Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]1(=[O:20])[O:15][C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]1=2>C(OCC)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]([C:11]2[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:20])=[C:4]([F:9])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Cl)cc1F
Solvent: CCOCC
Product: O=C(O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Reaction time: 1.5 h

Procedure:
4.8 Parts of 4-chloro-2-fluoroaniline were added to a solution of 5 parts of 3,4,5,6-tetrahydrophthalic anhydride in 150 parts of diethyl ether and stirred for 1.5 hours. The solution was evaporated under reduced pressure of 300 mm. Hg at 25° C to isolate 9 parts of 2-(4-chloro-2-fluorophenylaminocarbonyl)-cyclohexene-1-carboxylic acid as white crystals melting at 91°-93° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[CH2:10][NH:11][C:12](=[O:28])[C@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[NH:14][C:15](=[O:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CO.C(O)(=O)C>CO.[Pt](=O)=O>[CH2:1]([O:8][C:9](=[O:29])[CH2:10][NH:11][C:12](=[O:28])[C@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)[NH:14][C:15](=[O:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)NCC(=O)OCc1ccccc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)NCC(=O)OCc1ccccc1

Procedure:
Compound 14 (267 mg, 0.67 mmol) was dissolved in methanol (50 ml). Platinum dioxide (3% of weight of peptide) was added, and the mixture was hydrogenated at atmospheric pressure. After 4 hours TLC (chloroform/methanol/acetic acid: 85/10/5) showed a clean conversion to the amine. The catalyst was separated by decantation, and the solvent was removed under reduced pressure. Compound 15 was obtained in nearly quantitative yield as a glassy solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:18])[CH3:2].[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=2)[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4]1=[O:18]
Reactant: CCn1c(=O)[nH]c2cc(C(=O)OC)ccc2c1=O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCn1c(=O)c2ccc(C(=O)OC)cc2n(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 73 %

Procedure:
A mixture of 3-ethyl-7-(methoxycarbonyl)-2,4(1H,3H)-quinazolinedione (2.17 g), 2,4-dichlorobenzyl chloride (2.05 g), potassium iodide (1.45 g) and potassium carbonate (5.0 g) in acetone (80 ml) was heated under reflux for 1.5 hr. After cooling, water (50 ml) was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was washed with water (30 ml) and methyl t-butyl ether (30 ml) and dried to give the object compound (2.60 g).
Reaction SMILES: C1(OC)C=CC=CC=1.Cl.[NH2:10][C@@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=1)[C:12]([O:14]C(C)(C)C)=[O:13]>C(O)=O>[NH2:10][C@@H:11]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:24][CH:25]=1)[C:12]([OH:14])=[O:13]
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: COc1ccccc1
Solvent: O=CO
Product: CC#CCOc1ccc(C[C@H](N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 129.9 %

Procedure:
Formic acid (5 mL), and anisole (20 μL) were added to tert-butyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate HCl salt (200 mg) and the mixture was stirred at room temperature for 18 hours. Completion of the reaction was confirmed by detecting the target product by LCMS (LCMS m/z 234 (M+1), Rt 0.83 min.). The reaction solution was concentrated under reduced pressure to obtain (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionic acid (186 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Cl.[F:31][C:32]1([F:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][C:32]([F:38])([F:31])[CH2:33][CH2:34]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: FC1(F)CCNCC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCC(F)(F)CC2)c1OCCC(C)c1ccc(F)cc1
Yield: 31 %

Procedure:
Example 8a (56 mg, 0.12 mmol) was reacted with 4,4-difluoropiperidine hydrochloride (2.0 eq.) as described under General Procedure J to afford the title compound (19 mg, 31%) as a clear yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.05 (t, J=5.7 Hz, 2H), 3.97 (t, J=6.6 Hz, 2H), 3.84 (s, 3H), 3.11-2.89 (m, 1H), 2.66 (t, J=5.7 Hz, 2H), 2.58 (m, 4H), 2.49 (s, 3H), 2.18 (s, 3H), 2.05-1.92 (m, 6H), 1.30 (d, J=6.9 Hz, 3H). MS (ES+) m/z 528 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].B(F)(F)F.[CH3:18][CH2:19]OCC.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[CH2:5][CH2:6][C:7]([O:9][CH2:18][CH3:19])=[O:8]
Reactant: CCOCC
Reactant: Nc1ccc(CCC(=O)O)cc1F
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)c(F)c1

Procedure:
A solution of 3-fluoro-4-aminohydrocinnamic acid in 100 ml. of absolute ethanol containing 16 ml. of boron trifluoride etherate is heated to reflux for 48 hours. The solution is then cooled, poured into 5% aqueous sodium carbonate and extracted with methylene chloride. Evaporation of the organic extracts yields ethyl 3-fluoro-4-aminohydrocinnamate.
Reaction SMILES: OC1C(C(OC)=O)=C(C=CC=1)OC/C=C/C1C=C(C2ON=C(C(OCC)=O)C=2)C=CC=1.[OH:32][C:33]1[C:34]([C:59]([O:61][CH3:62])=[O:60])=[C:35]([CH:56]=[CH:57][CH:58]=1)[O:36][CH2:37][CH2:38][NH:39][C:40]1[CH:41]=[C:42]([C:46]2[O:50][N:49]=[C:48]([C:51]([O:53]CC)=[O:52])[CH:47]=2)[CH:43]=[CH:44][CH:45]=1>>[OH:32][C:33]1[C:34]([C:59]([O:61][CH3:62])=[O:60])=[C:35]([CH:56]=[CH:57][CH:58]=1)[O:36][CH2:37][CH2:38][NH:39][C:40]1[CH:41]=[C:42]([C:46]2[O:50][N:49]=[C:48]([C:51]([OH:53])=[O:52])[CH:47]=2)[CH:43]=[CH:44][CH:45]=1
Reactant: CCOC(=O)c1cc(-c2cccc(NCCOc3cccc(O)c3C(=O)OC)c2)on1
Agent: CCOC(=O)c1cc(-c2cccc(/C=C/COc3cccc(O)c3C(=O)OC)c2)on1
Product: COC(=O)c1c(O)cccc1OCCNc1cccc(-c2cc(C(=O)O)no2)c1

Procedure:
The titled compound was prepared according to the procedure described in Example 1F, substituting the ester from Example 1E for the ester from Example 3C. MS (ESI(+)) m/e 399 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.30 (s, 1H), 7.25 (t, J=8.4 Hz, 1H), 7.18 (t, J=8.4 Hz, 1H), 7.08–7.14 (m, 2H), 6.78 (dt, J=6.9, 1.5 Hz, 1H), 6.55 (d, J=5.8 Hz, 1H), 6.51 (d, J=5.8 Hz, 1H), 4.12 (t, J=5.7 Hz, 2H), 3.70 (s, 3H), 3.6–3.3 (overlapping m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]2=[N:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=3)=[CH:16][N:10]2[N:9]=1)=[O:6].[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:39]([O:38][C:34](=[O:37])[CH:35]=[CH:36][C:2]1[CH:33]=[CH:32][CH:31]=[C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]3=[N:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=4)=[CH:16][N:10]3[N:9]=2)[CH:3]=1)[CH3:40]
Reactant: C=CC(=O)OCC
Reactant: Cc1ccc(-c2cn3nc(NC(=O)c4cccc(Br)c4)ccc3n2)cc1NC(=O)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1cccc(C(=O)Nc2ccc3nc(-c4ccc(C)c(NC(=O)C(C)(C)C)c4)cn3n2)c1
Temperature: 110 °C
Yield: 30.4 %

Procedure:
To a mixture of 3-bromo-N-[2-[3-(2,2-dimethylpropanoylamino)-4-methyl-phenyl]imidazo[2,1-f]pyridazin-6-yl]benzamide (0.126 g, 0.25 mmol), Ethyl acrylate (0.272 mL, 2.5 mmol), palladium(II) acetate (2.8 mg, 0.01 mmol), tri(o-tolyl)phosphine (0.0152 g, 0.05 mmol) in DMF (1.45 mL) is added DIPEA (0.174 mL, 1 mmol). The mixture is degassed with N2 then sealed and heated at 110° C. for 18 hours. The reaction mixture is cooled, saturated aqueous NaHCO3 (50 mL) added and extracted with EtOAc (×3). Organic layers are combined and washed with water, NaHCO3, brine, then dried, concentrated and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.040 g). LCMS (m/z)=526.6 [M+H]+, tR=2.92 min.
Reaction SMILES: CO[C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([Br:18])=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=[O:4]>N1CCCC1>[N:10]1([C:3]([C:5]2[N:13]=[CH:12][C:11]3[NH:10][C:9]4[N:14]=[CH:15][C:16]([Br:18])=[CH:17][C:8]=4[C:7]=3[CH:6]=2)=[O:4])[CH2:11][CH2:7][CH2:8][CH2:9]1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Solvent: C1CCNC1
Product: O=C(c1cc2c(cn1)[nH]c1ncc(Br)cc12)N1CCCC1

Procedure:
3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (140 mg, 0.458 mmol) was dissolved in pyrrolidine (6 mL) and the mixture heated to reflux for 2 h. The mixture was allowed to cool and concentrated in vacuo to afford a bright orange oily solid. The residue was used without purification.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:13][C:12]1[NH:11][C:10](=[O:14])[NH:9][C:8]=1[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:3][CH:4]=1
Reactant: C1CCNCC1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(N2CCCCC2)cc1

Procedure:
A suspension of 11.0 g (0.05 mole) of 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one in 30 ml of piperidine is stirred at reflux temperature for 24 hours. Excess piperidine is evaporated under reduced pressure and the residue is recrystallized twice from a mixture of isopropanol and water to give 11.9 g of the title compound. M.P. 260°-263° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:3]1[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[CH2:30]([O:32][CH:33]([O:36][CH2:37][CH3:38])[CH2:34]Br)[CH3:31]>>[CH2:30]([O:32][CH:33]([O:36][CH2:37][CH3:38])[CH2:34][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13](=[O:18])[C:14]([CH3:17])([CH3:15])[CH3:16])[CH2:4][CH:3]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C:2]1=[O:1])[CH3:31]
Reactant: CC(C)(C)C(=O)N1CC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Reactant: CCOC(CBr)OCC
Product: CCOC(CN1C(=O)C(NC(=O)OCc2ccccc2)CN(C(=O)C(C)(C)C)c2ccccc21)OCC

Procedure:
Step 2 of Example 1 was repeated except that 2-oxo-3-benzyloxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine was used instead of 2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, and that bromoacetaldehyde diethylacetal was used instead of 2-bromo-2′-methylacetophenone, to thereby obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:18]=[O:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:18]=[O:19]
Reactant: Brc1ccncc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cnccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
A suspension of 4-bromopyridine (13.7 g, 86.8 mmol) in 300 mL THF was purged with N2 and cooled to −78° C. under an atmosphere of dry N2. A solution of lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 43.4 mL, 86.8 mmol) was added over about 3 minutes. After 30 minutes, DMF (dimethylformamide) was added. The reaction mixture was maintained at −78° C. for 3 hours before allowing it to warm to ambient temperature overnight. The reaction mixture was quenched with saturated NH4Cl and concentrated under reduced pressure to remove most of the THF. The aqueous mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, evaporated, and chromatographed (150 g Analogix silica gel column eluting with a gradient of 100% heptane to 30% EtOAc/heptane over 45 minutes). Fractions containing the product were combined and evaporated to give 2.20 g (13.6%) of the title compound. MS m/z 186 (M+H)+.
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1)([O-])=O>[Zn].O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.O>[NH2:6][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: COC(=O)c1cccc(CN2CCOc3cc([N+](=O)[O-])ccc32)c1
Agent: Cl[Fe](Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(CN2CCOc3cc(N)ccc32)c1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 87.7 %

Procedure:
DMF (5 mL), water (5 mL), zinc (0.7 g, 10.7 mmol) and iron trichloride hexahydrate (0.12 g, 0.4 mmol) were added to methyl 3-[(7-nitro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (100a) (0.35 g, 1.07 mmol), and the mixture was stirred at 100° C. for 50 minutes. The insoluble matter was filtered off and ethyl acetate was added to the mother liquor, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 0.28 g of the crude title compound as a brown oily substance (88%).
Reaction SMILES: [Cl:1][O-].[Ca+2].Cl[O-].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:18](O)=[O:19]>O>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:18]([Cl:1])=[O:19]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: [O-]Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Solvent: O
Product: COc1ccc(C(=O)Cl)cc1F
Temperature: 55 °C
Reaction time: 0.08 h

Procedure:
The intermediate 3-fluoro-4-methoxybenzoyl chloride was prepared as follows: Fifty g. of calcium hypochlorite was dissolved by warming in 200 ml. of water to give a milky solution. A warm solution containing 35 g. of potassium carbonate and 10 g. of potassium hydroxide in 100 ml. of water was added; the resulting mixture was shaken for about 5 minutes and then filtered through a sintered glass funnel. The filtrate cake of calcium carbonate was washed with 40 ml. of water. The combined filtrates were placed in a one liter round bottom flask and stirred while heating on a steam bath to about 55° C. To the stirred solution was added 16.8 g. of 3-fluoro-4-methoxyacetophenone and the stirred suspension was cautiously warmed to 60° C. whereupon an exothermic reaction began. The reaction temperature was allowed to rise to 70° C. and the mixture was cooled to 60° C. using an ice bath; this was repeated several times until the reaction moderated. The stirred reaction mixture was then kept at 60°-70° C. on a steam bath for 30 minutes and then cooled to room temperature with continued stirring. The reaction mixture was filtered and to the filtrate was added 10 g. of sodium metabisulfite in 40 ml. of water to destroy the excess hypochlorite. The mixture was then acidified with 40 ml. of concentrated hydrochloric acid and additional water was added to facilitate stirring due to copious formation of white solid. The mixture was placed in a cold room and the solid was collected, washed with a little water, recrystallized from 150 ml. of acetonitrile and air-dried to yield 12.9 g. of 3-fluoro-4-methoxybenzoic acid, m.p. 211°-212° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.C1(C(C2C=CC(Cl)=CC=2)O)CC1>O1CCCC1>[CH:11]1([CH:4]([C:3]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=2[F:1])[OH:5])[CH2:13][CH2:12]1
Reactant: O=Cc1ccc(F)cc1F
Reactant: Br[Mg]C1CC1
Agent: OC(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1F)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (10.55 mmol) of 2,4-difluorobenzaldehyde and 31.7 ml (15.83 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 153A. 0.33 g (17% of theory) of the title compound was obtained.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([N:9]=O)[N:6]=[C:5]([NH2:11])[C:4]=1[NH2:12].[OH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.O>C(OCCO)C>[NH2:9][C:7]1[N:6]=[C:5]([NH2:11])[C:4]2[C:3](=[N:2][C:24]([NH2:25])=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][OH:13])=[CH:22][CH:21]=3)[N:12]=2)[N:8]=1
Reactant: N#CCc1ccc(OCCO)cc1
Reactant: Nc1nc(N=O)nc(N)c1N
Agent: [Na]
Solvent: CCOCCO
Solvent: O
Product: Nc1nc(N)c2nc(-c3ccc(OCCO)cc3)c(N)nc2n1

Procedure:
460 mg metallic sodium were dissolved while stirring in 150 ml 2-ethoxyethanol. Thereafter to it was added while stirring 3.1 g (0.02 mole) of triamino-nitrosopyrimidine and 2.5 g (0.02 mole) p-(2-hydroxyethoxy)-phenyl acetonitrile and the mixture was stirred and heated in the water bath at 60° C. The color of the mixture changed from violet to light brown. After 14 hours of stirring, the reaction was stopped. The mixture is then allowed to cool. Unreacted 2,4,6-triamino-nitrosopyrimidine is filtered and the clear solution is evaporated and its volume reduced. The precipitate was taken up in hot acetone and by addition of petroleum ether, the raw product precipitated. The purification consisted of one recrystallization in butanol and also by passage through a silica gel column (Kieselgel 60, Merck). The title compound is obtained as yellowish-brown crystals.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[C:9](Br)=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH2:14]([O:17][C:18]1[C:23]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][C:21]([CH2:28][CH3:29])=[CH:20][C:19]=1B(O)O)[CH2:15][CH3:16].C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:4]1[O:8][C:7]2[C:9]([C:19]3[CH:20]=[C:21]([CH2:28][CH3:29])[CH:22]=[C:23]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:18]=3[O:17][CH2:14][CH2:15][CH3:16])=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCOc1c(B(O)O)cc(CC)cc1C(C)(C)C
Reactant: CC(=O)c1cc2cccc(Br)c2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOc1c(-c2cccc3cc(C(C)=O)oc23)cc(CC)cc1C(C)(C)C
Temperature: 25 °C

Procedure:
To a mixture of 57 mg (0.049 mmol, 5%) of Pd(PPh3)4, 362 mg (1.26 mmol) of 2-acetyl-7-bromobenzo[b]furan and 2.52 mmol of 2-propoxy-3-tert-butyl-5-ethyl phenylboronic acid in 10 mL of toluene, and 5 mL of ethanol was added 1.3 mL of a 2N Na2CO3 aqueous solution. The mixture was heated to reflux for 3 hours and after cooling (room temperature) extracted with ethyl acetate. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was filtrated over a short silica plug (eluent: ethyl acetate/hexane: 10/90) and recrystallized from hexane to afford 2-acetyl-7-(2-propoxy-3-tert-butyl-5-ethylphenyl)benzo[b]furan as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[N:25][C:24](F)=[CH:23]2>C1COCC1>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[N:25][C:24]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)=[CH:23]2
Reactant: Fc1cc2cc(Br)ccc2cn1
Reactant: Cc1cc(N)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc3cc(Br)ccc3cn2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.2 %

Procedure:
A dry 40 mL scintillation vial equipped with a screw cap with a teflon insert was cooled under nitrogen, equipped with a stir bar and charged with 2-methylpyridine-4-amine (263 mg, 3.32 mmol) and anhydrous THF (27 mL) and maintained under a N2 atmosphere. LiHMDS was added as a solid (0.925 g, 5.53 mmol). The reaction mixture was stirred at RT under nitrogen for 5 min. To the mixture was added 6-bromo-3-fluoro isoquinoline (500 mg, 2.21 mmol), the vial was flushed with N2, tightly capped and placed in a pre-heated oil bath at 85° C. After 4 h at 85° C., additional 2-methylpyridine-4-amine (96 mg, total: 359 mg, 3.32 mmol) and LiHMDSi (185 mg, total: 1.11 g, 6.64 mmol) were added, and the reaction was heated an additional 2 h at 85° C. The reaction was cooled, and the THF was removed in vacuo. The crude reaction mixture was partitioned between water and DCM containing 10% MeOH. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was absorbed onto Celite® and purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 10% MeOH) to afford 196 mg (28%) of 6-bromo-N-(2-methylpyridin-4-yl)isoquinolin-3-amine (94) as a yellow solid, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:3]=1[C:4](=[NH:13])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.Br/[C:21](=[CH:24]/OC(C)C)/[CH:22]=[O:23].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(Cl)(Cl)Cl.O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[C:21]([CH:22]=[O:23])=[CH:24][N:13]=[C:4]2[C:3]2[C:14]([F:19])=[CH:15][CH:16]=[C:17]([F:18])[C:2]=2[F:1])=[CH:7][CH:8]=1
Reactant: CC(C)O/C=C(/Br)C=O
Reactant: N=C(Nc1ccc(F)cc1)c1c(F)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cnc(-c2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,3,6-trifluoro-N-(4-fluorophenyl)benzimidamide (25) (0.98 mg, 3.65 mmol), (E)-2-bromo-3-isopropoxyacrylaldehyde (1.1 g, 5.48 mmol), and potassium carbonate (0.76 g, 5.48 mmol) in chloroform (7 mL) and water (1 mL) was stirred at room temperature overnight. Dichloromethane and water were added and the layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-40% EtOAc in hexanes) to afford 1-(4-fluorophenyl)-2-(2,3,6-trifluorophenyl)-1H-imidazole-5-carbaldehyde (26).