Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[O:5][C:4]2[C:11]3[C:16]([CH:17]=[CH:18][C:3]1=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[H][H]>[Pd].COCCO>[O:5]1[CH:6]([C:8]([OH:10])=[O:9])[CH2:7][CH2:2][C:3]2[CH:18]=[CH:17][C:16]3[C:11]([C:4]1=2)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: [H][H]
Reactant: O=C(O)c1cc(=O)c2ccc3ccccc3c2o1
Agent: [Pd]
Solvent: COCCO
Product: O=C(O)C1CCc2ccc3ccccc3c2O1
Yield: 61.4 %

Procedure:
A mixture of 4-oxo-4H-naphto[1,2-b]pyran-2-carboxylic acid (12 g) and 2-methoxyethanol (100 ml) was hydrogenated at normal pressure and at room temperature in the presence of palladium on activated carbon 10% (2 g) as a catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 7 g (61.4%) of 3,4-dihydro-2H-naphto[1,2-b]pyran-2-carboxylic acid (interm. 9-a).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[Na+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O-:23])=[O:22])=[CH:16][CH:15]=1.O.CCO>C(OC(=O)C)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17](/[C:20](=[CH:6]\[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])/[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])Cc1ccc(Br)cc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)/C(=C/c1ccccc1[N+](=O)[O-])c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
64.7 g (0.43 mol) of 2-nitrobenzaldehyde and 105.7 g (0.43 mol) of 4-bromophenylacetic acid sodium salt are dissolved in 500 ml of acetic anhydride and stirred at 80° C. for 2 h. When the reaction is complete, the mixture is extended with 1000 ml of water and 750 ml of EtOH and heated to 110° C., and, after 20 min, the orange solid is filtered off with suction, washed with water and MeOH and dried, giving 107 g (71.8%) of a yellow powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[O:1]=[C:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1
Reactant: O=C1CCC(O)C(C(c2ccccc2)c2ccccc2)N1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=C1CCC(=O)C(C(c2ccccc2)c2ccccc2)N1
Reaction time: 4 h
Yield: 85.2 %

Procedure:
To a stirred solution of 2-oxo-5-hydroxy-6-benzhydryl piperidine (18.15 gm, 64.5 mmole) in acetone (150 ml) at -5° C. was added Jones reagent (2.67 M, 94 mmole), and the reaction mixture was further stirred for 4 hrs. At the end of this period, the excess reactant was decomposed with 2-propanol and the solution concentrated under vacuum to half of its volume. The contents of the flask were then dilutes with water (1000 ml) and extracted with methylene chloride (3×1000 ml). the combined organic phases were dried (anhyd. magnesium sulfate) and the methylene chloride was removed under vacuum to afford 2,5-dioxo-6-benzhydrylpiperidine (15.35 gm, 85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:35](OC(=O)C)([F:37])[F:36]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([O:17][CH:35]([F:37])[F:36])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of [3-(4-chlorobenzyl)-8-fluoro-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester (1.0 g), N7N-dimethylformamide (15 mL), potassium carbonate (0.89 g) and acetic acid chlorodifluoromethyl ester (1.1 mL) was stirred at 70° C. for 18 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (4:1 by volume) gave title compound as a white solid, 0.49 g.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]#[CH:36])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:36]#[C:35][CH2:34][CH2:33][N:30]4[CH2:29][CH2:28][CH:27]([CH2:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:32][CH2:31]4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCCN1CCC(Cc2ccccc2)CC1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(C#CCCN3CCC(Cc4ccccc4)CC3)ccc21
Yield: 80.3 %

Procedure:
A mixture of 1-benzenesulfonyl-5-bromoindole (1.34 g, 4 mmol), 4-benzyl-1-(3-butynyl)-piperidine (908 mg, 4 mmol) and tetrakis(triphenylphosphine)palladium (0) (600 mg) is stirred in pyrrolidine (50 mL) at 50° C. under N2 overnight. Most of the pyrrolidine is evaporated and the residue purified by medium-pressure column chromatography on silica gel eluting with 50% increasing to 100% EtOAc/hexanes to give the title compound as a pale yellow oil (1.55 g)
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[S:29]>CC(C)=O>[CH3:26][N:27]([CH3:31])[C:28]([O:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19])=[S:29]
Reactant: Cc1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Reactant: CN(C)C(=S)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2c(c1OC(=S)N(C)C)CCN(C(=O)C(F)(F)F)CC2
Yield: 89.5 %

Procedure:
Dissolve 6-hydroxy-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 3.66 mmol) in acetone (50 mL). Add potassium carbonate (1.517 g, 10.98 mmol) and dimethylthiocarbamoyl chloride (0.904 g, 7.32 mmol). Heat the mixture at reflux overnight. Remove the solvent in vacuo and partition the residue between water and DCM. Dry the organic phase over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a solid (1.18 g, 90%). MS (ES+) m/z: 361 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[N+:10]([C:12]([CH3:23])([CH3:22])[CH2:13][O:14][Si](C(C)(C)C)(C)C)[O-:11].N1C=CC=CC=1.F.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[N+:10]([C:12]([CH3:23])([CH3:22])[CH2:13][OH:14])[O-:11]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)[N+]([O-])=Cc1ccc(F)cc1F
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(CO)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 69.2 %

Procedure:
A solution of α-(2,4-difluorophenyl)-N-[dimethyl(t-butyldimethylsiloxymethyl) methyl]nitrone (688.3 mg, 2.00 mmol) in THF (20 ml) was cooled to 0° C. in ice-water bath. To the mixture was added carefully hydrogen fluoride-pyridine (1 ml). The mixture was gradually warmed to room temperature and stirred for 7 hours. The mixture was added to sat. NaHCO3 aqueous solution and extracted three times with ethyl acetate and dried over MgSO4. The solvent was evaporated and the white crystals were washed with hexane to give the title compound (317.3 mg; 69%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(C(C)C)CC)(C)C.Cl.[CH3:35][NH:36][O:37][CH3:38]>CN(C=O)C.C(OCC)(=O)C>[CH3:38][O:37][N:36]([CH3:35])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
Indazole-3-carboxylic acid (15 g, 0.0925 mol) was dissolved in DMF (40 mL) at room temperature. Carbonyldiimidazole (17 g, 0.104 mol) was added. A solution of diisopropylethylamine (18 mL, 0.104 mol) and N,O-dimethylhydroxylamine HCl (10 g, 0.104 mol) in DMF (10 mL) was added in portions. The reaction was stirred at room temperature overnight. The reaction was taken up in ethyl acetate and washed repeatedly with 2-N HCl, water, and brine. The organic layer was evaporated to a yellow oil, and passed through a pad of silica gel with hexane/ethyl acetate (1:2). The resulting solid was washed with ethyl acetate to give the desired product as a white solid (11.40 g, 0.056 mol).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:5]([O:4][C:2]([NH:12][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1(C(=O)O)CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC1(C(=O)O)CCCC1)OCc1ccccc1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A solution of benzyl chloroformate (0.290 g, 1.1 mmol) in dioxane (2.5 cm3) was added dropwise to a solution of 1-aminocyclopentanecarboxylic acid (Fluka) (0.2 g, 1.54 mmol) and sodium carbonate (0.490 g, 4.64 mmol) in water (5 cm3) at 0° C. Stirring was continued at room temperature overnight and the reaction mixture washed with ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate, dried (Na2SO4), filtered and the solvent removed to afford carbamate 21 (0.253 g, 62%) as an oil which solidified on standing. Carbamate 21 was shown to be a 70:30 mixture of conformers by 1H NMR analysis (the ratio was estimated from the integration of the resonances at δ 5.31 and 7.29-7.40, assigned to the N—H protons of the major and minor conformers, respectively): mp 70-80° C. (lit.1 82-86° C., ethyl acetate, petroleum ether); δH (400 MHz; CDCl3; Me4Si) 1.83 (4H, br s, 2× cyclopentyl-H2), 2.04 (2H, br s, cyclopentyl-H2), 2.20-2.40 (2H, m, cyclopentyl-H2), 5.13 (2H, br s, OCH2Ph), 5.31 (0.7H, br s, N—H) and 7.29-7.40 (5.3H, m, Ph and N—H*); δC (100 MHz; CDCl3) 24.6 (CH2, cyclopentyl-C), 37.5 (CH2, cyclopentyl-C), 66.0 (quat., cyclopentyl-C), 66.8 (CH2, OCH2Ph), 128.0 (CH, Ph), 128.1 (CH, Ph), 128.4 (CH, Ph), 136.1 (quat, Ph), 155.8 (quat., NCO2) and 179.5 (quat., CO2H). * denotes resonance assigned to minor conformer.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[N:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:26].[K+].[K+].OO.O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[N:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]=1[C:11]([NH2:12])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(OCc2ccccc2)cncc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1c(OCc2ccccc2)cncc1OCc1ccccc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
To a mixture of 3,5-bis(benzyloxy)isonicotinonitrile (2.5 g, 7.9 mmol, 1 eq.) and K2CO3 (4.37 g, 31.6 mmol, 4 eq.) in DMSO (10 mL) was added H2O2 (30% in water, 2.0 mL) at rt. The mixture was stirred at rt O/N and added water (50 mL). The solid was collected and dried to give 3,5-bis(benzyloxy)isonicotinamide (2.2 g, 83%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 2H), 7.59-7.33 (m, 10H), 5.83 (s, 2H), 5.25 (s, 4H), 4.81 (s, 2H). LRMS (M+H+) m/z 335.1
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=3)[C:5]=2[N:6]=1.Cl.Cl.[Cl:22][C:23]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>CC(N(C)C)=O.ClCCl>[Cl:19][C:14]1[CH:13]=[C:12]([C:7]2[C:5]3[N:6]=[C:2]([NH:35][CH:32]4[CH2:33][CH2:34][N:29]([C:27]5[CH:26]=[CH:25][N:24]=[C:23]([Cl:22])[CH:28]=5)[CH2:30][CH2:31]4)[S:3][C:4]=3[CH:10]=[C:9]([CH3:11])[CH:8]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Cc1cc(-c2ccc(F)c(Cl)c2)c2nc(Br)sc2c1
Reactant: NC1CCN(c2ccnc(Cl)c2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1cc(-c2ccc(F)c(Cl)c2)c2nc(NC3CCN(c4ccnc(Cl)c4)CC3)sc2c1
Temperature: 175 °C
Yield: 20.5 %

Procedure:
To a solution of 2-bromo-4-(3-chloro-4-fluorophenyl)-6-methylbenzo[d]thiazole (0.06 g, 0.2 mmol) in dimethylacetamide (1 mL) was added 1-(2-chloropyridin-4-yl)piperidin-4-amine dihydrochloride (0.05 g, 0.2 mmol) followed by triethylamine (70 L, 0.5 mmol) and the mixture was heated to 175° C. for 1 h in a microwave. The reaction was then diluted with dichloromethane, washed with water, brine, dried with sodium sulfate and concentrated. The product was purified by preparative HPLC to yield the title compound as light yellow solid (0.02 g, 24%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.[CH:13]([NH:16][CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH:13]([N:16]([CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1)[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)c1ccc(CCl)o1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CN(C(C)C)C(C)C)o1
Temperature: 100 °C
Yield: 56.1 %

Procedure:
In 10 ml of toluene was dissolved 3.0 g (15.9 mmol) of ethyl 5-chloromethyl-2-furancarboxylate, followed by addition of 10 ml (71.5 mmol) of diisopropylamine. The mixture was heated at 100° C. for 48 hours. After cooling, the reaction mixture was filtered to remove the precipitate and the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (chloroform-methanol =20:1) to give 2.26 g (56.1%) of ethyl 5-diisopropylaminomethyl-2-furancarboxylate (Compound f) as light tan-colored oil.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:28][N:35]=[C:31]([CH:32]([CH3:34])[CH3:33])[N:30]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(C)C(N)=NO
Product: CC(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 44A and 76 mg (0.75 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 144 mg (58% of theory)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:17]([CH2:29][CH2:30][CH3:31])=[N:18][C:19]3[C:24]([C:25]=2[C:26]([OH:28])=[O:27])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:45]=[N+:46]=[N-:47])(CCCC)CCCC)CCC.CO>CC1C=CC=CC=1C>[CH2:29]([C:17]1[C:16]([O:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[N:45]=[N:46][NH:47][N:2]=3)=[CH:14][CH:13]=2)=[C:25]([C:26]([OH:28])=[O:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)[CH2:30][CH3:31]
Reactant: CCCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1C
Product: CCCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 253.3 %

Procedure:
A solution of the title E compound of Example 1, 3-[(2'-cyano[1,1'-biphenyl]-4-yl)oxy]-2-propyl-4-quinolinecarboxylic acid (3.9 g, 9.6 mmol) and tri-n-butyltin azide (9.6 g, 28.9 mmol) in o-xylene (3.9 mL) was heated to 108° C. for 48 hours. After cooling to room temperature, methanol (15 mL) was added and the dark brown solution was stirred for 20 minutes. The methanol was removed under vacuum, more methanol was added (15 mL), the reaction mixture was stirred briefly and concentrated again. The residue was dissolved in ethyl acetate (500 mL), washed three times with 1.0M trisodium citrate solution, brine, dried over sodium sulfate, and concentrated to yield a brown, viscous oil (10.98 g). Flash chromatography on silica gel (659 g), eluting with 70:25:5 toluene:acetone:acetic acid yielded the title compound as a light yellow solid 2.14 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:11]([CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:4]=2[N:3]=[CH:2]1.[O:26]([C:33]([NH:35][OH:36])=O)C1C=CC=CC=1>C1COCC1>[OH:36][NH:35][C:33]([N:15]1[CH2:14][CH2:13][CH:12]([N:11]([CH2:10][C:9]2[C:4]3[N:3]=[CH:2][NH:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)[CH2:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16]1)=[O:26]
Reactant: Cc1cccnc1CN(Cc1cccc2[nH]cnc12)C1CCNCC1
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Product: Cc1cccnc1CN(Cc1cccc2[nH]cnc12)C1CCN(C(=O)NO)CC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 55 %

Procedure:
To a THF solution (3 mL) of the amine from above (100 mg, 0.300 mmol) was added N-(Phenoxycarbonyl)hydroxylamine (54.8 mg, 0.360 mmol), and the resultant solution was heated to 80° C. for 7 h and stirred at room temperature for 66 h. The solution was concentrated to dryness and the crude material was purified by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 80:10:10) to afford COMPOUND 288 (49 mg, 55%) as a white solid. 1H NMR (CDCl3) δ 1.36-1.55 (m, 2H), 1.75 (d, 2H, J=11.7 Hz), 2.34 (s, 3H), 2.50-2.74 (m, 3H), 3.92 (s, 2H), 3.95 (d, 2H, J=15 Hz), 4.02 (s, 2H), 6.83 (br s, 1H), 7.04 (d, 1H, J=7.2 Hz), 7.11-7.23 (m, 2H), 7.52 (d, 1H, J=7.2 Hz), 7.74 (d, 1H, J=7.8 Hz), 8.18 (s, 1H), 8.53 (d, 1H, J=4.5 Hz); 13C NMR (CDCl3) δ 18.78, 27.46, 43.88, 52.09, 53.87, 54.58, 56.25, 118.67, 121.91, 122.15, 122.64, 124.55, 132.19, 133.51, 139.04, 141.08, 143.03, 145.87, 157.78, 161.25; ES-MS m/z 395 (M+H). Anal. Calcd. for C21H26N6O.0.5H2O.0.2 CH2Cl2: C, 58.76; H, 6.41; N, 19.21. Found: C, 58.65; H, 6.36; N, 19.19.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O>[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1cc(C(F)(F)F)ccc1C(=O)O
Yield: 99.7 %

Procedure:
2-Nitro-4-trifluoromethyl-benzoic acid (3.07 g, 13.0 mmol) was stirred with Pd/C under hydrogen atmosphere for 2 hrs. The reaction mixture was filtered with celite to remove Pd/C. The filterate was concentrated in vacuo. The residue was extracted with CH2Cl2 (30 ml×3) and H2O (30 ml). The combined organic layer was dried over MgSO4 and then concentrated to yield title compound (2.66 g, 99%).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2C=C[C:27]([C:28]([OH:30])=[O:29])=[C:26](F)[CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.COC(C1[S:49]C(B(O)O)=CC=1)=O>>[NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[S:49][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)c1ccc(B(O)O)s1
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)s6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoic acid using 5-(methoxycarbonyl)thiophen-2-ylboronic acid as the coupling reagent in Step 1. The product was isolated as a white solid (2.7 mg, 44%). LCMS: m/e 536.30 (M+H)+, 2.25 min (method 10). 1H NMR (500 MHz, Acetic) δ 7.77 (d, J=4.0 Hz, 1H), 6.98 (d, J=3.7 Hz, 1H), 5.87 (d, J=4.3 Hz, 1H), 4.88 (s, 1H), 4.75 (s, 1H), 2.79 (td, J=10.5, 6.7 Hz, 1H), 2.35-2.13 (m, 4H), 1.98-1.85 (m, 4H), 1.83-1.07 (m, 14H), 1.77 (s, 3H), 1.19 (s, 3H), 1.14 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Reactant: ClCc1ccc(Cl)cc1
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(Cl)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl)amino]pyrimidine and 4-chlorobenzyl chloride
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]([O:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[O-:14][Mn](=O)(=O)=O.[K+].[OH-].[K+].Cl>O.CO>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:14])=[O:9])[C:5]([O:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCOc1ccc(C)nc1CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCOc1ccc(C)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 500 ml round-bottom flask [6-methyl-3-(propyloxy)-2-pyridinyl]methanol D14 (3.50 g) was suspended in water (16 ml) and KMnO4 (6.10 g, 38.60 mmol) and KOH (1 M aqueous solution, 19 ml, 19 mmol) were added. The mixture was stirred at room temperature for 2 hours. The pH was adjusted to pH=4 by addition of a 1 M aqueous HCl solution and then MeOH (100 ml) was added. The solid was filtered off, volatiles were removed under reduced pressure and the aqueous phase was extracted twice with DCM. The collected organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford the title compound D16 (2 g). MS: (ES/+) m/z: 196 (M+1). C10H13NO2 requires 195. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 12.96 (bs, 1 H), 7.49 (d, 1 H), 7.31 (d, 1 H), 3.98 (t, 2H), 2.40 (s, 3 H), 1.60-1.80 (m, 2 H), 0.96 (t, 3 H).