Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([Cu])#[N:12].[NH4+].[OH-]>CN1CCCC1=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[N:12])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: N#C[Cu]
Reactant: COc1cc(F)ccc1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1cc(F)ccc1C#N
Temperature: 180 °C
Reaction time: 5.5 h
Yield: 78.4 %

Procedure:
To a solution of 1-bromo-4-fluoro-2-methoxybenzene (9.0 g) in N-methylpyrrolidone (100 mL, Sure Seal; Aldrich) was added CuCN (6.6 g, 73.7 mmol, 1.8 eq.; Aldrich), and the mixture stirred at 180° C. under anhydrous nitrogen for 5.5 hrs. After cooling, 14% aqueous NH4OH (330 mL) was added and stirring continued for 45 min at room temperature. The mixture was extracted with ether (100 mL×3), and the combined extracts washed sequentially with dilute aqueous NH4OH, dilute HCl and brine, then dried (MgSO4), and concentrated to provide the title compound (5.2 g, Yield 85% in 2 steps) as a white solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.91 (3H, s, OMe), 6.69 (1H, dd, J=2.3 Hz, J=10.5 Hz, Ar—H), 6.72 (1H, dt, J=2.5 Hz, J=J=8.0 Hz, Ar—H), 7.55 (1H, dd, J=6.5 Hz, J=8.5 Hz, Ar—H); 13C NMR (CDCl3, 125.8 Hz) δ ppm: 56.49, 98.16, 100.06, 100.27, 108.31, 108.50, 115.83 135.37, 135.46, 163.25, 163.34 165.47, 167.50. An analytical sample was obtained by trituration with ether: Anal. calcd for C8H6FNO: C 63.57, H 4.00, N 9.26; found: C 63.36, H 3.91, N 9.16.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[CH:7]=1.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[CH:7]=3)=[CH:20][CH:19]=2)[CH2:17][CH2:16]1
Reactant: OB(O)c1ccc(C2CC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Br)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1nnc2ccc(-c3ccc(C4CC4)cc3)cn12
Temperature: 90 °C

Procedure:
A suspension of 6-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.19 mmol), 4-cyclopropyl phenylboronic acid (34 mg, 0.21 mmol), dppf(Pd)Cl2 (6.9 mg, 0.094 mmol), potassium carbonate (52 mg, 0.62 mmol) in degassed toluene (1 mL), degassed water (0.5 mL) and degassed ethanol (0.5 mL) was heated at 90° C. for 1 hour. The layers are separated, the organic layer was concentrated and the residue was purified by column chromatography to provide 6-(4-cyclopropylphenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=1.[CH2:20]([O:22][P:23]([O:27]CC)[O:24][CH2:25][CH3:26])[CH3:21]>>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][P:23](=[O:27])([O:24][CH2:25][CH3:26])[O:22][CH2:20][CH3:21])=[CH:11][CH:12]=1
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1ccc(Oc2cccc(CCl)c2)cc1
Product: CCOP(=O)(Cc1cccc(Oc2ccc(C(F)(F)F)cc2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
1-(Chloromethyl)-3-(4-(trifluoromethyl)phenoxy)benzene (1.3 g, 4.5 mmol) was treated neat with triethylphosphite (1.2 mL, 6.8 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and concentrated to give a residue. The residue was purified by silica gel chromatography (0-30%, EtOAc:CH2Cl2) to afford the title compound (1.76 g) as a clear oil.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH:14][CH2:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH2:16][CH:17]=[O:18])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12]
Reactant: CNCCC=O
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CN(CCC=O)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 0.08 h

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (6 grams), the dimethyl acetal of 3-methylaminopropionaldehyde (4.0 grams) and benzene (50 ml) are charged into a glass reaction flask equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 5 minutes. After this time the reaction mixture is stripped of benzene to yield a residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[C:9](=[O:14])[NH:10][NH:11][C:12]=2[CH3:13])=[CH:5][CH:4]=1)[CH3:2].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:17]([O:14][C:9]1[C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:16][CH:15]=2)=[C:12]([CH3:13])[NH:11][N:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: CCc1ccc(Cc2c(C)[nH][nH]c2=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c(OCc3ccccc3)n[nH]c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 1,2-dihydro-4-(4-ethylbenzyl)-5-methyl-3H-pyrazol-3-one (synthesized as described in WO0116147; 1.0 g, 4.6 mmol), benzyl alcohol (600 mg, 5.5 mmol) and triphenylphosphine (1.46 g, 5.5 mmol) in tetrahydrofuran (30 mL), diethyl azodicarboxylate (40% in toluene, 5.1 mmol) was added dropwise under ice cooling. After stirring overnight at room temperature, the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25 to 70:30) to give 3-benzyloxy-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole (550 mg, 39%) as a colorless powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14]
Reactant: O=c1oc2ccccc2n1CCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=c1oc2ccccc2n1CCCI
Yield: 82.7 %

Procedure:
To a solution of 3-(3-chloropropyl)benzo[d]oxazol-2(3H)-one (3.04 g, 14.36 mmol) in acetone (60 mL), was added sodium iodide (4.3 g, 28.73 mmol). After refluxing for 60 hours, the reaction mixture was filtered. The filtrate was washed with water and dried to obtain the title compound (3.6 g, 83%); 1H NMR (DMSO-d6): δ 2.19-2.24 (m, 2H), 3.28 (t, 2H, J=6.8 Hz), 3.87 (t, 2H, J=6.8 Hz), 7.11 (t, 1H, J=8 Hz), 7.22 (t, 1H, J=8 Hz), 7.32 (t, 2H, J=8.4 Hz). MS for C10H10INO2 m/z 304.33 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=[O:33].CO>[Pd]>[CH:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:16]=[CH:15]2)[CH2:12][CH2:13]1)=[O:33]
Reactant: Fc1ccc(-c2ncn(C3CCN(Cc4ccccc4)CC3)c2-c2ccncc2)cc1
Reactant: O=CO
Agent: [Pd]
Solvent: CO
Product: O=CN1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C

Procedure:
1-(1-Benzylpiperidin-4-yl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole (100 mg; prepared in Example 40) was dissolved in 10% formic acid/methanol under argon and palladium black (100 mg) mixed in 10% formic acid/methanol was added. The reaction was stirred under argon at room temperature for sixteen hours. The reaction mixture was evaporated and the residue mixed in H2O/ethyl acetate and the pH taken to 10. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were evaporated and the residue was flash chromatographed (silica gel/methylene chloride/methanol) to yield the title compound, an off-white solid. ES (+) MS m/e=351 (MH+)
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN1CCCC1=O.[Cl-].[Na+].O>[N:14]1([C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=3[N:3]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: O=[N+]([O-])c1cccc2[nH]c(Cl)nc12
Reactant: c1c[nH]cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc2[nH]c(-n3ccnc3)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of 2-chloro-4-nitro-1H-benzimidazole (300 mg) in N-methyl-2-pyrrolidone (4 ml) was added imidazole (517 mg) and the mixture was stirred at 80° C. for 8 hours. The reaction mixture was poured into brine and extracted with a mixture of chloroform and methanol. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (100-0−30-1) to give 2-(1-imidazolyl)-4-nitro-1H-benzimidazole (175 mg).
Reaction SMILES: I[CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH2:4]1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH2:4]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1OC(CI)CN1c1cc(F)c(-c2cccnc2)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1CN(c2cc(F)c(-c3cccnc3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(±)-5-(Iodomethyl)-3-[4-(3-pyridyl)-3,5-difluorophenyl]-2-oxazolidinone (PREPARATION 5, 577 mg, 1.31 mmol) in DMF (dried over 4A sieves, 15 ml) is combined with sodium azide (681 mg, 10.5 mmol, 8 eq). The reaction is placed under an atmosphere of nitrogen and heated to 55°. After 2 hr, the reaction is added to water (100 ml) and then extracted with ethyl acetate (4×25 ml). The combined organic extracts are combined and are washed with water then brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude azide is suitable for reduction without further purification. An analytical sample is prepared by prepatative TLC (silica gel) eluting with acetonitrile/chloroform (10/90). The appropriate fractions are pooled and concentrated to give the title compound, mp 97-98° ; FTIR (mull) cm-1 3483, 2110, 1746, 1640, 1417, 1237, 1064 and 716; MS (EI, m/z) 331, 274, 258, 232, 217, 190 and 43; NMR (CDCl3) 8.72, 8.63, 7.79, 7.42-7.38, 7.34, 4.90-4.82, 4.11, 3.88, 3.77 and 3.63 δ.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([OH:28])([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)[CH2:6][CH2:7][CH3:8])C.[OH-].[Li+]>O1CCCC1.O>[OH:28][C:5]([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)([CH2:6][CH2:7][CH3:8])[C:4]([OH:29])=[O:3]
Reactant: CCCC(O)(C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Yield: 61.1 %

Procedure:
A mixture of 600 mg (2 mmol) (R/S)-2-hydroxy-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid ethyl ester in 8 ml tetrahydrofuran and of 70.0 mg (2 mmol) lithiumhydroxide in 4 ml water was stirred overnight at room temperature. The solvent was evaporated and the residue extracted at pH 1 with ethylacetate to yield 450 mg (81%) (R/S)-2-hydroxy-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid, MS (m/e): 367.1 (M−H)−.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:28]=2[N:27]([CH3:29])[C:26]([CH3:30])=[C:25]3[CH3:31])[C:11]1=[O:32])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[O:32]=[C:11]1[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:33])=[O:3])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]1[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[N:27]([CH3:29])[C:26]([CH3:30])=[C:25]2[CH3:31]
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cccc3c(C)c(C)n(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cccc3c(C)c(C)n(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.4 %

Procedure:
To a solution of 3-[2-Oxo-3-(1,2,3-trimethyl-1H-indol-7-ylmethyl)-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid ethyl ester (50 mg, 0.11 mmol) in 1,4-dioxane (5 mL) and H2O (2 mL) was added LiOH (5.4 mg, 0.22 mmol). The solution was stirred at room temperature for 5 hours. The solution was concentrated and the residue was purified by CombiFlash with 10% MeOH in CH2Cl2 as the eluent to afford the desirable product 3-[2-Oxo-3-(1,2,3-trimethyl-1H-indol-7-ylmethyl)-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid (14.5 mg, 31%) as a white foam. LC-MS (M++1): 420.21.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)=O.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:28][C:4]1[C:3]([CH2:1][N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:27][N:6]2[C:5]=1[C:10]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=1)=[C:9]([C:25]#[N:26])[CH:8]=[N:7]2
Reactant: Cc1c(C=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1c(CN2CCN(C)CC2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 48 h
Yield: 66.6 %

Procedure:
A mixture of 6-formyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 8) (27 mg, 0.073 mmol) and 1-methyl-piperazine (8.1 μl, 0.073 mmol) in CH2Cl2 (2.5 ml) was stirred for 48 h, then treated with NaBH(OAc)3 (46.4 mg, 0.2 mmol) and stirred for 24 h. The mixture was diluted with CHCl3, washed with saturated NaHCO3 and H2O, dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (22 mg, 66%) (20% MeOH—CHCl3). It has a retention time of 4.90 min (standard LCl method, 8 min run). LCMS Found: (M+H)+=453.1
Reaction SMILES: [CH3:1][C:2](O)([CH3:14])[CH:3]=[C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH3:13])([CH3:12])[CH2:5]1.[Si]([N:20]=[N+:21]=[N-:22])(C)(C)C>C1C=CC=CC=1>[N:20]([C:2]([CH3:14])([CH3:1])[CH:3]=[C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)=[N+:21]=[N-:22]
Reactant: CC(C)(O)C=C1CC(C)(C)CC(C)(C)C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: c1ccccc1
Product: CC1(C)CC(=CC(C)(C)N=[N+]=[N-])CC(C)(C)C1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
BF3Et2O (0.3 ml, 2.4 mmol) was added to a solution of alcohol 29 (0.42 g, 2 mmol) and TMSN3 (0.31 ml, 2.4 mmol) in benzene (4.5 ml) during 3 min, while cooling with an ice bath. The reaction mixture was stirred at 5-10° C. for 1 h and filtered through a short silica gel column. The solution was evaporated and the residue was purified by flash chromatography on silica gel (light petroleum ether) to give 30 (0.30 g, 64%) as a colorless oil. 1H-NMR (CDCl3, TMS): 0.92 and 0.98 (total 12H, both s, c-Hex-3,5-CH3); 1.27 (2H, s, c-Hex-4-CH2); 1.40 (6H, s, —C(CH3)2N3); 1.85 and 2.23 (both 2H, both s, c-Hex-2,6-CH2) and 5.27 ppm (1H, s, ═CH—).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:17][C@@H:16]3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=2)[N:6]=[CH:5]1.[I:23]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[F:1][CH2:2][CH2:3][N:4]1[C:8]([I:23])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:17][C@@H:16]3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=2)[N:6]=[CH:5]1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(-c2cn(CCF)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(-c2ncn(CCF)c2I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.3 %

Procedure:
To a solution of ethyl (1S,2S)-2-{4-[1-(2-fluoroethyl)-1H-imidazol-4-yl]phenyl}cyclopropanecarboxylate (450 mg, 1.488 mmol) in dichloromethane (5 mL) was added N-iodosuccinimide (352 mg, 1.563 mmol) and three drops trifluoroacetic acid. The reaction was stirred at rt for 3 h. The mixture was neutralized with aqueous sodium bicarbonate and the organics were extracted with dichloromethane. The organics were then washed with aqueous sodium thiosulfate, followed by three washes with water. The organics were dried (MgSO4), concentrated, and purified on 20 g of silica gel eluting a gradient of 35-100% ethyl acetate in hexanes to give rise to the title compound as a brown oil (110 mg, 0.257 mmol). LCMS: [M+1]+=429.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH3:3].[Li]CCCC.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:3]
Reactant: CN(C)CCCn1ccnc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccn1CCCN(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
1-(N,N-Dimethylaminopropyl)imidazole (2 g) in THF (20 ml) at −78° C. was treated with nBuLi (8.6 ml, 1.6M) under nitrogen. After 30 minutes at −78° C., tri-n-butylstannyl chloride was added and the mixture allowed to warm to 20° C. The mixture was concentrated in vacuo, taken up in n-hexane and filtered. The filtrate was concentrated in vacuo to give the title compound (4.33 g) as a yellow oil; δH CDCl3 7.28 (1H,s), 7.09 (1H,s), 3.97 (2H,t), 2.25 (2H,t), 2.20 (6H,s), 1.90 (2H,m) 1.55 (6H,m), 1.34 (12H,m), 0.92 (9H,m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:25][N:26]([CH3:53])[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:39]=1)[CH2:31][CH2:30]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:25][N:26]([CH3:53])[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([C:17]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[O:18])=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[CH:39]=1)[CH2:31][CH2:30]2
Reactant: CN(C)c1ccc2c(c1)CCN(c1cccc(B3OC(C)(C)C(C)(C)O3)c1)C2=O
Reactant: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
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: O
Solvent: COCCOC
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(Nc4ccc(C(=O)N5CCOCC5)cn4)c(=O)n(C)c3)c1)C2=O
Yield: 40.6 %

Procedure:
5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (67 mg, 0.17 mmol), 6-Dimethylamino-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3,4-dihydro-2H-isoquinolin-1-one (67 mg, 0.17 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol), and sodium carbonate (54 mg, 0.51 mmol) in 2 mL 1,2-dimethoxyethane and 1 mL water was heated to 170° C. for 12.5 minutes in the microwave. The resulting mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 2 to 5% methanol/dichloromethane) to yield 6-Dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one (40 mg, 0.069 mmol). MS (ESI) 579.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[Cl:22][C:3]1[C:2]([NH:1][S:28]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)(=[O:30])=[O:29])=[CH:7][C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:5]([F:21])[CH:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NS(=O)(=O)c3cccs3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
In 5 ml of pyridine was dissolved 0.32 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, and then 0.19 g of 2-thiophensulfonyl chloride was added to the solution at 5 ° C. or lower. Thereafter, the temperature was increased to room temperature and the reaction was continued overnight. Then, pyridine was removed by distillation and the residue was dissolved in ethyl acetate. The solution was washed successively with water, diluted hydrochloric acid and a saturated saline solution, and dried over anhydrous sodium sulfate followed by removing ethyl acetate by distillation to obtain a crude product. This was washed with diisopropyl ether to obtain 0.3 g of the desired compound as white crystal.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[C:3]=1Br.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:3]2[C:4]3[O:8][CH:7]=[CH:6][C:5]=3[CH:9]=[CH:10][C:2]=2[F:1])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Fc1ccc2ccoc2c1Br
Product: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)ccc2ccoc12
Yield: 89.9 %

Procedure:
Beginning with 12.7 gm (59 mMol) 6-fluoro-7-bromobenzofuran and 13.2 gm (65 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 18 gm of the desired compound was prepared as an orange oil essentially as described in EXAMPLE 19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=O)[C:5]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[N:6][CH:7]=1.Cl.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:15]([OH:17])[C:9]([C:10]([F:13])([F:12])[F:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reaction time: 0.25 h

Procedure:
5-Chloro-3-nitro-2-(trifluoroacetamido)pyridine (2.7 grams), anhydrous stannous chloride (3.8 grams), and 4.0 milliliters of concentrated hydrochloric acid were mixed in 20 milliliters of acetic acid. The mixture was cooled to temperatures of 0°-10°C. and maintained thereat for 15 minutes. Water (50 milliliters) was then added to the reaction mixture, and the desired 6-chloro-1-hydroxy-2-(trifluoromethyl)imidazo(4,5-b)-pyridine product precipitated. It was separared and dried. The yield was 1.3 grams, 55 percent. The product so obtained melted at 264°-66°C.