Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([C:14]([F:17])([F:16])[F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[CH3:19][C:20]([S@:23]([NH:25][CH:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:18])([F:1])[C:14]([F:17])([F:16])[F:15])=[CH:6][CH:7]=1)[CH3:12])=[O:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (3.2 g, an off-white solid) from 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanone (3.0 g, 11.0 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: FC(F)(S(F)(=O)=O)[C:3](F)(F)[C:4](F)(F)[C:5]([F:8])(F)F.[F:18][C:19]1[N:24]=[C:23]([N:25]2[C@@H](CO)C[O:27][C:26]2=[O:32])[CH:22]=[CH:21][N:20]=1.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1.O>[F:8][CH2:5][C@H:4]1[CH2:3][O:32][C:26](=[O:27])[N:25]1[C:23]1[CH:22]=[CH:21][N:20]=[C:19]([F:18])[N:24]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C1OC[C@H](CO)N1c1ccnc(F)n1
Agent: F
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC[C@H](CF)N1c1ccnc(F)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
Perfluorobutanesulfonyl fluoride (0.18 mL, 0.98 mmol, 4 equiv) was added to a solution of (S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one (52 mg, 0.24 mmol) in THF (1.2 mL) at room temperature. Triethylamine trihydrofluoride (0.16 mL, 0.98 mmol, 4 equiv) and triethylamine (0.41 mL, 3.0 mmol, 12 equiv) were then added and the solution was stirred at 40° C. for 18 hours. The reaction was then cooled to room temperature and diluted with water (25 mL). The mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (10 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (0.021 g, colorless oil) in 40% yield. 1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J=5.7, 2.1 Hz, 1H), 8.18 (dd, J=5.7, 3.7 Hz, 1H), 5.08-4.93 (m, 2H), 4.91-4.72 (m, 1H), 4.66-4.55 (m, 2H). MS m/z 215.9 (M+H)+; Rt-0.57 min.
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[CH:28]([NH2:30])=[S:29].C(OCC)(=O)C>CO.ClCCl>[CH3:14][S:11]([O:10][C@H:8]1[CH2:7][N:6]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:5]([C:3]2[N:30]=[CH:28][S:29][CH:2]=2)[CH2:9]1)(=[O:12])=[O:13]
Reactant: NC=S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2cscn2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 4 h
Yield: 88 %

Procedure:
To a mixture of (2S,4R)-2-bromoacetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.15 g) in a mixture of methanol (20 ml) and dichloromethane (15 ml) was added thioformamide (453 mg) at room temperature. After stirring at the same temperature for 4 hours, the mixture was poured into ethyl acetate and washed in turn with saturated aqueous sodium bicarbonate and brine. The dried organic layer was evaporated and the resulting oil was crystallized from a mixture of n-hexane and dichloromethane (100:1 V/V) to give (2S,4R)-4-methanesulfonyloxy-2-(thiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (930 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(-c2ccccc2)oc(C)c1-c1ccc(F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(-c2ccccc2)oc(CBr)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-(4-fluorophenyl)-5-methyl-2-phenylfuran-3-carboxylate (19.06 g, 58.76 mmol), N-bromosuccinimide (10.5 g, 58.8 mmol) and 2,2′-azobis(isobutyronitrile) (50 mg) in carbon tetrachloride (50 ml) was heated under reflux for 0.5 hr. After cooling the reaction solution to room temperature, white precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was evaporated under reduced pressure to give a crude product of ethyl 5-(bromomethyl)-4-(4-fluorophenyl)-2-phenylfuran-3-carboxylate as a yellow liquid. The obtained liquid was dissolved in N,N-dimethylformamide (40 ml) and sodium acetate (9.64 g, 118 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the objective substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Br)c(C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-3-methyl-2-nitrophenol (2.200 g, 9.48 mmol) in acetone (35 mL) was added potassium carbonate (3.276 g, 23.70 mmol) and methyl iodide (1.47 mL, 23.70 mmol) and the mixture was heated to reflux for 4 h. The reaction was cooled to rt, filtered and the filtrate was evaporated under reduced pressure to afford the crude product. Purification of the crude product by column chromatography over silica gel eluting with EtOAc/hexane afforded pure 1-bromo-4-methoxy-2-methyl-3-nitrobenzene as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ=2.33 (s, 2H), 3.87 (s, 3H), 6.78 (d, J=8.84 Hz, 1H) and 7.58 (d, J=8.84 Hz, 1H); MS (ES+): m/z 247.26 [MH+].
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].O.O.C([O-])(=O)C.[Zn+2:16].C([O-])(=O)C>O>[Zn:16].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4]
Reactant: [Zn+2]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: CC(=O)[O-]
Solvent: O
Product: CC(C)(S)[C@H](N)C(=O)O
Product: [Zn]
Temperature: 40 °C

Procedure:
149.2 mg of solid D-penicillamine (Aldrich Chemical Co., Inc.) and 219.5 mg of zinc acetate dihydrate (Aldrich Chemical Co., Inc.) are dissolved in a minimum volume of doubly distilled water (~12 ml), heated to 40° C. for 45 minutes, and cooled to room temperature to form the complex Zn/penicillamine.
Reaction SMILES: [CH2:1]=O.Cl.[CH3:4][N:5]([CH3:28])[C:6](=[O:27])[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([NH:25][CH3:26])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:9]=1.[OH-].[Na+]>C(O)=O>[CH3:28][N:5]([CH3:4])[C:6](=[O:27])[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([N:25]([CH3:1])[CH3:26])[CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH:9]=1
Reactant: CNC(CCc1ccc(OC)cc1)c1cccc(OC(=O)N(C)C)c1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: COc1ccc(CCC(c2cccc(OC(=O)N(C)C)c2)N(C)C)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Formic acid (10 ml) and 35% aqueous formaldehyde solution (10 ml) were added to 3-[3-(4-methoxyphenyl)-1-methylaminopropyl]phenyl dimethylcarbamate (500 mg, 1.4 mmol) obtained from Example 2 and the mixture was stirred at 90° C. for 2 hours. After cooling the reaction mixture to room temperature the mixture was neutralized with 1N aqueous sodium hydroxide solution. The neutralized mixture was extracted with ether and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol=80:20 as the eluent to give 3-[1-dimethylamino-3-(4-methoxyphenyl)propyl]phenyl dimethylcarbamate. The product was treated with 1N hydrogen chloride/ethyl acetate solution to afford the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[N:22]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:49]=[CH:50][CH:51]=2)[CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:40]([CH3:43])=[N:41][N:42]=4)[C:34]=3[CH:33]=[C:32]2[C:44]2[CH:48]=[CH:47][NH:46][N:45]=2)[CH2:25][CH2:24][CH2:23]1.[C:52](#[N:55])[CH:53]=[CH2:54].N12CCCN=C1CCCCC2>CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[N:22]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:49]=[CH:50][CH:51]=2)[CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:40]([CH3:43])=[N:41][N:42]=4)[C:34]=3[CH:33]=[C:32]2[C:44]2[CH:48]=[CH:47][N:46]([CH2:54][CH2:53][C:52]#[N:55])[N:45]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: C=CC#N
Reactant: Cc1nnc2ccc3c(cc(-c4cc[nH]n4)n3Cc3cccc(CN4CCC4)c3)n12
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCC#N)n4)n3Cc3cccc(CN4CCC4)c3)n12

Procedure:
6-[3-(Azetidin-1-ylmethyl)benzyl]-1-methyl-7-(1H-pyrazol-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (7.0 mg, 0.018 mmol, from Example 182) in MeCN (0.23 mL) was treated with 2-propenenitrile (2.3 μL, 0.035 mmol, Aldrich) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 μL, 0.018 mmol, Aldrich) for 8 minutes. The product was purified via preparative HPLC-MS (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA). Yield: (9.8 mg, 82%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([CH:15]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=4)=[CH:37][C:36]=3[F:49])=[C:30]([CH2:50][CH2:51][CH3:52])[N:29]3[N:53]=[CH:54][N:55]=[C:28]23)[CH2:23][CH2:22]1)[C:16]([OH:19])([CH3:18])[CH3:17])[CH3:14]>O.C(OCC)(=O)C>[CH2:13]([CH:15]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]4[NH:3][C:4](=[O:7])[O:5][N:48]=4)=[CH:37][C:36]=3[F:49])=[C:30]([CH2:50][CH2:51][CH3:52])[N:29]3[N:53]=[CH:54][N:55]=[C:28]23)[CH2:23][CH2:22]1)[C:16]([OH:19])([CH3:17])[CH3:18])[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(CC)C(C)(C)O)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OC(CC)C(C)(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.37 g), sodium hydrogen carbonate (0.59 g, and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile (0.20 g) was added, and the mixture was stirred at 90° C. for 24 hr and then at room temperature for 40 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.069 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.064 mL) were added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.16 g, 73%).
Reaction SMILES: FC1C=C(F)C=C(F)C=1C(NC1C=CC=C([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])N=1)=O.C(N(CC)C(C1CCN(C)CC1)=O)C.[Br:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Br:49])[N:44]=1.Br>>[BrH:42].[Br:49][C:45]1[N:44]=[C:43]([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[CH:48]=[CH:47][CH:46]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Agent: Br
Agent: CCN(CC)C(=O)C1CCN(C)CC1
Product: CN1CCC(C(=O)c2cccc(Br)n2)CC1

Procedure:
The present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a salt thereof, further comprising the step of: reacting N,N-diethyl-1-methylpiperidine-4-carboxamide with a solution of 2,6-dibromopyridine and Grignard reagent followed by the addition hydrobromic acid to yield (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrobromide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=1.[H-].[Na+].[C:17]([Si:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28]I)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].O>CN(C=O)C>[C:17]([Si:21]([CH3:22])([CH3:23])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][N:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9][C:10]1=[O:14])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Reactant: O=c1nc(-c2ccccc2F)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCn1ccc(-c2ccccc2F)nc1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1H-pyrimidin-2-one (375 mg, 1.97 mmol) in dry DMF (50 ml), 60% NaH (103 mg, 2.56 mmol) was added portionwise. After heating the mixture at 100° C. for 1 hour, tert-butyl-(4-iodo-butoxy)-dimethyl-silane (664 μl 2.56 mmol) was added at room temperature and the mixture was stirred overnight. Water was added and the mixture extracted with diethyl ether; the organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography with petroleum ether-ethyl acetate (1-1) to give 370 mg of the title compound as a yellow solid (50% yield).
Reaction SMILES: CC([Si](C(C)C)([S:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][CH2:13][CH2:14][C:15]1[N:20]=[C:19](CN)[CH:18]=[CH:17][CH:16]=1)C(C)C)C.[F-].[CH2:30]([N+:34](CCCC)(CCCC)CCCC)CCC.Br[CH2:48][C:49](=[O:57])[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>C1COCC1>[CH3:30][NH:34][C:19]1[N:20]=[C:15]([CH2:14][CH2:13][O:12][C:11]2[CH:10]=[C:9]([S:8][CH2:48][C:49](=[O:57])[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)[Si](Sc1cccc(OCCc2cccc(CN)n2)c1)(C(C)C)C(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)CCC(=O)CBr
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)CSc1cccc(OCCc2cccc(NC)n2)c1
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
To a solution of [6-(2-{3-[1,1-bis(Methylethyl)-2-methyl-1-silapropylthio]phenoxy}ethyl)(2-pyridyl)]methylamine (1.34 g, 3.2 mmol) and THF (25 ml) under Argon, was added tetrabutylamonium floride (3.5 ml, 3.5 mmol, 1M in THF) at room temperature. After stirring for 15 minutes, a solution of ethyl 5-bromo-4-oxopentanoate (0.79 g, 3.5 mmol) in THF (5 ml) was added. The mixture was stirred for 3 h. The solvent was removed under vacuum and the remaining residue was chromatographed over silica gel to yield 830 mg (64%) of Ethyl 5-(3-{2-[6-(Methylamino)(2-pyridyl)]ethoxy }phenylthio)-4-oxopentanoate. NMR 1H Cl3CD δ: 7.38 (dd, 1H, J=7.2, 8.0 Hz), 7.17 (t, 1H, J=8.0 Hz), 6.89 (m, 2H), 6.71 (m, 1H), 6.54 (d, 1H, J=8.0 Hz), 6.25 (d, 1H, J=4.0 Hz), 4.30 (t, 2H, J=6.8 Hz), 4.13 (c, 2H, J=7.2 Hz), 3.72 (s, 2H), 3.07 (t, 2H, J=6.8 Hz), 2.91(m, 5H), 2.59 (t, 2H, J=6.8 Hz), 1.24 (t, 3H, J=7.2 Hz).
Reaction SMILES: [N:1]([C@H:4]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[C@:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[F:15])([OH:7])[CH3:6])=[N+]=[N-].CP(C)C>O1CCCC1.CCOCC>[NH2:1][C@H:4]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[C@:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[F:15])([OH:7])[CH3:6]
Reactant: C[C@](O)(c1cc(F)ccc1F)[C@H](N=[N+]=[N-])c1cncc(Br)c1
Agent: CP(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@](O)(c1cc(F)ccc1F)[C@H](N)c1cncc(Br)c1
Reaction time: 18 h
Yield: 93.3 %

Procedure:
To a solution of (1R,2S)-1-azido-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol (44 mg, 0.119 mmol) in tetrahydrofuran (2 mL) at 0° C. was added trimethylphosphine (0.179 mL, 0.179 mmol) drop wise. Ice bath was removed once no more nitrogen gas come out. One hour later, water (0.1000 mL) was added and continuously stirred for 18 hours. The reaction mixture was concentrated to afford a yellow oil that was redissolved in 5 mL ether then washed with 10 mL water. The ether layer was dried by magnesium sulfate, filtered, and concentrated to provide a light yellow of (1R,2S)-1-amino-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol (42.2 mg, 0.111 mmol, 93% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.36 (d, J=2.1 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.73 (t, J=2.0 Hz, 1H), 7.15 (ddd, J=11.1, 8.9, 4.7 Hz, 1H), 7.06-6.98 (m, 1H), 6.90 (ddd, J=9.9, 6.3, 3.4 Hz, 1H), 5.70 (s, 1H), 4.13 (s, 1H), 3.33 (s, 2H), 1.65 (d, J=1.5 Hz, 3H), Mass spec.: 345.1 (MH)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:14][CH2:15][CH2:16][CH3:17])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])#[N:2].[OH2:18].[OH-].[NH4+]>S(=O)(=O)(O)O>[C:1]([C:3]1[C:4]([O:14][CH2:15][CH2:16][CH3:17])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:13])[CH:10]([CH3:11])[CH3:12])(=[O:18])[NH2:2]
Reactant: CCCOc1nsc(NC(=O)C(C)C)c1C#N
Reactant: O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCCOc1nsc(NC(=O)C(C)C)c1C(N)=O

Procedure:
A mixture of 8.6 g of N-(4-cyano-3-propoxy-5-isothiazolyl)-2-methylpropanamide, from Example VII, in 20 ml of concentrated sulfuric acid was heated at 50° for 1 hour. Thin-layer chromatographic analysis indicated that the reaction was complete. The reaction mixture was poured into 200 ml of cold water. The solution was neutralized with ammonium hydroxide. The resulting precipitate was collected by filtration. The dried solid was recrystallized from toluene to give 7.7 g of N-(4-carbamoyl-3-propoxy-5-isothiazolyl)-2-methylpropanamide m.p. 153°-154°. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:3]=1
Reactant: CCCCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
To a solution of 3-bromophenol (0.500 g) in N,N-dimethylformamide (5.8 mL) was added potassium carbonate (1.20 g). Then 1-bromopentane (0.896 mL) was added, and the resulting mixture was stirred at room temperature for 18.5 hours. The reaction mixture was partitioned between diethyl ether (35 mL) and water (10 mL). The organic-layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (9.728 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][C:35]2[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[CH:39]=2)=[CH:32][CH:31]=1>CN(C)C=O.C(Cl)Cl>[Br:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][C:35]2[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[C:39]=2[C:7]([C:6]2[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:9])=[CH:32][CH:31]=1
Reactant: Cc1cc(Cc2ccc(Br)cc2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C(C)C
Yield: 77.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (1.03 g, 4.35 mmol, RN-117439-59-5), oxalyl chloride (0.417 mL, 4.79 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.560 mL, 4.79 mmol) and 2-(4-bromo-benzyl)-4,5-dimethyl-furan (1.15 g, 4.35 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 1.63 g (77%) of the title compound as a yellow clear oil. 1H NMR (DMSO-d6) δ1.16 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.28 (septet, 2H), 3.74 (s, 3H), 3.83 (s, 2H), 6.98 (d, 2H), 7.41 (dd, 2H), 7.44 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1I.[C:13]([C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1)#[CH:14].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[C:14]#[C:13][C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1
Reactant: COc1ccc(I)c(OC)c1F
Reactant: C#Cc1cnn(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2cnn(C)c2)c(OC)c1F
Reaction time: 1 h
Yield: 86 %

Procedure:
To a mixture of (0.95 mmol) of 2,4-dimethoxy-3-fluoro-iodo benzene, 0.122 g (1.15 mmol) of 4-ethynyl-1-methyl-1H-pyrazole, 0.028 g (0.04 mmol) of dichlorobis(triphenylphosphine)palladium (II) and 8 mg (0.042 mmol) of copper (I) iodide 4 mL of anhydrous acetonitrile and 2 mL of triethylamine were added under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 1 hour, when TLC indicated a consumption of the iodobenzene. The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography (silica gel; dichloromethane:ethyl acetate 9:1) to give the title compound in an 86% yield as creamy crystals. H1 NMR(CDCl3) 3.88 (s, 3H, Me); 3.89(s, 3H, MeO); 4.05 (d, 3H, MeO, J=1.34 Hz); 6.62 (tr, 1H, CH, J=8.2 Hz); 7.12 (dd, 1H, CH, J=8.2 Hz, J=2.55 Hz); 7.53 (s, 1H, CH pyr); 7.62 s, 1H, CH pyr).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][OH:6].[H-].[Na+].[H][H].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:5][O:6][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(CO)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](COCc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 120 %

Procedure:
To a solution of 2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (0.400 g, 1.82 mmol) in dimethylformamide (15 ml) was added sodium hydride (65%)(0.145 g, 3.64 mmol) at 0° C. after the evolution of hydrogen gas ceased, the freshly distilled benzyl bromide (0.449 g, 1.82 mmol) was added to the solution. The reaction mixture was stirred at 25–30° C. for 5 hr to give a clear solution The solvent was then removed under reduced pressure below 40° C. The residue was dissolved in water (30 ml) and the solution extracted with ethyl acetate (two 20 ml portions). The combined organic layers were further washed with brine and dried over anhydrous sodium sulfate. The ethyl acetate was then removed under reduced pressure to give the 3-(biphenyl-4-ylmethoxy)-(2S)-tert-butoxycarbonylamino-propionic acid methyl ester as colorless oil (0.421 g, 60%). LC/MS (m/z): 386(M+1).