Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.S(=O)(=O)(O)O.[Cl:7][CH2:8][CH:9]([OH:15])[CH2:10][O:11][CH2:12][CH2:13][CH3:14]>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6].[Cr]>[Cl:7][CH2:8][C:9]([CH2:10][O:11][CH2:12][CH2:13][CH3:14])=[O:15]
Reactant: CCCOCC(O)CCl
Agent: [Cr+6]
Agent: [Cr]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCCOCC(=O)CCl
Reaction time: 4 h
Yield: 94.7 %

Procedure:
8N Jones'reagent [30 ml.; prepared by mixing chromium trioxide (8.0 g.), water (15 ml.) and concentrated sulphuric acid (7.5 ml.) and then dilution with water to 30 ml. volume] was added dropwise to a stirred solution of 1-chloro-2-hydroxy-3-propoxypropane (9.1 g.) in acetone (30 ml.) over a period of 30 minutes, keeping the reaction temperature at 20° C. The mixture was then stirred for 4 hours, and then sufficient water to dissolve the precipitated chromium salts was added. The mixture was extracted three times with diethyl ether and the ether extracts dried over sodium sulphate, concentrated under reduced pressure, redried, and reconcentrated to give crude 1-chloro-3-propoxyacetone (8.5 g.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:14][CH2:13][C:12](=O)[CH2:11]2)=[CH:2]1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][CH:12]1[CH2:13][CH2:14][CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)C1
Reactant: NCc1ccccc1
Product: c1ccc(CNC2CCC(c3c[nH]c4ccccc34)C2)cc1
Yield: 107.9 %

Procedure:
This compound was prepared in similar manner as for Intermediate 17, using 3-(1H-indol-3-yl)-cyclopentanone (3.0 g, 15 mmol) and benzylamine (1.95 g, 18 mmol) to give 4.7 g of the desired product as a mixture of cis and trans isomers, which were separated by flash chromatography to afford 0.6 g of the cis isomer (first eluting) and 1.0 g of the trans isomer.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=2)[C:12]=1[CH3:13])=[O:7])C>O>[Cl:20][C:19]1[C:14]([N:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]2)=[N:15][CH:16]=[C:17]([Cl:21])[CH:18]=1
Reactant: CCOC(=O)c1cnn(-c2ncc(Cl)cc2Cl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1ncc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
4N Aqueous solution of sodium hydroxide (10 ml) and water (10 ml) were added to 1-(3,5-dichloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g) and stirred at 80° C. for 2.5 hours. The reaction solution was washed with ethyl acetate and 1N hydrochloric acid aqueous solution was added to the aqueous layer at 0° C. The precipitated solid was collected by filtration and washed with water to give the titled compound (680 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20]C=3)[N:12]=[N:11]2)[S:5][C:6]=1[C:7]([OH:9])=O.CC1N=C(N2C=C(CC(C3C=CC=CC=3)C)N=N2)SC=1C(O)=O.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][NH2:54])[CH:48]=1>>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:12]=[N:11]2)[S:5][C:6]=1[C:7]([NH:54][CH2:53][C:49]1[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=1)=[O:9]
Reactant: Cc1nc(-n2cc(CCCc3ccccc3)nn2)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(-n2cc(CC(C)c3ccccc3)nn2)sc1C(=O)O
Product: Cc1nc(-n2cc(CCc3ccccc3)nn2)sc1C(=O)NCc1cccnc1
Yield: 25 %

Procedure:
Following the procedure as described in Example 14, making variations as necessary to replace 4-methyl-2-(4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl)thiazole-5-carboxylic acid with 4-methyl-2-(4-(2-phenylpropyl)-1H-1,2,3-triazol-1-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 25% yield: mp 114-116° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59-8.53 (m, 2H), 8.02 (s, 1H), 7.75-7.72 (m, 1H), 7.33-7.18 (m, 6H), 5.57 (m, 1H), 4.64 (d, J=5.9 Hz, 2H), 3.13-3.02 (m, 4H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.2, 155.7, 153.9, 149.0, 148.9, 148.6, 140.5, 135.9, 133.6, 128.5, 128.4, 126.3, 123.8, 123.4, 118.6, 41.7, 35.0, 27.2, 17.5; MS (ES+) m/z 405.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15]>CO>[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: COCCN
Reactant: O=[N+]([O-])c1cnc(Br)cn1
Solvent: CO
Product: COCCNc1cnc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.9 %

Procedure:
A mixture of 2-bromo-5-nitropyrazine (500 mg, 2.45 mmol) and 2-methoxyethylamine (276 mg, 3.67 mmol) in methanol (15 mL) was stirred at 25° C. for 5 h. After such time, the reaction was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/3 to 1/4 hexanes/ethyl acetate) afforded (2-methoxy-ethyl)-(5-nitro-pyrazin-2-yl)-amine (291 mg, 60%) as a yellow solid: mp 116.0–117.3° C.; EI-HRMS m/e calcd for C7H10N4O3 (M+) 198.0753, found 198.0751.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[CH:16]=[O:17])[N:7]([CH3:18])[C:6]=2[CH:19]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[CH2:16][OH:17])[N:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: Cn1c(-c2cnccc2C=O)nc2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(-c2cnccc2CO)nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(6-chloro-1-methyl-1H-benzoimidazol-2-yl)-pyridine-4-carbaldehyde (50 mg, 0.184 mmol) in MeOH (4 mL) at 0° C. was added sodium borohydride (10.44 mg, 0.276 mmol). The mixture was stirred at room temperature for 30 min. The reaction was quenched with water (0.5 mL) and the mixture was concentrated in vacuo. The crude was taken up in MeOH (5 mL) and purified on HPLC using RP18 column and gradient 0.1% aqueous NH4OH in acetonitrile to afford pure product [3-(6-chloro-1-methyl-1H-benzoimidazol-2-yl)-pyridin-4-yl]-methanol as a white color solid. 1H NMR (400 MHz, MeOD) δ ppm 3.76 (s, 3H), 4.64 (s, 2H), 7.38 (dd, J=8.7, 1.9 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.84 (d, J=5.1 Hz, 1H), 8.69 (s, 1H), 8.79 (d, J=5.3 Hz, 1H); HRMS: (ESI) m/z 274.0739 [(M+H)+ Calcd for C14H12ClN3O 274.0747].
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:13]([CH2:19][CH:20]=[CH2:21])[C:14]([O:16]CC)=[O:15])[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[OH-].[Na+].Cl>CCO>[CH3:1][C:2]1[N:3]([CH:13]([CH2:19][CH:20]=[CH2:21])[C:14]([OH:16])=[O:15])[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=1
Reactant: C=CCC(C(=O)OCC)n1c(C)nc(C(F)(F)F)c1C=C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCC(C(=O)O)n1c(C)nc(C(F)(F)F)c1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To ethyl 2-[2-methyl-4-(trifluoromethyl)-5-vinyl-imidazol-1-yl]pent-4-enoate (127 mg, 0.42 mmol) was added EtOH (2 mL) and 5 N NaOH (0.5 mL), and the resulting solution was stirred at room temperature for 1 h. 12 N HCl was added slowly at room temperature until the solution reached pH 2, followed by concentration in vacuo to obtain 2-[2-methyl-4-(trifluoromethyl)-5-vinyl-imidazol-1-yl]pent-4-enoic acid (100 mg, crude) which was used as such in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([CH3:14])[S:13][C:9]=2[CH:8]=1.[OH-].[Na+].Cl>CCO>[CH3:14][C:12]1[S:13][C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:17])=[O:2])[CH:16]=[CH:15][C:10]=2[N:11]=1
Reactant: COC(=O)CCCc1ccc2nc(C)sc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(CCCC(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Next, to a solution of 4-(2-methyl-benzothiazol-6-yl)-butyric acid methyl ester in EtOH (4 mL) is added aqueous 1M NaOH (4 mL) and the mixture is stirred at room temperature for 2 hours. The solution is acidified to pH 2 with aqueous 1M HCl and is extracted with ethyl acetate. The organic layer is washed with water, brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure to give 4-(2-methyl-benzothiazol-6-yl)-butyric acid. MS 236.3 (M+1).
Reaction SMILES: [C:1]([OH:17])(=[O:16])[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:18]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[C:1]([O:17][CH3:18])(=[O:16])[C:2]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CI
Product: COC(=O)C(O)(c1ccccc1)c1ccccc1
Temperature: 21.5 °C
Reaction time: 24 h

Procedure:
90 g (0.394 mol) benzilic acid are dissolved in 900 ml acetonitrile and at 5° C. 109.6 g (0.72 mol) of DBU are added dropwise. After the addition of 204.4 g (1.44 mol) of methyl iodide the mixture is stirred for 24 hours at ambient temperature (about 20-23° C.). The solution is evaporated down to the residue, the residue is taken up in diethyl ether and extracted with water. The organic phase is washed with 5% aqueous sodium carbonate solution and water, dried and the solvent is distilled off. The product is purified by recrystallisation from cyclohexane. Yield: 77.19 g white crystals (=81% of theory) Melting point: 74°-76° C.
Reaction SMILES: Cl.[Br:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH:11]C(=O)C)=[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[CH:4]=1>C(O)(C)C>[Br:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH2:11])=[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[CH:4]=1
Reactant: CCc1ccc(Cc2cc(Br)c(OC)cc2NC(C)=O)cc1
Agent: Cl
Solvent: CC(C)O
Product: CCc1ccc(Cc2cc(Br)c(OC)cc2N)cc1

Procedure:
Half-concentrated hydrochloric acid (5 mL) is added to a solution of N-[4-bromo-2-(4-ethyl-benzyl)-5-methoxy-phenyl]-acetamide (2.8 g) in isopropanol (20 mL). The solution is heated at reflux temperature for 8 h and then concentrated under reduced pressure to remove most of the alcohol. Aqueous NaHCO3 solution is added to the rest and the resulting mixture is extracted twice with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:14][O:15][CH:16]([O:20][CH3:21])N(C)C>>[CH3:14][O:15][CH:16]([O:20][CH3:21])[N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:9][CH2:10]1
Reactant: COC(OC)N(C)C
Reactant: c1cn(CCC2CCNCC2)cn1
Product: COC(OC)N1CCC(CCn2ccnc2)CC1
Yield: 87 %

Procedure:
The free base 4[2-(imidazol-1-yl)ethyl]piperidine (5.1 g, 28.7 mM) and dimethylformamide dimethyl acetal (23 ml) was heated at 100° C. for 6 hours. Removal of the excess of dimethylformamide dimethyl acetal gave 4-[2-(imidazol-1-yl)ethyl]-1-piperidine carboxaldehyde dimethylacetal (6.32 g, 87%) which was dissolved in CH2Cl2 (27 ml) and added to the mixture of 6-aminopenicillanic acid (5.6 g, 258 mM) and diisopropylethylamine (3.41 ml) in CH2Cl2 (100 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr. and room temperature for 3 hrs. The solvent was then removed and water (100 ml) was added. After being washed with ethylacetate, the aqueous solution, acidified to pH 3, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4 -[2-(1H-imidazol-1-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrate hydrochloride (1.8 g, 16% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([N+:11]([O-])=O)=[C:5]2[C:4]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[CH3:23])=[CH:16][CH:15]=2)=[CH:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[C:6]2[N:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[C:4]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[CH3:23])=[CH:16][CH:15]=2)=[CH:3]1
Reactant: CN1CCc2ccc(-c3cn(C)c4nccc([N+](=O)[O-])c34)cc21
Agent: [Pd]
Solvent: CCO
Product: CN1CCc2ccc(-c3cn(C)c4nccc(N)c34)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.3 %

Procedure:
To a stirred suspension of 1-methyl-3-(1-methylindolin-6-yl)-4-nitro-1H-pyrrolo[2,3-b]pyridine (D18) (3.1 g, 10.05 mmol) in ethanol (75 mL) was added 10% palladium on carbon (1.070 g, 1.005 mmol). The mixture was then stirred under hydrogen environment (4 bar) at RT for ca. 24 hours. Extra 10% palladium on carbon (1.070 g, 1.005 mmol) was added and the mixture was stirred under hydrogen (4 bar) at RT for another 24 hours. Additional 10% palladium on carbon (1.070 g, 1.005 mmol) was added and the mixture continued stirring under hydrogen atmosphere at RT for overnight (ca. 16 hours). The reaction mixture was filtered through celite. Washed celite with excess ethanol and the filtrate was concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0-20% MeOH in DCM to give the title compound (1.21 g). LCMS (A): m/z (M+H)+ 279, C17H18N4 requires 278 (acidic).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:13])[C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[CH:8]=[CH:7][CH:6]=2.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][N:22]=2)[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([C:24]1[CH:23]=[N:22][C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]3)=[N:26][CH:25]=1)[NH:3][C:4]2=[O:13]
Reactant: Cc1cccc2c(=O)[nH]c(Cl)cc12
Reactant: CN1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1cccc2c(=O)[nH]c(-c3cnc(N4CCN(C)CC4)nc3)cc12
Yield: 32.1 %

Procedure:
3-Chloro-5-methyl-2H-isoquinolin-1-one (50 mg, 0.26 mmol), 2-(4-methylpiperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (118 mg, 0.39 mmol), K2CO3 (73 mg, 0.52 mmol) and Pd(dppf)Cl2 (10 mg, 0.013 mmol) in DME/EtOH/H2O 4:0.5:1 (2.75 mL) were added to a microwave vial and the reaction mixture purged with N2 for 10 min. The reaction mixture was irradiated using a microwave reactor (300 W, 100° C., 60 min). The reaction mixture was filtered through celite and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with CH2Cl2 and increasing the polarity to 50% MeOH/CH2Cl2. The crude material was trituared with MeOH and washed with isohexane to afford 5-methyl-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-2H-isoquinolin-1-one as an off-white solid (28 mg, 32%).
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])=[O:19])[CH2:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[N:15]1([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:28])([F:27])[F:29])=[O:19])[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Temperature: 75 °C
Yield: 86.2 %

Procedure:
Ammonium formate (15.5 g, 247.126 mmol) was added to (4-benzyl-piperazin-1-yl)-(2-trifluoromethyl-phenyl)-methanone (8.6 g, 24.71 mmol) in MeOH (40 mL). Pd/C (1.8 g in 2 mL water) was then added and the resulting mixture was heated to reflux at 75° C. for 4 hours. The reaction mixture was then filtered through a bed of celite bed and the methanol was removed. EtOAc and water were then added to the residue and the organic layer was extracted, washed with 10% NaOH solution, brine, dried over sodium sulphate, and concentrated to afford 5.5 g (86% yield) of piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1cccc(Br)n1
Product: COc1cccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)n1
Yield: 98 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 2-bromo-6-methoxypyridine, the title compound was formed in 98% yield ! as a white solid, mp 193°-195° C. (dec). free base: 1H NMR (CDCl3, 300 MHz) 7.57 (dd, J=7.6, 7.6 Hz, 1H), 7.23 (m, 4H), 6.94 (m, 5H), 6.63 (d, J=8.0 Hz, 1H), 4.75 (s, 1H), 4.28 (s, 1H), 3.95 (s, 3H), 3.49 (s, 2H), 2.94 (m, 2H), 2.77 (m, 2H), 2.64 (d, J=1.2 Hz, 2H), 2.04 (m, 2H), 1.63 (m, 2H) MS (CI, CH4) m/z 413 (M+1,100), 441 (M+29,12), 395 (18) hydrochloride salt:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]2[CH3:21])=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Br:29])[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[N:7][C:2]([NH:1][C:23]3[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Br:29])[CH:28]=3)=[CH:3][CH:4]=2)[C@@H:9]([CH3:21])[CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 105b (4.0 g, 13.7 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (5.5 g, 20.8 mmol), and cesium carbonate (11 g, 35 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, XantPhos (272 mg, 0.47 mmol) and tris(dibenzylideneacetone)dipalladium(0) (430 mg, 0.47 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (300 mL) and water (300 mL), and filtered. The aqueous layer was separated and extracted with ethyl acetate (150 mL×2). The organic layers were combined, washed with brine (150 mL), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with 50:1 CH2Cl2/methanol to afford 105c as a yellow solid (5.4 g, 83%). LCMS: [M+H]+ 478
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8](N4C(C)=NN(C)C4=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.IC1C=CC2C3N=C(N4C(C)=NN(C)C4=O)SC=3CCOC=2C=1.[CH:47]([C:50]1[NH:51][C:52](=[O:56])[N:53]([CH3:55])[N:54]=1)([CH3:49])[CH3:48].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([N:51]4[C:50]([CH:47]([CH3:49])[CH3:48])=[N:54][N:53]([CH3:55])[C:52]4=[O:56])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CC(C)c1nn(C)c(=O)[nH]1
Reactant: Cc1nn(C)c(=O)n1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cc1nn(C)c(=O)n1-c1nc2c(s1)CCOc1cc(I)ccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1nn(C)c(=O)n1-c1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
The title compound was prepared by a similar method to the mixture of 4-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one and 4-(8-iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one using 5-isopropyl-2-methyl-2,4-dihydro-[1,2,4]triazol-3-one and potassium carbonate. 4-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-5-isopropyl-2-methyl-2,4-dihydro-[1,2,4]triazol-3-one was isolated as a yellow solid (11 mg, 17%). LCMS: RT=5.19 min, [M+H]+=421/423
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[N:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Reactant: BrCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCCCCBr)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a chilled solution of 1-benzyl-4-tert-butoxycarbonylaminopiperidine (6.8 g, 23.4 mmol) in DMF (200 mL) was added sodium hydride (0.6 g, 60% dispersion in mineral oil). After 30 min, 1,7-dibromoheptane was added (12 mL) and the reaction mixture was stirred for 24 h. Another portion of sodium hydride (0.6 g, 60% dispersion in mineral oil) was added and the reaction mixture was stirred for 18 h. The DMF was removed in vacuo and the residue extracted with dichloromethane and 1 N HCl (3×). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give 18.5 g of the crude intermediate. This crude product was purified by silica gel column chromatography, eluting with 1% methanol in dichloromethane. The appropriate fractions were combined and concentrated to afford 4.7 g of the title intermediate (85% pure by HPLC, MS and NMR), which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[C:4]([Br:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:12][C:4]1[CH:5]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=[C:2]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:22])([F:21])[F:23])[CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: CC(=O)Nc1cc(Br)nc(Br)c1
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CC(=O)Nc1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Temperature: 100 °C
Yield: 49.9 %

Procedure:
A microwave tube was charged with a stir bar, N-(2,6-dibromopyridin-4-yl)acetamide (0.95 g, 3.23 mmol), 2-Amino-4-(trifluoromethyl)pyridine (0.576 g, 3.56 mmol), Pd(OAc)2 (0.073 g, 0.323 mmol), Xantphos (0.281 g, 0.485 mmol), and Cs2CO3 (2.106 g, 6.46 mmol). The mixture was vacuum-purged with argon 3 times, then degassed dioxane (6.46 mL) was added. The reaction was sealed and heated to 100° C. for 3 hours, after which time the reaction was cooled to rt, diluted with MeOH (10 mL) and concentrated under reduced pressure. The product was purified by silica gel chromatography using a gradient solvent system of 0-100% EtOAc/Hexanes. The product containing fractions were collected and concentrated to give N-(2-bromo-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-4-yl)acetamide (605 mg, 50%) as a white solid. MS ESI calcd for C13H10BrF3N4O [M+H]+ 375, found 375.