.81 (m, 1H), 1.21 (d, 6H); LRMS (APCI pos) m/e=437.1 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:19][C:18](=O)[NH:17][CH2:16][C@H:15]2[CH2:21]CC(O)=O)=[CH:10][CH:9]=1.[O:26]1CCCC1>>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:21][OH:26])=[CH:12][CH:13]=1
Reactant: C1CCOC1
Reactant: O=C(O)CC[C@@H]1CNC(=O)C[C@H]1c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1CNCCC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Lithium aluminum hydride (1.0 molar solution in tetrahydrofuran, 0.75 ml, 0.75 mmol) was added gradually to a solution of trans-4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one (0.25g, 0.836 mmol) in tetrahydrofuran (3 ml) keeping the temperature below 25° C. The reaction mixture was stirred for 1 hour at 25° C., then quenched with 1 drop of water, followed by 2 drops 15% sodium hydroxide solution, and finally with 5 drops of water. Extraction with dichloromethane (35 ml) followed by evaporation of the dichloromethane phase gave 0.21 g of the title compound. Yield 76%.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:18](Cl)(=[O:22])/[CH:19]=[CH:20]/[CH3:21]>C1COCC1>[C:18]([N:8]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])(=[O:22])/[CH:19]=[CH:20]/[CH3:21]
Reactant: C/C=C/C(=O)Cl
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a stirred solution of (4S)-4-phenyl-1,3-oxazolidin-2-one (12 g, 73.5 mmol) in THF (200 mL) was added n-BuLi (2.5 M, 29.4 mL, 73.5 mmol) dropwise via a syringe at −78° C. The resulting reaction mixture was stirred at −78° C. for 5 minutes before (2E)-but-2-enoyl chloride (8.46 mL, 88.0 mmol) was added dropwise via a syringe. The reaction mixture was allowed to warm to ambient temperature and was quenched by addition of brine (100 mL) and water (100 mL). A mixture of ethyl acetate and hexanes (1:2, 100 mL) was added to partition the mixture and the organics were separated, dried over sodium sulfate, filtered and concentrated. The resultant oil was recrystallized in 5% ethyl acetate in hexanes (after seeding with crystals obtained from earlier batches) to yield (4S)-3-[(2E)-but-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one (15.7 g, 67.9 mmol). 1H NMR (500 MHz, CDCl3) δ7.4 (m, 6H), 5.5 (m, 1H) 4.73 (t, J=8.8 Hz, 1H), 4.30 (m, 1H), 1.97 (dd, J=6.8, 1.5 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][NH:13][C:12](=[O:15])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:16]1([CH2:22][CH2:23][CH2:24]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]1([CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:3]=[C:4]([CH:10]3[CH2:14][NH:13][C:12](=[O:15])[CH2:11]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(C2CNC(=O)C2)cc1O
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2CNC(=O)C2)cc1OCCCc1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
A mixture of 4-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidone (42 mg, 0.2 mmol), 3-phenylpropyl bromide (44 mg, 0.22 mmol), potassium carbonate (83 mg, 0.6 mmol) and N,N-dimethylformamide (3 ml) is allowed to stir at 100° C. After 18 hours, the reaction mixture is cooled to 25° C. The solid is filtered off and the filtrate is concentrated under vacuum. The same working up procedure gives 47 mg (72%) of 4-(3-(3-phenylpropoxy)-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 5H), 6.82 (d, J=8.4 Hz, 1H), 6.78 (d, J=12 Hz, 1H), 6.70 (s, 1H), 6.02 (b, 1H), 4.03 (t, J=7.2 Hz, 2H), 3.84 (s, 3H), 3.75 (t, J=8.8 Hz, 1H), 3.63-3.55 (m, 1H), 3.36 (t, J=8.8 Hz, 1H), 2.82 (t, J=8.0 Hz, 2H), 2.71 (dd, J=16.8, 8.8 Hz, 2H), 2.47 (dd, J=16.6, 8.8 Hz), 2.20-2.13 (m, 2H).