Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:22]([F:25])([F:24])[F:23])/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[C:14]([CH3:21])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:8][C:6]1[CH:5]=[C:4]([CH:9]([C:22]([F:25])([F:24])[F:23])/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:29][CH2:28][C:27]([F:31])([F:30])[F:26])=[O:18])=[C:14]([CH3:21])[CH:13]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a stirred solution of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid in DMF was added 2,2,2-trifluoroethylamine, 1-hydroxybenzotriazole hydrate (HOBt.H2O), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) and DIPEA, and the reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with hexane:EtOAc afforded a white semi-solid (110 mg, 50%): 1H NMR (400 MHz, CDCl3) 7.40 (m, 2H), 7.26 (m, 3H), 6.56 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 5.82 (br s, 1H), 4.08 (m, 3H), 2.52 (s, 3H); ESIMS m/z 468.40 ([M−H]−); IR (thin film) 1657, 1113, 804 cm−1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[CH:2]=[N:19][C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:18]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccccc1N
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCO
Product: Brc1ccc(-c2cnc3ccccc3n2)cc1
Yield: 40.9 %

Procedure:
Ten grams (36 mmol) of 2,4′-dibromo acetophenone and 4.0 g (37 mmol) of 1,2-phenylenediamine were refluxed under heating among 20 milliliter of ethanol for 3.5 hours. After completion of the reaction, resultant crystals were separated with filtration, washed with ethanol, thereby obtaining 4.2 g of 2-(4-bromo-phenyl)-quinoxaline (yield: 41%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([F:10])[F:9])=[CH:4][N:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O.[C:49]([O:52][CH2:53]C)(=[O:51])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CS(C)=O.CO>[CH3:53][O:52][C:49]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([F:10])[F:9])=[CH:4][N:3]=1)=[O:51]
Reactant: FC(F)c1ccc(Br)nc1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(F)F)cn1

Procedure:
A mixture of 2-bromo-5-difluoromethyl-pyridine (1.8 g, 8.9 mmol) [Lemoine, R. C. et al., Bioorg. Med. Chem. Lett. (2010), 20(16), 4753-56], palladium(II)acetate (19.9 g, 0.089 mmol), triethylamine (9.4 ml, 66.7 mmol) and 1,3-bis(diphenyphosphino)propane (361 mg, 0.89 mmol) in a 2:1-mixture of dry methanol and dimethylsulfoxide (32.5 ml) was heated at 60° C. in an autoclave at 600 psi of carbonmonoxide pressure. After heating for 24 hours, the reaction mixture was cooled and the solid was filtered off. The filtrate was concentrated at reduced pressure to afford the crude product. Ethyl acetate (60 ml) was added and the solution washed successively with water (3×15 ml) to remove the dimethylsulfoxide. After drying over sodium sulphate and concentration at reduced pressure the crude material (5.0 g) was purified by column chromatography using a 1:4-mixture of ethyl acetate and hexane as the eluent. The 5-difluoromethyl-pyridine-2-carboxylic acid methyl ester was obtained as a light yellow oil (1 g, 63% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH:13]=O)=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:17][O:18][C:19]([C:21]1[NH:22][N:23]=[C:24]([NH2:26])[CH:25]=1)=[O:20].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:17][O:18][C:19]([C:21]1[NH:22][N:23]=[C:24]([NH:26][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:15])[CH:25]=1)=[O:20]
Reactant: Cc1onc(-c2ccc(F)cc2)c1C=O
Reactant: COC(=O)c1cc(N)n[nH]1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(NCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbaldehyde (1.75 g, 8.53 mmol) and the 5-amino-2H-pyrazole-3-carboxylic acid methyl ester hydrochloride (1.2 g, 8.53 mmol) in methanol (70 mL) at room temperature was added molecular sieves (2.5 g) and then after 1 h, acetic acid (6.8 mL, 119.4 mmol) was added. Then sodium cyanoborohydride (1.07 g, 17.1 mmol) was added portionwise and the mixture stirred at room temperature overnight. After evaporation, dichloromethane was added and the mixture washed with sodium hydrogen carbonate (saturated solution). The organic layer was then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, heptane:ethyl acetate 7:3 to 6:4) afforded 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid methyl ester (1.2 g, 44%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([Cu])#[N:13]>CC(N(C)C)=O.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Stir the mixture of 1,4-dibromo-2-nitro-benzene (3.56 mmol) and CuCN (3.74 mmol) in DMA (4 ml) at 100° C. for 5 hours. Cool to room temperature, dilute with EtOAc, filter through celite, wash the organic layer with brine, dry over Na2SO4, and concentrate under vacuum. Purify the residue by flash chromatography (4:1 hexanes/EtOAc) to give 4-bromo-2-nitro-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.OS([O-])=O.[Na+]>CC(N(C)C)=O>[F:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:17]([C:16]1[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([O:13][CH3:12])[CH:15]=1)[N:6]=[C:4]2[OH:5]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: NC(=O)c1cc(F)ccc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2nc(O)c3cc(F)ccc3n2)cc(OC)c1OC
Temperature: 140 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 2-amino-5-fluorobenzamide (13.02 g, 84.47 mmol, 1.00 equiv) in dimethylacetamide (200 mL), 3,4,5-trimethoxybenzaldehyde (17.97 g, 91.59 mmol, 1.08 equiv) and NaHSO3 (8.85 g). The resulting solution was stirred overnight at 140° C. in an oil bath. The reaction was then quenched by the addition of 400 mL of water/ice. The solids were collected by filtration. This resulted in 28 g (crude) of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol as a brown solid. MS (ESI) m/z 331 ([M+H]+).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].Cl[CH2:8][CH:9]([OH:12])[CH2:10][OH:11]>O>[OH:12][CH:9]([CH2:10][OH:11])[CH2:8][S:1]([O-:4])(=[O:3])=[O:2].[Na+:5]
Reactant: OCC(O)CCl
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CC(O)CO

Procedure:
Sodium sulfite (120 g, 924 mmol, content: 97.0%, produced by Wako Pure Chemical Industries, Ltd.) was dissolved in Water (400 mL), and 3-chloro-1,2-propanediol (107.2 g, 970 mmol, produced by Wako Pure Chemical Industries, Ltd.) was added thereto. The solution was refluxed by heating for 1 hour. After completion of the reaction, the reaction solution was concentrated, thereafter methanol (750 mL) was added to the concentrated residue. The crystal formed was filtered, and the resultant crystal was dried, to obtain sodium 2,3-dihydroxypropanesulfonate relevant to the above-described general formula [2] (202.6 g, content: 67.2%, yield: 82.7%) as a white crystal. It should be noted that content of sodium 2,3-dihydroxypropanesulfonate was obtained by 1H-NMR using the internal standard method. In addition, it was confirmed that the above-described white crystal contained crystal of sodium chloride as a by-product. Measurement results of 1H-NMR are shown below.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[CH:3]=1.[Cl:30]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:16])([F:17])[F:18])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][CH2:22][C:23]([F:28])([F:29])[C:24]([F:25])([F:27])[F:26])[C:3]=1[Cl:30]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2N)cc1SCC(F)(F)F
Solvent: CC#N
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)c(Cl)c2N)cc1SCC(F)(F)F
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
0.9 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 10 mL of acetonitrile, and 0.3g of N-chlorosuccinimide was added under cooling with ice. After stirring for 10minutes under cooling with ice, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.9 g of 5-amino-4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [F:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].CS([O-])(=O)=O.[CH2:24](O)[CH2:25][CH2:26][OH:27]>>[F:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:24][CH2:25][CH2:26][OH:27]
Reactant: OCCCO
Reactant: CC(F)CCCCCCCCCCCCCCO
Agent: CS(=O)(=O)[O-]
Product: CC(F)CCCCCCCCCCCCCCOCCCO

Procedure:
A general procedure for the preparation of penultimate fluorinated alkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated in Scheme 6, below. Fluoroalkoxyalkyl esters of acyclic nucleoside phosphonates such as 3-(15-fluoro-hexadecyloxy)propyl cidofovir 42 (15-F-HDP-CDV) and 3-(15-fluoro-hexadecyloxy)propyl (S)-HPMPA 43 (15-F-HDP-(S)-HPMPA) can be prepared using this process. Briefly, with reference to Scheme 6, commercially available 2-bromopropanoic acid 35 is reduced to the alcohol with borane:THF complex solution to provide 2-bromo-1-propanol 36. Fluorination of 36 is achieved with 1,1,2-trifluoro-2-chloroethyldiethylamine, a mild and safe reagent to convert 1-hydroxy-2-halogenoalkanes into the corresponding rearranged fluoride 37. Conversion of 37 into a Grignard reagent followed by reaction with 13-bromo-tridecanol in the presence of the catalyst provides 15-fluorohexadecanol 38. Conversion of alcohol 38 into the methanesulfonate derivative, followed by reaction with 1,3-propanediol provides 3-(15-fluorohexadecyloxy)propan-1-ol 39. Reaction of 39 with cyclic cidofovir or cyclic (S)-HPMPA as described generally in Example 2 (step a), provides the cyclic esters (40 and 41, respectively) which can then be converted to the desired compounds (42 and 43, respectively) using the general method set forth in Example 2 (step b).
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[N:4]=[CH:3]1.[CH3:14][NH:15][CH3:16].C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:14][N:15]([CH3:16])[C:11]([C:10]1[C:5]2[N:4]=[CH:3][NH:2][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:13]
Reactant: O=C(O)c1cccc2[nH]cnc12
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a stirred solution of 1H-benzoimidazole-4-carboxylic acid hydrochloride (1 g, 5.04 mmol), dimethylamine (2M in THF; 3.78 mL, 7.55 mmol) and ethyldiisopropylamine (3.51 mL, 20.1 mmol) in DMF (5.0 mL) at room temperature was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (1.95 g, 5.14 mmol) in a single portion. The mixture was stirred at room temperature overnight then concentrated in vacuo. The product was purified by SiO2 chromatography followed by trituration with Et2O providing 1H-benzoimidazole-4-carboxylic acid dimethylamide (730 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.[N:20]#[C:21][NH2:22].[Na]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:21]([NH:22][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1)#[N:20]
Reactant: CCCOc1ccc(-c2ccc(Cl)nn2)cc1OC
Reactant: N#CN
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc(NC#N)nn2)cc1OC

Procedure:
1.8 g 3-chloro-6-(3-methoxy-4-n-propoxyphenyl)pyridazine, 0.8 g sodium cyanamide and 3.6 g tetrabutylammonium chloride are boiled under reflux in 30 ml dry toluene for 5 hours. The reaction mixture is then evaporated in vacuo and the residue is boiled up briefly with 200 ml 2 N sodium hydrogen sulphate solution, while stirring thoroughly, the reaction product precipitating as a fine crystalline precipitate. The precipitate is filtered off with suction, washed with water and dried in vacuo. For purification, it is boiled up briefly with 50 ml isopropanol, filtered off with suction and dried in vacuo. This gives 1.5 g (83.3%) of the title compound of m.p. 187° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]1(=[O:40])[N:18]([C:19]2[N:24]=[C:23]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH2:33])[CH:22]=[CH:21][CH:20]=2)[C:17](=[O:35])[C:16]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:15]12>>[C:17]1(=[O:35])[N:18]([C:19]2[N:24]=[C:23]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][C:9](=[O:10])[C:8]3[CH:12]=[CH:13][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[CH:22]=[CH:21][CH:20]=2)[C:14](=[O:40])[C:15]2=[CH:39][CH:38]=[CH:37][CH:36]=[C:16]12
Reactant: Nc1ccccc1C(=O)Nc1cccc(N2C(=O)c3ccccc3C2=O)n1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(N3C(=O)c4ccccc4C3=O)n2)cc1
Yield: 123.1 %

Procedure:
Using the procedure described in Example 93, Part A, 4-tert-butylbenzoyl chloride (0.47 mmol) and N-(6-phthalimidopyridin-2-yl)-2-aminobenzamide (0.47 mmol) yielded 300 mg (100%) of the title product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([CH3:21])([CH3:20])[CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>C(OCC)C>[CH3:7][C:8]([CH3:21])([CH3:20])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:18][CH:19]=1
Reactant: CC(C)(C)CCOc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)CCOc1ccc(CN)cc1
Temperature: 0 °C
Yield: 88.1 %

Procedure:
Mix lithium aluminum hydride (1.0 g, 26.6 mmol) and anhydrous ethyl ether (70 mL) under nitrogen atmosphere. Stir and cool to 0° C. in an ice bath. Add dropwise a solution of 4-(3,3-dimethylbutoxy)-benzonitrile (1.8 g, 8.87 mmol) in anhydrous ethyl ether (20 mL). Stir for 2 h at 0° C., remove the ice bath and stir at ambient temperature for 18 h. Cool the reaction flask in an ice bath and add carefully dropwise and sequentially water (1 mL), 2N aqueous NaOH (1 mL), and water (2 mL). Stir for 30 min, filter, separate the organic layer, dry over Na2SO4 and concentrate in vacuo to obtain the title compound (1.62 g, 88%). MS (ES+) m/z: 191 (M+H—NH3)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[F:24])/[C:21]([OH:23])=O)[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10]1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[F:24])/[C:21]([NH:32][O:31][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)=[O:23])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10]1
Reactant: O=C(O)/C(F)=C/c1cnc(N[C@@H]2CCN(C3CCCC3)C2)c(Cl)c1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NOC1CCCCO1)/C(F)=C/c1cnc(N[C@@H]2CCN(C3CCCC3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.6 %

Procedure:
A mixture of (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid (658 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (229 mg), HOBt (264 mg) and EDCI (303 mg) in DMF (15 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (620 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]([NH2:14])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1cnc(OCC(F)(F)F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Temperature: 100 °C
Yield: 56 %

Procedure:
To a solution of 5-bromo-6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3-ylamine (2.1 g, 7.74 mmol) in DME, ethanol, water (3:1:1) (50 ml) in a sealed tube were added 4-chlorophenylboronic acid (CAS Registry No. 1679-18-1) (1.8 g, 11.62 mmol) and potassium phosphate (4.9 g, 23.22 mmol), and then the reaction mixture was purged with nitrogen for 15 min. Then Pd(dppf)2Cl2 (651 mg, 0.93 mmol) was added to the reaction mixture and heated at 100° C. for 4 h. The reaction mixture was filtered off and the filter cake was washed with ethyl acetate (3×20 ml). The organic layer was washed with water, brine, dried over Na2SO4 and evaporated in vacuo to get the crude (1.9 g). The crude was purified by column chromatography (20-25% ethyl acetate/hexane) to get the desired product (1.3 g, 56%) as brown liquid. MS (LC/MS): 303.0 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O>[NH2:2][C:3]1[CH:8]=[C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11]
Reactant: Cc1cc(Cl)cc(N)[n+]1[O-]
Reactant: C1COCCN1
Agent: Cl
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(N)[n+]1[O-]
Temperature: 180 °C
Yield: 27 %

Procedure:
A quantity (4.88 g., 0.025 mole) of 2-amino-4-chloro-6-methylpyridine-1-oxide hydrochloride (prepared in Part B, Example 1, above) with 20.0 ml. morpholine, and 20.0 ml. water was sealed in a reinforced bottle and heated in an oil bath at the temperature 180° C. for 6 hrs. The aqueous reaction mixture was cooled to 25° C. and then reheated to effect removal of excess morpholine and about one-half the water was removed by evaporation. This concentrate was then diluted with 50 ml. water and extracted with three 50-ml. portions of chloroform. The chloroform extracts were combined, dried over anhydrous sodium sulfate, treated with charcoal, and filtered. The chloroform was removed from the filtrate by evaporation under reduced pressure and the solid residue was triturated with acetone. The insolubles were collected on a filter. Testing via thin layer chromatography showed that there were three components. The components were separated by chromatography on a column of silica gel using a solvent mixture consisting of 1 part methanol and 9 parts methylene chloride. The fractions having the most rapidly moving component were collected and combined. The solvents were removed by evaporation. Chloroformic extraction of the original water-diluted reaction mixture was repeated followed by drying, treating with charcoal, filtration, and removal of chloroform was effected as before. This residue was combined with the residue from the chromatographic separation, and a crystallization and recrystallization from acetonitrile was effected. There was thus obtained 1.40 g. (27% yield) of 2-amino-6-methyl-4-morpholinopyridine-1-oxide as colorless needles having a melting point at 292° C. (with decomposition).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[C:16](C3C=CC(F)=CC=3)[N:17]=2)=[CH:9][CH:8]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](C2N=C(C3C=CC(C(O)=O)=CC=3)NC=2C2C=CN=CC=2)=[CH:37][CH:36]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)C(=O)CO>CN(C=O)C.O>[CH3:1][N:2]([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)[NH:17][CH:16]=[C:15]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[NH:14]2)=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: CN(C)C(=O)COC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: CN(C)C(=O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)c1ccc(C2(c3ccc(F)cc3)NC=C(c3ccncc3)N2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N-Dimethyl-4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzoyl-oxyacetamide--To a solution of 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzoic acid (0.15 g, 0.42 mmol) [See Ex. 9 above] in DMF(10 ml) was added carbonyldiimidazole (0.34 g, 2.1 mmol). After stirring for 18 h at rt, N,N-dimethylglycolamide (0.43 g, 4.2 mmol) was added and stirring was continued for an additional 3h at rt. The reaction mixture was poured into H2O, extracted with EtOAc and evaporated. The residue was purified by flash chromatography eluting with a solvent gradient of 2% MeOH/CHCl3 to afford the title compound: CIMS (NH3, m/z): 445 (M+ +H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([Mg]Br)([CH3:17])[CH3:16]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]([OH:14])[CH:15]([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Mg]Br
Reactant: O=Cc1cccn1Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(O)c1cccn1Cc1ccccc1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To 1-benzyl-1H-pyrrole-2-carbaldehyde (0.50 g, 2.7 mmol) in THF (20 mL) at 0° C. was added a solution of i-PrMgBr (5.4 mL, 1N in THF, 5.4 mmol). The reaction mixture was warmed to room temperature and after 1.5 h it was quenched with saturated aqueous ammonium chloride, extracted with EtOAc, dried (Na2SO4) and concentrated. Column chromatography (EtOAc/hexanes, 1:4) provided 0.345 g (56%) of 1-(1-benzyl-1H-pyrrol-2-yl)-2-methylpropan-1-ol as an oil.