Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:4])#[N:2].C[O-].[Na+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1.[H-].[Na+]>C(#N)C.C(OCC)C>[C:1]([C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])[CH2:19][CH:20]1[CH2:22][CH2:21]1)#[N:2]
Reactant: BrCC1CC1
Reactant: COC(=O)c1cccc(C(C)C#N)c1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)c1cccc(C(C)(C#N)CC2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
To a solution of methyl 3-(1-cyanoethyl)benzoate (1.5 g, 7.9=mol) in acetonitrile (20 mL) were added sodium methoxide (0.95 g, 17 mmol) and (bromomethyl)cyclopropane (1.3 g, 9.5 mmol), and the reaction mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium hydride (60% in oil, 0.7 g, 17 mmol) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with diethyl ether, and washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→40/60) to give the title compound (129 mg, 6.7%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: C1CNC1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CC#N
Product: Nc1nc(N2CCC2)c2nc[nH]c2n1
Temperature: 62 °C
Reaction time: 24 h

Procedure:
2-Amino-6-chloropurine (Sigma, lot #69F4064, 1.0 g, 5.8 mmol) was suspended in 50mL acetonitrile. Azetidine (Aldrich, lot #05606HV, 1.0 g, 17.5 mmol) was added and the reaction stirred at 62° C. for 24 hours. The solvents were evaporated to give a white solid which was recrystallized from methanol to yield 0.71 g (3.7 mmol, 65%); mp=280° C.
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:30])[CH:10]([CH:14]([C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=1)[CH3:15])[C:11](O)=O)[CH3:7].C=O.CCOC(C)=O>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:30])[C:10]([CH:14]([C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[CH:20][CH:21]=1)[CH3:15])=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(C(=O)O)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CCNCC
Solvent: ClCCl
Product: C=C(C(=O)OCC)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
Diethylamine (0.153 mL, 1.473 mmol) was added to a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-malonic acid monoethyl ester (423 mg, 1.2 mmol) and formaldehyde (132 mg, 1.626 mmol, 36% in water) in methylene chloride (2 mL) at 0° C. under argon. The mixture was stirred at room temperature over night. EtOAc was added and the solution was washed with water, NaHCO3 and brine, dried and concentrated under reduced pressure. Flash chromatography (toluene/EtOAc, 3:1) gave 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-acrylic acid ethyl ester (158 mg, 41%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)=[O:3].[CH3:15][O:16][CH2:17][CH2:18][NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:15][O:16][CH2:17][CH2:18][N:19]([CH3:20])[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CNCCOC
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCN(C)c1ccc(C(C)=O)cc1C(F)(F)F
Yield: 81.8 %

Procedure:
A solution of 4-fluoro-3-(trifluoromethyl)acetophenone (500 mg, 2.43 mmol), N-(2-methoxyethyl)methylamine (649 mg, 7.28 mmol) and potassium carbonate (335 mg, 2.43 mmol) in DMSO (6 mL) was stirred for 30 min at 150° C. in the microwave. The cooled reaction mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulphate, filtered and the solvent was removed under reduced pressure. Finally 547 mg (yield: 82%) of the title compound was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8][OH:9])(=[O:3])[CH3:2].O>CN(C)C=O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH:8]=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC=C(C)C=O
Yield: 91.2 %

Procedure:
To a solution of 4-acetoxy-2-methyl-2-buten-1-ol (6.69 g, 46.4 mmol) in dimethylformamide (40 ml) were added 2,2,6,6-tetramethyl-piperidine-1-oxy (0.39 g, 2.32 mmol, 5 mol %) and cuprous chloride (0.48 g, 4.64 mmol, 10 mol %). The mixture was subjected to reaction for 8 hours while bubbling oxygen at a rate of about 100 ml/min. After completion of the reaction, the reaction mixture was poured into ice-cooled water (30 ml) and extracted with ether (100 ml) three times. The extract was dried over anhydrous magnesium sulfate. Evaporation of the ether followed by purification by column chromatography (ethyl acetate-hexane (=1:3)) gave 4-acetoxy-2-methyl-2-buten-1-al (6.02 g, 42.3 mmol; Yield: 91.2%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].[C:19]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCCC1.C(OCC)C>[C:19]([N:29]1[CH2:30][CH2:31][C:32]([C:14]([CH3:16])([CH3:15])[C:13]([OH:18])=[O:17])([OH:35])[CH2:33][CH2:34]1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C(=O)O)C1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51.4 %

Procedure:
To a 100 ml flask maintained under argon are added 2.22 g of diisopropylamine and 15 ml tetrahydrofuran. The contents of the flask are cooled to 0° and are maintained at that temperature. A solution of 1.5 M n-butyllithium (14.7 ml) is added and the solution is stirred for five minutes. Isobutyric acid (0.88 g) is added and the mixture is stirred for 15 minutes at 20°. The mixture is cooled to -70° and a solution of 2.33 g of N-carbobenzyloxy-4-piperidone in 5 ml tetrahydrofuran is added at such a rate that the temperature remains below -50°. The mixture is allowed to warm to room temperature and is poured into 150 ml diethyl ether. This solution is extracted with two 150 ml portions of 1 N hydrochloric acid, 50 ml of water, and 100 ml of 2% sodium hydroxide. The basic layer is acidified with 10 N hydrochloric acid and the resulting mixture is extracted with three 50 ml portions of diethyl ether. Evaporation of the ether affords an oil which is triturated with 50 ml hexane to give 1.65 g 2-(1-carbobenzyloxy-4-hydroxypiperidin-4-yl)-2-methylpropionic acid, an oil.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][C:22](=[O:36])[C:23]4[N:28]([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[N:27]=[C:26]([CH3:35])[C:24]=4[N:25]=3)=[C:16]([O:37][CH3:38])[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:39]C(OC(Cl)C)=O>ClCCCl>[ClH:39].[CH:29]1([N:28]2[C:23]3[C:22](=[O:36])[NH:21][C:20]([C:17]4[CH:18]=[CH:19][C:14]([C:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=5)=[CH:15][C:16]=4[O:37][CH3:38])=[N:25][C:24]=3[C:26]([CH3:35])=[N:27]2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COc1cc(C2=CCN(Cc3ccccc3)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COc1cc(C2=CCNCC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Product: Cl
Yield: 58.9 %

Procedure:
To a 10 ml 1,2-dichloroethane solution of 80 mg (0.16 mmol) of the compound obtained in Example 272, 25.4 μl (0.24 mmol) of 1-chloroethyl chloroformate was added, and the mixture was heated under reflux for 40 minutes. Then, the reaction mixture was returned to room temperature, and concentrated under reduced pressure. Methanol (10 ml) was added to the residue, and the mixture was heated under reflux for 20 minutes. The reaction mixture was returned to room temperature, and concentrated under reduced pressure. Precipitated solids were washed with methanol/ether=1/4 to obtain 43 mg (60%) of the captioned compound.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[CH:4]=[CH:5][C:6]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=4)[N:15]=[CH:14][C:13]=3[CH:12]=[N:11]2)=[N:7][C:8]=1F.[NH:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28]1.CN1CCOCC1.O>CN1CCCC1=O>[F:26][CH:2]([F:1])[C:3]1[C:8]([N:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:28]2)=[N:7][C:6]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=4)[N:15]=[CH:14][C:13]=3[CH:12]=[N:11]2)=[CH:5][CH:4]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)F)c(F)n2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)F)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 1-[5-(difluoromethyl)-6-fluoro-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.0977 mmol; 34.8 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (0.147 mmol; 29.3 mg), and N-Methylmorpholine (0.244 mmol; 24.9 mg; 0.0271 mL) in 1-methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford tert-butyl N-[(3S)-1-[3-(difluoromethyl)-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (˜52.4 mg, 100%).
Reaction SMILES: CN(C)C=O.C(OC(=O)C)(=O)C.[N:13]([CH2:22][C:23]([OH:25])=[O:24])([CH2:18][C:19]([OH:21])=O)[CH2:14][C:15]([OH:17])=[O:16]>N1C=CC=CC=1>[O:24]=[C:23]1[O:25][C:19](=[O:21])[CH2:18][N:13]([CH2:14][C:15]([OH:17])=[O:16])[CH2:22]1
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CN1CC(=O)OC(=O)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottom flask is charged with dimethylformamide 72 g, acetic anhydride 25 g, pyridine 2 g, and nitrilotriacetic acid 38.2 g and the suspension is nitrogen purged for several minutes. The flask is stoppered and the mixture is stirred at room temperature for 3 days. A small amount of unreacted NTA is filtered out. The bulk of the solvent 79 ml is removed in vacuo at a bath temperature of 60°-70° C. The resulting viscous solution is twice roto-vacued after two successive additions of 40 ml dimethylformamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]([O:14][CH2:15][C:16]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[CH:18][C:17]=1[N:31]1[N:40]([CH3:41])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=2)[C:32]1=[O:46])(=[O:13])[CH3:12].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[C:11]([O:14][CH2:15][C:16]1[C:21]([C:2]2[CH:3]=[C:4]([C:8](=[O:9])[NH2:10])[N:5]([CH3:7])[CH:6]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[N:31]1[N:40]([CH3:41])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=2)[C:32]1=[O:46])(=[O:13])[CH3:12]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2CN1C
Reactant: Cn1cc(Br)cc1C(N)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2cc(C(N)=O)n(C)c2)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2CN1C
Temperature: 125 °C
Yield: 15.6 %

Procedure:
In a 10 ml microwave vial, 4-bromo-1-methyl-1H-pyrrole-2-carboxamide (82.5 mg, 406 μmol, Eq: 1.00), [prepared in Example 12, Step 1], 2-(6-tert-butyl-3-methyl-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (200 mg, 406 μmol, Eq: 1.00), X-phos (19.4 mg, 40.6 μmol, Eq: 0.10), and potassium phosphate tribasic (259 mg, 1.22 mmol, Eq: 3.00) were combined with 1,4-dioxane (5 ml) and water (0.5 ml) to give a dark brown suspension. The reaction mixture was stirred while purging with argon for 10 min. The reaction mixture was heated at 125° C. in the microwave for 30 min. The reaction mixture was diluted with 50 mL of dichloromethane and dried (MgSO4). Concentrated in vacuo. The crude material was purified by flash chromatography (silica, 20%-100% ethyl acetate/hexanes gradient) to give 2-(6-tert-butyl-3-methyl-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)-6-(5-carbamoyl-1-methyl-1H-pyrrol-3-yl)benzyl acetate (31 mg, 16%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9H) 1.98 (s, 3H) 2.68 (s, 3H) 3.99 (s, 2H) 5.28 (s, 2H) 6.72 (d, J=1.89 Hz, 1H) 6.84-6.94 (m, 1H) 7.23 (d, J=1.51 Hz, 1H) 7.27-7.52 (m, 5H) 7.61 (s, 1H) 8.04 (d, J=7.93 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.CCN(CC)CC.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[NH:14]1[CH:15]=[CH:16][CH:17]=[C:13]1/[CH:12]=[C:4]1\[C:5](=[O:11])[NH:6][C:7]2[C:3]\1=[C:2]([C:26]1[S:25][CH:29]=[CH:28][CH:27]=1)[CH:10]=[CH:9][CH:8]=2
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: OB(O)c1cccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2cccc(-c3cccs3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (36.9 mg, 0.110 mmol) (Starting Material 1), Et3N (46 μL, 0.329 mmol), tri-o-tolylphosphine (2.1 mg, 0.007 mmol) (Aldrich), Pd(OAc)2 (0.7 mg, 0.003 mmol) (Aldrich), and 2-thiopheneboronic acid (21.1 mg, 0.165 mmol) (Aldrich) in 439 μL of dry N,N-dimethylformamide was heated at 100° C. for 24 h. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo to remove N,N-dimethylformamide, and then directly purified by flash chromatography (Merck Silica gel 60, 70-230 mesh, 10% ethyl acetate-hexanes then 25% ethyl acetate-hexanes elution) to provide pure (Z)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-4-(2-thiophenyl)-2H-indol-2-one (Yield 26.8 mg, 83%) as an orange solid (mp 213-214° C.).
Reaction SMILES: [OH:1][C@H:2]([CH2:31][O:32]C1C=CN=C(/N=N/C2C=CC([N+]([O-])=O)=CC=2)C=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[H][H].[CH2:52](O)[CH3:53]>[Pd]>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:3][C@H:2]([OH:1])[CH2:31][O:32][C:13]3[CH:14]=[N:15][C:18]([NH2:20])=[CH:52][CH:53]=3)=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccnc(/N=N/c4ccc([N+](=O)[O-])cc4)c3)cc2)CC1
Reactant: [H][H]
Reactant: CCO
Agent: [Pd]
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(N)nc3)cc2)CC1

Procedure:
4-[4-(2-{[(2S)-2-Hydroxy-3-({2-[(E)-2-(4-nitrophenyl)diazenyl]-4-pyridinyl}oxy)propyl]amino}ethyl)anilino]-N-octyl-1-piperidinecarboxamide (0.1 g, 0.15 mmol) was dissolved in ethanol (10 mL) and 10% palladium on carbon (0.015 g) added. The solution was shaken in a Parr apparatus at 50 psi hydrogen atmosphere for 1.5 hours, filtered through a Celite pad and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel Merck-60 (eluant: 10:1 chloroform-methanol) to furnish the title compound (0.02 g, 0.037 mmol).
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.[C:24](O)(=O)C>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21]/[CH:24]=[C:1]2\[C:2](=[O:14])[NH:3][C:4]3[C:5]\2=[C:6]2[C:11](=[CH:12][CH:13]=3)[N:10]=[CH:9][CH:8]=[CH:7]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1Cc2c(ccc3ncccc23)N1
Reactant: CC(=O)O
Product: COc1ccc(N/C=C2\C(=O)Nc3ccc4ncccc4c32)cc1
Yield: 54 %

Procedure:
Prepared from the dimethylaminomethylene derivative (Procedure E) of 1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one (Procedure C) with 4-methoxyaniline according to Procedure G in acetic acid to give the title compound in 54% yield as the acetate salt. 1H NMR (DMSO-d6) δ: 1.88 (s, 3H); 3.75 (s, 3H); 6.97 (d, J=8.9 Hz, 2H); 7.39 (d, J=8.7 Hz, 1H); 7.43–7.5 (m, 3H); 7.68 (d, J=8.5 Hz, 1H); 8.70 (d, J=4.0 Hz, 1H); 8.75–8.82 (m, 2H); 10.9 (s, 1H); 11.75 (d, J=12 Hz, 1H); 11.9 (s, 1H). ES-MS: m/z 318 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C1C=CN=CC=1.O.CN(C)C=O>[O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([NH:22][CH:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:25][CH2:24]4)=[O:20])=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Agent: CN(C)c1ccncc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[(2,3-dihydro-2-oxo-1H-imidazo-[4,5-b]quinolin-7-yl)oxy]butyric acid (2 g, 7mmol), 4-amino-1-benzylpiperidine (1.59 g, 1.70 mL, 8.4 mmol), triethylamine (1.54 g, 2.12 mL, 15.2 mmol), diphenylphosphoryl azide (2.87 g, 2.25 mL, 10.4 mmol), 4-dimethylaminopyridine (catalytic quantity) and dimethylformamide (40 mL) was stirred at room temperature for 18 hours. The mixture was then diluted with water and the crude free base product collected. After air drying, the free base was suspended in methanol and acidified with a 10% solution of hydrogen chloride in ethanol. The solution was evaporated and the residue dissolved in methanol. Dilution of the methanol solution with diethyl ether gave 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yloxy)-N-[1-(phenylmethyl)-4-piperidinyl]butanamide as the hydrated dihydrochloride salt (3.00 g, 80%), mp. 202°-204 C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]2[N:15]=[C:16]([CH2:25][O:26][CH2:27][CH3:28])[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:4]2[N:3]=1.[CH3:29][CH2:30][N:31](C(C)C)C(C)C.NC([OH:41])C>C(#N)C>[CH2:27]([O:26][CH2:25][C:16]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:4]2[N:3]=[C:2]([NH:31][CH2:30][CH2:29][OH:41])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[N:5]2[N:15]=1)[CH3:28]
Reactant: CC(N)O
Reactant: CCOCc1nn2c(-c3ccc(F)cc3)cc(Cl)nc2c1-c1ccc(C)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOCc1nn2c(-c3ccc(F)cc3)cc(NCCO)nc2c1-c1ccc(C)cc1

Procedure:
5-Chloro-2-(ethoxymethyl)-7-(4-fluorophenyl)-3-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (20 mg), DIPEA (0.1 mL) and aminoethanol (0.1 mL) are stirred for 12 hours in an acetonitrile (7 mL) solvent at 84° C. The solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The collected organic layer is washed with brine and dehydrated with anhydrous MgSO4. The solvent is removed by distillation under reduced pressure and the remainder is purified by column chromatography to yield the target compound (15 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:16]([F:20])=[C:17]([F:19])[F:18]>C1COCC1.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.[Pd].[Zn]>[F:20][C:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:16]([F:20])=[C:17]([F:19])[F:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)=[C:17]([F:19])[F:18]
Reactant: FC(F)=C(F)I
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Pd]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)=C(F)c1ccc(-c2ccc(C(F)=C(F)F)cc2)cc1
Reaction time: 24 h

Procedure:
After 24 hours, a GC/MS of the mixture allows identification of all the reaction components. After 72 hours, the reaction seems to stop proceeding while excess diiodobiphenyl remains; another batch of iodotrifluoroethylene (25.0 g, 0.12 mole) is reacted with zinc in THF and added to the reaction mixture along with 1.0 g of palladium tetrakis(triphenylphosphine) catalyst. The reaction is allowed to stir an additional 12 hours, then is removed and evaporated to dryness under high vacuum on a rotary evaporator. REsidue from evaporation is added to a 3 fold volumetric excess of water. A heavy precipitate is formed which is filtered and air dried on a vacuum funnel. The precipitate is dissolved in THF and filtered. Resulting filtrate is coated on silica gel by adding the silica gel to the THF solution and evaporating to dryness. This silica gel is then eluted on a short silica gel column using hexane as eluent to remove the colored material from the product. A fine white crystalline material remains after evaporation of the hexane. This crystalline material is then chromatographed again carefully on an alumina column using hexane as an eluent. The first band to elute from the column is the desired monomer product CF2 =CF--Ph--Ph--CF=CF2. A total of 44.2 g of product is recovered (58.7% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].OS([O-])=O.[Na+].[C-:18]#[N:19].[K+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[C:18]#[N:19])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(O)C#N)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To 3,4-dimethoxybenzaldehyde (1.66 g, 10 mmol) in ethyl acetate (20 mL) was added NaHSO3 (5.2 g, 50 mmol) in water (20 mL), followed by potassium cyanide (3.26 g, 50 mmol) in water (20 mL). The mixture was stirred overnight at rt, then warmed to 50° C. for 6 h. The reaction was cooled to rt, diluted with ethyl acetate, and the layers were separated. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-50% ethyl acetate/hexanes) to provide 137A (1.25 g, 65%) and starting material (0.52 mg). LC-MS: 176.22 (M−H2O)+.
Reaction SMILES: N1C=CC=NC=1.CS([C:11]1[N:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][N:12]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[C:19]1([CH2:18][O:17][C:14]2[CH:13]=[N:12][C:11]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:16][CH:15]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1ncc(OCc2ccccc2)cn1
Reactant: C1CNCCN1
Solvent: c1cncnc1
Solvent: Cc1ccccc1
Product: c1ccc(COc2cnc(N3CCNCC3)nc2)cc1
Yield: 42 %

Procedure:
A mixture of the pyrimidine prepared in (a) above (24.5 g, 0.09 mole), piperazine (77.5 g, 0.9 mole), and toluene (160 mL) was heated at 150° C. in a stainless steel omb for 22 hr. The reaction mixture was filtered, concentrated in vacuo, and the residue crystallized from Skelly B to give 10.15 g (42%) off-white solid, m.p. 94°-97° C.