Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([O:19]C2C=CC([N+]([O-])=O)=CC=2)=O)=[CH:6][CH:5]=1.[NH2:30][C:31]1[C:36]([Cl:37])=[CH:35][N:34]=[CH:33][C:32]=1[Cl:38].[H-].[Na+].C(O)(=O)C>CN(C=O)C.O>[Cl:38][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:37])[C:31]=1[NH:30][C:17]([C:7]1[C:8]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:4]([O:3][CH:2]([F:29])[F:1])=[CH:5][CH:6]=1)=[O:19]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2oc3ccncc3c12
Reactant: Nc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c2oc3ccncc3c12
Reaction time: 0.58 h
Yield: 42.4 %

Procedure:
To a well stirred solution of 4-Nitrophenyl 6-difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (6.0 mg, 0.015 moles) and 4-amino-3,5-dichloropyridine (4.9 mg, 0.030 moles) in DMF (50.0 mL) was added sodium hydride (60% dispersion in mineral oil) (900 mg, 0.0225 moles) at −5° C. and stirred for 30-40 minutes. Excess of DMF was removed under reduce pressure, the residue obtained was diluted with water (500 mL) and acidified to pH 5-6 with acetic acid. The solid obtained was filtered, washed with water and dried to afford crude product (5.6 g). Purification thorough silica gel column using 25 Methanol in chloroform as eluent gave 2.7 g product as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH:13]([CH3:15])[NH:12][CH:11]([CH3:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:17][C:18]1[CH:45]=[CH:44][C:21]([CH2:22][NH:23][C:24]([C:26]2([CH2:39][CH2:40][CH2:41][CH2:42]Br)[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:25])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:24]([C:26]2([CH2:39][CH2:40][CH2:41][CH2:42][N:12]3[CH:11]([CH3:16])[CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)[CH2:14][CH:13]3[CH3:15])[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:25])=[CH:44][CH:45]=1
Reactant: COc1cccc(N2CC(C)NC(C)C2)n1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1cccc(N2CC(C)N(CCCCC3(C(=O)NCc4ccc(F)cc4)c4ccccc4-c4ccccc43)C(C)C2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methoxy-pyridin-2-yl)-3,5-dimethyl-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluorobenzyl-amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19]C(=O)OC(C)(C)C)[C:15]([CH3:18])([CH3:17])[CH3:16])[N:11]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH2:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[N:11]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1

Procedure:
(R)-tert-butyl 1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylcarbamate (5.05 g, 10.7 mmol) was treated with TFA (10 mL) in CH2Cl2 (30 ml). Once the reaction was complete, the reaction was concentrated in vacuo and then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organics were separated, then washed with H2O, brine, then dried over Na2SO4, filtered, and evaporated under reduced pressure to give (R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropan-1-amine which was directly used for the next step without further purification (2.55 g, 64%). LC/MS (uplc) MH+ 375.1, 0.83 min.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.C([Li])CCC.[CH:18](N1CCOCC1)=[O:19].Cl>C1COCC1>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH:18]=[O:19]
Reactant: O=CN1CCOCC1
Reactant: COc1ccc(F)c2c1OCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c2c1OCC2
Temperature: -74 °C
Reaction time: 1 h

Procedure:
To a solution of 665 mg of 4-fluoro-7-methoxy-2,3-dihydrobenzofuran and 740 mg of N,N,N′,N,N″-pentamethyldiethylenetriamine in 15 ml of THF there was added dropwise 1.66 ml of n-butyllithium (2.55 M, hexane solution) at −74° C. The mixture was stirred at −74° C. for 1 hour, and then 500 μl of N-formylmorpholine was added. After further stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture while cooling on ice, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (321 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:29])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1)([CH3:7])[C:3]([O:5]C)=O.[H-].[Na+]>CN(C=O)C>[OH:5][C:3]1[C:2]([CH3:7])([CH3:1])[NH:8][C:9](=[O:29])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)(C)NC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a stirred solution of methyl 2-methyl-2-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetamido)propanoate (5.0 g, 0.01 mol) in DMF (100 mL) was added NaH (913 mg, 0.03 mmol) at 0° C. under an inert atmosphere. The reaction mixture was then stirred for 2 h, diluted with ice water and then extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 4-hydroxy-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (2.0 g, 44%) as a white solid.
Reaction SMILES: C(O)C.[NH:4](C(OCC1C=CC=CC=1)=O)[C@H:5]([C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[CH2:12][CH2:13][CH3:14])=[O:9].[H][H]>[Pd].O>[NH2:4][C@H:5]([C:25]([OH:27])=[O:26])[CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH2:12][CH2:13][CH3:14])=[O:9]
Reactant: CCC[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a mixed solution of ethanol (150 mL) and water (30 mL), Z-Glu(Nva-OBzl)-OBzl (4.05 g) and 5% palladium on carbon (5% palladium/carbon, 0.70 g) was added, and a catalytic reducing reaction was carried out at 50° C. overnight (14 hours) in a hydrogen gas atmosphere. Water (50 mL) was added to the reaction system in small portions during the reaction. The palladium/carbon was removed from the reaction system through filtration and the resulting filtrate was concentrated under reduced pressure. The residue was recrystallized from a small amount of water and ethanol to thus give γ-Glu-Nva (1.50 g) as white crystals. Furthermore, the crystals were dissolved in water (100 mL) followed by the lyophilization of the solution to give γ-Glu-Nva (1.27 g, 5.16 mM) as white powder. The characteristic values thereof are given below:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[C:7]=1/[CH:8]=[N:9]/[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.[Cl-].[NH4+].[Cu]I>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:9]=[CH:8][C:7]=12
Reactant: Fc1ccc(N/N=C/c2c(Br)cncc2Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3c(Br)cncc32)cc1
Temperature: 120 °C

Procedure:
A mixture of N-[1-(3,5-dibromopyridin-4-yl)-meth-(E)-ylidene]-N′-(4-fluorophenyl)-hydrazine (2.0 g, 5.4 mmol), CuI (50.0 mg, 0.260 mmol), trans-N,N′-dimethylcyuclohexane-1,2-diamine (0.200 mL, 1.27 mmol), and K2CO3 (1.4 g, 0.010 mol) in NMP (10 mL) was warmed at 120° C. for 30 minutes. The reaction was monitored by HPLC-MS indicating the desired mass. The mixture was diluted with aqueous ammonium chloride (100 mL) and the resulting solid collected by filtration. The solid was dissolved in hot ethyl acetate (EtOAc), dried over magnesium sulfate, treated with activated carbon, filtered through diatomaceous earth and concentrated. The residue was passed through a pad of silica gel eluting with dichloromethane to afford 4-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O.[NH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:23]([OH:27])[C:24]([NH2:26])=[O:25].O[NH-].O=[N-]>>[NH2:26][C:24](=[O:25])[C:23](=[O:27])[CH:22]([NH:21][C:13]([C@H:8]1[CH2:9][CH2:10][C:11](=[O:12])[N:7]1[CH2:6][C:5]1[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:1])([F:20])[F:19])[CH:4]=1)=[O:15])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1cccc(C(F)(F)F)c1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1cccc(C(F)(F)F)c1

Procedure:
Coupling of (R)-1-(3-trifluoromethyl-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:4]([CH2:15][CH3:16])[C:3]=1[C:17](=[O:20])[CH2:18][CH3:19].C(O)C.[NH2:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]([CH2:15][CH3:16])[C:3]([C:17](=[O:20])[CH2:18][CH3:19])=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([S:25]([NH2:24])(=[O:27])=[O:26])=[CH:29][CH:30]=3)[C:6]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1CC
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1CC
Temperature: 25 °C
Yield: 32.9 %

Procedure:
To the solution of 1-(3-bromo-5-(4-chlorophenyl)-1-ethyl-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 51c, 0.5 g, 1.41 mmol) in a mixture of toluene:ethanol (3:12 ml) was added 4-aminosulfonylbenzene boronic acid (0.34 g, 1.69 mmol) and potassium carbonate (0.48 g, 3.52 mmol) at a temperature of about 25° C. in a sealed tube and a nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 90° C. to 95° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane (2×20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silicagel (100-200 mesh) using 30-35% ethyl acetate in hexanes as an eluent to obtain the title compound (0.2 g, 32.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]([CH3:21])[C:10]=2[CH2:22][CH3:23])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:22]([C:10]1[N:11]([CH3:21])[C:12]2[C:17]([C:18](=[O:19])[C:9]=1[C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)=[CH:16][C:15]([F:20])=[CH:14][CH:13]=2)[CH3:23]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCc1c(-c2cc(F)cc(F)c2)c(=O)c2cc(F)ccc2n1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1c(-c2cc(F)cc(F)c2)c(=O)c2cc(F)ccc2n1C
Temperature: 25 °C

Procedure:
3-(3,5-Difluorophenyl)-2-ethyl-6-fluoro-1-methylquinolin-4(1H)-one (120 mg, 0.38 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (76 mg, 0.7 eq) were suspended in carbon tetrachloride (5 mL). To the mixture was added benzoyl peroxide (9.2 mg, 0.1 eq) and the mixture was heated at reflux for 3 h. After cooling to rt, satd. aq sodium bicarbonate solution (5 mL) was added. The layers were separated and the aq layer was extracted with DCM (3 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concd under reduced pressure to give 2-(1-bromoethyl)-3-(3,5-difluorophenyl)-6-fluoro-1-methylquinolin-4(1H)-one as a yellow solid. Mass Spectrum (ESI) m/e=397 (M+1). The yellow solid was dissolved in DMF (5 mL) and treated with phthalimide potassium salt (140 mg, 2.0 eq) at 60° C. for 4 h. The reaction mixture was partitioned between water and EtOAc, The layers were separated and the aq layer was extracted with EtOAc (10 mL×2). The combined organic layers were washed with water (10 mL×2), brine (10 mL), dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by combiflash on silica gel (DCM/hexane, 0/1 to 1/1) to give 2-(1-(3-(3,5-difluorophenyl)-6-fluoro-1-methyl-4-oxo-1,4-dihydroquinolin-2-yl)ethyl)isoindoline-1,3-dione as a white solid. Mass Spectrum (ESI) m/e=463 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH2:18])=[O:17])(C)C.O.CCOC(C)=O>CO>[C:12]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH2:18])=[O:17])#[CH:11]
Reactant: C[Si](C)(C)C#Cc1cccc(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cccc(C(N)=O)c1
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
Potassium carbonate (1.84 g, 13.3 mmol) was added to a stirred solution of 3-((trimethylsilyl)ethynyl)benzamide (130) (1.45 g, 6.66 mmol) in MeOH (15 mL) at room temperature. The resulting suspension was stirred for 30 minutes then water (100 mL) and EtOAc (100 mL) were added. The resulting precipitate was collected via filtration and after air drying this was suspended in a 1:1 mix of acetone and methanol (15 mL). After sonication the resulting suspension was filtered to give the title compound (I31) (335 mg, 35%) which was used without additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][C:13]#[CH:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:15]([N:17]([CH3:21])[C:18](Cl)=[O:19])[CH3:16]>>[CH3:21][N:17]([CH2:15][CH3:16])[C:18]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][C:13]#[CH:14])[CH2:9]2)=[CH:4][CH:3]=1)=[O:19]
Reactant: CCN(C)C(=O)Cl
Reactant: C#CCN1CCc2ccc(O)cc2C1
Product: C#CCN1CCc2ccc(OC(=O)N(C)CC)cc2C1
Yield: 50 %

Procedure:
7-Hydroxy-N-propargyl-1,2,3,4-tetrahydroisoquinoline (8) was mixed homogeneously with N-ethyl-N-methyl-carbamoyl chloride (10a) and then carried out step (f-1). Purified on a silica gel column (EtOAc/n-hexane=2:1) gave propargyl- and N-Ethyl-N-methyl amino-containing 7-(N-Methyl-N-ethylcarbamoyloxy)-N-propargyl-1,2,3,4-tetrahydroisoquinoline (11a) (Yield 50%). 1H NMR (300 MHz, CDCl3) (NMR, Varian Gemini): δ 7.08 (d, J=8 Hz, 1H, Aryl H), 6.88 (d, J=7 Hz, 1H, Aryl H); 6.80 (s, 1H, Aryl H), 3.76 (s, 2H, Ph-CH2—N), 3.50 (d, J=2 Hz, 2H, N—CH2—CCH), 3.42 (q, J=7 Hz, 2H, N—CH2—CH3), 3.04-2.81 (m, 7H, N—CH3, Ph-CH2—CH2—N), 2.28-2.26 (m, 1H, C≡CH), 1.25-1.15 (m, 3H, N—CH2—CH3); IR (KBr): ν cm−1=3300, 2923, 1715. Fast Atom Bombardment Mass Spectrometry (FABMS) m/z: 273 (M+1) (C16H20N2O2).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH2:32]([NH2:36])[CH:33]([CH3:35])[CH3:34]>>[OH:27][C:23]1[CH:22]=[C:21]([CH:8]2[C:9]3[NH:10][C:11]4[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4)[C:17]=3[CH2:18][C:6]3([CH3:30])[C:5](=[O:31])[N:4]([CH2:3][CH2:2][NH:36][CH2:32][CH:33]([CH3:35])[CH3:34])[C:28](=[O:29])[N:7]23)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: CC(C)CN
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNCC(C)C)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and isobutyl amine as starting materials. MS: m/z (MH+)=477.2
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared from 4-hydroxybenzonitrile and 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate using a method similar to that described for D13.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[N:24]=[CH:25][O:26][C:27]=1[C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[CH:1]1([N:4]([CH:5]2[CH2:6][CH2:7][N:8]([C:11]3[O:15][N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=3)[CH2:9][CH2:10]2)[C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([C:27]3[O:26][CH:25]=[N:24][C:23]=3[CH3:22])=[CH:36][CH:35]=2)[CH2:3][CH2:2]1
Reactant: c1ccc(-c2noc(N3CCC(NC4CC4)CC3)n2)cc1
Reactant: Cc1ncoc1-c1ccc(C(=O)O)cc1
Product: Cc1ncoc1-c1ccc(C(=O)N(C2CC2)C2CCN(c3nc(-c4ccccc4)no3)CC2)cc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 4-(4-methyl-oxazol-5-yl)-benzoic acid following a procedure analogous to that described in Example 17. LC (method 11): tR=3.12 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([F:15])[F:14])=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(Br)nc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
A mixture of 2-bromo-5-hydroxypyridine (1.2 g, 6.9 mmol), sodium chlorodifluoroacetate (2.1 g, 13.8 mmol), and potassium carbonate (1.24 g, 8.97 mmol) in anhydrous DMF (10 ml) was stirred at 80° C. for 20 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was back extracted with EtOAc and the combined organics was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% EtOAc in hexane, to provide 2-bromo-5-(difluoromethoxy)pyridine (0.89 g, 4.0 mmol, 58% yield) as colorless oil. ESI (M+1) 225.8.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:9]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[C:13]([CH2:20]C)[C:12]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])C.C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[NH2:17][C:15]1[CH:14]=[C:13]([CH3:20])[C:12]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[C:11]([CH3:9])[CH:16]=1
Reactant: CCc1cc([N+](=O)[O-])cc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2c(C)cc(N)cc2C)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 27.2 %

Procedure:
A solution of sodium dithionite (772 mg) in water (6 mL) was added to a solution of N-(2,6-diethyl-4-nitro-phenyl)-4-methyl-benzenesulfonamide (309 mg) in tetrahydrofuran (6 mL) and the resulting mixture was stirred at 50° C. for 20 hours. After cooling, the water was saturated with potassium carbonate and extracted with ethyl acetate (2×10 mL). The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 70 mg (25%) of the title compound as a off-white solid. The product was used directly in the following reaction without spectral characterization.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccc2occ(C#N)c(=O)c2c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1ccc2occ(C#N)c(=O)c2c1
Temperature: 25 °C
Yield: 48 %

Procedure:
In carbon tetrachloride (300 ml) was suspended 6-isopropyl-4-oxo-4H-1-benzopyran-3-carbonitrile (10.65 g). To the suspension was added N-bromosuccinimide (8.90 g). The mixture was subjected to reflux for two hours under irradiation of infrared ray lamp (Toshiba, 100 V, 375 WR). The resultant was then cooled to room temperature, followed by removal of insolubles by filtration. The filtrate was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (150 ml), which was washed with water three times, dried and concentrated. The precipitating crystals were collected by filtration to give 6-(1-bromo-1-methylethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile as colorless prisms (7.0 g). Melting point: 115°-117° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].FC(F)(F)S(O[C:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH:22]=1)(=O)=O>>[CH3:32][O:31][C:26]1[CH:27]=[C:28]2[C:23]([CH:22]=[C:21]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[CH2:30][CH2:29]2)=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Product: COc1ccc2c(c1)CCC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 1-bromo-2-nitro-4-trifluoromethylbenzene according to an analogous synthetic method to Preparation Example 76, tributyl(2-nitro-4-rifluoromethylphenyl)tin (7.4 g) and 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (2.2 g) were used according to an analogous synthetic method to Preparation Example 77 to provide 7-methoxy-3-(2-nitro-4-trifluoromethylphenyl)-1,2-dihydronaphthalene (1.5 g). The total amount of this compound was used according to an analogous synthetic method to Example 30 to provide the title compound (1.0 g).