Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:10]=[C:11]([CH2:15][C:16](O)=[O:17])[CH:12]=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl.[H][H]>O1CCCC1>[F:1][C:2]([F:19])([F:20])[C:3]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=1)([OH:8])[C:4]([F:5])([F:7])[F:6]
Reactant: [H][H]
Reactant: O=C(O)Cc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Product: OCCc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Yield: 38.9 %

Procedure:
To one liter of 1M borane-tetrahydrofuran complex was added a solution of 100 g (0.33 mole) of 3-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzeneactic acid in 200 ml of tetrahydrofuran. The solution is refluxed for 16 hours under nitrogen. The solution is then refluxed with 400 ml of 6N hydrochloric acid until evolution of hydrogen is complete. The mixture is filtered and evaporated. The residue is refluxed with 500 ml of methanol containing 10 ml of concentrated hydrochloric acid until methyl borate is no longer evolved. The solution is evaporated, and the residue is distilled at 110°-115° (0.7 mm) to give 37 g of 2-{3-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=2)[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:18]1[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(OC)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.544 g, 2.89 mmol) and (5-methoxy-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.648 g, 2.81 mmol) in DMF (40 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (9.8 mL, 9.8 mmol) dropwise over 5 minutes. The mixture was stirred 8 h at room temperature and then heated at 65–70° C. for 15 h. The mixture was cooled to room temperature, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated to ˜30 mL. Upon standing 4 h, a bright red solid precipitated which was isolated by filtration and dried under vacuum at 80–100° C. overnight affording the title compound (0.421 g, 41%). 1H NMR (400 MHz, DMSO-d6) 11.81 (br s, 1H), 11.80 (s, 1H), 8.06 (d, J=3.1 Hz, 1H), 7.58, dd, J=7.5, 1 Hz, 1H), 7.31 (d, J=3 Hz, 1H), 7.22 (d, J=9 Hz, 1H), 6.93 (dd, J=7.5 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 6.53 (dd, J=9, 2.5 Hz, 1H), 6.50 (d, J=3 Hz, 1H), 5.80 (d, J=2.5 Hz, 1H), 3.80 (s, 3H), 2.70 (s, 3H). MS (electrospray, m/z) 372.1 (M++1), 370 (M−−1). HRMS 372.1345 (M++1, calcd for C22H18N3O3 372.1348). Anal. Calcd for C22H17N3O3: C, 71.15; H, 4.61; 11.31. Found: C, 71.05; H, 4.59; N, 11.17.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].[Br-].[C:30]([Zn+])([CH3:33])([CH3:32])[CH3:31]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:31][CH:30]([CH3:33])[CH3:32])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5]
Reactant: CC(C)(C)[Zn+]
Reactant: O=C(Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 73)(75 mg, 0.148 mmol) in THF (1 ml) was added tetrakis(triphenyl-phosphine)palladium (0) (17.1 mg, 0.015 mmol, Aldrich). To the solution was added 0.5 M t-butylzinc bromide in THF (0.6 ml, 0.30 mmol, Aldrich) and the mixture stirred at 80° C. under nitrogen for 3 h. A further amount of tetrakis (triphenylphosphine) palladium (0) (30 mg) and then 0.5 M t-butylzinc bromide in THF (1 ml, 0.5 mmol) was added to the mixture at ambient temperature. The mixture was heated to 80° C. for a further 3 h. The solvent was removed in vacuo and the residue dissolved in 1:1 MeOH:DMSO ml×2 and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a brown gum (12 mg); LCMS: (System 4) MH+=438, tRET=3.47 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:22]([O:24]CC)=[O:23].[OH-].[Li+].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(=O)NCCCOC)cn2)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCCNC(=O)c1ccc(-n2ncc(C(=O)O)c2OC)nc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 99.2 %

Procedure:
Combined ethyl 5-methoxy-1-(5-((3-methoxypropyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (2.4 g, 6.62 mmol) and dioxane (50 mL) and added 1.0 M aq. lithium hydroxide (29.8 mL, 29.8 mmol) and the mixture was stirred at 20° C. for 2 days. The reaction was acidified with 1 N aq. HCl (30 mL) and extracted with chloroform (100 mL then 2×50 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give the title compound (2.195 g, 99% yield) as an off-white solid. MS m/z 335 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.74 (quin, J=6.6 Hz, 2 H) 3.21 (s, 3 H) 3.30 (q, J=6.7 Hz, 2 H) 3.36 (t, J=6.3 Hz, 2 H) 4.10 (s, 3 H) 7.74 (dd, J=8.5, 0.6 Hz, 1 H) 7.94 (s, 1 H) 8.35 (dd, J=8.5, 2.4 Hz, 1 H) 8.72 (t, J=5.6 Hz, 1 H) 8.94 (dd, J=2.4, 0.6 Hz, 1 H) 12.64 (br. s., 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]1>CN(C=O)C>[CH3:41][C:37]1([CH3:42])[CH2:36][CH:35]([CH2:34][CH2:33][N:20]2[C:19]([O:23][CH3:24])=[N:18][C:17]3[C:21]2=[N:22][C:14]([O:13][C@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=3[NH2:25])[CH2:40][CH2:39][O:38]1
Reactant: CC1(C)CC(CCBr)CCO1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
2-{[(1R)-1-Methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate (100 mg, 0.274 mmol) was heated with potassium carbonate (37.8 mg, 0.274 mmol) in dry DMF (2 ml) at 60° C. under nitrogen for 1 hour and then cooled to room temperature. 4-(2-Bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (72.6 mg, 0.328 mmol) was added and the reaction mixture heated at 50° C., for 16 hours. LCMS indicated the reaction to be incomplete and more 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (35 mg) was added, and the reaction stirred at 50° C. for a further 5 hours and then partitioned between water (2 ml) and DCM (5 ml). The aqueous layer was further extracted with DCM (2×5 ml). The combined organic layers were combined and dried by passing through a hydrophobic frit and then evaporated to dryness using a nitrogen blowdown unit. The residue was dissolved in methanol (0.6 ml) and purified by mass directed autopreparation. Evaporation of the product containing fractions under a stream of nitrogen in a blowdown apparatus gave the title compound as a white solid (92 mg).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:27]COC)([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]1)=[O:4].[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43]3([CH3:50])[NH:47][C:46](=[O:48])[NH:45][C:44]3=[O:49])=[CH:42][C:37]=2[CH2:36][CH2:35]1>>[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43]3([CH3:50])[NH:47][C:46](=[O:48])[N:45]([CH2:2][C:3]([N:5]4[CH2:11][CH2:10][CH2:9][N:8]([C:12]5[CH:17]=[CH:16][C:15]([C:18]([OH:27])([C:19]([F:22])([F:20])[F:21])[C:23]([F:26])([F:24])[F:25])=[CH:14][C:13]=5[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]4)=[O:4])[C:44]3=[O:49])=[CH:42][C:37]=2[CH2:36][CH2:35]1
Reactant: CC1(c2ccc3c(c2)CCO3)NC(=O)NC1=O
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CBr)CC1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)CCO4)C2=O)CC1

Procedure:
2-Bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-1,4-diazepan-1-yl)ethanone and 5-(2,3-dihydrobenzofuran-5-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1Cl>COCCOC>[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[O:4][CH2:1][CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: COCOc1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCOc1ccncc1OCOC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
Under nitrogen atmosphere. 2-propen-1-ol (0.002 mol) was added dropwise to a stirred mixture of NaH 60% (0.002 mol) in DME (5ml). The mixture was stirred at room temperature for 15 minutes. A solution of 3-(methoxymethoxy)-4-chloropyridine (0.0017 mol) in DME (5 ml) was added dropwise. The resulting reaction mixture was stirred at reflux overnight. The mixture was washed with water and extracted with ethyl acetate. The organic layer was dried, filtered and evaporated till dryness. The residue was purified by open column chromatography (eluent: hexane/ethyl acetate 3/2; CH2Cl2/2-propanone 90/10; CH2Cl2/MeOH 96/4). The product fractions were collected and the solvent was evaporated, yielding 0.18 g of 3-(methoxymethoxy)-4-(2-propenyloxy)pyridine (intermediate 7).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:12]([C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[F:21])=[C:3]([CH:1]=[O:2])[CH:4]=1)=[O:7]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=O)c1
Temperature: 90 °C
Yield: 100.6 %

Procedure:
To a round bottle flask, was added methyl 3-formyl-4-(trifluoromethylsulfonyloxy)benzoate (6300 mg, 20 mmol), 2-fluoro-5-methoxyphenylboronic acid (10 g, 61 mmol) (commercially available from Aldrich), potassium phosphate tribasic (6.6 mL, 81 mmol) (granular) and tetrakis(triphenylphosphine)palladium (2.3 g, 2.0 mmol). The flask was flushed with nitrogen, DME was added, and the mixture was heated at 90° C. for 6 hours. The reaction mixture was diluted with EtOAc and water. The organic phase was washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to give a residue which was purified by chromatography to give the product as a yellow solid (5.80 g, 100%). MS ESI m/e: 289.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@H:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]([C:18]([OH:20])=O)[CH2:8][N:7]4[CH3:21])=[CH:3]1.P(Cl)(Cl)(Cl)=O.[NH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.[OH-].[NH4+]>CN(C)C=O>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][NH:27][C:18]([C@@H:9]2[CH2:10][C@H:11]3[C@@H:6]([CH2:5][C:4]4[C:17]5[C:16](=[CH:15][CH:14]=[CH:13][C:12]3=5)[N:2]([CH3:1])[CH:3]=4)[N:7]([CH3:21])[CH2:8]2)=[O:20])[CH:30]=1
Reactant: NCc1cccnc1
Reactant: CN1CC(C(=O)O)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1C[C@H](C(=O)NCc2cccnc2)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21
Reaction time: 0.5 h

Procedure:
One gram of 1,6-dimethylergoline-8-carboxylic acid was slurried with 40 ml of dimethylformamide under a nitrogen atmosphere. The mixture was cooled by means of an external ice/acetone bath. To the slurry were added 700 mcl of phosphorous oxychloride in dropwise fashion keeping the temperature below 0° C. After stirring for 30 minutes, 800 mcl of 3-(aminomethyl)pyridine were added. After stirring an additional two hours, the mixture was poured into approximately 200 ml of dilute ammonium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The residue was crystallized from ethyl acetate/hexane to provide 700 mg of the desired title product, m.p. 185°-187° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:4][C:3]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=2[CH3:1])=[CH:13][CH:12]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: O=Cc1ccc(Cl)cc1
Product: Cc1cc(Cl)ccc1N=Cc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
2-Methyl-4-chloroaniline (0.25 mole) and 4-chlorobenzaldehyde (0.25 mole) were ground in a mortar. The mixture was heated, with stirring in a water bath for 1.5 hours. Distillation at reduced pressure gave N-(p-chlorobenzylidene)-2-methyl-4-chloroaniline. Bp. 139° C./0.020 mm.; m.p. 75°-76° C.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](C(CC)(CC)C([O-])([O-])[O-])[CH3:35].C1CCN2C(=NCCC2)CC1>ClCCCl>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][C:25]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[N:1]=[C:34]2[CH3:35])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: COc1cc(-n2c(C)nc3cc(Oc4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1
Temperature: 100 °C

Procedure:
2-Amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide [Example C1] (50 mg, 0.11 mmol) was dissolved in 1,2-dichloroethane (5 ml) and treated with triethylorthoacetate [Aldrich] (2 ml) then heated to 100° C. for 12 h. The mixture was cooled and DBU (0.1 ml) introduced. The solvent was evaporated then the residue purified by flash chromatography on silica gel (eluting with aq. ammonia-methanol-dichloromethane) to obtain the title compound as a white solid;
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[NH:15][C:12]2=[CH:13][N:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.C(O)C>[NH2:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[OH:19])[NH:15][C:12]2=[CH:13][N:14]=1
Reactant: O=C(c1ccccc1)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Product: Nc1cc2cc(C(O)c3ccccc3)[nH]c2cn1

Procedure:
A mixture of [5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methanone (Example 55) (674 mg, 1.61 mmol), ammonium formate (2.04 g, 32.3 mmol) and 10% palladium on carbon (350 mg, 50% by wt.) in methanol (40.2 mL) and ethanol (40.2 mL) was heated under reflux for 1 h. The reaction mixture was filtered through diatomaceous earth to remove the catalyst. After concentration to dryness, the residue was treated with a small amount of methanol (ca. 3 mL) and a precipitate formed. The solid was filtered, rinsed with a small amount of methanol, and collected. Additional material was obtained from Biotage chromatography of the filtrate. This provided (5-amino-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanol (119 mg, 32%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ5.81 (1H, s), 5.94 (1H, s), 6.44 (1H, s), 7.27-7.53 (5H, m), 8.06 (1H, s), 8.20 (1H, s), 10.9 (1H, br s); ESI MS m/z 240 [C14H13N3O+H]+; HPLC (Method A) 89.0% (AUC), tR=14.0 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:29])[C:16]([O:26][CH2:27][CH3:28])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)(Cl)Cl>[CH2:1]([N+:8]1([O-:38])[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:29])[C:16]([O:26][CH2:27][CH3:28])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(C(=O)NC1CCN(Cc2ccccc2)CC1)(c1ccccc1)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(C(=O)NC1CC[N+]([O-])(Cc2ccccc2)CC1)(c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a dissolved solution of N-(1-benzyl-4-piperidinyl)-2-ethoxy-3-methyl-2-phenylbutanamide (invention compound, Compound No. 1) (400 mg, 1.01 mmole) in chloroform (20 ml) was added 70% m-chloroperbenzoic acid (271 mg, 1.1 mmole). The mixture was stirred at room temperature for 3 days. After the reaction was completed, the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure. The residue was purified by a silica gel column to obtain the invention compound (Compound No. 16, 316 mg, 77.0%) were obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH3:19])[C@@H:10]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:20]I>CN(C=O)C.O>[CH3:20][O:12][C:11](=[O:13])[C@H:10]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:19]
Reactant: C[C@H](c1ccc(Cl)c(Cl)c1)[C@@H](OS(C)(=O)=O)C(=O)O
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](OS(C)(=O)=O)[C@H](C)c1ccc(Cl)c(Cl)c1
Reaction time: 12 h

Procedure:
Jones reagent was prepared by mixing chromium (VI) oxide (2.87 g, 28.7 mmol), sulfuric acid (2.44 mL), and water (9.5 mL) for 10 min. The solution was used directly, and was added dropwise to a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butan-1-ol (1.50 g, 4.79 mmol) in acetone (100 mL). After 4 h, isopropanol (9 mL) was added and the mixture was concentrated. Water was added, and the aqueous layer was extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to give the crude acid. To a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butyric acid (1.57 g, 4.80 mmol) in DMF (20 mL) were added KHCO3 (1.44 g, 14.4 mmol) and MeI (0.90 mL, 14.4 mmol). After 12 h, the mixture was diluted with water and extracted with EtOAc (2×), and the combined organic phases were washed with brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography to give 1.13 g (69% over 2 steps) of the desired product. 1H NMR (400 MHz, CDCl3): 7.38 (d, J=8.3, 1H), 7.31 (d, J=2.1, 1H), 7.08 (dd, J=8.3, 2.1, 1H), 5.14 (d, J=4.7, 1H), 3.73 (s, 3H), 3.47-3.43 (m, 1H), 3.07 (s, 3H), 1.43 (d, J=7.2, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(N2CCC(O)CC2)cc1
Temperature: 95 °C

Procedure:
A 2 liter three necked flask fitted with a mechanical stirrer, thermometer and condenser is charged with 180 g of 4-hydroxypiperidine, 74.4 g of 4-fluorobenzaldehyde, 1 ml of Aliquot 336, 750 ml of dimethylsulfoxide and 82.8 g of anhydrous potassium carbonate. The mixture is heated at 95° C. for three days, then the product mixture is cooled and poured into 3 liters of ice water. The resultant solid precipitate is filtered, washed with water, and vacuum dried. The crude product is recrystallized from toluene, m.p. 115°-118° C.
Reaction SMILES: [N:1]([C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][NH:15]1>C1COCC1>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][N:15]1[C:2]([NH:1][C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)c1ccc(N=C=O)nn1
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-isocyanatopyridazine-3-carboxylate (5.26 g, 29.4 mmol) in THF (100 mL), a solution of isoindoline (5.24 g, 4.41 mmol) in THF (50 mL) was added at 0° C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and the precipitate was washed with cold EtOAc and dried in high vacuum to give the title compound as a solid.
Reaction SMILES: C([O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[N:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[N:14]=[C:13]1[CH2:22][N:23]1[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:26]=2[N:25]([CH:32]2[CH2:34][CH2:33]2)[C:24]1=[O:35])(=O)C(C)(C)C.[OH-].[Li+]>C1COCC1.O>[Cl:21][C:17]1[N:16]=[C:15]2[N:14]=[C:13]([CH2:22][N:23]3[C:27]4[CH:28]=[N:29][CH:30]=[CH:31][C:26]=4[N:25]([CH:32]4[CH2:34][CH2:33]4)[C:24]3=[O:35])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][OH:7])[C:20]2=[CH:19][CH:18]=1
Reactant: CC(C)(C)C(=O)OCCCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=c1n(Cc2nc3nc(Cl)ccc3n2CCCCO)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 3 (0.29 g, 0.58 mmol) was dissolved in THF (15 mL) and lithium hydroxide (40 mg, 1.6 mmol) dissolved in water (5 mL) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured in water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography using dichloromethane and methanol. The title compound 14 was isolated as a white powder (200 mg, 80%). m/z=414 (M+H)+.