Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([C:29](OC)=[O:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].CO>O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:15][CH:16]=2)[C:8]2[C:25]([CH2:29][OH:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nc2cccc(CO)c2n1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
To a solution of methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (10 g) and NaBH. (2.2 g) in tetrahydrofuran (100 ml) was added dropwise methanol (19 ml) during 80 minutes. The mixture was heated for 27 further hours under reflux, and the reaction mixture was concentrated to dryness. To the concentrate was added water, which was neutralized with conc. HCl. Crystals thus separated were collected by filtration. Recrystallization from methanol afforded colorless needles (8.8 g, 93%), m.p. 203°-204° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]2.[NH3:20]>C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([NH2:20])=[O:19])[NH:12]2
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc2c(Br)cccc2[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Oxalyl chloride (0.9 mL, 10 mmol) was added to a suspension of 4-bromo-1H-indole-2-carboxylic acid (2.1 g, 8.8 mmol) in DCM and the mixture was stirred for 2 h. The solution formed was added drop-wise to a stirring mixture of ammonia (37%, 50 mL) and ice (50 mL). The resulting mixture was allowed to stand for 3 days. The mixture was filtered and the filtrate extracted with EtOAc. The solid from the filtration was dissolved in EtOAc and the organic solutions were combined, dried (MgSO4) and then evaporated to afford the title compound as a brown solid (2.1 g, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]3[CH:20]=[CH:21][S:22][C:18]=3[CH2:17][CH2:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:19]3[CH:20]=[CH:21][S:22][C:18]=3[CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC(C3=NCCc4sccc43)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CN2CCC(c3nccc4sccc34)CC2)cc1
Reaction time: 0.83 h

Procedure:
6.5 g of the compound obtained in Step D and 0.3 g of Pd/C (5%) are heated for 40 minutes at 220-240° C. under nitrogen, and then 0.3 g of Pd/C is added again and the reaction is continued for 50 minutes. After returning to ambient temperature, taking up in ethanol, filtration over Celite and concentration under reduced pressure, chromatography of the residue on silica gel (dichloromethane/methanol: 95/5) enables the expected product to be isolated.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:21])[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][C:9](=[N:11][C:12]2[CH:16]=[CH:15][NH:14][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:16]=[CH:15][NH:14][N:13]=2)[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=Nc2cc[nH]n2)C=C(C(C)(C)C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Nc2cc[nH]n2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1.5 g quantity of 2,6-di-tert-butyl-4-(3-pyrazolylimino)-2,5-cyclohexadien-1-one (Compound 34a) was dissolved in 21 ml of tetrahydrofuran. To the solution was added a solution of 21 g of sodium hydrosulfite in 63 ml of water. The mixture was stirred at room temperature for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The resulting crude product was washed with hexane, giving 1.3 g of title compound (Compound 34) as a colorless solid.
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].O.Cl[CH:20]([CH3:24])[C:21]([NH2:23])=[O:22]>CN(C)C=O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH:20]([CH3:24])[C:21]([NH2:23])=[O:22]
Reactant: CC(Cl)C(N)=O
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a stirred solution containing 5 g (0.22 mole) of 3,5-ditrifluoromethylphenol, 1.6 g (0.024 mole) of 85% potassium hydroxide, 10 ml of water and 200 ml of N,N-dimethylformamide, 0.024 mole of 2-chloropropionamide was added in one portion. The stirred reaction mixture was heated at 120°-130° C. for 46 hours. After cooling to 0° C., 600 g of ice water was added and stirring continued at 0°-10° C. for 30 minutes. The resulting solid was collected by filtration, washed with water until neutral to litmus and air-dried at 25°-30° C. A product with a melting point of 84°-85° C. (determined after recrystallization from heptane) was obtained with a 48% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:20]1[CH2:22][CH2:21]1)([C:17]#[C:18][CH3:19])[OH:16].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C1COCC1>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:23](=[O:24])[O:16][C:15]([CH:20]4[CH2:22][CH2:21]4)([C:17]#[C:18][CH3:19])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC#CC(O)(c1cc(-c2cccc(Cl)c2)ccc1N)C1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC#CC1(C2CC2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-1-propynyl-methanol (0.02 g, 0.064 mmol) and 1,1′-carbonyldiimidazole (0.016 g, 0.096 mmol) in dry THF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. Upon completion of the reaction, the THF was removed and the residue purified via flash chromatography (silica gel, 40% ethyl acetate/hexane) to give 6-(3-chlorophenyl)-4-cyclopropyl-4-prop-1-ynyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.014 g, 56%) as a light yellow solid: mp 178-179° C.; 1H-NMR (DMSO-d6) δ 10.6 (s, 1H), 7.68 (m, 2H), 7.64 (bs, 1H), 7.59 (d, 1H, J=7.72 Hz), 7.49 (t, 1H, J=7.82 Hz), 7.42 (d, 1H, J=7.95 Hz), 7.02 (d, 1H, J=8.0 Hz), 1.86 (s, 3H), 1.66 (m, 1H), 0.82 (m, 1H), 0.66 (m, 3H); MS (ESI) m/z 336 ([M−H]−, 100%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:27]([O-])=O)[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:12]([O:25][CH3:26])[CH:11]=2)=[N:6][CH:7]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[I:1][C:2]1[CH:3]=[C:4]([NH2:27])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:12]([O:25][CH3:26])[CH:11]=2)=[N:6][CH:7]=1
Reactant: COc1cc(CNc2ncc(I)cc2[N+](=O)[O-])ccc1OCc1ccc(C)nc1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(CNc2ncc(I)cc2N)ccc1OCc1ccc(C)nc1
Temperature: 90 °C
Yield: 54.6 %

Procedure:
To a stirred suspension of 5-iodo-N-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amine (13.57 g, 26.80 mmol) in acetic acid (100 mL) was added iron powder (8.10 g, 145.0 mmol). The bright yellow suspension was gradually warmed to 90° C. After 30 min of heating, the dark brown reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (400 mL). The mixture was filtered through Celite with the aid of additional ethyl acetate (100 mL). The filtrate was then washed with water (2×150 mL) and 1N sodium hydroxide solution (2×200 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 6.97 g (55%) of 5-iodo-N2-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)pyridine-2,3-diamine as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([C:15]2[CH:29]=[CH:28][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:20])=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])[CH2:9][OH:10])=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:20])=[CH:28][CH:29]=2)[CH2:12][CH2:13][CH3:14])[CH2:9][O:10][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([F:40])([F:41])[F:42])=[CH:34][CH:33]=2)=[CH:6][CH:7]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(CO)c1ccc(Cl)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Solvent: ClCCl
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(COCc1ccc(OC(F)(F)F)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
The major diastereomer of methyl N-(4-{1-[1-(4-chlorophenyl)-2-hydroxyethyl]butyl}benzoyl)-β-alaninate (EXAMPLE 86, Step C, 80 mg, 0.19 mmol), 1-(bromomethyl)-4-(trifluoromethoxy)benzene (97 mg, 0.38 mmol) and Ag2O (87 mg, 0.38 mmol) in DCM (20 mL) was refluxed overnight. After cooling to room temperature, the mixture was filtered, then the filtrate was concentrated. The resulting residue was purified by PTLC to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=8 Hz, 2H); 7.22-7.31 (m, 6H); 7.05-7.12 (m, 4H); 6.90 (t, J=5.4 Hz, 1H); 4.10-4.24 (m, 2H); 332-3.77 (m, 5H); 3.22-3.29 (m, 2H); 2.94-2.98 (m, 2H); 2.67 (t, J=53 Hz, 2H); 1.32-1.44 (m, 2H); 0.88-0.94 (m, 2H); 0.65 (1, J=7.2 Hz, 3H). MS (M+H)+ 592.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Cl:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[C@H:12]([OH:25])[C@@H:11]1[OH:26]>C(O)(C)C>[OH:14][C@@H:13]1[CH2:12][CH2:11][CH2:7][C@H:6]1[NH:3][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[C:21]=1[N:22]=[CH:23][N:15]2[CH:13]1[C@H:12]([OH:25])[C@H:11]([OH:26])[C@@H:10]([CH2:9][Cl:8])[O:14]1
Reactant: CCN(CC)CC
Reactant: O[C@@H]1[C@H](O)[C@@H](CCl)O[C@H]1n1cnc2c(Cl)ncnc21
Solvent: CC(C)O
Product: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 309.8 %

Procedure:
To a suspension of (R,R)-2-aminopentanol hydrochloride (34.2 g, 249 mmol) in degassed isopropanol (100 ml) and distilled triethylamine (dried over calcium hydride, 95 ml, 69 g, 226 mmol) was added dropwise a solution of (4S,5S,2R,3R)-5-(chloromethyl)-2-(6-chloropurin-9-yl)oxolane-3,4-diol (36.3 g, 118.7 mmol) in 400 ml of isopropanol. The reaction mixture was stirred at room temperature for 30 minutes, and then refluxed (oil bath temperature: ˜80° C.) for 20 hours. After cooling the reaction mixture to ambient temperature, the solvent was removed under reduced pressure, and 1000 ml of water was added to the residue. The suspension was stirred at room temperature for 3.5 hours, and the solid material filtered off, washed with water (1×60 ml and 1×90 ml), and dried under vacuum over P2O5 for 3 days to yield 68.0 g (81%) of 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol as a light brown powder.
Reaction SMILES: [CH2:1]([N:8](C(C(C)(C)C)=O)[C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH2:1]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(Cc1ccccc1)C(=O)C(C)(C)C)C2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](NCc1ccccc1)C2
Reaction time: 7 h
Yield: 73 %

Procedure:
From N-benzyl-N-tert-butylcarbonyl-N-[(2S)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]amine: TFA (0.330 mL, 4.275 mmol) was added to a 0° C. cooled solution of starting material (0.381 g, 0.855 mmol) in CH2Cl2 (15 mL). The reaction was allowed to reach room temperature, and stirred at this temperature for 7 h. It was poured into H2O (20 mL), extracted with CH2Cl2 (1×25 mL) and washed with NaOH aqueous solution (10%, 2×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was flash chromatographed on silica gel (0-5-10% MeOH/CH2Cl2) to give 0.215 g of the title product (Rf=0.2 (10% MeOH/CH2Cl2), yellow oil, 73% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([O:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)[CH:15]=[C:16]([Cl:18])[CH:17]=2)[CH:5]=[CH:4][N:3]=1>[Pt]>[Cl:18][C:16]1[CH:15]=[C:14]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:31])[F:30])[CH:22]=2)[CH:13]=[C:12]([O:11][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=2[NH2:8])[CH:17]=1
Reactant: Nc1nccc(Oc2cc(Cl)cc(NC(=O)c3cccc(OC(F)(F)F)c3)c2)c1[N+](=O)[O-]
Agent: [Pt]
Product: Nc1nccc(Oc2cc(Cl)cc(NC(=O)c3cccc(OC(F)(F)F)c3)c2)c1N
Yield: 98 %

Procedure:
Method D was used with N-(3-(2-Amino-3-nitropyridin-4-yloxy)-5-chlorophenyl)-3-(trifluoromethoxy)benzamide and with 5% sulphided platinum on carbon as catalyst to afford the title compound (92 mg, 98%). 1H NMR δ (DMSO) 4.53 (s, 2H, NH2), 5.66 (s, 2H, NH2), 6.19 (d, 1H, Hpy,5, J=5.5 Hz), 6.82 (t, 1H, Harom, J=2 Hz), 7.31 (d, 1H, Hpy,6, J=5.5 Hz), 7.34 (t, 1H, Harom, J=2 Hz), 7.61 (d, 1H, Harom, J=8 Hz), 7.68 (t, 1H, Harom, J=8 Hz), 7.73 (t, 1H, Harom, J=2 Hz), 7.87 (s, 1H, Harom,2′), 7.97 (d, 1H, Harom, J=8 Hz), 10.51 (s, 1H, CONH). 19F NMR δ (DMSO)-56.37 (s, 3F, CF3). MS m/z 439/441 (M++1).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]([CH3:25])[CH3:24])[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:36])[CH2:27][C:28]1[N:32]=[C:31]([N+:33]([O-])=O)[NH:30][N:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:33][C:31]1[N:32]=[C:28]([CH2:27][C:26]([N:9]2[CH2:10][CH2:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]([CH3:24])[CH3:25])[CH:15]=3)[CH2:13][C@@H:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:36])[NH:29][N:30]=1
Reactant: COc1ccc(N2CCN(C(=O)Cc3n[nH]c([N+](=O)[O-])n3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(N2CCN(C(=O)Cc3nc(N)n[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
A solution of 1-[2(S)benzyl-4-(3-isopropoxy-4-methoxy-phenyl)-piperazin-1-yl]-2-(5-nitro-1H-[1,2,4]triazol-3-yl)-ethanone (Example 248, Compound 336) in MeOH (10 mL) was treated with 10% Palladium on Carbon (200 mg, 0.66 mmol) and ammonium formate (50 mg, 1.66 mmol). The reaction mixture was heated at 65 C for 1 h after which time the reaction was cooled and filtered with the aid of MeOH (20 mL) and EtOAc (20 mL). The organic portion was dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 5% then 10% MeOH/EtOAc as eluant to afford product as an oil. 1H NMR (CDCl3) 12.00-11.90 (br, 1H), 7.39-7.25 (m, 2H), 7.24-7.20 (m, 3H), 6.79 (d, J=8, 1H), 6.50-6.43 (m, 1H), 6.37-6.34 (m, 1H), 6.00-5.90 (br, 2H), 4.50-433 (m, 2H), 3.64 (s, 3H), 3.54-3.33 (m, 4H). 3.22-3.09 (m, 3H), 3.00-2.92 (m, 1H), 2.74-2.60 (m, 1H), 2.55-2.37 (m, 3H), 1.19 (d, J=6.4, 6H). LC/MS (Method B) 3.66 min, [M+1]+ 465. Potency class A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]=[N+]=[N-])=[CH:8][C:7]=1[CH3:16].[H][H]>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][C:7]=1[CH3:16]
Reactant: [H][H]
Reactant: COC(=O)CCc1ccc(CN=[N+]=[N-])cc1C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccc(CN)cc1C
Yield: 78.5 %

Procedure:
A mixture of 3-(4-Azidomethyl-2-methyl-phenyl)-propionic acid methyl ester (0.20 g, 0.86 mmol) and 5% Pd/C (32 mg) in EtOH (50 mL) is exposed to a hydrogen atmosphere (60 psi) at RT overnight. Upon filtering the mixture through Celite, the filtrate is concentrated to yield the title compound (0.14 g, 78%). The material is used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>ClCCl.NCCCCNC(=O)OC(C)(C)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
A solution of 6-benzyloxy-4-chloro-3-nitroquinoline (14.47 g, 46.29 mmol), prepared in Parts A-D of Example 57, and triethylamine (8.4 mL, 60.2 mmol) in dichloromethane (200 mL) was cooled to 0° C. tert-Butyl N-(4-aminobutyl)carbamate (8.71 g, 46.3 mmol) was added; the reaction was stirred for 15 minutes at 0° C. and then allowed to warm to ambient temperature and stirred for five hours. An analysis by TLC indicated the presence of starting material; therefore, additional tert-butyl N-(4-aminobutyl)carbamate (0.5 mL, 2.6 mmol) was added. The reaction was stirred overnight and then washed with water (2×200 mL). The combined washings were extracted with chloroform after the addition of sodium chloride. The combined organic solutions were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate (100 mL). The crystals were isolated by filtration and washed with cold hexanes to provide 17.62 g of tert-butyl [4-(6-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate as an orange powder.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:55])([F:54])[C:14]1[CH:15]=[C:16]([C@H:24]2[O:28][C:27](=[O:29])[N:26]([CH2:30][C:31]3[C:36]([N:37]([CH2:40][C@H:41]4[CH2:46][CH2:45][C@H:44]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43][CH2:42]4)[CH2:38][CH3:39])=[CH:35][CH:34]=[CH:33][N:32]=3)[C@H:25]2[CH3:53])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1>C(Cl)Cl>[F:55][C:13]([F:54])([F:12])[C:14]1[CH:15]=[C:16]([C@H:24]2[O:28][C:27](=[O:29])[N:26]([CH2:30][C:31]3[C:36]([N:37]([CH2:40][C@H:41]4[CH2:46][CH2:45][C@H:44]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43][CH2:42]4)[CH2:38][CH3:39])=[CH:35][CH:34]=[CH:33][N+:32]=3[O-:9])[C@H:25]2[CH3:53])[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc[n+]([O-])c2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Chloroperbenzoic acid (77%, 120 mg, 0.486 mmol) was added to a solution of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate (152.9 mg, 0.243 mmol) in dry CH2Cl2 (10 mL) at 0° C. under N2. After 15 min at 0° C., the reaction was stirred at room temperature for 5 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with saturated Na2SO3 (10 mL) and saturated K2CO3 (2×20 mL). The organic layers were dried (Na2SO4) and concentrated in vacuo to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-1-oxidopyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate. LCMS calc.=646.3; found=646.3 (M+1)+.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:25])([F:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[F:26][C:27]1([F:41])[C:31](=[CH2:32])[CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:28]1=[O:40].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:26][C:27]([F:41])([C:28](=[O:40])[C:23]1[C:18]([C:17]([F:25])([F:24])[F:16])=[N:19][CH:20]=[CH:21][CH:22]=1)[C:31](=[CH2:32])[CH2:30][NH:29][C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39]
Reactant: C=C1CN(C(=O)OC(C)(C)C)C(=O)C1(F)F
Reactant: FC(F)(F)c1ccccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(CNC(=O)OC(C)(C)C)C(F)(F)C(=O)c1cccnc1C(F)(F)F
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2,2,6,6-tetramethylpiperidine (10.2 g) in anhydrous tetrahydrofuran (100 mL) was added dropwise a 1.61 mol/L hexane solution (40.5 mL) of n-butyllithium at −78° C., and the mixture was stirred at the same temperature for 15 min. To the obtained solution was added dropwise a solution of 2-(trifluoromethyl)pyridine (10.2 g) in anhydrous tetrahydrofuran (10 mL) at the same temperature over 30 min, and the mixture was stirred for 2 hr. A solution of tert-butyl 3,3-difluoro-4-methylene-2-oxopyrrolidine-1-carboxylate (7.65 g) in anhydrous tetrahydrofuran (10 mL) solution was added dropwise to the obtained suspension at the same temperature, and the mixture was stirred for 2 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1) to give the title compound as a yellow oil (yield 10.8 g, 87%).