Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[F:39][C:40]([F:55])([F:54])[C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:42]=1B(O)O>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:42]2[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:48])[F:49])=[CH:46][C:41]=2[C:40]([F:39])([F:54])[F:55])[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-(tert-Butyl)-2-hydroxy-2′,4′-bis(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as an orange oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 2,4-bis(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>Cl.O1CCCC1>[CH2:26]([NH:33][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
2-Chloronicotinic acid (25 grams, 158.67 mmol) is placed into a 2L 4-neck round bottom flask equipped with mechanical stirring, thermometer, nitrogen inlet and a rubber septum and is charged with 800 ml of tetrahydrofuran (THF). The reaction is chilled to 0° C. N-methylmorpholine (16.05 grams, 158.67 mmol) is added via syringe. The reaction is chilled to -10° C. and isobutyl chloroformate (21.67 grams, 158.67 mmol) is added to the reaction via syringe while maintaining the temperature at less than 0° C. The reaction is allowed to stir at -10° C. for 30 minutes. Benzylamine (18.70 grams, 174.54 mmol) is then added via syringe while maintaining the temperature below 0° C. The reaction is allowed to slowly warm to room temperature. After stirring for 18 hours IN HCl (300 ml) is added to the reaction. This is then extracted with ethyl acetate (2×350 ml). The organics are combined and washed with 1N HCl (1×300 ml) and 12% sodium hydroxide (2×300 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to a white paste. The paste is triturated with diethyl ether to yield a solid. This is filtered and washed with diethyl ether (2×65 ml). The filtrates are concentrated and triturated with fresh diethyl ether to yield a second crop of compound which is combined with the first to yield 28.11 grams (71.8%) of N-benzyl-2-chloronicotinamide as a white crystalline solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:21])[CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>CCOC(C)=O.[Pt](=O)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C2=CCC3(CC2)OCCO3)cc1C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2CCC3(CC2)OCCO3)cc1C
Reaction time: 0.75 h

Procedure:
To a degassed solution of the title compound from Example 13 Step B (606 mg, 2.10 mmol) in EtOAc (15 mL) was added platinum(IV) oxide (150 mg). The reaction mixture was fitted with a 3-way adapter with a hydrogen balloon attached. The reaction flask was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, then was stirred vigorously. After 45 min, the reaction mixture was filtered through Celite, rinsing with EtOAc. The mixture was then concentrated in vacuo to provide the title compound, which was used without further purification: LCMS m/z 259.4 [M−CH3O]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:15][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]([CH3:30])[CH2:26][C:27]([OH:29])=O)[CH:21]=[CH:22][C:23]=1[Cl:24].C(N(CC)CC)C.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:15]([CH3:16])[C:27](=[O:29])[CH2:26][N:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH3:30])[CH2:9][N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(CN1CCCC1)c1cccc(Br)c1
Reactant: CN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1cccc(Br)c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54 %

Procedure:
[1-(3-Bromophenyl)-2-(1-pyrrolidinyl)ethyl]methylamine (0.65 g, 2.30 mmol) was added to a solution of N-(3,4-dichlorophenyl)-N-methylglycine (0.65 g, 2.30 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexaflurophosphate (BOP) (1.52 g, 3.40 mmol) and triethylamine (TEA) (0.70 g, 6.90 mmol) in N,N-dimethyl-formamide (DMF) (10 mL). The reaction mixture was stirred at RT for 12 h. Water (10 mL) was then added an the crude compound precipitated, was filtered and crystallized from ether and hexane to give the title compound as an off-white solid (0.62 g, 54%). MS (ES) m/e 499[M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.CN(C)CCN(C)C.CN(C)[CH:40]=[O:41]>CCOCC.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH:40]=[O:41])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cccc2ccc(OCc3ccccc3)cc12
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: O=Cc1cccc2ccc(OCc3ccccc3)cc12
Temperature: 5 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of 7-benzyloxy-1-iodo-naphthalene (4.60 g, 12.77 mmol) in ether (120 mL) is added 1.7 M tert-butyl-lithium in pentane (8.26 mL, 14.0 mmol) at −78° C. under nitrogen atmosphere and the resulting mixture is stirred for one hour while being warmed up to 5° C. The mixture is cooled to −78° C. again before tetramethylethylene-diamine (1.93 mL, 1.49 g, 12.79 mmol) is added. The mixture is stirred for 10 minutes before N, N-dimethylformamide (0.99 mL, 0.93 g, 12.78 mmol) is added. The mixture is gradually warmed up to room temperature and stirred over night. Ethyl acetate is added to reaction mixture, washed with saturated ammonium chloride, dried over sodium sulfate, filtered and concentrated. The crude product is purified by silica gel chromatography (Hexanes/EtOAc=20/1) to give 7-benzyloxy-naphthalene-1-carbaldehyde (1.95 g, 58.3% yield); 1H NMR 400 Hz (CDCl3) δ 5.27 (s, 2H), 7.33 (m, 2H), 7.42 (m, 2H), 7.52 (m, 3H), 7.83 (d, J=8.98 Hz, 1H), 7.95 (d, J=7.11 Hz, 1H), 8.03 (d, J=8.10 Hz, 1H), 10.32 (s, 1H); MS m/z (M+H+) 263.05.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:11]([OH:22])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH3:21])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C@@H:9]([CH3:10])[C@@H:11]([O:22][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccccc1CC[C@H](O)[C@H](C)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccccc1CC[C@H](OS(C)(=O)=O)[C@H](C)OCc1ccccc1
Temperature: 4 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled solution of (2S,3S)-2-benzyloxy-5-(2-(methylthio)phenyl)pentan-3-ol (0.64 g) in dichloromethane (12 ml) was added methanesulfonyl chloride (0.234 ml) followed by triethylamine (0.421 ml). The mixture was stirred at 4° C. for 40 min. The mixture was washed with water and brine, dried and concentrated in vacuo to give 2-[(3S,4S)-4-benzyloxy-3-(methanesulfonyloxy)pentyl]-thioanisole (0.92 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.[C:29](=[O:32])([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:20]3[CH:25]=[CH:24][C:23]([O:32][CH3:29])=[CH:22][CH:21]=3)[C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[CH:22][CH:21]=1
Reactant: NC(=O)C1CCN(c2c(Br)cncc2Br)CC1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cncc(-c3ccc(OC)cc3)c2N2CCC(C(N)=O)CC2)cc1

Procedure:
General procedure D was followed using 1-(3,5-dibromopyridin-4-yl)piperidine-4-carboxamide E27 (50 mg, 0.14 mmol), 4-methoxyphenylboronic acid (25 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (8 mg, 5 mol %), acetonitrile (1.4 mL) and 0.5 M sodium carbonate (0.27 mL, 0.16 mmol) for 30 min. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 98:2) to furnish the title compound as a white solid (39 mg), LC-MS (ESI, 3.5 min) Rt 1.68 min, m/z 418 (100%, [M+H]+).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.C1([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[CH2:16]2)C=CC=CC=1.IC>C1COCC1>[CH3:2][CH:16]1[CH2:15][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:24]
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1Cc2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A 2 M solution of LDA (21 mL, 1.05 eq, from Aldrich) was added dropwise to 3-phenyl-1-indanone (8.33 g, 40.0 mmol) in THF (300 mL) at −78° C. After 1 h at this temperature, iodomethane (3.00 mL, 1.2 eq) was added. The mixture was stirred at −78° C. for 2 h, at 0° C. for 30 min and quenched with sat NH4Cl (100 mL). After evaporation of THF in vacuo, the aqueous residue was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (20 mL), dried (MgSO4) and concentrated. Silica gel chromatography (EtOAc-Hex, 5:95 then 7:93 then 10:90) gave the 2-methylindanone (1.93 g, 22%). MS Found: (M+H)+=223.
Reaction SMILES: [C:1](#[N:7])[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH2:9][OH:10].[OH-].[Na+]>CCO.O.ClCCl>[OH:10][NH:9][C:1](=[NH:7])[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: NO
Reactant: CC(C)CCC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)CCC(=N)NO
Temperature: 25 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
A mixture of isocapronitrile (1.00 g, 10.30 mmol), hydroxylamine hydrochloride (0.786 g, 11.32 mmol), and sodium hydroxide (0.453 g, 11.32 mmol) in EtOH (21 mL) and water (5 mL) was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo to yield a white solid which was re-dissolved in dichloromethane (100 mL). The insoluble salt was removed by filtration. The organic layer was concentrated in vacuo to dryness. The title compound was obtained as a white solid in 55% yield (0.730 g). 1H NMR (300 MHz, CDCl3) δ 6.6 (br., s, 1H), 4.5 (br., s, 2H), 2.2 (m, 2H), 1.50 (m, 1H), 1.4 (m, 2H), 0.85 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([NH:33][NH2:34])=[O:32])[CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:34][NH:33][C:31]([CH:27]3[CH2:28][CH2:29][CH2:30][NH:25][CH2:26]3)=[O:32])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNC(=O)C1CCCNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=O)C1CCCNC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.25 g, 1.0 eq.) was dissolved in THF:EtOAc (15 mL, 2:1) and cooled to −60° C. where piperidine-3-carbohydrazide (0.113 g, 1.1 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.69 mL, 4 eq.) was added dropwise followed by DIPEA (0.25 mL, 2 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)—N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)piperidine-3-carbohydrazide (0.01 g, yield: 2.4%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([OH:16])[C:14]=1[I:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([OH:16])[C:14]=1[I:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)c(I)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)c(I)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
Sodium hydride (60% oil, 1.33 g) was added to a mixture of ethyl 3,5-dihydroxy-4-iodobenzoate (5.00 g) and DMF (50 mL), and the resultant mixture was stirred at 0° C. for 30 minutes in a nitrogen atmosphere. Benzyl bromide (2.78 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.94 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[C:24]4[C:23]5[CH:25]=[C:26]([NH:29][C:30]([C:32]6[C:37]([Cl:38])=[CH:36][CH:35]=[C:34](Cl)[N:33]=6)=[O:31])[CH:27]=[CH:28][C:22]=5[CH2:21][CH2:20][C:19]=4[C:18]([C:40]([NH2:42])=[O:41])=[N:17]3)=[CH:15][C:10]=2[O:9][CH2:8]1.CCO>CC(N(C)C)=O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[C:24]4[C:23]5[CH:25]=[C:26]([NH:29][C:30]([C:32]6[C:37]([Cl:38])=[CH:36][CH:35]=[C:34]([N:1]7[CH2:6][CH2:5][O:4][CH2:3][CH2:2]7)[N:33]=6)=[O:31])[CH:27]=[CH:28][C:22]=5[CH2:21][CH2:20][C:19]=4[C:18]([C:40]([NH2:42])=[O:41])=[N:17]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3nc(Cl)ccc3Cl)cc1-2
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3nc(N4CCOCC4)ccc3Cl)cc1-2
Reaction time: 36 h

Procedure:
The title compound was synthesized from 0.27 g of morpholine and the title compound of Example 216 (0.522 g) by the same procedure used for Example 207 except that EtOH was replaced by 0.5 ml of DMA. The reaction was carried out at 80° C. for 36 hours. The title compound, isolated by preparative HPLC, is a white solid (0.30 g, 52%), m.p. 260–262° C. (decomposition). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (CDCl3) δ 2.96 (m, 2H), 3.15 (m, 2H)), 3.48 (m, 4H), 3.86 (m, 4H), 5.41 (s, 1H), 6.74–6.86 (m, 2H), 6.90–7.04 (m, 2H), 7.16 (d, 1H, J=1 Hz), 7.28–7.35 (m, 2H), 7.54–7.22 (m, 2H), 9.32 (s, 1H). ESI mass spectrum for C29H26ClN6O5+: 573 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>CN(C)C(=O)C>[C:10]([C:9]1[CH:8]=[CH:15][C:14]([F:16])=[CH:13][C:12]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)#[N:11]
Reactant: N#Cc1ccc(F)cc1F
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(F)cc1N1CCNCC1
Temperature: 122 °C
Reaction time: 1.5 h

Procedure:
A mixture of piperazine (Aldrich; 3.99 g), 2,4-difluorobenzonitrile, and N,N-dimethylacetamide (20 mL) is stirred for 1.5 h at 122° C. After cooling, the mixture is partitioned between dichloromethane and satd. aq. sodium bicarbonate. The organic layers are dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel and the appropriate fractions are combined and concentrated to give 1.44 g of 1-(2-cyano-5-fluorophenyl)piperazine; 1H NMR (CDCl3) δ3.01, 3.30, 6.56, 6.63, 7.40.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2/[C:12](=[O:21])[C:13]3[C:18]([CH2:19]/2)=[CH:17][C:16]([OH:20])=[CH:15][CH:14]=3)=[CH:2]1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[CH2:35]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2/[C:12](=[O:21])[C:13]3[C:18]([CH2:19]/2)=[C:17]([CH2:35][N:32]2[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[CH2:30][CH2:31]2)[C:16]([OH:20])=[CH:15][CH:14]=3)=[CH:2]1
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Cc2cc(O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2C/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
A solution of (E)-2-[(1H-indol-3-yl)methylene]-5-hydroxy-2,3-dihydro-1H-inden-1-one (0.060 g, 0.22 mmol) in ethanol (3.0 mL) was added with 1-tert-butoxycarbonylpiperazine (0.049 g, 0.26 mmol), and 37% aqueous formaldehyde (0.020 g, 0.26 mmol), and the mixture was stirred overnight at 60° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain tert-butyl (E)-4-({2-[(1H-indol-3-yl)methylene]-5-hydroxy-1-oxo-2,3-dihydro-1H-inden-4-yl}methyl)piperazine-1-carboxylate (0.068 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[CH:4]=1.[Br:13]N1C(=O)CCC1=O>CC#N>[Br:13][C:8]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([CH3:12])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Solvent: CC#N
Product: COc1cc(C)c([N+](=O)[O-])cc1Br
Temperature: 140 °C
Reaction time: 8 h

Procedure:
To a solution of nitrobenzene 11 (2.2 g, 13.1 mmol) in CH3CN (8 mL) in a pressure tube was added N-bromosuccinimide (8.2 g, 45.8 mmol). The tube was sealed and the contents were heated to 140° C. overnight on an oil bath. The reaction mixture turned brownish-red overnight. After the reaction was quenched with saturated aqueous Na2S2O3 solution (150 mL), the product was extracted with Et2O (2×150 mL), dried (Na2SO4), and purified by chromatography (hexane/EtOAc 3:1) to afford brominated product 12 along with other byproducts that were not separable by chromatography (hexane/EtOAc 3:1). The product mixture (2.8 g, 87%) was used directly in the next step: Rf0.29 (hexane/EtOAc 3:1); 1H NMR (CDCl3) δ 2.66 (s, 3H), 3.98 (s, 3H), 6.76 (s, 1H), 8.31 (s, 1H); 13C NMR (CDCl3) δ 21.7, 56.8, 108.9, 114.3, 125.2, 130.4, 136.3, 141.9, 159.3; ESI-HRMS [M-Br—CH3—H]− C7H6NO3 calcd for m/z 152.0348, found 152.0349.
Reaction SMILES: COCCC(Cl)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]([CH2:27][CH2:28][O:29][CH3:30])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1.B1([C:37]2[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=2)OCCCO1>>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]([CH2:27][CH2:28][O:29][CH3:30])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1.[CH3:30][O:29][CH2:28][CH2:27][C:21]1[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[CH:18][C:17]=3[N:16]=[C:15]([NH2:19])[C:14]=2[N:20]=1
Reactant: c1cncc(B2OCCCO2)c1
Agent: COCCC(=O)Cl
Agent: COCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Product: COCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was prepared according to the procedures described in Parts A and B of Example 9 using methoxypropanoyl chloride instead of ethoxyacetyl chloride. 7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was coupled with pyridine-3-boronic acid 1,3-propanediol cyclic ester according to the method described in Examples 118-121. The reaction was heated at reflux overnight, and the work-up procedure described in Part F of Examples 125-131 was followed. The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 76:24) followed by recrystallization from methanol. The crystals were dried at 1.33 Pa and 98° C. to provide 2-(2-methoxyethyl)-1-(2-methylpropyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white needles, mp 207-208° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH2:3][C:4]#[N:5].CSC>C1COCC1>[NH2:5][CH2:4][CH2:3][CH:2]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[OH:1]
Reactant: N#CCC(O)c1cccc(O)c1
Solvent: CSC
Solvent: C1CCOC1
Product: NCCC(O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the nitrile 127 (25.0 g, 153 mmol) in THF (400 mL), cooled to 0° C., was added BH3.DMS (49.5 mL, 460 mmol), following which the cooling bath was removed. The resulting mixture was gradually warmed to reflux and maintained overnight. This was then cooled in an ice-bath and quenched by the slow addition of large excess of MeOH. After stirring at RT for about 2 h, the excess solvent was removed under reduced pressure. The residue was again treated with MeOH and evaporated. The process was repeated thrice. The brown oil was then applied onto a flash silica gel column and eluted (0 to 15% (9:1 MeOH—NH3)-DCM gradient) to give 3-(3-amino-1-hydroxypropyl)phenol (128) as a brown solid. Yield (25.0 g, 97%): 1H NMR (400 MHz, DMSO-d6) δ 7.04-7.09 (m, 1H), 6.74 (s, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.58 (dd, J=8.0, 2.0 Hz, 1H), 4.55 (dd, J=7.2, 5.6 Hz, 1H), 2.57-2.66 (m, 2H), 1.56-1.62 (m, 2H).